Tetracycline derivatives, and uses thereof

Abstract

The present disclosure relates generally to compounds that utilize a tetracycline scaffold, including specifically a minocycline or sancycline scaffold. Provided are also pharmaceutical compositions and methods of using such compounds. Certain compounds provided herein lack significant antibiotic activity.

Description

TETRACYCLINE DERIVATIVES, AND USES THEREOF CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims priority to and the benefit of U.S. Provisional Patent Application No.63 / 553,511, filed February 14, 2024, and U.S. Provisional Patent Application No.63 / 553,576, filed February 14, 2024, the disclosures of which are incorporated by reference herein in their entireties. FIELD

[0002] The present disclosure relates generally to tetracycline derivatives, and more specifically to compositions and methods that utilize the tetracycline scaffold, including minocycline and sancycline scaffolds. BACKGROUND

[0003] Minocycline and sancycline are next-generation, semi-synthetic tetracyclines. Currently, for example, minocycline is mainly used in the treatment of acne vulgaris and some sexually transmitted diseases. Certain tetracycline derivatives have been reported to exert a variety of biological actions that are independent of their anti-microbial activity, including anti-inflammatory and anti-apoptotic activities, and inhibition of proteolysis, angiogenesis and tumor metastasis. What is desired in the art are tetracycline derivatives that can serve as a new therapeutic approach beyond antibiotic uses. BRIEF SUMMARY

[0004] In some aspects, provided is a compound of Formula (I-a), (I-b), (II), (III), (IV-a), (IV-b), (V-a) or (V-b):or a pharmaceutically acceptable salt thereof, wherein the variables are as defined herein. In some variations, provided herein are isomers, including stereoisomers, and tautomers of the compounds provided herein.

[0005] In other aspects, compositions, including pharmaceutical compositions, and kits that include the compounds are also provided, as are methods of using and making the compounds. In some embodiments, the compounds lack significant antibiotic activity. In one embodiment, certain compounds may find use in treating peripheral diseases or conditions. In another embodiment, other compounds may find use in treating diseases or conditions of the central nervous system. DESCRIPTION OF THE DRAWINGS

[0006] The present application can be understood by reference to the following description taken in conjunction with the accompanying figures.

[0007] FIG.1 shows the effect of the test compound in open field testing.

[0008] FIG.2 shows the effect of the test compound in self-grooming.

[0009] FIG.3 shows the effect of the test compound in hyponeophagia.

[0010] FIG.4 shows the effect of the test compound in nesting.

[0011] FIG.5 shows the effect of the test compound in novel object recognition.

[0012] FIG.6 shows the effect of the test compound in partition test.

[0013] FIG.7 shows the effect of the test compound in aggression.

[0014] FIG.8 shows the effect of the test compounds in an audiogenic seizure study. DETAILED DESCRIPTION

[0015] The following description sets forth exemplary compositions, methods, parameters and the like. It should be recognized, however, that such description is not intended as a limitation on the scope of the present disclosure but is instead provided as a description of exemplary embodiments.

[0016] In some aspects, provided herein are compounds, and their corresponding compositions and methods, that utilize a tetracycline scaffold, including the minocycline and sancycline scaffolds. In some embodiments, the compounds provided herein lack significant antibiotic activity. In some variations, certain compounds are suitable for use in treatment of peripheral indications, and such compounds may not have a favorable capacity to cross the blood brain barrier. In other variations, other certain compounds are suitable for use in treatment indications of the central nervous system, and such compounds have a favorable capacity to cross the blood brain barrier. In yet other variations, the compounds provided herein are suitable for use in treating age-related diseases or diseases in which protein synthesis is dysregulated. For example, in one variation, such disease is Fragile X Syndrome.Compounds of Formula (I-a)

[0017] In some aspects, provided is a compound of Formula (I-a):or a pharmaceutically acceptable salt thereof, wherein: each R1and R2is independently H or optionally substituted alkyl; Ra2is ORm, wherein Rmis H or optionally substituted alkyl; Rb1is ORp, or NRqRs, wherein each Rp, Rqand Rsis independently H or optionally substituted alkyl; Rb2is H or ORx, wherein Rxis H or optionally substituted alkyl; Rd1is H, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted cycloalkyl, optionally substituted heterocyclyl, or NRtRu, wherein each Rtand Ruis independently H or optionally substituted alkyl; Rd2is H, NHRy, or halo, wherein Ryis H, or -C(=O)(CH2)nNRvRw, wherein n is an integer greater than or equal to 1; wherein each Rvand Rwis independently H or optionally substituted alkyl, or Rvand Rware taken together with the nitrogen atom to which they are attached to form an optionally substituted cyclic group; and Rd3is ORz, wherein Rzis H or optionally substituted alkyl.

[0018] In some embodiments, R1and R2are both H. In other embodiments, R1and R2are both optionally substituted alkyl. In other embodiments, R1and R2are both independently selected optionally substituted alkyl. In some variations, the alkyl is unsubstituted. In other variations, the alkyl is substituted with one or more (e.g., any of one, two, three, four, or five) halo (e.g., F, Cl, Br, or I). In certain variations of the foregoing, the alkyl is a C1-10 alkyl, or C1-4 alkyl In one variation R1and R2are both methyl

[0019] In some embodiments, Rmis H, and Ra2is OH. In other embodiments, Rmis optionally substituted alkyl. In some variations, the alkyl is unsubstituted. In other variations, the alkyl is substituted with one or more halo. In certain variations of the foregoing, the alkyl is a C1-10alkyl, or C1-4alkyl. In one variation, Rmis methyl.

[0020] In some embodiments, Rb1is ORp. In certain embodiments, Rpis H, and Rb1is OH. In other embodiments, Rpis optionally substituted alkyl. In some variations, the alkyl is unsubstituted. In other variations, the alkyl is substituted with one or more (e.g., any of one, two, three, four, or five) halo. In certain variations of the foregoing, the alkyl is a C1-10alkyl, or C1-4 alkyl. In one variation, Rpis methyl.

[0021] In some embodiments, Rb2is H. In other embodiments, Rxis H, and Rb2is OH. In other embodiments, Rxis optionally substituted alkyl. In some variations, the alkyl is unsubstituted. In other variations, the alkyl is substituted with one or more (e.g., any of one, two, three, four, or five) halo. In certain variations of the foregoing, the alkyl is a C1-10 alkyl, or C1-4alkyl.

[0022] In some embodiments, Rd1is H, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted cycloalkyl, optionally substituted heterocyclyl, or NRtRu,. In one embodiments, Rd1is other than halo.

[0023] In some embodiments, Rd1is H. In some embodiments, Rd1is other than H. In some variations, Rd1is haloalkyl, alkenyl, cycloalkyl, or heteroaryl, wherein the cycloalkyl and heteroaryl are optionally substituted with alkyl, haloalkyl, or halo. In some embodiments, Rd1is cycloalkyl (e.g., C3-12cycloalkyl, a C3-10cycloalkyl, or a C3-6cycloalkyl) optionally substituted with alkyl, haloalkyl, or halo. In some embodiments, Rd1is heteroaryl (e.g., 5- to 12-membered, a 5- to 10-membered, or a 5- to 6-membered heteroaryl) optionally substituted with alkyl, haloalkyl, or halo. In some embodiments, Rd1is unsubstituted heterocycloalkyl. In some embodiments, Rd1is heterocycloalkyl substituted with alkyl, haloalkyl, or halo. In some embodiments, Rd1is unsubstituted heterocycloalkenyl. In some embodiments, Rd1is heterocycloalkenyl substituted with alkyl, haloalkyl, or halo.

[0024] In other embodiments, Rd1is optionally substituted alkyl. In some variations, the alkyl is unsubstituted. In other variations, the alkyl is substituted with one or more (e.g., any of one, two, three, four, or five) halo (e.g., F or Cl). In certain variations of the foregoing, the alkyl is a C1-10alkyl C1-6alkyl or C1-4alkyl In some variations Rd1is haloalkyl In onevariation, Rd1 is (R)-3-trifluoro-2-propyl or (S)-3-trifluoro-2-propyl. In one embodiment, Rd1is CF3. In one embodiment, Rd1is CH(CH3)CF3.

[0025] In other embodiments, Rd1 is optionally substituted alkenyl. In some variations,the alkenyl is unsubstituted. In other variations, the alkenyl is substituted with one or more (e.g., any of one, two, three, four, or five) halo. In certain variations of the foregoing, the alkenyl is a C2-10 alkenyl, or C2-6 alkenyl.

[0026] In yet other embodiments, Rd1 is NRtRu. In some variations, Rt is H, and Ru is Hor optionally substituted alkyl. In some variations, the alkyl is unsubstituted. In other variations, the alkyl is substituted with one or more (e.g., any of one, two, three, four, or five) halo. In certain variations of the foregoing, the alkyl is a C1-10 alkyl, or C1-4 alkyl.

[0027] In some embodiments, Rd1 is:optionally substituted cyclopropyl, optionally substituted azetidinyl, optionally substituted oxetanyl, optionally substituted cyclobutyl, substituted cyclopentyl, optionally substituted heterocyclyl, wherein the heterocyclyl is selected from the group consisting of:wherein R is H or optionally substituted alkyl (e.g., C1-6alkyl optionally substituted with one or more halo), and wherein each of the heterocyclyl is optionally substituted.

[0028] In some variations, Rd1is optionally substituted azetidinyl. In certain variations, Rd1is unsubstituted azetidinyl. In one variation, Rd1is.

[0029] In some variations, Rd1is optionally substituted oxetanyl. In certain variations, Rd1is unsubstituted oxetanyl. In one variation, Rd1is.

[0030] In some embodiments, Rd1is optionally substituted heterocyclyl, wherein the, and , wherein R is H or optionally substituted alkyl (e.g., C1-6 alkyl optionally substituted with one or more halo), and wherein each of the heterocyclyl is optionally substituted. In some embodiments, Rd1is unsubstituted heterocyclyl. In some embodiments, Rd1is heterocyclyl substituted with one or more independently selected alkyl (e.g., C1-6alkyl), haloalkyl (e.g., C1-6alkyl optionally substituted with one or more halo such as F), halo (e.g., F, Cl, or Br), or -OH.

[0031] In one embodiment, Rd1is halo. In one embodiment, Rd1is F. In one embodiment, Rd1is Cl.

[0032] In one embodiment, Rd1is cycloalkyl (e.g., C3-C8cycloalkyl). In one embodiment, Rd1is cyclopropyl, optionally substituted with alkyl, haloalkyl or halo. In another embodiment, Rd1is cyclobutyl, optionally substituted with alkyl, haloalkyl or halo. In yet another embodiment, Rd1is cyclopentyl substituted with alkyl, haloalkyl or halo. In another embodiment, Rd1is heterocyclyl, optionally substituted with alkyl, haloalkyl, -OH, or halo.

[0033] In some variations, Rd1is other than unsubstituted oxazolyl, furanyl (unsubstituted or substituted), unsubstituted imdazolyl, unsubstituted cyclopentyl, or unsubstituted thienyl. In some variations, when Rd1is isoxazolyl, the isoxazolyl is unsubstituted, or substituted with other than dimethyl groups. In another embodiment, Rd1is heterocyclyl, optionally substituted with alkyl, haloalkyl or halo. In some embodiments, the heterocyclyl is aromatic (e.g., pyrazole). In some embodiments, the heterocyclyl is non-aromatic. In some embodiments, the heterocyclyl is connected to the rest of the compound by a heteroatom (e.g., an annular N atom). In some embodiments, the heterocyclyl is optionally substituted morpholine or pyrrolidine. In some embodiments, the heterocyclyl is optionally substituted cyclic amides, such as pyrrolidinones.

[0034] In some variations, Rd1is optionally substituted azetidinyl. In certain variations, Rd1is unsubstituted azetidinyl. In one variation,

[0035] In some variations, Rd1is optionally substituted oxetanyl. In certain variations, Rd1is unsubstituted oxetanyl. In one variation,

[0036] In some embodiments, Rd2is H or NHRy. In one embodiment, Rd2is H. In another embodiment, Rd2is NHRy. In one variation, Ryis H. In yet other variations, Ryis - C(=O)(CH2)nNRvRw. In one variation, n is 1. In certain variations, Rvand Rware both H. In other variations, Rvand Rware taken together with the nitrogen atom to which they are attached to form an optionally substituted heterocycloalkyl. In other variations, Rvand Rware taken together with the nitrogen atom to which they are attached to form an unsubstituted pyrrolidine.

[0037] In some embodiments, Rzis H, and Rd3is OH. In other embodiments, Rzis optionally substituted alkyl. In some variations, the alkyl is unsubstituted. In other variations, the alkyl is substituted with one or more (e.g., any of one, two, three, four, or five) halo. In certain variations of the foregoing, the alkyl is a C1-10alkyl, or C1-4alkyl. In one variation, Rzis methyl.

[0038] In some variations of Formula (I), when Rd3is OH, then Rd2is NHRy, wherein Ryis -C(=O)(CH2)nNRvRw, wherein each Rvand Rwis independently H, alkyl or haloalkyl; or Rvand Rware taken together with the nitrogen atom to which they are attached to form a cyclic group.

[0039] In some variations of Formula (I), when Rd2is H, then Rd3is ORz, wherein Rzis alkyl or haloalkyl.

[0040] In some embodiments of Formula (I), Ra2is ORm, wherein Rmis H, alkyl or haloalkyl; and Rb1is ORp, wherein each Rpis H, alkyl or haloalkyl. In some embodiments of the foregoing, Rpis unsubstituted alkyl. In some embodiments of the foregoing, Rpis methyl

[0041] It should generally be understood that compounds described herein generally have a fused ring structure, and the position of the ring carbon atoms and the ring numbering can be described as follows:

[0042] In some variations, compounds provided herein have a (S), (R) and (S) configuration at the 4a, 5a and 12a positions, respectively. In some variations, compounds provided herein have a (S) and (S) configuration at the 4a and 12a positions, respectively.

[0043] In certain aspects, provided is a compound of Formula (I-i-a):or a pharmaceutically acceptable salt thereof, wherein the variables are as defined for Formula (I-a) above.

[0044] In certain aspects, provided is a compound of Formula (I-i-16A) and (I-i-16B):or a pharmaceutically acceptable salt thereof, wherein the variables are as defined for Formula (I) above.

[0045] In certain aspects, provided is a composition, comprising a substantially pure enantiomer of the compound of Formula (I-i-a). In certain aspects, provided is a composition, comprising a substantially pure enantiomer of the compound of Formula (I-i-16A) or Formula (I-i-16B), or a pharmaceutically acceptable salt thereof. In some embodiments, less than 5%, less than 4%, less than 3%, less than 2%, less than 1%, less than 0.1% of the composition are other enantiomeric forms of the compound, or a pharmaceutically acceptable salt thereof. In certain variations, the composition does not have a detectable amount of the other enantiomeric forms of the compound, or a pharmaceutically acceptable salt thereof.

[0046] In certain aspects, provided is a compound of Formula (I-A-a):or a pharmaceutically acceptable salt thereof, wherein the variables are as defined for Formula (I) above.

[0047] In some embodiments of the compound of Formula (I-A-a): each R1and R2is independently H or optionally substituted alkyl; Ra2is ORm, wherein Rmis H or optionally substituted alkyl; Rb1is ORp, or NRqRs, wherein each Rp, Rqand Rsis independently H or optionally substituted alkyl; Rb2is H or ORx, wherein Rxis H or optionally substituted alkyl; Rd1is: optionally substituted cyclopropyl, optionally substituted azetidinyl, optionally substituted oxetanyl, optionally substituted cyclobutyl, substituted cyclopentyl, optionally substituted 5-membered heterocycloalkyl, oroptionally substituted heterocyclyl, wherein the heterocyclyl selected from the group consisting of:, wherein R is H or optionally substituted alkyl (e.g., C1-6alkyl optionally substituted with one or more halo), and wherein each of the heterocyclyl is optionally substituted, Rd2is H, or NHRy, wherein Ryis -C(=O)(CH2)nNRvRw, wherein n is an integer greater than or equal to 1; wherein each Rvand Rwis independently H or optionally substituted alkyl, or Rvand Rware taken together with the nitrogen atom to which they are attached to form an optionally substituted cyclic group; and Rd3is ORz, wherein Rzis H or optionally substituted alkyl.

[0048] In some variations, Rd1is optionally substituted azetidine. In certain variations, Rd1is unsubstituted azetidinyl. In one variation,

[0049] In some variations, Rd1is optionally substituted oxetane. In certain variations, Rd1is unsubstituted oxetanyl. In one variation,

[0050] In some variations, Rd1is optionally substituted 5-membered heterocycloalkyl. In certain variations, Rd1is unsubstituted pyrrolidinyl or tetrahydrofuranyl. In one variation, Rd1

[0051] In some embodiments, n is an integer between 1 to 4. In some embodiments, n is any of 1, 2, 3, or 4.

[0052] In some embodiments, each R1and R2is H; Ra2is OH; Rb1is OH; Rb2is OH; Rd2is H; and Rd3is OH.

[0053] In certain embodiments, Rd1is: unsubstituted cyclopropyl, or cyclopropyl substituted with one or more alkyl, haloalkyl or halo groups; unsubstituted azetidinyl, or azetidinyl substituted with one or more alkyl, haloalkyl or halo groups; unsubstituted oxetanyl, or oxetanyl substituted with one or more alkyl, haloalkyl or halo groups;unsubstituted cyclobutyl, or cycobutyl substituted with one or more alkyl, haloalkyl or halo groups; cyclopentyl substituted with one or more alkyl, haloalkyl or halo groups; unsubstituted 5-membered heterocycloalkyl, or 5-membered heterocycloalkyl substituted with one or more alkyl, haloalkyl or halo groups; unsubstituted heterocyclyl, or heterocyclyl substituted with one or more alkyl, haloalkyl, - OH, or halo groups; wherein the heterocyclyl is selected from the group consisting of, ,, , , , , , , , ,wherein R is H or optionally substituted alkyl.

[0054] In certain embodiments, Rd1is: unsubstituted cyclopropyl, or cyclopropyl substituted with one or more alkyl, haloalkyl or halo groups; unsubstituted cyclobutyl, or cycobutyl substituted with one or more alkyl, haloalkyl or halo groups; cyclopentyl substituted with one or more alkyl, haloalkyl or halo groups;unsubstituted 5-membered heterocycloalkyl, or 5-membered heterocycloalkyl substituted with one or more alkyl, haloalkyl or halo groups; unsubstituted 5-membered heteroaryl, or 5-membered heteroaryl substituted with one or more alkyl, haloalkyl or halo groups; or unsubstituted 6-membered heterocyclyl, or 6-membered heterocyclyl substituted with one or more alkyl, haloalkyl, -OH, or halo groups.

[0055] In certain embodiments, Rd1is pyrazolyl substituted with alkyl. In certain variations of the foregoing, the alkyl is a C1-10alkyl, or C1-4alkyl. In one variation, the alkyl is methyl.

[0056] In one aspect, provided is a compound of Formula (I-A-i):or a pharmaceutically acceptable salt thereof, wherein the variables are as defined for Formula (I) above.

[0057] In some embodiments of the compound of Formula (I-A-i): each R1and R2is independently H; and ring D5 is: substituted cyclopentyl, optionally substituted 5-membered heterocyclyl selected from the group consisting of:wherein R is H or optionally substituted alkyl. ,,each of the D5 is optionally substituted with one or more optionally substituted alkyl or halo groups, and wherein wherein R is H or alkyl. In certain embodiments, ring D5 iswherein R is alkyl. In one embodiment,wherein R is optionally substituted alkyl. In some variations, the alkyl is unsubstituted. In other variations, the alkyl is substituted with one or more halo. In certain variations of the foregoing, the alkyl is a C1-10alkyl, or C1-4alkyl.

[0059] In some embodiments, the cyclopentyl and heterocyclyl are substituted with one or more optionally substituted alkyl or halo groups. In some variations, the alkyl is unsubstituted. In other variations, the alkyl is substituted with one or more halo. In certain variations of the foregoing, the alkyl is a C1-10alkyl, or C1-4alkyl. In one variation, the alkyl is methyl.

[0060] In some variations, ring D5 is other than unsubstituted oxazolyl, furanyl (unsubstituted or substituted), unsubstituted imdazolyl, unsubstituted cyclopentyl, or unsubstituted thienyl. In some variations, when ring D5 is isoxazolyl, the isoxazolyl is unsubstituted, or substituted with other than dimethyl groups.

[0061] In another aspect, provided is a compound of Formula (I-A-ii):ii), or a pharmaceutically acceptable salt thereof, wherein the variables are as defined for Formula (I) above.

[0062] In some embodiments of the compound of Formula (I-A-ii): each R1and R2is independently H or alkyl; and ring D6 is optionally substituted 6-membered heterocyclyl selected from the group consisting of: ,wherein R is H or optionally substituted alkyl. In some variations, ring D6 is other than pyridinyl (unsubstituted or substituted), pyrimidinyl (unsubstituted or substituted), unsubstituted pyrazinyl, unsubstituted morpholino, or unsubstituted piperidinyl.

[0063] In some variations, Rd1is optionally substituted 7-membered heterocyclyl, wherein the 7-membered heterocyclyl is selected from the group consisting of:,

[0064] In some embodiments, the heterocyclyl is substituted with one or more optionally substituted alkyl, -OH, or halo groups. In some variations, the alkyl is unsubstituted. In other variations, the alkyl is substituted with one or more halo. In certain variations of the foregoing, the alkyl is a C1-10alkyl, or C1-4alkyl. In one variation, the alkyl is methyl. In some embodiments, the heterocyclyl is substituted with one or more -OH. Compounds of Formula (I-b)

[0065] In some aspects, provided is a compound of Formula (I-b):or a pharmaceutically acceptable salt thereof, wherein: each R1and R2is independently H or optionally substituted alkyl; Ra1is NRfRg, or =NORk, wherein each Rfand Rgis independently H, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, or - C(=O)R’,wherein R’ is H, optionally substituted alkyl, or optionally substituted alkoxy; or Rfand Rgare taken together with the nitrogen atom to which they are attached to form an optionally substituted cyclic group, wherein Rkis optionally substituted alkyl; Ra2is ORm, wherein Rmis H or optionally substituted alkyl; Rb1is ORp, or NRqRs, wherein each Rp, Rqand Rsis independently H or optionally substituted alkyl; Rb2is ORx, wherein Rxis H or optionally substituted alkyl; Rd1is H, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted cycloalkyl, optionally substituted heterocyclyl, halo, or NRtRu; wherein each Rtand Ruis independently H or optionally substituted alkyl; Rd2is H; and Rd3is ORz, wherein Rzis H or optionally substituted alkyl.

[0066] In some embodiments, R1and R2are both H. In other embodiments, R1and R2are both optionally substituted alkyl. In some variations, the alkyl is unsubstituted. In other variations, the alkyl is substituted with one or more (e.g., any of one, two, three, four, or five) halo. In certain variations of the foregoing, the alkyl is a C1-10alkyl, or C1-4alkyl. In one variation, R1and R2are both methyl.

[0067] In some embodiments, Ra1is NRfRg. In some embodiments, Ra1is NH2. In some embodiments, Ra1is NHRf, and Rfis independently optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, or -C(=O)R’, and wherein R’ is H, optionally substituted alkyl, or optionally substituted alkoxy. In some embodiments, Rfis -C(O)CH3. In some embodiments, Rfis cycloalkyl. In some embodiments, Rfis unsubstituted cyclobutyl. In some embodiments, Rfis cyclobutyl substituted with one or more alkyl (e.g., methyl, ethyl), halo, or CN, or any combination thereof. In some embodiments, Rfis cyclobutyl substituted with methyl and CN. In some embodiments, Rfis cyclobutyl substituted with halo (e.g., F). In some embodiments, Rfis alkyl substituted with C6-12aryl, wherein the C6-12 aryl is further substituted with -OH or alkoxyl. In some embodiments, Rfis. In some embodiments, Rfis alkyl substituted with heterocyclyl, such as a 3- to 10-membered heterocycle, 3- to 10-membered heterocycloalkyl or 3- to 6-membered heteroaryl, wherein the heterocyclyl is optionally substituted with alkyl. In some embodiments, Rfis alkyl substituted with, which is unsubstituted or substituted with methyl. In some embodiments, Rfis alkyl substitutedwhich is unsubstituted or substituted with methyl. In some embodiments, Rfis alkyl substituted with, which is unsubstituted or substituted with methyl. In some embodiments, Rfis optionally substituted heterocycloalkyl. In some embodiments,each of which is optionally substituted (e.g., by oxo, alkyl such as methyl, ethyl or haloalkyl such as CF3, or CH2CHF2), wherein R is H or alkyl (e.g., methyl, or ethyl). In some embodiments,which is substituted by one or more alkyl or unsubstituted. In some embodiments,some embodiments, Rfis tetrahydropyranyl. In some embodiments, Rfis -C(O)O-alkyl. In some embodiments, Rfis - C(O)OCH3.

[0068] In certain embodiments, Rfand Rgare taken together with the nitrogen atom to which they are attached to form a cyclic group, optionally substituted with one or more alkyl, haloalkyl, alkyl substituted with -OR, halo, -OR, -COOR, -C(=O)R, -SO2R, or oxo. In some variations, R, at each occurrence, is independently H or optionally substituted alkyl. In some variations, the alkyl is unsubstituted. In other variations, the alkyl is substituted with one or more halo. In certain variations of the foregoing, the alkyl is a C1-10 alkyl, or C1-4 alkyl. In one variation, R is methyl. In some embodiments, the cyclic group is . In some embodiments, the cyclic group is unsubstituted.

[0069] In certain embodiments, Ra1is an optionally substituted cyclic group having 3-10 ring atoms. In some variations, the cyclic group has one or more additional ring atoms that is a heteroatom independently selected from nitrogen and oxygen. In certain variations, the cyclic group has two fused rings. In other variations, the cyclic group is a bridge cyclic group. In certain embodiments, Ra1is an optionally substituted cyclic group, wherein the cyclic group is selected from the group consisting of:optionally substituted alkenyl, halo, C(=O)alkyl, C(=O)-O-alkyl, SO2(alkyl), optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, or optionally substituted alkoxy. In some variations, the alkyl, alkenyl, cycloalkyl and alkoxy are unsubstituted. In other variations, the alkyl, alkenyl, cycloalkyl and alkoxy are substituted with one or more halo, OH, or alkoxyl. In certain variations of the foregoing, the alkyl is a C1-10 alkyl, or C1-4 alkyl. In one variation, R10is methyl. In some embodiments, R10is -C(O)-O-CMe3. In some embodiments R10is -SO2CH3In some embodiments R10is -C(O)CH3In someembodiments, R10is -CH2CH2OCH3. In some embodiments, R10is cyclopropyl. In some embodiments, R10is oxetanyl.

[0070] In some embodiments, Rmis H, and Ra2is OH. In other embodiments, Rmis optionally substituted alkyl. In some variations, the alkyl is unsubstituted. In other variations, the alkyl is substituted with one or more halo. In certain variations of the foregoing, the alkyl is a C1-10 alkyl, or C1-4 alkyl. In one variation, Rmis methyl.

[0071] In some embodiments, Rb1is ORp. In certain embodiments, Rpis H, and Rb1is OH. In other embodiments, Rpis optionally substituted alkyl. In some variations, the alkyl is unsubstituted. In other variations, the alkyl is substituted with one or more (e.g., any of one, two, three, four, or five) halo. In certain variations of the foregoing, the alkyl is a C1-10 alkyl, or C1-4alkyl. In one variation, Rpis methyl. In some embodiments, Rb1is NRqRs, wherein each Rqand Rsis independently H or optionally substituted alkyl. In some variations, the alkyl is unsubstituted. In other variations, the alkyl is substituted with one or more halo. In some embodiments, Rb1is NH2.

[0072] In some embodiments, Rxis H, and Rb2is OH. In other embodiments, Rxis optionally substituted alkyl. In some variations, the alkyl is unsubstituted. In other variations, the alkyl is substituted with one or more halo. In certain variations of the foregoing, the alkyl is a C1-10alkyl, or C1-4alkyl.

[0073] In some embodiments, Rd1is H, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted cycloalkyl, optionally substituted heterocyclyl, or NRtRu. In some embodiments, Rd1is other than halo.

[0074] In some embodiments, Rd1is H. In some embodiments, Rd1is other than H. In some variations, Rd1is haloalkyl, alkenyl, cycloalkyl, heterocycloalkyl, or heteroaryl, wherein the cycloalkyl, heterocycloalkyl, and heteroaryl are optionally substituted with alkyl, haloalkyl, or halo.

[0075] In other embodiments, Rd1is optionally substituted alkyl. In some variations, the alkyl is unsubstituted. In other variations, the alkyl is substituted with one or more (e.g., any of one, two, three, four, or five) halo (e.g., F or Cl). In certain variations of the foregoing, the alkyl is a C1-10 alkyl, C1-6 alkyl, or C1-4 alkyl. In some variations, Rd1is haloalkyl. In one embodiment, Rd1is CF3. In one embodiment, Rd1is CH(CH3)CF3.

[0076] In other embodiments, Rd1 is optionally substituted alkenyl. In some variations,the alkenyl is unsubstituted. In other variations, the alkenyl is substituted with one or more halo. In certain variations of the foregoing, the alkenyl is a C2-10 alkenyl, or C2-6 alkenyl.

[0077] In yet other embodiments, Rd1 is NRtRu. In some variations, Rt is H, and Ru is Hor optionally substituted alkyl. In some variations, the alkyl is unsubstituted. In other variations, the alkyl is substituted with one or more halo. In certain variations of the foregoing, the alkyl is a C1-10alkyl, or C1-4alkyl.

[0078] In some embodiments, Rd1 is:optionally substituted cyclopropyl, optionally substituted azetidinyl, optionally substituted oxetanyl, optionally substituted cyclobutyl, optionally substituted cyclopentyl, optionally substituted heterocyclyl, wherein the heterocyclyl is selected from thegroup consisting of: ,, , , , , , ,wherein R is H or optionally substituted alkyl (e.g., C1-6alkyl optionally substituted with one or more halo), and wherein each of the heterocyclyl is optionally substituted.

[0079] In some variations, Rd1is optionally substituted azetidinyl. In certain variations, Rd1is unsubstituted azetidinyl. In one variation, Rd1is.

[0080] In some variations, Rd1is optionally substituted oxetanyl. In certain variations, Rd1is unsubstituted oxetanyl. In one variation, Rd1is.

[0081] In some embodiments, Rd1is optionally substituted heterocyclyl, wherein the, , , , , , , , ,wherein R is H or optionally substituted alkyl (e.g., C1-6alkyl optionally substituted with one or more halo), and wherein each of the heterocyclyl is optionally substituted. In some embodiments, Rd1is unsubstituted heterocyclyl. In some embodiments, Rd1is heterocyclyl substituted with one or more independently selected alkyl (e.g., C1-6 alkyl), haloalkyl (e.g., C1-6 alkyl optionally substituted with one or more halo such as F), halo (e.g., F, Cl, or Br), or -OH.

[0082] In one embodiment, Rd1is halo. In one embodiment, Rd1is F. In one embodiment, Rd1is Cl.

[0083] In one embodiment, Rd1is cycloalkyl (e.g., C3-C8 cycloalkyl). In one embodiment, Rd1is cyclopropyl, optionally substituted with alkyl, haloalkyl or halo. In another embodiment, Rd1is cyclobutyl, optionally substituted with alkyl, haloalkyl or halo. In yet another embodiment, Rd1is cyclopentyl substituted with alkyl, haloalkyl or halo.

[0084] In another embodiment, Rd1is heterocyclyl, optionally substituted with alkyl, haloalkyl or halo. In some embodiments, the heterocyclyl is aromatic (e.g., pyrazole). In some embodiments, the heterocyclyl is non-aromatic. In some embodiments, the heterocyclyl is connected to the rest of the compound by a heteroatom (e.g., an annular N atom). In some embodiments, the heterocyclyl is optionally substituted morpholine or pyrrolidine. In some embodiments, the heterocyclyl is optionally substituted cyclic amides, such as pyrrolidinones.

[0085] In some embodiments, Rzis H, and Rd3is OH. In other embodiments, Rzis optionally substituted alkyl. In some variations, the alkyl is unsubstituted. In other variations, the alkyl is substituted with one or more halo. In certain variations of the foregoing, the alkyl is a C1-10 alkyl, or C1-4 alkyl. In one variation, Rzis methyl.

[0086] It should generally be understood that compounds described herein generally have a fused ring structure, and the position of the ring carbon atoms and the ring numbering can be described as follows:

[0087] In some variations, compounds provided herein have a (S), (R) and (S) configuration at the 4a, 5a and 12a positions, respectively.

[0088] In certain aspects, provided is a compound of Formula (I-i-b):or a pharmaceutically acceptable salt thereof, wherein the variables are as defined for Formula (I) above.

[0089] In certain aspects, provided is a compound of Formula (I)-R:or a pharmaceutically acceptable salt thereof, wherein the variables are as defined for Formula (I-b) above, and wherein the carbon atom at * has a (R)-configuration.

[0090] In certain aspects, provided is a compound of Formula (I)-S:or a pharmaceutically acceptable salt thereof, wherein the variables are as defined for Formula (I-b) above, and wherein the carbon atom at * has a (S)-configuration. In some variations of the foregoing, when Ra1is N(CH3)2, then Rd1is other than unsubstituted cyclopropyl, unsubstituted cyclopentyl, unsubstituted thiazolyl, unsubstituted 4-isoxazolyl, 4- isoxazolyl substituted with dimethyl groups, unsubstituted thienyl, unsubstituted 4-pyrazolyl, N-methyl 4-pyrazolyl, and unsubstituted pyrrolidinyl.

[0091] In one aspect, provided is a compound of Formula (I-B)-S:or a pharmaceutically acceptable salt thereof, wherein the variables are as defined for Formula (I-b) above.

[0092] In some embodiments: the carbon atom at * has a (S)-configuration; each R1and R2is independently H or optionally substituted alkyl; Rfis H or optionally substituted alkyl; Rgis optionally substituted C2+alkyl, Ra2is ORm, wherein Rmis H or optionally substituted alkyl; Rb1is ORp, wherein Rpis H or optionally substituted alkyl; Rb2is ORx, wherein Rxis H or optionally substituted alkyl; Rd1is H, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted cycloalkyl, optionally substituted heterocyclyl, halo, or NRtRu; wherein each Rtand Ruis independently H or optionally substituted alkyl;and Rd3is ORz, wherein Rzis H or optionally substituted alkyl.

[0093] In some variations, when Rfis H, CH3, or CF3, then Rgis optionally substituted C4+ (e.g., C4-10) alkyl. In other variations, Ra1is other than N(CH3)2.

[0094] In some embodiments, Rd1is other than H.

[0095] In some embodiments, provided is a compound of Formula (I-B-i):or a pharmaceutically acceptable salt thereof, wherein the variables are as defined for Formula (I) above.

[0096] In another aspect, provided is a compound of Formula (I-C)-R:or a pharmaceutically acceptable salt thereof, wherein the variables are as defined for Formula (I) above.

[0097] In some embodiments: the carbon atom at * has a (R)-configuration; each R1and R2is independently H or optionally substituted alkyl; Rfis H, optionally substituted alkyl, or optionally substituted heterocycloalkyl; Rgis H or optionally substituted alkyl; or Rfand Rgare taken together with the nitrogen atom to which they are attached to form an optionally substituted heterocyclyl; Ra2is ORm, wherein Rmis H or optionally substituted alkyl;Rb1is ORp, wherein Rpis H or optionally substituted alkyl; Rb2is ORx, wherein Rxis H or optionally substituted alkyl; Rd1is H, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted cycloalkyl, optionally substituted heterocyclyl, halo, or NRtRu; wherein each Rt, Ru, Rnand Rois independently H or optionally substituted alkyl; Rd3is ORz, wherein Rzis H or optionally substituted alkyl.

[0098] In some embodiments: the carbon atom at * has a (R)-configuration; each R1and R2is independently H or optionally substituted alkyl; Rfis alkyl substituted with heterocyclyl, or heterocycloalkyl optionally substituted with alkyl; Rgis H or optionally substituted C1-3 alkyl; or Rfand Rgare taken together with the nitrogen atom to which they are attached to form an optionally sbstituted heterocycloalyl; Ra2is ORm, wherein Rmis H or optionally substituted alkyl; Rb1is ORp, wherein Rpis H or optionally substituted alkyl; Rb2is ORx, wherein Rxis H or optionally substituted alkyl; Rd1is H, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocyclyl, or halo; wherein each Rt, Ru, Rnand Rois independently H or optionally substituted alkyl; Rd3is ORz, wherein Rzis H or optionally substituted alkyl.

[0099] In some variations, Rd1is other than N(CH3)2. In some embodiments, Rd1is other than H.

[0100] In other embodiments, Ra1is other than N(CH3)2.

[0101] In some embodiments, provided is a compound of Formula (I-C-i):or a pharmaceutically acceptable salt thereof, wherein the variables are as defined for Formula (I) above.

[0102] In certain aspects, provided is a compound of Formula (I-D):or a pharmaceutically acceptable salt thereof, wherein the variables are as defined for Formula (I) above.

[0103] In some embodiments: each R1and R2is independently H or optionally substituted alkyl; Ra1is NRfRg, wherein each Rfand Rgis independently H, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, or - C(=O)R’, wherein R’ is H, alkyl, or alkoxy; or Rfand Rgare taken together with the nitrogen atom to which they are attached to form an optionally substituted cyclic group; Ra2is ORm, wherein Rmis H, optionally substituted alkyl or optionally substituted heteroaryl;Rb1is ORp, or NRqRs, wherein each Rp, Rqand Rsis independently H or optionally substituted alkyl; Rb2is ORx, wherein Rxis H or optionally substituted alkyl; Rd1is: optionally substituted cyclopropyl, optionally substituted azetidinyl, optionally substituted oxetanyl, optionally substituted cyclobutyl, optionally substituted cyclopentyl, optionally substituted heterocyclyl selected from the group consisting of:, wherein R is H or alkyl; Rd2is H; andRd3is ORz, wherein Rzis H or alkyl.

[0104] In some variations, Rd1is optionally substituted 5-membered heterocyclyl, wherein the 5-membered heterocyclyl is selected from the group consisting of:, ,, , , , , , , ,wherein R is H or alkyl. In some variations, Rd1is optionally substituted 6-membered heterocyclyl, wherein the 6-membered heterocyclyl is selected from the group consisting of:In some variations, Rd1is optionally substituted 7-membered heterocyclyl, wherein the 7- membered heterocyclyl is selected from the group consisting of:

[0105] In some variations, that when Rd1is cyclopropyl, cyclopentyl,, or, then (i) Ra1is other than N(CH3)2; or (ii) the compound has a (R)-configuration at the C4 position.

[0106] In certain aspects, provided is a compound of Formula (I-D-i):or a pharmaceutically acceptable salt thereof, wherein the variables are as defined for Formula (I) above.

[0107] In some embodiments, provided is a compound of Formula (I-D)-R:or a pharmaceutically acceptable salt thereof, wherein the variables are as defined for Formula (I) above, and wherein the carbon atom at * has a (R)-configuration.

[0108] In some embodiments, provided is a compound is of Formula (I-D)-S:or a pharmaceutically acceptable salt thereof, wherein the variables are as defined for Formula (I) above, and wherein the carbon atom at * has a (S)-configuration.

[0109] In some variations, provided is a composition comprising a substantially pure compound of Formula (I-D)-R. In certain variations, the composition has at least 90%, at least 95%, or at least 99% of the compound of Formula (I-D)-R. In certain variations, the composition has less than 10%, less than 5%, or less than 1% of the compound of Formula (I- D)-S. In certain variations, the composition does not have a detectable amount of the compound of Formula (I-D)-S.

[0110] In other aspects, provided is a compound is of Formula (I-E):or a pharmaceutically acceptable salt thereof, wherein the variables are as defined for Formula (I) above. In some embodiments Rkis unsubstituted alkyl. In some embodiments, Rkis methyl.

[0111] In some embodiments: each R1and R2is independently H or optionally substituted alkyl; Ra1is =NORk, Rkis optionally substituted alkyl; Ra2is ORm, wherein Rmis H or optionally substituted alkyl or optionally substituted heteroaryl;Rb1is ORp, or NRqRs, wherein each Rp, Rqand Rsis independently H or optionally substituted alkyl; Rb2is ORx, wherein Rxis H or optionally substituted alkyl; Rd1is H, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted cycloalkyl, optionally substituted heterocyclyl, halo, or NRtRu; wherein each Rtand Ruis independently H or optionally substituted alkyl; Rd2is H; and Rd3is ORz, wherein Rzis H or alkyl.

[0112] In some embodiments, provided a compound of Formula (I-E-i):or a pharmaceutically acceptable salt thereof, wherein the variables are as defined for Formula (I) above. Compounds of Formula (II)

[0113] In some aspects, provided is a compound of Formula (II):or a pharmaceutically acceptable salt thereof, wherein: each R1and R2is independently H or optionally substituted alkyl; Ra2is ORm, wherein Rmis H or optionally substituted alkyl;Rb1is ORp, wherein each Rpis H or optionally substituted alkyl; Rb2is ORx, wherein Rxis H or optionally substituted alkyl; Rd1is H, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted cycloalkyl, optionally substituted heterocyclyl, or NRtRu, wherein each Rtand Ruis independently H or optionally substituted alkyl; Rd2is H; and Rd3is ORz, wherein Rzis H or optionally substituted alkyl.

[0114] In some embodiments, R1and R2are both H. In other embodiments, R1and R2are both optionally substituted alkyl. In other embodiments, R1and R2are both independently selected optionally substituted alkyl. In some variations, the alkyl is unsubstituted. In other variations, the alkyl is substituted with one or more (e.g., any of one, two, three, four, or five) halo. In certain variations of the foregoing, the alkyl is a C1-10alkyl, or C1-4alkyl. In one variation, R1and R2are both methyl.

[0115] In some embodiments, Rmis H, and Ra2is OH. In other embodiments, Rmis optionally substituted alkyl. In some variations, the alkyl is unsubstituted. In other variations, the alkyl is substituted with one or more halo. In certain variations of the foregoing, the alkyl is a C1-10 alkyl, or C1-4 alkyl. In one variation, Rmis methyl.

[0116] In some embodiments, Rb1is ORp. In certain embodiments, Rpis H, and Rb1is OH. In other embodiments, Rpis optionally substituted alkyl. In some variations, the alkyl is unsubstituted. In other variations, the alkyl is substituted with one or more (e.g., any of one, two, three, four, or five) halo. In certain variations of the foregoing, the alkyl is a C1-10alkyl, or C1-4alkyl. In one variation, Rpis methyl.

[0117] In some embodiments, Rxis H, and Rb2is OH. In other embodiments, Rxis optionally substituted alkyl. In some variations, the alkyl is unsubstituted. In other variations, the alkyl is substituted with one or more (e.g., any of one, two, three, four, or five) halo . In certain variations of the foregoing, the alkyl is a C1-10 alkyl, or C1-4 alkyl.

[0118] In some embodiments, Rzis H, and Rd3is OH. In other embodiments, Rzis optionally substituted alkyl In some variations the alkyl is unsubstituted In othervariations, the alkyl is substituted with one or more halo. In certain variations of the foregoing, the alkyl is a C1-10 alkyl, or C1-4 alkyl. In one variation, Rzis methyl.

[0119] In some embodiments of Formula (II): Ra2is OH; Rb1is OH; Rb2is OH; Rd2is H; and Rd3is OH.

[0120] In some embodiments, Rd1is H. In some embodiments, Rd1is other than H. In some variations, Rd1is haloalkyl, alkenyl, cycloalkyl, or heteroaryl, wherein the cycloalkyl and heteroaryl are optionally substituted with alkyl, haloalkyl, or halo.

[0121] In other embodiments, Rd1is optionally substituted alkyl. In some variations, the alkyl is unsubstituted. In other variations, the alkyl is substituted with one or more halo. In certain variations of the foregoing, the alkyl is a C1-10alkyl, or C1-4alkyl. In some variations, Rd1is haloalkyl.

[0122] In other embodiments, Rd1is optionally substituted alkenyl. In some variations, the alkenyl is unsubstituted. In other variations, the alkenyl is substituted with one or more halo. In certain variations of the foregoing, the alkenyl is a C2-10alkenyl, or C2-6alkenyl.

[0123] In some embodiments, Rd1is optionally substituted cycloalkyl. In certain embodiments, the cycloalkyl is a C3-10 cycloalkyl, C3-9 cycloalkyl, C3-7 cycloalkyl, C3-6 cycloalkyl, or C3-5cycloalkyl. In certain variations, the cycloalkyl is unsubstituted. In certain variations, the cycloalkyl is substituted with alkyl, haloalkyl or halo. In one embodiment, Rd1is cyclopropyl, optionally substituted with alkyl, haloalkyl or halo. In another embodiment, Rd1is cyclobutyl, optionally substituted with alkyl, haloalkyl or halo. In yet another embodiment, Rd1is cyclopropyl substituted with alkyl, haloalkyl or halo. In another embodiment, Rd1is cyclohexyl, optionally substituted with alkyl, haloalkyl or halo.

[0124] In some embodiments, Rd1is optionally substituted heterocyclyl. In certain embodiments, the heterocyclyl is a C3-10heterocyclyl, C3-9heterocyclyl, C3-7heterocyclyl, C3-6 heterocyclyl, or C3-5 heterocyclyl. In some variations, the heterocyclyl has at least oneheteroatom independently selected from S, N or O. In certain variations, the heterocyclyl has at least one heteroatom independently selected from N or O. In one variation, theheterocyclyl has 1, 2 or 3 heteroatoms independently selected from N or O. In certainvariations, the heterocyclyl is unsubstituted. In certain variations, the heterocyclyl is substituted with alkyl, haloalkyl or halo.

[0125] In certain embodiments, Rd1 is optionally substituted heterocyclyl selected fromthe group consisting of:, wherein R is H or optionally substituted alkyl.

[0126] In some variations, R is H. In other variations, R is optionally substituted alkyl.In some variations, the alkyl is unsubstituted. In other variations, the alkyl is substituted withone or more halo. In certain variations of the foregoing, the alkyl is a C1-10alkyl, or C1-4alkyl.

[0127] In some embodiments, the heterocyclyl is substituted with one or more optionally substituted alkyl or halo groups. In some variations, the alkyl is unsubstituted. In other variations, the alkyl is substituted with one or more halo. In certain variations of the foregoing, the alkyl is a C1-10 alkyl, or C1-4 alkyl. In one variation, the alkyl is methyl.

[0128] In some embodiments, Rd1is halo. In one embodiment, Rd1is chloro. In one embodiment, Rd1is fluoro. In one embodiment, Rd1is bromo. In one embodiment, Rd1is iodo.

[0129] In yet other embodiments, Rd1is NRtRu. In some variations, Rtis H, and Ruis H or optionally substituted alkyl. In some variations, the alkyl is unsubstituted. In other variations, the alkyl is substituted with one or more halo. In certain variations of the foregoing, the alkyl is a C1-10 alkyl, or C1-4 alkyl.

[0130] In certain aspects, provided is a compound of Formula (II-i):or a pharmaceutically acceptable salt thereof, wherein the variables are as defined for Formula (II) above. Compounds of Formula (III)

[0131] In some aspects, provided a compound of Formula (III):or a pharmaceutically acceptable salt thereof, wherein: each R1and R2is independently H or optionally substituted alkyl; Ra1is NRfRg, wherein each Rfand Rgis independently H, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, or - C(=O)R’, wherein R’ is H, optionally substituted alkyl, or optionally substituted alkoxy; or Rfand Rgare taken together with the nitrogen atom to which they are attached to form an optionally substituted cyclic group, Ra2is ORm, wherein Rmis H or optionally substituted alkyl; Ra3is ORL, wherein RLis H or optionally substituted alkyl; Rb1is ORp, wherein each Rpis H or alkyl; Rd1is H, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted cycloalkyl, optionally substituted heterocyclyl, halo, or NRtRu; wherein each Rtand Ruis independently H or optionally substituted alkyl; Rd2is H; and Rd3is ORz, wherein Rzis H, or optionally substituted alkyl.

[0132] In some variations, when Ra1is N(CH3)2, then Rd1is other than H.

[0133] In some embodiments, R1and R2are both H. In other embodiments, R1and R2are both optionally substituted alkyl. In some variations, the alkyl is unsubstituted. In other variations, the alkyl is substituted with one or more halo. In certain variations of the foregoing, the alkyl is a C1-10 alkyl, or C1-4 alkyl. In one variation, R1and R2are both methyl.

[0134] In some embodiments, Ra1is NRfRg. In some embodiments, Ra1is NH2. In some embodiments, Ra1is NHRg, and Rgis independently optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, or -C(=O)R’, and wherein R’ is H, optionally substituted alkyl, or optionally substituted alkoxy. In some embodiments, Ra1is NHRg, and Rgis optionally substituted heterocycloalkyl. In some embodiments, the heterocycloalkyl

[0135] In certain embodiments, Rfand Rgare taken together with the nitrogen atom to which they are attached to form a cyclic group, optionally substituted with one or more alkyl, haloalkyl, alkyl substituted with -OR, halo, -OR, -COOR, -C(=O)R, -SO2R, or oxo. In some variations, R, at each occurrence, is independently H or optionally substituted alkyl. In certain embodiments, Rfand Rgare taken together with the nitrogen atom to which they are attached to form a cyclic group, optionally substituted with one or more alkyl, haloalkyl, halo, -COOR, -C(=O)R, -SO2R, or oxo. In some variations, R is H or optionally substituted alkyl. In some variations, the alkyl is unsubstituted. In other variations, the alkyl is substituted with one or more halo. In certain variations of the foregoing, the alkyl is a C1-10alkyl, or C1-4alkyl. In one variation, Rzis methyl. In other embodiments, Rfand Rgare taken together with the nitrogen atom to which they are attached to form an unsubstituted cyclic group. In some embodiments, the cyclic group is a heterocycloalkyl. In some embodiments, the cyclic group

[0136] In certain embodiments, Ra1is an optionally substituted cyclic group having 3-10 ring atoms. In some embodiments, the cyclic group is unsubstituted. In some variations, the cyclic group has one or more additional ring atoms that is heteroatom independently selected from nitrogen and oxygen. In certain variations, the cyclic group has two fused rings. In other variations, the cyclic group is a bridge cyclic group. In certain embodiments, Ra1is an optionally substituted cyclic group selected from the group consisting of:wherein R10is optionally substituted alkyl, optionally substituted alkenyl, halo, C(=O)alkyl, SO2(alkyl), optionally substituted cycloalkyl, or optionally substituted alkoxy. In some variations, the alkyl, alkenyl, cycloalkyl and alkoxy are unsubstituted. In other variations, the alkyl, alkenyl, cycloalkyl and alkoxy are substituted with one or more halo. In certain variations of the foregoing, the alkyl is a C1-10alkyl, or C1-4alkyl. In one variation, R10is methyl. In certain embodiments,

[0137] In some embodiments, Rmis H, and Ra2is OH. In other embodiments, Rmis optionally substituted alkyl. In some variations, the alkyl is unsubstituted. In other variations, the alkyl is substituted with one or more halo. In certain variations of the foregoing, the alkyl is a C1-10 alkyl, or C1-4 alkyl. In one variation, Rmis methyl.

[0138] In some embodiments, RLis H, and Ra3is OH. In other embodiments, RLis optionally substituted alkyl. In some variations, the alkyl is unsubstituted. In other variations, the alkyl is substituted with one or more halo. In certain variations of the foregoing, the alkyl is a C1-10 alkyl, or C1-4 alkyl. In one variation, RLis methyl.

[0139] In some embodiments, Rb1is ORp. In certain embodiments, Rpis H, and Rb1is OH. In other embodiments, Rpis optionally substituted alkyl. In some variations, the alkyl is unsubstituted. In other variations, the alkyl is substituted with one or more halo. In certain variations of the foregoing, the alkyl is a C1-10 alkyl, or C1-4 alkyl. In one variation, Rpis methyl.

[0140] In some embodiments, Rzis H, and Rd3is OH. In other embodiments, Rzis optionally substituted alkyl. In some variations, the alkyl is unsubstituted. In other variations, the alkyl is substituted with one or more halo. In certain variations of the foregoing, the alkyl is a C1-10alkyl, or C1-4alkyl. In one variation, Rzis methyl.

[0141] In some embodiments of Formula (III): Ra2is OH; Ra3is OH; Rb1is OH; and Rd3is OH.

[0142] In some embodiments, Rd1is H, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted cycloalkyl, optionally substituted heterocyclyl, or NRtRu. In other embodiments, Rd1is optionally substituted alkyl. In some variations, the alkyl is unsubstituted. In other variations, the alkyl is substituted with one or more halo. In certain variations of the foregoing, the alkyl is a C1-10alkyl, or C1-4alkyl. In some variations, Rd1is haloalkyl.

[0143] In other embodiments, Rd1is optionally substituted alkenyl. In some variations, the alkenyl is unsubstituted. In other variations, the alkenyl is substituted with one or more halo. In certain variations of the foregoing, the alkenyl is a C2-10alkenyl, or C2-6alkenyl.

[0144] In some embodiments, Rd1is optionally substituted cycloalkyl. In certain embodiments, the cycloalkyl is a C3-10 cycloalkyl, C3-9 cycloalkyl, C3-7 cycloalkyl, C3-6 cycloalkyl, or C3-5cycloalkyl. In certain variations, the cycloalkyl is unsubstituted. In certain variations, the cycloalkyl is substituted with alkyl, haloalkyl or halo. In one embodiment, Rd1is cyclopropyl, optionally substituted with alkyl, haloalkyl or halo. In another embodiment, Rd1is cyclobutyl, optionally substituted with alkyl, haloalkyl or halo. In yet another embodiment, Rd1is cyclopropyl substituted with alkyl, haloalkyl or halo. In another embodiment, Rd1is cyclohexyl, optionally substituted with alkyl, haloalkyl or halo.

