eIF4E inhibitors and uses thereof

Abstract

The present invention provides compounds that inhibit eIF4E activity, as well as compositions and methods of use thereof.

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims priority to U.S. Provisional Application No. 63 / 260,556, filed August 25, 2021, which is incorporated by reference in its entirety.

[0002] The present invention relates to compounds and methods useful for inhibiting eukaryotic translation initiation factor 4E (eIF4E). The present invention also provides pharmaceutically acceptable compositions comprising the compounds of the invention and methods of using the compositions in the treatment of various disorders. [Background technology]

[0003] Eukaryotic translation initiation factor 4E (eIF4E) is a 24 kDa protein that plays a key role in the initiation of translation of selected mRNAs. During the initiation of mRNA translation, eIF4E binds to the 7-methylguanosine cap at the 5' end of the mRNA and forms a complex (termed eIF4F) with proteins including the scaffolding protein eIF4G and the helicase eIF4A. Because formation of the 4F complex is required for cap-dependent translation initiation, the binding of eIF4E to its cognate partner is an essential event in eIF4E-mediated translation.

[0004] Several studies suggest that dysregulation of eIF4E is important in some cancer phenotypes, and therefore eIF4E is a potential target in the field of oncology. Summary of the Invention [Means for solving the problem]

[0005] It has now been found that compounds of the present invention, and pharmaceutically acceptable compositions thereof, are effective as eIF4E inhibitors. In one aspect, the present invention provides compounds of formula (I): [ka] or a pharmaceutically acceptable salt thereof, wherein each variable is as defined and described herein.

[0006] The compounds of the present invention, and pharmaceutically acceptable compositions thereof, are useful for treating a variety of diseases, disorders, or conditions associated with eIF4E, including cell proliferative disorders (e.g., cancer), such as those described herein. DETAILED DESCRIPTION OF THE INVENTION

[0007] 1. Overview of Certain Embodiments of the Invention: The compounds of the present invention and pharmaceutical compositions thereof are useful as inhibitors of eIF4E. Without wishing to be bound by any particular theory, it is believed that the compounds of the present invention and pharmaceutical compositions thereof inhibit the activity of eIF4E, and thus can treat certain diseases, such as cancer.

[0008] It has now been found that compounds of the present invention, and pharmaceutically acceptable compositions thereof, are effective as eIF4E inhibitors. In one aspect, the present invention provides compounds of formula I: [ka] or a pharmaceutically acceptable salt thereof, wherein X is C, CR 4 , or N, R 1 is optionally substituted 1 to 6 times by H, halogen, -OR, -N(R)2, or -C(O)-N(R)2; 1-6 is alkyl, R 2 is a 3- to 6-membered monocyclic saturated carbocyclic ring optionally substituted 1 to 6 times by halogen or -OR', C optionally substituted 1 to 6 times by halogen or -OR' 1-6 C optionally substituted once with alkyl or a 3- to 6-membered monocyclic saturated carbocyclic or phenyl ring 1-6alkyl, wherein the 3-6 membered monocyclic saturated carbocyclic ring and the phenyl ring are optionally substituted 1-6 times with halogen or -OR'; R 3 but, [ka] and Each R 4 are independently halogen, -OR 1 or C optionally substituted 1 to 6 times with halogen 1-6 is alkyl, Each R 5 are independently halogen, or C optionally substituted 1 to 6 times with halogen 1-6 is alkyl, C, where each R is independently substituted 1 to 6 times with H, optionally halogen, -OR', or -N(R')2; 1-6 a 3- to 6-membered monocyclic saturated carbocyclic ring optionally substituted 1 to 6 times with alkyl or halogen; C, where each R' is independently substituted 1 to 6 times with H or optionally halogen. 1-6 is alkyl, m is 0 or 1, n is 0, 1, or 2.

[0009] 2. Compounds and Definitions: Compounds of the present invention include those described generally herein and are further illustrated by the classes, subclasses, and species disclosed herein. As used herein, the following definitions shall apply unless otherwise specified. For purposes of this invention, chemical elements are defined as defined in the Periodic Table of the Elements, CAS version (Handbook of Chemistry and Physics, 75 th Additionally, general principles of organic chemistry are identified in "Organic Chemistry," Thomas Sorrell, University Science Books, Sausalito: 1999, and "March's Advanced Organic Chemistry," 5 thEd., Ed.: Smith, MB and March, J., John Wiley & Sons, New York: 2001, the entire contents of which are incorporated herein by reference.

[0010] As used herein, the term "aliphatic" or "aliphatic group" means a straight-chain (i.e., unbranched) or branched, substituted or unsubstituted hydrocarbon chain that is fully saturated or contains one or more units of unsaturation, having a single point of attachment to the rest of the molecule; or a monocyclic or bicyclic hydrocarbon that is fully saturated or contains one or more units of unsaturation, but is not aromatic (also referred to herein as "carbocyclic," "cycloaliphatic," or "cycloalkyl"). 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 still 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, "cycloaliphatic" (or "carbocycle" or "cycloalkyl") refers to a monocyclic C3-C6 hydrocarbon that is fully saturated or contains one or more units of unsaturation, but is not aromatic, with a single point of attachment to the rest of the molecule. Suitable aliphatic groups include, but are not limited to, linear or branched, substituted or unsubstituted alkyl, alkenyl, alkynyl groups, and hybrids thereof, such as (cycloalkyl)alkyl, (cycloalkenyl)alkyl, or (cycloalkyl)alkenyl.

[0011] As used herein, the term "bicyclic ring" or "bicyclic ring system" refers to any bicyclic ring system, i.e., carbocyclic or heterocyclic, saturated or containing one or more units of unsaturation, and having one or more atoms in common between the two rings of the ring system. Thus, the term includes any permissible ring fusion, such as ortho-fused or spirocyclic. As used herein, the term "heterobicyclic" is a subset of "bicyclic," requiring one or more heteroatoms to be present in one or both rings of the bicycle. Such heteroatoms may be present at ring junctions, 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 such as phosphates), boron, and the like. In some embodiments, bicyclic groups have 7 to 12 ring members and 0 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. As used herein, the term "bridged bicyclic" refers to any bicyclic ring system, i.e., carbocyclic or heterocyclic, saturated or partially unsaturated, having at least one bridge. As defined by IUPAC, a "bridge" is an unbranched chain or valence bond of atoms (or atoms) connecting two bridgeheads, where a "bridgehead" is any skeletal atom of the ring system that is bonded to three or more skeletal atoms (excluding hydrogen). In some embodiments, a bridged bicyclic group has 7 to 12 ring members and 0 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. Such bridged bicyclic groups are well known in the art and include the groups described below, where each group is attached to the remainder of the molecule at any substitutable carbon or nitrogen atom. Unless otherwise specified, a bridged bicyclic group is optionally substituted with one or more substituents, such as those described for aliphatic groups. Additionally or alternatively, any substitutable nitrogen of a bridged bicyclic group is optionally substituted. Exemplary bicyclic rings include: [ka] Exemplary bridged bicyclic compounds include: [ka]

[0012] The term "lower alkyl" refers to C 1-4 It refers to a straight-chain or branched alkyl group. Exemplary lower alkyl groups are methyl, ethyl, propyl, isopropyl, butyl, isobutyl, and tert-butyl.

[0013] The term "lower haloalkyl" refers to a C alkyl group substituted with one or more halogen atoms. 1-4 It refers to a straight-chain or branched alkyl group.

[0014] The term "heteroatom" refers to oxygen, sulfur, nitrogen, phosphorus, or silicon (any oxidized form of nitrogen, sulfur, phosphorus, or silicon; the quaternized form of any basic nitrogen; or a substitutable nitrogen of a heterocycle, e.g., N (as in 3,4-dihydro-2H-pyrrolyl), NH (as in pyrrolidinyl), or NR + (including as in N-substituted pyrrolidinyl)).

[0015] As used herein, the term "unsaturated" means that a moiety has one or more units of unsaturation.

[0016] As used herein, "divalent C 1-8 (or C 1-6 The term "saturated or unsaturated, straight or branched hydrocarbon chain" refers to divalent alkylene, alkenylene, and alkynylene chains, which are straight or branched, as defined herein.

[0017] The term "alkylene" refers to a divalent alkyl group. An "alkylene chain" is a polymethylene group, i.e., -(CH2) n-, where n is a positive integer, preferably 1 to 6, 1 to 4, 1 to 3, 1 to 2, or 2 to 3. A substituted alkylene chain is a polymethylene group in which one or more methylene hydrogen atoms have been replaced with a substituent. Suitable substituents include those described below for substituted aliphatic groups.

[0018] The term "alkenylene" refers to a divalent alkenyl group. A substituted alkenylene chain is a polymethylene group containing at least one double bond in which one or more hydrogen atoms are replaced with a substituent. Suitable substituents include those described below for substituted aliphatic groups.

[0019] As used herein, the term "cyclopropylenyl" refers to a group having the following structure: [ka] refers to a divalent cyclopropyl group.

[0020] The term "halogen" means F, Cl, Br, or I.

[0021] The term "aryl," used alone or as part of a larger moiety, as in "aralkyl," "aralkoxy," or "aryloxyalkyl," refers to a monocyclic or bicyclic ring system having a total of 5 to 14 ring members, in which at least one ring in the system is aromatic and each ring in the system contains 3 to 7 ring members. The term "aryl" may be used interchangeably with the term "aryl ring." In certain embodiments of the present invention, "aryl" refers to an aromatic ring system, including, but not limited to, phenyl, biphenyl, naphthyl, anthracyl, and the like, which may bear 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 indanyl, phthalimidyl, naphthoimidyl, phenanthridinyl, or tetrahydronaphthyl.

[0022] 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; groups having 6, 10, or 14 pi electrons shared in a cyclic arrangement; and groups having 1 to 5 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 a basic nitrogen. Heteroaryl groups include, but are not limited to, thienyl, furanyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolizinyl, purinyl, naphthyridinyl, and pteridinyl. As used herein, the terms "heteroaryl" and "heteroar-" also include groups in which a heteroaromatic ring is fused to one or more aryl, cycloaliphatic, or heterocyclyl rings, and the radical or point of attachment is on the heteroaromatic ring. Non-limiting examples include indolyl, isoindolyl, benzothienyl, benzofuranyl, dibenzofuranyl, indazolyl, benzimidazolyl, benzthiazolyl, quinolyl, isoquinolyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, 4H-quinolizinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl, phenoxazinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, and pyrido[2,3-b]-1,4-oxazin-3(4H)-one. Heteroaryl groups can be monocyclic or bicyclic. The term "heteroaryl" may be used interchangeably with the terms "heteroaryl ring," "heteroaryl group," or "heteroaromatic," any of which terms include rings that are optionally substituted. The term "heteroaralkyl" refers to an alkyl group substituted with a heteroaryl, wherein the alkyl and heteroaryl portions independently are optionally substituted.

[0023] As used herein, the terms "heterocycle," "heterocyclyl," "heterocyclic radical," and "heterocycle" are used interchangeably and refer to a stable 5- to 7-membered monocyclic or 7- to 10-membered bicyclic heterocyclic moiety that is either saturated or partially unsaturated and has, in addition to carbon atoms, one or more, preferably 1 to 4, heteroatoms, as defined above. When used in reference to a ring atom of a heterocycle, the term "nitrogen" includes substituted nitrogen. By way of example, in a saturated or partially unsaturated ring having 0 to 3 heteroatoms selected from oxygen, sulfur, or nitrogen, the nitrogen can be N (as in 3,4-dihydro-2H-pyrrolyl), NH (as in pyrrolidinyl), or + It may also be NR (as in N-substituted pyrrolidinyl).

[0024] A heterocycle can be attached to its pendant group at any heteroatom or carbon atom that results in a stable structure, and any of the ring atoms can be optionally substituted. Examples of such saturated or partially unsaturated heterocyclic radicals include, but are not limited to, tetrahydrofuranyl, tetrahydrothiophenyl, pyrrolidinyl, piperidinyl, pyrrolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, decahydroquinolinyl, oxazolidinyl, piperazinyl, dioxanyl, dioxolanyl, diazepinyl, oxazepinyl, thiazepinyl, morpholinyl, and quinuclidinyl. The terms "heterocycle," "heterocyclyl," "heterocyclyl ring," "heterocyclic group," "heterocyclic moiety," and "heterocyclic radical" are used interchangeably herein and also include groups in which a heterocyclyl ring is fused to one or more aryl, heteroaryl, or cycloaliphatic rings, such as indolinyl, 3H-indolyl, chromanyl, phenanthridinyl, or tetrahydroquinolinyl. Heterocyclyl groups can be monocyclic or bicyclic. The term "heterocyclylalkyl" refers to an alkyl group substituted with a heterocyclyl, wherein the alkyl and heterocyclyl portions independently are optionally substituted.

[0025] 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.

[0026] As described herein, compounds of the invention may contain "optionally substituted" moieties. In general, the term "substituted," whether preceded by the term "optionally," means that one or more hydrogens of the specified moiety may be replaced with a suitable substituent. Unless otherwise specified, 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 with more than one substituent selected from a specified group, the substituents may be the same or different at each and every position. Combinations of substituents envisioned by the present invention are preferably those that result in the formation of stable or chemically feasible compounds. As used herein, the term "stable" refers to compounds that are substantially unchanged when subjected to conditions that permit their production, detection, and, in certain embodiments, their recovery, purification, and use for one or more of the purposes disclosed herein.

[0027] Each optional substituent on a substitutable carbon is selected from the group consisting of halogen, -(CH2), 0-4 R°, -(CH2) 0-4 OR°, -O(CH2) 0-4 R°, -O-(CH2) 0-4 C(O)OR°, -(CH2) 0-4 CH(OR°)2, -(CH2) 0-4 SR°, -(CH2) 0-4 Ph (which may be replaced by R°), —(CH2) 0-4 O(CH2) 0-1Ph (which may be substituted with R°), -CH=CHPh (which may be substituted with R°), -(CH2) 0-4 O(CH2) 0-1 -pyridyl (which may be substituted with 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) 0-4 S(O)R°, -N(R°)S(O)2NR°2, -N(R°)S(O)2R°, -N(OR°)R°, -C(NH)NR°2, -P(O)2R°, -P(O)R°2, -OP(O)R°2, -OP(O)(OR°)2, SiR°3, -(C 1-4 Linear or branched alkylene)ON(R°)2, or -(C 1-4linear or branched alkylene)C(O)ON(R°)2.

[0028] Each R° is independently hydrogen, C 1-6 Aliphatic, -CH2Ph, -O(CH2) 0-1 Ph, -CH2- (a 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 instances of R° taken together with their intervening atom(s) 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 a saturated carbon atom of R° with a divalent substituent selected from ═O and ═S; or each R° is selected from halogen, -(CH2) 0-2 R ● ,-(Halo R ● ), -(CH2) 0-2 OH, -(CH2) 0-2 OR ● , -(CH2) 0-2 CH(OR ● )2, -O(HaloR ● ), -CN, -N3, -(CH2) 0-2 C(O)R ● , -(CH2) 0-2 C(O)OH, -(CH2) 0-2 C(O)OR ● , -(CH2) 0-2 SR ● , -(CH2) 0-2 SH, -(CH2) 0-2 NH2, -(CH2) 0-2 NHR ● , -(CH2) 0-2 NR ● 2, -NO2, -SiR ● 3. -OSiR ● 3. -C(O)SR ● 、 -(C 1-4 Linear or branched alkylene)C(O)OR ● , or -SSR● is optionally substituted with a monovalent substituent independently selected from

[0029] Each R ● independently, C 1-4 Aliphatic, -CH2Ph, -O(CH2) 0-1 Ph, or a 5-6 membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, wherein each R ● is unsubstituted or, if preceded by halo, is substituted with only one or more halogens, or the optional substituents on the saturated carbon are ═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 or the divalent substituent attached to a vicinal substitutable carbon of an "optionally substituted" group is -O(CR * 2) 2-3 O-, wherein R * Examples of each of these independently occurring are hydrogen, C 1-6 It is selected from an aliphatic or unsubstituted 5-6 membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0030] R * C 1-6 If aliphatic, R * is optionally a halogen, -R ● ,-(Halo R ● ), -OH, -OR ● , -O(HaloR ● ), -CN, -C(O)OH, -C(O)OR ● , -NH2, -NHR ● , -NR ●2, or -NO2, wherein each R ● independently, C 1-4 Aliphatic, -CH2Ph, -O(CH2) 0-1 Ph, or a 5-6 membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur; ● is unsubstituted or, when preceded by halo, substituted with only one or more halogens.

[0031] The optional substituents on the substitutable nitrogen are independently -R † , -NR † 2. -C(O)R † , -C(O)OR † , -C(O)C(O)R † , -C(O)CHC(O)R † , -S(O)2R † , -S(O)NR † 2. -C(S)NR † 2. -C(NH)NR † 2, or -N(R † )S(O)2R † where each R † are independently hydrogen, C 1-6 an aliphatic, unsubstituted -OPh, or an unsubstituted 5-6 membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur; or R † two independently occurring instances of, taken together with their intervening atom(s), form an unsubstituted 3-12 membered saturated, partially unsaturated, or aryl monocyclic or bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur; R † C 1-6 If aliphatic, R † is optionally a halogen, -R ● ,-(Halo R ● ), -OH, -OR ● , -O(HaloR ● ), -CN, -C(O)OH, -C(O)OR ● , -NH2, -NHR● , -NR ● 2, or -NO2, wherein each R ● independently, C 1-4 Aliphatic, -CH2Ph, -O(CH2) 0-1 Ph, or a 5-6 membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur; ● is unsubstituted or, when preceded by halo, substituted with only one or more halogens.

[0032] As used herein, the term "pharmaceutically acceptable salt" refers to a salt that is suitable, within the scope of sound medical judgment, for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response, etc., and that is commensurate with a reasonable benefit / risk ratio. Pharmaceutically acceptable salts are well known in the art. For example, S.M. Berge et al. describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 1977, 66, 1-19 (incorporated herein by reference). Pharmaceutically acceptable salts of the compounds of the present invention include those derived from suitable inorganic and organic acids and bases. Examples of pharmaceutically acceptable non-toxic acid addition salts are salts of amino groups formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, and perchloric acid, or with organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid, or malonic acid, or formed by using other methods used in the art, such as ion exchange. Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecyl sulfate, 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.

[0033] Salts derived from appropriate bases include alkali metal salts, alkaline earth metal salts, ammonium salts, and N + (C 1-4 Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, etc. Further pharmaceutically acceptable salts include non-toxic ammonium, quaternary ammonium, and amine cations, formed where appropriate using counterions such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, lower alkyl sulfonates, and aryl sulfonates.

[0034] Unless otherwise specified, structures depicted herein are also intended to include all isomeric (e.g., enantiomeric, diastereomeric, and geometric (or conformational)) forms of the structure, e.g., R and S configurations for each asymmetric center, Z and E double bond isomers, and Z and E conformational isomers. Accordingly, single stereochemical isomers as well as enantiomeric, diastereomeric, and geometric (or conformational) mixtures of the present compounds are within the scope of the invention. Unless otherwise specified, all tautomeric forms of the compounds of the invention are within the scope of the invention. Furthermore, unless otherwise specified, structures depicted herein are also intended to include compounds that differ only in the presence of one or more isotopically enriched atoms. For example, including the replacement of hydrogen with deuterium or tritium, or replacing a carbon with a methyl group. 13 C enrichment or 14 Compounds having the present structure, including replacement with C-enriched carbons, are within the scope of the present invention. Such compounds are useful, for example, as analytical tools, probes in biological assays, or as therapeutic agents in accordance with the present invention. In certain embodiments, the warhead moiety of provided compounds, R 1 contains one or more deuterium atoms.

[0035] As used herein, the term "inhibitor" is defined as a compound that binds to and / or inhibits eIF4E with measurable affinity. In certain embodiments, an inhibitor has an IC of less than about 100 μM, less than about 50 μM, less than about 22.5 μM, less than about 15 μM, or less than about 7.5 μM. 50 and / or have a binding constant.

[0036] As used herein, the terms "measurable affinity" and "measurably inhibit" refer to a measurable change in eIF4E activity between a sample containing a compound or composition thereof of the present invention and eIF4E and an equivalent sample containing eIF4E in the absence of the compound or composition thereof.

[0037] 3. Description of Exemplary Embodiments: In one aspect, the present invention provides a compound of formula I: [ka] or a pharmaceutically acceptable salt thereof, wherein X is C, CR 4 , or N, R 1 is optionally substituted 1 to 6 times by H, halogen, -OR, -N(R)2, or -C(O)-N(R)2; 1-6 is alkyl, R 2 is a 3- to 6-membered monocyclic saturated carbocyclic ring optionally substituted 1 to 6 times by halogen or -OR', C optionally substituted 1 to 6 times by halogen or -OR' 1-6 C optionally substituted once with alkyl or a 3- to 6-membered monocyclic saturated carbocyclic or phenyl ring 1-6 alkyl, wherein the 3-6 membered monocyclic saturated carbocyclic ring and the phenyl ring are optionally substituted 1-6 times with halogen or -OR'; R 3 but, [ka] and Each R4 are independently halogen, -OR 1 or C optionally substituted 1 to 6 times with halogen 1-6 is alkyl, Each R 5 are independently halogen, or C optionally substituted 1 to 6 times with halogen 1-6 is alkyl, C, where each R is independently substituted 1 to 6 times with H, optionally halogen, -OR', or -N(R')2; 1-6 a 3- to 6-membered monocyclic saturated carbocyclic ring optionally substituted 1 to 6 times with alkyl or halogen; C, where each R' is independently substituted 1 to 6 times with H or optionally halogen. 1-6 is alkyl, m is 0 or 1, n is 0, 1, or 2.

[0038] As generally defined above, X is C, CR 4 , or N, where R 4 is as defined and described in the embodiments herein.

[0039] In some embodiments, X is C. In some embodiments, X is CR 4 In some embodiments, X is N.

[0040] In some embodiments, X is selected from those shown in Table 1 below.

[0041] As generally defined above, R 1 is H, C optionally substituted 1 to 6 times with halogen, -OR, -N(R)2, or -C(O)-N(R)2 1-6 alkyl, where each R is independently as defined and described in the embodiments herein.

[0042] In some embodiments, R 1 is H. In some embodiments, R 1is optionally substituted 1, 2, 3, 4, 5, or 6 times by halogen, -OR, or -N(R)2; 1-6 In some embodiments, R 1 is the unsubstituted C 1-6 In some embodiments, R 1 is C substituted 1, 2, 3, 4, 5, or 6 times by halogen 1-6 In some embodiments, R 1 is C substituted 1, 2, 3, 4, 5, or 6 times by -OR 1-6 In some embodiments, R 1 is C substituted 1, 2, 3, 4, 5, or 6 times by -N(R)2 1-6 In some embodiments, R 1 is C substituted 1, 2, 3, 4, 5, or 6 times by -C(O)-N(R)2 1-6 It is alkyl.

[0043] In some embodiments, R 1 teeth, [ka] is selected from.

[0044] In some embodiments, R 1 teeth, [ka] is.

[0045] In some embodiments, R 1 is selected from those illustrated in Table 1 below.

[0046] As generally defined above, R 2 is a 3- to 6-membered monocyclic saturated carbocyclic ring optionally substituted 1 to 6 times by halogen or -OR', C optionally substituted 1 to 6 times by halogen or -OR' 1-6 C optionally substituted once with alkyl or a 3- to 6-membered monocyclic saturated carbocyclic or phenyl ring1-6 alkyl, wherein the 3-6 membered monocyclic saturated carbocyclic ring and the phenyl ring are optionally substituted 1-6 times with halogen or -OR', where each R' is independently as defined and described in the embodiments herein.

[0047] In some embodiments, R 2 is a 3-, 4-, 5-, or 6-membered monocyclic saturated carbocycle optionally substituted 1, 2, 3, 4, 5, or 6 times with halogen or -OR'. 2 is an unsubstituted 3-, 4-, 5-, or 6-membered monocyclic saturated carbocyclic ring. 2 is a 3-, 4-, 5-, or 6-membered monocyclic saturated carbocycle substituted 1-, 2-, 3-, 4-, 5-, or 6 times by F.

[0048] In some embodiments, R 2 is optionally substituted 1, 2, 3, 4, 5, or 6 times by halogen or -OR'; 1-6 In some embodiments, R 2 is the unsubstituted C 1-6 In some embodiments, R 2 is optionally substituted 1, 2, 3, 4, 5, or 6 times by F 1-6 It is alkyl.

[0049] In some embodiments, R 2 is a C optionally substituted once by a 3-, 4-, 5-, or 6-membered monocyclic saturated carbocyclic or phenyl ring; 1-6 alkyl, wherein the 3-, 4-, 5-, or 6-membered monocyclic saturated carbocyclic ring and the phenyl ring are optionally substituted 1, 2, 3, 4, 5, or 6 times with halogen or -OR'. 2 is a C optionally substituted once by an unsubstituted 3-, 4-, 5-, or 6-membered monocyclic saturated carbocyclic ring or an unsubstituted phenyl ring; 1-6 It is alkyl.

[0050] In some embodiments, R 2 teeth, [ka] In some embodiments, R 2 teeth, [ka] is.

[0051] In some embodiments, R 2 is selected from those illustrated in Table 1 below.

[0052] As generally defined above, R 3 teeth, [ka] where R 5 and m are each independently as defined and described in the embodiments herein.

[0053] In some embodiments, R 3 teeth, [ka] In some embodiments, R 3 teeth, [ka] In some embodiments, R 3 teeth, [ka] In some embodiments, R 3 teeth, [ka] In some embodiments, R 3 teeth, [ka] In some embodiments, R 3 teeth, [ka] In some embodiments, R 3 teeth, [ka] In some embodiments, R 3 teeth, [ka] In some embodiments, R 3 teeth, [ka] In some embodiments, R 3 teeth, [ka] is.

[0054] In some embodiments, R 3 teeth, [ka] is selected from.

[0055] In some embodiments, R 3 teeth, [ka] In some embodiments, R 3 teeth, [ka] In some embodiments, R 3 teeth, [ka] In some embodiments, R 3 teeth, [ka] In some embodiments, R 3 teeth, [ka] In some embodiments, R 3 teeth, [ka] is.

[0056] In some embodiments, R 3 teeth, [ka] is selected from.

[0057] In some embodiments, R 3 is selected from those illustrated in Table 1 below.

[0058] As generally defined above, each R 4 are independently halogen, -OR 1 or C optionally substituted 1 to 6 times with halogen 1-6 alkyl, where R 1 is as defined and described in the embodiments herein.

[0059] In some embodiments, R 4 is a halogen. In some embodiments, R 4 is F. In some embodiments, R 4 is Cl.

[0060] In some embodiments, R 4 -OR 1 In some embodiments, R 4 is —OH. In some embodiments, R 4 -OR 1 where R 1is C optionally substituted 1, 2, 3, 4, 5, or 6 times by halogen, -OR, -N(R)2, or -C(O)-N(R)2; 1-6 In some embodiments, R 4 -OR 1 where R 1 is the unsubstituted C 1-6 In some embodiments, R 4 -OR 1 where R 1 is C substituted 1, 2, 3, 4, 5, or 6 times by F 1-6 It is alkyl.

[0061] In some embodiments, R 4 is C optionally substituted 1, 2, 3, 4, 5, or 6 times with halogen 1-6 In some embodiments, R 4 is the unsubstituted C 1-6 In some embodiments, R 4 is C substituted 1, 2, 3, 4, 5, or 6 times by F 1-6 It is alkyl.

[0062] In some embodiments, R 4 are -OH, F, Cl, [ka] is selected from.

[0063] In some embodiments, R 4 is selected from those illustrated in Table 1 below.

[0064] As generally defined above, each R 5 are independently halogen or C optionally substituted 1 to 6 times with halogen 1-6 It is alkyl.

[0065] In some embodiments, R 5 is a halogen. In some embodiments, R 5is F. In some embodiments, R 5 is Cl.

[0066] In some embodiments, R 5 is C optionally substituted 1, 2, 3, 4, 5, or 6 times with halogen 1-6 In some embodiments, R 5 is the unsubstituted C 1-6 In some embodiments, R 5 is C substituted 1, 2, 3, 4, 5, or 6 times by F 1-6 In some embodiments, R 5 is -CH3. In some embodiments, R 5 is —CF. In some embodiments, R 5 is t-butyl.

[0067] In some embodiments, R 5 is -OR. In some embodiments, R 5 is -OCH3.

[0068] In some embodiments, R 5 is selected from those illustrated in Table 1 below.

[0069] As generally defined above, each R is independently a C optionally substituted 1 to 6 times with H, halogen, —OR′, or —N(R′)2. 1-6 and R' is a 3-6 membered monocyclic saturated carbocyclic ring optionally substituted 1-6 times with alkyl, or halogen, and each R' is independently as defined and described in the embodiments herein.

[0070] In some embodiments, R is H.

[0071] In some embodiments, R is a C optionally substituted 1, 2, 3, 4, 5, or 6 times with halogen, —OR′, or —N(R′)2. 1-6 In some embodiments, R is an unsubstituted C 1-6In some embodiments, R is C substituted 1, 2, 3, 4, 5, or 6 times with halogen. 1-6 In some embodiments, R is C substituted 1, 2, 3, 4, 5, or 6 times with F. 1-6 In some embodiments, R is C substituted 1, 2, 3, 4, 5, or 6 times with -OR'. 1-6 In some embodiments, R is alkyl. In some embodiments, R is C substituted 1, 2, 3, 4, 5, or 6 times with —N(R′) 1-6 It is alkyl.

[0072] In some embodiments, R is a 3-, 4-, 5-, or 6-membered monocyclic saturated carbocycle optionally substituted 1, 2, 3, 4, 5, or 6 times with halogen. In some embodiments, R is an unsubstituted 3-, 4-, 5-, or 6-membered monocyclic saturated carbocycle. In some embodiments, R is a 3-, 4-, 5-, or 6-membered monocyclic saturated carbocycle substituted 1, 2, 3, 4, 5, or 6 times with F.

[0073] In some embodiments, R is [ka] is selected from.

[0074] In some embodiments, R is selected from those depicted in Table 1 below.

[0075] Each R' is independently H, or C optionally substituted 1 to 6 times with halogen, as generally defined above. 1-6 It is alkyl.

[0076] In some embodiments, R' is hydrogen.

[0077] In some embodiments, R' is C optionally substituted 1, 2, 3, 4, 5, or 6 times with halogen. 1-6 In some embodiments, R' is an unsubstituted C 1-6In some embodiments, R' is C substituted 1, 2, 3, 4, 5, or 6 times with F. 1-6 It is alkyl.

[0078] In some embodiments, R' is [ka] is selected from.

[0079] In some embodiments, R' is selected from those depicted in Table 1 below.

[0080] As generally defined above, m is 0 or 1.

[0081] In some embodiments, m is 0. In some embodiments, m is 1.

[0082] In some embodiments, m is selected from those depicted in Table 1 below.

[0083] As generally defined above, n is 0, 1, or 2.

[0084] In some embodiments, n is 0. In some embodiments, n is 1. In some embodiments, n is 2.

[0085] In some embodiments, n is selected from those depicted in Table 1 below.

[0086] In some embodiments, the present invention provides a compound of formula II: [ka] or a pharmaceutically acceptable salt thereof, wherein R 1 , R 2 , R 4 , R 5 , m, and n, both singly and in combination, are as defined above and described in the embodiments herein.

[0087] In some embodiments, the present invention provides compounds of formula II-a to II-c: [ka] or a pharmaceutically acceptable salt thereof, wherein R 1 , R 2 , R 4 , R 5 , m, and n, both singly and in combination, are as defined above and described in the embodiments herein.

[0088] In some embodiments, the present invention provides a compound of formula III: [ka] or a pharmaceutically acceptable salt thereof, wherein R 1 , R 4 , R 5 , m, and n, both singly and in combination, are as defined above and described in the embodiments herein.

[0089] In some embodiments, the present invention provides compounds of formula III-a to III-c: [ka] or a pharmaceutically acceptable salt thereof, wherein R 1 , R 4 , R 5 , m, and n, both singly and in combination, are as defined above and described in the embodiments herein.

[0090] In some embodiments, the present invention provides compounds of formula IV-a to IV-f: [ka] or a pharmaceutically acceptable salt thereof, wherein R 1 and R 4Each of the following, both singly and in combination, is as defined above and described in the embodiments herein.

[0091] In some embodiments, the present invention provides a compound of formula V: [ka] or a pharmaceutically acceptable salt thereof, wherein R 11 H, halogen, C 1-6 Alkyl, -O-phenyl, or -OC 1-6 alkyl, where C 1-6 alkyl is optionally substituted with phenyl or -O-phenyl, where phenyl is optionally substituted, and X, R 2 , R 3 , R 4 Each of n, and n, both singly and in combination, is as defined above and described in the embodiments herein.

[0092] In some embodiments, R 11 is H. In some embodiments, R 11 is optionally replaced by C 1-6 In some embodiments, R 11 is the unsubstituted C 1-6 In some embodiments, R 11 is methyl, ethyl, propyl, isopropyl, butyl, isobutyl, or t-butyl. 11 is ethyl.

[0093] In some embodiments, R 11 is —O-phenyl, where the phenyl is unsubstituted. In some embodiments, R 11 is —O-phenyl, where phenyl is substituted with optional substituents described herein. In some embodiments, R 11 teeth, [ka] is.

[0094] In some embodiments, R 11 -OC 1-6 alkyl, where C 1-6 The alkyl is optionally substituted with phenyl. In some embodiments, R 11 -OC 1-6 alkyl, where C 1-6 The alkyl is optionally substituted with O-phenyl. In some embodiments, R 11 teeth, [ka] is.

[0095] In some embodiments, the present invention provides a compound of formula VI: [ka] or a pharmaceutically acceptable salt thereof, wherein R 12 and R 13 each independently represents H, or an optionally substituted C 1-6 alkyl, and R 2 and R 3 Each of the following, both singly and in combination, is as defined above and described in the embodiments herein.

[0096] In some embodiments, R 12 is H. In some embodiments, R 12 is optionally replaced by C 1-6 In some embodiments, R 12 is the unsubstituted C 1-6 In some embodiments, R 12 is methyl, ethyl, propyl, isopropyl, butyl, isobutyl, or t-butyl. 12 is methyl.

[0097] In some embodiments, R 13is H. In some embodiments, R 13 is optionally replaced by C 1-6 In some embodiments, R 13 is the unsubstituted C 1-6 In some embodiments, R 13 is methyl, ethyl, propyl, isopropyl, butyl, isobutyl, or t-butyl. 13 is methyl.

[0098] In some embodiments, R 12 is H and R 13 is optionally replaced by C 1-6 In some embodiments, R 12 and R 13 Each of the optionally substituted C 1-6 It is alkyl.

[0099] In some embodiments, R 12 and R 13 Each of R is H. 12 and R 13 Each of is methyl.

[0100] In some embodiments, the present invention provides a compound of formula VII-a or VII-b: [ka] or a pharmaceutically acceptable salt thereof, wherein each R 14 are independently H, -OH, halogen, -C 1-6 Alkyl, -OC 1-6 alkyl, or phenyl, where -C 1-6 Alkyl, -OC 1-6 alkyl, and phenyl are optionally substituted; R 2 , R 3 Each of n, and n, both singly and in combination, is as defined above and described in the embodiments herein.

[0101] In some embodiments, R 14 is H. In some embodiments, R 14 is —OH. In some embodiments, R 14 is a halogen. In some embodiments, R 14 is optionally replaced by -C 1-6 In some embodiments, R 14 is unsubstituted -C 1-6 In some embodiments, R 14 is methyl, ethyl, propyl, isopropyl, butyl, isobutyl, or t-butyl. 14 -OC 1-6 alkyl, where C 1-6 The alkyl is optionally substituted. In some embodiments, R 14 -OC 1-6 alkyl, where C 1-6 Alkyl is unsubstituted. In some embodiments, R 14 is optionally substituted phenyl.

[0102] In some embodiments, the present invention provides a compound of formula VIII: [ka] or a pharmaceutically acceptable salt thereof, wherein each R 15 are independently H, -OH, halogen, -C 1-6 Alkyl, or -OC 1-6 alkyl, where -C 1-6 Alkyl and -OC 1-6 The alkyl is optionally substituted and Y is O, CH, or CHR. 15 where t is 0, 1, 2, 3, or 4, and R 2 and R 3 Each of the following, both singly and in combination, is as defined above and described in the embodiments herein.

[0103] In some embodiments, R 15 is H. In some embodiments, R15 is —OH. In some embodiments, R 15 is a halogen. In some embodiments, R 15 is optionally replaced by -C 1-6 In some embodiments, R 15 is unsubstituted -C 1-6 In some embodiments, R 15 is methyl, ethyl, propyl, isopropyl, butyl, isobutyl, or t-butyl. 15 -OC 1-6 alkyl, where C 1-6 The alkyl is optionally substituted. In some embodiments, R 15 -OC 1-6 alkyl, where C 1-6 The alkyl is unsubstituted.

[0104] In some embodiments, Y is O, CH, or CHR 15 In some embodiments, Y is O. In some embodiments, Y is CH. In some embodiments, Y is CHR 15 is.

