MEK Kinase Inhibitors

Abstract

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

Description

[Technical field]

[0001] cross reference This application claims the benefit of U.S. Patent Application No. 63 / 316,607, filed March 4, 2022, which is incorporated by reference in its entirety. [Background technology]

[0002] Activation of MEK initiates the mitogen-activated protein kinase (MAPK) pathway, a key cell signaling pathway in regulating proliferation, cell growth, and survival. Because dysregulation of MAPK signaling has been shown to be a major driver of many cancers, it is hoped that therapeutics targeting MEK kinase activity can be used to treat cancer and other disorders characterized by aberrant MEK pathway signaling. Summary of the Invention

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

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

[0005] [ka] or a pharma- ceutically acceptable salt or solvate thereof, During the ceremony, R 1 is optionally substituted alkyl; R 2 is optionally substituted alkyl, and optionally R 1 and R 2 are linked by carbon-carbon bonds to form a phosphorus-containing ring, R 3is selected from hydrogen, halo, optionally substituted alkyl, optionally substituted cycloalkyl, or optionally substituted alkoxy; R 4 is selected from hydrogen, halo, optionally substituted alkyl, optionally substituted cycloalkyl, or optionally substituted alkoxy; R 5 is selected from hydrogen, halo, optionally substituted alkyl, optionally substituted cycloalkyl, or optionally substituted alkoxy; and R 11 , R 12 , R 13 , R 14 , and R 15 are independently selected from hydrogen, halo, optionally substituted alkynyl, optionally substituted alkyl, optionally substituted cycloalkyl, or a pharma- ceutically acceptable salt or solvate thereof.

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

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

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

[0009] As used herein and in the appended claims, the singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise. Thus, for example, a reference to an "agent" includes a plurality of such agents, a reference to a "cell" includes a reference to one or more cells (or cells), and equivalents thereof known to those of skill in the art, and so forth. When ranges are used herein for physical properties, such as molecular weight, or chemical properties, such as chemical formulas, all combinations and subcombinations of the ranges and specific embodiments within the ranges are intended to be included. The term "about," when referring to a numerical value or numerical range, means that the numerical value or numerical range referred to is an approximation within experimental error (or within statistical experimental error), and thus the numerical value or numerical range may vary, as the case may be, between 1% and 15% of the stated numerical value or numerical range. The term "comprising" (and related terms such as "comprise" or "comprises" or "having" or "including") is not intended to exclude other specific embodiments, such as embodiments of any composition of matter, composition, method, or process described herein, from "consisting of" or "consisting essentially of" the described features.

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

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

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

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

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

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

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

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

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

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

[0020] "Alkyl" refers to a straight or branched hydrocarbon chain radical, consisting solely of carbon and hydrogen atoms, containing no unsaturation, and having from 1 to 15 carbon atoms (e.g., C1-C 15 In certain embodiments, alkyl comprises 1 to 13 carbon atoms (e.g., C1-C 13 In certain embodiments, the alkyl comprises 1-8 carbon atoms (e.g., C1-C8 alkyl). In other embodiments, the alkyl comprises 1-5 carbon atoms (e.g., C1-C5 alkyl). In other embodiments, the alkyl comprises 1-4 carbon atoms (e.g., C1-C4 alkyl). In other embodiments, the alkyl comprises 1-3 carbon atoms (e.g., C1-C3 alkyl). In other embodiments, the alkyl comprises 1-2 carbon atoms (e.g., C1-C2 alkyl). In other embodiments, the alkyl comprises 1 carbon atom (e.g., C1 alkyl). In other embodiments, the alkyl comprises 5-15 carbon atoms (e.g., C5-C6 alkyl). 15In other embodiments, the alkyl group comprises 5-8 carbon atoms (e.g., C5-C8 alkyl). In other embodiments, the alkyl group comprises 2-5 carbon atoms (e.g., C2-C5 alkyl). In other embodiments, the alkyl group comprises 3-5 carbon atoms (e.g., C3-C5 alkyl). In other embodiments, the alkyl group comprises 5-8 carbon atoms (e.g., C5-C8 alkyl). In other embodiments, the alkyl group comprises 2-5 carbon atoms (e.g., C2-C5 alkyl). In other embodiments, the alkyl group comprises 3-5 carbon atoms (e.g., C3-C5 alkyl). In other embodiments, the alkyl group is selected from methyl, ethyl, 1-propyl (n-propyl), 1-methylethyl (iso-propyl), 1-butyl (n-butyl), 1-methylpropyl (sec-butyl), 2-methylpropyl (iso-butyl), 1,1-dimethylethyl (tert-butyl), and 1-pentyl (n-pentyl). The alkyl group is attached to the remainder of the molecule by a single bond. Unless otherwise specified in the specification, an alkyl group may be selected from the following substituents: halo, cyano, nitro, oxo, thioxo, imino, oximo, trimethylsilanyl, -OR, -O, -O- ... a , -SR a , -OC(O)-R a , -N(R a )2, -C(O)R a , -C(O)OR a , -C(O)N(R a )2, -N(R a )C(O)OR a , -OC(O)-N(R a )2, -N(R a )C(O)R a , -N(R a )S(O) t R a (t is 1 or 2), -S(O) t OR a (t is 1 or 2), -S(O) t R a (t is 1 or 2), and -S(O) t N(R a )2 (t is 1 or 2), where R aare each independently hydrogen, alkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), fluoroalkyl, carbocyclyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), carbocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aralkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heteroaryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), or heteroarylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl). In certain embodiments, the optionally substituted alkyl is haloalkyl. In other embodiments, the optionally substituted alkyl is a fluoroalkyl. In other embodiments, the optionally substituted alkyl is a -CF3 group.

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

[0043] "Heteroaryl" refers to a radical derived from a 3-18 membered aromatic ring radical containing 2-17 carbon atoms and 1-6 heteroatoms selected from nitrogen, oxygen, and sulfur. As used herein, a heteroaryl radical is a monocyclic, bicyclic, tricyclic, or tetracyclic ring system in which at least one of the rings in the ring system is fully unsaturated, i.e., contains a cyclic delocalized (4n+2) π-electron system according to the Hückel theory. Heteroaryl includes fused or bridged ring systems. The heteroatoms in a heteroaryl radical are optionally oxidized. The nitrogen atom or atoms, if present, are optionally quaternized. The heteroaryl is attached to the remainder of the molecule through any atom of the ring. Examples of heteroaryl include azepinyl, acridinyl, benzimidazolyl, benzindolyl, 1,3-benzodioxolyl, benzofuranyl, benzoxazolyl, benzo[d]thiazolyl, benzothiadiazolyl, benzo[b][1,4]dioxepinyl, benzo[b][1,4]oxazinyl, 1,4-benzodioxanyl, benzonaphthofuranyl, benzoxazolyl, benzodioxolyl, benzodioxinyl, benzopyranyl, benzopyranonyl, benzofuranyl, benzofuranonyl, benzothienyl (benzothiophenyl), benzothieno[3,2-d]pyrimidinyl, benzotriazolyl, benzo[4,6]imidazo[ 1,2-a]pyridinyl, carbazolyl, cinnolinyl, cyclopenta[d]pyrimidinyl, 6,7-dihydro-5H-cyclopenta[4,5]thieno[2,3-d]pyrimidinyl, 5,6-dihydrobenzo[h]quinazolinyl, 5,6-dihydrobenzo[h]cinnolinyl, 6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazinyl, dibenzofuranyl, dibenzothiophenyl, furanyl, furanonyl, furo[3,2-c]pyridinyl, 5,6,7,8,9,10-hexahydrocycloocta[d]pyrimidinyl, 5,6,7,8,9,10-hexahydrocycloocta[d]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-naphthyridinonyl, oxadiazolyl, 2-oxoazepine quinazolyl, oxazolyl, oxiranyl, 5,6,6a,7,8,9,10,10a-octahydrobenzo[h]quinazolinyl, 1-phenyl-1H-pyrrolyl, phenazinyl, phenothiazinyl, phenoxazinyl, phthalazinyl, pteridinyl, purinyl, pyrrolyl, pyrazolyl, pyrazolo[3,4-d]pyrimidinyl, pyridinyl, pyrido[3,2-d]pyrimidinyl, 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 (pyridinyl), and thiophenyl (i.e., thienyl). Unless otherwise specified in this specification, the term "heteroaryl" includes optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, halo, optionally substituted fluoroalkyl, optionally substituted haloalkenyl, optionally substituted haloalkynyl, oxo, thioxo, cyano, nitro, -R, b -OR a , -R b -OC(O)-R a ,-R b -OC(O)-OR a , -R b -OC(O)-N(R a )2, -Rb -N(R a )2, -R b -C(O)R a , -R b -C(O)OR a , -R b -C(O)N(R a )2, -R b -OR c -C(O)N(R a )2, -R b -N(R a )C(O)OR a , -R b -N(R a )C(O)R a , -R b -N(R a )S(O) t R a (t is 1 or 2), -R b -S(O) t R a (t is 1 or 2), -R b -S(O) t OR a (t is 1 or 2), and -R b -S(O) t N(R a t is 1 or 2, wherein R aare each independently hydrogen, alkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), fluoroalkyl, carbocyclyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), carbocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aralkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heteroaryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), or heteroarylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl); R b are each independently a direct bond or a straight or branched alkylene or alkenylene chain; R c is a straight or branched alkylene or alkenylene chain, and unless otherwise specified, R a , R b , or R c Each of the substituents is unsubstituted.

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

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

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

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

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

[0049] As used herein, "carboxylic acid bioisostere" refers to a functional group or moiety that exhibits similar physical, biological, and / or chemical properties as a carboxylic acid moiety. Examples of carboxylic acid bioisosteres include:

[0050] [ka] These include, but are not limited to:

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

[0052] [ka] Examples include:

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

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

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

[0056] In certain embodiments, the compounds disclosed herein are 2 Exchanged with H atom 1 Having some or all of the H atoms. Methods for synthesizing deuterium-containing compounds are known in the art, and non-limiting examples include the following synthetic methods:

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

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

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

[0060] [ka] As an example,

[0061] Deuterium transfer reagents such as lithium aluminum deuteride (LiAlD4) are utilized to deliver deuterium to reaction substrates under reducing conditions. The use of LiAlD4 can be seen, by way of example only, in the following reaction scheme:

[0062] [ka] As an example,

[0063] Deuterium gas and a palladium catalyst are used to reduce unsaturated carbon-carbon bonds, and by way of example only, the following reaction scheme:

[0064] [ka] is used to effect reductive displacement of an aryl carbon-halogen bond, as described in

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

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

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

[0068] "Pharmaceutically acceptable base addition salts" refer to salts that retain the biological effectiveness and properties of the free acids, which are not biologically or otherwise undesirable. These salts are prepared by adding an inorganic or organic base to the free acid. Pharmaceutically acceptable base addition salts are formed in some embodiments 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, primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, and basic ion exchange resins, such as isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, diethanolamine, 2-dimethylaminoethanol, 2-diethylaminoethanol, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, N,N-dibenzylethylenediamine, chloroprocaine, hydrabamine, choline, betaine, ethylenediamine, ethylenedianiline, N-methylglucamine, glucosamine, methylglucamine, theobromine, purines, piperazine, piperidine, N-ethylpiperidine, polyamine resins, and the like, see Berge et al., supra.

[0069] "Pharmaceutically acceptable solvate" refers to a composition of matter that is a solvent addition form. In some embodiments, the solvate contains either a stoichiometric or non-stoichiometric amount of a solvent and is formed during the manufacturing process with a pharma- ceutically acceptable solvent, such as water or ethanol. Hydrates are formed when the solvent is water, or alcoholates are formed when the solvent is alcohol. Solvates of the compounds described herein are conveniently prepared or formed during the processes described herein. The compounds provided herein exist in either unsolvated or solvated form.

[0070] The term "subject" or "patient" encompasses mammals. Examples of mammals include, but are not limited to, any animal belonging to the Mammalian class, such as humans, non-human primates such as chimpanzees, and other ape and monkey species, livestock animals such as cows, horses, sheep, goats, pigs, domestic animals such as rabbits, dogs, cats, and laboratory animals including rodents such as rats, mice, and guinea pigs. In one aspect, the mammal is a human.

[0071] As used herein, "treatment", "treating", "palliating" or "ameliorating" are used interchangeably. These terms refer to an approach to obtain a beneficial or desired result, including but not limited to therapeutic benefit and / or preventive benefit. "Therapeutic benefit" refers to eradication or amelioration of the underlying disease being treated. Furthermore, therapeutic benefit is achieved by eradication or amelioration of one or more of the physiological symptoms associated with the underlying disease, such that an improvement is observed in the patient, even though the patient still suffers from the underlying disease. In some embodiments, for preventive benefit, the composition is administered to a patient who is at risk of developing a particular disease, or who reports one or more of the physiological symptoms of the disease, even if the disease has not been diagnosed.