[0145] In some embodiments, Rd1is optionally substituted heterocyclyl. In certain embodiments, the heterocyclyl is a C3-10heterocyclyl, C3-9heterocyclyl, C3-7heterocyclyl, C3-6 heterocyclyl, or C3-5 heterocyclyl. In certain embodiments, the heterocyclyl is a 3- to 12- membered heterocyclyl, 3- to 9-membered heterocyclyl, 3- to 8-membered heterocyclyl, or 3-to 6-membered heterocyclyl. In certain variations, the heterocyclyl has at least one heteroatom independently selected from S, N or O. In certain variations, the heterocyclyl has at least one heteroatom independently selected from N or O. In one variation, the heterocyclyl has 1, 2 or 3 heteroatoms independently selected from N or O. In certain variations, the heterocyclyl is unsubstituted. In certain variations, the heterocyclyl is substituted with alkyl, haloalkyl or halo.

[0146] In certain embodiments, Rd1 is optionally substituted heterocyclyl, wherein theheterocyclyl is selected from the group consisting of:,,wherein R is H or optionally substituted alkyl. In certain embodiments, Rd1 is optionallysubstituted heterocyclyl, wherein the heterocyclyl is selected from the group consisting of:,wherein R is H or optionally substituted alkyl.

[0147] In certain embodiments, Rd1 is optionally substituted heterocyclyl, wherein theheterocyclyl is selected from the group consisting of, , ,wherein R is H or optionally substituted alkyl. d1In certain embodiments, R isoptionally substituted heterocyclyl, whereinthe heterocyclyl is selected from the groupwherein R is H or optionallysubstituted alkyl. In some variations, R is H. In other variations, R is optionally substituted alkyl. In some variations, the alkyl is unsubstituted. In other variations, the alkyl is substituted with one or more halo. In certain variations of the foregoing, the alkyl is a C1-10 alkyl, or C1-4alkyl.

[0148] In some embodiments, the heterocyclyl is substituted with one or more optionally substituted alkyl or halo groups. In some variations, the alkyl is unsubstituted. In other variations, the alkyl is substituted with one or more halo. In certain variations of the foregoing, the alkyl is a C1-10alkyl, or C1-4alkyl. In one variation, the alkyl is methyl.

[0149] In some embodiments, Rd1is halo. In one embodiment, Rd1is chloro. In one embodiment, Rd1is fluoro. In one embodiment, Rd1is bromo. In one embodiment, Rd1is iodo.

[0150] In yet other embodiments, Rd1is NRtRu. In some variations, Rtis H, and Ruis H or optionally substituted alkyl. In some variations, the alkyl is unsubstituted. In other variations, the alkyl is substituted with one or more halo. In certain variations of the foregoing, the alkyl is a C1-10alkyl, or C1-4alkyl.

[0151] In certain aspects, provided is a compound of Formula (III-i):or a pharmaceutically acceptable salt thereof, wherein the variables are as defined for Formula (III) above.Compounds of Formula (IV-a)

[0152] In certain aspects, provided is a compound of Formula (IV-a):or a pharmaceutically acceptable salt thereof, wherein: each R1and R2is independently H or optionally substituted alkyl; Ra2is ORm, wherein Rmis H or optionally substituted alkyl; Rb1is ORp, or NRqRs, wherein Rpis optionally substituted alkyl; wherein each Rqand Rsis independently H or optionally substituted alkyl; Rb2is ORx, wherein Rxis H or optionally substituted alkyl; Rd1is H, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted cycloalkyl, optionally substituted heterocyclyl, or NRtRu, wherein each Rtand Ruis independently H or optionally substituted alkyl; Rd2is H, NHRy, or halo, wherein Ryis H, or -C(=O)(CH2)nNRvRw, wherein n is an integer greater than or equal to 1; wherein each Rvand Rwis independently H or optionally substituted alkyl, or Rvand Rware taken together with the nitrogen atom to which they are attached to form an optionally substituted cyclic group; and Rd3is ORz, wherein Rzis H or optionally substituted alkyl.

[0153] In some embodiments, R1and R2are both H. In other embodiments, R1and R2are both optionally substituted alkyl. In some variations, the alkyl is unsubstituted. In other variations, the alkyl is substituted with one or more halo. In certain variations of the foregoing, the alkyl is a C1-10 alkyl, or C1-4 alkyl. In one variation, R1and R2are both methyl.

[0154] In some embodiments, Rmis H, and Ra2is OH. In other embodiments, Rmis optionally substituted alkyl. In some variations, the alkyl is unsubstituted. In other variations, the alkyl is substituted with one or more halo. In certain variations of the foregoing, the alkyl is a C1-10alkyl, or C1-4alkyl. In one variation, Rmis methyl.

[0155] In some embodiments, Rb1is ORp, where Rpis optionally substituted alkyl. In some variations, the alkyl is unsubstituted. In other variations, the alkyl is substituted with one or more halo. In certain variations of the foregoing, the alkyl is a C1-10alkyl, or C1-4alkyl. In one variation, the alkyl is methyl, and thus Rb1is methoxy.

[0156] In some embodiments, each Rqand Rsis H, and Rb1is NH2. In other embodiments, Rqis optionally substituted alkyl, and Rsis H or optionally substituted alkyl. In some variations, the alkyl is unsubstituted. In other variations, the alkyl is substituted with one or more halo. In certain variations of the foregoing, the alkyl is a C1-10 alkyl, or C1-4 alkyl. In one variation, the alkyl is methyl.

[0157] In some embodiments, Rxis H, and Rb2is OH. In other embodiments, Rxis optionally substituted alkyl. In some variations, the alkyl is unsubstituted. In other variations, the alkyl is substituted with one or more halo. In certain variations of the foregoing, the alkyl is a C1-10alkyl, or C1-4alkyl.

[0158] In some embodiments, Rd1is H, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted cycloalkyl, optionally substituted heterocyclyl, or NRtRu. In one embodiments, Rd1is other than halo.

[0159] In some embodiments, Rd1is H. In some embodiments, Rd1is other than H. In some variations, Rd1is haloalkyl, alkenyl, cycloalkyl, or heteroaryl, wherein the cycloalkyl and heteroaryl are optionally substituted with alkyl, haloalkyl, or halo.

[0160] In other embodiments, Rd1is optionally substituted alkyl. In some variations, the alkyl is unsubstituted. In other variations, the alkyl is substituted with one or more halo. In certain variations of the foregoing, the alkyl is a C1-10 alkyl, or C1-4 alkyl. In some variations, Rd1is haloalkyl. In one variation, Rd1is (R)-3-trifluoro-2-propyl or (S)-3-trifluoro-2-propyl.

[0161] In other embodiments, Rd1 is optionally substituted alkenyl. In some variations,the alkenyl is unsubstituted. In other variations, the alkenyl is substituted with one or more halo. In certain variations of the foregoing, the alkenyl is a C2-10 alkenyl, or C2-6 alkenyl.

[0162] In yet other embodiments, Rd1 is NRtRu. In some variations, Rt is H, and Ru is Hor optionally substituted alkyl. In some variations, the alkyl is unsubstituted. In other variations, the alkyl is substituted with one or more halo. In certain variations of the foregoing, the alkyl is a C1-10alkyl, or C1-4alkyl.

[0163] In some embodiments, Rd1 is:optionally substituted cyclopropyl, optionally substituted azetidinyl, optionally substituted oxetanyl, optionally substituted cyclobutyl, optionally substituted cyclopentyl, optionally substituted heterocyclyl selected from the group consisting of: , ,wherein R is H or optionally substituted alkyl.

[0164] In some variations, Rd1is optionally substituted azetidine. In certain variations, Rd1is unsubstituted azetidinyl. In one variation,

[0165] In some variations, Rd1is optionally substituted oxetane. In certain variations, Rd1is unsubstituted oxetanyl. In one variation,

[0166] In one embodiment, Rd1is cyclopropyl, optionally substituted with alkyl, haloalkyl or halo. In another embodiment, Rd1is cyclobutyl, optionally substituted with alkyl, haloalkyl or halo. In yet another embodiment, Rd1is cyclopropyl, optionally substituted with alkyl, haloalkyl or halo. In another embodiment, Rd1is cyclohexyl, optionally substituted with alkyl, haloalkyl or halo.

[0167] In some embodiments, Rd2is H or NHRy. In one embodiment, Rd2is H. In another embodiment, Rd2is NHRy. In one variation, Ryis H. In yet other variations, Ryis - C(=O)(CH2)nNRvRw. In one variation, n is 1. In certain variations, Rvand Rware both H. In other variations, Rvand Rware taken together with the nitrogen atom to which they are attached to form an optionally substituted heterocycloalkyl.

[0168] In some embodiments, Rzis H, and Rd3is OH. In other embodiments, Rzis optionally substituted alkyl. In some variations, the alkyl is unsubstituted. In other variations, the alkyl is substituted with one or more halo. In certain variations of the foregoing, the alkyl is a C1-10 alkyl, or C1-4 alkyl. In one variation, Rzis methyl.

[0169] In certain aspects, provided is a compound of Formula (IV-i-a):or a pharmaceutically acceptable salt thereof, wherein the variables are as defined for Formula (IV-a) above. Compounds of Formula (IV-b)

[0170] In certain aspects, provided is a compound of Formula (IV-b):or a pharmaceutically acceptable salt thereof, wherein: each R1and R2is independently H or optionally substituted alkyl; Ra1is NRfRg, wherein each Rfand Rgis independently H, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, or - C(=O)R’, wherein R’ is H, optionally substituted alkyl, or optionally substituted alkoxy; or Rfand Rgare taken together with the nitrogen atom to which they are attached to form an optionally substituted cyclic group, Ra2is ORm, wherein Rmis H or optionally substituted alkyl; Rb1is ORp, or NRqRs, wherein Rpis optionally substituted alkyl; wherein each Rqand Rsis independently H or optionally substituted alkyl; Rb2is ORx,wherein Rxis H or optionally substituted alkyl; Rd1is H, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted cycloalkyl, optionally substituted heterocyclyl, halo, or NRtRu; wherein each Rtand Ruis independently H or optionally substituted alkyl; Rd2is H; and Rd3is ORz, wherein Rzis H or optionally substituted alkyl.

[0171] In some embodiments, R1and R2are both H. In other embodiments, R1and R2are both optionally substituted alkyl. In some variations, the alkyl is unsubstituted. In other variations, the alkyl is substituted with one or more halo. In certain variations of the foregoing, the alkyl is a C1-10alkyl, or C1-4alkyl. In one variation, R1and R2are both methyl.

[0172] In some embodiments, Ra1is NH2. In certain embodiments, Rfand Rgare taken together with the nitrogen atom to which they are attached to form a cyclic group, optionally substituted with one or more alkyl, haloalkyl, halo, -COOR, -C(=O)R, -SO2R, or oxo. In some variations, R is H or optionally substituted alkyl. In some variations, the alkyl is unsubstituted. In other variations, the alkyl is substituted with one or more halo. In certain variations of the foregoing, the alkyl is a C1-10alkyl, or C1-4alkyl. In one variation, Rzis methyl.

[0173] In certain embodiments, Ra1is an optionally substituted cyclic group having 3-10 ring atoms. In some variations, the cyclic group has one or more additional ring atoms that is heteroatom independently selected from nitrogen and oxygen. In certain variations, the cyclic group has two fused rings. In other variations, the cyclic group is a bridge cyclic group. In certain embodiments, Ra1is an optionally substituted cyclic group selected from the group consisting of:wherein R10is optionally substituted alkyl, optionally substituted alkenyl, halo, C(=O)alkyl, SO2(alkyl), optionally substituted cycloalkyl, or optionally substituted alkoxy. In some variations, the alkyl, alkenyl, cycloalkyl and alkoxy are unsubstituted. In other variations, the alkyl, alkenyl, cycloalkyl and alkoxy are substituted with one or more halo. In certain variations of the foregoing, the alkyl is a C1-10alkyl, or C1-4alkyl. In one variation, R10is methyl.

[0174] In some embodiments, Rmis H, and Ra2is OH. In other embodiments, Rmis optionally substituted alkyl. In some variations, the alkyl is unsubstituted. In other variations, the alkyl is substituted with one or more halo. In certain variations of the foregoing, the alkyl is a C1-10 alkyl, or C1-4 alkyl. In one variation, Rmis methyl.

[0175] In some embodiments, Rb1is ORp, where Rpis optionally substituted alkyl. In some variations, the alkyl is unsubstituted. In other variations, the alkyl is substituted with one or more halo. In certain variations of the foregoing, the alkyl is a C1-10 alkyl, or C1-4 alkyl. In one variation, the alkyl is methyl, and thus Rb1is methoxy.

[0176] In some embodiments, each Rqand Rsis H, and Rb1is NH2. In other embodiments, Rqis optionally substituted alkyl, and Rsis H or optionally substituted alkyl. In some variations, the alkyl is unsubstituted. In other variations, the alkyl is substituted with one or more halo. In certain variations of the foregoing, the alkyl is a C1-10 alkyl, or C1-4 alkyl. In one variation, the alkyl is methyl.

[0177] In some embodiments, Rxis H, and Rb2is OH. In other embodiments, Rxis optionally substituted alkyl. In some variations, the alkyl is unsubstituted. In othervariations, the alkyl is substituted with one or more halo. In certain variations of the foregoing, the alkyl is a C1-10 alkyl, or C1-4 alkyl.

[0178] In some embodiments, Rd1is H, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted cycloalkyl, optionally substituted heterocyclyl, or NRtRu. In one embodiments, Rd1is other than halo. In other embodiments, Rd1is H, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted cycloalkyl, optionally substituted heterocyclyl, or NRtRu.

[0179] In some embodiments, Rd1is H. In some embodiments, Rd1is other than H. In some variations, Rd1is haloalkyl, alkenyl, cycloalkyl, or heteroaryl, wherein the cycloalkyl and heteroaryl are optionally substituted with alkyl, haloalkyl, or halo.

[0180] In other embodiments, Rd1is optionally substituted alkyl. In some variations, the alkyl is unsubstituted. In other variations, the alkyl is substituted with one or more halo. In certain variations of the foregoing, the alkyl is a C1-10 alkyl, or C1-4 alkyl. In some variations, Rd1is haloalkyl. In one variation, Rd1is (R)-3-trifluoro-2-propyl or (S)-3-trifluoro-2-propyl.

[0181] In other embodiments, Rd1is optionally substituted alkenyl. In some variations, the alkenyl is unsubstituted. In other variations, the alkenyl is substituted with one or more halo. In certain variations of the foregoing, the alkenyl is a C2-10alkenyl, or C2-6alkenyl.

[0182] In yet other embodiments, Rd1is NRtRu. In some variations, Rtis H, and Ruis H or optionally substituted alkyl. In some variations, the alkyl is unsubstituted. In other variations, the alkyl is substituted with one or more halo. In certain variations of the foregoing, the alkyl is a C1-10alkyl, or C1-4alkyl.

[0183] In some embodiments, Rd1is: optionally substituted cyclopropyl, optionally substituted azetidinyl, optionally substituted oxetanyl, optionally substituted cyclobutyl, optionally substituted cyclopentyl, optionally substituted heterocyclyl selected from the group consisting of, wherein R is H or optionally substituted alkyl.which is optionally substituted.

[0185] In some variations, Rd1 is optionally substituted azetidinyl. In certain variations,Rd1is unsubstituted azetidinyl. In one variation, Rd1is.

[0186] In some variations, Rd1is optionally substituted oxetanyl. In certain variations, Rd1is unsubstituted oxetanyl. In one variation, Rd1is.

[0187] In one embodiment, Rd1is cyclopropyl, optionally substituted with alkyl, haloalkyl or halo. In another embodiment, Rd1is cyclobutyl, optionally substituted with alkyl, haloalkyl or halo. In yet another embodiment, Rd1is cyclopropyl, optionally substituted with alkyl, haloalkyl or halo. In another embodiment, Rd1is cyclohexyl, optionally substituted with alkyl, haloalkyl or halo.

[0188] In some embodiments, Rzis H, and Rd3is OH. In other embodiments, Rzis optionally substituted alkyl. In some variations, the alkyl is unsubstituted. In other variations, the alkyl is substituted with one or more halo. In certain variations of the foregoing, the alkyl is a C1-10 alkyl, or C1-4 alkyl. In one variation, Rzis methyl.

[0189] In some embodiments: Ra2is OH; Ra3is OH; and Rd3is OH.

[0190] In some embodiments, provided is a compound of Formula (IV-i-b):or a pharmaceutically acceptable salt thereof, wherein the variables are as defined for Formula (IV-b) above.Compounds of Formula (V-a)

[0191] In certain aspects, provided is a compound of Formula (V-a):or a pharmaceutically acceptable salt thereof, wherein: each R1and R2is independently H or optionally substituted alkyl; Ra2is ORm, wherein Rmis H or optionally substituted alkyl; Rb2is H or ORx, wherein Rxis H or optionally substituted alkyl; Rd1is H, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted cycloalkyl, optionally substituted cycloalkenyl, optionally substituted heterocyclyl, or NRtRu, wherein each Rtand Ruis independently H or optionally substituted alkyl; Rd2is H, NHRy, or halo, wherein Ryis H, or -C(=O)(CH2)nNRvRw, wherein n is an integer greater than or equal to 1; wherein each Rvand Rwis independently H or optionally substituted alkyl, or Rvand Rware taken together with the nitrogen atom to which they are attached to form an optionally substituted cyclic group; and Rd3is ORz, wherein Rzis H or optionally substituted alkyl.

[0192] In some embodiments, R1and R2are both H. In other embodiments, R1and R2are both optionally substituted alkyl. In some variations, the alkyl is unsubstituted. In other variations, the alkyl is substituted with one or more halo. In certain variations of the foregoing, the alkyl is a C1-10alkyl, or C1-4alkyl. In one variation, R1and R2are both methyl.

[0193] In some embodiments, Rmis H, and Ra2is OH. In other embodiments, Rmis optionally substituted alkyl. In some variations, the alkyl is unsubstituted. In othervariations, the alkyl is substituted with one or more halo. In certain variations of the foregoing, the alkyl is a C1-10 alkyl, or C1-4 alkyl. In one variation, Rmis methyl.

[0194] In some embodiments, Rb2is H. In other embodiments, Rxis H, and Rb2is OH. In other embodiments, Rxis optionally substituted alkyl. In some variations, the alkyl is unsubstituted. In other variations, the alkyl is substituted with one or more halo. In certain variations of the foregoing, the alkyl is a C1-10 alkyl, or C1-4 alkyl.

[0195] In some embodiments, Rd1is H, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted cycloalkyl, optionally substituted heterocyclyl, or NRtRu. In one embodiments, Rd1is other than halo.

[0196] In some embodiments, Rd1is H. In some embodiments, Rd1is other than H. In some variations, Rd1is haloalkyl, alkenyl, cycloalkyl, cycloalkenyl, or heteroaryl, wherein the cycloalkyl, cycloalkenyl and heteroaryl are optionally substituted with alkyl, haloalkyl, or halo. In some embodiments, Rd1is cycloalkyl optionally substituted with alkyl, haloalkyl, or halo. In some embodiments, Rd1is a C3-12cycloalkenyl, a C3-10cycloalkenyl, or a C3-6cycloalkenyl. In some embodiments, Rd1is heteroaryl optionally substituted with alkyl, haloalkyl, or halo. In some embodiments, the heteroaryl is a 5- to 12-membered, a 5- to 10- membered, or a 5- to 6-membered heteroaryl.

[0197] In other embodiments, Rd1is optionally substituted alkyl. In some variations, the alkyl is unsubstituted. In other variations, the alkyl is substituted with one or more halo. In certain variations of the foregoing, the alkyl is a C1-10 alkyl, or C1-4 alkyl. In some variations, Rd1is haloalkyl. In one variation, Rd1is (R)-3-trifluoro-2-propyl or (S)-3-trifluoro-2-propyl.

[0198] In other embodiments, Rd1is optionally substituted alkenyl. In some variations, the alkenyl is unsubstituted. In other variations, the alkenyl is substituted with one or more halo. In certain variations of the foregoing, the alkenyl is a C2-10alkenyl, or C2-6alkenyl. In some embodiments, Rd1is C2-6alkenyl substituted with one to three F. In some embodiments, Rd1is 3,3,3-trifluoropropenyl.

[0199] In yet other embodiments, Rd1is NRtRu. In some variations, Rtis H, and Ruis H or optionally substituted alkyl. In some variations, the alkyl is unsubstituted. In other variations, the alkyl is substituted with one or more halo. In certain variations of the foregoing, the alkyl is a C1-10 alkyl, or C1-4 alkyl.

[0200] In some embodiments, Rd1 is:optionally substituted cyclopropyl, optionally substituted azetidinyl, optionally substituted oxetanyl, optionally substituted cyclobutyl, optionally substituted cyclopentyl, optionally substituted cyclopentenyl, optionally substituted heterocyclyl selected from the group consisting of:, ,wherein R is H or optionally substituted alkyl.

[0201] In some embodiments,each of which is optionally substituted.

[0202] In some variations, Rd1is optionally substituted azetidine. In certain variations, Rd1is unsubstituted azetidinyl. In one variation,

[0203] In some variations, Rd1is optionally substituted oxetane. In certain variations, Rd1is unsubstituted oxetanyl. In one variation,

[0204] In one embodiment, Rd1is cyclopropyl, optionally substituted with alkyl, haloalkyl or halo. In another embodiment, Rd1is cyclobutyl, optionally substituted with alkyl, haloalkyl or halo. In yet another embodiment, Rd1is cyclopropyl, optionally substituted with alkyl, haloalkyl or halo. In yet another embodiment, Rd1is cyclopentenyl, optionally substituted with alkyl, haloalkyl or halo. In another embodiment, Rd1is cyclohexyl, optionally substituted with alkyl, haloalkyl or halo.

[0205] In some embodiments, Rd2is H or NHRy. In one embodiment, Rd2is H. In another embodiment, Rd2is NHRy. In one variation, Ryis H. In yet other variations, Ryis - C(=O)(CH2)nNRvRw. In one variation, n is 1. In certain variations, Rvand Rware both H. In other variations, Rvand Rware taken together with the nitrogen atom to which they are attached to form an optionally substituted heterocycloalkyl.

[0206] In some embodiments, Rzis H, and Rd3is OH. In other embodiments, Rzis optionally substituted alkyl. In some variations, the alkyl is unsubstituted. In other variations, the alkyl is substituted with one or more halo. In certain variations of the foregoing, the alkyl is a C1-10 alkyl, or C1-4 alkyl. In one variation, Rzis methyl.

[0207] In certain aspects, provided is a compound of Formula (V-i-a):or a pharmaceutically acceptable salt thereof, wherein the variables are as defined for Formula (V-a) above.

[0208] It should be understood that the structures and other compounds and moieties discussed in this application also include all tautomers thereof. For example, in some variations, a tautomer of Formula (V-a) has the structure:, or a pharmaceutically acceptable salt thereof, wherein the variables are as defined for Formula (V-a) above. Compounds of Formula (V-b)

[0209] In certain aspects, provided is a compound of Formula (V-b):or a pharmaceutically acceptable salt thereof, wherein: each R1and R2is independently H or optionally substituted alkyl; Ra1is NRfRg, or =NORk,wherein each Rfand Rgis independently H, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, or - C(=O)R’, wherein R’ is H, optionally substituted alkyl, or optionally substituted alkoxy; or Rfand Rgare taken together with the nitrogen atom to which they are attached to form an optionally substituted cyclic group; wherein Rkis optionally substituted alkyl; Ra2is ORm, wherein Rmis H, or optionally substituted alkyl; Rb2is ORx, wherein Rxis H or optionally substituted alkyl; Rd1is H, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted cycloalkyl, optionally substituted heterocyclyl, or NRtRu, wherein each Rtand Ruis independently H or optionally substituted alkyl; Rd2is H; and Rd3is ORz, wherein Rzis H, or alkyl.

[0210] In some embodiments, R1and R2are both H. In other embodiments, R1and R2are both optionally substituted alkyl. In some variations, the alkyl is unsubstituted. In other variations, the alkyl is substituted with one or more (e.g., any of one, two, three, four, or five) halo. In certain variations of the foregoing, the alkyl is a C1-10 alkyl, or C1-4 alkyl. In one variation, R1and R2are both methyl.

[0211] In some embodiments, Ra1is =NORk. In some embodiments, Rkis optionally substituted alkyl. In some variations, the alkyl is unsubstituted. In other variations, the alkyl is substituted with one or more (e.g., any of one, two, three, four, or five) halo (e.g., F, Cl, Br, or I). In certain variations of the foregoing, the alkyl is a C1-10 alkyl, or C1-4 alkyl. In one variation, Rkis methyl.

[0212] In some embodiments, Ra1is NH2. In some embodiments, Ra1is NHRg, and Rgis independently optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, or -C(=O)R’, and wherein R’ is H, optionally substituted alkyl, or optionally substituted alkoxy. In some embodiments, Ra1is NRfRg, and both Rfand Rgareoptionally substituted alkyl. In some embodiments, Ra1is NRfRg, and both Rfand Rgare methyl.

[0213] In certain embodiments, Rfand Rgare taken together with the nitrogen atom to which they are attached to form a cyclic group, optionally substituted with one or more alkyl, haloalkyl, alkyl substituted with -OR, halo, -OR, -COOR, -C(=O)R, -SO2R, cycloalkyl,or oxo. In some variations, R, at each occurrence, is independently H or optionally substituted alkyl. In certain embodiments, Rfand Rgare taken together with the nitrogen atom to which they are attached to form a cyclic group, optionally substituted with one or more alkyl, haloalkyl, alkyl substituted with -OR, halo, -COOR, -C(=O)R, -SO2R, cycloalkyl, or oxo. In some variations, R is H or optionally substituted alkyl. In some variations, the alkyl is unsubstituted. In other variations, the alkyl is substituted with one or more halo. In certain variations of the foregoing, the alkyl is a C1-10 alkyl, or C1-4 alkyl. In one variation, R is methyl.

[0214] In certain embodiments, Ra1is an optionally substituted cyclic group having 3-10 ring atoms. In some variations, the cyclic group has one or more additional ring atoms that is heteroatom independently selected from nitrogen and oxygen. In certain variations, the cyclic group has two fused rings. In other variations, the cyclic group is a bridge cyclic group. In certain embodiments, Ra1is an optionally substituted cyclic group, and the cyclic group is selected from the group consisting of:wherein R10is optionally substituted alkyl, optionally substituted alkenyl, halo, C(=O)alkyl, SO2(alkyl), optionally substituted cycloalkyl, or optionally substituted alkoxy. In some variations, the alkyl, alkenyl, cycloalkyl and alkoxy are unsubstituted. In other variations, the alkyl, alkenyl, cycloalkyl and alkoxy are substituted with one or more halo. In certainvariations of the foregoing, the alkyl is a C1-10alkyl, or C1-4alkyl. In one variation, R10is methyl.

[0215] In certain embodiments, Ra1is an optionally substituted cyclic group and thecyclic group is selected from the group consisting of:each ofwhich is optionally substituted.

[0216] In some variations, Ra1is optionally substituted piperidinyl, optionally substituted piperazinyl, or optionally substituted morpholino.

[0217] In some embodiments, Rmis H, and Ra2is OH. In other embodiments, Rmis optionally substituted alkyl. In some variations, the alkyl is unsubstituted. In other variations, the alkyl is substituted with one or more halo. In certain variations of the foregoing, the alkyl is a C1-10 alkyl, or C1-4 alkyl. In one variation, Rmis methyl.

[0218] In some embodiments, Rxis H, and Rb2is OH. In other embodiments, Rxis optionally substituted alkyl. In some variations, the alkyl is unsubstituted. In other variations, the alkyl is substituted with one or more halo. In certain variations of the foregoing, the alkyl is a C1-10 alkyl, or C1-4 alkyl.

[0219] In some embodiments, Rd1is H, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted cycloalkyl, optionally substituted heterocyclyl, or NRtRu. In one embodiments, Rd1is other than halo.

[0220] In some embodiments, Rd1is H. In some embodiments, Rd1is other than H. In some variations, Rd1is haloalkyl, alkenyl, cycloalkyl, or heteroaryl, wherein the cycloalkyl and heteroaryl are optionally substituted with alkyl, haloalkyl, or halo.

[0221] In other embodiments, Rd1is optionally substituted alkyl. In some variations, the alkyl is unsubstituted. In other variations, the alkyl is substituted with one or more halo. In certain variations of the foregoing, the alkyl is a C1-10alkyl, or C1-4alkyl. In some variations, Rd1is haloalkyl. In one variation, Rd1is (R)-3-trifluoro-2-propyl or (S)-3-trifluoro-2-propyl.

[0222] In other embodiments, Rd1 is optionally substituted alkenyl. In some variations,the alkenyl is unsubstituted. In other variations, the alkenyl is substituted with one or more halo. In certain variations of the foregoing, the alkenyl is a C2-10 alkenyl, or C2-6 alkenyl.

[0223] In yet other embodiments, Rd1 is NRtRu. In some variations, Rt is H, and Ru is Hor optionally substituted alkyl. In some variations, the alkyl is unsubstituted. In other variations, the alkyl is substituted with one or more halo. In certain variations of the foregoing, the alkyl is a C1-10alkyl, or C1-4alkyl.

[0224] In some embodiments, Rd1 is:optionally substituted cyclopropyl, optionally substituted azetidinyl, optionally substituted oxetanyl, optionally substituted cyclobutyl, optionally substituted cyclopentyl, optionally substituted heterocyclyl selected from the group consisting of:, wherein R is H or optionally substituted alkyl.

[0225] In some variations, Rd1is optionally substituted azetidinyl. In certain variations, Rd1is unsubstituted azetidinyl. In one variation,

[0226] In some variations, Rd1is optionally substituted oxetanyl. In certain variations, Rd1is unsubstituted oxetanyl. In one variation,

[0227] In some embodiments, Rd1is optionally substituted heterocyclyl, wherein the heterocyclyl is selected from the group consisting of:wherein R is H or optionally substituted alkyl.

[0228] In one embodiment, Rd1is cyclopropyl, optionally substituted with alkyl, haloalkyl or halo. In another embodiment, Rd1is cyclobutyl, optionally substituted with alkyl, haloalkyl or halo. In yet another embodiment, Rd1is cyclopropyl, optionally substituted with alkyl, haloalkyl or halo. In another embodiment, Rd1is cyclohexyl, optionally substituted with alkyl, haloalkyl or halo.

[0229] In some embodiments, Rzis H, and Rd3is OH. In other embodiments, Rzis optionally substituted alkyl. In some variations, the alkyl is unsubstituted. In othervariations, the alkyl is substituted with one or more halo. In certain variations of the foregoing, the alkyl is a C1-10 alkyl, or C1-4 alkyl. In one variation, Rzis methyl.

[0230] In some embodiments: Ra2is OH; Ra3is OH; Rb1is OH; and Rd3is OH.

[0231] In some embodiments, provided is a compound of Formula (V-i-b):or a pharmaceutically acceptable salt thereof, wherein the variables are as defined for Formula (V-b) above.

[0232] It should be understood that the structures and other compounds and moieties discussed in this application also include all tautomers thereof. For example, in some variations, a tautomer of Formula (V-b) has the structure:, or a pharmaceutically acceptable salt thereof, wherein the variables are as defined for Formula (V-b) above.

[0233] It will be noted that the structure of some of the compounds of this invention includes asymmetric carbon atoms. It is to be understood accordingly that the isomers arising from such asymmetry (e.g., all enantiomers and diastereomers) are included within the scope of this invention, unless indicated otherwise. Such isomers can be obtained in substantiallypure form by classical separation techniques and by stereochemically controlled synthesis. For example, a single enantiomer or diastereomer, such as an optically active form, can be obtained by asymmetric synthesis or by resolution of the racemate. Resolution of racemates can be accomplished, for example, by conventional methods such as crystallization in the presence of a resolving agent, or chromatography, using, for example a chiral high pressure liquid chromatography (HPLC) column.

[0234] In certain aspects, provided are compositions comprising any of the compounds disclosed herein, including compounds of Formula (I-a), (I-b), (II), (III), (IV-a), (IV-b), (V- a), and (V-b), as well as compounds of Tables 1A and 1B, having a (R)-configuration at the C4 position. In some embodiments of the foregoing, less than 5%, less than 1% or less than 0.1% of the composition includes a compound having a (S)-configuration at the C4 position. In one variation, the compositions comprise substantially pure compounds having a (R)- configuration at the C4 position.

[0235] In other aspects, provided are compositions comprising any of the compounds disclosed herein, including compounds of Formula (I-a), (I-b), (II), (III), (IV-a), (IV-b), (V- a), and (V-b), as well as compounds of Tables 1A and 1B, having a (S)-configuration at the C4 position. In some embodiments of the foregoing, less than 5%, less than 1% or less than 0.1% of the composition includes a compound having a (R)-configuration at the C4 position. In one variation, the compositions comprise substantially pure compounds having a (S)- configuration at the C4 position.

[0236] As used herein, “alkyl” refers to a monoradical unbranched or branched saturated hydrocarbon chain. In some embodiments, alkyl has 1 to 20 carbon atoms (i.e., C1-20 alkyl), 1 to 8 carbon atoms (i.e., C1-8 alkyl), 1 to 6 carbon atoms (i.e., C1-6 alkyl), or 1 to 4 carbon atoms (i.e., C1-4alkyl). Examples of alkyl groups include methyl, ethyl, propyl, isopropyl, n- butyl, sec-butyl, tert-butyl, pentyl, 2-pentyl, isopentyl, neopentyl, hexyl, 2-hexyl, 3-hexyl, and 3-methylpentyl. When an alkyl residue having a specific number of carbons is named, all geometric isomers having that number of carbons may be encompassed; thus, for example, “butyl” can include n-butyl, sec-butyl, isobutyl and t-butyl; “propyl” can include n-propyl and isopropyl. In some embodiments, “C1+alkyl” refers to alkyl having at least 1 carbon atom, and includes, for example, methyl, ethyl, propyl, etc. Similarly, “C2+alkyl” refers to alkyl having at least 2 carbon atoms, and includes, for example, ethyl, propyl, butyl, etc.

[0237] “Haloalkyl” refers to an unbranched or branched alkyl group as defined above, wherein one or more hydrogen atoms are replaced by a halogen. For example, where a residue is substituted with more than one halogen, it may be referred to by using a prefix corresponding to the number of halogen moieties attached. Examples of a haloalkyl group include difluoromethyl (-CHF2) and trifluoromethyl (-CF3). It should be understood that trifluoromethyl (-CF3) may also be referred to as perfluoromethyl.

[0238] “Cyclic group”, as used herein, refers to cycloalkyl and heterocyclyl, including heterocycloalkyl and heteroaryl, as defined herein.

[0239] “Cycloalkyl” refers to a cyclic alkyl group. In some embodiments, cycloalkyl has from 3 to 20 ring carbon atoms (i.e., C3-20 cycloalkyl), or 3 to 12 ring carbon atoms (i.e., C3-12 cycloalkyl), or 3 to 8 ring carbon atoms (i.e., C3-8cycloalkyl). Examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

[0240] “Heterocyclyl” refers to a cyclic group, with one or more ring heteroatoms. In some embodiments, the ring heteroatoms are independently selected from nitrogen, sulfur and oxygen. Heterocyclyl includes heterocycloalkyl, heterocycloalkenyl, and heteroaryl.

[0241] “Heterocycloalkyl” refers to a cyclic alkyl group, with one or more ring heteroatoms. In some embodiments, the heterocycloalkyl has 2 to 20 ring carbon atoms (i.e., C2-20heterocycloalkyl), 2 to 12 ring carbon atoms (i.e., C2-12heterocycloalkyl), or 2 to 8 ring carbon atoms (i.e., C2-8 heterocycloalkyl); and 1 to 5 ring heteroatoms, 1 to 4 ring heteroatoms, 1 to 3 ring heteroatoms, 1 or 2 ring heteroatoms, or 1 ring heteroatom independently selected from nitrogen, sulfur and oxygen. In one example, a heterocycloalkyl has 2 to 8 ring carbon atoms, with 1 to 3 ring heteroatoms independently selected from nitrogen, sulfur and oxygen. Examples of heterocycloalkyl groups may include pyrrolidinyl, piperidinyl, piperazinyl, oxetanyl, dioxolanyl, azetidinyl, and morpholinyl.

[0242] “Heteroaryl” refers to an aromatic group having a single ring, multiple rings, or multiple fused rings, with one or more ring heteroatoms. In some embodiments, heteroaryl is an aromatic, monocyclic or bicyclic ring containing one or more heteroatoms independently selected from nitrogen, sulfur and oxygen with the remaining ring atoms being carbon. In certain embodiments, heteroaryl has 3 to 20 ring carbon atoms (i.e., C3-20 heteroaryl), 3 to 12 ring carbon atoms (i.e., C3-12 heteroaryl), or 3 to 8 carbon ring atoms (i.e., C3-8 heteroaryl); and 1 to 5 heteroatoms 1 to 4 heteroatoms 1 to 3 ring heteroatoms 1 or 2 ring heteroatomsor 1 ring heteroatom independently selected from nitrogen, sulfur and oxygen. In one example, a heteroaryl has 3 to 8 ring carbon atoms, with 1 to 3 ring heteroatoms independently selected from nitrogen, sulfur and oxygen. Examples of heteroaryl groups include pyridyl, pyridazinyl, pyrimidinyl, benzothiazolyl, and pyrazolyl. Heteroaryl does not encompass or overlap with aryl, which refers to an aromatic carbocyclic group having a single ring (e.g., phenyl), multiple rings (e.g., biphenyl), or multiple fused rings (e.g., naphthyl).

[0243] The term “substituted”, in some variations, means that any one or more hydrogen atoms on the designated atom or group is replaced with a moiety other than hydrogen, provided that the designated atom’s normal valence is not exceeded. In some variations, “substituted” may also encompasses the scenario where the substitution(s) does not replace a hydrogen. For example, in some embodiments, substitution encompasses the formation of N- oxide, S-oxide, and quaternized N. For example, heterocycle substituted with oxo group may encompass groups such

[0244] The symbol whether as a bond or displayed perpendicular to a bond indicates the point at which the displayed moiety is attached to the remainder of the molecule.

[0245] In some aspects, provided is a compound selected from a compound of Table 1A below, or a pharmaceutically acceptable salt thereof, including any isomers and tautomers thereof. In certain embodiments, provided is Compound 1, 2A, 2B, 3-15, 16-1, 16-2, 16A, 16B, and 17-48, or a pharmaceutically acceptable salt thereof. In some variations of the foregoing compounds (e.g., in Table 1A), the compounds are in salt form, such as an HCl salt, or in free base form. Table 1A. Exemplary Compounds

[0246] In some aspects, provided is a compound selected from a compound of Table 1B below, or a pharmaceutically acceptable salt thereof, including any isomers and tautomers thereof. In some variations of the foregoing compounds (e.g., in Table 1B), the compounds are in salt form, such as an HCl salt, or in free base form. Table 1B. Exemplary Compounds Cm Cm pdSTRUCTUREpdSTRUCTURENo. No. 1801-381282169170171172173174231232233234235236

[0247] In some embodiments, provided herein is a compound selected from the group consisting of: (4aS,5aR,12aS)-3,10,12,12a-tetrahydroxy-1,11-dioxo-7-(pyridazin-3-yl)- 1,4,4a,5,5a,6,11,12a-octahydrotetracene-2-carboxamide, (4aS,5aR,12aS)-3,10,12,12a-tetrahydroxy-1,11-dioxo-7-(pyrrolidin-1-yl)- 1,4,4a,5,5a,6,11,12a-octahydrotetracene-2-carboxamide, (4aS,5aR,12aS)-3,10,12,12a-tetrahydroxy-1,11-dioxo-7-(1H-pyrrol-1-yl)- 1,4,4a,5,5a,6,11,12a-octahydrotetracene-2-carboxamide, (4aS,5aR,12aS)-3,10,12,12a-tetrahydroxy-1,11-dioxo-7-(1H-pyrazol-4-yl)- 1,4,4a,5,5a,6,11,12a-octahydrotetracene-2-carboxamide, (4aS,5aR,12aS)-3,10,12,12a-tetrahydroxy-1,11-dioxo-7-(1H-pyrazol-3-yl)- 1,4,4a,5,5a,6,11,12a-octahydrotetracene-2-carboxamide, (4aS,5aR,12aS)-3,10,12,12a-tetrahydroxy-7-(1-methyl-1H-pyrazol-4-yl)-1,11-dioxo- 1,4,4a,5,5a,6,11,12a-octahydrotetracene-2-carboxamide, (4aS,5aR,12aS)-3,10,12,12a-tetrahydroxy-7-(1-methyl-1H-pyrazol-3-yl)-1,11-dioxo- 1,4,4a,5,5a,6,11,12a-octahydrotetracene-2-carboxamide, (4aS,5aR,12aS)-3,10,12,12a-tetrahydroxy-1,11-dioxo-7-(pyridazin-4-yl)- 1,4,4a,5,5a,6,11,12a-octahydrotetracene-2-carboxamide, (4aS,5aR,12aS)-7-cyclobutyl-3,10,12,12a-tetrahydroxy-1,11-dioxo-1,4,4a,5,5a,6,11,12a- octahydrotetracene-2-carboxamide,(4aS,5aR,12aS)-7-cyclopropyl-3,10,12,12a-tetrahydroxy-1,11-dioxo-1,4,4a,5,5a,6,11,12a- octahydrotetracene-2-carboxamide, (4aS,5aR,12aS)-3,10,12,12a-tetrahydroxy-7-(1-methyl-1H-pyrazol-5-yl)-1,11-dioxo- 1,4,4a,5,5a,6,11,12a-octahydrotetracene-2-carboxamide, (4aS,5aR,12aS)-3,10,12,12a-tetrahydroxy-7-(1-isopropyl-1H-pyrazol-3-yl)-1,11-dioxo- 1,4,4a,5,5a,6,11,12a-octahydrotetracene-2-carboxamide, (4aS,5aR,12aS)-7-(3,6-dihydro-2H-pyran-4-yl)-3,10,12,12a-tetrahydroxy-1,11-dioxo- 1,4,4a,5,5a,6,11,12a-octahydrotetracene-2-carboxamide, (4aS,5aR,12aS)-3,10,12,12a-tetrahydroxy-1,11-dioxo-7-(tetrahydro-2H-pyran-4-yl)- 1,4,4a,5,5a,6,11,12a-octahydrotetracene-2-carboxamide, (4aS,5aR,12aS)-3,10,12,12a-tetrahydroxy-1,11-dioxo-7-(tetrahydro-2H-pyran-4-yl)- 1,4,4a,5,5a,6,11,12a-octahydrotetracene-2-carboxamide, (4aS,5aR,12aS)-3,10,12,12a-tetrahydroxy-7-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-1,11- dioxo-1,4,4a,5,5a,6,11,12a-octahydrotetracene-2-carboxamide, (4aS,5aR,12aS)-3,10,12,12a-tetrahydroxy-1,11-dioxo-7-(3,3,3-trifluoroprop-1-en-2-yl)- 1,4,4a,5,5a,6,11,12a-octahydrotetracene-2-carboxamide, (4aS,5aR,12aS)-3,10,12,12a-tetrahydroxy-1,11-dioxo-7-(1,1,1-trifluoropropan-2-yl)- 1,4,4a,5,5a,6,11,12a-octahydrotetracene-2-carboxamide, (4aS,5aR,12aS)-3,10,12,12a-tetrahydroxy-1,11-dioxo-7-((S)-1,1,1-trifluoropropan-2-yl)- 1,4,4a,5,5a,6,11,12a-octahydrotetracene-2-carboxamide, (4aS,5aR,12aS)-3,10,12,12a-tetrahydroxy-1,11-dioxo-7-((R)-1,1,1-trifluoropropan-2-yl)- 1,4,4a,5,5a,6,11,12a-octahydrotetracene-2-carboxamide, (4aS,5aR,12aS)-3,10,12,12a-tetrahydroxy-7-(3-methylisoxazol-5-yl)-1,11-dioxo- 1,4,4a,5,5a,6,11,12a-octahydrotetracene-2-carboxamide, (4aS,5aR,12aS)-3,10,12,12a-tetrahydroxy-1,11-dioxo-7-vinyl-1,4,4a,5,5a,6,11,12a- octahydrotetracene-2-carboxamide, (4aS,5aR,12aS)-3,10,12,12a-tetrahydroxy-7-(1-methyl-1H-1,2,3-triazol-4-yl)-1,11-dioxo- 1,4,4a,5,5a,6,11,12a-octahydrotetracene-2-carboxamide, (4aS,5aR,12aS)-3,10,12,12a-tetrahydroxy-7-(2-methyl-2H-1,2,3-triazol-4-yl)-1,11-dioxo- 1,4,4a,5,5a,6,11,12a-octahydrotetracene-2-carboxamide, (4aS,5aR,12aS)-3,10,12,12a-tetrahydroxy-7-(3-methyl-1,2,4-oxadiazol-5-yl)-1,11-dioxo- 1,4,4a,5,5a,6,11,12a-octahydrotetracene-2-carboxamide, (4aS,5aR,12aS)-3,10,12,12a-tetrahydroxy-7-(3-isopropylisoxazol-5-yl)-1,11-dioxo- 144a55a61112a-octahydrotetracene-2-carboxamide(4aS,5aR,12aS)-3,12a-dihydroxy-10,12-dimethoxy-N,N-dimethyl-1,11-dioxo- 1,4,4a,5,5a,6,11,12a-octahydrotetracene-2-carboxamide, (4aS,5aR,12aS)-3,12,12a-trihydroxy-10-methoxy-1,11-dioxo-1,4,4a,5,5a,6,11,12a- octahydrotetracene-2-carboxamide, (4aS,5aR,12aS)-12,12a-dihydroxy-3,10-dimethoxy-1,11-dioxo-1,4,4a,5,5a,6,11,12a- octahydrotetracene-2-carboxamide, (4aS,5aR,12aS)-3,10,12,12a-tetrahydroxy-1,11-dioxo-9-(2-(pyrrolidin-1-yl)acetamido)- 1,4,4a,5,5a,6,11,12a-octahydrotetracene-2-carboxamide, (4aS,5aR,12aS)-9-(2-(tert-butylamino)acetamido)-3,10,12,12a-tetrahydroxy-1,11-dioxo- 1,4,4a,5,5a,6,11,12a-octahydrotetracene-2-carboxamide, (5aS,12aS)-3,10,12,12a-tetrahydroxy-1,11-dioxo-1,5,5a,6,11,12a-hexahydrotetracene-2- carboxamide, (4aS,12aS)-7-(cyclopent-1-en-1-yl)-3,10,11,12a-tetrahydroxy-1,12-dioxo-1,4,4a,5,12,12a- hexahydrotetracene-2-carboxamide, (4aS,12aS)-7-cyclopentyl-3,10,11,12a-tetrahydroxy-1,12-dioxo-1,4,4a,5,12,12a- hexahydrotetracene-2-carboxamide, (4aS,12aS)-3,10,11,12a-tetrahydroxy-1,12-dioxo-7-(tetrahydro-2H-pyran-4-yl)- 1,4,4a,5,12,12a-hexahydrotetracene-2-carboxamide, (4aS,12aS)-7-cyclobutyl-3,10,11,12a-tetrahydroxy-1,12-dioxo-1,4,4a,5,12,12a- hexahydrotetracene-2-carboxamide, (4aS,12aS)-3,10,11,12a-tetrahydroxy-1,12-dioxo-7-(3,3,3-trifluoroprop-1-en-2-yl)- 1,4,4a,5,12,12a-hexahydrotetracene-2-carboxamide, (12aS)-3,10,11,12a-tetrahydroxy-7-(3-isopropylisoxazol-5-yl)-1,12-dioxo-1,4,4a,5,12,12a- hexahydrotetracene-2-carboxamide, (4aS,5aR,12aS)-3,10,12,12a-tetrahydroxy-7-(4-isopropyl-1H-1,2,3-triazol-1-yl)-1,11-dioxo- 1,4,4a,5,5a,6,11,12a-octahydrotetracene-2-carboxamide, (4aS,12aS)-7-(3-cyclopropylisoxazol-5-yl)-3,10,11,12a-tetrahydroxy-1,12-dioxo- 1,4,4a,5,5a,6,12,12a-octahydrotetracene-2-carboxamide, (4aS,12aS)-3,10,11,12a-tetrahydroxy-1,12-dioxo-7-(1,1,1-trifluoropropan-2-yl)- 1,4,4a,5,12,12a-hexahydrotetracene-2-carboxamide, (4aS)-3,10,11-trihydroxy-1,12-dioxo-7-(1,1,1-trifluoropropan-2-yl)-1,4,4a,5,12,12a- hexahydrotetracene-2-carboxamide, (4aS,5aR,12aS)-3,10,12,12a-tetrahydroxy-7-morpholino-1,11-dioxo-1,4,4a,5,5a,6,11,12a- octahydrotetracene-2-carboxamide(5aR,12aS)-3,10,12,12a-tetrahydroxy-7-(4-hydroxypiperidin-1-yl)-1,11-dioxo- 1,4,4a,5,5a,6,11,12a-octahydrotetracene-2-carboxamide, (4aS,5aR,12aS)-7-(azetidin-1-yl)-3,10,12,12a-tetrahydroxy-1,11-dioxo-1,4,4a,5,5a,6,11,12a- octahydrotetracene-2-carboxamide, (4aS,5aR,12aS)-3,10,12,12a-tetrahydroxy-7-(3-hydroxyazetidin-1-yl)-1,11-dioxo- 1,4,4a,5,5a,6,11,12a-octahydrotetracene-2-carboxamide, (4aS,5aR)-7-cyclobutyl-3,10,12-trihydroxy-1,11-dioxo-1,4,4a,5,5a,6,11,12a- octahydrotetracene-2-carboxamide, (4aS,5aR)-1,3,10,12-tetrahydroxy-7-(3-isopropylisoxazol-5-yl)-11-oxo-4,4a,5,5a,6,11- hexahydrotetracene-2-carboxamide, (4aS,12aS)-7-cyclopropyl-3,10,11,12a-tetrahydroxy-1,12-dioxo-1,4,4a,5,12,12a- hexahydrotetracene-2-carboxamide, (4aS,5aR,12aS)-3,10,12,12a-tetrahydroxy-1,11-dioxo-7-(2-oxaspiro[3.3]hept-5-en-6-yl)- 1,4,4a,5,5a,6,11,12a-octahydrotetracene-2-carboxamide, (4aS,12aS)-3,10,12,12a-tetrahydroxy-1,11-dioxo-7-(2-oxaspiro[3.3]heptan-6-yl)- 1,4,4a,5,5a,6,11,12a-octahydrotetracene-2-carboxamide, (4aS,12aS)-3,10,12,12a-tetrahydroxy-1,11-dioxo-7-(2-oxaspiro[3.3]heptan-6-yl)- 1,4,4a,5,11,12a-hexahydrotetracene-2-carboxamide,

