Combination of METAP2 inhibitors and CDK4 / 6 inhibitors for cancer treatment

Abstract

This disclosure relates to combinations of MetAP2 inhibitors and CDK4 / 6 inhibitors for the treatment and prevention of cancer.

Description

[0001] Cross-reference to related applications

[0002] This application claims priority and interest in U.S. Provisional Application No. 63 / 112,217, filed November 11, 2020, and U.S. Provisional Application No. 63 / 166,060, filed March 25, 2021. The contents of each of the aforementioned patent applications are incorporated herein by reference in their entirety.

[0003] background

[0004] Inhibitors of cyclin-dependent kinases CDK4 and CDK6, referred to herein as CDK4 / 6 inhibitors, are used to treat breast cancer, such as metastatic, hormone receptor (HR)-positive, human epidermal growth factor 2 (HER2)-negative (HR+HER2-) breast cancer. Resistance to these drugs, such as palbociclib, the first CDK4 / 6 inhibitor approved by the FDA as a cancer therapy, and other CDK4 / 6 inhibitors (e.g., abeciclib, reboxil), has been reported to be mediated by a number of factors, including upregulation of CDK2 and cyclin D and E, increased autophagy, via Akt protein, via alterations to estrogen receptors, and other mechanisms. Furthermore, only limited improvements in overall survival (OS) have been observed with palbociclib or other CDK4 / 6 inhibitors, as resistance to these drugs develops in most patients, leading to eventual disease progression. Another proposed mediator of CDK4 / 6 resistance is increased intracellular protein reuse (autophagy), which allows cells to replicate at an accelerated rate. Therefore, there is a need in the art for compositions and methods that attenuate therapeutic resistance to CDK4 / 6 inhibitors and enhance their potency. This disclosure provides a combination of a MetAP2 inhibitor and a CDK4 / 6 inhibitor for the treatment of cancer.

[0005] Overview

[0006] This disclosure provides a combination for treating cancer comprising at least one MetAP2 inhibitor or a pharmaceutically acceptable salt thereof and at least one CDK 4 / 6 inhibitor or a pharmaceutically acceptable salt thereof.

[0007] This disclosure provides a method for treating cancer in a subject who requires it, the method comprising administering to the subject at least one therapeutically effective amount of at least one MetAP2 inhibitor or a pharmaceutically acceptable salt thereof and at least one therapeutically effective amount of at least one CDK4 / 6 inhibitor or a pharmaceutically acceptable salt thereof.

[0008] This disclosure provides a MetAP2 inhibitor or a pharmaceutically acceptable salt thereof for use in methods of treating cancer, wherein the method further comprises administering at least one CDK4 / 6 inhibitor or a pharmaceutically acceptable salt thereof.

[0009] This disclosure provides a CDK4 / 6 inhibitor or a pharmaceutically acceptable salt thereof for use in methods of treating cancer, wherein the method further comprises administering at least one MetAP2 inhibitor or a pharmaceutically acceptable salt thereof.

[0010] In some respects, at least one MetAP2 inhibitor or a pharmaceutically acceptable salt thereof and at least one CDK4 / 6 inhibitor or a pharmaceutically acceptable salt thereof are administered simultaneously or close in time.

[0011] This disclosure provides a method for treating cancer in a subject who requires it, the method comprising administering to the subject at least one therapeutically effective amount of at least one MetAP2 inhibitor or a pharmaceutically acceptable salt thereof and at least one therapeutically effective amount of at least one CDK4 / 6 inhibitor or a pharmaceutically acceptable salt thereof.

[0012] This disclosure provides a combination of at least one MetAP2 inhibitor or a pharmaceutically acceptable salt thereof for preparing a medicament for treating cancer, in combination with at least one CDK 4 / 6 inhibitor or a pharmaceutically acceptable salt thereof.

[0013] This disclosure provides a combination of at least one MetAP2 inhibitor or a pharmaceutically acceptable salt thereof for the treatment of cancer and at least one CDK4 / 6 inhibitor or a pharmaceutically acceptable salt thereof.

[0014] This disclosure provides combination therapies comprising at least one therapeutically effective amount of at least one MetAP2 inhibitor or a pharmaceutically acceptable salt thereof and at least one therapeutically effective amount of at least one CDK4 / 6 inhibitor or a pharmaceutically acceptable salt thereof.

[0015] This disclosure provides pharmaceutical compositions comprising at least one therapeutically effective amount of at least one MetAP2 inhibitor or a pharmaceutically acceptable salt thereof and at least one therapeutically effective amount of at least one CDK4 / 6 inhibitor or a pharmaceutically acceptable salt thereof.

[0016] This disclosure provides a kit comprising at least one therapeutically effective amount of at least one MetAP2 inhibitor or a pharmaceutically acceptable salt thereof and at least one therapeutically effective amount of at least one CDK4 / 6 inhibitor or a pharmaceutically acceptable salt thereof.

[0017] This disclosure provides a method for treating cancer in a subject who requires it, the method comprising administering to the subject who requires it at least one therapeutically effective amount of the combination therapy of claim 4, the pharmaceutical composition of claim 5, or the kit of claim 6.

[0018] MetAP2 inhibitors can be compounds represented by formula (I) or pharmaceutically acceptable salts, prodrugs, metabolites, analogs, or derivatives thereof:

[0019]

[0020] Among them, for each occurrence independently,

[0021] R4 is H or a C1-C6 alkyl group;

[0022] R5 is H or a C1-C6 alkyl group;

[0023] R6 is a C2-C6 hydroxyalkyl group;

[0024] Z is -NH-AA1-AA2-AA3-AA4-AA5-AA6-C(O)-L or -NH-AA1-AA2-AA3-AA4-AA5-AA6-C(O)-QXYC(O)-W;

[0025] AA1 is glycine, alanine, or H2N(CH2). m CO2H, where m is 2, 3, 4 or 5;

[0026] AA2 is a bond or alanine, cysteine, aspartic acid, glutamic acid, phenylalanine, glycine, histidine, isoleucine, lysine, leucine, methionine, asparagine, proline, glutamine, arginine, serine, threonine, valine, tryptophan, or tyrosine.

[0027] AA3 is a bond or alanine, cysteine, aspartic acid, glutamic acid, phenylalanine, glycine, histidine, isoleucine, lysine, leucine, methionine, asparagine, proline, glutamine, arginine, serine, threonine, valine, tryptophan, or tyrosine.

[0028] AA4 is a bond or alanine, cysteine, aspartic acid, glutamic acid, phenylalanine, glycine, histidine, isoleucine, lysine, leucine, methionine, asparagine, proline, glutamine, arginine, serine, threonine, valine, tryptophan, or tyrosine.

[0029] AA5 is a bond or glycine, valine, tyrosine, tryptophan, phenylalanine, methionine, leucine, isoleucine, or asparagine;

[0030] AA6 is a bond or alanine, asparagine, citrulline, glutamine, glycine, leucine, methionine, phenylalanine, serine, threonine, tryptophan, tyrosine, valine, or H2N(CH2). m CO2H, where m is 2, 3, 4 or 5;

[0031] L is -OH, -O-succinimide, -O-sulfosuccinimide, alkoxy, aryloxy, acyloxy, aryloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, -NH2, -NH (C2-C6 hydroxyalkyl), halide, or perfluoroalkoxy;

[0032] Q is NR, O, or S;

[0033] X is M-(C(R)2) p -MJM-(C(R)2) p -MV;

[0034] M is a bond or C(O);

[0035] J is a bond or ((CH2) q Q) r C5-C8 cycloalkyl, aryl, heteroaryl, NR, O or S;

[0036] Y is NR, O, or S;

[0037] R is H or an alkyl group;

[0038] V is a key or

[0039] R 9 It is an alkyl, aryl, aralkyl, or bond; or R 9 Together with Y, they form a heterocyclic ring;

[0040] R 10 It is an amide or bond;

[0041] R 11 It is H or alkyl;

[0042] W is a moiety or alkyl group of the MetAP2 inhibitor;

[0043] x is in the range of 1 to approximately 450;

[0044] y is in the range of 1 to approximately 30;

[0045] n is in the range of 1 to approximately 100;

[0046] p is between 0 and 20;

[0047] q is 2 or 3;

[0048] r can be 1, 2, 3, 4, 5, or 6.

[0049] MetAP2 inhibitors can be

[0050] (Compound 1), or a pharmaceutically acceptable salt, prodrug, metabolite, analog or derivative thereof.

[0051] MetAP2 inhibitors can be

[0052] (Compound 2), or a pharmaceutically acceptable salt, prodrug, metabolite, analogue or derivative thereof.

[0053] MetAP2 inhibitors can be

[0054] (Compound 3), or a pharmaceutically acceptable salt, prodrug, metabolite, analogue or derivative thereof.

[0055] MetAP2 inhibitors can be:

[0056] (Compound 4), or a pharmaceutically acceptable salt, analogue, derivative, salt or ester thereof.

[0057] In some embodiments, X can be in the range of 1 to about 450. In some embodiments, Y can be in the range of 1 to about 30. In some embodiments, n can be in the range of 1 to about 100.

[0058] In some implementations, the MetAP2 inhibitor may be

[0059]

[0060]

[0061] In some implementations, the MetAP2 inhibitor may be

[0062]

[0063] In some embodiments, R4 may be methyl. In some embodiments, R5 may be methyl. In some embodiments, R6 may be 2-hydroxypropyl.

[0064] In some embodiments, Z can be -NH-AA6-C(O)-QXYC(O)-W. In some embodiments, AA6 can be glycine.

[0065] In some implementations, Z can be

[0066] -NH-AA5-AA6-C(O)-QXYC(O)-W. In some embodiments, AA5 can be leucine and AA6 can be glycine. In some embodiments, AA5 can be valine and AA6 can be glycine. In some embodiments, AA5 can be phenylalanine and AA6 can be glycine. In some embodiments, AA5 can be glycine and AA6 can be glycine.

[0067] In some implementations, Z can be

[0068] -NH-AA3-AA4-AA5-AA6-C(O)-QXYC(O)-W. In some embodiments, AA5 may be leucine and each of AA3, AA4, or AA6 may be glycine. In some embodiments, AA5 may be valine and each of AA3, AA4, or AA6 may be glycine. In some embodiments, AA5 may be phenylalanine and each of AA3, AA4, or AA6 may be glycine. In some embodiments, AA3 may be glycine, AA4 may be phenylalanine, AA5 may be leucine, and AA6 may be glycine. In some embodiments, each of AA3, AA4, AA5, and AA6 may be glycine.

[0069] In some implementations, -QXY can be

[0070]

[0071] In some implementation schemes, W can be

[0072] In some implementations, the ratio of x to y can be in the range of about 30:1 to about 3:1. In some implementations, the ratio of x to y can be about 11:1.

[0073] CDK4 / 6 inhibitors can be selected from palbociclib, abemaciclib, ribociclib, trilaciclib, SHR-6390, FCN-437c, lerociclib, milaciclib, PF-06873600, XZP-3287, zotiraciclib, BEBT-209, BPI-16350, CS-3002, fadracic... lib, HS-10342, ON-123300, PF-06842874, TQ-05510, BPI-1178, JS-101, NUV-422, AU-294, CCT-68127, ETH-155008, HEC-80797, JRP-890, JS-104, NEOS-518, PF-07104091, PF-07220060, RMC-4550, SRX-3177, VS-2370, VS-2370 or pharmaceutically acceptable salts thereof. CDK4 / 6 inhibitors may be palbociclib or pharmaceutically acceptable salts thereof. CDK4 / 6 inhibitors may be abeciclib or pharmaceutically acceptable salts thereof. CDK4 / 6 inhibitors may be reboxiclib or pharmaceutically acceptable salts thereof.

[0074] MetAP2 inhibitors can be administered subcutaneously. CDK4 / 6 inhibitors can be administered orally.

[0075] Cancer can be carcinoma, lymphoma, blastoma, sarcoma, leukemia, brain cancer, breast cancer, blood cancer, bone cancer, lung cancer, skin cancer, liver cancer, ovarian cancer, bladder cancer, renal cancer, gastric cancer, thyroid cancer, pancreatic cancer, esophageal cancer, prostate cancer, cervical cancer, uterine cancer, soft tissue cancer, laryngeal cancer, small intestine cancer, testicular cancer, anal cancer, vulvar cancer, joint cancer, oral cancer, pharyngeal cancer, or colorectal cancer. Cancer can be breast cancer. Breast cancer can be HR+HER2- breast cancer.

[0076] This disclosure provides a method for treating breast cancer in a subject who requires it, the method comprising administering to the subject: a) at least one therapeutically effective amount of compound 1:

[0077] (compound 1), or a pharmaceutically acceptable salt, prodrug, metabolite, analog or derivative thereof, wherein x is in the range of 1 to about 450, y is in the range of 1 to about 30 and n is in the range of 1 to about 100; and b) at least one therapeutically effective amount of palbociclib or a pharmaceutically acceptable salt thereof.

[0078] This disclosure provides a method for treating breast cancer in a subject who requires it, the method comprising administering to the subject: a) at least one therapeutically effective amount of compound 1:

[0079] (a) compound 1, or a pharmaceutically acceptable salt, prodrug, metabolite, analog or derivative thereof, wherein x is in the range of 1 to about 450, y is in the range of 1 to about 30 and n is in the range of 1 to about 100; and b) at least one therapeutically effective amount of reboxil or a pharmaceutically acceptable salt thereof.

[0080] Any of the above aspects, or any other aspect described herein, may be combined with any other aspect.

[0081] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure pertains. In this specification, singular forms also include plural forms unless the context clearly indicates otherwise; by way of example, the terms “a,” “an,” and “the” are understood as singular or plural, and the term “or” is understood as inclusive. By way of example, “an element” refers to one or more elements. Throughout this specification, the word “comprising” or variations such as “including” or “containing” will be understood to imply inclusion of the stated element, integer, or step, or group of elements, integers, or steps, but does not exclude any other element, integer, or step, or group of elements, integers, or steps. “About” can be understood as within 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, 0.5%, 0.1%, 0.05%, or 0.01% of the stated value. Unless otherwise clearly indicated from the context, all numerical values ​​provided herein are modified by the term “about.”

[0082] Although similar or equivalent methods and materials to those described herein may be used in the practice or testing of this disclosure, suitable methods and materials are described below. All publications, patent applications, patents, and other references mentioned herein are incorporated herein by reference in their entirety. No prior art to the claimed invention is acknowledged in this document. In case of conflict, this specification (including definitions) shall prevail. Furthermore, the materials, methods, and embodiments are merely exemplary and are not intended to be limiting. Other features and advantages of this disclosure will become apparent from the following detailed description and claims. Brief description of the attached diagram

[0084] The above and other features will become clearer from the following detailed description when viewed in conjunction with the accompanying drawings.

[0085] Figure 1 A graph showing the MCF tumor volume in mice during treatment, wherein the mice were treated with a mediator control, a combination of compound 1 and palbociclib, compound 1 alone, or palbociclib alone.

[0086] Figure 2 A graph showing the MCF tumor volume in mice at the end of treatment, wherein the mice were treated with a mediator control, a combination of compound 1 and palbociclib, compound 1 alone, or palbociclib alone.

[0087] Figure 3 A graph showing the body weight of mice during treatment, wherein the mice were treated with a mediator control, a combination of compound 1 and palbociclib, compound 1 alone, or palbociclib alone.

[0088] Figure 4 A series of graphs showing the survival percentage of mice during treatment, wherein the mice were treated with a mediator control, a combination of compound 1 and palbociclib, compound 1 alone, or palbociclib alone.

[0089] Figure 5 A graph showing the expression levels of cyclin D1 protein in tumor samples collected at the end of treatment, wherein the mice were treated with a mediator control, a combination of compound 1 and palbociclib, compound 1 alone, or palbociclib alone.

[0090] Figure 6 A graph showing the expression levels of cyclin E1 protein in tumor samples collected at the end of treatment, wherein the mice were treated with a mediator control, a combination of compound 1 and palbociclib, compound 1 alone, or palbociclib alone.

[0091] Figure 7 A graph showing the expression levels of cyclin E2 protein in tumor samples collected at the end of treatment, wherein the mice were treated with a mediator control, a combination of compound 1 and palbociclib, compound 1 alone, or palbociclib alone.

[0092] Figure 8 A graph showing the expression levels of p21 protein in tumor samples collected at the end of treatment, wherein the mice were treated with a mediator control, a combination of compound 1 and palbociclib, compound 1 alone, or palbociclib alone.

[0093] Figure 9A graph showing the expression levels of CDK4 protein in tumor samples collected at the end of treatment, wherein the mice were treated with a mediator control, a combination of compound 1 and palbociclib, compound 1 alone, or palbociclib alone.

[0094] Figure 10 A graph showing the expression levels of CDK2 protein in tumor samples collected at the end of treatment, wherein the mice were treated with a mediator control, a combination of compound 1 and palbociclib, compound 1 alone, or palbociclib alone.

[0095] Figure 11 A graph showing the expression levels of Rb protein in tumor samples collected at the end of treatment, wherein the mice were treated with a mediator control, a combination of compound 1 and palbociclib, compound 1 alone, or palbociclib alone.

[0096] Figure 12 A graph showing the expression levels of LC3B protein in tumor samples collected at the end of treatment, wherein the mice were treated with a mediator control, a combination of compound 1 and palbociclib, compound 1 alone, or palbociclib alone.

[0097] Figure 13 A graph showing the expression levels of Akt protein in tumor samples collected at the end of treatment, wherein the mice were treated with a mediator control, a combination of compound 1 and palbociclib, compound 1 alone, or palbociclib alone.

[0098] Figure 14 A graph showing the expression levels of phosphorylated (Phospho)-Akt protein in tumor samples collected at the end of treatment, wherein the mice were treated with a mediator control, a combination of compound 1 and palbociclib, compound 1 alone, or palbociclib alone.

[0099] Figure 15 A graph showing the expression level of estrogen receptor α (ERα)-62kDa protein in tumor samples collected at the end of treatment, wherein the mice were treated with a mediator control, a combination of compound 1 and palbociclib, compound 1 alone, or palbociclib alone.

[0100] Figure 16 A graph showing the expression level of ERα-55kDa protein in tumor samples collected at the end of treatment, wherein the mice were treated with a mediator control, a combination of compound 1 and palbociclib, compound 1 alone, or palbociclib alone.

[0101] Figure 17A graph showing the sum of expression levels of ERα-55kDa and ERα-62kDa proteins in tumor samples collected at the end of treatment, wherein the mice were treated with a mediator control, a combination of compound 1 and palbociclib, compound 1 alone, or palbociclib alone.

[0102] Figure 18 A graph showing the expression levels of PHGDH protein in tumor samples collected at the end of treatment, wherein the mice were treated with a mediator control, a combination of compound 1 and palbociclib, compound 1 alone, or palbociclib alone.

[0103] Figure 19 A graph showing the amount of neutrophils in whole blood samples collected at the end of the study, wherein the mice were treated with a mediator control, a combination of compound 1 and palbociclib, compound 1 alone, or palbociclib alone.

[0104] Figure 20 A graph showing the expression levels of PHGDH in tumor samples collected at the end of treatment, wherein the mice were treated with a mediator control, a combination of compound 1 and palbociclib, compound 1 alone, or palbociclib alone.

[0105] Figure 21 A graph showing the expression levels of PSPH in tumor samples collected at the end of treatment, wherein the mice were treated with a mediator control, a combination of compound 1 and palbociclib, compound 1 alone, or palbociclib alone.

[0106] Figure 22 A graph showing the expression levels of TYMS in tumor samples collected at the end of treatment, wherein the mice were treated with a mediator control, a combination of compound 1 and palbociclib, compound 1 alone, or palbociclib alone.

[0107] Figure 23 A graph showing the expression level of MTHFD1L in tumor samples collected at the end of treatment, wherein the mice were treated with a mediator control, a combination of compound 1 and palbociclib, compound 1 alone, or palbociclib alone.

[0108] Figure 24 A graph showing the expression level of MTHFD1 in tumor samples collected at the end of treatment, wherein the mice were treated with a mediator control, a combination of compound 1 and palbociclib, compound 1 alone, or palbociclib alone.

[0109] Figure 25 A graph showing the expression level of MTHFD2 in tumor samples collected at the end of treatment, wherein the mice were treated with a mediator control, a combination of compound 1 and palbociclib, compound 1 alone, or palbociclib alone.

[0110] Figure 26 A graph showing the expression level of SHMT1 in tumor samples collected at the end of treatment, wherein the mice were treated with a mediator control, a combination of compound 1 and palbociclib, compound 1 alone, or palbociclib alone.

[0111] Figure 27 A graph showing the expression levels of SHMT2 in tumor samples collected at the end of treatment, wherein the mice were treated with a mediator control, a combination of compound 1 and palbociclib, compound 1 alone, or palbociclib alone.

[0112] Figure 28 A graph showing the expression level of PIK3IP1 in tumor samples collected at the end of treatment, wherein the mice were treated with a mediator control, a combination of compound 1 and palbociclib, compound 1 alone, or palbociclib alone.

[0113] Figure 29 A graph showing the expression levels of Greb1 in tumor samples collected at the end of treatment, wherein the mice were treated with a mediator control, a combination of compound 1 and palbociclib, compound 1 alone, or palbociclib alone.

[0114] Figure 30 Kaplan-Meier plots of ER+ breast cancer patients with high or low PHGDH expression (N=5526).

[0115] Figure 31 Kaplan-Meier plots of ER+ breast cancer patients with high or low TYMS expression (N=5526).

[0116] Figure 32 Kaplan-Meier plots of ER+ breast cancer patients with high or low PIK3IP1 expression (N=5526).

[0117] Figure 33 A graph showing the expression levels of DHFR in tumor samples collected at the end of treatment, wherein the mice were treated with a mediator control, a combination of compound 1 and palbociclib, compound 1 alone, or palbociclib alone.

[0118] Figure 34 A graph showing the expression levels of MybL2 in tumor samples collected at the end of treatment, wherein the mice were treated with a mediator control, a combination of compound 1 and palbociclib, compound 1 alone, or palbociclib alone.

[0119] Figure 35A graph showing the expression levels of BIRC5 / survivin in tumor samples collected at the end of treatment, wherein the mice were treated with a mediator control, a combination of compound 1 and palbociclib, compound 1 alone, or palbociclib alone.

[0120] Figure 36 A graph showing the expression levels of Ki-67 in tumor samples collected at the end of treatment, wherein the mice were treated with a mediator control, a combination of compound 1 and palbociclib, compound 1 alone, or palbociclib alone.

[0121] Figure 37 A graph showing the expression levels of CCNB1 / cyclin B1 in tumor samples collected at the end of treatment, wherein the mice were treated with a mediator control, a combination of compound 1 and palbociclib, compound 1 alone, or palbociclib alone.

[0122] Figure 38 A graph showing the expression level of SCUBE2 in tumor samples collected at the end of treatment, wherein the mice were treated with a mediator control, a combination of compound 1 and palbociclib, compound 1 alone, or palbociclib alone.

[0123] Figure 39 A graph showing the expression level of RRM2 in tumor samples collected at the end of treatment, wherein the mice were treated with a mediator control, a combination of compound 1 and palbociclib, compound 1 alone, or palbociclib alone.

[0124] Figure 40 A graph showing the expression levels of PCLAF in tumor samples collected at the end of treatment, wherein the mice were treated with a mediator control, a combination of compound 1 and palbociclib, compound 1 alone, or palbociclib alone.

[0125] Figure 41 A graph showing the expression levels of SLC7A5 / LAT1 in tumor samples collected at the end of treatment, wherein the mice were treated with a mediator control, a combination of compound 1 and palbociclib, compound 1 alone, or palbociclib alone.

[0126] Figure 42 A graph showing the expression level of SLC3A2 in tumor samples collected at the end of treatment, wherein the mice were treated with a mediator control, a combination of compound 1 and palbociclib, compound 1 alone, or palbociclib alone.

[0127] Figure 43 A graph showing the expression levels of EVL in tumor samples collected at the end of treatment, wherein the mice were treated with a mediator control, a combination of compound 1 and palbociclib, compound 1 alone, or palbociclib alone.

[0128] Figure 44 A graph showing the expression levels of ANP32E in tumor samples collected at the end of treatment, wherein the mice were treated with a mediator control, a combination of compound 1 and palbociclib, compound 1 alone, or palbociclib alone.

[0129] Figure 45 A graph showing the expression level of H2AZ1 in tumor samples collected at the end of treatment, wherein the mice were treated with a mediator control, a combination of compound 1 and palbociclib, compound 1 alone, or palbociclib alone.

[0130] Figure 46 A graph showing the expression levels of H2AX in tumor samples collected at the end of treatment, wherein the mice were treated with a mediator control, a combination of compound 1 and palbociclib, compound 1 alone, or palbociclib alone.

[0131] Figure 47 A graph showing the MCF tumor volume in mice during a 14-day treatment period, wherein the mice were treated with a mediator control, a combination of compound 1 and reboxil, compound 1 alone, or reboxil alone.

[0132] Figure 48 A graph showing the MCF tumor volume in mice on day 14 of treatment, wherein the mice were treated with a mediator control, a combination of compound 1 and reboxil, compound 1 alone, or reboxil alone.

[0133] Figure 49 A graph showing the MCF tumor volume in mice during 18 days of treatment, wherein the mice were treated with a mediator control, a combination of compound 1 and reboxil, compound 1 alone, or reboxil alone.

[0134] Figure 50 A graph showing the MCF tumor volume in mice on day 18 of treatment, wherein the mice were treated with a mediator control, a combination of compound 1 and reboxil, compound 1 alone, or reboxil alone.

[0135] Detailed description

[0136] This disclosure provides, among other things, methods for treating cancer or preventing treatment resistance to cancer, comprising administering to a subject in need at least one therapeutically effective amount of at least one MetAP2 inhibitor of this disclosure or a pharmaceutically acceptable salt thereof and at least one therapeutically effective amount of at least one CDK4 / 6 inhibitor or a pharmaceutically acceptable salt thereof.

[0137] This disclosure provides combination therapies comprising at least one therapeutically effective amount of at least one MetAP2 inhibitor of this disclosure or a pharmaceutically acceptable salt thereof and at least one therapeutically effective amount of at least one CDK4 / 6 inhibitor or a pharmaceutically acceptable salt thereof.

[0138] This disclosure provides a method for treating cancer in a subject who requires it, the method comprising administering at least one therapeutically effective amount of the aforementioned combination therapy to the subject who requires it.

