Compositions and Uses Thereof

Abstract

As used herein, the formula (I) [Formula 1] JPEG2025535263000074.jpg6899 or a pharmaceutically acceptable salt thereof, wherein the variables of formula (I) are as defined herein. Such compounds may be useful as anti-cancer agents.

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of U.S. Provisional Patent Application No. 63 / 380,351, filed October 20, 2022, which is incorporated herein by reference in its entirety. [Background technology]

[0002] Currently, small cytotoxic molecules for antibody-drug conjugates can include camptothecin derivatives, which have antitumor effects by inhibiting topoisomerase I. Camptothecin derivatives can be used in antibody-drug conjugates (ADCs). However, there is still a need for further development of camptothecin derivatives and ADC drugs with better efficacy and / or safety. Summary of the Invention

[0003] In one aspect, the present disclosure provides a compound of formula (I):

[0004] [ka] or a pharmaceutically acceptable salt thereof, wherein: L is (L 2 ) x -(L 2B ) z -(L 2C ) y -L 3 -L 4 -(L 5 ) m -(L 6 ) n -(L 7 ) p -R 2 and L 2 is C 1-6 alkylene; L 2B is (NR 4 ) tC(O)O—CH2-phenyl, wherein phenyl is selected from one or more R 5 optionally substituted with L 2C is selected from C(O)O—CH2-phenyl, wherein phenyl is selected from one or more R 6 optionally substituted with L 3 is selected from residues containing 1 to 7 amino acids, L 4 is an optionally substituted C 1-6 alkylene, wherein C 1-6 Alkylene is independently selected from halogen, -OH, -CN, -NO2, -NH2, oxo, -C 1-10 Haloalkyl, -OC 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 optionally substituted with one or more substituents selected from alkynyl, L 5 is (O-CH2-CH2-) q -(NR 3 ) s is selected from L 6 is an optionally substituted C 1-6 alkylene, wherein C 1-6 Alkylene is independently selected from halogen, -OH, -CN, -NO2, -NH2, oxo, C 1-10 Alkyl, -C 1-10 Haloalkyl, -OC 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 optionally substituted with one or more substituents selected from alkynyl, L 7 is C 5-6 selected from carbocycles, R 1 -O- and -NR 7 - selected from R 2 is selected from optionally substituted 5- to 6-membered heterocycles, wherein the 5- to 6-membered heterocycles are independently selected from halogen, —OH, —CN, —NO, —NH, oxo, C1-10 Alkyl, -C 1-10 Haloalkyl, -OC 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 optionally substituted with one or more substituents selected from alkynyl, R 3 is hydrogen and C 1-6 alkyl, R 4 is hydrogen and one or more SO2C 1-6 C optionally substituted with alkyl 1-6 alkyl, Each R 5 are independently selected from sugars; Each R 6 are independently halogen, -OH, -CN, -NO2, -NH2, oxo, -C 1-10 Haloalkyl, -OC 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 alkynyl, R 7 is hydrogen and C 1-6 alkyl, R 8 is selected from hydrogen and hydroxy; R 9 is selected from hydrogen and halogen, and R 8 or R 9 at least one of is hydrogen, m is selected from 0 and 1; n is selected from 0 and 1; p is selected from 0 and 1; q is selected from 0 to 8; s is selected from 0 and 1; t is selected from 0 and 1; x is selected from 0 and 1; y is selected from 0 and 1; z is selected from 0 and 1.

[0005] In some embodiments, formula (I) is

[0006] [ka] or a pharmaceutically acceptable salt thereof.

[0007] In some embodiments, formula (I) is

[0008] [ka] or a pharmaceutically acceptable salt thereof.

[0009] In some embodiments, formula (I) is

[0010] [ka] or a pharmaceutically acceptable salt thereof, wherein Lg is a ligand.

[0011] In some embodiments, the present disclosure provides a compound of formula (III):

[0012] [ka] or a pharmaceutically acceptable salt thereof, wherein: Lg is the ligand, L is (L 2 ) x -(L 2B ) z -(L 2C ) y -L 3 -L 4 -(L 5 ) m -(L 6 ) n -(L 7 ) p -R 2 and L 2 is C 1-6 alkylene; L 2Bis (NR 4 ) t C(O)OC 1-6 alkylene-phenyl, wherein phenyl is selected from one or more R 5 optionally substituted with L 2C is selected from C(O)O—CH2-phenyl, where phenyl is selected from halogen, —OH, —CN, —NO2, —NH2, oxo, —C 1-10 Haloalkyl, -OC 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 optionally substituted with alkynyl; L 3 is selected from residues containing 1 to 7 amino acids, L 4 is an optionally substituted C 1-6 alkylene, wherein C 1-6 Alkylene is independently selected from halogen, -OH, -CN, -NO2, -NH2, oxo, -C 1-10 Haloalkyl, -OC 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 optionally substituted with one or more substituents selected from alkynyl, L 5 is (O-CH2-CH2-) q -(NR 3 ) s is selected from L 6 is an optionally substituted C 1-6 alkylene, wherein C 1-6 Alkylene is independently selected from halogen, -OH, -CN, -NO2, -NH2, oxo, C 1-10 Alkyl, -C 1-10 Haloalkyl, -OC 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 optionally substituted with one or more substituents selected from alkynyl, L 7 is C 5-6 selected from carbocycles, R 1-O- and -NR 7 - selected from R 2 is selected from optionally substituted 5- to 6-membered heterocycles, wherein the 5- to 6-membered heterocycles are independently selected from halogen, —OH, —CN, —NO, —NH, oxo, C 1-10 Alkyl, -C 1-10 Haloalkyl, -OC 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 optionally substituted with one or more substituents selected from alkynyl, R 3 is hydrogen and C 1-6 alkyl, R 4 is hydrogen and one or more SO2C 1-6 C optionally substituted with alkyl 1-6 alkyl, Each R 5 are independently selected from sugars; R 7 is hydrogen and C 1-6 alkyl, R 8 is selected from hydrogen and hydroxy; R 9 is selected from hydrogen and halogen, and R 8 or R 9 at least one of is hydrogen, m is selected from 0 and 1; n is selected from 0 and 1; p is selected from 0 and 1; q is selected from 0 to 8; s is selected from 0 and 1; t is selected from 0 and 1; x is selected from 0 and 1; y is selected from 0 and 1; z is selected from 0 and 1.

[0013] In some embodiments, the ligand is selected from an antibody or an antigen-binding fragment thereof.

[0014] Optionally, the ligand is selected from the group consisting of a chimeric antibody, a humanized antibody, and a fully human antibody.

[0015] In some embodiments, there is a pharmaceutical composition comprising a compound or salt of Formula (I), Formula (IA), Formula (IB), Formula (II), Formula (III), Formula (III-A), Formula (IV-A), Formula (IV-B), Formula (IV-C), or Formula (IV-D), and a pharmaceutically acceptable excipient of any one thereof.

[0016] In some embodiments, the present disclosure provides a method of treating a subject having a tumor, comprising administering to a subject in need of tumor treatment a compound or salt of Formula (I), Formula (IA), Formula (IB), Formula (II), Formula (III), Formula (III-A), Formula (IV-A), Formula (IV-B), Formula (IV-C), or Formula (IV-D), or a pharmaceutical composition of any one thereof.

[0017] In some embodiments, the present disclosure provides a method of treating a subject having cancer, comprising administering to a subject in need of cancer treatment a compound or salt of Formula (I), Formula (IA), Formula (IB), Formula (II), Formula (III), Formula (III-A), Formula (IV-A), Formula (IV-B), Formula (IV-C), or Formula (IV-D), or a pharmaceutical composition of any one thereof.

[0018] Incorporation by Reference All publications, patents, and patent applications mentioned herein are incorporated by reference to the same extent as if each individual publication, patent, or patent application was specifically and individually indicated to be incorporated by reference. To the extent that the publications and patents or patent applications incorporated by reference conflict with the disclosure contained herein, the present specification is intended to supersede and / or take precedence over any such conflicting material. DETAILED DESCRIPTION OF THE INVENTION

[0019] The following description sets forth numerous example configurations, methods, parameters, etc. However, it should be recognized that such description is not intended as a limitation on the scope of the present disclosure, but rather is provided as a description of example embodiments.

[0020] In the following description, certain specific details are set forth in order to provide a thorough understanding of various embodiments of the present disclosure. However, it will be understood by those skilled in the art that the present disclosure may be practiced without these details.

[0021] definition Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. All patents and publications cited herein are incorporated by reference.

[0022] "Alkyl" refers to a straight or branched hydrocarbon chain radical consisting solely of carbon and hydrogen atoms, containing no unsaturation, and preferably having from 1 to 15 carbon atoms (i.e., C1-C 15 In certain embodiments, alkyl comprises 1 to 13 carbon atoms (i.e., C-C 13 In certain embodiments, alkyl contains 1 to 8 carbon atoms (i.e., C1-C8 alkyl). In other embodiments, alkyl contains 1 to 5 carbon atoms (i.e., C1-C5 alkyl). In other embodiments, alkyl contains 1 to 4 carbon atoms (i.e., C1-C4 alkyl). In other embodiments, alkyl contains 1 to 3 carbon atoms (i.e., C1-C3 alkyl). In other embodiments, alkyl contains 1 to 2 carbon atoms (i.e., C1-C2 alkyl). In other embodiments, alkyl contains 1 carbon atom (i.e., C1 alkyl). In other embodiments, alkyl contains 5 to 15 carbon atoms (i.e., C5-C 15In other embodiments, an alkyl contains 5 to 8 carbon atoms (i.e., a C5-C8 alkyl). In other embodiments, an alkyl contains 2 to 5 carbon atoms (i.e., a C2-C5 alkyl). In other embodiments, an alkyl contains 3 to 5 carbon atoms (i.e., a C3-C5 alkyl). In certain embodiments, an alkyl group is selected from methyl, ethyl, 1-propyl (n-propyl), 1-methylethyl (iso-propyl), 1-butyl (n-butyl), 1-methylpropyl (sec-butyl), 2-methylpropyl (iso-butyl), 1,1-dimethylethyl (tert-butyl), and 1-pentyl (n-pentyl). An alkyl is attached to the remainder of the molecule by a single bond.

[0023] The term “C x-y " when used in conjunction with a chemical moiety such as alkyl, alkenyl, or alkynyl, is meant to include groups containing x to y carbons in the chain. For example, the term "C 1-6 "Alkyl" refers to a substituted or unsubstituted saturated hydrocarbon group, including straight-chain alkyl and branched-chain alkyl groups, containing 1 to 6 carbons in the chain. The term -C x-y Alkylene- refers to a substituted or unsubstituted alkylene chain having x to y carbon atoms in the alkylene chain. For example, -C 1-6 Alkylene- may be selected from methylene, ethylene, propylene, butylene, pentylene, and hexylene, any one of which is optionally substituted.

[0024] "Alkoxy" refers to a radical attached through an oxygen atom of the formula --O-alkyl, where alkyl is an alkyl chain as defined above.

[0025] "Alkenyl" refers to a straight or branched hydrocarbon chain radical group consisting solely of carbon and hydrogen atoms, containing at least one carbon-carbon double bond, and preferably having from 2 to 12 carbon atoms (i.e., C2-C 12alkenyl). In certain embodiments, an alkenyl contains 2 to 8 carbon atoms (i.e., C2-C8 alkenyl). In certain embodiments, an alkenyl contains 2 to 6 carbon atoms (i.e., C2-C6 alkenyl). In other embodiments, an alkenyl contains 2 to 4 carbon atoms (i.e., C2-C4 alkenyl). An alkenyl is attached to the remainder of the molecule by a single bond, for example, ethenyl (i.e., vinyl), prop-1-enyl (i.e., allyl), but-1-enyl, pent-1-enyl, penta-1,4-dienyl, etc.

[0026] "Alkynyl" refers to a straight or branched hydrocarbon chain radical group consisting solely of carbon and hydrogen atoms, containing at least one carbon-carbon triple bond, and preferably having from 2 to 12 carbon atoms (i.e., C2-C 12 In certain embodiments, an alkynyl contains 2 to 8 carbon atoms (i.e., C2-C8 alkynyl). In other embodiments, an alkynyl contains 2 to 6 carbon atoms (i.e., C2-C6 alkynyl). In other embodiments, an alkynyl contains 2 to 4 carbon atoms (i.e., C2-C4 alkynyl). An alkynyl is attached to the rest of the molecule by a single bond, e.g., ethynyl, propynyl, butynyl, pentynyl, hexynyl, etc.

[0027] The term “C x-y alkenyl," and "C x-y "Alkynyl" refers to a substituted or unsubstituted unsaturated aliphatic group analogous in length and possible substitution to the alkyls described above, but containing at least one double or triple bond, respectively. x-y Alkenylene- refers to a substituted or unsubstituted alkenylene chain having x to y carbons in the alkenylene chain. For example, -C 2-6Alkenylene- may be selected from ethenylene, propenylene, butenylene, pentenylene, and hexenylene, any one of which is optionally substituted. The alkenylene chain may have one double bond or multiple double bonds within the alkenylene chain. The term -C x-y Alkynylene- refers to a substituted or unsubstituted alkynylene chain having x to y carbons in the alkenylene chain. For example, -C 2-6 Alkenylene- may be selected from ethynylene, propynylene, butynylene, pentynylene, and hexynylene, any one of which is optionally substituted. The alkynylene chain may have one triple bond or multiple triple bonds within the alkynylene chain.

[0028] "Alkylene" or "alkylene chain" refers to a straight or branched divalent hydrocarbon chain that connects the rest of the molecule to a radical group, consists solely of carbon and hydrogen, contains no unsaturation, and preferably has 1 to 12 carbon atoms, e.g., methylene, ethylene, propylene, n-butylene, etc. The alkylene chain is attached to the rest of the molecule through a single bond and to the radical group through a single bond. The points of attachment of the alkylene chain to the rest of the molecule and to the radical group can be through any two carbons within the chain. In certain embodiments, alkylene contains 1 to 10 carbon atoms (i.e., C1-C8 alkylene). In certain embodiments, alkylene contains 1 to 8 carbon atoms (i.e., C1-C8 alkylene). In other embodiments, alkylene contains 1 to 5 carbon atoms (i.e., C1-C5 alkylene). In other embodiments, alkylene contains 1 to 4 carbon atoms (i.e., C1-C4 alkylene). In other embodiments, alkylene contains 1 to 3 carbon atoms (i.e., C1-C3 alkylene). In other embodiments, alkylene contains 1 to 2 carbon atoms (i.e., C1-C2 alkylene). In other embodiments, alkylene contains 1 carbon atom (i.e., C1 alkylene). In other embodiments, alkylene contains 5 to 8 carbon atoms (i.e., C5-C8 alkylene). In other embodiments, alkylene contains 2 to 5 carbon atoms (i.e., C2-C5 alkylene). In other embodiments, alkylene contains 3 to 5 carbon atoms (i.e., C3-C5 alkylene).

[0029] "Alkenylene" or "alkenylene chain" refers to a straight or branched divalent hydrocarbon chain that connects the rest of the molecule to a radical group, consisting solely of carbon and hydrogen, contains at least one carbon-carbon double bond, and preferably has 2 to 12 carbon atoms. The alkenylene chain is attached to the rest of the molecule through a single bond and to the radical group through a single bond. The points of attachment of the alkenylene chain to the rest of the molecule and to the radical group can be through any two carbons within the chain. In certain embodiments, alkenylene contains 2 to 10 carbon atoms (i.e., C2-C 10alkenylene). In certain embodiments, alkenylene contains 2 to 8 carbon atoms (i.e., C2-C8 alkenylene). In other embodiments, alkenylene contains 2 to 5 carbon atoms (i.e., C2-C5 alkenylene). In other embodiments, alkenylene contains 2 to 4 carbon atoms (i.e., C2-C4 alkenylene). In other embodiments, alkenylene contains 2 to 3 carbon atoms (i.e., C2-C3 alkenylene). In other embodiments, alkenylene contains 2 carbon atoms (i.e., C2 alkenylene). In other embodiments, alkenylene contains 5 to 8 carbon atoms (i.e., C5-C8 alkenylene). In other embodiments, alkenylene contains 3 to 5 carbon atoms (i.e., C3-C5 alkenylene).

[0030] "Alkynylene" or "alkynylene chain" refers to a straight or branched divalent hydrocarbon chain that connects the rest of the molecule to a radical group, consists solely of carbon and hydrogen, contains at least one carbon-carbon triple bond, and has 2 to 12 carbon atoms. The alkynylene chain is attached to the rest of the molecule through a single bond and to the radical group through a single bond. The points of attachment of the alkynylene chain to the rest of the molecule and to the radical group can be through any two carbons within the chain. In certain embodiments, alkynylene contains 2 to 10 carbon atoms (i.e., C2-C 10 alkynylene). In certain embodiments, alkynylene contains 2 to 8 carbon atoms (i.e., C2-C8 alkynylene). In other embodiments, alkynylene contains 2 to 5 carbon atoms (i.e., C2-C5 alkynylene). In other embodiments, alkynylene contains 2 to 4 carbon atoms (i.e., C2-C4 alkynylene). In other embodiments, alkynylene contains 2 to 3 carbon atoms (i.e., C2-C3 alkynylene). In other embodiments, alkynylene contains 2 carbon atoms (i.e., C2 alkynylene). In other embodiments, alkynylene contains 5 to 8 carbon atoms (i.e., C5-C8 alkynylene). In other embodiments, alkynylene contains 3 to 5 carbon atoms (i.e., C3-C5 alkynylene).