[0248] Name with Stereochemistry (4R,4aS,5aR,12aS)-4-(diethylamino)-3,10,12,12a-tetrahydroxy-1,11-dioxo- 1,4,4a,5,5a,6,11,12a-octahydrotetracene-2-carboxamide, (5aR,12aS,Z)-3,10,12,12a-tetrahydroxy-4-(hydroxyimino)-1,11-dioxo-1,4,4a,5,5a,6,11,12a- octahydrotetracene-2-carboxamide, (4R,4aS,5aR,12aS)-4-amino-3,10,12,12a-tetrahydroxy-1,11-dioxo-1,4,4a,5,5a,6,11,12a- octahydrotetracene-2-carboxamide, (4R,4aS,5aR,12aS)-4-(ethylamino)-3,10,12,12a-tetrahydroxy-1,11-dioxo- 1,4,4a,5,5a,6,11,12a-octahydrotetracene-2-carboxamide, (4R,4aS,5aR,12aS)-4-(dipropylamino)-3,10,12,12a-tetrahydroxy-1,11-dioxo- 1,4,4a,5,5a,6,11,12a-octahydrotetracene-2-carboxamide, (4R,4aS,5aR,12aS)-3,10,12,12a-tetrahydroxy-1,11-dioxo-4-(propylamino)- 1,4,4a,5,5a,6,11,12a-octahydrotetracene-2-carboxamide,(4R,4aS,5aR,12aS)-3,10,12,12a-tetrahydroxy-1,11-dioxo-4-(pyrrolidin-1-yl)- 1,4,4a,5,5a,6,11,12a-octahydrotetracene-2-carboxamide, (4R,4aS,5aR,12aS)-3,10,12,12a-tetrahydroxy-1,11-dioxo-4-(piperidin-1-yl)- 1,4,4a,5,5a,6,11,12a-octahydrotetracene-2-carboxamide, (4R,4aS,5aR,12aS)-3,10,12,12a-tetrahydroxy-4-morpholino-1,11-dioxo-1,4,4a,5,5a,6,11,12a- octahydrotetracene-2-carboxamide, (4R,4aS,5aR,12aS)-4-acetamido-3,10,12,12a-tetrahydroxy-1,11-dioxo-1,4,4a,5,5a,6,11,12a- octahydrotetracene-2-carboxamide, methyl ((1R,4aS,11aR,12aS)-3-carbamoyl-2,4a,5,7-tetrahydroxy-4,6-dioxo- 1,4,4a,6,11,11a,12,12a-octahydrotetracen-1-yl)carbamate, (4R,4aS,5aR,12aS)-4-(cyclobutylamino)-3,10,12,12a-tetrahydroxy-1,11-dioxo- 1,4,4a,5,5a,6,11,12a-octahydrotetracene-2-carboxamide, (4R,4aS,5aR,12aS)-4-(cyclobutyl(methyl)amino)-3,10,12,12a-tetrahydroxy-1,11-dioxo- 1,4,4a,5,5a,6,11,12a-octahydrotetracene-2-carboxamide, (4S,4aS,5aR,12aS)-4-(dimethylamino)-3,10,12,12a-tetrahydroxy-1,11-dioxo-7-(1H-pyrazol- 3-yl)-1,4,4a,5,5a,6,11,12a-octahydrotetracene-2-carboxamide, (4R,4aS,5aR,12aS)-4-(dimethylamino)-3,10,12,12a-tetrahydroxy-1,11-dioxo-7-(1H-pyrazol- 3-yl)-1,4,4a,5,5a,6,11,12a-octahydrotetracene-2-carboxamide, (4R,4aS,5aR,12aS)-4-(dimethylamino)-3,10,12,12a-tetrahydroxy-7-(1-methyl-1H-pyrazol-4- yl)-1,11-dioxo-1,4,4a,5,5a,6,11,12a-octahydrotetracene-2-carboxamide, (4S,4aS,5aR,12aS)-4-(dimethylamino)-3,10,12,12a-tetrahydroxy-7-(1-methyl-1H-pyrazol-4- yl)-1,11-dioxo-1,4,4a,5,5a,6,11,12a-octahydrotetracene-2-carboxamide, (4aS,5aR,12aS,Z)-3,10,12,12a-tetrahydroxy-4-(methoxyimino)-1,11-dioxo- 1,4,4a,5,5a,6,11,12a-octahydrotetracene-2-carboxamide, (4R,4aR,5aR,12aR)-4-amino-3,10,12-trihydroxy-1,11-dioxo-1,4,4a,5,5a,6,11,12a- octahydrotetracene-2-carboxamide, (4R,4aR,5aR)-1,3,10,12-tetrahydroxy-11-oxo-4-(pyrrolidin-1-yl)-4,4a,5,5a,6,11- hexahydrotetracene-2-carboxamide, (4R,4aR,5aR)-1,3,10,12-tetrahydroxy-11-oxo-4-(piperidin-1-yl)-4,4a,5,5a,6,11- hexahydrotetracene-2-carboxamide, (4S,4aS,5aR,12aS)-4-(dimethylamino)-3,10,12,12a-tetrahydroxy-1,11-dioxo-7-(1H-pyrrol-1- yl)-1,4,4a,5,5a,6,11,12a-octahydrotetracene-2-carboxamide, (4R,4aS,5aR,12aS)-4-(dimethylamino)-3,10,12,12a-tetrahydroxy-1,11-dioxo-7-(1H-pyrrol-1- yl)-144a55a61112a-octahydrotetracene-2-carboxamide(4R,4aS,5aR,12aS)-4-(dimethylamino)-3,10,12,12a-tetrahydroxy-1,11-dioxo-7-(pyrrolidin-1- yl)-1,4,4a,5,5a,6,11,12a-octahydrotetracene-2-carboxamide, (4S,4aS,5aR,12aS)-4-(dimethylamino)-3,10,12,12a-tetrahydroxy-1,11-dioxo-7-(pyrrolidin-1- yl)-1,4,4a,5,5a,6,11,12a-octahydrotetracene-2-carboxamide, (4S,4aS,5aR,12aS)-7-cyclobutyl-4-(dimethylamino)-3,10,12,12a-tetrahydroxy-1,11-dioxo- 1,4,4a,5,5a,6,11,12a-octahydrotetracene-2-carboxamide, (4R,4aS,5aR,12aS)-7-cyclobutyl-4-(dimethylamino)-3,10,12,12a-tetrahydroxy-1,11-dioxo- 1,4,4a,5,5a,6,11,12a-octahydrotetracene-2-carboxamide, (4S,4aS,5aR,12aS)-3,10,12,12a-tetrahydroxy-1,11-dioxo-4-(pyrrolidin-1-yl)- 1,4,4a,5,5a,6,11,12a-octahydrotetracene-2-carboxamide, (4S,4aS,5aR,12aS)-4-(dimethylamino)-3,10,12,12a-tetrahydroxy-7-(1-methyl-1H-pyrazol-5- yl)-1,11-dioxo-1,4,4a,5,5a,6,11,12a-octahydrotetracene-2-carboxamide, (4R,4aS,5aR,12aS)-4-(dimethylamino)-3,10,12,12a-tetrahydroxy-7-(1-methyl-1H-pyrazol-5- yl)-1,11-dioxo-1,4,4a,5,5a,6,11,12a-octahydrotetracene-2-carboxamide, (4R,4aS,5aR,12aS)-7-cyclopropyl-4-(dimethylamino)-3,10,12,12a-tetrahydroxy-1,11-dioxo- 1,4,4a,5,5a,6,11,12a-octahydrotetracene-2-carboxamide, (4S,4aS,5aR,12aS)-7-cyclopropyl-4-(dimethylamino)-3,10,12,12a-tetrahydroxy-1,11-dioxo- 1,4,4a,5,5a,6,11,12a-octahydrotetracene-2-carboxamide, (4R,4aS,5aR,12aS)-4-amino-7-cyclopropyl-3,10,12,12a-tetrahydroxy-1,11-dioxo- 1,4,4a,5,5a,6,11,12a-octahydrotetracene-2-carboxamide, (4R,4aS,5aR,12aS)-7-cyclopropyl-4-(diethylamino)-3,10,12,12a-tetrahydroxy-1,11-dioxo- 1,4,4a,5,5a,6,11,12a-octahydrotetracene-2-carboxamide, (4R,4aS,5aR,12aS)-7-cyclopropyl-3,10,12,12a-tetrahydroxy-1,11-dioxo-4-(piperidin-1-yl)- 1,4,4a,5,5a,6,11,12a-octahydrotetracene-2-carboxamide, (4R,4aS,5aR,12aS)-4-amino-7-cyclobutyl-3,10,12,12a-tetrahydroxy-1,11-dioxo- 1,4,4a,5,5a,6,11,12a-octahydrotetracene-2-carboxamide, (4R,4aS,5aR,12aS)-7-cyclobutyl-3,10,12,12a-tetrahydroxy-1,11-dioxo-4-(piperidin-1-yl)- 1,4,4a,5,5a,6,11,12a-octahydrotetracene-2-carboxamide, (4R,4aS,5aR,12aS)-7-cyclopentyl-4-(dimethylamino)-3,10,12,12a-tetrahydroxy-1,11-dioxo- 1,4,4a,5,5a,6,11,12a-octahydrotetracene-2-carboxamide, (4S,4aS,5aR,12aS)-7-cyclopentyl-4-(dimethylamino)-3,10,12,12a-tetrahydroxy-1,11-dioxo- 1,4,4a,5,5a,6,11,12a-octahydrotetracene-2-carboxamide, (4R,4aR,5aR)-4-(diethylamino)-1,3,10,12-tetrahydroxy-11-oxo-4,4a,5,5a,6,11- hexahydrotetracene-2-carboxamide(4R,4aR,5aR)-4-amino-7-cyclopropyl-1,3,10,12-tetrahydroxy-11-oxo-4,4a,5,5a,6,11- hexahydrotetracene-2-carboxamide, (4R,4aR,5aR)-7-cyclopropyl-4-(dimethylamino)-1,3,10,12-tetrahydroxy-11-oxo- 4,4a,5,5a,6,11-hexahydrotetracene-2-carboxamide, (4R,4aR,5aR)-7-cyclopropyl-4-(diethylamino)-1,3,10,12-tetrahydroxy-11-oxo-4,4a,5,5a,6,11- hexahydrotetracene-2-carboxamide, (4aS,5aR,12aS,Z)-3,10,12,12a-tetrahydroxy-4-(methoxyimino)-1,11-dioxo-7-(pyrrolidin-1- yl)-1,4,4a,5,5a,6,11,12a-octahydrotetracene-2-carboxamide, (4R,4aR,5aR)-4-amino-1,3,10,12-tetrahydroxy-11-oxo-7-(pyrrolidin-1-yl)-4,4a,5,5a,6,11- hexahydrotetracene-2-carboxamide, tert-butyl 4-((1R,4aS,11aR,12aS)-3-carbamoyl-2,4a,5,7-tetrahydroxy-4,6-dioxo- 1,4,4a,6,11,11a,12,12a-octahydrotetracen-1-yl)piperazine-1-carboxylate, (4R,4aS,5aR,12aS)-3,10,12,12a-tetrahydroxy-1,11-dioxo-4-(piperazin-1-yl)- 1,4,4a,5,5a,6,11,12a-octahydrotetracene-2-carboxamide, (4R,4aS,5aR,12aS)-3,10,12,12a-tetrahydroxy-4-(4-methylpiperazin-1-yl)-1,11-dioxo- 1,4,4a,5,5a,6,11,12a-octahydrotetracene-2-carboxamide, (4R,4aS,5aR,12aS)-4-(4-acetylpiperazin-1-yl)-3,10,12,12a-tetrahydroxy-1,11-dioxo- 1,4,4a,5,5a,6,11,12a-octahydrotetracene-2-carboxamide, (4R,4aS,5aR,12aS)-3,10,12,12a-tetrahydroxy-4-(4-(methylsulfonyl)piperazin-1-yl)-1,11- dioxo-1,4,4a,5,5a,6,11,12a-octahydrotetracene-2-carboxamide, (4R,4aS,5aR,12aS)-4-(4-cyclopropylpiperazin-1-yl)-3,10,12,12a-tetrahydroxy-1,11-dioxo- 1,4,4a,5,5a,6,11,12a-octahydrotetracene-2-carboxamide, (4R,4aS,5aR,12aS)-3,10,12,12a-tetrahydroxy-4-(4-(2-methoxyethyl)piperazin-1-yl)-1,11- dioxo-1,4,4a,5,5a,6,11,12a-octahydrotetracene-2-carboxamide, (4R,4aS,5aR,12aS)-3,10,12,12a-tetrahydroxy-1,11-dioxo-4-(4-(2,2,2-trifluoroethyl)piperazin- 1-yl)-1,4,4a,5,5a,6,11,12a-octahydrotetracene-2-carboxamide, (4R,4aS,5aR,12aS)-4-amino-3,10,12,12a-tetrahydroxy-1,11-dioxo-7-(1H-pyrazol-3-yl)- 1,4,4a,5,5a,6,11,12a-octahydrotetracene-2-carboxamide, (4R,4aS,5aR,12aS)-4-amino-3,10,12,12a-tetrahydroxy-7-(1-methyl-1H-pyrazol-4-yl)-1,11- dioxo-1,4,4a,5,5a,6,11,12a-octahydrotetracene-2-carboxamide, (4aS,5aR,12aS,Z)-3,10,12,12a-tetrahydroxy-7-isopropyl-4-(methoxyimino)-1,11-dioxo- 1,4,4a,5,5a,6,11,12a-octahydrotetracene-2-carboxamide, (4R,4aS,5aR,12aS)-4-amino-3,10,12,12a-tetrahydroxy-7-isopropyl-1,11-dioxo- 144a55a61112a-octahydrotetracene-2-carboxamide(4R,4aS,5aR,12aS)-4-(dimethylamino)-3,10,12,12a-tetrahydroxy-7-isopropyl-1,11-dioxo- 1,4,4a,5,5a,6,11,12a-octahydrotetracene-2-carboxamide, (4R,4aS,5aR,12aS)-4-(diethylamino)-3,10,12,12a-tetrahydroxy-7-isopropyl-1,11-dioxo- 1,4,4a,5,5a,6,11,12a-octahydrotetracene-2-carboxamide, (4R,4aS,5aR,12aS)-3,10,12,12a-tetrahydroxy-7-isopropyl-1,11-dioxo-4-(pyrrolidin-1-yl)- 1,4,4a,5,5a,6,11,12a-octahydrotetracene-2-carboxamide, (4R,4aS,5aR,12aS)-3,10,12,12a-tetrahydroxy-7-isopropyl-1,11-dioxo-4-(piperidin-1-yl)- 1,4,4a,5,5a,6,11,12a-octahydrotetracene-2-carboxamide, (4R,4aS,5aR,12aS)-3,10,12,12a-tetrahydroxy-7-isopropyl-4-morpholino-1,11-dioxo- 1,4,4a,5,5a,6,11,12a-octahydrotetracene-2-carboxamide, (4aS,12aS,Z)-7-cyclopropyl-3,10,12,12a-tetrahydroxy-4-(methoxyimino)-1,11-dioxo- 1,4,4a,5,11,12a-hexahydrotetracene-2-carboxamide, (4R,4aS,12aS)-4-amino-7-cyclopropyl-3,10,12,12a-tetrahydroxy-1,11-dioxo-1,4,4a,5,11,12a- hexahydrotetracene-2-carboxamide, (4R,4aS,12aS)-7-cyclopropyl-4-(diethylamino)-3,10,11,12a-tetrahydroxy-1,12-dioxo- 1,4,4a,5,12,12a-hexahydrotetracene-2-carboxamide, (4R,4aS,12aS)-7-cyclopropyl-3,10,11,12a-tetrahydroxy-4-morpholino-1,12-dioxo- 1,4,4a,5,12,12a-hexahydrotetracene-2-carboxamide, (4S,4aS,5aR,12aS)-4-(dimethylamino)-3,10,12,12a-tetrahydroxy-7-(1-isopropyl-1H-pyrazol- 4-yl)-1,11-dioxo-1,4,4a,5,5a,6,11,12a-octahydrotetracene-2-carboxamide, (4R,4aS,5aR,12aS)-4-(dimethylamino)-3,10,12,12a-tetrahydroxy-7-(1-isopropyl-1H-pyrazol- 4-yl)-1,11-dioxo-1,4,4a,5,5a,6,11,12a-octahydrotetracene-2-carboxamide, (4R,4aS,5aR,12aS)-4-amino-3,10,12,12a-tetrahydroxy-7-(1-isopropyl-1H-pyrazol-3-yl)-1,11- dioxo-1,4,4a,5,5a,6,11,12a-octahydrotetracene-2-carboxamide, (4aS,12aS,Z)-3,10,11,12a-tetrahydroxy-4-(methoxyimino)-1,12-dioxo-1,4,4a,5,12,12a- hexahydrotetracene-2-carboxamide, (4S,4aS,12aS)-4-(dimethylamino)-3,10,11,12a-tetrahydroxy-1,12-dioxo-1,4,4a,5,12,12a- hexahydrotetracene-2-carboxamide, (4R,4aS,5aR,12aS)-7-cyclopropyl-3,10,12,12a-tetrahydroxy-1,11-dioxo-4-(piperazin-1-yl)- 1,4,4a,5,5a,6,11,12a-octahydrotetracene-2-carboxamide, (4R,4aS,5aR,12aS)-4-(4-acetylpiperazin-1-yl)-7-cyclopropyl-3,10,12,12a-tetrahydroxy-1,11- dioxo-1,4,4a,5,5a,6,11,12a-octahydrotetracene-2-carboxamide, (4R,4aS,5aR,12aS)-7-cyclopropyl-3,10,12,12a-tetrahydroxy-4-(4-(methylsulfonyl)piperazin- 1-yl)-111-dioxo-144a55a61112a-octahydrotetracene-2-carboxamide(4R,4aS,5aR,12aS)-4-amino-3,10,12,12a-tetrahydroxy-7-(3-methylisoxazol-5-yl)-1,11-dioxo- 1,4,4a,5,5a,6,11,12a-octahydrotetracene-2-carboxamide, (4R,4aS,5aR,12aS)-3,10,12,12a-tetrahydroxy-7-(3-methylisoxazol-5-yl)-4-morpholino-1,11- dioxo-1,4,4a,5,5a,6,11,12a-octahydrotetracene-2-carboxamide, (4R,4aS,12aS)-4-(4-acetylpiperazin-1-yl)-3,10,11,12a-tetrahydroxy-1,12-dioxo- 1,4,4a,5,12,12a-hexahydrotetracene-2-carboxamide, (4R,4aS,12aS)-3,10,11,12a-tetrahydroxy-4-(4-(methylsulfonyl)piperazin-1-yl)-1,12-dioxo- 1,4,4a,5,12,12a-hexahydrotetracene-2-carboxamide, (4R,4aS,12aS)-3,10,11,12a-tetrahydroxy-1,12-dioxo-4-(4-(2,2,2-trifluoroethyl)piperazin-1- yl)-1,4,4a,5,12,12a-hexahydrotetracene-2-carboxamide, (4R,4aS,12aS)-3,10,11,12a-tetrahydroxy-4-(4-(2-methoxyethyl)piperazin-1-yl)-1,12-dioxo- 1,4,4a,5,12,12a-hexahydrotetracene-2-carboxamide, (4R,4aS,12aS)-4-(4-cyclopropylpiperazin-1-yl)-3,10,11,12a-tetrahydroxy-1,12-dioxo- 1,4,4a,5,12,12a-hexahydrotetracene-2-carboxamide, (4R,4aS,5aR,12aS)-7-cyclopropyl-3,10,12,12a-tetrahydroxy-4-morpholino-1,11-dioxo- 1,4,4a,5,5a,6,11,12a-octahydrotetracene-2-carboxamide, (4R,12aS)-7-cyclobutyl-3,10,12,12a-tetrahydroxy-4-morpholino-1,11-dioxo- 1,4,4a,5,5a,6,11,12a-octahydrotetracene-2-carboxamide, (4R,12aS)-7-cyclobutyl-4-(diethylamino)-3,10,12,12a-tetrahydroxy-1,11-dioxo- 1,4,4a,5,5a,6,11,12a-octahydrotetracene-2-carboxamide, (4R,4aS,5aR,12aS)-4-amino-3,10,12,12a-tetrahydroxy-1,11-dioxo-7-(pyrrolidin-1-yl)- 1,4,4a,5,5a,6,11,12a-octahydrotetracene-2-carboxamide, (4S,4aS,5aR,12aS)-12-amino-4-(dimethylamino)-3,10,12a-trihydroxy-1,11-dioxo- 1,4,4a,5,5a,6,11,12a-octahydrotetracene-2-carboxamide, (4S,4aS,5aR,12aS)-4-(dimethylamino)-12,12a-dihydroxy-3,10-dimethoxy-1,11-dioxo- 1,4,4a,5,5a,6,11,12a-octahydrotetracene-2-carboxamide, (4R,4aS,5aR,12aS)-4-(dimethylamino)-12,12a-dihydroxy-3,10-dimethoxy-1,11-dioxo- 1,4,4a,5,5a,6,11,12a-octahydrotetracene-2-carboxamide, (4R,4aS,5aR,12aS)-3,10,12,12a-tetrahydroxy-4-((4-methoxybenzyl)amino)-1,11-dioxo- 1,4,4a,5,5a,6,11,12a-octahydrotetracene-2-carboxamide, (4R,4aS,5aR,12aS)-3,10,12,12a-tetrahydroxy-4-((4-methoxybenzyl)(methyl)amino)-1,11- dioxo-1,4,4a,5,5a,6,11,12a-octahydrotetracene-2-carboxamide, (4R,4aS,5aR,12aS)-3,10,12,12a-tetrahydroxy-4-(methylamino)-1,11-dioxo- 144a55a61112a-octahydrotetracene-2-carboxamide(4R,12aS)-7-cyclobutyl-3,10,12,12a-tetrahydroxy-1,11-dioxo-4-(piperazin-1-yl)- 1,4,4a,5,5a,6,11,12a-octahydrotetracene-2-carboxamide, (4R,12aS)-7-cyclobutyl-3,10,11,12a-tetrahydroxy-4-morpholino-1,12-dioxo-1,4,4a,5,12,12a- hexahydrotetracene-2-carboxamide, (4R,12aS)-4-(4-acetylpiperazin-1-yl)-7-cyclobutyl-3,10,12,12a-tetrahydroxy-1,11-dioxo- 1,4,4a,5,5a,6,11,12a-octahydrotetracene-2-carboxamide, (4aS,5aR,12aS,Z)-3,10,12,12a-tetrahydroxy-4-(methoxyimino)-7-(1-methyl-1H-1,2,3-triazol- 4-yl)-1,11-dioxo-1,4,4a,5,5a,6,11,12a-octahydrotetracene-2-carboxamide, (4R,4aS,5aR,12aS)-3,10,12,12a-tetrahydroxy-7-(1-methyl-1H-1,2,3-triazol-4-yl)-4- morpholino-1,11-dioxo-1,4,4a,5,5a,6,11,12a-octahydrotetracene-2-carboxamide, (4aS,5aR,12aS,Z)-3,10,12,12a-tetrahydroxy-4-(methoxyimino)-7-(2-methyl-2H-1,2,3-triazol- 4-yl)-1,11-dioxo-1,4,4a,5,5a,6,11,12a-octahydrotetracene-2-carboxamide, (4R,4aS,5aR,12aS)-3,10,12,12a-tetrahydroxy-7-(2-methyl-2H-1,2,3-triazol-4-yl)-4- morpholino-1,11-dioxo-1,4,4a,5,5a,6,11,12a-octahydrotetracene-2-carboxamide, (4R,4aS,5aR,12aS)-3,10,12,12a-tetrahydroxy-4-(1,4-oxazepan-4-yl)-1,11-dioxo- 1,4,4a,5,5a,6,11,12a-octahydrotetracene-2-carboxamide, (4R,4aS,5aR,12aS)-3,10,12,12a-tetrahydroxy-4-(1,4-oxazocan-4-yl)-1,11-dioxo- 1,4,4a,5,5a,6,11,12a-octahydrotetracene-2-carboxamide, (4R,4aS,5aR,12aS)-4-(azepan-1-yl)-3,10,12,12a-tetrahydroxy-1,11-dioxo- 1,4,4a,5,5a,6,11,12a-octahydrotetracene-2-carboxamide, (4R,4aS,5aR,12aS)-4-(azocan-1-yl)-3,10,12,12a-tetrahydroxy-1,11-dioxo- 1,4,4a,5,5a,6,11,12a-octahydrotetracene-2-carboxamide, (4R,4aS,5aR,12aS)-3,10,12,12a-tetrahydroxy-1,11-dioxo-4-((1S,5R)-7-oxo-3,6- diazabicyclo[3.2.1]octan-3-yl)-1,4,4a,5,5a,6,11,12a-octahydrotetracene-2-carboxamide, (4R,4aS,5aR,12aS)-4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-3,10,12,12a-tetrahydroxy-1,11- dioxo-1,4,4a,5,5a,6,11,12a-octahydrotetracene-2-carboxamide, (4R,4aS,5aR,12aS)-4-(4,4-difluoropiperidin-1-yl)-3,10,12,12a-tetrahydroxy-1,11-dioxo- 1,4,4a,5,5a,6,11,12a-octahydrotetracene-2-carboxamide, (4R,4aS,5aR,12aS)-4-((1R,5S)-3-azabicyclo[3.1.0]hexan-3-yl)-3,10,12,12a-tetrahydroxy- 1,11-dioxo-1,4,4a,5,5a,6,11,12a-octahydrotetracene-2-carboxamide, (4R,4aS,5aR,12aS)-3,10,12,12a-tetrahydroxy-1,11-dioxo-4-(5-oxo-1,4-diazepan-1-yl)- 1,4,4a,5,5a,6,11,12a-octahydrotetracene-2-carboxamide, (4R,4aS,5aR,12aS)-3,10,12,12a-tetrahydroxy-7-(3-methyl-1,2,4-oxadiazol-5-yl)-4- morpholino-111-dioxo-144a55a61112a-octahydrotetracene-2-carboxamide(4R,4aS,5aR,12aS)-3,10,12,12a-tetrahydroxy-7-(3-isopropylisoxazol-5-yl)-4-morpholino- 1,11-dioxo-1,4,4a,5,5a,6,11,12a-octahydrotetracene-2-carboxamide, (4R,4aS,5aR,12aS)-4-amino-3,10,12,12a-tetrahydroxy-7-(1-methyl-1H-1,2,3-triazol-4-yl)- 1,11-dioxo-1,4,4a,5,5a,6,11,12a-octahydrotetracene-2-carboxamide, (4R,4aS,12aS)-4-amino-3,10,11,12a-tetrahydroxy-7-isopropyl-1,12-dioxo-1,4,4a,5,12,12a- hexahydrotetracene-2-carboxamide, (4R,4aS,12aS)-3,10,11,12a-tetrahydroxy-7-isopropyl-4-morpholino-1,12-dioxo- 1,4,4a,5,12,12a-hexahydrotetracene-2-carboxamide, (4R,4aS,5aR,12aS)-3,10,12,12a-tetrahydroxy-7-(3-methylisothiazol-5-yl)-4-morpholino- 1,11-dioxo-1,4,4a,5,5a,6,11,12a-octahydrotetracene-2-carboxamide, (4R,4aS,5aR,12aS)-7-(dimethylamino)-3,10,11,12a-tetrahydroxy-4-morpholino-1,12-dioxo- 1,4,4a,5,5a,6,12,12a-octahydrotetracene-2-carboxamide, (4R,4aS,12aS)-3,10,11,12a-tetrahydroxy-7-(3-methylisoxazol-5-yl)-4-morpholino-1,12- dioxo-1,4,4a,5,12,12a-hexahydrotetracene-2-carboxamide, (4R,4aS,12aS)-3,10,11,12a-tetrahydroxy-4-(4-(2-methoxyethyl)piperazin-1-yl)-7-(3- methylisoxazol-5-yl)-1,12-dioxo-1,4,4a,5,12,12a-hexahydrotetracene-2-carboxamide, (4R,4aS,12aS)-3,10,11,12a-tetrahydroxy-7-isopropyl-4-(4-(2-methoxyethyl)piperazin-1-yl)- 1,12-dioxo-1,4,4a,5,12,12a-hexahydrotetracene-2-carboxamide, (4R,4aS,12aS)-4-amino-3,10,11,12a-tetrahydroxy-7-(3-methylisothiazol-5-yl)-1,12-dioxo- 1,4,4a,5,12,12a-hexahydrotetracene-2-carboxamide, (4R,4aS,12aS)-3,10,11,12a-tetrahydroxy-7-(3-methylisothiazol-5-yl)-4-morpholino-1,12- dioxo-1,4,4a,5,12,12a-hexahydrotetracene-2-carboxamide, (4R,4aS,12aS)-3,10,11,12a-tetrahydroxy-4-(4-(2-methoxyethyl)piperazin-1-yl)-7-(3- methylisothiazol-5-yl)-1,12-dioxo-1,4,4a,5,12,12a-hexahydrotetracene-2-carboxamide, (4R,4aS,12aS)-3,10,11,12a-tetrahydroxy-7-(3-isopropylisoxazol-5-yl)-4-morpholino-1,12- dioxo-1,4,4a,5,12,12a-hexahydrotetracene-2-carboxamide, (4R,4aS,5aR,12aS)-3,10,12,12a-tetrahydroxy-7-(3-isopropyl-1H-pyrazol-5-yl)-4-morpholino- 1,11-dioxo-1,4,4a,5,5a,6,11,12a-octahydrotetracene-2-carboxamide, (4R,4aS,12aS)-7-(3-cyclopropylisoxazol-5-yl)-3,10,11,12a-tetrahydroxy-4-morpholino-1,12- dioxo-1,4,4a,5,5a,6,12,12a-octahydrotetracene-2-carboxamide, (4R,4aS,12aS)-3,10,11,12a-tetrahydroxy-4-(4-(2-hydroxyethyl)piperazin-1-yl)-1,12-dioxo- 1,4,4a,5,12,12a-hexahydrotetracene-2-carboxamide, (4R,4aS,12aS)-3,10,11,12a-tetrahydroxy-4-(4-(oxetan-3-yl)piperazin-1-yl)-1,12-dioxo- 144a51212a-hexahydrotetracene-2-carboxamide(4R,4aS,5aR,12aS)-3,10,12,12a-tetrahydroxy-1,11-dioxo-4-((tetrahydro-2H-pyran-4- yl)amino)-1,4,4a,5,5a,6,11,12a-octahydrotetracene-2-carboxamide, (4R,4aS,5aR,12aS)-3,10,12,12a-tetrahydroxy-4-(methyl(tetrahydro-2H-pyran-4-yl)amino)- 1,11-dioxo-1,4,4a,5,5a,6,11,12a-octahydrotetracene-2-carboxamide, (4R,5aR,12aS)-3,10,12,12a-tetrahydroxy-4,7-dimorpholino-1,11-dioxo-1,4,4a,5,5a,6,11,12a- octahydrotetracene-2-carboxamide, (4R,4aS,5aR,12aS)-3,10,12,12a-tetrahydroxy-7-morpholino-1,11-dioxo-4-(pyrrolidin-1-yl)- 1,4,4a,5,5a,6,11,12a-octahydrotetracene-2-carboxamide, (4R,4aR,5aR)-1,3,10,12-tetrahydroxy-4-morpholino-11-oxo-4,4a,5,5a,6,11- hexahydrotetracene-2-carboxamide, (4R,5aR,12aS)-3,10,12,12a-tetrahydroxy-4-morpholino-1,11-dioxo-7-(pyrimidin-2-yl)- 1,4,4a,5,5a,6,11,12a-octahydrotetracene-2-carboxamide, (4R,4aS,5aR,12aS)-3,10,12,12a-tetrahydroxy-4-(4-hydroxypiperidin-1-yl)-1,11-dioxo- 1,4,4a,5,5a,6,11,12a-octahydrotetracene-2-carboxamide, (4R,4aS,5aR,12aS)-3,10,12,12a-tetrahydroxy-1,11-dioxo-4-((2,2,6,6-tetramethylpiperidin-4- yl)amino)-1,4,4a,5,5a,6,11,12a-octahydrotetracene-2-carboxamide, (4R,4aS,12aS)-3,10,12,12a-tetrahydroxy-4-(4-hydroxypiperidin-1-yl)-1,11-dioxo- 1,4,4a,5,11,12a-hexahydrotetracene-2-carboxamide, (4R,4aS,5aR,12aS)-3,10,12,12a-tetrahydroxy-1,11-dioxo-4,7-di(pyrrolidin-1-yl)- 1,4,4a,5,5a,6,11,12a-octahydrotetracene-2-carboxamide, (4R,4aS,5aR,12aS)-3,10,12,12a-tetrahydroxy-4-morpholino-1,11-dioxo-7-(pyrrolidin-1-yl)- 1,4,4a,5,5a,6,11,12a-octahydrotetracene-2-carboxamide, (4R,4aR,5aR)-1,3,10,12-tetrahydroxy-4-morpholino-11-oxo-7-(pyrrolidin-1-yl)- 4,4a,5,5a,6,11-hexahydrotetracene-2-carboxamide, (4R,4aS,5aR,12aS)-4-(ethylamino)-3,10,12,12a-tetrahydroxy-7-morpholino-1,11-dioxo- 1,4,4a,5,5a,6,11,12a-octahydrotetracene-2-carboxamide, (4R,4aS,5aR,12aS)-4-(dimethylamino)-3,10,12,12a-tetrahydroxy-7-morpholino-1,11-dioxo- 1,4,4a,5,5a,6,11,12a-octahydrotetracene-2-carboxamide, (4R,4aR,5aR)-1,3,10,12-tetrahydroxy-4,7-dimorpholino-11-oxo-4,4a,5,5a,6,11- hexahydrotetracene-2-carboxamide, (4R,4aS,5aR,12aS)-3,10,12,12a-tetrahydroxy-4-morpholino-7-(oxazol-2-yl)-1,11-dioxo- 1,4,4a,5,5a,6,11,12a-octahydrotetracene-2-carboxamide, (4R,5aR,12aS)-3,10,12,12a-tetrahydroxy-7-(isoxazol-4-yl)-4-morpholino-1,11-dioxo- 144a55a61112a-octahydrotetracene-2-carboxamide(4R,4aS,5aR,12aS)-4-amino-3,10,12,12a-tetrahydroxy-1,11-dioxo-7-(1H-pyrrol-2-yl)- 1,4,4a,5,5a,6,11,12a-octahydrotetracene-2-carboxamide, (4R,4aS,5aR,12aS)-3,10,12,12a-tetrahydroxy-4-(methyl(1,2,2,6,6-pentamethylpiperidin-4- yl)amino)-1,11-dioxo-1,4,4a,5,5a,6,11,12a-octahydrotetracene-2-carboxamide, (4R,4aR,5aR)-1,3,10,12-tetrahydroxy-7-(3-isopropylisoxazol-5-yl)-4-morpholino-11-oxo- 4,4a,5,5a,6,11-hexahydrotetracene-2-carboxamide, (4R,4aR,5aR)-1,3,10,12-tetrahydroxy-11-oxo-4,7-di(pyrrolidin-1-yl)-4,4a,5,5a,6,11- hexahydrotetracene-2-carboxamide, (4R,4aS,5aR,12aS)-3,10,11,12a-tetrahydroxy-7-(4-isopropyl-1H-1,2,3-triazol-1-yl)-4- morpholino-1,12-dioxo-1,4,4a,5,5a,6,12,12a-octahydrotetracene-2-carboxamide, (4R,4aR,5aR)-1,3,10,11-tetrahydroxy-7-(4-isopropyl-1H-1,2,3-triazol-1-yl)-4-morpholino- 12-oxo-4,4a,5,5a,6,12-hexahydrotetracene-2-carboxamide, (4R,4aS,5aR,12aS)-3,10,12,12a-tetrahydroxy-4-morpholino-1,11-dioxo-7-(1H-pyrrol-2-yl)- 1,4,4a,5,5a,6,11,12a-octahydrotetracene-2-carboxamide, (4S,4aS,5aR,12aS)-3,10,12,12a-tetrahydroxy-4-morpholino-1,11-dioxo-7-(1H-pyrrol-2-yl)- 1,4,4a,5,5a,6,11,12a-octahydrotetracene-2-carboxamide, (4R,4aS,12aS)-3,10,11,12a-tetrahydroxy-7-(4-isopropyl-1H-1,2,3-triazol-1-yl)-4- morpholino-1,12-dioxo-1,4,4a,5,12,12a-hexahydrotetracene-2-carboxamide, (4R,4aS,5aR,12aS)-3,10,12,12a-tetrahydroxy-7-(3-isopropylisoxazol-5-yl)-1,11-dioxo-4- ((tetrahydro-2H-pyran-4-yl)amino)-1,4,4a,5,5a,6,11,12a-octahydrotetracene-2-carboxamide (4R,4aR,5aR)-1,3,10,12-tetrahydroxy-7-(3-isopropylisoxazol-5-yl)-11-oxo-4-((tetrahydro- 2H-pyran-4-yl)amino)-4,4a,5,5a,6,11-hexahydrotetracene-2-carboxamide, (4R,4aR,5aR)-1,3,10,12-tetrahydroxy-11-oxo-4-((tetrahydro-2H-pyran-4-yl)amino)- 4,4a,5,5a,6,11-hexahydrotetracene-2-carboxamide, (4R,4aS,5aR,12aS)-3,10,12,12a-tetrahydroxy-7-(4-isopropylthiazol-2-yl)-4-morpholino-1,11- dioxo-1,4,4a,5,5a,6,11,12a-octahydrotetracene-2-carboxamide, (4R,4aR,5aR)-1,3,10,12-tetrahydroxy-7-(4-isopropylthiazol-2-yl)-4-morpholino-11-oxo- 4,4a,5,5a,6,11-hexahydrotetracene-2-carboxamide, (4R,5aR,12aS)-7-(azetidin-1-yl)-4-(dimethylamino)-3,10,12,12a-tetrahydroxy-1,11-dioxo- 1,4,4a,5,5a,6,11,12a-octahydrotetracene-2-carboxamide, (4R,4aS,5aR,12aS)-3,10,12,12a-tetrahydroxy-7-morpholino-1,11-dioxo-4-(piperidin-1-yl)- 1,4,4a,5,5a,6,11,12a-octahydrotetracene-2-carboxamide, (4R,4aS,5aR,12aS)-4-(diethylamino)-3,10,12,12a-tetrahydroxy-7-morpholino-1,11-dioxo- 144a55a61112a-octahydrotetracene-2-carboxamide(4R,4aS,5aR,12aS)-3,10,12,12a-tetrahydroxy-1,11-dioxo-7-(pyrrolidin-1-yl)-4-((tetrahydro- 2H-pyran-4-yl)amino)-1,4,4a,5,5a,6,11,12a-octahydrotetracene-2-carboxamide, (4R,4aR,5aR)-1,3,10,12-tetrahydroxy-11-oxo-7-(pyrrolidin-1-yl)-4-((tetrahydro-2H-pyran-4- yl)amino)-4,4a,5,5a,6,11-hexahydrotetracene-2-carboxamide, (4R,4aS,5aR,12aS)-3,10,12,12a-tetrahydroxy-4-(4-methoxypiperidin-1-yl)-1,11-dioxo- 1,4,4a,5,5a,6,11,12a-octahydrotetracene-2-carboxamide, (4R,4aS,12aS)-3,10,12,12a-tetrahydroxy-4-(4-methoxypiperidin-1-yl)-1,11-dioxo- 1,4,4a,5,11,12a-hexahydrotetracene-2-carboxamide, (4R,5aR,12aS)-4-(dimethylamino)-3,10,12,12a-tetrahydroxy-7-(4-hydroxypiperidin-1-yl)- 1,11-dioxo-1,4,4a,5,5a,6,11,12a-octahydrotetracene-2-carboxamide, (4R,5aR,12aR)-4-(dimethylamino)-3,10,12-trihydroxy-7-(4-hydroxypiperidin-1-yl)-1,11- dioxo-1,4,4a,5,5a,6,11,12a-octahydrotetracene-2-carboxamide, (4R,5aR,12aS)-7-(azetidin-1-yl)-3,10,12,12a-tetrahydroxy-4-morpholino-1,11-dioxo- 1,4,4a,5,5a,6,11,12a-octahydrotetracene-2-carboxamide, (4R,4aS,5aR,12aS)-7-(azetidin-1-yl)-3,10,12,12a-tetrahydroxy-1,11-dioxo-4-((tetrahydro- 2H-pyran-4-yl)amino)-1,4,4a,5,5a,6,11,12a-octahydrotetracene-2-carboxamide, (4R,4aS,5aR,12aS)-4-(dimethylamino)-3,10,12,12a-tetrahydroxy-1,11-dioxo-7-(pyrrolidin-1- yl)-1,4,4a,5,5a,6,11,12a-octahydrotetracene-2-carboxamide, (4R,5aR,12aS)-4,7-di(azetidin-1-yl)-3,10,12,12a-tetrahydroxy-1,11-dioxo- 1,4,4a,5,5a,6,11,12a-octahydrotetracene-2-carboxamide, (4R,4aS,5aR,12aS)-3,10,12,12a-tetrahydroxy-7-(3-isopropyl-1,2,4-oxadiazol-5-yl)-4- morpholino-1,11-dioxo-1,4,4a,5,5a,6,11,12a-octahydrotetracene-2-carboxamide, (4R,4aR,5aR)-3,10,12-trihydroxy-7-(3-isopropyl-1,2,4-oxadiazol-5-yl)-4-morpholino-1,11- dioxo-1,4,4a,5,5a,6,11,12a-octahydrotetracene-2-carboxamide, (4R,4aR,5aR)-4-(dimethylamino)-1,3,10,12-tetrahydroxy-11-oxo-7-(pyrrolidin-1-yl)- 4,4a,5,5a,6,11-hexahydrotetracene-2-carboxamide, (4R,4aR,5aR)-4-(dimethylamino)-1,3,10,11-tetrahydroxy-7-morpholino-12-oxo- 4,4a,5,5a,6,12-hexahydrotetracene-2-carboxamide, (4R,4aR,5aR)-7-(dimethylamino)-1,3,10,11-tetrahydroxy-4-morpholino-12-oxo- 4,4a,5,5a,6,12-hexahydrotetracene-2-carboxamide, (4R,4aS,5aR,12aS)-4-(azetidin-1-yl)-3,10,12,12a-tetrahydroxy-1,11-dioxo-7-(pyrrolidin-1- yl)-1,4,4a,5,5a,6,11,12a-octahydrotetracene-2-carboxamide, (4R,4aS,5aR,12aS)-3,10,12,12a-tetrahydroxy-1,11-dioxo-7-(1H-pyrrol-2-yl)-4-((tetrahydro- 2H-pyran-4-yl)amino)-144a55a61112a-octahydrotetracene-2-carboxamide(4R,4aS,5aR,12aS)-4-(dimethylamino)-3,10,12,12a-tetrahydroxy-1,11-dioxo-7-(1H-pyrrol-2- yl)-1,4,4a,5,5a,6,11,12a-octahydrotetracene-2-carboxamide, (4R,4aS,5aR,12aS)-3,10,12,12a-tetrahydroxy-7-(4-isopropyl-1H-pyrrol-2-yl)-1,11-dioxo-4- ((tetrahydro-2H-pyran-4-yl)amino)-1,4,4a,5,5a,6,11,12a-octahydrotetracene-2-carboxamide, (4R,4aS,5aR,12aS)-3,10,12,12a-tetrahydroxy-7-(4-isopropyl-1H-pyrrol-2-yl)-4-morpholino- 1,11-dioxo-1,4,4a,5,5a,6,11,12a-octahydrotetracene-2-carboxamide, (4R,4aS,5aR,12aS)-3,10,12,12a-tetrahydroxy-1,11-dioxo-7-(1H-pyrazol-5-yl)-4-((tetrahydro- 2H-pyran-4-yl)amino)-1,4,4a,5,5a,6,11,12a-octahydrotetracene-2-carboxamide, (4R,4aS,5aR,12aS)-3,10,12,12a-tetrahydroxy-4-morpholino-1,11-dioxo-7-(1H-pyrazol-5-yl)- 1,4,4a,5,5a,6,11,12a-octahydrotetracene-2-carboxamide, (4R,4aS,5aR,12aS)-3,10,12,12a-tetrahydroxy-7-(4-isopropyloxazol-2-yl)-4-morpholino-1,11- dioxo-1,4,4a,5,5a,6,11,12a-octahydrotetracene-2-carboxamide, (4R,4aS,5aR,12aS)-3,10,12,12a-tetrahydroxy-7-(1H-imidazol-2-yl)-1,11-dioxo-4- ((tetrahydro-2H-pyran-4-yl)amino)-1,4,4a,5,5a,6,11,12a-octahydrotetracene-2-carboxamide, (4R,4aS,5aR,12aS)-3,10,12,12a-tetrahydroxy-7-(1H-imidazol-2-yl)-4-morpholino-1,11- dioxo-1,4,4a,5,5a,6,11,12a-octahydrotetracene-2-carboxamide, (4R,4aS,5aR,12aS)-3,10,12,12a-tetrahydroxy-7-(1H-imidazol-5-yl)-4-morpholino-1,11- dioxo-1,4,4a,5,5a,6,11,12a-octahydrotetracene-2-carboxamide, (4R,4aS,5aR,12aS)-3,10,12,12a-tetrahydroxy-7-(1H-imidazol-5-yl)-1,11-dioxo-4- ((tetrahydro-2H-pyran-4-yl)amino)-1,4,4a,5,5a,6,11,12a-octahydrotetracene-2-carboxamide, (4R,4aS,5aR,12aS)-3,10,12,12a-tetrahydroxy-7-(4-isopropyloxazol-2-yl)-1,11-dioxo-4- ((tetrahydro-2H-pyran-4-yl)amino)-1,4,4a,5,5a,6,11,12a-octahydrotetracene-2-carboxamide, (4R,4aR,5aR,12aR)-3,10,12-trihydroxy-7-(4-isopropyloxazol-2-yl)-1,11-dioxo-4- ((tetrahydro-2H-pyran-4-yl)amino)-1,4,4a,5,5a,6,11,12a-octahydrotetracene-2-carboxamide, (4R,4aS,5aR,12aS)-3,10,12,12a-tetrahydroxy-7-(3-isopropyl-1,2,4-oxadiazol-5-yl)-1,11- dioxo-4-((tetrahydro-2H-pyran-4-yl)amino)-1,4,4a,5,5a,6,11,12a-octahydrotetracene-2- carboxamide, (4R,4aS,5aR,12aS)-3,10,12,12a-tetrahydroxy-7-(3-isopropylisoxazol-5-yl)-1,11-dioxo-4-(2- oxa-6-azaspiro[3.3]heptan-6-yl)-1,4,4a,5,5a,6,11,12a-octahydrotetracene-2-carboxamide, (4R,4aS,5aR,12aS)-4-(3,3-dimethylazetidin-1-yl)-3,10,12,12a-tetrahydroxy-7-(3- isopropylisoxazol-5-yl)-1,11-dioxo-1,4,4a,5,5a,6,11,12a-octahydrotetracene-2-carboxamide, (4R,4aS,5aR,12aS)-3,10,12,12a-tetrahydroxy-4-(4-methoxypiperidin-1-yl)-1,11-dioxo-7- (pyrrolidin-1-yl)-1,4,4a,5,5a,6,11,12a-octahydrotetracene-2-carboxamide,(4R,4aS,5aR,12aS)-3,10,12,12a-tetrahydroxy-7-(4-isopropyloxazol-2-yl)-4-(4- methoxypiperidin-1-yl)-1,11-dioxo-1,4,4a,5,5a,6,11,12a-octahydrotetracene-2-carboxamide, (4R,4aS,5aR,12aS)-3,10,12,12a-tetrahydroxy-7-(3-isopropyl-1,2,4-oxadiazol-5-yl)-4-(4- methoxypiperidin-1-yl)-1,11-dioxo-1,4,4a,5,5a,6,11,12a-octahydrotetracene-2-carboxamide, (4R,4aS,5aR,12aS)-3,10,12,12a-tetrahydroxy-4-(4-methoxypiperidin-1-yl)-1,11-dioxo-7- (1H-pyrazol-5-yl)-1,4,4a,5,5a,6,11,12a-octahydrotetracene-2-carboxamide, (4R,4aS,5aR,12aS)-4-(dimethylamino)-3,10,12,12a-tetrahydroxy-1,11-dioxo-7-(1H-pyrazol- 5-yl)-1,4,4a,5,5a,6,11,12a-octahydrotetracene-2-carboxamide, (4R,4aS,5aR,12aS)-7-cyclopentyl-3,10,12,12a-tetrahydroxy-1,11-dioxo-4-((tetrahydro-2H- pyran-4-yl)amino)-1,4,4a,5,5a,6,11,12a-octahydrotetracene-2-carboxamide, (4R,4aS,5aR,12aS)-7-cyclobutyl-3,10,12,12a-tetrahydroxy-1,11-dioxo-4-((tetrahydro-2H- pyran-4-yl)amino)-1,4,4a,5,5a,6,11,12a-octahydrotetracene-2-carboxamide, (4R,4aS,5aR,12aS)-7-(dimethylamino)-3,10,12,12a-tetrahydroxy-1,11-dioxo-4-((tetrahydro- 2H-pyran-4-yl)amino)-1,4,4a,5,5a,6,11,12a-octahydrotetracene-2-carboxamide, (4R,4aS,5aR,12aS)-3,10,12,12a-tetrahydroxy-1,11-dioxo-7-(pyrrolidin-1-yl)-4-(2-oxa-6- azaspiro[3.3]heptan-6-yl)-1,4,4a,5,5a,6,11,12a-octahydrotetracene-2-carboxamide, (4R,4aS,5aR,12aS)-7-(3,3-dimethylcyclobutyl)-3,10,11,12a-tetrahydroxy-1,12-dioxo-4- ((tetrahydro-2H-pyran-4-yl)amino)-1,4,4a,5,5a,6,12,12a-octahydrotetracene-2-carboxamide, (4R,4aS,5aR,12aS)-7-(3,3-dimethylcyclobutyl)-3,10,11,12a-tetrahydroxy-4-morpholino-1,12- dioxo-1,4,4a,5,5a,6,12,12a-octahydrotetracene-2-carboxamide, (4R,4aS,5aR,12aS)-4-((2-oxaspiro[3.3]heptan-6-yl)amino)-3,10,12,12a-tetrahydroxy-1,11- dioxo-7-(pyrrolidin-1-yl)-1,4,4a,5,5a,6,11,12a-octahydrotetracene-2-carboxamide, (4R,4aS,5aR,12aS)-3,10,12,12a-tetrahydroxy-4-(methyl(2-oxaspiro[3.3]heptan-6-yl)amino)- 1,11-dioxo-7-(pyrrolidin-1-yl)-1,4,4a,5,5a,6,11,12a-octahydrotetracene-2-carboxamide, (4R,4aS,5aR,12aS)-4-((1,1-dioxidotetrahydro-2H-thiopyran-4-yl)amino)-3,10,12,12a- tetrahydroxy-1,11-dioxo-7-(pyrrolidin-1-yl)-1,4,4a,5,5a,6,11,12a-octahydrotetracene-2- carboxamide, (4R,4aS,5aR,12aS)-4-((2-oxaspiro[3.3]heptan-6-yl)amino)-3,10,12,12a-tetrahydroxy-7-(3- isopropylisoxazol-5-yl)-1,11-dioxo-1,4,4a,5,5a,6,11,12a-octahydrotetracene-2-carboxamide, (4R,4aS,5aR,12aS)-4-((1,1-dioxidotetrahydro-2H-thiopyran-4-yl)amino)-3,10,12,12a- tetrahydroxy-7-(3-isopropylisoxazol-5-yl)-1,11-dioxo-1,4,4a,5,5a,6,11,12a- octahydrotetracene-2-carboxamide, (4R,4aS,5aR,12aS)-4-((3-cyano-3-methylcyclobutyl)amino)-3,10,12,12a-tetrahydroxy-7-(4- isopropyloxazol-2-yl)-111-dioxo-144a55a61112a-octahydrotetracene-2-carboxamide(4R,4aS,5aR,12aS)-7-cyclopentyl-4-((1-(2,2-difluoroethyl)piperidin-4-yl)amino)- 3,10,12,12a-tetrahydroxy-1,11-dioxo-1,4,4a,5,5a,6,11,12a-octahydrotetracene-2- carboxamide, (4R,4aS,5aR,12aS)-4-((1-(2,2-difluoroethyl)piperidin-4-yl)amino)-3,10,12,12a-tetrahydroxy- 7-(3-isopropylisoxazol-5-yl)-1,11-dioxo-1,4,4a,5,5a,6,11,12a-octahydrotetracene-2- carboxamide, (4R,4aS,5aR,12aS)-4-((3,3-difluorocyclobutyl)amino)-3,10,12,12a-tetrahydroxy-7-(3- isopropylisoxazol-5-yl)-1,11-dioxo-1,4,4a,5,5a,6,11,12a-octahydrotetracene-2-carboxamide, (4R,4aS,5aR,12aS)-4-((2-oxaspiro[3.3]heptan-6-yl)amino)-3,10,12,12a-tetrahydroxy-1,11- dioxo-1,4,4a,5,5a,6,11,12a-octahydrotetracene-2-carboxamide, (4R,4aS,5aR,12aS)-3,10,12,12a-tetrahydroxy-4-(methyl(2-oxaspiro[3.3]heptan-6-yl)amino)- 1,11-dioxo-1,4,4a,5,5a,6,11,12a-octahydrotetracene-2-carboxamide, (4R,4aS,5aR,12aS)-4-((1,1-dioxidotetrahydro-2H-thiopyran-4-yl)amino)-3,10,12,12a- tetrahydroxy-1,11-dioxo-1,4,4a,5,5a,6,11,12a-octahydrotetracene-2-carboxamide, (4R,4aS,5aR,12aS)-4-((1,1-dioxidotetrahydro-2H-thiopyran-4-yl)(methyl)amino)- 3,10,12,12a-tetrahydroxy-1,11-dioxo-1,4,4a,5,5a,6,11,12a-octahydrotetracene-2- carboxamide, (4R,4aS,5aR,12aS)-4-(((1s,3S)-3-cyano-3-methylcyclobutyl)amino)-3,10,12,12a- tetrahydroxy-1,11-dioxo-1,4,4a,5,5a,6,11,12a-octahydrotetracene-2-carboxamide, (4R,4aS,5aR,12aS)-4-(((1r,3R)-3-cyano-3-methylcyclobutyl)amino)-3,10,12,12a- tetrahydroxy-1,11-dioxo-1,4,4a,5,5a,6,11,12a-octahydrotetracene-2-carboxamide, (4R,4aS,5aR,12aS)-4-((1-(2,2-difluoroethyl)piperidin-4-yl)amino)-3,10,12,12a-tetrahydroxy- 1,11-dioxo-1,4,4a,5,5a,6,11,12a-octahydrotetracene-2-carboxamide, (4R,4aS,5aR,12aS)-3,10,12,12a-tetrahydroxy-1,11-dioxo-4-(2-oxa-6-azaspiro[3.3]heptan-6- yl)-1,4,4a,5,5a,6,11,12a-octahydrotetracene-2-carboxamide, (4R,4aS,5aR,12aS)-7-(dimethylamino)-3,10,12,12a-tetrahydroxy-1,11-dioxo-4-(2-oxa-6- azaspiro[3.3]heptan-6-yl)-1,4,4a,5,5a,6,11,12a-octahydrotetracene-2-carboxamide, (4R,4aS,5aR,12aS)-7-cyclopentyl-3,10,12,12a-tetrahydroxy-4-(methyl(tetrahydro-2H-pyran- 4-yl)amino)-1,11-dioxo-1,4,4a,5,5a,6,11,12a-octahydrotetracene-2-carboxamide, (4R,4aS,5aR,12aS)-3,10,12,12a-tetrahydroxy-7-isopropyl-1,11-dioxo-4-((tetrahydro-2H- pyran-4-yl)amino)-1,4,4a,5,5a,6,11,12a-octahydrotetracene-2-carboxamide, (4R,4aS,5aR,12aS)-3,10,12,12a-tetrahydroxy-7-isopropyl-4-(methyl(tetrahydro-2H-pyran-4- yl)amino)-1,11-dioxo-1,4,4a,5,5a,6,11,12a-octahydrotetracene-2-carboxamide,(4R,4aS,5aR,12aS)-3,10,12,12a-tetrahydroxy-7-isopropyl-4-morpholino-1,11-dioxo- 1,4,4a,5,5a,6,11,12a-octahydrotetracene-2-carboxamide, (4R,4aS,5aR,12aS)-3,10,12,12a-tetrahydroxy-4-morpholino-1,11-dioxo-7-propyl- 1,4,4a,5,5a,6,11,12a-octahydrotetracene-2-carboxamide, (4R,4aS,5aR,12aS)-3,10,12,12a-tetrahydroxy-7-isopropyl-1,11-dioxo-4-(2-oxa-6- azaspiro[3.3]heptan-6-yl)-1,4,4a,5,5a,6,11,12a-octahydrotetracene-2-carboxamide, (4R,4aS,5aR,12aS)-3,10,12,12a-tetrahydroxy-1,11-dioxo-4-((tetrahydro-2H-pyran-4- yl)amino)-7-((S)-1,1,1-trifluoropropan-2-yl)-1,4,4a,5,5a,6,11,12a-octahydrotetracene-2- carboxamide, (4R,4aS,5aR,12aS)-3,10,12,12a-tetrahydroxy-1,11-dioxo-4-((tetrahydro-2H-pyran-4- yl)amino)-7-((R)-1,1,1-trifluoropropan-2-yl)-1,4,4a,5,5a,6,11,12a-octahydrotetracene-2- carboxamide, (4R,4aS,5aR,12aS)-3,10,12,12a-tetrahydroxy-4-morpholino-1,11-dioxo-7-((S)-1,1,1- trifluoropropan-2-yl)-1,4,4a,5,5a,6,11,12a-octahydrotetracene-2-carboxamide, (4R,4aS,5aR,12aS)-3,10,12,12a-tetrahydroxy-4-morpholino-1,11-dioxo-7-((R)-1,1,1- trifluoropropan-2-yl)-1,4,4a,5,5a,6,11,12a-octahydrotetracene-2-carboxamide, (4R,4aS,5aR,12aS)-4-((2-oxaspiro[3.3]heptan-6-yl)amino)-3,10,12,12a-tetrahydroxy-7- isopropyl-1,11-dioxo-1,4,4a,5,5a,6,11,12a-octahydrotetracene-2-carboxamide, (4R,4aS,5aR,12aS)-3,10,12,12a-tetrahydroxy-1,11-dioxo-7-(2-oxopyrrolidin-1-yl)-4- ((tetrahydro-2H-pyran-4-yl)amino)-1,4,4a,5,5a,6,11,12a-octahydrotetracene-2-carboxamide, (4R,4aS,5aR,12aS)-3,10,12,12a-tetrahydroxy-4-(((3-methyloxetan-3-yl)methyl)amino)-1,11- dioxo-1,4,4a,5,5a,6,11,12a-octahydrotetracene-2-carboxamide, (4R,4aS,5aR,12aS)-3,10,12,12a-tetrahydroxy-4-(methyl((3-methyloxetan-3- yl)methyl)amino)-1,11-dioxo-1,4,4a,5,5a,6,11,12a-octahydrotetracene-2-carboxamide, (4R,4aS,5aR,12aS)-3,10,12,12a-tetrahydroxy-7-isopropyl-4-(methyl(2-oxaspiro[3.3]heptan- 6-yl)amino)-1,11-dioxo-1,4,4a,5,5a,6,11,12a-octahydrotetracene-2-carboxamide, (4R,4aS,5aR,12aS)-3,10,12,12a-tetrahydroxy-4-morpholino-1,11-dioxo-7-(2-oxopyrrolidin- 1-yl)-1,4,4a,5,5a,6,11,12a-octahydrotetracene-2-carboxamide, (4R,4aS,5aR,12aS)-4-((2-oxaspiro[3.3]heptan-6-yl)amino)-3,10,12,12a-tetrahydroxy-1,11- dioxo-7-(2-oxopyrrolidin-1-yl)-1,4,4a,5,5a,6,11,12a-octahydrotetracene-2-carboxamide, (4R,4aS,5aR,12aS)-4-((2-oxaspiro[3.3]heptan-6-yl)amino)-3,10,12,12a-tetrahydroxy-7-(4- isopropyloxazol-2-yl)-1,11-dioxo-1,4,4a,5,5a,6,11,12a-octahydrotetracene-2-carboxamide, (4R,4aS,5aR,12aS)-4-(cyclohexylamino)-3,10,12,12a-tetrahydroxy-7-(4-isopropyloxazol-2- yl)-111-dioxo-144a55a61112a-octahydrotetracene-2-carboxamide(4R,4aS,5aR,12aS)-4-((3,3-dimethylcyclobutyl)amino)-3,10,12,12a-tetrahydroxy-7-(4- isopropyloxazol-2-yl)-1,11-dioxo-1,4,4a,5,5a,6,11,12a-octahydrotetracene-2-carboxamide, (4R,4aS,5aR,12aS)-3,10,12,12a-tetrahydroxy-1,11-dioxo-4-((tetrahydro-2H-pyran-4- yl)amino)-7-(trifluoromethyl)-1,4,4a,5,5a,6,11,12a-octahydrotetracene-2-carboxamide, (4R,4aS,5aR,12aS)-7-fluoro-3,10,12,12a-tetrahydroxy-1,11-dioxo-4-((tetrahydro-2H-pyran- 4-yl)amino)-1,4,4a,5,5a,6,11,12a-octahydrotetracene-2-carboxamide, (4R,4aS,5aR,12aS)-7-chloro-3,10,12,12a-tetrahydroxy-1,11-dioxo-4-((tetrahydro-2H-pyran- 4-yl)amino)-1,4,4a,5,5a,6,11,12a-octahydrotetracene-2-carboxamide, (4R,4aS,5aR,12aS)-3,10,12,12a-tetrahydroxy-1,11-dioxo-4-((2,2,6,6-tetramethyltetrahydro- 2H-pyran-4-yl)amino)-1,4,4a,5,5a,6,11,12a-octahydrotetracene-2-carboxamide, (4R,4aS,5aR,12aS)-3,10,12,12a-tetrahydroxy-1,11-dioxo-7-(piperidin-1-yl)-4-((tetrahydro- 2H-pyran-4-yl)amino)-1,4,4a,5,5a,6,11,12a-octahydrotetracene-2-carboxamide, (4R,4aS,5aR,12aS)-3,10,12,12a-tetrahydroxy-7-morpholino-1,11-dioxo-4-((tetrahydro-2H- pyran-4-yl)amino)-1,4,4a,5,5a,6,11,12a-octahydrotetracene-2-carboxamide, (4R,4aS,5aR,12aS)-3,10,11,12a-tetrahydroxy-4-(((1-methyl-1H-pyrazol-4-yl)methyl)amino)- 1,12-dioxo-1,4,4a,5,5a,6,12,12a-octahydrotetracene-2-carboxamide, (4R,4aS,5aR,12aS)-3,10,11,12a-tetrahydroxy-4-(((1-methyl-1H-1,2,3-triazol-4- yl)methyl)amino)-1,12-dioxo-1,4,4a,5,5a,6,12,12a-octahydrotetracene-2-carboxamide, (4R,4aS,5aR,12aS)-3,10,12,12a-tetrahydroxy-4-(((1-methyl-1H-pyrazol-4-yl)methyl)amino)- 1,11-dioxo-7-(2-oxopyrrolidin-1-yl)-1,4,4a,5,5a,6,11,12a-octahydrotetracene-2-carboxamide, and (4R,4aS,5aR,12aS)-3,10,12,12a-tetrahydroxy-7-(1,4-oxazepan-4-yl)-1,11-dioxo-4- ((tetrahydro-2H-pyran-4-yl)amino)-1,4,4a,5,5a,6,11,12a-octahydrotetracene-2-carboxamide, or a pharmaceutically acceptable salt thereof.

