Peptide Drug Conjugates

Abstract

The present invention relates to a compound comprising a negatively charged cyclodextrin or a pharmaceutically acceptable derivative of a negatively charged cyclodextrin and a compound of formula (I) as specified herein. [Formula 1] and pharmaceutical preparations comprising the compound of formula (I) described in JPEG2025542006000072.jpg65170, as well as the use of such preparations in the treatment of diseases such as cancer. The invention also provides related compositions, kits, methods of treatment, and methods of manufacture. The invention finds particular use in the treatment of hematological cancers.

Description

[Technical Field]

[0001] The present invention relates to pharmaceutical preparations comprising a negatively charged cyclodextrin or a derivative thereof and a compound that is a peptide drug conjugate (PDC), and the use of such preparations in the treatment of diseases such as cancer. [Background technology]

[0002] The compounds of formula (I), as defined below, have been found to be potent anticancer agents. Specifically, the compounds of formula (I) exhibit excellent in vitro cytotoxicity against various hematological cancer cell lines. The compounds of formula (I) are also effective in reducing tumor growth in an in ovo chicken embryo xenograft model of lymphoma. Furthermore, the compounds of formula (I) are readily hydrolyzed in cancer cells to form metabolites that are preferably sequestered and retained intracellularly and have strong alkylating activity.

[0003] There remains a need to provide stable pharmaceutical preparations comprising compounds of formula (I) and their pharmaceutically acceptable salts, esters, amides, or carbamates, and salts of such esters, amides, or carbamates. Summary of the Invention

[0004] The present invention provides a pharmaceutical preparation comprising a negatively charged cyclodextrin, or a pharmaceutically acceptable derivative of a negatively charged cyclodextrin, and a compound according to formula (I), or a pharmaceutically acceptable salt, ester, amide, or carbamate thereof, or a salt of such an ester, amide, or carbamate.

[0005] The present invention further provides a composition comprising a pharmaceutical preparation according to the invention and a physiologically acceptable aqueous solvent or diluent.

[0006] The present invention further provides a kit comprising a pharmaceutical preparation according to the invention and a physiologically acceptable aqueous solvent or diluent.

[0007] The present invention further provides a pharmaceutical preparation, composition, or kit according to the present invention for use as a medicament.

[0008] The present invention further provides a pharmaceutical preparation, composition, or kit according to the present invention for use in the treatment or prevention of cancer.

[0009] The present invention further provides a method for treating a patient comprising administering a pharmaceutically effective amount of a pharmaceutical preparation or composition according to the invention.

[0010] The present invention relates to a method for the treatment or prevention of cancer, comprising administering an effective amount of a pharmaceutical preparation or composition according to the present invention, for example, cancers such as leukemia (e.g., acute lymphoblastic leukemia, including adult and childhood acute lymphoblastic leukemia; acute myeloid leukemia, including adult and childhood acute myeloid leukemia; chronic lymphocytic leukemia, such as B-cell chronic lymphocytic leukemia; chronic myeloid leukemia; and hairy cell leukemia), lymphoma (e.g., AIDS-related lymphoma, cutaneous T-cell lymphoma, Hodgkin's lymphoma, including adult and childhood Hodgkin's lymphoma and Hodgkin's lymphoma in pregnancy, adult and childhood non-Hodgkin's lymphoma), and the like. and non-Hodgkin's lymphoma, including non-Hodgkin's lymphoma during pregnancy, mycosis fungoides, Sézary syndrome, Waldenstrom's macroglobulinemia, primary mediastinal large B-cell lymphoma, mantle cell lymphoma, diffuse large B-cell lymphoma, and primary central nervous system lymphoma), and blood / blood cell cancers such as other hematological cancers (e.g., chronic myeloproliferative disorders, multiple myeloma / plasma cell neoplasms, myelodysplastic syndromes, and myelodysplastic / myeloproliferative disorders), osteosarcoma, ovarian cancer, breast cancer, lung cancer, glioblastoma, retinoblastoma, and any one of the metastases of the foregoing cancers.

[0011] The present invention further provides the above-described compositions, e.g., pharmaceutical compositions, or the above-described kits, for use in the treatment and / or prevention of hematological cancers, e.g., hematological cancers and related clonal disorders (such as MGUS or amyloidosis). Hematological cancers include, for example, plasma cell neoplasms and myelomas (e.g., MGUS, plasmacytoma, smoldering myeloma, multiple myeloma, relapsed / refractory multiple myeloma, light chain myeloma, or non-secretory myeloma and plasma cell leukemia), B-cell leukemias (e.g., acute lymphoblastic leukemia, including adult and pediatric acute lymphoblastic leukemia, chronic lymphocytic leukemia, and hairy cell leukemia), and lymphoid malignancies of B-cell origin (e.g., AIDS-related lymphoma, leukemia, and hairy cell leukemia). lymphoma, Hodgkin's lymphoma including adult and childhood Hodgkin's lymphoma and Hodgkin's lymphoma during pregnancy, non-Hodgkin's lymphoma including adult and childhood non-Hodgkin's lymphoma and non-Hodgkin's lymphoma during pregnancy, Waldenstrom's macroglobulinemia, primary mediastinal large B-cell lymphoma, diffuse large B-cell lymphoma, follicular lymphoma, mantle cell tumor, hairy cell lymphoma, and primary central nervous system lymphoma).

[0012] Hematological cancers may include, for example, plasma cell neoplasms and myelomas (e.g., multiple myeloma or relapsed / refractory multiple myeloma), B-cell leukemias (e.g., chronic lymphocytic leukemia (CLL), acute lymphoblastic leukemia, or hairy cell leukemia), and lymphoid malignancies of B-cell origin (e.g., diffuse large B-cell lymphoma, follicular lymphoma, mantle cell lymphoma, hairy cell lymphoma, and primary central nervous system lymphoma). Hematological cancers may, for example, be selected from the group consisting of plasma cell neoplasms or myelomas, B-cell leukemias, or lymphoid malignancies of B-cell origin, such as multiple myeloma, chronic lymphocytic leukemia (CLL), or diffuse large B-cell lymphoma. In one embodiment of the invention, the hematological cancer is multiple myeloma (e.g., relapsed / refractory multiple myeloma) or diffuse large B-cell lymphoma, e.g., multiple myeloma or e.g., diffuse large B-cell lymphoma.

[0013] The invention further provides the use of a pharmaceutical preparation, composition, or kit according to the invention for the manufacture of a medicament for the treatment or prevention of cancer, for example the cancer being selected from the group consisting of leukemia (e.g. acute lymphoblastic leukemia, including adult and childhood acute lymphoblastic leukemia, acute myeloid leukemia, including adult and childhood acute myeloid leukemia, chronic lymphocytic leukemia, such as B-cell chronic lymphocytic leukemia, chronic myeloid leukemia, and hairy cell leukemia), lymphoma (e.g. AIDS-related lymphoma, cutaneous T-cell lymphoma, Hodgkin's lymphoma, including adult and childhood Hodgkin's lymphoma and Hodgkin's lymphoma in pregnancy, adult and childhood non-Hodgkin's lymphoma, including non-Hodgkin's lymphoma and non-Hodgkin's lymphoma during pregnancy, mycosis fungoides, Sézary syndrome, Waldenstrom's macroglobulinemia, primary mediastinal large B-cell lymphoma, mantle cell lymphoma, diffuse large B-cell lymphoma, and primary central nervous system lymphoma), and blood / blood cell cancers such as other blood cancers (e.g., chronic myeloproliferative disorders, multiple myeloma / plasma cell neoplasm, myelodysplastic syndromes, and myelodysplastic / myeloproliferative disorders), osteosarcoma, ovarian cancer, breast cancer, lung cancer, glioblastoma, retinoblastoma, and metastases of any one of the foregoing cancers. [Brief explanation of the drawings]

[0014] [Figure 1] The figures show the results of measuring intracellular and extracellular concentrations of a metabolite compound (Example Compound 18) (identified after treatment with Example Compound 1 described herein) (Figure 1A), as well as bendamustine (Figure 1A) and melphalan (Figure 1B) comparators, following in vitro treatment of MM.1S cells. [Figure 2] Figure 1 shows the effect of Example Compound 1 (left panel) and bendamustine (right panel) on tumor growth on xenografts initiated from the SU-DHL-4 human lymphoma cell line in an in ovo chicken embryo model. [Figure 3A-G] 1 shows the results of measuring intracellular and extracellular concentrations of compounds described herein and their metabolites following in vitro treatment of MM.1S cells. [Figure 4A-C] 1 shows the results of an assay assessing DNA damage caused by compounds described herein and controls. [Figure 5A-B] Figure 5B shows the results of an assay evaluating DNA fragmentation induced by compounds described herein and a control. Figure 5B shows representative FACS histograms of Alexa fluor 488 intensity after treatment with a compound of formula (I) (top panel), bendamustine (middle panel), or a control (bottom panel). DETAILED DESCRIPTION OF THE INVENTION

[0015] The present invention provides a pharmaceutical preparation comprising a negatively charged cyclodextrin, or a pharmaceutically acceptable derivative of a negatively charged cyclodextrin, and a compound according to formula (I), or a pharmaceutically acceptable salt, ester, amide, or carbamate thereof, or a salt of such an ester, amide, or carbamate.

[0016] The inventors have now discovered a pharmaceutical preparation comprising a negatively charged cyclodextrin, or a pharmaceutically acceptable derivative of a negatively charged cyclodextrin, and a compound according to formula (I), or a pharmaceutically acceptable salt, ester, amide, or carbamate thereof, or a salt of such an ester, amide, or carbamate.

[0017] Compounds of formula (I) The compounds of formula (I) are a new class of PDCs that are highly cytotoxic to human cancer cells, particularly human hematological cancer cells, and are disclosed in detail in International Patent Application No. PCT / EP2022 / 066756, published as WO2022 / 263679.

[0018] The compounds described as preferred in International Patent Application No. PCT / EP2022 / 066756 are also preferred compounds for use in the preparations, compositions, kits, treatment methods, and uses described herein. Preferably, the compound of formula (I), or its ester, amide, or carbamate, is present as its pharmaceutically acceptable salt. Most preferably, the compound of formula (I), or its ester, amide, or carbamate, is present as a hydrochloride salt.

[0019] PCT / EP2022 / 066756 A new class of PDCs has been discovered that are highly cytotoxic to human cancer cells, particularly human blood cancer cells. As described in the Examples section (including cross-references to PCT Application No. PCT / EP2022 / 066756, published in WO2022 / 263679), various example compounds described herein have been synthesized and their cytotoxicity against several blood cancer cell lines tested in in vitro cytotoxicity assays. The compounds described herein have been found to be highly potent and selective against blood cancer cells, as demonstrated by the compounds' low cytotoxicity against the fibroblast cell line BJ. Example compound 1 has been found to be particularly effective in inhibiting tumor growth in an in ovo chicken embryo xenograft model using the human lymphoma cell line SU-DHL-4.

[0020] Further studies have found that the example compounds described herein were readily hydrolyzed in MM.1S cancer cells to form metabolites that were sequestered and retained intracellularly and had potent alkylating activity, thus demonstrating that the compounds described herein are an effective new class of PDCs for the treatment or prevention of cancer, particularly hematological cancers.

[0021] Compounds of formula (I) are described herein: [ka] (W1, W2, W3, and W4 are each CH, or one of W1, W2, W3, and W4 is N and the others are CH).

[0022] In one embodiment, W2, W3, and W4 are each CH and W1 is N.

[0023] It is easy to see that the -N(CH2CH2Cl)2 group is attached to the core part of the molecule via a carbon atom on the ring. For the related W group, the H in the CH group is correspondingly absent.

[0024] In a preferred embodiment, W1, W2, W3, and W4 are each CH, so that formula (I) is represented by formula (Ia): [ka] It has.

[0025] In a preferred embodiment, formula (I) is as set forth in formula (Ib). [ka]

[0026] In the compounds of formula (I), X is C 1-6 For example, X is C 1-4 Alkylene, C 1-3 Alkylene, C 1-2 The alkylene at the X position can be alkylene, C2 alkylene, or C1 alkylene. X can be linear or branched alkylene. The alkylene at the X position can be used to separate the imidazole portion of the compounds described herein from the peptide portion (i.e., R 3 The linkage forms between the X-position and the alkylene moiety. Alkylene linkers at the X-position that are one or two carbons in length have been found to be particularly effective. Thus, in preferred embodiments, X is a C alkylene (i.e., -CH-) or a linear C alkylene (i.e., -CH-CH-).

[0027] In compounds of formula (I), R 1 is optionally substituted by 1, 2, or 3 groups independently selected from H, halogen 1-4 Alkyl, and halogen (e.g., H, C 1-4 alkyl, and halogen). For example, R 1 may be selected from the group consisting of H, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, F, Cl, Br, and I. Optionally, these groups may be substituted with 1, 2, or 3 groups independently selected from halogen. In certain embodiments, R 1 is selected from the group consisting of H, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, F, and Cl. In certain preferred embodiments, R 1 is H.

[0028] In compounds of formula (I), R 2 is H, phenyl optionally substituted with 1, 2, or 3 groups independently selected from halogen, and —C optionally substituted with 1, 2, or 3 groups independently selected from halogen. 1-6 For example, R 2 is H, phenyl optionally substituted by 1, 2 or 3 F or Cl, and —C optionally substituted by 1, 2 or 3 F or Cl. 1-4 alkyl (e.g., methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, or tert-butyl). 2 is phenyl optionally substituted with 1, 2, or 3 groups independently selected from halogen, and —C optionally substituted with 1, 2, or 3 groups independently selected from halogen. 1-6 alkyl, e.g., —C optionally substituted with 1, 2, or 3 groups selected from halogen 1-4In certain embodiments, R 2 is unsubstituted -C 1-2 It is alkyl (eg, methyl) or unsubstituted phenyl.

[0029] In the compounds of formula (I), R 3 is represented by formula (II): [ka] or formula (III): [ka] is a group described in

[0030] In a preferred embodiment, R 3 is represented by formula (IIa): [ka] or formula (IIIa): [ka] is a group described in

[0031] For the avoidance of doubt, in formulas (II), (III), (IIa), and (IIIa), [ka] indicates the point of attachment of formula (II), (III), (IIa), or (IIIa) to formula (I), (Ia), or (IIa). In formulas (II), (IIa), (III), and (IIIa), R 4 is N(R c )(R d ) and formula (IV). [ka]

[0032] In a preferred embodiment, R 4is N(R c )(R d ) and formula (IVa): [ka]

[0033] For the avoidance of doubt, in formula (IV) and (IVa) [ka] indicates the point of attachment of formula (IV) or (IVa) to formula (II), (III), (IIa), or (IIIa).

[0034] In compounds of formula (I), R 4 is formula (IV) or (IVa), R 5 is R b is. R b -OH, -N(R e )(R f ), and -OC 1-6 Alkyl (halogen, -OH, -CN, -N(R e )(R f ), -C 6-10 aryl, or a 3-12 membered heterocycle containing one or more O, N, or S atoms and optionally substituted with 1, 2, or 3 halogens, and / or the alkyl is optionally interrupted by 1, 2, or 3 O, N, or S atoms.

[0035] For example, R 4 is formula (IV) or (IVa), R 5 (R b is -OH and -OC 1-4 alkyl (e.g., methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, or tert-butoxy). Preferably, R 4 is formula (IV) or (IVa), R 5-OH and -OC 1-3 alkyl (e.g., methoxy, ethoxy, propoxy, or isopropoxy). More preferably, R 4 is formula (IV) or (IVa), R 5 is selected from the group consisting of methoxy, ethoxy, or isopropoxy.

[0036] In compounds of formula (Ia), R 4 is N(R c )(R d ), then R 5 is R b and formula (V). [ka]

[0037] In a preferred embodiment, R 4 is N(R c )(R d ), then R 5 -OH, -OC 1-6 alkyl, or formula (Va): [ka]

[0038] For the avoidance of doubt, in formula (V) and (Va) [ka] indicates the point of attachment of formula (V) or (Va) to formula (II), (III), (IIa), or (IIIa).

[0039] In embodiments, R 4 is N(R c )(R d ) and R 5 (R b ) is -OH, -OC 1-4alkyl (e.g., methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, or tert-butoxy), or R 5 may be selected from formula (V) and formula (Va). Preferably, R 4 is N(R c )(R d ), then R 5 -OH, -OC 1-3 More preferably, R is selected from the group consisting of alkyl (e.g., methoxy, ethoxy, propoxy, or isopropoxy) and formula (Va): 4 is N(R c )(R d ), then R 5 is selected from the group consisting of methoxy, ethoxy, or isopropoxy.

[0040] R 4 But N(R c )(R d ), formula (IV) or (IVa), and R 5 (R b ) is -OC 1-3 Compounds of formula (I) that are alkyl (e.g., methoxy, ethoxy, or isopropoxy) have been found to be particularly cytotoxic to cancer cells. Thus, in certain preferred embodiments, in compounds of formula (I), R 5 -OC 1-3 alkyl (e.g., methoxy, ethoxy, or isopropoxy). That is, R 4 is N(R c )(R d ), when formula (IV) or (IVa), R 5 is preferably -OC 1-3 alkyl (eg, methoxy, ethoxy, or isopropoxy).

[0041] In certain embodiments, R 5 is -OH.

[0042] In the compounds of formula (I), each R a is H, C1-6 alkyl, -CH2-phenyl, or -CH2-3 to 12-membered heterocyclyl (containing 1, 2, 3, or 4 heteroatoms selected from N, O, and S), 1-6 Alkyl is -OH, -OC 1-6 and the phenyl or heterocyclyl is optionally substituted by 1, 2, or 3 substituents independently selected from the group consisting of alkyl, -NH, -NHC(=NH)NH, -C(O)OH, -C(O)NH, -SH, -SCH, and halogen; 1-6 In certain embodiments, each R a -H, -C 1-6 independently selected from the group consisting of alkyl, -CH-indolyl, -CH-phenyl, and -CH-5-membered heteroaryl (containing 1, 2, 3, or 4 N or S atoms); C 1-6 Alkyl is optionally substituted with -OH, -NH, -NHC(=NH)NH, -C(O)OH, -C(O)NH, -SH, -SCH, or halogen (e.g., F, Cl, Br, or I); phenyl is optionally substituted with halogen (e.g., F, Cl, Br, or I), -NH, -OH, -OC 1-6 Optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of alkyl, and -NO2. Preferably, each R a is H, C 1-4 alkyl, and -CH-phenyl, where alkyl or phenyl is optionally substituted with one or two halogens (e.g., F or Cl). For example, each R a may independently be methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, -CH-phenyl, -CH-fluorophenyl, -CH-chlorophenyl, -CH-difluorophenyl, or -CH-dichlorophenyl. In certain preferred embodiments, each R acan independently be isopropyl, isobutyl, sec-butyl, —CH 2 -phenyl, or —CH 2 -fluorophenyl (i.e., 2-fluorobenzyl, 3-fluorobenzyl, or 4-fluorobenzyl).

[0043] In the compounds of formula (I), R b -OH, -N(R e )(R f ), and -OC 1-6 Alkyl (halogen, -OH, -CN, -N(R e )(R f ), -C 6-10 aryl, or a 3-12 membered heterocycle containing one or more O, N, or S atoms and optionally substituted with 1, 2, or 3 halogens, and / or the alkyl is optionally interrupted by 1, 2, or 3 O, N, or S atoms. b is -OH or -OC 1-6 alkyl, optionally interrupted by 1, 2, or 3 O or N atoms. In certain further embodiments, R b is -OH or -OC 1-6 Alkyl, e.g., -OC 1-6 Preferably, R b -OC 1-4 alkyl. For example, R b can be methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, or sec-butoxy. In certain preferred embodiments, R b is methoxy, ethoxy, or isopropoxy. More preferably, R b is ethoxy.

[0044] In certain embodiments, R b is -OH.

[0045] R c and R d are H and -C, respectively. 1-6Alkyl, -C(O)C 1-6 In preferred compounds, R is independently selected from the group consisting of alkyl, and -CH-phenyl, wherein the alkyl or the phenyl is optionally substituted with 1, 2, or 3 groups selected from halogen. c is H and R d -H, -C 1-6 Alkyl, and -C(O)C 1-6 alkyl, which is optionally substituted with 1, 2, or 3 groups selected from halogen. For example, R c is H and R d -H, -C 1-4 Alkyl and C(O)C 1-4 For example, R c is H and R d is selected from H, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, —C(O)methyl, —C(O)ethyl, —C(O)propyl, —C(O)isopropyl, —C(O)butyl, —C(O)isobutyl, and —C(O)sec-butyl. Preferably, R c is H and R d is selected from H, methyl, and —C(O)methyl. Preferably, R c is H and R d is H.

[0046] In the compounds of formula (I), R e and R f are H and -C, respectively. 16 alkyl, optionally substituted with 1, 2, or 3 groups selected from halogen, or R e and R f together with the nitrogen atom to which they are attached form a 4-, 5-, or 6-membered heterocycle optionally substituted with 1, 2, or 3 groups selected from halogen. e and R fare each independently selected from the group consisting of H, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, and sec-butyl. For example, R e and R f are each independently selected from the group consisting of H and methyl. Preferably, R e and R f are both H, both methyl, or R e and R f One of them is H and the other is methyl.

[0047] In certain embodiments, the compounds described herein are compounds according to formula (Ia): (Wherein X is -C 1-2 alkylene (i.e., —CH— or —CH—CH—); R 1 is H, R 2 is optionally substituted by 1, 2, or 3 F; 1-2 alkyl, or phenyl optionally substituted by 1, 2, or 3 F, e.g., R 2 is unsubstituted -C 1-2 may be alkyl or unsubstituted phenyl; R 3 is of formula (IIa) or (IIIa), R 4 is N(R c )(R d ) and formula (IVa), R 4 is formula (IVa), R 5 (R b ) is -OC 1-4 alkyl, and R 4 is N(R c )(R d ), then R 5 -OC 1-4 alkyl or formula (Va), and each R a -H, -C 16alkyl, CH2-indolyl, CH2-phenyl, or -CH2-5-membered heteroaryl (containing 1, 2, 3, or 4 N or S atoms); 1-6 The alkyl is optionally substituted by OH, NH, -NHC(=NH)NH, -C(O)OH, -C(O)NH, -SH, -SCH, or halogen, and the phenyl is optionally substituted by halogen, -NH, -OH, -OC. 1-6 optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of alkyl, and -NO; R b -OC 1-6 alkyl, and R c is H and R d -H, -C 1-4 Alkyl, and -C(O)C 1-4 alkyl), or a pharmaceutically acceptable salt, ester, amide, or carbamate thereof (including a salt of such an ester, amide, or carbamate).

