PNU anthracycline derivatives and methods of use thereof

Abstract

The present disclosure relates to novel PNU anthracycline derivatives of formula (I): and pharmaceutically acceptable salts thereof, wherein R 1 and R 2 is as defined in this disclosure. The disclosure also relates to pharmaceutical compositions comprising PNU anthracycline derivatives and the use of these compounds and compositions in the prevention or treatment of cell proliferative disorders. [Formula 1] TIFF2026500987000090.tif46153

Description

[Technical Field]

[0001] The present disclosure relates to novel PNU anthracycline derivatives, compositions comprising at least one PNU anthracycline derivative, and methods of using the PNU anthracycline derivatives to treat or prevent cell proliferative disorders in a patient. [Background technology]

[0002] The global burden of cancer is continually increasing and is predicted to continue to rise over the coming decades, given the aging population and modern lifestyles. The American Cancer Society estimates that 1.9 million new cancer cases will be diagnosed and 609,360 cancer deaths will be recorded in the United States alone in 2022. Nearly 200 existing types of cancer share the fundamental characteristic of uncontrolled growth and spread, as cells progressively acquire the ability to multiply indefinitely and evade control mechanisms.

[0003] Exploiting the rapid replication of cancer cells as a selective characteristic, numerous antitumor drugs, such as alkylating agents, antimetabolites, intercalating agents, polymerase inhibitors, and the vast majority of available therapeutic agents, strategically disrupt core mechanisms to kill tumors while inherently affecting healthy tissues with high cell renewal rates. Despite several weaknesses, the discovery of cytotoxic agents remains a milestone in anticancer therapy. Many older but effective drugs remain clinically relevant and are still used, particularly in combination therapy, without being replaced by modern targeted therapies.

[0004] Anthracyclines, a class of drugs used in cancer chemotherapy extracted from the bacterium Streptomyces, are among the most effective anticancer therapeutics developed to date, demonstrating efficacy against more types of cancer than any other class of chemotherapy drug. Clinically, the most important anthracyclines are doxorubicin (adriamycin), daunorubicin (daunomycin), epirubicin, and idarubicin. These compounds are used to treat many cancers, including leukemia, lymphoma, breast cancer, gastric cancer, uterine cancer, bladder cancer, and lung cancer.

[0005] Anthracyclines act primarily by intercalating into DNA, inhibiting DNA metabolism and RNA production. Their cytotoxicity is primarily due to their inhibition of topoisomerase II after the enzyme induces DNA breaks, preventing rejoining of the breaks and leading to cell death. The basic structure of anthracyclines is a tetracyclic molecule with an anthraquinone backbone attached to a sugar moiety by a glycosidic linkage. Upon cellular uptake, the tetracyclic structure intercalates between DNA base pairs, with the sugar lodging in the minor groove and interacting with adjacent base pairs. Summary of the Invention [Problem to be solved by the invention]

[0006] However, the usefulness of anthracyclines is limited by their toxicity, the main side effects of which are cardiotoxicity, severe neutropenia, and vomiting. Due to this toxicity, very few anthracyclines or related DNA intercalating agents are available for clinical use.

[0007] Thus, there remains a need in the art for anthracycline compounds that have the potential to treat cancer, and the presently disclosed PNU anthracycline derivatives help to meet that need. [Means for solving the problem]

[0008] In one embodiment, there is provided a compound of formula (I): or a pharmaceutically acceptable salt thereof: [ka] During the ceremony, R 1 is H or C 1-6 is alkyl; R 2 is C1-C6 hydroxyalkyl, 5-11 ring bridged bicyclic heterocyclic alkyl, 5-11 ring fused bicyclic heterocyclic alkyl, C1-C6 aminoalkyl, -(C1-C6 alkylene)-NR 3 C(O)—(C1-C6 aminoalkyl), —(C1-C6 alkylene)-NHC(O)NHNH2, —(C1-C6 alkylene)-NR 3 , -(C1-C6 alkylene)-N(R 3 )-(C1-C6 alkylene)-N(R 3 )-NHC(O)-(C1-C6 aminoalkyl), -(C1-C6 haloalkylene)-NR 3 , -(C1-C6 alkylene) n -(3- to 7-membered monocyclic heterocyclic alkyl), -(C1-C6 alkylene)-NR 3 C(O)-(3- to 7-membered monocyclic heterocyclic alkyl), -(C1-C6 alkylene)-NR 3 C(O)—(C3-C7 monocyclic cycloalkyl), —(C1-C6 alkylene) n -(C5-C 11 Fused bicyclic cycloalkyl), -(C1-C6 alkylene) n -(C5-C 11 Bridged bicyclic cycloalkyl), -(C1-C6 alkylene) n -(C3-C7 monocyclic cycloalkyl), -(C1-C6 alkylene) n -(C6-C 10 aryl), -(C1-C6 alkylene) n -(5- or 6-membered monocyclic heteroaryl), and 5- to 11-membered spirocyclic heterocycloalkyl, wherein the 3- to 7-membered monocyclic heterocycloalkyl group, the 5- to 10-membered fused bicyclic heterocycloalkyl group, the 5- to 10-membered bridged bicyclic heterocycloalkyl group, the C3-C7 monocyclic cycloalkyl group, the C6-C710 an aryl group, the 5- or 6-membered monocyclic heteroaryl group, the C5-C 11 The bicyclic cycloalkyl group and the 5- to 11-membered spirocyclic heterocycloalkyl group each optionally and independently include one or more R A group, and the 3- to 7-membered monocyclic heterocycloalkyl group may have one or more ring carbon atoms substituted with an oxo group; Or, R 1 and R 2 are taken together with the common nitrogen atom to which they are each bonded to form (i) a 3- to 7-membered monocyclic heterocycloalkyl group, (ii) a 5- to 11-ring bridged bicyclic heterocycloalkyl group, (iii) a 5- to 11-ring fused bicyclic heterocycloalkyl group, or (iv) a 5- to 11-ring spirocyclic heterocycloalkyl group, and the 3- to 7-membered monocyclic heterocycloalkyl group, the 5- to 11-ring bicyclic heterocycloalkyl group, the 5- to 11-ring fused heterocycloalkyl group, and the 5- to 11-ring spirocyclic heterocycloalkyl group each optionally and independently contain one or more R B may be substituted with a group; R 3 In each case, independently, H or C 1-6 is alkyl; R A In each case, independently, C 1-6 Alkyl, halo, -CN, -OR 3 , -(C1-C6 alkylene) n -N(R 3 )2, C1-C6 aminoalkyl, -(C1-C6 alkylene)-NHC(O)-(C1-C6 aminoalkyl), -O-(C 1-6 and -(C-C alkylene)-(3- to 7-membered monocyclic heterocycloalkyl), wherein the 3- to 7-membered monocyclic heterocycloalkyl group is optionally and independently selected from one or more R c may be substituted with a group; R B In each case, independently, C 1-6 Alkyl, halo, -CN, -OR 3 , -N(R 3)2, C1-C6 aminoalkyl, -(C1-C6 alkylene)-NHC(O)-(C1-C6 aminoalkyl), -O-(C 1-6 and -(C-C alkylene)-(3- to 7-membered monocyclic heterocycloalkyl), wherein the 3- to 7-membered monocyclic heterocycloalkyl group is optionally and independently selected from one or more R c may be substituted with a group; R c In each case, independently, C 1-6 Alkyl, halo, -CN, -OR 3 , -N(R 3 )2, C1-C6 aminoalkyl, -O-(C 1-6 alkyl), -NHC(O)-(C1-C6 aminoalkyl), -(C1-C6 alkylene)-NHC(O)-(C1-C6 aminoalkyl), C 1-6 Alkyl, halo, -CN, -OR 3 , -N(R 3 )2, -O-(C 1-6 each instance of n is independently 0 or 1.

[0009] The compounds of formula (I) (also referred to herein as "anthracycline derivatives") and pharmaceutically acceptable salts thereof may be useful for treating or preventing cell proliferative disorders in a patient. Without being bound by theory, it is believed that anthracycline derivatives act as inhibitors of topoisomerase.

[0010] Accordingly, provided herein are methods for treating or preventing a cell proliferative disorder in a patient, comprising administering to the patient an effective amount of at least one anthracycline derivative.

[0011] Further details are provided in the accompanying detailed description below.

[0012] Although methods and materials similar to those described herein can be used in the practice or testing of anthracycline derivatives, exemplary methods and materials are described herein. Other embodiments, aspects, and features are further described in or will be apparent from the following description, examples, and appended claims. DETAILED DESCRIPTION OF THE INVENTION

[0013] Novel anthracycline derivatives, compositions comprising at least one anthracycline derivative, and methods of using the anthracycline derivatives to treat or prevent cell proliferative disorders in a patient are described.

[0014] Definitions and Abbreviations Terms used herein have their ordinary meanings, and the meaning of such terms is independent at each occurrence. Nevertheless, and unless otherwise stated, the following definitions apply throughout the specification and claims. Chemical names, common names, and chemical structures may be used interchangeably to describe the same structure. When a compound is referred to using both a chemical structure and a chemical name, and an ambiguity exists between the structure and the name, it should be understood that the structure takes precedence. These definitions apply regardless of whether the term is used alone or in combination with other terms, unless otherwise stated. Thus, the definition of "alkyl" applies to "alkyl" as well as the "alkyl" portions of "hydroxyalkyl," "haloalkyl," "-O-alkyl," etc.

[0015] As used throughout this specification and disclosure, the following terms, unless otherwise specified, shall be understood to have the following meanings:

[0016] A "patient" is a human or non-human mammal. In one embodiment, the patient is a human.

[0017] As used herein, the term "effective amount" refers to an amount of a PNU anthracycline derivative and / or additional therapeutic agent, or composition thereof, effective to produce a desired therapeutic, ameliorative, inhibitory, or prophylactic effect when administered to a patient suffering from a cell proliferative disorder. In the combination therapies described herein, the effective amount can refer to individual agents or the entire combination, where the amounts of all agents administered together are effective, but the component agents of the combination may not be present in individually effective amounts.

[0018] The term "prevention" as used herein with respect to a cell proliferative disorder refers to reducing the likelihood of a cell proliferative disorder.

[0019] As used herein, the term "alkyl" refers to an aliphatic hydrocarbon group in which one of its hydrogen atoms has been replaced with a bond. An alkyl group can be straight-chained or branched and can contain from about 1 to about 20 carbon atoms. In one embodiment, an alkyl group contains from about 1 to about 10 carbon atoms. In a different embodiment, an alkyl group can contain from 1 to 10 carbon atoms ("C1-C 10and about 1 to about 6 carbon atoms ("C1-C6 alkyl"). Non-limiting examples of alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, neopentyl, isopentyl, n-hexyl, isohexyl, and neohexyl. Alkyl groups can be unsubstituted or substituted with one or more substituents, which may be the same or different, each independently selected from the group consisting of halo, alkenyl, alkynyl, aryl, cycloalkyl, cyano, hydroxy, -O-alkyl, -O-aryl, -alkylene-O-alkyl, alkylthio, -NH, -NH(alkyl), -N(alkyl), NH(cycloalkyl), -OC(O)-alkyl, -OC(O)-aryl, -OC(O)-cycloalkyl, -C(O)OH, and -C(O)O-alkyl. In one embodiment, an alkyl group is linear. In another embodiment, an alkyl group is branched. Unless otherwise specified, alkyl groups are unsubstituted.

[0020] As used herein, the term "alkenyl" refers to an aliphatic hydrocarbon group containing at least one carbon-carbon double bond in which one of the hydrogen atoms has been replaced with a bond. Alkenyl groups can be straight-chained or branched and can contain from about 2 to about 15 carbon atoms. In one embodiment, an alkenyl group contains from about 2 to about 10 carbon atoms. In another embodiment, an alkenyl group contains from about 2 to about 6 carbon atoms. Non-limiting examples of alkenyl groups include ethenyl, propenyl, n-butenyl, 3-methylbut-2-enyl, n-pentenyl, octenyl, and decenyl. Alkenyl groups can be unsubstituted or substituted with one or more substituents, which can be the same or different. Each substituent is independently selected from the group consisting of halo, alkenyl, alkynyl, aryl, cycloalkyl, cyano, hydroxy, -O-alkyl, -O-aryl, -alkylene-O-alkyl, alkylthio, -NH, -NH(alkyl), -N(alkyl), -NH(cycloalkyl), -OC(O)-alkyl, -OC(O)-aryl, -OC(O)-cycloalkyl, -C(O)OH, and -C(O)O-alkyl. 10 The term "alkenyl" refers to an alkenyl group having from 2 to 10 carbon atoms. Unless otherwise specified, an alkenyl group is unsubstituted.

[0021] As used herein, the term "alkynyl" refers to an aliphatic hydrocarbon group containing at least one carbon-carbon triple bond and in which one of the hydrogen atoms has been replaced with a bond. Alkynyl groups are straight-chained or branched and contain from about 2 to about 15 carbon atoms. In one embodiment, an alkynyl group contains from about 2 to about 10 carbon atoms. In another embodiment, an alkynyl group contains from about 2 to about 6 carbon atoms. Non-limiting examples of alkynyl groups include ethynyl, propynyl, 2-butynyl, and 3-methylbutynyl. Alkynyl groups are optionally unsubstituted or substituted with one or more substituents, which may be the same or different, each substituent being independently selected from the group consisting of halo, alkenyl, alkynyl, aryl, cycloalkyl, cyano, hydroxy, -O-alkyl, -O-aryl, -alkylene-O-alkyl, alkylthio, -NH, -NH(alkyl), -N(alkyl), -NH(cycloalkyl), -OC(O)-alkyl, -OC(O)-aryl, -OC(O)-cycloalkyl, -C(O)OH and -C(O)O-alkyl. 10 The term "alkynyl" refers to an alkynyl group having from 2 to 10 carbon atoms. Unless otherwise specified, an alkynyl group is unsubstituted.

[0022] The term "alkylene," as used herein, refers to an alkyl group, as defined above, in which one of the hydrogen atoms has been replaced with a bond. Non-limiting examples of alkylene groups include -CH-, -CHCH-, -CHCHCH-, -CHCHCHCH-, -CH(CH)CHCH-, -CH(CH)-, and -CHCH(CH)CH-. In one embodiment, an alkylene group has from 1 to about 10 carbon atoms. In another embodiment, an alkylene group has from about 1 to about 6 carbon atoms. In another embodiment, an alkylene group is branched. In another embodiment, an alkylene group is linear. In one embodiment, an alkylene group is -CH-. The term "C1-C6 alkylene" refers to an alkylene group having from 1 to 6 carbon atoms.

[0023] The term "alkenylene," as used herein, refers to an alkenyl group, as defined above, in which one of the alkenyl group's hydrogen atoms has been replaced with a bond. Examples of alkylene groups include, but are not limited to, -CH=CH-, -CH=CHCH2-, -CH2CH2CH=CH-, and -CH2(CH3)C=CH-. In one embodiment, an alkenylene group has from 2 to about 6 carbon atoms. In one embodiment, an alkenylene group has from about 2 to about 10 carbon atoms. In another embodiment, an alkenylene group is branched. In another embodiment, an alkenylene group is linear. The term "C2-C6 alkenylene" refers to an alkenylene group having from 2 to 6 carbon atoms.

[0024] As used herein, the term "alkynylene" refers to an alkynyl group, as defined above, wherein one of the alkynyl group's hydrogen atoms has been replaced with a bond. Non-limiting examples of alkylene groups include -C≡C-, -C≡CCH2-, and -C≡CCH(CH3)2-. In one embodiment, an alkynylene group has from 2 to about 6 carbon atoms. In another embodiment, an alkynylene group has from 2 to about 10 carbon atoms. In another embodiment, an alkynylene group is branched. In another embodiment, an alkynylene group is linear. The term "C2-C6 alkynylene" refers to an alkynylene group having from 2 to 6 carbon atoms. "C2-C 10 The term "alkynylene" refers to an alkynylene group having 2 to 10 carbon atoms.

[0025] As used herein, the term "aminoalkyl" refers to an alkyl group, as defined above, wherein one of the alkyl group's hydrogen atoms is replaced with -NH, -NH(C-C alkyl), or -N(C-C alkyl). In one embodiment, an aminoalkyl group has 1 to 6 carbon atoms. Non-limiting examples of aminoalkyl groups include -CHNH, -CHN(CH), -CHCHNH, and -CHNH(CH). The term "C-C aminoalkyl" refers to an aminoalkyl group having 1 to 6 carbon atoms.

[0026] As used herein, the term "aryl" refers to an aromatic monocyclic or multicyclic ring system containing from about 6 to about 14 carbon atoms. In one embodiment, an aryl group contains from about 6 to about 10 carbon atoms ("C6-C 10 "aryl"). The aryl group can be substituted with one or more "ring system substituents" which may be the same or different and are defined herein below. In one embodiment, an aryl group can be fused to a cycloalkyl or cycloalkanoyl group. Non-limiting examples of aryl groups include phenyl and naphthyl. Examples of aryl groups fused to a cycloalkyl ring include: [ka]

[0027] In one embodiment, an aryl group is phenyl. In another embodiment, an aryl group is naphthalene. Unless otherwise specified, alkyl groups are unsubstituted.

[0028] As used herein, the term "cycloalkyl" refers to a non-aromatic monocyclic or polycyclic ring system containing from about 3 to about 11 ring carbon atoms. In one embodiment, a cycloalkyl contains from about 5 to about 11 ring carbon atoms. In another embodiment, a cycloalkyl is monocyclic and contains from about 3 to about 7 ring atoms. In another embodiment, a cycloalkyl is monocyclic and contains from about 5 to about 6 ring atoms. In another embodiment, a cycloalkyl is bicyclic and contains from about 4 to 10 ring atoms. Non-limiting examples of monocyclic cycloalkyls include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Non-limiting examples of polycyclic cycloalkyls include 1-decalinyl, norbornyl, and adamantyl. Cycloalkyl groups may be the same or different and may be substituted with one or more "ring system substituents," as defined herein below. Unless otherwise specified, a cycloalkyl group is unsubstituted. In one embodiment, a cycloalkyl group is unsubstituted. The term "3- to 7-membered monocyclic cycloalkyl" refers to a monocyclic cycloalkyl group having from 3 to 7 ring carbon atoms. The term "5- to 11-ring bicyclic cycloalkyl group" refers to a bicyclic cycloalkyl group having from 5 to 11 ring carbon atoms.

[0029] Polycyclic cycloalkyl groups can have fused rings, spirocyclically linked rings, and bridged rings. In one embodiment, a cycloalkyl group is a spirocyclic cycloalkyl group having from 5 to 11 ring carbon atoms ("C5-C 11 Illustrative examples of such bicyclic cycloalkyl groups include: [ka]

[0030] In another embodiment, the cycloalkyl group is a fused bicyclic cycloalkyl group having 5 to 11 ring carbon atoms ("C5-C 11Illustrative examples of such fused bicyclic cycloalkyl groups include: [ka]

[0031] In another embodiment, the cycloalkyl group is a bridged bicyclic cycloalkyl group having 5 to 11 ring carbon atoms ("C5-C 11 The group can be a bridged bicyclic cycloalkyl group, or a bridged tricyclic cycloalkyl group having 6 to 14 ring carbon atoms. Illustrative examples of such bridged bicyclic and tricyclic heterocycloalkyl groups include: [ka]

[0032] A ring carbon atom of a cycloalkyl group may be functionalized as a carbonyl group. Illustrative examples of such cycloalkyl groups (also referred to herein as "cycloalkanoyl" groups) include, but are not limited to, cyclobutanoyl. [ka]

[0033] As used herein, the term "cycloalkenyl" refers to a non-aromatic monocyclic or polycyclic ring system containing about 4 to about 10 ring carbon atoms and containing at least one endocyclic double bond. In one embodiment, a cycloalkenyl contains about 4 to about 7 ring carbon atoms. In another embodiment, a cycloalkenyl contains 5 or 6 ring atoms. Non-limiting examples of monocyclic cycloalkenyls include cyclopentenyl, cyclohexenyl, cyclohepta-1,3-dienyl, and the like. Cycloalkenyl groups are optionally substituted with one or more "ring system substituents," which may be the same or different, and are defined herein below. A ring carbon atom of a cycloalkyl group may be functionalized as a carbonyl group. In one embodiment, a cycloalkenyl group is cyclopentenyl. In another embodiment, a cycloalkenyl group is cyclohexenyl. The term "4- to 6-membered cycloalkenyl" refers to a cycloalkenyl group having 4 to 6 ring carbon atoms.

[0034] As used herein, the term "halo" means -F, -Cl, -Br or -I.

[0035] The term "haloalkyl," as used herein, refers to an alkyl group, as defined above, in which one or more of the hydrogen atoms has been replaced with a halogen. In one embodiment, a haloalkyl group has 1 to 10 carbon atoms. In another embodiment, a haloalkyl group has 1 to 6 carbon atoms. In another embodiment, a haloalkyl group is substituted with 1 to 6 F atoms. In a class of this embodiment, a haloalkyl group is substituted with 1 to 3 F atoms. Non-limiting examples of haloalkyl groups include -CH2CHF2, -CH2F, -CHF2, -CF3, -CH2Cl, and -CCl3. The term "C1-C6 haloalkyl" refers to a haloalkyl group having 1 to 6 carbon atoms.

[0036] The term "haloalkylene," as used herein, refers to a haloalkyl group, as defined above, in which one or more of the haloalkyl group's hydrogens has been replaced with a halogen. In one embodiment, a haloalkylene group has 1 to 10 carbon atoms. In another embodiment, a haloalkylene group has 1 to 6 carbon atoms. In another embodiment, a haloalkylene group is substituted with 1 to 6 F atoms. In a class of this embodiment, a haloalkylene group is substituted with 1 to 3 F atoms. Non-limiting examples of haloalkylene groups include -CHCHF, -CHF, -CHF, -CF, -CHCl, and -CCl. The term "C-C haloalkylene" refers to a haloalkylene group having 1 to 6 carbon atoms.

[0037] The term "hydroxyalkyl," as used herein, refers to an alkyl group, as defined above, in which one or more hydrogen atoms have been replaced with an -OH group. In one embodiment, a hydroxyalkyl group has from 1 to 10 carbon atoms. In another embodiment, a hydroxyalkyl group has 1 to 6 carbon atoms. Non-limiting examples of hydroxyalkyl groups include -CHOH, -CHCHOH, -CHCHCHOH, and -CHCH(OH)CH. "C1-C 10 The term "hydroxyalkyl" refers to a hydroxyalkyl group having from 1 to 10 carbon atoms.

[0038] As used herein, the term "heteroaryl" refers to an aromatic monocyclic or polycyclic ring system containing about 5 to about 14 ring atoms, wherein 1 to 4 of the ring atoms are independently O, N, or S, and the remaining ring atoms are carbon atoms. In one embodiment, a heteroaryl group has 5 to 10 ring atoms. In another embodiment, a heteroaryl group is monocyclic and has 5 or 6 ring atoms (a "5- or 6-membered monocyclic heteroaryl"). In another embodiment, a heteroaryl group is bicyclic and has 8 to 10 ring atoms (an "8- to 10-membered bicyclic heteroaryl"). In yet another embodiment, a heteroaryl group is bicyclic and has 9 or 10 ring atoms (a "9- or 10-membered bicyclic heteroaryl"). A heteroaryl group can be optionally substituted with one or more "ring system substituents" (defined herein below), which can be the same or different. A heteroaryl group is joined via a ring carbon atom, and any nitrogen atom of a heteroaryl can be optionally oxidized to the corresponding N-oxide. The term "heteroaryl" also encompasses heteroaryl groups as defined above fused to a benzene ring. Non-limiting examples of heteroaryl include pyridyl, pyrazinyl, furanyl, thienyl, pyrimidinyl, pyridone (e.g., N-substituted pyridone), isoxazolyl, isothiazolyl, oxazolyl, oxadiazolyl, thiazolyl, pyrazolyl, furazanyl, pyrrolyl, triazolyl, 1,2,4-thiadiazolyl, pyrazinyl, pyridazinyl, quinoxalinyl, phthalazinyl, oxindolyl, imidazo[1,2-a] Included are pyridinyl, imidazo[2,1-b]thiazolyl, benzofurazanyl, indolyl, azaindolyl, benzimidazolyl, benzothienyl, quinolinyl, imidazolyl, benzimidazolyl, thienopyridyl, quinazolinyl, thienopyrimidyl, pyrrolopyridyl, imidazopyridyl, isoquinolinyl, benzazindolyl, 1,2,4-triazinyl, benzothiazolyl, and the like, and all isomeric forms thereof. The term "heteroaryl" also refers to partially saturated heteroaryl moieties, such as tetrahydroisoquinolyl, tetrahydroquinolyl, and the like. In one embodiment, a heteroaryl group is a 5-membered heteroaryl.In another embodiment, the heteroaryl group is a 6-membered heteroaryl, such as pyridyl.