[0031] "Aryl" refers to a radical derived from an aromatic monocyclic or aromatic polycyclic hydrocarbon ring system by removing a hydrogen atom from a ring carbon atom. An aromatic monocyclic or aromatic polycyclic hydrocarbon ring system contains only hydrogen and carbon, has 5 to 18 carbon atoms, and at least one ring in the ring system is aromatic, i.e., contains a delocalized (4n+2) π-electron system according to Hückel theory. Ring systems from which aryl groups are derived include, but are not limited to, groups such as benzene, fluorene, indane, indene, tetralin, and naphthalene.

[0032] "Aralkyl" is a group of the formula -R c -aryl radical, where R c is an alkylene chain as defined above, for example, methylene, ethylene, etc.

[0033] "Aralkenyl" refers to a group of the formula -R d -aryl radical, where R d is an alkenylene chain as defined above. An "aralkynyl" is a group of the formula -R e -refers to the aryl radical, R e is an alkynylene chain as defined above.

[0034] "Carbocycle" refers to a saturated, unsaturated, or aromatic ring in which each atom of the ring is carbon. Carbocycles can include 3- to 10-membered monocyclic rings, 6- to 12-membered bicyclic rings, and 6- to 12-membered bridged rings. Each ring of a bicyclic carbocycle can be selected from saturated, unsaturated, and aromatic rings. An aromatic ring, e.g., phenyl, can be fused to a saturated or unsaturated ring, e.g., cyclohexane, cyclopentane, or cyclohexene. Any combination of saturated, unsaturated, and aromatic bicyclic rings is included in the definition of carbocycle, valence permitting. Exemplary carbocycles include cyclopentyl, cyclohexyl, cyclohexenyl, adamantyl, phenyl, indanyl, and naphthyl. A bicyclic carbocycle can be a fused, bridged, or spiro ring system. In some cases, the spirocyclic carbocycle has at least two rings with only one shared atom.

[0035] "Carbocyclene" refers to a divalent carbon ring linking the rest of the molecule to a radical group.

[0036] The term "unsaturated carbocycle" refers to a carbocycle, other than an aromatic carbocycle, that has a degree of unsaturation of at least 1. Examples of unsaturated carbocycles include cyclohexadiene, cyclohexene, and cyclopentene.

[0037] "Cycloalkyl" refers to a fully saturated monocyclic or polycyclic hydrocarbon radical, consisting solely of carbon and hydrogen atoms, including fused or bridged ring systems, preferably having 3 to 12 carbon atoms. In certain embodiments, cycloalkyls contain 3 to 10 carbon atoms. In other embodiments, cycloalkyls contain 5 to 7 carbon atoms. A cycloalkyl can be attached to the remainder of the molecule by a single bond. Examples of monocyclic cycloalkyls include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Polycyclic cycloalkyl radicals include, for example, adamantyl, norbornyl (i.e., bicyclo[2.2.1]heptanyl), norbornenyl, decalinyl, 7,7-dimethyl-bicyclo[2.2.1]heptanyl, and the like.

[0038] "Cycloalkenyl" refers to an unsaturated, non-aromatic, monocyclic or polycyclic hydrocarbon radical, consisting solely of carbon and hydrogen atoms, including fused or bridged ring systems, preferably having 3 to 12 carbon atoms and containing at least one double bond. In certain embodiments, a cycloalkenyl contains 3 to 10 carbon atoms. In other embodiments, a cycloalkenyl contains 5 to 7 carbon atoms. A cycloalkenyl may be attached to the remainder of the molecule by a single bond. Examples of monocyclic cycloalkenyls include, for example, cyclopentenyl, cyclohexenyl, cycloheptenyl, and cyclooctenyl.

[0039] "Cycloalkylalkyl" is R c is an alkylene chain as described above, the formula -R c -refers to the radical of cycloalkyl.

[0040] "Cycloalkylalkoxy" refers to a group of the formula -OR c -refers to a radical attached through an oxygen atom of a cycloalkyl, where R c is an alkylene chain as described above.

[0041] "Halo" or "halogen" refers to a substituent such as bromo, chloro, fluoro, or iodo.

[0042] As used herein, the term "haloalkyl" or "haloalkane" refers to an alkyl radical, as defined above, substituted with one or more halogen radicals, such as trifluoromethyl, dichloromethyl, bromomethyl, 2,2,2-trifluoroethyl, 1-fluoromethyl-2-fluoroethyl, etc. In some embodiments, the alkyl portion of the fluoroalkyl radical is optionally further substituted. Examples of halogen-substituted alkanes ("haloalkanes") include halomethanes (e.g., chloromethane, bromomethane, fluoromethane, iodomethane), dihalomethanes and trihalomethanes (e.g., trichloromethane, tribromomethane, trifluoromethane, triiodomethane), 1-haloethane, 2-haloethane, 1,2-dihaloethane, 1-halopropane, 2-halopropane, 3-halopropane, 1,2-dihalopropane, 1,3-dihalopropane, 2,3-dihalopropane, 1,2,3-trihalopropane, and any other suitable combination of an alkane (or substituted alkane) and a halogen (e.g., Cl, Br, F, I, etc.). When an alkyl group is substituted with multiple halogen radicals, each halogen may be independently selected, for example, 1-chloro, 2-fluoroethane.

[0043] "Fluoroalkyl" refers to an alkyl radical, as defined above, that is substituted by one or more fluoro radicals, for example, trifluoromethyl, difluoromethyl, fluoromethyl, 2,2,2-trifluoroethyl, 1-fluoromethyl-2-fluoroethyl, and the like.

[0044] "Aminoalkyl" refers to an alkyl radical, as defined above, substituted by one or more amine radicals, for example, propan-2-amine, butane-1,2,diamine, pentane-1,2,4-triamine, and the like.

[0045] "Hydroxyalkyl" refers to an alkyl radical, as defined above, that is substituted by one or more hydroxy radicals, for example, propan-1-ol, butane-1,4-diol, pentane-1,2,4-triol, and the like.

[0046] "Alkoxyalkyl" refers to an alkyl radical, as defined above, substituted by one or more alkoxy radicals, for example, methoxymethane, 1,3-dimethoxybutane, 1-methoxypropane, 2-ethoxypentane, and the like.

[0047] "Cyanoalkyl" refers to an alkyl radical, as defined above, substituted by one or more cyano radicals, for example, acetonitrile, 2-ethyl-3-methylsuccinonitrile, butyronitrile, and the like.

[0048] "Heterocycle" refers to a saturated, unsaturated, or aromatic ring containing one or more heteroatoms. Typical heteroatoms include N, O, Si, P, B, and S atoms. Heterocycles can include 3-10 membered monocyclic rings, 6-12 membered bicyclic rings, and 6-12 membered bridged rings. Each ring of a bicyclic heterocycle can be selected from saturated, unsaturated, and aromatic rings. Bicyclic heterocycles can be fused, bridged, or spiro ring systems. In some cases, spirocyclic heterocycles have at least two rings with only one shared atom. Spirocyclic heterocycles contain at least one heteroatom.

[0049] "Heterocyclene" refers to a divalent heterocycle linking the rest of the molecule to a radical group.

[0050] "Heteroaryl" or "heteroaromatic ring" refers to a radical derived from a heteroaromatic ring radical containing 1 to 11 carbon atoms and at least one heteroatom, which may be selected from N, O, and S. As used herein, heteroaryl rings may be selected from monocyclic or bicyclic, and fused or bridged ring systems, where at least one of the rings in the ring system is aromatic, i.e., contains a cyclic delocalized (4n+2) π-electron system according to Hückel theory. Heteroatoms in a heteroaryl radical may be optionally oxidized. One or more nitrogen atoms, if present, are optionally quaternized. A heteroaryl may be attached to the remainder of the molecule through any atom of the heteroaryl, such as a carbon or nitrogen atom of the heteroaryl, where valence allows. Examples of heteroaryls include, but are not limited to, pyridine, pyrimidine, oxazole, furan, pyran, thiophene, isoxazole, benzimidazole, benzthiazole, and imidazopyridine.

[0051] An "X-membered heteroaryl" refers to the number of endocylic atoms in the ring, i.e., X. For example, a 5-membered heteroaryl ring or a 5-membered heteroaromatic ring has 5 endocylic atoms, such as triazole, oxazole, thiophene, etc.

[0052] The term "unsaturated heterocycle" refers to a heterocycle that is unsaturated at least once and excludes aromatic heterocycles. Examples of unsaturated heterocycles include dihydropyrrole, dihydrofuran, oxazoline, pyrazoline, and dihydropyridine. The heterocycle can be optionally substituted with one or more substituents, such as those described herein.

[0053] The term "substituted" refers to a moiety having substituents replacing hydrogen on one or more carbons or substitutable heteroatoms, e.g., NH, of the structure. "Substituted" or "substituted with" includes the implicit proviso that such substitution is in accordance with the allowed valences of the replaced atom and substituent, and that the substitution results in a stable compound that does not spontaneously undergo transformation, e.g., by rearrangement, cyclization, elimination, etc. In certain embodiments, substituted refers to a moiety having substituents replacing two hydrogen atoms on the same carbon atom, such as replacing two hydrogen atoms on a single carbon with an oxo, imino, or thioxo group.

[0054] As used herein, the term "substituted" is intended to include all permissible substituents of organic compounds. In a broad aspect, the permissible substituents include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, aromatic and nonaromatic substituents of organic compounds. The permissible substituents can be one or more and the same or different for appropriate organic compounds. For purposes of this disclosure, heteroatoms such as nitrogen can have hydrogen substituents and / or any permissible substituents of organic compounds described herein that satisfy the valence of the heteroatom. In some embodiments, substituents can be any of the substituents described herein, e.g., halogen, hydroxy, oxo (=O), thioxo (=S), cyano (-CN), nitro (-NO), imino (=NH), oximo (=N-OH), hydrazino (=N-NH), -R b -OR a , -R b -OC(O)-Ra , -R b -OC(O)-OR a , -R b -OC(O)-N(R a )2, -R b -N(R a )2, -R b -C(O)R a , -R b -C(O)OR a , -R b -C(O)N(R a )2, -R b -OR c -C(O)N(R a )2, -R b -N(R a )C(O)OR a , -R b -N(R a )C(O)R a , -R b -N(R a )S(O) t R a (when t is 1 or 2), -R b -S(O) t R a (when t is 1 or 2), -R b -S(O) t OR a (when t is 1 or 2), and -R b -S(O) t N(R a )2 (when t is 1 or 2); and alkyl, alkenyl, alkynyl, aryl, aralkyl, aralkenyl, aralkynyl, cycloalkyl, cycloalkylalkyl, heterocycle, any of which may be alkyl, alkenyl, alkynyl, halogen, haloalkyl, haloalkenyl, haloalkynyl, oxo (=O), thioxo (=S), cyano (-CN), nitro (-NO2), imino (=NH), oximo (=N-OH), hydrazine (=N-NH2), -R b -OR a , -R b -OC(O)-R a , -R b -OC(O)-OR a , -R b -OC(O)-N(R a)2, -R b -N(R a )2, -R b -C(O)R a , -R b -C(O)OR a , -R b -C(O)N(R a )2, -R b -OR c -C(O)N(R a )2, -R b -N(R a )C(O)OR a , -R b -N(R a )C(O)R a , -R b -N(R a )S(O) t R a (when t is 1 or 2), -R b -S(O) t R a (when t is 1 or 2), -R b -S(O) t OR a (when t is 1 or 2) and -R b -S(O) t N(R a )2 (when t is 1 or 2), where each R a is independently selected from hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl, or heteroarylalkyl, wherein each R a is, where valence allows, alkyl, alkenyl, alkynyl, halogen, haloalkyl, haloalkenyl, haloalkynyl, oxo (=O), thioxo (=S), cyano (-CN), nitro (-NO2), imino (=NH), oximo (=N-OH), hydrazine (=N-NH2), -R b -OR a , -R b -OC(O)-R a , -R b -OC(O)-OR a , -R b -OC(O)-N(Ra )2, -R b -N(R a )2, -R b -C(O)R a , -R b -C(O)OR a , -R b -C(O)N(R a )2, -R b -OR c -C(O)N(R a )2, -R b -N(R a )C(O)OR a , -R b -N(R a )C(O)R a , -R b -N(R a )S(O) t R a (when t is 1 or 2), -R b -S(O) t R a (when t is 1 or 2), -R b -S(O) t OR a (when t is 1 or 2) and -R b -S(O) t N(R a )2 (when t is 1 or 2), and each R b is independently selected from a direct bond, or a straight or branched alkylene chain, alkenylene chain, or alkynylene chain; c is a straight or branched alkylene chain, alkenylene chain, or alkynylene chain.

[0055] As used in this specification and claims, the singular forms "a," "an," and "the" include the plural forms unless the context clearly indicates otherwise.

[0056] The term "salt" or "pharmaceutically acceptable salt" refers to salts derived from various organic and inorganic counterions well known in the art. Pharmaceutically acceptable acid addition salts can be formed with inorganic and organic acids. Inorganic acids from which salts can be derived include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like. Organic acids from which salts can be derived include, for example, acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, and the like. Pharmaceutically acceptable acid addition salts can be formed using inorganic and organic bases. Inorganic bases from which salts can be derived include, for example, sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum, and the like. Organic bases from which salts may be derived include, for example, primary, secondary, and tertiary amines, naturally occurring substituted amines, cyclic amines, substituted amines including basic ion exchange resins, and the like, specifically isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, and ethanolamine. In some embodiments, the pharmaceutically acceptable base addition salts are selected from ammonium, potassium, sodium, calcium, and magnesium salts.

[0057] As used herein, the phrases "parenteral administration" and "administered parenterally" refer to modes of administration other than enteral administration and topical administration, usually by injection, and include, but are not limited to, intravenous, intramuscular, intraarterial, intrathecal, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, transtracheal, subcutaneous, subcuticular, intraarticular, subcapsular, subarachnoid, intraspinal, and substernal injection and infusion.

[0058] The phrase "pharmaceutically acceptable" is used herein to refer to those compounds, materials, compositions, and / or dosage forms that are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without undue toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit-risk ratio.

[0059] As used herein, the phrase "pharmaceutically acceptable excipient" or "pharmaceutically acceptable carrier" refers to a pharmaceutically acceptable material, composition, or vehicle, such as a liquid or solid filler, diluent, excipient, solvent, or encapsulating material. Each carrier must be "acceptable" in the sense of being compatible with the other ingredients of the formulation and not harmful to the patient. Some examples of materials that can serve as pharmaceutically acceptable carriers include: (1) sugars such as lactose, glucose, and refined sucrose; (2) starches such as corn starch and potato starch; (3) cellulose and its derivatives such as sodium carboxymethylcellulose, ethylcellulose, and cellulose acetate; (4) powdered tragacanth; (5) malt; (6) gelatin; (7) talc; (8) excipients such as cocoa butter and suppository wax; (9) peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil, and (10) oils such as soybean oil, (11) polyols such as glycerin, sorbitol, mannitol, and polyethylene glycol, (12) esters such as ethyl oleate and ethyl laurate, (13) agar, (14) buffers such as magnesium hydroxide and aluminum hydroxide, (15) alginic acid, (16) pyrogen-free water, (17) isotonic saline, (18) Ringer's solution, (19) ethyl alcohol, (20) phosphate buffer, and (21) other non-toxic compatible substances employed in pharmaceutical formulations.

[0060] In certain embodiments, the terms "prevent" or "preventing" in relation to a disease or disorder may refer to a compound reducing the onset of the disorder or condition in a statistical sample in a treated sample compared to an untreated control sample, or delaying the onset of or reducing the severity of one or more symptoms of the disorder or condition compared to an untreated control sample.

[0061] The terms "treat," "treating," and "treatment," as used herein, include alleviating, reducing, or ameliorating the symptoms of a disease or condition, either prophylactically and / or therapeutically, preventing further symptoms, ameliorating or preventing the underlying cause of a condition, inhibiting a disease or condition, e.g., halting the progression of a disease or condition, relieving a disease or condition, causing a disease or condition to regress, alleviating a condition caused by a disease or condition, or arresting the symptoms of a disease or condition,

[0062] The term "ligand" generally refers to a macromolecular compound capable of recognizing and binding to an antigen or receptor associated with a target cell. Ligands can be used to deliver agents, including but not limited to protein hormones, lectins, growth factors, antibodies, or other substances capable of binding to cells, receptors, and / or antigen molecules, to a target cell population that binds to the ligand. A ligand can be an antibody. A ligand can be an antigen-binding fragment. A ligand can be a targeting moiety.

[0063] The term "targeting moiety" refers to a structure that has selective affinity for a target molecule compared to other non-target molecules. The targeting moiety binds to the target molecule. The targeting moiety may include, for example, an antibody, a peptide, a ligand, a receptor, or a binding portion thereof. The target biomolecule may be a biological receptor or other structure of a cell, such as a tumor antigen.

