MEK Inhibitors and Their Use

Abstract

The present disclosure provides MEK inhibitors, compositions thereof, and methods of using the same. Activation of the p42 / 44 MAPK signaling pathway, including mitogen-activated protein kinase / extracellular signal-regulated kinase (ERK) kinase (MEK)-ERK, has been implicated in the etiology and progression of various cancers. The MEK-ERK pathway is often activated by mutations in the upstream factors BRAF or Ras, or by signals from structurally activated cell surface receptors. Inhibition of MEK may be a promising strategy for controlling the growth of tumors, such as tumors associated with MEK pathway signaling.

Description

Technical Field

[0001] Cross - Reference to Related Applications This application claims the benefit of U.S. Provisional Application No. 63 / 488,807, filed on March 7, 2023; U.S. Provisional Application No. 63 / 479,131, filed on January 9, 2023; U.S. Provisional Application No. 63 / 375,875, filed on September 16, 2022; and U.S. Provisional Application No. 63 / 345,698, filed on May 25, 2022, the entire contents of each of which are hereby incorporated by reference herein.

[0002] The present disclosure relates to compounds and methods useful for inhibiting mitogen - activated protein kinase / extracellular signal - regulated kinase (MEK). The present disclosure also provides pharmaceutical compositions comprising the compounds of the present disclosure, and methods of using such compositions in the treatment of proliferative diseases such as cancer.

Background Art

[0003] Activation of the p42 / 44 MAPK signaling pathway, including mitogen - activated protein kinase / extracellular signal - regulated kinase (ERK) kinase (MEK) - ERK, has been implicated in the etiology and progression of various cancers. The MEK - ERK pathway is often activated by mutations in upstream factors BRAF or Ras, or by signals from structurally activated cell - surface receptors. Inhibition of MEK may be a promising strategy for controlling the growth of tumors, such as tumors associated with MEK pathway signaling.

Summary of the Invention

[0004] It has now been found that the compounds of the present disclosure, and pharmaceutical compositions thereof, are effective as MEK inhibitors.

[0005] In one aspect, the present disclosure provides a compound of formula (I):

Chemical Formula

[0006] In another aspect, the disclosure provides a compound of formula (II):

Chemical formula

[0007] Another disclosure of the invention provides a method for treating a MEK-mediated disorder in a subject. The method includes administering to a subject in need thereof a therapeutically effective amount of a compound described herein to treat a MEK-mediated disorder, as further described in the embodiments for carrying out the invention.

[0008] Another aspect of the disclosure provides a method for inhibiting MEK activity. The method includes contacting MEK or a KSR-MEK complex or a RAF-MEK complex with an effective amount of a compound described herein, as further described in the embodiments for carrying out the invention.

[0009] In some aspects, the compounds of the disclosure, and pharmaceutical compositions thereof, are useful for treating proliferative diseases such as cancer described herein.

Embodiments for Carrying Out the Invention

[0010] The compounds of the disclosure, and pharmaceutical compositions thereof, are useful as MEK inhibitors. Without wishing to be bound by any particular rationale, it is believed that the compounds of the disclosure can directly bind to the kinase suppressor of Ras (KSR) at the MEK interface, and KSR can remodel the prototype allosteric pocket of MEK inhibitors within the KSR-MEK complex. Without wishing to be bound by any particular rationale, it is believed that the compounds of the disclosure can bind to the KSR-MEK complex and disrupt the associated RAF-MEK complex.

[0011] I. Definitions When introducing elements of different aspects described in this specification, the articles "a", "an", "the", and "said" are intended to mean that one or more elements are present. The terms "comprising", "including", and "having" are intended to be inclusive and mean that additional elements other than the recited elements may exist.

[0012] Compounds of the present disclosure include those generally described herein and are further described by the classes, subclasses, and chemical species disclosed herein. Unless otherwise indicated, the following definitions apply when used herein. For the purposes of the present disclosure, chemical elements are identified according to the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 75 th Ed. Further, the general principles of organic chemistry are described in "Organic Chemistry", Thomas Sorrell, University Science Books, Sausalito: 1999, and "March’s Advanced Organic Chemistry", 5 th Ed., Ed.: Smith, M.B. and March, J., John Wiley & Sons, New York: 2001, the entire contents of which are incorporated herein by reference.

[0013] The term "aliphatic" or "aliphatic group", as used herein, means a straight-chain (i.e., unbranched) or branched-chain, substituted or unsubstituted hydrocarbon chain that is completely saturated, or has one or more unsaturated units, or is a monocyclic or bicyclic hydrocarbon that is completely saturated or contains one or more unsaturated units, but is not aromatic with a single point of attachment to the remainder of the molecule (also referred to herein as "carbocyclic", "alicyclic", or "cycloalkyl"). Unless otherwise specified, an aliphatic group contains from 1 to 6 aliphatic carbon atoms. In some embodiments, the aliphatic group contains from 1 to 5 aliphatic carbon atoms. In other embodiments, the aliphatic group contains from 1 to 4 aliphatic carbon atoms. In still other embodiments, the aliphatic group contains from 1 to 3 aliphatic carbon atoms, and in yet other embodiments, the aliphatic group contains from 1 to 2 aliphatic carbon atoms. In some embodiments, "alicyclic" (or "carbocyclic" or "cycloalkyl") means a monocyclic C3-C6 hydrocarbon that is completely saturated or contains one or more unsaturated units with a single point of attachment to the remainder of the molecule, but is not aromatic. Suitable aliphatic groups include, but are not limited to, straight-chain or branched, substituted or unsubstituted alkyl, alkenyl, alkynyl groups, and their hybrids, such as (cycloalkyl)alkyl, (cycloalkenyl)alkyl, or (cycloalkyl)alkenyl.

[0014] As used herein, the terms "bicyclic ring" or "bicyclic system" generally mean any bicyclic system, i.e., a carbocyclic or heterocyclic system, that is saturated or has one or more unsaturation units and has one or more atoms between two rings of the ring system. Thus, the term includes any acceptable ring fusion, such as ortho-fused or spirocyclic. As used herein, the term "heterobicyclic" is a subset of "bicyclic" where one or more heteroatoms must be present in one or both rings of the bicyclic. Such heteroatoms may be present at the ring junctions and may be substituted, and may be selected from nitrogen (including N-oxides), oxygen, sulfur (including oxidized forms such as sulfones and sulfonates), phosphorus (including oxidized forms such as phosphates), boron, etc. In some embodiments, the bicyclic group has from 7 to 12 ring members and from 0 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. As used herein, the term "bridged bicyclic" means any bicyclic system, i.e., a saturated or partially unsaturated carbocyclic or heterocyclic system having at least one bridge. As defined by IUPAC, a "bridge" is an acyclic chain of atoms, or an atom, or a valence bond that connects two bridgeheads, and a "bridgehead" is any skeletal atom of a ring system that is bonded to three or more skeletal atoms (excluding hydrogen). In some embodiments, the bridged bicyclic group has from 7 to 12 ring members and from 0 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. Such bridged bicyclic groups are well known in the art and include the groups described below, where each group is bonded to the remainder of the molecule at any substitutable carbon or nitrogen atom. Unless otherwise indicated, the bridged bicyclic group may be substituted with one or more of the substituents described for aliphatic groups. Further, or alternatively, any substitutable nitrogen of the bridged bicyclic group may be optionally substituted. Exemplary bicyclic rings include the following: [Chemical formula] Exemplary bridged bicyclics include the following: [Chemical formula]

[0015] The term "lower alkyl" means a C 1-4 linear or branched alkyl group. Exemplary lower alkyl groups are methyl, ethyl, isopropyl, butyl, isobutyl, and tert-butyl.

[0016] The term "lower haloalkyl" means a C 1-4 linear or branched alkyl group substituted by one or more halogen atoms.

[0017] The term "heteroatom" means one or more of oxygen, sulfur, nitrogen, phosphorus, or silicon (including any oxidized form of nitrogen, sulfur, phosphorus, or silicon; any quaternized form of any basic nitrogen; and any replaceable nitrogen of a heterocyclic ring, such as N (as in 3,4-dihydro-2H-pyrrolyl), NH (as in pyrrolidinyl), or NR + (as in N-substituted pyrrolidinyl)).

[0018] The term "unsaturated", as used in the present invention, means that the moiety has one or more unsaturated units.

[0019] As used herein, the term "divalent C 1-8 (or C 1-6 ) saturated or unsaturated, linear or branched hydrocarbon chain" means a linear or branched divalent alkylene, alkenylene, and alkynylene chain as defined herein.

[0020] The term "alkylene" means a divalent alkyl group. An "alkylene chain" is a polymethylene group, i.e., -(CH2) n -, where n is a positive integer, preferably 1 to 6, 1 to 4, 1 to 3, 1 to 2, or 2 to 3. A substituted alkylene chain is a polymethylene group in which one or more methylene hydrogen atoms are replaced by substituents. Suitable substituents include those described below as substituted aliphatic groups.

[0021] The term "alkenylene" means a divalent alkenyl group. A substituted alkenylene chain is a polymethylene group containing at least one double bond in which one or more hydrogen atoms are replaced by substituents. Suitable substituents include those described below as substituted aliphatic groups.

[0022] When used in the present invention, the term "cyclopropylenyl" has the following structure

Chemical formula

[0023] The term "halogen" means F, Cl, Br, or I.

[0024] The term "aryl", used alone or as part of a larger moiety such as in "aralkyl", "aralkoxy", or "aryloxyalkyl", means a monocyclic or bicyclic system having a total of 5 to 14 ring members, where at least one ring within the system is aromatic and each ring within the system contains 3 to 7 ring members. The term "aryl" may be used synonymously with the term "aryl ring". In certain embodiments of the present disclosure, "aryl" means an aromatic ring system including, but not limited to, phenyl, biphenyl, naphthyl, anthracyl, etc., and may have one or more substituents. The scope of the term "aryl" as used herein also includes groups in which the aromatic ring is fused to one or more non-aromatic rings, such as indanyl, phthalimidyl, naphthimidyl, phenanthridinyl, or tetrahydronaphthyl.

[0025] The terms "heteroaryl" and "heteroar-" used alone or as part of a larger moiety such as, for example, "heteroalkyl" or "heteroalkoxy" mean a group having 5 to 10 ring atoms, preferably 5, 6, or 9 ring atoms, having 6, 10 or 14 π electrons shared in a cyclic array, and having 1 to 5 heteroatoms in addition to carbon atoms. "Heteroatom" " means nitrogen, oxygen, or sulfur and includes any oxidized form of nitrogen or sulfur and any quaternized form of basic nitrogen. Examples of heteroaryl groups include, but are not limited to, thienyl, furanyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolizinyl, purinyl, naphthyridinyl, and pteridinyl. As used herein, the terms "heteroaryl" and "heteroar-" include groups in which a heteroaromatic ring is fused to one or more aryl, cycloaliphatic, or heterocyclyl rings and the radical or point of attachment is on the heteroaromatic ring. Non-limiting examples include indolyl, isoindolyl, benzothienyl, benzofuranyl, dibenzofuranyl, indazolyl, benzimidazolyl, benzothiazolyl, quinolyl, isoquinolyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, 4H-quinolizinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl, phenoxazinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, and pyrido[2,3-b]-1,4-oxazin-3(4H)-one. The heteroaryl group may be monocyclic or bicyclic. The term "heteroaryl" may be used in the same sense as the terms "heteroaryl ring", "heteroaryl group", or "heterocyclic aromatic compound", all of which include rings which may be substituted. The term "heteroalkyl" means an alkyl group substituted by heteroaryl, and the alkyl and heteroaryl moieties are independently optionally substituted.

[0026] As used herein, the terms "heterocyclic ring", "heterocyclyl", "heterocyclic radical", and "heterocyclic ring" are used interchangeably and mean a stable 5- to 7-membered monocyclic or 7- to 10-membered bicyclic heterocyclic moiety that is either saturated or partially unsaturated and that, in addition to carbon atoms, has one or more, e.g., 1 to 4, of the heteroatoms as defined above. When used with respect to the ring atoms of a heterocyclic ring, the term "nitrogen" includes substituted nitrogen. By way of example, in a saturated or partially unsaturated ring having from 0 to 3 heteroatoms selected from oxygen, sulfur or nitrogen, nitrogen can be N (such as in 3,4-dihydro-2H-pyrrolyl), NH (such as in pyrrolidinyl), or NR + (such as in N-substituted pyrrolidinyl).

[0027] A heterocyclic ring can be attached by any heteroatom or carbon atom to its pendant group, thereby providing a stable structure, and any of the ring atoms can optionally be substituted. Examples of such saturated or partially unsaturated heterocyclic radicals include, but are not limited to, tetrahydrofuranyl, tetrahydrothiophenyl, pyrrolidinyl, piperidinyl, pyrrolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, decahydroquinolinyl, oxazolidinyl, piperazinyl, dioxanyl, dioxolanyl, diazepinyl, oxazepinyl, thiazepinyl, morpholinyl, and quinuclidinyl. The terms "heterocyclic ring", "heterocyclyl", "heterocyclyl ring", "heterocyclic group", "heterocyclyl moiety", and "heterocyclic radical" are used interchangeably herein, and a heterocyclyl ring includes groups fused to one or more aryl, heteroaryl, or cycloaliphatic rings, e.g., indolinyl, 3H-indolyl, chromanyl, phenanthridinyl, or tetrahydroquinolinyl. A heterocyclyl group can be monocyclic or bicyclic. The term "heterocyclylalkyl" means an alkyl group substituted by a heterocyclyl, and the alkyl and heterocyclyl moieties can be independently optionally substituted.

[0028] As used herein, the term "partially unsaturated" relates to a ring moiety containing at least one double or triple bond. The term "partially unsaturated" is intended to encompass rings having multiple sites of unsaturation, but is not intended to include aryl or heteroaryl moieties as defined herein.

[0029] As described herein, the compounds of the present disclosure may contain "optionally substituted" moieties. In general, the term "substituted", whether preceded by the term "optionally", means that one or more hydrogens of the designated moiety are replaced with a suitable substituent. Unless otherwise specified, an "optionally substituted" group can have suitable substituents at each substitutable position of the group, and when more than one position in any given structure can be substituted with more than one substituent selected from a particular group, the substituents can be the same or different at all positions. Combinations of substituents contemplated by the present disclosure preferably result in the formation of stable or chemically suitable compounds. As used herein, the term "stable" relates to a compound that does not substantially change when subjected to the conditions that allow for its production, detection, and in certain embodiments, its recovery, purification, and use for one or more of the purposes provided by the present disclosure.

[0030] On a substitutable carbon, each optional substituent is halogen; -(CH2) 0-4 R°; -(CH2) 0-4 OR°; -O(CH2) 0-4 R°, -O-(CH2) 0-4 C(O)OR°; -(CH2) 0-4 CH(OR°)2; -(CH2) 0-4 SR°; optionally substituted with R° -(CH2) 0-4 Ph; optionally substituted with R° -(CH2) 0-4 O(CH2) 0-1-CH=CHPh which may be substituted with Ph;R°; -(CH2) which may be substituted with Ph;R° 0-4 O(CH2) 0-1 -pyridyl; -NO2; -CN; -N3; -(CH2) 0-4 N(R°)2; -(CH2) 0-4 N(R°)C(O)R°; -N(R°)C(S)R°; -(CH2) 0-4 N(R°)C(O)NR°2; -N(R°)C(S)NR°2; -(CH2) 0-4 N(R°)C(O)OR°; -N(R°)N(R°)C(O)R°; -N(R°)N(R°)C(O)NR°2; -N(R°)N(R°)C(O)OR°; -(CH2) 0-4 C(O)R°; -C(S)R°; -(CH2) 0-4 C(O)OR°; -(CH2) 0-4 C(O)SR°; -(CH2) 0-4 C(O)OSiR°3; -(CH2) 0-4 OC(O)R°; -OC(O)(CH2) 0-4 SR-; SC(S)SR°; -(CH2) 0-4 SC(O)R°; -(CH2) 0-4 C(O)NR°2; -C(S)NR°2; -C(S)SR°; -SC(S)SR°; -(CH2) 0-4 OC(O)NR°2; -C(O)N(OR°)R°; -C(O)C(O)R°; -C(O)CH2C(O)R°; -C(NOR°)R°; -(CH2) 0-4 SSR°; -(CH2) 0-4 S(O)2R°; -(CH2) 0-4 S(O)2OR°; -(CH2) 0-4 OS(O)2R°; -S(O)2NR°2; -S(O)(NR°)R°; -S(O)2N=C(NR°2)2; -(CH2) 0-4 S(O)R°; -N(R°)S(O)2NR°2; -N(R°)S(O)2R°; -N(OR°)R°; -C(NH)NR°2; -P(O)2R°; -P(O)R°2; -OP(O)R°2; -OP(O)(OR°)2; SiR°3; -(C 1-4 linear or branched alkylene)O-N(R°)2; or, -C( 1-4It is a monovalent substituent independently selected from (linear or branched alkylene)C(O)O-N(R°2).

[0031] Each R° is independently hydrogen, C 1-6 aliphatic, -CH2Ph, -O(CH2) 0-1 Ph, -CH2-(5- to 6-membered heteroaryl ring), or a 5- to 6-membered ring saturated, partially unsaturated, or aryl ring having 0 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or, regardless of the above definition, two independent occurrences of R° together with the intervening atom(s) form a 3- to 12-membered saturated, partially unsaturated, or aryl monocyclic or bicyclic ring having 0 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, and may be substituted on the saturated carbon atom of R° by a divalent substituent selected from =O and =S, or each R° is halogen, -(CH2) 0-2 R ● -, -(haloR ● ), -(CH2) 0-2 OH, -(CH2) 0-2 OR ● -, -(CH2) 0-2 CH(OR ● )2; O(haloR ● ), -CN, -N3, -(CH2) 0-2 C(O)R ● -, -(CH2) 0-2 C(O)OH, -(CH2) 0-2 C(O)OR ● -, -(CH2) 0-2 SR ● -, -(CH2) 0-2 SH, -(CH2) 0-2 NH2, -(CH2) 0-2 NHR ● -, -(CH2) 0-2 NR ● 2, -NO2, -SiR ● 3, -OSiR ● 3, -C(O)SR ● -, -(C 1-4 linear or branched alkylene)C(O)OR ● , or -SSR ●It may be substituted with a monovalent substituent independently selected therefrom.

[0032] Each R ● is C 1-4 aliphatic, -CH2Ph, -O(CH2) 0-1 Ph, or independently selected from a 5- to 6-membered saturated, partially unsaturated, or aryl ring having 0 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, and each R ● is unsubstituted or, where "halo" precedes, is substituted only by one or more halogens, or any substituent on a saturated carbon is =O, =S, =NNR * 2, =NNHC(O)R * 、=NNHC(O)OR * 、=NNHS(O)2R * 、=NR * 、=NOR * 、-O(C(R * 2)) 2-3 O-, or -S(C(R * 2)) 2-3 S- is a divalent substituent independently selected therefrom, or the divalent substituent bond to adjacent substitutable carbons in a "may be substituted" group is -O(CR * 2) 2-3 O-, and each independent occurrence of R 2 is selected from hydrogen, C 1-6 aliphatic, or an unsubstituted 5- to 6-membered saturated, partially unsaturated, or aryl ring having 0 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0033] R * When R 1-6 is C * aliphatic, R ● is halogen, -R ● 、-(haloR ● )、-OH、-OR ● )、-CN、-C(O)OH、-C(O)OR ● 、-NH2、-NHR ● 、-NR ●2. Optionally substituted with -NO2, where each R ● is C 1-4 aliphatic, -CH2Ph, -O(CH2) 0-1 Ph, or independently selected from a 5- to 6-membered saturated, partially unsaturated, or aryl ring having 0 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, and each R ● is unsubstituted or, where "halo" precedes, substituted only by one or more halogens.

[0034] Any substituent on a nitrogen that can be substituted is independently -R † , -NR † 2, -C(O)R † , -C(O)OR † , -C(O)C(O)R † , -C(O)CH2C(O)R † , -S(O)2R † , S(O)2NR † 2, -C(S)NR † 2, -C(NH)NR † , or -N(R † )S(O)2R † , where each R † is independently hydrogen, C1-C6 aliphatic, unsubstituted -OPh, or a 5- to 6-membered saturated, partially unsaturated, or aryl ring having 0 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or two independent occurrences of R † , together with the intervening atom(s), form an unsubstituted 3- to 12-membered saturated, partially unsaturated, or aryl mono- or bicyclic ring having 0 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, where, when R † is C 1 -C6 aliphatic, R † is halogen, -R ● , -(haloR ● ), -OH, -OR ● , -O(haloR ● ), -CN, -C(O)OH, -C(O)OR ● , -NH2, -NHR ● , -NR●2 or may be substituted with -NO2, wherein each R ● is C 1-4 aliphatic, -CH2Ph, -O(CH2) 0-1 Ph, or is independently selected from a 5- to 6-membered saturated, partially unsaturated, or aryl ring having 0 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, and each R ● is unsubstituted or, where "halo" precedes, is substituted only by one or more halogens.

[0035] In some embodiments, "alkyl," used alone or as part of a group, means a saturated monovalent hydrocarbon radical having a straight or branched hydrocarbon chain, or, when at least three carbon atoms are present, a cyclic hydrocarbon or combinations thereof, having from 1 to 20 carbon atoms (C1-C 20 alkyl), from 1 to 10 carbon atoms (C1-C 10 alkyl), from 1 to 8 carbon atoms (C1-C8 alkyl), from 1 to 6 carbon atoms (C1-C6 alkyl), or from 1 to 4 carbon atoms (C1-C4 alkyl). In some embodiments, examples of alkyl radicals include methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isoamyl, hexyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like.

[0036] In some embodiments, "alkoxy" means -O-(alkyl), where "alkyl" is as defined above.

[0037] In some embodiments, "cycloalkyl," used alone or in combination, means a saturated or partially saturated monocyclic, bicyclic, or tricyclic alkyl radical, where each cyclic moiety contains from 3 to 8 carbon atoms, or from 3 to 6 carbon atoms. In some embodiments, examples of cycloalkyl radicals include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like.

[0038] In some embodiments, the halogen or halo is F, Cl, Br, or I.

[0039] As used herein, the term "pharmaceutically acceptable salt" refers to those salts which, within the scope of sound medical judgment, are suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response, etc., and which are commensurate with a reasonable benefit / risk ratio. Pharmaceutically acceptable salts are well known in the art. For example, S.M. Berge et al. describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 1977, 66, 1-19, which is incorporated herein by reference. Pharmaceutically acceptable salts of the compounds of the present disclosure include those derived from suitable inorganic and organic acids and bases. Examples of pharmaceutically acceptable non-toxic acid addition salts are salts of amino groups formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid, or with organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid, or formed by other methods used in the art such as ion exchange. Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, laurylsulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate, etc.

[0040] Suitable salts derived from appropriate bases include alkali metals, alkaline earth metals, ammonium, and N + (C1-C4 alkyl)4 salts. Exemplary alkali metal salts or alkaline earth metal salts include sodium salts, lithium salts, potassium salts, calcium salts, magnesium salts, and the like. Further, pharmaceutically acceptable salts include, where appropriate, non-toxic ammonium, quaternary ammonium, and amine cations formed using counterions such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, lower alkyl sulfonates, and aryl sulfonates.

[0041] Unless otherwise specified, the structures described herein also intend to include all structural isomers (e.g., enantiomers, diastereomers, and geometric isomers (or conformational isomers)), e.g., R and S configurations for each chiral center, Z and E double bond isomers, and Z and E conformational isomers. Thus, in addition to individual stereoisomers, mixtures of enantiomers, diastereomers, and geometric isomers (or conformational isomers) of the compounds of the present invention are within the scope of this disclosure. Unless otherwise specified, all tautomeric forms of the compounds of this disclosure are within the scope of this disclosure. Further, unless otherwise specifically specified, the structures described herein also intend to include compounds that differ only in the presence of one or more isotope-enriched atoms. For example, compounds having such structures that include hydrogen exchange with deuterium or tritium, or 13 C or 14 carbon exchange with C-enriched carbon are within the scope of this disclosure. Such compounds are useful, for example, as analytical tools according to this disclosure, as probes in biological assays, or as therapeutic agents.

[0042] As used herein, the term "compounds provided" refers to any genus, subgenus, and / or species of MEK inhibitor described herein.

[0043] As used herein, the terms "inhibitor", or "MEK inhibitor", or "MEK antagonist" are defined as compounds that have a measurable affinity for, bind to, and / or inhibit MEK. In some embodiments, inhibition in the presence of a MEK inhibitor or MEK antagonist is observed in a dose-dependent manner. In some embodiments, the measured signal (e.g., signaling activity or biological activity) is at least about 5%, at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or at least 100% lower than the signal measured using a negative control under similar conditions. The ability of an inhibitor is typically defined by its IC 50 value (half maximal inhibitory concentration, i.e., the concentration required to inhibit 50% of the agonist response). The lower the IC 50 value, the higher the ability of the antagonist and the lower the concentration required to inhibit the maximal biological response. In certain embodiments, the inhibitor has an IC 50 and / or binding constant of less than about 100 μM, less than about 50 μM, less than about 1 μM, less than about 500 nM, less than about 100 nM, less than about 10 nM, or less than about 1 nM.

[0044] As used in this disclosure, the terms "measurable affinity" and "measurably inhibit" mean a measurable change or inhibition of MEK activity in a sample containing MEK and a compound or composition thereof of the invention, compared to an equivalent sample containing MEK in the absence of the compound or composition thereof.

[0045] As used herein, the term "effective amount" refers to an amount of a compound sufficient to produce a beneficial or desired result, such as a therapeutic, alleviating, inhibiting, or prophylactic result. The effective amount can be administered in one or more administrations, applications, or dosages and is not intended to be limited to a particular formulation or route of administration.

[0046] As used herein, the term "treat" includes any effect, such as reducing, lessening, modulating, improving, or eliminating, or ameliorating the symptoms thereof, that results in the improvement of a condition, disease, disorder, etc. In some embodiments, treatment can be administered after one or more symptoms have developed. In other embodiments, treatment can be administered in the absence of symptoms. For example, treatment can be administered to a susceptible individual prior to the onset of symptoms (e.g., as determined from the perspective of a history of symptoms and / or genetic or other susceptibility factors). Treatment can also be continued after symptoms have resolved, for example, to prevent or delay their recurrence.

[0047] As used herein, the term "MEK-mediated disorder", or "MEK-mediated disease", or "disease or disorder associated with MEK" refers to a disease or disorder associated with or mediated by MEK or MEK activity. Non-limiting examples of diseases or disorders mediated by MEK are MEK-mediated cancers.

[0048] As used herein, the term "pharmaceutical composition" refers to a combination of an active agent with an inert or active carrier that renders the composition essentially suitable for diagnostic or therapeutic use in vivo or ex vivo.

[0049] As used herein, the term "pharmaceutically acceptable carrier" means any of the standard pharmaceutical carriers such as phosphate buffered saline aqueous solution, water, emulsion (e.g., o / w or w / o emulsion), and various kinds of wetting agents. The composition can also contain stabilizers and preservatives. For examples of carriers, stabilizers and adjuvants, see, for example, Martin, Remington’s Pharmaceutical Sciences, 15th Ed., Mack Publ. Co., Easton, PA

[1975] .

[0050] As used herein, a "non-ATP-competitive" or "ATP non-competitive" MEK inhibitor refers to an inhibitor of MEK that does not bind in the ATP pocket of MEK, does not displace ATP from the active site of MEK, and can form a direct contact when binding simultaneously to the MEK-ATP complex. Non-ATP-competitive inhibition by the compounds of the present disclosure can be confirmed by methods recognized in the art such as enzyme chemistry studies, competitive assays, biophysical methods, including X-ray co-crystallography. Exemplary non-ATP-competitive inhibitors of the present disclosure have an IC 50 inhibiting recombinant MEK1 or MEK2 in the range of about 1 nM to about 50 μM. In some embodiments, exemplary non-ATP-competitive inhibitors of the present disclosure have an IC 50 inhibiting recombinant MEK1 or MEK2 in the range of about 1 nM to about 1000 nM, about 1 μM to about 50 μM, about 1 μM to about 25 μm, about 1 μM to about 10 μM, about 500 nM to about 5 μM, or about 10 nM to about 500 nM.

[0051] As used herein, "inhibitor pocket" refers to a structure formed at the interface of the interaction between MEK and KSR or BRAF or CRAF, which is involved by the inhibitor of the present disclosure.

[0052] As used herein, a compound of the present disclosure "binds allosterically to the inhibitor pocket" when the compound binds outside the active site, for example, outside or near the ATP binding site of the kinase.

[0053] As used herein, the term "inhibitor-inhibitor pocket complex" describes a species in which an inhibitor of the present disclosure binds allosterically to an inhibitor pocket formed at the interaction interface of human MEK (MEK1 or MEK2) and a human kinase suppressor of Ras (KSR1, KSR2, or the BRAF or CRAF KSR homolog) adjacent to ATP in the physiological complex of MEK and KSR.

[0054] As used herein, the term "trapping" means when an inhibitor of the present disclosure binds to and stabilizes the CRAF-MEK complex in an inactive conformation.

[0055] As used herein, when a moiety of an inhibitor "engages" with an amino acid residue of MEK and / or KSR and / or BRAF or CRAF within an inhibitor pocket, this interaction can be detected by X-ray crystallography, or by similar structural methods such as cryo-electron microscopy, NMR, or in silico docking including fragment linking and computational simulations, which indicate that the interaction defining the engagement is a separation between the inhibitor moiety and the amino acid residue of about 8 Å or less, including, for example, from about 2 Å to about 5 Å, or from 5 Å to about 8 Å. The distances provided herein can imply the inclusion of hydrogen atoms; however, hydrogen atoms are not included in current crystal models and this is appropriate except when the crystal diffracts at a very high resolution (i.e., higher than 1.5 angstroms). A literature search of drug-receptor atoms spanning all structures in the Protein Data Bank used a cutoff distance of 4-5 angstroms (PMID 29308120, 26517868, 19221587) to investigate reasonable low molecular weight hydrophobic binding interactions and found that intermolecular carbon-carbon interactions, similar to trametinib-KSR contacts, are the most frequently shown drug-receptor atoms in the Protein Data Bank. With respect to the interaction of the inhibitors of the present disclosure with the MEK-KSR and / or BRAF or CRAF complexes, based on the nature of the trametinib-KSR interaction and the nature of the precedence of known drug-receptor complexes, a contact of 4 angstroms is reasonable. This contact is within the range of known contacts defined by several independent groups (PMID 29308120, 26517868, 19221587).

[0056] II. Description of the Compounds In one aspect, the present disclosure provides a compound of formula (I):

Chemical formula

Chemical formula

Chemical formula

[0057] In some embodiments, the disclosure provides a compound of formula (I):

Chemical formula

Chemical formula

Chemical formula

[0058] Generally as defined above, X 1 , X 2 , X 3 and X 5 are independently CR 1 or N. In some embodiments, X 1 , X 2 , X 3 and X 5 are CR 1 In some embodiments, X 1 , X 3 and X 5 are CR 1 and X 2 is N. Generally as defined above, R 1 are independently hydrogen, halo, optionally substituted C1-C6 aliphatic, optionally substituted C1-C6 alkoxy, optionally substituted C3-C 10 cycloalkyl, optionally substituted C6-C 10 heterocycloalkyl, and optionally substituted C6-C 10 aryl. In some embodiments, R 1 is hydrogen, halo, or optionally substituted C1-C6 alkoxy. In some embodiments, R 1 is hydrogen, chloro, fluoro, methoxy, ethoxy, propoxy, ethoxy, or hexyloxy. In some embodiments, R 1 is hydrogen, fluoro, chloro, or methoxy.

[0059] Generally as defined above, each

Chemical formula

[0060] Generally as defined above, each A is independently,

Chem.

Chem.

[0061] In some embodiments, each A is independently an optionally substituted 5- to 6-membered heteroaryl. In some embodiments, each A is independently an optionally substituted 5- or 6-membered heteroaryl. In some embodiments, each A is independently an optionally substituted 5-membered heteroaryl. In some embodiments, each A is an optionally substituted imidazole. In some embodiments, each A is,

Chem.

[0062] Generally as defined above, X 6 is O or NH. In some embodiments, X 6 is O. In some embodiments, X6 is NH. In some embodiments, X 6 is C(O).

[0063] Generally, as defined above, X 7 is CH or N. In some embodiments, X 7 is CH. In some embodiments, X 7 is N.

[0064] Generally, as defined above, each R 1 is independently hydrogen, halo, optionally substituted C1-C6 aliphatic, optionally substituted C1-C6 alkoxy, optionally substituted C3-C 10 cycloalkyl, optionally substituted C6-C 10 heterocycloalkyl, or optionally substituted C6-C 10 aryl, and in some embodiments, R 1 is halo. In some embodiments, R 1 is fluoro, chloro, iodo, -OCF3, cyclopropyl, -CF3, or ethyne. In some embodiments, R 1 is fluoro or iodo. In some embodiments, R 1 is -CN.

[0065] Generally, as defined above, each R 1 is independently hydrogen, deuterium, halo, optionally substituted C1-C6 aliphatic, optionally substituted C1-C6 alkoxy, optionally substituted C3-C 10 cycloalkyl, optionally substituted C6-C 10 heterocycloalkyl, or optionally substituted C6-C 10 aryl, and in some embodiments, R 1 is halo. In some embodiments, R 1 is fluoro, chloro, iodo, -OCF3, cyclopropyl, -CF3, or ethyne. In some embodiments, R 1 is fluoro or iodo. In some embodiments, R 1 is -CN.

[0066] Generally, as defined above, R 2 is hydrogen, halo, optionally substituted C1-C6 aliphatic, optionally substituted C1-C6 alkoxy, optionally substituted C3-C 10 cycloalkyl, optionally substituted C6-C 10 heterocycloalkyl, or optionally substituted C6-C 10 aryl. In some embodiments, R 2 is optionally substituted C1-C6 aliphatic. In some embodiments, R 2 is methyl, ethyl, propyl, pentyl, butyl, or hexyl. In some embodiments, R 2 is methyl.

[0067] Generally, as defined above, R 2 is hydrogen, C( 2 D)3, OC( 2 D)3, halo, optionally substituted C1-C6 aliphatic, optionally substituted C1-C6 alkoxy, optionally substituted C3-C 10 cycloalkyl, optionally substituted C6-C 10 heterocycloalkyl, or optionally substituted C6-C 10 aryl. In some embodiments, R 2 is optionally substituted C1-C6 aliphatic. In some embodiments, R 2 is methyl, ethyl, propyl, pentyl, butyl, or hexyl. In some embodiments, R 2 is methyl.

[0068] Generally, as defined above, R 3 is hydrogen, optionally substituted C1-C6 aliphatic, optionally substituted C1-C6 alkoxy, optionally substituted C3-C 10 cycloalkyl, optionally substituted C6-C 10 heterocycloalkyl, and optionally substituted C6-C 10 aryl. In some embodiments, R 3 is optionally substituted C3-C10 is cycloalkyl. In some embodiments, R 3 is optionally substituted C3-C8 cycloalkyl. In some embodiments, R 3 is optionally substituted C3-C6 cycloalkyl. In some embodiments, R 3 is cyclopropyl, cyclopentyl, cyclobutyl, or cyclohexyl. In some embodiments, R 3 is cyclopropyl, or optionally substituted cyclopropyl. In some embodiments, R 3 is cyclopropyl. In some embodiments, R 3 is -(C3H3)F2.

