MEK inhibitors and uses thereof

Abstract

The present disclosure provides MEK inhibitors, compositions thereof, and methods of use thereof.

Description

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS

[0002] 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. Technical Field

[0003] The present disclosure relates to compounds and methods useful for inhibiting mitogen-activated protein kinase / extracellular signal-regulated kinase kinase (MEK). The present disclosure also provides pharmaceutically acceptable compositions comprising the compounds of the present disclosure and methods of using the compositions to treat proliferative disorders such as cancer. Background Art

[0004] Activation of the p42 / 44 MAPK signaling pathway, which includes mitogen-activated protein kinase / extracellular signal-regulated kinase (ERK) kinase (MEK)-ERK, is associated with the onset and progression of a variety of cancers. The MEK-ERK pathway is often activated by mutations in the upstream factors BRAF or Ras or by signals from constitutively activated cell surface receptors. Inhibition of MEK may be a promising strategy for controlling the growth of tumors, such as those associated with MEK pathway signaling. Summary of the invention

[0005] It has now been discovered that compounds of the present disclosure and pharmaceutically acceptable compositions thereof are effective as MEK inhibitors.

[0006] In one aspect, the present disclosure provides a compound of formula (I):

[0007]

[0008] or a pharmaceutically acceptable salt thereof, wherein each variable is as defined and described herein.

[0009] In another aspect, the present disclosure provides a compound of formula (II):

[0010]

[0011] or a pharmaceutically acceptable salt thereof, wherein each variable is as defined and described herein.

[0012] Another aspect of the present disclosure provides a method for treating a MEK-mediated disorder in a subject. The method comprises administering to a subject in need thereof a therapeutically effective amount of a compound described herein to treat the MEK-mediated disorder, as further described in the embodiments.

[0013] Another aspect of the present disclosure provides a method for inhibiting MEK activity, comprising contacting MEK or KSR-MEK complex or RAF-MEK complex with an effective amount of a compound described herein, as further described in the embodiments.

[0014] In some aspects, the compounds of the present disclosure and pharmaceutically acceptable compositions thereof can be used to treat a proliferative disorder, such as a cancer as described herein. DETAILED DESCRIPTION

[0015] The compounds of the present disclosure and their pharmaceutical compositions can be used as MEK inhibitors. Without wishing to be bound by any particular theory, it is believed that the compounds of the present disclosure can directly engage the Ras kinase inhibitor (KSR) at the MEK interface, and the KSR can reshape the prototype allosteric pocket of the MEK inhibitor in the KSR-MEK complex. Without wishing to be bound by any particular theory, it is believed that the compounds of the present disclosure can bind to the KSR-MEK complex and can destroy the related RAF-MEK complex.

[0016] I. Definitions

[0017] When introducing elements of various aspects as described herein, the articles "a," "an," and "the" mean that there are one or more elements. The terms "comprising," "including," and "having" are intended to be inclusive and mean that there may be additional elements other than the listed elements.

[0018] Compounds of the present disclosure include compounds generally described herein, and are further described by the classes, subclasses, and species disclosed herein. Unless otherwise indicated, as used herein, the following definitions shall apply. For the purposes of the present disclosure, chemical elements are identified according to the CAS version of the periodic table of the elements (Handbook of Chemistry and Physics, 75th edition). In addition, the general principles of organic chemistry are described in "Organic Chemistry", Thomas Sorrell, University Science Books, Sausalito: 1999; and "March's Advanced Organic Chemistry", 5th edition, editors: Smith, MB and March, J., John Wiley & Sons, New York: 2001, the complete contents of which are hereby incorporated by reference.

[0019] As used herein, the term "aliphatic" or "aliphatic group" refers to a straight chain (i.e., unbranched) or branched, substituted or unsubstituted hydrocarbon chain that is fully saturated or contains one or more unsaturated units, or a monocyclic hydrocarbon or bicyclic hydrocarbon (also referred to herein as "carbocycle", "cycloaliphatic" or "cycloalkyl") that is fully saturated or contains one or more unsaturated units but is not an aromatic group, which has a single point of connection to the rest of the molecule. Unless otherwise specified, an aliphatic group contains 1-6 aliphatic carbon atoms. In some embodiments, an aliphatic group contains 1-5 aliphatic carbon atoms. In other embodiments, an aliphatic group contains 1-4 aliphatic carbon atoms. In yet other embodiments, an aliphatic group contains 1-3 aliphatic carbon atoms, and in yet other embodiments, an aliphatic group contains 1-2 aliphatic carbon atoms. In some embodiments, a "cycloaliphatic" (or "carbocycle" or "cycloalkyl") refers to a monocyclic C3-C6 hydrocarbon that is fully saturated or contains one or more unsaturated units but is not an aromatic group, which has a single point of connection to the rest of the molecule. Suitable aliphatic groups include, but are not limited to, straight or branched, substituted or unsubstituted alkyl, alkenyl, alkynyl and mixtures thereof, such as (cycloalkyl)alkyl, (cycloalkenyl)alkyl or (cycloalkyl)alkenyl.

[0020] As used herein, the term "bicyclic" or "bicyclic system" refers to any bicyclic system, that is, carbocyclic or heterocyclic, saturated or with one or more unsaturated units, with one or more common atoms between the two rings of the ring system. Therefore, the term includes any allowed ring fusion, such as ortho-fusion or spirocyclic. As used herein, the term "heterobicyclic" is a subset of "bicyclic", which requires one or more heteroatoms to be present in one or both rings of the bicyclic. Such heteroatoms may be present in the ring junction and are optionally substituted, and may be selected from nitrogen (including N-oxides), oxygen, sulfur (including oxidized forms such as sulfones and sulfonates), phosphorus (including oxidized forms phosphates), boron, etc. In some embodiments, the bicyclic group has 7-12 ring members and 0-4 heteroatoms independently selected from nitrogen, oxygen or sulfur. As used herein, the term "bridged bicyclic" refers to any bicyclic system with at least one bridge, that is, carbocyclic or heterocyclic, saturated or partially unsaturated. According to the IUPAC definition, "bridge" is an unbranched chain or valence bond consisting of one or more atoms connecting two bridgeheads, wherein "bridgehead" is any backbone atom bonded to three or more backbone atoms (except hydrogen) in a ring system. In some embodiments, the bridged bicyclic group has 7-12 ring members and 0-4 heteroatoms independently selected from nitrogen, oxygen or sulfur. Such bridged bicyclic groups are well known in the art and include the groups described below, wherein each group is connected to the rest of the molecule at any substitutable carbon or nitrogen atom. Unless otherwise indicated, the bridged bicyclic group is optionally substituted by one or more substituents as described for aliphatic groups. Additionally or alternatively, any substitutable nitrogen of the bridged bicyclic group is optionally substituted. Exemplary bicyclics include:

[0021]

[0022] Exemplary bridged double rings include:

[0023]

[0024] The term "lower alkyl" refers to a C 1-4 Straight or branched chain alkyl. Exemplary lower alkyl groups are methyl, ethyl, propyl, isopropyl, butyl, isobutyl and tert-butyl.

[0025] The term "lower haloalkyl" refers to a C 1-4 Straight chain or branched chain alkyl.

[0026] The term "heteroatom" means one or more of oxygen, sulfur, nitrogen, phosphorus, or silicon (including any oxidized form of nitrogen, sulfur, phosphorus, or silicon; the quaternized form of any basic nitrogen; or a substitutable 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)).

[0027] As used herein, the term "unsaturated" means that a moiety has one or more units of unsaturation.

[0028] As used herein, the term "divalent C1-C8 (or C1-C6) saturated or unsaturated, straight or branched hydrocarbon chain" refers to a straight or branched divalent alkylene, alkenylene and alkynylene chain as defined herein.

[0029] The term "alkylene" refers to a divalent alkyl group. An "alkylene chain" is a polymethylene group, i.e., -(CH2) n -, wherein 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 chain in which one or more methylene hydrogen atoms are replaced by a substituent. Suitable substituents include the substituents described below for substituted aliphatic groups.

[0030] The term "alkenylene" refers to a divalent alkenyl group. A substituted alkenylene chain is a polymethylene group containing at least one double bond and in which one or more hydrogen atoms are replaced by a substituent. Suitable substituents include the substituents described below for substituted aliphatic groups.

[0031] As used herein, the term "cyclopropylene" refers to a divalent cyclopropyl radical having the following structure:

[0032] The term "halogen" means F, Cl, Br or I.

[0033] The term "aryl", used alone or as part of a larger moiety such as "aralkyl", "aralkyloxy" or "aryloxyalkyl", refers to a monocyclic or bicyclic ring system having a total of five to fourteen ring members, wherein at least one ring in the system is an aromatic ring and wherein each ring in the system contains 3 to 7 ring members. The term "aryl" can be used interchangeably with the term "aryl ring". In certain embodiments of the present disclosure, "aryl" refers to an aromatic ring system, which includes but is not limited to phenyl, biphenyl, naphthyl, anthracenyl, etc., which may carry one or more substituents. Also included within the scope of the term "aryl" as used herein are groups in which an aromatic ring is fused to one or more non-aromatic rings, such as dihydroindanyl, phthalimidyl, naphthimidyl, phenanthridinyl or tetrahydronaphthyl, etc.

[0034] The terms "heteroaryl" and "heteroar-", used alone or as part of a larger moiety such as "heteroaralkyl" or "heteroaralkoxy", refer to groups having 5 to 10 ring atoms, preferably 5, 6 or 9 ring atoms; having a total of 6, 10 or 14 π electrons in the ring array; and having one to five heteroatoms in addition to carbon atoms. The term "heteroatom" refers to nitrogen, oxygen or sulfur, and includes any oxidized form of nitrogen or sulfur, and any quaternized form of basic nitrogen. Heteroaryl includes, but is not limited to, thienyl, furanyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolizinyl, purinyl, naphthyridinyl and pteridinyl. As used herein, the terms "heteroaryl" and "heteroaryl-" also include groups in which a heteroaromatic ring is fused to one or more aryl, cycloaliphatic or heterocyclyl rings, wherein the connecting group 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, tetrahydroquinolyl, tetrahydroisoquinolyl and pyrido [2,3-b] -1,4-oxazine-3 (4H) -one. The heteroaryl group may be monocyclic or bicyclic. The term "heteroaryl" may be used interchangeably with the terms "heteroaryl ring," "heteroaryl group," or "heteroaromatic," any of which includes rings that are optionally substituted. The term "heteroaralkyl" refers to an alkyl group substituted with a heteroaryl group, wherein the alkyl and heteroaryl portions are independently optionally substituted.

[0035] As used herein, the terms "heterocycle", "heterocyclyl", "heterocyclic group" and "heterocyclic ring" are used interchangeably and refer to a 5- to 7-membered monocyclic or 7- to 10-membered bicyclic heterocyclic moiety that is saturated or partially unsaturated and has one or more, preferably one to four, heteroatoms as defined above in addition to carbon atoms. The term "nitrogen" when used as a ring atom of a heterocycle includes substituted nitrogen. For example, in a saturated or partially unsaturated ring having 0-3 heteroatoms selected from oxygen, sulfur or nitrogen, nitrogen may be N (as in 3,4-dihydro-2H-pyrrolyl), NH (as in pyrrolidinyl) or + NR (as in N-substituted pyrrolidinyl).

[0036] Heterocycle can be connected to its side group at any heteroatom or carbon atom producing a stable structure and any ring atom can be optionally substituted.The example of such saturated or partially unsaturated heterocyclic group includes but is not limited to tetrahydrofuranyl, tetrahydrothienyl, pyrrolidinyl, piperidinyl, pyrrolinyl, tetrahydroquinolyl, tetrahydroisoquinolyl, decahydroquinolyl, oxazolidinyl, piperazinyl, dioxanyl, dioxolane, diazepine, oxazepine, thiazepine, morpholinyl and quinuclidine.As used herein, the terms "heterocycle", "heterocyclic radical", "heterocyclic ring", "heterocyclic group (heterocyclicgroup)", "heterocyclic moiety" and "heterocyclic group (heterocyclic radical)" are used interchangeably herein, and also include a group in which a heterocyclic ring is fused with one or more aryl, heteroaryl or cycloaliphatic rings, such as indolinyl, 3H-indolyl, chromanyl, phenanthridinyl or tetrahydroquinolyl. The heterocyclyl group may be monocyclic or bicyclic.The term "heterocycloalkyl" refers to an alkyl group substituted by a heterocyclyl group, wherein the alkyl and heterocyclyl portions independently are optionally substituted.

[0037] As used herein, the term "partially unsaturated" refers to a ring moiety that includes at least one double or triple bond. The term "partially unsaturated" is intended to encompass rings with multiple sites of unsaturation, but is not intended to include aryl or heteroaryl moieties as defined herein.

[0038] As described herein, the compounds of the present disclosure may contain "optionally substituted" moieties. In general, the term "substituted", whether or not preceded by the term "optionally", means that one or more hydrogens of the specified moiety are replaced by a suitable substituent. Unless otherwise indicated, an "optionally substituted" group may have a suitable substituent at each substitutable position of the group, and when more than one position in any given structure may be substituted by more than one substituent selected from a specified group, the substituent at each position may be the same or different. The combination of substituents contemplated by the present disclosure is preferably such that a stable or chemically feasible compound is formed. As used herein, the term "stable" refers to a compound that does not substantially change when subjected to conditions that allow the compound to be produced, detected, and in certain embodiments, to be recovered, purified, and used for one or more purposes disclosed herein.

[0039] Each optional substituent on a substitutable carbon is independently selected from the following monovalent substituents: halogen; -(CH2) 0-4 R°; -(CH2) 0-4 OR°; -O(CH2) 0-4 R o ; -O-(CH2) 0-4 C(O)OR°; -(CH2) 0-4 CH(OR°)2; -(CH2)0- 4SR°; -(CH2) 0-4 Ph, which may be substituted by R°; -(CH2) 0-4 O(CH2) 0-1 Ph, which may be substituted by R°; -CH=CHPh, which may be substituted by R°; -(CH2) 0-4 O(CH2) 0-1 -pyridyl, which may be substituted by R°; -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) 0-4S(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 Straight or branched alkylene)ON(R°)2; or -(C 1-4 Straight or branched alkylene) C(O)ON(R°)2.

[0040] Each R° is independently hydrogen, C 1-6 Aliphatic, -CH2Ph, -O(CH2) 0-1 Ph, -CH2-(5-6 membered heteroaryl ring) or a 5-6 membered saturated, partially unsaturated or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen or sulfur, or, notwithstanding the above definition, two independently occurring R° together with their intervening atoms form a 3-12 membered saturated, partially unsaturated or aryl monocyclic or bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen or sulfur, which may be substituted on the saturated carbon atoms of R° by a divalent substituent selected from =O and =S; or each R° is optionally substituted by a monovalent substituent independently selected from: halogen, -(CH2) 0-2 R ● 、-(halogen R · )、-(CH2) 0-2 OH, -(CH2) 0-2 OR · 、-(CH2) 0-2 CH(OR · )2; -O(halogen R · )、-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 Straight or branched alkylene)C(O)OR ● or -SSR● .

[0041] Each R ● Independently selected from C 1-4 Aliphatic, -CH2Ph, -O(CH2) 0-1 Ph or a 5-6 membered saturated, partially unsaturated or aromatic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen or sulfur, and wherein each R ● unsubstituted or, if preceded by a halogen, substituted only by one or more halogens; or wherein the optional substituents on the saturated carbon are divalent substituents independently selected from the group consisting of: =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-, or a divalent substituent attached to an ortho-substitutable carbon of an "optionally substituted" group is -O(CR * 2) 2-3 O-, where R * at each independent occurrence is selected from hydrogen, C 1-6 aliphatic or an unsubstituted 5-6 membered saturated, partially unsaturated or aromatic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen or sulfur.

[0042] When R * It is C 1-6 When the aliphatic group * Optionally substituted by: halogen; -R ● ;-(halogen R ● ), -OH, -OR · ; -O(halogen R · ); -CN; -C(O)OH; -C(O)OR · ;-NH2;-NHR · ;-NR · 2; or -NO2; where each R · Independently selected from C 1-4 Aliphatic; -CH2Ph; -O(CH2) 0-1 Ph; or a 5-6 membered saturated, partially unsaturated or aromatic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen or sulfur, and wherein each R · Unsubstituted or, in the case of a halogen radical being present in front, only substituted by one or more halogen radicals.

[0043] The optional substituents on the substitutable nitrogen are independently

[0044] or Each of these independently hydrogen, C1-C6 aliphatic, unsubstituted -OPh, or an unsubstituted 5-6 membered saturated, partially unsaturated or aromatic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen or sulfur, or two independent occurrences of Together with its intervening atoms, it forms an unsubstituted 3-12 membered saturated, partially unsaturated or aromatic monocyclic or bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen or sulfur; wherein when When it is a C1-C6 aliphatic group, Optionally substituted by: halogen, -R · 、-(halogen R · ), -OH, -OR · 、-O(halogen R · )、-CN、-C(O)OH、-C(O)OR · 、-NH2、-NHR · 、-NR · 2 or -NO2, where each R · Independently selected from C 1-4 Aliphatic, -CH2Ph, -O(CH2) 0-1 Ph or a 5-6 membered saturated, partially unsaturated or aromatic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen or sulfur, and wherein each R · Unsubstituted or, in the case of a halogen radical being present in front, only substituted by one or more halogen radicals.

[0045] In some embodiments, "alkyl" used alone or as part of a group refers to a saturated monovalent hydrocarbon radical having a straight or branched hydrocarbon chain, or a cyclic hydrocarbon when there are at least 3 carbon atoms, or a combination thereof and containing 1 to 20 carbon atoms (C1-C 20 alkyl), 1 to 10 carbon atoms (C1-C 10 In some embodiments, the alkyl group includes methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, hexyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc.

[0046] In some embodiments, "alkoxy" refers to -O-(alkyl), where "alkyl" is as defined above.

[0047] In some embodiments, "cycloalkyl" used alone or in combination means a saturated or partially saturated monocyclic, bicyclic or tricyclic alkyl group, wherein each ring portion contains 3 to 8 carbon atoms or 3 to 6 carbon atoms. In some embodiments, cycloalkyl includes cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc.

[0048] In some embodiments, the halogen or halo is F, Cl, Br, or I.

[0049] As used herein, the term "pharmaceutically acceptable salt" refers to salts that are suitable for use in contact with the tissues of the human body or lower animals without excessive toxicity, irritation, allergic reaction, etc. and commensurate with a reasonable benefit / risk ratio within the scope of reasonable medical judgment. Pharmaceutically acceptable salts are well known in the art. For example, SM Berge et al. have described 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 disclosed herein include salts derived from suitable inorganic and organic acids and bases. Examples of pharmaceutically acceptable non-toxic acid addition salts are salts formed of amino groups 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 by using other methods used in the art such as ion exchange salts. 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, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate, and the like.

[0050] Salts derived from appropriate bases include alkali metal salts, alkaline earth metal salts, ammonium salts and N +(C1-C4 alkyl) 4 salt. Representative alkali metal salts or alkaline earth metal salts include sodium salts, lithium salts, potassium salts, calcium salts, magnesium salts, etc. Where appropriate, other pharmaceutically acceptable salts include non-toxic ammonium salts, quaternary ammonium salts and amine cation salts formed using counter ions such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, lower alkyl sulfonates and aryl sulfonates.

[0051] Unless otherwise stated, the structures depicted herein are also intended to include all isomeric (e.g., enantiomeric, diastereomeric, and geometric (or conformational)) forms of the structure; for example, R and S configurations for each asymmetric center, Z and E double bond isomers, and Z and E conformational isomers. Therefore, single stereochemical isomers as well as enantiomeric, diastereomeric, and geometric (or conformational) mixtures of the compounds of the present invention are within the scope of the present disclosure. Unless otherwise stated, all tautomeric forms of the compounds of the present disclosure are within the scope of the present disclosure. In addition, unless otherwise stated, the structures depicted herein are also intended to include compounds that differ only in the presence of one or more isotopically enriched atoms. For example, having the structures of the present invention and including hydrogen replaced by deuterium or tritium or carbon enriched 13 C- or 14 Compounds having a carbon substituted at C are within the scope of the present disclosure. Such compounds are useful, for example, as analytical tools, probes in biological assays, or therapeutic agents according to the present disclosure.

[0052] As used herein, the term "provided compounds" refers to any genus, subgenus, and / or species of MEK inhibitors described herein.

[0053] As used herein, the term "inhibitor" or "MEK inhibitor" or "MEK antagonist" is defined as a compound that binds and / or inhibits MEK with measurable affinity. In some embodiments, inhibition is observed in a dose-dependent manner in the presence of a MEK inhibitor or MEK antagonist. 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 about 100% lower than the signal measured using a negative control under comparable conditions. The potency of an inhibitor is usually measured by its IC 50 The IC value (half maximal inhibitory concentration or the concentration required to inhibit 50% of the agonist response) is defined. 50The lower the value, the more potent the antagonist is and the lower the concentration required to inhibit the maximal biological response. In certain embodiments, the inhibitor has an IC 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. 50 and / or binding constant.

[0054] As used herein, the terms "measurable affinity" and "measurably inhibit" mean a measurable change or inhibition of MEK activity between a sample comprising a disclosed compound or composition thereof and MEK and an equivalent sample comprising MEK in the absence of the compound or composition thereof.

[0055] As used herein, the term "effective amount" refers to an amount of a compound sufficient to achieve a beneficial or desired result (e.g., a therapeutic result, an ameliorative result, an inhibitory result, or a preventive result). An 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.

[0056] As used herein, the term "treatment" includes any effect that causes improvement in an illness, disease, condition, etc., or improves its symptoms, such as mitigation, reduction, regulation, improvement or elimination. In some embodiments, treatment can be applied after one or more symptoms have developed. In other embodiments, treatment can be applied in the absence of symptoms. For example, treatment can be applied to susceptible individuals before the onset of symptoms (e.g., based on symptom history and / or based on genetic or other susceptibility factors). Treatment can also be continued after symptoms subside, for example to prevent or delay their recurrence.

[0057] As used herein, the phrase "a condition mediated by MEK" or "a disease mediated by MEK" or "a MEK-related disease or condition" refers to a disease or condition associated with or mediated by MEK or MEK activity. A non-limiting example of a MEK-related disease or condition is a MEK-related cancer.

[0058] As used herein, the term "pharmaceutical composition" refers to the combination of an active agent with a carrier, which may be inert or active, making the composition particularly suitable for in vitro or ex vivo diagnostic or therapeutic use.

[0059] As used herein, the term "pharmaceutically acceptable carrier" refers to any standard pharmaceutical carrier, such as phosphate buffered saline solution, water, emulsions (e.g., oil / water or water / oil emulsions), and various types of wetting agents. The composition may also include stabilizers and preservatives. For examples of carriers, stabilizers, and adjuvants, see, e.g., Martin, Remington's Pharmaceutical Sciences, 15th Edition, Mack Publ. Co., Easton, PA

[1975] .

[0060] As used herein, "non-ATP competitive" or "ATP non-competitive" MEK inhibitors refer to MEK inhibitors that do not bind to the ATP pocket of MEK, or do not displace ATP in the active site of MEK, and can form direct contacts when co-bound to the MEK-ATP complex. The non-ATP competitive inhibition of the compounds of the present disclosure can be confirmed by recognized methods such as enzymatic studies, competition assays, biophysical methods (including X-ray co-crystallography). Exemplary non-ATP competitive inhibitors of the present disclosure inhibit recombinant MEK1 or MEK2 with an IC 50 In some embodiments, exemplary non-ATP competitive inhibitors of the present disclosure have an IC 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. 50 Inhibition of recombinant MEK1 or MEK2.

[0061] As used herein, "inhibitor pocket" refers to a structure formed at the interaction interface between MEK and KSR or BRAF or CRAF, to which the inhibitors of the present disclosure will bind.

[0062] As used herein, compounds of the present disclosure "allosterically bind to the inhibitor pocket" when the compound binds outside of the active site, including, for example, outside of or near the ATP binding site of the kinase.

[0063] As used herein, "inhibitor-inhibitor pocket complex" describes a species in which an inhibitor of the present disclosure allosterically binds to an inhibitor pocket in the form of a physiological complex of MEK and KSR formed at the interaction interface between human MEK (MEK1 or MEK2) and ATP-proximal human Ras kinase inhibitor (KSR1, KSR2, or KSR homologs BRAF or CRAF).

[0064] As used herein, the term "trapped" refers to the situation when the inhibitor of the present disclosure binds to the CRAF-MEK complex and stabilizes it in an inactive conformation.

[0065] As used herein, when a moiety on an inhibitor "engages" an amino acid residue of MEK and / or KSR and / or BRAF or CRAF in the inhibitor pocket, such interaction can be detected by X-ray crystallography or similar structural methods such as cryo-electron microscopy, NMR or computer simulation docking, including fragment binding and computational modeling, thereby demonstrating that the interaction defining the engagement is that the distance between the inhibitor moiety and the amino acid residue is no more than about 1:1. Including for example to about or to about The distance provided herein allows for the implicit inclusion of hydrogen atoms; however, hydrogen atoms are not included in the crystallographic model of the present invention, which is suitable unless the crystal diffraction reaches a very high resolution (i.e., better than 1.5 angstroms). A literature survey of drug-receptor atom pairs of all structures in the protein database used a distance cutoff of 4-5 angstroms (PMID 29308120, 26517868, 19221587) to evaluate reasonable small molecule hydrophobic bonding interactions, and found that the intermolecular carbon-carbon interaction is similar to the contact of trametinib-KSR, which is the most representative drug-receptor atom pair in the protein database. Regarding the interaction between the inhibitor of the present invention and MEK-KSR and / or BRAF or CRAF complexes, based on the nature of the trametinib-KSR interaction and the priority of the known drug-receptor complex, 4 angstrom contacts are reasonable. This contact is within the range of known contacts defined by several independent teams (PMID 29308120, 26517868, 19221587).

[0066] II. Description of Compounds

[0067] In one aspect, the present disclosure provides a compound of formula (I):

[0068]

[0069] or a pharmaceutically acceptable salt thereof, wherein:

[0070] Each are independently a single bond or a double bond;

[0071] Each A is independently or an optionally substituted 5-6 membered heteroaryl;

[0072] X 1 , X 2 , X 3 and X 5 Independently for CR 1 or N;

[0073] X 6 is C(O), O or NH;

[0074] X 7 is CH or N;

[0075] X 8 is N or O;

[0076] Each R 1 are independently hydrogen, halogen, 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;

[0077] R 2 , R 3 , R 4 and R 5 are 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;

[0078] Each R 6 are independently hydrogen, optionally substituted C1-C6 aliphatic, optionally substituted C1-C6 alkoxy, optionally substituted C3-C 10 Cycloalkyl, optionally substituted C6-C 10 Heterocycloalkyl, optionally substituted C6-C 10 Aryl, or two R 6 together with the atoms to which it is attached, form an optionally substituted 3-7 membered heterocycloalkyl ring, or

[0079] R 5 With R 6 Together with the atoms to which it is attached, it forms a 5-6 membered heterocycloalkyl ring; or

[0080] R 5 With X 5 or X 3 Together with the atoms to which it is attached, it forms a 5-6 membered fused heterocycloalkyl ring;

[0081] R 6 With X 5 or X 3 Together with the atoms to which they are attached, they form a 5-6 membered fused heterocycloalkyl ring; and

[0082] R 7 is O or an optionally substituted C1-C6 aliphatic group; and

[0083] R 8 is absent, hydrogen or optionally substituted C1-C6 aliphatic.

[0084] In some aspects, the present disclosure provides a compound of formula (I):

[0085]

[0086] or a pharmaceutically acceptable salt thereof, wherein:

[0087] Each are independently a single bond or a double bond;

[0088] Each A is independently or an optionally substituted 5-6 membered heteroaryl;

[0089] X 1 , X 2 , X 3 and X 5 Independently for CR 1 or N;

[0090] X 6 is C(O), O or NH;

[0091] X 7 is CH or N;

[0092] X 8 is N or O;

[0093] Each R 1 are 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;

[0094] R 2 , R 3 , R 4 and R 5 are independently hydrogen, C( 2 D)3, OC( 2 D) 3, optionally substituted C1-C6 aliphatic group, optionally substituted C1-C6 alkoxy group, optionally substituted C3-C 10 Cycloalkyl, optionally substituted C6-C 10 Heterocycloalkyl or optionally substituted C6-C10 Aryl;

[0095] Each R 6 are independently hydrogen, deuterium, C( 2 D) 3, optionally substituted C1-C6 aliphatic group, optionally substituted C1-C6 alkoxy group, optionally substituted C3-C 10 Cycloalkyl, optionally substituted C6-C 10 Heterocycloalkyl, optionally substituted C6-C 10 Aryl, or two R 6 together with the atoms to which it is attached, form an optionally substituted 3-7 membered heterocycloalkyl ring, or

[0096] R 5 With R 6 Together with the atoms to which it is attached, it forms a 5-6 membered heterocycloalkyl ring; or

[0097] R 5 With X 5 or X 3 Together with the atoms to which it is attached, it forms a 5-6 membered fused heterocycloalkyl ring;

[0098] R 6 With X 5 or X 3 Together with the atoms to which they are attached, they form a 5-6 membered fused heterocycloalkyl ring; and

[0099] R 7 is O or an optionally substituted C1-C6 aliphatic group; and

[0100] R 8 is absent, hydrogen, deuterium or an optionally substituted C1-C6 aliphatic group.

[0101] As generally defined above, X 1 , X 2 , X 3 and X 5 Independently for CR 1 Or N. In some embodiments, X 1 , X 2 , X 3 and X 5 Yes CR 1 In some embodiments, X 1 , X 3 and X 5 Yes CR 1 And X 2 is N. As generally defined above, R 1are independently hydrogen, halogen, 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 In some embodiments, R 1 is hydrogen, halo or optionally substituted C1-C6 alkoxy. 1 is hydrogen, chlorine, fluorine, methoxy, ethoxy, propoxy, ethoxy or hexyloxy. 1 is hydrogen, fluorine, chlorine or methoxy.

[0102] As generally defined above, each are independently a single bond or a double bond.

[0103] As generally defined above, each A is independently or an optionally substituted 5-6 membered heteroaryl. In some embodiments, each A is independently As generally 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 With R 8 Together with the N atom to which it is attached, it forms an optionally substituted 3-7 membered heterocycloalkyl ring. 8 is hydrogen, halogen or optionally substituted C1-C6 aliphatic. 8 is hydrogen or methyl.

[0104] In some embodiments, each A is independently an optionally substituted 5-6 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 independently an optionally substituted 5-membered heteroaryl. In some embodiments, each A is an optionally substituted imidazole. In some embodiments, each A is

[0105] As generally defined above, X 6 is O or NH. In some embodiments, X 6 is O. In some embodiments, X 6 In some embodiments, X 6 It is C(O).

[0106] As generally defined above, X7 is CH or N. In some embodiments, X 7 is CH. In some embodiments, X 7 It is N.

[0107] As generally defined above, each R 1 are independently hydrogen, halogen, 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 In some embodiments, R 1 In some embodiments, R 1 is fluorine, chlorine, iodine, -OCF3, cyclopropyl, -CF3 or acetylene. 1 is fluorine or iodine. In some embodiments, R 1 Yes-CN.

