Inhibitors of MEK kinase

Abstract

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

Description

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS

[0002] This application claims the benefit of U.S. Patent Application No. 63 / 316,607, filed on March 4, 2022, which is incorporated herein by reference in its entirety. Background Art

[0003] Activation of MEK initiates the mitogen-activated protein kinase (MAPK) pathway, a key cellular signaling pathway that regulates proliferation, cell growth, and survival. Given that dysregulation of MAPK signaling has been shown to be a key driver of many cancers, therapies targeting MEK kinase activity hold promise for the treatment of cancer and other conditions characterized by aberrant MEK pathway signaling. Summary of the invention

[0004] Provided herein are inhibitors of MEK kinase, pharmaceutical compositions comprising the inhibitory compounds, and methods of using the inhibitory compounds to treat diseases.

[0005] One embodiment provides a compound or a pharmaceutically acceptable salt or solvate thereof having the structure of formula (I):

[0006]

[0007] in,

[0008] R 1 is optionally substituted alkyl;

[0009] R 2 is optionally substituted alkyl; optionally, R 1 and R 2 connected with carbon-carbon bonds to form a phosphorus-containing ring;

[0010] R 3 is selected from hydrogen, halo, optionally substituted alkyl, optionally substituted cycloalkyl or optionally substituted alkoxy;

[0011] R 4 is selected from hydrogen, halo, optionally substituted alkyl, optionally substituted cycloalkyl or optionally substituted alkoxy;

[0012] R 5 is selected from hydrogen, halo, optionally substituted alkyl, optionally substituted cycloalkyl or optionally substituted alkoxy; and

[0013] R 11 , R 12 , R 13 , R 14 and R 15Independently selected from hydrogen, halo, optionally substituted alkynyl, optionally substituted alkyl, optionally substituted cycloalkyl.

[0014] One embodiment provides a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof and at least one pharmaceutically acceptable excipient.

[0015] One embodiment provides a method of treating a disease or condition in a patient in need thereof, comprising administering to the patient a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof. Another embodiment provides the method, wherein the disease or condition is cancer.

[0016] Incorporation by reference

[0017] All publications, patents, and patent applications mentioned in this specification are herein incorporated by reference for the specific purpose identified herein. DETAILED DESCRIPTION

[0018] 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, reference to "an agent" includes a plurality of such agents, reference to "the cell" includes reference to one or more cells (or reference to a plurality of cells) and equivalents thereof known to those skilled in the art, and so forth. When ranges are used herein for physical properties (such as molecular weight) or chemical properties (such as chemical formulae), all combinations and subcombinations of ranges and specific embodiments therein are intended to be included. When referring to numbers or numerical ranges, the term "about" means that the referenced numbers or numerical ranges are approximate within experimental variability (or within statistical experimental error), and thus, in some cases, the numbers or numerical ranges will vary between 1% and 15% of the stated numbers or numerical ranges. The term "comprising" (and related terms such as "comprise, comprises", or "having", or "including") is not intended to exclude that in certain other embodiments, for example, embodiments of any composition of matter, composition, method, process, etc. described herein "consist of" or "consist essentially of" the features.

[0019] definition

[0020] As used in the specification and the appended claims, the following terms have the following indicated meanings unless indicated to the contrary.

[0021] "Amino" refers to the -NH2 group.

[0022] "Cyano" refers to a -CN group.

[0023] "Nitro" refers to a -NO2 group.

[0024] "Oxa" refers to an -O- group.

[0025] "Oxo" refers to a =0 group.

[0026] "Thio" refers to a =S group.

[0027] "Imino" refers to a =NH group.

[0028] "Oximo" refers to a =N-OH group.

[0029] "Hydrazino" refers to the =N-NH2 radical.

[0030] "Alkyl" refers to a straight or branched hydrocarbon chain radical consisting solely of carbon and hydrogen atoms, containing no unsaturation, having from 1 to 15 carbon atoms (e.g., C1-C 15 In certain embodiments, the alkyl group contains from 1 to 13 carbon atoms (e.g., C1-C 13 In certain embodiments, the alkyl group contains 1 to 8 carbon atoms (e.g., C1-C8 alkyl). In other embodiments, the alkyl group contains 1 to 5 carbon atoms (e.g., C1-C5 alkyl). In other embodiments, the alkyl group contains 1 to 4 carbon atoms (e.g., C1-C4 alkyl). In other embodiments, the alkyl group contains 1 to 3 carbon atoms (e.g., C1-C3 alkyl). In other embodiments, the alkyl group contains 1 to 2 carbon atoms (e.g., C1-C2 alkyl). In other embodiments, the alkyl group contains 1 carbon atom (e.g., C1 alkyl). In other embodiments, the alkyl group contains 5 to 15 carbon atoms (e.g., C5-C 15 In other embodiments, the alkyl group contains 5 to 8 carbon atoms (e.g., C5-C8 alkyl). In other embodiments, the alkyl group contains 2 to 5 carbon atoms (e.g., C2-C5 alkyl). In other embodiments, the alkyl group contains 3 to 5 carbon atoms (e.g., C3-C5 alkyl). In other embodiments, the alkyl group is selected from methyl, ethyl, 1-propyl (n-propyl), 1-methylethyl (isopropyl), 1-butyl (n-butyl), 1-methylpropyl (sec-butyl), 2-methylpropyl (isobutyl), 1,1-dimethylethyl (tert-butyl), 1-pentyl (n-pentyl). The alkyl group is connected to the rest of the molecule by a single bond. Unless otherwise specifically stated in the specification, the alkyl group is optionally substituted by one or more of the following substituents: halo, cyano, nitro, oxo, thio, imino, oxime, trimethylsilyl, -OR a 、-SR a 、-OC(O)-R a 、-N(R a)2. -C(O)R a 、-C(O)OR a 、-C(O)N(R a )2、-N(R a )C(O)OR a 、-OC(O)-N(R a )2、-N(R a )C(O)R a 、-N(R a )S(O) t R a (where t is 1 or 2), -S(O) t OR a (where t is 1 or 2), -S(O) t R a (where t is 1 or 2) and -S(O) t N(R a )2 (where t is 1 or 2), where R a Each independently is hydrogen, alkyl (optionally substituted with halogen, hydroxyl, methoxyl or trifluoromethyl), fluoroalkyl, carbocyclyl (optionally substituted with halogen, hydroxyl, methoxyl or trifluoromethyl), carbocyclylalkyl (optionally substituted with halogen, hydroxyl, methoxyl or trifluoromethyl), aryl (optionally substituted with halogen, hydroxyl, methoxyl or trifluoromethyl), aralkyl (optionally substituted with halogen, hydroxyl, methoxyl or trifluoromethyl), heterocyclyl (optionally substituted with halogen, hydroxyl, methoxyl or trifluoromethyl), heterocyclylalkyl (optionally substituted with halogen, hydroxyl, methoxyl or trifluoromethyl), heteroaryl (optionally substituted with halogen, hydroxyl, methoxyl or trifluoromethyl) or heteroarylalkyl (optionally substituted with halogen, hydroxyl, methoxyl or trifluoromethyl). In certain embodiments, the optionally substituted alkyl is a haloalkyl. In other embodiments, the optionally substituted alkyl is a fluoroalkyl. In other embodiments, the optionally substituted alkyl is a -CF3 group.

[0031] "Alkoxy" refers to a group of the formula -O-alkyl bonded through an oxygen atom, wherein alkyl is an alkyl chain as defined above.

[0032] "Alkenyl" refers to a straight or branched hydrocarbon chain group consisting only of carbon and hydrogen atoms, containing at least one carbon-carbon double bond and having 2 to 12 carbon atoms. In certain embodiments, alkenyl comprises 2 to 8 carbon atoms. In other embodiments, alkenyl comprises 2 to 4 carbon atoms. Alkenyl is connected to the rest of the molecule by a single bond, such as ethenyl (i.e., vinyl (vinyl)), prop-1-enyl (i.e., allyl), but-1-enyl, penta-1-enyl, penta-1,4-dienyl, etc. Unless otherwise specifically stated in the specification, alkenyl is optionally substituted by one or more of the following substituents: halo, cyano, nitro, oxo, thio, imino, oxime, trimethylsilyl, -OR a 、-SR a 、-OC(O)-R a 、-N(R a )2. -C(O)R a 、-C(O)OR a 、-C(O)N(R a )2、-N(R a )C(O)OR a 、-OC(O)-N(R a )2、-N(R a )C(O)R a 、-N(R a )S(O) t R a (where t is 1 or 2), -S(O) t OR a (where t is 1 or 2), -S(O) t R a (where t is 1 or 2) and -S(O) t N(R a )2 (where t is 1 or 2), where R a Each is 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).

[0033] "Alkynyl" refers to a straight or branched hydrocarbon chain group consisting only of carbon and hydrogen atoms, containing at least one carbon-carbon triple bond, having 2 to 12 carbon atoms. In certain embodiments, the alkynyl group comprises 2 to 8 carbon atoms. In other embodiments, the alkynyl group comprises 2 to 6 carbon atoms. In other embodiments, the alkynyl group comprises 2 to 4 carbon atoms. The alkynyl group is connected to the rest of the molecule by a single bond, such as ethynyl, propynyl, butynyl, pentynyl, hexynyl, etc. Unless otherwise specifically stated in the specification, the alkynyl group is optionally substituted by one or more of the following substituents: halo, cyano, nitro, oxo, thio, imino, oxime, trimethylsilyl, -OR a 、-SR a 、-OC(O)-R a 、-N(R a )2. -C(O)R a 、-C(O)OR a 、-C(O)N(R a )2、-N(R a )C(O)OR a 、-OC(O)-N(R a )2、-N(R a )C(O)R a 、-N(R a )S(O) t R a (where t is 1 or 2), -S(O) t OR a (where t is 1 or 2), -S(O) t R a (where t is 1 or 2) and -S(O) t N(R a )2 (where t is 1 or 2), where R a Each is 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).

[0034] "Alkylene" or "alkylene chain" refers to a straight or branched divalent hydrocarbon chain connecting the rest of the molecule to a group, which consists only of carbon and hydrogen, does not contain unsaturation, and has 1 to 12 carbon atoms, such as methylene, ethylene, propylene, butylene, etc. The alkylene chain is connected to the rest of the molecule by a single bond and is connected to the group by a single bond. The connection point of the alkylene chain to the rest of the molecule and to the group is through a carbon in the alkylene chain or through any two carbons in the chain. In certain embodiments, the alkylene group comprises 1 to 8 carbon atoms (e.g., C1-C8 alkylene). In other embodiments, the alkylene group comprises 1 to 5 carbon atoms (e.g., C1-C5 alkylene). In other embodiments, the alkylene group comprises 1 to 4 carbon atoms (e.g., C1-C4 alkylene). In other embodiments, the alkylene group comprises 1 to 3 carbon atoms (e.g., C1-C3 alkylene). In other embodiments, the alkylene group comprises 1 to 2 carbon atoms (e.g., C1-C2 alkylene). In other embodiments, the alkylene group comprises 1 carbon atom (e.g., C1 alkylene). In other embodiments, the alkylene group comprises 5 to 8 carbon atoms (e.g., C5-C8 alkylene). In other embodiments, the alkylene group comprises 2 to 5 carbon atoms (e.g., C2-C5 alkylene). In other embodiments, the alkylene group comprises 3 to 5 carbon atoms (e.g., C3-C5 alkylene). Unless otherwise specifically stated in the specification, the alkylene chain is optionally substituted with one or more of the following substituents: halo, cyano, nitro, oxo, thio, imino, oxime, trimethylsilyl, -OR a 、-SR a 、-OC(O)-R a 、-N(R a )2. -C(O)R a 、-C(O)OR a 、-C(O)N(R a )2、-N(R a )C(O)OR a 、-OC(O)-N(R a )2、-N(R a )C(O)R a 、-N(R a )S(O) t R a (where t is 1 or 2), -S(O) t OR a (where t is 1 or 2), -S(O) t R a (where t is 1 or 2) and -S(O) t N(R a )2 (where t is 1 or 2), where R aEach is 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).

[0035] "Alkenylene" or "alkenylene chain" refers to a straight or branched divalent hydrocarbon chain connecting the rest of the molecule to a group, which consists only of carbon and hydrogen, contains at least one carbon-carbon double bond, and has 2 to 12 carbon atoms. The alkenylene chain is connected to the rest of the molecule by a single bond and is connected to the group by a single bond. In certain embodiments, the alkenylene comprises 2 to 8 carbon atoms (e.g., C2-C8 alkenylene). In other embodiments, the alkenylene comprises 2 to 5 carbon atoms (e.g., C2-C5 alkenylene). In other embodiments, the alkenylene comprises 2 to 4 carbon atoms (e.g., C2-C4 alkenylene). In other embodiments, the alkenylene comprises 2 to 3 carbon atoms (e.g., C2-C3 alkenylene). In other embodiments, the alkenylene comprises 2 carbon atoms (e.g., C2 alkenylene). In other embodiments, the alkenylene comprises 5 to 8 carbon atoms (e.g., C5-C8 alkenylene). In other embodiments, the alkenylene group contains 3 to 5 carbon atoms (e.g., C3-C5 alkenylene). Unless otherwise specifically stated in the specification, the alkenylene chain is optionally substituted with one or more of the following substituents: halo, cyano, nitro, oxo, thio, imino, oxime, trimethylsilyl, -OR a 、-SR a 、-OC(O)-R a 、-N(R a )2. -C(O)R a 、-C(O)OR a 、-C(O)N(R a )2、-N(R a )C(O)OR a 、-OC(O)-N(R a )2、-N(R a )C(O)R a 、-N(R a )S(O) t R a (where t is 1 or 2), -S(O)t OR a (where t is 1 or 2), -S(O) t R a (where t is 1 or 2) and -S(O) t N(R a )2 (where t is 1 or 2), where R a Each is 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).