[0069] Generally as defined above, R 4 is hydrogen, optionally substituted C1-C6 aliphatic, optionally substituted C1-C6 alkoxy, optionally substituted C3-C 10 cycloalkyl, optionally substituted C6-C 10 heterocycloalkyl, and optionally substituted C6-C 10 aryl. In some embodiments, R 4 is optionally substituted C1-C6 aliphatic. In some embodiments, R 4 is methyl, ethyl, propyl, pentyl, butyl, or hexyl. In some embodiments, R 4 is methyl. In some embodiments, R 4 is CF3.

[0070] Generally as defined above, R 4 is hydrogen, C( 2 D)3, OC( 2 D)3, optionally substituted C1-C6 aliphatic, optionally substituted C1-C6 alkoxy, optionally substituted C3-C 10 cycloalkyl, optionally substituted C6-C 10 heterocycloalkyl, and optionally substituted C6-C 10 aryl. In some embodiments, R 4is an optionally substituted C1-C6 aliphatic. In some embodiments, R 4 is methyl, ethyl, propyl, pentyl, butyl, or hexyl. In some embodiments, R 4 is methyl. In some embodiments, R 4 is CF3.

[0071] Generally as defined above, R 5 is hydrogen, an optionally substituted C1-C6 aliphatic, an optionally substituted C1-C6 alkoxy, an optionally substituted C3-C 10 cycloalkyl, an optionally substituted C6-C 10 heterocycloalkyl, and an optionally substituted C6-C 10 aryl. In some embodiments, R 5 is hydrogen, an optionally substituted C1-C6 aliphatic, or an optionally substituted C1-C6 alkoxy. In some embodiments, R 5 is hydrogen. In some embodiments, when X 7 is N which forms a double bond with a sulfur atom, R 5 is absent.

[0072] Generally as defined above, each R 6 is independently hydrogen, an optionally substituted C1-C6 aliphatic, an optionally substituted C1-C6 alkoxy, an optionally substituted C3-C 10 cycloalkyl, an optionally substituted C6-C 10 heterocycloalkyl, or an optionally substituted C6-C 10 aryl, or both R 6 together with the atom to which they are attached form a 3- to 7-membered heterocycloalkyl ring, or R 5 and R 6 together with the atom to which they are attached form a 5- to 6-membered heterocycloalkyl ring.

[0073] In some embodiments, each R 6 is independently hydrogen, or an optionally substituted C1-C6 aliphatic. In some embodiments, each R6 is independently hydrogen, methyl, or -(CH2)2N(CH3)2.

[0074] In some embodiments, both Rs 6 together with the atoms to which they are attached form a 3- to 7-membered heterocycloalkyl ring. In some embodiments, both Rs 6 together with the atoms to which they are attached form a 3-, 4-, 5-, 6-, or 7-membered heterocycloalkyl ring.

[0075] In some embodiments, R 5 and R 6 together with the atoms to which they are attached form a 5- to 6-membered heterocycloalkyl ring. In some embodiments, R 5 and R 6 together with the atoms to which they are attached form a 5- or 6-membered heterocycloalkyl ring. In some embodiments, R 5 and R 6 together with the atoms to which they are attached form a 5-membered heterocycloalkyl ring.

[0076] In some embodiments, R 5 , and X 5 or X 3 together with the atoms to which they are attached form a 5- to 6-membered fused heterocycloalkyl ring.

[0077] In some embodiments, R 5 , and X 5 or X 3 together with the atoms to which they are attached form a 5- to 6-membered fused aromatic heterocyclic ring.

[0078] In some embodiments, R 6 , and X 5 or X 3 together with the atoms to which they are attached form a 5- to 6-membered fused heterocycloalkyl ring.

[0079] Generally, as defined above, R 7is O, or an optionally substituted C1-C6 aliphatic. In some embodiments, R 7 is O. In some embodiments, R 7 is an optionally substituted C1-C6 aliphatic. In some embodiments, R 7 is methyl.

[0080] Generally as defined above, R 8 is absent, hydrogen, or an optionally substituted C1-C6 aliphatic. In some embodiments, R 8 is hydrogen or methyl.

[0081] Generally as defined above, R 8 is absent, hydrogen, deuterium, or an optionally substituted C1-C6 aliphatic. In some embodiments, R 8 is hydrogen or methyl.

[0082] In another aspect, the present disclosure provides a compound of formula (IA):

Chemical formula

Chemical formula

[0083] In another aspect, the present disclosure provides a compound of formula (IA): [Chemical formula] or a pharmaceutically acceptable salt thereof, wherein each [Chemical formula] is independently a single bond or a double bond, X 1 X 2 X 3 and X 5 are independently CR 1 or N, X 6 is C(O), O, or NH, X 7 is CH or N, X 8 is N or O, each R 1 is independently hydrogen, deuterium, halo, optionally substituted C1-C6 aliphatic, optionally substituted C1-C6 alkoxy, optionally substituted C3-C 10 cycloalkyl, optionally substituted C6-C 10 heterocycloalkyl, or optionally substituted C6-C 10 aryl, R 2 R 3 R 4 and R 5 are independently hydrogen, halo, C( 2 D)3, OC( 2 D)3, optionally substituted C1-C6 aliphatic, optionally substituted C1-C6 alkoxy, optionally substituted C3-C 10 cycloalkyl, optionally substituted C6-C 10 heterocycloalkyl, or optionally substituted C6-C 10 aryl, each R 6 is independently hydrogen, deuterium, C( 2 D)3, optionally substituted C1-C6 aliphatic, optionally substituted C1-C6 alkoxy, optionally substituted C3-C10 Cycloalkyl, optionally substituted C6-C 10 Heterocycloalkyl, or optionally substituted C6-C 10 is aryl, or both R 6 together with the atoms to which they are attached form an optionally substituted 3- to 7-membered heterocycloalkyl ring, or R 5 and R 6 together with the atoms to which they are attached form a 5- to 6-membered heterocycloalkyl ring, or R 5 , and X 5 or X 3 together with the atoms to which they are attached form a 5- to 6-membered fused heterocycloalkyl ring, and R 6 , and X 5 or X 3 together with the atoms to which they are attached form a 5- to 6-membered fused heterocycloalkyl ring, and R 7 is O, or optionally substituted C1-C6 aliphatic, and R 8 is absent, hydrogen, deuterium, or optionally substituted C1-C6 aliphatic.

[0084] Generally as defined above, X 1 , X 2 , X 3 , and X 5 are independently CR 1 or N. In some embodiments, X 1 , X 2 , X 3 , and X 5 are CR 1 . In some embodiments, X 1 , X 3 , and X 5 are CR 1 , and X 2 is N. Generally as defined above, R 1 are independently hydrogen, halo, optionally substituted C1-C6 aliphatic, optionally substituted C1-C6 alkoxy, optionally substituted C3-C10 Cycloalkyl, optionally substituted C6-C 10 heterocycloalkyl, and optionally substituted C6-C 10 is aryl. In some embodiments, R 1 is hydrogen, halo, or optionally substituted C1-C6 alkoxy. In some embodiments, R 1 is hydrogen, chloro, fluoro, methoxy, ethoxy, propoxy, ethoxy, or hexyloxy. In some embodiments, R 1 is hydrogen, fluoro, chloro, or methoxy.

[0085] Generally as defined above, each

Chemical formula

[0086] Generally as defined above, X 6 is O or NH. In some embodiments, X 6 is O. In some embodiments, X 6 is NH. In some embodiments, X 6 is C(O).

[0087] Generally as defined above, X 7 is CH or N. In some embodiments, X 7 is CH. In some embodiments, X 7 is N.

[0088] Generally as defined above, X 8 is N or O. In some embodiments, X 8 is N. In some embodiments, X 8 is O. In some embodiments, X 8 is N, and R 3 and R 8 together with the N atom to which they are attached form an optionally substituted 3- to 7-membered heterocycloalkyl ring.

[0089] Generally, as defined above, each R 1 is independently hydrogen, halo, optionally substituted C1-C6 aliphatic, optionally substituted C1-C6 alkoxy, optionally substituted C3-C 10 cycloalkyl, optionally substituted C6-C 10 heterocycloalkyl, or optionally substituted C6-C 10 aryl, and in some embodiments, R 1 is halo. In some embodiments, R 1 is fluoro, chloro, iodo, -OCF3, cyclopropyl, -CF3, or ethyne. In some embodiments, R 1 is fluoro or iodo. In some embodiments, R 1 is -CN.

[0090] Generally, as defined above, each R 1 is independently hydrogen, deuterium, halo, optionally substituted C1-C6 aliphatic, optionally substituted C1-C6 alkoxy, optionally substituted C3-C 10 cycloalkyl, optionally substituted C6-C 10 heterocycloalkyl, or optionally substituted C6-C 10 aryl, and in some embodiments, R 1 is halo. In some embodiments, R 1 is fluoro, chloro, iodo, -OCF3, cyclopropyl, -CF3, or ethyne. In some embodiments, R 1 is fluoro or iodo. In some embodiments, R 1 is -CN.

[0091] Generally, as defined above, R 2 is hydrogen, halo, optionally substituted C1-C6 aliphatic, optionally substituted C1-C6 alkoxy, optionally substituted C3-C 10 cycloalkyl, optionally substituted C6-C 10 heterocycloalkyl, or optionally substituted C6-C 10It is aryl. In some embodiments, R 2 is optionally substituted C1-C6 aliphatic. In some embodiments, R 2 is methyl, ethyl, propyl, pentyl, butyl, or hexyl. In some embodiments, R 2 is methyl.

[0092] Generally as defined above, R 2 is hydrogen, halo, C( 2 D)3, OC( 2 D)3, optionally substituted C1-C6 aliphatic, optionally substituted C1-C6 alkoxy, optionally substituted C3-C 10 cycloalkyl, optionally substituted C6-C 10 heterocycloalkyl, or optionally substituted C6-C 10 aryl. In some embodiments, R 2 is optionally substituted C1-C6 aliphatic. In some embodiments, R 2 is methyl, ethyl, propyl, pentyl, butyl, or hexyl. In some embodiments, R 2 is methyl.

[0093] Generally as defined above, R 3 is hydrogen, optionally substituted C1-C6 aliphatic, optionally substituted C1-C6 alkoxy, optionally substituted C3-C 10 cycloalkyl, optionally substituted C6-C 10 heterocycloalkyl, and optionally substituted C6-C 10 aryl. In some embodiments, R 3 is optionally substituted C3-C 10 cycloalkyl. In some embodiments, R 3 is optionally substituted C3-C8 cycloalkyl. In some embodiments, R 3 is optionally substituted C3-C6 cycloalkyl. In some embodiments, R 3 is cyclopropyl, cyclopentyl, cyclobutyl, or cyclohexyl. In some embodiments, R3 is cyclopropyl, or optionally substituted cyclopropyl. In some embodiments, R 3 is cyclopropyl. In some embodiments, R 3 is -(C3H3)F2.

[0094] Generally as defined above, R 4 is hydrogen, optionally substituted C1-C6 aliphatic, optionally substituted C1-C6 alkoxy, optionally substituted C3-C 10 cycloalkyl, optionally substituted C6-C 10 heterocycloalkyl, and optionally substituted C6-C 10 aryl. In some embodiments, R 4 is optionally substituted C1-C6 aliphatic. In some embodiments, R 4 is methyl, ethyl, propyl, pentyl, butyl, or hexyl. In some embodiments, R 4 is methyl. In some embodiments, R 4 is CF3. Generally as defined above, R 4 is hydrogen, C( 2 D)3, OC( 2 D)3, optionally substituted C1-C6 aliphatic, optionally substituted C1-C6 alkoxy, optionally substituted C3-C 10 cycloalkyl, optionally substituted C6-C 10 heterocycloalkyl, and optionally substituted C6-C 10 aryl. In some embodiments, R 4 is, optionally substituted C1-C6 aliphatic. In some embodiments, R 4 is methyl, ethyl, propyl, pentyl, butyl, or hexyl. In some embodiments, R 4 is methyl. In some embodiments, R 4 is CF3.

[0095] Generally as defined above, R 5is hydrogen, optionally substituted C1-C6 aliphatic, optionally substituted C1-C6 alkoxy, optionally substituted C3-C 10 cycloalkyl, optionally substituted C6-C 10 heterocycloalkyl, and optionally substituted C6-C 10 aryl. In some embodiments, R 5 is hydrogen, optionally substituted C1-C6 aliphatic, or optionally substituted C1-C6 alkoxy. In some embodiments, R 5 is hydrogen. In some embodiments, when X 7 is N which forms a double bond with a sulfur atom, R 5 is absent.

[0096] Generally as defined above, each R 6 is independently hydrogen, optionally substituted C1-C6 aliphatic, optionally substituted C1-C6 alkoxy, optionally substituted C3-C 10 cycloalkyl, optionally substituted C6-C 10 heterocycloalkyl, or optionally substituted C6-C 10 aryl, or both R 6 together with the atom to which they are attached form a 3- to 7-membered heterocycloalkyl ring, or R 5 and R 6 together with the atom to which they are attached form a 5- to 6-membered heterocycloalkyl ring.

[0097] Generally as defined above, each R 6 is independently hydrogen, deuterium, C( 2 D)3, optionally substituted C1-C6 aliphatic, optionally substituted C1-C6 alkoxy, optionally substituted C3-C 10 cycloalkyl, optionally substituted C6-C 10 heterocycloalkyl, or optionally substituted C6-C 10 aryl, or both R 6 together with the atom to which they are attached form a 3- to 7-membered heterocycloalkyl ring, or R 5 and R6 Together with the atoms to which they are attached, form a 5- to 6-membered heterocycloalkyl ring.

[0098] In some embodiments, each R 6 is independently hydrogen or optionally substituted C1-C6 aliphatic. In some embodiments, each R 6 is independently hydrogen, methyl, or -(CH2)2N(CH3)2.

[0099] In some embodiments, both Rs 6 together with the atoms to which they are attached, form a 3- to 7-membered heterocycloalkyl ring. In some embodiments, both Rs 6 together with the atoms to which they are attached, form a 3, 4, 5, 6, or 7-membered heterocycloalkyl ring.

[0100] In some embodiments, R 5 and R 6 together with the atoms to which they are attached, form a 5- to 6-membered heterocycloalkyl ring. In some embodiments, R 5 and R 6 together with the atoms to which they are attached, form a 5- or 6-membered heterocycloalkyl ring. In some embodiments, R 5 and R 6 together with the atoms to which they are attached, form a 5-membered heterocycloalkyl ring.

[0101] In some embodiments, R 5 , and X 5 or X 3 together with the atoms to which they are attached, form a 5- to 6-membered fused heterocycloalkyl ring.

[0102] In some embodiments, R 5 , and X 5 or X 3 together with the atoms to which they are attached, form a 5- to 6-membered fused aromatic heterocyclic ring.

[0103] In some embodiments, R6 and X 5 or X 3 forms, together with the atoms to which they are attached, a 5- to 6-membered fused heterocycloalkyl ring.

[0104] Generally, as defined above, R 7 is O, or an optionally substituted C1-C6 aliphatic. In some embodiments, R 7 is O. In some embodiments, R 7 is an optionally substituted C1-C6 aliphatic. In some embodiments, R 7 is methyl.

[0105] Generally, as defined above, R 8 is absent, hydrogen, or an optionally substituted C1-C6 aliphatic. In some embodiments, R 8 is hydrogen or methyl.

[0106] Generally, as defined above, R 8 is absent, hydrogen, deuterium, or an optionally substituted C1-C6 aliphatic. In some embodiments, R 8 is hydrogen or methyl.

[0107] In some embodiments, the present disclosure provides compounds of formula (IB)-(IE):

Chemical formula

Table 1-1

Table 1-2

Table 1-3

Table 1-4

Table 1-5

Table 1-6

Table 1-7

Table 1-8

Table 1-9

Table 1-10

Table 1-11

Table 1-12

Table 1-13

Table 1-14

Table 1-15

Table 1-16

Table 1-17

Table 1-18

Table 1-19

Table 1-20

Table 1-21

Table 1-22

Table 1-23

Table 1-24

Table 1-25

Table 1-26

Table 1-27

Table 1-28

Table 1-29

[0108] In some embodiments, the present disclosure provides the compounds described in Table 1 above, or pharmaceutically acceptable salts thereof.

[0109] In another aspect, the present disclosure provides a compound of formula (II):

Chemical formula

Chemical formula

Chemical formula

[0110] Generally as defined above, X 1 、 X 2 、 X 4 、 and X 5 are independently CR 1 or N. In some embodiments, X 1 、 X 2 、 X 4 、 and X 5 are CR 1 Generally as defined above, R 1 are independently hydrogen, halo, optionally substituted C1-C6 aliphatic, optionally substituted C1-C6 alkoxy, optionally substituted C3-C 10 cycloalkyl, optionally substituted C6-C 10 heterocycloalkyl, or optionally substituted C6-C 10 aryl, and in some embodiments, R 1 are hydrogen, halo, or optionally substituted C1-C6 alkoxy. In some embodiments, R 1 are hydrogen, chloro, fluoro, methoxy, ethoxy, propoxy, ethoxy, or hexyloxy. In some embodiments, R 1 are hydrogen, fluoro, chloro, or methoxy.

[0111] Generally as defined above, each

Chemical Structure

[0112] Generally, as defined above, each A is independently, [Chemical formula] or an optionally substituted 5- to 6-membered heteroaryl. In some embodiments, each A is independently, [Chemical formula] is. Generally, as defined above, X 8 is N or O. In some embodiments, X 8 is N. In some embodiments, X 8 is O. In some embodiments, X 8 is N, and R 3 and R 8 together with the N atom to which they are attached form an optionally substituted 3- to 7-membered heterocycloalkyl ring.

[0113] In some embodiments, each A is independently an optionally substituted 5- to 6-membered heteroaryl. In some embodiments, each A is independently an optionally substituted 5- or 6-membered heteroaryl. In some embodiments, each A is independently an optionally substituted 5-membered heteroaryl. In some embodiments, each A is an optionally substituted imidazole. In some embodiments, each A is, [Chemical formula] is.

[0114] Generally, as defined above, X 6 is O or NH. In some embodiments, X 6 is O. In some embodiments, X 6 is NH. In some embodiments, X 6 is C(O).

[0115] Generally, as defined above, X 7 is CH or N. In some embodiments, X 7is CH. In some embodiments, X 7 is N.

[0116] Generally as defined above, each R 1 is independently hydrogen, deuterium, halo, optionally substituted C1-C6 aliphatic, optionally substituted C1-C6 alkoxy, optionally substituted C3-C 10 cycloalkyl, optionally substituted C6-C 10 heterocycloalkyl, or optionally substituted C6-C 10 aryl, and in some embodiments, R 1 is halo. In some embodiments, R 1 is fluoro, chloro, iodo, -OCF3, cyclopropyl, -CF3, or ethyne. In some embodiments, R 1 is fluoro or iodo. In some embodiments, R 1 is -CN.

[0117] Generally as defined above, R 2 is hydrogen, halo, C( 2 D)3, OC( 2 D)3, optionally substituted C1-C6 aliphatic, optionally substituted C1-C6 alkoxy, optionally substituted C3-C 10 cycloalkyl, optionally substituted C6-C 10 heterocycloalkyl, or optionally substituted C6-C 10 aryl. In some embodiments, R 2 is optionally substituted C1-C6 aliphatic. In some embodiments, R 2 is methyl, ethyl, propyl, pentyl, butyl, or hexyl. In some embodiments, R 2 is methyl.

[0118] Generally as defined above, R 3 is hydrogen, optionally substituted C1-C6 aliphatic, optionally substituted C1-C6 alkoxy, optionally substituted C3-C 10 cycloalkyl, optionally substituted C6-C 10Heterocycloalkyl, and optionally substituted C6-C 10 aryl. In some embodiments, R 3 is optionally substituted C3-C 10 cycloalkyl. In some embodiments, R 3 is optionally substituted C3-C8 cycloalkyl. In some embodiments, R 3 is optionally substituted C3-C6 cycloalkyl. In some embodiments, R 3 is cyclopropyl, cyclopentyl, cyclobutyl, or cyclohexyl. In some embodiments, R 3 is cyclopropyl, or optionally substituted cyclopropyl. In some embodiments, R 3 is cyclopropyl. In some embodiments, R 3 is -(C3H3)F2.

[0119] Generally as defined above, R 4 is hydrogen, C( 2 D)3, OC( 2 D)3, optionally substituted C1-C6 aliphatic, optionally substituted C1-C6 alkoxy, optionally substituted C3-C 10 cycloalkyl, optionally substituted C6-C 10 heterocycloalkyl, and optionally substituted C6-C 10 aryl. In some embodiments, R 4 is optionally substituted C1-C6 aliphatic. In some embodiments, R 4 is methyl, ethyl, propyl, pentyl, butyl, or hexyl. In some embodiments, R 4 is methyl. In some embodiments, R 4 is CF3.

[0120] Generally as defined above, R 5 is hydrogen, optionally substituted C1-C6 aliphatic, optionally substituted C1-C6 alkoxy, optionally substituted C3-C 10 cycloalkyl, optionally substituted C6-C 10Heterocycloalkyl and optionally substituted C6-C 10 is aryl. In some embodiments, R 5 is hydrogen, optionally substituted C1-C6 aliphatic, or optionally substituted C1-C6 alkoxy. In some embodiments, R 5 is hydrogen. In some embodiments, when X 7 is N which forms a double bond with a sulfur atom, R 5 is absent.

[0121] Generally as defined above, each R 6 is independently hydrogen, optionally substituted C1-C6 aliphatic, optionally substituted C1-C6 alkoxy, optionally substituted C3-C 10 cycloalkyl, optionally substituted C6-C 10 heterocycloalkyl, or optionally substituted C6-C 10 aryl, or both R 6 together with the atoms to which they are attached form a 3- to 7-membered heterocycloalkyl ring, or R 5 and R 6 together with the atoms to which they are attached form a 5- to 6-membered heterocycloalkyl ring.

[0122] In some embodiments, each R 6 is independently hydrogen or optionally substituted C1-C6 aliphatic. In some embodiments, each R 6 is independently hydrogen, methyl, or -(CH2)2N(CH3)2.

[0123] In some embodiments, both R 6 together with the atoms to which they are attached form a 3- to 7-membered heterocycloalkyl ring. In some embodiments, both R 6 together with the atoms to which they are attached form a 3-, 4-, 5-, 6-, or 7-membered heterocycloalkyl ring.

[0124] In some embodiments, R 5 and R 6Together with the atoms to which they are attached, they form a 5- to 6-membered heterocycloalkyl ring. In some embodiments, R 5 and R 6 Together with the atoms to which they are attached, they form a 5- or 6-membered heterocycloalkyl ring. In some embodiments, R 5 and R 6 Together with the atoms to which they are attached, they form a 5-membered heterocycloalkyl ring.

[0125] In some embodiments, R 5 , and X 2 or X 4 Together with the atoms to which they are attached, they form a 5- to 6-membered fused heterocycloalkyl ring.

[0126] In some embodiments, R 5 , and X 2 or X 4 Together with the atoms to which they are attached, they form a 5- to 6-membered fused aromatic heterocyclic ring.

[0127] In some embodiments, R 6 , and X 2 or X 4 Together with the atoms to which they are attached, they form a 5- to 6-membered fused heterocycloalkyl ring.

[0128] Generally as defined above, R 7 is O, or an optionally substituted C1-C6 aliphatic. In some embodiments, R 7 is O. In some embodiments, R 7 is an optionally substituted C1-C6 aliphatic. In some embodiments, R 7 is methyl.

[0129] Generally as defined above, R 8 is absent, hydrogen, deuterium, or an optionally substituted C1-C6 aliphatic. In some embodiments, R 8 is hydrogen or methyl.

[0130] In another aspect, the present disclosure provides a compound having the formula (IIA), namely,

Chemical formula

Chemical formula

[0131] Generally as defined above, X 1 , X 2 , X 4 , and X 5 are independently CR 1 or N. In some embodiments, X 1 , X 2 , X 4 , and X 5 are CR 1 . Generally as defined above, R 1 are independently hydrogen, halo, optionally substituted C1-C6 aliphatic, optionally substituted C1-C6 alkoxy, optionally substituted C3-C 10 cycloalkyl, optionally substituted C6-C 10 heterocycloalkyl, or optionally substituted C6-C 10 aryl, and in some embodiments, R 1is hydrogen, halo, or optionally substituted C1-C6 alkoxy. In some embodiments, R 1 is hydrogen, chloro, fluoro, methoxy, ethoxy, propoxy, ethoxy, or hexyloxy. In some embodiments, R 1 is hydrogen, fluoro, chloro, or methoxy.

[0132] Generally as defined above, each

Chemical formula

[0133] Generally as defined above, each A is independently

Chemical formula

Chemical formula

[0134] In some embodiments, each A is independently an optionally substituted 5- to 6-membered heteroaryl. In some embodiments, each A is independently an optionally substituted 5- or 6-membered heteroaryl. In some embodiments, each A is independently an optionally substituted 5-membered heteroaryl. In some embodiments, each A is optionally substituted imidazole. In some embodiments, each A is [Chemistry] is as follows.

[0135] Generally, as defined above, X 6 is O or NH. In some embodiments, X 6 is O. In some embodiments, X 6 is NH. In some embodiments, X 6 is C(O).

[0136] Generally, as defined above, X 7 is CH or N. In some embodiments, X 7 is CH. In some embodiments, X 7 is N.

[0137] Generally, as defined above, each R 1 is independently hydrogen, deuterium, halo, optionally substituted C1-C6 aliphatic, optionally substituted C1-C6 alkoxy, optionally substituted C3-C 10 cycloalkyl, optionally substituted C6-C 10 heterocycloalkyl, or optionally substituted C6-C 10 aryl, and in some embodiments, R 1 is halo. In some embodiments, R 1 is fluoro, chloro, iodo, -OCF3, cyclopropyl, -CF3, or ethyne. In some embodiments, R 1 is fluoro or iodo. In some embodiments, R 1 is -CN.

[0138] Generally, as defined above, R 2 is hydrogen, C( 2 D)3, OC( 2 D)3, halo, optionally substituted C1-C6 aliphatic, optionally substituted C1-C6 alkoxy, optionally substituted C3-C 10 cycloalkyl, optionally substituted C6-C 10heterocycloalkyl, or optionally substituted C6-C 10 aryl. In some embodiments, R 2 is optionally substituted C1-C6 aliphatic. In some embodiments, R 2 is methyl, ethyl, propyl, pentyl, butyl, or hexyl. In some embodiments, R 2 is methyl.

[0139] Generally as defined above, R 3 is hydrogen, optionally substituted C1-C6 aliphatic, optionally substituted C1-C6 alkoxy, optionally substituted C3-C 10 cycloalkyl, optionally substituted C6-C 10 heterocycloalkyl, and optionally substituted C6-C 10 aryl. In some embodiments, R 3 is optionally substituted C3-C 10 cycloalkyl. In some embodiments, R 3 is optionally substituted C3-C8 cycloalkyl. In some embodiments, R 3 is optionally substituted C3-C6 cycloalkyl. In some embodiments, R 3 is cyclopropyl, cyclopentyl, cyclobutyl, or cyclohexyl. In some embodiments, R 3 is cyclopropyl, or optionally substituted cyclopropyl. In some embodiments, R 3 is cyclopropyl. In some embodiments, R 3 is -(C3H3)F2.

[0140] Generally as defined above, R 4 is hydrogen, C( 2 D)3, OC( 2 D)3, optionally substituted C1-C6 aliphatic, optionally substituted C1-C6 alkoxy, optionally substituted C3-C 10 cycloalkyl, optionally substituted C6-C 10 heterocycloalkyl, and optionally substituted C6-C10 is aryl. In some embodiments, R 4 is optionally substituted C1-C6 aliphatic. In some embodiments, R 4 is methyl, ethyl, propyl, pentyl, butyl, or hexyl. In some embodiments, R 4 is methyl. In some embodiments, R 4 is CF3.

[0141] Generally as defined above, R 5 is hydrogen, optionally substituted C1-C6 aliphatic, optionally substituted C1-C6 alkoxy, optionally substituted C3-C 10 cycloalkyl, optionally substituted C6-C 10 heterocycloalkyl, and optionally substituted C6-C 10 aryl. In some embodiments, R 5 is hydrogen, optionally substituted C1-C6 aliphatic, or optionally substituted C1-C6 alkoxy. In some embodiments, R 5 is hydrogen. In some embodiments, when X 7 is N which forms a double bond with a sulfur atom, R 5 is absent.

[0142] Generally as defined above, each R 6 is independently hydrogen, deuterium, C( 2 D)3, optionally substituted C1-C6 aliphatic, optionally substituted C1-C6 alkoxy, optionally substituted C3-C 10 cycloalkyl, optionally substituted C6-C 10 heterocycloalkyl, or optionally substituted C6-C 10 aryl, or both R 6 together with the atoms to which they are attached form a 3- to 7-membered heterocycloalkyl ring, or R 5 and R 6 together with the atoms to which they are attached form a 5- to 6-membered heterocycloalkyl ring.

[0143] In some embodiments, each R 6 is independently hydrogen or an optionally substituted C1-C6 aliphatic. In some embodiments, each R 6 is independently hydrogen, methyl, or -(CH2)2N(CH3)2.

[0144] In some embodiments, both Rs 6 together with the atom to which they are attached form a 3- to 7-membered heterocycloalkyl ring. In some embodiments, both Rs 6 together with the atom to which they are attached form a 3-, 4-, 5-, 6-, or 7-membered heterocycloalkyl ring.

[0145] In some embodiments, R 5 and R 6 together with the atom to which they are attached form a 5- to 6-membered heterocycloalkyl ring. In some embodiments, R 5 and R 6 together with the atom to which they are attached form a 5- or 6-membered heterocycloalkyl ring. In some embodiments, R 5 and R 6 together with the atom to which they are attached form a 5-membered heterocycloalkyl ring.

[0146] In some embodiments, R 5 , and X 2 or X 4 together with the atom to which they are attached form a 5- to 6-membered fused heterocycloalkyl ring.

[0147] In some embodiments, R 5 , and X 2 or X 4 together with the atom to which they are attached form a 5- to 6-membered fused aromatic heterocyclic ring.

[0148] In some embodiments, R 6 , and X 2 or X 4 together with the atom to which they are attached form a 5- to 6-membered fused heterocycloalkyl ring.

[0149] Generally, as defined above, R 7 is O, or an optionally substituted C1-C6 aliphatic. In some embodiments, R 7 is O. In some embodiments, R 7 is an optionally substituted C1-C6 aliphatic. In some embodiments, R 7 is methyl.

[0150] Generally, as defined above, R 8 is absent, hydrogen, deuterium, or an optionally substituted C1-C6 aliphatic. In some embodiments, R 8 is hydrogen or methyl. [Table 2-1] [Table 2-2] [Table 2-3] [Table 2-4] [Table 2-5] [Table 2-6]

[0151] In some embodiments, the present disclosure provides the compounds described in Table 2 above, or pharmaceutically acceptable salts thereof.

[0152] In another aspect, the present disclosure provides a compound of formula (III): [Chemical formula] or a pharmaceutically acceptable salt thereof, wherein ring B is C3-C 10Cycloalkyl, C3-C having 1 to 4 heteroatoms N, S, or O 10 A hetero-cycloalkyl, phenyl, 5- to 6-membered heteroaryl having 1 to 4 heteroatoms N, S, or O, or a 6- to 10-membered bicyclic heteroaryl having 1 to 4 heteroatoms N, S, or O, which is an optionally substituted ring, R 11 is H,

Chemical formula

[0153] In another aspect, the present disclosure provides a compound of formula (IIIA), (IIIB), or (IIIC):

Chemical formula

[0154] In some embodiments, ring B is an optionally substituted C3-C 10 cycloalkyl. In some embodiments, ring B is an optionally substituted C3-C 10 heterocycloalkyl having 1 to 4 heteroatoms N, S, or O. In some embodiments, ring B is an optionally substituted phenyl. In some embodiments, ring B is an optionally substituted 5- to 6-membered heteroaryl having 1 to 4 heteroatoms N, S, or O. In some embodiments, ring B is an optionally substituted 6- to 10-membered bicyclic heteroaryl having 1 to 4 heteroatoms N, S, or O.

[0155] In some embodiments, ring B is an optionally substituted

Chemical formula

Chemical formula

Chemical formula

[0156] In some embodiments, R 12 is H or an optionally substituted C1-C6 aliphatic. In some embodiments, R 12 is H. In some embodiments, R 12 is an optionally substituted C1-C6 aliphatic. In some embodiments, R 12 is an optionally substituted C1-C6 alkyl. In some embodiments, R 12is unsubstituted C1-C6 alkyl. In some embodiments, R 12 is methyl. [Table 2B-1] [Table 2B-2]

[0157] In some embodiments, the present disclosure provides a compound described in Table 2B above, or a pharmaceutically acceptable salt thereof.

[0158] III. USE, FORMULATION, AND ADMINISTRATION a. Pharmaceutically acceptable compositions According to another embodiment, the present disclosure provides a pharmaceutical composition comprising a compound of the present disclosure or a pharmaceutically acceptable derivative thereof and a pharmaceutically acceptable carrier, adjuvant, or vehicle. The amount of the compound in the composition of the present disclosure is an amount effective to measurably inhibit MEK, or a variant or mutant thereof, in a biological sample or in a patient. In certain embodiments, the amount of the compound in the composition of the present disclosure is an amount effective to measurably inhibit MEK, or a variant or mutant thereof, in a biological sample or in a patient. In certain embodiments, the composition of the present disclosure is formulated for administration to a patient in need of such a composition. In some embodiments, the composition of the present disclosure is formulated for oral administration to a patient.

[0159] As used herein, the terms "subject" and "patient" are used interchangeably and mean a living body treatable by the methods of the present disclosure. Such living bodies preferably include, but are not limited to, mammals (e.g., mice, monkeys, horses, cows, pigs, dogs, cats, etc.), and most preferably humans.

[0160] The term "pharmaceutically acceptable carrier, adjuvant, or vehicle" means a non-toxic carrier, adjuvant, or vehicle that does not abrogate the pharmacological activity of the compounds with which they are formulated. Pharmaceutically acceptable carriers, adjuvants or vehicles that may be used in the compositions of the present disclosure include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins such as human serum albumin, buffer substances such as phosphates, glycine, sorbic acid, potassium sorbate, saturated plant fatty acids such as protamine sulfate, water, salt or electrolyte partial glyceride mixtures, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinylpyrrolidone, cellulose substances, polyethylene glycol, sodium carboxymethyl cellulose, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, polyethylene glycol and lanolin.

[0161] "Pharmaceutically acceptable derivative" means any non-toxic salt, ester, salt of an ester, or other derivative of a compound of the present disclosure that is capable of providing, directly or indirectly, a compound of the present disclosure, or an active metabolite or residue thereof, upon administration to a recipient.

[0162] As used herein, the term "active metabolite or residue thereof" means that the metabolite or residue thereof also inhibits MEK, or a variant or mutant thereof.