[0139] This disclosure provides a method for preventing and / or mitigating treatment resistance in subjects who require it, the method comprising administering at least one therapeutically effective amount of the aforementioned combination therapy to the subject who requires it.

[0140] This disclosure provides pharmaceutical compositions comprising at least one therapeutically effective amount of at least one MetAP2 inhibitor of this disclosure or a pharmaceutically acceptable salt thereof and at least one therapeutically effective amount of at least one CDK4 / 6 inhibitor or a pharmaceutically acceptable salt thereof.

[0141] This disclosure provides a method for treating cancer in a subject who requires it, the method comprising administering at least one therapeutically effective amount of the aforementioned pharmaceutical composition to the subject who requires it.

[0142] This disclosure provides a method for preventing and / or mitigating treatment resistance in subjects who require it, the method comprising administering at least one therapeutically effective amount of the aforementioned pharmaceutical composition to the subject who requires it.

[0143] This disclosure provides a kit comprising at least one therapeutically effective amount of at least one MetAP2 inhibitor of this disclosure or a pharmaceutically acceptable salt thereof and at least one therapeutically effective amount of at least one CDK4 / 6 inhibitor or a pharmaceutically acceptable salt thereof.

[0144] This disclosure provides a method for treating cancer in subjects who require it, the method comprising administering at least one therapeutically effective amount of the aforementioned kit to the subjects who require it.

[0145] This disclosure provides a method for preventing and / or mitigating treatment resistance in subjects who require it, the method comprising administering at least one therapeutically effective amount of the aforementioned kit to the subject.

[0146] This disclosure provides a method for treating cancer in a subject in need of it, the method comprising administering to the subject at least one therapeutically effective amount of at least one MetAP2 inhibitor of this disclosure or a pharmaceutically acceptable salt thereof and at least one therapeutically effective amount of at least one CDK4 / 6 inhibitor or a pharmaceutically acceptable salt thereof.

[0147] This disclosure provides a method for preventing and / or mitigating treatment resistance in subjects who require it, the method comprising administering to the subject at least one therapeutically effective amount of at least one MetAP2 inhibitor of this disclosure or a pharmaceutically acceptable salt thereof and at least one therapeutically effective amount of at least one CDK4 / 6 inhibitor or a pharmaceutically acceptable salt thereof.

[0148] This disclosure provides the use of at least one MetAP2 inhibitor or a pharmaceutically acceptable salt thereof in combination with at least one CDK4 / 6 inhibitor or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating cancer.

[0149] This disclosure provides for the use of at least one MetAP2 inhibitor or a pharmaceutically acceptable salt thereof in combination with at least one CDK4 / 6 inhibitor or a pharmaceutically acceptable salt thereof in the preparation of a medicament for the prevention and / or mitigation of treatment resistance in subjects in need of it.

[0150] This disclosure provides the use of at least one CDK4 / 6 inhibitor or a pharmaceutically acceptable salt thereof in combination with at least one MetAP2 inhibitor or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating cancer.

[0151] This disclosure provides for use in the preparation of a medicament for the prevention and / or mitigation of treatment resistance in subjects who require it, in combination with at least one CDK4 / 6 inhibitor or a pharmaceutically acceptable salt thereof.

[0152] This disclosure provides a combination of at least one MetAP2 inhibitor or a pharmaceutically acceptable salt thereof for preparing a medicament for treating cancer, in combination with at least one CDK 4 / 6 inhibitor or a pharmaceutically acceptable salt thereof.

[0153] This disclosure provides for the preparation of a combination of at least one MetAP2 inhibitor or a pharmaceutically acceptable salt thereof for use in the prevention and / or mitigation of treatment resistance in subjects in need of the medicament, in combination with at least one CDK4 / 6 inhibitor or a pharmaceutically acceptable salt thereof.

[0154] In some aspects of the foregoing methods and uses, the treatment resistance may be resistance to treatment with CDK4 / 6 inhibitors.

[0155] This disclosure provides at least one MetAP2 inhibitor or a pharmaceutically acceptable salt thereof, in combination with at least one CDK4 / 6 inhibitor or a pharmaceutically acceptable salt thereof, for the treatment of cancer.

[0156] This disclosure provides at least one MetAP2 inhibitor or a pharmaceutically acceptable salt thereof, in combination with at least one CDK4 / 6 inhibitor or a pharmaceutically acceptable salt thereof, for the prevention and / or mitigation of treatment resistance in subjects in need of it.

[0157] This disclosure provides at least one CDK4 / 6 inhibitor or a pharmaceutically acceptable salt thereof, which, in combination with at least one MetAP2 inhibitor or a pharmaceutically acceptable salt thereof, is used for the treatment of cancer.

[0158] This disclosure provides at least one CDK4 / 6 inhibitor or a pharmaceutically acceptable salt thereof, which, in combination with at least one MetAP2 inhibitor or a pharmaceutically acceptable salt thereof, is used to prevent and / or reduce treatment resistance in subjects who require it.

[0159] This disclosure provides a combination of at least one MetAP2 inhibitor or a pharmaceutically acceptable salt thereof with at least one CDK4 / 6 inhibitor or a pharmaceutically acceptable salt thereof for the treatment of cancer.

[0160] This disclosure provides a combination of at least one MetAP2 inhibitor or a pharmaceutically acceptable salt thereof with at least one CDK4 / 6 inhibitor or a pharmaceutically acceptable salt thereof for the prevention and / or mitigation of treatment resistance in subjects in need of it.

[0161] This disclosure provides a combination for treating cancer comprising at least one MetAP2 inhibitor or a pharmaceutically acceptable salt thereof, and at least one CDK4 / 6 inhibitor or a pharmaceutically acceptable salt thereof. This disclosure provides a combination for treating cancer comprising at least one MetAP2 inhibitor or a pharmaceutically acceptable salt thereof, wherein the combination comprises at least one CDK4 / 6 inhibitor or a pharmaceutically acceptable salt thereof. This disclosure provides a combination for treating cancer comprising at least one CDK4 / 6 inhibitor or a pharmaceutically acceptable salt thereof, wherein the combination comprises at least one MetAP2 inhibitor or a pharmaceutically acceptable salt thereof. In some aspects, the at least one MetAP2 inhibitor or a pharmaceutically acceptable salt thereof and the at least one CDK4 / 6 inhibitor or a pharmaceutically acceptable salt thereof may be administered simultaneously, separately, or sequentially. In some aspects, the at least one MetAP2 inhibitor or a pharmaceutically acceptable salt thereof and the at least one CDK4 / 6 inhibitor or a pharmaceutically acceptable salt thereof may be administered simultaneously or close in time.

[0162] In some aspects of the aforementioned methods and uses, treatment resistance can be treatment resistance to at least one CDK4 / 6 inhibitor.

[0163] In some respects, MetAP2 inhibitors or their pharmaceutically acceptable salts and CDK4 / 6 inhibitors or their pharmaceutically acceptable salts can be administered via the same route of administration. In other respects, MetAP2 inhibitors or their pharmaceutically acceptable salts and CDK4 / 6 inhibitors or their pharmaceutically acceptable salts can be administered via different routes of administration.

[0164] In some respects, MetAP2 inhibitors or their pharmaceutically acceptable salts and CDK4 / 6 inhibitors or their pharmaceutically acceptable salts can be administered simultaneously.

[0165] In some respects, MetAP2 inhibitors or their pharmaceutically acceptable salts and CDK4 / 6 inhibitors or their pharmaceutically acceptable salts can be administered close together in time.

[0166] As used herein, the term "temporally proximate" means that the administration of one therapeutic agent (e.g., a MetAP2 inhibitor compound disclosed herein) occurs some time before or after the administration of another therapeutic agent (e.g., palbociclib), such that the therapeutic effect of one therapeutic agent overlaps with the therapeutic effect of the other. In some embodiments, the therapeutic effects of one therapeutic agent completely overlap with the therapeutic effects of the other. In some embodiments, "temporally proximate" means that the administration of one therapeutic agent occurs some time before or after the administration of another therapeutic agent, such that there is a synergistic effect between the two therapeutic agents. "Temporally proximate" can vary depending on a variety of factors, including but not limited to: the age, sex, weight, genetic background, medical condition, medical history, and treatment history of the subject to be administered the therapeutic agent; the disease or condition to be treated or improved; the therapeutic effect to be achieved; the dose, frequency, and duration of administration of the therapeutic agent; the pharmacokinetics and pharmacodynamics of the therapeutic agent; and the route (one or more) by which the therapeutic agent is administered. In some implementations, "temporally close" means within 15 minutes, within 30 minutes, within 1 hour, within 2 hours, within 4 hours, within 6 hours, within 8 hours, within 12 hours, within 18 hours, within 24 hours, within 36 hours, within 2 days, within 3 days, within 4 days, within 5 days, within 6 days, within 1 week, within 2 weeks, within 3 weeks, within 4 weeks, within 6 weeks, or within 8 weeks. In some implementations, multiple administrations of one therapeutic agent may occur temporally close to a single administration of another therapeutic agent. In some implementations, temporal closeness may vary during a treatment cycle or within an administration regimen.

[0167] In some aspects, administration of a combination of at least one MetAP2 inhibitor or a pharmaceutically acceptable salt thereof and at least one CDK4 / 6 inhibitor or a pharmaceutically acceptable salt thereof can result in a decrease in the expression level of at least one protein in at least one tumor in a subject. In some aspects, said at least one protein may comprise Rb protein, CDK2 protein, CDK4 protein, cyclin E1 protein, cyclin E2 protein, Akt protein, phosphorylated Akt, ERα-62, ERα-55, or any combination thereof. In some aspects, the decrease in the expression level of said at least one protein may be at least about 5%, or at least about 10%, or at least about 15%, or at least about 20%, or at least about 25%, or at least about 30%, or at least about 35%, or at least about 40%, or at least about 45%, or at least about 50%, or at least about 55%, or at least about 60%, or at least about 65%, or at least about 70%, or at least about 75%, or at least about 80%, or at least about 85%, or at least about 90%, or at least about 95%, or at least about 99%.

[0168] In some aspects, administration of a combination of at least one MetAP2 inhibitor or a pharmaceutically acceptable salt thereof and at least one CDK4 / 6 inhibitor or a pharmaceutically acceptable salt thereof can result in a decrease in the expression level of at least one gene encoding at least one protein in at least one tumor in a subject. In some aspects, said at least one protein may comprise Rb protein, CDK2 protein, CDK4 protein, cyclin E1 protein, cyclin E2 protein, Akt protein, phosphorylated Akt, ERα-62, ERα-55, PHGDH, or any combination thereof. In some respects, the decrease in the expression level of at least one gene encoding at least one protein may be at least about 5%, or at least about 10%, or at least about 15%, or at least about 20%, or at least about 25%, or at least about 30%, or at least about 35%, or at least about 40%, or at least about 45%, or at least about 50%, or at least about 55%, or at least about 60%, or at least about 65%, or at least about 70%, or at least about 75%, or at least about 80%, or at least about 85%, or at least about 90%, or at least about 95%, or at least about 99%.

[0169] In some aspects, administration of a combination of at least one MetAP2 inhibitor or a pharmaceutically acceptable salt thereof and at least one CDK4 / 6 inhibitor or a pharmaceutically acceptable salt thereof can result in a decrease in the expression level of at least one gene in at least one tumor in a subject. In some aspects, said at least one gene may comprise MTHFD1L, TYMS, ALDH1L1, MTHFD1, MTHFD2, GART, SHMT1, DHFR, MTR, SHMT2, and MTFMT, or any combination thereof. In some aspects, said at least one gene may comprise PHGDH, PSPH, TYMS, MTHFD1L, MTHFD1, MTHFD2, SHMT1, SHMT2, Greb1, DHFR, MybL2, BIRC5 / Survivin, Ki-67, CCNB1 / Cyclin B1, RRM2, PCLAF, SLC7A5 / LAT1, SLC3A2, ANP32E, H2AZ1, H2AX, or any combination thereof. In some aspects, the decrease in the expression level of the at least one gene may be at least about 5%, or at least about 10%, or at least about 15%, or at least about 20%, or at least about 25%, or at least about 30%, or at least about 35%, or at least about 40%, or at least about 45%, or at least about 50%, or at least about 55%, or at least about 60%, or at least about 65%, or at least about 70%, or at least about 75%, or at least about 80%, or at least about 85%, or at least about 90%, or at least about 95%, or at least about 99%.

[0170] In some aspects, following administration of at least one MetAP2 inhibitor or a pharmaceutically acceptable salt thereof and at least one CDK4 / 6 inhibitor or a pharmaceutically acceptable salt thereof, the decrease in expression level of at least one protein, at least one gene encoding at least one protein, or at least one gene may be a greater decrease in expression level compared to the decrease in expression level caused by administration of at least one MetAP2 inhibitor alone and / or administration of at least one CDK4 / 6 inhibitor alone. In some aspects, following administration of at least one MetAP2 inhibitor or a pharmaceutically acceptable salt thereof and at least one CDK4 / 6 inhibitor, the decrease in expression level may be at least about 25%, or at least about 50%, or at least about 75%, or at least about 100%, or at least about 125%, or at least about 150%, or at least about 175%, or at least about 200% or greater, compared to the decrease in expression level caused by administration of at least one MetAP2 inhibitor alone and / or administration of at least one CDK4 / 6 inhibitor alone.

[0171] In some aspects, administration of a combination of at least one MetAP2 inhibitor or a pharmaceutically acceptable salt thereof and at least one CDK4 / 6 inhibitor or a pharmaceutically acceptable salt thereof may result in a reduction of the increase in the expression level of at least one protein in at least one tumor in a subject caused by administration of at least one MetAP2 inhibitor alone and / or at least one CDK4 / 6 inhibitor alone. In some aspects, said at least one protein may comprise Rb protein, p21 protein, CDK2 protein, CDK4 protein, cyclin E1 protein, cyclin E2 protein, LC3B protein, estrogen receptor, Akt protein, or any combination thereof. In some respects, the reduction may be at least about 5%, or at least about 10%, or at least about 15%, or at least about 20%, or at least about 25%, or at least about 30%, or at least about 35%, or at least about 40%, or at least about 45%, or at least about 50%, or at least about 55%, or at least about 60%, or at least about 65%, or at least about 70%, or at least about 75%, or at least about 80%, or at least about 85%, or at least about 90%, or at least about 95%, or at least about 99%.

[0172] In some aspects, the administration of a combination of at least one MetAP2 inhibitor or a pharmaceutically acceptable salt thereof and at least one CDK4 / 6 inhibitor or a pharmaceutically acceptable salt thereof may result in a smaller increase in the expression of at least one protein compared to the increase in expression level caused by the administration of at least one MetAP2 inhibitor alone and / or the administration of at least one CDK4 / 6 inhibitor alone. In some aspects, said at least one protein may be p21, LC3B, or cyclin D1. In some aspects, the increase in expression following the administration of a combination of at least one MetAP2 inhibitor or a pharmaceutically acceptable salt thereof and at least one CDK4 / 6 inhibitor or a pharmaceutically acceptable salt thereof is at least about 10%, or at least about 25%, or at least about 50%, or at least about 75%, or at least about 100%, or at least about 125%, or at least about 150%, or at least about 175%, or at least about 200% less than the increase in expression following the administration of at least one MetAP2 inhibitor alone and / or the administration of at least one CDK4 / 6 inhibitor alone.

[0173] In some aspects, the administration of a combination of at least one MetAP2 inhibitor or a pharmaceutically acceptable salt thereof and at least one CDK4 / 6 inhibitor or a pharmaceutically acceptable salt thereof can attenuate the increase in expression of at least one protein, compared to an increase in expression level caused by the administration of at least one MetAP2 inhibitor alone and / or the administration of at least one CDK4 / 6 inhibitor alone. In some aspects, said at least one protein may be p21, Akt protein, or cyclin D1. In some aspects, said attenuation may be at least about 10%, or at least about 25%, or at least about 50%, or at least about 75%, or at least about 100%.

[0174] In some respects, administration of a combination of at least one MetAP2 inhibitor or a pharmaceutically acceptable salt thereof and at least one CDK4 / 6 inhibitor or a pharmaceutically acceptable salt thereof may result in an increase in the expression of at least one protein of not more than about 10%, or about 20%, or about 30%, or about 40%, or about 50%, or about 60%, or about 70%, or about 80%, or about 90%, or about 100%.

[0175] In some aspects, administration of a combination of at least one MetAP2 inhibitor or a pharmaceutically acceptable salt thereof and at least one CDK4 / 6 inhibitor or a pharmaceutically acceptable salt thereof may result in an increased number of neutrophils in a subject compared to the number of neutrophils in a subject who has already been administered at least one MetAP2 inhibitor and / or at least one CDK4 / 6 inhibitor alone. In some aspects, the number of neutrophils in a subject after administration of a combination of at least one MetAP2 inhibitor or a pharmaceutically acceptable salt thereof and at least one CDK4 / 6 inhibitor or a pharmaceutically acceptable salt thereof is at least about 5%, or at least about 10%, or at least about 15%, or at least about 20%, or at least about 25%, or at least about 30%, or at least about 35%, or at least about 40%, or at least about 45%, or at least about 50%, compared to the number of neutrophils in a subject who has already been administered at least one MetAP2 inhibitor and / or at least one CDK4 / 6 inhibitor alone. %, or at least about 55%, or at least about 60%, or at least about 65%, or at least about 70%, or at least about 75%, or at least about 80%, or at least about 85%, or at least about 90%, or at least about 95%, or at least about 100%, or at least about 125%, or at least about 150%, or at least about 175%, or at least about 200%, or at least about 225%, or at least about 250%, or at least about 275%, or at least about 300%, or at least about 325%, or at least about 350%, or at least about 375%, or at least about 400%, or at least about 425%, or at least about 450%.

[0176] In some aspects, administration of a combination of at least one MetAP2 inhibitor or a pharmaceutically acceptable salt thereof and at least one CDK4 / 6 inhibitor or a pharmaceutically acceptable salt thereof may result in an increase in the expression level of at least one gene. In some aspects, said at least one gene may comprise PIK3IP1, SCUBE2, or EVL. In some aspects, the increase in the expression level of said at least one protein may be at least about 5%, or at least about 10%, or at least about 15%, or at least about 20%, or at least about 25%, or at least about 30%, or at least about 35%, or at least about 40%, or at least about 45%, or at least about 50%, or at least about 55%, or at least about 60%, or at least about 65%, or at least about 70%, or at least about 75%, or at least about 80%, or at least about 85%, or at least about 90%, or at least about 95%, or at least about 99%.

[0177] MetAP2 inhibitors

[0178] Any MetAP2 inhibitor described herein can be used in the kits, pharmaceutical compositions, uses, and methods described herein.

[0179] In some respects, a MetAP2 inhibitor can be a compound of formula (I) or a pharmaceutically acceptable salt, analogue, derivative, salt or ester thereof, wherein formula I is represented by the following:

[0180]

[0181] In each instance, independently, R4 is H or a C1-C6 alkyl; R5 is H or a C1-C6 alkyl; R6 is a C2-C6 hydroxyalkyl; Z is -NH-AA1-AA2-AA3-AA4-AA5-AA6-C(O)-L or -NH-AA1-AA2-AA3-AA4-AA5-AA6-C(O)-QXYC(O)-W; AA1 is glycine, alanine, or H2N(CH2)mCO2H, where m is 2, 3, 4, or 5; AA2 is... The AA3 bond is a bond containing alanine, cysteine, aspartic acid, glutamic acid, phenylalanine, glycine, histidine, isoleucine, lysine, leucine, methionine, asparagine, proline, glutamine, arginine, serine, threonine, valine, tryptophan, or tyrosine; AA3 is a bond containing alanine, cysteine, aspartic acid, glutamic acid, phenylalanine, glycine, histidine, isoleucine, lysine, leucine, methionine, asparagine, proline, glutamine, arginine, serine, threonine, or valine. Acids, tryptophan, or tyrosine; AA4 is a bond or alanine, cysteine, aspartic acid, glutamic acid, phenylalanine, glycine, histidine, isoleucine, lysine, leucine, methionine, asparagine, proline, glutamine, arginine, serine, threonine, valine, tryptophan, or tyrosine; AA5 is a bond or glycine, valine, tyrosine, tryptophan, phenylalanine, methionine, leucine, isoleucine, or asparagine; AA6 is a bond or alanine, asparagine, citrulline, glutamine, etc. Amine, glycine, leucine, methionine, phenylalanine, serine, threonine, tryptophan, tyrosine, valine, or H2N(CH2)mCO2H, where m is 2, 3, 4, or 5; L is -OH, -O-succinimide, -O-sulfosuccinimide, alkoxy, aryloxy, acyloxy, aryloxycarbamoyloxy, -NH2, -NH (C2-C6 hydroxyalkyl), halide, or perfluoroalkoxy; Q is NR, O, or S; X is M-(C(R)2) p -MJM-(C(R)2) p -MV; M is a bond or C(O); J is a bond or ((CH2)) q Q) r C5-C8 cycloalkyl, aryl, heteroaryl, NR, O or S; Y is NR, O or S; R is H or alkyl; V is a bond or R 9 It is an alkyl, aryl, aralkyl, or bond; or R 9 Together with Y, they form a heterocyclic ring; R 10 It is an amide or bond; R 11H is an alkyl group; W is a MetAP2 inhibitor moiety or alkyl group; x is in the range of 1 to about 450; y is in the range of 1 to about 30; n is in the range of 1 to about 100; p is 0 to 20; q is 2 or 3; and r is 1, 2, 3, 4, 5 or 6. In some aspects, n is in the range of about 1 to about 90, about 1 to about 80, about 1 to about 70, about 1 to about 60, about 1 to about 55, or about 1 to about 50.

[0182] In some embodiments, R4 is a C1-C6 alkyl group. In some embodiments, R4 is methyl. In some embodiments, R5 is a C1-C6 alkyl group. In some embodiments, R5 is methyl. In some embodiments, R6 is 2-hydroxyethyl, 2-hydroxypropyl, or 3-hydroxypropyl. In some embodiments, R6 is 2-hydroxypropyl.

[0183] In some embodiments, the compound has a molecular weight greater than about 100 kDa. In some embodiments, the compound has a molecular weight less than about 100 kDa. In some embodiments, the molecular weight is less than about 95 kDa. In some embodiments, the molecular weight is less than about 90 kDa. In some embodiments, the molecular weight is less than about 80 kDa. In some embodiments, the molecular weight is less than about 70 kDa. In some embodiments, the molecular weight is less than about 65 kDa. In some embodiments, the molecular weight is less than about 60 kDa. In some embodiments, the molecular weight is less than about 45 kDa. In some embodiments, the molecular weight is less than about 35 kDa.

[0184] In some embodiments, the ratio of x to y is in the range of about 100:1 to about 1:1. In some embodiments, the ratio of x to y is in the range of about 30:1 to about 3:1. In some embodiments, the ratio of x to y is in the range of about 19:2 to about 7:2. In some embodiments, the ratio of x to y is in the range of about 9:1 to about 4:1. In some embodiments, the ratio of x to y is about 11:1. In some embodiments, the ratio of x to y is about 9:1. In some embodiments, the ratio of x to y is about 4:1. In some embodiments, the ratio of x to y is about 12:1. For example, in some implementations, the x:y ratio is approximately 3:1; the x:y ratio is approximately 4:1; the x:y ratio is approximately 5:1; the x:y ratio is approximately 6:1; the x:y ratio is approximately 7:1; the x:y ratio is approximately 8:1; the x:y ratio is approximately 9:1; the x:y ratio is approximately 10:1; the x:y ratio is approximately 11:1; the x:y ratio is approximately 12:1; the x:y ratio is approximately 13:1; the x:y ratio is approximately 14:1; the x:y ratio is approximately 15:1; the x:y ratio is approximately 16:1. 1; the ratio of x to y is approximately 17:1; the ratio of x to y is approximately 18:1; the ratio of x to y is approximately 19:1; the ratio of x to y is approximately 20:1; the ratio of x to y is approximately 21:1; the ratio of x to y is approximately 22:1; the ratio of x to y is approximately 23:1; the ratio of x to y is approximately 24:1; the ratio of x to y is approximately 25:1; the ratio of x to y is approximately 26:1; the ratio of x to y is approximately 27:1; the ratio of x to y is approximately 28:1; the ratio of x to y is approximately 29:1; or the ratio of x to y is approximately 30:1.

[0185] In some embodiments, Z is -NH-AA1-AA2-AA3-AA4-AA5-AA6-C(O)-L. In some embodiments, L is methoxy, ethoxy, pentafluorophenoxy, phenoxy, acetoxy, fluoride, chloride, methoxycarbonyloxy; ethoxycarbonyloxy, phenoxycarbonyloxy, 4-nitrophenoxy, trifluoromethoxy, pentafluoroethoxy, or trifluoroethoxy. In some embodiments, L is 4-nitrophenoxy.

[0186] In some embodiments, Z is -NH-AA1-AA2-AA3-AA4-AA5-AA6-C(O)-QXYC(O)-W. In some embodiments, AA1 is glycine. In some embodiments, AA2 is glycine. In some embodiments, AA3 is glycine. In some embodiments, AA4 is glycine or phenylalanine. In some embodiments, AA5 is leucine, phenylalanine, valine, or tyrosine. In some embodiments, AA6 is asparagine, citrulline, glutamine, glycine, leucine, methionine, threonine, or tyrosine. In some embodiments, AA5-AA6 are Leu-Cit, Leu-Gln, Leu-Gly, Leu-Leu, Leu-Met, Leu-Thr, Phe-Cit, Phe-Gln, Phe-Leu, Phe-Met, Phe-Thr, Val-Asn, Val-Cit, Val-Gln, Val-Leu, Val-Met, Val-Thr, Tyr-Cit, Tyr-Leu, or Tyr-Met. In some embodiments, AA1, AA3, and AA5 are glycine, valine, tyrosine, tryptophan, phenylalanine, methionine, leucine, isoleucine, or asparagine. In some embodiments, AA2, AA4, and AA6 are glycine, asparagine, citrulline, glutamine, glycine, leucine, methionine, phenylalanine, threonine, or tyrosine. In some embodiments, AA2 is a bond; and AA3 is a bond. In some implementations, AA1 is glycine; AA4 is phenylalanine; AA5 is leucine; and AA6 is glycine.

[0187] In some implementation schemes, W is

[0188]

[0189]

[0190]

[0191]

[0192]

[0193]

[0194] R2 is -OH or methoxy; and R3 is H, -OH or methoxy.

[0195] In some implementation schemes, W is

[0196]

[0197]

[0198] In some implementation schemes, W is

[0199] In some implementations, Q is NR. In some implementations, Q is S.