[0039] In one embodiment, the 8-10 membered bicyclic heteroaryl group includes a fused bicyclic heterocyclic group in which one of the two fused rings is phenyl or monocyclic heteroaryl, such as: [ka]

[0040] "9-14 membered tricyclic heteroaryl" includes 8-10 membered bicyclic heteroaryl groups in which a third ring is fused to one of the rings of the 8-10 membered bicyclic heteroaryl group. Such a third ring can be a cycloalkyl, heterocyclic alkyl, or heteroaryl ring. Examples of 9-14 membered tricyclic heteroaryl groups include: [ka]

[0041] As used herein, the term "heterocycloalkyl" refers to a non-aromatic, saturated, monocyclic or polycyclic ring system containing 3 to about 14 ring atoms, wherein 1 to 4 of the ring atoms are independently O, S, N, or Si, and the remaining ring atoms are carbon atoms. A heterocycloalkyl group may be linked through a ring carbon, ring silicon, or ring nitrogen atom. In one embodiment, a heterocycloalkyl group is monocyclic. In one embodiment, a heterocycloalkyl group is monocyclic and has about 3 to about 7 ring atoms (a "3- to 7-membered monocyclic heterocycloalkyl"). In another embodiment, a heterocycloalkyl group is monocyclic and has 5 or 6 ring atoms (a "5- or 6-membered monocyclic heterocycloalkyl"). In one embodiment, a heterocycloalkyl group is bicyclic. In another embodiment, a heterocycloalkyl group is bicyclic and has about 5 to about 11 ring atoms (a "5- to 11-ring bicyclic heterocycloalkyl"). In another embodiment, a heterocycloalkyl group is tricyclic and has about 10 to about 14 ring atoms ("10-14 membered tricyclic heterocycloalkyl"). There are no adjacent oxygen and / or sulfur atoms in the ring system. Any -NH group in a heterocycloalkyl ring may be present in a protected form, for example, with an -N(BOC), -N(CBz), or -N(Tos) group; such protected heterocycloalkyl groups are considered part of the present disclosure. A heterocycloalkyl group may be optionally substituted with one or more "ring system substituents" (defined herein below), which may be the same or different. The nitrogen or sulfur atom of a heterocycloalkyl may be optionally oxidized to the corresponding N-oxide, S-oxide, or S,S-dioxide. Non-limiting examples of monocyclic heterocycloalkyl rings include oxetanyl, piperidyl, pyrrolidinyl, piperazinyl, morpholinyl, thiomorpholinyl, thiazolidinyl, 1,4-dioxanyl, tetrahydrofuranyl, tetrahydrothiophenyl, δ-lactam, δ-lactone, silacyclopentane, silapyrrolidine, and the like, and all isomers thereof. Illustrative examples of silyl-containing heterocycloalkyl groups include: [ka]

[0042] A ring carbon atom of a heterocycloalkyl group may be functionalized as a carbonyl group ("oxo"). Illustrative examples of such heterocycloalkyl groups include, but are not limited to: [ka]

[0043] The ring sulfur atom of a heterocycloalkyl group may be functionalized as a sulfonyl group. Examples of such heterocycloalkyl groups are: [ka]

[0044] In one embodiment, a heterocycloalkyl group is a 5-membered monocyclic heterocycloalkyl. In another embodiment, a heterocycloalkyl group is a 6-membered monocyclic heterocycloalkyl.

[0045] Polycyclic heterocycloalkyl groups can have fused rings, spirocyclically linked rings, and bridged rings. In one embodiment, a heterocycloalkyl group can be a bicyclic spirocyclic heteroaryl group having 1 to 11 ring atoms. Illustrative examples of such bicyclic heterocycloalkyl groups include: [ka]

[0046] In another embodiment, the heterocycloalkyl group can be a fused bicyclic heterocycloalkyl group having 5 to 11 ring atoms (a "5- to 11-membered fused bicyclic heterocycloalkyl"). Illustrative examples of such fused bicyclic heterocycloalkyl groups include: [ka]

[0047] In another embodiment, the heterocycloalkyl group can be a bridged heterocycloalkyl group having 5 to 11 ring atoms (a "5- to 11-membered bridged bicyclic heterocycloalkyl"). Illustrative examples of such bridged bicyclic heterocycloalkyl groups include: [ka]

[0048] As used herein, the term "heterocycloalkenyl" refers to a heterocycloalkyl group, as defined above, containing 4 to 10 ring atoms and at least one endocyclic carbon-carbon or carbon-nitrogen double bond. A heterocycloalkenyl group can be linked via a ring carbon or ring nitrogen atom. In one embodiment, a heterocycloalkenyl group has 4 to 6 ring atoms. In another embodiment, a heterocycloalkenyl group is monocyclic and has 5 or 6 ring atoms. In another embodiment, a heterocycloalkenyl group is bicyclic. A heterocycloalkenyl group can be substituted with one or more ring system substituents, where "ring system substituent" is defined above. The nitrogen or sulfur atom of a heterocycloalkenyl group can be optionally oxidized to the corresponding N-oxide, S-oxide, or S,S-dioxide. A ring carbon atom of a heterocycloalkenyl group can be functionalized as a carbonyl group. Non-limiting examples of heterocyclic alkenyl groups include 1,2,3,4-tetrahydropyridinyl, 1,2-dihydropyridinyl, 1,4-dihydropyridinyl, 1,2,3,6-tetrahydropyridinyl, 1,4,5,6-tetrahydropyrimidinyl, 2-pyrrolinyl, 3-pyrrolinyl, 2-imidazolinyl, 2-pyrazolinyl, dihydroimidazolyl, dihydrooxazolyl, dihydrooxadiazolyl, dihydrothiazolyl, 3,4-dihydro-2H-pyranyl, dihydrofuranyl, fluoro-substituted dihydrofuranyl, 7-oxabicyclo[2.2.1]heptenyl, dihydrothiophenyl, dihydrothiopyranyl, and the like. In one embodiment, a heterocyclic alkenyl group is a 5-membered heterocyclic alkenyl. In another embodiment, a heterocyclic alkenyl group is a 6-membered heterocyclic alkenyl. The term "4- to 6-membered heterocycloalkenyl" refers to a heterocycloalkenyl group having 4 to 6 ring atoms.

[0049] The term "substituted" means that one or more hydrogens on the designated atom have been replaced with a choice from the list of indicated substituents, provided that the replacement does not exceed the normal valence of the designated atom in its current state, and that the substitution results in a stable compound. Combinations of substituents and / or variables are permissible only if such combinations result in stable compounds. A "stable compound" or "stable structure" means a compound that is sufficiently robust to survive isolation to a useful degree of purity from a reaction mixture, and formulation into an efficacious therapeutic agent.

[0050] As used herein, the term "in substantially purified form" refers to the physical state of a compound after it has been isolated from a synthetic process (e.g., a reaction mixture), a natural source, or a combination thereof. The term "in substantially purified form" also refers to the physical state of a compound after it has been obtained from a purification process(es) described herein or known to those of ordinary skill in the art (e.g., chromatography, recrystallization, etc.), such that the compound has a purity sufficient to be characterizable by standard analytical techniques described herein or known to those of ordinary skill in the art.

[0051] It should be noted that in the text, schemes, examples, and tables herein, all carbon and heteroatoms with unsatisfied valences are assumed to have sufficient hydrogen atoms to satisfy the valences.

[0052] When a functional group of a compound is referred to as being "protected," this means that the group is in a modified form so as to prevent undesired side reactions at the protected site when the compound is subjected to a reaction. Suitable protecting groups are known to those skilled in the art and can be found in standard texts, such as Greene et al., Protective Groups in Organic Synthesis, Wiley-Interscience, New York (1999).

[0053] Examples of "ring system substituents" include alkyl, alkenyl, alkynyl, aryl, heteroaryl, -alkylene-aryl, -arylene-alkyl, -alkylene-heteroaryl, -alkenylene-heteroaryl, -alkynylene-heteroaryl, -OH, hydroxyalkyl, haloalkyl, -O-alkyl, -O-haloalkyl, -alkylene-O-alkyl, -O-aryl, -O-alkylene-aryl, acyl, -C(O)- Aryl, halo, -NO2, -CN, -SF5, -C(O)OH, -C(O)O-alkyl, -C(O)O-aryl, -C(O)O-alkylene-aryl, -S(O)-alkyl, -S(O)2-alkyl, -S(O)-aryl, -S(O)2-aryl, -S(O)-heteroaryl, -S(O)2-heteroaryl, -S-alkyl, -S-aryl, -S-heteroaryl, -S-alkylene-aryl, -S-alkylenehetene -S(O)2-alkylene-aryl, -S(O)2-alkylene-heteroaryl, -Si(alkyl)2, -Si(aryl)2, -Si(heteroaryl)2, -Si(alkyl)(aryl), -Si(alkyl)(cycloalkyl), -Si(alkyl)(heteroaryl), cycloalkyl, heterocycloalkyl, -OC(O)-alkyl, -OC(O)-aryl, -OC(O)-cycloalkyl, -C=N-CN Examples include, but are not limited to, -NH, -C(=NH)-NH, -C(=NH)-NH(alkyl), -N(Y)(Y), -alkylene-N(Y)(Y), -C(O)N(Y)(Y), and -S(O)N(Y)(Y), where Y and Y may be the same or different and are independently selected from the group consisting of hydrogen, alkyl, aryl, cycloalkyl, and -alkylene-aryl. A "ring system substituent" can also refer to a single moiety that simultaneously replaces two available hydrogens on two adjacent carbon atoms of a ring system (one H on each carbon). Examples of such moieties are methylenedioxy, ethylenedioxy, -C(CH)-, and the like, which can be substituted, for example, [ka] It forms parts such as:

[0054] Substituents or variables (e.g., R 5 , n, etc.) occurs more than once in any constituent or in formula (I), and unless otherwise stated, its definition at each occurrence is independent of its definition at every other occurrence.

[0055] As used herein, the term "composition" is intended to encompass a product containing the specified ingredients in the specified amounts, as well as a product resulting from a combination of the specified ingredients in the specified amounts.

[0056] Prodrugs and solvates of the compounds of the present disclosure are also contemplated herein. Prodrugs are described in T. Higuchi and V. Stella, Pro-drugs as Novel Delivery Systems (1987). 14 of the ACS Symposium Series, and Bioreversible Carriers in Drug Design, (1987) Edward B. Roche ed., American Pharmaceutical Association and Pergamon Press. The term "prodrug" means a compound (e.g., a drug precursor) that is transformed in vivo to yield a PNU anthracycline derivative or a pharmaceutically acceptable salt or solvate of that compound. This transformation may occur by various mechanisms (e.g., by metabolic or chemical processes), such as, for example, by hydrolysis in blood.

[0057] For example, if a PNU anthracycline derivative or a pharmaceutically acceptable salt, hydrate, or solvate thereof contains a carboxylic acid functional group, a prodrug may be prepared in which the hydrogen atom of the acid group is replaced with, for example, a (C1-C8) alkyl, (C2-C 12) alkanoyloxymethyl, 1-(alkanoyloxy)ethyl having 4 to 9 carbon atoms, 1-methyl-1-(alkanoyloxy)-ethyl having 5 to 10 carbon atoms, alkoxycarbonyloxymethyl having 3 to 6 carbon atoms, 1-(alkoxycarbonyloxy)ethyl having 4 to 6 carbon atoms, 1-methyl-1-(alkoxycarbonyloxy)ethyl having 5 to 8 carbon atoms, N-(alkoxycarbonyl)aminomethyl having 3 to 9 carbon atoms, 4 to 10 carbon atoms with groups such as 1-(N-(alkoxycarbonyl)amino)ethyl, 3-phthalidyl, 4-crotonolactonyl, γ-butyrolactone-4-yl, di-N,N-(C1-C2)alkylamino(C2-C3)alkyl (such as β-dimethylaminoethyl), carbamoyl-(C1-C2)alkyl, N,N-di(C1-C2)alkylcarbamoyl-(C1-C2)alkyl, and piperidino-, pyrrolidino-, or morpholino(C2-C3)alkyl.

[0058] Similarly, if the PNU anthracycline derivative contains an alcohol functional group, the prodrug may be one in which the hydrogen atom of the alcohol group is replaced with, for example, (C1-C6)alkanoyloxymethyl, 1-((C1-C6)alkanoyloxy)ethyl, 1-methyl-1-((C1-C6)alkanoyloxy)ethyl, (C1-C6)alkoxycarbonyloxymethyl, N-(C1-C6)alkoxycarbonylaminomethyl, succinoyl, (C1-C6)alkanoyl, α-amino(C1 and α-amino(C1-C4)alkyl, α-amino(C1-C4)alkylene-aryl, arylacyl, and α-aminoacyl, or α-aminoacyl-α-aminoacyl (wherein each α-aminoacyl group is independently selected from naturally occurring L-amino acids, -P(O)(OH)2, -P(O)(O(C1-C6)alkyl)2, or glycosyl (a group resulting from removal of the hydroxyl group of a hemiacetal form of a carbohydrate), etc.).

[0059] When an amine functional group is incorporated into the PNU anthracycline derivative, the prodrug may replace a hydrogen atom of the amine group with, for example, R-carbonyl-, RO-carbonyl-, NRR′-carbonyl-, where R and R′ are each independently (C-C 10 ) alkyl, (C3-C7) cycloalkyl, benzyl, natural α-aminoacyl, -C(OH)C(O)OY 1 (In the formula, Y 1 is H, (C1-C6) alkyl or benzyl, -C(OY 2 )Y 3 (In the formula, Y 2 is (C1-C4) alkyl, and Y 3 is (C1-C6) alkyl); carboxy(C1-C6) alkyl; amino(C1-C4) alkyl or mono-N- or di-N,N-(C1-C6) alkylaminoalkyl; -C(Y 4 )Y 5 (In the formula, Y 4 is H or methyl and Y 5 is mono-N- or di-N,N-(C1-C6) alkylaminomorpholino); may be formed by substitution with groups such as piperidin-1-yl or pyrrolidin-1-yl.

[0060] Pharmaceutically acceptable esters of the compounds of the present invention include those of the following group: (1) carboxylic acid esters obtained by esterification of the hydroxy group of a hydroxyl compound, wherein the non-carbonyl portion of the carboxylic acid moiety of the ester group is selected from the group consisting of straight-chain or branched alkyl (e.g., methyl, ethyl, n-propyl, isopropyl, t-butyl, sec-butyl, or n-butyl), alkoxyalkyl (e.g., methoxymethyl), aralkyl (e.g., benzyl), aryloxyalkyl (e.g., phenoxymethyl), aryl (e.g., halogen, C 1-4 Alkyl or -OC 1-4(2) sulfonate esters, such as alkyl- or aralkylsulfonyl (e.g., methanesulfonyl); (3) amino acid esters (e.g., L-valyl or L-isoleucyl); (4) phosphate esters, and (5) mono-, di-, or triphosphate esters. The phosphate esters are, for example, C 1-20 Alcohol or its reactive derivative or 2,3-di(C 6-24 ) acylglycerols, which may be further esterified.

[0061] One or more compounds of the present disclosure may exist in unsolvated as well as solvated forms with pharmaceutically acceptable solvents (e.g., water, ethanol, etc.), and the present disclosure is intended to encompass both solvated and unsolvated forms. "Solvate" refers to a physical association of a compound of the present disclosure with one or more solvent molecules. This physical association involves varying degrees of ionic and covalent bonding (e.g., hydrogen bonding). In certain cases, solvates are capable of isolation, for example, when one or more solvent molecules are incorporated within the crystal lattice of a crystalline solid. "Solvate" encompasses both solution-phase and isolatable solvates. Non-limiting examples of solvates include ethanolates, methanolates, and the like. A "hydrate" is a solvate in which the solvent molecule is water.

[0062] One or more compounds of the present disclosure may be converted into a solvate. The preparation of solvates is generally known. Thus, for example, see M. Caira et al., J. Pharmaceutical Sci., 93(3) , 601-611 (2004) describes the preparation of solvates of the antifungal drug fluconazole in ethyl acetate as well as in water. Similar preparations of solvates, hemisolvates, hydrates, etc. are described in EC van Tonder et al., AAPS PharmSciTechours., 5(1), article 12 (2004); and AL Bingham et al., Chem. Commun., 603-604 (2001). A typical, non-limiting process involves dissolving a compound of the present invention in a desired amount of a desired solvent (organic or aqueous or a mixture thereof) at a temperature above room temperature, and cooling the solution at a rate sufficient to form crystals, which are then isolated by standard methods. For example, analytical techniques such as IR spectroscopy indicate the presence of the solvent (or water) in the crystals as a solvate (or hydrate).

[0063] PNU anthracycline derivatives can form salts, and such salts are also included within the scope of the present disclosure. As used herein, the term "salt(s)" refers to acidic salts formed with inorganic and / or organic acids and basic salts formed with inorganic and / or organic bases. Furthermore, when a PNU anthracycline derivative contains both a basic moiety (such as, but not limited to, pyridine or imidazole) and an acidic moiety (such as, but not limited to, a carboxylic acid), zwitterions ("internal salts") may be formed and are encompassed by the term "salt(s)" as used herein. In one embodiment, the salt is a pharmaceutically acceptable (i.e., non-toxic, physiologically acceptable) salt. In another embodiment, the salt is a salt other than a pharmaceutically acceptable salt. Salts of compounds of Formula (I) can be formed, for example, by reacting a PNU anthracycline derivative with an amount (e.g., an equivalent amount) of an acid or base in a medium (e.g., one in which the salt precipitates, or an aqueous medium), followed by lyophilization.

[0064] Exemplary acid addition salts include acetate, ammonium, ascorbate, benzoate, benzenesulfonate, bisulfate, borate, butyrate, citrate, camphorate, camphosulfonate, fumarate, hydrochloride, hydrobromide, hydroiodide, lactate, maleate, methanesulfonate (also called mesylate), naphthalenesulfonate, nitrate, oxalate, phosphate, propionate, salicylate, succinate, sulfate, tartrate, thiocyanate, toluenesulfonate (also known as tosylate), etc. Additionally, acids generally considered suitable for forming pharmaceutically useful salts from basic pharmaceutical compounds are described, for example, in P. Stahl et al., Camille G. (eds.) Handbook of Pharmaceutical Salts. Properties, Selection and Use. (2002) Zurich: Wiley-VCH; S. Berge et al., Journal of Pharmaceutical Sciences (1977) 66(1) 1-19; P. Gould, International J. of Pharmaceutics (1986) 33 201-217; Anderson et al., The Practice of Medicinal Chemistry (1996), Academic Press, New York; and The Orange Book (Food & Drug Administration, Washington, DC (online)), the disclosures of which are incorporated herein by reference. In one embodiment, the acid salt is an ammonium salt or a diammonium salt.

[0065] Exemplary basic salts include ammonium salts, alkali metal salts (such as sodium, lithium, and potassium salts), alkaline earth metal salts (such as calcium and magnesium salts), salts with organic bases (e.g., organic amines) (e.g., dicyclohexylamine, t-butylamine, choline, etc.), and salts with amino acids (arginine, lysine, etc.). Basic nitrogen-containing groups may be quaternized with agents such as lower alkyl halides (e.g., methyl, ethyl, and butyl chlorides, bromides, and iodides), dialkyl sulfates (e.g., dimethyl, diethyl, and dibutyl sulfate), long-chain halides (e.g., decyl chloride, bromide, and iodide, lauryl, and stearyl), aralkyl halides (e.g., benzyl and phenethyl bromides), and the like.

[0066] All such acid and base salts are intended to be pharmaceutically acceptable salts within the scope of this disclosure, and all acid and base salts are considered equivalent for purposes of this invention to the free forms of the corresponding compounds.

[0067] Diastereomeric mixtures can be separated into their individual diastereomers based on their physical chemical differences by methods known to those skilled in the art, such as chromatography and / or fractional crystallization. Enantiomers can also be separated by converting the enantiomeric mixture to a diastereomeric mixture by reaction with an appropriate optically active compound (e.g., a chiral auxiliary such as a chiral alcohol or Mosher's acid chloride), separating the diastereomers, and converting the individual diastereomers to the corresponding pure enantiomers (e.g., by hydrolysis). Stereochemically pure compounds can also be prepared by using chiral starting materials or salt resolution techniques. Some PNU anthracycline derivatives can also be atropisomers (e.g., substituted biaryls) and are considered part of the present disclosure. Enantiomers can also be directly separated using chiral chromatographic techniques.

[0068] The PNU anthracycline derivatives may also exist in different tautomeric forms, all of which are encompassed within the scope of the present disclosure. For example, all keto-enol and imine-enamine forms of the compounds are included in the present disclosure.

[0069] All stereoisomers (e.g., geometric isomers, optical isomers, etc.) of the compounds of the present invention (including salts, solvates, hydrates, esters, and prodrugs of the compounds, as well as salts, solvates, and esters of the prodrugs), such as those that may exist due to asymmetric carbons on various substituents, e.g., enantiomeric forms (which may exist even when there is no asymmetric carbon), rotamer forms, atropisomers, and diastereomeric forms, are contemplated within the scope of the present disclosure. When the PNU anthracycline derivatives incorporate double bonds or fused rings, both the cis- and trans-forms, as well as mixtures, are encompassed within the scope of the present disclosure.

[0070] Individual stereoisomers of the compounds of the present disclosure may, for example, be substantially free of other isomers, e.g., as a racemate or mixed with all other or selected stereoisomers. The chiral centers of the present invention may have the S or R configuration as defined by the IUPAC 1974 Recommendations. The use of terms such as "salt," "solvate," "ester," "prodrug," and the like is intended to apply equally to enantiomers, stereoisomers, rotamers, tautomers, positional isomers, racemates, or prodrug salts, solvates, esters, and prodrugs of the compounds of the present invention.

[0071] In the compounds of formula (I), atoms may exhibit their natural isotopic abundance, or one or more atoms may be artificially enriched in a particular isotope having the same atomic number but an atomic mass or mass number different from that predominantly found in nature. The present disclosure is intended to include all appropriate isotopic variations of the compounds of general formula I. For example, hydrogen ( 1 The different isotopic forms of H include protium (1 H) and deuterium ( 2 H). Protium is the predominant hydrogen isotope found in nature. Deuterium enrichment may confer certain therapeutic advantages (such as increased in vivo half-life or reduced dosage requirements) or may provide compounds useful as standards for characterizing biological samples. Isotopically enriched compounds of formula (I) may be prepared without undue experimentation by routine techniques known to those skilled in the art or by processes similar to those described in the schemes and examples herein, using appropriate isotopically enriched reagents and / or intermediates. In one embodiment, a compound of formula (I) has one or more hydrogen atoms replaced with deuterium.

[0072] Polymorphic forms of the PNU anthracycline derivatives, and of the salts, solvates, hydrates, esters and prodrugs of the PNU anthracycline derivatives, are intended to be included in this disclosure.