[0072] MEK kinase Phosphorylation of mitogen-activated protein kinases (MAPKs) is brought about by the action of MEK. MAPKs are localized in the cytoplasm of cells through the specific association of 1-32 residues of the MEK N-terminus in unstimulated cells. To date, seven MEK enzymes have been identified, which selectively phosphorylate serine / threonine / tyrosine residues within the activation loop of specific mitogen-activated protein kinase (MAPK) substrates. The MEK family genes consist of seven genes, with MEK1 and MEK2 being the more important genes. MEK1 is present on human chromosome 15q22.31 and is encoded by the gene MAP2K1. MEK2 is present on human chromosome 9q13.3 and is encoded by the gene MAP2K2.

[0073] The molecular weight of MEK proteins ranges between approximately 43 and 50 kDa. MEKs have amino- and carboxy-terminal domains that are more variable among different MEK proteins but share extensive homology with the kinase domain. MEK1 and MEK2 proteins are closely related and have three important domains: (1) the core protein kinase domain (containing the ATP-binding site and catalytic machinery), (2) the N-terminal domain (containing an inhibitory / allosteric segment, a nuclear export sequence, and a docking site (D domain) that helps bind ERK substrates), and (3) a shorter C-terminal region (containing a domain for versatile docking (DVD) that functions as a determinant binding site for upstream components of the Ras / Raf / MEK / ERK signaling cascade).

[0074] MEK3 and MEK6 are functionally similar to MEK1 and MEK2 and are encoded by the MAP2K3 and MAP2K6 genes located on chromosome 17q, respectively. MEK3 has 347 amino acid residues and MEK6 has 334 amino acid residues. MEK6 differs from MEK3 with respect to the C-terminal and N-terminal regions, but 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 RTKs, G protein-coupled receptors, intracellular receptors, and Toll-like receptors. The cascade can be activated in response to a variety of stimuli, including but not limited to tumor necrosis factor, interleukin-1, cytokines, UV irradiation, physical and chemical stress, and hormones. MEK3 and MEK6 can be activated by MPAK kinase kinase (MAPKKK), which in turn allows MEK3 and MEK to activate p38 MAPK. There are four isoforms of p38 MAP kinase (α, β, γ, and δ). MEK6 can activate all four isoforms, whereas MEK3 can activate only the p38α and p38β isoforms. MEK3 and MEK6, which comprise the p38 MAPK cascade, can promote p53-dependent growth arrest and arrest the cell cycle.

[0075] MEK4 and MEK7 are part of the stress-activated protein kinase (SAPK) signaling cascade. MEK4 is encoded by MAP2K4 located on chromosome 17p11.2, and MEK7 is encoded by MAP2K7 located on chromosome 19p13.3. MEK4 and MEK7 are homologous to other MEK inhibitors across the kinase domain, but differ in their N-terminal and C-terminal subunits. After activation by upstream kinases such as MAPKKK, Tpl-2, DLK, TAO1, TAO2, TAK1, ASK1, and ASK2, threonine residues in the activation segment of MEK4 and MEK7, or only MEK4, are phosphorylated. MEK4 and MEK7 can act synergistically to activate JNK protein kinases such as JK1, JNK2, and JNK3. In addition, MEK4 and MEK7 with the JNK signaling pathway can act as an important tumor suppressor pathway. MEK4 and MEK7, along with the substrate JNK, can promote apoptosis by phosphorylating and inactivating anti-apoptotic proteins, including but not limited to Bcl2, Bcl-XL, and Mcl-1. MEK4 activity has been shown to be involved in normal hepatogenesis, B and T cell lymphopoiesis, and erythropoiesis. MEK4 has also been shown to be downregulated in 75% of ovarian cancer cases. There is also a hypothesis that loss of the MEK4-p38MAPK signaling cascade may be associated with tumorigenesis.

[0076] MEK5 shares approximately 40% identity with 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) because it is twice as large as other MAPKs. The PB1 domain of MEK5 mediates MEK5 interaction with MEKK2, MEKK3, or ERK5. MEK5-ERK5 signaling can enhance cell cycle progression. Overexpression of MEK5 is associated with colon cancer, prostate cancer, breast cancer, lymphoma, and malignant mesothelioma.

[0077] MEK activation and intracellular signaling pathways Activation of MEK initiates the mitogen-activated protein kinase (MAPK) pathway, a key cell signaling pathway in regulating proliferation, cell growth, and survival. MEK transmits mitogenic signals from outside the cell to the nucleus via signal transduction pathways. MEK1 and MEK2 are involved in the Ras / Raf / MEK / ERK signaling cascade and are activated by ligands that bind to receptor tyrosine kinases (RTKs), which leads to receptor dimerization and autophosphorylation of specific tyrosine residues in their C-terminal regions. The activated receptor can then recruit and phosphorylate the adaptor proteins Grb2 and SOS, which interact with and activate the GTPase Ras. H-Ras, K-Ras, and N-Ras function as molecular switches when inactive Ras-GDP is converted to active Ras-GTP. In its active, GTP-bound form, Ras activates 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.

[0078] Activated ERK can translocate into the nucleus and 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 leads 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 mutagenic 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 approximately 20% of all cancers and more than 60% of melanomas. ERK1 and ERK2 can also be activated by MEK in solid tumors, including but not limited to melanoma, colon cancer, and lung cancer.

[0079] In tumor cells, specific growth factors bind to transmembrane receptors on the cell surface, resulting in increased RAS activation, and when 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 that form the RAS / RAF / MEK ERK signaling pathway. In addition, BRAF and KRAS are two important oncogenes in the MEK signaling pathway as well as the RAS / RAF / MAPK signaling pathway. Mutations in both the KRAS and BRAF genes result in tumor cell proliferation, differentiation, and apoptosis 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 in combination with chemotherapy treatment, BRAF inhibitors, immune checkpoint inhibitors, or epidermal growth factor receptor-tyrosine kinase inhibitors have been shown to improve clinical efficacy and cause delayed development of drug resistance (Han, J et al. J Hematol Oncol 14;1,2021).

[0080] The BRAF gene is a key gene in the MAPK pathway and is 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 therapies targeting BRAF and MEK have been studied and have demonstrated synergistic benefits. Combined inhibition of BRAF and MEK can delay or prevent resistance in patients who develop resistance when BRAF inhibitors are administered as single agents. The combination of BRAF and MEK inhibitors has 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). Furthermore, patients treated with a combination of BRAF and MEK inhibitors showed improved overall survival in metastatic melanoma.

[0081] MEK inhibitors Several drugs have been developed that target MEK, including small molecule inhibitors. Most small molecule inhibitors of MEK target MEK1 and / or MEK2 enzymes. 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 under clinical evaluation include TAK-733, binimetinib, cobimetinib, trametinib, and selumetinib.Other MEK inhibitors include midametinib and pimasertib, as well as compounds disclosed in WO2006 / 045514.Other compounds suitable as MEK inhibitors are also disclosed in U.S. Patent No. 5,525,625, WO98 / 43960, WO99 / 01421, WO99 / 01426, WO00 / 41505, WO00 / 42002, WO00 / 42003, WO00 / 41994, WO00 / 42005, WO00 / 42006, WO00 / 42007, WO00 / 42009, WO00 / 42010, WO00 / 42011, WO00 / 42012, WO00 / 42013, WO00 / 42014, WO00 / 42015, WO00 / 42016, WO00 / 42017, WO00 / 42019, WO00 / 42016, WO00 / 42015, WO00 / 42016, WO00 / 42017, WO00 / 42018, WO00 / 42019, WO00 / 42016, WO00 / 42019 ... These techniques are disclosed in WO00 / 42022, WO00 / 42029, WO00 / 68201, WO01 / 68619, WO02 / 06213, WO03 / 077855, WO03 / 077914, WO2004 / 005284, and WO2004 / O56789.

[0082] MEK inhibitors can be divided into two main classes: ATP-noncompetitive and ATP-competitive inhibitors. Most MEK inhibitors are ATP-noncompetitive and bind to an allosteric site adjacent to the ATP site. This allows for high specificity of noncompetitive MEK inhibitors.

[0083] Trametinib is an allosteric, ATP-noncompetitive inhibitor with potent activity against MEK1 and MEK2 kinases. Trametinib may induce cell cycle arrest through inhibition of p-ERK1 and p-ERK2. Pimasertib is a selective, allosteric, ATP-noncompetitive inhibitor of MEK1 and MEK2. Pimasertib may inhibit tumor growth and regression. Selumetinib is also a highly selective, ATP-noncompetitive inhibitor of MEK1 and MEK2. Studies have shown that its antitumor activity is associated with decreased phosphorylation of ERK1 and ERK2. Lefametinib is a cyclopropane-1-sulfonamide derivative that exhibits selective allosteric inhibition of MEK1 and MEK2. Lefametinib shows potent activity against human melanoma, colon, pancreatic, and skin cancer xenografts in tumor models.

[0084] PD-0325901 is a specific and potent synthetic analog of another MEK inhibitor, CI-1040. PD-0325901 also inhibits phosphorylation of ERK1 and ERK2 in melanoma and papillary thyroid cancer cell lines with B-RAF mutations. MEK162 is an inhibitor that targets MEK1 and MEK2. Studies have tested MEK162 in patients with N-Ras and B-Raf mutated advanced melanoma. RO5126766 is a highly potent dual MEK / RAF inhibitor that selectively binds to MEK1 and MEK2 to form a stable complex. Its primary mechanism was shown to be through cell cycle arrest. RO4987655 is a highly selective small molecule MEK inhibitor. This compound is a 3-oxo-oxazinane ring structure that confers metabolic stability and has antitumor effects. GDC-0973 is a derivative of methanone and is a potent small molecule inhibitor of MEK1. GDC-0973 has antitumor activity in BRAF- and KRAS-mutated cancer cell lines.AZD8330 is a newer inhibitor of MEK1 and MEK2 that is being studied in patients with advanced solid tumors.

[0085] E6201 is an ATP-competitive MEK inhibitor that shows potent activity against melanoma cells. Because melanoma has a high probability of metastasizing to the CNS, E6201 may be useful for penetrating an intact blood-brain barrier (BBB) ​​(Gampa, G. et al. Drug Metab Dispos., 46(5):658-666, 2018). E6201 may be beneficial in treating melanoma as a single agent or in combination with a BRAF inhibitor. Furthermore, E6201 may be capable of penetrating the BBB to achieve therapeutic activity levels.

[0086] Despite our increasing knowledge of cell signaling pathways, and the limited success in translating this knowledge into pharmaceuticals, there remains a large unmet medical need for therapies that act via selective MEK inhibition.

[0087] MEK Kinase Inhibitor Compounds In one aspect, provided herein are MEK kinase inhibitor compounds.

[0088] One embodiment is a compound of formula (I):

[0089] [ka] or a pharma- ceutically acceptable salt or solvate thereof, During the ceremony, R 1 is optionally substituted alkyl; R 2 is optionally substituted alkyl, and optionally R 1 and R 2 are linked by carbon-carbon bonds to form a phosphorus-containing ring, R 3 is selected from hydrogen, halo, optionally substituted alkyl, optionally substituted cycloalkyl, or optionally substituted alkoxy; R 4 is selected from hydrogen, halo, optionally substituted alkyl, optionally substituted cycloalkyl, or optionally substituted alkoxy; R 5 is selected from hydrogen, halo, optionally substituted alkyl, optionally substituted cycloalkyl, or optionally substituted alkoxy; and R 11 , R 12 , R 13 , R 14 , and R 15 are independently selected from hydrogen, halo, optionally substituted alkynyl, optionally substituted alkyl, optionally substituted cycloalkyl, or a pharma- ceutically acceptable salt or solvate thereof.

[0090] In this specification, R 1 Provided herein is a compound of formula (I), or a pharma- ceutically acceptable salt or solvate thereof, wherein R is optionally substituted C1-C3 alkyl. 2 Provided herein is a compound of formula (I), or a pharma- ceutically acceptable salt or solvate thereof, wherein R is optionally substituted C1-C3 alkyl. 1 Provided herein is a compound of formula (I), or a pharma- ceutically acceptable salt or solvate thereof, wherein R is CH3. 2 is CH3, or a pharma- ceutically acceptable salt or solvate thereof.

[0091] In this specification, R 1 is optionally substituted C1-C3 alkyl, and R 2 is optionally substituted C1-C3 alkyl, and R 1 and R 2 are linked by a carbon-carbon bond to form a phosphorus-containing ring. In one embodiment, a compound is provided, or a pharma- ceutically acceptable salt or solvate thereof, of formula (I), wherein the phosphorus-containing ring is a five-membered ring.

[0092] In this specification, R 3Provided herein is a compound of formula (I), or a pharma- ceutically acceptable salt or solvate thereof, wherein R is hydrogen. 3 Provided herein is a compound of formula (I), or a pharma- ceutically acceptable salt or solvate thereof, wherein R is halo. 3 is optionally substituted C1-C3 alkyl, or a pharma- ceutically acceptable salt or solvate thereof.