[0036] "Alkynylidene" or "alkynylene chain" refers to a straight or branched divalent hydrocarbon chain connecting the rest of the molecule to a group, which consists only of carbon and hydrogen, contains at least one carbon-carbon triple bond, and has 2 to 12 carbon atoms. The alkynylene chain is connected to the rest of the molecule by a single bond and is connected to the group by a single bond. In certain embodiments, the alkynylene comprises 2 to 8 carbon atoms (e.g., C2-C8 alkynylene). In other embodiments, the alkynylene comprises 2 to 5 carbon atoms (e.g., C2-C5 alkynylene). In other embodiments, the alkynylene comprises 2 to 4 carbon atoms (e.g., C2-C4 alkynylene). In other embodiments, the alkynylene comprises 2 to 3 carbon atoms (e.g., C2-C3 alkynylene). In other embodiments, the alkynylene comprises two carbon atoms (e.g., C2 alkynylene). In other embodiments, the alkynylene comprises 5 to 8 carbon atoms (e.g., C5-C8 alkynylene). In other embodiments, the alkynylene group contains 3 to 5 carbon atoms (e.g., C3-C5 alkynylene). Unless otherwise specifically stated in the specification, the alkynylene chain is optionally substituted with one or more of the following substituents: halo, cyano, nitro, oxo, thio, imino, oxime, trimethylsilyl, -OR a 、-SR a 、-OC(O)-R a 、-N(R a )2. -C(O)R a 、-C(O)OR a 、-C(O)N(R a )2、-N(R a )C(O)ORa 、-OC(O)-N(R a )2、-N(R a )C(O)R a 、-N(R a )S(O) t R a (where t is 1 or 2), -S(O) t OR a (where t is 1 or 2), -S(O) t R a (where t is 1 or 2) and -S(O) t N(R a )2 (where t is 1 or 2), where R a Each is 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).

[0037] "Aryl" refers to a group derived from an aromatic monocyclic or polycyclic hydrocarbon ring system by removing hydrogen atoms from ring carbon atoms. An aromatic monocyclic or polycyclic hydrocarbon ring system contains only hydrogen and carbons of 5 to 18 carbon atoms, wherein at least one ring in the ring system is fully unsaturated, i.e., according to Hückel theory, it contains a cyclic, delocalized (4n+2)π-electron system. Ring systems from which aryl groups are derived include, but are not limited to, groups such as benzene, fluorene, indane, indene, tetralin and naphthalene. Unless otherwise specifically stated in the specification, the term "aryl" or the prefix "ar-" (such as in "aralkyl") is intended to include aryl groups optionally substituted by one or more substituents independently selected from the following: 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(Ra 2. -R b -C(O)R a , -R b -C(O)OR a , -R b -C(O)N(R a 2. -R b -OR c -C(O)N(R a 2. -R b -N(R a )C(O)OR a , -R b -N(R a )C(O)R a , -R b -N(R a )S(O) t R a (where t is 1 or 2), -R b -S(O) t R a (where t is 1 or 2), -R b -S(O) t OR a (where t is 1 or 2) and -R b -S(O) t N(R a )2 (where t is 1 or 2), where R a each is independently hydrogen, alkyl (optionally substituted by halogen, hydroxy, methoxy or trifluoromethyl), fluoroalkyl, cycloalkyl (optionally substituted by halogen, hydroxy, methoxy or trifluoromethyl), cycloalkylalkyl (optionally substituted by halogen, hydroxy, methoxy or trifluoromethyl), aryl (optionally substituted by halogen, hydroxy, methoxy or trifluoromethyl), aralkyl (optionally substituted by halogen, hydroxy, methoxy or trifluoromethyl), heterocyclyl (optionally substituted by halogen, hydroxy, methoxy or trifluoromethyl), heterocyclylalkyl (optionally substituted by halogen, hydroxy, methoxy or trifluoromethyl), heteroaryl (optionally substituted by halogen, hydroxy, methoxy or trifluoromethyl) or heteroarylalkyl (optionally substituted by halogen, hydroxy, methoxy or trifluoromethyl), R b are each independently a direct bond or a straight or branched alkylene or alkenylene chain, and R c is a straight or branched alkylene or alkenylene chain, and wherein unless otherwise specified, R a , R b or R c Each of the substituents is unsubstituted.

[0038] "Arylalkyl" refers to a group of the formula -R c -aryl radical, wherein Rc is an alkylene chain as defined above, for example methylene, ethylene, etc. The alkylene chain part of the aralkyl group is optionally substituted as described above for the alkylene chain. The aryl part of the aralkyl group is optionally substituted as described above for the aryl group.

[0039] "Aralkenyl" refers to a group of the formula -R d -aryl radical, wherein R d is an alkenylene chain as defined above. The aryl part of the aralkenyl group is optionally substituted as described above for aryl. The alkenylene chain part of the aralkenyl group is optionally substituted as described above for alkenylene.

[0040] "Arylalkynyl" refers to a group of the formula -R e -aryl radical, wherein R e is an alkynylene chain as defined above. The aryl part of the aralkynyl group is optionally substituted as described above for aryl groups. The alkynylene chain part of the aralkynyl group is optionally substituted as described above for alkynylene chains.

[0041] "Aralkyloxy" refers to a radical of the formula -OR c -aryl radical, wherein R c is an alkylene chain as defined above, for example methylene, ethylene, etc. The alkylene chain part of the aralkyl group is optionally substituted as described above for the alkylene chain. The aryl part of the aralkyl group is optionally substituted as described above for the aryl group.

[0042] "Carbocyclyl" refers to a stable non-aromatic monocyclic or polycyclic hydrocarbon radical consisting only of carbon and hydrogen atoms, including condensed rings or bridged ring systems, with 3 to 15 carbon atoms. In certain embodiments, the carbocyclyl comprises 3 to 10 carbon atoms. In other embodiments, the carbocyclyl comprises 5 to 7 carbon atoms. The carbocyclyl is connected to the rest of the molecule by a single bond. The carbocyclyl is saturated (i.e., only containing a single C-C bond) or unsaturated (i.e., containing one or more double bonds or triple bonds). Fully saturated carbocyclyl is also referred to as "cycloalkyl". Examples of monocyclic cycloalkyls include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl. Unsaturated carbocyclyl is also referred to as "cycloalkenyl". Examples of monocyclic cycloalkenyls include, for example, cyclopentenyl, cyclohexenyl, cycloheptenyl and cyclooctenyl. Polycyclic carbocyclyl groups include, for example, adamantyl, norbornyl (i.e., bicyclo[2.2.1]heptyl), norbornenyl, decalinyl, 7,7-dimethyl-bicyclo[2.2.1]heptyl, etc. Unless otherwise specifically stated in the specification, the term "carbocyclyl" is intended to include carbocyclyl groups optionally substituted by one or more substituents independently selected from optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, halo, oxo, thio, cyano, nitro, -R b -OR a, -R b -OC(O)-R a , -R b -OC(O)-OR a , -R b -OC(O)-N(R a 2. -R b -N(R a 2. -R b -C(O)R a , -R b -C(O)OR a , -R b -C(O)N(R a 2. -R b -OR c -C(O)N(R a 2. -R b -N(R a )C(O)OR a , -R b -N(R a )C(O)R a , -R b -N(R a )S(O) t R a (where t is 1 or 2), -R b -S(O) t R a (where t is 1 or 2), -R b -S(O) t OR a (where t is 1 or 2) and -R b -S(O) t N(R a )2 (where t is 1 or 2), where R a each is independently hydrogen, alkyl (optionally substituted by halogen, hydroxy, methoxy or trifluoromethyl), fluoroalkyl, cycloalkyl (optionally substituted by halogen, hydroxy, methoxy or trifluoromethyl), cycloalkylalkyl (optionally substituted by halogen, hydroxy, methoxy or trifluoromethyl), aryl (optionally substituted by halogen, hydroxy, methoxy or trifluoromethyl), aralkyl (optionally substituted by halogen, hydroxy, methoxy or trifluoromethyl), heterocyclyl (optionally substituted by halogen, hydroxy, methoxy or trifluoromethyl), heterocyclylalkyl (optionally substituted by halogen, hydroxy, methoxy or trifluoromethyl), heteroaryl (optionally substituted by halogen, hydroxy, methoxy or trifluoromethyl) or heteroarylalkyl (optionally substituted by halogen, hydroxy, methoxy or trifluoromethyl), R b are each independently a direct bond or a straight or branched alkylene or alkenylene chain, and R cis a straight or branched alkylene or alkenylene chain, and wherein unless otherwise specified, R a , R b or R c Each of the substituents is unsubstituted.

[0043] "Carbocyclylalkyl" refers to a group of the formula -R c -Carbocyclic group, where R c is an alkylene chain as defined above. The alkylene chain and the carbocyclyl group are optionally substituted as defined above.

[0044] "Carbocyclylalkynyl" refers to a group of the formula -R c -Carbocyclic group, where R c is an alkynylene chain as defined above. The alkynylene chain and the carbocyclyl group are optionally substituted as defined above.

[0045] "Carbocyclylalkoxy" refers to a radical of the formula -OR bonded through an oxygen atom. c -Carbocyclic group, where R c is an alkylene chain as defined above. The alkylene chain and the carbocyclyl group are optionally substituted as defined above.

[0046] "Halo" or "halogen" refers to a bromo, chloro, fluoro, or iodo substituent.

[0047] "Fluoroalkyl" refers to an alkyl group as defined above substituted with one or more fluoro groups as defined above, for example, trifluoromethyl, difluoromethyl, fluoromethyl, 2,2,2-trifluoroethyl, 1-fluoromethyl-2-fluoroethyl, etc. In some embodiments, the alkyl portion of the fluoroalkyl group is optionally substituted as defined above for an alkyl group.

[0048] "Heterocyclyl" refers to a stable 3-18 membered non-aromatic ring radical containing 2 to 12 carbon atoms and 1 to 6 heteroatoms selected from nitrogen, oxygen and sulfur. Unless otherwise specifically stated in the specification, a heterocyclyl is a monocyclic, bicyclic, tricyclic or tetracyclic ring system, which optionally includes a fused ring or a bridged ring system. The heteroatoms in the heterocyclyl group are optionally oxidized. If present, one or more nitrogen atoms are optionally quaternized. The heterocyclyl group is partially or completely saturated. The heterocyclyl group is connected to the rest of the molecule through any atom of the ring. Examples of such heterocyclyl groups include, but are not limited to, dioxolanyl, thienyl[1,3]dithianyl, decahydroisoquinolinyl, imidazolinyl, imidazolidinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl, piperidinyl, piperazinyl, 4-piperidonyl, pyrrolidinyl, pyrazolidinyl, quinuclidinyl, thiazolidinyl, tetrahydrofuranyl, trithianyl, tetrahydropyranyl, thiomorpholinyl, thimorpholinyl, 1-oxo-thiomorpholinyl, and 1,1-dioxo-thiomorpholinyl. Unless otherwise specifically stated in the specification, the term "heterocyclyl" is intended to include heterocyclyl as defined above, which is optionally substituted by one or more substituents selected from the group consisting of optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, halo, fluoroalkyl, oxo, thioxo, cyano, nitro, -R b -OR a , -R b -OC(O)-R a , -R b -OC(O)-OR a , -R b -OC(O)-N(R a 2. -R b -N(R a 2. -R b -C(O)R a , -R b -C(O)OR a , -R b -C(O)N(R a 2. -R b -OR c -C(O)N(R a 2. -R b -N(R a )C(O)OR a , -R b -N(R a )C(O)R a , -R b -N(R a )S(O) t R a(where t is 1 or 2), -R b -S(O) t R a (where t is 1 or 2), -R b -S(O) t OR a (where t is 1 or 2) and -R b -S(O) t N(R a )2 (where t is 1 or 2), where R a each is independently hydrogen, alkyl (optionally substituted by halogen, hydroxy, methoxy or trifluoromethyl), fluoroalkyl, cycloalkyl (optionally substituted by halogen, hydroxy, methoxy or trifluoromethyl), cycloalkylalkyl (optionally substituted by halogen, hydroxy, methoxy or trifluoromethyl), aryl (optionally substituted by halogen, hydroxy, methoxy or trifluoromethyl), aralkyl (optionally substituted by halogen, hydroxy, methoxy or trifluoromethyl), heterocyclyl (optionally substituted by halogen, hydroxy, methoxy or trifluoromethyl), heterocyclylalkyl (optionally substituted by halogen, hydroxy, methoxy or trifluoromethyl), heteroaryl (optionally substituted by halogen, hydroxy, methoxy or trifluoromethyl) or heteroarylalkyl (optionally substituted by halogen, hydroxy, methoxy or trifluoromethyl), R b are each independently a direct bond or a straight or branched alkylene or alkenylene chain, and R c is a straight or branched alkylene or alkenylene chain, and wherein unless otherwise specified, R a , R b or R c Each of the substituents is unsubstituted.

[0049] "N-heterocyclyl" or "N-attached heterocyclyl" refers to a heterocyclyl as defined above containing at least one nitrogen, and wherein the point of attachment of the heterocyclyl to the rest of the molecule is through the nitrogen atom in the heterocyclyl. N-heterocyclyl groups are optionally substituted as described above for heterocyclyl groups. Examples of such N-heterocyclyl groups include, but are not limited to, 1-morpholinyl, 1-piperidinyl, 1-piperazinyl, 1-pyrrolidinyl, pyrazolidinyl, imidazolinyl, and imidazolidinyl.