[0073] The following abbreviations are used below and have the following meanings: [Table 1]

[0074] Compounds of formula (I) Provided herein are PNU anthracycline derivatives of formula (I) below and pharmaceutically acceptable salts and solvates thereof: [ka] During the ceremony, R 1 is H or C 1-6 is alkyl; R 2 is C1-C6 hydroxyalkyl, 5-11 ring bridged bicyclic heterocyclic alkyl, 5-11 ring fused bicyclic heterocyclic alkyl, C1-C6 aminoalkyl, -(C1-C6 alkylene)-NR 3C(O)—(C1-C6 aminoalkyl), —(C1-C6 alkylene)-NHC(O)NHNH2, —(C1-C6 alkylene)-NR 3 , -(C1-C6 alkylene)-N(R 3 )-(C1-C6 alkylene)-N(R 3 )-NHC(O)-(C1-C6 aminoalkyl), -(C1-C6 haloalkylene)-NR 3 , -(C1-C6 alkylene) n -(3- to 7-membered monocyclic heterocyclic alkyl), -(C1-C6 alkylene)-NR 3 C(O)-(3- to 7-membered monocyclic heterocyclic alkyl), -(C1-C6 alkylene)-NR 3 C(O)—(C3-C7 monocyclic cycloalkyl), —(C1-C6 alkylene) n -(C5-C 11 Fused bicyclic cycloalkyl), -(C1-C6 alkylene) n -(C5-C 11 Bridged bicyclic cycloalkyl), -(C1-C6 alkylene) n -(C3-C7 monocyclic cycloalkyl), -(C1-C6 alkylene) n -(C6-C 10 aryl), -(C1-C6 alkylene) n -(5- or 6-membered monocyclic heteroaryl), and 5- to 11-membered spirocyclic heterocycloalkyl, wherein the 3- to 7-membered monocyclic heterocycloalkyl group, the 5- to 10-membered fused bicyclic heterocycloalkyl group, the 5- to 10-membered bridged bicyclic heterocycloalkyl group, the C3-C7 monocyclic cycloalkyl group, the C6-C7 10 an aryl group, the 5- or 6-membered monocyclic heteroaryl group, the C5-C 11 The bicyclic cycloalkyl group and the 5- to 11-membered spirocyclic heterocycloalkyl group each optionally and independently include one or more R A group, and the 3- to 7-membered monocyclic heterocycloalkyl group may have one or more ring carbon atoms substituted with an oxo group; Or, R 1 and R 2are taken together with the common nitrogen atom to which they are each bonded to form (i) a 3- to 7-membered monocyclic heterocycloalkyl group, (ii) a 5- to 11-ring bridged bicyclic heterocycloalkyl group, (iii) a 5- to 11-ring fused bicyclic heterocycloalkyl group, or (iv) a 5- to 11-ring spirocyclic heterocycloalkyl group, and the 3- to 7-membered monocyclic heterocycloalkyl group, the 5- to 11-ring bicyclic heterocycloalkyl group, the 5- to 11-ring fused heterocycloalkyl group, and the 5- to 11-ring spirocyclic heterocycloalkyl group each optionally and independently contain one or more R B may be substituted with a group; R 3 In each case, independently, H or C 1-6 is alkyl; R A In each case, independently, C 1-6 Alkyl, halo, -CN, -OR 3 , -(C1-C6 alkylene) n -N(R 3 )2, C1-C6 aminoalkyl, -(C1-C6 alkylene)-NHC(O)-(C1-C6 aminoalkyl), -O-(C 1-6 and -(C-C alkylene)-(3- to 7-membered monocyclic heterocycloalkyl), wherein the 3- to 7-membered monocyclic heterocycloalkyl group is optionally and independently selected from one or more R c may be substituted with a group; R B In each case, independently, C 1-6 Alkyl, halo, -CN, -OR 3 , -N(R 3 )2, C1-C6 aminoalkyl, -(C1-C6 alkylene)-NHC(O)-(C1-C6 aminoalkyl), -O-(C 1-6 and -(C-C alkylene)-(3- to 7-membered monocyclic heterocycloalkyl), wherein the 3- to 7-membered monocyclic heterocycloalkyl group is optionally and independently selected from one or more R c may be substituted with a group; R c In each case, independently, C 1-6 Alkyl, halo, -CN, -OR 3 , -N(R3 )2, C1-C6 aminoalkyl, -O-(C 1-6 alkyl), -NHC(O)-(C1-C6 aminoalkyl), -(C1-C6 alkylene)-NHC(O)-(C1-C6 aminoalkyl), C 1-6 Alkyl, halo, -CN, -OR 3 , -N(R 3 )2, -O-(C 1-6 alkyl), and —NHC(O)CHOH; Each occurrence of n is independently 0 or 1.

[0075] In one embodiment, the compound of formula (I) has the formula (Ia): [ka]

[0076] In another embodiment, the compound of formula (I) has the following formula (Ib): [ka]

[0077] In one embodiment, R 1 is H and R 2 is C3-C7 monocyclic cycloalkyl, C5-C 11 Fused Bicyclic Cycloalkyl, C5-C 11 Bridged Bicyclic Cycloalkyl, C6-C 10 aryl, 3- to 7-membered monocyclic heterocycloalkyl, 5- to 11-ring bridged bicyclic heterocycloalkyl, 5- to 11-ring fused bicyclic heterocycloalkyl, 5- to 11-membered spirocyclic heterocycloalkyl, and 5- or 6-membered monocyclic heteroaryl; 11 Fused bicyclic cycloalkyl groups, the C5-C 11 Bridged bicyclic cycloalkyl groups, the C6-C 10The aryl group, the 3- to 7-membered monocyclic heterocycloalkyl group, the 5- to 10-membered fused bicyclic heterocycloalkyl group, the 5- to 10-membered bridged bicyclic heterocycloalkyl group, the 5- to 11-membered spirocyclic heterocycloalkyl group, and the 5- or 6-membered heteroaryl group each optionally and independently include one or more R A It may be substituted with a group.

[0078] In another embodiment, R 1 is H and R 2 is selected from the following: [ka] TIFF2026500987000022.tif121142

[0079] In another embodiment, R 1 is H and R 2 is C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, -(C1-C6 alkylene)-NR 3 C(O)-(C1-C6 aminoalkyl), -(C1-C6 alkylene)-NHC(O)NHNH2, -(C1-C6 alkylene)-N(R 3 )-(C1-C6 alkylene)-N(R 3 )-NHC(O)-(C1-C6 aminoalkyl), and -(C1-C6 haloalkylene)-NR 3 is selected from.

[0080] In a further embodiment, R 1 is H and R 2is -CH2CH2NHC(O)CH2NH2, -CH2CH2NHC(O)NHNH2, -CH2CH2NHC(O)CH(CH3)NH2, -(CH2)3NH(CH2)3NHC (O)CH2NH2, -CH2CH2N(CH3)C(O)C(CH3)(NH2)CH(CH3)2, -CH2CH2NHCH3, -(CH2)4NH2, -CH2C(CH3)2C selected from H2NH2, -(CH2)3N(CH3)CH2CH2CH2NH2, -CH2C(CH3)2NH2, -(CH2)3NH2, -CH2CH(NH2)CF3, -CH2CH(NH2)CHF2, -CH2CH2CH(NH2)CF3, -CH2CH2CH(NH2)CHF2, -(CH2)3NHCH3, -CH2CH2OH, and -CH2NH2.

[0081] In one embodiment, R 1 is H and R 2 is -(C1-C6 alkylene)-(3- to 7-membered monocyclic heterocyclic alkyl), -(C1-C6 alkylene)-NR 3 C(O)-(3- to 7-membered monocyclic heterocyclic alkyl), -(C1-C6 alkylene)-NR 3 C(O)-(C3-C7 monocyclic cycloalkyl), -(C1-C6 alkylene)-(C5-C 11 bridged bicyclic cycloalkyl group), -(C1-C6 alkylene)-(C3-C7 monocyclic cycloalkyl), -(C1-C6 alkylene)-(C6-C 10 any of the 3- to 7-membered monocyclic heterocycloalkyl groups, any of the C3-C7 monocyclic cycloalkyl groups, and any of the C6-C 10 The aryl group, and the 5- or 6-membered monocyclic heteroaryl group may each optionally and independently be one or more R A It may be substituted with a group.

[0082] In another embodiment, R 1 is H and R 2 is selected from the following: [ka]

[0083] In one embodiment, R 1 and R 2 are taken together with the common nitrogen atom to which they are each bonded to form a 3- to 7-membered monocyclic heterocycloalkyl group, a 5- to 11-ring bridged bicyclic heterocycloalkyl group, or a 5- to 11-ring fused bicyclic heterocycloalkyl group, and the 3- to 7-membered monocyclic heterocycloalkyl group, the 5- to 11-ring bridged bicyclic heterocycloalkyl group, and the 5- to 11-ring fused bicyclic heterocycloalkyl group each optionally and independently contain one or more R B It may be substituted with a group.

[0084] In another embodiment, R 1 and R 2 are taken together with the common nitrogen atom to which they are each attached to form a group selected from: [ka]

[0085] In one embodiment, for compounds of Formula (I), (Ia), and (Ib), R 1 is H and R 2 is -(C1-C 10 Alkylene)-(C6-C 10 aryl), -(C1-C 10 alkylene)-(3- to 7-membered monocyclic heterocyclic alkyl), 5- to 10-membered bicyclic cycloalkyl, -(C-C 10 alkylene)-(C3-C7 monocyclic cycloalkyl); and 5- or 6-membered monocyclic heteroaryl, wherein the C6-C 10 The aryl group, the 3- to 7-membered monocyclic heterocycloalkyl group, the 5- to 10-membered bicyclic cycloalkyl group, the C3-C7 monocyclic cycloalkyl group, and the 5- or 6-membered monocyclic heteroaryl group may be substituted with -NH2.

[0086] In another embodiment, for compounds of Formula (I), (Ia), and (Ib), R 1is H and R 2 is selected from the following: [ka]

[0087] In one embodiment, the compound of formula (I) is any of the compounds numbered 1 to 90 herein or a pharmaceutically acceptable salt thereof.

[0088] In one embodiment, the compound of formula (I) is in substantially pure form.

[0089] Other embodiments include:

[0090] (a) a pharmaceutical composition comprising an effective amount of a PNU anthracycline derivative and a pharmaceutically acceptable carrier;

[0091] (b) the pharmaceutical composition of (a), further comprising a second therapeutic agent selected from the group consisting of anticancer agents;

[0092] (c) the pharmaceutical composition of (b), wherein the anticancer agent is an anti-human PD-1 antibody (or an antigen-binding fragment thereof);

[0093] (d) a pharmaceutical combination that is (i) a PNU anthracycline derivative and (ii) a second therapeutic agent selected from the group consisting of anti-cancer agents, wherein the PNU anthracycline derivative and the second therapeutic agent are each used in an amount such that the combination is effective for inhibiting cancer cell replication or treating cancer and / or reducing the likelihood of or severity of symptoms of cancer;

[0094] (e) the combination of (d), wherein the second therapeutic agent is an anti-human PD-1 antibody (or an antigen-binding fragment thereof);

[0095] (f) a method for inhibiting cancer cell replication in a subject in need thereof, comprising administering to the subject an effective amount of a PNU anthracycline derivative;

[0096] (g) a method for treating and / or reducing the likelihood or severity of symptoms of cancer in a subject in need thereof, comprising administering to the subject an effective amount of a PNU anthracycline derivative;

[0097] (h) the method of (g), wherein the PNU anthracycline derivative is administered in combination with an effective amount of at least one second therapeutic agent selected from the group consisting of anticancer agents;

[0098] (i) the method of (h), wherein the treatment is an anti-human PD-1 antibody (or an antigen-binding fragment thereof);

[0099] (j) A method of inhibiting cancer cell replication in a subject in need thereof, comprising administering to the subject a pharmaceutical composition of (a), (b), or (c), or a combination of (d) or (e);

[0100] (k) A method for treating and / or reducing cancer and / or reducing the likelihood or severity of symptoms of cancer in a subject in need thereof, comprising administering to the subject a pharmaceutical composition of (a), (b), or (c), or a combination of (d) or (e). etc.

[0101] Also described herein are PNU anthracycline derivatives for use in (i) (a) a medicine, (b) inhibiting cancer cell replication, or (c) treating cancer and / or reducing the likelihood or severity of symptoms of cancer, (ii) as a medicine for such inhibition or treatment and / or reduction, or (iii) in the preparation of a medicine for such inhibition or treatment and / or reduction. In these uses, the PNU anthracycline derivatives may be used in combination with one or more additional therapeutic agents selected from anticancer agents.

[0102] It should further be understood that the composition and method embodiments set forth above as (a) through (k) are understood to include all embodiments of that compound (e.g., embodiments resulting from combinations of embodiments, etc.).

[0103] Non-limiting examples of compounds of formula (I) include compounds 1-90 set forth in the Examples below, as well as pharmaceutically acceptable salts thereof.

[0104] Methods for preparing compounds of formula (I) The compounds of formula (I) can be prepared from known or readily prepared starting materials according to methods known to those skilled in the art of organic synthesis. Methods useful for preparing compounds of formula (I) are described in the Examples below. Alternative synthetic routes and related structures will be apparent to those skilled in the art of organic synthesis.

[0105] Those skilled in the art of organic synthesis will appreciate that protection of certain functional groups (i.e., derivatization to render them chemically compatible with certain reaction conditions) may be necessary during the synthesis of the bicyclic heterocyclic core contained in compounds of formula (I). Suitable protecting groups for the various functional groups in these compounds and methods for their installation and removal are known in the art of organic chemistry. Many of these methods are summarized in Greene et al., Protective Groups in Organic Synthesis, Wiley-Interscience, New York, (1999).

[0106] It will also be apparent to those skilled in the art of organic synthesis that one route of synthesis of the bicyclic heterocyclic core of compounds of formula (I) may be more desirable depending on the choice of substituents added.

[0107] Furthermore, it will be apparent to one skilled in the art that in some cases the order of reactions can be varied from that described herein to avoid functional group incompatibilities and thereby adjust the synthetic route accordingly.

[0108] The preparation of polycyclic intermediates useful in preparing the bicyclic heterocyclic nucleus is described in the literature and abstracts such as "Comprehensive Heterocyclic Chemistry," Volumes I, II, and III, published by Elsevier and edited by A.R. Katritzky & R. J.K. Taylor. Manipulation of the required substitution patterns is also described in the available chemical literature summarized in abstracts such as "Comprehensive Organic Chemistry," published by Elsevier and edited by D.H. R. Barton and W.D. Ollis; "Comprehensive Organic Functional Group Transformations," edited by A.R. Katritzky & R. J.K. Taylor; and "Comprehensive Organic Transformation," 3rd Edition, published by Wiley-CVH and edited by R.C. Larock.

[0109] The starting materials used and the intermediates prepared using the methods described in the following examples can be isolated and purified if necessary using conventional techniques, including, but not limited to, filtration, distillation, crystallization, chromatography, etc. Such materials can be characterized using conventional means, including physical constants and spectral data.

[0110] Those skilled in the art will be aware of standard formulation techniques described in the published literature and in textbooks such as Zheng, "Formulation and Analytical Development for Low-dose Oral Drug Products," Wiley, 2009, ISBN. [Example]

[0111] general law Commercially available solvents, reagents and intermediates were used as received. Non-commercially available reagents and intermediates were prepared as described below. 1H-NMR spectra are reported as ppm from residual solvent with the number of protons, multiplicity, and coupling constants in Hertz indicated in parentheses. When LC / MS data are shown, the observed parent ion is provided. Unless otherwise noted, flash chromatography was performed on an ISCO, Analogix, or Biotage automated chromatography system using commercially available silica gel cartridges as columns. Reverse-phase preparative HPLC conditions are described herein. When aqueous solutions were concentrated, this was accomplished using a Genevac evaporator or by lyophilization.

[0112] Reaction progress and analysis of synthetic intermediates were monitored by LCMS (UV detection by ESI, APCI, or other mass detection) using MeCN / water gradients containing either TFA, formic acid, or NH4HCO3 modifiers, where applicable. Silica gel and reversed-phase flash column chromatography were performed using commercially available prepacked columns. Reverse-phase preparative HPLC purification was performed on a preparative HPLC instrument with UV and MS detection using MeCN / water gradients containing TFA, formic acid, or NH4OH modifiers. 1 H NMR spectra were collected at room temperature, chemical shifts are reported in ppm relative to the residual protein-solvent signal, and multiplicities, coupling constants (if applicable), and signal integrals are listed in parentheses. Unless otherwise noted, all ECs provided in the tables 50 Data are for the CellTiter-Glo® 2.0 cytotoxicity assay described in the biological assay section.

[0113] Preparation of intermediate compounds The following Examples 1-10 describe the synthesis of intermediate compounds useful for making exemplary compounds of the present disclosure.

[0114] Example 1 Preparation of intermediate compound vi [ka] Step A - Synthesis of Compound II

[0115] To a solution of 3-aminopyrrolidin-2-one (i, 50.0 mg, 0.499 mmol) and BocO (0.174 mL, 0.749 mmol) in MeOH (2 mL) was added TEA (0.209 mL, 1.50 mmol), and the resulting reaction was stirred at 70 °C for 16 h. The reaction mixture was then concentrated under reduced pressure, and the resulting residue was purified using flash silica gel chromatography (0% to 100% EtOAc / petroleum ether) to give tert-butyl (2-oxopyrrolidin-3-yl)carbamate ii. MS (ESI) m / z: 201.3 [M+H] + .

[0116] Step B - Synthesis of Compound iii To a stirred suspension of NaH (24 mg, 0.60 mmol) in THF (1 mL) was added compound ii (100 mg, 0.499 mmol) at 0 °C, and the resulting reaction was stirred at room temperature for 30 min under a N atmosphere. A solution of 2-bromoacetonitrile (71.9 mg, 0.599 mmol) and TBAI (36.9 mg, 0.100 mmol) in THF (1 mL) was added, and the resulting reaction was stirred at 25 °C for 3 h. Water (30 mL) was added, and the resulting mixture was extracted with ethyl acetate (2 x 100 mL). The combined organic extracts were washed with brine (2 x 100 mL), dried over NaSO, filtered, and concentrated under reduced pressure. The resulting residue was purified using flash silica gel chromatography (0% to 100% EtOAc / petroleum) to give tert-butyl (1-(cyanomethyl)-2-oxopyrrolidin-3-yl)carbamate iii.

[0117] Step C - Synthesis of compound iv To a solution of iii (1.3 g, 5.4 mmol) in EtOH (15 mL) was added platinum(IV) oxide (0.247 g, 1.09 mmol), and the resulting reaction was stirred at 25 °C under a H atmosphere (obtained using a balloon filled with H) for 16 h. The reaction mixture was filtered, and the filter cake was washed with ethanol (10 mL). The combined filtrate and washings were concentrated under reduced pressure, and the resulting residue was purified using preparative HPLC (Welch Xtimate C18 150 × 25 mm × 5 μm column, 8% to 100% ACN:water (containing TFA as a modifier)) and then lyophilized to give tert-butyl (1-(2-aminoethyl)-2-oxopyrrolidin-3-yl)carbamate iv. MS (ESI) m / z: 244.2 [M+H + ].

[0118] Step D - Synthesis of Compound v To a solution of iv (400 mg, 1.64 mmol) in DCM (5 mL) was added TFA (1.0 mL, 13 mmol), and the resulting reaction was stirred at 0° C. for 1 h. The reaction mixture was filtered, concentrated under reduced pressure, and lyophilized to give 3-amino-1-(2-aminoethyl)pyrrolidin-2-one v. LCMS (ESI) m / z: 144.1 [M+H] + .

[0119] Step E - Synthesis of Compound vi To a solution of compound v (200 mg, 1.40 mmol) in DCM (10 mL) was added TEA (0.389 mL, 2.79 mmol) at 0° C., followed by a solution of BocO (0.259 mL, 1.12 mmol) in DCM (10 mL), and the resulting reaction was stirred at 0° C. for 4 hours. The reaction mixture was concentrated under reduced pressure to give crude compound tert-butyl (2-(3-amino-2-oxopyrrolidin-1-yl)ethyl)carbamate vi, which was used without further purification. LCMS (ESI) m / z: 244.4 [M+H] + .

[0120] Example 2 Preparation of intermediate compounds ix-xvi [ka] Step A - Synthesis of Compound viii

[0121] To a solution of (((9H-fluoren-9-yl)methoxy)carbonyl)-L-proline (vii, 2.0 g, 5.9 mmol), 1H-benzo[d][1,2,3]triazol-1-ol (0.801 g, 5.93 mmol) in DCM (40 mL) was added tert-butyl(2-aminoethyl)carbamate (1.05 g, 6.52 mmol) in DCM (3 mL) and EDC (1.25 g, 6.52 mmol) at 0 °C. The resulting reaction was warmed to room temperature and stirred at 25 °C for 16 h. Saturated aqueous sodium bicarbonate (50 mL) was added, and the mixture was extracted with DCM (2 x 50 mL). The combined organic extracts were washed with aqueous HCl (0.1 M, 50 mL), dried over NaSO, filtered, and the solvent was evaporated under reduced pressure. The resulting residue was purified using flash silica gel chromatography (0% to 100% EtOAc / petroleum ether) to give (9H-fluoren-9-yl)methyl (S)-2-((2-((tert-butoxycarbonyl)amino)ethyl)carbamoyl)pyrrolidine-1-carboxylate (viii, 2.5 g, 5.21 mmol). MS (ESI): m / z [M+H] + 480.3.

[0122] Step B—Synthesis of Compound ix To a solution of compound viii (500 mg, 1.0 mmol) in DCM (6 mL) was added TFA (2.0 mL, 26.0 mmol), and the resulting reaction was stirred at 0° C. for 30 minutes. The reaction mixture was then concentrated under reduced pressure to give 9H-fluoren-9-yl)methyl (S)-2-((2-aminoethyl)carbamoyl)pyrrolidine-1-carboxylate ix, which was used without further purification. MS (ESI) m / z: 380.3 [M+H] + .

[0123] Using the methods described in Example 2, substituting the appropriate reactants and / or reagents, the following intermediate compounds of the disclosure were prepared. [Table 2]

[0124] Example 3 Preparation of intermediate compounds xx-xxii [ka] Step A - Synthesis of Compound xviii

[0125] To a solution of N1-(3-aminopropyl)propane-1,3-diamine (xvii, 5 g, 38.1 mmol) in THF (200 mL) was added tert-butyl 1H-imidazole-1-carboxylate (9.61 g, 57.2 mmol), and the resulting reaction was stirred at 70° C. for 16 hours. The reaction mixture was cooled to 20° C. and concentrated under reduced pressure to give tert-butyl (3-((3-aminopropyl)amino)propyl)carbamate-di-tert-butyl(azanediylbis(propane-3,1-diyl))dicarbamate (xviii, 15 g, 23.99 mmol) as an oil, which was used without further purification. LCMS (ESI) m / z: 232.1 [M+H] + .

[0126] Step B - Synthesis of Compound xix To a solution of compound xviii (15 g, 26.7 mmol) in THF (150 mL) was added KCO (11.1 g, 80.0 mmol) in HO (150 mL), and the reaction mixture was stirred at 20 °C for 17 h. The reaction mixture was diluted with EtOAc (200 mL), washed with HO (50 mL) and brine (50 mL), dried over NaSO, filtered, and concentrated under reduced pressure. The resulting residue was purified using flash silica gel chromatography (0% to 50% EtOAc / petroleum) to give compound (9H-fluoren-9-yl)methyl (3-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)propyl)(3-((tert-butoxycarbonyl)amino)propyl)carbamate (xix, 9.5 g, 13.35 mmol) as an oil. LCMS(ESI)m / z:676.3[M+H] + .

[0127] Step C - Synthesis of Compound xx A solution of compound xix (1.50 g, 2.22 mmol) and TFA (10 mL, 2.22 mmol) in DCM (50 mL) was stirred at 20° C. for 18 h. The reaction mixture was then concentrated under reduced pressure to provide (9H-fluoren-9-yl)methyl (3-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)propyl)(3-aminopropyl)carbamate (xx, 1.5 g, 2.0 mmol) as an oil, which was used without further purification. LCMS (ESI) m / z: 576.3 [M+H] + . 1 H NMR (400 MHz, CD3OD) δ 7.70-7.82 (m, 4H), 7.52-7.64 (m, 4H), 7.24-7.40 (m, 8H), 4.57-4.72 (m, 2H), 4.29-4.41 (m, 2H), 4.07-4.26 (m, 2H), 3.08-3.28 (m, 2H), 2.84-3.01 (m, 2H), 2.75 (br s, 2H), 2.42 (br s, 1H), 1.75 (br s, 1H), 1.31 (br s, 1H).