[0064] The term "linker" refers to a chemical moiety that can connect two different chemical moieties to each other. The linker can include a spacer and an amino acid. The linker can be a cleavable linker that facilitates the release of the compounds described herein. The linker can be used to form a covalent bond with a ligand (e.g., an antibody).

[0065] The term "antibody" refers to a whole antibody, an antigen-binding fragment (i.e., "antigen-binding portion") of an antibody, or a single-chain variant thereof. A whole antibody is a protein comprising at least two heavy (H) chains and two light (L) chains interconnected by disulfide bonds. Each heavy chain comprises a heavy chain variable region (VH) and a heavy chain constant region comprising three domains, CH1, CH2, and CH3. Each light chain comprises a light chain variable region (VL or Vk) and a light chain constant region comprising one single domain, CL. The VH and VL regions can be further subdivided into hypervariable regions called complementarity-determining regions (CDRs) and interspersed, more conserved framework regions (FRs). Each VH and VL comprises three CDRs and four FRs arranged from the amino terminus to the carboxy terminus in the following order: FR1, CDR1, FR2, CDR2, FR3, CDR3, and FR4. The variable regions contain the binding domains that interact with antigens. The constant regions may mediate the binding of the antibody to host tissues or factors, including various cells of the immune system (e.g., effector cells) and the first component (Clq) of the classical complement system. -8 M or less, more preferably 1×10 -8 M or less, preferably 6×10 -9 M or less, preferably 3×10 -9 M or less, and even more preferably 2×10 -9 An antibody is said to "specifically bind" to antigen X when it binds to antigen X with a KD of M or less. The antibody can be a chimeric antibody, a humanized antibody, or preferably a human antibody. The heavy chain constant region can be engineered to affect the type or degree of glycosylation, to extend antibody half-life, to enhance or reduce interaction with effector cells or the complement system, or to modulate some other property. Engineering can be achieved by substitution, addition, or deletion of one or more amino acids, or by replacing a domain with a domain from another immunoglobulin type, or by a combination of the foregoing.

[0066] The terms "antigen-binding fragment" and "antigen-binding portion" of an antibody (or simply "antibody portion" or "antibody fragment") refer to one or more fragments of an antibody that retain the ability to specifically bind to an antigen. The antigen-binding function of an antibody can be expressed in the following fragments of a full-length antibody: (i) a FAb fragment (a monovalent fragment consisting of the VL, VH, CL, and CH1 domains); (ii) a F(ab')2 fragment (a bivalent fragment containing two Fab fragments linked by a disulfide bridge at the hinge region); (iii) a Fab' fragment (essentially a Fab with part of the hinge region) (see, e.g., Abbas et al., Cellular and Molecular Immunology, 6th Ed., Saunders Elsevier 2007); (iv) a Fd fragment consisting of the VH and CH1 domains; (v) a Fv fragment consisting of the VL and VH domains of a single arm of an antibody; and (vi) a dAb fragment consisting of the VH domain (Ward et al., (1989) Nature 341:544-546), (vii) separated complementarity-determining regions (CDRs), and (viii) nanobodies (heavy chain variable regions comprising a single variable domain and two constant domains). Preferred antigen-binding fragments are Fab, F(ab')2, Fab', Fv, and Fd fragments. Furthermore, although the two domains of an Fv fragment, VL and VH, are encoded by separate genes, they can be joined using recombinant methods by a synthetic linker that allows them to be produced as a single protein chain in which the VL and VH domains pair to form a monovalent molecule (known as single-chain Fv or scFv; see, e.g., Bird et al. (1988) Science 242:423-426 and Huston et al. (1988) Proc. Natl. Acad. Sci. USA 85:5879-5883). Such single chain antibodies are also encompassed within the term "antigen-binding portion" of an antibody.

[0067] The term "isolated antibody" refers to an antibody that is substantially free of other antibodies having different antigen specificities (e.g., an isolated antibody that specifically binds antigen X is substantially free of antibodies that specifically bind antigens other than antigen X). However, an isolated antibody that specifically binds antigen X may have cross-reactivity to other antigens, such as antigen X molecules from other species. In certain embodiments, an isolated antibody specifically binds human antigen X and does not cross-react with other (non-human) antigen X antigens. Furthermore, an isolated antibody may be substantially free of other cellular material and / or chemicals.

[0068] The terms "monoclonal antibody" or "monoclonal antibody composition" refer to a preparation of antibody molecules of single molecular composition, displaying a single binding specificity and affinity for a particular epitope.

[0069] The term "human antibody" refers to an antibody having variable regions in which both the framework and CDR regions (and constant region, if present) are derived from human germline immunoglobulin sequences. Human antibodies may contain subsequent modifications, including natural or synthetic modifications. Human antibodies may include amino acid residues not encoded by human germline immunoglobulin sequences (e.g., mutations introduced by random or site-specific mutation in vitro or by somatic mutation in vivo). However, "human antibody" does not include antibodies in which CDR sequences derived from the germline of another mammalian species, such as a mouse, have been grafted onto human framework sequences.

[0070] The term "human monoclonal antibody" refers to antibodies displaying a single binding specificity which have variable regions in which both the framework and CDR regions are derived from human germline immunoglobulin sequences. In one embodiment, a human monoclonal antibody is produced by a hybridoma comprising B cells obtained from a transgenic non-human animal (e.g., a transgenic mouse) whose genome comprises human heavy chain and light chain transgenes fused to an immortalized cell.

[0071] Compounds of the Disclosure Below is a discussion of compounds and salts thereof that can be used in the methods of the present disclosure.

[0072] The present disclosure provides a compound of formula (I)

[0073] [ka] or a pharmaceutically acceptable salt thereof, wherein: L is (L 2 ) x -(L 2B ) z -(L 2C ) y -L 3 -L 4 -(L 5 ) m -(L 6 ) n -(L 7 ) p -R 2 and L 2 is C 1-6 alkylene; L 2B is (NR 4 ) t C(O)O—CH2-phenyl, wherein phenyl is selected from one or more R 5 optionally substituted with L 2C is selected from C(O)O—CH2-phenyl, wherein phenyl is selected from one or more R 6 optionally substituted with L 3 is selected from residues containing 1 to 7 amino acids, L 4 is an optionally substituted C 1-6 alkylene, wherein C 1-6 Alkylene is independently selected from halogen, -OH, -CN, -NO2, -NH2, oxo, -C 1-10 Haloalkyl, -OC 1-10 Alkyl, C 2-10 Alkenyl, C 2-10optionally substituted with one or more substituents selected from alkynyl, L 5 is (O-CH2-CH2-) q -(NR 3 ) s is selected from L 6 is an optionally substituted C 1-6 alkylene, wherein C 1-6 Alkylene is independently selected from halogen, -OH, -CN, -NO2, -NH2, oxo, C 1-10 Alkyl, -C 1-10 Haloalkyl, -OC 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 optionally substituted with one or more substituents selected from alkynyl, L 7 is C 5-6 selected from carbocycles, R 1 -O- and -NR 7 - selected from R 2 is selected from optionally substituted 5- to 6-membered heterocycles, wherein the 5- to 6-membered heterocycles are independently selected from halogen, —OH, —CN, —NO, —NH, oxo, C 1-10 Alkyl, -C 1-10 Haloalkyl, -OC 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 optionally substituted with one or more substituents selected from alkynyl, R 3 is hydrogen and C 1-6 alkyl, R 4 is hydrogen and one or more SO2C 1-6 C optionally substituted with alkyl 1-6 alkyl, Each R 5 are independently selected from sugars; Each R 6 are independently halogen, -OH, -CN, -NO2, -NH2, oxo, -C 1-10Haloalkyl, -OC 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 alkynyl, R 7 is hydrogen and C 1-6 alkyl, R 8 is selected from hydrogen and hydroxy; R 9 is selected from hydrogen and halogen, and R 8 or R 9 at least one of is hydrogen, m is selected from 0 and 1; n is selected from 0 and 1; p is selected from 0 and 1; q is selected from 0 to 8; s is selected from 0 and 1; t is selected from 0 and 1; x is selected from 0 and 1; y is selected from 0 and 1; z is selected from 0 and 1.

[0074] In some embodiments, formula (I) is

[0075] [ka] or a pharmaceutically acceptable salt thereof.

[0076] In some embodiments, formula (I) is

[0077] [ka] is expressed by

[0078] In some embodiments, for a compound or salt of Formula (I), Formula (IA), or Formula (IB), L is L 2 -(L 2B ) z -L3 -L 4 -(L 5 ) m -(L 6 ) n -(L 7 ) p -R 2 In some cases, L is 2 -L 3 -L 4 -L 5 -L 6 -L 7 -R 2 In some cases, L is 2 -L 3 -L 4 -L 5 -L 6 -R 2 In some cases, L is 2 -L 3 -L 4 -L 7 -R 2 In some cases, the linker is L 2 -L 3 -L 4 -R 2 In some cases, L is 2 -L 2B -L 3 -L 4 -L 5 -R 2 In some cases, L is 2 -L 2B -L 3 -L 4 -R 2 In some cases, L is 2B -L 3 -L 4 -R 2 is.

[0079] In some embodiments, for a compound or salt of Formula (I), Formula (IA), or Formula (IB), L is (L 2B ) z -L 3 -L 4 -(L 5 ) m -(L 6 ) n -(L7 ) p -R 2 In some cases, L is 2B -L 3 -L 4 -L 5 -L 6 -L 7 -R 2 In some cases, L is 2B -L 3 -L 4 -L 5 -L 6 -R 2 In some cases, L is 2B -L 3 -L 4 -L 5 -R 2 In some cases, L is 2B -L 3 -L 4 -R 2 is.

[0080] In some embodiments, for a compound or salt of Formula (I), Formula (IA), or Formula (IB), L is (L 2C ) y -L 3 -L 4 -(L 5 ) m -(L 6 ) n -(L 7 ) p -R 2 In some cases, L is 2C -L 3 -L 4 -L 5 -L 6 -L 7 -R 2 In some cases, L is 2C -L 3 -L 4 -L 5 -L 6 -R 2 In some cases, L is 2C -L 3 -L 4 -L 5 -R 2In some cases, L is 2C -L 3 -L 4 -R 2 In some cases, L is 2C -L 3 -L 4 -L 7 -R 2 In some cases, L is 3 -L 4 -R 2 is.

[0081] In some embodiments, for a compound or salt of Formula (I), Formula (IA), or Formula (IB), L 2 is C 1-6 Optionally, L is selected from alkylene. 2 is a C5 alkylene. 2 is C4 alkylene. 2 is C alkylene. 2 is C2 alkylene. 2 is a C1 alkylene.

[0082] In some embodiments, for a compound or salt of Formula (I), Formula (IA), Formula (IB), Formula (II), Formula (III), or Formula (III-A), z is 1. 2B is NR 4 C(O)O—CH2-phenyl, wherein phenyl is selected from one R 5 Optionally, L 2B is NR 4 C(O)O—CH2-phenylene, wherein phenylene is selected from one R 5 Optionally, L 2B is selected from C(O)O—CH2-phenyl, and phenyl is selected from one R 5 Optionally, L 2B teeth,

[0083] [ka] In some cases, L 2B teeth,

[0084] [ka] In some cases, L 2B teeth,

[0085] [ka] In some cases, L 2B teeth,

[0086] [ka] In some cases, L 2B teeth,

[0087] [ka] In some cases, L 2B teeth,

[0088] [ka] In some cases, each R 5 are independently selected from sugars. Optionally, the sugars are selected from monosaccharides and disaccharides. Optionally, the sugars are selected from monosaccharides. Optionally, the sugars are selected from fructose, galactose, glucose, glucuronic acid, maltose, sucrose, and sucrose. Optionally, the sugar is glucuronic acid. Optionally, R 5 teeth,

[0089] [ka] In some cases, R 5 teeth,

[0090] [ka] In some cases, z is 0. In some cases, R 4 is selected from hydrogen. 4 is one SO2C 1-6 C optionally substituted with alkyl 1-6 alkyl. 4 is one SO2C 1-6 C optionally substituted with alkyl 1-6 alkyl. 4 is a C substituted with one SO2 methyl 1-6 alkyl. 4 teeth,

[0091] [ka] is.

[0092] In some embodiments, for a compound or salt of Formula (I), Formula (IA), Formula (IB), Formula (II), Formula (III), or Formula (III-A), y is 1. 2C is selected from C(O)O—CH2-phenyl, wherein phenyl is selected from one or more R 6 Optionally, L 2C is selected from C(O)O—CH2-phenyl, and phenyl is selected from one R 6 Optionally, L 2C teeth,

[0093] [ka] In some cases, L 2C teeth,

[0094] [ka] is.

[0095] In some embodiments, for a compound or salt of Formula (I), Formula (IA), Formula (IB), Formula (II), Formula (III), or Formula (III-A), L 3 is selected from residues containing 1 to 7 amino acids. 3 is selected from residues containing 1 to 5 amino acids. 3 is selected from residues containing 1 to 4 amino acids. 3 is selected from residues containing 1 to 3 amino acids. 3 is selected from residues containing 1 to 2 amino acids. 3 is selected from residues containing 2 to 4 amino acids. 3 is selected from residues containing one amino acid. 3 is selected from residues comprising two amino acids. 3 is selected from residues comprising three amino acids. 3 is selected from residues comprising four amino acids. 3 is selected from residues comprising five amino acids. 3 is selected from residues comprising six amino acids. 3 is selected from residues comprising seven amino acids.

[0096] In some embodiments, for a compound or salt of Formula (I), Formula (IA), Formula (IB), Formula (II), Formula (III), or Formula (III-A), L 3 is selected from residues including natural and unnatural amino acids.

[0097] In some embodiments, for a compound or salt of Formula (I), Formula (IA), Formula (IB), Formula (II), Formula (III), or Formula (III-A), L 3 is selected from residues including naturally occurring amino acids. 3 is selected from residues containing alpha amino acids.3 is selected from residues including β-amino acids.

[0098] In some embodiments, for a compound or salt of Formula (I), Formula (IA), Formula (IB), Formula (II), Formula (III), or Formula (III-A), the amino acid is an unnatural amino acid.

[0099] In some embodiments, for a compound or salt of Formula (I), Formula (IA), Formula (IB), Formula (II), Formula (III), or Formula (III-A), L 3 is selected from the group consisting of alanine, arginine, asparagine, aspartic acid, cysteine, glutamic acid, glutamine, glycine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine, valine, citrulline, and β-alanine. 3 is selected from the group consisting of alanine, aspartic acid, cysteine, glutamic acid, glutamine, glycine, isoleucine, leucine, lysine, phenylalanine, serine, valine, citrulline, sarcosine, and β-alanine. 3 is selected from the group consisting of alanine, glycine, lysine, phenylalanine, serine, valine, citrulline, sarcosine, and β-alanine. 3 is selected from the group consisting of alanine, glycine, phenylalanine, valine, citrulline, and β-alanine. 3 is selected from the group consisting of alanine, valine, and citrulline. 3 is selected from the group consisting of glycine and phenylalanine. 3 is selected from the group consisting of glycine, phenylalanine, and sarcosine. 3 is selected from the group consisting of sarcosine.

[0100] In some embodiments, for a compound or salt of Formula (I), Formula (IA), Formula (IB), Formula (II), Formula (III), or Formula (III-A), L 3 contains four amino acids. 3 contains two amino acids. 3 contains one amino acid. 3 contains at least two different amino acids. 3 teeth,

[0101] [ka] In some cases, L 3 teeth,

[0102] [ka] In some cases, L 3 teeth,

[0103] [ka] In some cases, L 3 teeth,

[0104] [ka] is.

[0105] In some embodiments, for a compound or salt of Formula (I), Formula (IA), Formula (IB), Formula (II), Formula (III), or Formula (III-A), L 4 is an optionally substituted C 1-6 alkylene, wherein C 1-6 Alkylene is independently selected from halogen, -OH, -CN, -NO2, -NH2, oxo, -C 1-10 Haloalkyl, -OC 1-10 Alkyl, C 2-10 Alkenyl, C 2-10Optionally, L is optionally substituted with one or more substituents selected from alkynyl. 4 is an optionally substituted C 1-6 alkylene, wherein C 1-6 The alkylene is optionally substituted with one or more substituents independently selected from —OH, —NH, and oxo. 4 is an optionally substituted C 1-6 alkylene, wherein C 1-6 The alkylene is optionally substituted with oxo. 4 is selected from —C(O)—(CH2)2— and —C(O)—(CH2)5—. 4 is —C(O)—(CH2)2—. 4 is —C(O)—(CH2)3—. 4 is —C(O)—(CH2)4—. 4 is -C(O)-(CH2)5-.