[0048] In certain other embodiments, the compounds described herein are compounds according to formula (Ia): (Wherein X is -C 1-2 alkylene (i.e., —CH— or —CH—CH—); R 1 is H, R 2 is methyl or phenyl, R 3 is of formula (IIa) or (IIIa), R 4 is N(R c )(R d ) or formula (IVa), R 5 (R b ) is -OC 1-3 is alkyl, Each R a -H, -C 16independently selected from the group consisting of alkyl, CH2-indolyl, CH2-phenyl, or -CH2-5-membered heteroaryl (containing 1, 2, 3, or 4 N or S atoms); 1-6 Alkyl is optionally substituted by OH, NH, -NHC(=NH)NH, -C(O)OH, -C(O)NH, -SH, -SCH, or halogen; phenyl is optionally substituted by halogen, -NH, -OH, -OC 1-6 and -NO2), or a pharmaceutically acceptable salt, ester, amide, or carbamate thereof (including a salt of such an ester, amide, or carbamate).

[0049] The compounds described herein are those compounds according to formula (Ia): (Wherein X is -C 1-2 alkylene (i.e., —CH— or —CH—CH—); R 1 is H, R 2 is methyl or phenyl, R 3 is of formula (IIa) or (IIIa), R 4 is N(R c )(R d ) or formula (IVa), R 5 (R b ) is -OC 1-3 is alkyl, Each R a are independently selected from the group consisting of isopropyl, isobutyl, and —CH2-phenyl (optionally substituted with one F) (e.g., 2-fluorobenzyl, 3-fluorobenzyl, or 4-fluorobenzyl). or a pharmaceutically acceptable salt, ester, amide, or carbamate thereof (including salts of such esters, amides, or carbamates), have been found to be particularly cytotoxic to blood cancer cells in in vitro cytotoxicity assays and in an in ovo chicken embryo xenograft model of lymphoma.

[0050] In certain other embodiments, the compounds described herein are compounds according to formula (Ia): (Wherein X is -C 1-2 alkylene (i.e., —CH— or —CH—CH—); R 1 is H, R 2 is optionally substituted by 1, 2, or 3 F; 1-2 alkyl, or phenyl optionally substituted by 1, 2, or 3 F, e.g., R 2 is unsubstituted -C 1-2 may be alkyl or unsubstituted phenyl; R 3 is of formula (IIa), R 4 is NH2, R 5 (R b ) is -OC 1-4 is alkyl, Each R a -H, -C 16 independently selected from the group consisting of alkyl, CH2-indolyl, CH2-phenyl, or -CH2-5-membered heteroaryl (containing 1, 2, 3, or 4 N or S atoms); 1-6 Alkyl is optionally substituted by OH, NH, -NHC(=NH)NH, -C(O)OH, -C(O)NH, -SH, -SCH, or halogen; phenyl is optionally substituted by halogen, -NH, -OH, -OC 1-6and -NO2), or a pharmaceutically acceptable salt, ester, amide, or carbamate thereof (including a salt of such an ester, amide, or carbamate).

[0051] In certain other embodiments, the compounds described herein are compounds according to formula (Ia): (Wherein X is -C 1-2 alkylene (i.e., —CH— or —CH—CH—); R 1 is H, R 2 is optionally substituted by 1, 2, or 3 F; 1-2 alkyl, or phenyl optionally substituted by 1, 2, or 3 F, e.g., R 2 is unsubstituted -C 1-2 may be alkyl or unsubstituted phenyl; R 3 is of formula (IIIa), R 4 is NH2, R 5 -OC 1-4 is alkyl, Each R a -H, -C 16 independently selected from the group consisting of alkyl, CH2-indolyl, CH2-phenyl, or -CH2-5-membered heteroaryl (containing 1, 2, 3, or 4 N or S atoms); 1-6 Alkyl is optionally substituted by OH, NH, -NHC(=NH)NH, -C(O)OH, -C(O)NH, -SH, -SCH, or halogen; phenyl is optionally substituted by halogen, -NH, -OH, -OC 1-6 and -NO2), or a pharmaceutically acceptable salt, ester, amide, or carbamate thereof (including a salt of such an ester, amide, or carbamate).

[0052] In certain other embodiments, the compounds described herein are compounds according to formula (Ia): (Wherein X is -C 1-2 alkylene (i.e., —CH— or —CH—CH—); R 1 is H, R 2 is optionally substituted by 1, 2, or 3 F; 1-2 alkyl, or phenyl optionally substituted by 1, 2, or 3 F, e.g., R 2 is unsubstituted -C 1-2 may be alkyl or unsubstituted phenyl; R 3 is of formula (IIIa), R 4 is of formula (IVa), R 5 -OC 1-4 is alkyl, Each R a -H, -C 16 independently selected from the group consisting of alkyl, CH2-indolyl, CH2-phenyl, or -CH2-5-membered heteroaryl (containing 1, 2, 3, or 4 N or S atoms); 1-6 Alkyl is optionally substituted by OH, NH, -NHC(=NH)NH, -C(O)OH, -C(O)NH, -SH, -SCH, or halogen; phenyl is optionally substituted by halogen, -NH, -OH, -OC 1-6 and -NO2), or a pharmaceutically acceptable salt, ester, amide, or carbamate thereof (including a salt of such an ester, amide, or carbamate).

[0053] In certain preferred embodiments, the compound is Ethyl (2S)-2-[[(2S)-2-amino-4-[5-[bis(2-chloroethyl)amino]-1-methyl-benzimidazol-2-yl]butanoyl]amino]-4-methyl-pentanoate (Example compound 1), Ethyl (2S)-2-[[(2S)-2-amino-4-[5-[bis(2-chloroethyl)amino]-1-methyl-benzimidazol-2-yl]butanoyl]amino]-3-(4-fluorophenyl)propanoate (Example compound 2), Ethyl (2S)-2-[[(2S)-2-amino-4-[5-[bis(2-chloroethyl)amino]-1-methyl-benzimidazol-2-yl]butanoyl]amino]-3-methyl-butanoate (Example compound 3), Ethyl (2S)-2-[[(2S)-2-amino-3-[5-[bis(2-chloroethyl)amino]-1-methyl-benzimidazol-2-yl]propanoyl]amino]-4-methyl-pentanoate (Example compound 4), Ethyl (2S)-2-[[(2S)-2-amino-3-[5-[bis(2-chloroethyl)amino]-1-methyl-benzimidazol-2-yl]propanoyl]amino]-3-(4-fluorophenyl)propanoate (Example compound 5), Ethyl (2S)-2-[[(2S)-2-amino-3-[5-[bis(2-chloroethyl)amino]-1-methyl-benzimidazol-2-yl]propanoyl]amino]-3-methyl-butanoate (Example compound 6), Ethyl (2S)-2-[[(2S)-2-amino-4-methyl-pentanoyl]amino]-4-[5-[bis(2-chloroethyl)amino]-1-methyl-benzimidazol-2-yl]butanoate (Example compound 7), Ethyl (2S)-2-[[(2S)-2-amino-3-(4-fluorophenyl)propanoyl]amino]-4-[5-[bis(2-chloroethyl)amino]-1-methyl-benzimidazol-2-yl]butanoate (Example compound 8), Ethyl (2S)-2-[[(2S)-2-amino-3-methyl-butanoyl]amino]-4-[5-[bis(2-chloroethyl)amino]-1-methyl-benzimidazol-2-yl]butanoate (Example compound 9), Ethyl (2S)-2-[[(2S)-2-amino-4-methyl-pentanoyl]amino]-3-[5-[bis(2-chloroethyl)amino]-1-methyl-benzimidazol-2-yl]propanoate (Example compound 10), Ethyl (2S)-2-[[(2S)-2-amino-3-(4-fluorophenyl)propanoyl]amino]-3-[5-[bis(2-chloroethyl)amino]-1-methyl-benzimidazol-2-yl]propanoate (Example compound 11), Ethyl (2S)-2-[[(2S)-2-amino-3-methyl-butanoyl]amino]-3-[5-[bis(2-chloroethyl)amino]-1-methyl-benzimidazol-2-yl]propanoate (Example compound 12), Ethyl (2S)-2-[[(2S)-2-amino-4-[5-[bis(2-chloroethyl)amino]-1-phenyl-benzimidazol-2-yl]butanoyl]amino]-4-methyl-pentanoate (Example compound 13), Methyl (2S)-2-[[(2S)-2-amino-3-[5-[bis(2-chloroethyl)amino]-1-methyl-benzimidazol-2-yl]propanoyl]amino]-4-methyl-pentanoate (Example compound 14), Isopropyl (2S)-2-[[(2S)-2-amino-3-[5-[bis(2-chloroethyl)amino]-1-methyl-benzimidazol-2-yl]propanoyl]amino]-4-methyl-pentanoate (Example compound 15), Ethyl (2S)-2-[[(2S)-2-[[(2S)-2-amino-3-(4-fluorophenyl)propanoyl]amino]-4-methyl-pentanoyl]amino]-4-[5-[bis(2-chloroethyl)amino]-1-methyl-benzimidazol-2-yl]butanoate (Example compound 16), Ethyl (2S)-2-[[(2R)-2-[[(2S)-2-amino-3-(4-fluorophenyl)propanoyl]amino]-4-methyl-pentanoyl]amino]-4-[5-[bis(2-chloroethyl)amino]-1-methyl-benzimidazol-2-yl]butanoate (Example compound 21) Ethyl (2S)-2-[[(2S)-2-[[(2S)-2-amino-4-[5-[bis(2-chloroethyl)amino]-1-methyl-benzimidazol-2-yl]butanoyl]amino]-4-methyl-pentanoyl]amino]-3-(4-fluorophenyl)propanoate (Example compound 22) Ethyl (2S)-2-[[(2S)-2-[[(2S)-2-amino-4-[5-[bis(2-chloroethyl)amino]-1-methyl-benzimidazol-2-yl]butanoyl]amino]-4-methyl-pentanoyl]amino]-4-methyl-pentanoate (Example compound 23) 2-Morpholinoethyl (2S)-2-[[(2S)-2-amino-4-[5-[bis(2-chloroethyl)amino]-1-methyl-benzimidazol-2-yl]butanoyl]amino]-4-methyl-pentanoate (Example Compound 24) 2-Isopropoxyethyl (2S)-2-[[(2S)-2-amino-4-[5-[bis(2-chloroethyl)amino]-1-methyl-benzimidazol-2-yl]butanoyl]amino]-4-methyl-pentanoate (Example Compound 25) Isopropyl (2S)-2-[[(2S)-2-amino-4-[5-[bis(2-chloroethyl)amino]-1-methyl-benzimidazol-2-yl]butanoyl]amino]-4-methyl-pentanoate (Example Compound 26) Methyl (2S)-2-[[(2S)-2-amino-4-[5-[bis(2-chloroethyl)amino]-1-methyl-benzimidazol-2-yl]butanoyl]amino]-4-methyl-pentanoate (Example Compound 27) 3-(Dimethylamino)propyl(2S)-2-[[(2S)-2-amino-4-[5-[bis(2-chloroethyl)amino]-1-methyl-benzimidazol-2-yl]butanoyl]amino]-4-methyl-pentanoate (Example Compound 28) (2-Methoxy-1-methyl-ethyl)(2S)-2-[[(2S)-2-amino-4-[5-[bis(2-chloroethyl)amino]-1-methyl-benzimidazol-2-yl]butanoyl]amino]-4-methyl-pentanoate (Example Compound 29) (2S)-2-[[(2S)-2-amino-4-[5-[bis(2-chloroethyl)amino]-1-methyl-benzimidazol-2-yl]butanoyl]amino]-N,N,4-trimethyl-pentanamide (Example Compound 30) (2S)-2-[[(2S)-2-amino-4-[5-[bis(2-chloroethyl)amino]-1-methyl-benzimidazol-2-yl]butanoyl]amino]-N,4-dimethyl-pentanamide (Example Compound 31) Ethyl (2S)-2-[[(2S)-4-[5-[bis(2-chloroethyl)amino]-1-methyl-benzimidazol-2-yl]-2-(methylamino)butanoyl]amino]-4-methyl-pentanoate (Example compound 32) Ethyl (2S)-2-[[(2S)-2-acetamido-4-[5-[bis(2-chloroethyl)amino]-1-methyl-benzimidazol-2-yl]butanoyl]amino]-3-(4-fluorophenyl)propanoate (Example compound 34) Ethyl (2S)-2-[[(2S)-2-acetamido-3-[5-[bis(2-chloroethyl)amino]-1-methyl-benzimidazol-2-yl]propanoyl]amino]-4-methyl-pentanoate (Example Compound 35) Ethyl (2S)-2-[[(2S)-2-acetamido-3-[5-[bis(2-chloroethyl)amino]-1-methyl-benzimidazol-2-yl]propanoyl]amino]-3-(4-fluorophenyl)propanoate (Example compound 36) Ethyl (2S)-2-amino-4-[5-[bis(2-chloroethyl)amino]-1-methyl-benzimidazol-2-yl]butanoate (Example compound 38) Ethyl (2R)-2-[[(2S)-2-amino-4-[5-[bis(2-chloroethyl)amino]-1-methyl-benzimidazol-2-yl]butanoyl]amino]-4-methyl-pentanoate (Example Compound 45) Ethyl (2S)-2-[[(2R)-2-amino-4-[5-[bis(2-chloroethyl)amino]-1-methyl-benzimidazol-2-yl]butanoyl]amino]-4-methyl-pentanoate (Example compound 46) Ethyl (2R)-2-[[(2R)-2-amino-4-[5-[bis(2-chloroethyl)amino]-1-methyl-benzimidazol-2-yl]butanoyl]amino]-4-methyl-pentanoate (Example compound 47) Ethyl (2S)-2-[[(2S)-2-amino-4-[6-[bis(2-chloroethyl)amino]-3-methyl-imidazo[4,5-b]pyridin-2-yl]butanoyl]amino]-4-methyl-pentanoate (Example compound 48), and Ethyl (2S)-2-[[(2S)-2-amino-4-[5-[bis(2-chloro-1,1,2,2-tetradeuterio-ethyl)amino]-1-methyl-benzimidazol-2-yl]butanoyl]amino]-4-methyl-pentanoate (Example Compound 50) or a pharmaceutically acceptable salt, amide, or carbamate thereof (including a salt of such an amide or carbamate).

[0054] The compounds described herein can be prepared by methods known to those skilled in the art of organic chemistry.The exemplary procedures for preparing the compound of formula (I) are described in the Examples section (including cross-reference to PCT application No. PCT / EP2022 / 066756, published under WO2022 / 263679).

[0055] In embodiments, the compounds described herein may contain isotopic atoms. As defined herein, an isotopic atom is an atom of an element that is not the most common naturally occurring isotope. Deuterium is a safe and stable isotope of hydrogen. In one embodiment, the compounds described herein have a deuterium abundance level higher than the naturally occurring abundance of deuterium. The naturally occurring abundance of deuterium is 0.0156 mol%, where mol% is the percentage of the total moles of hydrogen in a sample that are deuterium. Thus, in 1 mole of naturally occurring hydrogen, 0.156 mmol is deuterium, or 6.022 x 10 23 A sample of naturally occurring hydrogen atoms contains 9.39 × 10 19 There are deuterium atoms present, or 1 deuterium atom present in a sample of 6413 naturally occurring hydrogen atoms. A deuterium abundance level higher than the naturally occurring abundance of deuterium can be at least 1 mol%, 5 mol%, 10 mol%, 50 mol%, 90 mol%, or 98 mol% deuterium. In certain embodiments, the compounds described herein have a deuterium abundance level of at least 1 mol%, 5 mol%, 10 mol%, 50 mol%, 90 mol%, or 98 mol%. Procedures for preparing deuterated compounds are known in the art. See, for example, Sajiki, New Horizons of Process Chemistry (2017), Springer, pg 29-40, and Hanson, The Organic Chemistry of Isotopic Labelling (2011), Chapter 3, RSC Publishing.

[0056] Depending on the substituents present in the compounds described herein, the compounds may form esters, amides, carbamates, and / or salts. Salts of the compounds described herein that are suitable for use in medicine are those in which the counterion is pharmaceutically acceptable. However, salts with pharmaceutically unacceptable counterions may be used, for example, as intermediates in the preparation of the compounds described herein and their pharmaceutically acceptable salts, as well as physiologically functional derivatives. The term "physiologically functional derivative" refers to a chemical derivative of the compounds described herein that has the same physiological function as the compounds described herein, for example, by being convertible thereto in the body. Esters, amides, and carbamates are examples of physiologically functional derivatives.

[0057] Suitable salt forms of the compounds described herein include those formed with organic or inorganic acids or bases. In particular, suitable salts formed with acids according to the present invention include those formed with mineral acids, such as alkanecarboxylic acids of 1 to 4 carbon atoms, unsubstituted or substituted, for example, by halogen, or saturated or unsaturated dicarboxylic acids, or hydroxycarboxylic acids, or amino acids, strong organic carboxylic acids, or organic sulfonic acids, such as (C1-C4) alkyl or aryl sulfonic acids, unsubstituted or substituted, for example, by halogen. Pharmaceutically acceptable acid addition salts include those formed from hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, citric acid, tartaric acid, acetic acid, phosphoric acid, lactic acid, pyruvic acid, acetic acid, trifluoroacetic acid, succinic acid, perchloric acid, fumaric acid, maleic acid, glycolic acid, lactic acid, salicylic acid, oxaloacetic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, formic acid, benzoic acid, malonic acid, naphthalene-2-sulfonic acid, benzenesulfonic acid, isethionic acid, ascorbic acid, malic acid, phthalic acid, aspartic acid, and glutamic acid, lysine, and arginine. Other acids, such as oxalic acid, while not themselves pharmaceutically acceptable, may be useful as intermediates in obtaining the compounds described herein and their pharmaceutically acceptable acid addition salts.

[0058] Pharmaceutically acceptable base salts include ammonium salts, alkali metal salts such as potassium and sodium salts, alkaline earth metal salts such as calcium and magnesium salts, and salts with organic bases such as dicyclohexylamine, N-methyl-D-glucamine, morpholine, thiomorpholine, piperidine, pyrrolidine, mono-, di-, or tri-lower alkylamines such as ethyl, tert-butyl, diethyl, diisopropyl, triethyl, tributyl, or dimethyl-propylamine, or mono-, di-, or trihydroxy-lower alkylamines such as mono-, di-, or triethanolamine. Corresponding inner salts can also be formed.

[0059] Preferred salts of the compounds described herein include acid addition salts such as those formed from hydrochloric acid, hydrobromic acid, acetic acid, p-toluenesulfonic acid, tartaric acid, sulfuric acid, succinic acid, phosphoric acid, oxalic acid, nitric acid, methanesulfonic acid, malic acid, maleic acid, and citric acid. More preferably, the salts of the compounds described in the present invention are hydrochloride salts (i.e., addition salts formed from hydrochloric acid).

[0060] Compounds that are inactive themselves but can be converted into active drug compounds upon administration to a recipient are known as "prodrugs." Prodrugs can be converted into active forms that have medical effects, for example, by hydrolysis in the body, for example, in the blood. Pharmaceutically acceptable prodrugs are described in T. Higuchi and V. Stella, "Prodrugs as Novel Delivery Systems," Vol. 14 of the ACS Symposium Series (1976); "Design of Prodrugs," ed. H. Bundgaard, Elsevier, 1985; and Edward B. Roche, ed., "Bioreversible Carriers in Drug Design," American Pharmaceutical Association and Pergamon Press, 1987.

[0061] Examples of prodrugs include esters, amides, and carbamates.

[0062] The compounds described herein may have suitable groups converted to esters, amides, or carbamates. Thus, typical ester and amide groups formed from acid groups in the compounds described herein include -COOR G ,CONR G 2. SO2OR G , or SO2N(R G )2, and in the compounds described herein, an OH group or an —NHR G Typical ester and amide groups and carbamate groups formed from groups include OC(O)R G , NR G C(O)R G , N.R. G CO2R G , OSO2R G , and -NR G SO2R G wherein R G is C 1-8 Alkyl, C 2-8 Alkenyl, C 28 Alkynyl, C 3-8 Cycloalkyl and C 3-8 Cycloalkyl C 1-8 Alkyl, HaloC 18 Alkyl, dihalo C 1-8 Alkyl, trihalo C 18 Alkyl, phenyl and phenyl C 14 alkyl, more preferably R G is C 1-6 Alkyl, C 26 Alkenyl, C 26 Alkynyl, C 3-8 Cycloalkyl, and C 3-8 Cycloalkyl C 1-6 alkyl.

[0063] Those skilled in the art of organic chemistry will appreciate that many organic compounds can form complexes with solvents with which they are reacted or from which they are precipitated or crystallized. These complexes are known as "solvates." For example, a complex with water is known as a "hydrate." The complex can incorporate the solvent in stoichiometric or non-stoichiometric amounts. Solvates are known as Water-Insoluble Drug Formulations, 2 nd edn, R. Lui, CRC Press, page 553 and Byrn et al., Pharm. Res., 12(7), 1995, 945-954. Before being prepared in solution, the compounds described herein, as well as their esters, amides, carbamates, and / or salts, may be in the form of solvates. Solvates of the compounds described herein that are suitable for pharmaceutical use are those in which the associated solvent is pharmaceutically acceptable. For example, hydrates are pharmaceutically acceptable solvates.

[0064] R 5 But, -OC 1-6 Alkyl, formula (V) [ka] and formula (Va) [ka] and R b But -N(R e )(R f ) and -OC 1-6 The compounds described herein, in which the group is selected from alkyl, have been found to be readily hydrolyzed in cancer cells to form metabolites that are preferentially sequestered and retained intracellularly and have potent alkylating activity.