[0128] Using the methods described in Example 3, substituting the appropriate reactants and / or reagents, the following intermediate compounds of the disclosure were prepared. [Table 3]

[0129] Example 4 Preparation of intermediate compounds xxiii-xxvii [ka] Step A - Synthesis of compound xxiv

[0130] To a solution of compound xxiii (4.67 g, 30.1 mmol) in MeOH (20 mL) were added triphenylmethanamine (10.2 g, 39.1 mmol), acetic acid (0.18 g, 3.0 mmol), and sodium triacetoxyborohydride (9.57 g, 45.2 mmol), and the mixture was stirred at 50° C. for 18 hours. Sodium cyanoborohydride (3.78 g, 60.2 mmol) was then added, and the reaction mixture was stirred at 50° C. for 18 hours. The reaction mixture was diluted with water (25 mL) and extracted with ethyl acetate (3×30 mL). The combined layers were washed with saturated aqueous sodium chloride (2 x 20 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give N-((1-methyl-4-nitro-1H-imidazol-2-yl)methyl)-1,1,1-triphenylmethanamine xxiv (8 g, 6.02 mmol) as a solid. LCMS (ESI) m / z: 421.3 [M+Na] + .

[0131] Step B - Synthesis of Compound xxv To a solution of xxiv (5.00 g, 12.6 mmol) in DCM (20 mL) was added TFA (4.0 mL, 52 mmol), and the mixture was stirred for 1 h at 25° C. The mixture was concentrated under reduced pressure to give (1-methyl-4-nitro-1H-imidazol-2-yl)methanamine xxv (2.6 g, 10 mmol) as an oil, which was used without further purification.

[0132] Step C - Synthesis of compound xxvi To a solution of xxvi (2.6 g, 10 mmol) in DCM (30 mL) was added triethylamine (4.18 mL, 30.0 mmol), followed by the slow dropwise addition of di-tert-butyl dicarbonate (4.64 mL, 20.0 mmol). The solution was stirred at 20 °C for 18 h. The reaction mixture was then purified using silica gel column chromatography (60%-90% EtOAc / petroleum ether) to give tert-butyl ((1-methyl-4-nitro-1H-imidazol-2-yl)methyl)carbamate xxvi (850 mg, 2.99 mmol) as a solid. LCMS (ESI) m / z: 257.2 [M+H] + .

[0133] Step D - Synthesis of compound xxvii To a mixture of xxvi (230 mg, 0.898 mmol) in trifluoroethanol (3 mL) was added 10% palladium on carbon (96 mg, 0.090 mmol), and the mixture was stirred under an H atmosphere (15 psi) at 20° C. for 0.5 h. The mixture was filtered through a short Celite® pad, and the filtrate was concentrated under reduced pressure to give tert-butyl ((4-amino-1-methyl-1H-imidazol-2-yl)methyl)carbamate xxvii (200 mg, 0.619 mmol) as a yellow solid, which was used without further purification. LCMS (ESI) m / z: 227.0 [M+H] + .

[0134] Example 5 Preparation of intermediate compounds xxviii to xxx [ka] Step A - Synthesis of Compounds xxix and xxx

[0135] To a solution of xxviii (200 mg, 1.22 mmol) in DCM (3 mL) were added triethylamine (0.169 mL, 1.22 mmol) and di-tert-butyl dicarbonate (0.423 mL, 1.82 mmol), and the reaction mixture was stirred at 20 °C for 2 h. The mixture was concentrated under reduced pressure, and the residue was purified by preparative SFC (DAICEL CHIRALPAK IC (250 mm × 30 mm × 10 μm) eluting with 20% 0.1% NH₃·H₂O·EtOH / acetonitrile at a flow rate of 70 mL / min) to give xxix (53 mg, 0.232 mmol) and xxx (58 mg, 0.254 mmol) as solids. The material was used directly in the next step. LCMS (ESI) m / z: 251.1 [M+H] + .

[0136] Example 6 Preparation of intermediate compounds xxxii-xxxiii [ka] Step A - Synthesis of Compound xxxii

[0137] To a stirring solution of tert-butyl (((1s,3s)-3-aminocyclobutyl)methyl)carbamate (xxxi, 150 mg, 0.749 mmol) in DCM (10 mL) was added DIPEA (0.392 mL, 2.25 mmol). The resulting solution was stirred at 20° C. for 10 minutes, and then N-(9-fluorenylmethoxycarbonyloxy)succinimide (303 mg, 0.899 mmol) was added. The resulting reaction was stirred at 20° C. for 18 hours and then concentrated under reduced pressure. The resulting residue was purified using flash silica gel chromatography (60% to 70% EtOAc / petroleum ether) to give tert-butyl (((1s,3s)-3-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)cyclobutyl)methyl)carbamate xxxii (180 mg, 0.405 mmol). MS(ESI)m / z:445.3[M+Na] + .

[0138] Step B - Synthesis of Compound xxxiii To a stirring solution of compound xxxii (170 mg, 0.402 mmol) in DCM (0.9 mL) was added TFA (0.300 mL, 3.89 mmol), and the resulting reaction was stirred at 25° C. for 2 hours. The reaction mixture was then concentrated under reduced pressure to provide (9H-fluoren-9-yl)methyl ((1s,3s)-3-(aminomethyl)cyclobutyl)carbamate xxxiii, which was used without further purification. MS (ESI) m / z: 323.1 [M+H] + .

[0139] Using the methods described in Example 6, substituting the appropriate reactants and / or reagents, the following intermediate compounds of the disclosure were prepared. [Table 4] TIFF2026500987000035.tif255149TIFF2026500987000036.tif91154

[0140] Example 7 Preparation of intermediate compound lxx [ka]

[0141] To a stirring solution of tert-butyl (1S,5R)-3,6-diazabicyclo[3.2.0]heptane-6-carboxylate (lxix, 200 mg, 1.01 mmol) in DCM (1.5 mL) was added TFA (0.500 mL, 6.49 mmol), and the resulting reaction was stirred for 2 h at 25° C. The reaction mixture was concentrated under reduced pressure to provide (1S,5R)-3,6-diazabicyclo[3.2.0]heptane (lxx), which was used without further purification.

[0142] Using the methods described in Example 7, substituting the appropriate reactants and / or reagents, the following intermediate compounds of the disclosure were prepared. [Table 5]

[0143] Example 8 Preparation of intermediate compound lxxxi [ka] Step A - Synthesis of compound lxxvii

[0144] To a solution of compound lxxvi (4.0 g, 17 mmol) in THF (20 mL) was added LAH (1.0 M in THF, 24.9 mL, 24.9 mmol) under N at 0 °C. The resulting reaction was stirred at 0 °C for 1 h. The following was then added to the reaction mixture: 1 mL of water, 1 mL of 15% aqueous NaOH, and 3 mL of water. The resulting suspension was filtered, washed with MeOH (50 mL), and the filtrate was concentrated under reduced pressure to give tert-butyl (3-(hydroxymethyl)bicyclo[1.1.1]pentan-1-yl)carbamate (lxxvi, 2.50 g, 10.6 mmol), which was used without further purification.

[0145] Step B - Synthesis of Compound lxxviii To a solution of compound lxxvi (1.50 g, 7.03 mmol) in THF (50 mL) was added isoindoline-1,3-dione (1.24 g, 8.44 mmol) and triphenylphosphine (2.77 mg, 10.6 mmol), followed by di-tert-butyldiazene-1,2-dicarboxylate (2.43 mg, 10.6 mmol), and the resulting reaction was stirred for 17 h at 20° C. The reaction mixture was diluted with EtOAc (300 mL), washed with water (50 mL) and brine (50 mL), dried over NaSO, filtered, and concentrated under reduced pressure. The resulting residue was purified using preparative HPLC (Boston Green ODS 150 x 30 mm x 5 μm, 30% to 50% ACN / water (containing 0.1% TFA as a modifier)) to give tert-butyl (3-((1,3-dioxoisoindolin-2-yl)methyl)bicyclo[1.1.1]pentan-1-yl)carbamate (lxxviii, 1.50 g, 3.94 mmol). LCMS (ESI) m / z: 287.1 [(M-56)+H] + .

[0146] Step C - Synthesis of compound lxxix To a solution of compound lxxviii (1.00 g, 2.92 mmol) in EtOH (30 mL) was added hydrazine hydrate (1.72 g, 29.2 mmol), and the resulting reaction was stirred at 20 °C for 17 h. The reaction mixture was filtered, and the filtrate was lyophilized to give tert-butyl (3-(aminomethyl)bicyclo[1.1.1]pentan-1-yl)carbamate (lxxix, 700 mg, 2.64 mmol), which was used without further purification. LCMS (ESI) m / z: 213.1 [M+H] + .

[0147] Step D - Synthesis of Compound lxxx To a solution of compound lxxix (200 mg, 0.942 mmol) in DCM (10 mL) was added DIEA (0.329 mL, 1.88 mmol), followed by 9-fluorenylmethyl chloroformate (366 mg, 1.41 mmol), and the resulting reaction was stirred at 20° C. for 17 hours. The reaction mixture was concentrated under reduced pressure, and the mixture was purified using preparative HPLC (Boston Green ODS 150×30 mm×5 μm, 20% to 40% ACN / water (containing 0.1% TFA as a modifier)) to give tert-butyl (3-(((((9H-fluoren-9-yl)methoxy)carbonyl)amino)methyl)bicyclo[1.1.1]pentan-1-yl)carbamate (lxxx, 250 mg, 0.518 mmol). LCMS (ESI) m / z: 457.2 [M+Na] + .

[0148] Step E - Synthesis of Compound lxxxi To a solution of compound lxxx (240 mg, 0.552 mmol) in DCM (1.5 mL) was added TFA (0.5 mL), and the resulting reaction was stirred at 20° C. for 1 hour. The reaction mixture was then concentrated under reduced pressure to provide (9H-fluoren-9-yl)methyl ((3-aminobicyclo[1.1.1]pentan-1-yl)methyl)carbamate (lxxxi, 235 mg, 0.512 mmol), which was used without further purification. LCMS (ESI) m / z: 335.2 [M+H] + .

[0149] Example 9 Preparation of intermediate compound lxxxiii [ka]

[0150] To a solution of (9H-fluoren-9-yl)methyl (6-cyanopyridin-3-yl)carbamate (lxxxii, 1.2 g, 3.5 mmol) in THF (10 mL) was added a solution of borane in THF (1.0 M, 14.1 mL, 14.1 mmol) at 25 °C under an argon atmosphere. The resulting reaction was warmed to 70 °C and stirred at this temperature for 6 hours. The reaction mixture was quenched with acetic acid (5 mL), and the resulting mixture was warmed to 70 °C and stirred at this temperature for 16 hours. The reaction mixture was concentrated under reduced pressure, and the resulting residue was purified using silica gel column chromatography eluting with 1-10% methanol in DCM to give (9H-fluoren-9-yl)methyl (6-(aminomethyl)pyridin-3-yl)carbamate (lxxxiii, 500 mg, 1.45 mmol). MS: m / z = 346.25 [M+H] + .

[0151] Example 10 Preparation of intermediate compound lxxxix [ka] Step A - Synthesis of Compound lxxxv

[0152] To a solution of ethyl 2-(3-(benzylamino)oxetan-3-yl)acetate (lxxxiv, 1.50 g, 6.02 mmol) in THF (5 mL) at 0 °C under N was added LAH (457 mg, 12.0 mmol). The resulting reaction was stirred at 0 °C for 1 h, then HO (0.5 mL), 15% NaOH (0.5 mL, aq.), and HO (1.5 mL) were added sequentially. The resulting suspension was filtered, washed with DCM (20 mL), and then concentrated under reduced pressure to give 2-(3-(benzylamino)oxetan-3-yl)ethan-1-ol (lxxxv, 1.1 g, 4.25 mmol) as an oil, which was used without further purification. LCMS (ESI) m / z: 208.1 [M+H] + .

[0153] Step B - Synthesis of Compound lxxxvi To a solution of compound lxxxv (1.00 g, 4.82 mmol) in THF (30 mL) was added isoindoline-1,3-dione (710 mg, 4.82 mmol) and triphenylphosphine (1.27 g, 4.82 mmol), followed by di-tert-butyldiazene-1,2-dicarboxylate (1.11 g, 4.82 mmol). The resulting reaction was stirred at 20 °C for 17 h, and then the reaction mixture was diluted with EtOAc (100 mL). The resulting solution was washed successively with HO (50 mL) and brine (50 mL), dried over NaSO, filtered, and concentrated under reduced pressure. The resulting residue was purified using silica gel chromatography (0-50% EtOAc / petroleum) to afford 2-(2-(3-(benzylamino)oxetan-3-yl)ethyl)isoindoline-1,3-dione (lxxxvi, 1.00 g, 2.68 mmol) as an oil. LCMS (ESI) m / z: 337.2 [M+H] + .

[0154] Step C - Synthesis of Compound lxxxvii To a solution of compound lxxxvi (1.00 g, 2.97 mmol) in MeOH (10 mL) was added hydrazinium hydroxide (558 mg, 8.92 mmol), and the resulting reaction was stirred at 20° C. for 17 hours. The reaction mixture was filtered and purified directly using preparative HPLC (YMC-Actus Triart C18 150×30 mm×5 μm, eluting with 0% to 60% MeCN / water (0.1% TFA)), followed by lyophilization to afford 3-(2-aminoethyl)-N-benzyloxetan-3-amine (lxxxvii, 400 mg, 1.745 mmol) as an oil. LCMS (ESI) m / z: 207.1 [M+H] + .

[0155] Step D - Synthesis of compound lxxxviii To a solution of compound lxxxvii (400 mg, 1.94 mmol) in CF3CH2OH (5 mL) under N2, Pd-C (103 mg, 0.0970 mmol) was added. The resulting reaction was purged with H2 three times, and the reaction was stirred at 20 °C under an H2 atmosphere (provided by a H2-filled balloon) for 9 h. The reaction mixture was filtered and concentrated under reduced pressure to give 3-(2-aminoethyl)oxetan-3-amine (lxxxviii, 250 mg, 1.93 mmol) as an oil, which was used without further purification. LCMS (ESI) m / z: 134.1 [M+H2O].

[0156] Example 11 Preparation of intermediate compound xcii [ka] Step A - Synthesis of Compound xc

[0157] To a solution of (9H-fluoren-9-yl)methylhydrazinecarboxylate (lxxxix, 3.00 g, 11.8 mmol) in DMF (50.0 mL) was added bis(2,5-dioxopyrrolidin-1-yl)carbonate (3.02 g, 11.8 mmol), and the resulting reaction was stirred for 1 hour at 25° C. The reaction mixture, containing 1-((9H-fluoren-9-yl)methyl)2-(2,5-dioxopyrrolidin-1-yl)hydrazine-1,2-dicarboxylate (xc, 4.66 g, 11.8 mmol), was used directly in the next step without further purification.

[0158] Step B—Synthesis of Compound xci To a solution of compound Xc (4.66 g, 11.8 mmol) in DMF (50 mL) was added tert-butyl (2-aminoethyl)carbamate (1.89 g, 11.8 mmol), and the resulting reaction mixture was stirred at 25 °C for 16 h. Water (50 mL) was added, and the resulting mixture was extracted with ethyl acetate (2 x 40 mL). The combined organic extracts were washed with brine (50 mL), dried over NaSO, filtered, and concentrated under reduced pressure. The resulting residue was purified using flash silica gel chromatography (5% MeOH / DCM) to afford (9H-fluoren-9-yl)methyl 11,11-dimethyl-4,9-dioxo-10-oxa-2,3,5,8-tetraazadodecanoate (Xci, 3.7 g, 8.40 mmol) as a solid. LCMS:MS(ESI)m / z:441.3[M+H] + .

[0159] Step C - Synthesis of compound xcii A solution of compound xci (1.00 g, 2.27 mmol) in TFA (3.00 mL) and DCM (10.0 mL) was stirred at 25° C. for 1 hour. The reaction mixture was then concentrated under reduced pressure to give (9H-fluoren-9-yl)methyl 2-((2-aminoethyl)carbamoyl)hydrazine-1-carboxylate (xcii, 770 mg, 2.262 mmol) as an oil, which was used without further purification. LCMS: MS (ESI) m / z: 341.1 [M+H] + .

[0160] Example 12 Preparation of intermediate compound xciv [ka]

[0161] To a solution of (8S,10S)-6,8,11-trihydroxy-8-(2-hydroxyacetyl)-1-methoxy-10-(((1S,3R,4aS,9S,9aR,10aS)-9-methoxy-1-methyloctahydro-1H-pyrano[4',3':4,5]oxazolo[2,3-c][1,4]oxazin-3-yl)oxy)-7,8,9,10-tetrahydrotetracene-5,12-dione (xciii, 200 mg, 0.312 mmol) in methanol (5 mL) and water (5 mL) was added a solution of sodium periodate (80 mg, 0.37 mmol) in water (1 mL). The resulting reaction was stirred at room temperature for 30 minutes, and then the solvent was slowly removed from the reaction mixture under reduced pressure at 25 °C over 18 hours. The resulting product, xciv, was used without further purification. LCMS(ESI)m / z:628.6[M+H] + .

[0162] Preparation of example compounds Examples 13-14 illustrate the synthesis of exemplary compounds of the present disclosure.

[0163] Example 13 Preparation of Compounds 1-60 [ka] Step A - Synthesis of Compound I-11a

[0164] To a solution of compound lxxxiii (200 mg, 0.319 mmol) in DMF (5 mL) was added HATU (242 mg, 0.637 mmol), (9H-fluoren-9-yl)methyl(3-(aminomethyl)phenyl)carbamate (132 mg, 0.382 mmol), and N-ethyl-N-isopropylpropan-2-amine (0.158 mL, 0.956 mmol) at room temperature under an argon atmosphere. The resulting reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was directly purified using reverse-phase Combiflash (column: C18 column, 40 g, 60 Å, 20–35 μm; 0% to 100% ACN / water) to give (9H-fluoren-9-yl)methyl (3-(((2S,4S)-2,5,12-trihydroxy-7-methoxy-4-(((1S,3R,4aS,9S,9aR,10aS)-9-methoxy-1-methyloctahydro-1H-pyrano[4′,3′:4,5]oxazolo[2,3-c][1,4]oxazin-3-yl)oxy)-6,11-dioxo-1,2,3,4,6,11-hexahydrotetracene-2-carboxamido)methyl)phenyl)carbamate (I-11a, 150 mg, 0.157 mmol). LCMS MS(ESI): m / z=954.55[M+H] + .

[0165] Step B—Synthesis of Compound 1 To a solution of compound I-11a (150 mg, 0.157 mmol) in DMF (6 mL) was added piperidine (0.20 mL, 0.16 mmol) under an argon atmosphere at 0° C. The resulting reaction was stirred at 0° C. for 20 minutes, and then the reaction mixture was concentrated under reduced pressure. The resulting residue was purified using reverse-phase Combiflash (Column: C18 column, 40 g, 60 Å, 20-35 μm; 0% to 60% ACN / water) to give (2S,4S)—N-(3-aminobenzyl)-2,5,12-trihydroxy-7-methoxy-4-(((1S,3R,4aS,9S,9aR,10aS)-9-methoxy-1-methyloctahydro-1H-pyrano[4′,3′:4,5]oxazolo[2,3-c][1,4]oxazin-3-yl)oxy)-6,11-dioxo-1,2,3,4,6,11-hexahydrotetracene-2-carboxamide (1, 56.7 mg, 0.077 mmol) as a solid. LCMS MS (ESI): m / z = 732.40 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 8.31 (t, J = 2.8 Hz, 1H), 7.92 - 7.91 (m, 2H), 7.65 (t, J = 3.2 Hz, 1H), 6.93 (t, J = 7.6 Hz, 1H), 6.46 - 6.41 (m, 3H), 5.38 (s, 1H), 5.27 - 5.24 (m, 1H), 5.00 (s, 3H), 4.58 (s, 1H), 4.23 - 3.92 (m, 8H), 3.66 - 3.52 (m, 3H), 3.39 - 3.31 (m, 5H), 3.10 - 2.68 (m, 3H), 2.31 - 2.21 (m, 2H), 1.87 - 1.65 (m, 3H), 1.20 (d, J = 6.4 Hz, 3H).

[0166] Using the methods described in Example 13, and substituting the appropriate reactants and / or reagents, the following exemplary compounds of the disclosure were prepared. [Table 6] TIFF2026500987000046.tif230153TIFF2026500987000047.tif243153TIFF2026500987000048.tif226154TIFF202 6500987000049.tif234154TIFF2026500987000050.tif250153TIFF2026500987000051.tif212153TIFF20265009870 00052.tif222153TIFF2026500987000053.tif216154TIFF2026500987000054.tif230153TIFF2026500987000055.t if225153TIFF2026500987000056.tif231154TIFF2026500987000057.tif219153TIFF2026500987000058.tif162153

[0167] Example 14 Preparation of compounds 61-90 [ka]

[0168] To a solution of (9H-fluoren-9-yl)methyl(3-(aminomethyl)phenyl)carbamate (150 mg, 0.239 mmol) in DMF (1 mL) was added HATU (109 mg, 0.287 mmol). The resulting solution was stirred at room temperature for 10 minutes, and then a solution of 2-methylpropane-1,2-diamine (I-61a, 21.1 mg, 0.239 mmol) in DMF (0.2 mL) was added, and the resulting reaction was stirred at room temperature for 10 minutes. DIEA (93 mg, 0.72 mmol) was added, and the resulting reaction was stirred at 25° C. for 20 minutes. The reaction mixture was then concentrated under reduced pressure, and the resulting residue was purified using preparative HPLC (C18-1, 150 × 30 mm × 5 μm column, eluting with 45% to 75% ACN:water (containing 7 mM HCOONH4 modifier)) to give (2S,4S)—N-(2-amino-2-methylpropyl)-2,5,12-trihydroxy-7-methoxy-4-(((1S,3R,4aS,9S,9aR,10aS)-9-methoxy-1-methyloctahydro-1H-pyrano[4′,3′:4,5]oxazolo[2,3-c][1,4]oxazin-3-yl)oxy)-6,11-dioxo-1,2,3,4,6,11-hexahydrotetracene-2-carboxamide (61, 29.8 mg, 0.041 mmol) as a solid. LCMS (ESI) m / z: 698.3 [M+H] + . 1H NMR (400 MHz, CDCl3) δ = 13.73 (s, 1H), 8.44 (s, 2H), 8.06 (br s, 1H), 7.89 (d, J=7.6 Hz, 1H), 7.68 (t, J=8.1 Hz, 1H), 7.23 (br d, J=8.5 Hz, 1H), 5.47 (br t, J=5.1 Hz, 1H), 5.19 (br s, 1H), 4.71 (d, J=1.4 Hz, 1H), 4.48 (d, J=1.5 Hz, 1H), 4.09 (br d, J=6.6 Hz, 2H), 3.98 - 3.87 (m, 4H), 3.62 - 3.53 (m, 2H), 3.48 - 3.39 (m, 5H), 3.21 - 3.02 (m, 2H), 2.86 - 2.67 (m, 2H), 2.47 - 2.24 (m, 2H), 2.04 - 1.90 (m, 1H), 1.90 - 1.81 (m, 1H), 1.47 - 1.39 (m, 8H), 1.35 (br d, J=6.4 Hz, 3H).

