Patent Application
20230061432
The Sequence Listing submitted Mar. 6, 2020 as a text file named “21105_0066P1_ST25.txt,” created on Feb. 29, 2020, and having a size of 8,049 bytes is hereby incorporated by reference pursuant to 37 C.F.R. § 1.52(e)(5).
Microtubules are cellular structures important for normal cellular metabolism, cellular transport, and cell division. Interrupting microtubule dependent processes causes cellular effects including inhibition of proliferation and cellular trafficking which, in turn, lead to initiation of cell death pathways. Microtubule disrupting agents such as microtubule stabilizers are one of the most important classes of anticancer therapeutics used in the clinic today. Additionally, microtubule stabilizers are used in other human diseases of hyperproliferation including, but not limited to, cardiovascular disease, where they are used to coat stents. The taxoid microtubule stabilizer paclitaxel (Taxol™) has been widely used in the treatment of solid tumors including breast, ovarian, and lung cancers, for over a decade as a single agent and in combination with targeted therapies. In spite of their clinical utility, the shortcomings of paclitaxel and the second generation semi-synthetic taxoid, docetaxel (Taxotere™), include innate and acquired drug resistance and dose-limiting toxicities (Fojo and Menefee, 2007). Two new microtubule stabilizers have recently been approved for clinical use—the epothilone ixabepilone (Ixempra) and the taxoid cabazitaxel (Jevtana), which circumvent some, but not all, of the shortcomings of first and second generation microtubule stabilizers (Morris and Fornier, 2008; Galsky et al., 2010; Shen et al., 2011). These microtubule stabilizing drugs all bind to the interior lumen of the intact microtubule at the taxoid binding site, which causes a stabilization of microtubule protofilament interactions and thereby decreases the dynamic nature of microtubules (Nogales et al., 1995).
Two additional classes of microtubule stabilizers have been isolated from nature: laulimalides/peloruside A and the taccalonolides. Laulimalide and peloruside A have recently been shown to bind to the exterior of the microtubule at a site distinct from the taxoid binding site, but result in microtubule stabilization effects nearly identical to the toxoids (Bennett et al., 2010). The microtubule stabilizing properties of the taccalonolides A, E, B, and N, together with their ability to overcome multiple clinically relevant mechanisms of drug resistance (Risinger et al. 2008) prompted further interest in identifying new taccalonolides.
Intense efforts over the past three decades have identified a large variety of interesting chemical compounds from the roots and rhizomes of Tacca species, including 25 taccalonolides, denoted as taccalonolides A-Y (Chen et al. 1987; Chen et al. 1988; Shen et al. 1991; Shen et al. 1996; Chen et al. 1997; WO/2001/040256; Huang and Liu 2002; Muhlbauer et al. 2003; Yang et al. 2008). However, there have been limited biological studies on the taccalonolides. In 2003, microtubule stabilizing activities of taccalonolides A and E were reported (Tinley et al. 2003). Follow-up studies showed preliminary structure-activity relationships (SARs) for the antiproliferative activities of taccalonolides A, E, B, and N. The antiproliferative potencies of these four taccalonolides in HeLa cells were all in the mid-nanomolar range (190 nM to 644 nM) (Risinger et al. 2008) and further studies showed that the taccalonolides A, E, and N have in vivo antitumor activity (Peng et al. 2011). The discovery that the C22,23 double bond in the naturally occurring taccalonolides could be epoxidated semi-synthetically led to the identification that this epoxide facilitated the direct, covalent interaction of the taccalonolides with tubulin/microtubules (Li et al. 2011; Risinger et al. 2013; Peng et al. 2014). Taccalonolides bearing this C22,23 epoxide have potency in the low nanomolar range and it is proposed that the activity of non-epoxidated compounds previously reported is due to minor amounts of epoxidated species present. However, a full understanding of the structure-activity relationships of the taccalonolides remains to be elucidated. Given that the biological activity profiles of known taccalonolides vary, and in view of the wide variety of diseases that may be treated or prevented with compounds having potent microtubule stabilization effects, and the high degree of unmet medical need represented within this variety of diseases, it is desirable to synthesize new compounds with diverse structures that may have improved biological activity profiles for the treatment of one or more indications and to generate tagged taccalonolide probes that retain functionality, both for use as a biological probe and as a means to target the taccalonolide to the desired site of action. These needs and others are met by the present invention.
In accordance with the purpose(s) of the invention, as embodied and broadly described herein, the invention, in one aspect, relates to taccalonolide microtubule stabilizers useful as cellular probes (e.g., for the detection, visualization, and/or quantification of a target). Such compounds are also useful in the treatment of hyperproliferative disorders including, but not limited to, cardiovascular diseases such as, for example, coronary heart disease, stroke, hypertensive heart disease, inflammatory heart disease, and rheumatic heart disease, and cancers such as, for example, sarcoma, a carcinoma, a hematological cancer, a solid tumor, breast cancer, cervical cancer, gastrointestinal cancer, colorectal cancer, brain cancer, skin cancer, prostate cancer, ovarian cancer, thyroid cancer, testicular cancer, pancreatic cancer, endometrial cancer, melanoma, glioma, leukemia, lymphoma, chronic myeloproliferative disorder, myelodysplastic syndrome, myeloproliferative neoplasm, and plasma cell neoplasm (myeloma).
Disclosed are compounds having a structure represented by a formula:
wherein each occurrence of - - - - - - is a single or double covalent bond; wherein X is selected from O, NRx, and C(Rx)2; wherein each occurrence of Rx, when present, is independently selected from hydrogen and C1-C6 alkyl; wherein R1 is selected from hydrogen, halogen, —OH, —CN, —NC, —NCO, —OCN, —NO2, —ONO2, —ONO, —NO, —N3, —NH2, —NH3, —N═NR31, —NHOH, C1-C12 alkyl, C2-C12 alkenyl, C2-C12 alkynyl, C1-C12 hydroxy, C1-C12 alkoxy, C1-C12 thioalkyl, C1-C12 alkylthiol, C1-C12 aminoalkyl, C1-C12 alkylamino, (C1-C12)(C1-C12) dialkylamino, —OC(O)(C1-C12 alkyl), —OP(O)(OR32)2, —OSO2R33, —C(O)(C1-C12 alkyl), —CO2R34, —C(O)NR35aR35b, —(C1-C12 alkyl)C(O)NR35aR35b, —OC(O)NR35aR35b, —(C1-C12 alkyl)OC(O)NR35aR35b, Cy1, Ar1, (C1-C12 alkyl)Ar1, and —OAr1; wherein each occurrence of R31, R32, R34, R35a, and R35b, when present, is independently selected from hydrogen and C1-C12 alkyl; wherein each occurrence of R33, when present, is independently selected from hydrogen, C1-C12 alkyl, and monocyclic aryl monosubstituted with a methyl group; wherein each occurrence of Cy1, when present, is heterocycloalkyl substituted with 0, 1, 2, or 3 groups independently selected from halogen, —OH, —NH2, C1-C4 alkoxy, C1-C4 hydroxy, C1-C4 aminoalkyl, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino; wherein each occurrence of Ar1, when present, is selected from monocyclic aryl, morpholinyl, anilinyl, indolyl, pyrrolyl, imidazolyl, benzimidazolyl, pyrazolyl, guanidinyl, and piperazinyl and substituted with 0, 1, 2, or 3 groups independently selected from halogen, —OH, —NH2, C1-C4 alkoxy, C1-C4 hydroxy, C1-C4 aminoalkyl, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino; and wherein R1′ is hydrogen; or wherein each of R1 and R1′ together comprise ═O or ═NR36; wherein each occurrence of R36, when present, is independently selected from hydrogen and C1-C12 alkyl; wherein each of R2 and R3 is independently selected from hydrogen, —OH, C1-C12 hydroxy, and halogen; or wherein each of R2 and R3 together comprise —O—; wherein R5 is selected from hydrogen, —OH, —NH2, C1-C9 alkyl, C1-C9 hydroxy, C1-C9 alkoxy, C1-C9 aminoalkyl, C1-C6 alkylamino, and (C1-C6)(C1-C6) dialkylamino; or wherein R5 is absent; wherein each of R6 and R6′ is independently selected from hydrogen, halogen, —OH, —CN, —NC, —NCO, —OCN, —NO2, —ONO2, —ONO, —NO, —N3, —NH2, —NH3, —N═NR41, —NHOH, C1-C30 alkyl, C2-C30 alkenyl, C2-C30 alkynyl, C1-C30 hydroxy, C1-C30 alkoxy, C1-C30 thioalkyl, C1-C30 alkylthiol, C1-C30 aminoalkyl, C1-C30 alkylamino, (C1-C30)(C1-C30) dialkylamino, —C(O)(C1-C30 alkyl), —OP(O)(OR32)2, —OSO2R33, —CO2R34, —C(O)NR35aR35b, —(C1-C30 alkyl)C(O)NR35aR35b, —OC(O)NR35aR35b, —(C1-C30 alkyl)OC(O)NR35aR35b, Cy1, Ar1, —(C1-C30 alkyl)Ar1, —OAr1, —OC(O)(C1-C30 alkyl), —OC(O)Ar2, —OC(O)(C1-C30 alkyl)Ar2, —OC(O)Ar3, —OC(O)(C1-C30 alkyl)NR42C(O)Ar3, —OC(O)(C1-C30 alkyl)OC(O)Ar3, —OC(O)R40, —NR41C(O)(C1-C30 alkyl), —NR41C(O)Ar2, —NR41C(O)(C1-C30 alkyl)Ar2, —NR41C(O)Ar3, —NR41C(O)(C1-C30 alkyl)OC(O)Ar3, —NR41C(O)(C1-C30 alkyl)NR42C(O)Ar3, and —NR41C(O)R40; wherein each occurrence of R40, when present, is independently a C1-C30 alkyl functionalized with a group selected from —N3, —SH, —OH, —NH2, —NHOH, an ester, a disulfide, a sulfonamide, a terminal alkyne, haloacetyl, maleimide, isothiocyanate, N-hydroxysuccinimde, an acylhydrazine, an acylhydrazone, a hydrazine, a hydrazone, and hydrazide; wherein each occurrence of R41 and R42, when present, is independently selected from hydrogen and C1-C12 alkyl; wherein each occurrence of Ar2, when present, is independently selected from aryl and heteroaryl, and is substituted with 0, 1, 2, or 3 groups independently selected from halogen, —OH, —NH2, C1-C4 alkoxy, C1-C4 hydroxy, C1-C4 aminoalkyl, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, —(C1-C12 alkyl)Ar4, and Ar4; wherein each occurrence of Ar4, when present, is a structure represented by a formula selected from:
wherein each of R50a, R50b, R50c, and R50d, when present, is independently selected from hydrogen, —F, and —Cl; wherein each of R51a and R51b, when present, is independently selected from hydrogen and —C(O)(C1-C12 alkyl); wherein each of R52a, R52b, R52c, and R52d, when present, is independently selected from hydrogen, —F, and —Cl; wherein each occurrence of Ar3, when present, is a structure represented by a formula selected from:
or wherein one of R6 and R6′ is absent; wherein R7 is selected from hydrogen, —OH, C1-C30 hydroxy, C1-C30 alkoxy, —OC(O)(C1-C30 alkyl), and —OC(O)NR35aR35b, and wherein R7′ is selected from hydrogen, —OH, C1-C30 hydroxy, C1-C30 alkoxy, and —OC(O)(C1-C30 alkyl); or wherein each of R7 and R7′ together comprise ═O; or wherein one of R7 and R7′ is absent; wherein each of R11 and R12 is independently selected from hydrogen, —OH, C1-C8 hydroxy, C1-C6 alkyl, C1-C8 alkoxy, and —OC(O)(C1-C8 alkyl); wherein R15 is selected from hydrogen, —OH, C1-C30 hydroxy, C1-C30 alkyl, C1-C30 alkoxy, —OC(O)(C1-C30 alkyl), —OC(O)NR35aR35b, —OC(O)Ar2, —OC(O)(C1-C4 alkyl)Ar2, and —OC(O)(C1-C8 azide); wherein R20 is selected from hydrogen, —OH, —OOH, C1-C8 alkyl, C1-C8 hydroxy, C1-C8 alkoxy, C1-C8 hydroperoxy, and —OC(O)(C1-C8 alkyl); wherein R21 is selected from hydrogen and C1-C6 alkyl; wherein R25 is selected from hydrogen, —OH, C1-C8 hydroxy, C1-C8 alkoxy, —OC(O)(C1-18 alkyl), —OC(O)NR35aR35b, —OC(O)Ar5, and —OC(O)(C1-C8 azide); wherein Ar5, when present, is selected from monocyclic 6-membered aryl and anthracene-9,10-dionyl, and is substituted with 0, 1, 2, or 3 groups independently selected from halogen, —OH, —NH2, C1-C4 alkoxy, C1-C4 hydroxy, C1-C4 aminoalkyl, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino; wherein each of R26 and R26′ is independently selected from hydrogen, —OH, C1-C8 hydroxy, and C1-C8 alkoxy; or wherein each of R26 and R26′ together comprise ═O; wherein R27 is selected from hydrogen and C1-C6 alkyl; wherein each of R28 and R29 is independently selected from hydrogen and halogen; or wherein each of R28 and R29 together comprise —O— or —N(R37)-; wherein R37, when present, is selected from hydrogen, C1-C4 alkyl, —SO2R71, and a structure having a formula:
and
wherein R71, when present, is selected from hydrogen, C1-C4 alkyl, —CH2CH2Si(CH3)3, and monocyclic aryl monosubstituted with a methyl group, provided that at least one of R6 and R6′ is —NR41C(O)(C1-C30 alkyl), —NR41C(O)Ar2, —NR41C(O)(C1-C30 alkyl)Ar2, —NR41C(O)Ar3, —NR41C(O)(C1-C30 alkyl)OC(O)Ar3, —NR41C(O)(C1-C30 alkyl)NR42C(O)Ar3, or —NR41C(O)R40, and provided that when one or both of R28 and R29 is hydrogen then the occurrence of - - - - - - at C-22/C-23 is a double covalent bond, or a pharmaceutically acceptable salt thereof.
Also disclosed are compounds having a structure represented by a formula:
wherein each occurrence of - - - - - - is a single or double covalent bond; wherein X is selected from O, NRx and C(RV)2; wherein each occurrence of Rx, when present, is independently selected from hydrogen and C1-C6 alkyl; wherein R1 is selected from hydrogen, halogen, —OH, —CN, —NC, —NCO, —OCN, —NO2, —ONO2, —ONO, —NO, —N3, —NH2, —NH3, —N═NR31, —NHOH, C1-C12 alkyl, C2-C12 alkenyl, C2-C12 alkynyl, C1-C12 hydroxy, C1-C12 alkoxy, C1-C12 thioalkyl, C1-C12 alkylthiol, C1-C12 aminoalkyl, C1-C12 alkylamino, (C1-C12)(C1-C12) dialkylamino, —OC(O)(C1-C12 alkyl), —OP(O)(OR32)2, —OSO2R33, —C(O)(C1-C12 alkyl), —CO2R34, —C(O)NR35aR35b, —(C1-C12 alkyl)C(O)NR35aR35b, —OC(O)NR35aR35b, —(C1-C12 alkyl)OC(O)NR35aR35b, Cy1, Ar1, (C1-C12 alkyl)Ar1, and —OAr1; wherein each occurrence of R31, R32, R34, R35a, and R35b, when present, is independently selected from hydrogen and C1-C12 alkyl; wherein each occurrence of R33, when present, is independently selected from hydrogen, C1-C12 alkyl, and monocyclic aryl monosubstituted with a methyl group; wherein each occurrence of Cy1, when present, is heterocycloalkyl substituted with 0, 1, 2, or 3 groups independently selected from halogen, —OH, —NH2, C1-C4 alkoxy, C1-C4 hydroxy, C1-C4 aminoalkyl, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino; wherein each occurrence of Ar1, when present, is selected from monocyclic aryl, morpholinyl, anilinyl, indolyl, pyrrolyl, imidazolyl, benzimidazolyl, pyrazolyl, guanidinyl, and piperazinyl and substituted with 0, 1, 2, or 3 groups independently selected from halogen, —OH, —NH2, C1-C4 alkoxy, C1-C4 hydroxy, C1-C4 aminoalkyl, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino; and wherein R1′ is hydrogen; or wherein each of R1 and R1′ together comprise ═O or ═NR36; wherein each occurrence of R36, when present, is independently selected from hydrogen and C1-C12 alkyl; wherein each of R2 and R3 is independently selected from hydrogen, —OH, C1-C12 hydroxy, and halogen; or wherein each of R2 and R3 together comprise —O—; wherein R5 is selected from hydrogen, —OH, —NH2, C1-C9 alkyl, C1-C9 hydroxy, C1-C9 alkoxy, C1-C9 aminoalkyl, C1-C6 alkylamino, and (C1-C6)(C1-C6) dialkylamino; or wherein R5 is absent; wherein each of R6 and R6′ is independently selected from hydrogen, halogen, —OH, —CN, —NC, —NCO, —OCN, —NO2, —ONO2, —ONO, —NO, —N3, —NH2, —NH3, —N═NR41, —NHOH, C1-C30 alkyl, C2-C30 alkenyl, C2-C30 alkynyl, C1-C30 hydroxy, C1-C30 alkoxy, C1-C30 thioalkyl, C1-C30 alkylthiol, C1-C30 aminoalkyl, C1-C30 alkylamino, (C1-C30)(C1-C30) dialkylamino, —C(O)(C1-C30 alkyl), —OP(O)(OR32)2, —OSO2R33, —CO2R34, —C(O)NR35aR35b, —(C1-C30 alkyl)C(O)NR35aR35b, —OC(O)NR35aR35b, —(C1-C30 alkyl)OC(O)NR35aR35b, Cy1, Ar1, —(C1-C30 alkyl)Ar1, —OAr1, —OC(O)(C1-C30 alkyl), —OC(O)Ar2, —OC(O)(C1-C30 alkyl)Ar2, —OC(O)Ar3, —OC(O)(C1-C30 alkyl)NR42C(O)Ar3, —OC(O)(C1-C30 alkyl)OC(O)Ar3, —OC(O)R40, —NR41C(O)(C1-C30 alkyl), —NR41C(O)Ar2, —NR41C(O)(C1-C30 alkyl)Ar2, —NR41C(O)Ar3, —NR41C(O)(C1-C30 alkyl)OC(O)Ar3, —NR41C(O)(C1-C30 alkyl)NR42C(O)Ar3, and —NR41C(O)R40; wherein each occurrence of R40, when present, is independently a C1-C30 alkyl functionalized with a group selected from —SH, —NH2, —NHOH, terminal alkyne, haloacetyl, maleimide, isothiocyanate, N-hydroxysuccinimde, succinimidyl ester, tetrafluorophenyl ester, sulfodichlorophenol ester, and hydrazide; wherein each occurrence of R41 and R42, when present, is independently selected from hydrogen and C1-C12 alkyl; wherein each occurrence of Ar2, when present, is independently selected from aryl and heteroaryl, and is substituted with 0, 1, 2, or 3 groups independently selected from halogen, —OH, —NH2, C1-C4 alkoxy, C1-C4 hydroxy, C1-C4 aminoalkyl, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, —(C1-C12 alkyl)Ar4, and Ar4; wherein each occurrence of Ar4, when present, is a structure represented by a formula:
wherein each of R50a, R50b, R50c, and R50d, when present, is independently selected from hydrogen, —F, and —Cl; wherein each of R51a and R51b, when present, is independently selected from hydrogen and —C(O)(C1-C12 alkyl); wherein each of R52a, R52b, R52c, and R52d, when present, is independently selected from hydrogen, —F, and —Cl; wherein each occurrence of Ar3, when present, is a structure represented by a formula selected from:
or wherein one of R6 and R6′ is absent; wherein R7 is selected from hydrogen, —OH, C1-C30 hydroxy, C1-C30 alkoxy, —OC(O)(C1-C30 alkyl), and —OC(O)NR35aR35b, and wherein R7′ is selected from hydrogen, —OH, C1-C30 hydroxy, C1-C30 alkoxy, and —OC(O)(C1-C30 alkyl); or wherein each of R7 and R7′ together comprise ═O; or wherein one of R7 and R7′ is absent; wherein each of R11 and R12 is independently selected from hydrogen, —OH, C1-C8 hydroxy, C1-C6 alkyl, C1-C8 alkoxy, and —OC(O)(C1-C8 alkyl); wherein R15 is selected from hydrogen, —OH, C1-C30 hydroxy, C1-C30 alkyl, C1-C30 alkoxy, —OC(O)(C1-C30 alkyl), —OC(O)NR35aR35b, —OC(O)Ar2, —OC(O)(C1-C4 alkyl)Ar2, and —OC(O)(C1-C8 azide); wherein R20 is selected from hydrogen, —OH, —OOH, C1-C8 alkyl, C1-C8 hydroxy, C1-C8 alkoxy, C1-C8 hydroperoxy, and —OC(O)(C1-C8 alkyl); wherein R21 is selected from hydrogen and C1-C6 alkyl; wherein R25 is selected from hydrogen, —OH, C1-C8 hydroxy, C1-C8 alkoxy, —OC(O)(C1-18 alkyl), —OC(O)NR35aR35b, —OC(O)Ar5, and —OC(O)(C1-C8 azide); wherein Ar1, when present, is selected from monocyclic 6-membered aryl and anthracene-9,10-dionyl, and is substituted with 0, 1, 2, or 3 groups independently selected from halogen, —OH, —NH2, C1-C4 alkoxy, C1-C4 hydroxy, C1-C4 aminoalkyl, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino; wherein each of R26 and R26′ is independently selected from hydrogen, —OH, C1-C8 hydroxy, and C1-C8 alkoxy; or wherein each of R26 and R26′ together comprise ═O; wherein R27 is selected from hydrogen and C1-C6 alkyl; wherein each of R28 and R29 is independently selected from hydrogen and halogen; or wherein each of R28 and R29 together comprise —O— or —N(R37)—; wherein R37, when present, is selected from hydrogen, C1-C4 alkyl, —SO2R71, and a structure having a formula:
and
wherein R71, when present, is selected from hydrogen, C1-C4 alkyl, —CH2CH2Si(CH3)3, and monocyclic aryl monosubstituted with a methyl group, provided that at least one of R6 and R6′ is —OC(O)R40 or —NR41C(O)R40, and provided that when one or both of R28 and R29 is hydrogen then the occurrence of at C-22/C-23 is a double covalent bond, or a pharmaceutically acceptable salt thereof.
Also disclosed are compounds having a structure represented by a formula:
wherein each occurrence of - - - - - - is a single or double covalent bond; wherein X is selected from O, NRx and C(Rx)2; wherein each occurrence of Rx, when present, is independently selected from hydrogen and C1-C6 alkyl; wherein R1 is selected from hydrogen, halogen, —OH, —CN, —NC, —NCO, —OCN, —NO2, —ONO2, —ONO, —NO, —N3, —NH2, —NH3, —N═NR31, —NHOH, C1-C12 alkyl, C2-C12 alkenyl, C2-C12 alkynyl, C1-C12 hydroxy, C1-C12 alkoxy, C1-C12 thioalkyl, C1-C12 alkylthiol, C1-C12 aminoalkyl, C1-C12 alkylamino, (C1-C12)(C1-C12) dialkylamino, —OC(O)(C1-C12 alkyl), —OP(O)(OR32)2, —OSO2R33, —C(O)(C1-C12 alkyl), —CO2R34, —C(O)NR35aR35b, —(C1-C12 alkyl)C(O)NR35aR35b, —OC(O)NR35aR35b, —(C1-C12 alkyl)OC(O)NR35aR35b, Cy1, Ar1, (C1-C12 alkyl)Ar1, and —OAr1; wherein each occurrence of R31, R32, R34, R35a, and R35b, when present, is independently selected from hydrogen and C1-C12 alkyl; wherein each occurrence of R33, when present, is independently selected from hydrogen, C1-C12 alkyl, and monocyclic aryl monosubstituted with a methyl group; wherein each occurrence of Cy1, when present, is heterocycloalkyl substituted with 0, 1, 2, or 3 groups independently selected from halogen, —OH, —NH2, C1-C4 alkoxy, C1-C4 hydroxy, C1-C4 aminoalkyl, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino; wherein each occurrence of Ar1, when present, is selected from monocyclic aryl, morpholinyl, anilinyl, indolyl, pyrrolyl, imidazolyl, benzimidazolyl, pyrazolyl, guanidinyl, and piperazinyl and substituted with 0, 1, 2, or 3 groups independently selected from halogen, —OH, —NH2, C1-C4 alkoxy, C1-C4 hydroxy, C1-C4 aminoalkyl, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino; and wherein R1′ is hydrogen; or wherein each of R1 and R1′ together comprise ═O or ═NR36; wherein each occurrence of R36, when present, is independently selected from hydrogen and C1-C12 alkyl; wherein each of R2 and R3 is independently selected from hydrogen, —OH, C1-C12 hydroxy, and halogen; or wherein each of R2 and R3 together comprise —O—; wherein R5 is selected from hydrogen, —OH, —NH2, C1-C9 alkyl, C1-C9 hydroxy, C1-C9 alkoxy, C1-C9 aminoalkyl, C1-C6 alkylamino, and (C1-C6)(C1-C6) dialkylamino; or wherein R5 is absent; wherein R7 is selected from hydrogen, —OH, C1-C30 hydroxy, C1-C30 alkoxy, —OC(O)(C1-C30 alkyl), and —OC(O)NR35aR35b, and wherein R7′ is selected from hydrogen, —OH, C1-C30 hydroxy, C1-C30 alkoxy, and —OC(O)(C1-C30 alkyl); or wherein each of R7 and R7′ together comprise ═O; or wherein one of R7 and R7′ is absent; wherein each of R8 and R8′ is independently selected from hydrogen, halogen, —OH, —CN, —NC, —NCO, —OCN, —NO2, —ONO2, —ONO, —NO, —N3, —NH2, —NH3, —N═NR41, —NHOH, C1-C30 alkyl, C2-C30 alkenyl, C2-C30 alkynyl, C1-C30 hydroxy, C1-C30 alkoxy, C1-C30 thioalkyl, C1-C30 alkylthiol, C1-C30 aminoalkyl, C1-C30 alkylamino, (C1-C30)(C1-C30) dialkylamino, —C(O)(C1-C30 alkyl), —OP(O)(OR32)2, —OSO2R33, —CO2R34, —C(O)NR35aR35b, —(C1-C30 alkyl)C(O)NR35aR35b, —OC(O)NR35aR35b, —(C1-C30 alkyl)OC(O)NR35aR35b, Cy1, Ar1, —(C1-C30 alkyl)Ar1, —OAr1, —OC(O)(C1-C30 alkyl), —OC(O)Ar2, —OC(O)(C1-C30 alkyl)Ar2, —OC(O)Ar3, —OC(O)(C1-C30 alkyl)NR42C(O)Ar3, —OC(O)(C1-C30 alkyl)OC(O)Ar3, —OC(O)(C1-C30 alkyl)-L-Z, —OC(O)(C1-C30 alkyl)-L-(C1-C30 alkyl)-Z, —OC(O)-L-(C1-C30 alkyl)-Z, —NR41C(O)(C1-C30 alkyl), —NR41C(O)Ar2, —NR41C(O)(C1-C30 alkyl)Ar2, —NR41C(O)Ar3, —NR41C(O)(C1-C30 alkyl)OC(O)Ar3, —NR41C(O)(C1-C30 alkyl)NR42C(O)Ar3, —NR41C(O)(C1-C30 alkyl)-L-Z, —NR41C(O)(C1-C30 alkyl)-L-(C1-C30 alkyl)-Z, and —NR41C(O)-L-(C1-C30 alkyl)-Z; wherein L is a linker; wherein Z is selected from an antibody, an antibody fragment, a vitamin, a hormone, a carbohydrate, a molecular ligand, an aptamer, a non-antibody protein, a peptide, a nucleic acid, a fluorophore, and a drug; wherein each occurrence of R41 and R42, when present, is independently selected from hydrogen and C1-C12 alkyl; wherein each occurrence of Ar2, when present, is independently selected from aryl and heteroaryl, and is substituted with 0, 1, 2, or 3 groups independently selected from halogen, —OH, —NH2, C1-C4 alkoxy, C1-C4 hydroxy, C1-C4 aminoalkyl, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, —(C1-C12 alkyl)Ar4, and Ar4; wherein each occurrence of Ar4, when present, is a structure represented by a formula:
wherein each of R50a, R50b, R50c, and R50d, when present, is independently selected from hydrogen, —F, and —Cl; wherein each of R51a and R51b, when present, is independently selected from hydrogen and —C(O)(C1-C12 alkyl); wherein each of R52a, R52b, R52c, and R52d, when present, is independently selected from hydrogen, —F, and —Cl; wherein each occurrence of Ar3, when present, is a structure represented by a formula selected from:
or wherein one of R8 and R8′ is absent; wherein each of R11 and R12 is independently selected from hydrogen, —OH, C1-C8 hydroxy, C1-C6 alkyl, C1-C8 alkoxy, and —OC(O)(C1-C8 alkyl); wherein R15 is selected from hydrogen, —OH, C1-C30 hydroxy, C1-C30 alkyl, C1-C30 alkoxy, —OC(O)(C1-C30 alkyl), —OC(O)NR35aR35b, —OC(O)Ar2, —OC(O)(C1-C4 alkyl)Ar2, and —OC(O)(C1-C8 azide); wherein R20 is selected from hydrogen, —OH, —OOH, C1-C8 alkyl, C1-C8 hydroxy, C1-C8 alkoxy, C1-C8 hydroperoxy, and —OC(O)(C1-C8 alkyl); wherein R21 is selected from hydrogen and C1-C6 alkyl; wherein R25 is selected from hydrogen, —OH, C1-C8 hydroxy, C1-C8 alkoxy, —OC(O)(C1-18 alkyl), —OC(O)NR35aR35b, —OC(O)Ar5, and —OC(O)(C1-C8 azide); wherein Ar5, when present, is selected from monocyclic 6-membered aryl and anthracene-9,10-dionyl, and is substituted with 0, 1, 2, or 3 groups independently selected from halogen, —OH, —NH2, C1-C4 alkoxy, C1-C4 hydroxy, C1-C4 aminoalkyl, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino; wherein each of R26 and R26′ is independently selected from hydrogen, —OH, C1-C8 hydroxy, and C1-C8 alkoxy; or wherein each of R26 and R26′ together comprise ═O; wherein R27 is selected from hydrogen and C1-C6 alkyl; wherein each of R28 and R29 is independently selected from hydrogen and halogen; or wherein each of R28 and R29 together comprise —O— or N(R37)—; wherein R37, when present, is selected from hydrogen, C1-C4 alkyl, —SO2R71, and a structure having a formula:
and
wherein R71, when present, is selected from hydrogen, C1-C4 alkyl, —CH2CH2Si(CH3)3, and monocyclic aryl monosubstituted with a methyl group, provided that one and only one of R8 and R8′ is —OC(O)(C1-C30 alkyl)-L-Z, —OC(O)(C1-C30 alkyl)-L-(C1-C30 alkyl)-Z, —OC(O)-L-(C1-C30 alkyl)-Z, —NR41C(O)(C1-C30 alkyl)-L-Z, —NR41C(O)(C1-C30 alkyl)-L-(C1-C30 alkyl)-Z, or —NR41C(O)-L-(C1-C30 alkyl)-Z, and provided that when one or both of R28 and R29 is hydrogen then the occurrence of - - - - - - at C-22/C-23 is a double covalent bond, or a pharmaceutically acceptable salt thereof.
Also disclosed are compounds having a structure selected from:
or a pharmaceutically acceptable salt thereof.
Also disclosed are compounds selected from:
or a pharmaceutically acceptable salt thereof.
Also disclosed are compounds selected from:
or a pharmaceutically acceptable salt thereof.
Also disclosed are methods of making a disclosed compound.
Also disclosed are pharmaceutical compositions comprising a therapeutically effective amount of a disclosed compound and a pharmaceutically acceptable carrier.
Also disclosed are methods for the treatment of a hyperproliferative disorder in a subject, the method comprising administering to the subject an effective amount of at least one disclosed compound.
Also disclosed are kits comprising at least one disclosed compound and one or more of: (a) at least one agent associated with the treatment of a hyperproliferative disorder; (b) instructions for administering the compound in connection with treating a hyperproliferative disorder; and (c) instructions for treating a hyperproliferative disorder.
Also disclosed are methods of making a conjugated taccalonolide compound having a structure represented by a formula:
wherein each occurrence of - - - - - - is a single or double covalent bond; wherein X is selected from O, NRx and C(Rx)2; wherein each occurrence of Rx, when present, is independently selected from hydrogen and C1-C6 alkyl; wherein R1 is selected from hydrogen, halogen, —OH, —CN, —NC, —NCO, —OCN, —NO2, —ONO2, —ONO, —NO, —N3, —NH2, —NH3, —N═NR31, —NHOH, C1-C12 alkyl, C2-C12 alkenyl, C2-C12 alkynyl, C1-C12 hydroxy, C1-C12 alkoxy, C1-C12 thioalkyl, C1-C12 alkylthiol, C1-C12 aminoalkyl, C1-C12 alkylamino, (C1-C12)(C1-C12) dialkylamino, —OC(O)(C1-C12 alkyl), —OP(O)(OR32)2, —OSO2R33, —C(O)(C1-C12 alkyl), —CO2R34, —C(O)NR35aR35b, —(C1-C12 alkyl)C(O)NR35aR35b, —OC(O)NR35aR35b, —(C1-C12 alkyl)OC(O)NR35aR35b, Cy1, Ar1, (C1-C12 alkyl)Ar1, and —OAr1; wherein each occurrence of R31, R32, R34, R35a, and R35b, when present, is independently selected from hydrogen and C1-C12 alkyl; wherein each occurrence of R33, when present, is independently selected from hydrogen, C1-C12 alkyl, and monocyclic aryl monosubstituted with a methyl group; wherein each occurrence of Cy1, when present, is heterocycloalkyl substituted with 0, 1, 2, or 3 groups independently selected from halogen, —OH, —NH2, C1-C4 alkoxy, C1-C4 hydroxy, C1-C4 aminoalkyl, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino; wherein each occurrence of Ar1, when present, is selected from monocyclic aryl, morpholinyl, anilinyl, indolyl, pyrrolyl, imidazolyl, benzimidazolyl, pyrazolyl, guanidinyl, and piperazinyl and substituted with 0, 1, 2, or 3 groups independently selected from halogen, —OH, —NH2, C1-C4 alkoxy, C1-C4 hydroxy, C1-C4 aminoalkyl, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino; and wherein R1′ is hydrogen; or wherein each of R1 and R1′ together comprise ═O or ═NR36; wherein each occurrence of R36, when present, is independently selected from hydrogen and C1-C12 alkyl; wherein each of R2 and R3 is independently selected from hydrogen, —OH, C1-C12 hydroxy, and halogen; or wherein each of R2 and R3 together comprise —O—; wherein R5 is selected from hydrogen, —OH, —NH2, C1-C9 alkyl, C1-C9 hydroxy, C1-C9 alkoxy, C1-C9 aminoalkyl, C1-C6 alkylamino, and (C1-C6)(C1-C6) dialkylamino; or wherein R5 is absent; or wherein each of R7 and R7′ together comprise ═O; or wherein one of R7 and R7′ is absent; wherein each of R8 and R8′ is independently selected from hydrogen, halogen, —OH, —CN, —NC, —NCO, —OCN, —NO2, —ONO2, —ONO, —NO, —N3, —NH2, —NH3, —N═NR41, —NHOH, C1-C30 alkyl, C2-C30 alkenyl, C2-C30 alkynyl, C1-C30 hydroxy, C1-C30 alkoxy, C1-C30 thioalkyl, C1-C30 alkylthiol, C1-C30 aminoalkyl, C1-C30 alkylamino, (C1-C30)(C1-C30) dialkylamino, —C(O)(C1-C30 alkyl), —OP(O)(OR32)2, —OSO2R33, —CO2R34, —C(O)NR35aR35b, —(C1-C30 alkyl)C(O)NR35aR35b, —OC(O)NR35aR35b, —(C1-C30 alkyl)OC(O)NR35aR35b, Cy1, Ar1, —(C1-C30 alkyl)Ar1, —OAr1, —OC(O)(C1-C30 alkyl), —OC(O)Ar2, —OC(O)(C1-C30 alkyl)Ar2, —OC(O)Ar3, —OC(O)(C1-C30 alkyl)NR42C(O)Ar3, —OC(O)(C1-C30 alkyl)OC(O)Ar3, —OC(O)(C1-C30 alkyl)-L-Z, —OC(O)(C1-C30 alkyl)-L-(C1-C30 alkyl)-Z, —OC(O)-L-(C1-C30 alkyl)-Z, —NR41C(O)(C1-C30 alkyl), —NR41C(O)Ar2, —NR41C(O)(C1-C30 alkyl)Ar2, —NR41C(O)Ar3, —NR41C(O)(C1-C30 alkyl)OC(O)Ar3, —NR41C(O)(C1-C30 alkyl)NR42C(O)Ar3, —NR41C(O)(C1-C30 alkyl)-L-Z, —NR41C(O)(C1-C30 alkyl)-L-(C1-C30 alkyl)-Z, and —NR41C(O)-L-(C1-C30 alkyl)-Z; wherein L is a linker; wherein Z is selected from an antibody, an antibody fragment, a vitamin, a hormone, a carbohydrate, a molecular ligand, an aptamer, a non-antibody protein, a peptide, a nucleic acid, a fluorophore, and a drug; wherein each occurrence of R41 and R42, when present, is independently selected from hydrogen and C1-C12 alkyl; wherein each occurrence of Ar2, when present, is independently selected from aryl and heteroaryl, and is substituted with 0, 1, 2, or 3 groups independently selected from halogen, —OH, —NH2, C1-C4 alkoxy, C1-C4 hydroxy, C1-C4 aminoalkyl, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, —(C1-C12 alkyl)Ar4, and Ar4; wherein each occurrence of Ar4, when present, is a structure represented by a formula:
wherein each of R50a, R50b, R50c, and R50d, when present, is independently selected from hydrogen, —F, and —Cl; wherein each of R51a and R51b, when present, is independently selected from hydrogen and —C(O)(C1-C12 alkyl); wherein each of R52a, R52b, R52c, and R52d, when present, is independently selected from hydrogen, —F, and —Cl; wherein each occurrence of Ar3, when present, is a structure represented by a formula selected from:
or wherein one of R8 and R8′ is absent; wherein R7 is selected from hydrogen, —OH, C1-C30 hydroxy, C1-C30 alkoxy, —OC(O)(C1-C30 alkyl), and —OC(O)NR35aR35b, and wherein R7′ is selected from hydrogen, —OH, C1-C30 hydroxy, C1-C30 alkoxy, and —OC(O)(C1-C30 alkyl); wherein each of R11 and R12 is independently selected from hydrogen, —OH, C1-C8 hydroxy, C1-C6 alkyl, C1-C8 alkoxy, and —OC(O)(C1-C8 alkyl); wherein R15 is selected from hydrogen, —OH, C1-C30 hydroxy, C1-C30 alkyl, C1-C30 alkoxy, —OC(O)(C1-C30 alkyl), —OC(O)NR35aR35b, —OC(O)Ar2, —OC(O)(C1-C4 alkyl)Ar2, and —OC(O)(C1-C8 azide); wherein R20 is selected from hydrogen, —OH, —OOH, C1-C8 alkyl, C1-C8 hydroxy, C1-C8 alkoxy, C1-C8 hydroperoxy, and —OC(O)(C1-C8 alkyl); wherein R21 is selected from hydrogen and C1-C6 alkyl; wherein R25 is selected from hydrogen, —OH, C1-C8 hydroxy, C1-C8 alkoxy, —OC(O)(C1-18 alkyl), —OC(O)NR35aR35b, —OC(O)Ar5, and —OC(O)(C1-C8 azide); wherein Ar1, when present, is selected from monocyclic 6-membered aryl and anthracene-9,10-dionyl, and is substituted with 0, 1, 2, or 3 groups independently selected from halogen, —OH, —NH2, C1-C4 alkoxy, C1-C4 hydroxy, C1-C4 aminoalkyl, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino; wherein each of R26 and R26′ is independently selected from hydrogen, —OH, C1-C8 hydroxy, and C1-C8 alkoxy; or wherein each of R26 and R26′ together comprise ═O; wherein R27 is selected from hydrogen and C1-C6 alkyl; wherein each of R28 and R29 is independently selected from hydrogen and halogen; or wherein each of R28 and R29 together comprise —O— or —N(R37)—; wherein R37, when present, is selected from hydrogen, C1-C4 alkyl, —SO2R71, and a structure having a formula:
and
wherein R71, when present, is selected from hydrogen, C1-C4 alkyl, —CH2CH2Si(CH3)3, and monocyclic aryl monosubstituted with a methyl group, provided that one and only one of R8 and R8′ is —OC(O)(C1-C30 alkyl)-L-Z, —OC(O)(C1-C30 alkyl)-L-(C1-C30 alkyl)-Z, —OC(O)-L-(C1-C30 alkyl)-Z, —NR41C(O)(C1-C30 alkyl)-L-Z, —NR41C(O)(C1-C30 alkyl)-L-(C1-C30 alkyl)-Z, or —NR41C(O)-L-(C1-C30 alkyl)-Z, and provided that when one or both of R28 and R29 is hydrogen then the occurrence of - - - - - - at C-22/C-23 is a double covalent bond, or a pharmaceutically acceptable salt thereof, the method comprising reacting a taccalonolide compound having a structure represented by a formula:
wherein each of R6 and R6′ is independently selected from hydrogen, halogen, —OH, —CN, —NC, —NCO, —OCN, —NO2, —ONO2, —ONO, —NO, —N3, —NH2, —NH3, —N═NR41, —NHOH, C1-C30 alkyl, C2-C30 alkenyl, C2-C30 alkynyl, C1-C30 hydroxy, C1-C30 alkoxy, C1-C30 thioalkyl, C1-C30 alkylthiol, C1-C30 aminoalkyl, C1-C30 alkylamino, (C1-C30)(C1-C30) dialkylamino, —C(O)(C1-C30 alkyl), —OP(O)(OR32)2, —OSO2R33, —CO2R34, —C(O)NR35aR35b, —(C1-C30 alkyl)C(O)NR35aR35b, —OC(O)NR35aR35b, —(C1-C30 alkyl)OC(O)NR35aR35b, Cy1, Ar1, —(C1-C30 alkyl)Ar1, —OAr1, —OC(O)(C1-C30 alkyl), —OC(O)Ar2, —OC(O)(C1-C30 alkyl)Ar2, —OC(O)Ar3, —OC(O)(C1-C30 alkyl)NR42C(O)Ar3, —OC(O)(C1-C30 alkyl)OC(O)Ar3, —OC(O)R40, —NR41C(O)(C1-C30 alkyl), —NR41C(O)Ar2, —NR41C(O)(C1-C30 alkyl)Ar2, —NR41C(O)Ar3, —NR41C(O)(C1-C30 alkyl)OC(O)Ar3, —NR41C(O)(C1-C30 alkyl)NR42C(O)Ar3, and —NR41C(O)R40; and wherein R40 is a C1-C30 alkyl functionalized with a group selected from —N3, —SH, —OH, —NH2, —NHOH, an ester, a disulfide, a sulfonamide, a terminal alkyne, haloacetyl, maleimide, isothiocyanate, N-hydroxysuccinimde, an acylhydrazine, an acylhydrazone, a hydrazine, a hydrazone, and hydrazide, provided that one and only one of R6 and R6′ is —OC(O)R40 or —NR41C(O)R40, with a nucleophile having a structure represented by a formula selected from:
H—(C1-C30 alkyl)-L-Z, H-L-(C1-C30 alkyl)-Z, and H—(C1-C30 alkyl)-L-(C1-C30 alkyl)-Z.
Still other objects and advantages of the present disclosure will become readily apparent by those skilled in the art from the following detailed description, wherein it is shown and described only the preferred embodiments, simply by way of illustration of the best mode. As will be realized, the disclosure is capable of other and different embodiments, and its several details are capable of modifications in various obvious respects, without departing from the disclosure. Accordingly, the description is to be regarded as illustrative in nature and not as restrictive.
The accompanying figures, which are incorporated in and constitute a part of this specification, illustrate several aspects and together with the description serve to explain the principles of the invention.
Additional advantages of the invention will be set forth in part in the description which follows, and in part will be obvious from the description, or can be learned by practice of the invention. The advantages of the invention will be realized and attained by means of the elements and combinations particularly pointed out in the appended claims. It is to be understood that both the foregoing general description and the following detailed description are exemplary and explanatory only and are not restrictive of the invention, as claimed.
The present invention can be understood more readily by reference to the following detailed description of the invention and the Examples included therein.
Before the present compounds, compositions, articles, systems, devices, and/or methods are disclosed and described, it is to be understood that they are not limited to specific synthetic methods unless otherwise specified, or to particular reagents unless otherwise specified, as such may, of course, vary. It is also to be understood that the terminology used herein is for the purpose of describing particular aspects only and is not intended to be limiting. Although any methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention, example methods and materials are now described.
While aspects of the present invention can be described and claimed in a particular statutory class, such as the system statutory class, this is for convenience only and one of skill in the art will understand that each aspect of the present invention can be described and claimed in any statutory class. Unless otherwise expressly stated, it is in no way intended that any method or aspect set forth herein be construed as requiring that its steps be performed in a specific order. Accordingly, where a method claim does not specifically state in the claims or descriptions that the steps are to be limited to a specific order, it is no way intended that an order be inferred, in any respect. This holds for any possible non-express basis for interpretation, including matters of logic with respect to arrangement of steps or operational flow, plain meaning derived from grammatical organization or punctuation, or the number or type of aspects described in the specification.
Throughout this application, various publications are referenced. The disclosures of these publications in their entireties are hereby incorporated by reference into this application in order to more fully describe the state of the art to which this pertains. The references disclosed are also individually and specifically incorporated by reference herein for the material contained in them that is discussed in the sentence in which the reference is relied upon. Nothing herein is to be construed as an admission that the present invention is not entitled to antedate such publication by virtue of prior invention. Further, the dates of publication provided herein may be different from the actual publication dates, which can require independent confirmation.
Listed below are definitions of various terms used to describe this invention. These definitions apply to the terms as they are used throughout this specification, unless otherwise limited in specific instances, either individually or as part of a larger group.
As used in the specification and the appended claims, the singular forms “a,” “an” and “the” include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to “a functional group,” “an alkyl,” or “a residue” includes mixtures of two or more such functional groups, alkyls, or residues, and the like.
Ranges can be expressed herein as from “about” one particular value, and/or to “about” another particular value. When such a range is expressed, another aspect includes from the one particular value and/or to the other particular value. Similarly, when values are expressed as approximations, by use of the antecedent “about,” it will be understood that the particular value forms another aspect. It will be further understood that the endpoints of each of the ranges are significant both in relation to the other endpoint, and independently of the other endpoint. It is also understood that there are a number of values disclosed herein, and that each value is also herein disclosed as “about” that particular value in addition to the value itself. For example, if the value “10” is disclosed, then “about 10” is also disclosed. It is also understood that each unit between two particular units are also disclosed. For example, if 10 and 15 are disclosed, then 11, 12, 13, and 14 are also disclosed.
References in the specification and concluding claims to parts by weight of a particular element or component in a composition denotes the weight relationship between the element or component and any other elements or components in the composition or article for which a part by weight is expressed. Thus, in a compound containing 2 parts by weight of component X and 5 parts by weight component Y, X and Y are present at a weight ratio of 2:5, and are present in such ratio regardless of whether additional components are contained in the compound.
A weight percent (wt. %) of a component, unless specifically stated to the contrary, is based on the total weight of the formulation or composition in which the component is included.
As used herein, the terms “optional” or “optionally” mean that the subsequently described event or circumstance can or cannot occur, and that the description includes instances where said event or circumstance occurs and instances where it does not.
As used herein, the term “subject” can be a vertebrate, such as a mammal, a fish, a bird, a reptile, or an amphibian. Thus, the subject of the herein disclosed methods can be a human, non-human primate, horse, pig, rabbit, dog, sheep, goat, cow, cat, guinea pig, or rodent. The term does not denote a particular age or sex. Thus, adult and newborn subjects, as well as fetuses, whether male or female, are intended to be covered. In one aspect, the subject is a mammal. A patient refers to a subject afflicted with a viral infection. The term “patient” includes human and veterinary subjects. In some aspects of the disclosed methods, the subject has been diagnosed with a need for treatment of one or more viral infections prior to the administering step. In various aspects, the one or more disorders is selected from chikungunya, Venezuelan equine encephalitis, dengue, influenza, and zika.
As used herein, the term “treatment” refers to the medical management of a patient with the intent to cure, ameliorate, stabilize, or prevent a disease, pathological condition, or disorder. This term includes active treatment, that is, treatment directed specifically toward the improvement of a disease, pathological condition, or disorder, and also includes causal treatment, that is, treatment directed toward removal of the cause of the associated disease, pathological condition, or disorder. In addition, this term includes palliative treatment, that is, treatment designed for the relief of symptoms rather than the curing of the disease, pathological condition, or disorder; preventative treatment, that is, treatment directed to minimizing or partially or completely inhibiting the development of the associated disease, pathological condition, or disorder; and supportive treatment, that is, treatment employed to supplement another specific therapy directed toward the improvement of the associated disease, pathological condition, or disorder. In various aspects, the term covers any treatment of a subject, including a mammal (e.g., a human), and includes: (i) preventing the disease from occurring in a subject that can be predisposed to the disease but has not yet been diagnosed as having it; (ii) inhibiting the disease, i.e., arresting its development; or (iii) relieving the disease, i.e., causing regression of the disease. In one aspect, the subject is a mammal such as a primate, and, in a further aspect, the subject is a human. The term “subject” also includes domesticated animals (e.g., cats, dogs, etc.), livestock (e.g., cattle, horses, pigs, sheep, goats, etc.), and laboratory animals (e.g., mouse, rabbit, rat, guinea pig, fruit fly, etc.).
As used herein, the term “prevent” or “preventing” refers to precluding, averting, obviating, forestalling, stopping, or hindering something from happening, especially by advance action. It is understood that where reduce, inhibit, or prevent are used herein, unless specifically indicated otherwise, the use of the other two words is also expressly disclosed.
As used herein, the term “diagnosed” means having been subjected to a physical examination by a person of skill, for example, a physician, and found to have a condition that can be diagnosed or treated by the compounds, compositions, or methods disclosed herein. In some aspects of the disclosed methods, the subject has been diagnosed with a need for treatment of a viral infection prior to the administering step. As used herein, the phrase “identified to be in need of treatment for a disorder,” or the like, refers to selection of a subject based upon need for treatment of the disorder. It is contemplated that the identification can, in one aspect, be performed by a person different from the person making the diagnosis. It is also contemplated, in a further aspect, that the administration can be performed by one who subsequently performed the administration.
As used herein, the terms “administering” and “administration” refer to any method of providing a pharmaceutical preparation to a subject. Such methods are well known to those skilled in the art and include, but are not limited to, oral administration, transdermal administration, administration by inhalation, nasal administration, topical administration, intravaginal administration, ophthalmic administration, intraaural administration, intracerebral administration, rectal administration, and parenteral administration, including injectable such as intravenous administration, intra-arterial administration, intramuscular administration, and subcutaneous administration. Administration can be continuous or intermittent. In various aspects, a preparation can be administered therapeutically; that is, administered to treat an existing disease or condition. In further various aspects, a preparation can be administered prophylactically; that is, administered for prevention of a disease or condition.
The term “treating” refers to relieving the disease, disorder, or condition, i.e., causing regression of the disease, disorder, and/or condition. The term “preventing” refers to preventing a disease, disorder, or condition from occurring in a human or an animal that may be predisposed to the disease, disorder and/or condition, but has not yet been diagnosed as having it; and/or inhibiting the disease, disorder, or condition, i.e., arresting its development.
The term “contacting” as used herein refers to bringing a disclosed compound and a cell, target receptor, or other biological entity together in such a manner that the compound can affect the activity of the target (e.g., receptor, cell, etc.), either directly; i.e., by interacting with the target itself, or indirectly; i.e., by interacting with another molecule, co-factor, factor, or protein on which the activity of the target is dependent.
As used herein, the terms “effective amount” and “amount effective” refer to an amount that is sufficient to achieve the desired result or to have an effect on an undesired condition. For example, a “therapeutically effective amount” refers to an amount that is sufficient to achieve the desired therapeutic result or to have an effect on undesired symptoms, but is generally insufficient to cause adverse side effects. The specific therapeutically effective dose level for any particular patient will depend upon a variety of factors including the disorder being treated and the severity of the disorder; the specific composition employed; the age, body weight, general health, sex and diet of the patient; the time of administration; the route of administration; the rate of excretion of the specific compound employed; the duration of the treatment; drugs used in combination or coincidental with the specific compound employed and like factors well known in the medical arts. For example, it is well within the skill of the art to start doses of a compound at levels lower than those required to achieve the desired therapeutic effect and to gradually increase the dosage until the desired effect is achieved. If desired, the effective daily dose can be divided into multiple doses for purposes of administration. Consequently, single dose compositions can contain such amounts or submultiples thereof to make up the daily dose. The dosage can be adjusted by the individual physician in the event of any contraindications. Dosage can vary, and can be administered in one or more dose administrations daily, for one or several days. Guidance can be found in the literature for appropriate dosages for given classes of pharmaceutical products. In further various aspects, a preparation can be administered in a “prophylactically effective amount”; that is, an amount effective for prevention of a disease or condition.
As used herein, “IC50,” is intended to refer to the concentration of a substance (e.g., a compound or a drug) that is required for 50% inhibition of a biological process, or component of a process, including a protein, subunit, organelle, ribonucleoprotein, etc. In one aspect, an IC50 can refer to the concentration of a substance that is required for 50% inhibition in vivo, as further defined elsewhere herein.
The term “comprising” (and its grammatical variations) as used herein is used in the inclusive sense of “having” or “including” and not in the exclusive sense of “consisting of.”
The compounds according to this disclosure may form prodrugs at hydroxyl or amino functionalities using alkoxy, amino acids, etc., groups as the prodrug forming moieties. For instance, the hydroxymethyl position may form mono-, di- or triphosphates and again these phosphates can form prodrugs. Preparations of such prodrug derivatives are discussed in various literature sources (examples are: Alexander et al., J. Med. Chem. 1988, 31, 318; Aligas-Martin et al., PCT WO 2000/041531, p. 30). The nitrogen function converted in preparing these derivatives is one (or more) of the nitrogen atoms of a compound of the disclosure.
“Derivatives” of the compounds disclosed herein are pharmaceutically acceptable salts, prodrugs, deuterated forms, radio-actively labeled forms, isomers, solvates and combinations thereof. The “combinations” mentioned in this context are refer to derivatives falling within at least two of the groups: pharmaceutically acceptable salts, prodrugs, deuterated forms, radio-actively labeled forms, isomers, and solvates. Examples of radio-actively labeled forms include compounds labeled with tritium, phosphorous-32, iodine-129, carbon-11, fluorine-18, and the like.
“Pharmaceutically acceptable salts” refer to derivatives of the disclosed compounds wherein the parent compound is modified by making acid or base salts thereof. The compounds of this disclosure form acid addition salts with a wide variety of organic and inorganic acids and include the physiologically acceptable salts which are often used in pharmaceutical chemistry. Such salts are also part of this disclosure. Typical inorganic acids used to form such salts include hydrochloric, hydrobromic, hydroiodic, nitric, sulfuric, phosphoric, hypophosphoric acid, and the like. Salts derived from organic acids, such as aliphatic mono- and dicarboxylic acids, phenyl substituted alkanoic acids, hydroxyalkanoic and hydroxyalkandioic acids, aromatic acids, aliphatic and aromatic sulfonic acids may also be used. Such pharmaceutically acceptable salts thus include acetate, phenylacetate, trifluoroacetate, acrylate, ascorbate, benzoate, chlorobenzoate, dinitrobenzoate, hydroxybenzoate, methoxybenzoate, methylbenzoate, o-acetoxybenzoate, naphthalene-2-benzoate, bromide, isobutyrate, phenylbutyrate, ρ-hydroxybutyrate, butyne-1,4-dioate, hexyne-1,4-dioate, caprate, caprylate, chloride, cinnamate, citrate, formate, fumarate, glycollate, heptanoate, hippurate, lactate, malate, maleate, hydroxymaleate, malonate, mandelate, mesylate, nicotinate, isonicotinate, nitrate, oxalate, phthalate, teraphthalate, phosphate, monohydrogenphosphate, dihydrogenphosphate, metaphosphate, pyrophosphate, propiolate, propionate, phenylpropionate, salicylate, sebacate, succinate, suberate, sulfate, bisulfate, pyrosulfate, sulfite, bisulfite, sulfonate, benzene-sulfonate, p-bromobenzenesulfonate, chlorobenzenesulfonate, ethanesulfonate, 2-hydroxyethanesulfonate, methanesulfonate, naphthalene-1-sulfonate, naphthalene-2-sulfonate, p-toleunesulfonate, xylenesulfonate, tartarate, and the like.
It is understood that the compounds of the present disclosure relate to all optical isomers and stereo-isomers at the various possible atoms of the molecule, unless specified otherwise. Compounds may be separated or prepared as their pure enantiomers or diastereomers by crystallization, chromatography or synthesis.
The term “leaving group” refers to an atom (or a group of atoms) with electron withdrawing ability that can be displaced as a stable species, taking with it the bonding electrons. Examples of suitable leaving groups include sulfonate esters, including triflate, mesylate, tosylate, brosylate, and halides.
As used herein, the term “substituted” is contemplated to include all permissible substituents of organic compounds. In a broad aspect, the permissible substituents include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, and aromatic and nonaromatic substituents of organic compounds. Illustrative substituents include, for example, those described below. The permissible substituents can be one or more and the same or different for appropriate organic compounds. For purposes of this disclosure, the heteroatoms, such as nitrogen, can have hydrogen substituents and/or any permissible substituents of organic compounds described herein which satisfy the valences of the heteroatoms. This disclosure is not intended to be limited in any manner by the permissible substituents of organic compounds. Also, the terms “substitution” or “substituted with” include the implicit proviso that such substitution is in accordance with permitted valence of the substituted atom and the substituent, and that the substitution results in a stable compound, e.g., a compound that does not spontaneously undergo transformation such as by rearrangement, cyclization, elimination, etc. It is also contemplated that, in certain aspects, unless expressly indicated to the contrary, individual substituents can be further optionally substituted (i.e., further substituted or unsubstituted).
In defining various terms, “A1,” “A2,” “A3,” and “A4” are used herein as generic symbols to represent various specific substituents. These symbols can be any substituent, not limited to those disclosed herein, and when they are defined to be certain substituents in one instance, they can, in another instance, be defined as some other substituents.
The term “alkyl” as used herein is a branched or unbranched saturated hydrocarbon group of 1 to 24 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, s-butyl, t-butyl, n-pentyl, isopentyl, s-pentyl, neopentyl, hexyl, heptyl, octyl, nonyl, decyl, dodecyl, tetradecyl, hexadecyl, eicosyl, tetracosyl, and the like. The alkyl group can also be substituted or unsubstituted. The alkyl group can be substituted with one or more groups including, but not limited to, optionally substituted alkyl, cycloalkyl, alkoxy, amino, ether, halide, hydroxy, nitro, silyl, sulfo-oxo, or thiol, as described herein. A “lower alkyl” group is an alkyl group containing from one to six (e.g., from one to four) carbon atoms.
Throughout the specification “alkyl” is generally used to refer to both unsubstituted alkyl groups and substituted alkyl groups; however, substituted alkyl groups are also specifically referred to herein by identifying the specific substituent(s) on the alkyl group. For example, the term “halogenated alkyl” specifically refers to an alkyl group that is substituted with one or more halide, e.g., fluorine, chlorine, bromine, or iodine. The term “alkoxyalkyl” specifically refers to an alkyl group that is substituted with one or more alkoxy groups, as described below. The term “alkylamino” specifically refers to an alkyl group that is substituted with one or more amino groups, as described below, and the like. When “alkyl” is used in one instance and a specific term such as “alkyl alcohol” is used in another, it is not meant to imply that the term “alkyl” does not also refer to specific terms such as “alkyl alcohol” and the like.
