EIF4E inhibitors and uses thereof

Abstract

The present invention provides compounds and compositions for inhibiting eIF4E activity and methods of using the same.

Description

Technical Field

[0001] The present invention relates to compounds and methods that can be used to inhibit eukaryotic initiation factor 4E (eIF4E). The present invention also provides pharmaceutically acceptable compositions comprising the compounds of the present invention and methods of using the compositions to treat various disorders. Background Art

[0002] Eukaryotic initiation factor 4E (eIF4E) is a 24kDa protein that plays a key role in initiating the translation of selected mRNAs. At the initiation of mRNA translation, eIF4E binds to the 7-methylguanosine cap at the 5' end of the mRNA and forms a complex (called eIF4F) with proteins including the backbone protein eIF4G and the helicase eIF4A. Cap-dependent translation initiation requires the formation of the 4F complex, so the binding of eIF4E to its cognate partner is a key event in eIF4E-mediated translation.

[0003] Several studies have shown that dysregulated eIF4E is important in some cancer phenotypes, and thus eIF4E is a potential target in the field of oncology. Summary of the invention

[0004] It has now been found that the compounds of the present invention and pharmaceutically acceptable compositions thereof are effective as eIF4E inhibitors. In one aspect, the present invention provides a compound of formula (I):

[0005]

[0006] or a pharmaceutically acceptable salt thereof, wherein the variables are as defined and described herein.

[0007] The compounds of the invention and pharmaceutically acceptable compositions thereof are useful for treating a variety of diseases, disorders or conditions associated with eIF4E. Such diseases, disorders or conditions include cell proliferative disorders (eg, cancer), such as those described herein. DETAILED DESCRIPTION

[0008] 1. General Description of Certain Embodiments of the Invention:

[0009] The compounds of the present invention and pharmaceutical compositions thereof are useful as eIF4E inhibitors. Without wishing to be bound by any particular theory, it is believed that the compounds of the present invention and pharmaceutical compositions thereof can inhibit the activity of eIF4E, thereby treating certain diseases, such as cancer.

[0010] It has now been found that the compounds of the present invention and pharmaceutically acceptable compositions thereof are effective as eIF4E inhibitors. In one aspect, the present invention provides a compound of formula I:

[0011]

[0012] or a pharmaceutically acceptable salt thereof, wherein:

[0013] Ring A is an optionally substituted ring selected from phenyl, a 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur, an 8-10 membered bicyclic aromatic carbocyclic ring, or an 8-10 membered bicyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur;

[0014] L 1 is a bond or an optionally substituted C 1-8 A divalent straight or branched hydrocarbon chain wherein 1, 2, 3 or 4 methylene units of the hydrocarbon chain are optionally and independently replaced by: -O-, -S-, -N(R)-, -C(O)- or -S(O) 2 -;

[0015] R 2 For halogen, R, -OR, -SR, -C(O)R, -C(O)OR, -C(O)N(R) 2 、-S(O) 2 R, -S(O) 2 OR or -S(O) 2 N(R) 2 ;

[0016] L 2 is a bond or an optionally substituted C 1-8 A divalent straight or branched hydrocarbon chain, wherein 1, 2, 3 or 4 methylene units of the hydrocarbon chain are optionally and independently replaced by: -O-, -S-, -N(R)-, -C(O)-, -S(O)- 2 -or-Cy-;

[0017] R 3 is -CN, -C(O)R, -C(O)OR, -C(O)N(R) 2 , -N(R)-C(O)-R, -N(R)-C(O)-OR, -S(O) 2 -N(R) 2 、-S(O) 2 -N(R)-C(O)R, -C(O)-N(R)-S(O) 2 R, -C(=NR)-N(R) 2 、-N(R)-C(=NR)-N(R) 2 or a 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur;

[0018] -Cy- is an optionally substituted divalent ring selected from phenylene, a 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur, a 3-6 membered monocyclic saturated or partially unsaturated carbocyclic ring, a 3-6 membered monocyclic saturated or partially unsaturated heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur, an 8-10 membered bicyclic aromatic carbocyclic ring, or an 8-10 membered bicyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur; and

[0019] R is hydrogen, optionally substituted -C 1-6 aliphatic or an optionally substituted ring selected from phenyl, a 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur, a 3-6 membered monocyclic saturated or partially unsaturated carbocyclic ring, or a 3-6 membered monocyclic saturated or partially unsaturated heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur.

[0020] 2. Compounds and Definitions:

[0021] The compounds of the present invention include those compounds generally described herein and further described by the classes, subclasses and species disclosed herein. As used herein, unless otherwise indicated, the following definitions shall apply. For the purposes of the present invention, chemical elements are identified according to the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 75th edition. In addition, the general principles of organic chemistry are described in "Organic Chemistry", Thomas Sorrell, University Science Books, Sausalito: 1999; and "March's Advanced Organic Chemistry", 5th edition, editors: Smith, MB and March, J., John Wiley & Sons, New York: 2001, the entire contents of which are incorporated herein by reference.

[0022] As used herein, the term "aliphatic" or "aliphatic group" means a straight chain (i.e., unbranched) or branched substituted or unsubstituted hydrocarbon chain (which is fully saturated or contains one or more unsaturated units) or a monocyclic hydrocarbon or bicyclic hydrocarbon (which is fully saturated or contains one or more unsaturated units) having a single point of attachment to the rest of the molecule, but which is not aromatic (also referred to herein as "carbocycle", "cycloaliphatic" or "cycloalkyl"). Unless otherwise specified, aliphatic groups contain 1-6 aliphatic carbon atoms. In some embodiments, aliphatic groups contain 1-5 aliphatic carbon atoms. In other embodiments, aliphatic groups contain 1-4 aliphatic carbon atoms. In other embodiments, aliphatic groups contain 1-3 aliphatic carbon atoms, and in yet other embodiments, aliphatic groups contain 1-2 aliphatic carbon atoms. In some embodiments, "cycloaliphatic" (or "carbocycle" or "cycloalkyl") refers to a monocyclic C alkyl group that is fully saturated or contains one or more unsaturated units, but is not aromatic. 3 -C 6 A hydrocarbon having a single point of attachment to the rest of the molecule. Suitable aliphatic groups include, but are not limited to, straight or branched chain, substituted or unsubstituted alkyl, alkenyl, alkynyl, and hybrids thereof such as (cycloalkyl)alkyl, (cycloalkenyl)alkyl, or (cycloalkyl)alkenyl.

[0023] As used herein, the term "bicyclic" or "bicyclic system" refers to any bicyclic system that is saturated or has one or more common atoms between the two rings of the ring system or has one or more unsaturated units, that is, carbocyclic or heterocyclic. Therefore, the term includes any permissible ring fusion, such as ortho-fused rings or spirocyclic rings. As used herein, the term "heterobicyclic" is a "bicyclic" subgroup that requires one or more heteroatoms to be present in one or both rings of the bicyclic. Such heteroatoms may be present at the ring junction and are optionally substituted and may be selected from nitrogen (including N-oxides), oxygen, sulfur (including oxidized forms, such as sulfones and sulfonates), phosphorus (including oxidized forms, such as phosphates), boron, etc. In some embodiments, the bicyclic group has 7-12 ring members and 0-4 heteroatoms independently selected from nitrogen, oxygen or sulfur. As used herein, the term "bridged bicyclic" refers to any bicyclic system that is saturated or partially unsaturated, that is, carbocyclic or heterocyclic, with at least one bridge bond. As defined by IUPAC, a "bridge" is a non-branched atomic chain or atom or valence bond connecting two bridgeheads, wherein a "bridgehead" is any backbone atom bonded to three or more backbone atoms (except hydrogen) of a ring system. In some embodiments, a bridged bicyclic group has 7-12 ring members and 0-4 heteroatoms independently selected from nitrogen, oxygen or sulfur. Such bridged bicyclic groups are well known in the art and include groups described below, wherein each group is connected to the rest 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 as described for an aliphatic group. Additionally or alternatively, any substitutable nitrogen of a bridged bicyclic group is optionally substituted. Exemplary bicyclics include:

[0024]

[0025] Exemplary bridged bicyclic rings include:

[0026]

[0027] The term "lower alkyl" refers to C 1-4 Straight or branched chain alkyl groups. Exemplary lower alkyl groups are methyl, ethyl, propyl, isopropyl, butyl, isobutyl and tert-butyl.

[0028] The term "lower haloalkyl" refers to a C 1-4 Straight chain or branched chain alkyl.

[0029] The term "heteroatom" means one or more of oxygen, sulfur, nitrogen, phosphorus, or silicon (including: any oxidized form of nitrogen, sulfur, phosphorus, or silicon; the quaternized form of any basic nitrogen; or a substitutable nitrogen of a heterocyclic ring, such as N (as in 3,4-dihydro-2H-pyrrolyl), NH (as in pyrrolidinyl), or NR + (as in N-substituted pyrrolidinyl)).

[0030] As used herein, the term "unsaturated" means that the moiety has one or more units of unsaturation.

[0031] As used herein, the term "divalent C 1-8 (or C 1-6 ) saturated or unsaturated straight or branched hydrocarbon chain" refers to divalent alkylene, alkenylene and alkynylene chains as defined herein, which are straight or branched.

[0032] The term "alkylene" refers to a divalent alkyl group. An "alkylene chain" is a polymethylene group, i.e., -(CH 2 ) n -, wherein n is a positive integer, preferably 1 to 6, 1 to 4, 1 to 3, 1 to 2 or 2 to 3. A substituted alkylene chain is a polymethylene chain in which one or more methylene hydrogen atoms are replaced by a substituent. Suitable substituents include those described below for substituted aliphatic groups.

[0033] 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 by a substituent. Suitable substituents include those described below for substituted aliphatic groups.

[0034] As used herein, the term "cyclopropylenyl" refers to a divalent cyclopropyl radical having the following structure:

[0035] The term "halogen" means F, Cl, Br or I.

[0036] The term "aryl", used alone or as part of a larger moiety as in "aralkyl", "aralkyloxy", or "aryloxyalkyl", refers to a monocyclic or bicyclic ring system having a total of five to fourteen ring members, wherein at least one ring in the system is aromatic and wherein each ring in the system contains 3 to 7 ring members. The term "aryl" may be used interchangeably with the term "aromatic ring". In certain embodiments of the present invention, "aryl" refers to an aromatic ring system including, but not limited to, phenyl, biphenyl, naphthyl, anthracenyl, and the like, which may carry one or more substituents. As used herein, also included within the scope of the term "aryl" are groups in which an aromatic ring is fused to one or more non-aromatic rings, such as indanyl, phthalimidyl, naphthimidyl, phenanthridinyl, or tetrahydronaphthyl, and the like.

[0037] The terms "heteroaryl" and "heteroar-", used alone or as part of a larger moiety (e.g., "heteroaralkyl" or "heteroaralkoxy"), refer to groups having 5 to 10 ring atoms, preferably 5, 6, or 9 ring atoms; having 6, 10, or 14 pi electrons shared in the cyclic array; and having one to five heteroatoms other than 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, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolizinyl, purinyl, naphthyridinyl, and pteridinyl. As used herein, the terms "heteroaryl" and "heteroar-" also include groups in which a heteroaryl ring is fused to one or more aryl, cycloaliphatic or heterocyclyl rings, wherein the radical or point of attachment is on the heteroaryl ring. Non-limiting examples include indolyl, isoindolyl, benzothienyl, benzofuranyl, dibenzofuranyl, indazolyl, benzimidazolyl, benzothiazolyl, quinolyl, isoquinolyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, 4H-quinolizinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl, phenoxazinyl, tetrahydroquinolyl, tetrahydroisoquinolyl and pyrido[2,3-b]-1,4-oxazin-3(4H)-one. The heteroaryl group may be monocyclic or bicyclic. The term "heteroaryl" may be used interchangeably with the terms "heteroaryl ring," "heteroaryl group," or "heteroaromatic," any of which include optionally substituted rings. The term "heteroaralkyl" refers to an alkyl group substituted with a heteroaryl, wherein the alkyl and heteroaryl portions are independently optionally substituted.

[0038] As used herein, the terms "heterocycle", "heterocyclyl", "heterocyclic group" and "heterocyclic ring" are used interchangeably and refer to a stable 5- to 7-membered monocyclic or 7-10-membered bicyclic heterocyclic moiety that is saturated or partially unsaturated and has one or more, preferably one to four, heteroatoms as defined above in addition to carbon atoms. When used with respect to a ring atom of a heterocycle, the term "nitrogen" includes substituted nitrogen. For example, in a saturated or partially unsaturated ring having 0 to 3 heteroatoms selected from oxygen, sulfur or nitrogen, nitrogen may be N (as in 3,4-dihydro-2H-pyrrolyl), NH (as in pyrrolidinyl) or + NR (as in N-substituted pyrrolidinyl).

[0039] The heterocyclic ring may be attached to its pendant group at any heteroatom or carbon atom that results in a stable structure, and any ring atom may be optionally substituted. Examples of such saturated or partially unsaturated heterocyclic groups include, but are not limited to, tetrahydrofuranyl, tetrahydrothiophenyl, pyrrolidinyl, piperidinyl, pyrrolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, decahydroquinolinyl, oxazolidinyl, piperazinyl, dioxanyl, dioxolanyl, diazepine, pyrrolidine, tetrahydroquinolinyl, tetrahydroisoquinolinyl, decahydroquinolinyl, oxazolidinyl, piperazinyl, dioxanyl, dioxolanyl, diazepine, pyrrolidine, tetrahydroquinolinyl, tetrahydroisoquinolinyl, decahydroquinolinyl, pyrrolidine ... Oxazepine Thiazepine The terms "heterocycle", "heterocyclyl", "heterocyclyl ring", "heterocyclic group", "heterocyclic moiety" and "heterocyclic radical" are used interchangeably herein and also include groups in which a heterocyclic ring is fused to one or more aryl, heteroaryl or cycloaliphatic rings, such as indolinyl, 3H-indolyl, chromanyl, phenanthridinyl or tetrahydroquinolinyl. The heterocyclic group may be monocyclic or bicyclic. The term "heterocyclylalkyl" refers to an alkyl substituted with a heterocyclic group, wherein the alkyl and heterocyclic moieties are independently and optionally substituted.

[0040] As used herein, the term "partially unsaturated" refers to a ring moiety that includes at least one double or triple bond. As defined herein, the term "partially unsaturated" is intended to encompass rings having multiple sites of unsaturation, but is not intended to include aryl or heteroaryl moieties.

[0041] As described herein, the compounds of the present invention may contain "optionally substituted" moieties. In general, the term "substituted", whether or not preceded by the term "optionally", means that one or more hydrogens of the indicated moiety are replaced with suitable substituents. Unless otherwise indicated, an "optionally substituted" group may have a suitable substituent at each substitutable position of the group, and when more than one position in any given structure may be substituted with more than one substituent selected from a specified group, the substituent at each position may be the same or different. The combination of substituents envisioned by the present invention is preferably a combination that forms a stable or chemically feasible compound. As used herein, the term "stable" refers to a compound that does not substantially change when subjected to conditions that allow it to be produced, detected, and in certain embodiments, recovered, purified, and used for one or more of the purposes disclosed herein.

[0042] Each optional substituent on a substitutable carbon is independently selected from the following monovalent substituents: halogen; -(CH 2 ) 0-4 R°;-(CH 2 )0-4 OR°; -O(CH 2 ) 0-4 R°, -O-(CH 2 ) 0-4 C(O)OR°;-(CH 2 ) 0-4 CH(OR°) 2 ;-(CH 2 ) 0- 4 SR°;-(CH 2 ) 0-4 Ph, which may be substituted by R°; -(CH 2 ) 0-4 O(CH 2 ) 0-1 Ph, which may be substituted by R°; -CH=CHPh, which may be substituted by R°; -(CH 2 ) 0-4 O(CH 2 ) 0-1 -pyridyl, which may be substituted by R°; -NO 2 ;-CN;-N 3 ;-(CH 2 ) 0-4 N(R°) 2 ;-(CH 2 ) 0-4 N(R°)C(O)R°; -N(R°)C(S)R°; -(CH 2 ) 0-4 N(R°)C(O)NR° 2 ;-N(R°)C(S)NR° 2 ;-(CH 2 ) 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°;-(CH 2 ) 0-4 C(O)R°;-C(S)R°;-(CH 2 ) 0-4 C(O)OR°;-(CH 2 ) 0-4 C(O)SR°;-(CH 2 ) 0-4 C(O)OSiR° 3 ;-(CH 2 ) 0-4 OC(O)R°; -OC(O)(CH 2 ) 0-4SR-, SC(S)SR°; -(CH 2 ) 0-4 SC(O)R°;-(CH 2 ) 0-4 C(O)NR° 2 ;-C(S)NR° 2 ;-C(S)SR°;-SC(S)SR°,-(CH 2 ) 0-4 OC(O)NR° 2 ;-C(O)N(OR°)R°;-C(O)C(O)R°;-C(O)CH 2 C(O)R°;-C(NOR°)R°;-(CH 2 ) 0-4 SSR°;-(CH 2 ) 0-4 S(O) 2 R°;-(CH 2 ) 0-4 S(O) 2 OR°;-(CH 2 ) 0-4 OS(O) 2 R°; -S(O) 2 NR° 2 ;-S(O)(NR°)R°;-S(O) 2 N=C(NR° 2 ) 2 ;-(CH 2 ) 0-4 S(O)R°;-N(R°)S(O) 2 NR° 2 ; -N(R°)S(O) 2 R°;-N(OR°)R°;-C(NH)NR° 2 ;-P(O) 2 R°; -P(O)R° 2 ;-OP(O)R° 2 ;-OP(O)(OR°) 2 ;SiR° 3 ;-(C 1-4 Straight or branched alkylene)ON(R°) 2 ; or -(C 1-4 Straight or branched alkylene) C(O)ON(R°) 2 .

[0043] Each R° is independently hydrogen, C 1-6 Aliphatic, -CH 2 Ph, -O(CH 2 ) 0-1Ph, -CH 2 -(5-6 membered heteroaromatic ring) or a 5-6 membered saturated, partially unsaturated or aromatic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen or sulfur, or, regardless of the above definition, two independent occurrences of R° together with their intervening atoms form a 3-12 membered saturated, partially unsaturated or aromatic monocyclic or bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen or sulfur, which may be substituted on the saturated carbon atom of R° with a divalent substituent selected from =O and =S; or each R° is optionally substituted with a monovalent substituent independently selected from the following: halogen, -(CH 2 ) 0-2 R · 、-(halogen R · )、-(CH 2 ) 0-2 OH, -(CH 2 ) 0-2 OR · 、-(CH 2 ) 0-2 CH(OR · ) 2 ; -O(halogen R · ), -CN, -N 3 、-(CH 2 ) 0-2 C(O)R · 、-(CH 2 ) 0-2 C(O)OH, -(CH 2 ) 0-2 C(O)OR · 、-(CH 2 ) 0-2 SR · 、-(CH 2 ) 0-2 SH, -(CH 2 ) 0-2 NH 2 、-(CH 2 ) 0-2 NHR · 、-(CH 2 ) 0-2 NR · 2 、-NO 2 、-SiR · 3 、-OSiR · 3 、-C(O)SR · 、-(C 1-4 Straight or branched alkylene)C(O)OR · or -SSR · .

[0044] Each R · Independently selected from C 1-4 Aliphatic, -CH 2 Ph, -O(CH 2 ) 0-1 Ph or a 5-6 membered saturated, partially unsaturated or aromatic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen or sulfur, and wherein each R · unsubstituted or, when preceded by a halogen, substituted only with one or more halogens; or wherein the optional substituents on the saturated carbon are divalent substituents independently selected from the group consisting of: =O, =S, =NNR * 2 、=NNHC(O)R * 、=NNHC(O)OR * 、=NNHS(O) 2 R * , =NR * , =NOR * 、-O(C(R * 2 )) 2-3 O-or-S(C(R * 2 )) 2-3 S-, or a divalent substituent attached to an ortho-substitutable carbon of an "optionally substituted" group is -O(CR * 2 ) 2-3 O-, where each independent occurrence of R * Selected from hydrogen, C 1-6 An aliphatic or unsubstituted 5-6 membered saturated, partially unsaturated or aromatic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen or sulfur.

[0045] When R * C 1-6 When aliphatic, R * Optionally, halogen, -R · 、-(halogen R · ), -OH, -OR · 、-O(halogen R · )、-CN、-C(O)OH、-C(O)OR · 、-NH 2 、-NHR · 、-NR · 2 or-NO 2 Substituted, where each R · Independently selected from C 1-4 Aliphatic, -CH 2 Ph, -O(CH 2 ) 0-1Ph or a 5-6 membered saturated, partially unsaturated or aromatic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen or sulfur, and wherein each R · Unsubstituted, or when preceded by a halogen group, substituted only by one or more halogen groups.

[0046] The optional substituents on the substitutable nitrogen are independently or Among them are independently hydrogen, C 1-6 aliphatic, unsubstituted -OPh, or an unsubstituted 5-6 membered saturated, partially unsaturated or aromatic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen or sulfur, or two independent occurrences of Together with its intervening atoms, it forms an unsubstituted 3-12 membered saturated, partially unsaturated or aromatic monocyclic or bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen or sulfur; wherein when C 1-6 When aliphatic, Optionally, halogen, -R · 、-(halogen R · ), -OH, -OR·, -O(halogen R·), -CN, -C(O)OH, -C(O)OR · 、-NH 2 、-NHR · 、-NR · 2 or-NO 2 substituted, wherein each R· is independently selected from C 1-4 Aliphatic, -CH 2 Ph, -O(CH 2 ) 0-1 Ph, or a 5-6 membered saturated, partially unsaturated or aromatic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen or sulfur, and wherein each R · Unsubstituted, or when preceded by a halogen group, substituted only by one or more halogen groups.

[0047] As used herein, the term "pharmaceutically acceptable salt" refers to salts that are suitable for contact with human and lower animal tissues within the scope of reasonable medical judgment without abnormal toxicity, irritation, allergic reaction, etc. and commensurate with a reasonable benefit / risk ratio. Pharmaceutically acceptable salts are well known in the art. For example, SM Berge et al. describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 1977, 66, 1-19, which is incorporated herein by reference. Pharmaceutically acceptable salts of the compounds of the present invention include salts derived from suitable inorganic and organic acids and bases. Examples of pharmaceutically acceptable non-toxic acid addition salts are salts formed of amino groups with inorganic acids (such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid) or organic acids (such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid), or salts 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, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate, and the like.

[0048] Salts derived from appropriate bases include alkali metal salts, alkaline earth metal salts, ammonium salts and N + (C 1-4 alkyl) 4 Salts. Representative alkali metal or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. Other pharmaceutically acceptable salts include, where appropriate, non-toxic ammonium, quaternary ammonium, and amine cations formed using counterions such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, lower alkyl sulfonates, and aryl sulfonates.

[0049] Unless otherwise stated, the structures depicted herein are also intended to include all isomeric (e.g., enantiomeric, diastereomeric, and geometric (or conformational)) forms of the structure; for example, R and S configurations for each asymmetric center, Z and E double bond isomers, and Z and E conformational isomers. Therefore, single stereochemical isomers as well as enantiomeric, diastereomeric, and geometric (or conformational) mixtures of the compounds of the invention are within the scope of the invention. Unless otherwise stated, all tautomeric forms of the compounds of the invention are within the scope of the invention. In addition, unless otherwise stated, the structures depicted herein are also intended to include compounds that differ only in the presence of one or more isotopically enriched atoms. For example, including replacement of hydrogen by deuterium or tritium or replacement of carbon by 13 C- or 14 Compounds having the structures of the present invention that are substituted with C-enriched carbons are within the scope of the present invention. Such compounds can be used, for example, as analytical tools, probes in biological assays, or therapeutic agents according to the present invention. In certain embodiments, the warhead portion R of the provided compounds is 1 Contains one or more deuterium atoms.

[0050] As used herein, the term "inhibitor" is defined as a compound that binds to and / or inhibits eIF4E with measurable affinity. In certain embodiments, the IC 50 and / or a binding constant 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.

[0051] As used herein, the terms "measurable affinity" and "measurably inhibit" mean a measurable change in eIF4E activity between a sample comprising a compound or composition thereof of the invention and eIF4E and an equivalent sample comprising eIF4E in the absence of the compound or composition thereof.

[0052] 3. Description of exemplary embodiments:

[0053] In one aspect, the present invention provides a compound of formula I:

[0054]

[0055] or a pharmaceutically acceptable salt thereof, wherein:

[0056] Ring A is an optionally substituted ring selected from phenyl, a 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur, an 8-10 membered bicyclic aromatic carbocyclic ring, or an 8-10 membered bicyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur;

[0057] L 1is a bond or an optionally substituted C 1-8 A divalent straight or branched hydrocarbon chain wherein 1, 2, 3 or 4 methylene units of the hydrocarbon chain are optionally and independently replaced by: -O-, -S-, -N(R)-, -C(O)- or -S(O) 2 -;

[0058] R 2 For halogen, R, -OR, -SR, -C(O)R, -C(O)OR, -C(O)N(R) 2 、-S(O) 2 R, -S(O) 2 OR or -S(O) 2 N(R) 2 ;

[0059] L 2 is a bond or an optionally substituted C 1-8 A divalent straight or branched hydrocarbon chain, wherein 1, 2, 3 or 4 methylene units of the hydrocarbon chain are optionally and independently replaced by: -O-, -S-, -N(R)-, -C(O)-, -S(O)- 2 -or-Cy-;

[0060] R 3 is -CN, -C(O)R, -C(O)OR, -C(O)N(R) 2 , -N(R)-C(O)-R, -N(R)-C(O)-OR, -S(O) 2 -N(R) 2 、-S(O) 2 -N(R)-C(O)R, -C(O)-N(R)-S(O) 2 R, -C(=NR)-N(R) 2 、-N(R)-C(=NR)-N(R) 2 or a 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur;

[0061] -Cy- is an optionally substituted divalent ring selected from phenylene, a 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur, a 3-6 membered monocyclic saturated or partially unsaturated carbocyclic ring, a 3-6 membered monocyclic saturated or partially unsaturated heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur, an 8-10 membered bicyclic aromatic carbocyclic ring, or an 8-10 membered bicyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur; and

[0062] R is hydrogen, optionally substituted -C 1-6aliphatic or an optionally substituted ring selected from phenyl, a 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur, a 3-6 membered monocyclic saturated or partially unsaturated carbocyclic ring, or a 3-6 membered monocyclic saturated or partially unsaturated heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur.

[0063] As generally defined above, Ring A is an optionally substituted ring selected from phenyl, a 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur, an 8-10 membered bicyclic aromatic carbocyclic ring, or an 8-10 membered bicyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur.

[0064] In some embodiments, Ring A is optionally substituted phenyl.

[0065] In some embodiments, Ring A is Among them, each R 1 are independently halogen, R, -N(R) 2 , -OR, -SR, -C(O)OR or -S(O) 2 R; n is 0, 1, 2, 3, 4 or 5; and each R is independently as described herein.

[0066] In some embodiments, R 1 In some embodiments, R 1 In some embodiments, R 1 is -F.

[0067] In some embodiments, R 1 is R as described herein. In some embodiments, R 1 -N(R) 2 , wherein each R is independently as described herein. In some embodiments, R 1 is -OR, wherein R is as described herein. In some embodiments, R 1 is -SR, wherein R is as described herein. In some embodiments, R 1 is -C(O)OR, wherein R is as described herein. In some embodiments, R 1 -S(O) 2 R, wherein R is as described herein.

[0068] In some embodiments, R 1 For hydrogen, -Cl, -CH 3 , -F, -CF 3 、-OCH 3 , -OH, -SCH 3 ,

[0069] In some embodiments, R 1 for

[0070] In some embodiments, R 1 Select from those depicted in Table 1 below.

[0071] In some embodiments, n is 0. In some embodiments, n is 1. In some embodiments, n is 2. In some embodiments, n is 3. In some embodiments, n is 4. In some embodiments, n is 5.

[0072] In some embodiments, Ring A is Where R 11 and R 12 Each of which is independently halogen, R, -N(R) 2 , -OR, -SR, -C(O)OR or -S(O) 2 , wherein each R is independently R as described herein.

[0073] In some embodiments, Ring A is Where R 11 and R 12 Each of which is independently halogen, R, -N(R) 2 , -OR, -SR, -C(O)OR or -S(O) 2 R, wherein each R is independently as described herein.

[0074] In some embodiments, R 11 In some embodiments, R 11 is R as described herein. In some embodiments, R 11 -N(R) 2 , wherein each R is independently as described herein. In some embodiments, R 11 is -OR, wherein R is as described herein. In some embodiments, R 11 is -SR, wherein R is as described herein. In some embodiments, R 11 is -C(O)OR, wherein R is as described herein. In some embodiments, R 11 -S(O) 2 R, wherein R is as described herein.

[0075] In some embodiments, R 12 In some embodiments, R 12 is R as described herein. In some embodiments, R 12-N(R) 2 , wherein each R is independently as described herein. In some embodiments, R 12 is -OR, wherein R is as described herein. In some embodiments, R 12 is -SR, wherein R is as described herein. In some embodiments, R 12 is -C(O)OR, wherein R is as described herein. In some embodiments, R 12 -S(O) 2 R, wherein R is as described herein.

[0076] In some embodiments, R 11 For hydrogen, -Cl, -CH 3 、-F、-OCH 3 , -OH, -SCH 3 ,

[0077] In some embodiments, R 11 For-CF 3 ,

[0078] In some embodiments, R 12 In some embodiments, at least one of R is not hydrogen. 12 -Cl, -OCH 3 ,H,-CH 3 , -F, or -CF 3 .

[0079] In some embodiments, Ring A is an optionally substituted 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur. In some embodiments, Ring A is an optionally substituted 5-membered monocyclic heteroaromatic ring having 1, 2 or 3 heteroatoms independently selected from nitrogen, oxygen and sulfur. In some embodiments, Ring A is an optionally substituted 6 membered monocyclic heteroaromatic ring having 1, 2 or 3 heteroatoms independently selected from nitrogen, oxygen and sulfur. In some embodiments, Ring A is an optionally substituted phenyl. In some embodiments, Ring A is an optionally substituted In some embodiments, Ring A is optionally substituted

[0080] In some embodiments, Ring A is an optionally substituted 8-10 membered bicyclic aromatic carbocycle. In some embodiments, Ring A is an optionally substituted 8-10 membered bicyclic aromatic carbocycle. In some embodiments, Ring A is an optionally substituted 9-membered bicyclic aromatic carbocycle. In some embodiments, Ring A is an optionally substituted 10-membered bicyclic aromatic carbocycle. In some embodiments, Ring A is an optionally substituted

[0081] In some embodiments, Ring A is an optionally substituted 8-10 membered bicyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur. In some embodiments, Ring A is an optionally substituted 8-membered bicyclic heteroaromatic ring having 1, 2 or 3 heteroatoms independently selected from nitrogen, oxygen and sulfur. In some embodiments, Ring A is an optionally substituted 9-membered bicyclic heteroaromatic ring having 1, 2 or 3 heteroatoms independently selected from nitrogen, oxygen and sulfur. In some embodiments, Ring A is an optionally substituted 10-membered bicyclic heteroaromatic ring having 1, 2 or 3 heteroatoms independently selected from nitrogen, oxygen and sulfur. In some embodiments, Ring A is an optionally substituted indole. In some embodiments, Ring A is an optionally substituted In some embodiments, Ring A is optionally substituted

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

[0083] As generally defined above, L 1 is a bond or an optionally substituted C 1-8 A divalent straight or branched hydrocarbon chain wherein 1, 2, 3 or 4 methylene units of the hydrocarbon chain are optionally and independently replaced by: -O-, -S-, -N(R)-, -C(O)- or -S(O) 2 -.

[0084] In some embodiments, L 1 is the key.

[0085] In some embodiments, L 1 is optionally substituted C 1-8 A divalent straight or branched hydrocarbon chain wherein 1, 2, 3 or 4 methylene units of the hydrocarbon chain are optionally and independently replaced by: -O-, -S-, -N(R)-, -C(O)- or -S(O) 2 -. In some embodiments, L 1 For unsubstituted C 1-8 In some embodiments, L 1 C 1-8A divalent straight or branched hydrocarbon chain, wherein one methylene unit of the hydrocarbon chain is replaced by: -O-, -S-, -N(R)-, -C(O)- or -S(O) 2 -. In some embodiments, L 1 C 1-8 A divalent straight or branched hydrocarbon chain, wherein two methylene units of the hydrocarbon chain are independently replaced by: -O-, -S-, -N(R)-, -C(O)- or -S(O) 2 -.

[0086] In some embodiments, L 1 -CH 2 -.

[0087] In some embodiments, L 1 Select from those depicted in Table 1 below.

[0088] As generally defined above, R 2 For halogen, R, -OR, -SR, -C(O)R, -C(O)OR, -C(O)N(R) 2 、-S(O) 2 R, -S(O) 2 OR or -S(O) 2 N(R) 2 .

[0089] In some embodiments, R 2 In some embodiments, R 2 is R. In some embodiments, R 2 In some embodiments, R 2 In some embodiments, R 2 In some embodiments, R 2 In some embodiments, R 2 -C(O)N(R) 2 In some embodiments, R 2 -S(O) 2 R. In some embodiments, R 2 -S(O) 2 In some embodiments, R 2 -S(O) 2 N(R) 2 .

[0090] In some embodiments, R 2 Not hydrogen.

[0091] In some embodiments, R 2 For H.

[0092] In an embodiment, R 2 for

[0093] In some embodiments, R 2 Select from those depicted in Table 1 below.

[0094] As generally defined above, L 2 is a bond or an optionally substituted C 1-8 A divalent straight or branched hydrocarbon chain, wherein 1, 2, 3 or 4 methylene units of the hydrocarbon chain are optionally and independently replaced by: -O-, -S-, -N(R)-, -C(O)-, -S(O)- 2 -or-Cy-.

[0095] In some embodiments, L 2 is the key.

[0096] In some embodiments, L 2 is optionally substituted C 1-8 A divalent straight or branched hydrocarbon chain, wherein 1, 2, 3 or 4 methylene units of the hydrocarbon chain are optionally and independently replaced by: -O-, -S-, -N(R)-, -C(O)-, -S(O)- 2 - or -Cy-. In some embodiments, L 2 For unsubstituted C 1-8 In some embodiments, L 2 is optionally substituted C 1-8 A divalent straight or branched hydrocarbon chain, wherein one methylene unit of the hydrocarbon chain is replaced by: -O-, -S-, -N(R)-, -C(O)-, -S(O) 2 - or -Cy-. In some embodiments, L 2 is optionally substituted C 1-8 A divalent straight or branched hydrocarbon chain, wherein two methylene units of the hydrocarbon chain are independently replaced by: -O-, -S-, -N(R)-, -C(O)-, -S(O) 2 - or -Cy-. In some embodiments, L 2 is optionally substituted C 1-8 A divalent straight or branched hydrocarbon chain, wherein the three methylene units of the hydrocarbon chain are independently replaced by: -O-, -S-, -N(R)-, -C(O)-, -S(O) 2 - or -Cy-. In some embodiments, L 2 is optionally substituted C1-8 A divalent straight or branched hydrocarbon chain, wherein the four methylene units of the hydrocarbon chain are independently replaced by: -O-, -S-, -N(R)-, -C(O)-, -S(O) 2 -or-Cy-.

[0097] In some embodiments, L 2 There is no linkage to the thiazole moiety through the carboxamide or sulfonamide moieties.

[0098] In some embodiments, L 2 The connection to the thiazole moiety is not through the oxadiazole moiety.

[0099] In some embodiments, L 2 is optionally substituted C 1-8 A divalent straight or branched hydrocarbon chain, wherein two methylene units of the hydrocarbon chain are independently replaced by: -N(R)- and -Cy-.

[0100] In some embodiments, L 2 is -Cy-N(R)-, wherein -Cy- and R are independently as described herein.

[0101] In some embodiments, L 2 for wherein R is as described herein. In some embodiments, L 2 for wherein R is as described herein.

[0102] In some embodiments, L 2 for

[0103] In some embodiments, L 2 Select from the following:

[0104]

[0105]

[0106]

[0107]

[0108] In some embodiments, L 2 Select from those depicted in Table 1 below.

[0109] As generally defined above, R 3 is -CN, -C(O)R, -C(O)OR, -C(O)N(R) 2, -N(R)-C(O)-R, -N(R)-C(O)-OR, -S(O) 2 -N(R) 2 、-S(O) 2 -N(R)-C(O)R, -C(O)-N(R)-S(O) 2 R, -C(=NR)-N(R) 2 、-N(R)-C(=NR)-N(R) 2 or a 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur.

[0110] In some embodiments, R 3 In some embodiments, R 3 In some embodiments, R 3 In some embodiments, R 3 -C(O)N(R) 2 In some embodiments, R 3 In some embodiments, R 3 In some embodiments, R 3 -S(O) 2 -N(R) 2 In some embodiments, R 3 -S(O) 2 -N(R)-C(O)R. In some embodiments, R 3 -C(O)-N(R)-S(O) 2 R. In some embodiments, R 3 -C(=NR)-N(R) 2 In some embodiments, R 3 -N(R)-C(=NR)-N(R) 2 In some embodiments, R 3 is a 5-6 membered monocyclic heteroaromatic ring having 1, 2, 3 or 4 heteroatoms independently selected from nitrogen, oxygen and sulfur.

[0111] In some embodiments, R 3 In some embodiments, R 3 For-CN,

[0112]

[0113] In some embodiments, R 3 Select from those depicted in Table 1 below.

[0114] As generally defined above, -Cy- is an optionally substituted bivalent ring selected from phenylene, a 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur, a 3-6 membered monocyclic saturated or partially unsaturated carbocyclic ring, a 3-6 membered monocyclic saturated or partially unsaturated heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur, an 8-10 membered bicyclic aromatic carbocyclic ring, or an 8-10 membered bicyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur.