[0105] In some embodiments, t is 0. In some embodiments, t is 1. In some embodiments, t is 2. In some embodiments, t is 3. In some embodiments, t is 4.

[0106] In some embodiments, the present invention provides a compound of Table 1, or a pharmaceutically acceptable salt thereof.

[0107] In some embodiments, the present invention provides a compound of Table 2, or a pharmaceutically acceptable salt thereof.

[0108] In some embodiments, the present invention provides a compound selected from those illustrated in the Examples section, or a pharmaceutically acceptable salt thereof. [Table 1A-1] [Table 1A-2] [Table 1A-3] [Table 1A-4] [Table 1A-5] [Table 1A-6] [Table 1A-7] [Table 2-1] [Table 2-2]

[0109] The compounds of the present invention may generally be prepared or isolated by synthetic and / or semi-synthetic methods known to those skilled in the art, by methods illustrated and set forth in the following schemes, and by methods detailed in the examples below. However, the scope of the present disclosure should not be construed as limited to the specific embodiments disclosed in these schemes, which are illustrative only. At least some of the compounds identified herein as "intermediates," e.g., compounds preceded by a number with "Int-," are contemplated as compounds of the present disclosure.

[0110] In the schemes, it is understood by one skilled in the art of organic synthesis that the functional groups present on various portions of the molecules should be compatible with the reagents and reactions proposed. Substituents that are incompatible with the reaction conditions will be apparent to one skilled in the art, and alternative methods (e.g., use of protecting groups or alternative reactions) are suggested accordingly. Protecting group chemistry and strategies are well known in the art, as detailed, for example, in "Protecting Groups in Organic Synthesis," T.W. Greene and P.G.M. Butts, 3rd edition, John Wiley & Sons, 1999, the entire contents of which are incorporated herein by reference. The starting materials in the schemes are either commercially available or readily prepared from known materials using standard methods by one skilled in the art of organic synthesis.

[0111] General principles of organic chemistry and synthesis well known in the art are described, for example, in "Organic Chemistry", Thomas Sorrell, University Science Books, Sausalito: 1999; "March's Advanced Organic Chemistry", 5th Ed., Ed.: Smith, M.B. and March, J., John Wiley & Sons, New York: 2001; and "Comprehensive Organic Synthesis", 2nd Ed., Ed.: Knochel, P. and Molander, G.A., Elsevier, Amsterdam: 2014, the entire contents of each of which are incorporated herein by reference. For example, certain embodiments below refer to leaving groups. Suitable leaving groups are well known in the art, for example, as described in the aforementioned references. Such leaving groups include, but are not limited to, halogen, alkoxy, sulfonyloxy, optionally substituted alkylsulfonyloxy, optionally substituted alkenylsulfonyloxy, optionally substituted arylsulfonyloxy, and diazonium moieties. Examples of suitable leaving groups include chloro, iodo, bromo, fluoro, methanesulfonyl (mesyl), tosyl, triflate, nitro-phenylsulfonyl (nosyl), and bromo-phenylsulfonyl (brosyl).

[0112] Scheme 1 [ka] In some embodiments, compounds of Formula I are prepared by the coupling reaction depicted in Scheme 1 above, wherein LG is a leaving group and X, n, R 1 , R 2 , R 3 , and R 4 are each independently as defined in an embodiment herein, and R 1 , R 2 , R 3 , and R 4 Each of optionally and independently includes a protecting group.

[0113] Scheme 2 [ka] In some embodiments, compounds of Formula I are prepared by the coupling reaction depicted in Scheme 2 above, wherein LG is a leaving group and X, n, R 1 , R 2 , R 3 , and R 4 are each independently as defined in an embodiment herein, and R 1 , R 2 , R 3 , and R 4 Each of optionally and independently includes a protecting group.

[0114] 4. Formulation and Administration 4.1 Pharmaceutically Acceptable Compositions According to another embodiment, the present invention provides a composition comprising a compound of the present invention, 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 invention is such that it is effective to measurably inhibit eIF4E or a variant thereof in a biological sample or in a patient. In certain embodiments, the amount of the compound in the composition of the present invention is such that it is effective to measurably inhibit eIF4E or a variant thereof in a biological sample or in a patient. In certain embodiments, the composition of the present invention is formulated for administration to a patient in need of such a composition. In some embodiments, the composition of the present invention is formulated for oral administration to a patient.

[0115] In some embodiments, the present invention provides a pharmaceutical composition comprising a compound of formula (I), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, adjuvant, or vehicle.

[0116] In some embodiments, the present invention provides a pharmaceutical composition comprising a compound of Formula (II)-(VII), (II-a)-(VII-a), (II-b)-(VII-b), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, adjuvant, or vehicle.

[0117] In some embodiments, the present invention provides a pharmaceutical composition comprising a compound of Table 1, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, adjuvant, or vehicle.

[0118] In some embodiments, the compounds of the invention or pharmaceutically acceptable derivatives or compositions thereof are administered in a single composition as a single dosage form.

[0119] The term "patient", as used herein, means an animal, preferably a mammal, and most preferably a human.

[0120] 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 with which it is formulated. Pharmaceutically acceptable carriers, adjuvants, or vehicles that can be used in the compositions of the present invention include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins such as human serum albumin, buffer substances such as phosphates, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, salts or electrolytes such as zinc salts, colloidal silica, magnesium trisilicate, polyvinylpyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethylcellulose, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, polyethylene glycol, and wool fat.

[0121] "Pharmaceutically acceptable derivative" means any non-toxic salt, ester, salt of an ester, or other derivative of a compound of the present invention which, upon administration to a recipient, is capable of providing, either directly or indirectly, the compound of the present invention or a metabolite or residue thereof which has inhibitory activity.

[0122] As used herein, the term "inhibitorily active metabolite or residue thereof" means that the metabolite or residue thereof is also an inhibitor of eIF4E or a mutant thereof.

[0123] The compositions of the present invention may be administered orally, parenterally, by inhalation spray, topically, rectally, nasally, buccally, vaginally, or via an implanted reservoir. As used herein, the term "parenteral" includes subcutaneous, intravenous, intramuscular, intra-articular, intrasynovial, intrasternal, intrathecal, intrahepatic, intralesional, and intracranial injection or infusion techniques. Preferably, the compositions are administered orally, intraperitoneally, or intravenously. Sterile injectable forms of the compositions of the present invention may be aqueous or oily suspensions. These suspensions may be formulated according to techniques known in the art using suitable dispersing or wetting agents and suspending agents. Sterile injectable preparations may also be sterile injectable solutions or suspensions in non-toxic parenterally acceptable diluents or solvents, for example, as solutions in 1,3-butanediol. Among the acceptable vehicles and solvents that may be used are water, Ringer's solution, and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally used as solvents or suspending media.

[0124] For this purpose, any bland fixed oil may be used, including synthetic mono- or diglycerides. Fatty acids such as oleic acid and its glyceride derivatives are useful for preparing injectables, as are natural pharmaceutically acceptable oils such as olive oil or castor oil, especially in their polyoxyethylated versions. These oil solutions or suspensions may also contain long-chain alcohol diluents or dispersants, such as carboxymethylcellulose or similar dispersants, which are commonly used to formulate pharmaceutically acceptable dosage forms, including emulsions and suspensions. Other commonly used surfactants, such as Tween®, Span®, and other emulsifiers or bioavailability enhancers, commonly used in the manufacture of pharmaceutically acceptable solid, liquid, or other dosage forms, may also be used for formulation purposes.

[0125] The pharmaceutically acceptable composition of the present invention can be orally administered in any orally acceptable dosage form, including but not limited to capsules, tablets, aqueous suspensions or aqueous solutions.For tablets intended for oral use, commonly used carriers include lactose and corn starch.Lubricants such as magnesium stearate are also typically added.For oral administration in capsule form, useful diluents include lactose and dried corn starch.When aqueous suspensions are required for oral use, active ingredients are combined with emulsifiers and suspending agents.If desired, certain sweeteners, flavorings or coloring agents can also be added.

[0126] Alternatively, the pharmaceutically acceptable compositions of the present invention may be administered in the form of suppositories for rectal administration. These can be prepared by mixing the drug with a suitable non-irritating excipient that is solid at room temperature but liquid at rectal temperature, thereby melting in the rectum and releasing the drug. Such materials include cocoa butter, beeswax, and polyethylene glycol.

[0127] The pharmaceutically acceptable compositions of this invention 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, the skin, or the lower intestinal tract. Suitable topical formulations are readily prepared for each of these areas or organs.

[0128] Topical application for the lower intestinal tract can be effected in a rectal suppository formulation (see above) or in a suitable enema formulation. Topical transdermal patches may also be used.

[0129] For topical application, the provided pharmaceutically acceptable composition may be formulated in a suitable ointment containing the active ingredient suspended or dissolved in one or more carriers.Carriers for topical administration of the compounds of the present invention include, but are not limited to, mineral oil, liquid petrolatum, white petrolatum, propylene glycol, polyoxyethylene, polyoxypropylene compounds, emulsifying wax, and water.Alternatively, the provided pharmaceutically acceptable composition may be formulated in a suitable lotion or cream containing the active ingredient suspended or dissolved in one or more pharmaceutically acceptable carriers.Suitable carriers include, but are not limited to, mineral oil, sorbitan monostearate, polysorbate 60, cetyl esters wax, cetearyl alcohol, 2-octyldodecanol, benzyl alcohol, and water.

[0130] For ophthalmic use, the provided pharmaceutically acceptable compositions may be formulated as a micronized suspension in isotonic, pH-adjusted, sterile saline, with or without a preservative such as benzylalkonium chloride, or preferably as a solution in isotonic, pH-adjusted, sterile saline. Alternatively, for ophthalmic use, the pharmaceutically acceptable compositions may be formulated in an ointment such as petrolatum.

[0131] The pharmaceutically acceptable compositions of this invention 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 as solutions in saline using benzyl alcohol or other suitable preservatives, absorption enhancers to enhance bioavailability, fluorocarbons, and / or other conventional solubilizing or dispersing agents.

[0132] Most preferably, the pharmaceutically acceptable compositions of the present invention are formulated for oral administration. Such formulations may be administered with or without food. In some embodiments, the pharmaceutically acceptable compositions of the present invention are administered without food. In other embodiments, the pharmaceutically acceptable compositions of the present invention are administered with food.

[0133] The amount of the compounds of the present invention that can be combined with the carrier materials to produce a composition in a single dosage form will vary depending upon the host being treated, the particular mode of administration, etc. Preferably, the compositions provided should be formulated so that a patient receiving these compositions can be administered a dosage of 0.01 to 100 mg / kg body weight / day of the inhibitor.

[0134] It should also be understood that the specific dosage and treatment regimen for any particular patient will depend on a variety of factors, including the activity of the specific compound employed, the age, body weight, general health, sex, diet, time of administration, rate of excretion, drug combination, as well as the judgment of the treating physician and the severity of the particular disease being treated. The amount of a compound of the invention in a composition will also depend on the particular compound in the composition.

[0135] 4.2. Co-administration with One or More Other Therapeutic Agents Depending on the particular condition, or disease, being treated, additional therapeutic agents, which are normally administered to treat that condition, may also be present in the compositions of this invention. As used herein, additional therapeutic agents that are normally administered to treat a particular disease, or condition, are known as "appropriate for the disease, or condition, being treated."

[0136] In some embodiments, the present invention provides a method for treating a disclosed disease or condition, the method comprising administering to a patient in need thereof an effective amount of a compound disclosed herein or a pharmaceutically acceptable salt thereof and simultaneously or sequentially co-administering an effective amount of one or more additional therapeutic agents (such as those described herein). In some embodiments, the method comprises co-administering one additional therapeutic agent. In some embodiments, the method comprises co-administering two additional therapeutic agents. In some embodiments, the combination of the disclosed compound and the additional therapeutic agent(s) acts synergistically.

[0137] The compounds of the present invention may also be used in combination with known therapeutic processes, such as the administration of hormones or radiation. In certain embodiments, provided compounds are used as radiosensitizers, especially for the treatment of tumors that exhibit insufficient sensitivity to radiation therapy.

[0138] The compound of the present invention can be administered alone or in combination with one or more other therapeutic compounds, and possible combination therapy can be in the form of a fixed combination of the compound of the present invention and one or more other therapeutic compounds, or administration that is time-delayed or administered independently, or a fixed combination and the combined administration of one or more other therapeutic compounds.Otherwise or in addition, the compound of the present invention can be administered in combination with chemotherapy, radiotherapy, immunotherapy, phototherapy, surgical intervention, or a combination thereof, especially for tumor treatment.In the context of other therapeutic strategies such as those mentioned above, long-term therapy is equally possible, as is adjuvant therapy.Other possible treatments are therapy to maintain the patient's condition after tumor regression, or even, for example, chemoprevention therapy in patients at risk.

[0139] One or more other therapeutic agents may be administered separately from the compound or composition of the present invention as part of a multiple dose regimen. Alternatively, one or more other therapeutic agents may be part of a single dosage form, mixed together with the compound of the present invention in a single composition. When administered as a multiple dose regimen, one or more other therapeutic agents and the compound or composition of the present invention may be administered simultaneously, sequentially, or within a period of time from each other, for example, within 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 18, 20, 21, 22, 23, or 24 hours from each other. In some embodiments, one or more other therapeutic agents and the compound or composition of the present invention are administered within an interval of more than 24 hours as a multiple dose regimen.

[0140] As used herein, the terms "combination," "combined," and related terms refer to simultaneous or sequential administration of therapeutic agents according to the present invention. For example, a compound of the present invention may be administered together with one or more other therapeutic agents in separate unit dosage forms or in a single unit dosage form, simultaneously or sequentially. Thus, the present invention provides a single unit dosage form comprising a compound of the present invention, one or more other therapeutic agents, and a pharmaceutically acceptable carrier, adjuvant, or vehicle.

[0141] The amount of a compound of the invention and one or more other therapeutic agents (in compositions containing additional therapeutic agents, as described above) that may be combined with the carrier materials to produce a single dosage form will vary depending upon the host treated and the particular mode of administration. Preferably, the compositions of the invention should be formulated so that a dosage of 0.01 to 100 mg / kg body weight / day of the compound of the invention can be administered.

[0142] In these compositions containing one or more other therapeutic agents, the one or more other therapeutic agents and the compound of the present invention 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 that therapeutic agent. In such compositions, a dosage of 0.01 to 1,000 μg / kg body weight / day of one or more other therapeutic agents may be administered.

[0143] The amount of one or more other therapeutic agents present in the compositions of the present invention may be less than or equal to the amount that would normally be administered in a composition comprising that therapeutic agent as the only active agent. Preferably, the amount of one or more other therapeutic agents in the compositions of the present disclosure will be in the range of about 50% to 100% of the amount that would normally be present in a composition comprising that agent as the only therapeutically active agent. In some embodiments, the one or more other therapeutic agents are administered at a dosage that is about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, or about 95% of the amount normally administered for that agent. As used herein, the phrase "normally administered" refers to the amount of an FDA-approved therapeutic agent approved for administration according to the FDA label insert.

[0144] The compounds of the present invention or pharmaceutical compositions thereof 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 are used to overcome restenosis (re-narrowing of the blood vessel wall after injury). However, patients who use stents or other implantable devices run the risk of clot formation or platelet activation. These undesirable effects can be prevented or mitigated by pre-coating the device with a pharmaceutically acceptable composition containing a kinase inhibitor. An implantable device coated with the compounds of the present invention is another embodiment of the present invention.

[0145] 4.2.1. Exemplary Other Therapeutic Agents In some embodiments, the one or more other therapeutic agents is a poly ADP-ribose polymerase (PARP) inhibitor. In some embodiments, the PARP inhibitor is selected from olaparib (Lynparza®, AstraZeneca), rucaparib (Rubraca®, Clovis Oncology), niraparib (Zejula®, Tesaro), talazoparib (MDV3800 / BMN 673 / LT00673, Medivation / Pfizer / Biomarin), veliparib (ABT-888, AbbVie), and BGB-290 (BeiGene, Inc.).

[0146] In some embodiments, the one or more other therapeutic agents is a histone deacetylase (HDAC) inhibitor. In some embodiments, the HDAC inhibitor is selected from vorinostat (Zolinza®, Merck), romidepsin (Istodax®, Celgene), panobinostat (Farydak®, Novartis), belinostat (Beleodaq®, Spectrum Pharmaceuticals), entinostat (SNDX-275, Syndax Pharmaceuticals) (NCT00866333), and chidamide (Epidaza®, HBI-8000, Chipscreen Biosciences, China).

[0147] In some embodiments, the one or more other therapeutic agents is a CDK inhibitor, such as a CDK4 / CDK6 inhibitor. In some embodiments, the CDK4 / 6 inhibitor is selected from palbociclib (Ibrance®, Pfizer), ribociclib (Kisqali®, Novartis), abemaciclib (Ly2835219, Eli Lilly), and trilaciclib (G1T28, G1 Therapeutics).

[0148] In some embodiments, the one or more other therapeutic agents is a phosphatidylinositol 3-kinase (PI3K) inhibitor. In some embodiments, the PI3K inhibitor is selected from idelalisib (Zydelig®, Gilead), alpelisib (BYL719, Novartis), taselisib (GDC-0032, Genentech / Roche), pictilisib (GDC-0941, Genentech / Roche), copanlisib (BAY806946, Bayer), duvelisib (formerly IPI-145, Infinity Pharmaceuticals), PQR309 (Piqur Therapeutics, Switzerland), and TGR1202 (formerly RP5230, TG Therapeutics).

[0149] In some embodiments, the one or more other therapeutic agents are platinum-based therapeutic agents, also known as platins. Platins cause cross-linking of DNA such that they inhibit DNA repair and / or DNA synthesis, primarily in rapidly replicating cells such as cancer cells. In some embodiments, the platinum-based therapeutic agent is selected from cisplatin (Platinol®, Bristol-Myers Squibb), carboplatin (Paraplatin®, Bristol-Myers Squibb; also Teva; Pfizer), oxaliplatin (Eloxitin®, Sanofi-Aventis), nedaplatin (Aqupla®, Shionogi), picoplatin (Poniard Pharmaceuticals), and satraplatin (JM-216, Agennix).

[0150] In some embodiments, the one or more other therapeutic agents are taxane compounds that cause disruption of microtubules, which are essential for cell division. In some embodiments, the taxane compounds are selected from paclitaxel (Taxol®, Bristol-Myers Squibb), docetaxel (Taxotere®, Sanofi-Aventis; Docefrez®, Sun Pharmaceutical), albumin-bound paclitaxel (Abraxane®, Abraxis / Celgene), cabazitaxel (Jevtana®, Sanofi-Aventis), and SID530 (SK Chemicals, Co.) (NCT00931008).

[0151] In some embodiments, the one or more other therapeutic agents are nucleoside inhibitors, i.e., therapeutic agents that interfere with normal DNA synthesis, protein synthesis, cell replication, or otherwise inhibit rapidly proliferating cells.

[0152] In some embodiments, the nucleoside inhibitor is trabectedin (a guanidine alkylating agent, Yondelis®, Janssen Oncology), mechlorethamine (an alkylating agent, Valchlor®, Aktelion Pharmaceuticals), vincristine (Oncovin®, Eli Lilly; Vincasar®, Teva Pharmaceuticals; Marqibo®, Talon Therapeutics), temozolomide (a prodrug of the alkylating agent 5-(3-methyltriazen-1-yl)-imidazole-4-carboxamide (MTIC), Temodar®, Merck), cytarabine injection (ara-C, an antimetabolite cytidine analog, Pfizer), lomustine (an alkylating agent, CeeNU®, Bristol-Myers Squibb; Gleostine®, NextSource), or vincristine (an alkylating agent, CeeNU®, Bristol-Myers Squibb; Gleostine®, NextSource). Biotechnology), azacitidine (a pyrimidine nucleoside analogue of cytidine, Vidaza®, Celgene), omacetaxine mepesuccinate (cephalotaxine ester) (a protein synthesis inhibitor, Synribo®, Teva Pharmaceuticals), asparaginase Erwinia chrysanthemi (an enzyme for asparagine depletion, Elspar®, Lundbeck;Erwinaze®, EUSA Pharma), eribulin mesylate (microtubule inhibitor, tubulin-based antimitotic agent, Halaven®, Eisai), cabazitaxel (microtubule inhibitor, tubulin-based antimitotic agent, Jevtana®, Sanofi-Aventis), capacetrine (thymidylate synthase inhibitor, Xeloda®, Genentech), bendamustine (bifunctional mechlorethamine derivative, thought to form DNA interstrand crosslinks, Treanda®, Cephalon / Teva), ixabepilone (semi-synthetic analogue of epothilone B, microtubule inhibitor, tubulin-based antimitotic agent, Ixempra®, Bristol-Myers Squibb), nelarabine (prodrug of a deoxyguanosine analog, a nucleoside metabolic inhibitor, Arranon®, Novartis), clorafabine (prodrug of a ribonucleotide reductase inhibitor, a competitive inhibitor of deoxycytidine, Clolar®, Sanofi-Aventis), and trifluridine and tipiracil (thymidine-based nucleoside analog and thymidine phosphorylase inhibitor, Lonsurf®, Taiho Oncology);

[0153] In some embodiments, the one or more other therapeutic agents are kinase inhibitors or VEGF-R antagonists. Approved VEGF inhibitors and kinase inhibitors useful in the present invention include the anti-VEGF monoclonal antibody bevacizumab (Avastin®, Genentech / Roche), the anti-VEGFR-2 antibody ramucirumab (Cyramza®, Eli Lilly), and ziv-aflibercept, also known as VEGF trap (Zaltrap®, Regeneron / Sanofi). VEGFR inhibitors such as regorafenib (Stivarga®, Bayer), vandetanib (Caprelsa®, AstraZeneca), axitinib (Inlyta®, Pfizer), and lenvatinib (Lenvima®, Eisai); sorafenib (Nexavar®, Bayer); Raf inhibitors such as AG and Onyx), dabrafenib (Tafinlar®, Novartis), and vemurafenib (Zelboraf®, Genentech / Roche); MEK inhibitors such as cobimetanib (Cotellic®, Exelexis / Genentech / Roche) and trametinib (Mekinist®, Novartis); Bcr-Abl tyrosine kinase inhibitors such as imatinib (Gleevec®, Novartis), nilotinib (Tasigna®, Novartis), dasatinib (Sprycel®, BristolMyersSquibb), bosutinib (Bosulif®, Pfizer), and ponatinib (Inclusig®, Ariad Pharmaceuticals);Gefitinib (Iressa®, AstraZeneca), erlotinib (Tarceeva®, Genentech / Roche / Astellas), lapatinib (Tykerb®, Novartis), afatinib (Gilotrif®, Boehringer Ingelheim), osimertinib (targeting activated EGFR, Tagrisso®, AstraZeneca), and brigatinib (Alunbrig®, Ariadne) are currently being investigated. Her2 and EGFR inhibitors such as Cabozanitib (Cometriq®, Exelexis); c-Met and VEGFR2 inhibitors such as Cabozanitib (Cometriq®, Exelexis); and multi-targeted kinase inhibitors such as sunitinib (Sutent®, Pfizer), pazopanib (Votrient®, Novartis); ALK inhibitors such as crizotinib (Xalkori®, Pfizer), ceritinib (Zykadia®, Novartis), and alectinib (Alecenza®, Genentech / Roche); Bruton's tyrosine kinase inhibitors such as ibrutinib (Imbruvica®, Pharmacyclics / Janssen); and Flt3 receptor inhibitors such as midostaurin (Rydapt®, Novartis).

[0154] Other kinase inhibitors and VEGF-R antagonists in development that may be used in the present invention include tivozanib (Aveo Pharmaceuticals), vatalanib (Bayer / Novartis), lucitanib (Clovis Oncology), dovitinib (TKI258, Novartis), chiauanib (Chipscreen Biosciences), CEP-11981 (Cephalon), linifanib (Abbott Laboratories), neratinib (HKI-272, Puma Biotechnology), radotinib (Supect®, IY5511, Il-Yang Pharmaceuticals, S.Korea), ruxolitinib (Jakafi®, Incyte Corporation), PTC299 (PTC Therapeutics), CP-547,632 (Pfizer), foretinib (Exelexis, GlaxoSmithKline), quizartinib (Daiichi Sankyo), and motesanib (Amgen / Takeda).

[0155] In some embodiments, the one or more other therapeutic agents are mTOR inhibitors that inhibit cell proliferation, angiogenesis, and glucose uptake. In some embodiments, the mTOR inhibitor is everolimus (Afinitor®, Novartis), temsirolimus (Torisel®, Pfizer), and sirolimus (Rapamune®, Pfizer).

[0156] In some embodiments, the one or more other therapeutic agents is a proteasome inhibitor. Approved proteasome inhibitors useful in the present invention include bortezomib (Velcade®, Takeda), carfilzomib (Kyprolis®, Amgen), and ixazomib (Ninlaro®, Takeda).

[0157] In some embodiments, the one or more other therapeutic agents are growth factor antagonists, such as antagonists 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 invention include olaratumab (Lartruvo®, Eli Lilly). Approved EGFR antagonists that can be used in the present invention include cetuximab (Erbitux®, Eli Lilly), necitumumab (Portrazza®, Eli Lilly), panitumumab (Vectibix®, Amgen), and osimertinib (targeting activated EGFR, Tagrisso®, AstraZeneca).

[0158] In some embodiments, the one or more other therapeutic agents is an aromatase inhibitor, hi some embodiments, the aromatase inhibitor is selected from exemestane (Aromasin®, Pfizer), anastrozole (Arimidex®, AstraZeneca), and letrozole (Femara®, Novartis).

[0159] In some embodiments, the one or more other therapeutic agents are hedgehog pathway antagonists. Approved hedgehog pathway inhibitors that may be used in the present invention include sonidegib (Odomzo®, Sun Pharmaceuticals) and vismodegib (Erivedge®, Genentech), both for the treatment of basal cell carcinoma.

[0160] In some embodiments, the one or more other therapeutic agents is a folate inhibitor. Approved folate inhibitors useful in the present invention include pemetrexed (Alimta®, Eli Lilly).

[0161] In some embodiments, the one or more other therapeutic agents are CC chemokine receptor 4 (CCR4) inhibitors. CCR4 inhibitors under investigation that may be useful in the present invention include mogamulizumab (Poteligeo®, Kyowa Hakko Kirin, Japan).

[0162] In some embodiments, the one or more other therapeutic agents are isocitrate dehydrogenase (IDH) inhibitors. IDH inhibitors under investigation that can be used in the present invention include AG120 (Celgene, NCT02677922), AG221 (Celgene, NCT02677922, NCT02577406), BAY1436032 (Bayer, NCT02746081), and IDH305 (Novartis, NCT02987010).

[0163] In some embodiments, the one or more other therapeutic agents are arginase inhibitors. Arginase inhibitors currently being investigated that can be used in the present invention include AEB1102 (pegylated recombinant arginase, Aeglea Biotherapeutics), which is currently being investigated in Phase 1 clinical trials for acute myeloid leukemia and myelodysplastic syndrome (NCT02732184) and solid tumors (NCT02561234), and CB-1158 (Calithera Biosciences).

[0164] In some embodiments, the one or more other therapeutic agents are glutaminase inhibitors. Glutaminase inhibitors under investigation that can be used in the present invention include CB-839 (Calithera Biosciences).

[0165] In some embodiments, the one or more other therapeutic agents are antibodies that bind to tumor antigens, i.e., proteins expressed on the cell surface of tumor cells. Approved antibodies that bind to tumor antigens that can be used in the present invention include rituximab (Rituxan®, Genentech / BiogenIdec), ofatumumab (anti-CD20, Arzerra®, GlaxoSmithKline), obinutuzumab (anti-CD20, Gazyva®, Genentech), ibritumomab (anti-CD20 and yttrium-90, Zevalin®, Spectrum Pharmaceuticals), daratumumab (anti-CD38, Darzalex®, Janssen Biotech), dinutuximab (anti-glycolipid GD2, Unituxin®, United Therapeutics), trastuzumab (anti-HER2, Herceptin®, Genentech), ado-trastuzumab emtansine (anti-HER2, fused to emtansine, Kadcyla®, Genentech), and pertuzumab (anti-HER2, Perjeta®, Genentech), and brentuximab vedotin (anti-CD30-drug conjugate, Adcetris®, Seattle Genetics).

[0166] In some embodiments, the one or more other therapeutic agents are topoisomerase inhibitors. Approved topoisomerase inhibitors useful in the present invention include irinotecan (Onivyde®, Merrimack Pharmaceuticals) and topotecan (Hycamtin®, GlaxoSmithKline). Topoisomerase inhibitors under investigation that may be used in the present invention include pixantrone (Pixuvri®, CTI Biopharma).

[0167] In some embodiments, the one or more other therapeutic agents are inhibitors of anti-apoptotic proteins, such as BCL-2. Approved anti-apoptotic drugs that may be used in the present invention include venetoclax (Venclexta®, AbbVie / Genentech) and blinatumomab (Blincyto®, Amgen). Other therapeutic agents that target apoptotic proteins that are undergoing clinical trials and may be used in the present invention include navitoclax (ABT-263, Abbott), a BCL-2 inhibitor (NCT02079740).

[0168] In some embodiments, the one or more other therapeutic agents are androgen receptor inhibitors. Approved androgen receptor inhibitors useful in the present invention include enzalutamide (Xtandi®, Astellas / Medivation), approved inhibitors of androgen synthesis include abiraterone (Zytiga®, Centocor / Ortho), and approved gonadotropin-releasing hormone (GnRH) receptor antagonists (degarelix, Firmagon®, Ferring Pharmaceuticals).

[0169] In some embodiments, the one or more other therapeutic agents are selective estrogen receptor modulators (SERMs), which interfere with the synthesis or activity of estrogen. Approved SERMs useful in the present invention include raloxifene (Evista®, Eli Lilly).

[0170] In some embodiments, the one or more other therapeutic agents are inhibitors of bone resorption. An approved therapeutic agent that inhibits bone resorption is denosumab (Xgeva®, Amgen), an antibody that binds to RANKL and prevents it from binding to its receptor RANK, found on the surface of osteoclasts, their precursors, and osteoclast-like giant cells, which mediates bone lesions in solid tumors with bone metastases. Other approved therapeutic agents that inhibit bone resorption include bisphosphonates, such as zoledronic acid (Zometa®, Novartis).

[0171] In some embodiments, the one or more other therapeutic agents are inhibitors of the interaction between MDMX and MDM2, two major p53 inhibitor proteins. Investigative inhibitors of p53 inhibitor proteins that may be used in the present invention include ALRN-6924 (Aileron), a stapled peptide that binds equipotently to MDMX and MDM2 and disrupts their interaction with p53. ALRN-6924 is currently being evaluated in clinical trials for the treatment of AML, advanced myelodysplastic syndrome (MDS), and peripheral T-cell lymphoma (PTCL) (NCT02909972, NCT02264613).

[0172] In some embodiments, the one or more other therapeutic agents are inhibitors of transforming growth factor-beta (TGF-beta or TGFβ). Investigative inhibitors of TGF-beta proteins that may be used in the present invention include NIS793 (Novartis), an anti-TGF-beta antibody currently being tested in clinical settings for the treatment of various cancers, including breast cancer, lung cancer, hepatocellular carcinoma, colorectal cancer, pancreatic cancer, prostate cancer, and renal cancer (NCT02947165). In some embodiments, the TGF-beta protein inhibitor is fresolimumab (GC1008, Sanofi-Genzyme), currently being studied for melanoma (NCT00923169), renal cell carcinoma (NCT00356460), and non-small cell lung cancer (NCT02581787). Furthermore, in some embodiments, the additional therapeutic agent is a TGF-beta trap, e.g., as described in Connolly et al. (2012) Int'l J. Biological Sciences 8:964-978. One therapeutic compound currently in clinical trials for the treatment of solid tumors is M7824 (Merck KgaA, formerly MSB0011459X), a bispecific anti-PD-L1 / TGFβ trap compound (NCT02699515) and (NCT02517398). M7824 consists of a fully human IgG1 antibody against PD-L1 fused to the extracellular domain of human TGF-beta receptor II, which functions as a TGFβ "trap."

[0173] In some embodiments, the one or more other therapeutic agents are selected from glembatumumab vedotin-monomethyl auristatin E (MMAE) (Celldex), an anti-glycoprotein NMB (gpNMB) antibody linked to a cytotoxic MMAE (CR011). gpNMB is a protein overexpressed in multiple tumor types that is associated with the ability of cancer cells to metastasize.

[0174] In some embodiments, the one or more other therapeutic agents are antiproliferative compounds. Such antiproliferative compounds include 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, antitumor antimetabolites, platin compounds, compounds that target / reduce protein or lipid kinase activity and further antiangiogenic compounds, compounds that target, reduce or inhibit the activity of protein or lipid phosphatases, gonadorelin agonists, antiandrogens, methionine aminopeptidase inhibitors; matrix metalloproteinase inhibitors; bisphosphonates; biological response modifiers; antiproliferative antibodies; heparanase inhibitors; inhibitors of oncogenic Ras isoforms; telomerase inhibitors; proteasome inhibitors; compounds used in the treatment of hematologic malignancies; compounds that target, decrease, or inhibit the activity of Flt-3; 17-AAG (17-allylaminogeldanamycin, NSC330507), 17-DMAG (17-dimethylaminoethylamino-17-demethoxy-geldanamycin, NSC707545), IPI-504, CNF1010, CNF2024, CNF1010 (Conforma Hsp90 inhibitors such as temozolomide (Temodal®) from GlaxoSmithKline; kinesin spindle protein 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.

[0175] The term "aromatase inhibitor" as used herein refers to compounds that inhibit estrogen production, for example, the conversion of the substrates androstenedione and testosterone to estrone and estradiol, respectively. This term includes, but is not limited to, steroids, particularly atamestane, exemestane, and formestane, and nonsteroids, particularly aminoglutethimide, rogletimide, pyridoglutethimide, trilostane, testolactone, ketoconazole, vorozole, fadrozole, anastrozole, and letrozole. Exemestane is marketed under the trade name Aromasin™. Formestane is marketed under the trade name Lentaron™. Fadrozole is marketed under the trade name Afema™. Anastrozole is marketed under the trade name Arimidex™. Letrozole is marketed under the trade name Femara™ or Femar™. Aminoglutethimide is marketed under the trade name Orimeten™. Combinations of the present invention that include a chemotherapeutic agent that is an aromatase inhibitor are particularly useful in the treatment of hormone receptor positive tumors, such as breast tumors.

[0176] The term "antiestrogen" as used herein refers to a compound that antagonizes the action of estrogen at the estrogen receptor level. This term includes, but is not limited to, tamoxifen, fulvestrant, raloxifene, and raloxifene hydrochloride. Tamoxifen is marketed under the trade name Nolvadex™. Raloxifene hydrochloride is marketed under the trade name Evista™. Fulvestrant may be administered under the trade name Faslodex™. The combinations of the present invention, which include chemotherapeutic agents that are antiestrogens, are particularly useful in treating estrogen receptor-positive tumors, such as breast tumors.

[0177] The term "antiandrogen" as used herein refers to any substance capable of inhibiting the biological effects of androgen hormones, including, but not limited to, bicalutamide (Casodex™). The term "gonadorelin agonist" as used herein includes, but is not limited to, abarelix, goserelin, and goserelin acetate. Goserelin may be administered under the trade name Zoladex™.

[0178] As used herein, the term "topoisomerase I inhibitor" includes, but is not limited to, topotecan, gimatecan, irinotecan, camptothecin and its analogs, 9-nitrocamptothecin, and the polymeric camptothecin conjugate PNU-166148. Irinotecan can be administered, for example, in the form as manufactured and marketed, for example, under the trademark Camptosar™. Topotecan is manufactured and marketed under the trademark Hycamptin™.

[0179] The term "topoisomerase II inhibitors" as used herein includes, but is not limited to, doxorubicin (including liposomal formulations such as Caelyx™), anthracyclines such as daunorubicin, epirubicin, idarubicin, and nemorubicin, the anthraquinones mitoxantrone and losoxantrone, and the podophyllotoxins etoposide and teniposide. Etoposide is marketed under the trade name Etopophos™. Teniposide is marketed under the trade name VM26-Bristol. Doxorubicin is marketed under the trade names Acriblastin™ or Adriamycin™. Epirubicin is marketed under the trade name Farmorubicin™. Idarubicin is marketed under the trade name Zavedos™. Mitoxantrone is marketed under the trade name Novantron™.

[0180] The term "microtubule active agent" refers to microtubule stabilizing compounds, microtubule destabilizing compounds, and microtubulin 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; discodermolide; colchicine and epothilones and their derivatives. Paclitaxel is marketed under the trade name Taxol™. Docetaxel is marketed under the trade name Taxotere™. Vinblastine sulfate is marketed under the trade name Vinblastin RP™. Vincristine sulfate is marketed under the trade name Farmistin™.

[0181] The term "alkylating agent" as used herein includes, but is not limited to, cyclophosphamide, ifosfamide, melphalan, or nitrosoureas (BCNU or Gliadel). Cyclophosphamide is marketed under the trade name Cyclostin™. Ifosfamide is marketed under the trade name Holoxan™.