This practice is also used for other groups described herein. That is, while a term such as “cycloalkyl” refers to both unsubstituted and substituted cycloalkyl moieties, the substituted moieties can, in addition, be specifically identified herein; for example, a particular substituted cycloalkyl can be referred to as, e.g., an “alkylcycloalkyl.” Similarly, a substituted alkoxy can be specifically referred to as, e.g., a “halogenated alkoxy,” a particular substituted alkenyl can be, e.g., an “alkenylalcohol,” and the like. Again, the practice of using a general term, such as “cycloalkyl,” and a specific term, such as “alkylcycloalkyl,” is not meant to imply that the general term does not also include the specific term.
The term “cycloalkyl” as used herein is a non-aromatic carbon-based ring composed of at least three carbon atoms. Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, norbornyl, and the like. The term “heterocycloalkyl” is a type of cycloalkyl group as defined above, and is included within the meaning of the term “cycloalkyl,” where at least one of the carbon atoms of the ring is replaced with a heteroatom such as, but not limited to, nitrogen, oxygen, sulfur, or phosphorus. The cycloalkyl group and heterocycloalkyl group can be substituted or unsubstituted. The cycloalkyl group and heterocycloalkyl group can be substituted with one or more groups including, but not limited to, optionally substituted alkyl, cycloalkyl, alkoxy, amino, ether, halide, hydroxy, nitro, silyl, sulfo-oxo, or thiol as described herein.
The term “polyalkylene group” as used herein is a group having two or more CH2 groups linked to one another. The polyalkylene group can be represented by the formula —(CH2)a—, where “a” is an integer of from 2 to 500.
The terms “alkoxy” and “alkoxyl” as used herein to refer to an alkyl or cycloalkyl group bonded through an ether linkage; that is, an “alkoxy” group can be defined as —OA1 where A1 is alkyl or cycloalkyl as defined above. “Alkoxy” also includes polymers of alkoxy groups as just described; that is, an alkoxy can be a polyether such as —OA1-OA2 or —OA1-(OA2)a-OA3, where “a” is an integer of from 1 to 200 and A1, A2, and A3 are alkyl and/or cycloalkyl groups.
The term “alkenyl” as used herein is a hydrocarbon group of from 2 to 24 carbon atoms with a structural formula containing at least one carbon-carbon double bond. Asymmetric structures such as (A1A2)C═C(A3A4) are intended to include both the E and Z isomers. This can be presumed in structural formulae herein wherein an asymmetric alkene is present, or it can be explicitly indicated by the bond symbol C═C. The alkenyl group can be substituted with one or more groups including, but not limited to, optionally substituted alkyl, cycloalkyl, alkoxy, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, heteroaryl, aldehyde, amino, carboxylic acid, ester, ether, halide, hydroxy, ketone, azide, nitro, silyl, sulfo-oxo, or thiol, as described herein.
The term “cycloalkenyl” as used herein is a non-aromatic carbon-based ring composed of at least three carbon atoms and containing at least one carbon-carbon double bound, i.e., C═C. Examples of cycloalkenyl groups include, but are not limited to, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclopentadienyl, cyclohexenyl, cyclohexadienyl, norbornenyl, and the like. The term “heterocycloalkenyl” is a type of cycloalkenyl group as defined above, and is included within the meaning of the term “cycloalkenyl,” where at least one of the carbon atoms of the ring is replaced with a heteroatom such as, but not limited to, nitrogen, oxygen, sulfur, or phosphorus. The cycloalkenyl group and heterocycloalkenyl group can be substituted or unsubstituted. The cycloalkenyl group and heterocycloalkenyl group can be substituted with one or more groups including, but not limited to, optionally substituted alkyl, cycloalkyl, alkoxy, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, heteroaryl, aldehyde, amino, carboxylic acid, ester, ether, halide, hydroxy, ketone, azide, nitro, silyl, sulfo-oxo, or thiol as described herein.
The term “alkynyl” as used herein is a hydrocarbon group of 2 to 24 carbon atoms with a structural formula containing at least one carbon-carbon triple bond. The alkynyl group can be unsubstituted or substituted with one or more groups including, but not limited to, optionally substituted alkyl, cycloalkyl, alkoxy, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, heteroaryl, aldehyde, amino, carboxylic acid, ester, ether, halide, hydroxy, ketone, azide, nitro, silyl, sulfo-oxo, or thiol, as described herein.
The term “cycloalkynyl” as used herein is a non-aromatic carbon-based ring composed of at least seven carbon atoms and containing at least one carbon-carbon triple bound. Examples of cycloalkynyl groups include, but are not limited to, cycloheptynyl, cyclooctynyl, cyclononynyl, and the like. The term “heterocycloalkynyl” is a type of cycloalkenyl group as defined above, and is included within the meaning of the term “cycloalkynyl,” where at least one of the carbon atoms of the ring is replaced with a heteroatom such as, but not limited to, nitrogen, oxygen, sulfur, or phosphorus. The cycloalkynyl group and heterocycloalkynyl group can be substituted or unsubstituted. The cycloalkynyl group and heterocycloalkynyl group can be substituted with one or more groups including, but not limited to, optionally substituted alkyl, cycloalkyl, alkoxy, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, heteroaryl, aldehyde, amino, carboxylic acid, ester, ether, halide, hydroxy, ketone, azide, nitro, silyl, sulfo-oxo, or thiol as described herein.
The term “aryl” as used herein is a group that contains any carbon-based aromatic group including, but not limited to, benzene, naphthalene, phenyl, biphenyl, phenoxybenzene, and the like. The term “aryl” also includes “heteroaryl,” which is defined as a group that contains an aromatic group that has at least one heteroatom incorporated within the ring of the aromatic group. Examples of heteroatoms include, but are not limited to, nitrogen, oxygen, sulfur, and phosphorus. Likewise, the term “non-heteroaryl,” which is also included in the term “aryl,” defines a group that contains an aromatic group that does not contain a heteroatom. The aryl group can be substituted or unsubstituted. The aryl group can be substituted with one or more groups including, but not limited to, optionally substituted alkyl, cycloalkyl, alkoxy, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, heteroaryl, aldehyde, amino, carboxylic acid, ester, ether, halide, hydroxy, ketone, azide, nitro, silyl, sulfo-oxo, or thiol as described herein. The term “biaryl” is a specific type of aryl group and is included in the definition of “aryl.” Biaryl refers to two aryl groups that are bound together via a fused ring structure, as in naphthalene, or are attached via one or more carbon-carbon bonds, as in biphenyl.
The term “aldehyde” as used herein is represented by the formula —C(O)H. Throughout this specification “C(O)” is a short hand notation for a carbonyl group, i.e., C═O.
The terms “amine” or “amino” as used herein are represented by the formula —NA1A2, where A1 and A2 can be, independently, hydrogen or alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, or heteroaryl group as described herein.
The term “alkylamino” as used herein is represented by the formula —NH(-alkyl) where alkyl is a described herein. Representative examples include, but are not limited to, methylamino group, ethylamino group, propylamino group, isopropylamino group, butylamino group, isobutylamino group, (sec-butyl)amino group, (tert-butyl)amino group, pentylamino group, isopentylamino group, (tert-pentyl)amino group, hexylamino group, and the like.
The term “dialkylamino” as used herein is represented by the formula —N(-alkyl)2 where alkyl is a described herein. Representative examples include, but are not limited to, dimethylamino group, diethylamino group, dipropylamino group, diisopropylamino group, dibutylamino group, diisobutylamino group, di(sec-butyl)amino group, di(tert-butyl)amino group, dipentylamino group, diisopentylamino group, di(tert-pentyl)amino group, dihexylamino group, N-ethyl-N-methylamino group, N-methyl-N-propylamino group, N-ethyl-N-propylamino group and the like.
The term “carboxylic acid” as used herein is represented by the formula —C(O)OH.
The term “ester” as used herein is represented by the formula —OC(O)A1 or —C(O)OA1, where A1 can be an optionally substituted alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, or heteroaryl group as described herein. The term “polyester” as used herein is represented by the formula -(A1O(O)C-A2-C(O)O)a— or -(A1O(O)C-A2-OC(O))a—, where A1 and A2 can be, independently, an optionally substituted alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, or heteroaryl group described herein and “a” is an integer from 1 to 500. “Polyester” is as the term used to describe a group that is produced by the reaction between a compound having at least two carboxylic acid groups with a compound having at least two hydroxyl groups.
The term “ether” as used herein is represented by the formula A1OA2, where A1 and A2 can be, independently, an optionally substituted alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, or heteroaryl group described herein. The term “polyether” as used herein is represented by the formula -(A1O-A2O)a—, where A1 and A2 can be, independently, an optionally substituted alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, or heteroaryl group described herein and “a” is an integer of from 1 to 500. Examples of polyether groups include polyethylene oxide, polypropylene oxide, and polybutylene oxide.
The term “halide” as used herein refers to the halogens fluorine, chlorine, bromine, and iodine.
The term “heterocycle,” as used herein refers to single and multi-cyclic aromatic or non-aromatic ring systems in which at least one of the ring members is other than carbon. Heterocycle includes pyridinde, pyrimidine, furan, thiophene, pyrrole, isoxazole, isothiazole, pyrazole, oxazole, thiazole, imidazole, oxazole, including, 1,2,3-oxadiazole, 1,2,5-oxadiazole and 1,3,4-oxadiazole, thiadiazole, including, 1,2,3-thiadiazole, 1,2,5-thiadiazole, and 1,3,4-thiadiazole, triazole, including, 1,2,3-triazole, 1,3,4-triazole, tetrazole, including 1,2,3,4-tetrazole and 1,2,4,5-tetrazole, pyridine, pyridazine, pyrimidine, pyrazine, triazine, including 1,2,4-triazine and 1,3,5-triazine, tetrazine, including 1,2,4,5-tetrazine, pyrrolidine, piperidine, piperazine, morpholine, azetidine, tetrahydropyran, tetrahydrofuran, dioxane, and the like.
The term “hydroxyl” as used herein is represented by the formula —OH.
The term “ketone” as used herein is represented by the formula A1C(O)A2, where A1 and A2 can be, independently, an optionally substituted alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, or heteroaryl group as described herein.
The term “azide” as used herein is represented by the formula —N3.
The term “nitro” as used herein is represented by the formula —NO2.
The term “nitrile” as used herein is represented by the formula —CN.
The term “silyl” as used herein is represented by the formula —SiA1A2A3, where A1, A2, and A3 can be, independently, hydrogen or an optionally substituted alkyl, cycloalkyl, alkoxy, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, or heteroaryl group as described herein.
The term “sulfo-oxo” as used herein is represented by the formulas —S(O)A1, —S(O)2A1, —OS(O)2A1, or —OS(O)2OA1, where A1 can be hydrogen or an optionally substituted alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, or heteroaryl group as described herein. Throughout this specification “S(O)” is a short hand notation for S═O. The term “sulfonyl” is used herein to refer to the sulfo-oxo group represented by the formula —S(O)2A1, where A1 can be hydrogen or an optionally substituted alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, or heteroaryl group as described herein. The term “sulfone” as used herein is represented by the formula A1S(O)2A2, where A1 and A2 can be, independently, an optionally substituted alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, or heteroaryl group as described herein. The term “sulfoxide” as used herein is represented by the formula A'S(O)A2, where A1 and A2 can be, independently, an optionally substituted alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, or heteroaryl group as described herein.
The term “thiol” as used herein is represented by the formula —SH.
“R1,” “R2,” “R3,” “Rn,” where n is an integer, as used herein can, independently, possess one or more of the groups listed above. For example, if R1 is a straight chain alkyl group, one of the hydrogen atoms of the alkyl group can optionally be substituted with a hydroxyl group, an alkoxy group, an alkyl group, a halide, and the like. Depending upon the groups that are selected, a first group can be incorporated within second group or, alternatively, the first group can be pendant (i.e., attached) to the second group. For example, with the phrase “an alkyl group comprising an amino group,” the amino group can be incorporated within the backbone of the alkyl group. Alternatively, the amino group can be attached to the backbone of the alkyl group. The nature of the group(s) that is (are) selected will determine if the first group is embedded or attached to the second group.
As described herein, compounds of the invention may contain “optionally substituted” moieties. In general, the term “substituted,” whether preceded by the term “optionally” or not, means that one or more hydrogens of the designated moiety are replaced with a suitable substituent. Unless otherwise indicated, an “optionally substituted” group may have a suitable substituent at each substitutable position of the group, and when more than one position in any given structure may be substituted with more than one substituent selected from a specified group, the substituent may be either the same or different at every position. Combinations of substituents envisioned by this invention are preferably those that result in the formation of stable or chemically feasible compounds. In is also contemplated that, in certain aspects, unless expressly indicated to the contrary, individual substituents can be further optionally substituted (i.e., further substituted or unsubstituted).
The term “stable,” as used herein, refers to compounds that are not substantially altered when subjected to conditions to allow for their production, detection, and, in certain aspects, their recovery, purification, and use for one or more of the purposes disclosed herein.
Suitable monovalent substituents on a substitutable carbon atom of an “optionally substituted” group are independently halogen; —(CH2)0-4R∘; —(CH2)0-4OR∘; —O(CH2)0-4R∘, —O—(CH2)0-4C(O)OR∘; —(CH2)0-4CH(OR∘)2; —(CH2)0-4SR∘; —(CH2)0-4Ph, which may be substituted with R∘; —(CH2)0-4O(CH2)0-1Ph which may be substituted with R∘; —CH═CHPh, which may be substituted with R∘; —(CH2)0-4O(CH2)0-1-pyridyl which may be substituted with R∘; —NO2; —CN; —N3; —(CH2)0-4N(R∘)2; —(CH2)0-4N(R∘)C(O)R∘; —N(R∘)C(S)R∘; —(CH2)0-4N(R∘)C(O)NR∘2; —N(R∘)C(S)NR∘2; —(CH2)0-4N(R∘)C(O)OR∘; —N(R∘)N(R∘)C(O)R∘; —N(R∘)N(R∘)C(O)NR∘2; —N(R∘)N(R∘)C(O)OR∘; —(CH2)0-4C(O)R∘; —C(S)R∘; —(CH2)0-4C(O)OR∘; —(CH2)0-4C(O)SR∘; —(CH2)0-4C(O)OSiR∘3; —(CH2)0-4OC(O)R∘; —OC(O)(CH2)0-4SR—, SC(S)SR∘; —(CH2)0-4SC(O)R∘; —(CH2)0-4C(O)NR∘2; —C(S)NR∘2; —C(S)SR∘; —SC(S)SR∘, —(CH2)0-4OC(O)NR∘2; —C(O)N(OR∘)R∘; —C(O)C(O)R∘; —C(O)CH2C(O)R∘; —C(NOR∘)R∘; —(CH2)0-4SSR∘; —(CH2)0-4S(O)2R∘; —(CH2)0-4S(O)2OR∘; —(CH2)0-4OS(O)2R∘; —S(O)2NR∘2; —(CH2)0-4S(O)R∘; —N(R∘)S(O)2NR∘2; —N(R∘)S(O)2R∘; —N(OR∘)R∘; —C(NH)NR∘2; —P(O)2R∘; —P(O)R∘2; —OP(O)R∘2; —OP(O)(OR∘)2; SiR∘3; —(C1-4 straight or branched alkylene)O—N(R∘)2; or —(C1-4 straight or branched alkylene)C(O)O—N(R∘)2, wherein each R∘ may be substituted as defined below and is independently hydrogen, C1-6 aliphatic, —CH2Ph, —O(CH2)0-1Ph, —CH2-(5-6 membered heteroaryl ring), or a 5-6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or, notwithstanding the definition above, two independent occurrences of R∘, taken together with their intervening atom(s), form a 3-12-membered saturated, partially unsaturated, or aryl mono- or bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, which may be substituted as defined below.
Suitable monovalent substituents on R∘ (or the ring formed by taking two independent occurrences of R∘ together with their intervening atoms), are independently halogen, —(CH2)0-2R●, -(haloR●), —(CH2)0-2OH, —(CH2)0-2OR●, —(CH2)0-2CH(OR●)2; —O(haloR●), —CN, —N3, —(CH2)0-2C(O)R●, —(CH2)0-2C(O)OH, —(CH2)0-2C(O)OR●, —(CH2)0-2SR●, —(CH2)0-2SH, —(CH2)0-2NH2, —(CH2)0-2NHR●, —(CH2)0-2NR●2, —NO2, —SiR●3, —OSiR●3, —C(O)SR●, —(C1-4 straight or branched alkylene)C(O)OR●, or —SSR● wherein each R● is unsubstituted or where preceded by “halo” is substituted only with one or more halogens, and is independently selected from C1-4 aliphatic, —CH2Ph, —O(CH2)0-1Ph, or a 5-6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. Suitable divalent substituents on a saturated carbon atom of R∘ include ═O and ═S.
Suitable divalent substituents on a saturated carbon atom of an “optionally substituted” group include the following: ═O, ═S, ═NNR*2, ═NNHC(O)R*, ═NNHC(O)OR*, ═NNHS(O)2R*, ═NR*, ═NOR*, —O(C(R*2))2-3O—, or —S(C(R*2))2-3S—, wherein each independent occurrence of R* is selected from hydrogen, C1-6 aliphatic which may be substituted as defined below, or an unsubstituted 5-6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. Suitable divalent substituents that are bound to vicinal substitutable carbons of an “optionally substituted” group include: —O(CR*2)2-3O—, wherein each independent occurrence of R* is selected from hydrogen, C1-6 aliphatic which may be substituted as defined below, or an unsubstituted 5-6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.
Suitable substituents on the aliphatic group of R* include halogen, —R●, -(haloR●), —OH, —OR●, —O(haloR●), —CN, —C(O)OH, —C(O)OR●, —NH2, —NHR●, —NR●2, or —NO2, wherein each R● is unsubstituted or where preceded by “halo” is substituted only with one or more halogens, and is independently C1-4 aliphatic, —CH2Ph, —O(CH2)0-1Ph, or a 5-6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.
Suitable substituents on a substitutable nitrogen of an “optionally substituted” group include —R†, —NR†2, —C(O)R†, —C(O)OR†, —C(O)C(O)R†, —C(O)CH2C(O)R†, —S(O)2R†, —S(O)2NR†2, —C(S)NR†2, —C(NH)NR†2, or —N(R†)S(O)2R†; wherein each R† is independently hydrogen, C1-6 aliphatic which may be substituted as defined below, unsubstituted —OPh, or an unsubstituted 5-6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or, notwithstanding the definition above, two independent occurrences of R†, taken together with their intervening atom(s) form an unsubstituted 3-12-membered saturated, partially unsaturated, or aryl mono- or bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.
Suitable substituents on the aliphatic group of R† are independently halogen, —R●, -(haloR●), —OH, —OR●, —O(haloR●), —CN, —C(O)OH, —C(O)OR●, —NH2, —NHR●, —NR●2, or —NO2, wherein each R● is unsubstituted or where preceded by “halo” is substituted only with one or more halogens, and is independently C1-4 aliphatic, —CH2Ph, —O(CH2)0-1Ph, or a 5-6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.
The term “organic residue” defines a carbon containing residue, i.e., a residue comprising at least one carbon atom, and includes but is not limited to the carbon-containing groups, residues, or radicals defined hereinabove. Organic residues can contain various heteroatoms, or be bonded to another molecule through a heteroatom, including oxygen, nitrogen, sulfur, phosphorus, or the like. Examples of organic residues include but are not limited alkyl or substituted alkyls, alkoxy or substituted alkoxy, mono or di-substituted amino, amide groups, etc. Organic residues can preferably comprise 1 to 18 carbon atoms, 1 to 15, carbon atoms, 1 to 12 carbon atoms, 1 to 8 carbon atoms, 1 to 6 carbon atoms, or 1 to 4 carbon atoms. In a further aspect, an organic residue can comprise 2 to 18 carbon atoms, 2 to 15, carbon atoms, 2 to 12 carbon atoms, 2 to 8 carbon atoms, 2 to 4 carbon atoms, or 2 to 4 carbon atoms
A very close synonym of the term “residue” is the term “radical,” which as used in the specification and concluding claims, refers to a fragment, group, or substructure of a molecule described herein, regardless of how the molecule is prepared. For example, a 2,4-thiazolidinedione radical in a particular compound has the structure:
regardless of whether thiazolidinedione is used to prepare the compound. In some embodiments the radical (for example an alkyl) can be further modified (i.e., substituted alkyl) by having bonded thereto one or more “substituent radicals.” The number of atoms in a given radical is not critical to the present invention unless it is indicated to the contrary elsewhere herein.
“Organic radicals,” as the term is defined and used herein, contain one or more carbon atoms. An organic radical can have, for example, 1-26 carbon atoms, 1-18 carbon atoms, 1-12 carbon atoms, 1-8 carbon atoms, 1-6 carbon atoms, or 1-4 carbon atoms. In a further aspect, an organic radical can have 2-26 carbon atoms, 2-18 carbon atoms, 2-12 carbon atoms, 2-8 carbon atoms, 2-6 carbon atoms, or 2-4 carbon atoms. Organic radicals often have hydrogen bound to at least some of the carbon atoms of the organic radical. One example, of an organic radical that comprises no inorganic atoms is a 5, 6, 7, 8-tetrahydro-2-naphthyl radical. In some embodiments, an organic radical can contain 1-10 inorganic heteroatoms bound thereto or therein, including halogens, oxygen, sulfur, nitrogen, phosphorus, and the like. Examples of organic radicals include but are not limited to an alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, mono-substituted amino, di-substituted amino, acyloxy, cyano, carboxy, carboalkoxy, alkylcarboxamide, substituted alkylcarboxamide, dialkylcarboxamide, substituted dialkylcarboxamide, alkylsulfonyl, alkylsulfinyl, thioalkyl, thiohaloalkyl, alkoxy, substituted alkoxy, haloalkyl, haloalkoxy, aryl, substituted aryl, heteroaryl, heterocyclic, or substituted heterocyclic radicals, wherein the terms are defined elsewhere herein. A few non-limiting examples of organic radicals that include heteroatoms include alkoxy radicals, trifluoromethoxy radicals, acetoxy radicals, dimethylamino radicals and the like.
“Inorganic radicals,” as the term is defined and used herein, contain no carbon atoms and therefore comprise only atoms other than carbon. Inorganic radicals comprise bonded combinations of atoms selected from hydrogen, nitrogen, oxygen, silicon, phosphorus, sulfur, selenium, and halogens such as fluorine, chlorine, bromine, and iodine, which can be present individually or bonded together in their chemically stable combinations. Inorganic radicals have 10 or fewer, or preferably one to six or one to four inorganic atoms as listed above bonded together. Examples of inorganic radicals include, but not limited to, amino, hydroxy, halogens, nitro, thiol, sulfate, phosphate, and like commonly known inorganic radicals. The inorganic radicals do not have bonded therein the metallic elements of the periodic table (such as the alkali metals, alkaline earth metals, transition metals, lanthanide metals, or actinide metals), although such metal ions can sometimes serve as a pharmaceutically acceptable cation for anionic inorganic radicals such as a sulfate, phosphate, or like anionic inorganic radical. Inorganic radicals do not comprise metalloids elements such as boron, aluminum, gallium, germanium, arsenic, tin, lead, or tellurium, or the noble gas elements, unless otherwise specifically indicated elsewhere herein.
Compounds described herein can contain one or more double bonds and, thus, potentially give rise to cis/trans (E/Z) isomers, as well as other conformational isomers. Unless stated to the contrary, the invention includes all such possible isomers, as well as mixtures of such isomers.
Unless stated to the contrary, a formula with chemical bonds shown only as solid lines and not as wedges or dashed lines contemplates each possible isomer, e.g., each enantiomer and diastereomer, and a mixture of isomers, such as a racemic or scalemic mixture. Compounds described herein can contain one or more asymmetric centers and, thus, potentially give rise to diastereomers and optical isomers. Unless stated to the contrary, the present invention includes all such possible diastereomers as well as their racemic mixtures, their substantially pure resolved enantiomers, all possible geometric isomers, and pharmaceutically acceptable salts thereof. Mixtures of stereoisomers, as well as isolated specific stereoisomers, are also included. During the course of the synthetic procedures used to prepare such compounds, or in using racemization or epimerization procedures known to those skilled in the art, the products of such procedures can be a mixture of stereoisomers.
Many organic compounds exist in optically active forms having the ability to rotate the plane of plane-polarized light. In describing an optically active compound, the prefixes D and L or R and S are used to denote the absolute configuration of the molecule about its chiral center(s). The prefixes d and 1 or (+) and (−) are employed to designate the sign of rotation of plane-polarized light by the compound, with (−) or meaning that the compound is levorotatory. A compound prefixed with (+) or d is dextrorotatory. For a given chemical structure, these compounds, called stereoisomers, are identical except that they are non-superimposable mirror images of one another. A specific stereoisomer can also be referred to as an enantiomer, and a mixture of such isomers is often called an enantiomeric mixture. A 50:50 mixture of enantiomers is referred to as a racemic mixture. Many of the compounds described herein can have one or more chiral centers and therefore can exist in different enantiomeric forms. If desired, a chiral carbon can be designated with an asterisk (*). When bonds to the chiral carbon are depicted as straight lines in the disclosed formulas, it is understood that both the (R) and (S) configurations of the chiral carbon, and hence both enantiomers and mixtures thereof, are embraced within the formula. As is used in the art, when it is desired to specify the absolute configuration about a chiral carbon, one of the bonds to the chiral carbon can be depicted as a wedge (bonds to atoms above the plane) and the other can be depicted as a series or wedge of short parallel lines is (bonds to atoms below the plane). The Cahn-Ingold-Prelog system can be used to assign the (R) or (S) configuration to a chiral carbon.
When the disclosed compounds contain one chiral center, the compounds exist in two enantiomeric forms. Unless specifically stated to the contrary, a disclosed compound includes both enantiomers and mixtures of enantiomers, such as the specific 50:50 mixture referred to as a racemic mixture. The enantiomers can be resolved by methods known to those skilled in the art, such as formation of diastereoisomeric salts which may be separated, for example, by crystallization (see, CRC Handbook of Optical Resolutions via Diastereomeric Salt Formation by David Kozma (CRC Press, 2001)); formation of diastereoisomeric derivatives or complexes which may be separated, for example, by crystallization, gas-liquid or liquid chromatography; selective reaction of one enantiomer with an enantiomer-specific reagent, for example enzymatic esterification; or gas-liquid or liquid chromatography in a chiral environment, for example on a chiral support for example silica with a bound chiral ligand or in the presence of a chiral solvent. It will be appreciated that where the desired enantiomer is converted into another chemical entity by one of the separation procedures described above, a further step can liberate the desired enantiomeric form. Alternatively, specific enantiomers can be synthesized by asymmetric synthesis using optically active reagents, substrates, catalysts or solvents, or by converting one enantiomer into the other by asymmetric transformation.
Designation of a specific absolute configuration at a chiral carbon in a disclosed compound is understood to mean that the designated enantiomeric form of the compounds can be provided in enantiomeric excess (e.e.). Enantiomeric excess, as used herein, is the presence of a particular enantiomer at greater than 50%, for example, greater than 60%, greater than 70%, greater than 75%, greater than 80%, greater than 85%, greater than 90%, greater than 95%, greater than 98%, or greater than 99%. In one aspect, the designated enantiomer is substantially free from the other enantiomer. For example, the “R” forms of the compounds can be substantially free from the “S” forms of the compounds and are, thus, in enantiomeric excess of the “S” forms. Conversely, “S” forms of the compounds can be substantially free of “R” forms of the compounds and are, thus, in enantiomeric excess of the “R” forms.
When a disclosed compound has two or more chiral carbons, it can have more than two optical isomers and can exist in diastereoisomeric forms. For example, when there are two chiral carbons, the compound can have up to four optical isomers and two pairs of enantiomers ((S,S)/(R,R) and (R,S)/(S,R)). The pairs of enantiomers (e.g., (S,S)/(R,R)) are mirror image stereoisomers of one another. The stereoisomers that are not mirror-images (e.g., (S,S) and (R,S)) are diastereomers. The diastereoisomeric pairs can be separated by methods known to those skilled in the art, for example chromatography or crystallization and the individual enantiomers within each pair may be separated as described above. Unless otherwise specifically excluded, a disclosed compound includes each diastereoisomer of such compounds and mixtures thereof.
Compounds described herein comprise atoms in both their natural isotopic abundance and in non-natural abundance. The disclosed compounds can be isotopically-labeled or isotopically-substituted compounds identical to those described, but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number typically found in nature. Examples of isotopes that can be incorporated into compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, fluorine and chlorine, such as 2H, 3H, 13C, 14C, 15N, 18O, 17O, 35S, 18F and 36Cl, respectively. Compounds further comprise prodrugs thereof, and pharmaceutically acceptable salts of said compounds or of said prodrugs which contain the aforementioned isotopes and/or other isotopes of other atoms are within the scope of this invention. Certain isotopically-labeled compounds of the present invention, for example those into which radioactive isotopes such as 3H and 14C are incorporated, are useful in drug and/or substrate tissue distribution assays. Tritiated, i.e., 3H, and carbon-14, i.e., 14C, isotopes are particularly preferred for their ease of preparation and detectability. Further, substitution with heavier isotopes such as deuterium, i.e., 2H, can afford certain therapeutic advantages resulting from greater metabolic stability, for example increased in vivo half-life or reduced dosage requirements and, hence, may be preferred in some circumstances. Isotopically labeled compounds of the present invention and prodrugs thereof can generally be prepared by carrying out the procedures below, by substituting a readily available isotopically labeled reagent for a non- isotopically labeled reagent.
The compounds described in the invention can be present as a solvate. “Solvates” refers to the compound formed by the interaction of a solvent and a solute and includes hydrates. Solvates are usually crystalline solid adducts containing solvent molecules within the crystal structure, in either stoichiometric or nonstoichiometric proportions. In some cases, the solvent used to prepare the solvate is an aqueous solution, and the solvate is then often referred to as a hydrate. The compounds can be present as a hydrate, which can be obtained, for example, by crystallization from a solvent or from aqueous solution. In this connection, one, two, three or any arbitrary number of solvate or water molecules can combine with the compounds according to the invention to form solvates and hydrates. Unless stated to the contrary, the invention includes all such possible solvates.
The term “co-crystal” means a physical association of two or more molecules which owe their stability through non-covalent interaction. One or more components of this molecular complex provide a stable framework in the crystalline lattice. In certain instances, the guest molecules are incorporated in the crystalline lattice as anhydrates or solvates, see e.g. “Crystal Engineering of the Composition of Pharmaceutical Phases. Do Pharmaceutical Co-crystals Represent a New Path to Improved Medicines?” Almarasson, O., et. al., The Royal Society of Chemistry, 1889-1896, 2004. Examples of co-crystals include p-toluenesulfonic acid and benzenesulfonic acid.
It is known that chemical substances form solids which are present in different states of order which are termed polymorphic forms or modifications. The different modifications of a polymorphic substance can differ greatly in their physical properties. The compounds according to the invention can be present in different polymorphic forms, with it being possible for particular modifications to be metastable. Unless stated to the contrary, the invention includes all such possible polymorphic forms.
In some aspects, a structure of a compound can be represented by a formula:
which is understood to be equivalent to a formula:
wherein n is typically an integer. That is, Rn is understood to represent five independent substituents, Rn(a), Rn(b), Rn(c), Rn(d), Rn(e). In each such case, each of the five Rn can be hydrogen or a recited substituent. By “independent substituents,” it is meant that each R substituent can be independently defined. For example, if in one instance Rn(a) is halogen, then Rn(b) is not necessarily halogen in that instance.
In some yet further aspects, a structure of a compound can be represented by a formula:
wherein RY represents, for example, 0-2 independent substituents selected from A1, A2, and A3, which is understood to be equivalent to the groups of formulae:
Again, by “independent substituents,” it is meant that each R substituent can be independently defined. For example, if in one instance Ry1 is A1, then Ry2 is not necessarily A1 in that instance.
In some further aspects, a structure of a compound can be represented by a formula,
wherein, for example, Q comprises three substituents independently selected from hydrogen and A, which is understood to be equivalent to a formula:
Again, by “independent substituents,” it is meant that each Q substituent is independently defined as hydrogen or A, which is understood to be equivalent to the groups of formulae:
Certain materials, compounds, compositions, and components disclosed herein can be obtained commercially or readily synthesized using techniques generally known to those of skill in the art. For example, the starting materials and reagents used in preparing the disclosed compounds and compositions are either available from commercial suppliers such as Aldrich Chemical Co., (Milwaukee, Wis.), Acros Organics (Morris Plains, N.J.), Fisher Scientific (Pittsburgh, Pa.), or Sigma (St. Louis, Mo.) or are prepared by methods known to those skilled in the art following procedures set forth in references such as Fieser and Fieser's Reagents for Organic Synthesis, Volumes 1-17 (John Wiley and Sons, 1991); Rodd's Chemistry of Carbon Compounds, Volumes 1-5 and Supplementals (Elsevier Science Publishers, 1989); Organic Reactions, Volumes 1-40 (John Wiley and Sons, 1991); March's Advanced Organic Chemistry, (John Wiley and Sons, 4th Edition); and Larock's Comprehensive Organic Transformations (VCH Publishers Inc., 1989).
Unless otherwise expressly stated, it is in no way intended that any method set forth herein be construed as requiring that its steps be performed in a specific order. Accordingly, where a method claim does not actually recite an order to be followed by its steps or it is not otherwise specifically stated in the claims or descriptions that the steps are to be limited to a specific order, it is no way intended that an order be inferred, in any respect. This holds for any possible non-express basis for interpretation, including: matters of logic with respect to arrangement of steps or operational flow; plain meaning derived from grammatical organization or punctuation; and the number or type of embodiments described in the specification.
Disclosed are the components to be used to prepare the compositions of the invention as well as the compositions themselves to be used within the methods disclosed herein. These and other materials are disclosed herein, and it is understood that when combinations, subsets, interactions, groups, etc. of these materials are disclosed that while specific reference of each various individual and collective combinations and permutation of these compounds cannot be explicitly disclosed, each is specifically contemplated and described herein. For example, if a particular compound is disclosed and discussed and a number of modifications that can be made to a number of molecules including the compounds are discussed, specifically contemplated is each and every combination and permutation of the compound and the modifications that are possible unless specifically indicated to the contrary. Thus, if a class of molecules A, B, and C are disclosed as well as a class of molecules D, E, and F and an example of a combination molecule, A-D is disclosed, then even if each is not individually recited each is individually and collectively contemplated meaning combinations, A-E, A-F, B-D, B-E, B-F, C-D, C-E, and C-F are considered disclosed. Likewise, any subset or combination of these is also disclosed. Thus, for example, the sub-group of A-E, B-F, and C-E would be considered disclosed. This concept applies to all aspects of this application including, but not limited to, steps in methods of making and using the compositions of the invention. Thus, if there are a variety of additional steps that can be performed it is understood that each of these additional steps can be performed with any specific embodiment or combination of embodiments of the methods of the invention.
It is understood that the compositions disclosed herein have certain functions. Disclosed herein are certain structural requirements for performing the disclosed functions, and it is understood that there are a variety of structures that can perform the same function that are related to the disclosed structures, and that these structures will typically achieve the same result.
In one aspect, the invention relates to taccalonolide microtubule stabilizers useful as cellular probes (e.g., for the detection, visualization, and/or quantification of a target). The disclosed compounds are also useful in the treatment of hyperproliferative disorders including, but not limited to, cardiovascular diseases such as, for example, coronary heart disease, stroke, hypertensive heart disease, inflammatory heart disease, and rheumatic heart disease, and cancers such as, for example, a sarcoma, a carcinoma, a hematological cancer, a solid tumor, breast cancer, cervical cancer, gastrointestinal cancer, colorectal cancer, brain cancer, skin cancer, prostate cancer, ovarian cancer, thyroid cancer, testicular cancer, pancreatic cancer, endometrial cancer, melanoma, glioma, leukemia, lymphoma, chronic myeloproliferative disorder, myelodysplastic syndrome, myeloproliferative neoplasm, and plasma cell neoplasm (myeloma).
In one aspect, the compounds of the invention are useful as a cellular probe such as, for example, a tubulin-labeling probe.
In one aspect, the compounds of the invention are useful as ADCs.
In one aspect, the compounds of the invention are useful in the treatment of cancers, as further described herein.
In one aspect, the compounds of the invention are useful in the treatment of cardiovascular disease, as further described herein.
It is contemplated that each disclosed derivative can be optionally further substituted. It is also contemplated that any one or more derivative can be optionally omitted from the invention. It is understood that a disclosed compound can be provided by the disclosed methods. It is also understood that the disclosed compounds can be employed in the disclosed methods of using.
1. Structure
In one aspect, disclosed are compounds having a structure represented by a formula:
wherein each occurrence of - - - - - - is a single or double covalent bond; wherein X is selected from O, NRx, and C(Rx)2; wherein each occurrence of Rx, when present, is independently selected from hydrogen and C1-C6 alkyl; wherein R1 is selected from hydrogen, halogen, —OH, —CN, —NC, —NCO, —OCN, —NO2, —ONO2, —ONO, —NO, —N3, —NH2, —NH3, —N═NR31, —NHOH, C1-C12 alkyl, C2-C12 alkenyl, C2-C12 alkynyl, C1-C12 hydroxy, C1-C12 alkoxy, C1-C12 thioalkyl, C1-C12 alkylthiol, C1-C12 aminoalkyl, C1-C12 alkylamino, (C1-C12)(C1-C12) dialkylamino, —OC(O)(C1-C12 alkyl), —OP(O)(OR32)2, —OSO2R33, —C(O)(C1-C12 alkyl), —CO2R34, —C(O)NR35aR35b, —(C1-C12 alkyl)C(O)NR35aR35b, —OC(O)NR35aR35b, —(C1-C12 alkyl)OC(O)NR35aR35b, Cy1, Ar1, (C1-C12 alkyl)Ar1, and —OAr1; wherein each occurrence of R31, R32, R34, R35a, and R35b, when present, is independently selected from hydrogen and C1-C12 alkyl; wherein each occurrence of R33, when present, is independently selected from hydrogen, C1-C12 alkyl, and monocyclic aryl monosubstituted with a methyl group; wherein each occurrence of Cy1, when present, is heterocycloalkyl substituted with 0, 1, 2, or 3 groups independently selected from halogen, —OH, —NH2, C1-C4 alkoxy, C1-C4 hydroxy, C1-C4 aminoalkyl, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino; wherein each occurrence of Ar1, when present, is selected from monocyclic aryl, morpholinyl, anilinyl, indolyl, pyrrolyl, imidazolyl, benzimidazolyl, pyrazolyl, guanidinyl, and piperazinyl and substituted with 0, 1, 2, or 3 groups independently selected from halogen, —OH, —NH2, C1-C4 alkoxy, C1-C4 hydroxy, C1-C4 aminoalkyl, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino; and wherein R1′ is hydrogen; or wherein each of R1 and R1′ together comprise ═O or ═NR36; wherein each occurrence of R36, when present, is independently selected from hydrogen and C1-C12 alkyl; wherein each of R2 and R3 is independently selected from hydrogen, —OH, C1-C12 hydroxy, and halogen; or wherein each of R2 and R3 together comprise —O—; wherein R5 is selected from hydrogen, —OH, —NH2, C1-C9 alkyl, C1-C9 hydroxy, C1-C9 alkoxy, C1-C9 aminoalkyl, C1-C6 alkylamino, and (C1-C6)(C1-C6) dialkylamino; or wherein R5 is absent; wherein each of R6 and R6′ is independently selected from hydrogen, halogen, —OH, —CN, —NC, —NCO, —OCN, —NO2, —ONO2, —ONO, —NO, —N3, —NH2, —NH3, —N═NR41, —NHOH, C1-C30 alkyl, C2-C30 alkenyl, C2-C30 alkynyl, C1-C30 hydroxy, C1-C30 alkoxy, C1-C30 thioalkyl, C1-C30 alkylthiol, C1-C30 aminoalkyl, C1-C30 alkylamino, (C1-C30)(C1-C30) dialkylamino, —C(O)(C1-C30 alkyl), —OP(O)(OR32)2, —OSO2R33, —CO2R34, —C(O)NR35aR35b, —(C1-C30 alkyl)C(O)NR35aR35b, —OC(O)NR35aR35b, —(C1-C30 alkyl)OC(O)NR35aR35b, Cy1, Ar1, —(C1-C30 alkyl)Ar1, —OAr1, —OC(O)(C1-C30 alkyl), —OC(O)Ar2, —OC(O)(C1-C30 alkyl)Ar2, —OC(O)Ar3, —OC(O)(C1-C30 alkyl)NR42C(O)Ar3, —OC(O)(C1-C30 alkyl)OC(O)Ar3, —OC(O)R40, —NR41C(O)(C1-C30 alkyl), —NR41C(O)Ar2, —NR41C(O)(C1-C30 alkyl)Ar2, —NR41C(O)Ar3, —NR41C(O)(C1-C30 alkyl)OC(O)Ar3, —NR41C(O)(C1-C30 alkyl)NR42C(O)Ar3, and —NR41C(O)R40; wherein each occurrence of R40, when present, is independently a C1-C30 alkyl functionalized with a group selected from —N3, —SH, —OH, —NH2, —NHOH, an ester, a disulfide, a sulfonamide, a terminal alkyne, haloacetyl, maleimide, isothiocyanate, N-hydroxysuccinimde, an acylhydrazine, an acylhydrazone, a hydrazine, a hydrazone, and hydrazide; wherein each occurrence of R41 and R42, when present, is independently selected from hydrogen and C1-C12 alkyl; wherein each occurrence of Ar2, when present, is independently selected from aryl and heteroaryl, and is substituted with 0, 1, 2, or 3 groups independently selected from halogen, —OH, —NH2, C1-C4 alkoxy, C1-C4 hydroxy, C1-C4 aminoalkyl, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, —(C1-C12 alkyl)Ar4, and Ar4; wherein each occurrence of Ar4, when present, is a structure represented by a formula selected from:
wherein each of R50a, R50b, R50c, and R50d, when present, is independently selected from hydrogen, —F, and —Cl; wherein each of R51a and R51b, when present, is independently selected from hydrogen and —C(O)(C1-C12 alkyl); wherein each of R52a, R52b, R52c, and R52d, when present, is independently selected from hydrogen, —F, and —Cl; wherein each occurrence of Ar3, when present, is a structure represented by a formula selected from:
or wherein one of R6 and R6′ is absent; wherein R7 is selected from hydrogen, —OH, C1-C30 hydroxy, C1-C30 alkoxy, —OC(O)(C1-C30 alkyl), and —OC(O)NR35aR35b, and wherein R7′ is selected from hydrogen, —OH, C1-C30 hydroxy, C1-C30 alkoxy, and —OC(O)(C1-C30 alkyl); or wherein each of R7 and R7′ together comprise ═O; or wherein one of R7 and R7′ is absent; wherein each of R11 and R12 is independently selected from hydrogen, —OH, C1-C8 hydroxy, C1-C6 alkyl, C1-C8 alkoxy, and —OC(O)(C1-C8 alkyl); wherein R15 is selected from hydrogen, —OH, C1-C30 hydroxy, C1-C30 alkyl, C1-C30 alkoxy, —OC(O)(C1-C30 alkyl), —OC(O)NR35aR35b, —OC(O)Ar2, —OC(O)(C1-C4 alkyl)Ar2, and —OC(O)(C1-C8 azide); wherein R20 is selected from hydrogen, —OH, —OOH, C1-C8 alkyl, C1-C8 hydroxy, C1-C8 alkoxy, C1-C8 hydroperoxy, and —OC(O)(C1-C8 alkyl); wherein R21 is selected from hydrogen and C1-C6 alkyl; wherein R25 is selected from hydrogen, —OH, C1-C8 hydroxy, C1-C8 alkoxy, —OC(O)(C1-18 alkyl), —OC(O)NR35aR35b, —OC(O)Ar5, and —OC(O)(C1-C8 azide); wherein Ar5, when present, is selected from monocyclic 6-membered aryl and anthracene-9,10-dionyl, and is substituted with 0, 1, 2, or 3 groups independently selected from halogen, —OH, —NH2, C1-C4 alkoxy, C1-C4 hydroxy, C1-C4 aminoalkyl, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino; wherein each of R26 and R26′ is independently selected from hydrogen, —OH, C1-C8 hydroxy, and C1-C8 alkoxy; or wherein each of R26 and R26′ together comprise ═O; wherein R27 is selected from hydrogen and C1-C6 alkyl; wherein each of R28 and R29 is independently selected from hydrogen and halogen; or wherein each of R28 and R29 together comprise —O— or —N(R37)—; wherein R37, when present, is selected from hydrogen, C1-C4 alkyl, —SO2R71, and a structure having a formula:
and
wherein R71, when present, is selected from hydrogen, C1-C4 alkyl, —CH2CH2Si(CH3)3, and monocyclic aryl monosubstituted with a methyl group, provided that at least one of R6 and R6′ is —NR41C(O)(C1-C30 alkyl), —NR41C(O)Ar2, —NR41C(O)(C1-C30 alkyl)Ar2, —NR41C(O)Ar3, —NR41C(O)(C1-C30 alkyl)OC(O)Ar3, —NR41C(O)(C1-C30 alkyl)NR42C(O)Ar3, or —NR41C(O)R40, and provided that when one or both of R28 and R29 is hydrogen then the occurrence of - - - - - - at C-22/C-23 is a double covalent bond, or a pharmaceutically acceptable salt thereof.
In one aspect, disclosed are compounds having a structure represented by a formula:
wherein each occurrence of - - - - - - is a single or double covalent bond; wherein X is selected from O, NRx and C(Rx)2; wherein each occurrence of Rx, when present, is independently selected from hydrogen and C1-C6 alkyl; wherein R1 is selected from hydrogen, halogen, —OH, —CN, —NC, —NCO, —OCN, —NO2, —ONO2, —ONO, —NO, —N3, —NH2, —NH3, —N═NR3, —NHOH, C1-C12 alkyl, C2-C12 alkenyl, C2-C12 alkynyl, C1-C12 hydroxy, C1-C12 alkoxy, C1-C12 thioalkyl, C1-C12 alkylthiol, C1-C12 aminoalkyl, C1-C12 alkylamino, (C1-C12)(C1-C12) dialkylamino, —OC(O)(C1-C12 alkyl), —OP(O)(OR32)2, —OSO2R33, —C(O)(C1-C12 alkyl), —CO2R34, —C(O)NR35aR35b, —(C1-C12 alkyl)C(O)NR35aR35b, —OC(O)NR35aR35b, —(C1-C12 alkyl)OC(O)NR35aR35b, Cy1, Ar1, (C1-C12 alkyl)Ar1, and —OAr1; wherein each occurrence of R31, R32, R34, R35a, and R35b, when present, is independently selected from hydrogen and C1-C12 alkyl; wherein each occurrence of R33, when present, is independently selected from hydrogen, C1-C12 alkyl, and monocyclic aryl monosubstituted with a methyl group; wherein each occurrence of Cy1, when present, is heterocycloalkyl substituted with 0, 1, 2, or 3 groups independently selected from halogen, —OH, —NH2, C1-C4 alkoxy, C1-C4 hydroxy, C1-C4 aminoalkyl, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino; wherein each occurrence of Ar1, when present, is selected from monocyclic aryl, morpholinyl, anilinyl, indolyl, pyrrolyl, imidazolyl, benzimidazolyl, pyrazolyl, guanidinyl, and piperazinyl and substituted with 0, 1, 2, or 3 groups independently selected from halogen, —OH, —NH2, C1-C4 alkoxy, C1-C4 hydroxy, C1-C4 aminoalkyl, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino; and wherein R1′ is hydrogen; or wherein each of R1 and R1′ together comprise ═O or ═NR36; wherein each occurrence of R36, when present, is independently selected from hydrogen and C1-C12 alkyl; wherein each of R2 and R3 is independently selected from hydrogen, —OH, C1-C12 hydroxy, and halogen; or wherein each of R2 and R3 together comprise —O—; wherein R5 is selected from hydrogen, —OH, —NH2, C1-C9 alkyl, C1-C9 hydroxy, C1-C9 alkoxy, C1-C9 aminoalkyl, C1-C6 alkylamino, and (C1-C6)(C1-C6) dialkylamino; or wherein R5 is absent; wherein each of R6 and R6′ is independently selected from hydrogen, halogen, —OH, —CN, —NC, —NCO, —OCN, —NO2, —ONO2, —ONO, —NO, —N3, —NH2, —NH3, —N═NR41, —NHOH, C1-C30 alkyl, C2-C30 alkenyl, C2-C30 alkynyl, C1-C30 hydroxy, C1-C30 alkoxy, C1-C30 thioalkyl, C1-C30 alkylthiol, C1-C30 aminoalkyl, C1-C30 alkylamino, (C1-C30)(C1-C30) dialkylamino, —C(O)(C1-C30 alkyl), —OP(O)(OR32)2, —OSO2R33, —CO2R34, —C(O)NR35aR35b, —(C1-C30 alkyl)C(O)NR35aR35b, —OC(O)NR35aR35b, —(C1-C30 alkyl)OC(O)NR35aR35b, Cy1, Ar1, —(C1-C30 alkyl)Ar1, —OAr1, —OC(O)(C1-C30 alkyl), —OC(O)Ar2, —OC(O)(C1-C30 alkyl)Ar2, —OC(O)Ar3, —OC(O)(C1-C30 alkyl)NR42C(O)Ar3, —OC(O)(C1-C30 alkyl)OC(O)Ar3, —OC(O)R40, —NR41C(O)(C1-C30 alkyl), —NR41C(O)Ar2, —NR41C(O)(C1-C30 alkyl)Ar2, —NR41C(O)Ar3, —NR41C(O)(C1-C30 alkyl)OC(O)Ar3, —NR41C(O)(C1-C30 alkyl)NR42C(O)Ar3, and —NR41C(O)R40; wherein each occurrence of R40, when present, is independently a C1-C30 alkyl functionalized with a group selected from —SH, —NH2, —NHOH, terminal alkyne, haloacetyl, maleimide, isothiocyanate, N-hydroxysuccinimde, succinimidyl ester, tetrafluorophenyl ester, sulfodichlorophenol ester, and hydrazide; wherein each occurrence of R41 and R42, when present, is independently selected from hydrogen and C1-C12 alkyl; wherein each occurrence of Ar2, when present, is independently selected from aryl and heteroaryl, and is substituted with 0, 1, 2, or 3 groups independently selected from halogen, —OH, —NH2, C1-C4 alkoxy, C1-C4 hydroxy, C1-C4 aminoalkyl, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, —(C1-C12 alkyl)Ar4, and Ar4; wherein each occurrence of Ar4, when present, is a structure represented by a formula:
wherein each of R50a, R50b, R50c, and R50d, when present, is independently selected from hydrogen, —F, and —Cl; wherein each of R51a and R51b, when present, is independently selected from hydrogen and —C(O)(C1-C12 alkyl); wherein each of R52a, R52b, R52c, and R52d, when present, is independently selected from hydrogen, —F, and —Cl; wherein each occurrence of Ar3, when present, is a structure represented by a formula selected from:
or wherein one of R6 and R6′ is absent; wherein R7 is selected from hydrogen, —OH, C1-C30 hydroxy, C1-C30 alkoxy, —OC(O)(C1-C30 alkyl), and —OC(O)NR35aR35b, and wherein R7′ is selected from hydrogen, —OH, C1-C30 hydroxy, C1-C30 alkoxy, and —OC(O)(C1-C30 alkyl); or wherein each of R7 and R7′ together comprise ═O; or wherein one of R7 and R7′ is absent; wherein each of R11 and R12 is independently selected from hydrogen, —OH, C1-C8 hydroxy, C1-C6 alkyl, C1-C8 alkoxy, and —OC(O)(C1-C8 alkyl); wherein R15 is selected from hydrogen, —OH, C1-C30 hydroxy, C1-C30 alkyl, C1-C30 alkoxy, —OC(O)(C1-C30 alkyl), —OC(O)NR35aR35b, —OC(O)Ar2, —OC(O)(C1-C4 alkyl)Ar2, and —OC(O)(C1-C8 azide); wherein R20 is selected from hydrogen, —OH, —OOH, C1-C8 alkyl, C1-C8 hydroxy, C1-C8 alkoxy, C1-C8 hydroperoxy, and —OC(O)(C1-C8 alkyl); wherein R21 is selected from hydrogen and C1-C6 alkyl; wherein R25 is selected from hydrogen, —OH, C1-C8 hydroxy, C1-C8 alkoxy, —OC(O)(C1-18 alkyl), —OC(O)NR35aR35b, —OC(O)Ar5, and —OC(O)(C1-C8 azide); wherein Ar5, when present, is selected from monocyclic 6-membered aryl and anthracene-9,10-dionyl, and is substituted with 0, 1, 2, or 3 groups independently selected from halogen, —OH, —NH2, C1-C4 alkoxy, C1-C4 hydroxy, C1-C4 aminoalkyl, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino; wherein each of R26 and R26′ is independently selected from hydrogen, —OH, C1-C8 hydroxy, and C1-C8 alkoxy; or wherein each of R26 and R26′ together comprise ═O; wherein R27 is selected from hydrogen and C1-C6 alkyl; wherein each of R28 and R29 is independently selected from hydrogen and halogen; or wherein each of R28 and R29 together comprise —O— or —N(R37)—; wherein R37, when present, is selected from hydrogen, C1-C4 alkyl, —SO2R71, and a structure having a formula:
and
wherein R71, when present, is selected from hydrogen, C1-C4 alkyl, —CH2CH2Si(CH3)3, and monocyclic aryl monosubstituted with a methyl group, provided that at least one of R6 and R6′ is —OC(O)R40 or —NR41C(O)R40, and provided that when one or both of R28 and R29 is hydrogen then the occurrence of - - - - - - at C-22/C-23 is a double covalent bond, or a pharmaceutically acceptable salt thereof.
In one aspect, disclosed are compounds having a structure represented by a formula:
wherein each occurrence of - - - - - - is a single or double covalent bond; wherein X is selected from O, NRx and C(Rx)2; wherein each occurrence of Rx, when present, is independently selected from hydrogen and C1-C6 alkyl; wherein Rx is selected from hydrogen, halogen, —OH, —CN, —NC, —NCO, —OCN, —NO2, —ONO2, —ONO, —NO, —N3, —NH2, —NH3, —N═NR31, —NHOH, C1-C12 alkyl, C2-C12 alkenyl, C2-C12 alkynyl, C1-C12 hydroxy, C1-C12 alkoxy, C1-C12 thioalkyl, C1-C12 alkylthiol, C1-C12 aminoalkyl, C1-C12 alkylamino, (C1-C12)(C1-C12) dialkylamino, —OC(O)(C1-C12 alkyl), —OP(O)(OR32)2, —OSO2R33, —C(O)(C1-C12 alkyl), —CO2R34, —C(O)NR35aR35b, —(C1-C12 alkyl)C(O)NR35aR35b, —OC(O)NR35aR35b, —(C1-C12 alkyl)OC(O)NR35aR35b, Cy1, Ar1, (C1-C12 alkyl)Ar1, and —OAr1; wherein each occurrence of R31, R32, R34, R35a, and R35b, when present, is independently selected from hydrogen and C1-C12 alkyl; wherein each occurrence of R33, when present, is independently selected from hydrogen, C1-C12 alkyl, and monocyclic aryl monosubstituted with a methyl group; wherein each occurrence of Cy1, when present, is heterocycloalkyl substituted with 0, 1, 2, or 3 groups independently selected from halogen, —OH, —NH2, C1-C4 alkoxy, C1-C4 hydroxy, C1-C4 aminoalkyl, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino; wherein each occurrence of Ar1, when present, is selected from monocyclic aryl, morpholinyl, anilinyl, indolyl, pyrrolyl, imidazolyl, benzimidazolyl, pyrazolyl, guanidinyl, and piperazinyl and substituted with 0, 1, 2, or 3 groups independently selected from halogen, —OH, —NH2, C1-C4 alkoxy, C1-C4 hydroxy, C1-C4 aminoalkyl, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino; and wherein R1′ is hydrogen; or wherein each of R1 and R1′ together comprise ═O or ═NR36; wherein each occurrence of R36, when present, is independently selected from hydrogen and C1-C12 alkyl; wherein each of R2 and R3 is independently selected from hydrogen, —OH, C1-C12 hydroxy, and halogen; or wherein each of R2 and R3 together comprise —O—; wherein R5 is selected from hydrogen, —OH, —NH2, C1-C9 alkyl, C1-C9 hydroxy, C1-C9 alkoxy, C1-C9 aminoalkyl, C1-C6 alkylamino, and (C1-C6)(C1-C6) dialkylamino; or wherein R5 is absent; wherein R7 is selected from hydrogen, —OH, C1-C30 hydroxy, C1-C30 alkoxy, —OC(O)(C1-C30 alkyl), and —OC(O)NR35aR35b, and wherein R7′ is selected from hydrogen, —OH, C1-C30 hydroxy, C1-C30 alkoxy, and —OC(O)(C1-C30 alkyl); or wherein each of R7 and R7′ together comprise ═O; or wherein one of R7 and R7′ is absent; wherein each of R8 and R8′ is independently selected from hydrogen, halogen, —OH, —CN, —NC, —NCO, —OCN, —NO2, —ONO2, —ONO, —NO, —N3, —NH2, —NH3, —N═NR41, —NHOH, C1-C30 alkyl, C2-C30 alkenyl, C2-C30 alkynyl, C1-C30 hydroxy, C1-C30 alkoxy, C1-C30 thioalkyl, C1-C30 alkylthiol, C1-C30 aminoalkyl, C1-C30 alkylamino, (C1-C30)(C1-C30) dialkylamino, —C(O)(C1-C30 alkyl), —OP(O)(OR32)2, —OSO2R33, —CO2R34, —C(O)NR35aR35b, —(C1-C30 alkyl)C(O)NR35aR35b, —OC(O)NR35aR35b, —(C1-C30 alkyl)OC(O)NR35aR35b, Cy1, Ar1, —(C1-C30 alkyl)Ar1, —OAr1, —OC(O)(C1-C30 alkyl), —OC(O)Ar2, —OC(O)(C1-C30 alkyl)Ar2, —OC(O)Ar3, —OC(O)(C1-C30 alkyl)NR42C(O)Ar3, —OC(O)(C1-C30 alkyl)OC(O)Ar3, —OC(O)(C1-C30 alkyl)-L-Z, —OC(O)(C1-C30 alkyl)-L-(C1-C30 alkyl)-Z, —OC(O)-L-(C1-C30 alkyl)-Z, —NR41C(O)(C1-C30 alkyl), —NR41C(O)Ar2, —NR41C(O)(C1-C30 alkyl)Ar2, —NR41C(O)Ar3, —NR41C(O)(C1-C30 alkyl)OC(O)Ar3, —NR41C(O)(C1-C30 alkyl)NR42C(O)Ar3, —NR41C(O)(C1-C30 alkyl)-L-Z, —NR41C(O)(C1-C30 alkyl)-L-(C1-C30 alkyl)-Z, and —NR41C(O)-L-(C1-C30 alkyl)-Z; wherein L is a linker; wherein Z is selected from an antibody, an antibody fragment, a vitamin, a hormone, a carbohydrate, a molecular ligand, an aptamer, a non-antibody protein, a peptide, a nucleic acid, a fluorophore, and a drug; wherein each occurrence of R41 and R42, when present, is independently selected from hydrogen and C1-C12 alkyl; wherein each occurrence of Ar2, when present, is independently selected from aryl and heteroaryl, and is substituted with 0, 1, 2, or 3 groups independently selected from halogen, —OH, —NH2, C1-C4 alkoxy, C1-C4 hydroxy, C1-C4 aminoalkyl, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, —(C1-C12 alkyl)Ar4, and Ar4; wherein each occurrence of Ar4, when present, is a structure represented by a formula:
wherein each of R50a, R50b, R50c, and R50d, when present, is independently selected from hydrogen, —F, and —Cl; wherein each of R51a and R51b, when present, is independently selected from hydrogen and —C(O)(C1-C12 alkyl); wherein each of R52a, R52b, R52c, and R52d, when present, is independently selected from hydrogen, —F, and —Cl; wherein each occurrence of Ar3, when present, is a structure represented by a formula selected from:
or wherein one of R8 and R8′ is absent; wherein each of R11 and R12 is independently selected from hydrogen, —OH, C1-C8 hydroxy, C1-C6 alkyl, C1-C8 alkoxy, and —OC(O)(C1-C8 alkyl); wherein R15 is selected from hydrogen, —OH, C1-C30 hydroxy, C1-C30 alkyl, C1-C30 alkoxy, —OC(O)(C1-C30 alkyl), —OC(O)NR35aR35b, —OC(O)Ar2, —OC(O)(C1-C4 alkyl)Ar2, and —OC(O)(C1-C8 azide); wherein R20 is selected from hydrogen, —OH, —OOH, C1-C8 alkyl, C1-C8 hydroxy, C1-C8 alkoxy, C1-C8 hydroperoxy, and —OC(O)(C1-C8 alkyl); wherein R21 is selected from hydrogen and C1-C6 alkyl; wherein R21 is selected from hydrogen, —OH, C1-C8 hydroxy, C1-C8 alkoxy, —OC(O)(C1-18 alkyl), —OC(O)NR35aR35b, —OC(O)Ar5, and —OC(O)(C1-C8 azide); wherein Ar5, when present, is selected from monocyclic 6-membered aryl and anthracene-9,10-dionyl, and is substituted with 0, 1, 2, or 3 groups independently selected from halogen, —OH, —NH2, C1-C4 alkoxy, C1-C4 hydroxy, C1-C4 aminoalkyl, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino; wherein each of R26 and R26′ is independently selected from hydrogen, —OH, C1-C8 hydroxy, and C1-C8 alkoxy; or wherein each of R26 and R26′ together comprise ═O; wherein R27 is selected from hydrogen and C1-C6 alkyl; wherein each of R28 and R29 is independently selected from hydrogen and halogen; or wherein each of R28 and R29 together comprise —O— or N(R37)—; wherein R37, when present, is selected from hydrogen, C1-C4 alkyl, —SO2R71, and a structure having a formula:
and
wherein R71, when present, is selected from hydrogen, C1-C4 alkyl, —CH2CH2Si(CH3)3, and monocyclic aryl monosubstituted with a methyl group, provided that one and only one of R8 and R8′ is —OC(O)(C1-C30 alkyl)-L-Z, —OC(O)(C1-C30 alkyl)-L-(C1-C30 alkyl)-Z, —OC(O)-L-(C1-C30 alkyl)-Z, —NR41C(O)(C1-C30 alkyl)-L-Z, —NR41C(O)(C1-C30 alkyl)-L-(C1-C30 alkyl)-Z, or —NR41C(O)-L-(C1-C30 alkyl)-Z, and provided that when one or both of R28 and R29 is hydrogen then the occurrence of - - - - - - at C-22/C-23 is a double covalent bond, or a pharmaceutically acceptable salt thereof.