[0093] In this specification, R 4 Provided herein is a compound of formula (I), or a pharma- ceutically acceptable salt or solvate thereof, wherein R is hydrogen. 4 Provided herein is a compound of formula (I), or a pharma- ceutically acceptable salt or solvate thereof, wherein R is halo. 4 Provided herein is a compound of formula (I), or a pharma- ceutically acceptable salt or solvate thereof, wherein R is optionally substituted C1-C3 alkyl. 4 is optionally substituted C1-C3 alkoxy, or a pharma- ceutically acceptable salt or solvate thereof.

[0094] In this specification, R 5 Provided herein is a compound of formula (I), or a pharma- ceutically acceptable salt or solvate thereof, wherein R is hydrogen. 5 Provided herein is a compound of formula (I), or a pharma- ceutically acceptable salt or solvate thereof, wherein R is halo. 5 Provided herein is a compound of formula (I), or a pharma- ceutically acceptable salt or solvate thereof, wherein R is optionally substituted C1-C3 alkyl. 5 is optionally substituted C1-C3 alkoxy, or a pharma- ceutically acceptable salt or solvate thereof.

[0095] In this specification, R 11 Provided herein is a compound of formula (I), or a pharma- ceutically acceptable salt or solvate thereof, wherein R is fluoro.11 is hydrogen, or a pharma- ceutically acceptable salt or solvate thereof.

[0096] In this specification, R 12 Provided herein is a compound of formula (I), or a pharma- ceutically acceptable salt or solvate thereof, wherein R is hydrogen or fluoro. 12 Provided herein is a compound of formula (I), or a pharma- ceutically acceptable salt or solvate thereof, wherein R is fluoro. 12 is hydrogen, or a pharma- ceutically acceptable salt or solvate thereof.

[0097] In this specification, R 13 is selected from iodo, bromo, optionally substituted C2-C3 alkynyl, optionally substituted C1-C3 alkyl, optionally substituted C3-C4 cycloalkyl, or a pharma- ceutically acceptable salt or solvate thereof. 13 Provided herein is a compound of formula (I), or a pharma- ceutically acceptable salt or solvate thereof, wherein R is iodo. 13 Provided herein is a compound of formula (I), or a pharma- ceutically acceptable salt or solvate thereof, wherein R is an optionally substituted C alkyl. 13 Provided herein is a compound of formula (I), or a pharma- ceutically acceptable salt or solvate thereof, wherein R is -CF3. 13 Provided herein is a compound of formula (I), or a pharma- ceutically acceptable salt or solvate thereof, wherein R is bromo. 13 is optionally substituted cyclopropyl, or a pharma- ceutically acceptable salt or solvate thereof.

[0098] In this specification, R 14 and R 15 is hydrogen, or a pharma- ceutically acceptable salt or solvate thereof.

[0099] One embodiment provides a MEK kinase inhibitor compound having a structure as shown in Table 1, or a pharma- ceutically acceptable salt or solvate thereof.

[0100] [Table 1-1]

[0101] [Table 1-2]

[0102] [Table 1-3]

[0103] [Table 1-4]

[0104] [Table 1-5]

[0105] Preparation of compounds The compounds used in the synthetic chemical reactions described herein are made according to organic synthesis techniques known to those skilled in the art, beginning with commercially available chemicals and / or compounds described in the chemical literature. "Commercially available chemicals" include Acros Organics (Pittsburgh, PA), Aldrich Chemical (Milwaukee, WI, including Sigma Chemical and Fluka), Apin Chemicals Ltd. (Milton Park, UK), Avocado Research (Lancashire, UK), BDH Inc. (Toronto, Canada), Bionet (Cornwall, UK), Chemservice Inc. (West Chester, PA), Crescent Chemical Co. (Hauppauge, NY), Eastman Organic Chemicals, Eastman Kodak Company (Rochester, NY), Fisher Scientific Co. (Pittsburgh, PA), Fisons Chemicals (Leicestershire, UK), Frontier Scientific (Logan, UT), ICN Biomedicals, Inc. (Costa Mesa, CA), Key Organics (Cornwall, UK), Lancaster Synthesis (Windham, NH), Maybridge Chemical Co. Ltd. (Cornwall, UK), Parish Chemical Co. (Orem, UT), Pfaltz & Bauer, Inc. (Waterbury, CT), Polyorganix (Houston, TX), Pierce Chemical Co. (Rockford, IL), Riedel de Haen AG (Hannover, Germany), Spectrum Quality Products, Inc. (New Brunswick, NJ), TCI America (Portland, OR), Trans World Chemicals, Inc. (Rockville, MD), and Wako Chemicals USA, Inc. (Richmond, VA).

[0106] Suitable references and papers detailing the synthesis of reactants useful in the preparation of the compounds described herein or providing references to articles describing their preparation include, for example, "Synthetic Organic Chemistry", John Wiley & Sons, Inc., New York; "Organic Functional Group Preparations" by S.R. Sandler et al., 2nd Edition, Academic Press, New York, 1983; "Modern Synthetic Reactions" by H.O. House, 2nd Edition, W.A. Benjamin, Inc. Menlo Park, Calif, 1972; "Heterocyclic Chemistry" by T.L. Gilchrist, 2nd Edition, John Wiley & Sons, New York, 1992; and "Advanced Organic Chemistry: Reactions, Mechanism and Structure" by J. March, 4th Edition, Wiley Interscience, New York, 1992. Additional suitable references and papers that detail the synthesis of reactants useful in the preparation of the compounds described herein or provide references to articles describing their preparation include, for example, "Organic Synthesis: Concepts, Methods, Starting Materials" by Fuhrhop, J. and Penzlin G., Second, Revised and Enlarged Edition (1994) John Wiley & Sons ISBN: 3-527-29074-5; "Organic Chemistry, An Intermediate Text" by Hoffman, RV (1996) Oxford University Press, ISBN 0-19-509618-5; "Comprehensive Organic Transformations: A Guide to Functional Group Preparations" by Larock, RC, Second 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, "Modern Carbonyl Chemistry" by Otera, J. (editor) (2000) Wiley-VCH, ISBN: 3-527-29871-1, "Patai's 1992 Guide to the Chemistry of Functional Groups" by Patai, S. (1992) Interscience ISBN: 0-471-93022-9, "Organic Chemistry" 7th edition (2000) John Wiley & Sons, ISBN: 0-471-19095-0, "Intermediate Organic Chemistry" by Stowell, JC, "Chemistry" 2nd edition (1993) Wiley-Interscience, ISBN: 0-471-57456-2, "Industrial Organic Chemicals: Starting Materials and Intermediates: An Ullmann's Encyclopedia" (1999) John Wiley & Sons, ISBN: 3-527-29645-X, 8 volumes in total, "Organic Reactions" (1942-2000) John Wiley & Sons, over 55 volumes in total, and "Chemistry of Functional Groups" John Wiley & Sons, 73 volumes in total.

[0107] Specific and similar reactants are optionally identified by an index of known chemicals and reactants prepared by the Chemical Abstract Service of the American Chemical Society, available in most public and university libraries, as well as through online databases (contact the American Chemical Society, Washington, DC, for more information). Chemicals that are known but not commercially available in a catalog are optionally prepared by special chemical synthesis facilities, where many of the standard chemical supply facilities (e.g., those listed above) offer special synthesis services. A useful reference for the preparation and selection of pharmaceutical salts of the compounds described herein is "Handbook of Pharmaceutical Salts" by PH Stahl & CG Wermuth, Verlag Helvetica Chimica Acta, Zurich 2002.

[0108] Pharmaceutical Compositions In certain embodiments, the MEK kinase inhibitor compounds described herein are administered as pure chemicals. In other embodiments, the MEK kinase inhibitor compounds described herein are administered as pure chemicals, e.g., as described in Remington: The Science and Practice of Pharmacy (Gennaro, 21 st The compositions are combined with a pharma- ceutically suitable or acceptable carrier (also referred to herein as a pharma- ceutically suitable (or acceptable) excipient, a physiologically suitable (or acceptable) excipient, or a physiologically suitable (or acceptable) carrier), selected in accordance with the chosen route of administration and standard pharmaceutical practice, as described in U.S. Pat. No. 6,333,311 (Ed. Mack Pub. Co., Easton, PA (2005)).

[0109] Provided herein are pharmaceutical compositions comprising at least one MEK kinase inhibitor compound described herein, or a stereoisomer, pharma- ceutically acceptable salt, hydrate, or solvate thereof, together with one or more pharma- ceutically acceptable carriers. A carrier (or excipient) is acceptable or suitable if it is compatible with the other ingredients of the composition and not deleterious to the recipient of the composition (i.e., the subject or patient).

[0110] One embodiment provides a pharmaceutical composition comprising a pharma- ceutically acceptable excipient and a compound of formula (I), or a pharma- ceutically acceptable salt or solvate thereof.

[0111] One embodiment provides a process for preparing a pharmaceutical composition comprising mixing a compound of formula (I), or a pharma- ceutically acceptable salt or solvate thereof, and a pharma- ceutically acceptable carrier.

[0112] In certain embodiments, the MEK kinase inhibitor compounds described by Formula (I), or pharma- ceutically acceptable salts or solvates thereof, are substantially pure in that they contain less than about 5%, or less than about 2%, or less than about 1%, or less than about 0.5%, or less than about 0.1%, of other small organic molecules, such as unreacted intermediates or synthetic by-products produced in one or more of the steps of the synthetic method.

[0113] One embodiment provides a pharmaceutical composition comprising a pharma- ceutically acceptable excipient and a compound of Table 1, or a pharma- ceutically acceptable salt or solvate thereof.

[0114] One embodiment provides a method of preparing a pharmaceutical composition comprising mixing a compound of Table 1, or a pharma- ceutically acceptable salt or solvate thereof, and a pharma- ceutically acceptable carrier.

[0115] In certain embodiments, the MEK kinase inhibitor compounds described by Table 1, or pharma- ceutically acceptable salts or solvates thereof, are substantially pure in that they contain less than about 5%, or less than about 2%, or less than about 1%, or less than about 0.5%, or less than about 0.1%, of other small organic molecules, such as unreacted intermediates or synthetic by-products produced in one or more of the steps of the synthetic method.

[0116] Suitable oral dosage forms include, for example, tablets, pills, sachets, or capsules of hard or soft gelatin, methylcellulose, or another suitable material that dissolves easily in the digestive tract. In some embodiments, suitable non-toxic solid carriers are used, including, for example, pharmaceutical grades of mannitol, lactose, starch, magnesium stearate, sodium saccharin, talcum, cellulose, glucose, sucrose, magnesium carbonate, and the like. (See, for example, Remington: The Science and Practice of Pharmacy (Gennaro, 21 st See Ed. Mack Pub. Co., Easton, PA (2005).

[0117] In some embodiments, the MEK kinase inhibitor compound described by formula (I) or Table 1, or its pharma- ceutically acceptable salt or solvate, is formulated for administration by injection. In some cases, the injection formulation is an aqueous formulation. In some cases, the injection formulation is a non-aqueous formulation. In some cases, the injection formulation is an oil-based formulation, such as sesame oil.

[0118] The dosage of the compositions comprising at least one MEK kinase inhibitor compound described herein will vary depending on the disease of the subject or patient (e.g., human), in some embodiments, such factors include health status, age, and other factors.

[0119] The pharmaceutical composition is administered in a manner appropriate for the disease to be treated (or prevented). The appropriate dose, as well as the appropriate duration and frequency of administration, shall be determined by factors such as the patient's disease, the type and severity of the patient's disease, the specific form of the active ingredient, and the method of administration. In general, the appropriate dose and treatment regimen provides the composition in an amount sufficient to provide therapeutic and / or preventive benefits (e.g., improved clinical outcomes, such as more frequent complete or partial remissions, or longer disease-free and / or overall survival, or reduced severity of symptoms). The optimal dose is generally determined using experimental models and / or clinical trials. The optimal dose varies depending on the patient's size, weight, or blood volume.

[0120] Oral doses typically range from about 1.0 mg to about 1000 mg, one to four or more times per day.

[0121] Treatment An embodiment provides a compound of formula (I), or a pharma- ceutically acceptable salt or solvate thereof, for use in a method of treatment of the human or animal body. An embodiment provides a compound of formula (I), or a pharma- ceutically acceptable salt or solvate thereof, for use in a method of treatment of cancer or neoplastic disease. An embodiment provides a pharmaceutical composition comprising a compound of formula (I), or a pharma- ceutically acceptable salt or solvate thereof, and a pharma- ceutically acceptable excipient, for use in a method of treatment of cancer or neoplastic disease. Some embodiments provide the use of a compound of formula (I), or a pharma- ceutically 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.

[0122] In some embodiments, a method of treating cancer in a patient in need of such treatment is provided, comprising administering to the patient a compound of formula (I), or a pharma- ceutically acceptable salt or solvate thereof. In some embodiments, a method of treating cancer in a patient in need of such treatment is provided, comprising administering to the patient a pharmaceutical composition comprising a compound of formula (I), or a pharma-ceutically acceptable salt or solvate thereof, and a pharma-ceutically acceptable excipient. Another embodiment provides a method, wherein the cancer is selected from lung cancer, breast cancer, skin cancer, melanoma, or leukemia.

