Rapamycin analogs and uses thereof

Abstract

To provide compounds and methods useful for treating mTORC-mediated disorders.SOLUTION: The present invention provides novel rapamycin analogs that are potent mTORC1 inhibitors as measured by pS6K. Unlike rapamycin and everolimus, these compounds do not inhibit pAKT at relatively long time points (for example, 24 hours and 48 hours). These compounds also exhibit improved solubility and improved pharmacokinetics compared to rapamycin.SELECTED DRAWING: None

Description

[Technical Field]

[0001] The present invention relates to compounds and methods useful for modulating mTORC1 activity. The present invention also provides pharmaceutically acceptable compositions comprising the compounds of the present invention, and Methods of using such compositions in the treatment of various disorders are provided. [Background technology]

[0002] mTOR complex 1 (mTORC1) regulates the biosynthesis of proteins, lipids, and organelles. by promoting many anabolic processes, including ATP, as well as catabolic processes such as autophagy. It positively regulates cell growth and proliferation by restricting the process of mTORC1. Much of our knowledge of its efficacy comes from the use of the bacterial macrolide rapamycin. Upon entering the cell, rapamycin binds to the FK506-binding protein of 12 kDa (FKBP12). It binds to the FKBP12-rapamycin binding domain (FRB) of mTOR. interact with and thus inhibit mTORC1 function (Guertin, DA & Sabatini, DM Cancer Cell 12(1): 9-22 (2007)). In contrast to its action on mTORC1 In general, FKBP12-rapamycin is physically distinct from mTOR complex 2 (mTORC2). It cannot interact with or strongly inhibit (Janinto, E. et al., Nat. Cell Bio., 6(11): 1122-8 (2004);SarbassoV, DD et al., Curr. Biol. 14(14): Based on these observations, mTORC1 and mTORC2 are have been characterized as rapamycin-sensitive and rapamycin-insensitive complexes. However, in some cases, prolonged rapamycin treatment blocks the assembly. This paradigm is completely compatible with the fact that mTORC2 activity can be inhibited by may not be accurate (SarbassoV, DD et al., Mol. Cell, 22(2): 159 -68 (2006)). Furthermore, recent reports have shown that an important function of mTORC1 is the rapamycin It has been proposed that the enzyme is resistant to inhibition by steroids (Choo, AY et al., Proc. Natl. Acad. Sci. 2015;11:111-112). tl. Acad. Sci., 105(45): 17414-9 (2008);Feldman, ME et al., PLoS Bi ol., 7(2):e38 (2009);Garcia-Martinez, JM et al., Biochem J., 421(1): 29-42 (2009);Thoreen, CC et al., J. Biol. Chem., 284(12): 8023-32 (2009)). Therefore, selective inhibition of mTORC1 reduces protein synthesis and It is now possible to treat diseases involving dysregulation of cellular metabolism. This detailed understanding of the regulation of activated pathways allows us to examine the activity of mTORC1 across the spectrum of its functions. The discovery of new strategies to regulate abnormal disease processes by modulating Makes it possible to see.

[0003] Many diseases are associated with abnormal cellular responses triggered by the above events. These diseases include, but are not limited to, autoimmune diseases, inflammatory diseases, bone diseases, Metabolic diseases, neurological and neurodegenerative diseases, cancer, cardiovascular diseases, allergies and asthma, Zheimer's disease and hormone-related disorders.

[0004] The mechanistic target of rapamycin complex 1 (mTORC1) mediates the regulation of growth factors, cell streptococci, and the primary sensor of diverse environmental cues, such as loess, as well as nutrition and energy levels. When activated, mTORC1 regulates various processes, including mRNA translation and lipid synthesis. It phosphorylates substrates that enhance anabolic processes and regulates catabolic processes such as autophagy. Dysregulation of mTORC1 is particularly important in diabetes, epilepsy, neurodegeneration, immune response, and bone This occurs in a variety of diseases, including suppression of skeletal muscle growth and cancer (Howell, JJ et al., Biochem. SOC. Trans., 41: 906-12 (2013);Kim, SG et al., Molecula r and cells, 35(6): 463-73 (2013);Laplante, M. & Sabatini, DM, Cell , 149(2): 274-93 (2012)).

[0005] Rapamycin was originally isolated from soil samples from Easter Island by the strain Streptomyces hydoreductase. It was discovered as an antifungal metabolite produced by Bacillus groscopicus. Rapamycin has been found to have immunosuppressive and antiproliferative properties in mammalian cells. This has sparked interest in identifying the mode of action of rapamycin. It was shown that ATP is a potent inhibitor of the phosphorylation of K1 in yeast and mammalian cells. The target of rapamycin (TOR) was identified in the 12 kDa It forms a gain-of-function complex with the FK506-binding protein (FKBP12) of The mammalian TOR (mTOR, also known as mechanistic TOR) complex 1 (mTORC 1) and specifically acts as its allosteric inhibitor.

[0006] Biochemical and genetic analysis of mTOR reveals that it is involved in two distinct functional pathways: The core components of mTORC1 are mTOR, a mammalian lethal factor. Sexual SEC-13 protein 8 (mammalian lethal with sec- 13 protein8) (mLST8) and TOR regulatory related protein (regulation latory-associated protein of TOR)(Raptor ). A further component is the DEP domain-containing mTOR-interacting protein (DEP -domain-containing mTOR-interacting prot ein) (DEPTOR) and a 40 kDa proline-rich Akt substrate (Prolin e-rich Akt substrate 40 kDa (PRAS40).

[0007] The core of mTOR complex 2 (mTORC2) is composed of mTOR, rapamycin-insensitive mTOR, and R companion (Rictor), stress-activated protein kinase-interacting protein It is composed of mSIN1 (mSIN1) and mLST8. Protein observed with rictor1 / 2 (protor1 / 2) and DEPTOR, S6 kinase 1 (S6K1) and eukaryotic translation initiation factor eIF4 are regulatory components involved in the transcription of mitochondrial endothelial cells. E-binding protein 1 (4E-BP1) binds two well-characterized subunits of mTORC1. AKT is a well-characterized substrate of mTORC2 (Li, J. et al. l., Cell Met., 19(3):373-9 (2014)).

[0008] Because FKBP12-rapamycin does not bind to mTORC2, rapamycin was initially It was thought to inhibit only mTORC1 (Sarbasso V, DD et al., Curr. Biol. , 14(14): 1296-302 (2004)). However, in 2006, rapamycin inhibited mTORC2 It has been shown to inhibit the assembly and function of pAkt and pAkt (Sarbasso V, D. D. et al., Molecular Cell, 22(2): 159-68 (2006)). In multiple cell lines, Akt (a substrate for mTORC2) at S473 and (a substrate for mTORC1) at T389 The effect of rapamycin on phosphorylation was compared in PC3, HEK-293T, and HeL In a and H460 cells, treatment with rapamycin for 1 or 24 h resulted in mT Consistent with the inhibition of ORC1, phosphorylation of S6K1 was inhibited. Selective inhibition of 1 should result in increased phosphorylation of Akt, and indeed, this is the case in HeL However, in PC3 cells, this drug inhibited the phosphorylation of Akt. significantly reduced oxidation, suggesting that rapamycin is not selective in this cell line. In HEK-293T cells, partial inhibition of pAKT is observed. It caused strong or partial inhibition of Akt phosphorylation in approximately one-third of cell lines, whereas it did not cause any significant inhibition in other cell lines. In cellular systems, the drug had no effect on or increased Akt phosphorylation. In primary and non-transformed cell lines, including skin and muscle cells, pAKT inhibition was also observed after 24 hours. Rapamycin has been shown to increase the number of tumors in the thymus, adipose tissue, and other organs in mice treated daily for one week. , and showed decreased Akt phosphorylation in the heart and lung, suggesting that pAKT These findings suggest that rapamycin inhibits Akt phosphorylation. Inhibition of ATP is common and occurs in normal cell lines, cancer cell lines, and in vivo. It was proven that:

[0009] Sarbassov et al. reported that rapamycin and its analogues (CCI779, Everoli) RAD001, AP23573, also known as Mus, is expressed in certain cell lines and tissues. It was concluded that the function of mTORC2 can be inhibited in this context. Mediated inhibition may help explain the side effects of this drug. This indicates that insulin-stimulated Akt activity plays a key role in the suppression of lipolysis in some tissues. In adipose tissue, which is a major target of rapamycin, it strongly inhibits the phosphorylation of Akt. Inhibition of Akt by cin may maintain high lipolysis even in the presence of insulin. This causes an accumulation of free fatty acids in the plasma, which are used by the liver to produce triglycerides. This can lead to the hyperlipidemia commonly seen in patients treated with rapamycin. The molecular mechanism of hypertension is presented.

[0010] Pereira et al. (Mol Cell Endocrinol., 355(1): 96-105 (2012)) Rapamycin inhibits glucose uptake in adipocytes obtained from donor fat biopsies and insulin signaling proteins. At 0.1 μM, rapamycin reduced the phosphorylation of Ser473 of AKT (PKB), Impaired insulin signaling reduces glucose uptake in human adipocytes It was reduced.

[0011] Lamming et al. (Science., 335(6076): 1638-1643 (2012)) reported that rapamycin , disruption of mTORC2 in vivo and insulin-mediated hepatic gluconeogenesis We demonstrated that mTORC2 was required for the inhibition.

[0012] Similar results have been shown in humans. Di Paolo et al. (JASN, 17(8): 2236-2244 (2006)). The main purpose of their research is to The effects of prolonged exposure to rapamycin on the activation of ATP were investigated in relation to the regulation of cell growth and survival, and its important role in cellular responses to nutrients and growth factors. They found that mTOR inhibition reduced basal and insulin-induced AKT activation. AKT is involved in the regulation of insulin metabolism. Because AKT is primarily responsible for many of the effects of vasculitis, decreased activation of AKT may contribute to the progression of vasculitis in kidney transplant recipients. It was concluded that the results were highly correlated with increased thrombus resistance.

[0013] Kennedy et al. recently reported on the role of mTORC1 and mTORC2 in metabolism and aging. The role of this enzyme is discussed (Cell Metab., 23(6): 990-1003 (2016)).

[0014] Surprisingly, the provided compounds were effective over long periods of time (e.g., 8 hours, 24 hours, 30 hours). inhibits mTORC1 for 48 hours (and 48 hours) but does not affect mTORC2 This novel The activity is based on the presence of a sufficiently large group at the C-7 position of rapamycin and its analogs. Small ions at this position, such as OMe, OEt, and OBn, are found in rapamycin. Smaller substituents do not confer selectivity for mTORC2 at 24 hours. Medium-length groups such as OH or OCH2CH2CH2OH increase mTORC activity over 24 hours. It shows partial selectivity over 2, but still exhibits some level of inhibition. Therefore, relatively large groups such as those of the present invention (e.g., I-19) are affected by pAKT. This results in significant selectivity for mTORC2 as measured by

[0015] The location of this substituent is also crucial for the observed selectivity. For example, The introduction of relatively large substituents of the formula (I) provides this unique selectivity profile claimed in this application. does not result in

[0016] For clarity, the structure of rapamycin is shown below with the C-7 and C-43 positions tagged: Reproduce. [ka]

[0017] In some embodiments, the present invention provides a potent mTORC1 inhibitor as measured by pS6K. The present invention provides novel rapamycin analogs which are different from rapamycin and everolimus. These compounds inhibited pAK at longer time points (e.g., 24 and 48 hours). These compounds also have improved solubility and activity compared to rapamycin. The pharmacokinetics are shown above. The activity of the compounds utilized in the present invention as inhibitors of mTORC1 is demonstrated in vitro. Assays may be performed in vivo or in cell lines. In vitro assays The present invention also includes an assay for determining the inhibition of mTORC1. The detailed conditions for assaying compounds utilized in the method are well known to those skilled in the art. A suitable method is described in Liu et al., Cancer Research, 73(8): 2574-86 (2013) and Liu et al. al., J. Biological Chemistry 287(13): 9742-52 (2012). [Prior art documents] [Non-patent literature]

[0018] [Non-Patent Document 1] Guertin, DA & Sabatini, DM Cancer Cell 12(1): 9-22 (2007) [Non-patent document 2] Janinto, E. et al., Nat. Cell Bio., 6(11): 1122-8 (2004) [Non-patent document 3] SarbassoV, DD et al., Curr. Biol. 14(14): 1296-302 (2004) Summary of the Invention [Means for solving the problem]

[0019] The compounds of the present invention and pharmaceutically acceptable compositions thereof are useful as inhibitors of mTORC1. Such compounds have been found to be effective. [ka] or a pharmaceutically acceptable salt thereof, wherein rings A and R 1 is defined and as described.

[0020] The compounds of the present invention and pharmaceutically acceptable compositions thereof are directed to the mTORC1-associated These compounds are useful for treating a variety of diseases, disorders or conditions. Conditions include those described herein. [Brief explanation of the drawings]

[0021] [Figure 1] Figure 1 shows a comparison of two Western blots performed after treating PC3 cells with rapamycin or a compound of the present invention (I-40) for 24 and 48 hours. The staining shows strong inhibition of the mTORC1 pathway for both rapamycin and I-40 at both time points. In contrast, the mTORC2 pathway was inhibited by rapamycin at both 24 and 48 hours, but not by I-40, as demonstrated by the lack of inhibition of Akt phosphorylation.