[0249] In some embodiments, provided herein is a compound selected from the group consisting of: 3,10,12,12a-tetrahydroxy-1,11-dioxo-7-(pyridazin-3-yl)-1,4,4a,5,5a,6,11,12a- octahydrotetracene-2-carboxamide, 3,10,12,12a-tetrahydroxy-1,11-dioxo-7-(pyrrolidin-1-yl)-1,4,4a,5,5a,6,11,12a- octahydrotetracene-2-carboxamide,3,10,12,12a-tetrahydroxy-1,11-dioxo-7-(1H-pyrrol-1-yl)-1,4,4a,5,5a,6,11,12a- octahydrotetracene-2-carboxamide, 3,10,12,12a-tetrahydroxy-1,11-dioxo-7-(1H-pyrazol-4-yl)-1,4,4a,5,5a,6,11,12a- octahydrotetracene-2-carboxamide, 3,10,12,12a-tetrahydroxy-1,11-dioxo-7-(1H-pyrazol-3-yl)-1,4,4a,5,5a,6,11,12a- octahydrotetracene-2-carboxamide, 3,10,12,12a-tetrahydroxy-7-(1-methyl-1H-pyrazol-4-yl)-1,11-dioxo-1,4,4a,5,5a,6,11,12a- octahydrotetracene-2-carboxamide, 3,10,12,12a-tetrahydroxy-7-(1-methyl-1H-pyrazol-3-yl)-1,11-dioxo-1,4,4a,5,5a,6,11,12a- octahydrotetracene-2-carboxamide, 3,10,12,12a-tetrahydroxy-1,11-dioxo-7-(pyridazin-4-yl)-1,4,4a,5,5a,6,11,12a- octahydrotetracene-2-carboxamide, 7-cyclobutyl-3,10,12,12a-tetrahydroxy-1,11-dioxo-1,4,4a,5,5a,6,11,12a-octahydrotetracene- 2-carboxamide, 7-cyclopropyl-3,10,12,12a-tetrahydroxy-1,11-dioxo-1,4,4a,5,5a,6,11,12a-octahydrotetracene- 2-carboxamide, 3,10,12,12a-tetrahydroxy-7-(1-methyl-1H-pyrazol-5-yl)-1,11-dioxo-1,4,4a,5,5a,6,11,12a- octahydrotetracene-2-carboxamide, 3,10,12,12a-tetrahydroxy-7-(1-isopropyl-1H-pyrazol-3-yl)-1,11-dioxo-1,4,4a,5,5a,6,11,12a- octahydrotetracene-2-carboxamide, 7-(3,6-dihydro-2H-pyran-4-yl)-3,10,12,12a-tetrahydroxy-1,11-dioxo-1,4,4a,5,5a,6,11,12a- octahydrotetracene-2-carboxamide, 3,10,12,12a-tetrahydroxy-1,11-dioxo-7-(tetrahydro-2H-pyran-4-yl)-1,4,4a,5,5a,6,11,12a- octahydrotetracene-2-carboxamide, 3,10,12,12a-tetrahydroxy-7-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-1,11-dioxo- 1,4,4a,5,5a,6,11,12a-octahydrotetracene-2-carboxamide, 3,10,12,12a-tetrahydroxy-1,11-dioxo-7-(3,3,3-trifluoroprop-1-en-2-yl)-1,4,4a,5,5a,6,11,12a- octahydrotetracene-2-carboxamide, 3,10,12,12a-tetrahydroxy-1,11-dioxo-7-(1,1,1-trifluoropropan-2-yl)-1,4,4a,5,5a,6,11,12a- octahydrotetracene-2-carboxamide, 3,10,12,12a-tetrahydroxy-7-(3-methylisoxazol-5-yl)-1,11-dioxo-1,4,4a,5,5a,6,11,12a- octahydrotetracene-2-carboxamide, 3,10,12,12a-tetrahydroxy-1,11-dioxo-7-vinyl-1,4,4a,5,5a,6,11,12a-octahydrotetracene-2- carboxamide3,10,12,12a-tetrahydroxy-7-(1-methyl-1H-1,2,3-triazol-4-yl)-1,11-dioxo- 1,4,4a,5,5a,6,11,12a-octahydrotetracene-2-carboxamide, 3,10,12,12a-tetrahydroxy-7-(2-methyl-2H-1,2,3-triazol-4-yl)-1,11-dioxo- 1,4,4a,5,5a,6,11,12a-octahydrotetracene-2-carboxamide, 3,10,12,12a-tetrahydroxy-7-(3-methyl-1,2,4-oxadiazol-5-yl)-1,11-dioxo-1,4,4a,5,5a,6,11,12a- octahydrotetracene-2-carboxamide, 3,10,12,12a-tetrahydroxy-7-(3-isopropylisoxazol-5-yl)-1,11-dioxo-1,4,4a,5,5a,6,11,12a- octahydrotetracene-2-carboxamide, 3,12a-dihydroxy-10,12-dimethoxy-N,N-dimethyl-1,11-dioxo-1,4,4a,5,5a,6,11,12a- octahydrotetracene-2-carboxamide, 3,12,12a-trihydroxy-10-methoxy-1,11-dioxo-1,4,4a,5,5a,6,11,12a-octahydrotetracene-2- carboxamide, 12,12a-dihydroxy-3,10-dimethoxy-1,11-dioxo-1,4,4a,5,5a,6,11,12a-octahydrotetracene-2- carboxamide, 3,10,12,12a-tetrahydroxy-1,11-dioxo-9-(2-(pyrrolidin-1-yl)acetamido)-1,4,4a,5,5a,6,11,12a- octahydrotetracene-2-carboxamide, 9-(2-(tert-butylamino)acetamido)-3,10,12,12a-tetrahydroxy-1,11-dioxo-1,4,4a,5,5a,6,11,12a- octahydrotetracene-2-carboxamide, 3,10,12,12a-tetrahydroxy-1,11-dioxo-1,5,5a,6,11,12a-hexahydrotetracene-2-carboxamide, 7-(cyclopent-1-en-1-yl)-3,10,11,12a-tetrahydroxy-1,12-dioxo-1,4,4a,5,12,12a- hexahydrotetracene-2-carboxamide, 7-cyclopentyl-3,10,11,12a-tetrahydroxy-1,12-dioxo-1,4,4a,5,12,12a-hexahydrotetracene-2- carboxamide, 3,10,11,12a-tetrahydroxy-1,12-dioxo-7-(tetrahydro-2H-pyran-4-yl)-1,4,4a,5,12,12a- hexahydrotetracene-2-carboxamide, 7-cyclobutyl-3,10,11,12a-tetrahydroxy-1,12-dioxo-1,4,4a,5,12,12a-hexahydrotetracene-2- carboxamide, 3,10,11,12a-tetrahydroxy-1,12-dioxo-7-(3,3,3-trifluoroprop-1-en-2-yl)-1,4,4a,5,12,12a- hexahydrotetracene-2-carboxamide, 3,10,11,12a-tetrahydroxy-7-(3-isopropylisoxazol-5-yl)-1,12-dioxo-1,4,4a,5,12,12a- hexahydrotetracene-2-carboxamide, 3,10,12,12a-tetrahydroxy-7-(4-isopropyl-1H-1,2,3-triazol-1-yl)-1,11-dioxo- 1,4,4a,5,5a,6,11,12a-octahydrotetracene-2-carboxamide,7-(3-cyclopropylisoxazol-5-yl)-3,10,11,12a-tetrahydroxy-1,12-dioxo-1,4,4a,5,5a,6,12,12a- octahydrotetracene-2-carboxamide, 3,10,11,12a-tetrahydroxy-1,12-dioxo-7-(1,1,1-trifluoropropan-2-yl)-1,4,4a,5,12,12a- hexahydrotetracene-2-carboxamide, 3,10,11-trihydroxy-1,12-dioxo-7-(1,1,1-trifluoropropan-2-yl)-1,4,4a,5,12,12a- hexahydrotetracene-2-carboxamide, 3,10,12,12a-tetrahydroxy-7-morpholino-1,11-dioxo-1,4,4a,5,5a,6,11,12a-octahydrotetracene- 2-carboxamide, 3,10,12,12a-tetrahydroxy-7-(4-hydroxypiperidin-1-yl)-1,11-dioxo-1,4,4a,5,5a,6,11,12a- octahydrotetracene-2-carboxamide, 7-(azetidin-1-yl)-3,10,12,12a-tetrahydroxy-1,11-dioxo-1,4,4a,5,5a,6,11,12a- octahydrotetracene-2-carboxamide, 3,10,12,12a-tetrahydroxy-7-(3-hydroxyazetidin-1-yl)-1,11-dioxo-1,4,4a,5,5a,6,11,12a- octahydrotetracene-2-carboxamide, 7-cyclobutyl-3,10,12-trihydroxy-1,11-dioxo-1,4,4a,5,5a,6,11,12a-octahydrotetracene-2- carboxamide, 1,3,10,12-tetrahydroxy-7-(3-isopropylisoxazol-5-yl)-11-oxo-4,4a,5,5a,6,11- hexahydrotetracene-2-carboxamide, 7-cyclopropyl-3,10,11,12a-tetrahydroxy-1,12-dioxo-1,4,4a,5,12,12a-hexahydrotetracene-2- carboxamide, 3,10,12,12a-tetrahydroxy-1,11-dioxo-7-(2-oxaspiro[3.3]hept-5-en-6-yl)-1,4,4a,5,5a,6,11,12a- octahydrotetracene-2-carboxamide, 3,10,12,12a-tetrahydroxy-1,11-dioxo-7-(2-oxaspiro[3.3]heptan-6-yl)-1,4,4a,5,5a,6,11,12a- octahydrotetracene-2-carboxamide, 3,10,12,12a-tetrahydroxy-1,11-dioxo-7-(2-oxaspiro[3.3]heptan-6-yl)-1,4,4a,5,11,12a- hexahydrotetracene-2-carboxamide, 4-(diethylamino)-3,10,12,12a-tetrahydroxy-1,11-dioxo-1,4,4a,5,5a,6,11,12a- octahydrotetracene-2-carboxamide, 3,10,12,12a-tetrahydroxy-4-(hydroxyimino)-1,11-dioxo-1,4,4a,5,5a,6,11,12a- octahydrotetracene-2-carboxamide, 4-amino-3,10,12,12a-tetrahydroxy-1,11-dioxo-1,4,4a,5,5a,6,11,12a-octahydrotetracene-2- carboxamide, 4-(ethylamino)-3,10,12,12a-tetrahydroxy-1,11-dioxo-1,4,4a,5,5a,6,11,12a- octahydrotetracene-2-carboxamide4-(dipropylamino)-3,10,12,12a-tetrahydroxy-1,11-dioxo-1,4,4a,5,5a,6,11,12a- octahydrotetracene-2-carboxamide, 3,10,12,12a-tetrahydroxy-1,11-dioxo-4-(propylamino)-1,4,4a,5,5a,6,11,12a- octahydrotetracene-2-carboxamide, 3,10,12,12a-tetrahydroxy-1,11-dioxo-4-(pyrrolidin-1-yl)-1,4,4a,5,5a,6,11,12a- octahydrotetracene-2-carboxamide, 3,10,12,12a-tetrahydroxy-1,11-dioxo-4-(piperidin-1-yl)-1,4,4a,5,5a,6,11,12a- octahydrotetracene-2-carboxamide, 3,10,12,12a-tetrahydroxy-4-morpholino-1,11-dioxo-1,4,4a,5,5a,6,11,12a-octahydrotetracene- 2-carboxamide, 4-acetamido-3,10,12,12a-tetrahydroxy-1,11-dioxo-1,4,4a,5,5a,6,11,12a-octahydrotetracene- 2-carboxamide, methyl 3-carbamoyl-2,4a,5,7-tetrahydroxy-4,6-dioxo-1,4,4a,6,11,11a,12,12a- octahydrotetracen-1-yl)carbamate, 4-(cyclobutylamino)-3,10,12,12a-tetrahydroxy-1,11-dioxo-1,4,4a,5,5a,6,11,12a- octahydrotetracene-2-carboxamide, 4-(cyclobutyl(methyl)amino)-3,10,12,12a-tetrahydroxy-1,11-dioxo-1,4,4a,5,5a,6,11,12a- octahydrotetracene-2-carboxamide, 4-(dimethylamino)-3,10,12,12a-tetrahydroxy-1,11-dioxo-7-(1H-pyrazol-3-yl)- 1,4,4a,5,5a,6,11,12a-octahydrotetracene-2-carboxamide, 4-(dimethylamino)-3,10,12,12a-tetrahydroxy-7-(1-methyl-1H-pyrazol-4-yl)-1,11-dioxo- 1,4,4a,5,5a,6,11,12a-octahydrotetracene-2-carboxamide, 3,10,12,12a-tetrahydroxy-4-(methoxyimino)-1,11-dioxo-1,4,4a,5,5a,6,11,12a- octahydrotetracene-2-carboxamide, 4-amino-3,10,12-trihydroxy-1,11-dioxo-1,4,4a,5,5a,6,11,12a-octahydrotetracene-2- carboxamide, 1,3,10,12-tetrahydroxy-11-oxo-4-(pyrrolidin-1-yl)-4,4a,5,5a,6,11-hexahydrotetracene-2- carboxamide, 1,3,10,12-tetrahydroxy-11-oxo-4-(piperidin-1-yl)-4,4a,5,5a,6,11-hexahydrotetracene-2- carboxamide, 4-(dimethylamino)-3,10,12,12a-tetrahydroxy-1,11-dioxo-7-(1H-pyrrol-1-yl)- 1,4,4a,5,5a,6,11,12a-octahydrotetracene-2-carboxamide, 4-(dimethylamino)-3,10,12,12a-tetrahydroxy-1,11-dioxo-7-(pyrrolidin-1-yl)- 144a55a61112a-octahydrotetracene-2-carboxamide7-cyclobutyl-4-(dimethylamino)-3,10,12,12a-tetrahydroxy-1,11-dioxo-1,4,4a,5,5a,6,11,12a- octahydrotetracene-2-carboxamide, 4-(dimethylamino)-3,10,12,12a-tetrahydroxy-7-(1-methyl-1H-pyrazol-5-yl)-1,11-dioxo- 1,4,4a,5,5a,6,11,12a-octahydrotetracene-2-carboxamide, 7-cyclopropyl-4-(dimethylamino)-3,10,12,12a-tetrahydroxy-1,11-dioxo-1,4,4a,5,5a,6,11,12a- octahydrotetracene-2-carboxamide, 4-amino-7-cyclopropyl-3,10,12,12a-tetrahydroxy-1,11-dioxo-1,4,4a,5,5a,6,11,12a- octahydrotetracene-2-carboxamide, 7-cyclopropyl-4-(diethylamino)-3,10,12,12a-tetrahydroxy-1,11-dioxo-1,4,4a,5,5a,6,11,12a- octahydrotetracene-2-carboxamide, 7-cyclopropyl-3,10,12,12a-tetrahydroxy-1,11-dioxo-4-(piperidin-1-yl)-1,4,4a,5,5a,6,11,12a- octahydrotetracene-2-carboxamide, 4-amino-7-cyclobutyl-3,10,12,12a-tetrahydroxy-1,11-dioxo-1,4,4a,5,5a,6,11,12a- octahydrotetracene-2-carboxamide, 7-cyclobutyl-3,10,12,12a-tetrahydroxy-1,11-dioxo-4-(piperidin-1-yl)-1,4,4a,5,5a,6,11,12a- octahydrotetracene-2-carboxamide, 7-cyclopentyl-4-(dimethylamino)-3,10,12,12a-tetrahydroxy-1,11-dioxo-1,4,4a,5,5a,6,11,12a- octahydrotetracene-2-carboxamide, 4-(diethylamino)-1,3,10,12-tetrahydroxy-11-oxo-4,4a,5,5a,6,11-hexahydrotetracene-2- carboxamide, 4-amino-7-cyclopropyl-1,3,10,12-tetrahydroxy-11-oxo-4,4a,5,5a,6,11-hexahydrotetracene-2- carboxamide, 7-cyclopropyl-4-(dimethylamino)-1,3,10,12-tetrahydroxy-11-oxo-4,4a,5,5a,6,11- hexahydrotetracene-2-carboxamide, 7-cyclopropyl-4-(diethylamino)-1,3,10,12-tetrahydroxy-11-oxo-4,4a,5,5a,6,11- hexahydrotetracene-2-carboxamide, 3,10,12,12a-tetrahydroxy-4-(methoxyimino)-1,11-dioxo-7-(pyrrolidin-1-yl)- 1,4,4a,5,5a,6,11,12a-octahydrotetracene-2-carboxamide, 4-amino-1,3,10,12-tetrahydroxy-11-oxo-7-(pyrrolidin-1-yl)-4,4a,5,5a,6,11- hexahydrotetracene-2-carboxamide, tert-butyl 4-(3-carbamoyl-2,4a,5,7-tetrahydroxy-4,6-dioxo-1,4,4a,6,11,11a,12,12a- octahydrotetracen-1-yl)piperazine-1-carboxylate, 3,10,12,12a-tetrahydroxy-1,11-dioxo-4-(piperazin-1-yl)-1,4,4a,5,5a,6,11,12a- octahydrotetracene-2-carboxamide3,10,12,12a-tetrahydroxy-4-(4-methylpiperazin-1-yl)-1,11-dioxo-1,4,4a,5,5a,6,11,12a- octahydrotetracene-2-carboxamide, 4-(4-acetylpiperazin-1-yl)-3,10,12,12a-tetrahydroxy-1,11-dioxo-1,4,4a,5,5a,6,11,12a- octahydrotetracene-2-carboxamide, 3,10,12,12a-tetrahydroxy-4-(4-(methylsulfonyl)piperazin-1-yl)-1,11-dioxo- 1,4,4a,5,5a,6,11,12a-octahydrotetracene-2-carboxamide, 4-(4-cyclopropylpiperazin-1-yl)-3,10,12,12a-tetrahydroxy-1,11-dioxo-1,4,4a,5,5a,6,11,12a- octahydrotetracene-2-carboxamide, 3,10,12,12a-tetrahydroxy-4-(4-(2-methoxyethyl)piperazin-1-yl)-1,11-dioxo- 1,4,4a,5,5a,6,11,12a-octahydrotetracene-2-carboxamide, 3,10,12,12a-tetrahydroxy-1,11-dioxo-4-(4-(2,2,2-trifluoroethyl)piperazin-1-yl)- 1,4,4a,5,5a,6,11,12a-octahydrotetracene-2-carboxamide, 4-amino-3,10,12,12a-tetrahydroxy-1,11-dioxo-7-(1H-pyrazol-3-yl)-1,4,4a,5,5a,6,11,12a- octahydrotetracene-2-carboxamide, 4-amino-3,10,12,12a-tetrahydroxy-7-(1-methyl-1H-pyrazol-4-yl)-1,11-dioxo- 1,4,4a,5,5a,6,11,12a-octahydrotetracene-2-carboxamide, 3,10,12,12a-tetrahydroxy-7-isopropyl-4-(methoxyimino)-1,11-dioxo-1,4,4a,5,5a,6,11,12a- octahydrotetracene-2-carboxamide, 4-amino-3,10,12,12a-tetrahydroxy-7-isopropyl-1,11-dioxo-1,4,4a,5,5a,6,11,12a- octahydrotetracene-2-carboxamide, 4-(dimethylamino)-3,10,12,12a-tetrahydroxy-7-isopropyl-1,11-dioxo-1,4,4a,5,5a,6,11,12a- octahydrotetracene-2-carboxamide, 4-(diethylamino)-3,10,12,12a-tetrahydroxy-7-isopropyl-1,11-dioxo-1,4,4a,5,5a,6,11,12a- octahydrotetracene-2-carboxamide, 3,10,12,12a-tetrahydroxy-7-isopropyl-1,11-dioxo-4-(pyrrolidin-1-yl)-1,4,4a,5,5a,6,11,12a- octahydrotetracene-2-carboxamide, 3,10,12,12a-tetrahydroxy-7-isopropyl-1,11-dioxo-4-(piperidin-1-yl)-1,4,4a,5,5a,6,11,12a- octahydrotetracene-2-carboxamide, 3,10,12,12a-tetrahydroxy-7-isopropyl-4-morpholino-1,11-dioxo-1,4,4a,5,5a,6,11,12a- octahydrotetracene-2-carboxamide, 7-cyclopropyl-3,10,12,12a-tetrahydroxy-4-(methoxyimino)-1,11-dioxo-1,4,4a,5,11,12a- hexahydrotetracene-2-carboxamide, 4-amino-7-cyclopropyl-3,10,12,12a-tetrahydroxy-1,11-dioxo-1,4,4a,5,11,12a- hexahydrotetracene-2-carboxamide7-cyclopropyl-4-(diethylamino)-3,10,11,12a-tetrahydroxy-1,12-dioxo-1,4,4a,5,12,12a- hexahydrotetracene-2-carboxamide, 7-cyclopropyl-3,10,11,12a-tetrahydroxy-4-morpholino-1,12-dioxo-1,4,4a,5,12,12a- hexahydrotetracene-2-carboxamide, 4-(dimethylamino)-3,10,12,12a-tetrahydroxy-7-(1-isopropyl-1H-pyrazol-4-yl)-1,11-dioxo- 1,4,4a,5,5a,6,11,12a-octahydrotetracene-2-carboxamide, 4-amino-3,10,12,12a-tetrahydroxy-7-(1-isopropyl-1H-pyrazol-3-yl)-1,11-dioxo- 1,4,4a,5,5a,6,11,12a-octahydrotetracene-2-carboxamide, 3,10,11,12a-tetrahydroxy-4-(methoxyimino)-1,12-dioxo-1,4,4a,5,12,12a-hexahydrotetracene- 2-carboxamide, 4-(dimethylamino)-3,10,11,12a-tetrahydroxy-1,12-dioxo-1,4,4a,5,12,12a- hexahydrotetracene-2-carboxamide, 7-cyclopropyl-3,10,12,12a-tetrahydroxy-1,11-dioxo-4-(piperazin-1-yl)-1,4,4a,5,5a,6,11,12a- octahydrotetracene-2-carboxamide, 4-(4-acetylpiperazin-1-yl)-7-cyclopropyl-3,10,12,12a-tetrahydroxy-1,11-dioxo- 1,4,4a,5,5a,6,11,12a-octahydrotetracene-2-carboxamide, 7-cyclopropyl-3,10,12,12a-tetrahydroxy-4-(4-(methylsulfonyl)piperazin-1-yl)-1,11-dioxo- 1,4,4a,5,5a,6,11,12a-octahydrotetracene-2-carboxamide, 4-amino-3,10,12,12a-tetrahydroxy-7-(3-methylisoxazol-5-yl)-1,11-dioxo- 1,4,4a,5,5a,6,11,12a-octahydrotetracene-2-carboxamide, 3,10,12,12a-tetrahydroxy-7-(3-methylisoxazol-5-yl)-4-morpholino-1,11-dioxo- 1,4,4a,5,5a,6,11,12a-octahydrotetracene-2-carboxamide, 4-(4-acetylpiperazin-1-yl)-3,10,11,12a-tetrahydroxy-1,12-dioxo-1,4,4a,5,12,12a- hexahydrotetracene-2-carboxamide, 3,10,11,12a-tetrahydroxy-4-(4-(methylsulfonyl)piperazin-1-yl)-1,12-dioxo-1,4,4a,5,12,12a- hexahydrotetracene-2-carboxamide, 3,10,11,12a-tetrahydroxy-1,12-dioxo-4-(4-(2,2,2-trifluoroethyl)piperazin-1-yl)- 1,4,4a,5,12,12a-hexahydrotetracene-2-carboxamide, 3,10,11,12a-tetrahydroxy-4-(4-(2-methoxyethyl)piperazin-1-yl)-1,12-dioxo-1,4,4a,5,12,12a- hexahydrotetracene-2-carboxamide, 4-(4-cyclopropylpiperazin-1-yl)-3,10,11,12a-tetrahydroxy-1,12-dioxo-1,4,4a,5,12,12a- hexahydrotetracene-2-carboxamide, 7-cyclopropyl-3,10,12,12a-tetrahydroxy-4-morpholino-1,11-dioxo-1,4,4a,5,5a,6,11,12a- octahydrotetracene-2-carboxamide7-cyclobutyl-3,10,12,12a-tetrahydroxy-4-morpholino-1,11-dioxo-1,4,4a,5,5a,6,11,12a- octahydrotetracene-2-carboxamide, 7-cyclobutyl-4-(diethylamino)-3,10,12,12a-tetrahydroxy-1,11-dioxo-1,4,4a,5,5a,6,11,12a- octahydrotetracene-2-carboxamide, 4-amino-3,10,12,12a-tetrahydroxy-1,11-dioxo-7-(pyrrolidin-1-yl)-1,4,4a,5,5a,6,11,12a- octahydrotetracene-2-carboxamide, 12-amino-4-(dimethylamino)-3,10,12a-trihydroxy-1,11-dioxo-1,4,4a,5,5a,6,11,12a- octahydrotetracene-2-carboxamide, 4-(dimethylamino)-12,12a-dihydroxy-3,10-dimethoxy-1,11-dioxo-1,4,4a,5,5a,6,11,12a- octahydrotetracene-2-carboxamide, 3,10,12,12a-tetrahydroxy-4-((4-methoxybenzyl)amino)-1,11-dioxo-1,4,4a,5,5a,6,11,12a- octahydrotetracene-2-carboxamide, 3,10,12,12a-tetrahydroxy-4-((4-methoxybenzyl)(methyl)amino)-1,11-dioxo- 1,4,4a,5,5a,6,11,12a-octahydrotetracene-2-carboxamide, 3,10,12,12a-tetrahydroxy-4-(methylamino)-1,11-dioxo-1,4,4a,5,5a,6,11,12a- octahydrotetracene-2-carboxamide, 7-cyclobutyl-3,10,12,12a-tetrahydroxy-1,11-dioxo-4-(piperazin-1-yl)-1,4,4a,5,5a,6,11,12a- octahydrotetracene-2-carboxamide, 7-cyclobutyl-3,10,11,12a-tetrahydroxy-4-morpholino-1,12-dioxo-1,4,4a,5,12,12a- hexahydrotetracene-2-carboxamide, 4-(4-acetylpiperazin-1-yl)-7-cyclobutyl-3,10,12,12a-tetrahydroxy-1,11-dioxo- 1,4,4a,5,5a,6,11,12a-octahydrotetracene-2-carboxamide, 3,10,12,12a-tetrahydroxy-4-(methoxyimino)-7-(1-methyl-1H-1,2,3-triazol-4-yl)-1,11-dioxo- 1,4,4a,5,5a,6,11,12a-octahydrotetracene-2-carboxamide, 3,10,12,12a-tetrahydroxy-7-(1-methyl-1H-1,2,3-triazol-4-yl)-4-morpholino-1,11-dioxo- 1,4,4a,5,5a,6,11,12a-octahydrotetracene-2-carboxamide, 3,10,12,12a-tetrahydroxy-4-(methoxyimino)-7-(2-methyl-2H-1,2,3-triazol-4-yl)-1,11-dioxo- 1,4,4a,5,5a,6,11,12a-octahydrotetracene-2-carboxamide, 3,10,12,12a-tetrahydroxy-7-(2-methyl-2H-1,2,3-triazol-4-yl)-4-morpholino-1,11-dioxo- 1,4,4a,5,5a,6,11,12a-octahydrotetracene-2-carboxamide, 3,10,12,12a-tetrahydroxy-4-(1,4-oxazepan-4-yl)-1,11-dioxo-1,4,4a,5,5a,6,11,12a- octahydrotetracene-2-carboxamide 3,10,12,12a-tetrahydroxy-4-(1,4-oxazocan-4-yl)-1,11-dioxo-1,4,4a,5,5a,6,11,12a- octahydrotetracene-2-carboxamide4-(azepan-1-yl)-3,10,12,12a-tetrahydroxy-1,11-dioxo-1,4,4a,5,5a,6,11,12a- octahydrotetracene-2-carboxamide, 4-(azocan-1-yl)-3,10,12,12a-tetrahydroxy-1,11-dioxo-1,4,4a,5,5a,6,11,12a- octahydrotetracene-2-carboxamide, (3,10,12,12a-tetrahydroxy-1,11-dioxo-4-(7-oxo-3,6-diazabicyclo[3.2.1]octan-3-yl)- 1,4,4a,5,5a,6,11,12a-octahydrotetracene-2-carboxamide, 4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-3,10,12,12a-tetrahydroxy-1,11-dioxo- 1,4,4a,5,5a,6,11,12a-octahydrotetracene-2-carboxamide, 4-(4,4-difluoropiperidin-1-yl)-3,10,12,12a-tetrahydroxy-1,11-dioxo-1,4,4a,5,5a,6,11,12a- octahydrotetracene-2-carboxamide, 4-(3-azabicyclo[3.1.0]hexan-3-yl)-3,10,12,12a-tetrahydroxy-1,11-dioxo-1,4,4a,5,5a,6,11,12a- octahydrotetracene-2-carboxamide, 3,10,12,12a-tetrahydroxy-1,11-dioxo-4-(5-oxo-1,4-diazepan-1-yl)-1,4,4a,5,5a,6,11,12a- octahydrotetracene-2-carboxamide, 3,10,12,12a-tetrahydroxy-7-(3-methyl-1,2,4-oxadiazol-5-yl)-4-morpholino-1,11-dioxo- 1,4,4a,5,5a,6,11,12a-octahydrotetracene-2-carboxamide, 3,10,12,12a-tetrahydroxy-7-(3-isopropylisoxazol-5-yl)-4-morpholino-1,11-dioxo- 1,4,4a,5,5a,6,11,12a-octahydrotetracene-2-carboxamide, 4-amino-3,10,12,12a-tetrahydroxy-7-(1-methyl-1H-1,2,3-triazol-4-yl)-1,11-dioxo- 1,4,4a,5,5a,6,11,12a-octahydrotetracene-2-carboxamide, 4-amino-3,10,11,12a-tetrahydroxy-7-isopropyl-1,12-dioxo-1,4,4a,5,12,12a- hexahydrotetracene-2-carboxamide, 3,10,11,12a-tetrahydroxy-7-isopropyl-4-morpholino-1,12-dioxo-1,4,4a,5,12,12a- hexahydrotetracene-2-carboxamide, 3,10,12,12a-tetrahydroxy-7-(3-methylisothiazol-5-yl)-4-morpholino-1,11-dioxo- 1,4,4a,5,5a,6,11,12a-octahydrotetracene-2-carboxamide, 7-(dimethylamino)-3,10,11,12a-tetrahydroxy-4-morpholino-1,12-dioxo-1,4,4a,5,5a,6,12,12a- octahydrotetracene-2-carboxamide, 3,10,11,12a-tetrahydroxy-7-(3-methylisoxazol-5-yl)-4-morpholino-1,12-dioxo- 1,4,4a,5,12,12a-hexahydrotetracene-2-carboxamide, 3,10,11,12a-tetrahydroxy-4-(4-(2-methoxyethyl)piperazin-1-yl)-7-(3-methylisoxazol-5-yl)- 1,12-dioxo-1,4,4a,5,12,12a-hexahydrotetracene-2-carboxamide, 3,10,11,12a-tetrahydroxy-7-isopropyl-4-(4-(2-methoxyethyl)piperazin-1-yl)-1,12-dioxo- 144a51212a-hexahydrotetracene-2-carboxamide4-amino-3,10,11,12a-tetrahydroxy-7-(3-methylisothiazol-5-yl)-1,12-dioxo-1,4,4a,5,12,12a- hexahydrotetracene-2-carboxamide, 3,10,11,12a-tetrahydroxy-7-(3-methylisothiazol-5-yl)-4-morpholino-1,12-dioxo- 1,4,4a,5,12,12a-hexahydrotetracene-2-carboxamide, 3,10,11,12a-tetrahydroxy-4-(4-(2-methoxyethyl)piperazin-1-yl)-7-(3-methylisothiazol-5-yl)- 1,12-dioxo-1,4,4a,5,12,12a-hexahydrotetracene-2-carboxamide, 3,10,11,12a-tetrahydroxy-7-(3-isopropylisoxazol-5-yl)-4-morpholino-1,12-dioxo- 1,4,4a,5,12,12a-hexahydrotetracene-2-carboxamide, 3,10,12,12a-tetrahydroxy-7-(3-isopropyl-1H-pyrazol-5-yl)-4-morpholino-1,11-dioxo- 1,4,4a,5,5a,6,11,12a-octahydrotetracene-2-carboxamide, 7-(3-cyclopropylisoxazol-5-yl)-3,10,11,12a-tetrahydroxy-4-morpholino-1,12-dioxo- 1,4,4a,5,5a,6,12,12a-octahydrotetracene-2-carboxamide, 3,10,11,12a-tetrahydroxy-4-(4-(2-hydroxyethyl)piperazin-1-yl)-1,12-dioxo-1,4,4a,5,12,12a- hexahydrotetracene-2-carboxamide, 3,10,11,12a-tetrahydroxy-4-(4-(oxetan-3-yl)piperazin-1-yl)-1,12-dioxo-1,4,4a,5,12,12a- hexahydrotetracene-2-carboxamide, 3,10,12,12a-tetrahydroxy-1,11-dioxo-4-((tetrahydro-2H-pyran-4-yl)amino)- 1,4,4a,5,5a,6,11,12a-octahydrotetracene-2-carboxamide, 3,10,12,12a-tetrahydroxy-4-(methyl(tetrahydro-2H-pyran-4-yl)amino)-1,11-dioxo- 1,4,4a,5,5a,6,11,12a-octahydrotetracene-2-carboxamide, 3,10,12,12a-tetrahydroxy-4,7-dimorpholino-1,11-dioxo-1,4,4a,5,5a,6,11,12a- octahydrotetracene-2-carboxamide, 3,10,12,12a-tetrahydroxy-7-morpholino-1,11-dioxo-4-(pyrrolidin-1-yl)-1,4,4a,5,5a,6,11,12a- octahydrotetracene-2-carboxamide, 1,3,10,12-tetrahydroxy-4-morpholino-11-oxo-4,4a,5,5a,6,11-hexahydrotetracene-2- carboxamide, 3,10,12,12a-tetrahydroxy-4-morpholino-1,11-dioxo-7-(pyrimidin-2-yl)-1,4,4a,5,5a,6,11,12a- octahydrotetracene-2-carboxamide, 3,10,12,12a-tetrahydroxy-4-(4-hydroxypiperidin-1-yl)-1,11-dioxo-1,4,4a,5,5a,6,11,12a- octahydrotetracene-2-carboxamide, 3,10,12,12a-tetrahydroxy-1,11-dioxo-4-((2,2,6,6-tetramethylpiperidin-4-yl)amino)- 1,4,4a,5,5a,6,11,12a-octahydrotetracene-2-carboxamide, 3,10,12,12a-tetrahydroxy-4-(4-hydroxypiperidin-1-yl)-1,11-dioxo-1,4,4a,5,11,12a- hexahydrotetracene-2-carboxamide3,10,12,12a-tetrahydroxy-1,11-dioxo-4,7-di(pyrrolidin-1-yl)-1,4,4a,5,5a,6,11,12a- octahydrotetracene-2-carboxamide, 3,10,12,12a-tetrahydroxy-4-morpholino-1,11-dioxo-7-(pyrrolidin-1-yl)-1,4,4a,5,5a,6,11,12a- octahydrotetracene-2-carboxamide, 1,3,10,12-tetrahydroxy-4-morpholino-11-oxo-7-(pyrrolidin-1-yl)-4,4a,5,5a,6,11- hexahydrotetracene-2-carboxamide, 4-(ethylamino)-3,10,12,12a-tetrahydroxy-7-morpholino-1,11-dioxo-1,4,4a,5,5a,6,11,12a- octahydrotetracene-2-carboxamide, 4-(dimethylamino)-3,10,12,12a-tetrahydroxy-7-morpholino-1,11-dioxo-1,4,4a,5,5a,6,11,12a- octahydrotetracene-2-carboxamide, 1,3,10,12-tetrahydroxy-4,7-dimorpholino-11-oxo-4,4a,5,5a,6,11-hexahydrotetracene-2- carboxamide, 3,10,12,12a-tetrahydroxy-4-morpholino-7-(oxazol-2-yl)-1,11-dioxo-1,4,4a,5,5a,6,11,12a- octahydrotetracene-2-carboxamide, 3,10,12,12a-tetrahydroxy-7-(isoxazol-4-yl)-4-morpholino-1,11-dioxo-1,4,4a,5,5a,6,11,12a- octahydrotetracene-2-carboxamide, 4-amino-3,10,12,12a-tetrahydroxy-1,11-dioxo-7-(1H-pyrrol-2-yl)-1,4,4a,5,5a,6,11,12a- octahydrotetracene-2-carboxamide, 3,10,12,12a-tetrahydroxy-4-(methyl(1,2,2,6,6-pentamethylpiperidin-4-yl)amino)-1,11-dioxo- 1,4,4a,5,5a,6,11,12a-octahydrotetracene-2-carboxamide, 1,3,10,12-tetrahydroxy-7-(3-isopropylisoxazol-5-yl)-4-morpholino-11-oxo-4,4a,5,5a,6,11- hexahydrotetracene-2-carboxamide, 1,3,10,12-tetrahydroxy-11-oxo-4,7-di(pyrrolidin-1-yl)-4,4a,5,5a,6,11-hexahydrotetracene-2- carboxamide, 3,10,11,12a-tetrahydroxy-7-(4-isopropyl-1H-1,2,3-triazol-1-yl)-4-morpholino-1,12-dioxo- 1,4,4a,5,5a,6,12,12a-octahydrotetracene-2-carboxamide, 1,3,10,11-tetrahydroxy-7-(4-isopropyl-1H-1,2,3-triazol-1-yl)-4-morpholino-12-oxo- 4,4a,5,5a,6,12-hexahydrotetracene-2-carboxamide, 3,10,12,12a-tetrahydroxy-4-morpholino-1,11-dioxo-7-(1H-pyrrol-2-yl)-1,4,4a,5,5a,6,11,12a- octahydrotetracene-2-carboxamide, 3,10,11,12a-tetrahydroxy-7-(4-isopropyl-1H-1,2,3-triazol-1-yl)-4-morpholino-1,12-dioxo- 1,4,4a,5,12,12a-hexahydrotetracene-2-carboxamide, 3,10,12,12a-tetrahydroxy-7-(3-isopropylisoxazol-5-yl)-1,11-dioxo-4-((tetrahydro-2H-pyran- 4-yl)amino)-144a55a61112a-octahydrotetracene-2-carboxamide1,3,10,12-tetrahydroxy-7-(3-isopropylisoxazol-5-yl)-11-oxo-4-((tetrahydro-2H-pyran-4- yl)amino)-4,4a,5,5a,6,11-hexahydrotetracene-2-carboxamide, 1,3,10,12-tetrahydroxy-11-oxo-4-((tetrahydro-2H-pyran-4-yl)amino)-4,4a,5,5a,6,11- hexahydrotetracene-2-carboxamide, 3,10,12,12a-tetrahydroxy-7-(4-isopropylthiazol-2-yl)-4-morpholino-1,11-dioxo- 1,4,4a,5,5a,6,11,12a-octahydrotetracene-2-carboxamide, 1,3,10,12-tetrahydroxy-7-(4-isopropylthiazol-2-yl)-4-morpholino-11-oxo-4,4a,5,5a,6,11- hexahydrotetracene-2-carboxamide, 7-(azetidin-1-yl)-4-(dimethylamino)-3,10,12,12a-tetrahydroxy-1,11-dioxo- 1,4,4a,5,5a,6,11,12a-octahydrotetracene-2-carboxamide, 3,10,12,12a-tetrahydroxy-7-morpholino-1,11-dioxo-4-(piperidin-1-yl)-1,4,4a,5,5a,6,11,12a- octahydrotetracene-2-carboxamide, 4-(diethylamino)-3,10,12,12a-tetrahydroxy-7-morpholino-1,11-dioxo-1,4,4a,5,5a,6,11,12a- octahydrotetracene-2-carboxamide, 3,10,12,12a-tetrahydroxy-1,11-dioxo-7-(pyrrolidin-1-yl)-4-((tetrahydro-2H-pyran-4- yl)amino)-1,4,4a,5,5a,6,11,12a-octahydrotetracene-2-carboxamide, 1,3,10,12-tetrahydroxy-11-oxo-7-(pyrrolidin-1-yl)-4-((tetrahydro-2H-pyran-4-yl)amino)- 4,4a,5,5a,6,11-hexahydrotetracene-2-carboxamide, 3,10,12,12a-tetrahydroxy-4-(4-methoxypiperidin-1-yl)-1,11-dioxo-1,4,4a,5,5a,6,11,12a- octahydrotetracene-2-carboxamide, 3,10,12,12a-tetrahydroxy-4-(4-methoxypiperidin-1-yl)-1,11-dioxo-1,4,4a,5,11,12a- hexahydrotetracene-2-carboxamide, 4-(dimethylamino)-3,10,12,12a-tetrahydroxy-7-(4-hydroxypiperidin-1-yl)-1,11-dioxo- 1,4,4a,5,5a,6,11,12a-octahydrotetracene-2-carboxamide, 4-(dimethylamino)-3,10,12-trihydroxy-7-(4-hydroxypiperidin-1-yl)-1,11-dioxo- 1,4,4a,5,5a,6,11,12a-octahydrotetracene-2-carboxamide, 7-(azetidin-1-yl)-3,10,12,12a-tetrahydroxy-4-morpholino-1,11-dioxo-1,4,4a,5,5a,6,11,12a- octahydrotetracene-2-carboxamide, 7-(azetidin-1-yl)-3,10,12,12a-tetrahydroxy-1,11-dioxo-4-((tetrahydro-2H-pyran-4-yl)amino)- 1,4,4a,5,5a,6,11,12a-octahydrotetracene-2-carboxamide, 4,7-di(azetidin-1-yl)-3,10,12,12a-tetrahydroxy-1,11-dioxo-1,4,4a,5,5a,6,11,12a- octahydrotetracene-2-carboxamide, 3,10,12,12a-tetrahydroxy-7-(3-isopropyl-1,2,4-oxadiazol-5-yl)-4-morpholino-1,11-dioxo- 144a55a61112a-octahydrotetracene-2-carboxamide3,10,12-trihydroxy-7-(3-isopropyl-1,2,4-oxadiazol-5-yl)-4-morpholino-1,11-dioxo- 1,4,4a,5,5a,6,11,12a-octahydrotetracene-2-carboxamide, 4-(dimethylamino)-1,3,10,12-tetrahydroxy-11-oxo-7-(pyrrolidin-1-yl)-4,4a,5,5a,6,11- hexahydrotetracene-2-carboxamide, 4-(dimethylamino)-1,3,10,11-tetrahydroxy-7-morpholino-12-oxo-4,4a,5,5a,6,12- hexahydrotetracene-2-carboxamide, 7-(dimethylamino)-1,3,10,11-tetrahydroxy-4-morpholino-12-oxo-4,4a,5,5a,6,12- hexahydrotetracene-2-carboxamide, 4-(azetidin-1-yl)-3,10,12,12a-tetrahydroxy-1,11-dioxo-7-(pyrrolidin-1-yl)- 1,4,4a,5,5a,6,11,12a-octahydrotetracene-2-carboxamide, 3,10,12,12a-tetrahydroxy-1,11-dioxo-7-(1H-pyrrol-2-yl)-4-((tetrahydro-2H-pyran-4- yl)amino)-1,4,4a,5,5a,6,11,12a-octahydrotetracene-2-carboxamide, 4-(dimethylamino)-3,10,12,12a-tetrahydroxy-1,11-dioxo-7-(1H-pyrrol-2-yl)- 1,4,4a,5,5a,6,11,12a-octahydrotetracene-2-carboxamide, 3,10,12,12a-tetrahydroxy-7-(4-isopropyl-1H-pyrrol-2-yl)-1,11-dioxo-4-((tetrahydro-2H- pyran-4-yl)amino)-1,4,4a,5,5a,6,11,12a-octahydrotetracene-2-carboxamide, 3,10,12,12a-tetrahydroxy-7-(4-isopropyl-1H-pyrrol-2-yl)-4-morpholino-1,11-dioxo- 1,4,4a,5,5a,6,11,12a-octahydrotetracene-2-carboxamide, 3,10,12,12a-tetrahydroxy-1,11-dioxo-7-(1H-pyrazol-5-yl)-4-((tetrahydro-2H-pyran-4- yl)amino)-1,4,4a,5,5a,6,11,12a-octahydrotetracene-2-carboxamide, 3,10,12,12a-tetrahydroxy-4-morpholino-1,11-dioxo-7-(1H-pyrazol-5-yl)- 1,4,4a,5,5a,6,11,12a-octahydrotetracene-2-carboxamide, 3,10,12,12a-tetrahydroxy-7-(4-isopropyloxazol-2-yl)-4-morpholino-1,11-dioxo- 1,4,4a,5,5a,6,11,12a-octahydrotetracene-2-carboxamide, 3,10,12,12a-tetrahydroxy-7-(1H-imidazol-2-yl)-1,11-dioxo-4-((tetrahydro-2H-pyran-4- yl)amino)-1,4,4a,5,5a,6,11,12a-octahydrotetracene-2-carboxamide, 3,10,12,12a-tetrahydroxy-7-(1H-imidazol-2-yl)-4-morpholino-1,11-dioxo- 1,4,4a,5,5a,6,11,12a-octahydrotetracene-2-carboxamide, 3,10,12,12a-tetrahydroxy-7-(1H-imidazol-5-yl)-4-morpholino-1,11-dioxo- 1,4,4a,5,5a,6,11,12a-octahydrotetracene-2-carboxamide, 3,10,12,12a-tetrahydroxy-7-(1H-imidazol-5-yl)-1,11-dioxo-4-((tetrahydro-2H-pyran-4- yl)amino)-1,4,4a,5,5a,6,11,12a-octahydrotetracene-2-carboxamide, 3,10,12,12a-tetrahydroxy-7-(4-isopropyloxazol-2-yl)-1,11-dioxo-4-((tetrahydro-2H-pyran-4- yl)amino)-144a55a61112a-octahydrotetracene-2-carboxamide3,10,12-trihydroxy-7-(4-isopropyloxazol-2-yl)-1,11-dioxo-4-((tetrahydro-2H-pyran-4- yl)amino)-1,4,4a,5,5a,6,11,12a-octahydrotetracene-2-carboxamide, 3,10,12,12a-tetrahydroxy-7-(3-isopropyl-1,2,4-oxadiazol-5-yl)-1,11-dioxo-4-((tetrahydro-2H- pyran-4-yl)amino)-1,4,4a,5,5a,6,11,12a-octahydrotetracene-2-carboxamide, 3,10,12,12a-tetrahydroxy-7-(3-isopropylisoxazol-5-yl)-1,11-dioxo-4-(2-oxa-6- azaspiro[3.3]heptan-6-yl)-1,4,4a,5,5a,6,11,12a-octahydrotetracene-2-carboxamide, 4-(3,3-dimethylazetidin-1-yl)-3,10,12,12a-tetrahydroxy-7-(3-isopropylisoxazol-5-yl)-1,11- dioxo-1,4,4a,5,5a,6,11,12a-octahydrotetracene-2-carboxamide, 3,10,12,12a-tetrahydroxy-4-(4-methoxypiperidin-1-yl)-1,11-dioxo-7-(pyrrolidin-1-yl)- 1,4,4a,5,5a,6,11,12a-octahydrotetracene-2-carboxamide, 3,10,12,12a-tetrahydroxy-7-(4-isopropyloxazol-2-yl)-4-(4-methoxypiperidin-1-yl)-1,11- dioxo-1,4,4a,5,5a,6,11,12a-octahydrotetracene-2-carboxamide, 3,10,12,12a-tetrahydroxy-7-(3-isopropyl-1,2,4-oxadiazol-5-yl)-4-(4-methoxypiperidin-1-yl)- 1,11-dioxo-1,4,4a,5,5a,6,11,12a-octahydrotetracene-2-carboxamide, 3,10,12,12a-tetrahydroxy-4-(4-methoxypiperidin-1-yl)-1,11-dioxo-7-(1H-pyrazol-5-yl)- 1,4,4a,5,5a,6,11,12a-octahydrotetracene-2-carboxamide, 4-(dimethylamino)-3,10,12,12a-tetrahydroxy-1,11-dioxo-7-(1H-pyrazol-5-yl)- 1,4,4a,5,5a,6,11,12a-octahydrotetracene-2-carboxamide, 7-cyclopentyl-3,10,12,12a-tetrahydroxy-1,11-dioxo-4-((tetrahydro-2H-pyran-4-yl)amino)- 1,4,4a,5,5a,6,11,12a-octahydrotetracene-2-carboxamide, 7-cyclobutyl-3,10,12,12a-tetrahydroxy-1,11-dioxo-4-((tetrahydro-2H-pyran-4-yl)amino)- 1,4,4a,5,5a,6,11,12a-octahydrotetracene-2-carboxamide, 7-(dimethylamino)-3,10,12,12a-tetrahydroxy-1,11-dioxo-4-((tetrahydro-2H-pyran-4- yl)amino)-1,4,4a,5,5a,6,11,12a-octahydrotetracene-2-carboxamide, 3,10,12,12a-tetrahydroxy-1,11-dioxo-7-(pyrrolidin-1-yl)-4-(2-oxa-6-azaspiro[3.3]heptan-6- yl)-1,4,4a,5,5a,6,11,12a-octahydrotetracene-2-carboxamide, 7-(3,3-dimethylcyclobutyl)-3,10,11,12a-tetrahydroxy-1,12-dioxo-4-((tetrahydro-2H-pyran-4- yl)amino)-1,4,4a,5,5a,6,12,12a-octahydrotetracene-2-carboxamide, 7-(3,3-dimethylcyclobutyl)-3,10,11,12a-tetrahydroxy-4-morpholino-1,12-dioxo- 1,4,4a,5,5a,6,12,12a-octahydrotetracene-2-carboxamide, 4-((2-oxaspiro[3.3]heptan-6-yl)amino)-3,10,12,12a-tetrahydroxy-1,11-dioxo-7-(pyrrolidin-1- yl)-1,4,4a,5,5a,6,11,12a-octahydrotetracene-2-carboxamide, 3,10,12,12a-tetrahydroxy-4-(methyl(2-oxaspiro[3.3]heptan-6-yl)amino)-1,11-dioxo-7- (pyrrolidin-1-yl)-144a55a61112a-octahydrotetracene-2-carboxamide4-((1,1-dioxidotetrahydro-2H-thiopyran-4-yl)amino)-3,10,12,12a-tetrahydroxy-1,11-dioxo-7- (pyrrolidin-1-yl)-1,4,4a,5,5a,6,11,12a-octahydrotetracene-2-carboxamide, 4-((2-oxaspiro[3.3]heptan-6-yl)amino)-3,10,12,12a-tetrahydroxy-7-(3-isopropylisoxazol-5- yl)-1,11-dioxo-1,4,4a,5,5a,6,11,12a-octahydrotetracene-2-carboxamide, 4-((1,1-dioxidotetrahydro-2H-thiopyran-4-yl)amino)-3,10,12,12a-tetrahydroxy-7-(3- isopropylisoxazol-5-yl)-1,11-dioxo-1,4,4a,5,5a,6,11,12a-octahydrotetracene-2-carboxamide, 4-((3-cyano-3-methylcyclobutyl)amino)-3,10,12,12a-tetrahydroxy-7-(4-isopropyloxazol-2- yl)-1,11-dioxo-1,4,4a,5,5a,6,11,12a-octahydrotetracene-2-carboxamide, 7-cyclopentyl-4-((1-(2,2-difluoroethyl)piperidin-4-yl)amino)-3,10,12,12a-tetrahydroxy-1,11- dioxo-1,4,4a,5,5a,6,11,12a-octahydrotetracene-2-carboxamide, 4-((1-(2,2-difluoroethyl)piperidin-4-yl)amino)-3,10,12,12a-tetrahydroxy-7-(3- isopropylisoxazol-5-yl)-1,11-dioxo-1,4,4a,5,5a,6,11,12a-octahydrotetracene-2-carboxamide, 4-((3,3-difluorocyclobutyl)amino)-3,10,12,12a-tetrahydroxy-7-(3-isopropylisoxazol-5-yl)- 1,11-dioxo-1,4,4a,5,5a,6,11,12a-octahydrotetracene-2-carboxamide, 4-((2-oxaspiro[3.3]heptan-6-yl)amino)-3,10,12,12a-tetrahydroxy-1,11-dioxo- 1,4,4a,5,5a,6,11,12a-octahydrotetracene-2-carboxamide, 3,10,12,12a-tetrahydroxy-4-(methyl(2-oxaspiro[3.3]heptan-6-yl)amino)-1,11-dioxo- 1,4,4a,5,5a,6,11,12a-octahydrotetracene-2-carboxamide, 4-((1,1-dioxidotetrahydro-2H-thiopyran-4-yl)amino)-3,10,12,12a-tetrahydroxy-1,11-dioxo- 1,4,4a,5,5a,6,11,12a-octahydrotetracene-2-carboxamide, 4-((1,1-dioxidotetrahydro-2H-thiopyran-4-yl)(methyl)amino)-3,10,12,12a-tetrahydroxy-1,11- dioxo-1,4,4a,5,5a,6,11,12a-octahydrotetracene-2-carboxamide, 4-((3-cyano-3-methylcyclobutyl)amino)-3,10,12,12a-tetrahydroxy-1,11-dioxo- 1,4,4a,5,5a,6,11,12a-octahydrotetracene-2-carboxamide, 4-((1-(2,2-difluoroethyl)piperidin-4-yl)amino)-3,10,12,12a-tetrahydroxy-1,11-dioxo- 1,4,4a,5,5a,6,11,12a-octahydrotetracene-2-carboxamide, 3,10,12,12a-tetrahydroxy-1,11-dioxo-4-(2-oxa-6-azaspiro[3.3]heptan-6-yl)- 1,4,4a,5,5a,6,11,12a-octahydrotetracene-2-carboxamide, 7-(dimethylamino)-3,10,12,12a-tetrahydroxy-1,11-dioxo-4-(2-oxa-6-azaspiro[3.3]heptan-6- yl)-1,4,4a,5,5a,6,11,12a-octahydrotetracene-2-carboxamide, 7-cyclopentyl-3,10,12,12a-tetrahydroxy-4-(methyl(tetrahydro-2H-pyran-4-yl)amino)-1,11- dioxo-1,4,4a,5,5a,6,11,12a-octahydrotetracene-2-carboxamide, 3,10,12,12a-tetrahydroxy-7-isopropyl-1,11-dioxo-4-((tetrahydro-2H-pyran-4-yl)amino)- 144a55a61112a-octahydrotetracene-2-carboxamide3,10,12,12a-tetrahydroxy-7-isopropyl-4-(methyl(tetrahydro-2H-pyran-4-yl)amino)-1,11- dioxo-1,4,4a,5,5a,6,11,12a-octahydrotetracene-2-carboxamide, 3,10,12,12a-tetrahydroxy-4-morpholino-1,11-dioxo-7-propyl-1,4,4a,5,5a,6,11,12a- octahydrotetracene-2-carboxamide, 3,10,12,12a-tetrahydroxy-7-isopropyl-1,11-dioxo-4-(2-oxa-6-azaspiro[3.3]heptan-6-yl)- 1,4,4a,5,5a,6,11,12a-octahydrotetracene-2-carboxamide, 3,10,12,12a-tetrahydroxy-1,11-dioxo-4-((tetrahydro-2H-pyran-4-yl)amino)-7-(1,1,1- trifluoropropan-2-yl)-1,4,4a,5,5a,6,11,12a-octahydrotetracene-2-carboxamide, 3,10,12,12a-tetrahydroxy-4-morpholino-1,11-dioxo-7-(1,1,1-trifluoropropan-2-yl)- 1,4,4a,5,5a,6,11,12a-octahydrotetracene-2-carboxamide, 4-((2-oxaspiro[3.3]heptan-6-yl)amino)-3,10,12,12a-tetrahydroxy-7-isopropyl-1,11-dioxo- 1,4,4a,5,5a,6,11,12a-octahydrotetracene-2-carboxamide, 3,10,12,12a-tetrahydroxy-1,11-dioxo-7-(2-oxopyrrolidin-1-yl)-4-((tetrahydro-2H-pyran-4- yl)amino)-1,4,4a,5,5a,6,11,12a-octahydrotetracene-2-carboxamide, 3,10,12,12a-tetrahydroxy-4-(((3-methyloxetan-3-yl)methyl)amino)-1,11-dioxo- 1,4,4a,5,5a,6,11,12a-octahydrotetracene-2-carboxamide, 3,10,12,12a-tetrahydroxy-4-(methyl((3-methyloxetan-3-yl)methyl)amino)-1,11-dioxo- 1,4,4a,5,5a,6,11,12a-octahydrotetracene-2-carboxamide, 3,10,12,12a-tetrahydroxy-7-isopropyl-4-(methyl(2-oxaspiro[3.3]heptan-6-yl)amino)-1,11- dioxo-1,4,4a,5,5a,6,11,12a-octahydrotetracene-2-carboxamide, 3,10,12,12a-tetrahydroxy-4-morpholino-1,11-dioxo-7-(2-oxopyrrolidin-1-yl)- 1,4,4a,5,5a,6,11,12a-octahydrotetracene-2-carboxamide, 4-((2-oxaspiro[3.3]heptan-6-yl)amino)-3,10,12,12a-tetrahydroxy-1,11-dioxo-7-(2- oxopyrrolidin-1-yl)-1,4,4a,5,5a,6,11,12a-octahydrotetracene-2-carboxamide, 4-((2-oxaspiro[3.3]heptan-6-yl)amino)-3,10,12,12a-tetrahydroxy-7-(4-isopropyloxazol-2-yl)- 1,11-dioxo-1,4,4a,5,5a,6,11,12a-octahydrotetracene-2-carboxamide, 4-(cyclohexylamino)-3,10,12,12a-tetrahydroxy-7-(4-isopropyloxazol-2-yl)-1,11-dioxo- 1,4,4a,5,5a,6,11,12a-octahydrotetracene-2-carboxamide, 4-((3,3-dimethylcyclobutyl)amino)-3,10,12,12a-tetrahydroxy-7-(4-isopropyloxazol-2-yl)- 1,11-dioxo-1,4,4a,5,5a,6,11,12a-octahydrotetracene-2-carboxamide, 3,10,12,12a-tetrahydroxy-1,11-dioxo-4-((tetrahydro-2H-pyran-4-yl)amino)-7- (trifluoromethyl)-1,4,4a,5,5a,6,11,12a-octahydrotetracene-2-carboxamide, 7-fluoro-3,10,12,12a-tetrahydroxy-1,11-dioxo-4-((tetrahydro-2H-pyran-4-yl)amino)- 144a55a61112a-octahydrotetracene-2-carboxamide7-chloro-3,10,12,12a-tetrahydroxy-1,11-dioxo-4-((tetrahydro-2H-pyran-4-yl)amino)- 1,4,4a,5,5a,6,11,12a-octahydrotetracene-2-carboxamide, 3,10,12,12a-tetrahydroxy-1,11-dioxo-4-((2,2,6,6-tetramethyltetrahydro-2H-pyran-4- yl)amino)-1,4,4a,5,5a,6,11,12a-octahydrotetracene-2-carboxamide, 3,10,12,12a-tetrahydroxy-1,11-dioxo-7-(piperidin-1-yl)-4-((tetrahydro-2H-pyran-4- yl)amino)-1,4,4a,5,5a,6,11,12a-octahydrotetracene-2-carboxamide, 3,10,12,12a-tetrahydroxy-7-morpholino-1,11-dioxo-4-((tetrahydro-2H-pyran-4-yl)amino)- 1,4,4a,5,5a,6,11,12a-octahydrotetracene-2-carboxamide, 3,10,11,12a-tetrahydroxy-4-(((1-methyl-1H-pyrazol-4-yl)methyl)amino)-1,12-dioxo- 1,4,4a,5,5a,6,12,12a-octahydrotetracene-2-carboxamide, 3,10,11,12a-tetrahydroxy-4-(((1-methyl-1H-1,2,3-triazol-4-yl)methyl)amino)-1,12-dioxo- 1,4,4a,5,5a,6,12,12a-octahydrotetracene-2-carboxamide, 3,10,12,12a-tetrahydroxy-4-(((1-methyl-1H-pyrazol-4-yl)methyl)amino)-1,11-dioxo-7-(2- oxopyrrolidin-1-yl)-1,4,4a,5,5a,6,11,12a-octahydrotetracene-2-carboxamide, and 3,10,12,12a-tetrahydroxy-7-(1,4-oxazepan-4-yl)-1,11-dioxo-4-((tetrahydro-2H-pyran-4- yl)amino)-1,4,4a,5,5a,6,11,12a-octahydrotetracene-2-carboxamide, or a pharmaceutically acceptable salt thereof.