[0108] As generally defined above, each R 1 are 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 and optionally substituted C6-C 10 In some embodiments, R 1 In some embodiments, R 1 is fluorine, chlorine, iodine, -OCF3, cyclopropyl, -CF3 or acetylene. 1 is fluorine or iodine. In some embodiments, R 1 Yes-CN.

[0109] As generally defined above, R 2 is hydrogen, halogen, 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 In some embodiments, R 2 is an optionally substituted C1-C6 aliphatic group. 2 is methyl, ethyl, propyl, pentyl, butyl or hexyl. 2 It's methyl.

[0110] As generally defined above, R 2 is hydrogen, C( 2 D)3, OC( 2 D) 3, halogen, 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 In some embodiments, R 2 is an optionally substituted C1-C6 aliphatic group. 2 is methyl, ethyl, propyl, pentyl, butyl or hexyl. 2 It's methyl.

[0111] As generally 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 In some embodiments, R 3 is optionally substituted C3-C 10 In some embodiments, R 3 is an optionally substituted C3-C8 cycloalkyl. 3 is an optionally substituted C3-C6 cycloalkyl. 3 is cyclopropyl, cyclopentyl, cyclobutyl or cyclohexyl. 3 is cyclopropyl or optionally substituted cyclopropyl. 3 In some embodiments, R 3 It is -(C3H3)F2.

[0112] As generally 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 In some embodiments, R 4 is an optionally substituted C1-C6 aliphatic group. 4 is methyl, ethyl, propyl, pentyl, butyl or hexyl.4 In some embodiments, R 4 It's CF3.

[0113] As generally defined above, R 4 is hydrogen, C( 2 D)3, OC( 2 D) 3, optionally substituted C1-C6 aliphatic group, optionally substituted C1-C6 alkoxy group, optionally substituted C3-C 10 Cycloalkyl, optionally substituted C6-C 10 Heterocycloalkyl and optionally substituted C6-C 10 In some embodiments, R 4 is an optionally substituted C1-C6 aliphatic group. 4 is methyl, ethyl, propyl, pentyl, butyl or hexyl. 4 In some embodiments, R 4 It's CF3.

[0114] As generally 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 In some embodiments, R 5 is hydrogen, optionally substituted C1-C6 aliphatic or optionally substituted C1-C6 alkoxy. 5 is hydrogen. In some embodiments, when X 7 When it is N that forms a double bond with the sulfur atom, R 5 Does not exist.

[0115] As generally defined above, each R 6 are independently hydrogen, optionally substituted C1-C6 aliphatic, optionally substituted C1-C6 alkoxy, optionally substituted C3-C 10 Cycloalkyl, optionally substituted C6-C 10 Heterocycloalkyl, optionally substituted C6-C 10 Aryl, or two R 6 Together with the atoms to which it is attached, it forms a 3-7 membered heterocycloalkyl ring, or R 5 With R 6 Together with the atoms to which it is attached, it forms a 5-6 membered heterocycloalkyl ring.

[0116] In some embodiments, each R6 R is independently hydrogen or an optionally substituted C1-C6 aliphatic group. 6 are independently hydrogen, methyl or -(CH2)2N(CH3)2.

[0117] In some embodiments, both R 6 Together with the atoms to which they are attached, they form a 3-7 membered heterocycloalkyl ring. 6 Together with the atoms to which it is attached, it forms a 3-, 4-, 5-, 6-, or 7-membered heterocycloalkyl ring.

[0118] In some embodiments, R 5 With R 6 Together with the atoms to which they are attached, they form a 5-6 membered heterocycloalkyl ring. 5 With R 6 Together with the atoms to which they are attached, they form a 5- or 6-membered heterocycloalkyl ring. 5 With R 6 Together with the atoms to which it is attached, it forms a 5-membered heterocycloalkyl ring.

[0119] In some embodiments, R 5 With X 5 or X 3 Together with the atoms to which it is attached, it forms a 5-6 membered fused heterocycloalkyl ring.

[0120] In some embodiments, R 5 With X 5 or X 3 Together with the atoms to which it is attached, it forms a 5-6 membered fused heteroaromatic ring.

[0121] In some embodiments, R 6 With X 5 or X 3 Together with the atoms to which it is attached, it forms a 5-6 membered fused heterocycloalkyl ring.

[0122] As generally defined above, R 7 is O or an optionally substituted C1-C6 aliphatic group. 7 is O. In some embodiments, R 7 is an optionally substituted C1-C6 aliphatic group. 7 It's methyl.

[0123] As generally defined above, R 8 is absent, hydrogen or optionally substituted C1-C6 aliphatic. 8 is hydrogen or methyl.

[0124] As generally defined above, R 8 is absent, hydrogen, deuterium or an optionally substituted C1-C6 aliphatic group. 8 is hydrogen or methyl.

[0125] In another aspect, the present disclosure provides a compound of formula (IA):

[0126]

[0127] or a pharmaceutically acceptable salt thereof, wherein:

[0128] Each are independently a single bond or a double bond;

[0129] X 1 , X 2 , X 3 and X 5 Independently for CR 1 or N;

[0130] X 6 is C(O), O or NH;

[0131] X 7 is CH or N;

[0132] X 8 is N or O;

[0133] Each R 1 are independently hydrogen, halogen, 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;

[0134] R 2 , R 3 , R 4 and R 5 are independently hydrogen, halogen, 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

[0135] Each R 6 are independently hydrogen, optionally substituted C1-C6 aliphatic, optionally substituted C1-C6 alkoxy, optionally substituted C3-C10 Cycloalkyl, optionally substituted C6-C 10 Heterocycloalkyl, optionally substituted C6-C 10 Aryl, or two R 6 together with the atoms to which it is attached, form an optionally substituted 3-7 membered heterocycloalkyl ring, or

[0136] R 5 With R 6 Together with the atoms to which it is attached, it forms a 5-6 membered heterocycloalkyl ring; or

[0137] R 5 With X 5 or X 3 Together with the atoms to which it is attached, it forms a 5-6 membered fused heterocycloalkyl ring;

[0138] R 6 With X 5 or X 3 Together with the atoms to which it is attached, it forms a 5-6 membered fused heterocycloalkyl ring;

[0139] R 7 is O or an optionally substituted C1-C6 aliphatic group; and

[0140] R 8 is absent, hydrogen or optionally substituted C1-C6 aliphatic.

[0141] In another aspect, the present disclosure provides a compound of formula (IA):

[0142]

[0143] or a pharmaceutically acceptable salt thereof, wherein:

[0144] Each are independently a single bond or a double bond;

[0145] X 1 , X 2 , X 3 and X 5 Independently for CR 1 or N;

[0146] X 6 is C(O), O or NH;

[0147] X 7 is CH or N;

[0148] X 8 is N or O;

[0149] Each R 1are 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;

[0150] R 2 , R 3 , R 4 and R 5 are independently hydrogen, halogen, C( 2 D)3, OC( 2 D) 3, optionally substituted C1-C6 aliphatic group, optionally substituted C1-C6 alkoxy group, optionally substituted C3-C 10 Cycloalkyl, optionally substituted C6-C 10 Heterocycloalkyl or optionally substituted C6-C 10 aryl; and

[0151] Each R 6 are independently hydrogen, deuterium, C( 2 D) 3, optionally substituted C1-C6 aliphatic group, optionally substituted C1-C6 alkoxy group, optionally substituted C3-C 10 Cycloalkyl, optionally substituted C6-C 10 Heterocycloalkyl, optionally substituted C6-C 10 Aryl, or two R 6 together with the atoms to which it is attached, form an optionally substituted 3-7 membered heterocycloalkyl ring, or

[0152] R 5 With R 6 Together with the atoms to which it is attached, it forms a 5-6 membered heterocycloalkyl ring; or

[0153] R 5 With X 5 or X 3 Together with the atoms to which it is attached, it forms a 5-6 membered fused heterocycloalkyl ring;

[0154] R 6 With X 5 or X 3 Together with the atoms to which it is attached, it forms a 5-6 membered fused heterocycloalkyl ring;

[0155] R 7 is O or an optionally substituted C1-C6 aliphatic group; and

[0156] R 8is absent, hydrogen, deuterium or an optionally substituted C1-C6 aliphatic group.

[0157] As generally defined above, X 1 , X 2 , X 3 and X 5 Independently for CR 1 Or N. In some embodiments, X 1 , X 2 , X 3 and X 5 Yes CR 1 In some embodiments, X 1 , X 3 and X 5 Yes CR 1 And X 2 is N. As generally defined above, R 1 are independently hydrogen, halogen, 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 In some embodiments, R 1 is hydrogen, halo or optionally substituted C1-C6 alkoxy. 1 is hydrogen, chlorine, fluorine, methoxy, ethoxy, propoxy, ethoxy or hexyloxy. 1 is hydrogen, fluorine, chlorine or methoxy.

[0158] As generally defined above, each are independently a single bond or a double bond.

[0159] As generally defined above, X 6 is O or NH. In some embodiments, X 6 is O. In some embodiments, X 6 In some embodiments, X 6 It is C(O).

[0160] As generally defined above, X 7 is CH or N. In some embodiments, X 7 is CH. In some embodiments, X 7 It is N.

[0161] As generally defined above, X 8 is N or O. In some embodiments, X 8 is N. In some embodiments, X 8is O. In some embodiments, X 8 is N; and R 3 With R 8 Together with the N atom to which it is attached, it forms an optionally substituted 3-7 membered heterocycloalkyl ring.

[0162] As generally defined above, each R 1 are independently hydrogen, halogen, 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 In some embodiments, R 1 In some embodiments, R 1 is fluorine, chlorine, iodine, -OCF3, cyclopropyl, -CF3 or acetylene. 1 is fluorine or iodine. In some embodiments, R 1 Yes-CN.

[0163] As generally defined above, each R 1 are 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 and optionally substituted C6-C 10 In some embodiments, R 1 In some embodiments, R 1 is fluorine, chlorine, iodine, -OCF3, cyclopropyl, -CF3 or acetylene. 1 is fluorine or iodine. In some embodiments, R 1 Yes-CN.

[0164] As generally defined above, R 2 is hydrogen, halogen, 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 In some embodiments, R 2 is an optionally substituted C1-C6 aliphatic group. 2 is methyl, ethyl, propyl, pentyl, butyl or hexyl. 2 It's methyl.

[0165] As generally defined above, R 2 is hydrogen, halogen, C( 2 D)3, OC( 2 D) 3, optionally substituted C1-C6 aliphatic group, optionally substituted C1-C6 alkoxy group, optionally substituted C3-C 10 Cycloalkyl, optionally substituted C6-C 10 Heterocycloalkyl or optionally substituted C6-C 10 In some embodiments, R 2 is an optionally substituted C1-C6 aliphatic group. 2 is methyl, ethyl, propyl, pentyl, butyl or hexyl. 2 It's methyl.

[0166] As generally 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 In some embodiments, R 3 is optionally substituted C3-C 10 In some embodiments, R 3 is an optionally substituted C3-C8 cycloalkyl. 3 is an optionally substituted C3-C6 cycloalkyl. 3 is cyclopropyl, cyclopentyl, cyclobutyl or cyclohexyl. 3 is cyclopropyl or optionally substituted cyclopropyl. 3 In some embodiments, R 3 It is -(C3H3)F2.

[0167] As generally 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 In some embodiments, R 4 is an optionally substituted C1-C6 aliphatic group. 4is methyl, ethyl, propyl, pentyl, butyl or hexyl. 4 In some embodiments, R 4 is CF3. As generally defined above, R 4 is hydrogen, C( 2 D)3, OC( 2 D) 3, optionally substituted C1-C6 aliphatic group, optionally substituted C1-C6 alkoxy group, optionally substituted C3-C 10 Cycloalkyl, optionally substituted C6-C 10 Heterocycloalkyl and optionally substituted C6-C 10 In some embodiments, R 4 is an optionally substituted C1-C6 aliphatic group. 4 is methyl, ethyl, propyl, pentyl, butyl or hexyl. 4 In some embodiments, R 4 It's CF3.

[0168] As generally 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 In some embodiments, R 5 is hydrogen, optionally substituted C1-C6 aliphatic or optionally substituted C1-C6 alkoxy. 5 is hydrogen. In some embodiments, when X 7 When it is N that forms a double bond with the sulfur atom, R 5 Does not exist.

[0169] As generally defined above, each R 6 are independently hydrogen, optionally substituted C1-C6 aliphatic, optionally substituted C1-C6 alkoxy, optionally substituted C3-C 10 Cycloalkyl, optionally substituted C6-C 10 Heterocycloalkyl, optionally substituted C6-C 10 Aryl, or two R 6 Together with the atoms to which it is attached, it forms a 3-7 membered heterocycloalkyl ring, or R 5 With R 6 Together with the atoms to which it is attached, it forms a 5-6 membered heterocycloalkyl ring.

[0170] As generally defined above, each R 6 are independently hydrogen, deuterium, C( 2 D) 3, optionally substituted C1-C6 aliphatic group, optionally substituted C1-C6 alkoxy group, optionally substituted C3-C 10 Cycloalkyl, optionally substituted C6-C 10 Heterocycloalkyl, optionally substituted C6-C 10 Aryl, or two R 6 Together with the atoms to which it is attached, it forms a 3-7 membered heterocycloalkyl ring, or R 5 With R 6 Together with the atoms to which it is attached, it forms a 5-6 membered heterocycloalkyl ring.

[0171] In some embodiments, each R 6 R is independently hydrogen or an optionally substituted C1-C6 aliphatic group. 6 are independently hydrogen, methyl or -(CH2)2N(CH3)2.

[0172] In some embodiments, both R 6 Together with the atoms to which they are attached, they form a 3-7 membered heterocycloalkyl ring. 6 Together with the atoms to which it is attached, it forms a 3-, 4-, 5-, 6-, or 7-membered heterocycloalkyl ring.

[0173] In some embodiments, R 5 With R 6 Together with the atoms to which they are attached, they form a 5-6 membered heterocycloalkyl ring. 5 With R 6 Together with the atoms to which they are attached, they form a 5- or 6-membered heterocycloalkyl ring. 5 With R 6 Together with the atoms to which it is attached, it forms a 5-membered heterocycloalkyl ring.

[0174] In some embodiments, R 5 With X 5 or X 3 Together with the atoms to which it is attached, it forms a 5-6 membered fused heterocycloalkyl ring.

[0175] In some embodiments, R 5 With X 5 or X 3 Together with the atoms to which it is attached, it forms a 5-6 membered fused heteroaromatic ring.

[0176] In some embodiments, R 6 With X 5 or X3 Together with the atoms to which it is attached, it forms a 5-6 membered fused heterocycloalkyl ring.

[0177] As generally defined above, R 7 is O or an optionally substituted C1-C6 aliphatic group. 7 is O. In some embodiments, R 7 is an optionally substituted C1-C6 aliphatic group. 7 It's methyl.

[0178] As generally defined above, R 8 is absent, hydrogen or optionally substituted C1-C6 aliphatic. 8 is hydrogen or methyl.

[0179] As generally defined above, R 8 is absent, hydrogen, deuterium or an optionally substituted C1-C6 aliphatic group. 8 is hydrogen or methyl.

[0180] In some embodiments, the present disclosure provides a compound of Formula (IB) to Formula (IE):

[0181]

[0182] or a pharmaceutically acceptable salt thereof, wherein each variable is independently as defined and described in the embodiments herein.

[0183]

[0184]

[0185]

[0186]

[0187]

[0188]

[0189]

[0190]

[0191]

[0192]

[0193]

[0194]

[0195]

[0196]

[0197]

[0198]

[0199]

[0200]

[0201]

[0202]

[0203]

[0204]

[0205]

[0206]

[0207]

[0208]

[0209] In some embodiments, the present disclosure provides a compound shown in Table 1 above or a pharmaceutically acceptable salt thereof.

[0210] In another aspect, the present disclosure provides a compound of formula (II):

[0211]

[0212] or a pharmaceutically acceptable salt thereof, wherein:

[0213] Each are independently a single bond or a double bond;

[0214] Each A is independently or an optionally substituted 5-6 membered heteroaryl;

[0215] X 1 , X 2 , X 4 and X 5 Independently for CR 1 or N;

[0216] X 6 is O or NH;

[0217] X 7 is CH or N;

[0218] X 8 is N or O;

[0219] Each R 1 are 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;

[0220] R 2 , R 3 , R 4 and R 5 are independently hydrogen, deuterium, 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

[0221] Each R 6 are independently hydrogen, optionally substituted C1-C6 aliphatic, optionally substituted C1-C6 alkoxy, optionally substituted C3-C 10 Cycloalkyl, optionally substituted C6-C 10 Heterocycloalkyl, optionally substituted C6-C 10 Aryl, or two R 6 Together with the atoms to which it is attached, it forms a 3-7 membered heterocycloalkyl ring, or

[0222] R 5 With R 6 Together with the atoms to which it is attached, it forms a 5-6 membered heterocycloalkyl ring; or

[0223] R 5 With X 2 or X 4 Together with the atoms to which it is attached, it forms a 5-6 membered fused heterocycloalkyl ring;

[0224] R 6 With X 2 or X 4 Together with the atoms to which it is attached, it forms a 5-6 membered fused heterocycloalkyl ring;

[0225] R 7 is O or an optionally substituted C1-C6 aliphatic group; and

[0226] R 8 is absent, hydrogen, deuterium or an optionally substituted C1-C6 aliphatic group.

[0227] As generally defined above, X 1 , X 2 , X 4 and X 5 Independently for CR 1 Or N. In some embodiments, X 1 , X 2 , X 4 and X 5 Yes CR 1 As generally defined above, R 1 are independently hydrogen, halogen, 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 In some embodiments, R 1 is hydrogen, halo or optionally substituted C1-C6 alkoxy. 1 is hydrogen, chlorine, fluorine, methoxy, ethoxy, propoxy, ethoxy or hexyloxy. 1 is hydrogen, fluorine, chlorine or methoxy.

[0228] As generally defined above, each are independently a single bond or a double bond.

[0229] As generally defined above, each A is independently or an optionally substituted 5-6 membered heteroaryl. In some embodiments, each A is independently As generally 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 With R 8 Together with the N atom to which it is attached, it forms an optionally substituted 3-7 membered heterocycloalkyl ring.

[0230] In some embodiments, each A is independently an optionally substituted 5-6 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 independently an optionally substituted 5-membered heteroaryl. In some embodiments, each A is an optionally substituted imidazole. In some embodiments, each A is

[0231] As generally defined above, X 6 is O or NH. In some embodiments, X 6 is O. In some embodiments, X 6 In some embodiments, X 6 It is C(O).

[0232] As generally defined above, X 7 is CH or N. In some embodiments, X 7 is CH. In some embodiments, X 7 It is N.

[0233] As generally defined above, each R 1 are 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 and optionally substituted C6-C 10 In some embodiments, R 1 In some embodiments, R 1 is fluorine, chlorine, iodine, -OCF3, cyclopropyl, -CF3 or acetylene. 1 is fluorine or iodine. In some embodiments, R 1 Yes-CN.

[0234] As generally defined above, R 2 is hydrogen, halogen, C( 2 D)3, OC( 2 D) 3, optionally substituted C1-C6 aliphatic group, optionally substituted C1-C6 alkoxy group, optionally substituted C3-C 10 Cycloalkyl, optionally substituted C6-C 10 Heterocycloalkyl or optionally substituted C6-C 10 In some embodiments, R 2 is an optionally substituted C1-C6 aliphatic group. 2 is methyl, ethyl, propyl, pentyl, butyl or hexyl.2 It's methyl.

[0235] As generally 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 In some embodiments, R 3 is optionally substituted C3-C 10 In some embodiments, R 3 is an optionally substituted C3-C8 cycloalkyl. 3 is an optionally substituted C3-C6 cycloalkyl. 3 is cyclopropyl, cyclopentyl, cyclobutyl or cyclohexyl. 3 is cyclopropyl or optionally substituted cyclopropyl. 3 In some embodiments, R 3 It is -(C3H3)F2.

[0236] As generally defined above, R 4 is hydrogen, C( 2 D)3, OC( 2 D) 3, optionally substituted C1-C6 aliphatic group, optionally substituted C1-C6 alkoxy group, optionally substituted C3-C 10 Cycloalkyl, optionally substituted C6-C 10 Heterocycloalkyl and optionally substituted C6-C 10 In some embodiments, R 4 is an optionally substituted C1-C6 aliphatic group. 4 is methyl, ethyl, propyl, pentyl, butyl or hexyl. 4 In some embodiments, R 4 It's CF3.

[0237] As generally 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 In some embodiments, R 5is hydrogen, optionally substituted C1-C6 aliphatic or optionally substituted C1-C6 alkoxy. 5 is hydrogen. In some embodiments, when X 7 When it is N that forms a double bond with the sulfur atom, R 5 Does not exist.

[0238] As generally defined above, each R 6 are independently hydrogen, optionally substituted C1-C6 aliphatic, optionally substituted C1-C6 alkoxy, optionally substituted C3-C 10 Cycloalkyl, optionally substituted C6-C 10 Heterocycloalkyl, optionally substituted C6-C 10 Aryl, or two R 6 Together with the atoms to which it is attached, it forms a 3-7 membered heterocycloalkyl ring, or R 5 With R 6 Together with the atoms to which it is attached, it forms a 5-6 membered heterocycloalkyl ring.

[0239] In some embodiments, each R 6 R is independently hydrogen or an optionally substituted C1-C6 aliphatic group. 6 are independently hydrogen, methyl or -(CH2)2N(CH3)2.

[0240] In some embodiments, both R 6 Together with the atoms to which they are attached, they form a 3-7 membered heterocycloalkyl ring. 6 Together with the atoms to which it is attached, it forms a 3-, 4-, 5-, 6-, or 7-membered heterocycloalkyl ring.

[0241] In some embodiments, R 5 With R 6 Together with the atoms to which they are attached, they form a 5-6 membered heterocycloalkyl ring. 5 With R 6 Together with the atoms to which they are attached, they form a 5- or 6-membered heterocycloalkyl ring. 5 With R 6 Together with the atoms to which it is attached, it forms a 5-membered heterocycloalkyl ring.

[0242] In some embodiments, R 5 With X 2 or X 4 Together with the atoms to which it is attached, it forms a 5-6 membered fused heterocycloalkyl ring.

[0243] In some embodiments, R 5 With X2 or X 4 Together with the atoms to which it is attached, it forms a 5-6 membered fused heteroaromatic ring.

[0244] In some embodiments, R 6 With X 2 or X 4 Together with the atoms to which it is attached, it forms a 5-6 membered fused heterocycloalkyl ring.

[0245] As generally defined above, R 7 is O or an optionally substituted C1-C6 aliphatic group. 7 is O. In some embodiments, R 7 is an optionally substituted C1-C6 aliphatic group. 7 It's methyl.

[0246] As generally defined above, R 8 is absent, hydrogen, deuterium or an optionally substituted C1-C6 aliphatic group. 8 is hydrogen or methyl.

[0247] In another aspect, the present disclosure provides a compound of formula (IIA):

[0248]

[0249] or a pharmaceutically acceptable salt thereof, wherein:

[0250] Each are independently a single bond or a double bond;

[0251] X 1 , X 2 , X 4 and X 5 Independently for CR 1 or N;

[0252] X 6 is O or NH;

[0253] X 7 is CH or N;

[0254] X 8 is N or O;

[0255] Each R 1 are 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-C10 Aryl;

[0256] R 2 , R 3 , R 4 and R 5 are independently hydrogen, C( 2 D)3, OC( 2 D) 3, optionally substituted C1-C6 aliphatic group, optionally substituted C1-C6 alkoxy group, optionally substituted C3-C 10 Cycloalkyl, optionally substituted C6-C 10 Heterocycloalkyl or optionally substituted C6-C 10 aryl; and

[0257] Each R 6 are independently hydrogen, deuterium, C( 2 D) 3, optionally substituted C1-C6 aliphatic group, optionally substituted C1-C6 alkoxy group, optionally substituted C3-C 10 Cycloalkyl, optionally substituted C6-C 10 Heterocycloalkyl, optionally substituted C6-C 10 Aryl, or two R 6 Together with the atoms to which it is attached, it forms a 3-7 membered heterocycloalkyl ring, or

[0258] R 5 With R 6 Together with the atoms to which it is attached, it forms a 5-6 membered heterocycloalkyl ring; or

[0259] R 5 With X 2 or X 4 Together with the atoms to which it is attached, it forms a 5-6 membered fused heterocycloalkyl ring;

[0260] R 6 With X 2 or X 4 Together with the atoms to which it is attached, it forms a 5-6 membered fused heterocycloalkyl ring;

[0261] R 7 is O or an optionally substituted C1-C6 aliphatic group; and

[0262] R 8 is absent, hydrogen, deuterium or an optionally substituted C1-C6 aliphatic group.

[0263] As generally defined above, X 1 , X 2 , X 4 and X 5 Independently for CR 1Or N. In some embodiments, X 1 , X 2 , X 4 and X 5 Yes CR 1 As generally defined above, R 1 are independently hydrogen, halogen, 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 In some embodiments, R 1 is hydrogen, halo or optionally substituted C1-C6 alkoxy. 1 is hydrogen, chlorine, fluorine, methoxy, ethoxy, propoxy, ethoxy or hexyloxy. 1 is hydrogen, fluorine, chlorine or methoxy.

[0264] As generally defined above, each are independently a single bond or a double bond.

[0265] As generally defined above, each A is independently or an optionally substituted 5-6 membered heteroaryl. In some embodiments, each A is independently As generally 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 With R 8 Together with the N atom to which it is attached, it forms an optionally substituted 3-7 membered heterocycloalkyl ring.

[0266] In some embodiments, each A is independently an optionally substituted 5-6 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 independently an optionally substituted 5-membered heteroaryl. In some embodiments, each A is an optionally substituted imidazole. In some embodiments, each A is

[0267] As generally defined above, X 6 is O or NH. In some embodiments, X 6 is O. In some embodiments, X 6 In some embodiments, X 6 It is C(O).

[0268] As generally defined above, X 7 is CH or N. In some embodiments, X 7 is CH. In some embodiments, X 7 It is N.

[0269] As generally defined above, each R 1 are 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 and optionally substituted C6-C 10 In some embodiments, R 1 In some embodiments, R 1 is fluorine, chlorine, iodine, -OCF3, cyclopropyl, -CF3 or acetylene. 1 is fluorine or iodine. In some embodiments, R 1 Yes-CN.

[0270] As generally defined above, R 2 is hydrogen, C( 2 D)3, OC( 2 D) 3, halogen, 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 In some embodiments, R 2 is an optionally substituted C1-C6 aliphatic group. 2 is methyl, ethyl, propyl, pentyl, butyl or hexyl. 2 It's methyl.

[0271] As generally 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 In some embodiments, R 3 is optionally substituted C3-C 10 In some embodiments, R 3is an optionally substituted C3-C8 cycloalkyl. 3 is an optionally substituted C3-C6 cycloalkyl. 3 is cyclopropyl, cyclopentyl, cyclobutyl or cyclohexyl. 3 is cyclopropyl or optionally substituted cyclopropyl. 3 In some embodiments, R 3 It is -(C3H3)F2.

[0272] As generally defined above, R 4 is hydrogen, C( 2 D)3, OC( 2 D) 3, optionally substituted C1-C6 aliphatic group, optionally substituted C1-C6 alkoxy group, optionally substituted C3-C 10 Cycloalkyl, optionally substituted C6-C 10 Heterocycloalkyl and optionally substituted C6-C 10 In some embodiments, R 4 is an optionally substituted C1-C6 aliphatic group. 4 is methyl, ethyl, propyl, pentyl, butyl or hexyl. 4 In some embodiments, R 4 It's CF3.

[0273] As generally 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 In some embodiments, R 5 is hydrogen, optionally substituted C1-C6 aliphatic or optionally substituted C1-C6 alkoxy. 5 is hydrogen. In some embodiments, when X 7 When it is N that forms a double bond with the sulfur atom, R 5 Does not exist.

[0274] As generally defined above, each R 6 are independently hydrogen, deuterium, C( 2 D) 3, optionally substituted C1-C6 aliphatic group, optionally substituted C1-C6 alkoxy group, optionally substituted C3-C 10 Cycloalkyl, optionally substituted C6-C10 Heterocycloalkyl, optionally substituted C6-C 10 Aryl, or two R 6 Together with the atoms to which it is attached, it forms a 3-7 membered heterocycloalkyl ring, or R 5 With R 6 Together with the atoms to which it is attached, it forms a 5-6 membered heterocycloalkyl ring.

[0275] In some embodiments, each R 6 R is independently hydrogen or an optionally substituted C1-C6 aliphatic group. 6 are independently hydrogen, methyl or -(CH2)2N(CH3)2.

[0276] In some embodiments, both R 6 Together with the atoms to which they are attached, they form a 3-7 membered heterocycloalkyl ring. 6 Together with the atoms to which it is attached, it forms a 3-, 4-, 5-, 6-, or 7-membered heterocycloalkyl ring.

[0277] In some embodiments, R 5 With R 6 Together with the atoms to which they are attached, they form a 5-6 membered heterocycloalkyl ring. 5 With R 6 Together with the atoms to which they are attached, they form a 5- or 6-membered heterocycloalkyl ring. 5 With R 6 Together with the atoms to which it is attached, it forms a 5-membered heterocycloalkyl ring.

[0278] In some embodiments, R 5 With X 2 or X 4 Together with the atoms to which it is attached, it forms a 5-6 membered fused heterocycloalkyl ring.

[0279] In some embodiments, R 5 With X 2 or X 4 Together with the atoms to which it is attached, it forms a 5-6 membered fused heteroaromatic ring.

[0280] In some embodiments, R 6 With X 2 or X 4 Together with the atoms to which it is attached, it forms a 5-6 membered fused heterocycloalkyl ring.

[0281] As generally defined above, R 7 is O or an optionally substituted C1-C6 aliphatic group. 7is O. In some embodiments, R 7 is an optionally substituted C1-C6 aliphatic group. 7 It's methyl.

[0282] As generally defined above, R 8 is absent, hydrogen, deuterium or an optionally substituted C1-C6 aliphatic group. 8 is hydrogen or methyl.

[0283]

[0284]

[0285]

[0286]

[0287]

[0288] In some embodiments, the present disclosure provides a compound shown in Table 2 above or a pharmaceutically acceptable salt thereof.

[0289] In another aspect, the present disclosure provides a compound of formula (III):

[0290]

[0291] or a pharmaceutically acceptable salt thereof, wherein Ring B is an optionally substituted ring selected from the group consisting of: C3-C 10 Cycloalkyl; C3-C4-C6 ... 10 heterocycloalkyl; phenyl; 5-6 membered heteroaryl having 1-4 heteroatoms N, S or O; or 6-10 membered bicyclic heteroaryl having 1-4 heteroatoms N, S or O; R 11 It is H. R 12 is H or an optionally substituted C1-C6 aliphatic group; and R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , X 6 and X 7 Each is independently as described above and in the embodiments herein.

[0292] In another aspect, the present disclosure provides a compound of Formula (IIIA), Formula (IIIB) or Formula (IIIC):

[0293]

[0294] or a pharmaceutically acceptable salt thereof, wherein Ring B is an optionally substituted ring selected from the group consisting of: C3-C 10 Cycloalkyl; C3-C4-C6 ... 10 heterocycloalkyl; phenyl; 5-6 membered heteroaryl having 1-4 heteroatoms N, S or O; or 6-10 membered bicyclic heteroaryl having 1-4 heteroatoms N, S or O; R 12 is H or an optionally substituted C1-C6 aliphatic group; and R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , X 6 and X 7 Each is independently as described above and in the embodiments herein.