[0065] Accordingly, also described herein are metabolites, which have a structure according to formula (I), (Ia), or (Ib), wherein: X is C 1-6 is alkylene, W1, W2, W3, and W4 are each CH, or one of W1, W2, W3, and W4 is N and the others are CH; R 1 is optionally substituted by 1, 2, or 3 groups independently selected from H, halogen 1-4 selected from the group consisting of alkyl, and halogen; R 2 is H, phenyl optionally substituted with 1, 2, or 3 groups independently selected from halogen, and C optionally substituted with 1, 2, or 3 groups independently selected from halogen. 1-6 is selected from the group consisting of alkyl, R 3 is a group according to formula (II), (III), (IIa), or (IIIa), R 4 is N(R c )(R d ), formula (IV), or (IVa), R 4 is formula (IV) or (IVa), R 5 is -OH and R 4 is N(R c )(R d ), then R 5 is —OH, formula (V), or (Va), Each R a -H, -C 16 alkyl, CH2-phenyl, or -CH2-3 to 12-membered heterocyclyl (containing 1, 2, 3, or 4 heteroatoms selected from N, O, and S), and the -C 1-6 Alkyl is -OH, -OC 1-6 and the phenyl or heterocyclyl is optionally substituted by 1, 2, or 3 substituents independently selected from the group consisting of alkyl, NH, —NHC(═NH)NH, —C(O)OH, —C(O)NH, —SH, —SCH, and halogen; 1-6optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of alkyl, and —NO2; R b is OH), or a salt thereof.

[0066] Preferred radicals within the immediately preceding metabolite compounds are as described above for compounds of formula (I), (Ia), and (Ib). For example, in certain embodiments, the metabolite has the structure set forth in formula (I), (Ia), or (Ib). (Wherein X is -C 1-2 alkylene (i.e., —CH— or —CH—CH—); R 1 is H, R 2 is methyl or phenyl, R 3 is of formula (IIa) or (IIIa), R 4 is N(R c )(R d ) or formula (IVa), R 4 is formula (IVa), R 5 is -OH and R 4 is N(R c )(R d ), then R 5 is —OH or formula (Va), Each R a -H, -C 16 independently selected from the group consisting of alkyl, CH2-indolyl, CH2-phenyl, or -CH2-5-membered heteroaryl (containing 1, 2, 3, or 4 N or S atoms); 1-6 Alkyl is optionally substituted by OH, NH, -NHC(=NH)NH, -C(O)OH, -C(O)NH, -SH, -SCH, or halogen; phenyl is optionally substituted by halogen, -NH, -OH, -OC 1-6 optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of alkyl, and -NO; R bis OH), or a salt thereof.

[0067] In certain embodiments, the metabolite has the structure according to formula (I), (Ia), or (Ib): (Wherein X is -C 1-2 alkylene (i.e., —CH— or —CH—CH—); R 1 is H, R 2 is methyl or phenyl, R 3 is of formula (IIa) or (IIIa), R 4 is NH or formula (IVa), R 5 is -OH, Each R a -H, -C 16 independently selected from the group consisting of alkyl, CH2-indolyl, CH2-phenyl, or -CH2-5-membered heteroaryl (containing 1, 2, 3, or 4 N or S atoms); 1-6 Alkyl is optionally substituted by OH, NH, -NHC(=NH)NH, -C(O)OH, -C(O)NH, -SH, -SCH, or halogen; phenyl is optionally substituted by halogen, -NH, -OH, -OC 1-6 and -NO2). Preferably, each R a is independently selected from the group consisting of isopropyl, isobutyl, and —CH-phenyl (optionally substituted with one F) (e.g., 2-fluorobenzyl, 3-fluorobenzyl, or 4-fluorobenzyl); or a salt thereof.

[0068] In certain preferred embodiments, the metabolite is (2S)-2-[[(2S)-2-amino-4-[5-[bis(2-chloroethyl)amino]-1-methyl-benzimidazol-2-yl]butanoyl]amino]-3-methyl-butanoic acid (Example compound 19), and (2S)-2-[[(2S)-2-amino-4-[5-[bis(2-chloroethyl)amino]-1-methyl-benzimidazol-2-yl]butanoyl]amino]-4-methyl-pentanoic acid (Example compound 20), (2S)-2-[[(2S)-4-[5-[bis(2-chloroethyl)amino]-1-methyl-benzimidazol-2-yl]-2-(methylamino)butanoyl]amino]-4-methyl-pentanoic acid (Example compound 33) (2S)-2-[[(2S)-2-amino-4-methyl-pentanoyl]amino]-4-[5-[bis(2-chloroethyl)amino]-1-methyl-benzimidazol-2-yl]butanoic acid (Example compound 37) (2S)-2-[[(2S)-2-amino-4-[5-[bis(2-chloroethyl)amino]-1-methyl-benzimidazol-2-yl]butanoyl]amino]-3-(4-fluorophenyl)propanoic acid (Example compound 39) (2S)-2-[[(2S)-2-amino-4-[5-[bis(2-chloroethyl)amino]-1-phenyl-benzimidazol-2-yl]butanoyl]amino]-4-methyl-pentanoic acid (Example Compound 40) 2S)-2-[[(2S)-2-amino-3-[5-[bis(2-chloroethyl)amino]-1-methyl-benzimidazol-2-yl]propanoyl]amino]-3-methyl-butanoic acid (Example compound 42) (2S)-2-[[(2S)-2-amino-4-methyl-pentanoyl]amino]-3-[5-[bis(2-chloroethyl)amino]-1-methyl-benzimidazol-2-yl]propanoic acid (Example Compound 43) (2S)-2-[[(2S)-2-amino-3-[5-[bis(2-chloroethyl)amino]-1-methyl-benzimidazol-2-yl]propanoyl]amino]-4-methyl-pentanoic acid (Example Compound 44), and (2S)-2-[[(2S)-2-amino-4-[5-[bis(2-chloro-1,1,2,2-tetradeuterio-ethyl)amino]-1-methyl-benzimidazol-2-yl]butanoyl]amino]-4-methyl-pentanoic acid (Example compound 51), or a salt thereof.

[0069] The compounds described herein have been found to be readily further hydrolyzed in cancer cells to form additional, more advanced metabolites that are preferentially sequestered and retained intracellularly and have potent alkylating activity. Accordingly, also described herein are metabolites having the structure described in formula (I), (Ia), or (Ib), wherein: X is C 1-6 is alkylene, W1, W2, W3, and W4 are each CH, or one of W1, W2, W3, and W4 is N and the others are CH; R 1 is optionally substituted with 1, 2, or 3 groups independently selected from H, halogen; 1-4 selected from the group consisting of alkyl, and halogen (e.g., F or Cl); R 2 is H, phenyl optionally substituted with 1, 2, or 3 groups independently selected from halogen (e.g., F or Cl), and —C optionally substituted with 1, 2, or 3 groups independently selected from halogen (e.g., F or Cl). 1-6 is selected from the group consisting of alkyl, R 3 is of formula (VIa), [ka] In the formula, R c and R d are H and -C, respectively. 1-6 Alkyl, -C(O)C 1-6and -CH2-phenyl, wherein the alkyl or the phenyl is optionally substituted with 1, 2, or 3 groups selected from halogen (preferably, R c and R d are both H), R g -H and -C 1-6 alkyl, optionally substituted with 1, 2, or 3 groups selected from halogen (preferably R g is H).

[0070] For the avoidance of doubt, in formula (VI) and (VIa) [ka] indicates the point of attachment of formula (VI) or (VIa) to formula (I), (Ia), or (Ib). In certain embodiments, the metabolite has a structure according to formula (I), (Ia), or (Ib), wherein: X is C 1-6 is alkylene, R 1 -H, -C 1-4 selected from the group consisting of alkyl, and halogen (e.g., F or Cl); R 2 is H, phenyl substituted with 1, 2, or 3 halogens (e.g., F or Cl), and —C substituted with 1, 2, or 3 halogens (e.g., F or Cl). 1-6 alkyl (e.g., phenyl substituted with 1, 2, or 3 halogens (e.g., F or Cl), and —C substituted with 1, 2, or 3 halogens (e.g., F or Cl); 1-6 alkyl), R 3 is of formula (VIa), R c and R d are both H), or a salt thereof.

[0071] In certain other embodiments, the metabolite has a structure according to formula (I), (Ia), or (Ib), wherein: X is a C alkylene (i.e., -CH-) or a C alkylene (i.e., -CH-CH-); R 1 -H, -C 1-4 selected from the group consisting of alkyl, and halogen (e.g., F or Cl); R 2 is H, phenyl optionally substituted with 1, 2, or 3 halogens (e.g., F or Cl), and —C optionally substituted with 1, 2, or 3 halogens (e.g., F or Cl). 1-6 is selected from the group consisting of alkyl, R 3 is of formula (VIa), R c and R d are both H), or a salt thereof.

[0072] Preferably, the compound is of one of formula (Ia) or (Ib).

[0073] Thus, also described herein are compounds having the structure according to formula (I), (Ia), or (Ib), wherein: X is C 2-6 is alkylene, W1, W2, W3, and W4 are each CH, or one of W1, W2, W3, and W4 is N and the others are CH; R 1 is optionally substituted with 1, 2, or 3 groups independently selected from H, halogen; 1-4 selected from the group consisting of alkyl, and halogen (e.g., F or Cl); R 2is H, phenyl optionally substituted with 1, 2, or 3 groups independently selected from halogen (e.g., F or Cl), and —C optionally substituted with 1, 2, or 3 groups independently selected from halogen (e.g., F or Cl). 1-6 is selected from the group consisting of alkyl, R 3 is of formula (VI), [ka] In the formula, R c and R d are H and -C, respectively. 1-6 Alkyl, -C(O)C 1-6 alkyl, and -CH2-phenyl, wherein the alkyl or the phenyl is optionally substituted with 1, 2, or 3 groups selected from halogen (e.g., R c and R d are both H), R g -H and -C 1-6 alkyl, which is optionally substituted with 1, 2, or 3 groups selected from halogen (e.g., R g is H).

[0074] negatively charged cyclodextrin A negatively charged cyclodextrin is a cyclodextrin or cyclodextrin derivative that has one or more negative charges.

[0075] For example, the negatively charged cyclodextrin or derivative thereof has 4 to 10 negative charges. Preferably, the negatively charged cyclodextrin or derivative thereof has 5 to 8 negative charges.

[0076] Preferably, the cyclodextrin or derivative thereof has one or more negative charges at a pH greater than 2, for example, from pH 2 to pH 8 or from pH 3 to pH 5.5.

[0077] Preferably, the negative charge is found on a substituent of the cyclodextrin, such as a carboxylic acid group or a sulfoalkyl group, preferably a sulfoalkyl group, such as a sulfobutyl group.

[0078] The average number of sulfoalkyl groups (e.g., sulfobutyl groups) per cyclodextrin ring, expressed as the average degree of substitution, is 4 to 10. Preferably, the average number of sulfoalkyl groups (e.g., sulfobutyl groups) per cyclodextrin ring, expressed as the average degree of substitution, is 5 to 8.

[0079] The negatively charged cyclodextrin or derivative thereof can be of any size, such as a negatively charged α-cyclodextrin or derivative thereof, a negatively charged β-cyclodextrin or derivative thereof, or a negatively charged γ-cyclodextrin or derivative thereof. Preferably, the negatively charged cyclodextrin or derivative thereof is a negatively charged β-cyclodextrin or derivative thereof.

[0080] Preferred negatively charged cyclodextrins are sulfoalkyl ether β-cyclodextrins, where the number of sulfoalkyl groups per cyclodextrin ring, expressed as the average degree of substitution, is 4 to 10. More preferably, the negatively charged cyclodextrin is sulfobutyl ether β-cyclodextrin, where the average number of sulfobutyl groups per cyclodextrin ring, expressed as the average degree of substitution, is 5 to 8. The structural formula of such sulfobutyl ether β-cyclodextrins is shown below, with exemplary values ​​for the degree of substitution being m: [ka]

[0081] One particularly preferred such negatively charged cyclodextrin is betadex sulfobutylether sodium (also known as "Dexolve" or "Captisol"), which is described in Handbook of Pharmaceutical excipients. 8th edn. London: Pharmaceutical Press (2017) pages 112-117.

[0082] Pharmaceutical preparations Preparations comprising the compound of formula (I) and a negatively charged cyclodextrin as described above have been found to be particularly stable.Accordingly, the present invention provides pharmaceutical preparations comprising a negatively charged cyclodextrin or a pharmaceutically acceptable derivative of a negatively charged cyclodextrin and a compound according to formula (I), or a pharmaceutically acceptable salt, ester, amide, or carbamate thereof, or a salt of such an ester, amide, or carbamate.

[0083] Preferably, the pharmaceutical preparation of the present invention comprises a negatively charged cyclodextrin or a pharmaceutically acceptable derivative of a negatively charged cyclodextrin having 4 to 10 negative charges, more preferably 5 to 8 negative charges.

[0084] Preferably, the pharmaceutical preparation of the present invention comprises a negatively charged cyclodextrin or a pharmaceutically acceptable derivative of a negatively charged cyclodextrin that has one or more negative charges at more than two pHs, for example, from pH 2 to pH 8 or from pH 3 to pH 5.5.

[0085] Preferably, the pharmaceutical preparations of the invention comprise a pharmaceutically acceptable derivative of a negatively charged cyclodextrin, such as a carboxylic acid-derivatized cyclodextrin or a sulfoalkyl ether-derivatized cyclodextrin. More preferably, the pharmaceutical preparations of the invention comprise a sulfoalkyl ether-derivatized cyclodextrin, such as a sulfobutyl ether-derivatized cyclodextrin.

[0086] When the pharmaceutical preparation of the present invention comprises a sulfoalkyl ether-derivatized cyclodextrin (e.g., a sulfobutyl ether-derivatized cyclodextrin), the average number of sulfoalkyl groups (e.g., sulfobutyl groups) per cyclodextrin ring, expressed as the average degree of substitution, is preferably 4 to 10, more preferably 5 to 8.

[0087] Preferably, the pharmaceutical preparations of the present invention comprise negatively charged α-cyclodextrin or a pharmaceutically acceptable derivative of negatively charged α-cyclodextrin, negatively charged β-cyclodextrin or a pharmaceutically acceptable derivative of β-cyclodextrin, or negatively charged γ-cyclodextrin or a pharmaceutically acceptable derivative of γ-cyclodextrin. More preferably, the pharmaceutical preparations of the present invention comprise negatively charged β-cyclodextrin or a pharmaceutically acceptable derivative of β-cyclodextrin.

[0088] Preferably, the pharmaceutical preparation of the present invention comprises a sulfoalkyl ether β-cyclodextrin, wherein the number of sulfoalkyl groups per cyclodextrin ring, expressed as the average degree of substitution, is between 4 and 10.

[0089] More preferably, the pharmaceutical preparation of the present invention comprises a sulfobutyl ether β-cyclodextrin, wherein the average number of sulfobutyl groups per cyclodextrin ring, expressed as the average degree of substitution, is 5-8.

[0090] Again more preferably, the pharmaceutical preparation of the present invention comprises a sulfobutyl ether β-cyclodextrin having the structure shown below (exemplary values ​​for the degree of substitution are m): [ka]

[0091] Most preferably, the pharmaceutical preparation of the present invention comprises betadex sulfobutylether sodium. The pharmaceutical preparation of the present invention comprises a compound according to formula (I), or a pharmaceutically acceptable salt, ester, amide, or carbamate thereof, or a salt of such an ester, amide, or carbamate, [ka] During the ceremony, X is C 1-6 is alkylene, W1, W2, W3, and W4 are each CH, or one of W1, W2, W3, and W4 is N and the others are CH; R 1 is optionally substituted by 1, 2, or 3 groups independently selected from H, halogen 1-4 selected from the group consisting of alkyl, and halogen; R 2 is H, phenyl optionally substituted with 1, 2, or 3 groups independently selected from halogen, and C optionally substituted with 1, 2, or 3 groups independently selected from halogen. 1-6 is selected from the group consisting of alkyl, R 3 is represented by formula (II): [ka] or formula (III): [ka] wherein R 4 is N(R c )(R d ) and formula (IV): [ka] and R 4 is formula (IV), then R 5 is R b and R 4 But N(Rc )(R d ), then R 5 is R b and formula (V): [ka] wherein each R a is H, C 16 alkyl, -CH2-phenyl, or -CH2-3 to 12-membered heterocyclyl (containing 1, 2, 3, or 4 heteroatoms selected from N, O, and S), 1-6 Alkyl is -OH, -OC 1-6 and the phenyl or heterocyclyl is optionally substituted by 1, 2, or 3 substituents independently selected from the group consisting of alkyl, NH, —NHC(═NH)NH, —C(O)OH, —C(O)NH, —SH, —SCH, and halogen; 1-6 optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of alkyl, and —NO2; R b -OH, -N(R e )(R f ), and -OC 1-6 Alkyl (halogen, -OH, -CN, -N(R e )(R f ), -C 6-10 aryl, or a 3-12 membered heterocycle containing one or more O, N, or S atoms and optionally substituted by 1, 2, or 3 halogens, and / or the alkyl is optionally interrupted by 1, 2, or 3 O, N, or S atoms; R c and R d are H and -C, respectively. 16 Alkyl, C(O)C 16alkyl, and -CH2-phenyl, wherein said alkyl or said phenyl is optionally substituted with 1, 2, or 3 groups selected from halogen; R e and R f are H and -C, respectively. 16 alkyl, optionally substituted with 1, 2, or 3 groups selected from halogen, or R e and R f together with the nitrogen atom to which they are attached form a 4-, 5-, or 6-membered heterocycle optionally substituted with 1, 2, or 3 groups selected from halogen.

[0092] Preferably, the pharmaceutical preparation of the present invention comprises a compound of formula (I), or a pharmaceutically acceptable salt, ester, amide, or carbamate thereof, or a salt of such an ester, amide, or carbamate, having the structure (Ia): [ka] For example, structure (Ib): [ka] It has.

[0093] Preferably, the pharmaceutical preparation of the present invention comprises a compound of formula (I), (Ia), or (Ib), or a pharmaceutically acceptable salt, ester, amide, or carbamate thereof, or a salt of such an ester, amide, or carbamate, wherein R 1 is H.

[0094] Preferably, the pharmaceutical preparation of the present invention comprises a compound of formula (I), (Ia), or (Ib), or a pharmaceutically acceptable salt, ester, amide, or carbamate thereof, or a salt of such an ester, amide, or carbamate, wherein R 2is phenyl optionally substituted with 1, 2, or 3 halogens, and —C optionally substituted with 1, 2, or 3 halogens. 1-6 Alkyl, e.g., —C optionally substituted with 1, 2, or 3 halogens 1-4 alkyl, for example, selected from the group consisting of methyl.

[0095] Preferably, the pharmaceutical preparations of the present invention comprise a compound of formula (I), (Ia), or (Ib), or a pharmaceutically acceptable salt, ester, amide, or carbamate thereof, or a salt of such an ester, amide, or carbamate, wherein X is -CH2- or -CH2-CH2-.

[0096] Preferably, the pharmaceutical preparation of the present invention comprises a compound of formula (I), (Ia), or (Ib), or a pharmaceutically acceptable salt, ester, amide, or carbamate thereof, or a salt of such an ester, amide, or carbamate, wherein R 3 is represented by formula (IIa): [ka] or formula (IIIa): [ka] is a group described in

[0097] Preferably, the pharmaceutical preparation of the present invention comprises a compound of formula (I), (Ia), or (Ib), or a pharmaceutically acceptable salt, ester, amide, or carbamate thereof, or a salt of such an ester, amide, or carbamate, wherein R 4 is N(R c )(R d ) and formula (IVa): [ka]

[0098] Preferably, the pharmaceutical preparation of the present invention comprises a compound of formula (I), (Ia), or (Ib), or a pharmaceutically acceptable salt, ester, amide, or carbamate thereof, or a salt of an ester, amide, or carbamate thereof, wherein R 4 is formula (IV) or (IVa), R 5 is R b and R 4 is N(R c )(R d ), then R 5 is R b and Formula (Va), wherein Formula (Va) has the following structure: [ka]

[0099] Preferably, the pharmaceutical preparation of the present invention comprises a compound of formula (I), (Ia), or (Ib), or a pharmaceutically acceptable salt, ester, amide, or carbamate thereof, or a salt of such an ester, amide, or carbamate, wherein R 4 is NH2.

[0100] Preferably, the pharmaceutical preparations of the present invention comprise a compound of formula (I), (Ia), or (Ib), or a pharmaceutically acceptable salt, ester, amide, or carbamate thereof, or a salt of such an ester, amide, or carbamate, wherein each R a is C 16 independently selected from the group consisting of alkyl and CH2-phenyl, 1-6 The alkyl is optionally substituted with OH, NH, -NHC(=NH)NH, -C(O)OH, -C(O)NH, -SH, -SCH, or halogen (e.g., F or Cl), and the phenyl is optionally substituted with halogen (e.g., F or Cl), -NH, -OH, -OC 1-6 Optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of alkyl, and -NO2.

[0101] Preferably, the pharmaceutical preparations of the present invention comprise a compound of formula (I), (Ia), or (Ib), or a pharmaceutically acceptable salt, ester, amide, or carbamate thereof, or a salt of such an ester, amide, or carbamate, wherein each R a -C 16 It is selected from the group consisting of alkyl and CH2-phenyl, wherein the phenyl is optionally substituted with 1, 2 or 3 halogen substituents.

[0102] Preferably, the pharmaceutical preparation of the present invention comprises a compound of formula (I), (Ia) or (Ib), or a pharmaceutically acceptable salt, ester, amide, or carbamate thereof, or a salt of such an ester, amide, or carbamate, wherein R 4 is formula (IV) or (IVa), R 5 Ha-OC 1-6 alkyl, and R 4 is NH2, R 5 -OC 1-6 alkyl, or of formula (V) or (Va).

[0103] Preferably, the pharmaceutical preparation of the present invention comprises a compound of formula (I), (Ia), or (Ib), or a pharmaceutically acceptable salt, ester, amide, or carbamate thereof, or a salt of such an ester, amide, or carbamate, and R b Ga-OC 1-6 When it is alkyl, it is selected from the group consisting of methoxy, ethoxy, and isopropoxy.