[0123] One embodiment provides a compound of Table 1, or a pharma- ceutically 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 pharma- ceutically 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 pharma- ceutically acceptable salt or solvate thereof, and a pharma- ceutically acceptable excipient, for use in a method of treatment of cancer or neoplastic disease. Some embodiments provide the use of a compound of Table 1, or a pharma- ceutically acceptable salt or solvate thereof, in the manufacture of a medicament for the treatment of cancer or neoplastic disease. Another embodiment provides a method, wherein the cancer is selected from lung cancer, breast cancer, skin cancer, melanoma, or leukemia.

[0124] In some embodiments, a method of treating cancer in a patient in need thereof is provided, comprising administering to the patient a compound of Table 1, or a pharma- ceutically acceptable salt or solvate thereof. In some embodiments, a method of treating cancer in a patient in need thereof is provided, comprising administering to the patient a pharmaceutical composition comprising a compound of Table 1, or a pharma- ceutically acceptable salt or solvate thereof, and a pharma- ceutically acceptable excipient. Another embodiment provides a method, wherein the cancer is selected from lung cancer, breast cancer, skin cancer, melanoma, or leukemia.

[0125] Methods are provided herein, where the pharmaceutical composition is administered orally.Methods are provided herein, where the pharmaceutical composition is administered by injection.

[0126] One embodiment provides a method of inhibiting a MEK kinase enzyme comprising contacting the MEK kinase enzyme with a compound of formula (I) or Table 1. Another embodiment provides a method of inhibiting a MEK kinase enzyme, wherein the MEK kinase enzyme is contacted in an in vivo setting. Another embodiment provides a method of inhibiting a MEK kinase enzyme, wherein the MEK kinase enzyme is contacted in an in vitro setting.

[0127] Other embodiments and uses will be apparent to those skilled in the art in light of the present disclosure. The following examples are provided merely as illustrations of various embodiments and should not be construed as limiting the invention in any way. EXAMPLES

[0128] 1.Chemical synthesis In some embodiments, the MEK kinase inhibitor compounds disclosed herein are synthesized according to the following examples: As used hereinafter, and throughout the description of the invention, the following abbreviations shall be understood to have the following meanings, unless otherwise indicated: ℃ Celsius δ H Chemical shift in parts per million downfield from tetramethylsilane DCM Dichloromethane (CH2Cl2) DMF Dimethylformamide DMSO Dimethyl sulfoxide EA Ethyl acetate ESI Electrospray Ionization Et Ethyl g grams h time HPLC High Performance Liquid Chromatography Hz Hertz J coupling constant (NMR spectroscopy) LCMS Liquid Chromatography Mass Spectrometry μ Micro m multiplet (spectrum), meter, millimeter M mole M + Parent molecular ion Me Methyl MHz Megahertz min mol mole, molecule (expressed as molecular weight) mL Milliliters MS mass spectrometry nm nanometer NMR nuclear magnetic resonance pH Hydrogen ion potential, a measure of the acidity or basicity of an aqueous solution PE Petroleum Ether RT room temperature s singlet (spectrum) t Triplet (spectrum) T temperature TFA Trifluoroacetic acid THF Tetrahydrofuran

[0129] Intermediate 1: Phosphorane 1-oxide

[0130] [ka]

[0131] To a stirred mixture of magnesium (3.61 g, 148.440 mmol) in tetrahydrofuran (45 mL) was added 1,3-dibromopropane (14.62 g, 72.41 mmol) in tetrahydrofuran (15 mL) at 15° C. under nitrogen atmosphere. The reaction mixture was stirred at room temperature for 1.5 h. Diethyl phosphonate (5.0 g, 36.20 mmol) in tetrahydrofuran (15 mL) was added to the mixture at 15° C. and the reaction mixture was stirred at room temperature for another 1 h. An ice-cold solution of potassium carbonate (21 g) in water (35 mL) was slowly added to give a heavy off-white precipitate of magnesium carbonate, which was quickly filtered off in air and washed with degassed ethanol (50 mL). The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with dichloromethane / methanol (10 / 1). Fractions containing the desired product were combined and concentrated to give phosphorane 1-oxide (1.3 g, 34%) as a colorless oil. 1 H NMR(400MHz,CDCl3)δ8.06(s,1H),2.15-1.94(m,4H),1.94-1.69(m,4H).

[0132] Intermediate 2: Ethyl(methyl)phosphine oxide

[0133] [ka]

[0134] To a stirred solution of 1M methylmagnesium bromide in tetrahydrofuran (27.76 mL, 27.76 mmol) was added dropwise at room temperature under nitrogen atmosphere ethyl methylphosphonate (2.0 g, 18.51 mmol) in tetrahydrofuran (6.0 mL). The reaction mixture was stirred at room temperature under nitrogen atmosphere for 1 h. A solution of potassium carbonate (12 g) in water (20 mL) was slowly added to give a heavy off-white precipitate of magnesium carbonate, which was quickly filtered in air and washed with degassed ethanol (30 mL). The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with dichloromethane / methanol (10 / 1). Fractions containing the desired product were combined and concentrated to give ethyl(methyl)phosphine oxide (1.0 g, 59%) as a colorless oil. 1 H NMR(400MHz,CDCl3)δ1.94-1.77(m,2H),1.60-1.56(m,3H),1.26-1.17(m,3H).

[0135] Intermediate 3: (3-aminopyridin-4-yl)dimethylphosphine oxide

[0136] [ka]

[0137] To a stirred mixture of 4-iodopyridin-3-amine (3.0 g, 13.64 mmol), (methylphosphonoyl)methane (1.28 g, 16.36 mmol), and palladium(II) acetate (0.15 g, 0.68 mmol) in N,N-dimethylformamide (30 mL) was added 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (0.39 g, 0.68 mmol) and potassium phosphate tribasic (3.18 g, 15.00 mmol). The reaction mixture was degassed with nitrogen three times and stirred at 120 °C for 1 h. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with dichloromethane / methanol (10 / 1). Fractions containing the desired product were combined and concentrated to give 4-(dimethylphosphoryl)pyridin-3-amine (2.18 g, 94%) as a pale yellow solid. C7H 11 N2OP[M+H] + MS ESI calculated value 171.06, measured value 171.05. 1 H NMR(400MHz,CDCl3)δ8.11(d,J=5.5Hz,1H),7.96(dd,J=5.0,3.6Hz,1H),6.87(dd,J=13.3,5.0Hz,1H),5.44(s,2H),1.80(s,3H),1.77(s,3H), 31 P NMR (162 MHz, CDCl3) δ 40.73.

[0138] The following compounds in Table 2 were prepared using procedures similar to those described for Intermediate 3 using the appropriate starting materials.

[0139] [Table 2]

[0140] Intermediate 8: 6-(Dimethylphosphoryl)-2,3-difluoroaniline

[0141] [ka]

[0142] To a stirred mixture of 6-bromo-2,3-difluoroaniline (0.70 g, 3.36 mmol) and (methylphosphonoyl)methane (0.31 g, 4.03 mmol) in N,N-dimethylformamide (1.00 mL) was added palladium acetate (37.78 mg, 0.16 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (97.36 mg, 0.16 mmol), and potassium phosphate (0.79 g, 3.70 mmol) at room temperature. The reaction mixture was stirred at 150° C. for 1 h. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography and eluted with dichloromethane / methanol (10 / 1). Fractions containing the desired product were combined and concentrated to give 6-(dimethylphosphoryl)-2,3-difluoroaniline (200 mg, 29%) as a grey solid. C8H 10 F2NOP[M+H] + MS ESI calculated value: 206.05, measured value: 206.05, 1 H NMR(400MHz,CDCl3)δ6.54-6.50(m,1H),5.26(s,2H),1.80(d,J=12.1Hz,6H), 19 F NMR(377MHz,CDCl3)δ-132.99(1F),-160.67(1F).

[0143] The following compounds in Table 3 were prepared using procedures similar to those described for Intermediate 8 using the appropriate starting materials.

[0144] [Table 3]

[0145] Example 1: 4-(Dimethylphosphoryl)-N-(2-fluoro-4-iodophenyl)pyridin-3-amine

[0146] [ka]

[0147] Step 1. 4-(Dimethylphosphoryl)-N-(2-fluorophenyl)pyridin-3-amine A solution of 4-(dimethylphosphoryl)pyridin-3-amine (2.18 g, 12.81 mmol), 1-bromo-2-fluorobenzene (3.36 g, 19.22 mmol), and methanesulfonato 2-dicyclohexylphosphino-3,6-dimethoxy-2'-4'-6'-tri-i-propyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II) (BrettPhos Pd) in 1,4-dioxane (25 mL) was added. To a stirred mixture of G3) (1.16 g, 1.28 mmol) and 2-(dicyclohexylphosphino)-3,6-dimethoxy-2'-4'-6'-tri-i-propyl-1,1'-biphenyl (BrettPhos) (1.38 g, 2.56 mmol) was added sodium tert-butoxide (3.69 g, 38.44 mmol). The reaction mixture was degassed with nitrogen three times and stirred at 100 °C for 1 h. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography and eluted with dichloromethane / methanol (10 / 1). Fractions containing the desired product were combined and concentrated to give 4-(dimethylphosphoryl)-N-(2-fluorophenyl)pyridin-3-amine (2.6 g, 77%) as a yellow oil. C 13 H 14 FN2OP[M+H] + MS ESI calculated value 265.08, measured value 265.00, 1 H NMR(400MHz,CDCl3)δ8.95(s,1H),8.41(d,J=5.3Hz,1H),8.12(t,J=4.3Hz,1H),7.36(t,J=7.7Hz,1H),7.16-7.04(m,4H),1.89(s,3H),1.86(s,3H), 19 F NMR (377MHz, CDCl3) δ-123.53.

[0148] Step 2. 4-(Dimethylphosphoryl)-N-(2-fluoro-4-iodophenyl)pyridin-3-amine To a stirred mixture of 4-(dimethylphosphoryl)-N-(2-fluorophenyl)pyridin-3-amine (2.6 g, 9.84 mmol) in tetrahydrofuran (25 mL) and methanol (25 mL), p-toluenesulfonic acid monohydrate (5.24 g, 27.55 mmol) and N-iodosuccinimide (6.64 g, 29.52 mmol) were added at room temperature. The reaction mixture was stirred at 60 °C for 1 h. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluted with dichloromethane / ethanol (10 / 1) to give the crude product (3.3 g), which was further purified by reversed-phase flash chromatography under the following conditions: column, C18 silica gel, mobile phase: acetonitrile in water (+ 10 mmol / L NH4HCO3), gradient from 15% to 50% in 30 min, detector: UV 254 / 220 nm. Fractions containing the desired product were combined and concentrated to give 4-(dimethylphosphoryl)-N-(2-fluoro-4-iodophenyl)pyridin-3-amine (1.08 g, >98% purity, 28%) as an off-white solid and approximately 1 g, 95% pure product. 13 H 13 FIN2OP[M+H] + MS ESI calculated value: 390.98, measured value: 391.05. 1 H NMR(400MHz,DMSO-d6)δ9.35(s,1H),8.47(d,J=5.2Hz,1H),8.20-8.18(m,1H),7.6 9-7.66(m,1H),7.50-7.45(m,2H),7.26(t,J=8.6Hz,1H),1.83(s,3H),1.80(s,3H), 19 F NMR(376MHz,DMSO-d6)δ-124.70.

[0149] The following compounds in Table 4 were prepared using procedures similar to those described in Example 1 using the appropriate starting materials.

[0150] [Table 4-1]

[0151] [Table 4-2]

[0152] Examples 8 and 9: (R)-4-[ethyl(methyl)phosphoryl]-N-(2-fluoro-4-iodophenyl)pyridin-3-amine and (S)-4-[ethyl(methyl)phosphoryl]-N-(2-fluoro-4-iodophenyl)pyridin-3-amine

[0153] [ka]

[0154] 4-[Ethyl(methyl)phosphoryl]-N-(2-fluoro-4-iodophenyl)pyridin-3-amine (54 mg) was purified by preparative chiral HPLC under the following conditions: column: CHIRALPAK IE, 2x25 cm, mobile phase A: hexane (0.5%, 2 M NH3-MeOH) --HPLC, mobile phase B: EtOH:DCM=1:1 --HPLC, flow rate: 20 mL / min, gradient: 30%B to 30%B in 14 min, wavelength: 220 / 254 nm, RT1 (min): 10.92, RT2 (min): 12.85, sample solvent: MeOH:DCM=1:1 --HPLC, injection volume: 0.3 mL. The faster peak (RT1: 10.92 min) containing the desired product was combined and concentrated to give one enantiomer (absolute chiral structure not determined) (19.9 mg, 36%) as a pale yellow semi-solid. 14 H 15 FIN2OP[M+H] + MS ESI calculated value 405.00, measured value 405.00, 1 H NMR(400MHz,DMSO-d6)δ9.45(s,1H),8.47(d,J=5.0Hz,1H),8.18(t,J=5.0Hz,1H),7.69-7.66(m,1H), 7.49-7.42(m,2H),7.27(t,J=8.6Hz,1H),2.08-2.00(m,2H),1.82(d,J=13.6Hz,3H)1.06-0.98(m,3H), 19F NMR(376MHz,DMSO-d6)δ-124.71. The later peak (RT2: 12.85 min) containing the desired product was combined and concentrated to give the second enantiomer (absolute chiral structure not determined) (19.8 mg, 36%) as a pale yellow semi-solid. 14 H 15 FIN2OP[M+H] + MS ESI calculated value 405.00, measured value 405.00, 1 H NMR(400MHz,DMSO-d6)δ9.45(s,1H),8.47(d,J=5.0Hz,1H),8.18(t,J=5.0Hz,1H),7.69-7.66(m,1H), 7.49-7.42(m,2H),7.27(t,J=8.6Hz,1H),2.08-2.00(m,2H),1.82(d,J=13.6Hz,3H)1.06-0.98(m,3H). 19 F NMR(376MHz,DMSO-d6)δ-124.68.