[0022] [Figure 2] Figure 2 shows a comparison of three Western blots performed after treating PC3 cells with rapamycin or a compound of the invention (I-40) for 30, 15, or 5 minutes. The staining shows a time-dependent inhibition of the mTORC1 pathway for both rapamycin and I-40.

[0023] [Figure 3]Figure 3 shows Western blots performed on PC3 cells after 24 hours of treatment with rapamycin, temsirolimus, everolimus, ridaforolimus, or a compound of the present invention (I-118). Staining shows strong inhibition of the mTORC1 pathway for all compounds, and moderate concentration-dependent inhibition of mTORC1 by I-118. Importantly, rapamycin, temsirolimus, everolimus, and ridaforolimus show dose-dependent inhibition of the mTORC2 pathway, whereas I-118 does not inhibit the mTORC2 pathway, as demonstrated by the lack of inhibition of Akt phosphorylation.

[0024] [Figure 4] Figure 4 shows Western blots performed after treating PC3 cells with rapamycin or compounds of the present invention (I-106, I-113, and I-118) for 24 hours. Staining shows strong inhibition of the mTORC1 pathway for each compound tested, but no inhibition of 4E-BP1 phosphorylation. Importantly, compounds of the present invention do not inhibit mTORC2, as demonstrated by the lack of inhibition of Akt phosphorylation.

[0025] [Figure 5] Figure 5 shows Western blots performed after treating PC3 cells with rapamycin or compounds of the present invention (I-117, I-102, I-103, and I-39) for 24 hours. Staining shows strong inhibition of the mTORC1 pathway for each compound tested, but no inhibition of 4E-BP1 phosphorylation. Importantly, compounds of the present invention do not inhibit mTORC2, as demonstrated by the lack of inhibition of Akt phosphorylation.

[0026] [Figure 6]Figure 6 shows Western blots performed after treating PC3 cells with rapamycin or compounds of the present invention (I-117, I-99, I-100, and I-101) for 24 hours. Staining shows strong inhibition of the mTORC1 pathway for rapamycin, I-117, I-100, and I-101, and discernible concentration-dependent inhibition of the mTORC1 pathway for I-99. Importantly, compounds of the present invention do not inhibit mTORC2, as demonstrated by the lack of inhibition of Akt phosphorylation.

[0027] [Figure 7] Figure 7 shows a Western blot performed after treating PC3 cells with rapamycin or a compound of the present invention (I-117) for 24 hours. The staining shows strong inhibition of the mTORC1 pathway for both compounds tested. Importantly, the compound of the present invention does not inhibit mTORC2, as demonstrated by the lack of inhibition of Akt phosphorylation.

[0028] [Figure 8] Figure 8 shows Western blots performed after treating PC3 cells with rapamycin or compounds of the present invention (I-39, I-101, and I-99) for 24 hours. Staining shows strong inhibition of the mTORC1 pathway for rapamycin and I-39, and discernible concentration-dependent inhibition of the mTORC1 pathway for I-101 and I-99. Importantly, compounds of the present invention do not inhibit mTORC2, as demonstrated by the lack of inhibition of Akt phosphorylation.

[0029] [Figure 9] Figure 9 shows Western blots performed after treating PC3 cells with rapamycin or compounds of the present invention (I-98 and I-97) for 24 hours. Staining shows strong inhibition of the mTORC1 pathway for rapamycin and I-98, and moderate concentration-dependent inhibition of the mTORC1 pathway for I-101 and I-99. Importantly, the compounds of the present invention do not inhibit mTORC2, as demonstrated by the lack of inhibition of Akt phosphorylation.

[0030] [Figure 10] Figure 10 shows Western blots performed after treating PC3 cells with rapamycin or compounds of the present invention (I-96 and I-100) for 24 hours. Staining shows strong inhibition of the mTORC1 pathway for all tested compounds. Importantly, compounds of the present invention do not inhibit mTORC2, as demonstrated by the lack of inhibition of Akt phosphorylation.

[0031] [Figure 11] Figure 11 shows Western blots performed after treating PC3 cells with rapamycin, everolimus, or a compound of the present invention (I-7) for 90 minutes. Staining shows strong inhibition of the mTORC1 pathway for rapamycin and everolimus, and moderate concentration-dependent inhibition of the mTORC1 pathway for I-7. Importantly, the compound of the present invention does not inhibit mTORC2, as demonstrated by the lack of inhibition of Akt phosphorylation.

[0032] [Figure 12] Figure 12 shows Western blots performed after treating PC3 cells with rapamycin, everolimus, or a compound of the present invention (I-7) for 24 hours. Staining shows strong inhibition of the mTORC1 pathway for rapamycin and everolimus, and moderate concentration-dependent inhibition of the mTORC1 pathway for I-7. Importantly, the compound of the present invention does not inhibit mTORC2, as demonstrated by the lack of inhibition of Akt phosphorylation.

[0033] [Figure 13] Figure 13 shows two Western blots performed after treating Jurkat cells with everolimus or compounds of the present invention (I-40 and I-117) for 24 hours. The staining shows strong inhibition of the mTORC1 pathway for all tested compounds. Importantly, the compounds of the present invention do not inhibit mTORC2, as demonstrated by the lack of inhibition of Akt phosphorylation.

[0034] [Figure 14] Figure 14 shows two Western blots performed after treating tuberous sclerosis complex (TSC2)-negative (TSC- / -) MEF cells with everolimus or compounds of the present invention (I-40, I-7, and I-117) for 90 minutes. The staining shows strong inhibition of the mTORC1 pathway for everolimus, I-40, and I-117, as well as noticeable concentration-dependent inhibition of the mTORC1 pathway for I-7. Importantly, the compounds of the present invention do not inhibit mTORC2, as demonstrated by the lack of inhibition of Akt phosphorylation.

[0035] [Figure 15] Figure 15 shows two Western blots performed after treating tuberous sclerosis type 2 (TSC2)-positive (TSC+ / +) MEF cells with everolimus or compounds of the present invention (I-40, I-7, and I-117) for 90 minutes. The staining shows strong inhibition of the mTORC1 pathway for everolimus and I-40, moderate concentration-dependent inhibition of the mTORC1 pathway for I-117, and noticeable concentration-dependent inhibition of the mTORC1 pathway for I-7. Importantly, the compounds of the present invention do not inhibit mTORC2, as demonstrated by the lack of inhibition of Akt phosphorylation.

[0036] [Figure 16] Figure 16 shows two Western blots performed after treating TSC- / - MEF cells with everolimus or compounds of the present invention (I-40, I-7, and I-117) for 24 hours. The staining shows strong inhibition of the mTORC1 pathway for everolimus, I-40, and I-117, as well as noticeable concentration-dependent inhibition of the mTORC1 pathway for I-7. Importantly, the compounds of the present invention do not inhibit mTORC2, as demonstrated by the lack of inhibition of Akt phosphorylation.

[0037] [Figure 17]Figure 17 shows two Western blots performed after treating TSC+ / + MEF cells with everolimus or compounds of the present invention (I-40 and I-7) for 24 hours. The staining shows strong inhibition of the mTORC1 pathway for everolimus, moderate concentration-dependent inhibition of the mTORC1 pathway for I-40, and slight concentration-dependent inhibition of the mTORC1 pathway for I-7. Importantly, the compounds of the present invention do not inhibit mTORC2, as demonstrated by the lack of inhibition of Akt phosphorylation.

[0038] [Figure 18] Figure 18 shows Western blots performed on TSC- / - MEF cells after treatment with everolimus, rapamycin, or compounds of the invention (I-2 and I-92) for 24 hours. Staining shows strong inhibition of the mTORC1 pathway for everolimus, rapamycin, and I-2, and moderate, concentration-dependent inhibition of the mTORC1 pathway for I-92.

[0039] [Figure 19] Figure 19 shows Western blots performed after treating TSC+ / + MEF cells with everolimus, rapamycin, or compounds of the present invention (I-2 and I-92) for 24 hours. Staining shows strong inhibition of the mTORC1 pathway for everolimus and rapamycin, and moderate concentration-dependent inhibition of the mTORC1 pathway for I-2 and I-92. Importantly, compounds of the present invention do not inhibit mTORC2, as demonstrated by the lack of inhibition of Akt phosphorylation.

[0040] [Figure 20]Figure 20 shows Western blots performed after treating TSC+ / + MEF cells with everolimus or compounds of the present invention (I-20, I-40, and I-36) for 24 hours. Staining shows strong inhibition of the mTORC1 pathway for everolimus, and moderate concentration-dependent inhibition of the mTORC1 pathway for I-20, I-40, and I-36. Importantly, compounds of the present invention do not inhibit mTORC2, as demonstrated by the lack of inhibition of Akt phosphorylation.

[0041] [Figure 21] Figure 21 shows Western blots performed after treating TSC+ / + MEF cells with everolimus or compounds of the present invention (I-35, I-7, and I-26) for 24 hours. Staining shows strong inhibition of the mTORC1 pathway for everolimus, and slight concentration-dependent inhibition of the mTORC1 pathway for I-35, I-7, and I-26. Importantly, compounds of the present invention do not inhibit mTORC2, as demonstrated by the lack of inhibition of Akt phosphorylation.

[0042] [Figure 22] Figure 22 shows Western blots performed after treating TSC+ / + MEF cells with everolimus or compounds of the present invention (I-9, I-97, and I-98) for 24 hours. Staining shows strong inhibition of the mTORC1 pathway for everolimus, and slight concentration-dependent inhibition of the mTORC1 pathway for I-9, I-97, and I-98. Importantly, compounds of the present invention do not inhibit mTORC2, as demonstrated by the lack of inhibition of Akt phosphorylation.

[0043] [Figure 23] Figure 23 shows Western blots performed after treating TSC+ / + MEF cells with everolimus or a compound of the present invention (I-91) for 90 minutes. Staining shows strong inhibition of the mTORC1 pathway for rapamycin and I-91. Interestingly, I-91 shows some inhibition of mTORC2, as demonstrated by inhibition of Akt phosphorylation.

[0044] [Figure 24] Figure 24 shows Western blots performed on TSC+ / + MEF cells after treatment with everolimus or a compound of the present invention (I-91) for 24 hours. Staining shows strong inhibition of the mTORC1 pathway for rapamycin and I-91. Interestingly, I-91 shows some inhibition of mTORC2, as demonstrated by inhibition of Akt phosphorylation.

[0045] [Figure 25] Figure 25 shows a Western blot performed after treating TSC+ / + MEF cells with everolimus or a compound of the present invention (I-105) for 90 minutes. Staining shows strong inhibition of the mTORC1 pathway for rapamycin and I-105. Importantly, the compound of the present invention does not inhibit mTORC2, as demonstrated by the lack of inhibition of Akt phosphorylation.

[0046] [Figure 26] Figure 26 shows a Western blot performed after treating TSC+ / + MEF cells with everolimus or a compound of the present invention (I-105) for 24 hours. Staining shows strong inhibition of the mTORC1 pathway for rapamycin and I-105. Importantly, the compound of the present invention does not inhibit mTORC2, as demonstrated by the lack of inhibition of Akt phosphorylation.

[0047] [Figure 27] Figure 27 shows two Western blots performed after treating PC3 cells with everolimus or compounds of the present invention (I-2 and I-92) for 24 hours. Staining shows strong inhibition of the mTORC1 pathway for each compound tested, but no inhibition of 4E-BP1 phosphorylation. Importantly, compounds of the present invention do not inhibit mTORC2, as demonstrated by the lack of inhibition of Akt phosphorylation.

[0048] [Figure 28]Figure 28 shows Western blots performed after treating TSC+ / + MEF cells with everolimus or a compound of the present invention (I-105) for 24 hours. Staining shows strong inhibition of the mTORC1 pathway for each compound tested, but no inhibition of 4E-BP1 phosphorylation. Importantly, compounds of the present invention do not inhibit mTORC2, as demonstrated by the lack of inhibition of Akt phosphorylation.

[0049] [Figure 29] Figure 29 shows Western blots performed after treating TSC+ / + MEF cells with everolimus or compounds of the present invention (I-90 and I-110) for 24 hours. Staining shows strong inhibition of the mTORC1 pathway for everolimus and I-90, and moderate concentration-dependent inhibition of the mTORC1 pathway for I-110. Importantly, compounds of the present invention do not inhibit mTORC2, as demonstrated by the lack of inhibition of Akt phosphorylation.

[0050] [Figure 30] Figure 30 shows Western blots performed after treating TSC+ / + MEF cells with everolimus or a compound of the present invention (I-115) for 24 hours. Staining shows strong inhibition of the mTORC1 pathway for everolimus and moderate concentration-dependent inhibition of the mTORC1 pathway for I-115. Importantly, the compound of the present invention does not inhibit mTORC2, as demonstrated by the lack of inhibition of Akt phosphorylation.

[0051] [Figure 31] Figure 31 shows Western blots performed after wild-type MEF cells were treated with everolimus or compounds of the present invention (I-105, I-117, I-40, and I-90) for 24 hours. The staining shows strong inhibition of the mTORC1 pathway for everolimus, and moderate inhibition of the mTORC1 pathway for I-105, I-117, I-40, and I-90. Importantly, the compounds of the present invention do not inhibit mTORC2, as demonstrated by the lack of inhibition of Akt phosphorylation.

[0052] [Figure 32] Figure 32 shows a Western blot performed after treating wild-type MEF cells with everolimus or compounds of the present invention (I-105, I-117, I-40, and I-90) for 24 hours. Staining shows strong inhibition of the mTORC1 pathway for each compound tested. Importantly, compounds of the present invention do not inhibit mTORC2, as demonstrated by the lack of inhibition of Akt phosphorylation.