[0050] "C-heterocyclyl" or "C-attached heterocyclyl" refers to a heterocyclyl as defined above containing at least one heteroatom and wherein the point of attachment of the heterocyclyl to the rest of the molecule is through a carbon atom in the heterocyclyl. C heterocyclyl groups are optionally substituted as described above for heterocyclyl groups. Examples of such C-heterocyclyl groups include, but are not limited to, 2-morpholinyl, 2- or 3- or 4-piperidinyl, 2-piperazinyl, 2- or 3-pyrrolidinyl, and the like.

[0051] "Heterocyclylalkyl" refers to a group of the formula -R c-heterocyclic group, wherein 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 group at the nitrogen atom. The alkylene chain of the heterocyclylalkyl is optionally substituted as described above for the alkylene chain. The heterocyclyl moiety of the heterocyclylalkyl is optionally substituted as described above for the heterocyclyl.

[0052] "Heterocyclylalkoxy" refers to a radical of the formula -OR bonded through an oxygen atom. c -heterocyclic group, wherein 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 group at the nitrogen atom. The alkylene chain of the heterocyclylalkoxy is optionally substituted as described above for the alkylene chain. The heterocyclyl moiety of the heterocyclylalkoxy is optionally substituted as described above for the heterocyclyl.

[0053] "Heteroaryl" refers to a group derived from a 3-18 membered aromatic ring group containing 2 to 17 carbon atoms and 1 to 6 heteroatoms selected from nitrogen, oxygen and sulfur. As used herein, a heteroaryl is a monocyclic, bicyclic, tricyclic or tetracyclic ring system, wherein at least one ring in the ring system is fully unsaturated, i.e., it contains a cyclic, delocalized (4n+2)π-electron system according to the Huckel theory. Heteroaryl includes fused or bridged ring systems. The heteroatoms in the heteroaryl group are optionally oxidized. If present, one or more nitrogen atoms are optionally quaternized. The heteroaryl group is attached to the rest of the molecule through any atom of the ring.Examples of heteroaryl groups include, but are not limited to, azepine, 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, benzopyrone, benzofuranyl, benzofuranone, 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]cycloheptatriene pyridazinyl, dibenzofuranyl, dibenzothiophenyl, furanyl, furanone, furano[3,2-c]pyridinyl, 5,6,7,8,9,10-hexahydrocyclooctatetraeno[d]pyrimidinyl, 5,6,7,8,9,10-hexahydrocyclooctatetraeno[d]pyridazinyl, 5,6,7,8,9,10-hexahydrocyclooctatetraeno[d] [d]pyridinyl, isothiazolyl, imidazolyl, indazolyl, indolyl, indazolyl, isoindolyl, indolyl, isoindolyl, isoquinolyl, indolizinyl, isoxazolyl, 5,8-methano-5,6,7,8-tetrahydroquinazolinyl, naphthyridinyl, 1,6-naphthyridinonyl, oxadiazolyl, 2-oxoaziridine, oxazolyl, oxirane, 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 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-cycloheptatrienol[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]pyridinyl, and thiophenyl (i.e., thienyl).Unless otherwise specifically stated in the specification, the term "heteroaryl" is intended to include heteroaryl groups as defined above, optionally substituted with one or more substituents selected from optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, halo, optionally substituted fluoroalkyl, optionally substituted haloalkenyl, optionally substituted haloalkynyl, oxo, thioxo, cyano, nitro, -R. b -OR a , -R b -OC(O)-R a , -R b -OC(O)-OR a , -R b -OC(O)-N(R a 2. -R b -N(R a 2. -R b -C(O)R a , -R b -C(O)OR a , -R b -C(O)N(R a 2. -R b -OR c -C(O)N(R a 2. -R b -N(R a )C(O)OR a , -R b -N(R a )C(O)R a , -R b -N(R a )S(O) t R a (where t is 1 or 2), -R b -S(O) t R a (where t is 1 or 2), -R b -S(O) t OR a (where t is 1 or 2) and -R b -S(O) t N(R a )2 (where t is 1 or 2), where R aeach is independently hydrogen, alkyl (optionally substituted by halogen, hydroxy, methoxy or trifluoromethyl), fluoroalkyl, cycloalkyl (optionally substituted by halogen, hydroxy, methoxy or trifluoromethyl), cycloalkylalkyl (optionally substituted by halogen, hydroxy, methoxy or trifluoromethyl), aryl (optionally substituted by halogen, hydroxy, methoxy or trifluoromethyl), aralkyl (optionally substituted by halogen, hydroxy, methoxy or trifluoromethyl), heterocyclyl (optionally substituted by halogen, hydroxy, methoxy or trifluoromethyl), heterocyclylalkyl (optionally substituted by halogen, hydroxy, methoxy or trifluoromethyl), heteroaryl (optionally substituted by halogen, hydroxy, methoxy or trifluoromethyl) or heteroarylalkyl (optionally substituted by halogen, hydroxy, methoxy or trifluoromethyl), R b are each independently a direct bond or a straight or branched alkylene or alkenylene chain, and R c is a straight or branched alkylene or alkenylene chain, and wherein unless otherwise specified, R a , R b or R c Each of the substituents is unsubstituted.

[0054] "N-heteroaryl" refers to a heteroaryl group as defined above containing at least one nitrogen, wherein the point of attachment of the heteroaryl group to the rest of the molecule is through the nitrogen atom in the heteroaryl group. N-heteroaryl groups are optionally substituted as described above for heteroaryl groups.

[0055] "C-heteroaryl" refers to a heteroaryl group as defined above, wherein the point of attachment of the heteroaryl group to the rest of the molecule is through a carbon atom in the heteroaryl group. C-heteroaryl groups are optionally substituted as described above for heteroaryl groups.

[0056] "Heteroarylalkyl" refers to a group of the formula -R c -heteroaryl radical, wherein R c is an alkylene chain as defined above. If the heteroaryl is a nitrogen-containing heteroaryl, the heteroaryl is optionally attached to the alkyl group at the nitrogen atom. The alkylene chain of the heteroarylalkyl is optionally substituted by an alkylene chain as defined above. The heteroaryl moiety of the heteroarylalkyl is optionally substituted by a heteroaryl as defined above.

[0057] "Heteroarylalkoxy" refers to a radical of the formula -OR bonded through an oxygen atom. c -heteroaryl radical, wherein R c is an alkylene chain as defined above. If the heteroaryl is a nitrogen-containing heteroaryl, the heteroaryl is optionally attached to the alkyl at the nitrogen atom. The alkylene chain of the heteroarylalkoxy is optionally substituted by an alkylene chain as defined above. The heteroaryl moiety of the heteroarylalkoxy is optionally substituted by a heteroaryl as defined above.

[0058] In some embodiments, the compounds disclosed herein contain one or more asymmetric centers, thus producing enantiomers, diastereomers and other stereoisomeric forms, which are defined as (R)- or (S)- according to absolute stereochemistry. Unless otherwise indicated, all stereoisomeric forms of the compounds disclosed herein are considered by the present disclosure. When the compounds described herein contain olefin double bonds, and unless otherwise indicated, the present disclosure is intended to include E and Z geometric isomers (e.g., cis or trans). Similarly, all possible isomers and their racemic and optically pure forms and all tautomeric forms are also included. The term "geometric isomer" refers to the E or Z geometric isomers (e.g., cis or trans) of the olefin double bond. The term "positional isomer" refers to the structural isomers around the central ring, such as the ortho, meta and para isomers around the benzene ring.

[0059] As used herein, "carboxylic acid bioisostere" refers to a functional group or moiety that exhibits physical, biological, and / or chemical properties similar to a carboxylic acid moiety. Examples of carboxylic acid bioisosteres include, but are not limited to:

[0060]

[0061] wait.

[0062] "Tautomers" refers to molecules in which a proton can move from one atom of a molecule to another atom of the same molecule. In certain embodiments, the compounds provided herein exist as tautomers. Where tautomerization is possible, a chemical equilibrium of tautomers will exist. The exact ratio of tautomers depends on several factors, including physical state, temperature, solvent, and pH. Some examples of tautomeric equilibrium include:

[0063]

[0064] In some embodiments, the compounds disclosed herein are used in different isotopically enriched forms, such as 2 H. 3 H. 11 C. 13 C and / or 14 C content. In a specific embodiment, the compound is deuterated at at least one position. Such deuterated forms can be prepared by the methods described in U.S. Patent Nos. 5,846,514 and 6,334,997. As described in U.S. Patent Nos. 5,846,514 and 6,334,997, deuteration can improve metabolic stability and / or efficacy, thereby increasing the duration of drug action.

[0065] Unless otherwise stated, structures depicted herein are intended to include compounds that differ only in the presence of one or more isotopically enriched atoms. For example, except for the replacement of hydrogen by deuterium or tritium or the replacement of carbon by 13 C- or 14 Compounds having the present structures other than C-enriched carbon substitutions are within the scope of this disclosure.

[0066] 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 be labeled with isotopes, such as, for example, deuterium ( 2 H), tritium ( 3 H), iodine-125 ( 125 I) or carbon-14 ( 14 C) Use 2 H. 11 C. 13 C. 14 C. 15 C. 12 N. 13 N. 15 N. 16 N. 16 O. 17 O. 14 F. 15 F. 16 F. 17 F. 18 F. 33 S. 34 S. 35 S. 36 S. 35 Cl, 37 Cl, 79 Br, 81 Br, 125 Isotopic substitutions of I are contemplated. In some embodiments, 18 Isotopic substitution of F. All isotopic variations of the compounds of the present invention, whether radioactive or not, are encompassed within the scope of the present invention.

[0067] In certain embodiments, some or all of the compounds disclosed herein 1 H atoms are 2 H atom substitution. Methods for the synthesis of deuterium containing compounds are known in the art and include the following synthetic methods by way of non-limiting example only.

[0068] Deuterium substituted compounds are synthesized using various methods, such as described in: Dean, Dennis C., ed., Recent Advances in the Synthesis and Applications of Radiolabeled Compounds for Drug Discovery and Development. [Curr., Pharm. Des., 2000; 6 (10)] 2000, p. 110; 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.

[0069] Deuterated starting materials are readily available and the synthetic methods described herein are performed to provide the synthesis of deuterated compounds. A large number of deuterated reagents and building blocks are commercially available from chemical suppliers such as Aldrich Chemical Co.

[0070] Deuterium transfer reagents suitable for nucleophilic substitution reactions, such as iodomethane-d3 (CD3I), are readily available and can be used to transfer a deuterium-substituted carbon atom to a reaction substrate under nucleophilic substitution reaction conditions. The use of CD3I is illustrated in the following reaction schemes only as an example.

[0071]

[0072] Deuterium transfer reagents such as lithium aluminum deuteride (LiAlD4) are used to transfer deuterium to the reaction substrate under reducing conditions. The use of LiAlD4 is illustrated in the following reaction schemes by way of example only.

[0073]

[0074] Deuterium gas and palladium catalysts are used to reduce unsaturated carbon-carbon bonds and to effect reductive substitution of aromatic carbon-halogen bonds as shown by way of example only in the following reaction schemes.

[0075]

[0076] In one embodiment, the compounds disclosed herein contain 1 deuterium atom. In another embodiment, the compounds disclosed herein contain 2 deuterium atoms. In another embodiment, the compounds disclosed herein contain 3 deuterium atoms. In another embodiment, the compounds disclosed herein contain 4 deuterium atoms. In another embodiment, the compounds disclosed herein contain 5 deuterium atoms. In another embodiment, the compounds disclosed herein contain 6 deuterium atoms. In another embodiment, the compounds disclosed herein contain more than 6 deuterium atoms. In another embodiment, the compounds disclosed herein are completely substituted with deuterium atoms and do not contain non-exchangeable 1 H hydrogen atom. In one embodiment, the deuterium incorporation level is determined by a synthesis method in which deuterated synthetic building blocks are used as starting materials.

[0077] "Pharmaceutically acceptable salts" include both acid addition salts and base addition salts. Pharmaceutically acceptable salts of any MEK kinase inhibitory compound described herein are intended to encompass any and all pharmaceutically suitable salt forms. Preferred pharmaceutically acceptable salts of the compounds described herein are pharmaceutically acceptable acid addition salts and pharmaceutically acceptable base addition salts.

[0078] "Pharmaceutically acceptable acid addition salts" refers to those salts which retain the biological effectiveness and properties of the free bases, which are not biologically or otherwise undesirable, and which are formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, hydroiodic acid, hydrofluoric acid, phosphorous acid, and the like. Also included are salts formed with organic acids such as aliphatic mono- and dicarboxylic acids, phenyl-substituted alkanoic acids, hydroxyalkanoic acids, alkanedioic acids, aromatic acids, aliphatic and aromatic sulfonic acids, and the like, and include, for example, acetic acid, trifluoroacetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, and the like. Thus, exemplary salts include sulfates, pyrosulfates, bisulfates, sulfites, bisulfites, nitrates, phosphates, monohydrogenphosphates, dihydrogenphosphates, metaphosphates, pyrophosphates, chlorides, bromides, iodides, acetates, trifluoroacetates, propionates, octanoates, isobutyrates, oxalates, malonates, succinates, suberates, sebacates, fumarates, maleates, mandelates, benzoates, chlorobenzoates, methylbenzoates, dinitrobenzoates, phthalates, benzenesulfonates, toluenesulfonates, phenylacetates, citrates, lactates, malates, tartrates, methanesulfonates, etc. Also contemplated are salts of amino acids such as arginates, gluconates, and galacturonates (see, e.g., Berge S. M. et al., "Pharmaceutical Salts," Journal of Pharmaceutical Science, 66: 1-19 (1997)). In some embodiments, the 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 skilled in the art.