In one aspect, disclosed are compounds having a structure selected from:
or a pharmaceutically acceptable salt thereof.
In one aspect, disclosed are compounds selected from:
or a pharmaceutically acceptable salt thereof.
In one aspect, disclosed are compounds selected from:
or a pharmaceutically acceptable salt thereof.
In a further aspect, the compound has a structure represented by a formula:
wherein R1 is selected from OH, C1-C12 alkoxy, and —OC(O)(C1-C12 alkyl); wherein each of R2 and R3 is independently selected from —OH and halogen; or wherein each of R2 and R3 together comprise —O—; wherein R5 is selected from hydrogen, —OH, —NH2, C1-C9 alkoxy, C1-C6 alkylamino, and (C1-C6)(C1-C6) dialkylamino; or wherein R5 is absent; wherein each of R6 and R6′ is independently selected from hydrogen, —OH, C1-C30 alkoxy, —OC(O)(C1-C30 alkyl), —NR41C(O)(C1-C30 alkyl), —NR41C(O)Ar2, —NR41C(O)(C1-C30 alkyl)Ar2, —NR41C(O)Ar3, —NR41C(O)(C1-C30 alkyl)OC(O)Ar3, —NR41C(O)(C1-C30 alkyl)NR42C(O)Ar3, and —NR41C(O)R40; or wherein one of R6 and R6′ is absent; wherein each of R7 and R7′ is independently selected from hydrogen, —OH, C1-C30 alkoxy, and —OC(O)(C1-C30 alkyl); or wherein each of R7 and R7′ together comprise ═O; or wherein one of R7 and R7′ is absent; wherein each of R11 and R12 is independently selected from hydrogen, —OH, C1-C6 alkyl, C1-C8 alkoxy, and —OC(O)(C1-C8 alkyl); wherein R15 is selected from hydrogen, —OH, C1-C30 alkyl, C1-C30 alkoxy, and —OC(O)(C1-C30 alkyl); wherein R20 is selected from hydrogen, —OH, —OOH, C1-C8 alkyl, C1-C8 alkoxy, and —OC(O)(C1-C8 alkyl); wherein R25 is selected from hydrogen, —OH, C1-C8 alkoxy, and —OC(O)(C1-C18 alkyl); and wherein each of R26 and R26′ is independently selected from hydrogen, —OH, and C1-C8 alkoxy; or wherein each of R26 and R26′ together comprise ═O, provided that at least one of R6 and R6′ is —NR41C(O)(C1-C30 alkyl), —NR41C(O)Ar2, —NR41C(O)(C1-C30 alkyl)Ar2, —NR41C(O)Ar3, —NR4′C(O)(C1-C30 alkyl)OC(O)Ar3, —NR41C(O)(C1-C30 alkyl)NR42C(O)Ar3, or —NR41C(O)R40, or a pharmaceutically acceptable salt thereof.
In a further aspect, the compound has structure represented by a formula:
wherein R1 is selected from —OH, C1-C12 hydroxy, C1-C12 alkoxy, and —OC(O)(C1-C12 alkyl); wherein R5 is selected from hydrogen, —OH, —NH2, C1-C6 alkyl, C1-C9 hydroxy, C1-C9 alkoxy, C1-C9 aminoalkyl, C1-C6 alkylamino, and (C1-C6)(C1-C6) dialkylamino; or wherein R5 is absent; wherein each of R6 and R6′ is independently selected from hydrogen, —OH, C1-C30 hydroxy, C1-C30 alkoxy, —OC(O)(C1-C30 alkyl), —OC(O)Ar2, —OC(O)(C1-C30 alkyl)Ar2, —OC(O)R40, —NR41C(O)(C1-C30 alkyl), —NR4′C(O)Ar2, —NR41C(O)(C1-C30 alkyl)Ar2, —NR41C(O)Ar3, —NR41C(O)(C1-C30 alkyl)OC(O)Ar3, —NR41C(O)(C1-C30 alkyl)NR42C(O)Ar3, and —NR4′C(O)R40; or wherein one of R6 and R6′ is absent; wherein each of R7 and R7′ is independently selected from hydrogen, —OH, C1-C30 hydroxy, C1-C30 alkoxy, and —OC(O)(C1-C30 alkyl); or wherein each of R7 and R7′ together comprise ═O; or wherein one of R7 and R7′ is absent, provided that at least one of R6 and R6′ is —NR41C(O)(C1-C30 alkyl), —NR41C(O)Ar2, —NR41C(O)(C1-C30 alkyl)Ar2, —NR41C(O)Ar3, —NR41C(O)(C1-C30 alkyl)OC(O)Ar3, —NR41C(O)(C1-C30 alkyl)NR42C(O)Ar3, or —NR41C(O)R40, or a pharmaceutically acceptable derivative thereof.
In a further aspect, the compound has a structure represented by a formula:
In a further aspect, the compound has a structure represented by a formula:
In a further aspect, the compound has a structure represented by a formula:
In a further aspect, the compound has a structure represented by a formula:
In a further aspect, the compound has a structure represented by a formula:
In a further aspect, the compound has a structure represented by a formula:
In a further aspect, the compound has a structure represented by a formula:
In a further aspect, the compound has a structure represented by a formula:
In a further aspect, the compound has a structure selected from:
In a further aspect, the compound has a structure selected from:
In a further aspect, the compound has a structure represented by a formula:
In a further aspect, the compound has a structure represented by a formula:
In a further aspect, the compound has a structure selected from:
In a further aspect, the compound has a structure selected from:
In a further aspect, the compound has a structure selected from:
In a further aspect, the compound has a structure selected from:
In a further aspect, the compound has a structure selected from:
In a further aspect, R20 is methyl and wherein R21 is hydrogen.
In a further aspect, L is selected from —NR61C(O)—, —C(O)NR61—, —NR61C(S)NR62—, —SCH2C(O)—, —C(O)SCH2—,
and each of R61 and R62, when present, is independently selected from hydrogen and C1-C12 alkyl.
In a further aspect, each occurrence of - - - - - - is a single covalent bond.
In a further aspect, the occurrence of - - - - - - at C-2/C-3 is a double covalent bond. In a still further aspect, the occurrence of - - - - - - at C-2/C-3 is a single covalent bond.
In a further aspect, the occurrence of - - - - - - at C-5/C-6 is a double covalent bond. In a still further aspect, the occurrence of - - - - - - at C-5/C-6 is a single covalent bond.
In a further aspect, the occurrence of - - - - - - at C-7/C-8 is a double covalent bond. In a still further aspect, the occurrence of - - - - - - at C-7/C-8 is a single covalent bond.
In a further aspect, the occurrence of - - - - - - at C-1l/C-12 is a double covalent bond. In a still further aspect, the occurrence of - - - - - - at C-11/C-12 is a single covalent bond.
In a further aspect, the occurrence of - - - - - - at C-22/C-23 is a double covalent bond. In a still further aspect, the occurrence of - - - - - - at C-22/C-23 is a single covalent bond.
a. L Groups
In one aspect, L is a linker. Examples of linkers include, but are not limited to, polyethers, small aryl groups (e.g., 1,4-linked benzyl), disulfides, ethers, thioethers, esters, sulfonamides, dipeptides, maleimidocaproyl, hydrazines, hydrazones, acylhydrazines, acylhydrazones, and 1,2,3-triazoles. In various aspects, the linker is a chemical linker known in relation to antibody-drug conjugates (ADCs). Thus, in a further aspect, the linker connects the Z group (i.e., the antibody, the antibody fragment, the vitamin, the hormone, the carbohydrate, the molecular ligand, the aptamer, the non-antibody protein, the peptide, the nucleic acid, the fluorophore, or the drug) to the compound (e.g., the central core of the compound). Desirable qualities of the linker include, but are not limited to, providing stability prior to entering a target cell, providing efficient payload release once inside the target cell (e.g., via endosomoal or lysosomal degradation), and compatibility with the Z group and the compound.
Examples of compounds having a variety of different linkers are shown below. Such examples are not meant to be limiting.
In a further aspect, the linker is cleavable (i.e., the linker relies on the physiological environment and releases a payload via hydrolyzation or proteoloysis in the target cells). Examples of cleavable linkers include, but are not limited to, chemically labile linkers (i.e., acid cleavable linkers such as hydrazines and silyl ethers and reducible linkers) and enzyme cleavable linkers (i.e., linkers that rely on the presence of hydrolytic enzymes in the cell). Enzyme cleavable linkers include, but are not limited to, peptide-based linkers (e.g. valine-citrulline) dipeptide linkers and phenylalanine-lysine dipeptide linkers) and beta-glucuronide linkers. In various aspects, a cleavable linker is broken down in the cells to release a compound.
In a further aspect, the linker is non-cleavable (i.e., the linker cannot be broken down outside a target cell). Advantages of a non-cleavable linker include, but are not limited to, increased plasma stability and larger therapeutic windows. In various aspects, a non-cleavable linker remains attached to a compound in cells.
In a further aspect, the linker is a tertiary amine linker (e.g., monomethyl auristatin E).
In various aspects, the linker is humanized IgG4, hP67/6 hydrazone; humanized IgG4, G5/44 hydrazone; milatuzamab hydrazine; humanized IgG1, huC242 disulfide; humanized IgG1, DS6 disulfide; anti-CD138 chimeric IgG4 disulfide, anti-mesothelin fully human IgG1 disulfide; anti-integrin, IgG1 disulfide; anti-cripto IgG1 disulfide; hu134, humanized IgG1 disulfide; anti-CD30 dipeptide; anti-CR011 dipeptide; anti-CD70 dipeptide; anti-nectin fully human IgG dipeptide; anti-PSMA fully human IgG1 dipeptide; trastuzumab, humanized IgG1 thioether; Ch1gG1 thioether; K7153A humanized IgG1 thioether; or anti-EGFRvIII fully human IgG1 thioether.
In a further aspect, the linker is a disulfide linker. Examples of disulfide linkers include, but are not limited to:
In a further aspect, the linker is a thioether linker. An example of a thioether linker is, but is not limited to:
In a further aspect, the linker is a dipeptide linker. An example of a dipeptide linker is, but is not limited to:
In a further aspect, the linker is a maleimidocaproyl linker. An example of a maleimidocaproyl linker is, but is not limited to:
In a further aspect, the linker is a hydrazone. Examples of hydrazone linkers include, but are not limited to:
In a further aspect, L is selected from —NR61C(O)—, —C(O)NR61—, —NR61C(S)NR62—, —SCH2C(O)—, —C(O)SCH2—,
In a further aspect, L is selected from
In a still further aspect, L is
In yet a further aspect, L is
In a further aspect, L is selected from —NR61C(O)—, —C(O)NR61—, —NR61C(S)NR62, —SCH2C(O)—, and —C(O)SCH2—. In a still further aspect, L is selected from —NR61C(O)— and —C(O)NR61—. In yet a further aspect, L is —NR61C(O)—. In an even further aspect, L is —C(O)NR61—.
In a further aspect, L is selected from —NR61C(S)NR62—, —SCH2C(O)—, and —C(O)SCH2—. In a still further aspect, L is selected from —SCH2C(O)— and —C(O)SCH2—. In yet a further aspect, L is —NR61C(S)NR62—. In an even further aspect, L is —SCH2C(O)—. In a still further aspect, L is —C(O)SCH2—.
b. X Groups
In one aspect, X is selected from O, NRx, and C(Rx)2. In a further aspect, X is selected from O and NRx. In a still further aspect, X is selected from O and C(Rx)2. In yet a further aspect, X is selected from NRx and C(Rx)2. In an even further aspect, X is O. In a still further aspect, X is NRx. In yet a further aspect, X is C(Rx)2.
c. Z Groups
In one aspect, Z is selected from an antibody, an antibody fragment, a vitamin, a hormone, a carbohydrate, a molecular ligand, an aptamer, a non-antibody protein, a peptide, a nucleic acid, a fluorophore, and a drug.
In a further aspect, Z is an antibody. As used herein, the term “antibody” means a protein made by plasma cells in response to an antigen that typically consist of four subunits including two heavy chains and two light chains. Examples of antibodies include, but are not limited to, bevacizumab, trastuzumab, rituximab, abciximab, adalimumab, alemtuzumab, basiliximab, belimumab, brentuximab vedotin, canakinumab, cetuximab, certolizumab pegol, daclizumab, denosumab, eculizumab, efalizumab, gemtuzumab, golimumab, ibritumomab tiuxetan, infliximab, ipilimumab, muromnonab-CD3, natalizumab, ofatumumab, omalizumab, palivizumab, panitumumab, ranibizumab, raxibacumab, tocilizumab, tositumomab and ustekinumab. Other examples of antibodies include, but are not limited to, 3F8, abagovomab, abatacept, acz885, adecatumumab, afelimomab, aflibercept, afutuzumab, alacizumab, altumomab, anatumomab, anrukinzumab, apolizumab, arcitumomab, aselizumab, atlizumab, atorolimumab, bapineuzumab, bavituximab, bectumomab, belatacept, bertilimumab, besilesomab, biciromab, bivatuzumab, blinatumomab, cantuzumab, capromab, catumaxomab, cedelizumab, citatuzumab, cixutumumab, clenoliximab, cnto1275(=ustekinumab), cntol48(=golimumab), conatumumab, dacetuzumab, detumomab, dorlimomab, dorlixizumab, ecromeximab, edobacomab, edrecolomab, efungumab, elsilimomab, enlimomab, epitumomab, epratuzumab, erlizumab, ertumaxomab, etanercept, etaracizumab, exbivirumab, fanolesomab, faralimomab, felvizumab, figitumumab, fontolizumab, foravirumab, galiximab, gantenerumab, gavilimomab, gomiliximab, ibalizumab, igovomab, imciromab, inolimomab, inotuzumab ozogamicin, iratumumab, keliximab, labetuzumab, lebrilizunab, lemalesomab, lerdelimumab, lexatumumab, libivirurnab, lintuzunab, lucatumumab, lumiliximab, mapatumumab, maslimomab, matuzumab, mepolizumab, metelimumab, milatuzumab, minretumomab, mitumomab, morolimumab, motavizumab, myo-029, nacolomab, naptumomab, nebacumab, necitumumab, nerelimomab, nimotuzumab, nofetumomab, ocrelizumab, odulimomab, oportuzumab, oregovomab, otelixizumab, pagibaximab, panobacumab, pascolizumab, pemtumomab, pertuzumab, pexelizumab, pintumomab, priliximab, pritumumab, pro-140, rafivirumab, ramucirumab, regavirumab, reslizumab, rilonacept, robatumumab, rovelizumab, rozrolimupab, ruplizumab, satumomab, sevirmmab, sibrotuzumab, siltuximab, siplizumab, solanezumab, sonepcizumab, sontuzumab, stamulumab, sulesomab, tacatuzumab, tadocizumab, talizumab, tanezumab, tapliturnomab, tefibazumab, telimomab, tenatumomab, teneliximab, teplizumab, tgn1412, ticilimumab (=tremelimumab), tigatuzumab, tnx-355 (=ibalizumab), tnx-650, tnx-901 (=talizumab), toralizumab, tremelimumab, tucotuzumab, tuvirumab, urtoxazumab, vapaliximab, vedolizumab, veltuzumab, vepalimomab, visilizumab, volociximab, votumumab, zalutumumab, zanolimumab, ziralimumab, and zolimomab.
In a further aspect, Z is an antibody fragment. As used herein, the term “antibody fragment” means a component derived from antigen-specific fragments of antibodies produced by recombinant processes. Three general types of fragments were observed, antigen-binding fragments (Fab), single chain variable fragments (scFv) and “third generation” (3G). Examples of antibody fragments include, but are not limited to, anti-HER2 scFv, Fv, Fab, Fab′, F(ab′)2, Fab′-SH, and scFv.
In a further aspect, Z is a vitamin. As used herein, the term “vitamin” means any of a group of organic compounds that are essential for normal growth and nutrition and are required in small quantities in the diet because they cannot be synthesized by the body. Examples of vitamins include, but are not limited to, vitamin A, vitamin BI, vitamin B2, vitamin B6, vitamin K, vitamin C, vitamin D, niacin, biotin, pantothenic acid, folic acid, and vitamin B12.
In a further aspect, Z is a hormone. As used herein, the term “hormone” means a chemical substance produced in the body that controls and regulates the activity of certain cells or organs. Examples of hormones include, but are not limited to, estrogen, testosterone, insulin, androgen, progestogen, corticosteroids, growth hormone, androgens, melatonin, throxine, eicosanoids, adrenaline, glucagen, and steroids.
In a further aspect, Z is a carbohydrate. As used herein, the term “carbohydrate” means a naturally occurring organic compound that occurs in foods and living tissues. Examples of carbohydrates include, but are not limited to, sugars such as, for example, sucrose, glucose, fructose, maltose, xylitol, trehalose, galactose, dextrates, and maltodextrins; starches such as, for example, corn, wheat, potato, tapioca, barley, arrowroot, and rice; and celluloses such as, for example, methylcellulose, ethyl cellulose, cellulose acetate, cellulose acetate-butyrate, cellulose acetate-propionate, and cellulose propionate.
In a further aspect, Z is a molecular ligand, although it is noted that other possible options of Z may include some molecular ligands, as well. As used herein, the term “molecular ligand” means a small molecule that transmits signals in-between or within cells. Examples of molecular ligands include, but are not limited to, epidermal growth factor, angiopoietin, bone morphogenetic proteins, insulin like growth factor, adenosine triphosphate, and nicotinamide-adenine-dinucleotide, Flavin mononucleotide.
In a further aspect, Z is an aptamer. As used herein, the term “aptamer” means an oligonucleotide or peptide molecule that binds to a specific target molecule, Examples of aptamers include, but are not limited to, EpCAM aptamer, nucleic acid aptamers (e.g., DNA aptamers and RNA aptamers) and peptide aptamers.
In a further aspect, Z is a non-antibody protein. As used herein, the term “non-antibody protein” means a large molecule composed of one or more chains of amino acids in a specific order that is not an antibody as defined herein above. Examples of non-antibody proteins include, but are not limited to, albumin, insulin, receptors, actin, and tubulin.
In a further aspect, Z is a peptide. As used herein, the term “peptide” means a molecule consisting of from about 2 to about 50 amino acids. Examples of peptides include, but are not limited to, somatostatin peptide, luteinizing hormone releasing hormone, fusion proteins, receptors, ligands of cell surface proteins, secreted proteins, and enzymes.
In a still further aspect, Z is a nucleic acid. As used herein, the term “nucleic acid” means a residue consisting of either one or two long chains of repeating units of a nitrogen base (i.e., a purine or a pyrimidine base) attached to a sugar phosphate. Examples of nucleic acids include, but are not limited to, E2 RNA, cyclic adenosine monophosphate, nucleoside triphosphates, Flavin adenine dinucleotide, and nicotinamide adenine dinucleotide phosphate.
In a further aspect, Z is a fluorophore. Examples of fluorophores include, but are not limited to, fluorescein, Oregon green, rhoadmine, eosin, Texas red, indocarbocyanine, oxacarbocyanine, thiacarbocyanine, merocyanine, a squaraine derivative, a naphthalene derivative (e.g., a dansyl or prodan derivative), a coumarin derivative, an oxadiazole derivative (e.g., pyridyloxazole, nitrobenzoxadiazole, benzoxadiazole), an anthracene derivative (e.g., an anthraquinone such as DRAQ5, DRAQ7, and CyTRAK Orange), cascade blue, Nile red, Nile blue, cresyl violate, oxazine 170, proflavin, acridine orange, acridine yellow, auramine, crystal violet, malachite green, prophin, phthalocyanine, and bilirubin.
In a further aspect, Z is a drug or a therapeutic agent. Examples of drugs or therapeutic agents include, but are not limited to, taxanes such as paclitaxel, monomethyl auristatin E, mertansine and calicheamicin.
In a further aspect, Z is selected from an antibody and an antibody fragment.
d. Rx Groups
In one aspect, each occurrence of R, when present, is independently selected from hydrogen and C1-C6 alkyl. In a further aspect, each occurrence of Rx, when present, is independently selected from hydrogen and C1-C4 alkyl. In a still further aspect, each occurrence of Rx, when present, is hydrogen.
In a further aspect, each occurrence of Rx, when present, is independently selected from hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, and tert-butyl. In a still further aspect, each occurrence of Rx, when present, is independently selected from hydrogen, methyl, ethyl, n-propyl, and isopropyl. In yet a further aspect, each occurrence of Rx, when present, is independently selected from hydrogen, methyl, and ethyl. In an even further aspect, each occurrence of Rx, when present, is independently selected from hydrogen and ethyl. In a still further aspect, each occurrence of Rx, when present, is independently selected from hydrogen and methyl.
In a further aspect, each occurrence of R, when present, is independently selected from C1-C6 alkyl. In a still further aspect, each occurrence of Rx, when present, is independently selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, and tert-butyl. In yet a further aspect, each occurrence of R, when present, is independently selected from methyl, ethyl, n-propyl, and isopropyl. In an even further aspect, each occurrence of Rx, when present, is independently selected from methyl and ethyl. In a still further aspect, each occurrence of Rx, when present, is ethyl. In yet a further aspect, each occurrence of Rx, when present, is methyl.
e. R1 and R1′ Groups
In one aspect. R1 is selected from hydrogen, halogen, —OH, —CN, —NC, —NCO, —OCN, —NO2, —ONO2, —ONO, —NO, —N3, —NH2, —NH3, —N═NR31, —NHOH, C1-C12 alkyl, C2-C12 alkenyl, C2-C12 alkynyl, C1-C12 hydroxy, C1-C12 alkoxy, C1-C12 thioalkyl, C1-C12 alkylthiol, C1-C12 aminoalkyl, C1-C12 alkylamino, (C1-C12)(C1-C12) dialkylamino, —OC(O)(C1-C12 alkyl), —OP(O)(OR32)2, —OSO2R33, —C(O)(C1-C12 alkyl), —CO2R37, —C(O)NR35aR35b, —(C1-C12 alkyl)C(O)NR35aR35b, —OC(O)NR35aR35b, —(C1-C12 alkyl)OC(O)NR35aR35b, Cy1, Ar1, (C1-C12 alkyl)Ar1, and —OAr1 and R1′ is hydrogen. In a further aspect, each of R1 and R1′ is hydrogen.
In one aspect, each of R1 and R1′ together comprise ═O or ═NR36. In a further aspect, each of R1 and R1′ together comprise ═O. In a still further aspect, each of R1 and R1′ together comprise ═NR36.
In a further aspect, R1 is selected from hydrogen, halogen, —OH, —CN, —NC, —NCO, —OCN, —NO2, —ONO2, —ONO, —NO, —N3, —NH2, —NH3, —N═NR3′, —NHOH, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C1-C8 hydroxy, C1-C8 alkoxy, C1-C8 thioalkyl, C1-C8 alkylthiol, C1-C8 aminoalkyl, C1-C8 alkylamino, (C1-C8)(C1-C8) dialkylamino, —OC(O)(C1-C8 alkyl), —OP(O)(OR32)2, —OSO2R33, —C(O)(C1-C8 alkyl), —CO2R34, —C(O)NR35aR35b, —(C1-C8 alkyl)C(O)NR35aR35b, —OC(O)NR35aR35b, —(C1-C8 alkyl)OC(O)NR35aR35b, Cy1, Ar1, (C1-C8 alkyl)Ar1, and —OAr1. In a still further aspect, R1 is selected from hydrogen, halogen, —OH, —CN, —NC, —NCO, —OCN, —NO2, —ONO2, —ONO, —NO, —N3, —NH2, —NH3, —N═NR3, —NHOH, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 hydroxy, C1-C4 alkoxy, C1-C4 thioalkyl, C1-C4 alkylthiol, C1-C4 aminoalkyl, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, —OC(O)(C1-C4 alkyl), —OP(O)(OR32)2, —OSO2R33, —C(O)(C1-C4 alkyl), —CO2R34, —C(O)NR35aR35b, —(C1-C8 alkyl)C(O)NR35aR35b, —OC(O)NR35aR35b, —(C1-C4 alkyl)OC(O)NR35aR35b, Cy1, Ar1, (C1-C4 alkyl)Ar1, and —OAr1, In yet a further aspect, R1 is selected from hydrogen, —F, —Cl, —OH, —CN, —NC, —NCO, —OCN, —NO2, —ONO2, —ONO, —NO, —N3, —NH2, —NH3, —N═NR31, —NHOH, methyl, ethyl, n-propyl, isopropyl, ethenyl, n-propenyl, isopropenyl, ethynyl, propynyl, —CH2OH, —CH2CH2OH, —CH(CH3)CH2OH, —CH2CF2CH2CH2OH, —OCH3, —OCH2CH3, —OCH(CH3)2, —OCH2CH2CH3, —SCH3, —SCH2CH3, —SCH(CH3)2, —SCH2CH2CH3, —CH2SH, —CH2CH2SH, —CH(CH3)CH2SH, —CH2CH2CH2SH, —CH2NH2, —CH2CH2NH2, —CH(CH3)CH2NH2, —CH2CH2CH2NH2—, —NHCH3, —NHCH2CH3, —NHCH(CH3), —NHCH2CH2CH3, —N(CH3)2, —N(CH3)CH2CH3N, —N(CH3)CH(CH3)2, —N(CH3)CH2CH2CH3, —OC(O)CH3, —OC(O)CH2CH3, —OC(O)CH(CH3)2, —OC(O)CH2CH2CH3, —OP(O)(OR32)2, —OSO2R33, —C(O)CH3, —C(O)CH2CH3, —C(O)CH(CH3)2, —C(O)CH2CH2CH3, —CO2R34, —C(O)NR35aR35b, —CH2C(O)NR35aR35b, —CH2CH2C(O)NR35aR35b, —CH(CH3)CH2C(O)NR35aR35b, —CH2CH2CH2C(O)NR35aR35b, —OC(O)NR35aR35b, —CH2OC(O)NR35aR35b, —CH2CH2OC(O)NR35aR35b, —CH(CH3)CH2OC(O)NR35aR35b, —CH2CH2CH2OC(O)NR35aR35b, Cy1, Ar1, —CH2Ar1, —CH2CH2Ar1, —CH(CH3)CH2Ar1, —CH2CH2CH2Ar1, and —OAr1. In an even further aspect. R1 is selected from hydrogen, —F, —Cl, —OH, —CN, —NC, —NCO, —OCN, —NO2, —ONO2, —ONO, —NO, —N3, —NH, —NH3, —N═NR31, —NHOH, methyl, ethyl, ethenyl, ethynyl, —CH2OH, —CH2CH2OH, —OCH3, —OCH2CH3, —SCH3, —SCH2CH3, —CH2SH, —CH2CH2SH, —CH2NH2, —CH2CH2NH2, —NHCH3, —NHCH2CH3, —N(CH3)2, —N(CH3)CH2CH3, —OC(O)CH3, —OC(O)CH2CH3, —OP(O)(OR3)2, —OSO2R33, —C(O)CH3, —C(O)CH2CH3, —CO2R34, —C(O)NR35aR35b, —CH2C(O)NR35aR35b, —CH2CH2C(O)NR35aR35b, —OC(O)NR35aR35b, —CH2OC(O)NR35aR35b, —CH2CH2C(O)NR35aR35b, Cy1, Ar1, —CH2Ar1, —CH2CH2Ar1, and —OAr1. In a still further aspect, R1 is selected from hydrogen, —F, —Cl, —OH, —CN, —NC, —NCO, —OCN, —NO2, —ONO2, —ONO, —NO, —N3, —NH2, —NH3, —N═NR31, —NHOH, methyl, —CH2OH, —OCH3, —SCH3, —CH2SH, —CH2NH2, —NHCH3, —N(CH3)2, —OC(O)CH3, —OP(O)(OR32)2, —OSO2R33, —C(O)CH3, —CO2R34, —C(O)NR35aR35b, —CH2C(O)NR35aR35b, —OC(O)NR35aR35b, —CH2OC(O)NR35aR35b, Cy1, Ar1, —CH2Ar1, and —OAr1.
In various aspects, R1 is selected from hydrogen, halogen. —OH, —CN, —NC, —NCO, —OCN, —NO2, —ONO2, —ONO, —NO, —N3, —NH2, —NH3, —N═NR31, —NHOH, C1-C12 alkyl, C2-C12 alkenyl, C2-C12 alkynyl, —OC(O)(C1-C12 alkyl), —OP(O)(OR32)2, —OSO2R33, —C(O)(C1-C12 alkyl), —CO2R34, —C(O)NR35aR35b, —(C1-C12 alkyl)C(O)NR35aR35b, —OC(O)NR35aR35b, —(C1-C12 alkyl)OC(O)NR35aR35b, Cy1, Ar1, (C1-C12 alkyl)Ar1, and —OAr1. In a further aspect, R1 is selected from hydrogen, halogen, —OH, —CN, —NC, —NCO, —OCN, —NO2, —ONO2, —ONO, —NO, —N3, —NH2, —NH3, —N═NR31, —NHOH, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, —OC(O)(C1-C8 alkyl), —OP(O)(OR32)2, —OS2R33, —C(O)(C1-C8 alkyl), —CO2R34, —C(O)NR35aR35b, —(C1-C8 alkyl)C(O)NR35aR35b, —OC(O)NR35aR35b, —(C1-C8 alkyl)OC(O)NR35aR35b, Cy1, Ar1, (C1-C8 alkyl)Ar1, and —OAr1. In a still further aspect, R1 is selected from hydrogen, halogen, —OH, —CN, —NC, —NCO, —OCN, —NO2, —ONO2, —ONO, —NO, —N3, —NH2, —NH3, —N═NR31, —NHOH, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, —OC(O)(C1-C4 alkyl), —OP(O)(OR32)2, —OSO2R33, —C(O)(C1-C4 alkyl), —CO2R34, —C(O)NR35aR35b, (C1-C8 alkyl)C(O)NR35aR35b, —OC(O)NR35aR35b, —(C1-C4 alkyl)OC(O)NR35aR35b, Cy1, Ar1, (C1-C4 alkyl)Ar1, and —OAr1. In yet a further aspect, R1 is selected from hydrogen, —F, —Cl, —OH, —CN, —NC, —NCO, —OCN, —NO2, —ONO2, —ONO, —NO, —N3, —NH2, —NH3, —N═NR31, —NHOH, methyl, ethyl, n-propyl, isopropyl, ethenyl, n-propenyl, isopropenyl, ethynyl, propynyl, —OC(O)CH3, —OC(O)CH2CH3, —OC(O)CH(CH3)2, —OC(O)CH2CH2CH3, —OP(O)(OR32)2, —OSO2R33, —C(O)CH3, —C(O))CH2CH3, —C(O)CH(CH3)2, —C(O)CH2CH2CH3, —CO2R34, —C(O)NR35aR35b, —CH2C(O)NR35aR35b, —CH2CH2C(O)NR35aR35b, —CH(CH3)CH2C(O)NR35aR35b, —CH2C(O)NR35aR35b, —OC(O)NR35aR35b, —CH2OC(O)NR35aR35b, —CH2CH2OC(O)NR35aR35b, —CH(CH3)CH2OC(O)NR35aR35b, —CH2CH2CH2OC(O)NR35aR35b, Cy1, Ar1, —CH2Ar1, —CH2CH2Ar1, —CH(CH3)CH2Ar1, —CH2CH2Ar1, and —OAr1. In an even further aspect, R1 is selected from hydrogen, —F, —Cl, —OH, —CN, —NC, —NCO, —OCN, —NO2, —ONO2, —ONO, —NO, —N3, —NH2, —NH3, —N═NR31, —NHOH, methyl, ethyl, ethenyl, ethynyl, —OC(O)CH3, —OC(O)CH2CH3, —OP(O)(OR32)2, —OSO2R33, —C(O)CH3, —C(O)CH2CH3, —CO2R34, —C(O)NR35aR35b, —CH2C(O)NR35aR35b, —CH2CH2C(O)NR35aR35b, —OC(O)NR35aR35b, —CH2OC(O)NR35aR35b, —CH2CH2OC(O)NR35aR35b, Cy1, Ar2, —CH2Ar1, —CH2CH2Ar1, and —OAr1. In a still further aspect, R1 is selected from hydrogen, —F, —Cl, —OH, —CN, —NC, —NCO, —OCN, —NO2, —ONO2, —ONO, —NO, —N3, —NH2, —NH3, —N═NR, —NHOH, methyl, —OC(O)CH3, —OP(O)(OR32)2, —OSO2R33, —C(O)CH3, —CO2R34, —C(O)NR35aR35b, —CH2C(O)NR35aR35b, —OC(O)NR35aR35b, —CH2OC(O)NR35aR35b, Cy1, Ar1, —CH2Ar1, and —OAr1.
In various aspects, R1 is selected from hydrogen, halogen, —OH, —CN, —NC, —NCO, —OCN, —NO2, —ONO2, —ONO, —NO, —N3, —NH2, —NH3, —N═NR_, —NHOH, C1-C12 hydroxy, C1-C12 alkoxy, C1-C12 thioalkyl, C1-C12 alkylthiol, C1-C12 aminoalkyl, C1-C12 alkylamino, (C1-C12)(C1-C12) dialkylamino, —OC(O)(C1-C12 alkyl), —OP(O)(OR32)2, —OSO2R33, —C(O)(C1-C12 alkyl), —CO2R34, —C(O)NR35aR35b, —(C1-C12 alkyl)C(O)NR35aR35b, —OC(O)NR35aR35b, (C1-C12 alkyl)OC(O)NR35aR35b, Cy1, Ar1, (C1-C12 alkyl)Ar1, and —OAr1. In a further aspect, R1 is selected from hydrogen, halogen, —OH, —CN, —NC, —NCO, —OCN, —NO2, —ONO2, —ONO, —NO, —N3, —NH2, —NH3, —N═NR3, —NHOH, C1-C8 hydroxy, C1-C8 alkoxy, C1-C8 thioalkyl, C1-C8 allylthiol, C1-C8 aminoalkyl, C1-C8 alkylamino, (C1-C8)(C1-C8) dialkylamino, —OC(O)(C1-C8 alkyl), —OP(O)(OR32)2, —OSO2R33, —C(O)(C1-C8 alkyl), —CO2R34, —C(O)NR35aR35b, —(C1-C8 alkyl)C(O)NR35aR35b, —OC(O)NR35aR35b, —(C1-C8 alkyl)OC(O)NR35aR35b, Cy1, Ar1, (C1-C8 alkyl)Ar1, and —OAr1. In a still further aspect, R1 is selected from hydrogen, halogen, —OH, —CN, —NC, —NCO, —OCN, —NO2, —ONO2, —ONO, —NO, —N3, —NH2, —NH3, —N═NR31, —NHOH, C1-C4 hydroxy, C1-C4 alkoxy, C1-C4 thioalkyl, C1-C4 allylthiol, C1-C4 aminoalkyl, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, —OC(O)(C1-C4 alkyl), —OP(O)(OR32)2, —OSO2R33, —C(O)(C1-C4 alkyl), —CO2R34, —C(O)NR35aR35b, —(C1-C8 alkyl)C(O)NR35aR35b, —OC(O)NR35aR35b, —(C1-C4 alkyl)OC(O)NR35aR35b, Cy1, Ar1, (C1-C4 alkyl)Ar1, and —OAr1. In yet a further aspect, R1 is selected from hydrogen, —F, —Cl, —OH, —CN, —NC, —NCO, —OCN, —NO2, —ONO2, —ONO, —NO, —N3, —NH2, —NH3, —N═NR31, —NHOH, —CH2OH, —CH2CH2OH, —CH(CH3)CH2OH, —CH2CH2CH2OH, —OCH3, —OCH2CH3, —OCH(CH3)2, —OCH2CH2CH3, —SCH3, —SCH2CH3, —SCH(CH3)2, —SCH2CH2CH3, —CH2SH, —CH2CH2SH, —CH(CH3)CH2SH, —CH2CH2CH2SH, —CH2NH2, —CH2CH2NH2, —CH(CH3)CH2NH2, —CH2CH2CH2NH2, —NHCH3, —NHCH2CH3, —NHCH(CH3)2, —NHCH2CH2CH3, —N(CH3)2, —N(CH3)CH2CH3, —N(CH3)CH(CH3)2, —N(CH3)CH2CH2CH3, —OC(O)CH3, —OC(O)CH2CH3, —OC(O)CH(CH3)2, —OC(O)CH2CH2CH3, —OP(O)(OR32)2, —OSO2R33, —C(O)CH3, —C(O)CH2CH3, —C(O)CH(CH3)2, —C(O)CH2CH2CH3, —CO2R34, —C(O)NR35aR35b, —CH2C(O)NR35aR35b, —CH2CH2C(O)NR35aR35b, —CH(CH3)CH2C(O)NR35aR35b, —CH2CH2CH2C(O)NR35aR35b, —OC(O)NR35aR35b, —CH2OC(O)NR35aR35b, —CH2CH2OC(O)NR35aR35b, —CH(CH3)CH2OC(O)NR35aR35b, —CH2CH2CH2OC(O)NR35aR35b, Cy1, Ar1, —CH2Ar1, —CH2CH2Ar1, —CH(CH3)CH2Ar1, —CH2CH2CH2Ar1, and —OAr1. In an even further aspect, R1 is selected from hydrogen, —F, —Cl, —OH, —CN, —NC, —NCO, —OCN, —NO2, —ONO2, —ONO, —NO, —N3, —NH2, —NH3, —N═NR3, —NHOH, —CH2OH, —CH2CH2OH, —OCH3, —OCH2CH3, —SCH3, —SCH2CH3, —CH2SH, —CH2CH2SH, —CH2NH2, —CH2CH2NH2, —NHCH3, —NHCH2CH3, —N(CH3)2, —N(CH3)CH2CH3, —OC(O)CH3, —OC(O)CH2CH3, —OP(O)(OR32)2, —OSO2R33, —C(O)CH3, —C(O)CH2CH3, —CO2R34, —C(O)NR35aR35b, —CH2C(O)NR35aR35b, —CH2CH2C(O)NR35aR35b, —OC(O)NR35aR35b, —CH2OC(O)NR35aR35b, —CH2CH2OC(O)NR35aR35b, Cy1, Ar1, —CH2Ar1, —CH2CH2Ar1, and —OAr1. In a still further aspect, R1 is selected from hydrogen, —F, —Cl, —OH, —CN, —NC, —NCO, —OCN, —NO2, —ONO2, —ONO, —NO, —N3, —NH2, —NH3, —NHOH, —CH2OH, —OCH3, —SCH3, —CH2SH, —CH2NH2, —NHCH3, —N(CH3)2, —OC(O)CH3, —OP(O)(OR32)2, —OSO2R33, —C(O)CH3, —CO2R34, C(O)NR35aR35b, —CH2C(O)NR35aR35b, —OC(O)NR35aR35b, —CH2OC(O)NR35aR35b, Cy1, Ar1, —CH2Ar1, and —OAr1.
In various aspects, R1 is selected from hydrogen, halogen, C1-C12 alkyl, C2-CH2 alkenyl, C2-C12 alkynyl, C1-C12 hydroxy. C1-C12 alkoxy, C1-C12 thioalkyl, C1-C12 alkylthiol, C1-C12 aminoalkyl, C1-C12 alkylamino, (C1-C12)(C1-C12) dialkylamino, —OC(O)(C1-C12 alkyl), —OP(O)(OR32)2, —OSO2R33, —C(O)(C1-C12 alkyl), —CO2R34, —C(O)NR35aR35b, —(C1-C12 alkyl)C(O)NR35aR35b, —OC(O)NR35aR35b, —(C1-C12 alkyl)OC(O)NR35aR35b, Cy1, Ar1, (C1-C12 alkyl)Ar1, and —OAr1. In a further aspect, R1 is selected from hydrogen, halogen, C1-C8 alkyl, C2-C8 alkenyl. C2-C8 alkynyl, C1-C8 hydroxy, C1-C8 alkoxy, C1-C8 thioalkyl, C1-C8 alkylthiol, C1-C8 aminoalkyl, C1-C8 alkylamino, (C1-C8)(C1-C8) dialkylamino, —OC(O)(C1-C8 alkyl), —OP(O)(OR32)2, —OSO2R33, —C(O)(C1-C8 alkyl), —CO2R34, —C(O)NR35aR35b, —(C1-C8 alkyl)C(O)NR35aR35b, —OC(O)NR35aR35b, —(C1-C8 alkyl)OC(O)NR35aR35b, Cy1, Ar1, (C1-C8 alkyl)Ar1, and —OAr1. In a still further aspect, R1 is selected from hydrogen, halogen, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 hydroxy, C1-C4 alkoxy, C1-C4 thioalkyl, C1-C4 alkylthiol, C1-C4 aminoalkyl, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, —OC(O)(C1-C4 alkyl), —OP(O)(OR32)2, —OSO2R33, —C(O)(C1-C4 alkyl), —CO2R34, —C(O)NR35aR35b, —(C1-C8 alkyl)C(O)NR35aR35b, —OC(O)NR35aR35b, —(C1-C4 alkyl)OC(O)NR35aR35b, Cy1, Ar1, (C1-C4 alkyl)Ar1, and —OAr1. In yet a further aspect, R1 is selected from hydrogen, —F, —Cl, methyl, ethyl, n-propyl, isopropyl, ethenyl, n-propenyl, isopropenyl, ethynyl, propynyl, —CH2OH, —CH2CH2OH, —CH(CH3)CH2OH, —CH2CH2CH2OH, —OCH3, —OCH2CH3, —OCH(CH3)2, —OCH2CH2CH3, —SCH3, —SCH2CH3, —SCH(CH3)2, —SCH2CH2CH3, —CH2SH—, —CH2CH2SH, —CH(CH3)CH2SH, —CH2CH2CH2SH, —CH2NH2, —CH2CH2NH2, —CH(CH3)CH2NH2, —CH2CH2CH2NH2, —NHCH3, —NiCH2CH3, —NHCH(CH3)2, —NHCH2CH2CH3, —N(CH3)2, —N(CH3)CH2CH3, —N(CH3)CH(CH3)2, —N(CH3)CH2CH2CH3, —OC(O)CH3, —OC(O)CH2CH3, —OC(O)CH(CH3)2, —OC(O)CH2CH2CH3, —OP(O)(OR32)2, —OSO2R33, —C(O)CH3, —C(O)CH2CH3, —C(O)CH(CH3)2, —C(O)CH2CH2CH3, —CO2R34, —C(O)NR35aR35b, —CH2C(O)NR35aR35b, —CH2CH2C(O)NR35aR35b, —CH(CH3)CH2C(O)NR35aR35b, —CH2CH2CH2C(O)NR35aR35b, —OC(O)NR35aR35b, —CH2OC(O)NR35aR35b, —CH2CH2OC(O)NR35aR35b, —CH(CH3)CH2OC(O)NR35aR35b, —CH2CH2CH2OC(O)NR35aR35b, Cy1, Ar1, —CH2Ar1, —CH2CH2Ar1, —CH(CH3)CH2Ar1, —CH2CH2CH2Ar1, and —OAr1. In an even further aspect, R1 is selected from hydrogen, —F, —Cl, methyl, ethyl, ethenyl, ethynyl, —CH2OH, —CH2CH2OH, —OCH3, —OCH2CH3, —SCH3, —SCH2CH3, —CH2SH, —CH2CH2SH, —CH2NH2, —CH2CH2NH2, —NHCH3, —NHCH2CH3, —N(CH3)2, —N(CH3)CH2CH3, —OC(O)CH3, —OC(O)CH2CH3, —OP(O)(OR32)2, —OSO2R33, —C(O)CH3, —C(O)CH2CH3, —CO2R34, —C(O)NR35aR35b, —CH2C(O)NR35aR35b, —CH2CH2C(O)NR35aR35b, —OC(O)NR35aR35b, —CH2OC(O)NR35aR35b, —CH2H2OC(O)NR35aR35b, Cy1, Ar1, —CH2Ar1, —CH2CH2Ar1, and —OAr1. In a still further aspect, R1 is selected from hydrogen, —F, —Cl, methyl, —CH2OH, —OCH3, —SCH3, —CH2SH, —CH2NH2, —NHCH3, —N(CH3)2, —OC(O)CH3, —OP(O)(OR32)2, —OSO2R33, —C(O)CH3, —CO2R34, —C(O)NR35aR35b, —CH2C(O)NR35aR35b, —OC(O)NR35aR35b, —CH2OC(O)NR35aR35b, Cy1, Ar1, —CH2Ar1, and —OAr1.
In various aspects, R1 is selected from hydrogen, —OH, C1-C12 hydroxy, C1-C12 alkoxy, —OC(O)(C1-C12 alkyl), —OP(O)(OR32)2, —OSO2R33, —C(O)(C1-C12 alkyl), —CO2R34, —C(O)NR35aR35b, —(C1-C12 alkyl)C(O)NR35aR35b, —OC(O)NR35aR35b, —(C1-C12 alkyl)OC(O)NR35aR35b, Cy1, Ar1, (C1-C12 alkyl)Ar1, and —OAr1. In a further aspect, R1 is selected from hydrogen, —OH, C1-C8 hydroxy, C1-C8 alkoxy, —OC(O)(C1-C8 alkyl), —OP(O)(OR32)2, —OSO2R33, —C(O)(C1-C8 alkyl), —CO2R34, —C(O)NR35aR35b, —(C1-C8 alkyl)C(O)NR35aR35b, —OC(O)NR35aR35b, —(C1-C8 alkyl)OC(O)NR35aR35b, Cy1, Ar1, (C1-C8 alkyl)Ar1, and —OAr1. In a still further aspect, R1 is selected from hydrogen, —OH, C1-C4 hydroxy, C1-C4 alkoxy, —OC(O)(C1-C4 alkyl), —OP(O)(OR32)2, —OSO2R3, —C(O)(C1-C4 alkyl), —CO2R34, —C(O)NR35aR35b, —(C1-C8 alkyl)C(O)NR35aR35b, —OC(O)NR35aR35b, —(C1-C4 alkyl)OC(O)NR35aR35b, Cy1, Ar1, (C1-C4 alkyl)Ar1, and —OAr1. In yet a further aspect, R1 is selected from hydrogen, —OH, —CH2OH, —CH2CH2OH, —CH(CH3)CH2OH, —CH2CH2CH2OH, —OCH3, —OCH2CH3, —OCH(CH3)2, —OCH2CH2CH3, —OC(O)CH3, —OC(O)CH2CH3, —OC(O)CH(CH3)2, —C(O)CH(CH3)2, —C(O)CH2CH2CH3, —OP(O)(OR32)2, —OSO2R33, —C(O)CH3, —C(O)CH2CH3, —C(O)CH(CH3)2, —C(O)CH2CH2CH3, —CO2R34, —C(O)NR35aR35b, —CH2CH2CH2C(O)NR35aR35b, —CH2CH2C(O)NR35aR35b, —CH(CH3)CH2C(O)NR35aR35b, —CH2CH2CH2C(O)NR35aR35b, —OC(O)NR35aR35b, —CH2OC(O)NR35aR35b, —CH2CH2OC(O)NR35aR35b, —CH(CH3)CH2OC(O)NR35aR35b, —CH2CH2CH2OC(O)NR35aR35b, Cy1, Ar1, —CH2Ar1, —CH2CH2Ar1, —CH(CH3)CH2Ar1, —CH2CH2CH2Ar1, and —OAr1. In an even further aspect, R1 is selected from hydrogen, —OH, —CH2OH, —CH2CH2OH, —OCH3, —OCH2CH3, —OC(O)CH3, —OC(O)CH2CH3, —OP(O)(OR32)2, —OSO2R33, —C(O)CH3, —C(O)CH2CH3, —CO2R34, —C(O)NR35aR35b, —CH2C(O)NR35aR35b, —CH2CH2C(O)NR35aR35b, —OC(O)NR35aR35b, —CH2OC(O)NR35aR35b, —CH2CH2OC(O)NR35aR35b, Cy1, Ar1, —CH2Ar1, —CH2CH2Ar1, and —OAr1. In a still further aspect, R1 is selected from hydrogen, —OH, —CH2OH, —OCH, —OC(O)CH3, —OP(O)(OR32)2, —OSO2R33, —C(O)CH3, —CO2R34, —C(O)NR)NR35aR35b, —CH2C(O)NR35aR35b, —OC(O)NR35aR35b, —CH2OC(O)NR35aR35b, Cy1, Ar1, —CH2Ar1, and —OAr1.
In various aspects, R1 is selected from hydrogen, —OH, C1-C12 hydroxy, C1-C12 alkoxy, —OC(O)(C1-C12 alkyl), —OP(O)(OR32), —OSO2R33, —OC(O)NR35aR35b, and —OAr1. In a further aspect, R1 is selected from hydrogen, —OH, C1-C8 hydroxy, C1-C8 alkoxy, —OC(O)(C1-C8 alkyl), —OP(O)(OR32)2, —OSO2R33, —OC(O)NR35aR35b, and —OAr1. In a still further aspect, R1 is selected from hydrogen, —OH, C1-C4 hydroxy, C1-C4 alkoxy, —OC(O)(C1-C4 alkyl), —OP(O)(OR32)2, —OSO2R33, —OC(O)NR35aR35b, and —OAr1. In yet a further aspect, R1 is selected from hydrogen, —OH, —CH2OH, —CH2CH2OH, —CH(CH3)CH2OH, —CH2CH2CH2OH, —OCH3, —OCH2CH3, —OCH(CH3), —OCH2CH2CH3, —OC(O)CH3, —OC(O)CH2—CH3, —OC(O)CH(CH3)2, —OC(O)CH2CH2CH3, —OP(O)(OR32)2, —OSO2R33, —OC(O)NR35aR35b, and —OAr1. In an even further aspect, R1 is selected from hydrogen, —OH, —CH2OH, —CH2CH2CH2OH, —OCH3, —OCH2CH3, —OC(O)CH3, —OC(O)CH2CH3, —OP(O)(OR32)2, —OSO2R33, —OC(O)NR35aR35b, and —OAr1. In a still further aspect, R1 is selected from hydrogen, —OH, —CH2OH, —OCH3—OC(O)CH3, —OP(O)(OR32)2, —OSO2R33, —OC(O)NR35aR35b, and —OAr1.
In various aspects, R1 is selected from —OH, C1-C12 hydroxy, C1-C12 alkoxy, and —OC(O)(C1-C12 alkyl). In a further aspect, R1 is selected from —OH, C1-C8 hydroxy, C1-C8 alkoxy, and —OC(O)(C1-C8 alkyl). In a still further aspect, R1 is selected from —OH, C1-C4 hydroxy, C1-C4 alkoxy, and —OC(O)(C1-C4 alkyl). In yet a further aspect, R1 is selected from —OH, —CH2OH, —CH2CH2OH, —CH(CH3)CH2OH, —CH2CH2CH2OH, —OCH3, —OCH2CH3, —OCH(CH3)2, —OCH2CH2CH3, —OC(O)CH3, —OC(O)CH2CH3, —OC(O)CH(CH3)2, and —OC(O)CH2CH2CH3. In an even further aspect, R1 is selected from —OH, —CH2OH, —CH2CH2OH, —OCH3, —OCH2CH3, —OC(O)CH3, and —OC(O)CH2CH3. In a still further aspect, R1 is selected from —OH, —CH2OH, —OCH3, and —OC(O)CH3.
In various aspects, R1 is selected from —OH and —OC(O)(C1-C12 alkyl). In a further aspect, R1 is selected from —OH and —OC(O)(C1-C8 alkyl). In a still further aspect, R1 is selected from —OH and —OC(O)(C1-C4 alkyl). In yet a further aspect, R1 is selected from —OH, —OC(O)CH3, —C(O)CH2CH3, —OC(O)CH(CH3)2, and —OC(O)CH2CH2CH3. In an even further aspect, R1 is selected from —OH, —OC(O)CH3, and —OC(O)CH2CH3. In a still further aspect, R1 is selected from —OH and —OC(O)CH3.
In various aspects, R1 is selected from —OC(O)(C1-C12 alkyl). In a further aspect, R1 is selected from —OC(O)(C1-C8 alkyl). In a still further aspect, R1 is selected from —OC(O)(C1-C4 alkyl). In yet a further aspect, R1 is selected from —OC(O)CH3, —OC(O)CH2CH3, —OC(O)CH(CH3), and —OC(O)CH2CH2CH2CH3. In an even further aspect, R1 is selected from —OC(O)CH3 and —OC(O)CH2CH3. In a still further aspect, R1 is —OC(O)CH3.
f. R2 and R3 Groups
In one aspect, each of R2 and R3 is independently selected from hydrogen, —OH. C1-C12 hydroxy, and halogen. In a further aspect, each of R2 and R3 is independently selected from hydrogen, —OH, C1-C6 hydroxy, and halogen. In a still further aspect, each of R2 and R3 is independently selected from hydrogen, —OH, C1-C4 hydroxy, and halogen. In yet a further aspect, each of R2 and R3 is hydrogen.
In one aspect, each of R2 and R3 together comprise —O—.
In a further aspect, each of R2 and R3 is independently selected from hydrogen, —OH, and C1-C12 hydroxy. In a still further aspect, each of R2 and R3 is independently selected from hydrogen, —OH, and C1-C6 hydroxy. In yet a further aspect, each of R2 and R3 is independently selected from hydrogen, —OH, and C1-C4 hydroxy. In an even further aspect, each of R2 and R3 is independently selected from hydrogen, —OH, methoxy, ethoxy, n-propoxy, and isopropoxy. In a still further aspect, each of R2 and R3 is independently selected from hydrogen, —OH, methoxy, and ethoxy. In yet a further aspect, each of R2 and R3 is independently selected from hydrogen, —OH, and ethoxy. In an even further aspect, each of R2 and R3 is independently selected from hydrogen, —OH, and methoxy.
In a further aspect, each of R2 and R3 is independently selected from hydrogen, —OH, and halogen. In a still further aspect, each of R2 and R3 is independently selected from hydrogen, —OH, —F, —Cl, and —Br. In yet a further aspect, each of R2 and R3 is independently selected from hydrogen, —OH, —F, and —Cl. In an even further aspect, each of R2 and R3 is independently selected from hydrogen, —OH, and —F.
In a further aspect, each of R2 and R3 is independently selected from —OH and C1-C12 hydroxy. In a still further aspect, each of R2 and R3 is independently selected from —OH and C1-C6 hydroxy. In yet a further aspect, each of R2 and R3 is independently selected from —OH and C1-C4 hydroxy. In an even further aspect, each of R2 and R3 is independently selected from —OH, methoxy, ethoxy, n-propoxy, and isopropoxy. In a still further aspect, each of R2 and R3 is independently selected from —OH, methoxy, and ethoxy. In yet a further aspect, each of R2 and R3 is independently selected from —OH and ethoxy. In an even further aspect, each of R2 and R3 is independently selected from —OH and methoxy.
In a further aspect, each of R2 and R3 is independently selected from hydrogen and halogen. In a still further aspect, each of R2 and R3 is independently selected from hydrogen, —F, —Cl, and —Br. In yet a further aspect, each of R2 and R3 is independently selected from hydrogen, —F, and —Cl. In an even further aspect, each of R2 and R3 is independently selected from hydrogen and —Cl. In a still further aspect, each of R2 and R3 is independently selected from hydrogen and —F.
g. R5 Groups
In one aspect, R5 is selected from hydrogen, —OH, —NH2, C1-C9 alkyl, C1-C9 hydroxy, C1-C9 alkoxy, C1-C9 aminoalkyl, C1-C9 alkylamino, and (C1-C9)(C1-C9) dialkylamino. In a further aspect, R5 is selected from hydrogen, —OH, —NH2, C1-C6 alkyl, C1-C6 hydroxy, C1-C6 alkoxy, C1-C6 aminoalkyl, C1-C6 alkylamino, and (C1-C6)(C1-C6) dialkylamino. In a still further aspect, R is selected from hydrogen, —OH, —NH2, C1-C4 alkyl, C1-C4 hydroxy, C1-C4 alkoxy, C1-C4 aminoalkyl, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino. In yet a further aspect, R is selected from hydrogen, —OH, —NIH, methyl, ethyl, n-propyl, isopropyl, —CH2OH, —CH2CH2OH, —CH(CH3)CH2OH, —CH2CH2CH2OH, —OCH3, —OCH2CH3, —OCH(CH3)2, —OCH2CH2CH3, —CH2NH2, —CH2CH2NH2, —CH(CH3)CH2NH2, —CH2CH2CH2NH2, —NHCH3, —NHCH2CH3, —NHCH(CH3)2, —NHCH2CH2CH3, —N(CH3)2, —N(CH3)CH2CH3, —N(CH3)CH(CH3), and —N(CH3)CH2CH2CH3. In an even further aspect, R is selected from hydrogen, —OH, —NH2, methyl, ethyl, —CH2OH, —CH2CH2OH, —OCH3, —OCH2CH3, —CH2NH2, —CH2CH2NH2, —NHCH3, —NHCH2CH3, —N(CH3), and —N(CH3)CH2CH3. In a still further aspect, R is selected from hydrogen, —OH, —NH2, methyl, —CH2OH, —OCH3, —CH2NH2, —NHCH3, and —N(CH3)2.
In one aspect, R5 is absent.
In various aspects, R5 is selected from hydrogen, —OH, —NH2, C1-C9 alkyl, C1-C9 hydroxy, and C1-C9 alkoxy. In a further aspect, R is selected from hydrogen, —OH, —NH2, C1-C6 alkyl, C1-C6 hydroxy, and C1-C6 alkoxy. In a still further aspect, R is selected from hydrogen, —OH, —NH2, C1-C4 alkyl, C1-C4 hydroxy, and C1-C4 alkoxy. In yet a further aspect, R5 is selected from hydrogen, —OH, —NH2, methyl, ethyl, n-propyl, isopropyl, —CH2OH, —CH2CH2OH, —CH(CH3)CH2OH, —CH2CH2CH2OH, —OCH3, —OCH2CH3, —OCH(CH3)2, and —OCH2CH2CH3. In an even further aspect, R5 is selected from hydrogen, —OH, —NH2, methyl, ethyl, —CH2OH, —CH2CH2OH, —OCH3, and —OCH2CH3. In a still further aspect, R5 is selected from hydrogen, —OH, —NH2, methyl, —CH2OH, and —OCH3.