[0155] Example 10: N-(4-bromo-2-fluorophenyl)-4-(dimethylphosphoryl)pyridin-3-amine

[0156] [ka]

[0157] To a stirred mixture of 4-(dimethylphosphoryl)pyridin-3-amine (0.25 g, 1.46 mmol) and 4-bromo-2-fluoro-1-iodobenzene (0.66 g, 2.20 mmol) in 1,4-dioxane (2.50 mL) was added 2-(dicyclohexylphosphino)-3,6-dimethoxy-2'-4'-6'-tri-i-propyl-1,1'-biphenyl (BrettPhos) (0.15 g, 0.29 mmol), methanesulfonato 2-dicyclohexylphosphino-3,6-dimethoxy-2'-4'-6'-tri-i-propyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II) (BrettPhos Pd G3) (0.13 g, 0.14 mmol), and sodium tert-butoxide (0.42 g, 4.40 mmol) were added in portions at room temperature. The reaction mixture was degassed with nitrogen three times and stirred at 100 °C for 1 h. The resulting mixture was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography under the following conditions: Column: Xselect CSH C18 OBD column 30x150 mm 5 μm, Mobile phase A: water (10 mmol / L ammonium bicarbonate), Mobile phase B: acetonitrile, Flow rate: 60 mL / min, Gradient: 27% B to 37% B in 11 min, Wavelength: 254 nm. Fractions containing the desired product were combined and concentrated to give N-(4-bromo-2-fluorophenyl)-4-(dimethylphosphoryl)pyridin-3-amine (10 mg, 2%) as a pale yellow oil. C 13 H 13 BrFN2OP[M+H] + MS ESI calculated values: 342.99, 344.99; measured values: 342.95, 344.95; 1 H NMR(400MHz,DMSO-d6)δ9.37(s,1H),8.46(d,J=5.2Hz,1H),8.19(dd,J=4.9,3.2Hz,1H),7.61( dd,J=10.8,2.2Hz,1H),7.53-7.38(m,2H),7.35(dd,J=8.8,2.2Hz,1H),1.82(d,J=13.7Hz,6H), 19 F NMR(377MHz,DMSO-d6)δ-123.94(1F).

[0158] The following compounds in Table 5 were prepared using procedures similar to those described in Example 10 using the appropriate starting materials.

[0159] [Table 5]

[0160] Example 14: (3-((4-ethynyl-2-fluorophenyl)amino)pyridin-4-yl)dimethylphosphine oxide

[0161] [ka]

[0162] Step 1. (3-((2-fluoro-4-((trimethylsilyl)ethynyl)phenyl)amino)pyridin-4-yl)dimethylphosphine oxide To a stirred mixture of 4-(dimethylphosphoryl)-N-(2-fluoro-4-iodophenyl)pyridin-3-amine (0.30 g, 0.77 mmol), trimethylsilylacetylene (0.23 g, 2.31 mmol), trans-dichlorobis(triphenylphosphine)palladium (53.97 mg, 0.08 mmol), and cuprous iodide (29.29 mg, 0.15 mmol) in N,N-dimethylformamide (3.00 mL) was added triethylamine (0.23 g, 2.31 mmol) at room temperature. The reaction mixture was degassed with nitrogen three times and stirred at 90 °C for 1 h. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with dichloromethane / methanol (10 / 1). Fractions containing the desired product were combined and concentrated to give (3-((2-fluoro-4-((trimethylsilyl)ethynyl)phenyl)amino)pyridin-4-yl)dimethylphosphine oxide (0.25 g, 90%) as a brown solid. 18 H 22 FN2OPSi[M+H] + MS ESI calculated: 361.12, measured: 361.10.

[0163] Step 2. (3-((4-ethynyl-2-fluorophenyl)amino)pyridin-4-yl)dimethylphosphine oxide To a stirred solution of (3-((2-fluoro-4-((trimethylsilyl)ethynyl)phenyl)amino)pyridin-4-yl)dimethylphosphine oxide (0.27 g, 0.75 mmol) in tetrahydrofuran (3.00 mL) was added TBAF in tetrahydrofuran (1.12 mL, 1 M) dropwise at room temperature. The reaction mixture was stirred at room temperature for 1 h. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with dichloromethane / methanol (10 / 1) to give the crude product. The crude product (0.20 g) was purified by preparative HPLC using the following conditions: Column: XBridge Prep OBD C18 column, 30x150 mm, 5 μm, Mobile phase A: water (10 mmol / L NH4HCO3), Mobile phase B: ACN, Flow rate: 60 mL / min, Gradient: 21% B to 31% B in 8 min, 31% B, Wavelength: 254 nm, RT: 7 min. Fractions containing the desired product were combined and concentrated to give (3-((4-ethynyl-2-fluorophenyl)amino)pyridin-4-yl)dimethylphosphine oxide (60.90 mg, 28%) as a pale yellow semi-solid. C 15 H 14 FN2OP[M+H] + MS ESI calculated value: 289.08, measured value: 289.05. 1 H NMR(400MHz,DMSO-d6)δ9.51(d,J=1.7Hz,1H),8.57(d,J=5.1Hz,1H),8.23(dd,J=4.9,3.2Hz,1H),7.51(dd ,J=13.2,4.9Hz,1H),7.46-7.36(m,2H),7.26(dd,J=8.3,1.9Hz,1H),4.18(s,1H),1.82(d,J=13.8Hz,6H).

[0164] The following compounds in Table 6 were prepared using procedures similar to those described in Example 14 using the appropriate starting materials.

[0165] [Table 6]

[0166] Examples 16 and 17: N-(4-bromo-2-fluorophenyl)-4-[(R)-ethyl(methyl)phosphoryl]pyridin-3-amine and N-(4-bromo-2-fluorophenyl)-4-[(S)-ethyl(methyl)phosphoryl]pyridin-3-amine

[0167] [ka]

[0168] Step 1. N-(4-bromo-2-fluorophenyl)-4-[ethyl(methyl)phosphoryl]pyridin-3-amine A solution of 4-[ethyl(methyl)phosphoryl]pyridin-3-amine (180 mg, 0.98 mmol) and methanesulfonato 2-dicyclohexylphosphino-3,6-dimethoxy-2'-4'-6'-tri-i-propyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II) (BrettPhos Pd To a stirred mixture of G3) (CAS: 1470372-59-8) (88.59 mg, 0.10 mmol), 2-(dicyclohexylphosphino)-3,6-dimethoxy-2'-4'-6'-tri-i-propyl-1,1'-biphenyl (BrettPhos) (CAS: 1070663-78-3) (104.92 mg, 0.20 mmol), and sodium tert-butoxide (281.77 mg, 2.93 mmol) was added 4-bromo-2-fluoro-1-iodobenzene (441.10 mg, 1.47 mmol) at room temperature. The reaction mixture was degassed with nitrogen three times and stirred at 100 °C for 2 h. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography and eluted with dichloromethane / methanol (10 / 1) to give the crude product. The crude product was purified by reverse flash chromatography under the following conditions: A: water (+10 mmol / L NH4HCO3), mobile phase B: ACN, flow rate: 60 mL / min, gradient: 28% B to 37% B in 8 min, 37% B, wavelength: 254 nm, RT1 (min): 7. Fractions containing the desired product were combined and concentrated to give N-(4-bromo-2-fluorophenyl)-4-[ethyl(methyl)phosphoryl]pyridin-3-amine (79 mg, 22%) as a colorless oil. 14 H 15 BrFN2OP[M+H] + MS ESI calculated values ​​357.01, 359.01, measured values ​​357.00, 359.00.

[0169] Step 2. N-(4-bromo-2-fluorophenyl)-4-[(R)-ethyl(methyl)phosphoryl]pyridin-3-amine and N-(4-bromo-2-fluorophenyl)-4-[(S)-ethyl(methyl)phosphoryl]pyridin-3-amine (N-(4-bromo-2-fluorophenyl)-4-[ethyl(methyl)phosphoryl]pyridin-3-amine) (79 mg) was purified by preparative HPLC under the following conditions: Column: CHIRALPAK IE, 2x25 cm, 5 μm, Mobile phase A: Methyl tert-butyl ether (0.5%, 2M in NH3-methyl alcohol)--HPLC, Mobile phase B: Ethyl alcohol:DCM=1:1--HPLC, Flow rate: 20 mL / min, Gradient: 20%B to 20%B in 12 min, Wavelength: 220 / 254 nm, RT1 (min): 9.29, RT2 (min): 11.34. The faster peak (RT1: 9.29 min) containing the desired product was combined and concentrated to give one enantiomer (19.5 mg, 25%) as a colorless oil. C 14 H 15 BrFN2OP[M+H] + MS ESI calculated values: 357.01, 359.01, measured values: 357.15, 359.15, 1 H NMR(400MHz,DMSO-d6)δ9.44(s,1H),8.46(d,J=5.1Hz,1H),8.18(dd,J=4.9,3.2Hz,1H),7.60(dd,J=10.7,2.2 Hz,1H),7.49-7.38(m,2H),7.35-7.29(m,1H),2.04-1.96(m,2H),1.82(d,J=13.3Hz,3H),1.03-0.98(m,3H)., 19 F NMR(376MHz,DMSO-d6)δ-123.83(1F).

[0170] The later peaks containing the desired product were combined and concentrated to give the second enantiomer (18 mg, 23%) as a colorless oil. 14 H 15 BrFN2OP[M+H] + MS ESI calculated values: 357.01, 359.01, measured values: 357.15, 359.15, 1H NMR(400MHz,DMSO-d6)δ9.44(s,1H),8.46(d,J=5.1Hz,1H),8.18(dd,J=4.9,3.2Hz,1H),7.60(dd,J=10.7,2. 2Hz,1H),7.49-7.38(m,2H),7.35-7.28(m,1H),2.04-1.95(m,2H),1.82(d,J=13.3Hz,3H),1.04-0.95(,3H)., 19 F NMR(376MHz,DMSO-d6)δ-123.83(1F).

[0171] Examples 19 and 20: 4-[(R)-Ethyl(methyl)phosphoryl]-N-(4-ethynyl-2-fluorophenyl)pyridin-3-amine and 4-[(S)-Ethyl(methyl)phosphoryl]-N-(4-ethynyl-2-fluorophenyl)pyridin-3-amine

[0172] [ka]

[0173] Step 1. 4-[Ethyl(methyl)phosphoryl]-N-{2-fluoro-4-[2-(trimethylsilyl)ethynyl]phenyl}pyridin-3-amine To a stirred mixture of 4-[ethyl(methyl)phosphoryl]-N-(2-fluoro-4-iodophenyl)pyridin-3-amine (400 mg, 0.99 mmol) and CuI (37.70 mg, 0.20 mmol) in DMF (4 mL) was added trimethylsilylacetylene (0.42 mL, 2.97 mmol) and triethylamine (0.41 mL, 2.97 mmol) dropwise at room temperature. The reaction mixture was degassed with nitrogen three times and stirred at 90° C. for 1 h. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography and eluted with dichloromethane / methanol (10 / 1). Fractions containing the desired product were combined and concentrated to give 4-[ethyl(methyl)phosphoryl]-N-{2-fluoro-4-[2-(trimethylsilyl)ethynyl]phenyl}pyridin-3-amine (270 mg, 73%) as a brown solid. C 19 H24 FN2OPSi[M+H] + MS ESI calculated 375.15, found 375.00.

[0174] Step 2. 4-[Ethyl(methyl)phosphoryl]-N-(4-ethynyl-2-fluorophenyl)pyridin-3-amine To a stirred solution of 4-[ethyl(methyl)phosphoryl]-N-{2-fluoro-4-[2(trimethylsilyl)ethynyl]phenyl}pyridin-3-amine (230 mg, 0.61 mmol) in tetrahydrofuran (2.3 mL) was added TBAF (0.92 mL, 0.92 mmol) dropwise at 0° C. The reaction mixture was stirred at room temperature for 1 h. The resulting mixture was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography under the following conditions: column: WelFlash™ C18-I, 20-40 μm, 120 g, eluent A: water (+10 mmol / L NH4HCO3), eluent B: ACN, gradient: 25% to 45% B in 25 min, flow rate: 60 mL / min, detector: 220 / 254 nm. Fractions containing the desired product were combined and concentrated to give 4-[ethyl(methyl)phosphoryl]-N-(4-ethynyl-2-fluorophenyl)pyridin-3-amine (90 mg, 48%) as a yellow solid. 16 H 16 FN2OP[M+H] + MS ESI calculated value 303.10, measured value 303.00.