[0104] Preferably, the pharmaceutical preparation of the present invention comprises a compound of formula (I) or a pharmaceutically acceptable salt, ester, amide, or carbamate thereof, or a salt of such an ester, amide, or carbamate, selected from the group consisting of: Ethyl (2S)-2-[[(2S)-2-amino-4-[5-[bis(2-chloroethyl)amino]-1-methyl-benzimidazol-2-yl]butanoyl]amino]-4-methyl-pentanoate (Example compound 1), Ethyl (2S)-2-[[(2S)-2-amino-4-[5-[bis(2-chloroethyl)amino]-1-methyl-benzimidazol-2-yl]butanoyl]amino]-3-(4-fluorophenyl)propanoate (Example compound 2), Ethyl (2S)-2-[[(2S)-2-amino-4-[5-[bis(2-chloroethyl)amino]-1-methyl-benzimidazol-2-yl]butanoyl]amino]-3-methyl-butanoate (Example compound 3), Ethyl (2S)-2-[[(2S)-2-amino-3-[5-[bis(2-chloroethyl)amino]-1-methyl-benzimidazol-2-yl]propanoyl]amino]-4-methyl-pentanoate (Example compound 4), Ethyl (2S)-2-[[(2S)-2-amino-3-[5-[bis(2-chloroethyl)amino]-1-methyl-benzimidazol-2-yl]propanoyl]amino]-3-(4-fluorophenyl)propanoate (Example compound 5), Ethyl (2S)-2-[[(2S)-2-amino-3-[5-[bis(2-chloroethyl)amino]-1-methyl-benzimidazol-2-yl]propanoyl]amino]-3-methyl-butanoate (Example compound 6), Ethyl (2S)-2-[[(2S)-2-amino-4-methyl-pentanoyl]amino]-4-[5-[bis(2-chloroethyl)amino]-1-methyl-benzimidazol-2-yl]butanoate (Example compound 7), Ethyl (2S)-2-[[(2S)-2-amino-3-(4-fluorophenyl)propanoyl]amino]-4-[5-[bis(2-chloroethyl)amino]-1-methyl-benzimidazol-2-yl]butanoate (Example compound 8), Ethyl (2S)-2-[[(2S)-2-amino-3-methyl-butanoyl]amino]-4-[5-[bis(2-chloroethyl)amino]-1-methyl-benzimidazol-2-yl]butanoate (Example compound 9), Ethyl (2S)-2-[[(2S)-2-amino-4-methyl-pentanoyl]amino]-3-[5-[bis(2-chloroethyl)amino]-1-methyl-benzimidazol-2-yl]propanoate (Example compound 10), Ethyl (2S)-2-[[(2S)-2-amino-3-(4-fluorophenyl)propanoyl]amino]-3-[5-[bis(2-chloroethyl)amino]-1-methyl-benzimidazol-2-yl]propanoate (Example compound 11), Ethyl (2S)-2-[[(2S)-2-amino-3-methyl-butanoyl]amino]-3-[5-[bis(2-chloroethyl)amino]-1-methyl-benzimidazol-2-yl]propanoate (Example compound 12), Ethyl (2S)-2-[[(2S)-2-amino-4-[5-[bis(2-chloroethyl)amino]-1-phenyl-benzimidazol-2-yl]butanoyl]amino]-4-methyl-pentanoate (Example compound 13), Methyl (2S)-2-[[(2S)-2-amino-3-[5-[bis(2-chloroethyl)amino]-1-methyl-benzimidazol-2-yl]propanoyl]amino]-4-methyl-pentanoate (Example compound 14), Isopropyl (2S)-2-[[(2S)-2-amino-3-[5-[bis(2-chloroethyl)amino]-1-methyl-benzimidazol-2-yl]propanoyl]amino]-4-methyl-pentanoate (Example compound 15), Ethyl (2S)-2-[[(2S)-2-[[(2S)-2-amino-3-(4-fluorophenyl)propanoyl]amino]-4-methyl-pentanoyl]amino]-4-[5-[bis(2-chloroethyl)amino]-1-methyl-benzimidazol-2-yl]butanoate (Example compound 16), Ethyl (2S)-2-[[(2R)-2-[[(2S)-2-amino-3-(4-fluorophenyl)propanoyl]amino]-4-methyl-pentanoyl]amino]-4-[5-[bis(2-chloroethyl)amino]-1-methyl-benzimidazol-2-yl]butanoate (Example compound 21) Ethyl (2S)-2-[[(2S)-2-[[(2S)-2-amino-4-[5-[bis(2-chloroethyl)amino]-1-methyl-benzimidazol-2-yl]butanoyl]amino]-4-methyl-pentanoyl]amino]-3-(4-fluorophenyl)propanoate (Example compound 22) Ethyl (2S)-2-[[(2S)-2-[[(2S)-2-amino-4-[5-[bis(2-chloroethyl)amino]-1-methyl-benzimidazol-2-yl]butanoyl]amino]-4-methyl-pentanoyl]amino]-4-methyl-pentanoate (Example compound 23) 2-Morpholinoethyl (2S)-2-[[(2S)-2-amino-4-[5-[bis(2-chloroethyl)amino]-1-methyl-benzimidazol-2-yl]butanoyl]amino]-4-methyl-pentanoate (Example Compound 24) 2-Isopropoxyethyl (2S)-2-[[(2S)-2-amino-4-[5-[bis(2-chloroethyl)amino]-1-methyl-benzimidazol-2-yl]butanoyl]amino]-4-methyl-pentanoate (Example Compound 25) Isopropyl (2S)-2-[[(2S)-2-amino-4-[5-[bis(2-chloroethyl)amino]-1-methyl-benzimidazol-2-yl]butanoyl]amino]-4-methyl-pentanoate (Example Compound 26) Methyl (2S)-2-[[(2S)-2-amino-4-[5-[bis(2-chloroethyl)amino]-1-methyl-benzimidazol-2-yl]butanoyl]amino]-4-methyl-pentanoate (Example Compound 27) 3-(Dimethylamino)propyl(2S)-2-[[(2S)-2-amino-4-[5-[bis(2-chloroethyl)amino]-1-methyl-benzimidazol-2-yl]butanoyl]amino]-4-methyl-pentanoate (Example Compound 28) (2-Methoxy-1-methyl-ethyl)(2S)-2-[[(2S)-2-amino-4-[5-[bis(2-chloroethyl)amino]-1-methyl-benzimidazol-2-yl]butanoyl]amino]-4-methyl-pentanoate (Example Compound 29) (2S)-2-[[(2S)-2-amino-4-[5-[bis(2-chloroethyl)amino]-1-methyl-benzimidazol-2-yl]butanoyl]amino]-N,N,4-trimethyl-pentanamide (Example Compound 30) (2S)-2-[[(2S)-2-amino-4-[5-[bis(2-chloroethyl)amino]-1-methyl-benzimidazol-2-yl]butanoyl]amino]-N,4-dimethyl-pentanamide (Example Compound 31) Ethyl (2S)-2-[[(2S)-4-[5-[bis(2-chloroethyl)amino]-1-methyl-benzimidazol-2-yl]-2-(methylamino)butanoyl]amino]-4-methyl-pentanoate (Example compound 32) Ethyl (2S)-2-[[(2S)-2-acetamido-4-[5-[bis(2-chloroethyl)amino]-1-methyl-benzimidazol-2-yl]butanoyl]amino]-3-(4-fluorophenyl)propanoate (Example compound 34) Ethyl (2S)-2-[[(2S)-2-acetamido-3-[5-[bis(2-chloroethyl)amino]-1-methyl-benzimidazol-2-yl]propanoyl]amino]-4-methyl-pentanoate (Example Compound 35) Ethyl (2S)-2-[[(2S)-2-acetamido-3-[5-[bis(2-chloroethyl)amino]-1-methyl-benzimidazol-2-yl]propanoyl]amino]-3-(4-fluorophenyl)propanoate (Example compound 36) Ethyl (2S)-2-amino-4-[5-[bis(2-chloroethyl)amino]-1-methyl-benzimidazol-2-yl]butanoate (Example compound 38) Ethyl (2R)-2-[[(2S)-2-amino-4-[5-[bis(2-chloroethyl)amino]-1-methyl-benzimidazol-2-yl]butanoyl]amino]-4-methyl-pentanoate (Example Compound 45) Ethyl (2S)-2-[[(2R)-2-amino-4-[5-[bis(2-chloroethyl)amino]-1-methyl-benzimidazol-2-yl]butanoyl]amino]-4-methyl-pentanoate (Example compound 46) Ethyl (2R)-2-[[(2R)-2-amino-4-[5-[bis(2-chloroethyl)amino]-1-methyl-benzimidazol-2-yl]butanoyl]amino]-4-methyl-pentanoate (Example compound 47) Ethyl (2S)-2-[[(2S)-2-amino-4-[6-[bis(2-chloroethyl)amino]-3-methyl-imidazo[4,5-b]pyridin-2-yl]butanoyl]amino]-4-methyl-pentanoate (Example compound 48), and Ethyl (2S)-2-[[(2S)-2-amino-4-[5-[bis(2-chloro-1,1,2,2-tetradeuterio-ethyl)amino]-1-methyl-benzimidazol-2-yl]butanoyl]amino]-4-methyl-pentanoate (Example Compound 50) or a pharmaceutically acceptable salt, amide, or carbamate thereof (including a salt of such an amide or carbamate).

[0105] Preferably, the pharmaceutical preparation of the present invention comprises a compound of formula (I) or a pharmaceutically acceptable salt, ester, amide, or carbamate thereof, or a salt of such an ester, amide, or carbamate, selected from the group consisting of: (2S)-2-[[(2S)-2-amino-4-[5-[bis(2-chloroethyl)amino]-1-methyl-benzimidazol-2-yl]butanoyl]amino]-3-methyl-butanoic acid (Example compound 19), and (2S)-2-[[(2S)-2-amino-4-[5-[bis(2-chloroethyl)amino]-1-methyl-benzimidazol-2-yl]butanoyl]amino]-4-methyl-pentanoic acid (Example compound 20), (2S)-2-[[(2S)-4-[5-[bis(2-chloroethyl)amino]-1-methyl-benzimidazol-2-yl]-2-(methylamino)butanoyl]amino]-4-methyl-pentanoic acid (Example compound 33) (2S)-2-[[(2S)-2-amino-4-methyl-pentanoyl]amino]-4-[5-[bis(2-chloroethyl)amino]-1-methyl-benzimidazol-2-yl]butanoic acid (Example compound 37) (2S)-2-[[(2S)-2-amino-4-[5-[bis(2-chloroethyl)amino]-1-methyl-benzimidazol-2-yl]butanoyl]amino]-3-(4-fluorophenyl)propanoic acid (Example compound 39) (2S)-2-[[(2S)-2-amino-4-[5-[bis(2-chloroethyl)amino]-1-phenyl-benzimidazol-2-yl]butanoyl]amino]-4-methyl-pentanoic acid (Example Compound 40) 2S)-2-[[(2S)-2-amino-3-[5-[bis(2-chloroethyl)amino]-1-methyl-benzimidazol-2-yl]propanoyl]amino]-3-methyl-butanoic acid (Example compound 42) (2S)-2-[[(2S)-2-amino-4-methyl-pentanoyl]amino]-3-[5-[bis(2-chloroethyl)amino]-1-methyl-benzimidazol-2-yl]propanoic acid (Example Compound 43) (2S)-2-[[(2S)-2-amino-3-[5-[bis(2-chloroethyl)amino]-1-methyl-benzimidazol-2-yl]propanoyl]amino]-4-methyl-pentanoic acid (Example Compound 44), and (2S)-2-[[(2S)-2-amino-4-[5-[bis(2-chloro-1,1,2,2-tetradeuterio-ethyl)amino]-1-methyl-benzimidazol-2-yl]butanoyl]amino]-4-methyl-pentanoic acid (Example Compound 51) or salts thereof.

[0106] Preferably, the pharmaceutical preparation of the present invention comprises a compound of formula (I) or a pharmaceutically acceptable salt, ester, amide, or carbamate thereof, or a salt of such an ester, amide, or carbamate, wherein: X is C 1-6 is alkylene, W1, W2, W3, and W4 are each CH, or one of W1, W2, W3, and W4 is N and the others are CH; R 1 is optionally substituted by 1, 2, or 3 groups independently selected from H, halogen 1-4 selected from the group consisting of alkyl, and halogen; R 2 is H, phenyl optionally substituted with 1, 2, or 3 groups independently selected from halogen, and C optionally substituted with 1, 2, or 3 groups independently selected from halogen. 1-6 is selected from the group consisting of alkyl, R 3 is of formula (VIa), [ka] In the formula, R c and R d are H and C, respectively. 16 Alkyl, C(O)C 16 alkyl, and -CH2-phenyl, wherein said alkyl or said phenyl is optionally substituted with 1, 2, or 3 groups selected from halogen; R g is H and C 16alkyl, optionally substituted with 1, 2, or 3 groups selected from halogen.

[0107] Preferably, the pharmaceutical preparation of the present invention comprises a compound of formula (Ia) or (Ib), or a pharmaceutically acceptable salt, ester, amide, or carbamate thereof, or a salt of such an ester, amide, or carbamate, [ka] In the formula, X is C 1-6 is alkylene, W1, W2, W3, and W4 are each CH, or one of W1, W2, W3, and W4 is N and the others are CH; R 1 is optionally substituted by 1, 2, or 3 groups independently selected from H, halogen 1-4 selected from the group consisting of alkyl, and halogen; R 2 is H, phenyl optionally substituted with 1, 2, or 3 groups independently selected from halogen, and C optionally substituted with 1, 2, or 3 groups independently selected from halogen. 1-6 is selected from the group consisting of alkyl, R 3 is of formula (VIa), [ka] In the formula, R c and R d are H and C, respectively. 16 Alkyl, C(O)C 16 alkyl, and -CH2-phenyl, wherein said alkyl or said phenyl is optionally substituted with 1, 2, or 3 groups selected from halogen; R g is H and C 16alkyl, optionally substituted with 1, 2, or 3 groups selected from halogen.

[0108] Preferably, the pharmaceutical preparation of the present invention comprises a compound of formula (I) or a pharmaceutically acceptable salt, ester, amide, or carbamate thereof, or a salt of such an ester, amide, or carbamate, wherein: X is C 1-6 is alkylene, W1, W2, W3, and W4 are each CH, or one of W1, W2, W3, and W4 is N and the others are CH; R 1 is H, R 2 is H, phenyl optionally substituted with 1, 2, or 3 groups independently selected from halogen, and C optionally substituted with 1, 2, or 3 groups independently selected from halogen. 1-6 is selected from the group consisting of alkyl, R 3 is of formula (VIa), [ka] In the formula, R c and R d are H, R g is H.

[0109] Preferably, the pharmaceutical preparation of the present invention comprises a compound of formula (I), or a pharmaceutically acceptable salt, ester, amide, or carbamate thereof, or a salt of such an ester, amide, or carbamate, wherein X is C 1-6 is alkylene, W1, W2, W3, and W4 are each CH, or one of W1, W2, W3, and W4 is N and the others are CH; R 1 is optionally substituted by 1, 2, or 3 groups independently selected from H, halogen 1-4selected from the group consisting of alkyl, and halogen; R 2 is phenyl optionally substituted with 1, 2, or 3 halogens, and C optionally substituted with 1, 2, or 3 halogens. 1-6 Alkyl (e.g., —C optionally substituted with 1, 2, or 3 halogens) 1-4 alkyl, for example, methyl); R 3 is of formula (VIa), [ka] In the formula, R c and R d are H, R g is H. Preferably, the pharmaceutical preparation of the present invention comprises a compound of formula (I) or a pharmaceutically acceptable salt, ester, amide, or carbamate thereof, or a salt of such an ester, amide, or carbamate, wherein X is —CH— or —CH—CH—; W1, W2, W3, and W4 are each CH, or one of W1, W2, W3, and W4 is N and the others are CH; R 1 is optionally substituted by 1, 2, or 3 groups independently selected from H, halogen 1-4 selected from the group consisting of alkyl, and halogen; R 2 is H, phenyl optionally substituted with 1, 2, or 3 groups independently selected from halogen, and C optionally substituted with 1, 2, or 3 groups independently selected from halogen. 1-6 is selected from the group consisting of alkyl, R 3 is of formula (VIa), [ka] In the formula, R c and Rd are H, R g is H.

[0110] Preferably, the pharmaceutical preparation of the present invention comprises a compound according to formula (I) or a salt or solvate thereof, wherein: X is C 1-6 is alkylene, W1, W2, W3, and W4 are each CH, or one of W1, W2, W3, and W4 is N and the others are CH; R 1 is optionally substituted with 1, 2, or 3 groups independently selected from H, halogen; 1-4 selected from the group consisting of alkyl, and halogen; R 2 is H, phenyl optionally substituted with 1, 2, or 3 groups independently selected from halogen, and —C optionally substituted with 1, 2, or 3 groups independently selected from halogen. 1-6 is selected from the group consisting of alkyl, R 3 is of formula (VI), [ka] In the formula, R c and R d are H and C, respectively. 16 Alkyl, C(O)C 16 alkyl, and -CH2-phenyl, wherein said alkyl or said phenyl is optionally substituted with 1, 2, or 3 groups selected from halogen; R g is H and C 16 alkyl, optionally substituted with 1, 2, or 3 groups selected from halogen.

[0111] Preferably, the pharmaceutical preparation of the present invention comprises a compound of formula (I) or a pharmaceutically acceptable salt, ester, amide, or carbamate thereof, or a salt of such an ester, amide, or carbamate, selected from the group consisting of: (2S)-2-amino-3-[5-[bis(2-chloroethyl)amino]-1-methyl-benzimidazol-2-yl]propanoic acid (Example compound 17), (S)-2-amino-4-(5-(bis(2-chloroethyl)amino)-1-methyl-1H-benzo[d]imidazol-2-yl)butanoic acid (Example compound 18), Ethyl (2S)-2-amino-4-[5-[bis(2-chloroethyl)amino]-1-methyl-benzimidazol-2-yl]butanoate (Example compound 38) (2S)-2-amino-4-[5-[bis(2-chloroethyl)amino]-1-phenyl-benzimidazol-2-yl]butanoic acid (Example Compound 41), and (2S)-2-amino-4-[5-[bis(2-chloro-1,1,2,2-tetradeuterio-ethyl)amino]-1-methyl-benzimidazol-2-yl]butanoic acid (Example compound 49), or salts thereof. Preferably, the pharmaceutical preparation of the present invention comprises ethyl (2S)-2-[[(2S)-2-amino-4-[5-[bis(2-chloroethyl)amino]-1-methyl-benzimidazol-2-yl]butanoyl]amino]-4-methyl-pentanoate (Example compound 1).

[0112] Preferably, the compound of formula (I), or an ester, amide, or carbamate thereof, is present in the pharmaceutical preparation of the present invention as a pharmaceutically acceptable salt, more preferably the compound of formula (I), or an ester, amide, or carbamate thereof, is present as the hydrochloride salt.

[0113] Preferably, the pharmaceutical preparation of the present invention comprises betadex sulfobutylether sodium and ethyl (2S)-2-[[(2S)-2-amino-4-[5-[bis(2-chloroethyl)amino]-1-methyl-benzimidazol-2-yl]butanoyl]amino]-4-methyl-pentanoate (Example compound 1).

[0114] Preferably, the pharmaceutical preparations of the present invention contain a compound of formula (I) or a pharmaceutically acceptable salt, ester, amide, or carbamate thereof, or a salt of such an ester, amide, or carbamate (excluding the mass of any counterion) in an amount of about 1 mg to 150 mg per dose. For example, 1 mg, 2 mg, 3 mg, 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 40 mg, 50 mg, 60 mg, 70 mg, 80 mg, 90 mg, 100 mg, 110 mg, 120 mg, 130 mg, 140 mg, or 150 mg. Alternatively, the compound of the present invention or a salt and / or solvate thereof (excluding the mass of any counterion or solvent) may be administered in a single high dose. The single high dose may be about 150 mg to 800 mg. For example, 150 mg, 200 mg, 300 mg, 400 mg, 500 mg, 600 mg, 700 mg, or 800 mg.

[0115] Preferably, the pharmaceutical preparations of the invention contain a weight ratio (w / w) of negatively charged cyclodextrin or a pharmaceutically acceptable derivative of a negatively charged cyclodextrin to a compound of Formula (I), or a pharmaceutically acceptable salt, ester, amide, or carbamate thereof, or a salt of such ester, amide, or carbamate, of about 1:1 to about 100:1. Typically, the pharmaceutical preparation contains a weight ratio (w / w) of the negatively charged cyclodextrin or a pharmaceutically acceptable derivative of a negatively charged cyclodextrin to a compound of Formula (I), or a pharmaceutically acceptable salt, ester, amide, or carbamate thereof, or a salt of such an ester, amide, or carbamate, of about 4:1 to about 80:1, about 3:1 to about 60:1, about 2:1 to about 50:1, about 4:1 to about 30:1, or about 5:1 to about 20:1.

[0116] Preferably, the pharmaceutical preparations of the invention contain a weight ratio (w / w) of negatively charged cyclodextrin or a pharmaceutically acceptable derivative of a negatively charged cyclodextrin to a compound of Formula (I), or a pharmaceutically acceptable salt, ester, amide, or carbamate thereof, or a salt of such ester, amide, or carbamate, of about 5:1 to about 20:1. In an exemplary embodiment, the pharmaceutical preparation of the invention comprises a negatively charged cyclodextrin or a pharmaceutically acceptable derivative of a negatively charged cyclodextrin in a weight ratio (w / w) of at least about 5:1 of negatively charged cyclodextrin or a pharmaceutically acceptable derivative of a negatively charged cyclodextrin to a compound of Formula (I), or a pharmaceutically acceptable salt, ester, amide, or carbamate thereof, or a salt of such ester, amide, or carbamate. The pharmaceutical preparations of the present invention may contain a weight ratio (w / w) of the negatively charged cyclodextrin or pharmaceutically acceptable derivative of a negatively charged cyclodextrin to a compound of Formula (I), a pharmaceutically acceptable salt, ester, amide, or carbamate thereof, or a salt of such an ester, amide, or carbamate, of about 5:1, about 6:1, about 7:1, about 8:1, about 9:1, about 10:1, about 11:1, about 12:1, about 13:1, about 14:1, about 15:1, about 16:1, about 17:1, about 18:1, about 19:1, about 20:1, about 21:1, about 22:1, about 23:1, about 24:1, or about 25:1 of the negatively charged cyclodextrin or pharmaceutically acceptable derivative of a negatively charged cyclodextrin to a compound of Formula (I), a pharmaceutically acceptable salt, ester, amide, or carbamate thereof, or a salt of such ester, amide, or carbamate.