In various aspects, R5 is selected from hydrogen, —OH, —NH2, C1-C9 aminoalkyl, C1-C9 alkylamino, and (C1-C9)(C1-C9) dialkylamino. In a further aspect, R5 is selected from hydrogen, —OH, —NH2, C1-C6 aminoalkyl, C1-C6 alkylamino, and (C1-C6)(C1-C6) dialkylamino. In a still further aspect, R is selected from hydrogen, —OH, —NH2, C1-C4 aminoalkyl, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino. In yet a further aspect, R5 is selected from hydrogen, —OH, —NH, —CH2NH, —CH2CH2NH2, —CH(CH3)CH2NH2, —CH2CH2CH2NH2, —NHCH3, —NHCH2CH3, —NHCH(CH3)2, —NHCH2CH2CH3, —N(CH3)2, —N(CH3)CH2CH3, —N(CH3)CH(CH3)2, and —N(CH3)CH2CH2CH3. In an even further aspect, R5 is selected from hydrogen, —OH, —NH2, —CH2NH2, —CH2CH2NH2, —NHCH3, —NHCH2CH3, —N(CH3)2, and —N(CH3)CH2CH3. In a still further aspect, R5 is selected from hydrogen, —OH, —NH2, —CH2NH2, —NHCH3, and —N(CH3)2.
In various aspects, R5 is selected from hydrogen, —OH, —NH2, and C1-C9 alkyl. In a further aspect, R5 is selected from hydrogen, —OH, —NH2, and C1-C6 alkyl. In a still further aspect, RP is selected from hydrogen, —I, —NH2, and C1-C4 alkyl. In yet a further aspect, R5 is selected from hydrogen, —OH, —NH2, methyl, ethyl, n-propyl, and isopropyl. In an even further aspect, R5 is selected from hydrogen, —OH, —NH2, methyl, and ethyl. In a still further aspect, R5 is selected from hydrogen, —OH, —NH2, and methyl.
In various aspects, R5 is selected from hydrogen and C1-C9 alkyl. In a further aspect, R5 is selected from hydrogen and C1-C6 alkyl. In a still further aspect, R5 is selected from hydrogen and C1-C4 alkyl. In yet a further aspect, R5 is selected from hydrogen, methyl, ethyl, n-propyl, and isopropyl. In an even further aspect, R5 is selected from hydrogen, methyl, and ethyl. In a still further aspect, R5 is selected from hydrogen and ethyl. In yet a further aspect, R5 is selected from hydrogen and methyl.
In a further aspect, R5 is hydrogen.
h. R6 and R6′ Groups
In one aspect, each of R6 and R6′ is independently selected from hydrogen, halogen, —OH, —CN, —NC, —NCO, —OCN, —NO2, —ONO2, —ONO, —NO, —N3, —NH2, —NH3, —N═NR41, —NHOH, C1-C30 alkyl, C2-C0 alkenyl, C2-C30 alkynyl, C1-C30 hydroxy, C1-C30 alkoxy, C1-C30 thioalkyl, C1-C30 alkylthiol, C1-C30 aminoalkyl, C1-C30 alkylamino, (C1-C30)(C1-C30) dialkylamino, —C(O)(C1-C30 alkyl), —OP(O)(OR32)2, —OSO2R33, —CO2R34, —C(O)NR35aR35b, —(C1-C30 alkyl)C(O)NR35aR35b, —OC(O)NR35aR35b, —(C1-C30 alkyl)OC(O)NR35aR35b, Cy1, Ar1, —(C1-C30 alkyl)Ar1, —OAr1, —OC(O)(C1-C30 alkyl), —OC(O)Ar2, —OC(O)(C1-C30 alkyl)Ar2, —OC(O)Ar3, —OC(O)(C1-C30 alkyl)NR42C(O)Ar3, —OC(O)(C1-C30 alkyl)OC(O)Ar3, —OC(O)R40, —NR41C(O)(C1-C30 alkyl), —NR41C(O)Ar2, —NR41C(O)(C1-C30 alkyl)Ar2, —NR41C(O)Ar3, —NR41C(O)(C1-C30 alkyl)OC(O)Ar3, —NR41C(O)(C1-C30 alkyl)NR42C(O)Ar3, and —NR41C(O)R40. In a further aspect, each of R6 and R6′ is independently selected from hydrogen, halogen, —OH, —CN, —NC, —NCO, —OCN, —NO2, —ONO2, —ONO, —NO, —N3, —NH2, —NH3, —N═NR41, —NHOH, C1-C15 alkyl, C2-C15 alkenyl, C2-C15 alkynyl, C1-C15 hydroxy, C1-C15 alkoxy, C1-C15 thioallyl, C1-C15 alkylthiol, C1-C15 aminoalkyl, C1-C15 alkylamino, (C1-C15)(C1-C15) dialkylamino, —C(O)(C1-C15 alkyl), —OP(O)(OR32)2, —OSO2R33, —CO2R34, —C(O)NR35aR35b, —(C1-C15 alkyl)C(O)NR35aR35b, —OC(O)NR35aR35b, —(C1-C15 alkyl)OC(O)NR35aR35b, Cy1, Ar1, —(C1-C15 alkyl)Ar1, —OAr1, —OC(O)(C1-C15 alkyl), —OC(O)Ar2, —OC(O)(C1-C15 alkyl)Ar2, —OC(O)Ar3, —OC(O)(C1-C15 alkyl)NR42C(O)Ar3, —OC(O)(C1-C15 alkyl)OC(O)Ar3, —OC(O)R40, —NR41C(O)(C1-C15 alkyl), —NR41C(O)Ar2, —NR41C(O)(C1-C15 alkyl)Ar2, —NR41C(O)Ar3, —NR41C(O)(C1-C15 alkyl)OC(O)Ar3, —NR41C(O)(C1-C15 alkyl)NR42C(O)Ar3, and —NR41C(O)R40. In a still further aspect, each of R6 and R6′ is independently selected from hydrogen, halogen, —OH, —CN, —NC, —NCO, —OCN, —NO2, —ONO2, —ONO, —NO, —N3, —NH2, —NH3, —N═NR41, —NHOH, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C1-C8 hydroxy, C1-C8 alkoxy, C1-C8 thioallyl, C1-C8 alkylthiol, C1-C8 aminoallyl, C1-C8 alkylamino, (C1-C8)(C1-C8) dialkylamino, —C(O)(C1-C8 allyl), —OP(O)(OR32)2, —OSO2R33, —CO2R34, —C(O)NR35aR35b, —(C1-C8 alkyl)C(O)NR35aR35b, —OC(O)NR35aR35b, —(C1-C8 alkyl)OC(O)NR35aR35b, Cy1, Ar1, —(C1-C8 alkyl)Ar1, —OAr1, —OC(O)(C1-C8 alkyl), —OC(O)Ar2, —OC(O)(C1-C8 alkyl)Ar2, —OC(O)Ar3, —OC(O)(C1-C8 alkyl)NR42C(O)Ar3, —OC(O)(C1-C8 alkyl)OC(O)Ar3, —OC(O)R40, —NR41C(O)(C1-C8 alkyl), —NR41C(O)Ar2, —NR41C(O)(C1-C8 alkyl)Ar2, —NR41C(O)Ar3, —NR41C(O)(C1-C8 alkyl)OC(O)Ar3, —NR41C(O)(C1-C8 alkyl)NR42C(O)Ar3, and —NR41C(O)R40. In yet a further aspect, each of R6 and R6′ is independently selected from hydrogen, halogen, —OH, —CN, —NC, —NCO, —OCN, —NO2, —ONO2, —ONO, —NO, —N3, —NH2, —NH3, —N═NR41, —NHOH, C1-C4 allyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 hydroxy, C1-C4 alkoxy, C1-C4 thioalkyl, C1-C4 alkylthiol, C1-C4 aminoalkyl, C1-C4 alkylamino, (C1-C4)(C1-C4) diallylamino, —C(O)(C1-C4 alkyl), —OP(O)(OR32)2, —OSO2R33, —CO2R34, —C(O)NR35aR35b, —(C1-C4 alkyl)C(O)NR35aR35b, —OC(O)NR35aR35b, —(C1-C4 alkyl)OC(O)NR35aR35b, Cy1, Ar1, —(C1-C4 alkyl)Ar1, —OAr1, —OC(O)(C1-C4 allyl), —OC(O)Ar2, —OC(O)(C1-C4 alkyl)Ar2, —OC(O)Ar3, —OC(O)(C1-C4 alkyl)NR42C(O)Ar3, —OC(O)(C1-C4 alkyl)OC(O)Ar3, —OC(O)R40, —NR41C(O)(C1-C4 alkyl), —NR41C(O)Ar2, —NR41C(O)(C1-C4 alkyl)Ar2, —NR41C(O)Ar3, —NR41C(O)(C1-C4 alkyl)OC(O)Ar3, —NR41C(O)(C1-C4 alkyl)NR42C(O)Ar3, and —NR41C(O)R40. In an even further aspect, each of R6 and R6′ is independently selected from hydrogen, halogen, —OH, —CN, —NC, —NCO, —OCN, —NO2, —ONO2, —ONO, —NO, —N3, —NH2, —NH3, —N═NR41, —NHOH, methyl, ethyl, n-propyl, isopropyl, ethenyl, n-propenyl, isopropenyl, ethynyl, propynyl, —CH2OH, —CH2CH2OH, —CH(CH3)CH2OH, —CH2CH2CH2OH, —OCH3, —OCH2CH3, —OCH(CH3)2, —OCH2CH2CH3, —SCH3, —SCH2CH3, —SCH(CH3)2, —SCH2CH2CH3, —CH2SH, —CH2CH2SH, —CH(CH3)CH2SH, —CH2CH2CH2SH, —CH2NH2, —CH2CH2NH2, —CH(CH3)CH2NH2, —CH2CH2CH2NH2, —NHCH3, —NHCH2CH3, —NHCH(CH3)2, —NHCH2CH2CH3, —N(CH3)2, —N(CH3)CH2CH3, —N(CH3)CH(CH3)2, —N(CH3)CH2CH2CH3, —C(O)CH3, —C(O)CH2CH3, —C(O)CH(CH3)2, —C(O)CH2CH2CH3, —OP(O)(OR32)2, —OSO2R33, —CO2R34, —C(O)NR35aR35b, —CH2C(O)NR35aR35b, —CH2CH2C(O)NR35aR35b, —CH(CH3)CH2C(O)NR35aR35b, —CH2CH2CH2C(O)NR35aR35b, —OC(O)NR35aR35b, —CH2OC(O)NR35aR35b, —CH2CH2OC(O)NR35aR35b, —CH(CH3)CH2OC(O)NR35aR35b, —CH2CH2CH2OC(O)NR35aR35b, Cy1, Ar1, —CH2Ar1, —CH2CH2Ar1, —CH(CH3)CH2Ar1, —CH2CH2CH2Ar1, —OAr1, —OC(O)CH3, —OC(O)CH2CH3, —OC(O)CH(CH3)2, —OC(O)CH2CH2CH3, —OC(O)Ar2, —OC(O)CH2Ar2, —OC(O)CH2CH2Ar2, —OC(O)CH(CH3)CH2Ar2, —OC(O)CH2CH2CH2Ar2, —OC(O)Ar3, —OC(O)CH2NR42C(O)Ar3, —OC(O)CH2CH2NR42C(O)Ar3, —OC(O)CH(CH3)CH2NR42C(O)Ar3, —OC(O)CH2CH2CH2NR42C(O)Ar3, —OC(O)CH2OC(O)Ar3, —OC(O)CH2CH2OC(O)Ar3, —OC(O)CH(CH3)CH2OC(O)Ar3, —OC(O)CH2CH2CH2OC(O)Ar3, —OC(O)R40, —NR41C(O)CH3, —NR41C(O)CH2CH3, —NR41C(O)CH(CH3)2, —NR41C(O)CH2CH2CH3, —NR41C(O)Ar2, —NR41C(O)CH2Ar2, —NR41C(O)CH2CH2Ar2, —NR41C(O)CH(CH3)CH2Ar2, —NR41C(O)CH2CH2CH2Ar2, —NR41C(O)Ar3, —NR41C(O)CH2OC(O)Ar3, —NR41C(O)CH2CH2OC(O)Ar3, —NR41C(O)CH(CH3)CH2OC(O)Ar3, —NR41C(O)CH2CH2CH2OC(O)Ar3, —NR41C(O)CH2NR42C(O)Ar3, —NR41C(O)CH2CH2NR42C(O)Ar3, —NR41C(O)CH(CH3)CH2NR42C(O)Ar3, —NR41C(O)CH2CH2CH2NR42C(O)Ar3, and —NR41C(O)R40. In a still further aspect, each of R6 and R6′ is independently selected from hydrogen, halogen, —OH, —CN, —NC, —NCO, —OCN, —NO2, —ONO2, —ONO, —NO, —N3, —NH2, —NH3, —N═NR41, —NHOH, methyl, ethyl, ethenyl, ethynyl, —CH2OH, —CH2CH2OH, —OCH3, —OCH2CH3, —SCH3, —SCH2CH3, —CH2SH, —CH2CH2SH, —CH2NH2, —CH2CH2NH2, —NHCH3, —NHCH2CH3, —N(CH3)2, —N(CH3)CH2CH3, —C(O)CH3, —C(O)CH2CH3, —OP(O)(OR32)2, —OSO2R33, —CO2R34, —C(O)NR35aR35b, —CH2C(O)NR35aR35b, —CH2CH2C(O)NR35aR35b, —OC(O)NR35aR35b, —CH2OC(O)NR35aR35b, —CH2CH2OC(O)NR35aR35b, Cy1, Ar1, —CH2Ar1, —CH2CH2Ar1, —OAr1, —OC(O)CH3, —OC(O)CH2CH3, —OC(O)Ar2, —OC(O)CH2Ar2, —OC(O)CH2CH2Ar2, —OC(O)Ar3, —OC(O)CH2NR42C(O)Ar2, —OC(O)CH2CH2NR42C(O)Ar3, —OC(O)CH2OC(O)Ar3, —OC(O)CH2CH2OC(O)Ar3, —OC(O)R40, —NR41C(O)CH3, —NR41C(O)CH2CH3, —NR41C(O)Ar2, —NR41C(O)CH2Ar2, —NR41C(O)CH2CH2Ar2, —NR41C(O)Ar3, —NR41C(O)CH2OC(O)Ar3, —NR41C(O)CH2CH2OC(O)Ar3, —NR41C(O)CH2NR42C(O)Ar3, —NR41C(O)CH2CH2NR42C(O)Ar3, and —NR41C(O)R40. In yet a further aspect, each of R6 and R6′ is independently selected from hydrogen, halogen, —OH, —CN, —NC, —NCO, —OCN, —NO2, —ONO2, —ONO, —NO, —N, —NH2, —NH3, —N═NR41, —NHOH, methyl, —CH2OH, —OCH3, —SCH3, —CH2SH, —CH2NH2, —NHCH3, —N(CH3)2, —C(O)CH3, —OP(O)(OR32)2, —OSO2R33, —CO2R34, —C(O)NR35aR35b, —CH2C(O)NR35aR35b, —OC(O)NR35aR35b, —CH2OC(O)NR35aR35b, Cy1, Ar1, —CH2Ar1, —OAr1, —OC(O)CH3, —OC(O)Ar2, —OC(O)CH2Ar2, —OC(O)Ar2, —OC(O)CH2NR42C(O)Ar2, —OC(O)CH2OC(O)Ar3, —OC(O)R40, —NR41C(O)CH3, —NR41C(O)Ar2, —NR41C(O)CH2Ar2, —NR41C(O)Ar3, —NR41C(O)CH2OC(O)Ar3, —NR41C(O)CH2NR42C(O)Ar3, and —NR41C(O)R40.
In one aspect, one of R6 and R6′ is absent.
In a further aspect, one of R6 and R6′ is —NR41C(O)(C1-C30 alkyl), —NR41C(O)Ar2, —NR41C(O)(C1-C30 alkyl)Ar2, —NR41C(O)Ar3, —NR41C(O)(C1-C30 alkyl)OC(O)Ar3, —NR41C(O)(C1-C30 alkyl)NR42C(O)Ar3, or —NR41C(O)R40. In a still further aspect, one of R6 and R6′ is —NR41C(O)(C1-C15 alkyl), —NR41C(O)Ar2, —NR41C(O)(C1-C15 alkyl)Ar2, —NR41C(O)Ar3, —NR41C(O)(C1-C15 alkyl)OC(O)Ar3, —NR41C(O)(C1-C15 alkyl)NR42C(O)Ar3, or —NR41C(O)R40. In yet a further aspect, one of R6 and R6′ is —NR41C(O)(C1-C8 alkyl), —NR41C(O)Ar3, —NR41C(O)(C1-C8 alkyl)Ar2, —NR41C(O)Ar3, —NR41C(O)(C1-C8 alkyl)OC(O)Ar3, —NR41C(O)(C1-C8 alkyl)NR42C(O)Ar3, or —NR41C(O)R40. In an even further aspect, one of R6 and R6′ is —NR41C(O)(C1-C4 alkyl), —NR41C(O)Ar2, —NR41C(O)(C1-C4 alkyl)Ar2, —NR41C(O)Ar3, —NR41C(O)(C1-C4 alkyl)OC(O)Ar3, —NR41C(O)(C1-C4 alkyl)NR42—C(O)Ar3, or —NR41C(O)R40. In a still further aspect, one of R6 and R6′ is —NR41C(O)CH3, —NR41C(O)CH2CH3, —NR41C(O)CH(CH3)2, —NR41C(O)CH2CH2CH3, —NR41C(O)Ar2, —NR41C(O)CH2Ar2, —NR41C(O)CH2CH2Ar2, —NR41C(O)CH(CH3)CH2Ar3, —NR41C(O)CH2CH2CH2Ar2, —NR41C(O)Ar3, —NR41C(O)CH2OC(O)Ar3, —NR41C(O)CH2CH2OC(O)Ar3, —NR41C(O)CH(CH3)CH2OC(O)Ar3, —NR41C(O)CH2CH2CH2OC(O)Ar3, —NR41C(O)CH2NR42C(O)Ar3, —NR41C(O)CH2CH2NR42C(O)Ar3, —NR41C(O)CH(CH3)CH2NR42C(O)Ar3, —NR41C(O)CH2CH2CH2NR42C(O)Ar3, or —NR41C(O)R40. In yet a further aspect, one of R6 and R6′ is —NR41C(O)CH3, —NR41C(O)CH2CH3, —NRC(O)Ar2, —NR41C(O)CH2Ar2, —NR41C(O)CH2CH2Ar2, —NR41C(O)Ar3, —NR41C(O)CH2OC(O)Ar3, —NR41C(O)CH2CH2OC(O)Ar3, —NR41C(O)CH2NR42C(O)Ar3, —NR41C(O)CH2CH2NR42C(O)Ar3, or —NR41C(O)R40. In an even further aspect, one of R6 and R6′ is —NR41C(O)CH3, —NR41C(O)Ar2, —NR41C(O)CH2Ar2, —NR41C(O)Ar3, —NR41C(O)CH2OC(O)Ar3, —NR41C(O)CH2NR42C(O)Ar3, or —NR41C(O)R40.
In a further aspect, R6 is selected from —NR41C(O)(C1-C30 alkyl), —NR41C(O)Ar2, —NR41C(O)(C1-C30 alkyl)Ar2, —NR41C(O)Ar3, —NR41C(O)(C1-C30 alkyl)OC(O)Ar3, —NR41C(O)(C1-C30 alkyl)NR42C(O)Ar3, or —NR41C(O)R40 and R6′ is hydrogen. In a still further aspect, R6 is —NR41C(O)(C1-C15 alkyl), —NR41C(O)Ar2, —NR41C(O)(C1-C15 alkyl)Ar2, —NR41C(O)Ar3, —NR41C(O)(C1-C15 alkyl)OC(O)Ar3, —NR41C(O)(C1-C15 alkyl)NR42C(O)Ar3, or —NR41C(O)R40 and R6′ is hydrogen. In yet a further aspect, R6 is —NR41C(O)(C1-C8 alkyl), —NR C(O)Ar3, —NR41C(O)(C1-C8 alkyl)Ar2, —NR41C(O)Ar3, —NR41C(O)(C1-C8 alkyl)OC(O)Ar3, —NR41C(O)(C1-C8 alkyl)NR42C(O)Ar3, or —NR41C(O)R40 and R6′ is hydrogen. In an even further aspect, R6 is —NR41C(O)(C1-C4 alkyl), —NR41C(O)Ar2, —NR41C(O)(C1-C4 alkyl)Ar2, —NR41C(O)Ar3, —NR41C(O)(C1-C4 alkyl)OC(O)Ar3, —NR41C(O)(C1-C4 alkyl)NR42C(O)Ar3, or —NR41C(O)R40 and R6′ is hydrogen. In a still further aspect, R6 is —NR41C(O)CH3, —NR41C(O)CH2CH3, —NR41C(O)CH(CH3)2, —NR41C(O)CH2CH2CH3, —NR41C(O)Ar2, —NR41C(O)CH2Ar2, —NR41C(O)CH2CH2Ar2, —NR41C(O)CH(CH3)CH2Ar2, —NR41C(O)CH2CH2CH2Ar2, —NR41C(O)Ar3, —NR41C(O)CH2OC(O)Ar3, —NR41C(O)CH2CH2OC(O)Ar3, —NR41C(O)CH2(CH3)CH2OC(O)Ar3, —NR41C(O)CH2CH2CH2OC(O)Ar3, —NR41C(O)CH2NR42C(O)Ar3, —NR41C(O)CH2CH2NR42C(O)Ar3, —NR41C(O)CH(CH3)CH2NR42C(O)Ar3, —NR41C(O)CH2CH2CH2NR42C(O)Ar3, or —NR41C(O)R40 and R6′ is hydrogen. In yet a further aspect, R6 is —NR41C(O)CH3, —NR41C(O)CH2CH3, —NR41C(O)Ar2, —NR41C(O)CH2Ar2, —NR41C(O)CH2CH2Ar2, —NR41C(O)Ar3, —NR41C(O)CH2OC(O)Ar3, —NR41C(O)CH2CH2OC(O)Ar3, —NR41C(O)CH2NR42C(O)Ar3, —NR41C(O)CH2CH2NR42C(O)Ar3, or —NR41C(O)R40 and R6′ is hydrogen. In an even further aspect, R6 is —NR41C(O)CH3, —NR41C(O)Ar2, —NR41C(O)CH2Ar2, —NR41C(O)Ar3, —NR41C(O)CH2OC(O)Ar3, —NR41C(O)CH2NR42C(O)Ar3, or —NR41C(O)R40 and R6′ is hydrogen.
In a further aspect, R6 is selected from —NR41C(O)(C1-C30 alkyl)Ar2, —NR41C(O)(C1-C30 alkyl)NR42C(O)Ar3, or —NR41C(O)R40 and wherein R6′ is hydrogen. In a still further aspect, R6 is —NR41C(O)(C1-C15 alkyl)Ar2, —NR41C(O)(C1-C15 alkyl)NR42C(O)Ar3, or —NR41C(O)R40 and R6′ is hydrogen. In yet a further aspect, R6 is —NR41C(O)(C1-C5 alkyl)Ar2, —NR41C(O)(C1-C8 alkyl)NR42C(O)Ar3, or —NR41C(O)R40 and R6′ is hydrogen. In an even further aspect, R6 is —NR41C(O)(C1-C4 alkyl)Ar2, —NR41C(O)(C1-C4 alkyl)NR42C(O)Ar3, or —NR41C(O)R40 and R6′ is hydrogen. In a still further aspect, R6 is —NR41C(O)CH2Ar2, —NR41C(O)CH2CH2NR42C(O)Ar3, —NR41C(O)CH(CH3)CH2Ar2, —NR41C(O)CH2CH2CH2Ar2, —NR41C(O)CH2NR42C(O)Ar3, —NR41C(O)CH2CH2NR42C(O)Ar3, —NR41C(O)CH(CH3)CH2NR42C(O)Ar3, —NR41C(O)CH2CH2CH2NR42C(O)Ar3, or —NR41C(O)R40 and R6′ is hydrogen. In yet a further aspect, R6 is —NR41C(O)CH2Ar2, —NR41C(O)CH2CH2Ar2, —NR41C(O)CH2NR42C(O)Ar3, —NR41C(O)CH2CH2NR42C(O)Ar3, or —NR41C(O)R40 and R6′ is hydrogen. In an even further aspect, R6 is —NR41C(O)CH2Ar2, —NR41C(O)CH2NR42C(O)Ar3, or —NR41C(O)R40 and R6′ is hydrogen.
In a further aspect, R6 is selected from —NR41C(O)(C1-C30 alkyl), —NR41C(O)Ar2, —NR41C(O)(C1-C30 alkyl)Ar2, —NR41C(O)Ar3, —NR41C(O)(C1-C30 alkyl)OC(O)Ar3, —NR41C(O)(C1-C30 alkyl)NR42C(O)Ar3, and —NR41C(O)R40. In a still further aspect, R6 is —NR41C(O)(C1-C15 alkyl), —NR41C(O)Ar2, —NR41C(O)(C1-C15 alkyl)Ar2, —NR41C(O)Ar3, —NR41C(O)(C1-C15 alkyl)OC(O)Ar3, —NR41C(O)(C1-C15 alkyl)NR42C(O)Ar3, or —NR41C(O)R40. In yet a further aspect, R6 is —NR41C(O)(C1-C8 alkyl), —NR41C(O)Ar2, —NR41C(O)(C1-C8 alkyl)Ar2, —NR41C(O)Ar3, —NR41C(O)(C1-C8 alkyl)OC(O)Ar3, —NR41C(O)(C1-C8 alkyl)NR42C(O)Ar3, or —NR41C(O)R40. In an even further aspect, R6 is —NR41C(O)(C1-C4 alkyl), —NR41C(O)Ar2, —NR41C(O)(C1-C4 alkyl)Ar2, —NR41C(O)Ar3, —NR41C(O)(C1-C4 alkyl)OC(O)Ar3, —NR41C(O)(C1-C4 alkyl)NR42C(O)Ar3, or —NR41C(O)R40. In a still further aspect, R6 is —NR41C(O)CH3, —NR41C(O)CH2CH3, —NR41C(O)CH(CH3)2, —NR41C(O)CH2CH2CH3, —NR41C(O)Ar2, —NR41C(O)CH2Ar2, —NR41C(O)CH2CH2Ar2, —NR41C(O)CH(CH3)CH2Ar2, —NR41C(O)CH2CH2CH2Ar2, —NR41C(O)Ar3, —NR41C(O)CH2OC(O)Ar3, —NR41C(O)CH2CH2OC(O)Ar3, —NR41C(CO)CH(CH3)CH2OC(O)Ar3, —NR41C(O)CH2CH2CH2OC(O)Ar3, —NR41C(O)CH2NR42C(O)Ar3, —NR41C(O)CH2CH2NR42C(O)Ar3, —NR41C(O)CH(CH3)CH2NR42C(O)Ar3, —NR41C(O)CH2CH2CH2NR42C(O)Ar3, or —NR41C(O)R40. In yet a further aspect, R6 is —NR41C(O)CH3, —NR41C(O)CH2CH3, —NR41C(O)Ar2, —NR41C(O)CH2Ar2, —NR41C(O)CH2CH2Ar2, —NR41C(O)Ar3, —NR41C(O)CH2OC(O)Ar3, —NR41C(O)CH2CH2OC(O)Ar3, —NR41C(O)CH2NR42C(O)Ar3, —NR41C(O)CH2CH2NR42C(O)Ar3, or —NR41C(O)R40. In an even further aspect, R6 is —NR41C(O)CH3, —NR41C(O)Ar2, —NR41C(O)CH2Ar2, —NR41C(O)Ar3, —NR41C(O)CH2OC(O)Ar3, —NR41C(O)CH2NR42C(O)Ar3, or —NR41C(O)R40.
In a further aspect, R6 is —NR41C(O)(C1-C30 alkyl)Ar2. In a still further aspect, R6 is —NR41C(O)(C1-C15 alkyl)Ar2. In yet a further aspect, R6 is —NR41C(O)(C1-C8 alkyl)Ar2. In an even further aspect, R6 is —NR41C(O)(C1-C4 alkyl)Ar2. In a still further aspect, R6 is —NR41C(O)CH2Ar2, —NR41C(O)CH2CH2Ar2, —NR41C(O)CH(CH3)CH2Ar2, or —NR41C(O)CH2CH2CH2Ar2. In yet a further aspect, R6 is —NR41C(O)CH2Ar2 or —NR41C(O)CH2CH2Ar2. In an even further aspect, R6 is —NRC(O)CH2Ar2.
In a further aspect, R6 is —NR41C(O)(C1-C30 alkyl)NR42C(O)Ar3. In a still further aspect, R6 is —NR41C(O)(C1-C15 alkyl)NR41C(O)Ar3. In yet a further aspect, R6 is —NR41C(O)(C1-C8 alkyl)NR42C(O)Ar3. In an even further aspect, R6 is —NR41C(O)(C1-C4 alkyl)NR42C(O)Ar3. In a still further aspect, R6 is —NR41C(O)CH2CH2NR42C(O)Ar3, —NR41C(O)CH(CH3)CH2NR42C(O)Ar3, or —NR41C(O)CH2CH2CH2NR41C(O)Ar3. In yet a further aspect, R6 is —NR41C(O)CH2NR41C(O)Ar3 or —NR41C(O)CH2CH2NR42C(O)Ar3. In an even further aspect, R6 is —NR41C(O)CH2NR42C(O)Ar3.
In a further aspect, one of R6 and R6′ is —OC(O)R40 or —NR41C(O)R40. In a still further aspect, one of R6 and R6′ is —OC(O)R40. In yet a further aspect, one of R6 and R6′ is —NR41C(O)R40.
In a further aspect, R6 is —NR41C(O)Ar3. In a still further aspect, R6 is —NR41C(O)R40.
In a further aspect, R6′ is hydrogen.
i. R7 and R7′ Groups
In one aspect, R7 is selected from hydrogen, —OH, C1-C30 hydroxy, C1-C30 alkoxy, —OC(O)(C1-C30 alkyl), and —OC(O)NR35aR35b, and R7′ is selected from hydrogen, —OH, C1-C30 hydroxy, C1-C30 alkoxy, and —OC(O)(C1-C30 alkyl). In a further aspect, R7 is selected from hydrogen, —OH, C1-C15 hydroxy, C1-C1S alkoxy, —OC(O)(C1-C15 alkyl), and —OC(O)NR35aR35b, and R7′ is selected from hydrogen, —OH, C1-C15 hydroxy, C1-C15 alkoxy, and —OC(O)(C1-C15 alkyl). In a still further aspect, R7 is selected from hydrogen, —OH, C1-C8 hydroxy, C1-C8 alkoxy, —OC(O)(C1-C8 alkyl), and —OC(O)NR35aR35b, and R7′ is selected from hydrogen, —OH, C1-C8 hydroxy, C1-C8 alkoxy, and —OC(O)(C1-C8 alkyl). In yet a further aspect, R7 is selected from hydrogen, —OH, C1-C4 hydroxy, C1-C4 alkoxy, —OC(O)(C1-C4 alkyl), and —OC(O)NR35aR35b, and R7′ is selected from hydrogen, —OH, C1-C4 hydroxy, C1-C4 alkoxy, and —OC(O)(C1-C4 alkyl). In an even further aspect, R7 is selected from hydrogen, —OH, —CH2OH, —CH2CH2OH, —CH(CH3)CH2OH, —CH2CH2CH2OH, —OCH3, —OCH2CH3, —OCH(CH3)2, —OCH2CH2CH3, —OC(O)CH3, —OC(O)CH2CH3, —OC(O)CH(CH3)2, —OC(O)CH2CH2CH3, and —OC(O)NR35aR35b, and R7′ is selected from hydrogen, —OH, —CH2OH, —CH2CH2OH, —CH(CH3)CH2OH, —CH2CH2CH2OH, —OCH3, —OCH2CH3, —OCH(CH3)2, —OCH2CH2CH3, —OC(O)CH3, —OC(O)CH2CH3, —OC(O)CH(CH3)2, and —OC(O)CH2CH2CH3. In a still further aspect, R7 is selected from hydrogen, —OH, —CH2OH, —CH2CH2OH, —OCH3, —OCH2CH3, —OC(O)CH3, —OC(O)CH2CH3, and —OC(O)NR35aR35b, and R7′ is selected from hydrogen, —OH, —CH2OH, —CH2CH2OH, —OCH3, —OCH2CH3, —OC(O)CH3, and —OC(O)CH2CH3. In yet a further aspect, R7 is selected from hydrogen, —OH, —CH2OH, —OCH3, —OC(O)CH3, and —OC(O)NR35aR35b, and R7′ is selected from hydrogen, —OH, —CH2OH, —OCH3, and —OC(O)CH3.
In one aspect, each of R7 and R7′ together comprise ═O.
In one aspect, one of R7 and R7′ is absent.
In various aspects, R7 is selected from hydrogen, —OH, and —OC(O)(C1-C30 alkyl), and R7′ is selected from hydrogen, —OH, and —OC(O)(C1-C30 alkyl). In a further aspect, R7 is selected from hydrogen, —OH, and —OC(O)(C1-C15 alkyl), and R7′ is selected from hydrogen, —OH, and —OC(O)(C1-C15 alkyl). In a still further aspect, R7 is selected from hydrogen, —OH, and —OC(O)(C1-C8 alkyl, and R7′ is selected from hydrogen, —OH, and —OC(O)(C1-C8 alkyl). In yet a further aspect, R7 is selected from hydrogen, —OH, and —OC(O)(C1-C4 alkyl), and R7′ is selected from hydrogen, —OH, and —OC(O)(C1-C4 alkyl). In an even further aspect, R7 is selected from hydrogen, —OH, —OC(O)CH3, —OC(O)CH2CH3, —OC(O)CH(CH3)2, and —OC(O)CH2CH2CH3, and R7′ is selected from hydrogen, —OH, —OC(O)CH3, —OC(O)CH2CH3, —OC(O)CH(CH3)2, and —OC(O)CH2CH2CH3. In a still further aspect, R7 is selected from hydrogen, —OH, —OC(O)CH3, and —OC(O)CH2CH3, and R7′ is selected from hydrogen, —OH, —OC(O)CH3, and —OC(O)CH2CH3. In yet a further aspect, R7 is selected from hydrogen, —OH, and —OC(O)CH3, and R7′ is selected from hydrogen, —OH, and —OC(O)CH3.
In various aspects, R7 is selected from hydrogen, —OH, C1-C30 hydroxy, C1-C30 alkoxy, —OC(O)(C1-C30 alkyl), and —OC(O)NR35aR35b, and R7′ is hydrogen. In a further aspect, R7 is selected from hydrogen, —OH, C1-C15 hydroxy, C1-C15 alkoxy, —OC(O)(C1-C15 alkyl), and —OC(O)NR35aR35b, and R7′ is hydrogen. In a still further aspect, R7 is selected from hydrogen, —OH, C1-C8 hydroxy, C1-C8 alkoxy, —OC(O)(C1-C8 alkyl), and —OC(O)NR35aR35b, and R7′ is hydrogen. In yet a further aspect, R7 is selected from hydrogen, —OH, C1-C4 hydroxy, C1-C4 alkoxy, —OC(O)(C1-C4 alkyl), and —OC(O)NR35aR35b, and R7′ is hydrogen. In an even further aspect, R7 is selected rom hydrogen, —OH, —CH2OH, —CH2CH2OH, —CH(CH3)CH2OH, —CH2CH2OH, —OCH3, —OCH2CH3, —OCH(CH3)2, —OCH2CH2CH3, —OC(O)CH3, —OC(O)CH2CH3, —OC(O)CH(CH3)2, —OC(O)CH2CH2CH3, and —OC(O)NR35aR35b, and R7′ is hydrogen. In a still further aspect, R7 is selected from hydrogen. —OH, —CH2OH, —CH2CH2OH, —OCH3, —OCH2CH3, —OC(O)CH3, —OC(O)CH2CH3, and —OC(O)NR35aR35b, and R7′ is hydrogen. In yet a further aspect, R7 is selected from hydrogen, —OH, —CH2OH, —OCH3, —OC(O)CH3, and —OC(O)NR35aR35b, and R7′ is hydrogen.
In various aspects, R7 is selected from —OH and —OC(O)(C1-C30 alkyl), and R7′ is hydrogen. In a further aspect, R7 is selected from —OH and —OC(O)(C1-C15 alkyl), and R7′ is hydrogen. In a still further aspect, R7 is selected from —OH and —OC(O)(C1-C8 alkyl), and R7′ is hydrogen. In yet a further aspect, R7 is selected from —OH and —OC(O)(C1-C4 alkyl), and R7′ is hydrogen. In an even further aspect. R7 is selected from —OH, —OC(O)CH3, —OC(O)CH2CH3, —OC(O)CH(CH3)2, and —OC(O)CH2CH2CH3, and R7′ is hydrogen. In a still further aspect, R7 is selected from —OH, —OC(O)CH3, and —OC(O)CH2CH3, and R7′ is hydrogen. In yet a further aspect, R7 is selected from —OH and —OC(O)CH3, and R7′ is hydrogen.
In various aspects, R7′ is selected from hydrogen, —OH, C1-C30 hydroxy, C1-C30 alkoxy, and —OC(O)(C1-C30 alkyl), and R7 is hydrogen. In a further aspect, R7′ is selected from hydrogen, —OH, C1-C15 hydroxy, C1-C15 alkoxy, —OC(O)(C1-C15 alkyl), and R7 is hydrogen. In a still further aspect, R7′ is selected from hydrogen, —OH, C1-C8 hydroxy, C1-C8 alkoxy, and —OC(O)(C1-C8 alkyl), and R7 is hydrogen. In yet a further aspect, R7′ is selected from hydrogen, —OH, C1-C4 hydroxy, C1-C4 alkoxy, and —OC(O)(C1-C4 alkyl), and R7 is hydrogen. In an even further aspect, R7′ is selected from hydrogen, —OH, —CH2OH, —CH2CH2OH, —CH(CH3)CH2OH, —CH2CH2CH2OH, —OCH3, —OCH2CH3, —OCH(CH3)2, —OCH2CH2CH3, —OC(O)CH3, —OC(O)CH2CH3, —OC(O)CH(CH3)2, and —OC(O)CH2CH2CH3, and wherein R7 is hydrogen. In a still further aspect, R7′ is selected from hydrogen, —OH, —CH2OH, —CH2CH2OH, —OCH3, —OCH2CH3, —OC(O)CH3, and —OC(O)CH2CH3, and R7 is hydrogen. In yet a further aspect, R7′ is selected from hydrogen, —OH, —CH2OH, —OCH3, and —OC(O)CH3, and R7 is hydrogen.
In various aspects, R7′ is selected from —OH and —OC(O)(C1-C30 alkyl), and R7 is hydrogen. In a further aspect, R7′ is selected from —OH and —OC(O)(C1-C15 alkyl), and R7 is hydrogen. In a still further aspect, R7′ is selected from —OH and —OC(O)(C1-C8 alkyl), and R7 is hydrogen. In yet a further aspect, R7′ is selected from —OH and —OC(O)(C1-C4 alkyl), and R7 is hydrogen. In an even further aspect, R7′ is selected from —OH, —OC(O)CH3, —OC(O)CH2CH3, —C(O)CH(CH3)2, and —OC(O)CH2CH2CH3, and R7 is hydrogen. In a still further aspect, R7′ is selected from —OH, —OC(O)CH3, and —OC(O)CH2CH3, and R7 is hydrogen. In yet a further aspect, R7′ is selected from —OH and —OC(O)CH3, and R7 is hydrogen.
In a further aspect, R7 is —OH and R7′ is hydrogen. In a still further aspect, R7′ is —OH and R7 is hydrogen.
j. R8 and R8′ Groups
In one aspect, each of R8 and R8′ is independently selected from hydrogen, halogen, —OH, —CN, —NC, —NCO, —CN, —NO2, —ONO2, —ONO, —NO, —N3, —NH2, —NH3, —N═NR41, —NHOH, C1-C30 alkyl, C2-C30 alkenyl, C2-C30 alkynyl, C1-C30 hydroxy, C1-C30 alkoxy, C1-C30 thioalkyl, C1-C30 alkylthiol, C1-C30 aminoalkyl, C1-C30 alkylamino, (C1-C30)(C1-C30) dialkylamino, —C(O)(C1-C30 alkyl), —OP(O)(OR32)2, —OSO2R33, —CO2R34, —C(O)NR35aR35b, —(C1-C30 alkyl)C(O)NR35aR35b, —OC(O)NR35aR35b, —(C1-C30 alkyl)OC(O)NR35aR35b, Cy1, Ar1, —(C1-C30 alkyl)Ar1, —OAr1, —OC(O)(C1-C30 alkyl), —OC(O)Ar2, —OC(O)(C1-C30 alkyl)Ar2, —OC(O)Ar3, —OC(O)(C1-C30 alkyl)NR42C(O)Ar3, —OC(O)(C1-C30 alkyl)OC(O)Ar3, —OC(O)(C1-C30 alkyl)-L-Z, —OC(O)(C1-C30 alkyl)-L-(C1-C30 alkyl)-Z, —NR41C(O)(C1-C30 alkyl), —NR41C(O)Ar2, —NR41C(O)(C1-C30 alkyl)Ar2, —NR41C(O)Ar3, —NR41C(O)(C1-C30 alkyl)OC(O)Ar3, —NR41C(O)(C1-C30 alkyl)NR42C(O)Ar3, —NR41C(O)(C1-C30 alkyl)-L-Z, and —NR41C(O)(C1-C30 alkyl)-L-(C1-C30 alkyl)-Z. In a further aspect, each of R8 and R8′ is independently selected from hydrogen, halogen, —OH, —CN, —NC, —NCO, —OCN, —NO2, —ONO2, —ONO, —NO, —N3, —NH2, —NH3, —N═NR41, —NHOH, C1-C15 alkyl, C2-C15 alkenyl, C2-C15 alkynyl, C1-C15 hydroxy, C1-C15 alkoxy, C1-C15 thioalkyl, C1-C15 alkylthiol, C1-C15 aminoalkyl, C1-C15 alkylamino, (C1-C15)(C1-C15) dialkylamino, —C(O)(C1-C15 alkyl), —OP(O)(OR32)2, —OSO2R33, —CO2R34, —C(O)NR35aR35b, —(C1-C15 alkyl)C(O)NR35aR35b, —OC(O)NR35aR35b, —(C1-C15 alkyl)OC(O)NR35aR35b, Cy1, Ar1, —(C1-C15 alkyl)Ar1, —OAr1, —OC(O)(C1-C15 alkyl), —OC(O)Ar2, —OC(O)(C1-C15 alkyl)Ar2, —OC(O)Ar3, —OC(O)(C1-C15 alkyl)NR42C(O)Ar3, —OC(O)(C1-C15 alkyl)OC(O)Ar3, —OC(O)(C1-C15 alkyl)-L-Z, —OC(O)(C1-C15 alkyl)-L-(C1l-C15 alkyl)-Z, —NR41C(O)(C1-C15 alkyl), —NR41C(O)Ar2, —NR41C(O)(C1-C15 alkyl)Ar2, —NR41C(O)Ar3, —NR41C(O)(C1-C15 alkyl)OC(O)Ar3, —NR41C(O)(C1-C15 alkyl)NR42C(O)Ar3, —NR41C(O)(C1-C15 alkyl)-L-Z, and —NR41C(O)(C1-C15 alkyl)-L-(C1-C15 alkyl)-Z. In a still further aspect, each of R8 and R8′ is independently selected from hydrogen, halogen, —OH, —CN, —NC, —NCO, —OCN, —NO2, —ONO2, —ONO, —NO, —N3, —NH2, —NH3, —N═NR41, —NHOH, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C1-C8 hydroxy, C1-C8 alkoxy, C1-C8 thioallyl, C1-C8 alkylthiol, C1-C8 aminoallyl, C1-C8 alkylamino, (C1-C8)(C1-C8) dialkylamino, —C(O)(C1-C8 allyl), —OP(O)(OR32)2, —OSO2R33, —CO2R34, —C(O)NR35aR35b, —(C1-C8 alkyl)C(O)NR35aR35b, —OC(O)NR35aR35b, —(C1-C8 alkyl)OC(O)NR35aR35b, Cy1, Ar1, —(C1-C8 alkyl)Ar1, —OAr1, —OC(O)(C1-C8 alkyl), —OC(O)Ar2, —OC(O)(C1-C8 alkyl)Ar2, —OC(O)Ar3, —OC(O)(C1-C8 alkyl)NR42C(O)Ar3, —OC(O)(C1-C8 alkyl)OC(O)Ar3, —OC(O)(C1-C8 alkyl)-L-Z, —OC(O)(C1-C8 alkyl)-L-(C1-C8 alkyl)-Z, —NR41C(O)(C1-C8 allyl), —NR41C(O)Ar2, —NR41C(O)(C1-C8 alkyl)Ar2, —NR41C(O)Ar3, —NR41C(O)(C1-C8 alkyl)OC(O)Ar3, —NR41C(O)(C1-C8 alkyl)NR42C(O)Ar3, —NR41C(O)(C1-C8 alkyl)-L-Z, and —NR41C(O)(C1-C8 alkyl)-L-(C1-C8 alkyl)-Z. In yet a further aspect, each of R8 and R8′ is independently selected from hydrogen, halogen, —OH, —CN, —NC, —NCO, —OCN, —NO2, —ONO2, —ONO, —NO, —N3, —NH2, —NH3, —N═NR41, —NHOH, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 hydroxy, C1-C4 alkoxy, C1-C4 thioalkyl, C1-C4 alkylthiol, C1-C4 aminoalkyl, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, —C(O)(C1-C4 alkyl), —OP(O)(OR32)2, —OSO2R33, —CO2R34, —C(O)NR35aR35b, —(C1-C4 alkyl)C(O)NR35aR35b, —OC(O)NR35aR35b, —(C1-C4 alkyl)OC(O)NR35aR35b, Cy1, Ar1, —(C1-C4 alkyl)Ar1, —OAr1, —OC(O)(C1-C4 alkyl), —OC(O)Ar2, —OC(O)(C1-C4 alkyl)Ar2, —OC(O)Ar3, —OC(O)(C1-C4 alkyl)NR42C(O)Ar3, —OC(O)(C1-C4 alkyl)OC(O)Ar3, —OC(O)(C1-C4 alkyl)-L-Z, —OC(O)(C1-C4 alkyl)-L-(C1-C4 alkyl)-Z, —NR41C(O)(C1-C4 alkyl), —NR41C(O)Ar2, —NR41C(O)(C1-C4 alkyl)Ar2, —NR41C(O)Ar3, —NR41C(O)(C1-C4 alkyl)OC(O)Ar3, —NR41C(O)(C1-C4 alkyl)NR42C(O)Ar3, —NR41C(O)(C1-C4 alkyl)-L-Z, and —NR41C(O)(C1-C4 alkyl)-L-(C1-C4 alkyl)-Z. In an even further aspect, each of R8 and R8′ is independently selected from hydrogen, halogen, —OH, —CN, —NC, —NCO, —OCN, —NO2, —ONO2, —ONO, —NO, —N3, —NH2, —NH3, —N═NR41, —NHOH, methyl, ethyl, n-propyl, isopropyl, ethenyl, n-propenyl, isopropenyl, ethynyl, propynyl, —CH2OH, —CH2CH2OH, —CH(CH3)CH2OH, —CH2CH2CH2OH, —OCH3, —OCH2CH3, —OCH(CH3)2, —OCH2CH2CH3, —SCH3, —SCH2CH3, —SCH(CH3)2, —SCH2CH2CH3, —CH2SH, —CH2CH2SH, —CH(CH3)CH2SH, —CH2CH2CH2SH, —CH2NH2, —CH2CH2NH2, —CH(CH3)CH2NH2, —CH2CH2CH2NH2, —NHCH3, —NHCH2CH3, —NHCH(CH3)2, —NHCH2CH2CH3, —N(CH3)2, —N(CH3)CH2CH3, —N(CH3)CH(CH3)2, —N(CH3)CH2CH2CH3, —C(O)CH3, —C(O)CH2CH3, —C(O)CH(CH3)2, —C(O)CH2CH2CH3, —OP(O)(OR32)2, —OSO2R33, —CO2R34, —C(O)NR35aR35b, —CH2C(O)NR35aR35b, —CH2CH2C(O)NR35aR35b, —CH(CH3)CH2C(O)NR35aR35b, —CH2CH2CH2C(O)NR35aR35b, —OC(O)NR35aR35b, —CH2OC(O)NR35aR35b, —CH2CH2OC(O)NR35aR35b, —CH(CH3)CH2OC(O)NR35aR35b, —CH2CH2CH2OC(O)NR35aR35b, Cy1, Ar1, —CH2Ar1, —CH2CH2Ar1, —CH(CH3)CH2Ar1, —CH2CH2CH2Ar1, —OAr1, —OC(O)CH3, —OC(O)CH2CH3, —OC(O)CH(CH3)2, —OC(O)CH2CH2CH3, —OC(O)Ar2, —OC(O)CH2Ar2, —OC(O)CH2CH2Ar2, —OC(O)CH(CH3)CH2Ar2, —OC(O)CH2CH2CH2Ar2, —OC(O)Ar3, —OC(O)CH2NR42C(O)Ar3, —OC(O)CH2CH2NR42C(O)Ar3, —OC(O)CH(CH3)CH2NR42C(O)Ar3, —OC(O)CH2CH2CH2NR42C(O)Ar3, —OC(O)CH2OC(O)Ar3, —OC(O)CH2CH2OC(O)Ar3, —OC(O)CH(CH3)CH2OC(O)Ar3, —OC(O)CH2CH2CH2OC(O)Ar3, —OC(O)CH2-L-Z, —OC(O)CH2CH2-L-Z, —OC(O)CH(CH3)CH2-L-Z, —OC(O)CH2CH2CH2-L-Z, —OC(O)CH2-L-CH2—Z, —OC(O)CH2CH2-L-CH2CH2—Z, —OC(O)CH2CH2-L-CH(CH3)CH2—Z, —OC(O)CH2CH2-L-CH2CH2CH2—Z, —NR41C(O)CH3, —NR41C(O)CH2CH3, —NR41C(O)CH(CH3)2, —NR41C(O)CH2CH2CH3, —NR41C(O)Ar2, —NR41C(O)CH2Ar2, —NR41C(O)CH2CH2Ar2, —NR41C(O)CH(CH3)CH2Ar2, —NR41C(O)CH2CH2CH2Ar2, —NR41C(O)Ar3, —NR41C(O)CH2OC(O)Ar3, —NR41C(O)CH2CH2OC(O)Ar3, —NR41C(O)CH(CH3)CH2OC(O)Ar3, —NR41C(O)CH2CH2CH2OC(O)Ar3, —NR41C(O)CH2NR42C(O)Ar3, —NR41C(O)CH2CH2NR42C(O)Ar3, —NR41C(O)CH(CH3)CH2NR42C(O)Ar3, —NR41C(O)CH2CH2CH2NR42C(O)Ar3, —NR41C(O)CH2-L-Z, —NR41C(O)CH2CH2-L-Z, —NR41C(O)CH(CH3)CH2-L-Z, —NR41C(O)CH2CH2CH2-L-Z, —NR41C(O)CH2-L-CH2—Z, —NR41C(O)CH2CH2-L-CH2CH2—Z, —NR41C(O)CH2CH2-L-CH(CH3)CH2—Z, and —NR41C(O)CH2CH2-L-CH2CH2CH2—Z. In a still further aspect, each of R8 and R8′ is independently selected from hydrogen, halogen, —OH, —CN, —NC, —NCO, —OCN, —NO2, —ONO2, —ONO, —NO, —N3, —NH2, —NH3, —N═NR41, —NHOH, methyl, ethyl, ethenyl, ethynyl, —CH2OH, —CH2CH2OH, —OCH3, —OCH2CH3, —SCH3, —SCH2CH3, —CH2SH, —CH2CH2SH, —CH2NH2, —CH2CH2NH2, —NHCH3, —NHCH2CH3, —N(CH3)2, —N(CH3)CH2CH3, —C(O)CH3, —C(O)CH2CH3, —OP(O)(OR32)2, —OSO2R33, —CO2R34, —C(O)NR35aR35b, —CH2C(O)NR35aR35b, —CH2CH2C(O)NR35aR35b, —OC(O)NR35aR35b, —CH2OC(O)NR35aR35b, —CH2CH2OC(O)NR35aR35b, Cy1, Ar1, —CH2Ar1, —CH2CH2Ar1, —OAr1, —OC(O)CH3, —OC(O)CH2CH3, —OC(O)Ar2, —OC(O)CH2Ar2, —OC(O)CH2CH2Ar2, —OC(O)Ar3, —OC(O)CH2NR42C(O)Ar3, —OC(O)CH2CH2NR42C(O)Ar3, —OC(O)CH2OC(O)Ar3, —OC(O)CH2CH2OC(O)Ar3, —OC(O)CH2-L-Z, —OC(O)CH2CH2-L-Z, —OC(O)CH2-L-CH2—Z, —OC(O)CH2CH2-L-CH2CH2—Z, —NR41C(O)CH3, —NR41C(O)CH2CH3, —NR41C(O)Ar2, —NR41C(O)CH2Ar2, —NR41C(O)CH2CH2Ar2, —NR41C(O)Ar3, —NR41C(O)CH2OC(O)Ar3, —NR41C(O)CH2CH2OC(O)Ar3, —NR41C(O)CH2NR42C(O)Ar3, —NR41C(O)CH2CH2NR42C(O)Ar3, —NR41C(O)CH2-L-Z, —NR41C(O)CH2CH2-L-Z, —NR41C(O)CH2-L-CH2—Z, and —NR41C(O)CH2CH2-L-CH2CH2—Z. In yet a further aspect, each of R8 and R8′ is independently selected from hydrogen, halogen, —OH, —CN, —NC, —NCO, —OCN, —NO2, —ONO2, —ONO, —NO, —N3, —NH2, —NH3, —N═NR41, —NHOH, methyl, —CH2OH, —OCH3, —SCH3, —CH2SH, —CH2NH2, —NHCH3, —N(CH3)2, —C(O)CH3, —OP(O)(OR32)2, —OSO2R33, —CO2R34, —C(O)NR35aR35b, —CH2C(O)NR35aR35b, —OC(O)NR35aR35b, —CH2OC(O)NR35aR35b, Cy1, Ar1, —CH2Ar1, —OAr1, —OC(O)CH3, —OC(O)Ar2, —OC(O)CH2Ar2, —OC(O)Ar3, —OC(O)CH2NR42C(O)Ar3, —OC(O)CH2OC(O)Ar3, —OC(O)CH2-L-Z, —OC(O)CH2-L-CH2—Z, —NR41C(O)CH3, —NR41C(O)Ar2, —NR41C(O)CH2Ar2, —NR41C(O)Ar3, —NR41C(O)CH2OC(O)Ar3, —NR41C(O)CH2NR42C(O)Ar3, —NR41C(O)CH2-L-Z, and —NR41C(O)CH2-L-CH2—Z.
In one aspect, one of R8 and R8′ is absent.
In a further aspect, one of R8 and R8′ is —OC(O)(C1-C30 alkyl)-L-Z, —OC(O)(C1-C30 alkyl)-L-(C1-C30 alkyl)-Z, —NR41C(O)(C1-C30 alkyl)-L-Z, or —NR41C(O)(C1-C30 alkyl)-L-(C1-C30 alkyl)-Z. In a still further aspect, one of R8 and R8′ is —OC(O)(C1-C15 alkyl)-L-Z, —OC(O)(C1-C15 alkyl)-L-(C1-C15 alkyl)-Z, —NR41C(O)(C1-C15 alkyl)-L-Z, or —NR41C(O)(C1-C15 alkyl)-L-(C1-C15 alkyl)-Z. In yet a further aspect, one of R8 and R8′ is —OC(O)(C1-C8 alkyl)-L-Z, —OC(O)(C1-C8 alkyl)-L-(C1-C8 alkyl)-Z, —NR41C(O)(C1-C8 alkyl)-L-Z, or —NR41C(O)(C1-C8 alkyl)-L-(C1-C8 alkyl)-Z. In an even further aspect, one of R8 and R8′ is —OC(O)(C1-C4 alkyl)-L-Z, —OC(O)(C1-C4 alkyl)-L-(C1-C4 alkyl)-Z, —NR41C(O)(C1-C4 alkyl)-L-Z, or —NR41C(O)(C1-C4 alkyl)-L-(C1-C4 alkyl)-Z. In a still further aspect, one of R8 and R8′ is —OC(O)CH2-L-Z, —OC(O)CH2CH2-L-Z, —OC(O)CH(CH3)CH-L-Z, —OC(O)CH2CH2-L-Z, —OC(O)CH2-L-CH2-Z, —OC(O)CH2CH2-L-CH2CH2—Z, —OC(O)CH2CH2-L-CH(CH3)CH2—Z, —OC(O)CH2CH2-L-CH2CH2CH2—Z, —NR41C(O)CH2-L-Z, —NR41C(O)CH2CH2-L-Z, —NR41C(O)CH(CH3)CH2-L-Z, —NR41C(O)CH2CH2CH2-L-Z, —NR41C(O)CH2-L-CH2—Z, —NR41C(O)CH2CH2-L-CH2CH2—Z, —NR41C(O)CH2CH2-L-CH(CH3)CH2—Z, or —NR41C(O)CH2CH2-L-CH2CH2CH2—Z. In yet a further aspect, one of R8 and R8′ is —OC(O)CH2-L-Z, —OC(O)CH2CH2-L-Z, —OC(O)CH2-L-CH2—Z, —OC(O)CH2CH2-L-CH2CH2—Z, —NR41C(O)CH2-L-Z, —NR41C(O)CH2CH2-L-Z, —NR41C(O)CH2-L-CH2—Z, or —NR41C(O)CH2CH2-L-CH2CH2—Z. In a still further aspect, one of R8 and R8′ is —OC(O)CH2-L-Z, —OC(O)CH2-L-CH2—Z, —NR41C(O)CH2-L-Z, or —NR41C(O)CH2-L-CH2—Z.
In a further aspect, one of R8 and R8′ is —OC(O)(C1-C30 alkyl)-L-Z or —OC(O)(C1-C30 alkyl)-L-(C1-C30 alkyl)-Z. In a still further aspect, one of R8 and R8′ is —OC(O)(C1-C15 alky)-L-Z or —OC(O)(C1-C15 alkyl)-L-(C1-C15 alkyl)-Z. In yet a further aspect, one of R8 and R8′ is —OC(O)(C1-C8 alkyl)-L-Z or —OC(O)(C1-C8 alkyl)-L-(C1-C8 alkyl)-Z. In an even further aspect, one of R8 and R8′ is —OC(O)(C1-C4 alkyl)-L-Z or —OC(O)(C1-C4 alkyl)-L-(C1-C4 alkyl)-Z. In a still further aspect, one of R8 and R8′ is —OC(O)CH2-L-Z, —OC(O)CH2CH2-L-Z, —OC(O)CH(CH3)CH2-L-Z, —OC(O)CH2CH2CH2-L-Z, —OC(O)CH2-L-CH2—Z, —OC(O)CH2CH2-L-CH2CH2—Z, —OC(O)CH2CH2-L-CH(CH3)CH2—Z, or —OC(O)CH2CH2-L-CH2CH2CH2—Z. In yet a further aspect, one of R8 and R8′ is —OC(O)CH2-L-Z, —OC(O)CH2CH2-L-Z, —OC(O)CH2-L-CH2—Z, or —OC(O)CH2CH2-L-CH2CH2—Z. In a still further aspect, one of R8 and R8′ is —OC(O)CH2-L-Z or —OC(O)CH2-L-CH2—Z.
In a further aspect, one of R8 and R8′ is —NR41C(O)(C1-C30 alkyl)-L-Z or —NR41C(O)(C1-C30 alkyl)-L-(C1-C30 alkyl)-Z. In a still further aspect, one of R8 and R8′ is —NR41C(O)(C1-C15 alkyl)-L-Z or —NR41C(O)(C1-C15 alkyl)-L-(C1-C15 alkyl)-Z. In yet a further aspect, one of R8 and R8′ is —NR41C(O)(C1-C8 alkyl)-L-Z or —NR41C(O)(C1-C8 alkyl)-L-(C1-C8 alkyl)-Z. In an even further aspect, one of R8 and R8′ is —NR41C(O)(C1-C4 alkyl)-L-Z or —NR41C(O)(C1-C4 alkyl)-L-(C1-C4 alkyl)-Z. In a still further aspect, one of R8 and R8′ is —NR41C(O)CH2-L-Z, —NR41C(O)CH2CH2-L-Z, —NR41C(O)CH(CH3)CH2-L-Z, —NR41C(O)CH2CH2CH2-L-Z, —NR41C(O)CH2-L-CH2—Z, —NR41C(O)CH2CH2-L-CH2CH2—Z, —NR41C(O)CH2CH2-L-CH(CH)CH2—Z, or —NR41C(O)CH2CH2-L-CH2CH2CH2—Z. In yet a further aspect, one of R8 and R1′ is —NR41C(O)CH2-L-Z, —NR41C(O)CH2CH2-L-Z, —NR41C(O)CH2-L-CH2—Z, or —NR41C(O)CH2CH2-L-CH2CH2—Z. In a still further aspect, one of R8 and R8′ is —NR41C(O)CH2-L-Z or —NR41C(O)CH2-L-CH2—Z.