[0175] Step 3. 4-[(R)-Ethyl(methyl)phosphoryl]-N-(4-ethynyl-2-fluorophenyl)pyridin-3-amine and 4-[(S)-Ethyl(methyl)phosphoryl]-N-(4-ethynyl-2-fluorophenyl)pyridin-3-amine 4-[Ethyl(methyl)phosphoryl]-N-(4-ethynyl-2-fluorophenyl)pyridin-3-amine (90 mg, 0.30 mmol) was purified by preparative HPLC under the following conditions: Column: CHIRALPAK IE, 2x25 cm, 5 μm, Mobile phase A: Hex (0.5%, 2 M NH3-MeOH)--HPLC, Mobile phase B: Methyl alcohol: Dichloromethane = 1:1--HPLC, Flow rate: 20 mL / min, Gradient: 30% B to 30% B in 13 min, Wavelength: 220 / 254 nm, RT1 (min): 10.21, RT2 (min): 11.86. Combining and concentrating the faster peak containing the desired product gave one enantiomer (12.2 mg, 13%) as a yellow solid. C 16 H 16 FN2OP[M+H] + MS ESI calculated value: 303.10, measured value: 303.05. 1 H NMR(400MHz,DMSO-d6)δ9.61(s,1H),8.58(d,J=5.0Hz,1H),8.23(dd,J=4.9,3.1Hz,1H),7.52-7.37(m, 3H),7.26(d,J=8.0Hz,1H),4.19(s,1H),2.04-1.98(m,2H),1.83(d,J=13.4Hz,3H),1.02-0.95(m,3H), 19 F NMR(376MHz,DMSO-d6)δ-127.61(1F), 31 P NMR(162MHz,DMSO-d6)δ49.17(1P).

[0176] The later peaks containing the desired product were combined and concentrated to give the second enantiomer (23 mg, 25%) as a yellow solid. 16 H 16 FN2OP[M+H] + MS ESI calculated value: 303.10, measured value: 303.05. 1H NMR(400MHz,DMSO-d6)δ9.61(s,1H),8.58(d,J=5.0Hz,1H),8.23(dd,J=4.9,3.1Hz,1H),7.52-7.37(m, 3H),7.26(d,J=8.0Hz,1H),4.19(s,1H),2.06-2.00(m,2H),1.83(d,J=13.4Hz,3H),1.04-0.99(m,3H), 19 F NMR(376MHz,DMSO-d6)δ-127.61(1F), 31 P NMR(162MHz,DMSO-d6)δ48.956(1P).

[0177] Example 23: N-(4-cyclopropyl-2-fluorophenyl)-4-(dimethylphosphoryl)pyridin-3-amine

[0178] [ka]

[0179] A stirred solution of 4-(dimethylphosphoryl)-N-(2-fluoro-4-iodophenyl)pyridin-3-amine (200 mg, 0.51 mmol), cyclopropylboronic acid (132.11 mg, 1.54 mmol), dichlorobis(triphenylphosphine)palladium(II) (83.52 mg, 0.10 mmol), and potassium phosphate tribasic (326.45 mg, 1.54 mmol) in dioxane (2 mL) and water (0.2 mL) was mixed at room temperature. The reaction mixture was degassed with nitrogen three times and stirred at 90° C. for 1 h. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with dichloromethane / methanol (12 / 1). The crude product was purified by preparative HPLC using the following conditions: Column: XBridge Prep OBD C18 column, 30x150mm, 5μm, Mobile phase A: water (+10mmol / L NH4HCO3), Mobile phase B: ACN, Flow rate: 60mL / min, Gradient: 23%B to 33%B in 8min, 33%B, Wavelength: 254nm. Fractions containing the desired product were combined and concentrated to give N-(4-cyclopropyl-2-fluorophenyl)-4-(dimethylphosphoryl)pyridin-3-amine (50.3mg) as an off-white solid. 16 H 18 FN2OP[M+H] + MS ESI calculated value: 305.11, measured value: 305.10. 1 H NMR(400MHz,DMSO-d6)δ8.28-8.22(m,1H),8.08(dd,J=4.9,3.3Hz,1H),7.40-7.36(m,1H),7.30(t,J=8.5Hz,1H),7.00(dd,J=1 2.5,2.1Hz,1H),6.93(dd,J=8.2,2.1Hz,1H),1.99-1.87(m,1H),1.81(d,J=13.7Hz,6H),1.01-0.89(m,2H),0.73-0.64(m,2H).

[0180] The following compounds in Table 7 were prepared using procedures similar to those described in Example 23 using the appropriate starting materials.

[0181] [Table 7]

[0182] Example 24: 4-(Dimethylphosphoryl)-5-fluoro-N-(2-fluoro-4-iodophenyl)pyridin-3-amine

[0183] [ka]

[0184] Step 1: N-(5-fluoropyridin-3-yl)-2,2-dimethylpropanamide To a stirred mixture of trifluoroacetic acid (27.08 g, 267.60 mmol) and 5-fluoropyridin-3-amine (10 g, 89.20 mmol) in dichloromethane (100 mL) was added 2,2-dimethylpropanoyl chloride (13.98 g, 115.96 mmol) dropwise at 0° C. The reaction mixture was stirred at room temperature for 1 h. The reaction was quenched by adding water (100 mL). The aqueous layer was extracted with dichloromethane (3×100 mL). The combined organic layers were washed with brine (3×100 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to give N-(5-fluoropyridin-3-yl)-2,2-dimethylpropanamide (9.35 g, crude product) as a yellow solid. C 10 H 13 FN2O[M+H] + MS ESI calculated value 197.10, measured value 197.25. 1 H NMR(400MHz,CDCl3)δ8.33-8.28(m,1H),8.22-8.20(m,2H),7.56(s,1H),1.35(s,9H).

[0185] Step 2. N-(5-fluoro-4-iodopyridin-3-yl)-2,2-dimethylpropanamide N-(5-fluoropyridin-3-yl)-2,2-dimethylpropanamide (5.00 g, 25.48 mmol) in tetrahydrofuran (15 mL) and N 1 ,N 1,N 2 ,N 2 To a stirred solution of n-tetramethylethane-1,2-diamine (8.88 g, 76.44 mmol), n-butyllithium (30.58 mL, 76.44 mmol, 2.5 M in hexane) was added dropwise over 1 h at −78° C. under nitrogen atmosphere. The resulting mixture was stirred at −78° C. for 1 h under nitrogen atmosphere. To the above mixture, iodine (19.40 g, 76.44 mmol) in THF (5 mL) was added dropwise over 30 min at −78° C. The resulting mixture was stirred at −78° C. for an additional 1 h. The reaction was quenched by adding water (50 mL) at −78° C. The resulting mixture was decolorized by adding sodium thiosulfate. The resulting mixture was extracted with ethyl acetate (3×100 mL). The combined organic layers were washed with brine (2×100 mL) and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography and eluted with petroleum ether / ethyl acetate (1 / 1). Fractions containing the desired product were combined and concentrated to give N-(5-fluoro-4-iodopyridin-3-yl)-2,2-dimethylpropanamide (4.7 g, 57%) as white crystals. 10 H 12 FN2O[M+H] + MS ESI calculated value: 323.00, measured value: 322.95. 1 H NMR(400MHz,CDCl3)δ9.24(s,1H),8.13(d,J=0.8Hz,1H),7.75(s,1H),1.42(d,J=0.8Hz,9H).

[0186] Step 3: 5-Fluoro-4-iodopyridin-3-amine A mixture of N-(5-fluoro-4-iodopyridin-3-yl)-2,2-dimethylpropanamide (4.7 g, 14.591 mmol, 1 equiv) in aqueous HCl (50 mL, 3 M) was stirred at 100° C. for 3 h. The resulting mixture was basified with aqueous sodium hydroxide (50 mL, 3 M) at room temperature. The resulting mixture was extracted with dichloromethane (3×50 mL). The combined organic layers were washed with brine (1×50 mL) and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure to give 5-fluoro-4-iodopyridin-3-amine (3.5 g, crude) as a white solid. C5H4FIN[M+H] + MS ESI calculated value: 238.94, measured value: 238.90. 1 H NMR (400MHz, CDCl3) δ7.85(s,1H),7.74(s,1H),4.35(s,2H).

[0187] Step 4: 4-(Dimethylphosphoryl)-5-fluoropyridin-3-amine To a stirred mixture of 5-fluoro-4-iodopyridin-3-amine (200 mg, 0.84 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (48 mg, 0.08 mmol), potassium phosphate tribasic (356 mg, 1.68 mmol), and chloro[9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene][2-amino-1,1-biphenyl-2-yl]palladium (74 mg, 0.08 mmol) in 1,4-dioxane (5 mL) was added (methylphosphonoyl)methane (98 mg, 1.26 mmol). The reaction mixture was degassed with nitrogen three times and stirred at 100° C. for 16 h. The resulting mixture was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography under the following conditions: column: WelFlash™ C18-I, 20-40 μm, 120 g, eluent A: water (+ 10 mmol / L formic acid), eluent B: acetonitrile, gradient: 2% to 15% B in 25 min, flow rate: 60 mL / min, detector: 220 / 254 nm. Fractions containing the desired product were combined and concentrated to give 4-(dimethylphosphoryl)-5-fluoropyridin-3-amine (130 mg, 82%) as a yellow oil. C7H 10 FN2OP[M+H] + MS ESI calculated value 189.05, measured value 189.05, 1 H NMR (400MHz, CDCl3) δ7.92(s,1H),7.77(s,1H),5.94(s,2H),1.90-1.86(m,6H).

[0188] Step 5: 4-(Dimethylphosphoryl)-5-fluoro-N-(2-fluorophenyl)pyridin-3-amine A solution of 4-(dimethylphosphoryl)-5-fluoropyridin-3-amine (130 g, 0.69 mmol) in 1,4-dioxane (2 mL) and methanesulfonato 2-dicyclohexylphosphino-3,6-dimethoxy-2'-4'-6'-tri-i-propyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II) (BrettPhos Pd To a stirred mixture of G3) (62 mg, 0.06 mmol), 2-(dicyclohexylphosphino)-3,6-dimethoxy-2'-4'-6'-tri-i-propyl-1,1'-biphenyl (BrettPhos) (37 mg, 0.06 mmol), and sodium tert-butoxide (199 mg, 2.07 mmol) was added benzene, 1-fluoro-2-iodo (153.40 g, 0.69 mmol). The reaction mixture was degassed with nitrogen three times and stirred at 60° C. for 1 h. The resulting mixture was concentrated under reduced pressure. The residue was purified by reverse-phase flash chromatography under the following conditions: column: WelFlash™ C18-I, 20-40 μm, 40 g, eluent A: water (+ 10 mmol / L ammonium bicarbonate), eluent B: acetonitrile, gradient: 30% to 60% B in 25 min, flow rate: 30 mL / min, detector: 220 / 254 nm, the desired fraction was collected at 50% B and concentrated under reduced pressure to give 4-(dimethylphosphoryl)-5-fluoro-N-(2-fluorophenyl)pyridin-3-amine (100 mg, 51%) as a yellow solid. 13 H 13 F2N2OP[M+H] + MS ESI calculated value: 283.07, measured value: 282.95. 1 H NMR(400MHz,CDCl3)δ9.78(s,1H),8.20-8.14(m,1H),7.89(d,J=4.4Hz,1H),7.40-7.38(m,1H),7.22-7.10(m,3H),1.96(dd,J=13.6,1.8Hz,6H).

[0189] Step 6: 4-(Dimethylphosphoryl)-5-fluoro-N-(2-fluoro-4-iodophenyl)pyridin-3-amine To a stirred mixture of 4-(dimethylphosphoryl)-5-fluoro-N-(2-fluorophenyl)pyridin-3-amine (100 mg, 0.35 mmol) and N-iodosuccinimide (79 mg, 0.35 mmol) in tetrahydrofuran (0.5 mL) and methyl alcohol (0.5 mL) was added p-toluenesulfonic acid monohydrate (188 mg, 0.99 mmol). The reaction mixture was stirred at 60° C. for 1 h. The resulting mixture was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography under the following conditions: column: WelFlash™ C18-I, 20-40 μm, 40 g, eluent A: water (+ 10 mmol / L ammonium bicarbonate), eluent B: acetonitrile, gradient: 30% to 60% B in 25 min, flow rate: 30 mL / min, detector: 220 / 254 nm. Fractions containing the desired product were combined and concentrated to give 4-(dimethylphosphoryl)-5-fluoro-N-(2-fluoro-4-iodophenyl)pyridin-3-amine (50 mg, 34%) as a white solid. 13 H 12 F2IN2OP[M+H] + MS ESI calculated value: 408.97, measured value: 408.95. 1 H NMR(400MHz,DMSO-d6)δ10.10(s,1H),8.25(d,J=3.6Hz,1H),8.08(d,J=4.4Hz,1H),7.71(dd,J =10.4,2.0Hz,1H),7.53(d,J=8.8Hz,1H),7.33(t,J=8.4Hz,1H),1.90(dd,J=14.0,1.8Hz,6H), 19 F NMR(376MHz,DMSO-d6)-119.12(1F),123.01(1F), 19 P-NMR(162MHz,DMSO-d6)43.20(1P).