[0115] In some embodiments, -Cy- is optionally substituted phenylene.

[0116] In some embodiments, -Cy- is an optionally substituted divalent 5-6 membered monocyclic heteroaromatic ring having 1, 2, 3 or 4 heteroatoms independently selected from nitrogen, oxygen and sulfur. In some embodiments, -Cy- is an optionally substituted divalent pyridine ring. In some embodiments, -Cy- is an optionally substituted divalent pyridazine ring. In some embodiments, -Cy- is an optionally substituted divalent thiophene ring.

[0117] In some embodiments, -Cy- is a bivalent optionally substituted 3-, 4-, 5-, or 6-membered monocyclic saturated or partially unsaturated carbocyclic ring.

[0118] In some embodiments, -Cy- is an optionally substituted divalent 3, 4, 5 or 6-membered monocyclic saturated or partially unsaturated heterocyclic ring having 1, 2, 3 or 4 heteroatoms independently selected from nitrogen, oxygen and sulfur. In some embodiments, -Cy- is an optionally substituted divalent morpholine ring. In some embodiments, -Cy- is an optionally substituted divalent piperazine ring.

[0119] In some embodiments, -Cy- is an optionally substituted divalent 8, 9, or 10 membered bicyclic aromatic carbocyclic ring. In some embodiments, -Cy- is an optionally substituted divalent benzothiophene ring.

[0120] In some embodiments, -Cy- is an optionally substituted divalent 8, 9, or 10 membered bicyclic heteroaryl ring having 1, 2, 3, or 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0121] In some embodiments, -Cy- is

[0122] In some embodiments, -Cy- is selected from those depicted in Table 1 below.

[0123] As generally defined above, R is hydrogen, optionally substituted -C 1-6aliphatic or an optionally substituted ring selected from phenyl, a 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur, a 3-6 membered monocyclic saturated or partially unsaturated carbocyclic ring, or a 3-6 membered monocyclic saturated or partially unsaturated heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur.

[0124] In some embodiments, R is hydrogen.

[0125] In some embodiments, R is optionally substituted -C 1-6 In some embodiments, R is an optionally substituted -C 1-6 In some embodiments, R is unsubstituted -C 1-6 In 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 with phenyl. 1-6 In some embodiments, R is -C substituted with phenyl. 1-6 In some embodiments, R is -CH 3 In some embodiments, R is -CH 2 CH 3 In some embodiments, R is -CF 3 In some embodiments, R is In some embodiments, R is In some embodiments, R is In some embodiments, R is In some embodiments, R is In some embodiments, R is

[0126] In some embodiments, R is optionally substituted phenyl. In some embodiments, R is unsubstituted phenyl. In some embodiments, R is phenyl substituted 1, 2, 3, 4, or 5 times with halogen. In some embodiments, R is -C 1-6 Alkyl substituted 1, 2, 3, 4 or 5 times phenyl, wherein -C 1-6 Alkyl is optionally substituted 1, 2, 3, 4, 5 or 6 times with halogen.

[0127] In some embodiments, R is an optionally substituted 8-10 membered bicyclic aromatic carbocyclic ring. In some embodiments, R is an optionally substituted 8 membered bicyclic aromatic carbocyclic ring. In some embodiments, R is an optionally substituted 9 membered bicyclic aromatic carbocyclic ring. In some embodiments, R is an optionally substituted 10 membered bicyclic aromatic carbocyclic ring. In some embodiments, R is an optionally substituted

[0128] In some embodiments, R is an optionally substituted 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R is an optionally substituted 5-6 membered monocyclic heteroaromatic ring having 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R is an optionally substituted 5-6 membered monocyclic heteroaromatic ring having 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, which is optionally substituted 1, 2, 3, 4, 5, or 6 times with halogen. In some embodiments, R is an optionally substituted In some embodiments, R is optionally substituted In some embodiments, R is optionally substituted In some embodiments, R is optionally substituted In some embodiments, R is optionally substituted

[0129] In some embodiments, R is an optionally substituted 3, 4, 5, or 6-membered monocyclic saturated or partially unsaturated carbocyclic ring. In some embodiments, R is a 3, 4, 5, or 6-membered monocyclic saturated or partially unsaturated carbocyclic ring substituted 1, 2, 3, 4, 5, or 6 times with halogen. In some embodiments, R is -C 1-6 A 3-, 4-, 5- or 6-membered monocyclic saturated or partially unsaturated carbocyclic ring (1, 2, 3, 4 or 5 times) substituted 1, 2, 3, 4, 5 or 6 times by alkyl, wherein -C 1-6 Alkyl is optionally substituted 1, 2, 3, 4, 5, or 6 times with halogen. In some embodiments, R is optionally substituted In some embodiments, R is optionally substituted In some embodiments, R is optionally substituted

[0130] In some embodiments, R is an optionally substituted 3, 4, 5 or 6-membered monocyclic saturated or partially unsaturated heterocyclic ring having 1, 2, 3 or 4 heteroatoms independently selected from nitrogen, oxygen and sulfur. In some embodiments, R is a 3, 4, 5 or 6-membered monocyclic saturated or partially unsaturated heterocyclic ring having 1, 2, 3 or 4 heteroatoms independently selected from nitrogen, oxygen and sulfur, which is substituted 1, 2, 3, 4, 5 or 6 times with halogen. In some embodiments, R is a 3, 4, 5 or 6-membered monocyclic saturated or partially unsaturated heterocyclic ring having 1, 2, 3 or 4 heteroatoms independently selected from nitrogen, oxygen and sulfur, which is substituted 1, 2, 3, 4, 5 or 6 times with halogen. 1-6 Alkyl is substituted 1, 2, 3, 4, 5 or 6 times, wherein -C 1-6 Alkyl is optionally substituted 1, 2, 3, 4, 5, or 6 times with halogen. In some embodiments, R is optionally substituted In some embodiments, R is optionally substituted In some embodiments, R is optionally substituted In some embodiments, R is optionally substituted In some embodiments, R is optionally substituted In some embodiments, R is In some embodiments, R is In some embodiments, R is In some embodiments, R is In some embodiments, R is -CF 3 In some embodiments, R is F. In some embodiments, R is Cl.

[0131] In some embodiments, R is selected from those depicted in Table 1 below.

[0132] In some embodiments, the present invention provides compounds of formula II:

[0133]

[0134] or a pharmaceutically acceptable salt thereof, wherein R 1 , R 2 , R 3 , L 1 , L 2 Each of and n is as defined above and described in the embodiments herein, both individually and in combination.

[0135] In some embodiments, the present invention provides compounds of Formula II-a to II-d:

[0136]

[0137] or a pharmaceutically acceptable salt thereof, wherein R11 , R 12 , R 2 , R 3 and L 2 Each of is as defined above and described in the embodiments herein, both individually and in combination.

[0138] In some embodiments, the present invention provides compounds of formula III:

[0139]

[0140] or a pharmaceutically acceptable salt thereof, wherein R 1 , R 3 , L 1 , L 2 Each of and n is as defined above and described in the embodiments herein, both individually and in combination.

[0141] In some embodiments, the present invention provides compounds of Formula III-a to III-d:

[0142]

[0143] or a pharmaceutically acceptable salt thereof, wherein R 11 , R 12 , R 3 and L 2 Each of is as defined above and described in the embodiments herein, both individually and in combination.

[0144] In some embodiments, the present invention provides a compound of formula IV:

[0145]

[0146] or a pharmaceutically acceptable salt thereof, wherein R 1 , R 3 , L 1 , L 2 Each of and n is as defined above and described in the embodiments herein, both individually and in combination.

[0147] In some embodiments, the present invention provides compounds of Formula IV-a to IV-d:

[0148]

[0149] or a pharmaceutically acceptable salt thereof, wherein R 11 , R 12 , R 3 and L 2 Each of is as defined above and described in the embodiments herein, both individually and in combination.

[0150] In some embodiments, the present invention provides compounds of formula V:

[0151]

[0152] or a pharmaceutically acceptable salt thereof, wherein R 1 , R 2 , R 3 , R, L 1 Each of and n is as defined above and described in the embodiments herein, both individually and in combination.

[0153] In some embodiments, the present invention provides compounds of Formula Va to Vd:

[0154]

[0155] or a pharmaceutically acceptable salt thereof, wherein R 11 , R 12 , R 2 , R 3 Each of and R is as defined above and described in the embodiments herein, both individually and in combination.

[0156] In some embodiments, the present invention provides a compound of formula VI:

[0157]

[0158] or a pharmaceutically acceptable salt thereof, wherein R 1 , R 2 , R 3 , R, L 1 Each of and n is as defined above and described in the embodiments herein, both individually and in combination.

[0159] In some embodiments, the present invention provides compounds of Formula VI-a to VI-d:

[0160]

[0161] or a pharmaceutically acceptable salt thereof, wherein R 11 , R 12 , R 2 , R 3 Each of and R is as defined above and described in the embodiments herein, both individually and in combination.

[0162] In some embodiments, the present invention provides a compound of formula VII:

[0163]

[0164] or a pharmaceutically acceptable salt thereof, wherein R 1 , R 2 , L 1 , L 2 Each of and n is as defined above and described in the embodiments herein, both individually and in combination.

[0165] In some embodiments, the present invention provides compounds of Formula VII-a to VII-d:

[0166]

[0167] or a pharmaceutically acceptable salt thereof, wherein R 11 , R 12 , R 2 and L 2 Each of is as defined above and described in the embodiments herein, both individually and in combination.

[0168] In some embodiments, the present invention provides a compound of formula VIII:

[0169]

[0170] or a pharmaceutically acceptable salt thereof, wherein R, R 2 , L 1 Each of and Ring A is as defined above and described in the embodiments herein, both individually and in combination.

[0171] In some embodiments, the present invention provides a compound of formula VIII-a:

[0172]

[0173] or a pharmaceutically acceptable salt thereof, wherein R, R 2 , R 1 Each of and n is as defined above and described in the embodiments herein, both individually and in combination.

[0174] In some embodiments, the present invention provides compounds of Formula VIII-b or VIII-C:

[0175]

[0176] or a pharmaceutically acceptable salt thereof, wherein R 2 , R 1 Each of and n is as defined above and described in the embodiments herein, both individually and in combination.

[0177] In some embodiments, the present invention provides a compound of formula VIII-d:

[0178]

[0179] or a pharmaceutically acceptable salt thereof, wherein R 2 , R 11 and R 12 Each of is as defined above and described in the embodiments herein, both individually and in combination. In some embodiments, R 11 In some embodiments, R 12 is -OR, wherein R is as described herein. In some embodiments, R 12 is -OR, wherein R is an optionally substituted -C 1-6 In some embodiments, R 12 is -OR, wherein R is an optionally substituted -C 1-6 In some embodiments, R 12 is -OR, wherein R is unsubstituted -C 1-6 Alkyl, or -C substituted 1, 2, 3, 4, 5 or 6 times by halogen 1-6 In some embodiments, R 12 is -OR, where R is -C 1-6 Alkyl wherein at least one methylene unit is replaced by -O-.

[0180] Exemplary compounds of the invention are described in Table 1 below.

[0181] In some embodiments, the present invention provides a compound of Table 1, or a pharmaceutically acceptable salt thereof.

[0182] In some embodiments, the present invention provides a compound selected from those depicted in the Examples section, or a pharmaceutically acceptable salt thereof.

[0183] Table 1. Exemplary compounds

[0184]

[0185]

[0186]

[0187]

[0188]

[0189]

[0190]

[0191]

[0192]

[0193]

[0194]

[0195]

[0196]

[0197]

[0198]

[0199] 4. Preparation and Administration

[0200] 4.1 Pharmaceutically Acceptable Compositions

[0201] 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 effectively inhibits eIF4E or its mutant in a biological sample or patient in a measurable manner. In certain embodiments, the amount of the compound in the composition of the present invention is such that it effectively inhibits eIF4E or its mutant in a biological sample or patient in a measurable manner. 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.

[0202] 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.

[0203] In some embodiments, the present invention provides a pharmaceutical composition comprising a compound of Formula (II) to (VII), (II-a) to (VII-a), (II-b) to (VII-b) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier, adjuvant or vehicle.

[0204] 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.

[0205] In some embodiments, the compounds of the present invention or pharmaceutically acceptable derivatives or compositions thereof are administered in a single composition as a single dosage form.

[0206] As used herein, the term "patient" means an animal, preferably a mammal, and most preferably a human.

[0207] The term "pharmaceutically acceptable carrier, adjuvant or vehicle" refers to a non-toxic carrier, adjuvant or vehicle that does not destroy the pharmacological activity of the compound formulated with it. Pharmaceutically acceptable carriers, adjuvants or vehicles that can be used in the compositions of the present 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, salts or electrolytes such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silicon dioxide, magnesium trisilicate, polyvinyl pyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethyl cellulose, polyacrylates, waxes, polyethylene-polyoxypropylene block polymers, polyethylene glycol and lanolin.

[0208] "Pharmaceutically acceptable derivative" means any non-toxic salt, ester, salt of an ester, or other derivative of a compound of the invention that is capable of providing, directly or indirectly, a compound of the invention or an inhibitorily active metabolite or residue thereof when administered to a recipient.

[0209] As used herein, the term "inhibitory active metabolite or residue thereof" means that the metabolite or residue thereof is also an inhibitor of eIF4E or a mutant thereof.

[0210] The composition of the present invention can be administered orally, parenterally, by inhalation spray, topically, rectally, nasally, buccally, vaginally or by means of an implanted reservoir. As used herein, the term "parenteral" includes subcutaneous, intravenous, intramuscular, intraarticular, intrasynovial, intrasternal, intrathecal, intrahepatic, intralesional and intracranial injection or infusion techniques. Preferably, the composition is administered orally, intraperitoneally or intravenously. The sterile injectable form of the composition of the present invention can be an aqueous or oily suspension. These suspensions can be prepared using suitable dispersants or wetting agents and suspending agents according to techniques known in the art. Sterile injectable preparations can also be sterile injectable solutions or suspensions in non-toxic parenteral acceptable diluents or solvents, such as solutions in 1,3-butanediol. Among acceptable vehicles and solvents, water, Ringer's solution and isotonic sodium chloride solution can be used. In addition, sterile non-volatile oils are commonly used as solvents or suspension media.

[0211] For this purpose, any gentle fixed oil can be used, including synthetic monoglycerides or diglycerides. Fatty acids such as oleic acid and their glyceride derivatives can be used to prepare injectables, such as natural pharmaceutically acceptable oils, such as olive oil or castor oil, especially in their polyoxyethylene forms. These oil solutions or suspensions can also contain long-chain alcohol diluents or dispersants, such as carboxymethyl cellulose or similar dispersants that are usually used in preparing pharmaceutically acceptable dosage forms (including emulsions and suspensions). Other conventional surfactants such as Tween, Span and other emulsifiers or bioavailability enhancers that are usually used to make pharmaceutically acceptable solids, liquids or other dosage forms can also be used for the purpose of preparation.

[0212] The pharmaceutically acceptable compositions of the present invention can be orally administered in any orally acceptable dosage form, including, but not limited to, capsules, tablets, aqueous suspensions or solutions. In the case of tablets for oral use, common carriers include lactose and corn starch. Lubricants such as magnesium stearate are also commonly added. For oral administration in capsule form, available diluents include lactose and dry corn starch. When aqueous suspensions are needed for oral use, the active ingredient is combined with an emulsifier and a suspending agent. If desired, certain sweeteners, flavorings or coloring agents may also be added.

[0213] Alternatively, the pharmaceutically acceptable compositions of the present invention can be used in the form of suppositories for rectal administration. These suppositories can be prepared by mixing the medicament with a suitable non-irritating excipient, which is solid at room temperature but liquid at rectal temperature and will therefore melt in the rectum to release the drug. Such materials include cocoa butter, beeswax, and polyethylene glycol.

[0214] 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 eyes, skin, or lower intestinal tract. Suitable topical formulations are readily prepared for each of these areas or organs.

[0215] Topical application for the lower intestinal tract may be effected in a rectal suppository formulation (see above) or in a suitable enema formulation.Topical transdermal patches may also be used.

[0216] For topical administration, the pharmaceutically acceptable compositions provided can be formulated in the form of a suitable ointment containing an active component 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 paraffin, white paraffin, propylene glycol, polyoxyethylene, polyoxypropylene compounds, emulsifying wax, and water. Alternatively, the pharmaceutically acceptable compositions provided can be formulated in the form of a suitable lotion or cream containing an active component suspended or dissolved in one or more pharmaceutically acceptable carriers. Suitable carriers include, but are not limited to, mineral oil, sorbitan monostearate, polysorbate 60, cetyl esters wax, cetearyl alcohol, 2-octyldodecanol, benzyl alcohol, and water.

[0217] For ophthalmic use, provided pharmaceutically acceptable compositions can be formulated as micronized suspensions in isotonic pH-adjusted sterile saline with or without preservatives such as benzylalkonium chloride, or preferably solutions in isotonic pH-adjusted sterile saline. Alternatively, for ophthalmic use, pharmaceutically acceptable compositions can be formulated in ointments such as paraffin.

[0218] The pharmaceutically acceptable compositions of the present 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 physiological saline using benzyl alcohol or other suitable preservatives, absorption promoters to enhance bioavailability, fluorocarbons and / or other conventional solubilizers or dispersants.

[0219] Most preferably, the pharmaceutically acceptable compositions of the present invention are formulated for oral administration. Such formulations may be administered in the presence or absence of food. In some embodiments, the pharmaceutically acceptable compositions of the present invention are administered in the absence of food. In other embodiments, the pharmaceutically acceptable compositions of the present invention are administered in the presence of food.

[0220] The amount of the compound of the invention that can be combined with carrier materials to produce a composition in a single dosage form will vary depending on the host being treated, the particular mode of administration. Preferably, provided compositions should be formulated so that a dosage of between 0.01-100 mg / kg body weight / day of the inhibitor can be administered to a patient receiving these compositions.

[0221] It is also 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, age, body weight, general health, sex, diet, time of administration, rate of excretion, drug combination, and the judgment of the treating physician and the severity of the specific disease being treated. The amount of the compound of the present invention in the composition also depends on the specific compound in the composition.

[0222] 4.2. Co-administration with one or more other therapeutic agents

[0223] Depending on the particular disorder or disease being treated, additional therapeutic agents that are normally administered to treat that disorder may also be present in the compositions of the invention. As used herein, additional therapeutic agents that are normally administered to treat a particular disease or disorder are referred to as "appropriate for the disease or disorder being treated."

[0224] In some embodiments, the present invention provides a method of treating a disclosed disease or disorder, 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 the therapeutic agents 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 compounds and one or more additional therapeutic agents acts synergistically.

[0225] The compounds of the invention may also be used in combination with known treatment methods, such as administration of hormones or radiation. In certain embodiments, provided compounds are used as radiosensitizers, particularly for treating tumors that exhibit poor sensitivity to radiation therapy.

[0226] The compounds of the present invention may be administered alone or in combination with one or more other therapeutic compounds, and possible combination therapies may be in the form of fixed combinations of the compounds of the present invention and one or more other therapeutic compounds or interlaced or independent administration, or a combination of fixed combinations and one or more other therapeutic compounds. In addition or in addition, the compounds of the present invention may be administered in combination with chemotherapy, radiotherapy, immunotherapy, phototherapy, surgical intervention, or a combination of these, particularly for tumor therapy. As described above, long-term therapy is also possible, as with adjuvant therapy in the case of other treatment strategies. Other possible treatments are therapies that maintain the patient's status after tumor regression, or even chemoprevention, for example, for patients at risk.

[0227] One or more other therapeutic agents can be used separately from the compounds or compositions of the present invention as part of a multiple dosing regimen. Alternatively, one or more other therapeutic agents can be a part of a single dosage form mixed with the compounds of the present invention in a single composition. If used as a multiple dosing regimen, one or more other therapeutic agents and the compounds or compositions of the present invention can be used simultaneously, sequentially or at intervals of a certain time period (e.g., 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). In some embodiments, one or more other therapeutic agents and the compounds or compositions of the present invention are used as a multiple dosing regimen at intervals exceeding 24 hours.

[0228] As used herein, the term "combination (combination / combined)" and related terms refer to the simultaneous or sequential administration of therapeutic agents according to the present invention. For example, the compound of the present invention can be administered simultaneously or sequentially with one or more other therapeutic agents in independent unit dosage forms or in a single unit dosage form together. Therefore, the present invention provides a single unit dosage form, which comprises a compound of the present invention, one or more other therapeutic agents and a pharmaceutically acceptable carrier, adjuvant or vehicle.

[0229] The amount of the compound of the invention and one or more other therapeutic agents (in those compositions comprising the additional therapeutic agents described above) that can be combined with a carrier material to produce a single dosage form will vary depending on the host being treated and the specific mode of administration. Preferably, the compositions of the invention should be formulated so that a dose of the compound of the invention between 0.01-100 mg / kg body weight / day can be administered.

[0230] In those compositions comprising one or more other therapeutic agents, the one or more other therapeutic agents and the compounds of the invention may act synergistically. Thus, the amount of one or more other therapeutic agents in such compositions may be lower than the amount required in a monotherapy utilizing only the therapeutic agent. In such compositions, the one or more other therapeutic agents may be administered at a dose of between 0.01-1,000 micrograms / kg body weight / day.

[0231] The amount of one or more other therapeutic agents present in the composition of the present invention may not exceed the amount that would normally be administered in a composition comprising the therapeutic agent as the sole active agent. Preferably, the amount of one or more other therapeutic agents in the composition disclosed herein will be within the range of about 50% to 100% of the amount normally present in a composition comprising the medicament as the sole therapeutic active agent. In some embodiments, the dosage of one or more other therapeutic agents 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 of the medicament normally administered. As used herein, the phrase "normally administered" means the approved dosage of the therapeutic agent approved by the FDA according to the FDA label insert.

[0232] The compounds of the present invention or their pharmaceutical compositions may also be incorporated into compositions for coating implantable medical devices, such as prostheses, artificial valves, vascular grafts, stents and catheters. Intravascular stents have been used, for example, to overcome restenosis (restenosis of the vascular wall after injury). However, patients using stents or other implantable devices have 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 comprising a kinase inhibitor. An implantable device coated with a compound of the present invention is another embodiment of the present invention.

[0233] 4.2.1. Exemplary Other Therapeutic Agents

[0234] In some embodiments, the one or more additional therapeutic agents are poly ADP ribose polymerase (PARP) inhibitors. In some embodiments, the PARP inhibitor is selected from olaparib ( AstraZeneca; rucaparib ( Clovis Oncology; niraparib ( Tesaro); ta lazoparib (MDV3800 / BMN 673 / LT00673, Medivation / Pfizer / Biomarin); veliparib (ABT-888, AbbVie); and BGB-290 (BeiGen e, Inc.).

[0235] In some embodiments, the one or more other therapeutic agents are histone deacetylase (HDAC) inhibitors. In some embodiments, the HDAC inhibitor is selected from vorinostat ( Merck; romidepsin ( Celgene; panobinostat ( Novartis; belinostat ( Spectrum Pharmaceuticals); entinostat (SNDX-275, Syndax Pharmaceuticals) (NCT00866333); and chidamide ( HBI-8000, Chipscreen Biosciences, China).

[0236] In some embodiments, the one or more additional therapeutic agents are CDK inhibitors, such as CDK4 / CDK6 inhibitors. In some embodiments, the CDK 4 / 6 inhibitor is selected from palbociclib ( Pfizer; ribociclib ( Novartis); abemaciclib (Ly2835219, Eli Lilly); and trilaciclib (G1T28, G1 Therapeutics).

[0237] In some embodiments, the one or more additional therapeutic agents are phosphatidylinositol 3-kinase (PI3K) inhibitors. In some embodiments, the PI3K inhibitor is selected from idelalisib ( 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).

[0238] In some embodiments, one or more additional therapeutic agents are platinum-based therapeutic agents, also known as platinum compounds (platins). Platinum causes cross-linking of DNA, such that it primarily inhibits DNA repair and / or DNA synthesis in rapidly reproducing cells (such as cancer cells). In some embodiments, the platinum-based therapeutic agent is selected from cisplatin ( Bristol-Myers Squibb; carboplatin ( Bristol-Myers Squibb; Teva; Pfizer); oxaliplatin ( Sanofi-Aventis; nedaplatin ( Shionogi); picoplatin (Poniard Pharmaceuticals); and satraplatin (JM-216, Agennix).

[0239] In some embodiments, the one or more additional therapeutic agents are taxane compounds, which cause disruption of microtubules, which are essential for cell division. In some embodiments, the taxane compound is selected from paclitaxel ( Bristol-Myers Squibb, docetaxel ( Sanofi-Aventis; Sun Pharmaceutical), albumin-bound paclitaxel ( Abraxis / Celgene), cabazitaxel ( Sanofi-Aventis) and SID530 (SK Chemicals, Co.) (NCT00931008).

[0240] In some embodiments, the one or more additional therapeutic agents are nucleoside inhibitors, or therapeutic agents that interfere with normal DNA synthesis, protein synthesis, cell replication, or otherwise inhibit rapidly proliferating cells.

[0241] In some embodiments, the nucleoside inhibitor is selected from trabectedin (a guanidinating agent; Janssen Oncology; mechlorethamine (alkylating agent; Aktelion Pharmaceuticals; vincristine ( Eli Lilly; Teva Pharmaceuticals; Talon Therapeutics; temozolomide (a prodrug of the alkylating agent 5-(3-methyltriazene-1-yl)-imidazole-4-carboxamide (MTIC); Merck); cytarabine injection (ara-C, an antimetabolite cytidine analog; Pfizer); lomustine (alkylating agent, Bristol-Myers Squibb; NextSource Biotechnology); azacitidine (a pyrimidine nucleoside analog of cytidine; Celgene; omacetaxine mepesuccinate (Omacetacil ester) (protein synthesis inhibitor, Teva Pharmaceuticals; asparaginase Erwinia chrysanthemi (enzyme for depletion of asparagine, Lundbeck; EUSAPharma); eribulin mesylate (microtubule inhibitor, tubulin-based antimitotic agent, Eisai); cabazitaxel (microtubule inhibitor, tubulin-based antimitotic agent, Sanofi-Aventis; capecitabine (thymidylate synthase inhibitor, Genentech; bendamustine (a bifunctional mustard derivative believed to form interstrand DNA crosslinks, Cephalon / Teva); ixabepilone (a semisynthetic analog of epothilone B, a microtubule inhibitor, a tubulin-based antimitotic agent, Bristol-Myers Squibb; nelarabine (prodrug of deoxyguanosine analog, nucleoside metabolism inhibitor, Novartis); clorafabine (ribonucleotide reductase inhibitor prodrug, competitive inhibitor of deoxycytidine, Sanofi-Aventis); and trifluridine and tipiracil (thymidine-based nucleoside analogs and thymidine phosphorylase inhibitors, Taiho Oncology).

[0242] In some embodiments, one or more additional therapeutic agents are kinase inhibitors or VEGF-R antagonists. Approved VEGF inhibitors and kinase inhibitors that can be used in the present invention include: bevacizumab ( Genentech / Roche), an anti-VEGF monoclonal antibody; ramucirumab ( Eli Lilly, an anti-VEGFR-2 antibody; and ziv-aflibercept, also known as VEGF Trap ( Regeneron / Sanofi). VEGFR inhibitors, such as regorafenib ( Bayer; Vandetanib ( AstraZeneca; axitinib ( Pfizer; and lenvatinib ( Eisai); Raf inhibitors, such as sorafenib ( Bayer AG and Onyx); dabrafenib ( Novartis; and vemurafenib ( Genentech / Roche); MEK inhibitors such as cobimetanib ( Exelexis / Genentech / Roche; trametinib ( Novartis); Bcr-Abl tyrosine kinase inhibitors such as imatinib ( Novartis; Nilotinib ( Novartis; dasatinib ( BristolMyersSquibb; bosutinib ( Pfizer; and ponatinib ( Ariad Pharmaceuticals); Her2 and EGFR inhibitors, such as gefitinib ( AstraZeneca; erlotinib ( Genentech / Roche / Astellas; Lapatinib ( Novartis; Afatinib ( Boehringer Ingelheim; osimertinib (targets activated EGFR, AstraZeneca; and brigatinib ( Ariad Pharmaceuticals); c-Met and VEGFR2 inhibitors, such as cabozantinib ( Exelexis); and multikinase inhibitors such as sunitinib ( Pfizer; pazopanib ( Novartis; ALK inhibitors such as crizotinib ( Pfizer; ceritinib ( Novartis; and alectinib ( Genentech / Roche); Bruton's tyrosine kinase inhibitors such as ibrutinib ( Pharmacyclics / Janssen); and Flt3 receptor inhibitors, such as midostaurin ( Novartis).

[0243] Other kinase inhibitors and VEGF-R antagonists under development and useful in the present invention include tivozanib (Aveo Pharmaecuticals); vatalanib (Bayer / Novartis); lucitanib (Clovis Oncology); dovitinib (TKI258, Novartis); chiauanib (Chipscreen Biosciences); CEP-11981 (Cephalon); linifanib (Abbott Laboratories); neratinib (HKI-272, Puma Biotechnology); radotinib ( IY5511, Il-Yang Pharmaceuticals, S.Korea); ruxolitinib ( Incyte Corporation); PTC299 (PTC Therapeutics); CP-547,632 (Pfizer); foretinib (Exelexis, GlaxoSmithKline); quizartinib (Daiichi Sankyo) and motesanib (Amgen / Takeda).

[0244] In some embodiments, the one or more additional therapeutic agents is an mTOR inhibitor, which inhibits cell proliferation, angiogenesis, and glucose uptake. In some embodiments, the mTOR inhibitor is everolimus ( Novartis; Temsirolimus ( Pfizer; and sirolimus ( Pfizer).

[0245] In some embodiments, one or more additional therapeutic agents are proteasome inhibitors. Approved proteasome inhibitors useful in the present invention include bortezomib ( Takeda; carfilzomib ( Amgen; and ixazomib ( Takeda).

[0246] In some embodiments, one or more of the other therapeutic agents is a growth factor antagonist, such as an antagonist of platelet-derived growth factor (PDGF) or epidermal growth factor (EGF) or its receptor (EGFR). Approved PDGF antagonists that can be used in the present invention include olaratumab ( Eli Lilly). Approved EGFR antagonists that can be used in the present invention include cetuximab ( Eli Lilly; necitumumab ( Eli Lilly; panitumumab ( Amgen); and osimertinib (targets activated EGFR, AstraZeneca).

[0247] In some embodiments, the one or more additional therapeutic agents are aromatase inhibitors. In some embodiments, the aromatase inhibitor is selected from exemestane ( Pfizer; Anastrozole ( AstraZeneca and letrozole ( Novartis).

[0248] In some embodiments, one or more of the other therapeutic agents is an antagonist of the hedgehog pathway. Approved hedgehog pathway inhibitors that can be used in the present invention include sonidegib ( Sun Pharmaceuticals; and vismodegib ( Genentech, both for the treatment of basal cell carcinoma.

[0249] In some embodiments, one or more additional therapeutic agents are folate inhibitors. Approved folate inhibitors that can be used in the present invention include pemetrexed ( Eli Lilly).

[0250] In some embodiments, one or more additional therapeutic agents is a CC chemokine receptor 4 (CCR4) inhibitor. CCR4 inhibitors under investigation for use in the present invention include mogamulizumab ( Kyowa Hakko Kirin, Japan).

[0251] In some embodiments, 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); IDH305 (Novartis, NCT02987010).

[0252] In some embodiments, one or more other therapeutic agents are arginase inhibitors. Arginase inhibitors under investigation that can be used in the present invention include AEB1102 (PEGylated recombinant arginase, Aeglea Biotherapeutics), which is being studied in Phase 1 clinical trials for acute myeloid leukemia and myelodysplastic syndrome (NCT02732184) and solid tumors (NCT02561234); and CB-1158 (Calithera Biosciences).

[0253] In some embodiments, the one or more additional therapeutic agents is a glutaminase inhibitor. Glutaminase inhibitors under investigation for use in the present invention include CB-839 (Calithera Biosciences).

[0254] 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 ( Genentech / BiogenIdec; ofatumumab (anti-CD20, GlaxoSmithKline; obinutuzumab (anti-CD20, Genentech; ibritumomab (anti-CD20 and yttrium-90, Spectrum Pharmaceuticals; daratumumab (anti-CD38, Janssen Biotech; dinutuximab (anti-glycolipid GD2, United Therapeutics; trastuzumab (anti-HER2, Genentech; ado-trastuzumab emtansine (anti-HER2, fused to emtansine, Genentech; and pertuzumab (anti-HER2, Genentech); and brentuximab vedotin (anti-CD30-drug conjugate, Seattle Genetics).

[0255] In some embodiments, one or more additional therapeutic agents are topoisomerase inhibitors. Approved topoisomerase inhibitors useful in the present invention include irinotecan ( Merrimack Pharmaceuticals; topotecan ( GlaxoSmithKline). Topoisomerase inhibitors under investigation for use in the present invention include pixantrone ( CTI Biopharma).

[0256] In some embodiments, one or more other therapeutic agents are anti-apoptotic proteins, such as inhibitors of BCL-2. Approved anti-apoptotic agents that can be used in the present invention include venetoclax ( AbbVie / Genentech and blinatumomab ( Other therapeutic agents targeting apoptotic proteins that have been clinically tested and can be used in the present invention include navitoclax (ABT-263, Abbott), a BCL-2 inhibitor (NCT02079740).

[0257] In some embodiments, one or more additional therapeutic agents are androgen receptor inhibitors. Approved androgen receptor inhibitors that can be used in the present invention include enzalutamide ( Astellas / Medivation; approved androgen synthesis inhibitors include abiraterone ( Centocor / Ortho; approved gonadotropin-releasing hormone (GnRH) receptor antagonists (degaralix, Ferring Pharmaceuticals).

[0258] In some embodiments, one or more other therapeutic agents are selective estrogen receptor modulators (SERMs), which interfere with the synthesis or activity of estrogen. Approved SERMs that can be used in the present invention include raloxifene ( Eli Lilly).

[0259] In some embodiments, the one or more additional therapeutic agents are bone resorption inhibitors. Approved therapeutic agents that inhibit bone resorption are Denosumab ( Amgen), an antibody that binds to RANKL, preventing RANKL from binding to the receptor RANK found on the surface of osteoclasts, their precursors, and osteoclast-like giant cells, which regulates bone pathology in solid tumors with bone metastases. Other approved therapeutic agents that inhibit bone resorption include bisphosphonates, such as zoledronic acid ( Novartis).

[0260] In some embodiments, one or more other therapeutic agents are inhibitors of the interaction between two primary p53 inhibitory proteins MDMX and MDM2. Inhibitors of p53 inhibitory proteins under investigation that can be used in the present invention include ALRN-6924 (Aileron), a stapled peptide that allelically binds to MDMX and MDM2 and interferes with the interaction of MDMX and MDM2 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).

[0261] In some embodiments, one or more additional therapeutic agents are inhibitors of transforming growth factor beta (TGF-β or TGFβ). Investigational TGF-β protein inhibitors that can be used in the present invention include NIS793 (Novartis), an anti-TGF-β antibody that is being tested in the clinic for the treatment of various cancers including breast cancer, lung cancer, hepatocellular carcinoma, colorectal cancer, pancreatic cancer, prostate cancer, and kidney cancer (NCT 02947165). In some embodiments, the TGF-β protein inhibitor is fresolimumab (GC1008; Sanofi-Genzyme), which is being studied for melanoma (NCT00923169), renal cell carcinoma (NCT00356460), and non-small cell lung cancer (NCT02581787). Additionally, in some embodiments, the additional therapeutic agent is a TGF-β trap, such as the TGF-β trap 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), which is a bispecific anti-PD-L1 / TGFβ trap compound (NCT02699515); and (NCT02517398). M7824 comprises a fully human IgG1 antibody directed against PD-L1 fused to the extracellular domain of the human TGF-β receptor II, which serves as a TGFβ "trap".

[0262] In some embodiments, the one or more additional therapeutic agents are selected from glembatumumab vedotin-monomethyl auristatin E (MMAE) (Celldex), an anti-glycoprotein NMB (gpNMB) antibody linked to the cytotoxic MMAE (CR011). gpNMB is a protein overexpressed by a variety of tumor types and associated with the metastatic ability of cancer cells.

[0263] In some embodiments, one or more additional therapeutic agents are antiproliferative compounds. Such antiproliferative compounds include, but are not limited to, aromatase inhibitors; antiestrogens; topoisomerase I inhibitors; topoisomerase II inhibitors; microtubule-active compounds; alkylating compounds; histone deacetylase inhibitors; compounds that induce cell differentiation processes; cyclooxygenase inhibitors; MMP inhibitors; mTOR inhibitors; anti-neoplastic antimetabolites; platinum compounds; compounds that target / reduce protein or lipid kinase activity and other anti-angiogenic compounds; compounds that target, reduce or inhibit protein or lipid phosphatase activity; gonadotropin-releasing hormone agonists; anti-androgens; methionine aminopeptidase inhibitors; matrix metalloproteinase inhibitors; bisphosphonates; biological response modifiers; antiproliferative antibodies; heparanase inhibitors; inhibitors of Ras oncogenic isoforms; telomerase inhibitors; proteasome inhibitors; compounds for the treatment of hematological malignancies; compounds that target, reduce or inhibit Flt-3 activity; Hsp90 inhibitors, such as from Conforma Therapeutics' 17-AAG (17-allylaminogeldanamycin, NSC330507), 17-DMAG (17-dimethylaminoethylamino-17-demethoxy-geldanamycin, NSC707545), IPI-504, CNF1010, CNF2024, CNF1010; temozolomide Kinesin spindle protein inhibitors, such as SB715992 or SB743921 from GlaxoSmithKline, or pentamidine / chlorpromazine from CombinatoRx; MEK inhibitors, such as ARRY142886 from Array BioPharma, AZd from AstraZeneca 6 244, PD181461 from Pfizer, and leucovorin.