[0053] [Figure 33] Figure 33 shows a Western blot performed after treating wild-type MEF cells with everolimus or compounds of the present invention (I-85 and I-83) for 90 minutes. Staining shows strong inhibition of the mTORC1 pathway for each compound tested. Importantly, compounds of the present invention do not inhibit mTORC2, as demonstrated by the lack of inhibition of Akt phosphorylation.

[0054] [Figure 34] Figure 34 shows a Western blot performed after treating wild-type MEF cells with everolimus or compounds of the present invention (I-85 and I-83) for 24 hours. Staining shows strong inhibition of the mTORC1 pathway for each compound tested. Importantly, compounds of the present invention do not inhibit mTORC2, as demonstrated by the lack of inhibition of Akt phosphorylation.

[0055] [Figure 35] Figure 35 shows a Western blot performed on PC3 cells after 24 hours of treatment with everolimus or compounds of the invention (I-85 and I-83). The staining shows strong inhibition of the mTORC1 pathway for each compound tested.

[0056] [Figure 36]Figure 36 shows Western blots performed after treating PC3 cells and wild-type MEF cells with everolimus or a compound of the present invention (I-115) for 24 hours. Staining shows strong inhibition of the mTORC1 pathway for each tested compound in PC3 cells, strong inhibition of the mTORC1 pathway for everolimus in WT MEF cells, and moderate concentration-dependent inhibition of the mTORC1 pathway for I-115 in WT MEF cells. Importantly, the compounds of the present invention do not inhibit mTORC2, as demonstrated by the lack of inhibition of Akt phosphorylation.

[0057] [Figure 37] Figure 37 shows a Western blot performed after treating PC3 cells with everolimus, a compound of the present invention (I-117), short-chain PEG, everolimus in combination with short-chain PEG, or I-117 in combination with short-chain PEG for 24 hours. Staining shows strong inhibition of the mTORC1 pathway for everolimus and I-117 alone and in combination with short-chain PEG. Short-chain PEG alone showed no inhibition of mTORC1 or mTORC2. Importantly, compounds of the present invention, alone or in combination with short-chain PEG, do not inhibit mTORC2, as demonstrated by the lack of inhibition of Akt phosphorylation.

[0058] [Figure 38] Figure 38 shows a Western blot performed after treating PC3 cells with everolimus or compounds of the present invention (I-71, I-73, and I-75) for 24 hours. Staining shows strong inhibition of the mTORC1 pathway for all compounds tested. Importantly, compounds of the present invention do not inhibit mTORC2, as demonstrated by the lack of inhibition of Akt phosphorylation.

[0059] [Figure 39]Figure 39 shows a Western blot performed after treating PC3 cells with everolimus or compounds of the present invention (I-85 and I-83) for 24 hours. Staining shows strong inhibition of the mTORC1 pathway for all compounds tested. Importantly, compounds of the present invention do not inhibit mTORC2, as demonstrated by the lack of inhibition of Akt phosphorylation.

[0060] [Figure 40] Figure 40 shows a Western blot performed after treating PC3 cells with everolimus or a compound of the present invention (I-65) for 24 hours. Staining shows strong inhibition of the mTORC1 pathway for both compounds tested. Importantly, the compound of the present invention does not inhibit mTORC2, as demonstrated by the lack of inhibition of Akt phosphorylation.

[0061] [Figure 41] Figure 41 shows a Western blot performed after treating PC3 cells with everolimus or compounds of the present invention (I-5, I-106, and I-102) for 24 hours. Staining shows strong inhibition of the mTORC1 pathway for all compounds tested. Importantly, compounds of the present invention do not inhibit mTORC2, as demonstrated by the lack of inhibition of Akt phosphorylation.

[0062] [Figure 42] Figure 42 shows a Western blot performed after treating PC3 cells with everolimus or compounds of the present invention (I-75, I-71, and I-62) for 24 hours. Staining shows strong inhibition of the mTORC1 pathway for all compounds tested. Importantly, compounds of the present invention do not inhibit mTORC2, as demonstrated by the lack of inhibition of Akt phosphorylation.

[0063] [Figure 43] FIG. 43 shows the time course of glucose tolerance and insulin sensitivity tests in lean C57B1 / 6 mice.

[0064] [Figure 44] Figure 44 shows the results of intraperitoneal glucose tolerance tests in lean C57B1 / 6 mice during chronic treatment with rapamycin, I-40, or vehicle. ***P<0.001; ****P<0.0001; one-way ANOVA, all bars represent mean and SD.

[0065] [Figure 45] Figure 45 shows the area under the curve (AUC) of glucose clearance in lean C57B1 / 6 mice during chronic treatment with rapamycin, I-40, or vehicle. ***P<0.001; T-test, all bars represent mean and SD.

[0066] [Figure 46] FIG. 46 shows Sirius red staining of kidney tissue from an AKI / CKD mouse model.

[0067] [Figure 47] Figure 47 shows the percent area of ​​fibrosis in kidney tissue in AKI / CKD mouse models after treatment with everolimus, I-40, I-117, or vehicle. *P=0.02 compared to vehicle, t-test.

[0068] [Figure 48] Figure 48 shows the mRNA expression of collagen I in AKI / CKD mouse models after treatment with vehicle or I-40. **P<0.01, ***P<0.001 vs. sham; ††P<0.01 vs. vehicle.

[0069] [Figure 49] Figure 49 shows collagen III mRNA expression in AKI / CKD mouse models after treatment with vehicle or I-40. **P<0.01 vs. sham; †P<0.05 vs. vehicle.

[0070] [Figure 50]Figure 50 shows fibronectin mRNA expression in AKI / CKD mouse models after treatment with vehicle or I-40. **P<0.01 vs. sham; †P<0.05 vs. vehicle.

[0071] [Figure 51] Figure 51 shows the area of ​​kidney tissue infiltrated by macrophages in AKI / CKD mouse models after treatment with vehicle or I-40. *P<0.05, ***P<0.001 vs. sham; ††P<0.05 vs. vehicle.

[0072] [Figure 52] FIG. 52 shows the percent inhibition of IFN-γ production in an allogeneic MLR assay following treatment with rapamycin, everolimus, I-40, or I-117. DETAILED DESCRIPTION OF THE INVENTION

[0073] I. General Description of Certain Embodiments of the Invention In certain embodiments, the present invention provides a compound of formula I: [ka] or a pharmaceutically acceptable salt thereof, Ring A is a monovalent derivative of rapamycin or an analog thereof (i.e., a rapalog). , R 1 is attached to rapamycin or its analogue at the C-7 hydroxyl position, R 1 is an optionally substituted, linear or branched, saturated or unsaturated monovalent C 3~30 is a hydrocarbon chain, R 1 One or more methylene units of and independently -N(R)-, -N(R)C(O)-, -C(O)N(R)-, -N(R) S(O)2-, -S(O)2N(R)-, -O-, -C(O)-, -OC(O)-, -C (O)O-, -S-, -S(O)-, -S(O)2-, or -P(O)(R)2, or or 1 to 6 heteroatoms independently selected from nitrogen, oxygen, or sulfur; replaced by a 6- to 18-membered saturated or partially unsaturated heterocyclic ring, or R 1 is the formula P-0: [ka] (In the formula, [ka] indicates the point of attachment to ring A, each Z is independently -O-, -S-, -NR-, or -SO2-; n is about 2 to about 300; Each R is independently hydrogen or an optionally substituted C 1~6 aliphatic groups) Select from to provide.

[0074] In some embodiments, the present invention provides [ka] The present invention provides compounds of formula I other than those selected from: 2. Compounds and definitions:

[0075] Compounds of the invention include those generally described herein and disclosed herein. As used herein, the term "antibody" is further exemplified by the classes, subclasses, and species that comprise it. Unless otherwise indicated, the following definitions shall apply: For purposes of the present invention, chemical elements The element is Handbook of Chemistry and Physics, 75 th Ed's CAS version of Elemental Circle Further, General Principles of Organic Chemistry is incorporated herein by reference in its entirety. Incorporated into the text, "Organic Chemistry", Thomas Sorrell, University of Science Books, Sausalito: 1999 and "March's Advanced Organic Chemistry", 5 th Ed., Ed.: Smith, MB and March, J., John Wiley & Sons, New York. : Described in 2001.

[0076] As used herein, the terms "aliphatic" or "aliphatic group" refer to a group that is fully saturated. linear (i.e., unbranched) or branched chains containing one or more unsaturated units. or branched, substituted or unsubstituted hydrocarbon chains, or fully saturated or It means a monocyclic or bicyclic hydrocarbon containing multiple unsaturated units, This is an aromatic (referred to herein as "carbocyclic," "alicyclic") ring that has one point of attachment to the rest of the molecule. Unless otherwise specified, it is not an aliphatic The group contains 1-6 aliphatic carbon atoms. In some embodiments, the aliphatic group contains 1-5 In other embodiments, the aliphatic groups contain 1-4 aliphatic carbon atoms. In yet other embodiments, aliphatic groups contain 1-3 aliphatic carbon atoms. In other embodiments, aliphatic groups contain 1-2 aliphatic carbon atoms. In this embodiment, "alicyclic" (or "carbocyclic" or "cycloalkyl") refers to a completely Monocyclic C3-C6 hydrocarbons that are saturated or contain one or more unsaturated units Although it refers to a fatty acid that is not aromatic, it has one point of attachment to the rest of the molecule. Aromatic groups include, but are not limited to, straight or branched, substituted or unsubstituted alkyl groups. alkyl, alkenyl, alkynyl groups, and (cycloalkyl)alkyl, (cycloalkene) groups. and hybrids thereof, such as (cycloalkyl)alkenyl or (cycloalkyl)alkenyl. can be.

[0077] The term "heteroatom" refers to any atom of oxygen, sulfur, nitrogen, phosphorus, or silicon (including nitrogen, sulfur, and any oxidized form of silicon or silicon, the quaternized form of any basic nitrogen, or a heterocyclic ring a substitutable nitrogen, for example N (as in 3,4-dihydro-2H-pyrrolyl), NH (as in pyrrolidinyl), or NR + (as in N-substituted pyrrolidinyl) "means one or more of the following:

[0078] As used herein, the term "unsaturated" means that a moiety contains one or more unsaturated It means that it has units.

[0079] As used herein, "divalent C" 1~8 (or C 1~6 ) saturated or unsaturated The term "a linear or branched hydrocarbon chain" refers to a linear or branched hydrocarbon chain, as defined herein. or branched divalent alkylene, alkenylene, and alkynylene chains.

[0080] The term "alkylene" refers to a divalent alkyl group. ethylene group, i.e., -(CH2) n - (wherein n is a positive integer, preferably 1 to 6, 1 to 4) , 1 to 3, 1 to 2, or 2 to 3). The substituted alkylene chain may be one or more A polymethylene group in which a methylene hydrogen atom is replaced with a substituent. Suitable substituents include , and substituted aliphatic groups as described below.

[0081] The term "alkenylene" refers to a divalent alkenyl group. A substituted alkenylene chain is Contains at least one double bond in which one or more hydrogen atoms are replaced by substituents Suitable substituents include those described below for substituted aliphatic groups. Examples include:

[0082] The term "halogen" means F, Cl, Br or I.

[0083] Alone or in the form of "aralkyl", "aralkoxy", or "aryloxyalkyl" The term "aryl" when used as part of a larger moiety, such as in "aryl," refers to a monocyclic or bicyclic ring system having a total of 5 to 14 ring members, wherein at least one of the ring members of the system One ring is aromatic, and wherein each ring in the system contains 3 to 7 ring members. The term "aryl ring" may be used interchangeably with the term "aryl ring." In certain embodiments, "aryl" can include, but is not limited to, one or more substituents. Aromatic ring systems including optionally substituted phenyl, biphenyl, naphthyl, anthracyl, etc. As used herein, the term "aryl" includes within its scope aromatic rings such as: indanyl, phthalimidyl, naphthimidyl, phenanthridinyl or tetrahydro Also included are groups fused to one or more non-aromatic rings, such as naphthyl.

[0084] "Heteroaryl" and "heteroaryl" used alone or as part of a larger moiety The term "heteroar-" (ra / ri / ru / re / ro) is used, for example, in the case of "heteroar-" "Heteroaralkoxy" or "heteroaralkoxy" refers to an alkyl group having 5 to 10 ring atoms, preferably 5, 6 or 9 ring atoms and have 6, 10, or 14 pi electrons shared in a cyclic arrangement; and The term "heteroatom" refers to a group that contains, in addition to carbon atoms, one to five heteroatoms. , refers to nitrogen, oxygen, or sulfur; any oxidized form of nitrogen or sulfur; and basic nitrogen Heteroaryl groups include, without limitation, thienyl, fluorine ... nyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolizinyl, purinyl, "Heteroaryl" and "heteroaryl" include naphthyridinyl and pteridinyl. As used herein, the term "(ra / ri / ru / re / ro)~(heteroar-)" means A heteroaromatic ring fused to one or more aryl, alicyclic, or heterocyclyl rings Also included are groups where the radical or point of attachment is on the heteroaromatic ring. Non-limiting examples include: Indolyl, isoindolyl, benzothienyl, benzofuranyl, dibenzofuranyl, isoindolyl thiazolyl, benzimidazolyl, benzthiazolyl, quinolyl, isoquinolyl, cinnamoyl linyl, phthalazinyl, quinazolinyl, quinoxalinyl, 4H-quinolizinyl, carbazo aryl, acridinyl, phenazinyl, phenothiazinyl, phenoxazinyl, tetrahydro tetrahydroisoquinolinyl, tetrahydroisoquinolinyl, and pyrido[2,3-b]-1,4-o Heteroaryl groups may be monocyclic or bicyclic. The term "heteroaryl" refers to a "heteroaryl ring," The terms "aryl group" and "heteroaromatic group" may be used interchangeably. All terms include optionally substituted rings. The term "heteroaralkyl" refers to an alkyl group substituted by a heteroaryl, wherein the alkyl and heteroaryl The reel portions are independently replaced as needed.