[0200] In some implementations, J is NR. In some implementations, J is ((CH2)). q Q) r In some embodiments, J is a C5-C8 cycloalkyl group. In some embodiments, J is an aryl group.

[0201] In some implementations, Y is NR. In some implementations, Y is S.

[0202] In some implementations, -QXY- is

[0203]

[0204]

[0205] V is:

[0206] OR key; R 12 It is H or Me; or R 12 With R 14 Together they form a piperidine ring; R 11 It is H or Me; and R 13 With R 12 Together they form a piperidine ring.

[0207] In some implementations, -QXY- is

[0208] In some implementations, -QXY- is

[0209] In some implementations, -QXY- is

[0210] In some implementations, -QXY is

[0211] In some implementations, -QXY- is In some implementations, -QXY- is

[0212] In some embodiments, R4 and R5 are methyl groups; R6 is 2-hydroxypropyl; Z is -NH-AA1-AA2-AA3-AA4-AA5-AA6-C(O)-QXYC(O)-W; AA1 is glycine; AA2 is a bond; AA3 is a bond; AA4 is phenylalanine; AA5 is leucine; AA6 is glycine; -QXY- is... And W is

[0213]

[0214] In some embodiments, R4 and R5 are methyl groups; R6 is 2-hydroxypropyl; Z is -NH-AA1-AA2-AA3-AA4-AA5-AA6-C(O)-QXYC(O)-W; AA1 is glycine; AA2 is a bond; AA3 is a bond; AA4 is phenylalanine; AA5 is leucine; AA6 is glycine; -QXY- is... And W is

[0215]

[0216] In some embodiments, R4 and R5 are methyl groups; R6 is 2-hydroxypropyl; Z is -NH-AA1-AA2-AA3-AA4-AA5-AA6-C(O)-QXYC(O)-W; AA1 is glycine; AA2 is a bond; AA3 is a bond; AA4 is phenylalanine; AA5 is leucine; AA6 is glycine; -QXY- is... And W is

[0217]

[0218] In some embodiments, R4 and R5 are methyl groups; R6 is 2-hydroxypropyl; Z is -NH-AA1-AA2-AA3-AA4-AA5-AA6-C(O)-QXYC(O)-W; AA1 is glycine; AA2 is a bond; AA3 is a bond; AA4 is phenylalanine; AA5 is leucine; AA6 is glycine; -QXY- is... And W is

[0219]

[0220] In some implementations, -QXY- is a self-immolating linker that releases the MetAP2 inhibitor in the form of a carbamate derivative, as shown in the following scheme:

[0221]

[0222] Another aspect of this disclosure provides conjugates having a linker having the structure: ZQXYC(O)-W; wherein, independently for each occurrence, Z is H2N-AA2-AA3-AA4-AA5-AA6-C(O)- or H; AA2 is a bond or alanine, cysteine, aspartic acid, glutamic acid, phenylalanine, glycine, histidine, isoleucine, lysine, leucine, methionine, asparagine, proline, glutamine, arginine, serine, threonine, valine, tryptophan, or tyrosine; AA3 is a bond or alanine, cysteine, aspartic acid, glutamic acid, phenylalanine, glycine, histidine, isoleucine, lysine, leucine, methionine, asparagine, proline, glutamine, arginine, serine, threonine, valine, arginine, serine, threonine, glutamic acid, valine, tryptophan, or tyrosine; AA4 is a compound amino acid, valine, tryptophan, or tyrosine; AA5 is a compound amino acid, valine, aspartic acid, glutamic acid, phenylalanine, glycine, histidine, isoleucine, lysine, leucine, methionine, asparagine, proline, glutamine, arginine, serine, threonine, valine, tryptophan, or tyrosine; AA6 is a compound amino acid, asparagine, citrulline, glutamine, glycine, leucine, methionine, phenylalanine, serine, threonine, tryptophan, valine, or H2N(CH2)mCO2H, where m is 2, 3, 4, or 5; Q is NR, O, or S; X is M-(C(R)2) p -MJM-(C(R)2) p -MV; M is a bond or C(O); J is a bond or ((CH2)) q Q) r C5-C8 cycloalkyl, aryl, heteroaryl, NR, O, or S; Y is NR, O, or S; R is H or alkyl; V is a bond or R 9 It is an alkyl, aryl, aralkyl, or bond; or R 9 Together with Y, they form a heterocyclic ring; R 10 It is an amide or bond; R 11 It is H or alkyl; W is the MetAP2 inhibitor moiety; p is 0 to 20; q is 2 or 3; and r is 1, 2, 3, 4, 5 or 6.

[0223] In some embodiments, Z is H2N-AA5-AA6-C(O)-. In some embodiments, AA5 is alanine, cysteine, glycine, isoleucine, leucine, methionine, phenylalanine, valine, tryptophan, or tyrosine, and AA6 is glycine. In some embodiments, AA5 is leucine, and AA6 is glycine. In some embodiments, AA5 is valine, and AA6 is glycine. In some embodiments, AA5 is phenylalanine, and AA6 is glycine. In some embodiments, AA5 is glycine, and AA6 is glycine. In some embodiments, AA5 is not valine.

[0224] In some embodiments, Z is H2N-AA3-AA4-AA5-AA6-C(O)-. In some embodiments, AA5 is alanine, cysteine, glycine, isoleucine, leucine, methionine, phenylalanine, valine, tryptophan, or tyrosine, and each of AA3, AA4, or AA6 is glycine. In some embodiments, AA5 is leucine, and each of AA3, AA4, or AA6 is glycine. In some embodiments, AA5 is valine, and each of AA3, AA4, or AA6 is glycine. In some embodiments, AA5 is phenylalanine, and each of AA3, AA4, or AA6 is glycine. In some embodiments, AA3 is glycine, AA4 is phenylalanine, AA5 is leucine, and AA6 is glycine. In some embodiments, each of AA3, AA4, AA5, and AA6 is glycine. In some embodiments, AA5 is not valine.

[0225] In some embodiments, Z is H. In some embodiments, Z is H2N-AA6-C(O)-. In some embodiments, AA6 is glycine.

[0226] In some implementations, Q is NR. In some implementations, M is the key. In some implementations, J is the key. In some implementations, Y is NR.

[0227] In some implementation schemes, W is:

[0228]

[0229]

[0230]

[0231]

[0232]

[0233]

[0234] R2 is -OH or methoxy; and R3 is H, -OH or methoxy.

[0235] In some implementation schemes, W is

[0236]

[0237]

[0238] In some implementation schemes, W is

[0239] In some implementations, -QXY- is

[0240]

[0241]

[0242] V is:

[0243] OR key; R 12 It is H or Me; or R 12 With R 14 Together they form a piperidine ring; R 11 It is H or Me; and R 13 With R 12 Together they form a piperidine ring.

[0244] In some implementations, Z is H2N-AA5-AA6-C(O)-; AA5 is leucine and AA6 is glycine; QXY is... And W is

[0245]

[0246] In some implementations, Z is H2N-AA5-AA6-C(O)-; AA5 is valine and AA6 is glycine; QXY is... And W is

[0247] In some implementations, Z is H2N-AA5-AA6-C(O)-; AA5 is phenylalanine and AA6 is glycine; QXY is... And W is

[0248] In some implementations, Z is H2N-AA5-AA6-C(O)-; AA5 is glycine and AA6 is glycine; QXY is... And W is

[0249] In some embodiments, Z is H2N-AA3-AA4-AA5-AA6-C(O)-; AA5 is leucine and each of AA3, AA4, or AA6 is glycine; QXY is And W is

[0250] In some embodiments, Z is H2N-AA3-AA4-AA5-AA6-C(O)-; AA5 is valine and each of AA3, AA4, or AA6 is glycine; QXY is And W is

[0251] In some embodiments, Z is H2N-AA3-AA4-AA5-AA6-C(O)-; AA5 is phenylalanine and each of AA3, AA4, or AA6 is glycine; QXY is And W is

[0252] In some implementations, Z is H2N-AA3-AA4-AA5-AA6-C(O)-; AA3 is glycine, AA4 is phenylalanine, AA5 is leucine, and AA6 is glycine; QXY is And W is

[0253] In some implementations, Z is H2N-AA3-AA4-AA5-AA6-C(O)-; each of AA3, AA4, AA5, and AA6 is glycine; QXY is And W is

[0254] In some implementations, Z is H2N-AA6-C(O)-; AA6 is glycine; QXY is... And W is

[0255] In some implementations, Z is H; QXY is And W is

[0256] In some implementations, Z is H2N-AA5-AA6-C(O)-; AA5 is leucine and AA6 is glycine; QXY is... And W is

[0257]

[0258] In some implementations, Z is H2N-AA5-AA6-C(O)-; AA5 is valine and AA6 is glycine; QXY is... And W is

[0259]

[0260] In some implementations, Z is H2N-AA5-AA6-C(O)-; AA5 is phenylalanine and AA6 is glycine; QXY is... And W is

[0261]

[0262] In some implementations, Z is H2N-AA5-AA6-C(O)-; AA5 is glycine and AA6 is glycine; QXY is... And W is

[0263]

[0264] In some embodiments, Z is H2N-AA3-AA4-AA5-AA6-C(O)-; AA5 is leucine and each of AA3, AA4, or AA6 is glycine; QXY is And W is

[0265] In some embodiments, Z is H2N-AA3-AA4-AA5-AA6-C(O)-; AA5 is valine and each of AA3, AA4, or AA6 is glycine; QXY is And W is

[0266] In some embodiments, Z is H2N-AA3-AA4-AA5-AA6-C(O)-; AA5 is phenylalanine and each of AA3, AA4, or AA6 is glycine; QXY is And W is

[0267] In some implementations, Z is H2N-AA3-AA4-AA5-AA6-C(O)-; AA3 is glycine, AA4 is phenylalanine, AA5 is leucine, and AA6 is glycine; QXY is And W is

[0268] In some implementations, Z is H2N-AA3-AA4-AA5-AA6-C(O)-; each of AA3, AA4, AA5, and AA6 is glycine; QXY is And W is

[0269] In some implementations, Z is H2N-AA6-C(O)-; AA6 is glycine;

[0270] QXY is And W is

[0271] In some implementations, Z is H; QXY is And W is

[0272] In some implementations, Z is H2N-AA5-AA6-C(O)-; AA5 is leucine and AA6 is glycine; QXY is... And W is

[0273] In some implementations, Z is H2N-AA5-AA6-C(O)-; AA5 is valine and AA6 is glycine; QXY is... And W is

[0274] In some implementations, Z is H2N-AA5-AA6-C(O)-; AA5 is phenylalanine and AA6 is glycine; QXY is... And W is

[0275] In some implementations, Z is H2N-AA5-AA6-C(O)-; AA5 is glycine and AA6 is glycine; QXY is... And W is

[0276] In some embodiments, Z is H2N-AA3-AA4-AA5-AA6-C(O)-; AA5 is leucine and each of AA3, AA4, or AA6 is glycine; QXY is And W is

[0277] In some embodiments, Z is H2N-AA3-AA4-AA5-AA6-C(O)-; AA5 is valine and each of AA3, AA4, or AA6 is glycine; QXY is And W is

[0278] In some embodiments, Z is H2N-AA3-AA4-AA5-AA6-C(O)-; AA5 is phenylalanine and each of AA3, AA4, or AA6 is glycine; QXY is And W is

[0279] In some implementations, Z is H2N-AA3-AA4-AA5-AA6-C(O)-; AA3 is glycine, AA4 is phenylalanine, AA5 is leucine, and AA6 is glycine; QXY is And W is

[0280] In some implementations, Z is H2N-AA3-AA4-AA5-AA6-C(O)-; each of AA3, AA4, AA5, and AA6 is glycine; QXY is And W is

[0281] In some implementations, Z is H2N-AA6-C(O)-; AA6 is glycine; QXY is... And W is

[0282] In some implementations, Z is H; QXY is And W is

[0283] In some implementations, Z is H2N-AA5-AA6-C(O)-; AA5 is leucine and AA6 is glycine; QXY is... And W is

[0284] In some implementations, Z is H2N-AA5-AA6-C(O)-; AA5 is valine and AA6 is glycine; QXY is... And W is

[0285] In some implementations, Z is H2N-AA5-AA6-C(O)-; AA5 is phenylalanine and AA6 is glycine; QXY is... And W is

[0286]

[0287] In some implementations, Z is H2N-AA5-AA6-C(O)-; AA5 is glycine and AA6 is glycine; QXY is... And W is

[0288] In some embodiments, Z is H2N-AA3-AA4-AA5-AA6-C(O)-; AA5 is leucine and each of AA3, AA4, or AA6 is glycine; QXY is And W is

[0289] In some embodiments, Z is H2N-AA3-AA4-AA5-AA6-C(O)-; AA5 is valine and each of AA3, AA4, or AA6 is glycine; QXY is And W is

[0290] In some embodiments, Z is H2N-AA3-AA4-AA5-AA6-C(O)-; AA5 is phenylalanine and each of AA3, AA4, or AA6 is glycine; QXY is And W is

[0291] In some implementations, Z is H2N-AA3-AA4-AA5-AA6-C(O)-; AA3 is glycine, AA4 is phenylalanine, AA5 is leucine, and AA6 is glycine; QXY is And W is

[0292] In some implementations, Z is H2N-AA3-AA4-AA5-AA6-C(O)-; each of AA3, AA4, AA5, and AA6 is glycine; QXY is And W is

[0293] In some implementations, Z is H2N-AA6-C(O)-; AA6 is glycine; QXY is... And W is

[0294]

[0295] In some implementations, Z is H; QXY is And W is

[0296] Other active moieties that can be modified for use in the conjugates disclosed herein include the following structures:

[0297]

[0298]

[0299] In some respects, MetAP2 inhibitors can be composed of one or more of the compounds represented by the formulas listed in Table 1, or pharmaceutically acceptable salts, analogs, derivatives, salts, or esters thereof:

[0300] Table 1

[0301]

[0302]

[0303]

[0304]

[0305]

[0306]

[0307]

[0308]

[0309]

[0310]

[0311]

[0312]

[0313]

[0314]

[0315]

[0316]

[0317]

[0318]

[0319]

[0320]

[0321]

[0322]

[0323]

[0324]

[0325]

[0326] *The polymer has the following structure:

[0327]

[0328] The following structure is preferred:

[0329]

[0330] In some respects, the MetAP2 inhibitor may be: (Compound 1), or a pharmaceutically acceptable salt, analogue, derivative, salt or ester thereof.

[0331] In some respects, the MetAP2 inhibitor may be:

[0332] (Compound 2), or a pharmaceutically acceptable salt, analogue, derivative, salt or ester thereof.

[0333] In some respects, the MetAP2 inhibitor may be:

[0334] (Compound 3), or a pharmaceutically acceptable salt, analogue, derivative, salt or ester thereof.

[0335] In some respects, the MetAP2 inhibitor may be:

[0336] (Compound 4), or a pharmaceutically acceptable salt, analogue, derivative, salt or ester thereof.

[0337] In some respects, the MetAP2 inhibitor may be:

[0338] Or a pharmaceutically acceptable salt, analogue, derivative, salt or ester thereof.

[0339] In some respects, the MetAP2 inhibitor may be:

[0340] Or a pharmaceutically acceptable salt, analogue, derivative, salt or ester thereof.

[0341] In some respects, the MetAP2 inhibitor may be:

[0342] Or a pharmaceutically acceptable salt, analogue, derivative, salt salt or ester thereof.

[0343] In some respects, the MetAP2 inhibitor may be:

[0344] Or a pharmaceutically acceptable salt, analogue, derivative, salt or ester thereof.

[0345] In some respects, the MetAP2 inhibitor may be:

[0346] Or a pharmaceutically acceptable salt, analogue, derivative, salt or ester thereof.

[0347] In some aspects, the MetAP2 inhibitor may be selected from cis-(3aRS,9bRS)-7-(benzenesulfonylamino)-1,3a,4,9b-tetrahydro-2H-furano[2,3-c]chromene-6-carboxylic acid; cis-(3aRS,9bRS)-7-[2-(3-diethylaminopropyl)-4-fluorobenzenesulfonylamino] ... bRS)-7-[2-(3-{pyrrolidin-1-yl}propyl)-4-fluorobenzenesulfonylamino]-1,3a,4,9b-tetrahydro-2H-furano[2,3-c]chromeno-6-carboxylic acid; cis-(3aRS,9bRS)-7-[2-((Z)-3-diethylaminopropyl-1-enyl)-4-fluorobenzenesulfonylamino]-1,3a,4,9b-tetrahydro-2H-furano[2,3-c]chromeno-6-carboxylic acid; cis-(3aR,9bR)-7 -[2-((Z)-3-diethylaminopropyl-1-enyl)-4-fluoro-benzenesulfonylamino]-1,3a,4,9b-tetrahydro-2H-furano[2,3-c]chromene-6-carboxylic acid; cis-(3aS,9bS)-7-[2-((Z)-3-diethylaminopropyl-1-enyl)-4-fluorobenzenesulfonylamino]-1,3a,4,9b-tetrahydro-2H-furano[2,3-c]chromene-6-carboxylic acid; 7-[2-((Z)-3-diethylamino] [2-((Z)-3-diethylaminoprop-1-enyl)-4-fluorobenzenesulfonylamino]-1,2-dihydrofurano[2,3-c]quinoline-6-carboxylic acid formate; 7-(benzenesulfonylamino)-1,2-dihydrofurano[2,3-c]quinoline-6-carboxylic acid formate; cis-(3aRS,9bRS)-7-[2-((Z)-3-diethylaminoprop-1-enyl)-4-fluorobenzenesulfonylamino]-1,2,3a,4,5,9b-hexahydrofurano[2,3-c]quinoline-6-carboxylic acid;

[0348] (1aRS,7bSR)-5-[2-((Z)-3-diethylaminopropyl-1-enyl)-4-fluorobenzenesulfonylamino]-1,1a,2,7b-tetrahydrocyclopropenyl[c]chromene-4-carboxylic acid; (1aR,7bS)-5-[2-((Z)-3-diethylaminopropyl-1-enyl)-4-fluorobenzenesulfonylamino]-1,1a,2,7b-tetrahydrocyclopropenyl[c]chromene-4-carboxylic acid; (1aS,7bR)-5-[2-((Z)-3-diethylaminopropyl-1-enyl)-4-fluorobenzenesulfonylamino]-1,1a,2,7b-tetrahydrocyclopropenyl[c]chromene-4-carboxylic acid; (1aRS,7bSR)-5-[2-((Z)-3-diethylaminopropyl-1-enyl)-4-fluorobenzenesulfonylamino]-1,1a,2,7b-tetrahydrocyclopropenyl[c]chromene-4-carboxylic acid; (1aRS,7bSR)-5-[2-((Z)-3-diethylaminopropyl-1-enyl)-4-fluorobenzenesulfonylamino]-1,1a,2,7b-tetrahydrocyclopropenyl[c]chromene-4-carboxylic acid; [Acylamino]-7b-methyl-1,1a,2,7b-tetrahydrocyclopropane[c]chromene-4-carboxylic acid; (1aRS,7bSR)-5-[2-((E)-3-diethylaminopropyl-1-enyl)-4-fluorobenzenesulfonylamino]-7b-methyl-1,1a,2,7b-tetrahydrocyclopropane[c]chromene-4-carboxylic acid; cis-(3aRS,9bRS)-7-[2-(4-dimethylamino-butylamino)-benzenesulfonylamino]-1,3a,4,9b-tetrahydro-2H-furano[2,3-c]chromene-6-carboxylic acid; (1aR,7bS)-5-[2-(3-diethylaminopropyl)-4-fluorobenzenesulfonyl-amino]-1,1a,2,7b-tetrahydrocyclopropane[c]chromene-4-carboxylic acid.

[0349] (1aRS,7bSR)-5-[2-((Z)-3-diethylaminopropyl-1-enyl)-4-fluorobenzene-sulfonylamino]-1,1-difluoro-1,1a,2,7b-tetrahydrocyclopropane[c]chromene-4-carboxylic acid; (1aR,7bS)-5-[2-((Z)-3-diethylaminopropyl-1-enyl)-4-fluorobenzene-sulfonylamino]-1,1-difluoro-1,1a,2,7b-tetrahydrocyclopropane[c]chromene-4-carboxylic acid; (1aS,7bR)-5-[2-((Z)-3-diethylaminopropyl-1-enyl)-4-fluorobenzene-sulfonylamino]-1,1-difluoro-1,1a,2,7b-tetrahydrocyclopropane[c]chromene-4-carboxylic acid;

[0350] (1aRS,7bSR)-5-[2((Z)-3-ethylaminopropyl-1-enyl)-4-fluoro-benzenesulfonylamino]-1,1a,2,7b-tetrahydrocyclopropane[c]chromene-4-carboxylic acid; (1aR,7bS)-5-[2((Z)-3-ethylaminopropyl-1-enyl)-4-fluorobenzenesulfonylamino]-1,1a,2,7b-tetrahydrocyclopropane[c]chromene-4-carboxylic acid;

[0351] (1aS,7bR)-5-[2((Z)-3-ethylaminopropyl-1-enyl)-4-fluorobenzenesulfonylamino]-1,1a,2,7b-tetrahydro-cyclopropenyl[c]chromenyl-4-carboxylic acid; (1aRS,7bSR)-5-{2[(Z)-3-(pyrrolidin-1-yl)propyl-1-enyl]-4-fluorobenzenesulfonylamino}-1,1a,2,7b-tetrahydro-cyclopropenyl[c]chromenyl-4-carboxylic acid; (1aR,7bS)-5-{2[(Z)-3-(pyrrolidin-1-yl)propyl-1-enyl]-4-fluorobenzenesulfonyl-amino}-1,1a,2,7b-tetrahydro-cyclopropenyl[c]chromenyl-4-carboxylic acid; Proprymethylene-4-carboxylic acid; (1aS,7bR)-5-{2[(Z)-3-(pyrrolid-1-yl)prop-1-enyl]-4-fluorobenzenesulfonylamino}-1,1a,2,7b-tetrahydro-cycloproprymethylene-4-carboxylic acid; (1aRS,7bSR)-5-[2-(3-dimethylaminopropylamino)benzenesulfonylamino]-1,1a,2,7b-tetrahydrocycloproprymethylene-4-carboxylic acid; (1aR,7bS)-5-[2-(3-dimethylaminopropylamino)benzenesulfonylamino]-1,1a,2,7b-tetrahydrocycloproprymethylene-4-carboxylic acid;

[0352] (1aS,7bR)-5-[2-(3-dimethylaminopropyl-amino)benzenesulfonylamino]-1,1a,2,7b-tetrahydrocyclopropion[c]chromene-4-carboxylic acid; (1aRS,7bSR)-5-[2-(4-dimethylaminobutylamino)benzenesulfonylamino]-1,1a,2,7b-tetrahydrocyclopropion[c]chromene-4-carboxylic acid; (1aR,7bS)-5-[2-(4-dimethylaminobutylamino)benzenesulfonylamino]-1,1a,2,7b-tetrahydrocyclopropion[c]chromene-4-carboxylic acid;

[0353] (1aS,7bR)-5-[2-(4-dimethylaminobutylamino]-1,1a,2,7b-tetrahydrocyclopropion[c]chromene-4-carboxylic acid; (1aRS,7bSR)-5-[2-(5-dimethylamino-pentylamino)benzene-sulfonylamino]-1,1a,2,7b-tetrahydrocyclopropion[c]chromene-4-carboxylic acid; (1aRS,7bSR)-5-{2[(Z)-3 -(propan-2-yl)aminopropyl-1-enyl]-4-fluorobenzenesulfonyl-amino}-1,1a,2,7b-tetrahydrocyclopropane[c]chromene-4-carboxylic acid; (1aRS,7bSR)-5-{2[(Z)-3-((S)-3-hydroxypyrrolidone-1-yl)aminopropyl-1-enyl]-4-fluorobenzenesulfonyl-amino}-1,1a,2,7b-tetrahydrocyclopropane[c]chromene-4-carboxylic acid;

[0354] (1aRS,7bSR)-5-{2[(Z)-3-((R)-3-hydroxypyrrolidin-1-yl)aminopropyl-1-enyl]-4-fluorobenzene-sulfonylamino}-1,1a,2,7b-tetrahydro-cyclopropion[c]chromene-4-carboxylic acid;

[0355] (1aRS,7bSR)-5-[2((Z)-4-diethylaminobut-1-enyl)-4-fluorobenzenesulfonyl-amino]-1,1a,2,7b-tetrahydrocyclopropionyl[c]chromene-4-carboxylic acid; (1aR,7bS)-5-[2((Z)-4-diethylaminobut-1-enyl)-4-fluorobenzenesulfonyl-amino]-1,1a,2,7b-tetrahydrocyclopropionyl[c]chromene-4-carboxylic acid;

[0356] (1aS,7bR)-5-[2((Z)-4-diethylaminobut-1-enyl)-4-fluorobenzenesulfonyl-amino]-1,1a,2,7b-tetrahydro-cyclopropionyl[c]chromene-4-carboxylic acid; (1aRS,7bSR)-5-{2-[2-(4-ethylpiperazin-1-yl)-ethyl]-4-fluorobenzenesulfonyl-amino}-1,1a,2,7b-tetrahydrocyclopropionyl[c]chromene-4-carboxylic acid;

[0357] (1aRS,7bSR)-5-{2[(Z)-3-(azacyclobutane-1-yl)propyl-1-enyl]-4-fluorobenzene-sulfonylamino}-1,1a,2,7b-tetrahydro-cyclopropane[c]chromene-4-carboxylic acid; (1aRS,7bSR)-5-{2[(Z)-3-(3-hydroxy-azacyclobutane-1-yl)propyl-1-enyl]-4-fluorobenzene-sulfonylamino}-1,1a,2,7b-tetrahydrocyclopropane[c]chromene-4-carboxylic acid; (1aRS,7bSR)-5-{2[(Z)-3-(azacyclobutane-1-yl)propyl]-4-fluorobenzene-sulfonylamino}-1,1a,2,7b-tetrahydrocyclopropane[c]chromene-4-carboxylic acid;

[0358] (1aRS,7bSR)-5-[2((Z)-4-diethylaminobutyl)-4-fluorobenzenesulfonylamino]-1,1a,2,7b-tetrahydrocyclopropane[c]chromene-4-carboxylic acid; (1aRS,7bSR)-5-{2-[N-(4-dimethylaminobutyl)-N-methylamino]-benzenesulfonyl-amino}-1,1a,2,7b-tetrahydrocyclopropane[c]chromene-4-carboxylic acid; (1aRS,7bSR)-5-{2-[((S)-1-ethylpyrrolidine-3-ylcarbamoyl)-methyl]-4-fluoro-benzenesulfonyl-amino}-1,1a,2,7b-tetrahydrocyclopropane[c]chromene-4-carboxylic acid;