[0264] As used herein, the term "aromatase inhibitor" refers to a compound that inhibits estrogen production, such as the conversion of the substrates androstenedione and testosterone to estrone and estradiol, respectively. The term includes, but is not limited to, steroids, particularly atamestane, exemestane and formestane; and particularly nonsteroidal, particularly aminoglutethimide, roglethimide, pyridoglutethimide, trilostane, testolactone, ketokonazole, vorozole, fadrozole, anastrozole and letrozole. Exemestane is marketed under the trade name Aromasin TM Formestane is sold under the brand name Lentaron TM Fadrozole is sold under the brand name Afema TM Anastrozole is sold under the brand name Arimidex TM Letrozole is sold under the brand name Femara TM or Femar TM Aminoglutethimide is sold under the trade name Orimeten TM The combination of the invention comprising a chemotherapeutic agent which is an aromatase inhibitor is particularly useful in the treatment of hormone receptor positive tumors, such as breast tumors.

[0265] As used herein, the term "anti-estrogen" refers to a compound that antagonizes the effects of estrogen at the estrogen receptor level. The term includes, but is not limited to, tamoxifen, fulvestrant, raloxifene, and raloxifene hydrochloride. Tamoxifen is marketed under the trade name Nolvadex TM Raloxifene hydrochloride is sold under the brand name Evista TM Fulvestrant is sold under the brand name Faslodex TM Administration. The combinations of the invention comprising a chemotherapeutic agent which is an antiestrogen are particularly useful in the treatment of estrogen receptor positive tumors, such as breast tumors.

[0266] As used herein, the term "antiandrogen" refers to any substance that is capable of inhibiting the biological effects of androgens and includes, but is not limited to, bicalutamide (Casodex TMAs used herein, the term "gonadotropin-releasing hormone agonist" includes, but is not limited to, abarelix, goserelin, and goserelin acetate. Goserelin is available under the brand name Zoladex TM Application.

[0267] As used herein, the term "topoisomerase I inhibitors" include, but are not limited to, topotecan, gimatecan, irinotecan, camptothecian and its analogs, 9-nitrocamptothecin and the macromolecular camptothecin conjugate PNU-166148. Irinotecan can be marketed, for example, in its marketed form, for example under the trademark Camptosar TM Topotecan is sold under the brand name Hycamptin TM Sale.

[0268] As used herein, the term "topoisomerase II inhibitors" include, but are not limited to, anthracyclines such as doxorubicin (including liposomal formulations such as Caelyx TM ), daunorubicin, epirubicin, idarubicin, and nemorubicin, the anthraquinones mitoxantrone and losoxantrone, and the podophyllotoxins etoposide and teniposide. Etoposide is marketed under the trade name Etopophos TM Teniposide is sold under the trade name VM 26-Bristol. Doxorubicin is sold under the trade name Acriblastin TM or Adriamycin TM Epirubicin is sold under the brand name Farmorubicin TM Idamycin is sold under the brand name Zavedos TM Mitoxantrone is sold under the trade name Novantron.

[0269] The term "microtubule active agent" refers to microtubule stabilizing, microtubule destabilizing compounds and microtubule 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; cochicine and epothilone and its derivatives. Pacific paclitaxel is sold under the trade name TaxolTM Docetaxel is sold under the brand name Taxotere TM Vinblastine sulfate is sold under the trade name Vinblastin RP TM Vincristine sulfate is sold under the trade name Farmistin TM Sale.

[0270] As used herein, the term "alkylating agent" includes, but is not limited to, cyclophosphamide, ifosfamide, melphalan, or nitrosourea (BCNU or Gliadel). Cyclophosphamide is marketed under the trade name Cyclostin. TM Ifosfamide is sold under the brand name Holoxan TM Sale.

[0271] The term "histone deacetylase inhibitor" or "HDAC inhibitor" relates to compounds that inhibit histone deacetylase and have antiproliferative activity. This includes, but is not limited to, suberoylanilide hydroxamic acid (SAHA).

[0272] The term "anti-neoplastic antimetabolites" includes, but is not limited to, 5-fluorouracil or 5-FU, capecitabine, gemcitabine, DNA demethylating compounds such as 5-azacytidine and decitabine, methotrexate and edatrexate, and folic acid antagonists such as pemetrexed. Capecitabine is marketed under the trade name Xeloda TM Gemcitabine is sold under the brand name Gemzar TM Sale.

[0273] As used herein, the term "platinum compound" includes, but is not limited to, carboplatin, cisplatin (cisplatinum) and oxaliplatin. Carboplatin can be marketed, for example, in its marketed form, for example under the trademark Carboplat TM Oxaliplatin can be used, for example, in the form in which it is marketed, for example under the trademark Eloxatin TM Application.

[0274] As used herein, the term "compounds that target / reduce protein or lipid kinase activity; or protein or lipid phosphatase activity; or other anti-angiogenic compounds" includes (but is not limited to) protein tyrosine kinase and / or serine and / or threonine kinase inhibitors or lipid kinase inhibitors, such as: a) compounds that target, reduce or inhibit the activity of platelet-derived growth factor receptor (PDGFR), such as compounds that target, reduce or inhibit the activity of PDGFR, especially compounds that inhibit PDGF receptor, such as N-phenyl-2-pyrimidine-amine derivatives a) compounds that target, reduce or inhibit the activity of fibroblast growth factor receptor (FGFR); c) compounds that target, reduce or inhibit the activity of insulin-like growth factor receptor I (IGF-IR), such as compounds that target, reduce or inhibit the activity of IGF-IR, especially compounds that inhibit the kinase activity of IGF-I receptor, or antibodies that target the extracellular domain of IGF-I receptor or its growth factor; d) compounds that target, reduce or inhibit the activity of Trk receptor tyrosine kinase. e) compounds that target, reduce or inhibit the activity of the AxI receptor tyrosine kinase family; f) compounds that target, reduce or inhibit the activity of the Ret receptor tyrosine kinase; g) compounds that target, reduce or inhibit the activity of the Kit / SCFR receptor tyrosine kinase, such as imatinib; h) compounds that target, reduce or inhibit the activity of the C-kit receptor tyrosine kinase, which is part of the PDGFR family, such as imatinib. Compounds that inhibit the activity of the c-Kit receptor tyrosine kinase family, especially compounds that inhibit the c-Kit receptor, such as imatinib; i) compounds that target, reduce or inhibit the activity of c-Abl family members, their gene fusion products (e.g., BCR-Abl kinase) and mutants, such as compounds that target, reduce or inhibit the activity of c-Abl family members and their gene fusion products, such as N-phenyl-2-pyrimidine-amine derivatives, such as imatinib or nilotinib (AMN107), PD180970, AG957, NSC 680410, PD173955 from ParkeDavis, or dasatinib (BMS-354825); j) compounds that target, decrease or inhibit the activity of members of the protein kinase C (PKC) and Raf families of serine / threonine kinases, MEK, SRC, JAK / pan-JAK, FAK, PDK1, PKB / Akt, Ras / MAPK, PI3K, SYK, TYK2, BTK and TEC families and / or members of the cyclin-dependent kinase family (CDK), including staurosporine derivatives such as midostaurin;Examples of other compounds include UCN-01, safingol, BAY43-9006, Bryostatin 1, Perifosine; Ilmofosine; RO 318220 and RO 320432; GO 6976; Isis 3521; LY333531 / LY379196; Isoquinoline compounds; FTI; PD184352 or QAN697 (P13K inhibitor) or AT7519 (CDK inhibitor); k) compounds that target, reduce or inhibit the activity of protein-tyrosine kinase inhibitors, for example compounds that target, reduce or inhibit the activity of protein-tyrosine kinase inhibitors include imatinib mesylate (Gleevec; TM ) or tyrphostin, such as Tyrphostin A23 / RG-50810; AG 99; Tyrphostin AG 213; Tyrphostin AG 1748; Tyrphostin AG 490; Tyrphostin B44; Tyrphostin B44(+) enantiomer; Tyrphostin AG 555; AG 494; Tyrphostin AG 556, AG957 and adaphostin (4-{[(2,5-dihydroxyphenyl)methyl]amino}-benzoic acid adamantyl ester; NSC 680410, adaphostin); 1) targeting, decreasing or inhibiting the epidermal growth factor family of receptor tyrosine kinases (EGFR 1 Compounds that inhibit the activity of EGF receptors, such as ErbB2, ErbB3, ErbB4, as homodimers or heterodimers) and their mutants, such as compounds that target, reduce or inhibit the activity of the epidermal growth factor receptor family, especially compounds, proteins or antibodies that inhibit EGF receptor tyrosine kinase family members, such as EGF receptor, ErbB2, ErbB3 and ErbB4, or bind to EGF or EGF-related ligands, CP 358774, ZD 1839, ZM 105180; trastuzumab (Herceptin TM ), Cetuximab (Erbitux TM), Iressa, Tarceva, OSI-774, Cl-1033, EKB-569, GW-2016, E1.1, E2.4, E2.5, E6.2, E6.4, E2.11, E6.3 or E7.6.3, and 7H-pyrrolo-[2,3-d]pyrimidine derivatives; m) compounds that target, decrease or inhibit the activity of c-Met receptors, such as compounds that target, decrease or inhibit the activity of c-Met, especially inhibiting the kinase activity of c-Met receptors n) compounds that target, reduce or inhibit the kinase activity of one or more JAK family members (JAK1 / JAK2 / JAK3 / TYK2 and / or pan-JAK), including (but not limited to) PRT-062070, SB-1578, baricitinib, pacritinib, momelotinib, VX-509, AZD-1480, T G-101348, tofacitinib and ruxolitinib; o) compounds that target, reduce or inhibit the kinase activity of PI3 kinase (PI3K), including (but not limited to) ATU-027, SF-1126, DS-7423, PBI-05204, GSK-2126458, ZSTK-474, buparlisib, pictrelisib, PF-4691502, BY L-719, dactolisib, XL-147, XL-765 and idelalisib; and q) compounds that target, reduce or inhibit the signaling effects of the hedgehog (Hh) or smoothened receptor (SMO) pathways, including but not limited to cyclopamine, vismodegib, itraconazole, erismodegib and IPI-926 (saridegib).

[0275] 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, PI3Kα, PI3Kγ, PI3Kδ, PI3Kβ, PI3K-C2α, PI3K-C2β, PI3K-C2γ, Vps34, p110-α, p110-β, p110-γ, p110-δ, p85-α, p85-β, p55-γ, p150, p101, and p87. Examples of PI3K inhibitors that can be used in the present invention include, but are not limited to, ATU-027, SF-1126, DS-7423, PBI-05204, GSK-2126458, ZSTK-474, buparcoxib, picoxib, PF-4691502, BYL-719, datoxib, XL-147, XL-765, and idecoxib.

[0276] As used herein, the term "Bcl-2 inhibitor" includes, but is not limited to, compounds that have inhibitory activity against B-cell lymphoma 2 protein (Bcl-2), including, but not limited to, ABT-199, ABT-731, ABT-737, apogossypol, Ascenta's pan-Bcl-2 inhibitor, curcumin (and its analogs), dual Bcl-2 / Bcl-xL inhibitor (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), In some embodiments, the Bcl-2 inhibitor is a small molecule therapeutic agent. In some embodiments, the Bcl-2 inhibitor is a peptide mimetic.

[0277] As used herein, the term "BTK inhibitor" includes, but is not limited to, compounds having inhibitory activity on Bruton's tyrosine kinase (BTK), including, but not limited to, AVL-292 and ibrutinib.

[0278] As used herein, the term "SYK inhibitor" includes, but is not limited to, compounds having inhibitory activity on spleen tyrosine kinase (SYK), including, but not limited to, PRT-062070, R-343, R-333, Excellair, PRT-062607, and fostamatinib.

[0279] Further examples of BTK inhibiting compounds and conditions that can be treated by combinations of such compounds with the compounds of the present invention can be found in WO2008039218 and WO2011090760, the entire contents of which are incorporated herein by reference.

[0280] Further examples of SYK inhibiting compounds and conditions treatable by combinations of such compounds with the compounds of the invention can be found in WO2003063794, WO2005007623 and WO2006078846, the entire contents of which are incorporated herein by reference.

[0281] Other examples of PI3K inhibitory compounds and conditions treatable by combinations of such compounds 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.

[0282] Further examples of JAK inhibitory compounds and conditions treatable by combinations of such compounds with the compounds of the invention can be found in WO2009114512, WO2008109943, WO2007053452, WO2000142246 and WO2007070514, the entire contents of which are incorporated herein by reference.

[0283] Other antiangiogenic compounds include compounds with another mechanism of activity (e.g., unrelated to protein or lipid kinase inhibition), such as thalidomide. TM ) and TNP-470.

[0284] Examples of proteasome inhibitors that can be used in combination with the compounds of the invention include, but are not limited to, bortezomib, disulfiram, epigallocatechin-3-gallate (EGCG), salinosporin A, carfilzomib, ONX-0912, CEP-18770, and MLN9708.

[0285] Compounds which target, decrease or inhibit the activity of a protein or lipid phosphatase are, for example, phosphatase 1 inhibitors, phosphatase 2A inhibitors or CDC25 inhibitors, such as okadaic acid or a derivative thereof.

[0286] 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.

[0287] As used herein, the term cyclooxygenase inhibitors includes, but is not limited to, Cox-2 inhibitors, 5-alkyl substituted 2-arylaminophenylacetic acids and derivatives such as celecoxib (Celebrex TM ), rofecoxib (Vioxx TM ), etoricoxib, valdecoxib or 5-alkyl-2-arylaminophenylacetic acid, such as 5-methyl-2-(2'-chloro-6'-fluoroanilino)phenylacetic acid, lumiracoxib.

[0288] As used herein, the term "bisphosphonates" includes, but is not limited to, etridonic 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 TM Clodronic acid is sold under the trade name Bonefos TM Tiludronic acid is sold under the brand name Skelid TM Pamidronate is sold under the brand name Aredia TM Alendronate is sold under the brand name Fosamax TM Ibandronic acid is sold under the brand name Bondranat TM Risedronate is sold under the brand name Actonel TM Zoledronic acid is sold under the brand name Zometa TM The term "mTOR inhibitor" relates to compounds that inhibit the mammalian target of rapamycin (mTOR) and have antiproliferative activity, such as sirolimus Everolimus (Certican TM ), CCI-779 and ABT578.

[0289] As used herein, the term "heparinase inhibitor" refers to a compound that targets, reduces or inhibits the degradation of heparan sulfate. The term includes (but is not limited to) PI-88. As used herein, the term "biological response modifier" refers to a lymphokine or an interferon.

[0290] As used herein, the term "inhibitor of Ras oncogenic isoforms" (such as H-Ras, K-Ras or N-Ras) refers to compounds that target, decrease or inhibit the oncogenic activity of Ras; for example, "farnesyl transferase inhibitors" such as L-744832, DK8G557 or R115777 (Zarnestra TM As used herein, the term "telomerase inhibitor" refers to a compound that targets telomerase, reduces or inhibits its activity. Compounds that target telomerase, reduce or inhibit its activity are particularly compounds that inhibit telomerase receptors, such as telomestatin.

[0291] As used herein, the term "methionine aminopeptidase inhibitor" refers to a compound that targets methionine aminopeptidase, reduces or inhibits its activity. Compounds that target methionine aminopeptidase, reduce or inhibit its activity include, but are not limited to, bengamide or its derivatives.

[0292] As used herein, the term "proteasome inhibitor" refers to a compound that targets the proteasome, reduces or inhibits its activity. Compounds that target the proteasome, reduce or inhibit its activity include, but are not limited to, bortezomib (Velcade TM ) and MLN 341.

[0293] As used herein, the term "matrix metalloproteinase inhibitors" or ("MMP" inhibitors) include, but are not limited to, collagen peptidomimetic and non-peptide mimetic inhibitors, tetracycline derivatives, such as the hydrooxalamic acid ester peptidomimetic inhibitor batimastat and its orally bioavailable analogs marimastat (BB-2516), prinomastat (AG3340), metastat (NSC 683551), BMS-279251, BAY 12-9566, TAA211, MMI270B or AAJ996.

[0294] As used herein, the term "compounds for treating hematological malignancies" includes, but is not limited to, FMS-like tyrosine kinase inhibitors, which are compounds that target, decrease or inhibit the activity of the FMS-like tyrosine kinase receptor (Flt-3R); interferons, 1-β-D-arabinofuranosylcytosine (ara-c) and busulfan; and ALK inhibitors, which are compounds that target, decrease or inhibit polymorphic lymphoma kinase.

[0295] Compounds that target the FMS-like tyrosine kinase receptor (Flt-3R), decrease or inhibit its activity are in particular compounds, proteins or antibodies that inhibit members of the Flt-3R receptor kinase family, such as PKC412, midostaurin, staurosporine derivatives, SU11248 and MLN518.

[0296] As used herein, the term "HSP90 inhibitor" includes, but is not limited to, compounds that target, reduce or inhibit the intrinsic ATPase activity of HSP90; compounds that degrade, target, reduce or inhibit HSP90 client proteins through the ubiquitin proteasome pathway. Compounds that target, reduce or inhibit the intrinsic ATPase activity of HSP90 are especially compounds, proteins or antibodies that inhibit the ATPase activity of HSP90, such as 17-allylamino, 17-demethoxygeldanamycin (17AAG) (a geldanamycin derivative); other geldanamycin-related compounds; radicicol and HDAC inhibitors.

[0297] As used herein, the term "anti-proliferative antibodies" includes, but is not limited to, trastuzumab (Herceptin TM ), trastuzumab-DM1, erbitux, bevacizumab (Avastin TM ), rituximab PRO64553 (anti-CD40) and 2C4 antibodies. Antibodies refer to intact monoclonal antibodies, polyclonal antibodies, multispecific antibodies formed from at least two intact antibodies, and antibody fragments as long as they exhibit the desired biological activity.

[0298] For the treatment of acute myeloid leukemia (AML), the compounds of the present invention can be combined with standard leukemia therapies, especially for the treatment of AML. Specifically, the compounds of the present invention can be used in combination with, for example, farnesyl transferase inhibitors and / or other drugs that can be used to treat AML, such as daunorubicin, adriamycin, Ara-C, VP-16, teniposide, mitoxantrone, idarubicin, carboplatin and PKC412.

[0299] Other anti-leukemia compounds include, for example, Ara-C, a pyrimidine analog that is a 2'-α-hydroxyribose (arabinoside) derivative of deoxycytidine. Also included are purine analogs of hypoxanthine, 6-mercaptopurine (6-MP) and fludarabine phosphate. Targeted histone deacetylase (HDAC) inhibitors, compounds that reduce or inhibit its activity, such as sodium butyrate and suberoylanilide hydroxamic acid (SAHA), inhibit the activity of an enzyme called histone deacetylase. Specific HDAC inhibitors include MS275, SAHA, FK228 (formerly FR901228), Trichostatin A and compounds disclosed in US 6,552,065, including (but not limited to) N-hydroxy-3-[4-[[[2-(2-methyl-1H-indol-3-yl)-ethyl]-amino]methyl]phenyl]-2E-2-acrylamide or a pharmaceutically acceptable salt thereof, and N-hydroxy-3-[4-[(2-hydroxyethyl){2-(1H-indol-3-yl)ethyl]-amino]methyl]phenyl]-2E-2-acrylamide or a pharmaceutically acceptable salt thereof, especially lactate. As used herein, somatostatin receptor antagonists refer to compounds that target, manipulate or inhibit somatostatin receptors, such as octreotide and SOM230. Tumor cell injury methods refer to methods such as ionizing radiation. The term "ionizing radiation" referred to above and below means ionizing radiation that occurs in the form of electromagnetic rays (such as X-rays and gamma rays) or particles (such as alpha particles and beta particles). Ionizing radiation is provided in (but not limited to) radiation therapy and is known in the art. See Hellman, Principles of Radiation Therapy, Cancer, in Principles and Practice of Oncology, Devita et al., eds., 4th edition, Vol. 1, pp. 248-275 (1993).

[0300] Also included are EDG binders and ribonucleotide reductase inhibitors. As used herein, the term "EDG binder" refers to a class of immunosuppressants that regulate lymphocyte recirculation, such as FTY720. The term "ribonucleotide reductase inhibitor" refers to pyrimidine or purine nucleoside analogs, including but not limited to fludarabine and / or cytosine arabinoside (ara-C), 6-thioguanine, 5-fluorouracil, cladribine, 6-mercaptopurine (especially in combination with ara-C to resist ALL) and / or pentostatin. Ribonucleotide reductase inhibitors are especially hydroxyurea or 2-hydroxy-1H-isoindole-1,3-dione derivatives.

[0301] Also specifically included are those compounds, proteins or monoclonal antibodies to VEGF, such as 1-(4-chloroanilino)-4-(4-pyridylmethyl)phthalazine or a pharmaceutically acceptable salt thereof; 1-(4-chloroanilino)-4-(4-pyridylmethyl)phthalazine succinate; Angiostatin TM ;Endostatin TM ; anthranilamide; ZD4190; Zd 6 474; 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 (RPI 4610) and bevacizumab (Avastin TM ).

[0302] As used herein, photodynamic therapy refers to a therapy that uses certain chemicals called photosensitizing compounds to treat or prevent cancer. Examples of photodynamic therapy include the use of drugs such as Visudyne TM and porfimer sodium.

[0303] As used herein, angiostatic steroids refer to compounds that block or inhibit angiogenesis, such as anecortave, triamcinolone, hydrocortisone, 11-α-epihydrocotisol, cortexolone, 17α-hydroxyprogesterone, corticosterone, desoxycorticosterone, testosterone estrogen, and dexamethasone.

[0304] Implants containing corticosteroids refer to compounds such as fluocinolone and dexamethasone.

[0305] Other chemotherapeutic compounds include, but are not limited to, plant alkaloids, hormone compounds and antagonists; biological response modifiers, preferably lymphokines or interferons; antisense oligonucleotides or oligonucleotide derivatives; shRNA or siRNA; or miscellaneous compounds or compounds with other or unknown mechanisms of action.

[0306] The structures of active compounds identified by code numbers, generic or trade names can be taken from the official standard compendium "The Merck Index" or from databases, for example Patents International (eg IMS World Publications).

[0307] 4.2.2. Exemplary Immuno-Oncology Agents

[0308] In some embodiments, one or more other therapeutic agents are immuno-oncology agents. As used herein, the term "immuno-oncology agent" refers to an agent that effectively enhances, stimulates and / or upregulates an immune response in a subject. In some embodiments, the administration of an immuno-oncology agent together with a compound of the invention has a synergistic effect in treating cancer.

[0309] The immuno-oncology agent can be, for example, a small molecule drug, an antibody, or a biological molecule or a small molecule. Examples of biological immuno-oncology agents include, but are not limited to, cancer vaccines, antibodies, and cytokines. In some embodiments, the antibody is a monoclonal antibody. In some embodiments, the monoclonal antibody is a humanized or human antibody.

[0310] In some embodiments, the immuno-oncology agent is (i) an agonist of a stimulatory (including co-stimulatory) receptor, or (ii) an antagonist of an inhibitory (including co-inhibitory) signal on T cells, both of which result in expansion of antigen-specific T cell responses.

[0311] Some stimulatory and inhibitory molecules are members of the immunoglobulin superfamily (IgSF). An important family of membrane-bound ligands that bind to costimulatory or co-inhibitory receptors is the B7 family, which includes B7-1, B7-2, B7-H1 (PD-L1), B7-DC (PD-L2), B7-H2 (ICOS-L), B7-H3, B7-H4, B7-H5 (VISTA) and B7-H6. Another family of membrane-bound ligands that bind to costimulatory or co-inhibitory receptors is a TNF family molecule that binds to homologous 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, OPG, RANK, RANKL, TWEAKR / Fn14, TWEAK, BAFFR, EDAR, XEDAR, TACI, APRIL, BCMA, LTβR, LIGHT, DcR3, HVEM, VEGI / TL1A, TRAMP / DR3 , EDAR, EDA1, XEDAR, EDA2, TNFR1, lymphotoxin α / TNFβ, TNFR2, TNFα, LTβR, lymphotoxin α1β2, FAS, FASL, RELT, DR6, TROY, NGFR.

[0312] In some embodiments, the immuno-oncology agent is a cytokine that inhibits T cell activation (eg, IL-6, IL-10, TGF-β, VEGF, and other immunosuppressive cytokines) or a cytokine that stimulates T cell activation to stimulate an immune response.

[0313] In some embodiments, the combination of a compound of the invention and an immuno-oncology agent can stimulate a T cell response. In some embodiments, the immuno-oncology agent is: (i) an antagonist of a protein that inhibits T cell activation (e.g., an immune checkpoint inhibitor), such as CTLA-4, PD-1, PD-L1, PD-L2, LAG-3, TIM-3, Galectin 9, CEACAM-1, BTLA, CD69, Galectin-1, TIGIT, CD113, GPR56, VISTA, 2B4, CD48, GARP, PD1H, LAIR1, TIM-1, and TIM-4; or (ii) an agonist of a protein that stimulates T cell activation, such as B7-1, B7-2, CD28, 4-1BB (CD137), 4-1BBL, ICOS, ICOS-L, OX40, OX40L, GITR, GITRL, CD70, CD27, CD40, DR3, and CD28H.

[0314] In some embodiments, the immuno-oncology agent is an antagonist of an inhibitory receptor on a NK cell or an agonist of an activating receptor on a NK cell. In some embodiments, the immuno-oncology agent is an antagonist of a KIR, such as lirilumab.

[0315] In some embodiments, the immuno-oncology 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).

[0316] In some embodiments, the immuno-oncology agent is selected from agonists that engage positive co-stimulatory receptors; blockers that attenuate signaling through inhibitory receptors, antagonists, and one or more agents that systemically increase the frequency of anti-tumor T cells; agents that overcome unique immunosuppressive pathways within the tumor microenvironment (e.g., blocking inhibitory receptor engagement (e.g., PD-L1 / PD-1 interaction), depleting or inhibiting Tregs (e.g., using anti-CD25 monoclonal antibodies (e.g., daclizumab) or by ex vivo anti-CD25 bead depletion), inhibiting metabolic enzymes such as IDO, or reversing / preventing T cell energy or exhaustion); and agents that trigger innate immune activation and / or inflammation at the tumor site.

[0317] In some embodiments, the immuno-oncology agent is a CTLA-4 antagonist. In some embodiments, the CTLA-4 antagonist is an antagonist CTLA-4 antibody. In some embodiments, the antagonist CTLA-4 antibody is YERVOY (ipilimumab) or tremelimumab.

[0318] In some embodiments, the immuno-oncology agent is a PD-1 antagonist. In some embodiments, the PD-1 antagonist is administered by infusion. In some embodiments, the immuno-oncology agent is an antibody or antigen-binding portion thereof that specifically binds to a programmed death-1 (PD-1) receptor and inhibits PD-1 activity. In some embodiments, the PD-1 antagonist is an antagonist PD-1 antibody. In some embodiments, the antagonist PD-1 antibody is OPDIVO (nivolumab), KEYTRUDA (pembrolizumab), or MEDI-0680 (AMP-514; WO2012 / 145493). In some embodiments, the immuno-oncology agent may be pidilizumab (CT-011). In some embodiments, the immuno-oncology agent is a recombinant protein composed of a fusion of the extracellular domain (B7-DC) of PD-L2 and the Fc portion of IgG1, referred to as AMP-224.

[0319] In some embodiments, the immuno-oncology agent is a PD-L1 antagonist. In some embodiments, the PD-L1 antagonist is an antagonist PD-L1 antibody. In some embodiments, the PD-L1 antibody is MPDL3280A (RG7446; WO2010 / 077634), durvalumab (MEDI4736), BMS-936559 (WO2007 / 005874), and MSB0010718C (WO2013 / 79174).

[0320] In some embodiments, the immuno-oncology agent is a LAG-3 antagonist. In some embodiments, the LAG-3 antagonist is an antagonist LAG-3 antibody. In some embodiments, the LAG3 antibody is BMS-986016 (WO10 / 19570, WO14 / 08218) or IMP-731 or IMP-321 (WO08 / 132601, WO009 / 44273).

[0321] In some embodiments, the immuno-oncology agent is a CD137 (4-1BB) agonist. In some embodiments, the CD137 (4-1BB) agonist is an agonistic CD137 antibody. In some embodiments, the CD137 antibody is urelumab or PF-05082566 (WO12 / 32433).

[0322] In some embodiments, the immuno-oncology agent is a GITR agonist. In some embodiments, the GITR agonist is an agonistic GITR antibody. In some embodiments, the GITR antibody is BMS-986153, BMS-986156, TRX-518 (WO006 / 105021, WO009 / 009116), or MK-4166 (WO11 / 028683).

[0323] In some embodiments, the immuno-oncology agent is an indoleamine (2,3)-dioxygenase (IDO) antagonist. In some embodiments, the IDO antagonist is selected from epacadostat (INCB024360, Incyte); indoximod (NLG-8189, NewLink Genetics Corporation); capmanitib (INC280, Novartis); GDC-0919 (Genentech / Roche); PF-06840003 (Pfizer); BMS:F001287 (Bristol-Myers Squibb); Phy906 / KD108 (Phytoceutica); Kynase (Kyn Therapeutics); and NLG-919 (WO09 / 73620, WO009 / 1156652, WO11 / 56652, WO12 / 142237).

[0324] In some embodiments, the immuno-oncology agent is an OX40 agonist. In some embodiments, the OX40 agonist is an agonistic OX40 antibody. In some embodiments, the OX40 antibody is MEDI-6383 or MEDI-6469.

[0325] In some embodiments, the immuno-oncology agent is an OX40L antagonist. In some embodiments, the OX40L antagonist is an antagonist OX40 antibody. In some embodiments, the OX40L antagonist is RG-7888 (WO06 / 029879).

[0326] In some embodiments, the immuno-oncology agent is a CD40 agonist. In some embodiments, the CD40 agonist is an agonistic CD40 antibody. In some embodiments, the immuno-oncology agent is a CD40 antagonist. In some embodiments, the CD40 antagonist is an antagonistic CD40 antibody. In some embodiments, the CD40 antibody is lucatumumab or dacetuzumab.

[0327] In some embodiments, the immuno-oncology agent is a CD27 agonist. In some embodiments, the CD27 agonist is an agonistic CD27 antibody. In some embodiments, the CD27 antibody is varlilumab.

[0328] In some embodiments, the immuno-oncology agent is MGA271 (directed against B7H3) (WO 11 / 109400).

[0329] In some embodiments, the immuno-oncology agent is abagovomab, adecatumumab, afutuzumab, alemtuzumab, anatumomab mafenatox, apolizumab, atezolimab, avelumab, blinatumomab, BMS-936559, catumaxomab, durvalumab, epacadostat, epratuzumab, inotuzumab, ozogamicin, intelumumab, ipilimumab, isatuximab, lambrolizumab, MED14736, MPDL3280A, nivolumab, obinutuzumab, ocaratuzumab, ofavumab, olatatumab, pembrolizumab, pilizumab, rituximab, ticilimumab, samalizumab, or tremelimumab.

[0330] In some embodiments, the immuno-oncology agent is an immunostimulatory agent. For example, antibodies that block the PD-1 and PD-L1 inhibitory axis can release activated tumor-reactive T cells and have been shown in clinical trials to induce durable anti-tumor responses in an increasing number of tumor tissue structures, including some tumor types that are not conventionally considered to be sensitive to immunotherapy. See, for example, Okazaki, T. et al. (2013) Nat. Immunol. 14, 1212-1218; Zou et al. (2016) Sci. Transl. Med. 8. The anti-PD-1 antibody nivolumab ( Bristol-Myers Squibb (also known as ONO-4538, MDX1106, and BMS-936558) has demonstrated the potential to improve overall survival in RCC patients who experience disease progression during or after anti-angiogenic therapy.

[0331] In some embodiments, the immunomodulatory therapeutic agent specifically induces apoptosis of tumor cells. Approved immunomodulatory therapeutic agents that can be used in the present invention include pomalidomide ( Celgene; lenalidomide ( Celgene; ingenol mebutate ( LEO Pharma).

[0332] In some embodiments, the immuno-oncology agent is a cancer vaccine. In some embodiments, the cancer vaccine is selected from sipuleucel-T ( Dendreon / Valeant Pharmaceuticals), which is approved for the treatment of asymptomatic or minimally symptomatic metastatic castration-resistant (hormone-refractory) prostate cancer; and talimogene laherparepvec ( BioVex / Amgen, formerly known as T-VEC), a genetically modified oncolytic virus therapy approved for the treatment of unresectable skin, subcutaneous and nodular lesions in melanoma. In some embodiments, the immuno-oncology agent is selected from oncolytic virus therapies such as pexastimogenedevacirepvec (PexaVec / JX-594, SillaJen / formerly Jennerex Biotherapeutics), a thymidine kinase (TK)-deficient poxvirus engineered to express GM-CSF for hepatocellular carcinoma (NCT02562755) and melanoma (NCT00429312); pelareorep ( Oncolytics Biotech, a respiratory orphan virus (reovirus) variant that does not replicate in RAS-inactivated cells in a number of cancers, including colorectal cancer (NCT01622543), prostate cancer (NCT01619813), head and neck squamous cell carcinoma (NCT01166542), pancreatic adenocarcinoma (NCT00998322), and non-small cell lung cancer (NSCLC) (NCT00861627); enadenotucirev (NG-348, PsiOxus, formerly ColoAd1), a recombinant human cytokine engineered to express the full 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 poxvirus engineered to express β-galactosidase (β-gal) / β-glucuronidase or β-gal / human sodium iodide symporter (hNIS), studied in peritoneal cancer (NCT01443260), fallopian tube cancer, ovarian cancer (NCT 02759588), respectively; or CG0070 (Cold Genesys), an adenovirus engineered to express GM-CSF, in bladder cancer (NCT02365818).

[0333] In some embodiments, the immuno-oncology agent is selected from JX-929 (SillaJen / formerly Jennerex Biotherapeutics), a TK- and vaccinia growth factor-deficient vaccinia virus engineered to express cytosine deaminase, which is capable of converting the prodrug 5-fluorocytosine into the cytotoxic drug 5-fluorouracil; TG01 and TG02 (Targovax / formerly Oncos), peptide-based immunotherapeutics targeting hard-to-treat RAS mutations; and TILT-123 (TILT Biotherapeutics), an engineered adenovirus designated: Ad5 / 3-E2F-δ24-hTNFα-IRES-hIL20; and VSV-GP (Vira Therapeutics), a vesicular stomatitis virus (VSV) engineered to express the glycoprotein (GP) of lymphocytic choriomeningitis virus (LCMV), which can be further engineered to express a protein designed to produce an antigen-specific CD8 + Antigens to which T cells respond.

[0334] In some embodiments, the immuno-oncology agent is a T cell engineered to express a chimeric antigen receptor or CAR. T cells engineered to express such a chimeric antigen receptor are called CAR-T cells.

[0335] The following CAR has been constructed, which consists of a binding domain that can be derived from a natural ligand, a single-chain variable fragment (scFv) derived from a monoclonal antibody specific for a cell surface antigen, and an intracellular domain as the functional end of a T cell receptor (TCR), such as a CD3-ζ signaling domain from TCR that can generate an activation signal in a T lymphocyte. Upon antigen binding, such CARs are connected to endogenous signaling pathways in effector cells and generate activation signals similar to those triggered by the TCR complex.

[0336] For example, in some embodiments, the CAR-T cell is one of the CAR-T cells described in U.S. Pat. No. 8,906,682 (June; incorporated herein by reference in its entirety), which discloses a CAR-T cell engineered to include an extracellular domain having an antigen binding domain (such as a domain that binds to CD19) fused to an intracellular signaling domain of a T cell antigen receptor complex ζ chain (such as CD3ζ). When expressed in T cells, the CAR is able to redirect antigen recognition based on antigen binding specificity. In the case of CD19, the antigen is expressed on malignant B cells. Currently, more than 200 clinical trials using CAR-T in various indications are in progress. [https: / / clinicaltrials.gov / ct2 / results?term=chimeric+antigen+receptors&pg=1].

[0337] In some embodiments, the immunostimulator is an activator of retinoic acid receptor-related orphan receptor gamma (RORγt). RORγt is a transcription factor that plays a key role in the differentiation and maintenance of type 17 effector subsets of CD4+ (Th17) and CD8+ (Tc17) T cells and the differentiation of innate immune cell subsets expressing IL-17 (such as NK cells). In some embodiments, the activator of RORγt is LYC-55716 (Lycera), which is currently being evaluated in clinical trials for the treatment of solid tumors (NCT02929862).

[0338] In some embodiments, the immunostimulator is an agonist or activator of a toll-like receptor (TLR). Suitable TLR activators include agonists or activators of TLR9, such as SD-101 (Dynavax). SD-101 is a kind of immunostimulatory CpG, which is being studied for use in B cell lymphoma, follicular lymphoma and other lymphomas (NCT02254772). The agonist or activator of TLR8 that can be used in the present invention includes motolimod (VTX-2337, VentiRx Pharmaceuticals), which is being studied for use in head and neck squamous cell carcinoma (NCT02124850) and ovarian cancer (NCT02431559).

[0339] Other immuno-oncology agents that can be used in the present invention include urelumab (BMS-663513, Bristol-Myers Squibb), an anti-CD137 monoclonal antibody; varitumumab (CDX-1127, Celldex Therapeutics), an anti-CD27 monoclonal antibody; BMS-986178 (Bristol-Myers Squibb), an anti-OX40 monoclonal antibody; lirilumab (IPH2102 / BMS-986015, Innate Pharma, Bristol-Myers Squibb), an anti-KIR monoclonal antibody; monalizumab (IPH2201, Innate Pharma, AstraZeneca), an anti-NKG2A monoclonal antibody; andecaliximab (GS-5745, Gilead Sciences) Sciences), an anti-MMP9 antibody; MK-4166 (Merck & Co.), an anti-GITR monoclonal antibody.