[0295] In some embodiments, Ring B is an optionally substituted C3-C 10 In some embodiments, Ring B is an optionally substituted C3-C4-cycloalkyl having 1-4 heteroatoms N, S or O. 10 In some embodiments, ring B is an optionally substituted phenyl. In some embodiments, ring B is an optionally substituted 5-6 membered heteroaryl having 1-4 heteroatoms N, S or O. In some embodiments, ring B is an optionally substituted 6-10 membered bicyclic heteroaryl having 1-4 heteroatoms N, S or O.

[0296] In some embodiments, Ring B is optionally substituted In some embodiments, Ring B is optionally substituted In some embodiments, Ring B is optionally substituted

[0297] In some embodiments, R 12 is H or an optionally substituted C1-C6 aliphatic group. 12 is H. In some embodiments, R 12 is an optionally substituted C1-C6 aliphatic group. 12 is an optionally substituted C1-C6 alkyl.12 is an unsubstituted C1-C6 alkyl. 12 It's methyl.

[0298]

[0299]

[0300]

[0301] In some embodiments, the present disclosure provides a compound shown in Table 2B above or a pharmaceutically acceptable salt thereof.

[0302] III. Use, Formulation and Administration

[0303] a. Pharmaceutically acceptable compositions

[0304] 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 such that the MEK or its variant or mutant in the biological sample or in the patient's body is effectively and measurably inhibited. In certain embodiments, the amount of the compound in the composition of the present disclosure is such that the MEK or its variant or mutant in the biological sample or in the patient's body is effectively and measurably inhibited. In certain embodiments, the composition of the present disclosure is formulated for administration to patients in need of such compositions. In some embodiments, the composition of the present disclosure is formulated for oral administration to patients.

[0305] As used herein, the term "subject" is used interchangeably with "patient" and refers to an organism to be treated using the methods of the present disclosure. Such organisms preferably include, but are not limited to, mammals (e.g., murines, apes, equines, bovines, porcines, canines, felines, etc.) and most preferably include humans.

[0306] The term "pharmaceutically acceptable carrier, adjuvant or vehicle" refers to a non-toxic carrier, adjuvant or vehicle that does not destroy the pharmacological activity of the compound formulated with it. Pharmaceutically acceptable carriers, adjuvants or vehicles that can be used in the compositions of the present disclosure include, but are not limited to, ion exchangers; aluminum oxide; aluminum stearate; lecithin; serum proteins, such as human serum albumin; buffer substances, such as phosphates, glycine, sorbic acid, potassium sorbate; partial glyceride mixtures of saturated vegetable fatty acids; water; salts or electrolytes, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts; colloidal silicon dioxide; magnesium trisilicate; polyvinyl pyrrolidone; cellulosic substances; polyethylene glycol; sodium carboxymethyl cellulose; polyacrylates; waxes; polyethylene-polyoxypropylene block copolymers; polyethylene glycol; and lanolin.

[0307] "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 after administration to a recipient.

[0308] 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.

[0309] The compositions of the present disclosure can be administered orally, parenterally, by inhalation spray, surface, rectal, nasal, buccal, vaginal or via an implanted reservoir. As used herein, the term "parenteral" includes subcutaneous, intravenous, intramuscular, intraarticular, intrasynovial, intrasternal, intrathecal, intrahepatic, intralesional and intracranial injection or infusion techniques. Preferably, the composition is administered orally, intraperitoneally or intravenously. The sterile injectable form of the compositions of the present disclosure may be an aqueous or oily suspension. These suspensions may be formulated using suitable dispersants or wetting agents and suspending agents according to techniques known in the art. Sterile injectable preparations may also be sterile injectable solutions or suspensions in parenterally acceptable nontoxic diluents or solvents, such as solutions in 1,3-butanediol. Acceptable vehicles and solvents that may be used include water, Ringer's solution and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium.

[0310] For this purpose, any gentle fixed oil can be used, including synthetic monoglycerides or diglycerides. Fatty acids such as oleic acid and its glyceride derivatives, and natural pharmaceutically acceptable oils such as olive oil or castor oil, especially its polyoxyethylated form, can be used to prepare injectables. These oil solutions or suspensions can also contain long-chain alcohol diluents or dispersants, such as carboxymethyl cellulose, or are commonly used in the preparation of similar dispersants for pharmaceutically acceptable dosage forms including emulsions and suspensions. For formulation purposes, other conventional surfactants commonly used in the manufacture of pharmaceutically acceptable solids, liquids or other dosage forms, such as Tweens, Spans and other emulsifiers or bioavailability enhancers can also be used.

[0311] The pharmaceutically acceptable compositions of the present disclosure may be in any orally acceptable dosage form, including but not limited to capsules, tablets, aqueous suspensions or solutions for oral administration. In the case of tablets for oral use, common carriers include lactose and corn starch. Lubricants such as magnesium stearate are also usually added. For oral administration in capsule form, useful diluents include lactose and dry corn starch. When an aqueous suspension is required for oral use, the active ingredient is combined with an emulsifier and a suspending agent. If necessary, certain sweeteners, flavorings or coloring agents may also be added.

[0312] Alternatively, the pharmaceutically acceptable compositions of the present disclosure may be administered in the form of suppositories for rectal administration. These compositions may be prepared by mixing the medicament with a suitable non-irritating excipient, which is solid at room temperature but liquid at rectal temperature and therefore melts in the rectum to release the drug. Such materials include, but are not limited to, cocoa butter, beeswax, and polyethylene glycol.

[0313] The pharmaceutically acceptable compositions of the present disclosure may also be administered topically, especially when the target of treatment includes areas or organs readily accessible by topical application, including diseases of the eye, skin, or lower intestinal tract. Topical formulations suitable for each of these areas or organs are readily prepared.

[0314] Topical application to the lower intestinal tract can be achieved in a rectal suppository formulation (see above) or in a suitable enema formulation.Topical transdermal patches may also be used.

[0315] For topical application, the pharmaceutically acceptable composition provided can be formulated into a suitable ointment form containing an active component suspended or dissolved in one or more carriers. Carriers for topical application of the disclosed compound 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 composition provided can be formulated into a suitable lotion or cream form containing an active component 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.

[0316] For ophthalmic use, the provided pharmaceutically acceptable compositions can be formulated as micronized suspensions in isotonic, pH-adjusted sterile saline, or preferably, as solutions in isotonic, pH-adjusted sterile saline, with or without the addition of preservatives such as benzylalkonium chloride. Alternatively, for ophthalmic use, the pharmaceutically acceptable compositions can be formulated in an ointment such as petrolatum.

[0317] The pharmaceutically acceptable compositions of the present disclosure may also be administered by nasal aerosol or inhalation. Such compositions are prepared according to techniques well known in the art of pharmaceutical formulation and may be prepared in the form of solutions in saline, using benzyl alcohol or other suitable preservatives, absorption promoters for enhancing bioavailability, fluorocarbons and / or other conventional solubilizing or dispersing agents.

[0318] 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 not administered with food. In other embodiments, the pharmaceutically acceptable compositions of the present disclosure are administered with food.

[0319] In some embodiments, the pharmaceutical composition of the present disclosure is a brain penetrant or CNS penetrant or provides brain exposure. As used herein, the term "brain penetrant", "CNS penetrant" or "brain exposure" refers to that the compounds and pharmaceutical compositions of the present disclosure are able to cross the blood-brain barrier (BBB), and can thus be used to treat brain or CNS diseases, disorders, injuries or conditions. In some embodiments, brain or CNS diseases, disorders, injuries or conditions are neurodegenerative diseases, neuronal damage, stroke, genetic disorders, mental abnormalities, developmental disorders, inflammation, infection or injury, as well as brain cancer, spinal cord injury (SCI) and traumatic brain injury (TBI). In certain embodiments, the brain disorder is selected from epilepsy; meningitis; encephalitis, including HIV encephalitis; progressive multifocal leukoencephalopathy; neuromyelitis optica; multiple sclerosis; advanced neuropathic 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.

[0320] In some embodiments, the brain or CNS disease, disorder, injury or condition is a neurological disorder affecting the CNS and / or having its etiology in the CNS, including but not limited to neuropathy, amyloidosis, cancer, ocular disease or disorder, viral or microbial infection, inflammation, ischemia, neurodegenerative disease, epileptic seizure, behavioral disorder and lysosomal storage disease. For the purposes of this application, it is understood that the CNS includes the eye, which is usually separated from the rest of the body by the blood-retinal barrier. Specific examples of neurological disorders include, but are not limited to, neurodegenerative diseases (including, but not limited to, Lewy body disease, post-polio syndrome, Shy-Draeger 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 syndrome, kuru, Gerstmann-Straussler-Scheinker disease, chronic wasting disease, and fatal familial insomnia), bulbar palsy, motor neuron disease, and heterogeneous degenerative disorders of the nervous system (including, but not limited to, Canavan disease, Huntington's disease, neuronal ceroid lipofuscinosis, Alexander's disease, Tourette's syndrome, syndrome, Menkes kinky hair syndrome, Cockayne syndrome, Halervorden-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 disorders), cancer (e.g., CNS and / or brain cancer, including brain metastases caused by cancer elsewhere in the body).

[0321] "Central nervous system" or "CNS" refers to the complex of nervous tissue that controls body functions and includes the brain and spinal cord.

[0322] The amount of the disclosed compounds that can be combined with carrier materials to produce a composition in a single dosage form will vary depending on the host being treated, the particular mode of administration. Preferably, provided compositions should be formulated so that a dosage of between 0.01-100 mg / kg body weight per day of the inhibitor can be administered to a patient receiving these compositions.

[0323] It is also understood that the specific dosage and treatment regimen for any particular patient depends 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 specific disease being treated. The amount of the compound of the present disclosure in the composition also depends on the specific compound in the composition.

[0324] b. Uses of the compounds and pharmaceutically acceptable compositions

[0325] In some embodiments, the present disclosure provides a method of treating a disease or condition associated with MEK using a compound as described herein. In some embodiments, the disease or condition associated with MEK is a proliferative disorder. In some embodiments, the disease or condition associated with MEK is cancer. In some embodiments, the disease or condition associated with MEK is cancer as described herein.

[0326] In some aspects and embodiments, provided herein is a method for treating a disease or condition characterized by or associated with increased MEK expression and / or increased MEK activity, or one or more symptoms of a disease or condition, reducing its severity, delaying its onset or inhibiting its progression, 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 for treating a disease or condition for which inhibition or antagonism of MEK activity would be beneficial, or one or more symptoms of a disease or condition, reducing its severity, delaying its onset or inhibiting its progression, 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.

[0327] In some embodiments, the compounds as described herein are "ATP non-competitive MEK inhibitors" that will stabilize or "glue" the complex formed between MEK and KSR and / or BRAF / CRAF. In some embodiments, the compounds as described herein allosterically bind to the "inhibitor pocket" in the form of a physiological complex between MEK and KSR (or BRAF or CRAF) formed at the interaction interface between human MEK (MEK1 or MEK2) and human Ras kinase inhibitors (KSR1 or KSR2 or KSR homologs BRAF or CRAF) adjacent to ATP. In some embodiments, the compounds as described herein are ATP non-competitive kinase inhibitors. In some embodiments, the compounds as described herein have a structure such that when bound to an inhibitor-inhibitor pocket complex, the complex comprises 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) at least one portion that binds to R234 of hMEK1 or R238 of hMEK2, wherein R234 is about 100 Å from any atom of hKSR1 or hKSR2 or BRAF or CRAF. to about The structures of complexes described herein, including, for example, MEK and KSR (or BRAF or CRAF) complexes and inhibitor-inhibitor pocket complexes, can be found in WO2021142345, the contents of which are incorporated herein by reference in their entirety. 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.

[0328] In some embodiments, the compounds as described herein do not bind one or more of: I216 in hMEK1 or I220 in hMEK2 and A825 in KSR1 or P878 in KSR2. In some embodiments, the compounds as described herein comprise a structural element according to (a) as described in the above paragraph, which is an H-bond acceptor, especially an oxygen or nitrogen atom, or a fluorine atom attached to an aromatic ring, or is an H-bond donor. In some embodiments, the compounds as described herein comprise a structural element according to (a) as described in the above paragraph, which is a portion of the main chain of the linker that directly or via water-mediated contact binds: A825 of hKSR1, or P878 of hKSR2, or R662 of hBRAF, or R554 of CRAF.

[0329] In some embodiments, the compounds as described herein comprise one or more of the following:

[0330] (c) at least one portion that binds M230 of hMEK1 or M234 of hMEK2, wherein M230 or M234 is about 100 μm from the terminal atom of A825 of KSR1 (CB), or P878 of hKSR2 (CG), or N661 of hBRAF (CG), or N553 of CRAF to about Inside;

[0331] (d) at least one moiety is an H-bond acceptor or donor that engages the backbone carbonyl group of N823 of hKSR1 or T876 of hKSR2 via water-mediated contact or directly engages the backbone amino group of R662 of hBRAF or R554 of hCRAF;

[0332] (e) at least one portion that binds to Q824 of hKSR1, or Q877 of hKSR2, or Q664 of hBRAF, or Q556 of hCRAF;

[0333] (f) at least one moiety that binds to a side chain atom of A826 of hKSR1, or A879 of hKSR2, or R662 of BRAF, or R554 of CRAF;

[0334] (g) at least one moiety is a heteroaryl group that binds to M143 of hMEK1 or M147 of hMEK2;

[0335] (h) at least one moiety is a heteroaryl group that is bound to F209 of hMEK1 or F213 of hMEK2;

[0336] (i) at least one moiety (particularly an H-bond acceptor) binds to the backbone amino group of S212 of hMEK1 or S216 of hMEK2;

[0337] (j) at least one portion that binds L215 of hMEK1 or L219 of hMEK2;

[0338] (k) at least one moiety that binds I216 of hMEK1 or I220 of hMEK2; and

[0339] (1) at least one portion that binds M219 of hMEK1 or M223 of hMEK2, wherein residues 215-219 of hMEK1 assume a helical conformation.

[0340] In some embodiments, the moiety corresponding to (c) as described above is selected from substituted or unsubstituted alkyl or cycloalkyl.

[0341] In some embodiments, the backbone CO residue of a compound as described herein is joined to T876 of hKSR2 or N823 of hKSR1.

[0342] In some embodiments, the compounds as described herein bind to a binding pocket lined with hMEK1 residues R234 and M230, or hMEK2 residues R238 and M234, and P877 of KSR2 or A825 of KSR1 or R662 of BRAF or R554 of CRAF.

[0343] In some embodiments, the compounds as described herein contact the binding pocket via multiple hydrogen bonds, including via water-mediated hydrogen bonds to Arg189 and Arg234 in hMEK1 or ARG193 and A238 of hMEK2, and direct H-bonding to the backbone of the pre-helix αG loop -NH- of Arg662 of BRAF or ARG 554 of CRAF.

[0344] In some embodiments, the compounds as described herein bind to A825 of hKSR1, or P878 of hKSR2, or R662 of BRAF, or R554 of CRAF. In some embodiments, the compounds as described herein have less than or equal to about to about The distances are: A825 of hKSR1, P878 of hKSR2, R662 of BRAF, and R554 of CRAF.

[0345] Thus, in some aspects and embodiments, the present disclosure provides a method for treating one or more conditions, diseases and / or disorders, wherein the conditions, diseases or disorders include but are not limited to cell proliferative disorders, the method comprising administering a MEK inhibitor as described herein or a pharmaceutically acceptable salt or composition thereof to a patient in need thereof. In some embodiments, the cell proliferative disorder is cancer. In some embodiments, the cancer is characterized by increased MEK expression and / or increased MEK activity, i.e., "increased activated MEK".

[0346] As used herein, the terms "increase", "elevate" or "enhance" are used interchangeably and encompass any measurable increase in biological function and / or biological activity 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 times, about 3 times, about 4 times, about 5 times, about 6 times, about 7 times, about 8 times, about 9 times, about 10 times, about 20 times, about 25 times, about 50 times, about 100 times or more relative to a control or baseline amount of a function, or activity, or concentration.

[0347] As used herein, the term "increased expression" and / or "increased activity" of a substance, such as MEK, in a sample or cancer or patient refers to an increase in the amount of the substance, such as MEK, by about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 40%, about 50%, about 60%, about 70%, about 80%, about 90%, about 100%, about 120%, about 130%, about 140%, about 150%, about 160%, about 170%, about 180%, about 190%, about 200%, about 210%, about 220%, about 230%, about 240%, about 250%, about 260%, about 270%, about 280%, about 290%, about 300%, about 310%, about 320%, about 330%, about 340%, about 350%, about 360%, about 370%, about 380%, about 390%, about 400%, about 410%, about 420%, about 430%, about 440%, about 450%, about 460%, about 470%, about 480%, about 490%, about 50 ... 0%, 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 times, about 3 times, about 4 times, about 5 times, about 6 times, about 7 times, about 8 times, about 9 times, about 10 times, about 20 times, about 25 times, about 50 times, about 100 times or more. If the expression and / or activity of MEK is increased by one standard deviation, two standard deviations, three standard deviations, four standard deviations, five standard deviations or more relative to the mean or median amount of MEK in a group of control samples or a group of baseline samples or in a retrospective analysis of patient samples, then the subject can also be determined to have "increased expression" and / or "increased activity" of MEK. As practiced in the art, such control or baseline expression levels may be determined in advance, or measured prior to measuring a sample or cancer or subject, or may be obtained from a database of such control samples.

[0348] c. Cancer

[0349] In some embodiments, the present disclosure provides a method for treating or preventing cancer in a patient or reducing the risk of cancer in a patient, the method comprising administering to the patient a compound of the present disclosure or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

[0350] As used herein, "cancer" refers to a large group of various diseases characterized by the uncontrolled growth of abnormal cells in the body. Unregulated cell division and growth division and growth lead to the formation of malignant tumors, which invade adjacent tissues and may also metastasize to distant parts of the body via the lymphatic system or bloodstream.

[0351] Cancers or proliferative disorders or tumors to be treated using the compounds and methods and uses described herein include, but are not limited to, hematological cancers, lymphomas, myelomas, leukemias, cancers of the nervous system, skin cancer, breast cancer, prostate cancer, colorectal cancer, lung cancer, head and neck cancer, gastrointestinal cancer, liver cancer, pancreatic cancer, cancers of the genitourinary tract, bone cancer, kidney cancer, and vascular cancer.

[0352] 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 with 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-RasG12R, 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 with 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 with 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-RasG12R, 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 mutant or variant K-RasG12D, K-Ras G12V, K-Ras G12C, K-Ras G12R, K-Ras G12A, K-Ras G12S, K-Ras G13D, K-RasG13C, K-Ras Q61H, K-Ras Q61R, K-Ras A146T, or any combination thereof.

[0353] In some embodiments, the cancer is a mutant B-Raf cancer. In some embodiments, the mutant B-Raf cancer comprises B-Raf amplification. As used herein, "B-Raf amplification" refers to a cancer or cancer cell comprising at least three B-Raf copies, at least four B-Raf copies, at least five B-Raf copies, at least six B-Raf copies, at least seven B-Raf copies, at least eight B-Raf copies, at least nine B-Raf copies, at least ten B-Raf copies or more. In some embodiments, the mutant B-Raf cancer is a cancer having a mutant or variant B-Raf V600 (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 the following: 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 also collectively referred to as "class II B-Raf mutations". In some embodiments, the mutant B-Raf cancer is a cancer having 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, a B-Raf fusion, such as a B-Raf fusion that combines the kinase domain of B-Raf with the N-terminal portion of a different gene product to allow RAS-independent B-Raf dimerization, or any combination thereof, which are also collectively referred to as "class II B-Raf mutations". In some embodiments, the mutant B-Raf K601 is B-Raf K601E, K601N, K601T, or any combination thereof. In some embodiments, the mutant B-Raf P367 is B-Raf P367L, P367S, or any combination thereof. In some embodiments, the mutant B-Raf G464 is B-Raf G464V, G464E, or any combination thereof. In some embodiments, the mutant B-Raf G496 is B-Raf G496V. In some embodiments, the mutant B-Raf L485 is L485W.In some embodiments, the mutant B-Raf E586 is E586K. In some embodiments, the mutant B-Raf T599 is T588TT, T588TS, T599I, T599K, or any combination thereof. In some embodiments, the mutant B-Raf L597 is B-Raf L597Q, L597R, L597S, L597V, or any combination thereof. In some embodiments, the mutant B-Raf G469 is B-Raf G469A, G469V, G469R, or any combination thereof. In some embodiments, the mutant B-Raf is a B-Raf fusion. In some embodiments, the mutant B-Raf cancer is a 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 also collectively referred to as "class III B-Raf mutations". In some embodiments, the mutant B-Raf D287 is B-Raf D287N. In some embodiments, the mutant B-Raf V459 is B-Raf B459L. In some embodiments, the mutant B-Raf G466 is B-Raf G466A, B-Raf G466E, B-Raf G466V, or any combination thereof. In some embodiments, the mutant B-Raf S467 is B-Raf S467L. In some embodiments, the mutant B-Raf G469 is B-Raf-G469E. In some embodiments, the mutant B-Raf N581 is B-Raf N581I, B-Raf N581S, B-Raf N581T, or any combination thereof. In some embodiments, the mutant B-Raf D594 is B-Raf D594A, B-Raf D594G, B-Raf D594H, B-Raf D594N, or any combination thereof. In some embodiments, the mutant B-Raf F595 is B-Raf F595L. In some embodiments, the mutant B-Raf G596 is B-Raf G596D, B-Raf G596R, or any combination thereof. In some embodiments, the mutant B-Raf cancer comprises B-Raf amplification and at least one B-Raf mutant or variant Class I, Class II, or Class III B-Raf mutation.

[0354] 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 with 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 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-RasG12R. In some embodiments, the mutant or variant N-Ras G12 is N-Ras 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 with 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 the following: mutant or variant N-Ras G12D, N-Ras G12V, N-RasG12C, N-Ras G12R, N-Ras G12A, N-Ras G12S, N-Ras Q61, or any combination thereof.

[0355] 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" refers to cancer cells comprising at least three C-Raf copies, at least four C-Raf copies, at least five C-Raf copies, at least six C-Raf copies, at least seven C-Raf copies, at least eight C-Raf copies, at least nine C-Raf copies, at least ten C-Raf copies or more. In some embodiments, the mutant C-Raf cancer is a cancer with 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 with 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.

[0356] In some embodiments, the cancer is a NF1 and / or NF2 mutant cancer. As used herein, "NF1 mutant cancer" refers to a cancer with a mutation or variant gene encoding a neurofibromin protein, and includes deletion mutations, loss of function mutations, microdeletion mutations, missense mutations, copy number loss mutations, and substitution mutations. As used herein, "NF2 mutant cancer" refers to a cancer with a mutation or variant gene encoding a Merlin protein (also known as a schwannomin protein), and includes deletion mutations, loss of function mutations, microdeletion mutations, missense mutations, copy number loss mutations, and substitution mutations.

[0357] 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, thyroid cancer, melanoma, multiple myeloma, acute myeloid leukemia (AML), low-grade serous ovarian cancer, neurofibroma, and glioma.

[0358] 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-Raf 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.

[0359] 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 mesothelioma, such as malignant mesothelioma.

[0360] In some embodiments, cancer includes, but is not limited to, leukemias (e.g., acute leukemias, acute lymphocytic leukemias, acute myeloid leukemias, acute myeloblastic leukemias, acute promyelocytic leukemias, acute myelomonocytic leukemias, acute monocytic leukemias, acute erythroleukemias, chronic leukemias, chronic myelocytic leukemias, chronic lymphocytic leukemias), polycythemia vera, lymphomas (e.g., Hodgkin's disease or non-Hodgkin's disease), Waldenstrom's macroglobulinemia, multiple myeloma, heavy chain disease, and solid tumors such as sarcomas and carcinomas (e.g., fibrosarcomas, myxosarcoma, liposarcoma, chondrosarcoma, osteogenic sarcoma, chordoma, angiosarcoma, endotheliosarcoma, lymphangiosarcoma, lymphangioendotheliosarcoma, synovioma, mesothelioma, Ewing's tumor, the ovarian, ovarian, prostate, squamous cell, basal cell, adenocarcinoma, sweat gland, sebaceous gland, papillary carcinoma, papillary adenocarcinoma, cystadenocarcinoma, medullary carcinoma, bronchogenic carcinoma, renal cell carcinoma, hepatoma, bile duct carcinoma, choriocarcinoma, seminoma, embryonal carcinoma, Wilm's tumor, cervical, uterine, testicular, lung, small cell lung cancer, bladder, epithelial carcinoma, glioma, astrocytoma, glioblastoma multiforme (GBM, also called glioblastoma), medulloblastoma, craniopharyngioma, ependymoma, pinealoma, hemangioblastoma, acoustic neuroma, oligodendroglioma, schwannoma, neurofibrosarcoma, meningioma, melanoma, neuroblastoma, and retinoblastoma).

[0361] In some embodiments, the cancer is a glioma, an astrocytoma, a glioblastoma multiforme (GBM, also called a glioblastoma), a medulloblastoma, a craniopharyngioma, an ependymoma, a pinealoma, a hemangioblastoma, an acoustic neuroma, an oligodendroglioma, a schwannoma, a neurofibrosarcoma, a meningioma, a melanoma, a neuroblastoma, or a retinoblastoma.

[0362] In some embodiments, the cancer is an acoustic neuroma, an astrocytoma (e.g., grade I-pilocytic astrocytoma, grade II-low-grade astrocytoma, grade III-anaplastic astrocytoma, or grade IV-glioblastoma (GBM)), a chordoma, a CNS lymphoma, a craniopharyngioma, a brainstem glioma, an ependymoma, a mixed glioma, an optic nerve glioma, a subependymoma, a medulloblastoma, a meningioma, a metastatic brain tumor, an oligodendroglioma, a pituitary tumor, a primitive neuroectodermal (PNET) tumor, or a schwannoma. In some embodiments, the cancer is a type that is more common in children than in adults, such as a brainstem glioma, a craniopharyngioma, an ependymoma, a juvenile pilocytic astrocytoma (JPA), a medulloblastoma, an optic nerve glioma, a pineal tumor, a primitive neuroectodermal tumor (PNET), or a rhabdoid tumor. In some embodiments, the patient is an adult. In some embodiments, the patient is a child or a pediatric patient.

[0363] In another embodiment, cancer includes, but is not limited to, mesothelioma, hepatobiliary (liver and bile duct) cancer, bone cancer, pancreatic cancer, skin cancer, head and neck cancer, cutaneous or intraocular melanoma, ovarian cancer, colon cancer, rectal cancer, cancer of the anal region, stomach cancer, gastrointestinal cancer (gastric cancer, colorectal cancer, and duodenal cancer), uterine cancer, fallopian tube cancer, endometrial cancer, cervical cancer, vaginal cancer, vulvar cancer, Hodgkin's disease, esophageal cancer, small intestine cancer, endocrine system cancer, thyroid cancer, parathyroid cancer, adrenal cancer, Adenocarcinoma, soft tissue sarcoma, urethral cancer, penile cancer, prostate cancer, testicular cancer, chronic or acute leukemia, chronic myeloid leukemia, lymphocytic lymphoma, bladder cancer, kidney cancer or ureteral cancer, renal cell carcinoma, renal pelvis cancer, non-Hodgkin lymphoma, spinal axis tumors, brain stem glioma, pituitary adenoma, adrenocortical carcinoma, gallbladder cancer, multiple myeloma, bile duct cancer, fibrosarcoma, neuroblastoma, retinoblastoma, or a combination of one or more of the foregoing cancers.

[0364] In some embodiments, the cancer is a solid tumor, such as a sarcoma, carcinoma, or lymphoma. Solid tumors typically contain abnormal tissue masses, which typically do not include cysts or fluid areas. In some embodiments, the cancer is selected from renal cell carcinoma or kidney cancer; hepatocellular carcinoma (HCC) or hepatoblastoma, or liver cancer; melanoma; breast cancer; colorectal carcinoma or colorectal 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, ovarian epithelial cancer, ovarian carcinoma, or fallopian tube cancer; papillary serous cystadenocarcinoma or uterine papillary serous carcinoma (UPSC); prostate cancer; testicular cancer ; gallbladder cancer; hepatobiliary cancer; synovial sarcoma of soft tissue and bone; rhabdomyosarcoma; osteosarcoma; chondrosarcoma; Ewing's sarcoma; anaplastic thyroid cancer; adrenocortical carcinoma; pancreatic cancer; pancreatic ductal carcinoma or pancreatic adenocarcinoma; gastrointestinal tract / 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); Waldenstrom's macroglobulinemia; or medulloblastoma.

[0365] 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 ovarian epithelial 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 hepatobiliary cancer. In some embodiments, the cancer is synovial sarcoma of soft tissue and bone. In some embodiments, the cancer is rhabdomyosarcoma. In some embodiments, the cancer is osteosarcoma. In some embodiments, the cancer is anaplastic 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 Waldenstrom's macroglobulinemia. In some embodiments, the cancer is medulloblastoma.

[0366] In some embodiments, the cancer is a virus-associated cancer, including human immunodeficiency virus (HIV)-associated solid tumors; human papillomavirus (HPV)-16-positive incurable solid tumors; and adult T-cell leukemia, which is caused by human T-cell leukemia virus type 1 (HTLV-I) and is a highly aggressive CD4+ T-cell leukemia characterized by clonal integration of HTLV-I in leukemic cells (see https: / / clinicaltrials.gov / ct2 / show / study / NCT02631746); and virus-associated tumors in gastric cancer, nasopharyngeal carcinoma, cervical cancer, vaginal cancer, vulvar cancer, head and neck squamous cell carcinoma, and Merkel cell carcinoma. (See https: / / clinicaltrials.gov / ct2 / show / study / NCT02488759; see also https: / / clinicaltrials.gov / ct2 / show / study / NCT0240886; https: / / clinicaltrials.gov / ct2 / show / NCT02426892).

[0367] In some embodiments, the methods or uses described herein inhibit or reduce or stagnate or improve the growth or spread of cancer or tumors. In some embodiments, the tumor is treated by stagnation, reduction or inhibition of further growth of cancer or tumors. In some embodiments, the methods or uses described herein increase or strengthen or activate one or more immune responses to inhibit or reduce or stagnate or improve the growth or spread of cancer or tumors. In some embodiments, the cancer or tumor is treated by reducing the size (e.g., volume or mass) of the cancer or tumor 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% relative to the size of the cancer or tumor before treatment. In some embodiments, cancer or tumors are treated by reducing the number of cancer or tumors in the patient's body 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% relative to the number of cancer or tumors before treatment.

[0368] In some embodiments, patients treated using the methods or uses described herein exhibit progression-free survival of at least about one 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 one year, at least about 18 months, at least about two years, at least about three years, at least about four years, or at least about five years after initiation of treatment. In some embodiments, patients treated using the methods or uses described herein exhibit overall survival of at least about one 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 one 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 two years, at least about three years, at least about four years, or at least about five years after initiation of treatment.

[0369] In some embodiments, patients treated using the methods or uses described herein exhibit an objective 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%.