[0359] (1aRS,7bSR)-5-[2-(1-ethylazacyclobutane-3-yl)-4-fluorobenzenesulfonylamino]-1,1a,2,7b-tetrahydro-cyclopropane[c]chromene-4-carboxylic acid; (1aRS,7bSR)-5-{2-[((R)-1-ethylpyrrolidine-3-ylcarbamoyl)methyl]-4-fluorobenzenesulfonyl-amino}-1,1a,2,7b-tetrahydro-cyclopropane[c]chromene-4-carboxylic acid; (1aRS,7bSR)-5-{2-[2-(pyrrolidine-1-yl)-ethyl]-4-fluorobenzenesulfonylamino}-1,1a,2,7b-tetrahydrocyclopropane[c]chromene-4-carboxylic acid; (1aRS,7bSR)-5-[2-((R)-1-ethylpyrrolidine-3-ylmethyl)-4-fluoro [1aS,7bR]-5-[2-((R)-1-ethylpyrrolidone-3-ylmethyl)-4-fluorobenzenesulfonyl-amino]-1,1a,2,7b-tetrahydro-cyclopropane[c]chromene-4-carboxylic acid; (1aS,7bS)-5-[2-((R)-1-ethylpyrrolidone-3-ylmethyl)-4-fluorobenzenesulfonyl-amino]-1,1a,2,7b-tetrahydro-cyclopropane[c]chromene-4-carboxylic acid; (1aR,7bS)-5-[2-((R)-1-ethylpyrrolidone-3-ylmethyl)-4-fluorobenzenesulfonyl-amino]-1,1a,2,7b-tetrahydro-cyclopropane[c]chromene-4-carboxylic acid; [(1aRS,7bSR)-5-{2-[((S)-1-ethylpyrrolidone-2-yl)carbonyl-aminomethyl]-4-fluorobenzenesulfonylamino}-1,1a,2,7b-tetrahydrocyclopropionyl[c]chromene-4-carboxylic acid;

[0360] (1aRS,7bSR)-5-[2-(4-dimethylaminobutyrylamino)-4-fluorobenzenesulfonyl-amino]-1,1a,2,7b-tetrahydrocyclopropane[c]chromene-4-carboxylic acid; (1aRS,7bSR)-5-[2-((S)-1-ethylpyrrolidine-3-ylmethyl)-4-fluorobenzenesulfonyl-amino]-1,1a,2,7b-tetrahydrocyclopropane[c] Chromene-4-carboxylic acid; (1aRS,7bSR)-5-[2-(3-dimethylaminopropylcarbamoyl)benzene-sulfonylamino]-1,1a,2,7b-tetrahydrocyclopropane[c]chromene-4-carboxylic acid; (1aRS,7bSR)-5-(2-{[N-((S)-1-ethyl-pyrrolidine-3-yl)-N-methylcarbamoyl]methyl}-4-fluoro-benzene-sulfonylamino (1aRS,7bSR)-1,1a,2,7b-tetrahydrocyclopropane[c]chromene-4-carboxylic acid; (1aRS,7bSR)-5-(2-{[N-((R)-1-ethyl-pyrrolidine-3-yl)-N-methylcarbamoyl]methyl}-4-fluoro-benzenesulfonylamino)-1,1a,2,7b-tetrahydrocyclopropane[c]chromene-4-carboxylic acid; (1aRS,7bSR)-5-{2-[ 2-((S)-1-ethylpyrrolidine-2-yl)ethylamino]-benzenesulfonyl-amino}-1,1a,2,7b-tetrahydrocyclopropionyl[c]chromene-4-carboxylic acid; (1aRS,7bSR)-5-{2-[2-((R)-1-ethylpyrrolidine-2-yl)ethylamino]-benzenesulfonyl-amino}-1,1a,2,7b-tetrahydrocyclopropionyl[c]chromene-4-carboxylic acid;

[0361] (1aRS,7bSR)-5-[2-(3-N,N,-diethylaminopropylamino)benzene-sulfonylamino]-1,1a,2,7b-tetrahydrocyclopropane[c]chromene-4-carboxylic acid; (1aRS,7bSR)-5-(2-{[((R)-1-ethylpyrrolidine-2-yl)carbonyl-amino]methyl}-4-fluorobenzenesulfonylamino)-1,1a,2,7b-tetrahydrocyclopropane[c]chromene-4-carboxylic acid; (1aRS,7bSR)-5-{2-[(1-ethylazacyclobutane-3-ylmethyl)amino]benzene-sulfonylamino}-1,1a,2,7b-tetrahydrocyclopropane[c]chromene-4-carboxylic acid;

[0362] (1aS,7bR)-5-[2-((Z)-3-diethylaminopropyl-1-enyl)benzenesulfonylamino]-1,1a,2,7b-tetrahydrocyclopropane[c]chromene-4-carboxylic acid; (1aR,7bS)-5-[2-((Z)-3-diethylaminopropyl-1-enyl)benzenesulfonylamino]-1,1a,2,7b-tetrahydrocyclopropane[c]chromene-4-carboxylic acid;

[0363] (1aRS,7bSR)-5-(2-{N-[((R)-1-ethylpyrrolidone-2-yl)carbonyl]-N-methyl-aminomethyl}-4-fluorobenzenesulfonylamino)-1,1a,2,7b-tetrahydrocyclopropionen-4-carboxylic acid;

[0364] (1aRS,7bSR)-5-(2-{N-[((S)-1-ethylpyrrolidin-2-yl)carbonyl]-N-methylamino-methyl}-4-fluorobenzenesulfonylamino)-1,1a,2,7b-tetrahydrocyclopropionen-4-carboxylic acid;

[0365] (1aRS,7bSR)-5-[2-(4-dimethylaminobutylamino)-4-fluorobenzenesulfonyl-amino]-1,1a,2,7b-tetrahydrocyclopropenyl[c]chromene-4-carboxylic acid; (1aRS,7bSR)-5-{2-[((R)-1-ethylpyrrolidine-3-ylmethyl)amino]-benzenesulfonylamino}-1,1a,2,7b-tetrahydrocyclopropenyl[c]chromene-4-carboxylic acid; (1aRS,7bSR)-5-{2-[((S)-1-ethylpyrrolidine-3-ylmethyl)amino]-benzenesulfonylamino}-1,1a,2,7b-tetrahydrocyclopropenyl[c]chromene-4-carboxylic acid; (1aRS,7bSR)-5-[2-(4-ethyl-2-oxopirazin-1-ylmethyl)-4-fluorobenzenesulfonylamino] ...]-1,1a,2,7b-tetrahydrocyclopropenyl[c]chromene-4-carboxylic acid]-1,1a,2,7b-tetrahydrocyclopropenyl[c]chromene-4-carboxylic acid]-5-[2-(4-ethyl-2-oxopirazin-1-ylmethyl)-4-fluorobenzenesulfonylamino]-1,1a,2,7b-tetrahydrocyclopropenyl[c]chromene-4-carboxylic acid]-1 [-sulfonylamino]-1,1a,2,7b-tetrahydrocyclopropane[c]chromene-4-carboxylic acid; (1aRS,7bSR)-5-[2-(1-ethylpiperidin-4-ylmethyl)-4-fluoro-benzenesulfonylamino]-1,1a,2,7b-tetrahydrocyclopropane[c]chromene-4-carboxylic acid; (1aRS,7bSR)-5-{2-[2-(1-ethylazacyclobutane-3-yl)ethyl]-4-fluoro-benzenesulfonyl-amino}-1,1a,2,7b-tetrahydrocyclopropane[c]chromene-4-carboxylic acid; (1aRS,7bSR)-5-{2-[((S)-1-azabicyclo[2.2.2]oct-3-yl)amino]benzenesulfonyl-amino}-1,1a,2,7b-tetrahydrocyclopropane[c]chromene-4-carboxylic acid;

[0366] (1aRS,7bSR)-5-{2-[((R)-1-azabicyclo-[2.2.2]oct-3-yl)amino]benzenesulfonyl-amino}-1,1a,2,7b-tetrahydrocyclopropane[c]chromene-4-carboxylic acid; (1aRS,7bSR)-5-(2-{[((S)-1-ethylpyrrolidine-3-carbonyl)amino]methyl}-4-fluoro-benzenesulfonylamino)-1,1a,2,7b-tetrahydrocyclopropane[c]chromene-4-carboxylic acid; (1aRS,7bSR)-5-{2-[2-((R)-1-ethylpyrrolidine-3-ylamino)ethyl]-4-fluoro-benzenesulfonylamino}-1,1a,2,7b-tetrahydrocyclopropane[c]chromene-4-carboxylic acid;

[0367] (1aRS,7bSR)-5-{2-[((R)-1-ethylpyrrolidine-3-yl)amino]-benzenesulfonylamino}-1,1a,2,7b-tetrahydrocyclopropane[c]chromene-4-carboxylic acid; (1aRS,7bSR)-5-{2-[((S)-1-ethylpyrrolidine-3-yl)amino]-benzenesulfonylamino}-1,1a,2,7b-tetrahydrocyclopropane[c]chromene-4-carboxylic acid; (1aRS,7bSR)-5-(2-{[((R)-1-ethylpyrrolidine-3-carbonyl)amino]-methyl)}-4-fluoro-benzenesulfonylamino)-1,1a,2,7b-tetrahydro-cyclopropane[c]chromene-4-carboxylic acid;

[0368] (1aRS,7bSR)-5-[2-((Z)-3-diethylamino-2-methylprop-1-enyl)-4-fluorobenzene-sulfonylamino]-1,1a,2,7b-tetrahydrocyclopropane[c]chromene-4-carboxylic acid; (1aRS,7bSR)-5-{2-[2-((R)-1-ethylpyrrolidine-3-yl)ethylamino]-benzenesulfonylamino}-1,1a,2,7b-tetrahydrocyclopropane[c]chromene-4-carboxylic acid; (1aRS,7bSR)-5-{2-[2-((S)-1-ethylpyrrolidine-3-yl)ethylamino]-benzenesulfonylamino}-1,1a,2,7b-tetrahydrocyclopropane[c]chromene-4-carboxylic acid;

[0369] (1aR,7bS)-5-[2-((S)-1-ethylpyrrolidine-3-yloxymethyl)-4-fluoro-benzenesulfonylamino]-1,1a,2,7b-tetrahydrocyclopropionyl[c]chromene-4-carboxylic acid; (1aR,7bS)-5-[2-((R)-1-ethylpyrrolidine-3-yloxymethyl)-4-fluoro-benzenesulfonylamino]-1,1a,2,7b-tetrahydrocyclopropionyl[c]chromene-4-carboxylic acid; (1aR,7bS) )-5-[2-(1-ethylpiperidin-3-ylmethyl)-4-fluorobenzene-sulfonylamino]-1,1a,2,7b-tetrahydrocyclopropion[c]chromene-4-carboxylic acid; (1aR,7bS)-5-{2-[2-((R)-1-ethylpyrrolidine-2-yl)ethyl]-4-fluorobenzene-sulfonylamino}-1,1a,2,7b-tetrahydrocyclopropion[c]chromene-4-carboxylic acid; and pharmaceutically acceptable salts, stereoisomers, esters and prodrugs thereof.

[0370] In some respects, the MetAP2 inhibitor may be selected from:

[0371]

[0372]

[0373] Or a pharmaceutically acceptable salt, analogue, derivative, salt or ester thereof.

[0374] For the purposes of this disclosure, the information is based on the Periodic Table of the Elements, CAS edition, Handbook of Chemistry and Physics, 67th edition.

[0375] 1986-87 (inner cover) Identification of chemical elements.

[0376] The term "alkyl" refers to a fully saturated branched or unbranched carbon chain group having a specified number of carbon atoms, or at most 30 carbon atoms if not specified. For example, "lower alkyl" refers to alkyl groups having 1 to 10 carbon atoms, such as methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, and octyl, as well as those that are positional isomers of these alkyl groups. Alkyl groups with 10 to 30 carbon atoms include decyl, undecyl, dodecyl, tridecyl, tetradecyl, pentadecyl, hexadecyl, heptadecanyl, octadecyl, nonadecanyl, eicosyl, dodecyl, tridecyl, and tetradecyl. In some respects, straight-chain or branched alkyl groups have 30 or fewer carbon atoms in their main chain (e.g., C1-C for straight chains). 30 For sidechains, C3-C 30( ), and more preferably 20 or fewer. Similarly, some cycloalkyl groups have 3-10 carbon atoms in their ring structure, and may have 5, 6 or 7 carbon atoms in the ring structure.

[0377] Unless otherwise specified, as used herein, "lower alkyl" means an alkyl group as defined above but having one to ten carbon atoms or one to six carbon atoms in its main chain structure, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, and tert-butyl. Similarly, "lower alkenyl" and "lower alkynyl" have similar chain lengths. Throughout this application, certain alkyl groups are lower alkyl. In some respects, substituents designated herein as alkyl are lower alkyl.

[0378] As used herein, the term "carbon ring" refers to an aromatic or non-aromatic ring in which each atom of the ring is carbon.

[0379] As used herein, the term "aryl" includes 5-, 6-, and 7-membered monocyclic aromatic groups that may contain zero to four heteroatoms, such as benzene, pyrrole, furan, thiophene, imidazole, oxazole, thiazole, triazole, pyrazole, pyridine, pyrazine, pyridazine, and pyrimidine. Those aryl groups having heteroatoms in their ring structure may also be referred to as "aryl heterocycles" or "heteroaromatic compounds." The aromatic ring may be substituted at one or more ring positions with substituents such as those described above, including halogens, azides, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, alkoxy, amino, nitro, mercapto, imino, amide, phosphonate, hypophosphonate, carbonyl, carboxyl, silyl, ether, alkylthio, sulfonyl, sulfonamide, ketone, aldehyde, ester, heterocyclic group, aromatic or heteroaromatic moiety, -CF3, -CN, etc. The term "aryl" also includes polycyclic cyclic systems having two or more rings, wherein two or more carbons are common to two linked rings (these rings are "fused rings"), wherein at least one ring is aromatic, and for example, the other ring may be cycloalkyl, cycloalkenyl, cycloalkynyl, aryl and / or heterocyclic.

[0380] "Alkenyl" means any branched or unbranched unsaturated carbon chain group having a specified number of carbon atoms, or at most 26 carbon atoms if no limit is specified; and having one or more double bonds in the group. Examples of alkenyl groups with 6 to 26 carbon atoms are hexenyl, heptenyl, octenyl, nonenyl, decenyl, undecenyl, dodecenyl, tridecenyl, tetradecenyl, pentadecenyl, hexadecenyl, heptadecenyl, octadecenyl, nonadecenyl, eicosene, dodecenyl, dodecenyl, tridecenyl, tetradecenyl, octadecenyl, nonadecenyl, eicosene, dodecenyl, tridecenyl, and dodecenyl, in their various isomers, wherein one or more unsaturated bonds may be located at any position in the group and may have (Z) or (E) configurations with respect to one or more double bonds.

[0381] The term "alkynyl" refers to a hydrocarbon group within the alkenyl range, but with one or more triple bonds.

[0382] As used herein, the term "alkoxyl" or "alkoxy" refers to an alkyl group as defined below, having an oxygen radical attached to it. Representative alkoxy groups include methoxy, ethoxy, propoxy, tert-butoxy, etc. An "ether" is two hydrocarbons covalently linked by oxygen. Therefore, the substituent of the alkyl group that makes it an ether is or similar to an alkoxy group, such as -O-alkyl, -O-alkenyl, -O-ynyl, -O-(CH2) m -R1 is a representation where m and R1 are as follows.

[0383] The term "heterocyclic group" or "heterocyclic group" refers to a 3- to 10-membered ring structure, more preferably a 3- to 7-membered ring, whose ring structure includes 1 to 4 heteroatoms. Heterocyclic rings can also be polycyclic. Heterocyclic groups include, for example, thiophene, thiathrone, furan, pyran, isobenzofuran, chromene, xanthan, phenoxazine, pyrrole, imidazole, pyrazole, isothiazine, isoxazine, pyridine, pyrazine, pyrimidine, pyridazine, indazine, isoindole, indole, indazole, purine, quinazine, isoquinoline, quinoline, phthalazine, naphthidine, quinoxaline, quinazolin, cinnamic acid, pteridine, carbazole, caroline, phenanthridine, acridine, pyrimidine, phenanthroxaline, phenazine, phenpyrazine, phenthiazine, furazine, phenoxazine, pyrrolidine, oxacyclopentane, thiocyclopentane, oxazole, piperidine, piperazine, morpholine, lactone, lactams such as azacyclobutanone and pyrrolidone, sulfonamide, sulfonyl lactone, etc. The heterocycle may be substituted at one or more positions with substituents such as those described above, which are, for example, halogens, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, amino, nitro, mercapto, imino, amide, phosphate, phosphonate, hypophosphonate, carbonyl, carboxyl, silyl, aminosulfonyl, sulfinyl, ether, alkylthio, sulfonyl, ketone, aldehyde, ester, heterocyclic, aromatic or heteroaromatic moiety, -CF3, -CN, or the like.

[0384] The term "alkathioyl" refers to an alkyl group as defined above, having a sulfur group attached to it. In some aspects, the "alkathioyl" moiety is composed of -(S)-alkyl, -(S)-alkenyl, -(S)-ynyl, and -(S)-(CH2). m -R1 is one of the following, where m and R1 are defined as follows. Representative alkylthio groups include methylthio, ethylthio, etc.

[0385] As used herein, the term “nitro” means -NO2; the term “halogen” indicates F, Cl, Br or I; the term “thiol” means -SH; the term “hydroxyl” means -OH; and the term “sulfonyl” means -SO2-.

[0386] The terms "amine" and "amino" are generally accepted in the art and refer to both unsubstituted and substituted amines, for example, portions that can be represented by the following general formula:

[0387]

[0388] R3, R5, and R6 each independently represent hydrogen, alkyl, alkenyl, and -(CH2). m -R1, or R3 and R5 together with the N atom to which they are attached, complete a heterocycle having 4 to 8 atoms in the ring structure; R1 represents an alkenyl, aryl, cycloalkyl, cycloalkenyl, heterocyclic, or polycyclic group; m is 0 or an integer in the range of 1-8. In some respects, only one of R3 or R5 can be a carbonyl group, for example, R3, R5, and nitrogen together do not form an imide. In some respects, R3 and R5 (and optionally R6) each independently represent hydrogen, alkyl, alkenyl, or -(CH2). m -R1. Therefore, as used herein, the term "alkylamine" means an amino group as defined above, having a substituted or unsubstituted alkyl group attached thereto, i.e., at least one of R3 and R5 is an alkyl group. In some respects, the amino group or alkylamine is basic, meaning that it has > 7.00 PK a The protonated forms of these functional groups have a pK ratio higher than 7.00 relative to water. a .

[0389] The term "carbonyl" (C(O)) is recognized in the art and includes parts such as those that can be represented by the following general formula:

[0390]

[0391] Where X is a bond or represents oxygen or sulfur, and R7 represents hydrogen, alkyl, alkenyl, or -(CH2). m -R1 represents a pharmaceutically acceptable salt, and R8 represents hydrogen, alkyl, alkenyl, or -(CH2). m-R1, where m and R1 are as defined above. When X is oxygen and R7 or R8 is not hydrogen, the formula represents an "ester group". When X is oxygen and R7 is as defined above, the portion is referred to herein as a carboxyl group, and particularly when R7 is hydrogen, the formula represents a "carboxylic acid". When X is oxygen and R8 is hydrogen, the formula represents a "formate". Generally, when the oxygen atom in the above formula is replaced by sulfur, the formula represents a "thiocarbonyl" group. When X is sulfur and R7 or R8 is not hydrogen, the formula represents a "thioester" group. When X is sulfur and R7 is hydrogen, the formula represents a "thiocarboxylic acid" group. When X is sulfur and R8 is hydrogen, the formula represents a "thioformate" group. On the other hand, when X is a bond and R7 is not hydrogen, the above formula represents a "ketone" group. When X is a bond and R7 is hydrogen, the above formula represents an "aldehyde" group.

[0392] As used herein, the term “substitution” is considered to include all permissible substituents of an organic compound. In a broad sense, permissible substituents include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, aromatic and non-aromatic substituents of an organic compound. Exemplary substituents include, for example, those described above. Permissible substituents can be one or more, and the same or different, for a suitable organic compound. For the purposes of this disclosure, heteroatoms such as nitrogen may have hydrogen substituents and / or any permissible substituents of the organic compounds described herein, said substituents satisfying the valence of the heteroatom. This disclosure is not intended to be limited in any way to permissible substituents of an organic compound. It will be understood that “substitution” or “replaced with…” includes the implicit condition that such substitution is based on the permissible valence of the substituted atom and the substituent, and that said substitution produces a stable compound, for example, which does not spontaneously transform by, for example, rearrangement, cyclization, elimination, etc.

[0393] The term "aminosulfonyl" is recognized in the art and includes a portion that can be represented by the following general formula:

[0394]

[0395] R3 and R5 are defined as above.

[0396] The term "sulfate" is recognized in the art and includes portions that can be represented by the following general formula:

[0397]

[0398] R7 is defined as above.

[0399] The term "sulfonamide" is recognized in the art and includes portions that can be represented by the following general formula:

[0400]

[0401] R2 and R4 are defined as above.

[0402] The term "sulfonate" is recognized in the art and includes portions that can be represented by the following general formula:

[0403]

[0404] R7 can be an electron pair, hydrogen, alkyl, cycloalkyl, or aryl.

[0405] As used herein, the terms "sulfonyl" or "sulfinyl" denote a portion that can be represented by the following general formula:

[0406]

[0407] Where R 12 It is selected from hydrogen, alkyl, alkenyl, ynyl, cycloalkyl, heterocyclic, aralkyl, or aryl.

[0408] Similar substitutions can be made to the alkenyl and alkynyl groups to produce, for example, aminoalkenyl, aminoalkynyl, amide alkenyl, amide alkynyl, iminoalkenyl, iminoalkynyl, thioalkenyl, thioalkynyl, carbonyl-substituted alkenyl or alkynyl groups.

[0409] As used herein, when a term (such as alkyl, m, n, etc.) appears more than once in any structure, its definition is expected to be independent of its definition at other positions in the same structure.

[0410] The term "amino acid" is intended to encompass all compounds, whether natural or synthetic, including amino acid analogs and derivatives, that include both amino and acid functional groups. In some respects, the amino acids considered in this disclosure are those naturally occurring amino acids found in proteins, or naturally occurring synthetic or catabolitic products of such amino acids containing both amino and carboxyl groups. Naturally occurring amino acids are identified throughout the text using conventional three-letter and / or single-letter abbreviations corresponding to their common names, according to the list below. These abbreviations are accepted in the peptide field and recommended by the IUPAC-IUB committee in its biochemical nomenclature.

[0411] The term "amino acid residue" refers to an amino acid. Generally, the abbreviations used herein to indicate naturally occurring amino acids are based on the IUPAC-IUB committee recommendations on biochemical nomenclature (see Biochemistry (1972) 11:1726-1732). For example, Met, Ile, Leu, Ala, and Gly represent "residues" of methionine, isoleucine, leucine, alanine, and glycine, respectively. A residue signifies a group derived from the corresponding α-amino acid by removing the OH portion of the carboxyl group and the H portion of the α-amino group.

[0412] The term "amino acid side chain" refers to the portion of the amino acid residue that does not include the main chain, as defined by KDKopple, "Peptides and Amino Acids," WABenjamin Inc., New York and Amsterdam, 1966, pp. 2 and 33. Examples of such side chains for common amino acids are -CH2CH2SCH3 (methionine side chain), -CH2(CH3)-CH2CH3 (isoleucine side chain), -CH2CH(CH3)2 (leucine side chain), or H- (glycine side chain). These side chains are dangling over the Cα carbon of the main chain.

[0413] As used herein, the term "peptide" refers to a sequence of amino acid residues linked together by peptide bonds or modified peptide bonds. The term "peptide" is intended to encompass peptide analogs, peptide derivatives, peptide mimics, and peptide variants. The term "peptide" is understood to include peptides of any length. The peptide sequences listed herein are written according to generally accepted convention, with the N-terminal amino acid on the left and the C-terminal amino acid on the right (e.g., H2N-AA1-AA2-AA3-AA4-AA5-AA6-CO2H).

[0414] Certain compounds disclosed herein may exist in specific geometric or stereoisomeric forms. This disclosure contemplates all such compounds, including cis- and trans-isomers, R- and S-enantiomers, diastereomers, (D)-isomers, (L)-isomers, racemic mixtures thereof, and other mixtures thereof, which fall within the scope of this disclosure. Additional asymmetric carbon atoms may be present in substituents such as alkyl groups. All such isomers and mixtures thereof are intended to be included in this disclosure. Any representation of a particular isomer is merely exemplary (e.g., examples of trans isomers also cover cis isomers).

[0415] For example, if a particular enantiomer of the compound of this disclosure is desired, it can be prepared by asymmetric synthesis or by derivatization with a chiral auxiliary, wherein the resulting mixture of diastereomers is separated and auxiliary groups are cleaved to provide the pure desired enantiomer. Alternatively, in the case where the molecule contains a basic functional group such as an amino group or an acidic functional group such as a carboxyl group, a salt of the diastereomer is formed with a suitable optically active acid or base, and the resulting diastereomer is then resolved by stepwise crystallization or chromatography, as well as methods well known in the art, and the pure enantiomer is subsequently recovered.

[0416] As used herein, the term "substituted" means that any one or more hydrogen atoms on a specified atom are replaced by an option of a specified group, provided that the substitution does not exceed the normal valence of the specified atom and that the substitution produces a stable compound. When the substituent is a ketone group (i.e., =O), then two hydrogen atoms on the atom are replaced. Ketone substituents are not present on aromatic moieties. As used herein, a cyclic double bond is a double bond formed between two adjacent ring atoms (e.g., C=C, C=N, or N=N). "Stable compound" and "stable structure" mean a compound that is robust enough to withstand separation from the reaction mixture to a useful purity and formulation into an effective therapeutic agent.