[0182] The term "histone deacetylase inhibitors" or "HDAC inhibitors" relates to compounds which inhibit histone deacetylase and which possess antiproliferative activity, including, but not limited to, suberoylanilide hydroxamic acid (SAHA).

[0183] The term "antineoplastic antimetabolite" includes, but is not limited to, 5-fluorouracil or 5-FU, DNA demethylating compounds such as capecitabine, gemcitabine, 5-azacytidine, and decitabine, methotrexate and edatrexate, and folate antagonists such as pemetrexed. Capecitabine is marketed under the trade name Xeloda™. Gemcitabine is marketed under the trade name Gemzar™.

[0184] The term "platin compound" as used herein includes, but is not limited to, carboplatin, cis-platin, cisplatinum, and oxaliplatin. For example, carboplatin can be administered, for example, in the form as it is manufactured and marketed under the trademark Carboplat™. For example, oxaliplatin can be administered, for example, in the form as it is manufactured and marketed under the trademark Eloxatin™.

[0185] The term "compounds which target / reduce protein or lipid kinase activity, or protein or lipid phosphatase activity, or further anti-angiogenic compounds" as used herein includes protein tyrosine kinase and / or serine and / or threonine kinase inhibitors or lipid kinase inhibitors, such as a) compounds which target, reduce or inhibit the activity of platelet-derived growth factor receptors (PDGFR), e.g. compounds which target, reduce or inhibit the activity of PDGFR, especially PDGF receptors; a) compounds which target, reduce or inhibit the activity of fibroblast growth factor receptors (FGFRs), e.g., N-phenyl-2-pyrimidine-amine derivatives, e.g., imatinib, SU101, SU6668, and GFB-111; b) compounds which target, reduce or inhibit the activity of fibroblast growth factor receptors (FGFRs); c) compounds which target, reduce or inhibit the activity of insulin-like growth factor receptor I (IGF-IR), e.g., compounds which target, reduce or inhibit the activity of IGF-IR, especially compounds which inhibit the kinase activity of the IGF-I receptor, or IGF d) compounds which target, reduce or inhibit the activity of the Trk receptor tyrosine kinase family or ephrin B4 inhibitors; e) compounds which target, reduce or inhibit the activity of the AxI receptor tyrosine kinase family; f) compounds which target, reduce or inhibit the activity of the Ret receptor tyrosine kinase; g) compounds which target, reduce or inhibit the activity of the Kit / SCFR receptor tyrosine kinase, e.g. h) compounds which target, decrease or inhibit the activity of the C-kit receptor tyrosine kinase (which is part of the PDGFR family), for example compounds which target, decrease or inhibit the activity of the c-Kit receptor tyrosine kinase family, in particular compounds which inhibit the c-Kit receptor, for example imatinib; i) compounds which target, decrease or inhibit the activity of members of the c-Abl family, their gene fusion products (for example BCR-Abl kinase) and mutants, for examplecompounds that target, decrease, or inhibit the activity of c-Abl family members and their gene fusion products, such as N-phenyl-2-pyrimidine-amine derivatives, e.g., imatinib or nilotinib (AMN107); PD180970, AG957, NSC680410, PD173955 from ParkeDavis; or dasatinib (BMS-354825); j) members of the protein kinase C (PKC) and Raf families of serine / threonine kinases, MEK, SRC, JAK / pan-JAK, FAK, P Compounds that target, decrease, or inhibit the activity of members of the cyclin-dependent kinase family (CDK), including members of the DK1, PKB / Akt, Ras / MAPK, PI3K, SYK, TYK2, BTK, and TEC families, and / or staurosporine derivatives, e.g., midostaurin (further exemplary compounds include UCN-01, safingol, BAY43-9006, bryostatin 1, perifosine; llmofosine; RO318220 and RO320432; GO6976; lsis35 21; LY333531 / LY379196; isoquinoline compounds; FTIs; PD184352 or QAN697 (P13K inhibitors) or AT7519 (CDK inhibitors), k) compounds that target, decrease or inhibit the activity of protein tyrosine kinase inhibitors, such as imatinib mesylate (Gleevec™), or tyrphostins, such as tyrphostin A23 / RG-50810; AG99; tyrphostin AG213; tyrphostin AG1748; tyrphostin AG4 90; tyrphostin B44; tyrphostin B44 (+) enantiomer; tyrphostin AG555; AG494; tyrphostin AG556, AG957, and adaphostin (4-{[(2,5-dihydroxyphenyl)methyl]amino}-benzoic acid adamantyl ester; NSC680410, adaphostin), l) compounds that target, decrease, or inhibit the activity of protein tyrosine kinase inhibitors, including epidermal growth factor family receptor tyrosine kinases (EGFR1, ErbB2, ErbB3 as homo- or heterodimers,compounds that target, decrease, or inhibit the activity of members of the epidermal growth factor receptor family, especially compounds, proteins, or antibodies that inhibit members of the EGF receptor tyrosine kinase family, such as EGF receptor, ErbB2, ErbB3, and ErbB4, or that bind to EGF or EGF-related ligands, such as CP358774, ZD1839, ZM105180; trastuzumab (Herceptin™), cetethazolamide; ximab (Erbitux™), 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 which target, decrease or inhibit the activity of the c-Met receptor, for example compounds which target, decrease or inhibit the activity of c-Met, in particular compounds which inhibit the kinase activity of the c-Met receptor, or compounds which inhibit the extracellular domain of c-Met. n) antibodies that target or bind to HGF; n) compounds that target, decrease, or inhibit the kinase activity of one or more JAK family members (JAK1 / JAK2 / JAK3 / TYK2 and / or pan-JAK), including but not limited to PRT-062070, SB-1578, baricitinib, pacritinib, momelotinib, VX-509, AZD-1480, TG-101348, tofacitinib, and ruxolitinib; o) compounds that target, decrease, 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 ATU-027, SF-1126, DS-7423, PBI-05204, G q) compounds that target, decrease or inhibit the kinase activity of PI3 kinase (PI3K), including but not limited to SK-2126458, ZSTK-474, buparlisib, pictrelisib, PF-4691502, BYL-719, dactolisib, XL-147, XL-765, and idelalisib; and q) compounds that target, decrease or inhibit the kinase activity of PI3K, including but not limited to cyclopamine, vismodegib, itraconazole, erismodegib, and IPI-926 (saridegib),These include, but are not limited to, compounds that target, decrease, or inhibit the signaling effects of the Hedgehog (Hh) or Smoothened receptor (SMO) pathways.

[0186] As used herein, the term "PI3K inhibitor" includes, but is not limited to, compounds that have inhibitory activity against one or more enzymes in the phosphatidylinositol-3-kinase family, including, but not limited to, PI3K α, PI3K γ, PI3K δ, PI3K β, 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 invention include, but are not limited to, ATU-027, SF-1126, DS-7423, PBI-05204, GSK-2126458, ZSTK-474, buparlisib, pictrelisib, PF-4691502, BYL-719, dactolisib, XL-147, XL-765, and idelalisib.

[0187] As used herein, the term "Bcl-2 inhibitors" includes but is not limited to ABT-199, ABT-731, ABT-737, apogossypol, the pan-Bcl-2 inhibitors of Ascenta, curcumin (and its analogs), dual Bcl-2 / Bcl-xL inhibitors (Infinity Pharmaceuticals / Novartis Pharmaceuticals), Genasense (G3139), HA14-1 (and its analogs, see WO2008118802), navitoclax (and its analogs, see US7390799), NH-1 (Shenayng Pharmaceutical University), obatoclax (and its analogs, see WO2004106328), S-001 (Gloria Pharmaceuticals), the TW series of compounds (Univ. of Examples of compounds that have inhibitory activity against B-cell lymphoma 2 protein (Bcl-2) include, but are not limited to, compounds that have inhibitory activity against B-cell lymphoma 2 protein (Bcl-2), including, but not limited to, venetoclax ...

[0188] As used herein, the term "BTK inhibitor" includes, but is not limited to, compounds that have inhibitory activity against Bruton's tyrosine kinase (BTK), including, but not limited to, AVL-292 and ibrutinib.

[0189] As used herein, the term "SYK inhibitor" includes, but is not limited to, compounds that have inhibitory activity against spleen tyrosine kinase (SYK), including, but not limited to, PRT-062070, R-343, R-333, Excellair, PRT-062607, and fostamatinib.

[0190] Further examples of BTK inhibitor compounds, and conditions treatable by such compounds in combination with the compounds of the present invention, can be found in WO2008039218 and WO2011090760, which are incorporated herein by reference in their entireties.

[0191] Further examples of SYK inhibitor compounds, and conditions treatable by such compounds in combination with the compounds of the present invention, can be found in WO2003063794, WO2005007623, and WO2006078846, which are incorporated herein by reference in their entireties.

[0192] Further examples of PI3K inhibitor compounds, and conditions treatable by such compounds in combination with the compounds of the present invention, can be found in WO2004019973, WO2004089925, WO2007016176, US8138347, WO2002088112, WO2007084786, WO2007129161, WO2006122806, WO2005113554, and WO2007044729, the entire contents of which are incorporated herein by reference.

[0193] Further examples of JAK inhibitor compounds and conditions treatable by such compounds in combination with the compounds of the present invention can be found in WO2009114512, WO2008109943, WO2007053452, WO2000142246, and WO2007070514, the entire contents of which are incorporated herein by reference.

[0194] Additional anti-angiogenic compounds include compounds that have other mechanisms for their activity, eg, unrelated to protein or lipid kinase inhibition, such as thalidomide (Thalomid™) and TNP-470.

[0195] Examples of proteasome inhibitors useful in combination with the compounds of the invention include, but are not limited to, bortezomib, disulfiram, epigallocatechin-3-gallate (EGCG), salinosporamide A, carfilzomib, ONX-0912, CEP-18770, and MLN9708.

[0196] Compounds which target, decrease or inhibit the activity of a protein or lipid phosphatase are eg inhibitors of phosphatase 1, phosphatase 2A or CDC25, such as okadaic acid or a derivative thereof.

[0197] Compounds that induce cell differentiation processes include, but are not limited to, retinoic acid, α-, γ-, or δ-tocopherol, or α-, γ-, or δ-tocotrienol.

[0198] The term cyclooxygenase inhibitors as used herein includes, but is not limited to, Cox-2 inhibitors, 5-alkyl substituted 2-arylaminophenylacetic acids and derivatives, such as celecoxib (Celebrex™), rofecoxib (Vioxx™), etoricoxib, valdecoxib, or 5-alkyl-2-arylaminophenylacetic acids, such as 5-methyl-2-(2'-chloro-6'-fluoroanilino)phenylacetic acid, lumiracoxib.

[0199] The term "bisphosphonate" as used herein includes, but is not limited to, etidronic acid, clodronic acid, tiludronic acid, pamidronic acid, alendronic acid, ibandronic acid, risedronic acid, and zoledronic acid. Etidronic acid is marketed under the trade name Didronel™. Clodronic acid is marketed under the trade name Bonefos™. Tiludronic acid is marketed under the trade name Skelid™. Pamidronic acid is marketed under the trade name Aredia™. Alendronic acid is marketed under the trade name Fosamax™. Ibandronic acid is marketed under the trade name Bondranat™. Risedronic acid is marketed under the trade name Actonel™. Zoledronic acid is marketed under the trade name Zometa™. The term "mTOR inhibitors" relates to compounds which inhibit the mammalian target of rapamycin (mTOR) and which possess antiproliferative activity, such as sirolimus (Rapamune®), everolimus (Certican™), CCI-779, and ABT578.

[0200] As used herein, the term "heparanase inhibitor" refers to a compound that targets, reduces, or inhibits the degradation of heparin sulfate. This term includes, but is not limited to, PI-88. As used herein, the term "biological response modifier" refers to a lymphokine or interferon.

[0201] As used herein, the term "inhibitor of oncogenic Ras isoforms," ​​such as H-Ras, K-Ras, or N-Ras, refers to compounds that target, reduce, or inhibit the oncogenic activity of Ras, e.g., "farnesyltransferase inhibitors," such as L-744832, DK8G557, or R115777 (Zarnestra™). As used herein, the term "telomerase inhibitor" refers to compounds that target, reduce, or inhibit the activity of telomerase. Compounds that target, reduce, or inhibit the activity of telomerase are, among others, compounds that inhibit the telomerase receptor, such as telomestatin.

[0202] The term "methionine aminopeptidase inhibitor" as used herein refers to a compound that targets, decreases or inhibits the activity of methionine aminopeptidase. Compounds that target, decreases or inhibit the activity of methionine aminopeptidase include, but are not limited to, bengamide or its derivatives.

[0203] As used herein, the term "proteasome inhibitor" refers to a compound that targets, decreases, or inhibits the activity of the proteasome. Compounds that target, decrease, or inhibit the activity of the proteasome include, but are not limited to, bortezomib (Velcade™) and MLN341.

[0204] The term "matrix metalloproteinase inhibitors" or ("MMP" inhibitors) as used herein includes, but is not limited to, collagen peptidomimetic and non-peptidomimetic inhibitors, tetracycline derivatives, such as the hydroxamate peptidomimetic inhibitor batimastat and its orally bioavailable analogs marimastat (BB-2516), prinomastat (AG3340), metastat (NSC683551), BMS-279251, BAY12-9566, TAA211, MMI270B, or AAJ996.

[0205] As used herein, the term "compounds used in the treatment of hematological malignancies" includes, but is not limited to, FMS-like tyrosine kinase inhibitors, which are compounds that target, decrease, or inhibit the activity of FMS-like tyrosine kinase receptor (Flt-3R); interferon, 1-β-D-arabinofuranosylcytosine (ara-c), and busulfan; and ALK inhibitors, which are compounds that target, decrease, or inhibit anaplastic lymphoma kinase.

[0206] Compounds that target, decrease, or inhibit the activity of the FLT-3R-like tyrosine kinase receptor are compounds, proteins, or antibodies that inhibit members of the Flt-3R receptor kinase family, such as PKC412, midostaurin, staurosporine derivatives, SU11248, and MLN518, among others.

[0207] The term "HSP90 inhibitor" as used herein includes, but is not limited to, compounds that target, reduce, or inhibit the intrinsic ATPase activity of HSP90; compounds that degrade, target, reduce, or inhibit HSP90 client proteins via the ubiquitin proteosome pathway. Compounds that target, reduce, or inhibit the intrinsic ATPase activity of HSP90 include, among others, compounds, proteins, or antibodies that inhibit the ATPase activity of HSP90, such as 17-allylamino, 17-demethoxygeldanamycin (17AAG), geldanamycin derivatives; other geldanamycin-related compounds; radicicol, and HDAC inhibitors.

[0208] As used herein, the term "antiproliferative antibody" includes, but is not limited to, trastuzumab (Herceptin™), trastuzumab-DM1, Erbitux, bevacizumab (Avastin™), rituximab (Rituxan®), PRO64553 (anti-CD40), and 2C4 antibodies. By antibody is meant intact monoclonal antibodies, polyclonal antibodies, multispecific antibodies formed from at least two intact antibodies, and antibody fragments so long as they exhibit the desired biological activity.

[0209] For the treatment of acute myeloid leukemia (AML), the compounds of the present invention can be used in combination with standard leukemia therapies, particularly those used for the treatment of AML. In particular, the compounds of the present invention can be administered in combination with, for example, farnesyltransferase inhibitors and / or other drugs useful in the treatment of AML, such as daunorubicin, adriamycin, Ara-C, VP-16, teniposide, mitoxantrone, idarubicin, carboplatinum, and PKC412.

[0210] Other anti-leukemia compounds include, for example, the pyrimidine analog Ara-C, which is a 2'-alpha-hydroxyribose (arabinoside) derivative of deoxycytidine. Also included are 6-mercaptopurine (6-MP), a purine analog of hypoxanthine, and fludarabine phosphate. Compounds that target, decrease, or inhibit the activity of histone deacetylase (HDAC) inhibitors, such as sodium butyrate and suberoylanilide hydroxamic acid (SAHA), inhibit the activity of enzymes known as histone deacetylases. Specific HDAC inhibitors include compounds disclosed in US Pat. No. 6,552,065, including, but not limited to, MS275, SAHA, FK228 (formerly known as FR901228), trichostatin A, and N-hydroxy-3-[4-[[[2-(2-methyl-1H-indol-3-yl)-ethyl]-amino]methyl]phenyl]-2E-2-propenamide or a pharmaceutically acceptable salt thereof, and N-hydroxy-3-[4-[(2-hydroxyethyl){2-(1H-indol-3-yl)ethyl]-amino]methyl]phenyl]-2E-2-propenamide or a pharmaceutically acceptable salt thereof, particularly the lactate salt. As used herein, somatostatin receptor antagonist refers to compounds that target, treat, or inhibit somatostatin receptors, such as octreotide and SOM230. Tumor cell damaging techniques refer to techniques such as ionizing radiation. The term "ionizing radiation" referred to above and hereafter means ionizing radiation that occurs either as electromagnetic waves (such as X-rays and gamma rays) or particles (such as alpha and beta particles). Ionizing radiation is provided in, but is not limited to, radiation therapy, which is known in the art. Hellman, Principles of Radiation Therapy, Cancer, in Principles and Practice of Oncology, Devita et al., Eds., 4 th Edition, Vol. 1, pp. 248-275 (1993).

[0211] Also included are EDG binders and ribonucleotide reductase inhibitors. As used herein, the term "EDG binder" refers to a class of immunosuppressants that modulate lymphocyte recirculation, such as FTY720. The term "ribonucleotide reductase inhibitor" refers to a pyrimidine or purine nucleoside analog, including, but not limited to, fludarabine and / or cytosine arabinoside (ara-C), 6-thioguanine, 5-fluorouracil, cladribine, 6-mercaptopurine (especially in combination with ara-C for ALL), and / or pentostatin. Ribonucleotide reductase inhibitors are, inter alia, hydroxyurea or 2-hydroxy-1H-isoindole-1,3-dione derivatives.

[0212] Also included are, inter alia, VEGF compounds, proteins, or monoclonal antibodies, such as 1-(4-chloroanilino)-4-(4-pyridylmethyl)phthalazine or its pharmaceutically acceptable salt 1-(4-chloroanilino)-4-(4-pyridylmethyl)phthalazine succinate; Angiostatin™; Endostatin™; anthranilic acid amide; ZD4190; Zd6474; SU5416; SU6668; bevacizumab; or anti-VEGF antibodies or anti-VEGF receptor antibodies, such as rhuMAb and RHUFab, VEGF aptamers, such as Macugon; FLT-4 inhibitors, FLT-3 inhibitors, VEGFR-2 IgGI antibodies, Angiozyme (RPI4610), and bevacizumab (Avastin™).

[0213] As used herein, photodynamic therapy refers to a treatment that uses certain chemicals known as photosensitizing compounds to treat or prevent cancer. Examples of photodynamic therapy include treatment with compounds such as Visudyne™ and porfimer sodium.

[0214] Antiangiogenic steroids, as used herein, refer to compounds that block or inhibit angiogenesis, such as, for example, anecortave, triamcinolone, hydrocortisone, 11-α-epihydrocotisol, cortexolone, 17α-hydroxyprogesterone, corticosterone, desoxycorticosterone, testosterone, estrone, and dexamethasone.

[0215] Corticosteroid-containing implants refer to compounds such as fluocinolone and dexamethasone.

[0216] Other chemotherapeutic compounds include, but are not limited to, plant alkaloids, hormonal 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.

[0217] The structures of the active compounds identified by code numbers, generic names or trade names may be taken from the actual edition of the standard encyclopedia "Merck Index" or from databases such as Patents International (eg IMS World Publications).

[0218] 4.2.2. Exemplary Cancer Immunotherapeutic Agents In some embodiments, the one or more other therapeutic agents are cancer immunotherapeutic agents. As used herein, the term "cancer immunotherapeutic agent" refers to an agent that is effective in enhancing, stimulating, and / or upregulating immune response in a subject. In some embodiments, the administration of a cancer immunotherapeutic agent with a compound of the present invention has a synergistic effect in the treatment of cancer.

[0219] The cancer immunotherapeutic agent can be, for example, a small molecule drug, an antibody, or a biologic or small molecule. Examples of biologic cancer immunotherapeutics include, but are not limited to, cancer vaccines, antibodies, and cytokines. In some embodiments, the antibody is a monoclonal antibody. In some embodiments, the monoclonal antibody is humanized or human.

[0220] In some embodiments, the cancer immunotherapeutic agent is either (i) an agonist of a stimulatory (including costimulatory) receptor or (ii) an antagonist of an inhibitory (including co-inhibitory) signal on a T cell, either of which results in amplification of the antigen-specific T cell response.

[0221] Certain stimulatory and inhibitory molecules are members of the immunoglobulin superfamily (IgSF). One important family of membrane-bound ligands that bind to costimulatory or costimulatory 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 costimulatory or coinhibitory receptors are the TNF family of molecules that bind to their cognate TNF receptor family members, 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, and OPG. , RANK, RANKL, TWEAKR / Fn14, TWEAK, BAFFR, EDAR, XEDAR, TACI, APRIL, BCMA, LTβR, LIGHT, DcR3, HVEM, VEGI / TL1A, TRAMP / DR 3, including EDAR, EDA1, XEDAR, EDA2, TNFR1, lymphotoxin α / TNFβ, TNFR2, TNFα, LTβR, lymphotoxin α1β2, FAS, FASL, RELT, DR6, TROY, NGFR.

[0222] In some embodiments, the cancer immunotherapeutic agent is a cytokine that inhibits T cell activation (e.g., IL-6, IL-10, TGF-β, VEGF, and other immunosuppressive cytokines) or a cytokine that stimulates T cell activation to stimulate an immune response.

[0223] In some embodiments, the combination of a compound of the invention and a cancer immunotherapeutic agent can stimulate a T cell response. In some embodiments, the cancer immunotherapeutic agent is (i) an antagonist (e.g., an immune checkpoint inhibitor) of a protein that inhibits T cell activation, 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.

[0224] In some embodiments, the cancer immunotherapeutic agent is an antagonist of an inhibitory receptor on NK cells or an agonist of an activating receptor on NK cells, hi some embodiments, the cancer immunotherapeutic agent is an antagonist of a KIR, such as lirilumab.

[0225] In some embodiments, the cancer immunotherapeutic agent is an agent that inhibits or depletes macrophages or monocytes, including but not limited to CSF-1R antagonists such as CSF-1R antagonist antibodies, including RG7155 (WO11 / 70024, WO11 / 107553, WO11 / 131407, WO13 / 87699, WO13 / 119716, WO13 / 132044) or FPA-008 (WO11 / 140249, WO13169264, WO14 / 036357).

[0226] In some embodiments, the cancer immunotherapeutic agent is selected from agonistic agents that bind to positive costimulatory receptors, blocking agents 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 unique immunosuppressive pathways within the tumor microenvironment (e.g., blocking inhibitory receptor binding (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 activate innate immunity and / or induce inflammation at the tumor site.

[0227] In some embodiments, the cancer immunotherapeutic agent is a CTLA-4 antagonist. In some embodiments, the CTLA-4 antagonist is an antagonistic CTLA-4 antibody. In some embodiments, the antagonistic CTLA-4 antibody is YERVOY (ipilimumab) or tremelimumab.

[0228] In some embodiments, the cancer immunotherapeutic agent is a PD-1 antagonist. In some embodiments, the PD-1 antagonist is administered by infusion. In some embodiments, the cancer immunotherapeutic agent is an antibody or antigen-binding portion thereof that specifically binds to the programmed death-1 (PD-1) receptor and inhibits PD-1 activity. In some embodiments, the PD-1 antagonist is an antagonistic PD-1 antibody. In some embodiments, the antagonistic PD-1 antibody is OPDIVO (nivolumab), KEYTRUDA (pembrolizumab), or MEDI-0680 (AMP-514, WO 2012 / 145493). In some embodiments, the cancer immunotherapeutic agent can be pidilizumab (CT-011). In some embodiments, the cancer immunotherapeutic agent is a recombinant protein called AMP-224, composed of the extracellular domain of PD-L2 (B7-DC) fused to the Fc portion of IgG1.

[0229] In some embodiments, the cancer immunotherapeutic agent is a PD-L1 antagonist. In some embodiments, the PD-L1 antagonist is an antagonistic PD-L1 antibody. In some embodiments, the PD-L1 antibody is MPDL3280A (RG7446, WO2010 / 077634), durvalumab (MEDI4736), BMS-936559 (WO2007 / 005874), or MSB0010718C (WO2013 / 79174).

[0230] In some embodiments, the cancer immunotherapeutic agent is a LAG-3 antagonist. In some embodiments, the LAG-3 antagonist is an antagonistic 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).

[0231] In some embodiments, the cancer immunotherapeutic 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).

[0232] In some embodiments, the cancer immunotherapeutic 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).

[0233] In some embodiments, the cancer immunotherapeutic agent is an indoleamine (2,3)-dioxygenase (IDO) antagonist. In some embodiments, the IDO antagonist is selected from epacadostat (INCB024360, Incyte), indoximod (NLG-8189, NewLink Genetics Corporation), 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, Kyn Therapeutics), and NLG-919 (WO09 / 73620, WO009 / 1156652, WO11 / 56652, WO12 / 142237).

[0234] In some embodiments, the cancer immunotherapeutic 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.

[0235] In some embodiments, the cancer immunotherapeutic agent is an OX40L antagonist. In some embodiments, the OX40L antagonist is an antagonistic OX40 antibody. In some embodiments, the OX40L antagonist is RG-7888 (WO06 / 029879).

[0236] In some embodiments, the cancer immunotherapeutic agent is a CD40 agonist. In some embodiments, the CD40 agonist is an agonistic CD40 antibody. In some embodiments, the cancer immunotherapeutic agent is a CD40 antagonist. In some embodiments, the CD40 antagonist is an antagonistic CD40 antibody. In some embodiments, the CD40 antibody is lucatumumab or dacetuzumab.

[0237] In some embodiments, the cancer immunotherapeutic agent is a CD27 agonist. In some embodiments, the CD27 agonist is an agonistic CD27 antibody. In some embodiments, the CD27 antibody is varlilumab.

[0238] In some embodiments, the cancer immunotherapeutic is MGA271 (directed against B7H3) (WO11 / 109400).

[0239] In some embodiments, the cancer immunotherapeutic agent is abagovomab, adecatumumab, afutuzumab, alemtuzumab, anatumomab mafenatox mafenatox, apolizumab, atezolimab, avelumab, blinatumomab, BMS-936559, catumaxomab, durvalumab, epacadostat, epratuzumab, indoximod, inotuzumab ozogamicin, intelumumab, ipilimumab, isatuximab, lambrolizumab, MED14736, MPDL3280A, nivolumab, obinutuzumab, ocaratuzumab, ofatumumab, olatatumab, pembrolizumab, pidilizumab, rituximab, ticilimumab, samalizumab, or tremelimumab.

[0240] In some embodiments, the cancer immunotherapeutic agent is an immunostimulatory agent. For example, antibodies that block the PD-1 and PD-L1 inhibitory axis can unleash activated tumor-reactive T cells and have been shown in clinical trials to induce durable anti-tumor responses in an increasing number of tumor histologies, including several tumor types not traditionally considered sensitive to immunotherapy. See, e.g., Okazaki, T. et al. (2013) Nat. Immunol. 14, 1212-1218; Zou et al. (2016) Sci. Transl. Med. 8. The anti-PD-1 antibody nivolumab (Opdivo®, Bristol-Myers Squibb, also known as ONO-4538, MDX1106, and BMS-936558) has shown the potential to improve overall survival in patients with RCC who have experienced disease progression during or after prior antiangiogenic therapy.

[0241] In some embodiments, the immunomodulatory therapeutic specifically induces apoptosis of tumor cells. Approved immunomodulatory therapeutics that may be used in the present invention include pomalidomide (Pomalyst®, Celgene), lenalidomide (Revlimid®, Celgene), and ingenol mebutate (Picato®, LEO Pharma).

[0242] In some embodiments, the cancer immunotherapeutic agent is a cancer vaccine, hi some embodiments, the cancer vaccine is selected from sipuleucel-T (Provenge®, Dendreon / Valeant Pharmaceuticals), approved for the treatment of asymptomatic or minimally symptomatic metastatic castration-resistant (hormone-refractory) prostate cancer, and talimogene laherparepvec (Imlygic®, BioVex / Amgen, formerly T-VEC), a genetically modified oncolytic virotherapy approved for the treatment of cutaneous, subcutaneous, and nodal lesions of unresectable melanoma. In some embodiments, the cancer immunotherapeutic agent is an oncolytic virotherapy agent, such as pexastimogene devacirepvec (PexaVec / JX-594, SillaJen / formerly Jennerex Biotherapeutics), a thymidine kinase- (TK-) deficient vaccinia virus engineered to express GM-CSF, for hepatocellular carcinoma (NCT02562755) and melanoma (NCT00429312); colorectal cancer (NCT01622543), prostate cancer (NCT01619813), head and neck squamous cell carcinoma (NCT01166542), pancreatic adenocarcinoma (NCT00998322), and non-small cell lung cancer (NSCLC) (NCT peraleorep (Reolysin®, Oncolytics Biotech), a variant of respiratory enteric orphan virus (reovirus) that does not replicate in cells in which RAS is not activated, in numerous cancers, including (NCT00861627); enadenotucirev (NG-348, PsiOxus, formerly ColoAd1), an adenovirus engineered to express full-length CD80 and antibody fragments 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); GL-ONC1 (GLV-1h68 / GLV-1h153, Genelux GmbH), a vaccinia virus engineered to express beta-galactosidase (beta-gal) / beta-glucuronidase or beta-gal / human sodium iodide symporter (hNIS), respectively, studied in peritoneal carcinomatosis (NCT01443260), fallopian tube cancer, and ovarian cancer (NCT 02759588); or CG0070 (Cold Genesys), an adenovirus engineered to express GM-CSF in bladder cancer (NCT02365818). ;

[0243] In some embodiments, the cancer immunotherapeutic agent is JX-929 (SillaJen, formerly Jennerex Biotherapeutics), a TK-deficient and vaccinia growth factor-deficient vaccinia virus engineered to express cytosine deaminase that can convert the prodrug 5-fluorocytosine to the cytotoxic drug 5-fluorouracil; TG01 and TG02 (Targovax, formerly Oncos), peptide-based immunotherapeutics targeted to hard-to-treat RAS mutations; and TILT-123 (TILT Biotherapeutics), an engineered adenovirus designated Ad5 / 3-E2F-delta24-hTNFα-IRES-hIL20; and antigen-specific CD8 + and VSV-GP (ViraTherapeutics), a vesicular stomatitis virus (VSV) engineered to express the glycoprotein (GP) of lymphocytic choriomeningitis virus (LCMV), which can be further engineered to express antigens designed to elicit T cell responses.

[0244] In some embodiments, the cancer immunotherapeutic agent is a T cell engineered to express a chimeric antigen receptor, or CAR. Such T cells engineered to express a chimeric antigen receptor are referred to as CAR-T cells.

[0245] CARs have been constructed that consist of a binding domain (which may be derived from a natural ligand) that is a single-chain variable fragment (scFv) derived from a monoclonal antibody specific for a cell surface antigen fused to an endodomain (such as the CD3-zeta signaling domain from the TCR), which is a functional end of the T cell receptor (TCR) that can generate an activation signal in T lymphocytes. Upon binding to the antigen, such CARs couple to the endogenous signaling pathway of the effector cell and generate an activation signal similar to that initiated by the TCR complex.

[0246] For example, in some embodiments, the CAR-T cells are one of those described in U.S. Patent No. 8,906,682 (June, incorporated herein by reference in its entirety), which discloses CAR-T cells engineered to contain an extracellular domain bearing an antigen-binding domain (such as a domain that binds to CD19) fused to the intracellular signaling domain of the zeta chain of the T cell antigen receptor complex (such as CD3 zeta). When expressed in T cells, CARs can redirect antigen recognition based on antigen-binding specificity. In the case of CD19, the antigen is expressed on malignant B cells. More than 200 clinical trials using CAR-T in a wide range of indications are currently underway [https: / / clinicaltrials.gov / ct2 / results?term=chimeric+antigen+receptors&pg=1].

[0247] In some embodiments, the immunostimulatory agent 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, as well as the differentiation of IL-17-expressing innate immune cell subpopulations, such as NK cells. In some embodiments, the activator of RORγt is LYC-55716 (Lycera), which is currently being evaluated in clinical trials for the treatment of solid tumors (NCT02929862).

[0248] In some embodiments, the immunostimulatory agent is a Toll-like receptor (TLR) agonist or activator. Suitable TLR activators include TLR9 agonists or activators, such as SD-101 (Dynavax). SD-101 is an immunostimulatory CpG being investigated for B-cell lymphoma, follicular lymphoma, and other lymphomas (NCT02254772). TLR8 agonists or activators that can be used in the present invention include motolimod (VTX-2337, VentiRx Pharmaceuticals), which is being investigated for squamous cell carcinoma of the head and neck (NCT02124850) and ovarian cancer (NCT02431559).

[0249] Other cancer immunotherapeutic agents that can be used in the present invention include the anti-CD137 monoclonal antibody urelumab (BMS-663513, Bristol-Myers Squibb), the anti-CD27 monoclonal antibody varlilumab (CDX-1127, Celldex Therapeutics), the anti-OX40 monoclonal antibody BMS-986178 (Bristol-Myers Squibb), the anti-KIR monoclonal antibody lirilumab (IPH2102 / BMS-986015, Innate Pharma, Bristol-Myers Squibb), the anti-NKG2A monoclonal antibody monalizumab (IPH2201, Innate Pharma, AstraZeneca), the anti-MMP9 antibody andecaliximab (GS-5745, Gilead Sciences), and the anti-GITR monoclonal antibody MK-4166 (Merck & Co.).

[0250] 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.

[0251] In some embodiments, the immunostimulatory therapeutic is recombinant human interleukin-15 (rhIL-15). rhIL-15 is being tested in clinical settings as a treatment 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 is heterodimeric IL-15 (hetIL-15, Novartis / Admune), a fusion complex composed of a synthetic form of endogenous IL-15 complexed to the IL-15 receptor alpha chain, a soluble IL-15 binding protein, which is being tested in Phase 1 clinical trials 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.

[0252] In some embodiments, the cancer immunotherapeutic agent is selected from those described in Jerry L. Adams ET.AL., "Big opportunities for small molecules in immuno-oncology," Cancer Therapy 2015, Vol. 14, pages 603-622, the contents of which are incorporated herein by reference in their entirety. In some embodiments, the cancer immunotherapeutic agent is selected from the examples described in Table 1 of Jerry L. Adams ET.AL. In some embodiments, the cancer immunotherapeutic agent is a small molecule that targets a cancer immunotherapy target selected from those listed in Table 2 of Jerry L. Adams ET.AL. In some embodiments, the cancer immunotherapeutic agent is a small molecule agent selected from those listed in Table 2 of Jerry L. Adams ET.AL.

[0253] In some embodiments, the cancer immunotherapeutic agent is selected from the small molecule cancer immunotherapeutic agents described in Peter L. Toogood, "Small molecule immuno-oncology therapeutic agents," Bioorganic & Medicinal Chemistry Letters 2018, Vol. 28, pages 319-329, the contents of which are incorporated herein by reference in their entirety. In some embodiments, the cancer immunotherapeutic agent is an agent that targets a pathway such as those described in Peter L. Toogood.

[0254] In some embodiments, the cancer immunotherapeutic agent is selected from those described in Sandra L. Ross et al., "Bispecific T cell engager (BiTE®) antibody constructs can mediate bystander tumor cell killing," PLoS ONE 12(8):e0183390, the contents of which are incorporated herein by reference in their entirety. In some embodiments, the cancer immunotherapeutic agent is a bispecific T cell engager (BiTE®) antibody construct. In some embodiments, the bispecific T cell engager (BiTE®) antibody construct is a CD19 / CD3 bispecific antibody construct. In some embodiments, the bispecific T cell engager (BiTE®) antibody construct is an EGFR / CD3 bispecific antibody construct. In some embodiments, the bispecific T cell engager (BiTE®) antibody construct activates T cells. In some embodiments, the bispecific T cell engager (BiTE®) antibody construct activates T cells, which 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 (BiTE®) antibody construct activates T cells, which results in inducible bystander cell lysis. In some embodiments, the bystander cells are within a solid tumor. In some embodiments, the bystander cells undergoing lysis are in proximity to BiTE®-activated T cells. In some embodiments, the bystander cells comprise tumor-associated antigen (TAA)-negative cancer cells. In some embodiments, the bystander cells comprise EGFR-negative cancer cells. In some embodiments, the cancer immunotherapeutic is an antibody that blocks the PD-L1 / PD1 axis and / or CTLA4. In some embodiments, the cancer immunotherapeutic is ex vivo expanded tumor-infiltrating T cells. In some embodiments, the cancer immunotherapeutic agent is a bispecific antibody construct or a chimeric antigen receptor (CAR) that directly links T cells to tumor-associated surface antigens (TAA).

[0255] Exemplary Immune Checkpoint Inhibitors In some embodiments, the cancer immunotherapeutic is an immune checkpoint inhibitor as described herein.