In a further aspect, R8 is —OC(O)(C1-C30 alkyl)-L-Z, —OC(O)(C1-C30 alkyl)-L-(C1-C30 alkyl)-Z, —NR41C(O)(C1-C30 alkyl)-L-Z, or —NR41C(O)(C1-C30 alkyl)-L-(C1-C30 alkyl)-Z and R8′ is hydrogen. In a still further aspect, R8 is —OC(O)(C1-C15 alkyl)L-Z, —OC(O)(C1-C15 alkyl)-L-(C1-C15 alkyl)-Z, —NR41C(O)(C1-C15 alkyl)-L-Z, or —NR41C(O)(C1-C15 alkyl)-L-(C1-C15 alkyl)-Z and R8′ is hydrogen. In yet a further aspect, R8 is —OC(O)(C1-C8 alkyl)-L-Z, —OC(O)(C1-C8 alkyl)-L-(C1-C8 alkyl)-Z, —NR41C(O)(C1-C8 alkyl)-L-Z, or —NR41C(O)(C1-C8 alkyl)-L-(C1-C8 alkyl)-Z and R8′ is hydrogen. In an even further aspect, R8 is —OC(O)(C1-C4 alkyl)-L-Z, —OC(O)(C1-C4 alkyl)-L-(C1-C4 alkyl)-Z, —NR41C(O)(C1-C4 alkyl)-L-Z, or —NR41C(O)(C1-C4 alkyl)-L-(C1-C4 alkyl)-Z and R8′ is hydrogen. In a still further aspect, R8 is —OC(O)CH2-L-Z, —OC(O)CH2CH2-L-Z, —OC(O)CH(CH3)CH2-L-Z, —OC(O)CH2CH2CH2-L-Z, —OC(O)CH2-L-CH2—Z, —OC(O)CH2CH2-L-CH2CH2—Z, —OC(O)CH2CH2-L-CH(CH3)CH2—Z, —OC(O)CH2CH2-L-CH2CH2CH2—Z, —NR41C(O)CH2-L-Z, —NR41C(O)CH2CH2-L-Z, —NR41C(O)CH(CH3)CH2-L-Z, —NR41C(O)CH2CH2CH2-L-Z, —NR41C(O)CH2-L-CH2—Z, —NR41C(O)CH2CH2-L-CH2CH2—Z, —NR41C(O)CH2CH2-L-CH(CH3)CH2—Z, or —NR41C(O)CH2CH2-L-CH2CH2CH2—Z and R8′ is hydrogen. In yet a further aspect, R8 is —OC(O)CH2-L-Z, —OC(O)CH2CH2-L-Z, —OC(O)CH2-L-CH2—Z, —OC(O)CH2CH2-L-CH2CH2—Z, —NR41C(O)CH2-L-Z, NR4C(O)CH2CH2-L-Z, —NR41C(O)CH2-L-CH2—Z, or —NR41C(O)CH2CH2-L-CH2CH2—Z and R8′ is hydrogen. In a still further aspect, R8 is —OC(O)CH2-L-Z, —OC(O)CH2-L-CH2—Z, —NR41C(O)CH2-L-Z, or —NR41C(O)CH2-L-CH2—Z and R8′ is hydrogen.
In a further aspect, R8′ is hydrogen.
k. R11 and R12 Groups
In one aspect, each of R11 and R12 is independently selected from hydrogen, —OH, C1-C8 hydroxy, C1-C6 alkyl, C1-C8 alkoxy, and —OC(O)(C1-C8 alkyl). In a further aspect, each of R11 and R12 is independently selected from hydrogen, —OH, C1-C4 hydroxy, C1-C4 alkyl, C1-C4 alkoxy, and —OC(O)(C1-C4 alkyl). In a still further aspect, each of R11 and R12 is independently selected from hydrogen, —OH, methyl, ethyl, n-propyl, isopropyl, —CH2OH, —CH2CH2OH, —CH(CH3)CH2OH, —CH2CH2CH2OH, —OCH3, —OCH2CH3, —OCH(CH3)2, —OCH2CH2CH3, —OC(O)CH—, —OC(O)CH2CH3, —OC(O)CH(CH3), and —OC(O)CH2CH2CH3. In yet a further aspect, each of R11 and R12 is independently selected from hydrogen, —OH, methyl, ethyl, —CH2OH, —CH2OH, —OCH3, —OCH2CH3, —OC(O)CH3, and —OC(O)CH2CH3. In an even further aspect, each of R11 and R12 is independently selected from hydrogen, —OH, methyl, —CH2OH, —OCH3, and —OC(O)CH3.
In a further aspect, each of R11 and R12 is the same. In a still further aspect, each of R11 and R12 is different.
In various aspects, each of R11 and R12 is independently selected from hydrogen, —OH, and —OC(O)(C1-C8 alkyl). In a further aspect, each of R11 and R12 is independently selected from hydrogen, —OH, and —OC(O)(C1-C4 alkyl). In a still further aspect, each of R11 and R12 is independently selected from hydrogen, —OH, —OC(O)CH3, —OC(O)CH2CH3, —OC(O)CH(CH3)2, and —OC(O)CH2CH2CH3. In yet a further aspect, each of R11 and R12 is independently selected from hydrogen, —OH, —OC(O)CH3, and —OC(O)CH2CH3. In an even further aspect, each of R11 and R12 is independently selected from hydrogen, —OH, and —OC(O)CH3.
In various aspects, each of R11 and R2 is independently selected from hydrogen and —OC(O)(C1-C8 alkyl). In a further aspect, each of R11 and R12 is independently selected from hydrogen and —OC(O)(C1-C4 alkyl). In a still further aspect, each of R11 and R12 is independently selected from hydrogen, —OC(O)CH3, —OC(O)CH2CH3, —OC(O)CH(CH3)2, and —OC(O)CH2CH2CH3. In yet a further aspect, each of R11 and R12 is independently selected from hydrogen, —OC(O)CH3, and —OC(O)CH2CH3. In an even further aspect, each of R11 and R12 is independently selected from hydrogen and —OC(O)CH3.
In various aspects, each of R11 and R12 is independently selected from —OH and —OC(O)(C1-C8 alkyl). In a further aspect, each of R11 and R12 is independently selected from —OH and —OC(O)(C1-C4 alkyl). In a still further aspect, each of R11 and R12 is independently selected from —OH, —OC(O)CH3, —OC(O)CH2CH3, —OC(O)CH(CH3)2, and —OC(O)CH2CH2CH3. In yet a further aspect, each of R11 and R12 is independently selected from —OH, —OC(O)CH3, and —OC(O)CH2CH3. In an even further aspect, each of R11 and R12 is independently selected from —OH and —OC(O)CH3.
In various aspects, each of R11 and R12 is independently selected from —OC(O)(C1-C8 alkyl). In a further aspect, each of R11 and R12 is independently selected from —OC(O)(C1-C4 alkyl). In a still further aspect, each of R11 and R12 is independently selected from —OC(O)CH3, —OC(O)CH2CH3, —OC(O)CH(CH3)2, and —OC(O)CH2CH2CH3. In yet a further aspect, each of R11 and R12 is independently selected from —OC(O)CH3 and —OC(O)CH2CH3. In an even further aspect, each of R11 and R12 is —OC(O)CH3.
l. R15 Groups
In one aspect, R15 is selected from hydrogen, —OH, C1-C30 hydroxy, C1-C30 alkyl, C1-C30 alkoxy, —OC(O)(C1-C30 alkyl), —OC(O)NR35aR35b, —OC(O)Ar2, —OC(O)(C1-C4 alkyl)Ar2, and —OC(O)(C1-C8 azide). In a further aspect, R15 is selected from hydrogen, —OH, C1-C15 hydroxy, C1-C15 alkyl, C1-C15 alkoxy, —OC(O)(C1-C15 alkyl), —OC(O)NR35aR35b, —OC(O)Ar2, —OC(O)(C1-C4 alkyl)Ar2, and —OC(O)(C1-C8 azide). In a still further aspect, R15 is selected from hydrogen, —OH, C1-C8 hydroxy, C1-C8 alkyl, C1-C8 alkoxy, —OC(O)(C1-C8 alkyl), —OC(O)NR35aR35b, —OC(O)Ar2, —OC(O)(C1-C4 alkyl)Ar2, and —OC(O)(C1-C8 azide). In yet a further aspect, R15 is selected from hydrogen, —OH, C1-C4 hydroxy, C1-C4 alkyl, C1-C4 alkoxy, —OC(O)(C1-C4 alkyl), —OC(O)NR35aR35b, —OC(O)Ar2, —OC(O)(C1-C4 alkyl)Ar2, and —OC(O)(C1-C4 azide). In an even further aspect, R15 is selected from hydrogen, —OH, methyl, ethyl, n-propyl, isopropyl, —CH2OH, —CH2CH2OH, —CH(CH3)CH2OH, —CH2CH2CH2OH, —OCH3, —OCH2CH3, —OCH(CH3)2, —OCH2CH2CH3, —OC(O)CH3, —OC(O)CH2CH3, —OC(O)CH(CH3)2, —OC(O)CH2CH2CH3, —OC(O)NR35aR35b, —OC(O)Ar2, —OC(O)CH2Ar2, —OC(O)CH2CH2Ar2, —OC(O)CH(CH3)CH2Ar2, —OC(O)CH2CH2CH2Ar2, —CH2N3, —CH2CH2N3, —CH(CH3)CH2N3, and —CH2CH2CH2N3. In a still further aspect, R15 is selected from hydrogen, —OH, methyl, ethyl, —CH2OH, —CH2CH2OH, —OCH3, —OCH2CH3, —OC(O)CH3, —OC(O)CH2CH3, —OC(O)NR35aR35b, —OC(O)Ar2, —OC(O)CH2Ar2, —OC(O)CH2CH2Ar2, —CH2N3, and —CH2CH2N3. In yet a further aspect, R15 is selected from hydrogen, —OH, methyl, —CH2OH, —OCH3, —OC(O)CH3, —OC(O)NR35aR35b, —OC(O)Ar2, —OC(O)CH2Ar2, and —CH2N3.
In various aspects, R15 is selected from hydrogen, —OH, —OC(O)(C1-C30 alkyl), —OC(O)NR35aR35b, —OC(O)Ar2, —OC(O)(C1-C4 alkyl)Ar2, and —OC(O)(C1-C8 azide). In a further aspect, R15 is selected from hydrogen, —OH, —OC(O)(C1-C15 alkyl), —OC(O)NR35aR35b, —OC(O)Ar2, —OC(O)(C1-C4 alkyl)Ar2, and —OC(O)(C1-C8 azide). In a still further aspect, R15 is selected from hydrogen, —OH, —OC(O)(C1-C8 alkyl), —OC(O)NR35aR35b, —OC(O)Ar2, —OC(O)(C1-C4 alkyl)Ar2, and —OC(O)(C1-C8 azide). In yet a further aspect, R15 is selected from hydrogen, —OH, —OC(O)(C1-C4 alkyl), —OC(O)NR35aR35b, —OC(O)Ar2, —OC(O)(C1-C4 alkyl)Ar2, and —OC(O)(C1-C4 azide). In an even further aspect, R15 is selected from hydrogen, —OH, —OC(O)CH3, —OC(O)CH2CH3, —OC(O)CH(CH3)2, —OC(O)CH2CH2CH3, —OC(O)NR35aR35b, —OC(O)Ar2, —OC(O)CH2Ar2, —OC(O)CH2CH2Ar2, —OC(O)CH(CH3)CH2Ar2, —OC(O)CH2CH2CH2Ar2, —CH2N3, —CH2CH2N3, —CH(CH3)CH2N3, and —CH2CH2CH2N3. In a still further aspect, R15 is selected from hydrogen, —OH, —OC(O)CH3, —OC(O)CH2CH3, —OC(O)NR35aR35b, —OC(O)Ar2, —OC(O)CH2Ar2, —OC(O)CH2CH2Ar2, —CH2N3, and —CH2CH2N3. In yet a further aspect, R15 is selected from hydrogen, —OH, —OC(O)CH3, —OC(O)NR35aR35b, —OC(O)Ar2, —OC(O)CH2Ar2, and —CH2N3.
In various aspects, R15 is selected from hydrogen, —OH, and —OC(O)(C1-C30 alkyl). In a further aspect, R15 is selected from hydrogen, —OH, and —OC(O)(C1-C15 alkyl). In a still further aspect, R15 is selected from hydrogen, —OH, and —OC(O)(C1-C8 alkyl). In yet a further aspect, R15 is selected from hydrogen, —OH, and —OC(O)(C1-C4 alkyl). In an even further aspect, R15 is selected from hydrogen, —OH, —OC(O)CH3, —OC(O)CH2CH3, —OC(O)CH(CH3)2, and —OC(O)CH2CH2CH3. In a still further aspect, R15 is selected from hydrogen, —OH, —OC(O)CH3, and —OC(O)CH2CH3. In yet a further aspect, R15 is selected from hydrogen, —OH, and —OC(O)CH3.
In various aspects, R15 is selected from —OH and —OC(O)(C1-C30 alkyl). In a further aspect, R15 is selected from —OH and —OC(O)(C1-C15 alkyl). In a still further aspect, R15 is selected from —OH and —OC(O)(C1-C8 alkyl). In yet a further aspect, R15 is selected from —OH and —OC(O)(C1-C4 alkyl). In an even further aspect, R15 is selected from —OH, —OC(O)CH3, —OC(O)CH2CH3, —OC(O)CH(CH3)2, and —OC(O)CH2CH2CH3. In a still further aspect, R15 is selected from —OH, —OC(O)CH3, and —OC(O)CH2CH3. In yet a further aspect, R15 is selected from —OH and —OC(O)CH3.
In various aspects, R15 is selected from —OC(O)(C1-C30 alkyl). In a further aspect, R15 is selected from —OC(O)(C1-C15 alkyl). In a still further aspect, R15 is selected from —OC(O)(C1-C8 alkyl). In yet a further aspect, R15 is selected from —OC(O)(C1-C4 alkyl). In an even further aspect, R15 is selected from —OC(O)CH3, —OC(O)CH2CH3, —OC(O)CH(CH3)2, and —OC(O)CH2CH2CH3. In a still further aspect, R15 is selected from —OC(O)CH3 and —OC(O)CH2CH3. In yet a further aspect, R15 is —OC(O)CH3.
In a further aspect, R15 is —OH.
m. R20 Groups
In one aspect, R20 is selected from hydrogen, —OH, —OOH, C1-C8 alkyl, C1-C8 hydroxy, C1-C8 alkoxy, C1-C8 hydroperoxy, and —OC(O)(C1-C8 alkyl). In a further aspect, R20 is selected from hydrogen, —OH, —OOH, C1-C4 alkyl, C1-C4 hydroxy, C1-C4 alkoxy, C1-C4 hydroperoxy, and —OC(O)(C1-C4 alkyl). In a still further aspect, R20 is selected from hydrogen, —OH, —OOH, methyl, ethyl, n-propyl, isopropyl, —CH2OH, —CH2CH2OH, —CH(CH3)CH2OH, —CH2CH2CH2OH, —OCH3, —OCH2CH3, —OCH(CH3)2, —OCH2CH2CH3, —CH2OOH, —CH2CH2OOH, —CH(CH3)CH2OOH, —CH2CH2CH2OOH, —OC(O)CH3, —OC(O)CH2CH3, —OC(O)CH(CH3)2, and —OC(O)CH2CH2CH3. In yet a further aspect, R20 is selected from hydrogen, —OH, —OOH, methyl, ethyl, —CH2OH, —CH2CH2OH, —OCH3, —OCH2CH3, —CH2OOH, —CH2CH2OOH, —OC(O)CH3, and —OC(O)CH2CH3. In an even further aspect, R20 is selected from hydrogen, —OH, —OOH, methyl, —CH2OH, —OCH3, —CH2OOH, and —OC(O)CH3.
In various aspects, R20 is selected from hydrogen, —OH, C1-C8 alkyl, C1-C8 hydroxy, C1-C8 alkoxy, and —OC(O)(C1-C8 alkyl). In a further aspect, R20 is selected from hydrogen, —OH, C1-C4 alkyl, C1-C4 hydroxy, C1-C4 alkoxy, and —OC(O)(C1-C4 alkyl). In a still further aspect, R20 is selected from hydrogen, —OH, methyl, ethyl, n-propyl, isopropyl, —CH2OH, —CH2CH2OH, —CH(CH3)CH2OH, —CH2CH2CH2OH, —OCH3, —OCH2CH3, —OCH(CH3)2, —OCH2CH2CH3, —OC(O)CH3, —OC(O)CH2CH3, —OC(O)CH(CH3)2, and OC(O)CH2CH2CH3. In yet a further aspect, R20 is selected from hydrogen, —OH, methyl, ethyl, —CH2OH, —CH2CH2OH, —OCH3, —OCH2CH3, —OC(O)CH3, and —OC(O)CH2CH3. In an even further aspect, R20 is selected from hydrogen, —OH, methyl, —CH2OH, —OCH3, and —OC(O)CH3.
In various aspects, R20 is selected from hydrogen, —OH, C1-C8 alkyl, and —OC(O)(C1-C8 alkyl). In a further aspect, R20 is selected from hydrogen, —OH, C1-C4 alkyl, and —OC(O)(C1-C4 alkyl). In a still further aspect, R20 is selected from hydrogen, —OH, methyl, ethyl, n-propyl, isopropyl, —OC(O)CH2CH3, —OC(O)CH(CH3)2, and —OC(O)CH2CH2CH3. In yet a further aspect, R20 is selected from hydrogen, —OH, methyl, ethyl, —OC(O)CH3, and —OC(O)CH2CH3. In an even further aspect, R20 is selected from hydrogen, —OH, methyl, and —OC(O)CH3.
In various aspects, R20 is selected from hydrogen and C1-C8 alkyl. In a further aspect, R20 is selected from hydrogen and C1-C4 alkyl. In a still further aspect, R20 is selected from hydrogen, methyl, ethyl, n-propyl, and isopropyl. In yet a further aspect, R20 is selected from hydrogen, methyl, and ethyl. In an even further aspect, R20 is selected from hydrogen and ethyl. In a still further aspect, R20 is selected from hydrogen and methyl.
In various aspects, R20 is selected from C1-C8 alkyl. In a further aspect, R20 is selected from C1-C4 alkyl. In a still further aspect, R20 is selected from methyl, ethyl, n-propyl, and isopropyl. In yet a further aspect, R20 is selected from methyl and ethyl. In an even further aspect, R20 is ethyl. In a still further aspect, R20 is methyl.
n. R21 Groups
In one aspect, R21 is selected from hydrogen and C1-C6 alkyl. In a further aspect, R21 is selected from hydrogen and C1-C4 alkyl. In a still further aspect, R21 is selected from hydrogen, methyl, ethyl, n-propyl, and isopropyl. In yet a further aspect, R21 is selected from hydrogen, methyl, and ethyl. In an even further aspect, R21 is selected from hydrogen and ethyl. In a still further aspect, R21 is selected from hydrogen and methyl.
In a further aspect, R21 is hydrogen.
In a further aspect, R21 is C1-C6 alkyl. In a still further aspect, R21 is C1-C4 alkyl. In yet a further aspect, R21 is selected from methyl, ethyl, n-propyl, and isopropyl. In an even further aspect, R21 is selected from methyl and ethyl. In a still further aspect, R21 is ethyl. In yet a further aspect, R21 is methyl.
o. R25 Groups
In one aspect, R25 is selected from hydrogen, —OH, C1-C8 hydroxy, C1-C8 alkoxy, —OC(O)(C1-18 alkyl), —OC(O)NR35aR35b, —OC(O)Ar5, and —OC(O)(C1-C8 azide). In a further aspect, R25 is selected from hydrogen, —OH, C1-C15 hydroxy, C1-C15 alkoxy, —OC(O)(C1-C15 alkyl), —OC(O)NR35aR35b, —OC(O)Ar5, and —OC(O)(C1-C8 azide). In a still further aspect, R25 is selected from hydrogen, —OH, C1-C8 hydroxy, C1-C8 alkoxy, —OC(O)(C1-C8 alkyl), —OC(O)NR35aR35b, —OC(O)Ar5, and —OC(O)(C1-C8 azide). In yet a further aspect, R25 is selected from hydrogen, —OH, C1-C4 hydroxy, C1-C4 alkoxy, —OC(O)(C1-C4 alkyl), —OC(O)NR35aR35b, —OC(O)Ar5, and —OC(O)(C1-C4 azide). In an even further aspect, R25 is selected from hydrogen, —OH, —CH2OH, —CH2CH2OH, —CH(CH3)CH2OH, —CH2CH2CH2OH, —OCH3, —OCH2CH3, —OCH(CH3)2, —OCH2CH2CH3, —OC(O)CH3, —OC(O)CH2CH3, —OC(O)CH(CH3)2, —OC(O)CH2CH2CH3, —OC(O)NR35aR35b, —OC(O)Ar5, —CH2N3, —CH2CH2N3, —CH(CH3)CH2N3, and —CH2CH2CH2N3. In a still further aspect, R25 is selected from hydrogen, —OH, —CH2OH, —CH2CH2OH, —OCH3, —OCH2CH3, —OC(O)CH3, —OC(O)CH2CH3, —OC(O)NR35aR35b, —OC(O)Ar5, —CH2N3, and —CH2CH2N3. In yet a further aspect, R25 is selected from hydrogen, —OH, —CH2OH, —OCH3, —OC(O)CH3, —OC(O)NR35aR35b, —OC(O)Ar5, and —CH2N3.
In various aspects, R25 is selected from hydrogen, —OH, —OC(O)(C1-C30 alkyl), —OC(O)NR35aR35b, —OC(O)Ar5, and —OC(O)(C1-C8 azide). In a further aspect, R25 is selected from hydrogen, —OH, —OC(O)(C1-C15 alkyl), —OC(O)NR35aR35b, —OC(O)Ar5, and —OC(O)(C1-C8 azide). In a still further aspect, R25 is selected from hydrogen, —OH, —OC(O)(C1-C8 alkyl), —OC(O)NR35aR356, —OC(O)Ar5, and —OC(O)(C1-C8 azide). In yet a further aspect, R25 is selected from hydrogen, —OH, —OC(O)(C1-C4 alkyl), —OC(O)NR35aR35b, —OC(O)Ar2, —OC(O)(C1-C4 alkyl)Ar2, and —OC(O)(C1-C4 azide). In an even further aspect, R25 is selected from hydrogen, —OH, —OC(O)CH3, —OC(O)CH2CH3, —OC(O)CH(CH3)2, —OC(O)CH2CH2CH3, —OC(O)NR35aR35b, —OC(O)Ar5, —CH2N3, —CH2CH2N3, —CH(CH3)CH2N3, and —CH2CH2CH2N3. In a still further aspect, R25 is selected from hydrogen, —OH, —OC(O)CH3, —OC(O)CH2CH3, —OC(O)NR35aR35b, —OC(O)Ar5, —CH2N3, and —CH2CH2N3. In yet a further aspect, R25 is selected from hydrogen, —OH, —OC(O)CH3, —OC(O)NR35aR35b, —OC(O)Ar5, and —CH2N3.
In various aspects, R25 is selected from hydrogen, —OH, and —OC(O)(C1-C30 alkyl). In a further aspect, R25 is selected from hydrogen, —OH, and —OC(O)(C1-C15 alkyl). In a still further aspect, R25 is selected from hydrogen, —OH, and —OC(O)(C1-C8 alkyl). In yet a further aspect, R25 is selected from hydrogen, —OH, and —OC(O)(C1-C4 alkyl). In an even further aspect, R25 is selected from hydrogen, —OH, —OC(O)CH3, —OC(O)CH2CH3, —OC(O)CH(CH3)2, and —OC(O)CH2CH2CH3. In a still further aspect, R25 is selected from hydrogen, —OH, —OC(O)CH3, and —OC(O)CH2CH3. In yet a further aspect, R25 is selected from hydrogen, —OH, and —OC(O)CH3.
In various aspects, R25 is selected from —OH and —OC(O)(C1-C30 alkyl). In a further aspect, R25 is selected from —OH and —OC(O)(C1-C15 alkyl). In a still further aspect, R25 is selected from —OH and —OC(O)(C1-C8 alkyl). In yet a further aspect, R25 is selected from —OH and —OC(O)(C1-C4 alkyl). In an even further aspect, R25 is selected from —OH, —OC(O)CH3, —OC(O)CH2CH3, —OC(O)CH(CH3)2, and —OC(O)CH2CH2CH3. In a still further aspect, R25 is selected from —OH, —OC(O)CH3, and —OC(O)CH2CH3. In yet a further aspect, R25 is selected from —OH and —OC(O)CH3.
In various aspects, R25 is selected from —OC(O)(C1-C30 alkyl). In a further aspect, R25 is selected from —OC(O)(C1-C15 alkyl). In a still further aspect, R25 is selected from —OC(O)(C1-C8 alkyl). In yet a further aspect, R25 is selected from —OC(O)(C1-C4 alkyl). In an even further aspect, R25 is selected from —OC(O)CH3, —OC(O)CH2CH3, —OC(O)CH(CH3)2, and —OC(O)CH2CH2CH3. In a still further aspect, R25 is selected from OC(O)CH3 and —OC(O)CH2CH3. In yet a further aspect, R25 is —OC(O)CH3.
In a further aspect, R25 is —OH.
p. R26 and R26′ Groups
In one aspect, each of R26 and R26′ is independently selected from hydrogen, —OH, C1-C8 hydroxy, and C1-C8 alkoxy. In a further aspect, each of R26 and R26′ is independently selected from hydrogen, —OH, C1-C4 hydroxy, and C1-C4 alkoxy. In a still further aspect, each of R26 and R26′ is independently selected from hydrogen, —OH, —CH2OH, —CH2CH2OH, —CH(CH3)CH2OH, —CH2CH2CH2OH, —OCH3, —OCH2CH3, —OCH(CH3)2, and —OCH2CH2CH3. In yet a further aspect, each of R26 and R26′ is independently selected from hydrogen, —OH, —CH2OH, —CH2CH2OH, —OCH3, and —OCH2CH3. In an even further aspect, each of R26 and R26′ is independently selected from hydrogen, —OH, —CH2OH, and —OCH3.
In various aspects, each of R26 and R26′ is independently selected from hydrogen, —OH, and C1-C8 hydroxy. In a further aspect, each of R26 and R26′ is independently selected from hydrogen, —OH, and C1-C4 hydroxy. In a still further aspect, each of R26 and R26′ is independently selected from hydrogen, —OH, —CH2OH, —CH2CH2OH, —CH(CH3)CH2OH, and —CH2CH2CH2OH. In yet a further aspect, each of R26 and R26′ is independently selected from hydrogen, —OH, —CH2OH, and —CH2CH2OH. In an even further aspect, each of R26 and R26′ is independently selected from hydrogen, —OH, and —CH2OH.
In a further aspect, each of R26 and R26′ is independently selected from hydrogen and —OH.
In one aspect, each of R26 and R26′ together comprise ═O.
q. R27 Groups
In one aspect, R27 is selected from hydrogen and C1-C6 alkyl. In a still further aspect, each occurrence of R27 is selected from hydrogen and C1-C4 alkyl. In yet a further aspect, R27 is selected from hydrogen, methyl, ethyl, n-propyl, and isopropyl. In an even further aspect, R27 is selected from hydrogen, methyl, and ethyl. In a still further aspect, R27 is selected from hydrogen and ethyl. In yet a further aspect, R27 is selected from hydrogen and methyl.
In a further aspect, R27 is selected from C1-C6 alkyl. In yet a further aspect, R27 is selected from C1-C4 alkyl. In an even further aspect, R27 is selected from methyl, ethyl, n-propyl, and isopropyl. In a still further aspect, R27 is selected from methyl and ethyl. In yet a further aspect, R27 is ethyl. In an even further aspect, R27 is methyl.
In a further aspect, R27 is hydrogen.
r. R28 and R29 Groups
In one aspect, each of R28 and R29 is independently selected from hydrogen and halogen. In a further aspect, each of R28 and R29 is independently selected from hydrogen, —F, —Cl, and —Br. In a still further, each of R28 and R29 is independently selected from hydrogen, —F, and —Cl. In yet a further aspect, each of R28 and R29 is independently selected from hydrogen and —F. In an even further aspect, each of R28 and R29 is independently selected from hydrogen and —Cl.
In one aspect, each of R28 and R29 together comprise —O— or —N(R37)—. In a further aspect, each of R28 and R29 together comprise —O—. In a still further aspect, each of R28 and R29 together comprise —N(R37)—.
In a further aspect, each of R28 and R29 is hydrogen.
In a further aspect, each of R28 and R29 is independently halogen. In a still further aspect, each of R28 and R29 is independently selected from —F, —Cl, and —Br. In yet a further aspect, each of R28 and R29 is independently selected from —F and —Cl. In an even further aspect, each of R28 and R29 is —F. In a still further aspect, each of R28 and R29 is —Cl.
s. R31, R32, R34, R35a, and R35b Groups
In one aspect, each occurrence of R3, R2, R34, R35a, and R35b, when present, is independently selected from hydrogen and C1-C12 alkyl. In a further aspect, each occurrence of R31, R32, R34, R35a, and R35b, when present, is independently selected from hydrogen and C1-C6 alkyl. In a still further aspect, each occurrence of R31, R32, R34, R3a, and R35b, when present, is independently selected from hydrogen and C1-C4 alkyl. In yet a further aspect, each occurrence of R31, R32, R34, R35a, and R3Sb, when present, is independently selected from hydrogen, methyl, ethyl, n-propyl, and isopropyl. In an even further aspect, each occurrence of R31, R32, R34, R35a, and R35b, when present, is independently selected from hydrogen, methyl, and ethyl. In a still further aspect, each occurrence of R31, R32, R34, R35a, and R35b, when present, is independently selected from hydrogen and ethyl. In yet a further aspect, each occurrence of R31, R32, R34, R35a, and R35b, when present, is independently selected from hydrogen and methyl.
In a further aspect, each occurrence of R31, R32, R34, R35a, and R35b, when present, is independently selected from C1-C12 alkyl. In a still further aspect, each occurrence of R31, R32, R34, R35a, and R35b, when present, is independently selected from C1-C6 alkyl. In yet a further aspect, each occurrence of R31, R32, R34, R35a, and R35b, when present, is independently selected from C1-C4 alkyl. In an even further aspect, each occurrence of R31, R32, R34, R35a, and R35b, when present, is independently selected from methyl, ethyl, n-propyl, and isopropyl. In a still further aspect, each occurrence of R31, R32, R34, R35a, and R35b, when present, is independently selected from methyl and ethyl. In yet a further aspect, each occurrence of R31, R3, R34, R35a, and R35b, when present, is ethyl. In an even further aspect, each occurrence of R31, R32, R34, R35b, and R35b, when present, is methyl.
In a further aspect, each occurrence of R31, R32, R34, R35a, and R35b, when present, is hydrogen.
t. R33 Groups
In one aspect, each occurrence of R33, when present, is independently selected from hydrogen, C1-C12 alkyl, and monocyclic aryl monosubstituted with a methyl group. In a further aspect, each occurrence of R33, when present, is independently selected from hydrogen, C1-C8 alkyl, and monocyclic aryl monosubstituted with a methyl group. In a still further aspect, each occurrence of R33, when present, is independently selected from hydrogen, C1-C4 alkyl, and monocyclic aryl monosubstituted with a methyl group. In yet a further aspect, each occurrence of R33, when present, is independently selected from hydrogen, methyl, ethyl, n-propyl, isopropyl, and monocyclic aryl monosubstituted with a methyl group. In an even further aspect, each occurrence of R33, when present, is independently selected from hydrogen, methyl, ethyl, and monocyclic aryl monosubstituted with a methyl group. In a still further aspect, each occurrence of R33, when present, is independently selected from hydrogen, methyl, and monocyclic aryl monosubstituted with a methyl group.
In various aspects, each occurrence of R33, when present, is independently selected from hydrogen and C1-C12 alkyl. In a further aspect, each occurrence of R33, when present, is independently selected from hydrogen and C1-C8 alkyl. In a still further aspect, each occurrence of R33, when present, is independently selected from hydrogen and C1-C4 alkyl. In yet a further aspect, each occurrence of R33, when present, is independently selected from hydrogen, methyl, ethyl, n-propyl, and isopropyl. In an even further aspect, each occurrence of R33, when present, is independently selected from hydrogen, methyl, and ethyl. In a still further aspect, each occurrence of R33, when present, is independently selected from hydrogen and ethyl. In yet a further aspect, each occurrence of R33, when present, is independently selected from hydrogen and methyl.
In a further aspect, each occurrence of R33, when present, is independently selected from hydrogen and monocyclic aryl monosubstituted with a methyl group.
In a further aspect, each occurrence of R33, when present, is hydrogen.
u. R36 Groups
In one aspect, each occurrence of R36, when present, is independently selected from hydrogen and C1-C12 alkyl. In a further aspect, each occurrence of R36, when present, is independently selected from hydrogen and C1-C6 alkyl. In a still further aspect, each occurrence of R36, when present, is independently selected from hydrogen and C1-C4 alkyl. In yet a further aspect, each occurrence of R36, when present, is independently selected from hydrogen, methyl, ethyl, n-propyl, and isopropyl. In an even further aspect, each occurrence of R36, when present, is independently selected from hydrogen, methyl, and ethyl. In a still further aspect, each occurrence of R36, when present, is independently selected from hydrogen and ethyl. In yet a further aspect, each occurrence of R36, when present, is independently selected from hydrogen and methyl.
In a further aspect, each occurrence of R36, when present, is independently selected from C1-C12 alkyl. In a still further aspect, each occurrence of R36, when present, is independently selected from C1-C6 alkyl. In yet a further aspect, each occurrence of R36, when present, is independently selected from C1-C4 alkyl. In an even further aspect, each occurrence of R36, when present, is independently selected from methyl, ethyl, n-propyl, and isopropyl. In a still further aspect, each occurrence of R36, when present, is independently selected from methyl and ethyl. In yet a further aspect, each occurrence of R36, when present, is ethyl. In an even further aspect, each occurrence of R36, when present, is methyl.
In a further aspect, each occurrence of R36, when present, is hydrogen.
v. R37 Groups
In one aspect, R37, when present, is selected from hydrogen, C1-C4 alkyl, —SO2R51, and a structure having a formula:
In a further aspect, R37, when present, is selected from hydrogen and C1-C4 alkyl. In a still further aspect, R37, when present, is selected from hydrogen, methyl, ethyl, n-propyl, and isopropyl. In yet a further aspect, R37, when present, is selected from hydrogen, methyl, and ethyl. In an even further aspect, R37, when present, is selected from hydrogen and ethyl. In a still further aspect, R37, when present, is selected from hydrogen and methyl.
In a further aspect, R37, when present, is C1-C4 alkyl. In a still further aspect, R37, when present, is selected from methyl, ethyl, n-propyl, and isopropyl. In yet a further aspect, R37, when present, is selected from methyl and ethyl. In an even further aspect, R37, when present, is ethyl. In a still further aspect, R37, when present, is methyl.
In a further aspect, R37, when present, is hydrogen.
In a further aspect, R37, when present, is selected from hydrogen and —SO2R51. In a still further aspect, R37, when present, is —SO2R51.
In a further aspect, R37, when present, is a structure having a formula:
w. R40 Groups
In one aspect, each occurrence of R40, when present, is independently a C1-C30 alkyl functionalized with a group selected from —N3, —SH, —OH, —NH2, —NHOH, an ester, a disulfide, a sulfonamide, a terminal alkyne, haloacetyl, maleimide, isothiocyanate, N-hydroxysuccinimde, an acylhydrazine, an acylhydrazone, a hydrazine, a hydrazone, and hydrazide. In a further aspect, each occurrence of R40, when present, is independently a C1-C15 alkyl functionalized with a group selected from —N3, —SH, —OH, —NH2, —NHOH, an ester, a disulfide, a sulfonamide, a terminal alkyne, haloacetyl, maleimide, isothiocyanate, N-hydroxysuccinimde, an acylhydrazine, an acylhydrazone, a hydrazine, a hydrazone, and hydrazide. In a still further aspect, each occurrence of R40, when present, is independently a C1-C8 alkyl functionalized with a group selected from —N3, —SH, —OH, —NH2, —NHOH, an ester, a disulfide, a sulfonamide, a terminal alkyne, haloacetyl, maleimide, isothiocyanate, N-hydroxysuccinimde, an acylhydrazine, an acylhydrazone, a hydrazine, a hydrazone, and hydrazide. In yet a further aspect, each occurrence of R40, when present, is independently a C1-C4 alkyl functionalized with a group selected from —N3, —SH, —OH, —NH2, —NHOH, an ester, a disulfide, a sulfonamide, a terminal alkyne, haloacetyl, maleimide, isothiocyanate, N-hydroxysuccinimde, an acylhydrazine, an acylhydrazone, a hydrazine, a hydrazone, and hydrazide. In an even further aspect, each occurrence of R40, when present, is independently a methyl, ethyl, n-propyl, or isopropyl and is functionalized with a group selected from —N3, —SH, —OH, —NH2, —NHOH, an ester, a disulfide, a sulfonamide, a terminal alkyne, haloacetyl, maleimide, isothiocyanate, N-hydroxysuccinimde, an acylhydrazine, an acylhydrazone, a hydrazine, a hydrazone, and hydrazide. In a still further aspect, each occurrence of R40, when present, is independently a methyl or ethyl and is functionalized with a group selected from —N3, —SH, —OH, —NH2, —NHOH, an ester, a disulfide, a sulfonamide, a terminal alkyne, haloacetyl, maleimide, isothiocyanate, N-hydroxysuccinimde, an acylhydrazine, an acylhydrazone, a hydrazine, a hydrazone, and hydrazide. In yet a further aspect, each occurrence of R40, when present, is independently an ethyl functionalized with a group selected from —N3, —SH, —OH, —NH2, —NHOH, an ester, a disulfide, a sulfonamide, a terminal alkyne, haloacetyl, maleimide, isothiocyanate, N-hydroxysuccinimde, an acylhydrazine, an acylhydrazone, a hydrazine, a hydrazone, and hydrazide. In an even further aspect, each occurrence of R40, when present, is independently a methyl functionalized with a group selected from —N3, —SH, —OH, —NH2, —NHOH, an ester, a disulfide, a sulfonamide, a terminal alkyne, haloacetyl, maleimide, isothiocyanate, N-hydroxysuccinimde, an acylhydrazine, an acylhydrazone, a hydrazine, a hydrazone, and hydrazide.
In one aspect, each occurrence of R40, when present, is independently a C1-C30 alkyl functionalized with a group selected from —SH, —NH2, —NHOH, terminal alkyne, haloacetyl, maleimide, isothiocyanate, N-hydroxysuccinimde, succinimidyl ester, tetrafluorophenyl ester, sulfodichlorophenol ester, and hydrazide. In a further aspect, each occurrence of R40, when present, is independently a C1-C15 alkyl functionalized with a group selected from —SH, —NH2, —NHOH, terminal alkyne, haloacetyl, maleimide, isothiocyanate, N-hydroxysuccinimde, succinimidyl ester, tetrafluorophenyl ester, sulfodichlorophenol ester, and hydrazide. In a still further aspect, each occurrence of R40, when present, is independently a C1-C8 alkyl functionalized with a group selected from —SH, —NH2, —NHOH, terminal alkyne, haloacetyl, maleimide, isothiocyanate, N-hydroxysuccinimde, succinimidyl ester, tetrafluorophenyl ester, sulfodichlorophenol ester, and hydrazide. In yet a further aspect, each occurrence of R40, when present, is independently a C1-C4 alkyl functionalized with a group selected from —SH, —NH2, —NHOH, terminal alkyne, haloacetyl, maleimide, isothiocyanate, N-hydroxysuccinimde, succinimidyl ester, tetrafluorophenyl ester, sulfodichlorophenol ester, and hydrazide. In an even further aspect, each occurrence of R40, when present, is independently a methyl, ethyl, n-propyl, or isopropyl and is functionalized with a group selected from —SH, —NH2, —NHOH, terminal alkyne, haloacetyl, maleimide, isothiocyanate, N-hydroxysuccinimde, succinimidyl ester, tetrafluorophenyl ester, sulfodichlorophenol ester, and hydrazide. In a still further aspect, each occurrence of R40, when present, is independently a methyl or ethyl and is functionalized with a group selected from —SH, —NH2, —NHOH, terminal alkyne, haloacetyl, maleimide, isothiocyanate, N-hydroxysuccinimde, succinimidyl ester, tetrafluorophenyl ester, sulfodichlorophenol ester, and hydrazide. In yet a further aspect, each occurrence of R40, when present, is independently an ethyl functionalized with a group selected from —SH, —NH2, —NHOH, terminal alkyne, haloacetyl, maleimide, isothiocyanate, N-hydroxysuccinimde, succinimidyl ester, tetrafluorophenyl ester, sulfodichlorophenol ester, and hydrazide. In an even further aspect, each occurrence of R40, when present, is independently a methyl functionalized with a group selected from —SH, —NH2, —NHOH, terminal alkyne, haloacetyl, maleimide, isothiocyanate, N-hydroxysuccinimde, succinimidyl ester, tetrafluorophenyl ester, sulfodichlorophenol ester, and hydrazide.
In a further aspect, R40 is a C1-C30 alkyl functionalized with a maleimide group. In a still further aspect, R40 is a C1-C15 alkyl functionalized with a maleimide group. In yet a further aspect, R40 is a C1-C8 alkyl functionalized with a maleimide group. In an even further aspect, R40 is a C1-C4 alkyl functionalized with a maleimide group. In a still further aspect, R40 is selected from the group consisting of methyl, ethyl, n-propyl, and isopropyl and is functionalized with a maleimide group. In yet a further aspect, R40 is selected from the group consisting of methyl and ethyl and is functionalized with a maleimide group. In an even further aspect, R40 is ethyl functionalized with a maleimide group. In a still further aspect, R40 is methyl functionalized with a maleimide group.
In a further aspect, R40 is a structure:
In a further aspect, R40 is functionalized with an ester selected from a succinimidyl ester, a tetrafluorophenyl ester, and a sulfodichlorophenol ester.
x. R41 and R42 Groups
In one aspect, each occurrence of R41 and R42, when present, is independently selected from hydrogen and C1-C12 alkyl. In a further aspect, each occurrence of R41 and R42, when present, is independently selected from hydrogen and C1-C6 alkyl. In a still further aspect, each occurrence of R41 and R42, when present, is independently selected from hydrogen and C1-C4 alkyl. In yet a further aspect, each occurrence of R41 and R42, when present, is independently selected from hydrogen, methyl, ethyl, n-propyl, and isopropyl. In an even further aspect, each occurrence of R41 and R42, when present, is independently selected from hydrogen, methyl, and ethyl. In a still further aspect, each occurrence of R41 and R42, when present, is independently selected from hydrogen and ethyl. In yet a further aspect, each occurrence of R41 and R42, when present, is independently selected from hydrogen and methyl.
In a further aspect, each occurrence of R41 and R42, when present, is independently selected from C1-C12 alkyl. In a still further aspect, each occurrence of R41 and R42, when present, is independently selected from C1-C6 alkyl. In yet a further aspect, each occurrence of R41 and R42, when present, is independently selected from C1-C4 alkyl. In an even further aspect, each occurrence of R41 and R42, when present, is independently selected from methyl, ethyl, n-propyl, and isopropyl. In a still further aspect, each occurrence of R41 and R42, when present, is independently selected from methyl and ethyl. In yet a further aspect, each occurrence of R41 and R42, when present, is ethyl. In an even further aspect, each occurrence of R41 and R42, when present, is methyl.
In a further aspect, each occurrence of R41 and R42, when present, is hydrogen.
y. R50a, R50b, R50c, And R50d Groups
In one aspect, each of R50a, R50b, R50c, and R50d, when present, is independently selected from hydrogen, —F, and —Cl. In a further aspect, each of R50a, R50b, R50c, and R50d, when present, is independently selected from hydrogen and —F. In a still further aspect, each of R50a, R50b, R50c, and R50d, when present, is independently selected from hydrogen and —Cl. In yet a further aspect, each of R50a, R50b, R50c, and R50d, when present, is hydrogen.
In a further aspect, each of R50a, R50b, R50c, and R50d, when present, is independently selected from —F and —Cl. In a still further aspect, each of R50a, R50b, R50c, and R50d, when present, is —F. In yet a further aspect, each of R50a, R50b, R50c, and R50d, when present, is —Cl.
z. R51a and R51b Groups
In one aspect, each of R51a and R51b, when present, is independently selected from hydrogen and —C(O)(C1-C12 alkyl). In a further aspect, each of R51a and R51b, when present, is independently selected from hydrogen and —C(O)(C1-C6 alkyl). In a still further aspect, each of R51a and R51b, when present, is independently selected from hydrogen and —C(O)(C1-C4 alkyl). In yet a further aspect, each of R51a and R51b, when present, is independently selected from hydrogen, —C(O)CH3, —C(O)CH2CH3, —C(O)CH2CH2CH3, and —C(O)CH(CH3)2. In a still further aspect, each of R51a and R51b, when present, is independently selected from hydrogen, —C(O)CH3, and —C(O)CH2CH3. In yet a further aspect, each of R51a and R51b, when present, is independently selected from hydrogen and —C(O)CH2CH3. In a still further aspect, each of R15a and R51b, when present, is independently selected from hydrogen and —C(O)CH3. In yet a further aspect, each of R51a and R51b, when present, is hydrogen.
aa. R52a, R52b, R52c, and R52d Groups
In one aspect, each of R52a, R52b, R52c, and R52d, when present, is independently selected from hydrogen, —F, and —Cl. In a further aspect, each of R52a, R52b, R52c, and R52d, when present, is independently selected from hydrogen and —F. In a still further aspect, each of R52a, R52b, R52c, and R52d, when present, is independently selected from hydrogen and —Cl. In yet a further aspect, each of R52a, R52b, R52c, and R52d, when present, is hydrogen.
In a further aspect, each of R52a, R52b, R52c, and R52d, when present, is independently selected from —F and —Cl. In a still further aspect, each of R52a, R52b, R52c, and R52d, when present, is —F. In yet a further aspect, each of R52a, R52b, R52c, and R52d, when present, is —Cl.
bb. R61 and R62 Groups
In one aspect, each of R61 and R62, when present, is independently selected from hydrogen and C1-C12 alkyl. In a further aspect, each of R61 and R62, when present, is independently selected from hydrogen and C1-C6 alkyl. In a still further aspect, each of R61 and R62, when present, is independently selected from hydrogen and C1-C4 alkyl. In yet a further aspect, each of R61 and R62, when present, is independently selected from hydrogen, methyl, ethyl, n-propyl, and isopropyl. In an even further aspect, each of R61 and R62, when present, is independently selected from hydrogen, methyl, and ethyl. In a still further aspect, each of R61 and R62, when present, is independently selected from hydrogen and ethyl. In yet a further aspect, each of R61 and R62, when present, is independently selected from hydrogen and methyl.
In a further aspect, each of R61 and R62, when present, is independently selected from C1-C12 alkyl. In a still further aspect, each of R61 and R62, when present, is independently selected from C1-C6 alkyl. In yet a further aspect, each of R61 and R62, when present, is independently selected from C1-C4 alkyl. In an even further aspect, each of R61 and R62, when present, is independently selected from methyl, ethyl, n-propyl, and isopropyl. In a still further aspect, each of R61 and R62, when present, is independently selected from methyl and ethyl. In yet a further aspect, each of R61 and R62, when present, is ethyl. In an even further aspect, each of R61 and R62, when present, is methyl.
In a further aspect, each of R61 and R62, when present, is hydrogen.
cc. R71 Groups
In one aspect, R71, when present, is selected from hydrogen, C1-C4 alkyl, —CH2CH2Si(CH3)3, and monocyclic aryl monosubstituted with a methyl group. In a further aspect, R71, when present, is selected from hydrogen, methyl, ethyl, n-propyl, isopropyl, —CH2CH2Si(CH3)3, and monocyclic aryl monosubstituted with a methyl group. In a still further aspect, R71, when present, is selected from hydrogen, methyl, ethyl, —CH2CH2Si(CH3)3, and monocyclic aryl monosubstituted with a methyl group. In yet a further aspect, R71, when present, is selected from hydrogen, methyl, —CH2CH2Si(CH3)3, and monocyclic aryl monosubstituted with a methyl group.
In various aspects, R71, when present, is selected from hydrogen and C1-C4 alkyl. In a further aspect, R71, when present, is selected from hydrogen, methyl, ethyl, n-propyl, and isopropyl. In a still further aspect, R71, when present, is selected from hydrogen, methyl, and ethyl. In yet a further aspect, R71, when present, is selected from hydrogen and methyl.
In various aspects, R71, when present, is C1-C4 alkyl. In a further aspect, R71, when present, is selected from methyl, ethyl, n-propyl, and isopropyl. In a still further aspect, R71, when present, is selected from methyl and ethyl. In yet a further aspect, R71, when present, is methyl.
In a further aspect, R71, when present, is selected from hydrogen and —CH2CH2Si(CH3)3. In a still further aspect, R71, when present, is —CH2CH2Si(CH3)3.
In a further aspect, R71, when present, is selected from hydrogen and monocyclic aryl monosubstituted with a methyl group. In a still further aspect, R71, when present, is monocyclic aryl monosubstituted with a methyl group.
In a further aspect, R71, when present, is hydrogen.
dd. Cy1 Groups
In one aspect, each occurrence of Cy1, when present, is heterocycloalkyl substituted with 0, 1, 2, or 3 groups independently selected from halogen, —OH, —NH2, C1-C4 alkoxy, C1-C4 hydroxy, C1-C4 aminoalkyl, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino. Examples of heterocycloalkyls include, but are not limited to, aziridinyl, pyrrolidinyl, pyrrolidino, piperidinyl, piperidino, piperazinyl, piperazino, morpholinyl, morpholino, thiomorpholinyl, thiomorpholino, tetrahydrofuranyl, tetrahydrothiofuranyl, tetrahydropyranyl, and pyranyl. In a further aspect, each occurrence of Cy1, when present, is heterocycloalkyl substituted with 0, 1, or 2 groups independently selected from halogen, —OH, —NH2, C1-C4 alkoxy, C1-C4 hydroxy, C1-C4 aminoalkyl, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino. In a still further aspect, each occurrence of Cy1, when present, is heterocycloalkyl substituted with 0 or 1 group selected from halogen, —OH, —NH2, C1-C4 alkoxy, C1-C4 hydroxy, C1-C4 aminoalkyl, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino. In yet a further aspect, each occurrence of Cy1, when present, is heterocycloalkyl monosubstituted with a group selected from halogen, —OH, —NH2, C1-C4 alkoxy, C1-C4 hydroxy, C1-C4 aminoalkyl, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino. In an even further aspect, each occurrence of Cy1, when present, is unsubstituted heterocycloalkyl.
Ee. Ar1 Groups
In one aspect, each occurrence of Ar1, when present, is selected from monocyclic aryl, morpholinyl, anilinyl, indolyl, pyrrolyl, imidazolyl, benzimidazolyl, pyrazolyl, guanidinyl, and piperazinyl and substituted with 0, 1, 2, or 3 groups independently selected from halogen, —OH, —NH2, C1-C4 alkoxy, C1-C4 hydroxy, C1-C4 aminoalkyl, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino. In a further aspect, each occurrence of Ar1, when present, is selected from monocyclic aryl, morpholinyl, anilinyl, indolyl, pyrrolyl, imidazolyl, benzimidazolyl, pyrazolyl, guanidinyl, and piperazinyl and substituted with 0, 1, or 2 groups independently selected from halogen, —OH, —NH2, C1-C4 alkoxy, C1-C4 hydroxy, C1-C4 aminoalkyl, CT-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino. In a still further aspect, each occurrence of Ar1, when present, is selected from monocyclic aryl, morpholinyl, anilinyl, indolyl, pyrrolyl, imidazolyl, benzimidazolyl, pyrazolyl, guanidinyl, and piperazinyl and substituted with 0 or 1 group selected from halogen, —OH, —NH2, C1-C4 alkoxy, C1-C4 hydroxy, C1-C4 aminoalkyl, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino. In yet a further aspect, each occurrence of Ar1, when present, is selected from monocyclic aryl, morpholinyl, anilinyl, indolyl, pyrrolyl, imidazolyl, benzimidazolyl, pyrazolyl, guanidinyl, and piperazinyl and is monosubstituted with a group selected from halogen, —OH, —NH2, C1-C4 alkoxy, C1-C4 hydroxy, C1-C4 aminoalkyl, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino. In an even further aspect, each occurrence of Ar1, when present, is selected from monocyclic aryl, morpholinyl, anilinyl, indolyl, pyrrolyl, imidazolyl, benzimidazolyl, pyrazolyl, guanidinyl, and piperazinyl and is unsubstituted.
In various aspects, each occurrence of Ar1, when present, is monocyclic aryl substituted with 0, 1, 2, or 3 groups independently selected from halogen, —OH, —NH2, C1-C4 alkoxy, C1-C4 hydroxy, C1-C4 aminoalkyl, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino. In a further aspect, each occurrence of Ar1, when present, is monocyclic aryl substituted with 0, 1, or 2 groups independently selected from halogen, —OH, —NH2, C1-C4 alkoxy, C1-C4 hydroxy, C1-C4 aminoalkyl, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino. In a still further aspect, each occurrence of Ar1, when present, is monocyclic aryl substituted with 0 or 1 group selected from halogen, —OH, —NH2, C1-C4 alkoxy, C1-C4 hydroxy, C1-C4 aminoalkyl, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino. In yet a further aspect, each occurrence of Ar1, when present, is monocyclic aryl monosubstituted with a group selected from halogen, —OH, —NH2, C1-C4 alkoxy, C1-C4 hydroxy, C1-C4 aminoalkyl, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino. In an even further aspect, each occurrence of Ar1, when present, is unsubstituted monocyclic aryl.
In various aspects, each occurrence of Ar1, when present, is selected from morpholinyl, anilinyl, indolyl, pyrrolyl, imidazolyl, benzimidazolyl, pyrazolyl, guanidinyl, and piperazinyl and substituted with 0, 1, 2, or 3 groups independently selected from halogen, —OH, —NH2, C1-C4 alkoxy, C1-C4 hydroxy, C1-C4 aminoalkyl, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino. In a further aspect, each occurrence of Ar1, when present, is selected from morpholinyl, anilinyl, indolyl, pyrrolyl, imidazolyl, benzimidazolyl, pyrazolyl, guanidinyl, and piperazinyl and substituted with 0, 1, or 2 groups independently selected from halogen, —OH, —NH2, C1-C4 alkoxy, C1-C4 hydroxy, C1-C4 aminoalkyl, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino. In a still further aspect, each occurrence of Ar1, when present, is selected from morpholinyl, anilinyl, indolyl, pyrrolyl, imidazolyl, benzimidazolyl, pyrazolyl, guanidinyl, and piperazinyl and substituted with 0 or 1 group selected from halogen, —OH, —NH2, C1-C4 alkoxy, C1-C4 hydroxy, C1-C4 aminoalkyl, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino. In yet a further aspect, each occurrence of Ar1, when present, is selected from morpholinyl, anilinyl, indolyl, pyrrolyl, imidazolyl, benzimidazolyl, pyrazolyl, guanidinyl, and piperazinyl and is monosubstituted with a group selected from halogen, —OH, —NH2, C1-C4 alkoxy, C1-C4 hydroxy, C1-C4 aminoalkyl, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino. In an even further aspect, each occurrence of Ar1, when present, is selected from morpholinyl, anilinyl, indolyl, pyrrolyl, imidazolyl, benzimidazolyl, pyrazolyl, guanidinyl, and piperazinyl and is unsubstituted.
Ff. Ar2 Groups
In one aspect, each occurrence of Ar2, when present, is independently selected from aryl and heteroaryl, and is substituted with 0, 1, 2, or 3 groups independently selected from halogen, —OH, —NH2, C1-C4 alkoxy, C1-C4 hydroxy, C1-C4 aminoalkyl, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, —(C1-C12 alkyl)Ar4, and Ar4. In a further aspect, each occurrence of Ar2, when present, is independently selected from aryl and heteroaryl, and is substituted with 0, 1, or 2 groups independently selected from halogen, —OH, —NH2, C1-C4 alkoxy, C1-C4 hydroxy, C1-C4 aminoalkyl, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, —(C1-C12 alkyl)Ar4, and Ar4. In a still further aspect, each occurrence of Ar2, when present, is independently selected from aryl and heteroaryl, and is substituted with 0 or 1 group selected from halogen, —OH, —NH2, C1-C4 alkoxy, C1-C4 hydroxy, C1-C4 aminoalkyl, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, —(C1-C12 alkyl)Ar4, and Ar4. In yet a further aspect, each occurrence of Ar2, when present, is independently selected from aryl and heteroaryl, and is monosubstituted with a group selected from halogen, —OH, —NH2, C1-C4 alkoxy, C1-C4 hydroxy, C1-C4 aminoalkyl, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, —(C1-C12 alkyl)Ar4, and Ar4. In an even further aspect, each occurrence of Ar2, when present, is independently selected from aryl and heteroaryl, and is unsubstituted.
In various aspects, each occurrence of Ar2, when present, is independently selected from aryl substituted with 0, 1, 2, or 3 groups independently selected from halogen, —OH, —NH2, C1-C4 alkoxy, C1-C4 hydroxy, C1-C4 aminoalkyl, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, —(C1-C12 alkyl)Ar4, and Ar4. In a further aspect, each occurrence of Ar2, when present, is independently selected from aryl substituted with 0, 1, or 2 groups independently selected from halogen, —OH, —NH2, C1-C4 alkoxy, C1-C4 hydroxy, C1-C4 aminoalkyl, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, —(C1-C12 alkyl)Ar4, and Ar4. In a still further aspect, each occurrence of Ar2, when present, is independently selected from aryl substituted with 0 or 1 group selected from halogen, —OH, —NH2, C1-C4 alkoxy, C1-C4 hydroxy, C1-C4 aminoalkyl, CT-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, —(C1-C12 alkyl)Ar4, and Ar4. In yet a further aspect, each occurrence of Ar2, when present, is independently selected from aryl monosubstituted with a group selected from halogen, —OH, —NH2, C1-C4 alkoxy, C1-C4 hydroxy, C1-C4 aminoalkyl, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, —(C1-C12 alkyl)Ar4, and Ar4. In an even further aspect, each occurrence of Ar2, when present, is unsubstituted aryl.
In various aspects, each occurrence of Ar2, when present, is independently selected from phenyl substituted with 0, 1, 2, or 3 groups independently selected from halogen, —OH, —NH2, C1-C4 alkoxy, C1-C4 hydroxy, C1-C4 aminoalkyl, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, —(C1-C12 alkyl)Ar4, and Ar4. In a further aspect, each occurrence of Ar2, when present, is independently selected from phenyl substituted with 0, 1, or 2 groups independently selected from halogen, —OH, —NH2, C1-C4 alkoxy, C1-C4 hydroxy, C1-C4 aminoalkyl, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, —(C1-C12 alkyl)Ar4, and Ar4. In a still further aspect, each occurrence of Ar2, when present, is independently selected from phenyl substituted with 0 or 1 group selected from halogen, —OH, —NH2, C1-C4 alkoxy, C1-C4 hydroxy, C1-C4 aminoalkyl, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, —(C1-C12 alkyl)Ar4, and Ar4. In yet a further aspect, each occurrence of Ar2, when present, is independently selected from phenyl monosubstituted with a group selected from halogen, —OH, —NH2, C1-C4 alkoxy, C1-C4 hydroxy, C1-C4 aminoalkyl, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, —(C1-C12 alkyl)Ar4, and Ar4. In an even further aspect, each occurrence of Ar2, when present, is unsubstituted phenyl.