[0106] In some embodiments, for a compound or salt of Formula (I), Formula (IA), Formula (IB), Formula (II), Formula (III), or Formula (III-A), L 5 is -(O-CH2-CH2-) q -(NR 3 ) s -, q is selected from 0 to 8, and s is selected from 0 and 1. 5 is -(O-CH2-CH2-) q -(NR 3 ) s -, q is selected from 0 to 8, and s is 0. 5 is -(O-CH2-CH2-) q -(NR 3 ) s-, q is selected from 0 to 8, and s is 1. Optionally, q is 1. Optionally, q is 2. Optionally, q is 3. Optionally, q is 4. Optionally, q is 5. Optionally, q is 6. Optionally, L 5 is -(O-CH-CH-)-NH-. 5 is -(O-CH2-CH2-)3-NH-. 5 is -(O-CH2-CH2-)4-NH-. 5 is -(O-CH2-CH2-)5-NH-. 5 is -(O-CH2-CH2-)6-NH-. 5 is -(O-CH2-CH2-)7-NH-. 5 is -(O-CH2-CH2-)8-NH-. 5は , -(O-CH2-CH2-) 1-8 In some cases, s is 0. In some cases, s is 1.

[0107] In some embodiments, for a compound or salt of Formula (I), Formula (IA), Formula (IB), Formula (II), Formula (III), or Formula (III-A), L 6 is an optionally substituted C 1-6 alkylene, wherein C 1-6 Alkylene is independently selected from halogen, -OH, -CN, -NO2, -NH2, oxo, -C 1-10 Haloalkyl, -OC 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Optionally, L is optionally substituted with one or more substituents selected from alkynyl. 6 is an optionally substituted C 1-6 alkylene, wherein C 1-6 The alkylene is optionally substituted with one or more substituents independently selected from —OH, —NH, and oxo. 6is an optionally substituted C 1-6 alkylene, wherein C 1-6 The alkylene is optionally substituted with oxo. 6 is selected from —C(O)—(CH2)2— and —C(O)—(CH2)5—. 6 is —C(O)—(CH2)2—. 6 is —C(O)—(CH2)3—. 6 is —C(O)—(CH2)4—. 6 is -C(O)-(CH2)5-.

[0108] In some embodiments, for a compound or salt of Formula (I), Formula (IA), Formula (IB), Formula (II), Formula (III), or Formula (III-A), L 7 is C 5-6 Optionally, L is selected from carbocycles. 7 is C 5-6 Optionally, L is selected from carbocyclene. 7 is selected from C6 carbocycles. 7 is phenyl. 7 is phenylene. 7 is cyclohexyl. 7 teeth,

[0109] [ka] In some cases, L 7 teeth,

[0110] [ka] is.

[0111] In some embodiments, for a compound or salt of Formula (I), Formula (IA), Formula (IB), Formula (II), or Formula (III), R 2is selected from optionally substituted 5- to 6-membered heterocycles, wherein the 5- to 6-membered heterocycles are independently selected from halogen, —OH, —CN, —NO, —NH, oxo, C 1-10 Alkyl, -C 1-10 Haloalkyl, -OC 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Optionally, R is substituted with one or more substituents selected from alkynyl. 2 is selected from optionally substituted 5- to 6-membered heterocyclenes, wherein the 5- to 6-membered heterocyclenes are independently selected from halogen, —OH, —CN, —NO, —NH, oxo, C 1-10 Alkyl, -C 1-10 Haloalkyl, -OC 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Optionally, R is substituted with one or more substituents selected from alkynyl. 2 is selected from optionally substituted 5- to 6-membered heterocycles, wherein the 5- to 6-membered heterocycles are optionally substituted with one or more substituents independently selected from oxo and halogen. 2 is selected from optionally substituted 5- to 6-membered heterocyclenes, where the 5- to 6-membered heterocyclenes are optionally substituted with one or more substituents independently selected from oxo and halogen. 2 is selected from optionally substituted 5-membered heterocycles, wherein the 5-membered heterocycles are optionally substituted with one or more substituents independently selected from oxo. 2 is selected from optionally substituted 5-membered heterocyclene, wherein the 5-membered heterocyclene is optionally substituted with one or more substituents independently selected from oxo. Optionally, the 5-membered heterocycle has at least one double bond. Optionally, the 5-membered heterocycle has one double bond. Optionally, R 2 is maleimide. 2 teeth,

[0112] [ka] In some cases, R 2 teeth,

[0113] [ka] where Lg is a ligand. 2 is a reactive moiety capable of forming new bonds. 2 is a reactive moiety that can form a new bond from an existing double bond.

[0114] In some embodiments, for a compound or salt of Formula (I), Formula (IA), Formula (IB), Formula (II), Formula (III), or Formula (III-A), L 2 -L 3 -L 4 -R 2 teeth,

[0115] [ka] In some cases, L 2 -L 3 -L 4 teeth,

[0116] [ka] is.

[0117] In some embodiments, for a compound or salt of Formula (I), Formula (IA), Formula (IB), Formula (II), Formula (III), or Formula (III-A), L 2 -L 3 -L 4 teeth,

[0118] [ka] In some cases, L2 -L 3 teeth,

[0119] [ka] is.

[0120] In some embodiments, for a compound or salt of Formula (I), Formula (IA), Formula (IB), Formula (II), or Formula (III), L 2 -L 3 -L 4 -L 5 -L 6 -L 7 -R 2 teeth,

[0121] [ka] In some cases, L 2 -L 3 -L 4 -L 5 -L 6 -L 7 teeth,

[0122] [ka] In some cases, L 2 -L 3 -L 4 -L 5 -L 6 teeth,

[0123] [ka] In some cases, L 2 -L 3 -L 4 -L 5 teeth,

[0124] [ka] In some cases, L 2 -L3 -L 4 -L 5 teeth,

[0125] [ka] is.

[0126] In some embodiments, for a compound or salt of Formula (I), Formula (IA), Formula (IB), Formula (II), or Formula (III), L 2 -L 2B -L 3 -L 4 -R 2 teeth,

[0127] [ka] In some cases, L 2 -L 2B -L 3 -L 4 teeth,

[0128] [ka] In some cases, L 2 -L 2B -L 3 teeth,

[0129] [ka] In some cases, L 2 -L 2B teeth,

[0130] [ka] In some cases, L 2B teeth,

[0131] [ka] is.

[0132] In some embodiments, for a compound or salt of Formula (I), Formula (IA), Formula (IB), Formula (II), or Formula (III), L is

[0133] [ka] is.

[0134] In some embodiments, for a compound or salt of Formula (I), Formula (IA), Formula (IB), Formula (II), or Formula (III), L is L 2C -L 3 -L 4 -R 2 , L 2C -L 3 -L 4 -L 7 -R 2 , and L 2C -L 3 -L 4 -L 5 -L 6 -L 7 -R 2 wherein L is selected from 2C teeth,

[0135] [ka] is selected from.

[0136] In some embodiments, formula (I) is

[0137] [ka] or a pharmaceutically acceptable salt thereof, wherein Lg is a ligand.

[0138] In one aspect, the present disclosure provides a compound of formula (III):

[0139] [ka] or a pharmaceutically acceptable salt thereof, wherein: Lg is the ligand, L is (L 2 ) x -(L 2B ) z -(L 2C ) y -L 3 -L 4 -(L 5 ) m -(L 6 ) n -(L 7 ) p -R 2 and L 2 is C 1-6 alkylene; L 2B is (NR 4 ) t C(O)OC 1-6 alkylene-phenyl, wherein phenyl is selected from one or more R 5 optionally substituted with L 2C is selected from C(O)O—CH2-phenyl, where phenyl is selected from halogen, —OH, —CN, —NO2, —NH2, oxo, —C 1-10 Haloalkyl, -OC 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 optionally substituted with alkynyl; L 3 is selected from residues containing 1 to 7 amino acids, L 4 is an optionally substituted C 1-6 alkylene, wherein C 1-6 Alkylene is independently selected from halogen, -OH, -CN, -NO2, -NH2, oxo, -C 1-10 Haloalkyl, -OC 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 optionally substituted with one or more substituents selected from alkynyl; L 5 is (O-CH2-CH2-) q-(NR 3 ) s is selected from L 6 is an optionally substituted C 1-6 alkylene, wherein C 1-6 Alkylene is independently selected from halogen, -OH, -CN, -NO2, -NH2, oxo, C 1-10 Alkyl, -C 1-10 Haloalkyl, -OC 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 optionally substituted with one or more substituents selected from alkynyl, L 7 is C 5-6 selected from carbocycles, R 1 -O- and -NR 7 - selected from R 2 is selected from optionally substituted 5- to 6-membered heterocycles, wherein the 5- to 6-membered heterocycles are independently selected from halogen, —OH, —CN, —NO, —NH, oxo, C 1-10 Alkyl, -C 1-10 Haloalkyl, -OC 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 optionally substituted with one or more substituents selected from alkynyl, R 3 is hydrogen and C 1-6 alkyl, R 4 is hydrogen and one or more SO2C 1-6 C optionally substituted with alkyl 1-6 alkyl, Each R 5 are independently selected from sugars; R 7 is hydrogen and C 1-6 alkyl, R 8 is selected from hydrogen and hydroxy; R 9 is selected from hydrogen and halogen, and R 8 or R9 at least one of is hydrogen, m is selected from 0 and 1; n is selected from 0 and 1; p is selected from 0 and 1; q is selected from 0 to 8; s is selected from 0 and 1; t is selected from 0 and 1; x is selected from 0 and 1; y is selected from 0 and 1; z is selected from 0 and 1.

[0140] In some embodiments, formula (III) is

[0141] [ka] or a pharmaceutically acceptable salt thereof.

[0142] In one aspect, the present disclosure provides a compound of formula (IV-A):

[0143] [ka] or a pharmaceutically acceptable salt thereof.

[0144] In one aspect, the present disclosure provides a compound of formula (IV-B):

[0145] [ka] or a pharmaceutically acceptable salt thereof.

[0146] In one aspect, the present disclosure provides a compound of formula (IV-C):

[0147] [ka] or a pharmaceutically acceptable salt thereof.

[0148] In one aspect, the present disclosure provides a compound of formula (IV-D):

[0149] [ka] or a pharmaceutically acceptable salt thereof.

[0150] The present disclosure includes salts of the compounds described herein, particularly pharmaceutically acceptable salts.The compounds of the present invention that have sufficiently acidic, sufficiently basic, or both functional groups can react with some inorganic bases, and inorganic and organic acids to form salts.Alternatively, compounds that are inherently charged, such as those with quaternary nitrogen, can form salts with suitable counterions, for example, halides such as bromide, chloride, or fluoride, especially bromide.

[0151] Chemical entities having a carbon-carbon double bond or a carbon-nitrogen double bond can exist in Z- or E-forms (or cis- or trans-forms). Additionally, some chemical entities can exist in various tautomeric forms. Unless otherwise specified, the compounds described herein are intended to include Z-, E-, and tautomeric forms as well.

[0152] "Tautomer" refers to a molecule capable of proton transfer from one atom of a molecule to another atom of the same molecule. The compounds presented herein exist as tautomers in certain embodiments. In situations where tautomerization is possible, a chemical equilibrium of tautomers exists. The exact ratio of tautomers depends on several factors, including physical conditions, temperature, solvent, and pH. Some examples of tautomeric equilibrium include the following:

[0153] [ka]

[0154] The compounds disclosed herein may, in some embodiments, be administered in different isotopically enriched forms, e.g.,2 H, 3 H, 11 C. 13 C, and / or 14 The compound is used enriched in C content. In one particular embodiment, the compound is deuterated at at least one position. Such deuterated forms can be prepared by the procedures described in U.S. Patent Nos. 5,846,514 and 6,334,997. As described in U.S. Patent Nos. 5,846,514 and 6,334,997, deuteration can improve metabolic stability or efficacy, thereby increasing the duration of action of pharmaceuticals.

[0155] Unless otherwise stated, the compounds described herein are intended to include compounds which differ only in the presence of one or more isotopically enriched atoms, for example, the replacement of hydrogen by deuterium or tritium, or 13 C- or 14 Compounds having the present structures except for the replacement of a carbon with a C-enriched carbon are within the scope of this disclosure.

[0156] The compounds of the present disclosure optionally contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute such compounds. For example, the compounds may contain, for example, deuterium ( 2 H), tritium ( 3 H), iodine-125( 125 I). or carbon-14 ( 14 It can be labeled with an isotope such as C. 2 H, 11 C. 13 C. 14 C. 15 C. 12 N, 13 N, 15 N, 16 N, 16 O. 17 O. 14 F, 15 F, 16 F, 17 F, 18 F, 33 S, 34 S, 35 S, 36S, 35 Cl, 37 Cl, 79 Br, 81 Br, and 125 All isotopic substitutions at I are contemplated. All isotopic variations of the compounds of the present invention, whether radioactive or not, are encompassed within the scope of the present invention.

[0157] In certain embodiments, the compounds disclosed herein are 1 Some or all of the H atoms 2 It is substituted with an H atom. Methods for the synthesis of compounds containing deuterium are known in the art and include, by way of non-limiting example only, the synthesis methods described below.

[0158] Deuterium-substituted compounds are synthesized using a variety of methods, such as those described in Dean, Dennis C.; Editor. Recent Advances in the Synthesis and Applications of Radiolabeled Compounds for Drug Discovery and Development. [In: Curr., Pharm. Des., 2000; 6(10)] 2000, 110 pp; George W.; Varma, Rajender S. The Synthesis of Radiolabeled Compounds via Organometallic Intermediates, Tetrahedron, 1989, 45(21), 6601-21, and Evans, E. Anthony. Synthesis of radiolabeled compounds, J. Radioanal. Chem., 1981, 64(1-2), 9-32.

[0159] Deuterated starting materials are readily available and can be subjected to the synthetic methods described herein to provide for the synthesis of deuterium-containing compounds. Many deuterium-containing reagents and building blocks are commercially available from chemical suppliers such as Aldrich Chemical Co.

[0160] The compounds of the present invention also include crystalline and amorphous forms of these compounds, pharmaceutically acceptable salts, and active metabolites of these compounds, having the same type of activity, including, for example, polymorphs, pseudopolymorphs, solvates, hydrates, nonsolvated polymorphs (including anhydrates), conformational polymorphs, and amorphous forms of the compounds, and mixtures thereof.

[0161] The compounds described herein may, in some cases, exist as diastereomers, enantiomers, or other stereoisomeric forms. When absolute stereochemistry is not specified, the compounds presented herein include all diastereomeric, enantiomeric, and epimeric forms, as well as the appropriate mixtures thereof. Separation of stereoisomers can be carried out by chromatography, by forming diastereomers and separating them by recrystallization, by chromatography, or by any combination thereof. (Jean Jacques, Andre Collet, Samuel H. Wilen, "Enantiomers, Racemates, and Resolutions," John Wiley and Sons, Inc., 1981, incorporated by reference for this disclosure). Stereoisomers may also be obtained by stereoselective synthesis.

[0162] The methods and compositions described herein include the use of amorphous forms as well as crystalline forms (also known as polymorphs). The compounds described herein may be in the form of pharmaceutically acceptable salts. Similarly, in some embodiments, active metabolites of these compounds having the same type of activity are included within the scope of the present disclosure. In addition, the compounds described herein can exist in unsolvated forms as well as solvated forms containing pharmaceutically acceptable solvents such as water, ethanol, etc. Solvated forms of the compounds presented herein are also considered to be disclosed herein.

[0163] In certain embodiments, a compound or a salt of a compound may be a prodrug, in which a hydroxyl in the parent compound is presented as an ester or carbonate, or a carboxylic acid in the parent compound is presented as an ester. The term "prodrug" is intended to encompass compounds that are converted into the pharmaceuticals of the present disclosure under physiological conditions. One method for creating a prodrug is to include one or more selected moieties that are hydrolyzed under physiological conditions to reveal the desired molecule. In other embodiments, the prodrug is converted by the enzymatic activity of a host animal, such as a specific target cell in the host animal. For example, esters or carbonates (e.g., esters or carbonates of alcohols or carboxylic acids, and esters of phosphonic acids) are preferred prodrugs of the present disclosure.

[0164] Prodrug forms of the compounds described herein are included within the scope of the claims, where the prodrug is metabolized in vivo to produce a compound described herein. In some cases, some of the compounds described herein may be prodrugs of another derivative or active compound.

[0165] Prodrugs are often useful because, in some situations, they may be easier to administer than the parent drug. Prodrugs may be bioavailable, for example, by oral administration, whereas the parent drug may not. Prodrugs may serve to improve cell permeability to the compound compared to the parent drug. Prodrugs may also have improved solubility in pharmaceutical compositions compared to the parent drug. Prodrugs may be designed as reversible drug derivatives for use as modifiers to improve drug transport to site-specific tissues or increase drug retention within cells.

[0166] In some embodiments, the prodrug design improves the lipophilicity of the pharmaceutical agent, hi some embodiments, the prodrug design increases the effective aqueous solubility. For example, Fedorak et al., Am.J.Physiol.,269:G210-218(1995), McLoed et al.,Gastroenterol,106:405-413(1994), Hochhaus et al.,Biomed.Chrom.,6:283-286(1992), J.Larsen and H.Bundgaard, Int.J.Pharmaceutics,37,87(1987), J.Larsen et al.,Int.J.Pharmaceutics,47,103(1988), Sinkula et al.,J.Pharm.Sci.,64:181-210(1975), T.Higuchi and V.Stella,Pro-drugs as Novel Delivery Systems,Vol.14 of the ACSSymposium Series, and Edward See B. Roche, Bioreversible Carriers in Drug Design, American Pharmaceutical Association and Pergamon Press, 1987, all of which are incorporated herein by reference. According to another embodiment, the present disclosure provides a method for producing the compounds defined above. The compounds may be synthesized using conventional techniques. Advantageously, these compounds are conveniently synthesized from readily available starting materials.