[0256] The term "checkpoint inhibitors" as used herein refers to drugs that are useful in preventing cancer cells from evading the patient's immune system. One of the main mechanisms of anti-tumor immunity destruction is known as "T cell exhaustion", which results from chronic exposure to antigens leading to the upregulation of inhibitory receptors. These inhibitory receptors act as immune checkpoints to prevent uncontrolled immune responses.

[0257] PD-1 and other 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), and lymphocyte-activation gene-3 (Lag-3, CD223), are often referred to as checkpoint regulators. They act as molecular “gatekeepers” that allow extracellular signals to dictate whether cell cycle progression and other intracellular signaling processes should proceed.

[0258] In some embodiments, the immune checkpoint inhibitor is an antibody against PD-1, which binds to the programmed death 1 receptor (PD-1) and prevents the receptor from binding to the inhibitory ligand PDL-1, thus abolishing the ability of the tumor to suppress the host anti-tumor immune response.

[0259] In one embodiment, the checkpoint inhibitor is a biotherapeutic or small molecule. In another embodiment, the checkpoint inhibitor is a monoclonal antibody, a humanized antibody, a fully human antibody, a fusion protein, or a combination thereof. In a further embodiment, the checkpoint inhibitor inhibits a checkpoint protein selected from CTLA-4, PDL1, PDL2, PD1, B7-H3, B7-H4, BTLA, HVEM, TIM3, GAL9, LAG3, VISTA, KIR, 2B4, CD160, CGEN-15049, CHK1, CHK2, A2aR, B-7 family ligand, or a combination thereof. In additional embodiments, the checkpoint inhibitor interacts with a ligand of a checkpoint protein selected from CTLA-4, PDL1, PDL2, PD1, B7-H3, B7-H4, BTLA, HVEM, TIM3, GAL9, LAG3, VISTA, KIR, 2B4, CD160, CGEN-15049, CHK1, CHK2, A2aR, a B-7 family ligand, or a combination thereof. In certain embodiments, the checkpoint inhibitor is an immunostimulant, a T cell growth factor, an interleukin, an antibody, a vaccine, or a combination thereof. In further embodiments, the interleukin is IL-7 or IL-15. In a specific embodiment, the interleukin is glycosylated IL-7. In additional embodiments, the vaccine is a dendritic cell (DC) vaccine.

[0260] Checkpoint inhibitors include any agent that blocks or inhibits an 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. Exemplary checkpoint molecules that can be targeted for blockage or inhibition include CTLA-4, PDL1, PDL2, PD1, B7-H3, B7-H4, BTLA, HVEM, GAL9, LAG3, TIM3, VISTA, KIR, 2B4 (a member of the CD2 family of molecules, which inhibits all NK, gamma delta, and memory CD8 +(expressed on αβ)T cells), CD160 (also known as BY55), CGEN-15049, CHK1 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 to and block or inhibit the activity of one or more of CTLA-4, PDL1, PDL2, PD1, BTLA, HVEM, TIM3, GAL9, LAG3, VISTA, KIR, 2B4, CD160, and CGEN-15049. Exemplary immune checkpoint inhibitors include tremelimumab (a CTLA-4 blocking antibody), anti-OX40, PD-L1 monoclonal antibody (anti-B7-H1, MEDI4736), MK-3475 (a PD-1 blocker), nivolumab (an anti-PD1 antibody), CT-011 (an anti-PD1 antibody), BY55 monoclonal antibody, AMP224 (an anti-PDL1 antibody), BMS-936559 (an anti-PDL1 antibody), MPLDL3280A (an anti-PDL1 antibody), MSB0010718C (an anti-PDL1 antibody), and ipilimumab (an anti-CTLA-4 checkpoint inhibitor). Checkpoint protein ligands include, but are not limited to, PD-L1, PD-L2, B7-H3, B7-H4, CD28, CD86, and TIM-3.

[0261] In certain embodiments, the immune checkpoint inhibitor is selected from a PD-1 antagonist, a PD-L1 antagonist, and a CTLA-4 antagonist. In some embodiments, the checkpoint inhibitor is selected from the group consisting of nivolumab (Opdivo®), ipilimumab (Yervoy®), and pembrolizumab (Keytruda®). In some embodiments, the checkpoint inhibitor is selected from nivolumab (anti-PD-1 antibody, Opdivo®, Bristol-Myers Squibb), pembrolizumab (anti-PD-1 antibody, Keytruda®, Merck), ipilimumab (anti-CTLA-4 antibody, Yervoy®, Bristol-Myers Squibb), durvalumab (anti-PD-L1 antibody, Imfinzi®, AstraZeneca), and atezolizumab (anti-PD-L1 antibody, Tecentriq®, Genentech).

[0262] In some embodiments, the checkpoint inhibitor is selected from the group consisting of lambrolizumab (MK-3475), nivolumab (BMS-936558), pidilizumab (CT-011), AMP-224, MDX-1105, MEDI4736, MPDL3280A, BMS-936559, ipilimumab, lirilumab, IPH2101, pembrolizumab (Keytruda®), and tremelimumab.

[0263] In some embodiments, the immune checkpoint inhibitor is REGN2810 (Regeneron), an anti-PD-1 antibody that has been studied 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 to PD-1, in clinical trials for diffuse large B-cell lymphoma and multiple myeloma; avelumab (Bavencio®, Pfizer / Merck), a fully human IgG1 anti-PD-L1 antibody 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. KGaA), also known as MSB0010718C; or PDR001 (Novartis), an inhibitory antibody that binds to PD-1, which 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 is being studied in clinical trials for several indications, including mesothelioma, colorectal cancer, renal cancer, breast cancer, lung and non-small cell lung cancer, pancreatic ductal adenocarcinoma, pancreatic cancer, germ cell cancer, squamous cell carcinoma of the head and neck, hepatocellular carcinoma, prostate cancer, endometrial cancer, metastatic cancer of the liver, liver cancer, 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 being investigated in a Phase 1 clinical trial for advanced solid tumors (NCT02694822).

[0264] 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 invention include TSR-022, LY3321367, and MBG453. TSR-022 (Tesaro) is an anti-TIM-3 antibody being investigated in solid tumors (NCT02817633). LY3321367 (Eli Lilly) is an anti-TIM-3 antibody being investigated in solid tumors (NCT03099109). MBG453 (Novartis) is an anti-TIM-3 antibody being investigated in advanced malignancies (NCT02608268).

[0265] In some embodiments, the checkpoint inhibitor is an inhibitor of T cell immunoreceptor with Ig and ITIM domains (or TIGIT), an immunoreceptor on certain T cells and NK cells. TIGIT inhibitors that can be used in the present invention include BMS-986207 (Bristol-Myers Squibb), anti-TIGIT monoclonal antibody (NCT02913313), OMP-313M32 (Oncomed), and anti-TIGIT monoclonal antibody (NCT03119428).

[0266] 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 invention include BMS-986016, REGN3767, and IMP321. BMS-986016 (Bristol-Myers Squibb), an anti-LAG-3 antibody, is being investigated in glioblastoma and gliosarcoma (NCT02658981). REGN3767 (Regeneron) is also an anti-LAG-3 antibody and is being investigated in malignant tumors (NCT03005782). IMP321 (Immutep SA) is a LAG-3-Ig fusion protein that is being investigated in melanoma (NCT02676869), adenocarcinoma (NCT02614833), and metastatic breast cancer (NCT00349934).

[0267] Checkpoint inhibitors that can be used in the present invention include OX40 agonists. OX40 agonists currently being investigated in clinical trials include PF-04518600 / PF-8600 (Pfizer), an anti-OX40 agonist antibody, in metastatic kidney cancer (NCT03092856) and advanced cancers and neoplasms (NCT02554812, NCT05082566); GSK3174998 (Merck), an anti-OX40 agonist antibody, in a Phase 1 cancer trial (NCT02528357); and OX40 agonist EGFR-1000 (Gibberish, Germany), in advanced solid tumors (NCT02318394 and NCT02705482). These include MEDI0562 (Medimmune / AstraZeneca), an anti-OX40 agonist antibody, in patients with colorectal cancer (NCT02559024), breast cancer (NCT01862900), head and neck cancer (NCT02274155), and metastatic prostate cancer (NCT01303705); and BMS-986178 (Bristol-Myers Squibb), an anti-OX40 agonist antibody, in advanced cancers (NCT02737475).

[0268] Checkpoint inhibitors that can be used in the present invention include CD137 (also known as 4-1BB) agonists. CD137 agonists currently being investigated in clinical trials include the anti-CD137 agonist antibody utomilumab (PF-05082566, Pfizer) in diffuse large B-cell lymphoma (NCT02951156) and advanced cancers and neoplasms (NCT02554812 and NCT05082566); and the anti-CD137 agonist antibody urelumab (BMS-663513, Bristol-Myers Squibb) in melanoma and skin cancer (NCT02652455) and glioblastoma and gliosarcoma (NCT02658981).

[0269] Checkpoint inhibitors that can be used in the present invention include CD27 agonists. CD27 agonists currently being investigated in clinical trials include the anti-CD27 agonist antibody varlilumab (CDX-1127, Celldex Therapeutics) in head and neck squamous cell carcinoma, ovarian cancer, colorectal cancer, renal cell carcinoma, and glioblastoma (NCT02335918), lymphoma (NCT01460134), and glioma and astrocytoma (NCT02924038).

[0270] Checkpoint inhibitors that may be used in the present invention include glucocorticoid-induced tumor necrosis factor receptor (GITR) agonists. GITR agonists currently being investigated in clinical trials include the agonist anti-GITR antibody TRX518 (Leap Therapeutics) in melanoma and other malignant solid tumors (NCT01239134 and NCT02628574); the agonist anti-GITR antibody GWN323 (Novartis) in solid tumors and lymphomas (NCT02740270); the agonist anti-GITR antibody INCAGN01876 (Incyte / Agenus) in advanced cancers (NCT02697591 and NCT03126110); the agonist anti-GITR antibody MK-4166 (Merck) in solid tumors (NCT02132754); and the human IgG1 This includes MEDI1873 (Medimmune / AstraZeneca), an agonistic hexameric GITR ligand molecule with an Fc domain.

[0271] The checkpoint inhibitors that can be used in the present invention include inducible T cell costimulator (ICOS, also known as CD278) agonists.ICOS agonists currently being studied in clinical trials include MEDI-570 (Medimmune), an anti-ICOS agonist antibody, in lymphoma (NCT02520791); GSK3359609 (Merck), an anti-ICOS agonist antibody, in Phase 1 (NCT02723955); JTX-2011 (Jounce Therapeutics), an anti-ICOS agonist antibody, in Phase 1 (NCT02904226).

[0272] Checkpoint inhibitors that may be used in the present invention include killer IgG-like receptor (KIR) inhibitors. KIR inhibitors being investigated in clinical trials include the anti-KIR antibody lirilumab (IPH2102 / BMS-986015, Innate Pharma / Bristol-Myers Squibb) in leukemia (NCT01687387, NCT02399917, NCT02481297, NCT02599649), multiple myeloma (NCT02252263), and lymphoma (NCT01592370); IPH2101 (1-7F9, Innate Pharma) in myeloma (NCT01222286 and NCT01217203); and IPH4102 (Innate Pharma), an anti-KIR antibody that binds to the three domains of the long cytoplasmic tail (KIR3DL2), in lymphoma (NCT02593045).

[0273] Checkpoint inhibitors that can be used in the present invention include CD47 inhibitors of the interaction between CD47 and signal-regulatory protein alpha (SIRPa). CD47 / SIRPa inhibitors currently being investigated in clinical trials include ALX-148 (Alexo Therapeutics), an antagonistic variant of (SIRPa) that binds to CD47 and blocks CD47 / SIRPa-mediated signaling, in Phase 1 clinical trials (NCT03013218); TTI-621 (SIRPa-Fc, Trillium), a soluble recombinant fusion protein created by linking the N-terminal CD47-binding domain of SIRPa to the Fc domain of human IgG1, which acts by binding to human CD47 and preventing it from delivering "don't eat me" signals to macrophages, in Phase 1 clinical trials (NCT02890368 and NCT02663518). Therapeutics); CC-90002 (Celgene), an anti-CD47 antibody, in leukemia (NCT02641002); and Hu5F9-G4 (Forty Seven, Inc.) in colorectal neoplasia and solid tumors (NCT02953782), acute myeloid leukemia (NCT02678338), and lymphoma (NCT02953509).

[0274] Checkpoint inhibitors that can be used in the present invention include CD73 inhibitors. CD73 inhibitors currently being studied in clinical trials include MEDI9447 (Medimmune), an anti-CD73 antibody in solid tumors (NCT02503774); and BMS-986179 (Bristol-Myers Squibb), an anti-CD73 antibody in solid tumors (NCT02754141).

[0275] Checkpoint inhibitors that can be used in the present invention include agonists of the stimulator of interferon genes protein (STING, also known as transmembrane protein 173, or TMEM173). STING agonists currently being investigated in clinical trials include MK-1454 (Merck), an agonistic synthetic cyclic dinucleotide, in lymphoma (NCT03010176); and ADU-S100 (MIW815, Aduro Biotech / Novartis), an agonistic synthetic cyclic dinucleotide, in Phase 1 studies (NCT02675439 and NCT03172936).

[0276] Checkpoint inhibitors that can be used in the present invention include CSF1R inhibitors. CSF1R inhibitors currently being investigated in clinical trials include pexidartinib (PLX3397, Plexxikon), a CSF1R small molecule inhibitor, in colorectal cancer, pancreatic cancer, metastatic and advanced cancers (NCT02777710), melanoma, non-small cell lung cancer, head and neck squamous cell carcinoma, gastrointestinal stromal tumor (GIST), and ovarian cancer (NCT02452424); and pancreatic cancer (NCT03153410), melanoma (NCT03101254). and IMC-CS4 (LY3022855, Lilly), an anti-CSF-1R antibody, in solid tumors (NCT02718911); and BLZ945 (4-[2((1R,2R)-2-hydroxycyclohexylamino)-benzothiazol-6-yloxyl]-pyridine-2-carboxylic acid methylamide, Novartis), an orally available inhibitor of CSF1R, in advanced solid tumors (NCT02829723).

[0277] Checkpoint inhibitors that can be used in the present invention include NKG2A receptor inhibitors. NKG2A receptor inhibitors currently being studied in clinical trials include the anti-NKG2A antibody monalizumab (IPH2201, Innate Pharma) in head and neck neoplasms (NCT02643550) and chronic lymphocytic leukemia (NCT02557516).

[0278] In some embodiments, the immune checkpoint inhibitor is selected from nivolumab, pembrolizumab, ipilimumab, avelumab, durvalumab, atezolizumab, or pidilizumab.

[0279] 5.Use The compounds and compositions described herein are generally useful for inhibiting eIF4E or a mutant thereof.

[0280] The activity of the compounds utilized in the present invention as inhibitors of eIF4E or its mutants can be assayed in vitro, in vivo, or in cell lines. In vitro assays include assays that determine the inhibition of eIF4E or its mutants. An alternative in vitro assay quantifies the ability of an inhibitor to bind to eIF4E. Detailed conditions for assaying the compounds utilized in the present invention as inhibitors of eIF4E or its mutants are set forth in the Examples below.

[0281] The provided compounds are inhibitors of eIF4E and are therefore useful for treating one or more disorders associated with the activity of eIF4E. Thus, in certain embodiments, the present invention provides a method for treating an eIF4E-mediated disorder, comprising administering to a patient in need thereof a compound of the present invention or a pharmaceutically acceptable composition thereof. In certain embodiments, the eIF4E-mediated disorder is an eIF4E-mediated cancer. In some embodiments, the eIF4E-mediated cancer is selected from breast cancer, colorectal cancer, lung cancer, glioblastoma, sarcoma, melanoma, prostate cancer, and lymphoma. In some embodiments, the eIF4E-mediated cancer is breast cancer.

[0282] As used herein, the terms "treatment," "treat," and "treating" refer to ameliorating, alleviating, delaying the onset of, or arresting the progression of a disease or disorder as described herein, or one or more symptoms thereof. In some embodiments, treatment may be administered after one or more symptoms have developed. In other embodiments, treatment may be administered in the absence of symptoms. For example, treatment may be administered to a susceptible individual prior to the onset of symptoms (e.g., in light of a history of symptoms and / or in light of genetic or other susceptibility factors). Treatment may also be continued after symptoms have resolved, e.g., to prevent or delay their recurrence.

[0283] As used herein, the term "eIF4E-mediated" disorder, disease, and / or condition means any disease or other deleterious condition in which eIF4E or a variant thereof is known to play a role, including, but not limited to, a cell proliferative disorder. In some embodiments, the cell proliferative disorder is cancer, as described herein.

[0284] cancer Cancers, in some embodiments, include, but are not limited to, leukemia (e.g., acute leukemia, acute lymphocytic leukemia, acute myelocytic leukemia, acute myeloblastic leukemia, acute promyelocytic leukemia, acute myelomonocytic leukemia, acute monocytic leukemia, acute erythroleukemia, chronic leukemia, chronic myelocytic leukemia, chronic lymphocytic leukemia), polycythemia vera, lymphoma (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., fibrosarcoma, myxosarcoma, liposarcoma, chondrosarcoma, osteogenic sarcoma, chordoma, angiosarcoma, endothelial sarcoma, lymphangiosarcoma, lymphangioendothelial ... heliosarcoma), synovium, mesothelioma, Ewing's tumor, leiomyosarcoma, rhabdomyosarcoma, colon cancer, pancreatic cancer, breast cancer, ovarian cancer, prostate cancer, squamous cell carcinoma, basal cell carcinoma, adenocarcinoma, sweat gland carcinoma, sebaceous gland carcinoma, papillary carcinoma, papillary adenocarcinoma, cystadenocarcinoma, medullary carcinoma, bronchogenic carcinoma, renal cell carcinoma, hepatocellular carcinoma, cholangiocarcinoma, choriocarcinoma, seminoma, embryonal carcinoma, Wilms' tumor, cervical cancer, uterine cancer, testicular cancer, lung cancer, small cell lung carcinoma, bladder cancer, epithelial carcinoma, glioma, astrocytoma, glioblastoma multiforme (GBM, also known as glioblastoma), medulloblastoma, craniopharyngioma, ependymoma, pinealoma, hemangioblastoma, acoustic neuroma, oligodendroglioma, schwannoma, neurofibrosarcoma, meningioma, melanoma, neuroblastoma, and retinoblastoma.

[0285] In some embodiments, the cancer is a glioma, astrocytoma, glioblastoma multiforme (GBM, also known as glioblastoma), medulloblastoma, craniopharyngioma, ependymoma, pinealoma, hemangioblastoma, acoustic neuroma, oligodendroglioma, schwannoma, neurofibrosarcoma, meningioma, melanoma, neuroblastoma, or retinoblastoma.

[0286] In some embodiments, the cancer is acoustic neuroma, astrocytoma (e.g., Grade I—pilocytic astrocytoma, Grade II—low-grade astrocytoma, Grade III—anaplastic astrocytoma, or Grade IV—glioblastoma (GBM)), chordoma, CNS lymphoma, craniopharyngioma, brain stem glioma, ependymoma, mixed glioma, optic nerve glioma, subependymoma, medulloblastoma, meningioma, metastatic brain tumor, oligodendroglioma, pituitary tumor, primitive neuroectodermal tumor (PNET), or schwannoma. In some embodiments, the cancer is a type that is more common in children than adults, such as brain stem glioma, craniopharyngioma, ependymoma, juvenile pilocytic astrocytoma (JPA), medulloblastoma, optic nerve glioma, pineal tumor, primitive neuroectodermal tumor (PNET), or rhabdoid tumor. In some embodiments, the patient is an adult human. In some embodiments, the patient is a child or pediatric patient.

[0287] Cancers include, in another embodiment, but are not limited to, mesothelioma, hepatobiliary cancer (liver and bile duct), bone cancer, pancreatic cancer, skin cancer, head and neck cancer, cutaneous or intraocular melanoma, ovarian cancer, colon cancer, rectal cancer, anal cancer, stomach cancer, gastrointestinal cancer (stomach, colorectum, and duodenum), uterine cancer, fallopian tube cancer, endometrial cancer, cervical cancer, vaginal cancer, vulvar cancer, Hodgkin's disease, esophageal cancer, small intestine cancer, cancer of the endocrine system, thyroid cancer, parathyroid cancer, adrenal cancer, soft tissue cancer, Included are sarcoma, urethral cancer, penile cancer, prostate cancer, testicular cancer, chronic or acute leukemia, chronic myeloid leukemia, lymphocytic lymphoma, bladder cancer, kidney or urethral cancer, renal cell carcinoma, renal pelvis cancer, non-Hodgkin's lymphoma, spinal axis tumor, brain stem glioma, pituitary adenoma, adrenocortical carcinoma, gallbladder cancer, multiple myeloma, cholangiocarcinoma, fibrosarcoma, neuroblastoma, retinoblastoma, or a combination of one or more of the foregoing cancers.

[0288] In some embodiments, the cancer is selected from hepatocellular carcinoma, ovarian cancer, epithelial ovarian cancer, or fallopian tube cancer; serous papillary cystadenocarcinoma or uterine serous papillary carcinoma (UPSC); prostate cancer; testicular cancer; gallbladder cancer; hepatocholangiocarcinoma; synovial sarcoma of soft tissue and bone; rhabdomyosarcoma; osteosarcoma; chondrosarcoma; Ewing's sarcoma; anaplastic thyroid carcinoma; adrenocortical adenoma; pancreatic cancer; pancreatic ductal carcinoma or pancreatic adenocarcinoma; gastrointestinal / gastric (GIST) cancer; lymphoma; squamous cell carcinoma of the head and neck (SCCHN); salivary gland cancer; glioma, or brain tumor; neurofibromatosis-1-associated malignant peripheral nerve sheath tumor (MPNST); Waldenstrom's macroglobulinemia; or medulloblastoma.

[0289] In some embodiments, the cancer is selected from hepatocellular carcinoma (HCC), hepatoblastoma, colon cancer, rectal cancer, ovarian cancer, epithelial ovarian cancer, fallopian tube cancer, serous papillary cystadenocarcinoma, uterine serous papillary carcinoma (UPSC), hepatic cholangiocarcinoma, synovial sarcoma of soft tissue and bone, rhabdomyosarcoma, osteosarcoma, anaplastic thyroid carcinoma, adrenocortical adenoma, pancreatic cancer, pancreatic ductal carcinoma, pancreatic adenocarcinoma, glioma, neurofibromatosis-1 associated malignant peripheral nerve sheath tumor (MPNST), Waldenstrom's macroglobulinemia, or medulloblastoma.

[0290] In some embodiments, the cancer is a solid tumor, such as a sarcoma, carcinoma, or lymphoma. Solid tumors generally comprise a mass of abnormal tissue that typically does not contain cysts or liquid areas. In some embodiments, the cancer is renal cell carcinoma or kidney cancer; hepatocellular carcinoma (HCC) or hepatoblastoma, or liver cancer; melanoma; breast cancer; colorectal carcinoma or 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, epithelial ovarian cancer, ... carcinoma), or fallopian tube cancer; serous papillary cystadenocarcinoma or uterine serous papillary carcinoma (UPSC); prostate cancer; testicular cancer; gallbladder cancer; hepato-cholangiocarcinoma; synovial sarcoma of soft tissue and bone; rhabdomyosarcoma; osteosarcoma; chondrosarcoma; Ewing's sarcoma; anaplastic thyroid carcinoma; adrenocortical carcinoma; pancreatic cancer; pancreatic ductal carcinoma or pancreatic adenocarcinoma; gastrointestinal / gastric (GIST) cancer; lymphoma; squamous cell carcinoma of the head and neck (SCCHN); salivary gland cancer; glioma or brain tumor; neurofibromatosis-1-associated malignant peripheral nerve sheath tumor (MPNST); Waldenstrom's macroglobulinemia; or medulloblastoma.

[0291] In some embodiments, the cancer is selected from renal cell carcinoma, hepatocellular carcinoma (HCC), hepatoblastoma, colorectal carcinoma, colorectal cancer, colon cancer, rectal cancer, anal cancer, ovarian cancer, epithelial ovarian cancer, ovarian cancer, fallopian tube cancer, serous papillary cystadenocarcinoma, uterine serous papillary carcinoma (UPSC), hepatic cholangiocarcinoma, synovial sarcoma of soft tissue and bone, rhabdomyosarcoma, osteosarcoma, chondrosarcoma, anaplastic thyroid carcinoma, adrenocortical carcinoma, pancreatic cancer, pancreatic ductal carcinoma, pancreatic adenocarcinoma, glioma, brain tumor, neurofibromatosis-1 associated malignant peripheral nerve sheath tumor (MPNST), Waldenstrom's macroglobulinemia, or medulloblastoma.

[0292] In some embodiments, the cancer is selected from hepatocellular carcinoma (HCC), hepatoblastoma, colon cancer, rectal cancer, ovarian cancer, epithelial ovarian cancer, ovarian carcinoma, fallopian tube carcinoma, serous papillary cystadenocarcinoma, uterine serous papillary carcinoma (UPSC), hepatic cholangiocarcinoma, synovial sarcoma of soft tissue and bone, rhabdomyosarcoma, osteosarcoma, anaplastic thyroid carcinoma, adrenocortical carcinoma, pancreatic carcinoma, pancreatic ductal carcinoma, pancreatic adenocarcinoma, glioma, neurofibromatosis-1 associated malignant peripheral nerve sheath tumor (MPNST), Waldenstrom's macroglobulinemia, or medulloblastoma.

[0293] In some embodiments, the cancer is hepatocellular carcinoma (HCC). In some embodiments, the cancer is hepatoblastoma. In some embodiments, the cancer is colon cancer. In some embodiments, the cancer is rectal cancer. In some embodiments, the cancer is ovarian cancer or ovarian carcinoma. In some embodiments, the cancer is epithelial ovarian cancer. In some embodiments, the cancer is fallopian tube carcinoma. In some embodiments, the cancer is serous papillary cystadenocarcinoma. In some embodiments, the cancer is uterine serous papillary carcinoma (UPSC). In some embodiments, the cancer is hepatocholangiocarcinoma. 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 carcinoma. 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 a glioma. In some embodiments, the cancer is a malignant peripheral nerve sheath tumor (MPNST). In some embodiments, the cancer is a neurofibromatosis-1 associated MPNST. In some embodiments, the cancer is Waldenstrom's macroglobulinemia. In some embodiments, the cancer is a medulloblastoma.

[0294] In some embodiments, the cancer is acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), adrenocortical carcinoma, anal cancer, appendix cancer, atypical teratoid / rhabdoid tumor, basal cell carcinoma, cholangiocarcinoma, bladder cancer, bone cancer, brain tumor, astrocytoma, brain and spinal cord tumor, brain stem glioma, central nervous system atypical teratoid / rhabdoid tumor, central nervous system embryonal tumor, breast cancer, bronchial tumor, Burkitt's lymphoma, or thyroid cancer. tumor, carcinoid tumor, cancer of unknown primary, central nervous system cancer, cervical cancer, childhood cancer, chordoma, chronic lymphocytic leukemia (CLL), chronic myeloid leukemia (CML), chronic myeloproliferative disorder, colon cancer, colorectal cancer, craniopharyngioma, cutaneous T-cell lymphoma, ductal carcinoma in situ (DCIS), embryonal tumor, endometrial cancer, ependymoblastoma, ependymoma, esophageal cancer, nasal neuroblastoma, Ewing's sarcoma, head Extracerebrospinal germ cell tumor, extragonadal germ cell tumor, extrahepatic bile duct cancer, eye cancer, fibrous histiocytoma of bone, gallbladder cancer, gastric cancer, gastrointestinal carcinoid tumor, gastrointestinal stromal tumor (GIST), germ cell tumor, ovarian germ cell tumor, gestational trophoblastic tumor, glioma, hairy cell leukemia, head and neck cancer, cardiac cancer, hepatocellular carcinoma, histiocytosis, Langerhans cell carcinoma, Hodgkin's lymphoma, hypopharyngeal cancer, intraocular melanoma, pancreatic islet cell tumor, Pozi's sarcoma, kidney cancer, Langerhans cell histiocytosis, laryngeal cancer, leukemia, lip and oral cavity cancer, liver cancer, lobular carcinoma in situ (LCIS), lung cancer, lymphoma, AIDS-related lymphoma, macroglobulinemia, male breast cancer, medulloblastoma, medulloepithelioma, melanoma, Merkel cell carcinoma, malignant mesothelioma, metastatic squamous cell carcinoma of unknown primary origin, midline duct carcinoma (MIDTC) involving the NUT gene Tract Carcinoma Involving NUT Gene), Oral Cancer, Multiple Endocrine Neoplasia Syndrome, Multiple Myeloma / Plasma Cell Neoplasm, Mycosis Fungoides, Myelodysplastic Syndrome, Myelodysplastic / Myeloproliferative Neoplasm, Chronic Myeloid Leukemia (CML), Acute Myeloid Leukemia (AML), Myeloma, Multiple Myeloma, Chronic Myeloproliferative Disorder, Nasal Cavity Cancer, Paranasal Sinus Cancer, Nasopharyngeal Cancer, Neuroblastoma, Non-Hodgkin's Lymphoma, Non-Small Cell Lung Cancer, Oral Cancer, Oral Cavity CancerCancer), lip cancer, oropharyngeal cancer, osteosarcoma, ovarian cancer, pancreatic cancer, papilloma, paraganglioma, paranasal sinus cancer, nasal cavity cancer, parathyroid cancer, penile cancer, pharyngeal cancer, pheochromocytoma, intermediately differentiated pineal parenchymal tumor, pineoblastoma, pituitary tumor, plasma cell tumor, pleuropulmonary blastoma, breast cancer, primary central nervous system (CNS) lymphoma, prostate cancer, rectal cancer, renal cell carcinoma, clear cell renal cell carcinoma, renal pelvis cancer, ureter cancer, transitional cell carcinoma, retinoblastoma, rhabdomyosarcoma, salivary gland cancer, sarcoma, Sézary syndrome, skin cancer , small cell lung cancer, small intestine cancer, soft tissue sarcoma, squamous cell carcinoma, cervical squamous cell carcinoma of unknown primary, head and neck squamous cell carcinoma (HNSCC), gastric cancer, supratentorial primitive neuroectodermal tumor, T-cell lymphoma, testicular cancer, throat cancer, thymoma, thymic carcinoma, thyroid cancer, transitional cell carcinoma of the renal pelvis and ureter, triple-negative breast cancer (TNBC), gestational trophoblastic tumor, unknown primary, rare childhood cancers, urethral cancer, uterine cancer, uterine sarcoma, Waldenstrom's macroglobulinemia, or Wilms' tumor.

[0295] In certain embodiments, the cancer is selected from bladder cancer, breast cancer (including TNBC), cervical cancer, colorectal cancer, chronic lymphocytic leukemia (CLL), diffuse large B-cell lymphoma (DLBCL), esophageal adenocarcinoma, glioblastoma, head and neck cancer, leukemia (acute and chronic), low-grade glioma, lung cancer (including adenocarcinoma, non-small cell lung cancer, and squamous cell carcinoma), Hodgkin's lymphoma, non-Hodgkin's lymphoma (NHL), melanoma, multiple myeloma (MM), ovarian cancer, pancreatic cancer, prostate cancer, renal cancer (including clear cell renal carcinoma and papillary renal cell carcinoma), and gastric cancer.

[0296] In some embodiments, the cancer is small cell lung cancer, non-small cell lung cancer, colorectal cancer, multiple myeloma, acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL), pancreatic cancer, liver cancer, hepatocellular carcinoma, neuroblastoma, other solid tumors or other blood cancers.

[0297] In some embodiments, the cancer is small cell lung cancer, non-small cell lung cancer, colorectal cancer, multiple myeloma, or AML.

[0298] The present invention relates to virus-associated cancers, including human immunodeficiency virus (HIV)-associated solid tumors, incurable human papillomavirus (HPV)-16-positive solid tumors, and adult T-cell leukemia, an aggressive form of CD4+ T-cell leukemia caused by human T-cell leukemia virus type I (HTLV-I) and characterized by clonal integration of HTLV-I within leukemia cells (see https: / / clinicaltrials.gov / ct2 / show / study / NCT02631746); as well as virus-associated tumors in gastric cancer, nasopharyngeal cancer, cervical cancer, vaginal cancer, vulvar cancer, squamous cell carcinoma of the head and neck, and Merkel cell carcinoma. (See https: / / clinicaltrials.gov / ct2 / show / study / NCT02488759; see also https: / / clinicaltrials.gov / ct2 / show / study / NCT0240886, https: / / clinicaltrials.gov / ct2 / show / NCT02426892).

[0299] In some embodiments, the present invention provides a method for treating a tumor in a patient in need thereof, the method comprising administering to the patient Compound I, or a pharmaceutical salt or composition thereof, and a cancer immunotherapeutic agent as described herein. In some embodiments, the tumor comprises any of the cancers described herein. In some embodiments, the tumor comprises melanoma cancer. In some embodiments, the tumor comprises breast cancer. In some embodiments, the tumor comprises lung cancer. In some embodiments, the tumor comprises small cell lung cancer (SCLC). In some embodiments, the tumor comprises non-small cell lung cancer (NSCLC).

[0300] In some embodiments, tumors are treated by halting further tumor growth. In some embodiments, tumors are treated by reducing tumor size (e.g., volume or bulk) by at least 5%, 10%, 25%, 50%, 75%, 90%, or 99% compared to the tumor size before treatment. In some embodiments, tumors are treated by reducing tumor burden in a patient by at least 5%, 10%, 25%, 50%, 75%, 90%, or 99% compared to the tumor burden before treatment.

[0301] In some embodiments, the eIF4E-mediated disorder, disease, and / or condition is obesity. See, e.g., Conn et al., "The major cap-binding protein eIF4E regulates lipid homeostasis and diet-induced obesity," Nature Metabolism volume 3, pages 244-257, the contents of which are incorporated herein by reference in their entirety.

[0302] In some embodiments, the eIF4E-mediated disorder, disease, and / or condition is a fibrotic disease. See, e.g., Nho et al., "Translational control of the fibroblast-extracellular matrix association: An application to pulmonary fibrosis," Translation 2013;1:e23934, the contents of which are incorporated herein by reference in their entirety. In some embodiments, the eIF4E-mediated disorder, disease, and / or condition is idiopathic pulmonary fibrosis (IPF). In some embodiments, the eIF4E-mediated disorder, disease, and / or condition is pulmonary hypertension. In some embodiments, the eIF4E-mediated disorder, disease, and / or condition is renal fibrosis. In some embodiments, the eIF4E-mediated disorder, disease, and / or condition is liver fibrosis. In some embodiments, the eIF4E-mediated disorder, disease, and / or condition is osteogenesis imperfecta. In some embodiments, the eIF4E-mediated disorder, disease, and / or condition is scurvy. In some embodiments, the eIF4E-mediated disorder, disease, and / or condition is scleroderma or systemic sclerosis. In some embodiments, the eIF4E-mediated disorder, disease, and / or condition is keloid. In some embodiments, the compounds described herein are used to regulate the binding of fibroblasts to the extracellular matrix.

[0303] In some embodiments, the eIF4E-mediated disorder, disease, and / or condition is a cardiac disease. See, e.g., Zeitz et al., "Translating Translation to Mechanisms of Cardiac Hypertrophy," J. Cardiovasc. Dev. Dis. 2020, 7, 9; doi:10.3390 / jcdd7010009, the contents of which are incorporated herein by reference in their entirety. In some embodiments, the eIF4E-mediated disorder, disease, and / or condition is cardiac hypertrophy. In some embodiments, the eIF4E-mediated disorder, disease, and / or condition is heart failure. In some embodiments, the eIF4E-mediated disorder, disease, and / or condition is arrhythmia. In some embodiments, the eIF4E-mediated disorder, disease, and / or condition is ischemia. In some embodiments, the eIF4E-mediated disorder, disease, and / or condition is cardiac stress.

[0304] In some embodiments, the eIF4E-mediated disorder, disease, and / or condition is pain or neuroinflammation. See, e.g., Mody et al., "eIF4E phosphorylation modulates pain and neuroinflammation in the aged," GeroScience (2020) 42:1663-1674, the contents of which are incorporated herein by reference in their entirety. In some embodiments, the eIF4E-mediated disorder, disease, and / or condition is chronic pain. In some embodiments, the eIF4E-mediated disorder, disease, and / or condition is acute pain. In some embodiments, the eIF4E-mediated disorder, disease, and / or condition is inflammatory pain in the elderly. In some embodiments, the eIF4E-mediated disorder, disease, and / or condition is neuropathic pain. In some embodiments, the eIF4E-mediated disorder, disease, and / or condition is age-related low-grade inflammation. In some embodiments, the eIF4E-mediated disorder, disease, and / or condition is chronic inflammation. In some embodiments, the eIF4E-mediated disorder, disease, and / or condition is acute inflammation.