[0169] Using the methods described in Example 14, substituting the appropriate reactants and / or reagents, the following exemplary compounds of the disclosure were prepared. [Table 7] TIFF2026500987000061.tif222154TIFF2026500987000062.tif230153TIFF2026500987000063.tif229154TIFF2026500987 000064.tif221154TIFF2026500987000065.tif211154TIFF2026500987000066.tif228153TIFF2026500987000067.tif59154

[0170] Example 15 CellTiter-Glo® 2.0 Cytotoxicity Assay Step 1: Seeding the plates

[0171] On day 0, Jeko-1 cells were quickly thawed in cryovials by incubating them in a 37°C water bath for less than 1 minute, leaving only a small amount of ice in the vial. The vials were quickly removed and wiped with 70% ethanol. The cells were transferred from the vials to sterile centrifuge tubes containing 8 mL of pre-warmed cell culture medium. An additional 1 mL of medium was added to the vial to completely transfer the cells to the centrifuge tube. The cells were then centrifuged at 150 x g for 5 minutes. The supernatant was aspirated, and the cell pellet was resuspended in 10–20 mL of cell culture medium. Cells were counted using Vi-cell and counted at 6.6 x 10 cells per well. 4 A concentration of 3000 cells / mL was prepared. Next, 45 μL of cells were added to a Corning® 384-well low flange white flat bottom polystyrene TC-treated microplate (Corning, catalog no. 3570) using a Standard Cassette Combi. (If necessary, add 20 μL to a blank plate to normalize the Combi at medium speed.) The plate was centrifuged at 150 x g for 30 seconds.

[0172] Step 2: Addition of example compounds to seeded plates On day 1, the compound plate and reference compound stocks were removed and thawed at room temperature. Tubes were centrifuged at 2000 x g for 30 seconds. A 10x intermediate assay plate (Greiner plate, catalog no. 781280) was prepared using an Echo liquid handler. Serial dilutions were made using the appropriate buffer (HBSS (Gibco, catalog no. 14025-092) + 10 mM HEPES (Gibco, catalog no. 15630-080) + 0.1% BSA (Sigma, catalog no. A9576)). Media (without cells) was used for Max_E. Compounds (5 μL of 10x) were transferred from the intermediate plate to the assay plate using a Bravo liquid handler at very low speed to avoid disturbing the cell monolayer. Plates were centrifuged at 150 x g for 30 seconds.

[0173] Step 3: Perform the CellTiter-Glo 2.0 assay (Promega, Cat. No. G9242).

[0174] On day 4 or 5, CellTiter-Glo® 2.0 Reagent (from a CellTiter-Glo kit stored at -70°C) was thawed overnight at 4°C, taking care not to expose the reagent to temperatures above 25°C. The kit was allowed to equilibrate at room temperature for approximately 30 minutes. CellTiter-Glo® 2.0 Reagent (20 μL) was added to 50 μL of medium containing the cells using a Standard Cassette Combi. The contents were mixed on an orbital shaker for 2-3 minutes to induce cell lysis. The plate was centrifuged at 150 x g for 30 seconds. The plate was incubated at room temperature for 5 minutes to stabilize the luminescence signal. Luminescence was recorded, and EC was determined using an integration time of 0.25-1 second per well as a guideline. 50 values ​​were calculated.

[0175] Exemplary compounds of the present invention were tested in the above assays, the results of which are provided in the table below. [Table 8]

[0176] Use of PNU anthracycline derivatives Treatment or prevention of cell proliferative disorders

[0177] The present disclosure also relates to a method for treating a cell proliferative disorder, comprising administering a PNU anthracycline derivative to a subject in need of treatment.

[0178] The PNU anthracycline derivatives disclosed herein may be useful in the treatment of diseases or disorders, such as, but not limited to, cell proliferative disorders, including, but not limited to, cancer, benign papillomatosis, and gestational trophoblastic disease. The terms "cancer," "cancerous," or "malignant" refer to or describe the physiological condition in mammals that is typically characterized by unregulated cell growth.

[0179] In certain embodiments, the cell proliferative disorder is selected from cancer, benign papillomatosis, benign neoplastic disease, and gestational trophoblastic disease. In certain embodiments, the gestational trophoblastic disease is selected from the group consisting of hydatidiform mole and gestational trophoblastic neoplasia (e.g., invasive mole, choriomas, placental site trophoblastic tumors, and epithelioid trophoblastic tumors).

[0180] In certain embodiments, the cell proliferative disorder being treated is cancer.

[0181] Thus, in one embodiment, a method of treating cancer in a patient is provided, comprising administering to the patient an effective amount of a PNU anthracycline derivative. In certain embodiments, the amount administered is effective to treat cancer in the patient. In another specific embodiment, the amount administered is effective to inhibit cancer cell replication or cancer cell metastasis in the patient.

[0182] In one embodiment, described herein is the use of a PNU anthracycline derivative, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment of cancer.

[0183] In another embodiment, described herein are PNU anthracycline derivatives for use in the treatment of cancer.

[0184] In one embodiment, the cancer is metastatic. In another embodiment, the cancer is recurrent. In another embodiment, the cancer is refractory. In yet another embodiment, the cancer is both recurrent and refractory.

[0185] In one embodiment, the patient has previously been treated for cancer. In another embodiment, the patient has not previously been treated for cancer.

[0186] In one embodiment, the patient has previously received systemic treatment for cancer. In another embodiment, the patient has not previously received systemic treatment for cancer.

[0187] In other embodiments, the cancer is in an adult patient, and in additional embodiments, the cancer is in a pediatric patient.

[0188] The compounds, compositions, and methods provided herein are useful in the treatment of cancer. Cancers treatable using the compounds, compositions, and methods disclosed herein include: (1) heart: sarcoma (angiosarcoma, fibrosarcoma, rhabdomyosarcoma, liposarcoma), myxoma, rhabdomyoma, fibroma, lipoma, and teratoma; (2) lung: bronchogenic carcinoma (squamous cell carcinoma, undifferentiated small cell carcinoma, undifferentiated large cell carcinoma, adenocarcinoma), alveolar (bronchiolar) carcinoma, bronchial adenoma, sarcoma, lymphoma, chondroitin hamartoma, mesothelioma, and non-small cell carcinoma; (3) gastrointestinal tract: esophagus (squamous cell carcinoma, adenocarcinoma, leiomyosarcoma, lymphoma), and esophageal cancer. ), stomach (carcinoma, lymphoma, leiomyosarcoma), pancreas (ductal adenocarcinoma, islet cell adenoma, glucagonoma, gastrinoma, carcinoid tumor, vipoma), small intestine (adenocarcinoma, lymphoma, carcinoid tumor, Kaposi's sarcoma, leiomyoma, hemangioma, lipoma, neurofibroma, fibroma), large intestine (adenocarcinoma, tubular adenoma, villous adenoma, hamartoma, leiomyoma), colon, colorectum, rectum; (4) genitourinary tract: kidney (adenocarcinoma, Wilms' tumor [nephroblastoma], lymphoma, leukemia), bladder and urethra ( (5) Liver: Hepatocellular carcinoma (liver cancer), cholangiocarcinoma, hepatoblastoma, angiosarcoma, hepatocellular adenoma, hemangioma; (6) Bone: Osteogenic sarcoma (osteosarcoma), fibrosarcoma, malignant fibrous histiocytoma, chondrosarcoma, Ewing's sarcoma, malignant lymphoma (reticulum cell sarcoma), multiple myeloma, malignant giant cell tumor, chordoma, osteocarcinoma, sarcoma ... Osteoma (osteochondroma), benign chondroma, chondroblastoma, chondromyxoid fibroma, osteoid osteoma, and giant cell tumor; (7) nervous system: skull (osteoma, hemangioma, granuloma, xanthomas, osteitis deformans), meninges (meningiomas, meningeal sarcomas, gliomatosis), brain (astrocytomas, medulloblastomas, gliomas, ependymoma, germinomas [pinealomas], glioblastoma multiforme, oligodendroglioma, schwannomas, retinoblastomas, congenital tumors), spinal cord neurofibromas, meningiomas, gliomas, sarcomas);(8) Gynecology: Uterus (endometrial cancer), Cervix (cervical cancer, preneoplastic cervical dysplasia), Ovaries (ovarian cancer [serous cystadenocarcinoma, mucinous cystadenocarcinoma, unclassified carcinoma], granulosa-theca cell tumor, Sertoli-Leydegg cell tumor, dysgerminoma, malignant teratoma), Vulva (squamous cell carcinoma, carcinoma in situ, adenocarcinoma, fibrosarcoma, melanoma), Vagina (clear cell carcinoma, squamous cell carcinoma, botryoid sarcoma (embryonal sarcoma) (9) hematology: blood (myeloid leukemia [acute and chronic], acute lymphocytic leukemia, chronic lymphocytic leukemia, chronic myelomonocytic leukemia (CMML), myeloproliferative disorders, multiple myeloma, myelodysplastic syndrome), Hodgkin's disease, non-Hodgkin's lymphoma [malignant lymphoma]; (10) skin: malignant melanoma, basal cell carcinoma, squamous cell carcinoma, Kaposi's sarcoma, moles dysplastic nevi, lipoma, hemangioma, dermatofibroma, keloid, psoriasis; and (11) adrenal gland: neuroblastoma. Examples of cancers treatable using the compounds, compositions, and methods described herein include thyroid cancer, anaplastic thyroid cancer, epidermoid cancer, head and neck cancer (e.g., squamous cell carcinoma of the head and neck), sarcoma, teratocarcinoma (tetracarcinoma), liver cancer, and multiple myeloma.

[0189] As used herein, the term "cancer cell" includes a cell afflicted by any of the above-identified conditions.

[0190] In certain embodiments, the cancer is selected from brain and spinal cord cancer, head and neck cancer, leukemia and blood cancers, skin cancer, cancer of the reproductive system, cancer of the digestive system, liver and bile duct cancer, kidney and bladder cancer, bone cancer, lung cancer, metastatic microsatellite instability-high (MSI-H) cancer, mismatch repair deficient cancer, malignant mesothelioma, sarcoma, lymphoma, adenocarcinoma, thyroid cancer, cardiac tumor, germ cell tumor, malignant neuroendocrine (carcinoid) tumor, midline carcinoma, and cancer of unknown primary origin (i.e., cancer in which metastasis has been found but the site of original cancer is unknown). In certain embodiments, the cancer is an AIDS-related cancer.

[0191] In one embodiment, the cancer is bladder cancer. In another embodiment, the cancer is breast cancer. In yet another embodiment, the cancer is NSCLC. In yet another embodiment, the cancer is CRC. In another embodiment, the cancer is RCC. In another embodiment, the cancer is HCC. In one embodiment, the cancer is skin cancer. In another embodiment, the skin cancer is melanoma. In another embodiment, the cancer is ovarian cancer. In yet another embodiment, the cancer is pancreatic cancer. In another embodiment, the cancer is primary or metastatic brain cancer. In yet another embodiment, the cancer is CRC.

[0192] In one embodiment, provided herein is a method of treating unresectable or metastatic melanoma in a human patient. In some embodiments, the method comprises treating resected high-risk Stage III melanoma.

[0193] In one embodiment, a method for treating metastatic non-small cell lung cancer (NSCLC) in a human patient is provided. In some embodiments, the NSCLC is a non-squamous cell carcinoma. In other embodiments, the NSCLC is a squamous cell carcinoma.

[0194] In some embodiments, the cancer has high PD-L1 expression [(Tumor Proportion Score (TPS) ≧ 50%)] and has not been previously treated with platinum-containing chemotherapy. In alternative embodiments, the patient has a tumor with PD-L1 expression (TPS ≧ 1%) and has been previously treated with platinum-containing chemotherapy. In certain embodiments, the patient's disease has progressed during or after receiving platinum-containing chemotherapy.

[0195] In certain embodiments, PD-L1 TPS is determined by an FDA-approved test.

[0196] In certain embodiments of the methods of treating NSCLC, the patient's tumor does not have an EGFR or ALK genomic abnormality.

[0197] In certain embodiments of the methods of treating NSCLC, the patient's tumor has an EGFR or ALK genomic aberration and has had disease progression on or after receiving treatment for the EGFR or ALK aberration prior to receiving the combination therapy described herein.

[0198] In one embodiment, provided herein are methods of treating recurrent or metastatic head and neck squamous cell carcinoma (HNSCC) in a human patient. In some embodiments, the patient has previously been treated with platinum-containing chemotherapy. In certain embodiments, the patient has progressed during or after platinum-containing chemotherapy.

[0199] In one embodiment, provided herein is a method of treating refractory classical Hodgkin's lymphoma (cHL) in a human patient. In certain embodiments, the patient has relapsed after one, two, three, or more treatments for cHL. In certain embodiments, the patient is an adult patient. In alternative embodiments, the patient is a pediatric patient.

[0200] In one embodiment, provided herein is a method for treating locally advanced or metastatic urothelial carcinoma in a human patient. In certain embodiments, the patient is ineligible to receive cisplatin-containing chemotherapy. In further embodiments, the patient has disease progression during or after platinum-containing chemotherapy, or within 12 months of neoadjuvant or adjuvant platinum-containing chemotherapy. In certain embodiments, the patient's tumor expresses PD-L1 (CPS>10).

[0201] In one embodiment, provided herein is a method of treating an unresectable or metastatic, microsatellite instability-high (MSI-H) or mismatch repair deficient solid tumor in a human patient. In certain embodiments, the patient has experienced disease progression after prior anti-cancer therapy.

[0202] In one embodiment, provided herein is a method of treating unresectable or metastatic, microsatellite instability-high (MSI-H) or mismatch repair-deficient colorectal cancer in a human patient. In certain embodiments, the patient has had disease progression after prior treatment with a fluoropyrimidine, oxaliplatin, and irinotecan.

[0203] In one embodiment, provided herein are methods of treating recurrent locally advanced or metastatic gastric cancer or recurrent locally advanced or metastatic gastroesophageal junction adenocarcinoma in a human patient. In certain embodiments, the patient's tumor expresses PD-L1 [combined positive score (CPS) > 1]. In some embodiments, the patient has progressed disease on or after two or more prior lines of therapy, including fluoropyrimidine and platinum-containing chemotherapy. In some embodiments, the patient has progressed disease on or after two or more prior lines of therapy, including HER2 / neu targeted therapy.

[0204] In one embodiment, provided herein is a method of treating non-Hodgkin's lymphoma in a human patient. In a specific embodiment, the non-Hodgkin's lymphoma is primary mediastinal large B-cell lymphoma.

[0205] In one embodiment, provided herein is a method for treating breast cancer in a human patient. In certain embodiments, the breast cancer is triple-negative breast cancer. In other specific embodiments, the breast cancer is ER+ / HER2- breast cancer.

[0206] In one embodiment, provided herein is a method of treating cancer in a patient with a tumor with a high mutational burden.

[0207] In certain embodiments, the cancer is selected from brain cancer and spinal cord cancer. In certain embodiments, the brain cancer and spinal cord cancer is selected from the group consisting of anaplastic astrocytoma, glioblastoma, astrocytoma, and olfactory neuroblastoma (also known as olfactory blastoma). In certain embodiments, the brain tumor is selected from the group consisting of astrocytic tumors (e.g., pilocytic astrocytoma, subependymal giant cell astrocytoma, diffuse astrocytoma, pleomorphic xanthoastrocytoma, anaplastic astrocytoma, astrocytoma, giant cell glioblastoma, glioblastoma, secondary glioblastoma, primary adult glioblastoma, and primary pediatric glioblastoma), oligodendroglioma (e.g., oligodendroglioma and anaplastic oligodendroglioma), oligoastrocytic tumor ( For example, oligoastrocytoma, and anaplastic oligoastrocytoma), ependymoma (e.g., myxopapillary ependymoma, and anaplastic ependymoma); medulloblastoma, primitive neuroectodermal tumor, schwannoma, meningioma, atypical meningioma, anaplastic meningioma, pituitary adenoma, brain stem glioma, cerebellar astrocytoma, cerebral astrocytoma / malignant glioma, visual pathway and hypothalamic glioma, and primary central nervous system lymphoma. In certain examples of these embodiments, the brain tumor is selected from the group consisting of glioma, glioblastoma multiforme, paraganglioma, and supratentorial primitive neuroectodermal tumor (sPNET). In one embodiment, the brain or spinal cord cancer is a metastatic brain tumor or multiple tumors.

[0208] In certain embodiments, the cancer is selected from head and neck cancers, such as recurrent or metastatic head and neck squamous cell carcinoma (HNSCC), nasopharyngeal cancer, nasal cavity and paranasal sinus cancer, hypopharyngeal cancer, oral cavity cancer (e.g., squamous cell carcinoma, lymphoma, and sarcoma), lip cancer, oropharyngeal cancer, salivary gland tumors, laryngeal cancer (e.g., laryngeal squamous cell carcinoma, rhabdomyosarcoma), and eye or ocular cancer. In certain embodiments, the ocular cancer is selected from the group consisting of intraocular melanoma and retinoblastoma.

[0209] In certain embodiments, the cancer is selected from leukemia and hematological cancer. In certain embodiments, the cancer is selected from the group consisting of myeloproliferative neoplasms, myelodysplastic syndromes, myelodysplastic / myeloproliferative neoplasms, acute myeloid leukemia (AML), myelodysplastic syndromes (MDS), chronic myeloid leukemia (CML), myeloproliferative neoplasms (MPN), post-MPN AML, post-MDS AML, del(5q)-associated high-risk MDS or AML, blast phase chronic myeloid leukemia, angioimmunoblastic lymphoma, acute lymphoblastic leukemia, Langeran cell histiocytosis, hairy cell leukemia, and plasma cell neoplasms such as plasmacytoma and multiple myeloma. The leukemias referred to herein can be acute or chronic.

[0210] In certain embodiments, the cancer is selected from skin cancer. In certain embodiments, the skin cancer is selected from the group consisting of melanoma, squamous cell carcinoma, and basal cell carcinoma. In certain embodiments, the skin cancer is unresectable or metastatic melanoma.

[0211] In certain embodiments, the cancer is selected from cancers of the reproductive system. In certain embodiments, the cancer is selected from the group consisting of breast cancer, cervical cancer, vaginal cancer, ovarian cancer, endometrial cancer, prostate cancer, penile cancer, and testicular cancer. In certain examples of these embodiments, the cancer is breast cancer selected from the group consisting of ductal carcinoma and phyllodes tumor. In certain examples of these embodiments, the breast cancer can be male breast cancer or female breast cancer. In some examples of these embodiments, the breast cancer is triple-negative breast cancer. In other examples, the breast cancer is ER+ / HER2- breast cancer. In certain examples of these embodiments, the cancer is cervical cancer selected from the group consisting of squamous cell carcinoma and adenocarcinoma. In certain examples of these embodiments, the cancer is ovarian cancer selected from the group consisting of epithelial cancers.

[0212] In certain embodiments, the cancer is selected from cancers of the digestive system. In certain embodiments, the cancer is selected from the group consisting of esophageal cancer, gastric cancer (also known as stomach cancer), gastrointestinal carcinoid tumor, pancreatic cancer, gallbladder cancer, colorectal cancer, and anal cancer. In exemplary of these embodiments, the cancer is selected from the group consisting of esophageal squamous cell carcinoma, esophageal adenocarcinoma, gastric adenocarcinoma, gastrointestinal carcinoid tumor, gastrointestinal stromal tumor, gastric lymphoma, gastrointestinal lymphoma, pancreatic cancer, including solid pseudopapillary tumor of the pancreas, pancreatoblastoma, islet cell tumor, acinar cell carcinoma, and ductal adenocarcinoma, gallbladder adenocarcinoma, colorectal adenocarcinoma, microsatellite-stable colorectal cancer, advanced microsatellite-stable colorectal cancer, metastatic microsatellite-stable colorectal cancer, and anal squamous cell carcinoma.

[0213] In certain embodiments, the cancer is selected from liver cancer and cholangiocarcinoma. In certain embodiments, the cancer is liver cancer (also known as hepatocellular carcinoma). In certain embodiments, the cancer is cholangiocarcinoma (also known as cholangiocarcinoma), and in exemplary of these embodiments, the cholangiocarcinoma is selected from the group consisting of intrahepatic cholangiocarcinoma and extrahepatic cholangiocarcinoma.

[0214] In certain embodiments, the cancer is selected from kidney cancer and bladder cancer. In certain embodiments, the cancer is kidney cancer selected from the group consisting of renal cell carcinoma, Wilms' tumor, and transitional cell carcinoma. In certain embodiments, the cancer is bladder cancer selected from the group consisting of urothelial carcinoma (transitional cell carcinoma), squamous cell carcinoma, and adenocarcinoma.

[0215] In certain embodiments, the cancer is selected from bone cancer, hi certain embodiments, the bone cancer is selected from the group consisting of osteosarcoma, malignant fibrous histiocytoma of bone, Ewing's sarcoma, and chordoma (cancer of the bones along the spine).

[0216] In certain embodiments, the cancer is selected from lung cancer. In certain embodiments, the lung cancer is selected from the group consisting of non-small cell lung cancer, small cell lung cancer, bronchial tumor, and pleuropulmonary blastoma.

[0217] In certain embodiments, the cancer is selected from the group consisting of malignant mesothelioma, hi certain embodiments, the cancer is selected from the group consisting of epithelial mesothelioma and sarcomatoid carcinoma.

[0218] In certain embodiments, the cancer is selected from a sarcoma, hi certain embodiments, the sarcoma is selected from the group consisting of central chondrosarcoma, central and periosteal chondroma, fibrosarcoma, clear cell sarcoma of the tendon sheath, and Kaposi's sarcoma.

[0219] In certain embodiments, the cancer is selected from lymphoma. In certain embodiments, the cancer is selected from the group consisting of Hodgkin's lymphoma (e.g., classical Hodgkin's refractory lymphoma), non-Hodgkin's lymphoma (e.g., diffuse large B-cell lymphoma, follicular lymphoma, mycosis fungoides, Sézary syndrome, primary central nervous system lymphoma), cutaneous T-cell lymphoma, and primary central nervous system lymphoma.

[0220] In certain embodiments, the cancer is selected from an adenocarcinoma, hi certain embodiments, the cancer is selected from the group consisting of adrenocortical carcinoma (also called adrenocortical carcinoma or adrenocortical carcinoma), pheochromocytoma, paraganglioma, pituitary tumor, thymoma, and thymic carcinoma.

[0221] In certain embodiments, the cancer is selected from thyroid cancer, hi certain embodiments, the thyroid cancer is selected from the group consisting of medullary thyroid cancer, papillary thyroid cancer, and follicular thyroid cancer.

[0222] In certain embodiments, the cancer is selected from a germ cell tumor. In certain embodiments, the cancer is selected from the group consisting of malignant extracranial germ cell tumor and malignant extragonadal germ cell tumor. In certain examples of these embodiments, the malignant extragonadal germ cell tumor is selected from the group consisting of nonseminoma and seminoma.

[0223] In certain embodiments, the cancer is selected from a cardiac tumor, hi certain embodiments, the cardiac tumor is selected from the group consisting of malignant teratoma, lymphoma, rhabdomyosarcoma, angiosarcoma, chondrosarcoma, infantile fibrosarcoma, and synovial sarcoma.

[0224] In embodiments, the cancer is a metastatic tumor, for example, liver metastasis from colon or pancreatic cancer, and brain metastasis from lung or breast cancer.

[0225] In embodiments, the cancer is selected from the group consisting of solid tumors and lymphomas. In particular embodiments, the cancer is selected from the group consisting of advanced or metastatic solid tumors and lymphomas. In more particular embodiments, the cancer is selected from the group consisting of malignant melanoma, head and neck squamous cell carcinoma, breast adenocarcinoma, and lymphoma. In aspects of such embodiments, the lymphoma is selected from the group consisting of diffuse large B-cell lymphoma, follicular lymphoma, mantle cell lymphoma, small lymphocytic lymphoma, mediastinal large B-cell lymphoma, splenic marginal zone B-cell lymphoma, extranodal marginal zone B-cell lymphoma of mucosa-associated lymphoid tissue (malt), nodal marginal zone B-cell lymphoma, lymphoplasmacytic lymphoma, primary effusion lymphoma, Burkitt's lymphoma, anaplastic large cell lymphoma (primary cutaneous type), anaplastic large cell lymphoma (systemic type), peripheral T-cell lymphoma, angioimmunoblastic T-cell lymphoma, adult T-cell lymphoma / leukemia, extranodal nasal NK / T-cell lymphoma, enteropathy-associated T-cell lymphoma, gamma / delta hepatosplenic T-cell lymphoma, subcutaneous panniculitis-like T-cell lymphoma, mycosis fungoides, and Hodgkin's lymphoma.