[0340] 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.

[0341] In some embodiments, the immunostimulatory therapeutic agent is recombinant human interleukin 15 (rhIL-15). rhIL-15 has been tested in the clinic as a therapy for melanoma and renal cell carcinoma (NCT01021059 and NCT01369888) and leukemia (NCT02689453). In some embodiments, the immunostimulatory agent is recombinant human interleukin 12 (rhIL-12). In some embodiments, the IL-15-based immunotherapeutic agent is heterodimeric IL-15 (hetIL-15, Novartis / Admune), a fusion complex composed of a synthetic form of endogenous IL-15 and a soluble IL-15 binding protein IL-15 receptor α chain (IL15:sIL-15RA), which has been 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.

[0342] In some embodiments, the immuno-oncology agent is selected from the immuno-oncology agents described in Jerry L. Adams et al., "Big opportunities for small molecules in immuno-oncology", Cancer Therapy 2015, Vol. 14, pp. 603-622, the contents of which are incorporated herein by reference in their entirety. In some embodiments, the immuno-oncology agent is selected from the examples described in Table 1 of Jerry L. Adams et al. In some embodiments, the immuno-oncology agent is a small molecule selected from those small molecules targeting immuno-oncology targets listed in Table 2 of Jerry L. Adams et al. In some embodiments, the immuno-oncology agent is a small molecule selected from those small molecule agents listed in Table 2 of Jerry L. Adams et al.

[0343] In some embodiments, the immuno-oncology agent is selected from the small molecule immuno-oncology agents described in Peter L. Toogood, "Small molecule immuno-oncology therapeutic agents", Bioorganic & Medicinal Chemistry Letters 2018, Vol. 28, pp. 319-329, the contents of which are incorporated herein by reference in their entirety. In some embodiments, the immuno-oncology agent is an agent targeting a pathway as described in Peter L. Toogood.

[0344] In some embodiments, the immuno-oncology agent is selected from Sandra L. Ross et al., "Bispecific T cell engager Antibody constructs can mediate bystander tumor cell killing”, PLoS ONE 12(8):e0183390, the contents of which are incorporated herein by reference in their entirety. In some embodiments, the immuno-oncology agent is a bispecific T cell engager. Antibody Constructs. In some embodiments, the bispecific T cell engager The antibody construct is a CD19 / CD3 bispecific antibody construct. In some embodiments, the bispecific T cell engager The antibody construct is an EGFR / CD3 bispecific antibody construct. In some embodiments, the bispecific T cell engager Antibody constructs activate T cells. In some embodiments, the bispecific T cell engager The antibody construct activates T cells, which release cytokines that induce upregulation of intercellular adhesion molecule 1 (ICAM-1) and FAS on neighboring cells. In some embodiments, the bispecific T cell engager The antibody construct activates T cells, inducing bystander cell lysis. In some embodiments, the bystander cells are in a solid tumor. In some embodiments, the lysed bystander cells are near Activated T cells. In some embodiments, the adjacent cells include tumor-associated antigen (TAA) negative cancer cells. In some embodiments, the adjacent cells include EGFR negative cancer cells. In some embodiments, the immuno-oncology agent is an antibody that blocks the PD-L1 / PD1 axis and / or CTLA4. In some embodiments, the immuno-oncology agent is a tumor-infiltrating T cell that is expanded ex vivo. In some embodiments, the immuno-oncology agent is a bispecific antibody construct or a chimeric antigen receptor (CAR) that directly connects T cells to tumor-associated surface antigens (TAA).

[0345] Exemplary immune checkpoint inhibitors

[0346] In some embodiments, the immuno-oncology agent is an immune checkpoint inhibitor as described herein.

[0347] As used herein, the term "checkpoint inhibitor" refers to an agent that can be used to prevent cancer cells from evading the patient's immune system. One of the main mechanisms of anti-tumor immune destruction is called "T cell exhaustion", which is caused by the upregulation of inhibitory receptors caused by long-term exposure to antigens. These inhibitory receptors serve as immune checkpoints to prevent uncontrolled immune responses.

[0348] PD-1 and co-inhibitory receptors such as cytotoxic T lymphocyte antigen 4 (CTLA-4), B and T lymphocyte attenuator (BTLA; CD272), T cell immunoglobulin and mucin domain-3 (Tim-3), lymphocyte activation gene-3 (Lag-3; CD223) and other receptors are often referred to as checkpoint regulators. They act as molecular "gatekeepers" that allow extracellular information to indicate whether cell cycle progression and other intracellular signaling processes should proceed.

[0349] In some embodiments, the immune checkpoint inhibitor is an antibody to PD-1. PD-1 binds to the programmed cell death 1 receptor (PD-1) to prevent the receptor from binding to the inhibitory ligand PDL-1, thereby suppressing the tumor's ability to suppress the host's anti-tumor immune response.

[0350] In one aspect, the checkpoint inhibitor is a biotherapeutic agent or a small molecule. On the other hand, the checkpoint inhibitor is a monoclonal antibody, a humanized antibody, a fully human antibody, a fusion protein, or a combination thereof. On the other hand, the checkpoint inhibitor inhibits a checkpoint protein selected from the following: CTLA-4, PDL1, PDL2, PD1, B7-H3, B7-H4, BTLA, HVEM, TIM3, GAL9, LAG3, VISTA, KIR, 2B4, CD160, CGEN-15049, CHK1, CHK2, A2aR, B-7 family ligand, or a combination thereof. In an additional aspect, the checkpoint inhibitor interacts with a ligand selected from the following checkpoint proteins: CTLA-4, PDL1, PDL2, PD1, B7-H3, B7-H4, BTLA, HVEM, TIM3, GAL9, LAG3, VISTA, KIR, 2B4, CD160, CGEN-15049, CHK1, CHK2, A2aR, B-7 family ligands, or a combination thereof. On the one hand, the checkpoint inhibitor is an immunostimulant, a T cell growth factor, an interleukin, an antibody, a vaccine, or a combination thereof. On the other hand, the interleukin is IL-7 or IL-15. In a specific aspect, the interleukin is glycosylated IL-7. In an additional aspect, the vaccine is a dendritic cell (DC) vaccine.

[0351] Checkpoint inhibitors include any agent that blocks or inhibits the inhibitory pathway of the immune system in a statistically significant manner. Such inhibitors may include small molecule inhibitors, or may include antibodies or antigen binding fragments thereof that bind to and block or inhibit immune checkpoint receptors, or antibodies that bind to and block or inhibit immune checkpoint receptor ligands. Illustrative checkpoint molecules that can be targeted for blocking or inhibition include, but are not limited to, CTLA-4, PDL1, PDL2, PD1, B7-H3, B7-H4, BTLA, HVEM, GAL9, LAG3, TIM3, VISTA, KIR, 2B4 (belonging to the CD2 molecule family and expressed in all NK, γδ and memory CD8 +(αβ) T cells), CD160 (also known as BY55), CGEN-15049, CHK1 and CHK2 kinases, A2aR, and various B-7 family ligands. 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 one or more of the following and block or inhibit the activity of one or more of the following: CTLA-4, PDL1, PDL2, PD1, BTLA, HVEM, TIM3, GAL9, LAG3, VISTA, KIR, 2B4, CD 160, and CGEN-15049. Illustrative immune checkpoint inhibitors include tremelimumab (CTLA-4 blocking antibody), anti-OX40, PD-L1 monoclonal antibody (anti-B7-H1; MEDI4736), MK-3475 (PD-1 blocker), nivolumab (anti-PD1 antibody), CT-011 (anti-PD1 antibody), BY55 monoclonal antibody, AMP224 (anti-PDL1 antibody), BMS-936559 (anti-PDL1 antibody), MPLDL3280A (anti-PDL1 antibody), MSB0010718C (anti-PDL1 antibody) and ipilimumab (anti-CTLA-4 checkpoint inhibitor). Checkpoint protein ligands include (but are not limited to) PD-L1, PD-L2, B7-H3, B7-H4, CD28, CD86 and TIM-3.

[0352] In certain embodiments, the immune checkpoint inhibitor is selected from a PD-1 antagonist, a PD-L1 antagonist, and a CTLA-4 antagonist. In some embodiments, the checkpoint inhibitor is selected from the group consisting of: nivolumab Ipilimumab and pembrolizumab In some embodiments, the checkpoint inhibitor is selected from nivolumab (anti-PD-1 antibody, Bristol-Myers Squibb; Pembrolizumab (anti-PD-1 antibody, Merck); Ipilimumab (anti-CTLA-4 antibody, Bristol-Myers Squibb; Durvalumab (anti-PD-L1 antibody, AstraZeneca); and atezolizumab (anti-PD-L1 antibody, Genentech).

[0353] In some embodiments, the checkpoint inhibitor is selected from the group consisting of: lambrolizumab (MK-3475), nivolumab (BMS-936558), pilizumab (CT-011), AMP-224, MDX-1105, MEDI4736, MPDL3280A, BMS-936559, ipilimumab, lirelumab, IPH2101, pembrolizumab and tremelimumab.

[0354] In some embodiments, the immune checkpoint inhibitor is REGN2810 (Regeneron), an anti-PD-1 antibody being tested in patients with basal cell carcinoma (NCT03132636); NSCLC (NCT03088540); cutaneous squamous cell carcinoma (NCT02760498); lymphoma (NCT02651662); and melanoma (NCT03002376); pilizumab (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 ( Pfizer / Merck KGaA), also known as MSB0010718C, 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; or PDR001 (Novartis), an inhibitory antibody that binds to PD-1 in clinical trials for non-small cell lung cancer, melanoma, triple-negative breast cancer, and advanced or metastatic solid tumors. Tremelimumab (CP-675,206; Astrazeneca) is a fully human monoclonal antibody against CTLA-4 that has been studied in clinical trials for multiple indications, including: mesothelioma, colorectal cancer, renal cancer, breast cancer, lung cancer, and non-small cell lung cancer, pancreatic duct adenocarcinoma, pancreatic cancer, germ cell cancer, head and neck squamous cell carcinoma, hepatocellular carcinoma, prostate cancer, endometrial cancer, metastatic cancer in the liver, hepatocellular carcinoma, large B-cell lymphoma, ovarian cancer, cervical cancer, metastatic undifferentiated 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 studied in a Phase 1 clinical trial for advanced solid tumors (NCT02694822).

[0355] In some embodiments, the checkpoint inhibitor is an inhibitor of protein-3 (TIM-3) containing T cell immunoglobulin mucin. TIM-3 inhibitors available in the present invention include TSR-022, LY3321367 and MBG453. TSR-022 (Tesaro) is an anti-TIM-3 antibody studied in solid tumors (NCT02817633). LY3321367 (Eli Lilly) is an anti-TIM-3 antibody studied in solid tumors (NCT03099109). MBG453 (Novartis) is an anti-TIM-3 antibody studied in advanced malignancies (NCT02608268).

[0356] In some embodiments, the checkpoint inhibitor is a T cell immunoreceptor with Ig and ITIM domains, or an inhibitor of 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), an anti-TIGIT monoclonal antibody (NCT02913313); OMP-313M32 (Oncomed); and anti-TIGIT monoclonal antibody (NCT03119428).

[0357] 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 and REGN3767 and IMP321. BMS-986016 (Bristol-Myers Squibb), an anti-LAG-3 antibody, is being studied in glioblastoma and gliosarcoma (NCT02658981). REGN3767 (Regeneron) is also an anti-LAG-3 antibody and is being studied in malignant diseases (NCT03005782). IMP321 (Immutep SA) is a LAG-3-Ig fusion protein that is being studied in melanoma (NCT02676869), adenocarcinoma (NCT02614833) and metastatic breast cancer (NCT00349934).

[0358] Checkpoint inhibitors that can be used in the present invention include OX40 agonists. OX40 agonists being studied in clinical trials include: PF-04518600 / PF-8600 (Pfizer), an agonistic anti-OX40 antibody, in metastatic renal cancer (NCT03092856) and advanced cancer and tumors (NCT02554812; NCT05082566); GSK3174998 (Merck), an agonistic anti-OX40 antibody, in a Phase 1 cancer trial (NCT02528357); MEDI0562 (Medimmune / AstraZeneca ), an agonist anti-OX40 antibody, in advanced solid tumors (NCT02318394 and NCT02705482); MEDI6469, an agonist anti-OX40 antibody (Medimmune / AstraZeneca), in patients with colorectal cancer (NCT02559024), breast cancer (NCT01862900), head and neck cancer (NCT02274155), and metastatic prostate cancer (NCT01303705); and BMS-986178 (Bristol-Myers Squibb), an agonist anti-OX40 antibody, in advanced cancers (NCT02737475).

[0359] Checkpoint inhibitors that can be used in the present invention include CD137 (also known as 4-1BB) agonists. CD137 agonists being studied in clinical trials include: utomilumab (PF-05082566, Pfizer), an agonistic anti-CD137 antibody, in diffuse large B-cell lymphoma (NCT02951156) and advanced cancers and tumors (NCT02554812 and NCT05082566); urelumab (BMS-663513, Bristol-Myers Squibb), an agonistic anti-CD137 antibody, in melanoma and skin cancer (NCT02652455) and glioblastoma and gliosarcoma (NCT02658981).

[0360] Checkpoint inhibitors that can be used in the present invention include CD27 agonists. CD27 agonists being studied in clinical trials include: varimumab (CDX-1127, Celldex Therapeutics), an agonistic anti-CD27 antibody, in head and neck squamous cell carcinoma, ovarian cancer, colorectal cancer, renal cell carcinoma and glioblastoma (NCT02335918); lymphoma (NCT01460134); and glioma and astrocytoma (NCT02924038).

[0361] Checkpoint inhibitors useful in the present invention include glucocorticoid-induced tumor necrosis factor receptor (GITR) agonists. GITR agonists being studied in clinical trials include: TRX518 (Leap Therapeutics), an agonist anti-GITR antibody in malignant melanoma and other solid tumor malignancies (NCT01239134 and NCT02628574); GWN323 (Novartis), an agonist anti-GITR antibody in solid tumors and lymphomas (NCT 02740270); INCAGN01876 (Incyte / Agenus), an agonist anti-GITR antibody in advanced cancers (NCT02697591 and NCT03126110); MK-4166 (Merck), an agonist anti-GITR antibody in solid tumors (NCT02132754); and MEDI1873 (Medimmune / AstraZeneca), an agonist anti-GITR antibody with human IgG1 Agonistic hexameric GITR-ligand molecule with Fc domain in advanced solid tumors (NCT02583165).

[0362] Checkpoint inhibitors that can be used in the present invention include inducible T cell co-stimulator (ICOS, also known as CD278) agonists. ICOS agonists being studied in clinical trials include: MEDI-570 (Medimmune), an agonistic anti-ICOS antibody, in lymphoma (NCT02520791); GSK3359609 (Merck), an agonistic anti-ICOS antibody, in Phase 1 (NCT02723955); JTX-2011 (Jounce Therapeutics), an agonistic anti-ICOS antibody, in Phase 1 (NCT02904226).

[0363] Checkpoint inhibitors useful in the present invention include killer IgG-like receptor (KIR) inhibitors. KIR inhibitors being studied in clinical trials include: levofloxacin (IPH2102 / BMS-986015, Innate Pharma / Bristol-Myers Squibb), an anti-KIR antibody, in leukemias (NCT01687387, NCT02399917, NCT02481297, NCT02599649), multiple myeloma (NCT02252263), and lymphoma (NCT01592370); IPH2101 (1-7F9, Innate Pharma), in myeloma (NCT01222286 and NCT01217203); and IPH4102 (Innate Pharma), an anti-KIR antibody that binds to three domains of the long cytoplasmic tail (KIR3DL2), in lymphoma (NCT02593045).

[0364] Checkpoint inhibitors useful in the present invention include CD47 inhibitors of the interaction between CD47 and signal regulatory protein alpha (SIRPα). CD47 / SIRPa inhibitors being studied in clinical trials include: ALX-148 (Alexo Therapeutics), an antagonist variant of (SIRPa) that binds to CD47 and prevents CD47 / SIRPa-mediated signaling, in Phase 1 (NCT03013218); TTI-621 (SIRPa-Fc, Trillium Therapeutics), a soluble recombinant fusion protein generated by linking the N-terminus of the CD47 binding domain of SIRPa to the Fc domain of human IgG1, which acts by binding to human CD47 and preventing it from delivering its "do not eat" signal to macrophages, in Phase 1 clinical trials (NCT02890368 and NCT02663518); CC-90002 (Celgene), an anti-CD47 antibody, in leukemia (NCT02641002); and Hu5F9-G4 (Forty Seven, Inc.), in colorectal neoplasms and solid tumors (NCT02953782), acute myeloid leukemia (NCT02678338), and lymphoma (NCT02953509).

[0365] Checkpoint inhibitors that can be used in the present invention include CD73 inhibitors. CD73 inhibitors being studied in clinical trials include MEDI9447 (Medimmune), an anti-CD73 antibody, in solid tumors (NCT02503774); and BMS-986179 (Bristol-Myers Squibb), an anti-CD73 antibody, in solid tumors (NCT02754141).

[0366] Checkpoint inhibitors that can be used in the present invention include agonists of stimulator of interferon genes protein (STING, also known as transmembrane protein 173 or TMEM173). Agonists of STING that are being studied in clinical trials include: MK-1454 (Merck), an agonist synthetic cyclic dinucleotide, in lymphoma (NCT03010176); and ADU-S100 (MIW815, Aduro Biotech / Novartis), an agonist synthetic cyclic dinucleotide, in Phase 1 (NCT02675439 and NCT03172936).

[0367] Checkpoint inhibitors that can be used in the present invention include CSF1R inhibitors. CSF1R inhibitors being studied in clinical trials include: pexidartinib (PLX3397, Plexxikon), a small molecule inhibitor of CSF1R, in colorectal cancer, pancreatic cancer, metastatic and advanced cancer (NCT02777710) and melanoma, non-small cell lung cancer, head and neck squamous cell carcinoma, gastrointestinal stromal tumor (GIST) and ovarian cancer (NCT02452424); and IMC-CS4 (LY302285 5, Lilly), an anti-CSF-1R antibody, in pancreatic cancer (NCT03153410), melanoma (NCT03101254), and solid tumors (NCT02718911); and BLZ945 (4-[2((1R,2R)-2-hydroxycyclohexylamino)-benzothiazol-6-yloxy]-pyridine-2-carboxylic acid methylamide, Novartis), an orally available inhibitor of CSF1R, in advanced solid tumors (NCT02829723).

[0368] Checkpoint inhibitors that can be used in the present invention include NKG2A receptor inhibitors. NKG2A receptor inhibitors being studied in clinical trials include monazumab (IPH2201, Innate Pharma), an anti-NKG2A antibody, in head and neck neoplasms (NCT02643550) and chronic lymphocytic leukemia (NCT02557516).

[0369] In some embodiments, the immune checkpoint inhibitor is selected from nivolumab, pembrolizumab, ipilimumab, avelumab, durvalumab, atezolizumab, or pirizumab.

[0370] 5. Purpose

[0371] The compounds and compositions described herein are generally useful for inhibiting eIF4E or mutants thereof.

[0372] The activity of compounds used as inhibitors of eIF4E or its mutants in the present invention can be analyzed in vitro, in vivo or in cell lines. In vitro assays include assays that determine inhibition of eIF4E or its mutants. Alternative in vitro assays quantify the ability of the inhibitors to bind to eIF4E. Detailed conditions for analyzing compounds used as inhibitors of eIF4E or its mutants in the present invention are described in the following examples.

[0373] The compounds provided are inhibitors of eIF4E and are therefore useful for treating one or more conditions associated with eIF4E activity. Thus, in certain embodiments, the present invention provides methods for treating eIF4E-mediated conditions, the methods comprising the step of administering a compound of the present invention or a pharmaceutically acceptable composition thereof to a patient in need thereof. In certain embodiments, the eIF4E-mediated condition 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.

[0374] As used herein, the term "treatment / treat / treating" refers to reversing, alleviating, delaying the onset of, or inhibiting the progression of a disease or disorder as described herein or one or more symptoms thereof. In some embodiments, therapy may be administered after one or more symptoms have occurred. In other embodiments, treatment may be administered when symptoms are absent. For example, treatment may be administered to susceptible individuals before the onset of symptoms (e.g., based on a history of symptoms and / or based on hereditary or other susceptibility factors). Treatment may also be continued after symptoms subside, for example to prevent or delay their recurrence.

[0375] As used herein, the term "eIF4E-mediated" disorder, disease and / or condition means any disease or other deleterious condition in which eIF4E or a mutant thereof is known to play a role, including but not limited to cell proliferative disorders. In some embodiments, the cell proliferative disorder is a cancer described herein.

[0376] cancer

[0377] In some embodiments, cancer includes, but is 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 (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, endotheliosarcoma, lymphangiosarcoma, lymphoendotheliosarcoma, synovioma, mesothelioma, Ewing's tumor, leiomyosarcoma, rhabdomyosarcoma, colon cancer, pancreatic cancer, breast cancer, ovarian cancer, prostate cancer, squamous cell carcinoma, basal cell carcinoma, adenocarcinoma, sweat gland carcinoma, sebaceous gland carcinoma, papillary carcinoma, papillary adenocarcinoma, cystadenocarcinoma, medullary carcinoma, bronchogenic carcinoma, renal cell carcinoma, hepatoma, bile duct carcinoma, choriocarcinoma, seminoma, embryonal tumor, Wilms' tumor, tumor), cervical cancer, uterine cancer, testicular cancer, lung cancer, small cell lung cancer, bladder cancer, epithelial cancers, gliomas, astrocytomas, glioblastoma multiforme (GBM, also called glioblastoma), medulloblastoma, craniopharyngioma, ependymoma, pinealoma, hemangioblastoma, acoustic neuroma, oligodendroglioma, schwannoma, neurofibrosarcoma, meningioma, melanoma, neuroblastoma, and retinoblastoma).

[0378] In some embodiments, the cancer is a glioma, an astrocytoma, a glioblastoma multiforme (GBM, also called a glioblastoma), a medulloblastoma, a craniopharyngioma, an ependymoma, a pinealoma, a hemangioblastoma, an acoustic neuroma, an oligodendroglioma, a schwannoma, a neurofibrosarcoma, a meningioma, a melanoma, a neuroblastoma, or a retinoblastoma.

[0379] In some embodiments, the cancer is an acoustic neuroma, an astrocytoma (e.g., grade I-pilocytic astrocytoma, grade II-low-grade astrocytoma, grade III-pleomorphic astrocytoma, or grade IV-glioblastoma (GBM)), a chordoma, a CNS lymphoma, a craniopharyngioma, a brainstem glioma, an ependymoma, a mixed glioma, an optic nerve glioma, a subependymoma, a medulloblastoma, a meningioma, a metastatic brain tumor, an oligodendroglioma, a pituitary tumor, a primary neuroectodermal (PNET) tumor, or a schwannoma. In some embodiments, the cancer is a type that is more common in children than in adults, such as a brainstem glioma, a craniopharyngioma, an ependymoma, a juvenile pilocytic astrocytoma (JPA), a medulloblastoma, an optic nerve glioma, a pineal tumor, a primary neuroectodermal tumor (PNET), or a rhabdoid tumor. In some embodiments, the patient is an adult. In some embodiments, the patient is a child or a pediatric patient.

[0380] In another embodiment, cancers include, but are not limited to, mesothelioma, hepatobiliary (liver and bile duct) cancer, bone cancer, pancreatic cancer, skin cancer, cancer of the head or neck, cutaneous or intraocular melanoma, ovarian cancer, colon cancer, rectal cancer, cancer of the anal region, stomach cancer, gastrointestinal tract (stomach, colorectal and duodenum) cancer, uterine cancer, fallopian tube cancer, endometrial cancer, cervical cancer, vaginal cancer, vulvar cancer, Hodgkin's disease, esophageal cancer, small intestine cancer, endocrine system cancer, thyroid cancer, parathyroid cancer, adrenal cancer, soft tissue sarcoma, urethral cancer, penile cancer, prostate cancer, testicular cancer, chronic or acute leukemia, chronic myeloid leukemia, lymphocytic lymphoma, bladder cancer, kidney or ureter cancer, renal cell carcinoma, renal pelvis cancer, non-Hodgkin's lymphoma, spinal axis tumors (spinal axis tumors), tumor), brain stem glioma, pituitary adenoma, adrenocortical carcinoma, gallbladder cancer, multiple myeloma, bile duct cancer, fibrosarcoma, neuroblastoma, retinoblastoma, or a combination of one or more of the foregoing cancers.

[0381] In some embodiments, the cancer is selected from the group consisting of hepatocellular carcinoma, ovarian cancer, ovarian epithelial carcinoma, or fallopian tube cancer; papillary serous cystadenocarcinoma or uterine papillary serous carcinoma (UPSC); prostate cancer; testicular cancer; gallbladder cancer; hepatocholangiocarcinoma; synovial sarcoma of soft tissue and bone; rhabdomyosarcoma; osteosarcoma; chondrosarcoma; Ewing's sarcoma; anaplastic thyroid cancer; adrenocortical adenoma; pancreatic cancer; pancreatic duct carcinoma or pancreatic adenocarcinoma; gastrointestinal tract / gastric (GIST) cancer; lymphoma; squamous cell carcinoma of the head and neck (SCCHN); salivary gland cancer; glioma or brain cancer; neurofibroma-1-associated malignant peripheral nerve sheath tumor (MPNST); Waldenstrom's macroglobulinemia, or medulloblastoma.

[0382] In some embodiments, the cancer is selected from hepatocellular carcinoma (HCC), hepatoblastoma, colon cancer, rectal cancer, ovarian cancer, ovarian epithelial carcinoma, fallopian tube carcinoma, serous papillary cystadenoma, uterine papillary serous carcinoma (UPSC), cholangiohepatoma, synovial sarcoma of soft tissue and bone, rhabdomyosarcoma, osteosarcoma, anaplastic thyroid cancer, adrenocortical adenoma, pancreatic cancer, pancreatic duct carcinoma, pancreatic adenocarcinoma, glioma, neurofibroma-1-associated malignant peripheral nerve sheath tumor (MPNST), Waldenstrom's macroglobulinemia, or medulloblastoma.

[0383] In some embodiments, the cancer is a solid tumor, such as a sarcoma, carcinoma, or lymphoma. Solid tumors generally contain abnormal tissue masses that do not usually include cysts or fluid areas. In some embodiments, the cancer is selected from: renal cell carcinoma or kidney cancer; hepatocellular carcinoma (HCC) or hepatoblastoma or liver cancer; melanoma; breast cancer; colorectal carcinoma or colorectal cancer. cancer); colon cancer; rectal cancer; anal cancer; lung cancer, such as non-small cell lung cancer (NSCLC) or small cell lung cancer (SCLC); ovarian cancer, epithelial ovarian cancer, ovarian cancer, or fallopian tube cancer; serous papillary cystadenoma or uterine papillary serous carcinoma (UPSC); prostate cancer; testicular cancer; gallbladder cancer; cholangiohepatoma; synovial sarcoma of soft tissue and bone; rhabdomyosarcoma; osteosarcoma; chondrosarcoma; Ewing's sarcoma; anaplastic thyroid cancer; adrenocortical carcinoma; pancreatic cancer; pancreatic duct carcinoma or pancreatic adenocarcinoma; gastrointestinal tract / gastric (GIST) cancer; lymphoma; squamous cell carcinoma of the head and neck (SCCHN); salivary gland cancer; glioma or brain cancer; neurofibroma-1-associated malignant peripheral nerve sheath tumor (MPNST); Waldenstrom's macroglobulinemia or medulloblastoma.

[0384] 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, ovarian epithelial cancer, ovarian cancer, fallopian tube cancer, serous papillary cystadenoma, uterine papillary serous carcinoma (UPSC), bile duct hepatoma, synovial sarcoma of soft tissue and bone, rhabdomyosarcoma, osteosarcoma, chondrosarcoma, anaplastic thyroid cancer, adrenocortical carcinoma, pancreatic cancer, pancreatic duct carcinoma, pancreatic adenocarcinoma, glioma, brain cancer, neurofibroma-1-associated malignant peripheral nerve sheath tumor (MPNST), Waldenstrom's macroglobulinemia, or medulloblastoma.

[0385] In some embodiments, the cancer is selected from hepatocellular carcinoma (HCC), hepatoblastoma, colon cancer, rectal cancer, ovarian cancer, ovarian epithelial cancer, ovarian cancer, fallopian tube cancer, serous papillary cystadenoma, uterine papillary serous carcinoma (UPSC), cholangiohepatoma, synovial sarcoma of soft tissue and bone, rhabdomyosarcoma, osteosarcoma, anaplastic thyroid cancer, adrenocortical carcinoma, pancreatic cancer, pancreatic duct carcinoma, pancreatic adenocarcinoma, glioma, neurofibroma-1-associated malignant peripheral nerve sheath tumor (MPNST), Waldenstrom's macroglobulinemia, or medulloblastoma.

[0386] 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 (ovarian cancer / ovarian carcinoma). In some embodiments, the cancer is ovarian epithelial cancer. In some embodiments, the cancer is fallopian tube cancer. In some embodiments, the cancer is serous papillary cystadenoma. In some embodiments, the cancer is uterine papillary serous carcinoma (UPSC). In some embodiments, the cancer is bile duct hepatoma. In some embodiments, the cancer is synovial sarcoma of soft tissue and bone. In some embodiments, the cancer is rhabdomyosarcoma. In some embodiments, the cancer is osteosarcoma. In some embodiments, the cancer is anaplastic thyroid cancer. In some embodiments, the cancer is adrenocortical carcinoma. In some embodiments, the cancer is pancreatic cancer or pancreatic duct cancer. In some embodiments, the cancer is pancreatic adenocarcinoma. In some embodiments, the cancer is glioma. In some embodiments, the cancer is malignant peripheral nerve sheath tumor (MPNST). In some embodiments, the cancer is neurofibromatosis-1-associated MPNST. In some embodiments, the cancer is Waldenstrom's macroglobulinemia. In some embodiments, the cancer is medulloblastoma.

[0387] 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, bile duct cancer, bladder cancer, bone cancer, brain tumor, astrocytoma, brain and spinal cord tumor, brain stem glioma, atypical teratoid / rhabdoid tumor of the central nervous system, embryonal tumor of the central nervous system, breast cancer, bronchial tumor, Burkitt lymphoma (Burkitt lymphoma). Lymphoma), carcinoid tumors, cancer of unknown primary site, central nervous system cancer, cervical cancer, childhood cancer, chordoma, chronic lymphocytic leukemia (CLL), chronic myeloid leukemia (CML), chronic myeloproliferative disease, colon cancer, colorectal cancer, craniopharyngioma, cutaneous T-cell lymphoma, ductal carcinoma in situ (DCIS), embryonal tumors, endometrial cancer, ependymoblastoma, ependymoma, esophageal cancer, sensitive neuroblastoma, Ewing's sarcoma, extracranial germ cell tumor, extragonadal germ cell tumor, extrahepatic bile duct cancer, eye cancer, fibrohistiocytoma 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, heart cancer, hepatocellular carcinoma, histiocytosis, Langerhans Cell carcinoma Cancer), Hodgkin's lymphoma, hypopharyngeal cancer, intraocular melanoma, islet cell tumor, Kaposi's sarcomaSarcoma), kidney cancer, Langerhans cell histiocytosis, laryngeal cancer, leukemia, lip and oral 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, occult primary metastatic squamous neck cancer, midline tract cancer involving the 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 bone Myeloproliferative disorders, nasal cancer, paranasal sinus cancer, nasopharyngeal cancer, neuroblastoma, non-Hodgkin's lymphoma, non-small cell lung cancer, oral cancer, oral cancer, lip cancer, oropharyngeal cancer, osteosarcoma, ovarian cancer, pancreatic cancer, papilloma, paraganglioma, paranasal sinus cancer, nasal cancer, parathyroid cancer, penile cancer, pharyngeal cancer, pheochromocytoma, moderately differentiated pineal parenchymal tumor, pinealoblastoma, 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, ureteral cancer, transitional cell carcinoma, retinoblastoma, rhabdomyosarcoma, salivary gland cancer, sarcoma, Sezary syndrome Syndrome), skin cancer, small cell lung cancer, small intestine cancer, soft tissue sarcoma, squamous cell carcinoma, occult primary squamous neck cancer, head and neck squamous cell carcinoma (HNSCC), gastric cancer, supratentorial primitive neuroectodermal tumor, T-cell lymphoma, testicular cancer, pharyngeal cancer, thymoma, thymic carcinoma, thyroid cancer, transitional cell carcinoma of the renal pelvis and ureter, triple-negative breast cancer (TNBC), gestational trophoblastic tumor, childhood anomaly cancer of unknown primary, urethral cancer, uterine cancer, uterine sarcoma, Waldenstrom's macroglobulinemia, or Wilms' tumor.

[0388] 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, kidney cancer (including renal clear cell carcinoma and renal papillary cell carcinoma) and gastric cancer.

[0389] 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.

[0390] In some embodiments, the cancer is small cell lung cancer, non-small cell lung cancer, colorectal cancer, multiple myeloma, or AML.

[0391] The invention further features methods and compositions for the diagnosis, prognosis, and treatment of virus-associated cancers, including: human immunodeficiency virus (HIV)-associated solid tumors; human papillomavirus (HPV)-16-positive incurable solid tumors; and adult T-cell leukemia, which is caused by human T-cell leuke mia virus type I (HTLV-I) and is a highly aggressive form of CD4+ T-cell leukemia characterized by clonal integration of HTLV-I in leukemic cells (see https: / / clinicaltrials.gov / ct2 / show / study / NCT02631746); and virus-associated tumors in gastric cancer, nasopharyngeal cancer, cervical cancer, vaginal cancer, vulvar cancer, head and neck squamous cell carcinoma, and Merkel cell carcinoma. (See https: / / clinicaltrials.gov / ct2 / show / study / NCT02488759; also see https: / / clinicaltrials.gov / ct2 / show / study / NCT0240886; https: / / clinicaltrials.gov / ct2 / show / NCT02426892)

[0392] In some embodiments, the present invention provides a method for treating a tumor in a patient in need thereof, the method comprising administering Compound II or its pharmaceutical salt or composition to the patient, and an immuno-oncology agent as described herein. In some embodiments, the tumor comprises any one of the cancers described herein. In some embodiments, the tumor comprises a 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).

[0393] In some embodiments, a tumor is treated by suppressing further growth of the tumor. In some embodiments, a tumor is treated by reducing the size (e.g., volume or mass) of the tumor by at least 5%, 10%, 25%, 50%, 75%, 90%, or 99% relative to the size of the tumor before treatment. In some embodiments, a tumor is treated by reducing the amount of the patient's tumor by at least 5%, 10%, 25%, 50%, 75%, 90%, or 99% relative to the amount of the tumor before treatment.

[0394] The compounds and compositions according to the methods of the present invention can be administered using any amount and any route of administration that is effective for treating or reducing the severity of cancer. The exact amount required will vary from individual to individual depending on factors such as the species, age and general condition of the individual, the severity of the disease or illness, the specific agent, its mode of administration, etc. The compounds and compositions according to the methods of the present invention are preferably formulated in unit dosage form for ease of administration and uniform dosage. As used herein, the expression "unit dosage form" refers to a physical discrete unit of a medicament suitable for a patient to be treated. However, it should be understood that the total daily dosage of the compounds and compositions can be determined by the attending physician within the scope of reasonable medical judgment. The specific effective dose for any particular patient or organism will be determined according to a variety of factors, including the condition to be treated and the severity of the condition; the activity of the specific compound used; the specific composition used; the patient's age, weight, general health, sex and diet; the administration time, administration route and excretion rate of the specific compound used; the duration of treatment; drugs used in combination or simultaneously with the specific compound used; and factors as are well known in the medical technology. As used herein, the term "patient" means an animal, preferably a mammal, and most preferably a human.

[0395] The pharmaceutically acceptable compositions of the present invention can be administered to humans and other animals orally, rectally, parenterally, intracisternal, intravaginal, intraperitoneal, topically (such as by powder, ointment or drops), buccally (such as oral or nasal spray), etc., depending on the severity of the disease or condition being treated. In certain embodiments, the compounds of the present invention can be administered orally or parenterally at the following dosage levels to obtain the desired therapeutic effect: about 0.01 mg to about 50 mg per kg of subject body weight per day, once or more per day, and preferably about 1 mg to about 25 mg.

[0396] Liquid dosage forms for oral administration include, but are not limited to, pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups, and elixirs. In addition to the active compound, the liquid dosage form may contain inert diluents commonly used in the art, such as water or other solvents; solubilizers and emulsifiers, such as ethanol, isopropanol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils (especially cottonseed oil, peanut oil, corn oil, germ oil, olive oil, castor oil, and sesame oil), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycol, and fatty acid esters of sorbitan; and mixtures thereof. In addition to inert diluents, oral compositions may also include adjuvants, such as wetting agents, emulsifiers and suspending agents, sweeteners, flavoring agents, and aromatics.

[0397] Injectable preparations, such as sterile injectable aqueous or oily suspensions, can be prepared using suitable dispersants or wetting agents and suspending agents according to known techniques. Sterile injectable preparations can also be sterile injectable solutions, suspensions or emulsions in nontoxic parenteral acceptable diluents or solvents, such as solutions in 1,3-butanediol. Among acceptable vehicles and solvents, water, USP Ringer's solution and isotonic sodium chloride solution can be used. In addition, sterile fixed oils are commonly used as solvents or suspension media. For this purpose, any mild fixed oil can be used, including synthetic monoglycerides or diglycerides. In addition, fatty acids such as oleic acid are used to prepare injectables.

[0398] The injectable formulations can be sterilized, for example, by filtration through a bacteria-retaining filter or by incorporating sterilizing agents in the form of sterile solid compositions that can be dissolved or dispersed in sterile water or other sterile injectable medium immediately prior to use.