[0117] Preferably, the pharmaceutical preparations of the invention contain a weight ratio (w / w) of negatively charged cyclodextrin or a pharmaceutically acceptable derivative of a negatively charged cyclodextrin to a compound of formula (I), or a pharmaceutically acceptable salt, ester, amide, or carbamate thereof, or a salt of such an ester, amide, or carbamate, of about 5:1, about 10:1, or about 20:1.

[0118] Preferably, the pharmaceutical preparation of the present invention contains betadex sulfobutylether sodium and ethyl (2S)-2-[[(2S)-2-amino-4-[5-[bis(2-chloroethyl)amino]-1-methyl-benzimidazol-2-yl]butanoyl]amino]-4-methyl-pentanoate (Example Compound 1) in a weight ratio of 5:1 to 20:1.

[0119] Preferably, the pharmaceutical preparation of the present invention contains betadex sulfobutylether sodium and ethyl (2S)-2-[[(2S)-2-amino-4-[5-[bis(2-chloroethyl)amino]-1-methyl-benzimidazol-2-yl]butanoyl]amino]-4-methyl-pentanoate (Example compound 1) in a weight ratio of 10:1.

[0120] In an exemplary embodiment, the pharmaceutical preparation of the invention comprises a negatively charged cyclodextrin or pharmaceutically acceptable derivative thereof in a weight ratio (w / w) of about 5:1 to about 20:1 of the negatively charged cyclodextrin or pharmaceutically acceptable derivative of the negatively charged cyclodextrin to the compound of Formula (I), or a pharmaceutically acceptable salt, ester, amide, or carbamate thereof, or a salt of such an ester, amide, or carbamate, such that the pharmaceutical preparation may contain, for example, 1 mg to 50 mg of the compound of Formula (I), or a pharmaceutically acceptable salt, ester, amide, or carbamate thereof, or a salt of such an ester, amide, or carbamate (excluding the mass of any counterion), and about 5 mg to about 1000 mg of the negatively charged cyclodextrin or pharmaceutically acceptable derivative of the negatively charged cyclodextrin. For example, a pharmaceutical preparation containing 20 mg of a compound of formula (I), or a pharmaceutically acceptable salt, ester, amide, or carbamate thereof, or a salt of such an ester, amide, or carbamate (excluding the mass of any counterion), can contain from about 100 mg to about 400 mg of a negatively charged cyclodextrin or a pharmaceutically acceptable derivative of a negatively charged cyclodextrin (e.g., from about 200 mg to about 300 mg of a negatively charged cyclodextrin or a pharmaceutically acceptable derivative of a negatively charged cyclodextrin).

[0121] Additional excipients may be included in the pharmaceutical preparations of the present invention, for example, to improve the dissolution rate of the compound of formula (I), or a pharmaceutically acceptable salt, ester, amide, or carbamate thereof, or a salt of such an ester, amide, or carbamate, in aqueous solution and / or to improve the stability of the compound of formula (I), or a pharmaceutically acceptable salt, ester, amide, or carbamate thereof, or a salt of such an ester, amide, or carbamate, when in lyophilized form.

[0122] The one or more additional pharmaceutically acceptable excipients may be selected from the group consisting of polysorbate 80, propylene glycol, sucrose, trehalose dihydrate, MgCl, CaCl, citric acid, salts of citric acid (such as trisodium citrate dihydrate), lactic acid and salts of lactic acid, tartaric acid and salts of tartaric acid, phosphoric acid and salts of phosphoric acid, glycine, maleic acid, succinic acid and salts of succinic acid, aspartic acid, benzoic acid and salts of benzoic acid. Preferably, the additional pharmaceutically acceptable excipient is selected from citric acid and salts of citric acid (such as trisodium citrate dihydrate).

[0123] Typically, when a pharmaceutical preparation of the invention includes one or more additional excipients in addition to a negatively charged cyclodextrin or a pharmaceutically acceptable derivative of a negatively charged cyclodextrin, the one or more additional excipients are each independently present in the preparation in a weight ratio (w / w) of excipient to compound of Formula (I), or a pharmaceutically acceptable salt, ester, amide, or carbamate thereof, or a salt of such ester, amide, or carbamate, of about 0.1:1 to about 100:1, e.g., about 1:1 to about 50:1, e.g., about 1:1 to about 30:1, about 1:1 to about 20:1, or about 1:1 to about 10:1, e.g., about 1.0:1 to about 7.5:1, about 1.0:1 to about 5:1, or about 1.0:1 to about 2.0:1.

[0124] In certain embodiments, the pharmaceutical preparation of the present invention is a lyophilized powder. It has been found that a negatively charged cyclodextrin or a pharmaceutically acceptable derivative of a negatively charged cyclodextrin can be included in a lyophilized formulation of the compound of formula (I), or its pharmaceutically acceptable salt, ester, amide, or carbamate, or a salt of such an ester, amide, or carbamate. Reconstitution of the lyophilized powder provides an aqueous solution in which the compound of formula (I), or its pharmaceutically acceptable salt, ester, amide, or carbamate, or a salt of such an ester, amide, or carbamate, is particularly stable.

[0125] The pharmaceutical preparation of the invention, when in the form of a lyophilized powder, can consist essentially of the compound of formula (I), or a pharmaceutically acceptable salt, ester, amide, or carbamate thereof, or a salt of such an ester, amide, or carbamate, and a negatively charged cyclodextrin or a pharmaceutically acceptable derivative of a negatively charged cyclodextrin. Alternatively, the pharmaceutical preparation of the invention, when in the form of a lyophilized powder, can comprise one or more additional excipients in addition to the negatively charged cyclodextrin or a pharmaceutically acceptable derivative of a negatively charged cyclodextrin. The one or more further excipients may be selected from the group consisting of sucrose, polysorbate 80, propylene glycol, trehalose dihydrate, MgCl, CaCl, citric acid or salts of citric acid (such as trisodium citrate dihydrate), lactic acid and salts of lactic acid, tartaric acid and salts of tartaric acid, phosphoric acid and salts of phosphoric acid, glycine, maleic acid, succinic acid and salts of succinic acid, aspartic acid, benzoic acid and salts of benzoic acid. Preferably, the further excipient is selected from citric acid or salts of citric acid (such as trisodium citrate dihydrate).

[0126] Preferably, the pharmaceutical preparation of the present invention comprises betadex sulfobutylether sodium, ethyl (2S)-2-[[(2S)-2-amino-4-[5-[bis(2-chloroethyl)amino]-1-methyl-benzimidazol-2-yl]butanoyl]amino]-4-methyl-pentanoate (Example compound 1), citric acid, and trisodium citrate dihydrate.

[0127] Preferably, the pharmaceutical preparation of the present invention comprises betadex sulfobutylether sodium, ethyl (2S)-2-[[(2S)-2-amino-4-[5-[bis(2-chloroethyl)amino]-1-methyl-benzimidazol-2-yl]butanoyl]amino]-4-methyl-pentanoate (Example Compound 1), citric acid, and trisodium citrate dihydrate, wherein betadex sulfobutylether sodium and ethyl (2S)-2-[[(2S)-2-amino-4-[5-[bis(2-chloroethyl)amino]-1-methyl-benzimidazol-2-yl]butanoyl]amino]-4-methyl-pentanoate (Example Compound 1) are present in a weight ratio of 5:1 to 20:1. The additional excipients, citric acid and salts of citric acid (such as trisodium citrate dihydrate), are present, for example, in a weight ratio to the compound of Formula (I), or a pharmaceutically acceptable salt, ester, amide, or carbamate thereof, or a salt of such an ester, amide, or carbamate (e.g., Example Compound 1), of about 0.1:1 to about 100:1. For example, the ratio can be about 1:1 to about 50:1, e.g., about 1:1 to about 30:1, about 1:1 to about 20:1, or about 1:1 to about 10:1, e.g., about 1.0:1 to about 7.5:1, about 1.0:1 to about 5:1, or about 1.0:1 to about 2.0:1.

[0128] Preferably, the pharmaceutical preparation of the present invention comprises betadex sulfobutylether sodium, ethyl (2S)-2-[[(2S)-2-amino-4-[5-[bis(2-chloroethyl)amino]-1-methyl-benzimidazol-2-yl]butanoyl]amino]-4-methyl-pentanoate (Example Compound 1), citric acid, and trisodium citrate dihydrate, wherein betadex sulfobutylether sodium and ethyl (2S)-2-[[(2S)-2-amino-4-[5-[bis(2-chloroethyl)amino]-1-methyl-benzimidazol-2-yl]butanoyl]amino]-4-methyl-pentanoate (Example Compound 1) are present in a weight ratio of 10:1. The additional excipients, citric acid and salts of citric acid (such as trisodium citrate dihydrate), are present, for example, in a weight ratio to the compound of Formula (I), or a pharmaceutically acceptable salt, ester, amide, or carbamate thereof, or a salt of such an ester, amide, or carbamate (e.g., Example Compound 1), of about 0.1:1 to about 100:1. For example, the ratio can be about 1:1 to about 50:1, e.g., about 1:1 to about 30:1, about 1:1 to about 20:1, or about 1:1 to about 10:1, e.g., about 1.0:1 to about 7.5:1, about 1.0:1 to about 5:1, or about 1.0:1 to about 2.0:1.

[0129] Preferably, in embodiments, the pharmaceutical preparation is a lyophilized powder, and the pharmaceutical preparation is free or substantially free of any organic solvent. By "free" of any organic solvent, it is meant that the lyophilized powder pharmaceutical preparation does not contain any measurable amount of organic solvent. By "substantially free" of any organic solvent, it is meant that the lyophilized powder pharmaceutical preparation contains only trace amounts of organic solvent, e.g., less than about 0.1% total organic solvents.

[0130] In certain embodiments, the pharmaceutical preparation of the present invention is a liquid pharmaceutical formulation, i.e., the formulation is in liquid form when stored at room temperature.

[0131] The present invention also provides a composition comprising the pharmaceutical preparation of the present invention and a physiologically acceptable aqueous solvent or diluent. Preferably, the composition of the present invention comprises a compound of formula (I) as defined herein, or a pharmaceutically acceptable salt, ester, amide, or carbamate thereof, or a salt of such an ester, amide, or carbamate, a negatively charged cyclodextrin, or a pharmaceutically acceptable derivative of a negatively charged cyclodextrin, and a physiologically acceptable aqueous solvent.

[0132] Preferably, the physiologically acceptable aqueous solvent for use in the compositions of the present invention is a glucose solution, a saline solution, or a mixture thereof.

[0133] The compositions of the present invention may be suitable for parenteral administration to a subject. Injection and infusion solutions can be prepared by diluting the lyophilized powder or liquid pharmaceutical formulation of the present invention with one or more physiologically acceptable solvents or diluents. Exemplary solvents or diluents include mannitol, glucose, 1,3-butanediol, water, Ringer's solution, isotonic sodium chloride solution, or other suitable dispersing or wetting agents and suspending agents, including synthetic mono- or diglycerides, and fatty acids, including oleic acid, or Cremaphor.

[0134] In certain embodiments, the pharmaceutical preparations of the present invention are administered to a subject, for example, after dilution with a physiologically acceptable aqueous solvent or diluent, such as saline solution, glucose solution, or a mixture thereof. Any such solvent or diluent may optionally be buffered.

[0135] Preferably, the physiologically acceptable solvent is an aqueous solution such as a glucose solution (e.g., a 5% glucose solution (w / v) in water), a saline solution (e.g., a 0.9% sodium chloride solution (w / v) in water), or a mixture thereof.

[0136] The pharmaceutical preparations of the invention may be diluted with a physiologically acceptable solvent prior to administration to a subject to a concentration of, for example, about 0.001 mg / mL to about 3 mg / mL (e.g., 0.01 mg / mL to 2 mg / mL, 0.05 mg / mL to 1.4 mg / mL, 0.05 mg / mL to 1.2 mg / mL, 0.05 mg / mL to 1 mg / mL, 0.05 mg / mL to 0.9 mg / mL, 0.05 mg / mL to 0.8 mg / mL, 0.1 mg / mL to 0.4 mg / mL, or 0.1 mg / mL to 0.3 mg / mL) of the compound of Formula (I), or a pharmaceutically acceptable salt, ester, amide, or carbamate thereof, or a salt of such an ester, amide, or carbamate (excluding the mass of any counterion).

[0137] Compositions of the present invention suitable for parenteral administration are preferably suitable for administration by infusion or injection, and are particularly suitable for administration by intravenous infusion.

[0138] In certain embodiments, injection and infusion solutions of the compound of formula (I), or a pharmaceutically acceptable salt, ester, amide, or carbamate thereof, or a salt of such an ester, amide, or carbamate, may be prepared by diluting a lyophilized powder of the compound of formula (I), or a pharmaceutically acceptable salt, ester, amide, or carbamate thereof, or a salt of such an ester, amide, or carbamate, that does not contain a negatively charged cyclodextrin or a pharmaceutically acceptable derivative of a negatively charged cyclodextrin, with one or more physiologically acceptable solvents or diluents that contain a negatively charged cyclodextrin or a pharmaceutically acceptable derivative of a negatively charged cyclodextrin. For example, the compound of formula (I), or a pharmaceutically acceptable salt, ester, amide, or carbamate thereof, or a salt of such an ester, amide, or carbamate, may be a lyophilized powder comprising (or consisting essentially of) the compound of formula (I), or a pharmaceutically acceptable salt, ester, amide, or carbamate thereof, or such an ester, amide, or carbamate.

[0139] In embodiments in which the one or more physiologically acceptable solvents or diluents contain a negatively charged cyclodextrin or a pharmaceutically acceptable derivative of a negatively charged cyclodextrin, the negatively charged cyclodextrin or a pharmaceutically acceptable derivative of a negatively charged cyclodextrin may be present at a concentration of about 0.1 mg / mL to 10 mg / mL. For example, the negatively charged cyclodextrin or pharmaceutically acceptable derivative of a negatively charged cyclodextrin is present in a concentration of about 0.1 mg / mL to 3 mg / mL, e.g., about 0.1 mg / mL, 0.2 mg / mL, 0.3 mg / mL, 0.4 mg / mL, 0.5 mg / mL, 0.6 mg / mL, 0.7 mg / mL, 0.8 mg / mL, 0.9 mg / mL, 1 mg / mL, 1.5 mg / mL, 2 mg / mL, 2.5 mg / mL, 3 mg / mL, 4 mg / mL, or 5 mg / mL.

[0140] Alternatively or additionally, the negatively charged cyclodextrin or a pharmaceutically acceptable derivative of a negatively charged cyclodextrin may be added directly to the injection or infusion solution after reconstitution and / or dilution of the compound of formula (I), or a pharmaceutically acceptable salt, ester, amide, or carbamate thereof, or a salt of such an ester, amide, or carbamate, with a suitable physiologically acceptable solvent or diluent, or the compound of formula (I), or a pharmaceutically acceptable salt, ester, amide, or carbamate thereof, or a salt of such an ester, amide, or carbamate, may be added directly to the injection or infusion solution after reconstitution and / or dilution of the negatively charged cyclodextrin or a pharmaceutically acceptable derivative of a negatively charged cyclodextrin with a suitable physiologically acceptable solvent or diluent. Thus, the present invention also provides an injection or infusion solution comprising a compound of formula (I) or a pharmaceutically acceptable salt, ester, amide, or carbamate thereof, or a salt of such an ester, amide, or carbamate, a negatively charged cyclodextrin or a pharmaceutically acceptable derivative of a negatively charged cyclodextrin, one or more physiologically acceptable solvents or diluents, and optionally one or more further excipients.

[0141] The negatively charged cyclodextrin or a pharmaceutically acceptable derivative of a negatively charged cyclodextrin is added directly to the injection or infusion solution after reconstitution and / or dilution of the compound of formula (I), or a pharmaceutically acceptable salt, ester, amide, or carbamate thereof, or a salt of such ester, amide, or carbamate, with a suitable physiologically acceptable solvent or diluent, or the compound of formula (I), or a pharmaceutically acceptable salt, ester, amide, or carbamate thereof, or a salt of such ester, amide, or carbamate, is added directly to the injection or infusion solution after reconstitution and / or dilution with a suitable physiologically acceptable solvent or diluent. In embodiments where the pharmaceutically acceptable derivative of phosphorus or negatively charged cyclodextrin is reconstituted and / or diluted with a suitable physiologically acceptable solvent or diluent before being added directly to the injection or infusion solution, the compound of formula (I), or a pharmaceutically acceptable salt, ester, amide, or carbamate thereof, or a salt of such an ester, amide, or carbamate, may be in the form of a pharmaceutical preparation, for example, a lyophilized powder comprising the compound of formula (I), or a pharmaceutically acceptable salt, ester, amide, or carbamate thereof, or a salt of such an ester, amide, or carbamate.

[0142] In embodiments providing an injection or infusion solution comprising a compound of formula (I), or a pharmaceutically acceptable salt, ester, amide, or carbamate thereof, or such ester, amide, or carbamate, a negatively charged cyclodextrin or a pharmaceutically acceptable derivative of a negatively charged cyclodextrin, one or more physiologically acceptable solvents or diluents, and optionally one or more additional excipients, the injection or infusion solution preferably comprises a ratio of the negatively charged cyclodextrin or the pharmaceutically acceptable derivative of a negatively charged cyclodextrin to the negatively charged cyclodextrin or the pharmaceutically acceptable derivative of a negatively charged cyclodextrin in a ratio of about 1:1 to about 100:1. For example, the negatively charged cyclodextrin or pharmaceutically acceptable derivative of a negatively charged cyclodextrin may be in a weight ratio (w / w) of from about 4:1 to about 80:1, or from about 2:1 to about 50:1 of a negatively charged cyclodextrin or a pharmaceutically acceptable derivative of a negatively charged cyclodextrin to a compound of formula (I) or a pharmaceutically acceptable salt, ester, amide, or carbamate thereof, or a salt of such an ester, amide, or carbamate. In one embodiment, the injection or infusion solution comprises a weight ratio (w / w) of negatively charged cyclodextrin or a pharmaceutically acceptable derivative of a negatively charged cyclodextrin to a compound of Formula (I), or a pharmaceutically acceptable salt, ester, amide, or carbamate thereof, or a salt of such ester, amide, or carbamate, of about 4:1 to about 80:1, or about 5:1 to about 20:1.For example, the injection or infusion solution comprises a weight ratio (w / w) of the negatively charged cyclodextrin or a pharmaceutically acceptable derivative of a negatively charged cyclodextrin to the compound of Formula (I), its pharmaceutically acceptable salt, ester, amide, or carbamate, or a salt of such ester, amide, or carbamate, of about 5:1, about 10:1, about 11:1, about 12:1, about 13:1, about 14:1, about 15:1, about 16:1, about 17:1, about 18:1, about 19:1, about 20:1, about 21:1, about 22:1, about 23:1, about 24:1, or about 25:1 of the negatively charged cyclodextrin or a pharmaceutically acceptable derivative of a negatively charged cyclodextrin to the compound of Formula (I), its pharmaceutically acceptable salt, ester, amide, or carbamate, or a salt of such ester, amide, or carbamate. In one preferred embodiment, the weight ratio (w / w) of the negatively charged cyclodextrin or a pharmaceutically acceptable derivative of a negatively charged cyclodextrin to the compound of formula (I), or a pharmaceutically acceptable salt, ester, amide, or carbamate thereof, or a salt of such an ester, amide, or carbamate, is about 5:1, about 10:1, or about 20:1.

[0143] Additional therapeutic agents While the compound of formula () or a salt thereof may be present as the sole active ingredient in the pharmaceutical preparation of the present invention, it is also possible for the pharmaceutical preparation to further contain one or more additional therapeutic agents. Such agents are known in the art. Examples of additional therapeutic agents for use in the present invention include steroids (prednisone, prednisolone, and dexamethasone), IMiDs (thalidomide, lenalidomide, and pomalidomide), PIs (bortezomib, carfilzomib, and ixazomib), histone deacetylase (HDAC) inhibitors (panobinostat), conventional chemotherapy (alkylating agents (e.g., melflufen, melphalan, cyclophosphamide, bendamustine), doxorubicin), checkpoint inhibitors, nuclear transport inhibitors (selinexor), anti-apoptotic inhibitors, adoptive cell therapy, bispecific T cell engagers (BiTEs), B cell targeting agents, and monoclonal antibodies.

[0144] Thus, in certain embodiments, the pharmaceutical preparations of the present invention comprise a compound of formula (I) or a pharmaceutically acceptable salt, ester, amide, or carbamate thereof, or a salt of such an ester, amide, or carbamate, a negatively charged cyclodextrin, or a pharmaceutically acceptable derivative of a negatively charged cyclodextrin, and a steroid (prednisone, prednisolone, and dexamethasone), an IMiD (thalidomide, lenalidomide, and pomalidomide), a PI (bortezomib, cambogia, cyclodextrin), or a steroid (prednisone, prednisolone, and dexamethasone), an IMiD (thalidomide, lenalidomide, and pomalidomide), a PI (bortezomib, cambogia, cyclodextrin), or a steroid (prednisone, prednisolone, and dexamethasone), an IMiD (thalidomide, lenalidomide, and pomalidomide), a PI (bortezomib, cambogia, cyclodextrin), or a steroid (prednisone, prednisolone, and dexamethasone), or ...steroid (prednisone, prednisolone, and dexamethasone), or a steroid (prednisone, prednisolone, and dex and ixazomib), histone deacetylase (HDAC) inhibitors (panobinostat), conventional chemotherapy (alkylating agents (e.g., melflufen, melfarfan, cyclophosphamide, bendamustine), doxorubicin), checkpoint inhibitors, nuclear transport inhibitors (selinexor), anti-apoptotic inhibitors, adoptive cell therapy, bispecific T cell engagers (BiTEs), B cell targeting agents, and monoclonal antibodies.

[0145] Preferably, the pharmaceutical preparations of the present invention comprise a compound of formula (I), or a pharmaceutically acceptable salt, ester, amide, or carbamate thereof, or a salt of such an ester, amide, or carbamate, a negatively charged cyclodextrin, or a pharmaceutically acceptable derivative of a negatively charged cyclodextrin, and one or more additional therapeutic agents selected from the group consisting of a proteasome inhibitor (PI), an immunomodulatory drug (IMiD), a B-cell targeting agent, a steroid, a histone deacetylase (HDAC) inhibitor, and a monoclonal antibody.