[0417] When the bond with a substituent is shown to be an intersecting bond with two atoms in the linking ring, then such a substituent may be bonded to any atom in the ring. When a substituent is listed without specifying the atoms through which such a substituent is bonded to the remainder of the compound in the given formula, then such a substituent may be bonded to any atom in such a formula. Combinations of substituents and / or variables are permitted, but only if such combinations produce a stable compound.

[0418] When any variable (e.g., R1) appears more than once in any composition or formula of a compound, its definition for each occurrence is independent of its definition for every other occurrence. Therefore, for example, if a group is shown to be substituted by 0-2 R1 moieties, then that group may optionally be substituted by at most two R1 moieties, and R1 is independently selected from its definition each time it appears. Furthermore, combinations of substituents and / or variables are permitted, but only if such combinations produce a stable compound.

[0419] In this specification, in some cases for convenience, the structural formula of a compound represents a certain isomer, but this disclosure includes all isomers, such as geometric isomers, optical isomers based on asymmetric carbon, stereoisomers, tautomers, etc. Furthermore, polymorphic forms may exist for compounds represented by the formula. It should be noted that any crystalline form, mixture of crystalline forms, or its anhydrides or hydrates are included within the scope of this disclosure. Additionally, so-called metabolites generated by the degradation of the compounds of the present invention in vivo are included within the scope of this disclosure.

[0420] Isomerism refers to compounds with the same molecular formula but different atomic bonding sequences or spatial arrangements. Isomers with different spatial arrangements of atoms are called "stereoisomers." Stereoisomers that are not mirror images of each other are called "diastereomers," and stereoisomers that are non-overlapping mirror images of each other are called "enantiomers" or sometimes optical isomers. A mixture containing equal amounts of single enantiomers with opposite chirality is called a "racemic mixture."

[0421] A carbon atom bonded to four different substituents is called a "chiral center".

[0422] "Chiral isomer" refers to a compound having at least one chiral center. Compounds having more than one chiral center can exist as a single diastereomer or as a mixture of diastereomers (referred to as a "diastereomer mixture"). When a chiral center is present, the stereoisomer can be characterized by the absolute configuration (R or S) of that chiral center. The absolute configuration refers to the spatial arrangement of the substituents connected to the chiral center. The substituents connected to the chiral center under consideration are ordered according to the Cahn, Ingold, and Prelog sequence rule. (Cahn et al., Angew. Chem. Inter. Edit. 1966, 5, 385; Errata 511; Cahn et al., Angew. Chem. 1966, 78, 413; Cahn and Ingold, J. Chem. Soc. 1951 (London), 612; Cahn et al., Experientia 1956, 12, 81; Cahn, J. Chem. Educ. 1964, 41, 116).

[0423] "Geometric isomers" refers to diastereomers whose existence is attributable to hindered rotation around the double bond. According to the Cahn-Ingold-Prelog rule, these configurations are distinguished in their names by the prefixes cis and trans or Z and E, which indicate that the groups are located on the same or opposite sides of the double bond in the molecule.

[0424] Furthermore, the structures and other compounds discussed in this disclosure include all their transisomers. A “transisomer” is a type of stereoisomer in which the atoms of the two isomers are arranged differently in space. The existence of transisomers is attributed to restricted rotation resulting from the impeded rotation of the large group around the central bond. Such transisomers are usually present as mixtures, but as a result of recent advances in chromatographic techniques, mixtures of two transisomers can now be separated under certain conditions.

[0425] A tautomer is one of two or more structural isomers that exist in equilibrium and readily transform from one isomer to another. This transformation results in the migration of hydrogen atoms, accompanied by the conversion of adjacent conjugated double bonds. Tautomers exist in solution as a mixture of tautomer combinations. In solid form, one tautomer is usually dominant. In solutions in which tautomerization is possible, a chemical equilibrium of tautomers will be reached. The exact ratio of tautomers depends on several factors, including temperature, solvent, and pH. The concept of tautomers that can interconvert through tautomerization is called tautomerism.

[0426] Of the various possible types of tautomerism, two are commonly observed. In keto-enol tautomerism, simultaneous shifts of electrons and hydrogen atoms occur. Ring-chain tautomerism results from the reaction of an aldehyde group (-CHO) in a sugar molecule with one of the hydroxyl groups (-OH) in the same molecule, causing it to form a ring (cyclic) structure, as exhibited by glucose.

[0427] Common tautomer pairs include: keto-enol, amide-nitrile, lactam-lactamimide, amide-imine tautomerism in heterocycles (e.g., in nucleobases such as guanine, thymine, and cytosine), amine-enamine, and enamine-enamine.

[0428] It will be understood that the compounds of this disclosure may be described as different tautomers. It should also be understood that when a compound has tautomers, all tautomers are intended to be included within the scope of this disclosure, and the naming of the compound does not exclude any tautomer form.

[0429] The terms "crystalline polymorph," "polymorph," or "crystalline form" refer to crystalline structures in which a compound (or its salts or solvates) can crystallize in different crystalline arrangements, all having the same elemental composition. Different crystalline forms typically exhibit different X-ray diffraction patterns, infrared spectra, melting points, densities, hardness, crystal shapes, optical and electrical properties, stability, and solubility. Recrystallization solvents, crystallization rates, storage temperatures, and other factors can cause one crystalline form to dominate. Crystalline polymorphs of compounds can be prepared by crystallizing under different conditions.

[0430] Furthermore, the compounds disclosed herein, such as salts of the compounds, may exist in hydrated or non-hydrated (anhydrous) forms or as solvates with other solvent molecules. Non-limiting examples of hydrates include monohydrates, dihydrates, etc. Non-limiting examples of solvates include ethanol solvates, acetone solvates, etc.

[0431] "Solvate" refers to a solvation form containing stoichiometric or non-stoichiometric amounts of solvent. Some compounds have a tendency to trap a fixed molar ratio of solvent molecules in their crystalline solid state to form solvates. If the solvent is water, the formed solvate is a hydrate; and if the solvent is an alcohol, the formed solvate is an alcohol. Hydrates are formed by the combination of one or more water molecules with a substance molecule, where the water retains its molecular state as H₂O.

[0432] As used herein, the term "analogue" refers to a chemical compound that is structurally similar to another but has a slightly different composition (e.g., the substitution of an atom with an atom of a different element or the presence of a specific functional group, or the substitution of one functional group by another). Thus, an analogue is a compound that is similar or equivalent to a reference compound in function and appearance (but not in structure or origin).

[0433] As defined herein, the term “derivative” refers to a compound having a common core structure and being substituted by various groups as described herein.

[0434] The term "bioisostere" refers to a compound resulting from the exchange of one atom or group of atoms with another substantially similar atom or group of atoms. The aim of bioisostere substitution is to create new compounds with biological properties similar to those of the parent compound. Bioisostere substitution can be based on physicochemical or topological principles. Examples of carboxylic acid bioisosteres include, but are not limited to, acylsulfonamides, tetrazolium, sulfonates, and phosphonates. See, for example, Patani and LaVoie, Chem. Rev. 96, 3147-3176, 1996.

[0435] In some cases, MetAP2 inhibitors can be administered via subcutaneous injection (SC).

[0436] In some cases, MetAP2 inhibitors can be administered approximately every 4 days (Q4D).

[0437] In some cases, MetAP2 inhibitors can be administered approximately once daily (QD), approximately every 2 days (Q2D), approximately every 3 days (Q3D), approximately every 4 days (Q4D), approximately every 5 days (Q5D), approximately every 6 days (Q6D), approximately every 7 days (Q7D), approximately every 8 days (Q8D), approximately every 9 days (Q9D), approximately every 10 days (Q10D), approximately every 11 days (Q11D), approximately every 12 days (Q12D), approximately every 13 days (Q13D), approximately every 14 days (Q14D), or approximately every 15 days (Q15D). In some cases, MetAP2 inhibitors can be administered approximately every 7 days (Q7D). In some cases, MetAP2 inhibitors can be administered approximately every 14 days (Q14D).

[0438] In some aspects, it can be at approximately 1 mg / m 2 or about 2mg / m 2 or about 3mg / m 2 or about 4mg / m 2 or about 5mg / m 2 or about 6mg / m 2 or about 7mg / m 2 or about 8mg / m 2 or about 9mg / m 2 or about 10mg / m 2 or about 11 mg / m 2 or about 12mg / m 2 or approximately 13 mg / m² 2 or approximately 14 mg / m 2 or about 15mg / m 2 or approximately 16 mg / m³ 2 or approximately 17 mg / m³ 2 or approximately 18 mg / m 2 or approximately 19 mg / m³ 2 or about 20mg / m 2 or approximately 21 mg / m 2 or approximately 22 mg / m 2 or approximately 23 mg / m 2 or approximately 24 mg / m 2 or about 25mg / m 2 or approximately 26 mg / m 2 or approximately 27 mg / m 2 or approximately 28 mg / m 2 or approximately 29 mg / m 2 or about 30mg / m 2 or approximately 31 mg / m 2 or approximately 32 mg / m 2or approximately 33 mg / m 2 or approximately 34 mg / m 2 or about 35mg / m 2 or approximately 36 mg / m 2 or approximately 37 mg / m 2 or approximately 38 mg / m 2 or approximately 39 mg / m³ 2 or about 40mg / m 2 or approximately 41 mg / m 2 or approximately 42 mg / m 2 or approximately 43 mg / m 2 or approximately 44 mg / m 2 or about 45mg / m 2 or approximately 46 mg / m 2 or approximately 47 mg / m 2 or approximately 48 mg / m 2 or approximately 49 mg / m 2 or about 50mg / m 2 or approximately 51 mg / m 2 or approximately 52 mg / m 2 or approximately 53 mg / m 2 or approximately 54 mg / m 2 or about 55mg / m 2 or approximately 56 mg / m 2 or approximately 57 mg / m 2 or approximately 58 mg / m 2 or approximately 59 mg / m 2 or about 60mg / m 2 or approximately mg / m 2 or approximately 61 mg / m³ 2 or approximately 62 mg / m 2 or approximately 63 mg / m 2 or approximately 64 mg / m 2 or approximately 65 mg / m 2 or approximately 66 mg / m³ 2 or approximately 67 mg / m³ 2 or approximately 68 mg / m³ 2 or approximately 69 mg / m³ 2 or about 70mg / m 2 or approximately 81 mg / m³ 2 or approximately 82 mg / m³ 2 or approximately 83 mg / m³ 2 or approximately 84 mg / m 2 or approximately 85 mg / m 2 or approximately 86 mg / m³ 2 or approximately 87 mg / m³2 or approximately 88 mg / m³ 2 or approximately 89 mg / m³ 2 or approximately 90 mg / m 2 or approximately 91 mg / m³ 2 or approximately 92 mg / m 2 or approximately 93 mg / m³ 2 or approximately 94 mg / m 2 or approximately 95 mg / m 2 or approximately 96 mg / m³ 2 or approximately 97 mg / m³ 2 or approximately 98 mg / m³ 2 or approximately 99 mg / m³ 2 or approximately 100 mg / m 2 The dosage of MetAP2 inhibitor was administered.

[0439] In some aspects, it can be at approximately 49 mg / m 2 MetAP2 inhibitors are administered at doses of approximately 39 mg / m². In some cases, this can be achieved with a dose of approximately 39 mg / m². 2 Approximately 59 mg / m 2 MetAP2 inhibitors are administered at doses of approximately 44 mg / m². In some cases, this can be achieved with a dose of approximately 44 mg / m². 2 Approximately 54 mg / m 2 The dosage of MetAP2 inhibitor was administered.

[0440] In some aspects, it can be at approximately 36 mg / m 2 MetAP2 inhibitors can be administered at doses of approximately 26 mg / m². 2 Approximately 49 mg / m 2 MetAP2 inhibitors are administered at doses of approximately 31 mg / m². 2 Approximately 65 mg / m 2 The dosage of MetAP2 inhibitor was administered.

[0441] In some aspects, it can be at approximately 65 mg / m 2 MetAP2 inhibitors are administered at doses of approximately 55 mg / m². 2 Approximately 75 mg / m 2 MetAP2 inhibitors are administered at doses of approximately 60 mg / m². In some cases, this can be achieved with a dose of approximately 60 mg / m². 2 Approximately 70 mg / m 2 The dosage of MetAP2 inhibitor was administered.

[0442] In some respects, the effective therapeutic dose of MetAP2 inhibitors can be approximately 1 mg / m². 2 or about 2mg / m 2 or about 3mg / m2 or about 4mg / m 2 or about 5mg / m 2 or about 6mg / m 2 or about 7mg / m 2 or about 8mg / m 2 or about 9mg / m 2 or about 10mg / m 2 or about 11 mg / m 2 or about 12mg / m 2 or approximately 13 mg / m² 2 or approximately 14 mg / m 2 or about 15mg / m 2 or approximately 16 mg / m³ 2 or approximately 17 mg / m³ 2 or approximately 18 mg / m 2 or approximately 19 mg / m³ 2 or about 20mg / m 2 or approximately 21 mg / m 2 or approximately 22 mg / m 2 or approximately 23 mg / m 2 or approximately 24 mg / m 2 or about 25mg / m 2 or approximately 26 mg / m 2 or approximately 27 mg / m 2 or approximately 28 mg / m 2 or approximately 29 mg / m 2 or about 30mg / m 2 or approximately 31 mg / m 2 or approximately 32 mg / m 2 or approximately 33 mg / m 2 or approximately 34 mg / m 2 or about 35mg / m 2 or approximately 36 mg / m 2 or approximately 37 mg / m 2 or approximately 38 mg / m 2 or approximately 39 mg / m³ 2 or about 40mg / m 2 or approximately 41 mg / m 2 or approximately 42 mg / m 2 or approximately 43 mg / m 2 or approximately 44 mg / m 2 or about 45mg / m 2 or approximately 46 mg / m 2 or approximately 47 mg / m 2 or approximately 48 mg / m 2or approximately 49 mg / m 2 or about 50mg / m 2 or approximately 51 mg / m 2 or approximately 52 mg / m 2 or approximately 53 mg / m 2 or approximately 54 mg / m 2 or about 55mg / m 2 or approximately 56 mg / m 2 or approximately 57 mg / m 2 or approximately 58 mg / m 2 or approximately 59 mg / m 2 or about 60mg / m 2 or approximately mg / m 2 or approximately 61 mg / m³ 2 or approximately 62 mg / m 2 or approximately 63 mg / m 2 or approximately 64 mg / m 2 or approximately 65 mg / m 2 or approximately 66 mg / m³ 2 or approximately 67 mg / m³ 2 or approximately 68 mg / m³ 2 or approximately 69 mg / m³ 2 or about 70mg / m 2 or approximately 81 mg / m³ 2 or approximately 82 mg / m³ 2 or approximately 83 mg / m³ 2 or approximately 84 mg / m 2 or approximately 85 mg / m 2 or approximately 86 mg / m³ 2 or approximately 87 mg / m³ 2 or approximately 88 mg / m³ 2 or approximately 89 mg / m³ 2 or approximately 90 mg / m 2 or approximately 91 mg / m³ 2 or approximately 92 mg / m 2 or approximately 93 mg / m³ 2 or approximately 94 mg / m 2 or approximately 95 mg / m 2 or approximately 96 mg / m³ 2 or approximately 97 mg / m³ 2 or approximately 98 mg / m³ 2 or approximately 99 mg / m³ 2 or approximately 100 mg / m 2 .

[0443] In some respects, the effective therapeutic dose of MetAP2 inhibitors can be approximately 49 mg / m². 2 In some respects, the effective therapeutic dose of MetAP2 inhibitors can be approximately 39 mg / m². 2 Approximately 59 mg / m 2 In some respects, the effective therapeutic dose of MetAP2 inhibitors can be approximately 44 mg / m². 2 Approximately 54 mg / m 2 .

[0444] In some respects, the effective therapeutic dose of MetAP2 inhibitors can be approximately 36 mg / m². 2 In some respects, the effective therapeutic dose of a MetAP2 inhibitor can be approximately 26 mg / m². 2 Approximately 49 mg / m 2 In some respects, the effective therapeutic dose of MetAP2 inhibitors can be approximately 31 mg / m². 2 Approximately 49 mg / m 2 .

[0445] In some respects, the effective therapeutic dose of MetAP2 inhibitors can be approximately 65 mg / m². 2 In some respects, the effective therapeutic dose of MetAP2 inhibitors can be approximately 55 mg / m². 2 Approximately 75 mg / m 2 In some respects, the effective therapeutic dose of MetAP2 inhibitors can be approximately 60 mg / m². 2 Approximately 70 mg / m 2 .

[0446] In some respects, MetAP2 inhibitors may be administered in amounts of about 10 mg, or about 20 mg, or about 30 mg, or about 40 mg, or about 50 mg, or about 60 mg, or about 70 mg, or about 80 mg, or about 90 mg, or about 100 mg, or about 110 mg, or about 120 mg, or about 130 mg, or about 140 mg, or about 150 mg, or about 160 mg, or about 170 mg, or about 180 mg, or about 190 mg, or about 200 mg. In some respects, MetAP2 inhibitors may be administered in amounts of about 80 mg. In some respects, MetAP2 inhibitors may be administered in amounts of about 70 mg to about 90 mg. In some respects, MetAP2 inhibitors may be administered in amounts of about 75 mg to about 85 mg.

[0447] In some respects, the therapeutically effective dose of a MetAP2 inhibitor may be about 10 mg, or about 20 mg, or about 30 mg, or about 40 mg, or about 50 mg, or about 60 mg, or about 70 mg, or about 80 mg, or about 90 mg, or about 100 mg. In some respects, the therapeutically effective dose of a MetAP2 inhibitor may be about 80 mg. In some respects, the therapeutically effective dose of a MetAP2 inhibitor may be about 70 mg to about 90 mg. In some respects, the therapeutically effective dose of a MetAP2 inhibitor may be about 75 mg to about 85 mg.

[0448] CDK4 / 6 inhibitors

[0449] As used herein, the term "CDK4 / 6 inhibitor" is used to refer to compounds that inhibit cyclin-dependent kinase CDK4 and / or cyclin-dependent kinase CDK6.

[0450] As those skilled in the art will understand, CDK4 / 6 inhibitors have also been shown to inhibit cyclin-dependent kinase CDK2 in some cases. Therefore, as used herein, the term CDK4 / 6 inhibitor may also refer to compounds that inhibit cyclin-dependent kinase CDK4 and / or cyclin-dependent kinase CDK6 and / or cyclin-dependent kinase CDK2.

[0451] In some respects, CDK4 / 6 inhibitors can be selected from palbociclib, abexicillin, ripociclib, trelaciclib, SHR-6390, FCN-437c, leroxib, rimizine, PF-06873600, XZP-3287, zoteracilib, BEBT-209, BPI-16350, CS-3002, fadraciclib, HS-10342, ON-123300, and PF-0684. 2874, TQ-05510, BPI-1178, JS-101, NUV-422, AU-294, CCT-68127, ETH-155008, HEC-80797, JRP-890, JS-104, NEOS-518, PF-07104091, PF-07220060, RMC-4550, SRX-3177, VS-2370, VS-2370. In some respects, CDK4 / 6 inhibitors may be selected from any pharmaceutically acceptable salt of the aforementioned compounds.

[0452] In some respects, CDK4 / 6 inhibitors can be palbociclib or its pharmaceutically acceptable salts.

[0453] In some cases, palbociclib can be administered orally. In some cases, palbociclib can be administered once daily. In some cases, palbociclib can be administered at a dose of about 75 mg / day, or about 100 mg / day, or about 125 mg / day, or about 150 mg / day, or about 175 mg / day, or about 200 mg / day. In some cases, palbociclib can be administered at a dose of about 125 mg / day. In some cases, palbociclib can be administered at a dose of about 50 mg / day to about 150 mg / day, or about 75 mg / day to about 175 mg / day, or about 100 mg / day to about 200 mg / day, or about 125 mg / day to about 225 mg / day, or about 150 mg / day to about 250 mg / day. In some cases, palbociclib can be administered once daily for about 21 days, followed by about 7 days without administration.

[0454] In some respects, the effective therapeutic dose of palbociclib may be about 75 mg / day, or about 100 mg / day, or about 125 mg / day, or about 150 mg / day, or about 175 mg / day, or about 200 mg / day. In some respects, the effective therapeutic dose of palbociclib may be about 125 mg / day. In some respects, the effective therapeutic dose of palbociclib may be about 50 mg / day to about 150 mg / day, or about 75 mg / day to about 175 mg / day, or about 100 mg / day to about 200 mg / day, or about 125 mg / day to about 225 mg / day, or about 150 mg / day to about 250 mg / day.

[0455] In some respects, the therapeutically effective dose of palbociclib may be about 75 mg, or about 100 mg, or about 125 mg, or about 150 mg, or about 175 mg, or about 200 mg. In some respects, the therapeutically effective dose of palbociclib may be about 125 mg. In some respects, the therapeutically effective dose of palbociclib may be about 50 mg to about 150 mg, or about 75 mg to about 175 mg, or about 100 mg to about 200 mg, or about 125 mg to about 225 mg, or about 150 mg to about 250 mg.

[0456] In some respects, CDK4 / 6 inhibitors can be abexilide or a pharmaceutically acceptable salt thereof.

[0457] In some cases, abexilide can be administered orally. In some cases, abexilide can be administered twice daily. In some cases, abexilide can be administered at doses of approximately 75 mg twice daily (approximately 150 mg / day), or approximately 100 mg twice daily (approximately 200 mg / day), or approximately 125 mg twice daily (approximately 250 mg / day), or approximately 150 mg twice daily (approximately 300 mg / day), or approximately 175 mg twice daily (approximately 350 mg / day), or approximately 200 mg twice daily (approximately 400 mg / day), or approximately 225 mg twice daily (approximately 450 mg / day). In some respects, it can be administered at about 50 mg / day to about 150 mg / day, or about 75 mg / day to about 175 mg / day, or about 100 mg / day to about 200 mg / day, or about 125 mg / day to about 225 mg / day, or about 150 mg / day to about 250 mg / day, or about 175 mg / day to about 275 mg / day, or about 200 mg / day to about 300 mg / day, or about 225 mg / day to about 325 mg / day, or about 250 mg / day or about 350 mg / day, or about 275 mg / day or about 375 mg / day, or about 300 mg / day to about 400 mg / day, or about 325 mg / day to about 4 Abecitabine is administered at doses of 25 mg / day, or about 350 mg / day to about 450 mg / day, or about 375 mg / day to about 475 mg / day, or about 400 mg / day to about 500 mg / day, or about 425 mg / day to about 525 mg / day, or about 450 mg / day to about 550 mg / day, or about 475 mg / day to about 575 mg / day, or about 500 mg / day to about 600 mg / day, or about 525 mg / day to about 625 mg / day, or about 550 mg / day to about 650 mg / day, or about 575 mg / day to about 675 mg / day, or about 600 mg / day to about 700 mg / day.

[0458] In some respects, the effective therapeutic dose of abexicillin may be approximately 75 mg / day, or approximately 100 mg / day, or approximately 125 mg / day, or approximately 150 mg / day, or approximately 175 mg / day, or approximately 200 mg / day, or approximately 225 mg / day, or approximately 250 mg / day, or approximately 275 mg / day, or approximately 300 mg / day, or approximately 325 mg / day, or approximately 350 mg / day, or approximately 375 mg / day, or approximately 400 mg / day, or approximately 425 mg / day, or approximately 450 mg / day, or approximately 475 mg / day, or approximately 500 mg / day. In some respects, the effective therapeutic dose of abexicillin can be about 50 mg / day to about 150 mg / day, or about 75 mg / day to about 175 mg / day, or about 100 mg / day to about 200 mg / day, or about 125 mg / day to about 225 mg / day, or about 150 mg / day to about 250 mg / day, or about 175 mg / day to about 275 mg / day, or about 200 mg / day to about 300 mg / day, or about 225 mg / day to about 325 mg / day, or about 250 mg / day or about 350 mg / day, or about 275 mg / day or about 375 mg / day, or about 300 mg / day to about 400 mg / day, or about 3 25 mg / day to about 425 mg / day, or about 350 mg / day to about 450 mg / day, or about 375 mg / day to about 475 mg / day, or about 400 mg / day to about 500 mg / day, or about 425 mg / day to about 525 mg / day, or about 450 mg / day to about 550 mg / day, or about 475 mg / day to about 575 mg / day, or about 500 mg / day to about 600 mg / day, or about 525 mg / day to about 625 mg / day, or about 550 mg / day to about 650 mg / day, or about 575 mg / day to about 675 mg / day, or about 600 mg / day to about 700 mg / day.

[0459] In some respects, the therapeutically effective dose of abecilibaly may be about 75 mg, or about 100 mg, or about 125 mg, or about 150 mg, or about 175 mg, or about 200 mg, or about 225 mg, or about 250 mg, or about 275 mg, or about 300 mg, or about 325 mg, or about 350 mg, or about 375 mg, or about 400 mg, or about 425 mg, or about 450 mg, or about 475 mg, or about 500 mg. In some respects, the therapeutically effective dose of abexicillin can be about 50 mg to about 150 mg, or about 75 mg to about 175 mg, or about 100 mg to about 200 mg, or about 125 mg to about 225 mg, or about 150 mg to about 250 mg, or about 175 mg to about 275 mg, or about 200 mg to about 300 mg, or about 225 mg to about 325 mg, or about 250 mg or about 350 mg, or about 275 mg or about 375 mg, or about 300 mg to about 400 mg. Or about 325 mg to about 425 mg, or about 350 mg to about 450 mg, or about 375 mg to about 475 mg, or about 400 mg to about 500 mg, or about 425 mg to about 525 mg, or about 450 mg to about 550 mg, or about 475 mg to about 575 mg, or about 500 mg to about 600 mg, or about 525 mg to about 625 mg, or about 550 mg to about 650 mg, or about 575 mg to about 675 mg, or about 600 mg to about 700 mg.

[0460] In some respects, CDK4 / 6 inhibitors may be reboxil or a pharmaceutically acceptable salt thereof. In some respects, the pharmaceutically acceptable salt may be reboxil succinate.