[0163] The compositions of the present disclosure can be administered orally, parenterally, by inhalation spray, topically, rectally, nasally, intraorally, vaginally, or via an implanted reservoir. As used herein, the term "parenteral" includes subcutaneous, intravenous, intramuscular, intra-articular, intrasynovial, intrasternal, intramedullary, intraliver, intralesional, and intracranial injection or infusion techniques. Preferably, the compositions are administered orally, intraperitoneally, or intravenously. The sterile injectable form of the compositions of the present disclosure can be an aqueous or oily suspension. These suspensions can be formulated according to techniques known in the art using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation can also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent, for example, a solution in 1,3-butanediol. Among the acceptable vehicles and solvents that can be used are water, Ringer's solution, and isotonic sodium chloride solution. Also, a sterile fixed oil has conventionally been used as a solvent or suspending medium.

[0164] For this purpose, any non-irritating fixed oil containing mono- or diglycerides can be used. Fatty acids such as oleic acid and its glyceride derivatives are useful in the preparation of injectables, as are natural pharmaceutically acceptable oils such as olive oil or castor oil (especially their polyoxyethylated products). These oily solutions or suspensions can also contain long-chain alcohol diluents or dispersing agents commonly used in the formulation of pharmaceutically acceptable dosage forms, including emulsions and suspensions, for example, carboxymethyl cellulose or similar dispersing agents. Other commonly used surfactants, such as Tween®, Span®, and other emulsifying agents, or bioavailability enhancers commonly used in the manufacture of pharmaceutically acceptable solid, liquid, or other dosage forms can also be used for formulation purposes.

[0165] The pharmaceutically acceptable compositions of the present disclosure can be administered orally in any orally acceptable dosage form including, but not limited to, capsules, tablets, aqueous suspensions or solutions. In the case of tablets for oral use, carriers commonly used include lactose and corn starch. Lubricants such as magnesium stearate are also generally added. For oral administration in capsule form, useful diluents include lactose and dried corn starch. When an aqueous suspension is required for oral use, the active ingredient is combined with emulsifying and suspending agents. If desired, certain sweetening, flavoring, or coloring agents may also be added.

[0166] Alternatively, the pharmaceutically acceptable compositions of the present disclosure can be administered in the form of suppositories for rectal administration. These can be prepared by mixing the drug with suitable non-irritating excipients that are solid at room temperature but liquid at rectal temperature and thereby melt in the rectum to release the drug. Such substances include cocoa butter, beeswax and polyethylene glycol.

[0167] The pharmaceutically acceptable compositions of the present disclosure can also be administered topically, particularly when the target of treatment includes areas or organs that are readily accessible by topical application, including diseases of the eye, skin, or lower intestinal tract. Suitable topical formulations are readily prepared for each of these areas or organs.

[0168] Topical application for the lower intestinal tract can be achieved with rectal suppository formulations (see above) or suitable enema formulations. Topical transdermal patches can also be used.

[0169] For topical use, the pharmaceutically acceptable compositions provided can be formulated as suitable ointments containing the active ingredient suspended or dissolved in one or more carriers. Carriers for topical administration of the compounds of the present disclosure include, but are not limited to, mineral oil, liquid petrolatum, white petrolatum, propylene glycol, polyoxyethylene, polyoxypropylene compounds, emulsifying wax, and water. Alternatively, the pharmaceutically acceptable compositions provided can be formulated as suitable lotions or creams containing the active ingredient suspended or dissolved in one or more pharmaceutically acceptable carriers. Suitable carriers include, but are not limited to, mineral oil, sorbitan monostearate, polysorbate 60, cetyl ester wax, cetearyl alcohol, 2-octyldodecanol, benzyl alcohol, and water.

[0170] For ocular use, the pharmaceutically acceptable compositions provided can be formulated as a micronized suspension in isotonic, pH-adjusted, sterile saline, or, preferably, as a solution in isotonic, pH-adjusted, sterile saline with or without a preservative such as benzalkonium chloride. Alternatively, for ocular use, the pharmaceutically acceptable compositions can be formulated as an ointment such as petrolatum.

[0171] The pharmaceutically acceptable compositions of the present disclosure can also be administered by nasal aerosol or inhalant. Such compositions are prepared according to techniques well known in the art of pharmaceutical formulation and can be prepared as solutions in saline using benzyl alcohol or other suitable preservatives, absorption promoters to enhance bioavailability, fluorocarbons, and / or other conventional solubilizing or dispersing agents.

[0172] Most preferably, the pharmaceutically acceptable compositions of the present disclosure are formulated for oral administration. Such formulations may be administered with or without food. In some embodiments, the pharmaceutically acceptable compositions of the present disclosure are administered without food. In other embodiments, the pharmaceutically acceptable compositions of the present disclosure are administered with food.

[0173] In some embodiments, the pharmaceutical compositions of the present disclosure are brain permeable or CNS permeable, or result in brain exposure. As used herein, the terms "brain permeable," "CNS permeable," or "brain exposure" mean that the compounds and pharmaceutical compositions of the present disclosure can cross the blood-brain barrier (BBB) and are thus useful for treating brain or CNS diseases, conditions, injuries, or disorders. In some embodiments, the brain or CNS diseases, conditions, injuries, or disorders are neurodegenerative diseases, nerve injuries, stroke, genetic diseases, mental disorders, developmental disorders, inflammation, infections or injuries, and brain tumors, spinal cord injury (SCI), and traumatic brain injury (TBI). In certain embodiments, the brain disorders are selected from epilepsy, meningitis, encephalitis including HIV encephalitis, progressive multifocal leukoencephalopathy, neuromyelitis optica, multiple sclerosis, late-stage nervous system trypanosomiasis, amyotrophic lateral sclerosis (ALS), progressive bulbar palsy (PBP), primary lateral sclerosis (PLS), progressive muscular atrophy (PMA), Alzheimer's disease, Parkinson's disease, Huntington's disease, De Vivo disease, and any type of tumor, cancer, or hyperproliferative disease in the brain or CNS.

[0174] In some embodiments, the brain or CNS disease, condition, injury, or disorder is a neurological disease that affects and / or has an etiology in the CNS, including but not limited to neuropathy, amyloidosis, cancer, eye disease or disorder, viral or microbial infection, inflammation, ischemia, neurodegeneration, spasm, movement disorder, and lysosomal storage disease. For the purposes of this application, the CNS is generally understood to include the eyes, which are isolated from the rest of the body by the blood-retinal barrier. Specific examples of neurological diseases include neurodegenerative diseases (including but not limited to Lewy body disease, post-polio syndrome, Shy-Drager syndrome, olivopontocerebellar atrophy, Parkinson's disease, multiple system atrophy, striatonigral degeneration, tauopathies (including but not limited to Alzheimer's disease and supranuclear palsy), prion diseases (including but not limited to bovine spongiform encephalopathy, scrapie, Creutzfeldt-Jakob disease, kuru, Gerstmann-Straussler-Scheinker syndrome, chronic wasting disease, and fatal familial insomnia), bulbar palsy, motor neuron disease, and nervous system heterotrophic degenerative disorders (including but not limited to Canavan disease, Huntington's disease, neuronal ceroid lipofuscinosis, Alexander disease, Tourette syndrome, Menkes kinky hair syndrome, Cockayne syndrome, Hallervorden-Spatz syndrome, Lafora disease, Rett syndrome, hepatolenticular degeneration, Lesch-Nyhan syndrome, and Unverricht-Lundborg syndrome), dementia (including but not limited to Pick's disease and spinocerebellar ataxia), cancer (including but not limited to those of the CNS and / or brain, including brain metastases arising from cancer elsewhere in the body), etc., but not limited thereto.

[0175] The "central nervous system" or "CNS" means a complex of nerve tissues that control the functions of the body, including the brain and spinal cord.

[0176] The amount of the compounds of the present disclosure that can be combined with a carrier substance to produce a composition in a single dosage form will vary depending on the host being treated and the particular mode of administration. Preferably, the compositions provided should be formulated so that a patient receiving these compositions can be administered an inhibitor at a dosage of 0.01 to 100 mg / kg body weight per day.

[0177] It should also be understood that the specific dosage and treatment regimen for any particular patient will depend on a variety of factors including the activity of the specific compound used, age, body weight, general health, sex, diet, time of administration, rate of excretion, drug combination, and the judgment of the treating physician, as well as the severity of the particular disease being treated. The amount of the compounds of the present disclosure in the composition also depends on the specific compound in the composition.

[0178] b. Use of the Compounds and Pharmaceutically Acceptable Compositions In some embodiments, the present disclosure provides methods of using the compounds described herein for treating diseases or disorders associated with MEK. In some embodiments, the diseases or disorders associated with MEK are proliferative disorders. In some embodiments, the diseases or disorders associated with MEK are cancers. In some embodiments, the diseases or disorders associated with MEK described herein are the cancers described herein.

[0179] In some aspects and embodiments, provided herein is a method of treating a disease or disorder characterized by, or associated with, an increase in MEK expression and / or an increase in MEK activity, or one or more symptoms thereof, a method of reducing the severity thereof, a method of delaying the onset thereof, or a method of inhibiting the progression thereof, the method comprising administering to a patient in need thereof a therapeutically effective amount of a compound of the present disclosure, or a pharmaceutically acceptable composition thereof. In some aspects and embodiments, provided herein is a method of treating a disease or disorder, or one or more symptoms thereof, in which inhibition or antagonism of MEK activity is beneficial, a method of reducing the severity thereof, a method of delaying the onset thereof, or a method of inhibiting the progression thereof, the method comprising administering to a patient in need thereof a therapeutically effective amount of a compound of the present disclosure, or a pharmaceutically acceptable composition thereof.

[0180] In some embodiments, the compounds described herein are "ATP non-competitive MEK inhibitors" that stabilize or "bind" the complexes formed between MEK and KSR and / or BRAF / CRAF. In some embodiments, the compounds described herein allosterically bind to an inhibitor pocket formed at the interaction interface between human MEK (MEK1 or MEK2) and the human kinase suppressor of Ras (KSR1, or KSR2, or BRAF or CRAF of the KSR homolog) adjacent to ATP in the physiological complex of MEK and KSR (or BRAF or CRAF), forming an inhibitor-inhibitor pocket complex. In some embodiments, the compounds described herein are ATP non-competitive kinase inhibitors. In some embodiments, when binding to the inhibitor-inhibitor pocket complex, the complex has a structure that includes the following structural elements: (a) at least one portion of the inhibitor that binds to A825 of hKSR1, or P878 of hKSR2, or R662 of BRAF, or R554 of CRAF; (b) R234 of hMEK1 or R238 of hMEK2 (where R234 is within about 5 Å to about 8 Å of an atom of any of hKSR1 or hKSR2 or BRAF or CRAF). For example, the structure of the complexes described herein, including the MEK and KSR (or BRAF or CRAF) complexes and the inhibitor-inhibitor pocket complex, can be found in WO 2021142345, the entire content of which is incorporated herein by reference. The reference Uniprot sequences for human MEK1, human MEK2, human KSR1, human KSR2, human BRAF, and human CRAF are Uniprot ID Q02750, Uniprot ID P36507, Uniprot ID Q8IVT5, Uniprot ID Q6VAB6, Uniprot ID P15056, and Uniprot ID P04049, respectively.

[0181] In some embodiments, the compounds described herein do not bind to one or more of I216 of hMEK1 or I220 of hMEK2, and A825 of KSR1 or P878 of KSR2. In some embodiments, the compounds described herein include a structural element as described in the previous paragraph that is (a) an H-bond acceptor, in particular an oxygen or nitrogen atom, or a fluorine atom bonded to an aromatic ring, or an H-bond donor. In some embodiments, the compounds described herein include a structural element as described in the previous paragraph that is a moiety of a linker that binds directly or by water-mediated contact to the backbone of A825 of hKSR1, or P878 of hKSR2, or R662 of hBRAF, or R554 of CRAF.

[0182] In some embodiments, the compounds described herein include one or more of the following: (c) at least one moiety that binds to M230 of hMEK1 or M234 of hMEK2 (M230 or M234 is within about 5 Å to about 8 Å from the terminal atom (CB) of A825 of KSR1 or (CG) of P878 of hKSR2, or (CG) of N661 of hBRAF, or N553 of CRAF); (d) at least one moiety is an H-bond acceptor or donor that binds by water-mediated contact to the backbone carbonyl of N823 of hKSR1, or T876 of hKSR2, or binds directly to the backbone amino group of R662 of hBRAF, or R554 of hCRAF; (e) at least one moiety that binds to Q824 of hKSR1, or Q877 of hKSR2, or Q664 of hBRAF, or Q556 of hCRAF; (f) at least one moiety that binds to the side chain atom of A826 of hKSR1, or A879 of hKSR2, or R662 of BRAF, or R554 of CRAF; (g) at least one moiety is a heteroaryl group that binds to M143 of hMEK1 or M147 of hMEK2; (h) At least one moiety is a heteroaryl group that binds to F209 of hMEK1 or F213 of hMEK2; (i) At least one moiety (especially a hydrogen bond acceptor) binds to the backbone amino group of S212 of hMEK1 or S216 of hMEK2; (j) At least one moiety that binds to L215 of hMEK1 or L219 of hMEK2; (k) At least one moiety that binds to I216 of hMEK1 or I220 of hMEK2; and (l) At least one moiety that binds to M219 of hMEK1 or M223 of hMEK2 (residues 215 - 219 of hMEK1 adopt a helical conformation).

[0183] In some embodiments, the moiety corresponding to (c) above is selected from substituted or unsubstituted alkyl or cycloalkyl.

[0184] In some embodiments, the backbone CO residue of the compounds described herein binds to T876 of hKSR2, or N823 of hKSR1.

[0185] In some embodiments, the compounds described herein bind to a binding pocket that is formed by R234 and M320 of hMEK1 residues, or R238 and M234 of hMEK2 residues, and P877 of KSR2, or A825 of KSR1, or R662 of BRAF, or R554 of CRAF.

[0186] In some embodiments, the compounds described herein bind to the binding pocket through multiple hydrogen bond contacts, including water-mediated hydrogen bonds to Arg189 and Arg234 in hMEK1, or AKG193 or A238 in hMEK2, and direct hydrogen bonds to the backbone of the pre - helix αG loop - NH - of Arg662 of BRAF, or ARG554 of CRAF.

[0187] In some embodiments, the compounds described herein bind to A825 of hKSR1, or P878 of hKSR2, or R662 of BRAF, or R554 of CRAF. In some embodiments, the compounds described herein have a distance of about 5 Å to about 8 Å or less from at least one moiety selected from A825 of hKSR1, P878 of hKSR2, as well as R662 of BRAF, and R554 of CRAF.

[0188] Accordingly, in some aspects and embodiments, the present disclosure provides a method of treating one or more disorders, diseases, and / or conditions including, but not limited to, cell proliferative disorders, by administering to a patient in need thereof a MEK inhibitor compound described herein, or a pharmaceutically acceptable salt or composition thereof. In some embodiments, the cell proliferative disorder is cancer. In some embodiments, the cancer is characterized by an increase in MEK expression and / or an increase in MEK activity, i.e., "increased activated MEK".

[0189] As used herein, the terms "increased", "elevated", or "enhanced" are used interchangeably and include any measurable increase in a biological function, and / or bioactivity, and / or concentration. For example, the increase can be at least about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, about 96%, about 97%, about 98%, about 99%, about 100%, about 2-fold, about 3-fold, about 4-fold, about 5-fold, about 6-fold, about 7-fold, about 8-fold, about 9-fold, about 10-fold, about 20-fold, about 25-fold, about 50-fold, about 100-fold, or higher compared to the control or baseline amount of the function, or activity, or concentration.

[0190] As used herein, the terms "increased expression" and / or "increased activity" of a substance, such as MEK, in a sample or in cancer or a patient, refer to an increase in the amount of a substance, such as TEAD, of about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, about 96%, about 97%, about 98%, about 99%, about 100%, about 2-fold, about 3-fold, about 4-fold, about 5-fold, about 6-fold, about 7-fold, about 8-fold, about 9-fold, about 10-fold, about 20-fold, about 25-fold, about 50-fold, about 100-fold, or higher, as measured by techniques known in the art, compared to the amount of a substance, such as TEAD, in a control sample (s), such as an individual or population not suffering from a disease or disorder (e.g., cancer), or an internal control. The expression and / or activity of TEAD is increased by 1 standard deviation, 2 standard deviations, 3 standard deviations, 4 standard deviations, 5 standard deviations, or more, compared to the mean (average) or median amount of MEK in a control group of samples, or a baseline group of samples, or in a retrospective study of patient samples, the subject is also said to have an "increased expression" or "increased activity" of TEAD and can also be measured. As practiced in the art, such control or baseline expression levels can be determined in advance, or measured prior to measurement in a sample or in cancer or a subject, or obtained from a database of such control samples.

[0191] c. cancer In some embodiments, the disclosure provides a method of treating, preventing, or reducing the risk of cancer in a patient, the method comprising administering to the patient a compound of the disclosure, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

[0192] As used herein, "cancer" refers to a broad group of various diseases characterized by the uncontrolled growth of abnormal cells in the body. Uncontrolled cell division and proliferation lead to the formation of malignant tumors that invade adjacent tissues and can also metastasize to distant parts of the body via the lymphatic system or bloodstream.

[0193] Cancers or proliferative disorders or tumors treated with the compounds, methods, and uses described herein include, but are not limited to, blood cancers, lymphomas, myelomas, leukemias, neurocancers, skin cancers, breast cancers, prostate cancers, colorectal cancers, lung cancers, head and neck cancers, gastrointestinal cancers, liver cancers, pancreatic cancers, genitourinary cancers, osteosarcomas, kidney cancers, and angiosarcomas.

[0194] In some embodiments, the cancer is a K-Ras mutant cancer. In some embodiments, the K-Ras mutant cancer is an activated mutant K-Ras cancer. In some embodiments, the K-Ras mutant cancer is a cancer having a mutant or variant K-Ras G12. In some embodiments, the mutant or variant K-Ras G12 is K-Ras G12D, K-Ras G12V, K-Ras G12C, K-Ras G12R, K-Ras G12A, or any combination thereof. In some embodiments, the mutant or variant K-Ras G12 is K-Ras G12D, K-Ras G12V, K-Ras G12C, K-Ras G12R, K-Ras G12A, K-Ras G12S, or any combination thereof. In some embodiments, the mutant or variant K-Ras G12 is K-Ras G12D. In some embodiments, the mutant or variant K-Ras G12 is K-Ras G12V. In some embodiments, the mutant or variant K-Ras G12 is K-Ras G12C. In some embodiments, the mutant or variant K-Ras G12 is K-Ras G12R. In some embodiments, the mutant or variant K-Ras G12 is K-Ras G12A. In some embodiments, the mutant or variant K-Ras G12 is K-Ras G12S. In some embodiments, the K-Ras mutant cancer is a cancer having a mutant or variant K-Ras G13. In some embodiments, the mutant or variant K-Ras G13 is K-Ras G13D, K-Ras G13C, or any combination thereof. In some embodiments, the K-Ras mutant cancer is a cancer having a mutant or variant K-Ras Q61. In some embodiments, the mutant or variant K-Ras Q61 is K-Ras Q61H, K-Ras Q61R, or any combination thereof. In some embodiments, the K-Ras mutant cancer is a cancer having a mutant or variant K-Ras A146. In some embodiments, the mutant or variant K-Ras A146 is K-Ras A146T.In some embodiments, the K-Ras mutant cancer is a cancer having a mutant or variant K-Ras G12D, K-Ras G12V, K-Ras G12C, K-Ras G12R, K-Ras G12A, K-Ras G13D, K-Ras G13C, K-Ras Q61H, K-Ras Q61R, K-Ras A146T, or any combination thereof. In some embodiments, the K-Ras mutant cancer is a cancer having a mutant or variant K-Ras G12D, K-Ras G12V, K-Ras G12C, K-Ras G12R, K-Ras G12A, K-Ras G12S, K-Ras G13D, K-Ras G13C, K-Ras Q61H, K-Ras Q61R, K-Ras A146T, or any combination thereof.

[0195] In some embodiments, the cancer is mutant B-Raf cancer. In some embodiments, the mutant B-Raf cancer includes B-Raf amplification. As used herein, "B-Raf amplification" means a cancer or cancer cell that includes at least 3 copies of B-Raf, at least 4 copies of B-Raf, at least 5 copies of B-Raf, at least 6 copies of B-Raf, at least 7 copies of B-Raf, at least 8 copies of B-Raf, at least 9 copies of B-Raf, at least 10 copies of B-Raf, or more. In some embodiments, the mutant B-Raf cancer is a cancer having a mutant or variant B-RafV600, also referred to as a "class I B-Raf mutation." In some embodiments, the mutant or variant B-Raf V600 is B-Raf V600E, V600K, V600D, V600R, or any combination thereof. In some embodiments, the mutant or variant B-Raf V600 is B-Raf V600E, V600K, V600D, V600R, V600M, or any combination thereof. In some embodiments, the mutant B-Raf cancer is a cancer having a mutant or variant B-Raf K601, B-Raf P367, B-Raf G464, B-Raf L485, B-Raf E586, B-Raf T588, B-Raf T599, B-Raf L597, B-Raf G469, or any combination thereof, which are collectively also referred to as "class II B-Raf mutations." In some embodiments, the mutant B-Raf cancer is a cancer having a mutant or variant B-Raf K601, B-Raf P367, B-Raf G464, B-Raf G469, B-Raf G496, B-Raf L485, B-Raf E586, B-Raf T588, B-Raf T599, B-Raf L597, for example, a B-Raf fusion such as a B-Raf fusion that combines the kinase domain of B-Raf with the N-terminal portion of an endogenous gene product that enables B-Raf dimerization independent of RAS, or any combination thereof, which are collectively also referred to as "class II B-Raf mutations."In some embodiments, mutant B-Raf K601 is B-Raf K601E, K601N, K601T, or any combination thereof. In some embodiments, mutant B-Raf P367 is B-Raf P367L, P367S, or any combination thereof. In some embodiments, mutant B-Raf G464 is B-Raf G464V, G464E, or any combination thereof. In some embodiments, mutant B-Raf G496 is B-Raf G496V. In some embodiments, mutant B-Raf L485 is L485W. In some embodiments, mutant B-Raf E586 is E586K. In some embodiments, mutant B-Raf T599 is T588TT, T588TS, T599I, T599K, or any combination thereof. In some embodiments, mutant B-Raf L597 is B-Raf L597Q, L597R, L597S, L597V, or any combination thereof. In some embodiments, mutant B-Raf G469 is B-Raf G469A, G469V, G469R, or any combination thereof. In some embodiments, mutant B-Raf is a B-Raf fusion. In some embodiments, mutant B-Raf cancer is cancer having mutant or variant B-Raf D287, B-Raf V459, B-Raf G466, B-Raf S467, B-Raf G469, B-Raf N581, B-Raf D594, B-Raf F595, B-Raf G596, or any combination thereof, which are collectively also referred to as "class III B-Raf mutations". In some embodiments, mutant B-Raf D287 is B-Raf D287N. In some embodiments, mutant B-Raf V459 is B-Raf B459L. In some embodiments, mutant B-Raf G466 is B-Raf G466A, B-Raf G466E, B-Raf G466V, or any combination thereof. In some embodiments, mutant B-Raf S467 is B-Raf S467L.In some embodiments, mutant B-Raf G469 is B-Raf-G469E. In some embodiments, mutant B-Raf N581 is B-Raf N581I, B-Raf N581S, B-Raf N581T, or any combination thereof. In some embodiments, mutant B-Raf D594 is B-Raf D594A, B-Raf D594G, B-Raf D594H, B-Raf D594N, or any combination thereof. In some embodiments, mutant B-Raf F595 is B-Raf F595L. In some embodiments, mutant B-Raf G596 is B-Raf G596D, B-Raf G596R, or any combination thereof. In some embodiments, mutant B-Raf cancer comprises B-Raf amplification and at least one B-Raf mutant or variant B-Raf class I, class II, or class III mutation.

[0196] In some embodiments, the cancer is an N-Ras mutant cancer. In some embodiments, the N-Ras mutant cancer is an activated mutant N-Ras cancer. In some embodiments, the N-Ras mutant cancer is a cancer having a mutant or variant N-Ras G12. In some embodiments, the mutant or variant N-Ras G12 is N-Ras G12D, N-Ras G12V, N-Ras G12C, N-Ras G12A, N-Ras G12R, N-Ras G12S, or any combination thereof. In some embodiments, the mutant or variant N-Ras G12 is N-Ras G12D. In some embodiments, the mutant or variant N-Ras G12 is N-Ras G12V. In some embodiments, the mutant or variant N-Ras G12 is N-Ras G12C. In some embodiments, the mutant or variant N-Ras G12 is N-Ras G12R. In some embodiments, the mutant or variant N-Ras G12 is N-Ras G12A. In some embodiments, the mutant or variant N-Ras G12 is N-Ras G12S. In some embodiments, the N-Ras mutant cancer is a cancer having a mutant or variant N-Ras Q61. In some embodiments, the mutant or variant N-Ras Q61 is N-Ras Q61R, N-Ras Q61K, N-Ras Q61L, N-Ras Q61H, N-Ras Q61P, or any combination thereof. In some embodiments, the mutant or variant N-Ras Q61 is N-Ras Q61R. In some embodiments, the mutant or variant N-Ras Q61 is N-Ras Q61K. In some embodiments, the mutant or variant N-Ras Q61 is N-Ras Q61L. In some embodiments, the mutant or variant N-Ras Q61 is N-Ras Q61H. In some embodiments, the mutant or variant N-Ras Q61 is N-Ras Q61P.In some embodiments, the N-Ras mutant cancer is a cancer having a mutant or variant N-Ras G12D, N-Ras G12V, N-Ras G12C, N-Ras G12R, N-Ras G12A, N-Ras G12S, N-Ras Q61, or any combination thereof.

[0197] In some embodiments, the cancer is a C-Raf mutant cancer. In some embodiments, the mutant C-Raf cancer comprises C-Raf amplification. As used herein, "C-Raf amplification" means cancer cells comprising at least 3 copies of C-Raf, at least 4 copies of C-Raf, at least 5 copies of C-Raf, at least 6 copies of C-Raf, at least 7 copies of C-Raf, at least 8 copies of C-Raf, at least 9 copies of C-Raf, at least 10 copies of C-Raf, or more. In some embodiments, the mutant C-Raf cancer is a cancer having a mutant or variant C-Raf S427. In some embodiments, the mutant or variant C-Raf S427 is C-Raf S427G. In some embodiments, the mutant C-Raf cancer is a cancer having a mutant or variant C-Raf I448. In some embodiments, the mutant C-Raf I448 is C-Raf I448V. In some embodiments, the mutant C-Raf cancer comprises C-Raf amplification and / or at least one C-Raf mutant or variant C-Raf.

[0198] In some embodiments, the cancer is NF1 and / or NF2 mutant cancer. As used herein, "NF1 mutant cancer" means a cancer having a mutant or variant gene encoding the neurofibromin protein, including deletion mutations, loss-of-function mutations, microdeletion mutations, missense mutations, copy number loss mutations, and substitution mutations. As used herein, "NF2 mutant cancer" means a cancer having a mutant or variant gene encoding the Merlin protein (also known as schwannomin protein), including deletion mutations, loss-of-function mutations, microdeletion mutations, missense mutations, copy number loss mutations, and substitution mutations.

[0199] In some embodiments of the methods and uses described herein, the cancer is selected from non-small cell lung cancer (NSCLC), pancreatic cancer, colorectal cancer (CRC), uterine cancer, endometrial cancer, bladder cancer, head and neck cancer, endometrial cancer, melanoma, multiple myeloma, acute myeloid leukemia (AML), low-grade serous ovarian cancer, neurofibroma, and glioma.

[0200] In some embodiments of the methods and uses described herein, the cancer is K-Ras mutant non-small cell lung cancer (NSCLC). In some embodiments of the methods and uses described herein, the cancer is K-Ras mutant pancreatic cancer. In some embodiments of the methods and uses described herein, the cancer is K-Ras mutant colorectal cancer. In some embodiments of the methods and uses described herein, the cancer is K-Ras mutant uterine cancer. In some embodiments of the methods and uses described herein, the cancer is K-Ras mutant endometrial cancer. In some embodiments of the methods and uses described herein, the cancer is K-Ras mutant bladder cancer. In some embodiments of the methods and uses described herein, the cancer is K-Ras mutant head and neck cancer. In some embodiments of the methods and uses described herein, the cancer is K-Ras mutant thyroid cancer. In some embodiments of the methods and uses described herein, the cancer is K-Ras mutant low-grade serous ovarian cancer. In some embodiments of the methods and uses described herein, the cancer is N-Ras mutant melanoma. In some embodiments of the methods and uses described herein, the cancer is N-Ras mutant multiple myeloma. In some embodiments of the methods and uses described herein, the cancer is N-Ras mutant acute myeloid leukemia (AML). In some embodiments of the methods and uses described herein, the cancer is N-Ras mutant bladder cancer. In some embodiments of the methods and uses described herein, the cancer is K-Ras mutant low-grade serous ovarian cancer. In some embodiments of the methods and uses described herein, the cancer is B-Ras mutant non-small cell lung cancer (NSCLC). In some embodiments of the methods and uses described herein, the cancer is C-Raf mutant bladder cancer. In some embodiments of the methods and uses described herein, the cancer is NF1 mutant glioma. In some embodiments of the methods and uses described herein, the cancer is NF1 mutant non-small cell lung cancer (NSCLC). In some embodiments of the methods and uses described herein, the cancer is NF2 mutant neurofibroma.

[0201] In some embodiments of the methods and uses described herein, the cancer is lung cancer, thyroid cancer, ovarian cancer, colorectal cancer, prostate cancer, pancreatic cancer, esophageal cancer, liver cancer, breast cancer, skin cancer, or mesothelioma. In some embodiments, the cancer is a mesothelioma such as malignant mesothelioma.

[0202] In some embodiments, the cancers include, but are not limited to, leukemia (e.g., acute leukemia, acute lymphocytic leukemia, acute myeloid leukemia, acute myeloblastic leukemia, acute promyelocytic leukemia, acute myelomonocytic leukemia, acute monocytic leukemia, acute erythroleukemia, chronic leukemia, chronic myeloid leukemia, chronic lymphocytic leukemia), polycythemia vera, lymphoma (e.g., Hodgkin's disease or non-Hodgkin's disease), Waldenström macroglobulinemia, multiple myeloma, heavy chain disease, and solid tumors such as sarcomas and carcinomas (e.g., fibrosarcoma, myxosarcoma, liposarcoma, chondrosarcoma, osteogenic sarcoma, chordoma, angiosarcoma, endotheliosarcoma, lymphangiosarcoma, lymphangioendotheliosarcoma, synovioma, mesothelioma, Ewing's tumor, leiomyosarcoma, rhabdomyosarcoma, colon cancer, pancreatic cancer, breast cancer, ovarian cancer, prostate cancer, squamous cell carcinoma, basal cell carcinoma, adenocarcinoma, sweat gland carcinoma, sebaceous gland carcinoma, papillary carcinoma, papillary adenocarcinoma, cystadenocarcinoma, medullary carcinoma, bronchogenic carcinoma, renal cell carcinoma, liver cancer, cholangiocarcinoma, choriocarcinoma, seminoma, embryonal carcinoma, Wilms' tumor, cervical cancer, uterine cancer, testicular cancer, lung cancer, small cell lung cancer, bladder cancer, epithelial carcinoma, glioma, astrocytoma, glioblastoma multiforme (GBM, also known as glioblastoma), medulloblastoma, craniopharyngioma, ependymoma, pinealoma, hemangioblastoma, acoustic neuroma, oligodendroglioma, schwannoma, neurofibrosarcoma, meningioma, melanoma, neuroblastoma, and retinoblastoma).

[0203] In some embodiments, the cancer is glioma, astrocytoma, glioblastoma multiforme (GBM, also known as glioblastoma), medulloblastoma, craniopharyngioma, ependymoma, pinealoma, hemangioblastoma, acoustic neuroma, oligodendroglioma, schwannoma, neurofibrosarcoma, meningioma, melanoma, neuroblastoma, or retinoblastoma.

[0204] In some embodiments, the cancer is a vestibular schwannoma, astrocytoma (e.g., grade I - pilocytic astrocytoma, grade II - low - grade astrocytoma, grade III - anaplastic astrocytoma, or grade IV - glioblastoma multiforme (GBM)), chordoma, CNS lymphoma, craniopharyngioma, brainstem glioma, ependymoma, mixed glioma, optic glioma, subependymoma, medulloblastoma, meningioma, metastatic brain tumor, oligodendroglioma, pituitary tumor, primitive neuroectodermal (PNET) tumor, or schwannoma. In some embodiments, the cancer is a type more commonly found in children than in adults, such as a brainstem glioma, craniopharyngioma, ependymoma, juvenile pilocytic astrocytoma (JPA), medulloblastoma, optic glioma, pineal tumor, primitive neuroectodermal tumor (PNET), or rhabdoid tumor. In some embodiments, the patient is an adult human. In some embodiments, the patient is a child or pediatric patient.

[0205] In another embodiment, cancers include, but are not limited to, mesothelioma, hepatobiliary (liver and bile duct), bone cancer, pancreatic cancer, skin cancer, head and neck cancer, skin or intraocular melanoma, ovarian cancer, colon cancer, rectal cancer, cancer of the anal region, gastric cancer, gastrointestinal (stomach, colorectal, and duodenum), uterine cancer, fallopian tube cancer, endometrial cancer, cervical cancer, vaginal cancer, vulvar cancer, Hodgkin's disease, esophageal cancer, small intestine cancer, endocrine cancer, thyroid cancer, parathyroid cancer, adrenal cancer, soft tissue sarcoma, urethral cancer, penile cancer, prostate cancer, testicular cancer, chronic or acute leukemia, chronic myelogenous leukemia, lymphocytic lymphoma, bladder cancer, kidney or ureteral cancer, renal cell cancer, renal pelvis cancer, non - Hodgkin's lymphoma, spinal cord axis tumor, brainstem glioma, pituitary adenoma, adrenocortical carcinoma, gallbladder cancer, multiple myeloma, cholangiocarcinoma, fibrosarcoma, neuroblastoma, retinoblastoma, or one or more combinations of the aforementioned cancers.

[0206] In some embodiments, the cancer is a solid tumor, such as a sarcoma, carcinoma, or lymphoma. The tumor typically comprises an abnormal mass of tissue that does not usually contain cysts or fluid regions. In some embodiments, the cancer is renal cell carcinoma, or kidney cancer; hepatocellular carcinoma (HCC) or hepatoblastoma, or liver cancer; melanoma; breast cancer; colorectal carcinoma, or colon cancer; colon cancer; rectal cancer; anal cancer; lung cancer, such as non-small cell lung cancer (NSCLC) or small cell lung cancer (SCLC); ovarian cancer, epithelial ovarian cancer, ovarian carcinoma, or fallopian tube cancer; papillary serous cystadenocarcinoma or uterine papillary serous carcinoma (UPSC); prostate cancer; testicular cancer; gallbladder cancer; cholangiocarcinoma; soft tissue and bone synovial sarcoma; rhabdomyosarcoma; osteosarcoma; chondrosarcoma; Ewing sarcoma; undifferentiated thyroid cancer; adrenocortical carcinoma; pancreatic cancer; pancreatic ductal carcinoma or pancreatic adenocarcinoma; gastrointestinal / gastric (GIST) cancer; lymphoma; squamous cell carcinoma of the head and neck (SCCHN); salivary gland cancer; glioma, or brain cancer; neurofibromatosis-1 associated malignant peripheral nerve sheath tumor (MPNST); Waldenström macroglobulinemia; or medulloblastoma.