[0146] More preferably, the pharmaceutical preparations of the present invention comprise a compound of formula (I), or a pharmaceutically acceptable salt, ester, amide, or carbamate thereof, or a salt of such an ester, amide, or carbamate, a negatively charged cyclodextrin, or a pharmaceutically acceptable derivative of a negatively charged cyclodextrin, and one or more additional therapeutic agents selected from the group consisting of a proteasome inhibitor (PI), a steroid, and a monoclonal antibody.

[0147] For example, a pharmaceutical preparation of the invention can consist essentially of a compound of formula (I), or a pharmaceutically acceptable salt, ester, amide, or carbamate thereof, or a salt of such an ester, amide, or carbamate, a negatively charged cyclodextrin, or a pharmaceutically acceptable derivative of a negatively charged cyclodextrin, and one or more additional therapeutic agents. Alternatively, for example, a pharmaceutical preparation of the invention can consist essentially of a compound of formula (I), or a pharmaceutically acceptable salt, ester, amide, or carbamate thereof, or a salt of such an ester, amide, or carbamate, a negatively charged cyclodextrin, or a pharmaceutically acceptable derivative of a negatively charged cyclodextrin, one or more further excipients, and one or more additional therapeutic agents.

[0148] The exact amounts and concentrations of additional therapeutic agents that may be present in the pharmaceutical formulations of the invention may vary depending on the administration schedule, the potency of the particular agent selected, the age, size, sex, and condition of the subject (typically a mammal, e.g., a human), the nature and severity of the disease or condition, and other relevant medical and physical factors. One of ordinary skill in the art can readily determine the amounts and concentrations of a compound of formula (I), or a pharmaceutically acceptable salt, ester, amide, or carbamate thereof, or a salt of such an ester, amide, or carbamate, and optionally one or more additional therapeutic agents, that are suitable for use in accordance with the present invention.

[0149] treatment The pharmaceutical preparations, compositions and kits of the present invention find use as medicines.

[0150] In certain embodiments, the pharmaceutical preparations, compositions, and kits of the present invention find use in the treatment and / or prevention of diseases or conditions that can be treated with conventional chemotherapeutic agents, such as alkylating agents (e.g., melphalan, cyclophosphamide, and bendamustine).

[0151] In certain embodiments, the pharmaceutical preparations and compositions of the present invention find use in the treatment and / or prevention of cancer, the reduction of tumor growth, the killing of tumor cells, and / or the treatment and / or prevention of amyloidosis. For example, the pharmaceutical preparations and compositions of the present invention find use in the treatment and / or prevention of cancer, the reduction of tumor growth, and / or the killing of tumor cells. Thus, the pharmaceutical preparations and compositions of the present invention can be used to cure and / or prolong the survival of patients suffering from cancer diseases.

[0152] In embodiments, the pharmaceutical preparations, compositions, and kits of the invention find use in the treatment and / or prevention of cancer. Specific examples of cancers that can be treated or prevented by administering a compound or composition of the invention include carcinoma, sarcoma, myeloma, leukemia, lymphoma, or mixed-type cancer. Exemplary cancers that can be treated or prevented by administering a compound or composition of the invention include leukemia (e.g., acute lymphoblastic leukemia, including adult and childhood acute lymphoblastic leukemia; acute myeloid leukemia, including adult and childhood acute myeloid leukemia; chronic lymphocytic leukemia, such as B-cell chronic lymphocytic leukemia; chronic myeloid leukemia; and hairy cell leukemia), lymphoma (e.g., AIDS-related lymphoma, cutaneous T-cell lymphoma, Hodgkin's lymphoma, including adult and childhood Hodgkin's lymphoma and Hodgkin's lymphoma during pregnancy, adult and childhood non-Hodgkin's lymphoma, and cancers during pregnancy). non-Hodgkin's lymphoma, including non-Hodgkin's lymphoma, mycosis fungoides, Sézary syndrome, Waldenstrom's macroglobulinemia, primary mediastinal large B-cell lymphoma, mantle cell lymphoma, diffuse large B-cell lymphoma, and primary central nervous system lymphoma), and blood / blood cell cancers such as other hematological cancers (e.g., chronic myeloproliferative disorders, multiple myeloma / plasma cell neoplasms, myelodysplastic syndromes, and myelodysplastic / myeloproliferative disorders), osteosarcoma, ovarian cancer, breast cancer, lung cancer, glioblastoma, retinoblastoma, and metastases of the foregoing cancers.

[0153] The pharmaceutical preparations, compositions, and kits of the present invention are particularly cytotoxic to hematological cancer cells, and are therefore particularly useful for treating or preventing one or more of the aforementioned hematological cancers.

[0154] In embodiments, the pharmaceutical preparations, compositions, and kits of the present invention are used to treat cancer (e.g., leukemia (e.g., acute lymphoblastic leukemia, including adult and childhood acute lymphoblastic leukemia; acute myeloid leukemia, including adult and childhood acute myeloid leukemia; chronic lymphocytic leukemia, such as B-cell chronic lymphocytic leukemia; chronic myeloid leukemia; and hairy cell leukemia), lymphoma (e.g., AIDS-related lymphoma, cutaneous T-cell lymphoma, Hodgkin's lymphoma, including adult and childhood Hodgkin's lymphoma and Hodgkin's lymphoma in pregnancy; non-Hodgkin's lymphoma, including adult and childhood non-Hodgkin's lymphoma and non-Hodgkin's lymphoma in pregnancy; mycosis fungoides; Sézary syndrome; Waldenstrom's macroglobulinemia; primary mediastinal large B-cell lymphoma; mantle cell lymphoma), When used in the treatment or prevention of hematological cancers (e.g., selected from blood / blood cell cancers such as chronic myeloproliferative disorders, multiple myeloma / plasma cell neoplasms, myelodysplastic syndromes, and myelodysplastic / myeloproliferative disorders), osteosarcoma, ovarian cancer, breast cancer, lung cancer, glioblastoma, retinoblastoma, and metastases of the foregoing cancers), the preparation or composition is administered (e.g., simultaneously, sequentially, or separately) with one or more additional therapeutic agents, such as steroids, IMiDs, PIs, HDAC inhibitors, conventional chemotherapy, checkpoint inhibitors, nuclear transport inhibitors, anti-apoptosis inhibitors, adoptive cell therapy, BiTEs, B-cell targeting agents, and monoclonal antibodies.

[0155] The amount of a compound of formula (I), or a pharmaceutically acceptable salt, ester, amide, or carbamate thereof, or a salt of such an ester, amide, or carbamate, required to achieve a therapeutic effect will vary depending on the particular route of administration and the characteristics of the subject being treated, such as the species, age, weight, sex, medical condition, the particular disease, and its severity, and other relevant medical and physical factors. An ordinarily skilled physician can readily determine and administer the effective amount of a compound of formula (I), or a pharmaceutically acceptable salt, ester, amide, or carbamate thereof, or a salt of such an ester, amide, or carbamate, required to treat or prevent cancer.

[0156] The pharmaceutical preparations and compositions of the invention find utility in methods for treating a subject, comprising administering to the subject a pharmaceutically effective amount of the pharmaceutical preparation or composition of the invention. Typically, the pharmaceutical preparations of the invention are administered after dilution in a physiologically acceptable solvent or diluent (e.g., saline solution or glucose solution).

[0157] Unit Dose The pharmaceutical preparations of the invention may be presented as unit doses, with preferred unit doses being those containing the required amount of a compound of formula (I) suitable for use according to the invention or a pharmaceutically acceptable salt, ester, amide, or carbamate thereof, or a salt of such an ester, amide, or carbamate.

[0158] In a preferred embodiment, the pharmaceutical preparations of the present invention may be provided in vials containing a unit dose of a compound of formula (I) or a pharmaceutically acceptable salt, ester, amide, or carbamate thereof, or a salt of such an ester, amide, or carbamate. For example, the pharmaceutical preparations of the present invention may be provided in vials containing a unit dose of 1 to 800 mg of a compound of formula (I) or a pharmaceutically acceptable salt, ester, amide, or carbamate thereof, or a salt of such an ester, amide, or carbamate (excluding the mass of any counterion), for example, vials containing 1 mg, 2 mg, 3 mg, 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 40 mg, 50 mg, 60 mg, 70 mg, 80 mg, 90 mg, 100 mg, 110 mg, 120 mg, 130 mg, 140 mg, 150 mg, 160 mg, 170 mg, 180 mg, 190 mg, 210 mg, 220 mg, 230 mg, 240 mg, 250 mg, 260 mg, 270 mg, 280 mg, 290 mg, 300 mg, 310 mg, 320 mg, 330 mg, 340 mg, 350 mg, 360 mg, 370 mg, 380 mg, 390 mg, 400 mg, 410 mg, 420 mg, 430 mg, 440 mg, 450 mg, 460 mg, 470 mg, 480 mg, 490 mg, 500 mg, 510 mg, 520 mg, 530 mg, 540 mg, 550 mg, 560 mg, 570 mg, 580 mg, 5 The unit dose may contain 100 mg, 80 mg, 90 mg, 100 mg, 110 mg, 120 mg, 130 mg, 140 mg, 150 mg, 200 mg, 300 mg, 400 mg, 500 mg, 600 mg, 700 mg, or 800 mg of a compound of formula (I), or a pharmaceutically acceptable salt, ester, amide, or carbamate thereof, or a salt of such ester, amide, or carbamate (excluding the mass of any counterion).

[0159] kit The present invention provides a kit suitable for preparing a pharmaceutical preparation according to the present invention. The kit of the present invention comprises a compound of formula (I) or a pharmaceutically acceptable salt, ester, amide, or carbamate thereof, or a salt of such an ester, amide, or carbamate, and a negatively charged cyclodextrin or a pharmaceutically acceptable derivative of a negatively charged cyclodextrin. The compound of formula (I) or a pharmaceutically acceptable salt, ester, amide, or carbamate thereof, or a salt of such an ester, amide, or carbamate, and the negatively charged cyclodextrin or a pharmaceutically acceptable derivative of a negatively charged cyclodextrin in the kit can be provided together as a mixture, or they can be provided separately, for example, in separate vials that are subsequently combined prior to use of the kit (e.g., combined to prepare a pharmaceutical preparation or composition of the present invention prior to use in a method or use of the present invention as defined herein).

[0160] In certain embodiments, the kits of the present invention further comprise one or more physiologically acceptable aqueous solvents or diluents, such as a glucose solution or a physiological saline solution. Typically, the physiologically acceptable aqueous solvent or diluent is provided separately from the compound of formula (I), or a pharmaceutically acceptable salt, ester, amide, or carbamate thereof, or a salt of such an ester, amide, or carbamate, and the negatively charged cyclodextrin or a pharmaceutically acceptable derivative of the negatively charged cyclodextrin in the kit, or the physiologically acceptable aqueous solvent or diluent is provided together as a mixture with the negatively charged cyclodextrin or a pharmaceutically acceptable derivative of the negatively charged cyclodextrin in the kit, and the compound of formula (I), or a pharmaceutically acceptable salt, ester, amide, or carbamate thereof, The compound of formula (I), or a pharmaceutically acceptable salt, ester, amide, or carbamate thereof, or a salt of such an ester, amide, or carbamate, may be provided separately, for example, in a separate vial that is subsequently combined with a composition comprising a negatively charged cyclodextrin or a pharmaceutically acceptable derivative of a negatively charged cyclodextrin, and a physiologically acceptable aqueous solvent or diluent, prior to use of the kit (e.g., combined to prepare a composition of the invention prior to use in a method or use of the invention as defined herein).

[0161] In one embodiment of the present invention, the kit of the present invention further comprises one or more additional therapeutic agents described herein. The one or more additional therapeutic agents in the kit may be provided together as a mixture with one or both of the compound of Formula (I), or a pharmaceutically acceptable salt, ester, amide, or carbamate thereof, or a salt of such an ester, amide, or carbamate, and the negatively charged cyclodextrin or a pharmaceutically acceptable derivative of the negatively charged cyclodextrin, or may be provided separately.

[0162] Preferably, the kit of the present invention comprises a compound of formula (I) as described herein, or a pharmaceutically acceptable salt, ester, amide, or carbamate thereof, or a salt of such an ester, amide, or carbamate, as a lyophilized preparation comprising (or consisting essentially of) a compound of formula (I) as described herein, or a pharmaceutically acceptable salt, ester, amide, or carbamate thereof, or a salt of such an ester, amide, or carbamate, and sucrose.

[0163] For the avoidance of doubt, the compound of formula (I), or a pharmaceutically acceptable salt, ester, amide, or carbamate thereof, or a salt of such an ester, amide, or carbamate, the negatively charged cyclodextrin or a pharmaceutically acceptable derivative of a negatively charged cyclodextrin, the optional physiologically acceptable aqueous solvent or diluent, the optional one or more pharmaceutically acceptable organic solvents, and the optional one or more further therapeutic agents are present in the kit according to the invention in forms and amounts suitable for the preparation of a pharmaceutical preparation according to the invention. Those skilled in the art can readily determine the amounts of the compound of formula (I), or a pharmaceutically acceptable salt, ester, amide, or carbamate thereof, or such an ester, amide, or carbamate, the pharmaceutically acceptable organic solvent, and the optional one or more further therapeutic agents suitable for use according to the invention.

[0164] The present invention also provides kits suitable for preparing injection and infusion solutions containing a compound of formula (I) or a pharmaceutically acceptable salt, ester, amide, or carbamate thereof, or a salt of such an ester, amide, or carbamate, and a negatively charged cyclodextrin or a pharmaceutically acceptable derivative of a negatively charged cyclodextrin. Such kits include a compound of formula (I) or a pharmaceutically acceptable salt, ester, amide, or carbamate thereof, or a salt of such an ester, amide, or carbamate, a negatively charged cyclodextrin, or a pharmaceutically acceptable derivative of a negatively charged cyclodextrin, and one or more physiologically acceptable aqueous solvents or diluents, such as a glucose solution or a physiological saline solution. The compound of formula (I), or a pharmaceutically acceptable salt, ester, amide, or carbamate thereof, or a salt of such an ester, amide, or carbamate, the negatively charged cyclodextrin, or a pharmaceutically acceptable derivative of a negatively charged cyclodextrin, and one or more physiologically acceptable aqueous solvents or diluents may be provided as a mixture or separately. For example, the compound of formula (I), or a pharmaceutically acceptable salt, ester, amide, or carbamate thereof, or a salt of such an ester, amide, or carbamate, and the negatively charged cyclodextrin, or a pharmaceutically acceptable derivative of a negatively charged cyclodextrin, may be provided together as a mixture, and one or more physiologically acceptable aqueous solvents or diluents may be provided separately. Alternatively, the negatively charged cyclodextrin or pharmaceutically acceptable derivative of a negatively charged cyclodextrin and one or more physiologically acceptable aqueous solvents or diluents can be provided as a mixture (i.e., provided as a composition comprising the negatively charged cyclodextrin or pharmaceutically acceptable derivative of a negatively charged cyclodextrin and one or more physiologically acceptable aqueous solvents or diluents), and the compound of formula (I), or a pharmaceutically acceptable salt, ester, amide, or carbamate thereof, or a salt of such an ester, amide, or carbamate, can be provided separately.

[0165] Preferably, the pharmaceutically acceptable aqueous solvent is a 5% glucose solution (w / v in water) or a 0.9% sodium chloride solution (w / v in water). Preferably, such a solution is suitable for intravenous injection and / or infusion into a subject.

[0166] In such kits, preferably, the compound of formula (I), or a pharmaceutically acceptable salt, ester, amide, or carbamate thereof, or a salt of such an ester, amide, or carbamate, and the negatively charged cyclodextrin or a pharmaceutically acceptable derivative of the negatively charged cyclodextrin are provided as a pharmaceutical preparation of the invention, e.g., a lyophilized powder of the invention, or a liquid pharmaceutical formulation of the invention. Thus, the invention provides kits suitable for preparing injection and infusion solutions, as described herein, comprising the pharmaceutical preparation of the invention (e.g., the lyophilized powder of the invention) and one or more physiologically acceptable aqueous solvents or diluents, such as glucose solution or saline solution.

[0167] Alternatively, the present invention provides kits suitable for preparing injection and infusion solutions, comprising a pharmaceutical preparation comprising a compound of Formula (I) or a pharmaceutically acceptable salt, ester, amide, or carbamate thereof, or a salt of such an ester, amide, or carbamate, as described herein (e.g., a lyophilized pharmaceutical preparation comprising a compound of Formula (I) or a pharmaceutically acceptable salt, ester, amide, or carbamate thereof, or a salt of such an ester, amide, or carbamate, and optionally sucrose), a composition comprising a negatively charged cyclodextrin or a pharmaceutically acceptable derivative of a negatively charged cyclodextrin, and one or more physiologically acceptable aqueous solvents or diluents, such as a glucose solution or a saline solution.

[0168] Alternatively, the present invention provides kits suitable for preparing injection and infusion solutions, comprising a pharmaceutical preparation comprising a compound of Formula (I), or a pharmaceutically acceptable salt, ester, amide, or carbamate thereof, or a salt of such an ester, amide, or carbamate, as described herein (e.g., a lyophilized pharmaceutical preparation comprising a compound of Formula (I), or a pharmaceutically acceptable salt, ester, amide, or carbamate thereof, or a salt of such an ester, amide, or carbamate, and optionally sucrose), and a composition comprising a negatively charged cyclodextrin or a pharmaceutically acceptable derivative of a negatively charged cyclodextrin, and one or more physiologically acceptable aqueous solvents or diluents, such as a glucose solution or a saline solution.

[0169] In one embodiment of the present invention, kits of the invention suitable for preparing injection and infusion solutions further comprise one or more additional therapeutic agents as described herein.

[0170] Preferably, the kits of the invention include instructions, e.g., instructions instructing a user to mix a described amount of a compound of formula (I), or a pharmaceutically acceptable salt, ester, amide, or carbamate thereof, or a salt of such an ester, amide, or carbamate, with a described amount of a negatively charged cyclodextrin or a pharmaceutically acceptable derivative of a negatively charged cyclodextrin.

[0171] Such instructions may also provide guidance on storage conditions and / or administration instructions.

[0172] For the avoidance of doubt, the compound of formula (I), or a pharmaceutically acceptable salt, ester, amide, or carbamate thereof, or a salt of such an ester, amide, or carbamate, the negatively charged cyclodextrin or a pharmaceutically acceptable derivative of a negatively charged cyclodextrin, one or more physiologically acceptable aqueous solvents or diluents, and optionally one or more further therapeutic agents are present in the kit according to the invention in forms and amounts suitable for the preparation of a solution suitable for use as an injection or infusion solution. Those skilled in the art can readily determine the amounts of the compound of formula (I), or a pharmaceutically acceptable salt, ester, amide, or carbamate thereof, or a salt of such an ester, amide, or carbamate, the negatively charged cyclodextrin or a pharmaceutically acceptable derivative of a negatively charged cyclodextrin, the physiologically acceptable aqueous solvent, and optionally one or more further therapeutic agents suitable for use according to the invention.

[0173] Finally, in embodiments of the invention in which a kit is provided, the kit of the invention may comprise a negatively charged cyclodextrin or a pharmaceutically acceptable derivative of a negatively charged cyclodextrin in a weight ratio (w / w) of about 1:1 to about 100:1 of the negatively charged cyclodextrin or the pharmaceutically acceptable derivative of a negatively charged cyclodextrin to a compound of Formula (I), or a pharmaceutically acceptable salt, ester, amide, or carbamate thereof, or a salt of such ester, amide, or carbamate, e.g., The kit may comprise a weight ratio (w / w) of negatively charged cyclodextrin or a pharmaceutically acceptable derivative of a negatively charged cyclodextrin to a compound of Formula (I), or a pharmaceutically acceptable salt, ester, amide, or carbamate thereof, or a salt of such an ester, amide, or carbamate, of about 4:1 to about 80:1, about 2:1 to about 50:1, or about 5:1 to about 20:1, wherein the amount of compound of Formula (I), or a pharmaceutically acceptable salt, ester, amide, or carbamate thereof, or a salt of such an ester, amide, or carbamate, is that amount present in the kit. For example, the kits of the present invention can contain a weight ratio (w / w) of negatively charged cyclodextrin or a pharmaceutically acceptable derivative of a negatively charged cyclodextrin to a compound of Formula (I), a pharmaceutically acceptable salt, ester, amide, or carbamate thereof, or a salt of such an ester, amide, or carbamate of about 10:1, about 11:1, about 12:1, about 13:1, about 14:1, about 15:1, about 16:1, about 17:1, about 18:1, about 19:1, about 20:1, about 21:1, about 22:1, about 23:1, about 24:1, or about 25:1 of negatively charged cyclodextrin or a pharmaceutically acceptable derivative of a negatively charged cyclodextrin to a compound of Formula (I), a pharmaceutically acceptable salt, ester, amide, or carbamate thereof, or a salt of such ester, amide, or carbamate.In one preferred embodiment, the weight ratio (w / w) of the negatively charged cyclodextrin or pharmaceutically acceptable derivative of a negatively charged cyclodextrin to the compound of formula (I), or a pharmaceutically acceptable salt, ester, amide, or carbamate thereof, or a salt of such an ester, amide, or carbamate, is about 5:1, about 10:1, or about 20:1, and the amount of the compound of formula (I), or a pharmaceutically acceptable salt, ester, amide, or carbamate thereof, or a salt of such an ester, amide, or carbamate, is that amount present in the kit.

[0174] equivalent The present invention has been described broadly and generically herein. Those skilled in the art will readily appreciate that all parameters, dimensions, materials, and configurations described herein are meant to be exemplary, and that the actual parameters, dimensions, materials, and / or configurations will depend on the specific application or applications for which the teachings of the present invention are used. Those skilled in the art will recognize, or be able to ascertain using no more than routine experimentation, many equivalents to the specific embodiments of the invention described herein. Accordingly, it is to be understood that the foregoing embodiments are presented by way of example only, and that, within the scope of the appended claims and their equivalents, the invention may be practiced otherwise than as specifically described and claimed. The present invention is directed to each individual feature, system, article, material, kit, and / or method described herein. In addition, any combination of two or more such features, systems, articles, materials, kits, and / or methods is within the scope of the invention, provided that such features, systems, articles, materials, kits, and / or methods are not mutually inconsistent. Moreover, each of the narrower species and subgeneric groupings falling within the scope of the generic disclosure also form part of the invention. This includes the generic description of the invention with any provisos or negative limitations removing any subject matter from the genus, regardless of whether the omitted material is specifically recited herein.