[0370] According to the methods of the present disclosure, any dosage and any route of administration that effectively inhibits MEK and treats a disease (e.g., a disease described herein) or reduces the severity of the disease can be used to administer the compounds and compositions. 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 illness, the specific agent, its mode of administration, and the like. In order to facilitate administration and uniform dosage, the compounds of the present disclosure are preferably formulated in dosage unit form. As used herein, the expression "dosage unit form" refers to a physically discrete dosage unit suitable for a patient to be treated. However, it should be understood that the total daily dosage of the compounds and compositions of the present disclosure will be determined by the attending physician within the scope of reasonable medical judgment. The specific effective dosage level for any particular patient or organism will depend on a variety of factors, including the condition being treated and the severity of the condition; the activity of the specific compound used; the specific composition used; the patient's age, weight, general health, sex, and diet; the time of administration; the route of administration; and the excretion rate of the specific compound used; the duration of treatment; the drugs used in combination with or simultaneously with the specific compound used; and similar factors well known in the medical field. As used herein, the term "patient" refers to an animal, preferably a mammal, and most preferably a human.

[0371] Depending on the severity of the disease or condition being treated, the pharmaceutically acceptable compositions of the present disclosure can be administered orally, rectally, parenterally, intracisternal, intravaginal, intraperitoneal, topically (such as by powder, ointment or drops), buccally, in the form of oral or nasal sprays to humans and other animals. In certain embodiments, the compounds of the present disclosure can be administered orally or parenterally at a dosage level of about 0.01 mg to about 50 mg per kilogram of subject body weight per day, and preferably about 1 mg to about 25 mg per kilogram of subject body weight per day, once or more a day to obtain the desired therapeutic effect.

[0372] 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, the liquid dosage form may also contain inert diluents commonly used in the art, such as water or other solvents; solubilizers and emulsifiers, such as ethanol, isopropanol, 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 polysorbate fatty acid esters, and mixtures thereof. In addition to inert diluents, oral compositions may also include adjuvants, such as wetting agents, emulsifiers and suspending agents, sweeteners, flavoring agents, and aromatics.

[0373] Injectable preparations, such as sterile injectable aqueous or oily suspensions, can be prepared according to known techniques using suitable dispersants or wetting agents and suspending agents. Sterile injectable preparations can also be sterile injectable solutions, suspensions or emulsions in non-toxic parenteral acceptable diluents or solvents, such as solutions in 1,3-butanediol. Acceptable vehicles and solvents that can be used are water, Ringer's solution, USP and isotonic sodium chloride solution. In addition, sterile fixed oils are usually used as solvents or suspension media. For this purpose, any mild fixed oil can be used, including synthetic monoglycerides or diglycerides. In addition, fatty acids such as oleic acid are used in injectable preparations.

[0374] The injectable formulations can be sterilized by, for example, filtration through a bacteria-retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions which can be dissolved or dispersed in sterile water or other sterile injectable medium prior to use.

[0375] To prolong the effects of the compounds of the present disclosure, it is generally necessary to slow down the absorption of the subcutaneous or intramuscularly injected compound. This can be achieved using a liquid suspension of crystalline or amorphous material with weak water solubility. The absorption rate of the compound depends on its dissolution rate, which in turn can depend on the crystal size and crystalline form. Alternatively, delayed absorption of the compound form administered parenterally is achieved by dissolving or suspending the compound in an oil vehicle. Injectable storage forms are prepared by forming a microencapsulation matrix of the compound in a biodegradable polymer such as polylactide-polyglycolide. Depending on the ratio of the compound to the polymer and the properties of the specific polymer used, the rate of compound release can be controlled. Examples of other biodegradable polymers include poly(orthoesters) and poly(anhydrides). Depot injectable formulations can also be prepared by encapsulating the compound in a liposome or microemulsion compatible with body tissues.

[0376] Compositions for rectal or vaginal administration are preferably suppositories which can be prepared by mixing a compound of the disclosure with a suitable non-irritating excipient or carrier such as cocoa butter, polyethylene glycol or a suppository wax which is solid at ambient temperature but liquid at body temperature and therefore melts in the rectum or vaginal cavity and releases the active compound.

[0377] Solid dosage forms for oral administration include capsules, tablets, pills, powders and granules. In such solid dosage forms, the active compound is mixed with at least one pharmaceutically acceptable inert excipient or carrier such as sodium citrate or dicalcium phosphate and / or the following: a) fillers or bulking agents such as starch, lactose, sucrose, glucose, mannitol and / or silicic acid; b) binders such as carboxymethylcellulose, alginates, gelatin, polyvinyl pyrrolidone, sucrose and gum arabic; c) humectants such as glycerol; d) disintegrants such as agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates and sodium carbonate; e) dissolution delay agents such as paraffin; f) absorption promoters such as quaternary ammonium compounds; g) wetting agents such as cetyl alcohol and glyceryl monostearate; h) adsorbents such as kaolin and bentonite; 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 comprise buffering agents.

[0378] Also can use the excipient such as lactose or milk sugar and high molecular weight polyethylene glycol etc., the solid composition of similar type is used as the filler in soft filling and hard filling gelatin capsule.The solid dosage form of tablet, dragee, capsule, pill and granule can be prepared into and has coating and shell as well-known other coating in enteric coating and pharmaceutical preparation field.They can optionally contain opacifier and can also have the composition that makes it only in or preferentially in a certain part of intestinal tract, optionally release active ingredient in the mode of postponement.The example of spendable embedded composition comprises polymeric substance and wax.Also can use the excipient such as lactose or milk sugar and high molecular weight polyethylene glycol etc., the solid composition of similar type is used as the filler in soft filling and hard filling gelatin capsule.

[0379] The active compound may also be in a microencapsulated form with one or more of the above-mentioned excipients. The solid dosage forms of tablets, dragees, capsules, pills and granules may be prepared to have coatings and shells, such as enteric coatings, controlled release coatings and other coatings well known in the field of pharmaceutical formulation. In such solid dosage forms, the active compound may be mixed with at least one inert diluent such as sucrose, lactose or starch. As in common practice, such dosage forms may also include additional materials except the inert diluent, such as tabletting lubricants and other tabletting aids, such as magnesium stearate and microcrystalline cellulose. In the case of capsules, tablets and pills, the dosage form may also include a buffer. They may optionally contain an emulsifier and may also have a composition that allows it to release the active ingredient only or preferentially in a certain part of the intestinal tract, optionally in a delayed manner. Examples of usable embedded compositions include polymeric substances and waxes.

[0380] The dosage form for surface or transdermal administration of the compound of the present disclosure includes ointment, paste, cream, lotion, gel, powder, solution, spray, inhalant or patch. Under aseptic conditions, the active ingredient is mixed with a pharmaceutically acceptable carrier and any required preservative or buffer as required. Ophthalmic preparations, ear drops and eye drops are also included in the scope of the present disclosure. In addition, the present disclosure encompasses the use of transdermal patches, which have the additional advantage of controlled delivery of compounds to the body. The dosage form can be prepared by dissolving or dispersing the compound in a suitable medium. Absorption enhancers can also be used to increase the flux of the compound through the skin. The rate can be controlled by providing a rate-controlled membrane, or by dispersing the compound in a polymer matrix or gel.

[0381] d. Co-administration with one or more other therapeutic agents

[0382] Depending on the particular disorder or disease to be treated, additional therapeutic agents that are normally administered to treat that disorder also may 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 disorder are referred to as "appropriate for the disease or disorder being treated."

[0383] In some embodiments, the present disclosure provides a method of treating a disclosed disease or disorder, comprising administering an effective amount of a compound disclosed herein or a pharmaceutically acceptable salt thereof to a patient in need thereof, and co-administering an effective amount of an additional therapeutic agent, such as a therapeutic agent described herein, simultaneously or sequentially. 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 disclosed compounds act synergistically in combination with one or more additional therapeutic agents.

[0384] The compounds of the present disclosure may be administered alone or in combination with one or more other therapeutic compounds, possible combination therapy being in the form of a fixed combination, or the compounds of the present disclosure and one or more other therapeutic compounds being staggered or administered independently of one another, or in combination with a fixed combination and one or more other therapeutic compounds.

[0385] One or more other therapeutic agents can be administered separately from the compounds or compositions of the present disclosure as part of a multiple dose regimen. Alternatively, one or more other therapeutic agents can be used as part of a single dosage form, mixed in a single composition with the compounds of the present disclosure. If administered in a multiple dose regimen, one or more other therapeutic agents and the compounds or compositions of the present disclosure can be administered simultaneously, sequentially or at intervals of a period of time, for example, at intervals of 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. In some embodiments, one or more other therapeutic agents and the compounds or compositions of the present disclosure are administered in more than 24 hours with multiple dose regimens.

[0386] As used herein, the terms "combination", "combined" and related terms refer to the simultaneous or sequential administration of therapeutic agents according to the present disclosure. For example, the compounds of the present disclosure can be administered simultaneously or sequentially with one or more other therapeutic agents in separate unit dosage forms or together in a single unit dosage form. Thus, the present disclosure provides a single unit dosage form comprising a compound of the present disclosure, one or more other therapeutic agents and a pharmaceutically acceptable carrier, adjuvant or vehicle.

[0387] The amount of the compound of the present disclosure and one or more other therapeutic agents (in a composition comprising additional therapeutic agents as described above) that can be combined with a carrier material to produce a single unit dosage form varies depending on the host being treated and the particular mode of administration. Preferably, the composition of the present disclosure should be formulated to enable administration of a dose of between 0.01-100 mg of the compound of the present disclosure per kilogram of body weight per day.

[0388] In those compositions comprising one or more other therapeutic agents, the one or more other therapeutic agents and the compounds of the present disclosure may act synergistically. Thus, the amount of one or more other therapeutic agents in such compositions may be less than the amount required in a monotherapy utilizing only the therapeutic agent. In such compositions, the one or more other therapeutic agents may be administered at a dose of between 0.01-1,000 g per kg of body weight per day.

[0389] The amount of one or more other therapeutic agents in the composition of the present disclosure may not exceed the amount normally applied in the composition comprising the therapeutic agent as the sole active agent. Preferably, the amount of one or more other therapeutic agents in the currently disclosed composition is within the range of about 50% to 100% of the amount normally present in the composition comprising the medicament as the sole therapeutic active agent. In some embodiments, one or more other therapeutic agents are administered at a dosage of about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90% or about 95% of the normally applied amount of the medicament. As used herein, the phrase "normally applied" means that the amount of the FDA-approved therapeutic agent is approved to be given according to the FDA label insert.

[0390] Compounds of the present disclosure or their pharmaceutical compositions may also be incorporated into compositions for coating implantable medical devices such as prostheses, artificial valves, vascular grafts, stents and catheters. For example, vascular stents have been used to overcome restenosis (re-narrowing of the vessel wall after injury). However, patients using stents or other implantable devices have the risk of thrombosis or platelet activation. These unwanted effects can be prevented or mitigated by pre-coating the device with a pharmaceutically acceptable composition comprising a kinase inhibitor. An implantable device coated with a compound of the present disclosure is another embodiment of the present disclosure.

[0391] e. Exemplary Other Therapeutic Agents

[0392] In some embodiments, the one or more other therapeutic agents are TEAD inhibitors. In certain embodiments, the TEAD inhibitor is selected from the inhibitors described in WO 2020 / 243415, and the contents of the document are incorporated herein by reference in their entirety. In certain embodiments, the TEAD inhibitor is selected from the inhibitors described in WO 2020 / 243423, and the contents of the document are incorporated herein by reference in their entirety. In certain embodiments, the TEAD inhibitor is selected from the inhibitors described in U.S. Patent No. 11,247,082, and the contents of the document are incorporated herein by reference in their entirety. In certain embodiments, the TEAD inhibitor is selected from the inhibitors described in WO 2022 / 120353, and the contents of the document are incorporated herein by reference in their entirety. In certain embodiments, the TEAD inhibitor is selected from the inhibitors described in WO 2022 / 120354, and the contents of the document are incorporated herein by reference in their entirety.

[0393] In certain embodiments, the second anticancer agent is a TEAD degrader. In certain embodiments, the TEAD degrader is selected from the degraders described in WO 2022 / 120355, the contents of which are incorporated herein by reference in their entirety.

[0394] TEAD inhibitors can be produced by organic synthesis methods known to those of ordinary skill in the art. In addition, certain TEAD inhibitors can be 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 Asso ciate 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 TEAD 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 HippoPathwaySignaling", Cell Rep orts 2020,31,107809; WO 2017 / 053706, WO 2017 / 111076, WO2018 / 204532, WO 2018 / 235926, US20190010136, WO 2019 / 040380, WO 2019 / 113236、WO2019 / 222431、WO 2019 / 232216、WO 2020 / 051099、WO 2020 / 081572、WO 2020 / 097389、WO2020 / 190774、WO 2020 / 214734, PCT / US2020 / 35098 and PCT / US2020 / 35111, the contents of each of which are incorporated herein by reference in their entirety.

[0395] In some embodiments, the one or more other therapeutic agents are ERK5 inhibitors. In certain embodiments, the ERK5 inhibitor is selected from the inhibitors described in WO 2022 / 051567, the contents of which are incorporated herein by reference in their entirety. In certain embodiments, the ERK5 inhibitor is selected from the inhibitors described in WO 2022 / 051565, the contents of which are incorporated herein by reference in their entirety. In certain embodiments, the ERK5 inhibitor is selected from the inhibitors described in WO2022 / 051569, the contents of which are incorporated herein by reference in their entirety. In certain embodiments, the ERK5 inhibitor is selected from the inhibitors described in WO 2022 / 051568, the contents of which are incorporated herein by reference in their entirety.

[0396] In some embodiments, the one or more other therapeutic agents are KRAS inhibitors, such as KRAS G12C inhibitors. As used herein, "KRAS G12C inhibitor" refers to any inhibitor or blocker or antagonist that binds to and / or inhibits signaling via KRAS. In certain embodiments, the KRAS G12C inhibitor is selected from adagrasib ( Mirati Therapeutics), sotorasib ( and Amgen), or a pharmaceutically acceptable salt and / or solvate of any of the foregoing. Examples of KR AS 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 Phar maceuticals), 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 Ingelhe imGmbh), BPI-421286 (Betta Pharmaceuticals), D3S-001 (D3 Bio), ERAS-3490 (Regents of the University of California), GEC-255 (Ge nEros BioPhrma LTD) and JS116 (Shanghai Junshi Biosceinces). Other examples of KRAS G12C inhibitors for use in the methods and uses described herein include, but are not limited to, inhibitors described in International Patent Publication No. WO 2021 / 120890, the contents of each of which are incorporated herein by reference in their entirety.

[0397] In some embodiments, the one or more other therapeutic agents are pan-RAF inhibitors. As used herein, "pan-RAF inhibitors" refer to 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 anticancer 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 a pharmaceutically acceptable salt and / or solvate of any of the foregoing. In certain embodiments, the pan-RAF inhibitor is selected from tovorafenib TAK-632, rifilafenib, errafenib or a pharmaceutically acceptable salt and / or solvate of any of the foregoing. Other examples of pan-RAF inhibitors for use in the compositions, methods and uses described herein include, but are not limited to, inhibitors described in International Patent Publications WO2015 / 075483, WO2015 / 075483 and WO2014 / 151616, the contents of each of which are incorporated herein by reference in their entirety.

[0398] In some embodiments, the one or more additional therapeutic agents are poly ADP ribose polymerase (PARP) inhibitors. In some embodiments, the PARP inhibitor is selected from olaparib ( AstraZeneca; rucaparib ( Clovis Oncology; niraparib ( Tesaro); talazoparib (MDV3800 / BMN 673 / LT00673, Medivation / Pfizer / Biomarin); veliparib (ABT-888, AbbVie); and BGB-290 (BeiGene, Inc.).

[0399] In some embodiments, the one or more other therapeutic agents are histone deacetylase (HDAC) inhibitors. In some embodiments, the HDAC inhibitor is selected from vorinostat (vorin ostat) ( Merck; romidepsin ( Celgene; panobinostat ( Novartis; belinostat ( Spectrum Pharmaceuticals); entinostat (SNDX-275, Syndax Pharmaceuticals) (NCT00866333); and chidamide ( HBI-8000, Chipscreen Biosciences, China).

[0400] In some embodiments, the one or more additional therapeutic agents are CDK inhibitors, such as CDK4 / CDK6 inhibitors. In some embodiments, the CDK 4 / 6 inhibitor is selected from palbociclib ( Pfizer; ribociclib ( Novartis); abemaciclib (Ly2835219, Eli Lilly); and trilaciclib (G1T28, G1 Therapeutics).

[0401] In some embodiments, the one or more additional therapeutic agents are phosphatidylinositol 3-kinase (PI3K) inhibitors. In some embodiments, the PI3K inhibitor is selected from ide lalisib ( Gilead), alpelisib (BYL719, Novartis), taselisib (GDC-0032, Genentech / Roche); pic tilisib (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 ( Gilead), apellisib (BYL719, Novartis), taseliib (GDC-0032, Genentech / Roche); picoxib (GDC-0941, Genentech / Roche); cupanisib (BAY806946, Bayer); duvelisib (formerly IPI-145, Infinity Pharmaceuticals); PQR309 (Piqur Therapeutics, Switzerland); and TG R1202 (formerly RP5230, TG Therapeutics).

[0402] In some embodiments, the one or more additional therapeutic agents are platinum-based therapeutic agents, also known as platinum agents. Platinum agents cause cross-linking of DNA, thereby making them primarily inhibit DNA repair and / or DNA synthesis in rapidly multiplying cells, such as cancer cells.

[0403] In some embodiments, the platinum therapeutic agent is selected from cisplatin ( Bristol-Myers Squibb; carboplatin ( Bristo l-Myers Squibb; also Teva; Pfizer); oxaliplatin ( Sanofi-Aventis; nedaplatin ( Shionogi), picoplatin (Poniard Pharmaceuticals); and satraplatin (JM-216, Agennix).

[0404] In some embodiments, the one or more additional therapeutic agents are taxane compounds, which cause disruption of microtubules, which are essential for cell division. In some embodiments, the taxane compound is selected from paclitaxel ( Bristol-Myers Squibb), docetaxel ( Sanofi-Aventis; Sun Pharmaceutical), albumin-bound paclitaxel ( Abraxis / Celgene), cabazitaxel (ca bazitaxel) Sanofi-Aventis) and SID530 (SK Chemicals, Co.) (NCT00931008).

[0405] In some embodiments, the one or more additional therapeutic agents are nucleoside inhibitors or therapeutic agents that interfere with normal DNA synthesis, protein synthesis, cell replication, or would otherwise inhibit rapidly proliferating cells.

[0406] In some embodiments, the nucleoside inhibitor is selected from trabectedin (a guanidinating agent, Janssen Oncology), mechlorethamine (alkylating agent, Aktelion Pharmaceuticals; vin cristine ( Eli Lilly; Teva Pharmaceuticals; Talon Therapeutics; temozolomide (a prodrug of the alkylating agent 5-(3-methyltriazene-1-yl)-imidazole-4-carboxamide (MTIC), Merck); cytarabine injection (ara-C, an antimetabolite cytidine analog, Pfizer); lomustine (alkylating agent, Bristol-Myers Squibb; NextSource Biotechnology); azacitidine (a pyrimidine nucleoside analog of cytidine, Celgene; omacetaxine mepesuccinate (cephalotaxin e ester) (protein synthesis inhibitor, Teva Pharmaceuticals; asparaginase from Erwinia chrysanthemi (an enzyme that depletes asparagine, Lundbeck; EUSAPharm a); eribulin mesylate (microtubule inhibitor, tubulin-based antimitotic agent, Eisai); cabazitaxel (microtubule inhibitor, tubulin-based antimitotic agent, Sanofi-Aventis); capacetrine (thymidylate synthase inhibitor, Genentech; bendamustine (a bifunctional nitrogen mustard derivative believed to form interstrand DNA crosslinks, Cephalon / Teva); ixabepilone (a semisynthetic analog of epothilone B, a microtubule inhibitor, a tubulin-based antimitotic agent, Bristol-Myers Squibb; nelarabine (prodrug of deoxyguanosine analog, nucleoside metabolite inhibitor, Novartis; clorafabine (ribonucleotide reductase inhibitor prodrug, competitive inhibitor of deoxycytidine, Sanofi-Aventis); and trifluridine and tipiracil (thymidine-based nucleoside analogs and thymidine phosphorylase inhibitors, Taiho Oncology).

[0407] In some embodiments, one or more additional therapeutic agents are kinase inhibitors or VEGF-R antagonists. Approved VEGF inhibitors and kinase inhibitors that can be used in the present disclosure include: bevacizumab ( Genentech / Roche), an anti-VEGF monoclonal antibody; ramucirumab ( Eli Lilly, an anti-VEGFR-2 antibody; and ziv-aflibercept, also known as VEGF Trap ( Regeneron / Sanofi). VEGFR inhibitors, such as regorafenib ( Bayer; vandetanib ( AstraZeneca; axitinib ( Pfizer; and lenvatinib ( Eisai; Raf inhibitors, such as sorafenib ( Bayer AG and Onyx; dabrafenib ( Novartis; and vemurafenib ( Genentech / Roche; MEK inhibitors, such as cobimetanib ( Exelexis / Genentech / Roche; trametinib ( Novartis); Bcr-Abl tyrosine kinase inhibitors, such as imatinib ( Novartis; nilotinib ( Novartis; dasatinib ( BristolMyersSquibb; bosutinib ( Pfizer; and ponatinib ( Ariad Pharmaceuticals); Her2 and EGFR inhibitors, such as gefitinib ( AstraZeneca; erlotinib ( Genentech / Roche / Astellas; Lapatinib ( Novartis; afatinib ( Boehringer Ingelheim; osimertinib (targeting activated EGFR, AstraZeneca a); and brigatinib ( Ariad Pharmaceuticals); c-Met and VEGFR2 inhibitors, such as cabozantinib ( Exelexis; and multikinase inhibitors, such as sunitinib ( Pfizer; pazopanib ( Novartis; ALK inhibitors, such as crizotinib ( Pfizer; ceritinib ( Novartis; and alectinib ( Genent ech / Roche); Bruton's tyrosine kinase inhibitors, such as ibrutinib ( Pharmacyclics / Janssen); and Flt3 receptor inhibitors, such as midostaurin ( Novartis).

[0408] Other kinase inhibitors and VEGF-R antagonists that are in development and can be used in the present disclosure include tivozanib (Aveo Pharmaecuticals); vatalanib (Bayer / Novartis); lucitanib (Clovis Oncology); dovitinib (TKI258, Novartis); chiauanib (Chipscreen Biosciences); CEP-11981 (Cephalon); linifanib (Abbott Laboratories); neratinib (HKI-272, Puma Biotechnology); radotinib ( IY5511, Il-Yang Pharmaceuticals, S.Korea); ruxolitinib ( Incyte Corporation); PTC299 (PTC Therapeutics); CP-547,632 (Pfizer); foretinib (Exelexis, GlaxoSmithKline); quizartinib (Daiichi Sankyo); and motesanib (Amgen / Takeda).

[0409] In some embodiments, one or more other therapeutic agents are EGFR inhibitors. As used herein, "EGFR inhibitor" refers to any inhibitor or blocker or antagonist that binds and / or inhibits epidermal growth factor receptor (EGFR). In some embodiments, EGFR inhibitors are selected from inhibitors 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, and the contents of the document are incorporated herein by reference as a whole. In some embodiments, EGFR inhibitors are selected from cetuximab, necitumumab, panitumumab, zalutumumab, ni motuzumab and matuzumab. In some embodiments, EGFR inhibitors are cetuximab. In some embodiments, EGFR inhibitors are 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.

[0410] 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.

[0411] In some embodiments, the EGFR inhibitor is a "first generation EGFR tyrosine kinase inhibitor" ("first generation TKI"). First generation TKI refers to reversible EGFR inhibitors, such as gefitinib and erlotinib, which are effective in the first-line treatment of NSCLC with EGFR activating mutations, such as exon 19 deletions and exon 21 L858R mutations, for example.

[0412] In some embodiments, the EGFR inhibitor is a "2nd generation EGFR tyrosine kinase inhibitor" ("2nd generation TKI"). 2nd generation TKI refers to covalent irreversible EGFR inhibitors, such as afatinib and dacomitinib, which are effective in the first-line treatment of NSCLC with EGFR activating mutations, such as exon 19 deletions and exon 21 L858R mutations.

[0413] In some embodiments, the EGFR inhibitor is a "3rd generation EGFR tyrosine kinase inhibitor" ("3rd generation TKI"). 3rd generation TKI refers to covalent irreversible EGFR inhibitors, such as osimertinib and lazertinib, which are selective for EGFR activating mutations alone (e.g., exon 19 deletions and exon 21 L858R) or a combination of the mutations and the T790M mutation and have lower inhibitory activity against wild-type EGFR.

[0414] In some embodiments, the one or more additional therapeutic agents are mTOR inhibitors, which inhibit cell proliferation, angiogenesis, and glucose uptake. In some embodiments, the mTOR inhibitor is everolimus ( Novartis; temsirolimus ( Pfizer; and sirolimus ( Pfizer).

[0415] In some embodiments, one or more other therapeutic agents are SOS1 (son of sevenless 1) inhibitors. In some embodiments, the SOS1 inhibitor is 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 disclosures WO2020180768A1, WO2021130731A1, WO2022271679A1, WO2022266248A1, WO2022058344A1 and WO2019122129A1, the contents of each of which are incorporated herein by reference in their entirety.

[0416] In some embodiments, one or more other therapeutic agents are SHP2 (protein tyrosine phosphatase containing Src homolog 2 domain) 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 the compositions, methods and uses described herein include, but are not limited to, the SHP2 inhibitors described in the following patent disclosures: WO2017211303A1, WO2017216706A1, WO2018013597A1, WO2018057884A1, WO2018172984A1, WO2018081091A1, WO2018136265A1, WO201813626 4A1, WO2019051084A1, WO2019067843A1, WO2019075265A1, WO2019118909A1, WO2019165073A1, WO2019 183367A1, WO2019183364A1, WO2019233810A1, WO2020022323A1, WO2020061103A1, WO2020063760A1, WO 2020108590A1, WO2020081848A1, WO2020156242A1, WO2020156243A1, WO2021033153A1, WO 2021061515A1, WO2021074227A1, WO2021110796A1, WO2021143680A1, WO2021143823A1, WO 2021218752A1, WO2021218755A1, WO2021249449A1, WO2022017444A1, WO2022033430A1, WO2022089389A1, WO2022089406A1, WO2022161222A1, WO2023280283A1 and WO2023282702A1, the contents of each of which are incorporated herein by reference in their entirety.

[0417] In some embodiments, one or more additional therapeutic agents are proteasome inhibitors. Approved proteasome inhibitors that can be used in the present disclosure include bortezomib ( Takeda; carfilzomib ( Amgen; and ixazomib ( Takeda).

[0418] In some embodiments, one or more of the other therapeutic agents is a growth factor antagonist, such as an antagonist of platelet-derived growth factor (PDGF) or epidermal growth factor (EGF) or its receptor (EGFR). Approved PDGF antagonists that can be used in the present disclosure include olaratumab ( Eli Lilly). Approved EGFR antagonists that can be used in the present disclosure include cetuximab ( Eli Lilly; Nexituzumab ( Eli Lilly; Panitumumab ( Amgen); and osimertinib (targets activated EGFR, AstraZeneca).

[0419] In some embodiments, the one or more additional therapeutic agents are aromatase inhibitors. In some embodiments, the aromatase inhibitor is selected from exemestane ( Pfizer; anastazole ( AstraZeneca and letrozole ( Novartis).

[0420] In some embodiments, one or more of the other therapeutic agents is a hedgehog pathway antagonist. Approved hedgehog pathway inhibitors that can be used in the present disclosure include sonidegi ( Sun Pharmaceuticals; and vismodegib ( Genentech), both used to treat basal cell carcinoma.

[0421] In some embodiments, one or more other therapeutic agents are folate inhibitors. Approved folate antagonists that can be used in the present disclosure include pemetrexed ( Eli Lilly).

[0422] In some embodiments, one or more additional therapeutic agents are CC chemokine receptor 4 (CCR4) inhibitors. CCR4 inhibitors studied for use in the present disclosure include mogamulizumab ( Kyowa Hakko Kirin, Japan).

[0423] In some embodiments, one or more other therapeutic agents are isocitrate dehydrogenase (IDH) inhibitors. IDH inhibitors studied that can be used in the present disclosure include AG120 (Celgene; NCT02677922); AG221 (Celgene, NCT02677922; NCT02577406); BAY1436032 (Bayer, NCT02746081); IDH305 (Novartis, NCT02987010).

[0424] In some embodiments, one or more other therapeutic agents are arginase inhibitors. Arginase inhibitors studied that can be used in the present disclosure include AEB1102 (PEGylated recombinant arginase, Aeglea Biotherapeutics), which is being studied in Phase 1 clinical trials for acute myeloid leukemia and myelodysplastic syndrome (NCT02732184) and solid tumors (NCT02561234); and CB-1158 (Calithera Biosciences).

[0425] In some embodiments, the one or more additional therapeutic agents is a glutaminase inhibitor. Glutaminase inhibitors investigated for use in the present disclosure include CB-839 (Calithera Biosciences).

[0426] In some embodiments, 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 ( Genentech / BiogenIdec; ofatumumab (anti-CD20, GlaxoSmithKline; obinutuzumab (anti-CD20, Genentech; ibritumomab (anti-CD20 and yttrium-90, Spectrum Pharmaceuticals); daratumumab (anti-CD38, Janssen Biotech; dinutuximab (anti-glycolipid GD2, UnitedTherapeutics; trastuzumab (anti-HER2, Genentech; ado-trastuzumab emtansine (anti-HER2, fused to emtansine, Genentech); and pertuzumab (anti-HER2, Genentech); and brentuximab vedotin (anti-CD30-drug conjugate, Seattle Genetics).

[0427] In some embodiments, one or more additional therapeutic agents are topoisomerase inhibitors. Approved topoisomerase inhibitors that can be used in the present disclosure include irinotecan ( Merrimack Pharmaceuticals; topotecan ( GlaxoSmithKline). Topoisomerase inhibitors studied for use in the present disclosure include pixantrone ( CTI Biopharma).

[0428] In some embodiments, one or more other therapeutic agents are inhibitors of anti-apoptotic proteins such as BC L-2. Approved anti-apoptotic proteins that can be used in the present disclosure include venetoclax ( AbbVie / Genentech); and blina tumomab ( Amgen). Other therapeutic agents targeting apoptotic proteins that have undergone clinical testing and can be used in the present disclosure include navitoclax (ABT-263, Abbott), a BCL-2 inhibitor (NCT02079740).

[0429] In some embodiments, one or more additional therapeutic agents are androgen receptor inhibitors. Approved androgen receptor inhibitors that can be used in the present disclosure include enzalutamide ( Astellas / Medivation; approved androgen synthesis inhibitors include abiraterone ( Centocor / Ortho; approved gonadotropin-releasing hormone (GnRH) receptor antagonists (degaralix, Ferring Pharmaceuticals).

[0430] In some embodiments, one or more other therapeutic agents are selective estrogen receptor modulators (SERMs), which interfere with the synthesis or activity of estrogen. Approved SERMs that can be used in the present disclosure include raloxifene ( Eli Lilly).