[0167] Synthetic chemistry transformations and methods useful for synthesizing the compounds described herein are known in the art and include, for example, those described in R. Larock, Comprehensive Organic Transformations (1989), T.W. Greene and P.G.M. Wuts, Protective Groups in Organic Synthesis, 2d. Ed. (1991), L. Fieser and M. Fieser, Fieser and Fieser's Reagents for Organic Synthesis (1994), and L. Paquette, ed., Encyclopedia of Reagents for Organic Synthesis (1995).

[0168] Ligand In some embodiments, for a compound or salt of Formula (I), Formula (IA), Formula (IB), Formula (II), Formula (III), or Formula (III-A), the ligand is selected from an antibody or an antigen-binding fragment thereof. Optionally, the ligand is selected from the group consisting of a chimeric antibody, a humanized antibody, and a human antibody.

[0169] In some embodiments, the ligand (e.g., an antibody) serves a targeting function. By binding to the target tissue or cell where its antigen or receptor is located, the ligand guides the conjugate there. In some cases, when the ligand is an antibody, the compound may be referred to as an antibody-drug conjugate (ADC) or immunoconjugate. Preferably, the target tissue or cell is a cancer tissue or cell, and the antigen or receptor is a tumor-associated antigen, i.e., an antigen that is uniquely expressed by cancer cells or overexpressed by cancer cells compared to non-cancerous cells. In some cases, the conjugate is internalized into the target cell by endocytosis, and cleavage occurs within the target cell. In some cases, the ligand is selected from UC-961, PTK-7, trastuzumab, brentuximab, loncustuximab, rosopatamab, rituximab, pinatuzumab, polatuzumab, and naratuximab. In some cases, the ligand is selected from trastuzumab, brentuximab, loncastuximab, rosopatamab, rituximab, pinatuzumab, polatuzumab, and naratuximab. In some cases, the ligand is trastuzumab.

[0170] In some embodiments, the ligand is an antibody against a tumor-associated antigen, allowing selective targeting of cancer cells. Examples of such antigens include mesothelin, prostate-specific membrane antigen (PSMA), CD19, CD22, CD30, CD70, B7H3, B7H4 (also known as O8E), protein tyrosine kinase 7 (PTK7), glypican-3, RG1, fucosyl-GM1, CTLA-4, and CD44. The antibody can be an animal (e.g., mouse), chimeric, humanized, or preferably human antibody. The antibody is preferably a monoclonal antibody, particularly a monoclonal human antibody. Preparations of human monoclonal antibodies against some of the aforementioned antigens are described in Korman et al., U.S. Pat. No. 8,609,816 B2 (2013, B7H4, also known as O8E; particularly antibodies 2A7, 1G11, and 2F9), Rao-Naik et al., U.S. Pat. No. 8,097,703 B2 (2012, CD19, particularly antibodies 5G7, 13F1, 46E8, 21D4, 21D4a, 47G4, 27F3, and 3C10), King et al., U.S. Pat. No. 8,481,683 B2 (2013, CD22, particularly antibodies 12C5, 19A3, 16F7, and 23C6), Keler et al. al., U.S. Patent No. 7,387,776 B2 (2008, CD30, particularly antibodies 5F11, 2H9, and 17G1); Terrett et al., U.S. Patent No. 8,124,738 B2 (2012, CD70, particularly antibodies 2H5, 10B4, 8B5, 18E7, and 69A7); Korman et al., U.S. Patent No. 6,984,720 B1 (2006, CTLA-4, particularly antibodies 10D1, 4B6, and 1E2); Vistica et al., U.S. Patent No. 8,383,118 B2 (2013, Fucosyl-GM1, particularly antibodies 5B1, 5B1a, 7D4, 7E4, 13B8, and 18D5); Korman et al. al., U.S. Patent No. 8,008,449 B2 (2011, PD-1, particularly antibodies 17D8, 2D3, 4H1, 5C4, 4A11, 7D3, and 5F4); Huang et al., US2009 / 0297438A1 (2009, PSMA, particularly antibodies 1C3, 2A10, 2F5, and 2C6); Cardarelli et al., U.S. Patent No. 7,875,278 B2 (2011, PSMA, particularly antibodies 4A3, 7F12, 8C12, 8A11, 16F9, 2A10, 2C6, 2F5, and 1C3); Terrett et al., U.S. Patent No. 8,222,375 B2 (2012, PTK7, particularly antibodies 3G8, 4D5, 12C6, 12C6a, and 7C8); Terrett et al., U.S. Patent No. 8,680,247 B2 (2014, glypican-3, particularly antibodies 4A6, 11E7, and 16D10); Harkins et al., U.S. Patent No. 7,335,748 B2 (2008, RG1, particularly antibodies A, B, C, and D); Terrett et al. al., U.S. Patent No. 8,268,970 B2 (2012, mesothelin, particularly antibodies 3C10, 6A4, and 7B1); Xu et al., U.S. Patent No. US2010 / 0092484 A1 (2010, CD44, particularly antibodies 14G9.B8.B4, 2D1.A3.D12, and 1A9.A6.B9); Deshpande et al., U.S. Patent No. 8,258,266 B2 (2012, IP10, particularly antibodies 1D4, 1E1, 2G1, 3C4, 6A5, 6A8, 7C10, 8F6, 10A12, 10A2S, and 13C4); Kuhne et al. al., U.S. Patent No. 8,450,464 B2 (2013, CXCR4, particularly antibodies F7, F9, D1, and E2), and Korman et al., U.S. Patent No. 7,943,743 B2 (2011, PD-L1, particularly antibodies 3G10, 12A4, 10A5, 5F8, 10H10, 1B12, 7H1, 11E6, 12B7, and 13G4), the disclosures of which are incorporated herein by reference.

[0171] In some embodiments, the ligand may also be an antibody fragment or antibody mimetic, such as an affibody, domain antibody (dAb), nanobody, unibody, DARPin, anticalin, versabody, duocalin, lipocalin, or avimer.

[0172] In some embodiments, any one of several different reactive groups on the ligand can be the conjugation site, including the ε-amino group in lysine residues, pendant carbohydrate moieties, carboxylic acid groups, disulfide groups, and thiol groups. Each type of reactive group represents a trade-off and has some advantages and some disadvantages. For a review of antibody reactive groups suitable for conjugation, see, for example, Garnett, Adv. Drug Delivery Rev. 53 (2001), 171-216 and Dubowchik and Walker, Pharmacology & Therapeutics 83 (1999), 67-123, the disclosures of which are incorporated herein by reference.

[0173] In some embodiments, the ligand is conjugated via a lysine ε-amino group. Most antibodies have multiple lysine ε-amino groups, which can be conjugated via amide, urea, thiourea, or carbamate bonds using techniques known in the art. However, it is difficult to control which ε-amino groups and how many ε-amino groups react, which can lead to batch-to-batch variations in conjugate preparations. In addition, conjugation can cause neutralization of protonated ε-amino groups, which are important for maintaining the native conformation of the antibody, or can occur at lysines near or at the antigen-binding site, both of which are undesirable.

[0174] In some embodiments, because many antibodies are glycosylated, ligands can be conjugated via carbohydrate side chains. Carbohydrate side chains can be oxidized with periodate to generate aldehyde groups, which can then react with amines to form imine groups such as semicarbazones, oximes, or hydrazones. If necessary, the imine groups can be converted to more stable amine groups by reduction with sodium cyanoborohydride. For further disclosure regarding conjugation via carbohydrate side chains, see, for example, Rodwell et al., Proc. Nat'l Acad. Sci. USA 83, 2632-2636 (1986), the disclosure of which is incorporated herein by reference. As with the lysine ε-amino group, there are concerns regarding the reproducibility and stoichiometry of the location of the conjugation site.

[0175] In some embodiments, the ligand can be conjugated via a carboxylic acid group. In some cases, the terminal carboxylic acid group is functionalized to generate a carbohydrazide, which is then reacted with an aldehyde-containing conjugation moiety. See Fisch et al., Bioconjugate Chemistry 1992, 3, 147-153.

[0176] In some embodiments, antibodies can be conjugated via disulfide groups that bridge cysteine ​​residues on the antibody with sulfur on other parts of the conjugate or compound. Some antibodies do not have free thiol (sulfhydryl) groups, but have disulfide groups, for example, in the hinge region. In such cases, free thiol groups can be generated by reducing the natural disulfide groups. The thiol groups thus generated can then be used for conjugation. See, for example, Packard et al., Biochemistry 1986, 25, 3548-3552; King et al., Cancer Res. 54, 6176-6185 (1994); and Doronina et al., Nature Biotechnol. 21(7), 778-784 (2003), the disclosures of which are incorporated herein by reference. Many methods are known for introducing free thiol groups into antibodies without disrupting the natural disulfide bonds, and these methods can be implemented using the ligands of the present invention. Depending on the method utilized, it may be possible to introduce a predictable number of free sulfhydryls at predetermined positions. In one approach, mutant antibodies are prepared in which cysteines are substituted for other amino acids. For example, Eigenbrot et al., US Pat. No. 7,521,541 B2 (2009), Chilkoti et al., Bioconjugate Chem. 1994, 5,504-507, Urnovitz et al., US Pat. No. 4,698,420 (1987), Stimmel et al. al., J. Biol. Chem., 275(39), 30445-30450 (2000), Bam et al., US Patent No. 7,311,902 B2 (2007), Kuan et al., J. Biol. See al., J. Biol. Chem., 270(15), 8571-8577 (1995). In another approach, an extra cysteine ​​is added to the C-terminus.See, for example, Cumber et al., J. Immunol., 149, 120-126 (1992); King et al., Cancer Res., 54, 6176-6185 (1994); Li et al., Bioconjugate Chem., 13, 985-995 (2002); Yang et al., Protein Engineering, 16, 761-770 (2003); and Olafson et al., Protein Engineering Design & Selection, 17, 21-27 (2004). A preferred method for introducing a free cysteine ​​is that taught by Liu et al., WO 2009 / 026274A1, in which a cysteine-containing amino acid sequence is added to the C-terminus of the antibody heavy chain. This method introduces a known number of cysteine ​​residues (one per heavy chain) at a known position away from the antigen-binding site. The disclosures of all documents cited in this paragraph are incorporated herein by reference.

[0177] In some embodiments, lysine ε-amino groups can be modified with reagents such as 2-iminothiolane or N-succinimidyl-3-(2-pyridyldithio)propionate (SPDP) to convert the ε-amino group to a thiol or disulfide group, generating a cysteine ​​surrogate in situ.

[0178] Linker The compounds and salts of Formula (I), Formula (IA), Formula (IB), Formula (II), Formula (III), or Formula (III-A) may include a linker (e.g., L). The linker may be as described elsewhere herein. In some cases, L is a peptide linker. In some embodiments, the linker is also attached to a ligand (e.g., an antibody), referred to as an antibody-drug conjugate or conjugate. The linker of the conjugates described herein may not affect the binding of the active moiety of the conjugate, e.g., an antigen-binding domain, an Fc domain, a target-binding domain, an antibody, an agonist, etc., to the target, which may be a cognate binding partner such as an antigen. The conjugate may include multiple linkers, each having one or more compounds attached thereto. These linkers may be the same or different linkers.

[0179] In some embodiments, the linker can be short, flexible, rigid, cleavable, non-cleavable, hydrophilic, or hydrophobic. The linker can contain segments with different properties, such as flexible or rigid segments. The linker can be chemically stable to the extracellular environment, for example, in the bloodstream, or can contain bonds that are not stable or selectively stable. The linker can contain bonds designed to specifically or nonspecifically cleave, immolate, or otherwise degrade inside the cell. The cleavable linker can be sensitive to enzymes. The cleavable linker can be cleaved by enzymes such as proteases. The cleavable linker can include a valine-citrulline linker or a valine-alanine peptide. The valine-citrulline- or valine-alanine-containing linker can contain a maleimide or succinimide group.

[0180] In some embodiments, the non-cleavable linker may be protease-insensitive. The non-cleavable linker may be a maleimidocaproyl linker. The maleimidocaproyl linker may include N-maleimidomethylcyclohexane-1-carboxylate. The maleimidocaproyl linker may contain a succinimide group. The maleimidocaproyl linker may contain a pentafluorophenyl group. The linker may be a combination of a maleimidocaproyl group and one or more polyethylene glycol molecules. The linker may be a maleimido-PEG4 linker. The linker may be a combination of a maleimidocaproyl linker containing a succinimide group and one or more polyethylene glycol molecules. The linker may be a combination of a maleimidocaproyl linker containing a pentafluorophenyl group and one or more polyethylene glycol molecules. The linker may contain a maleimide bonded to a polyethylene glycol molecule, where the polyethylene glycol may allow for increased flexibility of the linker or may be used to extend the linker. The linker can be a (maleimidocaproyl)-(valine-citrulline)-(para-aminobenzyloxycarbonyl) linker. The linker can be a linker suitable for attachment to an engineered cysteine ​​(THIOMAB). The THIOMAB linker can be a (maleimidocaproyl)-(valine-citrulline)-(para-aminobenzyloxycarbonyl)-linker.

[0181] In some embodiments, the linker may also include alkylene, alkenylene, alkynylene, polyether, polyester, polyamide groups, and / or polyamino acids, polypeptides, cleavable peptides, or aminobenzyl carbamates. The linker may contain a maleimide at one end and an N-hydroxysuccinimidyl ester at the other end. The linker may contain a lysine with an acetylated N-terminal amine and a valine-citrulline cleavage site. The linker may be a bond created by microbial transglutaminase, where the bond may be created between an amine-containing moiety and a moiety engineered to contain glutamine as a result of the enzyme catalyzing bond formation between the acyl group of the glutamine side chain and the primary amine of the lysine chain. The linker may contain a reactive primary amine. The linker may be a sortase A linker. The sortase A linker may be created by the sortase A enzyme, which fuses an LXPTG recognition motif to an N-terminal GGG motif to regenerate a native amide bond. Thus, the linker created can join a moiety attached to the LXPTG recognition motif to a moiety attached to the N-terminal GGG motif.

[0182] In some embodiments, a compound or salt of any one of the formulas described herein is linked to an antibody construct by a linker, also referred to herein as L or linker. As used herein, L may be selected from any of the linker moieties discussed herein. The linker linking the compound or salt to the antibody construct of the conjugate may be short, long, hydrophobic, hydrophilic, flexible, or rigid, or may be composed of segments each independently having one or more of the above-mentioned properties, such that the linker may contain segments with different characteristics. The linker may be multivalent to covalently link multiple compounds or salts to a single site on the antibody construct, or monovalent to covalently link a single compound or a pharmaceutically acceptable salt thereof to a single site on the antibody construct.

[0183] In some embodiments, the linker may have about 10 to about 500 atoms in the linker, for example, about 10 to about 400 atoms in the linker, for example, about 10 to about 300 atoms in the linker. In some embodiments, the linker may have about 30 to about 400 atoms in the linker, for example, about 30 to about 300 atoms.

[0184] In some embodiments, a linker described herein may attach a compound or salt of any one of the formulas described herein to a ligand (e.g., an antibody) by a covalent bond between the linker and the antibody construct and the compound. The linker may include a functional group capable of covalently binding to a ligand (e.g., an antibody).

[0185] In some embodiments, by way of example and not limitation, some cleavable and non-cleavable linkers that may be included in the conjugates described herein are described below.

[0186] In some embodiments, the cleavable linker can be cleavable in vitro and in vivo. The cleavable linker can include a chemically or enzymatically unstable or degradable bond. The cleavable linker can depend on an internal process within the cell to release the benzazepine compound, such as reduction in the cytoplasm, exposure to acidic conditions in lysosomes, or cleavage by specific proteases or other enzymes within the cell. The cleavable linker can incorporate one or more chemical bonds that can be cleaved chemically or enzymatically, while the remaining part of the linker can be uncleavable.

[0187] In some embodiments, the linker may contain a chemically labile group, such as a hydrazone and / or disulfide group. Linkers containing chemically labile groups can take advantage of the differential properties between plasma and some cytoplasmic compartments. Cleavable linkers may also contain disulfide groups.

[0188] In some embodiments, acid-labile groups such as hydrazones can remain intact during systemic circulation in the neutral pH environment of blood (pH 7.3-7.5) and undergo hydrolysis, releasing the benzazepine compound upon internalization of the antibody construct-benzazepine compound conjugate into the moderately acidic endosomal (pH 5.0-6.5) and lysosomal (pH 4.5-5.0) compartments of cells. This pH-dependent release mechanism can be associated with nonspecific release of the drug. To increase the stability of the hydrazone group of the linker, the linker can be altered by chemical modification, e.g., substitution, thereby minimizing loss during circulation and achieving more efficient release in the lysosome. Hydrazone-containing linkers can contain additional cleavage sites, e.g., additional acid-labile and / or enzyme-labile cleavage sites. Other acid-labile groups that can be included in linkers include cis-aconityl-containing linkers. cis-aconityl chemistry can utilize a carboxylic acid juxtaposed to the amide bond to accelerate amide hydrolysis under acidic conditions.