[0305] In some embodiments, the eIF4E-mediated disorder, disease, and / or condition is an inflammatory disease. See, e.g., William et al., "eIF4E-Binding Proteins 1 and 2 Limit Macrophage Anti-Inflammatory Responses through Translational Repression of IL-10 and Cyclooxygenase-2," J Immunol 2018;200:4102-4116, the contents of which are incorporated by reference in their entirety. In some embodiments, the eIF4E-mediated disorder, disease, and / or condition is an autoimmune disease.

[0306] In some embodiments, the eIF4E-mediated disorder, disease, and / or condition is Alzheimer's disease (AD). See, e.g., Ghosh et al., "Alzheimer's disease-related dysregulation of mRNA translation causes key pathological features with aging," Translational Psychiatry (2020) 10:192, the contents of which are incorporated herein by reference in their entirety. In some embodiments, the eIF4E-mediated disorder, disease, and / or condition is a neurodegenerative condition. In some embodiments, the compounds described herein are used to reduce or clear amyloid-β (Aβ) plaques and / or phosphorylated tau aggregates.

[0307] Viral infections In certain embodiments, the eIF4E-mediated disorder, disease, and / or condition is a viral infection. Accordingly, in certain embodiments, the present invention provides a method for treating a viral infection, the method comprising administering to a patient in need thereof a compound of the present invention, or a pharmaceutically acceptable composition thereof. In some embodiments, the viral infection is a viral infection of the respiratory tract. In some embodiments, the viral infection is an infection of the upper respiratory tract. In some embodiments, the viral infection is an infection of the lower respiratory tract.

[0308] In some embodiments, the present invention provides a method for treating a disease or condition associated with a viral infection, the method comprising administering to a patient in need thereof a compound of the present invention, or a pharmaceutically acceptable composition thereof, hi some embodiments, the disease or condition associated with a viral infection is pneumonia.

[0309] In certain embodiments, the present invention provides a method for inhibiting viral replication, the method comprising administering to a patient in need thereof a compound of the present invention, or a pharmaceutically acceptable composition thereof.

[0310] As used herein, the term "virus" refers to a microscopic infectious organism that grows inside living cells. A virus consists essentially of a core of nucleic acid surrounded by a protein coat and has the ability to replicate only inside living cells, e.g., as a viral infection.

[0311] As used herein, the term "viral replication" refers to the production of additional viruses through the occurrence of at least one viral life cycle. For example, during viral infection, a virus can interfere with the normal function of a host cell, causing the cell to behave in a manner determined by the virus. For example, viral infection can cause a cell to produce or respond to cytokines when an uninfected cell would not normally do so. Many viruses (e.g., influenza and many animal viruses) have a viral envelope that surrounds their protein capsid. The envelope typically derives from portions of the host cell membrane (phospholipids and proteins) but also contains some viral glycoproteins. Functionally, the viral envelope is used to help the virus enter host cells. Glycoproteins on the surface of the envelope serve to identify and bind to receptor sites on the host membrane. The viral envelope then fuses with the host membrane, allowing the capsid and viral genome to enter and infect the host.

[0312] In some embodiments, the virus is an enveloped virus selected from DNA viruses, such as herpesviruses, poxviruses, and hepadnaviruses; RNA viruses, such as flaviviruses, togaviruses, coronaviruses, hepatitis D, orthomyxoviruses, paramyxoviruses, rhabdoviruses, bunyaviruses, filoviruses, and retroviruses.

[0313] In some embodiments, the virus is a human pathogen, such as influenza, RSV, HIV, rotavirus, Newcastle disease virus, Marek's disease virus, metapneumovirus, parainfluenza virus, coronavirus (including, for example, SARS-CoV, SARS-CoV-2, HcoV-HKU1, HcoV-NL63, and TGEV), hepatitis C virus, flavivirus (such as dengue virus, Japanese encephalitis virus, Kunjin virus, yellow fever virus, and West Nile virus), filovirus (such as Ebola virus and Marek's disease virus), or a combination thereof. Rubruggillus, etc.), Calicivirus (including Norovirus and Sapovirus), Human Papillomavirus, Epstein-Barr virus, Cytomegalovirus, Varicella-Zoster virus, and Herpes Simplex virus (amon), Birnaviridae, Chrysoviridae, Cystoviridae, Hypoviridae, Partitiviridae, Reoviridae (e.g., Rotavirus), Totiviridae, Nidovirales, Arteriviridae, Coronaviridae (e.g., Coronavirus and SARS), Ronivirus Family: Astroviridae, Barnaviridae, Bromoviridae, Caliciviridae, Closteroviridae, Comoviridae, Dicistroviridae, Flaviviridae (e.g., yellow fever virus, West Nile virus, hepatitis C virus, and dengue virus), Flexiviridae, Hepeviridae (e.g., hepatitis E virus), Leviviridae, Luteoviridae, Marnaviridae, Narnaviridae, Nodaviridae, Picornaviridae (e.g., poliovirus), viruses, common cold viruses, and hepatitis A viruses, etc.), Potyviridae, Sequiviridae, Tetraviridae, Togaviridae (rubella virus and Ross River virus, etc.), Tombusviridae, and Tymoviridae, Bornaviridae (Borna disease virus, etc.), Filoviridae (Ebola virus and Marburg virus, etc.), Paramyxoviridae (measles virus and mumps virus, etc.), Rhabdoviridae (rabies virus, etc.), Arenaviridae (Lassa fever virus, etc.),The family Bunyaviridae (e.g., Hantavirus) and the family Orthomyxoviridae (e.g., influenza virus).

[0314] In some embodiments, the virus is a coronavirus. In some embodiments, the coronavirus is selected from: Alpha coronavirus Colacovirus Bat coronavirus CDPHE15 Decacovirus Bat coronavirus HKU10 Horseshoe bat alphacoronavirus HuB-2013 Duvinacovirus Human coronavirus 229E Luchacovirus Lucheng Rn rat coronavirus Minacovirus Ferret coronavirus Mink coronavirus 1 Minunacovirus Long-fingered bat coronavirus 1 Long-fingered bat coronavirus HKU8 Myotacovirus Rickett's bigfoot bat (Myotis ricketti) alphacoronavirus Sax-2011 Nyctacovirus Central long-eared bat (Nyctalus velutinus) alphacoronavirus SC-2013 Pedakovirus Porcine epidemic diarrhea virus Yellow house bat (Scotophilus bat) coronavirus 512 Rhinacovirus Horseshoe bat (Rhinolophus bat) coronavirus HKU2 Setracovirus Human coronavirus NL63 NL63-related bat coronavirus strain BtKYNL63-9b Tegaco virus Alphacoronavirus 1-type species Beta coronavirus Envecovirus Betacoronavirus 1 Human coronavirus OC43 Chinese brown rat coronavirus HKU24 Human coronavirus HKU1 Murine coronavirus - type species Hibeko virus Bat Hp-beta coronavirus Zhejiang 2013 Melbecovirus Hedgehog coronavirus 1 Middle East Respiratory Syndrome-associated Coronavirus (MERS-CoV) Pipistrellus coronavirus HKU5 Bamboo bat (Tylonycteris bat) coronavirus HKU4 Nobecovirus Rousettus bat coronavirus GCCDC1 Rouset fruit bat coronavirus HKU9 Sarbecovirus Severe acute respiratory syndrome-associated coronavirus Severe acute respiratory syndrome coronavirus (SARS-CoV) Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2, COVID-19) Delta coronavirus Andecovirus Wigeon coronavirus HKU20 Buldecovirus Brown-eared bulbul coronavirus HKU11-type species Porcine coronavirus HKU15 Munia coronavirus HKU13 White-eye coronavirus HKU16 Herdecovirus Night Heron Coronavirus HKU19 Moordecovirus Common moorhen coronavirus HKU21 Gamma coronavirus ○Cegacovirus Beluga coronavirus SW1 Igacovirus Avian coronavirus - type species

[0315] In some embodiments, the coronavirus is SARS-CoV (Severe Acute Respiratory Syndrome Coronavirus). In some embodiments, the coronavirus is SARS-CoV-2, the virus string that caused COVID-19 (Coronavirus Disease 2019).

[0316] In some embodiments, the virus is a human rhinovirus. In some embodiments, the virus is an influenza virus. In some embodiments, the virus is a picornavirus (e.g., a rhinovirus). In some embodiments, the virus is a human parainfluenza virus. In some embodiments, the virus is a human respiratory syncytial virus. In some embodiments, the virus is an adenovirus. In some embodiments, the virus is an enterovirus. In some embodiments, the virus is a metapneumovirus.

[0317] In some embodiments, the virus is Ebola and Marburg viruses (Filoviridae); Ross River virus, Chikungunya virus, Sindbis virus, Eastern Equine Encephalitis virus (Togaviridae, Alphavirus), Vesicular Stomatitis virus (Rhabdoviridae, Vesiculovirus), Amapari virus, Pichinde virus, Tacaribe virus, Arbovirus, Machupo virus (Arenaviridae, Mamarenavirus), West Nile virus, Dengue virus, Yellow fever virus (Flaviviridae, Flaviviridae). Human immunodeficiency virus type 1 (Retroviridae, Lentivirus); Moloney murine leukemia virus (Retroviridae, Gammaretrovirus); Influenza A virus (Orthomyxoviridae); Respiratory syncytial virus (Paramyxoviridae, Pneumovirinae, Pneumovirus); Vaccinia virus (Poxviridae, Chordopoxvirinae, Orthopoxvirus); Herpes simplex virus type 1, herpes simplex virus type 2 (Herpesviridae, Alphaherpesvirinae, Simplexvirus) Human cytomegalovirus (Herpesviridae, Betaherpesvirinae, Cytomegalovirus); Cytomegalovirus nucleopolyhedrovirus (Baculoviridae, Alphabaculoviridae) (insect viruses); Ebola and Marburg viruses (Filoviridae); Semliki Forest virus, Ross River virus, Chikungunya virus, O'nyong-nyong virus, Sindbis virus, Eastern / Western / Venezuelan equine encephalitis virus (Togaviridae, Alphavirus); Rubella (three-day measles) virus (Togaviridae, Rubivirus) Rabies virus, Lagos bat virus, Mokola virus (Rhabdoviridae, Lyssavirus); Amapari virus, Pichinde virus, Tacaribe virus, Arbovirus, Machupo virus, Guanarito virus, Sabia virus, Lassa virus (Arenaviridae, Mam arenavirus); West Nile virus, Dengue virus, Yellow fever virus, Zika virus, Japanese encephalitis virus, St. Louis encephalitis virus, Tick-borne encephalitis virus, Omsk hemorrhagic fever virus, Kyasanur Forest virus (Flaviviridae, Flavivirus);Human hepatitis C virus (Flaviviridae, Hepacivirus); Human immunodeficiency virus type 1 (Retroviridae, Lentivirus); Influenza A / B viruses (Orthomyxoviridae, Common influenza viruses); Respiratory syncytial virus (Paramyxoviridae, Pneumovirinae, Pneumovirus); Hendra virus, Nipah virus (Paramyxoviridae, Paramyxovirinae, Henipavirus); Measles virus (Paramyxoviridae, Paramyxovirinae, Morbillivirus); Variola major Selected from the group consisting of: (Variola) virus (family Poxviridae, subfamily Chordopoxvirinae, Orthopoxvirus); human hepatitis B virus (family Hepadnaviridae, Orthohepadnavirus); hepatitis delta virus (family Hepadnaviridae) (family Unclassified, Deltavirus); herpes simplex virus type 1, herpes simplex virus type 2 (family Herpesviridae, subfamily Alphaherpesvirinae, simplevirus); human cytomegalovirus (family Herpesviridae, subfamily Betaherpesvirinae, Cytomegalovirus);

[0318] In some embodiments, the virus is selected from the following virus families: Adenoviridae, Papillomaviridae, Polyomaviridae, Herpesviridae, and Poxviridae (these include, but are not limited to, adenovirus, herpes simplex-1, herpes simplex-2, varicella-zoster, Epstein-Barr virus, cytomegalovirus, human herpesvirus 8, human papillomavirus, BK virus, JC virus, chickenpox, and smallpox); • Hepadnaviridae (including but not limited to hepatitis B virus); Parvoviridae (including but not limited to human bocavirus and parvovirus B19), Astroviridae, Caliciviridae, Picornaviridae, Coronaviridae, Flaviviridae, Retroviridae, Togaviridae, Hepeviridae (including, but not limited to, human astrovirus, Norwalk virus, Coxsackievirus, hepatitis A, poliovirus, rhinovirus, severe acute respiratory syndrome virus (SARS), hepatitis C virus, yellow fever virus, dengue virus, West Nile virus, rubella virus, and hepatitis E virus), Arenaviridae, Bunyaviridae, Filoviridae, Orthomyxoviridae, and Paramyxovirus and Rhabdoviridae (including, but not limited to, influenza virus, Guanarito virus, Arbovirus, Lassa virus, Machupo virus, Sabia virus, Crimean-Congo hemorrhagic fever virus, Ebola virus, Marburg virus, Measles virus, Mumps virus, Parainfluenza virus, Respiratory syncytial virus, Human metapneumovirus, Hendra virus, Hipah virus, and Rabies virus), Reoviridae (including, but not limited to, Toravirus, Orbivirus, Coltivirus, and Bannavirus), and Hepatitis D virus. Additional viruses include Rhabdoviridae (including, but not limited to, Vesicular stomatitis virus), Picornaviridae (including, but not limited to, Foot-and-Mouth Disease virus), and Pestiviridae (including, but not limited to, Classical swine fever and bovine viral diarrhea). Arteriviridae (including but not limited to equine arteritis virus, porcine reproductive and respiratory syndrome virus, lactate dehydrogenase-elevating virus, and simian hemorrhagic fever virus), Coronaviridae (including but not limited to infectious bronchitis virus, transmissible gastroenteritis coronavirus (coronoavirus), bovine coronavirus, feline coronavirus, canine coronavirus, and moust hepatitis virus), Toroviridae (including but not limited to Berne virus and Breda virus).Orthomyxoviridae (including but not limited to avian influenza virus and swine influenza virus); Reoviridae (including but not limited to bluetongue virus); Circoviridae (including but not limited to chicken anemia virus, porcine circovirus-1, porcine circovirus-2, psittacine beak and feather disease virus, pigeon circovirus, canary circovirus, and goose circovirus); Asfarviridae (including but not limited to African swine fever virus); Retroviridae (including but not limited to avian leukosis virus, Rous sarcoma virus, mouse mammary tumor virus, murine leukemia virus, feline leukemia virus, boine leukemia virus, walleye cutaneous sarcoma virus, simian and feline immunodeficiency virus, and simian foamy virus). Flaviviridae (including but not limited to tick-borne encephalitis virus, Japanese encephalitis virus, St. Louis encephalitis virus, Israeli-Turkish meningoencephalomyelitis virus, Sitiawan virus, Wesselsbron virus, and sheep louping ill virus); Paramyxoviridae (including but not limited to canine distemper virus, seal distemper virus, whale morbillivirus, Newcastle disease virus, and rinderpest virus).Most confirmed PS-Interception-Susceptible enveloped viruses are RNA viruses, including Ebola and Marburg viruses (Filoviridae); Ross River virus, Chikungunya virus, Sindbis virus, and Eastern Equine Encephalitis virus (Togaviridae, Alphavirus); Vesicular Stomatitis virus (Rhabdoviridae, Vesiculovirus); Amapari virus, Pichinde virus, Tacaribe virus, Arbovirus; Machupo virus (Arenaviridae, Mamarenavirus); West Nile virus, Dengue virus, and Yellow Fever virus (Flaviviridae, Flavivirus); Human Immunodeficiency Virus Type 1 (Retroviridae, Lentivirus); Moloney Murine Leukemia Virus (Retroviridae, Gammaretrovirus); Influenza A virus (Orthomyxoviridae); and Respiratory Syncytial Virus (Paramyxoviridae, Pneumovirinae, Pneumovirus). Confirmed enveloped DNA viruses susceptible to PS interference include: vaccinia virus (family Poxviridae, subfamily Chordopoxvirinae, orthopoxvirus); herpes simplex virus type 1, herpes simplex virus type 2 (family Herpesviridae, subfamily Alphaherpesvirinae, simplex virus); human cytomegalovirus (family Herpesviridae, subfamily Betaherpesvirinae, cytomegalovirus); and cytomegalovirus nucleopolyhedrovirus (family Baculoviridae, family Alphabaculoviridae) (insect virus).Important enveloped RNA viruses that are likely susceptible to PS interference include Ebola and Marburg viruses (Filoviridae); Semliki Forest virus, Ross River virus, Chikungunya virus, O'nyong-nyong virus, Sindbis virus, Eastern / Western / Venezuelan equine encephalitis virus (Togaviridae, Alphavirus); Rubella (three-day measles) virus (Togaviridae, Rubivirus); Rabies virus, Lagos bat virus, Mokola virus (Rhabdoviridae, Lyssavirus); Amapari virus, Pichinde virus, Tacaribe virus, Arbovirus, Machupo virus, Guanarito virus, Sabia virus, Lassa virus (Arenaviridae, Mam arenavirus); West Nile virus, Dengue virus, yellow fever virus, Zika virus, Japanese encephalitis virus, St. Louis encephalitis virus, tick-borne encephalitis virus, Omsk hemorrhagic fever virus, Kyasanur Forest virus (Flaviviridae, Flavivirus); human hepatitis C virus (Flaviviridae, Hepacivirus); human immunodeficiency virus type 1 (Retroviridae, Lentivirus); influenza A / B viruses (Orthomyxoviridae, Common influenza virus); respiratory syncytial virus (Paramyxoviridae, Pneumovirinae, Pneumovirus); Hendra virus, Nipah virus (Paramyxoviridae, Paramyxovirinae, Henipavirus); measles virus (Paramyxoviridae, Paramyxovirinae, Morbillivirus). Potential enveloped DNA viruses susceptible to PS interference include: Variola major (Variola) virus (Family: Poxviridae, Subfamily: Chordopoxvirinae, Orthopoxvirus); human hepatitis B virus (Family: Hepadnaviridae, Orthohepadnavirus); hepatitis delta virus (Hepatitis D virus) (Family: Unclassified, Deltavirus); herpes simplex virus type 1, herpes simplex virus type 2 (Family: Herpesviridae, Subfamily: Alphaherpesvirinae, Simplevirus); and human cytomegalovirus (Family: Herpesviridae, Subfamily: Betaherpesvirinae, Cytomegalovirus).

[0319] In some embodiments, the present invention provides methods for treating a viral infection, the methods comprising administering to the eye (retina, sclera, lens, iris, pupil, cornea, macula, retinal blood vessels, optic nerve), ear (ear canal, bones of the middle ear, tympanic membrane, Eustachian tube, cochlear nerve, vestibular nerve, semicircular canals, cochlea), nose (nostrils, vestibule, nasal turbinates, paranasal sinuses), oral cavity and oropharynx (lips, gums, hard and soft palate, salivary glands, uvula, tonsils, adenoids, teeth), central nervous system and associated structures (brain, cerebrum, cerebellum, olfactory bulb, olfactory bulb, sclera, retina, optic nerve, ear), nose (nostrils, vestibule, nasal conchae, paranasal sinuses), central nervous system and associated structures (brain, cerebrum, cerebellum, olfactory bulb, sclera ... bulb), hypothalamus, reticular formation, medulla oblongata, meninges, ventricles, thalamus, pineal gland), peripheral and enteric nervous systems (autonomic nerves, sympathetic nerves, parasympathetic nerves, sensory nerves, ganglion cells, ganglia), skin (epidermis, dermis, appendicular structures, sebaceous glands, hair follicles, stratum corneum, granular cells, spinous cells, sweat glands), respiratory tract (larynx, trachea, bronchi, bronchioles, lungs, alveoli, pleura), digestive tract (pharynx, esophagus, stomach, small intestine, Dideum, jejunum, ileum, colon, rectum, appendix, anus), liver (intracerebrospinal fluid, gallbladder, liver, hepatocytes, ductules, ducts of Hering), pancreas (endocrine pancreas, exocrine pancreas, pancreatic ducts, pancreatic acini), urinary tract (renal cortex, tubules, renal pelvis, glomeruli, ureters, bladder, urethra), male reproductive tract (prostate, testes, scrotum, epididymis, vas deferens, glans, foreskin, corpus spongiosum, corpus cavernosum, Cowper's gland), female This includes treating diseases caused by virus-induced or virus-related damage and disease (necrosis, inflammation, sclerosis) in tissues including, but not limited to, the reproductive tract (ovaries, fimbria, fallopian tubes, uterus, endometrium, endocervix, cervical glands, cervix, cervico-vaginal region, vagina, labia, placenta), endocrine system (pineal gland, pituitary gland, thyroid gland, parathyroid gland, adrenal glands, adrenal cortex, adrenal medulla), cardiovascular system (heart, pericardium, myocardium, endocardium, atria, ventricles, coronary arteries, tricuspid valve, aortic valve, mitral valve, pulmonary valve, aorta, arteries, arterioles, capillaries, venules, veins, inferior vena cava, superior vena cava, pulmonary artery, pulmonary vein), musculoskeletal system (bones, tendons, ligaments, skeletal muscle, smooth muscle, fascia), and blood (platelets, red blood cells, white blood cells, and all their precursors, and bone marrow).

[0320] In certain embodiments, a compound or composition of the invention is administered to a patient intranasally, hi other embodiments, a compound or composition of the invention is administered to a patient via pulmonary inhalation.

[0321] The compounds and compositions according to the methods of the present invention may be administered in any amount and using any route of administration effective for treating or reducing the severity of a disease, disorder, and / or condition. 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 condition, the particular drug, its mode of administration, and the like. The compounds and compositions according to the methods of the present invention are preferably formulated in unit dosage form for ease of administration and uniformity of dosage. As used herein, the term "unit dosage form" refers to a physically discrete unit of drug appropriate for the patient being treated. However, it will be understood that the total daily usage of the compounds and compositions will be determined by the attending physician within the scope of sound medical judgment. The specific effective dosage level for any particular patient or organism will depend on a variety of factors, including the disorder and severity of the disorder being treated; 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, route of administration, and excretion rate of the specific compound used; the duration of treatment; drugs used in combination with or concurrently with the specific compound used, and similar factors well known in the medical field. The term "patient", as used herein, means an animal, preferably a mammal, and most preferably a human.

[0322] The pharmaceutically acceptable compositions of the present invention can be administered to humans and other animals orally, rectally, parenterally, intracisternally, intravaginally, intraperitoneally, topically (such as by powder, ointment, or drops), bucally, as an oral or nasal spray, etc., depending on the severity of the disease or disorder being treated. In certain embodiments, the compounds of the present invention may be administered orally or parenterally at dosage levels of about 0.01 mg / kg to about 50 mg / kg, preferably about 1 mg / kg to about 25 mg / kg of subject body weight per day, one or more times daily to achieve the desired therapeutic effect.

[0323] Liquid dosage forms for oral administration include, but are not limited to, pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups, and elixirs.In addition to the active compound, liquid dosage forms may contain inert diluents commonly used in the art, such as water or other solvents, solubilizers and emulsifiers, such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils (especially cottonseed oil, peanut oil, corn oil, germ oil, olive oil, castor oil, and sesame oil), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycol, and fatty acid esters of sorbitan, and mixtures thereof.In addition to inert diluents, oral compositions may also contain adjuvants, such as wetting agents, emulsifiers and suspending agents, sweeteners, flavoring agents, and aromatics.

[0324] Injectable preparations, for example, sterile injectable aqueous or oleaginous suspensions, may be formulated according to known techniques using suitable dispersing or wetting agents and suspending agents. Sterile injectable preparations may also be sterile injectable solutions, suspensions, or emulsions in non-toxic parenterally acceptable diluents or solvents, for example, as a solution in 1,3-butanediol. Among the acceptable vehicles and solvents that may be used are water, Ringer's solution (USP), and isotonic sodium chloride solution. In addition, sterile fixed oils are conventionally used as solvents or suspending media. For this purpose, any non-irritating fixed oil, including synthetic mono- or diglycerides, may be used. In addition, fatty acids such as oleic acid may be used in the preparation of injectables.

[0325] Injectable preparations can be sterilized, for example, by filtration through a bacterial-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 before use.

[0326] To prolong the effect of compounds as described herein, it is often desirable to slow the absorption of the compound from subcutaneous or intramuscular injection. This may be accomplished by using a liquid suspension of crystalline or amorphous material with poor water solubility. The rate of absorption of the compound then depends on its dissolution rate, which may in turn depend on crystal size and crystalline form. Alternatively, delayed absorption of a parenterally administered compound form can be accomplished by dissolving or suspending the compound in an oil vehicle. Injectable depot forms are made by forming microencapsulated matrices of the compound in biodegradable polymers such as polylactide-polyglycolide. Depending on the ratio of compound to polymer and the nature of the particular polymer used, the release rate of the compound can be controlled. Examples of other biodegradable polymers include poly(orthoesters) and poly(anhydrides). Depot injectable formulations can also be prepared by entrapping the compound in liposomes or microemulsions that are compatible with body tissues.

[0327] Compositions for rectal or vaginal administration are preferably suppositories, which can be prepared by mixing a compound of the invention 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 to release the active compound.

[0328] 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 inert pharmaceutically acceptable excipient or carrier such as sodium citrate or dicalcium phosphate, and / or a) fillers or extenders such as starches, lactose, sucrose, glucose, mannitol, and silicic acid; b) binders such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidinone, sucrose, and acacia; c) humectants such as glycerol; d) disintegrating agents such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate; e) solution retarding agents such as paraffin; f) absorption accelerators such as quaternary ammonium compounds; g) humectants such as, for example, cetyl alcohol and glycerol monostearate; h) absorbents such as kaolin and bentonite clay; and i) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof. In the case of capsules, tablets and pills, the dosage form may also comprise buffering agents.

[0329] Solid compositions of a similar type may also be used as fillers in soft- and hard-filled gelatin capsules using excipients such as lactose or milk sugar, and high molecular weight polyethylene glycols, and the like. Solid dosage forms such as tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells, such as enteric coatings and other coatings well known in the pharmaceutical formulating art. They may optionally contain opacifying agents and can also be of a composition that they release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally in a delayed manner. Examples of embedding compositions that can be used include polymeric substances and waxes. Solid compositions of a similar type may also be used as fillers in soft- and hard-filled gelatin capsules using excipients such as lactose or milk sugar, and high molecular weight polyethylene glycols, and the like.

[0330] The active compound may also be in microencapsulated form with one or more of the excipients described above. Solid dosage forms such as tablets, dragees, capsules, pills, and granules may be prepared with coatings and shells, such as enteric coatings, release-controlling coatings, and other coatings well known in the art of pharmaceutical formulation. In such solid dosage forms, the active compound may be admixed with at least one inert diluent, such as sucrose, lactose, or starch. Such dosage forms may also contain, as is common practice, additional substances other than inert diluents, such as tableting lubricants and other tableting aids, such as magnesium stearate and microcrystalline cellulose. In the case of capsules, tablets, and pills, the dosage forms may also contain buffering agents. They may optionally contain opacifying agents and may be of a composition that releases the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally in a delayed manner. Examples of embedding compositions that may be used include polymeric substances and waxes.

[0331] Dosage forms for topical or transdermal administration of the compounds of the present invention include ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalants, or patches. The active ingredient is admixed under sterile conditions with a pharmaceutically acceptable carrier and any needed preservatives or buffers, if required. Ophthalmic formulations, ear drops, and eye drops are also contemplated within the scope of the present invention. Furthermore, the present invention contemplates the use of transdermal patches, which have the added advantage of providing controlled delivery of the compound to the body. Such dosage forms can be made by dissolving or dispensing the active compound in the proper medium. Absorption enhancers can also be used to increase the flux of the compound across the skin. The rate can be controlled by either providing a rate-controlling membrane or by dispersing the compound in a polymer matrix or gel.

[0332] The following examples are provided for illustrative purposes only and should not be construed as limiting the invention in any way. [Example]

[0333] As illustrated in the Examples below, in certain exemplary embodiments, compounds are prepared according to the following general procedures. While these general methods are illustrated for the synthesis of certain specific compounds of the invention, it will be understood that the following general methods, and other methods known to those skilled in the art, are applicable to all compounds as described herein, and each subclass and species of these compounds. Example 1. Synthesis of certain compounds Scheme 1: Route for compound 787 [ka] Scheme 2: Route for compounds 723-s, 730-s, 736-s, 737-s, 745-s, 757-s [ka] Scheme 3: Route for compound 724-s [ka] Scheme 4: Route for compound 726-s [ka] Scheme 5: Route for compound 731-s [ka] Scheme 6: Route for compound 733-s [ka] Scheme 7: Routes for compounds 711-s, 746-s, 747-s, and 751-s [ka] Scheme 8: Route for compound 744-s [ka] Scheme 9: Route for compounds 749-s, 760-s, and 772-s [ka] Scheme 10: Route for compound 750-s [ka] Scheme 11: Route for compound 756-s [ka] Scheme 12: Route for compound 758-s [ka] Scheme 13: Route for compounds 761-s to 764-s, 767-s, 770-s, 778-s to 783-s, and 791-s to 792-s [ka] Scheme 14: Route for compound 766-s [ka] Scheme 15: Routes for compounds I-1, I-2, I-5 to I-16, I-18, I-20 to I-52, I-54, I-55, I-57 to I-59 [ka] Scheme 16: Route to Compounds I-4 and I-19 [ka] Scheme 17: Route for Compound I-3 [ka] Scheme 18: Route for compound I-17 [ka] Scheme 19: Route for compound I-53 [ka] Scheme 20: Route for Compound I-56 [ka]

[0334] General Information: All evaporations were performed in vacuo using a rotary evaporator. Analytical samples were dried in vacuo (1-5 mmHg) at room temperature. Thin-layer chromatography (TLC) was performed on silica gel plates, and spots were visualized by UV light (214 and 254 nm). Column and flash chromatographic purifications were performed using silica gel (200-300 mesh). Solvent systems are reported as mixtures by volume. All NMR spectra were recorded on a Bruker 400 (400 MHz) spectrometer. 1H chemical shifts are reported as δ values ​​in ppm using deuterated solvents as internal standards. Data are reported as follows: chemical shift, multiplicity (s = singlet, d = doublet, t = triplet, q = quartet, br = broad, m = multiplet), coupling constant (Hz), and integration.

[0335] General Information: All evaporations were performed in vacuo using a rotary evaporator. Analytical samples were dried in vacuo (1-5 mmHg) at room temperature. Thin-layer chromatography (TLC) was performed on silica gel plates, and spots were visualized by UV light (214 and 254 nm). Column and flash chromatographic purifications were performed using silica gel (200-300 mesh). Solvent systems are reported as mixtures by volume. All NMR spectra were recorded on a Bruker 400 (400 MHz) spectrometer. 1H chemical shifts are reported as δ values ​​in ppm using deuterated solvents as internal standards. Data are reported as follows: chemical shift, multiplicity (s = singlet, d = doublet, t = triplet, q = quartet, br = broad, m = multiplet), coupling constant (Hz), and integration.

[0336] LCMS spectra were obtained on an Agilent 1200 series 6110 or 6120 mass spectrometer using electrospray ionization, and unless otherwise specified, general LCMS conditions were as follows: Method A (Agilent LCMS 1200-6110, column: Waters X-Bridge C18 (50 mm × 4.6 mm × 3.5 μm); column temperature: 40 °C; flow rate: 3.0 mL / min; mobile phase: 95% [water + 0.05% TFA] and 5% [CH3CN + 0.05% TFA] in 0.8 min to 0% [water + 0.05% TFA] and 100% [CH3CN + 0.05% TFA], then under these conditions for 0.4 min, and finally changed to 95% [water + 0.05% TFA] and 5% [CH3CN + 0.05% TFA] in 0.01 min). Method B (Agilent LCMS 1200-6110, column: Waters X-Bridge C18 (50 mm × 4.6 mm × 3.5 μm); column temperature: 40 °C; flow rate: 2.0 mL / min; mobile phase: 95% [water + 0.05% TFA] and 5% [CH3CN + 0.05% TFA] in 1.6 min to 0% [water + 0.05% TFA] and 100% [CH3CN + 0.05% TFA], then under these conditions for 1.4 min, and finally 95% [water + 0.05% TFA] and 5% [CH3CN + 0.05% TFA] in 0.05 min, and under these conditions for 0.7 min). Method C (Agilent LCMS 1200-6120, column: Waters X-Bridge C18 (50 mm × 4.6 mm × 3.5 μm); column temperature: 40 °C; flow rate: 2.0 mL / min; mobile phase: from 95% [water + 10 mM NH4HCO3] and 5% [CH3CN] in 1.6 min to 0% [water + 10 mM NH4HCO3] and 100% [CH3CN], then under these conditions for 1.4 min, and finally under these conditions for 0.1 min to 95% [water + 10 mM NH4HCO3] and 5% [CH3CN], and then under these conditions for 0.7 min). Method D (Agilent LCMS 1200-6120, column: Waters X-Bridge C18 (50 mm × 4.6 mm × 3.5 μm); column temperature: 45 °C; flow rate: 2.3 mL / min; mobile phase: from 95% [water + 10 mM NH4HCO3] and 5% [CH3CN] in 1.75 min to 0% [water + 10 mM NH4HCO3] and 100% [CH3CN], then under these conditions for 0.8 min, and finally under these conditions for 0.1 min to 95% [water + 10 mM NH4HCO3] and 5% [CH3CN], and then under these conditions for 0.1 min).

[0337] Experimental section Synthesis of methyl 3-amino-6-(thiophen-2-yl)pyrazine-2-carboxylate (787) [ka] A mixture of SM (1.0 g, 4.31 mmol), 4,4,5,5-tetramethyl-2-(thiophen-2-yl)-1,3,2-dioxaborolane (1.36 g, 6.47 mmol), Pd(dppf)Cl (315 mg, 0.431 mmol), and NaCO (1.84 g, 8.62 mmol) in dioxane / HO (v / v = 5 / 1, 10.0 mL) was stirred at 85 °C for 16 h under a N atmosphere. Upon completion of the reaction, it was concentrated and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 3 / 1) to give 787 (670 mg, 66.1% yield) as a brown solid.

[0338] Synthesis of 1-(4-(difluoromethoxy)phenyl)-3-methylbutan-1-ol (723-2) [ka] To a solution of 723-1 (2.0 g, 11.6 mmol) in THF (20.0 mL) was added isobutylmagnesium bromide (1.0 M in THF, 17.4 mL, 17.4 mmol). The reaction was stirred at room temperature overnight. Upon completion, it was poured into aqueous NH4Cl (saturated, 50.0 mL) and extracted with EtOAc (80.0 mL × 3). The organic phases were combined, washed with HO (50.0 mL) and brine (80.0 mL), then dried over anhydrous Na2SO4 and concentrated to give the crude product, which was used directly in the next step without further purification to give 723-2 (1.30 g, 48.6% yield) as a yellow oil.

[0339] Synthesis of 1-(4-(difluoromethoxy)phenyl)-3-methylbutan-1-one (723-3) [ka] To a solution of 723-2 (1.30 g, 5.65 mmol) in CHCl (100 mL) was added PCC (2.43 g, 11.3 mmol). The reaction was stirred at room temperature for 2 hours. Upon completion of the reaction, it was concentrated and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 50 / 1) to give 723-3 (1.20 g, 93.1% yield) as a colorless oil.

[0340] Synthesis of 2-bromo-1-(4-(difluoromethoxy)phenyl)-3-methylbutan-1-one (723-4) [ka] A mixture of 723-3 (1.20 g, 5.26 mmol) and PTAT (2.96 g, 7.89 mmol) in THF (50.0 mL) was stirred at room temperature for 16 hours. Upon completion of the reaction, it was concentrated, and the residue was dissolved in HO (30.0 mL) and then extracted with EtOAc (50.0 mL × 2). The organic layers were combined, washed with HO (30.0 mL × 2) and brine (30.0 mL), and then dried over anhydrous NaSO. The solution was concentrated to give the crude product, which was used directly in the next step without further purification to give 723-4 (1.61 g, 100% yield) as a brown oil.

[0341] Synthesis of 1-(4-(difluoromethoxy)phenyl)-3-methyl-2-thiocyanatobutan-1-one (723-5) [ka] A mixture of 723-4 (1.61 g, 5.24 mmol) and NaSCN (849 mg, 10.5 mmol) in EtOH (50.0 mL) was stirred for 3 h at 80° C. When the reaction was complete, it was concentrated and purified by silica gel column chromatography (petroleum ether / ethyl acetate=3 / 1) to give 723-5 (1.10 g, 73.5% yield) as a yellow solid.

[0342] Synthesis of 2-bromo-4-(4-(difluoromethoxy)phenyl)-5-isopropylthiazole (723-s) [ka] A mixture of 723-5 (1.10 g, 3.86 mmol) and HBr (2.0 M in AcOH, 5.0 mL) in AcOH (10.0 mL) was stirred at 60 °C for 1 h. Upon completion of the reaction, it was poured into HO (100 mL) and extracted with EtOAc (100 mL × 3). The organic phases were combined, washed with HO (80.0 mL) and brine (80.0 mL), then dried over anhydrous NaSO, concentrated, and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 10 / 1) to give 723-s (1.0 g, 74.5% yield) as a yellow oil.