[0226] In certain embodiments, the cancer is classified as stage III cancer or stage IV cancer. In some examples of these embodiments, the cancer cannot be surgically removed.

[0227] Compositions and Administration When administered to a patient, a PNU anthracycline derivative can be administered as a component of a pharmaceutical composition comprising a pharmaceutically acceptable excipient. Thus, in one embodiment, the invention provides a pharmaceutical composition comprising an effective amount of a PNU anthracycline derivative and one or more pharmaceutically acceptable carriers or excipients.

[0228] The PNU anthracycline derivatives are useful for the manufacture of a medicament useful for the treatment of a cell proliferative disorder. In one embodiment, the PNU anthracycline derivatives are also useful for the manufacture of a medicament useful for the treatment of cancer.

[0229] In the pharmaceutical compositions and methods of the present disclosure, the active ingredient is typically administered in admixture with a suitable carrier material appropriately selected for the intended dosage form, i.e., oral tablet, capsule (either solid-filled, semi-solid-filled, or liquid-filled), powder for structuring, oral gel, elixir, dispersible granules, syrup, suspension, etc., and consistent with conventional pharmaceutical practice. For example, for oral administration in tablet or capsule form, the active drug ingredient can be combined with any oral, non-toxic, pharmaceutically acceptable inert carrier, such as lactose, starch, sucrose, cellulose, magnesium stearate, dicalcium phosphate, calcium sulfate, talc, mannitol, ethyl alcohol (liquid form), and the like. Solid formulations include powders, tablets, dispersible granules, capsules, cachets, and suppositories. Powders and tablets may comprise from about 0.5 to about 95 percent of the compositions of the present invention. Tablets, powders, cachets and capsules can be used as solid dosage forms suitable for oral administration.

[0230] Furthermore, if desired or necessary, suitable binders, lubricants, disintegrating agents and coloring agents may be incorporated into the mixture.Suitable binders include starch, gelatin, natural sugars, corn sweeteners, natural and synthetic gums such as acacia, sodium alginate, carboxymethylcellulose, polyethylene glycol and waxes.Suitable lubricants include boric acid, sodium benzoate, sodium acetate, sodium chloride and the like.Disintegrating agents include starch, methylcellulose, guar gum and the like.Sweeteners, flavoring agents and preservatives may also be included where appropriate.

[0231] It also includes solid form preparations which are intended to be converted, shortly before use, to liquid form preparations for either oral or parenteral administration. Such liquid forms include solutions, suspensions, and emulsions.

[0232] For preparing suppositories, a low melting wax (such as a mixture of fatty acid glycerides or cocoa butter) is first melted and the active ingredient is dispersed homogeneously therein. The molten mixture is then poured into convenient sized molds, allowed to cool, and thereby solidify.

[0233] Furthermore, the pharmaceutical compositions of the present disclosure may be formulated in sustained release form to provide rate-controlled release of any one or more components or active ingredients to optimize therapeutic efficacy (i.e., anti-cancer activity, etc.) Formulations suitable for sustained release include layered tablets comprising layers of different disintegration rates or controlled release polymer matrices impregnated with the active ingredient and formed into tablet form or capsules comprising such impregnated or encapsulated porous polymer matrices.

[0234] In one embodiment, the PNU anthracycline derivative is administered orally. In another embodiment, the PNU anthracycline derivative is administered orally in a capsule. In another embodiment, the PNU anthracycline derivative is administered orally in a tablet.

[0235] In another embodiment, the PNU anthracycline derivative is administered intravenously.

[0236] In another embodiment, the PNU anthracycline derivative is administered by subcutaneous injection.

[0237] In another embodiment, the PNU anthracycline derivative is administered by intratumoral injection.

[0238] In another embodiment, the PNU anthracycline derivative is administered topically. In certain embodiments, the PNU anthracycline derivative is formulated as a topically applicable cream.

[0239] In yet another embodiment, the PNU anthracycline derivative is administered sublingually.

[0240] In one embodiment, the pharmaceutical preparation containing the PNU anthracycline derivative is in unit dosage form. In such form, the preparation is subdivided into unit doses containing an effective amount of the active ingredient.

[0241] The compositions can be prepared using techniques such as conventional mixing, granulation, or coating methods, and by using solid dispersions based on the guidance provided herein. In one embodiment, the compositions of the invention can contain from about 0.1% to about 99% by weight or volume of a PNU anthracycline derivative. In various embodiments, the compositions of the invention can contain, in one embodiment, from about 1% to about 70%, or from about 5% to about 60%, or from about 10% to about 50% by weight or volume of a PNU anthracycline derivative.

[0242] In one embodiment, the present invention provides a composition comprising a PNU anthracycline derivative, a pharmaceutically acceptable carrier, and one or more additional therapeutic agents. In another embodiment, the present invention provides a composition comprising a PNU anthracycline derivative, a pharmaceutically acceptable carrier, and one additional therapeutic agent. In another embodiment, the present disclosure provides a composition comprising a PNU anthracycline derivative, a pharmaceutically acceptable carrier, and two additional therapeutic agents.

[0243] The amount of PNU anthracycline derivative in a unit dose of the formulation can vary or be adjusted from about 1 mg to about 2500 mg, and in various embodiments, the amount is from about 10 mg to about 1000 mg, 1 mg to about 500 mg, 1 mg to about 100 mg, 1 mg to about 50 mg, 1 mg to about 20 mg, and 1 mg to about 10 mg.

[0244] Safe and effective administration methods for most of these chemotherapeutic agents are known to those skilled in the art. Furthermore, their administration is described in standard literature. For example, the administration of many chemotherapeutic agents is described in the "Physicians' Desk Reference" (PDR), e.g., Physicians' Desk Reference, 71st Edition, 2017 (published by PDR Network, LLC at Montvale, NJ 07645-1725), currently accessible via www.pdr.net, the disclosures of which are incorporated herein by reference.

[0245] If the patient is responding or stable after a treatment cycle is completed, the treatment cycle may be repeated according to the judgment of a skilled clinician. After multiple treatment cycles are completed, the patient may continue treatment with the PNU anthracycline derivative at the same dose administered in the treatment protocol. This maintenance dose may be continued until the patient improves or can no longer tolerate the dose (in which case the dose may be reduced and the patient may continue on the reduced dose).

[0246] The dosage and administration method of the additional therapeutic agent used in the combination therapy described herein for the treatment of cell proliferative disorders can be determined by the attending physician, taking into account the dosage and administration method approved in the package insert; the patient's age, sex, and general health condition; and the type and severity of the cell proliferative disorder. When administered in combination with one or more additional therapeutic agents, the PNU anthracycline derivative and the additional therapeutic agent(s) may be administered simultaneously (i.e., in the same composition or in separate compositions, one immediately after the other) or sequentially. This is particularly useful when the components of the combination are administered on different dosing schedules (e.g., one component is administered once a day and another component is administered every 6 hours) or when the preferred pharmaceutical compositions are different (e.g., one component is administered as a tablet and another component is administered as a capsule). Therefore, a kit containing separate formulations can be advantageous.

[0247] In determining whether treatment is effective at the dose administered, the attending clinical personnel will consider the patient's overall health as well as more definitive signs such as relief of cancer-related symptoms (e.g., pain), inhibition of tumor growth, actual shrinkage of the tumor, or inhibition of metastasis. Tumor size can be measured by standard methods, such as radiological tests, e.g., CAT or MRI scans. Serial measurement data can be used to determine whether tumor growth is slowing or regressing. Relief of disease-related symptoms, such as pain, and improvement in overall condition can also help determine the effectiveness of treatment.

[0248] Generally, the total daily dosage of a PNU anthracycline derivative, when administered alone or in combination therapy, ranges from about 1 to about 2500 mg per day, but will necessarily vary depending on the treatment target, the patient, and the route of administration. In one embodiment, the dosage is about 10 to about 1000 mg / day, administered as a single dose or in 2 to 4 divided doses. In another embodiment, the dosage is about 1 to about 500 mg / day, administered as a single dose or in 2 to 4 divided doses. In yet another embodiment, the dosage is about 1 to about 100 mg / day, administered as a single dose or in 2 to 4 divided doses. In yet another embodiment, the dosage is about 1 to about 50 mg / day, administered as a single dose or in 2 to 4 divided doses. In another embodiment, the dosage is about 500 to about 1500 mg / day, administered as a single dose or in 2 to 4 divided doses. In yet another embodiment, the dosage is about 500 to about 1000 mg / day, administered as a single dose or in 2 to 4 divided doses. In yet another embodiment, the dosage is about 100 to about 500 mg / day, administered in a single dose or in 2 to 4 divided doses.

[0249] For convenience, the total daily dose can be divided and administered in portions throughout the day, if desired. In one embodiment, the total daily dose is administered in one dose. In another embodiment, the total daily dose is administered in two doses over a 24-hour period. In another embodiment, the total daily dose is administered in three doses over a 24-hour period. In yet another embodiment, the total daily dose is administered in four doses over a 24-hour period.

[0250] The dosage and frequency of administration of the PNU anthracycline derivative will be adjusted according to the judgment of the attending physician, taking into consideration factors such as the age, condition and size of the patient, and the severity of the condition being treated.

[0251] Combination therapy In one embodiment, the method of the present invention for treating a cell proliferative disorder can further comprise the administration of one or more additional therapeutic agents other than a PNU anthracycline derivative.

[0252] Accordingly, in one embodiment, the present disclosure provides a method for treating a cell proliferative disorder in a patient, comprising administering to the patient (i) a PNU anthracycline derivative or a pharmaceutically acceptable salt thereof, and (ii) at least one additional therapeutic agent other than a PNU anthracycline derivative, wherein the amounts administered are together effective to treat the cell proliferative disorder. In one embodiment, the cell proliferative disorder being treated is cancer.

[0253] When administering the combination therapies disclosed herein to a patient, the combined therapeutic agents, or pharmaceutical compositions or compositions comprising the therapeutic agents, can be administered in any order, e.g., sequentially, simultaneously, concomitantly, or simultaneously. The amounts of the various active agents in such combination therapies can be different amounts (different dosage amounts) or the same amounts (same dosage amounts). Thus, by way of non-limiting example, a PNU anthracycline derivative and an additional therapeutic agent can be present in fixed amounts (dosage amounts) in a single dosage unit (e.g., capsule, tablet, etc.).

[0254] In one embodiment, a PNU anthracycline derivative is administered while an additional therapeutic agent exerts a prophylactic or therapeutic effect, or vice versa.

[0255] In another embodiment, the PNU anthracycline derivative and the additional therapeutic agent are administered in dosages commonly used when such agents are used as monotherapy for the treatment of cancer.

[0256] In another embodiment, the PNU anthracycline derivative and the additional therapeutic agent are administered at doses that are lower than those typically used when such agents are used as monotherapy for the treatment of cancer.

[0257] In one embodiment, the PNU anthracycline derivative and the additional therapeutic agent are present in the same composition. In one embodiment, the composition is suitable for oral administration. In another embodiment, the composition is suitable for intravenous administration. In another embodiment, the composition is suitable for intratumoral administration. In another embodiment, the composition is suitable for subcutaneous administration. In yet another embodiment, the composition is suitable for parenteral administration.

[0258] Cancers and proliferative disorders that can be treated or prevented using the combination therapies of the present disclosure include, but are not limited to, those listed above.

[0259] The PNU anthracycline derivative and the additional therapeutic agent can act additively or synergistically. A synergistic combination allows for the use of lower dosages of one or more agents in the combination therapy, or for the administration of one or more agents less frequently. Reducing the dosage or administration frequency of one or more agents can reduce the toxicity of the treatment without reducing the efficacy of the treatment. Thus, in one embodiment, the PNU anthracycline derivative and the additional therapeutic agent act synergistically and are administered at dosages lower than those typically used when such agents are used as monotherapies in the treatment of cancer.

[0260] In one embodiment, administration of a PNU anthracycline derivative and an additional therapeutic agent can inhibit the resistance of the cancer to these agents.

[0261] PNU anthracycline derivatives can be used in combination with one or more other active agents (collectively referred to herein as "additional therapeutic agents"), including, but not limited to, other therapeutic agents used in the prevention, treatment, control, amelioration, or risk reduction of a particular disease or condition (e.g., cancer). In one embodiment, a PNU anthracycline derivative is combined with one or more other therapeutic agents for use in the prevention, treatment, inhibition, amelioration, or risk reduction of a particular disease or condition for which a PNU anthracycline derivative is useful. Such other active agents can be administered simultaneously or sequentially with the compounds of the present disclosure, by a route and in an amount commonly used therefor.

[0262] Combinations of PNU anthracycline derivatives with one or more anti-cancer agents are within the scope of this disclosure. Examples of such additional anti-cancer agents are found in Cancer Principles and Practice of Oncology by VT Devita and S. Hellman (editors), 9 th edition (May 16, 2011), Lippincott Williams & Wilkins Publishers. A person of ordinary skill in the art would be able to discern which additional therapeutic agent combinations would be useful based on the particular characteristics of the agents and the cancer involved. Such additional therapeutic agents include estrogen receptor modulators, programmed cell death protein 1 (PD-1) inhibitors, programmed death-ligand 1 (PD-L1) inhibitors, androgen receptor modulators, retinoid receptor modulators, cytotoxic / cytostatic agents, antiproliferative agents, prenyl protein transferase inhibitors, HMG-CoA reductase inhibitors and other angiogenesis inhibitors, HIV protease inhibitors, reverse transcriptase inhibitors, inhibitors of cell proliferation and survival signaling, bisphosphonates, aromatase inhibitors, siRNA therapeutics, gamma-secretase inhibitors, agents that interfere with receptor tyrosine kinases (RTKs), and agents that interfere with cell cycle checkpoints.

[0263] All of the additional therapeutic agents, and types of additional therapeutic agents, disclosed herein below are useful in the combination therapies described herein.

[0264] "Androgen receptor modulators" refers to compounds that interfere with or inhibit the binding of androgens to the receptor, regardless of mechanism. Examples of androgen receptor modulators include finasteride and other 5α-reductase inhibitors, nilutamide, flutamide, bicalutamide, liarozole, and abiraterone acetate.

[0265] "Estrogen receptor modulators" refers to compounds that interfere with or inhibit the binding of estrogen to the receptor, regardless of mechanism. Examples of estrogen receptor modulators include, but are not limited to, tamoxifen, raloxifene, idoxifene, LY353381, LY117081, toremifene, fulvestrant, 4-[7-(2,2-dimethyl-1-oxopropoxy-4-methyl-2-[4-[2-(1-piperidinyl)ethoxy]phenyl]-2H-1-benzopyran-3-yl]-phenyl-2,2-dimethylpropanoate, 4,4'-dihydroxybenzophenone-2,4-dinitrophenylhydrazone, and SH646.

[0266] In the treatment of breast cancer (e.g., postmenopausal and premenopausal breast cancer, e.g., hormone-dependent breast cancer), the compounds of Formula (1) can be used in combination with an effective amount of at least one antihormonal agent selected from the group consisting of (a) an aromatase inhibitor, (b) an antiestrogens, and (c) an LHRH analog; and, optionally, an effective amount of at least one chemotherapeutic agent. Examples of aromatase inhibitors include, but are not limited to, anastrozole (e.g., Arimidex), letrozole (e.g., Femara), exemestane (e.g., Aromasin), fadrozole, and formestane (e.g., Lentaron). Examples of antiestrogens include, but are not limited to, tamoxifen (e.g., Norvadex), fulvestrant (e.g., Faslodex), raloxifene (e.g., Evista), and acolbifene.

[0267] Examples of LHRH analogs include, but are not limited to, goserelin (e.g., Zoladex) and leuprolide (e.g., leuprolin acetate, e.g., Lupron or Lupron Depot). Examples of additional therapeutic agents useful in the compositions and methods of the invention include, but are not limited to, the following chemotherapeutic agents: trastuzumab (e.g., Herceptin), gefitinib (e.g., Iressa), erlotinib (e.g., erlotinib HCl, e.g., Tarceva), bevacizumab (e.g., Avastin), cetuximab (e.g., Erbitux), and bortezomib (e.g., Velcade).

[0268] "Retinoid receptor modulators" refer to compounds that interfere with or inhibit the binding of retinoids to receptors, regardless of mechanism. Examples of such retinoid receptor modulators include bexarotene, tretinoin, 13-cis-retinoic acid, 9-cis-retinoic acid, α-difluoromethylornithine, ILX23-7553, trans-N-(4'-hydroxyphenyl)retinamide, and N-4-carboxyphenylretinamide.

[0269] "Cytotoxic / cytostatic agents" refers to compounds that cause cell death or inhibit cell proliferation primarily by directly interfering with cellular function or by inhibiting or disrupting cellular mitosis, and include alkylating agents, tumor necrosis factors, intercalators, hypoxia-activated compounds, microtubule inhibitors / microtubule stabilizers, mitotic kinesin inhibitors, inhibitors of kinases involved in growth factor and cytokine signaling pathways, antimetabolites; biological response modifiers; hormone / antihormonal therapeutic agents, hematopoietic growth factors, monoclonal antibody-targeted therapeutic agents, topoisomerase inhibitors, proteosome inhibitors, ubiquitin ligase inhibitors, and aurora kinase inhibitors.

[0270] Examples of cytotoxic / cytostatic agents include sertenef, cachectin, ifosfamide, tasonermin, lonidamine, carboplatin, altretamine, prednimastine, dibromodulcitol, ranimustine, fotemcitine, nedaplatin, oxaliplatin, temozolomide, heptaplatin, estramustine, improsulfan tosylate, trofosfamide, sfamide), nimustine, dibrospidium chloride, pumitepa, lobaplatin, satraplatin, profilomycin, cisplatin, irofulven, dexifosfamide, cis-aminedichloro(2-methyl-pyridine)platinum, benzylguanine, glufosfamide, GPX100, (trans, trans, trans)-bis-mu-(hexane-1,6-diamine)-mu-[diamine-platinum(II)]bis[diamine(chloro)platinum(II)]tetrachloride, diarylidinyl spermine, arsenic trioxide, 1-(11-dodecylamino-10-hydroxyundecyl)-3,7-dimethylxanthine, zorubicin, idarubicin, daunorubicin, These include, but are not limited to, bisantrene, mitoxantrone, pirarubicin, pinafide, valrubicin, amrubicin, antineoplaston, 3'-deamino-3'-morpholino-13-deoxo-10-hydroxycarminomycin, annamycin, galarubicin, elinafide, MEN10755, 4-demethoxy-3-deamino-3-aziridinyl-4-methylsulfonyl-daunorubicin (see WO 00 / 50032), Raf kinase inhibitors (such as Bay 43-9006) and mTOR inhibitors (such as Wyeth's CCI-779).

[0271] An example of a hypoxia-activated compound is tirapazamine.

[0272] Examples of proteosome inhibitors include, but are not limited to, lactacystin and MLN-341 (Velcade).

[0273] Examples of microtubule inhibitors / microtubule-stabilizing agents include paclitaxel, vindesine sulfate, 3',4'-didehydro-4'-deoxy-8'-norvincaleukoblastine, docetaxol, rhizoxin, dolastatin, mivobulin isethionate, auristatin, cemadotin, RPR109881, BMS 184476, vinflunine, cryptophycin, 2,3,4,5,6-pentafluoro-N-(3-fluoro-4-methoxyphenyl)benzenesulfonamide, anhydrovinblastine, TDX258, epothilones (e.g., U.S. Pat. Nos. 6,284,781 and 6,288,237), and BMS 188797. In one example, epothilones are not included in the microtubule inhibitors / microtubule-stabilizing agents.

[0274] Some examples of topoisomerase inhibitors are topotecan, hycaptamine, irinotecan, rubitecan, 6-ethoxypropionyl-3',4'-O-exo-benzylidene-chartreusin, 9-methoxy-N,N-dimethyl-5-nitropyrazolo[3,4,5-kl]acridine-2-(6H)propanamine, 1-amino-9-ethyl-5-fluoro-2,3-dihydro-9-hydroxy-4-methyl-1H,12H-benzo[de]pyrano[3',4' :b,7]-indolizino[1,2b]quinoline-10,13(9H,15H)dione, lurtotecan, 7-[2-(N-isopropylamino)ethyl]-(20S)camptothecin, BNP1350, BNPI1100, BN80915, BN80942, etoposide phosphate, teniposide, sobuzoxane, 2′-dimethylamino-2′-deoxy-etoposide, GL331, N-[2-(dimethylamino)ethyl]-9-hydroxy-5,6-dimethyl-6H-pyrido[4,3-b]carbazole-1-carboxamide, Asulacrine, (5a,5aB,8aa,9b)-9-[2-[N-[2-(dimethylamino)ethyl]-N-methylamino]ethyl]-5-[4-hydroxy-3,5-dimethoxyphenyl]-5,5a,6,8,8a,9-hexahydrofuro(3',4':6,7)naphtho(2,3-d)-1,3-dioxol-6-one, 2,3-(methylenedioxy)-5-methyl-7-hydroxy-8-methoxybenzo[c]-phenanthridinium, 6,9-bis[(2-aminoethyl)amino]benzo[ g] Isoquinoline-5,10-dione, 5-(3-aminopropylamino)-7,10-dihydroxy-2-(2-hydroxyethylaminomethyl)-6H-pyrazolo[4,5,1-de]acridin-6-one, N-[1-[2(diethylamino)ethylamino]-7-methoxy-9-oxo-9H-thioxanthen-4-ylmethyl]formamide, N-(2-(dimethylamino)ethyl)acridine-4-carboxamide, 6-[[2-(dimethylamino)ethyl]amino]-3-hydroxy-7H-indeno[2,1-c]quinolin-7-one and dimesna.

[0275] Examples of inhibitors of mitotic kinesins, in particular the human mitotic kinesin KSP, are described in publications WO03 / 039460, WO03 / 050064, WO03 / 050122, WO03 / 049527, WO03 / 049679, WO03 / 049678, WO04 / 039774, WO03 / 079973, WO03 / 099211, WO03 / 1 05855, WO03 / 106417, WO04 / 037171, WO04 / 058148, WO04 / 058700, WO04 / 126699, WO05 / 018638, WO05 / 019206, WO05 / 019205, WO05 / 018547, WO05 / 017190, US2005 / 0176776. In one example, inhibitors of mitotic kinesins include, but are not limited to, inhibitors of KSP, inhibitors of MKLP1, inhibitors of CENP-E, inhibitors of MCAK, and inhibitors of Rab6-KIFL.

[0276] Examples of "histone deacetylase inhibitors" include, but are not limited to, SAHA, TSA, oxamflatin, PXD101, MG98, and scriptaid. Other histone deacetylase inhibitors are described in the following manuscript: Miller, TA et al. J. Med. Chem. 46(24):5097-5116(2003).

[0277] "Inhibitors of kinases involved in mitotic progression" include, but are not limited to, inhibitors of Aurora kinases, inhibitors of Polo-like kinases (PLK; particularly inhibitors of PLK-1), inhibitors of bub-1, and inhibitors of bub-R1. An example of an "Aurora kinase inhibitor" is VX-680 (tozasertib).

[0278] "Antiproliferative agents" include antisense RNA and DNA oligonucleotides such as G3139, ODN698, GEM231, and INX3001, as well as enocitabine, carmofur, tegafur, pentostatin, doxifluridine, trimetrexate, fludarabine, capecitabine, galocitabine, cytarabine ocphosphate, fosteabine sodium hydrate, raltitrexed, paltitrexid, emitefur ( emitefur, tiazofurin, decitabine, nolatrexed, pemetrexed, nelzarabine, 2'-deoxy-2'-methylidenecystidine, 2'-fluoromethylene-2'-deoxycystidine, N-[5-(2,3-dihydrobenzofuryl)sulfonyl]-N'-(3,4-dichlorophenyl)urea, N6-[4-deoxy-4-[N2-[2(E),4(E)-tetradecadienoyl]glycylamino]-1-glycol Lysero-BL-manno-heptopyranosyl]adenine, aplidine, ecteinascidin, troxacitabine, 4-[2-amino-4-oxo-4,6,7,8-tetrahydro-3H-pyrimidino[5,4-b][1,4]thiazin-6-yl-(S)-ethyl]-2,5-thienoyl-L-glutamic acid, aminopterin, 5-fluorouracil, alanosine, 11-acetyl-8-(carbamoyloxymethyl)-4-phosphatase These include antimetabolites such as lumyl-6-methoxy-14-oxa-1,11-diazatetracyclo(7.4.1.0.0)-tetradeca-2,4,6-trien-9-yl acetate, swainsonine, lometrexol, dexrazoxane, methioninase, 2'-cyano-2'-deoxy-N4-palmitoyl-1-BD-arabinofuranosylcytosine, 3-aminopyridine-2-carboxaldehyde thiosemicarbazone, and transizumab.