[0189] In some embodiments, the linker may be specifically cleaved by an enzyme. For example, the linker may be cleaved by a lysosomal enzyme. Such a linker may be peptide-based or may contain a peptide region that can act as an enzyme substrate. Peptide-based linkers may be more stable in plasma and extracellular environments than chemically unstable linkers. Peptide bonds may have good serum stability because lysosomal protease activity may be significantly lower in blood due to endogenous inhibitors and the unfavorable high pH of blood compared to lysosomes. Release of the compounds described herein from the antibody-drug conjugates may occur through the action of lysosomal proteases, such as cathepsin and plasmin. These proteases may be present at elevated levels in certain tumor tissues. The linker may be cleavable by a lysosomal enzyme. The lysosomal enzyme may be, for example, cathepsin B, cathepsin S, β-glucuronidase, or β-galactosidase. The cleavable peptide can be selected from tetrapeptides such as Gly-Phe-Leu-Gly, Ala-Leu-Ala-Leu, or dipeptides such as Val-Cit, Val-Ala, and Phe-Lys. Dipeptides can be less hydrophobic than longer peptides. Various dipeptide-based cleavable linkers can be used in the antibody-drug conjugates described herein. The enzymatically cleavable linker can be a β-glucuronic acid-based linker.

[0190] In some embodiments, a cleavable linker may include a non-cleavable moiety or segment, and / or a cleavable segment or moiety may be included in an otherwise non-cleavable linker to render it cleavable.

[0191] In some embodiments, the linker may contain an enzymatically cleavable peptide moiety. The peptide may be selected from natural amino acids, unnatural amino acids, or combinations thereof. In certain embodiments, the peptide may be selected from a dipeptide, a tripeptide, or a tetrapeptide. In certain embodiments, the dipeptide may comprise an L-amino acid and may be selected from Val-Cit, Cit-Val, Ala-Ala, Ala-Cit, Cit-Ala, Asn-Cit, Cit-Asn, Cit-Cit, ValGlu, Glu-Val, Ser-Cit, Cit-Ser, Lys-Cit, Cit-Lys, Asp-Cit, Cit-Asp, Ala-Val, Val-Ala, Phe-Lys, Lys-Phe, Val-Lys, Lys-Val, Ala-Lys, Lys-Ala, Phe-Cit, Cit-Phe, Leu-Cit, Cit-Leu, Ile-Cit, Cit-Ile, Phe-Arg, Arg-Phe, Cit-Trp, and Trp-Cit, or a salt thereof.

[0192] Pharmaceutical preparations Provided herein, in certain embodiments, are compositions comprising a therapeutically effective amount of a compound or salt (also referred to herein as a "medicament") of any one of Formula (I), Formula (IA), Formula (IB), Formula (II), Formula (III), Formula (III-A), Formula (IV-A), Formula (IV-B), Formula (IV-C), or Formula (IV-D).

[0193] Pharmaceutical compositions may be formulated using one or more physiologically acceptable carriers, including excipients and auxiliaries that facilitate the processing of pharmaceuticals into pharmaceutical preparations.Suitable formulations depend on the route of administration selected.Summary of pharmaceutical compositions described herein can be found, for example, in Remington: The Science and Practice of Pharmacy, Nineteenth Edition (Easton, Pa., Mack Publishing Company, 1995); Hoover, John E., Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton, Pennsylvania 1975; Liberman, HA and Lachman, L., Eds., Pharmaceutical Dosage Forms, Marcel Decker, New York, NY, 1980, and Pharmaceutical Dosage Forms and Drug Delivery Systems, Seventh Edition (Lippincott Williams & Wilkins 1999) (Lippincott Williams & Wilkins, 1999).

[0194] The compositions and methods of the present disclosure can be used to treat individuals in need of treatment. In certain embodiments, the individual is a mammal, such as a human or a non-human mammal. When administered to an animal, such as a human, the composition or pharmaceutical is preferably administered as a pharmaceutical composition, for example, comprising a pharmaceutical agent and a pharmaceutically acceptable carrier or excipient. Pharmaceutically acceptable carriers are well known in the art and include, for example, aqueous solutions such as water or physiologically buffered saline, or other solvents or vehicles, such as glycols, glycerol, olive oil, or injectable organic esters. In a preferred embodiment, when such pharmaceutical compositions are intended for administration to humans, particularly for invasive administration routes, such as injection or implantation, which avoid transport or diffusion through epithelial barriers, the aqueous solution is pyrogen-free or substantially pyrogen-free. The excipient can be selected, for example, to provide delayed release of the drug or to selectively target one or more cells, tissues, or organs. The pharmaceutical composition may be in dosage unit form such as tablets, capsules, granules, lyophilized formulations for reconstitution, powders, solutions, syrups, suppositories, injections, etc. The composition may also be present in a transdermal delivery system, such as a skin patch. The composition may also be present in a solution suitable for topical administration, such as eye drops.

[0195] Pharmaceutically acceptable excipients may contain physiologically acceptable agents that stabilize, improve solubility, or enhance absorption of compounds, such as pharmaceuticals. Such physiologically acceptable agents include, for example, carbohydrates such as glucose, sucrose, or dextran; antioxidants such as ascorbic acid or glutathione; chelating agents; low-molecular-weight proteins; or other stabilizers or excipients. The choice of pharmaceutically acceptable excipients, including physiologically acceptable agents, depends, for example, on the route of administration of the composition. The preparation or pharmaceutical composition may be a self-emulsifying or self-microemulsifying drug delivery system. The pharmaceutical composition (preparation) may also be, for example, a liposome or other polymer matrix into which the compound of the present invention can be incorporated. For example, liposomes containing phospholipids or other lipids are non-toxic, physiologically acceptable, and metabolizable carriers that are relatively simple to prepare and administer.

[0196] Pharmaceutical compositions (preparations) can be administered to subjects by any of a number of routes of administration, including, for example, oral administration, including drench, tablet, capsule, including sprinkle capsule and gelatin capsule in aqueous or non-aqueous solution or suspension, bolus, powder, granule, paste for application to the tongue; absorption through oral mucosa, for example, sublingual absorption; anal, rectal or vaginal administration, for example, as pessary, cream or foam; parenteral administration, including intramuscular, intravenous, subcutaneous or intrathecal administration, for example, as sterile solution or suspension; nasal administration; intraperitoneal administration; subcutaneous administration; transdermal administration, for example, as a patch applied to the skin; and topical administration, for example, as cream, ointment or spray applied to the skin, or as eye drops.Compounds can also be formulated for inhalation.In certain embodiments, compound can be simply dissolved or suspended in sterile water.

[0197] The pharmaceutical composition may be a sterile aqueous or non-aqueous solution, suspension, or emulsion, such as a microemulsion. The excipients described herein are examples and are by no means limiting. An effective amount or a therapeutically effective amount refers to the amount of one or more pharmaceutical agents administered to a subject, either as a single dose or as part of a series, that is effective to produce the desired therapeutic effect.

[0198] Subjects can generally be monitored for treatment effectiveness using assays and methods appropriate for the disease being treated, which assays will be familiar to those skilled in the art and are described herein. The pharmacokinetics of a pharmaceutical agent, or one or more metabolites thereof, administered to a subject can be monitored by determining the level of the pharmaceutical agent or metabolite in a biological fluid, e.g., blood, a blood fraction, e.g., serum, and / or urine, and / or other biological sample or tissue from the subject. Any method for detecting pharmaceutical agents practiced in the art and described herein can be used to measure the level of the pharmaceutical agent or metabolite during the course of treatment.

[0199] The dosage of the pharmaceuticals described herein for treating a disease or disorder may vary depending on the subject's condition, i.e., the stage of the disease, the severity of symptoms caused by the disease, the subject's overall health, as well as the subject's age, sex, and weight, as well as other factors apparent to those skilled in the medical field. Pharmaceutical compositions can be administered in a manner appropriate to the disease being treated, as determined by those skilled in the medical field. In addition to the factors described herein and above regarding the use of pharmaceuticals to treat a disease or disorder, the appropriate duration and frequency of pharmaceutical administration can also be determined or adjusted depending on factors such as the patient's illness, the type and severity of the patient's illness, the specific form of the active ingredient, and the method of administration. The optimal dosage of a pharmaceutical agent can generally be determined using experimental models and / or clinical trials. The optimal dosage may vary depending on the subject's body mass, weight, or blood volume. It is usually preferable to use the minimum dosage sufficient to provide effective treatment. The design and execution of preclinical and clinical trials for pharmaceuticals described herein, including those administered for prophylactic benefit, is within the skill of those skilled in the relevant art. When two or more pharmaceutical agents are administered to treat a disease or disorder, the optimal dosage of each agent may differ, e.g., may be less than when either agent is administered alone as monotherapy. In certain embodiments, the two combined pharmaceutical agents may act synergistically or additively, and either agent may be used in a lower amount than when administered alone. The amount of pharmaceutical agent that can be administered daily can be, for example, between about 0.01 mg / kg and 100 mg / kg of body weight, e.g., between about 0.1 mg / kg and 1 mg / kg, between about 1 mg / kg and 10 mg / kg, between about 10 mg / kg and 50 mg / kg, or between about 50 mg / kg and 100 mg / kg. In other embodiments, the amount of pharmaceutical agent that can be administered daily can be between about 0.01 mg / kg and 1000 mg / kg, between about 100 and 500 mg / kg, or between about 500 and 1000 mg / kg of body weight. The optimal dosage per day or per course of treatment may vary depending on the disease or disorder to be treated, and may also vary with the route of administration and treatment regimen.

[0200] Pharmaceutical compositions containing pharmaceutical agents can be formulated in a manner suitable for delivery method by using techniques routinely practiced in the art.The composition can be in the form of a solid, such as a tablet, a capsule, a semi-solid, such as a gel, a liquid, or a gas, such as an aerosol.In other embodiments, the pharmaceutical composition is administered as a bolus injection.

[0201] Pharmaceutically acceptable excipients are well known in the pharmaceutical arts and are described, for example, in Rowe et al., Handbook of Pharmaceutical Excipients: A Comprehensive Guide to Uses, Properties, and Safety, 5 th Ed., 2006, and in Remington: The Science and Practice of Pharmacy (Gennaro, 21 st Ed. Mack Pub. Co., Easton, PA (2005). Exemplary pharmaceutically acceptable excipients include sterile saline and phosphate-buffered saline at physiological pH. Preservatives, stabilizers, dyes, buffers, etc. may be provided in the pharmaceutical composition. Additionally, antioxidants and suspending agents may also be used. Generally, the type of excipient is selected based on the mode of administration and the chemical composition of the active ingredient. Alternatively, the compositions described herein may be formulated as a lyophilizate. The compositions described herein may be lyophilized or formulated as a lyophilized product using one or more appropriate excipient solutions to solubilize and / or dilute the pharmaceutical agent of the composition upon administration. In other embodiments, the pharmaceutical agent may be encapsulated in a liposome using techniques known and practiced in the art. In certain embodiments, the pharmaceutical agent is not formulated in a liposome for application to a stent used to treat severely, but not completely, blocked arteries. The pharmaceutical compositions may be formulated for any suitable mode of administration described herein and in the art.

[0202] For example, pharmaceutical compositions for oral administration, or for injection, infusion, subcutaneous delivery, intramuscular delivery, intraperitoneal delivery, or other methods may be in liquid form. Liquid pharmaceutical compositions may contain one or more of the following: water, saline, preferably physiological saline, Ringer's solution, isotonic saline, sterile diluents such as fixed oils, polyethylene glycol, glycerin, propylene glycol, or other solvents serving as a solvent or suspension medium, antibacterial agents, antioxidants, chelating agents, buffers for adjusting tonicity, such as sodium chloride or dextrose, and agents. Parenteral compositions may be packaged in ampoules, disposable syringes, or multiple-dose vials made of glass or plastic. Physiological saline is preferred, and injectable pharmaceutical compositions are preferably sterilized. In another embodiment, liquid pharmaceutical compositions may be applied to the eye in the form of eye drops for the treatment of ophthalmic diseases or disorders. Liquid pharmaceutical compositions may be delivered orally.

[0203] For oral formulations, at least one of the pharmaceuticals described herein may be used alone or in combination with suitable additives to prepare tablets, powders, granules, or capsules, and optionally in combination with diluents, buffers, wetting agents, preservatives, colorants, and flavoring agents.The pharmaceutical may be formulated with a buffer to protect the compound from the low pH of the stomach environment and / or enteric coating.The pharmaceutical contained in the pharmaceutical composition may be formulated for oral delivery, for example, with a flavoring agent in a liquid, solid, or semi-solid formulation, and / or with an enteric coating.

[0204] Pharmaceutical compositions containing any one of the pharmaceutical agents described herein may be formulated for sustained or slow release, also known as sustained or controlled release. Such compositions may generally be prepared using well-known techniques and administered, for example, by oral, rectal, intradermal, or subcutaneous implantation, or by implantation at a desired target site. Sustained-release formulations may contain the compound dispersed in a carrier matrix and / or contained within a reservoir surrounded by a rate-controlling membrane. Excipients for use within such formulations may be biocompatible and biodegradable, and preferably the formulation provides a relatively constant level of active ingredient release. The amount of pharmaceutical agent contained within a sustained-release formulation will vary depending on the site of implantation, the rate and expected duration of release, and the nature of the disease, condition, or disorder to be treated or prevented.

[0205] In certain embodiments, the pharmaceutical composition containing the pharmaceutical agent is formulated for transdermal, intradermal, or topical administration.The composition can be administered as powder / talc or other solid, liquid, spray, aerosol, ointment, foam, cream, gel, or paste using a syringe, bandage, transdermal patch, insert, or syringe-like applicator.It is preferably administered topically or in the form of a controlled-release or sustained-release formulation that is directly injected, for example, intradermally or subcutaneously, into the skin adjacent to or within the area to be treated.The active composition can also be delivered via iontophoresis.Antiseptics can be used to prevent the growth of fungi and other microorganisms. Suitable preservatives include, but are not limited to, benzoic acid, butylparaben, ethylparaben, methylparaben, propylparaben, sodium benzoate, sodium propionate, benzalkonium chloride, benzethonium chloride, benzyl alcohol, cetylpyridinium chloride, chlorobutanol, phenol, phenylethyl alcohol, thimerosal, and combinations thereof.

[0206] Pharmaceutical compositions containing pharmaceutical agents can be formulated as emulsions for topical application. Emulsions contain one liquid dispersed in the body of a second liquid. The emulsion may be an oil-in-water emulsion or a water-in-oil emulsion. Either or both of the oil and aqueous phases may contain one or more surfactants, emulsifiers, emulsion stabilizers, buffers, and other excipients. The oil phase may also contain other oily pharmaceutically approved excipients. Suitable surfactants include, but are not limited to, anionic surfactants, nonionic surfactants, cationic surfactants, and amphoteric surfactants. Compositions for topical application may also contain at least one suitable suspending agent, antioxidant, chelating agent, emollient, or humectant.

[0207] Ointments and creams can be formulated, for example, with aqueous or oily bases, with the addition of suitable thickeners and / or gelling agents.Lotions can be formulated with aqueous or oily bases, and generally also contain one or more emulsifiers, stabilizers, dispersants, suspending agents, thickeners, or colorants.Liquid sprays can be delivered from pressurized packs, for example, through specially shaped closures.Oil-in-water emulsions can also be used in compositions, patches, bandages, and articles.These systems are semisolid emulsions, microemulsions, or foam emulsion systems.

[0208] In some embodiments, the pharmaceuticals described herein can be formulated as inhalants. Inhalation methods can deliver drugs directly to the respiratory tract. Pharmaceuticals can be formulated as aerosols, microspheres, liposomes, or nanoparticles. Pharmaceuticals can be formulated with solvents, gases, nitrates, or any combination thereof. The compositions described herein are optionally formulated for delivery as liquid aerosols or inhalable dry powders. Liquid aerosol formulations are optionally atomized to particle sizes that can be delivered primarily to the terminal and respiratory bronchioles. Liquid aerosol formulations and inhalable dry powders are preferably delivered throughout the bronchial tree, to the terminal bronchioles and ultimately to the parenchymal tissue.

[0209] The aerosolized formulations described herein are optionally delivered using an aerosol-forming device, such as a jet, vibrating porous plate nebulizer, or ultrasonic nebulizer, preferably selected to enable the formation of aerosol particles having a mass median average diameter primarily between 1 μm and 5 μm. Furthermore, the formulations preferably have a balanced osmotic ionic strength and chloride concentration, as well as a minimum aerosolizable volume capable of delivering an effective dose of pharmaceutical agent. Furthermore, the aerosolized formulations preferably do not adversely impair airway functionality or cause undesirable side effects.