[0343] Synthesis of tert-butyl (2-(4-(2-bromo-5-isobutylthiazol-4-yl)-2-chlorophenoxy)ethyl)carbamate (724-1) [ka] A mixture of 568-8 (300 mg, 0.865 mmol), tert-butyl (2-bromoethyl)carbamate (233 mg, 1.04 mmol), and K2CO3 (239 mg, 1.73 mmol) in DMF (5.0 mL) was stirred at 60 °C for 16 h. Upon completion of the reaction, it was poured into HO (80.0 mL) and extracted with EtOAc (80.0 mL × 3). The combined organic phases were washed with HO (50.0 mL) and brine (50.0 mL), then dried over anhydrous Na2SO4, concentrated, and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 8 / 1) to give 724-1 (290 mg, 68.4% yield) as a colorless oil.

[0344] Synthesis of tert-butyl (2-(4-(2-bromo-5-isobutylthiazol-4-yl)-2-chlorophenoxy)ethyl)(methyl)carbamate (724-s) [ka] A mixture of 724-1 (200 mg, 0.408 mmol) and NaH (60% in mineral oil, 24.5 mg, 0.612 mmol) in THF (8.0 mL) was stirred at room temperature for 1 h. Then MeI (69.6 mg, 0.490 mmol) was added to the reaction. The mixture was stirred at 60 °C for 16 h. Upon completion of the reaction, it was quenched with HO (50.0 mL) and extracted with EtOAc (80.0 mL × 3). The organic phases were combined, washed with HO (50.0 mL) and brine (50.0 mL), then dried over anhydrous NaSO and concentrated to give the crude product, which was used directly in the next step without further purification to give 724-s (180 mg, 87.5% yield) as a colorless oil.

[0345] Synthesis of 3,5-dichloro-4-methoxybenzaldehyde (726-2) [ka] A mixture of 726-1 (3.0 g, 15.7 mmol), CHCl (3.34 g, 23.6 mmol), and KCO (4.33 g, 31.4 mmol) in DMF (10.0 mL) was stirred at room temperature for 16 h. Upon completion of the reaction, it was poured into HO (100 mL) and extracted with EtOAc (100 mL × 3). The organic phases were combined, washed with HO (80.0 mL) and brine (80.0 mL), then dried over anhydrous NaSO, and concentrated to give the crude product, which was used directly in the next step without further purification to give 726-2 (2.10 g, 65.2% yield) as a yellow oil.

[0346] Synthesis of 1-(3,5-dichloro-4-methoxyphenyl)-4-methylpentan-1-ol (726-3) [ka] To a solution of 726-2 (2.10 g, 10.2 mmol) in THF (20.0 mL) was added isopentylmagnesium bromide (1.0 M in THF, 15.4 mL, 15.4 mmol). The reaction was stirred at room temperature overnight. Upon completion, it was poured into aqueous NH4Cl (saturated, 50.0 mL) and extracted with EtOAc (80.0 mL × 3). The organic phases were combined, washed with HO (50.0 mL) and brine (50.0 mL), then dried over anhydrous Na2SO4, concentrated, and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 8 / 1) to give 726-3 (1.60 g, 59.4% yield) as a yellow oil.

[0347] Synthesis of 1-(3,5-dichloro-4-methoxyphenyl)-4-methylpentan-1-one (726-4) [ka] To a solution of 726-3 (1.60 g, 5.77 mmol) in CHCl (80.0 mL) was added PCC (2.49 g, 11.5 mmol). The reaction was stirred at room temperature for 1 h. Upon completion of the reaction, it was concentrated and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 20 / 1) to give 726-4 (1.30 g, 81.8% yield) as a yellow solid.

[0348] Synthesis of 2-bromo-1-(3,5-dichloro-4-methoxyphenyl)-4-methylpentan-1-one (726-5) [ka] A mixture of 726-4 (1.30 g, 4.73 mmol) and PTAT (2.66 g, 7.09 mmol) in THF (100 mL) was stirred at room temperature for 1 h. Upon completion of the reaction, it was concentrated, and the residue was dissolved in HO (50 mL) and then extracted with EtOAc (80 mL × 2). The organic layers were combined, washed with HO (30 mL × 2) and brine (50 mL), and then dried over anhydrous NaSO. The solution was concentrated to give the crude product, which was used directly in the next step without further purification to give 726-5 (1.60 g, 100% yield) as a brown oil.

[0349] Synthesis of 4-(3,5-dichloro-4-methoxyphenyl)-5-isobutylthiazol-2-amine (726-s) [ka] A mixture of 726-5 (1.60 g, 4.51 mmol) and thiourea (687 mg, 9.04 mmol) in EtOH (20.0 mL) was stirred for 1 h at 90° C. Upon completion of the reaction, it was concentrated and purified by silica gel column chromatography (petroleum ether / ethyl acetate=3 / 1) to give 726-s (800 mg, 53.4% ​​yield) as a yellow solid.

[0350] Synthesis of 1-(6-methoxypyridin-3-yl)-4-methylpentan-1-ol (731-2) [ka] To a solution of 731-1 (4.0 g, 29.2 mmol) in THF (40.0 mL) was added isobutylmagnesium bromide (1.0 M in THF, 43.8 mL, 43.8 mmol). The reaction was stirred at room temperature overnight. Upon completion, it was poured into aqueous NH4Cl (saturated, 100 mL) and extracted with EtOAc (80.0 mL × 3). The organic phases were combined, washed with HO (50.0 mL) and brine (80.0 mL), then dried over anhydrous Na2SO4, concentrated, and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 8 / 1) to give 731-2 (4.30 g, 70.4% yield) as a yellow oil.

[0351] Synthesis of 1-(6-methoxypyridin-3-yl)-4-methylpentan-1-one (731-3) [ka] To a solution of 731-2 (4.30 g, 20.5 mmol) in CHCl (150 mL) was added PCC (8.86 g, 41.1 mmol). The reaction was stirred at room temperature for 2 h. Upon completion of the reaction, it was concentrated and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 20 / 1) to give 731-3 (4.0 g, 93.9% yield) as a yellow solid.

[0352] Synthesis of 2-bromo-1-(6-methoxypyridin-3-yl)-4-methylpentan-1-one (731-4) [ka] A mixture of 731-3 (2.0 g, 9.66 mmol) and Br (1.68 g, 10.6 mmol) in CHCl (100 mL) was stirred at 80 °C for 16 h. Upon completion of the reaction, it was concentrated and dissolved in EtOAc (100 mL). The organic phase was washed with HO (50.0 mL) and brine (50.0 mL), then dried over anhydrous NaSO and concentrated to give the crude product, which was used directly in the next step without further purification to give 731-4 (2.76 g, 100% yield) as a brown oil.

[0353] Synthesis of 1-(6-hydroxypyridin-3-yl)-4-methyl-2-thiocyanatopentan-1-one (731-5) [ka] A mixture of 731-4 (2.76 g, 9.66 mmol) and NaSCN (1.57 g, 19.3 mmol) in EtOH (80.0 mL) was stirred for 3 h at 80° C. When the reaction was complete, it was concentrated and purified by silica gel column chromatography (petroleum ether / ethyl acetate=1 / 1) to give 731-5 (540 mg, 22.4% yield) as a yellow solid.

[0354] Synthesis of 5-(2-bromo-5-isobutylthiazol-4-yl)pyridin-2-ol (731-6) [ka] A mixture of 731-5 (540 mg, 2.16 mmol) and HBr (2.0 M in AcOH, 2.0 mL) in AcOH (5.0 mL) was stirred at 40 °C for 1 h. Upon completion of the reaction, it was poured into HO (50.0 mL) and extracted with EtOAc (80.0 mL × 3). The organic phases were combined, washed with HO (50.0 mL) and brine (50.0 mL), then dried over anhydrous NaSO, concentrated, and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 6 / 1) to give 731-6 (230 mg, 34.0% yield) as a yellow oil.

[0355] Synthesis of 2-bromo-5-isobutyl-4-(6-methoxypyridin-3-yl)thiazole (731-s) [ka] A mixture of 731-6 (230 mg, 0.734 mmol), CHCl (156 mg, 1.10 mmol), and KCO (203 mg, 1.47 mmol) in DMF (3.0 mL) was stirred at room temperature for 16 h. Upon completion of the reaction, it was poured into HO (50.0 mL) and extracted with EtOAc (80.0 mL × 3). The combined organic phases were washed with HO (50.0 mL) and brine (50.0 mL), then dried over anhydrous NaSO, concentrated, and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 10 / 1) to give 731-s (165 mg, 68.7% yield) as a yellow oil.

[0356] Synthesis of 1-(4-methoxyphenyl)-4-methylpentan-1-ol (733-2) [ka] To a solution of 733-1 (10.0 g, 73.4 mmol) in THF (100 mL) was added isopentylmagnesium bromide (1.0 M in THF, 110 mL, 110 mmol). The reaction was stirred at room temperature overnight. Upon completion, it was poured into aqueous NH4Cl (saturated, 200 mL) and extracted with EtOAc (150 mL × 3). The organic phases were combined, washed with HO (100 mL) and brine (100 mL), then dried over anhydrous Na2SO4, concentrated, and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 12 / 1) to give 733-2 (13.5 g, 88.3% yield) as a yellow oil.

[0357] Synthesis of 1-(4-methoxyphenyl)-4-methylpentan-1-one (733-3) [ka] To a solution of 733-2 (13.5 g, 65.5 mmol) in CHCl (500 mL) was added PCC (28.3 g, 13.1 mmol). The reaction was stirred at room temperature for 2 hours. Upon completion of the reaction, it was concentrated and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 30 / 1) to give 733-3 (13.3 g, 99.5% yield) as a yellow solid.

[0358] Synthesis of 2-bromo-1-(4-methoxyphenyl)-4-methylpentan-1-one (733-4) [ka] A mixture of 733-3 (11.0 g, 53.4 mmol) and PTAT (30.0 g, 80.1 mmol) in THF (300 mL) was stirred at room temperature for 16 hours. Upon completion of the reaction, it was concentrated, and the residue was dissolved in HO (150 mL) and then extracted with EtOAc (200 mL × 2). The organic layers were combined, washed with HO (100 mL × 2) and brine (150 mL), and then dried over anhydrous NaSO. The solution was concentrated to give the crude product, which was used directly in the next step without further purification to give 733-4 (15.2 g, 100% yield) as a brown oil.

[0359] Synthesis of 5-isobutyl-4-(4-methoxyphenyl)thiazol-2-amine (733-5) [ka]

[0360] A mixture of 733-4 (15.2 g, 53.4 mmol) and thiourea (8.12 g, 106.8 mmol) in EtOH (200 mL) was stirred for 16 h at 70° C. When the reaction was complete, it was concentrated and purified by silica gel column chromatography (petroleum ether / ethyl acetate=3 / 1) to give 733-5 (14.0 g, 100% yield) as a yellow solid.

[0361] Synthesis of 2-bromo-5-isobutyl-4-(4-methoxyphenyl)thiazole (733-6) [ka] A mixture of 733-5 (14.0 g, 53.4 mmol), t-BuONO (8.25 g, 80.0 mmol), and CuBr (17.9 g, 80.0 mmol) in CHCN (200 mL) was stirred at room temperature for 2 h. Upon completion of the reaction, it was concentrated to give the crude product, which was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 20 / 1) to give 733-6 (4.80 g, 27.6% yield) as a yellow oil.

[0362] Synthesis of 4-(2-bromo-5-isobutylthiazol-4-yl)phenol (733-7) [ka] A mixture of 733-6 (2.40 g, 7.36 mmol) and BBr (17% in CHCl, 18.4 mL, 18.4 mmol) in CHCl (80.0 mL) was stirred at room temperature for 16 h. When the reaction was complete, it was washed with HO (50.0 mL × 3). The organic layer was concentrated and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 6 / 1) to give 733-7 (800 mg, 34.8% yield) as a yellow oil.

[0363] Synthesis of 2-bromo-5-isobutyl-4-(4-(2,2,2-trifluoroethoxy)phenyl)thiazole (733-s) [ka] A mixture of 733-7 (200 mg, 0.641 mmol), 2,2,2-trifluoroethyl trifluoromethanesulfonate (223 mg, 0.961 mmol), and KCO (177 mg, 1.28 mmol) in DMF (3.0 mL) was stirred at room temperature for 16 hours. Upon completion of the reaction, it was poured into HO (50.0 mL) and extracted with EtOAc (80.0 mL × 3). The combined organic phases were washed with HO (50.0 mL) and brine (50.0 mL), then dried over anhydrous NaSO, concentrated, and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 10 / 1) to give 733-s (183 mg, 72.5% yield) as a yellow oil.

[0364] Synthesis of 2-bromo-4-(4-ethoxyphenyl)-5-isobutylthiazole (741-s) [ka] A mixture of 733-7 (180 mg, 0.576 mmol), iodoethane (135 mg, 0.865 mmol), and KCO (159 mg, 1.15 mmol) in DMF (3.0 mL) was stirred at room temperature for 16 h. Upon completion of the reaction, it was poured into HO (50.0 mL) and extracted with EtOAc (80.0 mL × 3). The combined organic phases were washed with HO (50.0 mL) and brine (50.0 mL), then dried over anhydrous NaSO, concentrated, and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 10 / 1) to give 741-s (170 mg, 86.7% yield) as a colorless oil.

[0365] Synthesis of 4-cyclopropoxybenzaldehyde (744-2) [ka] A mixture of 744-1 (5.0 g, 40.9 mmol), bromocyclopropane (9.91 g, 81.9 mmol), and CsCO (26.7 g, 81.9 mmol) in DMF (30.0 mL) was stirred in a sealed state at 200 °C for 8 h. Upon completion of the reaction, it was poured into HO (300 mL) and extracted with EtOAc (200 mL × 3). The organic phases were combined, washed with HO (100 × 2 mL) and brine (150 mL), then dried over anhydrous NaSO and concentrated to give the crude product, which was used directly in the next step without further purification to give 744-2 (3.40 g, 51.2% yield) as a colorless oil.

[0366] Synthesis of 1-(4-cyclopropoxyphenyl)-4-methylpentan-1-ol (744-3) [ka] To a solution of 744-2 (4.0 g, 24.7 mmol) in THF (30.0 mL) was added isobutylmagnesium bromide (1.0 M in THF, 37.0 mL, 37.0 mmol). The reaction was stirred at room temperature for 16 h. Upon completion, it was poured into aqueous NH4Cl (saturated, 100 mL) and extracted with EtOAc (80.0 mL × 3). The organic phases were combined, washed with HO (50.0 mL) and brine (80.0 mL), then dried over anhydrous Na2SO4 and concentrated to give the crude product, which was used directly in the next step without further purification to give 744-3 (3.80 g, 65.8% yield) as a yellow oil.

[0367] Synthesis of 1-(4-cyclopropoxyphenyl)-4-methylpentan-1-one (744-4) [ka] To a solution of 744-3 (3.80 g, 16.2 mmol) in CHCl (200 mL) was added PCC (6.99 g, 32.4 mmol). The reaction was stirred at room temperature for 2 hours. Upon completion of the reaction, it was concentrated and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 20 / 1) to give 744-4 (3.50 g, 92.8% yield) as a yellow solid.

[0368] Synthesis of 2-bromo-1-(4-cyclopropoxyphenyl)-4-methylpentan-1-one (744-5) [ka] A mixture of 744-4 (3.50 g, 15.1 mmol) and PTAT (8.49 g, 22.6 mmol) in THF (200 mL) was stirred at room temperature for 16 hours. Upon completion of the reaction, it was concentrated, and the residue was dissolved in HO (100 mL) and then extracted with EtOAc (100 mL × 2). The organic layers were combined, washed with HO (50.0 mL × 2) and brine (80.0 mL), and then dried over anhydrous NaSO. The solution was concentrated to give the crude product, which was used directly in the next step without further purification to give 744-5 (4.69 g, 100% yield) as a brown oil.

[0369] Synthesis of 4-(4-cyclopropoxyphenyl)-5-isobutylthiazol-2-amine (744-6) [ka] A mixture of 744-5 (4.69 g, 15.1 mmol) and thiourea (2.29 g, 30.2 mmol) in EtOH (100 mL) was stirred for 12 h at 70° C. When the reaction was complete, it was concentrated and purified by silica gel column chromatography (petroleum ether / ethyl acetate=3 / 1) to give 744-6 (2.80 g, 64.4% yield) as a yellow solid.

[0370] Synthesis of 2-bromo-4-(4-cyclopropoxyphenyl)-5-isobutylthiazole (744-s) [ka] A mixture of 744-6 (2.80 g, 9.71 mmol), t-BuONO (1.50 g, 14.6 mmol), and CuBr (3.26 g, 14.6 mmol) in CHCN (100 mL) was stirred at room temperature for 2 h. Upon completion of the reaction, it was concentrated to give the crude product, which was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 20 / 1) to give 744-s (1.20 g, 35.1% yield) as a yellow oil.

[0371] Synthesis of 2-cyclopropyl-1-(4-methoxyphenyl)ethanol (749-2) [ka] To a solution of 733-1 (5.0 g, 36.7 mmol) in THF (50.0 mL) was added (cyclopropylmethyl)magnesium bromide (1.0 M in THF, 55.1 mL, 55.1 mmol). The reaction was stirred at room temperature for 16 h. Upon completion, it was poured into aqueous NH4Cl (saturated, 150 mL) and extracted with EtOAc (100 mL × 3). The organic phases were combined, washed with HO (80.0 mL) and brine (80.0 mL), then dried over anhydrous Na2SO4 and concentrated to give the crude product, which was used directly in the next step without further purification to give 749-2 (5.50 g, 77.9% yield) as a yellow oil.

[0372] Synthesis of 2-cyclopropyl-1-(4-methoxyphenyl)ethanone (749-3) [ka] To a solution of 749-2 (5.50 g, 28.6 mmol) in CHCl (100 mL) was added PCC (12.3 g, 57.2 mmol). The reaction was stirred at room temperature for 2 h. Upon completion of the reaction, it was concentrated and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 30 / 1) to give 749-3 (4.50 g, 82.7% yield) as a yellow solid.

[0373] Synthesis of 2-bromo-2-cyclopropyl-1-(4-methoxyphenyl)ethanone (749-4) [ka] A mixture of 749-3 (4.50 g, 23.7 mmol) and PTAT (13.3 g, 35.5 mmol) in THF (150 mL) was stirred at room temperature for 16 hours. Upon completion of the reaction, it was concentrated, and the residue was dissolved in HO (100 mL) and then extracted with EtOAc (100 mL × 2). The organic layers were combined, washed with HO (50.0 mL) and brine (80.0 mL), and then dried over anhydrous NaSO. The solution was concentrated to give the crude product, which was used directly in the next step without further purification to give 749-4 (6.37 g, 100% yield) as a yellow oil.

[0374] Synthesis of 2-cyclopropyl-1-(4-methoxyphenyl)-2-thiocyanatoethanone (749-5) [ka] A mixture of 749-4 (2.50 g, 9.29 mmol) and NaSCN (1.50 g, 18.6 mmol) in EtOH (80.0 mL) was stirred for 2 h at 50° C. When the reaction was complete, it was concentrated and purified by silica gel column chromatography (petroleum ether / ethyl acetate=3 / 1) to give 749-5 (1.50 g, 65.3% yield) as a yellow solid.

[0375] Synthesis of 2-chloro-5-cyclopropyl-4-(4-methoxyphenyl)thiazole (749-s) [ka] A mixture of 749-5 (1.0 g, 4.04 mmol) in HCl / dioxane (4.0 M, 10.0 mL) was stirred for 2 h at 50° C. When the reaction was complete, it was concentrated and purified by silica gel column chromatography (petroleum ether / ethyl acetate=10 / 1) to give 749-s (400 mg, 37.2% yield) as a yellow oil.

[0376] Synthesis of 1-(4-cyclopropoxyphenyl)-2-cyclopropylethanol (750-1) [ka] To a solution of 744-2 (2.0 g, 12.3 mmol) in THF (20.0 mL) was added isobutylmagnesium bromide (1.0 M in THF, 18.5 mL, 18.5 mmol). The reaction was stirred at room temperature for 16 h. Upon completion, it was poured into aqueous NH4Cl (saturated, 100 mL) and extracted with EtOAc (80.0 mL × 3). The organic phases were combined, washed with HO (50.0 mL) and brine (80.0 mL), then dried over anhydrous Na2SO4 and concentrated to give the crude product, which was used directly in the next step without further purification to give 750-1 (2.30 g, 85.4% yield) as a yellow oil.

[0377] Synthesis of 1-(4-cyclopropoxyphenyl)-2-cyclopropylethanone (750-2) [ka] To a solution of 750-1 (2.30 g, 10.5 mmol) in CHCl (100 mL) was added PCC (4.54 g, 21.1 mmol). The reaction was stirred at room temperature for 2 hours. Upon completion of the reaction, it was concentrated and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 20 / 1) to give 750-2 (2.0 g, 87.8% yield) as a yellow solid.

[0378] Synthesis of 2-bromo-1-(4-cyclopropoxyphenyl)-2-cyclopropylethanone (750-3) [ka] A mixture of 750-2 (2.0 g, 9.26 mmol) and PTAT (5.21 g, 13.9 mmol) in THF (100 mL) was stirred at room temperature for 16 hours. Upon completion of the reaction, it was concentrated, and the residue was dissolved in HO (80 mL) and then extracted with EtOAc (100 mL × 2). The organic layers were combined, washed with HO (50 mL) and brine (80 mL), and then dried over anhydrous NaSO. The solution was concentrated to give the crude product, which was used directly in the next step without further purification to give 750-3 (2.73 g, 100% yield) as a brown oil.

[0379] Synthesis of 4-(4-cyclopropoxyphenyl)-5-cyclopropylthiazol-2-amine (750-s) [ka] A mixture of 750-3 (2.73 g, 9.25 mmol) and thiourea (1.41 g, 18.5 mmol) in EtOH (50.0 mL) was stirred for 2 h at 80° C. When the reaction was complete, it was concentrated and purified by silica gel column chromatography (petroleum ether / ethyl acetate=3 / 1) to give 750-s (2.30 g, 91.3% yield) as a yellow solid.

[0380] Synthesis of 4-(2-chloro-5-cyclopropylthiazol-4-yl)phenol (756-s) [ka] A mixture of 749-s (2.60 g, 9.78 mmol) and BBr (17% in CHCl, 19.6 mL, 19.6 mmol) in CHCl (80.0 mL) was stirred at room temperature overnight. Upon completion of the reaction, it was washed with HO (50.0 mL × 3). The organic layer was concentrated and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 6 / 1) to give 756-s (900 mg, 36.5% yield) as a yellow oil.

[0381] Synthesis of 4-(2-bromo-5-cyclopropylthiazol-4-yl)-3-fluorophenol (758-1) [ka] A mixture of 757-s (400 mg, 1.22 mmol) and BBr (17% in CHCl, 2.44 mL, 2.44 mmol) in CHCl (10.0 mL) was stirred at room temperature for 5 h. When the reaction was complete, it was washed with HO (20.0 mL × 2). The organic layer was concentrated and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 6 / 1) to give 758-1 (250 mg, 65.3% yield) as a yellow oil.

[0382] Synthesis of 2-bromo-5-cyclopropyl-4-(2-fluoro-4-(2-methoxyethoxy)phenyl)thiazole (758-s) [ka] A mixture of 758-1 (250 mg, 0.796 mmol), 1-bromo-2-methoxyethane (166 mg, 1.19 mmol), and K2CO3 (220 mg, 1.59 mmol) in DMF (3.0 mL) was stirred at room temperature for 16 h. Upon completion of the reaction, it was poured into HO (50.0 mL) and extracted with EtOAc (80.0 mL × 3). The combined organic phases were washed with HO (50.0 mL) and brine (50.0 mL), then dried over anhydrous Na2SO4, concentrated, and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 10 / 1) to give 758-s (300 mg, 100% yield) as a colorless oil.

[0383] Synthesis of 3-fluoro-4-(2-methoxyethoxy)benzaldehyde (761-2) [ka] A mixture of 761-1 (20.0 g, 143 mmol), 1-bromo-2-methoxyethane (29.8 g, 214 mmol), and K2CO3 (39.5 g, 286 mmol) in DMF (200 mL) was stirred at room temperature for 16 h. Upon completion of the reaction, it was poured into HO (2.0 L) and extracted with EtOAc (800 mL × 3). The organic phases were combined, washed with HO (500 mL) and brine (800 mL), then dried over anhydrous Na2SO4 and concentrated to give the crude product, which was used directly in the next step without further purification to give 761-2 (28.0 g, 99.0% yield) as a colorless oil.

[0384] Synthesis of 2-cyclopropyl-1-(3-fluoro-4-(2-methoxyethoxy)phenyl)ethanol (761-3) [ka] To a solution of 761-2 (3.0 g, 15.1 mmol) in THF (20.0 mL) was added isobutylmagnesium bromide (1.0 M in THF, 22.7 mL, 22.7 mmol). The reaction was stirred at room temperature for 16 h. Upon completion, it was poured into aqueous NH4Cl (saturated, 80.0 mL) and extracted with EtOAc (80.0 mL × 3). The organic phases were combined, washed with HO (50.0 mL) and brine (80.0 mL), then dried over anhydrous Na2SO4, concentrated, and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 8 / 1) to give 761-3 (2.10 g, 54.6% yield) as a yellow oil.

[0385] Synthesis of methyl 2-cyclopropyl-1-(3-fluoro-4-(2-methoxyethoxy)phenyl)ethanone (761-4) [ka] To a solution of 761-3 (2.10 g, 8.26 mmol) in CHCl (100 mL) was added PCC (3.56 g, 16.5 mmol). The reaction was stirred at room temperature for 1 h. Upon completion of the reaction, it was concentrated and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 20 / 1) to give 761-4 (2.0 g, 96.0% yield) as a yellow solid.

[0386] Synthesis of 2-bromo-2-cyclopropyl-1-(3-fluoro-4-(2-methoxyethoxy)phenyl)ethanone (761-5) [ka] A mixture of 761-4 (2.0 g, 7.94 mmol) and PTAT (4.46 g, 11.9 mmol) in THF (100 mL) was stirred at room temperature for 1 h. Upon completion of the reaction, it was concentrated, and the residue was dissolved in HO (50 mL) and then extracted with EtOAc (80 mL × 2). The organic layers were combined, washed with HO (30 mL × 2) and brine (50 mL), and then dried over anhydrous NaSO. The solution was concentrated to give the crude product, which was used directly in the next step without further purification to give 761-5 (2.63 g, 100% yield) as a brown oil.

[0387] Synthesis of 2-cyclopropyl-1-(3-fluoro-4-(2-methoxyethoxy)phenyl)-2-thiocyanatoethanone (761-6) [ka] A mixture of 761-5 (2.63 g, 7.94 mmol) and NaSCN (1.29 g, 15.9 mmol) in EtOH (80.0 mL) was stirred for 3 h at 90° C. When the reaction was complete, it was concentrated and purified by silica gel column chromatography (petroleum ether / ethyl acetate=3 / 1) to give 761-6 (2.0 g, 81.4% yield) as a yellow solid.

[0388] Synthesis of 2-chloro-5-cyclopropyl-4-(3-fluoro-4-(2-methoxyethoxy)phenyl)thiazole (761-s) [ka] A mixture of 761-6 (2.0 g, 6.46 mmol) in HCl / dioxane (20.0 mL) was stirred at room temperature overnight. Upon completion of the reaction, it was concentrated and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 10 / 1) to give 761-s (1.80 g, 84.9% yield) as a yellow oil.

[0389] Synthesis of 2-chloro-4-(4-(difluoromethoxy)phenyl)-5-isobutylthiazole (766-s) [ka] A mixture of 723-5 (2.0 g, 6.68 mmol) in HCl / dioxane (20.0 mL) was stirred at room temperature overnight. Upon completion of the reaction, it was concentrated and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 10 / 1) to give 766-s (1.60 g, 75.4% yield) as a yellow oil. [Table 1-1] [Table 1-2] [Table 1-3]

[0390] Synthesis of methyl 2-((4-(3-chloro-4-hydroxyphenyl)-5-isobutylthiazol-2-yl)amino)-5-(thiophen-2-yl)nicotinate (721-2) [ka] A mixture of 568-8 (150 mg, 0.433 mmol), methyl 2-amino-5-(thiophen-2-yl)nicotinate (102 mg, 0.433 mmol), Pd(dba) (40.3 mg, 0.0433 mmol), X-phos (37.5 mg, 0.065 mmol), and CsCO (282 mg, 0.866 mmol) in toluene (5.0 mL) was stirred at 110 °C for 16 h under a N atmosphere. Upon completion of the reaction, it was concentrated and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 8 / 1) to give 721-2 (100 mg, 46.2% yield) as a yellow solid.

[0391] Synthesis of 2-((4-(3-chloro-4-hydroxyphenyl)-5-isobutylthiazol-2-yl)amino)-5-(thiophen-2-yl)nicotinic acid (I-1) [ka] To a solution of 721-2 (100 mg, 0.20 mmol) in MeOH / THF / HO (v / v / v = 4 / 1 / 1, 5.0 mL) was added NaOH (2.0 M in HO, 1.0 mL). The reaction was stirred at room temperature for 2 h. Upon completion, the resulting mixture was concentrated, then diluted with HO (15.0 mL), and the pH was adjusted to 4-5 with HCl (1.0 M). The mixture was extracted with EtOAc (10.0 mL × 2), and the combined organic phase was washed with brine (10.0 mL), dried over anhydrous NaSO, concentrated, and the residue was purified by washing with MeOH to give I-1 (20.0 mg, 20.6% yield) as a white solid.

[0392] Synthesis of methyl 2-((4-(4-(2-((tert-butoxycarbonyl)(methyl)amino)ethoxy)-3-chlorophenyl)-5-isobutylthiazol-2-yl)amino)-5-(thiophen-2-yl)nicotinate (724-2) [ka] A mixture of 724-s (186 mg, 0.369 mmol), methyl 2-amino-5-(thiophen-2-yl)nicotinate (86.7 mg, 0.369 mmol), Pd(dba) (34.3 mg, 0.0369 mmol), X-phos (32.0 mg, 0.0554 mmol), and CsCO (240 mg, 0.738 mmol) in toluene (5.0 mL) was stirred at 110 °C for 16 h under a N atmosphere. Upon completion of the reaction, it was concentrated and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 6 / 1) to give 724-2 (135 mg, 55.6% yield) as a yellow solid.

[0393] Synthesis of methyl 2-((4-(3-chloro-4-(2-(methylamino)ethoxy)phenyl)-5-isobutylthiazol-2-yl)amino)-5-(thiophen-2-yl)nicotinate (724-3) [ka] A mixture of 724-2 (135 mg, 0.205 mmol) in HCl / dioxane (5.0 mL) was stirred at room temperature for 4 hours. Upon completion of the reaction, it was filtered and the solid was dried to give the crude product, which was used directly in the next step without further purification to give 724-3 (85.0 mg, 74.3% yield) as a yellow solid.

[0394] Synthesis of 2-((4-(3-chloro-4-(2-(methylamino)ethoxy)phenyl)-5-isobutylthiazol-2-yl)amino)-5-(thiophen-2-yl)nicotinic acid (I-3) [ka] To a solution of 724-3 (85.0 mg, 0.153 mmol) in MeOH / THF / HO (v / v / v = 4 / 1 / 1, 3.0 mL) was added LiOH (2.0 M in HO, 1.0 mL). The reaction was stirred at room temperature for 2 h. Upon completion, the resulting mixture was concentrated, then diluted with HO (15.0 mL), and the pH was adjusted to 4–5 with HCl (1.0 M). The mixture was extracted with EtOAc (10.0 mL × 2). The combined organic phase was washed with brine (10.0 mL), dried over anhydrous NaSO, concentrated, and the residue was purified by preparative HPLC and washed with MeOH to give I-3 (25.0 mg, 30.2% yield) as a brown solid.

[0395] Synthesis of 2-((4-(4-(2-amino-2-oxoethoxy)phenyl)-5-isobutylthiazol-2-yl)amino)-5-(thiophen-2-yl)nicotinic acid (I-17) [ka] A mixture of 747-s (130 mg, 0.352 mmol), 2-amino-5-(thiophen-2-yl)nicotinic acid (93.0 mg, 0.422 mmol), Pd(dba) (32.7 mg, 0.0352 mmol), X-phos (30.5 mg, 0.0528 mmol), and CsCO (172 mg, 0.528 mmol) in toluene (5.0 mL) was stirred at 110 °C for 16 h under a N atmosphere. Upon completion of the reaction, it was concentrated and purified by preparative HPLC to afford I-17 (4.0 mg, 2.23% yield) as a yellow solid.

[0396] Synthesis of methyl 2-((4-(3-fluoro-4-(2-methoxyethoxy)phenyl)-5-isobutylthiazol-2-yl)amino)-5-(thiophen-2-yl)nicotinate (I-53) [ka] A mixture of 786-s (200 mg, 0.547 mmol), 2-chloro-5-(trifluoromethyl)nicotinic acid (148 mg, 0.657 mmol), Pd(dba) (50.9 mg, 0.0547 mmol), X-phos (47.4 mg, 0.0821 mmol), and CsCO (267 mg, 0.821 mmol) in toluene (5.0 mL) was stirred at 110 °C for 16 h under a N atmosphere. Upon completion of the reaction, it was concentrated and purified by preparative HPLC to afford I-53 (30.0 mg, 9.52% yield) as a yellow solid.

[0397] Synthesis of 2-((4-(3-fluoro-4-(2-methoxyethoxy)phenyl)-5-isobutylthiazol-2-yl)amino)-N-(2-(methylamino)ethyl)-5-(thiophen-2-yl)nicotinamide (I-56) [ka] To a mixture of 762-7 (200 mg, 0.369 mmol) and N-methylethane-1,2-diamine (32.8 mg, 0.443 mmol) in toluene (5.0 mL) was added (CH)Al (2.5 M in toluene, 0.369 mL, 0.923 mmol). The reaction was stirred at room temperature overnight. Upon completion, it was concentrated and purified by preparative HPLC to afford I-56 (25.0 mg, 11.6% yield) as a yellow solid. [Table 4-1] [Table 4-2] [Table 4-3] [Table 4-4] [Table 4-5] [Table 4-6] [Table 4-7] [Table 4-8] [Table 4-9] [Table 4-10] [Table 4-11] [Table 4-12]

[0398] Example 2. Synthesis of certain compounds Scheme 1: Route for compounds 787, 798, 808, 809 [ka] Scheme 2: Route for compounds 794-s, 796-s, 812-s, 813-s, 817-s, 822-s, 830-s, 831-s, 841-s, 842-s [ka] Scheme 3: Route for compound 795-s [ka] Scheme 4: Route for compound 797-s [ka] Scheme 5: Route for compounds 802-s to 805-s and 811-s [ka] Scheme 6: Route for compounds 814-s, 818-s to 820-s, 823-s, 824-s, 826-s, 827-s, 829-s, 835-s to 837-s, 840-s [ka] Scheme 7: Route for compounds 815-s, 825-s [ka] Scheme 8: Route for compound 816-B [ka] Scheme 9: Route for compounds 816-s, 828-s [ka] Scheme 10: Route for compound 833-s [ka] Scheme 11: Route for compounds I-60 to I-75, I-78 to I-84, I-86, I-87, I-89 to I-101 [ka] Scheme 12: Routes for compounds I-76, I-77, I-85, I-88 [ka] General Information: All evaporations were performed in vacuo using a rotary evaporator. Analytical samples were dried in vacuo (1-5 mmHg) at room temperature. Thin-layer chromatography (TLC) was performed on silica gel plates, and spots were visualized by UV light (214 and 254 nm). Column and flash chromatographic purifications were performed using silica gel (200-300 mesh). Solvent systems are reported as mixtures by volume. All NMR spectra were recorded on a Bruker 400 (400 MHz) spectrometer. 1H chemical shifts are reported as δ values ​​in ppm using deuterated solvents as internal standards. Data are reported as follows: chemical shift, multiplicity (s = singlet, d = doublet, t = triplet, q = quartet, br = broad, m = multiplet), coupling constant (Hz), and integration.