[0207] In some embodiments, the cancer is hepatocellular carcinoma (HCC). In some embodiments, the cancer is hepatoblastoma. In some embodiments, the cancer is colon cancer. In some embodiments, the cancer is rectal cancer. In some embodiments, the cancer is ovarian cancer, or ovarian carcinoma. In some embodiments, the cancer is epithelial ovarian cancer. In some embodiments, the cancer is fallopian tube cancer. In some embodiments, the cancer is papillary serous cystadenocarcinoma. In some embodiments, the cancer is uterine papillary serous carcinoma (UPSC). In some embodiments, the cancer is cholangiocarcinoma. In some embodiments, the cancer is soft tissue and bone synovial sarcoma. In some embodiments, the cancer is rhabdomyosarcoma. In some embodiments, the cancer is osteosarcoma. In some embodiments, the cancer is undifferentiated thyroid cancer. In some embodiments, the cancer is adrenocortical carcinoma. In some embodiments, the cancer is pancreatic cancer, or pancreatic ductal carcinoma. In some embodiments, the cancer is pancreatic adenocarcinoma. In some embodiments, the cancer is glioma. In some embodiments, the cancer is malignant peripheral nerve sheath tumor (MPNST). In some embodiments, the cancer is neurofibromatosis-1 associated MPNST. In some embodiments, the cancer is Waldenström macroglobulinemia. In some embodiments, the cancer is medulloblastoma.

[0208] In some embodiments, the cancer is an adult T-cell leukemia, a highly aggressive form of CD4+ T-cell leukemia caused by human immunodeficiency virus (HIV)-associated solid tumors, human papillomavirus (HPV) 16-positive incurable solid tumors, and human T-cell leukemia virus type I (HTLV-I), characterized by clonal integration of HTLV-I in leukemic cells (see https: / / clinicaltrials.gov / ct2 / show / study / NCT02631746); gastric cancer, nasopharyngeal cancer, cervical cancer, vaginal cancer, vulvar cancer, squamous cell carcinoma of the head and neck, and Merkel cell carcinoma (see https: / / clinicaltrials.gov / ct2 / show / study / NCT02488759; https: / / clinicaltrials.gov / ct2 / show / study / NCT0240886; also see https: / / clinicaltrials.gov / ct2 / show / NCT02426892).

[0209] In some embodiments, the methods or uses described herein inhibit, reduce, or stop, or alleviate, cancer or tumor growth or spread. In some embodiments, tumors are treated by stopping, reducing, or inhibiting further growth of the cancer or tumor. In some embodiments, the methods or uses described herein inhibit, reduce, or stop, or alleviate, cancer or tumor growth or spread by increasing, enhancing, or activating one or more immune responses. In some embodiments, a cancer or tumor is treated by reducing the cancer or tumor size (e.g., volume or mass) by at least 5%, at least 10%, at least 25%, at least 50%, at least 75%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% compared to the size of the cancer or tumor prior to treatment. In some embodiments, a cancer or tumor is treated by reducing the amount of cancer or tumor in a patient by at least 5%, at least 10%, at least 25%, at least 50%, at least 75%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% compared to the amount of cancer or tumor prior to treatment.

[0210] In some embodiments, a patient treated using the methods or uses described herein exhibits a progression-free survival period of at least about 1 month, at least about 2 months, at least about 3 months, at least about 4 months, at least about 5 months, at least about 6 months, at least about 7 months, at least about 8 months, at least about 9 months, at least about 10 months, at least about 11 months, at least about 1 year, at least about 18 months, at least about 2 years, at least about 3 years, at least about 4 years, or at least about 5 years after the start of treatment. In some embodiments, a patient treated using the methods or uses described herein exhibits an overall survival period of at least about 1 month, at least about 2 months, at least about 3 months, at least about 4 months, at least about 5 months, at least about 6 months, at least about 7 months, at least about 8 months, at least about 9 months, at least about 10 months, at least about 11 months, at least about 1 year, at least about 14 months, at least about 16 months, at least about 18 months, at least about 20 months, at least about 22 months, at least about 2 years, at least about 3 years, at least about 4 years, or at least about 5 years after the start of treatment.

[0211] In some embodiments, a patient treated using the methods or uses described herein exhibits an objective overall response rate (ORR) of at least about 15%, at least about 20%, at least about 25%, at least about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, or about 100%.

[0212] The compounds and compositions according to the methods of the present disclosure can be administered, for example, in any amount effective to inhibit MEK and treat or reduce the severity of a disease, and by any route of administration, as described herein. The exact amount required will vary from subject to subject depending on the species, age, and general condition of the subject, the severity of the disease or disorder, the particular agent, the mode of its administration, and the like. The compounds of the present disclosure are preferably formulated in dosage unit form for ease of administration and uniformity of dosage. The expression "dosage unit form" as used herein refers to physically discrete units suitable for the patient to be treated. However, it will be understood that the overall daily usage of the compounds and compositions of the present disclosure will be determined by the attending physician within the scope of sound medical judgment. The specific effective dosage level for any particular patient or organism will depend upon a variety of factors including the disorder being treated and the severity of the disorder; the activity of the specific compound employed; the specific composition employed; the age, body weight, general health, sex and diet of the patient; the time of administration, route of administration, and rate of excretion of the specific compound employed; the duration of the treatment; drugs used in combination with or concurrently with the specific compound employed, and like factors well known in the medical arts. The term "patient" as used herein means an animal, preferably a mammal, and most preferably a human.

[0213] The pharmaceutically acceptable compositions of the present disclosure can be administered to humans and other animals orally, rectally, parenterally, intracystically, intravaginally, intraperitoneally, topically (by powder, ointment, or droplet), buccally, as an oral or nasal spray, etc., depending on the severity of the disease or disorder being treated. In certain embodiments, the compounds of the present disclosure can be administered orally or parenterally one or more times a day at dosage levels of about 0.01 mg / kg of subject body weight to about 50 mg / kg of subject body weight per day and preferably about 1 mg / kg of subject body weight to about 25 mg / kg of subject body weight to obtain the desired therapeutic effect.

[0214] Liquid dosage forms for oral administration include, but are not limited to, pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups, and elixirs. In addition to the active compound, liquid dosage forms may contain inert diluents commonly used in the art such as water or other solvents, solubilizing agents, and emulsifying agents such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3 - butylene glycol, dimethylformamide, oils (especially cottonseed oil, peanut oil, corn oil, germ oil, olive oil, castor oil, and sesame oil), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycol, and sorbitan fatty acid esters, and mixtures thereof. In addition to inert diluents, oral compositions may also contain adjuvants such as wetting agents, emulsifying agents, and suspending agents, sweetening agents, flavoring agents, and perfuming agents.

[0215] Injectable preparations, for example, sterile injectable aqueous or oily suspensions, can be formulated according to known techniques using suitable dispersing or wetting agents and suspending agents. Sterile injectable preparations can also be in the form of sterile injectable solutions, suspensions, or emulsions in a non - toxic parenterally acceptable diluent or solvent, for example, in solution in 1,3 - butanediol. Among the acceptable vehicles and solvents that can be used are water, Ringer's solution, U.S.P., and isotonic sodium chloride solution. Also, sterile fixed oils have conventionally been used as solvents or suspending media. For this purpose, any brand of fixed oil containing synthetic mono - or diglycerides can be used. Furthermore, fatty acids such as oleic acid can be used in the preparation of injectables.

[0216] Injectable formulations can be sterilized, for example, by filtration through a bacteria - retaining filter or by incorporating a sterilizing agent in the form of a sterile solid composition that can be dissolved or dispersed in sterile water or other sterile injectable medium before use.

[0217] To extend the effect of the compounds of the present disclosure, it is often desirable to delay the absorption of the compounds from subcutaneous or intramuscular injection. This can be achieved by the use of crystals having poor water solubility, or a liquid suspension of amorphous material. The absorption rate of the compound is thus dependent on its dissolution rate, which can be dependent on the crystal size and crystal form. Alternatively, the absorption delay of the parenterally administered compound form is achieved by dissolving or suspending the compound in an oily vehicle. Injectable depot forms are prepared by forming a microencapsulated matrix of the compound in a biodegradable polymer such as polylactide-polyglycolide. The rate of compound release can be adjusted according to the ratio of the compound to the polymer and the nature of the particular polymer used. Other examples of biodegradable polymers include poly(orthoesters) and poly(anhydrides). Depot injectable formulations are also prepared by encapsulating the compound in liposomes or microemulsions compatible with body tissues.

[0218] Compositions for rectal or vaginal administration are preferably suppositories prepared by mixing a compound of the present disclosure with a suitable non-irritating excipient or carrier, such as cocoa butter, polyethylene glycol or suppository wax, which is solid at ambient temperature but liquid at body temperature, so as to dissolve in the rectal or vaginal cavity and release the active compound.

[0219] Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In such solid dosage forms, the active compound is combined with at least one inert pharmaceutically acceptable excipient or carrier such as sodium citrate or dicalcium phosphate, and / or a) fillers or bulking agents such as starch, lactose, sucrose, glucose, mannitol, and silicic acid, b) binders such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose, and acacia, c) wetting agents such as glycerol, d) disintegrants such as agar, calcium carbonate, potato starch or tapioca starch, e) solution retarders such as paraffin, f) absorption promoters such as quaternary ammonium compounds, g) wetting agents such as, for example, cetyl alcohol and glycerol monostearate, h) absorbents such as kaolin and bentonite clay, and i) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium lauryl sulfate, and mixtures thereof. In the case of capsules, tablets, and pills, the dosage form may also include buffering agents.

[0220] Similar types of solid compositions can also be used as fillers in soft and hard gelatin capsules using lactose or milk sugar, as well as high molecular weight polyethylene glycol and similar excipients. Solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings and other coatings known in the art of formulation. They can optionally contain opacifying agents or, preferably, can be compositions that release the active ingredient(s) optionally in a delayed manner only in a specific part of the intestinal tract. Examples of encapsulating compositions that can be used include polymeric substances and waxes. Similar types of solid compositions can also be used as fillers in soft and hard gelatin capsules using lactose or milk sugar, as well as high molecular weight polyethylene glycol and similar excipients.

[0221] The active compound can also be in micro-encapsulated form with one or more of the excipients described above. Solid dosage forms such as tablets, dragees, capsules, pills, and granules can be prepared using coatings and shells such as enteric coatings, release control coatings, and other coatings well-known in the pharmaceutical formulation art. In such solid dosage forms, the active compound may be mixed with at least one inert diluent such as sucrose, lactose, or starch. According to conventional methods, such dosage forms may also contain additional substances other than the inert diluent, such as tableting lubricants and other tableting aids such as magnesium stearate and microcrystalline cellulose. In the case of capsules, tablets, and pills, the dosage form may also contain buffering agents. They may optionally contain opacifying agents or, preferably, may be compositions that release the active ingredient(s) optionally in a delayed manner only in a specific part of the intestinal tract. Examples of encapsulating compositions that can be used include polymeric substances and waxes.

[0222] Dosage forms for topical or transdermal administration of the compounds of the present disclosure include ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalants or patches. The active ingredient is mixed under aseptic conditions with a pharmaceutically acceptable carrier and any necessary preservatives or buffering agents as required. Ophthalmic formulations, ear drops, and eye drops are also considered to be within the scope of the present disclosure. Furthermore, the present disclosure contemplates the use of transdermal patches that have the further advantage of providing controlled delivery of the compound to the body. Such dosage forms can be prepared by dissolving or dispensing the compound in a suitable medium. Absorption enhancers can also be used to increase the flow of the compound across the skin. The rate can be controlled either by providing a rate controlling membrane or by dispersing the compound in a polymeric matrix or gel.

[0223] d. Co-administration with one or more other therapeutic agent(s) Co-administration with one or more other therapeutic agent(s) Depending on the particular medical condition or disease being treated, additional therapeutic agents that are normally administered to treat the condition may also be present in the compositions of the present disclosure. As used herein, additional therapeutic agents that are normally administered to treat a particular disease or medical condition are known as being "appropriate for the disease or medical condition being treated."

[0224] In some embodiments, the present disclosure provides a method of treating a disclosed disease or medical condition comprising administering to a patient in need thereof an effective amount of a compound disclosed herein or a pharmaceutically acceptable salt thereof and co-administering simultaneously or sequentially an effective amount of one or more additional therapeutic agents such as those described herein. In some embodiments, the method comprises co-administering one additional therapeutic agent. In some embodiments, the method comprises co-administering two additional therapeutic agents. In some embodiments, the combination of the disclosed compound and additional therapeutic agent(s) act synergistically.

[0225] The compounds of the present disclosure can be administered alone or in combination with one or more other therapeutic compounds, and possible combination therapies take the form of a fixed combination or administration of the compounds of the present disclosure with one or more other therapeutic compounds administered at staggered or independent times, or co-administration of a fixed combination with one or more other therapeutic compounds.

[0226] One or more other therapeutic agents (plural available) can be administered separately from the compounds or compositions of the present disclosure as part of multiple dosing regimens. Alternatively, one or more other therapeutic agents (plural available) can be part of a single dosage form and can be mixed with the compounds of the present disclosure in a single composition. When administered as multiple dosing regimens, one or more other therapeutic agents (plural available), and the compounds or compositions of the present disclosure can be administered simultaneously, sequentially, or within a certain time period of each other, for example, within 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, or 24 hours of each other. In some embodiments, one or more other therapeutic agents (therapeutic agents), and the compounds or compositions of the present disclosure are administered as multiple dosing regimens at intervals exceeding 24 hours.

[0227] As used herein, the terms "in combination", "combined", and related terms mean the simultaneous or sequential administration of therapeutic agents according to the present disclosure. For example, the compounds of the present disclosure can be administered with one or more other therapeutic agents (plural available) simultaneously or sequentially in individual unit dosage forms, or together in a single unit dosage form. Accordingly, the present disclosure provides a single unit dosage form comprising a compound of the present disclosure, one or more other therapeutic agents (plural available), and a pharmaceutically acceptable carrier, adjuvant, or vehicle.

[0228] The amounts of the compounds of the present disclosure, and one or more other therapeutic agents (plural available) (in compositions containing the additional therapeutic agents described above) that can be combined with a carrier material to produce a single dosage form will vary depending on the host being treated and the particular method of administration. Preferably, the compositions of the present disclosure need to be formulated such that the compounds of the present disclosure can be administered at a dosage of 0.01 to 100 mg / kg body weight / day.

[0229] In a composition comprising one or more other therapeutic agents (plural possible), the one or more other therapeutic agents (plural possible) and the compounds of the present disclosure can act synergistically. Thus, the amount of the one or more other therapeutic agents (plural possible) in such a composition may be less than the amount required in a monotherapy using only that therapeutic agent. In such a composition, the one or more other therapeutic agents (plural possible) can be administered at a dose of 0.01 to 1,000 g / kg body weight / day.

[0230] The amount of the one or more therapeutic agents (plural possible) present in the composition of the present disclosure cannot be more than the amount that would typically be administered in a composition containing that therapeutic agent as the sole active agent. Preferably, the amount of the one or more therapeutic agents (plural possible) in the composition of the present disclosure is in the range of about 50% to 100% of the amount normally present in a composition containing that therapeutic agent as the sole therapeutic active agent. In some embodiments, the one or more other therapeutic agents (plural possible) are administered at a dose of about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, or about 95% of the amount normally administered for that agent. As used herein, the phrase "normally administered" means the amount approved for administration of an FDA-approved therapeutic agent according to the FDA label insert.

[0231] The compounds of the present disclosure, or pharmaceutical compositions thereof, can also be incorporated into compositions for coating implantable medical devices such as prostheses, artificial valves, artificial blood vessels, stents, and catheters. Vascular stents, for example, have been used to overcome restenosis (the narrowing of the blood vessel wall again after injury). However, patients using stents or other implantable devices are at risk of blood clot formation or platelet activation. These unwanted effects can be prevented or mitigated by pre-coating the device with a pharmaceutically acceptable composition containing a kinase inhibitor. An implantable device coated with a compound of the present disclosure is another embodiment of the present disclosure.

[0232] e. Exemplary other therapeutic agents In some embodiments, the one or more other therapeutic agents are TEAD inhibitors. In certain embodiments, the TEAD inhibitor is selected from those described in WO 2020 / 243415, the entire content of which is incorporated herein by reference. In certain embodiments, the TEAD inhibitor is selected from those described in WO 2020 / 243423, the entire content of which is incorporated herein by reference. In certain embodiments, the TEAD inhibitor is selected from those described in U.S. Patent No. 11,247,082, the entire content of which is incorporated herein by reference. In certain embodiments, the TEAD inhibitor is selected from those described in WO 2022 / 120353, the entire content of which is incorporated herein by reference. In certain embodiments, the TEAD inhibitor is selected from those described in WO 2022 / 120354, the entire content of which is incorporated herein by reference.

[0233] In certain embodiments, the second anti-cancer agent is a TEAD degrader. In certain embodiments, the TEAD degrader is selected from those described in WO 2022 / 120355, the entire content of which is incorporated herein by reference.

[0234] TEAD inhibitors can be manufactured by synthetic methods known to those skilled in the art. Further, certain TEAD inhibitors are prepared as described in Pobbati et al., “Targeting the Central Pocket in Human Transcription Factor TEAD as a Potential Cancer Therapeutic Strategy,” Structure 2015, 23, 2076 - 2086; Gibault et al., “Targeting Transcriptional Enhanced Associate Domains (TEADs),” J. Med. Chem. 2018, 61, 5057 - 5072; Bum-Erdene et al., Small-Molecule Covalent Modification of Conserved Cysteine Leads to Allosteric Inhibition of the TEADoYap Protein-Protein Interaction, Cell Chemical Biology 2019, 26, 1 - 12; Holden et al., “Small Molecule Dysregulation of TEAD Lipidation Induces a Dominant-Negative Inhibition of Hippo Pathway Signaling,” Cell Reports 2020, 31, 107809; WO 2017 / 053706, WO 2017 / 111076, WO 2018 / 204532, WO 2018 / 235926, US 20190010136, WO 2019 / 040380, WO 2019 / 113236, WO 2019 / 222431, WO 2019 / 232216, WO 2020 / 051099, WO 2020 / 081572, WO 2020 / 097389, WO 2020 / 190774, WO 2020 / 214734, PCT / US2020 / 35098, and PCT / US2020 / 35111, the entire contents of each of which are hereby incorporated by reference.

[0235] In some embodiments, the one or more other therapeutic agents are ERK5 inhibitors. In certain embodiments, the ERK5 inhibitor is selected from those described in WO 2022 / 051567, the entire content of which is incorporated herein by reference. In certain embodiments, the ERK5 inhibitor is selected from those described in WO 2022 / 051565, the entire content of which is incorporated herein by reference. In certain embodiments, the ERK5 inhibitor is selected from those described in WO 2022 / 051569, the entire content of which is incorporated herein by reference. In certain embodiments, the ERK5 inhibitor is selected from those described in WO 2022 / 051568, the entire content of which is incorporated herein by reference.

[0236] In some embodiments, the one or more other therapeutic agents are KRAS inhibitors such as KRAS G12C inhibitors. As used herein, "KRAS G12C inhibitor" means any inhibitor or blocker or antagonist that binds to KRAS and / or inhibits signal transduction through KRAS. In certain embodiments, the KRAS G12C inhibitor is selected from adagrasib (KRAZATI®, Mirati Therapeutics), sotorasib (LUMAKRAS® and LUMYKRAS®, Amgen), or any pharmaceutically acceptable salt and / or solvate of the foregoing. Other examples of KRAS G12C inhibitors for use in the methods and uses described herein include, but are not limited to, JDQ-443 (Novartis AG), D-1553 (Inventisbio Shanghai), GF-105 (GenFleet Therapeutics), GH-35 (Suzhou GenHouse Bio Co.), JAB-21822 (Jacobio Pharmaceuticals), JMKX-001899 (Shanghi Jiyu Pharmaceuticals), TAS-119 (Taiho Pharmaceuticals), XNW-14010 (Suzhou Sinovent Pharmaceuticals), YL-15293 (Shanghai Yingli Pharmaceuticals), ZG-19018 (Suzhou Zelgen Biopharma), BEBT-607 (Guangzhou Bibet Pharmaceuticals), BI-1701963 (Forma Therapeutics Holdings), BI-1823911 (Boehringer Ingelheim Gmbh), BPI-421286 (Betta Pharmaceuticals), D3S-001 (D3 Bio), ERAS-3490 (Regents of the University of California), GEC-255 (GenEros BioPhrma LTD), and JS116 (Shanghai Junshi Biosceinces).Other examples of KRAS G12C inhibitors in the methods and uses described herein include, but are not limited to, those described in International Patent Publication No. WO 2021 / 120890, the entire contents of each of which are incorporated herein by reference.

[0237] In some embodiments, one or more other therapeutic agents are pan-RAF inhibitors. As used herein, "pan-RAF inhibitor" means any inhibitor or blocker or antagonist that binds to all known members of the serine / threonine protein kinase Raf family, including A-Raf, B-Raf, and C-Raf protein kinases, and has potential anti-tumor activity. In certain embodiments, the pan-RAF inhibitor is selected from tovorafenib (TAK580, Day One Biopharmaceuticals), TAK-632 (Takeda Pharmaceuticals), lifirafenib (BGB-283, BeiGene), exarafenib (Kinnate Biopharma), naporafenib (LXH-254, Erasca), or any pharmaceutically acceptable salt and / or solvate thereof. In certain embodiments, the pan-RAF inhibitor is selected from tovorafenib, TAK-632, lifirafenib, exarafenib, or any pharmaceutically acceptable salt and / or solvate thereof. Other examples of pan-RAF inhibitors useful in the compositions, methods, and uses described herein include, but are not limited to, those described in International Patent Publications No. WO2015 / 075483, No. WO2015 / 075483, and No. WO2014 / 151616, the entire contents of each of which are incorporated herein by reference.

[0238] In some embodiments, one or more other therapeutic agents are poly(ADP-ribose) polymerase (PARP) inhibitors. In some embodiments, the PARP inhibitor is selected from olaparib (Lynparza®, AstraZeneca); rucaparib (Rubraca®, Clovis Oncology); niraparib (Zejula®, Tesaro); talazoparib (MDV3800 / BMN 673 / LT00673, Medivation / Pfizer / Biomarin); veliparib (ABT-888, AbbVie); and BGB-290 (BeiGene, Inc.).

[0239] In some embodiments, one or more other therapeutic agents are histone deacetylase (HDAC) inhibitors. In some embodiments, the HDAC inhibitor is selected from vorinostat (Zolinza®, Merck); romidepsin (Istodax®, Celgene); panobinostat (Farydak®, Novartis); belinostat (Beleodaq®, Spectrum Pharmaceuticals); entinostat (SNDX-275, Syndax Pharmaceuticals) (NCT00866333); and chidamide (Epidaza®, HBI-8000, Chipscreen Biosciences, China).

[0240] In some embodiments, one or more other therapeutic agents are CDK inhibitors such as CDK4 / CDK6 inhibitors. In some embodiments, the CDK4 / 6 inhibitor is selected from palbociclib (Ibrance®, Pfizer); ribociclib (Kisqali®, Novartis); abemaciclib (Ly2835219, Eli Lilly); and trilaciclib (G1T28, G1 Therapeutics).

[0241] In some embodiments, one or more other therapeutic agents are phosphatidylinositol 3-kinase (PI3K) inhibitors. In some embodiments, the PI3K inhibitor is selected from idelalisib (Zydelig®, Gilead), alpelisib (BYL719, Novartis), taselisib (GDC-0032, Genentech / Roche); pictilisib (GDC-0941, Genentech / Roche); copanlisib (BAY806946, Bayer); duvelisib (formerly IPI-145, Infinity Pharmaceuticals); PQR309 (Piqur Therapeutics, Switzerland); and TGR1202 (formerly RP5230, TG Therapeutics). In some embodiments, the PI3K inhibitor is selected from inavolisib (GDC-077, Genentech), idelalisib (Zydelig®, Gilead), alpelisib (BYL719, Novartis), taselisib (GDC-0032, Genentech / Roche); pictilisib (GDC-0941, Genentech / Roche); copanlisib (BAY806946, Bayer); duvelisib (formerly IPI-145, Infinity Pharmaceuticals); PQR309 (Piqur Therapeutics, Switzerland); and TGR1202 (formerly RP5230, TG Therapeutics).

[0242] In some embodiments, one or more other therapeutic agents are platinum-based therapeutic agents, also referred to as platinums. Platinums cause DNA cross-linking and inhibit DNA repair and / or DNA synthesis, mainly in rapidly proliferating cells such as cancer cells.

[0243] In some embodiments, the platinum-based therapeutic agent is selected from cisplatin (Platinol®, Bristol-Myers Squibb); carboplatin (Paraplatin®, Bristol-Myers Squibb; also made by Teva; Pfizer); oxaliplatin (Eloxatin®, Sanofi-Aventis); nedaplatin (Aqupla®, Shionogi), picoplatin (Poniard Pharmaceuticals); and satraplatin (JM-216, Agennix).

[0244] In some embodiments, the one or more other therapeutic agents are taxane compounds, which cause disruption of microtubules essential for cell division. In some embodiments, the taxane compound is selected from paclitaxel (Taxol®, Bristol-Myers Squibb), docetaxel (Taxotere®, Sanofi-Aventis; Docefrez®, Sun Pharmaceutical), albumin-bound paclitaxel (Abraxane®; Abraxis / Celgene), cabazitaxel (Jevtana®, Sanofi-Aventis), and SID530 (SK Chemicals, Co.) (NCT00931008).

[0245] In some embodiments, the one or more other therapeutic agents are nucleoside inhibitors, or therapeutic agents that interfere with normal DNA synthesis, protein synthesis, cell replication, or otherwise inhibit rapid cell growth.

[0246] In some embodiments, the nucleoside inhibitor is trabectedin (a guanidine alkylating agent, Yondelis®, Janssen Oncology), mechlorethamine (an alkylating agent, Valchlor®, Aktelion Pharmaceuticals); vincristine (Oncovin®, Eli Lilly; Vincasar®, Teva Pharmaceuticals; Marqibo®, Talon Therapeutics); temozolomide (a prodrug for the alkylating agent 5-(3-methyltriazen-1-yl)-imidazole-4-carboxamide (MTIC), Temodar®, Merck); cytarabine injection (ara-C, a metabolic antagonist cytidine analogue, Pfizer); lomustine (an alkylating agent, CeeNU®, Bristol-Myers Squibb; Gleostine®, NextSource Biotechnology); azacitidine (a pyrimidine nucleoside analogue of cytidine, Vidaza®, Celgene); omacetaxine mepesuccinate (a cephalotaxine ester) (a protein synthesis inhibitor, Synribo®; Teva Pharmaceuticals); asparaginase Erwinia chrysanthemi (an enzyme for asparagine depletion, Elspar®, Lundbeck; Erwinaze®, EUSA Pharma); eribulin mesylate (a microtubule inhibitor, a tubulin-based cell division inhibitor, Halaven®, Eisai); cabazitaxel (a microtubule inhibitor, a tubulin-based cell division inhibitor, Jevtana®, Sanofi-Aventis); capecitabine (a thymidylate synthase inhibitor, Xeloda®, Genentech); bendamustine (a bifunctional mechlorethamine derivative, thought to form interstrand DNA crosslinks, Treanda®, Cephalon / Teva); ixabepilone (a semi-synthetic analogue of epothilone B, a microtubule inhibitor, a tubulin-based cell division inhibitor, Ixempra®, Bristol-Myers Squibb);Selected from nelarabine (prodrug of deoxyguanosine analog, nucleoside metabolic inhibitor, Arranon (registered trademark), Novartis); cladribine (prodrug of ribonucleotide reductase inhibitor, antagonist inhibitor of deoxycytidine, Clolar (registered trademark), Sanofi-Aventis); and trifluridine and tipiracil (thymidine nucleoside analog and thymidine phosphorylase inhibitor, Lonsurf (registered trademark), Taiho Oncology).;

[0247] In some embodiments, the one or more other therapeutic agents are kinase inhibitors or VEGF-R antagonists. Approved VEGF inhibitors and kinase inhibitors useful in the present disclosure include bevacizumab (Avastin®, Genentech / Roche), an anti-VEGF monoclonal antibody; ramucirumab (Cyramza®, Eli Lilly), an anti-VEGF antibody; aflibercept, also known as VEGF Trap (Zaltrap®; Regeneron / Sanofi); VEGFR inhibitors such as regorafenib (Stivarga®, Bayer); vandetanib (Caprelsa®, AstraZeneca); axitinib (Inlyta®, Pfizer); and lenvatinib (Lenvima®, Eisai); Raf inhibitors such as sorafenib (Nexavar®, Bayer AG and Onyx); dabrafenib (Tafinlar®, Novartis); and vemurafenib (Zelboraf®, Genentech / Roche); MEK inhibitors such as cobimetinib (Cotellic®, Exelexis / Genentech / Roche); trametinib (Mekinist®, Novartis); Bcr-Abl tyrosine kinase inhibitors such as imatinib (Gleevec®, Novartis); nilotinib (Tasigna®, Novartis); dasatinib (Sprycel®, BristolMyersSquibb); bosutinib (Bosulif®, Pfizer); and ponatinib (Inclusig®, Ariad Pharmaceuticals); Her2 and EGFR inhibitors such as gefitinib (Iressa®, AstraZeneca); erlotinib (Tarceeva®, Genentech / Roche / Astellas); lapatinib (Tykerb®, Novartis); afatinib (Gilotrif®, Boehringer Ingelheim);Osimertinib (targeting activated EGFR, Tagrisso (registered trademark), AstraZeneca); and brigatinib (Alunbrig (registered trademark), Ariad Pharmaceuticals); c-Met and VEGFR2 inhibitors, such as cabozantinib (Cometriq (registered trademark), Exelexis); and multi-kinase inhibitors, such as sunitinib (Sutent (registered trademark), Pfizer); pazopanib (Votrient (registered trademark), Novartis); ALK inhibitors, such as crizotinib (Xalkori (registered trademark), Pfizer); ceritinib (Zykadia (registered trademark), Novartis); and alectinib (Alecenza (registered trademark), Genentech / Roche); tyrosine kinase inhibitors, such as ibrutinib (Imbruvica (registered trademark), Pharmacyclics / Janssen); and Flt3 receptor inhibitors, such as midostaurin (Rydapt (registered trademark), Novartis).;

[0248] Other kinase inhibitors and VEGF antagonists that are under development and can be used in the present disclosure include tibiozanib (Aveo Pharmaecuticals); batatinib (Bayer / Novartis); lucitanib (Clovis Oncology); dovitinib (TKI258, Novartis); thiauanib (Chipscreen Biosciences); CEP-11981 (Cephalon); linifanib (Abbott Laboratories); neratinib (HKI-272, Puma Biotechnology); radotinib (Supect (registered trademark), IY5511, Il-Yang Pharmaceuticals, S. Korea); ruxolitinib (Jakafi (registered trademark), Incyte Corporation); PTC299 (PTC Therapeutics); CP-547,632 (Pfizer); foretinib (Exelexis, GlaxoSmithKline); quizartinib (Daiichi Sankyo), and motesanib (Amgen / Takeda).

[0249] In some embodiments, the one or more other therapeutic agents are EGFR inhibitors. As used herein, "EGFR inhibitor" means any inhibitor or blocker or antagonist that binds to and / or inhibits the epidermal growth factor receptor (EGFR). In some embodiments, the EGFR inhibitor is selected from those described in Ayati et al., "A review on progression of epidermal growth factor receptor (EGFR) inhibitors as an efficient approach in cancer targeted therapy," Bioorganic Chemistry 2020, 99: 103811, which is hereby incorporated by reference in its entirety. In some embodiments, the EGFR inhibitor is selected from cetuximab, necitumumab, panitumumab, zalutumumab, nimotuzumab, and matuzumab. In some embodiments, the EGFR inhibitor is cetuximab. In some embodiments, the EGFR inhibitor is necitumumab. In some embodiments, the EGFR inhibitor is panitumumab. In some embodiments, the EGFR inhibitor is zalutumumab. In some embodiments, the EGFR inhibitor is nimotuzumab. In some embodiments, the EGFR inhibitor is matuzumab.

[0250] In some embodiments, the EGFR inhibitor is selected from osimertinib, gefitinib, erlotinib, lapatinib, neratinib, vandetanib, afatinib, brigatinib, dacomitinib, and icotinib. In some embodiments, the EGFR inhibitor is osimertinib. In some embodiments, the EGFR inhibitor is gefitinib. In some embodiments, the EGFR inhibitor is erlotinib. In some embodiments, the EGFR inhibitor is lapatinib. In some embodiments, the EGFR inhibitor is neratinib. In some embodiments, the EGFR inhibitor is vandetanib. In some embodiments, the EGFR inhibitor is afatinib. In some embodiments, the EGFR inhibitor is brigatinib. In some embodiments, the EGFR inhibitor is dacomitinib. In some embodiments, the EGFR inhibitor is icotinib.

[0251] In some embodiments, the EGFR inhibitor is a "first-generation EGFR tyrosine kinase inhibitor" (first-generation TKI). The first-generation TKI refers to reversible EGFR inhibitors such as gefitinib and erlotinib that are effective in the first-line treatment of NSCLC with EGFR activating mutations such as deletions in exon 19 and exon 21 L858R mutations.

[0252] In some embodiments, the EGFR inhibitor is a "second-generation EGFR tyrosine kinase inhibitor" (second-generation TKI). The second-generation TKI refers to covalent irreversible EGFR inhibitors such as afatinib and dacomitinib that are effective in the first-line treatment of NSCLC with EGFR activating mutations such as deletions in exon 19 and exon 21 L858R mutations.

[0253] In some embodiments, the EGFR inhibitor is a "third-generation EGFR tyrosine kinase inhibitor" (third-generation TKI). The third-generation TKI refers to a covalent irreversible EGFR inhibitor such as osimertinib and lazertinib that is selective for EGFR activating mutations, such as deletions in exon 19 and exon 21 L858R, alone or in combination with the T790M mutation, and has low inhibitory activity against wild-type EGFR.

[0254] In some embodiments, the one or more other therapeutic agents are mTOR inhibitors, which inhibit cell proliferation, angiogenesis, and glucose uptake. In some embodiments, the mTOR inhibitors are everolimus (Afinitor®, Novartis); temsirolimus (Torisel®, Pfizer); and sirolimus (Rapamune®, Pfizer).

[0255] In some embodiments, the one or more other therapeutic agents are SOS1 (son of sevenless 1) inhibitors. In some embodiments, the SOS1 inhibitors are selected from BI-3406, BAY-293, MRTX0902, and BI-1701963. Other exemplary SOS1 inhibitors for use in the compositions, methods, and uses described herein include, but are not limited to, the SOS1 inhibitors described in Patent Publication Nos. WO2020180768A1, WO2021130731A1, WO2022271679A1, WO2022266248A1, WO2022058344A1, and WO2019122129A1, the entire contents of each of which are incorporated herein by reference.