[0085] As used herein, "heterocycle," "heterocyclyl," "heterocyclic radical" and the terms "heterocyclic ring" are used interchangeably and refer to saturated or partially unsaturated, and in addition to the carbon atoms, one or more, preferably 1 to 4, hetero atoms as defined above. refers to a stable 5- to 7-membered monocyclic or 7- to 10-membered bicyclic heterocyclic moiety containing a cyclic atom When used in reference to a ring atom of a heterocycle, the term "nitrogen" includes a substituted nitrogen. saturated or substituted alkyl groups having 0 to 3 heteroatoms selected from oxygen, sulfur, or nitrogen as the heteroatom; In the partially unsaturated ring, the nitrogen is NH (as in pyrrolidinyl) or + NR (N-substituted pyrrolidinyl) It may be the case that

[0086] A heterocyclic ring may have its pendant heteroatom or carbon atom attached at any heteroatom or carbon atom that results in a stable structure. Any of the ring atoms may be optionally substituted. Examples of saturated or partially unsaturated heterocyclic radicals include, without limitation, tetrahydrofuran, furanyl, tetrahydrothiophenyl, pyrrolidinyl, piperidinyl, pyrrolinyl, tetrahydrothiophenyl tetrahydroquinolinyl, tetrahydroisoquinolinyl, decahydroquinolinyl, oxazo Lysinyl, piperazinyl, dioxanyl, dioxolanyl, diazepinyl, oxazepinyl Examples of "heterocyclic", "heterocyclic", "heterocyclic", "thiazepinyl", "morpholinyl" and "quinuclidinyl" include "heterocyclic", ... "heterocyclyl," "heterocyclyl ring," "heterocyclic group," "heterocyclic moiety," and "heterocyclyl" are The terms "heterocyclic radical" and "heterocyclyl radical" are used interchangeably herein and refer to a heterocyclyl ring that is Indolinyl, 3H-indolyl, chromanyl, phenanthridinyl, or tetrahydro fused to one or more aryl, heteroaryl, or alicyclic rings, such as quinolinyl The heterocyclyl group may be monocyclic or bicyclic. The term "heterocyclylalkyl" refers to an alkyl group substituted by a heterocyclyl. wherein the alkyl and heterocyclyl moieties are independently and optionally substituted. can be.

[0087] As used herein, the term "partially unsaturated" refers to at least one double bond. The term "partially unsaturated" refers to a ring portion that contains a bond or triple bond. It is intended to encompass rings having sites of saturation, but is not intended to encompass aryl or aryl rings as defined herein. is not intended to include heteroaryl moieties.

[0088] As described herein, the compounds of the present invention may contain "optionally substituted" moieties. Generally, the term "substituted" is used in conjunction with the term "optionally." Whether preceded or not, one or more hydrogens of the specified moiety may be replaced by a suitable substitution. Unless otherwise indicated, "optionally substituted" means substituted with a group. A group may have suitable substituents at each substitutable position of the group, and in any given structure, More than one position in the Where possible, the substituents may be the same or different at all positions. Combinations of substituents thus envisioned preferably result in stable or chemically feasible groups. The term "stable" as used herein means , their production, detection, and in certain embodiments, their recovery, purification and When subjected to conditions that permit its use for one or more of the purposes disclosed in the specification , refers to a compound that is substantially unchanged.

[0089] Suitable monovalent substituents on a substitutable carbon atom of an "optionally substituted" group are independently and halogen, -(CH2) 0~4 R°;-(CH2) 0~4 OR°;-O(CH2) 0~4 R o , -O-(CH2) 0~4 C(O)OR°;-(CH2) 0~4 CH(OR° )2;-(CH2) 0~4 SR°; optionally substituted with R° -(CH2) 0~4 Ph;R ° may be substituted with -(CH2) 0~4 O(CH2) 0~1 Even if substituted with Ph;R° -CH=CHPh; R may be substituted with -(CH) 0~4 O(CH2) 0~1 -pyridyl; -NO2; -CN; -N3; ​​-(CH2) 0~4 N(R°)2;-(CH2 ) 0~4N(R°)C(O)R°; -N(R°)C(S)R°; -(CH2) 0~4 N( R°)C(O)NR°2; -N(R°)C(S)NR°2; -(CH2) 0~4 N(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) 0~4 C(O)R °; -C(S)R°; -(CH2) 0~4 C(O)OR°; -(CH2) 0~4 C(O) SR°; -(CH2) 0~4 C(O)OSiR°3; -(CH2) 0~4 OC(O)R° ; -OC(O)(CH2) 0~4 SR-、SC(S)SR°; -(CH2) 0~4 SC( O)R°; -(CH2) 0~4 C(O)NR°2; -C(S)NR°2; -C(S)SR °; -SC(S)SR°、-(CH2) 0~4 OC(O)NR°2; -C(O)N(OR °)R°; -C(O)C(O)R°; -C(O)CH2C(O)R°; -C(NOR°) R°; -(CH2) 0~4 SSR°; -(CH2) 0~4 S(O)2R°; -(CH2) 0~4 S(O)2OR°; -(CH2) 0~4 OS(O)2R°; -S(O)2NR°2 ; -(CH2) 0~4 S(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; -(C 1~ 4 linear or branched alkylene)O-N(R°)2; or -(C1~4 Linear or branched alkylene)C(O)ON(R°)2, where each R° is as defined below and independently may be substituted with hydrogen, C 1~6 Aliphatic, -CH2Ph, -O(CH 2) 0~1 Ph, -CH2- (5-6 membered heteroaryl ring), or nitrogen, oxygen, if 5-6 membered saturated moieties having 0-4 heteroatoms independently selected from aryl, arylsulfur, or aryl ring, or, notwithstanding the above definition, two independent The occurrences of R° taken together with their intervening atoms form a substituent as defined below. 0 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, Forming a 3- to 12-membered saturated, partially unsaturated, or aryl monocyclic or bicyclic ring having Complete.

[0090] R° (or two independent occurrences of R° together with their intervening atoms) Suitable monovalent substituents on the ring (wherein the ring is a cyclic ring) are independently halogen, —(CH) 0~2 R ● ,- (Haro R ● ), -(CH2) 0~2 OH, -(CH2) 0~2 OR ● , -(CH2) 0~ 2CH(OR ● )2;-O(HaloR ● ), -CN, -N3, -(CH2) 0~2 C(O) R ● , -(CH2) 0~2 C(O)OH, -(CH2) 0~2 C(O)OR ● , -(CH 2) 0~2 SR ● , -(CH2) 0~2 SH, -(CH2)0~2 NH2, -(CH2) 0~2 NHR ● , -(CH2) 0~2 NR ● 2, -NO2, -SiR ● 3. -OSiR ● 3. -C(O)SR ● , -(C 1~4 Linear or branched alkylene)C(O)OR ● , or -SSR ● and each R ● is unsubstituted, or if preceded by "halo" substituted only with one or more halogens and independently C 1~4 Aliphatic, -CH2Ph , -O(CH2) 0~1 Ph, or independently selected from nitrogen, oxygen, or sulfur 5-6 membered saturated, partially unsaturated, or aryl rings containing 0-4 heteroatoms Suitable divalent substituents on a saturated carbon atom of R° include ═O and ═S.

[0091] 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 * , =NNH S(O)2R * , =NR * , =NOR * , -O(C(R * 2)) 2~3 O- or -S (C(R * 2)) 2~3 S- is mentioned, R * Each independent occurrence of is hydrogen, defined below C may be substituted so that 1~6 Aliphatic or free from nitrogen, oxygen, or sulfur 5-6 membered saturated, partially unsaturated, or or an aryl ring. Suitable divalent carbon-bonded substituents include -O(CR * 2) 2~3 O- and R * Each independent occurrence of is hydrogen, which may be substituted as defined below. 1~6 aliphatic or having 0 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur The ring is selected from 5- to 6-membered saturated, partially unsaturated, or aryl rings.

[0092] R * Suitable substituents on the aliphatic group include halogen, -R ● ,-(Halo R ● ), -OH , -OR ● , -O(HaloR ● ), -CN, -C(O)OH, -C(O)OR ● , -NH2 , -NHR ● , -NR ● 2, or -NO2, and each R ● is non-substituted or is substituted only with one or more halogens when preceded by "halo" and independently with C 1~4 Aliphatic, -CH2Ph, -O(CH2) 0~1 Ph, or nitrogen, oxygen, or 5-6 membered saturated, partially unsaturated alkyl groups having 0-4 heteroatoms independently selected from sulfur It is a saturated or aryl ring.

[0093] 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)C H2C(O)R † , -S(O)2R † , -S(O)NR † 2. -C(S)NR † 2,- C(NH)NR † 2, or -N(R † )S(O)2R † are listed, and each R † is independent , hydrogen, optionally substituted as defined below C 1~6 Aliphatic, unsubstituted -OPh or or 0 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur; 5-6 membered saturated, partially unsaturated, or aryl ring, or as defined above Regardless, two independent R † The appearance of, together with their intervening atoms, nitrogen unsubstituted 3-(2-(2-methyl-1-propanol)-2-yl)-1,2-diol having 0 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur; Forming a 12-membered saturated, partially unsaturated, or aryl monocyclic or bicyclic ring .

[0094] R † Suitable substituents on the aliphatic group are independently halogen, —R ● ,-(Halo R ● ), -OH, -OR ● , -O(HaloR ● ), -CN, -C(O)OH, -C(O)OR ● ,- NH2, -NHR ● , -NR ● 2, or -NO2, and each R ● is either unsubstituted or or if preceded by "halo", substituted with one or more halogens only, and independently TeC 1~4 Aliphatic, -CH2Ph, -O(CH2) 0~1Ph, or nitrogen, oxygen, if 5-6 membered saturated, partially saturated alkyl arylsulfonates having 0-4 heteroatoms independently selected from arylsulfonates and sulfur is a fully unsaturated or aryl ring.

[0095] As used herein, the term "pharmaceutically acceptable salt" means a salt that is pharmaceutically acceptable based on sound medical judgment. within the limits of scientific knowledge, without excessive toxicity, irritation, allergic responses, etc., to humans and lower animals. salts suitable for use in contact with tissues of the body and with a reasonable benefit / risk ratio Pharmaceutically acceptable salts are well known in the art. See, for example, S.M. Berge et al. J. Pharmaceutical Sciences, 1977, 66, which is incorporated herein by reference. Pharmaceutically acceptable salts of the compounds of the present invention are described in detail in Sections 1-19. Suitable salts include those derived from suitable inorganic and organic acids and bases. Examples of environmentally acceptable, non-toxic acid addition salts are hydrochloric, hydrobromic, phosphoric, sulfuric, and peracid salts. With inorganic acids such as chloric acid, or with acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, amber acid Used in the art with organic acids such as malonic acid or ion exchange. Other pharmaceutically acceptable salts are salts of amino groups formed using other methods. These include adipate, alginate, ascorbate, aspartate, benzenesulfonate, Sulfonate, benzoate, hydrogen sulfate, borate, butyrate, camphorate, camphor Sulfonate, citrate, cyclopentanepropionate, digluconate, dodecyl Sulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate Salt, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxybenzoate Hydroxyethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate Acid salts, malates, maleates, malonates, methanesulfonates, 2-naphthalene Sulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate acid salts, pectinates, persulfates, 3-phenylpropionates, phosphates, pivalates, Propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p -toluenesulfonate, undecanoate, valerate, etc.

[0096] Salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium and and N + (C 1~4 Typical examples of alkali or alkaline earth metal salts include: Metal salts include sodium, lithium, potassium, calcium, magnesium, etc. Further pharmaceutically acceptable salts include, where appropriate, non-toxic ammonium, quaternary Ammonium, as well as halides, hydroxides, carboxylate ions, sulfate ions, and phosphorus Acid ions, nitrate ions, lower alkyl sulfonate ions, and aryl sulfonate ions and the like.

[0097] Unless otherwise stated, structures depicted herein include all isomers of the structure (e.g., , enantiomers, diastereomers, and geometric (or conformational) forms, e.g., R and S configurations of each asymmetric center, Z and E double bond isomers, and Z and E conformations isomers are also intended to include. Thus, single stereochemical isomers of the compounds of the present invention, and enantiomeric, diastereomeric and geometric (or conformational) mixtures are not included in this specification. Within the scope of the invention. Unless otherwise stated, all tautomeric forms of the compounds of the invention are It is within the scope of the present invention. Furthermore, unless otherwise stated, structures depicted herein are It is also intended to include compounds that differ only in the presence of one or more isotopically enriched atoms. For example, substitution of hydrogen by deuterium or tritium, or 13 C or 14 Rich in C Compounds having the present structures containing carbon-for-carbon replacements are within the scope of this invention. Such compounds can be used, for example, as analytical tools, as probes in biological assays, Or, it is useful as a therapeutic agent according to the present invention.