[0250] In some embodiments, provided is a compound, a tautomer or stereoisomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein the compound is:

[0251] In some embodiments, provided is a compound, a tautomer or stereoisomerthereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein the compound

[0252] In some embodiments, the compound is selected from the group consisting of:(4R,4aS,5aR,12aS)-3,10,12,12a-tetrahydroxy-4-morpholino-1,11-dioxo-1,4,4a,5,5a,6,11,12a- octahydrotetracene-2-carboxamide, (4R,4aS,5aR,12aS)-3,10,12,12a-tetrahydroxy-7-(3-isopropylisoxazol-5-yl)-4-morpholino- 1,11-dioxo-1,4,4a,5,5a,6,11,12a-octahydrotetracene-2-carboxamide, (4R,4aS,12aS)-7-(3-cyclopropylisoxazol-5-yl)-3,10,11,12a-tetrahydroxy-4-morpholino-1,12- dioxo-1,4,4a,5,5a,6,12,12a-octahydrotetracene-2-carboxamide, (4R,4aS,5aR,12aS)-3,10,12,12a-tetrahydroxy-1,11-dioxo-4-((tetrahydro-2H-pyran-4- yl)amino)-1,4,4a,5,5a,6,11,12a-octahydrotetracene-2-carboxamide, (4R,4aS,5aR,12aS)-3,10,11,12a-tetrahydroxy-7-(4-isopropyl-1H-1,2,3-triazol-1-yl)-4- morpholino-1,12-dioxo-1,4,4a,5,5a,6,12,12a-octahydrotetracene-2-carboxamide, (4R,4aS,5aR,12aS)-3,10,12,12a-tetrahydroxy-7-(3-isopropylisoxazol-5-yl)-1,11-dioxo-4- ((tetrahydro-2H-pyran-4-yl)amino)-1,4,4a,5,5a,6,11,12a-octahydrotetracene-2-carboxamide, (4R,4aS,5aR,12aS)-7-(azetidin-1-yl)-3,10,12,12a-tetrahydroxy-1,11-dioxo-4-((tetrahydro- 2H-pyran-4-yl)amino)-1,4,4a,5,5a,6,11,12a-octahydrotetracene-2-carboxamide, (4R,4aS,5aR,12aS)-3,10,12,12a-tetrahydroxy-7-isopropyl-4-(methyl(tetrahydro-2H-pyran-4- yl)amino)-1,11-dioxo-1,4,4a,5,5a,6,11,12a-octahydrotetracene-2-carboxamide, (4R,4aS,5aR,12aS)-3,10,12,12a-tetrahydroxy-4-morpholino-1,11-dioxo-7-propyl- 1,4,4a,5,5a,6,11,12a-octahydrotetracene-2-carboxamide, and (4R,4aS,5aR,12aS)-3,10,12,12a-tetrahydroxy-7-isopropyl-1,11-dioxo-4-(2-oxa-6- azaspiro[3.3]heptan-6-yl)-1,4,4a,5,5a,6,11,12a-octahydrotetracene-2-carboxamide, or a pharmaceutically acceptable salt thereof.

[0253] In some embodiments, the compound is selected from the group consisting of: 3,10,12,12a-tetrahydroxy-4-morpholino-1,11-dioxo-1,4,4a,5,5a,6,11,12a-octahydrotetracene- 2-carboxamide, 3,10,12,12a-tetrahydroxy-7-(3-isopropylisoxazol-5-yl)-4-morpholino-1,11-dioxo- 1,4,4a,5,5a,6,11,12a-octahydrotetracene-2-carboxamide, 7-(3-cyclopropylisoxazol-5-yl)-3,10,11,12a-tetrahydroxy-4-morpholino-1,12-dioxo- 1,4,4a,5,5a,6,12,12a-octahydrotetracene-2-carboxamide, 3,10,12,12a-tetrahydroxy-1,11-dioxo-4-((tetrahydro-2H-pyran-4-yl)amino)- 1,4,4a,5,5a,6,11,12a-octahydrotetracene-2-carboxamide, 3,10,11,12a-tetrahydroxy-7-(4-isopropyl-1H-1,2,3-triazol-1-yl)-4-morpholino-1,12-dioxo- 1,4,4a,5,5a,6,12,12a-octahydrotetracene-2-carboxamide,3,10,12,12a-tetrahydroxy-7-(3-isopropylisoxazol-5-yl)-1,11-dioxo-4-((tetrahydro-2H-pyran- 4-yl)amino)-1,4,4a,5,5a,6,11,12a-octahydrotetracene-2-carboxamide, 7-(azetidin-1-yl)-3,10,12,12a-tetrahydroxy-1,11-dioxo-4-((tetrahydro-2H-pyran-4-yl)amino)- 1,4,4a,5,5a,6,11,12a-octahydrotetracene-2-carboxamide, 3,10,12,12a-tetrahydroxy-7-isopropyl-4-(methyl(tetrahydro-2H-pyran-4-yl)amino)-1,11- dioxo-1,4,4a,5,5a,6,11,12a-octahydrotetracene-2-carboxamide, 3,10,12,12a-tetrahydroxy-4-morpholino-1,11-dioxo-7-propyl-1,4,4a,5,5a,6,11,12a- octahydrotetracene-2-carboxamide, and 3,10,12,12a-tetrahydroxy-7-isopropyl-1,11-dioxo-4-(2-oxa-6-azaspiro[3.3]heptan-6-yl)- 1,4,4a,5,5a,6,11,12a-octahydrotetracene-2-carboxamide, or a pharmaceutically acceptable salt thereof.

[0254] The term “pharmaceutically acceptable salts” includes salts of the active compounds prepared with relatively nontoxic acids or bases, depending on the particular substituents found on the compounds described herein. In some embodiments, the salt is a chloride salt. In other embodiments, the salt is an acetate salt. Pharmaceutical Compositions

[0255] In certain aspects, provided is a pharmaceutical composition comprising any of the compounds, or pharmaceutically acceptable salts thereof, or compositions, including pharmaceutical compositions, described herein; and at least one pharmaceutically acceptable excipient. Such compounds include the compounds of Formula (I-a), (I-b), (II), (III), (IV-a), (IV-b), (V-a), and (V-b), as well as the compounds of Tables 1A and 1B, or pharmaceutically acceptable salts thereof.

[0256] The term “pharmaceutically acceptable excipient” infers that the excipient is not biologically or otherwise undesirable; for example, the material may be added to a pharmaceutical composition and administered to a subject without causing significant undesirable effects.

[0257] The compounds or pharmaceutical compositions of the present disclosure may be administered by various methods including, for example, oral, rectal, buccal, intranasal, and transdermal routes. In certain embodiments, the pharmaceutical composition may be administered intravenously, intraperitoneally, parenterally, intramuscularly, subcutaneously, orally, topically, or as an inhalant.

[0258] Compounds and pharmaceutical compositions of the present disclosure may be administered to individuals in any form of generally accepted oral compositions (for example, tablets, coated tablets, gel capsules in a hard or in soft shell, emulsions or suspensions). Methods of Treatment

[0259] In certain aspects, provided is a method of treating a disease or condition in a subject in need thereof, comprising administering a therapeutically effective amount of any of the compounds, or pharmaceutically acceptable salts thereof, or compositions, including pharmaceutical compositions, described herein. In some embodiments, such compounds include the compounds of Formula (I-a), (I-b), (II), (III), (IV-a), (IV-b), (V-a), and (V-b), as well as the compounds of Tables 1A and 1B, or pharmaceutically acceptable salts thereof. In certain embodiments, such compounds include one or more of the synthetic intermediates provided in the Examples below.

[0260] In some embodiments, the subject is a human.

[0261] In some embodiments, the compounds provided herein lack significant antibiotic activity. In some variations, the compounds have a minimal effect on the growth of bacteria normally sensitive to minocycline and / or sancycline antibiotics. The present compounds that lack antibiotic activity will have less than 50%, and in some variations, less than 10% of the antibacterial activity of a related tetracycline antibiotic, as measured in a standard MIC assay. In certain embodiments, the compounds are substantially not antibiotic, which refers to a compound having little or no antibiotic activity at suitable concentrations as measured in standard antibiotic sensitivity tests using cultured microorganisms such as E. coli S. aureus, etc. In some variations, the compounds have less than 10%, less than 5%, or less than 1% antibiotic activity at suitable concentrations as measured in standard antibiotic sensitivity tests using cultured microorganisms such as E. coli S. aureus, etc. In some embodiments, compounds provided herein are suitable for treating non-infective indications.

[0262] In some variations, certain compounds provided herein are suitable for use in treatment of peripheral indications, and such compounds may not have a favorable capacity to cross the blood brain barrier.

[0263] In other variations, other certain compounds provided herein are suitable for use in treatment of central nervous system indications, and such compounds have a favorable capacity to cross the blood brain barrier.

[0264] In some embodiments, compounds provided herein inhibit translation activity in cells, such as eukaryotic cells or neuron cells. In some embodiments, compounds provided herein are eukaryotic translation inhibitor. In some embodiments, the compounds specifically inhibit polysomal translation. In some embodiments, the compounds are polysomal translational inhibitor. In some embodiments, the compounds lack significant antibiotic activity and are suitable for treating non-infective indications.

[0265] In some embodiments, the compounds are suitable for treating disease or disorder associated with excess translation activity in cells, such as excess translation in neurons. In some embodiments, the disease or condition is Rheumatoid Arthritis, Inflammatory Bowel Disease, Epilepsy, Acute Ischemic Stroke, Traumatic Brain Injury, Neuropathic Pain, Fragile X Syndrome, Anti-psychotic-induced Hyperphagia, Prader-Willi Syndrome, Parkinson’s Disease, Huntington’s Disease, Amyotrophic Lateral Sclerosis, Alzheimer’s Disease, Multiple Sclerosis, Spinal Cord Injury, Diabetic Macular Edema, Dermatitis, Periodonitis, Osteoporosis, Atherosclerosis, Oncology / Cancer, Malaria, HIV, Light-Chain Amyloidosis, Transthyretin Amyloidosis, Schizophrenia, Bipolar Disorder, or Depression. In some embodiments, the disease or condition is Fragile X Syndrome (FXS). In some embodiments, compounds provided herein are capable of reversing FXS behavioral phenotypes. In some embodiments, the disease or condition is epilepsy. In some embodiments, the compounds provided herein exhibit high brain exposure (e.g., stronger central nervous system effect) and are suitable for treating seizure and / or epilepsy. In some embodiments, the epilepsy is pharmacoresistant epilepsy, such as pharmacoresistant temporal lobe epilepsy and Infection- induced epilepsy.

[0266] In some embodiments, provided herein is a method of treating a disease or disorder associated with excess translation activity in cells, such as excess translation in neurons, wherein the method comprises administering to a subject in need thereof a therapeutically effective amount of one of more of the following compounds or apharmaceutically acceptable salt thereof:some embodiments, the disease or disorder is Fragile X Syndrome (FXS). In some embodiments, the disease or disorder is Rheumatoid Arthritis. In some embodiments, the disease or disorder is Alzheimer’s Disease.

[0267] In some embodiments, provided herein is a method of treating a disease ordisorder associated with excess translation activity in cells, such as excess translation in neurons, wherein the method comprises administering to a subject in need thereof a therapeutically effective amount of one of more of the following compounds or a pharmaceutically acceptable salt thereof:, ,, , ,. In some embodiments, the disease or disorder is Fragile X Syndrome (FXS). In some embodiments, the disease or disorder is Rheumatoid Arthritis. In some embodiments, the disease or disorder is Alzheimer’s Disease.

[0268] In some variations, the term “therapeutically effective” applied to dose or amountrefers to that quantity of a compound or pharmaceutical formulation, such as those described elsewhere herein, that is sufficient to result in a desired clinical benefit after administration to a patient in need thereof. It is to be understood that an effective amount may be in one or more doses, e.g., a single dose or multiple doses may be needed to achieve the desired treatment endpoint.

[0269] The specific safe and effective amount or therapeutically effective amount willvary with such factors as the particular condition being treated, the physical condition of the subject, the duration of the treatment, the nature of concurrent therapy (if any), and the specific formulations employed and the structure of the compounds or its derivatives.

[0270] The terms “treating” or “treatment”, as used herein, refer to a method or procedurefor obtaining beneficial or desired results—for example, clinical results. Beneficial or desired results may include: (1) alleviating one or more symptoms caused by or associated with a disease, disorder, or condition; (2) reducing the extent of the disease, disorder, or condition; (3) slowing or stopping the development or progression of one or more symptoms caused by or associated with the disease, disorder, or condition (for example, stabilizing the disease, disorder, or condition); and (4) relieving the disease, for example, by causing the regression of one or more clinical symptoms (e.g., ameliorating the disease state, enhancing the effect of another medication, delaying or stopping the progression of the disease, increasing the quality of life, and / or prolonging survival rates).

[0271] In some embodiments, the treatments described herein is effective to ameliorate one or more symptoms of Fragile X Syndrome (FXS) in a patient. For example, treatment with a therapeutically effective amount of the compounds described herein is effective to improve hyperactivity, anxiety, hippocampal dependent activity of daily living, cognition, social memory, stereotype, and / or aggression. In some embodiments, the treatments described herein is effective to ameliorate one or more symptoms of Rheumatoid Arthritis in a patient. For example, treatment with a therapeutically effective amount of the compounds described herein is effective to improve arthritis lesion, clinical score, and or pathology result.

[0272] In some embodiments, provided herein is the use of a compound or a pharmaceutical composition, as described elsewhere herein, in any of the methods described elsewhere herein. In other embodiments, provided herein is a compound or a pharmaceutical composition, as described elsewhere herein, for use in the manufacture of a medicament for use in any of the methods described elsewhere herein. In other embodiments, provided herein is a compound or a pharmaceutical composition, as described elsewhere herein, for use in any of the methods described herein.

[0273] In certain aspects, articles of manufacture are also provided herein, wherein the article of manufacture comprises any of the compounds, or pharmaceutically acceptable salts thereof, or compositions, including pharmaceutical compositions, described herein, in a suitable container. The container may be a vial, jar, ampoule, preloaded syringe, or intravenous bag.

[0274] The present disclosure further provides kits for carrying out the methods of the invention. The kits may comprise any of the compounds, or pharmaceutically acceptable salts thereof, or compositions, including pharmaceutical compositions, described herein, and suitable packaging. The kits may comprise one or more containers comprising any compound described herein. In one aspect, a kit includes a compound of the disclosure or a pharmaceutically acceptable salt thereof, and a label and / or instructions for use of the compound in the treatment of a disease or condition described herein. The kits may comprise a unit dosage form of the compound.

[0275] In certain aspects, provided herein are articles of manufacturing (such as kits), comprising: (i) an effective amount of any of the compounds, or pharmaceutically acceptablesalts thereof, or compositions, including pharmaceutical compositions, described herein; and (ii) instructions for use in treating a disease or condition described herein. EXAMPLES

[0276] The presently disclosed subject matter will be better understood by reference to the following Examples, which are provided as exemplary of the invention, and not by way of limitation. It is to be understood that Examples 1A-48A provide exemplary synthesis and characterization of compounds or free base thereof disclosed in Table 1A and Examples 1B- 238B provide exemplary synthesis and characterization of compounds or free base thereof disclosed in Table 1B. Example 1A: Synthesis and Characterization of (4aS,5aR,12aS)-3,10,12,12a- tetrahydroxy-1,11-dioxo-7-pyridazin-3-yl-4a,5,5a,6-tetrahydro-4H-tetracene-2- carboxamide

[0277] The solution of (4S,4aS,5aR,12aS)-4-(dimethylamino)-3,10,12,12a-tetrahydroxy- 1,11-dioxo-4a,5,5a,6-tetrahydro-4H-tetracene-2-carboxamide (1.0 eq) and MeI (10 eq) in acetone was stirred at 30°C for 48 hours. The reaction mixture was concentrated under reduced pressure. The crude product was triturated with acetone / petrol ether (1:1). (1S,4aS,11aR,12aS)-3-carbamoyl-2,4a,5,7-tetrahydroxy-N,N,N-trimethyl-4,6-dioxo- 1,4,4a,6,11,11a,12,12a-octahydrotetracen-1-aminium iodide (74.5% yield) was obtained as a yellow solid.1H NMR (400 MHz, DMSO-d6): δ 15.01 (s, 1H), 11.50 (s, 1H), 9.70-9.20 (m, 2H), 7.72 (s, 1H), 7.50-7.43 (m, 1H), 6.88-6.79 (m, 2H), 2.89-2.56 (m, 2H), 4.39 (s, 1H), 3.50 (s, 9H), 3.25-2.90 (m, 4H), 2.85-2.70 (m, 1H), 2.30-2.10 (m, 1 H), 1.60-1.35 (m, 1 H).

[0278] The solution of (1S,4aS,11aR,12aS)-3-carbamoyl-2,4a,5,7-tetrahydroxy-N,N,N- trimethyl-4,6-dioxo-1,4,4a,6,11,11a,12,12a-octahydrotetracen-1-aminium iodide (1.0 eq) and Zn (4.1 eq) in HOAc (3 mL) and H2O (3 mL) was stirred at 25°C for 30 min. The reaction mixture was diluted with H2O (15 mL) and filtered, the filtrate was concentrated under reduced pressure. The residue was purified by prep-HPLC. (4aS,5aR,12aS)-3,10,12,12a- tetrahydroxy-1,11-dioxo-4a,5,5a,6-tetrahydro-4H-tetracene-2-carboxamide (15.7% yield) was obtained as a yellow solid. LC-MS (ESI+) m / z: 372.0 [M+H]+.HPLC: 98.5% purity at 254 nm.1H NMR (400 MHz, DMSO-d6): δ 15.02 (s, 1H), 11.58 (s, 1H), 8.95-8.76 (m, 2H), 7.46- 7.40 (m, 1H), 6.82-6.69 (m, 3H), 3.21-3.01 (m, 1H), 2.89-2.56 (m, 2H), 2.45-2.20 (m, 3H), 2.03-1.85 (m, 1H), 1.55-1.30 (m, 1H).

[0279] NIS (1.0 eq) was slowly added to the solution of (4aS,5aR,12aS)-3,10,12,12a- tetrahydroxy-1,11-dioxo-4a,5,5a,6-tetrahydro-4H-tetracene-2-carboxamide (1.0 eq) in TFA (30 mL) at 0oC. The resulting solution was then warmed to 25oC and stirred at 25oC for 16 hours. The reaction solution was diluted with H2O (100 mL) and filtered. The obtained yellow solid was washed with H2O (15 mL x 3) and dried under reduced pressure. (4aS,5aR,12aS)-3,10,12,12a-tetrahydroxy-7-iodo-1,11-dioxo-4a,5,5a,6-tetrahydro-4H- tetracene-2-carboxamide (60.1% yield) was obtained as a yellow solid. LC-MS (ESI+) m / z: 497.9 [M+H]+. HPLC: 99.6% purity at 254 nm.1H NMR (400 MHz, DMSO-d6) δ 14.88 (1H, brs), 11.84 (s, 1H), 9.13-8.71 (m, 2H), 7.89 (d, J = 8.8 Hz, 1H), 6.79-6.63 (m, 2H), 4. 22- 4.00 (m, 1H), 3.13-3.03 (m, 1H), 2.98-2.83 (m, 2H), 2.43-2.30 (m, 3H), 2.09-1.97 (m, 1H), 1.55-1.38 (m, 1H).

[0280] The solution of (4aS,5aR,12aS)-3,10,12,12a-tetrahydroxy-7-iodo-1,11-dioxo- 4a,5,5a,6-tetrahydro-4H-tetracene-2-carboxamide (1.0 eq), Pd(dppf)Cl2 (0.1 eq), tributyl(pyridazin-3-yl)stannane (1.2 eq) and CuI (0.05 eq) in dioxane (3 mL) was stirred at 110oC for 6 hours under N2. The reaction mixture was concentrated under reduced pressure. The residue was purified by prep-HPLC (HCOOH). (4aS,5aR,12aS)-3,10,12,12a- tetrahydroxy-1,11-dioxo-7-pyridazin-3-yl-4a,5,5a,6-tetrahydro-4H-tetracene-2-carboxamide (14.3% yield) was obtained as a yellow solid. LC-MS (ESI+) m / z: 449.9 [M+H]+.1H NMR (400 MHz, DMSO-d6): δ 14.95 (s, 1H), 11.99 (s, 1H), 9.24 (s, 1H), 8.81-8.76 (m, 2H), 7.90- 7.65 (m, 3H), 7.02 (d, J = 8.8 Hz, 1H), 6.71 (s, 1H), 3.21-3.01 (m, 1H), 2.89-2.50 (m, 3H), 2.45-2.20 (m, 2H), 2.03-1.85 (m, 1H), 1.55-1.30 (m, 1H).Example 2A: Synthesis and Characterization of (4aS,5aR,12aS)-3,10,12,12a- tetrahydroxy-1,11-dioxo-7-pyrrolidin-1-yl-4a,5,5a,6-tetrahydro-4H-tetracene-2- carboxamide and (4aS,5aR,12aS)-3,10,12,12a-tetrahydroxy-1,11-dioxo-7-pyrrol-1-yl- 4a,5,5a,6-tetrahydro-4H-tetracene-2-carboxamide

[0281] KNO3 (1.2 eq) was slowly added to the solution of (4aS, 5aR,12aS)-3,10,12,12a- tetrahydroxy-1,11-dioxo-4a,5,5a,6-tetrahydro-4H-tetracene-2-carboxamide (1.0 eq) in H2SO4(40 mL) and MeOH (10 mL) at 0oC. The reaction mixture was stirred at 0oC for 3 hours. The reaction mixture was diluted with H2O (200 mL) and extracted with EtOAc (100 mL x 3).The combined organic layers were concentrated under reduced pressure. The residue was purified by prep-HPLC. (4aS,5aR,12aS)-3,10,12,12a-tetrahydroxy-7-nitro-1,11-dioxo-4a,5,5a,6- tetrahydro-4H-tetracene-2-carboxamide (7.6% yield) was obtained as a yellow solid. LC-MS (ESI+) m / z: 417.0 (M+H)+.

[0282] The reaction mixture of (4aS,5aR,12aS)-3,10,12,12a-tetrahydroxy-7-nitro-1,11- dioxo-4a,5,5a,6-tetrahydro-4H-tetracene-2-carboxamide (1.0 eq) and Pd(OH)2 (0.1 eq) in dioxane (6 mL) and MeOH (6 mL) with a H2 balloon was stirred at 25oC for 1 hour. The reaction mixture was filtered and concentrated under reduced pressure. The desired product was obtained as a yellow solid (95.8% yield) which was used for the next step without further purification. LC-MS (ESI+) m / z: 387.0 (M+H)+.

[0283] Aqueous H2SO4(2.5 eq) was added to the solution of 2,5- dimethoxytetrahydrofuran (3.0 eq) in THF (1 mL) and MeOH (1 mL) at 0oC. The resulting solution was added to the solution of (4aS,5aR,12aS)-7-amino-3,10,12,12a-tetrahydroxy- 1,11-dioxo-4a,5,5a,6-tetrahydro-4H-tetracene-2-carboxamide (1.0 eq) in THF (1 mL) and MeOH (1 mL) and then NaBH3CN (4.0 eq) was added. The reaction solution was warmed to25oC and stirred at 25oC for 12 h. The reaction was concentrated under reduced pressure. The residue was purified by prep-HPLC to separate the two desired compounds.

[0284] (4aS,5aR,12aS)-3,10,12,12a-tetrahydroxy-1,11-dioxo-7-pyrrolidin-1-yl-4a,5,5a,6- tetrahydro-4H-tetracene-2-carboxamide (3% yield) was obtained as a yellow solid. LC-MS (ESI+) m / z: 441.0 (M+H)+.1H NMR (400 MHz, MeOD) δ 7.75 (d, J = 8.8 Hz, 1H), 7.01 (d, J = 8.8 Hz, 1H), 3.95-3.40 (m, 4H), 3.25-2.15 (m, 2H), 3.05–2.85 (m, 1H), 2.60–2.35 (m, 3H), 2.35–2.20 (m, 4H), 2.20-2.07 (m, 1H), 1.75-1.55 (m, 1H).

[0285] (4aS,5aR,12aS)-3,10,12,12a-tetrahydroxy-1,11-dioxo-7-pyrrol-1-yl-4a,5,5a,6- tetrahydro-4H-tetracene-2-carboxamide (2% yield) was obtained as a yellow solid. LC-MS (ESI+) m / z: 437.0 (M+H)+.1H NMR (400 MHz, MeOD) δ 7.40 (d, J = 8.8 Hz, 1H), 6.89 (d, J = 8.8 Hz, 1H), 6.74 (s, 2H), 6.24 (s, 2H), 2.90-2.70 (m, 1H), 2.50-2.25 (m, 4H), 2.08-1.80 (m, 2H), 1.60-1.42 (m, 1H). Example 3A: Synthesis and Characterization of (4aS,5aR,12aS)-3,10,12,12a- tetrahydroxy-1,11-dioxo-7-(1H-pyrazol-4-yl)-4a,5,5a,6-tetrahydro-4H-tetracene-2- carboxamide

[0286] To a solution of (4aS,5aR,12aS)-3,10,12,12a-tetrahydroxy-7-iodo-1,11-dioxo- 4a,5,5a,6-tetrahydro-4H-tetracene-2-carboxamide (1 eq.) in dioxane (2 mL) and H2O (0.2 mL) was added 1H-pyrazol-4-ylboronic acid (2 eq.), Xantphos-Pd-G3 (0.125 eq.) and K3PO4(3 eq.). The mixture was degassed and purged with N2three times. The mixture was stirred at 60oC for 3 h under N2 atmosphere. The reaction mixture was concentrated under reduced pressure to give a residue. It was purified by prep-HPLC. Most of CH3CN was removed under reduced pressure, the remaining solvent was removed by lyophilization to give (4aS,5aR,12aS)-3,10,12,12a-tetrahydroxy-1,11-dioxo-7-(1H-pyrazol-4-yl)-4a,5,5a,6- tetrahydro-4H-tetracene-2-carboxamide (7% yield) as a yellow solid. LC-MS (ESI+) m / z: 438.0 (M+H)+.1H NMR (500 MHz, CD3CN) δ 14.85 (1H, brs), 11.85 - 12.03 (1H, m), 9.01(1H, brs), 7.78 (2H, brs), 7.52 (1H, brd, J = 8.1 Hz), 6.90 (1H, brd, J = 8.4 Hz), 6.79 (1H, brs), 3.13 - 3.24 (1H, m), 2.97 (1H, brd, J = 16.0 Hz), 2.75 - 2.88 (2H, m), 2.54 (2H, brd, J = 15.6 Hz), 2.46 (2H, brs), 1.98 (2H, brs), 1.55 - 1.61 (1H, m). Example 4A: Synthesis and Characterization of (4aS,5aR,12aS)-3,10,12,12a- tetrahydroxy-1,11-dioxo-7-(1H-pyrazol-3-yl)-4a,5,5a,6-tetrahydro-4H-tetracene-2- carboxamide

[0287] To a solution of (4aS,5aR,12aS)-3,10,12,12a-tetrahydroxy-7-iodo-1,11-dioxo- 4a,5,5a,6-tetrahydro-4H-tetracene-2-carboxamide (1 eq.) in dioxane (2 mL) and H2O (0.2 mL) was added 1H-pyrazol-3-ylboronic acid (2 eq.), Xantphos-Pd-G3 and K3PO4 (3 eq.). The mixture was degassed and purged with N2three times. The mixture was stirred at 60oC for 3 h under N2atmosphere. The reaction mixture was concentrated under reduced pressure to give a residue. It was purified by prep-HPLC. Most of CH3CN was removed under reduced pressure, the remaining solvent was removed by lyophilization to give (4aS,5aR,12aS)- 3,10,12,12a-tetrahydroxy-1,11-dioxo-7-(1H-pyrazol-3-yl)-4a,5,5a,6-tetrahydro-4H-tetracene- 2-carboxamide (5% yield) as a yellow solid. LC-MS (ESI+) m / z: 438.0 (M+H)+.1H NMR (400 MHz, CD3CN) δ 14.83 (s, 1H), 12.03 (brs, 1H), 8.99 (brs, 1H), 7.86 (brs, 1H), 7.60 (d, J = 8.4 Hz, 1H), 6.89 (d, J = 8.4 Hz, 1H), 6.78 (brs, 1H), 6.51 (brs, 1H), 3.18 (dd, J = 18.4, 5.6 Hz, 1H), 3.00 (dd, J = 15.6, 4.4 Hz, 1H), 2.80 (dt, J = 9.2, 4.67 Hz, 2H), 2.62-2.58 (2H, m), 2.12 (brs, 2H), 1.88-1.62 (m, 2H), 1.57-1.49 (m, 1H). Example 5A: Synthesis and Characterization of (12aS)-3,10,12,12a-tetrahydroxy-7-(1- methylpyrazol-4-yl)-1,11-dioxo-4a,5,5a,6-tetrahydro-4H-tetracene-2-carboxamide

[0288] A mixture of (12aS)-3,10,12,12a-tetrahydroxy-7-iodo-1,11-dioxo-4a,5,5a,6- tetrahydro-4H-tetracene-2-carboxamide (1.0 eq.), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)pyrazole (2.0 eq.), K3PO4 (2.5 eq.), XantPhos-Pd-G3 (0.1 eq.) in dioxane (60 mL) and H2O (30 mL) was degassed and purged with N23 times, then the mixture was stirred at 70°C for 4 hour under N2atmosphere. The reaction mixture was concentrated under reduced pressure. The residue was purified by reversed phase column to remove the catalyst, followed by prep-HPLC. (12aS)-3,10,12,12a-tetrahydroxy-7-(1-methylpyrazol-4-yl)-1,11- dioxo-4a,5,5a,6-tetrahydro-4H-tetracene-2-carboxamide (28% yield) was obtained as a yellow solid. LC-MS (ESI+) m / z: 452.2 (M+H)+.1H NMR (400MHz, MeOD) δ 1.48 - 1.68 (m, 1 H), 1.91 - 2.04 (m, 1 H), 2.31 - 2.55 (m, 3 H), 2.71 - 2.88 (m, 1 H), 2.96 - 3.09 (m, 1 H), 3.19 - 3.30 (m, 1 H), 3.91 - 4.09 (m, 3 H), 6.76 - 6.94 (m, 1 H), 7.39 - 7.52 (m, 1 H), 7.59 - 7.69 (m, 1 H), 7.74 - 7.85 (m, 1 H). Example 6A: Synthesis and Characterization of (4aS,5aR,12aS)-3,10,12,12a- tetrahydroxy-7-(1-methylpyrazol-3-yl)-1,11-dioxo-4a,5,5a,6-tetrahydro-4H-tetracene-2- carboxamide

[0289] To a solution of (4aS,5aR,12aS)-3,10,12,12a-tetrahydroxy-7-iodo-1,11-dioxo- 4a,5,5a,6-tetrahydro-4H-tetracene-2-carboxamide (1 eq.) in H2O (0.1 mL) and dioxane (1 mL) was added 1-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazole (1.5 eq.), Xantphos-Pd-G3 (0.125 eq.) and K3PO4 (3.0 eq.). The mixture was degassed and purged with N2 three times. The mixture was stirred at 60oC for 5 h under N2 atmosphere. The reaction mixture was concentrated under reduced pressure to give a residue. It was purified by prep- HPLC. Most of CH3CN was removed under reduced pressure, and the remaining solvent was removed by lyophilization to give (4aS,5aR,12aS)-3,10,12,12a-tetrahydroxy-7-(1- methylpyrazol-3-yl)-1,11-dioxo-4a,5,5a,6-tetrahydro-4H-tetracene-2-carboxamide (16% yield) as a yellow solid. LC-MS (ESI+) m / z: 452.0 (M+H)+.1H NMR (400 MHz, CD3CN) δ 14.79 (brs, 1H), 12.06 (brs, 1H), 8.97 (brs, 1H), 7.75 (s, 1H), 7.68 (d, J = 8.4 Hz, 1H), 6.91 (d J = 88 Hz 1H) 681 (brs 1H) 648 (s 1H) 407 (s 3H) 317 (d J = 160 Hz 1H) 305(dd, J = 16.0, 4.0 Hz, 1H), 2.95-2.74 (m, 1H), 2.62 (brs, 2H), 2.57-2.55 (m, 2H), 2.09-1.97 (m, 2H), 1.64-1.49 (m, 1H), Example 7A: Synthesis and Characterization of (4aS, 5aR, 12aS)-3,10,12,12a- tetrahydroxy-1,11-dioxo-7-pyridazin-4-yl-4a,5,5a,6-tetrahydro-4H-tetracene-2- carboxamide

[0290] To a solution of (4aS,5aR,12aS)-3,10,12,12a-tetrahydroxy-7-iodo-1,11-dioxo- 4a,5,5a,6-tetrahydro-4H-tetracene-2-carboxamide (1 eq.), 4-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)pyridazine (1.5 eq.) and XantPhos-Pd-G3 in dioxane (2 mL) and Water (0.2 mL) at 20°C was added K3PO4(3 eq.), and the mixture was purged and degassed with N2three times and then stirred at 80°C for 16 h. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC. (4aS, 5aR, 12aS)-3,10,12,12a-tetrahydroxy-1,11-dioxo-7-pyridazin-4-yl-4a,5,5a,6-tetrahydro-4H- tetracene-2-carboxamide (12% yield) was obtained as a yellow solid. LC-MS (ESI+) m / z: 450.0 (M+H)+.1H NMR (400 MHz, DMSO-d6): δ 14.93 (br s, 1H), 11.95 (s, 1H), 9.32 - 9.09 (m, 2H), 9.02 - 8.65 (m, 2H), 7.69 (dd, J = 2.54, 5.2 Hz, 1H), 7.58 (d, J = 8.4 Hz, 1H), 7.00 (d, J = 8.4 Hz, 1H), 6.84 - 6.57 (m, 1H), 2.78 - 2.65 (m, 2H), 2.57 (br d, J = 11.2 Hz, 2H), 2.39 - 2.26 (m, 2H), 1.90 (br d, J = 12.4 Hz, 1H), 1.47 - 1.33 (m, 1H). Example 8A: Synthesis and Characterization of (4aS,5aR,12aS)-7-cyclobutyl- 3,10,12,12a-tetrahydroxy-1,11-dioxo-4a,5,5a,6-tetrahydro-4H-tetracene-2-carboxamide

[0291] InCl3(1.2 eq) was dried at 120oC under reduced pressure before bromo(cyclobutyl)magnesium (0.5M in THF, 3.6 eq) was added slowly at -78oC. The resulting solution was stirred at -78oC for 15 min and warmed to 25oC. The solution was stirred at 25oC for 15 min, then (4aS,5aR,12aS)-3,10,12,12a-tetrahydroxy-7-iodo-1,11-dioxo- 4a,5,5a,6-tetrahydro-4H-tetracene-2-carboxamide (1.0 eq) and Pd[P(t-Bu)3]2(0.1 eq) was added. The reaction mixture was stirred at 70oC for 2 hours. The reaction mixture was quenched by H2O (2 mL) and concentrated under reduced pressure. The residue was purified by prep-HPLC and further purified by SFC (column: DAICEL CHIRALCEL OD- H(250mm*30mm,5um);mobile phase: [0.1%NH3H2O ETOH];B%: 30%-30%,min). (4aS,5aR,12aS)-7-cyclobutyl-3,10,12,12a-tetrahydroxy-1,11-dioxo-4a,5,5a,6-tetrahydro-4H- tetracene-2-carboxamide (7% yield) was obtained as a yellow solid LC-MS (ESI+) m / z: 426.0 [M+H]+.1H NMR (400 MHz, DMSO-d6): δ 14.94 (s, 1H), 11.61 (s, 1H), 8.99-8.76 (m, 2H), 7.41(d, J = 8.8 Hz, 1H), 6.80 (d, J = 8.8 Hz, 1H), 6.71 (s, 1H), 3.60-3.45 (m, 1H), 3.25-3.01 (m, 1H), 2.95-2.60 (m, 3H), 2.45-2.10 (m, 5H), 2.05-1.80 (m, 3H), 1.80-1.65 (m, 1H), 1.60- 1.31 (m, 1H). Example 9A: Synthesis and Characterization of (4aS,5aR,12aS)-7-cyclopropyl- 3,10,12,12a-tetrahydroxy-1,11-dioxo-4a,5,5a,6-tetrahydro-4H-tetracene-2-carboxamide

[0292] InCl3 (1.2 eq) was dried at 120oC under reduced pressure before bromo(cyclopropyl)magnesium (0.5M in THF, 1.2 eq) was slowly added at -78oC. The resulting solution was stirred at -78oC for 15 min, then warmed to 25oC and stirred at 25oC for 15 min. (4aS,5aR,12aS)-3,10,12,12a-tetrahydroxy-7-iodo-1,11-dioxo-4a,5,5a,6- tetrahydro-4H-tetracene-2-carboxamide (1.0 eq) and Pd[P(t-Bu)3]2(0.2 eq) was added. The resulting solution was stirred at 70oC for 2 hours. The reaction mixture was quenched by H2O (0.5 mL) and concentrated under reduced pressure. The residue was purified by prep-HPLC and further purified by SFC (column: DAICEL CHIRALCEL OD- H(250mm*30mm,5um);mobile phase: [0.1%NH3H2O ETOH];B%: 40%-40%,min). (4aS,5aR,12aS)-7-cyclopropyl-3,10,12,12a-tetrahydroxy-1,11-dioxo-4a,5,5a,6-tetrahydro-4H-tetracene-2-carboxamide (19% yield) was obtained as a yellow solid. LC-MS (ESI+) m / z: 412.0 [M+H]+.1H NMR (400 MHz, DMSO-d6): δ 14.97 (s, 1H), 11.64 (s, 1H), 8.99-8.76 (m, 2H), 7.22 (d, J = 8.8 Hz, 1H), 6.72 (d, J = 8.8 Hz, 1H), 6.68 (s, 1H), 3.25-3.00 (m, 1H), 2.90- 2.72 (m, 1H), 2.45-2.20 (m, 3H), 2.10-1.95 (m, 1H), 1.85-1.70 (m, 1H), 1.60-1.33 (m, 1H), 0.95-0.65 (m, 2H), 0.65-0.40 (m, 2H). Example 10A: Synthesis and Characterization of (4aS,5aR,12aS)-3,10,12,12a- tetrahydroxy-7-(2-methylpyrazol-3-yl)-1,11-dioxo-4a,5,5a,6-tetrahydro-4H-tetracene-2-

[0293] (4aS,5aR,12aS)-3,10,12,12a-tetrahydroxy-7-iodo-1,11-dioxo-4a,5,5a,6- tetrahydro-4H-tetracene-2-carboxamide (1 eq.), 1-methyl-5-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)pyrazole (2.5 eq.), K3PO4(2.5 eq.), XantPhos-Pd-G3 (0.1 eq.) were added in mixture of dioxane (6 mL) and H2O (2 mL), the reaction mixture was stirred at 80°C for 10 hours under N2. The reaction mixture was concentrated under reduced pressure to removed solvent. The residue was purified by prep-HPLC (HCl condition). (4aS,5aR,12aS)- 3,10,12,12a-tetrahydroxy-7-(2-methylpyrazol-3-yl)-1,11-dioxo-4a,5,5a,6-tetrahydro-4H- tetracene-2-carboxamide (19% yield) was obtained as a yellow solid. LC-MS (ESI+) m / z: 452.0 (M+H)+.1H NMR (400 MHz, DMSO-d6): δ 14.98 (s, 1H), 11.89 (s, 1H), 8.95-8.75 (m, 2H), 7.50-7.43 (m, 2H), 6.98-6.92 (m, 1H), 6.69 (br, 1H), 6.24-6.22 (m, 1H), 3.58 (s, 3H), 3.17-3.05 (m, 1H), 2.82-2.78 (m, 1H), 2.42-2.30 (m, 4H), 1.90-1.88 (m, 1H), 1.42-1.38 (m, 1H). Example 11A: Synthesis and Characterization of (4aS,5aR,12aS)-3,10,12,12a- tetrahydroxy-7-(1-isopropylpyrazol-3-yl)-1,11-dioxo-4a,5,5a,6-tetrahydro-4H-tetracene- 2-carboxamide

[0294] 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (1 eq.) was added in DMF (10 mL), NaH (1.5 eq.) was added in, the reaction mixture was stirred at 25 °C for 30 min, i-PrI (1.2 eq.) was added in, the reaction mixture was stirred at 25°C for 11.5 hours. The reaction mixture was quenched by H2O, diluted with EtOAc (100 mL), washed by H2O (30 mL x 2), brine (30 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to removed solvent.1-isopropyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan- 2-yl)pyrazole (32.9% yield) was obtained as a light yellow solid which was used in next step without further purification.