[0079] "Pharmaceutically acceptable base addition salts" refer to those salts which retain the biological effectiveness and properties of the free acids and which are not biologically or otherwise undesirable. These salts are prepared by adding inorganic or organic bases to the free acids. In some embodiments, pharmaceutically acceptable base addition salts are formed with metals or amines such as alkali metals and alkaline earth metals or organic amines. Salts derived from inorganic bases include, but are not limited to, sodium salts, potassium salts, lithium salts, ammonium salts, calcium salts, magnesium salts, iron salts, zinc salts, copper salts, manganese salts, aluminum salts, and the like. Salts derived from organic bases include, but are not limited to, salts of primary, secondary, and tertiary amines, substituted amines (including naturally occurring substituted amines), cyclic amines, and basic ion exchange resins, such as isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, diethanolamine, 2-dimethylaminoethanol, 2-diethylaminoethanol, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, N,N-dibenzylethylenediamine, chloroprocaine, hydrabamine, choline, betaine, ethylenediamine, ethylenedianiline, N-methylglucamine, glucosamine, methylglucamine, theobromine, purines, piperazine, piperidine, N-ethylpiperidine, polyamine resins, and the like. See Berge et al., supra.

[0080] "Pharmaceutically acceptable solvate" refers to a composition of matter in the form of a solvent addition. In some embodiments, the solvate contains a stoichiometric or non-stoichiometric amount of a solvent and is formed during preparation with a pharmaceutically acceptable solvent such as water, ethanol, etc. 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 in the methods described herein. The compounds provided herein exist in unsolvated forms as well as solvated forms.

[0081] The term "subject" or "patient" includes mammals. Examples of mammals include, but are not limited to, any member of the class Mammalia: humans, non-human primates such as chimpanzees and other apes and monkey species; farm animals such as cattle, horses, sheep, goats, pigs; livestock such as rabbits, dogs and cats; laboratory animals including rodents such as rats, mice and guinea pigs, etc. In one aspect, the mammal is a human.

[0082] As used herein, "treatment," "treating," "palliating," or "ameliorating" are used interchangeably. These terms refer to methods of obtaining beneficial or desired results, including but not limited to therapeutic benefit and / or preventive benefit. "Therapeutic benefit" refers to the eradication or amelioration of the underlying condition being treated. In addition, a therapeutic benefit is achieved by eradication or amelioration of one or more physiological symptoms associated with the underlying condition, such that an improvement is observed in the patient, even though the patient still suffers from the underlying condition. In some embodiments, for preventive benefit, the composition is administered to a patient at risk of developing a particular disease, or to a patient reporting one or more physiological symptoms of a disease, even if a diagnosis of the disease has not yet been made.

[0083] MEK kinase

[0084] Phosphorylation of mitogen-activated protein kinase (MAPK) occurs through the action of MEK. MAPK is localized in the cytoplasm of cells through its specific binding to the N-terminal 1-32 residues of MEK in unstimulated cells. To date, 7 MEK enzymes have been identified, and these enzymes selectively phosphorylate serine / threonine and tyrosine residues within the activation loop of their specific mitogen-activated protein kinase (MAPK) substrates. The MEK gene family consists of seven genes, of which MEK1 and MEK2 are the more important genes. MEK1 is present in human chromosome 15q22.31 and is encoded by the gene MAP2K1. MEK2 is present in human chromosome 9q13.3 and is encoded by the gene MAP2K2.

[0085] MEK proteins have molecular weights ranging from about 43 to 50 kDa. MEK can have amino- and carboxyl-terminal domains that are more diverse between different MEK proteins but share extensive homology with the kinase domain. The MEK1 and MEK2 proteins are closely related and have three important domains: (1) a core protein kinase domain that contains an ATP binding site and a catalyst; (2) an N-terminal domain that contains an inhibitory / allosteric segment, a nuclear export sequence, and a docking site (D domain) that facilitates binding to ERK substrates, and (3) a shorter C-terminal region that contains a domain for multifunctional docking (DVD), which serves as a critical binding site for upstream components of the Ras / Raf / MEK / ERK signaling cascade.

[0086] MEK3 and MEK6 are functionally similar to MEK1 and MEK2 and are encoded by the MAP2K3 and MAP2K6 genes, respectively, located on chromosome 17q. MEK3 has 347 amino acid residues and MEK6 has 334 amino acid residues. Although MEK6 differs from MEK3 in terms of the C- and N-terminal regions, the serine / threonine and tyrosine catalytic sites and the ATP binding site are conserved. The 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, ultraviolet irradiation, physical and chemical stress, and hormones. MEK3 and MEK6 can be activated by MPAK kinase kinases (MAPKKKs), 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 only activate the p38α and p38β isoforms. MEK3 and MEK6 with the p38 MAPK cascade can promote p53-dependent growth arrest to arrest the cell cycle.

[0087] 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 through the kinase domain, but differ in the N- 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 fragments of MEK4 and MEK7 or only MEK4 are phosphorylated. MEK4 and MEK7 can work synergistically to activate JNK protein kinases (such as JK1, JNK2, and JNK3). In addition, MEK4 and MEK7 with the JNK signaling pathway can serve as key tumor suppressor pathways. MEK4 and MEK7, as well as the substrate JNK, can promote apoptosis by phosphorylating and inactivating anti-apoptotic proteins such as, but not including, Bcl-2, Bcl-XL, and Mcl-1. Normal hepatopoiesis, B and T cell lymphopoiesis, and erythropoiesis show MEK4 activity. MEK4 has also been shown to be downregulated in 75% of ovarian cancer cases. It has also been hypothesized that loss of the MEK4-p38 MAPK signaling cascade may be associated with tumorigenesis.

[0088] MEK5 shares approximately 40% identity with other MEK protein kinases and has a sequence of 448 amino acids. 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 the size of other MAPKs. The PB1 domain of MEK5 mediates the interaction of MEK5 with MEKK2, MEKK3, or ERK5. MEK5-ERK5 signaling can enhance progression through the cell cycle. Overexpression of MEK5 is associated with colon cancer, prostate cancer, breast cancer, lymphoma, and malignant mesothelioma.

[0089] MEK activation and intracellular signaling pathways

[0090] Activation of MEK triggers the mitogen-activated protein kinase (MAPK) pathway, which is a key cell signaling pathway that regulates proliferation, cell growth and survival. MEK transmits mitogenic signals from the extracellular space to the nucleus through the signaling pathway. MEK1 and MEK2 participate in the Ras / Raf / MEK / ERK signal transduction cascade and are activated by ligands that bind to receptor tyrosine kinases (RTKs), which can lead to dimerization of the receptor and autophosphorylation of specific tyrosine residues in its C-terminal region. The activated receptor can then recruit and phosphorylate the adapter proteins Grb2 and SOS, which interact with the GTPase Ras to activate it. When the inactive Ras-GDP is converted to active Ras-GTP, H-Ras, K-Ras and N-Ras act as molecular switches. In the activated 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.

[0091] Activated ERK can translocate to the nucleus to trigger cellular responses such as apoptosis, angiogenesis, motility, cell proliferation, survival, differentiation, and stress responses. The Raf / MEK / ERP MAP kinase pathway promotes cell survival by blocking NF-kB, which will lead to increased transcription of anti-apoptotic and pro-survival genes (such as Bcl-2 and Mcl-1). The Ras / Raf / MEK / ERK signaling pathway is activated by several different mechanisms in human cancers. For example, increases in ERK1 and ERK2 signaling are often due to direct mutation 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).

[0092] In tumor cells, specific growth factors bind to transmembrane receptors on the cell surface, resulting in increased RAS activation, and once RAS is activated, the plasma membrane of the cell secretes and activates the downstream molecule RAF kinase. The activation of RAF kinase stimulates a series of protein kinases, which form the RAS / RAF / MEK ERK signaling pathway. In addition, BRAF and KRAS are two key oncogenes in the MEK signaling pathway and the RAS / RAF / MAPK signaling pathway. Mutations in both KRAS and BRAF genes lead to proliferation, differentiation and apoptosis of tumor cells by activating the MEK / RAS / RAF / ERK signaling pathway. KRAS and BRAF gene mutations have also been identified in non-small cell lung cancer (NSCLC). MEK inhibitors have been used in combination with chemotherapy, BRAF inhibitors, immune checkpoint inhibitors or epidermal growth factor receptor tyrosine kinase inhibitors to show improved clinical efficacy and delay the occurrence of drug resistance (Han, J. et al. J Hematol Oncol 14; 1, 2021).

[0093] The BRAF gene is an important gene in the MAPK pathway and is associated with a variety of 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. Combination blockade of BRAF and MEK can delay or prevent resistance in patients who develop resistance when BRAF inhibitors are administered as a single agent. The combination of BRAF and MEK inhibitors has been approved by the FDA for cancer types, including but not limited to BRAF mutations in melanoma, NSCLC, and ATC (Subbiah, V. et al. Trends in Cancer, 2020 Vol. 6 No. 9). In addition, patents for combined treatment with BRAF and MEK inhibitors have shown an overall survival rate for metastatic melanoma.

[0094] MEK inhibitors

[0095] Several agents targeting MEK have been developed, 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, JTP74057, 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 approved by the FDA or undergoing clinical evaluation include TAK-733, binimetinib, cobimetinib, trametinib and selumetinib. Other MEK inhibitors include mirdametinib and pimacitinib, as well as compounds disclosed in WO2006 / 045514. Other compounds suitable as MEK inhibitors are also disclosed in US 5,525,625; WO 98 / 43960; WO 99 / 01421; WO 99 / 01426; WO 00 / 41505; WO 00 / 42002; WO 00 / 42003; WO 00 / 41994; WO 00 / 42022; WO 00 / 42029; WO 00 / 68201; WO 01 / 68619; WO02 / 06213; WO 03 / 077855; WO03 / 077914; WO2004 / 005284; and WO2004 / 056789.

[0096] MEK inhibitors can be divided into two major categories, ATP non-competitive inhibitors and ATP competitive inhibitors. Most MEK inhibitors are ATP non-competitive and bind to an allosteric site near the ATP site. This makes non-competitive MEK inhibitors highly specific.

[0097] Trametinib is an allosteric ATP non-competitive inhibitor with potent activity against MEK1 and MEK2 kinases. Trametinib can induce cell cycle arrest by inhibiting p-ERK1 and p-ERK2. Pimacitinib is a selective allosteric ATP non-competitive inhibitor of MEK1 and MEK2. Pimacitinib can inhibit tumor growth and regression. Selumetinib is also an ATP non-competitive inhibitor that is highly selective for MEK1 and MEK2. Studies have shown that its anti-tumor activity is associated with reduced phosphorylation of ERK1 and ERK2. Rafametinib is a cyclopropane-1-sulfonamide derivative that exhibits selective allosteric inhibition of MEK1 and MEK2. Rafametinib has shown potent activity against xenografts of human melanoma, colon cancer, pancreatic cancer, and skin cancer in tumor models.

[0098] 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 examined MEK162 in patients with advanced melanoma with N-Ras and B-Raf mutations. RO5126766 is a very potent MEK / RAF dual inhibitor and selectively binds to MEK1 and MEK2 to form a stable complex. The main mechanism was shown to be through cell cycle arrest. RO4987655 is a highly selective small molecule MEK inhibitor. The compound is a 3-oxo-oxazinane ring structure that confers metabolic stability and has anti-tumor efficacy. GDC-0973 is a derivative of ketone and is a potent small molecule inhibitor of MEK1. GDC-0973 has antitumor activity in BRAF and KRAS mutant cancer cell lines. AZD8330 is a newer inhibitor of MEK1 and MEK2 that has been studied in patients with advanced solid tumors.

[0099] E6201 is an ATP competitive MEK inhibitor and shows potent activity against melanoma cells. Since melanoma has a high probability of metastasizing to the CNS, E6201 can be used to penetrate the intact blood-brain barrier (BBB) ​​(Gampa, G. et al. Drug Metab Dispos., 46 (5): 658-666, 2018). E6201 as a single agent or in combination with BRAF inhibitors may be beneficial for the treatment of melanoma. In addition, E6201 may be able to penetrate the BBB to achieve therapeutic activity levels.

[0100] Despite increased understanding of cellular signaling pathways and limited success in translating this knowledge into drugs, there is a large unmet medical need for treatment via selective MEK inhibition.

[0101] MEK kinase inhibitory compounds

[0102] In one aspect, provided herein is a MEK kinase inhibitory compound.

[0103] One embodiment provides a compound or a pharmaceutically acceptable salt or solvate thereof having the structure of formula (I):

[0104]

[0105] in,

[0106] R 1 is optionally substituted alkyl;

[0107] R 2 is optionally substituted alkyl; optionally, R 1 and R 2 connected with carbon-carbon bonds to form a phosphorus-containing ring;

[0108] R 3 is selected from hydrogen, halo, optionally substituted alkyl, optionally substituted cycloalkyl or optionally substituted alkoxy;

[0109] R 4 is selected from hydrogen, halo, optionally substituted alkyl, optionally substituted cycloalkyl or optionally substituted alkoxy;

[0110] R 5 is selected from hydrogen, halo, optionally substituted alkyl, optionally substituted cycloalkyl or optionally substituted alkoxy; and

[0111] R 11 , R 12 , R 13 , R 14 and R 15 Independently selected from hydrogen, halo, optionally substituted alkynyl, optionally substituted alkyl, optionally substituted cycloalkyl.