[0098] The terms "measurable affinity" and "measurably inhibit" are used herein. In this case, the compound of the present invention or a composition thereof and a sample containing mTORC1 are used in combination with the compound. mTORC1 between an equivalent sample containing mTORC1 in the absence of the substance or composition thereof It means a measurable change in activity. 3. Description of Exemplary Embodiments:

[0099] As noted above, in certain embodiments, the present invention provides compounds of formula I: [ka] or a pharmaceutically acceptable salt thereof, Ring A is a monovalent derivative of rapamycin or an analog thereof (i.e., a rapalog). , R 1 is attached to rapamycin or its analogue at the C-7 hydroxyl position, R 1is an optionally substituted, linear or branched, saturated or unsaturated monovalent C 3~30 is a hydrocarbon chain, R 1 One or more methylene units of and independently -N(R)-, -N(R)C(O)-, -C(O)N(R)-, -N(R) S(O)2-, -S(O)2N(R)-, -O-, -C(O)-, -OC(O)-, -C (O)O-, -S-, -S(O)-, -S(O)2-, or -P(O)(R)2, or or 1 to 6 heteroatoms independently selected from nitrogen, oxygen, or sulfur; replaced by a 6- to 18-membered saturated or partially unsaturated heterocyclic ring, or R 1 is the formula P-0: [ka] (In the formula, [ka] indicates the point of attachment to ring A, each Z is independently -O-, -S-, -NR-, or -SO2-; n is about 2 to about 300; Each R is independently hydrogen or an optionally substituted C 1~6 aliphatic groups) Select from to provide.

[0100] The term "rapamycin" and its structure as described throughout this specification refers to rapamycin. It is understood that syn and its analogs are intended to be encompassed.

[0101] For clarity, the displayed R 1 a moiety attached to the C-7 hydroxyl position, Formula II is reproduced below. Thus, the present invention provides a compound of formula II: [ka] or a pharmaceutically acceptable salt thereof, R 1 is an optionally substituted, linear or branched, saturated or unsaturated monovalent C 3~30 is a hydrocarbon chain, R 1 One or more methylene units of and independently -N(R)-, -N(R)C(O)-, -C(O)N(R)-, -N(R) S(O)2-, -S(O)2N(R)-, -O-, -C(O)-, -OC(O)-, -C (O)O-, -S-, -S(O)-, -S(O)2-, or -P(O)(R)2, or or 1 to 6 heteroatoms independently selected from nitrogen, oxygen, or sulfur; replaced by a 6- to 18-membered saturated or partially unsaturated heterocyclic ring, or R 1 is the formula P-0: [ka] (In the formula, [ka] indicates the point of attachment to the C-7 hydroxyl position, each Z is independently -O-, -S-, -NR-, or -SO2-; n is about 2 to about 300; Each R is independently hydrogen or an optionally substituted C 1~6 aliphatic groups) Select from to provide.

[0102] In some embodiments, the present invention provides a compound of formula II-a or II-b: [ka] or a pharmaceutically acceptable salt thereof, 1 Each of the is defined above , as described herein in classes and subclasses).

[0103] The term "rapamycin" and its structure as described throughout this specification refers to rapamycin. It is understood that the term "anti-inflammatory drug" is intended to encompass anti-inflammatory drugs and their analogs. In certain embodiments, Ring A is rapamycin. In some embodiments, Ring A is everolimus. In some embodiments, Ring A is temsirolimus. In some embodiments, Ring B is temsirolimus. A is ridaforolimus. In some embodiments, ring A is umirolimus.

[0104] The analogs of rapamycin (i.e., rapalogs) described above are for illustrative purposes only. , are not intended to limit the present invention.

[0105] As defined above, R 1 is an optionally substituted, linear or branched saturated or unsaturated monovalent C 3~30 is a hydrocarbon chain, R 1 One or more methylene units The positions may optionally and independently be -N(R)-, -N(R)C(O)-, -C(O) N(R)-, -N(R)S(O)2-, -S(O)2N(R)-, -O-, -C(O)- , -OC(O)-, -C(O)O-, -S-, -S(O)-, or -S(O)2-, or having 1 to 6 heteroatoms independently selected from nitrogen, oxygen, or sulfur , are replaced by 6 to 18 saturated or partially unsaturated heterocyclic rings.

[0106] In certain embodiments, R 1is an optionally substituted, linear or branched saturated Saturated or unsaturated monovalent C 3~30 is a hydrocarbon chain, R 1 One or more methylene The units may be, as appropriate and independently, -N(R)-, -N(R)C(O)-, -C(O )N(R)-, -N(R)S(O)2-, -S(O)2N(R)-, -O-, -C(O) -, -OC(O)-, -C(O)O-, -S-, -S(O)-, -S(O)2-, or In some embodiments, R 1 If necessary, is a branched, saturated, monovalent hydrocarbon chain substituted with R 1 One or more methyl groups The alkylene units may optionally and independently be -N(R)-, -N(R)C(O)-, -C( O)N(R)-, -N(R)S(O)2-, -S(O)2N(R)-, -O-, -C(O )-, -OC(O)-, -C(O)O-, -S-, -S(O)-, -S(O)2-, and is replaced by -P(O)(R). In some embodiments, R 1 If necessary, is a linear, unsaturated, monovalent hydrocarbon chain optionally substituted with R 1 One or more of the The ethylene units may optionally and independently be -N(R)-, -N(R)C(O)-, - C(O)N(R)-, -N(R)S(O)2-, -S(O)2N(R)-, -O-, -C (O)-, -OC(O)-, -C(O)OS-, -S(O)-, -S(O)2-, and is replaced by -P(O)(R). In some embodiments, R 1 If necessary, is a branched, unsaturated, monovalent hydrocarbon chain optionally substituted with R 1 One or more of the The ethylene units may optionally and independently be -N(R)-, -N(R)C(O)-, - C(O)N(R)-, -N(R)S(O)2-, -S(O)2N(R)-, -O-, -C (O)-, -OC(O)-, -C(O)O-, -S-, -S(O)-, -S(O)2-, or -P(O)(R). In some embodiments, R 1 is necessary is a linear saturated monovalent hydrocarbon chain substituted according to 1 One or more of Methylene units are optionally and independently replaced by -O-.

[0107] In some embodiments, R 1 teeth [ka] In some embodiments, R 1 teeth [ka] In some embodiments, R 1 teeth [ka] In some embodiments, R 1 teeth [ka] In some embodiments, R 1 teeth [ka] In some embodiments, R 1 teeth [ka] is.

[0108] In some embodiments, R1 teeth [ka] is.

[0109] In some embodiments, R 1 teeth [ka] In some embodiments, R 1 teeth [ka] In some embodiments, R 1 teeth [ka] In some embodiments, R 1 teeth [ka] is.

[0110] In some embodiments, R 1 teeth [ka] In some embodiments, R 1 teeth [ka] In some embodiments, R 1 teeth [ka] In some embodiments, R 1 teeth [ka] is.

[0111] In certain embodiments, R 1teeth [ka] In some embodiments, R 1 teeth [ka] In some embodiments, R 1 teeth [ka] In some embodiments, R 1 teeth [ka] In some embodiments, R 1 teeth [ka] In some embodiments, R 1 teeth [ka] is.

[0112] In some embodiments, R 1 teeth [ka] is.

[0113] In certain embodiments, R 1 is the formula P-0: [ka] (In the formula, [ka] indicates the point of attachment to ring A, each Z is independently -O-, -S-, -NR-, or -SO2-; n is about 2 to about 300; Each R is independently hydrogen or an optionally substituted C 1~6 aliphatic groups) It is of the type.

[0114] In some embodiments, n is from about 2 to about 10, from about 10 to about 20, from about 20 to about 30, or about 30. ~approx. 40, approx. 40~approx. 50, approx. 50~approx. 60, approx. 60~approx. 70, approx. 70~approx. 80, approx. 80 ~approx. 90, approx. 90~approx. 100, approx. 110~approx. 120, approx. 120~approx. 130, approx. 140~approx. 150, approx. 150 to approx. 160, approx. 170 to approx. 180, approx. 180 to approx. 190, approx. 190 to approx. 200, 200 to approx. 210, approx. 210 to approx. 220, approx. 220 to approx. 230, approx. 230 to approx. 2 40, approx. 240 to approx. 250, approx. 250 to approx. 260, approx. 260 to approx. 270, approx. 270 to approx. 2 80, about 280 to about 290, or about 290 to about 300.

[0115] In some embodiments, R 1 teeth [ka] where n and R are as described herein.

[0116] In some embodiments, R 1 teeth [ka] In some embodiments, R 1 teeth [ka] In some embodiments, R 1 teeth [ka] In some embodiments, R 1 teeth [ka] In some embodiments, R 1 teeth [ka] In some embodiments, R 1 teeth [ka] In some embodiments, R 1 teeth [ka] In some embodiments, R 1 teeth [ka] In some embodiments, R 1 teeth [ka] In some embodiments, R 1 teeth [ka] In some embodiments, R 1 teeth [ka] In some embodiments, R 1 teeth [ka] In some embodiments, R 1 teeth [ka] In some embodiments, R 1 teeth [ka] In some embodiments, R 1 teeth [ka] In some embodiments, R 1 teeth [ka] In some embodiments, R 1 teeth [ka] In some embodiments, R 1 teeth [ka] In some embodiments, R 1 teeth [ka] In some embodiments, R 1 teeth [ka] In some embodiments, R 1 teeth [ka] In some embodiments, R 1 teeth [ka] In some embodiments, R 1 teeth [ka] In some embodiments, R 1 teeth [ka] In some embodiments, R1 teeth [ka] In some embodiments, R 1 teeth [ka] In some embodiments, R 1 teeth [ka] In some embodiments, R 1 teeth [ka] In some embodiments, R 1 teeth [ka] In some embodiments, R 1 teeth [ka] In some embodiments, R 1 teeth [ka] In some embodiments, R 1 teeth [ka] In some embodiments, R 1 teeth [ka] In some embodiments, R 1 teeth [ka] In some embodiments, R 1 teeth [ka] In some embodiments, R 1 teeth [ka] In some embodiments, R 1 teeth [ka] In some embodiments, R 1 teeth [ka] In some embodiments, R 1 teeth [ka] is.

[0117] In some embodiments, R 1 teeth [ka] In some embodiments, R 1 teeth [ka] In some embodiments, R 1 teeth [ka] In some embodiments, R 1 teeth [ka] In some embodiments, R 1 teeth [ka] In some embodiments, R 1 teeth [ka] In some embodiments, R 1 teeth [ka] In some embodiments, R 1 teeth [ka] In some embodiments, R 1 teeth [ka] In some embodiments, R 1 teeth [ka] In some embodiments, R 1 teeth [ka] In some embodiments, R 1 teeth [ka] In some embodiments, R 1 teeth [ka] In some embodiments, R 1 teeth [ka] In some embodiments, R 1 teeth [ka] In some embodiments, R 1 teeth [ka] In some embodiments, R 1 teeth [ka] In some embodiments, R 1 teeth [ka] In some embodiments, R 1 teeth [ka] In some embodiments, R 1 teeth [ka] In some embodiments, R 1 teeth [ka] In some embodiments, R 1 teeth [ka] In some embodiments, R 1 teeth [ka] In some embodiments, R 1 teeth [ka] In some embodiments, R 1 teeth [ka] In some embodiments, R 1 teeth [ka] In some embodiments, R 1 teeth [ka] In some embodiments, R 1 teeth [ka] In some embodiments, R 1 teeth [ka] In some embodiments, R 1 teeth [ka] In some embodiments, R 1 teeth [ka] In some embodiments, R 1 teeth [ka] In some embodiments, R 1 teeth [ka] In some embodiments, R 1 teeth [ka] In some embodiments, R 1 teeth [ka] In some embodiments, R 1 teeth [ka] In some embodiments, R1 teeth [ka] In some embodiments, R 1 teeth [ka] In some embodiments, R 1 teeth [ka] is.

[0118] In some embodiments, R 1 teeth [ka] In some embodiments, R 1 teeth [ka] is.

[0119] In some embodiments, R 1 teeth [ka] In some embodiments, R 1 teeth [ka] is.

[0120] In some embodiments, R 1 teeth [ka] In some embodiments, R 1 teeth [ka] In some embodiments, R 1teeth [ka] In some embodiments, R 1 teeth [ka] In some embodiments, R 1 teeth [ka] In some embodiments, R 1 teeth [ka] is.

[0121] In some embodiments, R 1 teeth [ka] In some embodiments, R 1 teeth [ka] is.

[0122] In some embodiments, R 1 teeth [ka] is.

[0123] In certain embodiments, R 1 are independently selected from nitrogen, oxygen, and sulfur. A 6- to 18-membered saturated or partially unsaturated heterocyclic ring containing up to 6 heteroatoms. be.

[0124] In some embodiments, R 1 teeth [ka] In some embodiments, R 1 teeth [ka] In some embodiments, R 1 teeth [ka] In some embodiments, R 1 teeth [ka] is.

[0125] In some embodiments, R 1 are selected from those shown in Table 1 below.