[0295] (4aS,5aR,12aS)-3,10,12,12a-tetrahydroxy-7-iodo-1,11-dioxo-4a,5,5a,6- tetrahydro-4H-tetracene-2-carboxamide (1 eq.), 1-isopropyl-3-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)pyrazole (1.5 eq.), [2-(2-aminophenyl)phenyl]-methylsulfonyloxy- palladium;(5-diphenylphosphanyl-9,9-dimethyl-xanthen-4-yl)-diphenyl-phosphane (0.1 eq.), K3PO4(2 eq.) were added in mixture of dioxane (6 mL) and H2O (3 mL), the reaction mixture was stirred at 80°C for 12 hours under N2. The reaction mixture was concentrated under reduced pressure to removed solvent. The residue was purified by prep-HPLC (HCl condition). Re-purified by prep-HPLC, (4aS,5aR,12aS)-3,10,12,12a-tetrahydroxy-7-(1- isopropylpyrazol-3-yl)-1,11-dioxo-4a,5,5a,6-tetrahydro-4H-tetracene-2-carboxamide (10% yield) was obtained as a yellow solid. LC-MS (ESI+) m / z: 480.0 (M+H)+.1H NMR (400 MHz, DMSO-d6): δ 14.91 (br, 1H), 11.90 (br, 1H), 8.97-8.78 (m, 2H), 7.81-7.80 (m, 1H), 7.69-7.66 (m, 1H), 6.89-6.86 (m, 1H), 6.67 (br, 1H), 6.37 (s, 1H), 4.55-4.47 (m, 1H), 3.26- 3.20 (m, 1H), 2.75-2.72 (m, 2H), 2.40-2.33 (m, 3H), 1.95-1.92 (m, 1H), 1.47-1.42 (m, 7H).Example 12A: Synthesis and Characterization of (4aS,5aR,12aS)-7-(3,6-dihydro-2H- pyran-4-yl)-3,10,12,12a-tetrahydroxy-1,11-dioxo-4a,5,5a,6-tetrahydro-4H-tetracene-2- carboxamide

[0296] LDA (1.0 M in THF, 14.98 mL, 3.0 eq) was slowly added to a solution of tributylstannane (4.36 g, 14.98 mmol, 3.96 mL, 3.0 eq) in THF (30 mL). The reaction mixutre was cooled to -78oC before tetrahydropyran-4-one (0.50 g, 4.99 mmol, 458.7 uL, 1.0 eq) was added. The reaction mixture was stirred at -78oC for 30 min. Then MeSO2Cl (2.29 g, 19.98 mmol, 1.55 mL, 4.0 eq) and TEA (3.79 g, 37.46 mmol, 5.21 mL, 7.5 eq) was added. The reaction mixture was warmed to 25oC and stirred at 25oC for 20 hours. The reaction mixture was extracted with EtOAc (50 mL x 3). The combined organic layers were concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate=10 / 1 to 5 / 1). Tributyl(3,6-dihydro-2H-pyran-4- yl)stannane (700 mg, 37.5% yield) was obtained as a colorless oil.1H NMR (400 MHz, CDCl3): δ 5.75 (s, 1H), 4.07 (s, 2H), 3.75-3.65 (m, 2H), 2.62 (s, 2H), 1.56-1.10 (m, 13H), 0.95-0.65 (m, 15H).

[0297] A solution of (4aS,5aR,12aS)-3,10,12,12a-tetrahydroxy-7-iodo-1,11-dioxo- 4a,5,5a,6-tetrahydro-4H-tetracene-2-carboxamide (1.0 eq), Pd(dppf)Cl2(0.1 eq), tributyl(3,6- dihydro-2H-pyran-4-yl)stannane (1.2 eq) and CuI (0.05 eq) in DMF (2 mL) was stirred at 70oC for 8 hours. The reaction mixture was quenched by aqueous KF solution (1 M, 10 mL) and extracted with EtOAc. The combined organic layers were concentrated under reduced pressure The residue was purified by prep-HPLC and further separated by SFC (column: DAICEL CHIRALCEL OD-H(250mm*30mm,5um);mobile phase: [0.1%NH3H2O ETOH];B%: 55%-55%,min). (4aS,5aR,12aS)-7-(3,6-dihydro-2H-pyran-4-yl)-3,10,12,12a-tetrahydroxy-1,11-dioxo-4a,5,5a,6-tetrahydro-4H-tetracene-2-carboxamide (7% yield) was obtained as a yellow solid. LC-MS (ESI+) m / z: 454.0 [M+H]+.1H NMR (400 MHz, DMSO- d6): δ 14.85 (s, 1H), 11.72 (s, 1H), 8.96-8.74 (m, 2H), 7.32 (d, J = 8.4 Hz, 1H), 6.81 (d, J = 8.4 Hz, 1H), 6.68 (s, 1H), 5.59 (s, 1H), 4.15 (s, 2H), 3.79 (s, 2H), 3.20-3.00 (m, 1H), 2.90- 2.60 (m, 3H), 2.45-2.21 (m, 4H), 2.15-1.88 (m, 2H), 1.55-1.30 (m, 1H). Example 13A: Synthesis and Characterization of (4aS,5aR,12aS)-3,10,12,12a- tetrahydroxy-1,11-dioxo-7-tetrahydropyran-4-yl-4a,5,5a,6-tetrahydro-4H-tetracene-2- carboxamide

[0298] The reaction of (4aS,5aR,12aS)-7-(3,6-dihydro-2H-pyran-4-yl)-3,10,12,12a- tetrahydroxy-1,11-dioxo-4a,5,5a,6-tetrahydro-4H-tetracene-2-carboxamide (1.0 eq) and Pd / C (0.2 eq) in MeOH (3 mL) and EtOAc (3 mL) with a H2 balloon was stirred at 25oC for 30 min. The reaction mixture was filtered, then the filtrate was concentrated under reduced pressure. The residue was purified by prep-HPLC. (4aS,5aR,12aS)-3,10,12,12a-tetrahydroxy- 1,11-dioxo-7-tetrahydropyran-4-yl-4a,5,5a,6-tetrahydro-4H-tetracene-2-carboxamide (12% yield) was obtained as a yellow solid LC-MS (ESI+) m / z: 456.2 [M+H]+.1H NMR (400 MHz, DMSO-d6): δ 14.91 (s, 1H), 11.80 (s, 1H), 9.00 (s, 1H), 7.46 (d, J = 8.8 Hz, 1H), 6.84-6.81 (m, 2H), 4.05-3.85 (m, 2H), 3.6-3.39 (m, 2H), 3.30-3.10 (m, 2H), 2.55-2.40 (m, 2H), 2.40- 2.25 (m, 1H), 2.15-2.00 (m, 1H), 1.85-1.70 (m, 1H), 1.65-1.40 (m, 4H). Example 14A: Synthesis and Characterization of (4aS,5aR,12aS)-3,10,12,12a- tetrahydroxy-1,11-dioxo-7-(1,2,3,6-tetrahydropyridin-4-yl)-4a,5,5a,6-tetrahydro-4H- tetracene-2-carboxamide

[0299] LDA (4 eq.) was added in THF (100 mL) at 0°C, tributyltin hydride (4 eq.) was added slowly at 0°C, then the reaction mixture was cooled to -78°C, tert-butyl 4- oxopiperidine-1-carboxylate (1 eq.) was added in at -78°C. The reaction was warmed to 25°C, then methanesulfonyl chloride (8 eq.) and TEA were added in the reaction mixture. The reaction mixture was stirred at 25°C for 12 hours. The reaction mixture was quenched by KF (aq), transferred to a separatory funnel with hexane (100 mL) and washed with water (3 × 100 mL) (brine was used to separate emulsions). The combined aqueous layers were extracted with hexane (100 mL) and the combined organic layers were washed with brine (30 mL) and concentrated under reduced pressure. The crude reaction mixture was purified via silica gel column chromatography. Tert-butyl 4-tributylstannyl-3,6-dihydro-2H-pyridine-1- carboxylate (34% yield) was obtained as an off-white oil.

[0300] (4aS,5aR,12aS)-3,10,12,12a-tetrahydroxy-7-iodo-1,11-dioxo-4a,5,5a,6- tetrahydro-4H-tetracene-2-carboxamide (1 eq.), tert-butyl 4-tributylstannyl-3,6-dihydro-2H- pyridine-1-carboxylate (1.2 eq.), Pd(dppf)Cl2 (0.1 eq.), CuI (0.05 eq.) were added in DMF (3 mL) and the reaction mixture was stirred at 70°C for 10 hours under N2. The reaction mixture was concentrated under reduced pressure. The residue was purified by prep-HPLC (HCl). Tert-butyl 4-[(6aS,10aS,11aR)-8-carbamoyl-4,6,6a,9-tetrahydroxy-5,7-dioxo-10a,11,11a,12- tetrahydro-10H-tetracen-1-yl]-3,6-dihydro-2H-pyridine-1-carboxylate (32% yield) was obtained as a yellow solid. LC-MS (ESI+) m / z: 553.0 (M+H)+.

[0301] Tert-butyl 4-[(6aS,10aS,11aR)-8-carbamoyl-4,6,6a,9-tetrahydroxy-5,7-dioxo- 10a,11,11a,12-tetrahydro-10H-tetracen-1-yl]-3,6-dihydro-2H-pyridine-1-carboxylate (1eq.) was added to 4M HCl / MeOH (2 mL) and the reaction was stirred at 25°C for 1 hour. The reaction mixture was concentrated under reduced pressure to removed solvent. The residuewas purified by prep-HPLC (HCl). The HCl salt of (4aS,5aR,12aS)-3,10,12,12a- tetrahydroxy-1,11-dioxo-7-(1,2,3,6-tetrahydropyridin-4-yl)-4a,5,5a,6-tetrahydro-4H- tetracene-2-carboxamide (44% yield) was obtained as a yellow solid. LC-MS (ESI+) m / z: 453.0 (M+H)+.1H NMR (400 MHz, DMSO-d6): δ 13.92 (br, 1H), 9.15 (s, 1H), 8.19 (s, 1H), 7.10-6.66 (m, 2H), 5.48 (s, 1H), 3.65 (s, 2H), 3.01-2.98 (m, 1H), 2.77-2.63 (m, 3H), 2.26- 2.12 (m, 6H), 1.81-1.78 (m, 1H), 1.48-1.44 (m, 1H). Example 15A: Synthesis and Characterization of (4aS,5aR,12aS)-3,10,12,12a- tetrahydroxy-7-(1-methyl-3,6-dihydro-2H-pyridin-4-yl)-1,11-dioxo-4a,5,5a,6- tetrahydro-4H-tetracene-2-carboxamide

[0302] (4aS,5aR,12aS)-3,10,12,12a-tetrahydroxy-1,11-dioxo-7-(1,2,3,6- tetrahydropyridin-4-yl)-4a,5,5a,6-tetrahydro-4H-tetracene-2-carboxamide (1 eq.) was added to THF (2 mL), then HCHO (10 eq.) was added in, followed by NaBH3CN (2 eq.). The reaction mixture was stirred at 25°C for 2 hours. The reaction mixture was quenched with 2N HCl then concentrated under reduced pressure to removed solvent. The residue was purified by prep-HPLC (HCOOH condition). (4aS,5aR,12aS)-3,10,12,12a-tetrahydroxy-7-(1-methyl- 3,6-dihydro-2H-pyridin-4-yl)-1,11-dioxo-4a,5,5a,6-tetrahydro-4H-tetracene-2-carboxamide (49% yield) was obtained as a yellow solid. LC-MS (ESI+) m / z: 467.0 (M+H)+.1H NMR (400 MHz, DMSO-d6): δ 12.34 (br, 1H), 9.06 (s, 1H), 8.69 (s, 1H), 8.15 (s, 1H), 3.93-3.90 (m, 4H), 3.10-3.07 (m, 4H), 2.82 (s, 3H). Example 16A: Synthesis and Characterization of (4aS,5aR,12aS)-3,10,12,12a- tetrahydroxy-1,11-dioxo-7-[(1S*)-2,2,2-trifluoro-1-methyl-ethyl]-4a,5,5a,6-tetrahydro- 4H-tetracene-2-carboxamide and (4aS,5aR,12aS)-3,10,12,12a-tetrahydroxy-1,11-dioxo- 7-[(1R*)-2,2,2-trifluoro-1-methyl-ethyl]-4a,5,5a,6-tetrahydro-4H-tetracene-2- carboxamide (*stereochemistry randomly assigned)

[0303] (4aS,5aR,12aS)-3,10,12,12a-tetrahydroxy-7-iodo-1,11-dioxo-4a,5,5a,6- tetrahydro-4H-tetracene-2-carboxamide (1 eq), tributyl-[1-(trifluoromethyl)vinyl]stannane (1.2 eq.), Pd(dppf)Cl2 (0.1 eq.) and CuI (0.05 eq.) were added in DMF (2 mL), the reaction mixture was stirred at 90°C for 8 hours under N2. The reaction mixture was concentrated under reduced pressure to removed solvent. The residue was purified by prep-HPLC (HCl condition). (4aS,5aR,12aS)-3,10,12,12a-tetrahydroxy-1,11-dioxo-7-[1- (trifluoromethyl)vinyl]-4a,5,5a,6-tetrahydro-4H-tetracene-2-carboxamide (22% yield) was obtained as a yellow solid. LC-MS (ESI+) m / z: 465.9 (M+H)+.1H NMR (400 MHz, MeOD): δ 7.36-7.33 (m, 1H), 6.88-6.85 (m, 1H), 6.20 (s, 1H), 5.60 (s, 1H), 3.29-3.22 (m, 1H), 2.92- 2.84 (m, 2H), 2.49-2.36 (m, 3H), 2.06-2.01 (m, 1H), 1.62-1.30 (m, 1H).

[0304] A solution of (4aS,5aR,12aS)-3,10,12,12a-tetrahydroxy-1,11-dioxo-7-[1- (trifluoromethyl)vinyl]-4a,5,5a,6-tetrahydro-4H-tetracene-2-carboxamide (1.0 eq) and Pd(OH)2 (0.1 eq) in MeOH (5 mL) was stirred at 25oC for 2 h with a H2 balloon. The reaction mixture was filtered and concentrated under reduced pressure to give crude 16-2. The residue was purified by SFC (column: DAICEL CHIRALPAK IG (250mm*30mm,10um);mobile phase: [0.1%NH3H2O ETOH];B%: 50%-50%,min), providing Compound 16A at retention time 1.021 min and Compound 16B at retention time 2.050 min. As indicated by the asterisks, the absolute stereochemistry of the stereocenter produced was not determined for16A or 16B, and have been randomly assigned in the drawings to indicate that they are distinct stereoisomers.

[0305] Compound 16A: (4aS,5aR,12aS)-3,10,12,12a-tetrahydroxy-1,11-dioxo-7-[(1S*)- 2,2,2-trifluoro-1-methyl-ethyl]-4a,5,5a,6-tetrahydro-4H-tetracene-2-carboxamide (8% yield) was obtained as a yellow solid. LC-MS (ESI+) m / z: 468.1 (M+H)+.1H NMR (400 MHz, MeOD) δ 7.58 (d, J = 8.8 Hz, 1H), 6.88 (d, J = 8.8 Hz, 1H), 4.10-3.85 (m, 1H), 3.35-3.07 (m, 2H), 2.93–2.75 (m, 1H), 2.65–2.35 (m, 2H), 2.35–2.18 (m, 1H), 2.15-2.00 (m, 1H), 1.70-1.55 (m, 1H), 1.51 (d, J= 7.2 Hz, 3H). (*stereochemistry randomly assigned)

[0306] Compound 16B (4aS,5aR,12aS)-3,10,12,12a-tetrahydroxy-1,11-dioxo-7-[(1R*)- 2,2,2-trifluoro-1-methyl-ethyl]-4a,5,5a,6-tetrahydro-4H-tetracene-2-carboxamide (11% yield) was obtained as a yellow solid. LC-MS (ESI+) m / z: 468.1 (M+H)+.1H NMR (400 MHz, MeOD) δ 7.56 (d, J = 8.8 Hz, 1H), 6.87 (d, J = 8.8 Hz, 1H), 4.07-3.85 (m, 1H), 3.35-3.10 (m, 2H), 2.90–2.75 (m, 1H), 2.55–2.25 (m, 3H), 2.23–1.95 (m, 1H), 1.70-1.55 (m, 1H), 1.32 (d, J = 7.2 Hz, 3H). (*stereochemistry randomly assigned). Example 17A: Synthesis and Characterization of (4aS,5aR,12aS)-3,10,12,12a- tetrahydroxy-7-(3-methylisoxazol-5-yl)-1,11-dioxo-1,4,4a,5,5a,6,11,12a- octahydrotetracene-2-carboxamide

[0307] The reaction mixture of 3-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)isoxazole (1.5 eq), (4aS,5aR,12aS)-3,10,12,12a-tetrahydroxy-7-iodo-1,11-dioxo-4a,5,5a,6- tetrahydro-4H-tetracene-2-carboxamide (1.0 eq), XantPhos Pd G3 (0.1 eq) and K3PO4 (2.0 eq) in dioxane (2 mL) and H2O (1 mL) was stirred at 90oC for 3 hours. The reaction mixture was diluted with H2O (10 mL) and extracted with EtOAc (10 mL x 3). The combined layers were concentrated under reduced pressure. The residue was purified by prep-HPLC. (4aS,5aR,12aS)-3,10,12,12a-tetrahydroxy-7-(3-methylisoxazol-5-yl)-1,11-dioxo-4a,5,5a,6- tetrahydro-4H-tetracene-2-carboxamide (9% yield) was obtained as a yellow solid. LC-MS (ESI+) m / z: 4532 (M+H)+HPLC: 980% purity at 254 nm1H NMR (400 MHz CD3OD) δppm 7.72 (d, J = 8.8 Hz, 1H), 6.93 (d, J = 8.8 Hz, 1H), 6.39 (s, 1H), 3.33-3.05 (m, 2 H), 2.95- 2.75 (m, 1H), 2.60-2.35 (m, 3 H), 2.33 (s, 3 H), 2.08-1.95 (m, 1 H), 1.61 (q, J = 11.8 Hz, 1 H). Example 18A: Synthesis and Characterization of (4aS,5aR,12aS)-3,10,12,12a- tetrahydroxy-1,11-dioxo-7-vinyl-1,4,4a,5,5a,6,11,12a-octahydrotetracene-2-carboxamide

[0308] To a solution of (4aS,5aR,12aS)-3,10,12,12a-tetrahydroxy-7-iodo-1,11-dioxo- 4a,5,5a,6-tetrahydro-4H-tetracene-2-carboxamide (1 eq.), tributyl(vinyl)stannane (2 eq.) and Pd(dppf)Cl2(0.1 eq.) in toluene (2 mL) at 20°C was added CuI (0.1 eq), and the mixture was purged and degassed with N2 three times and then stirred at 100°C for 6 h. The reaction mixture was cooled to 20°C, then quenched with saturated KF solution (20 mL) and then extracted with EtOAc (20 mL ×3). The combined organic layers were washed with brine (20 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC). (4aS, 5aR, 12aS)-3,10,12,12a- tetrahydroxy-1,11-dioxo-7-vinyl-4a,5,5a,6-tetrahydro-4H-tetracene-2-carboxamide (14% yield) was obtained as a yellow solid. LC-MS (ESI+) m / z: 398.0 (M+H)+. HPLC: 99.7% purity at 254 nm.1H NMR (400 MHz, DMSO-d6): δ 14.92 (br s, 1H), 11.88 (s, 1H), 9.30 - 8.56 (m, 2H), 7.70 (br d, J = 8.8 Hz, 1H), 6.93 - 6.81 (m, 2H), 6.79 - 6.62 (m, 1H), 5.60 (br d, J = 17.2 Hz, 1H), 5.27 (br d, J = 11.2 Hz, 1H), 3.23 - 3.11 (m, 1H), 3.07 (br dd, J = 4.0, 15.6 Hz, 1H), 2.86 - 2.73 (m, 1H), 2.44 - 2.36 (m, 2H), 2.35 - 2.21 (m, 2H), 2.05 - 1.97 (m, 1H), 1.52 - 1.39 (m, 1H).

[0309] To a solution of (4aS, 5aR, 12aS)-3,10,12,12a-tetrahydroxy-1,11-dioxo-7-vinyl- 4a,5,5a,6-tetrahydro-4H-tetracene-2-carboxamide (1 eq.) in EtOH (2 mL) at 20°C was added Pd / C (05 eq) and the mixture was purged and degassed with H2 three times and then stirredat 20°C under H2(15 Psi) for 2 h. The reaction mixture was filtered to remove the Pd / C and the filtrate was concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC. (4aS, 5aR, 12aS)-7-ethyl-3,10,12,12a-tetrahydroxy-1,11-dioxo- 4a,5,5a,6-tetrahydro-4H-tetracene-2-carboxamide (25% yield) was obtained as a yellow solid. LC-MS (ESI+) m / z: 400.0 (M+H)+. HPLC: 93.4% purity at 254 nm.1H NMR (400 MHz, CD3CN): δ 14.94 (s, 1H), 11.71 (s, 1H), 9.01 (br d, J = 2.4 Hz, 1H), 7.36 (d, J = 8.8 Hz, 1H), 6.77 (br d, J = 8.6 Hz, 2H), 4.70 (br d, J = 4.6 Hz, 1H), 3.22 (br dd, J = 6.6, 18.8 Hz, 1H), 3.02 (dd, J = 4.3, 15.9 Hz, 1H), 2.87 (dq, J = 4.4, 9.4 Hz, 1H), 2.63 - 2.56 (m, 2H), 2.55 - 2.46 (m, 2H), 2.33 (br d, J = 15.3 Hz, 3H), 1.68 - 1.58 (m, 1H), 1.13 (t, J = 7.4 Hz, 3H). Example 19A: Synthesis and Characterization of (4aS,5aR,12aS)-3,10,12,12a- tetrahydroxy-7-(1-methyl-1H-1,2,3-triazol-4-yl)-1,11-dioxo-1,4,4a,5,5a,6,11,12a- octahydrotetracene-2-carboxamide

[0310] To a mixture of (4aS,5aR,12aS)-3,10,12,12a-tetrahydroxy-7-iodo-1,11-dioxo- 4a,5,5a,6-tetrahydro-4H-tetracene-2-carboxamide (500 mg, 1.01 mmol, 1.0 eq), ethynyl(trimethyl)silane (395.1 mg, 4.0 mmol, 557.2 uL, 4.0 eq) and TEA (356.1 mg, 3.5 mmol, 489.9 uL, 3.5 eq) in DMF (5 mL) was added CuI (38.3 mg, 201.1 umol, 0.2 eq) and Pd(PPh3)2Cl2(141.2 mg, 201.1 umol, 0.2 eq). The reaction mixture was degassed and purged with N23 times, and stirred at 90°C for 2 hr under N2 atmosphere. TBAF (3.94 g, 15.08 mmol, 4.14 mL, 15 eq) was added. The mixture was stirred at 25°C for 2 hr. The reaction mixture was concentrated under reduced pressure to give a residue. The crude product was purified by reverse-phase column to remove the catalyst, followed by prep-HPLC (column:YMC-Actus Triart C18150*30mm*5um; mobile phase: [water(HCl)-ACN]; B%: 38%-78%, 9 min). (4aS,5aR,12aS)-7-ethynyl-3,10,12,12a-tetrahydroxy-1,11-dioxo-4a,5,5a,6-tetrahydro- 4H-tetracene-2-carboxamide (38% yield) was obtained as yellow solid.

[0311] To a solution of (4aS,5aR,12aS)-7-ethynyl-3,10,12,12a-tetrahydroxy-1,11-dioxo- 4a,5,5a,6-tetrahydro-4H-tetracene-2-carboxamide (100 mg, 253 umol, 1.0 eq) and azidomethyl(trimethyl)silane (163.4 mg, 1.26 mmol, 187.9 uL, 5.0 eq) in DMSO (1.5 mL) was added DIEA (65.4 mg, 505.9 umol, 88.1 uL, 2.0 eq) and CuI (9.6 mg, 50.6 umol, 0.2 eq) under N2. It was stirred at 25°C for 2 hr, then TBAF (1 M, 1.52 mL, 6.0 eq) was added. The resulting solution was stirred at 25°C for 2 hr. The reaction mixture was filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep- HPLC (column: YMC-Actus Triart C18150*30mm*5um; mobile phase: [water(HCl)-ACN]; B%: 18%-58%, 9 min). (4aS,5aR,12aS)-3,10,12,12a-tetrahydroxy-7-(1-methyltriazol-4-yl)- 1,11-dioxo-4a,5,5a,6-tetrahydro-4H-tetracene-2-carboxamide (37.6 % yield) was obtained as yellow solid. LCMS: calc. for C22H20N4O7: 452.1, found: [M+H]+453.1.1H NMR (400 MHz, MeOD) δ 8.01 (s, 1 H), 7.66 (d, J = 8.6 Hz, 1 H), 6.90 (d, J = 8.4 Hz, 1 H), 4.15 (s, 3 H), 3.20 - 3.27 (m, 1 H), 3.05 (dd, J = 15.9, 4.3 Hz, 1 H), 2.75 - 2.93 (m, 1 H), 2.31 - 2.56 (m, 3 H), 1.98 (br d, J = 13.4 Hz, 1 H), 1.48 - 1.67 (m, 1 H), 1.20 - 1.42 (m, 1 H). Example 20A: Synthesis and Characterization of (4aS,5aR,12aS)-3,10,12,12a- tetrahydroxy-7-(2-methyl-2H-1,2,3-triazol-4-yl)-1,11-dioxo-1,4,4a,5,5a,6,11,12a- octahydrotetracene-2-carboxamide

[0312] To a solution of 4-bromo-2-methyl-triazole (500 mg, 3.1 mmol) in THF (5 mL) was added butyllithium (2.5 M, 2.5 mL) and stirred at -78°C for 0.5 hour under N2. Then trimethyl borate (962 mg, 9.3 mmol) was added, the mixture was stirred at -78°C, then it was allowed to warm to 25°C over 16 hours under N2. The mixture was quenched with water (10 ml), filtered and concentrated under reduced pressure to give a residue. The crude product (2-methyltriazol-4-yl)boronic acid was used into the next step without further purification. LC- MS (ESI+) m / z: 128.0 (M+H)+.

[0313] A mixture of (2-methyltriazol-4-yl)boronic acid (130 mg, 1 mmol), (4aS,5aR,12aS)-3,10,12,12a-tetrahydroxy-7-iodo-1,11-dioxo-4a,5,5a,6-tetrahydro-4H- tetracene-2-carboxamide (101.4 mg, 204 umol), Pd(dppf)Cl2(74.6 mg, 102 umol), and KOAc (300.3 mg, 3.1 mmol) in dioxane (2 mL) and H2O (0.2 mL) was degassed and purged with N2 3 times, and then the mixture was stirred at 80°C for 2 hours under N2atmosphere. The reaction mixture was concentrated under reduced pressure to remove solvent. The crude product was purified by prep-HPLC (HCl) to afford the product, (4aS,5aR,12aS)- 3,10,12,12a-tetrahydroxy-7-(2-methyltriazol-4-yl)-1,11-dioxo-4a,5,5a,6-tetrahydro-4H- tetracene-2-carboxamide (1% yield), as a yellow solid. MS: calc. for C22H20N4O7: 452.13, found: [M+H]+453.1.1H NMR (DMSO-d6, 400MHz): δ 14.9 (s, 1H), 11.92 (s, 1H), 8.60- 9.15 (m, 1H), 7.92 (s, 1H), 7.70(d, J = 8.8 Hz, 1H), 6.94 (d, J = 8.8 Hz, 1H),6.69 (s, 1H), 4.18 (s, 3H), 2.99-3.10 (m, 2H), 2.74-2.82 (m,1H), 2.29-2.42 (m, 3H), 1.95-2.03 (m, 2H), 1.43- 1.50 (m, 1H). Example 21A: Synthesis and Characterization of (4aS,5aR,12aS)-3,10,12,12a- tetrahydroxy-7-(3-methyl-1,2,4-oxadiazol-5-yl)-1,11-dioxo-1,4,4a,5,5a,6,11,12a- octahydrotetracene-2-carboxamide

[0314] A mixture of (4aS,5aR,12aS)-3,10,12,12a-tetrahydroxy-7-iodo-1,11-dioxo- 4a,5,5a,6-tetrahydro-4H-tetracene-2-carboxamide (500 mg, 1.0 mmol) ,1-hydroxypyrrolidine-2,5-dione (520.8 mg, 4.5 mmol) , Pd(PPh3)4(232.4 mg, 0.2 mmol) , DIEA (259.9 mg, 2.0 mmol, 0.35 mL) in NMP (3 mL) was stirred at 60 °C for 1 h under CO (15 Psi). The reaction mixture was filtered and concentrated under reduced pressure to give a residue, (2,5-dioxopyrrolidin-1-yl)(6aS,10aS,11aR)-8-carbamoyl-4,6,6a,9-tetrahydroxy-5,7- dioxo-10a,11,11a,12-tetrahydro-10H-tetracene-1-carboxylate, (500 mg, 0.98 mmol) as yellow liquid, which was used into the next step without further purification. LCMS: calc. for C24H20N2O11: 512.11, found: [M+H]+512.9.

[0315] A mixture of (2,5-dioxopyrrolidin-1-yl) (6aS,10aS,11aR)-8-carbamoyl-4,6,6a,9- tetrahydroxy-5,7-dioxo-10a,11,11a,12-tetrahydro-10H-tetracene-1-carboxylate (500 mg, 0.98 mmol), N-hydroxyacetamidine (159 mg, 2.2 mmol) in NMP (3 mL) was stirred at 25°C for 12 hours. The crude was concentrated under reduced pressure to give a residue. The crude product was purified by reverse-phase HPLC (FA). (6aS,10aS,11aR)-4,6,6a,9-tetrahydroxy- N1-[(E)-N-hydroxy-C-methyl-carbonimidoyl]-5,7-dioxo-10a,11,11a,12-tetrahydro-10H- tetracene-1,8-dicarboxamide (56% yield) was obtained as a yellow solid . LCMS: calc. for C22H21N3O9: 471.13, found: [M+H]+472.3.

[0316] A mixture of (6aS,10aS,11aR)-4,6,6a,9-tetrahydroxy-N1-[(E)-N-hydroxy-C- methyl-carbonimidoyl]-5,7-dioxo-10a,11,11a,12-tetrahydro-10H-tetracene-1,8- dicarboxamide (100 mg, 0.2 mmol) in dioxane (6 mL) was stirred at 130°C for 8 hours. The mixture was concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC: Welch Ultimate C18150 * 25mm * 5um;mobile phase: [water(FA)- ACN];B%: 34% - 64%,10 min. (4aS,5aR,12aS)-3,10,12,12a-tetrahydroxy-7-(3-methyl-1,2,4- oxadiazol-5-yl)-1,11-dioxo-4a,5,5a,6-tetrahydro-4H-tetracene-2-carboxamide (23%) was obtained as a yellow solid. LCMS: calc. for C22H19N3O8: 453.12, found: [M+H]+453.91H NMR (400MHz, acetonitrile-d3) δ = 14.75 (s, 1H), 12.47 (s, 1H), 9.01 (s, 1H), 8.11 (d, J = 8.8 Hz, 1H), 7.01 (d, J = 8.8 Hz, 1H), 6.77 (s, 1H), 4.71 (s, 1H), 3.83 -3.77 (m, 1H), 3.25 - 3.19 (m, 1H), 2.94 - 2.88 (m, 1H), 2.62 - 2.49 (m, 2H), 2.49 (s, 3H), 2.05 (d, J = 13.6 Hz, 2H), 1.74 - 1.63 (m, 1H) Example 22A: Synthesis and Characterization of (4aS,5aR,12aS)-3,10,12,12a- tetrahydroxy-7-(3-isopropylisoxazol-5-yl)-1,11-dioxo-1,4,4a,5,5a,6,11,12a- octahydrotetracene-2-carboxamide

[0317] A mixture of (4aS,5aR,12aS)-3,10,12,12a-tetrahydroxy-7-iodo-1,11-dioxo- 4a,5,5a,6-tetrahydro-4H-tetracene-2-carboxamide (100 mg, 0.2 mmol), Xantphos Pd G3 (19.1 mg, 20.1 umol, 0.1 eq), 3-propan-2-yl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)- 1,2-oxazole (71.5 mg, 0.3 mmol, 1.5 eq) and K3PO4 (213.5 mg, 1.0 mmol, 5 eq) in DMF (2 mL) and H2O (0.5 mL) was degassed and purged with N23 times, and then the mixture was stirred at 60°C for 16 hours under N2 atmosphere. It was then filtered and concentrated under reduced pressure to give a residue. The crude product was purified by reverse-phase HPLC (column: Welch Xtimate C18150*25mm*5um; mobile phase: [water (TFA)-ACN]; B%: 28%-58%, 23 min). (4aS,5aR,12aS)-3,10,12,12a-tetrahydroxy-7-(3-isopropylisoxazol-5-yl)- 1,11-dioxo-4a,5,5a,6-tetrahydro-4H-tetracene-2-carboxamide (2% yield) was obtained as a white solid. LCMS: calc. for C25H24N2O8: 480.15, found: [M+H]+481.1.1H NMR (400 MHz, METHANOL-d4) δ = 7.74 (d, J = 8.8 Hz, 1H), 7.04 - 6.89 (m, 1H), 6.52 - 6.41 (m, 1H), 3.20 - 3.02 (m, 2H), 2.96 - 2.79 (m, 1H), 2.65 - 2.32 (m, 3H), 2.13 - 1.93 (m, 1H), 1.71 - 1.52 (m, 1H), 1.46 - 1.23 (m, 7H). Example 23A: Synthesis and Characterization of (4aS,5aR,12aS)-3,12a-dihydroxy- 10,12-dimethoxy-N,N-dimethyl-1,11-dioxo-4a,5,5a,6-tetrahydro-4H-tetracene-2- carboxamide

[0318] (4aS,5aR,12aS)-3,10,12,12a-tetrahydroxy-1,11-dioxo-4a,5,5a,6-tetrahydro-4H- tetracene-2-carboxamide (1 eq.) was added in DMF (4 mL), then NaH (10 eq.) was added, the reaction mixture was stirred at 20 °C for 30 min before MeI (8 eq.) was added in, thereaction mixture was stirred at 40°C for 1 hour. The reaction mixture was concentrated under reduced pressure to removed solvent. The residue was purified by prep-HPLC (HCl condition). (4aS,5aR,12aS)-3,12a-dihydroxy-10,12-dimethoxy-N,N-dimethyl-1,11-dioxo- 4a,5,5a,6-tetrahydro-4H-tetracene-2-carboxamide (17% yield) was obtained as a yellow solid. LC-MS (ESI+) m / z: 428.1 (M+H)+. LCMS: calc. for C23H25NO7: 427.2, found: [M+H]+428.1. HPLC: 97.2% purity at 254 nm.1H NMR (400 MHz, DMSO-d6): δ 7.50-7.44 (m, 1H), 7.04 (d, J = 8.4 Hz, 1H), 6.87 (d, J = 7.6 Hz, 1H), 3.83 (s, 3H), 3.26 (s, 3H), 2.96-2.94 (m, 1H), 2.82 (s, 6H), 2.78-2.68 (m, 3H), 2.40-2.28 (m, 2H), 2.04-2.02 (m, 1H), 1.47-1.38 (m, 1H). Example 24A: Synthesis and Characterization of (4aS,5aR,12aS)-3,12,12a-trihydroxy- 10-methoxy-1,11-dioxo-1,4,4a,5,5a,6,11,12a-octahydrotetracene-2-carboxamide

[0319] (4aS,5aR,12aS)-3,10,12,12a-tetrahydroxy-1,11-dioxo-4a,5,5a,6-tetrahydro-4H- tetracene-2-carboxamide (1 eq.) was stirred in DMF (2 mL), then NaH (2 eq.) was added and the reaction mixture was stirred at 25°C for 15 min before MeI (1.5 eq) was added. The reaction mixture was stirred at 60°C for 45 min. The reaction mixture was concentrated under reduced pressure to removed solvent. The residue was purified by prep-HPLC (HCl condition). (4aS,5aR,12aS)-3,12,12a-trihydroxy-10-methoxy-1,11-dioxo-4a,5,5a,6- tetrahydro-4H-tetracene-2-carboxamide (11% yield) was obtained as a yellow solid. LC-MS (ESI+) m / z: 386.0 (M+H)+. HPLC: 93.3% purity at 254 nm.1H NMR (400 MHz, DMSO-d6): δ 8.93 (br, 1H), 8.71 (br, 1H), 7.48-7.44 (m, 1H), 7.03 (d, J = 8.0 Hz, 1H), 6.87 (d, J = 8.0 Hz, 1H), 6.53 (br, 1H), 3.83 (s, 3H), 3.14-3.10 (m, 1H), 2.74-2.68 (m, 2H), 2.43-2.34 (m, 3H), 1.99-1.96 (m, 1H), 1.44-1.34 (m, 1H). Example 25A: Synthesis and Characterization of (4aS,5aR,12aS)-12,12a-dihydroxy- 3,10-dimethoxy-1,11-dioxo-1,4,4a,5,5a,6,11,12a-octahydrotetracene-2-carboxamide

[0320] (4aS,5aR,12aS)-3,10,12,12a-tetrahydroxy-1,11-dioxo-4a,5,5a,6-tetrahydro-4H- tetracene-2-carboxamide (1 eq.) was stirred in DMF (4 mL), then NaH (5 eq.) was added, and then the reaction mixture was stirred at 2 °C for 15 min before MeI (4 eq.) was added. The reaction mixture was stirred at 60°C for 45 min. The reaction mixture was concentrated under reduced pressure to removed solvent. The residue was purified by prep-HPLC (HCl condition). (4aS,5aR,12aS)-12,12a-dihydroxy-3,10-dimethoxy-1,11-dioxo-4a,5,5a,6- tetrahydro-4H-tetracene-2-carboxamide (12% yield) was obtained as a yellow solid. LC-MS (ESI+) m / z: 400.0 (M+H)+. HPLC: 98.4% purity at 254 nm.1H NMR (400 MHz, DMSO-d6): δ 8.96-8.82 (m, 2H), 7.48-7.44 (m, 1H), 7.03 (d, J = 8.4 Hz, 1H), 6.87 (d, J = 7.6 Hz, 1H), 3.83 (s, 3H), 3.25 (s, 3H), 3.03-2.98 (m, 1H), 2.74-2.68 (m, 2H), 2.43-2.34 (m, 3H), 2.07- 2.01 (m, 1H), 1.47-1.34 (m, 1H). Example 26A: Synthesis and Characterization of (4aS,5aR,12aS)-3,10,12,12a- tetrahydroxy-1,11-dioxo-9-(2-(pyrrolidin-1-yl)acetamido)-1,4,4a,5,5a,6,11,12a- octahydrotetracene-2-carboxamide hydrochloride

[0321] KNO3(1.5 eq) was slowly added to the solution of (4S,4aS,5aR,12aS)-4- (dimethylamino)-3,10,12,12a-tetrahydroxy-1,11-dioxo-4a,5,5a,6-tetrahydro-4H-tetracene-2- carboxamide (1.0 eq) in H2SO4 (8 mL) at 0oC. The reaction mixture was stirred at 0oC for 2h. The reaction mixture was added dropwise to a stirring solution of cold petroleum ether (150 mL). The obtained solid was filtered and concentrated under reduced pressure. The crude product was purified by prep-HPLC to give (4S,4aS,5aR,12aS)-4-(dimethylamino)- 3,10,12,12a-tetrahydroxy-9-nitro-1,11-dioxo-4a,5,5a,6-tetrahydro-4H-tetracene-2- carboxamide (45% yield) as a yellow solid.LC-MS (ESI+) m / z: 460.0 (M+H)+.

[0322] To a solution of (4aS,5aR,12aS)-3,10,12,12a-tetrahydroxy-9-nitro-1,11-dioxo- 4a,5,5a,6-tetrahydro-4H-tetracene-2-carboxamide (1.0 eq) in dioxane (2 mL) and MeOH (2 mL) was added Pd(OH)2(0.1 eq). The mixture was degassed and purged with H2three times and stirred at 25°C for 30 minutes under H2 atmosphere. The reaction mixture was filtered and concentrated under reduced pressure. (12aS)-9-amino-3,10,12,12a-tetrahydroxy-1,11- dioxo-4a,5,5a,6-tetrahydro-4H-tetracene-2-carboxamide (37% yield) was obtained as a red solid. LC-MS (ESI+) m / z: 386.9 (M+H)+.1H NMR (400MHz, DMSO-d6): δ 15.06 (brs, 1H), 11.62 (brs, 1H), 9.11-8.59 (m, 2H), 6.80 (d, J = 7.6 Hz, 1H), 6.62 (brs, 1H), 6.51 (d, J = 7.6 Hz, 1H), 5.34-4.37 (m, 2H), 3.12 (d, J = 16.0 Hz, 1H), 2.83-2.73 (m, 1H), 2.62 (dd, J = 4.4, 15.1 Hz, 2H), 2.42-2.22 (m, 3H), 1.94 (d, J = 8.8 Hz, 1H), 1.46-1.34 (m, 1H).

[0323] To a solution of 2-pyrrolidin-1-ylacetic acid (1.0 eq) in DCM (3 mL) at 25°C was added DMF (0.1 eq) and oxalyl dichloride (2.0 eq). The mixture was stirred at 25°C for 2 hours. The reaction mixture was concentrated under reduced pressure.2-Pyrrolidin-1-ylacetyl chloride (95% yield) was obtained as a white solid.

[0324] To a solution of (4aS,5aR,12aS)-9-amino-3,10,12,12a-tetrahydroxy-1,11-dioxo- 4a,5,5a,6-tetrahydro-4H-tetracene-2-carboxamide (1.0 eq) in H2O (2 mL) and CH3CN (1 mL) was added NaHCO3 (10.0 eq) and 2-pyrrolidin-1-ylacetyl chloride (6.0 eq). The mixture was stirred at 25°C for 4 hours. The reaction mixture was filtered and concentrated under reduced pressure and separated by SFC (column: DAICEL CHIRALCEL OJ(250mm*30mm,10um);mobile phase: [0.1%NH3H2O ETOH];B%: 50%-50%,min). (4aS,5aR,12aS)-3,10,12,12a-tetrahydroxy-1,11-dioxo-9-[(2-pyrrolidin-1-ylacetyl)amino]- 4a,5,5a,6-tetrahydro-4H-tetracene-2-carboxamide (21% yield) was obtained as a yellow solid. LC-MS (ESI+) m / z: 498.1 (M+H)+.1H NMR (400MHz, MeOD): δ 8.26 (d, J = 8.0 Hz, 1H), 6.72 (d, J = 8.4 Hz, 1H), 3.42 (s, 2H), 3.24 (dd, J = 6.0, 18.1 Hz, 1H), 2.87 (d, J = 9.6 Hz, 1H), 2.80 (s, 5H), 2.53-2.34 (m, 3H), 2.02 (d, J = 9.2 Hz, 1H).Example 27A: Synthesis and Characterization of (4aS,5aR,12aS)-9-(2-(tert- butylamino)acetamido)-3,10,12,12a-tetrahydroxy-1,11-dioxo-1,4,4a,5,5a,6,11,12a- octahydrotetracene-2-carboxamide

[0325] To a solution of 2-(tert-butylamino)acetic acid (1.0 eq) in DCM (3 mL) at 25°C was added DMF (0.1 eq) and oxalyl dichloride (2.0 eq). The mixture was stirred at 25°C for 2 hours. The reaction mixture was concentrated under reduced pressure. 2-(tert- butylamino)acetyl chloride (83% yield) was obtained as a white solid which was used without further purification.

[0326] To a solution of (4aS,5aR,12aS)-9-amino-3,10,12,12a-tetrahydroxy-1,11-dioxo- 4a,5,5a,6-tetrahydro-4H-tetracene-2-carboxamide (1.0 eq) in H2O (2 mL) and CH3CN (1 mL) was added NaHCO3 (10.0 eq) and 2-(tert-butylamino)acetyl chloride (6.0 eq). The mixture was stirred at 25°C for 3 hours. The reaction mixture was filtered and concentrated under reduced pressure, then purified by prep-HPLC. (4aS,5aR,12aS)-9-(2-(tert- butylamino)acetamido)-3,10,12,12a-tetrahydroxy-1,11-dioxo-1,4,4a,5,5a,6,11,12a- octahydrotetracene-2-carboxamide was obtained as a yellow solid (26% yield). LC-MS (ESI+) m / z: 500.1 (M+H)+. HPLC: 98.5% purity at 254 nm.1H NMR (400MHz, MeOD): δ 8.18 (d, J = 8.0 Hz, 1H), 6.75 (d, J = 8.0 Hz, 1H), 4.06 (s, 2H), 3.35-3.16 (m, 1H), 3.01-2.72 (m, 2H), 2.58-2.30 (m, 3H), 2.10-1.98 (m, 1H), 1.65-1.47 (m, 1H), 1.43 (s, 9 H). Example 28A: Synthesis and Characterization of (5aS,12aS)-3,10,12,12a-tetrahydroxy- 1,11-dioxo-1,5,5a,6,11,12a-hexahydrotetracene-2-carboxamide

[0327] A solution of (1S,4aS,11aR,12aS)-3-carbamoyl-2,4a,5,7-tetrahydroxy-N,N,N- trimethyl-4,6-dioxo-1,4,4a,6,11,11a,12,12a-octahydrotetracen-1-aminium iodide (1.0 eq) and NaN3 (11.7 mg, 179.7 umol, 2.0 eq) in NMP (2 mL) was stirred at 100°C for 16 hours. The reaction mixture was extracted with EtOAc (3 mL) and concentrated under reduced pressure. The residue was purified by prep-HPLC. (5aS,12aS)-3,10,12,12a-tetrahydroxy-1,11-dioxo- 5a,6-dihydro-5H-tetracene-2-carboxamide (38% yield) was obtained as a yellow solid. LCMS: calc. for C19H15NO7: 369.1, found: [M+H]+370.0. HPLC: 94.9% purity at 254 nm.1H NMR (400 MHz, DMSO-d6): δ 11.9 (s, 1H), 9.36 (s, 1H), 9.50-8.90 (m, 2H), 7.70-7.50 (m, 1H), 7.04-6.90 (m, 2 H), 6.53 (s, 1H), 3.91 (s, 1H), 3.35-3.00 (m, 3 H), 2.90-2.74 (m, 1H), 2.45-2.30 (m, 1H), 1.75-1.58 (m, 1H). Example 29A: Synthesis and Characterization of (4aS,12aS)-7-(cyclopenten-1-yl)- 3,10,11,12a-tetrahydroxy-1,12-dioxo-4a,5-dihydro-4H-tetracene-2-carboxamide

[0328] A mixture of (4aS,12aS)-3,10,11,12a-tetrahydroxy-7-iodo-1,12-dioxo-4a,5- dihydro-4H-tetracene-2-carboxamide (80 mg, 161.5 umol), 2-(cyclopenten-1-yl)-4,4,5,5- tetramethyl-1,3,2-dioxaborolane (156.8 mg, 808 umol, 5 eq), K2CO3 (111.6 mg, 808 umol, 5 eq) and Pd(PPh3)4(18.7 mg, 16.2 umol, 0.1 eq) in DMF (1.0 mL) and H2O (1.0 mL) was degassed and purged with N23 times, and then the mixture was stirred at 70°C for 16 hoursunder N2atmosphere. It was then filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Phenomenex Luna C18 200*40mm*10um; mobile phase: [water(TFA)-ACN];B%: 40%-70%,10min). (4aS,12aS)-7- (Cyclopenten-1-yl)-3,10,11,12a-tetrahydroxy-1,12-dioxo-4a,5-dihydro-4H-tetracene-2- carboxamide (28% yield) was obtained as a yellow solid. LCMS: calc. for C24H21NO7: 435.13, found: [M+H]+436.0.1H NMR (400 MHz, CD3OD-d4) δ 7.31 - 7.25 (m, 1H), 7.24 - 7.21 (m, 1H), 6.71 - 6.64 (m, 1H), 5.72 - 5.66 (m, 1H), 3.40 - 3.28 (m, 1H), 2.95 - 2.81 (m, 2H), 2.78 - 2.72 (m, 1H), 2.64 - 2.57 (m, 2H), 2.53 - 2.48 (m, 2H), 2.46 - 2.39 (m, 1H), 2.05 - 1.95 (m, 2H). Example 30A: Synthesis and Characterization of (4aS,12aS)-7-cyclopentyl-3,10,11,12a- tetrahydroxy-1,12-dioxo-4a,5-dihydro-4H-tetracene-2-carboxamide

[0329] A mixture of (4aS,12aS)-7-(cyclopenten-1-yl)-3,10,11,12a-tetrahydroxy-1,12- dioxo-4a,5-dihydro-4H-tetracene-2-carboxamide (25 mg, 57.4 umol, 1 eq) and Pd(OH)2 / C (8.1 mg, 57.4 umol, 1 eq) in dioxane (0.5 mL) was degassed and purged with H23 times, and then the mixture was stirred at 25°C for 0.5 hr under H2atmosphere. It was then filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep- HPLC (column: Welch Xtimate C18150*25mm*5um;mobile phase: [water(HCl)-ACN];B%: 45%-75%,17min). (4aS,12aS)-7-Cyclopentyl-3,10,11,12a-tetrahydroxy-1,12-dioxo-4a,5- dihydro-4H-tetracene-2-carboxamide (29% yield) was obtained as a yellow solid. LCMS: calc. for C24H23NO7: 437.15, found: [M+H]+438.0.1H NMR (400 MHz, CD3CN-d3) δ 15.08 - 14.93 (m, 1H), 9.55 (s, 1H), 9.04 - 8.94 (m, 1H), 7.60 - 7.53 (m, 1H), 7.51 - 7.46 (m, 1H), 6.93 - 6.86 (m, 1H), 6.84 - 6.81 (m, 1H), 5.20 - 5.12 (m, 1H), 3.62 - 3.55 (m, 1H), 3.55 - 3.47 (m, 1H), 3.09 - 2.98 (m, 1H), 2.96 - 2.87 (m, 2H), 2.73 - 2.59 (m, 1H), 1.83 - 1.74 (m, 5H), 1.72 - 1.60 (m, 4H). Example 31A: Synthesis and Characterization of (4aS,12aS)-3,10,11,12a-tetrahydroxy- 1,12-dioxo-7-tetrahydropyran-4-yl-4a,5-dihydro-4H-tetracene-2-carboxamide

[0330] A mixture of (4aS,12aS)-3,10,11,12a-tetrahydroxy-7-iodo-1,12-dioxo-4a,5- dihydro-4H-tetracene-2-carboxamide (100 mg, 201.9 umol, 1 eq), 2-(3,6-dihydro-2H-pyran- 4-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (212. mg, 1.0 mmol, 5 eq), K2CO3 (139.5 mg, 1.0 mmol, 5 eq) and Pd(PPh3)4 (23.3 mg, 20.2 umol, 0.1 eq) in DMF (1.0 mL) and H2O (1.0 mL) was degassed and purged with N2three times, and then the mixture was stirred at 70°C for 2 hours under N2atmosphere. It was then filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Phenomenex Luna C18200*40mm*10um;mobile phase: [water(TFA)-ACN];B%: 40%-60%,10min). (4aS,12aS)-7-(3,6-dihydro-2H-pyran-4-yl)-3,10,11,12a-tetrahydroxy-1,12-dioxo-4a,5- dihydro-4H-tetracene-2-carboxamide (22% yield) was obtained as a yellow solid.