[0461] In some cases, repocidide can be administered orally. In some cases, repocidide can be administered once daily. In some cases, repocidide can be administered at doses of approximately 100 mg / day, or approximately 200 mg / day, or approximately 300 mg / day, or approximately 400 mg / day, or approximately 500 mg / day, or approximately 600 mg / day, or approximately 700 mg / day. In some cases, repocidide can be administered at a dose of approximately 600 mg / day. In some respects, it can be administered at about 50 mg / day to about 150 mg / day, or about 75 mg / day to about 175 mg / day, or about 100 mg / day to about 200 mg / day, or about 125 mg / day to about 225 mg / day, or about 150 mg / day to about 250 mg / day, or about 175 mg / day to about 275 mg / day, or about 200 mg / day to about 300 mg / day, or about 225 mg / day to about 325 mg / day, or about 250 mg / day or about 350 mg / day, or about 275 mg / day or about 375 mg / day, or about 300 mg / day to about 400 mg / day, or about 325 mg / day to about 4 Rebociclib can be administered at doses of 25 mg / day, or about 350 mg / day to about 450 mg / day, or about 375 mg / day to about 475 mg / day, or about 400 mg / day to about 500 mg / day, or about 425 mg / day to about 525 mg / day, or about 450 mg / day to about 550 mg / day, or about 475 mg / day to about 575 mg / day, or about 500 mg / day to about 600 mg / day, or about 525 mg / day to about 625 mg / day, or about 550 mg / day to about 650 mg / day, or about 575 mg / day to about 675 mg / day, or about 600 mg / day to about 700 mg / day. In some cases, palbociclib can be administered once daily for about 21 days, followed by about 7 days without administration.

[0462] In some cases, the effective therapeutic dose of repocidide may be approximately 100 mg / day, or approximately 200 mg / day, or approximately 300 mg / day, or approximately 400 mg / day, or approximately 500 mg / day, or approximately 600 mg / day, or approximately 700 mg / day. In other cases, the effective therapeutic dose of repocidide may be approximately 600 mg / day. In some respects, the therapeutically effective dose of reboxil can be about 50 mg / day to about 150 mg / day, or about 75 mg / day to about 175 mg / day, or about 100 mg / day to about 200 mg / day, or about 125 mg / day to about 225 mg / day, or about 150 mg / day to about 250 mg / day, or about 175 mg / day to about 275 mg / day, or about 200 mg / day to about 300 mg / day, or about 225 mg / day to about 325 mg / day, or about 250 mg / day or about 350 mg / day, or about 275 mg / day or about 375 mg / day, or about 300 mg / day to about 400 mg / day, or about 3 25 mg / day to about 425 mg / day, or about 350 mg / day to about 450 mg / day, or about 375 mg / day to about 475 mg / day, or about 400 mg / day to about 500 mg / day, or about 425 mg / day to about 525 mg / day, or about 450 mg / day to about 550 mg / day, or about 475 mg / day to about 575 mg / day, or about 500 mg / day to about 600 mg / day, or about 525 mg / day to about 625 mg / day, or about 550 mg / day to about 650 mg / day, or about 575 mg / day to about 675 mg / day, or about 600 mg / day to about 700 mg / day.

[0463] In some respects, the therapeutically effective dose of repoxid may be about 100 mg, or about 200 mg, or about 300 mg, or about 400 mg, or about 500 mg, or about 600 mg, or about 700 mg. In some respects, the therapeutically effective dose of repoxid may be about 600 mg. In some respects, the therapeutically effective dose of repoxid may be about 50 mg to about 150 mg, or about 75 mg to about 175 mg, or about 100 mg to about 200 mg, or about 125 mg to about 225 mg, or about 150 mg to about 250 mg, or about 175 mg to about 275 mg, or about 200 mg to about 300 mg, or about 225 mg to about 325 mg, or about 250 mg or about 350 mg, or about 275 mg or about 375 mg, or about 300 mg to about 400 mg. Or about 325 mg to about 425 mg, or about 350 mg to about 450 mg, or about 375 mg to about 475 mg, or about 400 mg to about 500 mg, or about 425 mg to about 525 mg, or about 450 mg to about 550 mg, or about 475 mg to about 575 mg, or about 500 mg to about 600 mg, or about 525 mg to about 625 mg, or about 550 mg to about 650 mg, or about 575 mg to about 675 mg, or about 600 mg to about 700 mg.

[0464] The CDK4 / 6 inhibitor can be further administered in combination with at least one additional therapeutic agent. Therefore, the compositions of this disclosure may comprise a combination of at least one MetAP2 inhibitor, at least one CDK4 / 6 inhibitor, and at least one additional therapeutic agent.

[0465] In some respects, the at least one additional therapeutic agent may include hormone therapy.

[0466] In some aspects, the at least one additional therapeutic agent may comprise an aromatase inhibitor. In some aspects, the aromatase inhibitor may comprise a nonsteroidal aromatase inhibitor.

[0467] In some respects, aromatase inhibitors may include anastrozole, exemestane, letrozole, or any combination thereof.

[0468] In some aspects, the at least one additional therapeutic agent may comprise a selective estrogen receptor degrader (SERD). In some aspects, the SERD may comprise fulvestrant.

[0469] In some aspects, the at least one additional therapeutic agent may comprise a gonadotropin-releasing hormone agonist. In some aspects, the gonadotropin-releasing hormone agonist may comprise goserelin.

[0470] In some respects, the at least one additional therapeutic agent may comprise a PI3K inhibitor, an AKT inhibitor, an mTOR inhibitor, or a PI3K / Akt / mTOR pathway inhibitor.

[0471] In some aspects, the at least one additional therapeutic agent may comprise serabelisib (TAK-117), BYL-719, AZD5363 (capavasertib), parsethiate (ipaseratib) (GDC0068), (paclitaxel + sirolimus + tanespimycin)), (paclitaxel + sirolimus + tanespimycin), A-443654, AB-610, ACP-2127, ADC-0008830, AE-116, AEZS-126, AEZS-127, afuresertib + trametinib, AL-58203, AL-58805, AL-58922, ALM-301, AP-185 AP-23675, AP-23841, apitolisib, ARQ-751, ASP-7486, AST-0669, AT-104, AT-13148, AUM-302, AZD-3147, AZD-8055, AZD-8154, BAY-1001931, BAY-1125976, BAY-1125976, BGT-226, bimiralisib, BN-107, BN-108, borussertib, buformin, BVD-723, capivasertib, CC-115, CC-2141, CC-2142, Certican ODT, CL-27, COTI-2, CT-365, dactolisib (tosylate) tosylate), DC-120, DHM-25, dihydroartemisinin, DS-3078, DS-7423, duvelisib, EM-101, everolimus, FP-208, FT-1518, FXY-1, galarmin, GDC-0349, gedatolisib, GM-6, GNE-317, GNE- 555, GSK-690693, GT-0486, HD-148 series, HEC-68498, HM-032, HM-5016699, HMPL-518, Parta-Seretide, IPI-549, ISC-4, J-9, JRP-890, KIT-2014, KS-99, LD-101, Lithium Carbonate, LY-2503029, LY-2780301, M-2698, ME-344, Miransertib Mesylatemesylate), MK-2206, MKC-1, monepantel, NISC-6, nPT-mTOR, NSC-765844, NV-128, onatasertib, ONC-201, ONC-222, ONC-235, OSU-53, OT-043, OT-043, P-7170, PBD-1226, perifo sine), PF-04691502, pimaertib hydrochloride + voxtalisib, PKI-179, PQR-311, PQR-316, PQR-401, PQR-4XX, PQR-514, PQR-530, PQR-620, PWT-33597, PX-316, recilisib sodium, RES-529 Ridaforolimus, RMC-5552, RP-6503, RV-1729, RX-0183, RX-0201, RX-0201N, RX-0301, RX-1792, RX-8243, samotolisib, sapanisertib, SB-2602, SCC-31, SF-1126, SF-2523, SN-202, SPR -965, SR-13668, STP-503, SX-MTR1, TAFA-93, TAM-01, TAM-03, TAS-117, TASP-0415914, TE-7105, temsirolimus, tenalisib, TOP-216, trametinib dimethyl sulfoxide + uprosertib, riciribine phosphate Phosphate), UB-1201, Uprosite, VCC-405567, VCC-668662, vistusertib, VLI-27, votasiib, VS-5584, WX-008, WXFL-10030390, X-387, X-414, X-480, XL-388, XL-418, XP-105, Y-31, Zortress or any combination thereof.

[0472] Treatment subjects and cancer

[0473] In some respects, the subjects for whom it is required are animals. In some respects, the animals may be mammals. In some respects, the subjects for whom it is required are humans.

[0474] In some respects, the subjects who require it are persons aged 18 or older. In other respects, the subjects who require it are persons under 18 years of age.

[0475] In some aspects, the subject requiring the treatment has cancer. In some aspects, the cancer is characterized by the presence of at least one tumor in the subject.

[0476] The terms “cancer” and “cancerous” refer to or describe a physiological condition in mammals that is typically characterized by disordered cell growth. This definition includes both benign and malignant cancers. Examples of cancer include, but are not limited to, carcinoma, lymphoma, blastoma, sarcoma, leukemia, and germ cell tumors. More specific examples of this type of cancer include: adrenocortical carcinoma, urothelial carcinoma of the bladder, invasive breast cancer, squamous cell carcinoma of the cervix, endocervical adenocarcinoma, cholangiocarcinoma, colon adenocarcinoma, diffuse large B-cell lymphoma with lymphoid vegetations, esophageal carcinoma, glioblastoma multiforme, squamous cell carcinoma of the head and neck, kidney chromophobe, clear cell carcinoma of the kidney, papillary cell carcinoma of the kidney, acute myeloid leukemia, low-grade glioma of the brain, hepatocellular carcinoma of the liver, lung adenocarcinoma, lung squamous cell carcinoma, mesothelioma, ovarian serous cyst adenocarcinoma, pancreatic adenocarcinoma, pheochromocytoma, paraganglioma, prostate adenocarcinoma, rectal adenocarcinoma, sarcoma, melanoma of the skin, gastric adenocarcinoma, testicular germ cell tumor, thyroid carcinoma, thymoma, uterine carcinosarcoma, and uveal melanoma. Other examples include breast cancer, lung cancer, lymphoma, melanoma, liver cancer, colorectal cancer, ovarian cancer, bladder cancer, kidney cancer, or gastric cancer.Further examples of cancer include neuroendocrine carcinoma, non-small cell lung cancer (NSCLC), small cell lung cancer, thyroid cancer, endometrial cancer, biliary cancer, esophageal cancer, anal cancer, salivary gland cancer, vulvar cancer, cervical cancer, acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), adrenal tumors, anal cancer, biliary duct cancer, bladder cancer, bone cancer, colorectal cancer, brain tumors, breast cancer, cancer of unknown primary origin (CUP), cancer that has spread to bone, cancer that has spread to the brain, cancer that has spread to the liver, cancer that has spread to the lungs, carcinoid tumors, cervical cancer, childhood cancer, chronic lymphocytic leukemia (CLL), chronic myeloid leukemia (CML), colorectal cancer, ear cancer, endometrial cancer, eye cancer, follicular dendritic cell sarcoma, gallbladder cancer, and gastric cancer. Cancer, gastroesophageal junction cancer, germ cell tumor, gestational trophoblastic disease (GIT), hairy cell leukemia, head and neck cancer, Hodgkin's lymphoma, Kaposi's sarcoma, kidney cancer, laryngeal cancer, leukemia, leukoderma, liver cancer, lung cancer, lymphoma, malignant Schwann cell tumor, mediastinal germ cell tumor, melanoma, skin cancer, male cancer, Merkel cell skin cancer, mesothelioma, hydatidiform mole, oral and oropharyngeal cancer, myeloma, nasal and paranasal sinus cancer, nasopharyngeal cancer, neuroblastoma, neuroendocrine tumor, non-Hodgkin's lymphoma (NHL), esophageal cancer, ovarian cancer, pancreatic cancer, penile cancer, persistent trophoblastic disease and choriocarcinoma, pheochromocytoma, prostate cancer, pseudomyxoma peritonei, rectal cancer, retinoblastoma, salivary gland cancer, secondary cancer, signet cell cancer, skin cancer, small intestine cancer, soft tissue sarcoma, stomach cancer. Cancer), T-cell childhood non-Hodgkin lymphoma (NHL), testicular cancer, thymic cancer, thyroid cancer, tongue cancer, tonsil cancer, adrenal tumors, uterine cancer, vaginal cancer, vulvar cancer, Wilms' tumor, uterine cancer, and gynecological cancers.Examples of cancers include, but are not limited to, hematologic malignancies, lymphomas, cutaneous T-cell lymphomas, peripheral T-cell lymphomas, Hodgkin lymphomas, non-Hodgkin lymphomas, multiple myeloma, chronic lymphocytic leukemia (Chrome lymphocytic leukemia), chronic myeloid leukemia, acute myeloid leukemia, myelodysplastic syndrome, myelofibrosis, biliary tract cancer, hepatocellular carcinoma, colorectal cancer, breast cancer, lung cancer, non-small cell lung cancer, ovarian cancer, thyroid cancer, renal cell carcinoma, pancreatic cancer, bladder cancer, skin cancer, malignant melanoma, Merkel cell carcinoma, uveal melanoma, or glioblastoma multiforme.

[0477] In some respects, the cancers referred to are carcinoma, lymphoma, blastoma, sarcoma, leukemia, brain cancer, breast cancer, blood cancer, bone cancer, lung cancer, skin cancer, liver cancer, ovarian cancer, bladder cancer, renal cancer, gastric cancer, thyroid cancer, pancreatic cancer, esophageal cancer, prostate cancer, cervical cancer, uterine cancer, stomach cancer, soft tissue cancer, laryngeal cancer, small intestine cancer, testicular cancer, anal cancer, vulvar cancer, joint cancer, oral cancer, pharyngeal cancer, or colorectal cancer.

[0478] In some respects, the cancer in question is breast cancer.

[0479] In some respects, the breast cancer referred to herein is metastatic breast cancer. As used herein, metastatic breast cancer is stage III or IV breast cancer that has spread to another part of the body, including but not limited to the liver, brain, and bones.

[0480] In some respects, the breast cancer referred to is human epidermal growth factor 2 (HER2)-negative breast cancer.

[0481] In some respects, the breast cancer mentioned is HR+HER2- breast cancer.

[0482] In some aspects, the breast cancer may be Luminal A breast cancer. In some aspects, the breast cancer may be Luminal B breast cancer. In some aspects, the breast cancer may be triple-negative or basaloid breast cancer. In some aspects, the breast cancer may be HER2-enriched breast cancer.

[0483] In some respects, the cancer in question is head and neck cancer.

[0484] In some respects, the cancer in question is non-small cell lung cancer.

[0485] In some respects, the cancer is brain cancer. In other respects, the brain cancer can be a recurrent brain metastasis.

[0486] In some respects, the cancer in question is squamous cell carcinoma.

[0487] In some respects, the cancer in question is a tumor of the central nervous system.

[0488] In some respects, the cancer in question is liposarcoma.

[0489] In some respects, the cancer in question is endometrial cancer.

[0490] In some respects, the cancer in question is a neuroendocrine tumor.

[0491] In some respects, the cancer in question is small cell lung cancer (SCLC).

[0492] General definition

[0493] It will be understood that the compounds of this disclosure can be described as different tautomers. It should also be understood that when a compound has tautomer forms, all tautomer forms are intended to be included within the scope of this disclosure, and the naming of the compound does not exclude any tautomer form. It will be understood that some tautomers may have higher activity levels than others.

[0494] As used herein, the terms "crystalline polymorph," "polymorph," or "crystalline form" refer to crystalline structures in which a compound (or its salts or solvates) can crystallize in different crystalline packing arrangements, all having the same elemental composition. Different crystalline forms typically exhibit different X-ray diffraction patterns, infrared spectra, melting points, densities, hardness, crystal shapes, optical and electrical properties, stability, and solubility. Recrystallization solvents, crystallization rates, storage temperatures, and other factors can cause one crystalline form to dominate. Crystalline polymorphs of compounds can be prepared by crystallizing under different conditions.

[0495] It will be understood that compounds of any kind described herein include the compounds themselves, as well as their salts and their solvates (if applicable). For example, salts can be formed between an anion and a positively charged group (e.g., an amino group) on the substituted benzene compound. Suitable anions include chloride, bromide, iodide, sulfate, hydrogen sulfate, aminosulfonate, nitrate, phosphate, citrate, methanesulfonate, trifluoroacetate, glutamate, glucuronate, glutarate, malate, maleate, succinate, fumarate, tartrate, toluenesulfonate, salicylate, lactate, naphthalenesulfonate, and acetate (e.g., trifluoroacetate).

[0496] As used herein, the term "pharmaceutically acceptable anion" refers to an anion suitable for forming a pharmaceutically acceptable salt. Similarly, salts can also be formed between a cation and a negatively charged group (e.g., a carboxyl group) on the substituted benzene compound. Suitable cations include sodium, potassium, magnesium, calcium, and ammonium cations such as tetramethylammonium ions. Substituted benzene compounds also include those salts containing a quaternary nitrogen atom.

[0497] It will be understood that the compounds of this disclosure, such as salts of the compounds, may exist in hydrated or non-hydrated (anhydrous) form or as solvates with other solvent molecules. Non-limiting examples of hydrates include monohydrates, dihydrates, etc. Non-limiting examples of solvates include ethanol solvates, acetone solvates, etc.

[0498] As used herein, the term "solvent" refers to a solvation form containing stoichiometric or non-stoichiometric amounts of solvent. Some compounds have a tendency to trap a fixed molar ratio of solvent molecules in their crystalline solid state to form solvates. If the solvent is water, the formed solvate is a hydrate; and if the solvent is an alcohol, the formed solvate is an alcohol. Hydrates are formed by the combination of one or more water molecules with a substance molecule, wherein the water retains its molecular state as H₂O.

[0499] As used herein, the term "analogue" refers to a chemical compound that is structurally similar to another but has a slightly different composition (e.g., the substitution of an atom with an atom of a different element or the presence of a specific functional group, or the substitution of one functional group by another). Thus, an analogue is a compound that is similar or equivalent to a reference compound in function and appearance (but not in structure or origin).

[0500] As used herein, the term “derivative” refers to a compound having a common core structure and being substituted by various groups as described herein.

[0501] As used herein, the term "bioisostere" refers to a compound resulting from the exchange of one atom or group of atoms with another substantially similar atom or group of atoms. The aim of bioisostere substitution is to create new compounds with biological properties similar to those of the parent compound. Bioisostere substitution can be based on physicochemical or topological principles. Examples of carboxylic acid bioisosteres include, but are not limited to, acylsulfonylimides, tetrazolium, sulfonates, and phosphonates. See, for example, Patani and LaVoie, Chem. Rev. 96, 3147-3176, 1996.

[0502] It will be understood that this disclosure is intended to include all isotopes of atoms present in the compounds of the present invention. Isotopes include those atoms having the same atomic number but different mass numbers. By way of general example and not limitation, isotopes of hydrogen include tritium and deuterium, and isotopes of carbon include C-13 and C-14.

[0503] As used herein, unless otherwise indicated, the expressions “one or more of A, B or C”, “one or more A, B or C”, “one or more of A, B and C”, “one or more A, B and C”, “selected from the group consisting of A, B and C”, “selected from A, B and C”, etc., are used interchangeably and all refer to selection from the group consisting of A, B and / or C, i.e., one or more A, one or more B, one or more C or any combination thereof.

[0504] It will be understood that this disclosure provides methods for synthesizing compounds of any formula described herein. This disclosure also provides detailed methods for synthesizing the various disclosed compounds of this disclosure according to the following schemes and those shown in the examples.

[0505] It will be understood that throughout this specification, when a composition is described as having, including, or comprising a specific component, it is contemplated that the composition is also substantially composed of or consisting of said component. Similarly, when a method or process is described as having, including, or comprising specific process steps, the process is also substantially composed of or consisting of said processing steps. Furthermore, it should be understood that the order of the steps or the order in which certain actions are performed is not important as long as the invention remains operational. Moreover, two or more steps or actions may be performed simultaneously.

[0506] It will be understood that the synthetic methods of this disclosure are accommodating to a wide variety of functional groups, and therefore can utilize a variety of substituted starting materials. The methods typically provide the desired final compound at or near the end of the process, although in some cases it may be desirable to further convert the compound into its pharmaceutically acceptable salt.

[0507] It will be understood that the compounds of this disclosure can be prepared in a variety of ways using standard synthetic methods and procedures, using commercially available starting materials, compounds known in the literature, or from readily prepared intermediates, which are known to those skilled in the art or will be apparent to those proficient in the teachings herein. Standard synthetic methods and procedures for the preparation of organic molecules, as well as for the transformation and manipulation of functional groups, are available from relevant scientific literature or standard textbooks in the art. Although not limited to any one or a few sources, classic textbooks such as Smith, MB, March, J., March's Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, 5th ed., John Wiley & Sons: New York, 2001; Greene, TW, Wuts, PGM, Protective Groups in Organic Synthesis, 3rd ed., John Wiley & Sons: New York, 1999; R. Larock, Comprehensive Organic Transformations, VCH Publishers (1989); L. Fieser and M. Fieser, Fieser and Fieser's Reagents for Organic Synthesis, John Wiley and Sons (1994); and L. Paquette, ed., Encyclopedia of Reagents for Organic Synthesis, John Wiley and Sons (1995) (incorporated herein by reference) are known and widely accepted reference textbooks for organic synthesis by those skilled in the art.

[0508] It will be understood that, unless otherwise stated, any description of a treatment method includes the use of the said compound to provide a treatment or prevention as described herein, as well as the use of the said compound to prepare a drug for treating or preventing such a condition. Treatment includes treating human or non-human animals, including rodents and other disease models.

[0509] As used herein, the term "subject" may be used interchangeably with the term "subject requiring it," both of which refer to a subject who has a disease or has an increased risk of developing a disease. "Subject" includes mammals. Mammals can be, for example, humans or suitable non-human mammals such as primates, mice, rats, dogs, cats, cattle, horses, goats, camels, sheep, or pigs. Subjects can also be birds or poultry. In one embodiment, the mammal is a human.

[0510] As used herein, the terms “treating” or “treat” describe the management and care of a patient for the purpose of combating a disease, symptom, or disorder, and include the administration of compounds of this disclosure or their pharmaceutically acceptable salts, polymorphs, or solvates to alleviate or eliminate symptoms or complications of a disease, symptom, or disorder. The term “treating” may also include treatment in in vitro cell or animal models.

[0511] It will be understood that the compounds of this disclosure or their pharmaceutically acceptable salts, polymorphs or solvates may or may not be used to prevent related diseases, symptoms or disorders, or to identify suitable candidates for such purposes.

[0512] As used in this article, the terms “preventing,” “prevent,” or “protection from” describe reducing or eliminating the onset of symptoms or complications of such diseases, conditions, or disorders.

[0513] It will be understood that for a detailed description of the known or equivalent techniques discussed herein, those skilled in the art may refer to general reference texts. These texts include Ausubel et al., Current Protocols in Molecular Biology, John Wiley and Sons, Inc. (2005); Sambrook et al., Molecular Cloning, A Laboratory Manual (3rd ed.), Cold Spring Harbor Press, Cold Spring Harbor, New York (2000); Coligan et al., Current Protocols in Immunology, John Wiley & Sons, NY; Enna et al., Current Protocols in Pharmacology, John Wiley & Sons, NY; Fingle et al., The Pharmacological Basis of Therapeutics (1975), Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton, PA, 18th ed. (1990); Mandell et al., Principles and Practice of Infectious Diseases, Saunders Publishing (8th ed., 2014). Of course, these texts may also be referenced when creating or using any aspect of this disclosure.

[0514] As used herein, the terms "combination therapy" or "combined treatment" include the administration of a compound of this disclosure or a pharmaceutically acceptable salt, polymorph, or solvate thereof, and at least a second agent as part of a particular treatment regimen intended to provide a beneficial effect from the combined action of these therapeutic agents. The beneficial effect of the combination includes, but is not limited to, the combined pharmacokinetic or pharmacodynamic effect resulting from the combination of therapeutic agents.

[0515] It will be understood that this disclosure also provides pharmaceutical compositions comprising any of the compounds described herein in combination with at least one pharmaceutically acceptable excipient or carrier.

[0516] As used herein, the term "pharmaceutical composition" is a formulation containing a compound of the present disclosure, in a form suitable for administration to a subject. In one embodiment, the pharmaceutical composition is in bulk or unit dosage form. Unit dosage forms are any of a variety of forms, including, for example, capsules, IV bags, tablets, single pumps on an aerosol inhaler, or tubular bottles. The amount of active ingredient (e.g., a formulation of the disclosed compound or its salts, hydrates, solvates, or isomers) in a unit dose of the composition is an effective amount and varies depending on the specific treatment involved. Those skilled in the art will understand that, depending on the patient's age and condition, it is sometimes necessary to make routine variations in dosage. Dosage will also depend on the route of administration. A variety of routes are considered, including oral, pulmonary, rectal, parenteral, transdermal, subcutaneous, intravenous, intramuscular, intraperitoneal, inhalation, buccal, sublingual, intrapleural, intrathecal, intranasal, etc. Dosage forms for topical or transdermal application of the compounds used in this disclosure include powders, sprays, ointments, pastes, creams, lotions, gels, solutions, patches, and inhalants. In one embodiment, the active compound is mixed under sterile conditions with a pharmaceutically acceptable carrier and with any desired preservatives, buffers, or propellants.

[0517] The terms “effective amount” and “therapeutic effective amount” for a drug or compound are used in the broadest sense to refer to a non-toxic but sufficient amount of an active agent or compound that provides the desired effect or benefit.

[0518] The term “benefit” is used in the broadest sense and refers to any desired effect, specifically including clinical benefit as defined herein. Clinical benefit can be measured by assessing a variety of endpoints, such as some degree of inhibition of disease progression, including slowing and complete cessation; a reduction in the number of disease attacks and / or symptoms; a reduction in lesion size; inhibition (i.e., reduction, slowing, or complete cessation) of disease cell infiltration into adjacent organs and / or tissues; inhibition (i.e., reduction, slowing, or complete cessation) of disease spread; a reduction in autoimmune response, which may (but not necessarily) lead to regression or ablation of disease lesions; some degree of relief of one or more symptoms associated with the disorder; an increase in the duration of disease-free presentation (e.g., progression-free survival) after treatment; increased overall survival; higher response rates; and / or reduced mortality at a given time point after treatment.

[0519] As used herein, the term “pharmaceutically acceptable” means, to a reasonable extent of medical judgment, those compounds, anionic, cationic, materials, compositions, carriers and / or dosage forms that are suitable for contact with human and animal tissues without excessive toxicity, irritation, allergic reactions or other problems or complications, in proportion to a reasonable benefit / risk ratio.

[0520] As used herein, the term "pharmaceuticalally acceptable excipient" means an excipient that can be used to prepare pharmaceutical compositions that are generally safe, non-toxic, and not biologically or otherwise undesirable, and includes excipients acceptable for both veterinary and human pharmaceutical applications. As used in this specification and claims, "pharmaceuticalally acceptable excipient" includes one or more such excipients.