[0279] Examples of monoclonal antibody targeted therapeutic agents include therapeutic agents having a cytotoxic agent or radioisotope attached to a cancer cell-specific or target cell-specific monoclonal antibody. In one embodiment, a monoclonal antibody targeted therapeutic agent includes bexar.

[0280] "HMG-CoA reductase inhibitors" refers to inhibitors of 3-hydroxy-3-methylglutaryl-CoA reductase. Examples of HMG-CoA reductase inhibitors that can be used include, but are not limited to, lovastatin, simvastatin, pravastatin, fluvastatin, atorvastatin, rosuvastatin, and cerivastatin. The structural formulae of these and other HMG-CoA reductase inhibitors that can be used in the methods of the present invention are described on page 87 of M. Yalpani, "Cholesterol Lowering Drugs," Chemistry & Industry, pp. 85-89 (February 5, 1996), and in U.S. Pat. Nos. 4,782,084 and 4,885,314. As used herein, the term HMG-CoA reductase inhibitor includes all pharmaceutically acceptable lactone and open acid forms (i.e., where the lactone ring is opened to form the free acid), as well as salt and ester forms, of compounds that have HMG-CoA reductase inhibitory activity, and therefore, the use of such salts, esters, open acid and lactone forms is within the scope of this disclosure.

[0281] "Prenyl protein transferase inhibitor" refers to a compound that inhibits one or any combination of prenyl protein transferase enzymes, such as farnesyl protein transferase (FPTase), geranylgeranyl protein transferase type I (GGPTase-I), and geranylgeranyl protein transferase type II (GGPTase-II, also known as RabGGPTase). For an example of the role of prenyl protein transferase inhibitors in angiogenesis, see European Journal of Cancer, Vol. 35, No. 9, pp. 1394-1401 (1999).

[0282] "Angiogenesis inhibitors" refers to compounds that inhibit the formation of new blood vessels, regardless of mechanism. Examples of angiogenesis inhibitors include tyrosine kinase inhibitors, such as inhibitors of the tyrosine kinase receptors Flt-1 (VEGFR1) and Flk-1 / KDR (VEGFR2), inhibitors of epidermal-derived, fibroblast-derived, or platelet-derived growth factors, MMP (matrix metalloproteinase) inhibitors, integrin blockers, cyclooxygenase inhibitors such as interferon-α, interleukin-12, pentosan polysulfate, nonsteroidal anti-inflammatory drugs (NSAIDs) such as aspirin and ibuprofen, and celecoxib and and selective cyclooxygenase-2 inhibitors such as rofecoxib, steroidal anti-inflammatory drugs (corticosteroids, mineralocorticoids, dexamethasone, prednisone, prednisolone, methylpred, betamethasone), carboxyamidotriazoles, combretastatin A-4, squalamine, 6-O-(chloroacetyl-carbonyl)-fumagillol, thalidomide, angiostatin, troponin-1, and angiotensin II antagonists.

[0283] Other examples of angiogenesis inhibitors useful in the combination include endostation, ukrain, ranpinase, IM862, 5-methoxy-4-[2-methyl-3-(3-methyl-2-butenyl)oxiranyl]-1-oxaspiro[2,5]oct-6-yl(chloroacetyl)carbamate, acetyldinanaline, 5-amino-1-[[3,5-dichloro-4-(4-chlorobenzoyl)phenyl]methyl]-1H-1,2,3-triazole-4- Carboxamide, CM101, squalamine, combretastatin, RPI4610, NX31838, sulfated manopentaose phosphate, 7,7-(carbonyl-bis[imino-N-methyl-4,2-pyrrolocarbonylimino[N-methyl-4,2-pyrrole]-carbonylimino]-bis-(1,3-naphthalene disulfonate), and 3-[(2,4-dimethylpyrrol-5-yl)methylene]-2-indolinone (SU5416), or pharmaceutically acceptable salts thereof.

[0284] Additional therapeutic agents that modulate or inhibit angiogenesis and that may be used in combination with PNU anthracycline derivatives include agents that modulate or inhibit the coagulation and fibrinolysis systems (see review in Clin. Chem. La. Med. 38: 679-692 (2000)). Examples of such agents include, but are not limited to, heparin, low molecular weight heparins, and carboxypeptidase U inhibitors (also referred to as inhibitors of activated thrombin-activated fibrinolysis inhibitor [TAFIa]).

[0285] Further examples of angiogenesis inhibitors include tyrosine kinase inhibitors, epidermal-derived growth factor inhibitors, fibroblast-derived growth factor inhibitors, platelet-derived growth factor inhibitors, MMP (matrix metalloproteinase) inhibitors, integrin blockers, interferon-α, interleukin-12, pentosan polysulfate, cyclooxygenase inhibitors, carboxyamidotriazoles, combretastatin A-4, squalamine, 6-O-chloroacetylcarbonyl)-fumagillol, thalidomide, angiostatin, antibodies against troponin-1 or VEGF.

[0286] "Cell cycle checkpoint inhibitors" refer to compounds that sensitize cancer cells to DNA-damaging drugs by inhibiting protein kinases that transduce cell cycle checkpoint signals. Such agents include inhibitors of ATR, ATM, Chkl, and Chk2 kinases, as well as cdk and cdc kinase inhibitors, such as 7-hydroxystaurosporine, flavopiridol, CYC202 (Cycracel), and BMS-387032.

[0287] "Agents that interfere with receptor tyrosine kinases (RTKs)" refer to compounds that inhibit RTKs and therefore mechanisms involved in oncogenesis and tumor progression. Such agents include inhibitors of c-Kit, Eph, PDGF, Flt3, and c-Met. Further agents include inhibitors of RTKs described by Bume-Jensen and Hunter, Nature, 411:355-365, 2001. Specific examples of tyrosine kinase inhibitors include N-(trifluoromethylphenyl)-5-methylisoxazole-4-carboxamide, 3-[(2,4-dimethylpyrrol-5-yl)methylidenyl]indolin-2-one, 17-(allylamino)-17-demethoxygeldanamycin, 4-(3-chloro-4-fluorophenylamino)-7-methoxy-6-[3-(4-morpholinyl)propoxyl]quinazoline, N-(3-ethynylphenyl)-6,7-bis(2-methoxyethoxy)-4-quinazolinamine, BIBX1382, 2,3,9,10,11,12-hexahydro-10-(hydroxymethyl)-10-hydroxy-9-methyl-9,12-epoxy -1H-diindolo[1,2,3-fg:3′,2′,1′-kl]pyrrolo[3,4-i][1,6]benzodiazocin-1-one, SH268, genistein, STI571, CEP2563, 4-(3-chlorophenylamino)-5,6-dimethyl-7H-pyrrolo[2,3-d]pyrimidine methanesulfonate, 4-(3-bromo-4-hydroxyphenyl)amino-6,7-dimethoxyquinazoline, 4-(4′-hydroxyphenyl)amino-6,7-dimethoxyquinazoline, SU6668, STI571A, N-4-chlorophenyl-4-(4-pyridylmethyl)-1-phthalazinamine, and EMD121974, or a pharmaceutically acceptable salt thereof.

[0288] "Inhibitors of cell proliferation and survival signaling pathways" refer to compounds that inhibit signaling cascades downstream of cell surface receptors. Such agents include inhibitors of serine / threonine kinases (WO02 / 083064, WO02 / 083139, WO02 / 083140, US2004-0116432, WO02 / 083138, US2004-0102360, WO03 / 086404, WO03 / 086279, WO03 / 086394, WO03 / 084473, WO03 / 086403, WO2004 / 041162, WO2004 / 096131, WO2004 / 096129, WO2004 / 096 135, WO2004 / 096130, WO2005 / 100356, WO2005 / 100344, US 7,454,431, US 7,589,068), inhibitors of Raf kinase (e.g., BAY-43-9006), inhibitors of MEK (e.g., CI-1040 and PD-098059), inhibitors of mTOR (e.g., Wyeth CCI-779), and inhibitors of PI3K (e.g., LY294002).

[0289] The present disclosure also encompasses combination therapies that include an NSAID that is a selective COX-2 inhibitor. For purposes of this specification, an NSAID that is a selective COX-2 inhibitor is defined as an NSAID that has an IC50 or IC60 activity for COX-1 as assessed by a cell or microsomal assay. 50 IC for COX-2 50This method is defined as having at least a 100-fold specificity for COX-2 inhibition over COX-1 inhibition, as measured by the ratio of COX-1 to COX-2. COX-2 inhibitors useful in this method are 3-phenyl-4-(4-(methylsulfonyl)phenyl)-2-(5H)-furanone and 5-chloro-3-(4-methylsulfonyl)phenyl-2-(2-methyl-5-pyridinyl)pyridine, or a pharmaceutically acceptable salt thereof. Compounds described as specific inhibitors of COX-2 and therefore useful in this disclosure include, but are not limited to, rofecoxib, etoricoxib, parecoxib, BEXTRA®, and CELEBREX®, or a pharmaceutically acceptable salt thereof.

[0290] As used herein, an "integrin blocker" refers to an integrin that blocks the physiological ligand α v Compounds that selectively antagonize, inhibit, or interfere with binding to β3 integrin; physiological ligand α v Compounds that antagonize, inhibit, or interfere with binding to β5 integrin; physiological ligand α v β3 and α v β5 integrin; as well as compounds that antagonize, inhibit or interfere with the activity of certain integrins expressed on capillary endothelial cells. v β6, α v The term also refers to antagonists of β8, α1β1, α2β1, α5β1, α6β1 and α6β4 integrins. v β3, α v β5, α v β6, α v It also refers to antagonists of any combination of β8, α1β1, α2β1, α5β1, α6β1 and α6β4 integrins.

[0291] Combinations with additional therapeutic agents other than anticancer agents are also contemplated in the methods of the present invention. For example, combinations of PNU anthracycline derivatives with PPAR-γ (i.e., PPAR-gamma) agonists and PPAR-δ (i.e., PPAR-delta) agonists are useful in the treatment of certain malignancies. PPAR-γ and PPAR-δ are the nuclear peroxisome proliferator-activated receptors γ and δ. PPAR-γ agonists have been shown to inhibit the angiogenic response to VEGF in vitro. Both troglitazone and rosiglitazone maleate inhibit the development of retinal neovascularization in mice (Arch. Ophthamol. 2001; 119: 709-717). Examples of PPAR-γ agonists and PPAR-γ / α agonists include thiazolidinediones (such as DRF2725, CS-011, troglitazone, rosiglitazone, and pioglitazone), fenofibrate, gemfibrozil, clofibrate, GW2570, SB219994, AR-H039242, JTT-501, MCC-555, GW2331, GW409544, NN2344, KRP297, NP0110, DRF4158, NN622, GI262570, PNU 182716, DRF552926, 2-[(5,7-dipropyl-3-trifluoromethyl-1,2-benzisoxazol-6-yl)oxy]-2-methylpropionic acid (disclosed in USSN 09 / 782856) and 2(R)-7-(3-(2-chloro-4-(4-fluorophenoxy)phenoxy)propoxy)-2-ethylchroman-2-carboxylic acid (disclosed in USSN 60 / 235708 and 60 / 244697) or a pharmaceutically acceptable salt thereof.

[0292] Another embodiment of the present disclosure is the use of PNU anthracycline derivatives in combination with gene therapy for cancer treatment. For a review of genetic strategies for cancer treatment, see Hall et al. (Am J Hum Genet 61: 785-789, 1997) and Kufe et al. (Cancer Medicine, 5th Ed., pp. 876-889, BC Decker, Hamilton, 2000). Gene therapy can be used to deliver tumor suppressor genes. Examples of such genes include, but are not limited to, p53 (e.g., U.S. Pat. No. 6,069,134), uPA / uPAR antagonists ("Adenovirus-Mediated Delivery of a uPA / uPAR Antagonist Suppresses Angiogenesis-Dependent Tumor Growth and Dissemination in MICE," GENE Therapy, August 1998; 5(8): 1105-13), and interferon-γ (J Immunol 2000; 164: 217-222), which can be delivered via recombinant virus-mediated gene transfer.

[0293] PNU anthracycline derivatives can also be administered in combination with inhibitors of intrinsic multidrug resistance (MDR), particularly MDR associated with high levels of transporter protein expression, including p-glycoprotein (P-gp) inhibitors such as LY335979, XR9576, OC144-093, R101922, VX853, and PSC833 (valspodar), or pharmaceutically acceptable salts thereof.

[0294] The PNU anthracycline derivatives may also be administered with immune enhancers such as levamisole, isoprinosine and Zadaxin or pharmaceutically acceptable salts thereof.

[0295] The PNU anthracycline derivatives may also be useful in treating or preventing cancer in combination with a P450 inhibitor such as a xenobiotic, quinidine, tyramine, ketoconazole, testosterone, quinine, metyrapone, caffeine, phenelzine, doxorubicin, troleandomycin, cyclobenzaprine, erythromycin, cocaine, furafylline, cimetidine, dextromethorphan, ritonavir, indinavir, amprenavir, diltiazem, terfenadine, verapamil, cortisol, itraconazole, mibefradil, nefazodone, and nelfinavir or a pharmaceutically acceptable salt thereof.

[0296] PNU anthracycline derivatives include cyclosporine A, PSC833, GF120918, Cremophor EL, fumitremorgin C, Ko132, Ko134, Iressa, imatinib mesylate, EKI-785, Cl1033, novobiocin, diethylstilbestrol, tamoxifen, reserpine, VX-710, tryprostatin A, flavonoids, ritonavir, saquinavir, nelfinavir, omeprazole, quinidine, and benzamidine. They may also be useful in treating or preventing cancer in combination with Pgp and / or BCRP inhibitors such as rapamil, terfenadine, ketoconazole, nifidepine, FK506, amiodarone, XR9576, indinavir, amprenavir, cortisol, testosterone, LY335979, OC144-093, erythromycin, vincristine, digoxin, and talinolol or a pharmaceutically acceptable salt thereof.

[0297] PNU anthracycline derivatives may also be useful in treating or preventing cancer, such as osteosarcoma, in combination with bisphosphonates such as, but not limited to, etidronate (Didronel), pamidronate (Aredia), alendronate (Fosamax), risedronate (Actonel), zoledronate (Zometa), ibandronate (Boniva), incadronate or cimadronate, clodronate, EB-1053, minodronate, neridronate, piridronate, and tiludronate, including all pharmaceutically acceptable salts, derivatives, hydrates, and mixtures thereof.

[0298] PNU anthracycline derivatives may also be useful in treating or preventing breast cancer in combination with aromatase inhibitors, including, but not limited to, anastrozole, letrozole, and exemestane, or pharmaceutically acceptable salts thereof.

[0299] PNU anthracycline derivatives may also be useful in treating or preventing cancer in combination with siRNA therapeutics.

[0300] PNU anthracycline derivatives can also be administered in combination with gamma secretase inhibitors and / or inhibitors of NOTCH signaling, including those described in WO01 / 90084, WO02 / 30912, WO01 / 70677, WO03 / 013506, WO02 / 36555, WO03 / 093252, WO03 / 093264, WO03 / 093251, WO03 / 093253, WO2004 / 039800, WO2004 / 039370, WO2005 / 030731, WO2005 / 014553, USSN 10 / 95 7,251, WO2004 / 089911, WO02 / 081435, WO02 / 081433, WO03 / 018543, WO2004 / 031137, WO2004 / 031139, WO2004 / 031138, WO2004 / 101538, WO2004 / 101539 and WO02 / 47671 (including LY-450139), or pharmaceutically acceptable salts thereof.

[0301] In one embodiment, specific anti-cancer agents useful in the combination therapy include pembrolizumab (Keytruda®), abarelix; (Plenaxis Depot®); aldesleukin (Prokine®); aldesleukin (Proleukin®); alemtuzumab (Campath®); alitretinoin (Panretin®); allopurinol (Zyloprim®); altretamine (Hexalen®); amifostine (Ethyol®); anastrozole (Arimidex®); arsenic trioxide (Trisenox®); asparaginase (Elspar®); azacitidine (Vidaza®). Registered Trademark); bevacuzimab (Avastin®); bexarotene capsules (Targretin®); bexarotene gel (Targretin®); bleomycin (Blenoxane®); bortezomib (Velcade®); busulfan intravenous (Busulfex®); busulfan oral (Myleran®); calsterone (Methosarb®); capecitabine (Xeloda®); carboplatin (Paraplatin®); carmustine (BCNU®, BiCNU®); carmustine (Gliadel®); carmustine + Polifeprosan 20 implant (Gliadel wafer®); celecoxib (Celebrex®); cetuximab (Erbitux®); chlorambucil (Leukeran®); cisplatin (Platinol®); cladribine (Leustatin®, 2-CdA®); clofarabine (Clolar®); cyclophosphamide (Cytoxan®, Neosar®); cyclophosphamide (Cytoxan injection®); cyclophosphamide (Cytoxan tablets®); cytarabine (Cytosar-U®); cytarabine liposome (DepoCyt®);Dacarbazine (DTIC-Dome®); Dactinomycin, Actinomycin D (Cosmegen®); Darbepoetin alfa (Aranesp®); Daunorubicin liposomal (DanuoXome®); Daunorubicin, daunomycin (Daunorubicin®); Daunorubicin, daunomycin (Cerubidine®); Denileukin diftitox (Ontak®); Dexrazoxane (Zinecard®); Docetaxel (Taxotere®); Doxorubicin (Adriamycin PFS®); Doxorubicin (Adriamycin®, Rubex®); Doxorubicin (Adriamycin PFS Injection®); Doxorubicin Liposomal (Doxil®); Dromostanolone Propionate (Dromostanolone®); Dromostanolone Propionate (Masterone Injection®); Elliot's B Solution (Elliot's B Solution®); Epirubicin (Ellence®); Epoetin Alfa (Epogen®); Erlotinib (Tarceva®); Estramustine (Emcyt®); Etoposide Phosphate (Etopophos®); Etoposide, VP-16 (Vepesid®); Exemestane (Aromasin®); Filgrastim (Neupog en®); floxuridine (arterial administration) (FUDR®); fludarabine (Fludara®); fluorouracil, 5-FU (Adrucil®); fulvestrant (Faslodex®); gefitinib (Iressa®); gemcitarabine (Gemzar®); gemtuzumab ozogamicin (Mylotarg®); goserelin acetate (Zoladex implant®); goserelin acetate (Zoladex®); histrelin acetate (Histrelin implant®); hydroxyurea (Hydrea®); ibritumomab tiuxetan (Zevalin®);Idarubicin (Idamycin®); Ifosfamide (IFEX®); Imatinib mesylate (Gleevec®); Interferon alfa-2a (RoferonA®); Interferon alfa-2b (IntronA®); Irinotecan (Camptosar®); Lenalidomide (Revlimid®); Letrozole (Femara®); Leucovorin (Wellcovorin®, Leucovorin®); Leuprolide acetate (Eligard®); Levamisole (Ergamisol®); Lomustine, CCNU (CeeBU®); Mechlorethamine, Nitrogen Mustard (Mustargen®); Megestrol acetate (Megace®); Melphalan, L-PAM (Alkeran®); Mercaptopurine, 6-MP (Purinethol®); Meth Mesna (Mesnex®); Mesna (Mesnextabs®); Methotrexate (Methotrexate®); Methoxsalen (Uvadex®); Mitomycin C (Mutamycin®); Mitotane (Lysodren®); Mitoxantrone (Novantrone®); Nandrolone phenpropionate (Durabolin-50®); Nelarabine (Arranon®) ); nofetumomab (Verluma®); oprelvekin (Neumega®); oxaliplatin (Eloxatin®); paclitaxel (Paxene®); paclitaxel (Taxol®); paclitaxel protein-bound particles (Abraxane®); palifermin (Kepivance®); pamidronate (Aredia®); pegademase (Adagen (Pegademase Bovine)®); pegaspargase (Oncaspar®); pegfilgrastin (Neulasta®); pemetrexed disodium (Alimta®); pentostatin (Nipent®);Pipobroman (Vercyte®); Plicamycin, Mitalamycin (Mithracin®); Porfimer sodium (Photofrin®); Procarbazine (Matulane®); Quinacrine (Atabrine®); Rasburicase (Elitek®); Rituximab (Rituxan®); Ridaforolimus; Sargramostin (Leukine®); Sargramostin (Prokine®); Sorafenib (Nexavar®); Streptozocin (Zanosar®); Sunitinib maleate (Sutent®); Talc (Sclerosol®) trademark); tamoxifen (Nolvadex®); temozolomide (Temodar®); teniposide, VM-26 (Vumon®); testolactone (Teslac®); thioguanine, 6-TG (Thioguanine®); thiotepa (Thioplex®); topotecan (Hycamtin®); toremifene (Fareston®); tositumomab (Bexxar®); tositumomab / I-131 tositumomab (Bexxar®); trastuzumab (Herceptin®); tretinoin, ATRA (Vesanoid®); uracil mustard (Uracil Mustard Capsules®); valrubicin (Valstar®); vinblastine (Velban®); vincristine (Oncovin®); vinorelbine (Navelbine®); vorinostat (Zolinza®) and zoledronate (Zometa®) or pharmaceutically acceptable salts thereof;

[0302] Thus, the scope of the present disclosure encompasses the use of PNU anthracycline derivatives in combination with a second compound selected from estrogen receptor modulators, androgen receptor modulators, retinoid receptor modulators, cytotoxic agents, cytotoxic / cytostatic agents, antiproliferative agents, prenyl protein transferase inhibitors, HMG-CoA reductase inhibitors, HIV protease inhibitors, reverse transcriptase inhibitors, angiogenesis inhibitors, PPAR-γ agonists, PPAR-δ agonists, intrinsic multidrug resistance inhibitors, antiemetics, agents useful for treating anemia, agents useful for treating neutropenia, immune enhancers, inhibitors of cell proliferation and survival signaling, bisphosphonates, aromatase inhibitors, siRNA therapeutics, gamma-secretase and / or NOTCH inhibitors, agents that interfere with receptor tyrosine kinases (RTKs), agents that interfere with cell cycle checkpoints, and any of the therapeutic agents listed above.

[0303] Yet another example of the present disclosure is a method of treating cancer comprising administering a therapeutically effective amount of a PNU anthracycline derivative in combination with paclitaxel or trastuzumab.

[0304] The therapeutic combinations disclosed herein can be used in combination with, but are not limited to, other anti-cancer agents used in the prevention, treatment, inhibition, amelioration, or risk reduction of a particular disease or condition (e.g., a cell proliferative disorder). In one embodiment, a PNU anthracycline derivative is combined with one or more other anti-cancer agents used in the prevention, treatment, inhibition, amelioration, or risk reduction of a particular disease or condition for which a PNU anthracycline derivative is useful. Such other active agents can be administered prior to, simultaneously with, or sequentially with the compounds of the present disclosure, by a route and in an amount commonly used therefor.

[0305] The present disclosure also includes pharmaceutical compositions useful for treating or preventing cancer, comprising a therapeutically effective amount of a PNU anthracycline derivative and a second compound selected from an estrogen receptor modulator, an androgen receptor modulator, a retinoid receptor modulator, a cytotoxic / cytostatic agent, an antiproliferative agent, a prenyl protein transferase inhibitor, an HMG-CoA reductase inhibitor, an HIV protease inhibitor, a reverse transcriptase inhibitor, an angiogenesis inhibitor, a PPAR-γ agonist, a PPAR-δ agonist, an inhibitor of cell proliferation and survival signaling, a bisphosphonate, an aromatase inhibitor, an siRNA therapeutic agent, a γ-secretase and / or NOTCH inhibitor, an agent that interferes with a receptor tyrosine kinase (RTK), an agent that interferes with a cell cycle checkpoint, and any of the therapeutic agents listed herein.