[0126] In certain embodiments, R is independently hydrogen, or C 1~6 Selected from aliphatic , an optionally substituted group. In some embodiments, R is hydrogen. In some embodiments, R is methyl. In some embodiments, R is ethyl. In some embodiments, R is propyl. [ka] is.

[0127] In some embodiments, R is selected from those shown in Table 1 below.

[0128] In some embodiments, the present invention provides a compound of formula III: [ka] or a pharmaceutically acceptable salt thereof, R 1 are as described herein) to provide.

[0129] In some embodiments, the present invention provides a compound of formula III-a or III-b: [ka] or a pharmaceutically acceptable salt thereof, R 1 are as described herein) to provide.

[0130] In some embodiments, the present invention provides a compound of formula IV: [ka] or a pharmaceutically acceptable salt thereof, R 1 are as described herein) to provide.

[0131] In some embodiments, the present invention provides a compound of formula IV-a or IV-b: [ka] or a pharmaceutically acceptable salt thereof, R 1 are as described herein) to provide.

[0132] In some embodiments, the present invention provides a compound of formula V: [ka] or a pharmaceutically acceptable salt thereof, R 1 are as described herein) to provide.

[0133] In some embodiments, the present invention provides a compound of formula Va or Vb: [ka] or a pharmaceutically acceptable salt thereof, R 1 are as described herein) to provide.

[0134] In some embodiments, the present invention provides a compound of formula VI: [ka] or a pharmaceutically acceptable salt thereof, R 1 are as described herein) to provide.

[0135] In some embodiments, the present invention provides a compound of formula VI-a or VI-b: [ka] or a pharmaceutically acceptable salt thereof, R 1 are as described herein) to provide.

[0136] In some embodiments, the present invention provides a compound of formula VII: [ka] or a pharmaceutically acceptable salt thereof, R 1 are as described herein) to provide.

[0137] In some embodiments, the present invention provides a compound of formula VII-a or VII-b: [ka] or a pharmaceutically acceptable salt thereof, R 1 are as described herein) to provide.

[0138] In some embodiments, the present invention provides a compound of formula VIII: [ka] or a pharmaceutically acceptable salt thereof, R 1 are as described herein) to provide.

[0139] In some embodiments, the present invention provides a compound of formula VIII-a or VIII-b: [ka] or a pharmaceutically acceptable salt thereof, R 1 are as described herein) to provide.

[0140] In some embodiments, the present invention provides a compound of formula IX-a, IX-b, IX-c, IX-d, IX- e, IX-f, or IX-g: [ka] [ka] [ka] or a pharmaceutically acceptable salt thereof, R 1 are as described herein) to provide.

[0141] In some embodiments, the present invention provides a compound of formula Xa, Xb, Xc, Xd, Xe, Xf or Xg: [ka] [ka] [ka] or a pharmaceutically acceptable salt thereof, R 1 are as described herein) to provide.

[0142] In some embodiments, the present invention provides a compound of formula XI-a, XI-b, XI-c, XI-d, XI- e, XI-f or XI-g: [ka] [ka] [ka] or a pharmaceutically acceptable salt thereof, P-0 is as described herein) to provide.

[0143] In some embodiments, the present invention provides a compound of formula XII: [ka] or a pharmaceutically acceptable salt thereof, R and n are as described herein. to provide.

[0144] In some embodiments, the present invention provides a compound of formula XII-a or XII-b: [ka] or a pharmaceutically acceptable salt thereof, R and n are as described herein. to provide.

[0145] In some embodiments, the present invention provides a compound of formula XIII: [ka] or a pharmaceutically acceptable salt thereof, R and n are as described herein. to provide.

[0146] In some embodiments, the present invention provides a compound of formula XIII-a or XIII-b: [ka] or a pharmaceutically acceptable salt thereof, R and n are as described herein. to provide.

[0147] In some embodiments, the present invention provides a compound of formula XIV: [ka] or a pharmaceutically acceptable salt thereof.

[0148] In some embodiments, the present invention provides a compound of formula XIV-a or XIV-b: [ka] or a pharmaceutically acceptable salt thereof.

[0149] In some embodiments, the present invention provides a compound of formula XV: [ka] or a pharmaceutically acceptable salt thereof.

[0150] In some embodiments, the present invention provides a compound of formula XV-a or XV-b: [ka] [ka] or a pharmaceutically acceptable salt thereof.

[0151] Rapamycin is commercially available under the trade name Rapamune® (generic name sirolimus). Rapamycin is known for its antiproliferative and immunosuppressive activity. FDA approved for the treatment of stents and for coating stents to prevent restenosis. Apart from the proven benefits of rapamycin, it has been shown to reduce a number of serious It is well known that steroids are associated with adverse side effects, such as decreased glucose tolerance. These include diabetes-like symptoms such as hypoglycemia and decreased insulin sensitivity. The inhibitor activates the Akt signaling pathway (including activation of Akt and ERK), which It has been reported that this increases the risk of cancer in patients.

[0152] As used herein, the phrase "rapamycin alone" refers to a compound of the present invention administered in the presence of: It is intended to be compared to rapamycin, or alternatively, an analog thereof.

[0153] In some embodiments, the compounds of formula I, II, III, IV, V, VI, VII, VI Compounds II, XII, XIII, XIV, or XV are more effective than rapamycin alone In some embodiments, the compounds of formula II-a, III-a, IV-a, Va, VI-a, VII-a, VIII-a, XII-a, XIII-a, XIV-a or X The compounds of formula Va are more effective than rapamycin alone. Formula II-b, III-b, IV-b, Vb, VI-b, VII-b, VIII-b Compounds XII-b, XIII-b, XIV-b, or XV-b inhibit the activity of rapamycin alone. is more effective than

[0154] In some embodiments, the compounds of formula IX-a, IX-b, IX-c, IX-d, IX- Compounds IX-e, IX-f, or IX-g are more effective than rapamycin alone.

[0155] In some embodiments, the compounds of formula Xa, Xb, Xc, Xd, Xe, Xf Alternatively, compounds Xg are more effective than rapamycin alone.

[0156] In some embodiments, the compounds of formula XI-a, XI-b, XI-c, XI-d, XI- Compounds XI-e, XI-f, or XI-g are more effective than rapamycin alone.

[0157] In some embodiments, provided compounds of Formula II-a or II-b are rapamycin In some embodiments, the compounds of formula III-a or III-b are more effective than those of formula III-a or III-b alone. In some embodiments, the compound of formula b is more effective than rapamycin alone. Compounds of formula IV-a or IV-b are more effective than rapamycin alone. In embodiments, compounds of formula Va or Vb are provided that are more effective than rapamycin alone. In some embodiments, provided compounds of formula VI-a or VI-b are In some embodiments, the compounds of formula VII-a or VII-b are more effective than cyclohexyl 4-aminobenzoate alone. Compound VII-b is more effective than rapamycin alone. The provided compounds of formula VIII-a or VIII-b are more effective than rapamycin alone. In some embodiments, the provided compound of formula XII-a or XII-b is In some embodiments, the compounds of formula XIII-a or XIII-b are more effective than ribamycin alone. In some embodiments, compounds of formula XIII-b and XIII-c are more effective than rapamycin alone. The compounds of formula XIV-a or XIV-b are provided as compounds that are more effective than rapamycin alone. In some embodiments, provided compounds of formula XV-a or XV-b are rapamycin-containing compounds. It is more effective than cyclomycin alone.

[0158] In some embodiments, the compounds of formula I, II, III, IV, V, VI, VII, VI Compounds II, XII, XIII, XIV or XV, when administered to a patient, It results in fewer and / or less severe side effects than when isin is administered.

[0159] In some embodiments, the compounds of formula IX-a, IX-b, IX-c, IX-d, IX- Compounds IX-e, IX-f, and IX-g, when administered to a patient, are effective in preventing the administration of rapamycin. results in fewer and / or less severe side effects than when

[0160] In some embodiments, the compounds of formula Xa, Xb, Xc, Xd, Xe, Xf or compound Xg, when administered to patients, showed a greater effect than rapamycin. resulting in fewer and / or less severe side effects.

[0161] In some embodiments, the compounds of formula XI-a, XI-b, XI-c, XI-d, XI- Compounds XI-e, XI-f, and XI-g, when administered to a patient, are effective in preventing the administration of rapamycin. results in fewer and / or less severe side effects than when

[0162] Exemplary compounds of the present invention are set forth in Table 1 below. Table 1. Exemplary compounds [Table 1-1] [Table 1-2] [Table 1-3] [Table 1-4] [Table 1-5] [Table 1-6] [Table 1-7] [Table 1-8] [Table 1-9] [Table 1-10] [Table 1-11] [Table 1-12] [Table 1-13] [Table 1-14] [Table 1-15] [Table 1-16] Table 1-17 Table 1-18 Table 1-19 Table 1-20 Table 1-21 Table 1-22 Table 1-23 Table 1-24 Table 1-25 Table 1-26 Table 1-27 Table 1-28 Table 1-29 Table 1-30 Table 1-31 Table 1-32 Table 1-33 Table 1-34 Table 1-35 Table 1-36 Table 1-37 Table 1-38 Table 1-39 Table 1-40 Table 1-41 Table 1-42 Table 1-43 Table 1-44 Table 1-45 Table 1-46 Table 1-47 Table 1-48 Table 1-49 Table 1-50 [Table 1-51] [Table 1-52] [Table 1-53]

[0163] In some embodiments, the present invention provides a compound described in Table 1 above, or a pharmaceutically acceptable salt thereof. The present invention also provides compounds listed in Table 1 above as racemic mixtures at the C7 position, and acceptable salts thereof. It is understood that the present invention provides the compound described above or a pharmaceutically acceptable salt thereof. The compounds listed in Table 1 above as racemic mixtures at the C7 hydroxyl position can be prepared by a variety of methods. The diastereomers may be separated, for example, by chiral chromatography. It is understood that: 4. Uses, Formulation and Administration Pharmaceutically acceptable compositions

[0164] According to another embodiment, the present invention provides a compound of the present invention or a pharmaceutically acceptable derivative thereof. and a pharmaceutically acceptable carrier, adjuvant, or vehicle. The amount of compound in the composition of the present invention is adjusted to detect mTORC1 activity in a biological sample or in a patient. In certain embodiments, the present invention The amount of compound in the disclosed composition is sufficient to measurably increase mTORC1 activity in a biological sample or patient. In certain embodiments, the compositions of the present invention are effective in inhibiting the activity of The product is formulated for administration to a patient in need of such a composition. In some embodiments, the compositions of the invention are formulated for oral administration to a patient.

[0165] The term "patient," as used herein, refers to an animal, preferably a mammal, most preferably a mammalian animal. Preferably, it means a human.

[0166] The term "pharmaceutically acceptable carrier, adjuvant, or vehicle" is used A non-toxic carrier, adjuvant, or vehicle that does not impair the pharmacological activity of the compound to be formulated. The term "pharmaceutically acceptable carrier, adjuvant or or vehicles, including but not limited to ion exchangers, alumina, stearic acid Aluminum, lecithin, serum proteins such as human serum albumin, phosphate, glycerin Partial glyceride mixtures of saturated vegetable fatty acids, such as sorbic acid, potassium sorbate, Buffer substances such as water, protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, salt Sodium chloride, zinc salt, colloidal silica, magnesium trisilicate, polyvinylpyrrolide Cellulose-based materials, polyethylene glycol, sodium carboxymethyl cellulose Rubber, polyacrylate, wax, polyethylene-polyoxypropylene-block polymer Examples of suitable electrolytes include cellulose, salts or electrolytes such as polyethylene glycol, and wool fat.

[0167] The compositions of the present invention may be administered orally, parenterally, by inhalation spray, topically, rectally, nasally, bucally, It may also be administered vaginally or via an implanted reservoir. The term "parenteral" is used herein. When used in writing, subcutaneous, intravenous, intramuscular, intra-articular, intra-synovial, intrasternal, and subarachnoid These include intracavitary, intrahepatic, intralesional, and intracranial injection or infusion techniques. Preferably, the composition comprises: The compositions of the present invention may be administered orally, intraperitoneally, or intravenously. Sterile injectable forms of the compositions of the present invention may be aqueous or These suspensions may contain suitable dispersing or wetting agents and suspending agents. Sterile injectable preparations may be formulated according to techniques known in the art using It is also possible to prepare a sterile injectable solution or It may also be present as a suspension, for example as a solution in 1,3-butanediol. Among the acceptable vehicles and solvents are water, Ringer's solution, and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium.

[0168] For this purpose, any bland fixed oil may be used including synthetic mono- or diglycerides. Fatty acids, such as oleic acid and its glyceride derivatives, may be used in the preparation of injectables. and in particular their polyoxyethylated versions such as olive oil or castor oil. These oil solutions or suspensions may also contain carbohydrates. hydroxymethylcellulose, or pharmaceutically acceptable agents, including emulsions and suspensions. Long chain alcohol diluents or dispersants, such as similar dispersants commonly used in formulations of Other commonly used emulsifiers such as Tween, Span and other emulsifiers may also be included. surfactants commonly used in the manufacture of pharmaceutically acceptable solid, liquid or other dosage forms; Bioavailability enhancers used in may also be used for formulation.

[0169] Pharmaceutically acceptable compositions of the present invention include, but are not limited to, capsules, tablets, It may be orally administered in any orally acceptable dosage form, including aqueous suspensions or solutions. For oral tablets, commonly used carriers are lactose and corn denat. Lubricating agents, such as magnesium stearate, are also typically added. For oral administration in cell form, useful diluents include lactose and dried corn starch. When aqueous suspensions are required for oral use, the active substance may be added to emulsifying agents and starches. If desired, certain sweetening, flavoring or coloring agents may also be added. may be added.