[0190] Example 25: (2-Fluoro-3-((2-fluoro-4-iodophenyl)amino)pyridin-4-yl)dimethylphosphine oxide

[0191] [ka]

[0192] Step 1: tert-Butyl (2-fluoro-4-iodopyridin-3-yl)carbamate To a stirred mixture of 2-fluoro-4-iodopyridine-3-carboxylic acid (3 g, 11.24 mmol) and DPPA (3.09 g, 11.24 mmol) in t-BuOH (30.00 mL) was added TEA (1.14 g, 11.24 mmol) dropwise at room temperature under nitrogen atmosphere. The reaction mixture was stirred at 80° C. under nitrogen atmosphere for 16 h. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography and eluted with petroleum ether / ethyl acetate (5 / 1). Fractions containing the desired product were combined and concentrated to give tert-butyl (2-fluoro-4-iodopyridin-3-yl)carbamate (2.1 g, 55%) as a brown oil. C 10 H 12 FIN2O2[M+H] + MS ESI calculated 338.99, found 338.95.

[0193] Step 2: 2-Fluoro-4-iodopyridin-3-amine hydrochloride To a stirred solution of tert-butyl (2-fluoro-4-iodopyridin-3-yl)carbamate (2.1 g, 6.21 mmol) in DCM (10 mL) was added 4M HCl(g) (20.99 mL, 83.97 mmol) dropwise at room temperature. The reaction mixture was stirred at room temperature for 1 h. The precipitated solid was collected by filtration and washed with DCM (3x30 mL). The crude product 2-fluoro-4-iodopyridin-3-amine hydrochloride (1.7 g, crude) was used directly in the next step without further purification. C5H5ClFIN2[M+H-HCl] + MS ESI calculated 238.94, found 239.05.

[0194] Step 3: (3-amino-2-fluoropyridin-4-yl)dimethylphosphine oxide To a stirred mixture of 2-fluoro-4-iodopyridin-3-amine hydrochloride (0.7 g, 2.94 mmol), (methylphosphonoyl)methane (0.28 g, 3.53 mmol), Pd(OAc)2 (33.02 mg, 0.15 mmol), and Xantphos (85.09 mg, 0.15 mmol) in DMF (7.00 mL) was added K3PO4 (1.25 g, 5.88 mmol) in small portions at room temperature. The reaction mixture was degassed with nitrogen three times and stirred at 120 °C for 1 h. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography and eluted with dichloromethane / methanol (10 / 1). Fractions containing the desired product were combined and concentrated to give 4-(dimethylphosphoryl)-2-fluoropyridin-3-amine (170 mg, 31%) as a brown solid. C7H 10 FN2OP[M+H] + MS ESI calculated 189.05, measured 189.15.

[0195] Step 4: (2-fluoro-3-((2-fluorophenyl)amino)pyridin-4-yl)dimethylphosphine oxide A solution of 4-(dimethylphosphoryl)-2-fluoropyridin-3-amine (150 mg, 0.80 mmol), 2-(dicyclohexylphosphino)-3,6-dimethoxy-2'-4'-6'-tri-i-propyl-1,1'-biphenyl (BrettPhos) (42.80 mg, 0.08 mmol), t-BuONa (229.86 mg, 2.39 mmol), and methanesulfonato 2-dicyclohexylphosphino-3,6-dimethoxy-2'-4'-6'-tri-i-propyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II) (BrettPhos Pd) in dioxane (1.50 mL) was added. To a stirred mixture of 1-bromo-2-fluorobenzene (167.43 mg, 0.95 mmol) and 1-fluoro-2-fluorobenzene (167.43 mg, 0.95 mmol) was added dropwise at room temperature. The reaction mixture was degassed with nitrogen three times and stirred at 100° C. for 1 h. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography and eluted with dichloromethane / methanol (10 / 1). Fractions containing the desired product were combined and concentrated to give (2-fluoro-3-((2-fluorophenyl)amino)pyridin-4-yl)dimethylphosphine oxide (130 mg, 58%) as a brown solid. C 13 H 13 FN2OP[M+H] + MS ESI calculated 283.07, found 283.10.

[0196] Step 5: (2-fluoro-3-((2-fluoro-4-iodophenyl)amino)pyridin-4-yl)dimethylphosphine oxide To a stirred mixture of (2-fluoro-3-((2-fluorophenyl)amino)pyridin-4-yl)dimethylphosphine oxide (110 mg, 0.39 mmol) and NIS (157.84 mg, 0.70 mmol) in THF (0.5 mL) and MeOH (0.5 mL) was added TsOH.H2O (207.58 mg, 1.09 mmol) at room temperature under nitrogen atmosphere. The reaction mixture was stirred at 60° C. for 1 h under nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with dichloromethane / methanol (10 / 1) to give the crude product. The crude product was purified by preparative HPLC using the following conditions: Column: XBridge Prep OBD C18 column, 30x150mm, 5μm, Mobile phase A: water (10mmol / L NH4HCO3), Mobile phase B: ACN, Flow rate: 60mL / min, Gradient: 32%B to 42%B in 8min, 42%B, Wavelength: 254nm, RT1: 7min. Fractions containing the desired product were combined and concentrated to give (2-fluoro-3-((2-fluoro-4-iodophenyl)amino)pyridin-4-yl)dimethylphosphine oxide (34mg, 21%) as an off-white solid. 13 H 12 F2IN2OP[M+H] + MS ESI calculated value: 408.97, measured value: 409.00. 1 H NMR(400MHz,DMSO-d6)δ8.84(s,1H),8.06-8.02(m,1H),7.64-7.55(m,2H),7.39(dd,J=8.0,1.8Hz,1H),6.61-6.56(m,1H),1.79(d,J=13.9Hz,6H), 19 F NMR(376MHz,DMSO-d6)δ-71.75,-128.11, 31 P NMR (162MHz, DMSO-d6) δ 41.15.

[0197] Example 30: 4-(Dimethylphosphoryl)-N-(2-fluoro-4-iodophenyl)-5-methylpyridin-3-amine

[0198] [ka]

[0199] Step 1: 3-Bromo-4-iodo-5-nitropyridine A stirred solution of 3-bromo-4-chloro-5-nitropyridine (5 g, 21.06 mmol) and potassium iodide (69.91 g, 421.16 mmol) in acetonitrile (300 mL) was stirred at 80° C. for 16 h. The resulting mixture was filtered and the filter cake was washed with acetonitrile (50 mL). The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with petroleum ether / ethyl acetate (10 / 1). Fractions containing the desired product were combined and concentrated to give 3-bromo-4-iodo-5-nitropyridine (6 g, 87%) as a pale yellow solid. C5H2BrIN2O2[M+H] + MS ESI calculated values: 328.83, 330.83; measured values: 328.80, 330.80; 1 H NMR(400MHz,CDCl3)δ8.83(s,1H),8.70(s,1H).

[0200] Step 2: 5-Bromo-4-iodopyridin-3-amine A stirred solution of 3-bromo-4-iodo-5-nitropyridine (2.4 g, 7.30 mmol), iron (1.63 g, 29.19 mmol), and ammonium chloride (1.95 g, 36.485 mmol) in ethanol (24 mL) and water (2.4 mL) was mixed at room temperature. The resulting mixture was stirred at 80° C. for 1 h. The resulting mixture was filtered and the filter cake was washed with ethyl acetate (2×100 mL). The resulting mixture was extracted with ethyl acetate (1×100 mL). The combined organic layers were washed with brine (1×200 mL) and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluted with petroleum ether / ethyl acetate (3 / 2). The fractions containing the desired product were combined and concentrated to give 5-bromo-4-iodopyridin-3-amine (2.5 g, 80%) as a yellow solid. C5H4BrIN2[M+H] +MS ESI calculated values: 298.86, 300.86; measured values: 298.80, 300.80; 1 H NMR(400MHz,CDCl3)δ8.04(s,1H),7.88(s,1H),4.37(s,2H).

[0201] Step 3: 5-Bromo-4-(dimethylphosphoryl)pyridin-3-amine To a stirred solution of 5-bromo-4-iodopyridin-3-amine (2.2 g, 7.36 mmol), (methylphosphonoyl)methane (861.69 mg, 11.04 mmol), chloro[(4,5-bis(diphenylphosphino)-9,9-dimethylxanthene)-2-(2-amino-1,1-biphenyl)]palladium(II) (654.11 mg, 0.74 mmol), and 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (425.88 mg, 0.74 mmol) in N,N-dimethylformamide (88 mL) was added potassium phosphate tribasic (3.12 g, 14.72 mmol) at room temperature. The reaction mixture was degassed with nitrogen three times and stirred at 100° C. for 16 h. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with dichloromethane / methanol (12 / 1). Fractions containing the desired product were combined and concentrated to give 5-bromo-4-(dimethylphosphoryl)pyridin-3-amine (1 g, 54%) as a yellow solid. 10 BrN2OP[M+H] + MS ESI calculated values: 248.97, 250.97, measured values: 248.90, 250.90, 1 H NMR(400MHz, CDCl3) δ7.95(t,J=4.3Hz,2H),6.23(s,2H),2.04(d,J=13.6Hz,6H).

[0202] Step 4: 4-(Dimethylphosphoryl)-5-methylpyridin-3-amine A stirred solution of 5-bromo-4-(dimethylphosphoryl)pyridin-3-amine (300 mg, 1.21 mmol), methylboronic acid (72.11 mg, 1.21 mmol), 1,1'-bis(diphenylphosphino)ferrocene-palladium(II) dichloride dichloromethane complex (98.13 mg, 0.12 mmol), and potassium carbonate (499.44 mg, 3.62 mmol) in dioxane (3 mL) and water (0.3 mL) was mixed at room temperature. The reaction mixture was degassed with nitrogen three times and stirred at 80 °C for 3 h. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography and eluted with dichloromethane / methanol (9 / 1). Fractions containing the desired product were combined and concentrated to give 4-(dimethylphosphoryl)-5-methylpyridin-3-amine (240 mg, 92%) as a black semi-solid. C8H 13 N2OP[M+H] + MS ESI calculated value 185.08, measured value 185.05. 1 H NMR (400MHz, CDCl3) δ7.94(s,1H),7.72(s,1H),6.00(s,2H),2.29(s,3H),1.88(d,J=13.2Hz,6H).

[0203] Step 5: 4-(Dimethylphosphoryl)-N-(2-fluorophenyl)-5-methylpyridin-3-amine A solution of 4-(dimethylphosphoryl)-5-methylpyridin-3-amine (170 g, 0.92 mmol), 1-bromo-2-fluorobenzene (242.29 g, 1.39 mmol), and methanesulfonato(2-dicyclohexylphosphino-3,6-dimethoxy-2',4',6'-tri-i-propyl-1,1'-biphenyl)(2'-amino- To a stirred solution of 1,1'-biphenyl-2-yl)palladium(II) (83.67 mg, 0.09 mmol) and 2-(dicyclohexylphosphino)-3,6-dimethoxy-2'-4'-6'-tri-i-propyl-1,1'-biphenyl (99.09 mg, 0.19 mmol) was added sodium tert-butoxide (266.12 mg, 2.77 mmol) at room temperature. The reaction mixture was degassed with nitrogen three times and stirred at 60° C. for 3 h. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography and eluted with dichloromethane / methanol (12 / 1). Fractions containing the desired product were combined and concentrated to give 4-(dimethylphosphoryl)-N-(2-fluorophenyl)-5-methylpyridin-3-amine (250 mg, 97%) as a yellow solid. C 14 H 16 FN2OP[M+H] + MS ESI calculated value: 279.10, measured value: 279.05. 1 H NMR(400MHz,CDCl3)δ10.03(s,1H),8.27(d,J=3.2,1H),7.86(d,J=4.8Hz,1H ),7.36-7.35(m,1H),7.17-6.98(m,3H),2.36(s,3H),1.95(d,J=13.2Hz,6H).