[0399] To prolong the effects of the compounds described herein, it is generally desirable to slow down the absorption of the compounds from subcutaneous or intramuscular injections. This can be achieved by using a liquid suspension of crystalline or amorphous materials with poor water solubility. In this way, the absorption rate of the compound is determined according to its dissolution rate, which can be determined according to the crystal size and crystalline form. Alternatively, delayed absorption of the compound administered parenterally is achieved by dissolving or suspending the compound in an oil vehicle. Injectable storage forms are manufactured by forming a microcapsule matrix of the compound in a biodegradable polymer such as polylactide-polyglycolide. Depending on the ratio of the compound to the polymer and the properties of the specific polymer used, the compound release rate can be controlled. Examples of other biodegradable polymers include poly(orthoesters) and poly(anhydrides). Storage tank injectable preparations are also prepared by embedding the compound in a liposome or microemulsion compatible with body tissues.

[0400] Compositions for rectal or vaginal administration are preferably suppositories which can be prepared by mixing the compounds of the present invention with suitable non-irritating excipients or carriers such as cocoa butter, polyethylene glycol; or suppository waxes which are solid at ambient temperature but liquid at body temperature and therefore melt in the rectum or vaginal cavity and release the active compound.

[0401] 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 starch, lactose, sucrose, glucose, mannitol and silicic acid, b) binders, such as carboxymethylcellulose, alginates, gelatin, polyvinyl pyrrolidone, sucrose and acacia; c) humectants, such as glycerol, d) disintegrators, such as agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates and sodium carbonate, e) disintegrators, such as paraffin, f) absorption promoters, such as quaternary ammonium compounds, g) wetting agents, such as cetyl alcohol and glyceryl monostearate, h) absorbents, such as kaolin and bentonite, and / or 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.

[0402] Solid compositions of similar types can also be used as fillers in soft-filled and hard-filled gelatin capsules using excipients such as lactose (lactose or milk sugar) and high molecular weight polyethylene glycol. Solid dosage forms of tablets, dragees, capsules, pills and granules can be prepared with coatings and shells, such as other coatings known in enteric coatings and pharmaceutical formulation technology. It can optionally contain an opacifier and can also have a composition that releases the active ingredient only or preferentially in a certain part of the intestinal tract or optionally in a delayed manner. Examples of usable embedded compositions include polymeric substances and waxes. Solid compositions of similar types can also be used as fillers in soft-filled and hard-filled gelatin capsules using excipients such as lactose and high molecular weight polyethylene glycol.

[0403] The active compound may also be present in a microencapsulated form together with one or more excipients as indicated above. The solid dosage forms of tablets, dragees, capsules, pills and granules may be prepared with coatings and shells (such as enteric coatings, release-control coatings and other coatings known in pharmaceutical formulation techniques). In such solid dosage forms, the active compound may be blended with at least one inert diluent (such as sucrose, lactose or starch). According to conventional practice, such dosage forms may also include additional substances in addition to the inert diluent, such as tableting lubricants and other tableting aids, such as magnesium stearate and microcrystalline cellulose. In the case of capsules, tablets and pills, the dosage form may also include a buffer. It may optionally contain an opacifier, and may also have a composition that releases the active ingredient only in or preferentially in a certain part of the intestinal tract or optionally in a delayed manner. Examples of usable embedded compositions include polymeric substances and waxes.

[0404] The dosage form for topical or transdermal administration of the compound of the present invention includes ointment, paste, cream, lotion, gel, powder, solution, spray, inhalant or patch. The active component is blended with a pharmaceutically acceptable carrier and any desired preservative or buffer as required under sterile conditions. Ophthalmic preparations, ear drops and eye drops are also encompassed within the scope of the present invention. In addition, the present invention encompasses the use of transdermal patches, which have the additional advantage of controlling the delivery of compounds to the body. Such dosage forms can be prepared by dissolving or distributing the compound in an appropriate medium. Absorption enhancers can also be used to increase the transdermal amount of the compound. The rate can be controlled by providing a rate-controlling membrane or by dispersing the compound in a polymer matrix or gel.

[0405] The following examples are provided for illustrative purposes only and are not to be construed as limiting the present invention in any way.

[0406] Example

[0407] As depicted in the following examples, in certain exemplary embodiments, compounds are prepared according to the following general procedures. It should be understood that although the general methods depict the synthesis of certain compounds of the present invention, the following general methods and other methods generally known to those skilled in the art can be applied to all compounds as described herein and subclasses and species of each of these compounds.

[0408] Example 1. Synthesis of compounds I-1 to I-48

[0409] Process 1: Pathways a, b, c, e, and f

[0410]

[0411] Process 2: Path 1, 2, 3, 4, 5

[0412]

[0413] Scheme 3: Pathway to compound 6

[0414]

[0415] Process 4: Pathways 7, 8, 9, and 10

[0416]

[0417] Process 5: Routes from I-1 to I-6, I-11 to I-15, I-18 to I-23, I-28 to I-33, I-38 to I-43

[0418]

[0419] Process 6: Routes from I-7 to I-10, I-16, I-17, I-24 to I-27, I-34 to I-37, I-44 to I-46

[0420]

[0421] General Information: All evaporations were performed in vacuo using a rotary evaporator. Analytical samples were dried in vacuo (1-5 mmHg) at rt. Thin layer chromatography (TLC) was performed on silica gel plates and spots were observed by UV light (214 nm and 254 nm). Column and flash chromatography 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 with 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), integral value.

[0422] LCMS spectra were obtained on an Agilent 1200 series 6110 or 6120 mass spectrometer with electrospray ionization and unless otherwise specified, general LCMS conditions were as follows:

[0423] 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% [CH 3 CN + 0.05% TFA] to 0% [water + 0.05% TFA] and 100% [CH 3CN+0.05% TFA], followed by 0.4 min under this condition, and finally 95% [water+0.05% TFA] and 5% [CH 3 CN + 0.05% TFA]).

[0424] 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% [CH 3 CN + 0.05% TFA] to 0% [water + 0.05% TFA] and 100% [CH 3 CN+0.05% TFA], followed by 1.4 min under this condition, and finally changed to 95% [water+0.05% TFA] and 5% [CH 3 CN+0.05% TFA] and 0.7 min under this condition).

[0425] 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: 95% [water + 10 mM NH 4 HCO 3 ] and 5% [CH 3 CN] to 0% [water + 10 mM NH 4 HCO 3 ] and 100% [CH 3 CN], then under this condition for 1.4 min, and finally changed to 95% [water + 10 mM NH 4 HCO 3 ] and 5% [CH 3 CN], and 0.7min under this condition. )

[0426] Synthesis of 1-(3,4-dichlorophenyl)-3-methylbutan-1-one (a-1)

[0427]

[0428] To a solution of s-1 (10.0 g, 58.1 mmol) in THF (100 mL) was added isobutylmagnesium bromide (1.0 M in THF, 87.1 mL, 87.1 mmol). The reaction was stirred at room temperature for 16 h. When the reaction was complete, it was poured into NH4 The mixture was added with aqueous Cl solution (saturated, 500 mL) and extracted with EtOAc (100 mL × 3). The organic phases were combined and washed with H 2 O (100 mL) and brine (80 mL), followed by anhydrous Na 2 SO 4 Drying, concentration and purification by silica gel column chromatography (petroleum ether / ethyl acetate=20 / 1) gave a-1 (7.50 g, 55.8% yield) as a yellow oil.

[0429] Synthesis of 2-bromo-1-(3,4-dichlorophenyl)-3-methylbutan-1-one (a-2)

[0430]

[0431] A mixture of a-1 (7.50 g, 32.5 mmol) and PTAT (18.3 g, 48.7 mmol) in THF (150 mL) was stirred at room temperature overnight. When the reaction was complete, it was concentrated and the residue was dissolved in H 2 O (100 mL), and then extracted with EtOAc (100 mL × 2). The organic layers were combined and washed with H 2 O (60 mL x 2) and brine (80 mL), and then anhydrous Na 2 SO 4 The solution was concentrated to give the crude product, which was used directly in the next step without further purification to afford a-2 (10.1 g, 100% yield) as a brown oil.

[0432] Synthesis of 1-(3,4-dichlorophenyl)-3-methyl-2-thiocyanatobutan-1-one (a)

[0433]

[0434] A mixture of a-2 (10.1 g, 32.5 mmol) and NaSCN (5.26 g, 64.9 mmol) in EtOH (100.0 mL) was stirred at 100° C. for 6 h. When the reaction was completed, it was concentrated and purified by silica gel column chromatography (petroleum ether / ethyl acetate=10 / 1) to give a (5.32 g, 57.0% yield) as a white solid.

[0435] Table 1-1: Characterization data of compounds af

[0436]

[0437] Synthesis of (Z)-2-cyano-3-phenylacrylate (1-2)

[0438]

[0439] To a mixture of 1-1 (5.00 g, 47.2 mmol) and methyl 2-cyanoacetate (5.61 g, 56.6 mmol) in MeOH (100 mL) was added piperidine (5 drops). The reactant was stirred at room temperature for 4 h. When the reaction was complete, the reaction mixture was filtered, and the residue was washed with MeOH (2.0 mL×2) and dried to give 1-2 (6.50 g, 73.7% yield) as a white solid.

[0440] Synthesis of methyl 3-amino-2-benzylpropionate (1)

[0441]

[0442] In H 2 A mixture of 1-2 (6.50 g, 34.7 mmol) and Raney nickel (2.00 g) in MeOH (800 mL) was stirred overnight at room temperature under atmosphere. When the reaction was complete, the mixture was filtered, and the filtrate was concentrated to give a crude product, which was purified by silica gel column chromatography (CH 2 Cl 2 / CH 3 OH=50 / 1) to afford 1 (550 mg, 7.5% yield) as a colorless oil.

[0443] Synthesis of methyl 2-cyano-4-phenylbutyrate (6-2)

[0444]

[0445] 6-1 (4.00 g, 21.6 mmol), methyl 2-cyanoacetate (10.7 g, 108.1 mmol) and K 2 CO 3 A mixture of (8.95 g, 64.8 mmol) in MeCN (200 mL) was stirred overnight at 70° C. When the reaction was completed, the mixture was concentrated and purified by silica gel column chromatography (petroleum ether / ethyl acetate=30 / 1) to give 6-2 (3.20 g, 72.8% yield) as a yellow oil.

[0446] Synthesis of methyl 2-(aminomethyl)-4-phenylbutyrate (6)

[0447]

[0448] In H 2 A mixture of 6-2 (3.20 g, 34.7 mmol) and Raney nickel (2.00 g) in MeOH (1000 mL) was stirred overnight at room temperature under atmosphere. When the reaction was complete, the mixture was filtered, and the filtrate was concentrated to give a crude product, which was purified by silica gel column chromatography (CH2 Cl 2 / CH 3 OH=30 / 1) to afford 6 (2.00 g, 61.3% yield) as a colorless oil.

[0449] Synthesis of tert-butyl 7-formyl-1H-indole-1-carboxylate (7-2)

[0450]

[0451] To a mixture of 7-1 (4.00 g, 27.6 mmol) and DMAP (5.05 g, 41.3 mmol) in MeCN (150 mL) was added Boc 2 O (6.61 g, 30.3 mmol). The reactant was stirred at room temperature for 3 h. When the reaction was completed, the reaction mixture was filtered, and the residue was washed with MeOH (2.0 mL×2) and dried to give 7-2 (3.60 g, 53.3% yield) as a white solid.

[0452] Synthesis of (Z)-7-(2-cyano-3-methoxy-3-oxoprop-1-enyl)-1H-indole-1-carboxylic acid tert-butyl ester (7-3)

[0453]

[0454] To a mixture of 7-2 (3.60 g, 14.7 mmol) and methyl 2-cyanoacetate (1.75 g, 17.6 mmol) in MeOH (80 mL) was added piperidine (3 drops). The reactants were stirred at room temperature for 4 h. When the reaction was complete, the reaction mixture was filtered, and the residue was washed with MeOH (2.0 mL × 2) and dried to give 7-3 (4.00 g, 83.5% yield) as a white solid.

[0455] Synthesis of tert-butyl 7-(2-(aminomethyl)-3-methoxy-3-oxopropyl)-1H-indole-1-carboxylate (7)

[0456]

[0457] In H 2 A mixture of 7-3 (4.00 g, 12.3 mmol) and Raney nickel (2.00 g) in MeOH (1000 mL) was stirred overnight at room temperature under atmosphere. When the reaction was complete, the mixture was filtered, and the filtrate was concentrated to give a crude product, which was purified by silica gel column chromatography (CH 2 Cl 2 / CH 3 OH=30 / 1) to afford 7 (1.40 g, 34.4% yield) as a colorless oil.

[0458] Table 1-2: Characterization data of compounds 1-10

[0459]

[0460]

[0461] Synthesis of methyl 2-benzyl-3-(4-(3,4-dichlorophenyl)-5-isopropylthiazol-2-ylamino)propanoate (1a)

[0462]

[0463] A mixture of a (100 mg, 0.347 mmol) and 1 (80.5 mg, 0.416 mmol) in EtOH (4.00 mL) was stirred at 60 °C overnight. When the reaction was complete, the mixture was analyzed by preparative TLC (CH 2 Cl 2 / CH 3 OH=120 / 1) to afford 1a (80.0 mg, 49.8% yield) as a yellow solid.

[0464] Synthesis of 2-benzyl-3-(4-(3,4-dichlorophenyl)-5-isopropylthiazol-2-ylamino)propionic acid (I-1)

[0465]

[0466] 1a (80.0 mg, 0.173 mmol) was dissolved in THF / MeOH / H 2 LiOH (2.0 M in HO) was added to the solution in HO (v / v / v = 4 / 1 / 1, 10 mL). 2 O, 0.22 mL). The reaction was stirred at room temperature for 4 h. When the reaction was complete, the resulting reaction was concentrated and then washed with H 2 O (10 mL), and the pH was adjusted to 4-5 with HCl (1.0 M). The mixture was extracted with EtOAc (40 mL×2), and the combined organic phases were washed with brine (30 mL), and dried over anhydrous Na 2 SO 4 After drying and concentration, the residue was purified by preparative HPLC to give 1-1 (30.0 mg, 38.7% yield) as a white solid.

[0467] Table 1-3: Characterization data of compounds

[0468]

[0469]

[0470]

[0471]

[0472]

[0473]

[0474]

[0475]

[0476]

[0477] Synthesis of tert-butyl 7-(2-((4-(3,4-dichlorophenyl)-5-isopropylthiazol-2-ylamino)methyl)-3-methoxy-3-oxopropyl)-1H-indole-1-carboxylate (7a-1)

[0478]

[0479] A mixture of a (100 mg, 0.347 mmol) and 7 (138 mg, 0.416 mmol) in EtOH (4.00 mL) was stirred at 60 °C overnight. When the reaction was complete, the mixture was analyzed by preparative TLC (CH 2 Cl 2 / CH 3 OH=120 / 1) to afford 7a-1 (100.0 mg, 47.8% yield) as a yellow solid.

[0480] Synthesis of 3-(1-(tert-butoxycarbonyl)-1H-indol-7-yl)-2-((4-(3,4-dichlorophenyl)-5-isopropylthiazol-2-ylamino)methyl)propanoic acid (7a-2)

[0481]

[0482] 7a-1 (100.0 mg, 0.166 mmol) was dissolved in THF / MeOH / H 2 LiOH (2.0 M in HO) was added to the solution in HO (v / v / v = 4 / 1 / 1, 10 mL). 2 O, 0.21 mL). The reaction was stirred at room temperature for 4 h. When the reaction was complete, the resulting reaction was concentrated and then washed with H 2 O (10.0 mL), and the pH was adjusted to 4-5 with HCl (1.0 M). The mixture was extracted with EtOAc (40.0 mL×2), and the combined organic phases were washed with brine (30.0 mL), and dried over anhydrous Na 2 SO4 Drying and concentration gave 7a-2 (80.0 mg, 81.9% yield) as a white solid.

[0483] Synthesis of 2-((1H-indol-7-yl)methyl)-3-(4-(3,4-dichlorophenyl)-5-isopropylthiazol-2-ylamino)propanoic acid (I-7)

[0484]

[0485] A mixture of 7a-2 (80.0 mg, 0.136 mmol) in HCl (4.0 M in dioxane, 5.00 mL) was stirred overnight at 40° C. When the reaction was complete, it was concentrated to give a crude product, which was purified by preparative HPLC to give I-7 (15.0 mg, 22.6% yield) as an off-white solid.

[0486] Table 1-4: Characterization data of compounds

[0487]

[0488]

[0489]

[0490]

[0491]

[0492]

[0493] Example 2. Synthesis of compounds I-49 to I-118

[0494] Scheme 1: Pathways to compounds a, b, c, 100-107, 115, 119, 128

[0495]

[0496] Scheme 2: Pathway to compounds 108 and 109

[0497]

[0498] Scheme 3: Pathway to compound 110

[0499]

[0500] Scheme 4: Pathway to compound 129

[0501]

[0502] Scheme 5: Pathway to compound 137

[0503]

[0504] Scheme 6: Pathway to compound 144

[0505]

[0506] Scheme 7: Pathways of compounds b-1 to b-5, b-7 to b-11, b-16 to b-18, b-23, b-37 to b-40

[0507]

[0508] Scheme 8: Pathways to compounds b-6, b-12, b-14, b-15, b-22, b-26, b-29, b-31, b-32, b-35

[0509]

[0510] Scheme 9: Pathway to compounds b-19 and b-20

[0511]

[0512] Scheme 10: Pathway to compounds b-21 and b-24

[0513]

[0514] Scheme 10: Pathway to compounds b-27 and b-36

[0515]

[0516] Scheme 11: Pathway to compound b-28

[0517]

[0518] Scheme 12: Pathway to compound b-30

[0519]

[0520] Scheme 13: Pathway to compound b-33

[0521]

[0522] Scheme 13: Pathway to compound b-34

[0523]

[0524] Process 14: Pathways from I-47 to I-52, I-56, I-57, I-59 to I-109, I-86 to I-88, I-93 to I-96, I-98, I-100, I-103, I-105 to I-109, I-111, I-112, I-117

[0525]

[0526] Process 15: Path from I-53 to I-55 and I-110

[0527]

[0528] Process 16: I-58 and I-118 pathways

[0529]

[0530] Process 17: I-85 Pathway

[0531]

[0532] Process 18: Pathway from I-89 to I-92

[0533]

[0534] Process 19: I-97 Pathway

[0535]

[0536] Process 20: I-99 Pathway

[0537]

[0538] Process 20: I-101 Pathway

[0539]

[0540] Process 21: I-104 Pathway

[0541]

[0542] Process 22: Pathway from I-113 to I-116

[0543]

[0544] General Information: All evaporations were performed in vacuo using a rotary evaporator. Analytical samples were dried in vacuo (1-5 mmHg) at rt. Thin layer chromatography (TLC) was performed on silica gel plates and spots were observed by UV light (214 nm and 254 nm). Column and flash chromatography 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 with 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), integral value.

[0545] LCMS spectra were obtained on an Agilent 1200 series 6110 or 6120 mass spectrometer with electrospray ionization and unless otherwise specified, general LCMS conditions were as follows:

[0546] 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% [CH 3 CN + 0.05% TFA] to 0% [water + 0.05% TFA] and 100% [CH 3 CN+0.05% TFA], followed by 0.4 min under this condition, and finally 95% [water+0.05% TFA] and 5% [CH 3 CN + 0.05% TFA]).

[0547] 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% [CH 3 CN + 0.05% TFA] to 0% [water + 0.05% TFA] and 100% [CH 3 CN+0.05% TFA], followed by 1.4 min under this condition, and finally changed to 95% [water+0.05% TFA] and 5% [CH 3 CN+0.05% TFA] and 0.7 min under this condition).

[0548] 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: 95% [water + 10 mM NH 4 HCO 3 ] and 5% [CH 3 CN] to 0% [water + 10 mM NH 4 HCO 3 ] and 100% [CH 3 CN], then under this condition for 1.4 min, and finally changed to 95% [water + 10 mM NH 4 HCO 3 ] and 5% [CH 3 CN], and 0.7min under this condition. )

[0549] Synthesis of 1-(3,4-dichlorophenyl)-3-methylbutan-1-one (a-1)

[0550]

[0551] To a solution of s-1 (10.0 g, 58.1 mmol) in THF (100 mL) was added isobutylmagnesium bromide (1.0 M in THF, 87.1 mL, 87.1 mmol). The reaction was stirred at room temperature for 16 h. When the reaction was complete, it was poured into NH 4 The mixture was added with aqueous Cl solution (saturated, 500 mL) and extracted with EtOAc (100 mL × 3). The organic phases were combined and washed with H 2 O (100 mL) and brine (80 mL), followed by anhydrous Na 2 SO 4 Drying, concentration and purification by silica gel column chromatography (petroleum ether / ethyl acetate=20 / 1) gave a-1 (7.50 g, 56% yield) as a yellow oil.

[0552] Synthesis of 2-bromo-1-(3,4-dichlorophenyl)-3-methylbutan-1-one (a-2)

[0553]

[0554] A mixture of a-1 (7.50 g, 32.5 mmol) and PTAT (18.3 g, 48.7 mmol) in THF (150 mL) was stirred at room temperature overnight. When the reaction was complete, it was concentrated and the residue was dissolved in H 2O (100 mL), and then extracted with EtOAc (100 mL × 2). The organic layers were combined and washed with H 2 O (60 mL x 2) and brine (80 mL), followed by anhydrous Na 2 SO 4 The solution was concentrated to give the crude product, which was used directly in the next step without further purification to afford a-2 (10.1 g, 100% yield) as a brown oil.

[0555] Synthesis of 1-(3,4-dichlorophenyl)-3-methyl-2-thiocyanatobutan-1-one (a)

[0556]

[0557] A mixture of a-2 (10.1 g, 32.5 mmol) and NaSCN (5.26 g, 64.9 mmol) in EtOH (100.0 mL) was stirred at 100° C. for 6 h. When the reaction was completed, it was concentrated and purified by silica gel column chromatography (petroleum ether / ethyl acetate=10 / 1) to give a (5.32 g, 57% yield) as a white solid.

[0558] Synthesis of 4-methyl-1-(pyridin-3-yl)pentan-1-ol (108-1)

[0559]

[0560] To a solution of 108-s (2.14 g, 20.0 mmol) in THF (50 mL) was added isobutylmagnesium bromide (1.0 M in THF, 40.0 mL, 40.0 mmol). The reaction was stirred at room temperature for 16 h. When the reaction was complete, it was poured into NH 4 Cl aqueous solution (saturated, 200 mL) and extracted with EtOAc (100 mL × 3). The organic phases were combined and washed with H 2 O (100 mL) and brine (80 mL), followed by anhydrous Na 2 SO 4 Drying and concentration gave 108-1 (2.10 g, 59% yield) as a yellow oil, which was used directly in the next step without further purification.

[0561] Synthesis of 4-methyl-1-(pyridin-3-yl)pentan-1-one (108-2)

[0562]

[0563] 108-1 (2.10 g, 11.7 mmol) was added to CH 2 Cl 2PCC (3.79 g, 17.6 mmol) was added to a solution of 4% paraformaldehyde (150 mL). The reaction was stirred at room temperature for 3 h. When the reaction was complete, it was concentrated and purified by silica gel column chromatography (petroleum ether / ethyl acetate=300 / 1) to give 108-2 (800 mg, 39% yield) as a yellow oil.

[0564] Synthesis of 2-bromo-4-methyl-1-(pyridin-3-yl)pentan-1-one (108-3)

[0565]

[0566] 108-2 (800 mg, 4.52 mmol) was added to CHCl 3 Br was added to the solution (150 mL) 2 (867 mg, 5.42 mmol). The reaction was stirred at 80 °C overnight. When the reaction was complete, it was concentrated and washed with H 2 O (100 mL) and brine (80 mL), followed by anhydrous Na 2 SO 4 Drying and concentration gave 108-3 (1.0 g, 100% yield) as a brown oil, which was used directly in the next step without further purification.

[0567] Synthesis of 4-methyl-1-(pyridin-3-yl)-2-thiocyanatopentan-1-one (108)

[0568]

[0569] A mixture of 108-3 (1.0 g, 3.91 mmol) and NaSCN (633 mg, 7.81 mmol) in THF (100.0 mL) was stirred at room temperature for 2 h. When the reaction was complete, it was concentrated and purified by silica gel column chromatography (petroleum ether / ethyl acetate=50 / 1) to give 108 (400 mg, 44% yield) as a brown oil.

[0570] Synthesis of 1-Tosyl-1H-indole-5-carbonitrile (110-1)

[0571]

[0572] 110-s (5.0 g, 35.2 mmol), TEBA (800 mg, 3.52 mmol) and NaOH (2.54 g, 63.4 mmol) were added to CH 2 Cl 2TsCl (8.0 g, 42.3 mmol) was added to the mixture in 4% paraformaldehyde (100.0 mL). The reaction was stirred at room temperature for 4 h. When the reaction was completed, it was concentrated and purified by silica gel column chromatography (petroleum ether / ethyl acetate=80 / 1) to give 110-1 (2.50 g, 71% yield) as a white solid.

[0573] Synthesis of 4-methyl-1-(1-tosyl-1H-indol-5-yl)pentan-1-one (110-2)

[0574]

[0575] To a solution of 110-1 (4.0 g, 13.5 mmol) in THF (30 mL) was added isobutylmagnesium bromide (1.0 M in THF, 27 mL, 27.0 mmol). The reaction was stirred at room temperature for 8 h. When the reaction was complete, it was poured into NH 4 The mixture was added with aqueous Cl solution (saturated, 500 mL) and extracted with EtOAc (100 mL × 3). The organic phases were combined and washed with H 2 O (100 mL) and brine (80 mL), followed by anhydrous Na 2 SO 4 Drying, concentration and purification by silica gel column chromatography (petroleum ether / ethyl acetate=100 / 1) gave 110-2 (1.0 g, 37% yield) as a white solid.

[0576] Synthesis of 2-bromo-4-methyl-1-(1-tosyl-1H-indol-5-yl)pentan-1-one (110-3)

[0577]

[0578] A mixture of 110-2 (0.60 g, 1.52 mmol) and PTAT (682 mg, 1.82 mmol) in THF (50 mL) was stirred at room temperature for 2 h. When the reaction was complete, it was concentrated and the residue was dissolved in H 2 O (100 mL), and then extracted with EtOAc (100 mL × 2). The organic layers were combined and washed with H 2 O (60 mL x 2) and brine (80 mL), followed by anhydrous Na 2 SO 4 The solution was concentrated to give the crude product, which was used directly in the next step without further purification to give 110-3 (677 mg, 100% yield) as a yellow oil.

[0579] Synthesis of 4-methyl-2-thiocyanato-1-(1-tosyl-1H-indol-5-yl)pentan-1-one (110)

[0580]

[0581] A mixture of 110-3 (677 mg, 1.52 mmol) and NaSCN (245 mg, 3.03 mmol) in EtOH (50.0 mL) was stirred at 100° C. for 3 h. When the reaction was completed, it was concentrated and purified by silica gel column chromatography (petroleum ether / ethyl acetate=30 / 1) to give 110 (320 mg, 47% yield) as a white solid.

[0582] Synthesis of 3-chloro-4-phenoxybenzonitrile (129-1)

[0583]

[0584] 129-s (5.0 g, 32.3 mmol), phenol (3.34 g, 35.5 mmol) and K 2 CO 3 A mixture of (5.30 g, 38.7 mmol) in DMSO (50.0 mL) was stirred at 90° C. for 16 h. When the reaction was completed, it was concentrated and purified by silica gel column chromatography (petroleum ether / ethyl acetate=100 / 1) to give 129-1 (1.80 g, 45% yield) as a yellow oil.

[0585] Synthesis of 1-(3-chloro-4-phenoxyphenyl)-4-methylpentan-1-one (129-2)

[0586]

[0587] To a solution of 129-1 (2.50 g, 10.9 mmol) in THF (30 mL) was added isobutylmagnesium bromide (1.0 M in THF, 21.8 mL, 21.8 mmol). The reaction was stirred at room temperature for 16 h. When the reaction was complete, it was poured into NH 4 The mixture was added with aqueous Cl solution (saturated, 500 mL) and extracted with EtOAc (100 mL × 3). The organic phases were combined and washed with H 2 O (100 mL) and brine (80 mL), followed by anhydrous Na 2 SO 4 Drying, concentration and purification by silica gel column chromatography (petroleum ether / ethyl acetate=20 / 1) gave 129-2 (0.70 g, 47% yield) as a yellow oil.

[0588] Synthesis of 2-bromo-1-(3-chloro-4-phenoxyphenyl)-4-methylpentan-1-one (129-3)

[0589]

[0590] A mixture of 129-2 (1.10 g, 3.64 mmol) and PTAT (1.64 g, 4.37 mmol) in THF (50 mL) was stirred at room temperature overnight. When the reaction was complete, it was concentrated and the residue was dissolved in H 2 O (100 mL), and then extracted with EtOAc (100 mL × 2). The organic layers were combined and washed with H 2 O (60 mL x 2) and brine (80 mL), followed by anhydrous Na 2 SO 4 The solution was concentrated to give the crude product, which was used directly in the next step without further purification to afford 129-3 (1.40 g, 100% yield) as a brown oil.

[0591] Synthesis of 1-(3-chloro-4-phenoxyphenyl)-4-methyl-2-thiocyanopentan-1-one (129)

[0592]

[0593] A mixture of 129-3 (1.40 g, 3.64 mmol) and NaSCN (590 mg, 7.28 mmol) in EtOH (20.0 mL) was stirred at 90° C. for 3 h. When the reaction was completed, it was concentrated and purified by silica gel column chromatography (petroleum ether / ethyl acetate=10 / 1) to give 129 (1.30 g, 78% yield) as a yellow solid.

[0594] Synthesis of 4-methyl-1-(3,4,5-trichlorophenyl)pentan-1-ol (137-1)

[0595]

[0596] To a solution of 137-s (750 mg, 3.60 mmol) in THF (10 mL) was added isobutylmagnesium bromide (1.0 M in THF, 7.2 mL, 7.20 mmol). The reaction was stirred at room temperature for 16 h. When the reaction was complete, it was poured into NH 4 The mixture was added into aqueous Cl solution (saturated, 50 mL) and extracted with EtOAc (20 mL × 3). The organic phases were combined and washed with H 2 O (20 mL) and brine (20 mL), followed by anhydrous Na 2 SO 4 Drying and concentration gave 137-1 (800 mg, 100% yield) as a yellow oil, which was used directly in the next step without further purification.

[0597] Synthesis of 4-methyl-1-(3,4,5-trichlorophenyl)pentan-1-one (137-2)

[0598]

[0599] 137-1 (800 mg, 3.60 mmol) was added to CH 2 Cl 2 PCC (930 mg, 4.30 mmol) was added to a solution in 4% paraformaldehyde (30 mL). The reaction was stirred at room temperature for 3 h. When the reaction was complete, it was concentrated and purified by silica gel column chromatography (petroleum ether / ethyl acetate=20 / 1) to give 137-2 (190 mg, 23% yield) as a yellow oil.

[0600] Synthesis of 2-bromo-4-methyl-1-(3,4,5-trichlorophenyl)pentan-1-one (137-3)

[0601]

[0602] A mixture of 137-2 (190 mg, 0.68 mmol) and PTAT (310 mg, 0.82 mmol) in THF (20 mL) was stirred at room temperature for 16 h. When the reaction was complete, it was concentrated and the residue was dissolved in H 2 O (20 mL), and then extracted with EtOAc (30 mL × 2). The organic layers were combined and washed with H 2 O (20 mL x 2) and brine (20 ml), followed by anhydrous Na 2 SO 4 The solution was concentrated to give the crude product, which was used directly in the next step without further purification to give 137-3 (241 mg, 100% yield) as a yellow solid.

[0603] Synthesis of 4-methyl-2-thiocyanato-1-(3,4,5-trichlorophenyl)pentan-1-one (137)

[0604]

[0605] A mixture of 137-3 (241 mg, 0.68 mmol) and NaSCN (110 mg, 1.36 mmol) in EtOH (10.0 mL) was stirred at 100° C. for 6 h. When the reaction was completed, it was concentrated and purified by silica gel column chromatography (petroleum ether / ethyl acetate=20 / 1) to give 137 (130 mg, 28% yield) as a white solid.

[0606] Synthesis of 4-(Benzyloxy)benzonitrile (144-1)

[0607]

[0608] 144-s (10.0 g, 9.50 mmol), (bromomethyl)benzene (13.0 g, 12.0 mmol) and K 2 CO 3 A mixture of (11.0 g, 18.0 mmol) in DMSO (50.0 mL) was stirred at 90° C. for 6 h. When the reaction was completed, it was concentrated and purified by silica gel column chromatography (petroleum ether / ethyl acetate=10 / 1) to give 144-1 (8.0 g, 67% yield) as a white solid.

[0609] Synthesis of 1-(4-(Benzyloxy)phenyl)-4-methylpentan-1-one (144-2)

[0610]

[0611] To a solution of 144-1 (5.0 g, 17.8 mmol) in THF (50 mL) was added isobutylmagnesium bromide (1.0 M in THF, 26.0 mL, 26.0 mmol). The reaction was stirred at room temperature for 16 h. When the reaction was complete, it was poured into NH 4 The mixture was added with aqueous Cl solution (saturated, 500 mL) and extracted with EtOAc (100 mL × 3). The organic phases were combined and washed with H 2 O (100 mL) and brine (80 mL), followed by anhydrous Na 2 SO 4 Drying, concentration and purification by silica gel column chromatography (petroleum ether / ethyl acetate=60 / 1) gave 144-2 (4.0 g, 46% yield) as a colorless oil.

[0612] Synthesis of 1-(4-hydroxyphenyl)-4-methylpentan-1-one (144-3)

[0613]

[0614] In H 2 A mixture of 144-2 (2.0 g, 7.08 mmol) and Pd / C (200 mg) in MeOH (100 mL) was stirred overnight at room temperature under atmosphere. When the reaction was complete, it was filtered, the filtrate was concentrated and purified by silica gel column chromatography (petroleum ether / ethyl acetate=20 / 1) to give 144-3 (400 mg, 29% yield) as a colorless oil.

[0615] Synthesis of 2-bromo-1-(4-hydroxyphenyl)-4-methylpentan-1-one (144-4)

[0616]

[0617] A mixture of 144-3 (400 mg, 2.08 mmol) and PTAT (1.17 g, 3.12 mmol) in THF (50 mL) was stirred at room temperature overnight. When the reaction was complete, it was concentrated and the residue was dissolved in H 2 O (50 mL), and then extracted with EtOAc (50 mL × 2). The organic layers were combined and washed with H 2 O (30 mL x 2) and brine (30 mL), followed by anhydrous Na 2 SO 4 The solution was concentrated to give the crude product, which was used directly in the next step without further purification to give 144-4 (600 mg, 100% yield) as a brown oil.

[0618] Synthesis of 1-(4-hydroxyphenyl)-4-methyl-2-thiocyanatopentan-1-one (144)

[0619]

[0620] A mixture of 144-4 (600 mg, 2.21 mmol) and NaSCN (359 mg, 4.43 mmol) in EtOH (20.0 mL) was stirred at 100° C. for 6 h. When the reaction was completed, it was concentrated and purified by silica gel column chromatography (petroleum ether / ethyl acetate=10 / 1) to give 144 (200 mg, 36% yield) as a white solid.

[0621] Table 2-1: Characterization data of compounds

[0622]

[0623]

[0624]

[0625] Synthesis of ethyl 3-(benzylamino)propionate (b-1)

[0626]

[0627] 1-1 (3.0 g, 28.3 mmol) and ethyl 3-aminopropionate hydrochloride (4.50 g, 31.0 mmol) were added to CH 2 Cl 2 DIPEA (4.50 g, 33 mmol) was added to the mixture in 4% paraformaldehyde (100 mL). The reaction was stirred at room temperature for 4 h. When the reaction was complete, it was filtered, and the residue was concentrated and dissolved in EtOH (100 mL). NaBH 4(1.10 g, 28.3 mmol). The reactants were stirred at room temperature overnight. When the reaction was complete, it was concentrated and purified by silica gel column chromatography (CH 2 Cl 2 / CH 3 OH=50 / 1) to obtain b-1 (1.20 g, 61% yield) as a colorless oil.

[0628] Synthesis of ethyl 3-(phenylethylamino)propionate (b-6)

[0629]

[0630] 6-1 (1.0 g, 5.40 mmol), ethyl 3-aminopropionate hydrochloride (1.60 g, 10.8 mmol) and K 2 CO 3 A mixture of (2.20 g, 16.2 mmol) in DMF (10 mL) was stirred at 80 °C overnight. When the reaction was complete, it was poured into H 2 O (100 mL), and then extracted with EtOAc (100 mL × 2). The organic layers were combined and washed with H 2 O (60 mL x 2) and brine (80 mL), followed by anhydrous Na 2 SO 4 The solution was concentrated to give a crude product, which was purified by silica gel column chromatography (CH 2 Cl 2 / CH 3 OH=50 / 1) to obtain b-6 (800 mg, 63% yield) as a colorless oil.

[0631] Synthesis of methyl 3-(2-hydroxyethylamino)propionate (b-19)

[0632]

[0633] A mixture of 19-1 (1.0 g, 16.4 mmol) and methyl acrylate (1.96 g, 19.6 mmol) was stirred at room temperature overnight. When the reaction was complete, the mixture was concentrated and purified by silica gel column chromatography (petroleum ether / ethyl acetate=8 / 1) to give b-19 (600 mg, 25% yield) as a colorless oil.