[0170] Alternatively, the pharmaceutically acceptable compositions of the present invention may be administered in the form of suppositories for rectal administration. These may be used to prepare drugs that are solid at room temperature but liquid at rectal temperature, but prepared by mixing with a suitable non-irritating excipient which will melt in the rectum and release the drug. Such materials include cocoa butter, beeswax, and polyethylene. Glycols are included.

[0171] The pharmaceutically acceptable compositions of the present invention are also useful in treating ulcerative colitis, ... and ulcerative colitis, particularly when the target of treatment is the eye, skin, or lower intestine. Areas or organs readily accessible by topical application, including diseases of the ducts, Suitable topical formulations are readily available for each of these areas or organs. It is prepared.

[0172] Topical application for the lower intestinal tract can be effected in a rectal suppository formulation (see above) or in a suitable enema formulation. Topically-transdermal patches may also be used.

[0173] For topical application, the pharmaceutically acceptable compositions provided are suspended in one or more carriers. The composition of the present invention may also be formulated in a suitable ointment containing the active ingredient suspended or dissolved therein. Carriers for topical administration of the compound include, but are not limited to, mineral oil, liquid petrolatum, white Colored petrolatum, propylene glycol, polyoxyethylene, polyoxypropylene compounds , emulsifying wax and water. Alternatively, provided are pharmaceutically acceptable compositions contains the active ingredient suspended or dissolved in one or more pharmaceutically acceptable carriers. The composition can be formulated in a suitable lotion or cream. These include, but are not limited to, mineral oil, sorbitan monostearate, polysorbate 60, cetyl alcohol, and the like. Ester Wax, Cetearyl Alcohol, 2-Octyldodecanol, Benzyl Alcohol Coal and water.

[0174] For ophthalmic use, the pharmaceutically acceptable compositions provided include those containing benzoylalkonium chloride, Micronized suspension in isotonic, pH-adjusted sterile saline, with or without any preservatives. Formulated as a suspension or, preferably, as a solution in isotonic, pH-adjusted sterile saline Alternatively, for ophthalmic use, the pharmaceutically acceptable composition may be a liquid such as petrolatum. It may also be formulated in an ointment.

[0175] The pharmaceutically acceptable compositions of this invention may be administered by nasal aerosol or inhalation. Such compositions may be prepared by techniques well known in the art of pharmaceutical formulation, and Benzyl alcohol, or other suitable preservative, to enhance bioavailability absorption enhancers, fluorocarbons, and / or other conventional solubilizing or dispersing agents For convenience, it may be prepared as a solution in saline.

[0176] Most preferably, the pharmaceutically acceptable compositions of the present invention are formulated for oral administration. Such formulations may be administered with or without food. In other embodiments, the pharmaceutically acceptable compositions of the present invention are administered without food. In this case, the pharmaceutically acceptable compositions of the present invention are administered with food.

[0177] The compounds of the present invention may be combined with carrier materials to produce a composition in single dosage form. The amount of the compound will vary depending on the host being treated, the particular mode of administration. The compositions are administered to patients receiving these compositions at dosages of 0.01 to 100 mg / kg body weight / day. The compound should be formulated so that the inhibitor can be administered.

[0178] Also, the particular dosage and treatment regimen for any particular patient will vary depending on the particular compound utilized. activity of the substance, age, weight, general health, sex, diet, time of administration, excretion rate, drug combination and the judgment of the treating physician, and various factors, including the severity of the particular condition being treated. It should be understood that the amount of a compound of the present invention in a composition will also depend upon the particular It depends on the specific compound. Uses of the Compounds and Pharmaceutically Acceptable Compositions

[0179] As used herein, the terms "treatment," "treat," and "treating" The term refers to a disease or disorder described herein, or one or more symptoms thereof. In some embodiments, the term "prevent" refers to reverse, alleviate, delay the onset of, or inhibit the progression of a disease. In some embodiments, treatment may be administered after one or more symptoms have occurred. In some cases, treatment may be administered in the absence of symptoms. For example, treatment may be administered to a susceptible individual. before the onset of symptoms (e.g., in light of a history of symptoms and / or genetic or other predisposing factors) Treatment may also be administered to, for example, prevent or delay the recurrence of the disease. It may be continued after symptoms have resolved to prolong the treatment.

[0180] The compounds provided are inhibitors of mTORC1 and therefore inhibit the activity of mTORC1. It is useful for treating one or more disorders associated with certain In one embodiment, the present invention provides a method for administering a compound of the present invention, or a pharmaceutical composition thereof, to a patient in need thereof. and a method for treating an mTORC1-mediated disorder, comprising administering a therapeutically acceptable composition to a subject. This provides a method for

[0181] As used herein, "mTORC1-mediated" disorders, diseases and / or condition refers to any disease in which mTORC1 is known to play a role. or other deleterious conditions. Accordingly, another embodiment of the present invention provides a method for treating mTORC Treating or lessening the severity of one or more diseases in which IL-1 is known to play a role. In certain embodiments, the present invention relates to treating mTORC1-mediated disorders, diseases and / or or condition according to Matt Kaeberlin, Scientifica, vol. 2013, Article ID 849186 The compound is selected from those described below.

[0182] The methods described herein include methods for treating cancer in a subject. As used herein, "treating" means improving or reducing at least one symptom or clinical parameter of cancer. For example, treatment can be to improve or enhance tumor size or growth rate. Treatment may result in a reduction in the severity of cancer in all subjects or in a 100% reduction in the severity of cancer. It is not necessary to achieve a % probability of remission.

[0183] As used herein, the term "cancer" refers to cells with the capacity for autonomous growth, i.e. That is, it refers to an abnormal situation or condition characterized by rapidly proliferating cell growth. The term refers to the development of cancer or carcinogenic processes, regardless of histopathological type or stage of invasiveness. processes, metastatic tissues, or any type of malignantly transformed cell, tissue, or organ The term "tumor" as used herein refers to cancerous cells, e.g. It refers to a mass of cancer cells.

[0184] Cancers that may be treated or diagnosed using the methods described herein include lung, breast, Afflictions in various organ systems, including those affecting the thyroid gland, lymphatic system, gastrointestinal tract, and genitourinary tract most colon, renal cell, prostate, and / or testicular cancers, These include adenocarcinomas, which include malignant tumors such as non-small cell carcinoma of the lung, cancer of the small intestine, and cancer of the esophagus.

[0185] In some embodiments, the methods described herein treat or diagnose carcinoma in a subject. The term "carcinoma" is art-recognized and includes cancers of the respiratory system, Gastrointestinal system carcinoma, genitourinary system carcinoma, testicular carcinoma, breast carcinoma, prostate carcinoma, endocrine system carcinoma, and It refers to a malignant tumor of epithelial or endocrine tissue, including melanoma. Exemplary carcinomas include cervical, lung, prostate, breast, head and neck, renal carcinoma, and melanoma. These include those formed from colon and ovarian tissue. The term also refers to, for example, cancerous and "Adenocarcinoma" refers to a tumor derived from glandular tissue, including carcinosarcomas, which include malignant tumors composed of sarcomatous tissue. Or refers to a carcinoma in which the tumor cells form recognizable glandular structures.

[0186] The term "sarcoma" is art-recognized and refers to malignant tumors of mesenchymal origin .

[0187] In some embodiments, the cancer treated by the methods described herein is a cancer that inhibits mTOR Increased levels of C1 or mTO compared with normal tissue or other cancers of the same tissue Cancers in which RC1 expression or activity is increased. These cancers can be identified using the methods described herein. The method includes steps of obtaining tissue containing cancer cells, determining mTORC1 activity in the sample, and and administering a treatment described herein (e.g., a provided inhibitor of mTORC1). In some embodiments, the cancer is a cancer characterized by a level of mTORC1 activity as described herein. This indicates an increase in the signal level.

[0188] In some embodiments, the present invention provides a method for treating one or more disorders, diseases and / or conditions. wherein the disorder, disease or condition includes, but is not limited to, cell proliferation The present invention provides methods for treating reproductive disorders, including: Cell proliferative disorders

[0189] The present invention relates to methods for the diagnosis and prognosis of cell proliferative disorders (e.g., cancer), and the detection and treatment of mTOR. The present invention features methods and compositions for treating these disorders by inhibiting C1 activity. The cell proliferative disorders described herein include, for example, cancer, obesity, and proliferation-dependent disorders. Such disorders may be diagnosed using methods known in the art. That's fine. cancer

[0190] Cancers include, but are not limited to, leukemia (e.g., acute leukemia, acute lymphocytic leukemia, , acute myeloid leukemia, acute myeloblastic leukemia, acute promyelocytic leukemia, acute myelomonocytic leukemia Blood diseases, acute monocytic leukemia, acute erythroleukemia, chronic leukemia, chronic myeloid leukemia, chronic lymphocytic leukemia leukemia), polycythemia vera, lymphoma (e.g., Hodgkin's disease or non-Hodgkin's disease), Waldenstrom's macroglobulinemia, multiple myeloma, heavy chain disease, and sarcomas and Carcinomas (e.g., fibrosarcoma, myxosarcoma, liposarcoma, chondrosarcoma, osteosarcoma, chordoma, angiosarcoma) , Lymphangiosarcoma, Lymphangioendothelial sarcoma, Synovial tumor, Mesothelioma, Ewing's tumor, Hira Leiomyosarcoma, rhabdomyosarcoma, colon cancer, pancreatic cancer, breast cancer, ovarian cancer, prostate cancer, squamous cell carcinoma, Basal cell carcinoma, adenocarcinoma, sweat gland carcinoma, sebaceous gland carcinoma, papillary carcinoma, papillary adenocarcinoma, cystadenocarcinoma, medullary carcinoma, bronchial carcinoma , renal cell carcinoma, hepatocellular carcinoma, cholangiocarcinoma, choriocarcinoma, seminoma, embryonal carcinoma, Wilms' tumor, cervical Cancer, uterine cancer, testicular cancer, lung cancer, small cell lung cancer, bladder cancer, epithelial cancer, glioma, astrocytoma , medulloblastoma, craniopharyngioma, ependymoma, pinealoma, hemangioblastoma, acoustic neuroma, oligodendroglioma, solid tumors such as leukemia, meningioma, melanoma, neuroblastoma, and retinoblastoma In some embodiments, the cancer is melanoma or breast cancer. fibrotic disorders

[0191] Idiopathic pulmonary fibrosis (IPF). The PI3K pathway is activated in fibrotic lesions, which are the primary lesions of IPF. The mTOR kinase inhibitor GSK2126458 inhibits the growth of lung fibroblasts derived from IPF. Inhibition of mTOR reduces PI3K pathway signaling and functional responses in cells Reduces collagen expression in IPF patient models. In the rhesus monkey model, rapamycin treatment was antifibrotic, and rapamycin also inhibited fibroblast growth. Decreased expression of α-smooth muscle actin and fibronectin by cells in vitro Can.

[0192] In some embodiments, mTORC1 activity is regulated to treat idiopathic pulmonary fibrosis (IPF). (Mercer, PF et al., Thorax., 71(8): 701-11 ( 2016); Patel, AS, et al., PLoS One, 7(7): e41394 (2012) Accordingly, in some embodiments, the present invention provides a method for the treatment of rheumatoid arthritis, particularly in patients in need thereof. and a method for treating intercurrent pulmonary fibrosis (IPF) comprising administering to a subject a compound or a pharmaceutical composition thereof. administering to said patient an acceptable salt.

[0193] Renal fibrosis. mTORC1 is activated in myofibroblasts, the primary pathogenic cell type in renal fibrosis. Inhibition of mTOR by rapamycin in a mouse model of renal fibrosis (UUO) attenuated the expression of markers of fibrosis and tubulointerstitial injury.

[0194] In some embodiments, the method of inhibiting mTORC1 activity to treat renal fibrosis includes used (Jiang, L., et al., J Am Soc Nephrol, 24(7): 1114-26 (2013) ;Wu, MJ et al., Kidney International, 69(11): 2029-36 (2006);Chen, G. et al., PLoS One, 7(3): e33626 (2012);Liu, CF et al., Clin I (See, for example, Journal of Clinical Oncology, 37(34): E142-53 (2014)). In one aspect, the present invention provides a method of treating renal fibrosis in a patient in need thereof, comprising: administering to said patient a provided compound or a pharmaceutically acceptable salt thereof. Provide a method for

[0195] In some embodiments, methods of inhibiting mTORC1 activity are used to treat scleroderma. (Mitra, A., et al., J Invest Dermatol. 135(11): 2873-6 (2015) (See, for example, US Pat. No. 6,299,499, filed on Dec. 1, 2003.) Accordingly, in some embodiments, the present invention provides a method for treating a patient in need thereof. A method of treating scleroderma in a patient, comprising administering to the patient a compound or a compound thereof as provided herein. The present invention provides a method comprising administering a physiologically acceptable salt thereof.

[0196] In some embodiments, mTORC1 is used to treat hypertrophic scar and keloid diseases. A method for inhibiting the activity of the steroid hormone is used (Syed, F., et al., Am J Pathol. 181(5): 1 642-58 (2012). Accordingly, in some embodiments, the present invention provides 1. A method of treating hypertrophic scar and keloid disease in a patient in need thereof, comprising: Administering to a patient a provided compound or a pharmaceutically acceptable salt thereof. Provide the law.