[0256] In some embodiments, the one or more other therapeutic agents are SHP2 (Src homology 2 domain-containing protein tyrosine phosphatase) inhibitors. In some embodiments, the SHP2 inhibitor is selected from RMC-4550, RMC-4630, BBP-398, SHP836, SHP099, SHP394, BPI-442096, and ETS-001. Other exemplary SHP2 inhibitors for use in the compositions, methods, and uses described herein include those described in Patent Publications WO2017211303A1, WO2017216706A1, WO2018013597A1, WO2018057884A1, WO2018172984A1, WO2018081091A1, WO2018136265A1, WO2018136264A1, WO2019051084A1, WO2019067843A1, WO2019075265A1, WO2019118909A1, WO2019165073A1, WO2019183367A1, WO2019183364A1, WO2019233810A1, WO2020022323A1, WO2020061103A1, WO2020063760A1, WO2020108590A1, WO2020081848A1, WO2020156242A1, WO2020156243A1, WO2021033153A1, WO2021061515A1, WO2021074227A1, WO2021110796A1, WO2021143680A1, WO2021143823A1, WO2021218752A1, WO2021218755A1, WO2021249449A1, WO2022017444A1, WO2022033430A1, WO2022089389A1, WO2022089406A1, WO2022161222A1, WO2023280283A1, and WO2023282702A1, but are not limited thereto, and the contents of each of these are hereby incorporated by reference in their entirety.

[0257]

[0257] In some embodiments, one or more other therapeutic agents are proteasome inhibitors. Approved proteasome inhibitors useful in the present disclosure include bortezomib (Velcade®, Takeda); carfilzomib (Kyprolis®, Amgen); and ixazomib (Ninlaro®, Takeda).

[0258]

[0258] In some embodiments, one or more other therapeutic agents are growth factor agonists, such as platelet-derived growth factor (PDGF), or an antagonist of epidermal growth factor (EGF) or its receptor (EGFR). Approved PDGF antagonists that can be used in the present disclosure include lartruvo (Lartruvo®; Eli Lilly). Approved EGFR antagonists that can be used in the present disclosure include cetuximab (Erbitux®, Eli Lilly); necitumumab (Portrazza®, Eli Lilly), panitumumab (Vectibix®, Amgen); and osimertinib (targeting activated EGFR, Tagrisso®, AstraZeneca).

[0259]

[0259] In some embodiments, one or more other therapeutic agents are aromatase inhibitors. In some embodiments, the aromatase inhibitor is selected from exemestane (Aromasin®, Pfizer); anastrozole (Arimidex®, AstraZeneca), and letrozole (Femara®, Novartis).

[0260] In some embodiments, one or more other therapeutic agents are antagonists of the hedgehog pathway. Approved hedgehog pathway inhibitors that can be used in the present disclosure include, both, sonidegib (Odomzo®, Sun Pharmaceuticals) for treating basal cell carcinoma; and vismodegib (Erivedge®, Genentech).

[0261] In some embodiments, one or more other therapeutic agents are folic acid inhibitors. Approved folic acid inhibitors useful in the present disclosure include pemetrexed (Alimta®, Eli Lilly).

[0262] In some embodiments, one or more other therapeutic agents are CC chemokine receptor 4 (CCR4) inhibitors. CCR4 inhibitors that have been studied as being potentially useful in the present disclosure include mogamulizumab (Poteligeo®, Kyowa Hakko Kirin, Japan).

[0263] In some embodiments, one or more other therapeutic agents are isocitrate dehydrogenase (IDH) inhibitors. IDH inhibitors that have been studied as being usable in the present disclosure include AG120 (Celgene; NCT02677922); AG221 (Celgene, NCT02677922; NCT02577406); BAY1436032 (Bayer, NCT02746081); IDH305 (Novartis, NCT02987010).

[0264] In some embodiments, one or more other therapeutic agents are arginase inhibitors. Arginase inhibitors that have been studied as being potentially usable in the present disclosure include AEB1102 (PEGylated recombinant arginase, Aeglea Biotherapeutics), which is being tested in a Phase I clinical trial against acute myeloid leukemia and myelodysplastic syndromes (NCT02732184) and solid tumors (NCT02561234); and CB-1158 (Calithera Biosciences).

[0265] In some embodiments, one or more other therapeutic agents are glutaminase inhibitors. Glutaminase inhibitors that are usable in the present disclosure include CB-839 (Calithera Biosciences).

[0266] In some embodiments, the one or more other therapeutic agents are antibodies that bind to tumor antigens, i.e., proteins expressed on the cell surface of tumor cells. Approved antibodies that bind to tumor antigens that can be used in the present disclosure include rituximab (Rituxan®, Genentech / Biogen Idec); ofatumumab (anti-CD20, Arzerra®, GlaxoSmithKline); obinutuzumab (anti-CD20, Gazyva®, Genentech), ibritumomab (anti-CD20 and yttrium 90, Zevalin®, Spectrum Pharmaceuticals); daratumumab (anti-CD38, Darzalex®, Janssen Biotech); dinutuximab (anti-glycolipid GD2, Unituxin®, United Therapeutics); trastuzumab (anti-HER2, Herceptin®, Genentech); ado-trastuzumab emtansine (anti-HER2, fused to emtansine, Kadcyla®, Genentech); and pertuzumab (anti-HER2, Perjeta®, Genentech); and brentuximab vedotin (anti-CD30-drug conjugate, Adcetris®, Seattle Genetics).

[0267] In some embodiments, the one or more other therapeutic agents are topoisomerase inhibitors. Approved topoisomerase inhibitors that are useful in the present disclosure include irinotecan (Onivyde®, Merrimack Pharmaceuticals); topotecan (Hycamtin®, GlaxoSmithKline). Topoisomerase inhibitors that have been studied for use in the present disclosure include pixantrone (Pixuvri®, CTI Biopharma).

[0268] In some embodiments, one or more other therapeutic agents are inhibitors of anti-apoptotic proteins such as BCL-2. Approved anti-apoptotic drugs that can be used in the present disclosure include Venetoclax (Venclexta®, AbbVie / Genentech); and Blinatumomab (Blincyto®, Amgen). Other therapeutic agents that target apoptotic proteins and are undergoing clinical trials and can be used in the present disclosure include Navitoclax (ABT-263, Abbott), a BCL-2 inhibitor (NCT02079740).

[0269] In some embodiments, one or more other therapeutic agents are androgen receptor inhibitors. Approved androgen receptor inhibitors that are useful in the present disclosure include Enzalutamide (Xtandi®, Astellas / Medivation); approved inhibitors of androgen synthesis include Abiraterone (Zytiga®, Centocor / Ortho); approved antagonists of gonadotropin-releasing hormone (GnRH) receptors (degarelix, Firmagon®, Ferring Pharmaceuticals) are included.

[0270] In some embodiments, one or more other therapeutic agents are selective estrogen receptor modulators (SERMs), which interfere with estrogen synthesis or activity. An approved SERM that is useful in the present disclosure includes Raloxifene (Evista®, Eli Lilly).

[0271] In some embodiments, one or more other therapeutic agents are bone resorption inhibitors. An approved therapeutic agent that inhibits bone resorption is denosumab (Xgeva®, Amgen), which is found on the surface of osteoclasts, their precursors, and osteoclast-like giant cells and is an antibody that binds to RANKL and prevents its binding to its receptor RANK, intervening in the bone condition in solid tumors with bone metastases. Other approved therapeutic agents that inhibit bone resorption include bisphosphonates such as zoledronic acid (Zometa®, Novartis).

[0272] In some embodiments, one or more other therapeutic agents are inhibitors of the interaction between MDMX and MDM2, which are two main p53 suppressor proteins. An inhibitor of p53-suppressing proteins that has been studied for use in the present disclosure is the stapled peptide ALRN-6924 (Aileron), which binds equally to MDMX and MDM2 and equally inhibits the interaction of MDMX and MDM2 with p53. ALRN-6924 is currently being investigated in clinical trials for the treatment of AML, myelodysplastic syndrome (MDS), and peripheral T-cell lymphoma (PTCL) (NCT02909972; NCT02264613).

[0273] In some embodiments, one or more other therapeutic agents are inhibitors of transforming growth factor beta (TGF-beta or TGF-β). Inhibitors of TGF-beta proteins that have been studied for use in the present disclosure include the anti-TGF-beta antibody NIS793 (Novartis), which is in clinical trials for the treatment of various cancers including breast cancer, lung cancer, hepatocellular carcinoma, colon cancer, pancreatic cancer, prostate cancer, and renal cancer (NCT 02947165). In some embodiments, the inhibitor of the TGF-beta protein is fresolimumab (GC1008; Sanofi-Genzyme), which has been studied for melanoma (NCT00923169); renal cell carcinoma (NCT00356460); and non-small cell lung cancer (NCT02581787). Further, in some embodiments, the additional therapeutic agent is a TGF-beta trap as described in Connolly et al. (2012) Int’l J. Biological Sciences 8:964-978. Therapeutic compounds currently in clinical trials for the treatment of solid tumors are the bispecific anti-PD-L1 / TGF-β trap compound (NCT02699515); and M7824 (Merck KgaA - formerly MSB0011459X) (NCT02517398). M7824 is composed of a fully human IgG1 antibody against PD-L1 fused to the extracellular domain of human TGF-beta receptor II, which functions as a TGF-β “trap”.

[0274] In some embodiments, one or more other therapeutic agents are selected from glembatumumab vedotin - monomethyl auristatin E (MMAE) (Celldex), an anti-glycoprotein NMB (gpNMB) antibody (CR011) conjugated to the cytotoxic MMAE. gpNMB is a protein overexpressed by multiple types of tumors associated with the ability of cancer cells to metastasize.

[0275] In some embodiments, one or more other therapeutic agents are anti-proliferative compounds. Such anti-proliferative compounds include aromatase inhibitors; anti-estrogen drugs; topoisomerase I inhibitors; topoisomerase II inhibitors; microtubule-active compounds; alkylating compounds; histone deacetylase inhibitors; compounds that induce cell differentiation processes; cyclooxygenase inhibitors; MMP inhibitors; mTOR inhibitors; anti-tumor antimetabolites; platinum compounds; compounds that target / reduce protein or lipid kinase activity, and additional anti-angiogenic compounds; compounds that target, reduce, or inhibit the activity of protein or lipid phosphatases; gonadorelin agonists; anti-androgen agents; methionine aminopeptidase inhibitors; matrix metalloproteinase inhibitors; bisphosphonates; biological response modifiers; anti-proliferative antibodies; heparanase inhibitors; inhibitors of Ras oncogenic isoforms; telomerase inhibitors; proteasome inhibitors; compounds used in the treatment of hematological malignancies; compounds that target, reduce, or inhibit the activity of Flt-3; Hsp90 inhibitors such as 17-AAG (17-allylaminogeldanamycin, NSC330507), 17-DMAG (17-dimethylaminoethylamino-17-demethoxy-geldanamycin, NSC707545), IPI-504, CNF1010, CNF2024, CNF1010, etc. manufactured by Conforma Therapeutics; temozolomide (Temodal®); kinesin spindle protein inhibitors such as SB715992 or SB743921 manufactured by GlaxoSmithKline, or pentamidine / chlorpromazine manufactured by CombinatoRx; MEK inhibitors such as ARRY142886 manufactured by Array BioPharma, AZd6244 manufactured by AstraZeneca, PD181461 manufactured by Pfizer, and leucovorin, but are not limited thereto.

[0276] As used herein, the term "aromatase inhibitor" relates to a compound that inhibits estrogen production, e.g., the conversion of the substrates androstenedione and testosterone to estrone and estradiol, respectively. This term includes, but is not limited to, steroids, particularly atamestane, exemestane, and formestane, and, particularly, non-steroids, particularly aminoglutethimide, logretimide, pyridoglutethimide, trilostane, testolactone, ketoconazole, vorozole, fadrozole, anastrozole, and letrozole. Exemestane is sold under the trade name Aromasin™. Formestane is sold under the trade name Lentaron™. Fadrozole is sold under the trade name Afema™. Anastrozole is sold under the trade name Arimidex™. Letrozole is sold under the trade name Femara™ or Femar™. Aminoglutethimide is sold under the trade name Orimeten™. The combinations of the present disclosure that include a chemotherapeutic agent that is an aromatase inhibitor are particularly useful for the treatment of hormone receptor-positive tumors such as breast tumors.

[0277] As used herein, the term "antiestrogen" means a compound that antagonizes the effects of estrogen at the estrogen receptor level. This term includes, but is not limited to, tamoxifen, fulvestrant, raloxifene, and raloxifene hydrochloride. Tamoxifen is sold under the trade name Nolvadex™. Raloxifene hydrochloride is sold under the trade name Evista™. Fulvestrant can be administered under the trade name Faslodex™. The combinations of the present disclosure that include a chemotherapeutic agent that is an antiestrogen are particularly useful for the treatment of estrogen receptor-positive tumors such as breast tumors.

[0278] As used herein, the term "antiandrogen agent" relates to any substance capable of inhibiting the biological effects of androgen hormones, including but not limited to bicalutamide (Casodex (trademark)). As used herein, the term "gonadorelin agonist" includes but is not limited to abarelix, goserelin, and goserelin acetate. Goserelin can be administered under the trade name Zoladex (trademark).

[0279] As used herein, the term "topoisomerase I inhibitor" includes but is not limited to topotecan, gemitecan, irinotecan, camptothecin and its analogs, 9-nitrocamptothecin, and the macromolecular camptothecin conjugate PNU-166148. Irinotecan can be administered, for example, in the form as sold under the trade name Camptosar (trademark). Topotecan is sold under the trade name Hycamptin (trademark).

[0280] As used herein, the term "topoisomerase II inhibitor" includes but is not limited to anthracyclines, such as doxorubicin (including liposomal formulations such as Caelyx (trademark)), daunorubicin, epirubicin, idarubicin, and nemorubicin; mitoxantrone and losoxantrone of anthraquinones; and etoposide and teniposide of podophyllotoxins. Etoposide is sold under the trade name Etopophos (trademark). Teniposide is sold under the trade name VM 26-Bristol. Doxorubicin is sold under the trade name Acriblastin (trademark) or Adriamycin (trademark). Epirubicin is sold under the trade name Farmorubicin (trademark). Idarubicin is sold under the trade name Zavedos (trademark). Mitoxantrone is sold under the trade name Novantron (trademark).

[0281] The term "microtubule agent", without limitation, includes taxanes such as paclitaxel and docetaxel; vinca alkaloids such as vinblastine or vinblastine sulfate, vincristine or vincristine sulfate, and vinorelbine; discodermolide; colchicine and epothilone, and derivatives thereof, and relates to microtubule stabilizing, microtubule destabilizing compounds, and polymerization inhibitors. Paclitaxel is sold under the trade name Taxol™. Docetaxel is sold under the trade name Taxotere™. Vinblastine sulfate is sold under the trade name Vinblastin R.P™. Vincristine sulfate is sold under the trade name Farmistin™.

[0282] As used herein, the term "alkylating agent" includes, but is not limited to, cyclophosphamide, ifosfamide, melphalan, or nitrosourea (BCNU or Gliadel). Cyclophosphamide is sold under the trade name Cyclostin™. Ifosfamide is sold under the trade name Holoxan™.

[0283] The term "histone deacetylase inhibitor" or "HDAC inhibitor" relates to compounds that inhibit histone deacetylases and have anti-proliferative activity. This term includes, but is not limited to, hydroxamic acid suberoyl anilide (SAHA).

[0284] The term "antineoplastic antimetabolite" includes, but is not limited to, 5-fluorouracil or 5-FU, capecitabine, gemcitabine, DNA demethylating compounds such as 5-azacitidine and decitabine; methotrexate and edatrexate; and folic acid antagonists such as pemetrexed. Capecitabine is sold under the trade name Xeloda™. Gemcitabine is sold under the trade name Gemzar™.

[0285] As used herein, the term "platinum compound" includes, but is not limited to, carboplatin, cisplatin, cisplatinum, and oxaliplatin. Carboplatin can be administered, for example, in the form as sold under the trade name Carboplat(™). Oxaliplatin can be administered, for example, in the form as sold under the trade name Eloxatin(™).

[0286] As used herein, the term "compound that targets / reduces protein or lipid kinase activity; or protein or lipid phosphatase activity; or further anti-angiogenic compound" refers to a protein tyrosine kinase and / or serine and / or threonine kinase inhibitor or lipid kinase inhibitor, e.g., a) a compound that targets, reduces, or inhibits the activity of platelet-derived growth factor receptor (PDGFR), e.g., a compound that targets, reduces, or inhibits the activity of PDGFR, particularly a compound that inhibits the PDGF receptor, e.g., an N-phenyl-2-pyrimidin-amine derivative, e.g., imatinib, SU101, SU6668, and GFB-111; b) a compound that targets, reduces, or inhibits the activity of fibroblast growth factor receptor (FGFR); c) a compound that targets, reduces, or inhibits the activity of insulin-like growth factor receptor I (IGF-IR), e.g., a compound that targets, reduces, or inhibits the activity of IGF-IR, particularly a compound that inhibits the kinase activity of the IGF-I receptor, or an antibody that targets the extracellular domain of the IGF-I receptor or its growth factor; d) a compound that targets, reduces, or inhibits the activity of the Trk receptor-type tyrosine kinase family, or an Ephrin B4 inhibitor; e) a compound that targets, reduces, or inhibits the activity of the AxI receptor-type tyrosine kinase family; f) a compound that targets, reduces, or inhibits the activity of the Ret receptor-type tyrosine kinase; g) a compound that targets, reduces, or inhibits the activity of the Kit / SCFR receptor-type tyrosine kinase, e.g., imatinib; h) a compound that targets, reduces, or inhibits the activity of the c-Kit receptor-type tyrosine kinase, which is part of the PDGFR family, e.g., a compound that targets, reduces, or inhibits the activity of the c-Kit receptor-type tyrosine kinase family, particularly a compound that inhibits the c-Kit receptor, e.g., imatinib;i) Compounds that target, reduce, or inhibit the activity of members of the c-Abl family, these gene fusion products (e.g., BCR-Abl kinase), such as compounds that target, reduce, or inhibit the activity of c-Abl family members and these gene fusion products, such as N-phenyl-2-pyrimidine-amine derivatives, such as imatinib or nilotinib (AMN107) manufactured by ParkeDavis; PD180970; AG957; NSC680410; PD173955; or dasatinib (BMS-354825); j) Compounds that target, reduce, or inhibit the activity of members of the protein kinase C (PKC) and Raf family of serine / threonine kinases, MEK, SRC, JAK / pan-JAK, FAK, PDK1, PKB / Akt, Ras / MAPK, PI3K, SYK, TYK2, BTK, and members of the TEC family, and / or members of the cyclin-dependent kinase family (CDK) including staurosporine derivatives, such as midostaurin; (Examples of additional compounds include UCN-01, safingol, BAY 43-9006, bryostatin 1, perifosine; ilmofosine; RO 318220 and RO 320432; GO 6976; lsis 3521; LY333531 / LY379196; isoquinoline compounds; FTIs; PD184352 or QAN697 (P13K inhibitor) or AT7519 (CDK inhibitor).); k) Compounds that target, reduce, or inhibit the activity of protein-tyrosine kinase inhibitors, such as imatinib mesylate (Gleevec (trademark)) or tyrphostin, such as Tyrphostin A23 / RG-50810; AG 99; Tyrphostin AG 213; Tyrphostin AG 1748; Tyrphostin AG 490; Tyrphostin B44; Tyrphostin B44 (+) enantiomer; Tyrphostin AG 555; AG 494; Tyrphostin AG 556, AG957, and adaphostin (4-{[(2,5-dihydroxyphenyl)methyl]amino}-benzoic acid adamantyl ester;Compounds that target, reduce, or inhibit the activity of protein-tyrosine kinases, including NSC 680410, adafostin; compounds that target, reduce, or inhibit the activity of receptor tyrosine kinases of the epidermal growth factor family (EGFR1, ErbB2, ErbB3, ErbB4 as homo- or heterodimers, and variants thereof), for example, compounds that target, reduce, or inhibit the activity of the epidermal growth factor receptor family, particularly compounds that inhibit members of the EGF receptor tyrosine kinase family, such as the EGF receptor, ErbB2, ErbB3, and ErbB4, or compounds, proteins, or antibodies that bind to EGF or EGF-related ligands, namely, CP 358774, ZD 1839, ZM 105180; trastuzumab (Herceptin (trademark)), cetuximab (Erbitux (trademark)), Iressa, Tarceva, OSI-774, Cl-1033, EKB-569, GW-2016, E1.1, E2.4, E2.5, E6.2, E6.4, E2.11, E6.3 or E7.6.3, and 7H-pyrrolo-[2,3-d]pyrimidine derivatives; m) compounds that target, reduce, or inhibit the activity of the c-Met receptor, for example, compounds that target, reduce, or inhibit the activity of c-Met, particularly compounds that inhibit the kinase activity of the c-Met receptor, or antibodies that target the extracellular domain of c-Met or bind to HGF; n) compounds that target, reduce, or inhibit the kinase activity of one or more JAK family members (JAK1 / JAK2 / JAK3 / TYK2, and / or pan-JAK), including but not limited to PRT-062070, SB-1578, baricitinib, pacritinib, momelotinib, VX-509, AZD-1480, TG-101348, tofacitinib, and ruxolitinib; o) compounds that target, reduce, or inhibit PI3 kinase (PI3K), including but not limited to ATU-027, SF-1126, DS-7423, PBI-05204, GSK-2126458, ZSTK-474, buparlisib, pictilisib, PF-4691502, BYL-719, dactolisib, XL-147, XL-765, and idelalisib.and; and, q) compounds that target, reduce, or inhibit the signaling effects of the Hedgehog protein (Hh) or Smoothened receptor (SMO) pathway, including but not limited to cyclopamine, vismodegib, itraconazole, erismodegib, IPI-926 (salidegib).;

[0287] As used herein, the term "PI3K inhibitor" includes, but is not limited to, compounds having inhibitory activity against one or more enzymes in the phosphatidylinositol-3-kinase family, including PI3Kα, PI3Kγ, PI3Kδ, PI3Kβ, PI3K-C2α, PI3K-C2β, PI3K-C2γ, Vps34, p110-α, p110-β, p110-γ, p110-δ, p85-α, p85-β, p55-γ, p150, p101, and p87. Examples of PI3K inhibitors useful in the present disclosure include, but are not limited to, ATU-027, SF-1126, DS-7423, PBI-05204, GSK-2126458, ZSTK-474, buparlisib, pictilisib, PF-4691502, BYL-719, dactolisib, XL-147, XL-765, and idelalisib.

[0288] As used herein, the term "Bcl-2 inhibitor" includes, but is not limited to, ABT-199, ABT-731, ABT-737, apogossypol, the pan-Bcl-2 inhibitor from Ascenta, curcumin (and its analogs), dual Bcl-2 / Bcl-xL inhibitors (Infinity Pharmaceuticals / Novartis Pharmaceuticals), Genasense (G3139), HA14-1 (and its analogs; see WO2008118802), navitoclax (and its analogs; see US7390799), NH-1 (Shenayng Pharmaceutical University), obatoclax (and its analogs; see WO2004106328), S-001 (Gloria Pharmaceuticals), TW series compounds (Univ. of Michigan), and venetoclax, and includes, but is not limited to, compounds having inhibitory activity against B-cell lymphoma 2 protein (Bcl-2). In some embodiments, the Bcl-2 inhibitor is a small molecule therapeutic agent. In some embodiments, the Bcl-2 inhibitor is a peptidomimetic.

[0289] As used herein, the term "BTK inhibitor" includes, but is not limited to, compounds having inhibitory activity against Bruton's tyrosine kinase (BTK), including, but not limited to, AVL-292 and ibrutinib.

[0290] As used herein, the term "SYK inhibitor" includes, but is not limited to, compounds having inhibitory activity against spleen tyrosine kinase (SYK), including, but not limited to, PRT-062070, R-343, R-333, Excellair, PRT-062607, and fostamatinib.

[0291] BTK inhibitory compounds, and, in combination with the compounds of the present disclosure, the medical conditions treatable by such compounds can be found in WO2008039218 and WO2011090760, which are hereby incorporated by reference in their entirety.

[0292] SYK inhibitory compounds, and, in combination with the compounds of the present disclosure, the medical conditions treatable by such compounds can be found in WO2003063794, WO2005007623, and WO2006078846, which are hereby incorporated by reference in their entirety.

[0293] PI3K inhibitory compounds, and, in combination with the compounds of the present disclosure, the medical conditions treatable by such compounds can be found in WO2004019973, WO2004089925, WO2007016176, US8138347, WO2002088112, WO2007084786, WO2007129161, WO2006122806, WO2005113554, and WO2007044729, which are hereby incorporated by reference in their entirety.

[0294] JAK inhibitory compounds, and, in combination with the compounds of the present disclosure, the medical conditions treatable by such compounds can be found in WO2009114512, WO2008109943, WO2007053452, WO2000142246, and WO2007070514, which are hereby incorporated by reference in their entirety.

[0295] Further anti-angiogenic compounds include those having a different mechanism of action with respect to activity, for example, compounds unrelated to protein or lipid kinase inhibition, such as thalidomide (Thalomid (trademark)) and TNP-470.

[0296] Examples of proteasome inhibitors useful for use in combination with the compounds of the present disclosure include, but are not limited to, bortezomib, disulfiram, epigallocatechin-3-gallate (EGCG), salinosporamide A, carfilzomib, ONX-0912, CEP-18770, and MLN9708.

[0297] Compounds that target, reduce, or inhibit the activity of a protein or lipid phosphatase are, for example, inhibitors of phosphatase 1, phosphatase 2A, or CDC25, such as okadaic acid or derivatives thereof.

[0298] Compounds that induce a cell differentiation process include, but are not limited to, retinoic acid, α-, γ-, or δ-tocopherol, or α-, γ, or δ-tocotrienol.

[0299] As used herein, the term "cyclooxygenase inhibitor" includes, but is not limited to, Cox-2 inhibitors, 5-alkyl-substituted 2-arylaminophenylacetic acids and derivatives, such as celecoxib (trademark), rofecoxib (Vioxx (trademark)), etoricoxib, valdecoxib, or 5-alkyl-2-arylaminophenylacetic acids, such as 5-methyl-2-(2'-chloro-6'-fluoroanilino)phenylacetic acid, lumiracoxib.

[0300] As used herein, the term "bisphosphonate" includes, but is not limited to, etidronic acid, clodronic acid, tiludronic acid, pamidronic acid, alendronic acid, ibandronic acid, risedronic acid, and zoledronic acid. Etidronic acid is sold under the trade name Didronel™. Clodronic acid is sold under the trade name Bonefos™. Tiludronic acid is sold under the trade name Skelid™. Pamidronic acid is sold under the trade name Aredia™. Alendronic acid is sold under the trade name Fosamax™. Ibandronic acid is sold under the trade name Bondranat™. Risedronic acid is sold under the trade name Actonel™. Zoledronic acid is sold under the trade name Zometa™. The term "mTOR inhibitor" relates to compounds that inhibit the mammalian target of rapamycin (mTOR) and have antiproliferative activity, such as sirolimus (Rapamune®), everolimus (Certican™), CCI-779, and ABT578.

[0301] As used herein, the term "heparanase inhibitor" means a compound that targets, reduces, or inhibits heparan sulfate degradation. This term includes, but is not limited to, PI-88. As used herein, the term "biological response modifier" means a lymphokine or an interferon.

[0302] As used herein, the term "inhibitor of Ras oncogenic isoform", such as H-Ras, K-Ras, or N-Ras, means a compound that targets, reduces, or inhibits the oncogenic activity of Ras; for example, it means "farnesyltransferase inhibitor" such as L-744832, DK8G557, or R115777 (Zarnestra (trademark)). As used herein, the term "telomerase inhibitor" means a compound that targets, reduces, or inhibits the activity of telomerase. Compounds that target, reduce, or inhibit the activity of telomerase are, in particular, compounds that inhibit telomerase receptors, such as telomestatin.

[0303] As used herein, the term "methionine aminopeptidase inhibitor" means a compound that targets, reduces, or inhibits methionine aminopeptidase. Examples of compounds that target, reduce, or inhibit the activity of methionine aminopeptidase include, but are not limited to, bengamide or its derivatives.

[0304] As used herein, the term "proteasome inhibitor" means a compound that targets, reduces, or inhibits the activity of proteasome. Examples of compounds that target, reduce, or inhibit the activity of proteasome include, but are not limited to, bortezomib (Velcade (trademark)) and MLN341.

[0305] As used herein, the term "matrix metalloproteinase inhibitor", or ("MMP" inhibitor), includes, but is not limited to, collagen peptide mimetics and non-peptide mimetic inhibitors, tetracycline derivatives, such as batimastat, a hydroxamate peptide mimetic inhibitor, and marimastat (BB-2516), a orally administrable analog thereof, prinomastat (AG3340), metastat (NSC 683551), BMS-279251, BAY 12-9566, TAA211, MMI270B, or AAJ996.

[0306] As used herein, the term "compound for use in the treatment of hematological malignancies" refers to FMS-like tyrosine kinase inhibitors, which are compounds that target, reduce, or inhibit the activity of the FMS-like tyrosine kinase receptor (Flt-3R); interferon, 1-β-D-arabinofuranosylcytosine (ara-c), and busulfan; and ALK inhibitors, which are compounds that target, reduce, or inhibit the activity of anaplastic lymphoma kinase, but are not limited thereto.

[0307] Compounds that target, reduce, or inhibit the activity of the FMS-like tyrosine kinase receptor (Flt-3R) are, in particular, compounds, proteins, or antibodies that inhibit members of the Flt-3R receptor kinase family, such as PKC412, midostaurin, staurosporine derivatives, SU11248, and MLN518.

[0308] As used herein, the term "HSP90 inhibitor" refers to, but is not limited to, compounds that target, reduce, or inhibit the intrinsic ATPase activity of HSP90; compounds that target, reduce, or inhibit the degradation of HSP90 clients through the ubiquitin proteasome pathway. Compounds that target, reduce, or inhibit the intrinsic ATPase activity of HSP90 are, in particular, compounds, proteins, or antibodies that inhibit the ATPase activity of HSP90, such as 17-allylamino,17-demethoxygeldanamycin (17AAG), geldanamycin derivatives; other geldanamycin-related compounds: radicicol and HDAC inhibitors.

[0309] As used herein, the term "anti-proliferative activity antibody" includes, but is not limited to, trastuzumab (Herceptin™), trastuzumab-DM1, Erbitux, bevacizumab (Avastin™), rituximab (Rituxan®), PRO64553 (anti-CD40), and 2C4 antibody. An antibody means a full-length monoclonal antibody, polyclonal antibody, multispecific antibody formed from at least two intact antibodies and, as long as it exhibits the desired biological activity, antibody fragments.

[0310] Regarding the treatment of acute myeloid leukemia (AML), the compounds of the present disclosure can be used in combination with standard leukemia treatment methods, in particular, in combination with treatment methods used for the treatment of AML. In particular, the compounds of the present disclosure can be administered in combination with, for example, farnesyl transferase inhibitors and / or other drugs useful for the treatment of AML, such as daunorubicin, adriamycin, Ara-C, VP-16, teniposide, mitoxantrone, idarubicin, carboplatinum, and PKC412.

[0311] Other anti-leukemia compounds include, for example, the pyrimidine analogue Ara-C, which is a 2'-α-hydroxyribose (arabinoside) derivative of deoxycytidine. Also included are the purine analogues of hypoxanthine, 6-mercaptopurine (6-MP) and fludarabine phosphate esters. Compounds that target, reduce, or inhibit the activity of histone deacetylase (HDAC) inhibitors, such as sodium butyrate and hydroxamic acid suberoyl anilide (SAHA), inhibit the activity of the enzyme known as histone deacetylase. Specific HDAC inhibitors include MS275, SAHA, FK228 (formerly FR901228), trichostatin A; and N-hydroxy-3-[4-[[[2-(2-methyl-1H-indol-3-yl)-ethyl]-amino]methyl]phenyl]-2E-2-propenamide, or a pharmaceutically acceptable salt thereof, and N-hydroxy-3-[4-[(2-hydroxyethyl){2-(1H-indol-3-yl)ethyl]-amino]methyl]phenyl]-2E-2-propenamide, or a pharmaceutically acceptable salt thereof, particularly the lactate salt, including but not limited to the compounds disclosed in US 6,552,065. As used herein, a somatostatin receptor antagonist means a compound that targets, reduces, or inhibits a somatostatin receptor, such as octreotide and SOM230. An "approach that damages tumor cells" means an approach such as ionizing radiation. The term "ionizing radiation" as referred to hereinbefore and hereinafter in this specification means ionizing radiation that occurs as either electromagnetic radiation (such as X-rays and gamma rays) or particles (such as alpha and beta particles). Ionizing radiation is provided, although not limited to, by radiation therapy and is known in the art. See Hellman, Principles of Radiation Therapy, Cancer, in Principles and Practice of Oncology, Devita et al., Eds., 4 th Edition, Vol.1, pp.248-275 (1993).

[0312] Also included are EDG binders and ribonucleotide reductase inhibitors. As used herein, the term "EDG binder" means a class of immunosuppressive agents that regulate lymphocyte recirculation, such as FTY720. The term "ribonucleotide reductase inhibitor" means pyrimidine or purine nucleoside analogs including, but not limited to, fludarabine and / or cytosine arabinoside (ara-C), 6-thioguanine, 5-fluorouracil, cladribine, 6-mercaptopurine (especially in combination with ara-C for ALL), and / or pentostatin. Ribonucleotide reductase inhibitors are, in particular, hydroxyurea, or 2-hydroxy-1H-isoindole-1,3-dione derivatives.

[0313] In particular, 1-(4-chloroanilino)-4-(4-pyridylmethyl)phthalazine or a pharmaceutically acceptable salt thereof, 1-(4-chloroanilino)-4-(4-pyridylmethyl)phthalazine succinate; Angiostatin (trademark); Endostatin (trademark); anthranilic acid amide; ZD4190; Zd6474; SU5416; SU6668; bevacizumab; or anti-VEGF antibodies or anti-VEGF receptor antibodies such as rhuMAb and RHUFab, VEGF aptamers (such as Macugon); compounds, proteins, or monoclonal antibodies of VEGF such as FLT-4 inhibitors, FLT-3 inhibitors, VEGFR-2 IgGI antibodies, Angiozyme (RPI 4610) and bevacizumab (Avastin (trademark)) are also included.

[0314] As used herein, "photodynamic therapy" means a treatment method using certain chemical substances known as photosensitive compounds for treating or preventing cancer. Examples of photodynamic therapy include treatment with compounds such as Visudyne (trademark) and porfimer sodium.

[0315] As used herein, an anti-angiogenic steroid means a compound that blocks or inhibits angiogenesis, such as, for example, anecortave acetate, triamcinolone, hydrocortisone, 11-α-epihydrocortisol, cortisone, 17α-hydroxyprogesterone, corticosterone, deoxycorticosterone, testosterone, estrone, and dexamethasone.

[0316] An implant containing a corticosteroid means a compound such as fluocinolone and dexamethasone.

[0317] Other chemotherapeutic compounds include, but are not limited to, plant alkaloids, hormone compounds, and antagonists; biological response modifiers, preferably lymphokines or interferons; antisense oligonucleotides or oligonucleotide derivatives; shRNA or siRNA; and various miscellaneous compounds (plural) having other or unknown mechanisms of action.

[0318] The structure of an active compound identified by a code number, gene name, or trade name can be obtained from "The Merck Index" of standard specifications or from a database such as Patents International (e.g., IMS World Publications).