[0431] In some embodiments, one or more additional therapeutic agents are bone resorption inhibitors. Approved therapeutic agents that inhibit bone resorption are Denosumab ( Amgen), which binds to RANKL, preventing binding to its receptor RANK found on the surface of osteoclasts, their precursors and osteoclast-like giant cells, which mediates bone pathology in solid tumors with bone metastasis. Other approved therapeutic agents that inhibit bone resorption include bisphosphonates, such as zoledronic acid ( Novartis).

[0432] In some embodiments, one or more other therapeutic agents are inhibitors of the interaction between two major p53 inhibitory proteins MDMX and MDM2. The p53 inhibitory protein inhibitors studied that can be used in the present disclosure include ALRN-6924 (Aileron), which is a stapled peptide that binds and destroys the interaction of MDMX and MDM2 with p53 equivalently. ALRN-6924 is currently being evaluated in clinical trials (NCT02909972; NCT02264613) for the treatment of AML, advanced myelodysplastic syndrome (MDS), and peripheral T-cell lymphoma (PTCL).

[0433] In some embodiments, one or more other therapeutic agents are inhibitors of transforming growth factor-β (TGF-beta or TGF-β). TGF-β protein inhibitors studied that can be used in the present disclosure include NIS793 (Novartis), an anti-TGF-β antibody inhibitor that is being tested clinically in the treatment of various cancers including breast cancer, lung cancer, hepatocellular carcinoma, colorectal cancer, pancreatic cancer, prostate cancer, and renal cancer (NCT 02947165). In some embodiments, the TGF-β protein inhibitor is fresolimumab (GC1008; Sanofi-Genzyme), which is being studied for melanoma (NCT00923169); renal cell carcinoma (NCT00356460); and non-small cell lung cancer (NCT02581787). Additionally, in some embodiments, the additional therapeutic agent is a TGF-β trap, as described in Connolly et al., (2012) Int'l J. Biological Sciences 8:964-978. A therapeutic compound currently in clinical trials for the treatment of solid tumors is M7824 (Merck KgaA-formerly MSB0011459X), which is a bispecific anti-PD-L1 / TGF-β trap compound (NCT02699515); and (NCT02517398). M7824 comprises a fully human IgG1 antibody directed against PD-L1 fused to the extracellular domain of human TGF-β receptor II, which acts as a TGF-β "trap".

[0434] In some embodiments, the one or more additional therapeutic agents are selected from glembatumumab vedotin-monomethyl auristatin E (MMAE) (Celldex), which is an anti-glycoprotein NMB (gpNMB) antibody (CR011) linked to the cytotoxic MMAE. gpNMB is a protein overexpressed by a variety of tumor types and associated with the ability of cancer cells to metastasize.

[0435] In some embodiments, one or more additional therapeutic agents are anti-proliferative compounds. Such anti-proliferative compounds include, but are not limited to, aromatase inhibitors; antiestrogens; 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-cancer antimetabolites; platinum compounds; compounds that target / reduce the activity of protein or lipid kinases and other anti-angiogenic compounds; compounds that target, reduce or inhibit the activity of protein or lipid phosphatases; gonadal release hormone agonists; anti-androgens; methionine aminopeptidase inhibitors; matrix metalloproteinase inhibitors; bisphosphonates salts; biological response modifiers; antiproliferative antibodies; heparanase inhibitors; inhibitors of Ras oncogenic isoforms; telomerase inhibitors; proteasome inhibitors; compounds for the treatment of hematological malignancies; compounds that target, decrease or inhibit Flt-3 activity; Hsp90 inhibitors, such as 17-AAG (17-allylaminogeldanamycin, NSC330507), 17-DMAG (17-dimethylaminoethylamino-17-demethoxy-geldanamycin, NSC707545), IPI-504, CNF1010, CNF2024, CNF1010 (from Conforma Therapeutics); temozolomide Spindle activin inhibitors, such as SB715992 or SB743921 from GlaxoSmithKline, or pentamidine / chlorpromazine from CombinatoRx; MEK inhibitors, such as ARRY142886 from Array BioPharma, AZd6244 from AstraZeneca, PD181461 from Pfizer, and leucovorin.

[0436] As used herein, the term "aromatase inhibitor" refers to a compound that inhibits estrogen production, such as converting the substrates androstenedione and testosterone into estrone and estradiol, respectively. The term includes, but is not limited to, steroids, especially atamestane, exemestane and formestane, and particularly non-steroids, especially aminogluteth imide, roglethimide, pyridoglutethimide, trilostane, testolactone, ketokonazole, vorozole, fadrozole, anastrozole and letrozole. Exemestane is marketed under the trade name AROMASIN TM Formestane is sold under the trade name LENTARON TM Fadrozole is sold under the trade name AFEMA TM Anastrozole is sold under the trade name ARIMIDEX TM Letrozole is sold under the trade name FEMARA TM or FEM Ar TM Aminoglutethimide is sold under the trade name ORIMETEN TM The combinations of the present disclosure comprising a chemotherapeutic agent that is an aromatase inhibitor are particularly useful in the treatment of hormone receptor positive tumors, such as breast tumors.

[0437] As used herein, the term "anti-estrogen" refers to a compound that antagonizes the effects of estrogen at the level of the estrogen receptor. The term includes, but is not limited to, tamoxifen, fulvestrant, raloxifene, and raloxifene hydrochloride. Tamoxifen is available under the trade name NOLVADEX TM Raloxifene is sold under the trade name EVISTA TM Fulvestrant is available under the trade name FASLODEX TM Fulvestrant is available under the trade name FASLODEX TM Administration. Combinations of the present disclosure comprising a chemotherapeutic agent that is an antiestrogen are particularly useful in treating estrogen receptor positive tumors, such as breast tumors.

[0438] As used herein, the term "antiandrogen" refers to any substance that is capable of inhibiting the biological effects of androgens and includes, but is not limited to, bicalutamide (CASODEX TMAs used herein, the term "gonadotropin-releasing hormone agonist" includes, but is not limited to, abarelix, goserelin, and goserelin acetate. Goserelin is available under the trade name ZOLADEX TM Application.

[0439] As used herein, the term "topoisomerase I inhibitor" includes, but is not limited to, topotecan, gimatecan, irinotecan, camptothecine and its analogs, 9-nitrocamptothecin and the macromolecular camptothecin conjugate PNU-166148. Irinotecan can be marketed, for example, in the form in which it is marketed, for example under the trademark CAMPTOSAR. TM Topotecan is marketed under the trade name HYCAMPTIN TM Sale.

[0440] As used herein, the term "topoisomerase II inhibitors" includes, but is not limited to, anthracyclines such as doxorubicin (including liposomal formulations such as CA ELYX TM ), daunorubicin, epirubicin, idarubicin, and nemorubicin; the anthraquinones, mitoxantrone and losoxantrone; and the podophillotoxines, etoposide and teniposide. Etoposide is sold under the trade name ET OPOPHOS TM Teniposide is sold under the trade name VM 26-Bristol. Doxorubicin is sold under the trade name ACRIBLASTIN TM or ADRIAMYCIN TM Epirubicin is sold under the trade name FARMORUBICIN TM Idarubicin is sold under the trade name ZAVED OS TM Mitoxantrone is sold under the trade name NOVANTRON TM Sale.

[0441] The term "microtubule active agent" refers to microtubule stabilizing, microtubule destabilizing compounds and tubulin polymerization inhibitors, including but not limited to taxanes, such as paclitaxel and docetaxel; vinca alkaloids, such as vinblastine or vinblastine sulfate, vincristine or vincristine sulfate, and vinorelbine; discodermolides; cochicine and epothilones, and derivatives thereof. Pacific paclitaxel is sold under the trade name TAXOL TM Docetaxel is sold under the trade name TAXOTERE TM Vinblastine sulfate is sold under the trade name VINBLASTIN RP TM Vincristine sulfate is sold under the trade name FARMISTIN TM Sale.

[0442] As used herein, the term "alkylating agent" includes, but is not limited to, cyclophosphamide, ifosfamide, melphalan, or nitrosourea (BCNU or Gliadel). Cyclophosphamide is available under the trade name CYCLOSTIN TM Ifosfamide is sold under the trade name HOLOXAN TM Sale.

[0443] The term "histone deacetylase" or "HDAC inhibitor" refers to compounds that inhibit histone deacetylase and have antiproliferative activity. This includes, but is not limited to, suberoylanilide hydroxamic acid (SAHA).

[0444] The term "anticancer antimetabolites" includes, but is not limited to, 5-fluorouracil or 5-FU, capecitabine, gemcitabine, DNA demethylating compounds such as 5-azacytidine and decitabine, methotrexate and edatrexate, and folic acid antagonists such as pemetrexed. Capecitabine is marketed under the trade name XELODA TM Gemcitabine is sold under the trade name GEMZAR TM Sale.

[0445] As used herein, the term "platinum compound" includes, but is not limited to, carboplatin, cis-platin, cisplatinum, and oxaliplatin. Carboplatin can be marketed, for example, under the trademark CARBOPLAT. TMOxaliplatin can be administered, e.g., in the form as it is marketed, e.g. under the trademark ELOXATIN TM Sales form application.

[0446] As used herein, the term "compounds that target / reduce the activity of a protein or lipid kinase, or a protein or lipid phosphatase; or other anti-angiogenic compounds" includes, but is not limited to, protein tyrosine kinase and / or serine and / or threonine kinase inhibitors or lipid kinase inhibitors, such as a) compounds that target, reduce or inhibit the activity of platelet-derived growth factor receptor (PDGFR), such as compounds that target, reduce or inhibit the activity of PDGFR, especially compounds that inhibit PDGF receptor, such as N-phenyl-2-pyrimidine-amine derivatives, such as imatinib, SU101, SU6668 and GFB-111; b) compounds that target, reduce or inhibit the activity of fibroblast growth factor receptor (FGFR); c) compounds that target, reduce or inhibit the activity of insulin-like growth factor receptor I (IGF-IR), such as compounds that target, reduce or inhibit the activity of IGF-IR, especially compounds that inhibit the kinase activity of IGF-I receptor, or antibodies that target the extracellular domain of IGF-I receptor or its growth factor; d) compounds that target, reduce or inhibit Trk receptor tyrosine kinase; e) compounds that target, reduce or inhibit the activity of the AxI receptor tyrosine kinase family; f) compounds that target, reduce or inhibit the activity of the Ret receptor tyrosine kinase; g) compounds that target, reduce or inhibit the activity of the Kit / SCFR receptor tyrosine kinase, such as imatinib; h) compounds that target, reduce or inhibit the activity of the c-kit receptor tyrosine kinase, which is part of the PDGFR family, such as compounds that target, reduce or inhibit the activity of the c-Kit receptor tyrosine kinase, i) compounds that target, reduce or inhibit the activity of c-Abl family members, their gene fusion products (e.g. BCR-Abl kinase) and mutants, for example, compounds that target, reduce or inhibit the activity of c-Abl family members and their gene fusion products, such as N-phenyl-2-pyrimidine-amine derivatives, such as imatinib or nilotinib (AMN107); PD180970; AG957; NSC 680410; PD173955 from ParkeDavis; or dasatinib (BMS-354825); j) compounds that target, decrease or inhibit the activity of protein kinase C (PKC) and Raf serine and / or threonine kinase family members, MEK, SRC, JAK / pan-JAK, FAK, PDK1, PKB / Akt, Ras / MAPK, PI3K, SYK, TYK2, BTK and TEC family members and / or cyclin-dependent kinase family (CDK) members, including staurosporine derivatives such as midostaurin;Examples of other compounds include UCN-01, safingol, BAY 43-9006, Bryostatin 1, Perifosine; Ilmofosine; RO 318220 and RO 320432; GO 6976; Isis 3521; LY333531 / LY379196; isocholine compounds; FTI; PD184352 or QAN697 (P13K inhibitor) or AT7519 (CDK inhibitor); k) compounds that target, decrease or inhibit the activity of protein tyrosine kinase inhibitors, for example compounds that target, decrease or inhibit the activity of protein tyrosine kinase inhibitors include imatinib mesylate (GLEEVEC; TM ) or tyrphostins, 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; NSC 680410, adaphostin); l) targeting, decreasing or inhibiting the epidermal growth factor receptor tyrosine kinase family (EGFR1 in the form of homodimers or heterodimers) Compounds that inhibit the activity of epidermal growth factor receptor family, such as compounds that target, reduce or inhibit the activity of EGF receptor tyrosine kinase family members such as EGF receptor, ErbB2, ErbB3 and ErbB4, or compounds, proteins or antibodies that bind to EGF or EGF-related ligands, CP 358774, ZD 1839, ZM 105180; trastuzumab (HERCEPTIN TM ), Cetuximab (ERBITUX TM), 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, decrease or inhibit the activity of c-Met receptors, such as compounds that target, decrease or inhibit the activity of c-Met, especially compounds that inhibit c-Met receptors kinase activity, or antibodies targeting the extracellular domain of c-Met or binding 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- o) compounds that target, reduce or inhibit the kinase activity of PI3 kinase (PI3K), including but not limited to ATU-027, SF-1126, DS-7423, PBI-05204, GSK-2126458, ZSTK-474, buparlisib, pictrelisib, PF-46 91502, BYL-719, dactolisib, XL-147, XL-765 and idelalisib; and q) compounds that target, decrease or inhibit the signaling effects of the hedgehog (Hh) or smoothened receptor (SMO) pathways, including but not limited to cyclopamine, vismodegib, itraconazole, erismodegib and IPI-926 (saridegib).

[0447] 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, but not limited to, 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, bupanixiba, picoxib, PF-4691502, BYL-719, daclis, XL-147, XL-765, and idelalisib.

[0448] As used herein, the term "Bcl-2 inhibitor" includes, but is not limited to, compounds having inhibitory activity against B-cell lymphoma 2 protein (Bcl-2), including, but not limited to, ABT-199, ABT-731, ABT-737, apogossypol, Ascenta's pan-Bcl-2 inhibitor, curcumin (and analogs thereof), Bcl-2 / Bcl-xL dual inhibitor (Infinity Pharmaceuticals / Novartis Pharmaceuticals), Genasense (G3139), HA14-1 (and analogs thereof, see WO2008118802), navitoclax (and analogs thereof, see US7390799), NH-1 (Shenayng Pharmaceutical University), obatoclax (and analogs thereof, see WO2004106328), S-001 (Gloria Pharmaceuticals), TW series compounds (Univ. of Michigan) and venetoclax. In some embodiments, the Bcl-2 inhibitor is a small molecule therapeutic. In some embodiments, the Bcl-2 inhibitor is a peptidomimetic.

[0449] 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.

[0450] 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.

[0451] Other examples of BTK inhibitory compounds and conditions that can be treated by combinations of such compounds with the compounds of the present disclosure can be found in WO2008039218 and WO2011090760, the entire contents of which are incorporated herein by reference.

[0452] Other examples of SYK inhibiting compounds and conditions that can be treated by combinations of such compounds with the compounds of the present disclosure can be found in WO2003063794, WO2005007623 and WO2006078846, the entire contents of which are incorporated by reference.

[0453] Other examples of PI3K inhibitory compounds and conditions that can be treated by combinations of such compounds with the compounds of the present disclosure can be found in WO2004019973, WO2004089925, WO2007016176, US8138347, WO2002088112, WO2007084786, WO2007129161, WO2006122806, WO2005113554 and WO2007044729, the entire contents of which are incorporated by reference.

[0454] Other examples of JAK inhibitory compounds and conditions that can be treated by combinations of such compounds with the compounds of the present disclosure can be found in WO2009114512, WO2008109943, WO2007053452, WO2000142246 and WO2007070514, the entire contents of which are incorporated by reference.

[0455] Other antiangiogenic compounds include compounds that have another mechanism of activity, for example, one that is not related to protein or lipid kinase inhibition, such as thalidomide. TM ) and TNP-470.

[0456] Examples of proteasome inhibitors that can be used 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.

[0457] Compounds which target, decrease 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 a derivative thereof.

[0458] Compounds that induce cell differentiation processes include, but are not limited to, retinoic acid, alpha-, gamma- or delta-tocopherol, or alpha-, gamma- or delta-tocotrienol.

[0459] As used herein, the term cyclooxygenase inhibitors includes, but is not limited to, Cox-2 inhibitors, 5-alkyl substituted 2-arylaminophenylacetic acids and derivatives such as celecoxib (CELEBREX TM ), rofecoxib (VIOXX TM ), etoricoxib, valdecoxib or 5-alkyl-2-arylaminophenylacetic acid, such as 5-methyl-2-(2'-chloro-6'-fluoroanilino)phenylacetic acid, lumiracoxib.

[0460] As used herein, the term "bisphosphonates" includes, but is not limited to, etridonic, clodronic, tiludronic, pamidronic, alendronic, ibandronic, risedronic, and zoledronic acid. TM Clodronic acid is sold under the trade name BONEFOS TM Tiludronic acid is sold under the trade name Skelid TM Pamidronic acid is sold under the trade name AREDIA TM Alendronate is sold under the trade name FOSAMAX TM Ibandronic acid is sold under the trade name BONDRANAT TM Risedronate is sold under the trade name ACTONEL TM Zoledronic acid is sold under the trade name ZOMETA TMThe term "mTOR inhibitor" refers to compounds that inhibit the mammalian target of rapamycin (mTOR) and have antiproliferative activity, such as sirolimus Everolimus (CERTICAN TM ), CCI-779 and ABT578.

[0461] As used herein, the term "heparinase inhibitor" refers to a compound that targets, reduces or inhibits the degradation of heparan sulfate. The term includes, but is not limited to, PI-88. As used herein, the term "biological response modifier" refers to a lymphokine or an interferon.

[0462] As used herein, the term "Ras oncogenic isoform inhibitor" refers to a compound that targets, decreases or inhibits the oncogenic activity of Ras; for example, a "farnesyl transferase inhibitor" such as L-744832, DK8G557 or R115777 (ZARNESTRA TM ), wherein the oncogenic isoform of Ras is, for example, H-Ras, K-Ras or N-Ras. As used herein, the term "telomerase inhibitor" refers to a compound that targets, reduces or inhibits the activity of telomerase. Compounds that target, reduce or inhibit the activity of telomerase are particularly compounds that inhibit the telomerase receptor, such as telomestatin.

[0463] As used herein, the term "methionine aminopeptidase inhibitor" refers to a compound that targets, reduces or inhibits the activity of methionine aminopeptidase. Compounds that target, reduce or inhibit the activity of methionine aminopeptidase include, but are not limited to, bengamide or its derivatives.

[0464] As used herein, the term "proteasome inhibitor" refers to a compound that targets, decreases or inhibits proteasome activity. Compounds that target, decrease or inhibit proteasome activity include, but are not limited to, bortezomib (VELCADE TM ) and MLN341.

[0465] As used herein, the term "matrix metalloproteinase inhibitors" or ("MMP" inhibitors) includes, but is not limited to, collagen peptidomimetics and non-peptidomimetic inhibitors, tetracycline derivatives, such as the hydroxamate peptidomimetic inhibitor batimastat and its orally bioavailable analogs marimastat (BB-2516), prinomastat (AG3340), metastat (NSC 683551) BMS-279251, BAY 12-9566, TAA211, MMI270B or AAJ996.

[0466] As used herein, the term "compounds for treating hematological malignancies" includes, but is not limited to, FMS-like tyrosine kinase inhibitors, which are compounds that target, decrease or inhibit the FMS-like tyrosine kinase receptor (Flt-3R); interferons, 1-β-D-arabinofuranosylcytosine (ara-c) and bisulfan; and ALK inhibitors, which are compounds that target, decrease or inhibit anaplastic lymphoma kinase.

[0467] Compounds that target, decrease or inhibit the activity of 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 (a staurosporine derivative), SU11248 and MLN518.

[0468] As used herein, the term "HSP90 inhibitor" includes, but is not limited to, compounds that target, reduce or inhibit the intrinsic ATPase activity of HSP90; degrade, target, reduce or inhibit HSP90 client proteins via the ubiquitin proteasome pathway. Compounds that target, reduce or inhibit the intrinsic ATPase activity of HSP90 are especially compounds, proteins or antibodies that inhibit the ATPase activity of HSP90, such as 17-allylamino, 17-demethoxygeldanamycin (17AAG), a geldanamycin derivative; other geldanamycin-related compounds; radicicol and HDAC inhibitors.

[0469] As used herein, the term "anti-proliferative antibodies" includes, but is not limited to, trastuzumab (HERCEPTIN TM ), trastuzumab-DM1, erbitux, bevacizumab (AVASTIN TM ), rituximab PRO64553 (anti-CD40) and 2C4 antibodies. Antibodies refer to intact monoclonal antibodies, polyclonal antibodies, multispecific antibodies formed from at least two intact antibodies, and antibody fragments, as long as they exhibit the desired biological activity.

[0470] For the treatment of acute myeloid leukemia (AML), the compounds of the present disclosure can be used in combination with standard leukemia therapies, especially in combination with therapies for the treatment of AML. Specifically, the compounds of the present disclosure can be used in combination with, for example, farnesyl transferase inhibitors and / or other drugs that can be used to treat AML, such as daunomycin, doxorubicin, Ara-C, VP-16, teniposide, mitoxantrone, idarubicin, carboplatin and PKC412.

[0471] Other anti-leukemic compounds include, for example, Ara-C, which is a pyrimidine analog and a 2'-α-hydroxyribose (arabinoside) derivative of deoxycytidine. Also included are the purine analogs hypoxanthine, 6-mercaptopurine (6-MP) and fludarabine phosphate. Compounds that target, reduce or inhibit the activity of histone deacetylase (HDAC) inhibitors, such as sodium butyrate and suberoylanilide hydroxamic acid (SAHA), inhibit the activity of an enzyme called histone deacetylase. Specific HDAC inhibitors include MS275, SAHA, FK228 (formerly known as FR901228), Trichostatin A, and compounds disclosed in U.S. Pat. No. 6,552,065, including but not limited to N-hydroxy-3-[4-[[[2-(2-methyl-1H-indol-3-yl)-ethyl]-amino]methyl]phenyl]-2E-2-acrylamide or a pharmaceutically acceptable salt thereof, and N-hydroxy-3-[4-[(2-hydroxyethyl){2-(1H-indol-3-yl)ethyl]-amino]methyl]phenyl]-2E-2-acrylamide or a pharmaceutically acceptable salt thereof, especially lactate. As used herein, somatostatin receptor antagonists refer to compounds that target, treat or inhibit somatostatin receptors, such as octreotide and SOM230. Tumor cell destruction methods refer to methods such as ionizing radiation. The term "ionizing radiation" referred to above and below refers to ionizing radiation in the form of electromagnetic rays (such as X-rays and gamma rays) or particles (such as alpha and beta particles). Ionizing radiation is provided in, but not limited to, radiotherapy and is known in the art. See Hellman, Principles of Radiation Therapy, Cancer, in Principles and Practice of Oncology, Devita et al., eds., 4th edition, volume 1, pages 248-275 (1993).

[0472] Also included are EDG binders and ribonucleotide reductase inhibitors. As used herein, the term "EDG binder" refers to a class of immunosuppressants that regulate lymphocyte recirculation, such as FTY720. The term "ribonucleotide reductase inhibitor" refers to pyrimidine or purine nucleoside analogs, including but not limited to fludarabine and / or cytarabine (ara-C), 6-thioguanine, 5-fluorouracil, cladribine, 6-mercaptopurine (especially in combination with ara-C to combat ALL) and / or pentostatin. Ribonucleotide reductase inhibitors are especially hydroxyurea or 2-hydroxy-1H-isoindole-1,3-dione derivatives.

[0473] It also specifically includes compounds, proteins or monoclonal antibodies against VEGF, such as 1-(4-chloroanilino)-4-(4-pyridylmethyl)phthalazine or its pharmaceutically acceptable salt, 1-(4-chloroanilino)-4-(4-pyridylmethyl)phthalazine succinate; ANGIOSTATIN TM ENDOSTATIN TM ; anthranilamide; ZD4190; Zd6474; SU5416; SU6668; bevacizumab; or anti-VEGF antibodies or anti-VEGF receptor antibodies, such as rhuMAb and RHUFab; VEGF aptamers, such as Macugon; FLT-4 inhibitors, FLT-3 inhibitors, VEGFR-2 IgG1 antibodies, Angiozyme (RPI 4610) and bevacizumab (AVASTIN TM ).

[0474] As used herein, photodynamic therapy refers to a therapy that uses certain chemicals called photosensitizing compounds to treat or prevent cancer. Examples of photodynamic therapy include the use of compounds such as VISUDYNE TM and porfimer sodium.

[0475] As used herein, angiostatic steroids refer to compounds that block or inhibit angiogenesis, such as anecortave, triamcinolone, hydrocortisone, 11-α-epihydrocortisone, cortexolone, 17α-hydroxyprogesterone, corticosterone, deoxycorticosterone, testosterone, estrone, and dexamethasone.

[0476] Implants containing corticosteroids refer to compounds such as fluocinolone and dexamethasone.

[0477] 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; or miscellaneous compounds or compounds with other or unknown mechanisms of action.

[0478] The structures of the active compounds identified by code names, generic names or trade names can be taken from the actual version of the standard compendium "The Merck Index" or from databases, such as international patents (eg IMS World Publications).

[0479] f. Exemplary Immuno-Oncology Agents

[0480] In some embodiments, one or more other therapeutic agents are immuno-oncology agents. As used herein, the term "immuno-oncology agent" refers to an agent that effectively enhances, stimulates and / or upregulates an immune response in a subject. In some embodiments, administration of an immuno-oncology agent and a compound of the present disclosure has a synergistic effect in treating cancer.

[0481] The immuno-oncology agent can be, for example, a small molecule drug, an antibody or a biologic or a small molecule. Examples of biological immuno-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 a humanized or human antibody.

[0482] In some embodiments, the immuno-oncology agent is (i) an agonist of a stimulatory (including co-stimulatory) receptor or (ii) an antagonist of an inhibitory (including co-inhibitory) signal on T cells, both of which expand antigen-specific T cell responses.

[0483] Certain stimulatory and inhibitory molecules are members of the immunoglobulin superfamily (IgSF). An important family of membrane-bound ligands that bind to co-stimulatory or co-inhibitory receptors 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 family of TNF molecules that bind to members of the homologous TNF receptor family, including 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, RANK L, TWEAKR / Fn14, TWEAK, BAFFR, EDAR, XEDAR, TACI, APRIL, BCMA, LTβR, LIGHT, DcR3, HVEM, VEGI / TL1A, TRAMP / DR 3. EDAR, EDA1, XEDAR, EDA2, TNFR1, lymphotoxin α / TNFβ, TNFR2, TNFα, LTβR, lymphotoxin α1β2, FAS, FASL, RELT, DR6, TROY, NGFR.

[0484] 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 for stimulating an immune response.

[0485] In some embodiments, the combination of a compound of the present disclosure and 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), such as 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, such as B7-1, B7-2, CD28, 4-1BB (CD137), 4-1BBL, ICOS, ICOS-L, OX40, OX40L, GITR, GITRL, CD70, CD27, CD40, DR3, and CD28H.

[0486] 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 a KIR antagonist, such as lirilumab.

[0487] In some embodiments, the immuno-oncology agent is an agent that inhibits or depletes macrophages or monocytes, including but not limited to a CSF-1R antagonist, such as a CSF-1R antagonist antibody, including RG7155 (WO11 / 70024, WO11 / 107553, WO11 / 131407, WO13 / 87699, WO13 / 119716, WO13 / 132044) or FPA-008 (WO11 / 140249; WO13169264; WO14 / 036357).

[0488] In some embodiments, the immuno-oncology agent is selected from agonists that bind positive co-stimulatory receptors; blockers that attenuate signaling through inhibitory receptors; antagonists; and one or more agents that systemically increase the frequency of anti-tumor T cells; agents that overcome different immunosuppressive pathways within the tumor microenvironment (e.g., blocking inhibitory receptor engagement (e.g., PD-L1 / PD-1 interaction), depleting or inhibiting Tregs (e.g., using anti-CD25 monoclonal antibodies (e.g., daclizumab) or by ex vivo anti-CD25 bead depletion), inhibiting metabolic enzymes such as IDO, or reversing / preventing T cell energy or exhaustion); and agents that trigger innate immune activation and / or inflammation at the tumor site.

[0489] 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.

[0490] 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 death protein-1 (PD-1) receptor and inhibits the activity of PD-1. 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 is pidilizumab (CT-011). In some embodiments, the immuno-oncology agent is a recombinant protein consisting of the extracellular domain of PD-L2 (B7-DC) fused to the Fc portion of IgG1, referred to as AMP-224.

[0491] 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).

[0492] 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).

[0493] In some embodiments, the immuno-oncology agent is a CD137 (4-1BB) agonist. In some embodiments, the CD137 (4-1BB) agonist is an agonistic CD137 antibody. In some embodiments, the CD137 antibody is urelumab or PF-05082566 (WO12 / 32433).

[0494] In some embodiments, the immuno-oncology agent is a GITR agonist. In some embodiments, the GITR agonist is an agonistic GITR antibody. In some embodiments, the GITR antibody is BMS-986153, BMS-986156, TRX-518 (WO006 / 105021, WO009 / 009116) or MK-4166 (WO11 / 028683).

[0495] In some embodiments, the immuno-oncology agent is an indoleamine (2,3)-dioxygenase (IDO) antagonist. In some embodiments, the IDO antagonist is selected from epacado stat (INCB024360, Incyte); indoximod (NLG-8189, New Link Genetics Corporation); capmanitib (INC280, Novartis); GDC-0919 (Genentech / Roche); PF-06840003 (Pfizer); BMS:F001287 (Bristol-Myers Squibb); Phy906 / KD108 (Phytoceutica); an enzyme that breaks down kynurenine (Kynase, Ikena Oncology, formerly known as Kyn Therapeutics); and NLG-919 (WO09 / 73620, WO009 / 1156652, WO11 / 56652, WO12 / 142237).

[0496] In some embodiments, the immuno-oncology agent is an OX40 agonist. In some embodiments, the OX40 agonist is an agonistic OX40 antibody. In some embodiments, the OX40 antibody is MEDI-6383 or MEDI-6469.

[0497] 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).

[0498] In some embodiments, the immuno-oncology agent is a CD40 agonist. In some embodiments, the CD40 agonist is an agonistic 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 lucamumab or dasizumab.

[0499] In some embodiments, the immuno-oncology agent is a CD27 agonist. In some embodiments, the CD27 agonist is an agonistic CD27 antibody. In some embodiments, the CD27 antibody is variruzumab.

[0500] In some embodiments, the immuno-oncology agent is MGA271 (directed against B7H3) (WO 11 / 109400).

[0501] In some embodiments, the immuno-oncology agent is abagovomab, adecatumumab, afutuzumab, alemtuzumab, anatumomab mafenatox, apolizumab, atezolizumab, avelumab, blinatumomab, BMS-936559, catumaxomab, durvalumab, epacadostat, epratu zumab, indoximod, inotuzumab ozogamici n), intelumumab, ipilimumab, isatuximab, lambrolizumab, MED14736, MPDL3280A, nivolumab, obinutuzumab, ocaratuzumab, ofatumumab, olatatumab, pembrolizumab, pidilizumab, rituximab, tic ilimumab, samalizumab, or tremelimumab.