[0112] Provided herein are compounds of formula (I) or pharmaceutically acceptable salts or solvates thereof, wherein R 1 is an optionally substituted C1-C3 alkyl. Provided herein are compounds of formula (I) or pharmaceutically acceptable salts or solvates thereof, wherein R 2 is an optionally substituted C1-C3 alkyl. Provided herein are compounds of formula (I) or pharmaceutically acceptable salts or solvates thereof, wherein R 1is CH3. Provided herein are compounds of formula (I) or pharmaceutically acceptable salts or solvates thereof, wherein R 2 It is CH3.

[0113] Provided herein are compounds of formula (I) or pharmaceutically acceptable salts or solvates thereof, wherein R 1 is an optionally substituted C1-C3 alkyl group, R 2 is an optionally substituted C1-C3 alkyl group, and R 1 and R 2 The phosphorus-containing ring is connected by a carbon-carbon bond to form a phosphorus-containing ring. In one embodiment is a compound or a pharmaceutically acceptable salt or solvate thereof, wherein the phosphorus-containing ring is a 5-membered ring.

[0114] Provided herein are compounds of formula (I) or pharmaceutically acceptable salts or solvates thereof, wherein R 3 Provided herein are compounds of formula (I) or pharmaceutically acceptable salts or solvates thereof, wherein R 3 Provided herein are compounds of formula (I) or pharmaceutically acceptable salts or solvates thereof, wherein R 3 is an optionally substituted C1-C3 alkyl group.

[0115] Provided herein are compounds of formula (I) or pharmaceutically acceptable salts or solvates thereof, wherein R 4 Provided herein are compounds of formula (I) or pharmaceutically acceptable salts or solvates thereof, wherein R 4 Provided herein are compounds of formula (I) or pharmaceutically acceptable salts or solvates thereof, wherein R 4 is an optionally substituted C1-C3 alkyl. Provided herein are compounds of formula (I) or pharmaceutically acceptable salts or solvates thereof, wherein R 4 is an optionally substituted C1-C3 alkoxy group.

[0116] Provided herein are compounds of formula (I) or pharmaceutically acceptable salts or solvates thereof, wherein R 5 Provided herein are compounds of formula (I) or pharmaceutically acceptable salts or solvates thereof, wherein R 5 Provided herein are compounds of formula (I) or pharmaceutically acceptable salts or solvates thereof, wherein R 5 is an optionally substituted C1-C3 alkyl. Provided herein are compounds of formula (I) or pharmaceutically acceptable salts or solvates thereof, wherein R 5 is an optionally substituted C1-C3 alkoxy group.

[0117] Provided herein are compounds of formula (I) or pharmaceutically acceptable salts or solvates thereof, wherein R 11Provided herein are compounds of formula (I) or pharmaceutically acceptable salts or solvates thereof, wherein R 11 It's hydrogen.

[0118] Provided herein are compounds of formula (I) or pharmaceutically acceptable salts or solvates thereof, wherein R 12 is hydrogen or fluorine. Provided herein are compounds of formula (I) or pharmaceutically acceptable salts or solvates thereof, wherein R 12 Provided herein are compounds of formula (I) or pharmaceutically acceptable salts or solvates thereof, wherein R 12 It's hydrogen.

[0119] Provided herein are compounds of formula (I) or pharmaceutically acceptable salts or solvates thereof, wherein R 13 is selected from iodine, bromine, optionally substituted C2-C3 alkynyl, optionally substituted C1-C3 alkyl, optionally substituted C3-C4 cycloalkyl. Provided herein are compounds of formula (I) or pharmaceutically acceptable salts or solvates thereof, wherein R 13 is iodine. Provided herein are compounds of formula (I) or pharmaceutically acceptable salts or solvates thereof, wherein R 13 is an optionally substituted C1 alkyl. Provided herein is a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, wherein R 13 Provided herein are compounds of formula (I) or pharmaceutically acceptable salts or solvates thereof, wherein R 13 Provided herein are compounds of formula (I) or pharmaceutically acceptable salts or solvates thereof, wherein R 13 is optionally substituted cyclopropyl.

[0120] Provided herein are compounds of formula (I) or pharmaceutically acceptable salts or solvates thereof, wherein R 14 and R 15 It's hydrogen.

[0121] One embodiment provides a MEK kinase inhibitory compound, or a pharmaceutically acceptable salt or solvate thereof, having the structure provided in Table 1.

[0122] Table 1

[0123]

[0124]

[0125]

[0126]

[0127]

[0128]

[0129] Preparation of compounds

[0130] The compounds used in the synthetic chemistry reactions described herein are prepared according to organic synthesis techniques known to those skilled in the art, starting from commercially available chemicals and / or from compounds described in the chemical literature. “Commercially available chemicals” were obtained from standard commercial sources, including Acros Organics (Pittsburgh, PA), Aldrich Chemical (Milwaukee, WI, including Sigma Chemical and Fluka), Apin Chemicals Ltd. (Milton Park, UK), Avocado Research (Lancashire, 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, CN), Polyorganix (Houston, TX), Pierce Chemical Co. (Rockford, IL), Riedel de Haen AG (Hanover, Germany), Spectrum Quality Product, Inc. (New Brunswick, NJ), TCI America (Portland, OR), Trans World Chemicals, Inc. (Rockville, MD), and Wako Chemicals USA, Inc. (Richmond, VA).

[0131] Suitable reference books and papers detailing the synthesis of reactants that can be used to prepare the compounds described herein, or providing references to articles describing such preparations, include, for example, "Synthetic Organic Chemistry", John Wiley & Sons, Inc., New York; SR Sandler et al., "Organic Functional Group Preparations," 2nd edition, Academic Press, New York, 1983; H O House, "Modern Synthetic Reactions," 2nd edition, WA Benjamin, Inc. Menlo Park, Calif. 1972; TL Gilchrist, "Heterocyclic Chemistry," 2nd edition, John Wiley & Sons, New York, 1992; J. March, "Advanced Organic Chemistry: Reactions, Mechanisms and Structure," 4th edition, Wiley-Interscience, New York, 1992. Other suitable reference books and papers that detail the synthesis of reactants that can be used to prepare the compounds described herein or provide references to articles describing the preparations include, for example, Fuhrhop, J. and Penzlin G. "Organic Synthesis: Concepts, Methods, Starting Materials", 2nd Revised and Expanded Edition (1994) John Wiley & Sons ISBN: 3-527-29074-5; Hoffman, RV "Organic Chemistry, An Intermediate Text" (1996) Oxford University Press, ISBN 0-19-509618-5; Larock, RC "Comprehensive Organic Transformations: A Guide to Functional Group Preparations" 2nd Edition (1999) Wiley-VCH, ISBN: 0-471-19031-4; March, J. "Advanced Organic Chemistry: Reactions, Mechanisms, and Structure" 4th Edition (1992) John Wiley & Sons, ISBN: 0-471-60180-2; Otera, J.(Editor) "Modern Carbonyl Chemistry" (2000) Wiley-VCH, ISBN: 3-527-29871-1; Patai, S. "Patai's 1992Guide to the Chemistry of Functional Groups" (1992) Interscience ISBN: 0-471-93022-9; Solomons, TWG "Organic Chemistry" 7th edition (2000) John Wiley & Sons, ISBN: 0-471-19095-0; Stowell, JC, "Intermediate Organic Chemistry" 2nd edition (1993) Wiley-Interscience, ISBN: 0-471-57456-2; "Industrial Organic Chemicals: Starting Materials and Intermediates: An Ullmann's Encyclopedia"(1999)John Wiley & Sons, ISBN: 3-527-29645-X, in 8 volumes; "Organic Reactions" (1942-2000) John Wiley & Sons, in more than 55 volumes; and "Chemistry of Functional Groups" John Wiley & Sons, in 73 volumes. .

[0132] Specific and similar reactants are optionally identified by an index of known chemicals prepared by the Chemical Abstract Service of the American Chemical Society, which is available in most public and university libraries and through online databases (contact the American Chemical Society in Washington, DC for more details). Chemicals known but not commercially available in the catalog are optionally prepared by custom chemical synthesis agencies, many of which provide custom synthesis services for standard chemical supply agencies (e.g., those listed above). References for the preparation and selection of pharmaceutical salts of the compounds described herein are P.H. Stahl & C.G. Wermuth "Handbook of Pharmaceutical Salts", Verlag Helvetica Chimica Acta, Zurich, 2002.

[0133] Pharmaceutical composition

[0134] In certain embodiments, the MEK kinase inhibitory compounds described herein are administered as pure chemicals. In other embodiments, the MEK kinase inhibitory compounds described herein are combined with a pharmaceutically suitable or acceptable carrier (also referred to herein as a pharmaceutically suitable (or acceptable) excipient, a physiologically suitable (or acceptable) excipient, or a physiologically suitable (or acceptable) carrier), which is selected based on the selected route of administration and standard pharmaceutical practice as described, for example, in Remington: The Science and Practice of Pharmacy (Gennaro, 21st Edition Mack Pub. Co., Easton, PA (2005)).

[0135] Provided herein are pharmaceutical compositions comprising at least one MEK kinase inhibitory compound described herein or a stereoisomer, pharmaceutically acceptable salt, hydrate or solvate thereof and one or more pharmaceutically acceptable carriers. A carrier (or excipient) is acceptable or suitable if it is compatible with the other ingredients of the composition and is not harmful to the recipient (i.e., subject or patient) of the composition.

[0136] One embodiment provides a pharmaceutical composition comprising a pharmaceutically acceptable excipient and a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof.

[0137] One embodiment provides a method for preparing a pharmaceutical composition, which comprises mixing a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof with a pharmaceutically acceptable carrier.

[0138] In certain embodiments, the MEK kinase inhibitory compound as described in Formula (I) or a pharmaceutically acceptable salt or solvate thereof is substantially pure in that it contains less than about 5%, or less than about 2%, or less than about 1%, or less than about 0.5%, or less than about 0.1% of other small organic molecules, such as, for example, unreacted intermediates or synthesis by-products produced in one or more steps of the synthesis method.

[0139] One embodiment provides a pharmaceutical composition comprising a pharmaceutically acceptable excipient and a compound of Table 1 or a pharmaceutically acceptable salt or solvate thereof.

[0140] One embodiment provides a method for preparing a pharmaceutical composition, comprising mixing a compound of Table 1 or a pharmaceutically acceptable salt or solvate thereof with a pharmaceutically acceptable carrier.

[0141] In certain embodiments, the MEK kinase inhibitory compound as described in Table 1, or a pharmaceutically acceptable salt or solvate thereof, is substantially pure in that it contains less than about 5%, or less than about 2%, or less than about 1%, or less than about 0.5%, or less than about 0.1% of other small organic molecules, such as, for example, unreacted intermediates or synthesis by-products produced in one or more steps of the synthesis method.

[0142] Suitable oral dosage forms include, for example, tablets, pills, sachets, or capsules of hard or soft gelatin, methylcellulose or other suitable materials that dissolve easily in the digestive tract. In some embodiments, suitable non-toxic solid carriers are used, which include, for example, pharmaceutical grade mannitol, lactose, starch, magnesium stearate, sodium saccharin, talcum, cellulose, glucose, sucrose, magnesium carbonate, etc. (See, for example, Remington: The Science and Practice of Pharmacy (Gennaro, 21st Edition Mack Pub. Co., Easton, PA (2005)).

[0143] In some embodiments, the MEK kinase inhibitory compound described in Formula (I) or Table 1 or a pharmaceutically acceptable salt or solvate thereof 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, etc.

[0144] The dosage of the composition comprising at least one MEK kinase inhibitory compound as described herein varies depending on the condition of the subject or patient (eg, human). In some embodiments, such factors include general health, age, and other factors.

[0145] The pharmaceutical composition is applied in a manner suitable for the disease to be treated (or prevented). Suitable dosage and suitable duration and frequency of application will be determined by factors such as the patient's condition, the type and severity of the patient's disease, the specific form of the active ingredient and the method of administration. Typically, suitable dosage and treatment regimen provide a composition of the amount sufficient to provide treatment and / or prevention benefits (e.g., improved clinical outcomes, such as more frequent complete or partial remissions, or longer disease-free and / or overall survival, or mitigation of symptom severity). Optimal dose is typically determined using experimental models and / or clinical trials. Optimal dose depends on the patient's body mass, body weight or blood volume.

[0146] Oral dosages are generally from about 1.0 mg to about 1000 mg, one to four times a day or more.

[0147] Treatment

[0148] One embodiment provides a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, which is used in a method for treating a human or animal body. One embodiment provides a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, which is used in a method for treating a cancer or a tumor disease. One embodiment provides a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof and a pharmaceutically acceptable excipient, which is used in a method for treating a cancer or a tumor disease. One embodiment provides a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof for use in the preparation of a medicament for treating a cancer or a tumor disease. Another embodiment provides use, wherein the cancer is selected from lung cancer, breast cancer, skin cancer, melanoma or leukemia.

[0149] In some embodiments, a method of treating cancer in a patient in need is provided, comprising administering to the patient a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, a method of treating cancer in a patient in need is provided, comprising administering to the patient a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof and a pharmaceutically acceptable excipient. Another embodiment provides a method, wherein the cancer is selected from lung cancer, breast cancer, skin cancer, melanoma or leukemia.

[0150] One embodiment provides a compound of Table 1 or a pharmaceutically acceptable salt or solvate thereof for use in a method of treating a human or animal body. One embodiment provides a compound of Table 1 or a pharmaceutically acceptable salt or solvate thereof for use in a method of treating cancer or a neoplastic disease. One embodiment provides a pharmaceutical composition comprising a compound of Table 1 or a pharmaceutically acceptable salt or solvate thereof and a pharmaceutically acceptable excipient for use in a method of treating cancer or a neoplastic disease. One embodiment provides the use of a compound of Table 1 or a pharmaceutically acceptable salt or solvate thereof in the preparation of a medicament for treating cancer or a neoplastic disease. Another embodiment provides a method wherein the cancer is selected from lung cancer, breast cancer, skin cancer, melanoma, or leukemia.