[0521] It will be understood that the pharmaceutical compositions of this disclosure are formulated to be compatible with their intended route of administration. Examples of routes of administration include parenteral, such as intravenous, intradermal, subcutaneous, oral (e.g., inhalation), transdermal (topical), and transmucosal administration. Solutions or suspensions for parenteral, intradermal, or subcutaneous application may include the following components: sterile diluents, such as water for injection, saline solution, non-volatile oils, polyethylene glycol, glycerol, propylene glycol, or other synthetic solvents; antibacterial agents, such as benzyl alcohol or methylparaben; antioxidants, such as ascorbic acid or sodium bisulfite; chelating agents, such as ethylenediaminetetraacetic acid; buffers, such as acetates, citrates, or phosphates; and agents for adjusting the pH, such as sodium chloride or dextran. The pH may be adjusted with acids or bases, such as hydrochloric acid or sodium hydroxide. Parenteral preparations may be encapsulated in ampoules, disposable syringes, or multi-dose tubular bottles made of glass or plastic.

[0522] It will be understood that the compounds or pharmaceutical compositions of this disclosure can be administered to a subject using many well-known methods currently used for chemotherapeutic treatments. For example, the compounds of this disclosure can be injected into the bloodstream or body cavity, or taken orally, or applied through the skin as a patch. The chosen dose should be sufficient to constitute an effective treatment, but should not be high enough to cause unacceptable side effects. Preferably, the status of the disease and the patient's health should be closely monitored during treatment and for a reasonable period after treatment.

[0523] As used herein, the term "therapeutic effective dose" refers to a dose of medicine that treats, improves, or prevents an identified disease or condition, or that exhibits a detectable therapeutic or inhibitory effect. This effect can be detected by any assay method known in the art. The precise effective dose for a subject will depend on the subject's weight, size, and health; the nature and severity of the condition; and the therapeutic agent or combination of therapeutic agents chosen for administration. The therapeutic effective dose for a given situation can be determined through routine laboratory testing within the skill and judgment of a clinician.

[0524] It will be understood that, for any compound, the therapeutically effective dose can initially be estimated in a cell culture assay (e.g., a culture assay of proliferative cells) or in an animal model (typically a rat, mouse, rabbit, dog, or pig). The animal model can also be used to determine the appropriate concentration range and route of administration. This information can then be used to determine the useful dose and route of administration in humans. Therapeutic / prophylactic efficacy and toxicity, such as ED, can be determined using standard pharmaceutical procedures in cell cultures or laboratory animals. 50 (Therapeutic effective dose in 50% of the population) and LD 50 (The 50% lethal dose for a population). The dose ratio between toxic effects and therapeutic effects is the therapeutic index, and it can be expressed as a ratio, LD50. 50 / ED 50 Pharmaceutical compositions exhibiting a high therapeutic index are preferred. The dosage may vary within this range depending on the dosage form used, patient sensitivity, and route of administration.

[0525] Adjust the dosage and administration to provide adequate levels of (one or more) active agents or maintain the desired effect. Factors to consider include the severity of the disease state, the subject's general health, the subject's age, weight and sex, diet, timing and frequency of administration, combination of (one or more) drugs, sensitivity to response, and tolerance / response to the therapy. Depending on the half-life and clearance rate of the specific formulation, long-acting drug compositions may be administered every 3 to 4 days, weekly, or bi-weekly.

[0526] Pharmaceutical compositions containing the active compounds disclosed herein can be prepared in ways commonly known, such as by means of conventional mixing, dissolving, granulation, pelleting, grinding, emulsification, encapsulation, embedding, or lyophilization processes. The pharmaceutical compositions can be formulated in a conventional manner using one or more pharmaceutically acceptable carriers, said carriers containing excipients and / or adjuvants that facilitate the processing of the active compound into a pharmaceutically usable formulation. Of course, the appropriate formulation depends on the chosen route of administration.

[0527] Suitable pharmaceutical compositions for injection include sterile aqueous solutions (in the water-soluble case) or dispersions, and sterile powders for immediate preparation of sterile injectable solutions or dispersions. For intravenous administration, suitable carriers include physiological saline, antibacterial water, and Cremophor EL. TM(BASF, Parsippany, NJ) or phosphate-buffered saline (PBS). In all cases, the composition must be sterile and should be fluid enough to be readily injectable. It must be stable under preparation and storage conditions and must be protected from contamination by microorganisms such as bacteria and fungi. The carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyols (e.g., glycerol, propylene glycol, and liquid polyethylene glycol), and suitable mixtures thereof. Appropriate flowability can be maintained, for example, by using coatings such as lecithin, by maintaining the desired particle size in the case of dispersions, and by using surfactants. The protection against microorganisms can be achieved by various antibacterial and antifungal agents, such as parabens, chlorobutanol, phenol, ascorbic acid, thimerosal, etc. In many cases, it will be preferred to include isotonic agents in the composition, such as sugars, polyols such as mannitol and sorbitol, and sodium chloride. The absorption of injectable compositions can be prolonged by including agents that delay absorption, such as aluminum monostearate and gelatin, in the composition.

[0528] Sterile injectable solutions can be prepared by incorporating the active compound in the desired amount, along with one or more of the components listed above (as needed), into a suitable solvent, followed by sterile filtration. Typically, dispersions are prepared by incorporating the active compound into a sterile medium, the medium carrier containing a base dispersion medium and other desired components from those listed above. In the case of sterile powders used to prepare sterile injectable solutions, the preparation method is vacuum drying and freeze-drying, which yields a powder from its previously sterile filtered solution containing the active ingredient plus any other desired components.

[0529] Oral compositions typically include an inert diluent or an edible, pharmaceutically acceptable carrier. They may be encapsulated in gelatin capsules or compressed into tablets. For oral therapeutic administration, the active compound may be blended with excipients and used in the form of tablets, lozenges, or capsules. Oral compositions may also be prepared using liquid carriers for use as mouthwashes, wherein the compound in the fluid carrier is administered orally and spat out or swallowed after rinsing. Pharmaceutically compatible binders and / or adjuvants may be included as part of the composition. The tablets, pills, capsules, lozenges, etc., may contain any of the following ingredients or compounds with similar properties: binders, such as microcrystalline cellulose, tragacanth gum, or gelatin; excipients, such as starch or lactose; disintegrants, such as alginate, Primogel, or corn starch; lubricants, such as magnesium stearate or sterotes; gliding agents, such as colloidal silica; sweeteners, such as sucrose or saccharin; or flavoring agents, such as peppermint, methyl salicylate, or orange flavoring.

[0530] For administration by inhalation, the compound is delivered as an aerosol spray from a pressurized container or a dispenser (e.g., a gas, such as carbon dioxide) or a sprayer containing a suitable propellant.

[0531] Systemic application can also be achieved via transmucosal or transdermal routes. For transmucosal or transdermal application, a penetrant suitable for the barrier to be penetrated is used in the formulation. Such penetrants are generally known in the art and include, for example, detergents, bile salts, and fusidic acid derivatives for transmucosal application. Transmucosal application can be accomplished by using nasal sprays or suppositories. For transdermal application, the active compound is formulated into ointments, creams, gels, or lotions generally known in the art.

[0532] The active compound can be prepared together with a pharmaceutically acceptable carrier that will protect the compound from rapid elimination from the body, such as a controlled-release formulation, including implants and microencapsulated delivery systems. Biodegradable, biocompatible polymers such as ethylene-vinyl acetate, polyanhydride, polyglycolic acid, collagen, polyorthoesters, and polylactic acid can be used. Methods for preparing such formulations will be understood by those skilled in the art. The materials are also commercially available from Alza Corporation and Nova Pharmaceuticals, Inc. Liposome suspensions (including liposomes targeting infected cells with monoclonal antibodies against viral antigens) can also be used as pharmaceutically acceptable carriers. These can be prepared according to methods known to those skilled in the art, such as those described in U.S. Patent No. 4,522,811.

[0533] Particularly advantageous is that the oral or parenteral compositions are formulated in dose units for ease of administration and uniform dosage. The dose unit form used herein refers to a physically discrete unit suitable as a unit dose for a subject to be treated; each unit contains a predetermined amount of active compound, calculated to produce the desired therapeutic effect, in combination with the desired pharmaceutical carrier. Specifications of the dose unit form with respect to this disclosure depend on and are directly dependent on the unique characteristics of the active compound and the specific therapeutic effect to be achieved.

[0534] In therapeutic applications, the dosage of the pharmaceutical composition used according to this disclosure varies depending on factors such as the drug itself, the recipient patient's age, weight, and clinical condition, the experience and judgment of the clinician or practitioner administering the therapy, and other factors influencing the selected dosage. Generally, the dosage should be sufficient to cause a slowing and preferably remission of the symptoms of the disease, and even more preferably, complete remission of the disease. An effective amount of a pharmaceutical agent is the amount that provides an objectively identifiable improvement noticeable to a clinician or other qualified observer. Improvement in survival and growth indicates remission. As used herein, the term "dosage-effective manner" refers to the amount of active compound that produces the desired biological effect in a subject or cell.

[0535] It will be understood that the pharmaceutical composition may be included in a container, pouch, or dispenser along with the instructions for use.

[0536] It will be understood that all these forms are also considered within the scope of the claimed disclosure for compounds of this disclosure that are capable of further forming salts.

[0537] As used herein, the term "pharmaceuticalally acceptable salt" refers to a derivative of a compound of this disclosure, wherein the parent compound is modified by preparing its acid or base salt. In some embodiments, a pharmaceutically acceptable salt of a compound (e.g., a β-lactam compound or probenecid described herein) is also a prodrug of said compound. Examples of pharmaceutically acceptable salts include, but are not limited to, inorganic or organic acid salts of basic residues such as amines, and alkali metal or organic salts of acidic residues such as carboxylic acids. Pharmaceutically acceptable salts include, for example, conventional non-toxic salts or quaternary ammonium salts of parent compounds formed from non-toxic inorganic or organic acids. For example, such conventional non-toxic salts include, but are not limited to, those derived from inorganic and organic acids, wherein the acids are selected from 2-acetoxybenzoic acid, 2-hydroxyethanesulfonic acid, acetic acid, ascorbic acid, benzenesulfonic acid, benzoic acid, bicarbonate, carbonic acid, citric acid, edemaic acid, ethanedisulfonic acid, 1,2-ethanesulfonic acid, fumaric acid, glucoheponic acid, gluconic acid, glutamic acid, glycolic acid, glycolylarsanilic acid, hexylresorcinic acid, hydra... Bamic acid, hydrobromic acid, hydrochloric acid, hydroiodic acid, hydroxymaleic acid, hydroxynaphthyl carboxylic acid, hydroxyethanesulfonic acid, lactic acid, lactobionic acid, lauryl sulfonic acid, maleic acid, malic acid, mandelic acid, methanesulfonic acid, naphthalenesulfonic acid, nitric acid, oxalic acid, primordial acid, pantothenic acid, phenylacetic acid, phosphoric acid, polygalacturonic acid, propionic acid, salicylic acid, stearic acid, acetic acid, succinic acid, aminosulfonic acid, p-aminobenzenesulfonic acid, sulfuric acid, tannic acid, tartaric acid, toluenesulfonic acid, and common amino acids such as glycine, alanine, phenylalanine, and arginine.

[0538] As used herein, the term "metabolite" means a metabolite of the compounds of this disclosure or a pharmaceutically acceptable salt, solvate, diastereomer, or polymorph thereof that exhibits similar activity in vivo to the compounds of this disclosure or their pharmaceutically acceptable salts, solvates, diastereomers, or polymorphs thereof.

[0539] Other examples of pharmaceutically acceptable salts include hexanoic acid, cyclopentanepropionic acid, pyruvate, malonic acid, 3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, 4-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid, 4-toluenesulfonic acid, camphorsulfonic acid, 4-methylbicyclo-[2.2.2]-oct-2-en-1-carboxylic acid, 3-phenylpropionic acid, trimethylacetic acid, tert-butylacetic acid, mucoconic acid, etc. This disclosure also covers salts formed when an acidic proton present in the parent compound is replaced by a metal ion (e.g., an alkali metal ion, an alkaline earth metal ion, or an aluminum ion), or when coordinated with an organic base such as ethanolamine, diethanolamine, triethanolamine, tromethamine, N-methylglucosamine, etc. In the salt form, it is understood that the ratio of the compound to the cation or anion of the salt can be 1:1, or any ratio other than 1:1, such as 3:1, 2:1, 1:2, or 1:3.

[0540] It should be understood that all pharmaceutically acceptable salts mentioned include the same salt in solvation form (solvent) or crystalline form (polymorph) as defined herein.

[0541] As used herein, the term "prodrug" refers to any agent (e.g., any of the fumonisin derivatives described herein) that is completely or partially converted into the target compound when administered to a mammal. In some embodiments, the prodrug of the compound (e.g., any of the fumonisin derivatives described herein) is also a pharmaceutically acceptable salt of the compound.

[0542] It will be understood that the compounds of this disclosure can also be prepared into esters, such as pharmaceutically acceptable esters. For example, the carboxylic acid functional group in the compound can be converted into its corresponding ester, such as methyl ester, ethyl ester, or other esters. The alcohol group in the compound can also be converted into its corresponding ester, such as acetate, propionate, or other esters.

[0543] The compound or a pharmaceutically acceptable salt thereof may be administered orally, nasally, transdermally, pulmonaryly, by inhalation, buccally, sublingually, intraperitoneally, subcutaneously, intramuscularly, intravenously, rectally, intrapleurally, intrathecally, or parenterally. In one embodiment, the compound is administered orally. Those skilled in the art will recognize the advantages of certain routes of administration.

[0544] The dosage regimen of the compound is selected based on a number of factors, including patient type, species, age, weight, body surface area (BSA), sex, and medical condition; the severity of the condition to be treated; route of administration; patient's renal and hepatic function; and the specific compound or its salt used. A general practitioner or veterinarian can readily determine and prescribe the effective amount of the drug required to prevent, counteract, or halt disease progression.

[0545] The techniques for formulating and administering the disclosed compounds described herein can be found in Remington: The Science and Practice of Pharmacy, 19th Edition, Mack Publishing Co., Easton, PA (1995). In one embodiment, the compounds described herein, and their pharmaceutically acceptable salts, are combined with a pharmaceutically acceptable carrier or diluent for use in a pharmaceutical formulation. Suitable pharmaceutically acceptable carriers include inert solid fillers or diluents and sterile aqueous or organic solutions. The compounds will be present in such pharmaceutical compositions in an amount sufficient to provide the desired dose within the range described herein.

[0546] Other features and advantages of this disclosure will be apparent from the various embodiments. The provided embodiments illustrate different components and methodologies useful in practicing this disclosure. The embodiments do not limit the claimed disclosure. Based on this disclosure, those skilled in the art can identify and employ other components and methods useful in practicing this disclosure.

[0547] In the synthetic schemes described herein, compounds may be drawn using a specific configuration for the sake of brevity. Such a specific configuration should not be construed as limiting this disclosure to one or more isomers, tautomers, regioisomers, or stereoisomers, nor does it exclude mixtures of isomers, tautomers, regioisomers, or stereoisomers; however, it will be understood that a given isomer, tautomer, regioisomer, or stereoisomer may have a higher level of activity than another isomer, tautomer, regioisomer, or stereoisomer.

[0548] Once compounds designed, selected, and / or optimized using the methods described above are generated, they can be characterized using a variety of assays known to those skilled in the art to determine whether the compounds possess biological activity. For example, the molecules can be characterized by conventional assays, including but not limited to those described herein, to determine whether they possess predicted or unexpected activity, target-binding activity, and / or binding specificity.

[0549] Furthermore, high-throughput screening can be used to accelerate analyses using such assays. As a result, the activity of molecules described herein can be rapidly screened using techniques known in the art. General methods for performing high-throughput screening are described, for example, in Devlin (1998) High Throughput Screening, Marcel Dekker; and U.S. Patent No. 5,763,263. High-throughput assays can be performed using one or more different assay techniques, including but not limited to those described below. Example

[0550] Example 1

[0551] The following are non-limiting examples demonstrating that the MetAP2 inhibitor and CDK4 / 6 inhibitor of this disclosure can be used in combination to treat cancer. Furthermore, the following non-limiting examples demonstrate that the combination of the MetAP2 inhibitor and CDK4 / 6 inhibitor of this disclosure unexpectedly exhibits superior antitumor activity compared to using either agent alone.

[0552] In the following experiments, mice carrying MCF-7 tumors were treated with a vector control, compound 1 alone, palbociclib alone, or a combination of compound 1 and palbociclib. Three days prior to cell inoculation, female nude mice (Charles River) were first implanted with a 90-day (0.72 mg) β-estradiol pellet. MCF-7 cells (5 x 10⁻⁶) were then... 6 One sample (in 1:1 PBS / Matrigel) was injected into the fourth mammary gland of mice. The average tumor volume in the group was 125-175 mm. 3 And no tumor <100mm 3 At that time, quantitative administration of various therapeutic agents began. Throughout the experiment, tumor volume and body weight were measured twice weekly, and general observations were made daily. At the end of the study, whole blood was collected from the treated mice via cardiac puncture for complete blood cell count (CBC). Furthermore, tumors from the mice were dissected and analyzed.

[0553] The experimental design is summarized in Table 2.

[0554] Table 2.

[0555]

[0556] The first group of mice (group #1) were administered the medium via oral feeding once daily (QD) from day 2 of the study until the end of the study.

[0557] Compound 1 was administered to mice in the second group (group #2) via subcutaneous injection every 4 days (Q4D) at a dose of 8 mg / kg from day 1 of the study until the end of the study.

[0558] Compound 1 was administered to mice in group 3 (group #3) via subcutaneous injection every 4 days at a dose of 8 mg / kg from day 1 of the study until the end of the study, and palbociclib was administered via oral tube feeding once daily (QD) at a dose of 20 mg / kg from day 2 of the study until the end of the study.

[0559] Compound 1 was administered to mice in group 4 (group #4) via subcutaneous injection every 4 days from day 1 of the study until the end of the study, and palbociclib was administered via oral feeding once daily (QD) at a dose of 40 mg / kg from day 2 of the study until the end of the study.

[0560] From day 2 of the study until the end of the study, mice in group 5 (group #5) were administered palbociclib once daily (QD) at a dose of 20 mg / kg via oral tube feeding.

[0561] From day 2 of the study until the end of the study, mice in group 6 (group #6) were given palbociclib once daily (QD) at a dose of 40 mg / kg via oral tube feeding.

[0562] Compound 1 was dissolved in a 5% mannitol aqueous solution (w / v), sterile filtered, and then administered to mice via subcutaneous injection.

[0563] Palbociclib was dissolved in lactate buffer (50 mM, pH 4.0), sterile filtered, and then administered to mice via oral feeding.

[0564] Figure 1 The analysis of MCF tumor volume during the study is shown. Figure 2 The MCF tumor volume is shown at the end of the study (day 31). (As shown in...) Figure 1 and Figure 2 As shown, the combination of compound 1 (Cmpd.1) and palbociclib resulted in a greater reduction in tumor volume compared to compound 1 alone or palbociclib alone.

[0565] Figure 3 The changes in body weight were shown for each experimental group.

[0566] Figure 4 It shows the survival percentage of each experimental group during the study.

[0567] As those skilled in the art will understand, several genetic and cellular pathways are involved in acquired resistance to CDK4 / 6 inhibitors such as palbociclib and reboxiclib, including but not limited to cyclin E1, CDK2, CDK4, Akt signaling, autophagy pathways, and cancer stem cell initiation pathways. For this purpose, the expression levels of various proteins were analyzed in tumor samples collected at the end of the study to determine how administration of the combination of the MetAP2 inhibitor and the CDK4 / 6 inhibitor disclosed herein might affect the expression of various proteins involved in CDK4 / 6 inhibitor resistance.

[0568] Figure 5 The expression levels of cyclin D1 protein in tumor samples collected at the end of the study in each experimental group are shown.

[0569] Figure 6 The expression levels of cyclin E1 protein in tumor samples collected at the end of the study in each experimental group are shown. As a skilled technician will understand, cyclin E1 expression levels in metastatic breast cancer have been associated with response to palbociclib. Specifically, in clinical trials in women with ER+ / Her2- metastatic breast cancer, the efficacy of palbociclib + fulvestrant was significantly lower (shorter progression-free survival) when tumors expressed high levels of cyclin E1 compared to tumors with low cyclin E1 expression (Turner, DOI:10.1200 / JCO.18.00925 Journal of Clinical Oncology 37, Vol.14 (May 10, 2019) 1169-1178.).

[0570] Figure 7 The expression levels of cyclin E2 protein in tumor samples collected at the end of the study in each experimental group are shown. (See also...) Figure 7 As shown, compared with the mediator control, treatment with compound 1 alone or palbociclib alone, the combination therapy with compound 1 and palbociclib resulted in lower levels of cyclin E2 protein in tumor samples. As those skilled in the art will understand, cyclin E2 expression levels are associated with tumor progression in ER+ breast cancer, and shorter overall survival or recurrence-free survival has been observed in patients with high cyclin E2 expression (Sieuwerts, 2006, Clinical Cancer Research 12 3319-3328. (https: / / doi.org / 10.1158 / 1078-0432.CCR-06-0225; Millioli, Endocrine-Related Cancer (2020) 27, R93-R112).

[0571] Figure 8 The expression level of p21 protein in tumor samples collected at the end of the study in each experimental group is shown.

[0572] Figure 9 The expression levels of CDK4 protein in tumor samples collected at the end of the study are shown in each experimental group. (See figure...) Figure 9 As shown, compared with the mediator control, treatment with compound 1 alone or palbociclib alone, the combination therapy with compound 1 and palbociclib resulted in lower levels of CDK4 protein in tumor samples.

[0573] Figure 10 The expression levels of CDK2 protein in tumor samples collected at the end of the study are shown in each experimental group. (See also...) Figure 10 As shown, compared with the mediator control, treatment with compound 1 alone or palbociclib alone, the combination therapy with compound 1 and palbociclib resulted in lower levels of CDK2 protein in tumor samples.

[0574] Figure 11 The expression levels of Rb protein in tumor samples collected at the end of the study in each experimental group are shown. (See figure...) Figure 11 As shown, compared with the mediator control, treatment with compound 1 alone or palbociclib alone resulted in lower levels of Rb protein in tumor samples. As those skilled in the art will understand, Rb protein expression levels in metastatic breast cancer have been associated with response to palbociclib. Specifically, in clinical trials in women with ER+ / Her2- metastatic breast cancer, the efficacy of palbociclib + fulvestrant was significantly lower (shorter progression-free survival) if tumors expressed high levels of Rb protein compared to tumors with low Rb protein expression (Turner, DOI:10.1200 / JCO.18.00925 Journal of Clinical Oncology 37, Vol. 14 (May 10, 2019) 1169-1178.).

[0575] Figure 12The changes in the autophagy protein LC3B measured in tumor tissue at the end of the study are shown. As a skilled technician will understand, LC3B is a marker of autophagy. As a skilled technician will understand, CDK4 / 6 inhibitors can induce autophagy (Vijayaraghavan, S. et al. CDK4 / 6 and autophagy inhibitors synergistically induce senescence in Rb positive cytoplasmic cyclin E negative cancers: Nat. Commun. 8, 15916 doi:10.1038 / ncomms15916 (2017)). Figure 12 As shown, the combination of palbociclib and compound 1 reduces the induction of LC3B autophagy protein.

[0576] Figure 13 The expression levels of Akt protein in tumor samples collected at the end of the study in each experimental group are shown. (See figure...) Figure 13 As shown, compared with the mediator control, treatment with compound 1 alone or palbociclib alone, the combination therapy with compound 1 and palbociclib resulted in lower levels of Akt protein in tumor samples.

[0577] Figure 14 The expression levels of phosphorylated-Akt protein in tumor samples collected at the end of the study in each experimental group are shown. (See figure...) Figure 14 As shown, treatment with either compound 1 alone or in combination with a high dose of palbociclib resulted in lower levels of phosphorylated-Akt protein compared to the combination of compound 1 with a low dose of palbociclib and palbociclib alone.

[0578] Figure 15 The expression levels of estrogen receptor α (ERα)-62 kDa protein in tumor samples collected at the end of the study in each experimental group are shown. (See also...) Figure 15 As shown, combination therapy with compound 1 and palbociclib resulted in a decrease in ERα-62kDa protein levels.

[0579] Figure 16 The expression levels of ERα-55kDa protein in tumor samples collected at the end of the study in each experimental group are shown. (See also...) Figure 16 As shown, combination therapy with compound 1 and 20 mg / kg palbociclib resulted in a decrease in ERα-55kDa protein levels, which was greater than the decrease in ERα-55kDa protein levels after treatment with 20 mg / kg palbociclib alone.

[0580] Figure 17The sum of expression levels of ERα-55kDa and ERα-62kDa proteins in tumor samples collected at the end of the study in each experimental group is shown.

[0581] Figure 18 The expression levels of PHGDH protein in tumor samples collected at the end of the study in each experimental group are shown. (See figure...) Figure 18 As shown, combination therapy with compound 1 and palbociclib resulted in a decrease in PHGDH protein levels that was greater than the decrease in PHGDH protein levels after treatment with compound 1 alone or palbociclib alone.

[0582] Figure 19 This shows the number of neutrophils in whole blood collected at the end of the study in each experimental group. (As shown in...) Figure 19 As shown, palbociclib alone and SDX-7320 reduced neutrophil levels by 30-40% compared to mice treated with the vector, while the combination of SDX-7320 and palbociclib (40 mg / kg) increased neutrophils by 49% compared to mice treated with the vector. As those skilled in the art will understand, neutropenia is a major side effect of palbociclib. Therefore, not wishing to be bound by theory, these results indicate that the combination of compound 1 and palbociclib may alleviate palbociclib-induced neutropenia, thereby providing an improved hematological safety profile.

[0583] The results presented in this embodiment demonstrate that the combination of the MetAP2 inhibitor of this disclosure with a CDK4 / 6 inhibitor (more specifically, palbociclib) can be used to treat cancer and prevent CDK4 / 6 therapy resistance. Furthermore, the results presented in this embodiment demonstrate that the combination of the MetAP2 inhibitor and CDK4 / 6 inhibitor of this disclosure induces gene expression changes consistent with increased patient survival and decreased CDK4 / 6 inhibitor resistance levels. Not to be bound by theory, these gene expression changes demonstrate that administration of the combination of the MetAP2 inhibitor and CDK4 / 6 inhibitor of this disclosure can overcome existing limitations of CDK4 / 6 inhibitor therapy.