[0319] f. Exemplary immuno-oncology agents In some embodiments, one or more other therapeutic agents are immuno-oncology agents. As used herein, the term "immuno-oncology agent" means an agent effective to enhance, stimulate, and / or upregulate an immune response in a subject. In some embodiments, administering an immuno-oncology agent in combination with a compound of the present disclosure has a synergistic effect in the treatment of cancer.

[0320] Immune-oncology agents can be, for example, small molecule drugs, antibodies, or biological molecules or small molecules. Examples of biological immune-oncology agents include, but are not limited to, cancer vaccines, antibodies, and cytokines. In some embodiments, the antibody is a monoclonal antibody. In some embodiments, the monoclonal antibody is humanized or human.

[0321] In some embodiments, the immune-oncology agent is (i) an agonist of a stimulatory (co-stimulatory including) receptor, or (ii) an antagonist of an inhibitory (co-inhibitory including) signal on T cells, both of which result in amplification of the antigen-specific T cell response.

[0322] Certain stimulatory and inhibitory molecules are members of the immunoglobulin superfamily (IgSF). Among the membrane-bound ligands that bind to co-stimulatory or co-inhibitory receptors, an important family is the B7 family, which includes B7-1, B7-2, B7-H1 (PD-L1), B7-DC (PD-L2), B7-H2 (ICOS-L), B7-H3, B7-H4, B7-H5 (VISTA), and B7-H6. Another family of membrane-bound ligands that bind to co-stimulatory or co-inhibitory receptors is the TNF family of molecules that bind to members of the TNF receptor superfamily, which includes CD40 and CD40L, OX-40, OX-40L, CD70, CD27L, CD30, CD30L, 4-1BBL, CD137 (4-1BB), TRAIL / Apo2-L, TRAILR1 / DR4, TRAILR2 / DR5, TRAILR3, TRAILR4, OPG, RANK, RANKL, TWEAKR / Fn14, TWEAK, BAFFR, EDAR, XEDAR, TACI, APRIL, BCMA, LTβR, LIGHT, DcR3, HVEM, VEGI / TL1A, TRAMP / DR3, EDAR, EDA1, XEDAR, EDA2, TNFR1, lymphotoxin α / TNFβ, TNFR2, TNFα, LTβR, lymphotoxin α1β2, FAS, FASL, RELT, DR6, TROY, NGFR.

[0323] In some embodiments, the immuno-oncology agent is a cytokine that inhibits T cell activation (e.g., IL-6, IL-10, TGF-β, VEGF, and other immunosuppressive cytokines), or a cytokine that stimulates T cell activation to stimulate an immune response.

[0324] In some embodiments, combining the compounds of the present disclosure with an immuno-oncology agent can stimulate a T cell response. In some embodiments, the immuno-oncology agent is (i) an antagonist of a protein that inhibits T cell activation (e.g., an immune checkpoint inhibitor), e.g., CTLA-4, PD-1, PD-L1, PD-L2, LAG-3, TIM-3, galectin 9, CEACAM-1, BTLA, CD69, galectin-1, TIGIT, CD113, GPR56, VISTA, 2B4, CD48, GARP, PD1H, LAIR1, TIM-1, and TIM-4; or (ii) an agonist of a protein that stimulates T cell activation, e.g., B7-1, B7-2, CD28, 4-1BB (CD137), 4-1BBL, ICOS, ICOS-L, OX40, OX40L, GITR, GITRL, CD70, CD27, CD40, DR3, and CD28H.

[0325] In some embodiments, the immuno-oncology agent is an antagonist of an inhibitory receptor on NK cells, or an agonist of an activating receptor on NK cells. In some embodiments, the immuno-oncology agent is an antagonist of KIR, such as lirilumab.

[0326] In some embodiments, the immuno-oncology agent is an agent that inhibits or depletes macrophages or monocytes, including but not limited to CSF-1R antagonist antibodies, such as RG7155 (WO11 / 70024, WO11 / 107553, WO11 / 131407, WO13 / 87699, WO13 / 119716, WO13 / 132044), or FPA-008 (WO11 / 140249; WO13169264; WO14 / 036357), which are CSF-1R antagonists.

[0327] In some embodiments, the immuno-oncology agent is an agonist agent that ligates a positive co-stimulatory receptor, an inhibitory receptor, an antagonist, and a blocking agent that attenuates signaling by one or more agents that systemically increase the frequency of anti-tumor T cells, an agent that overcomes an innate immunosuppressive pathway within the tumor microenvironment (e.g., blocks the involvement of inhibitory receptors (e.g., PD-L1 / PD-1 interaction), depletes or inhibits Tregs (e.g., using an anti-CD25 monoclonal antibody (e.g., daclizumab) or by depletion of ex vivo anti-CD25 beads), inhibits a metabolic enzyme such as IDO, or reverses / prevents T cell anergy or exhaustion), and an agent that causes innate immune activation and / or inflammation at the tumor site.

[0328] In some embodiments, the immuno-oncology agent is a CTLA-4 antagonist. In some embodiments, the CTLA-4 antagonist is an antagonist CTLA-4 antibody. In some embodiments, the antagonist CTLA-4 antibody is Yervoy (ipilimumab) or tremelimumab.

[0329] In some embodiments, the immuno-oncology agent is a PD-1 antagonist. In some embodiments, the PD-1 antagonist is administered by infusion. In some embodiments, the immuno-oncology agent is an antibody or antigen-binding portion thereof that specifically binds to the programmed cell death 1 (PD-1) receptor and inhibits PD-1 activity. In some embodiments, the PD-1 antagonist is an antagonist PD-1 antibody. In some embodiments, the antagonist PD-1 antibody is OPDIVO (nivolumab), KEYTRUDA (pembrolizumab), or MEDI-0680 (AMP-514; WO2012 / 145493). In some embodiments, the immuno-oncology agent may be pidilizumab (CT-011). In some embodiments, the immuno-oncology agent is a recombinant protein composed of the extracellular domain of PD-L2 (B7-DC) fused to the Fc portion of IgG1, called AMP-224.

[0330] In some embodiments, the immuno-oncology agent is a PD-L1 antagonist. In some embodiments, the PD-L1 antagonist is an antagonist PD-L1 antibody. In some embodiments, the PD-L1 antibody is MPDL3280A (RG7446; WO2010 / 077634), durvalumab (MEDI4736), BMS-936559 (WO2007 / 005874), and MSB0010718C (WO2013 / 79174).

[0331] In some embodiments, the immuno-oncology agent is a LAG-3 antagonist. In some embodiments, the LAG-3 antagonist is an antagonist LAG-3 antibody. In some embodiments, the LAG3 antibody is BMS-986016 (WO10 / 19570, WO14 / 08218), or IMP-731 or IMP-321 (WO08 / 132601, WO009 / 44273).

[0332] In some embodiments, the immuno-oncology agent is a CD137 (4-1BB) agonist. In some embodiments, the CD137 (4-1BB) agonist is an agonist CD137 antibody. In some embodiments, the CD137 antibody is urelumab or PF-05082566 (WO12 / 32433).

[0333] In some embodiments, the immuno-oncology agent is a GITR agonist. In some embodiments, the GITR agonist is an agonist GITR antibody. In some embodiments, the GITR antibody is BMS-986153, BMS-986156, TRX-518 (WO006 / 105021, WO009 / 009116), or MK-4166 (WO11 / 028683).

[0334] In some embodiments, the immuno-oncology agent is an indoleamine (2,3)-dioxygenase (IDO) antagonist. In some embodiments, the IDO antagonist is selected from epacadostat (INCB024360, Incyte); indoximod (NLG-8189, NewLink Genetics Corporation); capmatinib (INC280, Novartis); GDC-0919 (Genentech / Roche); PF-06840003 (Pfizer); BMS: F001287 (Bristol-Myers Squibb); Phy906 / KD108 (Phytoceutica); an enzyme that destroys quinurenine (Kynase, previously known as Kyn Therapeutics); and NLG-919 (WO09 / 73620, WO009 / 1156652, WO11 / 56652, WO12 / 142237).

[0335] In some embodiments, the immuno-oncology agent is an OX40 agonist. In some embodiments, the OX40 agonist is an agonist OX40 antibody. In some embodiments, the OX40 antibody is MEDI-6383 or MEDI-6469.

[0336] In some embodiments, the immuno-oncology agent is an OX40L antagonist. In some embodiments, the OX40L antagonist is an antagonist OX40 antibody. In some embodiments, the OX40L antagonist is RG-7888 (WO06 / 029879).

[0337] In some embodiments, the immuno-oncology agent is a CD40 agonist. In some embodiments, the CD40 agonist is an agonist CD40 antibody. In some embodiments, the immuno-oncology agent is a CD40 antagonist. In some embodiments, the CD40 antagonist is an antagonist CD40 antibody. In some embodiments, the CD40 antibody is lucatumumab or dacetuzumab.

[0338] In some embodiments, the immuno-oncology agent is a CD27 agonist. In some embodiments, the CD27 agonist is an agonist CD27 antibody. In some embodiments, the CD27 antibody is balstilimab.

[0339] In some embodiments, the immuno-oncology agent is MGA271 (against B7H3) (WO11 / 109400).

[0340] In some embodiments, the immuno-oncology agent is abagovomab, adecatumumab, afutuzumab, alemtuzumab, anatumomab mafenatox, apolizumab, atezolizumab, avelumab, blinatumomab, BMS-936559, catumaxomab, durvalumab, epacadostat, epratuzumab, indoximod, inotuzumab ozogamicin, intelmab, ipilimumab, izatuximab, lanbritumomab, MED14736, MPDL3280A, nivolumab, obinutuzumab, ocaratuzumab, ofatumumab, oratuzumab, pembrolizumab, pidilizumab, rituximab, tislelizumab, samalizumab, or tremelimumab.

[0341] In some embodiments, the immuno-oncology agent is an immune activator. For example, antibodies that block the PD-1 and PD-L1 inhibitory axes can liberate activated tumor-reactive T cells and have been shown in clinical trials to induce durable anti-tumor responses in increasing tumor tissue architectures, including some tumor types that were not previously considered to be sensitive in immunotherapy. See, for example, Okazaki, T. et al. (2013) Nat. Immunol. 14, 1212-1218; Zou et al. (2016) Sci. Transl. Med. 8. Nivolumab (Opdivo®), a PD-1 antibody (also known as Bristol-Myers Squibb; ONO-4538, MDX1106, and BMS-936558), has been shown to improve overall survival in patients with RCC who experienced disease progression during or after anti-angiogenic therapy.

[0342] In some embodiments, the immunomodulatory therapeutic agent specifically induces apoptosis of tumor cells. Approved immunomodulatory therapeutic agents that can be used in the present disclosure include pomalidomide (Pomalyst®, Celgene); lenalidomide (Revlimid®, Celgene); ingenol mebutate (Picato®, LEO Pharma).

[0343] In some embodiments, the immuno-oncology agent is a cancer vaccine. In some embodiments, the cancer vaccine is Sipuleucel-T (Provenge®, Dendreon / Valeant Pharmaceuticals), which is approved for the treatment of asymptomatic or minimally symptomatic metastatic castration-resistant (hormone-refractory) prostate cancer; and talimogene laherparepvec (Imlygic®, BioVex / Amgen, previously known as T-VEC), which is a recombinant oncolytic viral therapy approved for the treatment of unresectable cutaneous, subcutaneous, and nodal lesions of melanoma, selected from.In some embodiments, the immuno-oncology agent is a tumor-lytic viral therapy, for example, PexaVec / JX-594, a thymidine kinase (TK−) -deficient vaccinia virus recombinant to express GM-CSF, against hepatocellular carcinoma (NCT02562755) and melanoma (NCT00429312); colorectal cancer (NCT01622543); prostate cancer (NCT01619813); head and neck squamous cell carcinoma (NCT01166542); pancreatic adenocarcinoma (NCT00998322); and a number of cancers including non-small cell lung cancer (NSCLC) (NCT 00861627), a variant of respiratory enteric orphan virus (reovirus) that does not replicate in cells with non-activated RAS, Reolysin® (Oncolytics Biotech); Enadenotucirev (NG-348, PsiOxus, formerly known as ColoAd1), an adenovirus recombinant to express full-length CD80 and an antibody fragment specific for the T cell receptor CD3 protein, in ovarian cancer (NCT02028117); metastatic or advanced epithelial tumors such as colorectal cancer, bladder cancer, head and neck squamous cell carcinoma, and salivary gland cancer (NCT02636036); melanoma (NCT03003676); and peritoneal disease, colorectal cancer, or ovarian cancer (NCT02963831), ONCOS-102 (Targovax / formerly Oncos), an adenovirus recombinant to express GM-CSF; peritoneal carcinomatosis (NCT01443260): fallopian tube cancer, ovarian cancer (NCT 02759588); or GL-ONC1 (GLV-1h68 / GLV-1h153, Genelux GmbH), a vaccinia virus recombinant to express β-galactosidase (β-gal) / β-glucuronidase or β-gal / sodium iodide symporter (hNIS), respectively, being studied in CG0070 (Cold Genesys); selected from adenoviruses recombinant to express GM-CSF in bladder cancer (NCT02365818).

[0344] In some embodiments, the immuno-oncology agent is JX-929 (SillaJen / formerly Jennerex Biotherapeutics), a TK and vaccinia growth factor-deficient vaccinia virus recombinantly engineered to express cytosine deaminase, which can convert the prodrug 5-fluorocytosine to the cytotoxic drug 5-fluorouracil; TG01 and TG02 (Targovax / formerly Oncos), peptide-based immunotherapeutic agents targeting treatment-refractory RAS mutations; and TILT-123 (TILT Biotherapeutics), a recombinant adenovirus named Ad5 / 3-E2F-δ24-hTNFα-IRES-hIL20; and VSV-GP (ViraTherapeutics), a vesicular stomatitis virus (VSV) recombinantly engineered to express the glycoprotein (GP) of lymphocytic choriomeningitis virus (LCMV), which can be further recombinantly engineered to express antigens designed to increase antigen-specific CD8 + T cell responses.

[0345] In some embodiments, the immuno-oncology agent is a T cell recombinantly engineered to express a chimeric antigen receptor, or CAR. T cells recombinantly engineered to express such a chimeric antigen receptor are referred to as CAR-T cells.

[0346] A CAR is constructed that is composed of a binding domain derived from a single-chain variable fragment (scFv) of a monoclonal antibody specific for a cell surface antigen, fused to an endodomain that is the functional terminus of a T cell receptor (TCR), such as the CD3ζ signaling domain of the TCR, which can generate an activating signal in T lymphocytes upon binding to the natural ligand. Upon antigen binding, such a CAR binds to endogenous signaling pathways within effector cells and generates an activating signal similar to that initiated by the TCR complex.

[0347] For example, in some embodiments, the CAR-T cell is one of those disclosed in U.S. Patent No. 8,906,682 (June et al., which is incorporated herein by reference in its entirety), which discloses a CAR-T cell recombinantly engineered to include an extracellular domain having an antigen-binding domain (such as a domain that binds CD19) fused to the intracellular signaling domain of the ζ chain (such as CD3ζ) of the T cell antigen receptor complex. When expressed within a T cell, the CAR is capable of redirecting antigen recognition based on antigen-binding specificity. In the case of CD19, the antigen is expressed on malignant B cells. In a wide range of indications, over 200 clinical trials using CAR-T are currently underway [https: / / clinicaltrials.gov / ct2 / results?term=chimeric+antigen+receptors&pg=1].

[0348] In some embodiments, the immunostimulant is an activator of retinoic acid receptor-related orphan receptor γ (RORγt). RORγt is a transcription factor that plays an important role in the differentiation and maintenance of the 17-type effector subsets of CD4+ (Th17) and CD8+ (Tc17) T cells, as well as in the differentiation of IL-17-expressing innate immune cell subpopulations such as NK cells. In some embodiments, the activator of RORγt is LYC-55716 (Lycera), which is currently being investigated in clinical trials for the treatment of solid tumors (NCT02929862).

[0349] In some embodiments, the immunostimulant is an agonist or activator of a toll-like receptor (TLR). Suitable activators of TLR include agonists or activators of TLR9, such as SD-101 (Dynavax). SD-101 is an immunostimulatory CpG that has been studied against B cells, follicular and other lymphomas (NCT02254772). Agonists or activators of TLR8 that can be used in the present disclosure include motolimod (VTX-2337, VentiRx Pharmaceuticals), which has been studied against head and neck squamous cell carcinoma (NCT02124850) and ovarian cancer (NCT02431559).

[0350] Other immuno-oncology agents that can be used in the present disclosure include urelumab (BMS-663513, Bristol-Myers Squibb), an anti-CD137 monoclonal antibody; balstilimab (CDX-1127, Celldex Therapeutics), an anti-CD27 monoclonal antibody; BMS-986178 (Bristol-Myers Squibb), an anti-OX40 monoclonal antibody; lirilumab (IPH2102 / BMS-986015, Innate Pharma, Bristol-Myers Squibb), an anti-KIR monoclonal antibody; monalizumab (IPH2201, Innate Pharma, AstraZeneca), an anti-NKG2A monoclonal antibody; andecaliximab (GS-5745, Gilead Sciences), an anti-MMP9 antibody; and MK-4166 (Merck & Co.), an anti-GITR monoclonal antibody.

[0351] In some embodiments, the immunostimulant is selected from elotuzumab, mifamurtide, an agonist or activator of a toll-like receptor, and an activator of RORγt.

[0352] In some embodiments, the immunostimulatory therapeutic agent is recombinant human interleukin 15 (rhIL-15). rhIL-15 has been clinically tested as a treatment for melanoma and renal cell carcinoma (NCT01021059 and NCT01369888), as well as leukemia (NCT02689453). In some embodiments, the immunostimulant is recombinant human interleukin 12 (rhIL-12). In some embodiments, the IL-15-based immunotherapeutic agent is a heterodimeric IL-15 (hetIL-15, Novartis / Admune), a fusion complex composed of a synthetic form of endogenous IL-15 (IL15:sIL-15RA) complexed with the soluble IL-15 binding protein IL-15 receptor alpha chain, which has been tested in a Phase I clinical trial against melanoma, renal cell carcinoma, non-small cell lung cancer, and head and neck squamous cell carcinoma (NCT02452268). In some embodiments, the recombinant human interleukin 12 (rhIL-12) is NM-IL-12 (Neumedicines, Inc.), NCT02544724, or NCT02542124.

[0353] In some embodiments, the immuno-oncology agent is selected from those described in Jerry L. Adams et al., “Big opportunities for small molecules in immuno-oncology,” Cancer Therapy 2015, Vol. 14, pages 603-622, the entire contents of which are incorporated herein by reference. In some embodiments, the immuno-oncology agent is selected from the examples described in Table 1 of Jerry L. Adams et al. In some embodiments, the immuno-oncology agent is a small molecule that targets an immuno-oncology target selected from those listed in Table 2 of Jerry L. Adams et al. In some embodiments, the immuno-oncology agent is a small molecule agent selected from those listed in Table 2 of Jerry L. Adams et al.

[0354] In some embodiments, the immuno-oncology agent is selected from small molecule immuno-oncology agents described in Peter L. Toogood, “Small molecule immuno-oncology therapeutic agents,” Bioorganic & Medicinal Chemistry Letters 2018, Vol. 28 (pages 319 - 329), the entire content of which is incorporated herein by reference. In some embodiments, the immuno-oncology agent is an agent that targets the pathways described by Peter L. Toogood.

[0355] In some embodiments, the immuno-oncology agent is selected from those described in Sandra L. Ross et al., “Bispecific T cell engager (BiTE®) antibody constructs can mediate bystander tumor cell killing”, PLoS ONE 12(8): e0183390, the entire content of which is incorporated herein by reference. In some embodiments, the immuno-oncology agent is a bispecific T cell engager (BiTE®) antibody construct. In some embodiments, the bispecific T cell engager (BiTE®) antibody construct is a CD19 / CD3 bispecific antibody construct. In some embodiments, the bispecific T cell engager (BiTE®) antibody construct is an EGFR / CD3 bispecific antibody construct. In some embodiments, the bispecific T cell engager (BiTE®) antibody construct activates T cells. In some embodiments, the bispecific T cell engager (BiTE®) antibody construct activates T cells, thereby releasing cytokines that induce upregulation of intercellular adhesion molecule 1 (ICAM-1) and FAS in bystander cells. In some embodiments, the bispecific T cell engager (BiTE®) antibody construct activates T cells, thereby resulting in lysis of induced bystander cells. In some embodiments, the bystander cells are present within a solid tumor. In some embodiments, the bystander cells to be lysed are present near BiTE®-activated T cells. In some embodiments, the bystander cells include tumor-associated antigen (TAA)-negative cancer cells. In some embodiments, the bystander cells include EGFR-negative cancer cells. In some embodiments, the immuno-oncology agent is an antibody that blocks the PD-L1 / PD1 axis and / or CTLA4. In some embodiments, the immuno-oncology agent is ex vivo-expanded tumor-infiltrating T cells. In some embodiments, the immuno-oncology agent is a bispecific antibody construct or a chimeric antigen receptor (CAR) that directly links T cells to a tumor-associated surface antigen (TAA). g. Exemplary Immune Checkpoint Inhibitors

[0356] In some embodiments, the immuno-oncology agent is an immune checkpoint inhibitor as described herein.

[0357] As used herein, the term "checkpoint inhibitor" means an agent useful for preventing cancer cells from evading the patient's immune system. One of the main mechanisms of the disruption of anti-tumor immunity is known as "T cell exhaustion", which results in long-term exposure to antigens that have led to upregulation of inhibitory receptors. These inhibitory receptors function as immune checkpoints to prevent uncontrolled immune responses.

[0358] PD-1 and co-inhibitory receptors such as cytotoxic T lymphocyte antigen 4 (CTLA-4, B and T lymphocyte attenuator (BTLA; CD272), T cell immunoglobulin and mucin domain-3 (Tim-3), lymphocyte activation gene-3 (Lag-3; CD223), and others are often referred to as checkpoint regulators. These serve as molecular "gatekeepers" that determine whether extracellular signals proceed with cell cycle progression and other intracellular signaling processes.

[0359] In some embodiments, the immune checkpoint inhibitor is an antibody against PD-1. PD-1 binds to the programmed cell death 1 receptor (PD-1), preventing the receptor from binding to the inhibitory ligand PDL-1, thereby disabling the tumor's ability to suppress the host's anti-tumor immune response.

[0360] In one aspect, the checkpoint inhibitor is a biologic or a small molecule. In another aspect, the checkpoint inhibitor is a monoclonal antibody, a humanized antibody, a fully human antibody, a fusion protein, or a combination thereof. In a further aspect, the checkpoint inhibitor inhibits a checkpoint protein selected from CTLA-4, PDL1, PDL2, PD1, B7-H3, B7-H4, BTLA, HVEM, TIM3, GAL9, LAG3, VISTA, KIR, 2B4, CD160, CGEN-15049, CHK 1, CHK2, A2aR, B-7 family ligands, or a combination thereof. In a further aspect, the checkpoint inhibitor interacts with a ligand of a checkpoint protein selected from CTLA-4, PDL1, PDL2, PD1, B7-H3, B7-H4, BTLA, HVEM, TIM3, GAL9, LAG3, VISTA, KIR, 2B4, CD160, CGEN-15049, CHK 1, CHK2, A2aR, B-7 family ligands, or a combination thereof. In one aspect, the checkpoint inhibitor is an immunostimulant, a T cell growth factor, an interleukin, an antibody, a vaccine, or a combination thereof. In a further aspect, the interleukin is IL-7 or IL-15. In a particular aspect, the interleukin is glycosylated IL-7. In a further aspect, the vaccine is a dendritic cell (DC) vaccine.

[0361] Checkpoint inhibitors include any agent that blocks or inhibits an inhibitory pathway of the immune system in a statistically significant manner. Such inhibitors can include small molecule inhibitors, or antibodies or antigen-binding fragments thereof that bind to and block or inhibit immune checkpoint receptors, or antibodies that bind to and block or inhibit immune checkpoint receptor ligands. Exemplary checkpoint molecules that can be targeted for blocking or inhibition include CTLA-4, PDL1, PDL2, PD1, B7-H3, B7-H4, BTLA, HVEM, GAL9, LAG3, TIM3, VISTA, KIR, 2B4 (which belongs to the CD2 family of molecules and is present on all NK, γδ, and memory CD8 +(αβ) T cells), CD160 (also known as BY55), CGEN-15049, CHK1 and CHK2 kinases, A2aR, and various B-7 family ligands, including but not limited to these. Examples of B7 family ligands include, but are not limited to, B7-1, B7-2, B7-DC, B7-H1, B7-H2, B7-H3, B7-H4, B7-H5, B7-H6, and B7-H7. Checkpoint inhibitors include antibodies or antigen-binding fragments thereof, other binding proteins, biological therapeutics, or small molecules that bind to one or more of CTLA-4, PDL1, PDL2, PD1, BTLA, HVEM, TIM3, GAL9, LAG3, VISTA, KIR, 2B4, CD160, and CGEN-15049 and block or inhibit their activities. Exemplary immune checkpoint inhibitors include tremelimumab (a CTLA-4 blocking antibody), anti-OX40, a PD-L1 monoclonal antibody (anti-B7-Hl; MEDI4736), MK-3475 (a PD-1 blocker), nivolumab (an anti-PD1 antibody), CT-011 (an anti-PD1 antibody), a BY55 monoclonal antibody, AMP224 (an anti-PDL1 antibody), BMS-936559 (an anti-PDL1 antibody), MPLDL3280A (an anti-PDL1 antibody), MSB0010718C (an anti-PDL1 antibody), and ipilimumab (an anti-CTLA-4 checkpoint inhibitor), including but not limited to these. Checkpoint protein ligands include, but are not limited to, PD-L1, PD-L2, B7-H3, B7-H4, CD28, CD86, and TIM-3.

[0362] In certain embodiments, the immune checkpoint inhibitor is selected from a PD-1 antagonist, a PD-L1 antagonist, and a CTLA-4 antagonist. In some embodiments, the checkpoint inhibitor is selected from the group consisting of nivolumab (Opdivo®), ipilimumab (Yervoy®), and pembrolizumab (Keytruda®). In some embodiments, the checkpoint inhibitor is selected from nivolumab (anti-PD-1 antibody, Opdivo®, Bristol-Myers Squibb); pembrolizumab (anti-PD-1 antibody, Keytruda®, Merck); ipilimumab (anti-CTLA-4 antibody, Yervoy®, Bristol-Myers Squibb); durvalumab (anti-PD-L1 antibody, Imfinzi®, AstraZeneca); and atezolizumab (anti-PD-L1 antibody, Tecentriq®, Genentech).

[0363] In some embodiments, the checkpoint inhibitor is selected from the group consisting of lambrolizumab (MK-3475), nivolumab (BMS-936558), pidilizumab (CT-011), AMP-224, MDX-1105, MEDI4736, MPDL3280A, BMS-936559, ipilimumab, lirilumab, IPH2101, pembrolizumab (Keytruda®), and tremelimumab.

[0364] In some embodiments, the immune checkpoint inhibitor is REGN2810 (Regeneron), an anti-PD-1 antibody that has been tested in patients with basal cell carcinoma (NCT03132636); NSCLC (NCT03088540); squamous cell carcinoma (NCT02760498); lymphoma (NCT02651662); and melanoma (NCT03002376); pidilizumab (CureTech), also known as CT-011, an antibody that binds to PD-1 and is in clinical trials for diffuse large B-cell lymphoma and multiple myeloma; avelumab (Bavencio®, Pfizer / Merck KGaA), also known as MSB0010718C, a fully human IgG1 anti-PD-L1 antibody that is in clinical trials for non-small cell lung cancer, Merkel cell carcinoma, mesothelioma, solid tumors, renal cancer, ovarian cancer, bladder cancer, head and neck cancer, and gastric cancer; or PDR001 (Novartis), an inhibitory antibody that binds to PD-1 and is in clinical trials for non-small cell lung cancer, melanoma, triple-negative breast cancer, and advanced or metastatic solid tumors. Tremelimumab (CP-675,206; AstraZeneca) is a fully human monoclonal antibody against CTLA-4 that has been studied in clinical trials for a number of indications, including mesothelioma, colorectal cancer, renal cancer, breast cancer, lung cancer and non-small cell lung cancer, pancreatic ductal adenocarcinoma, pancreatic cancer, germ cell cancer, head and neck squamous cell carcinoma, hepatocellular carcinoma, prostate cancer, endometrial cancer, liver metastatic cancer, liver cancer, large B-cell lymphoma, ovarian cancer, cervical cancer, metastatic undifferentiated thyroid cancer, urothelial cancer, fallopian tube cancer, multiple myeloma, bladder cancer, soft tissue sarcoma, and melanoma. AGEN-1884 (Agenus) is an anti-CTLA4 antibody that has been studied in a Phase I clinical trial for advanced solid tumors (NCT02694822).

[0365] In some embodiments, the checkpoint inhibitor is an inhibitor of T cell immunoglobulin and mucin domain-containing protein 3 (TIM-3). Examples of TIM-3 inhibitors that can be used in the present invention include TSR-022, LY3321367, and MBG453. TSR-022 (Tesaro) is an anti-TIM-3 antibody being studied in solid tumors (NCT02817633). LY3321367 (Eli Lilly) is an anti-TIM-3 antibody being studied in solid tumors (NCT03099109). MBG453 (Novartis) is an anti-TIM-3 antibody being studied in advanced malignancies (NCT02608268).

[0366] In some embodiments, the checkpoint inhibitor is an inhibitor of the T cell immunoreceptor with Ig and ITIM domains, or TIGIT, an immunoreceptor on certain T cells and NK cells. Examples of TIGIT inhibitors that can be used in the present disclosure include BMS-986207 (Bristol-Myers Squibb), an anti-TIGIT monoclonal antibody (NCT02913313); OMP-313M32 (Oncomed); and an anti-TIGIT monoclonal antibody (NCT03119428).

[0367] In some embodiments, the checkpoint inhibitor is an inhibitor of lymphocyte activation gene 3 (LAG-3). Examples of LAG-3 inhibitors that can be used in the present disclosure include BMS-986016, REGN3767, and IMP321. BMS-986016 (Bristol-Myers Squibb), an anti-LAG-3 antibody, is being studied in glioblastoma and sarcoma (NCT02658981). REGN3767 (Regeneron) is also an anti-LAG-3 antibody and is being studied in malignancies (NCT03005782). IMP321 (Immutep S.A.) is a LAG-3-Ig fusion protein being studied in melanoma (NCT02676869); adenocarcinoma (NCT02614833); and metastatic breast cancer (NCT00349934).

[0368] Checkpoint inhibitors that can be used in the present disclosure include OX40 agonists. OX40 agonists being studied in clinical trials include PF-04518600 / PF-8600 (Pfizer), an agonist anti-OX40 antibody in metastatic renal cancer (NCT03092856) and in advanced cancer and tumors (NCT02554812; NCT05082566); GSK3174998 (Merck), an agonist anti-OX40 antibody in a Phase 1 cancer trial (NCT02528357); MEDI0562 (Medimmune / AstraZeneca), an agonist anti-OX40 antibody in progressive solid tumors (NCT02318394 and NCT02705482); MEDI6469 (Medimmune / AstraZeneca), an agonist anti-OX40 antibody in patients with colorectal cancer (NCT02559024), breast cancer (NCT01862900), head and neck cancer (NCT02274155), and metastatic prostate cancer (NCT01303705); and BMS-986178 (Bristol-Myers Squibb), an agonist anti-OX40 antibody in advanced cancer (NCT02737475).

[0369] Checkpoint inhibitors that can be used in the present disclosure include CD137 (also called 4-1BB). CD137 agonists being studied in clinical trials include utomilumab (PF-05082566, Pfizer), an agonist anti-CD137 antibody in diffuse large B-cell lymphoma (NCT02951156) and in advanced cancer and tumors (NCT02554812 and NCT05082566); urelumab (BMS-663513, Bristol-Myers Squibb), an agonist anti-CD137 antibody in melanoma and skin cancer (NCT02652455) and in glioblastoma and sarcoma (NCT02658981); and CTX-471 (Compass Therapeutics), an agonist anti-CD137 antibody in metastatic or locally advanced malignancies (NCT03881488).

[0370] Checkpoint inhibitors that can be used in the present disclosure include CD27 agonists. CD27 agonists being studied in clinical trials include balstilimab (CDX-1127, Celldex Therapeutics), an agonist anti-CD27 antibody in squamous cell head and neck cancer, ovarian cancer, colorectal cancer, renal cell cancer, and glioblastoma (NCT02335918); lymphoma (NCT01460134); and glioma and astrocytoma (NCT02924038).

[0371] Checkpoint inhibitors that can be used in the present disclosure include glucocorticoid-induced tumor necrosis factor receptor (GITR) agonists. GITR agonists being studied in clinical trials include TRX518 (Leap Therapeutics), an agonist anti-GITR antibody in melanoma and other malignant solid tumors (NCT01239134 and NCT02628574); GWN323 (Novartis), an agonist anti-GITR antibody in solid tumors and lymphoma (NCT 02740270); INCAGN01876 (Incyte / Agenus), an agonist anti-GITR antibody in advanced cancer (NCT02697591 and NCT03126110); MK-4166 (Merck), an agonist anti-GITR antibody in solid tumors (NCT02132754); and MEDI1873 (Medimmune / AstraZeneca), an agonist hexameric GITR-ligand molecule containing the human IgG1 Fc domain in progressive solid tumors (NCT02583165).

[0372] Checkpoint inhibitors that can be used in the present disclosure include inducible T cell co-stimulatory factor (ICOS, also known as CD278) agonists. ICOS agonists being studied in clinical trials include MEDI-570 (Medimmune), an agonist anti-ICOS antibody in lymphoma (NCT02520791); GSK3359609 (Merck), an agonist anti-ICOS antibody in Phase 1 (NCT02723955); and JTX-2011 (Jounce Therapeutics), an agonist anti-ICOS antibody in Phase 1 (NCT02904226).

[0373] Checkpoint inhibitors that can be used in the present disclosure include killer IgG-like receptor (KIR) inhibitors. KIR inhibitors being studied in clinical trials include lirilumab (IPH2102 / BMS-986015, Innate Pharma / Bristol-Myers Squibb), an anti-KIR antibody in leukemia (NCT01687387, NCT02399917, NCT02481297, NCT02599649), multiple myeloma (NCT02252263), and lymphoma (NCT01592370); IPH2101 (1-7F9, Innate Pharma) in myeloma (NCT01222286 and NCT01217203); and IPH4102 (Innate Pharma), an anti-KIR antibody that binds to three domains of the long cytoplasmic tail (KIR3DL2) in lymphoma (NCT02593045).

[0374] Checkpoint inhibitors that can be used in the present disclosure include CD47 inhibitors that target the interaction between CD47 and signal regulatory protein alpha (SIRPa). CD47 / SIRPa inhibitors being studied in clinical trials include ALX-148 (Alexo Therapeutics), an antagonist variant of (SIRPa) that binds to CD47 and prevents CD47 / SIRPa-mediated signal transduction in Phase I (NCT03013218); TTI-621 (SIRPa-Fc, Trillium Therapeutics), a soluble recombinant fusion protein in Phase I clinical trials (NCT02890368 and NCT02663518) that is created by binding the N-terminal CD47-binding domain of SIRPa to the Fc domain of human IgG1, acts by binding to human CD47, and prevents the delivery of a "don't eat me" signal to macrophages; CC-90002 (Celgene), an anti-CD47 antibody in leukemia (NCT02641002); and Hu5F9-G4 (Forty Seven, Inc.) in colon tumors and solid tumors (NCT02953782), acute myeloid leukemia (NCT02678338), and lymphoma (NCT02953509).