[0502] In some embodiments, the immuno-oncology agent is an immunostimulatory agent. For example, antibodies that block the PD-1 and PD-L1 inhibitory axis can suddenly release activated tumor-reactive T cells and have been shown in clinical trials to induce durable anti-tumor responses in a growing number of tumor histologies, including some tumor types that are not conventionally considered to be sensitive to immunotherapy. See, for example, Okazaki, T. et al. (2013) Nat. Immunol. 14, 1212-1218; Zou et al. (2016) Sci. Transl. Med. 8. The anti-PD-1 antibody nivolumab ( Bristol-Myers Squibb (also known as ONO-4538, MDX1106, and BMS-936558) has shown the potential to improve overall survival in RCC patients who have experienced disease progression during or after prior anti-angiogenic therapy.

[0503] 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 ( Celgene; lenalidomide ( Celgene; ingenol mebutate ( LEO Pharma).

[0504] In some embodiments, the immuno-oncology agent is a cancer vaccine. In some embodiments, the cancer vaccine is selected from sipuleucel-T ( Dendreon / Valeant Pharmaceuticals), which is approved for the treatment of asymptomatic or minimally symptomatic metastatic castration-resistant (hormone-refractory) prostate cancer; and talimogene laherparepvec ( BioVex / Amgen, formerly known as T-VEC), a genetically modified oncolytic virus therapy approved for the treatment of unresectable skin, subcutaneous, and lymph node lesions in melanoma. In some embodiments, the immuno-oncology agent is selected from an oncolytic virus therapy, such as pexastimogenedevacirepvec (PexaVec / JX-594, SillaJen / formerly Jennerex Biotherapeutics), a thymidine kinase-(TK-) deficient vaccinia virus engineered to express GM-CSF, for use in hepatocellular carcinoma (NCT02562755) and melanoma (NCT00429312); pelareorep ( Oncolytics Biotech, a variant of the respiratory enteric orphan virus (reovirus), which is unable to be used in cancers including colorectal cancer (NCT01622543), prostate cancer (NCT01619813), head and neck squamous cell carcinoma (NCT01166542), pancreatic adenocarcinoma (NCT00998322), and non-small cell lung cancer (NSCLC) (NCT 00861627), an adenovirus engineered 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), ONCOS-102 (Targovax / formerly Oncos), an adenovirus engineered to express GM-CSF in melanoma (NCT03003676) and peritoneal disease, colorectal cancer, or ovarian cancer (NCT02963831), and GL-ONC1 (GLV-1h68 / GLV-1h153, Genelux Biotechnology, Inc., Inc., San Diego, CA). GmbH), which is a vaccinia virus engineered to express β-galactosidase (β-gal) / β-glucuronidase or β-gal / human sodium iodide symporter (hNIS), studied in peritoneal carcinoma (NCT01443260); fallopian tube cancer, ovarian cancer (NCT 02759588), or CG0070 (Cold Genesys), which is an adenovirus engineered to express GM-CSF in bladder cancer (NCT02365818).

[0505] In some embodiments, the immuno-oncology agent is selected from JX-929 (SillaJen / formerly Jennerex Biotherapeutics), which is a TK and vaccinia growth factor-deficient vaccinia virus engineered to express cytosine deaminase, which is capable of converting the prodrug 5-fluorocytosine to the cytotoxic drug 5-fluorouracil; TG01 and TG02 (Targovax / formerly Oncos), which are peptide immunotherapeutics targeting difficult-to-treat RAS mutations; and TILT-123 (TILT Biotherapeutics), which is an engineered adenovirus designated: Ad5 / 3-E2F-δ24-hTNFα-IRES-hIL20; and VSV-GP (Vira Therapeutics), which is a vesicular stomatitis virus (VSV) engineered to express the glycoprotein (GP) of lymphocytic choriomeningitis virus (LCMV), which can be further engineered to express a protein designed to produce antigen-specific CD8 + Antigens to which T cells respond.

[0506] In some embodiments, the immuno-oncology agent is a T cell engineered to express a chimeric antigen receptor or CAR. T cells engineered to express such a chimeric antigen receptor are called CAR-T cells.

[0507] The constructed CAR consists of the following: a binding domain, which can be derived from a natural ligand; a single-chain variable fragment (scFv) derived from a monoclonal antibody specific for a cell surface antigen, which is fused to an intracellular domain (TCR) as the functional end of a T cell receptor, such as the CD3-ζ signaling domain from the TCR, which can generate activation signals in T lymphocytes. After antigen binding, such CARs are connected to endogenous signaling pathways in effector cells and generate activation signals similar to those triggered by the TCR complex.

[0508] For example, in some embodiments, the CAR-T cell is one of the cells described in U.S. Pat. No. 8,906,682 (June et al.; hereby incorporated by reference in its entirety), which discloses an extracellular domain engineered to include an antigen binding domain (e.g., a domain that binds to CD19) fused to an intracellular signaling domain of a T cell antigen receptor complex ζ chain (e.g., CD3ζ). When expressed in T cells, CARs are able to redirect antigen recognition based on antigen binding specificity. In the case of CD19, the antigen is expressed on malignant B cells. There are currently more than 200 clinical trials using CAR-T in a variety of indications. [https: / / clinicaltrials.gov / ct2 / results?term=chimeric+antigen+receptors&pg=1].

[0509] In some embodiments, the immunostimulator is an activator of retinoic acid receptor-related orphan receptor gamma (RORγt). RORγt is a transcription factor that plays a key role in the differentiation and maintenance of type 17 effector subsets of CD4+ (Th17) and CD8+ (Tc17) T cells and the differentiation of innate immune cell subsets expressing IL-17, such as NK cells. In some embodiments, the activator of RORγt is LYC-55716 (Lycera), which is currently being evaluated in clinical trials for the treatment of solid tumors (NCT02929862).

[0510] In some embodiments, the immunostimulant is an agonist or activator of a toll-like receptor (TLR). Suitable TLR activators include agonists or activators of TLR9, such as SD-101 (Dynavax). SD-101 is an immunostimulatory CpG that is being studied for B-cell lymphoma, follicular lymphoma, and other lymphomas (NCT02254772). TLR8 agonists or activators that can be used in the present disclosure include motolimod (VTX-2337, VentiRx Pharmaceuticals), which are being studied for head and neck squamous cell carcinoma (NCT02124850) and ovarian cancer (NCT02431559).

[0511] Other immuno-oncology agents that can be used in the present disclosure include urelumab (BMS-663513, Bristol-Myers Squibb), an anti-CD137 monoclonal antibody; varlilumab (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) Sciences), an anti-MMP9 antibody; MK-4166 (Merck & Co.), an anti-GITR monoclonal antibody.

[0512] In some embodiments, the immunostimulatory agent is selected from elotuzumab, mifamurtide, an agonist or activator of a toll-like receptor, and an activator of RORγt.

[0513] In some embodiments, the immunostimulatory therapeutic agent is recombinant human interleukin 15 (rhIL-15). RhIL-15 has been tested clinically as a therapy for melanoma and renal cell carcinoma (NCT01021059 and NCT01369888) and leukemia (NCT02689453). In some embodiments, the immunostimulatory agent 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), which is a fusion complex consisting of a synthetic form of endogenous IL-15 complexed with a soluble IL-15 binding protein IL-15 receptor α chain (IL15: sIL-15RA), which has been tested in a Phase 1 clinical trial for 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.

[0514] 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, pp. 603-622, the contents of which are incorporated herein by reference in their entirety. 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 targeting an immuno-oncology target selected from the targets listed in Table 2 of Jerry L. Adams et al. In some embodiments, the immuno-oncology agent is a small molecule agent selected from the agents described in Table 2 of Jerry L. Adams et al.

[0515] In some embodiments, the immuno-oncology agent is selected from the small molecule immuno-oncology agents described in Peter L. Toogood, "Small molecule immuno-oncology therapeutic agents", Bioorganic & Medicinal Chemistry Letters 2018, Vol. 28, pp. 319-329, the contents of which are incorporated herein by reference in their entirety. In some embodiments, the immuno-oncology agent is an agent targeting a pathway as described in Peter L. Toogood.

[0516] In some embodiments, the immuno-oncology agent is selected from Sandra L. Ross et al., "Bispecific T cell engager Antibody constructs can mediate bystander tumor cell killing”, PLoS ONE 12(8):e0183390, the contents of which are incorporated herein by reference in their entirety. In some embodiments, the immuno-oncology agent is a bispecific T cell engager Antibody Constructs. In some embodiments, the bispecific T cell engager The antibody construct is a CD19 / CD3 bispecific antibody construct. In some embodiments, the bispecific T cell engager The antibody construct is an EGFR / CD3 bispecific antibody construct. In some embodiments, the bispecific T cell engager Antibody constructs activate T cells. In some embodiments, the bispecific T cell engager The antibody construct activates T cells, causing them to release cytokines that induce upregulation of intercellular adhesion molecule 1 (ICAM-1) and FAS on bystander cells. In some embodiments, the bispecific T cell engager The antibody construct activates T cells, thereby inducing bystander cell lysis. In some embodiments, the bystander cells are in a solid tumor. In some embodiments, the lysed bystander cells are adjacent to Activated T cells. In some embodiments, bystander cells include tumor-associated antigen (TAA) negative cancer cells. In some embodiments, 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 a tumor-infiltrating T cell that is amplified ex vivo. In some embodiments, the immuno-oncology agent is a bispecific antibody construct or a chimeric antigen receptor (CAR) that directly connects T cells to tumor-associated surface antigens (TAA).

[0517] g. Exemplary Immune Checkpoint Inhibitors

[0518] In some embodiments, the immuno-oncology agent is an immune checkpoint inhibitor as described herein.

[0519] As used herein, the term "checkpoint inhibitor" refers to an agent that can be used to prevent cancer cells from evading the patient's immune system. One major mechanism of anti-tumor immune subversion is called "T cell exhaustion," which is caused by long-term exposure to antigens that lead to upregulation of inhibitory receptors. These inhibitory receptors act as immune checkpoints to prevent uncontrolled immune responses.

[0520] 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 generally referred to as checkpoint regulators. They act as molecular “gatekeepers” that allow extracellular information to dictate whether cell cycle progression and other intracellular signaling processes should proceed.

[0521] In some embodiments, the immune checkpoint inhibitor is an anti-PD-1 antibody. PD-1 binds to the programmed cell death protein 1 receptor (PD-1), preventing the receptor from binding to the inhibitory ligand PDL-1, thereby overcoming the tumor's ability to suppress the host's anti-tumor immune response.

[0522] In one aspect, the checkpoint inhibitor is a biotherapeutic agent 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 another aspect, the checkpoint inhibitor inhibits a checkpoint protein selected from the following: 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 ligand, or a combination thereof. In another aspect, the checkpoint inhibitor interacts with a ligand selected from the following checkpoint proteins: 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. On the other hand, the interleukin is IL-7 or IL-15. In a specific aspect, the interleukin is glycosylated IL-7. On the other hand, the vaccine is a dendritic cell (DC) vaccine.

[0523] Checkpoint inhibitors include any agent that blocks or inhibits the inhibitory pathway of the immune system in a statistically significant manner. Such inhibitors may include small molecule inhibitors, or may include 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. Illustrative checkpoint molecules that can be targeted for blocking or inhibition include but are not limited to CTLA-4, PDL1, PDL2, PD1, B7-H3, B7-H4, BTLA, HVEM, GAL9, LAG3, TIM3, VISTA, KIR, 2B4 (belonging to the CD2 molecule family and in all NK, γδ and memory CD8 +(αβ) T cells), CD160 (also known as BY55), CGEN-15049, CHK 1 and CHK2 kinases, A2aR, and various B-7 family ligands. 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, biotherapeutics, or small molecules that bind and block or inhibit the activity of one or more of the following: CTLA-4, PDL1, PDL2, PD1, BTLA, HVEM, TIM3, GAL9, LAG3, VISTA, KIR, 2B4, CD 160, and CGEN-15049. Illustrative immune checkpoint inhibitors include, but are not limited to, tremelimumab (CTLA-4 blocking antibody), anti-OX40, PD-L1 monoclonal antibody (anti-B7-H1; MEDI4736), MK-3475 (PD-1 blocker), nivolumab (anti-PD1 antibody), CT-011 (anti-PD1 antibody), BY55 monoclonal antibody, AMP224 (anti-PDL1 antibody), BMS-936559 (anti-PDL1 antibody), MPLDL3280A (anti-PDL1 antibody), MSB0010718C (anti-PDL1 antibody) and ipilimumab (anti-CTLA-4 checkpoint inhibitor). Checkpoint protein ligands include, but are not limited to, PD-L1, PD-L2, B7-H3, B7-H4, CD28, CD86, and TIM-3.

[0524] 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 Ipilimumab and pembrolizumab In some embodiments, the checkpoint inhibitor is selected from nivolumab (anti-PD-1 antibody, Bristol-Myers Squibb; pembrolizumab (anti-PD-1 antibody, Merck); Ipilimumab (anti-CTLA-4 antibody, Bristol-Myers Squibb; Durvalumab (anti-PD-L1 antibody, AstraZeneca); and atezolizumab (anti-PD-L1 antibody, Genentech).

[0525] In some embodiments, the checkpoint inhibitor is selected from the group consisting of: lanlorizumab (MK-3475), nivolumab (BMS-936558), pilizumab (CT-011), AMP-224, MDX-1105, MEDI4736, MPDL3280A, BMS-936559, ipilimumab, lirelumab, IPH2101, pembrolizumab and tremelimumab.

[0526] In some embodiments, the immune checkpoint inhibitor is REGN2810 (Regeneron), an anti-PD-1 antibody being tested in patients with basal cell carcinoma (NCT03132636), NSCLC (NCT03088540), cutaneous squamous cell carcinoma (NCT02760498), lymphoma (NCT02651662), and melanoma (NCT03002376); pidilizumab (CureTech), also known as CT-011, an antibody that binds PD-1 and is being tested in clinical trials for diffuse large B-cell lymphoma and multiple myeloma; avelumab ( Pfizer / Merck KGaA), also known as MSB0010718C), which is 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), which is 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 multiple 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 metastases, hepatocellular carcinoma, large B-cell lymphoma, ovarian cancer, cervical cancer, metastatic anaplastic thyroid cancer, urothelial carcinoma, fallopian tube cancer, multiple myeloma, bladder cancer, soft tissue sarcoma, and melanoma. AGEN-1884 (Agenus) is an anti-CTLA4 antibody that is being studied in a Phase 1 clinical trial (NCT02694822) for advanced solid tumors.

[0527] In some embodiments, the checkpoint inhibitor is an inhibitor of T cell immunoglobulin mucin-containing protein-3 (TIM-3). TIM-3 inhibitors that can be used in the present disclosure include TSR-022, LY3321367, and MBG453. TSR-022 (TESARO) is an anti-TIM-3 antibody that is being studied in solid tumors (NCT02817633). LY3321367 (Eli Lilly) is an anti-TIM-3 antibody that is being studied in solid tumors (NCT03099109). MBG453 (Novartis) is an anti-TIM-3 antibody that is being studied in advanced malignant diseases (NCT02608268).

[0528] In some embodiments, the checkpoint inhibitor is an inhibitor of a T cell immunoreceptor with Ig and ITIM domains or TIGIT (immunoreceptor on certain T cells and NK cells). TIGIT inhibitors useful in the present disclosure include BMS-986207 (Bristol-Myers Squibb), an anti-TIGIT monoclonal antibody (NCT02913313); OMP-313M32 (Oncomed); and anti-TIGIT monoclonal antibody (NCT03119428).

[0529] In some embodiments, the checkpoint inhibitor is an inhibitor of lymphocyte activation gene-3 (LAG-3). LAG-3 inhibitors that can be used in the present disclosure include BMS-986016 and REGN3767 and IMP321. BMS-986016 (Bristol-Myers Squibb) is an anti-LAG-3 antibody that is being studied in glioblastoma and gliosarcoma (NCT02658981). REGN3767 (Regeneron) is also an anti-LAG-3 antibody and is being studied in malignant diseases (NCT03005782). IMP321 (Immutep SA) is a LAG-3-Ig fusion protein that is being studied in melanoma (NCT02676869), adenocarcinoma (NCT02614833) and metastatic breast cancer (NCT00349934).

[0530] Checkpoint inhibitors useful in the present disclosure include OX40 agonists. OX40 agonists being studied in clinical trials include PF-04518600 / PF-8600 (Pfizer), an agonistic anti-OX40 antibody for metastatic renal cancer (NCT03092856) and advanced cancers and neoplasms (NCT02554812; NCT05082566); GSK3174998 (Merck), an agonistic anti-OX40 antibody in a Phase 1 cancer trial (NCT02528357); MEDI0562 (Medimmune / AstraZeneca) ca), an agonist anti-OX40 antibody for advanced solid tumors (NCT02318394 and NCT02705482); MEDI6469, an agonist anti-OX40 antibody (Medimmune / AstraZeneca) for 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 for advanced cancers (NCT02737475).

[0531] Checkpoint inhibitors useful in the present disclosure include CD137 (also known as 4-1BB) agonists. CD137 agonists being studied in clinical trials include urerulumab (PF-05082566, Pfizer), an agonistic anti-CD137 antibody for diffuse large B-cell lymphoma (NCT02951156) and advanced cancers and neoplasms (NCT02554812 and NCT05082566); urerulumab (BMS-663513, Bristol-Myers Squibb), an agonistic anti-CD137 antibody for melanoma and skin cancer (NCT02652455) and glioblastoma and gliosarcoma (NCT02658981); and CTX-471 (Compass Therapeutics), an agonistic anti-CD137 antibody for metastatic or locally advanced malignant disease (NCT03881488).

[0532] Checkpoint inhibitors useful in the present disclosure include CD27 agonists. CD27 agonists being studied in clinical trials include varlilumab (CDX-1127, Cell dex Therapeutics), an agonistic anti-CD27 antibody for squamous cell head and neck cancer, ovarian cancer, colorectal cancer, renal cell carcinoma, and glioblastoma (NCT02335918); lymphoma (NCT01460134); and glioma and astrocytoma (NCT02924038).

[0533] 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 agonistic anti-GITR antibody for malignant melanoma and other malignant solid tumors (NCT01239134 and NCT02628574); GWN323 (Novartis), an agonistic anti-GITR antibody for solid tumors and lymphomas (NCT 02740270); INCAGN01876 (Incyte / Agenus), an agonistic anti-GITR antibody for advanced cancers (NCT02697591 and NCT03126110); MK-4166 (Merck), an agonistic anti-GITR antibody for solid tumors (NCT02132754); and MEDI1873 (Medimmune / AstraZeneca), a human IgG1 An agonistic hexameric GITR ligand molecule with an Fc domain for advanced solid tumors (NCT02583165).

[0534] Checkpoint inhibitors useful in the present disclosure include inducible T cell co-stimulator (ICOS, also known as CD278) agonists. ICOS agonists being studied in clinical trials include MEDI-570 (Medimmune), an agonistic anti-ICOS antibody for lymphoma (NCT02520791); GSK3359609 (Merck), an agonistic anti-ICOS antibody in Phase 1 study (NCT02723955); JTX-2011 (Jounce Therapeutics), an agonistic anti-ICOS antibody in Phase 1 study (NCT02904226).

[0535] Checkpoint inhibitors useful in the present disclosure include killer IgG-like receptor (KIR) inhibitors. KIR inhibitors being studied in clinical trials include livolumab (IPH2102 / BMS-986015, Innate Pharma / Bristol-Myers Squibb), an anti-KIR antibody for leukemias (NCT01687387, NCT02399917, NCT02481297, NCT02599649), multiple myeloma (NCT02252263), and lymphoma (NCT01592370); IPH2101 (1-7F9, Innate Pharma), for myeloma (NCT01222286 and NCT01217203); and IPH4102 (Innate Pharma), an anti-KIR antibody that binds three domains of the long cytoplasmic tail (KIR3DL2), for lymphoma (NCT02593045).

[0536] Checkpoint inhibitors useful in the present disclosure include CD47 inhibitors of the interaction between CD47 and signal regulatory protein alpha (SIRPα). CD47 / SIRPa inhibitors being studied in clinical trials include ALX-148 (Alexo Therapeutics), an antagonist variant that binds to CD47 and blocks CD47 / SIRPa-mediated signaling (SIRPa), in Phase 1 studies (NCT03013218); TTI-621 (SIRPa-Fc, Trillium Therapeutics), a soluble recombinant fusion protein generated by linking the N-terminal CD47 binding domain of SIRPa to the Fc domain of human IgG1, which works by binding to human CD47 and blocking it from sending its “don’t eat” signal to macrophages, in Phase 1 clinical trials (NCT02890368 and NCT02663518); CC-90002 (Celgene), an anti-CD47 antibody for leukemia (NCT02641002); and Hu5F9-G4 (Forty Seven, Inc.) for colorectal neoplasms and solid tumors (NCT02953782), acute myeloid leukemia (NCT02678338), and lymphoma (NCT02953509).

[0537] Checkpoint inhibitors useful in the present disclosure include CD73 agonists. CD73 inhibitors being studied in clinical trials include MEDI9447 (Medimmune), an anti-CD73 antibody for solid tumors (NCT02503774); and BMS-986179 (Bristol-Myers Squibb), an anti-CD73 antibody for solid tumors (NCT02754141).

[0538] Checkpoint inhibitors useful in the present disclosure include agonists of stimulator of interferon genes (STING, also known as transmembrane protein 173, or TMEM173). STING agonists being studied in clinical trials include MK-1454 (Merck), an agonist synthetic cyclic dinucleotide for lymphoma (NCT03010176); and ADU-S100 (MIW815, AduroBiotech / Novartis), an agonist synthetic cyclic dinucleotide in Phase 1 studies (NCT02675439 and NCT03172936).

[0539] Checkpoint inhibitors useful in the present disclosure include CSF1R inhibitors. CSF1R inhibitors being studied in clinical trials include Pexidartinib (PLX3397, Plexxikon), a CSF1R small molecule inhibitor for colorectal cancer, pancreatic cancer, metastatic and advanced cancers (NCT02777710), as well as melanoma, non-small cell lung cancer, squamous cell head and neck cancer, gastrointestinal stromal tumors (GIST), and ovarian cancer (NCT02452424); and IMC-CS4 (LY3022855, Lilly), an anti-CSF-1R antibody for pancreatic cancer (NCT03153410), melanoma (NCT03101254), and solid tumors (NCT02718911); and BLZ945 (4-[2((1R,2R)-2-hydroxycyclohexylamino)-benzothiazol-6-yloxy]-pyridine-2-carboxylic acid carboxamide, Novartis), an orally available CSF1R inhibitor for advanced solid tumors (NCT02829723).

[0540] Checkpoint inhibitors useful 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 for head and neck neoplasms (NCT02643550) and chronic lymphocytic leukemia (NCT02557516).

[0541] In some embodiments, the immune checkpoint inhibitor is selected from nivolumab, pembrolizumab, ipilimumab, avelumab, durvalumab, atezolizumab, or pidilizumab.

[0542] Example

[0543] The following examples are included to demonstrate various aspects of the present disclosure. It will be appreciated by those skilled in the art that the techniques disclosed in the following examples represent techniques that the inventors have found to work well in the practice of the present disclosure, and therefore can be considered to constitute preferred modes of practice thereof. However, it will be appreciated by those skilled in the art that, in accordance with the present disclosure, many modifications may be made to the disclosed specific embodiments without departing from the spirit and scope of the present disclosure, and still obtaining the same or similar results.

[0544] Methods for preparing the compounds described herein are shown in the following synthetic schemes. The schemes are provided for the purpose of illustrating the present 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 sources or can be prepared based on procedures described in the literature.

[0545] In the scheme, it will be understood by those skilled in the art of organic synthesis that the functional groups present on the various parts of the molecule should be compatible with the proposed reagents and reactions. Substituents that are incompatible with the reaction conditions will be apparent to those skilled in the art, and therefore alternative methods (e.g., using protecting groups or alternative reactions) are indicated. Protecting group chemistry and strategies are well known in the art, such as described in detail in "Protecting Groups in Organic synthesis", TW Greene and PGM Wuts, 3rd edition, John Wiley & Sons, 1999, the entire contents of which are hereby incorporated by reference.

[0546] Example 1: N-cyclopropyl-2-((2-fluoro-4-iodophenyl)amino)-1,5-dimethyl-4-(3-((N-methylaminosulfonyl)amino)-1,5-dimethyl Synthesis of (1-(4 ...

[0547]

[0548] Step 1 :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 trifluoromethanesulfonate

[0549]

[0550] Under nitrogen atmosphere, Et3N (4.2g, 41.39mmol, 4.0 equivalents) was added to a solution of 3-cyclopropyl-1-(2-fluoro-4-iodophenyl)-5-hydroxy-6,8-dimethylpyrido[2,3-d]pyrimidine-2,4,7-trione (5.0g, 10.34mmol, 1.0 equivalents) and phenyl(trifluoromethanesulfonyloxy)aminotrifluoromethanesulfonate (8.0g, 20.69mmol, 2.0 equivalents) in DCM (100.0mL) at room temperature. Under nitrogen atmosphere, the resulting mixture was stirred at room temperature for 30 minutes. The reaction was monitored by LCMS. At room temperature, the reaction was quenched by adding water (20mL). The resulting mixture was extracted with CH2Cl2 (3x 30mL). The combined organic layer was washed with brine (30mL) 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 (2:1) to give 3-cyclopropyl-1-(2-fluoro-4-iodophenyl)-6,8-dimethyl-2,4,7-trioxopyrido[2,3-d]pyrimidin-5-yl trifluoromethanesulfonate (5.0 g, 78%) as a white solid. ES-LCMS m / z 616 [M+H] + .

[0551] 1 H NMR(400MHz,DMSO-d6)δ7.99-7.92(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).

[0552] 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

[0553]

[0554] Under nitrogen atmosphere, CsF (1.9 g, 12.19 mmol, 3.0 equivalents) was added 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 (2.5 g, 4.06 mmol, 1.0 equivalent) and 3-nitrophenol (1.1 g, 8.13 mmol, 2.0 equivalents) in THF (30.0 mL) at room temperature. The resulting mixture was stirred for 1 hour at 60 ° C under nitrogen atmosphere. The reaction was monitored by LCMS. The mixture was cooled to room temperature and quenched by adding water (50 mL). The resulting mixture was extracted with EtOAc (3 x 50 mL). The combined organic layer was 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 (1:1) to give 3-cyclopropyl-1-(2-fluoro-4-iodophenyl)-6,8-dimethyl-5-(3-nitrophenoxy)pyrido[2,3-d]pyrimidine-2,4,7-trione (1.3 g, 52%) as a white solid. ES-LCMS m / z 605 [M+H] + .

[0555] 1 H NMR(300MHz,DMSO-d6)δ8.01-7.87(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).

[0556] 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

[0557]

[0558] Under air atmosphere, Fe (831 mg, 14.89 mmol, 10.0 equiv) was added to a stirred solution of 3-cyclopropyl-1-(2-fluoro-4-iodophenyl)-6,8-dimethyl-5-(3-nitrophenoxy)pyrido[2,3-d]pyrimidine-2,4,7-trione (900 mg, 1.49 mmol, 1.0 equiv) in AcOH (10.0 mL) at 50 ° C. Under nitrogen atmosphere, the resulting mixture was stirred for 1 hour at 50 ° C. The reaction was monitored by LCMS. The mixture was cooled to room temperature and quenched by adding water (50 mL) at room temperature. The mixture was neutralized to pH 7 with saturated NaHCO (aqueous solution). The resulting mixture was extracted with EtOAc (3x 50 mL). The combined organic layer was washed with brine (3x50 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 give 5-(3-aminophenoxy)-3-cyclopropyl-1-(2-fluoro-4-iodophenyl)-6,8-dimethylpyrido[2,3-d]pyrimidine-2,4,7-trione (690 mg, 80%) as a white solid. ES-LCMS m / z 575 [M+H] + .

[0559] 1 H NMR(400MHz,DMSO-d6)δ7.96(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).

[0560] 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

[0561]

[0562] Under nitrogen atmosphere, to 5-(3-aminophenoxy)-3-cyclopropyl-1-(2-fluoro-4-iodophenyl)-6,8-dimethylpyrido[2,3-d]pyrimidine-2,4,7-trione (320mg, 0.55mmol, 1.0 equivalent) and TEA (169mg, 1.67mmol, 3.0 equivalent) in DCM (5.0mL) was added N-methylsulfamoyl chloride (86mg, 0.67mmol, 1.2 equivalent) at 0°C. At room temperature, the resulting mixture was stirred for 1 hour. The reaction was quenched with water (10mL) and then extracted with EtOAc (3x10 mL). The organic layer was dried over anhydrous NaSO, filtered and the filtrate was concentrated under reduced pressure. 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, 53%, crude) was obtained as a yellow solid. The crude product was used directly in the next step without further purification. ES-LCMS m / z 668 [M+H] + .

[0563] Step 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

[0564]

[0565] 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 equiv), LiOH.HO (125 mg, 3.00 mmol, 10.0 equiv), THF (2.0 mL) and HO (2.0 mL) were added to a 40 mL vial at room temperature. The resulting mixture was stirred for 30 minutes at room temperature. The residue was diluted with HO (20 mL). The resulting mixture was extracted with EtOAc (3 x 20 mL). The combined organic layers were washed with brine (30 mL) and dried over anhydrous NaSO. 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: 15% B to 50% B over 15 minutes, wavelength: 254 / 220 nm] to give 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] + .

[0566] 1 H NMR (400MHz, DMSO-d6) δ9.76 (s, 1H), 8.63 (s, 1H), 8.05 (d, J = 3.5Hz, 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),2.4 7(s,3H),2.28-2.18(m,1H),1.86(s,3H),0.46-0.37(m,2H),0.02--0.05(m,2H).

[0567] Example 2: (R)-4-(3-((amino(methyl)oxy-λ6-sulfenyl)amino)phenoxy)-N-cyclopropyl-2- Synthesis of ((2-fluoro-4-iodophenyl)amino)-1,5-dimethyl-6-oxo-1,6-dihydropyridine-3-carboxamide (I-8)

[0568]

[0569] Step 1: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)methanesulfenamide

[0570]

[0571] Under nitrogen atmosphere, to a stirred solution of 5-(3-aminophenoxy)-3-cyclopropyl-1-(2-fluoro-4-iodophenyl)-6,8-dimethylpyrido[2,3-d]pyrimidine-2,4,7-trione (500 mg, 0.87 mmol, 1.0 equiv) and TEA (264 mg, 2.61 mmol, 3.0 equiv) in DCM (10.0 mL) was added dropwise methanesulfenyl chloride (102 mg in 1.0 mL DCM, 1.04 mmol, 1.2 equiv) at -40 ° C. The resulting mixture was stirred for 0.5 hours at -40 ° C. The reaction was monitored by LCMS. The reaction was quenched with water at -40 ° C. The resulting mixture was extracted with EtOAc (3 x 10 mL). The combined organic layer was washed with brine (10 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 give N-(3-{[3-cyclopropyl-1-(2-fluoro-4-iodophenyl)-6,8-dimethyl-2,4,7-trioxopyrido[2,3-d]pyrimidin-5-yl]oxy}phenyl)methanesulfenamide (390 mg, 70%) as a yellow solid. ES-LCMS m / z 637 [M+H] + .