[0175] Incorporation by Reference The contents of the articles, patents, and patent applications, and all other documents and electronically available information mentioned or cited herein are incorporated by reference herein in their entirety as if each individual publication were specifically and individually indicated to be incorporated by reference. Applicant reserves the right to physically incorporate into this application any and all materials and information from such articles, patents, patent applications, or other physical and electronic documents.

[0176] The following examples illustrate the invention. [Example]

[0177] All of the following example compounds and biological examples are disclosed in International Patent Application No. PCT / EP2022 / 066756, published under WO2022 / 263679. The example preparations are illustrative of the pharmaceutical preparations claimed herein.

[0178] Example Compounds The compounds described herein can be prepared according to methods known to those skilled in the art. Other reaction schemes, as well as a variety of different solvents, temperatures, and other reaction conditions, can be readily devised by those skilled in the art.

[0179] The compounds of formula (I) above can be prepared according to the protocol described in International Patent Application No. PCT / EP2022 / 066756, published under WO2022 / 263679. The synthetic methods of example compounds 1-51 described on pages 37-132 of WO2022 / 263679 are incorporated herein by reference. For completeness, the structures of the compounds are shown in Table 1 below.

[0180] Biological Examples Biological Example 1 - Evaluation of in vitro cytotoxicity performance in the MM.1S cell viability assay: Methods: MM.1S cells were cultured in RPMI medium 1640 (IX) supplemented with 10 μg / μL penicillin / streptomycin, 10% heat-inactivated FBS, 0.1 mM sodium pyruvate, 1× MEM NEAA (ThermoFisher), and 1 mM HEPES. Cells were grown to logarithmic phase and then exposed to test compounds.

[0181] Test compounds (Example Compounds 1-36, 38-41, and 45-48) and comparison compounds (bendamustine, busulfan, melphalan, chlorambucil, and 4-hydroperoxycyclophosphamide) were dissolved in 100% DMSO and added to a 384-well assay plate. Additional DMSO was added to maintain the same final DMSO concentration (0.2%) in all wells. 25 μL of cell suspension at a concentration of 100,000 cells / mL was added to each well. Cells were cultured at 37°C in a CO2 incubator for 72 hours. The plate was equilibrated to room temperature for 30 minutes, and 20 μL of CellTiter-Glo® 2.0 (Promega) reagent was added to all wells. The plate was then allowed to stabilize for 20 minutes before luminescence (emission filter 700 nm) was recorded on an Envision plate reader. Plate reader data were normalized to the negative control (no treatment) versus the positive control (cells treated with 400 μM chlorpromazine for 72 h) to obtain IC 50 was obtained from a four-parameter logistic regression curve fit.

[0182] Results: Test compounds were evaluated for their ability to inhibit MM.1S cell proliferation and cause cytotoxicity in vitro. Dose responses could be extracted from the experiments and are shown in Table 1 below. Test compounds demonstrated good cytotoxicity against MM.1S cells. Example compounds 1-16, 21-32, 34-36, 38, and 45-48 were found to be more cytotoxic than bendamustine, busulfan, melphalan, chlorambucil, and 4-hydroperoxycyclophosphamide in this assay.

[0183] [Table 1-1]

[0184] Table 1-2

[0185] Table 1-3

[0186] Table 1-4

[0187] Table 1-5

[0188] Table 1-6

[0189] Table 1-7

[0190] Table 1-8

[0191] Table 1-9

[0192] Table 1-10

[0193] Table 1-11

[0194] Biological Example 2 - Evaluation of in vitro cytotoxicity in hematological cell lines, human peripheral blood mononuclear cells, and normal fibroblasts: Methods: The cell lines used in these experiments are listed in Table 2 below. All cells were cultured in RPMI medium 1640 (IX). All media were supplemented with 10 μg / μl penicillin / streptomycin, 10% heat-inactivated FBS, 0.1 mM sodium pyruvate, 1×MEM NEAA (ThermoFisher), and 1 mM HEPES. DERL-2 cells had higher FBS (20%) and were supplemented with 40 ng / mL IL-2. hPBMCs were thawed, conditioned overnight, and then stimulated with 10 μg / mL PHA-M and 40 ng / mL IL-2 for 4 hours before exposure to test compounds. All cells except hPBMCs were grown to log phase before exposure to test compounds.

[0195] [Table 2]

[0196] Test compounds were dissolved in 100% DMSO and added to a 384-well assay plate. Additional DMSO was added to maintain the same final DMSO concentration (0.2%) in all wells. 25 μL of cell suspension at a concentration of 100,000 cells / mL was added to each well. Cells were cultured for 72 hours at 37°C in a CO2 incubator. The plate was equilibrated to room temperature for 30 minutes, and 20 μL of CellTiter-Glo® 2.0 (Promega) reagent was added to all wells. The plate was then allowed to stabilize for 20 minutes before recording luminescence (Em filter 700 nm) on an Envision plate reader. Plate reader data were normalized to the negative control (no treatment) versus the positive control (cells treated with 400 μM chlorpromazine for 72 hours) to determine the IC. 50 was obtained from a four-parameter logistic regression curve fit.

[0197] Results: Test compounds were evaluated for their ability to inhibit cell proliferation in vitro using several different cell lines of hematological origin. Cytotoxicity was also evaluated in non-malignant human peripheral blood mononuclear cells (hPBMC) and fibroblasts (BJ). Table 3 shows the dose-response extracted from the experiments for all compounds tested. In the table, results are given as cytotoxicity IC50 μM + / - standard deviation (number of tests). nd = value not determined.

[0198] [Table 3a]

[0199] [Table 3b]

[0200] The compound of formula (I) is found to be consistently more cytotoxic than the two prior art compounds.

[0201] Biological Examples 3-18 (after treatment in Example 1), Bendamustine, and Melphalan Cellular Retention / Efflux Assessment: Method: 2×10 6 MM.1S cells at 1000 cells / mL were seeded into a 96-well plate at 250 μL per well. Cells were incubated in the presence of test compounds for 5, 15, and 60 minutes, after which the cells were pelleted by centrifugation at +4°C for 5 minutes. The cell culture medium was immediately collected into a second plate and stored at -80°C until further analysis. The pelleted cells were washed once with ice-cold PBS and then stored at -80°C until further analysis.

[0202] Cells were lysed and proteins in the medium were precipitated using acetonitrile:dimethylformamide (9:1) containing an internal standard. Samples were centrifuged and the supernatants were analyzed by LC-MS / MS (ACQUITY UPLC-Xevo TQ-S micro) to determine compound concentrations.

[0203] Example compound 1, bendamustine, and melphalan were used as test compounds.

[0204] Results: The results are shown in Figure 1. Figure 1(A) shows the intracellular and extracellular concentrations of a metabolite compound (Example Compound 18) formed from bendamustine and Example Compound 1. It can be seen that Example Compound 18 was rapidly formed intracellularly after treatment with Example Compound 1, and low levels of the compound were found in the extracellular medium. These results indicate that hydrolysis of Example Compound 1 occurred intracellularly and that the metabolite of Example Compound 1 was retained intracellularly. Low intracellular concentrations of bendamustine could be detected, and the levels decreased over time. The extracellular concentration of bendamustine was very high and decreased over time.

[0205] Figure 1(B) shows the intracellular and extracellular concentrations of melphalan over the time course of the experiment. After in vitro treatment of MM.1S cells with melphalan, low intracellular concentrations of melphalan were detected. Extracellular concentrations of melphalan remained high and constant throughout the experiment.

[0206] Biological Example 4 - In vivo evaluation of cytotoxicity of test compounds in a chicken embryo xenograft model: Methods: Fertilized White Leghorn eggs were inoculated with 3 × 10 6 This was performed using SU-DHL-4 tumor cells. Live eggs were injected with 100 μL of either Example Compound 1 (8.4 μM (0.008 mg / kg), 33.5 μM (0.033 mg / kg), 167.5 μM (0.164 mg / kg)), bendamustine (8.4 μM (0.005 mg / kg), 33.5 μM (0.02 mg / kg), 167.5 μM (0.1 mg / kg)), or vehicle on days 11, 13, 15, and 17. On day 18, tumors were removed and weighed.

[0207] Results: A dose-dependent effect on tumor weight was evident for Example Compound 1 (Figure 2). For Example Compound 1, tumor reduction compared to vehicle was 38%, 70%, and 82% at 8.4 μM, 33.5 μM, and 167.5 μM, respectively. For bendamustine, tumor reduction compared to vehicle was evident only at 33.5 μM and 167.5 μM, representing 30% and 76% reduction, respectively. Thus, Example Compound 1 exhibits potent tumor cytotoxicity in this model.

[0208] Biological Example 5 - Assessment of Cellular Retention / Efflux of PDC Compounds and Metabolites: Methods: Methods described in Biological Example 3. Example compounds 1, 2, 3, 4, 6, 7, and 10 were examined. Intracellular metabolites were formed from all tested compounds. The compounds used in cell treatment were metabolized to an ester hydrolysis compound (referred to herein as Metabolite A) and an amide hydrolysis compound (referred to as Metabolite B). The structures of the example compounds and the two metabolites for each compound are shown in Table 4. Metabolite B, formed under the conditions tested, was a compound with the structure shown in Examples 17 and 18: [ka]

[0209] [Table 4-1]

[0210] [Table 4-2]

[0211] The intracellular concentrations of the metabolites slowly decreased over time. Little or no detectable extracellular concentrations of the metabolites could be detected in the extracellular medium. These results indicate that hydrolysis of the example compounds occurred intracellularly and that the metabolites of the example compounds were retained intracellularly.

[0212] Biological Example 6 - Assessment of Direct DNA Damage by Test Compounds: Methods: DNA was prepared from MM.1S cells using a QIAGEN genomic tip 20 / G according to the protocol described by Furda et al., Methods Mol Biol, 2012. 1 μg of DNA was treated with 0.25 μM compound for 30 minutes at 37°C. DMSO was used as a control treatment. 20 ng of treated DNA was PCR amplified using Phusion Hot Start II High Fidelity PCR Master Mix (Thermo Scientific) to generate 10.4 or 8.9 kb fragments using primers directed against HPRT or mitochondrial DNA (mtDNA), respectively. PCR reactions were separated on a 1% agarose gel and visualized using a ChemiDoc™ MP Imaging System (BioRad). Example compounds 1, 2, and 38 were investigated, as were compounds 18 and 20, metabolites of compound 1. These were compared with bendamustine, melphalan, and DMSO controls. The results for compounds 1, 2, 18, and 20 using HPRT primers are shown in Figure 4(A), and the results for compounds 18 and 38 using mtDNA primers are shown in Figure 4(B). The results for compounds 18 and 38 using HPRT and mtDNA primers are shown in Figure 4(C).

[0213] Results: In Figure 4, it can be seen that melphalan and bendamustine had no or very little effect on DNA damage in both nuclear and mitochondrial DNA at the concentrations tested. Example compounds 1 and 2 had strong DNA-damaging effects on both nuclear and mitochondrial DNA, as indicated by the fact that no PCR bands could be detected on the gel. Example compounds 18 and 38 effectively damaged both nuclear and mitochondrial DNA, with only weak PCR bands being detectable. Example compound 20 also had a DNA-damaging effect, although to a lesser extent compared to Example compounds 1, 2, and 18, but greater than bendamustine or melphalan.

[0214] Biological Example 7 - Evaluation of DNA Fragmentation Induced by Test Compounds Method: 1×10 6 MM.1S cells (CRL-2974, ATCC) were treated with 0.006, 0.06, 0.6, or 6 μM of Example Compound 1 or bendamustine for 24 hours. After incubation, cells were washed with PBS (10010-015, Gibco), fixed in flow cytometry fixation buffer (FC004, R&D Systems) for 10 minutes, and stored in 70% ethanol at -20°C overnight. Deoxythymidine analog (BrdUTP) was present in the experiments to label DNA break sites. The next day, cells were washed and stained using the APO-BrdU™ TUNEL Assay Kit (A23210, Invitrogen) according to the manufacturer's protocol, followed by analysis using a BD FACSCanto™ II. The percentage of TUNEL-positive cells indicates the percentage of cells with fragmented DNA.

[0215] Results: The dose-response effects of Example Compound 1 and bendamustine on DNA damage after 24 hours of incubation are shown in Figure 5(A). All data are expressed as means with SD (n=2). 24 hours of exposure to Example Compound 1 induced DNA damage in a dose-dependent manner, but no clear effect of bendamustine on DNA damage was found after 24 hours of incubation. Representative FACS histograms of Alexa fluor 488 intensity after 24 hours of treatment with 0.6 μM of test compound or bendamustine (n=2) are shown in Figure 5(B). The top pair of the FACS histograms is Example Compound 1, the middle pair is bendamustine, and the bottom pair is the DMSO control. Notably, 24 hours of treatment with 0.6 μM of Example Compound 1 caused DNA breaks in more than 90% of the test cells, but not bendamustine. Example Compound 1 is more potent in causing DNA damage. Preparation Examples: Example Preparation 1 Example Compound 1*: 20 mg (free base) Betadex sulfobutylether sodium: 200mg Water for injection 10mL *Ethyl (2S)-2-[[(2S)-2-amino-4-[5-[bis(2-chloroethyl)amino]-1-methyl-benzimidazol-2-yl]butanoyl]amino]-4-methyl-pentanoate Example Preparation 2 (pH 4.5) Example Compound 1*: 20 mg (free base) Betadex sulfobutylether sodium: 200mg Citric acid: 11.0 mg Trisodium citrate dihydrate: 17.2 mg Water for injection 10mL Example Preparation 3 (pH 4.9) Example Compound 1*: 20 mg (free base) Betadex sulfobutylether sodium: 200mg Citric acid: 8.2mg Trisodium citrate dihydrate: 21.8 mg Water for injection 10mL

[0216] Stability of Example Compound 1 with various excipients Ethyl (2S)-2-[[(2S)-2-amino-4-[5-[bis(2-chloroethyl)amino]-1-methyl-benzimidazol-2-yl]butanoyl]amino]-4-methyl-pentanoate (Example 1, 19.2 mg, 16.7 mg of free base) was dissolved in dimethylacetamide (419 μL) to give a 40 mg / mL stock solution.

[0217] A 0.4 mg / mL solution of Example Compound 1 was prepared by diluting the stock solution in dimethylacetamide (40 mg / mL, 10 μL) with different solutions (990 μL) according to Table 5 and analyzed by HPLC for stability after 4 hours at room temperature. (Analytical HPLC was performed on an Agilent Series 1100 system using a Kinetex XB C18 (2.6 μm, 3.0 × 50 mm) column with 0.1% TFA in HO / CH3CN as the mobile phase (acid conditions) (flow rate 1 mL / min). Excipients are reported as the weight ratio of excipient:Example Compound 1 (free base).

[0218] [Table 5]

[0219] Experiments show that the best excipient in ultrapure water is betadex sulfobutylether sodium, with very little material decomposing after 4 hours at room temperature.

Claims

1. 1. A pharmaceutical preparation comprising a negatively charged cyclodextrin or a pharmaceutically acceptable derivative of a negatively charged cyclodextrin and a compound according to formula (I) or a pharmaceutically acceptable salt, ester, amide, or carbamate thereof, or a salt of such an ester, amide, or carbamate, 【Chemistry 1】 During the ceremony, X is C １－６ is alkylene, W １ , W ２ , W ３ , and W ４ are each CH or W １ , W ２ , W ３ , and W ４ one of which is N and the other is CH; R １ is C optionally substituted with 1, 2, or 3 groups independently selected from H, halogen １－４ selected from the group consisting of alkyl, and halogen; R ２ is H, phenyl optionally substituted with 1, 2, or 3 groups independently selected from halogen, and C optionally substituted with 1, 2, or 3 groups independently selected from halogen. １－６ is selected from the group consisting of alkyl, R ３ is represented by formula (II): 【Chemistry 2】 Or formula (III): 【Transformation 3】 is a group according to R ４ is N(R ｃ ) (R ｄ ) and formula (IV): 【Chemistry 4】 and R ４ is formula (IV), then R ５ is R ｂ and R ４ But N(R ｃ ) (R ｄ ), then R ５ is R ｂ and formula (V): 【Transformation 5】 wherein each R ａ is H, C １－６ Alkyl, —CH ２ -phenyl, or -CH ２ - 3- to 12-membered heterocyclyl (containing 1, 2, 3, or 4 heteroatoms selected from N, O, and S), １－６ Alkyl is —OH, —OC １－６ Alkyl, —NH ２ , -NHC(=NH)NH ２ , -C(O)OH, -C(O)NH ２ , -SH, -SCH ３ and halogen, wherein said phenyl or heterocyclyl is optionally substituted by 1, 2, or 3 substituents independently selected from the group consisting of halogen, —NH ２ , —OH, —OC １－６ Alkyl, and —NO ２ optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of: R ｂ is -OH, -N(R ｅ ) (R ｆ ), and -OC １－６ Alkyl (halogen, —OH, —CN, —N(R ｅ ) (R ｆ ), -C ６－１０ aryl, or a 3- to 12-membered heterocycle containing one or more O, N, or S atoms and optionally substituted by 1, 2, or 3 halogens, and / or said alkyl is optionally interrupted by 1, 2, or 3 O, N, or S atoms; R ｃ and R ｄ are H and -C, respectively. １－６ Alkyl, C(O)C １－６ Alkyl, and —CH ２ -phenyl, wherein said alkyl or said phenyl is optionally substituted with 1, 2, or 3 groups selected from halogen; R ｅ and R ｆ are H and -C, respectively. １－６ alkyl, wherein said alkyl is optionally substituted with 1, 2, or 3 groups selected from halogen, or R ｅ and R ｆ together with the nitrogen atom to which they are attached form a 4-, 5-, or 6-membered heterocycle optionally substituted with 1, 2, or 3 groups selected from halogen.

2. The compound of formula (I), or the pharmaceutically acceptable salt, ester, amide, or carbamate thereof, or a salt of such an ester, amide, or carbamate, has the structure (Ia): 【Transformation 6】 For example, structure (Ib): 【Transformation 7】 2. The pharmaceutical preparation of claim 1, having the formula:

3. R １ The pharmaceutical preparation according to claim 1 or 2, wherein is H.

4. R ２ is optionally substituted with 1, 2, or 3 halogens, and —C optionally substituted with 1, 2, or 3 halogens. １－６ Alkyl, e.g., —C optionally substituted with 1, 2, or 3 halogens １－４ The pharmaceutical preparation according to any one of claims 1 to 3, wherein the alkyl group is selected from the group consisting of alkyl, for example methyl.

5. X is -CH ２ - or -CH ２ -CH ２ The pharmaceutical preparation according to any one of claims 1 to 4, wherein

6. R ３ is represented by formula (IIa): 【Transformation 8】 or formula (IIIa): 【Chemistry 9】 6. The pharmaceutical preparation according to claim 1, wherein the hydroxyl group is a group according to

7. R ４ But N(R ｃ ) (R ｄ ) and formula (IVa): 【Chemistry 10】 The pharmaceutical preparation according to any one of claims 1 to 6, selected from the group consisting of:

8. R ４ is formula (IV) or (IVa), R ５ is R ｂ and R ４ But N(R ｃ ) (R ｄ ), then R ５ But, R ｂ and formula (Va), wherein formula (Va) has the following structure: 【Chemistry 11】 8. The pharmaceutical preparation according to any one of claims 1 to 7, having

9. R ４ But NH ２ The pharmaceutical preparation according to any one of claims 1 to 8, wherein

10. Each R ａ But C １－６ Alkyl and -CH ２ -phenyl, wherein said C １－６ The alkyl is —OH, —NH ２ , -NHC(=NH)NH ２ , -C(O)OH, -C(O)NH ２ , -SH, -SCH ３ or halogen (e.g., F or Cl), wherein said phenyl is optionally substituted with halogen (e.g., F or Cl), —NH ２ , —OH, —O—C １－６ Alkyl, and —NO ２ 10. The pharmaceutical preparation of any one of claims 1 to 9, optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of:

11. Each R ａ But, -C １－６ Alkyl and -CH ２ -phenyl, wherein said phenyl is optionally substituted with 1, 2, or 3 halogen substituents.

12. R ４ is formula (IV) or (IVa), R ５ Is -OC １－６ alkyl, and R ４ But NH ２ If R ５ Is -OC １－６ The pharmaceutical preparation according to any one of claims 1 to 11, wherein the alkyl is of formula (V) or (Va).

13. R ｂ But, -OC １－６ 13. The pharmaceutical preparation of claim 12, wherein when alkyl, it is selected from the group consisting of methoxy, ethoxy, and isopropoxy.