[0306] The present disclosure further relates to a method of treating cancer in a human patient, comprising administering to the patient a PNU anthracycline derivative and a PD-1 antagonist. The compound of the disclosure and the PD-1 antagonist can be administered simultaneously or sequentially.

[0307] In certain embodiments, the PD-1 antagonist is an anti-PD-1 antibody, or an antigen-binding fragment thereof. In alternative embodiments, the PD-1 antagonist is an anti-PD-L1 antibody, or an antigen-binding fragment thereof. In some embodiments, the PD-1 antagonist is an anti-PD-1 antibody independently selected from pembrolizumab, nivolumab, cemiplimab, sintilimab, tislelizumab, atezolizumab (MPDL3280A), camrelizumab, and toripalimab. In other embodiments, the PD-L1 antagonist is an anti-PD-L1 antibody independently selected from atezolizumab, durvalumab, and avelumab.

[0308] In one embodiment, the PD-1 antagonist is pembrolizumab. In a particular subembodiment, the method comprises administering 200 mg of pembrolizumab to the patient about every three weeks. In another subembodiment, the method comprises administering 400 mg of pembrolizumab to the patient about every six weeks.

[0309] In a further subembodiment, the method comprises administering 2 mg / kg of pembrolizumab to the patient about every 3 weeks. In a particular subembodiment, the patient is a pediatric patient.

[0310] In some embodiments, the PD-1 antagonist is nivolumab. In certain subembodiments, the method comprises administering 240 mg of nivolumab to the patient about every two weeks. In other subembodiments, the method comprises administering 480 mg of nivolumab to the patient about every four weeks.

[0311] In some embodiments, the PD-1 antagonist is cemiplimab. In certain embodiments, the method comprises administering 350 mg of cemiplimab to the patient about every three weeks.

[0312] In some embodiments, the PD-1 antagonist is atezolizumab. In certain subembodiments, the method comprises administering 1200 mg of atezolizumab to the patient about every three weeks.

[0313] In some embodiments, the PD-1 antagonist is durvalumab. In certain subembodiments, the method comprises administering 10 mg / kg of durvalumab to the patient about every two weeks.

[0314] In some embodiments, the PD-1 antagonist is avelumab. In certain subembodiments, the method comprises administering 800 mg of avelumab to the patient about every two weeks.

[0315] When a PNU anthracycline derivative is administered in combination with an anti-human PD-1 antibody (or antigen-binding fragment thereof), the anti-human PD-1 antibody (or antigen-binding fragment thereof) can be administered simultaneously with, before, or after the PNU anthracycline derivative. The anti-human PD-1 antibody (or antigen-binding fragment thereof) and / or the PNU anthracycline derivative, or a pharmaceutically acceptable salt thereof, can be administered separately, by the same or different administration routes, or together with other drugs in the same pharmaceutical composition. The weight ratio of the anti-human PD-1 antibody (or antigen-binding fragment thereof) to the PNU anthracycline derivative compound can vary and will depend on the therapeutically effective dose of each drug. Generally, a therapeutically effective dose of each is used. Combinations comprising at least one anti-human PD-1 antibody (or antigen-binding fragment thereof), a PNU anthracycline derivative, and optionally other active agents typically contain a therapeutically effective dose of each active agent. In such combinations, the anti-human PD-1 antibody (or antigen-binding fragment thereof), PNU anthracycline derivative, and other active agent can be administered separately or in combination. Furthermore, the administration of one element can be prior to, concurrent with, or subsequent to the administration of the other agent.

[0316] In one embodiment, the disclosure provides an anti-human PD-1 antibody (or antigen-binding fragment thereof), and / or a PNU anthracycline derivative, and at least one other active agent as a combined preparation for simultaneous, separate, or sequential use in the treatment of cancer.

[0317] The present disclosure also provides for the use of a PNU anthracycline derivative of the present disclosure for the treatment of cancer, where the patient has previously been treated (e.g., within 24 hours) with an anti-human PD-1 antibody (or antigen-binding fragment thereof). The present disclosure also provides for the use of an anti-human PD-1 antibody (or antigen-binding fragment thereof) for the treatment of a cell proliferative disorder, where the patient has previously been treated (e.g., within 24 hours) with a PNU anthracycline derivative of the present disclosure.

[0318] The present invention further relates to a method of treating cancer, comprising administering to a subject in need thereof a combination therapy comprising (a) a PNU anthracycline derivative of the present disclosure, and (b) an anti-human PD-1 antibody (or antigen-binding fragment thereof), wherein the anti-human PD-1 antibody (or antigen-binding fragment thereof) is administered once every 21 days.

[0319] Furthermore, the present disclosure relates to a method of treating cancer, comprising administering to a subject in need thereof a combination therapy comprising (a) a PNU anthracycline derivative of the present disclosure and (b) an anti-human PD-1 antibody (or antigen-binding fragment thereof). In certain embodiments, the cancer arises as one or more solid tumors or lymphomas. In further particular embodiments, the cancer is selected from the group consisting of advanced or metastatic solid tumors and lymphomas. In even further particular embodiments, the cancer is selected from the group consisting of malignant melanoma, head and neck squamous cell carcinoma, MSI-H cancer, MMR-deficient cancer, non-small cell lung cancer, urothelial carcinoma, gastric or gastroesophageal junction adenocarcinoma, breast adenocarcinoma, and lymphoma. In additional embodiments, the lymphoma is selected from the group consisting of diffuse large B-cell lymphoma, follicular lymphoma, mantle cell lymphoma, small lymphocytic lymphoma, mediastinal large B-cell lymphoma, splenic marginal zone B-cell lymphoma, extranodal marginal zone B-cell lymphoma of mucosa-associated lymphoid tissue (MALT), nodal marginal zone B-cell lymphoma, lymphoplasmacytic lymphoma, primary effusion lymphoma, Burkitt's lymphoma, anaplastic large cell lymphoma (primary cutaneous type), anaplastic large cell lymphoma (systemic type), peripheral T-cell lymphoma, angioimmunoblastic T-cell lymphoma, adult T-cell lymphoma / leukemia, extranodal nasal NK / T-cell lymphoma, enteropathy-associated T-cell lymphoma, gamma / delta hepatosplenic T-cell lymphoma, subcutaneous panniculitis-like T-cell lymphoma, mycosis fungoides, and Hodgkin's lymphoma. In certain embodiments, the cell proliferative disorder is a metastatic cancer, e.g., liver metastasis from colorectal cancer. In additional embodiments, the cell proliferative disorder is a cancer classified as stage III or stage IV cancer. In these embodiments, the cancer cannot be surgically removed.

[0320] In embodiments of the methods disclosed herein, the anti-human PD-1 antibody (or antigen-binding fragment thereof) is administered by intravenous infusion or subcutaneous injection.

[0321] In one embodiment, the disclosure provides a composition comprising a PNU anthracycline derivative, a pharmaceutically acceptable carrier, and an anti-human PD-1 antibody (or antigen-binding fragment thereof).

[0322] In another embodiment, the present disclosure provides a composition comprising a PNU anthracycline derivative, a pharmaceutically acceptable carrier, and pembrolizumab.

[0323] In one embodiment, the disclosure provides a composition comprising a PNU anthracycline derivative, a pharmaceutically acceptable carrier, and two additional therapeutic agents, one of which is an anti-human PD-1 antibody (or antigen-binding fragment thereof) and the other of which is independently selected from the group consisting of an anti-cancer agent.

[0324] The compounds of the present disclosure can be used in combination with antiemetic agents to treat nausea or vomiting, such as acute, delayed, delayed-phase, and anticipatory emesis, which may result from the use of the compounds of the present disclosure alone or in combination with radiation therapy. For the prevention or treatment of emesis, the compounds of the present disclosure can be used in combination with other antiemetic agents, particularly neurokinin-1 receptor antagonists, 5HT3 receptor antagonists (such as ondansetron, granisetron, tropisetron, and zatisetron), GABAB receptor agonists (such as baclofen), corticosteroids (such as Decadron (dexamethasone), Kenalog, Aristocort, Nasalide, Preferid, and Betham). The compounds may be used in combination with antidopaminergic agents such as Benecorten or other agents such as those disclosed in U.S. Patent Nos. 2,789,118, 2,990,401, 3,048,581, 3,126,375, 3,929,768, 3,996,359, 3,928,326, and 3,749,712, phenothiazines (e.g., prochlorperazine, fluphenazine, thioridazine, and mesoridazine), metoclopramide, or dronabinol. In another example, combination therapy with an antiemetic selected from a neurokinin-1 receptor antagonist, a 5HT3 receptor antagonist, and a corticosteroid is disclosed for the treatment or prevention of emesis that may result from administration of a PNU anthracycline derivative.

[0325] PNU anthracycline derivatives can also be administered with agents useful in the treatment of anemia, such as continuous erythropoiesis receptor activators (e.g., epoetin alfa).

[0326] PNU anthracycline derivatives can also be administered with drugs useful for treating neutropenia, such as hematopoietic growth factors that regulate neutrophil production and function, such as human granulocyte colony-stimulating factor (G-CSF). Examples of G-CSF include filgrastim.

[0327] PNU anthracycline derivatives may be useful in combination with other therapies, including, but not limited to, radiation therapy, surgery, and gene therapy. Thus, in one embodiment, the cancer treatment methods described herein can optionally include the administration of an effective amount of radiation therapy, unless otherwise specified. Gamma radiation is preferred for radiation therapy.

[0328] The methods for treating cancer described herein may include administering an effective amount of radiation (i.e., the methods for treating cancer described herein may include administering radiation therapy).

[0329] Methods of treating cancer described herein include methods of treating cancer comprising administering a therapeutically effective amount of a PNU anthracycline derivative in combination with radiation therapy and / or in combination with a second compound selected from the group consisting of an estrogen receptor modulator, an androgen receptor modulator, a retinoid receptor modulator, a cytotoxic / cytostatic agent, an antiproliferative agent, a prenyl protein transferase inhibitor, an HMG-CoA reductase inhibitor, an HIV protease inhibitor, a reverse transcriptase inhibitor, an angiogenesis inhibitor, a PPAR-γ agonist, a PPAR-δ agonist, an intrinsic multidrug resistance inhibitor, an antiemetic agent, an agent useful for treating anemia, an agent useful for treating neutropenia, an immune enhancing agent, an inhibitor of cell proliferation and survival signaling, a bisphosphonate, an aromatase inhibitor, an siRNA therapeutic agent, a gamma secretase and / or NOTCH inhibitor, an agent that interferes with a receptor tyrosine kinase (RTK), an agent that interferes with a cell cycle checkpoint, and any of the additional therapeutic agents listed herein.

[0330] Further embodiments of the present disclosure include the pharmaceutical compositions, combinations, uses, and methods described above, with the understanding that each embodiment can be combined with one or more other embodiments, provided that such combination is consistent with the description of the embodiment. It is further understood that the embodiments provided above include all embodiments, including embodiments resulting from combinations of embodiments.

[0331] kit In one embodiment, a kit is provided that includes a therapeutically effective amount of a PNU anthracycline derivative or a pharmaceutically acceptable salt, solvate, or ester of said compound, and a pharmaceutically acceptable carrier, vehicle, or diluent.

[0332] In another aspect, a kit is provided that includes an amount of a PNU anthracycline derivative and an amount of at least one additional therapeutic agent listed above, wherein the amounts of the two or more active ingredients are such that a desired therapeutic effect is achieved. In one embodiment, the PNU anthracycline derivative and the one or more additional therapeutic agents are provided in the same container. In one embodiment, the PNU anthracycline derivative and the one or more additional therapeutic agents are provided in separate containers.

Claims

1. A compound having the following structural formula (I): or a pharmaceutically acceptable salt of said compound: 【Chemistry 1】 [In the formula, R １ is H or C １－６ is alkyl; R ２ is C １ -C ６ Hydroxyalkyl, 5- to 11-ring bridged bicyclic heterocyclic alkyl, 5- to 11-ring fused bicyclic heterocyclic alkyl, C １ -C ６ Aminoalkyl, -(C １ -C ６ alkylene)-NR ３ C(O)-(C １ -C ６ aminoalkyl), -(C １ -C ６ alkylene)-NHC(O)NHNH ２ , -(C １ -C ６ alkylene)-NR ３ , -(C １ -C ６ alkylene)-N(R ３ )-(C １ -C ６ alkylene)-N(R ３ )-NHC(O)-(C １ -C ６ aminoalkyl), -(C １ -C ６ haloalkylene)-NR ３ , -(C １ -C ６ alkylene) ｎ -(3- to 7-membered monocyclic heterocyclic alkyl), -(C １ -C ６ alkylene)-NR ３ C(O)-(3- to 7-membered monocyclic heterocyclic alkyl), -(C １ -C ６ alkylene)-NR ３ C(O)-(C ３ -C ７ monocyclic cycloalkyl), -(C １ -C ６ alkylene) ｎ -(C ５ -C １１ fused bicyclic cycloalkyl), -(C １ -C ６ alkylene) ｎ -(C ５ -C １１ Bridged bicyclic cycloalkyl), -(C １ -C ６ alkylene) ｎ -(C ３ -C ７ monocyclic cycloalkyl), -(C １ -C ６ alkylene) ｎ -(C ６ -C １０ aryl), -(C １ -C ６ alkylene) ｎ -(5- or 6-membered monocyclic heteroaryl), and 5- to 11-membered spirocyclic heterocycloalkyl, wherein the 3- to 7-membered monocyclic heterocycloalkyl group, the 5- to 10-membered fused bicyclic heterocycloalkyl group, the 5- to 10-membered bridged bicyclic heterocycloalkyl group, the C ３ -C ７ monocyclic cycloalkyl group, ６ -C １０ an aryl group, the 5- or 6-membered monocyclic heteroaryl group, the C ５ -C １１ The bicyclic cycloalkyl group, and the 5- to 11-membered spirocyclic heterocycloalkyl group each optionally and independently comprise one or more R Ａ and the 3- to 7-membered monocyclic heterocycloalkyl group may have one or more ring carbon atoms substituted with an oxo group; Or, R １ and R ２ are taken together with the common nitrogen atom to which they are each bonded to form (i) a 3- to 7-membered monocyclic heterocycloalkyl group, (ii) a 5- to 11-ring bridged bicyclic heterocycloalkyl group, (iii) a 5- to 11-ring fused bicyclic heterocycloalkyl group, or (iv) a 5- to 11-ring spirocyclic heterocycloalkyl group, wherein the 3- to 7-membered monocyclic heterocycloalkyl group, the 5- to 11-ring bicyclic heterocycloalkyl group, the 5- to 11-ring fused heterocycloalkyl group, and the 5- to 11-ring spirocyclic heterocycloalkyl group each optionally and independently contain one or more R Ｂ may be substituted with a group; R ３ In each case, independently, H or C １－６ is alkyl; R Ａ In each case, independently, C １－６ Alkyl, halo, -CN, -OR ３ , -(C １ -C ６ alkylene) ｎ -N(R ３ ) ２ , C １ -C ６ Aminoalkyl, -(C １ -C ６ alkylene)-NHC(O)-(C １ -C ６ aminoalkyl), —O—(C １－６ alkyl), —NHC(O)CH ２ OH, and -(C １ -C ６ and (3- to 7-membered monocyclic heterocycloalkyl) groups, each of which is optionally and independently selected from one or more R ｃ may be substituted with a group; R Ｂ In each case, independently, C １－６ Alkyl, halo, -CN, -OR ３ , -N(R ３ ) ２ , C １ -C ６ Aminoalkyl, -(C １ -C ６ alkylene)-NHC(O)-(C １ -C ６ aminoalkyl), —O—(C １－６ alkyl), —NHC(O)CH ２ OH, and -(C １ -C ６ and (3- to 7-membered monocyclic heterocycloalkyl) groups, each of which is optionally and independently selected from one or more R ｃ may be substituted with a group; R ｃ In each case, independently, C １－６ Alkyl, halo, -CN, -OR ３ , -N(R ３ ) ２ , C １ -C ６ aminoalkyl, —O—(C １－６ alkyl), -NHC(O)-(C １ -C ６ aminoalkyl), -(C １ -C ６ alkylene)-NHC(O)-(C １ -C ６ aminoalkyl), C １－６ Alkyl, halo, -CN, -OR ３ , -N(R ３ ) ２ , —O—(C １－６ alkyl), and —NHC(O)CH ２ OH; Each occurrence of n is independently 0 or 1.

2. 2. The compound of claim 1, having the following structural formula (Ia): or a pharmaceutically acceptable salt thereof: 【Chemistry 2】

3. 2. The compound of claim 1, having the following structural formula (Ib): or a pharmaceutically acceptable salt thereof: 【Transformation 3】

4. R １ The compound of any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof, wherein

5. R ２ But C ３ -C ７ Monocyclic cycloalkyl, C ５ -C １１ Fused Bicyclic Cycloalkyl, C ５ -C １１ Bridged Bicyclic Cycloalkyl, C ６ -C １０ aryl, 3- to 7-membered monocyclic heterocycloalkyl, 5- to 11-ring bridged bicyclic heterocycloalkyl, 5- to 11-ring fused bicyclic heterocycloalkyl, 5- to 11-membered spirocyclic heterocycloalkyl, and 5- or 6-membered monocyclic heteroaryl; ３ -C ７ monocyclic cycloalkyl group, ５ -C １１ fused bicyclic cycloalkyl group, ５ -C １１ Bridged bicyclic cycloalkyl group, ６ -C １０ The aryl group, the 3- to 7-membered monocyclic heterocycloalkyl group, the 5- to 10-membered fused bicyclic heterocycloalkyl group, the 5- to 10-membered bridged bicyclic heterocycloalkyl group, the 5- to 11-membered spirocyclic heterocycloalkyl group, and the 5- or 6-membered heteroaryl group each optionally and independently comprise one or more R Ａ 5. The compound of claim 4, or a pharmaceutically acceptable salt thereof, optionally substituted with a group.

6. R ２ 6. The compound of claim 5, wherein is selected from the following: 【Chemistry 4】

7. R ２ But C １ -C ６ Hydroxyalkyl, C １ -C ６ Aminoalkyl, -(C １ -C ６ alkylene)-NR ３ C(O)-(C １ -C ６ aminoalkyl), -(C １ -C ６ alkylene)-NHC(O)NHNH ２ , -(C １ -C ６ alkylene)-N(R ３ )-(C １ -C ６ alkylene)-N(R ３ )-NHC(O)-(C １ -C ６ aminoalkyl), and -(C １ -C ６ haloalkylene)-NR ３ 5. The compound of claim 4, selected from: or a pharmaceutically acceptable salt thereof.

8. R ２ が、-CH ２ CH ２ NHC(O)CH ２ NH ２ 、-CH ２ CH ２ NHC(O)NHNH ２ 、-CH ２ CH ２ NHC(O)CH(CH) ３ )NH ２ 、-(CH ２ ) ３ NH(CH) ２ ) ３ NHC(O)CH ２ NH ２ 、-CH ２ CH ２ N(CH) ３ )C(O)C(CH ３ (NH ２ )CH(CH ３ ) ２ 、-CH ２ CH ２ NHCH ３ 、-(CH ２ ) ４ NH ２ 、-CH ２ C(CH) ３ ) ２ CH ２ NH ２ 、-(CH ２ ) ３ N(CH) ３ )CH ２ CH ２ CH ２ NH ２ 、-CH ２ C(CH) ３ ) ２ NH ２ 、-(CH ２ ) ３ NH ２ 、-CH ２ CH(NH) ２ CF ３ 、-CH ２ CH(NH) ２ CHF ２ 、-CH ２ CH ２ CH(NH) ２ CF ３ 、-CH ２ CH ２ CH(NH ２ ) CHF ２ , -(CH ２ ) ３ NHCH ３ , -CH ２ CH ２ OH, and -CH ２ NH ２ 8. The compound of claim 7, selected from:

9. R ２ But -(C １ -C ６ alkylene)-(3- to 7-membered monocyclic heterocyclic alkyl), -(C １ -C ６ alkylene)-NR ３ C(O)-(3- to 7-membered monocyclic heterocyclic alkyl), -(C １ -C ６ alkylene)-NR ３ C(O)-(C ３ -C ７ monocyclic cycloalkyl), -(C １ -C ６ alkylene)-(C ３ -C ７ monocyclic cycloalkyl), -(C １ -C ６ alkylene)-(C ６ -C １０ aryl), -(C １ -C ６ alkylene)-(C ５ -C １１ fused bicyclic cycloalkyl groups), and -(C １ -C ６ any of the 3- to 7-membered monocyclic heterocycloalkyl groups selected from the group consisting of alkylene-(5- or 6-membered monocyclic heteroaryl) and C ３ -C ７ Any of the monocyclic cycloalkyl groups may be selected from the group C ６ -C １０ aryl group, the C ５ -C １１ The fused bicyclic cycloalkyl group and the 5- or 6-membered monocyclic heteroaryl group each optionally and independently comprise one or more R Ａ 5. The compound of claim 4, or a pharmaceutically acceptable salt thereof, optionally substituted with a group.

10. R ２ 10. The compound of claim 9, wherein is selected from the following: 【Transformation 5】

11. R １ and R ２ are taken together with the common nitrogen atom to which they are each bonded to form a 3- to 7-membered monocyclic heterocycloalkyl group, a 5- to 11-ring bridged bicyclic heterocycloalkyl group, or a 5- to 11-ring fused bicyclic heterocycloalkyl group, and the 3- to 7-membered monocyclic heterocycloalkyl group, the 5- to 11-ring bridged bicyclic heterocycloalkyl group, and the 5- to 11-ring fused bicyclic heterocycloalkyl group each optionally and independently contain one or more R Ｂ The compound according to any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof, optionally substituted with a group.

12. R １ and R ２ or a pharmaceutically acceptable salt thereof, wherein: 【Transformation 6】

13. R １ is H; R ２ But -(C １ -C １０ alkylene)-(C ６ -C １０ aryl), -(C １ -C １０ alkylene)-(3- to 7-membered monocyclic heterocycloalkyl), 5- to 10-membered bicyclic cycloalkyl, -(C １ -C １０ alkylene)-(C ３ -C ７ monocyclic cycloalkyl); and 5- or 6-membered monocyclic heteroaryl, wherein C ６ -C １０ an aryl group, the 3- to 7-membered monocyclic heterocyclic alkyl group, the 5- to 10-membered bicyclic cycloalkyl group, the C ３ -C ７ monocyclic cycloalkyl group; and the 5- or 6-membered monocyclic heteroaryl group is -NH ２ The compound according to any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof, optionally substituted by:

14. R ２ 14. The compound of claim 13, wherein is selected from the following: 【Transformation 7】

15. A compound which is: or a pharmaceutically acceptable salt of said compound. 【Transformation 8】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】

16. A pharmaceutical composition comprising an effective amount of a compound according to any one of claims 1 to 15 or a pharmaceutically acceptable salt of said compound, and a pharmaceutically acceptable carrier.

17. 17. The pharmaceutical composition of claim 16, further comprising one or more additional therapeutic agents, wherein the additional therapeutic agents are selected from anti-cancer agents.

18. 16. A method of treating cancer in a patient in need thereof, comprising administering to said patient an effective amount of a compound of any one of claims 1 to 15 or a pharmaceutically acceptable salt of said compound.

19. 20. The method of claim 18, further comprising administering one or more additional therapeutic agents, wherein the additional therapeutic agents are selected from anti-cancer agents.

20. 18. The pharmaceutical composition of claim 17, wherein the additional therapeutic agent comprises pembrolizumab.

21. 20. The method of claim 19, wherein the additional therapeutic agent comprises pembrolizumab.

22. Use of the compound according to any one of claims 1 to 15 or a pharmaceutically acceptable salt of said compound, or the pharmaceutical composition according to claim 16, for the manufacture of a medicament for the treatment or prevention of cancer or tumor.

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