[0634] Synthesis of ethyl 3-(3-hydroxypropylamino)propionate (b-21)

[0635]

[0636] 21-1 (1.0 g, 5.50 mmol), 3-aminopropan-1-ol (830 mg, 11.0 mmol) and K2 CO 3 A mixture of (2.30 g, 16.5 mmol) in DMF (20 mL) was stirred at room temperature overnight. When the reaction was complete, it was poured into H 2 O (100 mL), and then extracted with EtOAc (100 mL × 2). The organic layers were combined and washed with H 2 O (60 mL x 2) and brine (80 mL), followed by anhydrous Na 2 SO 4 The solution was concentrated to give a crude product, which was purified by silica gel column chromatography (CH 2 Cl 2 / CH 3 OH=5 / 1) to obtain b-21 (320 mg, 33% yield) as a colorless oil.

[0637] Synthesis of 3,5-dimethylphenethyl methanesulfonate (27-2)

[0638]

[0639] 27-1 (1.50 g, 10.0 mmol) and TEA (2.0 g, 20.0 mmol) were added to CH at 0 °C. 2 Cl 2 MsCl (1.70 g, 15.0 mmol) was added to the mixture in 4% paraformaldehyde (150 mL). The reaction was stirred at room temperature for 1 h. When the reaction was completed, the reaction mixture was concentrated to give 27-2 (2.20 g, 96% yield) as a white solid, which was used directly in the next step without further purification.

[0640] Synthesis of ethyl 3-(3,5-dimethylphenethylamino)propionate (b-27)

[0641]

[0642] 27-2 (2.20 g, 9.60 mmol), ethyl 3-aminopropionate hydrochloride (2.90 g, 19.2 mmol) and K 2 CO 3 A mixture of (3.90 g, 28.2 mmol) in DMF (30 mL) was stirred at 90 °C overnight. When the reaction was complete, it was poured into H 2 O (50 mL), and then extracted with EtOAc (50 mL × 2). The organic layers were combined and washed with H 2 O (30 mL x 2) and brine (20 mL), followed by anhydrous Na 2 SO 4 The solution was concentrated to give a crude product, which was purified by silica gel column chromatography (CH2 Cl 2 / CH 3 OH=50 / 1) to obtain b-27 (1.50 g, 63% yield) as a colorless oil.

[0643] Synthesis of 1-tert-butyl 3-methyl 4-methylpiperazine-1,3-dicarboxylate (28-2)

[0644]

[0645] 28-1 (1.0 g, 4.30 mmol) and K 2 CO 3 To a mixture of 1.80 g, 12.9 mmol) in DMF (15 mL) was added iodomethane (1.50 g, 10.8 mmol). The reaction was stirred at room temperature for 1 h. When the reaction was complete, it was poured into H 2 O (100 mL), and then extracted with EtOAc (100 mL × 2). The organic layers were combined and washed with H 2 O (60 mL x 2) and brine (80 mL), followed by anhydrous Na 2 SO 4 The solution was concentrated to give a crude product, which was purified by silica gel column chromatography (CH 2 Cl 2 / CH 3 OH=50 / 1) to afford 28-2 (500 mg, 61% yield) as a colorless oil.

[0646] Synthesis of 1-methylpiperazine-2-carboxylic acid methyl ester (b-28)

[0647]

[0648] A mixture of 28-2 (500 mg, 1.94 mmol) in HCl (4.0 M in dioxane, 3.00 mL) was stirred at room temperature for 3 h. When the reaction was complete, it was concentrated to give a crude product, which was purified by silica gel column chromatography (CH 2 Cl 2 / CH 3 OH=20 / 1) to obtain b-28 (100 mg, 33% yield) as a yellow oil.

[0649] Synthesis of methyl 3-((1-methylpiperidin-4-yl)methylamino)propanoate (b-30)

[0650]

[0651] 30-1 (1.0 g, 7.80 mmol), methyl 3-bromopropionate (644 mg, 3.90 mmol) and K 2 CO 3 A mixture of (2.20 g, 15.6 mmol) in DMF (10 mL) was stirred at 90 °C overnight. When the reaction was complete, it was poured into H 2 O (100 mL), and then extracted with EtOAc (80 mL × 2). The organic layers were combined and washed with H 2 O (60 mL x 2) and brine (80 mL), followed by anhydrous Na 2 SO 4 The solution was concentrated to give a crude product, which was purified by silica gel column chromatography (CH 2 Cl 2 / CH 3 OH=20 / 1) to obtain b-30 (600 mg, 51% yield) as a yellow oil.

[0652] Synthesis of 2-(Benzylamino)ethanesulfonamide (b-33)

[0653]

[0654] 33-1 (2.0 g, 18.8 mmol), 2-aminoethanesulfonamide (2.5 g, 20 mmol) and NaBH 3 A mixture of CN (2.3 g, 37.6 mmol) in EtOH (25 mL) was stirred at 90° C. for 2 h. When the reaction was complete, it was concentrated to give a crude product, which was purified by silica gel column chromatography (CH 2 Cl 2 / CH 3 OH=30 / 1) to obtain b-33 (1.40 g, 34% yield) as a colorless oil.

[0655] Synthesis of N-benzyl-2-(1H-tetrazolyl-5-yl)ethylamine (b-34)

[0656]

[0657] 34-1 (150 mg, 1.10 mmol), phenylmethylamine (243 mg, 2.20 mmol) and K 2 CO 3 A mixture of (379 mg, 2.70 mmol) in DMF (30 mL) was stirred at 90 °C overnight. When the reaction was complete, it was poured into H 2 O (50 mL), and then extracted with EtOAc (50 mL × 2). The organic layers were combined and washed with H 2O (30 mL x 2) and brine (20 mL), followed by anhydrous Na 2 SO 4 The solution was concentrated to give a crude product, which was purified by silica gel column chromatography (CH 2 Cl 2 / CH 3 OH=5 / 1) to afford b-34 (100 mg, 49% yield) as a white solid.

[0658] Scheme 2: Characterization data of compounds

[0659]

[0660]

[0661]

[0662]

[0663] Synthesis of ethyl 3-(benzyl(4-(3,4-dichlorophenyl)-5-isobutylthiazol-2-yl)amino)propanoate (061-1)

[0664]

[0665] A mixture of c (150 mg, 0.50 mmol), b-1 (144 mg, 0.75 mmol) and AcOH (60 mg, 1.0 mmol) in i-PrOH (3.00 mL) was stirred at 90 °C for 16 h. When the reaction was complete, the mixture was analyzed by preparative TLC (CH 2 Cl 2 / CH 3 OH=120 / 1) to obtain 061-1 (80.0 mg, 33% yield) as a yellow solid.

[0666] Synthesis of 3-(Benzyl(4-(3,4-dichlorophenyl)-5-isobutylthiazol-2-yl)amino)propionic acid (I-47)

[0667]

[0668] 061-1 (80.0 mg, 0.163 mmol) was dissolved in THF / MeOH / H 2 LiOH (2.0 M in HO) was added to the solution in HO (v / v / v = 4 / 1 / 1, 8 mL). 2 O, 0.22 mL). The reaction was stirred at room temperature for 4 h. When the reaction was complete, the resulting reaction was concentrated and then washed with H 2O (10 mL), and the pH was adjusted to 4-5 with HCl (1.0 M). The mixture was extracted with EtOAc (40 mL×2), and the combined organic phases were washed with brine (30 mL), and dried over anhydrous Na 2 SO 4 Dried and concentrated, the residue was purified by preparative HPLC to give 1-47 (30.0 mg, 40% yield) as a white solid.

[0669] Synthesis of tert-butyl 4-(((4-(3,4-dichlorophenyl)-5-isobutylthiazol-2-yl)(3-ethoxy-3-oxopropyl)amino)methyl)-1H-indole-1-carboxylate (068-1)

[0670]

[0671] A mixture of c (100 mg, 0.33 mmol), b-8 (138 mg, 0.39 mmol) and AcOH (40 mg, 0.66 mmol) in i-PrOH (4.00 mL) was stirred at 90 °C for 16 h. When the reaction was completed, the mixture was analyzed by preparative TLC (CH 2 Cl 2 / CH 3 OH=120 / 1) to obtain 068-1 (95.0 mg, 45% yield) as a yellow solid.

[0672] Synthesis of 3-(((1-(tert-Butyloxycarbonyl)-1H-indol-4-yl)methyl)(4-(3,4-dichlorophenyl)-5-isobutylthiazol-2-yl)amino)propanoic acid (068-2)

[0673]

[0674] 068-1 (95.0 mg, 0.151 mmol) was dissolved in THF / MeOH / H 2 LiOH (2.0 M in HO) was added to the solution in HO (v / v / v = 4 / 1 / 1, 8 mL). 2 O, 0.21 mL). The reaction was stirred at room temperature for 4 h. When the reaction was complete, the resulting reaction was concentrated and then washed with H 2 O (10.0 mL), and the pH was adjusted to 4-5 with HCl (1.0 M). The mixture was extracted with EtOAc (40 mL×2), and the combined organic phases were washed with brine (30.0 mL), and dried over anhydrous Na 2 SO 4 Drying and concentration gave 068-2 (60.0 mg, 66% yield) as a white solid.

[0675] Synthesis of 3-(((1H-indol-4-yl)methyl)(4-(3,4-dichlorophenyl)-5-isobutylthiazol-2-yl)amino)propanoic acid (I-53)

[0676]

[0677] A mixture of 068-2 (60.0 mg, 0.10 mmol) in HCl (4.0 M in dioxane, 5.00 mL) was stirred overnight at 40° C. When the reaction was complete, it was concentrated to give a crude product, which was purified by preparative HPLC to give I-53 (13.0 mg, 26% yield) as a white solid.

[0678] Synthesis of 3,3'-(4-(3,4-dichlorophenyl)-5-isobutylthiazol-2-ylnitrogendiyl)dipropionic acid (I-58)

[0679]

[0680] A mixture of c (120 mg, 0.399 mmol), b-13 (77.2 mg, 0.479 mmol) and AcOH (47.9 mg, 0.798 mmol) in i-PrOH (2.00 mL) was stirred at 90° C. for 16 h. When the reaction was complete, the mixture was purified by preparative HPLC to give I-58 (10.0 mg, 5.6% yield) as a white solid.

[0681] Synthesis of ethyl 3-(benzyl(5-isobutyl-4-(1-tosyl-1H-indol-5-yl)thiazol-2-yl)amino)propanoate (110-1)

[0682]

[0683] A mixture of 110 (200 mg, 0.44 mmol), b-1 (110 mg, 0.53 mmol) and AcOH (53.0 mg, 0.88 mmol) in i-PrOH (3.00 mL) was stirred at 90 °C for 16 h. When the reaction was complete, the mixture was analyzed by preparative TLC (CH 2 Cl 2 / CH 3 OH=120 / 1) to afford 110-1 (110 mg, 49% yield) as a yellow solid.

[0684] Synthesis of 3-(Benzyl(5-isobutyl-4-(1-tosyl-1H-indol-5-yl)thiazol-2-yl)amino)propanoic acid (110-2)

[0685]

[0686] 110-1 (110 mg, 0.179 mmol) was dissolved in THF / MeOH / H 2 LiOH (2.0 M in HO) was added to the solution in HO (v / v / v = 4 / 1 / 1, 10 mL). 2 O, 0.21 mL). The reaction was stirred at room temperature for 4 h. When the reaction was complete, the resulting reaction was concentrated and then washed with H 2 O (10.0 mL), and the pH was adjusted to 4-5 with HCl (1.0 M). The mixture was extracted with EtOAc (40 mL×2), and the combined organic phases were washed with brine (30.0 mL), and dried over anhydrous Na 2 SO 4 Drying and concentration gave 110-2 (90.0 mg, 86% yield) as a white solid.

[0687] Synthesis of 3-((4-(1H-indol-5-yl)-5-isobutylthiazol-2-yl)(benzyl)amino)propanoic acid (I-85)

[0688]

[0689] 110-2 (90.0 mg, 0.153 mmol) and K 2 CO 3 A mixture of (42.3 mg, 0.306 mmol) in MeOH (10 mL) was stirred at 80° C. for 16 h. When the reaction was complete, it was concentrated to give the crude product, which was purified by preparative HPLC to give I-85 (20.0 mg, 30% yield) as a white solid.

[0690] Synthesis of ethyl 3-(benzyl(4-(3,4-dichlorophenyl)thiazol-2-yl)amino)propanoate (115-1)

[0691]

[0692] A mixture of 115 (500 mg, 2.03 mmol), b-1 (505 mg, 2.44 mmol) and AcOH (244 mg, 4.06 mmol) in i-PrOH (10.0 mL) was stirred overnight at 90° C. When the reaction was complete, the mixture was purified by silica gel column chromatography (petroleum ether / ethyl acetate=15 / 1) to give 115-1 (190 mg, 22% yield) as a yellow solid.

[0693] Synthesis of ethyl 3-(benzyl(4-(3,4-dichlorophenyl)-5-formylthiazol-2-yl)amino)propanoate (115-2)

[0694]

[0695] 115-1 (200 mg, 0.46 mmol) and POCl 3 A mixture of (177 mg, 1.16 mmol) in DMF (15 mL) was stirred at room temperature for 4 h. When the reaction was complete, the mixture was analyzed by preparative TLC (CH 2 Cl 2 / CH 3 OH=100 / 1) to afford 115-2 (120 mg, 62% yield) as a yellow solid.

[0696] Synthesis of ethyl 3-(benzyl(4-(3,4-dichlorophenyl)-5-(hydroxymethyl)thiazol-2-yl)amino)propanoate (115-3)

[0697]

[0698] 115-2 (1.0 g, 0.45 mmol) and NaBH 4 A mixture of (380 mg, 0.88 mmol) in THF (30 mL) was stirred at room temperature for 4 h. When the reaction was complete, the mixture was analyzed by preparative TLC (CH 2 Cl 2 / CH 3 OH=60 / 1) to afford 115-3 (700 mg, 87% yield) as a yellow oil.

[0699] Synthesis of ethyl 3-(benzyl(4-(3,4-dichlorophenyl)-5-((dimethylamino)methyl)thiazol-2-yl)amino)propanoate (115-4)

[0700]

[0701] 115-3 (200 mg, 0.43 mmol), MsCl (100 mg, 0.86 mmol) and Et 3 N (109 mg, 1.08 mmol) in CH 2 Cl 2 The mixture in 4% ethyl acetate (5 mL) was stirred at room temperature for 2 h. When the reaction was complete, the mixture was concentrated and dissolved in THF (10 mL). Dimethylamine (1.0 M in THF, 0.65 mL, 0.65 mmol) and K were added to the reaction. 2 CO 3 (119 mg, 0.86 mmol). The reaction was stirred at room temperature for 4 h. When the reaction was complete, it was analyzed by preparative TLC (CH 2 Cl 2 / CH 3OH=100 / 1) to afford 115-4 (130 mg, 61% yield) as a white solid.

[0702] Synthesis of 3-(Benzyl(4-(3,4-dichlorophenyl)-5-((dimethylamino)methyl)thiazol-2-yl)amino)propanoic acid (I-89)

[0703]

[0704] 115-4 (130 mg, 0.263 mmol) was dissolved in THF / MeOH / H 2 LiOH (2.0 M in HO) was added to the solution in HO (v / v / v = 4 / 1 / 1, 10 mL). 2 O, 0.25 mL). The reaction was stirred at room temperature for 2 h. When the reaction was complete, the resulting reaction was concentrated and then washed with H 2 O (10.0 mL), and the pH was adjusted to 4-5 with HCl (1.0 M). The mixture was extracted with EtOAc (40.0 mL×2), and the combined organic phases were washed with brine (30.0 mL), and dried over anhydrous Na 2 SO 4 Drying, concentration and purification by preparative HPLC gave 1-89 (80.0 mg, 65% yield) as a white solid.

[0705] Synthesis of 3-(Benzyl(4-(3,4-dichlorophenyl)-5-isobutylthiazol-2-yl)amino)-N-(methylsulfonyl)propionamide (I-97)

[0706]

[0707] A mixture of I-47 (25.0 mg, 0.054 mmol), methanesulfonamide (6.18 mg, 0.065 mmol), HATU (41.1 mg, 0.108 mmol) and DIPEA (20.9 mg, 0.162 mmol) in DMF (2.0 mL) was stirred at room temperature overnight. When the reaction was complete, it was poured into H 2 O (100 mL), and then extracted with EtOAc (100 mL × 2). The organic layers were combined and washed with H 2 O (60 mL x 2) and brine (80 mL), followed by anhydrous Na 2 SO 4 The solution was concentrated to give the crude product, which was purified by preparative HPLC to afford 1-97 (5.0 mg, 16% yield) as a yellow solid.

[0708] Synthesis of N-(2-(Benzyl(4-(3,4-dichlorophenyl)-5-isobutylthiazol-2-yl)amino)ethylsulfonyl)acetamide (I-99)

[0709]

[0710] I-98 (60.0 mg, 0.120 mmol) and pyridine (0.2 mL) were stirred in CH 2 Cl 2 To the mixture in 4% paraformaldehyde (1.0 mL) was added acetic anhydride (36.0 mg, 0.360 mmol). The reaction was stirred at room temperature overnight. When the reaction was complete, the mixture was purified by preparative HPLC to give I-99 (15.0 mg, 36% yield) as a white solid.

[0711] Synthesis of ethyl 3-(benzyl(4-(4'-fluorobiphenyl-4-yl)-5-isobutylthiazol-2-yl)amino)propanoate (127-4)

[0712]

[0713] 119-4 (350 mg, 0.76 mmol), 4-fluorophenylboronic acid (160 mg, 1.14 mmol), Pd(OAc) 2 (17 mg, 0.076 mmol), PCy 3 (43 mg, 0.152 mmol) and K 3 PO 4 (484 mg, 2.28 mmol) in toluene / H 2 O (v / v = 10 / 1, 22.0 mL) in N 2 The mixture was stirred at 120° C. for 3 h under atmosphere. When the reaction was completed, the mixture was purified by silica gel column chromatography (petroleum ether / ethyl acetate=10 / 1) to give 127-4 (160 mg, 53% yield) as a yellow solid.

[0714] Synthesis of 3-(Benzyl(4-(4'-fluorobiphenyl-4-yl)-5-isobutylthiazol-2-yl)amino)propanoic acid (I-101)

[0715]

[0716] 127-4 (160 mg, 0.310 mmol) was dissolved in THF / MeOH / H 2 LiOH (2.0 M in HO) was added to the solution in HO (v / v / v = 4 / 1 / 1, 10 mL). 2 O, 0.30 mL). The reaction was stirred at room temperature for 4 h. When the reaction was complete, the resulting reaction was concentrated and then washed with H2 O (10.0 mL), and the pH was adjusted to 4-5 with HCl (1.0 M). The mixture was extracted with EtOAc (40.0 mL×2), and the combined organic phases were washed with brine (30.0 mL), and dried over anhydrous Na 2 SO 4 Drying, concentration and purification by preparative HPLC gave 1-101 (34.0 mg, 28% yield) as a white solid.

[0717] Synthesis of a mixture of 3-(benzyl(4-(2-chloro-4'-fluorobiphenyl-4-yl)-5-isobutylthiazol-2-yl)amino)propanoic acid and 3-(benzyl(4-(6-chloro-4'-fluorobiphenyl-3-yl)-5-isobutylthiazol-2-yl)amino)propanoic acid (I-104)

[0718]

[0719] I-47 (200 mg, 0.432 mmol), 4-fluorophenylboronic acid (121 mg, 0.866 mmol), Pd(OAc) 2 (9.7 mg, 0.0433 mmol), PCy 3 (25.2 mg, 0.0866 mmol) and K 3 PO 4 (184 mg, 0.866 mmol) in toluene / H 2 O (v / v = 10 / 1, 2.20 mL) in N 2 The mixture was stirred at 120° C. overnight under atmosphere. When the reaction was complete, the mixture was purified by preparative HPLC to give I-104 (60.0 mg, 27% yield) as a white solid.

[0720] Synthesis of 2-(tert-butoxycarbonylamino)-3-(4-(3,4-dichlorophenyl)-5-isobutylthiazol-2-ylamino)propanoic acid (142-1)

[0721]

[0722] A mixture of c (600 mg, 1.99 mmol), 3-amino-2-(tert-butoxycarbonylamino)propanoic acid (448 mg, 2.19 mmol) and AcOH (239 mg, 3.99 mmol) in i-PrOH (5.0 mL) was stirred at 90 ° C. for 16 h. When the reaction was complete, it was concentrated to give 142-1 (800 mg, 82% yield) as a yellow oil, which was used directly in the next step without further purification.

[0723] Synthesis of 2-amino-3-(4-(3,4-dichlorophenyl)-5-isobutylthiazol-2-ylamino)propionic acid (I-115)

[0724]

[0725] A mixture of 142-1 (800 mg, 1.64 mmol) in HCl (4.0 M in dioxane, 10.0 mL) was stirred at room temperature for 1 h. When the reaction was complete, it was concentrated to give a crude product, which was purified by preparative HPLC to give I-115 (600 mg, 94% yield) as a white solid.

[0726] Synthesis of 2-(Benzylamino)-3-(4-(3,4-dichlorophenyl)-5-isobutylthiazol-2-ylamino)propanoic acid (I-113)

[0727]

[0728] I-115 (100 mg, 0.26 mmol), benzaldehyde (30.2 mg, 0.28 mmol) and NaBH 4 A mixture of (9.82 mg, 0.26 mmol) in EtOH (5.0 mL) was stirred at room temperature for 48 h. When the reaction was complete, it was concentrated to give the crude product, which was purified by preparative HPLC to give I-113 (30 mg, 24% yield) as a white solid.

[0729] Synthesis of 2-(Benzyl(methyl)amino)-3-(4-(3,4-dichlorophenyl)-5-isobutylthiazol-2-ylamino)propanoic acid (I-114)

[0730]

[0731] I-113 (180 mg, 0.377 mmol), formaldehyde (37% in H 2 O, 34 mg, 0.414 mmol) and NaBH 4 A mixture of (14.3 mg, 0.377 mmol) in EtOH (5.0 mL) was stirred at room temperature for 12 h. When the reaction was complete, it was concentrated to give the crude product, which was purified by preparative HPLC to give I-114 (20 mg, 11% yield) as a white solid.

[0732] Synthesis of 3-(4-(3,4-dichlorophenyl)-5-isobutylthiazol-2-ylamino)-2-(dimethylamino)propanoic acid (I-116)

[0733]

[0734] I-115 (200 mg, 0.517 mmol), formaldehyde (37% in H 2 O, 105 mg, 1.29 mmol) and NaBH 4 A mixture of (39.3 mg, 1.03 mmol) in EtOH (15.0 mL) was stirred at room temperature for 24 h. When the reaction was complete, it was concentrated to give the crude product, which was purified by preparative HPLC to give I-116 (110 mg, 51% yield) as a white solid.

[0735] Table 2-3: Characterization data of compounds

[0736]

[0737]

[0738]

[0739]

[0740]

[0741]

[0742]

[0743]

[0744]

[0745]

[0746]

[0747]

[0748]

[0749]

[0750]

[0751]

[0752]

[0753]

[0754]

[0755] Example 3. Synthesis of Compounds I-119 to I-198

[0756] Scheme 1: Pathways to compounds c, 115, 159, 161, 217, 218, and 220

[0757]

[0758] Scheme 2: Pathway to compound 219

[0759]

[0760] Scheme 3: Pathway to compound b-157

[0761]

[0762] Scheme 4: Pathway from compound b-184 to b-187

[0763]

[0764] Scheme 5: Pathway of compound 1, b-188 to b-196, b-198 to b-201, b-203 to b-205, b-211, b-212, b-214, b-215, s-1

[0765]

[0766] Scheme 6: Pathway to compound b-208

[0767]

[0768] Scheme 7: Pathway to compounds b-213 and b-216

[0769]

[0770] Scheme 8: Pathway to compound b-229

[0771]

[0772] Scheme 9: Pathway to compound b-233

[0773]

[0774] Scheme 10: Pathway to compound b-235

[0775]

[0776] Scheme 11: Pathway to compound b-242

[0777]

[0778] Scheme 12: Pathway to compound b-243

[0779]

[0780] Scheme 13: Pathway to compounds 152-s and 227-s

[0781]

[0782] Scheme 14: Pathway to compound 178-s

[0783]

[0784] Scheme 15: Pathway to compound 224-s

[0785]

[0786] Scheme 16: Pathway to Compound I-119

[0787]

[0788] Scheme 17: Pathway from compound I-120 to I-122 and I-130

[0789]

[0790] Scheme 18: Pathway to Compound I-123

[0791]

[0792] Scheme 19: Pathway to Compound I-124

[0793]

[0794] Scheme 20: Pathway to Compound I-125

[0795]

[0796] Scheme 21: Pathways of compounds I-126, I-127, I-150 to I-158, I-160, I-163, I-165, I-170, I-171 to I-180

[0797]

[0798] Scheme 22: Pathway to Compound I-128

[0799]

[0800] Scheme 23: Pathway to Compound I-129

[0801]

[0802] Scheme 24: Pathways to compounds I-131, I-132, I-134, I-135, I-192

[0803]

[0804] Scheme 25: Pathway to compounds I-133, I-189, I-193 to I-195

[0805]

[0806] Scheme 26: Pathway to Compounds I-136 and I-140

[0807] Scheme 27: Pathway to Compounds I-137 and I-190

[0808]

[0809] Scheme 28: Pathway to Compound I-138

[0810]

[0811] Scheme 29: Pathway to Compound I-139

[0812]

[0813] Scheme 30: Pathway to Compound I-141

[0814]

[0815] Scheme 31: Pathway to Compound I-142

[0816]

[0817] Scheme 32: Pathway to compounds I-143 and I-144

[0818]

[0819] Scheme 33: Pathway to Compound I-145

[0820]

[0821] Scheme 34: Pathway to Compounds I-146 and I-148

[0822]

[0823] Scheme 35: Pathway to Compounds I-147 and I-149

[0824]

[0825] Scheme 36: Pathway to compounds I-159, I-162, and I-164

[0826]

[0827] Scheme 37: Pathway from Compound I-166 to I-167

[0828]

[0829] Scheme 38: Pathway from Compound I-168 to I-169

[0830]

[0831] Scheme 39: Pathway to Compound I-181

[0832]

[0833] Scheme 40: Pathway to compounds I-182 and I-183

[0834]

[0835] Scheme 41: Pathway to Compound I-184

[0836]

[0837] Scheme 42: Pathway to Compound I-185

[0838]

[0839] Scheme 43: Pathway to Compound I-186

[0840]

[0841] Scheme 44: Pathway to Compounds I-187 and I-188

[0842]

[0843] Scheme 45: Pathway to Compound I-190

[0844]

[0845] Scheme 46: Pathway to Compound I-191

[0846]

[0847] Scheme 47: Pathway to Compound I-196

[0848]

[0849] Scheme 48: Pathway from Compound I-197 to I-198

[0850]

[0851] General Information: All evaporations were performed in vacuo using a rotary evaporator. Analytical samples were dried in vacuo (1-5 mmHg) at rt. Thin layer chromatography (TLC) was performed on silica gel plates and spots were observed by UV light (214 nm and 254 nm). Column and flash chromatography 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 with 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), integral value.

[0852] LCMS spectra were obtained on an Agilent 1200 series 6110 or 6120 mass spectrometer with electrospray ionization and unless otherwise specified, general LCMS conditions were as follows:

[0853] 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% [CH 3 CN + 0.05% TFA] to 0% [water + 0.05% TFA] and 100% [CH 3 CN+0.05% TFA], followed by 0.4 min under this condition, and finally 95% [water+0.05% TFA] and 5% [CH 3 CN + 0.05% TFA]).

[0854] 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% [CH 3 CN + 0.05% TFA] to 0% [water + 0.05% TFA] and 100% [CH 3 CN+0.05% TFA], followed by 1.4 min under this condition, and finally changed to 95% [water+0.05% TFA] and 5% [CH 3 CN+0.05% TFA] and 0.7 min under this condition).

[0855] 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: 95% [water + 10 mM NH 4 HCO 3 ] and 5% [CH 3 CN] to 0% [water + 10 mM NH 4 HCO 3 ] and 100% [CH 3 CN], then under this condition for 1.4 min, and finally changed to 95% [water + 10 mM NH 4 HCO 3 ] and 5% [CH 3 CN], and under this condition 0.7min. )

[0856] Synthesis of 1-(3,4-dichlorophenyl)-4-methylpentan-1-one (c-1)

[0857]

[0858] To a solution of a (25.0 g, 145 mmol) in THF (200 mL) was added isobutylmagnesium bromide (1.0 M in THF, 218 mL, 218 mmol). The reaction was stirred at room temperature for 16 h. When the reaction was complete, it was poured into NH 4 The organic phases were combined and washed with H 2 O (100 mL) and brine (80.0 mL), followed by anhydrous Na 2 SO 4Drying, concentration and purification by silica gel column chromatography (petroleum ether / ethyl acetate=100 / 1) gave c-1 (15.0 g, 42% yield) as a yellow oil.

[0859] Synthesis of 2-bromo-1-(3,4-dichlorophenyl)-4-methylpentan-1-one (c-2)

[0860]

[0861] A mixture of c-1 (15.0 g, 61.2 mmol) and PTAT (34.4 g, 91.8 mmol) in THF (300 mL) was stirred at room temperature for 16 h. When the reaction was complete, it was concentrated and the residue was dissolved in H 2 O (300 mL), and then extracted with EtOAc (200 mL × 3). The organic layers were combined and washed with H 2 O (100 mL x 2) and brine (100 mL), followed by anhydrous Na 2 SO 4 The solution was concentrated to give the crude product, which was used directly in the next step without further purification to afford c-2 (20.0 g, 100% yield) as a brown oil.

[0862] Synthesis of 1-(3,4-dichlorophenyl)-4-methyl-2-thiocyanopentan-1-one (c)

[0863]

[0864] A mixture of c-2 (20.0 g, 61.7 mmol) and NaSCN (10.0 g, 123 mmol) in EtOH (200 mL) was stirred at 100° C. for 6 h. When the reaction was completed, it was concentrated and purified by silica gel column chromatography (petroleum ether / ethyl acetate=10 / 1) to give c (6.90 g, 37% yield) as a white solid.

[0865] Synthesis of (E)-3-cyclopropyl-1-(3,4-dichlorophenyl)prop-2-en-1-one (219-2)

[0866]

[0867] A mixture of 219-1 (1.00 g, 5.29 mmol), cyclopropanecarboxaldehyde (370 mg, 5.29 mmol) and piperidine (5.0 mL) in THF (100 mL) was stirred at room temperature overnight. When the reaction was complete, it was concentrated and purified by silica gel column chromatography (petroleum ether / ethyl acetate=100 / 1) to give 219-2 (800 mg, 63% yield) as a yellow solid.

[0868] Synthesis of 3-cyclopropyl-1-(3,4-dichlorophenyl)propan-1-ol (219-3)

[0869]

[0870] To a solution of 219-2 (800 mg, 3.32 mmol) in MeOH (50.0 mL) was added NaBH at 0 °C. 4 (1.26 g, 33.2 mmol). The reaction was stirred at room temperature overnight. When the reaction was complete, it was concentrated and the residue was dissolved in H 2 O (100 mL), and then extracted with EtOAc (50.0 mL × 3). The organic layers were combined and washed with H 2 O (50.0 mL x 2) and brine (50.0 mL), followed by anhydrous Na 2 SO 4 The solution was concentrated to give the crude product, which was used directly in the next step without further purification to give 219-3 (814 mg, 100% yield) as a colorless oil.

[0871] Synthesis of 3-cyclopropyl-1-(3,4-dichlorophenyl)propan-1-one (219-4)

[0872]

[0873] 219-3 (814 mg, 3.32 mmol) was added to CH 2 Cl 2 PCC (1.07 g, 4.98 mmol) was added to a solution of 4% paraformaldehyde (100 mL). The reaction was stirred at room temperature for 1 h. When the reaction was complete, it was concentrated and purified by silica gel column chromatography (petroleum ether / ethyl acetate=300 / 1) to give 219-4 (400 mg, 46% yield) as a yellow solid.

[0874] Synthesis of 2-bromo-3-cyclopropyl-1-(3,4-dichlorophenyl)propan-1-one (219-5)

[0875]

[0876] 219-4 (400 mg, 1.65 mmol) was added to CH 2 Cl 2 Br was added to the solution (100 mL) 2 (320 mg, 1.97 mmol). The reaction was stirred at room temperature for 2 h. When the reaction was complete, it was washed with H 2 O (100 mL x 2) and brine (100 mL), followed by anhydrous Na 2SO 4 The solution was concentrated to give the crude product, which was used directly in the next step without further purification to afford 219-5 (530 mg, 100% yield) as a yellow oil.

[0877] Synthesis of 3-cyclopropyl-1-(3,4-dichlorophenyl)-2-thiocyanatopropan-1-one (219)

[0878]

[0879] A mixture of 219-5 (530 mg, 1.65 mmol) and NaSCN (266 mg, 3.29 mmol) in EtOH (20.0 mL) was stirred at 90° C. for 2 h. When the reaction was completed, it was concentrated and purified by silica gel column chromatography (petroleum ether / ethyl acetate=20 / 1) to give 219 (160 mg, 32% yield) as a yellow solid.

[0880] Table 3-1: Characterization data of compounds

[0881]

[0882] Synthesis of 2-(4-bromobutyl)isoindoline-1,3-dione (157-2)

[0883]

[0884] 157-1 (1.00 g, 6.54 mmol), isoindoline-1,3-dione (1.44 g, 9.80 mmol), PPh 3 A mixture of 157-2 (2.57 g, 9.80 mmol) and DEAD (1.71 g, 9.80 mmol) in THF (100 mL) was stirred at room temperature overnight. When the reaction was complete, it was concentrated and purified by silica gel column chromatography (petroleum ether / ethyl acetate=50 / 1) to give 157-2 (700 mg, 63% yield) as a white solid.

[0885] Synthesis of methyl 2-cyano-6-(1,3-dioxoisoindolin-2-yl)hexanoate (157-3)

[0886]

[0887] 157-2 (500 mg, 1.78 mmol), methyl 2-cyanoacetate (351 mg, 3.55 mmol) and K 2 CO 3 A mixture of (368 mg, 2.67 mmol) in DMF (10.0 mL) was stirred at 75 °C for 2 h. When the reaction was complete, it was poured into H 2O (100 mL), and then extracted with EtOAc (50.0 mL × 2). The organic layers were combined and washed with H 2 O (50.0 mL x 2) and brine (50.0 mL), followed by anhydrous Na 2 SO 4 The solution was concentrated and purified by silica gel column chromatography (petroleum ether / ethyl acetate=20 / 1) to give 157-3 (400 mg, 51% yield) as a yellow solid.

[0888] Synthesis of methyl 2-(aminomethyl)-6-(1,3-dioxoisoindolin-2-yl)hexanoate (b-157)

[0889]

[0890] In H 2 A mixture of 157-3 (400 mg, 1.32 mmol) and Raney nickel (200 mg) in MeOH (50.0 mL) was stirred overnight at room temperature under atmosphere. When the reaction was complete, the mixture was filtered and the filtrate was concentrated to give a crude product, which was purified by silica gel column chromatography (CH 2 Cl 2 / MeOH=50 / 1) to obtain b-157 (250 mg, 49% yield) as a yellow oil.

[0891] Synthesis of ethyl 3-(4-(tert-butoxycarbonylamino)butylamino)propionate (b-184)

[0892]

[0893] 184-1 (1.00 g, 5.31 mmol), ethyl 3-bromopropionate (1.15 g, 6.37 mmol) and Et 3 N (1.07 g, 10.6 mmol) in CH 2 Cl 2 The mixture in (100 mL) was stirred at room temperature for 8 h. When the reaction was completed, it was concentrated and purified by silica gel column chromatography (petroleum ether / ethyl acetate=1 / 1) to give b-184 (310 mg, 20% yield) as a colorless oil.

[0894] Synthesis of (Z)-2-cyano-3-phenylacrylate (1-2)

[0895]

[0896] To a mixture of 1-1 (5.00 g, 47.2 mmol) and methyl 2-cyanoacetate (5.61 g, 56.6 mmol) in MeOH (100 mL) was added piperidine (5 drops). The reactants were stirred at room temperature for 4 h. When the reaction was complete, the reaction mixture was filtered, and the residue was washed with MeOH (2.0 mL×2) and dried to give 1-2 (6.50 g, 74% yield) as a white solid.

[0897] Synthesis of methyl 3-amino-2-benzylpropionate (1)

[0898]

[0899] In H 2 A mixture of 1-2 (6.50 g, 34.7 mmol) and Raney nickel (2.00 g) in MeOH (800 mL) was stirred overnight at room temperature under atmosphere. When the reaction was complete, the mixture was filtered, and the filtrate was concentrated to give a crude product, which was purified by silica gel column chromatography (CH 2 Cl 2 / MeOH=50 / 1) to afford 1 (550 mg, 7.5% yield) as a colorless oil.

[0900] Synthesis of 1-tert-butyl 3-methyl 4-phenylpiperazine-1,3-dicarboxylate (208-2)

[0901]

[0902] 208-1 (1.00 g, 4.09 mmol), phenylboronic acid (749 mg, 6.14 mmol) and Cu(AcO) were mixed. 2 (74.5 mg, 0.41 mmol) in CH 2 Cl 2 The mixture in 4% paraformaldehyde (50.0 mL) was stirred at room temperature overnight. When the reaction was completed, it was concentrated and purified by silica gel column chromatography (petroleum ether / ethyl acetate=20 / 1) to give 208-2 (100 mg, 7.6% yield) as a yellow oil.