[0375] Checkpoint inhibitors that can be used in the present disclosure include CD73 inhibitors. CD73 inhibitors being studied in clinical trials include MEDI9447 (Medimmune), an anti-CD73 antibody in solid tumors (NCT02503774); and BMS-986179 (Bristol-Myers Squibb), an anti-CD73 antibody in solid tumors (NCT02754141).

[0376] Checkpoint inhibitors that can be used in the present disclosure include agonists of stimulators of the interferon gene protein (STING, transmembrane protein 173, also known as TMEM173). Agonists of STING being studied in clinical trials include MK-1454 (Merck), an agonist synthetic cyclic dinucleotide in lymphoma (NCT03010176); and ADU-S100 (MIW815, Aduro Biotech / Novartis), an agonist synthetic cyclic dinucleotide in Phase I (NCT02675439 and NCT03172936).

[0377] Checkpoint inhibitors that can be used in the present disclosure include CSF1R inhibitors. CSF1R inhibitors being studied in clinical trials include ribociclib (PLX3397, Plexxikon), a small molecule inhibitor of CSF1R in colorectal cancer, pancreatic cancer, metastatic and advanced cancer (NCT02777710) and melanoma, non-small cell lung cancer, squamous cell head and neck cancer, gastrointestinal stromal tumor (GIST) and ovarian cancer (NCT02452424); as well as IMC-CS4 (LY3022855, Lilly), an anti-CSF-1R antibody in pancreatic cancer (NCT03153410), melanoma (NCT03101254), solid tumors (NCT02718911); and BLZ945 (4-[2((1R,2R)-2-hydroxycyclohexylamino)-benzothiazol-6-yloxyl]-pyridine-2-carboxylic acid methylamide, Novartis), an orally ingestible inhibitor of CSF1R in advanced solid tumors (NCT02829723).

[0378] Checkpoint inhibitors used in the present disclosure include NKG2A receptor inhibitors. NKG2A receptor inhibitors being studied in clinical trials include monalizumab (IPH2201, Innate Pharma), an anti-NKG2A antibody in head and neck tumors (NCT02643550) and chronic lymphocytic leukemia (NCT02557516).

[0379] In some embodiments, the immune checkpoint inhibitor is selected from nivolumab, pembrolizumab, ipilimumab, avelumab, durvalumab, atezolizumab, or pidilizumab.

Example

[0380] The following examples are included to illustrate various aspects of the present disclosure. The techniques disclosed in the following examples represent techniques developed by the inventors of the present application to function well in the practice of the present disclosure, and thus, it should be understood by those skilled in the art that they can be considered to constitute preferred modes for their implementation. However, those skilled in the art should understand that, in light of the present disclosure, many changes can be made in the specific examples disclosed without departing from the spirit and scope of the present disclosure, and still obtain similar or analogous results.

[0381] The preparation methods of the compounds described herein are shown in the following synthetic schemes. The schemes are provided to illustrate the disclosure and are not intended to limit the scope or spirit of the present disclosure. The starting materials shown in the schemes can be obtained from commercial suppliers or prepared based on procedures described in the literature.

[0382] In the schemes, it is understood by those skilled in the art of organic synthesis that the functional groups present in various parts of the molecule must be compatible with the reagents and reactions presented. Substituents that are not compatible with the reaction conditions are apparent to those skilled in the art, and thus, alternative methods (e.g., the use of protecting groups or alternative reactions) are shown. The chemistry and strategy of protecting groups are well known in the art, as detailed, for example, in “Protecting Groups in Organic synthesis”, T. W. Greene and P. G. M. Wuts, 3rd edition, John Wiley & Sons, 1999, and the entire content is incorporated herein by reference.

[0383] Example 1: Synthesis of N-cyclopropyl-2-((2-fluoro-4-iodophenyl)amino)-1,5-dimethyl-4-(3-((N-methylsulfamoyl)amino)phenoxy)-6-oxo-1,6-dihydropyridine-3-carboxamide (I-5)

Chemical formula

Chemical formula

[0384] 11H NMR (400 MHz, DMSO-d6) δ 7.99 - 7.92 (m, 1H), 7.77 - 7.69 (m, 1H), 7.36 - 7.23 (m, 2H), 2.77 (s, 3H), 2.74 - 2.64 (m, 1H), 2.02 (s, 3H), 1.13 - 0.96 (m, 2H), 0.70 - 0.56 (m, 2H).

[0385] Step 2: 3-Cyclopropyl-1-(2-fluoro-4-iodophenyl)-6,8-dimethyl-5-(3-nitrophenoxy)pyrido[2,3-d]pyrimidine-2,4,7(1H,3H,8H)-trione

Chemical Structure

[0386] 11H NMR (300 MHz, DMSO-d6) δ 8.01 - 7.87 (m, 2H), 7.81 - 7.71 (m, 2H), 7.68 - 7.57 (m, 1H), 7.53 - 7.44 (m, 1H), 7.42 - 7.31 (m, 1H), 2.59-2.52 (s, 3H), 2.54 (m,1H), 1.84 (s, 3H), 0.94 - 0.85 (m, 2H), 0.65 - 0.27 (m, 2H).

[0387] Step 3: 5-(3-Aminophenoxy)-3-cyclopropyl-1-(2-fluoro-4-iodophenyl)-6,8-dimethylpyrido[2,3-d]pyrimidine-2,4,7(1H,3H,8H)-trione

Chemical Structure

[0388] 1 1H NMR (400 MHz, DMSO-d6) δ 7.96 (dd, 1H), 7.74 (dd, 1H), 7.37 - 7.28 (m, 1H), 6.95 - 6.86 (m, 1H), 6.28 - 6.21 (m, 1H), 6.21 - 6.16 (m, 1H), 6.11 - 6.04 (m, 1H), 5.27 (s, 2H), 2.80 (s, 3H), 2.59 - 2.52 (m, 1H), 1.80 (s, 3H), 0.96 - 0.82 (m, 2H), 0.59 - 0.38 (m, 2H).

[0389] Step 4: 3-Cyclopropyl-1-(2-fluoro-4-iodophenyl)-6,8-dimethyl-5-{3-[(methylsulfamoyl)amino]phenoxy}pyrido[2,3-d]pyrimidine-2,4,7-trione

Chemical Structure

[0390] Project 5: N-Cyclopropyl-2-((2-fluoro-4-iodophenyl)amino)-1,5-dimethyl-4-(3-((N-methylsulfamoyl)amino)phenoxy)-6-oxo-1,6-dihydropyridine-3-carboxamide [Chemical formula] To a 40 mL vial, 3-cyclopropyl-1-(2-fluoro-4-iodophenyl)-6,8-dimethyl-5-{3-[(methylsulfamoyl)amino]phenoxy}pyrido[2,3-d]pyrimidine-2,4,7-trione (200 mg, 0.30 mmol, 1.0 equivalent), LiOH.H2O (125 mg, 3.00 mmol, 10.0 equivalents), THF (2.0 mL) and H2O (2.0 mL) were added at room temperature. The resulting mixture was stirred at room temperature for 30 minutes. The residue was diluted with H2O (20 mL). The resulting mixture was extracted with EtOAc (3 × 20 mL). The combined organic layers were washed with brine (30 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The crude product was purified by preparative HPLC [column: Welch XB-C18, 50*250 mm, 10 μm mobile phase A: water (0.1% TFA), mobile phase B: ACN; flow rate: 90 mL / min: gradient: from 15% B to 50% B in 15 minutes, wavelength: 254 / 220 nm] to obtain N-cyclopropyl-2-[(2-fluoro-4-iodophenyl)amino]-1,5-dimethyl-4-{3-[(methylsulfamoyl)amino]phenoxy}-6-oxopyridine-3-carboxamide (120 mg, TFA salt, 62%) as an off-white solid. ES-LCMS m / z 642.2 [M+H] + .

[0391] 11H NMR (400 MHz, DMSO-d6) δ 9.76 (s, 1H), 8.63 (s, 1H), 8.05 (d, J = 3.5 Hz, 1H), 7.64 - 7.57 (m, 1H), 7.40 - 7.33 (m, 1H), 7.32 - 7.27 (m, 1H), 7.25 - 7.17 (m, 1H), 6.92 - 6.85 (m, 1H), 6.77 - 6.72 (m, 1H), 6.63 - 6.54 (m, 1H), 6.52 - 6.44 (m, 1H), 3.38 (s, 3H), 2.47 (s, 3H), 2.28 - 2.18 (m, 1H), 1.86 (s, 3H), 0.46 - 0.37 (m, 2H), 0.02 - -0.05 (m, 2H).

[0392] Example 2: Synthesis of (R)-4-(3-((Amino(methyl)oxo-λ6-sulfanylidene)amino)phenoxy)-N-cyclopropyl-2-((2-fluoro-4-iodophenyl)amino)-1,5-dimethyl-6-oxo-1,6-dihydropyridine-3-carboxamide (I-8)

Chemical Structure

Chemical Structure

[0393] Step 2: N-(3-((3-Cyclopropyl-1-(2-fluoro-4-iodophenyl)-6,8-dimethyl-2,4,7-trioxo-1,2,3,4,7,8-hexahydropyrido[2,3-d]pyrimidin-5-yl)oxy)phenyl)methanesulfonimidamide [Chemical formula] A stirred solution of N-(3-{[3-cyclopropyl-1-(2-fluoro-4-iodophenyl)-6,8-dimethyl-2,4,7-trioxopyrido[2,3-d]pyrimidin-5-yl]oxy}phenyl)methanesulfinamide (370 mg, 0.58 mmol, 1.0 equiv) in THF (5.0 mL) was treated dropwise with t-butyl hypochlorite (94 mg, 0.87 mmol, 1.5 equiv in 1.0 mL of THF) at 0 °C under a nitrogen atmosphere. The resulting mixture was stirred at 0 °C for 1.5 h. Next, the reaction mass was cooled to -78 °C and NH3(g) (0.5 M) in THF (5.0 mL) was added and the mixture was slowly brought to room temperature within 1 h. The reaction was quenched with water at 0 °C. The resulting mixture was extracted with EtOAc (3 × 20 mL). The combined organic layers were washed with brine (30 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE / EA (1:1) to afford N-(3-{[3-cyclopropyl-1-(2-fluoro-4-iodophenyl)-6,8-dimethyl-2,4,7-trioxopyrido[2,3-d]pyrimidin-5-yl]oxy}phenyl)methanesulfonimidamide (300 mg, 79%) as a yellow solid. ES-LCMS m / z 652 [M+H] + 。

[0394] Step 3: 4-(3-((Amino(methyl)oxo-λ6-sulfaneylidene)amino)phenoxy)-N-cyclopropyl-2-((2-fluorophenyl)amino)-1,5-dimethyl-6-oxo-1,6-dihydropyridine-3-carboxamide

Chemical Structure

[0395] Step 4: (R)-4-(3-((amino(methyl)oxo-λ6-sulfanilylidene)amino)phenoxy)-N-cyclopropyl-2-((2-fluoro-4-iodophenyl)amino)-1,5-dimethyl-6-oxo-1,6-dihydropyridine-3-carboxamide [Chemical formula] 4-(3-{[Amino(methyl)oxo-λ6-sulfanilylidene]amino}phenoxy)-N-cyclopropyl-2-[(2-fluoro-4-iodophenyl)amino]-1,5-dimethyl-6-oxopyridine-3-carboxamide (150 mg) was purified by chiral-HPLC under the following conditions (column: CHIRALPAK IE, 3 * 25 cm, 5 μm; mobile phase A: HEX:DCM = 3:1, mobile phase B: EtOH; flow rate: 30 mL / min; gradient: 30% B to 30% B in 16 minutes; wavelength: 220 / 254 nm; RT1 (min): 12; RT2 (min): 14; sample solvent: EtOH:DCM = 1:1; injection volume: 1.5 mL; number of runs: 8) to obtain (R)-4-(3-((amino(methyl)oxo-λ6-sulfanilylidene)amino)phenoxy)-N-cyclopropyl-2-((2-fluoro-4-iodophenyl)amino)-1,5-dimethyl-6-oxo-1,6-dihydropyridine-3-carboxamide (47 mg, 31%) as an off-white solid. ES-LCMS m / z 626.2 [M+H] + 。

[0396] 1 H NMR (400 MHz, DMSO-d6) δ 8.64 (s, 1H), 7.91 (d, J = 3.7 Hz, 1H), 7.60 - 7.53 (m, 1H), 7.37 - 7.30 (m, 1H), 7.09 - 7.00 (m, 1H), 6.81 - 6.66 (m, 3H), 6.57 - 6.48 (m, 1H), 6.45 - 6.40 (m, 1H), 6.35 - 6.28 (m, 1H), 3.33 (s, 3H), 3.09 (s, 3H), 2.31 - 2.22 (m, 1H), 1.80 (s, 3H), 0.44 - 0.35 (m, 2H), 0.05 - 0.01 (m, 2H).

[0397] Example 3: Synthesis of (S)-4-(3-((Amino(methyl)oxo-λ6-sulfanelylidene)amino)phenoxy)-N-cyclopropyl-2-((2-fluoro-4-iodophenyl)amino)-1,5-dimethyl-6-oxo-1,6-dihydropyridine-3-carboxamide (I-7)

Chemical formula

Chemical formula

[0398] 11H NMR (400 MHz, DMSO-d6) δ 8.64 (s, 1H), 7.91 (d, J = 3.7 Hz, 1H), 7.61 - 7.53 (m, 1H), 7.37 - 7.30 (m, 1H), 7.09 - 7.00 (m, 1H), 6.82 - 6.65 (m, 3H), 6.57 - 6.48 (m, 1H), 6.45 - 6.40 (m, 1H), 6.35 - 6.28 (m, 1H), 3.33 (s, 3H), 3.09 (s, 3H), 2.31 - 2.22 (m, 1H), 1.80 (s, 3H), 0.44 - 0.35 (m, 2H), 0.05 - 0.01 (m, 2H).

[0399] Example 4: Synthesis of N-cyclopropyl-2-((2-fluoro-4-iodophenyl)amino)-1,5-dimethyl-4-(3-((N-methylsulfamoyl)methyl)phenoxy)-6-oxo-1,6-dihydropyridine-3-carboxamide (I-23)

Chem.

Chem.

[0400] Step 2: 1-(3-(Benzyloxy)phenyl)-N-methylmethanesulfonamide

Chemical formula

[0401] Step 3: 1-(3-Hydroxyphenyl)-N-methylmethanesulfonamide

Chemical formula

[0402] Step 4: 1-(3-((3-Cyclopropyl-1-(2-fluoro-4-iodophenyl)-6,8-dimethyl-2,4,7-trioxo-1,2,3,4,7,8-hexahydropyrido[2,3-d]pyrimidin-5-yl)oxy)phenyl)-N-methylmethanesulfonamide [Chemistry] A solution of 3-cyclopropyl-1-(2-fluoro-4-iodophenyl)-6,8-dimethyl-2,4,7-trioxopyrido[2,3-d]pyrimidin-5-yl trifluoromethanesulfonate (200 mg, 0.32 mmol, 1.0 equiv), 1-(3-hydroxyphenyl)-N-methylmethanesulfonamide (116 mg, 0.57 mmol, 1.7 equiv), and cesium fluoride (148 mg, 0.975 mmol, 3 equiv) in THF was stirred at 60 °C for 30 minutes. The reaction was quenched with water (20 mL) and extracted with EA (3 × 20 mL). The combined organic layers were washed with brine (20 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with PE / THF (1:1), to give 1-(3-{[3-cyclopropyl-1-(2-fluoro-4-iodophenyl)-6,8-dimethyl-2,4,7-trioxopyrido[2,3-d]pyrimidin-5-yl]oxy}phenyl)-N-methylmethanesulfonamide (106 mg, 48%) as an off-white solid. ES-LCMS m / z 667 [M+H] + .

[0403] Step 5: N-Cyclopropyl-2-((2-fluorophenyl)amino)-1,5-dimethyl-4-(3-((N-methylsulfamoyl)methyl)phenoxy)-6-oxo-1,6-dihydropyridine-3-carboxamide [Chemistry] To a stirred solution of 1-(3-{[3-cyclopropyl-1-(2-fluoro-4-iodophenyl)-6,8-dimethyl-2,4,7-trioxopyrido[2,3-d]pyrimidin-5-yl]oxy}phenyl)-N-methylmethanesulfonamide (106 mg, 0.15 mmol, 1.0 equiv) in THF (2.0 mL) and water (2.0 mL) was added LiOH (38 mg, 1.59 mmol, 10.0 equiv) portionwise at room temperature. The resulting mixture was stirred at room temperature for 30 min and dissolved in H2O (20 mL). The resulting mixture was extracted with EtOAc (3 × 20 mL). The combined organic layers were washed with brine (30 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The crude product was purified by preparative HPLC [column: Welch XB-C18, 50*250 mm, 10 μm mobile phase A: water (0.1% TFA), mobile phase B: ACN; flow rate: 90 mL / min: gradient: from 15% B to 50% B in 15 min, wavelength: 254 / 220 nm] to give N-cyclopropyl-2-[(2-fluoro-4-iodophenyl)amino]-1,5-dimethyl-4-{3-[(methylsulfamoyl)methyl]phenoxy}-6-oxopyridine-3-carboxamide (53 mg, 52%) as an off-white solid. ES-LCMS m / z 641.2 [M+H] + .

[0404] 1 H NMR (400 MHz, DMSO-d6) δ 8.50 (s, 1H), 7.94 (d, J = 3.7 Hz, 1H), 7.59 - 7.52 (m, 1H), 7.36 - 7.26 (m, 2H), 7.08 - 7.01 (m, 1H), 6.88 - 6.79 (m, 3H), 6.60 - 6.49 (m, 1H), 4.30 (s, 2H), 3.36 (s, 3H), 2.53 (s, 3H), 2.21 - 2.14 (m, 1H), 1.82 (s, 3H), 0.41 - 0.31 (m, 2H), -0.03 - -0.08 (m, 1H).

[0405] Example 5: Synthesis of N-cyclopropyl-4-((2,2-dioxide-3,4-dihydro-1H-benzo[c][1,2,6]thiadiazin-7-yl)oxy)-2-((2-fluoro-4-iodophenyl)amino)-1,5-dimethyl-6-oxo-1,6-dihydropyridine-3-carboxamide (I-14)

Chemical formula

Chemical formula

[0406] Step 2: 7-Hydroxy-3,4-dihydro-1H-benzo[c][1,2,6]thiadiazine 2,2-dioxide

Chemical formula

[0407] Step 3: 3-Cyclopropyl-5-((2,2-dioxide-3,4-dihydro-1H-benzo[c][1,2,6]thiadiazin-7-yl)oxy)-1-(2-fluoro-4-iodophenyl)-6,8-dimethylpyrido[2,3-d]pyrimidine-2,4,7(1H,3H,8H)-trione [Chemical formula] A solution of 7-hydroxy-3,4-dihydro-1H-2λ6,1,3-benzothiadiazine-2,2-dione (84 mg, 0.42 mmol, 1.3 equiv) in THF was treated with NaH (23 mg, 0.97 mmol, 3.0 equiv) at 0 °C for 15 min, followed by dropwise addition of 3-cyclopropyl-1-(2-fluoro-4-iodophenyl)-6,8-dimethyl-2,4,7-trioxopyrido[2,3-d]pyrimidin-5-yl trifluoromethanesulfonate (200 mg, 0.32 mmol, 1.0 equiv in THF) at 0 °C. The resulting mixture was stirred at 60 °C for an additional 30 min. Next, water (20 mL) was added to quench, and the mixture was extracted with EA (3 × 20 mL). The combined organic layers were washed with brine (20 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with PE / THF (1:1), to afford 3-cyclopropyl-5-[(2,2-dioxo-3,4-dihydro-1H-2λ6,1,3-benzothiadiazin-7-yl)oxy]-1-(2-fluoro-4-iodophenyl)-6,8-dimethylpyrido[2,3-d]pyrimidine-2,4,7-trione (170 mg, 78%) as an off-white solid. ES-LCMS m / z 666 [M+H] + 。

[0408] Step 4: N-Cyclopropyl-4-((2,2-dioxide-3,4-dihydro-1H-benzo[c][1,2,6]thiadiazin-7-yl)oxy)-2-((2-fluoro-4-iodophenyl)amino)-1,5-dimethyl-6-oxo-1,6-dihydropyridine-3-carboxamide

Chemical Structure

[0409] 1 H NMR (300 MHz, DMSO-d6) δ 7.99 (d, J = 3.8 Hz, 1H), 7.63 - 7.53 (m, 1H), 7.39 - 7.30 (m, 1H), 7.07 - 6.99 (m, 1H), 6.61 - 6.49 (m, 1H), 6.44 - 6.35 (m, 1H), 6.22 - 6.15 (m, 1H), 4.34 (s, 2H), 3.35 (s, 3H), 2.31 - 2.23 (m, 1H), 1.80 (s, 3H), 0.48 - 0.36 (m, 2H), 0.11 - 0.03 (m, 2H).

[0410] Example 6: Synthesis of N-cyclopropyl-4-{2-fluoro-3-[(methylsulfamoyl)amino]phenoxy}-2-[(2-fluoro-4-iodophenyl)amino]-1,5-dimethyl-6-oxopyridine-3-carboxamide (I-4) [Chemical formula] Step 1: 3-Cyclopropyl-5-(2-fluoro-3-nitrophenoxy)-1-(2-fluoro-4-iodophenyl)-6,8-dimethylpyrido[2,3-d]pyrimidine-2,4,7-trione [Chemical formula] Cesium fluoride (0.9 g, 6.09 mmol, 3.0 equivalents) was added portionwise to a stirred solution of 3-cyclopropyl-1-(2-fluoro-4-iodophenyl)-6,8-dimethyl-2,4,7-trioxopyrido[2,3-d]pyrimidin-5-yl trifluoromethanesulfonate (1.2 g, 2.03 mmol, 1.0 equivalent) and 2-fluoro-3-nitrophenol (0.6 g, 4.06 mmol, 2.0 equivalents) in THF (15.0 mL) at room temperature. The reaction mixture was stirred at 60 °C for an additional 1 hour. The mixture was cooled to room temperature and quenched by the addition of water (50 mL). The resulting mixture was extracted with EtOAc (3 × 50 mL). The combined organic layers were washed with brine (50 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with PE / EA (3:1), to give 3-cyclopropyl-5-(2-fluoro-3-nitrophenoxy)-1-(2-fluoro-4-iodophenyl)-6,8-dimethylpyrido[2,3-d]pyrimidine-2,4,7-trione (370 mg, 29%) as a white solid. ES-LCMS m / z 623 [M+H] + .

[0411] Step 2: 5-(3-Amino-2-fluorophenoxy)-3-cyclopropyl-1-(2-fluoro-4-iodophenyl)-6,8-dimethylpyrido[2,3-d]pyrimidine-2,4,7-trione [Chemical formula] To a stirred solution of 3-cyclopropyl-5-(2-fluoro-3-nitrophenoxy)-1-(2-fluoro-4-iodophenyl)-6,8-dimethylpyrido[2,3-d]pyrimidine-2,4,7-trione (370 mg, 0.54 mmol, 1.0 equiv) in AcOH (4.0 mL), Fe (304 mg, 5.46 mmol, 10.0 equiv) was added portionwise at 50 °C under an air atmosphere. The reaction mixture was stirred at room temperature for an additional 1 h. The resulting mixture was diluted with water (50 mL), neutralized to pH 7 with saturated Na2CO3 (aqueous solution), and then extracted with DCM (3 × 50 mL). The combined organic layers were washed with brine (50 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with PE / THF (2:1), to give 5-(3-amino-2-fluorophenoxy)-3-cyclopropyl-1-(2-fluoro-4-iodophenyl)-6,8-dimethylpyrido[2,3-d]pyrimidine-2,4,7-trione (180 mg, 55%) as a white solid. ES-LCMS m / z 593 [M+H] + .

[0412] Step 3: 3-Cyclopropyl-5-{2-fluoro-3-[(methylsulfamoyl)amino]phenoxy}-1-(2-fluoro-4-iodophenyl)-6,8-dimethylpyrido[2,3-d]pyrimidine-2,4,7-trione [Chemical formula] A stirred solution of 5-(3-amino-2-fluorophenoxy)-3-cyclopropyl-1-(2-fluoro-4-iodophenyl)-6,8-dimethylpyrido[2,3-d]pyrimidine-2,4,7-trione (270 mg, 0.45 mmol, 1.0 equiv) and triethylamine (138 mg, 1.36 mmol, 3.0 equiv) in DCM (25.0 mL) was treated dropwise with N-methylsulfamoyl chloride (177 mg, 1.36 mmol, 3.0 equiv) at 0 °C. The resulting mixture was stirred for an additional 0.5 h at room temperature. The resulting mixture was quenched with water (0.5 mL) and concentrated under reduced pressure. The crude product was used directly in the next step without further purification. ES-LCMS m / z 686 [M+H] + .

[0413] Step 4: N-Cyclopropyl-4-{2-fluoro-3-[(methylsulfamoyl)amino]phenoxy}-2-[(2-fluoro-4-iodophenyl)amino]-1,5-dimethyl-6-oxopyridine-3-carboxamide [Chemical formula] To a stirred solution of 3-cyclopropyl-5-{2-fluoro-3-[(methylsulfamoyl)amino]phenoxy}-1-(2-fluoro-4-iodophenyl)-6,8-dimethylpyrido[2,3-d]pyrimidine-2,4,7-trione (230 mg, 0.33 mmol, 1.0 equiv) in THF (3 mL) was added LiOH (41.2 mg, 1.72 mmol, 10 equiv) in 3.0 mL of H2O at room temperature under an air atmosphere. The resulting mixture was stirred at room temperature for 30 minutes. Next, the resulting mixture was diluted with water (30 mL) and extracted with EtOAc (3 × 30 mL). The combined organic layers were washed with brine (30 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The crude product was purified by preparative HPLC (YMC C18 30*150 mm, 5 um, mobile phase A: water (0.05% NH3·H2O), mobile phase B: ACN; flow rate: 35 mL / min; gradient: 40% B to 80% B in 8 minutes, wavelength: 254 / 220 nm) to give N-cyclopropyl-4-{2-fluoro-3-[(methylsulfamoyl)amino]phenoxy}-2-[(2-fluoro-4-iodophenyl)amino]-1,5-dimethyl-6-oxopyridine-3-carboxamide (53.2 mg, 24%) as a white solid. ES-LCMS m / z 660.2 [M+H] + 。

[0414] 1 H NMR (400 MHz, DMSO-d6) δ 9.87 (br, s, 1H), 8.41 (s, 1H), 8.02 (d, J = 3.5 Hz, 1H), 7.59 - 7.51 (m, 1H), 7.35 - 7.27 (m, 2H), 7.14 - 7.06 (m, 1H), 7.01 - 6.92 (m, 1H), 6.60 - 6.48 (m, 2H), 3.35 (s, 3H), 2.53 (d, 3H), 2.23 - 2.15 (m, 1H), 1.81 (s, 3H), 0.43 - 0.34 (m, 2H), -0.01 - -0.05 (m, 2H).

[0415] Example 7: Synthesis of 4-(2-chloro-3-((N-methylsulfamoyl)amino)phenoxy)-N-cyclopropyl-2-((2-fluoro-4-iodophenyl)amino)-1,5-dimethyl-6-oxo-1,6-dihydropyridine-3-carboxamide (I-2) [Chemical formula] Step 1: 5-(2-Chloro-3-nitrophenoxy)-3-cyclopropyl-1-(2-fluoro-4-iodophenyl)-6,8-dimethylpyrido[2,3-d]pyrimidine-2,4,7(1H,3H,8H)-trione [Chemical formula] Cesium fluoride (0.74 g, 4.87 mmol, 3.0 equiv) was added portionwise to a stirred mixture of 3-cyclopropyl-1-(2-fluoro-4-iodophenyl)-6,8-dimethyl-2,4,7-trioxopyrido[2,3-d]pyrimidin-5-yl trifluoromethanesulfonate (1.00 g, 1.62 mmol, 1.0 equiv) and 2-chloro-5-nitrophenol (0.85 g, 4.87 mmol, 3.0 equiv) in THF at 60 °C. The reaction mixture was stirred at 60 °C for an additional 30 minutes. The resulting mixture was diluted with water (30 mL) and extracted with EA (3 × 30 mL). The combined organic layers were washed with brine (50 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with PE / THF (1:1), to give 5-(2-chloro-3-nitrophenoxy)-3-cyclopropyl-1-(2-fluoro-4-iodophenyl)-6,8-dimethylpyrido[2,3-d]pyrimidine-2,4,7-trione (540 mg, 52%) as a pale yellow solid. ES-LCMS m / z 639 [M+H] + .

[0416] Step 2: 5-(3-Amino-2-chlorophenoxy)-3-cyclopropyl-1-(2-fluoro-4-iodophenyl)-6,8-dimethylpyrido[2,3-d]pyrimidine-2,4,7(1H,3H,8H)-trione

Chem.

[0417] Step 3: 5-{2-Chloro-3-[(methylsulfamoyl)amino]phenoxy}-3-cyclopropyl-1-(2-fluoro-4-iodophenyl)-6,8-dimethylpyrido[2,3-d]pyrimidine-2,4,7-trione

Chem.

[0418] Step 4: 4-(2-Chloro-3-((N-methylsulfamoyl)amino)phenoxy)-N-cyclopropyl-2-((2-fluoro-4-iodophenyl)amino)-1,5-dimethyl-6-oxo-1,6-dihydropyridine-3-carboxamide

Chem.

[0419] 1 H NMR (400 MHz, DMSO-d6) δ 9.01 (br, s, 1H), 8.41 (br, s, 1H), 7.98 (d, J = 3.6 Hz, 1H), 7.59 - 7.51 (m, 1H), 7.39 - 7.27 (m, 2H), 7.23 - 7.12 (m, 2H), 6.63 - 6.55 (m, 1H), 6.55 - 6.48 (m, 1H), 3.36 (s, 3H), 2.53 (d, J = 2.6 Hz, 3H), 2.21 - 2.11 (m, 1H), 1.76 (s, 3H), 0.42 - 0.33 (m, 2H), -0.01 - -0.05 (m, 2H).

[0420] Example 8: Synthesis of N-cyclopropyl-2-((2-fluoro-4-iodophenyl)amino)-N,1,5-trimethyl-4-(2-methyl-3-((N-methylsulfamoyl)amino)phenoxy)-6-oxo-1,6-dihydropyridine-3-carboxamide (I-28) [Chemical Structure] Step 1: 3-Cyclopropyl-1-(2-fluoro-4-iodophenyl)-6,8-dimethyl-5-(2-methyl-3-nitrophenoxy)pyrido[2,3-d]pyrimidine-2,4,7(1H,3H,8H)-trione [Chemical Structure] Cesium fluoride (740 mg, 4.87 mmol, 3.0 equiv) was added portionwise to a stirred mixture of 3-cyclopropyl-1-(2-fluoro-4-iodophenyl)-6,8-dimethyl-2,4,7-trioxopyrido[2,3-d]pyrimidin-5-yl trifluoromethanesulfonate (1.00 g, 1.62 mmol, 1.0 equiv) and 2-methyl-3-nitrophenol (497 mg, 3.25 mmol, 2.0 equiv) in THF at 80 °C. The reaction mixture was stirred at 80 °C for an additional 30 min. The resulting mixture was diluted with water (30 mL) and extracted with EA (3 × 30 mL). The combined organic layers were washed with brine (50 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with PE / THF (1:1), to give 3-cyclopropyl-1-(2-fluoro-4-iodophenyl)-6,8-dimethyl-5-(2-methyl-3-nitrophenoxy)pyrido[2,3-d]pyrimidine-2,4,7-trione (470 mg, 46%) as a brown solid. ES-LCMS m / z 619 [M+H] + .

[0421] Process 2: N-Cyclopropyl-2-[(2-fluoro-4-iodophenyl)amino]-1,5-dimethyl-4-(2-methyl-3-nitrophenoxy)-6-oxo-1,6-dihydropyridine-3-carboxamide [Chemical formula] To a stirred mixture of 3-cyclopropyl-1-(2-fluoro-4-iodophenyl)-6,8-dimethyl-5-(2-methyl-3-nitrophenoxy)pyrido[2,3-d]pyrimidine-2,4,7-trione (470 mg, 0.76 mmol, 1.0 equiv) in THF (2.0 mL) and water (2.0 mL), LiOH (182 mg, 7.60 mmol, 10.0 equiv) was added portionwise at room temperature. The reaction mixture was stirred for an additional 30 minutes at room temperature. The resulting mixture was diluted with water (10 mL) and extracted with EA (3 × 10 mL). The combined organic layers were washed with brine (20 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. This gave N-cyclopropyl-2-[(2-fluoro-4-iodophenyl)amino]-1,5-dimethyl-4-(2-methyl-3-nitrophenoxy)-6-oxopyridine-3-carboxamide (175 mg, crude, 38%) as a pale yellow solid. ES-LCMS m / z 593 [M+H] + .

[0422] Process 3: N-Cyclopropyl-2-[(2-fluoro-4-iodophenyl)amino]-N,3,5-trimethyl-6-(2-methyl-3-nitrophenoxy)-4-oxocyclohexa-1,5-diene-1-carboxamide [Chemical formula] A solution of N-cyclopropyl-2-[(2-fluoro-4-iodophenyl)amino]-1,5-dimethyl-4-(2-methyl-3-nitrophenoxy)-6-oxopyridine-3-carboxamide (175 mg, crude, 0.29 mmol, 1.0 equiv) in THF was treated with sodium hydride (28 mg, 1.18 mmol, 4.0 equiv) at 0 °C for 30 minutes, and then methyl iodide (251 mg, 1.77 mmol, 6.0 equiv) was added dropwise at 0 °C. The reaction mixture was stirred at room temperature for an additional 30 minutes. The resulting mixture was diluted with water (10 mL) and extracted with EA (3 × 10 mL). The combined organic layers were washed with brine (20 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with PE / THF (1:1), to give N-cyclopropyl-2-[(2-fluoro-4-iodophenyl)amino]-N,1,5-trimethyl-4-(2-methyl-3-nitrophenoxy)-6-oxopyridine-3-carboxamide (100 mg, 55%) as a light brown solid. ES-LCMS m / z 607 [M+H] + 。

[0423] Step 4: 4-(3-Amino-2-methylphenoxy)-N-cyclopropyl-2-[(2-fluoro-4-iodophenyl)amino]-N,1,5-trimethyl-6-oxo-1,6-dihydropyridine-3-carboxamide

Chem.

[0424] Step 5: N-cyclopropyl-2-((2-fluoro-4-iodophenyl)amino)-N,1,5-trimethyl-4-(2-methyl-3-((N-methylsulfamoyl)amino)phenoxy)-6-oxo-1,6-dihydropyridine-3-carboxamide

Chemical formula

[0425] 11H NMR (300 MHz, DMSO-d6) δ 8.93 - 8.74 (m, 1H), 8.24 - 8.12 (m, 1H), 7.59 - 7.46 (m, 1H), 7.41 - 7.26 (m, 1H), 7.15 - 6.96 (m, 3H), 6.73 - 6.58 (m, 1H), 6.53 - 6.39 (m, 1H), 3.53 - 3.40 (m, 3H), 3.30 - 3.21 (m, 3H), 2.89 - 2.70 (m, 1H), 2.66 - 2.53 (m, 3H), 2.20 (s, 3H), 1.80 - 1.56 (m, 3H), 0.68 - 0.48 (m, 2H), 0.45 - 0.32 (m, 1.5H), 0.01 - -0.31 (m, 0.5H).