[0331] A mixture of (4aS,12aS)-7-(3,6-dihydro-2H-pyran-4-yl)-3,10,11,12a- tetrahydroxy-1,12-dioxo-4a,5-dihydro-4H-tetracene-2-carboxamide (15 mg, 33.2 umol, 1 eq) and Pd(OH)2 (4.7 mg, 33.3 umol, 1 eq) in dioxane (0.5 mL) and MeOH (0.5 mL) was degassed and purged with H23 times, and then the mixture was stirred at 25°C for 1 hour under H2atmosphere. It was then filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Welch Xtimate C18 150*25mm*5um;mobile phase: [water(HCl)-ACN];B%: 22%-52%,17min). (4aS,12aS)- 3,10,11,12a-tetrahydroxy-1,12-dioxo-7-tetrahydropyran-4-yl-4a,5-dihydro-4H-tetracene-2- carboxamide (23% yield) was obtained as a yellow solid. LCMS: calc. for C24H23NO8: 453.14, found: [M+H]+454.0.1H NMR (400 MHz, ACETONITRILE-d3) δ = 15.09 - 14.96(m, 1H), 9.67 - 9.54 (m, 1H), 9.09 - 8.93 (m, 1H), 7.54 (d, J = 8.3 Hz, 1H), 7.48 (s, 1H), 6.96 - 6.89 (m, 1H), 6.85 (d, J = 8.3 Hz, 1H), 5.26 - 5.11 (m, 1H), 4.09 - 3.99 (m, 2H), 3.71 - 3.60 (m, 2H), 3.57 - 3.47 (m, 1H), 3.46 - 3.36 (m, 1H), 3.10 - 2.99 (m, 1H), 2.90 (br s, 2H), 2.72 - 2.59 (m, 1H), 1.86 - 1.75 (m, 5H). Example 32A: Synthesis and Characterization of (4aS,12aS)-7-cyclobutyl-3,10,11,12a- tetrahydroxy-1,12-dioxo-4a,5-dihydro-4H-tetracene-2-carboxamide

[0332] Indium trichloride (201 mg, 909 umol, 58 uL, 1.5 eq) was mixed with cyclobutylmagnesium bromide (434 mg, 2.7 mmol, 4.5 eq) at -78°C for 15 minutes, and then to the mixture was added palladium bis((tri-t-butyl)phosphine) (61.9 mg, 121 umol, 0.2 eq) and (4aS,12aS)-3,10,11,12a-tetrahydroxy-7-iodo-1,12-dioxo-4a,5-dihydro-4H-tetracene-2- carboxamide (300 mg, 606 umol, 1.0 eq) at 25°C over 15 minutes. The mixture was stirred at 70°C for 2 hours. The reaction mixture was filtered and concentrated under reduced pressure. The residue was purified by prep-HPLC (column: Phenomenex Synergi C18 100*30mm*4um;mobile phase: [water(HCl)-ACN];B%: 62%-92%,9.5min). (4aS,12aS)-7- cyclobutyl-3,10,11,12a-tetrahydroxy-1,12-dioxo-4a,5-dihydro-4H-tetracene-2-carboxamide (41% yield) was obtained as a yellow solid. LC-MS (ESI+) m / z: 424.0 (M+H)+. LCMS: calc. for C23H21NO7: 423.1, found: [M+H]+424.0.1H NMR (400 MHz, CD3OD-d4) δ 7.42 (d, J = 8.1 Hz, 1H), 7.25 - 7.16 (m, 1H), 6.90 - 6.68 (m, 1H), 4.01 - 3.85 (m, 1H), 3.49 - 3.41 (m, 1H), 3.07 - 2.96 (m, 2H), 2.90 - 2.82 (m, 1H), 2.59 - 2.42 (m, 3H), 2.24 - 2.09 (m, 3H), 1.94 - 1.81 (m, 1H). Example 33A: Synthesis and Characterization of (4aS, 12aS)-3,10,11,12a-tetrahydroxy- 1,12-dioxo-7-[1-(trifluoromethyl)vinyl]-4a,5-dihydro-4H-tetracene-2-carboxamide

[0333] A mixture of (12aS)-3,10,11,12a-tetrahydroxy-7-iodo-1,12-dioxo-4a,5-dihydro- 4H-tetracene-2-carboxamide (250 mg, 505 umol, 1 eq), tributyl-[1- (trifluoromethyl)vinyl]stannane (583 mg, 1.5 mmol, 3 eq), CuI (14.4 mg, 75.7 umol, 0.15 eq), Pd(PPh3)2Cl2 (53.2 mg, 75.7 umol, 0.15 eq) in DMF (8 mL) was degassed and purged with N23 times, and then the mixture was stirred at 70°C for 5 hours under N2atmosphere. The reaction mixture was filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Phenomenex Synergi C18 100*30mm*4um;mobile phase: [water(HCl)-ACN];B%: 45%-75%,8min). (4aS, 12aS)- 3,10,11,12a-tetrahydroxy-1,12-dioxo-7-[1-(trifluoromethyl)vinyl]-4a,5-dihydro-4H- tetracene-2-carboxamide (27% yield) was obtained as a yellow solid. LC-MS (ESI-) m / z: 462.0 (M-1)-. LCMS: calc. for C28H31N5O8: 463.36, found: [M-H]- 462.0.1H NMR (400 MHz, METHANOL-d4) δ ppm 2.38 - 2.50 (m, 1 H) 2.71 - 2.81 (m, 1 H) 2.83 - 2.97 (m, 2 H) 3.28 - 3.35 (m, 1 H) 5.55 - 5.61 (m, 1 H) 6.14 - 6.28 (m, 1 H) 6.68 - 6.84 (m, 1 H) 6.98 - 7.15 (m, 1 H) 7.29 - 7.43 (m, 1 H) Example 34A: Synthesis and Characterization of (12aS)-3,10,11,12a-tetrahydroxy-7-(3- isopropylisoxazol-5-yl)-1,12-dioxo-4a,5-dihydro-4H-tetracene-2-carboxamide

[0334] A mixture of 3-isopropyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)isoxazole (96 mg, 404 umol, 2 eq), Pd(t-Bu3P)2 (10.3 mg, 20.2 umol, 0.1 eq), K3PO4 (107 mg 505 umol 25 eq) in dioxane (4 mL) and H2O (2 mL) was degassed and purged with N23times, and then the mixture was stirred at 80°C for 4 hours under N2atmosphere. The reaction mixture was filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Phenomenex Synergi C18 100*30mm*4um;mobile phase: [water(HCl)-ACN];B%: 55%-85%,7.8min). (12aS)- 3,10,11,12a-tetrahydroxy-7-(3-isopropylisoxazol-5-yl)-1,12-dioxo-4a,5-dihydro-4H- tetracene-2-carboxamide (18% yield) was obtained as a yellow solid LC-MS (ESI+) m / z: 479.0 (M+H)+. LCMS: calc. for C25H22N2O8: 478.1, found: [M+H]+479.0..1H NMR (400 MHz, DMSO-d6) δ ppm 1.13 - 1.25 (m, 1 H) 1.28 - 1.31 (m, 3 H) 1.31 - 1.33 (m, 3 H) 2.81 - 2.87 (m, 1 H) 2.94 - 3.03 (m, 2 H) 3.05 - 3.17 (m, 2 H) 6.81 - 6.86 (m, 1 H) 6.90 - 6.99 (m, 1 H) 7.36 - 7.47 (m, 1 H) 7.79 - 7.90 (m, 1 H) 8.79 - 9.17 (m, 2 H). Example 35A: Synthesis and Characterization of (4aS, 12aS)-3,10,12,12a-tetrahydroxy- 7-(4-isopropyltriazol-1-yl)-1,11-dioxo-4a,5,5a,6-tetrahydro-4H-tetracene-2-carboxamide

[0335] (4S,12aS)-4-(dimethylamino)-3,10,12,12a-tetrahydroxy-1,11-dioxo-4a,5,5a,6- tetrahydro-4H-tetracene-2-carboxamide (5.0 g, 12.1 mmol, 1 eq) and dibenzyl azodicarboxylate (4.32 g, 14.48 mmol, 1.2 eq) were dissolved in TFA (100 mL), and then the mixture was stirred at 0°C for 8 hours. The reaction mixture was concentrated under reduced pressure to give a residue. Benzyl N-[(6aS,10S)-8-carbamoyl-10-(dimethylamino)-4,6,6a,9- tetrahydroxy-5,7-dioxo-10a,11,11a,12-tetrahydro-10H-tetracen-1-yl]-N-(benzyloxycarbonylamino)carbamate (8.6 g) was obtained as a yellow solid. LC-MS (ESI+) m / z: 713.2 (M+H)+. The crude compound was used the next step.

[0336] A mixture of benzyl N-[(6aS,10S)-8-carbamoyl-10-(dimethylamino)-4,6,6a,9- tetrahydroxy-5,7-dioxo-10a,11,11a,12-tetrahydro-10H-tetracen-1-yl]-N- (benzyloxycarbonylamino)carbamate (8.0 g, 11.2 mmol, 1 eq) and Pd / C (1.2 g, 1.1 mmol, 10%, 0.1 eq) in MeOH (100 mL) was stirred at 25°C for 3 hours under H2 atmosphere. The reaction mixture was filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Welch Xtimate C18100*40mm*3um;mobile phase: [water(HCl)-ACN];B%: 0%-25%,8min). (4S,12aS)-7-amino-4-(dimethylamino)- 3,10,12,12a-tetrahydroxy-1,11-dioxo-4a,5,5a,6-tetrahydro-4H-tetracene-2-carboxamide (tetra62.2% yield) was obtained as a red solid. LC-MS (ESI+) m / z: 430.0 (M+H)+.

[0337] A mixture of (4S,12aS)-7-amino-4-(dimethylamino)-3,10,12,12a-tetrahydroxy- 1,11-dioxo-4a,5,5a,6-tetrahydro-4H-tetracene-2-carboxamide (2.8 g, 6.5 mmol, 1 eq), tetrafluoroboric acid aq. solution (3.6 g, 19.6 mmol, 2.5 mL, 48%, 3 eq), tert-butyl nitrite (1.0 g, 9.8 mmol, 1.2 mL, 1.5 eq) and NaN3(466.3 mg, 7.2 mmol, 1.1 eq) in MeOH (70.00 mL) was degassed and purged with N23 times, and then the mixture was stirred at 0°C for 6 hours under N2atmosphere. The reaction mixture was filtered to remove the solid, and the filtrate was dried under reduced pressure to give a residue. The reaction mixture was stirred with ether (200 mL), then filtered and solvent removed to give a residue. (4S,12aS)-7-azido-4- (dimethylamino)-3,10,12,12a-tetrahydroxy-1,11-dioxo-4a,5,5a,6-tetrahydro-4H-tetracene-2- carboxamide (84% yield) was obtained as a red solid. LC-MS (ESI+) m / z: 456.0 (M+H)+.

[0338] A mixture of 3-methylbut-1-yne (2.09 g, 30.7 mmol, 3.14 mL, 10 eq), (4S,12aS)- 7-azido-4-(dimethylamino)-3,10,12,12a-tetrahydroxy-1,11-dioxo-4a,5,5a,6-tetrahydro-4H- tetracene-2-carboxamide (1.4 g, 3.1 mmol, 1 eq), sodium ascorbate (2.44 g, 12.3 mmol, 4 eq), copper sulfate (981 mg, 6.2 mmol) in H2O (10 mL) and MeOH (5 mL) was degassed and purged with N23 times, and then the mixture was stirred at 25°C for 16 hours under N2 atmosphere. The reaction mixture was filtered to give a filtrate, then the filtrate was concentrated under reduced pressure to give a residue. The residue was purified by reverse phase column (HCl condition). (4S,12aS)-4-(dimethylamino)-3,10,12,12a-tetrahydroxy-7-(4- isopropyltriazol-1-yl)-1,11-dioxo-4a,5,5a,6-tetrahydro-4H-tetracene-2-carboxamide (42% yield) was obtained as a yellow solid. LC-MS (ESI+) m / z: 524.2 (M+H)+.

[0339] To a solution of (4S,12aS)-4-(dimethylamino)-3,10,12,12a-tetrahydroxy-7-(4- isopropyltriazol-1-yl)-1,11-dioxo-4a,5,5a,6-tetrahydro-4H-tetracene-2-carboxamide (80 mg, 153 umol, 1 eq) in HOAc (1.5 mL) and H2O (1.5 mL) was added Zn (50 mg, 763 umol, 5 eq).The mixture was stirred at 25°C for 16 hours. The reaction mixture was filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep- HPLC (column: Phenomenex Synergi C18100*30mm*4um;mobile phase: [water(HCl)- ACN];B%: 40%-70%,7.8min). (4aS, 12aS)-3,10,12,12a-tetrahydroxy-7-(4-isopropyltriazol-1- yl)-1,11-dioxo-4a,5,5a,6-tetrahydro-4H-tetracene-2-carboxamide (8% yield) was obtained as a yellow solid. LC-MS (ESI+) m / z: 481.1 (M+H)+. LCMS: calc. for C24H24N4O7: 480.16, found: [M+H]+481.1.1H NMR (400 MHz, METHANOL-d4) δ ppm 1.35 - 1.38 (m, 3 H) 1.39 - 1.42 (m, 3 H) 1.47 - 1.59 (m, 1 H) 1.87 - 2.01 (m, 1 H) 2.32 - 2.51 (m, 4 H) 2.79 - 2.94 (m, 1 H) 3.14 - 3.28 (m, 2 H) 6.97 - 7.11 (m, 1 H) 7.50 - 7.64 (m, 1 H) 8.00 - 8.10 (m, 1 H) Example 36A: Synthesis and Characterization of (4aS, 12aS)-7-(3-cyclopropylisoxazol- 5-yl)-3,10,11,12a-tetrahydroxy-1,12-dioxo-4a,5,5a,6-tetrahydro-4H-tetracene-2- carboxamide

[0340] To a solution of cyclopropanecarboxaldehyde (10 g, 143 mmol, 10.7 mL) in EtOH (50 mL) was added hydroxylamine hydrochloride (19.8 g, 285.4 mmol) and Na2CO3 (60.5 g, 570.7 mmol). The mixture was stirred at 25°C for 12 hr .The reaction mixture was diluted with H2O (50 mL) and extracted with EtOAc (50mL x 3). The combined organic layers werewashed with brine (100mL x 2), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give a residue. (E)-cyclopropanecarbaldehyde oxime (29% yield) was obtained as a white solid. The residue was used for the next step without further purification.

[0341] To a solution of (E)-cyclopropanecarboxaldehyde oxime (500 mg, 5.9 mmol) in DCM (25 mL) was added benzyltrimethylammonium tetrachloroiodate (2.46 g, 5.9 mmol). The mixture was stirred at 25°C for 1 hr . Then diisopropyl ether (44 mL) was added. The reaction mixture was filtered and concentrated under reduced pressure to give a residue. (Z)- N-hydroxycyclopropanecarboximidoyl chloride (17% yield) was obtained as a yellow oil. The residue was used for the next step without further purification.

[0342] To a solution of (Z)-N-hydroxycyclopropanecarboximidoyl chloride (197.3 mg, 1.7 mmol) and tributyl(ethynyl)stannane (400 mg, 1.3 mmol) in DCM (5 mL) was added K2CO3 (193 mg, 1.4 mmol) .The mixture was stirred at 25°C for 24 hr . The reaction mixture was quenched by addition of H2O (18 mL) at 25°C and was then extracted with DCM (15 mL x 3). The combined organic layers were washed with brine (50 mL x 2), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 40 g SepaFlash® Silica Flash Column, Eluent of 20~25% DCM / Petroleum ethergradient @ 40 mL / min). tributyl-(3- cyclopropylisoxazol-5-yl) stannane (40% yield) was obtained as a colorless oil.

[0343] A mixture of tributyl-(3-cyclopropylisoxazol-5-yl)stannane (144 mg, 362 umol) , (12aS)-3,10,11,12a-tetrahydroxy-7-iodo-1,12-dioxo-4a,5,5a,6-tetrahydro-4H-tetracene-2- carboxamide (150 mg, 302 umol) , DIEA (78 mg, 603 umol, 105 uL), CuI (5.8 mg, 30.2 umol) and Pd(dppf)Cl2 (33.1 mg, 45.3 umol) in DMF (3 mL) was degassed and purged with N23 times, and then the mixture was stirred at 70°C for 3 hr under N2atmosphere. The reaction mixture was filtered and concentrated under reduced pressure to give a residue. The crude product was purified by reverse-phase HPLC (column: Welch Xtimate C18 100*40mm*3um; mobile phase: [water (HCl)-ACN]; B%: 40%-70%, 8min). (4aS, 12aS)-7- (3-cyclopropylisoxazol-5-yl)-3,10,11,12a-tetrahydroxy-1,12-dioxo-4a,5,5a,6-tetrahydro-4H- tetracene-2-carboxamide (14% yield) was obtained as a yellow solid. LC-MS (ESI+) m / z: 479.0 (M+H)+. LCMS: calc. for C25H22N2O8.(HCl): 478.14, found: [M+H]+479.0.1H NMR (400MHz, MeOD): 7.61-7.80 (m, 1H), 6.94 (br d, 1H), 6.18-6.36 (m, 1H), 3.26 (br m, 1H),3.05-3.13 (m, 1H), 2.79-2.93 (m, 1H), 2.36-2.59 (m, 3H), 2.00-2.09 (m, 2H), 1.55-1.71 (m, 1H), 1.05-1.16 (m, 2H), 0.84-0.93 (m, 2H). Example 37A: Synthesis and Characterization of (4aS,12aS)-3,10,11,12a-tetrahydroxy- 1,12-dioxo-7-(2,2,2-trifluoro-1-methyl-ethyl)-4a,5-dihydro-4H-tetracene-2-carboxamide

[0344] A mixture of (4aS,12aS)-3,10,11,12a-tetrahydroxy-7-iodo-1,12-dioxo-4a,5- dihydro-4H-tetracene-2-carboxamide (300 mg, 606 umol, 1.0 eq), tributyl[1- (trifluoromethyl)ethenyl]stannane (700 mg, 1.8 mmol, 3.0 eq), copper iodide (17.3 mg, 90.8 umol, 0.1 eq) and

[0345] [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (63.7 mg, 90.8 umol, 0.1 eq) in DMF (8 mL) was degassed and purged with N23 times, and then the mixture was stirred at 70°C for 5 hours under N2 atmosphere. The reaction mixture was filtered and concentrated under reduced pressure. The residue was purified by prep-HPLC (Phenomenex Synergi C18100*30mm*4um;mobile phase: [water(HCl)-ACN];B%: 50%-80%,8min). (4aS,12aS)-3,10,11,12a-tetrahydroxy-1,12-dioxo-7-(2,2,2-trifluoro-1-methyl-ethyl)-4a,5- dihydro-4H-tetracene-2-carboxamide (8.5% yield) was obtained as yellow solid. LC-MS (ESI+) m / z: 466.1 (M+H)+. LCMS: calc. for C22H18NO7F3: 465.1, found: [M+H]+466.1.1H NMR (400 MHz, MEOD-d4) δ 7.68 (d, J = 8.4 Hz, 1H), 7.47 - 7.40 (m, 1H), 6.88 (d, J = 8.4 Hz, 1H), 4.38 (td, J = 7.8, 15.6 Hz, 1H), 3.52 - 3.46 (m, 1H), 3.13 - 2.99 (m, 2H), 2.92 - 2.83 (m, 1H), 2.63 - 2.51 (m, 1H), 1.56 (d, J = 7.0 Hz, 3H). Example 38A: Synthesis and Characterization of (4aS)-3,10,11-trihydroxy-1,12-dioxo- 7-(2,2,2-trifluoro-1-methyl-ethyl)-4,4a,5,12a-tetrahydrotetracene-2-carboxamide

[0346] To a mixture of (4aS,12aS)-3,10,11,12a-tetrahydroxy-1,12-dioxo-7-(2,2,2- trifluoro-1-methyl-ethyl)-4a,5-dihydro-4H-tetracene-2-carboxamide (20 mg, 43 μmol, 1.0 eq) in HOAc (1.0 mL) and H2O (1.0 mL)was added Zn (96 mg, 1.7 mmol, 40 eq). The mixture was stirred at 25°C for 36 hours. The reaction mixture was filtered and concentrated under reduced pressure. The residue was purified by prep-HPLC (Phenomenex Synergi C18 100*30mm*4um;mobile phase: [water(HCl)-ACN];B%: 60%-90%,10min). (4aS)-3,10,11- trihydroxy-1,12-dioxo-7-(2,2,2-trifluoro-1-methyl-ethyl)-4,4a,5,12a-tetrahydrotetracene-2- carboxamide (4.7% yield) was obtained as a yellow solid LC-MS (ESI+) m / z: 450.0 (M+H)+. LCMS: calc. for C22H18NO6F3: 449.1, found: [M+H]+450.0.1H NMR (400 MHz, MEOD-d4) δ 7.61 - 7.55 (m, 1H), 7.44 - 7.39 (m, 1H), 6.95 - 6.77 (m, 1H), 4.45 - 4.30 (m, 1H), 3.39 - 3.36 (m, 1H), 3.22 - 3.13 (m, 2H), 3.10 - 3.05 (m, 1H), 2.74 - 2.70 (m, 1H), 1.61 - 1.55 (m, 3H) Example 39A: Synthesis and Characterization of (4aS,5aR,12aS)-3,10,12,12a- tetrahydroxy-7-morpholino-1,11-dioxo-4a,5,5a,6-tetrahydro-4H-tetracene-2- carboxamide

[0347] A mixture of (4aS,5aR,12aS)-7-amino-3,10,12,12a-tetrahydroxy-1,11-dioxo- 4a,5,5a,6-tetrahydro-4H-tetracene-2-carboxamide (60 mg, 0.16 mmol), 1-bromo-2-(2- bromoethoxy)ethane (54 mg, 0.23 mmol), NaI (46.6 mg, 0.31 mmol), DIEA (100 mg, 0.78 mmol) in DMF(1 mL) was purged with N23 times, then stirred at 65°C for 12 hours. The reaction mixture was filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC column: Phenomenex luna C18150*25 mm* 10um;mobile phase: [water(FA)-ACN];B%: 33%-63%,10min. (4aS,5aR,12aS)-3,10,12,12a- tetrahydroxy-7-morpholino-1,11-dioxo-4a,5,5a,6-tetrahydro-4H-tetracene-2-carboxamide (14% yield) was obtained as a yellow solid. LCMS: calc. for C23H24N2O8:456.15, found: [M+H]+457.0.1H NMR (400 MHz, METHANOL-d4) δ 7.38 (d, J = 9.2 Hz, 1H), 6.81 (d, J = 8.8 Hz, 1H), 4.52 - 4.48 (m, 1H), 3.84 (s, 2H), 3.80 - 3.76 (m, 2H), 3.46 - 3.41 (m 1H), 3.29 - 3.25 (m, 1H), 3.00 - 2.85 (m, 2H), 2.80 (d, J = 3.6 Hz, 1H), 2.70 (d, J = 6.4 Hz, 2H), 2.50 - 2.40 ( m, 2H), 2.18 - 2.07 (m, 2H) 1.68 - 1.62 (m, 1H). Example 40A: Synthesis and Characterization of (5aR,12aS)-3,10,12,12a-tetrahydroxy- 7-(4-hydroxy-1-piperidyl)-1,11-dioxo-4a,5,5a,6-tetrahydro-4H-tetracene-2-carboxamide

[0348] To a mixture of (4aS,5aR,12aS)-7-amino-3,10,12,12a-tetrahydroxy-1,11-dioxo- 4a,5,5a,6-tetrahydro-4H-tetracene-2-carboxamide (60 mg, 0.16 mmol), 3-hydroxypentanedial (288.5 mg, 1.24 mmol) in H2O (1.5 mL) and THF (1.5 mL) was added NaBH3CN (48.8 mg, 0.78 mmol) at 0°C and was then stirred at 0°C for 1 hr. The reaction mixture was filtered and concentrated under reduced pressure. The residue was purified by prep-HPLC column: Welch Xtimate C18150 * 25 mm * 5 um ; mobile phase: [water(HCl)-ACN];B%: 3%-33%,10 min. (5aR,12aS)-3,10,12,12a-tetrahydroxy-7-(4-hydroxy-1-piperidyl)-1,11-dioxo-4a,5,5a,6- tetrahydro-4H-tetracene-2-carboxamide (19% yield) was obtained as a yellow solid. LCMS: calc. for C24H26N2O8: 470.17, found: [M+H]+471.1.1H NMR (400 MHz, CD3OD-d4) δ 7.88- 7.83 (m, 1H), 7.05-7.04 (m, 1H), 4.19-4.05 (m, 2H), 3.83-3.63 (m, 2H), 3.53-3.45 (m, 2H), 3.27 (s, 2H), 2.97-2.94 (m, 1H), 2.52 ( d, J = 7.2 Hz, 2H), 2.44 ( d, J = 18.4 Hz, 2H), 2.17 ( d, J = 11.2 Hz, 2H), 2.06 ( d, J = 7.2 Hz, 2H), 1.73 - 1.64 (m, 1H). Example 41A: Synthesis and Characterization of (12aS)-7-(azetidin-1-yl)-3,10,12,12a- tetrahydroxy-1,11-dioxo-4a,5,5a,6-tetrahydro-4H-tetracene-2-carboxamide

[0349] To a mixture of (12aS)-7-amino-3,10,12,12a-tetrahydroxy-1,11-dioxo-4a,5,5a,6- tetrahydro-4H-tetracene-2-carboxamide (100 mg, 259 μmol, 1.0 eq) and 1,3-dibromopropane (78.3 mg, 388 μmol, 39.5 μL, 1.5 eq) in DMF (3.0 mL) was added NaI (193.9 mg, 1.29 mmol, 5.0 eq) and DIEA (167 mg, 1.3 mmol, 225 μL, 5.0 eq). The mixture was stirred at 70°C for 2 hours. The reaction mixture was filtered and concentrated under reduced pressure. The residue was purified by prep-HPLC (1_Welch Xtimate 75*40mm*3um;mobile phase: [water(FA)-ACN];gradient:15%-45% B over 8 min). (12aS)-7-(azetidin-1-yl)-3,10,12,12a- tetrahydroxy-1,11-dioxo-4a,5,5a,6-tetrahydro-4H-tetracene-2-carboxamide (4% yield) was obtained as a yellow solid LC-MS (ESI+) m / z: 427.0 (M+H)+. LCMS: calc. for C22H22N2O7: 426.1, found: [M+H]+427.0.1H NMR (400 MHz, CD3OD-d4) δ 7.04 - 6.96 (m, 1H), 6.83 - 6.75 (m, 1H), 3.95 (q, J = 7.3 Hz, 2H), 3.63 (q, J = 7.0 Hz, 2H), 3.30 - 3.22 (m, 1H), 2.90 ( J = 4.3, 15.3 Hz, 1H), 2.85 - 2.74 (m, 1H), 2.53 - 2.41 (m, 2H), 2.27 (quin, J = 6.9 Hz, 2H), 2.21 - 2.07 (m, 2H), 1.65 - 1.54 (m, 1H). Example 42A: Synthesis and Characterization of (4aS,5aR,12aS)-3,10,12,12a- tetrahydroxy-7-(3-hydroxyazetidin-1-yl)-1,11-dioxo-4a,5,5a,6-tetrahydro-4H-tetracene- 2-carboxamide

[0350] A mixture of (4aS,5aR,12aS)-7-amino-3,10,12,12a-tetrahydroxy-1,11-dioxo- 4a,5,5a,6-tetrahydro-4H-tetracene-2-carboxamide (50 mg, 129 μmol, 1 eq), 1,3- dibromopropan-2-ol (141 mg, 0.65 mmol), NaI (77.6 mg, 0.52 mmol), DIEA (134 mg, 1.04 mmol) in DMF (1 mL) was purged with N23 times, then stirred at 65°C for 12 hours. The reaction mixture was filtered under reduced pressure. The residue was purified by prep-HPLC column: Phenomenex luna C18150 * 25 mm * 10um; mobile phase: [water(FA)- ACN]; gradient:10%-40% B over min. (4aS,5aR,12aS)-3,10,12,12a-tetrahydroxy-7-(3- hydroxyazetidin-1-yl)-1,11-dioxo-4a,5,5a,6-tetrahydro-4H-tetracene-2-carboxamide (21% yield) was obtained as a yellow solid. LCMS: calc. for C22H22N2O8: 442.14, found: [M+H]+443.2.1H NMR (400 MHz, CD3OD-d4) δ 6.93 (d, J = 8.8 Hz, 1H), 6.73 (d, J = 8.8 Hz, 1H), 4.59 - 4.52 (m, 2H), 4.15 ( s, 1H), 3.88 - 3.85 (m, 1H), 3.65 - 3.62 (m, 1H), 3.54 - 3.49 (m, 1H), 2.91 - 2.87 (m, 1H), 2.78 - 2.72 (m, 1H), 2.46 - 2.35 (m, 2H), 2.17 - 2.02 (m, 2H), 1.60 ( d, J = 12 Hz, 1H). Example 43A: Synthesis and Characterization of (4aS,5aR)-7-cyclobutyl-3,10,12- trihydroxy-1,11-dioxo-4,4a,5,5a,6,12a-hexahydrotetracene-2-carboxamide

[0351] To a solution of (4aS,5aR,12aS)-7-cyclobutyl-3,10,12,12a-tetrahydroxy-1,11- dioxo-4a,5,5a,6-tetrahydro-4H-tetracene-2-carboxamide (180 mg, 423.10 μmol) in H2O (5 mL) and AcOH (5 mL) was added Zn (415 mg, 6.4 mmol). The mixture was stirred at 25°C for 16 hours. The reaction mixture was concentrated under reduced pressure. The residue was purified by prep-HPLC (column: Phenomenex Synergi C18100*30mm*4um;mobile phase: [water(HCl)-ACN];gradient:60%-90% B over 10 min). (4aS,5aR)-7-cyclobutyl-3,10,12- trihydroxy-1,11-dioxo-4,4a,5,5a,6,12a-hexahydrotetracene-2-carboxamide (12% yield) was obtained as a yellow solid. LC-MS (ESI+) m / z: 410.0 (M+H) +. LCMS: calc. for C23H23NO6: 409.15, found: [M+H]+410.0.1H NMR (400 MHz, CD3OD-d4): δ 7.51-7.35 (m, 1H), 6.77 (t, J = 7.9 Hz, 1H), 3.69 - 3.58 (m, 1H), 3.13 (dd, J = 1.8, 3.3 Hz, 1H), 3.03 - 2.93 (m, 1H), 2.51 (d, J = 18.8 Hz, 1H), 2.41 - 2.34 (m, 1H), 2.31 - 2.24 (m, 1H), 2.23 - 2.14 (m, 2H), 2.05 - 2.01 (m, 1H), 1.88 - 1.79 (m, 1H), 1.64 - 1.55 (m, 1H), 1.33 (s, 3H). Example 44A: Synthesis and Characterization of (4aS,5aR)-1,3,10,12-tetrahydroxy-7- (3-isopropylisoxazol-5-yl)-11-oxo-4a,5,5a,6-tetrahydro-4H-tetracene-2-carboxamide

[0352] To a solution of (4aS,5aR,12aS)-3,10,12,12a-tetrahydroxy-7-(3- isopropylisoxazol-5-yl)-1,11-dioxo-4a,5,5a,6-tetrahydro-4H-tetracene-2-carboxamide (190 mg, 0.4 mmol) in AcOH (2 mL) and H2O (2 mL) was added Zn (1.03 g, 15.82 mmol). The mixture was stirred at 25°C for 16 hours. The reaction mixture was concentrated under reduced pressure. The residue was purified by prep-HPLC (column: Phenomenex Synergi C18100*30mm*4um;mobile phase: [water(HCl)-ACN];gradient:60%-90% B over 8 min). (4aS,5aR)-1,3,10,12-tetrahydroxy-7-(3-isopropylisoxazol-5-yl)-11-oxo-4a,5,5a,6-tetrahydro- 4H-tetracene-2-carboxamide (17% yield) was obtained as a yellow solid. LC-MS (ESI+) m / z: 465.1 (M+H) +. LCMS: calc. for C25H24N2O7: 464.16, found: [M+H]+465.1.1H NMR (400 MHz, CD3OD-d4): δ 7.77 - 7.64 (m, 1H), 6.96 - 6.88 (m, 1H), 6.53 - 6.46 (m, 1H), 4.87 - 4.85 (m, 1H), 3.71 - 3.61 (m, 1H), 3.21 - 3.03 (m, 3H), 2.85 - 2.72 (m, 1H), 2.59 - 2.55 (m, 1H), 2.50 - 2.49 (m, 1H), 2.58 - 2.45 (m, 3H), 1.96 - 1.84 (m, 1H), 1.62 - 1.49 (m, 1H), 1.39 - 1.32 (m, 7H). Example 45A: Synthesis and Characterization of (4aS,12aS)-7-cyclopropyl-3,10,11,12a- tetrahydroxy-1,12-dioxo-1,4,4a,5,12,12a-hexahydrotetracene-2-carboxamide

[0353] A mixture of (4aS,12aS)-3,10,11,12a-tetrahydroxy-7-iodo-1,12-dioxo-4a,5- dihydro-4H-tetracene-2-carboxamide (100.0 mg, 0.20 mmol) , cyclopropylboronic acid (173.5 mg, 2.02 mmol) , K2CO3 (139.5 mg, 1.01 mmol) , palladium bis((tri-t- butyl)phosphine) (103.2 mg, 0.2 mmol) in dioxane (4 mL) was degassed and purged with N2times, and then the mixture was stirred at 120°C for 12 hours under N2 atmosphere. Thereaction mixture was filtered and concentrated under reduced pressure. The residue was purified by prep-HPLC column: Welch Xtimate C18150 * 25mm * 5um; mobile phase: [water(HCl)-ACN];B%: 30%-60%,19 min. (4aS,12aS)-7-cyclopropyl-3,10,11,12a- tetrahydroxy-1,12-dioxo-4a,5-dihydro-4H-tetracene-2-carboxamide (11% yield) was obtained as a yellow solid. LCMS: calc. for C22H19NO7: 409.12, found: [M+H]+409.8.1H NMR (400MHz, ACETONITRILE-d3) δ = 14.97 (s, 1H), 9.49 (s, 1H), 8.99 (s, 1H), 7.73 (s, 1H), 7.39 (d, J = 8.0 Hz, 1H), 6.94 (s, 1H), 6.76 (d, J = 8.0 Hz, 1H), 5.19 ( s, 1H), 3.53 (d, J = 17.6 Hz, 1H), 3.10 - 3.01 (m, 1H), 2.96 - 2.89 (m, 2H), 2.67 - 2.59 (m, 1H), 2.66 - 2.64 (m, 1H), 2.66 - 2.64 (m, 1H), 2.65 - 2.59 (m, 1H), 1.05 - 1.01 (m, 2H), 0.67 - 0.63 (m, 2H). Example 46A: Synthesis and Characterization of (4aS,5aR,12aS)-3,10,12,12a- tetrahydroxy-7-(2-oxaspiro[3.3] hept-6-en-6-yl)-1,11-dioxo-4a,5,5a,6-tetrahydro-4H- tetracene-2-carboxamide

[0354] To the mixture of 2-oxaspiro[3.3]heptan-6-one (400 mg, 3.57 mmol) in THF (5.0 mL) was added KHMDS (1.0 M in THF, 4.3 mL, 4.3 mmol) at -78oC under N2, The mixture was stirred at -78 °C for 0.5 hour under N2, PhNTf2 (1.53 g, 4.3 mmol) in THF (1.0 mL) was added dropwise at -78oC. The reaction mixture was stirred at -78 °C for 2 hours under N2. The reaction mixture was quenched by addition H2O (30 mL) at 0 °C, and then extracted with EtOAc (20 mL x 3). The combined organic layers were washed with brine (30 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. which was purified by flash silica gel chromatography (ethyl acetate in petroleum ether = 0% to 40%) to afford 2-oxaspiro[3.3]hept-6-en-6-yl trifluoromethanesulfonate (32.1% yield) as a colorless oil.1H NMR (400 MHz, CDCl3-d) δ 5.51 (s, 1H), 4.85 - 4.70 (m, 4H), 3.01 (s, 2H).

[0355] (4aS,12aS)-3,10,11,12a-tetrahydroxy-7-iodo-1,12-dioxo-4a,5,5a,6-tetrahydro- 4H-tetracene-2-carboxamide (200 mg, 0.4 mmol), 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (306.4 mg, 1.2 mmol), XPhos (19.2 mg, 40.2 μmol), Pd[(t-Bu)3P)]2 (20.6 mg, 40.2 μmol) and AcOK (79.0 mg, 0.8 mmol) were placed in DMSO (3.0 mL) and the mixture was stirred at 100 °C for 2 hours under N2 by microwave. The mixture was filtered and purified by prep-HPLC(HCl) to afford (4aS,5aR,12aS)- 3,10,12,12a-tetrahydroxy-1,11-dioxo-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)- 4a,5,5a,6-tetrahydro-4H-tetracene-2-carboxamide (60% yield) as a yellow solid. LCMS: calc. for C25H28BNO9: 497.19, found: [M+H]+498.2.

[0356] (4aS,5aR,12aS)-3,10,12,12a-tetrahydroxy-1,11-dioxo-7-(4,4,5,5-tetramethyl- 1,3,2-dioxaborolan-2-yl)-4a,5,5a,6-tetrahydro-4H-tetracene-2-carboxamide (150 mg, 0.3 mmol), 2-oxaspiro[3.3]hept-6-en-6-yl trifluoromethanesulfonate (110.5 mg, 0.45 mmol), Cs2CO3(294.8 mg, 0.9 mmol), Pd(dppf)Cl2(22.1 mg, 30.2 μmol) were placed in dioxane (3.0 mL) and H2O (1.0 mL) and the reaction mixture was stirred at 95 °C for 6 hours under N2. The reaction mixture was filtered and purified by reverse phase column (FA) & prep-HPLC (FA) to afford (4aS,5aR,12aS)-3,10,12,12a-tetrahydroxy-7-(2-oxaspiro[3.3] hept-6-en-6-yl)- 1,11-dioxo-4a,5,5a,6-tetrahydro-4H-tetracene-2-carboxamide (11.8% yield) as a yellow solid. LCMS: calc. for C25H23NO8: 465.14, found: [M+H]+466.2 HPLC: 97.4% purity at 254 nm.1H NMR (400 MHz, CD3OD-d4) δ 7.43 (d, J = 8.8 Hz, 1H), 6.82 (d, J = 8.8 Hz, 1H), 6.27 (s, 1H), 4.92 (d, J = 1.6 Hz, 2H), 4.89 ( s, 2H), 3.55 - 3.44 (m, 1H), 3.28 - 3.25 (m, 1H), 3.17 (d, J = 12.8 Hz, 1H), 3.00 (d, J = 12.8 Hz, 1H), 2.92 - 2.82 (m, 1H), 2.53 - 2.46 (m, 1H), 2.45 - 2.32 (m, 2H), 2.12 - 2.07 (m, 1H), 1.70 - 1.61 (m, 1H). Example 47A: Synthesis and Characterization of (4aS,5aR,12aS)-3,10,12,12a- tetrahydroxy-7-(2-oxaspiro[3.3]heptan-6-yl)-1,11-dioxo-4a,5,5a,6-tetrahydro-4H- tetracene-2-carboxamide

[0357] A mixture of (4aS,5aR,12aS)-3,10,12,12a-tetrahydroxy-7-(2-oxaspiro[3.3]hept-6- en-6-yl)-1,11-dioxo-4a,5,5a,6-tetrahydro-4H-tetracene-2-carboxamide (40.0 mg, 85.9 μmol), PtO2(120 mg 5285 μmol) in THF (50 mL) was degassed and purged with H23 times andthen the mixture was stirred at 20 °C for 12 hours under H2atmosphere. The reaction mixture was filtered and concentrated under reduced pressure to give a residue. The crude product was purified by reverse-phase HPLC (FA) to afford (4aS,5aR,12aS)-3,10,12,12a- tetrahydroxy-7-(2-oxaspiro[3.3]heptan-6-yl)-1,11-dioxo-4a,5,5a,6-tetrahydro-4H-tetracene- 2-carboxamide (16.6% yield) as a yellow solid. LC-MS (ESI+) m / z: 468.3 (M+H)+. LCMS: calc. for C25H25NO8: 467.16, found: [M+H]+468.3. HPLC: 98.2% purity at 254 nm.1H NMR (400MHz, CD3OD): δ 8.40 (s, 1.0H), 7.38 (d, J = 8.4 Hz, 1.0H), 6.79 (d, J = 8.4 Hz, 0.9H), 4.51-4.72 (m, 4.0H), 3.44 (t, J =8.8 Hz, 0.9H), 3.22-3.32 (m, 3.0H), 2.94 (dd, J =15.6, 4.4 Hz, 1.0H), 2.76-2.88 (m, 1.0H), 2.58-2.74 (m, 2.0H), 2.45-2.52 (m, 1.0H), 2.38-2.44 (m, 1.0H), 2.31-2.38 (m, 1.0H), 2.12-2.45 (m, 4.0H), 2.12-2.28 (m, 2.0H), 2.07-2.11 (m, 1.0H), 1.55- 1.68 ppm (m, 1.2H). Example 48A: Synthesis and Characterization of (4aS,12aS)-3,10,12,12a-tetrahydroxy- 7-(2-oxaspiro[3.3]heptan-6-yl)-1,11-dioxo-4a,5-dihydro-4H-tetracene-2-carboxamide

[0358] A mixture of (4aS,12aS)-3,10,12,12a-tetrahydroxy-7-iodo-1,11-dioxo-4a,5- dihydro-4H-tetracene-2-carboxamide (400 mg, 752.3 μmol), 4,4,5,5-tetramethyl-2-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (382.1 mg, 1.5 mmol), AcOK (147.7 mg, 1.5 mmol), Pd[(t-Bu)3P]2 (38.5 mg, 75.2 μmol) and XPhos (35.9 mg, 75.2 μmol) in DMSO (7.0 mL) was degassed and purged with N23 times, and then the mixture was stirred at 100 °C for 2 hours under N2atmosphere under MW. The reaction mixture was filtered to give a residue. The crude product was purified by prep-HPLC (FA). (4aS,12aS)- 3,10,12,12a-tetrahydroxy-1,11-dioxo-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-4a,5- dihydro-4H-tetracene-2-carboxamide (169 mg) was obtained as a yellow solid. LC-MS (ESI+) m / z: 496.2 (M+H)+.

[0359] To a solution of 2-oxaspiro[3.3]hept-6-en-6-yl trifluoromethanesulfonate (124.5 mg, 509.8 μmol) and (4aS,5aR,12aS)-3,10,11,12a-tetrahydroxy-1,12-dioxo-7-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)-4a,5,5a,6-tetrahydro-4H-tetracene-2-carboxamide (169 mg, 339.8 μmol, 1 eq) in dioxane (10.0 mL) and H2O (3.0 mL) was added Pd(dppf)Cl2(24.9 mg, 34.0 μmol) and Cs2CO3(332.2 mg, 1.0 mmol). The mixture was degassed and purged with N23 times, and then the mixture was stirred at 95 °C for 3 hours under N2 atmosphere. The reaction mixture was filtered to give a residue. The crude product was purified by reverse-phase HPLC (column: C18150×30mm; mobile phase: [Water (FA)-MeCN]; gradient: 18%-58% B over 9 min). (4aS,12aS)-3,10,11,12a-tetrahydroxy-7-(2- oxaspiro[3.3]hept-6-en-6-yl)-1,12-dioxo-4a,5-dihydro-4H-tetracene-2-carboxamide (88.9% yield) was obtained as a green solid. LC-MS (ESI+) m / z: 463.9 (M+H)+.

[0360] A mixture of (4aS,12aS)-3,10,12,12a-tetrahydroxy-7-(2-oxaspiro[3.3]hept-6-en-6- yl)-1,11-dioxo-4a,5-dihydro-4H-tetracene-2-carboxamide (100 mg, 215.8 μmol), PtO2 (147 mg, 647.3 μmol) in THF (5.0 mL) was degassed and purged with H23 times, and then the mixture was stirred at 20 °C for 12 hours under H2atmosphere. The reaction mixture was filtered and concentrated under reduced pressure to give a residue. The crude product was purified by reverse-phase HPLC (column: C18150×30mm;mobile phase: [Water(FA)- MeCN];gradient:17%-57% B over 9 min). (4aS,12aS)-3,10,12,12a-tetrahydroxy-7-(2- oxaspiro[3.3]heptan-6-yl)-1,11-dioxo-4a,5-dihydro-4H-tetracene-2-carboxamide (4.4% yield) was obtained as a yellow solid. LCMS: calc. for C25H23NO8: 465.14, found: [M+H]+466.1. HPLC: 97.0% purity at 254 nm.1H NMR (400MHz, CD3OD): δ 7.4-7.5 (m, 1H), 7.21 (s, 1H), 6.7-6.9 (m, 1H), 4.63 (s, 3H), 3.7-3.8 (m, 1H), 3.4-3.6 (m, 1H), 3.0-3.1 (m, 2H), 2.8-2.9 (m, 4H), 2.5-2.6 (m, 1H), 2.3-2.4 (m, 3H). Example 1B: Synthesis and Characterization of (4R, 4aS, 5aR, 12aS)-4- (diethylamino)-3,10,12,12a-tetrahydroxy-1,11-dioxo-4a,5,5a,6-tetrahydro-4H-tetracene- 2-carboxamide

[0361] To a solution of (4S, 4aS, 5aR, 12aS)-4-(dimethylamino)-3,10,12,12a- tetrahydroxy-1,11-dioxo-4a,5,5a,6-tetrahydro-4H-tetracene-2-carboxamide (1 eq.) in DMF (0.5 mL) at 20°C was added hydroxylamine (15 M, 50% purity), and the mixture was stirred at 80°C for 0.5 h under air. The reaction mixture was acidified with 2 N HCl to pH = 5-6, and then concentrated under reduced pressure to give a residue. The residue was purified by prep- HPLC. (4Z, 4aS, 5aR, 12aS)-3,10,12,12a-tetrahydroxy-4-hydroxyimino-1,11-dioxo-4a,5,5a,6- tetrahydrotetracene-2-carboxamide (24.7% yield) was obtained as a yellow solid. LC-MS (ESI+) m / z: 400.9 (M+H)+.1H NMR (400 MHz, DMSO-d6): δ 14.96 (br s, 1H), 12.95 (br s, 1H), 11.55 (s, 1H), 9.10 - 8.54 (m, 2H), 7.44 (t, J = 7.6 Hz, 1H), 6.98 (d, J = 6.0 Hz, 1H), 6.79 (dd, J = 7.6, 19.2 Hz, 2H), 3.73 (d, J = 12.0 Hz, 1H), 3.06 - 2.73 (m, 3H), 2.45 - 2.38 (m, 1H), 2.10 - 1.97 (m, 1H), 1.38 - 1.26 (m, 1H).

[0362] To a solution of (4Z, 4aS, 5aR, 12aS)-3,10,12,12a-tetrahydroxy-4-hydroxyimino- 1,11-dioxo-4a,5,5a,6-tetrahydrotetracene-2-carboxamide (1 eq) in MeOH (5 mL) at 30°C was added AcOH (5 eq.) and Pd / C (2 eq.), and the mixture was purged and degassed with H2 for 3 times and then stirred at 30°C for 72 h under H2 (50 Psi). The reaction mixture was filtered to remove the Pd / C and the filtrate was concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC. (4aS, 5aR, 12aS)-4-amino-3,10,12,12a- tetrahydroxy-1,11-dioxo-4a,5,5a,6-tetrahydro-4H-tetracene-2-carboxamide (3.4% yield) was obtained as a yellow solid. LC-MS (ESI+) m / z: 386.9 (M+H)+.1H NMR (400 MHz, DMSO- d6): δ 12.68 - 11.59 (m, 1H), 8.84 (br s, 1H), 8.16 (s, 1H), 7.39 (br t, J = 7.6 Hz, 1H), 7.13 - 6.61 (m, 3H), 4.21 (br d, J = 4.4 Hz, 1H), 2.79 - 2.63 (m, 3H), 2.40 - 2.30 (m, 1H), 2.05 (br d, J = 12.8 Hz, 1H), 1.38 - 1.19 (m, 1H).

[0363] To a solution of (4R, 4aS, 5aR, 12aS)-4-amino-3,10,12,12a-tetrahydroxy-1,11- dioxo-4a,5,5a,6-tetrahydro-4H-tetracene-2-carboxamide (1 eq.) in THF (1 mL) at 20 °C wasadded acetaldehyde (4 eq.) and NaBH3CN (9 theoretical eq), and the mixture was stirred at 20°C for 2 h. The reaction mixture was quenched with water (1 mL) and then concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC. The product (4R, 4aS, 5aR, 12aS)-4-(diethylamino)-3,10,12,12a-tetrahydroxy-1,11-dioxo- 4a,5,5a,6-tetrahydro-4H-tetracene-2-carboxamide (17.2% yield) was obtained as a yellow solid. LC-MS (ESI+) m / z: 443.2 (M+H)+.1H NMR (400 MHz, CD3CN): δ 14.92 (s, 1H), 11.52 (s, 1H), 11.06 - 10.59 (m, 1H), 9.53 - 9.07 (m, 1H), 8.00 - 7.59 (m, 1H), 7.41 (dd, J = 7.6, 8.4 Hz, 1H), 6.77 (dd, J = 8.0, 14.0 Hz, 2H), 4.91 - 4.59 (m, 1H), 3.61 - 3.26 (m, 3H), 3.26 - 3.04 (m, 2H), 3.01 - 2.87 (m, 2H), 2.82 - 2.76 (m, 1H), 2.59 - 2.54 (m, 2H), 1.62 - 1.51 (m, 1H), 1.47 (br t, J = 7.2 Hz, 3H), 1.38 (br d, J = 6.0 Hz, 3H). Example 2B: Synthesis and Characterization of (4R, 4aS, 5aR, 12aS)-4-(ethylamino)- 3,10,12,12a-tetrahydroxy-1,11-dioxo-4a,5,5a,6-tetrahydro-4H-tetracene-2-carboxamide

[0364] To a solution of (4aS, 5aR, 12aS)-4-amino-3,10,12,12a-tetrahydroxy-1,11-dioxo- 4a,5,5a,6-tetrahydro-4H-tetracene-2-carboxamide (1 eq.) in EtOH (1 mL) at 20°C was added acetaldehyde (3 eq.) and Pd / C, and the mixture was purged and degassed with H2 for 3 times and then stirred at 20°C for 20 h under H2(15 Psi). The reaction mixture was filtered to remove the Pd / C and the filtrate was concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC. (4R, 4aS, 5aR, 12aS)-4-(ethylamino)-3,10,12,12a- tetrahydroxy-1,11-dioxo-4a,5,5a,6-tetrahydro-4H-tetracene-2-carboxamide (42.5% yield) was obtained as a yellow solid. LC-MS (ESI+) m / z: 415.2 (M+H)+.1H NMR (400 MHz, DMSO- d6): δ 15.06 (br s, 1H), 11.48 (s, 1H), 9.82 - 9.57 (m, 1H), 9.54 (br s, 1H), 9.40 (br s, 1H), 9.22 (br s, 1H), 7.46 (t, J = 7.6 Hz, 1H), 7.28 (br s, 1H), 6.82 (dd, J = 4.0, 7.6 Hz, 2H), 4.57 (br s, 1H), 3.25 - 3.08 (m, 2H), 3.02 - 2.92 (m, 1H), 2.90 - 2.82 (m, 1H), 2.79 - 2.70 (m, 1H), 2.58 (br t, J = 14.8 Hz, 2H), 2.15 (br dd, J = 1.6, 11.2 Hz, 1H), 1.29 (br t, J = 7.2 Hz, 3H). Example 3B: Synthesis and Characterization of (4R, 4aS, 5aR, 12aS)-4- (dipropylamino)-3,10,12,12a-tetrahydroxy-1,11-dioxo-4a,5,5a,6-tetrahydro-4H- tetracene-2-carboxamide

[0365] To a solution of (4R, 4aS, 5aR, 12aS)-4-amino-3,10,12,12a-tetrahydroxy-1,11- dioxo-4a,5,5a,6-tetrahydro-4H-tetracene-2-carboxamide (1 eq.) in THF (5 mL) at 20°C was added propanal (3 eq.) and NaBH3CN (9 theoretical eq.), and the mixture was stirred at 20°C for 16 h. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC. (4R, 4aS, 5aR, 12aS)-4-(dipropylamino)- 3,10,12,12a-tetrahydroxy-1,11-dioxo-4a,5,5a,6-tetrahydro-4H-tetracene-2-carboxamide (9.8 mg, 18.9 umol, 32.0% yield, 98% purity, HCl) was obtained as a yellow solid. LC-MS (ESI+) m / z: 471.1 (M+H)+.1H NMR (400 MHz, CD3OD): δ 7.41 (t, J = 8.0 Hz, 1H), 6.83 - 6.72 (m, 2H), 5.01 (br d, J = 4.0 Hz, 1H), 3.42 - 3.32 (m, 3H), 3.17 - 3.09 (m, 1H), 3.06 - 2.98 (m, 1H), 2.96 - 2.91 (m, 1H), 2.86 (dd, J = 4.4, 15.2 Hz, 1H), 2.62 - 2.53 (m, 1H), 2.24 (td, J = 2.4, 11.2 Hz, 1H), 2.03 - 1.81 (m, 4H), 1.74 - 1.57 (m, 1H), 1.05 (t, J = 7.2 Hz, 6H). Example 4B: Synthesis and Characterization of (4R, 4aS, 5aR, 12aS)-3,10,12,12a- tetrahydroxy-1,11-dioxo-4-(propylamino)-4a,5,5a,6-tetrahydro-4H-tetracene-2- carboxamide

[0366] To a solution of (4R, 4aS, 5aR, 12aS)-4-amino-3,10,12,12a-tetrahydroxy-1,11- dioxo-4a,5,5a,6-tetrahydro-4H-tetracene-2-carboxamide (1 eq.) in THF (1 mL) at 20°C was added propanal (3 eq.) and NaBH3CN (9 theoretical eq.), and the mixture was stirred at 20°C for 16 h. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (4R, 4aS, 5aR, 12aS)-3,10,12,12a-tetrahydroxy-1,11- dioxo-4-(propylamino)-4a,5,5a,6-tetrahydro-4H-tetracene-2-carboxamide (8.0% yield) were obtained as a yellow solid. LC-MS (ESI+) m / z: 429.1 (M+H)+.1H NMR (400 MHz, DMSO- d6): δ 11.64 (br s, 1H), 9.14 (br d, J = 1.6 Hz, 1H), 8.13 (s, 1H), 7.43 (t, J = 7.6 Hz, 1H), 6.78 (br t, J = 8.4 Hz, 3H), 4.12 (br d, J = 3.6 Hz, 1H), 2.77 (br d, J = 13.2 Hz, 4H), 2.62 - 2.53(m, 2H), 2.16 - 2.07 (m, 1H), 1.57 (br d, J = 3.2 Hz, 2H), 1.26 - 1.10 (m, 1H), 0.91 (t, J = 7.2 Hz, 3H). 6% of Compound 3 could also be isolated from this reaction. Example 5B: Synthesis and Characterization of (4R, 4aS, 5aR, 12aS)-3,10,12,12a- tetrahydroxy-1,11-dioxo-4-pyrrolidin-1-yl-4a,5,5a,6-tetrahydro-4H-tetracene-2- carboxamide

[0367] To a solution of (4R, 4aS, 5aR, 12aS)-4-amino-3,10,12,12a-tetrahydroxy-1,11- dioxo-4a,5,5a,6-tetrahydro-4H-tetracene-2-carboxamide (1 eq.) in THF (2 mL) and at 20°C was added butanedial (3 eq.) and then NaBH3CN (9 theoretical eq.), and the mixture was stirred at 20 °C for 2 h. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC. (4R, 4aS, 5aR, 12aS)-3,10,12,12a- tetrahydroxy-1,11-dioxo-4-pyrrolidin-1-yl-4a,5,5a,6-tetrahydro-4H-tetracene-2-carboxamide (17.0% yield) was obtained as a yellow solid. LC-MS (ESI+) m / z: 440.9 (M+H)+.1H NMR (400 MHz, DMSO-d6): δ 15.05 (br s, 1H), 11.47 (s, 1H), 10.91 (br d, J = 1.6 Hz, 1H), 9.49 (br s, 1H), 9.34 (br s, 1H), 7.46 (t, J = 7.6 Hz, 1H), 6.84 - 6.79 (m, 2H), 4.87 (br dd, J = 3.6, 7.6 Hz, 1H), 4.09 - 4.00 (m, 1H), 3.56 (br d, J = 4.4 Hz, 1H), 3.11 (br d, J = 5.6 Hz, 1H), 2.98 - 2.88 (m, 2H), 2.78 - 2.72 (m, 1H), 2.58 (br t, J = 14.8 Hz, 1H), 2.39 - 2.19 (m, 1H), 2.01 (br d, J = 5.2 Hz, 3H), 1.91 - 1.61 (m, 1H), 1.46 - 1.34 (m, 1H). Example 6B: Synthesis and Characterization of (4R, 4aS, 5aR, 12aS)-3,10,12,12a- tetrahydroxy-1,11-dioxo-4-(1-piperidyl)-4a,5,5a,6-tetrahydro-4H-tetracene-2- carboxamide

[0368] To a solution of (4R, 4aS, 5aR, 12aS)-4-amino-3,10,12,12a-tetrahydroxy-1,11- dioxo-4a,5,5a,6-tetrahydro-4H-tetracene-2-carboxamide (1 eq.) in THF (1 mL) at 20 °C was added pentanedial (3 eq) and NaBH3CN (9 theoretical eq) and the mixture was stirred at20°C for 2 h. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC. (4R, 4aS, 5aR, 12aS)-3,10,12,12a- tetrahydroxy-1,11-dioxo-4-(1-piperidyl)-4a,5,5a,6-tetrahydro-4H-tetracene-2-carboxamide as a hydrochloride salt (9.1% yield) was obtained as a yellow solid. LC-MS (ESI+) m / z: 455.0 (M+H)+.1H NMR (400 MHz, CD3CN): δ 14.94 (s, 1H), 11.52 (s, 1H), 10.46 - 10.22 (m, 1H), 9.33 - 9.09 (m, 1H), 7.61 (br s, 1H), 7.46 - 7.37 (m, 1H), 6.78 (dd, J = 7.6, 14.0 Hz, 2H), 4.72 - 4.62 (m, 1H), 3.92 (br dd, J = 3.6, 12.4 Hz, 1H), 3.44 - 3.37 (m, 1H), 3.26 - 3.10 (m, 2H), 3.08 - 3.01 (m, 1H), 3.00 - 2.83 (m, 2H), 2.79 (dd, J = 4.4, 15.2 Hz, 1H), 2.58 (br d, J = 14.0 Hz, 1H), 2.53 - 2.45 (m, 2H), 2.12 - 2.07 (m, 1H), 1.86 - 1.75 (m, 3H), 1.58 - 1.49 (m, 2H). Example 7B: Synthesis and Characterization of (4R,4aS,5aR,12aS)-3,10,12,12a- tetrahydroxy-4-morpholino-1,11-dioxo-4a,5,5a,6-tetrahydro-4H-tetracene-2- carboxamide

[0369] To a solution of tetrahydrofuran-3,4-diol (1 eq.) in H2O (2 mL) at 20 °C was added sodium periodate (1 eq.), and the mixture was stirred at 20°C for 16 h. The solid NaHCO3was added to the reaction mixture until the reaction mixture pH = 7-8, then diluted with ACN (5 mL), and then filtered to remove the solid. The filtrate was concentrated under reduced pressure to give a residue. The product, 2-(2-oxoethoxy) acetaldehyde (99.9% yield), was obtained as colorless oil, which was used directly for next step.