In various aspects, each occurrence of Ar2, when present, is independently selected from heteroaryl substituted with 0, 1, 2, or 3 groups independently selected from halogen, —OH, —NH2, C1-C4 alkoxy, C1-C4 hydroxy, C1-C4 aminoalkyl, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, —(C1-C12 alkyl)Ar4, and Ar4. Examples of heteroaryls include, but are not limited to, pyrrolyl, furanyl, thiophenyl, indolyl, benzofuranyl, benzothiophenyl, triazolyl, imidazolyl, oxazolyl, thiazolyl, pyrazolyl, isoxazolyl, isothiazolyl, pyridinyl, quinolinyl, and isoquinolinyl. In a further aspect, each occurrence of Ar2, when present, is independently selected from heteroaryl substituted with 0, 1, or 2 groups independently selected from halogen, —OH, —NH2, C1-C4 alkoxy, C1-C4 hydroxy, C1-C4 aminoalkyl, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, —(C1-C12 alkyl)Ar4, and Ar4. In a still further aspect, each occurrence of Ar2, when present, is independently selected from heteroaryl substituted with 0 or 1 group selected from halogen, —OH, —NH2, C1-C4 alkoxy, C1-C4 hydroxy, C1-C4 aminoalkyl, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, —(C1-C12 alkyl)Ar4, and Ar4. In yet a further aspect, each occurrence of Ar2, when present, is independently selected from heteroaryl monosubstituted with a group selected from halogen, —OH, —NH2, C1-C4 alkoxy, C1-C4 hydroxy, C1-C4 aminoalkyl, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, —(C1-C12 alkyl)Ar4, and Ar4. In an even further aspect, each occurrence of Ar2, when present, is unsubstituted heteroaryl.
In a further aspect, each occurrence of Ar2, when present, is triazolyl substituted with 0, 1, 2, or 3 groups independently selected from halogen, —OH, —NH2, C1-C4 alkoxy, C1-C4 hydroxy, C1-C4 aminoalkyl, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, —(C1-C12 alkyl)Ar3, and Ar3. In a still further aspect, each occurrence of Ar2, when present, is triazolyl substituted with 0, 1, or 2 groups independently selected from halogen, —OH, —NH2, C1-C4 alkoxy, C1-C4 hydroxy, C1-C4 aminoalkyl, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, —(C1-C12 alkyl)Ar3, and Ar3. In yet a further aspect, each occurrence of Ar2, when present, is triazolyl substituted with 0 or 1 group selected from halogen, —OH, —NH2, C1-C4 alkoxy, C1-C4 hydroxy, C1-C4 aminoalkyl, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, —(C1-C12 alkyl)Ar3, and Ar3. In an even further aspect, each occurrence of Ar2, when present, is triazolyl monosubstituted with a group selected from halogen, —OH, —NH2, C1-C4 alkoxy, C1-C4 hydroxy, C1-C4 aminoalkyl, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, —(C1-C12 alkyl)Ar3, and Ar3. In a still further aspect, each occurrence of Ar2, when present, is unsubstituted triazolyl.
In a further aspect, each occurrence of Ar2, when present, is triazolyl substituted with 0, 1, 2, or 3 groups independently selected from —(C1-C12 alkyl)Ar3 and Ar3. In a still further aspect, each occurrence of Ar2, when present, is triazolyl substituted with 0, 1, or 2 groups independently selected from —(C1-C12 alkyl)Ar3 and Ar3. In yet a further aspect, each occurrence of Ar2, when present, is triazolyl substituted with 0 or 1 group selected from —(C1-C12 alkyl)Ar3 and Ar3. In an even further aspect, each occurrence of Ar2, when present, is triazolyl monosubstituted with a group selected from —(C1-C12 alkyl)Ar3 and Ar3.
In a further aspect, each occurrence of Ar2, when present, is triazolyl substituted with 1 Ar3 group.
Gg. Ar3 Groups
In one aspect, each occurrence of Ar3, when present, is a structure represented by a formula selected from:
In a further aspect, each occurrence of Ar3, when present, is a structure represented by a formula selected from:
In a further aspect, each occurrence of Ar3, when present, is a structure represented by a formula:
hh. Ar4 Groups
In one aspect, each occurrence of Ar4, when present, is a structure represented by a formula selected from:
In a further aspect, In one aspect, each occurrence of Ar4, when present, is a structure represented by a formula selected from:
In a further aspect, each occurrence of Ar4, when present, is a structure represented by a formula:
In a further aspect, each occurrence of Ar4, when present, is a structure represented by a formula:
In a further aspect, each occurrence of Ar4, when present, is a structure represented by a formula:
II. Ar5 Groups
In one aspect, Ar5, when present, is selected from monocyclic 6-membered aryl and anthracene-9,10-dionyl, and is substituted with 0, 1, 2, or 3 groups independently selected from halogen, —OH, —NH2, C1-C4 alkoxy, C1-C4 hydroxy, C1-C4 aminoalkyl, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino. In a further aspect, Ar5, when present, is selected from monocyclic 6-membered aryl and anthracene-9,10-dionyl, and is substituted with 0, 1, or 2 groups independently selected from halogen, —OH, —NH2, C1-C4 alkoxy, C1-C4 hydroxy, C1-C4 aminoalkyl, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino. In a still further aspect, Ar5, when present, is selected from monocyclic 6-membered aryl and anthracene-9,10-dionyl, and is substituted with 0 or 1 group selected from halogen, —OH, —NH2, C1-C4 alkoxy, C1-C4 hydroxy, C1-C4 aminoalkyl, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino. In yet a further aspect, Ar5, when present, is selected from monocyclic 6-membered aryl and anthracene-9,10-dionyl, and is monosubstituted with a group selected from halogen, —OH, —NH2, C1-C4 alkoxy, C1-C4 hydroxy, C1-C4 aminoalkyl, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino. In an even further aspect, Ar5, when present, is selected from monocyclic 6-membered aryl and anthracene-9,10-dionyl, and is unsubstituted.
In various aspects, Ar5, when present, is monocyclic 6-membered aryl substituted with 0, 1, 2, or 3 groups independently selected from halogen, —OH, —NH2, C1-C4 alkoxy, C1-C4 hydroxy, C1-C4 aminoalkyl, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino. In a further aspect, Ar5, when present, is monocyclic 6-membered aryl substituted with 0, 1, or 2 groups independently selected from halogen, —OH, —NH2, C1-C4 alkoxy, C1-C4 hydroxy, C1-C4 aminoalkyl, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino. In a still further aspect, Ar5, when present, is monocyclic 6-membered aryl substituted with 0 or 1 group selected from halogen, —OH, —NH2, C1-C4 alkoxy, C1-C4 hydroxy, C1-C4 aminoalkyl, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino. In yet a further aspect, Ar5, when present, is monocyclic 6-membered aryl monosubstituted with a group selected from halogen, —OH, —NH2, C1-C4 alkoxy, C1-C4 hydroxy, C1-C4 aminoalkyl, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino. In an even further aspect, Ar5, when present, is unsubstituted monocyclic 6-membered aryl.
In various aspects, Ar5, when present, is anthracene-9,10-dionyl substituted with 0, 1, 2, or 3 groups independently selected from halogen, —OH, —NH2, C1-C4 alkoxy, C1-C4 hydroxy, C1-C4 aminoalkyl, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino. In a further aspect, Ar5, when present, is anthracene-9,10-dionyl substituted with 0, 1, or 2 groups independently selected from halogen, —OH, —NH2, C1-C4 alkoxy, C1-C4 hydroxy, C1-C4 aminoalkyl, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino. In a still further aspect, Ar5, when present, is anthracene-9,10-dionyl substituted with 0 or 1 group selected from halogen, —OH, —NH2, C1-C4 alkoxy, C1-C4 hydroxy, C1-C4 aminoalkyl, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino. In yet a further aspect, Ar5, when present, is anthracene-9,10-dionyl monosubstituted with a group selected from halogen, —OH, —NH2, C1-C4 alkoxy, C1-C4 hydroxy, C1-C4 aminoalkyl, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino. In an even further aspect, Ar5, when present, is unsubstituted anthracene-9,10-dionyl.
2. Example Compounds
In one aspect, a compound can be present as one or more of the following structures:
or a pharmaceutically acceptable salt thereof.
In one aspect, a compound can be present as one or more of the following structures:
or a pharmaceutically acceptable salt thereof.
In one aspect, a compound can be present as one or more of the following structures:
or a pharmaceutically acceptable salt thereof.
In one aspect, a compound can be present as:
In one aspect, the invention relates to pharmaceutical compositions comprising a therapeutically effective amount at least one disclosed compound and a pharmaceutically acceptable carrier. In a further aspect, a pharmaceutical composition can be provided comprising a therapeutically effective amount of at least one disclosed compound. In a still further aspect, a pharmaceutical composition can be provided comprising a prophylactically effective amount of at least one disclosed compound. In yet a further aspect, the invention relates to pharmaceutical compositions comprising a pharmaceutically acceptable carrier and a compound, wherein the compound is present in an effective amount.
Thus, in one aspect, disclosed are pharmaceutical compositions comprising a therapeutically effective amount of a compound having a structure represented by a formula:
wherein each occurrence of - - - - - - is a single or double covalent bond; wherein X is selected from O, NRx, and C(Rx)2; wherein each occurrence of Rx, when present, is independently selected from hydrogen and C1-C6 alkyl; wherein R1 is selected from hydrogen, halogen, —OH, —CN, —NC, —NCO, —OCN, —NO2, —ONO2, —ONO, —NO, —N3, —NH2, —NH3, —N═NR31, —NHOH, C1-C12 alkyl, C2-C12 alkenyl, C2-C12 alkynyl, C1-C12 hydroxy, C1-C12 alkoxy, C1-C12 thioalkyl, C1-C12 alkylthiol, C1-C12 aminoalkyl, C1-C12 alkylamino, (C1-C12)(C1-C12) dialkylamino, —OC(O)(C1-C12 alkyl), —OP(O)(OR32)2, —OSO2R33, —C(O)(C1-C12 alkyl), —CO2R34, —C(O)NR35aR35b, —(C1-C12 alkyl)C(O)NR35aR35b, —OC(O)NR35aR35b, —(C1-C12 alkyl)OC(O)NR35aR35b, Cy1, Ar1, (C1-C12 alkyl)Ar1, and —OAr1; wherein each occurrence of R31, R32, R34, R35a, and R35b, when present, is independently selected from hydrogen and C1-C12 alkyl; wherein each occurrence of R33, when present, is independently selected from hydrogen, C1-C12 alkyl, and monocyclic aryl monosubstituted with a methyl group; wherein each occurrence of Cy1, when present, is heterocycloalkyl substituted with 0, 1, 2, or 3 groups independently selected from halogen, —OH, —NH2, C1-C4 alkoxy, C1-C4 hydroxy, C1-C4 aminoalkyl, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino; wherein each occurrence of Ar1, when present, is selected from monocyclic aryl, morpholinyl, anilinyl, indolyl, pyrrolyl, imidazolyl, benzimidazolyl, pyrazolyl, guanidinyl, and piperazinyl and substituted with 0, 1, 2, or 3 groups independently selected from halogen, —OH, —NH2, C1-C4 alkoxy, C1-C4 hydroxy, C1-C4 aminoalkyl, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino; and wherein R1′ is hydrogen; or wherein each of R1 and R1′ together comprise ═O or ═NR36; wherein each occurrence of R36, when present, is independently selected from hydrogen and C1-C12 alkyl; wherein each of R2 and R3 is independently selected from hydrogen, —OH, C1-C12 hydroxy, and halogen; or wherein each of R2 and R3 together comprise —O—; wherein R5 is selected from hydrogen, —OH, —NH2, C1-C9 alkyl, C1-C9 hydroxy, C1-C9 alkoxy, C1-C9 aminoalkyl, C1-C6 alkylamino, and (C1-C6)(C1-C6) dialkylamino; or wherein R5 is absent; wherein each of R6 and R6′ is independently selected from hydrogen, halogen, —OH, —CN, —NC, —NCO, —OCN, —NO2, —ONO2, —ONO, —NO, —N3, —NH2, —NH3, —N═NR41, —NHOH, C1-C30 alkyl, C2-C30 alkenyl, C2-C30 alkynyl, C1-C30 hydroxy, C1-C30 alkoxy, C1-C30 thioalkyl, C1-C30 alkylthiol, C1-C30 aminoalkyl, C1-C30 alkylamino, (C1-C30)(C1-C30) dialkylamino, —C(O)(C1-C30 alkyl), —OP(O)(OR32)2, —OSO2R33, —CO2R34, —C(O)NR35aR35b, —(C1-C30 alkyl)C(O)NR35aR35b, —OC(O)NR35aR35b, (C1-C30 alkyl)OC(O)NR35aR35b, Cy1, Ar1, —(C1-C30 alkyl)Ar1, —OAr1, —OC(O)(C1-C30 alkyl), —OC(O)Ar2, —OC(O)(C1-C30 alkyl)Ar2, —OC(O)Ar3, —OC(O)(C1-C30 alkyl)NR42C(O)Ar3, —OC(O)(C1-C30 alkyl)OC(O)Ar3, —OC(O)R40, —NR41C(O)(C1-C30 alkyl), —NR41C(O)Ar2, —NR41C(O)(C1-C30 alkyl)Ar2, —NR41C(O)Ar3, —NR41C(O)(C1-C30 alkyl)OC(O)Ar3, —NR41C(O)(C1-C30 alkyl)NR42C(O)Ar3, and —NR41C(O)R40; wherein each occurrence of R40, when present, is independently a C1-C30 alkyl functionalized with a group selected from —N3, —SH, —OH, —NH2, —NHOH, an ester, a disulfide, a sulfonamide, a terminal alkyne, haloacetyl, maleimide, isothiocyanate, N-hydroxysuccinimde, an acylhydrazine, an acylhydrazone, a hydrazine, a hydrazone, and hydrazide; wherein each occurrence of R41 and R42, when present, is independently selected from hydrogen and C1-C12 alkyl; wherein each occurrence of Ar2, when present, is independently selected from aryl and heteroaryl, and is substituted with 0, 1, 2, or 3 groups independently selected from halogen, —OH, —NH2, C1-C4 alkoxy, C1-C4 hydroxy, C1-C4 aminoalkyl, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, —(C1-C12 alkyl)Ar4, and Ar4; wherein each occurrence of Ar4, when present, is a structure represented by a formula selected from:
wherein each of R50a, R50b, R50c, and R50d, when present, is independently selected from hydrogen, —F, and —Cl; wherein each of R51a and R51b, when present, is independently selected from hydrogen and —C(O)(C1-C12 alkyl); wherein each of R52a, R52b, R52c, and R52d, when present, is independently selected from hydrogen, —F, and —Cl; wherein each occurrence of Ar3, when present, is a structure represented by a formula selected from:
or wherein one of R6 and R6′ is absent; wherein R7 is selected from hydrogen, —OH, C1-C30 hydroxy, C1-C30 alkoxy, —OC(O)(C1-C30 alkyl), and —OC(O)NR35aR35b, and wherein R7′ is selected from hydrogen, —OH, C1-C30 hydroxy, C1-C30 alkoxy, and —OC(O)(C1-C30 alkyl); or wherein each of R7 and R7′ together comprise ═O; or wherein one of R7 and R7′ is absent; wherein each of R11 and R12 is independently selected from hydrogen, —OH, C1-C8 hydroxy, C1-C6 alkyl, C1-C8 alkoxy, and —OC(O)(C1-C8 alkyl); wherein R15 is selected from hydrogen, —OH, C1-C30 hydroxy, C1-C30 alkyl, C1-C30 alkoxy, —OC(O)(C1-C30 alkyl), —OC(O)NR35aR35b, —OC(O)Ar2, —OC(O)(C1-C4 alkyl)Ar2, and —OC(O)(C1-C8 azide); wherein R20 is selected from hydrogen, —OH, —OOH, C1-C8 alkyl, C1-C8 hydroxy, C1-C8 alkoxy, C1-C8 hydroperoxy, and —OC(O)(C1-C8 alkyl); wherein R21 is selected from hydrogen and C1-C6 alkyl; wherein R25 is selected from hydrogen, —OH, C1-C8 hydroxy, C1-C8 alkoxy, —OC(O)(C1-18 alkyl), —OC(O)NR35aR35b, —OC(O)Ar5, and —OC(O)(C1-C8 azide); wherein Ar5, when present, is selected from monocyclic 6-membered aryl and anthracene-9,10-dionyl, and is substituted with 0, 1, 2, or 3 groups independently selected from halogen, —OH, —NH2, C1-C4 alkoxy, C1-C4 hydroxy, C1-C4 aminoalkyl, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino; wherein each of R26 and R26′ is independently selected from hydrogen, —OH, C1-C8 hydroxy, and C1-C8 alkoxy; or wherein each of R26 and R26′ together comprise ═O; wherein R27 is selected from hydrogen and C1-C6 alkyl; wherein each of R28 and R29 is independently selected from hydrogen and halogen; or wherein each of R28 and R29 together comprise —O— or —N(R37)—; wherein R37, when present, is selected from hydrogen, C1-C4 alkyl, —SO2R71, and a structure having a formula:
and
wherein R71, when present, is selected from hydrogen, C1-C4 alkyl, —CH2CH2Si(CH3)3, and monocyclic aryl monosubstituted with a methyl group, provided that at least one of R6 and R6′ is —NR41C(O)(C1-C30 alkyl), —NR41C(O)Ar2, —NR41C(O)(C1-C30 alkyl)Ar2, —NR41C(O)Ar3, —NR41C(O)(C1-C30 alkyl)OC(O)Ar3, —NR41C(O)(C1-C30 alkyl)NR42C(O)Ar3, or —NR41C(O)R40, and provided that when one or both of R28 and R29 is hydrogen then the occurrence of - - - - - - at C-22/C-23 is a double covalent bond, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
In one aspect, disclosed are pharmaceutical compositions comprising a therapeutically effective of a compound having a structure represented by a formula:
wherein each occurrence of - - - - - - is a single or double covalent bond; wherein X is selected from O, NRx and C(Rx)2; wherein each occurrence of Rx, when present, is independently selected from hydrogen and C1-C6 alkyl; wherein R1 is selected from hydrogen, halogen, —OH, —CN, —NC, —NCO, —OCN, —NO2, —ONO2, —ONO, —NO, —N3, —NH2, —NH3, —N═NR31, —NHOH, C1-C12 alkyl, C2-C12 alkenyl, C2-C12 alkynyl, C1-C12 hydroxy, C1-C12 alkoxy, C1-C12 thioalkyl, C1-C12 alkylthiol, C1-C12 aminoalkyl, C1-C12 alkylamino, (C1-C12)(C1-C12) dialkylamino, —OC(O)(C1-C12 alkyl), —OP(O)(OR32)2, —OSO2R33, —C(O)(C1-C12 alkyl), —CO2R34, —C(O)NR35aR35b, —(C1-C12 alkyl)C(O)NR35aR35b, —OC(O)NR35aR35b, —(C1-C12 alkyl)OC(O)NR35aR35b, Cy1, Ar1, (C1-C12 alkyl)Ar1, and —OAr1; wherein each occurrence of R31, R32, R34, R35a, and R35b, when present, is independently selected from hydrogen and C1-C12 alkyl; wherein each occurrence of R33, when present, is independently selected from hydrogen, C1-C12 alkyl, and monocyclic aryl monosubstituted with a methyl group; wherein each occurrence of Cy1, when present, is heterocycloalkyl substituted with 0, 1, 2, or 3 groups independently selected from halogen, —OH, —NH2, C1-C4 alkoxy, C1-C4 hydroxy, C1-C4 aminoalkyl, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino; wherein each occurrence of Ar1, when present, is selected from monocyclic aryl, morpholinyl, anilinyl, indolyl, pyrrolyl, imidazolyl, benzimidazolyl, pyrazolyl, guanidinyl, and piperazinyl and substituted with 0, 1, 2, or 3 groups independently selected from halogen, —OH, —NH2, C1-C4 alkoxy, C1-C4 hydroxy, C1-C4 aminoalkyl, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino; and wherein R1′ is hydrogen; or wherein each of R1 and R1′ together comprise ═O or ═NR36; wherein each occurrence of R36, when present, is independently selected from hydrogen and C1-C12 alkyl; wherein each of R2 and R3 is independently selected from hydrogen, —OH, C1-C12 hydroxy, and halogen; or wherein each of R2 and R3 together comprise —O—; wherein R5 is selected from hydrogen, —OH, —NH2, C1-C9 alkyl, C1-C9 hydroxy, C1-C9 alkoxy, C1-C9 aminoalkyl, C1-C6 alkylamino, and (C1-C6)(C1-C6) dialkylamino; or wherein R5 is absent; wherein each of R6 and R6′ is independently selected from hydrogen, halogen, —OH, —CN, —NC, —NCO, —OCN, —NO2, —ONO2, —ONO, —NO, —N3, —NH2, —NH3, —N═NR41, —NHOH, C1-C30 alkyl, C2-C30 alkenyl, C2-C30 alkynyl, C1-C30 hydroxy, C1-C30 alkoxy, C1-C30 thioalkyl, C1-C30 alkylthiol, C1-C30 aminoalkyl, C1-C30 alkylamino, (C1-C30)(C1-C30) dialkylamino, —C(O)(C1-C30 alkyl), —OP(O)(OR32)2, —OSO2R33, —CO2R34, —C(O)NR35aR35b, —(C1-C30 alkyl)C(O)NR35aR35b, —OC(O)NR35aR35b, (C1-C30 alkyl)OC(O)NR35aR35b, Cy1, Ar1, —(C1-C30 alkyl)Ar1, —OAr1, —OC(O)(C1-C30 alkyl), —OC(O)Ar2, —OC(O)(C1-C30 alkyl)Ar2, —OC(O)Ar3, —OC(O)(C1-C30 alkyl)NR42C(O)Ar3, —OC(O)(C1-C30 alkyl)OC(O)Ar3, —OC(O)R40, —NR41C(O)(C1-C30 alkyl), —NR41C(O)Ar2, —NR41C(O)(C1-C30 alkyl)Ar2, —NR41C(O)Ar3, —NR41C(O)(C1-C30 alkyl)OC(O)Ar3, —NR41C(O)(C1-C30 alkyl)NR42C(O)Ar3, and —NR41C(O)R40; wherein each occurrence of R40, when present, is independently a C1-C30 alkyl functionalized with a group selected from —SH, —NH2, —NHOH, terminal alkyne, haloacetyl, maleimide, isothiocyanate, N-hydroxysuccinimde, succinimidyl ester, tetrafluorophenyl ester, sulfodichlorophenol ester, and hydrazide; wherein each occurrence of R41 and R42, when present, is independently selected from hydrogen and C1-C12 alkyl; wherein each occurrence of Ar2, when present, is independently selected from aryl and heteroaryl, and is substituted with 0, 1, 2, or 3 groups independently selected from halogen, —OH, —NH2, C1-C4 alkoxy, C1-C4 hydroxy, C1-C4 aminoalkyl, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, —(C1-C12 alkyl)Ar4, and Ar4; wherein each occurrence of Ar4, when present, is a structure represented by a formula:
wherein each of R50a, R50b, R50c, and R50d, when present, is independently selected from hydrogen, —F, and —Cl; wherein each of R51a and R51b, when present, is independently selected from hydrogen and —C(O)(C1-C12 alkyl); wherein each of R52a, R52b, R52c, and R52d, when present, is independently selected from hydrogen, —F, and —Cl; wherein each occurrence of Ar3, when present, is a structure represented by a formula selected from:
or wherein one of R6 and R6′ is absent; wherein R7 is selected from hydrogen, —OH, C1-C30 hydroxy, C1-C30 alkoxy, —OC(O)(C1-C30 alkyl), and —OC(O)NR35aR35b, and wherein R7′ is selected from hydrogen, —OH, C1-C30 hydroxy, C1-C30 alkoxy, and —OC(O)(C1-C30 alkyl); or wherein each of R7 and R7′ together comprise ═O; or wherein one of R7 and R7′ is absent; wherein each of R11 and R12 is independently selected from hydrogen, —OH, C1-C8 hydroxy, C1-C6 alkyl, C1-C8 alkoxy, and —OC(O)(C1-C8 alkyl); wherein R15 is selected from hydrogen, —OH, C1-C30 hydroxy, C1-C30 alkyl, C1-C30 alkoxy, —OC(O)(C1-C30 alkyl), —OC(O)NR35aR35b, —OC(O)Ar2, —OC(O)(C1-C4 alkyl)Ar2, and —OC(O)(C1-C8 azide); wherein R20 is selected from hydrogen, —OH, —OOH, C1-C8 alkyl, C1-C8 hydroxy, C1-C8 alkoxy, C1-C8 hydroperoxy, and —OC(O)(C1-C8 alkyl); wherein R21 is selected from hydrogen and C1-C6 alkyl; wherein R25 is selected from hydrogen, —OH, C1-C8 hydroxy, C1-C8 alkoxy, —OC(O)(C1-18 alkyl), —OC(O)NR35aR35b, —OC(O)Ar5, and —OC(O)(C1-C8 azide); wherein Ar5, when present, is selected from monocyclic 6-membered aryl and anthracene-9,10-dionyl, and is substituted with 0, 1, 2, or 3 groups independently selected from halogen, —OH, —NH2, C1-C4 alkoxy, C1-C4 hydroxy, C1-C4 aminoalkyl, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino; wherein each of R26 and R26′ is independently selected from hydrogen, —OH, C1-C8 hydroxy, and C1-C8 alkoxy; or wherein each of R26 and R26′ together comprise ═O; wherein R27 is selected from hydrogen and C1-C6 alkyl; wherein each of R28 and R29 is independently selected from hydrogen and halogen; or wherein each of R28 and R29 together comprise —O— or —N(R37)—; wherein R37, when present, is selected from hydrogen, CT-C4 alkyl, —SO2R71, and a structure having a formula:
and
wherein R71, when present, is selected from hydrogen, C1-C4 alkyl, —CH2CH2Si(CH3)3, and monocyclic aryl monosubstituted with a methyl group, provided that at least one of R6 and R6′ is —OC(O)R40 or —NR41C(O)R40, and provided that when one or both of R28 and R29 is hydrogen then the occurrence of - - - - - - at C-22/C-23 is a double covalent bond, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
In one aspect, disclosed are pharmaceutical compositions comprising a therapeutically effective amount of a compound having a structure represented by a formula:
wherein each occurrence of - - - - - - is a single or double covalent bond; wherein X is selected from O, NRx and C(Rx)2; wherein each occurrence of Rx, when present, is independently selected from hydrogen and C1-C6 alkyl; wherein Rx is selected from hydrogen, halogen, —OH, —CN, —NC, —NCO, —OCN, —NO2, —ONO2, —ONO, —NO, —N3, —NH2, —NH3, —N═NR31, —NHOH, C1-C12 alkyl, C2-C12 alkenyl, C2-C12 alkynyl, C1-C12 hydroxy, C1-C12 alkoxy, C1-C12 thioalkyl, C1-C12 alkylthiol, C1-C12 aminoalkyl, C1-C12 alkylamino, (C1-C12)(C1-C12) dialkylamino, —OC(O)(C1-C12 alkyl), —OP(O)(OR32)2, —OSO2R33, —C(O)(C1-C12 alkyl), —CO2R34, —C(O)NR35aR35b, —(C1-C12 alkyl)C(O)NR35aR35b, —OC(O)NR35aR35b, —(C1-C12 alkyl)OC(O)NR35aR35b, Cy1, Ar1, (C1-C12 alkyl)Ar1, and —OAr1; wherein each occurrence of R31, R32, R34, R35a, and R35b, when present, is independently selected from hydrogen and C1-C12 alkyl; wherein each occurrence of R33, when present, is independently selected from hydrogen, C1-C12 alkyl, and monocyclic aryl monosubstituted with a methyl group; wherein each occurrence of Cy1, when present, is heterocycloalkyl substituted with 0, 1, 2, or 3 groups independently selected from halogen, —OH, —NH2, C1-C4 alkoxy, C1-C4 hydroxy, C1-C4 aminoalkyl, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino; wherein each occurrence of Ar1, when present, is selected from monocyclic aryl, morpholinyl, anilinyl, indolyl, pyrrolyl, imidazolyl, benzimidazolyl, pyrazolyl, guanidinyl, and piperazinyl and substituted with 0, 1, 2, or 3 groups independently selected from halogen, —OH, —NH2, C1-C4 alkoxy, C1-C4 hydroxy, C1-C4 aminoalkyl, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino; and wherein R1′ is hydrogen; or wherein each of R1 and R1′ together comprise ═O or ═NR36; wherein each occurrence of R36, when present, is independently selected from hydrogen and C1-C12 alkyl; wherein each of R2 and R3 is independently selected from hydrogen, —OH, C1-C12 hydroxy, and halogen; or wherein each of R2 and R3 together comprise —O—; wherein R5 is selected from hydrogen, —OH, —NH2, C1-C9 alkyl, C1-C9 hydroxy, C1-C9 alkoxy, C1-C9 aminoalkyl, C1-C6 alkylamino, and (C1-C6)(C1-C6) dialkylamino; or wherein R5 is absent; wherein R7 is selected from hydrogen, —OH, C1-C30 hydroxy, C1-C30 alkoxy, —OC(O)(C1-C30 alkyl), and —OC(O)NR35aR35b, and wherein R7′ is selected from hydrogen, —OH, C1-C30 hydroxy, C1-C30 alkoxy, and —OC(O)(C1-C30 alkyl); or wherein each of R7 and R7′ together comprise ═O; or wherein one of R7 and R7′ is absent; wherein each of R8 and R8′ is independently selected from hydrogen, halogen, —OH, —CN, —NC, —NCO, —OCN, —NO2, —ONO2, —ONO, —NO, —N3, —NH2, —NH3, —N═NR41, —NHOH, C1-C30 alkyl, C2-C30 alkenyl, C2-C30 alkynyl, C1-C30 hydroxy, C1-C30 alkoxy, C1-C30 thioalkyl, C1-C30 alkylthiol, C1-C30 aminoalkyl, C1-C30 alkylamino, (C1-C30)(C1-C30) dialkylamino, —C(O)(C1-C30 alkyl), —OP(O)(OR32)2, —OSO2R33, —CO2R34, —C(O)NR35aR35b, —(C1-C30 alkyl)C(O)NR35aR35b, —OC(O)NR35aR35b, —(C1-C30 alkyl)OC(O)NR35aR35b, Cy1, Ar1, —(C1-C30 alkyl)Ar1, —OAr1, —OC(O)(C1-C30 alkyl), —OC(O)Ar2, —OC(O)(C1-C30 alkyl)Ar2, —OC(O)Ar3, —OC(O)(C1-C30 alkyl)NR42C(O)Ar3, —OC(O)(C1-C30 alkyl)OC(O)Ar3, —OC(O)(C1-C30 alkyl)-L-Z, —OC(O)(C1-C30 alkyl)-L-(C1-C30 alkyl)-Z, —OC(O)-L-(C1-C30 alkyl)-Z, —NR41C(O)(C1-C30 alkyl), —NR41C(O)Ar2, —NR41C(O)(C1-C30 alkyl)Ar2, —NR41C(O)Ar3, —NR41C(O)(C1-C30 alkyl)OC(O)Ar3, —NR41C(O)(C1-C30 alkyl)NR42C(O)Ar3, —NR41C(O)(C1-C30 alkyl)-L-Z, —NR41C(O)(C1-C30 alkyl)-L-(C1-C30 alkyl)-Z, and —NR41C(O)-L-(C1-C30 alkyl)-Z; wherein L is a linker; wherein Z is selected from an antibody, an antibody fragment, a vitamin, a hormone, a carbohydrate, a molecular ligand, an aptamer, a non-antibody protein, a peptide, a nucleic acid, a fluorophore, and a drug; wherein each occurrence of R41 and R42, when present, is independently selected from hydrogen and C1-C12 alkyl; wherein each occurrence of Ar2, when present, is independently selected from aryl and heteroaryl, and is substituted with 0, 1, 2, or 3 groups independently selected from halogen, —OH, —NH2, C1-C4 alkoxy, C1-C4 hydroxy, C1-C4 aminoalkyl, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, —(C1-C12 alkyl)Ar4, and Ar4; wherein each occurrence of Ar4, when present, is a structure represented by a formula:
wherein each of R50a, R50b, R50c, and R50d, when present, is independently selected from hydrogen, —F, and —Cl; wherein each of R51a and R51b, when present, is independently selected from hydrogen and —C(O)(C1-C12 alkyl); wherein each of R52a, R52b, R52c, and R52d, when present, is independently selected from hydrogen, —F, and —Cl; wherein each occurrence of Ar3, when present, is a structure represented by a formula selected from:
or wherein one of R8 and R8′ is absent; wherein each of R11 and R12 is independently selected from hydrogen, —OH, C1-C8 hydroxy, C1-C6 alkyl, C1-C8 alkoxy, and —OC(O)(C1-C8 alkyl); wherein R15 is selected from hydrogen, —OH, C1-C30 hydroxy, C1-C30 alkyl, C1-C30 alkoxy, —OC(O)(C1-C30 alkyl), —OC(O)NR35aR35b, —OC(O)Ar2, —OC(O)(C1-C4 alkyl)Ar2, and —OC(O)(C1-C8 azide); wherein R20 is selected from hydrogen, —OH, —OOH, C1-C8 alkyl, C1-C8 hydroxy, C1-C8 alkoxy, C1-C8 hydroperoxy, and —OC(O)(C1-C8 alkyl); wherein R21 is selected from hydrogen and C1-C6 alkyl; wherein R25 is selected from hydrogen, —OH, C1-C8 hydroxy, C1-C8 alkoxy, —OC(O)(C1-18 alkyl), —OC(O)NR35aR35b, —OC(O)Ar5, and —OC(O)(C1-C8 azide); wherein Ar5, when present, is selected from monocyclic 6-membered aryl and anthracene-9,10-dionyl, and is substituted with 0, 1, 2, or 3 groups independently selected from halogen, —OH, —NH2, C1-C4 alkoxy, C1-C4 hydroxy, C1-C4 aminoalkyl, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino; wherein each of R26 and R26′ is independently selected from hydrogen, —OH, C1-C8 hydroxy, and C1-C8 alkoxy; or wherein each of R26 and R26′ together comprise ═O; wherein R27 is selected from hydrogen and C1-C6 alkyl; wherein each of R28 and R29 is independently selected from hydrogen and halogen; or wherein each of R28 and R29 together comprise —O— or —N(R37)—; wherein R37, when present, is selected from hydrogen, C1-C4 alkyl, —SO2R71, and a structure having a formula:
and
wherein R71, when present, is selected from hydrogen, C1-C4 alkyl, —CH2CH2Si(CH3)3, and monocyclic aryl monosubstituted with a methyl group, provided that one and only one of R8 and R8′ is —OC(O)(C1-C30 alkyl)-L-Z, —OC(O)(C1-C30 alkyl)-L-(C1-C30 alkyl)-Z, —OC(O)-L-(C1-C30 alkyl)-Z, —NR41C(O)(C1-C30 alkyl)-L-Z, —NR41C(O)(C1-C30 alkyl)-L-(C1-C30 alkyl)-Z, or —NR41C(O)-L-(C1-C30 alkyl)-Z, and provided that when one or both of R28 and R29 is hydrogen then the occurrence of - - - - - - at C-22/C-23 is a double covalent bond, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
In one aspect, disclosed are pharmaceutical compositions comprising a therapeutically effective amount of a compound having a structure selected from:
or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
In one aspect, disclosed are pharmaceutical compositions comprising a therapeutically effective amount of a compound having a structure selected from:
or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
In one aspect, disclosed are pharmaceutical compositions comprising a therapeutically effective amount of a compound selected from:
or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
Pharmaceutically acceptable salts of the compounds are conventional acid-addition salts or base-addition salts that retain the biological effectiveness and properties of the compounds and are formed from suitable non-toxic organic or inorganic acids or organic or inorganic bases. Exemplary acid-addition salts include those derived from inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, sulfamic acid, phosphoric acid and nitric acid, and those derived from organic acids such as p-toluenesulfonic acid, salicylic acid, methanesulfonic acid, oxalic acid, succinic acid, citric acid, malic acid, lactic acid, fumaric acid, and the like. Example base-addition salts include those derived from ammonium, potassium, sodium and, quaternary ammonium hydroxides, such as for example, tetramethylammonium hydroxide. Chemical modification of a pharmaceutical compound into a salt is a known technique to obtain improved physical and chemical stability, hygroscopicity, flowability and solubility of compounds. See, e.g., H. Ansel et. al., Pharmaceutical Dosage Forms and Drug Delivery Systems (6th Ed. 1995) at pp. 196 and 1456-1457.
The pharmaceutical compositions comprise the compounds in a pharmaceutically acceptable carrier. A pharmaceutically acceptable carrier refers to sterile aqueous or nonaqueous solutions, dispersions, suspensions or emulsions, as well as sterile powders for reconstitution into sterile injectable solutions or dispersions just prior to use. Examples of suitable aqueous and nonaqueous carriers, diluents, solvents or vehicles include water, ethanol, polyols (such as glycerol, propylene glycol, polyethylene glycol and the like), carboxymethylcellulose and suitable mixtures thereof, vegetable oils (such as olive oil) and injectable organic esters such as ethyl oleate. The compounds can be formulated with pharmaceutically acceptable carriers or diluents as well as any other known adjuvants and excipients in accordance with conventional techniques such as those disclosed in Remington: The Science and Practice of Pharmacy, 19th Edition, Gennaro, Ed., Mack Publishing Co., Easton, Pa., 1995.
In a further aspect, the pharmaceutical composition is administered to a mammal. In a still further aspect, the mammal is a human. In an even further aspect, the human is a patient.
In a further aspect, the pharmaceutical composition is administered following identification of the mammal in need of treatment of cancer. In a still further aspect, the mammal has been diagnosed with a need for treatment of cancer prior to the administering step.
In various aspects, the disclosed pharmaceutical compositions comprise the disclosed compounds (including pharmaceutically acceptable salt(s) thereof) as an active ingredient, a pharmaceutically acceptable carrier, and, optionally, other therapeutic ingredients or adjuvants. The instant compositions include those suitable for oral, rectal, topical, and parenteral (including subcutaneous, intramuscular, and intravenous) administration, although the most suitable route in any given case will depend on the particular host, and nature and severity of the conditions for which the active ingredient is being administered. The pharmaceutical compositions can be conveniently presented in unit dosage form and prepared by any of the methods well known in the art of pharmacy.
The choice of carrier will be determined in part by the particular method used to administer the composition. Accordingly, there is a wide variety of suitable formulations of the pharmaceutical composition of the present invention. The following formulations for oral, aerosol, parenteral, subcutaneous, intravenous, intraarterial, intramuscular, intraperitoneal, intrathecal, rectal, and vaginal administration are merely exemplary and are in no way limiting.
Formulations suitable for oral administration can consist of (a) liquid solutions, such as an effective amount of the compound dissolved in diluents, such as water, saline, or orange juice; (b) capsules, sachets, tablets, lozenges, and troches, each containing a predetermined amount of the active ingredient, as solids or granule; (c) powders; (d) suspensions in an appropriate liquid; and (e) suitable emulsions. Liquid formulations may include diluents, such as water, cyclodextrin, dimethyl sulfoxide and alcohols, for example, ethanol, benzyl alcohol, propylene glycol, glycerin, and the polyethylene alcohols including polyethylene glycol, either with or without the addition of a pharmaceutically acceptable surfactant, suspending agent, or emulsifying agent. Capsule forms can be of the ordinary hard- or soft-shelled gelatin type containing, for example, surfactants, lubricants, and inert fillers, such as lactose, sucrose, calcium phosphate, and corn starch. Tablet forms can include one or more of the following: lactose, sucrose, mannitol, corn starch, potato starch, alginic acid, microcrystalline cellulose, acacia, gelatin, guar gum, colloidal silicon dioxide, croscarmellose sodium, talc, magnesium stearate, calcium stearate, zinc stearate, stearic acid, and other excipients, colorants, diluents, buffering agents, disintegrating agents, moistening agents, preservatives, flavoring agents, and pharmacologically compatible carriers. Lozenge forms can comprise the active ingredient in a flavor, usually sucrose and acacia or tragacanth, as well as pastilles comprising the active ingredient in an inert base, such as gelatin and glycerin, or sucrose and acadia, emulsions, and gels containing, the addition to the active ingredient in an inert base, such as gelatin and glycerin, or sucrose and acadia, emulsions, and gels containing, in addition to the active ingredient, such carriers as are known in the art.
The compounds of the present disclosure alone or in combination with other suitable components, can be made into aerosol formulations to be administered via inhalation. These aerosol formulations can be placed into pressurized acceptable propellants, such as dichlorodifluoromethane, propane, and nitrogen. They also may be formulated as pharmaceuticals for non-pressured preparations, such as in a nebulizer or an atomizer.
Formulations suitable for parenteral administration include aqueous and non-aqueous, isotonic sterile injection solutions, which can contain anti-oxidants, buffers, bacteriostats, and solutes that render the formulation isotonic with the blood of the intended recipient, and aqueous and non-aqueous sterile suspensions that can include suspending agents, solubilizers, thickening agents, stabilizers, and preservatives. The compound can be administered in a physiologically acceptable diluent in a pharmaceutical carrier, such as a sterile liquid or mixture of liquids, including water, saline, aqueous dextrose and related sugar solutions, an alcohol, such as ethanol, isopropanol, or hexadecyl alcohol, glycols, such as propylene glycol or polyethylene glycol such as poly(ethyleneglycol) 400, glycerol ketals, such as 2,2-dimethyl-1, 3-dioxolane-4-methanol, ethers, an oil, a fatty acid, a fatty acid ester or glyceride, or an acetylated fatty acid glyceride with or without the addition of a pharmaceutically acceptable surfactant, such as a soap or a detergent, suspending agent, such as pectin, carbomers, methylcellulose, hydroxypropylmethylcellulose, or carboxymethylcellulose, or emulsifying agents and other pharmaceutical adjuvants.
Oils which can be used in parenteral formulations include petroleum, animal, vegetable, or synthetic oils. Specific examples of oils include peanut, soybean, sesame, cottonseed, corn, olive, petrolatum, and mineral. Suitable fatty acids for use in parenteral formulations include oleic acid, stearic acid, and isostearic acid. Ethyl oleate and isopropyl myristate are examples of suitable fatty acid esters. Suitable soaps for use in parenteral formulations include fatty alkali metal, ammonium, and triethanolamine salts, and suitable detergents include (a) cationic detergents such as, for example, dimethyldiallylammonium halides, and alkylpyridinium halides, (b) anionic detergents such as, for example, alkyl, aryl, and olefin sulfonates, alkyl olefin, ether, and monoglyceride sulfates, and sulfosuccinates, (c) nonionic detergents such as, for example, fatty amine oxides, fatty acid alkanolamides, and polyoxyethylene polypropylene copolymers, (d) amphoteric detergents such as, for example, alkyl β-aminopropionates, and 2-alkylimidazoline quaternary ammonium salts, and (e) mixtures thereof.
The parenteral formulations typically contain from about 0.5% to about 25% by weight of the active ingredient in solution. Suitable preservatives and buffers can be used in such formulations. In order to minimize or eliminate irritation at the site of injection, such compositions may contain one or more nonionic surfactants having a hydrophile-lipophile balance (HLB) of from about 12 to about 17. The quantity of surfactant in such formulations ranges from about 5% to about 15% by weight. Suitable surfactants include polyethylene sorbitan fatty acid esters, such as sorbitan monooleate and the high molecular weight adducts of ethylene oxide with a hydrophobic base, formed by the condensation of propylene oxide with propylene glycol.
Pharmaceutically acceptable excipients are also well-known to those who are skilled in the art. The choice of excipient will be determined in part by the particular compound, as well as by the particular method used to administer the composition. Accordingly, there is a wide variety of suitable formulations of the pharmaceutical composition of the present disclosure. The following methods and excipients are merely exemplary and are in no way limiting. The pharmaceutically acceptable excipients preferably do not interfere with the action of the active ingredients and do not cause adverse side-effects. Suitable carriers and excipients include solvents such as water, alcohol, and propylene glycol, solid absorbants and diluents, surface active agents, suspending agent, tableting binders, lubricants, flavors, and coloring agents.
The formulations can be presented in unit-dose or multi-dose sealed containers, such as ampules and vials, and can be stored in a freeze-dried (lyophilized) condition requiring only the addition of the sterile liquid excipient, for example, water, for injections, immediately prior to use. Extemporaneous injection solutions and suspensions can be prepared from sterile powders, granules, and tablets. The requirements for effective pharmaceutical carriers for injectable compositions are well known to those of ordinary skill in the art. See Pharmaceutics and Pharmacy Practice, J.B. Lippincott Co., Philadelphia, Pa., Banker and Chalmers, Eds., 238-250 (1982) and ASHP Handbook on Injectable Drugs, Toissel, 4th ed., 622-630 (1986).
Formulations suitable for topical administration include lozenges comprising the active ingredient in a flavor, usually sucrose and acacia or tragacanth; pastilles comprising the active ingredient in an inert base, such as gelatin and glycerin, or sucrose and acacia; and mouthwashes comprising the active ingredient in a suitable liquid carrier; as well as creams, emulsions, and gels containing, in addition to the active ingredient, such carriers as are known in the art.
Additionally, formulations suitable for rectal administration may be presented as suppositories by mixing with a variety of bases such as emulsifying bases or water-soluble bases. Formulations suitable for vaginal administration may be presented as pessaries, tampons, creams, gels, pastes, foams, or spray formulas containing, in addition to the active ingredient, such carriers as are known in the art to be appropriate.
One skilled in the art will appreciate that suitable methods of exogenously administering a compound of the present disclosure to an animal are available, and, although more than one route can be used to administer a particular compound, a particular route can provide a more immediate and more effective reaction than another route.
As regards these applications, the present method includes the administration to an animal, particularly a mammal, and more particularly a human, of a therapeutically effective amount of the compound effective in the treatment of a hyperproliferative disorder. The method also includes the administration of a therapeutically effect amount of the compound for the treatment of patient having a predisposition for being afflicted with a hyperproliferative disorder. The dose administered to an animal, particularly a human, in the context of the present invention should be sufficient to affect a therapeutic response in the animal over a reasonable time frame. One skilled in the art will recognize that dosage will depend upon a variety of factors including the condition of the animal, the body weight of the animal, as well as the severity and stage of the virus.
The total amount of the compound of the present disclosure administered in a typical treatment is preferably between about 10 mg/kg and about 1000 mg/kg of body weight for mice, and between about 100 mg/kg and about 500 mg/kg of body weight, and more preferably between 200 mg/kg and about 400 mg/kg of body weight for humans per daily dose. This total amount is typically, but not necessarily, administered as a series of smaller doses over a period of about one time per day to about three times per day for about 24 months, and preferably over a period of twice per day for about 12 months.
The size of the dose also will be determined by the route, timing and frequency of administration as well as the existence, nature and extent of any adverse side effects that might accompany the administration of the compound and the desired physiological effect. It will be appreciated by one of skill in the art that various conditions or disease states, in particular chronic conditions or disease states, may require prolonged treatment involving multiple administrations.
In a further aspect, the composition further comprises at least one agent known to treat a hyperproliferative disorder. In a still further aspect, the composition further comprises at least one agent known to have a side effect of increasing the risk of a hyperproliferative disorder.
In a further aspect, the composition further comprises at least one agent known to treat cancer. In a still further aspect, the cancer is selected from a sarcoma, a carcinoma, a hematological cancer, a solid tumor, breast cancer, cervical cancer, gastrointestinal cancer, colorectal cancer, brain cancer, skin cancer, prostate cancer, ovarian cancer, thyroid cancer, testicular cancer, pancreatic cancer, endometrial cancer, melanoma, glioma, leukemia, lymphoma, chronic myeloproliferative disorder, myelodysplastic syndrome, myeloproliferative neoplasm, and plasma cell neoplasm (myeloma). In a still further aspect, the cancer is selected from a leukemia, colorectal cancer, pancreatic cancer, ovarian cancer, non-small cell lung carcinoma, and breast cancer.
In a further aspect, the composition further comprises at least one agent known to have a side effect of increasing the risk of cancer.
In a further aspect, the composition further comprises at least one agent known to treat a cardiovascular disease. Examples of cardiovascular diseases include, but are not limited to, coronary heart disease, stroke, hypertensive heart disease, inflammatory heart disease, and rheumatic heart disease,
In a further aspect, the composition further comprises at least one agent known to have a side effect of increasing the risk of cardiovascular disease.
In a further aspect, the composition comprises at least 50 wt % of the compound, based on the total weight of the composition. In a still further aspect, wherein the composition comprises at least 60 wt % of the compound, based on the total weight of the composition. In yet a further aspect, wherein the composition comprises at least 70 wt % of the compound, based on the total weight of the composition. In an even further aspect, wherein the composition comprises at least 80 wt % of the compound, based on the total weight of the composition. In a still further aspect, wherein the composition comprises at least 90 wt % of the compound, based on the total weight of the composition. In yet a further aspect, wherein the composition comprises at least 95 wt % of the compound, based on the total weight of the composition. In an even further aspect, wherein the composition comprises at least 99 wt % of the compound, based on the total weight of the composition.
It is understood that the disclosed compositions can be prepared from the disclosed compounds. It is also understood that the disclosed compositions can be employed in the disclosed methods of using.
In various aspects, the inventions relates to methods of making compounds useful as cellular probes (e.g., fluorescence, biotin) and as antibody-drug conjugates (ADCs). The disclosed compounds are also useful to treat hyperproliferative disorders such as, for example, cardiovascular diseases such as, for example, coronary heart disease, stroke, hypertensive heart disease, inflammatory heart disease, and rheumatic heart disease, and cancers such as, for example, a sarcoma, a carcinoma, a hematological cancer, a solid tumor, breast cancer, cervical cancer, gastrointestinal cancer, colorectal cancer, brain cancer, skin cancer, prostate cancer, ovarian cancer, thyroid cancer, testicular cancer, pancreatic cancer, endometrial cancer, melanoma, glioma, leukemia, lymphoma, chronic myeloproliferative disorder, myelodysplastic syndrome, myeloproliferative neoplasm, and plasma cell neoplasm (myeloma). Thus, in one aspect, disclosed are methods of making a disclosed compound.
Compounds according to the present disclosure can, for example, be prepared by the several methods outlined below. A practitioner skilled in the art will understand the appropriate use of protecting groups [see: Greene and Wuts, Protective Groups in Organic Synthesis] and the preparation of known compounds found in the literature using the standard methods of organic synthesis. There may come from time to time the need to rearrange the order of the recommended synthetic steps, however this will be apparent to the judgment of a chemist skilled in the art of organic synthesis. The following examples are provided so that the invention might be more fully understood, are illustrative only, and should not be construed as limiting.
In one aspect, the disclosed compounds comprise the products of the synthetic methods described herein. In a further aspect, the disclosed compounds comprise a compound produced by a synthetic method described herein. In a still further aspect, the invention comprises a pharmaceutical composition comprising a therapeutically effective amount of the product of the disclosed methods and a pharmaceutically acceptable carrier. In a still further aspect, the invention comprises a method for manufacturing a medicament comprising combining at least one compound of any of disclosed compounds or at least one product of the disclosed methods with a pharmaceutically acceptable carrier or diluent.
1. Route I
In one aspect, taccalonolide analogs can be prepared as shown below.
Compounds are represented in generic form, wherein R is C1-C30 alkyl, Ar2, —(C1-C30 alkyl)Ar2, Ar3, —(C1-C30 alkyl)OC(O)Ar3, —(C1-C30 alkyl)NR42C(O)Ar3, or R40 and with other substituents as noted in compound descriptions elsewhere herein. A more specific example is set forth below.
In one aspect, compounds of type 1.10, and similar compounds, can be prepared according to reaction Scheme 1B above. Thus, compounds of type 1.5 can be prepared by reductive amination of an appropriate ketone, e.g., 1.4 as shown above. Appropriate ketones are commercially available or prepared by methods known to one skilled in the art. The reductive amination is carried out in the presence of an appropriate reducing agent, e.g., sodium cyanoborohydride, and appropriate amine source, e.g., ammonium acetate, and an appropriate solvent, e.g., methanol, for an appropriate period of time, e.g., 16 hours. Compounds of type 1.7 can be prepared by amidation of an appropriate amine, e.g., 1.5 as shown above, and an appropriate succinimide, e.g., 1.6 as shown above. Appropriate succinimides are commercially available or prepared by methods known to one skilled in the art. The amidation is carried out in the presence of an appropriate base, e.g., N,N-diisopropylethylamine (DIPEA), in an appropriate solvent, e.g., dichloromethane (DCM), for an appropriate period of time, e.g., 16 hours. Compounds of type 1.9 can be prepared by cyclization of an appropriate azide, e.g., 1.7 as shown above, and an appropriate alkyne, e.g., 1.8 as shown above. Appropriate alkynes are commercially available or prepared by methods known to one skilled in the art. The cyclization is carried out in the presence of an appropriate catalyst, e.g., copper sulfate, and an appropriate acid, e.g., ascorbic acid, in an appropriate solvent system, e.g., t-butanol and water, for an appropriate period of time, e.g., 16 hours. Compounds of type 1.10 can be prepared by epoxidation of an appropriate alkene, e.g., 1.9 as shown above. The epoxidation is carried out in the presence of an appropriate oxidizing agent, e.g., dimethyldioxirane (DMDO) as shown above, in an appropriate solvent, e.g., acetone, at an appropriate temperature, e.g., −20° C., for an appropriate period of time, e.g., 4 hours. As can be appreciated by one skilled in the art, the above reaction provides an example of a generalized approach wherein compounds similar in structure to the specific reactants above (compounds similar to compounds of type 1.1 and 1.2), can be substituted in the reaction to provide substituted taccalonolide analogs similar to Formula 1.3.
2. Route II
In one aspect, taccalonolide analogs can be prepared as shown below.
Compounds are represented in generic form, with substituents as noted in compound descriptions elsewhere herein. A more specific example is set forth below.
In one aspect, compounds of type 2.6, and similar compounds, can be prepared according to reaction Scheme 2B above. Thus, compounds of type 2.4 can be prepared by reduction of an appropriate ketone, e.g., 1.4 as shown above. Appropriate ketones are commercially available or prepared by methods known to one skilled in the art. The reduction is carried out in the presence of an appropriate reducing agent, e.g., sodium borohydride. Compounds of type 2.6 can be prepared by esterification of an appropriate alcohol, e.g., 2.4 as shown above, using an appropriate carboxylic acid, e.g., 2.5 as shown above. Appropriate carboxylic acids are commercially available or prepared by methods known to one skilled in the art. The esterification is carried out in the presence of an appropriate activating agent, e.g., 4-dimethylaminopyridine (DMAP), and an appropriate coupling agent, e.g., 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDCI). As can be appreciated by one skilled in the art, the above reaction provides an example of a generalized approach wherein compounds similar in structure to the specific reactants above (compounds similar to compounds of type 1.1 and 2.1), can be substituted in the reaction to provide substituted taccalonolide analogs similar to Formula 2.3.
3. Route III
In one aspect, taccalonolide analogs can be prepared as shown below.
Compounds are represented in generic form, wherein R is O or NR41, wherein R′ is —(C1-C30 alkyl)-L-Z, —(C1-C30 alkyl)-L-(C1-C30 alkyl)-Z, or -L-(C1-C30)-Z, and with other substituents as noted in compound descriptions elsewhere herein. A more specific example is set forth below.
In one aspect, compounds of type 3.4, and similar compounds, can be prepared according to reaction Scheme 3B above. Thus, compounds of type 3.4 can be prepared by cyclization of an appropriate azide, e.g., 3.3 as shown above, and an appropriate alkyne, e.g., alkyne-terminated luteinizing hormone receptor hormone as shown above. Appropriate alkynes are commercially available or prepared by methods known to one skilled in the art. The cyclization is carried out in the presence of an appropriate catalyst, e.g., copper sulfate, and an appropriate acid, e.g., ascorbic acid, in an appropriate solvent system, e.g., t-butanol and water, for an appropriate period of time, e.g., 16 hours). As can be appreciated by one skilled in the art, the above reaction provides an example of a generalized approach wherein compounds similar in structure to the specific reactants above (compounds similar to compounds of type 3.3), can be substituted in the reaction to provide substituted taccalonolide analogs similar to Formula 3.4.
The compounds and pharmaceutical compositions of the invention are useful as cellular probes (e.g., for the detection, visualization, and/or quantification of a target). The disclosed compounds are also useful in treating or controlling hyperproliferative disorders such as, for example, cardiovascular diseases such as, for example, coronary heart disease, stroke, hypertensive heart disease, inflammatory heart disease, and rheumatic heart disease, and cancers such as, for example, a sarcoma, a carcinoma, a hematological cancer, a solid tumor, breast cancer, cervical cancer, gastrointestinal cancer, colorectal cancer, brain cancer, skin cancer, prostate cancer, ovarian cancer, thyroid cancer, testicular cancer, pancreatic cancer, endometrial cancer, melanoma, glioma, leukemia, lymphoma, chronic myeloproliferative disorder, myelodysplastic syndrome, myeloproliferative neoplasm, and plasma cell neoplasm (myeloma).
Examples of cancers for which the compounds and compositions can be useful in treating, include, but are not limited to carcinoma, lymphoma, blastoma, sarcoma, and leukemia. More particular examples of such cancers include breast cancer, prostate cancer, colon cancer, squamous cell cancer, small-cell lung cancer, non-small cell lung cancer, gastrointestinal cancer, pancreatic cancer, cervical cancer, ovarian cancer, peritoneal cancer, liver cancer, e.g., hepatic carcinoma, bladder cancer, colorectal cancer, endometrial carcinoma, kidney cancer, and thyroid cancer.
In various aspects, further examples of cancers are basal cell carcinoma, biliary tract cancer; bone cancer; brain and CNS cancer; choriocarcinoma; connective tissue cancer; esophageal cancer; eye cancer; cancer of the head and neck; gastric cancer; intra-epithelial neoplasm; larynx cancer; lymphoma including Hodgkin's and Non-Hodgkin's lymphoma; melanoma; myeloma; neuroblastoma; oral cavity cancer (e.g., lip, tongue, mouth, and pharynx); retinoblastoma; rhabdomyosarcoma; rectal cancer; cancer of the respiratory system; sarcoma; skin cancer; stomach cancer; testicular cancer; uterine cancer; cancer of the urinary system, as well as other carcinomas and sarcomas.
To treat or control the disorder, the compounds and pharmaceutical compositions comprising the compounds are administered to a subject in need thereof, such as a vertebrate, e.g., a mammal, a fish, a bird, a reptile, or an amphibian. The subject can be a human, non-human primate, horse, pig, rabbit, dog, sheep, goat, cow, cat, guinea pig or rodent. The term does not denote a particular age or sex. Thus, adult and newborn subjects, as well as fetuses, whether male or female, are intended to be covered. The subject is preferably a mammal, such as a human. Prior to administering the compounds or compositions, the subject can be diagnosed with a need for treatment of a cancer or of a fibrotic disorder.
The compounds or compositions can be administered to the subject according to any method. Such methods are well known to those skilled in the art and include, but are not limited to, oral administration, transdermal administration, administration by inhalation, nasal administration, topical administration, intravaginal administration, ophthalmic administration, intraaural administration, intracerebral administration, rectal administration, sublingual administration, buccal administration and parenteral administration, including injectable such as intravenous administration, intra-arterial administration, intramuscular administration, and subcutaneous administration. Administration can be continuous or intermittent. A preparation can be administered therapeutically; that is, administered to treat an existing disease or condition. A preparation can also be administered prophylactically; that is, administered for prevention of a cancer, immune dysfunction, or a fibrotic disorder.
The therapeutically effective amount or dosage of the compound can vary within wide limits. Such a dosage is adjusted to the individual requirements in each particular case including the specific compound(s) being administered, the route of administration, the condition being treated, as well as the patient being treated. In general, in the case of oral or parenteral administration to adult humans weighing approximately 70 Kg or more, a daily dosage of about 10 mg to about 10,000 mg, preferably from about 200 mg to about 1,000 mg, should be appropriate, although the upper limit may be exceeded. The daily dosage can be administered as a single dose or in divided doses, or for parenteral administration, as a continuous infusion. Single dose compositions can contain such amounts or submultiples thereof of the compound or composition to make up the daily dose. The dosage can be adjusted by the individual physician in the event of any contraindications. Dosage can vary, and can be administered in one or more dose administrations daily, for one or several days.