[0399] LCMS spectra were obtained on an Agilent 1200 series 6110 or 6120 mass spectrometer using electrospray ionization, and unless otherwise specified, general LCMS conditions were as follows: Method A (Agilent LCMS 1200-6110, column: Waters X-Bridge C18 (50 mm × 4.6 mm × 3.5 μm); column temperature: 40 °C; flow rate: 3.0 mL / min; mobile phase: 95% [water + 0.05% TFA] and 5% [CH3CN + 0.05% TFA] in 0.8 min to 0% [water + 0.05% TFA] and 100% [CH3CN + 0.05% TFA], then under these conditions for 0.4 min, and finally changed to 95% [water + 0.05% TFA] and 5% [CH3CN + 0.05% TFA] in 0.01 min). Method B (Agilent LCMS 1200-6110, column: Waters X-Bridge C18 (50 mm × 4.6 mm × 3.5 μm); column temperature: 40 °C; flow rate: 2.0 mL / min; mobile phase: 95% [water + 0.05% TFA] and 5% [CH3CN + 0.05% TFA] in 1.6 min to 0% [water + 0.05% TFA] and 100% [CH3CN + 0.05% TFA], then under these conditions for 1.4 min, and finally 95% [water + 0.05% TFA] and 5% [CH3CN + 0.05% TFA] in 0.05 min, and under these conditions for 0.7 min). Method C (Agilent LCMS 1200-6120, column: Waters X-Bridge C18 (50 mm × 4.6 mm × 3.5 μm); column temperature: 40 °C; flow rate: 2.0 mL / min; mobile phase: from 95% [water + 10 mM NH4HCO3] and 5% [CH3CN] in 1.6 min to 0% [water + 10 mM NH4HCO3] and 100% [CH3CN], then under these conditions for 1.4 min, and finally under these conditions for 0.1 min to 95% [water + 10 mM NH4HCO3] and 5% [CH3CN], and then under these conditions for 0.7 min). Method D (Agilent LCMS 1200-6120, column: Waters X-Bridge C18 (50 mm × 4.6 mm × 3.5 μm); column temperature: 45 °C; flow rate: 2.3 mL / min; mobile phase: from 95% [water + 10 mM NH4HCO3] and 5% [CH3CN] in 1.75 min to 0% [water + 10 mM NH4HCO3] and 100% [CH3CN], then under these conditions for 0.8 min, and finally under these conditions for 0.1 min to 95% [water + 10 mM NH4HCO3] and 5% [CH3CN], and then under these conditions for 0.1 min).

[0400] Experimental section Synthesis of methyl 3-amino-6-(thiophen-2-yl)pyrazine-2-carboxylate (787) [ka] A mixture of SM (1.0 g, 4.31 mmol), 4,4,5,5-tetramethyl-2-(thiophen-2-yl)-1,3,2-dioxaborolane (1.36 g, 6.47 mmol), Pd(dppf)Cl (315 mg, 0.431 mmol), and NaCO (1.84 g, 8.62 mmol) in dioxane / HO (v / v = 5 / 1, 10.0 mL) was stirred at 85 °C for 16 h under a N atmosphere. Upon completion of the reaction, it was concentrated and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 3 / 1) to give 787 (670 mg, 66.1% yield) as a brown solid.

[0401] Synthesis of 1-(3-fluoro-4-methoxyphenyl)-4-methylpentan-1-ol (794-2) [ka] To a solution of 794-1 (2.0 g, 13.0 mmol) in THF (20.0 mL) was added isopentylmagnesium bromide (1.0 M in THF, 19.5 mL, 19.5 mmol). The reaction was stirred at room temperature for 4 h. Upon completion, it was poured into aqueous NH4Cl (saturated, 50.0 mL) and extracted with EtOAc (80.0 mL × 3). The combined organic phases were washed with HO (50.0 mL) and brine (80.0 mL), then dried over anhydrous Na2SO4, concentrated, and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 10 / 1) to give 794-2 (2.50 g, 85.1% yield) as a yellow oil.

[0402] Synthesis of 1-(3-fluoro-4-methoxyphenyl)-4-methylpentan-1-one (794-3) [ka] To a solution of 794-2 (2.50 g, 11.0 mmol) in CHCl (100 mL) was added PCC (4.76 g, 22.1 mmol). The reaction was stirred at room temperature for 2 hours. Upon completion of the reaction, it was concentrated and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 30 / 1) to give 794-3 (2.30 g, 92.8% yield) as a colorless oil.

[0403] Synthesis of 2-bromo-1-(3-fluoro-4-methoxyphenyl)-4-methylpentan-1-one (794-4) [ka] A mixture of 794-3 (2.30 g, 10.3 mmol) and PTAT (5.78 g, 15.4 mmol) in THF (50.0 mL) was stirred at room temperature for 2 hours. Upon completion of the reaction, it was concentrated, and the residue was dissolved in HO (30.0 mL) and then extracted with EtOAc (50.0 mL × 2). The organic layers were combined, washed with HO (30.0 mL × 2) and brine (30.0 mL), and then dried over anhydrous NaSO. The solution was concentrated to give the crude product, which was used directly in the next step without further purification to give 794-4 (3.30 g, 100% yield) as a brown oil.

[0404] Synthesis of 1-(3-fluoro-4-methoxyphenyl)-4-methyl-2-thiocyanatopentan-1-one (794-5) [ka] A mixture of 794-4 (3.30 g, 10.9 mmol) and NaSCN (1.76 g, 21.8 mmol) in EtOH (50.0 mL) was stirred for 5 h at 90° C. When the reaction was complete, it was concentrated and purified by silica gel column chromatography (petroleum ether / ethyl acetate=3 / 1) to give 794-5 (2.50 g, 81.6% yield) as a yellow solid.

[0405] Synthesis of 2-chloro-4-(3-fluoro-4-methoxyphenyl)-5-isobutylthiazole (794-s) [ka] A mixture of 794-5 (2.50 g, 8.90 mmol) in HCl / dioxane (4.0 M, 30.0 mL) was stirred at room temperature for 4 hours. Upon completion of the reaction, it was concentrated and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 10 / 1) to give 794-s (2.30 g, 86.3% yield) as a yellow oil.

[0406] Synthesis of 3-chloro-4-methoxybenzaldehyde (795-1) [ka] A mixture of SM1 (3.0 g, 19.2 mmol), CHI (4.08 g, 28.7 mmol), and KCO (5.29 g, 38.3 mmol) in DMF (10.0 mL) was stirred at room temperature for 16 h. Upon completion of the reaction, it was poured into HO (100 mL) and extracted with EtOAc (100 mL × 3). The combined organic phases were washed with HO (80.0 mL) and brine (80.0 mL), then dried over anhydrous NaSO, concentrated, and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 30 / 1) to give 795-1 (3.10 g, 94.8% yield) as a colorless oil.

[0407] Synthesis of 1-(3-chloro-4-methoxyphenyl)-5-methylhexan-1-ol (795-2) [ka] To a solution of 795-1 (3.10 g, 18.2 mmol) in THF (30.0 mL) was added (4-methylpentyl)magnesium bromide (1.0 M in THF, 27.4 mL, 27.4 mmol) at 0 °C. The reaction was stirred at room temperature for 16 h. Upon completion of the reaction, it was poured into aqueous NH4Cl (saturated, 50.0 mL) and extracted with EtOAc (80.0 mL × 3). The organic phases were combined, washed with HO (50.0 mL) and brine (80.0 mL), then dried over anhydrous Na2SO4, concentrated, and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 10 / 1) to give 795-2 (3.0 g, 64.1% yield) as a colorless oil.

[0408] Synthesis of 1-(3-chloro-4-methoxyphenyl)-5-methylhexan-1-one (795-3) [ka] To a solution of 795-2 (3.0 g, 9.74 mmol) in CHCl (100 mL) was added PCC (4.20 g, 19.5 mmol). The reaction was stirred at room temperature for 2 hours. Upon completion of the reaction, it was concentrated and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 30 / 1) to give 795-3 (2.50 g, 84.0% yield) as a white solid.

[0409] Synthesis of 2-bromo-1-(3-chloro-4-methoxyphenyl)-5-methylhexan-1-one (795-4) [ka] A mixture of 795-3 (2.50 g, 9.81 mmol) and PTAT (5.52 g, 14.7 mmol) in THF (50.0 mL) was stirred at room temperature for 2 hours. Upon completion of the reaction, it was concentrated, and the residue was dissolved in HO (30.0 mL) and then extracted with EtOAc (50.0 mL × 2). The organic layers were combined, washed with HO (30.0 mL × 2) and brine (30.0 mL), and then dried over anhydrous NaSO. The solution was concentrated to give the crude product, which was used directly in the next step without further purification to give 795-4 (3.30 g, 100% yield) as a brown oil.

[0410] Synthesis of 4-(3-chloro-4-methoxyphenyl)-5-isopentylthiazol-2(3H)-one (795-5) [ka] A mixture of 795-4 (3.30 g, 9.89 mmol) and NaSCN (1.60 g, 19.8 mmol) in EtOH (50.0 mL) was stirred for 5 h at 90° C. When the reaction was complete, it was concentrated and purified by silica gel column chromatography (petroleum ether / ethyl acetate=10 / 1) to give 795-5 (800 mg, 25.9% yield) as a yellow solid.

[0411] Synthesis of 2-chloro-4-(3-chloro-4-methoxyphenyl)-5-isopentylthiazole (795-s) [ka] A mixture of 795-5 (800 mg, 0.865 mmol) in POCl (10.0 mL) was stirred at 100 °C for 5 h. Upon completion of the reaction, it was concentrated, poured into HO (80.0 mL), and extracted with EtOAc (80.0 mL × 3). The organic phases were combined, washed with HO (50.0 mL) and brine (50.0 mL), then dried over anhydrous NaSO, concentrated, and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 20 / 1) to give 795-s (450 mg, 53.1% yield) as a colorless oil.

[0412] Synthesis of 1-(3-fluoro-4-(2-methoxyethoxy)phenyl)ethanone (797-1) [ka] A mixture of SM2 (5.0 g, 32.4 mmol), 1-bromo-2-methoxyethane (5.41 g, 38.9 mmol), and K2CO3 (8.96 g, 64.9 mmol) in DMF (20.0 mL) was stirred at room temperature overnight. Upon completion of the reaction, it was poured into HO (200 mL) and extracted with EtOAc (150 mL × 3). The organic phases were combined, washed with HO (100 mL) and brine (100 mL), then dried over anhydrous Na2SO4 and concentrated to give the crude product, which was used directly in the next step without further purification to give 797-1 (6.0 g, 87.1% yield) as a colorless oil.

[0413] Synthesis of (E)-1-(3-fluoro-4-(2-methoxyethoxy)phenyl)-3-phenylprop-2-en-1-one (797-2) [ka] To a solution of 797-1 (6.0 g, 28.3 mmol) and benzaldehyde (3.00 g, 28.3 mmol) in MeOH (750 mL) was added KOH (6.0 M in HO, 110 mL). The reaction was stirred at room temperature overnight. Upon completion of the reaction, it was filtered, and the residue was washed with HO (5.0 mL) and cold MeOH (10.0 mL) to give 797-2 (2.00 g, 23.6% yield) as a white solid.

[0414] Synthesis of 1-(3-fluoro-4-(2-methoxyethoxy)phenyl)-3-phenylpropan-1-one (797-3) [ka] A mixture of 797-2 (2.00 g, 6.66 mmol) and Pt / C (200 mg) in MeOH (50.0 mL) was stirred under a H atmosphere at room temperature for 2 h. Upon completion of the reaction, it was filtered, and the filtrate was concentrated to give the crude product, which was used directly in the next step without further purification to give 797-3 (1.60 g, 79.5% yield) as a colorless oil.

[0415] Synthesis of 2-bromo-1-(3-fluoro-4-(2-methoxyethoxy)phenyl)-3-phenylpropan-1-one (797-4) [ka] A mixture of 797-3 (1.60 g, 6.62 mmol) and PTAT (3.72 g, 9.92 mmol) in THF (50.0 mL) was stirred at room temperature for 2 hours. Upon completion of the reaction, it was concentrated, and the residue was dissolved in HO (30.0 mL) and then extracted with EtOAc (50.0 mL × 2). The organic layers were combined, washed with HO (30.0 mL × 2) and brine (30.0 mL), and then dried over anhydrous NaSO. The solution was concentrated to give the crude product, which was used directly in the next step without further purification to give 797-4 (2.00 g, 100% yield) as a brown oil.

[0416] Synthesis of 1-(3-fluoro-4-(2-methoxyethoxy)phenyl)-3-phenyl-2-thiocyanatopropan-1-one (797-5) [ka] A mixture of 797-4 (2.00 g, 5.25 mmol) and NaSCN (850 mg, 10.5 mmol) in EtOH (50.0 mL) was stirred for 5 h at 90° C. When the reaction was complete, it was concentrated and purified by silica gel column chromatography (petroleum ether / ethyl acetate=3 / 1) to give 797-5 (1.00 g, 53.0% yield) as a yellow solid.

[0417] Synthesis of 5-benzyl-2-chloro-4-(3-fluoro-4-(2-methoxyethoxy)phenyl)thiazole (797-s) [ka] A mixture of 797-5 (1.00 g, 2.78 mmol) in HCl / dioxane (4.0 M, 10.0 mL) was stirred at room temperature for 4 hours. Upon completion of the reaction, it was concentrated and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 10 / 1) to give 797-s (600 mg, 57.1% yield) as a colorless oil.

[0418] Synthesis of 3-fluoro-4-(2-methoxyethoxy)benzaldehyde (802-1) [ka] A mixture of SM3 (1.50 g, 10.7 mmol), 1-bromo-2-methoxyethane (1.79 g, 12.8 mmol), and K2CO3 (2.96 g, 21.4 mmol) in DMF (10.0 mL) was stirred at room temperature for 16 h. Upon completion of the reaction, it was poured into HO (100 mL) and extracted with EtOAc (100 mL × 3). The organic phases were combined, washed with HO (80.0 mL) and brine (80.0 mL), then dried over anhydrous Na2SO4, and concentrated to give the crude product, which was used directly in the next step without further purification to give 802-1 (2.00 g, 94.3% yield) as a colorless oil.

[0419] Synthesis of 1-(3-fluoro-4-(2-methoxyethoxy)phenyl)-4,4-dimethylpentan-1-ol (802-2) [ka] To a solution of 802-1 (2.00 g, 10.1 mmol) in THF (20.0 mL) was added (3,3-dimethylbutyl)magnesium bromide (1.0 M in THF, 15.1 mL, 15.1 mmol). The reaction was stirred at room temperature for 16 hours. Upon completion of the reaction, it was poured into aqueous NH4Cl (saturated, 50.0 mL) and extracted with EtOAc (80.0 mL × 3). The organic phases were combined, washed with HO (50.0 mL) and brine (80.0 mL), then dried over anhydrous Na2SO4, concentrated, and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 8 / 1) to give 802-2 (2.90 g, 100% yield) as a yellow oil.

[0420] Synthesis of 1-(3-fluoro-4-(2-methoxyethoxy)phenyl)-4,4-dimethylpentan-1-one (802-3) [ka] To a solution of 802-2 (2.90 g, 10.2 mmol) in CHCl (100 mL) was added PCC (4.40 g, 20.4 mmol). The reaction was stirred at room temperature for 2 hours. Upon completion of the reaction, it was concentrated and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 30 / 1) to give 802-3 (2.40 g, 83.4% yield) as a colorless oil.

[0421] Synthesis of 2-bromo-1-(3-fluoro-4-(2-methoxyethoxy)phenyl)-4,4-dimethylpentan-1-one (802-4) [ka] A mixture of 802-3 (2.40 g, 8.50 mmol) and PTAT (4.78 g, 12.8 mmol) in THF (50.0 mL) was stirred at room temperature for 2 hours. When the reaction was complete, it was concentrated, and the residue was dissolved in HO (30.0 mL) and then extracted with EtOAc (50.0 mL × 2). The organic layers were combined, washed with HO (30.0 mL × 2) and brine (30.0 mL), and then dried over anhydrous NaSO. The solution was concentrated to give the crude product, which was used directly in the next step without further purification to give 802-4 (3.10 g, 100% yield) as a brown oil.

[0422] Synthesis of 1-(3-fluoro-4-(2-methoxyethoxy)phenyl)-4,4-dimethyl-2-thiocyanatopentan-1-one (802-5) [ka] A mixture of 802-4 (3.10 g, 8.58 mmol) and NaSCN (1.39 g, 17.2 mmol) in EtOH (80.0 mL) was stirred for 5 h at 90° C. When the reaction was complete, it was concentrated and purified by silica gel column chromatography (petroleum ether / ethyl acetate=3 / 1) to give 802-5 (1.70 g, 42.9% yield) as a yellow solid.

[0423] Synthesis of 2-chloro-4-(3-fluoro-4-(2-methoxyethoxy)phenyl)-5-neopentylthiazole (802-s) [ka] A mixture of 802-5 (1.70 g, 5.01 mmol) in HCl / dioxane (4.0 M, 10.0 mL) was stirred at room temperature for 4 hours. Upon completion of the reaction, it was concentrated and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 10 / 1) to give 802-s (1.50 g, 83.7% yield) as a yellow oil.

[0424] Synthesis of 2-chloro-5-(2-chloro-5-isobutylthiazol-4-yl)phenol (814-1) [ka] A mixture of 813-s (4.70 g, 14.9 mmol) and BBr (17% in CHCl, 22.3 mL, 22.3 mmol) in CHCl (80.0 mL) was stirred at room temperature overnight. When the reaction was complete, it was washed with HO (50.0 mL × 3). The organic layer was concentrated and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 6 / 1) to give 814-1 (1.70 g, 37.8% yield) as a yellow oil.

[0425] Synthesis of 2-chloro-4-(4-chloro-3-(2-methoxyethoxy)phenyl)-5-isobutylthiazole (814-s) [ka] A mixture of 814-1 (850 mg, 2.81 mmol), 1-bromo-2-methoxyethane (469 mg, 3.38 mmol), and K2CO3 (776 mg, 5.6331.4 mmol) in DMF (8.0 mL) was stirred at room temperature overnight. Upon completion of the reaction, it was poured into HO (100 mL) and extracted with EtOAc (100 mL × 3). The combined organic phases were washed with HO (80.0 mL) and brine (80.0 mL), then dried over anhydrous Na2SO4, concentrated, and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 20 / 1) to give 814-s (1.00 g, 98.7% yield) as a yellow oil.

[0426] Synthesis of 2-(3-methoxy-4-(trifluoromethyl)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (816-B) [ka] A mixture of SM4 (5.0 g, 19.6 mmol), (Pin)2B (7.47 g, 29.4 mmol), Pd(dppf)Cl2 (1.43 g, 1.96 mmol), and KOAc (3.84 g, 39.2 mmol) in dioxane (50.0 mL) was stirred overnight at 90 °C under a N2 atmosphere. Upon completion of the reaction, it was concentrated and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 5 / 1) to give 816-B (5.50 g, 100% yield) as a yellow solid.

[0427] Synthesis of N-(4-chloro-5-formylthiazol-2-yl)acetamide (816-2) [ka] To a mixture of 816-1 (5.00 g, 30.8 mmol) in pyridine (20.0 mL) was added AcO (4.70 g, 46.1 mmol). The reaction was stirred at room temperature overnight. Upon completion of the reaction, it was poured into HO (200 mL) and extracted with EtOAc (150 mL × 3). The organic phases were combined, washed with HO (100 mL) and brine (80.0 mL), then dried over anhydrous NaSO, concentrated, and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 10 / 1) to give 816-2 (5.50 g, 87.4% yield) as a white solid.

[0428] Synthesis of N-(4-chloro-5-(1-hydroxy-2-methylpropyl)thiazol-2-yl)acetamide (816-3) [ka] To a solution of 816-2 (5.50 g, 26.9 mmol) in THF (40.0 mL) was added isopropylmagnesium bromide (1.0 M in THF, 40.3 mL, 40.3 mmol). The reaction was stirred at room temperature for 16 h. Upon completion, it was poured into aqueous NH4Cl (saturated, 100 mL) and extracted with EtOAc (80.0 mL × 3). The organic phases were combined, washed with HO (80.0 mL) and brine (80.0 mL), then dried over anhydrous Na2SO4, concentrated, and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 3 / 1) to give 816-3 (4.50 g, 67.3% yield) as a yellow solid.

[0429] Synthesis of N-(4-chloro-5-isobutylthiazol-2-yl)acetamide (816-4) [ka] A solution of 816-3 (4.50 g, 18.1 mmol) in TFA / TES (v / v=4 / 1, 50.0 mL) was stirred at room temperature for 1 h. Upon completion of the reaction, it was concentrated and purified by silica gel column chromatography (petroleum ether / ethyl acetate=8 / 1) to give 816-4 (4.00 g, 95.0% yield) as a white solid.

[0430] Synthesis of N-(5-isobutyl-4-(3-methoxy-4-(trifluoromethyl)phenyl)thiazol-2-yl)acetamide (816-5) [ka] A mixture of 816-4 (1.00 g, 4.30 mmol), 816-B (1.95 g, 6.45 mmol), Pd(OAc) (96.5 mg, 0.430 mmol), PCy (241 mg, 0.860 mmol), and KPO (1.83 g, 8.60 mmol) in toluene / HO (v / v = 10 / 1, 50.0 mL) was stirred at 150 °C for 4 h under N atmosphere in a microwave. Upon completion of the reaction, it was concentrated and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 10 / 1) to give 816-5 (700 mg, 43.7% yield) as a yellow solid.

[0431] Synthesis of 5-isobutyl-4-(3-methoxy-4-(trifluoromethyl)phenyl)thiazol-2-amine (816-s) [ka] A mixture of 816-5 (400 mg, 1.07 mmol) and NaOH (2.0 M in HO, 3.0 mL) in EtOH (10.0 mL) was stirred overnight at 70° C. Upon completion of the reaction, it was concentrated and purified by silica gel column chromatography (petroleum ether / ethyl acetate=3 / 1) to give 816-s (300 mg, 84.5% yield) as a yellow solid.

[0432] Synthesis of N-(4-(3-hydroxy-4-(trifluoromethyl)phenyl)-5-isobutylthiazol-2-yl)acetamide (815-1) [ka] A mixture of 816-5 (900 mg, 2.42 mmol) and BBr (17% in CHCl, 3.63 mL, 3.63 mmol) in CHCl (30.0 mL) was stirred at room temperature overnight. When the reaction was complete, it was washed with HO (20.0 mL × 3). The organic layer was concentrated and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 10 / 1) to give 815-1 (440 mg, 50.8% yield) as a yellow solid.

[0433] Synthesis of N-(5-isobutyl-4-(3-(2-methoxyethoxy)-4-(trifluoromethyl)phenyl)thiazol-2-yl)acetamide (815-2) [ka] A mixture of 815-1 (440 mg, 1.23 mmol), 1-bromo-2-methoxyethane (205 mg, 1.47 mmol), and K2CO3 (339 mg, 2.46 mmol) in DMF (5.0 mL) was stirred at room temperature overnight. Upon completion of the reaction, it was poured into HO (80.0 mL) and extracted with EtOAc (80.0 mL × 3). The combined organic phases were washed with HO (50.0 mL) and brine (50.0 mL), then dried over anhydrous Na2SO4, concentrated, and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 8 / 1) to give 815-2 (240 mg, 46.9% yield) as a yellow solid.

[0434] Synthesis of 5-isobutyl-4-(3-(2-methoxyethoxy)-4-(trifluoromethyl)phenyl)thiazol-2-amine (815-s) [ka] A mixture of 815-2 (240 mg, 0.576 mmol) and NaOH (2.0 M in HO, 2.0 mL) in EtOH (5.0 mL) was stirred overnight at 70° C. Upon completion of the reaction, it was concentrated and purified by silica gel column chromatography (petroleum ether / ethyl acetate=3 / 1) to give 815-s (160 mg, 74.2% yield) as a yellow solid.

[0435] Synthesis of 1-(4-chloro-3-methoxyphenyl)-4,4-dimethylpentan-1-ol (833-2) [ka] To a solution of 833-1 (2.50 g, 14.7 mmol) in THF (20.0 mL) was added (3,3-dimethylbutyl)magnesium bromide (1.0 M in THF, 22.0 mL, 22.0 mmol). The reaction was stirred at room temperature for 16 h. Upon completion, it was poured into aqueous NH4Cl (saturated, 50.0 mL) and extracted with EtOAc (80.0 mL × 3). The combined organic phases were washed with HO (50.0 mL) and brine (80.0 mL), then dried over anhydrous Na2SO4, concentrated, and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 8 / 1) to give 833-2 (3.00 g, 79.7% yield) as a yellow oil.

[0436] Synthesis of 1-(4-chloro-3-methoxyphenyl)-4,4-dimethylpentan-1-one (833-3) [ka] To a solution of 833-2 (3.00 g, 11.7 mmol) in CHCl (100 mL) was added PCC (5.04 g, 23.4 mmol). The reaction was stirred at room temperature for 2 hours. Upon completion of the reaction, it was concentrated and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 50 / 1) to give 833-3 (2.80 g, 94.1% yield) as a colorless oil.

[0437] Synthesis of 2-bromo-1-(4-chloro-3-methoxyphenyl)-4,4-dimethylpentan-1-one (833-4) [ka] A mixture of 833-3 (2.80 g, 11.0 mmol) and PTAT (6.18 g, 16.5 mmol) in THF (50.0 mL) was stirred at room temperature for 16 hours. Upon completion of the reaction, it was concentrated, and the residue was dissolved in HO (30.0 mL) and then extracted with EtOAc (50.0 mL × 2). The organic layers were combined, washed with HO (30.0 mL × 2) and brine (30.0 mL), and then dried over anhydrous NaSO. The solution was concentrated to give the crude product, which was used directly in the next step without further purification to give 833-4 (3.70 g, 100% yield) as a brown oil.

[0438] Synthesis of 1-(4-chloro-3-methoxyphenyl)-4,4-dimethyl-2-thiocyanatopentan-1-one (833-5) [ka] A mixture of 833-4 (3.70 g, 11.0 mmol) and NaSCN (1.80 g, 22.2 mmol) in EtOH (80.0 mL) was stirred for 3 h at 90° C. When the reaction was complete, it was concentrated and purified by silica gel column chromatography (petroleum ether / ethyl acetate=3 / 1) to give 833-5 (2.20 g, 63.6% yield) as a yellow solid.

[0439] Synthesis of 2-chloro-4-(4-chloro-3-methoxyphenyl)-5-neopentylthiazole (833-6) [ka] A mixture of 833-5 (2.20 g, 4.04 mmol) in HCl / dioxane (4.0 M, 20.0 mL) was stirred at room temperature for 4 hours. Upon completion of the reaction, it was concentrated and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 10 / 1) to give 833-6 (1.30 g, 60.1% yield) as a yellow oil.

[0440] Synthesis of 2-chloro-5-(2-chloro-5-neopentylthiazol-4-yl)phenol (833-7) [ka] A mixture of 833-6 (1.30 g, 3.94 mmol) and BBr (17% in CHCl, 5.90 mL, 5.90 mmol) in CHCl (30.0 mL) was stirred at room temperature overnight. When the reaction was complete, it was washed with HO (20.0 mL × 3). The organic layer was concentrated and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 6 / 1) to give 833-7 (560 mg, 45.0% yield) as a yellow oil.

[0441] Synthesis of 2-chloro-4-(4-chloro-3-ethoxyphenyl)-5-neopentylthiazole (833-s) [ka] A mixture of 833-7 (180 mg, 0.569 mmol), EtI (133 mg, 0.854 mmol), and KCO (157 mg, 1.14 mmol) in DMF (5.0 mL) was stirred at room temperature for 16 h. Upon completion of the reaction, it was poured into HO (80.0 mL) and extracted with EtOAc (80.0 mL × 3). The combined organic phases were washed with HO (50.0 mL) and brine (50.0 mL), then dried over anhydrous NaSO, concentrated, and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 10 / 1) to give 833-s (140 mg, 71.4% yield) as a yellow oil. [Table 5-1] [Table 5-2] [Table 5-3] [Table 5-4] [Table 5-5]

[0442] Synthesis of methyl 3-((4-(3-fluoro-4-methoxyphenyl)-5-isobutylthiazol-2-yl)amino)-6-(thiophen-2-yl)pyrazine-2-carboxylate (794-6) [ka] A mixture of 794-s (200 mg, 0.667 mmol), methyl 3-amino-6-(thiophen-2-yl)pyrazine-2-carboxylate (157 mg, 0.667 mmol), Pd(dba) (62.0 mg, 0.0667 mmol), X-phos (57.8 mg, 0.100 mmol), and CsCO (326 mg, 1.00 mmol) in toluene (10.0 mL) was stirred at 120 °C for 4 h under a N atmosphere. Upon completion of the reaction, it was concentrated and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 8 / 1) to give 794-6 (120 mg, 36.1% yield) as a yellow solid.

[0443] Synthesis of 3-((4-(3-fluoro-4-methoxyphenyl)-5-isobutylthiazol-2-yl)amino)-6-(thiophen-2-yl)pyrazine-2-carboxylic acid (I-60) [ka] To a solution of 794-6 (120 mg, 0.241 mmol) in MeOH / THF / HO (v / v / v = 4 / 1 / 1, 5.0 mL) was added LiOH (2.0 M in HO, 1.0 mL). The reaction was stirred at room temperature for 2 h. Upon completion, the resulting mixture was concentrated, then diluted with HO (15.0 mL), and the pH was adjusted to 4-5 with HCl (1.0 M). The mixture was extracted with EtOAc (10.0 mL × 2), and the combined organic phase was washed with brine (10.0 mL), dried over anhydrous NaSO, concentrated, and the residue was purified by washing with MeOH to give I-60 (55.0 mg, 47.2% yield) as a yellow solid.

[0444] Synthesis of methyl 2-((5-isobutyl-4-(3-(2-methoxyethoxy)-4-(trifluoromethyl)phenyl)thiazol-2-yl)amino)-5-(thiophen-2-yl)nicotinate (815-3) [ka] A mixture of 815-s (160 mg, 0.427 mmol), methyl 2-chloro-5-(thiophen-2-yl)nicotinate (108 mg, 0.427 mmol), Pd(dba) (39.7 mg, 0.0427 mmol), X-phos (37.0 mg, 0.0641 mmol), and CsCO (209 mg, 0.641 mmol) in toluene (10.0 mL) was stirred at 120 °C for 4 h under a N atmosphere. Upon completion of the reaction, it was concentrated and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 8 / 1) to give 815-3 (100 mg, 39.6% yield) as a yellow solid.

[0445] Synthesis of 2-((5-isobutyl-4-(3-(2-methoxyethoxy)-4-(trifluoromethyl)phenyl)thiazol-2-yl)amino)-5-(thiophen-2-yl)nicotinic acid (I-76) [ka] To a solution of 815-3 (100 mg, 0.169 mmol) in MeOH / THF / HO (v / v / v = 4 / 1 / 1, 3.0 mL) was added LiOH (2.0 M in HO, 1.0 mL). The reaction was stirred at room temperature for 2 h. Upon completion, the resulting mixture was concentrated, then diluted with HO (15.0 mL), and the pH was adjusted to 4-5 with HCl (1.0 M). The mixture was extracted with EtOAc (10.0 mL × 2), and the combined organic phase was washed with brine (10.0 mL), dried over anhydrous NaSO, concentrated, and the residue was purified by washing with MeOH to give I-76 (60.0 mg, 61.5% yield) as an off-white solid. [Table 6-1] [Table 6-2] [Table 6-3] [Table 6-4] [Table 6-5] [Table 6-6] [Table 6-7] [Table 6-8]

[0446] Example 3. Testing of compounds in the human eIF4E / 4G2 binding assay Human eIF4E (aa 28-217) with a C-terminal His-tag was expressed in E. coli as inclusion bodies. The protein was solubilized in 8 M urea and purified under denaturing conditions using a nickel-charged HisTrap HP column (GE Healthcare). The purified protein was then diluted in 20 mM Hepes (pH 7.0), 0.5 M NaCl, 1 mM DTT, 1 mM EDTA, 0.5 M arginine + 6 M urea, and then refolded by overnight dialysis into the same buffer without urea. The protein was further dialyzed into 20 mM Hepes (pH 6.5), 50 mM NaCl, 1 mM EDTA, 1 mM DTT, and concentrated using a Hitrap SP Sepharose FF column (GE Healthcare). The concentrated protein was dialyzed into 20 mM Hepes (pH 7.0), 0.5 M NaCl, 5 mM DTT, and 10% glycerol and stored at −80° C. until use.

[0447] Test compounds (3.43 mM stock solution in DMSO) were serially diluted 2-fold in DMSO (10 concentration points). Compound solutions (1.2 μl / well) were added to a 384-well black polypropylene microplate (Matrix, Thermal Scientific). Assay buffer (50 mM NaPi (pH 6.5), 50 mM KCl, 1 mM DTT, and 0.5 mg / ml gamma globulin) was added at 22 μL per well, and purified eIF4E (82.5 nM in assay buffer) was added at 8 μL per well. Samples were incubated at room temperature (20-23°C) for 4 hours. Biotin-labeled 4G2 peptide (Ac-Lys-Gln-Tyr-Asp-Arg-Glu-Phe-Leu-Leu-Asp-Phe-Gln-Phe-Met-Pro-Lys(Aha-Bio)-NH2, 1.75 μM stock solution in DMSO) was diluted to 0.14 μM in assay buffer (without DTT) and 5 μl was added per well. Samples were incubated for 20 minutes at room temperature. Then, 6.4 nM Eu-streptavidin (Eu-SA, Perkin Elmer) and 80 nM allophycocyanin (APC)-anti-His antibody (Columbia Biosciences) in assay buffer (without DTT) were added at 5 microliters per well, and samples were incubated for 20 minutes at room temperature.

[0448] The assay signal was monitored by reading fluorescence at 340 nm excitation and 615 and 665 nm emission on an Envision reader (Perkin Elmer). The normalized TR-FRET (time-resolved fluorescence resonance energy transfer) assay signal (Rn) was calculated by the following formula: Rn=[(A-Ba-C×D) / (D-Bd)]×(Dc-Bd) where A is the fluorescence intensity of the sample at 665 nm; D is the fluorescence intensity of the sample at 615 nm, Ba and Bd are the plate background at 665 nm and 615 nm, respectively; Dc is the fluorescence intensity of 0.78 nM Eu-SA in the assay buffer at 615 nm. The crosstalk factor (C) is determined by the following formula. C = (Ac - Ba) / (Dc - Bd) Where Ac is the fluorescence intensity of 0.78 nM Eu-SA in the assay buffer at 665 nm.

[0449] The IC50 value was calculated using the xLFit program (IDBS). Table 2 below lists the EC50 of some compounds. In the table, A represents IC50 ≤ 0.5 μM, B represents 0.5 μM < IC50 ≤ 1 μM, and C represents IC50 > 1 μM.

Table 2-3

Table 2-4

[0450] Example 4. Synthesis of a specific compound Scheme 1: Route for Compound I-130

Chemical formula

Chemical formula

Chemical formula

Chemical formula

[0451] LCMS spectra were obtained on an Agilent 1200 series 6110 or 6120 mass spectrometer using electrospray ionization, and unless otherwise specified, general LCMS conditions were as follows:

[0452] Method A (Agilent LCMS 1200-6110, column: Waters X-Bridge C18 (50 mm × 4.6 mm × 3.5 μm); column temperature: 40 °C; flow rate: 3.0 mL / min; mobile phase: 95% [water + 0.05% TFA] and 5% [CH3CN + 0.05% TFA] in 0.8 min to 0% [water + 0.05% TFA] and 100% [CH3CN + 0.05% TFA], then under these conditions for 0.4 min, and finally changed to 95% [water + 0.05% TFA] and 5% [CH3CN + 0.05% TFA] in 0.01 min).

[0453] Method B (Agilent LCMS 1200-6110, column: Waters X-Bridge C18 (50 mm × 4.6 mm × 3.5 μm); column temperature: 40 °C; flow rate: 2.0 mL / min; mobile phase: 95% [water + 0.05% TFA] and 5% [CH3CN + 0.05% TFA] in 1.6 min to 0% [water + 0.05% TFA] and 100% [CH3CN + 0.05% TFA], then under these conditions for 1.4 min, and finally 95% [water + 0.05% TFA] and 5% [CH3CN + 0.05% TFA] in 0.05 min, and under these conditions for 0.7 min).

[0454] Method C (Agilent LCMS 1200-6120, column: Waters X-Bridge C18 (50 mm × 4.6 mm × 3.5 μm); column temperature: 40 °C; flow rate: 2.0 mL / min; mobile phase: from 95% [water + 10 mM NH4HCO3] and 5% [CH3CN] in 1.6 min to 0% [water + 10 mM NH4HCO3] and 100% [CH3CN], then under these conditions for 1.4 min, and finally under these conditions for 0.1 min to 95% [water + 10 mM NH4HCO3] and 5% [CH3CN], and then under these conditions for 0.7 min).

[0455] Experimental section Synthesis of methyl 2-amino-5-(thiophen-2-yl)isonicotinate (130) [ka]

[0456] A mixture of 130-1 (1.00 g, 4.33 mmol), thiophen-2-ylboronic acid (831 mg, 6.49 mmol), Pd(dppf)Cl (316 mg, 0.433 mmol), and NaCO (918 mg, 8.66 mmol) in dioxane / HO (v / v = 5 / 1, 30.0 mL) was stirred at 85 °C for 16 h under a N atmosphere. Upon completion of the reaction, it was concentrated and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 3 / 1) to give 130 (600 mg, 59.2% yield) as a yellow solid.

[0457] Synthesis of methyl 2-amino-6-(thiophen-2-yl)nicotinate (131) [ka]

[0458] A mixture of 131-1 (300 mg, 1.61 mmol), thiophen-2-ylboronic acid (309 mg, 2.41 mmol), Pd(dppf)Cl (118 mg, 0.161 mmol), and NaCO (341 mg, 3.22 mmol) in dioxane / HO (v / v = 5 / 1, 10.0 mL) was stirred at 85 °C for 2 h under a N atmosphere. Upon completion of the reaction, it was concentrated and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 3 / 1) to give 131 (200 mg, 53.2% yield) as a yellow solid.