[0204] Step 6: 4-(Dimethylphosphoryl)-N-(2-fluoro-4-iodophenyl)-5-methylpyridin-3-amine To a stirred solution of 4-(dimethylphosphoryl)-N-(2-fluorophenyl)-5-methylpyridin-3-amine (220 mg, 0.79 mmol) and N-iodosuccinimide (533.62 mg, 2.37 mmol) in tetrahydrofuran (2.20 mL) and methanol (2.20 mL) was added p-toluenesulfonic acid.H2O (421.07 mg, 2.22 mmol). The reaction mixture was stirred at 60° C. for 1 h. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with dichloromethane / methanol (9 / 1) to give the crude product. The crude product was purified by preparative HPLC using the following conditions: Column: Xbridge Shield RP18 OBD Column, 30x150mm, 5μm, Mobile phase A: water (+10mmol / L NH4HCO3), Mobile phase B: ACN, Flow rate: 60mL / min, Gradient: 30%B to 42%B, 42%B in 8min, Wavelength: 254nm. Fractions containing the desired product were combined and concentrated to give 4-(dimethylphosphoryl)-N-(2-fluoro-4-iodophenyl)-5-methylpyridin-3-amine (53.8mg, 17%) as an off-white solid. 14 H 15 FIN2OP[M+H] + MS ESI calculated value 405.00, measured value 415.15. 1 H NMR(400MHz,DMSO-d6)δ10.23(s,1H),8.26(d,J=4.8Hz,1H),7.98(d,J=4.8Hz,1H),7.64(dd,J=1 0.5,1.9Hz,1H),7.45(d,J=9.2,1H),7.15(t,J=8.8Hz,1H),2.38(s,3H),1.89(d,J=13.6Hz,6H).

[0205] II. Biological Evaluation Example 1: Cellular assay

[0206] To measure the effect of MEK inhibitor compounds disclosed herein on cellular MAPK signaling downstream of MEK, an assay monitoring phosphorylation of ERK was used. The 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 μL growth medium in 384-well plates and allowed to adhere overnight at 37°C, 5% CO2. The following day, compounds were serially diluted into a 10-point, 3-fold dilution curve in 384-well plates. Compounds were transferred to cell plates using an Echo550 to a final concentration range of 0.508 nM to 10 mM in 0.1% DMSO, with 0.1% DMSO used as a negative control. Cells were incubated with compounds for 1 hour at 37°C, 5% CO2. Cells were lysed by adding 8 μL of 4x lysis buffer + 1x protease / phosphatase inhibitor cocktail provided with the HTRF kit (Advanced phospho-ERK (Thr202 / Tyr204) Cell Kit, Cisbio, Cat#64AERPEH). 20 μL of lysate was transferred to the HTRF plate, followed by the addition of 2.5 μL each of anti-ERK1 / 2-Europium / Terbium Cryptate and anti-phospho-ERK1 / 2 antibody solutions according to the manufacturer's instructions and incubation. Specific signals were measured at 665 nm (donor) and 620 nm (acceptor) in a Perkin Elmer Envision 2105, and the ratios were calculated as IC within the Dotmatics Knowledge Solutions Studies curve fitting environment (Dotmatics, Bishops Stortford, UK CM23). 50 The values ​​were used to calculate the values ​​shown in Table 8.

[0207] [Table 8]

[0208] III. Preparation of Pharmaceutical Dosage Forms Example 1: Oral Capsules

[0209] The active ingredient is a compound of Table 1, or a pharma- ceutically acceptable salt or solvate thereof. Capsules for oral administration are 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 suitable for oral administration, such as a hard gelatin capsule.

[0210] Example 2: Injectable solution

[0211] The active ingredient is a compound of Table 1, or a pharma- ceutically acceptable salt or solvate thereof, formulated as a solution in sesame oil at a concentration of 50 mg equivalents / mL.

[0212] The examples and embodiments described herein are for illustrative purposes only, and various modifications or alterations suggested to those skilled in the art are intended to be included within the spirit and scope of this application and the appended claims.

Claims

1. Formula (I): 【Chemistry 1】 or a pharmaceutically acceptable salt or solvate thereof, During the ceremony, R １ is optionally substituted alkyl; R ２ is optionally substituted alkyl, and optionally R １ and R ２ are joined by a carbon-carbon bond to form a phosphorus-containing ring, R ３ is selected from hydrogen, halo, optionally substituted alkyl, optionally substituted cycloalkyl, or optionally substituted alkoxy; R ４ is selected from hydrogen, halo, optionally substituted alkyl, optionally substituted cycloalkyl, or optionally substituted alkoxy; R ５ is selected from hydrogen, halo, optionally substituted alkyl, optionally substituted cycloalkyl, or optionally substituted alkoxy, and R １１ , R １２ , R １３ , R １４ , and R １５ is independently selected from hydrogen, halo, optionally substituted alkynyl, optionally substituted alkyl, optionally substituted cycloalkyl, or a pharmaceutically acceptable salt or solvate thereof.

2. R １ 2. The compound of claim 1, or a pharmaceutically acceptable salt or solvate thereof, wherein is optionally substituted C1-C3 alkyl.

3. R ２ 2. The compound of claim 1, or a pharmaceutically acceptable salt or solvate thereof, wherein is optionally substituted C1-C3 alkyl.

4. R １ is CH ３ 2. The compound of claim 1, wherein:

5. R ２ is CH ３ 2. The compound of claim 1, wherein:

6. The compound of claim 1, or a pharmaceutically acceptable salt or solvate thereof, wherein R 3 is hydrogen.

7. The compound of claim 1, or a pharmaceutically acceptable salt or solvate thereof, wherein R 3 is halo.

8. The compound of claim 1, or a pharmaceutically acceptable salt or solvate thereof, wherein R 3 is optionally substituted C1-C3 alkyl.

9. The compound of claim 1, or a pharmaceutically acceptable salt or solvate thereof, wherein R 4 is hydrogen.

10. The compound of claim 1, or a pharmaceutically acceptable salt or solvate thereof, wherein R 4 is halo.

11. The compound of claim 1, or a pharmaceutically acceptable salt or solvate thereof, wherein R 5 is hydrogen.

12. The compound of claim 1, or a pharmaceutically acceptable salt or solvate thereof, wherein R 5 is halo.

13. The compound of claim 1, or a pharmaceutically acceptable salt or solvate thereof, wherein R 11 is fluoro.

14. The compound of claim 1, or a pharmaceutically acceptable salt or solvate thereof, wherein R 11 is hydrogen.

15. The compound of claim 1, or a pharmaceutically acceptable salt or solvate thereof, wherein R 12 is hydrogen or fluoro.

16. The compound of claim 1, or a pharmaceutically acceptable salt or solvate thereof, wherein R 13 is selected from iodo, bromo, optionally substituted C2-C3 alkynyl, optionally substituted C1-C3 alkyl, and optionally substituted C3-C4 cycloalkyl.

17. The compound of claim 1, or a pharmaceutically acceptable salt or solvate thereof, wherein R 13 is iodine.

18. The compound of claim 1, or a pharmaceutically acceptable salt or solvate thereof, wherein R 13 is optionally substituted C1 alkyl.

19. The compound according to claim 1, or a pharmaceutically acceptable salt or solvate thereof, wherein R 13 is —CF 3 .

20. The compound of claim 1, or a pharmaceutically acceptable salt or solvate thereof, wherein R 13 is bromo.

21. The compound of claim 1, or a pharmaceutically acceptable salt or solvate thereof, wherein R 13 is optionally substituted cyclopropyl.

22. The compound of claim 1, or a pharmaceutically acceptable salt or solvate thereof, wherein R 14 and R 15 are hydrogen.

23. The compound of claim 1, 4-(dimethylphosphoryl)-N-(2-fluoro-4-iodophenyl)pyridin-3-amine, N-(2,3-difluoro-4-iodophenyl)-4-(dimethylphosphoryl)pyridin-3-amine, 1-(3-((2-fluoro-4-iodophenyl)amino)pyridin-4-yl)phosphorane 1-oxide, 4-(diethylphosphoryl)-N-(2-fluoro-4-iodophenyl)pyridin-3-amine, 4-[ethyl(methyl)phosphoryl]-N-(2-fluoro-4-iodophenyl)pyridin-3-amine, (R)-4-[ethyl(methyl)phosphoryl]-N-(2-fluoro-4-iodophenyl)pyridin-3-amine, (S)-4-[ethyl(methyl)phosphoryl]-N-(2-fluoro-4-iodophenyl)pyridin-3-amine, N-(4-bromo-2-fluorophenyl)-4-(dimethylphosphoryl)pyridin-3-amine, N-(4-bromo-2-fluorophenyl)-4-(diethylphosphoryl)pyridin-3-amine, 1-(3-((4-bromo-2-fluorophenyl)amino)pyridin-4-yl)phosphorane 1-oxide, 5-chloro-4-(dimethylphosphoryl)-N-(2-fluoro-4-iodophenyl)pyridin-3-amine, (3-((4-ethynyl-2-fluorophenyl)amino)pyridin-4-yl)dimethylphosphine oxide, 1-(3-((4-ethynyl-2-fluorophenyl)amino)pyridin-4-yl)phosphorane 1-oxide, N-(4-bromo-2-fluorophenyl)-4-[(R)-ethyl(methyl)phosphoryl]pyridin-3-amine, N-(4-bromo-2-fluorophenyl)-4-[(S)-ethyl(methyl)phosphoryl]pyridin-3-amine, 4-(diethylphosphoryl)-N-(4-ethynyl-2-fluorophenyl)pyridin-3-amine, 4-[(R)-ethyl(methyl)phosphoryl]-N-(4-ethynyl-2-fluorophenyl)pyridin-3-amine, 4-[(S)-ethyl(methyl)phosphoryl]-N-(4-ethynyl-2-fluorophenyl)pyridin-3-amine, (2-fluoro-5-((2-fluoro-4-iodophenyl)amino)pyridin-4-yl)dimethylphosphine oxide, 4-(dimethylphosphoryl)-N-(4-iodophenyl)pyridin-3-amine, N-(4-cyclopropyl-2-fluorophenyl)-4-(dimethylphosphoryl)pyridin-3-amine, 4-(dimethylphosphoryl)-5-fluoro-N-(2-fluoro-4-iodophenyl)pyridin-3-amine, (2-fluoro-3-((2-fluoro-4-iodophenyl)amino)pyridin-4-yl)dimethylphosphine oxide, N-(4-bromo-2-chlorophenyl)-4-(dimethylphosphoryl)-5-fluoropyridin-3-amine, N-(4-bromo-2-chlorophenyl)-4-(dimethylphosphoryl)pyridin-3-amine, N-(4-bromo-2-chlorophenyl)-5-chloro-4-(dimethylphosphoryl)pyridin-3-amine, (3-((4-bromo-2-fluorophenyl)amino)-5-chloropyridin-4-yl)dimethylphosphine oxide, 4-(dimethylphosphoryl)-N-(2-fluoro-4-iodophenyl)-5-methylpyridin-3-amine, 4-(dimethylphosphoryl)-N-(4-ethynyl-2-fluorophenyl)-5-fluoropyridin-3-amine, and (3-chloro-5-((4-cyclopropyl-2-fluorophenyl)amino)pyridin-4-yl)dimethylphosphine oxide 2. The compound of claim 1, selected from the group consisting of: or a pharmaceutically acceptable salt or solvate thereof.

24. The compound of claim 1, (R)-4-[ethyl(methyl)phosphoryl]-N-(2-fluoro-4-iodophenyl)pyridin-3-amine, 5-chloro-4-(dimethylphosphoryl)-N-(2-fluoro-4-iodophenyl)pyridin-3-amine, 4-(dimethylphosphoryl)-N-(2-fluoro-4-iodophenyl)pyridin-3-amine, 4-(dimethylphosphoryl)-5-fluoro-N-(2-fluoro-4-iodophenyl)pyridin-3-amine, (S)-4-[ethyl(methyl)phosphoryl]-N-(2-fluoro-4-iodophenyl)pyridin-3-amine, and (2-fluoro-5-((2-fluoro-4-iodophenyl)amino)pyridin-4-yl)dimethylphosphine oxide 24. The compound of claim 23, selected from the group consisting of: or a pharmaceutically acceptable salt or solvate thereof.

25. The compound of claim 24, or a pharmaceutically acceptable salt or solvate thereof, wherein the compound is 4-(dimethylphosphoryl)-N-(2-fluoro-4-iodophenyl)pyridin-3-amine.

26. A pharmaceutical composition comprising the compound of claim 1, or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable excipient.

27. A pharmaceutical composition comprising the compound of claim 25, or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable excipient. 。

28. Use of a compound of claim 1, or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition of claim 26 or 27, in the manufacture of a medicament for treating cancer in a subject.

29. The method of claim 28, wherein the cancer is selected from lung cancer, breast cancer, skin cancer, melanoma, or leukemia.

30. A method for inhibiting a MEK kinase enzyme, comprising contacting the MEK kinase enzyme with a compound of claim 1, or a pharmaceutically acceptable salt or solvate thereof, wherein the MEK kinase enzyme is contacted in an in vitro environment.

31. Use of a compound of claim 1, or a pharmaceutically acceptable salt or solvate thereof, in the manufacture of a medicament for inhibiting a MEK kinase enzyme in a subject, wherein the inhibition comprises contacting the MEK kinase enzyme with the compound, or a pharmaceutically acceptable salt or solvate thereof, and wherein the MEK kinase enzyme is contacted in an in vivo environment.

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