1. Use as Cellular Probes
The compound disclosed herein are useful as cellular probes such as, for example, tubulin-labeling probes (e.g., fluorescence, biotin). Thus, in various aspects, a taccalonolide compound is covalently attached to an antibody, an antibody fragment, a vitamin, a hormone, a carbohydrate, a molecular ligand, an aptamer, a non-antibody protein, a peptide, a nucleic acid, a fluorophore, or a drug. In this way, a target can be “found,” allowing for detection, visualization, and/or quantification.
Thus, for example, in various aspects, a taccalonolide compound is covalently attached to a molecule that facilitates detection (e.g., fluorophore, biotin) to generate a probe. Such probes have found widespread application in the study of cell biological processes in the study of disease indications including, but not limited to, oncological disorders and hematological disorders. The development of probes can be challenging because many factors such as, for example, linkage stability, which can have a significant impact on targeting and detection. One major limitation of current small molecule tubulin-based fluorescent probes is their sensitivity to cold-induced microtubule depolymerization and drug efflux pumps. These needs and others are met by the instant invention.
Thus, in various aspects, disclosed is use of a compound as a cellular probe, wherein the compound has a structure represented by a formula:
wherein each occurrence of - - - - - - is a single or double covalent bond; wherein X is selected from O, NRx and C(Rx)2; wherein each occurrence of Rx, when present, is independently selected from hydrogen and C1-C6 alkyl; wherein Rx is selected from hydrogen, halogen, —OH, —CN, —NC, —NCO, —OCN, —NO2, —ONO2, —ONO, —NO, —N3, —NH2, —NH3, —N═NR31, —NHOH, C1-C12 alkyl, C2-C12 alkenyl, C2-C12 alkynyl, C1-C12 hydroxy, C1-C12 alkoxy, C1-C12 thioalkyl, C1-C12 alkylthiol, C1-C12 aminoalkyl, C1-C12 alkylamino, (C1-C12)(C1-C12) dialkylamino, —OC(O)(C1-C12 alkyl), —OP(O)(OR32)2, —OSO2R33, —C(O)(C1-C12 alkyl), —CO2R34, —C(O)NR35aR35b, —(C1-C12 alkyl)C(O)NR35aR35b, —OC(O)NR35aR35b, —(C1-C12 alkyl)OC(O)NR35aR35b, Cy1, Ar1, (C1-C12 alkyl)Ar1, and —OAr1; wherein each occurrence of R31, R32, R34, R35a, and R35b, when present, is independently selected from hydrogen and C1-C12 alkyl; wherein each occurrence of R33, when present, is independently selected from hydrogen, C1-C12 alkyl, and monocyclic aryl monosubstituted with a methyl group; wherein each occurrence of Cy1, when present, is heterocycloalkyl substituted with 0, 1, 2, or 3 groups independently selected from halogen, —OH, —NH2, C1-C4 alkoxy, C1-C4 hydroxy, C1-C4 aminoalkyl, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino; wherein each occurrence of Ar1, when present, is selected from monocyclic aryl, morpholinyl, anilinyl, indolyl, pyrrolyl, imidazolyl, benzimidazolyl, pyrazolyl, guanidinyl, and piperazinyl and substituted with 0, 1, 2, or 3 groups independently selected from halogen, —OH, —NH2, C1-C4 alkoxy, C1-C4 hydroxy, C1-C4 aminoalkyl, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino; and wherein R1′ is hydrogen; or wherein each of R1 and R1′ together comprise ═O or ═NR36; wherein each occurrence of R36, when present, is independently selected from hydrogen and C1-C12 alkyl; wherein each of R2 and R3 is independently selected from hydrogen, —OH, C1-C12 hydroxy, and halogen; or wherein each of R2 and R3 together comprise —O—; wherein R5 is selected from hydrogen, —OH, —NH2, C1-C9 alkyl, C1-C9 hydroxy, C1-C9 alkoxy, C1-C9 aminoalkyl, C1-C6 alkylamino, and (C1-C6)(C1-C6) dialkylamino; or wherein R5 is absent; wherein R7 is selected from hydrogen, —OH, C1-C30 hydroxy, C1-C30 alkoxy, —OC(O)(C1-C30 alkyl), and —OC(O)NR35aR35b, and wherein R7′ is selected from hydrogen, —OH, C1-C30 hydroxy, C1-C30 alkoxy, and —OC(O)(C1-C30 alkyl); or wherein each of R7 and R7′ together comprise ═O; or wherein one of R7 and R7′ is absent; wherein each of R8 and R8′ is independently selected from hydrogen, halogen, —OH, —CN, —NC, —NCO, —OCN, —NO2, —ONO2, —ONO, —NO, —N3, —NH2, —NH3, —N═NR41, —NHOH, C1-C30 alkyl, C2-C30 alkenyl, C2-C30 alkynyl, C1-C30 hydroxy, C1-C30 alkoxy, C1-C30 thioalkyl, C1-C30 alkylthiol, C1-C30 aminoalkyl, C1-C30 alkylamino, (C1-C30)(C1-C30) dialkylamino, —C(O)(C1-C30 alkyl), —OP(O)(OR32)2, —OSO2R33, —CO2R34, —C(O)NR35aR35b, —(C1-C30 alkyl)C(O)NR35aR35b, —OC(O)NR35aR35b, —(C1-C30 alkyl)OC(O)NR35aR35b, Cy1, Ar1, —(C1-C30 alkyl)Ar1, —OAr1, —OC(O)(C1-C30 alkyl), —OC(O)Ar2, —OC(O)(C1-C30 alkyl)Ar2, —OC(O)Ar3, —OC(O)(C1-C30 alkyl)NR42C(O)Ar3, —OC(O)(C1-C30 alkyl)OC(O)Ar3, —OC(O)(C1-C30 alkyl)-L-Z, —OC(O)(C1-C30 alkyl)-L-(C1-C30 alkyl)-Z, —OC(O)-L-(C1-C30 alkyl)-Z, —NR41C(O)(C1-C30 alkyl), —NR41C(O)Ar2, —NR41C(O)(C1-C30 alkyl)Ar2, —NR41C(O)Ar3, —NR41C(O)(C1-C30 alkyl)OC(O)Ar3, —NR41C(O)(C1-C30 alkyl)NR42C(O)Ar3, —NR41C(O)(C1-C30 alkyl)-L-Z, —NR41C(O)(C1-C30 alkyl)-L-(C1-C30 alkyl)-Z, and —NR41C(O)-L-(C1-C30 alkyl)-Z; wherein L is a linker; wherein Z is selected from an antibody and an antibody fragment; wherein each occurrence of R41 and R42, when present, is independently selected from hydrogen and C1-C12 alkyl; wherein each occurrence of Ar2, when present, is independently selected from aryl and heteroaryl, and is substituted with 0, 1, 2, or 3 groups independently selected from halogen, —OH, —NH2, C1-C4 alkoxy, C1-C4 hydroxy, C1-C4 aminoalkyl, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, —(C1-C12 alkyl)Ar4, and Ar4; wherein each occurrence of Ar4, when present, is a structure represented by a formula:
wherein each of R50a, R50b, R50c, and R50d, when present, is independently selected from hydrogen, —F, and —Cl; wherein each of R51a and R51b, when present, is independently selected from hydrogen and —C(O)(C1-C12 alkyl); wherein each of R52a, R52b, R52c, and R52d, when present, is independently selected from hydrogen, —F, and —Cl; wherein each occurrence of Ar3, when present, is a structure represented by a formula selected from:
or wherein one of R8 and R8′ is absent; wherein each of R11 and R12 is independently selected from hydrogen, —OH, C1-C8 hydroxy, C1-C6 alkyl, C1-C8 alkoxy, and —OC(O)(C1-C8 alkyl); wherein R15 is selected from hydrogen, —OH, C1-C30 hydroxy, C1-C30 alkyl, C1-C30 alkoxy, —OC(O)(C1-C30 alkyl), —OC(O)NR35aR35b, —OC(O)Ar2, —OC(O)(C1-C4 alkyl)Ar2, and —OC(O)(C1-C8 azide); wherein R20 is selected from hydrogen, —OH, —OOH, C1-C8 alkyl, C1-C8 hydroxy, C1-C8 alkoxy, C1-C8 hydroperoxy, and —OC(O)(C1-C8 alkyl); wherein R21 is selected from hydrogen and C1-C6 alkyl; wherein R21 is selected from hydrogen, —OH, C1-C8 hydroxy, C1-C8 alkoxy, —OC(O)(C1-18 alkyl), —OC(O)NR35aR35b, —OC(O)Ar5, and —OC(O)(C1-C8 azide); wherein Ar5, when present, is selected from monocyclic 6-membered aryl and anthracene-9,10-dionyl, and is substituted with 0, 1, 2, or 3 groups independently selected from halogen, —OH, —NH2, C1-C4 alkoxy, C1-C4 hydroxy, C1-C4 aminoalkyl, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino; wherein each of R26 and R26′ is independently selected from hydrogen, —OH, C1-C8 hydroxy, and C1-C8 alkoxy; or wherein each of R26 and R26′ together comprise ═O; wherein R27 is selected from hydrogen and C1-C6 alkyl; wherein each of R28 and R29 is independently selected from hydrogen and halogen; or wherein each of R28 and R29 together comprise —O— or —N(R37)—; wherein R37, when present, is selected from hydrogen, C1-C4 alkyl, —SO2R71, and a structure having a formula:
and
wherein R71, when present, is selected from hydrogen, C1-C4 alkyl, —CH2CH2Si(CH3)3, and monocyclic aryl monosubstituted with a methyl group, provided that one and only one of R8 and R8′ is —OC(O)(C1-C30 alkyl)-L-Z, —OC(O)(C1-C30 alkyl)-L-(C1-C30 alkyl)-Z, —OC(O)-L-(C1-C30 alkyl)-Z, —NR41C(O)(C1-C30 alkyl)-L-Z, —NR41C(O)(C1-C30 alkyl)-L-(C1-C30 alkyl)-Z, or —NR41C(O)-L-(C1-C30 alkyl)-Z, and provided that when one or both of R28 and R29 is hydrogen then the occurrence of - - - - - - at C-22/C-23 is a double covalent bond, or a pharmaceutically acceptable salt thereof.
In a further aspect, disclosed is use of a compound as an antibody-drug conjugate.
2. Treatment Methods
The compounds disclosed herein are useful for treating or controlling hyperproliferative disorders such as, for example, cardiovascular diseases such as, for example, coronary heart disease, stroke, hypertensive heart disease, inflammatory heart disease, and rheumatic heart disease, and cancers such as, for example, a sarcoma, a carcinoma, a hematological cancer, a solid tumor, breast cancer, cervical cancer, gastrointestinal cancer, colorectal cancer, brain cancer, skin cancer, prostate cancer, ovarian cancer, thyroid cancer, testicular cancer, pancreatic cancer, endometrial cancer, melanoma, glioma, leukemia, lymphoma, chronic myeloproliferative disorder, myelodysplastic syndrome, myeloproliferative neoplasm, and plasma cell neoplasm (myeloma). Thus, provided is a method comprising administering a therapeutically effective amount of a composition comprising a disclosed compound to a subject. In a further aspect, the method can be a method for treating cancer. In a still further aspect, the method can be a method for treating a cardiovascular disease.
a. Treating Hyperproliferative Disorders
In one aspect, disclosed are methods of treating a hyperproliferative disorder in a mammal, the method comprising the step of administering to the mammal an effective amount of at least one disclosed compound, or a pharmaceutically acceptable salt thereof.
In one aspect, disclosed are methods for the treatment of a hyperproliferative disorder in a subject, the method comprising administering to the subject an effective amount of at least one compound having a structure represented by a formula:
wherein each occurrence of - - - - - - is a single or double covalent bond; wherein X is selected from O, NRx, and C(Rx)2; wherein each occurrence of Rx, when present, is independently selected from hydrogen and C1-C6 alkyl; wherein R1 is selected from hydrogen, halogen, —OH, —CN, —NC, —NCO, —OCN, —NO2, —ONO2, —ONO, —NO, —N3, —NH2, —NH3, —N═NR31, —NHOH, C1-C12 alkyl, C2-C12 alkenyl, C2-C12 alkynyl, C1-C12 hydroxy, C1-C12 alkoxy, C1-C12 thioalkyl, C1-C12 alkylthiol, C1-C12 aminoalkyl, C1-C12 alkylamino, (C1-C12)(C1-C12) dialkylamino, —OC(O)(C1-C12 alkyl), —OP(O)(OR32)2, —OSO2R33, —C(O)(C1-C12 alkyl), —CO2R34, —C(O)NR35aR35b, —(C1-C12 alkyl)C(O)NR35aR35b, —OC(O)NR35aR35b, —(C1-C12 alkyl)OC(O)NR35aR35b, Cy1, Ar1, (C1-C12 alkyl)Ar1, and —OAr1; wherein each occurrence of R31, R32, R34, R35a, and R35b, when present, is independently selected from hydrogen and C1-C12 alkyl; wherein each occurrence of R33, when present, is independently selected from hydrogen, C1-C12 alkyl, and monocyclic aryl monosubstituted with a methyl group; wherein each occurrence of Cy1, when present, is heterocycloalkyl substituted with 0, 1, 2, or 3 groups independently selected from halogen, —OH, —NH2, C1-C4 alkoxy, C1-C4 hydroxy, C1-C4 aminoalkyl, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino; wherein each occurrence of Ar1, when present, is selected from monocyclic aryl, morpholinyl, anilinyl, indolyl, pyrrolyl, imidazolyl, benzimidazolyl, pyrazolyl, guanidinyl, and piperazinyl and substituted with 0, 1, 2, or 3 groups independently selected from halogen, —OH, —NH2, C1-C4 alkoxy, C1-C4 hydroxy, C1-C4 aminoalkyl, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino; and wherein R1 is hydrogen; or wherein each of R1 and R1′ together comprise ═O or ═NR36; wherein each occurrence of R36, when present, is independently selected from hydrogen and C1-C12 alkyl; wherein each of R2 and R3 is independently selected from hydrogen, —OH, C1-C12 hydroxy, and halogen; or wherein each of R2 and R3 together comprise —O—; wherein R5 is selected from hydrogen, —OH, —NH2, C1-C9 alkyl, C1-C9 hydroxy, C1-C9 alkoxy, C1-C9 aminoalkyl, C1-C6 alkylamino, and (C1-C6)(C1-C6) dialkylamino; or wherein R5 is absent; wherein each of R6 and R6′ is independently selected from hydrogen, halogen, —OH, —CN, —NC, —NCO, —OCN, —NO2, —ONO2, —ONO, —NO, —N3, —NH2, —NH3, —N═NR41, —NHOH, C1-C30 alkyl, C2-C30 alkenyl, C2-C30 alkynyl, C1-C30 hydroxy, C1-C30 alkoxy, C1-C30 thioalkyl, C1-C30 alkylthiol, C1-C30 aminoalkyl, C1-C30 alkylamino, (C1-C30)(C1-C30) dialkylamino, —C(O)(C1-C30 alkyl), —OP(O)(OR32)2, —OSO2R33, —CO2R34, —C(O)NR35aR35b, —(C1-C30 alkyl)C(O)NR35aR35b, —OC(O)NR35aR35b, (C1-C30 alkyl)OC(O)NR35aR35b, Cy1, Ar1, —(C1-C30 alkyl)Ar1, —OAr1, —OC(O)(C1-C30 alkyl), —OC(O)Ar2, —OC(O)(C1-C30 alkyl)Ar2, —OC(O)Ar3, —OC(O)(C1-C30 alkyl)NR42C(O)Ar3, —OC(O)(C1-C30 alkyl)OC(O)Ar3, —OC(O)R40, —NR41C(O)(C1-C30 alkyl), —NR41C(O)Ar2, —NR41C(O)(C1-C30 alkyl)Ar2, —NR41C(O)Ar3, —NR41C(O)(C1-C30 alkyl)OC(O)Ar3, —NR41C(O)(C1-C30 alkyl)NR42C(O)Ar3, and —NR41C(O)R40; wherein each occurrence of R40, when present, is independently a C1-C30 alkyl functionalized with a group selected from —N3, —SH, —OH, —NH2, —NHOH, an ester, a disulfide, a sulfonamide, a terminal alkyne, haloacetyl, maleimide, isothiocyanate, N-hydroxysuccinimde, an acylhydrazine, an acylhydrazone, a hydrazine, a hydrazone, and hydrazide; wherein each occurrence of R41 and R42, when present, is independently selected from hydrogen and C1-C12 alkyl; wherein each occurrence of Ar2, when present, is independently selected from aryl and heteroaryl, and is substituted with 0, 1, 2, or 3 groups independently selected from halogen, —OH, —NH2, C1-C4 alkoxy, C1-C4 hydroxy, C1-C4 aminoalkyl, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, —(C1-C12 alkyl)Ar4, and Ar4; wherein each occurrence of Ar4, when present, is a structure represented by a formula selected from:
wherein each of R50a, R50b, R50c, and R50d, when present, is independently selected from hydrogen, —F, and —Cl; wherein each of R51a and R51b, when present, is independently selected from hydrogen and —C(O)(C1-C12 alkyl); wherein each of R52a, R52b, R52c, and R52d, when present, is independently selected from hydrogen, —F, and —Cl; wherein each occurrence of Ar3, when present, is a structure represented by a formula selected from:
or wherein one of R6 and R6′ is absent; wherein R7 is selected from hydrogen, —OH, C1-C30 hydroxy, C1-C30 alkoxy, —OC(O)(C1-C30 alkyl), and —OC(O)NR35aR35b, and wherein R7′ is selected from hydrogen, —OH, C1-C30 hydroxy, C1-C30 alkoxy, and —OC(O)(C1-C30 alkyl); or wherein each of R7 and R7′ together comprise ═O; or wherein one of R7 and R7′ is absent; wherein each of R11 and R12 is independently selected from hydrogen, —OH, C1-C8 hydroxy, C1-C6 alkyl, C1-C8 alkoxy, and —OC(O)(C1-C8 alkyl); wherein R15 is selected from hydrogen, —OH, C1-C30 hydroxy, C1-C30 alkyl, C1-C30 alkoxy, —OC(O)(C1-C30 alkyl), —OC(O)NR35aR35b, —OC(O)Ar2, —OC(O)(C1-C4 alkyl)Ar2, and —OC(O)(C1-C8 azide); wherein R20 is selected from hydrogen, —OH, —OOH, C1-C8 alkyl, C1-C8 hydroxy, C1-C8 alkoxy, C1-C8 hydroperoxy, and —OC(O)(C1-C8 alkyl); wherein R21 is selected from hydrogen and C1-C6 alkyl; wherein R25 is selected from hydrogen, —OH, C1-C8 hydroxy, C1-C8 alkoxy, —OC(O)(C1-18 alkyl), —OC(O)NR35aR35b, —OC(O)Ar5, and —OC(O)(C1-C8 azide); wherein Ar5, when present, is selected from monocyclic 6-membered aryl and anthracene-9,10-dionyl, and is substituted with 0, 1, 2, or 3 groups independently selected from halogen, —OH, —NH2, C1-C4 alkoxy, C1-C4 hydroxy, C1-C4 aminoalkyl, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino; wherein each of R26 and R26′ is independently selected from hydrogen, —OH, C1-C8 hydroxy, and C1-C8 alkoxy; or wherein each of R26 and R26′ together comprise ═O; wherein R27 is selected from hydrogen and C1-C6 alkyl; wherein each of R28 and R29 is independently selected from hydrogen and halogen; or wherein each of R28 and R29 together comprise —O— or —N(R37)—; wherein R37, when present, is selected from hydrogen, C1-C4 alkyl, —SO2R71, and a structure having a formula:
and
wherein R71, when present, is selected from hydrogen, C1-C4 alkyl, —CH2CH2Si(CH3)3, and monocyclic aryl monosubstituted with a methyl group, provided that at least one of R6 and R6′ is —NR41C(O)(C1-C30 alkyl), —NR41C(O)Ar2, —NR41C(O)(C1-C30 alkyl)Ar2, —NR41C(O)Ar3, —NR41C(O)(C1-C30 alkyl)OC(O)Ar3, —NR41C(O)(C1-C30 alkyl)NR42C(O)Ar3, or —NR41C(O)R40, and provided that when one or both of R28 and R29 is hydrogen then the occurrence of - - - - - - at C-22/C-23 is a double covalent bond, or a pharmaceutically acceptable salt thereof.
In one aspect, disclosed are methods for the treatment of a hyperproliferative disorder in a subject, the method comprising administering to the subject an effective amount of at least one compound having a structure represented by a formula:
wherein each occurrence of - - - - - - is a single or double covalent bond; wherein X is selected from O, NRx and C(Rx)2; wherein each occurrence of Rx, when present, is independently selected from hydrogen and C1-C6 alkyl; wherein R1 is selected from hydrogen, halogen, —OH, —CN, —NC, —NCO, —OCN, —NO2, —ONO2, —ONO, —NO, —N3, —NH2, —NH3, —N═NR31, N HOH, C1-C12 alkyl, C2-C12 alkenyl, C2-C12 alkynyl, C1-C12 hydroxy, C1-C12 alkoxy, C1-C12 thioalkyl, C1-C12 alkylthiol, C1-C12 aminoalkyl, C1-C12 alkylamino, (C1-C12)(C1-C12) dialkylamino, —OC(O)(C1-C12 alkyl), —OP(O)(OR32)2, —OSO2R33, —C(O)(C1-C12 alkyl), —CO2R34, —C(O)NR35aR35b, —(C1-C12 alkyl)C(O)NR35aR35b, —OC(O)NR35aR35b, —(C1-C12 alkyl)OC(O)NR35aR35b, Cy1, Ar1, (C1-C12 alkyl)Ar1, and —OAr1; wherein each occurrence of R31, R32, R34, R35a, and R35b, when present, is independently selected from hydrogen and C1-C12 alkyl; wherein each occurrence of R33, when present, is independently selected from hydrogen, C1-C12 alkyl, and monocyclic aryl monosubstituted with a methyl group; wherein each occurrence of Cy1, when present, is heterocycloalkyl substituted with 0, 1, 2, or 3 groups independently selected from halogen, —OH, —NH2, C1-C4 alkoxy, C1-C4 hydroxy, C1-C4 aminoalkyl, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino; wherein each occurrence of Ar1, when present, is selected from monocyclic aryl, morpholinyl, anilinyl, indolyl, pyrrolyl, imidazolyl, benzimidazolyl, pyrazolyl, guanidinyl, and piperazinyl and substituted with 0, 1, 2, or 3 groups independently selected from halogen, —OH, —NH2, C1-C4 alkoxy, C1-C4 hydroxy, C1-C4 aminoalkyl, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino; and wherein R1′ is hydrogen; or wherein each of R1 and R1′ together comprise ═O or ═NR36; wherein each occurrence of R36, when present, is independently selected from hydrogen and C1-C12 alkyl; wherein each of R2 and R3 is independently selected from hydrogen, —OH, C1-C12 hydroxy, and halogen; or wherein each of R2 and R3 together comprise —O—; wherein R5 is selected from hydrogen, —OH, —NH2, C1-C9 alkyl, C1-C9 hydroxy, C1-C9 alkoxy, C1-C9 aminoalkyl, C1-C6 alkylamino, and (C1-C6)(C1-C6) dialkylamino; or wherein R5 is absent; wherein each of R6 and R6′ is independently selected from hydrogen, halogen, —OH, —CN, —NC, —NCO, —OCN, —NO2, —ONO2, —ONO, —NO, —N3, —NH2, —NH3, —N═NR41, —NHOH, C1-C30 alkyl, C2-C30 alkenyl, C2-C30 alkynyl, C1-C30 hydroxy, C1-C30 alkoxy, C1-C30 thioalkyl, C1-C30 alkylthiol, C1-C30 aminoalkyl, C1-C30 alkylamino, (C1-C30)(C1-C30) dialkylamino, —C(O)(C1-C30 alkyl), —OP(O)(OR32)2, —OSO2R33, —CO2R34, —C(O)NR35aR35b, —(C1-C30 alkyl)C(O)NR35aR35b, —OC(O)NR35aR35b, (C1-C30 alkyl)OC(O)NR35aR35b, Cy1, Ar1, —(C1-C30 alkyl)Ar1, —OAr1, —OC(O)(C1-C30 alkyl), —OC(O)Ar2, —OC(O)(C1-C30 alkyl)Ar2, —OC(O)Ar3, —OC(O)(C1-C30 alkyl)NR42C(O)Ar3, —OC(O)(C1-C30 alkyl)OC(O)Ar3, —OC(O)R40, —NR41C(O)(C1-C30 alkyl), —NR41C(O)Ar2, —NR41C(O)(C1-C30 alkyl)Ar2, —NR41C(O)Ar3, —NR41C(O)(C1-C30 alkyl)OC(O)Ar3, —NR41C(O)(C1-C30 alkyl)NR42C(O)Ar3, and —NR41C(O)R40; wherein each occurrence of R40, when present, is independently a C1-C30 alkyl functionalized with a group selected from —SH, —NH2, —NHOH, terminal alkyne, haloacetyl, maleimide, isothiocyanate, N-hydroxysuccinimde, succinimidyl ester, tetrafluorophenyl ester, sulfodichlorophenol ester, and hydrazide; wherein each occurrence of R41 and R42, when present, is independently selected from hydrogen and C1-C12 alkyl; wherein each occurrence of Ar2, when present, is independently selected from aryl and heteroaryl, and is substituted with 0, 1, 2, or 3 groups independently selected from halogen, —OH, —NH2, C1-C4 alkoxy, C1-C4 hydroxy, C1-C4 aminoalkyl, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, —(C1-C12 alkyl)Ar4, and Ar4; wherein each occurrence of Ar4, when present, is a structure represented by a formula:
wherein each of R50a, R50b, R50c, and R50d, when present, is independently selected from hydrogen, —F, and —Cl; wherein each of R51a and R51b, when present, is independently selected from hydrogen and —C(O)(C1-C12 alkyl); wherein each of R52a, R52b, R52c, and R52d, when present, is independently selected from hydrogen, —F, and —Cl; wherein each occurrence of Ar3, when present, is a structure represented by a formula selected from:
or wherein one of R6 and R6′ is absent; wherein R7 is selected from hydrogen, —OH, C1-C30 hydroxy, C1-C30 alkoxy, —OC(O)(C1-C30 alkyl), and —OC(O)NR35aR35b, and wherein R7′ is selected from hydrogen, —OH, C1-C30 hydroxy, C1-C30 alkoxy, and —OC(O)(C1-C30 alkyl); or wherein each of R7 and R7′ together comprise ═O; or wherein one of R7 and R7′ is absent; wherein each of R11 and R12 is independently selected from hydrogen, —OH, C1-C8 hydroxy, C1-C6 alkyl, C1-C8 alkoxy, and —OC(O)(C1-C8 alkyl); wherein R15 is selected from hydrogen, —OH, C1-C30 hydroxy, C1-C30 alkyl, C1-C30 alkoxy, —OC(O)(C1-C30 alkyl), —OC(O)NR35aR35b, —OC(O)Ar2, —OC(O)(C1-C4 alkyl)Ar2, and —OC(O)(C1-C8 azide); wherein R20 is selected from hydrogen, —OH, —OOH, C1-C8 alkyl, C1-C8 hydroxy, C1-C8 alkoxy, C1-C8 hydroperoxy, and —OC(O)(C1-C8 alkyl); wherein R21 is selected from hydrogen and C1-C6 alkyl; wherein R25 is selected from hydrogen, —OH, C1-C8 hydroxy, C1-C8 alkoxy, —OC(O)(C1-18 alkyl), —OC(O)NR35aR35b, —OC(O)Ar5, and —OC(O)(C1-C8 azide); wherein Ar5, when present, is selected from monocyclic 6-membered aryl and anthracene-9,10-dionyl, and is substituted with 0, 1, 2, or 3 groups independently selected from halogen, —OH, —NH2, C1-C4 alkoxy, C1-C4 hydroxy, C1-C4 aminoalkyl, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino; wherein each of R26 and R26′ is independently selected from hydrogen, —OH, C1-C8 hydroxy, and C1-C8 alkoxy; or wherein each of R26 and R26′ together comprise ═O; wherein R27 is selected from hydrogen and C1-C6 alkyl; wherein each of R28 and R29 is independently selected from hydrogen and halogen; or wherein each of R28 and R29 together comprise —O— or —N(R37)—; wherein R37, when present, is selected from hydrogen, C1-C4 alkyl, —SO2R71, and a structure having a formula:
and
wherein R71, when present, is selected from hydrogen, C1-C4 alkyl, —CH2CH2Si(CH3)3, and monocyclic aryl monosubstituted with a methyl group, provided that at least one of R6 and R6′ is —OC(O)R40 or —NR41C(O)R40, and provided that when one or both of R28 and R29 is hydrogen then the occurrence of - - - - - - at C-22/C-23 is a double covalent bond, or a pharmaceutically acceptable salt thereof.
In one aspect, disclosed are methods for the treatment of a hyperproliferative disorder in a subject, the method comprising administering to the subject an effective amount of at least one compound having a structure represented by a formula:
wherein each occurrence of - - - - - - is a single or double covalent bond; wherein X is selected from O, NRx and C(Rx)2; wherein each occurrence of Rx, when present, is independently selected from hydrogen and C1-C6 alkyl; wherein R1 is selected from hydrogen, halogen, —OH, —CN, —NC, —NCO, —OCN, —NO2, —ONO2, —ONO, —NO, —N3, —NH2, —NH3, —N═NR31, —NHOH, C1-C12 alkyl, C2-C12 alkenyl, C2-C12 alkynyl, C1-C12 hydroxy, C1-C12 alkoxy, C1-C12 thioalkyl, C1-C12 alkylthiol, C1-C12 aminoalkyl, C1-C12 alkylamino, (C1-C12)(C1-C12) dialkylamino, —OC(O)(C1-C12 alkyl), —OP(O)(OR32)2, —OSO2R31, —C(O)(C1-C12 alkyl), —CO2R34, —C(O)NR35aR35b, —(C1-C12 alkyl)C(O)NR35aR35b, —OC(O)NR35aR35b, (C1-C12 alkyl)OC(O)NR35aR35b, Cy1, Ar1, (C1-C12 alkyl)Ar1, and —OAr1; wherein each occurrence of R31, R32, R34, R35a, and R35b, when present, is independently selected from hydrogen and C1-C12 alkyl; wherein each occurrence of R33, when present, is independently selected from hydrogen, C1-C12 alkyl, and monocyclic aryl monosubstituted with a methyl group; wherein each occurrence of Cy1, when present, is heterocycloalkyl substituted with 0, 1, 2, or 3 groups independently selected from halogen, —OH, —NH2, C1-C4 alkoxy, C1-C4 hydroxy, C1-C4 aminoalkyl, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino; wherein each occurrence of Ar1, when present, is selected from monocyclic aryl, morpholinyl, anilinyl, indolyl, pyrrolyl, imidazolyl, benzimidazolyl, pyrazolyl, guanidinyl, and piperazinyl and substituted with 0, 1, 2, or 3 groups independently selected from halogen, —OH, —NH2, C1-C4 alkoxy, C1-C4 hydroxy, C1-C4 aminoalkyl, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino; and wherein R1′ is hydrogen; or wherein each of R1 and R1′ together comprise ═O or ═NR36; wherein each occurrence of R36, when present, is independently selected from hydrogen and C1-C12 alkyl; wherein each of R2 and R3 is independently selected from hydrogen, —OH, C1-C12 hydroxy, and halogen; or wherein each of R2 and R3 together comprise —O—; wherein R5 is selected from hydrogen, —OH, —NH2, C1-C9 alkyl, C1-C9 hydroxy, C1-C9 alkoxy, C1-C9 aminoalkyl, C1-C6 alkylamino, and (C1-C6)(C1-C6) dialkylamino; or wherein R5 is absent; wherein R7 is selected from hydrogen, —OH, C1-C30 hydroxy, C1-C30 alkoxy, —OC(O)(C1-C30 alkyl), and —OC(O)NR35aR35b, and wherein R7′ is selected from hydrogen, —OH, C1-C30 hydroxy, C1-C30 alkoxy, and —OC(O)(C1-C30 alkyl); or wherein each of R7 and R7′ together comprise ═O; or wherein one of R7 and R7′ is absent; wherein each of R8 and R8′ is independently selected from hydrogen, halogen, —OH, —CN, —NC, —NCO, —OCN, —NO2, —ONO2, —ONO, —NO, —N3, —NH2, —NH3, —N═NR41, —NHOH, C1-C30 alkyl, C2-C30 alkenyl, C2-C30 alkynyl, C1-C30 hydroxy, C1-C30 alkoxy, C1-C30 thioalkyl, C1-C30 alkylthiol, C1-C30 aminoalkyl, C1-C30 alkylamino, (C1-C30)(C1-C30) dialkylamino, —C(O)(C1-C30 alkyl), —OP(O)(OR32)2, —OSO2R33, —CO2R34, —C(O)NR35aR35b, —(C1-C30 alkyl)C(O)NR35aR35b, —OC(O)NR35aR35b, —(C1-C30 alkyl)OC(O)NR35aR35b, Cy1, Ar1, —(C1-C30 alkyl)Ar1, —OAr1, —OC(O)(C1-C30 alkyl), —OC(O)Ar2, —OC(O)(C1-C30 alkyl)Ar2, —OC(O)Ar3, —OC(O)(C1-C30 alkyl)NR42C(O)Ar3, —OC(O)(C1-C30 alkyl)OC(O)Ar3, —OC(O)(C1-C30 alkyl)-L-Z, —OC(O)(C1-C30 alkyl)-L-(C1-C30 alkyl)-Z, —OC(O)-L-(C1-C30 alkyl)-Z, —NR41C(O)(C1-C30 alkyl), —NR41C(O)Ar2, —NR41C(O)(C1-C30 alkyl)Ar2, —NR41C(O)Ar3, —NR41C(O)(C1-C30 alkyl)OC(O)Ar3, —NR41C(O)(C1-C30 alkyl)NR42C(O)Ar3, —NR41C(O)(C1-C30 alkyl)-L-Z, —NR41C(O)(C1-C30 alkyl)-L-(C1-C30 alkyl)-Z, and —NR41C(O)-L-(C1-C30 alkyl)-Z; wherein L is a linker; wherein Z is selected from an antibody, an antibody fragment, a vitamin, a hormone, a carbohydrate, a molecular ligand, an aptamer, a non-antibody protein, a peptide, a nucleic acid, a fluorophore, and a drug; wherein each occurrence of R41 and R42, when present, is independently selected from hydrogen and C1-C12 alkyl; wherein each occurrence of Ar2, when present, is independently selected from aryl and heteroaryl, and is substituted with 0, 1, 2, or 3 groups independently selected from halogen, —OH, —NH2, C1-C4 alkoxy, C1-C4 hydroxy, C1-C4 aminoalkyl, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, —(C1-C12 alkyl)Ar4, and Ar4; wherein each occurrence of Ar4, when present, is a structure represented by a formula:
wherein each of R50a, R50b, R50c, and R50d, when present, is independently selected from hydrogen, —F, and —Cl; wherein each of R51a and R51b, when present, is independently selected from hydrogen and —C(O)(C1-C12 alkyl); wherein each of R52a, R52b, R52c, and R52d, when present, is independently selected from hydrogen, —F, and —Cl; wherein each occurrence of Ar3, when present, is a structure represented by a formula selected from:
or wherein one of R8 and R8′ is absent; wherein each of R11 and R12 is independently selected from hydrogen, —OH, C1-C8 hydroxy, C1-C6 alkyl, C1-C8 alkoxy, and —OC(O)(C1-C8 alkyl); wherein R15 is selected from hydrogen, —OH, C1-C30 hydroxy, C1-C30 alkyl, C1-C30 alkoxy, —OC(O)(C1-C30 alkyl), —OC(O)NR35aR35b, —OC(O)Ar2, —OC(O)(C1-C4 alkyl)Ar2, and —OC(O)(C1-C8 azide); wherein R20 is selected from hydrogen, —OH, —OOH, C1-C8 alkyl, C1-C8 hydroxy, C1-C8 alkoxy, C1-C8 hydroperoxy, and —OC(O)(C1-C8 alkyl); wherein R21 is selected from hydrogen and C1-C6 alkyl; wherein R25 is selected from hydrogen, —OH, C1-C8 hydroxy, C1-C8 alkoxy, —OC(O)(C1-18 alkyl), —OC(O)NR35aR35b, —OC(O)Ar5, and —OC(O)(C1-C8 azide); wherein Ar5, when present, is selected from monocyclic 6-membered aryl and anthracene-9,10-dionyl, and is substituted with 0, 1, 2, or 3 groups independently selected from halogen, —OH, —NH2, C1-C4 alkoxy, C1-C4 hydroxy, C1-C4 aminoalkyl, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino; wherein each of R26 and R26′ is independently selected from hydrogen, —OH, C1-C8 hydroxy, and C1-C8 alkoxy; or wherein each of R26 and R26′ together comprise ═O; wherein R27 is selected from hydrogen and C1-C6 alkyl; wherein each of R28 and R29 is independently selected from hydrogen and halogen; or wherein each of R28 and R29 together comprise —O— or N(R37 wherein R37, when present, is selected from hydrogen, C1-C4 alkyl, —SO2R71, and a structure having a formula:
and
wherein R71, when present, is selected from hydrogen, C1-C4 alkyl, —CH2CH2Si(CH3)3, and monocyclic aryl monosubstituted with a methyl group, provided that one and only one of R8 and R8′ is —OC(O)(C1-C30 alkyl)-L-Z, —OC(O)(C1-C30 alkyl)-L-(C1-C30 alkyl)-Z, —OC(O)-L-(C1-C30 alkyl)-Z, —NR41C(O)(C1-C30 alkyl)-L-Z, —NR41C(O)(C1-C30 alkyl)-L-(C1-C30 alkyl)-Z, or —NR41C(O)-L-(C1-C30 alkyl)-Z, and provided that when one or both of R28 and R29 is hydrogen then the occurrence of - - - - - - at C-22/C-23 is a double covalent bond, or a pharmaceutically acceptable salt thereof.
In one aspect, disclosed are methods for the treatment of a hyperproliferative disorder in a subject, the method comprising administering to the subject an effective amount of at least one compound having a structure selected from:
or a pharmaceutically acceptable salt thereof.
In one aspect, disclosed are methods for the treatment of a hyperproliferative disorder in a subject, the method comprising administering to the subject an effective amount of at least one compound selected from:
or a pharmaceutically acceptable salt thereof.
In one aspect, disclosed are methods for the treatment of a hyperproliferative disorder in a subject, the method comprising administering to the subject an effective amount of at least one compound having a structure selected from:
or a pharmaceutically acceptable salt thereof.
In a further aspect, the hyperproliferative disorder is a cardiovascular disease. Examples of cardiovascular disease include, but are not limited to, coronary heart disease, stroke, hypertensive heart disease, inflammatory heart disease, and rheumatic heart disease.
In a further aspect, the hyperproliferative disorder is a cancer. Examples of cancers include, but are not limited to, carcinoma, lymphoma, blastoma, sarcoma, and leukemia. More particular examples of such cancers include breast cancer, prostate cancer, colon cancer, squamous cell cancer, small-cell lung cancer, non-small cell lung cancer, gastrointestinal cancer, pancreatic cancer, cervical cancer, ovarian cancer, peritoneal cancer, liver cancer, e.g., hepatic carcinoma, bladder cancer, colorectal cancer, endometrial carcinoma, kidney cancer, and thyroid cancer.
In various aspects, further examples of cancers are basal cell carcinoma, biliary tract cancer; bone cancer; brain and CNS cancer; choriocarcinoma; connective tissue cancer; esophageal cancer; eye cancer; cancer of the head and neck; gastric cancer; intra-epithelial neoplasm; larynx cancer; lymphoma including Hodgkin's and Non-Hodgkin's lymphoma; melanoma; myeloma; neuroblastoma; oral cavity cancer (e.g., lip, tongue, mouth, and pharynx); retinoblastoma; rhabdomyosarcoma; rectal cancer; cancer of the respiratory system; sarcoma; skin cancer; stomach cancer; testicular cancer; uterine cancer; cancer of the urinary system, as well as other carcinomas and sarcomas
In a further aspect, the cancer is a hematological cancer. In a still further aspect, the hematological cancer is selected from acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL), chronic myeloid leukemia (CML), chronic lymphocytic leukemia (CLL), hairy cell leukemia, chronic myelomonocytic leukemia (CMML), juvenile myelomonocytic leukemia (JMML), Hodgkin lymphoma, Non-Hodgkin lymphoma, multiple myeloma, solitary myeloma, localized myeloma, and extramedullary myeloma. In a still further aspect, the cancer is selected from chronic lymphocytic leukemia, small lymphocytic lymphoma, B-cell non-Hodgkin lymphoma, and large B-cell lymphoma.
In a further aspect, the cancer is a cancer of the brain. In a still further aspect, the cancer of the brain is selected from a glioma, medulloblastoma, primitive neuroectodermal tumor (PNET), acoustic neuroma, glioma, meningioma, pituitary adenoma, schwannoma, CNS lymphoma, primitive neuroectodermal tumor, craniopharyngioma, chordoma, medulloblastoma, cerebral neuroblastoma, central neurocytoma, pineocytoma, pineoblastoma, atypical teratoid rhabdoid tumor, chondrosarcoma, chondroma, choroid plexus carcinoma, choroid plexus papilloma, craniopharyngioma, dysembryoplastic neuroepithelial tumor, gangliocytoma, germinoma, hemangioblastoma, hemangiopercytoma, and metastatic brain tumor. In a yet further aspect, the glioma is selected from ependymoma, astrocytoma, oligodendroglioma, and oligoastrocytoma. In an even further aspect, the glioma is selected from juvenile pilocytic astrocytoma, subependymal giant cell astrocytoma, ganglioglioma, subependymoma, pleomorphic xanthoastrocytom, anaplastic astrocytoma, glioblastoma multiforme, brain stem glioma, oligodendroglioma, ependymoma, oligoastrocytoma, cerebellar astrocytoma, desmoplastic infantile astrocytoma, subependymal giant cell astrocytoma, diffuse astrocytoma, mixed glioma, optic glioma, gliomatosis cerebri, multifocal gliomatous tumor, multicentric glioblastoma multiforme tumor, paraganglioma, and ganglioglioma.
In one aspect, the cancer can be a cancer selected from cancers of the blood, brain, genitourinary tract, gastrointestinal tract, colon, rectum, breast, kidney, lymphatic system, stomach, lung, pancreas, and skin. In a further aspect, the cancer is selected from prostate cancer, glioblastoma multiforme, endometrial cancer, breast cancer, and colon cancer. In a further aspect, the cancer is selected from a cancer of the breast, ovary, prostate, head, neck, and kidney. In a still further aspect, the cancer is selected from cancers of the blood, brain, genitourinary tract, gastrointestinal tract, colon, rectum, breast, liver, kidney, lymphatic system, stomach, lung, pancreas, and skin. In a yet further aspect, the cancer is selected from a cancer of the lung and liver. In an even further aspect, the cancer is selected from a cancer of the breast, ovary, testes, and prostate. In a still further aspect, the cancer is a cancer of the breast. In a yet further aspect, the cancer is a cancer of the ovary. In an even further aspect, the cancer is a cancer of the prostate. In a still further aspect, the cancer is a cancer of the testes.
In a further aspect, the cancer is selected from a cancer of the breast, cervix, gastrointestinal tract, colorectal tract, brain, skin, prostate, ovary, thyroid, testes, genitourinary tract, pancreas, and endometrias. In a still further aspect, the cancer is a cancer of the breast. In yet a further aspect, the cancer of the breast is a hormone resistant cancer. In an even further aspect, the cancer of the breast is a hormone resistant cancer. In a still further aspect, the cancer is a cancer of the cervix. In yet a further aspect, the cancer is a cancer of the ovary. In an even further aspect, the cancer is a cancer of the endometrias. In a still further aspect, the cancer is a cancer of the genitourinary tract. In yet a further aspect, the cancer is a cancer of the colorectal tract. In an even further aspect, the cancer of the colorectal tract is a colorectal carcinoma. In a still further aspect, the cancer is a cancer of the gastrointestinal tract. In yet a further aspect, the cancer of the gastrointestinal tract is a gastrointestinal stromal tumor. In an even further aspect, the cancer is a cancer of the skin. In a still further aspect, the cancer of the skin is a melanoma. In yet a further aspect, the cancer is a cancer of the brain. In an even further aspect, the cancer of the brain is a glioma. In a still further aspect, the glioma is glioblastoma multiforme. In yet a further aspect, glioma is selected from is selected from an ependymoma, astrocytoma, oligodendroglioma, and oligoastrocytoma. In an even further aspect, the cancer of the brain is selected from acoustic neuroma, glioma, meningioma, pituitary adenoma, schwannoma, CNS lymphoma, primitive neuroectodermal tumor, craniopharyngioma, chordoma, medulloblastoma, cerebral neuroblastoma, central neurocytoma, pineocytoma, pineoblastoma, atypical teratoid rhabdoid tumor, chondrosarcoma, chondroma, choroid plexus carcinoma, choroid plexus papilloma, craniopharyngioma, dysembryoplastic neuroepithelial tumor, gangliocytoma, germinoma, hemangioblastoma, and hemangiopercytoma. In a still further aspect, the hematological cancer is selected from a leukemia, lymphoma, chronic myeloproliferative disorder, myelodysplastic syndrome, myeloproliferative neoplasm, and plasma cell neoplasm (myeloma). In yet a further aspect, the hematological cancer is leukemia. In an even further aspect, the leukemia is selected from acute leukemia, acute lymphocytic leukemia, acute myelocytic leukemia, myeloblastic leukemia, promyelocytic leukemia, myelomonocytic leukemia, monocytic leukemia, erythroleukemia, chronic leukemia, chronic myelocytic (granulocytic) leukemia, and chronic lymphocytic leukemia. In a still further aspect, the leukemia is acute lymphocytic leukemia. In yet a further aspect, the hematological cancer is lymphoma. In an even further aspect, the hematological cancer is myeloma. In a still further aspect, the myeloma is multiple myeloma.
In a further aspect, the carcinoma is selected from colon carcinoma, squamous cell carcinoma, basal cell carcinoma, adenocarcinoma, sweat gland carcinoma, sebaceous gland carcinoma, papillary carcinoma, papillary adenocarcinomas, cystadenocarcinoma, medullary carcinoma, bronchogenic carcinoma, renal cell carcinoma, bile duct carcinoma, choriocarcinoma, seminoma, embryonal carcinoma, lung carcinoma, small cell lung carcinoma, bladder carcinoma, and epithelial carcinoma.
In a further aspect, the cancer is selected from breast cancer, cervical cancer, gastrointestinal cancer, colorectal cancer, brain cancer, skin cancer, prostate cancer, ovarian cancer, thyroid cancer, testicular cancer, pancreatic cancer, endometrial cancer, melanoma, glioma, leukemia, lymphoma, chronic myeloproliferative disorder, myelodysplastic syndrome, myeloproliferative neoplasm, and plasma cell neoplasm (myeloma).
In a further aspect, the subject has been diagnosed with a need for treatment of a hyperproliferative disorder prior to the administering step.
In a further aspect, the subject is a mammal. In a still further aspect, the mammal is a human.
In a further aspect, the method further comprises the step of identifying a subject in need of treatment of a hyperproliferative disorder.
In a further aspect, the method further comprises the step of administering a therapeutically effective amount of at least one chemotherapeutic agent. Examples of chemotherapeutic agents include, but are not limited to, alkylating agents such as busulfan, cis-platin, mitomycin C, and carboplatin; antimitotic agents such as colchicine, vinblastine, paclitaxel (e.g., TAXOL®), and docetaxel; topoisomerase I inhibitors such as camptothecin and topotecan; topoisomerase II inhibitors such as doxorubicin and etoposide; RNA/DNA antimetabolites such as 5-azacytidine, 5-fluorouracil and methotrexate; DNA antimetabolites such as 5-fluoro-2′-deoxy-uridine, ara-C, hydroxyurea, gemcitabine, capecitabine and thioguanine; antibodies such as HERCEPTIN® and RITUXAN®, as well as other known chemotherapeutics such as photofrin, melphalan, chlorambucil, cyclophosamide, ifosfamide, vincristine, mitoguazone, epirubicin, aclarubicin, bleomycin, mitoxantrone, elliptinium, fludarabine, octreotide, retinoic acid, tamoxifen and alanosine.
In a further aspect, the at least one compound and the at least one agent are administered sequentially. In a still further aspect, the at least one compound and the at least one agent are administered simultaneously.
In a further aspect, the at least one compound and the at least one agent are co-formulated. In a still further aspect, the at least one compound and the at least one agent are co-packaged.
In a further aspect, the effective amount is a therapeutically effective amount. In a still further aspect, the effective amount is a prophylactically effective amount.
3. Additional Uses of Compounds
In one aspect, the invention relates to the use of a disclosed compound or a product of a disclosed method. In a further aspect, a use is as a probe. In a still further aspect, a use is as an ADC. In yet a further aspect, a use relates to the manufacture of a medicament for the treatment of a hyperproliferative disorder in a mammal. In a still further aspect, a use relates to the manufacture of a medicament for the treatment of cancer in a mammal. In yet a further aspect, the use relates to the manufacture of a medicament for the treatment of cardiovascular disease in a mammal.
Also provided are the uses of the disclosed compounds and products. In one aspect, the invention relates to use of at least one disclosed compound; or a pharmaceutically acceptable salt, hydrate, solvate, or polymorph thereof. In a further aspect, the compound used is a product of a disclosed method of making.
In a further aspect, the use relates to a process for preparing a pharmaceutical composition comprising a therapeutically effective amount of a disclosed compound or a product of a disclosed method of making, or a pharmaceutically acceptable salt, solvate, or polymorph thereof, for use as a medicament.
In a further aspect, the use relates to a process for preparing a pharmaceutical composition comprising a therapeutically effective amount of a disclosed compound or a product of a disclosed method of making, or a pharmaceutically acceptable salt, solvate, or polymorph thereof, wherein a pharmaceutically acceptable carrier is intimately mixed with a therapeutically effective amount of the compound or the product of a disclosed method of making.
In various aspects, the use relates to a treatment of a disorder in a mammal. In one aspect, the use is characterized in that the mammal is a human. In one aspect, the use is characterized in that the disorder is a hyperproliferative disorder. In one aspect, the use is characterized in that the disorder is a cancer or a cardiovascular disease.
In a further aspect, the use relates to the manufacture of a medicament for the treatment of a hyperproliferative disorder in a mammal.
It is understood that the disclosed uses can be employed in connection with the disclosed compounds, products of disclosed methods of making, methods, compositions, and kits. In a further aspect, the invention relates to the use of a disclosed compound or a disclosed product in the manufacture of a medicament for the treatment of a hyperproliferative disorder such as, for example, cancer or cardiovascular disease, in a mammal. In a further aspect, the cancer is selected from multiple myeloma and hematologic malignancy.
4. Manufacture of a Medicament
In one aspect, the invention relates to a method for the manufacture of a medicament for treating a hyperproliferative disorder in a mammal, the method comprising combining a therapeutically effective amount of a disclosed compound or product of a disclosed method with a pharmaceutically acceptable carrier or diluent.
As regards these applications, the present method includes the administration to an animal, particularly a mammal, and more particularly a human, of a therapeutically effective amount of the compound effective in the treatment of a hyperproliferative disorder such as, for example, cancer or cardiovascular disease. The dose administered to an animal, particularly a human, in the context of the present invention should be sufficient to affect a therapeutic response in the animal over a reasonable time frame. One skilled in the art will recognize that dosage will depend upon a variety of factors including the condition of the animal and the body weight of the animal.
The total amount of the compound of the present disclosure administered in a typical treatment is preferably between about 10 mg/kg and about 1000 mg/kg of body weight for mice, and between about 100 mg/kg and about 500 mg/kg of body weight, and more preferably between 200 mg/kg and about 400 mg/kg of body weight for humans per daily dose. This total amount is typically, but not necessarily, administered as a series of smaller doses over a period of about one time per day to about three times per day for about 24 months, and preferably over a period of twice per day for about 12 months.
The size of the dose also will be determined by the route, timing and frequency of administration as well as the existence, nature and extent of any adverse side effects that might accompany the administration of the compound and the desired physiological effect. It will be appreciated by one of skill in the art that various conditions or disease states, in particular chronic conditions or disease states, may require prolonged treatment involving multiple administrations.
Thus, in one aspect, the invention relates to the manufacture of a medicament comprising combining a disclosed compound or a product of a disclosed method of making, or a pharmaceutically acceptable salt, solvate, or polymorph thereof, with a pharmaceutically acceptable carrier or diluent.
5. Kits
In one aspect, disclosed are kits comprising at least one disclosed compound and one or more of: (a) at least one agent associated with the treatment of a hyperproliferative disorder; (b) instructions for administering the compound in connection with treating a hyperproliferative disorder; and (c) instructions for treating a hyperproliferative disorder.
In a further aspect, the hyperproliferative disorder is a cancer. Examples of cancers for which the compounds and compositions can be useful in treating, include, but are not limited to carcinoma, lymphoma, blastoma, sarcoma, and leukemia. More particular examples of such cancers include breast cancer, prostate cancer, colon cancer, squamous cell cancer, small-cell lung cancer, non-small cell lung cancer, gastrointestinal cancer, pancreatic cancer, cervical cancer, ovarian cancer, peritoneal cancer, liver cancer, e.g., hepatic carcinoma, bladder cancer, colorectal cancer, endometrial carcinoma, kidney cancer, and thyroid cancer.
In various aspects, further examples of cancers are basal cell carcinoma, biliary tract cancer; bone cancer; brain and CNS cancer; choriocarcinoma; connective tissue cancer; esophageal cancer; eye cancer; cancer of the head and neck; gastric cancer; intra-epithelial neoplasm; larynx cancer; lymphoma including Hodgkin's and Non-Hodgkin's lymphoma; melanoma; myeloma; neuroblastoma; oral cavity cancer (e.g., lip, tongue, mouth, and pharynx); retinoblastoma; rhabdomyosarcoma; rectal cancer; cancer of the respiratory system; sarcoma; skin cancer; stomach cancer; testicular cancer; uterine cancer; cancer of the urinary system, as well as other carcinomas and sarcomas
In a further aspect, the agent associated with the treatment of a hyperproliferative disorder is a chemotherapeutic agent. Examples of chemotherapeutic agents include, but are not limited to, alkylating agents such as busulfan, cis-platin, mitomycin C, and carboplatin; antimitotic agents such as colchicine, vinblastine, paclitaxel (e.g., TAXOL®), and docetaxel; topoisomerase I inhibitors such as camptothecin and topotecan; topoisomerase II inhibitors such as doxorubicin and etoposide; RNA/DNA antimetabolites such as 5-azacytidine, 5-fluorouracil and methotrexate; DNA antimetabolites such as 5-fluoro-2′-deoxy-uridine, ara-C, hydroxyurea, gemcitabine, capecitabine and thioguanine; antibodies such as HERCEPTIN® and RITUXAN®, as well as other known chemotherapeutics such as photofrin, melphalan, chlorambucil, cyclophosamide, ifosfamide, vincristine, mitoguazone, epirubicin, aclarubicin, bleomycin, mitoxantrone, elliptinium, fludarabine, octreotide, retinoic acid, tamoxifen and alanosine. In a further aspect, the chemotherapeutic agent is selected from an alkylating agent, an antimetabolite agent, an antineoplastic antibiotic agent, a mitotic inhibitor agent, and a mTor inhibitor agent.
In a further aspect, the antineoplastic antibiotic agent is selected from doxorubicin, mitoxantrone, bleomycin, daunorubicin, dactinomycin, epirubicin, idarubicin, plicamycin, mitomycin, pentostatin, and valrubicin, or a pharmaceutically acceptable salt thereof.
In a further aspect, the antimetabolite agent is selected from gemcitabine, 5-fluorouracil, capecitabine, hydroxyurea, mercaptopurine, pemetrexed, fludarabine, nelarabine, cladribine, clofarabine, cytarabine, decitabine, pralatrexate, floxuridine, methotrexate, and thioguanine, or a pharmaceutically acceptable salt thereof.
In a further aspect, the alkylating agent is selected from carboplatin, cisplatin, cyclophosphamide, chlorambucil, melphalan, carmustine, busulfan, lomustine, dacarbazine, oxaliplatin, ifosfamide, mechlorethamine, temozolomide, thiotepa, bendamustine, and streptozocin, or a pharmaceutically acceptable salt thereof.
In a further aspect, the mitotic inhibitor agent is selected from irinotecan, topotecan, rubitecan, cabazitaxel, docetaxel, paclitaxel, etopside, vincristine, ixabepilone, vinorelbine, vinblastine, and teniposide, or a pharmaceutically acceptable salt thereof.
In a further aspect, the mTor inhibitor agent is selected from everolimus, siroliumus, and temsirolimus, or a pharmaceutically acceptable salt, hydrate, solvate, or polymorph thereof.
In a further aspect, the at least one compound and the at least one agent are co-formulated. In a further aspect, the at least one compound and the at least one agent are co-packaged.
In a further aspect, the compound and the agent are administered sequentially. In a still further aspect, the compound and the agent are administered simultaneously.
The kits can also comprise compounds and/or products co-packaged, co-formulated, and/or co-delivered with other components. For example, a drug manufacturer, a drug reseller, a physician, a compounding shop, or a pharmacist can provide a kit comprising a disclosed compound and/or product and another component for delivery to a patient.
It is understood that the disclosed kits can be prepared from the disclosed compounds, products, and pharmaceutical compositions. It is also understood that the disclosed kits can be employed in connection with the disclosed methods of using.
The foregoing description illustrates and describes the disclosure. Additionally, the disclosure shows and describes only the preferred embodiments but, as mentioned above, it is to be understood that it is capable to use in various other combinations, modifications, and environments and is capable of changes or modifications within the scope of the invention concepts as expressed herein, commensurate with the above teachings and/or the skill or knowledge of the relevant art. The embodiments described herein above are further intended to explain best modes known by applicant and to enable others skilled in the art to utilize the disclosure in such, or other, embodiments and with the various modifications required by the particular applications or uses thereof. Accordingly, the description is not intended to limit the invention to the form disclosed herein. Also, it is intended to the appended claims be construed to include alternative embodiments.
All publications and patent applications cited in this specification are herein incorporated by reference, and for any and all purposes, as if each individual publication or patent application were specifically and individually indicated to be incorporated by reference. In the event of an inconsistency between the present disclosure and any publications or patent application incorporated herein by reference, the present disclosure controls.
Many successful therapeutics, including aspirin, β-lactam antibiotics, esomeprazole (Nexium), and clopidogrel (Plavix) (Singh, et al. (2011) Nat. Rev. Drug. Discov. 10, 307-317; Robertson, J. G. (2005) Biochemistry 44, 5561-5571) bind covalently to their drug targets. However, the irreversible nature of their binding prompts safety concerns due to potential off-target reactivity and unanticipated side effects. Therefore, one of the most critical steps in the covalent drug discovery process is the effective evaluation of their target specificity and assessment of useful de-risking strategies (Bauer, R. A. (2015) Drug. Discov. Today 20, 1061-1073; Johnson, et al. (2010) Future Med. Chem. 2, 949-964). The development of modern ‘targeted covalent inhibitors’ (TCIs) (Baillie, T. A. (2016) Angew. Chem. Int. Ed. Engl. 55, 13408-13421; Lonsdale, et al. (2018) Chem. Soc. Rev. 47, 3816-3830) has led to significant progress including the successful launch of several preclinical and clinical studies for covalent EGFR inhibitors, such as the FDA approved afatinib (Giltrif) and osimertinib (Tagrisso), which exhibited promising therapeutic effects against resistant cancer models expressing EGFR mutations (Irie, H. et al. (2019) Mol. Cancer Ther. 18, 733-742; Murakami, H. et al. (2017) Ann. Oncol. 28; Ito, K. et al. (2019) Mol. Cancer Ther. 18, 920-928). The systematic studies of TCIs have also revealed that the safety of covalent drugs needs to be evaluated on a case-by-case basis and the complexity of the covalent systems often urge innovative approaches (Ziegler, et al. (2013) Angew. Chem. Int. Edit. 52, 2744-2792; Bottcher, et al. (2010) Angew. Chem. Int. Edit. 49, 2680-2698; Wright, et al. (2016) Nat. Prod. Rep. 33, 681-708) as necessary complements to conventional preclinical and clinical studies.