[0426] Example 9: Synthesis of N-cyclopropyl-2-[(2-fluoro-4-iodophenyl)amino]-4-(3-methanesulfonimidamide phenoxy)-1,5-dimethyl-6-oxopyridine-3-carboxamide (I-20)

Chemical formula

Chemical formula

[0427] Step 2: N-(tert-butyldimethylsilyl)methanesulfonimidoyl chloride [Chemical formula] A solution of PPh3 (26.18 g, 99.8 mmol, 1.1 equivalents) and hexachloroethane (23.63 g, 99.8 mmol, 1.1 equivalents) in CHCl3 (50.0 mL) was stirred at 70 °C for 5 h under a nitrogen atmosphere, and the formation of a white suspension was observed. The mixture was cooled to room temperature, and TEA (13.77 g, 136.1 mmol, 1.5 equivalents) was added. After stirring for 10 min, the mixture was cooled to 0 °C, and a solution of N-(tert-butyldimethylsilyl)methanesulfonamide (19.00 g, 90.7 mmol, 1.0 equivalent) in CHCl3 (200.0 mL) was added dropwise. The reaction mixture was stirred at 0 °C for 30 min. The resulting mixture was used directly in the next step without further purification.

[0428] Step 3: 1-(N-(tert-butyldimethylsilyl)-S-methylsulfonimidoyl)-1H-imidazole [Chemical formula] A solution of N-(tert-butyldimethylsilyl)methanesulfonimidoyl chloride (5.00 g, 21.8 mmol, 1.0 equiv) in THF (17.0 mL) was added to imidazole (1.48 g, 21.8 mmol, 1.0 equiv) and TEA (2.20 g, 21.7 mmol, 1.0 equiv). The mixture was stirred at room temperature for 18 h. The resulting mixture was concentrated under reduced pressure. The residue was dissolved in CH2Cl2 and washed with H2O. The organic phase was dried over anhydrous Na2SO4 and concentrated under reduced pressure. The residue was purified by flash chromatography (10:90 petroleum ether / THF) to give (tert-butyldimethylsilyl)[imidazol-1-yl(methyl)oxo-λ6-sulfanilidene]amine (0.40 g, 7%) as a colorless solid. ES-LCMS m / z 260 [M+H] + . 1 H NMR (400 MHz, chloroform-d) δ 7.95 (s, 1H), 7.30 (s, 1H), 7.14 (s, 1H), 3.24 (s, 3H), 0.94 (s, 9H), 0.11 (s, 6H).

[0429] Step 4: 1-(N-(tert-butyldimethylsilyl)-S-methylsulfonimidoyl)-3-methyl-1H-imidazol-3-ium trifluoromethanesulfonate [Chemical formula] A solution of (tert-butyldimethylsilyl)[imidazol-1-yl(methyl)oxo-λ6-sulfaniliden]amine (375.00 mg, 1.5 mmol, 1.0 equiv) in Et2O (2.0 mL) was cooled to 0 °C under a nitrogen atmosphere. Methyl trifluoromethanesulfonate (237.19 mg, 1.5 mmol, 1.0 equiv) in Et2O (2.0 mL) was added dropwise, and the resulting mixture was stirred at 0 °C for 1 hour. The resulting solid was filtered, washed with Et2O and dried under vacuum. Thereby, 1-(N-(tert-butyldimethylsilyl)-S-methylsulfonimidoyl)-3-methyl-1H-imidazol-3-ium trifluoromethanesulfonate (380 mg, 95%) was obtained as a white solid.

[0430] Step 5: N'-(tert-butyldimethylsilyl)-N-(3-((3-cyclopropyl-1-(2-fluoro-4-iodophenyl)-6,8-dimethyl-2,4,7-trioxo-1,2,3,4,7,8-hexahydropyrido[2,3-d]pyrimidin-5-yl)oxy)phenyl)methanesulfonimidamide

Chemical formula

[0431] Step 6: 4-{3-[N-(tert-Butyldimethylsilyl)methanesulfonimidamide]phenoxy}-N-cyclopropyl-2-[(2-fluoro-4-iodophenyl)amino]-1,5-dimethyl-6-oxopyridine-3-carboxamide

Chemical Structure

[0432] Step 7: N-Cyclopropyl-2-[(2-fluoro-4-iodophenyl)amino]-4-(3-methanesulfonimidamidephenoxy)-1,5-dimethyl-6-oxopyridine-3-carboxamide [Chemical formula] To an 8 mL vial was added 4-{3-[N-(tert-butyldimethylsilyl)methanesulfonimidamide]phenoxy}-N-cyclopropyl-2-[(2-fluoro-4-iodophenyl)amino]-1,5-dimethyl-6-oxopyridine-3-carboxamide (90 mg, 0.1 mmol, 1.0 equiv) and HCl (4 M in 1,4-dioxane) (1.0 mL). The reaction mixture was stirred at room temperature for 30 minutes. The resulting mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC (column: YMC C18 30*150 mm, 5 um, mobile phase A: water (0.05% NH3·H2O), mobile phase B: ACN; flow rate: 35 mL / min; gradient: 40% B to 80% B in 8 minutes, wavelength: 254 / 220 nm) to give N-cyclopropyl-2-[(2-fluoro-4-iodophenyl)amino]-4-(3-methanesulfonimidamidephenoxy)-1,5-dimethyl-6-oxopyridine-3-carboxamide (17.7 mg, 23%) as a white solid. ES-LCMS m / z 626.2.

[0433] 1 H NMR (400 MHz, DMSO-d6) δ 8.64 (s, 1H), 7.91 (d, J = 3.6 Hz, 1H), 7.60 - 7.53 (m, 1H), 7.37 - 7.30 (m, 1H), 7.09 - 7.00 (m, 1H), 6.81 - 6.65 (m, 3H), 6.57 - 6.48 (m, 1H), 6.44 - 6.40 (m, 1H), 6.35 - 6.28 (m, 1H), 3.33 (s, 3H), 3.09 (s, 3H), 2.31 - 2.22 (m, 1H), 1.80 (s, 3H), 0.44 - 0.35 (m, 2H), 0.05 - 0.00 (m, 2H).

[0434] Example 10: SPR assay MEK-RAF binding assay The compound effects on the binding affinity of MEK to BRAF or CRAF were according to surface plasmon resonance (SPR) including single-cycle kinetic analysis. GST-BRAF or GST-CRAF was immobilized on the chip, and His-tagged MEK1 was flowed over the sensor chip while increasing its concentration. 500 mM ATP was added to the running buffer. The dissociation constant of MEK1 binding to either BRAF or CRAF was calculated in the absence and presence of the compound. The analysis was performed on a Biacore 8K instrument. The sensorgrams were double-referenced and DMSO-corrected. The data was fitted to a single-cycle kinetic model. The activities were classified into A to D, where A represents IC 50 <100 nM, B represents 100 nM ≤ IC 50 <1 μM, C represents 1 ≤ IC 50 <10 μM, D represents IC 50 ≥ 10 μM.

[0435] The experimental results are shown in Table 3 below.

Table 3-1

Table 3-2

[0436] MEK-KSR Binding Assay The compound effects on the binding affinity of MEK to KSR1 or KSR2 are according to surface plasmon resonance (SPR) including single-cycle kinetic analysis. GST-KSR1 or GST-KSR2 is immobilized on the chip, and His-tagged MEK1 is flowed over the sensor chip while increasing its concentration. 500 mM ATP is added to the running buffer. The dissociation constant of MEK1 binding to either BRAF or CRAF is calculated in the absence and presence of the compound. The analysis is performed on a Biacore 8K instrument. The sensorgrams are double-referenced and DMSO-corrected. The data is fitted to a single-cycle kinetic model.

[0437] Example 11: Immunoprecipitation Assay In a 6-well plate, immunoprecipitation experiments were performed by plating approximately 450,000 HCT116 cells per well. The cells were plated for 48 hours and transfected after reaching approximately 70% confluence. Then, 24 hours after transfection, the cells were treated with vehicle (0.1% DMSO) or compound (approximately 200 nM) for 1 hour. After washing the cells twice with cold PBS, they were transferred to pre-cooled tubes in 0.6 mL of PBS solution. The cells were spun at 1,800 g for 10 minutes in a cooled centrifuge, and the supernatant was aspirated. To lyse the cells, the pellet was resuspended in NP-40 buffer (50 mM Tris (pH 7.8), 100 mM NaCl, 0.5% (v / v) NP-40, 10% (v / v) glycerol, 1 mM EDTA) supplemented with protease and phosphatase inhibitor cocktail (Thermo Fisher, 78440) and incubated on ice for 30 minutes. The lysate was centrifuged at 2,100 g for 20 minutes, and the supernatant was collected. Using BSA as a standard, the clear lysate was quantified using a BCA reagent (Pierce, 23225). 5 micrograms of rabbit anti-MEK1 antibody (Millipore-Sigma, 07-641) or rabbit IgG (Millipore Sigma, 12-370) was immobilized with 50 μL of sepharose protein A resin (Thermo Fisher, 53139), washed three times with 300 μL of NP-40 buffer, and then immunoprecipitation was initiated.

[0438] Next, for MEK1 immunoprecipitation, 250 μg of whole cell lysate with a total volume of 0.6 mL was mixed with a pre-fixed anti-MEK1 antibody pre-conjugated with protein A resin. The sample was incubated on a rotary shaker at 4 °C for 4 hours and then washed three times with NP-40 buffer with a volume of 0.6 mL. Next, the protein was denatured, 80 μL of 1x SDS sample buffer was added, and it was released from the resin. After the sample was boiled at 90 °C for 2 minutes and spun, it was applied to a 4-12% bis-tris glycine gel (Bio-Rad, 3450125) and run in MOPS-SDS buffer (Thermo Fisher, NP0001) at 150 V for 60 minutes. Next, the gel was transferred to nitrocellulose in 20% methanol in Tris-glycine buffer (95 V, 250 A). After confirming the transfer using Ponceau Red, it was analyzed by Western blot. Signals for MEK, Flag-tagged protein, BRAF, and GAPDH were detected by enhanced chemiluminescence with a ChemDoc XRS+ imaging system (Biorad). The activity was classified into A to D, where A represents IC 50 <100 nM, B represents 100 nM ≤ IC 50< 1 μM, C represents 1 ≤ IC 50 <10 μM, D represents IC 50 ≥ 10 μM.

[0439] The experimental results are shown in Table 4 below.

Table 4

[0440] 4-hour pERK1 / 2 HTRF assay AsPC1 cells were seeded in 96-well plates at 20,000 cells / well overnight and then treated with a 12-point dose-response of the compound (starting dose of 3000 nM and 3-fold dilutions) for 4 hours. AsPC1 cells are a K-Ras mutant cell line. Phosphorylation of ERK1 / 2 at residues Thr202 and Tyr204 was detected using a homogeneous time-resolved fluorescence (HTRF) assay (Cisbio catalog number 64ERKPEG). Briefly, Eu3+ - Phosphorylation of ERK was detected using a sandwich assay format with two phospho - ERK - specific antibodies, one labeled with a cryptate (donor) and the other labeled with d2 (acceptor). Fluorescence resonance energy transfer (FRET) to the d2 acceptor was detected at a wavelength of 665 nm. The ERK1 / 2 phosphorylation level was normalized to the total ERK1 / 2 protein level in each well. IC 50 values were measured by fitting to a variable slope, four - parameter curve of compound concentration versus normalized phospho - ERK1 / 2 relationship. Activity was classified into A - D, where A represents IC 50 <100 nM, B represents 100 nM ≤ IC 50 <1 μM, C represents 1 ≤ IC 50 <10 μM, D represents IC 50 ≥ 10 μM. The experimental results are shown in Table 5 below.

Table 5 - 1

Table 5 - 2

[0441] 4 - hour - pMEK1 / 2 MSD assay AsPC1 cells were seeded in 96 - well plates at 10,000 cells / well overnight and then treated with a 12 - point dose - response of the compound (starting dose of 1000 nM and 3 - fold dilutions) for 4 hours. AsPC1 cells are a K - Ras mutant (G12D) pancreatic cancer cell line. MesoScale Discovery (MSD) assay (MSD catalog number K15129D - 2) was used to detect phosphorylation of MEK1 / 2 at residues Ser217 and Ser221. The MEK1 / 2 phosphorylation level was normalized to the total MEK1 / 2 protein detected in each well of the same MSD plate. IC 50 values were measured by fitting to a variable slope, four - parameter curve of compound concentration versus normalized phospho - MEK1 / 2 relationship. Activity was classified into A - D, where A represents IC 50represents <100 nM, and B is 100 nM ≤ IC 50 represents <1 μM, and C is 1 ≤ IC 50 represents <10 μM, and D is IC 50 ≥ 10 μM. The experimental results are shown in Table 6 below.

Table 6

[0442] Example 12: Synthesis of 4-{2-chloro-3-[(methylsulfamoyl)amino]phenoxy}-N-cyclopropyl-2-[(2-fluoro-4-iodophenyl)amino]-1,5-dimethyl-6-oxopyridine-3-carboxamide (I-2) Alternative synthesis of I-2.

Chemical formula

[0443] Step 1: N-cyclopropyl-2-[(2-fluoro-4-iodophenyl)amino]-4-hydroxy-1,5-dimethyl-6-oxopyridine-3-carboxamide

Chemical formula

[0444] ES-LCMS m / z 458 [M+H] + 。

[0445] Step 2: 3-(Cyclopropylcarbamoyl)-2-[(2-fluoro-4-iodophenyl)amino]-1,5-dimethyl-6-oxopyridin-4-yl trifluoromethanesulfonate

Chemical formula

[0446] ES-LCMS m / z 590[M+H] + 。

[0447] 1 H NMR (300 MHz, DMSO-d6) δ 8.49 (s, 1H), 8.36 - 8.24 (m, 1H), 7.62 - 7.54 (m, 1H), 7.39 - 7.32 (m, 1H), 6.62 - 6.54 (m, 1H), 3.38 (s, 3H), 2.44 - 2.33 (m, 1H), 2.06 (s, 3H), 0.59 - 0.45 (m, 2H), 0.26 - 0.13 (m, 2H).

[0448] Step 3: 4-(2-Chloro-3-nitrophenoxy)-N-cyclopropyl-2-[(2-fluoro-4-iodophenyl)amino]-1,5-dimethyl-6-oxopyridine-3-carboxamide [Chem.] A stirred solution of 3-(cyclopropylcarbamoyl)-2-[(2-fluoro-4-iodophenyl)amino]-1,5-dimethyl-6-oxopyridin-4-yl trifluoromethanesulfonate (11.5 g, 19 mmol, 1.0 equiv) and TEA (5.9 g, 58 mmol, 3.0 equiv) in ACN (200 mL) was added dropwise with 2-chloro-3-nitrophenol (6.8 g, 39 mmol, 2.0 equiv) at room temperature under a nitrogen atmosphere. The resulting mixture was stirred at 50 °C for 2 hours under a nitrogen atmosphere. The reaction was monitored by LCMS. The mixture was cooled to room temperature and quenched by adding water (200 mL) at room temperature. The resulting mixture was extracted with EtOAc (3 × 100 mL). The combined organic layers were washed with brine (3 × 100 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. Next, it was purified by silica gel column chromatography, eluted with PE / EA (1:1), and 4-(2-chloro-3-nitrophenoxy)-N-cyclopropyl-2-[(2-fluoro-4-iodophenyl)amino]-1,5-dimethyl-6-oxopyridin-3-carboxamide (6.8 g, 56%) was obtained as a white solid.

[0449] ES-LCMS m / z 613 [M+H] + .

[0450] Step 4: 4-(3-Amino-2-chlorophenoxy)-N-cyclopropyl-2-[(2-fluoro-4-iodophenyl)amino]-1,5-dimethyl-6-oxopyridin-3-carboxamide [Chem.] To a stirred solution of 4-(2-chloro-3-nitrophenoxy)-N-cyclopropyl-2-[(2-fluoro-4-iodophenyl)amino]-1,5-dimethyl-6-oxopyridine-3-carboxamide (8.0 g, 13 mmol, 1.0 equiv) in AcOH (50 mL) was added Fe (7.3 g, 130 mmol, 10.0 equiv) portionwise at 50 °C under an air atmosphere. The resulting mixture was stirred at 50 °C under an air atmosphere for 2 h. The reaction was monitored by LCMS. The mixture was cooled to room temperature and quenched by the addition of water (100 mL) at room temperature. The mixture was neutralized to pH 7 with saturated NaHCO3. The resulting mixture was extracted with EtOAc (3 × 100 mL). The combined organic layers were washed with brine (1 × 100 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. This gave 4-(3-amino-2-chlorophenoxy)-N-cyclopropyl-2-[(2-fluoro-4-iodophenyl)amino]-1,5-dimethyl-6-oxopyridine-3-carboxamide (6.5 g, 85%) as a white solid.

[0451] ES-LCMS m / z 583[M+H] + 。

[0452] Step 5: 4-{2-chloro-3-[(methylsulfamoyl)amino]phenoxy}-N-cyclopropyl-2-[(2-fluoro-4-iodophenyl)amino]-1,5-dimethyl-6-oxopyridine-3-carboxamide

Chemical formula

[0453] ES-LCMS m / z 676.2[M+H] + 。

[0454] 1H NMR (300 MHz, methanol-d4) δ 7.53 - 7.43 (m, 1H), 7.43 - 7.29 (m, 2H), 7.14 (t, J = 8.3 Hz, 1H), 6.60 (t, J = 8.6 Hz, 1H), 6.52 - 6.42 (m, 1H), 3.53 (s, 3H), 2.63 (s, 3H), 2.24 - 2.10 (m, 1H), 1.92 (s, 3H), 0.52 - 0.43 (m, 2H), 0.09 - 0.03 (m, 2H).

[0455] Example 13: Pharmacokinetic Study The exemplified compounds were tested and their pharmacokinetic properties in mice were measured using a cassette dosing procedure. The assay procedures and results are described below.

[0456] Part I - Procedure for cassette pharmacokinetic study The test compound was administered to each mouse, and a pharmacokinetic study was conducted using a cassette dosing procedure. The treatment groups consisted of 3 animals (Balb / c male mice, approximately 6 - 8 weeks old, approximately 20 - 30 g) per administration route. For IV and PO administrations, the compound was formulated in 5% DMSO and 95% PEG400 at a final concentration of 0.5 mg / mL. The compound was administered at 2 mg / kg for IV administration and 5 mg / kg for PO administration. Blood samples were collected at 0.083, 0.25, 0.5, 1.0, 2.0, 4.0, 6.0, 8.0, and 24 hours after IV administration, and at 0.25, 0.5, 1.0, 2.0, 4.0, 6.0, 8.0, and 24 hours after PO administration. The blood samples were centrifuged at 4,000 g for 5 minutes at 4°C to obtain plasma samples. The plasma samples were diluted with acetonitrile containing an internal standard, vortexed for 30 seconds, and then centrifuged at 4,000 rpm for 15 minutes at 4°C. The supernatant was diluted with water, and the concentration of the compound was measured by HPLC / MS / MS by comparison with calibration standards in the range of 0.5 - 1,000 ng / mL.

[0457] Part II - Results The experimental results are shown in Table 7 below. When listing the route as "IV*", the compound was administered IV at 1 mg / kg.

Table 7 - 1

Table 7 - 2

[0458] Example 14: In vivo efficacy study using human MIA PaCa - 2 xenograft in mice Using a human cell line derived from a xenograft grown from the MIA PaCa-2 cell line in immunodeficient mice, the antitumor activity of MEK inhibitor compounds was evaluated in vivo. The MIA PaCa-2 cells are a K-Ras mutant (G12C) pancreatic tumor cell line. The tumor cell line is maintained in vitro as a monolayer culture in medium at 37 °C in an atmosphere of 5% CO2 in air. Prior to confluence by trypsin-EDTA treatment, the tumor cells are routinely passaged no more than 4-5 passages. Cells growing in the exponential growth phase are harvested for tumor seeding. MIA PaCa-2 tumor cells (1×10 6 cells) are subcutaneously implanted into the right flank of Nu / Nu nude mice as a 1:1 mixture with Matrigel. The tumors are grown to approximately 250 mm 3 . At this point, the mice are assigned to groups so that the average tumor volume is the same for each treatment group (n = 8 mice / mouse). The compound is administered to the mice bearing tumors by QD forced oral administration at a dose of 1 mg / kg. Ten days after administration, when the tumors in the vehicle control mice reach the lethal endpoint (average tumor volume exceeding 1500 mm 3 ), all the mice are sacrificed and the final measurements are recorded. Throughout the study, the body weight and tumor volume of the mice are recorded. The tumor size is measured twice a week using calipers and recorded. The tumor volume (mm 3 ) is estimated using the formula: TV = a × b 2 / 2, where "a" and "b" are the major and minor diameters of the tumor, respectively.

[0459] The tumor growth inhibition (TGI) rates (%) for the exemplary MEK inhibitors containing I-2 measured on day 10 were shown to be 86.2%, 96.2%, and 82.3%. The average weight loss observed on day 10 for the exemplary MEK inhibitors containing I-2 was 5.5%, 2.5%, and 3.8%, respectively.

[0460] Example 15: Stabilization of the MEK1-CRAF Complex Assay In the absence and presence of exemplary MEK inhibitor compounds, the dissociation constants (K DBy comparing [(

[0461] Part I. Experimental Procedures Preparation of 4× stock solutions of reagents: All reagents were diluted with AlphaLISA buffer. MEK1 was diluted to 4 nM, and nickel chelate donor beads and glutathione acceptor beads were diluted to 80 μg / mL. CRAF was diluted to a maximum concentration of 160 nM, which was subsequently diluted to 80, 40, 20, 10, 5, 2.5, 1.25, and 0.625 nM by serial 1:2 dilutions.

[0462] Based on a reaction mixture with a total volume of 20 μL, exemplary MEK inhibitor compounds (0, 0.01, 0.1, or 1 μM) were added to a 384 - AlphaPlate (PerkinElmer, 6008350) using a digital liquid dispenser (Tecan D300e).

[0463] 5 μL of 4× MEK1 stock solution was added to wells A1 - P20 using a multi - channel pipette. The plate was sealed with transparent olefin sealing tape (Thermo Scientific, 232701), centrifuged at 1000 rpm for 1 minute, and incubated at room temperature for 30 minutes.

[0464] 5 μL of 4× CRAF stock solution at different concentrations, or 5 μL or 10 μL of AlphaLISA buffer, was added using a multi - channel pipette. The plate was sealed, centrifuged at 1000 rpm for 1 minute, and incubated at room temperature for 60 minutes.

[0465] Using a multi-channel pipette, 5 μL of 4× glutathione acceptor beads were first added to all wells. Then, the ambient light was adjusted to less than 100 lux (using an illuminance meter), and then 5 μL of 4× nickel chelated donor beads were added to the same wells. From this step, the plate was covered with a black plate cover, centrifuged at 1000 rpm for 1 minute, and incubated at room temperature for 60 minutes.

[0466] Part II. Data Collection Using an AlphaLISA module (excitation: 680 nm, emission: 615 nm), data was collected on a PHERAStar FSX (BMG LABTECH) with a gain of 3600. The excitation time was 0.30 seconds, and data collection was started 0.04 seconds after the delay, with a total integration time of 0.60 seconds.

[0467] Part III. Data Analysis The individual AlphaLISA counts of wells conta...

Claims

1. Compound of formula (I): 【Chemical 95】 or a pharmaceutically acceptable salt thereof [In the formula, each 【Chemistry 96】 These are independently single or double bonds, Each A is independent 【Chemistry 97】 Alternatively, it is an arbitrarily substituted 5-6 member heteroaryl, X １ , X ２ , X ３ , and X ５ CR is independent １ or N, X ６ is C(O), O, or NH, X ７ is CH or N, X ８ is N or O, or when X ８ is N, R ３ and R ８ together with the N atom to which they are attached form an optionally substituted 3- to 7-membered heterocycloalkyl ring, and each R １ is independently hydrogen, deuterium, halo, -CN, optionally substituted C １ -C ６ -aliphatic, optionally substituted C １ -C ６ -alkoxy, optionally substituted C ３ -C １０ -cycloalkyl, optionally substituted C ６ -C １０ -heterocycloalkyl, or optionally substituted C ６ -C １０ -aryl, and R ２ , R ３ , R ４ , and R ５ They are independently hydrogen, C( ２ D) ３ , OC ( ２ D) ３ , arbitrarily substituted C １ -C ６ Aliphatic, arbitrarily substituted C １ -C ６ alkoxy, optionally substituted C ３ -C １０ Cycloalkyl, optionally substituted C ６ -C １０ Heterocycloalkyl or optionally substituted C ６ -C １０ Is it Ale, or X? ７ However, if N forms a double bond with the sulfur atom, then R ５ It does not exist. Each R ６ They are independently hydrogen, deuterium, and C( ２ D) ３ , arbitrarily substituted C １ -C ６ Aliphatic, arbitrarily substituted C １ -C ６ alkoxy, optionally substituted C ３ -C １０ Cycloalkyl, optionally substituted C ６ -C １０ Heterocycloalkyl or optionally substituted C ６ -C １０ Either all or both R ６ They, together with the atoms to which they are bonded, form an optionally substituted 3- to 7-membered heterocycloalkyl ring, or R ５ and R ６ They form a 5-6 membered heterocycloalkyl ring with the atoms to which they are bonded, or R ５ , and X ５ or X ３ Together with the atoms to which they are bonded, they form a 5-6 membered condensed heterocycloalkyl ring or aromatic heterocycle. R ６ , and X ５ or X ３ Together with the atoms to which they are bonded, they form a 5-6 membered condensed heterocycloalkyl ring. R ７ is O, or optionally replaced by C １ -C ６ It is aliphatic, R ８ It is either absent, or C is replaced by hydrogen, deuterium, or optionally substituted. １ -C ６ It is aliphatic.

2. Compound of formula (II): 【Chem.98】 or a pharmaceutically acceptable salt thereof [In the formula, each 【Chem.99】 These are independently single or double bonds, Each A is independent 【Chemistry 100】 Alternatively, it is an arbitrarily substituted 5-6 member heteroaryl, X １ , X ２ , X ３ , X ４ , and X ５ CR is independent １ or N, X ６ is O or NH, X ７ is CH or N, X ８ is N or O, or when X ８ is N, R ３ and R ８ together with the N atom to which they are attached form an optionally substituted 3- to 7-membered heterocycloalkyl ring, and each R １ is independently hydrogen, deuterium, halo, -CN, an optionally substituted C １ -C ６ aliphatic, an optionally substituted C １ -C ６ alkoxy, an optionally substituted C ３ -C １０ cycloalkyl, an optionally substituted C ６ -C １０ heterocycloalkyl, or an optionally substituted C ６ -C １０ aryl, and R ２ 、R ３ 、R ４ 、and R ５ are each independently hydrogen, C( ２ D) ３ 、OC( ２ D) ３ 、optionally substituted C １ -C ６ aliphatic, optionally substituted C １ -C ６ alkoxy, optionally substituted C ３ -C １０ cycloalkyl, optionally substituted C ６ -C １０ heterocycloalkyl, or optionally substituted C ６ -C １０ aryl, or when X ７ is N which forms a double bond with a sulfur atom, R ５ is absent, Each R ６ They are independently hydrogen, deuterium, and C( ２ D) ３ , arbitrarily substituted C １ -C ６ Aliphatic, arbitrarily substituted C １ -C ６ alkoxy, optionally substituted C ３ -C １０シ Chloalkyl, optionally substituted C ６ -C １０ Heterocycloalkyl or optionally substituted C ６ -C １０ Either all or both R ６ They, together with the atoms to which they are bonded, form a 3- to 7-membered heterocycloalkyl ring, or R ５ and R ６ They form a 5-6 membered heterocycloalkyl ring with the atoms to which they are bonded, or R ５ , and X ２ or X ４ Together with the atoms to which they are bonded, they form a 5-6 membered condensed heterocycloalkyl ring or aromatic heterocycle. R ６ , and X ２ or X ４ Together with the atoms to which they are bonded, they form a 5-6 membered condensed heterocycloalkyl ring. R ７ is O, or optionally replaced by C １ -C ６ It is aliphatic, R ８ It is either absent, or C is replaced by hydrogen, deuterium, or optionally substituted. １ -C ６ It is aliphatic.

3. Compounds of formula (III), (IIIA), (IIIB), or (IIIC): 【Chemistry 101】 or a pharmaceutically acceptable salt thereof [In the formula, Ring B is C ３ -C １０ Cycloalkyl, C having 1 to 4 heteroatoms N, S, or O ３ -C １０ An optionally substituted ring selected from heterocycloalkyls, phenyls, 5-6 membered heteroaryls having 1-4 heteroatoms N, S, or O, or 6-10 membered bicyclic heteroaryls having 1-4 heteroatoms N, S, or O, R １１ H, 【Chemical Engineering 102】 And, R １２ is H, or optionally replaced by C １ -C ６ It is aliphatic, Each A is independent 【Chemistry 103】 Alternatively, it is an arbitrarily substituted 5-6 member heteroaryl, X ６ is C(O), O, or NH, X ７ is CH or N, X ８ is N or O, or X ８ When R is N, ３ and R ８ Together with the N atoms to which they are bonded, they form an optionally substituted 3- to 7-membered heterocycloalkyl ring, and each R １ These are independently hydrogen, halo, -CN, and optionally substituted C. １ -C ６ Aliphatic, arbitrarily substituted C １ -C ６ alkoxy, optionally substituted C ３ -C １０ Cycloalkyl, optionally substituted C ６ -C １０ Heterocycloalkyl or optionally substituted C ６ -C １０ It is Ariel, R ２ , R ３ , R ４ , and R ５ These are independently hydrogen, optionally substituted C １ -C ６ Aliphatic, arbitrarily substituted C １ -C ６ alkoxy, optionally substituted C ３ -C １０ Cycloalkyl, optionally substituted C ６ -C １０ Heterocycloalkyl or optionally substituted C ６ -C １０ Is it Ale, or X? ７ However, if N forms a double bond with the sulfur atom, then R ５ It does not exist. Each R ６ These are independently hydrogen, optionally substituted C １ -C ６ Aliphatic, arbitrarily substituted C １ -C ６ alkoxy, optionally substituted C ３ -C １０ Cycloalkyl, optionally substituted C ６ -C １０ Heterocycloalkyl, optionally substituted C ６ -C １０ Either all or both R ６ They, together with the atoms to which they are bonded, form an optionally substituted 3- to 7-membered heterocycloalkyl ring, or R ５ and R ６ Together with the atoms to which they are bonded, they form a 5-6 membered heterocycloalkyl ring. R ７ is O, or optionally replaced by C １ -C ６ It is aliphatic, R ８ It is either absent, or a hydrogen atom, or optionally substituted C １ -C ６ It is aliphatic.

4. X １ , X ２ , X ３ , and X ５ CR １ The compound according to claim 1.

5. X １ , X ２ , X ４ , and X ５ CR １ The compound according to claim 2.

6. R １ C is substituted with hydrogen, a halo, or optionally. １ -C ６ The compound according to claim 1, wherein it is an alkoxy.

7. R １ The compound according to claim 1, wherein is hydrogen, fluoro, chloro, or methoxy.

8. X ６ The compound according to claim 1, wherein is O.

9. X ６ The compound according to claim 1, wherein is NH.

10. X ７ The compound according to claim 1, wherein is CH.

11. X ７ The compound according to claim 1, wherein is N.

12. A 【Chemical 104】 The compound according to claim 1.

13. X ８ The compound according to claim 12, wherein is N.

14. R ３ However, C is arbitrarily substituted. ３ -C １０ The compound according to claim 12, wherein it is a cycloalkyl compound.

15. R ３ The compound according to claim 14, wherein is cyclopropyl or optionally substituted cyclopropyl.

16. R ８ C is substituted with hydrogen or optionally. １ -C ６ The compound according to claim 12, which is aliphatic.

17. R ８ The compound according to claim 16, wherein is hydrogen or methyl.

18. R １ C is substituted with hydrogen, a halo, or optionally. １ -C ６ The compound according to claim 1, wherein it is an alkoxy.

19. R １ The compound according to claim 18, wherein is fluoro or iodine.

20. R ２ C is arbitrarily substituted. １ -C ６ The compound according to claim 1, which is aliphatic.

21. R ２ The compound according to claim 20, wherein is methyl.

22. R ３ C is arbitrarily substituted. ３ -C １０ The compound according to claim 1, wherein it is a cycloalkyl compound.

23. R ３ The compound according to claim 22, wherein is cyclopropyl.

24. R ４ C is arbitrarily substituted. １ -C ６ The compound according to claim 1, which is aliphatic.

25. R ４ The compound according to claim 24, wherein is methyl.

26. R ５ The compound according to claim 1, wherein the compound is hydrogen.

27. Each R ６ These are independently hydrogen or optionally substituted C １ -C ６ The compound according to claim 1, which is aliphatic.

28. Each R ６ The compound according to claim 27, wherein is independently hydrogen or methyl.

29. The compound according to claim 1, wherein the compound is a compound selected from those listed in Table 1, Table 2, or Table 2B, or a pharmaceutically acceptable salt thereof.

30. A pharmaceutical composition comprising a compound according to any one of claims 1 to 29, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, auxiliary agent, or vehicle.

31. A composition or pharmaceutical composition for treating a MEK-mediated disorder in a subject requiring treatment of a MEK-mediated disorder, wherein the composition comprises a compound according to any one of claims 1 to 29 or a pharmaceutically acceptable salt thereof, and the pharmaceutical composition comprises a compound according to any one of claims 1 to 29 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, auxiliary agent, or vehicle.

32. The composition or pharmaceutical composition according to claim 31, wherein the disorder is cancer.

33. The composition or pharmaceutical composition according to claim 32, wherein the cancer is a K-Ras mutant cancer, a B-Raf mutant cancer, an N-Ras mutant cancer, a C-Raf mutant cancer, an NF1 and / or NF2 mutant cancer, or any combination thereof.

34. The composition or pharmaceutical composition according to claim 32, wherein the cancer is selected from non-small cell lung cancer (NSCLC), pancreatic cancer, colorectal cancer (CRC), uterine carcinoma, endometrial cancer, bladder cancer, head and neck cancer, melanoma, multiple myeloma, acute myeloid leukemia (AML), low-grade serous ovarian cancer, neurofibroma, and glioma.

35. A composition or pharmaceutical composition for treating cancer in a patient, wherein the composition comprises a compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 29, and the pharmaceutical composition comprises a compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 29, and a pharmaceutically acceptable carrier, adjuvant, or vehicle.

36. A composition or pharmaceutical composition for use in a method for inhibiting MEK activity, wherein the composition comprises a compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 29, and the pharmaceutical composition comprises a compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 29 and a pharmaceutically acceptable carrier, auxiliary agent, or vehicle, wherein the method comprises contacting MEK, or a KSR-MEK complex, or a RAF-MEK complex with the composition or pharmaceutical composition.

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