[0903] Synthesis of 1-phenylpiperazine-2-carboxylic acid methyl ester (b-208)

[0904]

[0905] A mixture of 208-2 (100 mg, 0.31 mmol) in HCl (4.0 M in dioxane, 10.0 mL) was stirred at room temperature for 2 h. When the reaction was complete, it was concentrated and the residue was dissolved in H 2O (20.0 mL), and then washed with MTBE (20.0 mL × 3). The aqueous layer was washed with NaHCO 3 The aqueous solution was adjusted to pH = 8, and then extracted with EtOAc (20.0 mL x 3). The organic layers were combined and washed with anhydrous Na 2 SO 4 Drying followed by concentration afforded b-208 (600 mg, 94% yield) as a yellow oil.

[0906] Synthesis of 3-cyanobenzenesulfonamide (213-2)

[0907]

[0908] To a solution of 213-1 (2.00 g, 9.92 mmol) in THF (20.0 mL) was added NH 3 OH (20.0 mL). The reaction was stirred at room temperature for 2 h. When the reaction was completed, it was concentrated to give the crude product, which was used directly in the next step without further purification to give 213-2 as a white solid (2.00 g, 100% yield).

[0909] Synthesis of 3-Formylbenzenesulfonamide (213-3)

[0910]

[0911] A mixture of 213-2 (2.00 g, 10.9 mmol) and Raney nickel (2.00 g) in HCOOH (800 mL) was stirred at 4 °C for 2 h. 2 Refluxed under atmosphere for 1 hour. When the reaction was complete, the mixture was cooled to room temperature and filtered, and the filtrate was concentrated to give a crude product, which was purified by silica gel column chromatography (petroleum ether / ethyl acetate=10 / 1) to give 213-3 (1.70 g, 76% yield) as a white solid.

[0912] Synthesis of (E)-2-cyano-3-(3-sulfamoylphenyl) methyl acrylate (213-4)

[0913]

[0914] To a mixture of 213-3 (880 mg, 4.75 mmol) and methyl 2-cyanoacetate (471 mg, 4.75 mmol) in MeOH (50 mL) was added piperidine (0.3 mL). The reactants were stirred at room temperature overnight. When the reaction was complete, the reaction mixture was filtered, and the residue was washed with MeOH (2.0 mL × 2) and dried to give 213-4 (1.20 g, 95% yield) as a yellow solid.

[0915] Synthesis of methyl 3-amino-2-(3-sulfamoylbenzyl)propionate (b-213)

[0916]

[0917] A mixture of 213-4 (1.20 g, 4.51 mmol) and Raney nickel (1.20 g) in MeOH (400 mL) was stirred at 4 ℃ for 1 h. 2 Stir at room temperature for 24 h under atmosphere. When the reaction was complete, the mixture was filtered and the filtrate was concentrated to give a crude product, which was purified by silica gel column chromatography (CH 2 Cl 2 / MeOH=50 / 1) to obtain b-213 (260 mg, 21% yield) as a yellow oil.

[0918] Synthesis of 3-(1,3-dioxoisoindolin-2-yl)propane-1-sulfonamide (b-229)

[0919]

[0920] 229-1 (400 mg, 2.54 mmol), isoindoline-1,3-dione (411 mg, 2.79 mmol) and K 2 CO 3 A mixture of (701 mg, 5.08 mmol) in DMF (10.0 mL) was stirred at room temperature overnight. When the reaction was complete, it was poured into H 2 O (100 mL), and then extracted with EtOAc (50.0 mL × 2). The organic layers were combined and washed with H 2 O (50.0 mL x 2) and brine (50.0 mL), followed by anhydrous Na 2 SO 4 The solution was concentrated and purified by silica gel column chromatography (CH 2 Cl 2 / MeOH=50 / 1) to afford b-229 (700 mg, 63% yield) as a white solid.

[0921] Synthesis of 3-amino-2-hydroxypropionic acid methyl ester (233-2)

[0922]

[0923] To a solution of 233-1 (1.00 g, 9.52 mmol) in MeOH (5.00 mL) was added SOCl at 0 °C. 2 (2.0 mL). The reaction was stirred at room temperature for 12 h. When the reaction was complete, it was concentrated to give 233-2 (1.20 g, 100% yield) as a colorless oil.

[0924] Synthesis of 3-(Benzylamino)-2-hydroxypropionic acid (b-233)

[0925]

[0926] 233-2 (1.20 g, 10.1 mmol), benzaldehyde (1.07 g, 10.1 mmol) and Et 3 To a solution of N (2.03 g, 20.1 mmol) in MeOH (50.0 mL) was added NaBH 4 (1.91 g, 50.4 mmol). The reaction was stirred at room temperature overnight. When the reaction was complete, it was concentrated and purified by silica gel column chromatography (CH 2 Cl 2 / MeOH=5 / 1) to afford 219-3 (1.00 g, 60% yield) as a white solid.

[0927] Synthesis of tert-butyl 3-(benzylamino)propylcarbamate (b-235)

[0928]

[0929] To a solution of 235-1 (1.00 g, 9.43 mmol) and tert-butyl 3-aminopropylcarbamate (1.81 g, 10.4 mmol) in EtOH (50.0 mL) was added NaBH at 0 °C. 4 (358 mg, 9.43 mmol). The reaction was stirred at room temperature overnight. When the reaction was complete, it was concentrated and purified by silica gel column chromatography (CH 2 Cl 2 / MeOH=50 / 1) to afford b-235 (300 mg, 12% yield) as a yellow solid.

[0930] Synthesis of tert-butyl (2-aminoethylamino)(tert-butoxycarbonylamino)methylenecarbamate (b-242)

[0931]

[0932] 242-1 (60.0 mg, 1.00 mmol) and a (319 mg, 1.10 mmol) were dissolved in CH 2 Cl 2 The mixture in 4% paraformaldehyde (30.0 mL) was stirred at room temperature for 3 h. When the reaction was complete, the reaction mixture was filtered and the residue was purified by washing with CH 2 Cl 2 The mixture was washed with 1% paraformaldehyde (2.0 mL x 2) and dried to obtain b-242 (300 mg, 90% yield) as a yellow solid.

[0933] Synthesis of tert-butyl 2-sulfamoylethylcarbamate (b-243)

[0934]

[0935] 243-1 (200 mg, 1.61 mmol), (Boc) 2 O (387 mg, 1.77 mmol) and Et 3 A mixture of N (325 mg, 3.22 mmol) in THF (10.0 mL) was stirred at room temperature overnight. When the reaction was complete, the reaction mixture was concentrated to give the crude product, which was used directly in the next step without further purification to give b-243 (300 mg, 83% yield) as a yellow solid.

[0936] Synthesis of tert-butyl 3-(3-benzoylthioureido)-2-benzylpropionate (152-2)

[0937]

[0938] A mixture of s-2 (5.00 g, 21.2 mmol) and benzocyanic acid thioanhydride (4.19 g, 25.5 mmol) in THF (100 mL) was stirred at room temperature for 1 h. When the reaction was complete, the reaction mixture was filtered and the residue was purified by CH 2 Cl 2 (3.0 mL×2) and dried to obtain 152-2 (6.00 g, 71% yield) as a white solid.

[0939] Synthesis of tert-butyl 2-benzyl-3-thioureidopropionate (152-s)

[0940]

[0941] 152-2 (6.00 g, 15.1 mmol) and Na 2 CO 3 A mixture of (3.19 g, 30.1 mmol) in MeOH (100 mL) was stirred at room temperature for 4 h. When the reaction was complete, the reaction mixture was filtered and the filtrate was concentrated to give the crude product, which was purified by silica gel column chromatography (petroleum ether / ethyl acetate=10 / 1) to give 152-s (1.00 g, 23% yield) as a white solid.

[0942] Synthesis of 4-(3,4-dichlorophenyl)-5-isobutylthiazol-2-amine (178-s)

[0943]

[0944] A mixture of c-2 (2.00 g, 6.17 mmol) and thiourea (564 mg, 7.41 mmol) in EtOH (50.0 mL) was stirred at 90° C. for 3 h. When the reaction was completed, it was concentrated to give a crude product, which was purified by silica gel column chromatography (petroleum ether / ethyl acetate=5 / 1) to give 178-s (1.20 g, 65% yield) as a white solid.

[0945] Synthesis of methyl 2-benzyl-3-(4-(3,4-dichlorophenyl)thiazol-2-ylamino)propanoate (224-4)

[0946]

[0947] A mixture of 115 (1.00 g, 3.47 mmol) and 1 (805 mg, 4.16 mmol) in EtOH (50.0 mL) was stirred overnight at 60° C. When the reaction was completed, it was concentrated and purified by silica gel column chromatography (petroleum ether / ethyl acetate=10 / 1) to give 224-4 (800 mg, 47% yield) as a yellow oil.

[0948] Synthesis of methyl 2-benzyl-3-(5-bromo-4-(3,4-dichlorophenyl)thiazol-2-ylamino)propanoate (224-s)

[0949]

[0950] A mixture of 224-4 (800 mg, 1.90 mmol) and NBS (338 mg, 1.90 mmol) in AcOH (10.0 mL) was stirred at room temperature for 1 h. When the reaction was complete, it was concentrated and purified by silica gel column chromatography (petroleum ether / ethyl acetate=10 / 1) to give 224-s (600 mg, 63% yield) as a colorless oil.

[0951] Table 3-2: Characterization data of compounds

[0952]

[0953]

[0954]

[0955]

[0956] Synthesis of 3-(Benzyl(4-(3,4-dichlorophenyl)-5-formylthiazol-2-yl)amino)propionic acid (I-119)

[0957]

[0958] 115-2 (80.0 mg, 0.173 mmol) was dissolved in THF / MeOH / H 2 LiOH (2.0 M in H 2 O) was added to the solution in H 2 O (v / v / v = 4 / 1 / 1, 10.0 mL). 2 O, 0.22 mL). The reaction was stirred at room temperature for 2 h. When the reaction was complete, the resulting reaction was concentrated and then washed with H 2 O (10 mL), and the pH was adjusted to 4-5 with HCl (1.0 M). The mixture was extracted with EtOAc (40.0 mL×2), and the combined organic phases were washed with brine (30.0 mL), and dried over anhydrous Na 2 SO 4 After drying and concentration, the residue was purified by preparative HPLC to give 1-119 (30.0 mg, 40% yield) as a white solid.

[0959] Synthesis of ethyl 3-(benzyl(4-(3,4-dichlorophenyl)-5-(methoxymethyl)thiazol-2-yl)amino)propanoate (149-1)

[0960]

[0961] To 115-3 (250 mg, 0.54 mmol) and Et 3 N (109 mg, 1.07 mmol) in CH 2 Cl 2 MsCl (123 mg, 1.07 mmol) was added to the solution in (10.0 mL). The reactant was stirred at room temperature for 3 h. When the reaction was complete, it was concentrated. The residue was dissolved with MeOH (10.0 mL). The reactant was stirred at room temperature for 16 h. When the reaction was complete, it was concentrated to give a crude product, which was purified by silica gel column chromatography (petroleum ether / ethyl acetate=10 / 1) to give 149-1 (75.0 mg, 29% yield) as a yellow oil.

[0962] Synthesis of 3-(Benzyl(4-(3,4-dichlorophenyl)-5-(methoxymethyl)thiazol-2-yl)amino)propanoic acid (I-120)

[0963]

[0964] 149-1 (75.0 mg, 0.156 mmol) was dissolved in THF / MeOH / H 2 LiOH (2.0 M in H 2 O) was added to the solution in H 2 O (v / v / v = 4 / 1 / 1, 10.0 mL). 2O, 0.20 mL). The reaction was stirred at room temperature for 6 h. When the reaction was complete, the resulting reaction was concentrated and then washed with H 2 O (10.0 mL), and the pH was adjusted to 4-5 with HCl (1.0 M). The mixture was extracted with EtOAc (40 mL×2), and the combined organic phases were washed with brine (30 mL), and dried over anhydrous Na 2 SO 4 After drying and concentration, the residue was purified by preparative HPLC to give 1-120 (15.0 mg, 21% yield) as a white solid.

[0965] Synthesis of ethyl 3-(3,4-dichlorophenyl)-3-oxopropionate (152-2)

[0966]

[0967] To a mixture of 152-1 (5.00 g, 26.4 mmol) and t-BuOK (1.0 M in THF, 52.9 mL, 52.9 mmol) in THF (50.0 mL) at room temperature, diethyl carbonate (4.69 g, 39.7 mmol) was added. The reactants were stirred at 60 ° C for 6 h. When the reaction was complete, the mixture was concentrated and purified by silica gel column chromatography (petroleum ether / ethyl acetate=50 / 1) to give 152-2 (3.50 g, 51% yield) as a yellow oil.

[0968] Synthesis of ethyl 2-bromo-3-(3,4-dichlorophenyl)-3-oxopropionate (152-3)

[0969]

[0970] A mixture of 152-2 (1.00 g, 3.83 mmol) and PTAT (2.15 g, 5.74 mmol) in THF (100 mL) was stirred at room temperature for 1 h. When the reaction was complete, it was concentrated and the residue was dissolved in H 2 O (100 mL), and then extracted with EtOAc (100 mL × 3). The organic layers were combined and washed with H 2 O (50.0 mL x 2) and brine (50.0 mL), followed by anhydrous Na 2 SO 4 The solution was concentrated and purified by silica gel column chromatography (petroleum ether / ethyl acetate=50 / 1) to give 152-3 (850 mg, 65% yield) as a yellow oil.

[0971] Synthesis of ethyl 2-(benzyl(3-tert-butoxy-3-oxopropyl)amino)-4-(3,4-dichlorophenyl)thiazole-5-carboxylate (152-4)

[0972]

[0973] A mixture of 152-3 (500 mg, 1.47 mmol) and 152-s (433 mg, 1.47 mmol) in t-BuOH (20.0 mL) was stirred at 90° C. for 1 h. When the reaction was complete, the mixture was purified by silica gel column chromatography (petroleum ether / ethyl acetate=10 / 1) to give 152-4 (430 mg, 55% yield) as a yellow oil.

[0974] Synthesis of 2-(Benzyl(2-carboxyethyl)amino)-4-(3,4-dichlorophenyl)thiazole-5-carboxylic acid (152-5)

[0975]

[0976] To a solution of 152-4 (80.0 mg, 0.149 mmol) in THF / MeOH (v / v / v=4 / 1, 5.0 mL) was added NaOH (2.0 M in H 2 O, 0.37 mL). The reaction was stirred at room temperature for 16 h. When the reaction was complete, the resulting reaction was concentrated and then washed with H 2 O (10.0 mL), and the pH was adjusted to 4-5 with HCl (1.0 M). The mixture was extracted with EtOAc (40 mL×2), and the combined organic phases were washed with brine (30.0 mL), and dried over anhydrous Na 2 SO 4 Drying and concentration gave 152-5 (45.0 mg, 67% yield) as a yellow oil.

[0977] Synthesis of 2-(Benzyl(3-(methylamino)-3-oxopropyl)amino)-4-(3,4-dichlorophenyl)-N-methylthiazole-5-carboxamide (I-123)

[0978]

[0979] A mixture of 152-5 (10.0 mg, 0.022 mmol), methylamine (1.03 mg, 0.033 mmol), HATU (16.7 mg, 0.044 mmol) and DIPEA (8.51 mg, 0.066 mmol) in DMF (1.00 mL) was stirred at room temperature for 16 h. When the reaction was complete, it was poured into H 2 O (10.0 mL), and then extracted with EtOAc (20.0 mL × 2). The organic layers were combined and washed with H 2O (10.0 mL x 2) and brine (10.0 mL), followed by anhydrous Na 2 SO 4 The solution was concentrated to give the crude product, which was purified by preparative HPLC to afford 1-123 (3.5 mg, 26% yield) as a white solid.

[0980] Synthesis of tert-butyl 3-(benzyl(5-carbamoyl-4-(3,4-dichlorophenyl)thiazol-2-yl)amino)propanoate (154-1)

[0981]

[0982] 152-4 (70.0 mg, 0.131 mmol) and NH 3 A mixture of (7.0 M in MeOH, 1.00 mL) in MeOH (1.00 mL) was stirred at 80° C. for 16 h. When the reaction was complete, the mixture was concentrated and purified by preparative TLC to give 154-1 (23.0 mg, 38% yield) as a yellow oil.

[0983] Synthesis of 3-(Benzyl(5-carbamoyl-4-(3,4-dichlorophenyl)thiazol-2-yl)amino)propionic acid (I-124)

[0984]

[0985] 154-1 (23.0 mg, 0.050 mmol) was dissolved in THF / MeOH / H 2 LiOH (2.0 M in HO) was added to the solution in HO (v / v / v = 4 / 1 / 1, 2.0 mL). 2 O, 0.062 mL). The reaction was stirred at room temperature for 6 h. When the reaction was complete, the resulting reaction was concentrated and then washed with H 2 O (10.0 mL), and the pH was adjusted to 4-5 with HCl (1.0 M). The mixture was extracted with EtOAc (40 mL×2), and the combined organic phases were washed with brine (30 mL), and dried over anhydrous Na 2 SO 4 After drying and concentration, the residue was purified by preparative HPLC to give 1-124 (9.0 mg, 40% yield) as a white solid.

[0986] Synthesis of methyl 2-((4-(3,4-dichlorophenyl)-5-isobutylthiazol-2-ylamino)methyl)-6-(1,3-dioxoisoindolin-2-yl)hexanoate (157-1)

[0987]

[0988] A mixture of b-157 (300 mg, 0.985 mmol), c (326 mg, 1.08 mmol) and AcOH (118 mg, 1.97 mmol) in i-PrOH (10.0 mL) was stirred at 90° C. for 3 h. When the reaction was completed, the mixture was purified by preparative TLC (petroleum ether / ethyl acetate=8 / 1) to give 157-1 (250 mg, 43% yield) as a yellow solid.

[0989] Synthesis of methyl 6-amino-2-((4-(3,4-dichlorophenyl)-5-isobutylthiazol-2-ylamino)methyl)hexanoate (157-2)

[0990]

[0991] A mixture of 157-1 (250 mg, 0.425 mmol) and hydrazine hydrate (106 mg, 2.12 mmol) in MeOH (10.0 mL) was stirred at 60 °C for 2 h. When the reaction was complete, it was concentrated to give a crude product, which was purified by heating with H 2 O (2.00 mL x 3) to obtain 157-2 (120 mg, 62% yield) as a yellow oil.

[0992] Synthesis of 6-amino-2-((4-(3,4-dichlorophenyl)-5-isobutylthiazol-2-ylamino)methyl)hexanoic acid (I-125)

[0993]

[0994] 157-2 (120 mg, 0.050 mmol) was dissolved in THF / MeOH / H 2 LiOH (2.0 M in H 2 O) was added to the solution in H 2 O (v / v / v = 4 / 1 / 1, 5.0 mL). 2 O, 0.33 mL). The reaction was stirred at room temperature for 6 h. When the reaction was complete, the resulting reaction was concentrated and then washed with H 2 O (10.0 mL), and the pH was adjusted to 4-5 with HCl (1.0 M). The mixture was extracted with EtOAc (40 mL×2), and the combined organic phases were washed with brine (30 mL), and dried over anhydrous Na 2 SO 4 After drying and concentration, the residue was purified by preparative HPLC to give 1-125 (30.0 mg, 26% yield) as a white solid.

[0995] Synthesis of ethyl 3-(benzyl(5-isobutyl-4-(4-(thiophen-3-yl)phenyl)thiazol-2-yl)amino)propanoate (159-1)

[0996]

[0997] A mixture of b-1 (98.6 mg, 0.476 mmol), 159 (150 mg, 0.476 mmol) and AcOH (57.1 mg, 0.951 mmol) in i-PrOH (2.0 mL) was stirred overnight at 90° C. When the reaction was complete, the mixture was purified by preparative TLC (petroleum ether / ethyl acetate=8 / 1) to give 159-1 (100 mg, 42% yield) as a yellow solid.

[0998] Synthesis of 3-(Benzyl(5-isobutyl-4-(4-(thiophen-3-yl)phenyl)thiazol-2-yl)amino)propanoic acid (I-126)

[0999]

[1000] 159-1 (100 mg, 0.198 mmol) was dissolved in THF / MeOH / H 2 LiOH (2.0 M in H 2 O) was added to the solution in H 2 O (v / v / v = 4 / 1 / 1, 5.0 mL). 2 O, 0.25 mL). The reaction was stirred at room temperature for 6 h. When the reaction was complete, the resulting reaction was concentrated and then washed with H 2 O (10.0 mL), and the pH was adjusted to 4-5 with HCl (1.0 M). The mixture was extracted with EtOAc (40 mL×2), and the combined organic phases were washed with brine (30 mL), and dried over anhydrous Na 2 SO 4 After drying and concentration, the residue was purified by preparative HPLC to give 1-126 (16.0 mg, 17% yield) as a white solid.

[1001] Synthesis of ethyl 3-(benzyl(5-isobutyl-4-(4-(methylsulfonyl)phenyl)thiazol-2-yl)amino)propanoate (162-1)

[1002]

[1003] 161-1 (500 mg, 1.07 mmol) was added to CH at 0 °C. 2 Cl 2 m-CPBA (552 mg, 3.20 mmol) was added to the solution in 4% paraformaldehyde (15.0 mL). The reaction was stirred at room temperature overnight. When the reaction was complete, the mixture was concentrated and analyzed by preparative TLC (CH 2 Cl 2 / MeOH=100 / 1) to afford 162-1 (200 mg, 37% yield) as a white solid.

[1004] Synthesis of 3-(Benzyl(5-isobutyl-4-(4-(methylsulfonyl)phenyl)thiazol-2-yl)amino)propanoic acid (I-128)

[1005]

[1006] 162-1 (200 mg, 0.399 mmol) was dissolved in THF / MeOH / H 2 LiOH (2.0 M in H 2 O) was added to the solution in H 2 O (v / v / v = 4 / 1 / 1, 10.0 mL). 2 O, 0.50 mL). The reaction was stirred at room temperature for 6 h. When the reaction was complete, the resulting reaction was concentrated and then washed with H 2 O (10.0 mL), and the pH was adjusted to 4-5 with aqueous HCl (1.0 M). The mixture was extracted with EtOAc (40.0 mL×2), and the combined organic phases were washed with brine (30.0 mL), and dried over anhydrous Na 2 SO 4 Drying, concentration and purification by preparative HPLC gave 1-128 (50.0 mg, 26% yield) as a white solid.

[1007] Synthesis of ethyl 3-(benzyl(4-(3,4-dichlorophenyl)-5-(1-hydroxyethyl)thiazol-2-yl)amino)propanoate (163-1)

[1008]

[1009] To a solution of 115-2 (350 mg, 0.755 mmol) in THF (20.0 mL) was added methylmagnesium bromide (1.0 M in THF, 1.13 mL, 1.13 mmol) at -40 °C. The reaction was stirred at room temperature overnight. When the reaction was complete, it was washed with NH 4 The mixture was quenched with aqueous Cl solution (20.0 mL), followed by extraction with EtOAc (100 mL×2). The organic layers were combined and washed with H 2 O (60.0 mL x 2) and brine (80.0 mL), followed by anhydrous Na 2 SO 4 The solution was concentrated to give a crude product, which was purified by preparative TLC (petroleum ether / ethyl acetate=8 / 1) to give 163-1 (80.0 mg, 22% yield) as a yellow solid.

[1010] Synthesis of 3-(Benzyl(4-(3,4-dichlorophenyl)-5-vinylthiazol-2-yl)amino)propionic acid (I-129)

[1011]

[1012] 163-1 (80.0 mg, 0.167 mmol) was dissolved in THF / MeOH / H 2 LiOH (2.0 M in H 2 O) was added to the solution in H 2 O (v / v / v = 4 / 1 / 1, 5.0 mL). 2 O, 0.21 mL). The reaction was stirred at room temperature for 6 h. When the reaction was complete, the resulting reaction was concentrated and then washed with H 2 O (10.0 mL), and the pH was adjusted to 4-5 with HCl (1.0 M). The mixture was extracted with EtOAc (40.0 mL×2), and the combined organic phases were washed with brine (30.0 mL), and dried over anhydrous Na 2 SO 4 Drying, concentration and purification by preparative HPLC afforded 1-129 (12.0 mg, 17% yield) as a white solid.

[1013] Synthesis of tert-butyl 2-(3-(benzyl(4-(3,4-dichlorophenyl)-5-isobutylthiazol-2-yl)amino)propionamido)ethylcarbamate (168-1)

[1014]

[1015] A mixture of I-47 (250 mg, 0.539 mmol), tert-butyl 2-aminoethylcarbamate (130 mg, 0.809 mmol), HATU (410 mg, 1.08 mmol) and DIPEA (209 mg, 1.62 mmol) in DMF (5.00 mL) was stirred at room temperature overnight. When the reaction was complete, it was poured into H 2 O (100 mL), and then extracted with EtOAc (200 mL × 2). The organic layers were combined and washed with H 2 O (100 mL x 2) and brine (100 mL), followed by anhydrous Na 2 SO 4 The solution was concentrated to give the crude product, which was used directly in the next step without further purification to give 168-1 (200 mg, 61% yield) as a yellow solid.

[1016] Synthesis of N-(2-aminoethyl)-3-(benzyl(4-(3,4-dichlorophenyl)-5-isobutylthiazol-2-yl)amino)propanamide (I-131)

[1017]

[1018] A mixture of 168-1 (200 mg, 0.330 mmol) in HCl (4.0 M in dioxane, 5.00 mL) was stirred at room temperature for 2 h. When the reaction was complete, it was concentrated to give a crude product, which was purified by preparative HPLC to give I-131 (60.0 mg, 36% yield) as a white solid.

[1019] Synthesis of 3-(Benzyl(4-(3,4-dichlorophenyl)-5-isobutylthiazol-2-yl)amino)-1-(4-methylpiperazin-1-yl)propan-1-one (I-133)

[1020]

[1021] A mixture of I-47 (150 mg, 0.324 mmol), 1-methylpiperazine (48.6 mg, 0.486 mmol), HATU (246 mg, 0.648 mmol) and DIPEA (125 mg, 0.972 mmol) in DMF (5.00 mL) was stirred at room temperature for 16 h. When the reaction was complete, it was poured into H 2 O (100 mL), and then extracted with EtOAc (200 mL × 2). The organic layers were combined and washed with H 2 O (100 mL x 2) and brine (100 mL), followed by anhydrous Na 2 SO 4 The solution was concentrated to give the crude product, which was purified by preparative HPLC to afford 1-133 (75 mg, 42% yield) as a white solid.

[1022] Synthesis of 2-Benzamido-3-(4-(3,4-dichlorophenyl)-5-isobutylthiazol-2-ylamino)propionic acid (I-136)

[1023]

[1024] I-115 (200 mg, 0.515 mmol) and Et 3 To a mixture of N (156 mg, 1.55 mmol) in THF (10.0 mL) was added benzoyl chloride (145 mg, 1.03 mmol). The reaction was stirred at room temperature for 2 h. When the reaction was complete, it was concentrated and purified by preparative HPLC to give I-136 (25 mg, 9.9% yield) as a white solid.

[1025] Synthesis of 2-(tert-butoxycarbonylamino)-3-(4-(3,4-dichlorophenyl)-5-isobutylthiazol-2-ylamino)propanoic acid (I-137)

[1026]

[1027] A mixture of c (500 mg, 1.66 mmol), 3-amino-2-(tert-butoxycarbonylamino)propanoic acid (407 mg, 1.99 mmol) and AcOH (199 mg, 3.32 mmol) in i-PrOH (20.0 mL) was stirred overnight at 90° C. When the reaction was complete, the mixture was purified by preparative HPLC to give I-137 (96.0 mg, 12% yield) as a white solid.

[1028] Synthesis of 2-(benzyloxycarbonylamino)-3-(4-(3,4-dichlorophenyl)-5-isobutylthiazol-2-ylamino)propanoic acid (I-138)

[1029]

[1030] I-115 (200 mg, 0.515 mmol) and K were added at 0 °C. 2 CO 3 (214 mg, 1.55 mmol) in THF / H 2 Benzyl carbonate 2,5-dioxopyrrolidin-1-yl ester (257 mg, 1.03 mmol) was added to the mixture in 0 (v / v=4 / 1, 10.0 mL). The reaction was stirred at room temperature for 2 h. When the reaction was complete, it was concentrated and purified by preparative HPLC to give I-138 (65.0 mg, 24% yield) as a white solid.

[1031] Synthesis of 1-(4-(3,4-dichlorophenyl)-5-isobutylthiazol-2-yl)-2-oxoazetidin-3-ylcarbamic acid ethyl ester (I-139)

[1032]

[1033] I-115 (300 mg, 0.773 mmol) and Et 3 To a mixture of N (234 mg, 2.32 mmol) in THF (10.0 mL) was added ethyl chloroformate (168 mg, 1.55 mmol). The reaction was stirred at room temperature for 2 h. When the reaction was complete, it was concentrated and purified by preparative HPLC to give I-139 (50.0 mg, 15% yield) as a white solid.

[1034] Synthesis of 2-(4-(3,4-dichlorophenyl)-5-isobutylthiazol-2-ylamino)benzonitrile (178-1)

[1035]

[1036] 178-s (500 mg, 1.66 mmol), 2-fluorobenzonitrile (241 mg, 1.99 mmol) and Cs 2 CO 3 A mixture of (1.08 g, 3.32 mmol) in DMF (10.0 mL) was stirred at 150 °C under microwave for 1 h. When the reaction was complete, it was poured into H 2 O (100 mL), and then extracted with EtOAc (100 mL × 2). The organic layers were combined and washed with H 2 O (50.0 mL x 2) and brine (50.0 mL), followed by anhydrous Na 2 SO 4 The solution was concentrated and purified by silica gel column chromatography (petroleum ether / ethyl acetate=10 / 1) to give 178-1 (220 mg, 33% yield) as a yellow solid.

[1037] Synthesis of 2-(4-(3,4-dichlorophenyl)-5-isobutylthiazol-2-ylamino)benzoic acid (I-141)

[1038]

[1039] 178-1 (100 mg, 0.25 mmol) and NaOH (5.0 M in H 2 O, 0.25 mL, 1.24 mmol) in EtOH / H 2 The mixture in 2% CO 2 (2.00 mL) was stirred at 90° C. overnight. When the reaction was complete, the mixture was purified by preparative HPLC to give I-141 (15.0 mg, 14% yield) as a yellow solid.

[1040] Synthesis of methyl 3-(4-(3,4-dichlorophenyl)-5-isobutylthiazol-2-ylamino)benzoate (179-1)

[1041]

[1042] 178-s (300 mg, 0.996 mmol), methyl 3-iodobenzoate (313 mg, 1.20 mmol), Pd catalyst (CAS: 1310584-14-5, 15.7 mg, 0.199 mmol) and Cs 2 CO 3A mixture of (649 mg, 1.99 mmol) in DMF (5.0 mL) was stirred at 90 °C under microwave for 3 h. When the reaction was complete, it was poured into H 2 O (80.0 mL), and then extracted with EtOAc (100 mL × 2). The organic layers were combined and washed with H 2 O (50.0 mL x 2) and brine (50.0 mL), followed by anhydrous Na 2 SO 4 The solution was concentrated and purified by silica gel column chromatography (petroleum ether / ethyl acetate=10 / 1) to give 179-1 (58.0 mg, 13% yield) as a yellow solid.

[1043] Synthesis of 3-(4-(3,4-dichlorophenyl)-5-isobutylthiazol-2-ylamino)benzoic acid (I-142)

[1044]

[1045] 179-1 (58.0 mg, 0.133 mmol) was dissolved in THF / MeOH / H 2 LiOH (2.0 M in H 2 O) was added to the solution in H 2 O (v / v / v = 4 / 1 / 1, 5.0 mL). 2 O, 0.17 mL). The reaction was stirred at room temperature for 6 h. When the reaction was complete, the resulting reaction was concentrated and then washed with H 2 O (10.0 mL), and the pH was adjusted to 4-5 with aqueous HCl (1.0 M). The mixture was extracted with EtOAc (40.0 mL×2), and the combined organic phases were washed with brine (30.0 mL), and dried over anhydrous Na 2 SO 4 Drying, concentration and purification by preparative HPLC gave 1-142 (10.0 mg, 18% yield) as a white solid.

[1046] Synthesis of N-Benzyl-4-(3,4-dichlorophenyl)-5-isobutylthiazol-2-amine (180-1)

[1047]

[1048] A mixture of c (500 mg, 1.66 mmol) and phenylmethylamine (214 mg, 1.99 mmol) in i-PrOH (20.0 mL) was stirred overnight at 90° C. When the reaction was complete, the mixture was purified by preparative TLC (petroleum ether / ethyl acetate=8 / 1) to give 180-1 (200 mg, 31% yield) as a yellow solid.

[1049] Synthesis of tert-butyl 3-(benzyl(4-(3,4-dichlorophenyl)-5-isobutylthiazol-2-yl)amino)-3-oxopropanoate (180-2)

[1050]

[1051] 180-1 (200 mg, 0.511 mmol) and Et 3 N (103 mg, 1.02 mmol) in CH 2 Cl 2 To the mixture in 4% paraformaldehyde (10.0 mL) was added tert-butyl 3-chloro-3-oxopropanoate (137 mg, 0.767 mmol). The reactant was refluxed for 5 h. When the reaction was complete, it was concentrated and purified by preparative TLC (petroleum ether / ethyl acetate=8 / 1) to give 180-2 (100 mg, 37% yield) as a yellow solid.

[1052] Synthesis of 3-(Benzyl(4-(3,4-dichlorophenyl)-5-isobutylthiazol-2-yl)amino)-3-oxopropanoic acid (I-143)

[1053]

[1054] A mixture of 180-2 (100 mg, 0.187 mmol) in HCl (4.0 M in dioxane, 3.00 mL) was stirred at room temperature for 5 h. When the reaction was complete, it was concentrated to give a crude product, which was purified by preparative HPLC to give I-143 (32.0 mg, 36% yield) as a white solid.

[1055] Synthesis of methyl 2-((4-(3,4-dichlorophenyl)-5-isobutylthiazol-2-ylamino)methyl)-6-(dimethylamino)hexanoate (183-1)

[1056]

[1057] 157-2 (200 mg, 0.436 mmol) and formaldehyde (37% in H 2 O, 74.4 mg, 0.916 mmol) in MeOH (50.0 mL) was added with NaBH 4 (33.1 mg, 0.872 mmol). The reaction was stirred at room temperature for 4 h. When the reaction was completed, it was concentrated and purified by preparative TLC (petroleum ether / ethyl acetate=8 / 1) to give 183-1 (100 mg, 47% yield) as a yellow solid.

[1058] Synthesis of 2-((4-(3,4-dichlorophenyl)-5-isobutylthiazol-2-ylamino)methyl)-6-(dimethylamino)hexanoic acid (I-145)

[1059]

[1060] 183-1 (100 mg, 0.206 mmol) was dissolved in THF / MeOH / H 2 LiOH (2.0 M in H 2 O) was added to the solution in H 2 O (v / v / v = 4 / 1 / 1, 10.0 mL). 2 O, 0.26 mL). The reaction was stirred at room temperature for 6 h. When the reaction was complete, the resulting reaction was concentrated and then washed with H 2 O (10.0 mL), and the pH was adjusted to 4-5 with HCl (1.0 M). The mixture was extracted with EtOAc (40.0 mL×2), and the combined organic phases were washed with brine (30.0 mL), and dried over anhydrous Na 2 SO 4 Drying and concentration gave the crude product, which was purified by preparative HPLC to afford 1-145 (20.0 mg, 21% yield) as a white solid.

[1061] Synthesis of ethyl 3-((4-(tert-butoxycarbonylamino)butyl)(4-(3,4-dichlorophenyl)-5-isobutylthiazol-2-yl)amino)propanoate (184-2)

[1062]

[1063] A mixture of c (324 mg, 1.07 mmol) and b-184 (310 mg, 1.07 mmol) in i-PrOH (10.0 mL) was stirred at 70° C. for 16 h. When the reaction was completed, the mixture was purified by preparative TLC (petroleum ether / ethyl acetate=8 / 1) to give 184-2 (180 mg, 29% yield) as a yellow solid.

[1064] Synthesis of 3-((4-(tert-butoxycarbonylamino)butyl)(4-(3,4-dichlorophenyl)-5-isobutylthiazol-2-yl)amino)propanoic acid (184-3)

[1065]

[1066] 184-2 (180 mg, 0.314 mmol) was dissolved in THF / MeOH / H 2 LiOH (2.0 M in H 2 O) was added to the solution in H 2 O (v / v / v = 4 / 1 / 1, 10.0 mL). 2O, 0.39 mL). The reaction was stirred at room temperature for 6 h. When the reaction was complete, the resulting reaction was concentrated and then washed with H 2 O (10.0 mL), and the pH was adjusted to 4-5 with HCl (1.0 M). The mixture was extracted with EtOAc (40.0 mL×2), and the combined organic phases were washed with brine (30.0 mL), and dried over anhydrous Na 2 SO 4 Drying and concentration gave the crude product, which was used directly in the next step without further purification to afford 184-3 (180 mg, 100% yield) as a white solid.

[1067] Synthesis of 3-((4-aminobutyl)(4-(3,4-dichlorophenyl)-5-isobutylthiazol-2-yl)amino)propanoic acid (I-146)

[1068]

[1069] 184-3 (180 mg, 0.331 mmol) and HCl (4.0 M in dioxane, 5.00 mL) were dissolved in CH 2 Cl 2 The mixture in 4% paraformaldehyde (10.0 mL) was stirred at room temperature for 16 h. When the reaction was complete, it was concentrated to give the crude product, which was purified by preparative HPLC to afford I-146 (20.0 mg, 14% yield) as a white solid.

[1070] Synthesis of ethyl 3-((4-(3,4-dichlorophenyl)-5-isobutylthiazol-2-yl)(4-(dimethylamino)butyl)amino)propanoate (185-1)

[1071]

[1072] A mixture of c (181 mg, 0.601 mmol) and b-185 (130 mg, 0.601 mmol) in i-PrOH (5.0 mL) was stirred at 70 °C for 16 h. When the reaction was complete, the mixture was analyzed by preparative TLC (CH 2 Cl 2 / MeOH=80 / 1) to afford 185-1 (30.0 mg, 10% yield) as a yellow solid.