[0459] Synthesis of 1-(3-methoxy-5-(trifluoromethyl)phenyl)-4-methylpentan-1-ol (104-2) [ka]

[0460] To a solution of 104-1 (2.00 g, 9.80 mmol) in THF (15.0 mL) was added isopentylmagnesium bromide (1.0 M in THF, 14.7 mL, 14.7 mmol). The reaction was stirred at room temperature for 4 h. Upon completion, it was poured into aqueous NH4Cl (saturated, 30.0 mL) and extracted with EtOAc (60.0 mL × 3). The organic phases were combined, washed with HO (50.0 mL) and brine (50.0 mL), then dried over anhydrous Na2SO4, concentrated, and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 10 / 1) to give 104-2 (1.80 g, 66.5% yield) as a yellow oil.

[0461] Synthesis of 1-(3-methoxy-5-(trifluoromethyl)phenyl)-4-methylpentan-1-one (104-3) [ka]

[0462] To a solution of 104-2 (1.80 g, 6.51 mmol) in CHCl (100 mL) was added PCC (2.81 g, 13.0 mmol). The reaction was stirred at room temperature for 2 h. Upon completion of the reaction, it was concentrated and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 20 / 1) to give 104-3 (1.40 g, 78.3% yield) as a colorless oil.

[0463] Synthesis of 2-bromo-1-(3-methoxy-5-(trifluoromethyl)phenyl)-4-methylpentan-1-one (104-4) [ka]

[0464] A mixture of 104-3 (1.40 g, 5.10 mmol) and PTAT (2.87 g, 7.66 mmol) in THF (50.0 mL) was stirred at room temperature for 2 h. Upon completion of the reaction, it was concentrated, and the residue was dissolved in HO (30.0 mL) and then extracted with EtOAc (50.0 mL × 2). The organic layers were combined, washed with HO (30.0 mL × 2) and brine (30.0 mL), and then dried over anhydrous NaSO. The solution was concentrated to give the crude product, which was used directly in the next step without further purification to give 104-4 (1.80 g, 100% yield) as a brown oil.

[0465] Synthesis of 1-(3-methoxy-5-(trifluoromethyl)phenyl)-4-methyl-2-thiocyanatopentan-1-one (104-5) [ka]

[0466] A mixture of 104-4 (1.80 g, 5.11 mmol) and NaSCN (828 mg, 10.2 mmol) in EtOH (30.0 mL) was stirred for 5 h at 90° C. When the reaction was complete, it was concentrated and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 3 / 1) to give 104-5 (1.20 g, 70.9% yield) as a yellow solid.

[0467] Synthesis of 2-chloro-5-isobutyl-4-(3-methoxy-5-(trifluoromethyl)phenyl)thiazole (104-s) [ka]

[0468] A mixture of 104-5 (1.20 g, 3.63 mmol) in HCl / dioxane (4.0 M, 10.0 mL) was stirred at room temperature for 4 h. Upon completion of the reaction, it was concentrated and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 10 / 1) to give 104-s (1.00 g, 79.0% yield) as a yellow oil.

[0469] Synthesis of 3-(2-chloro-5-isobutylthiazol-4-yl)phenol (102-1) [ka]

[0470] A mixture of 1 (1.10 g, 3.73 mmol) and BBr (17% in CHCl, 9.32 mL, 9.32 mmol) in CHCl (30.0 mL) was stirred at room temperature overnight. When the reaction was complete, it was washed with HO (50.0 mL × 3). The organic layer was concentrated and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 4 / 1) to give 102-1 (600 mg, 60.3% yield) as a yellow solid.

[0471] Synthesis of 2-chloro-5-isobutyl-4-(3-(2,2,2-trifluoroethoxy)phenyl)thiazole (102-s) [ka]

[0472] A mixture of 102-1 (250 mg, 0.936 mmol), 2,2,2-trifluoroethyl trifluoromethanesulfonate (326 mg, 1.40 mmol), and K2CO3 (388 mg, 2.81 mmol) in DMF (5.0 mL) was stirred at room temperature overnight. Upon completion of the reaction, it was poured into HO (80.0 mL) and extracted with EtOAc (50.0 mL × 3). The combined organic phases were washed with HO (50.0 mL) and brine (50.0 mL), then dried over anhydrous Na2SO4, concentrated, and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 15 / 1) to give 102-s (310 mg, 94.9% yield) as a colorless oil.

[0473] Synthesis of 4-ethyl-3-methoxybenzaldehyde (110-2) [ka]

[0474] A mixture of 110-1 (4.00 g, 18.6 mmol), ethylboronic acid (2.07 g, 27.9 mmol), Pd(dppf)Cl (1.36 g, 1.86 mmol), and NaCO (3.94 g, 37.2 mmol) in toluene (30.0 mL) was stirred overnight at 100 °C under a N atmosphere. Upon completion of the reaction, it was concentrated and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 20 / 1) to give 110-2 (1.80 g, 59.0% yield) as a black oil.

[0475] Synthesis of 1-(4-ethyl-3-methoxyphenyl)-4-methylpentan-1-ol (110-3) [ka]

[0476] To a solution of 110-2 (1.80 g, 11.0 mmol) in THF (20.0 mL) was added isopentylmagnesium bromide (1.0 M in THF, 16.5 mL, 16.5 mmol). The reaction was stirred at room temperature for 4 h. Upon completion, it was poured into aqueous NH4Cl (saturated, 50.0 mL) and extracted with EtOAc (80.0 mL × 3). The combined organic phases were washed with HO (50.0 mL) and brine (80.0 mL), then dried over anhydrous Na2SO4, concentrated, and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 10 / 1) to give 110-3 (1.90 g, 73.4% yield) as a colorless oil.

[0477] Synthesis of 1-(4-ethyl-3-methoxyphenyl)-4-methylpentan-1-one (110-4) [ka]

[0478] To a solution of 110-3 (1.90 g, 8.05 mmol) in CHCl (100 mL) was added PCC (3.47 g, 16.1 mmol). The reaction was stirred at room temperature for 2 h. Upon completion of the reaction, it was concentrated and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 20 / 1) to give 110-4 (1.70 g, 90.2% yield) as a colorless oil.

[0479] Synthesis of 2-bromo-1-(4-ethyl-3-methoxyphenyl)-4-methylpentan-1-one (110-5) [ka]

[0480] A mixture of 110-4 (1.70 g, 7.26 mmol) and PTAT (4.09 g, 10.9 mmol) in THF (50.0 mL) was stirred at room temperature for 2 h. Upon completion of the reaction, it was concentrated, and the residue was dissolved in HO (30.0 mL) and then extracted with EtOAc (50.0 mL × 2). The organic layers were combined, washed with HO (30.0 mL × 2) and brine (30.0 mL), and then dried over anhydrous NaSO. The solution was concentrated to give the crude product, which was used directly in the next step without further purification to give 110-5 (2.30 g, 100% yield) as a brown oil.

[0481] Synthesis of 1-(4-ethyl-3-methoxyphenyl)-4-methyl-2-thiocyanatopentan-1-one (110-6) [ka]

[0482] A mixture of 110-5 (2.30 g, 7.37 mmol) and NaSCN (1.19 g, 14.7 mmol) in EtOH (60.0 mL) was stirred for 5 h at 90° C. When the reaction was complete, it was concentrated and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 3 / 1) to give 110-6 (1.40 g, 65.3% yield) as a yellow solid.

[0483] Synthesis of 2-chloro-4-(4-ethyl-3-methoxyphenyl)-5-isobutylthiazole (110-s) [ka]

[0484] A mixture of 110-6 (1.40 g, 4.81 mmol) in HCl / dioxane (4.0 M, 30.0 mL) was stirred at room temperature for 4 h. Upon completion of the reaction, it was concentrated and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 10 / 1) to give 110-s (1.20 g, 80.6% yield) as a yellow oil.

[0485] Synthesis of N-(4-(benzo[d][1,3]dioxol-5-yl)-5-isobutylthiazol-2-yl)acetamide (124-1) [ka]

[0486] A mixture of 1 (600 mg, 2.59 mmol), 2-(benzo[d][1,3]dioxol-5-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (962 mg, 3.88 mmol), Pd(OAc) (58.1 mg, 0.259 mmol), PCy (145 mg, 0.518 mmol), and KPO (1.10 g, 5.18 mmol) in toluene / HO (v / v = 10 / 1, 10.0 mL) was stirred at 150 °C for 12 h under N atmosphere in a microwave. Upon completion of the reaction, it was concentrated and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 3 / 1) to give 124-1 (600 mg, 73.0% yield) as a yellow solid.

[0487] Synthesis of 4-(benzo[d][1,3]dioxol-5-yl)-5-isobutylthiazol-2-amine (124-s) [ka]

[0488] A mixture of 124-1 (600 mg, 1.89 mmol) and NaOH (2.0 M in HO, 4.0 mL) in EtOH (20.0 mL) was stirred overnight at 90° C. Upon completion of the reaction, it was concentrated and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 1) to give 124-s (300 mg, 57.6% yield) as a yellow solid.

[0489] Synthesis of 3-isopropoxy-4-methylbenzaldehyde (114-2) [ka]

[0490] A mixture of 114-1 (3.00 g, 22.1 mmol), 2-iodopropane (5.62 g, 33.1 mmol), and K2CO3 (9.13 g, 66.2 mmol) in DMF (15.0 mL) was stirred at room temperature overnight. Upon completion of the reaction, it was poured into HO (200 mL) and extracted with EtOAc (100 mL × 3). The combined organic phases were washed with HO (80.0 mL) and brine (80.0 mL), then dried over anhydrous Na2SO4, concentrated, and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 30 / 1) to give 114-2 (3.40 g, 86.6% yield) as a colorless oil.

[0491] Synthesis of 1-(3-isopropoxy-4-methylphenyl)-4-methylpentan-1-ol (114-3) [ka]

[0492] To a solution of 114-2 (3.40 g, 19.1 mmol) in THF (30.0 mL) was added isopentylmagnesium bromide (1.0 M in THF, 28.7 mL, 28.7 mmol). The reaction was stirred at room temperature for 4 h. Upon completion, it was poured into aqueous NH4Cl (saturated, 50.0 mL) and extracted with EtOAc (80.0 mL × 3). The combined organic phases were washed with HO (50.0 mL) and brine (80.0 mL), then dried over anhydrous Na2SO4, concentrated, and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 10 / 1) to give 114-3 (3.10 g, 64.9% yield) as a colorless oil.

[0493] Synthesis of 1-(3-isopropoxy-4-methylphenyl)-4-methylpentan-1-one (114-4) [ka]

[0494] To a solution of 114-3 (3.10 g, 12.4 mmol) in CHCl (200 mL) was added PCC (5.35 g, 24.8 mmol). The reaction was stirred at room temperature for 2 h. Upon completion of the reaction, it was concentrated and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 20 / 1) to give 114-4 (3.00 g, 97.6% yield) as a colorless oil.

[0495] Synthesis of 2-bromo-1-(3-isopropoxy-4-methylphenyl)-4-methylpentan-1-one (114-5) [ka]

[0496] A mixture of 114-4 (3.00 g, 12.1 mmol) and PTAT (6.80 g, 18.1 mmol) in THF (100 mL) was stirred at room temperature for 2 h. Upon completion of the reaction, it was concentrated, and the residue was dissolved in HO (80 mL) and then extracted with EtOAc (80 mL × 2). The organic layers were combined, washed with HO (30 mL × 2) and brine (30 mL), and then dried over anhydrous NaSO. The solution was concentrated to give the crude product, which was used directly in the next step without further purification to give 114-5 (3.94 g, 100% yield) as a brown oil.

[0497] Synthesis of 1-(3-isopropoxy-4-methylphenyl)-4-methyl-2-thiocyanatopentan-1-one (114-6) [ka]

[0498] A mixture of 114-5 (3.94 g, 12.1 mmol) and NaSCN (1.96 g, 24.2 mmol) in EtOH (80.0 mL) was stirred for 5 h at 90° C. When the reaction was complete, it was concentrated and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 3 / 1) to give 114-6 (2.50 g, 67.8% yield) as a yellow solid.

[0499] Synthesis of 2-chloro-5-isobutyl-4-(3-isopropoxy-4-methylphenyl)thiazole (114-s) [ka]

[0500] A mixture of 114-6 (2.50 g, 8.20 mmol) in HCl / dioxane (4.0 M, 30.0 mL) was stirred at room temperature for 4 h. Upon completion of the reaction, it was concentrated and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 10 / 1) to give 114-s (1.50 g, 56.6% yield) as a yellow oil.

[0501] Synthesis of 4-(3-(2-(2-bromoethoxy)ethoxy)phenyl)-2-chloro-5-isobutylthiazole (116-1)

[0502] [ka]

[0503] A mixture of 102-1 (600 mg, 2.25 mmol), 1-bromo-2-(2-bromoethoxy)ethane (1.41 g, 3.37 mmol), and K2CO3 (930 mg, 6.74 mmol) in DMF (10.0 mL) was stirred at 60 °C for 16 h. Upon completion of the reaction, it was poured into HO (100 mL) and extracted with EtOAc (100 mL × 3). The combined organic phases were washed with HO (80.0 mL) and brine (80.0 mL), then dried over anhydrous Na2SO4, concentrated, and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 10 / 1) to give 116-1 (400 mg, 61.3% yield) as a colorless oil.

[0504] Synthesis of 2-(2-(3-(2-chloro-5-isobutylthiazol-4-yl)phenoxy)ethoxy)-N,N-dimethylethanamine (116-s) [ka]

[0505] A mixture of 116-1 (400 mg, 0.957 mmol), (CH)NH.HCl (117 mg, 1.44 mmol), and KCO (396 mg, 2.87 mmol) in DMF (10.0 mL) was stirred at room temperature for 16 h. Upon completion of the reaction, it was poured into HO (100 mL) and extracted with EtOAc (100 mL × 3). The combined organic phases were washed with HO (80.0 mL) and brine (80.0 mL), then dried over anhydrous NaSO, concentrated, and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 30 / 1) to give 116-s (280 mg, 76.6% yield) as a yellow oil. [Table 9-1] [Table 9-2] [Table 9-3]

[0506] Synthesis of methyl 2-((5-isobutyl-4-(3-methoxy-5-(trifluoromethyl)phenyl)thiazol-2-yl)amino)-5-(thiophen-2-yl)nicotinate (104-6) [ka]

[0507] A mixture of 104-s (250 mg, 0.716 mmol), methyl 2-amino-5-(thiophen-2-yl)nicotinate (168 mg, 0.716 mmol), Pd(dba) (66.6 mg, 0.0716 mmol), X-Phos (62.1 mg, 0.107 mmol), and CsCO (467 mg, 1.43 mmol) in toluene (10.0 mL) was stirred at 120 °C for 4 h under a N atmosphere. Upon completion of the reaction, it was concentrated and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 8 / 1) to give 104-6 (300 mg, 76.6% yield) as a yellow solid.

[0508] Synthesis of 2-((5-isobutyl-4-(3-methoxy-5-(trifluoromethyl)phenyl)thiazol-2-yl)amino)-5-(thiophen-2-yl)nicotinic acid (I-104) [ka]

[0509] To a solution of 104-6 (300 mg, 0.548 mmol) in THF / MeOH (v / v = 4 / 1, 10.0 mL) was added LiOH (2.0 M in HO, 2.0 mL). The reaction was stirred at room temperature for 2 h. Upon completion, the resulting mixture was concentrated, then diluted with HO (15.0 mL), and the pH was adjusted to 4-5 with HCl (1.0 M). The mixture was extracted with EtOAc (10.0 mL × 2), and the combined organic phase was washed with brine (10.0 mL), dried over anhydrous NaSO, concentrated, and the residue was purified by washing with MeOH to give I-104 (250 mg, 85.5% yield) as a yellow solid.

[0510] Synthesis of methyl 2-((4-(benzo[d][1,3]dioxol-5-yl)-5-isobutylthiazol-2-yl)amino)-5-(thiophen-2-yl)nicotinate (124-2) [ka]

[0511] A mixture of 124-s (300 mg, 1.09 mmol), methyl 2-chloro-5-(thiophen-2-yl)nicotinate (276 mg, 1.09 mmol), Pd(dba) (101 mg, 0.109 mmol), X-Phos (94.5 mg, 0.164 mmol), and CsCO (533 mg, 1.64 mmol) in toluene (20 mL) was stirred at 120 °C for 4 h under a N atmosphere. Upon completion of the reaction, it was concentrated and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 8 / 1) to give 124-2 (150 mg, 28.0% yield) as a yellow solid.

[0512] Synthesis of 2-((4-(benzo[d][1,3]dioxol-5-yl)-5-isobutylthiazol-2-yl)amino)-5-(thiophen-2-yl)nicotinic acid (I-124) [ka]

[0513] To a solution of 124-2 (150 mg, 0.304 mmol) in THF / MeOH (v / v = 4 / 1, 5.0 mL) was added LiOH (2.0 M in HO, 1.0 mL). The reaction was stirred at room temperature for 2 h. Upon completion, the resulting mixture was concentrated, then diluted with HO (15.0 mL), and the pH was adjusted to 4–5 with HCl (1.0 M). The mixture was extracted with EtOAc (10.0 mL × 2), and the combined organic phase was washed with brine (10.0 mL), dried over anhydrous NaSO, concentrated, and the residue was purified by washing with MeOH to give I-124 (30.0 mg, 20.6% yield) as a yellow solid.

[0514] Synthesis of methyl 2-((5-isobutyl-4-(3-phenoxyphenyl)thiazol-2-yl)amino)-5-(thiophen-2-yl)nicotinate (129-1) [ka]

[0515] A mixture of 111-6 (120 mg, 0.258 mmol), phenylboronic acid (94.3 mg, 0.773 mmol), Cu(OAc) (77.2 mg, 0.387 mmol), and TEA (130 mg, 1.29 mmol) in CHCl (10.0 mL) was stirred overnight at room temperature under a N atmosphere. Upon completion of the reaction, it was concentrated and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 3 / 1) to give 129-1 (40.0 mg, 28.7% yield) as a yellow solid.

[0516] Synthesis of 2-((5-isobutyl-4-(3-phenoxyphenyl)thiazol-2-yl)amino)-5-(thiophen-2-yl)nicotinic acid (I-129) [ka]

[0517] To a solution of 129-1 (40.0 mg, 0.0738 mmol) in THF / MeOH (v / v = 4 / 1, 3.0 mL) was added LiOH (2.0 M in HO, 1.0 mL). The reaction was stirred at room temperature for 2 h. Upon completion, the resulting mixture was concentrated, then diluted with HO (15.0 mL), and the pH was adjusted to 4-5 with HCl (1.0 M). The mixture was extracted with EtOAc (10.0 mL × 2), and the combined organic phase was washed with brine (10.0 mL), dried over anhydrous NaSO, concentrated, and the residue was purified by washing with MeOH to give I-129 (20.0 mg, 51.3% yield) as a yellow solid.

[0518] Synthesis of methyl 2-((4-(3-ethoxyphenyl)-5-isobutylthiazol-2-yl)amino)-5-(thiophen-2-yl)isonicotinate (130-1) [ka]

[0519] A mixture of 1 (300 mg, 1.02 mmol), 130 (239 mg, 1.02 mmol), Pd(dba) (94.9 mg, 0.102 mmol), X-Phos (88.4 mg, 0.153 mmol), and CsCO (499 mg, 1.53 mmol) in toluene (10.0 mL) was stirred at 120 °C under N atmosphere in a microwave for 3 h. Upon completion of the reaction, it was concentrated and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 8 / 1) to give 130-1 (120 mg, 23.9% yield) as a yellow solid.

[0520] Synthesis of 2-((4-(3-ethoxyphenyl)-5-isobutylthiazol-2-yl)amino)-5-(thiophen-2-yl)isonicotinic acid (I-130) [ka]

[0521] To a solution of 130-1 (120 mg, 0.243 mmol) in THF / MeOH (v / v = 4 / 1, 5.0 mL) was added LiOH (2.0 M in HO, 1.0 mL). The reaction was stirred at room temperature for 2 h. Upon completion, the resulting mixture was concentrated, then diluted with HO (15.0 mL), and the pH was adjusted to 4-5 with HCl (1.0 M). The mixture was extracted with EtOAc (10.0 mL × 2), and the combined organic phase was washed with brine (10.0 mL), dried over anhydrous NaSO, concentrated, and the residue was purified by washing with MeOH to give I-130 (60.0 mg, 51.5% yield) as a yellow solid.

[0522] Synthesis of methyl 2-((4-(3-ethoxyphenyl)-5-isobutylthiazol-2-yl)amino)-6-(thiophen-2-yl)nicotinate (131-2) [ka]

[0523] A mixture of 1 (250 mg, 0.847 mmol), methyl 2-amino-6-(thiophen-2-yl)nicotinate (198 mg, 0.847 mmol), Pd(dba) (78.8 mg, 0.0847 mmol), X-Phos (73.4 mg, 0.127 mmol), and CsCO (414 mg, 1.27 mmol) in toluene (10 mL) was stirred at 150 °C under N atmosphere in a microwave for 4 h. Upon completion of the reaction, it was concentrated and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 8 / 1) to give 131-2 (80.0 mg, 19.1% yield) as a yellow solid.

[0524] Synthesis of 2-((4-(3-ethoxyphenyl)-5-isobutylthiazol-2-yl)amino)-6-(thiophen-2-yl)nicotinic acid (I-131) [ka]

[0525] To a solution of 131-2 (80.0 mg, 0.162 mmol) in THF / MeOH (v / v = 4 / 1, 3.0 mL) was added LiOH (2.0 M in HO, 1.0 mL). The reaction was stirred at room temperature for 2 h. Upon completion, the resulting mixture was concentrated, then diluted with HO (15.0 mL), and the pH was adjusted to 4-5 with HCl (1.0 M). The mixture was extracted with EtOAc (10.0 mL × 2), and the combined organic phase was washed with brine (10.0 mL), dried over anhydrous NaSO, concentrated, and the residue was purified by washing with MeOH to give I-131 (30.0 mg, 38.6% yield) as an off-white solid.

[0526] Synthesis of methyl 5-(tert-butyl)-3-((4-(3-ethoxyphenyl)-5-isobutylthiazol-2-yl)amino)thiophene-2-carboxylate (132-1) [ka]

[0527] A mixture of 1 (250 mg, 0.847 mmol), methyl 3-amino-6-(thiophen-2-yl)pyrazine-2-carboxylate (181 mg, 0.847 mmol), Pd(dba) (78.8 mg, 0.0847 mmol), X-Phos (73.4 mg, 0.127 mmol), and CsCO (414 mg, 1.27 mmol) in toluene (10 mL) was stirred overnight at 120 °C under a N atmosphere. Upon completion of the reaction, it was concentrated and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 8 / 1) to give 132-1 (100 mg, 25.0% yield) as a yellow solid.

[0528] Synthesis of 5-(tert-butyl)-3-((4-(3-ethoxyphenyl)-5-isobutylthiazol-2-yl)amino)thiophene-2-carboxylic acid (I-132) [ka]

[0529] To a solution of 132-1 (100 mg, 0.212 mmol) in THF / MeOH (v / v = 4 / 1, 5.0 mL) was added LiOH (2.0 M in HO, 1.0 mL). The reaction was stirred at 50 °C for 12 h. Upon completion, the resulting mixture was concentrated, then diluted with HO (15.0 mL), and the pH was adjusted to 4-5 with HCl (1.0 M). The mixture was extracted with EtOAc (10.0 mL × 2), and the combined organic phase was washed with brine (10.0 mL), dried over anhydrous NaSO, concentrated, and the residue was purified by washing with MeOH to give I-132 (50.0 mg, 51.5% yield) as a yellow solid.

[0530] Synthesis of methyl 2-((4-(3-ethoxyphenyl)-5-isobutylthiazol-2-yl)amino)-5-(trifluoromethyl)nicotinate (133-1) [ka]

[0531] A mixture of 1 (250 mg, 0.847 mmol), methyl 2-amino-5-(trifluoromethyl)nicotinate (186 mg, 0.847 mmol), Pd(dba) (78.8 mg, 0.0847 mmol), X-Phos (73.4 mg, 0.127 mmol), and CsCO (414 mg, 1.27 mmol) in toluene (10 mL) was stirred at 120 °C for 3 h under a N atmosphere. Upon completion of the reaction, it was concentrated and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 8 / 1) to give 133-1 (150 mg, 37.0% yield) as a yellow solid.

[0532] Synthesis of 2-((4-(3-ethoxyphenyl)-5-isobutylthiazol-2-yl)amino)-5-(trifluoromethyl)nicotinic acid (I-133) [ka]

[0533] To a solution of 133-1 (150 mg, 0.313 mmol) in THF / MeOH (v / v = 4 / 1, 5.0 mL) was added LiOH (2.0 M in HO, 1.0 mL). The reaction was stirred at room temperature for 2 h. Upon completion, the resulting mixture was concentrated, then diluted with HO (15.0 mL), and the pH was adjusted to 4-5 with HCl (1.0 M). The mixture was extracted with EtOAc (10.0 mL × 2), and the combined organic phase was washed with brine (10.0 mL), dried over anhydrous NaSO, concentrated, and the residue was purified by washing with MeOH to give I-133 (80.0 mg, 54.9% yield) as a white solid.

[0534] Synthesis of methyl 5-bromo-3-((4-(3,4-dichlorophenyl)-5-isobutylthiazol-2-yl)amino)thiophene-2-carboxylate (138-1) [ka]

[0535] A mixture of 1 (3.50 g, 9.59 mmol), methyl 3-amino-5-bromothiophene-2-carboxylate (2.26 g, 9.59 mmol), Pd(dba) (891 mg, 0.959 mmol), X-Phos (831 mg, 1.44 mmol), and CsCO (4.68 g, 14.4 mmol) in toluene (100 mL) was stirred at 110 °C for 16 h under a N atmosphere. Upon completion of the reaction, it was concentrated and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 6 / 1) to give 138-1 (1.50 g, 30.1% yield) as a yellow solid.

[0536] Synthesis of methyl 3-((4-(3,4-dichlorophenyl)-5-isobutylthiazol-2-yl)amino)-5-(3-methoxyphenyl)thiophene-2-carboxylate (138-2) [ka]

[0537] A mixture of 138-1 (200 mg, 0.384 mmol), (3-methoxyphenyl)boronic acid (87.6 mg, 0.577 mmol), Pd(dppf)Cl (28.1 mg, 0.0384 mmol), and NaCO (81.4 mg, 0.768 mmol) in dioxane / HO (v / v = 5 / 1, 10.0 mL) was stirred overnight at 85 °C under a N atmosphere. Upon completion of the reaction, it was concentrated and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 3 / 1) to give 138-2 (70.0 mg, 33.3% yield) as a yellow solid.

[0538] Synthesis of 3-((4-(3,4-dichlorophenyl)-5-isobutylthiazol-2-yl)amino)-5-(3-methoxyphenyl)thiophene-2-carboxylic acid (I-138) [ka]

[0539] To a solution of 138-2 (70.0 mg, 0.128 mmol) in THF / MeOH (v / v = 4 / 1, 3.0 mL) was added LiOH (2.0 M in HO, 1.0 mL). The reaction was stirred at room temperature for 2 h. Upon completion, the resulting mixture was concentrated, then diluted with HO (15.0 mL), and the pH was adjusted to 4-5 with HCl (1.0 M). The mixture was extracted with EtOAc (10.0 mL × 2), and the combined organic phase was washed with brine (10.0 mL), dried over anhydrous NaSO, concentrated, and the residue was purified by washing with MeOH to give I-138 (25.0 mg, 36.7% yield) as a yellow solid.

[0540] Synthesis of methyl 2-((5-isobutyl-4-(thiophen-2-yl)thiazol-2-yl)amino)nicotinate (145-1) [ka]

[0541] A mixture of 126-s (250 mg, 0.970 mmol), methyl 2-aminonicotinate (148 mg, 0.970 mmol), Pd(dba) (90.1 mg, 0.097 mmol), X-Phos (84.1 mg, 0.146 mmol), and CsCO (474 ​​mg, 1.46 mmol) in toluene (20 mL) was stirred at 120 °C for 16 h under a N atmosphere. Upon completion of the reaction, it was concentrated and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 8 / 1) to give 145-1 (180 mg, 49.7% yield) as a white solid.

[0542] Synthesis of 2-((5-isobutyl-4-(thiophen-2-yl)thiazol-2-yl)amino)nicotinic acid (I-145) [ka]

[0543] To a solution of 145-1 (180 mg, 0.482 mmol) in THF / MeOH (v / v = 4 / 1, 5.0 mL) was added NaOH (2.0 M in HO, 1.0 mL). The reaction was stirred at room temperature for 2 h. Upon completion, the resulting mixture was concentrated, then diluted with HO (15.0 mL), and the pH was adjusted to 4-5 with HCl (1.0 M). The mixture was extracted with EtOAc (10.0 mL × 2), and the combined organic phase was washed with brine (10.0 mL), dried over anhydrous NaSO, concentrated, and the residue was purified by washing with MeOH to give I-145 (150 mg, 86.6% yield) as a yellow solid.

[0544] Synthesis of methyl 1-(5-isobutyl-4-(thiophen-2-yl)thiazol-2-yl)piperidine-3-carboxylate (146-1) [ka]

[0545] A mixture of 126-s (300 mg, 1.16 mmol), methyl piperidine-3-carboxylate (167 mg, 1.16 mmol), Pd(dba) (108 mg, 0.116 mmol), X-Phos (101 mg, 0.174 mmol), and CsCO (567 mg, 1.74 mmol) in toluene (20 mL) was stirred at 110 °C for 16 h under a N atmosphere. Upon completion of the reaction, it was concentrated and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 8 / 1) to give 146-1 (160 mg, 37.7% yield) as a yellow solid.

[0546] Synthesis of 1-(5-isobutyl-4-(thiophen-2-yl)thiazol-2-yl)piperidine-3-carboxylic acid (I-146) [ka]

[0547] To a solution of 883-1 (160 mg, 0.438 mmol) in THF / MeOH (v / v = 4 / 1, 3.0 mL) was added LiOH (2.0 M in HO, 1.0 mL). The reaction was stirred at room temperature for 2 h. Upon completion, the resulting mixture was concentrated, then diluted with HO (15.0 mL), and the pH was adjusted to 4-5 with HCl (1.0 M). The mixture was extracted with EtOAc (10.0 mL × 2), and the combined organic phase was washed with brine (10.0 mL), dried over anhydrous NaSO, concentrated, and the residue was purified by washing with MeOH to give I-146 (120 mg, 78.0% yield) as a yellow solid.

[0548] Synthesis of methyl 2-((4-(cyclohex-1-en-1-yl)-5-isobutylthiazol-2-yl)amino)-5-(trifluoromethyl)nicotinate (147-1) [ka]

[0549] A mixture of 139-s (175 mg, 0.740 mmol), methyl 2-chloro-5-(trifluoromethyl)nicotinate (177 mg, 0.740 mmol), Pd(dba) (68.8 mg, 0.074 mmol), X-Phos (64.2 mg, 0.111 mmol), and CsCO (362 mg, 1.11 mmol) in toluene (20 mL) was stirred at 120 °C for 4 h under a N atmosphere. Upon completion of the reaction, it was concentrated and purified by ...

Claims

1. Formula I: 【256】 or a pharmaceutically acceptable salt thereof, wherein X is C or N; R １ is H, optionally halogen, —OR, —N(R) ２ , or —C(O)—N(R) ２ C substituted 1 to 6 times by １－６ is alkyl, R ２ is a 3- to 6-membered monocyclic saturated carbocyclic ring optionally substituted 1 to 6 times by halogen or -OR'; C is optionally substituted 1 to 6 times by halogen or -OR'; １－６ C optionally substituted once by alkyl or a 3- to 6-membered monocyclic saturated carbocyclic or phenyl ring １－６ alkyl, wherein said 3-6 membered monocyclic saturated carbocyclic ring and said phenyl ring are optionally substituted 1-6 times with halogen or -OR'; R ３ but, 【Chemistry 257】 and Each R ４ are independently halogen, —OR １ or C optionally substituted 1 to 6 times with halogen １－６ is alkyl, Each R ５ are independently halogen, or C optionally substituted 1 to 6 times with halogen １－６ is alkyl, Each R is independently H, optionally halogen, —OR′, or —N(R′). ２ C substituted 1 to 6 times by １－６ a 3- to 6-membered monocyclic saturated carbocyclic ring optionally substituted 1 to 6 times by alkyl or halogen; C, where each R' is independently H, or optionally substituted 1 to 6 times with halogen. １－６ is alkyl, m is 0 or 1; The compound, or a pharmaceutically acceptable salt thereof, wherein n is 0, 1, or 2.

2. Formula V, VI, VII-a, VII-b, or VIII: 【Chemical 258】 or a pharmaceutically acceptable salt thereof, wherein R １１ H, halogen, C １－６ alkyl, —O-phenyl, or —O—C １－６ alkyl, where C １－６ alkyl is optionally substituted with phenyl or -O-phenyl, wherein phenyl is optionally substituted; R １２ and R １３ each independently represents H, or an optionally substituted C １－６ is alkyl, Each R １４ are independently H, —OH, halogen, —C １－６ Alkyl, —O—C １－６ alkyl, or phenyl, where -C １－６ Alkyl, —O—C １－６ alkyl, and phenyl are optionally substituted; Each R １５ are independently H, —OH, halogen, —C １－６ Alkyl, or —O—C １－６ alkyl, where -C １－６ Alkyl and —O—C １－６ alkyl is optionally substituted; Y is O, CH ２ , or CHR １５ and t is 0, 1, 2, 3, or 4; X is C or N; R ２ is a 3- to 6-membered monocyclic saturated carbocyclic ring optionally substituted 1 to 6 times by halogen or -OR'; C is optionally substituted 1 to 6 times by halogen or -OR'; １－６ C optionally substituted once by alkyl or a 3- to 6-membered monocyclic saturated carbocyclic or phenyl ring １－６ alkyl, wherein said 3-6 membered monocyclic saturated carbocyclic ring and said phenyl ring are optionally substituted 1-6 times with halogen or -OR'; R ３ but, 【Chemical 259】 and Each R ４ are independently halogen, —OR １ or C optionally substituted 1 to 6 times with halogen １－６ is alkyl, Each R ５ are independently halogen, or —C optionally substituted 1 to 6 times with halogen １－６ is alkyl, Each R is independently H, optionally halogen, —OR′, or —N(R′). ２ C substituted 1 to 6 times by １－６ a 3- to 6-membered monocyclic saturated carbocyclic ring optionally substituted 1 to 6 times by alkyl or halogen; each R' is independently H, -OR, or -C optionally substituted 1 to 6 times with halogen; １－６ is alkyl, m is 0 or 1; The compound, or a pharmaceutically acceptable salt thereof, wherein n is 0, 1, or 2.

3. X is C or CR ４ 3. The compound of claim 1 or 2, wherein

4. R １ is optionally halogen, —OR, or —N(R) ２ C substituted 1 to 6 times by １－６ 3. The compound of claim 1 or 2, wherein the compound is alkyl.

5. R １ is unsubstituted C １－６ The compound of claim 4, wherein the compound is alkyl.

6. R ２ is optionally substituted 1 to 6 times by halogen or —OR′ １－６ 3. The compound of claim 1 or 2, wherein the compound is alkyl.

7. R ２ is optionally substituted once by a 3- to 6-membered monocyclic saturated carbocyclic ring １－６ The compound of claim 1 or 2, wherein said 3-6 membered monocyclic saturated carbocyclic ring is alkyl, and said 3-6 membered monocyclic saturated carbocyclic ring is optionally substituted 1-6 times with halogen or -OR'.

8. R ２ but, 【Chemistry 260】 3. The compound of claim 1 or 2, wherein

9. R ３ but, 【Chemical 261】 3. The compound of claim 1 or 2, wherein

10. Each R ４ are independently halogen or —OR １ 3. The compound of claim 1 or 2, wherein

11. Each R ４ are independently —OH, F, Cl, 【Chemical 262】 3. The compound of claim 1 or 2, selected from:

12. 3. The compound of claim 1 or 2, wherein m is 0.

13. 3. The compound of claim 1 or 2, wherein n is 1.

14. The compound has the formula II, II-a, II-b, or II-c: 【Chemical 263】 2. The compound of claim 1, wherein the compound is:

15. The compound has the formula III, III-a, III-b, or III-c: 【Chemical Formula 264】 2. The compound of claim 1, wherein the compound is:

16. The compound has the formula IV-a to IV-f: 【Chemical 265】 2. The compound of claim 1, wherein the compound is:

17. 3. The compound of claim 1 or 2, wherein the compound is selected from those in Table 1 or Table 2, or a pharmaceutically acceptable salt thereof.

18. 10. A pharmaceutical composition comprising a compound of claim 1 or 2, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, adjuvant, or vehicle.

19. A pharmaceutical composition for use in treating an eIF4E-mediated disease, disorder, and / or condition in a patient, the pharmaceutical composition comprising a compound of claim 1 or 2, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, adjuvant, or vehicle.

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