[0572] 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)methanesulfonyl imide amide

[0573]

[0574] To 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)methanesulfenamide (370 mg, 0.58 mmol, 1.0 equiv) in THF (5.0 mL) was added tert-butyl hypochlorite (94 mg in 1.0 mL THF, 0.87 mmol, 1.5 equiv) dropwise at 0°C under a nitrogen atmosphere. The resulting mixture was stirred for 1.5 hours at 0°C. The reactants were then cooled to -78°C and a solution of NH3(g) in THF (0.5 M) (5.0 mL) was added, and the mixture was slowly warmed to room temperature over 1 hour. The reaction was quenched with water at 0°C. The resulting mixture was extracted with EtOAc (3 x 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 and eluted with PE / EA (1:1) to give N-(3-{[3-cyclopropyl-1-(2-fluoro-4-iodophenyl)-6,8-dimethyl-2,4,7-trioxopyrido[2,3-d]pyrimidin-5-yl]oxy}phenyl)methanesulfonyl imide amide (300 mg, 79%) as a yellow solid. ES-LCMS m / z 652[M+H] + .

[0575] Step 3 :4-(3-((amino(methyl)oxy-λ6-sulfenyl)amino)phenoxy)-N-cyclopropyl-2-((2-fluoro-4-iodophenyl)amino)-1,5-dimethyl-6-oxo-1,6-dihydropyridine-3-carboxamide

[0576]

[0577] N-(3-{[3-cyclopropyl-1-(2-fluoro-4-iodophenyl)-6,8-dimethyl-2,4,7-trioxopyrido[2,3-d]pyrimidin-5-yl]oxy}phenyl)methanesulfonyl imide amide (300 mg, 0.46 mmol, 1.0 equiv), LiOH.HO (110 mg, 4.61 mmol, 10.0 equiv), THF (2.0 mL) and HO (2.0 mL) were added to a 40 mL vial at room temperature. The resulting mixture was stirred for 30 minutes at room temperature. The residue was dissolved in HO (20 mL). The resulting mixture was extracted with EtOAc (3 x 20 mL). The combined organic layers were washed with brine (30 mL) and dried over anhydrous NaSO. After filtration, the filtrate was concentrated under reduced pressure. The crude product was purified by HPLC to give 4-(3-{[amino(methyl)oxy-λ6-sulfanylidene]amino}phenoxy)-N-cyclopropyl-2-[(2-fluoro-4-iodophenyl)amino]-1,5-dimethyl-6-oxopyridine-3-carboxamide (150 mg, 52%) as a yellow solid. ES-LCMS m / z 626 [M+H] + .

[0578] Step 4 :(R)-4-(3-((amino(methyl)oxy-λ6-sulfylidene)amino)phenoxy)-N-cyclopropyl-2-((2-fluoro-4-iodophenyl)amino)-1,5-dimethyl-6-oxo-1,6-dihydropyridine-3-carboxamide

[0579]

[0580] 4-(3-{[amino(methyl)oxo-λ6-imino]amino}phenoxy)-N-cyclopropyl-2-[(2-fluoro-4-iodophenyl)amino]-1,5-dimethyl-6-oxopyridine-3-carboxamide (150 mg) was purified by chiral HPLC using 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% C over 16 minutes; column ... B; wavelength: 220 / 254nm; RT1(min): 12; RT2(min): 14; sample solvent: EtOH:DCM=1:1; injection volume: 1.5mL; number of operations: 8) to obtain (R)-4-(3-((amino(methyl)oxy-λ6-iminosulfanyl)amino)phenoxy)-N-cyclopropyl-2-((2-fluoro-4-iodophenyl)amino)-1,5-dimethyl-6-oxo-1,6-dihydropyridine-3-carboxamide (47mg, 31%) as an off-white solid. ES-LCMS m / z 626.2[M+H]+ .

[0581] 1 H NMR (400MHz, DMSO-d6) δ8.64 (s, 1H), 7.91 (d, J = 3.7Hz, 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).

[0582] Example 3: (S)-4-(3-((amino(methyl)oxy-λ6-sulfenyl)amino)phenoxy)-N-cyclopropyl-2- ((2-Fluoro-4-iodophenyl)amino)-1,5-dimethyl-6-oxo-1,6-dihydropyridine-3- Formamide Synthesis of (I-7)

[0583]

[0584] Step 1 :(S)-4-(3-((amino(methyl)oxy-λ6-sulfenyl)amino)phenoxy)-N-cyclopropyl-2-((2-fluoro-4-iodophenyl)amino)-1,5-dimethyl-6-oxo-1,6-dihydropyridine-3-carboxamide

[0585]

[0586] 4-(3-{[amino(methyl)oxo-λ6-imino]amino}phenoxy)-N-cyclopropyl-2-[(2-fluoro-4-iodophenyl)amino]-1,5-dimethyl-6-oxopyridine-3-carboxamide (150 mg) was purified by chiral HPLC using 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% C over 16 minutes; column ... B; wavelength: 220 / 254nm; RT1(min): 12; RT2(min): 14; sample solvent: EtOH:DCM=1:1; injection volume: 1.5mL; number of operations: 8) to obtain (S)-4-(3-((amino(methyl)oxy-λ6-iminosulfanyl)amino)phenoxy)-N-cyclopropyl-2-((2-fluoro-4-iodophenyl)amino)-1,5-dimethyl-6-oxo-1,6-dihydropyridine-3-carboxamide (49mg, 32%) as an off-white solid. ES-LCMS m / z 626.2[M+H] + .

[0587] 1 H NMR (400MHz, DMSO-d6) δ8.64 (s, 1H), 7.91 (d, J = 3.7Hz, 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).

[0588] Example 4: N-cyclopropyl-2-((2-fluoro-4-iodophenyl)amino)-1,5-dimethyl-4-(3-((N-methylaminosulfonyl)amino)-1,5-dimethyl Synthesis of (1-(2-Acyl)methyl)phenoxy)-6-oxo-1,6-dihydropyridine-3-carboxamide (I-23)

[0589]

[0590] Step 1 :(3-(Benzyloxy)phenyl)methanesulfonyl chloride

[0591]

[0592] A solution of 1-(benzyloxy)-3-(bromomethyl)benzene (2.60 g, 9.38 mmol, 1.0 equiv) and sodium sulfonate (1.30 g, 10.31 mmol, 1.1 equiv) in water (20.0 mL) and acetone (20.0 mL) was stirred for 3 hours at 80° C. The resulting mixture was concentrated in vacuo to afford sodium [3-(benzyloxy)phenyl]methanesulfonate (2.80 g, crude, 99%), which was used directly in the next step without further purification. Next, sodium [3-(benzyloxy)phenyl]methanesulfonate (2.80 g, crude, 9.32 mmol, 1.0 equiv) was added to a stirred solution of tetrabutylammonium hydrogen sulfate (2.26 g, 9.32 mmol, 1.0 equiv) and NaOH (3.73 g, 93.24 mmol, 10.0 equiv) in DCM (40.0 mL) and water (10.0 mL) at room temperature. The resulting mixture was stirred for another 15 minutes at room temperature. The resulting mixture was extracted with DCM (3 x 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 to give tetrabutylammonium ion sodium [3-(benzyloxy)phenyl]methanesulfonate (2.50 g, crude, 51%), which was used directly in the next step without further purification. Then, to a stirred solution of tetrabutylammonium ion [3-(benzyloxy)phenyl]methanesulfonate (1.20 g, crude, 2.30 mmol, 1.0 equiv) in DCM was added pentachloro-λ5-phosphine (0.48 g, 2.30 mmol, 1.0 equiv) dropwise at -20°C. The resulting mixture was stirred for 0.5 h at -20°C and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE / THF (1:1) to give [3-(benzyloxy)phenyl]methanesulfonyl chloride (361 mg, 52%) as an off-white solid.

[0593] Step 2 :1-(3-(Benzyloxy)phenyl)-N-methylmethanesulfonamide

[0594]

[0595] A solution of [3-(benzyloxy)phenyl]methanesulfonyl chloride (360 mg, 0.67 mmol, 1.0 equiv) in methylamine (2.0 mL, 2M in THF) and THF (1.0 mL) was stirred at room temperature for 30 minutes. The solvent was removed under vacuum to give 1-[3-(benzyloxy)phenyl]-N-methylmethanesulfonamide (300 mg, crude, 84%), which was used directly in the next step without further purification. ES-LCMS m / z 290 [MH] - .

[0596] Step 3 :1-(3-Hydroxyphenyl)-N-methylmethanesulfonamide

[0597]

[0598] To a solution of 1-[3-(benzyloxy)phenyl]-N-methylmethanesulfonamide (300 mg, 1.03 mmol, 1.0 equiv) in MeOH (4.0 mL) was added Pd / C (10%, 0.05 g) in a pressure vessel. The mixture was hydrogenated at 30 psi hydrogen pressure at room temperature for 30 min, filtered through a pad of celite and concentrated under reduced pressure. The resulting mixture was filtered and the filter cake was washed with MeOH (3 x 5 mL). The filtrate was concentrated under reduced pressure. The crude product was purified by preparative HPLC [column: YMC-Actus Triart C18 ExRS, 30*150 mm, 5 μm; mobile phase A: water (10 mmol / L NH4HCO3 + 0.1% NH3.H2O), mobile phase B: ACN; flow rate: 30 mL / min; gradient: 15% B to 55% B over 9 minutes; detector, UV 220 and 254 nm] to give 1-(3-hydroxyphenyl)-N-methylmethanesulfonamide (116 mg, 55%) as a light brown solid. ES-LCMS m / z 200 [MH] - .

[0599] 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

[0600]

[0601] At 60 ° C, a solution of trifluoromethanesulfonic acid 3-cyclopropyl-1-(2-fluoro-4-iodophenyl)-6,8-dimethyl-2,4,7-trioxopyrido[2,3-d]pyrimidin-5-yl ester (200 mg, 0.32 mmol, 1.0 equivalent), 1-(3-hydroxyphenyl)-N-methylmethanesulfonamide (116 mg, 0.57 mmol, 1.7 equivalents) and cesium fluoride (148 mg, 0.975 mmol, 3 equivalents) in THF was stirred for 30 minutes. The reaction was quenched with water (20 mL) and extracted with EA (3x 20 mL). The combined organic layer was 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] + .

[0602] Step 5 :N-cyclopropyl-2-((2-fluoro-4-iodophenyl)amino)-1,5-dimethyl-4-(3-((N-methylsulfamoyl)methyl)phenoxy)-6-oxo-1,6-dihydropyridine-3-carboxamide

[0603]

[0604] 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) in portions at room temperature. The resulting mixture was stirred for 30 minutes at room temperature and dissolved in H2O (20 mL). The resulting mixture was extracted with EtOAc (3x20 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: 15% B to 50% B over 15 minutes, 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] + .

[0605] 1 H NMR (400MHz, DMSO-d6) δ8.50 (s, 1H), 7.94 (d, J = 3.7Hz, 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).

[0606] Example 5: N-cyclopropyl-4-((2,2-dioxo-3,4-dihydro-1H-benzo[c][1,2,6]thiadiazine-7- 2-((2-fluoro-4-iodophenyl)amino)-1,5-dimethyl-6-oxo-1,6-dihydro Pyridine-3-carboxamide (I- 14) Synthesis

[0607]

[0608] Step 1 :3-amino-4-(aminomethyl)phenol

[0609]

[0610] A solution of 2-amino-4-hydroxybenzamide (600 mg, 3.94 mmol, 1.0 equiv) in THF (2.0 mL) and BH3·Me2S (2.0 mL) was stirred at 80°C for 4 hours. The reaction was quenched with MeOH (20 mL) at 0°C and concentrated under reduced pressure to give 3-amino-4-(aminomethyl)phenol (370 mg, 67%) as an off-white solid. The crude product was used directly in the next step without further purification. ES-LCMS m / z 139 [M+H] + .

[0611] Step 2 :7-Hydroxy-3,4-dihydro-1H-benzo[c][1,2,6]thiadiazine 2,2-dioxide

[0612]

[0613] A solution of 3-amino-4-(aminomethyl)phenol (370 mg, 2.67 mmol, 1.0 equiv) and sulfonamide (772 mg, 8.03 mmol, 3.0 equiv) in pyridine (10.0 mL) was stirred at 120 ° C for 6 hours. The reaction was monitored by LCMS. After the reaction was completed, the mixture was then concentrated under reduced pressure. The residue was purified by reverse phase flash chromatography using the following conditions: column: C18 silica gel; mobile phase: MeCN / water (10 mmol / L NH4HCO3), 10% to 40% gradient over 10 minutes; detector: UV254nm. 7-hydroxy-3,4-dihydro-1H-2λ6,1,3-benzothiadiazine-2,2-dione (270 mg, 50%) was obtained as an off-white solid. ES-LCMS m / z 201[M+H] + .

[0614] Step 3 :3-cyclopropyl-5-((2,2-dioxo-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

[0615]

[0616] At 0 ° C, 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) for 15 minutes, followed by the addition of trifluoromethanesulfonic acid 3-cyclopropyl-1-(2-fluoro-4-iodophenyl)-6,8-dimethyl-2,4,7-trioxopyrido[2,3-d]pyrimidin-5-yl ester (200 mg in THF, 0.32 mmol, 1.0 equiv) at 0 ° C. The resulting mixture was stirred for another 30 minutes at 60 ° C. Then, it was quenched by adding water (20 mL) and extracted with EA (3 x 20 mL). The combined organic layer was 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 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] + .

[0617] Step 4 :N-cyclopropyl-4-((2,2-dioxo-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

[0618]

[0619] To a stirred solution of 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, 0.25 mmol, 1.0 equiv) in THF (1.0 mL) and water (1.0 mL) was added LiOH (61 mg, 2.55 mmol, 10.0 equiv) in portions at room temperature. The resulting mixture was stirred for another 30 minutes at room temperature. The residue was dissolved in H2O (20 mL) and extracted with EA (3 x 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 crude product 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 75% B over 8 minutes, wavelength: 254 / 220 nm] to give N-cyclopropyl-4-[(2,2-dioxo-3,4-dihydro-1H-2λ6,1,3-benzothiadiazin-7-yl)oxy]-2-[(2-fluoro-4-iodophenyl)amino]-1,5-dimethyl-6-oxopyridine-3-carboxamide (40 mg, 24%) as an off-white solid. ES-LCMS m / z 640.2 [M+H] + .

[0620] 1 H NMR(300MHz, DMSO-d6)δ7.99(d,J=3.8Hz,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).

[0621] Example 6: N-cyclopropyl-4-{2-fluoro-3-[(methylsulfamoyl)amino]phenoxy}-2-[(2-fluoro-4-iodo Synthesis of [(phenyl)amino]-1,5-dimethyl-6-oxopyridine-3-carboxamide (I-4)

[0622]

[0623] 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

[0624]

[0625] At room temperature, cesium fluoride (0.9 g, 6.09 mmol, 3.0 equiv) was added 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 equiv) and 2-fluoro-3-nitrophenol (0.6 g, 4.06 mmol, 2.0 equiv) in THF (15.0 mL) in portions. The reaction mixture was stirred for another hour at 60 ° C. The mixture was cooled to room temperature and quenched by adding water (50 mL). The resulting mixture was extracted with EtOAc (3 x 50 mL). The combined organic layer was 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] + .

[0626] 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

[0627]

[0628] 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) was added Fe (304 mg, 5.46 mmol, 10.0 equiv) in portions at 50 °C under air atmosphere. The reaction mixture was stirred for another hour at room temperature. The resulting mixture was diluted with water (50 mL) and neutralized to pH 7 with saturated Na2CO3(aq) and then extracted with DCM (3 x 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] + .

[0629] 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

[0630]

[0631] To 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 added N-methylsulfamoyl chloride (177 mg, 1.36 mmol, 3.0 equiv) dropwise at 0 °C. The resulting mixture was stirred for another 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] + .

[0632] Step 4 :N-cyclopropyl-4-{2-fluoro-3-[(methylsulfamoyl)amino]phenoxy}-2-[(2-fluoro-4-iodophenyl)amino]-1,5-dimethyl-6-oxopyridine-3-carboxamide

[0633]

[0634] 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 in 3.0 mL H2O, 1.72 mmol, 10 equiv) at room temperature under air atmosphere. The resulting mixture was stirred for 30 minutes at room temperature. Then, the resulting mixture was diluted with water (30 mL) and extracted with EtOAc (3 x 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*150mm, 5um, mobile phase A: water (0.05% NH3.H2O), mobile phase B: ACN; flow rate: 35mL / min; gradient: 40% B to 80% B over 8 minutes, wavelength: 254 / 220nm) to give N-cyclopropyl-4-{2-fluoro-3-[(methylsulfamoyl)amino]phenoxy}-2-[(2-fluoro-4-iodophenyl)amino]-1,5-dimethyl-6-oxopyridine-3-carboxamide (53.2mg, 24%) as a white solid. ES-LCMS m / z 660.2[M+H] + .

[0635] 1 H NMR(400MHz,DMSO-d6)δ9.87(br,s,1H),8.41(s,1H),8.02(d,J=3.5Hz,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).

[0636] Example 7: 4-(2-chloro-3-((N-methylsulfamoyl)amino)phenoxy)-N-cyclopropyl-2-((2-fluoro-4- Synthesis of (1,5-dimethyl-6-oxo-1,6-dihydropyridine-3-carboxamide (I-2)

[0637]

[0638] 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

[0639]

[0640] 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 was added cesium fluoride (0.74 g, 4.87 mmol, 3.0 equiv) in portions at 60 °C. The reaction mixture was stirred for another 30 minutes at 60 °C. The resulting mixture was diluted with water (30 mL) and extracted with EA (3x30 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 light yellow solid. ES-LCMS m / z 639 [M+H] + .

[0641] 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

[0642]

[0643] To a stirred mixture of 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, 0.84 mmol, 1.0 equiv) in AcOH at 50 °C was added iron (472 mg, 8.45 mmol, 10.0 equiv) in portions. The resulting mixture was stirred for another 30 min at 50 °C. The mixture was diluted with water (50 mL) and neutralized to pH 7 with saturated NaHCO3(aq) followed by extraction with EA (3 x 20 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. This resulted in 5-(3-amino-2-chlorophenoxy)-3-cyclopropyl-1-(2-fluoro-4-iodophenyl)-6,8-dimethylpyrido[2,3-d]pyrimidine-2,4,7-trione (195 mg, crude, 37%) as a light brown solid. ES-LCMS m / z 609 [M+H] + .

[0644] 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

[0645]

[0646] To a stirred mixture of 5-(3-amino-2-chlorophenoxy)-3-cyclopropyl-1-(2-fluoro-4-iodophenyl)-6,8-dimethylpyrido[2,3-d]pyrimidine-2,4,7-trione (195 mg, crude, 0.32 mmol, 1.0 equiv) in DCM at 0° C. was added triethylamine (64 mg, 0.64 mmol, 2.0 equiv) followed by dropwise addition of N-methylsulfamoyl chloride (83 mg, 0.64 mmol, 2.0 equiv) at 0° C. over 2 minutes. The reaction mixture was stirred for an additional 30 minutes at 0° C. The reaction was quenched with water (10 mL) and then extracted with EtOAc (3×10 mL). The organic layer was dried over anhydrous Na2SO4, filtered and the filtrate was concentrated under reduced pressure to give 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 (130 mg, crude, 57%). The crude product mixture was used directly in the next step without further purification. ES-LCMS m / z 702[M+H] + .

[0647] 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

[0648]

[0649] To a stirred solution of 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 (130 mg, 0.18 mmol, 1.0 equiv) in THF (1.0 mL) and water (1.0 mL) was added LiOH (44 mg, 1.85 mmol, 10.0 equiv) in portions at room temperature. The reaction mixture was stirred for another 30 minutes at room temperature. The resulting mixture was diluted with water (10 mL) and extracted with EA (3 x 10 mL). The combined organic layers were washed with brine (1 x 20 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The crude product 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 75% B over 8 minutes, wavelength: 254 / 220 nm] to give 4-{2-chloro-3-[(methylsulfamoyl)amino]phenoxy}-N-cyclopropyl-2-[(2-fluoro-4-iodophenyl)amino]-1,5-dimethyl-6-oxopyridine-3-carboxamide (51 mg, 41%) as an off-white solid. ES-LCMS m / z 676.1 [M+H] + .

[0650] 1 H NMR(400MHz, DMSO-d6)δ9.01(br,s,1H),8.41(br,s,1H),7.98(d,J=3.6Hz,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=2.6Hz,3H),2 .21-2.11(m,1H),1.76(s,3H),0.42-0.33(m,2H),-0.01--0.05(m,2H).

[0651] Example 8: N-cyclopropyl-2-((2-fluoro-4-iodophenyl)amino)-N,1,5-trimethyl-4-(2-methyl-3- Synthesis of ((N-methylsulfamoyl)amino)phenoxy)-6-oxo-1,6-dihydropyridine-3-carboxamide (I-28)

[0652]

[0653] 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

[0654]

[0655] 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 was added cesium fluoride (740 mg, 4.87 mmol, 3.0 equiv) in portions at 80 °C. The reaction mixture was stirred for another 30 minutes at 80 °C. The resulting mixture was diluted with water (30 mL) and extracted with EA (3x30 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] + .

[0656] Step 2 :N-cyclopropyl-2-((2-fluoro-4-iodophenyl)amino)-1,5-dimethyl-4-(2-methyl-3-nitrophenoxy)-6-oxo-1,6-dihydropyridine-3-carboxamide

[0657]

[0658] 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) was added LiOH (182 mg, 7.60 mmol, 10.0 equiv) in portions at room temperature. The reaction mixture was stirred for another 30 minutes at room temperature. The resulting mixture was diluted with water (10 mL) and extracted with EA (3 x 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 resulted in 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 light yellow solid. ES-LCMS m / z 593 [M+H] + .

[0659] Step 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

[0660]

[0661] 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) for 30 minutes at 0 ° C, followed by dropwise addition of iodomethane (251 mg, 1.77 mmol, 6.0 equiv) at 0 ° C. The reaction mixture was stirred for another 30 minutes at room temperature. The resulting mixture was diluted with water (10 mL) and extracted with EA (3x10 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] + .

[0662] 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

[0663]

[0664] To a stirred mixture of N-cyclopropyl-2-[(2-fluoro-4-iodophenyl)amino]-N,1,5-trimethyl-4-(2-methyl-3-nitrophenoxy)-6-oxopyridine-3-carboxamide (100 mg, 0.16 mmol, 1.0 equiv) in AcOH at 50 °C was added Fe powder (92 mg, 1.65 mmol, 10.0 equiv) in portions. The reaction mixture was stirred for another 30 minutes at 50 °C. The mixture was diluted with water (10 mL) and neutralized to pH 7 with saturated NaHCO3(aq) and extracted with EA (3 x 20 mL). The combined organic layers were washed with brine (10 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. This resulted in 4-(3-amino-2-methylphenoxy)-N-cyclopropyl-2-[(2-fluoro-4-iodophenyl)amino]-N,1,5-trimethyl-6-oxopyridine-3-carboxamide (67 mg, crude, 70%) as an off-white solid.

[0665] 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

[0666]

[0667] To a stirred mixture of 4-(3-amino-2-methylphenoxy)-N-cyclopropyl-2-[(2-fluoro-4-iodophenyl)amino]-N,1,5-trimethyl-6-oxopyridine-3-carboxamide (67 mg, crude, 0.11 mmol, 1.0 equiv) in DCM was added triethylamine (35 mg, 0.34 mmol, 3.0 equiv) at 0 ° C, followed by N-methylsulfamoyl chloride (22 mg, 0.17 mmol, 1.5 equiv) at 0 ° C. The reaction mixture was stirred for another 30 minutes at room temperature. The resulting mixture was diluted with water (20 mL) and extracted with EA (3 x 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 crude product was purified by preparative HPLC [column: YMC C18 30*150 mm, 5 μm, mobile phase A: water (0.05% NH3.H2O), mobile phase B: ACN; flow rate: 35 mL / min; gradient: 40% B to 80% B over 8 minutes, wavelength: 254 / 220 nm] to give N-cyclopropyl-2-[(2-fluoro-4-iodophenyl)amino]-N,1,5-trimethyl-4-{2-methyl-3-[(methylsulfamoyl)amino]phenoxy}-6-oxopyridine-3-carboxamide (17 mg, 21%) as an off-white solid. ES-LCMS m / z 670.2 [M+H] + .

[0668] 1 H NMR(300MHz,DMSO-d6)δ8.93-8.74(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).

[0669] Example 9: N-cyclopropyl-2-[(2-fluoro-4-iodophenyl)amino]-4-(3-methanesulfonimide (acylaminophenoxy)-1,5-dimethyl-6-oxopyridine-3-carboxamide Synthesis of (I-20)

[0670]

[0671] Step 1:N-(tert-butyldimethylsilyl)methanesulfonamide

[0672]

[0673] In a 250mL round-bottom flask, a solution of TBSCl (18.54g, 123.0mmol, 1.2 equivalents) in toluene (20.0mL) was added dropwise to a stirred solution of methanesulfonamide (10.00g, 105.1mmol, 1.2 equivalents) and Et3N (21.28g, 210.3mmol, 2.0 equivalents) in THF (50.0mL). At 60°C, the reaction mixture was stirred overnight. The reaction was cooled to room temperature and filtered. The filter cake was washed with THF and then ground with hexane. After filtration, the final solid was collected. This produced N- (tert-butyldimethylsilyl) methanesulfonamide (19.00g, 86%) as a white solid. 1 H NMR (300 MHz, CHLOROFORM-d) δ 4.71 (s, 1H), 3.02 (s, 3H), 0.95 (s, 9H), 0.29 (s, 6H).

[0674] Step 2 :N-(tert-butyldimethylsilyl)methanesulfonyl imide chloride

[0675]

[0676] Under nitrogen atmosphere, a solution of PPh3 (26.18 g, 99.8 mmol, 1.1 equiv) and hexachloroethane (23.63 g, 99.8 mmol, 1.1 equiv) in CHCl3 (50.0 mL) was stirred at 70 ° C for 5 hours, and a white suspension was observed to form. The mixture was cooled to room temperature and TEA (13.77 g, 136.1 mmol, 1.5 equiv) was added. After stirring for 10 minutes, the mixture was cooled to 0 ° C and a solution of N-(tert-butyldimethylsilyl)methanesulfonamide (19.00 g, 90.7 mmol, 1.0 equiv) in CHCl3 (200.0 mL) was added dropwise. The reaction mixture was stirred for 30 minutes at 0 ° C. The resulting mixture was used directly in the next step without further purification.

[0677] Step 3 :1-(N-(tert-butyldimethylsilyl)-S-methylsulfonylimide)-1H-imidazole

[0678]

[0679] To a solution of N-(tert-butyldimethylsilyl)methanesulfonylimide chloride (5.00 g, 21.8 mmol, 1.0 equiv) in THF (17.0 mL) was added 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 for 18 hours at room temperature. 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-sulfenyl]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).

[0680] Step 4 :1-(N-(tert-butyldimethylsilyl)-S-methylsulfonylimide)-3-methyl-1H-imidazol-3-ium trifluoromethanesulfonate

[0681]

[0682] Under nitrogen atmosphere, a solution of (tert-butyldimethylsilyl)[imidazol-1-yl(methyl)oxo-λ6-sulfenyl]amine (375.00 mg, 1.5 mmol, 1.0 equiv) in Et2O (2.0 mL) was cooled to 0 ° C. 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 in vacuo. This produced 1-(N-(tert-butyldimethylsilyl)-S-methylsulfonylimide)-3-methyl-1H-imidazol-3-ium trifluoromethanesulfonate (380 mg, 95%) as a white solid.

[0683] 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)methanesulfonyl imide amide

[0684]

[0685] To a solution of 5-(3-aminophenoxy)-3-cyclopropyl-1-(2-fluoro-4-iodophenyl)-6,8-dimethylpyrido[2,3-d]pyrimidine-2,4,7-trione (235 mg, 0.4 mmol, 1.0 equiv) and TEA (124 mg, 1.2 mmol, 3.0 equiv) in CH3CN (4.5 mL) was added 1-(N-(tert-butyldimethylsilyl)-S-methylsulfonylimide)-3-methyl-1H-imidazol-3-ium trifluoromethanesulfonate (449 mg, 1.6 mmol, 4.0 equiv) on an ice bath. The resulting mixture was stirred at room temperature under nitrogen atmosphere for 2 hours. The resulting mixture was concentrated under reduced pressure to give 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)methanesulfonyl imide amide (240 mg, 76%) as a white crude solid. The crude product was used directly in the next step without further purification. ES-LCMS m / z 766 [M+H] + .

[0686] Step 6 :4-{3-[N-(tert-butyldimethylsilyl)methanesulfonyl imide amino]phenoxy}-N-cyclopropyl-2-[(2-fluoro-4-iodophenyl)amino]-1,5-dimethyl-6-oxopyridine-3-carboxamide

[0687]

[0688] To a solution of N-(tert-butyldimethylsilyl)-N-(3-{[3-cyclopropyl-1-(2-fluoro-4-iodophenyl)-6,8-dimethyl-2,4,7-trioxopyrido[2,3-d]pyrimidin-5-yl]oxy}phenyl)methanesulfonyl imide amide (240 mg, 0.3 mmol, 1.0 equiv) in THF (2.0 mL) and H2O (3.0 mL) was added LiOH (75 mg, 3.1 mmol, 10.0 equiv). The reaction mixture was stirred at room temperature for 30 minutes. The resulting mixture was diluted with water (10 mL) and extracted with EtOAc (3x10 mL). The combined organic layers were washed with brine and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by preparative TLC (PE:THF=1:1) to give 4-{3-[N-(tert-butyldimethylsilyl)methanesulfonylimidoylamino]phenoxy}-N-cyclopropyl-2-[(2-fluoro-4-iodophenyl)amino]-1,5-dimethyl-6-oxopyridine-3-carboxamide (90 mg, 38%) as a yellow solid. ES-LCMS m / z 740 [M+H] + .

[0689] Step 7 :N-cyclopropyl-2-[(2-fluoro-4-iodophenyl)amino]-4-(3-methanesulfonyl imide aminophenoxy)-1,5-dimethyl-6-oxopyridine-3-carboxamide

[0690]

[0691] To an 8 mL vial was added 4-{3-[N-(tert-butyldimethylsilyl)methanesulfonylimidoylamino]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 (4M 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 C1830*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 over 8 minutes, wavelength: 254 / 220 nm) to give N-cyclopropyl-2-[(2-fluoro-4-iodophenyl)amino]-4-(3-methanesulfonyl imide amidophenoxy)-1,5-dimethyl-6-oxopyridine-3-carboxamide (17.7 mg, 23%) as a white solid. ES-LCMS m / z 626.2.

[0692] 1H NMR (400MHz, DMSO-d6) δ8.64 (s, 1H), 7.91 (d, J = 3.6Hz, 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).

[0693] Example 10: SPR assay

[0694] MEK-RAF binding assay

[0695] The effect of the compound on the binding affinity of MEK to BRAF or CRAF was followed by surface plasmon resonance (SPR) and single cycle kinetic analysis. GST-BRAF or GST-CRAF was fixed on the chip and increasing concentrations of His-tagged MEK1 were flowed through the sensor chip. 500mM ATP was added to the electrophoresis buffer. The dissociation constant of MEK1 binding to BRAF or CRAF was calculated in the absence and presence of the compound. The analysis was performed on a Biacore 8K instrument. The sensorgram was subjected to dual reference and DMSO correction. The data was fitted to a single cycle kinetic model. The activity was classified as AD, where A represents IC 50 <100nM; B means 100nM≤IC 50 <1uM; C means 1≤IC 50 <10uM; and D indicates IC 50 ≥10uM.

[0696] The experimental results are provided in Table 3 below.

[0697] Table 3.