[0151] 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 pharmaceutically 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 pharmaceutically acceptable salt or solvate thereof and a pharmaceutically acceptable excipient. Another embodiment provides the method, wherein the cancer is selected from lung cancer, breast cancer, skin cancer, melanoma, or leukemia.

[0152] Provided herein are methods wherein the pharmaceutical composition is administered orally. Provided herein are methods wherein the pharmaceutical composition is administered by injection.

[0153] One embodiment provides a method of inhibiting MEK kinase comprising contacting MEK kinase with a compound of Formula (I) or Table 1. Another embodiment provides a method of inhibiting MEK kinase, wherein the MEK kinase is contacted in an in vivo environment. Another embodiment provides a method of inhibiting MEK kinase, wherein the MEK kinase is contacted in an in vitro environment.

[0154] Other embodiments and uses will be apparent to those skilled in the art in light of this disclosure.The following examples are provided merely as illustrations of various embodiments and should not be construed as limiting the invention in any way.

[0155] Example

[0156] I. Chemical Synthesis

[0157] In some embodiments, the MEK kinase inhibitory compounds disclosed herein are synthesized according to the following examples. As used below and throughout the description of the present invention, unless otherwise indicated, the following abbreviations should be understood to have the following meanings:

[0158] ℃ Celsius

[0159] δ H Chemical shift downfield of tetramethylsilane (parts per million)

[0160] DCM Dichloromethane (CH2Cl2)

[0161] DMF Dimethylformamide

[0162] DMSO Dimethyl sulfoxide

[0163] EA Ethyl acetate

[0164] ESI Electrospray ionization

[0165] Et Ethyl

[0166] g

[0167] h hour

[0168] HPLC High Performance Liquid Chromatography

[0169] Hz Hertz

[0170] J Coupling constant (NMR spectroscopy)

[0171] LCMS Liquid chromatography mass spectrometry

[0172] μ micro

[0173] m multiplet (spectrum); meter; millimeter

[0174] M Moore

[0175] M + Ions of the parent molecule

[0176] Me Methyl

[0177] MHz Megahertz

[0178] min

[0179] mol mole; molecular weight (measured in mol wt)

[0180] mL milliliters

[0181] MS

[0182] nm nanometer

[0183] NMR Nuclear Magnetic Resonance

[0184] pH The electrical potential of hydrogen; a measure of the acidity or alkalinity of an aqueous solution

[0185] PE Petroleum Ether

[0186] RT Room temperature

[0187] s singlet (spectrum)

[0188] t triplet (spectrum)

[0189] T Temperature

[0190] TFA Trifluoroacetic acid

[0191] THF Tetrahydrofuran

[0192] Intermediate 1: Phosphorolane 1-oxide

[0193]

[0194] At 15 ° C, under a nitrogen atmosphere, 1,3-dibromopropane (14.62 g, 72.41 mmol) in tetrahydrofuran (15 mL) was added to a stirred mixture of magnesium (3.61 g, 148.440 mmol) in tetrahydrofuran (45 mL). The reaction mixture was stirred at room temperature for 1.5 h. At 15 ° C, diethyl phosphonate (5.0 g, 36.20 mmol) in tetrahydrofuran (15 mL) was added to the mixture 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 gradually added to generate a heavy off-white magnesium carbonate precipitate, 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 phospholane 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).

[0195] Intermediate 2: Ethyl (methyl) phosphine oxide

[0196]

[0197] At room temperature, under a nitrogen atmosphere, ethyl methylphosphinate (2.0 g, 18.51 mmol) in tetrahydrofuran (6.0 mL) was added dropwise to a stirred solution of 1M ethylmagnesium bromide in tetrahydrofuran (27.76 mL, 27.76 mmol). At room temperature, under a nitrogen atmosphere, the reaction mixture was stirred for 1 h. Potassium carbonate (12 g) solution gradually added in water (20 mL) generates a heavy off-white magnesium carbonate precipitate, which is quickly filtered off in the air and washed with degassed ethanol (30 mL). The filtrate is concentrated under reduced pressure. The residue is purified by silica gel column chromatography, eluted with dichloromethane / methanol (10 / 1). The fractions containing the desired product are combined and concentrated to obtain 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).

[0198] Intermediate 3: (3-aminopyridin-4-yl)dimethylphosphine oxide

[0199]

[0200] To a stirred mixture of 4-iodopyridine-3-amine (3.0 g, 13.64 mmol), (methylphosphonyl)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 tripotassium phosphate (3.18 g, 15.00 mmol). The reaction mixture was degassed three times with nitrogen 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, eluted with dichloromethane / methanol (10 / 1). The fractions containing the desired product were combined and concentrated to give 4-(dimethylphosphoryl)pyridine-3-amine (2.18 g, 94%) as a light yellow solid. CH 11 N2OP[M+H] + MS ESI calculated value 171.06, found 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.

[0201] The compounds in Table 2 below were prepared using procedures similar to those described in Intermediate 3 using appropriate starting materials.

[0202] Table 2

[0203]

[0204] Intermediate 8: 6-(Dimethylphosphoryl)-2,3-difluoroaniline

[0205]

[0206] To a stirred mixture of 6-bromo-2,3-difluoroaniline (0.70 g, 3.36 mmol) and (methylphosphonyl)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, eluted with dichloromethane / methanol (10 / 1). The fractions containing the desired product were combined and concentrated to give 6-(dimethylphosphoryl)-2,3-difluoroaniline (200 mg, 29%) as a gray solid. CH 10 F2NOP[M+H] + MS ESI calculated value 206.05, found 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).

[0207] The compounds in Table 3 below were prepared using procedures similar to those described in Intermediate 8 using appropriate starting materials.

[0208] Table 3

[0209]

[0210] Example 1: 4-(Dimethylphosphoryl)-N-(2-fluoro-4-iodophenyl)pyridin-3-amine

[0211]

[0212] Step 1. 4-(Dimethylphosphoryl)-N-(2-fluorophenyl)pyridin-3-amine was prepared by heating 4-(dimethylphosphoryl)pyridin-3-amine (2.18 g, 12.81 mmol), 1-bromo-2-fluorobenzene (3.36 g, 19.22 mmol), methanesulfonic acid (2-dicyclohexylphosphino-3,6-dimethoxy-2'-4'-6'-triisopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II) (BrettPhosPd To a stirred mixture of 4-(4-(2-(4-(2-fluorophenyl)pyridin-3-yl)-2-(4-(2-fluorophenyl)pyridin-4-yl)-4-nitropropene (BrettPhos) (1.38 g, 2.56 mmol) and 1,4-dioxane (25 mL) was added sodium tert-butoxide (3.69 g, 38.44 mmol). The reaction mixture was degassed three times with nitrogen 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 eluting with dichloromethane / methanol (10 / 1). The 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. 13 H 14 FN2OP[M+H] + MS ESI calculated value 265.08, found 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.

[0213] 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) was added p-toluenesulfonic acid monohydrate (5.24 g, 27.55 mmol) and N-iodosuccinimide (6.64 g, 29.52 mmol) 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, eluting with dichloromethane / ethanol (10 / 1) to give the crude product (3.3 g), which was further purified by reverse phase flash chromatography under the following conditions: column, C18 silica gel; mobile phase: acetonitrile in water (plus 10 mmol / L NH4HCO3), 15% to 50% gradient in 30 min; detector: UV 254 / 220 nm. The 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 about 1 g of 95% pure product. C 13 H 13 FIN2OP[M+H] + The MS ESI calculated value was 390.98, the found value was 391.05; 1 HNMR (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.

[0214] The compounds in Table 4 below were prepared using procedures similar to those described in Example 1 using appropriate starting materials.

[0215] Table 4

[0216]

[0217]

[0218] 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

[0219]

[0220] 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, 2 x 25 cm; mobile phase A: hexane (0.5% 2M 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 containing the desired product (RT1: 10.92 min) was combined and concentrated to give one enantiomer (absolute chiral configuration undetermined) as a light yellow semisolid (19.9 mg, 36%). C 14 H 15 FIN2OP[M+H] + MS ESI calculated value 405.00, found 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-124.71.

[0221] The slower peak containing the desired product (RT2: 12.85 min) was combined and concentrated to give the second enantiomer as a light yellow semisolid (absolute chiral configuration undetermined) (19.8 mg, 36%). 14 H 15 FIN2OP[M+H] + MS ESI calculated value 405.00, found value 405.00; 1H 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.

[0222] Example 10: N-(4-bromo-2-fluorophenyl)-4-(dimethylphosphoryl)pyridin-3-amine

[0223]

[0224] 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) at room temperature were added 2-(dicyclohexylphosphino)-3,6-dimethoxy-2'-4'-6'-triisopropyl-1,1'-biphenyl (BrettPhos) (0.15 g, 0.29 mmol), methanesulfonic acid (2-dicyclohexylphosphino-3,6-dimethoxy-2'-4'-6'-triisopropyl-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) portionwise. The reaction mixture was degassed three times with nitrogen and stirred at 100 ° 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: Xselect CSH C18 OBD column 30x 150mm 5μm; mobile phase A: water (10mmol / L ammonium bicarbonate), mobile phase B: acetonitrile; flow rate: 60mL / min; gradient: 27% B to 37% B in 11min; wavelength: 254nm. The fractions containing the desired product were combined and concentrated to give N-(4-bromo-2-fluorophenyl)-4-(dimethylphosphoryl)pyridin-3-amine (10mg, 2%) as a light yellow oil. 13 H 13 BrFN2OP[M+H] + The MS ESI calculated values ​​were 342.99, 344.99, and the found values ​​were 342.95, 344.95; 1H 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).

[0225] The compounds in Table 5 below were prepared using procedures similar to those described in Example 10 using appropriate starting materials.

[0226] Table 5

[0227]

[0228] Example 14: (3-((4-ethynyl-2-fluorophenyl)amino)pyridin-4-yl)dimethylphosphine oxide

[0229]

[0230] 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 three times with nitrogen 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 calcd. 361.12, found 361.10.

[0231] 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 (1.12 mL, 1 M) in tetrahydrofuran 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 under the following conditions: column: XBridge Prep OBD C18 column, 30 x 150 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, 31% B in 8 min; wavelength: 254 nm; RT: 7 min. The 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 light yellow semisolid. 15 H 14 FN2OP[M+H] + MS ESI calculated value 289.08, found 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).

[0232] The compounds in Table 6 below were prepared using procedures similar to those described in Example 14 using appropriate starting materials.

[0233] Table 6

[0234]

[0235] 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

[0236]

[0237] Step 1. N-(4-bromo-2-fluorophenyl)-4-[ethyl(methyl)phosphoryl]pyridin-3-amine was heated to 4-[ethyl(methyl)phosphoryl]pyridin-3-amine (180 mg, 0.98 mmol), methanesulfonic acid (2-dicyclohexylphosphino-3,6-dimethoxy-2'-4'-6'-triisopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II) (BrettPhos To a stirred mixture of PdG3) (CAS: 1470372-59-8) (88.59 mg, 0.10 mmol), 2-(dicyclohexylphosphino)-3,6-dimethoxy-2'-4'-6'-triisopropyl-1,1'-biphenyl (BrettPhos) (CAS: 1070663-78-3) (104.92 mg, 0.20 mmol) and sodium tert-butoxide (281.77 mg, 2.93 mmol) in 1,4-dioxane (1.8 mL) was added 4-bromo-2-fluoro-1-iodobenzene (441.10 mg, 1.47 mmol). The reaction mixture was degassed three times with nitrogen 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 eluted with dichloromethane / methanol (10 / 1) to give a crude product. The crude product was purified by reverse phase flash chromatography under the following conditions: A: water (plus 10 mmol / L NH4HCO3), mobile phase B: ACN; flow rate: 60 mL / min; gradient: 28% B to 37% B, 37% B in 8 min; wavelength: 254 nm: RT1 (min): 7. The 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] + The MS ESI calculated values ​​were 357.01 and 359.01, and the found values ​​were 357.00 and 359.00.

[0238] 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, 2 x 25 cm, 5 μm; Mobile phase A: methyl tert-butyl ether (0.5% 2M NH3-methanol)--HPLC, Mobile phase B: ethanol: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 containing the desired product (RT1: 9.29 min) was combined and concentrated to give one enantiomer as a colorless oil (19.5 mg, 25%). 14 H 15 BrFN2OP[M+H] + The MS ESI calculated values ​​were 357.01 and 359.01, and the found values ​​were 357.15 and 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).

[0239] The slower peaks containing the desired product were combined and concentrated to give the second enantiomer as a colorless oil (18 mg, 23%). 14 H 15 BrFN2OP[M+H] + The MS ESI calculated values ​​were 357.01 and 359.01, and the found values ​​were 357.15 and 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).

[0240] 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

[0241]

[0242] Step 1. 4-[Ethyl(methyl)phosphoryl]-N-{2-fluoro-4-[2-(trimethylsilyl)ethynyl]phenyl}pyridin-3-amine

[0243] Trimethylsilyl acetylene (0.42 mL, 2.97 mmol) and triethylamine (0.41 mL, 2.97 mmol) were added dropwise to a stirred mixture of 4-[ethyl(methyl)phosphoryl]-N-(2-fluoro-4-iodophenyl)pyridine-3-amine (400 mg, 0.99 mmol) and CuI (37.70 mg, 0.20 mmol) in DMF (4 mL) at room temperature. The reaction mixture was degassed three times with nitrogen 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). The fractions containing the desired product were combined and concentrated to give 4-[ethyl(methyl)phosphoryl]-N-{2-fluoro-4-[2-(trimethylsilyl)ethynyl]phenyl}pyridine-3-amine (270 mg, 73%) as a brown solid. 19 H 24 FN2OPSi[M+H] + MS ESI calcd. 375.15, found 375.00.