[0370] To a solution of (4R,4aS,5aR,12aS)-4-amino-3,10,12,12a-tetrahydroxy-1,11- dioxo-4a,5,5a,6-tetrahydro-4H-tetracene-2-carboxamide (1 eq.) in THF (3 mL) at 20°C was added 2-(2-oxoethoxy)acetaldehyde (1.5 eq) and then NaBH3CN (9 theoretical eq.), and the mixture was stirred at 20°C for 5 h. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC. (4R,4aS,5aR,12aS)- 3,10,12,12a-tetrahydroxy-4-morpholino-1,11-dioxo-4a,5,5a,6-tetrahydro-4H-tetracene-2- carboxamide as a hydrochloride salt (13.4% yield) was obtained as a yellow solid. LC-MS (ESI+) m / z: 4570 (M+H)+ 1H NMR (400 MHz CD3OD): δ 740 (t J = 80 Hz 1H) 6836.69 (m, 2H), 4.90 (br s, 1H), 4.23 - 3.96 (m, 4H), 3.88 - 3.64 (m, 1H), 3.42 (br s, 3H), 3.07 - 2.92 (m, 2H), 2.90 - 2.79 (m, 1H), 2.64 - 2.51 (m, 1H), 2.14 - 1.97 (m, 1H), 1.65 - 1.42 (m, 1H). Example 8B: Synthesis and Characterization of (4R, 4aS, 5aR, 12aS)-4-acetamido- 3,10,12,12a-tetrahydroxy-1,11-dioxo-4a,5,5a,6-tetrahydro-4H-tetracene-2-carboxamide

[0371] The solution of (4aS, 5aR, 12aS)-4-amino-3,10,12,12a-tetrahydroxy-1,11-dioxo- 4a,5,5a,6-tetrahydro-4H-tetracene-2-carboxamide (1 eq.) in Ac2O (0.5 mL) was stirred at 20°C for 2 h. The reaction mixture was diluted with EtOH (5 mL) and then concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC. (4R, 4aS, 5aR, 12aS)-4-acetamido-3,10,12,12a-tetrahydroxy-1,11-dioxo-4a,5,5a,6-tetrahydro-4H- tetracene-2-carboxamide (21.8% yield) was obtained as a yellow solid. LC-MS (ESI+) m / z: 429.1 (M+H)+.1H NMR (400 MHz, DMSO-d6): δ 15.16 - 14.94 (m, 1H), 11.54 (s, 1H), 9.60 - 8.91 (m, 3H), 8.26 (br d, J = 9.2 Hz, 1H), 7.43 (t, J = 8.0 Hz, 1H), 6.93 (br s, 1H), 6.79 (br t, J = 8.4 Hz, 2H), 5.49 - 5.30 (m, 1H), 2.80 - 2.71 (m, 2H), 2.45 - 2.30 (m, 2H), 2.17 - 2.05 (m, 1H), 1.95 (s, 3H), 1.26 - 1.10 (m, 1H). Example 9B: Synthesis and Characterization of Methyl N-[(1R, 4aS, 11aR, 12aS)-3- carbamoyl-2,4a,5,7-tetrahydroxy-4,6-dioxo-11,11a,12,12a-tetrahydro-1H-tetracen-1- yl]carbamate

[0372] To a solution of (4R, 4aS, 5aR, 12aS)-4-amino-3,10,12,12a-tetrahydroxy-1,11- dioxo-4a,5,5a,6-tetrahydro-4H-tetracene-2-carboxamide (1 eq.) in THF (2 mL) at 20 °C was added methyl chloroformate (2 eq.), and the mixture was stirred at 20°C for 16 h. The reaction mixture was quenched with MeOH (2 mL) and then concentrated under reducedpressure to give a residue. The residue was purified by prep-HPLC. Methyl N-[(1R, 4aS, 11aR, 12aS)-3-carbamoyl-2,4a,5,7-tetrahydroxy-4,6-dioxo-11,11a,12,12a-tetrahydro-1H- tetracen-1-yl]carbamate (22.9% yield) was obtained as a yellow solid. LC-MS (ESI+) m / z: 445.1 (M+H)+.1H NMR (400 MHz, DMSO-d6): δ 15.05 (br s, 1H), 11.54 (s, 1H), 9.78 - 8.85 (m, 3H), 7.72 - 7.52 (m, 1H), 7.43 (t, J = 8.0 Hz, 1H), 7.02 - 6.87 (m, 1H), 6.79 (dd, J = 5.2, 8.0 Hz, 2H), 5.09 (br dd, J = 2.0, 3.6 Hz, 1H), 3.60 (s, 3H), 2.84 - 2.70 (m, 2H), 2.53 (br d, J = 6.4 Hz, 1H), 2.44 - 2.36 (m, 1H), 2.15 (br d, J = 11.2 Hz, 1H), 1.15 (q, J = 12.8 Hz, 1H). Example 10B: Synthesis and Characterization of (4R, 4aS, 5aR, 12aS)-4- (cyclobutylamino)-3,10,12,12a-tetrahydroxy-1,11-dioxo-4a,5,5a,6-tetrahydro-4H- tetracene-2-carboxamide

[0373] To a solution of (4R, 4aS, 5aR, 12aS)-4-amino-3,10,12,12a-tetrahydroxy-1,11- dioxo-4a,5,5a,6-tetrahydro-4H-tetracene-2-carboxamide (1 eq.) in THF (2 mL) at 20 °C was added cyclobutanone (3 eq.), HOAc (2 eq.) and then NaBH3CN (9 theoretical eq.), and the mixture was stirred at 20°C for 2 h. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC. (4R, 4aS, 5aR, 12aS)-4- (cyclobutylamino)-3,10,12,12a-tetrahydroxy-1,11-dioxo-4a,5,5a,6-tetrahydro-4H-tetracene- 2-carboxamide (12.5% yield) was obtained as a yellow solid. LC-MS (ESI+) m / z: 440.9 (M+H)+.1H NMR (400 MHz, CD3OD): δ 7.41 (t, J = 8.0 Hz, 1H), 6.85 - 6.69 (m, 2H), 4.62 (d, J = 4.0 Hz, 1H), 4.13 - 4.00 (m, 1H), 2.98 - 2.90 (m, 1H), 2.89 - 2.74 (m, 2H), 2.64 - 2.53 (m, 1H), 2.50 - 2.24 (m, 4H), 2.10 - 1.85 (m, 3H), 1.53 - 1.36 (m, 1H). Example 11B: Synthesis and Characterization of (4R,4aS,5aR,12aS)-4- [cyclobutyl(methyl)amino]-3,10,12,12a-tetrahydroxy-1,11-dioxo-4a,5,5a,6-tetrahydro- 4H-tetracene-2-carboxamide

[0374] To a solution of (4R,4aS,5aR,12aS)-4-(cyclobutylamino)-3,10,12,12a- tetrahydroxy-1,11-dioxo-4a,5,5a,6-tetrahydro-4H-tetracene-2-carboxamide (1 eq.) in THF (3 mL) at 20 °C was added formaldehyde (3 eq.), HOAc (2 eq.) and then NaBH3CN (9 theor. eq.), and the mixture was stirred at 20°C for 16 h. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC. (4R,4aS,5aR,12aS)-4-[cyclobutyl(methyl)amino]-3,10,12,12a-tetrahydroxy-1,11-dioxo- 4a,5,5a,6-tetrahydro-4H-tetracene-2-carboxamide (5.5% yield) was obtained as a yellow solid. LC-MS (ESI+) m / z: 455.0 (M+H)+.1H NMR (400 MHz, CD3OD): δ 7.41 (t, J = 7.6 Hz, 1H), 6.83 - 6.70 (m, 2H), 4.89 (br s, 1H), 4.25 - 4.12 (m, 1H), 3.14 - 3.01 (m, 2H), 3.00 - 2.90 (m, 3H), 2.85 (dd, J = 4.4, 15.2 Hz, 1H), 2.63 - 2.52 (m, 1H), 2.49 - 2.10 (m, 5H), 1.97 - 1.79 (m, 2H), 1.75 - 1.60 (m, 1H). Example 12B: Synthesis and Characterization of (4S,4aS,5aR,12aS)-4- (dimethylamino)-3,10,12,12a-tetrahydroxy-1,11-dioxo-7-(1H-pyrazol-3-yl)-4a,5,5a,6- tetrahydro-4H-tetracene-2-carboxamide

[0375] (4S,4aS,5aR,12aS)-4-(dimethylamino)-3,10,12,12a-tetrahydroxy-7-iodo-1,11- dioxo-4a,5,5a,6-tetrahydro-4H-tetracene-2-carboxamide [Nelson, et.al. Journal of Organic Chemistry, 2003, vol.68, # 15, p.5838 - 5851] (1 eq.), 3-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)-1H-pyrazole (2 eq.), Pd(PPh3)4 (0.1 eq.), K2CO3 (2 eq.) were added in mixture of toluene (8 mL) and H2O (2 mL), EtOH (2 mL), the reaction mixture was stirred at 100°C for 3 hours under N2. The reaction mixture was concentrated under reduced pressure to removed solvent. The residue was purified by prep-HPLC (HCl condition). (4S,4aS,5aR,12aS)-4-(dimethylamino)-3,10,12,12a-tetrahydroxy-1,11-dioxo-7-(1H-pyrazol- 3-yl)-4a,5,5a,6-tetrahydro-4H-tetracene-2-carboxamide (39.4% yield) was obtained as a yellow solid. LC-MS (ESI+) m / z: 481.0 (M+H)+. Example 13B: Synthesis and Characterization of (4R,4aS,5aR,12aS)-4- (dimethylamino)-3,10,12,12a-tetrahydroxy-1,11-dioxo-7-(1H-pyrazol-3-yl)-4a,5,5a,6- tetrahydro-4H-tetracene-2-carboxamide

[0378] (4S,4aS,5aR,12aS)-4-(dimethylamino)-3,10,12,12a-tetrahydroxy-7-iodo-1,11- dioxo-4a,5,5a,6-tetrahydro-4H-tetracene-2-carboxamide [Nelson, et.al. Journal of Organic Chemistry, 2003, vol.68, # 15, p.5838 - 5851] (1 eq.), (1-methylpyrazol-4-yl)boronic acid (2 eq.), Pd(PPh3)4 (0.1 eq.), K2CO3 (2 eq.) were added in mixture of toluene (8 mL) and H2O (2 mL), EtOH (2 mL), the reaction mixture was stirred at 100°C for 8 hours under N2. The reaction mixture was concentrated under reduced pressure to removed solvent. The residue was purified by prep-HPLC (HCl condition). (4S,4aS,5aR,12aS)-4-(dimethylamino)- 3,10,12,12a-tetrahydroxy-7-(1-methylpyrazol-4-yl)-1,11-dioxo-4a,5,5a,6-tetrahydro-4H-tetracene-2-carboxamide (22.2% yield) was obtained as a yellow solid. LC-MS (ESI+) m / z: 495.0 (M+H)+.

[0379] (4S,4aS,5aR,12aS)-4-(dimethylamino)-3,10,12,12a-tetrahydroxy-7-(1- methylpyrazol-4-yl)-1,11-dioxo-4a,5,5a,6-tetrahydro-4H-tetracene-2-carboxamide (1 eq.) was added in MeOH (4 mL) and aqueous NaH2PO4(1 M, 2 mL), the reaction mixture was stirred at 25°C for 36 hours. The reaction mixture was concentrated under reduced pressure to removed solvent. The residue was purified by prep-HPLC (HCl condition). (4R,4aS,5aR,12aS)-4-(dimethylamino)-3,10,12,12a-tetrahydroxy-7-(1-methylpyrazol-4-yl)- 1,11-dioxo-4a,5,5a,6-tetrahydro-4H-tetracene-2-carboxamide (15.6% yield) was obtained as a yellow solid. LC-MS (ESI+) m / z: 495.0 (M+H)+.1H NMR (400 MHz, DMSO-d6): δ 14.95 (s, 1H), 11.65 (s, 1H), 10.37 (s, 1H), 9.5-9.24 (m, 2H), 7.82 (s, 1H), 7.54-7.52 (m, 2H), 6.91- 6.83 (m, 1H), 4.76-7.64 (m, 1H), 3.85 (s, 3H), 3.08-2.81 (m, 10H), 2.07-2.05 (m, 1H), 1.48- 1.37 (m, 1H). Example 15B: Synthesis and Characterization of 4Z,4aS,5aR,12aS)-3,10,12,12a- tetrahydroxy-4-methoxyimino-1,11-dioxo-4a,5,5a,6-tetrahydrotetracene-2-carboxamide

[0380] To a solution of (4S,4aS,5aR,12aS)-4-(dimethylamino)-3,10,12,12a-tetrahydroxy- 1,11-dioxo-4a,5,5a,6-tetrahydro-4H-tetracene-2-carboxamide (1 eq.) in DMF (10 mL) at 20°C was added O-methylhydroxylamine HCl (1.5 eq) and TEA (1.5 eq.), and the mixture was stirred at 80°C for 4 hours under air (15 Psi). The reaction mixture was concentrated to remove the solvent. The residue was diluted with water (20 mL) and EtOAc (20 mL), then acidified with 2 N HCl to pH = 3-4, and then filtered to collect the solid, which was dried in vacuum to give a residue. The sample was purified by prep-HPLC. The product (4Z,4aS,5aR,12aS)-3,10,12,12a-tetrahydroxy-4-methoxyimino-1,11-dioxo-4a,5,5a,6- tetrahydrotetracene-2-carboxamide (16.3 % yield) was obtained as a yellow solid. LC-MS (ESI+) m / z: 414.9 (M+H)+.1H NMR (400 MHz, DMSO-d6): δ 14.94 (s, 1H), 11.54 (s, 1H), 9.48 - 8.48 (m, 2H), 7.45 (t, J = 8.0 Hz, 1H), 7.25 - 6.90 (m, 1H), 6.86 - 6.73 (m, 2H), 4.07 (s, 3H), 3.68 (br dd, J = 2.4, 13.2 Hz, 1H), 2.93 (ddd, J = 4.4, 10.8, 18.4 Hz, 2H), 2.83 (br dd, J = 4.4, 15.6 Hz, 1H), 2.45 - 2.41 (m, 1H), 2.06 - 1.98 (m, 1H), 1.44 - 1.31 (m, 1H).Example 16B: Synthesis and Characterization of (4R,4aR,5aR)-4-amino-1,3,10,12- tetrahydroxy-11-oxo-4,4a,5,5a,6,11-hexahydrotetracene-2-carboxamide formate

[0381] The solution of (4Z,4aS,5aR,12aS)-3,10,12,12a-tetrahydroxy-4-methoxyimino- 1,11-dioxo-4a,5,5a,6-tetrahydrotetracene-2-carboxamide (1.0 eq) and zinc dust (5.0 eq) in H2O (10 mL) and acetic acid (10 mL) was stirred at 25oC for 16 h. The reaction solution was filtered and concentrated under reduced pressure. The residue was purified by prep-HPLC. (4R,4aR,5aR)-4-amino-1,3,10,12-tetrahydroxy-11-oxo-4,4a,5,5a,6,11-hexahydrotetracene-2- carboxamide formate (25.1% yield) was obtained as a yellow solid. LC-MS (ESI+) m / z: 370.9 (M+H)+.1H NMR (400 MHz, DMSO-d6) δ 12.94 (s, 1 H), 9.31 (s, 1H), 8.50 - 7.55 (m, 3 H), 7.73 (d, J = 4.4 Hz, 1 H), 7.13 (t, J = 8.0 Hz, 1 H), 6.70 - 6.50 (m, 2 H), 3.27 (s, 1 H), 2.98 - 2.80 (m, 1 H), 2.80 - 2.54 (m, 2 H), 2.45 - 2.35 (m, 1 H), 2.85 - 2.99 (m, 2 H), 2.53 - 2.64 (m, 1 H), 2.13 - 2.29 (m, 2 H), 2.12 - 2.30 (m, 1 H), 1.90 - 1.75 (m, 1 H), 1.50 - 1.30 (m, 1 H) Example 17B: Synthesis and Characterization of (4Z,4aS,5aR,12aS)-3,10,12,12a- tetrahydroxy-4-methoxyimino-1,11-dioxo-7-(1H-pyrazol-3-yl)-4a,5,5a,6- tetrahydrotetracene-2-carboxamide

[0382] The reaction of (4R,4aR,5aR)-4-amino-1,3,10,12-tetrahydroxy-11-oxo-4a,5,5a,6- tetrahydro-4H-tetracene-2-carboxamide (1.0 eq) and aqueous butanedial (20.0 eq) in THF (1.50 mL) was added NaBH3CN (5.0 eq) at 0°C , and the reaction mixture was stirred at 0°C for 1 h. The reaction mixture was filtered and concentrated under reduced pressure. The residue was purified by prep-HPLC. (4Z,4aS,5aR,12aS)-3,10,12,12a-tetrahydroxy-4- methoxyimino-1,11-dioxo-7-(1H-pyrazol-3-yl)-4a,5,5a,6-tetrahydrotetracene-2-carboxamide was obtained as a yellow solid and then purified by a second prep-HPLC (HCl), the desiredproduct was obtained as a yellow solid as an HCl salt (5%). LC-MS (ESI+) m / z: 425.0 (M+H)+.1H NMR (400 MHz, CD3OD) δ 7.41 (t, J = 7.9 Hz, 1H), 6.72 - 6.86 (m, 2H), 4.68 (d, J = 3.9 Hz, 1H), 4.30 - 4.40 (m, 1H), 3.84 (d, J = 3.8 Hz, 1H), 3.80 - 3.88 (m, 1H), 3.63 - 3.71 (m, 1H), 3.56 - 3.62 (m, 1H), 3.26 - 3.32 (m, 1H), 3.05 (d, J=11.0 Hz, 1H), 2.85 - 2.99 (m, 2H), 2.53 - 2.64 (m, 1H), 2.13 - 2.29 (m, 2H), 2.12 - 2.30 (m, 1H), 1.95 - 2.08 (m, 2H), 1.45 - 1.56 (m, 1H). Example 18B: Synthesis and Characterization of (4R,4aR,5aR)-1,3,10,12- tetrahydroxy-11-oxo-4-(1-piperidyl)-4a,5,5a,6-tetrahydro-4H-tetracene-2-carboxamide

[0383] To a solution of (4R,4aR,5aR)-4-amino-1,3,10,12-tetrahydroxy-11-oxo-4a,5,5a,6- tetrahydro-4H-tetracene-2-carboxamide (1.0 eq) in THF (0.5 mL) at 0°C was added pentanedial (20.0 eq) and then NaBH3CN (5.0 eq), and the mixture was stirred at 0 °C for 1 h. The reaction mixture was quenched by HCl / MeOH (4 M, 0.5 mL) and concentrated to remove the solvent. The residue was purified by prep-HPLC (HCl condition). (4R,4aR,5aR)- 1,3,10,12-tetrahydroxy-11-oxo-4-(1-piperidyl)-4a,5,5a,6-tetrahydro-4H-tetracene-2- carboxamide (4%) was obtained as a yellow solid. LC-MS (ESI+) m / z: 439.0 (M+H)+.1H NMR (400 MHz, MeOD): δ 7.50-7.35 (m, 1H), 6.90-6.75 (m, 2H), 4.62 (d, J = 3.6 Hz, 1H), 4.15-4.00 (m, 1H), 3.85 (d, J = 3.2 Hz, 1H), 3.50-3.40 (m, 1H), 3.21-3.00 (m, 3H), 2.95-2.75 (m, 2H), 2.65-2.50 (m, 1H), 2.11-1.80 (m, 6H), 1.65-1.41 (m, 2H). Example 19B: Synthesis and Characterization of (4R*,4aS,5aR,12aS)-4- (dimethylamino)-3,10,12,12a-tetrahydroxy-1,11-dioxo-7-pyrrol-1-yl-4a,5,5a,6- tetrahydro-4H-tetracene-2-carboxamide and (4S*,4aS,5aR,12aS)-4-(dimethylamino)-3,10,12,12a-tetrahydroxy-1,11-dioxo-7- pyrrol-1-yl-4a,5,5a,6-tetrahydro-4H-tetracene-2-carboxamide

[0384] Benzyl (NE)-N-benzyloxycarbonyliminocarbamate (1.2 eq) was added to TFA (10 mL) at 0oC. (4S,4aS,5aR,12aS)-4-(dimethylamino)-3,10,12,12a-tetrahydroxy-1,11-dioxo- 4a,5,5a,6-tetrahydro-4H-tetracene-2-carboxamide (1.0 eq) was then added by portions. The reaction solution was stirred at 0oC for 5 hours. The reaction mixture was concentrated under reduced pressure. The crude product was obtained as a yellow solid which can be used for the next step without further purification. Benzyl N-[(6aS,10S,10aS,11aR)-8-carbamoyl-10- (dimethylamino)-4,6,6a,9-tetrahydroxy-5,7-dioxo-10a,11,11a,12-tetrahydro-10H-tetracen-1- yl]-N-(benzyloxycarbonylamino)carbamate was obtained as a yellow solid. LC-MS (ESI+) m / z: 713.1 [M+H]+.

[0385] Pd / C (0.1 eq) was added to MeOH (10 mL) at 25℃. Benzyl N- [(6aS,10S,10aS,11aR)-8-carbamoyl-10-(dimethylamino)-4,6,6a,9-tetrahydroxy-5,7-dioxo- 10a,11,11a,12-tetrahydro-10H-tetracen-1-yl]-N-(benzyloxycarbonylamino)carbamate (1 eq) was then added. The reaction solution was stirred at 25oC for 3 hours with H2at 40 psi. The reaction solution was filtered and concentrated under reduced pressure. The product (61.8% yield) was obtained as a gray solid which can be used for the next step without further purification. LC-MS (ESI+) m / z: 429.9 [M+H]+.

[0386] H2SO4(2.5 M, 2.5 eq) was added to the solution of 2,5-dimethoxytetrahydrofuran (1.3 eq) in THF (1 mL) and MeOH (1 mL) at 0oC. The resulting solution was added to the solution of (4S,4aS,5aR,12aS)-7-amino-4-(dimethylamino)-3,10,12,12a-tetrahydroxy-1,11- dioxo-4a,5,5a,6-tetrahydro-4H-tetracene-2-carboxamide (1.0 eq) in THF (1 mL) and MeOH (1 mL) and then NaBH3CN (12 theoretical eq) was added by one portion. The reaction solution was warmed to 25oC and stirred at 25oC for 12 hours. The reaction solution was filtered and concentrated under reduced pressure. The residue was purified by prep-HPLC. The two isomers were separated, and absolute stereochemistry at the C4 position wasrandomly assigned. Compound 19A had a retention time of 6.99 min. and Compound 19B of 6.71 min.

[0387] Compound 19A, drawn as (4S*,4aS,5aR,12aS)-4-(dimethylamino)-3,10,12,12a- tetrahydroxy-1,11-dioxo-7-pyrrol-1-yl-4a,5,5a,6-tetrahydro-4H-tetracene-2-carboxamide (7.3% yield) was also obtained as a gray solid. LC-MS (ESI+) m / z: 480.0 : [M+H]+.1H NMR (400 MHz, MeOD): δ 7.32 (d, J = 8.8 Hz, 1H), 6.80 (d, J = 8.8 Hz, 1H), 6.63 (s, 2H), 6.12 (s, 2H), 3.95 (s, 1H), 3.00-2.70 (m, 8H), 2.55-2.40 (m, 1H), 2.35-2.15 (m, 1 H), 2.05-1.85 (m, 1H), 1.55-1.30 (m, 1 H).

[0388] Compound 19B, drawn as (4R*,4aS,5aR,12aS)-4-(dimethylamino)-3,10,12,12a- tetrahydroxy-1,11-dioxo-7-pyrrol-1-yl-4a,5,5a,6-tetrahydro-4H-tetracene-2-carboxamide (4.7% yield) was obtained as a gray solid. LC-MS (ESI+) m / z: 480.0 [M+H]+.1H NMR (400 MHz, MeOD): δ 7.43 (d, J = 8.8 Hz, 1H), 6.92 (d, J = 8.8 Hz, 1H), 6.75 (s, 2H), 6.23 (s, 2H), 3.18 (s, 3H), 3.10-2.80 (m, 5H), 2.65-2.55 (m, 1H), 2.50-2.35 (m, 1 H), 2.95-1.80 (m, 1H), 1.65-1.45 (m, 1 H). Example 20B: Synthesis and Characterization of (4R,4aS,5aR,12aS)-4-(dimethylamino)- 3,10,12,12a-tetrahydroxy-1,11-dioxo-7-pyrrolidin-1-yl-4a,5,5a,6-tetrahydro-4H- tetracene-2-carboxamide

[0389] The solution of 2,5-dimethoxytetrahydrofuran (6.0 eq) and H2SO4(2.5 eq) in THF (2.5 mL) and H2O (2 mL) was added dropwise to the solution of (4S,4aS,5aR,12aS)-7- amino-4-(dimethylamino)-3,10,12,12a-tetrahydroxy-1,11-dioxo-4a,5,5a,6-tetrahydro-4H- tetracene-2-carboxamide (1.0 eq) in MeOH (4 mL) and THF (4 mL) at 0℃. Then NaBH3CN (4.0 eq) was added by portions. The resulting solution was stirred at 0oC for 2 hours. The reaction mixture was quenched by aqueous HCl (2 N, 2 mL) and concentrated under reducedpressure. The residue was purified by prep-HPLC. (4S,4aS,5aR,12aS)-4-(dimethylamino)- 3,10,12,12a-tetrahydroxy-1,11-dioxo-7-pyrrolidin-1-yl-4a,5,5a,6-tetrahydro-4H-tetracene-2- carboxamide (13.5%) was obtained as a yellow solid. LC-MS (ESI+) m / z: 484.1 [M+H]+.1H NMR (400 MHz, MeOD): δ 7.85-7.65 (m, 1H), 7.10-6.95 (m, 1H), 3.80-3.55 (m, 4H), 3.50- 3.35 (m, 1H), 3.21-2.91 (m, 9H), 2.60-2.40 (m, 1H), 2.40-2.15 (m, 5H), 1.75-1.60 (m, 1 H).

[0390] The solution of (4S,4aS,5aR,12aS)-4-(dimethylamino)-3,10,12,12a-tetrahydroxy- 1,11-dioxo-7-pyrrolidin-1-yl-4a,5,5a,6-tetrahydro-4H-tetracene-2-carboxamide (1.0 eq) and aqueous NaH2PO4(19.3 eq) in MeOH (4 mL) was stirred at 25oC for 24 hours. The reaction mixture was concentrated under reduced pressure. The residue was purified by SFC (column: DAICEL CHIRALPAK IG (250mm*30mm,10um);mobile phase: [0.1%NH3H2O ETOH];B%: 60%-60%,min). The fraction was quenched by aqueous HCl (12 N, 5 mL) immediately and concentrated under reduced pressure. The residue was purified by prep- HPLC (HCl) to remove the NH4Cl. (4R,4aS,5aR,12aS)-4-(dimethylamino)-3,10,12,12a- tetrahydroxy-1,11-dioxo-7-pyrrolidin-1-yl-4a,5,5a,6-tetrahydro-4H-tetracene-2-carboxamide (18.2% yield) was obtained as a gray solid. LC-MS (ESI+) m / z: 484.1 [M+H]+.1H NMR (400 MHz, MeOD): δ 7.78 (d, J = 8.8 Hz, 1H), 7.05 (d, J = 8.8 Hz, 1H), 3.90-3.55 (m, 4H), 3.55- 3.40 (m, 1H), 3.32 (s, 3H), 3.15-2.90 (m, 5H), 2.58-2.45 (m, 1H), 2.35-2.17 (m, 5 H), 1.68 (q, J = 11.2 Hz, 1H). Example 21B: Synthesis and Characterization of (4S,4aS,5aR,12aS)-7-cyclobutyl-4- (dimeth...

Claims

CLAIMS What is claimed is:

1. A compound of Formula (I)-R:or a pharmaceutically acceptable salt thereof, wherein: the carbon atom at * has a (R)-configuration; each R1and R2is independently H or optionally substituted alkyl; Ra1is NRfRg, wherein each Rfand Rgis independently H, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, or - C(=O)R’, wherein R’ is H, optionally substituted alkyl, or optionally substituted alkoxy; or Rfand Rgare taken together with the nitrogen atom to which they are attached to form an optionally substituted cyclic group, Ra2is ORm, wherein Rmis H or optionally substituted alkyl; Rb1is ORp, or NRqRs, wherein each Rp, Rqand Rsis independently H or optionally substituted alkyl; Rb2is ORx, wherein Rxis H or optionally substituted alkyl; Rd1is H, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted cycloalkyl, optionally substituted heterocyclyl, halo, or NRtRu; wherein each Rtand Ruis independently H or optionally substituted alkyl; Rd2is H; and Rd3is ORz, wherein Rzis H or optionally substituted alkyl.

2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R1and R2are both H.

3. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R1and R2are both optionally substituted alkyl.

4. The compound of claim 3, or a pharmaceutically acceptable salt thereof, wherein R1and R2are both methyl.

5. The compound of any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof, wherein Rmis H.

6. The compound of any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof, wherein Rmis methyl.

7. The compound of any one of claims 1 to 6, or a pharmaceutically acceptable salt thereof, wherein Rb1is ORp.

8. The compound of claim 7, or a pharmaceutically acceptable salt thereof, wherein Rpis H.

9. The compound of claim 7, or a pharmaceutically acceptable salt thereof, wherein Rpis methyl.

10. The compound of any one of claims 1 to 9, or a pharmaceutically acceptable salt thereof, wherein Rxis H.

11. The compound of any one of claims 1 to 10, or a pharmaceutically acceptable salt thereof, wherein Rd1is H.

12. The compound of any one of claims 1 to 10, or a pharmaceutically acceptable salt thereof, wherein Rd1is haloalkyl.

13. The compound of any one of claims 1 to 10, or a pharmaceutically acceptable salt thereof, wherein Rd1is: optionally substituted cyclopropyl, optionally substituted azetidinyl, optionally substituted oxetanyl, optionally substituted cyclobutyl, optionally substituted cyclopentyl, or optionally substituted heterocyclyl selected from the group consisting of:, wherein R is H or optionally substituted alkyl.

14. The compound of any one of claims 1 to 13, or a pharmaceutically acceptable salt thereof, wherein Rzis H.

15. The compound of any one of claims 1 to 13, or a pharmaceutically acceptable salt thereof, wherein Rzis methyl.

16. The compound of any one of claims 1 to 15, a pharmaceutically acceptable salt thereof, wherein Rfand Rgare taken together with the nitrogen atom to which they are attached to form a cyclic group, optionally substituted with one or more alkyl, haloalkyl, alkyl is substituted with -OR, halo, -OR, -COOR, -C(=O)R, -SO2R, or oxo, wherein R is H or optionally substituted alkyl.

17. The compound of any one of claims 1 to 15, or a pharmaceutically acceptable salt thereof, wherein Ra1is an optionally substituted cyclic group having 3-10 ring atoms.

18. The compound of claim 17, or a pharmaceutically acceptable salt thereof, wherein Ra1is an optionally substituted cyclic group having 3-10 ring atoms, and one or more additional ring atoms that is heteroatom independently selected from nitrogen and oxygen.

19. The compound of claim 17 or 18, or a pharmaceutically acceptable salt thereof, wherein the cyclic group has two fused rings.

20. The compound of claim 17 or 18, or a pharmaceutically acceptable salt thereof, wherein the cyclic group is a bridge cyclic group.

21. The compound of any one of claims 1 to 20, or a pharmaceutically acceptable salt thereof, wherein Ra1is an optionally substituted cyclic group selected from the group consisting of:wherein R10is optionally substituted alkyl, optionally substituted alkenyl, halo, C(=O)alkyl, C(=O)-O-alkyl, SO2(alkyl), optionally substituted cycloalkyl, or optionally substituted alkoxy.

22. The compound of any one of claims 1 to 15, a pharmaceutically acceptable salt thereof, wherein Rfis C1-3alkyl substituted with 3- to 10-membered heterocycle and Rgis H.

23. The compound of claim 22, a pharmaceutically acceptable salt thereof, wherein Rfis24. The compound of any one of claims 1 to 15, a pharmaceutically acceptable salt thereof, wherein Rfis heterocycloalkyl and Rgis H.

25. The compound of claim 24, a pharmaceutically acceptable salt thereof, wherein Rfiseach of which is optionally substituted with one or more C1-3alkyl or C1-3haloalkyl, and wherein R is H or C1-3alkyl.

26. The compound of any one of claims 1 to 25, or a pharmaceutically acceptable salt thereof, wherein the compound is a compound of Formula (I-i)-R:or a pharmaceutically acceptable salt thereof.

27. A compound of Formula (I-C)-R:or a pharmaceutically acceptable salt thereof, wherein: the carbon atom at * has a (R)-configuration; each R1and R2is independently H or optionally substituted alkyl; Rfis H, optionally substituted alkyl, or optionally substituted heterocycloalkyl; Rgis optionally substituted alkyl, Ra2is ORm, wherein Rmis H or optionally substituted alkyl; Rb1is ORp, wherein Rpis H or optionally substituted alkyl; Rb2is ORx, wherein Rxis H or optionally substituted alkyl;Rd1is H, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted cycloalkyl, optionally substituted heterocyclyl, halo, or NRtRu; wherein each Rt, Ru, Rnand Rois independently H or optionally substituted alkyl; Rd3is ORz, wherein Rzis H or optionally substituted alkyl.

28. The compound of claim 27, or a pharmaceutically acceptable salt thereof, wherein the compound is a compound of Formula (I-C-i):or a pharmaceutically acceptable salt thereof.

29. A compound of Formula (I-D):or a pharmaceutically acceptable salt thereof, wherein: each R1and R2is independently H or optionally substituted alkyl; Ra1is NRfRg, wherein each Rfand Rgis independently H, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, or - C(=O)R’, wherein R’ is H, alkyl, or alkoxy; or Rfand Rgare taken together with the nitrogen atom to which they are attached to form an optionally substituted cyclic group, Ra2is ORm, wherein Rmis H, optionally substituted alkyl or optionally substituted heteroaryl; Rb1is ORp, or NRqRs,wherein each Rp, Rqand Rsis independently H or optionally substituted alkyl; Rb2is ORx, wherein Rxis H or optionally substituted alkyl; Rd1is: optionally substituted cyclopropyl, optionally substituted azetidinyl, optionally substituted oxetanyl, optionally substituted cyclobutyl, optionally substituted cyclopentyl, optionally substituted heterocyclyl selected from the group consisting of:, wherein R is H or alkyl; Rd2is H; and Rd3is ORz, wherein Rzis H or alkyl,provided that when Rd1 is cyclopropyl, cyclopentyl, a1Ris other than N(CH3)2.

30. A compound of Formula (I-D)-R:or a pharmaceutically acceptable salt thereof, wherein: the carbon atom at * has a (R)-configuration, each R1and R2is independently H or optionally substituted alkyl; Ra1is NRfRg, wherein each Rfand Rgis independently H, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, or - C(=O)R’, wherein R’ is H, alkyl, or alkoxy; or Rfand Rgare taken together with the nitrogen atom to which they are attached to form an optionally substituted cyclic group, Ra2is ORm, wherein Rmis H, optionally substituted alkyl or optionally substituted heteroaryl; Rb1is ORp, or NRqRs, wherein each Rp, Rqand Rsis independently H or optionally substituted alkyl; Rb2is ORx, wherein Rxis H or optionally substituted alkyl; Rd1is: optionally substituted cyclopropyl, optionally substituted azetidinyl, optionally substituted oxetanyl, optionally substituted cyclobutyl,optionally substituted cyclopentyl, optionally substituted heterocyclyl selected from the group consisting of:, wherein R is H or alkyl; Rd2is H; and Rd3is ORz, wherein Rzis H or alkyl.

31. A compound of Formula (I-E):or a pharmaceutically acceptable salt thereof, wherein:each R1and R2is independently H or optionally substituted alkyl; Rkis optionally substituted alkyl; Ra2is ORm, wherein Rmis H or optionally substituted alkyl or optionally substituted heteroaryl; Rb1is ORp, or NRqRs, wherein each Rp, Rqand Rsis independently H or optionally substituted alkyl; Rb2is ORx, wherein Rxis H or optionally substituted alkyl; Rd1is H, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted cycloalkyl, optionally substituted heterocyclyl, halo, or NRtRu; wherein each Rtand Ruis independently H or optionally substituted alkyl; Rd2is H; and Rd3is ORz, wherein Rzis H or alkyl.

32. The compound of claim 31, or a pharmaceutically acceptable salt thereof, wherein the compound is a compound of Formula (I-E-i):or a pharmaceutically acceptable salt thereof.

33. A compound of Formula (III):or a pharmaceutically acceptable salt thereof, wherein: each R1and R2is independently H or optionally substituted alkyl; Ra1is NRfRg,wherein each Rfand Rgis independently H, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, or - C(=O)R’, wherein R’ is H, optionally substituted alkyl, or optionally substituted alkoxy; or Rfand Rgare taken together with the nitrogen atom to which they are attached to form an optionally substituted cyclic group, Ra2is ORm, wherein Rmis H or optionally substituted alkyl; Ra3is ORL, wherein RLis H or optionally substituted alkyl; Rb1is ORp, wherein each Rpis H or alkyl; Rd1is H, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted cycloalkyl, optionally substituted heterocyclyl, halo, or NRtRu; wherein each Rtand Ruis independently H or optionally substituted alkyl; wherein each Rtand Ruis independently H or optionally substituted alkyl; Rd2is H; and Rd3is ORz, wherein Rzis H, or optionally substituted alkyl, provided that when Ra1is N(CH3)2, then Rd1is other than H.

34. The compound of claim 33, or a pharmaceutically acceptable salt thereof, wherein Ra1is NH2.

35. The compound of claim 33, or a pharmaceutically acceptable salt thereof, wherein Rfand Rgare taken together with the nitrogen atom to which they are attached to form heterocycloalkyl.

36. The compound of any one of claims 33 to 35, or a pharmaceutically acceptable salt thereof, wherein Rd1is cycloalkyl.

37. The compound of any one of claims 33 to 36, or a pharmaceutically acceptable salt thereof, wherein Ra2is OH; Ra3is OH; Rb1is OH; andRd3is OH.

38. The compound of any one of claims 33 to 37, or a pharmaceutically acceptable salt thereof, wherein the compound is a compound of Formula (III-i):or a pharmaceutically acceptable salt thereof.

39. A compound of Formula (IV):or a pharmaceutically acceptable salt thereof, wherein: each R1and R2is independently H or optionally substituted alkyl; Ra1is NRfRg, wherein each Rfand Rgis independently H, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, or - C(=O)R’, wherein R’ is H, optionally substituted alkyl, or optionally substituted alkoxy; or Rfand Rgare taken together with the nitrogen atom to which they are attached to form an optionally substituted cyclic group, Ra2is ORm, wherein Rmis H or optionally substituted alkyl; Rb1is ORp, or NRqRs, wherein Rpis optionally substituted alkyl; wherein each Rqand Rsis independently H or optionally substituted alkyl; Rb2is ORx, wherein Rxis H or optionally substituted alkyl;Rd1is H, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted cycloalkyl, optionally substituted heterocyclyl, halo, or NRtRu; wherein each Rtand Ruis independently H or optionally substituted alkyl; wherein each Rt, Ru, Rnand Rois independently H or optionally substituted alkyl; Rd2is H; and Rd3is ORz, wherein Rzis H or optionally substituted alkyl.

40. The compound of claim 39, or a pharmaceutically acceptable salt thereof, wherein: Ra2is OH; Ra3is OH; and Rd3is OH.

41. The compound of claim 39 or 40, or a pharmaceutically acceptable salt thereof, wherein the compound is a compound of Formula (IV-i):or a pharmaceutically acceptable salt thereof.

42. A compound of Formula (V):or a pharmaceutically acceptable salt thereof, wherein: each R1and R2is independently H or optionally substituted alkyl; Ra1is NRfRg, or =NORk, wherein each Rfand Rgis independently H, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, or - C(=O)R’,wherein R’ is H, optionally substituted alkyl, or optionally substituted alkoxy; or Rfand Rgare taken together with the nitrogen atom to which they are attached to form an optionally substituted cyclic group; wherein Rkis optionally substituted alkyl; Ra2is ORm, wherein Rmis H, or optionally substituted alkyl; Rb2is ORx, wherein Rxis H or optionally substituted alkyl; Rd1is H, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted cycloalkyl, optionally substituted heterocyclyl, or NRtRu; wherein each Rtand Ruis independently H or optionally substituted alkyl; Rd2is H; and Rd3is ORz, wherein Rzis H, or alkyl.

43. The compound of claim 42, or a pharmaceutically acceptable salt thereof, wherein: Rfand Rgare taken together with the nitrogen atom to which they are attached to form a cyclic group, optionally substituted with one or more alkyl, haloalkyl, alkyl substituted with - OR, halo, -COOR, -C(=O)R, -SO2R, cycloalkyl, or oxo, wherein R is H or optionally substituted alkyl.

44. The compound of claim 42, or a pharmaceutically acceptable salt thereof, wherein: Rfand Rgare taken together with the nitrogen atom to which they are attached to form an optionally substituted heterocyclyl group.

45. The compound of claim 42, or a pharmaceutically acceptable salt thereof, wherein: Ra1is optionally substituted piperidinyl, optionally substituted piperazinyl, or optionally substituted morpholino.

46. The compound of claim 42, or a pharmaceutically acceptable salt thereof, wherein: Rd1is an unsubstituted cycloalkyl.

47. The compound of any one of claims 42 to 46, or a pharmaceutically acceptable salt thereof, wherein: Ra2is OH; Ra3is OH; Rb1is OH; and Rd3is OH48. The compound of any one of claims 42 to 47, or a pharmaceutically acceptable saltthereof, wherein the compound is a compound of Formula (V-i):or a pharmaceutically acceptable salt thereof.

49. A compound selected from a compound of Table 1B, or a pharmaceuticallyacceptable salt thereof.

50. A compound, or a pharmaceutically acceptable salt thereof, wherein the compound is:or a pharmaceutically acceptable salt thereof, wherein: each R1and R2is independently H or optionally substituted alkyl;Ra2is ORm, wherein Rmis H or optionally substituted alkyl; Rb1is ORp, or NRqRs, wherein each Rp, Rqand Rsis independently H or optionally substituted alkyl; Rb2is H or ORx, wherein Rxis H or optionally substituted alkyl; Rd1is: optionally substituted cyclopropyl, optionally substituted azetidinyl, optionally substituted oxetanyl, optionally substituted cyclobutyl, substituted cyclopentyl, optionally substituted 5-membered heterocycloalkyl, optionally substituted heterocyclyl, wherein the heterocyclyl is selected from the group consisting of:,wherein R is H or optionally substituted alkyl, Rd2is H, or NHRy, wherein Ryis -C(=O)(CH2)nNRvRw, wherein n is an integer greater than or equal to 1; wherein each Rvand Rwis independently H or optionally substituted alkyl, or Rvand Rware taken together with the nitrogen atom to which they are attached to form an optionally substituted cyclic group; and Rd3is ORz, wherein Rzis H or optionally substituted alkyl.

52. The compound of claim 51, or a pharmaceutically acceptable salt thereof, wherein: each R1and R2is H; Ra2is OH; Rb1is OH; Rb2is OH; Rd2is H; and Rd3is OH.

53. The compound of claim 51 or 52, or a pharmaceutically acceptable salt thereof, wherein Rd1is: unsubstituted cyclopropyl, or cyclopropyl substituted with one or more alkyl, haloalkyl or halo groups; unsubstituted azetidinyl, or azetidinyl substituted with one or more alkyl, haloalkyl or halo groups; unsubstituted oxetanyl, or oxetanyl substituted with one or more alkyl, haloalkyl or halo groups; unsubstituted cyclobutyl, or cycobutyl substituted with one or more alkyl, haloalkyl or halo groups; cyclopentyl substituted with one or more alkyl, haloalkyl or halo groups; unsubstituted 5-membered heterocycloalkyl, or 5-membered heterocycloalkyl substituted with one or more alkyl, haloalkyl or halo groups; unsubstituted heterocyclyl, or heterocyclyl substituted with one or more alkyl, haloalkyl, -OH, or halo groups; wherein the heterocyclyl is selected from the group.

54. The compound of claim 51 or 52, or a pharmaceutically acceptable salt thereof, wherein Rd1is pyrazolyl substituted with alkyl.

55. A compound of Formula (I-A-i):or a pharmaceutically acceptable salt thereof, wherein: each R1and R2is H; and ring D5 is: substituted cyclopentyl, optionally substituted 5-membered heterocyclyl selected from the group consisting of:wherein R is H or optionally substituted alkyl.

56. The compound of claim 55, or a pharmaceutically acceptable salt thereof, wherein:ringsubstituted alkyl.

57. The compound of claim 55, or a pharmaceutically acceptable salt thereof, wherein: ringwherein R is optionally substituted alkyl.

58. A compound of Formula (I-A-ii):ii), or a pharmaceutically acceptable salt thereof, wherein: each R1and R2is H; andring D6 is optionally substituted 6-membered heterocyclyl selected from the group consisting of: ,wherein R is H or optionally substituted alkyl.

59. The compound of any one of claims 55 to 58, or a pharmaceutically acceptable salt thereof, wherein the heterocyclyl is substituted with one or more alkyl, haloalkyl or halo groups.

60. A compound of Formula (II):or a pharmaceutically acceptable salt thereof, wherein: each R1and R2is independently H or optionally substituted alkyl; Ra2is ORm, wherein Rmis H, or optionally substituted alkyl; Rb1is ORp, wherein each Rpis H or optionally substituted alkyl; Rb2is ORx, wherein Rxis H or optionally substituted alkyl; Rd1is H, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted cycloalkyl, optionally substituted heterocyclyl, or NRtRu, wherein each Rtand Ruis independently H or optionally substituted alkyl; Rd2is H; and Rd3is ORz,wherein Rzis H, or optionally substituted alkyl.

61. The compound of claim 60, or a pharmaceutically acceptable salt thereof, wherein: Ra2is OH; Rb1is OH; Rb2is OH; Rd2is H; and Rd3is OH.

62. The compound of claim 60 or 61, or a pharmaceutically acceptable salt thereof, wherein the compound is a compound of Formula (II-i):or a pharmaceutically acceptable salt thereof.

63. A compound of Formula (IV):or a pharmaceutically acceptable salt thereof, wherein: each R1and R2is independently H or optionally substituted alkyl; Ra2is ORm, wherein Rmis H or optionally substituted alkyl; Rb1is ORp, or NRqRs, wherein Rpis optionally substituted alkyl; wherein each Rqand Rsis independently H or optionally substituted alkyl; Rb2is ORx, wherein Rxis H or optionally substituted alkyl; Rd1is H, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted cycloalkyl, optionally substituted heterocyclyl, or NRtRu,wherein each Rtand Ruis independently H or optionally substituted alkyl; Rd2is H, NHRy, or halo, wherein Ryis H, or -C(=O)(CH2)nNRvRw, wherein n is an integer greater than or equal to 1; wherein each Rvand Rwis independently H or optionally substituted alkyl, or Rvand Rware taken together with the nitrogen atom to which they are attached to form an optionally substituted cyclic group; and Rd3is ORz, wherein Rzis H or optionally substituted alkyl.

64. The compound of claim 63, or a pharmaceutically acceptable salt thereof, wherein the compound is a compound of Formula (IV-i):or a pharmaceutically acceptable salt thereof.

65. A compound of Formula (V):or a tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein: each R1and R2is independently H or optionally substituted alkyl; Ra2is ORm, wherein Rmis H, or optionally substituted alkyl; Rb2is H or ORx, wherein Rxis H or optionally substituted alkyl; Rd1is H, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted cycloalkyl, optionally substituted cycloalkenyl, optionally substituted heterocyclyl, or NRtRu, wherein each Rtand Ruis independently H or optionally substituted alkyl;Rd2is H, NHRy, or halo, wherein Ryis H, or -C(=O)(CH2)nNRvRw, wherein n is an integer greater than or equal to 1; wherein each Rvand Rwis independently H or optionally substituted alkyl, or Rvand Rware taken together with the nitrogen atom to which they are attached to form an optionally substituted cyclic group; and Rd3is ORz, wherein Rzis H, or alkyl.

66. The compound of claim 65, or a pharmaceutically acceptable salt thereof, wherein: Ra2is OH; and Rd3is OH.

67. The compound of claim 65 or 66, or a pharmaceutically acceptable salt thereof, wherein: Rd1is H or optionally substituted cycloalkyl.

68. The compound of any one of claims 65 to 67, or a pharmaceutically acceptable salt thereof, wherein the compound is a compound of Formula (V-i):or a pharmaceutically acceptable salt thereof.

69. A compound selected from a compound of Table 1A, or a pharmaceutically acceptable salt thereof.

70. A composition, comprising a compound of Formula (I-i-16A) or (I-i-16B):or a pharmaceutically acceptable salt thereof.

71. A composition, comprising a substantially pure enantiomer of the compound of Formula (I-i-16A) according to claim 70, or a pharmaceutically acceptable salt thereof.

72. A composition, comprising a substantially pure enantiomer of the compound of Formula (I-i-16B) according to claim 70, or a pharmaceutically acceptable salt thereof.

73. The composition of claim 71 or 72, wherein less than 5% of the composition are other enantiomeric forms of the compound, or a pharmaceutically acceptable salt thereof.

74. A pharmaceutical composition, comprising: a compound of any one of claims 1 to 69, or a pharmaceutically acceptable salt thereof, or a composition of any one of claims 70 to 73; and at least one pharmaceutically acceptable excipient.

75. A method of treating a disease or condition in a subject in need thereof, wherein the disease or condition is Rheumatoid Arthritis, Inflammatory Bowel Disease, Epilepsy, Acute Ischemic Stroke, Traumatic Brain Injury, Neuropathic Pain, Fragile X Syndrome, Anti- psychotic-induced Hyperphagia, Prader-Willi Syndrome, Parkinson’s Disease, Huntington’s Disease, Amyotrophic Lateral Sclerosis, Alzheimer’s Disease, Multiple Sclerosis, Spinal Cord Injury, Diabetic Macular Edema, Dermatitis, Periodonitis, Osteoporosis, Atherosclerosis, Oncology / Cancer, Malaria, HIV, Light-Chain Amyloidosis, Transthyretin Amyloidosis, Schizophrenia, Bipolar Disorder, or Depression, wherein the method comprises:administering a therapeutically effective amount a compound of any one of claims 1 to 69, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable composition of claim 74, to the subject.

76. The method of claim 75, wherein the disease or condition is Fragile X Syndrome.

77. The method of claim 75, wherein the disease or condition is Rheumatoid Arthritis.

78. The method of claim 75, wherein the disease or condition is Alzheimer’s Disease.

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