14. The compound of formula (I), or the pharmaceutically acceptable salt, ester, amide, or carbamate thereof, or the salt of such ester, amide, or carbamate, Ethyl (2S)-2-[[(2S)-2-amino-4-[5-[bis(2-chloroethyl)amino]-1-methyl-benzimidazol-2-yl]butanoyl]amino]-4-methyl-pentanoate (Example Compound 1), Ethyl (2S)-2-[[(2S)-2-amino-4-[5-[bis(2-chloroethyl)amino]-1-methyl-benzimidazol-2-yl]butanoyl]amino]-3-(4-fluorophenyl)propanoate (Example compound 2), Ethyl (2S)-2-[[(2S)-2-amino-4-[5-[bis(2-chloroethyl)amino]-1-methyl-benzimidazol-2-yl]butanoyl]amino]-3-methyl-butanoate (Example compound 3), Ethyl (2S)-2-[[(2S)-2-amino-3-[5-[bis(2-chloroethyl)amino]-1-methyl-benzimidazol-2-yl]propanoyl]amino]-4-methyl-pentanoate (Example compound 4), Ethyl (2S)-2-[[(2S)-2-amino-3-[5-[bis(2-chloroethyl)amino]-1-methyl-benzimidazol-2-yl]propanoyl]amino]-3-(4-fluorophenyl)propanoate (Example compound 5), Ethyl (2S)-2-[[(2S)-2-amino-3-[5-[bis(2-chloroethyl)amino]-1-methyl-benzimidazol-2-yl]propanoyl]amino]-3-methyl-butanoate (Example compound 6), Ethyl (2S)-2-[[(2S)-2-amino-4-methyl-pentanoyl]amino]-4-[5-[bis(2-chloroethyl)amino]-1-methyl-benzimidazol-2-yl]butanoate (Example compound 7), Ethyl (2S)-2-[[(2S)-2-amino-3-(4-fluorophenyl)propanoyl]amino]-4-[5-[bis(2-chloroethyl)amino]-1-methyl-benzimidazol-2-yl]butanoate (Example compound 8), Ethyl (2S)-2-[[(2S)-2-amino-3-methyl-butanoyl]amino]-4-[5-[bis(2-chloroethyl)amino]-1-methyl-benzimidazol-2-yl]butanoate (Example compound 9), Ethyl (2S)-2-[[(2S)-2-amino-4-methyl-pentanoyl]amino]-3-[5-[bis(2-chloroethyl)amino]-1-methyl-benzimidazol-2-yl]propanoate (Example compound 10), Ethyl (2S)-2-[[(2S)-2-amino-3-(4-fluorophenyl)propanoyl]amino]-3-[5-[bis(2-chloroethyl)amino]-1-methyl-benzimidazol-2-yl]propanoate (Example compound 11), Ethyl (2S)-2-[[(2S)-2-amino-3-methyl-butanoyl]amino]-3-[5-[bis(2-chloroethyl)amino]-1-methyl-benzimidazol-2-yl]propanoate (Example compound 12), Ethyl (2S)-2-[[(2S)-2-amino-4-[5-[bis(2-chloroethyl)amino]-1-phenyl-benzimidazol-2-yl]butanoyl]amino]-4-methyl-pentanoate (Example compound 13), Methyl (2S)-2-[[(2S)-2-amino-3-[5-[bis(2-chloroethyl)amino]-1-methyl-benzimidazol-2-yl]propanoyl]amino]-4-methyl-pentanoate (Example compound 14), Isopropyl (2S)-2-[[(2S)-2-amino-3-[5-[bis(2-chloroethyl)amino]-1-methyl-benzimidazol-2-yl]propanoyl]amino]-4-methyl-pentanoate (Example compound 15), Ethyl (2S)-2-[[(2S)-2-[[(2S)-2-amino-3-(4-fluorophenyl)propanoyl]amino]-4-methyl-pentanoyl]amino]-4-[5-[bis(2-chloroethyl)amino]-1-methyl-benzimidazol-2-yl]butanoate (Example compound 16), Ethyl (2S)-2-[[(2R)-2-[[(2S)-2-amino-3-(4-fluorophenyl)propanoyl]amino]-4-methyl-pentanoyl]amino]-4-[5-[bis(2-chloroethyl)amino]-1-methyl-benzimidazol-2-yl]butanoate (Example compound 21) Ethyl (2S)-2-[[(2S)-2-[[(2S)-2-amino-4-[5-[bis(2-chloroethyl)amino]-1-methyl-benzimidazol-2-yl]butanoyl]amino]-4-methyl-pentanoyl]amino]-3-(4-fluorophenyl)propanoate (Example compound 22) Ethyl (2S)-2-[[(2S)-2-[[(2S)-2-amino-4-[5-[bis(2-chloroethyl)amino]-1-methyl-benzimidazol-2-yl]butanoyl]amino]-4-methyl-pentanoyl]amino]-4-methyl-pentanoate (Example compound 23) 2-Morpholinoethyl (2S)-2-[[(2S)-2-amino-4-[5-[bis(2-chloroethyl)amino]-1-methyl-benzimidazol-2-yl]butanoyl]amino]-4-methyl-pentanoate (Example Compound 24) 2-Isopropoxyethyl (2S)-2-[[(2S)-2-amino-4-[5-[bis(2-chloroethyl)amino]-1-methyl-benzimidazol-2-yl]butanoyl]amino]-4-methyl-pentanoate (Example Compound 25) Isopropyl (2S)-2-[[(2S)-2-amino-4-[5-[bis(2-chloroethyl)amino]-1-methyl-benzimidazol-2-yl]butanoyl]amino]-4-methyl-pentanoate (Example Compound 26) Methyl (2S)-2-[[(2S)-2-amino-4-[5-[bis(2-chloroethyl)amino]-1-methyl-benzimidazol-2-yl]butanoyl]amino]-4-methyl-pentanoate (Example Compound 27) 3-(Dimethylamino)propyl(2S)-2-[[(2S)-2-amino-4-[5-[bis(2-chloroethyl)amino]-1-methyl-benzimidazol-2-yl]butanoyl]amino]-4-methyl-pentanoate (Example Compound 28) (2-Methoxy-1-methyl-ethyl)(2S)-2-[[(2S)-2-amino-4-[5-[bis(2-chloroethyl)amino]-1-methyl-benzimidazol-2-yl]butanoyl]amino]-4-methyl-pentanoate (Example Compound 29) (2S)-2-[[(2S)-2-amino-4-[5-[bis(2-chloroethyl)amino]-1-methyl-benzimidazol-2-yl]butanoyl]amino]-N,N,4-trimethyl-pentanamide (Example compound 30) (2S)-2-[[(2S)-2-amino-4-[5-[bis(2-chloroethyl)amino]-1-methyl-benzimidazol-2-yl]butanoyl]amino]-N,4-dimethyl-pentanamide (Example compound 31) Ethyl (2S)-2-[[(2S)-4-[5-[bis(2-chloroethyl)amino]-1-methyl-benzimidazol-2-yl]-2-(methylamino)butanoyl]amino]-4-methyl-pentanoate (Example compound 32) Ethyl (2S)-2-[[(2S)-2-acetamido-4-[5-[bis(2-chloroethyl)amino]-1-methyl-benzimidazol-2-yl]butanoyl]amino]-3-(4-fluorophenyl)propanoate (Example compound 34) Ethyl (2S)-2-[[(2S)-2-acetamido-3-[5-[bis(2-chloroethyl)amino]-1-methyl-benzimidazol-2-yl]propanoyl]amino]-4-methyl-pentanoate (Example compound 35) Ethyl (2S)-2-[[(2S)-2-acetamido-3-[5-[bis(2-chloroethyl)amino]-1-methyl-benzimidazol-2-yl]propanoyl]amino]-3-(4-fluorophenyl)propanoate (Example compound 36) Ethyl (2S)-2-amino-4-[5-[bis(2-chloroethyl)amino]-1-methyl-benzimidazol-2-yl]butanoate (Example compound 38) Ethyl (2R)-2-[[(2S)-2-amino-4-[5-[bis(2-chloroethyl)amino]-1-methyl-benzimidazol-2-yl]butanoyl]amino]-4-methyl-pentanoate (Example Compound 45) Ethyl (2S)-2-[[(2R)-2-amino-4-[5-[bis(2-chloroethyl)amino]-1-methyl-benzimidazol-2-yl]butanoyl]amino]-4-methyl-pentanoate (Example compound 46) Ethyl (2R)-2-[[(2R)-2-amino-4-[5-[bis(2-chloroethyl)amino]-1-methyl-benzimidazol-2-yl]butanoyl]amino]-4-methyl-pentanoate (Example Compound 47) Ethyl (2S)-2-[[(2S)-2-amino-4-[6-[bis(2-chloroethyl)amino]-3-methyl-imidazo[4,5-b]pyridin-2-yl]butanoyl]amino]-4-methyl-pentanoate (Example compound 48), and Ethyl (2S)-2-[[(2S)-2-amino-4-[5-[bis(2-chloro-1,1,2,2-tetradeuterio-ethyl)amino]-1-methyl-benzimidazol-2-yl]butanoyl]amino]-4-methyl-pentanoate (Example Compound 50) or a pharmaceutically acceptable salt, amide, or carbamate thereof (including a salt of such an amide or carbamate).

15. The compound of formula (I), or the pharmaceutically acceptable salt, ester, amide, or carbamate thereof, or the salt of such ester, amide, or carbamate, (2S)-2-[[(2S)-2-amino-4-[5-[bis(2-chloroethyl)amino]-1-methyl-benzimidazol-2-yl]butanoyl]amino]-3-methyl-butanoic acid (Example compound 19), and (2S)-2-[[(2S)-2-amino-4-[5-[bis(2-chloroethyl)amino]-1-methyl-benzimidazol-2-yl]butanoyl]amino]-4-methyl-pentanoic acid (Example compound 20), (2S)-2-[[(2S)-4-[5-[bis(2-chloroethyl)amino]-1-methyl-benzimidazol-2-yl]-2-(methylamino)butanoyl]amino]-4-methyl-pentanoic acid (Example compound 33) (2S)-2-[[(2S)-2-amino-4-methyl-pentanoyl]amino]-4-[5-[bis(2-chloroethyl)amino]-1-methyl-benzimidazol-2-yl]butanoic acid (Example compound 37) (2S)-2-[[(2S)-2-amino-4-[5-[bis(2-chloroethyl)amino]-1-methyl-benzimidazol-2-yl]butanoyl]amino]-3-(4-fluorophenyl)propanoic acid (Example compound 39) (2S)-2-[[(2S)-2-amino-4-[5-[bis(2-chloroethyl)amino]-1-phenyl-benzimidazol-2-yl]butanoyl]amino]-4-methyl-pentanoic acid (Example compound 40) (2S)-2-[[(2S)-2-amino-3-[5-[bis(2-chloroethyl)amino]-1-methyl-benzimidazol-2-yl]propanoyl]amino]-3-methyl-butanoic acid (Example compound 42) (2S)-2-[[(2S)-2-amino-4-methyl-pentanoyl]amino]-3-[5-[bis(2-chloroethyl)amino]-1-methyl-benzimidazol-2-yl]propanoic acid (Example compound 43) (2S)-2-[[(2S)-2-amino-3-[5-[bis(2-chloroethyl)amino]-1-methyl-benzimidazol-2-yl]propanoyl]amino]-4-methyl-pentanoic acid (Example Compound 44), and (2S)-2-[[(2S)-2-amino-4-[5-[bis(2-chloro-1,1,2,2-tetradeuterio-ethyl)amino]-1-methyl-benzimidazol-2-yl]butanoyl]amino]-4-methyl-pentanoic acid (Example compound 51) 2. The pharmaceutical preparation of claim 1, wherein the compound is selected from the group consisting of:

16. 1. A pharmaceutical preparation comprising a negatively charged cyclodextrin or a pharmaceutically acceptable derivative of a negatively charged cyclodextrin and a compound according to formula (I) or a pharmaceutically acceptable salt, ester, amide, or carbamate thereof, or a salt of such an ester, amide, or carbamate, 【Chemistry 12】 During the ceremony, X is C １－６ is alkylene, W １ , W ２ , W ３ , and W ４ are each CH or W １ , W ２ , W ３ , and W ４ one of which is N and the other is CH; R １ is C optionally substituted with 1, 2, or 3 groups independently selected from H, halogen １－４ selected from the group consisting of alkyl, and halogen; R ２ is H, phenyl optionally substituted with 1, 2, or 3 groups independently selected from halogen, and C optionally substituted with 1, 2, or 3 groups independently selected from halogen. １－６ is selected from the group consisting of alkyl, R ３ is of formula (VIa), 【Chemistry 13】 In the formula, R ｃ and R ｄ are H and -C, respectively. １－６ Alkyl, C(O)C １－６ Alkyl, and —CH ２ -phenyl, wherein said alkyl or said phenyl is optionally substituted with 1, 2, or 3 groups selected from halogen; R ｇ is H and -C １－６ A pharmaceutical preparation wherein the alkyl is selected from the group consisting of: alkyl, wherein the alkyl is optionally substituted with 1, 2, or 3 groups selected from halogen.

17. The compound of formula (I), or the pharmaceutically acceptable salt, ester, amide, or carbamate thereof, or the salt of such an ester, amide, or carbamate, has the structure (Ia) or (Ib), as shown in claim 2, or R １ , R ２ or X is any one of claims 3 to 5, ｃ and R ｄ are each H and R ｇ The pharmaceutical preparation of claim 16, wherein is H.

18. The compound of formula (I), or the pharmaceutically acceptable salt, ester, amide, or carbamate thereof, or the salt of such ester, amide, or carbamate, (2S)-2-amino-3-[5-[bis(2-chloroethyl)amino]-1-methyl-benzimidazol-2-yl]propanoic acid (Example compound 17), (S)-2-amino-4-(5-(bis(2-chloroethyl)amino)-1-methyl-1H-benzo[d]imidazol-2-yl)butanoic acid (Example compound 18), Ethyl (2S)-2-amino-4-[5-[bis(2-chloroethyl)amino]-1-methyl-benzimidazol-2-yl]butanoate (Example compound 38) (2S)-2-amino-4-[5-[bis(2-chloroethyl)amino]-1-phenyl-benzimidazol-2-yl]butanoic acid (Example Compound 41), and (2S)-2-amino-4-[5-[bis(2-chloro-1,1,2,2-tetradeuterio-ethyl)amino]-1-methyl-benzimidazol-2-yl]butanoic acid (Example compound 49), or salts thereof.

19. 10. A pharmaceutical preparation according to any one of the preceding claims, wherein the compound of formula (I), or an ester, amide, or carbamate thereof, is present as a pharmaceutically acceptable salt.

20. 20. The pharmaceutical preparation of claim 19, wherein the compound of formula (I), or an ester, amide, or carbamate thereof, is present as a hydrochloride salt.

21. 10. A pharmaceutical preparation according to any one of the preceding claims, comprising a pharmaceutically acceptable derivative of a negatively charged cyclodextrin.

22. 22. The pharmaceutical preparation of claim 21, wherein the pharmaceutically acceptable derivative of a negatively charged cyclodextrin is a sulfoalkyl ether derivatized cyclodextrin.

23. 23. The pharmaceutical preparation of claim 22, wherein the pharmaceutically acceptable derivative of a negatively charged cyclodextrin is a sulfobutyl ether derivatized cyclodextrin.

24. 24. The pharmaceutical preparation according to claim 22 or 23, wherein the average number of sulfoalkyl groups per cyclodextrin ring, expressed as the average degree of substitution, is 5 to 8.

25. 10. The pharmaceutical preparation according to any one of the preceding claims, wherein the negatively charged cyclodextrin or a pharmaceutically acceptable derivative of a negatively charged cyclodextrin is a negatively charged β-cyclodextrin or a pharmaceutically acceptable derivative of a negatively charged β-cyclodextrin.

26. 10. A pharmaceutical preparation according to any one of the preceding claims, wherein the negatively charged cyclodextrin or a pharmaceutically acceptable derivative of a negatively charged cyclodextrin is betadex sulfobutylether sodium.

27. 10. A pharmaceutical preparation according to any one of the preceding claims, comprising citric acid and / or one or more salts of citric acid (such as trisodium citrate dihydrate).

28. 10. The pharmaceutical preparation according to any one of the preceding claims, wherein the weight ratio (w / w) of the negatively charged cyclodextrin or pharmaceutically acceptable derivative of the negatively charged cyclodextrin to the compound of formula (I) or the pharmaceutically acceptable salt, ester, amide, or carbamate thereof, or the salt of such ester, amide, or carbamate (excluding the mass of any counterion) is from 1:1 to 100:1, from 2:1 to 50:1, or from 5:1 to 20:

1.

29. 10. The pharmaceutical preparation according to any one of the preceding claims, wherein the pharmaceutical preparation is a lyophilized powder.

30. 30. The pharmaceutical preparation of claim 29, wherein the pharmaceutical preparation comprises 1 mg to 150 mg of the compound of formula (I), or the pharmaceutically acceptable salt, ester, amide, or carbamate thereof, or a salt of such ester, amide, or carbamate (excluding the mass of any counterion).

31. 31. The pharmaceutical preparation of claim 29 or 30, which is substantially free of organic solvents.

32. 10. The pharmaceutical preparation of any one of the preceding claims, comprising one or more additional therapeutic agents selected from the group consisting of steroids, immunomodulatory drugs (IMiDs), proteasome inhibitors (PIs), histone deacetylase (HDAC) inhibitors, conventional chemotherapy, checkpoint inhibitors, nuclear transport inhibitors, anti-apoptotic inhibitors, adoptive cell therapy, bispecific T cell engagers (BiTEs), B cell targeting agents, and monoclonal antibodies.

33. A composition comprising a pharmaceutical preparation according to any one of the preceding claims and a physiologically acceptable aqueous solvent or diluent.

34. 21. A composition comprising a compound of formula (I) according to any one of claims 1 to 20, or a pharmaceutically acceptable salt, ester, amide, or carbamate thereof, or a salt of such an ester, amide, or carbamate, a negatively charged cyclodextrin or a pharmaceutically acceptable derivative of a negatively charged cyclodextrin, and a physiologically acceptable aqueous solvent.

35. 35. The composition of claim 33 or 34, wherein the physiologically acceptable aqueous solvent is a glucose solution, a saline solution, or a mixture thereof.

36. A kit comprising the pharmaceutical preparation of any one of claims 1 to 32 and a physiologically acceptable aqueous solvent or diluent.

37. 21. A kit comprising a compound of formula (I) according to any one of claims 1 to 20, or a pharmaceutically acceptable salt, ester, amide, or carbamate thereof, or a salt of such an ester, amide, or carbamate, a negatively charged cyclodextrin or a pharmaceutically acceptable derivative of a negatively charged cyclodextrin, and optionally one or more physiologically acceptable aqueous solvents or diluents.

38. 38. The kit of claim 37, wherein the compound of formula (I), or a pharmaceutically acceptable salt, ester, amide, or carbamate thereof, or a salt of such an ester, amide, or carbamate, is provided as a lyophilized preparation comprising (or consisting essentially of) the compound of formula (I), or a pharmaceutically acceptable salt, ester, amide, or carbamate thereof, or such an ester, amide, or carbamate, and optionally sucrose.

39. A pharmaceutical preparation according to any one of claims 1 to 32, or a composition according to any one of claims 33 to 35, or a kit according to any one of claims 36 to 38, for use as a medicament.

40. A pharmaceutical preparation according to any one of claims 1 to 32, or a composition according to any one of claims 33 to 35, or a kit according to any one of claims 36 to 38, for use in the treatment or prevention of cancer.

41. The cancer is selected from the group consisting of leukemia (e.g., acute lymphoblastic leukemia, including adult and childhood acute lymphoblastic leukemia, acute myeloid leukemia, including adult and childhood acute myeloid leukemia, chronic lymphocytic leukemia, such as B-cell chronic lymphocytic leukemia, chronic myeloid leukemia, and hairy cell leukemia), lymphoma (e.g., AIDS-related lymphoma, cutaneous T-cell lymphoma, Hodgkin's lymphoma, including adult and childhood Hodgkin's lymphoma and Hodgkin's lymphoma in pregnancy, non-Hodgkin's lymphoma, including adult and childhood non-Hodgkin's lymphoma and non-Hodgkin's lymphoma in pregnancy), mycosis fungoides, Sezari syndrome, and leukemia.

41. The pharmaceutical preparation, composition, or kit for use according to claim 40, wherein the cancer is selected from the group consisting of blood / blood cell cancers such as B-cell lymphoma, leukemia, leukemia-associated lymphoma ...

42. 42. The pharmaceutical preparation, composition, or kit for use according to claim 40 or 41, wherein the preparation or composition is administered together (e.g., simultaneously, sequentially, or separately) with one or more additional therapeutic agents, such as steroids, IMiDs, PIs, HDAC inhibitors, conventional chemotherapy, checkpoint inhibitors, nuclear transport inhibitors, anti-apoptotic inhibitors, adoptive cell therapy, BiTEs, B-cell targeting agents, and monoclonal antibodies.

43. A method for treating a patient, comprising administering a pharmaceutically effective amount of a pharmaceutical preparation according to any one of claims 1 to 32 or a composition according to any one of claims 33 to 35.

44. A method for the treatment or prevention of cancer, comprising administering an effective amount of a pharmaceutical preparation according to any one of claims 1 to 32 or a composition according to any one of claims 33 to 35, wherein the cancer is selected from the group consisting of leukemia (e.g. acute lymphoblastic leukemia including adult and childhood acute lymphoblastic leukemia, acute myeloid leukemia including adult and childhood acute myeloid leukemia, chronic lymphocytic leukemia such as B-cell chronic lymphocytic leukemia, chronic myeloid leukemia, and hairy cell leukemia), lymphoma (e.g. AIDS-related lymphoma, cutaneous T-cell lymphoma, adult and childhood Hodgkin's lymphoma and Hodgkin's lymphoma in pregnancy), and / or leukemia (e.g. leukemia, ... lymphoma, non-Hodgkin's lymphoma including adult and childhood non-Hodgkin's lymphoma and non-Hodgkin's lymphoma of pregnancy, mycosis fungoides, Sezary syndrome, Waldenstrom's macroglobulinemia, primary mediastinal large B-cell lymphoma, mantle cell lymphoma, diffuse large B-cell lymphoma, and primary central nervous system lymphoma), and blood / blood cell cancers such as other hematological cancers (e.g., chronic myeloproliferative disorders, multiple myeloma / plasma cell neoplasms, myelodysplastic syndromes, and myelodysplastic / myeloproliferative disorders), osteosarcoma, ovarian cancer, breast cancer, lung cancer, glioblastoma, retinoblastoma, and metastases of the foregoing cancers.

45. Use of the pharmaceutical preparation of any one of claims 1 to 32, the composition of any one of claims 33 to 35, or the kit of any one of claims 36 to 38 for the manufacture of a medicament for the treatment or prevention of cancer, wherein the cancer is selected from the group consisting of leukemia (e.g. acute lymphoblastic leukemia, including adult and childhood acute lymphoblastic leukemia, acute myeloid leukemia, including adult and childhood acute myeloid leukemia, chronic lymphocytic leukemia, such as B-cell chronic lymphocytic leukemia, chronic myeloid leukemia, and hairy cell leukemia), lymphoma (e.g. AIDS-related lymphoma, cutaneous T-cell lymphoma, adult and childhood Hodgkin's lymphoma, and Hodgkin's lymphoma during pregnancy), and the like. non-Hodgkin's lymphoma including adult and childhood non-Hodgkin's lymphoma and non-Hodgkin's lymphoma during pregnancy, mycosis fungoides, Sézary syndrome, Waldenstrom's macroglobulinemia, primary mediastinal large B-cell lymphoma, mantle cell lymphoma, diffuse large B-cell lymphoma, and primary central nervous system lymphoma), and blood / blood cell cancers such as other hematological cancers (e.g., chronic myeloproliferative disorders, multiple myeloma / plasma cell neoplasms, myelodysplastic syndromes, and myelodysplastic / myeloproliferative disorders), osteosarcoma, ovarian cancer, breast cancer, lung cancer, glioblastoma, retinoblastoma, and metastases of the foregoing cancers.

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