[1073] Synthesis of 3-((4-(3,4-dichlorophenyl)-5-isobutylthiazol-2-yl)(4-(dimethylamino)butyl)amino)propionic acid (I-147)

[1074]

[1075] 185-1 (30.0 mg, 0.0599 mmol) was dissolved in THF / MeOH / H 2 LiOH (2.0 M in HO) was added to the solution in HO (v / v / v = 4 / 1 / 1, 1.0 mL). 2 O, 0.07 mL). The reaction was stirred at room temperature for 4 h. When the reaction was complete, the resulting reaction was concentrated and then washed with H 2 O (5.0 mL), and the pH was adjusted to 4-5 with HCl (1.0 M). The mixture was extracted with EtOAc (20.0 mL×2), and the combined organic phases were washed with brine (10.0 mL), and dried over anhydrous Na 2 SO 4 Drying and concentration gave the crude product, which was purified by preparative HPLC to afford 1-147 (3.20 mg, 11% yield) as a white solid.

[1076] Synthesis of methyl 3-(4-(3,4-dichlorophenyl)-5-isobutylthiazol-2-ylamino)-2-((2-hydroxypyrimidin-5-yl)methyl)propanoate (197-1)

[1077]

[1078] A mixture of 198-1 (150 mg, 0.294 mmol), TsOH (254 mg, 1.47 mmol) and LiCl (62.3 mg, 1.47 mmol) in DMF (5.0 mL) was stirred at 120 °C for 2 h. When the reaction was complete, it was poured into H 2 O (80.0 mL), and then extracted with EtOAc (100 mL × 2). The organic layers were combined and washed with H 2 O (50.0 mL x 2) and brine (50.0 mL), followed by anhydrous Na 2 SO 4 The solution was concentrated to give the crude product, which was used directly in the next step without further purification to afford 197-1 (150 mg, 100% yield) as a yellow oil.

[1079] Synthesis of 3-(4-(3,4-dichlorophenyl)-5-isobutylthiazol-2-ylamino)-2-((2-hydroxypyrimidin-5-yl)methyl)propanoic acid (I-159)

[1080]

[1081] 197-1 (150 mg, 0.303 mmol) was dissolved in THF / MeOH / H 2LiOH (2.0 M in H 2 O) was added to the solution in H 2 O (v / v / v = 4 / 1 / 1, 5.0 mL). 2 O, 0.38 mL). The reaction was stirred at room temperature for 6 h. When the reaction was complete, the resulting reaction was concentrated and then washed with H 2 O (5.0 mL), and the pH was adjusted to 4-5 with HCl (1.0 M). The mixture was extracted with EtOAc (20.0 mL×2), and the combined organic phases were washed with brine (10.0 mL), and dried over anhydrous Na 2 SO 4 Drying and concentration gave the crude product, which was purified by preparative HPLC to afford 1-159 (70.0 mg, 48% yield) as a white solid.

[1082] Synthesis of methyl 4-(3-tert-butoxy-2-((4-(3,4-dichlorophenyl)-5-isobutylthiazol-2-ylamino)methyl)-3-oxopropyl)benzoate (204-1)

[1083]

[1084] A mixture of c (462 mg, 1.53 mmol) and b-204 (450 mg, 1.53 mmol) in EtOH (15 mL) was stirred at 90° C. for 16 h. When the reaction was completed, the mixture was purified by preparative TLC (petroleum ether / ethyl acetate=2 / 1) to give 204-1 (400 mg, 45% yield) as a yellow solid.

[1085] Synthesis of 4-(3-tert-butoxy-2-((4-(3,4-dichlorophenyl)-5-isobutylthiazol-2-ylamino)methyl)-3-oxopropyl)benzoic acid (204-2)

[1086]

[1087] 204-1 (400 mg, 0.0599 mmol) was dissolved in MeOH / H 2 LiOH (2.0 M in H 2 O) was added to the solution in H 2 O (v / v = 1 / 1, 20.0 mL). 2 O, 0.07 mL). The reaction was stirred at room temperature for 2 h. When the reaction was complete, the resulting reaction was concentrated and then washed with H 2 O (20.0 mL), and the pH was adjusted to 4-5 with HCl (1.0 M). The mixture was extracted with EtOAc (30.0 mL×2), and the combined organic phases were washed with brine (20.0 mL), and dried over anhydrous Na 2 SO 4Drying and concentration gave the crude product, which was used directly in the next step without further purification to afford 204-2 (300 mg, 77% yield) as a yellow solid.

[1088] Synthesis of tert-butyl 2-(4-carbamoylbenzyl)-3-(4-(3,4-dichlorophenyl)-5-isobutylthiazol-2-ylamino) propanoate (204-3)

[1089]

[1090] 204-2 (130 mg, 0.231 mmol), NH 4 A mixture of Cl (18.5 mg, 0.346 mmol), HATU (176 mg, 0.462 mmol) and DIPEA (89.4 mg, 0.693 mmol) in DMF (3.00 mL) was stirred at room temperature overnight. When the reaction was complete, it was poured into H 2 O (50.0 mL), and then extracted with EtOAc (100 mL × 2). The organic layers were combined and washed with H 2 O (50.0 mL x 2) and brine (50.0 mL), followed by anhydrous Na 2 SO 4 The solution was concentrated to give the crude product, which was purified by preparative TLC (petroleum ether / ethyl acetate=1 / 1) to give 204-3 (70.0 mg, 54% yield) as a white solid.

[1091] Synthesis of 2-(4-carbamoylbenzyl)-3-(4-(3,4-dichlorophenyl)-5-isobutylthiazol-2-ylamino)propanoic acid (I-166)

[1092]

[1093] A mixture of 204-3 (70.0 mg, 0.124 mmol) in HCl (4.0 M in dioxane, 3.00 mL) was stirred at room temperature for 5 h. When the reaction was complete, it was concentrated to give a crude product, which was purified by preparative HPLC to give I-166 (20.0 mg, 32% yield) as a white solid.

[1094] Synthesis of tert-butyl 3-(4-(3,4-dichlorophenyl)-5-isobutylthiazol-2-ylamino)-2-(3-(dimethylcarbamoyl)benzyl)propanoate (206-1)

[1095]

[1096] A mixture of 205-2 (200 mg, 0.355 mmol), dimethylamine (24.0 mg, 0.533 mmol), HATU (270 mg, 0.710 mmol) and DIPEA (137 mg, 1.07 mmol) in DMF (5.00 mL) was stirred at room temperature overnight. When the reaction was complete, it was poured into H 2 O (100 mL), and then extracted with EtOAc (200 mL × 2). The organic layers were combined and washed with H 2 O (80.0 mL x 2) and brine (50.0 mL), followed by anhydrous Na 2 SO 4 The solution was concentrated to give the crude product, which was used directly in the next step without further purification to give 206-1 (200 mg, 95% yield) as a yellow solid.

[1097] Synthesis of 3-(4-(3,4-dichlorophenyl)-5-isobutylthiazol-2-ylamino)-2-(3-(dimethylcarbamoyl)benzyl)propanoic acid (I-168)

[1098]

[1099] A mixture of 206-1 (200 mg, 0.339 mmol) in HCl (4.0 M in dioxane, 5.0 mL) was stirred at room temperature for 5 h. When the reaction was complete, it was concentrated to give a crude product, which was purified by preparative HPLC to give I-168 (30.0 mg, 17% yield) as a white solid.

[1100] Synthesis of methyl 2-benzyl-3-((5-bromo-4-(3,4-dichlorophenyl)thiazol-2-yl)(tert-butoxycarbonyl)amino)propanoate (224-6)

[1101]

[1102] 224-s (1.0 g, 2.00 mmol), (Boc 2 A mixture of 0 (458 mg, 2.10 mmol) and DMAP (366 mg, 3.00 mmol) in THF (20.0 mL) was stirred at room temperature for 2 h. When the reaction was complete, it was concentrated to give a crude product, which was purified by preparative TLC (petroleum ether / ethyl acetate=6 / 1) to give 224-6 (700 mg, 58% yield) as a yellow solid.

[1103] Synthesis of methyl 2-benzyl-3-(tert-butoxycarbonyl(4-(3,4-dichlorophenyl)-5-(methylthio)thiazol-2-yl)amino)propanoate (221-1)

[1104]

[1105] A mixture of 224-6 (200 mg, 0.333 mmol) and NaSMe (28.0 mg, 0.400 mmol) in DMF (2.0 mL) was stirred at 60 °C for 1 h. When the reaction was complete, it was poured into H 2 O (100 mL), and then extracted with EtOAc (200 mL × 2). The organic layers were combined and washed with H 2 O (80.0 mL x 2) and brine (50.0 mL), followed by anhydrous Na 2 SO 4 The solution was concentrated and purified by preparative TLC (petroleum ether / ethyl acetate=5 / 1) to give 221-1 (100 mg, 53% yield) as a yellow oil.

[1106] Synthesis of methyl 2-benzyl-3-(4-(3,4-dichlorophenyl)-5-(methylthio)thiazol-2-ylamino)propanoate (221-2)

[1107]

[1108] A mixture of 221-1 (100 mg, 0.176 mmol) in HCl (4.0 M in dioxane, 3.0 mL) was stirred at room temperature for 5 h. When the reaction was complete, it was concentrated to give the crude product, which was used directly in the next step without further purification to give 221-2 (90.0 mg, 100% yield) as a white solid.

[1109] Synthesis of methyl 2-benzyl-3-(4-(3,4-dichlorophenyl)-5-(methylsulfonyl)thiazol-2-ylamino)propanoate (221-3)

[1110]

[1111] 221-2 (90.0 mg, 0.193 mmol) was added to CH 2 Cl 2 mCPBA (83.1 mg, 0.481 mmol) was added to the solution in 1% ethanol (10.0 mL). The reaction was stirred at room temperature for 3 h. When the reaction was complete, the mixture was concentrated and analyzed by preparative TLC (CH 2 Cl 2 / MeOH=80 / 1) to afford 221-3 (60.0 mg, 62% yield) as a white solid.

[1112] Synthesis of 2-benzyl-3-(4-(3,4-dichlorophenyl)-5-(methylsulfonyl)thiazol-2-ylamino)propionic acid (I-181)

[1113]

[1114] 221-3 (60.0 mg, 0.120 mmol) was dissolved in THF / MeOH / H 2 LiOH (2.0 M in H 2 O) was added to the solution in H 2 O (v / v / v = 4 / 1 / 1, 5.0 mL). 2 O, 0.15 mL). The reaction was stirred at room temperature for 6 h. When the reaction was complete, the resulting reaction was concentrated and then washed with H 2 O (10.0 mL), and the pH was adjusted to 4-5 with HCl (1.0 M). The mixture was extracted with EtOAc (40 mL×2), and the combined organic phases were washed with brine (30 mL), and dried over anhydrous Na 2 SO 4 Dried and concentrated, the residue was purified by prep-HPLC to give 1-181 (7.00 mg, 12% yield) as a white solid.

[1115] Synthesis of 2-benzyl-3-(4-(3,4-dichlorophenyl)-5-(ethoxycarbonyl)thiazol-2-ylamino)propanoic acid (I-182)

[1116]

[1117] 152-4 (250 mg, 0.467 mmol) and HCl (4.0 M in dioxane, 2.0 mL) were dissolved in CH 2 Cl 2 The mixture in 4% paraformaldehyde (10.0 mL) was stirred at room temperature for 16 h. When the reaction was complete, it was concentrated to give the crude product, which was purified by preparative HPLC to afford I-182 (125 mg, 56% yield) as a white solid.

[1118] Synthesis of 2-(2-carboxy-3-phenylpropylamino)-4-(3,4-dichlorophenyl)thiazole-5-carboxylic acid (I-183)

[1119]

[1120] I-182 (50.0 mg, 0.104 mmol) was dissolved in THF / MeOH / H 2 NaOH (2.0 M in H 2 O) was added to the solution in H 2 O (v / v / v = 4 / 1 / 1, 2.0 mL). 2O, 0.13 mL). The reaction was stirred at room temperature for 6 h. When the reaction was complete, the resulting reaction was concentrated and then washed with H 2 O (10.0 mL), and the pH was adjusted to 4-5 with HCl (1.0 M). The mixture was extracted with EtOAc (40.0 mL×2), and the combined organic phases were washed with brine (30.0 mL), and dried over anhydrous Na 2 SO 4 Dried and concentrated, the residue was purified by silica gel column chromatography (EtOAc) to give 1-183 (38.0 mg, 81% yield) as a white solid.

[1121] Synthesis of 1-(3,4-dichlorophenyl)-4,4,4-trifluoro-3-hydroxybutan-1-one (227-2)

[1122]

[1123] 1-Ethoxy-2,2,2-trifluoroethanol (1.99 g, 13.8 mmol) was added to a mixture of 227-1 (2.60 g, 13.8 mmol) and pyrrolidine (687 mg, 9.66 mmol) in THF (50.0 mL). The reactant was refluxed for 48 h. When the reaction was complete, it was concentrated and purified by silica gel column chromatography (petroleum ether / ethyl acetate=30 / 1) to give 227-2 (2.50 g, 63% yield) as a colorless oil.

[1124] Synthesis of (E)-1-(3,4-dichlorophenyl)-4,4,4-trifluorobut-2-en-1-one (227-3)

[1125]

[1126] 227-2 (2.40 g, 8.36 mmol) was added to CH at 0 °C. 2 Cl 2 To the mixture in 50.0 mL was added TFAA (3.51 g, 16.7 mmol) and Et 3 N (2.53 g, 25.1 mmol). The reaction was stirred at room temperature for 6 h. When the reaction was completed, it was concentrated and purified by silica gel column chromatography (petroleum ether / ethyl acetate=50 / 1) to give 227-3 (2.00 g, 63% yield) as a yellow oil.

[1127] Synthesis of 1-(3,4-dichlorophenyl)-4,4,4-trifluorobutan-1-ol (227-4)

[1128]

[1129] 227-3 (2.00 g, 7.43 mmol) and NaBH 4 A mixture of 4-(2.82 g, 74.3 mmol) in EtOH (50.0 mL) was stirred at room temperature overnight. When the reaction was complete, it was concentrated and the residue was dissolved in EtOAc (100 mL), which was washed with H 2 O (50.0 mL × 2) and brine (30.0 mL). The organic layer was washed with anhydrous Na 2 SO 4 Drying and concentration gave the crude product, which was used directly in the next step without further purification to afford 227-4 (2.00 g, 99% yield) as a colorless oil.

[1130] Synthesis of 1-(3,4-dichlorophenyl)-4,4,4-trifluorobutan-1-one (227-5)

[1131]

[1132] 227-4 (2.00 g, 7.32 mmol) was added to CH 2 Cl 2 PCC (2.37 g, 11.0 mmol) was added to a solution of 4% paraformaldehyde (150 mL). The reaction was stirred at room temperature for 3 h. When the reaction was complete, it was concentrated and purified by silica gel column chromatography (petroleum ether / ethyl acetate=100 / 1) to give 227-5 (1.30 g, 65% yield) as a yellow oil.

[1133] Synthesis of 2-bromo-1-(3,4-dichlorophenyl)-4,4,4-trifluorobutan-1-one (227-6)

[1134]

[1135] 227-5 (1.00 g, 3.69 mmol) and Br 2 A mixture of (619 mg 3.87 mmol) in AcOH (10.0 mL) was stirred at 80° C. overnight. When the reaction was complete, it was concentrated and the residue was dissolved with EtOAc (150 mL), which was washed with H 2 O (80.0 mL × 2) and brine (50.0 mL). The organic layer was washed with anhydrous Na 2 SO 4 Drying and concentration gave the crude product, which was purified by silica gel column chromatography (petroleum ether / ethyl acetate=100 / 1) to give 227-6 (720 mg, 56% yield) as a yellow oil.

[1136] Synthesis of tert-butyl 2-benzyl-3-(5-(3,4-dichlorophenyl)-4-(2,2,2-trifluoroethyl)thiazol-2-ylamino)propanoate (227-7)

[1137]

[1138] A mixture of 227-6 (250 mg, 0.713 mmol) and 152-s (210 mg, 0.713 mmol) in EtOH (2.0 mL) was stirred overnight at 80° C. When the reaction was complete, the mixture was concentrated to give the crude product, which was used directly in the next step without further purification to give 227-7 (300 mg, 77% yield) as a yellow oil.

[1139] Synthesis of 2-benzyl-3-(4-(3,4-dichlorophenyl)-5-(2,2,2-trifluoroethyl)thiazol-2-ylamino)propanoic acid (I-184)

[1140]

[1141] 227-7 (300 mg, 0.550 mmol) and HCl (4.0 M in dioxane, 5.0 mL) were dissolved in CH 2 Cl 2 The mixture in 4% paraformaldehyde (10.0 mL) was stirred at room temperature for 16 h. When the reaction was complete, it was concentrated to give the crude product, which was purified by preparative HPLC to afford I-184 (55.0 mg, 20% yield) as a white solid.

[1142] Synthesis of methyl 2-benzyl-3-(4-(3,4-dichlorophenyl)-5-(prop-1-en-2-yl)thiazol-2-ylamino)propanoate (228-1)

[1143]

[1144] A mixture of 224-s (200 mg, 0.400 mmol), tributyl(prop-1-en-2-yl)stannane (199 mg, 0.600 mmol), Pd catalyst (CAS: 1310584-14-5, 62.9 mg, 0.080 mmol) and CsF (122 mg, 0.800 mmol) in DME (5.0 mL) was stirred at 120 °C under microwave for 2 h. When the reaction was complete, it was poured into H 2 O (80 mL), and then extracted with EtOAc (100 mL × 2). The organic layers were combined and washed with H 2 O (50.0 mL x 2) and brine (50.0 mL), followed by anhydrous Na 2 SO 4The solution was concentrated and purified by silica gel column chromatography (petroleum ether / ethyl acetate=10 / 1) to give 228-1 (55.0 mg, 30% yield) as a yellow solid.

[1145] Synthesis of 2-benzyl-3-(4-(3,4-dichlorophenyl)-5-(prop-1-en-2-yl)thiazol-2-ylamino)propanoic acid (I-185)

[1146]

[1147] 228-1 (55.0 mg, 0.119 mmol) was dissolved in THF / MeOH / H 2 LiOH (2.0 M in HO) was added to the solution in HO (v / v / v = 4 / 1 / 1, 2.0 mL). 2 O, 0.15 mL). The reaction was stirred at room temperature for 6 h. When the reaction was complete, the resulting reaction was concentrated and then washed with H 2 O (10.0 mL), and the pH was adjusted to 4-5 with HCl (1.0 M). The mixture was extracted with EtOAc (40 mL×2), and the combined organic phases were washed with brine (30 mL), and dried over anhydrous Na 2 SO 4 After drying and concentration, the residue was purified by preparative HPLC to give 1-185 (10.0 mg, 19% yield) as a white solid.

[1148] Synthesis of 3-(Benzyl(4-(3,4-dichlorophenyl)-5-isobutylthiazol-2-yl)amino)-N-(3-(1,3-dioxoisoindolin-2-yl)propylsulfonyl)propionamide (229-1)

[1149]

[1150] A mixture of I-47 (294 mg, 0.634 mmol), b-229 (170 mg, 0.634 mmol), HATU (482 mg, 1.27 mmol) and DIPEA (245 mg, 1.90 mmol) in DMF (5.00 mL) was stirred at room temperature for 48 h. When the reaction was complete, it was poured into H 2 O (100 mL), and then extracted with EtOAc (200 mL × 2). The organic layers were combined and washed with H 2 O (80.0 mL x 2) and brine (50.0 mL), followed by anhydrous Na 2 SO 4 The solution was concentrated to obtain a crude product, which was purified by silica gel column chromatography (CH 2 Cl 2 / MeOH=100 / 1) to afford 229-1 (45.0 mg, 10% yield) as a yellow solid.

[1151] Synthesis of N-(3-aminopropylsulfonyl)-3-(benzyl(4-(3,4-dichlorophenyl)-5-isobutylthiazol-2-yl)amino)propanamide (I-186)

[1152]

[1153] A mixture of 229-1 (45.0 mg, 0.063 mmol) and hydrazine hydrate (6.31 mg, 0.126 mmol) in EtOH (2.0 mL) was stirred at 90° C. for 2 h. When the reaction was complete, it was concentrated to give a crude product, which was purified by preparative HPLC to give I-186 (4.0 mg, 11% yield) as a white solid.

[1154] Synthesis of tert-butyl 2-(2-(benzyl(4-(3,4-dichlorophenyl)-5-isobutylthiazol-2-yl)amino)ethylsulfonamido)-2-oxoethylcarbamate (230-1)

[1155]

[1156] A mixture of I-98 (200 mg, 0.401 mmol), 2-(tert-butoxycarbonylamino)acetic acid (84.3 mg, 0.481 mmol), HATU (305 mg, 0.802 mmol) and DIPEA (155 mg, 1.20 mmol) in DMF (5.00 mL) was stirred at room temperature for 48 h. When the reaction was complete, it was poured into H 2 O (100 mL), and then extracted with EtOAc (200 mL × 2). The organic layers were combined and washed with H 2 O (80.0 mL x 2) and brine (50.0 mL), followed by anhydrous Na 2 SO 4 The solution was concentrated to give the crude product, which was used directly in the next step without further purification to give 230-1 (200 mg, 76% yield) as a yellow solid.

[1157] Synthesis of 2-amino-N-(2-(benzyl(4-(3,4-dichlorophenyl)-5-isobutylthiazol-2-yl)amino)ethylsulfonyl)acetamide (I-187)

[1158]

[1159] A mixture of 230-1 (200 mg, 0.305 mmol) in HCl (4.0 M in dioxane, 3.0 mL) was stirred at room temperature for 2 h. When the reaction was complete, it was concentrated to give a crude product, which was purified by preparative HPLC to give I-187 (100 mg, 59% yield) as a white solid.

[1160] Synthesis of 3-(Benzyl(4-(3,4-dichlorophenyl)-5-isobutylthiazol-2-yl)amino)-2-hydroxypropionic acid (I-190)

[1161]

[1162] A mixture of c (771 mg, 2.56 mmol) and b-233 (500 mg, 2.56 mmol) in i-PrOH (15.0 mL) was stirred overnight at 90° C. When the reaction was complete, the mixture was purified by prep-HPLC to give I-190 (200 mg, 16% yield) as a white solid.

[1163] Synthesis of tert-butyl 3-(benzyl(4-(3,4-dichlorophenyl)-5-isobutylthiazol-2-yl)amino)propylcarbamate (235-2)

[1164]

[1165] A mixture of c (228 mg, 0.757 mmol) and b-235 (200 mg, 0.757 mmol) in i-PrOH (5.0 mL) was stirred at 90 °C overnight. When the reaction was complete, the mixture was analyzed by preparative TLC (CH 2 Cl 2 / MeOH=100 / 1) to afford 235-2 (80.0 mg, 19% yield) as a white solid.

[1166] Synthetic N 1 -Benzyl-N 1 -(4-(3,4-dichlorophenyl)-5-isobutylthiazol-2-yl)propane-1,3-diamine (I-191)

[1167]

[1168] A mixture of 235-2 (80.0 mg, 0.146 mmol) in HCl (4.0 M in dioxane, 3.0 mL) was stirred at room temperature for 2 h. When the reaction was complete, it was concentrated to give a crude product, which was purified by preparative HPLC to give I-191 (10.0 mg, 15% yield) as a white solid.

[1169] Synthesis of ethyl 3-(3-(benzyl(4-(3,4-dichlorophenyl)-5-isobutylthiazol-2-yl)amino)propionamido)propionate (241-1)

[1170]

[1171] A mixture of I-47 (150 mg, 0.324 mmol), ethyl 3-aminopropanoate hydrochloride (59.8 mg, 0.389 mmol), HATU (246 mg, 0.648 mmol) and DIPEA (125 mg, 0.972 mmol) in DMF (2.00 mL) was stirred at room temperature overnight. When the reaction was complete, it was poured into H 2 O (50.0 mL), and then extracted with EtOAc (80.0 mL × 2). The organic layers were combined and washed with H 2 O (50.0 mL x 2) and brine (50.0 mL), followed by anhydrous Na 2 SO 4 The solution was concentrated to give the crude product, which was used directly in the next step without further purification to give 241-1 (30.0 mg, 16% yield) as a yellow solid.

[1172] Synthesis of 3-(3-(Benzyl(4-(3,4-dichlorophenyl)-5-isobutylthiazol-2-yl)amino)propionamido)propionic acid (I-196)

[1173]

[1174] 241-1 (30.0 mg, 0.0533 mmol) was dissolved in THF / MeOH / H 2 LiOH (2.0 M in HO) was added to the solution in HO (v / v / v = 4 / 1 / 1, 1.0 mL). 2 O, 0.067 mL). The reaction was stirred at room temperature for 6 h. When the reaction was complete, the resulting reaction was concentrated and then washed with H 2 O (5.0 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 phases were washed with brine (10.0 mL), and dried over anhydrous Na 2 SO 4 After drying and concentration, the residue was purified by preparative HPLC to give 1-196 (10.0 mg, 35% yield) as a white solid.

[1175] Synthesis of tert-butyl 2-(4-(3,4-dichlorophenyl)-5-isobutylthiazol-2-yl)-14,14-dimethyl-5,12-dioxo-1-phenyl-13-oxa-2,6,9,11-tetraazapentadecan-10-ylidenecarbamate (242-1)

[1176]

[1177] A mixture of I-47 (230 mg, 0.496 mmol), b-242 (150 mg, 0.496 mmol), HATU (377 mg, 0.992 mmol) and DIPEA (192 mg, 1.49 mmol) in DMF (10.0 mL) was stirred at room temperature overnight. When the reaction was complete, it was poured into H 2 O (150 mL), and then extracted with EtOAc (100 mL × 2). The organic layers were combined and washed with H 2 O (100 mL x 2) and brine (50 mL), followed by anhydrous Na 2 SO 4 The solution was concentrated to give the crude product, which was used directly in the next step without further purification to give 241-1 (300 mg, 81% yield) as a yellow solid.

[1178] Synthesis of 3-(Benzyl(4-(3,4-dichlorophenyl)-5-isobutylthiazol-2-yl)amino)-N-(2-guanidinoethyl)propionamide (I-197)

[1179]

[1180] A mixture of 242-1 (300 mg, 0.401 mmol) in HCl (4.0 M in dioxane, 10.0 mL) was stirred at room temperature overnight. When the reaction was complete, it was concentrated to give a crude product, which was purified by preparative HPLC to give I-197 (100 mg, 46% yield) as a white solid.

[1181] Table 3-3: Characterization data of compounds

[1182]

[1183]

[1184]

[1185]

[1186]

[1187]

[1188]

[1189]

[1190]

[1191]

[1192]

[1193]

[1194]

[1195]

[1196]

[1197]

[1198]

[1199]

[1200]

[1201]

[1202]

[1203]

[1204]

[1205] Example 4. Synthesis of Compounds I-199 to I-285

[1206] Scheme 1: Pathway to compounds c, 115, and 343

[1207]

[1208] Scheme 2: Pathway to compound 346

[1209]

[1210] Scheme 3: Pathway to compound b-244

[1211]

[1212] Scheme 4: Pathway to compound b-250

[1213]

[1214] Scheme 5: Pathway to compound b-257

[1215] Scheme 6: Pathway to compound b-260

[1216]

[1217] Scheme 7: Pathway to compound b-263

[1218]

[1219] Scheme 8: Pathway to compound b-264

[1220]

[1221] Scheme 9: Pathways to compounds b-268, b-269, b-299, b-309, b-348, b-349, b-357, b-358, b-380

[1222]

[1223] Scheme 10: Pathway to compound b-270

[1224]

[1225] Scheme 11: Pathway to compounds b-288 and b-289

[1226]

[1227] Scheme 12: Pathway to compound b-290

[1228]

[1229] Scheme 13: Pathway to compound b-291

[1230]

[1231] Scheme 14: Pathway to compound b-292

[1232]

[1233] Scheme 15: Pathway to compound b-294

[1234]

[1235] Scheme 16: Pathway to compound b-295

[1236]

[1237] Scheme 17: Pathway to compound b-300

[1238]

[1239] Scheme 18: Pathway to compound b-301

[1240]

[1241] Scheme 19: Pathway to compound b-287

[1242]

[1243] Scheme 20: Pathway to compounds b-302 and b-306

[1244]

[1245] Scheme 21: Pathway to compound b-310

[1246]

[1247] Scheme 22: Pathway to compound b-313

[1248]

[1249] Scheme 23: Pathway to compound b-332

[1250]

[1251] Scheme 24: Pathway to compound b-361

[1252]

[1253] Scheme 25: Pathway to compound b-372

[1254]

[1255] Scheme 26: Pathway to compound b-378

[1256]

[1257] Scheme 27: Pathway to compounds 253-s and 343-s

[1258]

[1259] Scheme 28: Pathway to compound 316-s

[1260]

[1261] Scheme 29: Pathways to compounds 344-s, 356-s, and 366-s

[1262]

[1263] Scheme 30: Pathway to Compound I-199

[1264]

[1265] Scheme 31: Pathway to Compound I-200

[1266]

[1267] Scheme 32: Pathway to compounds I-201 and I-202

[1268]

[1269] Scheme 33: Pathways of compounds I-203, I-225 to I-227, I-237, I-265 to I-268, I-270, I-273, I-278

[1270]

[1271] Scheme 34: Pathway to Compound I-204

[1272]

[1273] Scheme 35: Pathway to Compound I-205

[1274]

[1275] Scheme 36: Pathway to Compound I-206

[1276]

[1277] Scheme 37: Compounds I-207 to I-214, I-217, I-219, I-220, I-222, I-236, I-241, I-243, Route from I-254 to I-256, I-258, I-261, I-263, I-264, I-274, I-280, I-281, I-283

[1278]

[1279] Scheme 38: Pathway to compounds I-215 and I-216

[1280]

[1281] Scheme 39: Pathway to Compound I-218

[1282]

[1283] Scheme 40: Pathway to compounds I-221, I-229, I-239, I-242

[1284] Scheme 41: Pathway to Compound I-223

[1285]

[1286] Scheme 42: Pathway to compounds I-224, I-238, and I-240

[1287]

[1288] Scheme 43: Pathway to compounds I-228 and I-229

[1289]

[1290] Scheme 44: Pathway to Compound I-230

[1291]

[1292] Scheme 45: Pathway to Compound I-231

[1293]

[1294] Scheme 46: Pathway to Compound I-232

[1295]

[1296] Scheme 47: Pathway to compounds I-234 and I-235

[1297]

[1298] Scheme 48: Pathway to Compound I-244

[1299]

[1300] Scheme 49: Pathway to Compound I-245

[1301]

[1302] Scheme 50: Pathway from Compound I-246 to I-250

[1303]

[1304] Scheme 51: Pathway to compounds I-251 and I-252

[1305]

[1306] Scheme 52: Pathway to Compound I-253

[1307]

[1308] Scheme 53: Pathway to Compound I-257

[1309]

[1310] Scheme 54: Pathway to compounds I-259 and I-260

[1311]

[1312] Scheme 55: Pathway to Compound I-262

[1313]

[1314] Scheme 56: Pathway to compounds I-269, I-271, I-272, I-275

[1315]

[1316] Scheme 57: Pathway to compounds I-276 and I-277

[1317]

[1318] Scheme 58: Pathway to Compound I-279

[1319]

[1320] Scheme 59: Pathway to Compound I-282

[1321]

[1322] Scheme 60: Pathway to compounds I-284 and I-285

[1323]

[1324] General Information: All evaporations were performed in vacuo using a rotary evaporator. Analytical samples were dried in vacuo (1-5 mmHg) at rt. Thin layer chromatography (TLC) was performed on silica gel plates and spots were observed by UV light (214 nm and 254 nm). Column and flash chromatography 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 with 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), integral value.

[1325] LCMS spectra were obtained on an Agilent 1200 series 6110 or 6120 mass spectrometer with electrospray ionization and unless otherwise specified, general LCMS conditions were as follows:

[1326] 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% [CH 3 CN + 0.05% TFA] to 0% [water + 0.05% TFA] and 100% [CH 3 CN+0.05% TFA], followed by 0.4 min under this condition, and finally 95% [water+0.05% TFA] and 5% [CH 3 CN + 0.05% TFA]).

[1327] 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% [CH 3 CN + 0.05% TFA] to 0% [water + 0.05% TFA] and 100% [CH 3 CN+0.05% TFA], followed by 1.4 min under this condition, and finally changed to 95% [water+0.05% TFA] and 5% [CH 3 CN+0.05% TFA] and 0.7 min under this condition).

[1328] 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: 95% [water + 10 mM NH 4 HCO 3 ] and 5% [CH 3 CN] to 0% [water + 10 mM NH 4 HCO 3 ] and 100% [CH 3 CN], then under this condition for 1.4 min, and finally changed to 95% [water + 10 mM NH 4 HCO 3 ] and 5% [CH 3 CN], and under this condition 0.7min. )

[1329] Synthesis of 1-(3,4-dichlorophenyl)-4-methylpentan-1-one (c-1)

[1330]

[1331] To a solution of a (25.0 g, 145 mmol) in THF (200 mL) ...

Claims

1. A compound of formula I: or a pharmaceutically acceptable salt thereof, wherein: Ring A is Each R 1 are independently halogen, R, -N(R)2, -OR, -SR, -C(O)OR or -S(O)2R; n is 0, 1, 2, 3, 4 or 5; L 1 is a bond or -CH2-; R 2 For -C 1-6 Aliphatic, or -C substituted 1, 2, 3, 4, 5 or 6 times by halogen 1-6 alkyl; L 2 Selected from: R 3 -COOH, -CN, -OH or and R is hydrogen, -C 1-6 Aliphatic, halogen-substituted 1, 2, 3, 4, 5 or 6 times -C 1-6 Alkyl or a ring selected from phenyl, a 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur, a 3-6 membered monocyclic saturated or partially unsaturated carbocyclic ring, or a 3-6 membered monocyclic saturated or partially unsaturated heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur.

2. The compound according to claim 1, wherein ring A is Where R 11 and R 12 Each of which is independently halogen, R, -N(R)2, -OR, -SR, -C(O)OR or -S(O)2R.

3. The compound as claimed in claim 2, wherein R 12 At least one of is not hydrogen.

4. The compound of claim 1, wherein L 1 is the key.

5. The compound as claimed in claim 1, wherein R 2 for 6. The compound of claim 1, wherein L 2 for 7. The compound of claim 1, wherein R 3 It is -COOH.

8. The compound of claim 1, wherein R is hydrogen or -C 1-6 Aliphatic.

9. The compound of claim 1, wherein the compound has Formula II: or a pharmaceutically acceptable salt thereof.

10. The compound of claim 1, wherein the compound has formula II-a to II-d: or a pharmaceutically acceptable salt thereof, wherein R 11 and R 12 Each of which is independently halogen, R, -N(R)2, -OR, -SR, -C(O)OR or -S(O)2R.

11. The compound of claim 1, wherein the compound has Formula III: or a pharmaceutically acceptable salt thereof.

12. The compound of claim 1, wherein the compound has formula III-a to III-d: or a pharmaceutically acceptable salt thereof, wherein R 11 and R 12 Each of which is independently halogen, R, -N(R)2, -OR, -SR, -C(O)OR or -S(O)2R.

13. The compound of claim 1, wherein the compound has Formula IV: or a pharmaceutically acceptable salt thereof.

14. The compound of claim 1, wherein the compound has Formula IV-a to IV-d: or a pharmaceutically acceptable salt thereof, wherein R 11 and R 12 Each of which is independently halogen, R, -N(R)2, -OR, -SR, -C(O)OR or -S(O)2R.

15. The compound of claim 1, wherein the compound has Formula V: or a pharmaceutically acceptable salt thereof.

16. The compound of claim 1, wherein the compound has formula Va to Vd: or a pharmaceutically acceptable salt thereof, wherein R 11 and R 12 Each of which is independently halogen, R, -N(R)2, -OR, -SR, -C(O)OR or -S(O)2R.

17. The compound of claim 1, wherein the compound has Formula VI: or a pharmaceutically acceptable salt thereof.

18. The compound of claim 1, wherein the compound has Formula VI-a to VI-d: or a pharmaceutically acceptable salt thereof, wherein R 11 and R 12 Each of which is independently halogen, R, -N(R)2, -OR, -SR, -C(O)OR or -S(O)2R.

19. The compound of claim 1, wherein the compound has Formula VII: or a pharmaceutically acceptable salt thereof.

20. The compound of claim 1, wherein the compound has Formula VII-a to VII-d: or a pharmaceutically acceptable salt thereof, wherein R 11 and R 12 Each of which is independently halogen, R, -N(R)2, -OR, -SR, -C(O)OR or -S(O)2R.

21. The compound of claim 1, wherein the compound has Formula VIII: or a pharmaceutically acceptable salt thereof.

22. The compound of claim 1, wherein the compound has Formula VIII-a to VIII-d: or a pharmaceutically acceptable salt thereof, wherein R 11 and R 12 Each of which is independently halogen, R, -N(R)2, -OR, -SR, -C(O)OR or -S(O)2R.

23. A compound as described in any one of claims 2, 10, 12, 14, 16, 18, 20 and 22, wherein R 12 is -OR, where R is –C 1-6 alkyl.

24. A compound, or a pharmaceutically acceptable salt thereof, selected from:

25. A pharmaceutical composition comprising a compound as claimed in any one of claims 1 to 22 or 24 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, adjuvant or vehicle.

26. Use of a compound according to any one of claims 1 to 22 or 24 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 25, in the preparation of a medicament for treating cancer in a patient.

27. The use of claim 26, wherein the cancer is multiple myeloma, breast cancer, colorectal cancer, lung cancer, glioblastoma, sarcoma, melanoma, prostate cancer or lymphoma.

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