[0244] 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 reverse phase flash chromatography under the following conditions: column: WelFlash TMC18-I, 20-40 μm, 120 g; eluent A: water (plus 10 mmol / L NH4HCO3); eluent B: ACN; gradient: 25%-45% B in 25 min; flow rate: 60 mL / min; detector: 220 / 254 nm. The 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 calcd. 303.10, found 303.00.

[0245] 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, 2 x 25 cm, 5 μm; Mobile phase A: Hex (0.5% 2M NH3-MeOH)--HPLC, Mobile phase B: Methanol: dichloromethane = 1:1--HPLC; Flow rate: 20 mL / min; Gradient: 30% B to 30% in 13 min B; Wavelength: 220 / 254 nm: RT1 (min): 10.21; RT2 (min): 11.86. The faster peaks containing the desired product were combined and concentrated to give one enantiomer as a yellow solid (12.2 mg, 13%). 16 H 16 FN2OP[M+H] + MS ESI calculated value 303.10, found 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),2.04-1.98(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).

[0246] The slower peaks containing the desired product were combined and concentrated to give the second enantiomer as a yellow solid (23 mg, 25%). 16 H 16 FN2OP[M+H] + MS ESI calculated value 303.10, found 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),2.06-2.00(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).

[0247] Example 23: N-(4-cyclopropyl-2-fluorophenyl)-4-(dimethylphosphoryl)pyridin-3-amine

[0248]

[0249] At room temperature, to 4-(dimethylphosphoryl)-N-(2-fluoro-4-iodophenyl)pyridine-3-amine (200mg, 0.51mmol) and cyclopropylboric acid (132.11mg, 1.54mmol) and dichlorobis(triphenylphosphine)palladium(II) (83.52mg, 0.10mmol) and tripotassium phosphate (326.45mg, 1.54mmol) in dioxane (2mL) and water (0.2mL) in a stirred solution. The reaction mixture was degassed three times with nitrogen and stirred at 90°C for 1h. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with dichloromethane / methanol (12 / 1). The crude product was purified by preparative HPLC under the following conditions: column: XBridge Prep OBD C18 column, 30 x 150 mm, 5 μm; mobile phase A: water (plus 10 mmol / L NH4HCO3), mobile phase B: ACN; flow rate: 60 mL / min; gradient: 23% B to 33% B, 33% B in 8 min; wavelength: 254 nm. The fractions containing the desired product were combined and concentrated to give N-(4-cyclopropyl-2-fluorophenyl)-4-(dimethylphosphoryl)pyridin-3-amine (50.3 mg) as an off-white solid. 16 H 18 FN2OP[M+H] + MS ESI calculated value 305.11, found value 305.10; 1 HNMR(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= 12.5, 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).

[0250] The compounds in Table 7 below were prepared using procedures similar to those described in Example 23 using appropriate starting materials.

[0251] Table 7

[0252]

[0253] Example 24: 4-(Dimethylphosphoryl)-5-fluoro-N-(2-fluoro-4-iodophenyl)pyridin-3-amine

[0254]

[0255] Step 1: N-(5-fluoropyridin-3-yl)-2,2-dimethylpropionamide At 0 ° C, 2,2-dimethylpropanoyl chloride (13.98 g, 115.96 mmol) was added dropwise 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). 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 x 100 mL). The combined organic layers were washed with brine (3 x 100 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to obtain N-(5-fluoropyridin-3-yl)-2,2-dimethylpropionamide (9.35 g, crude product) as a yellow solid. 10 H 13 FN2O[M+H] + MS ESI calculated value 197.10, found 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).

[0256] Step 2: N-(5-fluoro-4-iodopyridin-3-yl)-2,2-dimethylpropanamide was reacted with N-(5-fluoropyridin-3-yl)-2,2-dimethylpropanamide (5.00 g, 25.48 mmol) and N-(5-fluoro-4-iodopyridin-3-yl)-2,2-dimethylpropanamide at -78 °C under nitrogen atmosphere for 1 h. 1 ,N 1 ,N 2 ,N 2-Tetramethylethane-1,2-diamine (8.88g, 76.44mmol) was added dropwise to a stirred solution in tetrahydrofuran (15mL) with n-butyllithium (30.58mL, 76.44mmol, 2.5M in hexane). The resulting mixture was stirred for 1h at -78°C under a nitrogen atmosphere. Iodine (19.40g, 76.44mmol) in THF (5mL) was added dropwise to the above mixture over 30min at -78°C. The resulting mixture was stirred for another 1h at -78°C. At -78°C, the reaction was quenched by adding water (50mL). The resulting mixture was decolorized by adding sodium thiosulfate. The resulting mixture was extracted with ethyl acetate (3x 100mL). The combined organic layer was washed with brine (2x 100mL) and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with petroleum ether / ethyl acetate (1 / 1). The 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, found 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).

[0257] Step 3: 5-Fluoro-4-iodopyridin-3-amine

[0258] A mixture of N-(5-fluoro-4-iodopyridin-3-yl)-2,2-dimethylpropanamide (4.7 g, 14.591 mmol, 1 equivalent) in aqueous HCl solution (50 mL, 3 M) was stirred at 100 ° C for 3 h. At room temperature, the resulting mixture was alkalized with aqueous sodium hydroxide solution (50 mL, 3 M). The resulting mixture was extracted with dichloromethane (3 x 50 mL). The combined organic layer was washed with brine (1 x 50 mL) and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure to obtain 5-fluoro-4-iodopyridin-3-amine (3.5 g, crude product) as a white solid. CHFIN[M+H] + The MS ESI calculated value was 238.94, and the found value was 238.90; 1 H NMR (400MHz, CDCl3) δ7.85(s,1H),7.74(s,1H),4.35(s,2H).

[0259] Step 4: 4-(Dimethylphosphoryl)-5-fluoropyridin-3-amine

[0260] 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), tripotassium phosphate (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 (methylphosphono)methane (98 mg, 1.26 mmol). The reaction mixture was degassed three times with nitrogen and stirred at 100 ° C for 16 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, 120 g; eluent A: water (plus 10 mmol / L formic acid); eluent B: acetonitrile; gradient: 2%-15% B in 25 min; flow rate: 60 mL / min; detector: 220 / 254 nm. The fractions containing the desired product were combined and concentrated to give 4-(dimethylphosphoryl)-5-fluoropyridin-3-amine (130 mg, 82%) as a yellow oil. 10 FN2OP[M+H] + MS ESI calculated value 189.05, found 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).

[0261] Step 5: 4-(Dimethylphosphoryl)-5-fluoro-N-(2-fluorophenyl)pyridin-3-amine was prepared by mixing 4-(dimethylphosphoryl)-5-fluoropyridin-3-amine (130 mg, 0.69 mmol), methanesulfonic acid (2-dicyclohexylphosphino-3,6-dimethoxy-2'-4'-6'-triisopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II) (BrettPhos Pd G3) (62 mg, 0.06 mmol), 2-(dicyclohexylphosphino)-3,6-dimethoxy-2'-4'-6'-triisopropyl-1,1'-biphenyl (BrettPhos) (37 mg, 0.06 mmol) and sodium tert-butoxide (199 mg, 2.07 mmol) in a stirred mixture of 1,4-dioxane (2 mL) were added benzene, 1-fluoro-2-iodo- (153.40 mg, 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 (plus 10 mmol / L ammonium bicarbonate); eluent B: acetonitrile; gradient: 30%-60% B in 25 min; flow rate: 30 mL / min; detector: 220 / 254 nm; the desired fractions were 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, found 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).

[0262] 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 methanol (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 reverse phase flash chromatography under the following conditions: column: WelFlash™ C18-I, 20-40 μm, 40 g; eluent A: water (plus 10 mmol / L ammonium bicarbonate); eluent B: acetonitrile; gradient: 30%-60% B in 25 min; flow rate: 30 mL / min; detector: 220 / 254 nm. The 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, found 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).

[0263] Example 25: (2-Fluoro-3-((2-fluoro-4-iodophenyl)amino)pyridin-4-yl)dimethylphosphine oxide

[0264]

[0265] Step 1: tert-Butyl (2-fluoro-4-iodopyridin-3-yl)carbamate TEA (1.14 g, 11.24 mmol) was added dropwise to a stirred mixture of 2-fluoro-4-iodopyridin-3-carboxylic acid (3 g, 11.24 mmol) and DPPA (3.09 g, 11.24 mmol) in t-BuOH (30.00 mL) at room temperature under a nitrogen atmosphere. The reaction mixture was stirred for 16 h at 80 ° C. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with petroleum ether / ethyl acetate (5 / 1). The 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. 10 H 12 FIN2O2[M+H] + MS ESI calculated value 338.99, found value 338.95.

[0266] Step 2: 2-Fluoro-4-iodopyridin-3-amine hydrochloride

[0267] At room temperature, 4M HCl (g) (20.99mL, 83.97mmol) was added dropwise to a stirred solution of (2-fluoro-4-iodopyridin-3-yl) tert-butyl carbamate (2.1g, 6.21mmol) in DCM (10mL). The reaction mixture was stirred at room temperature for 1h. The precipitated solid was collected by filtration and washed with DCM (3x 30mL). The crude product 2-fluoro-4-iodopyridin-3-amine hydrochloride (1.7g, crude product) was directly used in the next step without further purification. C5H5ClFIN2[M+H-HCl] + MS ESI calculated value 238.94, found value 239.05.

[0268] Step 3: (3-amino-2-fluoropyridin-4-yl)dimethylphosphine oxide was added in batches to a stirred mixture of 2-fluoro-4-iodopyridin-3-amine hydrochloride (0.7 g, 2.94 mmol), (methylphosphonyl)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) at room temperature. K3PO4 (1.25 g, 5.88 mmol) was added. The reaction mixture was degassed three times with nitrogen 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). The fractions containing the desired product were combined and concentrated to give 4-(dimethylphosphoryl)-2-fluoropyridin-3-amine (170 mg, 31%) as a brown solid. C7H10 FN2OP[M+H] + MS ESI calculated value 189.05, found value 189.15.

[0269] Step 4: 4-(Dimethylphosphoryl)-2-fluoropyridin-3-amine (150 mg, 0.80 mmol), 2-(dicyclohexylphosphino)-3,6-dimethoxy-2'-4'-6'-triisopropyl-1,1'-biphenyl (BrettPhos) (42.80 mg, 0.08 mmol), t-BuONa (229.86 mg, 2.39 mmol) and (2-fluoro-3-((2-fluorophenyl)amino)pyridin-4-yl)dimethylphosphine oxide were added to 4-(dimethylphosphoryl)-2-fluoropyridin-3-amine (150 mg, 0.80 mmol), 2-(dicyclohexylphosphino)-3,6-dimethoxy-2'-4'-6'-triisopropyl-1,1'-biphenyl (BrettPhos) (42.80 mg, 0.08 mmol), t-BuONa (229.86 mg, 2.39 mmol) and methanesulfonic acid (2-dicyclohexylphosphino)-3,6-dimethoxy-2'-4'-6'-triisopropyl-1,1'-biphenyl) (2'-amino-1,1'-biphenyl-2-yl) palladium (II) (BrettPhos Pd G3) (72.27 mg, 0.08 mmol) was added dropwise to a stirred mixture of dioxane (1.50 mL) with 1-bromo-2-fluorobenzene (167.43 mg, 0.95 mmol). The reaction mixture was degassed three times with nitrogen 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, eluting with dichloromethane / methanol (10 / 1). The 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. 13 H 13 FN2OP[M+H] + MS ESI calcd. 283.07, found 283.10.

[0270] Step 5: To a stirred mixture of (2-fluoro-3-((2-fluoro-4-iodophenyl)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.HO (207.58 mg, 1.09 mmol) at room temperature under nitrogen atmosphere. The reaction mixture was stirred at 60°C under nitrogen atmosphere 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 was purified by preparative HPLC under the following conditions: column: XBridge Prep OBD C18 column, 30 x 150 mm, 5 μm; mobile phase A: water (10 mmol / L NH4HCO3), mobile phase B: ACN; flow rate: 60 mL / min; gradient: 32% B to 42% B, 42% B in 8 min; wavelength: 254 nm: RT1: 7 min. The fractions containing the desired product were combined and concentrated to give (2-fluoro-3-((2-fluoro-4-iodophenyl)amino)pyridin-4-yl)dimethylphosphine oxide (34 mg, 21%) as an off-white solid. 13 H 12 F2IN2OP[M+H] + MS ESI calculated value 408.97, found 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) δ41.15.

[0271] Example 30: 4-(Dimethylphosphoryl)-N-(2-fluoro-4-iodophenyl)-5-methylpyridin-3-amine

[0272]

[0273] Step 1: 3-Bromo-4-iodo-5-nitropyridine

[0274] A stirring solution of 3-bromo-4-chloro-5-nitropyridine (5g, 21.06mmol) and potassium iodide (69.91g, 421.16mmol) in acetonitrile (300mL) was stirred at 80 ° C for 16h. The resulting mixture was filtered and the filter cake was washed with acetonitrile (50mL). The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with petroleum ether / ethyl acetate (10 / 1). The fractions containing the desired product were combined and concentrated to give 3-bromo-4-iodo-5-nitropyridine (6g, 87%) as a yellow solid. C5H2BrIN2O2[M+H] + The MS ESI calculated values ​​were 328.83 and 330.83, and the found values ​​were 328.80 and 330.80; 1 H NMR (400MHz, CDCl3) δ8.83 (s, 1H), 8.70 (s, 1H).