[0210] Aerosolization devices suitable for administering the aerosol formulations described herein include, for example, jet, vibrating porous plate, ultrasonic nebulizers, and energized dry powder inhalers, which can nebulize the formulation into aerosol particles primarily ranging in size from 1 to 5 μm. Predominantly, this application means that at least 70%, preferably more than 90%, of all generated aerosol particles are within the 1 to 5 μm range. Jet nebulizers operate by air pressure to break up liquid solutions into aerosol droplets. Vibrating porous plate nebulizers operate by using a sonic vacuum created by a rapidly vibrating porous plate to force solvent droplets through a porous plate. Ultrasonic nebulizers operate by piezoelectric crystals that shear liquids into small aerosol droplets. A variety of suitable devices are available, including, for example, AeroNeb™ and AeroDose™ vibrating perforated plate nebulizers (AeroGen, Inc., Sunnyvale, CA), Sidestream® nebulizer (Medic-Aid Ltd., West Sussex, UK), Pari LC® and Pari LC Star® jet nebulizers (Pari Respiratory Equipment, Inc., Richmond, VA), and Aerosonic™ (DeVilbiss Medizinische Produkte (Deutschland) GmbH, Heiden, Germany) and UltraAire® (Omron Healthcare, Inc., Vernon Hills, IL) ultrasonic nebulizers.

[0211] In some embodiments, pharmaceutical agents can be formulated with an oily base or ointment to form a semi-solid composition having a desired shape. In addition to the pharmaceutical agent, these semi-solid compositions can contain dissolved and / or suspended bactericides, preservatives, and / or buffer systems. The petrolatum component can be any paraffin with a wide range of viscosities, from mineral oil incorporating isobutylene, colloidal silica, or stearates to paraffin wax. Absorbent bases can be used with oily systems. Additives include cholesterol, lanolin (lanolin derivatives), beeswax, fatty alcohols, wool wax alcohols, low HLB (hydrophobic-lipophobic balance) emulsifiers, and various ionic and non-ionic surfactants, alone or in combination.

[0212] Controlled-release or sustained-release transdermal or topical formulations can be achieved by adding sustained-release additives, such as polymer structures and matrices, available in the art. For example, the composition can be administered using a hot-melt extrusion, such as a bioadhesive hot-melt extrusion film. The formulation can include a cross-linked polycarboxylic acid polymer formulation. The cross-linking agent can be present in an amount that provides sufficient adhesion to allow the system to remain attached to the surface of target epithelial or endothelial cells for a sufficient time to allow the desired release of the compound.

[0213] The insert, transdermal patch, bandage, or article may contain a polymer blend or coating that releases the pharmaceutical agent at a constant rate over an extended period of time. In some embodiments, the article, transdermal patch, or insert contains a water-soluble pore-forming agent, such as polyethylene glycol (PEG), that may be blended with a water-insoluble polymer to improve the durability of the insert and extend the release of the active ingredient.

[0214] Transdermal devices (inserts, patches, bandages) may also contain water-insoluble polymers. Rate-controlling polymers may be useful for administration to sites where release can be achieved using pH changes. These rate-controlling polymers may be applied using a continuous coating film during the process of spraying with the active compound and drying. In one embodiment, the coating formulation is used to coat pellets containing the active ingredient, which are compressed to form a solid biodegradable insert.

[0215] Polymer formulations can also be utilized to provide controlled or sustained release. Bioadhesive polymers described in the art can be used. For example, sustained-release gels and compounds can be incorporated into polymer matrices, such as hydrophobic polymer matrices. Examples of polymer matrices include microparticles. The microparticles can be microspheres, where the core can be a different material from the polymer shell. Alternatively, the polymer can be cast as a thin slab or film, a powder produced by milling or other standard techniques, or a gel, such as a hydrogel. The polymer can also be in the form of a coating or part of a bandage, stent, catheter, vascular graft, or other device to facilitate delivery of the pharmaceutical agent. Matrices can be formed by solvent evaporation, spray drying, solvent extraction, and other methods known to those skilled in the art.

[0216] The kit provided has a unit dose of one or more drugs as described herein, usually in oral or injectable dose.Such kit can include a container that contains a unit dose, an information package insert that describes the use of drug in treating disease and its associated benefits, and optionally the instrument or device for delivering the composition.

[0217] Treatment method In some embodiments, the present disclosure provides a method of treating a subject having a tumor. In some cases, treating a subject having a tumor comprises administering to the subject in need thereof a compound or salt of any one of Formula (I), Formula (IA), Formula (IB), Formula (II), Formula (III), Formula (III-A), (IV-A), (IV-B), Formula (IV-C), or (IV-D), or a pharmaceutical composition thereof. In some cases, the tumor is associated with cancer. In some cases, the cancer is selected from the group consisting of lung cancer, kidney cancer, urethral cancer, colorectal cancer, prostate cancer, glioblastoma multiforme, ovarian cancer, pancreatic cancer, breast cancer, melanoma, liver cancer, bladder cancer, gastric cancer, and esophageal cancer.

[0218] In some embodiments, the compounds described herein are useful in treating cancers of the head and neck, including tumors of the head, neck, nasal cavity, paranasal sinuses, nasopharynx, oral cavity, oropharynx, larynx, hypopharynx, salivary glands, and paraganglioma; cancers of the liver and biliary system, particularly hepatocellular carcinoma; intestinal cancer, particularly colorectal cancer; ovarian cancer; small cell and non-small cell lung cancer (SCLC and NSCLC); fibrosarcoma, malignant fibrous histiocytoma, embryonal rhabdomyosarcoma, leiomyosarcoma, neurofibrosarcoma, osteosarcoma, synovial sarcoma, liposarcoma, and breast carcinosarcoma, such as alveolar soft part sarcoma; acute promyelocytic leukemia (APL); The compositions may be used to treat diseases such as, but not limited to, leukemias such as acute myeloid leukemia (AML), acute lymphocytic leukemia (ALL), and chronic myeloid leukemia (CML), neoplasms of the central nervous system, particularly brain cancer, multiple myeloma (MM), hyperproliferative diseases including lymphomas such as Hodgkin's lymphoma, lymphoplasmacytic lymphoma, follicular lymphoma, mucosa-associated lymphoid tissue lymphoma, mantle cell lymphoma, B-lineage large cell lymphoma, Burkitt's lymphoma, and T-cell anaplastic large cell lymphoma. Clinically, practice of the methods and use of the compositions described herein will result in a reduction in the size or number of cancerous growths (where applicable) and / or a reduction in associated symptoms. Pathologically, practice of the methods and use of the compositions described herein will result in pathologically relevant responses, such as inhibition of cancer cell proliferation, reduction in cancer or tumor size, prevention of further metastasis, and inhibition of tumor angiogenesis. The method for treating such a disease comprises administering a therapeutically effective amount of the combination of the present invention to a subject. This method may be repeated as necessary. The cancer may be kidney cancer, lung cancer, stomach cancer, or ovarian cancer.

[0219] In some embodiments, treating a subject with a tumor inhibits tumor growth by at least about 20%, more preferably at least about 40%, even more preferably at least about 60%, and even more preferably at least about 80% compared to an untreated subject. A therapeutically effective amount of a therapeutic compound may reduce tumor size or otherwise alleviate symptoms in a subject, which is typically a human, but may be another mammal.

[0220] In some embodiments, the compounds described herein may be administered in combination with other therapeutic agents, including antibodies, alkylating agents, angiogenesis inhibitors, antimetabolites, DNA cleaving agents, DNA cross-linking agents, DNA intercalating agents, DNA minor groove binders, enediynes, heat shock protein 90 inhibitors, histone deacetylase inhibitors, immunomodulators, microtubule stabilizers, nucleoside (purine or pyrimidine) analogs, nuclear export inhibitors, proteasome inhibitors, topoisomerase (I or II) inhibitors, tyrosine kinase inhibitors, and serine / threonine kinase inhibitors. Specific therapeutic agents include adalimumab, ansamitocin P3, auristatin, bendamustine, bevacizumab, bicalutamide, bleomycin, bortezomib, busulfan, kallistatin A, camptothecin, capecitabine, carboplatin, carmustine, cetuximab, cisplatin, cladribine, cytarabine, cryptophycin, dacarbazine, dasatinib, daunorubicin, docetaxel, doxorubicin, duocarmycin, dynemycin A, epothilone, etoposide, floxuridine, fludarabine, 5-fluorouracil, gefitinib, These include gemcitabine, ipilimumab, hydroxyurea, imatinib, infliximab, interferon, interleukin, beta-lapachone, lenalidomide, irinotecan, maytansine, mechlorethamine, melphalan, 6-mercaptopurine, methotrexate, mitomycin C, nilotinib, oxaliplatin, paclitaxel, procarbazine, suberoylanilide hydroxamic acid (SAHA), 6-thioguanidine, thiotepa, teniposide, topotecan, trastuzumab, trichostatin A, vinblastine, vincristine, and vindesine.

[0221] The compounds described herein can be used to prepare a medicament for the prevention or treatment of a disease or disorder. Furthermore, a method for treating any of the diseases or disorders described herein in a subject in need of such treatment comprises administering to the subject a therapeutically effective amount of a pharmaceutical composition containing at least one compound described herein, or a pharmaceutically acceptable salt, a pharmaceutically acceptable prodrug, or a pharmaceutically acceptable solvate thereof.

[0222] The compositions containing the compounds described herein can be administered for prophylactic and / or therapeutic treatments. In therapeutic applications, the compositions are administered to a patient already suffering from a disease or condition in an amount sufficient to cure or at least partially arrest the symptoms of the disease or condition. Amounts effective for this use will depend on the severity and course of the disease or condition, previous treatments, the patient's health status, weight, and response to the drugs, and the judgment of the treating physician.

[0223] In prophylactic applications, compositions containing the compounds described herein are administered to a patient susceptible to or at risk of a particular disease, disorder, or condition. Such an amount is defined to be a "prophylactically effective amount or dose." For this use, the precise amounts will vary depending on the patient's condition, weight, and the like. When used in a patient, the amount effective for this use will depend on the severity and course of the disease, disorder, or condition, previous treatment, the patient's health status and response to the medications, and the judgment of the treating physician.

[0224] If the patient's disease does not improve, at the discretion of the physician, administration of the compound may be administered chronically, i.e., for an extended period of time, including throughout the patient's life, to alleviate or otherwise control or limit the symptoms of the patient's disease or disorder.

[0225] Once improvement of the patient's disease has occurred, a maintenance dose is administered if necessary. Thereafter, the dosage or frequency of administration, or both, can be reduced, depending on the symptoms, to a level at which the improved disease, disorder, or condition is maintained. However, the patient may require intermittent treatment on a long-term basis upon any recurrence of symptoms.

[0226] The amount of a given agent that would correspond to such an amount will vary depending on factors such as the particular compound, the disease or condition and its severity, the identity (e.g., body weight) of the subject or host requiring treatment, and the like, but can nevertheless be determined in an art-recognized manner according to the particular circumstances surrounding the case, including, for example, the particular agent being administered, the route of administration, the condition being treated, and the subject or host being treated. In general, however, dosages utilized in adult human treatment typically range from about 0.02 to about 5000 mg per day, and in some embodiments, from about 1 to about 1500 mg per day. The desired dosage may conveniently be presented in a single dose or as divided doses, administered simultaneously (or closely spaced) or at appropriate intervals, e.g., as two, three, four, or more sub-doses per day.

[0227] The pharmaceutical compositions described herein may be in unit dosage form suitable for single administration of precise dosage amounts. In unit dosage form, the formulation is divided into unit doses containing appropriate amounts of one or more compounds. The unit dose may be in the form of a package containing discrete amounts of the formulation. Non-limiting examples are packaged tablets or capsules, and powders in vials or ampoules. Aqueous suspension compositions can be in single-dose non-reclosable containers. Alternatively, multi-dose reclosable containers can be used, in which case it is typical to include a preservative in the composition. By way of example only, formulations for parenteral injection can be provided in unit dosage form, including, but not limited to, ampoules, or in multi-dose containers with added preservatives.

[0228] The toxicity and therapeutic efficacy of such treatment regimens are discussed in detail below. 50 (the dose that causes death in 50% of the population) and ED 50 The dose ratio between toxic and therapeutic effects is the therapeutic index, which can be determined by standard pharmaceutical procedures in cell cultures or experimental animals, including, but not limited to, determination of the LD (the dose therapeutically effective in 50% of the population). The dose ratio between toxic and therapeutic effects is the therapeutic index, which is the LD 50 and ED 50The therapeutic index may be expressed as a ratio of the ED to the ED. Compounds that exhibit large therapeutic indices are preferred. The data obtained from cell culture assays and animal studies can be used to formulate a dosage range for use in humans. The dose of such compounds is preferably within the ED range that results in minimal toxicity. 50 The dosage may vary within this range depending upon the dosage form employed and the route of administration utilized.

[0229] In certain embodiments, the present invention provides a method of treating or preventing a disease, condition, or illness in a patient in need thereof, comprising administering to the patient an effective amount of a compound according to any one of the embodiments of the present invention, or a pharmaceutically acceptable salt thereof. The disease, condition, or illness may be selected from the group described elsewhere herein.

[0230] Compound preparation The compounds of the present disclosure can generally be prepared by several methods well known to those skilled in the art of organic synthesis. For example, the compounds of the present disclosure can be synthesized using the methods described herein, together with synthetic methods known in the art of synthetic organic chemistry, or variations thereof as understood by those skilled in the art. The compounds of the present disclosure can be prepared as described in the schemes and examples described elsewhere herein.

[0231] The following examples further illustrate the present invention but, of course, should not be construed as in any way limiting its scope. [Example]

[0232] The following synthetic schemes are provided for illustrative purposes, not for limitation. The following examples illustrate various methods for making the compounds described herein. It is understood that those skilled in the art can make these compounds by similar methods or by combining other methods known to those skilled in the art. It is also understood that those skilled in the art can make them in a similar manner to those described below by using appropriate starting materials and modifying the synthetic route as necessary. Generally, starting materials and reagents can be obtained from commercial suppliers, or can be synthesized according to sources known to those skilled in the art, or can be prepared as described herein.

[0233] Example 1: Synthesis of Compound 7

[0234] [ka] Compound 3: A mixture of compound 1 (211 mg, 1.52 mmol), p-toluenesulfonic acid (143 mg, 0.76 mmol), and compound 2 (400 mg, 1.52 mmol) was refluxed in 20 mL of toluene for 24 h. The solvent was removed in vacuo, and the remaining residue was purified by RP-HPLC to give compound 3 (280 mg) as a tan solid.

[0235] Compound 4: To a solution of compound 3 (280 mg, 0.76 mmol) in methanol (8 mL), water (6 mL), concentrated sulfuric acid (3.4 mL), hydrogen peroxide (30%, 0.66 mL), and ferrous sulfate (278, 1.0 mmol) were added. The mixture was stirred at room temperature for 1 day. The mixture was then directly purified by RP-HPLC to give compound 4 (277 mg) as a tan solid.

[0236] Compound 5: A solution of compound 4 (277 mg, 0.70 μmol) in acetic acid (40 mL) was heated under reflux for 3 hours. The solvent was evaporated in vacuo, and the resulting residue was purified by RP-HPLC to give compound 5 as a pale yellow solid (155 mg).

[0237] Compound 6: To a suspension of Yb(OTf)3 (16 mg, 0.03 mmol) in 5 mL of anhydrous DCM containing 4 Å molecular sieves, a solution of compound 5 (100 mg, 0.25 mmol) in 20 mL of DCM was added, followed by a solution of hydroxylamine (0.25 mmol) in 5 mL of DCM. The resulting mixture was stirred at room temperature for 2 h. After filtering off the sieves, the solvent was evaporated under vacuum, and the resulting residue was dissolved in 10 mL of methanol. Then, 20 mg of 10% Pd / C was added, and the resulting mixture was stirred under a hydrogen atmosphere for 1 h. The catalyst was filtered off, and the solvent was evaporated under vacuum. The resulting residue was purified by RP-HPLC to give compound 6 (68 mg) as a pale yellow solid.

[0238] Compound 7: To a solution of compound 6 (TFA salt, 20 mg, 39 μmol) in anhydrous DMF (2 mL) was added N-Fmoc-glycine (12 mg, 39 μmol), PyAOP (21 mg, 39 μmol), and DIEA (28 μL, 156 μmol). The mixture was stirred at room temperature for 20 minutes. Piperidine was then added (0.2 mL), and stirring was continued for an additional 10 minutes. The mixture was then directly purified by RP-HPLC to give compound 7 as a tan solid (17 mg). MS: 453.3 [M+H] + .

[0239] Example 2: Synthesis of Compound 8

[0240] [ka] To a solution of compound 6 (TFA salt, 20 mg, 39 μmol) in anhydrous DMF (2 mL) was added glycolic acid (3 mg, 39 μmol), PyAOP (21 mg, 39 μmol), and DIEA (28 μL, 156 μmol). The mixture was stirred at room temperature for 20 minutes. The mixture was then directly purified by RP-HPLC to give compound 8 as a tan solid (21 mg). MS: 454.0 [M+H] + .

[0241] Example 3: Synthesis of Compound 13

[0242] [ka] Compound 10: To a solution of compound 9 (280 mg, 0.76 mmol) in methanol (8 mL), water (6 mL), concentrated sulfuric acid (3.4 mL), hydrogen peroxide (30%, 0.66 mL), and ferrous sulfate (278, 1.0 mmol) were added. The mixture was stirred at room temperature for 1 day. The mixture was then directly purified by RP-HPLC to give compound 10 as a tan solid (257 mg).