[0698]

[0699]

[0700] MEK-KSR binding assay

[0701] The effect of compound on the binding affinity of MEK to KSR1 or KSR2 was followed by surface plasmon resonance (SPR) and single cycle kinetic analysis. GST-KSR1 or GST-KSR2 was fixed on the chip, and increasing concentrations of His-tagged MEK1 were flowed through the sensor chip. 500mM ATP was added to the electrophoresis buffer. The dissociation constant of MEK1 binding to BRAF or CRAF was calculated in the absence and presence of compound. The analysis was performed on a Biacore 8K instrument. The sensorgram was subjected to dual reference and DMSO correction. The data were fitted to a single cycle kinetic model.

[0702] Example 11: Immunoprecipitation assay

[0703] Immunoprecipitation experiments were performed by inoculating approximately 450,000 HCT116 cells in each well of a 6-well plate. The cells were plated, kept for 48 hours, reached approximately 70% confluence, and then transfected. Then, 24 hours after transfection, the cells were treated with vehicle (0.1% DMSO) or compound (approximately 200 nM) for 1 hour. The cells were washed twice in cold PBS and then transferred to a 0.6 ml PBS solution in a pre-cooled tube. The cells were briefly centrifuged at 1,800 g for 10 minutes in a cold 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 a cocktail of protease and phosphatase inhibitors (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. The clear lysate was quantified using BCA reagent (Pierce, 23225) with BSA as a standard. Five micrograms of rabbit anti-MEK1 antibody (Millipore-Sigma, 07-641) or rabbit IgG (Millipore Sigma, 12-370) was immobilized on 50 μl of Sepharose Protein A resin (Thermo Fisher, 53139) and washed three times in 300 μl of NP-40 buffer before initiating immunoprecipitation.

[0704] Next, for MEK1 immunoprecipitation, 250 μg of total cell lysate (total volume 0.6 ml) was mixed with pre-fixed anti-MEK1 antibodies pre-conjugated to protein A resin. The samples were incubated on an end-over-endrotator at 4 ° C for 4 hours, followed by washing three times in 0.6 ml volume of NP-40 buffer. Next, the protein was denatured and released from the resin by adding 80 μl volume of 1×SDS sample buffer. The samples were boiled at 90 ° C for 2 minutes, centrifuged briefly, and then applied to a 4-12% bis-tris glycine gel (Bio-Rad, 3450125) operated at 150V in MOPS-SDS buffer (Thermo Fisher, NP0001) for 60 minutes. Next, the gel was transferred to nitrocellulose (95V, 250A) in Tris-glycine buffer containing 20% ​​methanol. Metastasis was determined using Ponceau and then analyzed by western blot. Signals for MEK, Flag-tagged proteins, BRAF, and GAPDH were detected by enhanced chemiluminescence on a ChemDoc XRS+ imaging system (Biorad). Activity was classified as AD, where A represents IC 50 <100nM; B means 100nM≤IC 50 <1uM; C means 1≤IC 50 <10uM; and D indicates IC 50 ≥10uM.

[0705] The experimental results are provided in Table 4 below.

[0706] Table 4.

[0707]

[0708]

[0709] 4 hr-pERK1 / 2 HTRF assay

[0710] AsPC1 cells were seeded at 20,000 cells / well in 96-well plates overnight and then treated for 4 hours with a 12-point dose response of compounds (starting at 3000 nM and 3-fold dilutions). AsPC1 cells are a K-Ras mutant cell line. ERK1 / 2 phosphorylation at Thr202 and Tyr204 residues was detected using a homogeneous time-resolved fluorescence (HTRF) assay (Cisbio catalog number 64ERKPEG). Briefly, ERK phosphorylation was detected using a sandwich assay format using two phosphorylated ERK-specific antibodies, one of which was labeled with Eu 3+-cryptate (donor) and the other labeled with d2 (acceptor). Fluorescence resonance energy transfer (FRET) towards the d2 receptor was detected at a wavelength of 665 nm. ERK1 / 2 phosphorylation levels were normalized to total ERK1 / 2 protein levels in each well. IC was determined by fitting a variable slope, four-parameter curve to the compound concentration versus normalized phosphorylation-ERK1 / 2 relationship. 50 Activity is classified as AD, where A represents IC 50 <100nM; B means 100nM≤IC 50 <1uM; C means 1≤IC 50 <10uM; and D indicates IC 50 ≥10uM. The experimental results are provided in Table 5 below.

[0711] Table 5.

[0712]

[0713]

[0714]

[0715] 4 hr-pERK1 / 2 MSD assay

[0716] AsPC1 cells were seeded at 10,000 cells / well in 96-well plates overnight and then treated for 4 hours with a 12-point dose response of compounds (starting at 1000 nM and 3-fold dilutions). AsPC1 cells are a K-Ras mutant (G12D) pancreatic cancer cell line. Phosphorylation of MEK1 / 2 at Ser217 and Ser221 residues was detected using the MesoScale Discovery (MSD) assay (MSD catalog number K15129D-2). MEK1 / 2 phosphorylation levels were normalized to the total MEK1 / 2 protein detected in each well on the same MSD plate. IC was determined by fitting a variable slope, four-parameter curve to the compound concentration versus the normalized phosphorylation-MEK1 / 2 relationship. 50 Activity is classified as AD, where A represents IC 50 <100nM; B means 100nM≤IC 50 <1uM; C means 1≤IC 50 <10uM; and D indicates IC 50 ≥10uM. The experimental results are provided in Table 6 below.

[0717] Table 6.

[0718] Compound pMEK IC50(nM) I-1 A I-2 A

[0719] Embodiment 12: 4-{2-chloro-3-[(methylsulfamoyl)amino]phenoxy}-N-cyclopropyl-2-[(2-fluoro-4-iodophenyl)amino]-1,5-dimethyl-6-oxopyridine-3-carboxamide Synthesis of (I-2)

[0720] Alternative synthesis of 1-2.

[0721]

[0722] Step 1 :N-cyclopropyl-2-[(2-fluoro-4-iodophenyl)amino]-4-hydroxy-1,5-dimethyl-6-oxopyridine-3-carboxamide

[0723]

[0724] Under air atmosphere, 3-cyclopropyl-1-(2-fluoro-4-iodophenyl)-5-hydroxy-6,8-dimethylpyrido [2,3-d] pyrimidine-2,4,7-trione (8.0g, 16mmol, 1.0eq) and LiOH.HO (6.9g, 165mmol, 10.0eq) were added dropwise to a stirred solution in THF (100mL) at room temperature. Under air atmosphere, the resulting mixture was stirred for 30 minutes at room temperature and the reaction was monitored by LCMS. After the reaction was completed, the resulting mixture was extracted with EtOAc (3x 100mL) and dried over anhydrous NaSO. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by grinding with hexane (200mL). The precipitated solid was collected by filtration and washed with hexane (2x 30mL). This resulted in N-cyclopropyl-2-[(2-fluoro-4-iodophenyl)amino]-4-hydroxy-1,5-dimethyl-6-oxopyridine-3-carboxamide (7.5 g, 99%) as a white solid.

[0725] ES-LCMS m / z 458[M+H] + .

[0726] Step 2 :3-(cyclopropylcarbamoyl)-2-[(2-fluoro-4-iodophenyl)amino]-1,5-dimethyl-6-oxopyridin-4-yl trifluoromethanesulfonate

[0727]

[0728] Under air atmosphere, 1,1,1-trifluoro-N-phenyl-N-trifluoromethanesulfonylmethanesulfonamide (8.4g, 23mmol, 1.5eq) in DCM (100mL) was added dropwise to N-cyclopropyl-2-[(2-fluoro-4-iodophenyl)amino]-4-hydroxy-1,5-dimethyl-6-oxopyridine-3-carboxamide (7.2g, 15mmol, 1.0eq) and DMAP (0.96g, 7.8mmol, 0.5eq) in DCM (100mL) at 0°C through a stirred solution. Under air atmosphere, the resulting mixture was stirred at room temperature for 30 minutes. The reaction was monitored by LCMS. After the reaction was completed, it was quenched by adding water (50mL), and then extracted with EtOAc (3x 100mL). The combined organic layer was washed with brine (3x 100mL) 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 (3:1) to give 3-(cyclopropylcarbamoyl)-2-[(2-fluoro-4-iodophenyl)amino]-1,5-dimethyl-6-oxopyridin-4-yl trifluoromethanesulfonate (8.0 g, 86%) as a white solid.

[0729] ES-LCMS m / z 590[M+H] + .

[0730] 1 H NMR(300MHz,DMSO-d6)δ8.49(s,1H),8.36-8.24(m,1H),7.62-7.54(m,1H),7.39-7.32(m,1H),6.6 2-6.54(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).

[0731] Step 3 :4-(2-chloro-3-nitrophenoxy)-N-cyclopropyl-2-[(2-fluoro-4-iodophenyl)amino]-1,5-dimethyl-6-oxopyridine-3-carboxamide

[0732]

[0733] Under nitrogen atmosphere, 2-chloro-3-nitrophenol (6.8g, 39mmol, 2.0eq) was added dropwise to a stirred solution of trifluoromethanesulfonic acid 3-(cyclopropylcarbamoyl)-2-[(2-fluoro-4-iodophenyl)amino]-1,5-dimethyl-6-oxopyridin-4-yl ester (11.5g, 19mmol, 1.0eq) and TEA (5.9g, 58mmol, 3.0eq) in ACN (200mL) at room temperature. Under nitrogen atmosphere, the resulting mixture was stirred at 50°C for 2 hours. The reaction was monitored by LCMS. The mixture was cooled to room temperature and quenched by adding water (200mL) at room temperature. The resulting mixture was extracted with EtOAc (3x 100mL). The combined organic layer was washed with brine (3x 100mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. Then, it was purified by silica gel column chromatography eluting with PE / EA (1:1) to give 4-(2-chloro-3-nitrophenoxy)-N-cyclopropyl-2-[(2-fluoro-4-iodophenyl)amino]-1,5-dimethyl-6-oxopyridine-3-carboxamide (6.8 g, 56%) as a white solid.

[0734] ES-LCMS m / z 613[M+H] + .

[0735] Step 4 :4-(3-amino-2-chlorophenoxy)-N-cyclopropyl-2-[(2-fluoro-4-iodophenyl)amino]-1,5-dimethyl-6-oxopyridine-3-carboxamide

[0736]

[0737] Under air atmosphere, Fe (7.3 g, 130 mmol, 10.0 eq) was added 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 eq) in AcOH (50 mL) at 50 ° C. Under air atmosphere, the resulting mixture was stirred for 2 hours at 50 ° C. The reaction was monitored by LCMS. The mixture was cooled to room temperature and quenched by adding water (100 mL) at room temperature. The mixture was neutralized to pH 7 with saturated NaHCO3. The resulting mixture was extracted with EtOAc (3 x 100 mL). The combined organic layer was washed with brine (1 x 100 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. This resulted in 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.

[0738] ES-LCMS m / z 583[M+H] + .

[0739] Step 5 :4-{2-chloro-3-[(methylsulfamoyl)amino]phenoxy}-N-cyclopropyl-2-[(2-fluoro-4-iodophenyl)amino]-1,5-dimethyl-6-oxopyridine-3-carboxamide

[0740]

[0741] Under air atmosphere, to 4-(3-amino-2-chlorophenoxy)-N-cyclopropyl-2-[(2-fluoro-4-iodophenyl)amino]-1,5-dimethyl-6-oxopyridine-3-carboxamide (6.5g, 11mmol, 1.0eq) and pyridine (3.4g, 33mmol, 3.0eq) in DMF (80mL) was added dropwise N-methylsulfamoyl chloride (2.2g, 16.7mmol, 1.5eq) in ACN (5mL) at 0°C. Under air atmosphere, the resulting mixture was stirred for 30 minutes at 0°C. The reaction was monitored by LCMS. After the reaction was completed, the reaction mixture was diluted with water. The solid was collected by filtration and then ground with isopropyl ether (100mL). The precipitated solid was collected by filtration to give 4-{2-chloro-3-[(methylsulfamoyl)amino]phenoxy}-N-cyclopropyl-2-[(2-fluoro-4-iodophenyl)amino]-1,5-dimethyl-6-oxopyridine-3-carboxamide (5.3 g, 71%) as a white solid.

[0742] ES-LCMS m / z 676.2[M+H] + .

[0743] 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).

[0744] Example 13: Pharmacokinetic studies

[0745] Exemplary compounds were tested in mice using a cassette dosing regimen to determine their pharmacokinetic properties. The assay procedures and results are described below.

[0746] Part I - Procedure for Cassette Pharmacokinetic Studies

[0747] Pharmacokinetic study was performed using a cassette dosing regimen, wherein the test compound was administered to each mouse. The treatment group was 3 mice per route of administration (approximately 6-8 weeks old, approximately 20-30g Balb / c male mice). For IV and PO administration, the compound was formulated in 5% DMSO and 95% PEG400, and its final concentration was 0.5mg / mL. For IV administration, 2mg / kg compound was administered and for PO administration, 5mg / kg compound was administered. Blood samples were drawn 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. Blood samples were centrifuged at 4°C for 5 minutes at 4,000g to obtain plasma samples. Plasma samples were diluted with the internal standard in acetonitrile, 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 compound concentration was determined by HPLC / MS / MS and compared to a calibration standard of 0.5-1,000 ng / mL.

[0748] Part II - Results

[0749] The experimental results are provided below in Table 7. Where the route is listed as "IV*", the compound was administered IV at 1 mg / kg.

[0750] Table 7.

[0751]

[0752]

[0753] Example 14: In vivo efficacy studies using human MIA PaCa-2 xenografts in mice

[0754] The antitumor activity of MEK inhibitor compounds was evaluated in vivo using human cell line derived xenografts grown from the MIA PaCa-2 cell line in immunodeficient mice. MIA PaCa-2 cells are a K-Ras mutant (G12C) pancreatic tumor cell line. The tumor cell line was maintained in vitro as a monolayer culture in culture medium at 37°C and an atmosphere of 5% CO2 in air. Tumor cells were routinely subcultured by trypsin-EDTA treatment before confluence, not exceeding 4-5 generations. Cells growing in the exponential growth phase were collected for tumor inoculation. MIA PaCa-2 tumor cells (1 x 10 6 The tumor cells were subcutaneously implanted into the right flank of Nu / Nu nude mice in a 1:1 mixture with Matrigel. The tumors were allowed to grow to approximately 250 mm 3 At this point, mice were assigned to groups so that the mean tumor volume was the same for each treatment group (n = 8 mice / group). Tumor-bearing mice were administered a 1 mg / kg dose of the compound via QD oral gavage. Ten days after dosing, when tumors in the vehicle control group reached ethical endpoints (mean tumor volume > 1500 mm 3 ), all mice were sacrificed and the final measurements were recorded. Mouse body weight and tumor volume were recorded throughout the study. Tumor size was measured twice a week using a caliper and recorded. Tumor volume (mm) was estimated using the following formula 3 ):TV=axb 2 / 2, where "a" and "b" are the long and short diameters of the tumor, respectively.

[0755] As measured on day 10, exemplary MEK inhibitors including 1-2 showed percentages of tumor growth inhibition (TGI) of 86.2%, 96.2%, and 82.3%. For exemplary MEK inhibitors including 1-2, mean body weight loss was observed on day 10 of 5.5%, 2.5%, and 3.8%, respectively.

[0756] Example 15: Stabilization assay of MEK1-CRAF complex

[0757] The dissociation constants (K) of MEK1 and CRAF were compared in the absence and presence of exemplary MEK inhibitor compounds. D ) to test exemplary MEK inhibitor compounds to determine the role of the MEK inhibitor compounds in stabilizing the MEK1-CRAF complex.

[0758] Part I. Experimental Procedure

[0759] Preparation of 4× reagent stocks: All reagents were diluted in 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, followed by dilutions to 80, 40, 20, 10, 5, 2.5, 1.25, and 0.625 nM via a 1:2 serial dilution.

[0760] 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) based on a total reaction mixture volume of 20 μL.

[0761] 5 μL of 4× MEK1 stock solution was added to each well of A1-P20 using a multichannel pipette.The plate was sealed with clear olefin sealing tape (Thermo Scientific, 232701), centrifuged at 1000 rpm for 1 minute, and incubated at room temperature for 30 minutes.

[0762] 5 μL of 4×CRAF stock solution of different concentrations or 5 μL or 10 μL of AlphaLISA buffer were added using a multichannel pipette. The plate was sealed, centrifuged at 1000 rpm for 1 minute, and incubated at room temperature for 60 minutes.

[0763] First, 5 μL of 4× glutathione acceptor was added to all wells using a multichannel pipette. Subsequently, the ambient light was adjusted to <100 lux (light meter), and then 5 μL of 4× nickel chelate donor beads were added to the same wells. From this step on, the plate was covered with a black plate cover, centrifuged at 1000 rpm for 1 minute, and incubated at room temperature for 60 minutes.

[0764] Part II. Data Collection

[0765] Data were collected on a PHERAStar FSX (BMG LABTECH) using the AlphaLISA module (excitation: 680 nm, emission: 615 nm) with a gain of 3600. The excitation time was 0.30 s and data collection started after a 0.04 s delay with a total integration time of 0.60 s.

[0766] Part III. Data Analysis

[0767] The AlphaLISA signal / background ratio (S / B) was obtained by dividing the individual AlphaLISA counts of wells with the exemplary MEK inhibitor compound by the average AlphaLISA counts of wells without the compound. The dissociation constant (K) of MEK1-CRAF was calculated using nonlinear regression curve fitting in 9.0 software. D ).

[0768] Part IV. Results

[0769] The experimental results are provided in Table 8 below. The corresponding KD ratios of the compounds (0.01, 0.1 or 1 μM) to DMSO were calculated and provided in Table 8 below. The symbol n represents the number of independent experiments performed for each exemplary MEK inhibitor compound. The data obtained from multiple experiments using the same compound were averaged and processed into a single value (n for compound I-1 is 3; n for compound I-2 is 7; n for compound I-45 is 3; n for compound I-45 is 3; n for compound I-43 is 3; n for compound I-55 is 3; n for compound I-41 is 3; n for compound I-54 is 3; and n for compound I-40 is 3).

[0770] Table 8.

[0771]

[0772]

[0773] *N / D Not determined

[0774] Example 16: In vivo efficacy studies using human xenografts in mice

[0775] The anti-tumor activity of exemplary MEK inhibitor compounds was evaluated in vivo using human cell line-derived xenografts (CDX) grown in immunodeficient mice. For these studies, AsPC1 (pancreatic cell line containing KRAS G12D mutation), NCI-H2122 (lung cell line containing KRAS G12C mutation) and 5637 (bladder cell line containing CRAF amplification) models were used. In addition, HCT-116 (colorectal cell line containing KRAS G13D mutation), SKM-1 (AML cell line containing KRAS K117N mutation) and OCI-AML-3 (AML cell line containing NRAS Q61L mutation) models were also used. Tumor cell lines (AsPC-1, NCI-H2122, 5637 and HCT-116 cells) were maintained in culture medium in vitro as monolayer cultures in an atmosphere of air containing 5% CO2 at 37°C. Tumor cell lines (SKM-1 and OCI-AML-3 cells) were maintained in suspension in culture medium in vitro at 37°C in an atmosphere of air containing 5% CO2. Tumor cells were routinely subcultured by trypsin-EDTA treatment before confluence, not exceeding 4-5 generations. Cells growing in the exponential growth phase were collected for tumor inoculation. AsPC1, NCI-H2122, and OCI-AML-3 tumors were implanted in Balb / c nude mice. HCT-116 tumors were implanted in Nu / Nu mice. 5637 and SKM-1 tumors were implanted in NOG mice. A 1:1 mixture of tumor cells and matrix gel was subcutaneously inoculated on the right flank of each mouse. Tumors were grown to approximately 150-200mm 3 At this point, mice were assigned to groups so that the mean tumor volume was the same for each treatment group. Tumor-bearing mice were treated with MEK inhibitor compounds by oral gavage. Mouse body weights and tumor volumes were recorded throughout the study. Tumor size measurements were taken twice a week using a caliper and recorded. Tumor volume (mm) was estimated using the following formula 3 ):TV=axb 2 / 2, where "a" and "b" are the long and short diameters of the tumor, respectively.

[0776] In the AsPC-1 model, an exemplary MEK inhibitor 1-2 was treated at 3 mg / kg QD and a TGI (tumor growth inhibition) percentage of 83.4% was observed on day 21. The average body weight gain observed on day 21 was 2.4%.

[0777] In the NCI-H2122 model, an exemplary MEK inhibitor 1-2 was treated at 3 mg / kg QD and a TGI percentage of 104% was observed on day 31. The average body weight loss observed on day 31 was 1.5%.

[0778] In the 5637 model, the exemplary MEK inhibitor 1-2 was treated at 3 mg / kg QD and a TGI percentage of 111% was observed on day 21. The average body weight loss observed on day 21 was 6.8%.

[0779] In the HCT-116 model, the exemplary MEK inhibitor I-2 was treated at 2 mg / kg QD, 3 mg / kg QOD, or 6 mg / kg QOD, and TGI percentages of 102.9%, 98.1%, and 98% were observed, respectively, on day 20. The mean body weight gains observed on day 20 were 4%, 5.5%, and 12.1%, respectively.

[0780] In the SKM-1 model, the exemplary MEK inhibitor I-2 was treated at 1 mg / kg QD, 3 mg / kg QD, or 6 mg / kg QOD, and venetoclax was treated at 100 mg / kg QD, and TGI percentages of 97.7%, 98.4%, 96.2%, and 46.6%, respectively, were observed on Day 22. On Day 22, a mean body weight loss of 1.2% was observed in the 3 mg / kg QD group, while body weight gains were observed in the 1 mg / kg QD, 6 mg / kg QOD, and venetoclax groups (1.2%, 3.9%, and 7.5%, respectively).

[0781] In the OCI-AML-3 model, the exemplary MEK inhibitor 1-2 was treated at 1 mg / kg QD, 3 mg / kg QD, or 6 mg / kg QOD, and venetoclax was treated at 100 mg / kg QD, and TGI percentages of 94.8%, 98.6%, 95.2%, and 13%, respectively, were observed on day 15. On day 15, mean body weight losses of 2.9% and 7.8% were observed in the 1 mg / kg and 3 mg / kg QD groups, respectively, while body weight gains were observed in the 6 mg / kg QOD and venetoclax groups (3.3% and 8.3%, respectively).

[0782] Example 17: Assay for Assessing Stabilization of MEK1-BRAF and CRAF Complexes

[0783] The dissociation constants (K) of MEK1 and CRAF were compared in the absence and presence of exemplary MEK inhibitor compounds. D ) to test exemplary MEK inhibitor compounds to determine the role of the MEK inhibitor compounds in stabilizing the MEK1-CRAF complex.

[0784] Part I. Experimental Procedure

[0785] Preparation of 4× reagent stocks: All reagents w...

Claims

1. A compound of formula (I): or a pharmaceutically acceptable salt thereof, wherein: Each are independently a single bond or a double bond; Each A is independently or an optionally substituted 5-6 membered heteroaryl; X 1 , X 2 , X 3 and X 5 Independently for CR 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 When N is 3 With R 8 Together with the N atom to which it is attached, it forms an optionally substituted 3-7 membered heterocycloalkyl ring; Each R 1 are independently hydrogen, deuterium, halo, -CN, 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, C( 2 D)3, OC( 2 D) 3, optionally substituted C1-C6 aliphatic group, optionally substituted C1-C6 alkoxy group, optionally substituted C3-C 10 Cycloalkyl, optionally substituted C6-C 10 Heterocycloalkyl or optionally substituted C6-C 10 Aryl; or when X 7 When it is N that forms a double bond with the sulfur atom, R 5 does not exist; Each R 6 are independently hydrogen, deuterium, C( 2 D) 3, optionally substituted C1-C6 aliphatic group, optionally substituted C1-C6 alkoxy group, optionally substituted C3-C 10 Cycloalkyl, optionally substituted C6-C 10 Heterocycloalkyl, optionally substituted C6-C 10 Aryl, or two R 6 together with the atoms to which it is attached, form an optionally substituted 3-7 membered heterocycloalkyl ring, or R 5 With R 6 Together with the atoms to which it is attached, it forms a 5-6 membered heterocycloalkyl ring; or R 5 With X 5 or X 3 Together with the atoms to which it is attached, it forms a 5-6 membered fused heterocycloalkyl or heteroaromatic ring; R 6 With X 5 or X 3 Together with the atoms to which they are attached, they form a 5-6 membered fused heterocycloalkyl ring; and R 7 is O or an optionally substituted C1-C6 aliphatic group; and R 8 is absent, hydrogen, deuterium or an optionally substituted C1-C6 aliphatic group.

2. A compound of formula (II): or a pharmaceutically acceptable salt thereof, wherein: Each are independently a single bond or a double bond; Each A is independently or an optionally substituted 5-6 membered heteroaryl; X 1 , X 2 , X 3 , X 4 and X 5 Independently for CR 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 When N is 3 With R 8 Together with the N atom to which it is attached, it forms an optionally substituted 3-7 membered heterocycloalkyl ring; Each R 1 are independently hydrogen, deuterium, halogen, -CN; 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, C( 2 D)3, OC( 2 D) 3, optionally substituted C1-C6 aliphatic group, optionally substituted C1-C6 alkoxy group, optionally substituted C3-C 10 Cycloalkyl, optionally substituted C6-C 10 Heterocycloalkyl or optionally substituted C6-C 10 Aryl; or when X 7 When it is N that forms a double bond with the sulfur atom, R 5 does not exist; and Each R 6 are independently hydrogen, deuterium, C( 2 D) 3, optionally substituted C1-C6 aliphatic group, optionally substituted C1-C6 alkoxy group, optionally substituted C3-C 10 Cycloalkyl, optionally substituted C6-C 10 Heterocycloalkyl, optionally substituted C6-C 10 Aryl, or two R 6 Together with the atoms to which it is attached, it forms a 3-7 membered heterocycloalkyl ring, or R 5 With R 6 Together with the atoms to which it is attached, it forms a 5-6 membered heterocycloalkyl ring; or R 5 With X 2 or X 4 Together with the atoms to which it is attached, it forms a 5-6 membered fused heterocycloalkyl or heteroaromatic ring; R 6 With X 2 or X 4 Together with the atoms to which it is attached, it forms a 5-6 membered fused heterocycloalkyl ring; R 7 is O or an optionally substituted C1-C6 aliphatic group; and R 8 is absent, hydrogen, deuterium or an optionally substituted C1-C6 aliphatic group.

3. A compound of formula (III), formula (IIIA), formula (IIIB) or formula (IIIC): or a pharmaceutically acceptable salt thereof, wherein: Ring B is an optionally substituted ring selected from the group consisting of: C3-C 10 Cycloalkyl; C3-C4-C6 ... 10 Heterocycloalkyl; phenyl; 5-6 membered heteroaryl having 1-4 heteroatoms N, S or O; or 6-10 membered bicyclic heteroaryl having 1-4 heteroatoms N, S or O; R 11 It is H. R 12 is H or an optionally substituted C1-C6 aliphatic group; Each A is independently or an optionally substituted 5-6 membered heteroaryl; X 6 is C(O), O or NH; X 7 is CH or N; X 8 is N or O; or when X 8 When N is 3 With R 8 Together with the N atom to which it is attached, it forms an optionally substituted 3-7 membered heterocycloalkyl ring; Each R 1 are independently hydrogen, halogen, -CN, 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, 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 when X 7 When it is N that forms a double bond with the sulfur atom, R 5 does not exist; Each R 6 are independently hydrogen, optionally substituted C1-C6 aliphatic, optionally substituted C1-C6 alkoxy, optionally substituted C3-C 10 Cycloalkyl, optionally substituted C6-C 10 Heterocycloalkyl, optionally substituted C6-C 10 Aryl, or two R 6 together with the atoms to which it is attached, form an optionally substituted 3-7 membered heterocycloalkyl ring, or R 5 With R 6 Together with the atoms to which it is attached, it forms a 5-6 membered heterocycloalkyl ring; R 7 is O or an optionally substituted C1-C6 aliphatic group; and R 8 is absent, hydrogen or optionally substituted C1-C6 aliphatic.

4. The compound of claim 1, wherein X 1 , X 2 , X 3 and X 5 Yes CR 1 .

5. The compound as claimed in claim 2, wherein X 1 , X 2 , X 4 and X 5 Yes CR 1 .

6. A compound as described in any one of claims 1 to 5, wherein R 1 is hydrogen, halogen or optionally substituted C1-C6 alkoxy.

7. A compound as described in any one of claims 1 to 6, wherein R 1 is hydrogen, fluorine, chlorine or methoxy.

8. A compound as claimed in any one of claims 1 to 7, wherein X 6 It's O.

9. The compound of any one of claims 1 to 8, wherein X 6 It's NH.

10. The compound of any one of claims 1 to 9, wherein X 7 It is CH.

11. The compound of any one of claims 1 to 9, wherein X 7 It is N.

12. A compound as described in any one of claims 1 to 11, wherein A is 13. The compound of claim 12, wherein X 8 It is N.

14. The compound of claim 12 or 13, wherein R 3 is optionally substituted C3-C 10 Cycloalkyl.

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

16. A compound as claimed in any one of claims 12 to 15, wherein R 8 is hydrogen or an optionally substituted C1-C6 aliphatic group.

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

18. A compound as claimed in any one of claims 1 to 17, wherein R 1 is hydrogen, halogen or optionally substituted C1-C6 alkoxy.

19. The compound of claim 18, wherein R 1 It is fluorine or iodine.

20. A compound as claimed in any one of claims 1 to 19, wherein R 2 is an optionally substituted C1-C6 aliphatic group.

21. The compound of claim 20, wherein R 2 It's methyl.

22. A compound as described in any one of claims 1 to 21, wherein R 3 is optionally substituted C3-C 10 Cycloalkyl.

23. The compound of claim 22, wherein R 3 It is cyclopropyl.

24. A compound as described in any one of claims 1 to 23, wherein R 4 is an optionally substituted C1-C6 aliphatic group.

25. The compound of claim 24, wherein R 4 It's methyl.

26. A compound as described in any one of claims 1 to 25, wherein R 5 It's hydrogen.

27. A compound as described in any one of claims 1 to 26, wherein each R 6 are independently hydrogen or an optionally substituted C1-C6 aliphatic group.

28. The compound of claim 27, wherein each R 6 are independently hydrogen or methyl.

29. The compound of any one of claims 1 to 28, wherein the compound is a compound selected from the compounds 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, adjuvant or vehicle.

31. A method of treating a condition mediated by MEK, the method comprising administering to a subject in need thereof a therapeutically effective amount of a compound according to any one of claims 1 to 29 or a pharmaceutical composition according to claim 30 to treat the condition.

32. The method of claim 31 , wherein the disorder is cancer.

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

34. The method of claim 32, wherein 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, thyroid cancer, melanoma, multiple myeloma, acute myeloid leukemia (AML), low-grade serous ovarian cancer, neurofibroma, and glioma.

35. A method for treating cancer in a patient, the method comprising administering to the patient a compound of any one of claims 1 to 29, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of claim 30.

36. A method for inhibiting MEK activity, the method comprising contacting MEK or KSR-MEK complex or RAF-MEK complex with an effective amount of the compound of any one of claims 1 to 29 or the pharmaceutical composition of claim 30 to inhibit MEK activity.

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