[0584] Example 2

[0585] The following are non-limiting examples demonstrating that the MetAP2 inhibitor and CDK4 / 6 inhibitor of this disclosure can be used in combination for the treatment of cancer. Furthermore, the following non-limiting examples demonstrate that the combination of the MetAP2 inhibitor and CDK4 / 6 inhibitor of this disclosure exhibits unexpectedly superior antitumor activity compared to using either agent alone. As those skilled in the art will understand, several gene and cellular pathways have been involved in acquired resistance to CDK4 / 6 inhibitors such as palbociclib and reboxil, including but not limited to cyclin E1, CDK2, CDK4, Akt signaling, autophagy pathways, and cancer stem cell initiation pathways. For this purpose, the expression levels of various proteins were analyzed in tumor samples collected at the end of the study to determine how administration of the combination of the MetAP2 inhibitor and CDK4 / 6 inhibitor of this disclosure might affect the expression of various genes involved in CDK4 / 6 inhibitor resistance.

[0586] Tumor samples from mice treated in Example 1 were subjected to further analysis. Briefly, tumors isolated from mice were placed in RNALater solution and then frozen at -70°C. PolyA+ RNA was then isolated and reverse transcribed into cDNA. The cDNA was then analyzed by sequencing. The sequencing data were aligned against the human genome (GRCh38) to provide relative RNA expression levels for each animal and for each gene mentioned in GRCh38. Statistical analysis was then performed to identify genes and pathways that were uniquely regulated when mice were treated with the combination of compound 1 and palbociclib relative to mice treated with monotherapy.

[0587] As those skilled in the art will understand, gene set enrichment analysis (GSEA) was performed using standard methods in the art. Specifically, the gene set KEGG_ONE_CARBON_POOL_BY_FOLATE was analyzed in tumors from two treatment groups: mice receiving a combination of compound 1 (SC) at 8 mg / kg and palbociclib (PO) at 40 mg / kg, and mice treated with palbociclib (PO) alone at 40 mg / kg. GSEA analysis confirmed that the genes MTHFD1L, TYMS, ALDH1L1, MTHFD1, MTHFD2, GART, SHMT1, DHFR, MTR, SHMT2, and MTFMT were expressed at lower levels in tumors from mice treated with the combination of compound 1 and palbociclib compared to tumors from mice treated with palbociclib alone. As those skilled in the art will understand, the aforementioned genes are biologically related to metabolism.

[0588] Based on the foregoing analysis, the expression levels of genes PHGDH, PSPH, TYMS, MTHFD1L, MTHFD1, MTHFD2, SHMT1, SHMT2 and DHFR were analyzed in tumor samples isolated from each treatment group described in Example 1.

[0589] Figure 20 The expression levels of PHGDH (phosphoglycerate dehydrogenase) in tumor samples collected at the end of the study in each experimental group described in Example 1 are shown. Figure 20 As shown, treatment with the combination of compound 1 and palbociclib resulted in a greater decrease in PHGDH levels compared to treatment with either compound 1 alone or palbociclib alone. As a skilled practitioner will understand, a decrease in PHGDH reduces the de novo synthesis of serine and glycine, which has been shown to be involved in multiple cellular processes in cancer cells (see Zhao X, Fu J, Du J, Xu W. Int J Biol Sci. 2020; 16(9):1495-1506). Furthermore, as in... Figure 30 As shown, an increased risk of recurrence exists in ER+ breast cancer patients with high PHGDH expression levels. Therefore, not wanting to be bound by theory, the decrease in PHGDH expression induced by combination therapy with compound 1 and a CDK4 / 6 inhibitor may help reduce the risk of recurrence and prolong survival in patients with cancers including ER+ breast cancer.

[0590] Figure 21 The expression levels of PSPH (phosphoserine phosphatase) in tumor samples collected at the end of the study in each experimental group described in Example 1 are shown. (As in...) Figure 21 As shown, the combination therapy with compound 1 and palbociclib resulted in a greater decrease in PSPH levels compared to treatment with compound 1 alone or palbociclib alone.

[0591] Figure 22 The expression levels of TYMS (thymidine monophosphate synthase) in tumor samples collected at the end of the study in each experimental group described in Example 1 are shown. Figure 22 As shown, treatment with the combination of compound 1 and palbociclib resulted in a greater decrease in TYMS levels compared to treatment with either compound 1 alone or palbociclib alone. As a skilled practitioner will understand, reduced TYMS1 expression slows the production of pyrimidine nucleotides essential for DNA synthesis and cell growth, particularly in the case of cancer cells. Furthermore, as in... Figure 31As shown, an increased risk of recurrence exists in ER+ breast cancer patients with high TYMS expression levels. Therefore, not wanting to be bound by theory, the TYMS expression reduction induced by combination therapy with compound 1 and a CDK4 / 6 inhibitor may help reduce the risk of recurrence and prolong survival in patients with cancers including ER+ breast cancer.

[0592] Figure 23 The expression levels of MTHFD1L (methylenetetrahydrofolate dehydrogenase-like 1) in tumor samples collected at the end of the study in each experimental group described in Example 1 are shown. Figure 23 As shown, treatment with a combination of compound 1 and a higher dose of palbociclib resulted in a greater decrease in MTHFD1L levels compared to treatment with either high or low doses of palbociclib. Treatment with compound 1 alone resulted in an increase in MTHFD1L expression.

[0593] Figure 24 The expression levels of MTHFD1 (methylenetetrahydrofolate dehydrogenase) in tumor samples collected at the end of the study in each experimental group described in Example 1 are shown. Figure 24 As shown, treatment with a combination of compound 1 and a higher dose of palbociclib resulted in a greater decrease in MTHFD1 levels compared to treatment with compound 1 alone or palbociclib alone.

[0594] Figure 25 The expression levels of MTHFD2 (methylenetetrahydrofolate dehydrogenase (NADP+ dependent) 2) in tumor samples collected at the end of the study in each experimental group described in Example 1 are shown. Figure 25 As shown, combination therapy with compound 1 and a higher dose of palbociclib resulted in a greater decrease in MTHFD2 levels compared to treatment with a higher dose of palbociclib alone. Treatment with compound 1 alone and a lower dose of palbociclib resulted in an increase in MTHFD2 expression.

[0595] Figure 26 The expression levels of SHMT1 (serine hydroxymethyltransferase 1) in tumor samples collected at the end of the study in each experimental group described in Example 1 are shown. Figure 26 As shown, the combination therapy of compound 1 and palbociclib resulted in a greater decrease in SHMT1 levels compared to treatment with palbociclib alone.

[0596] Figure 27 The expression levels of SHMT2 (serine hydroxymethyltransferase 2) in tumor samples collected at the end of the study in each experimental group described in Example 1 are shown. Figure 27As shown, combination therapy with compound 1 and a higher dose of palbociclib resulted in a greater decrease in SHMT2 levels compared to treatment with palbociclib alone. Treatment with compound 1 alone resulted in an increase in SHMT2 expression.

[0597] Figure 33 The expression levels of DHFR (dihydrofolate reductase) in tumor samples collected at the end of the study in each experimental group described in Example 1 are shown. Figure 33 As shown, treatment with a combination of compound 1 and a higher dose of palbociclib resulted in a greater decrease in DHFR levels compared to treatment with a higher dose of palbociclib alone and compound 1 alone.

[0598] Furthermore, sequencing analysis of tumor samples revealed that the enzymes 3-phosphoglycerate dehydrogenase (PHGDH) and thymidine synthase (TYMS) were downregulated in tumors from mice treated with a combination of compound 1 and palbociclib, compared to tumors from mice treated with compound 1 alone. Without being bound by theory, and as those skilled in the art will understand, reduced PHGDH decreases the de novo synthesis of serine and glycine, known to be dependent on the synthesis of multiple cellular processes in cancer cells, and reduced expression of the enzyme TS slows the production of purine nucleotides essential for DNA synthesis and cell growth.

[0599] The expression levels of genes in the PI3K pathway were also analyzed in tumor samples isolated from each treatment group described in Example 1.

[0600] Figure 28 The expression levels of PIK3IP1 in tumor samples collected at the end of the study in each experimental group described in Example 1 are shown. (As in...) Figure 28 As shown, combination therapy with compound 1 and a higher dose of palbociclib resulted in a significant increase in PIK3IP1 expression compared to treatment with either compound 1 alone or palbociclib alone. As a skilled practitioner will understand, PIK3IP1 is an endogenous PI3K inhibitor and a tumor development suppressor protein (see He X, Zhu Z, Johnson C et al. Cancer Res. 2008; 68(14):5591-5598). Therefore, combination therapy with compound 1 and palbociclib unexpectedly led to increased expression of the tumor suppressor protein. As shown in... Figure 32 As shown, there is an increased risk of recurrence in ER+ breast cancer patients with low PIK3IP1 expression levels. Therefore, not wanting to be bound by theory, the increased PIK3IP1 expression induced by combination therapy with compound 1 and a CDK4 / 6 inhibitor may help reduce the risk of recurrence and prolong survival in patients with ER+ breast cancer.

[0601] Figure 29 The expression levels of Greb1 in tumor samples collected at the end of the study in each experimental group described in Example 1 are shown. (As in...) Figure 29 As shown, combination therapy with compound 1 and a higher dose of palbociclib resulted in a greater decrease in Greb1 levels compared to treatment with palbociclib alone. Treatment with compound 1 alone resulted in an increase in Greb1 expression. As those skilled in the art will understand, Greb1 is known to be an estrogen-regulated growth promoter in breast cancer and has been shown in vitro to be a PI3K activator (see Haines et al., Carcinogenesis, 2020, Vol. 41, No. 12, 1660-1670). Therefore, combination therapy with compound 1 and palbociclib unexpectedly led to a decrease in the expression of the tumor promoter.

[0602] In addition to the genes mentioned above, genes in the OnctoType 21 gene set for breast cancer recurrence were also analyzed (see Paik, 2004, NEJM, 351(27):2817-26). These genes include MybL2, Ki-67, BIRC5 / survivin, CCNB1 / cyclin B1, and SCUBE2.

[0603] Figure 34 The expression levels of MybL2 (MYB proto-oncogene-like 2) in tumor samples collected at the end of the study in each experimental group described in Example 1 are shown. Figure 34 As shown, compared with treatment with palbociclib alone, combination therapy with compound 1 and a higher dose of palbociclib resulted in a greater decrease in MybL2 levels.

[0604] Figure 35 The expression levels of BIRC5 / survivin (containing baculovirus IAP repeat 5) in tumor samples collected at the end of the study in each experimental group described in Example 1 are shown. Figure 35 As shown, treatment with a combination of compound 1 and a higher dose of palbociclib resulted in a greater decrease in BIRC5 / survivin levels compared to treatment with palbociclib alone and compound 1 alone.

[0605] Figure 36 The expression levels of Ki-67 in tumor samples collected at the end of the study in each experimental group described in Example 1 are shown. (As in...) Figure 36 As shown, compared with treatment using palbociclib alone and compound 1 alone, combination therapy using compound 1 and a higher dose of palbociclib resulted in a greater decrease in Ki-67 levels.

[0606] Figure 37The expression levels of CCNB1 / cyclin B1 in tumor samples collected at the end of the study in each experimental group described in Example 1 are shown. Figure 37 As shown, compared with treatment using palbociclib alone and compound 1 alone, combination therapy using compound 1 and a higher dose of palbociclib resulted in a greater decrease in CCNB1 / cyclin B1 levels.

[0607] Figure 38 The expression levels of SCUBE2 in tumor samples collected at the end of the study in each experimental group described in Example 1 are shown. (As in...) Figure 38 As shown, combination therapy with compound 1 and a higher dose of palbociclib resulted in a greater increase in SCUBE2 levels compared to treatment with palbociclib alone and compound 1 alone. As will be understood by a skilled technician, SCUBE2 is a tumor suppressor protein that plays a role in breast cancer through coordinated inhibition of BMP and β-catenin signaling pathways (see Cheng, Cancer Res 2009 April 15 (69)(8) 3634-3641).

[0608] In addition to the genes mentioned above, several other genes that regulate cell proliferation, cell metabolism, cell metastasis, and / or cell viability were analyzed.

[0609] Figure 39 The expression levels of RRM2, a subunit of ribonucleotide reductase (RNR), are shown in tumor samples collected at the end of the study in each experimental group described in Example 1. Figure 39 As shown, treatment with a combination of compound 1 and palbociclib resulted in a greater decrease in RRM2 levels compared to treatment with palbociclib alone and compound 1 alone. As a skilled practitioner will understand, several chemotherapeutic agents inhibit the activity of RNRs, establishing them as drug targets in cancer treatment.

[0610] Figure 40 The expression levels of PCLAF (PCNA-associated factor) in tumor samples collected at the end of the study in each experimental group described in Example 1 are shown. (As in...) Figure 40 As shown, combination therapy with compound 1 and a higher dose of palbociclib resulted in a greater decrease in PCLAF levels compared to treatment with palbociclib alone and compound 1 alone. As a skilled technician will understand, PCLAF expression is elevated in breast cancer and is associated with cancer stem cell (CSC) characteristics (CSC is associated with early recurrence of the disease) and with poorer patient outcomes (see Wang, Nat Commun. 2016; 7:10633).

[0611] Figure 41 The expression levels of SLC7A5 / LAT1 in tumor samples collected at the end of the study in each experimental group described in Example 1 are shown. (As in...) Figure 41 As shown, combination therapy with compound 1 and a higher dose of palbociclib resulted in a greater decrease in SLC7A5 / LAT1 levels compared to treatment with palbociclib alone. Furthermore, treatment with compound 1 alone resulted in an increase in SLC7A5 / LAT1 expression. As those skilled in the art will understand, SLC7A5 / LAT1 is an amino acid transporter that is upregulated in ER+ breast cancer. Higher expression is associated with the development of resistance to endocrine therapy and a significantly higher risk of breast cancer recurrence (see Mihaly, Breast Cancer ResTreat. 2013; 140:219-232 and El Ansari et al. Breast Cancer Research (2018)).

[0612] 20(1):21).

[0613] Figure 42 The expression levels of SLC3A2 in tumor samples collected at the end of the study in each experimental group described in Example 1 are shown. (As in...) Figure 42 As shown, combination therapy with compound 1 and a higher dose of palbociclib resulted in a greater decrease in SLC3A2 levels compared to treatment with palbociclib alone. Furthermore, treatment with compound 1 alone resulted in an increase in SLC3A2 expression. As those skilled in the art will understand, SLC3A2 binds to SLC7A5 to form a functional amino acid transporter complex.

[0614] Figure 43 The expression levels of EVL (Ena-VASP-like) in tumor samples collected at the end of the study in each experimental group described in Example 1 are shown. (As in...) Figure 43 As shown, the combination therapy with compound 1 and palbociclib resulted in a greater increase in EVL levels compared to treatment with palbociclib alone. As a skilled technician will understand, EVL is an actin-binding protein that regulates the cytoskeleton of cells. EVL, along with profilin-2, inhibits metastatic behavior in breast cancer, and patients with the lowest EVL expression have a significantly higher risk of adverse outcomes (see Padilla-Rodriguez, Nat Commun. 2018; 9(1):2980 and Mouneimne, Cancer Cell. 2012; 22(5):615-630).

[0615] Figure 44The expression levels of ANP32E (acidic leucine-rich nucleophosphorus protein 32) in tumor samples collected at the end of the study in each experimental group described in Example 1 are shown. (As in...) Figure 44 As shown, combination therapy with compound 1 and a higher dose of palbociclib resulted in a greater decrease in ANP32E levels compared to treatment with palbociclib alone and compound 1 alone. As will be understood by those skilled in the art, ANP32E is a specific histone chaperone protein of the variant histone protein H2AZ1, removing H2AZ1 from DNA. Increased ANP32E expression in breast cancer is associated with metastasis and worse outcomes relative to tumors with lower expression (see Obri, Nature, 2014, 505:648-653; Xiong, Molecular Oncology, 2018, 12:896-912).

[0616] Figure 45 The expression levels of H2AZ1 in tumor samples collected at the end of the study in each experimental group described in Example 1 are shown. (As in...) Figure 45 As shown, combination therapy with compound 1 and a higher dose of palbociclib resulted in a greater decrease in ANP32E levels compared to treatment with palbociclib alone and compound 1 alone. As a skilled technician will understand, H2AZ1 promotes cell proliferation by regulating cyclin transcription and also regulates epithelial-mesenchymal transition (EMT), a cellular mechanism that initiates metastasis. H2AZ1 expression is upregulated in many cancers, including breast cancer, and elevated expression is associated with adverse outcomes in breast cancer (see Quénet D., Int Rev Cell MolBiol. 2018; 335:1-39).

[0617] Figure 46 The expression levels of H2AX in tumor samples collected at the end of the study in each experimental group described in Example 1 are shown. (As in...) Figure 46 As shown, combined treatment with compound 1 and a higher dose of palbociclib resulted in a greater decrease in H2AX levels compared to treatment with palbociclib alone and compound 1 alone. As will be understood by those skilled in the art, H2AX is known for its role in the response to DNA damage and in the formation of the mitotic spindle assembly, which regulates the mitotic process during cell division. Lower levels of H2AX can lead to chromosomal aberrations, increased sensitivity to radiation, and impaired response to double-strand breaks (DSBs) in DNA (see Ferrand, Cells, 2020; 9(11):2424).

[0618] The results presented in this embodiment confirm that the combination of the MetAP2 inhibitor and the CDK4 / 6 inhibitor of this disclosure can be used to treat cancer, as combined treatment with the MetAP2 inhibitor and the CDK4 / 6 inhibitor resulted in changes in gene expression associated with tumor reduction, metastasis reduction, and increased patient survival. Not wishing to be bound by theory, these changes in gene expression confirm that administration of the combination of the MetAP2 inhibitor and the CDK4 / 6 inhibitor of this disclosure can overcome existing limitations of CDK4 / 6 inhibitor therapy. More specifically, the above results confirm that the combination of compound 1 and the CDK4 / 6 inhibitor resulted in a surprisingly greater decrease in gene expression on which tumor cell survival and metastasis depend, which was not observed after treatment with either compound alone. As those skilled in the art will understand, this effect on gene expression following administration of both compound 1 and the CDK4 / 6 inhibitor can contribute to increased tumor reduction.

[0619] Example 3

[0620] The following are non-limiting examples demonstrating that the MetAP2 inhibitor and CDK4 / 6 inhibitor of this disclosure can be used in combination for the treatment of cancer. Furthermore, the following non-limiting examples demonstrate that the combination of the MetAP2 inhibitor and CDK4 / 6 inhibitor of this disclosure exhibits unexpectedly superior antitumor activity compared to using a MetAP2 inhibitor alone.

[0621] In the following experiments, mice carrying MCF-7 tumors were treated with a mediator control, compound 1 alone, reboxil alone, or a combination of compound 1 and reboxil.

[0622] MCF-7 cells were cultured in DMEM supplemented with 10% FBS. On the day of implantation, cells were washed once with phosphate-buffered saline (PBS). After washing, the cell pellet was centrifuged (1000 rpm, room temperature, 5 min) and then counted using a hemocytometer. Cells were counted at 5 x 10⁻⁶ cells per mouse. 6 The cell concentrations were resuspended in an appropriate amount of PBS and 1:1 Matrigel. The suspension was kept on ice until implantation. 48 hours before cell implantation, 17-β estradiol pellets (0.36 mg 60-day sustained-release pellets) were subcutaneously implanted between the scapulae of each female Nu / j mouse.

[0623] Mice were anesthetized in the induction chamber using a combination of 4% isoflurane and 2.5 L / min O2. Once anesthetized, the mice were placed ventrally upwards and anesthesia was maintained via a suitable nasal cone. MCF-7 cell suspensions were prepared with 5 x 10⁻⁶ cells of O2. 6 One cell per mouse, or 100 μl, was injected into the mammary fat pad.

[0624] Starting 5 days after cell implantation, measurements were recorded using a wireless digital diameter measuring device combined with UWAVE-R, with tumor (length x width) measured twice weekly. Once the average tumor volume reached approximately 50 mm... 3 ((length x width) 2 Animals were randomly assigned to six treatment groups of 10 mice each, based on their average tumor volume (π / 6).

[0625] The first day of treatment was designated "Day 1". Mice were administered the drug subcutaneously (SC), orally (PO), or via both routes of administration, as summarized in Table 3 for the designed experiments. Dosage was calculated based on individual body weight.

[0626] Table 3.

[0627]

[0628]

[0629] The first group of mice (group #1) were given the medium via oral administration once daily (QD) as a control.

[0630] Compound 1 was administered to the second group of mice (group #2) via subcutaneous injection every 4 days (Q4D) at a dose of 8 mg / kg.

[0631] Compound 1 was administered to mice in the third group (group #3) via subcutaneous injection at a dose of 8 mg / kg every 4 days and via oral administration at a dose of 35 mg / kg once daily (QD).

[0632] Compound 1 was administered to mice in group 4 (group #4) via subcutaneous injection at a dose of 8 mg / kg every 4 days and via oral administration at a dose of 70 mg / kg once daily (QD).

[0633] Reboxil was administered orally to mice in group 5 (group #5) at a dose of 35 mg / kg once daily (QD).

[0634] Reboxil was administered orally to mice in group 6 (group #6) at a dose of 70 mg / kg once daily (QD).

[0635] During the study period, body weight and tumor measurements were recorded twice weekly. Quantitative administration and measurements were performed until the tumor reached 1000 mm. 3Mice were euthanized when the maximum volume of blood sample was reached or an adverse health event was observed (e.g., >20% weight loss, extreme lethargy, tumor necrosis, etc.). Following euthanasia, the maximum volume of terminal blood sample was obtained via cardiac puncture. For half of the mice, 200 μL was aliquoted into K2EDTA MiniCollect tubes for plasma separation, and 420 μL into MiniCollect serum separation tubes for clinical chemistry analysis. For the other half of the mice, >200 μL of blood was collected into K2EDTA MiniCollect tubes (LTT) for CBC analysis. The MiniCollect blood tubes used for plasma and serum were centrifuged at 8000 rpm for 5 minutes. Plasma was retained at -80°C for biomarker analysis, and serum and whole blood were subjected to further analysis (LTT). Additionally, tumors from the mice were dissected, weighed, and divided into two halves. One half of the tumors was placed in buffered formalin and stored at room temperature. The other half of the tumors was rapidly frozen in liquid nitrogen and stored at -80°C. The adipose tissue (abdominal pelvis, retroperitoneum, and groin) was also dissected and weighed. Finally, a preliminary autopsy was performed to examine for tumor metastases (lungs, liver, lymph nodes).

[0636] Table 4 shows the tumor growth inhibition (TGI%) measured on day 14 of the study in each treatment group. As shown in Table 4, combination therapy with compound 1 and a low dose of reboxil resulted in 63% tumor growth inhibition, while combination therapy with compound 1 and a high dose of reboxil resulted in 72% tumor growth inhibition. Figure 47 The analysis of MCF tumor volume during the first 14 days of the study is shown. Figure 48 The MCF tumor volume is shown on day 14 of the study.

[0637] Table 4

[0638] Experimental group number TGI% 1 - 2 41 3 63 4 72 5 57 6 70

[0639] On day 16 of the study, mice in experimental groups 3, 4, 5, and 6 received 10 times the dose of reboxil shown in Table 3. That is, mice in experimental groups 2 and 5 received 350 mg / kg of reboxil, and mice in experimental groups 4 and 6 received 700 mg / kg of reboxil. On day 17, mice in experimental groups 3, 4, 5, and 6 received the dose of reboxil shown in Table 3. On day 18, tumors in the mice were measured. Table 5 shows the tumor growth inhibition (TGI%) as measured on day 18 of the study in each treatment group. As shown in Table 5, treatment using the combination of compound 1 and a low dose of reboxil resulted in 71% tumor growth inhibition, and treatment using the combination of compound 1 and a high dose of reboxil resulted in 79% tumor growth inhibition. Figure 49The analysis of MCF tumor volume during the first 18 days of the study is shown. Figure 50 The MCF tumor volume is shown on day 18 of the study.

[0640] Table 5

[0641] Experimental group number TGI% 1 - 2 44 3 71 4 79 5 60 6 70

[0642] The results presented in this embodiment confirm that the combination of the MetAP2 inhibitor of this disclosure with a CDK4 / 6 inhibitor (more specifically, reboxil) can be used to treat cancer and prevent CDK4 / 6 treatment resistance.

Claims

1. Use in the manufacture of a medicament for the treatment of breast cancer, comprising at least one MetAP2 inhibitor or a pharmaceutically acceptable salt thereof and at least one CDK 4 / 6 inhibitor or a pharmaceutically acceptable salt thereof. The at least one MetAP2 inhibitor is (Compound 1), or its pharmaceutically acceptable salt, wherein x is in the range of 1 to about 450, y is in the range of 1 to about 30, and n is in the range of 1 to about 100. The CDK4 / 6 inhibitor mentioned therein is palbociclib, or a pharmaceutically acceptable salt thereof.

2. The use according to claim 1, wherein the at least one MetAP2 inhibitor or a pharmaceutically acceptable salt thereof and the at least one CDK4 / 6 inhibitor or a pharmaceutically acceptable salt thereof are administered simultaneously or close in time.

3. The use as described in any of the preceding claims, wherein the ratio of x to y is in the range of about 30:1 to about 3:

1.

4. The use as claimed in claim 3, wherein the ratio of x to y is approximately 11:

1.

5. The use as described in any of the preceding claims, wherein the MetAP2 inhibitor is for administration by subcutaneous injection.

6. The use as described in any of the preceding claims, wherein the CDK4 / 6 inhibitor is for oral administration.

7. The use according to any one of the preceding claims, wherein the breast cancer is selected from... i) HR+HER2- breast cancer; ii) ER+ breast cancer; iii) HER2-negative breast cancer; iv) Luminal type A breast cancer; v) Luminal type B breast cancer; vi) Triple-negative breast cancer; vii) Basal-like breast cancer; viii) HER2-enriched breast cancer.

8. The use as described in any of the preceding claims, wherein the breast cancer is metastatic breast cancer.

9. The use according to any one of the preceding claims, wherein the MetAP2 inhibitor is administered in the following amounts: i) Approximately 27 mg / m 2 ; ii) Approximately 36 mg / m 2 ; iii) Approximately 49 mg / m 2 ;or iv) Approximately 65 mg / m 2 .

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