[0243] Compound 11: A solution of compound 10 (257 mg, 0.66 μmol) in acetic acid (40 mL) was heated under reflux for 3 hours. The solvent was evaporated in vacuo, and the resulting residue was purified by RP-HPLC to give compound 11 as a pale yellow solid (140 mg).

[0244] Compound 12: To a suspension of Yb(OTf)3 (22 mg, 0.04 mmol) in 5 mL of anhydrous DCM containing 4A molecular sieves was added a solution of compound 11 (140 mg, 0.35 mmol) in 20 mL of DCM, followed by a solution of hydroxylamine (0.35 mmol) in 5 mL of DCM. The resulting mixture was stirred at room temperature for 2 h. After filtering off the sieves, the solvent was evaporated under vacuum, and the resulting residue was dissolved in 10 mL of methanol. Then, 20 mg of 10% Pd / C was added, and the resulting mixture was stirred under a hydrogen atmosphere for 1 h. The catalyst was filtered off, and the solvent was evaporated under vacuum. The resulting residue was purified by RP-HPLC to give compound 12 as a pale yellow solid (72 mg).

[0245] Compound 13: To a solution of compound 12 (TFA salt, 20 mg, 39 μmol) in anhydrous DMF (2 mL), N-Fmoc-glycine (12 mg, 39 μmol), PyAOP (21 mg, 39 μmol), and DIEA (28 μL, 156 μmol) were added. The mixture was stirred at room temperature for 20 minutes. Piperidine was then added (0.2 mL), and stirring was continued for an additional 10 minutes. The mixture was then directly purified by RP-HPLC to give compound 13 as a tan solid (20 mg). MS: 451.1 [M+H] + .

[0246] Example 4: Synthesis of Compound 14

[0247] [ka] To a solution of compound 12 (TFA salt, 20 mg, 39 μmol) in anhydrous DMF (2 mL) was added glycolic acid (3 mg, 39 μmol), PyAOP (21 mg, 39 μmol), and DIEA (28 μL, 156 μmol). The mixture was stirred at room temperature for 20 minutes. The mixture was then directly purified by RP-HPLC to give compound 14 as a tan solid (14 mg). MS: 452.4 [M+H] + .

[0248] Example 5: Cytotoxicity measurements The ability of compounds to inhibit cell proliferation was measured using an in vitro cytotoxicity assay.

[0249] Cells were cultured in logarithmic growth phase and plated into 96-well plates. Each cell line was seeded at slightly different concentrations, with a maximum of 5x10 cells / well. 3 ~50x10 4The concentrations ranged from 1000 to 3000 nanomolar cells / well. Cells were incubated in duplicate with 3-fold serial dilutions of specific immunoconjugates (3000, 1000, 333, 111, 37, 12.3, 4.1, 1.37, 0.46, 0.15 nanomolar) starting at 3000 or 1000 nanomolar concentrations for 72 hours at 37°C and 5% CO2. After treatment, cells were incubated with an equal volume of CellTiter-Glo® reagent (Promega Inc.) for 15 minutes at room temperature, and viability was determined by luminometry. EC50 values ​​for SKBR3, a breast cancer cell line, are shown in Table 1.

[0250] [Table 1]

Claims

1. Formula (I) 【Chemical 1】 or a pharmaceutically acceptable salt thereof, wherein L is (L ２ ) ｘ - (L ２Ｂ ) ｚ - (L ２Ｃ ) ｙ -L ３ -L ４ - (L ５ ) ｍ - (L ６ ) ｎ - (L ７ ) ｐ -R ２ and L ２ is C １－６ alkylene; L ２Ｂ (NR ４ ) ｔ C(O)O-CH ２ -phenyl, wherein phenyl is selected from one or more R ５ optionally substituted with L ２Ｃ is C(O)O-CH ２ -phenyl, wherein phenyl is selected from one or more R ６ optionally substituted with L ３ is selected from residues comprising 1 to 7 amino acids, L ４ is an optionally substituted C １－６ alkylene, １－６ Alkylene independently represents a halogen, —OH, —CN, or —NO ２ , -NH ２ , oxo, -C １－１０ Haloalkyl, —O—C １－１０ Alkyl, C ２－１０ Alkenyl, C ２－１０ optionally substituted with one or more substituents selected from alkynyl; L ５ is (O-CH ２ -CH ２ -) ｑ - (NR ３ ) ｓ is selected from L ６ is an optionally substituted C １－６ alkylene, １－６ Alkylene independently represents a halogen, —OH, —CN, or —NO ２ , -NH ２ , oxo, C １－１０ Alkyl, —C １－１０ Haloalkyl, —O—C １－１０ Alkyl, C ２－１０ Alkenyl, C ２－１０ optionally substituted with one or more substituents selected from alkynyl; L ７ is C ５－６ selected from carbocycles, R １ is —O— and —NR ７ - is selected from, R ２ is selected from optionally substituted 5- to 6-membered heterocycles, wherein the 5- to 6-membered heterocycles are independently selected from halogen, —OH, —CN, —NO ２ , -NH ２ , oxo, C １－１０ Alkyl, —C １－１０ Haloalkyl, —O—C １－１０ Alkyl, C ２－１０ Alkenyl, C ２－１０ optionally substituted with one or more substituents selected from alkynyl; R ３ is hydrogen and C １－６ alkyl, R ４ is hydrogen and one or more SO ２ C １－６ C optionally substituted with alkyl １－６ alkyl, Each R ５ are independently selected from sugars; Each R ６ are independently halogen, —OH, —CN, —NO ２ , -NH ２ , oxo, -C １－１０ Haloalkyl, —O—C １－１０ Alkyl, C ２－１０ Alkenyl, C ２－１０ alkynyl, R ７ is hydrogen and C １－６ alkyl, R ８ is selected from hydrogen and hydroxy; R ９ is selected from hydrogen and halogen, R ８ or R ９ at least one of is hydrogen, m is selected from 0 and 1; n is selected from 0 and 1; p is selected from 0 and 1; q is selected from 0 to 8; s is selected from 0 and 1; t is selected from 0 and 1; x is selected from 0 and 1; y is selected from 0 and 1; or a pharmaceutically acceptable salt thereof, wherein z is selected from 0 and 1.

2. Formula (I) 【Chemistry 2】 2. The compound of claim 1, represented by: or a pharmaceutically acceptable salt thereof.

3. Formula (I) 【Chemistry 3】 2. The compound of claim 1, represented by: or a pharmaceutically acceptable salt thereof.

4. L is L ２ - (L ２Ｂ ) ｚ -L ３ -L ４ - (L ５ ) ｍ - (L ６ ) ｎ - (L ７ ) ｐ -R ２ 4. The compound according to any one of claims 1 to 3, wherein:

5. L is L ２ -L ３ -L ４ -R ２ 5. The compound of claim 4, wherein:

6. L is L ２ -L ３ -L ４ -L ７ -R ２ 5. The compound of claim 4, wherein:

7. L is L ２ -L ３ -L ４ -L ５ -L ６ -L ７ -R ２ 5. The compound of claim 4, wherein:

8. L is L ２ -L ２Ｂ -L ３ -L ４ -R ２ 5. The compound of claim 4, wherein:

9. L ２ But C １ 9. The compound of any one of claims 1 to 8, or a pharmaceutically acceptable salt thereof, which is alkylene.

10. L is L ２Ｂ -L ３ -L ４ -R ２ and t is 0, or a pharmaceutically acceptable salt thereof.

11. L is L ２Ｃ -L ３ -L ４ -R ２ 4. The compound of claim 1 or 3, wherein:

12. L is L ２Ｃ -L ３ -L ４ -L ７ -R ２ 4. The compound of claim 1 or 3, wherein:

13. L is L ２Ｃ -L ３ -L ４ -L ５ -L ６ -L ７ -R ２ 4. The compound of claim 1 or 3, wherein:

14. L ２Ｃ is C(O)O-CH ２ 14. The compound of any one of claims 1, 3, or 10-13, or a pharmaceutically acceptable salt thereof, wherein R is -phenyl.

15. L ３ The compound according to any one of claims 1 to 14, or a pharmaceutically acceptable salt thereof, wherein is selected from residues comprising 1 to 5 amino acids.

16. 16. The compound according to any one of claims 1 to 15, or a pharmaceutically acceptable salt thereof, wherein the amino acid is an unnatural amino acid.

17. 17. The compound according to any one of claims 1 to 16, or a pharmaceutically acceptable salt thereof, wherein the amino acid is selected from alpha amino acids and beta amino acids.

18. 18. The compound of claim 17, or a pharmaceutically acceptable salt thereof, wherein the amino acid is selected from the group consisting of alanine, arginine, asparagine, aspartic acid, cysteine, glutamic acid, glutamine, glycine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine, valine, citrulline, sarcosine, and β-alanine.

19. L ３ 19. The compound of any one of claims 1 to 18, or a pharmaceutically acceptable salt thereof, wherein said amino acid is selected from the group consisting of glycine and phenylalanine.

20. L ３ or a pharmaceutically acceptable salt thereof.

21. L ３ or a pharmaceutically acceptable salt thereof, wherein the residues of

22. L ３ but, 【Chemistry 4】 21. The compound according to any one of claims 1 to 9, or 11 to 20, wherein:

23. L ３ 11. The compound of claim 10, or a pharmaceutically acceptable salt thereof, wherein is selected from the group consisting of sarcosine.

24. L ３ or a pharmaceutically acceptable salt thereof.

25. L ３ but, 【Chemistry 5】 25. The compound of claim 24, wherein:

26. L ２Ｂ However, (NR ４ ) ｔ C(O)O-C １ alkylene-phenyl, wherein phenyl is selected from one R ５ and t is 1; or a pharmaceutically acceptable salt thereof.

27. R ５ but, 【Chemistry 6】 27. The compound of claim 26, wherein:

28. L ４ is -C(O)-(CH ２ ) ２ - and -C(O)-(CH ２ ) ５ 28. The compound of any one of claims 1 to 27, or a pharmaceutically acceptable salt thereof, selected from:

29. L ５ But -(O-CH ２ -CH ２ -) ４ 8. The compound of claim 1 or 7, or a pharmaceutically acceptable salt thereof, wherein:

30. L ６ is -C(O)-(CH ２ ) ２ - and -C(O)-(CH ２ ) ５ 8. The compound of claim 1 or 7, or a pharmaceutically acceptable salt thereof, selected from:

31. L ６ is selected from -C(O)-(CH ２ ) ２ 25. The compound of claim 24, wherein: - or a pharmaceutically acceptable salt thereof.

32. L ７ 8. The compound of claim 1, 6, or 7, or a pharmaceutically acceptable salt thereof, wherein is phenyl.

33. R ２ 33. The compound of any one of claims 1 to 32, or a pharmaceutically acceptable salt thereof, wherein is selected from optionally substituted 5-membered heterocycles.

34. R ２ 33. The compound of claim 32, or a pharmaceutically acceptable salt thereof, wherein is selected from a 5-membered heterocycle substituted with at least two oxo.

35. R ２ but, 【Chemistry 7】 35. The compound of claim 34, wherein:

36. L, 【Chemistry 8】 3. The compound of claim 1 or 2, or a pharmaceutically acceptable salt thereof, selected from:

37. L is L ２Ｃ -L ３ -L ４ -R ２ , L ２Ｃ -L ３ -L ４ -L ７ -R ２ and L ２Ｃ -L ３ -L ４ -L ５ -L ６ -L ７ -R ２ is selected from L ２Ｃ but, 【Chemistry 9】 4. The compound of claim 1 or 3, or a pharmaceutically acceptable salt thereof, selected from:

38. 38. The compound of any one of claims 1 to 37, or a pharmaceutically acceptable salt thereof, further comprising a ligand.

39. 39. The compound or pharmaceutically acceptable salt thereof of any one of claims 1 to 38, wherein the compound or pharmaceutically acceptable salt thereof is further modified by a ligand.

40. 40. The compound of any one of claims 1 to 39, or a pharmaceutically acceptable salt thereof, wherein the compound or a pharmaceutically acceptable salt thereof is covalently bound to a ligand.

41. 41. The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 40, wherein the compound or pharmaceutically acceptable salt thereof reacts with a ligand to form a covalent bond.

42. Formula (I) 【Chemistry 10】 or a pharmaceutically acceptable salt thereof, wherein: Lg is the ligand; 42. The compound according to any one of claims 38 to 41, or a pharmaceutically acceptable salt thereof.

43. Formula (III) 【Chemistry 11】 or a pharmaceutically acceptable salt thereof, wherein Lg is a ligand; L is (L ２ ) ｘ - (L ２Ｂ ) ｚ - (L ２Ｃ ) ｙ -L ３ -L ４ - (L ５ ) ｍ - (L ６ ) ｎ - (L ７ ) ｐ -R ２ and L ２ is C １－６ alkylene; L ２Ｂ (NR ４ ) ｔ C(O)O-C １－６ alkylene-phenyl, wherein phenyl is selected from one or more R ５ optionally substituted with L ２Ｃ is C(O)O-CH ２ -phenyl, wherein phenyl is selected from halogen, —OH, —CN, —NO ２ , -NH ２ , oxo, -C １－１０ Haloalkyl, —O—C １－１０ Alkyl, C ２－１０ Alkenyl, C ２－１０ optionally substituted with alkynyl; L ３ is selected from residues comprising 1 to 7 amino acids, L ４ is an optionally substituted C １－６ alkylene, １－６ Alkylene independently represents a halogen, —OH, —CN, or —NO ２ , -NH ２ , oxo, -C １－１０ Haloalkyl, —O—C １－１０ Alkyl, C ２－１０ Alkenyl, C ２－１０ optionally substituted with one or more substituents selected from alkynyl; L ５ is (O-CH ２ -CH ２ -) ｑ - (NR ３ ) ｓ is selected from L ６ is an optionally substituted C １－６ alkylene, １－６ Alkylene independently represents a halogen, —OH, —CN, or —NO ２ , -NH ２ , oxo, C １－１０ Alkyl, —C １－１０ Haloalkyl, —O—C １－１０ Alkyl, C ２－１０ Alkenyl, C ２－１０ optionally substituted with one or more substituents selected from alkynyl; L ７ is C ５－６ selected from carbocycles, R １ is —O— and —NR ７ - is selected from, R ２ is selected from optionally substituted 5- to 6-membered heterocycles, wherein the 5- to 6-membered heterocycles are independently selected from halogen, —OH, —CN, —NO ２ , -NH ２ , oxo, C １－１０ Alkyl, —C １－１０ Haloalkyl, —O—C １－１０ Alkyl, C ２－１０ Alkenyl, C ２－１０ optionally substituted with one or more substituents selected from alkynyl; R ３ is hydrogen and C １－６ alkyl, R ４ is hydrogen and one or more SO ２ C １－６ C optionally substituted with alkyl １－６ alkyl, Each R ５ are independently selected from sugars; R ７ is hydrogen and C １－６ alkyl, R ８ is selected from hydrogen and hydroxy; R ９ is selected from hydrogen and halogen, R ８ or R ９ at least one of is hydrogen, m is selected from 0 and 1; n is selected from 0 and 1; p is selected from 0 and 1; q is selected from 0 to 8; s is selected from 0 and 1; t is selected from 0 and 1; x is selected from 0 and 1; y is selected from 0 and 1; z is selected from 0 and 1; The compound or a pharmaceutically acceptable salt thereof.

44. Formula (III) is 【Chemistry 12】 or a pharmaceutically acceptable salt thereof.

44. The compound of claim 43, represented by:

45. 45. The compound of any one of claims 38 to 44, or a pharmaceutically acceptable salt thereof, wherein the ligand is selected from an antibody or an antigen-binding fragment thereof.

46. 46. ​​The compound of claim 45, or a pharmaceutically acceptable salt thereof, wherein the ligand is selected from the group consisting of a chimeric antibody, a humanized antibody, and a fully human antibody.

47. Formula (IV-A) 【Chemistry 13】 or a pharmaceutically acceptable salt thereof.

48. Formula (IV-B) 【Chemistry 14】 or a pharmaceutically acceptable salt thereof.

49. Formula (IV-C) 【Chemistry 15】 or a pharmaceutically acceptable salt thereof.

50. Formula (IV-D) 【Chemistry 16】 or a pharmaceutically acceptable salt thereof.

51. 51. A pharmaceutical composition comprising a compound according to any one of claims 1 to 50, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

52. Use of a compound according to any one of claims 1 to 50 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 51, in the treatment of tumors.

53. 52. Use of a compound according to any one of claims 1 to 50 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 51, in the treatment of cancer.

54. 52. A method of treating a subject having a tumor, comprising administering to the subject in need thereof a compound according to any one of claims 1 to 50 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 51.

55. 52. A method of treating a subject having cancer, comprising administering to the subject in need thereof a compound according to any one of claims 1 to 50 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 51.

56. 56. The method of claim 55, wherein the cancer is selected from the group consisting of lung cancer, renal cancer, urethral cancer, colorectal cancer, prostate cancer, glioblastoma multiforme, ovarian cancer, pancreatic cancer, breast cancer, melanoma, liver cancer, bladder cancer, gastric cancer, and esophageal cancer.

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