[0275] Step 2: 5-Bromo-4-iodopyridin-3-amine

[0276] At room temperature, 3-bromo-4-iodo-5-nitropyridine (2.4g, 7.30mmol) and iron (1.63g, 29.19mmol) and ammonium chloride (1.95g, 36.485mmol) are added to a stirred solution in ethanol (24mL) and water (2.4mL). The resulting mixture is stirred at 80°C for 1h. The resulting mixture is filtered and the filter cake is washed with ethyl acetate (2x 100mL). The resulting mixture is extracted with ethyl acetate (1x 100mL). The combined organic layer is washed with brine (1x 200mL) and dried over anhydrous sodium sulfate. After filtration, the filtrate is concentrated under reduced pressure. The residue is purified by silica gel column chromatography and eluted with petroleum ether / ethyl acetate (3 / 2). The fractions containing the desired product are combined and concentrated to obtain 5-bromo-4-iodopyridine-3-amine (2.5g, 80%) as a yellow solid. C5H4BrIN2[M+H] + The MS ESI calculated values ​​were 298.86 and 300.86, and the found values ​​were 298.80 and 300.80; 1 H NMR (400MHz, CDCl3) δ8.04(s,1H),7.88(s,1H),4.37(s,2H).

[0277] Step 3: 5-Bromo-4-(dimethylphosphoryl)pyridin-3-amine

[0278] To a stirred solution of 5-bromo-4-iodopyridin-3-amine (2.2 g, 7.36 mmol) and (methylphosphono)methane (861.69 mg, 11.04 mmol) and 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 tripotassium phosphate (3.12 g, 14.72 mmol) at room temperature. The reaction mixture was degassed three times with nitrogen 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] + The MS ESI calculated values ​​were 248.97 and 250.97, and the found values ​​were 248.90 and 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).

[0279] Step 4: 4-(Dimethylphosphoryl)-5-methylpyridin-3-amine

[0280] At room temperature, 5-bromo-4-(dimethylphosphoryl)pyridine-3-amine (300mg, 1.21mmol) and methylboronic acid (72.11mg, 1.21mmol) and 1,1'-bis(diphenylphosphino)ferrocene-dichloropalladium(II) dichloromethane complex (98.13mg, 0.12mmol) and potassium carbonate (499.44mg, 3.62mmol) were added to a stirred solution of dioxane (3mL) and water (0.3mL). The reaction mixture was degassed with nitrogen three times and stirred at 80°C for 3h. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with dichloromethane / methanol (9 / 1). The fractions containing the desired product were combined and concentrated to give 4-(dimethylphosphoryl)-5-methylpyridine-3-amine (240mg, 92%) as a black semisolid. CH 13 N2OP[M+H] + MS ESI calculated value 185.08, found value 185.05; 1H 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).

[0281] Step 5: 4-(Dimethylphosphoryl)-N-(2-fluorophenyl)-5-methylpyridin-3-amine was added to 4-(dimethylphosphoryl)-5-methylpyridin-3-amine (170 mg, 0.92 mmol) and 1-bromo-2-fluorobenzene (242.29 mg, 1.39 mmol) and methanesulfonic acid (2-dicyclohexylphosphino-3,6-dimethoxy-2',4',6'-triisopropyl-1,1'- To a stirred solution of (2-(dicyclohexylphosphino)-3,6-dimethoxy-2'-4'-6'-triisopropyl-1,1'-biphenyl (99.09 mg, 0.19 mmol) in dioxane (1.70 mL) was added sodium tert-butoxide (266.12 mg, 2.77 mmol). The reaction mixture was degassed three times with nitrogen 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, eluting with dichloromethane / methanol (12 / 1). The 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. 14 H 16 MS ESI calculated value of FN2OP[M+H]+ 279.10, found 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).

[0282] 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.HO (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 a crude product. The crude product was purified by preparative HPLC under the following conditions: column: XBridge Shield RP18 OBD column, 30 x 150 mm, 5 μm; mobile phase A: water (plus 10 mmol / L NH4HCO3), mobile phase B: ACN; flow rate: 60 mL / min; gradient: 30% B to 42% B, 42% B in 8 min; wavelength: 254 nm. The fractions containing the desired product were combined and concentrated to give 4-(dimethylphosphoryl)-N-(2-fluoro-4-iodophenyl)-5-methylpyridin-3-amine (53.8 mg, 17%) as an off-white solid. 14 H 15 FIN2OP[M+H] + The calculated MSESI value is 405.00, and the measured value is 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).

[0283] II. Biological Evaluation

[0284] Example 1: Cellular assay

[0285] To determine the effects of the MEK inhibitor compounds disclosed herein on cellular MAPK signaling downstream of MEK, an assay monitoring ERK phosphorylation was used. A melanoma-derived cell line A-375 (ATCC: Catalog No. CRL-1619; American Type Culture Collection; Manassas, VA 20110) containing a BRAF V600 activating mutation was cultured and maintained as specified by the supplier. Cells were seeded in 24 μL growth medium in a 384-well plate at 8,000 cells / well and allowed to adhere overnight at 37°C and 5% CO2. The next day, the compounds were serially diluted into a 10-point 3-fold dilution curve in a 384-well plate. Compounds were transferred to the cell plate using an Echo550 so that the final concentration range was 0.508 nM to 10 mM in 0.1% DMSO, with 0.1% DMSO being used as a negative control. Cells were incubated with the compounds for 1 hour at 37°C and 5% CO2. Cells were lysed by adding 8 μL of 4X lysis buffer plus 1X protease / phosphatase inhibitor cocktail provided by the HTRF kit (Advanced Phospho-ERK (Thr202 / Tyr204) Cell Kit; Cisbio; Catalog No. 64AERPEH). 20 μL of lysate was transferred to an HTRF plate, followed by 2.5 μL each of anti-ERK1 / 2-Europium / Terbium cryptate and anti-phospho-ERK1 / 2 antibody solutions and incubated, according to the manufacturer's instructions. Specific signals were measured at 665 nm (donor) and 620 nm (acceptor) on a Perkin Elmer Envision 2105 and used to calculate IC in the Dotmatics KnowledgeSolutions Studies curve fitting environment (Dotmatics, Bishops Stortford, UK, CM23). 50 The ratios of the values ​​are shown in Table 8.

[0286] Table 8

[0287]

[0288] A: >0.010μM C: >0.10μM to ≤1μM

[0289] B: >0.01μM to ≤0.10μM D: ≤1μM

[0290] III. Preparation of pharmaceutical dosage forms

[0291] Example 1: Oral capsules

[0292] The active ingredient is a compound of Table 1 or a pharmaceutically acceptable salt or solvate thereof. Capsules for oral administration are prepared by mixing 1-1000 mg of the active ingredient with starch or other suitable powder blends. The mixture is incorporated into oral dosage units suitable for oral administration, such as hard gelatin capsules.

[0293] Example 2: Solution for injection

[0294] The active ingredient is a compound of Table 1 or a pharmaceutically acceptable salt or solvate thereof and is formulated as a solution in sesame oil at a concentration of 50 mg-eq / mL.

[0295] The examples and embodiments described herein are for illustrative purposes only, and various modifications or changes suggested by those skilled in the art are intended to be included within the spirit and purview of this application and the scope of the appended claims.

Claims

1. A compound or a pharmaceutically acceptable salt or solvate thereof having a structure of formula (I): in, R 1 is optionally substituted alkyl; R 2 is optionally substituted alkyl; optionally, R 1 and R 2 connected with 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 Independently selected from hydrogen, halo, optionally substituted alkynyl, optionally substituted alkyl, optionally substituted cycloalkyl.

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

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

4. The compound according to claim 1, 2 or 3, or a pharmaceutically acceptable salt or solvate thereof, wherein R 1 Yes CH 3 .

5. A compound as claimed in any one of the preceding claims, or a pharmaceutically acceptable salt or solvate thereof, wherein R 2 Yes CH 3 .

6. The compound according to claim 1 or a pharmaceutically acceptable salt or solvate thereof, wherein R 1 is an optionally substituted C1-C3 alkyl group, R 2 is an optionally substituted C1-C3 alkyl group, and R 1 and R 2 Connected by carbon-carbon bonds to form a phosphorus-containing ring.

7. The compound according to claim 6 or a pharmaceutically acceptable salt or solvate thereof, wherein the phosphorus-containing ring is a 5-membered ring.

8. A compound as claimed in any one of the preceding claims, or a pharmaceutically acceptable salt or solvate thereof, wherein R 3 It's hydrogen.

9. The compound according to any one of claims 1 to 8, or a pharmaceutically acceptable salt or solvate thereof, wherein R 3 It is halogenated.

10. The compound according to any one of claims 1 to 8, or a pharmaceutically acceptable salt or solvate thereof, wherein R 3 is an optionally substituted C1-C3 alkyl group.

11. A compound as claimed in any one of the preceding claims, or a pharmaceutically acceptable salt or solvate thereof, wherein R 4 It's hydrogen.

12. The compound according to any one of claims 1 to 10, or a pharmaceutically acceptable salt or solvate thereof, wherein R 4 It is halogenated.

13. The compound according to any one of claims 1 to 10, or a pharmaceutically acceptable salt or solvate thereof, wherein R 4 is an optionally substituted C1-C3 alkyl group.

14. The compound according to any one of claims 1 to 10, or a pharmaceutically acceptable salt or solvate thereof, wherein R 4 is an optionally substituted C1-C3 alkoxy group.

15. A compound as claimed in any one of the preceding claims, or a pharmaceutically acceptable salt or solvate thereof, wherein R 5 It's hydrogen.

16. The compound according to any one of claims 1 to 10, or a pharmaceutically acceptable salt or solvate thereof, wherein R 5 It is halogenated.

17. The compound according to any one of claims 1 to 10, or a pharmaceutically acceptable salt or solvate thereof, wherein R 5 is an optionally substituted C1-C3 alkyl group.

18. The compound according to any one of claims 1 to 10, or a pharmaceutically acceptable salt or solvate thereof, wherein R 5 is an optionally substituted C1-C3 alkoxy group.

19. A compound as claimed in any one of the preceding claims, or a pharmaceutically acceptable salt or solvate thereof, wherein R 11 It's fluorine.

20. The compound according to any one of claims 1 to 18, or a pharmaceutically acceptable salt or solvate thereof, wherein R 11 It's hydrogen.

21. The compound according to any one of claims 1 to 20, or a pharmaceutically acceptable salt or solvate thereof, wherein R 12 It is hydrogen or fluorine.

22. A compound as claimed in any one of the preceding claims, or a pharmaceutically acceptable salt or solvate thereof, wherein R 13 Selected from iodine, bromine, optionally substituted C2-C3 alkynyl, optionally substituted C1-C3 alkyl, optionally substituted C3-C4 cycloalkyl.

23. A compound according to any one of claims 1 to 21, or a pharmaceutically acceptable salt or solvate thereof, wherein R 13 It's iodine.

24. A compound according to any one of claims 1 to 21, or a pharmaceutically acceptable salt or solvate thereof, wherein R 13 is an optionally substituted C1 alkyl group.

25. A compound according to any one of claims 1 to 21, or a pharmaceutically acceptable salt or solvate thereof, wherein R 13 Yes - CF 3 .

26. A compound according to any one of claims 1 to 21, or a pharmaceutically acceptable salt or solvate thereof, wherein R 13 It's bromine.

27. A compound according to any one of claims 1 to 21, or a pharmaceutically acceptable salt or solvate thereof, wherein R 13 is optionally substituted cyclopropyl.

28. A compound as claimed in any one of the preceding claims, or a pharmaceutically acceptable salt or solvate thereof, wherein R 14 and R 15 It's hydrogen.

29. A compound or a pharmaceutically acceptable salt or solvate thereof as provided in Table 1.

30. A pharmaceutical composition comprising a compound according to any one of claims 1 to 29 or a pharmaceutically acceptable salt or solvate thereof and a pharmaceutically acceptable excipient.

31. A method for preparing a pharmaceutical composition, comprising mixing a compound according to any one of claims 1 to 29 or a pharmaceutically acceptable salt or solvate thereof with a pharmaceutically acceptable carrier.

32. A compound as claimed in any one of claims 1 to 29, or a pharmaceutically acceptable salt or solvate thereof, for use in a method of treatment of the human or animal body.

33. A compound according to any one of claims 1 to 29, or a pharmaceutically acceptable salt or solvate thereof, for use in a method for treating cancer or a neoplastic disease.

34. Use of a compound according to any one of claims 1 to 29 or a pharmaceutically acceptable salt or solvate thereof in the preparation of a medicament for treating cancer or a tumor disease.

35. A method of treating cancer in a patient in need thereof, comprising administering to the patient a compound of any one of claims 1-29, or a pharmaceutically acceptable salt or solvate thereof.

36. A method of treating cancer in a patient in need thereof, comprising administering to the patient a pharmaceutical composition comprising a compound as described in any one of claims 1-29, or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable excipient.

37. The use of claim 33 or 34, or the method of claim 35 or 36, wherein the cancer is selected from lung cancer, breast cancer, skin cancer, melanoma or leukemia.

38. A method of inhibiting MEK kinase comprising contacting the enzyme with a compound of any one of claims 1-29, wherein the MEK kinase is contacted in an in vitro environment.

39. A method of inhibiting MEK kinase comprising contacting the enzyme with a compound of any one of claims 1-29, wherein the MEK kinase is contacted in an in vivo environment.

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