The taxane class of microtubule stabilizers is a mainstay in the clinical treatment of solid tumors even in the era of targeted therapy and immunotherapy (Broggini-Tenzer, A. et al. (2015) J. Natl. Cancer. Inst. 107, dju504; Jhaveri, K. et al. (2017) Breast Cancer Res. 19, 89; Rohena, et al. (2014) Nat. Prod. Rep. 31, 335-355; Schmid, P. et al. (2018) N. Engl. J. Med. 379, 2108-2121). However, a major limitation of the taxanes is acquired drug resistance. The taccalonolides are a class of microtubule stabilizers that covalently bind β-tubulin (Risinger, A. L. et al. (2013) Cancer Res. 73, 6780-6792; Wang, Y. et al. (2017) Nat. Commun. 8, 15787) and effectively circumvent clinically relevant models of resistance to taxanes both in vitro and in vivo (Tinley, T. L. et al. (2003) Cancer Res. 63, 3211-3220; Risinger, A. L. et al. (2008) Cancer Res. 68, 8881-8888; Ola, A. R. B. et al. (2018) J. Nat. Prod. 81, 579-593). Despite their promising therapeutic potential, the covalent nature of taccalonolide binding has hampered the ability to perform detailed binding studies using conventional approaches (de Jong, L. A. A., et al. (2005) J. Chromatogr. B 829, 1-25; Pollard, T. D. (2010) Mol. Biol. Cell 21, 4061-4067). Consequently, it urged the development of a functional and rigorous activity-based approach to elucidate the target specificity and drug-target interactions of the taccalonolides. Here, the synthesis and optimization of a fluorogenic taccalonolide probe, Flu-tacca-7 (11) is described. This stable, cell-permeable probe is used for activity-based protein profiling (ABPP) in human cancer cell lines to confirm the specificity of covalent binding of the taccalonolides to β-tubulin and evaluate key β-tubulin residues and taccalonolide moieties that mediate taccalonolide-tubulin binding. Flu-tacca-7 (11) represents a class of irreversible microtubule labeling probes that are superior to commercially available options, providing a valuable tool for cellular evaluations of this important drug target.
The following preparations and examples are given to enable those skilled in the art to more clearly understand and to practice the present invention. They should not be considered as limiting the scope of the invention, but merely as being illustrative and representative.
Optical rotations were measured on a Rudolph Research Autopol III automatic polarimeter. NMR data were obtained on Varian VNMR spectrometers (400 and 500 MHz for 1H, 100 and 125 MHz for 13C) with broad band and triple resonance probes. Preparative HPLC separations were performed on a Shimadzu system using a SCL-10A VP controller and a Gemini 5 μm C18 or a Kinetex F5 5 μm C18 column (110 Å, 250×21.2 mm) with flow rate of 10 mL/min. Semi-preparative HPLC separations were performed on a Waters 1525 system using a 2998 PDA detector and Gemini 5 μm C18 or a Kinetex F5 5 μm C18 column (110 A, 250×10.0 mm) with flow rate of 4 mL/min. All solvents were of ACS grade or better. HRESIMS (high-resolution electrospray ionization mass spectrometry) data were collected on an Agilent 6538 high-mass-resolution QTOF mass spectrometer. X-ray Intensity data were collected using a diffractometer with a Bruker APEX ccd area detector and graphite-monochromated Mo Kα radiation (λ=0.71073 Å).
a. Compound Nos. 152E and 152D
b. Compound No. 154B
c. Compound No. 154C
d. Compound No. 154J
e. Compound No. 155F
f. Compound No. 155G
g. Compound No. 158E
h. Compound No. 158F
i. Compound no. 162C
j. Compound No. 163D
k. Compound No. 163E
l. Compounds No. 164A and 164B
152A is a mixture of two 6-amino epimers resulted from the reductive amination of taccalonolide B. A sample of 152A (1 eq.) was stirred with 5-carboxyfluorescein di-trimethylacetate (1.5 eq.) and HATU (1 eq.) in a 1:1 mixture of DCM/pyridine at room temperature overnight. The solvents were removed in vacuo and the residue was purified by prep-HPLC using a C-18 column to yield compounds 164A (˜9% yield) and 164B (˜27% yield). Compound 164A: white powder; 1H NMR (500 MHz, methanol-d4) δ 8.51 (1H, s), 8.24 (1H, d, J=8.0 Hz), 7.37 (1H, d, J=8.0 Hz), 7.16 (2H, br s), 6.85-6.91 (4H, m), 5.33 (1H, dd, J=2.9, 12.0 Hz), 5.17 (1H, d, J=2.8 Hz), 4.73 (1H, d, J=5.3 Hz), 4.35 (1H, t, J=8.7 Hz), 4.02 (1H, t, J=11.1 Hz), 3.45 (1H, t, J=4.8 Hz), 4.39 (1H, t, J=10.0 Hz), 3.32 (1H, m), 3.30 (1H, m), 2.30 (1H, t, J=11.2 Hz), 2.23 (1H, dd, J=4.6, 15.4 Hz), 2.11 (3H, s), 2.09 (3H, s), 2.09-2.11 (2H, m), 1.97 (1H, dd, J=8.8, 10.5 Hz), 1.91 (3H, s), 1.87-1.93 (2H, m), 1.79 (1H, d, J=15.4 Hz), 1.74 (3H, s), 1.56 (1H, m), 1.35 (18H, s), 1.26 (3H, s), 1.02 (3H, s), 1.00 (3H, s, J=7.3 Hz), 0.90 (3H, s); Compound 164B: white powder; 1H NMR (500 MHz, methanol-d4) δ 8.36 (1H, s), 8.10 (1H, dd, J=1.6, 8.0 Hz), 7.35 (1H, d, J=8.0 Hz), 7.17 (2H, s), 6.85-6.91 (4H, m), 5.30 (1H, dd, J=2.9, 11.2 Hz), 5.16 (1H, d, J=2.9 Hz), 4.69 (1H, d, J=5.5 Hz), 4.60 (1H, m), 4.27 (1H, t, J=8.9 Hz), 3.78 (1H, dd, J=4.8, 10.0 Hz), 3.40 (1H, dd, J=3.8, 5.6 Hz), 3.33 (1H, m), 3.30 (1H, m), 2.29-2.37 (1H, m), 2.12 (3H, s), 2.11 (3H, s), 2.05-2.12 (5H, m), 1.97 (1H, t, J=9.3 Hz), 1.91 (3H, s), 1.74 (3H, s), 1.55 (1H, m), 1.35 (18H, s), 1.24 (3H, s), 1.08 (3H, s), 1.00 (3H, s, J=7.3 Hz), 0.91 (3H, s).
m. Compound No. 164E
n. Compound No. 167C
o. Conjugated Compound No. 167C
p. Compound No. 171B_TFA
Taccalonolide B (13, 50 mg, 1 equiv) was mixed with ammonium acetate (165 mg, 30 equiv), sodium cyanoborohydride (45 mg, 10 equiv), and 4 Å molecular sieves (500 mg) in anhydrous methanol (MeOH) (4 mL). The reactant mixture was stirred at 35° C. overnight and the solvent was removed in vacuo. The residue was purified by preparative HPLC using a Luna 5 μm C1S column [isocratic, 40% acetonitrile (MeCN) in 0.1% trifluoroacetic acid (TFA)] to yield the TFA salt TFA-14 (45 mg) which was identified as a 3:1 mixture of the 6S and 6R epimers by analysis of 1D and 2D NMR data. The TFA salt was then stirred with the AMBERLYST™ A21 resin (450 mg) in methanol (4 mL) for 2 h at room temperature. The resin was filtered and washed with methanol (4 mL×2). The combined methanol filtrates were evaporated in vacuo to yield the free amine 6-NH2-taccalonolide B (14) (33 mg).
6-NH2-taccalonolide B (14): colorless solid; 1H and 13C NMR data of TFA-14, see Table i; HRESIMS (m/z): [M+H]+ calcd. for C34H48NO12, 662.3177; found 662.3177.
Trimellitic anhydride (436 mg, 1 equiv) and resorcinol (500 mg, 2 equiv) were stirred in methanesulfonic acid (12 mL) at 80° C. for 24 h. The resulted mixture was poured into ice water (H2O). The precipitate was collected and washed with water to yield the crude 5(6)-carboxyfluorescein (15) (820 mg).
5(6)-carboxyfluorescein (15): yellow powder; 1H NMR (500 MHz, methanol-d4): δ 8.59 (d, J=1.5 Hz, 1H), 8.37 (dd, J=8.0, 1.5 Hz, 1H), 8.31 (dd, J=8.0, 1.5 Hz, 1H), 8.09 (d, J=8.0 Hz, 1H), 7.74 (s, 1H), 7.30 (d, J=8.0 Hz, 1H), 6.70-6.72 (d, J=9.7 Hz, 4H), 6.60-6.42 (br s, 4H), 6.53-6.57 (m, 4H). See also (Ueno, et al. (2004) Synthesis-Stuttgart, 2591-2593, doi:10.1055/s-2004-829194.
5(6)-carboxyfluorescein (15) (490 mg) was stirred in trimethylacetic anhydride (8 mL, 30 equiv) at 110° C. for 3 h. The resulted mixture was then stirred in the mixed solution of water (15 mL) and THE (30 mL) at room temperature for 2 days. The solvents were removed in vacuo and the residue was purified by preparative HPLC using a Luna 5 μm C18 column (isocratic, 80% MeCN in 0.1% TFA) to yield 5-carboxyfluorescein dipivalate (16) (221 mg) and 6-carboxyfluorescein dipivalate (198 mg).
5-carboxyfluorescein dipivalate (16): yellow powder; 1H NMR (400 MHz, methanol-d4): δ 8.56 (s, 1H), 8.23 (d, J=8.0 Hz, 1H), 7.12 (dd, J=8.0, 1.6 Hz, 1H), 7.05 (br s, 2H), 6.75-6.80 (m, 4H), 1.28 (s, 18H); 13C NMR (100 MHz, methanol-d4): δ 177.7, 169.6, 167.6, 157.6, 154.1, 152.6, 137.6, 134.4, 130.0, 127.6, 127.5, 125.3, 119.1, 116.8, 111.4, 83.1, 40.0, 27.4. See also Oberg, et al. (2003) Bioconjugate Chem 14, 1289-1297, doi:10.1021/bc034130j.
5(6)-carboxyfluorescein (15) (320 mg) and pyridine (260 μL) were stirred in acetic anhydride (5 mL) at 80° C. for 5 min. The solvents were removed in vacuo and the residue was purified by preparative HPLC using a Luna 5 μm C18 column (isocratic, 50% MeCN in 0.1% formic acid) to yield 5-carboxyfluorescein diacetate (117) (161 mg) and 6-carboxyfluorescein diacetate (152 mg).
5-carboxyfluorescein diacetate (17): yellow powder; 1H NMR (400 MHz, methanol-d4): δ 8.61 (s, 1H), 8.37 (d, J=8.0 Hz, 1H), 7.32 (d, J=8.0 Hz, 1H), 7.18 (br s, 2H), 6.88 (br s, 4H), 2.28 (s, 6H).
Trimellitic anhydride (375 mg, 1 equiv) and 4-fluororesorcinol (18) (500 mg, 2 equiv) were stirred in methanesulfonic acid (12 mL) at 80° C. for 24 h. The resulted mixture was poured into ice water. The precipitate was collected and washed with water to yield the crude 5(6)-carboxy-Oregon Green 488 (19) (930 mg).
5(6)-carboxy-Oregon Green 488 (19): yellow powder; 1H NMR (500 MHz, methanol-d4): δ 8.61 (d, J=1.5 Hz, 1H), 8.31 (dd, J=8.0, 1.5 Hz, 11H), 8.25 (dd, J=8.0, 1.5 Hz, 1H), 8.11 (d, J=8.0 Hz, 11H), 7.81 (s, 1H), 7.30 (d, J=8.0 Hz, 1H), 6.83 (s, 11H), 6.81 (s, 2H), 6.80 (s, 1H), 6.51 (s, 1H), 6.50 (s, 1H), 6.49 (s, 1H), 6.48 (s, 1H). See also Sun, et al. (1997). J Org Chem 62, 6469-6475, doi:DOI 10.1021/jo9706178.
5(6)-carboxy-Oregon green (19) (167 mg) and pyridine (130 uL) were stirred in acetic anhydride (3.8 mL) at 80° C. for 5 min. The solvents were removed in vacuo to yield the crude 5(6)-carboxy-Oregon green diacetate (198 mg). A portion of the crude 5(6)-carboxy-Oregon green diacetate (30 mg) was stirred with N-hydroxysuccinimide (NHS) (8.3 mg, 1.2 equiv) and 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDAC) (14 mg, 1.2 equiv) in dichloromethane (DCM) (2 mL) at room temperature for 3 h and then beta-alanine (54 mg, 10 equiv) and pyridine (2 mL) were added into the mixture which was further stirred at 40° C. overnight. The solvents were removed in vacuo and the residue was purified by preparative HPLC using a Luna 5 μm C18 column (isocratic, 35% MeCN in 0.1% TFA) to yield diacetyl-5-(2-carboxyethylaminocarbonyl) Oregon Green 488 (20) (15.2 mg) and diacetyl-6-(2-carboxyethylaminocarbonyl) Oregon Green 488 (13.4 mg).
diacetyl-5-(2-carboxyethylaminocarbonyl) Oregon Green 488 (20): yellow powder; 1H NMR (500 MHz, methanol-d4): δ 8.44 (d, J=1.6 Hz, 1H), 8.20 (dd, J=8.0, 1.6 Hz, 1H), 7.39 (d, J=8.0 Hz, 1H), 7.32 (s, 1H), 7.31 (s, 1H), 6.76 (s, 1H), 6.74 (s, 11H), 3.68 (t, J=6.8 Hz, 1H), 2.68 (t, J=6.8 Hz, 1H), 2.32 (s, 6H). See also Wu, X. L. et al. (2014) J Fluoresc 24, 775-786, doi:10.1007/s10895-014-1351-x.
Compound 20 (24 mg) was stirred with NHS (5.6 mg, 1.2 equiv) and EDAC (7.8 mg, 1.2 equiv) in DCM (2 mL) at room temperature for 4 h followed by the removal of the solvent in vacuo. The residue was resuspended in saturated brine (2 mL) and partitioned with ethyl acetate (EtOAc) (4 mL×3). The combined organic layers were dried down in vacuo to yield the crude diacetyl-5-(2-carboxyethylaminocarbonyl) Oregon Green 488 succinimidyl ester which was directly mixed with 14 (11 mg) in a DCM (2 mL)/pyridine (2 mL) solution. The reactant mixture was further stirred at 40° C. for 24 h. The solvents were removed in vacuo and the residue was purified by semi-preparative HPLC using a Kinetex 5 μm F5 column (isocratic, 50% MeCN in 0.1% formic acid) to yield compound 21 (2.6 mg).
Ac-OG-beta-ala-tacca (21): light yellow solid; 1H NMR data, see Table ii; 13C NMR (125 MHz, methanol-d4) (some carbons were not detectable due to limited amount of material): δ 177.4, 175.3, 172.3, 171.6, 171.5, 169.4, 169.3, 168.1, 155.9, 153.1, 151.2, 148.4, 141.8, 138.5, 136.0, 127.5, 125.5, 125.4, 117.3, 117.2, 115.5, 115.4, 114.2, 83.9, 80.3, 75.6, 75.3, 73.6, 72.6, 72.5, 58.1, 54.1, 54.0, 51.9, 51.4, 49.2, 45.7, 42.1, 38.3, 38.1, 36.8, 36.4, 34.4, 32.2, 27.1, 25.4, 22.1, 21.5, 21.0, 20.7, 20.6, 20.2, 13.7, 13.5; HRESIMS (m/z): [M+Na]+ calcd. for C62H64F2N2NaO21, 1233.3862; found 1233.3859.
Compound 21 (2.6 mg) was dissolved in 0.3 mL DCM and pre-chilled to −20° C. prior to the addition of 0.3 mL DMDO-acetone solution. The epoxidation reagent dimethyldioxirane (DMDO) was prepared as previous described5. The mixture was incubated at −20° C. for 4 h and then blown down by N2. The residue was purified by semi-preparative HPLC using a Kinetex 5 μm F5 column (isocratic, 50% MeCN) to yield compound 4 (1.6 mg).
Flu-tacca-2 (4): light yellow solid; 1H NMR data, see Table ii; HRESIMS (m/z): [M+Na]+ calcd. for C62H64F2N2NaO22, 1249.3811; found 1249.3814.
5-Carboxyfluorescein diacetate (17) (28 mg) was stirred with NHS (8.3 mg, 1.2 equiv) and EDAC (14 mg, 1.2 equiv) in DCM (2 mL) at room temperature for 3 h and then beta-alanine (54 mg, 10 equiv) and pyridine (2 mL) were added into the mixture which was further stirred at 40° C. overnight. The solvents were removed in vacuo and the residue was purified by preparative HPLC using a Luna 5 μm C18 column (isocratic, 50% MeCN in 0.1% formic acid) to yield diacetyl-5-(2-carboxyethylaminocarbonyl) fluorescein (22) (20 mg).
Diacetyl-5-(2-carboxyethylaminocarbonyl) fluorescein (22): light yellow powder; 1H NMR (400 MHz, methanol-d4): δ 8.43 (d, J=1.6 Hz, 1H), 8.17 (dd, J=8.0, 1.6 Hz, 1H), 7.30 (d, J=8.0 Hz, 1H), 7.16 (s, 2H), 6.86 (m, 4H), 3.67 (t, J=6.8 Hz, 1H), 2.67 (t, J=6.8 Hz, 1H), 2.27 (s, 6H); 13C NMR (100 MHz, methanol-d4): δ 170.5, 170.0, 168.2, 156.6, 154.0, 152.8, 138.2, 135.9, 130.0, 127.7, 125.5, 125.1, 119.4, 117.1, 111.6, 83.3, 37.3, 20.9. See also Wu, X. L. et al. (2014) J Fluoresc 24, 775-786, doi:10.1007/s10895-014-1351-x.
Compound 22 (20 mg) was stirred with NHS (5.2 mg, 1.2 equiv) and EDAC (8.7 mg, 1.2 equiv) in DCM (2 mL) at room temperature for 4 h followed by the removal of the solvent in vacuo. The residue was resuspended in saturated brine (2 mL) and partitioned with EtOAc (4 mL×3). The combined organic layers were dried down in vacuo to yield the crude diacetyl-5-(2-carboxyethylaminocarbonyl) fluorescein succinimidyl ester (24 mg) which was directly mixed with 14 (9 mg) in a DCM (2 mL)/pyridine (2 mL) solution. The reactant mixture was further stirred at 40° C. overnight. The solvents were removed in vacuo and the residue was purified by semi-preparative HPLC using a Kinetex 5 μm F5 column (isocratic, 45% MeCN in 0.1% formic acid) to yield compound 23 (5.0 mg).
Ac-fluor-beta-ala-tacca (23): light yellow solid; 1H NMR data, see Table iii; 13C NMR (125 MHz, methanol-d4): δ 177.3, 175.3, 172.3, 171.6, 171.5, 170.5, 170.4, 169.9, 168.0, 156.0, 155.9, 154.1, 152.8, 138.0, 135.9, 129.9, 129.8, 127.7, 125.6, 125.1, 119.5, 119.4, 117.0, 112.1, 111.8, 111.7, 83.3, 80.3, 75.6, 75.4, 73.6, 72.6, 72.5, 58.1, 54.1, 54.0, 51.9, 51.4, 49.3, 45.7, 42.1, 38.3, 38.1, 36.8, 36.4, 34.4, 32.2, 27.1, 25.4, 22.1, 21.5, 21.0, 20.9, 20.7, 20.6, 13.7, 13.5; HRESIMS (m/z): [M+Na]1 calcd. for C62H66N2NaO21, 1197.4050; found 1197.4055.
Compound 23 (5.0 mg) was epoxidized in 1 mL DMDO-acetone/DCM (1:1) solution as previously described. The product was purified by semi-preparative HPLC using a Kinetex 5 μm F5 column (isocratic, 45% MeCN) to yield compound 5 (4.2 mg).
Flu-tacca-3 (5): light yellow solid; 1H NMR data, see Table viii; HRESIMS (m/z): [M+Na]+ calcd. for C62H66N2NaO22, 1213.3999; found 1213.4006.
Compound 23 (11 mg) was dissolved in 3 mL MeOH/H2O (2:1) followed by the addition of 50 μL ammonia hydroxide (NH3.H2O). The mixture was stirred at room temperature for 1 h and then the solvents were removed in vacuo. The residue was purified by preparative HPLC using a Kinetex 5 μm F5 column (isocratic, 40% MeCN in 0.1% TFA) to yield compound 24 (9.5 mg).
Fluor-beta-ala-tacca (24): yellow solid; 1H NMR data, see Table iv; HRESIMS (m/z): [M+Na]+ calcd. for C58H62N2NaO19, 1113.3839; found 1113.3830.
Compound 24 (6.0 mg) was epoxidized in 1 mL DMDO-acetone/DCM (1:1) solution as previously described. The product was purified by preparative HPLC using a Kinetex 5 μm F5 column (isocratic, 45% MeCN in 0.1% TFA) to yield compound 6 (5.2 mg).
Flu-tacca-4 (6): yellow solid; 1H NMR data, see Table iv; HRESIMS (m/z): [M+Na]4 calcd. for C58H62N2NaO20, 1129.3788; found 1129.3799.
5-Carboxyfluorescein dipivalate (16) (33 mg) was stirred with NHS (8.3 mg, 1.2 equiv) and EDAC (14 mg, 1.2 equiv) in DCM (2 mL) at room temperature for 3 h and then beta-alanine (54 mg, 10 equiv) and pyridine (2 mL) were added into the mixture which was further stirred at 40° C. overnight. The solvents were removed in vacuo and the residue was purified by preparative HPLC using a Luna 5 μm C18 column (isocratic, 85% MeCN in 0.1% formic acid) to yield dipivalyl-5-(2-carboxyethylaminocarbonyl) fluorescein (25) (27 mg).
Dipivalyl-5-(2-carboxyethylaminocarbonyl) fluorescein (25): white powder; 1H NMR (400 MHz, methanol-d4): δ 8.44 (d, J=1.6 Hz, 1H), 8.17 (dd, J=8.0, 1.6 Hz, 1H), 7.30 (d, J=8.0 Hz, 1H), 7.13 (d, J=2.1 Hz, 2H), 6.86 (d, J=8.7 Hz, 2H), 6.86 (d, J=8.7 Hz, 2H), 6.83 (dd, J=8.7, 2.1 Hz, 2H), 3.67 (t, J=6.8 Hz, 1H), 2.67 (t, J=6.8 Hz, 1H), 1.34 (s, 18H); 13C NMR (100 MHz, methanol-d4): δ 177.9, 169.9, 168.1, 156.6, 154.3, 152.8, 138.1, 135.9, 130.1, 127.8, 125.5, 125.1, 119.3, 117.1, 111.5, 83.3, 40.2, 37.3, 27.4. See also Wu, X. L. et al. (2014) J Fluoresc 24, 775-786, doi:10.1007/s10895-014-1351-x.
Compound 25 (27 mg) was stirred with NHS (6.0 mg, 1.2 equiv) and EDAC (10 mg, 1.2 equiv) in DCM (2 mL) at room temperature for 4 h followed by the removal of the solvent in vacuo. The residue was resuspended in saturated brine (2 mL) and partitioned with EtOAc (4 mL×3). The combined organic layers were dried down in vacuo to yield the crude dipivalyl-5-(2-carboxyethylaminocarbonyl) fluorescein succinimidyl ester which was directly mixed with 14 (11 mg) in a DCM (2 mL)/pyridine (2 mL) solution. The reactant mixture was further stirred at 40° C. overnight. The solvents were removed in vacuo and the residue was purified by semi-preparative HPLC using a Kinetex 5 μm F5 column (isocratic, 55% MeCN in 0.1% formic acid) to yield compound 7 (6.8 mg).
Piv-fluor-beta-ala-tacca (7): white solid; 1H NMR data, see Table v; 13C NMR (125 MHz, methanol-d4): δ 177.9 (2C), 177.3, 175.3, 172.4, 171.5, 171.4, 169.9, 167.9, 156.9, 155.9, 154.4, 152.8, 138.0, 135.9, 130.0, 129.9, 127.8, 125.7, 125.0, 119.4, 119.3, 117.0, 116.9, 112.1, 111.7, 111.6, 83.4, 80.3, 75.6, 75.4, 73.6, 72.6, 72.5, 58.1, 54.1, 54.0, 51.9, 51.3, 49.3, 45.7, 42.1, 40.2, 38.3, 38.1, 36.8, 36.4, 34.4, 32.2, 27.4, 27.1, 25.4, 22.1, 21.6, 21.0, 20.7, 20.6, 13.8, 13.6; HRESIMS (m/z): [M+Na]+ calcd. for C68H78N2NaO21, 1281.4989; found 1281.5015.
Compound 7 (6.0 mg) was epoxidized in 1 mL DMDO-acetone/DCM (1:1) solution as previously described. The product was purified by semi-preparative HPLC using a Kinetex 5 μm F5 column (isocratic, 65% MeCN) to yield compound 8 (5.8 mg).
Flu-tacca-5 (8): light yellow solid; 1H NMR data, see Table v; HRESIMS (m/z): [M+Na]+ calcd. for C68H78N2NaO22, 1297.4938; found 1297.4880.
Compound 14 (10 mg) was stirred with Fmoc-Gly-OH (6.7 mg, 1.5 equiv), NHS (2.7 mg, 1.5 equiv) and EDAC (4.3 mg, 1.5 equiv) in 2 mL DCM/pyridine (1:1) at room temperature overnight followed by the removal of the solvents in vacuo. The residue was re-dissolved in MeCN and purified by semi-preparative HPLC using a Kinetex 5 μm F5 column (isocratic, 50% acetonitrile in 0.1% formic acid) to yield compound 26 (4.5 mg).
Fmoc-Gly-tacca (26): white solid; 1H NMR (500 MHz, methanol-d4): δ 7.79 (d, J=7.4 Hz, 2H), 7.65 (d, J=7.4 Hz, 2H), 7.39 (t, J=7.4 Hz, 2H), 7.32 (d, J=7.4 Hz, 2H), 5.27 (dd, J=11.8, 2.8 Hz, 1H), 5.23 (d, J=2.8 Hz, 1H), 4.63 (d, J=5.6 Hz, 1H), 4.40 (m, 2H), 4.32 (m, 1H), 4.27 (m, 1H), 4.24 (d, J=6.7 Hz, 1H), 3.83 (m, 2H), 3.63 (dd, J=10.1, 4.4 Hz, 1H), 3.35 (m, 1H), 3.25 (m, 1H), 2.42 (dd, J=13.4, 10.4 Hz, 1H), 2.25 (t, J=10.9 Hz, 1H), 2.19 (m, 1H), 2.09 (s, 3H), 2.07 (s, 3H), 1.99 (m, 1H), 1.96 (m, 1H), 1.95 (m, 1H), 1.91 (s, 3H), 1.81 (dd, J=13.4, 9.6 Hz, 1H), 1.61 (s, 3H), 1.24 (s, 3H), 0.98 (s, 3H), 0.90 (s, 3H), 0.88 (d, J=6.4 Hz, 3H); 13C NMR (125 MHz, methanol-d4): δ 177.3, 173.6, 171.6, 171.5, 159.4, 155.9, 145.2, 145.1, 142.6, 128.9, 128.3, 128.2, 126.2, 126.1, 121.0, 112.0, 80.3, 75.7, 75.2, 73.7, 72.5, 72.4, 68.3, 57.9, 54.3, 54.1, 51.9, 51.4, 49.3, 48.3, 45.7, 45.2, 42.0, 38.3, 36.5, 34.2, 32.2, 26.9, 25.4, 22.1, 21.5, 21.0, 20.7, 20.6, 14.0, 13.5; HRESIMS (m/z): [M+Na]+ calcd. for C51H60N2NaO15, 963.3886; found 963.3892. See also Lee, et al. (2017) Angew Chem Int Edit 56, 6927-6931, doi:10.1002/anie.201703298.
Compound 26 (10 mg) was stirred with MP-piperazine resin (200 mg) in DCM (1 mL) at 40° C. for 24 h followed by the removal of the solvent in vacuo. The residue was washed with MeOH (2 mL×3) and the combined MeOH wash was dried down in vacuo to yield the crude Gly-tacca which was directly mixed with the crude dipivalyl-5-carboxyfluorescein succinimidyl ester (13 mg) (prepared from 16 using the same method as previously described) in 2 mL DCM/pyridine (1:1). The reactant mixture was further stirred at 40° C. overnight. The solvents were removed in vacuo and the residue was purified by semi-preparative HPLC using a Kinetex 5 μm Biphenyl column (isocratic, 65% MeCN in 0.1% formic acid) to yield compound 27 (3.0 mg).
Piv-fluor-Gly-tacca (27): white solid; 1H NMR data, see Table vi; 13C NMR (125 MHz, methanol-d4) (some carbons were not detectable due to limited amount of material): δ 177.9, 177.3, 172.9, 172.3, 171.6, 171.5, 169.9, 168.8, 157.0, 155.9, 154.4, 152.8, 137.5, 136.0, 130.0, 127.8, 125.7, 125.3, 119.4, 117.0, 112.1, 111.6, 83.4, 80.3, 75.7, 75.3, 73.8, 72.5, 72.4, 57.9, 54.5, 54.1, 51.9, 51.5, 51.3, 49.1, 45.7, 44.8, 42.1, 40.2, 38.4, 36.6, 34.3, 32.2, 27.4, 27.0, 25.4, 22.1, 21.5, 21.0, 20.7, 20.6, 14.1, 13.6; HRESIMS (m/z): [M+Na]+ calcd. for C67H76N2NaO21, 1267.4833; found 1267.4845.
Compound 27 (3.0 mg) was epoxidized in 0.6 mL DMDO-acetone/DCM (1:1) solution as previously described. The product was purified by semi-preparative HPLC using a Kinetex 5 μm F5 column (isocratic, 65% MeCN) to yield compound 9 (1.8 mg).
Flu-tacca-6 (9): light yellow solid; 1H NMR data, see Table vi; HRESIMS (m/z): [M+Na]+ calcd. for C67H76N2NaO22, 1283.4782; found 1283.4718.
Compound 14 (10 mg) was stirred with 16 (13 mg, 1.5 equiv) and HATU (5.5 mg, 1.5 equiv) in 2 mL EtOAc/pyridine (1:1) at 35° C. overnight. The solvents were removed in vacuo and the residue was purified by preparative HPLC using a Kinetex 5 μm F5 column (isocratic, 70% MeCN in 0.1% formic acid) to yield compound 10 (3.8 mg).
Piv-fluor-tacca (10): white solid; 1H NMR data, see Table vii; 13C NMR (125 MHz, acetonitrile-d3) (some carbons were not detectable due to limited amount of material): δ 177.5, 176.6, 171.4, 171.0, 170.7, 169.1, 156.3, 155.6, 154.0, 152.4, 138.2, 136.2, 130.0, 127.1, 125.4, 125.0, 119.3, 116.9, 111.6, 111.5, 82.5, 80.0, 75.0, 74.6, 74.1, 72.2, 72.0, 57.5, 54.7, 53.4, 51.7, 51.0, 51.7, 48.6, 45.3, 41.6, 39.8, 38.0, 36.5, 33.8, 31.9, 27.3, 26.6, 25.4, 22.4, 21.6, 21.1, 20.8, 20.4, 14.4, 13.7; HRESIMS (m/z): [M+Na]+ calcd. for C65H73NNaO20, 1210.4618; found 1210.4676.
Compound 10 (3.0 mg) was epoxidized in 0.6 mL DMDO-acetone/DCM (1:1) solution as previously described. The product was purified by semi-preparative HPLC using a Kinetex 5 μm F5 column (isocratic, 70% MeCN) to yield compound 11 (1.4 mg).
Flu-tacca-7 (11): light yellow solid; 1H NMR data, see Table vii; HRESIMS (m/z): [M+Na]t calcd. for C65H73NNaO21, 1226.4567; found 1226.4578.
Compound 14 (9.5 mg) was stirred with 17 (9.9 mg, 1.5 equiv) and HATU (8.2 mg, 1.5 equiv) in 2 mL EtOAc/pyridine (1:1) at 35° C. overnight. The solvents were removed in vacuo to yield the crude Ac-fluor-tacca which was re-dissolved in 3 mL MeOH/H2O (2:1) followed by the addition of 50 μL ammonia hydroxide (NH3.H2O). The mixture was stirred at room temperature for 1 h and then the solvents were removed in vacuo. The residue was purified by preparative HPLC using a Kinetex 5 μm F5 column (isocratic, 45% MeCN in 0.1% TFA) to yield compound 28 (7.1 mg).
Fluor-tacca (28): yellow solid; 1H NMR data, see Table viii; HRESIMS (m/z): [M+Na]+ calcd. for C55H57NNaO19, 1042.3468; found 1042.3427.
Compound 28 (7.0 mg) was epoxidized in 1 mL DMDO-acetone/DCM (1:1) solution as previously described. The product was purified by preparative HPLC using a Kinetex 5 μm F5 column (isocratic, 50% MeCN in 0.1% TFA) to yield compound 12 (6.2 mg).
Flu-tacca-8 (12): yellow solid; 1H NMR data, see Table viii; HRESIMS (m/z): [M+Na]+ calcd. for C55H57NNaO18, 1058.3417; found 1058.34176.
Both 1D (1H and 13C) and 2D (1H-1H COSY, HSQC, and HMBC) NMR data were collected for key new compounds to confirm their structures and assign the 1H NMR data (Tables i-viii). In case of new compounds with sensitive structural features (i.e., 22,23-epoxide) and/or low quantities (<2 mg), time-consuming 13C NMR data were not collected to avoid potential structural decompositions under the NMR conditions. Instead, besides 1H NMR data, the fast 2D NMR data (1H-1H COSY and HSQC) were also collected to confirm their structures and unambiguously assign their 1H NMR data (Table ii-viii). TD and 2D NMR spectra for all synthetic compounds were attached as references and evidence of compound purity (95% or better). HRFSIMS data were collected and listed for key new compounds to confirm their identity
Exemplary results of the fluorescence assays are illustrated in
Exemplary results of the 51818 tubulin polymerization assay are illustrated in
The computational modeling experiments were conducted using the Schrödinger Small-Molecule Drug Discovery Suite (2018-4). The crystal structure 5EZY was downloaded from PDB and optimized using the Protein Preparation Wizard following the standard protocol (Sastry, et al. (2013) J. Comput. Aid. Mol. Des. 27, 221-234). Briefly, the structure was first preprocessed by assigning bond orders, adding hydrogen atoms, creating zero-bond orders to metals, and creating disulfide bonds between two sulfur atoms within 3.2 Å from each other. Prime was used to predict and fill in the missing side chains. Water molecules beyond 5 Å from het groups were removed. To further optimize the model, the H-bond assignment was optimized by sampling water orientations and using PROPKA to assign protonation states of side chains at pH 7.0. All Asp, Glu, Arg, and Lys residues were left in their charged state and the proper His tautomer was also manually selected to maximize hydrogen bonding. Next, a brief relaxation was performed on the structure. This is a two-part procedure that consists of optimizing hydroxyl and thiol torsions in the first stage followed by an all-atom constrained minimization in the second stage to relieve clashes. The minimization was terminated when the RMSD reached a maximum value of 0.30 Å. The optimized protein structure was simplified by only retaining chain B comprising the taccalonolide AJ-β-tubulin complex and removing the other 5 chains. All water molecules were removed except for the one that formed H-bonds between β-tubulin T223 and the 26-carbonyl group of taccalonolide AJ.
The ligand structures were optimized using the Ligand Preparation Wizard (LigPrep) (Sastry, et al. (2013) J. Comput. Aid. Mol. Des. 27, 221-234). Briefly, energy minimization of the ligands was conducted using the OPLS3 force field. The ionization states were generated at pH 7.0 using Epik and the dominating tautomer of each ligand was retained for docking experiments.
Further covalent docking experiments were performed using CovDock (Zhu, K. et al. (2014) J. Chem. Inf. Model. 54, 1932-1940). In the CovDock wizard, D226 was selected as the reactive residue. The docking box was centered on the coordinates X 3.2/Y −63.5/Z 22.6 in the length of 20 Å. The covalent reaction was defined as an epoxide opening reaction that was constrained to take place only on C-22 of the ligands. The “thorough” docking mode was used for the optimization of poses. The cutoff of 2.5 kcal/mol was applied for retaining poses for further optimization in each cycle. The top 10 low-energy poses were generated and retained for each docking experiment. All the 10 docking models were visually checked for the binding interactions of the taccalonolide core structure to filter out the inappropriate binding models with the taccalonolide core structures that were significantly rotated or positioned outside the binding pocket. The lowest-energy pose showing correct spatial arrangement of the taccalonolide core structure was selected for analysis of the ligand-protein binding modes.
HCC1806 (CRL-2335) and HCC1937 (CRL-2336) human triple-negative breast cancer cells, HeLa (CCL-2) cervical cancer cells and SK-OV-3 (HTB-77) ovarian cancer cells were obtained from ATCC (Manassas, Va.) and validated by STR profiling (Genetica). SK-OV-3 cells stably overexpressing Pgp by adenoviral-mediated expression of MDR1 were obtained from Dr. Susan Kane and subcloned by limiting dilution to isolate the single-cell clones utilized in these studies as SK-OV-3-MDR-1-6/6 (Risinger, A. L. et al. (2008) Cancer Res. 68, 8881-8888). A single-cell clone from transfection of HeLa cells with βIII-tubulin, designated wild type βIII, was constructed and obtained from Dr. Richard Luduena (Risinger, A. L. et al. (2008) Cancer Res. 68, 8881-8888). HCC1806 and HCC1937 cells were cultured in RPMI 1640 media (Corning) with 10% FBS (Cellgro) and 50 μg/mL gentamicin (Gibco). HeLa, Q111-tubulin expressing HeLa, SK-OV-3 and SK-OV-3/MDR-1-6/6 cells were grown in BME media with Earle's salts (Gibco) with 10% FBS, 1× final 1% GlutaMax™ Supplement (Gibco), and 50 sg/mL gentamicin. The use of HeLa cells allows for the direct comparison of the in vitro potency as compared to other compounds of this class, which have been predominantly reported in this line and compound potencies are consistent among three additional cancer cell lines. HeLa cells were also used for ectopic expression of tubulin mutants due to the high degree of transfectability of this cell line. Cells were tested for mycoplasma contamination using the Mycoplasma Detection Kit-Quick Test (Cat: B39032, Lot: JW004).
The sulforhodamine B (SRB) assay was utilized to examine the antiproliferative and cytotoxic effects of the compounds (Skehan, P. et al. (1990) J. Natl. Cancer Inst. 82, 1107-1112; Vichai and Kirtikara (2006) Nat. Protoc. 1, 1112-1116). Approximately 2,000 cells per well (for SK-OV-3, HeLa and βIII-tubulin expressing HeLa) or 4,000 cells per well (for HCC1806 and HCC1937) were seeded in 96-well plates. For each biological replicate, cells were treated in triplicate with each concentration of compound or vehicle control for 48 h in a final volume of 200 μL. The plates were fixed with 10% trichloroacetic acid for protein precipitation of adherent cells and then washed with distilled water. 100 μL of SRB dye, which binds protein stoichiometrically, was added and then unbound dye removed with 1% acetic acid followed by the addition of 200 μL 10 mM Tris to solubilize the dye, which was quantified by absorbance at 560 nm. The percent growth of treated cells relative to the density at the time of drug addiction was calculated as compared to vehicle treated cells. Concentration-response curves were generated by non-linear regression analysis using Prism software 7.04 (GraphPad) and the GI50 of each compound was calculated and defined as the concentration that caused a 50% decrease in cellular proliferation in the 48 h of drug incubation in comparison to vehicle control from 3 independent experiments.
HCC1937, SK-OV-3, and SK-OV-3/MDR-1-6/6 cells were plated in PerkinElmer cell carrier imaging 96-well plates at a density of 8,000-10,000 cells/well. HeLa and HeLa 111-tubulin overexpressing human cervical cancer cells were plated in PerkinElmer cell carrier imaging 96-well plates at a density of 4,000 cells/well. Cells were treated with vehicle control or compounds at the indicated final concentration for each individual experiment. Tubulin Tracker Green and siR-Tubulin stock solutions were prepared in anhydrous DMSO (Sigma Aldrich) at concentrations of 2 mM or 1 mM, respectively. Pluronic® F-127 (Invitrogen) was added at a 1:1 ratio from a 20% (w/v) DMSO stock solution where indicated. For live cell imaging, cells were imaged 5 h after treatment with compound and then washed with fresh media or Hank's Balanced Salt Solution (HBSS) (Sigma-Aldrich) supplemented with 2 mM CaCl2 and 0.8 mM MgSO4 and imaged on the Operetta high content imager using Harmony software (PerkinElmer). HeLa and HeLa βIII-tubulin overexpressing human cervical cancer cells were treated with vehicle (ethanol), 0.5 μM or 5 μM of probes respectively for 5 h treatment in HBSS. Wells were washed prior to fixing with methanol. Images were taken with the Operetta at 20×. For co-localization experiments, cells were fixed with methanol after treatment and subjected to immunofluorescence for β-tubulin at 1:1000 (Sigma T-4026) with goat anti-mouse IgG (H+L) cross-absorbed secondary antibody, Texas Red-X at 1:200 (Invitrogen T-862), while the fluorescein-tagged taccalonolide was directly detected. Probe treated SK-OV-3 cells were imaged in medium prior to wash or in PBS after washing or chilling at −20° C. for 20 min and fixed with methanol. For confocal imaging, HCC1937 cells were treated with 0.05-5 μM taccalonolide probes for 6-24 h on glass coverslips in a 6-well plate and fixed with methanol prior to β-tubulin immunofluorescence at 1:1000 (Sigma T-4026) using goat anti-mouse IgG (H+L) cross-absorbed secondary antibody, Texas Red-X at 1:200 (Invitrogen T-862). Confocal images were acquired using a SP8 Leica DMi8 microscope using a 63× oil objective. All images are representative of the phenotypes observed from examining multiple fields from at least 2 independent experiments.
Biochemical tubulin polymerization assays were performed using purified porcine brain tubulin (Cytoskeleton). In individual wells of a 96-well plate, 1 μL of each 100× drug stock was incubated with 20 μM porcine brain tubulin in GPEM glycerol buffer (1 mM GTP, 10% glycerol, 80 mM PIPES pH 6.9, 2 mM MgCl2 and 0.5 mM EGTA) in a final volume of 100 μL. Pure porcine tubulin was prepared on ice at 4° C. to inhibit tubulin polymerization until the assay was initiated, while the plate reader was pre-warmed to 37° C. Tubulin polymerization was measured every minute for an hour by light scattering at 340 nm in a Spectramax plate reader using SoftMax software (Molecular Devices). Light scattering was normalized to the initial measurement for each well. For the probe-tubulin binding assay, samples were prepared on ice in tubes instead of a 96 well plate, and moved to a 37° C. heat block to initiate binding and polymerization. The time zero (0′) sample consisted of tubulin polymerization buffer prior to addition of taccalonolide probe. At each designated time point, 2 μL of the sample was added to 50 ML NuPAGE sample buffer with 20% Q-Mercaptoethanol and 10% of the resulting sample was subjected to PAGE and immunoblotted for β-tubulin at 1:1000 (abeam, ab6046) or fluorescein at 1:500 (abeam, ab19491) with IRDye 680 or 800 goat anti-rabbit secondary antibodies at 1:10,000 (LI-COR Biosciences) and imaged on an Odyssey FC (LI-COR Biosciences).
The QuikChange II XL Site-Directed Mutagenesis Kit (Agilent Technologies) was used according to the manufacturer's directions with any changes noted. The template for mutagenesis was the human TUBB1 ORF mammalian expression plasmid, C-GFPSpark tag from Sino Biological Inc. (HGI 1626-ACG) using the primers listed in Table 1. After Dpn I digestion, amplification products were stored at 4° C. until transformation into DH10B or XL10-Gold competent cells. DNA constructs were isolated using the QIAGEN Plasmid Midi Kit and Thermo Scientific GeneJet Plasmid Mini Kit. DNA concentrations were measured using a NanoDrop 2000 (Thermo Fisher Scientific). All constructs were sequenced using GENEWIZ and sequences verified using SnapGene.
For cellular binding studies, HeLa cells were seeded to 80-90% confluence in 6-well dishes and transiently transfected with the wild type or mutant tubulin constructs using Lipofectamine 3000 Transfection Reagent (Thermo Fisher Scientific) for 16-18 h. Media with the lipofectamine reagent were removed from the wells and replaced with fresh BME media for approximately 24 h prior to drug treatment. Cells were treated with 1 μM 11, 1 μM taccalonolide AJ or EtOH vehicle for 1-8 h, respectively. Cells were collected by scraping with a cell lifter and lysed with cell extraction buffer (Invitrogen) supplemented with protease inhibitor cocktail (Sigma-Aldrich), 50 mM NaF, 200 μM Na3VO4 (Sigma-Aldrich), and 1 mM phenylmethylsulfonyl fluoride (PMSF) (Sigma-Aldrich). Protein concentration was determined by a Coomassie Plus assay kit (Thermo Scientific), equal amounts of protein resolved by SDS-PAGE on NuPage Bolt 10% Bis-Tris gels (Life Technologies), and transferred to Immobilion-FL PVDF membranes (Millipore). Membranes were blocked in Odyssey blocking buffer (LI-COR Biosciences, Lincoln, Nebr., USA) and probed with anti-fluorescein at 1:500 (abcam, ab19491) or β-tubulin 1:1000 (abcam, ab6046) with IRDye 680 or 800 goat anti-rabbit secondary antibodies at 1:10,000 (LI-COR Biosciences, T8660) and imaged on an Odyssey FC (LI-COR Biosciences). βIII-tubulin was detected using a monoclonal antibody produced in mouse (1:400) (Sigma-Aldrich) clone SDL.3D10, ascites fluid.
Revert total protein staining was utilized to demonstrate relative equal total protein for each lysate (LI-COR Biosciences). The relative binding ratio of mutants was calculated as: (fluorescein signalmutant/tubulin signalmutant)/(fluorescein signalwildtype/tubulinwildtype) and expressed as percent of the wildtype signal for each independent experiment. For imaging studies, wild type or mutant TUBB1-GFP constructs were transfected into HeLa cells (40,000 cells/well in a 96-well plate) using Lipofectamine 3000 for 16-18 h prior to washing and replacing with fresh media. After 7 h recovery, cells were imaged before and after treatment with vehicle or 100 nM taccalonolide AJ for 22 h using the Operetta. Uncropped blots can be found in the source data file.
HCC1937 cells were grown to 90% confluence then treated with vehicle (ethanol), or 1 μM 10 for 8 h in a total volume of 5 mL. The media was harvested while the cell pellet was lysed by dounce homogenization in a hypotonic buffer (1 mM EGTA and 1 mM MgSO4, pH7) after 2 washes with 1×PBS. The cell lysates were extracted by ethyl acetate. The organic layers were dried down and re-dissolved in MeOH for LCMS analysis.
RNA was isolated from SK-OV-3 and SK-OV-3/MDR-1-6/6 ovarian cancer cells by Trizol and chloroform extraction. The RNA pellet was resuspended in nuclease-free water and quantified using a Nanodrop 2000. RNA was converted to cDNA with iScript Reverse Transcription Supermix for RT-qPCR (Bio-Rad) and qRT-PCR was completed using iTaq Universal SYBr Green Supermix (Bio-Rad). Human Pgp primers (Sigma-Aldrich) were generated based on previous reports (He, S. et al. (2010) Int. J. Mol. Sci. 11, 3309-3051) as Pgp1: 5′-AAAGCGACTGAATGTTCAGTGG-3′ (SEQ ID NO:17) and Pgp2: 5′-AATAGATGCCTTTCTGTGCCAG-3′ (SEQ ID NO:18) and specificity was confirmed using NCBI Primer-BLAST. Human GAPDH primers: 5′-GCAAATTCCATGGCACCGT-3′ (SEQ ID NO:19) and 5′-TCGCCCCACTTGATTTTGG-3′ (SEQ ID NO:20). Relative hPgp mRNA transcript levels were evaluated and presented from two biologically independent experiments, each performed in duplicate.
For binding studies, a one-way ANOVA with Tukey's multiple comparison post-hoc test and adjustment for multiple comparisons were used to determine statistical significance between each condition and significance of mutants as compared to wild type depicted in the figure. Exact n values and P values are in Table 2. For qRT-PCR comparing human Pgp (hPgp) expression in SK-OV-3 and SK-OV-3/MDR-1-6/6 cell lines a one-tailed t-test was performed to give a P value of 0.0307.
Referring to Table 2, multiply adjusted P values for the binding of 11 to ectopically expressed mutant tubulin (
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While strategies for generating an optimal taccalonolide-based chemical probe were being explored, Wang et al. reported the crystal structure (PDB ID: 5EZY) of tubulin complexed with taccalonolide AJ (2) (
Referring to
The strategy to functionally characterize taccalonolide-tubulin binding using fluorescent taccalonolide probes is based on the well-established activity-based protein profiling (ABPP) approach (Bottcher, et al. (2010) Angew. Chem. Int. Edit. 49, 2680-2698), which facilitates determination of drug-target interactions in a cellular context and is particularly suited to compounds that covalently bind their targets. Initial attempts to generate a stable taccalonolide probe by modification of taccalonolide C-6 led to the synthesis of Flu-tacca-1 (3) (
2100 ± 20026
adata from 4 independent experiments
Referring to Table 3, concentrations (nM) of taccalonolide probes that cause a 50% decrease in the proliferation (GI50) of HeLa or SK-OV-3 cells are shown. GI50 values were obtained from three independent experiments (unless otherwise noted) each performed in triplicate and presented as mean±SEM.
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The synthesis of the amide-based probes, Flu-tacca-2 (4) and Flu-tacca-3 (5), was inspired by the structure of the commercial taxane-based probe, Tubulin Tracker Green (Thermo Fisher Scientific, Oregon Green™ 488 Taxol, Bis-Acetate). Specifically, a protected fluorescent moiety (Oregon Green 488 for 4 and fluorescein for 5, diacetyl form) was conjugated with 14 via a β-alanine linker. According to the manufacturer's description (ThermoFisher. www.thermofisher.com/order/catalog/product/T34075?SID=srch-srp-T34075), the diacetyl protection on Oregon Green is intended to quench fluorescence prior to intracellular hydrolysis of the acetyl groups by esterases to decrease background fluorescence of any unincorporated probe. However, the Oregon Green probe 4 was rapidly hydrolyzed even in methanol solutions likely due to the relatively low pKa of the Oregon Green moiety (Oregon Green, pKa 4.8 and fluorescein, pKa 6.5, unprotected form) (Mottram, L. F., et al. (2006) Org. Lett. 8, 581-584) and did not have antiproliferative potency up to the concentration of 20 μM. In contrast, the fluorescein probe 5 showed improved stability in organic solutions but was readily hydrolyzed to yield the deprotected form 6 in a 50% methanol/PBS solution and in the RPMI 1640 medium (
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As efficient separation protocols for the synthetic isomeric mixture 5(6)-carboxyfluorescein (15) (
Inspired by a recent publication showing improved antiproliferative activities can be achieved for taxane-based probes by replacing a β-alanine linker with a shorter glycine linker (Lee, et al. (2017) Angew. Chem. Int. Edit. 56, 6927-6931), two dipivaloyl-protected taccalonolide probes were synthesized, including Flu-tacca-6 (9) utilizing a glycine linker and Flu-tacca-7 (11) featuring direct conjugation of the fluorescein moiety with the taccalonolide skeleton by an amide bond (
Referring to
To determine whether the differences in cellular potency among the taccalonolide probes correlated with target engagement, the potency and efficacy of the unprotected probes 6 and 12 and dipivaloyl-protected probes 8 and 11 was evaluated as compared to 2 in a biochemical tubulin polymerization assay. The untagged taccalonolide AJ (2) promoted the polymerization of purified tubulin (20 μM) in a concentration-dependent manner over a range of 5-20 μM (
Referring to
Covalent docking using CovDock was employed to rationalize the increased potency of the taccalonolide probes 6 and 12 for biochemical tubulin polymerization as compared to the unmodified taccalonolide 2. The top 10 low-energy poses (ligand-receptor binding models) were generated for 6, 8, 11 and 12, respectively, that were docked into the optimized 5EZY structure. The representative lowest-energy pose obtained from each docking experiment was displayed (
The finding that the dipivaloyl-protected fluorogenic probes 11 and 8 are unable to directly interact with and polymerize tubulin or exhibit fluorescence in the medium, but effectively stabilize microtubules and exhibit fluorescence in cellular assays suggests that upon cellular entry these probes are activated via the hydrolysis of the dipivaloyl groups, likely by cellular esterases, (
Referring to
The generation of the potent fluorogenic taccalonolide probe Flu-tacca-7 (11) provides the opportunity to evaluate the covalent binding specificity of the taccalonolides in cell-based assays and fully define the key structural elements of both taccalonolides and β-tubulin that are essential for drug binding. The 22,23-epoxide moiety has been suggested to be critical for the antiproliferative and microtubule stabilizing effects of the taccalonolides (Wang, Y. et al. (2017) Nat. Commun. 8, 15787; Li, J. et al. (2011) J. Am. Chem. Soc. 133, 19064-19067); Peng, J., et al. (2014) J. Med. Chem. 57, 6141-6149). Thus, the antiproliferative activities, cellular localization, and proteome reactivity profiles of Flu-tacca-7 (11) and its 22,23-ene analogue 10 were compared. The single replacement of 22,23-epoxide in 11 by 22,23-ene in 10 completely abrogated the antiproliferative activities in all four human cancer cell lines (i.e., HeLa, SK-OV-3, HCC1806, and HCC1937) up to 20 μM (see Table 3 and
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Inspired by the ability to detect the cellular binding of Flu-tacca-7 (11) to endogenous β-tubulin by immunoblot, a system to evaluate the relative contribution of individual β-tubulin amino acid residues to taccalonolide binding was engineered by performing site-directed mutagenesis on an ectopically expressed β-tubulin construct tagged with GFP at the C-terminus to distinguish it by size on an immunoblot. In order to test the feasibility of this approach, the D226 residue of β-tubulin was first mutagenized to either an asparagine or alanine (see Table 1). HeLa cells that expressed wild type or mutant GFP-tubulin constructs were treated with the probe 11 at 1 μM for 8 h followed by immunoblotting using anti-β-tubulin and anti-fluorescein antibodies. In the β-tubulin immunoblot, bands were detected for each of the GFP-tagged form of β-tubulin (wild type, D226N, or D226A) at 77 kDa that were distinct from endogenous β-tubulin (50 kDa) (
Encouraged by the results of the D226 mutagenesis, additional β-tubulin mutants were constructed in a similar fashion. The analysis of the 5EZY crystal structure (Wang, Y. et al. (2017) AJ. Nat. Commun. 8, 15787) and the covalent docking models of both 2 (
For all of the samples, the probe bound to the endogenous β-tubulin at a similar level (
Referring to
Without wishing to be bound by theory, the analysis above suggests that the structures of the taccalonolide rings E and F and their direct interactions with β-tubulin residues (e.g., K19 and L219) are critical for the correct positioning of the taccalonolide core structure into its binding pocket to facilitate the covalent reaction between D226 and the 22,23-epoxide. It is also reasonable to hypothesize that other β-tubulin residues, including L217, H229, and R278, that interact with the taccalonolides at sites relatively remote from the site of the covalent interaction (
The Flu-tacca probes represent a class of irreversible, fluorogenic microtubule probes that can be utilized for cellular microtubule imaging and binding studies under conditions that have conventionally been unfavorable for the use of non-covalent probes. To demonstrate the utility of these cell-permeable probes for cellular imaging applications, the cellular microtubule staining activities of Flu-tacca-7 (11) were compared to Tubulin Tracker Green (Thermo Fisher Scientific, Oregon Green™ 488 Taxol, Bis-Acetate) and the far-red probe siR-Tubulin (Cytoskeleton), two commercial taxane-based probes commonly used for microtubule imaging in live cells. Tubulin Tracker Green was not amenable to visualization prior to washing excess probe from the media (
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A summary of the activity of representative taccalonolide analogs is shown below.
In sum, stable tacca-conjugates that retain the biological properties of taccalonolides have been prepared. Without wishing to be bound by theory, this linking technology can generate stable tacca-ADC conjugates, which may lead to new tumor-targeted therapeutic methods, especially for taxol-resistant cancers. In addition, the disclosed protocols can be useful in generating new tubulin labeling probes (e.g., fluorescent tags and biotin) that exhibit distinct and superior biological properties compared to the commercial taxol-based probes. As the taxol-based probes bind tubulin non-covalently (i.e., unstable) they often provide inconsistent labeling results, especially for quantificational studies. In contrast, the disclosed tacca-based probes generate permanent (i.e., covalent binding) labeling of tubulin and won't be compromised during sample processing/manipulation and retain efficacy under conditions that limit the use of commercial taxane probes, including cold and in the presence of drug efflux pumps. Thus, the disclosed analogs may be particularly good for quantificational studies.
While three distinct classes of covalent microtubule stabilizing agents (i.e. the taccalonolides, cyclostreptin and dactylolide/zampanolide) have been evaluated for their potential as cancer therapeutics that circumvent taxane associated drug resistance in biochemical and cellular assays32, the taccalonolides are the only class that has demonstrated in vivo efficacy in both drug sensitive and resistant tumor models17,20,21,25. Here we describe the development of a combinatorial chemical proteomics approach that enabled confirmation of the target specificity of taccalonolide binding to β-tubulin in cellular assays and identification of key structural features of both the taccalonolides and β-tubulin that are critical for drug-target binding. Our combinatorial strategy to empirically establish the key taccalonolide binding residues in cell-based assays should be broadly useful for detailed ligand-protein binding studies and structure-based optimization of quite a number of existing drugs and/or drug candidates that covalently modify their targets.
While the immunofluorescence and immunoblotting with the Flu-tacca probes clearly demonstrate that the predominant cellular target of the taccalonolides is indeed a covalent interaction with β-tubulin, we cannot rule out the possibility of other minor covalent or non-covalent targets. One important consideration is the finding that taccalonolides lacking the critical covalent binding moiety, the 22,23-epoxide, show no antiproliferative, cytotoxic, or microtubule bundling activities in cells and do not directly interact with tubulin in biochemical assays. The lack of any detectable target engagement or bioactivity of probes lacking this epoxide in the current study lends further support to this point.
An unanticipated finding from the generation of the Flu-tacca probes in this study is the identification of a strategy to improve the binding affinity and microtubule stabilizing potency of the taccalonolides by targeting a binding pocket nearby the taccalonolide binding site that engages the M-loop of β-tubulin, which is integral in pharmacological microtubule stabilization18,35. These findings provide an opportunity to develop additional ‘drug-like’ taccalonolide analogues with sub-nanomolar cellular potency, which is desired for targeted drug delivery strategies (i.e. peptide- and antibody-drug conjugates) and paves the way for further development of the taccalonolides as microtubule stabilizers for cancer therapy. A further evaluation of the critical taccalonolide moieties and β-tubulin residues that mediate binding and biological activity will continue to provide mechanistic insight to optimize our models of taccalonolide binding and design more optimal semi-synthetic and possibly fully-synthetic taccalonolide-like compounds that could have efficacy in drug resistant models due to their irreversible target binding. Additionally, the fluorogenic taccalonolide-based probes represent highly specific, irreversible tubulin-labeling probes that have superior utilities as compared to commercial taxane-based probes.
It will be apparent to those skilled in the art that various modifications and variations can be made in the present invention without departing from the scope or spirit of the invention. Other aspects of the invention will be apparent to those skilled in the art from consideration of the specification and practice of the invention disclosed herein. It is intended that the specification and examples be considered as exemplary only, with a true scope and spirit of the invention being indicated by the following claims.
This application claims the benefit of U.S. Application No. 62/815,833, filed on Mar. 8, 2019, the contents of which are hereby incorporated by reference in their entirety.
This invention was made with government support under grant number 1R01 CA219948 awarded by the National Institutes of Health. The government has certain rights in the invention.
| Filing Document | Filing Date | Country | Kind |
|---|---|---|---|
| PCT/US2020/021522 | 3/6/2020 | WO |
| Number | Date | Country | |
|---|---|---|---|
| 62815833 | Mar 2019 | US |