[0197] In some embodiments, the method comprises inhibiting mTORC1 activity to treat myocardial fibrosis. is used (see Yano, T., et al., J Mol Cell Cardiol. 91: 6-9 (2016) Accordingly, in some embodiments, the present invention provides a method for treating a patient in need thereof. 10. A method for treating myocardial fibrosis in a patient, comprising administering to said patient a compound provided herein or a compound thereof. The present invention provides a method comprising administering a physiologically acceptable salt thereof. Other proliferative disorders

[0198] Other proliferative disorders include obesity, benign prostatic hyperplasia, psoriasis, dyskeratinization, lymphoma, and Proliferative disorders (e.g., disorders in which there is abnormal proliferation of cells of the lymphatic system), rheumatoid arthritis These include vascular disease, arteriosclerosis, restenosis, and diabetic retinopathy. Proliferative disorders that may be present include those described in U.S. Patents 5,639,600 and 7,087,644. Examples include those described in No. 8. Other disorders

[0199] Other disorders include, but are not limited to, Pompe disease, Gaucher disease, mucopolysaccharidosis, and polymorphisms. Lysosomal storage disorders including sulfatase deficiency, Parkinson's disease, Alzheimer's disease, Diabetic diseases such as Chinton's disease, alpha-1 antitrypsin deficiency, and spinal-bulbar muscular atrophy Degenerative diseases include:

[0200] In some embodiments, the method of inhibiting mTORC1 activity is used to treat asthma. (See Hua, W., et al., Respirology, 20(7): 1055-65 (2015) Accordingly, in some embodiments, the present invention provides a method for treating asthma in a patient in need thereof. 10. A method of treating a patient suffering from a rheumatoid arthritis, comprising administering to said patient a compound provided herein or a pharmaceutically acceptable salt thereof. The method includes administering a salt.

[0201] In some embodiments, mTORC1 activity is inhibited to treat lysosomal storage diseases. The method used is (Sardiello, M., Annals of the New York Academy of Sciences iences, 1371(1): 3-14 (2016);Awad, O., et al., Hum Mol Genet. 24(20): 5775-88 (2015);Spampanato, C., et al., EMBO Mol Med., 5(5): 691-706 (2013); Medina, DL, et al., Dev Cell., 21(3): 421-30 (2011). Accordingly, in some embodiments, the present invention provides a method for the treatment of a patient in need thereof. a method for treating a lysosomal storage disease comprising administering to said patient a compound provided herein or The present invention provides a method comprising administering a pharmaceutically acceptable salt thereof.

[0202] In some embodiments, mTORC1 activity is inhibited to treat Parkinson's disease. The method used is (Decressac, M., et al., Proc Natl Acad Sci U S A., 1 10(19):E1817-26 (2013). Accordingly, in some embodiments, the present invention The present invention relates to a method of treating Parkinson's disease in a patient in need thereof, the method comprising administering to the patient administering a provided compound or a pharmaceutically acceptable salt thereof to provide.

[0203] In some embodiments, mTORC1 activity is inhibited to treat Alzheimer's disease. The method used is (Polito, VA, et al., EMBO Mol Med. 6(9):1142-60 (20 14)). Accordingly, in some embodiments, the present invention provides 1. A method of treating Alzheimer's disease in a patient comprising administering to said patient a compound provided The present invention provides a method for treating a rheumatoid arthritis comprising administering to a patient a compound or a pharmaceutically acceptable salt thereof.

[0204] In some embodiments, mTORC1 activity is inhibited to treat Huntington's disease. The method used is (Tsunemi, T., et al., Sci Transl Med., 4(142): 142ra97 (2012). Accordingly, in some embodiments, the present invention provides 1. A method of treating Huntington's disease in a patient comprising administering to said patient a compound provided The present invention provides a method comprising administering a compound or a pharmaceutically acceptable salt thereof to a patient in need thereof.

[0205] In some embodiments, mT is used to treat alpha-1-antitrypsin deficiency. A method to inhibit ORC1 activity is used (Pastore, N. et al., EMBO Mol Med., 5(3): 397-412 (2013). Accordingly, in some embodiments, the present invention Ming treats alpha-1-antitrypsin deficiency in patients in need thereof administering to said patient a provided compound or a pharmaceutically acceptable salt thereof. The present invention provides a method comprising the steps of:

[0206] In some embodiments, mTORC1 activity is inhibited to treat spinal and bulbar muscular atrophy. The method used is (Cortes, CJ, et al., Nat Neurosci., 17(9): 1180-9 ( 2014). Accordingly, in some embodiments, the present invention provides 1. A method of treating spinal and bulbar muscular atrophy in a patient, comprising administering to said patient a compound provided The present invention provides a method comprising administering a compound or a pharmaceutically acceptable salt thereof to a patient in need thereof.

[0207] In some embodiments, the compounds of the invention bind to FKBP12 to form a complex. In some embodiments, the complex of the compound of the present invention with FKBP12 inhibits the FK50 of mTOR. Interacts with the 6-rapamycin binding domain.

[0208] In some embodiments, the compounds of the present invention bind to FKBP12 and inhibit FRAP and FKBP 12. In some embodiments, the R 1 The group interacts with both FRAP and FKBP12.

[0209] The present invention relates to an inhibitor of mTORC1 activity, and is directed to pS6K inhibition (a measure of mTORC1 activity). ) and pAKT activation (a measure of mTORC2 activity). In some embodiments, compounds are provided that have been shown to selectively inhibit mTORC1 more than mTORC1. In the present invention, the provided compounds selectively inhibit mTORC1 over mTORC2. In some embodiments, provided compounds do not measurably inhibit mTORC2. In embodiments, provided compounds are IC 50 shows pAKT activation >10 μM. In embodiments, provided compounds inhibit mTOR with >10-fold selectivity over mTORC2. In some embodiments, provided compounds inhibit mTORC2 by >20 fold. In some embodiments, provided compounds inhibit mTORC1 with selectivity similar to that of mT In some embodiments, the present invention provides a method for inhibiting mTORC1 with >50-fold selectivity over mTORC2. The compounds shown inhibit mTORC1 with >100-fold selectivity over mTORC2. In some embodiments, provided compounds inhibit mTORC2 with >150-fold selectivity. In some embodiments, provided compounds inhibit mTORC2 by >20 In some embodiments, provided compounds inhibit mTORC1 with greater than 10-fold selectivity. , inhibits mTORC1 with >500-fold selectivity over mTORC2. The compounds provided inhibit mTORC1 with >1,000-fold selectivity over mTORC2. To inhibit.

[0210] In some embodiments, provided compounds inhibit mTORC activation after prolonged treatment or exposure. In some embodiments, provided compounds inhibit mTORC1 selectively over 2. Selectively inhibiting mTORC1 over mTORC2 after approximately 24 hours of treatment or exposure In some embodiments, provided compounds exhibit a phenotype of m after about 36 hours of treatment or exposure. In some embodiments, the compounds provided herein selectively inhibit mTORC1 over mTORC2. The compound selectively inhibited mTORC1 over mTORC2 after 48 hours of treatment or exposure. In some embodiments, provided compounds inhibit the expression of IL-16 after about 72 hours of treatment or exposure. In some embodiments, the provided The compounds selectively inhibit mTO over mTORC2 after approximately 96 hours of treatment or exposure. In some embodiments, provided compounds inhibit RC1. selectively inhibits mTORC1 over mTORC2 after exposure. The compounds provided selectively inhibit mTORC2 after about 144 hours of treatment or exposure. In some embodiments, provided compounds selectively inhibit mTORC1. After treatment or exposure, it selectively inhibits mTORC1 over mTORC2. In embodiments, provided compounds inhibit mTORC activation after treatment or exposure for greater than about 1 week. It inhibits mTORC1 more selectively than 2.

[0211] In some embodiments, provided compounds are less immunosuppressive than existing rapalogs. In some embodiments, provided compounds are less immunosuppressive than rapamycin. In some embodiments, provided compounds are less immunosuppressive than everolimus. In embodiments, provided compounds are less immunosuppressive than temsirolimus. In some embodiments, provided compounds are less immunosuppressive than ridaforolimus. In some forms, provided compounds are less immunosuppressive than umirolimus.

[0212] In some embodiments, provided compounds inhibit interferon cancer to a lesser extent than rapalogs. In some embodiments, provided compounds inhibit rapamycin (IFN-γ) production. In some embodiments, provided compounds inhibit IFN-γ production to a lesser extent than In some embodiments, the compounds provided suppress IFN-γ production to a lesser extent than everolimus. The compound suppresses IFN-γ production to a lesser extent than temsirolimus. The compounds provided suppress IFN-γ production to a lesser extent than ridaforolimus. In some embodiments, provided compounds inhibit IFN-γ production to a lesser extent than umirolimus.

[0213] In some embodiments, provided compounds are biomarkers of fibrosis in damaged tissue. In some embodiments, provided compounds reduce the expression of collagen in damaged tissue. In some embodiments, the compounds provided herein reduce the expression of COLIA2. reduces the expression of collagen III (COL3A1) in damaged tissue. In embodiments, provided compounds inhibit the expression of fibronectin (FN1) in injured tissue. Reduces.

[0214] In some embodiments, provided compounds reduce the propensity of immune cells to infiltrate damaged tissue. In some embodiments, provided compounds induce macrophage cells to infiltrate damaged tissue. Reduces tendency to moisten.

[0215] In some embodiments, provided compounds induce glucose tolerance to a lesser extent than rapalogs. In some embodiments, provided compounds induce glucose tolerance to a lesser extent than rapamycin. In some embodiments, provided compounds induce glucose tolerance to a lesser extent than everolimus. In some embodiments, provided compounds induce glucose tolerance to a lesser extent than temsirolimus. In some embodiments, provided compounds induce glucose tolerance to a lesser extent than ridaforolimus. In some embodiments, provided compounds induce glucose tolerance to a lesser extent than umirolimus. In some embodiments, provided compounds improve glucose tolerance more than placebo or vehicle alone. It does not induce significantly more.

[0216] Accordingly, in some embodiments, the present invention provides a method for treating disorders associated with mTORC1. 1. A method of treating a patient, the method comprising administering to the patient a compound that inhibits mTORC1. and wherein the compound does not inhibit mTORC2. Mycobacterium typhimurium and rapalogs have demonstrated benefit in either animal models or human disease settings. Such indications include:

[0217] Treatment of metabolic diseases (insulin resistance in obesity and type 2 diabetes). Inhibition of this pathway extends survival in yeast, flies, and mice, and calorie restriction increases lifespan and Improves insulin sensitivity. The underlying mechanism is through regulating mTORC1 activation. It has been proposed that rapamycin-induced insulin resistance is mediated by mTOR. It has been shown that this is mediated by the inhibition of mTORC1. It is predicted to improve insulin sensitivity and glucose homeostasis.

[0218] In some embodiments, the present invention provides a method for treating metabolic disorders (such as obesity and insulin resistance in type 2 diabetes) To treat this condition, methods that inhibit mTORC1 activity are used (Yu, Z., et al., J Gerontol A Biol Sci Med Sci, 70(4), 410-20 (2015);Fok, WC, et a l., Aging Cell 13 (2): 311-9 (2014);Shum, M., et al., Diabetologia, 59(3):592-603 (2016);Lamming, DW, et al., Science 335(6076): 1638-43 (2012). Accordingly, in some embodiments, the present invention provides Treating metabolic diseases (insulin resistance in obesity and type 2 diabetes) in patients with comprising administering to said patient a provided compound or a pharmaceutically acceptable salt thereof. The present invention provides a method comprising the steps of:

[0219] Neurofibromatosis. Neurofibromatosis type 1 (NF1) is caused by mutations in the NF1 gene. Its protein product, neurofibromin, functions as a tumor suppressor. mTOR inhibitors reduce tumor size and ultimately lead to constitutive upregulation of mTOR. and induce antiproliferative effects in NF1-associated plexiform neurofibromas. is shown.

[0220] In some embodiments, methods for inhibiting mTORC1 activity are used to treat neurofibromatosis. The method used is (Franz, DN, et al., Curr Neurol Neurosci Rep., 12(3): 294-301 (2012); see Varin, J., et al., Oncotarget., 7: 35753-67 (2016) Accordingly, in some embodiments, the present invention provides a method for the treatment of a patient in need thereof. 10. A method of treating neurofibromatosis in a patient, comprising administering to said patient a compound provided herein or a compound thereof. The present invention provides a method comprising administering a physiologically acceptable salt thereof.

[0221] Cardiomyopathy and skeletal muscular dystrophy, Emery-Dreifuss muscular dystrophy model ( LMNA - / - Mutations in LMNA are associated with limb-girdle muscular dystrophy (LGMD1B), Emery-Dreifuss muscular dystrophy (EDMD2 / 3), dilated cardiomyopathy (DCM), and and conduction system disease (CMD1A), lipodystrophy, Charcot-Marie-Tooth disease and several human diseases, including Hutchinson-Gilford progeria syndrome (HGPS). Bring. Lmna - / - Mice have elevated mTORC1 activity and Lmna - / - Ma Short-term treatment with rapamycin in mice reduces mTORC1 signaling and myocardial and improved skeletal muscle function, as well as an approximately 50% increase in survival rate.

[0222] In some embodiments, mTOR is used to treat cardiomyopathies and skeletal muscular dystrophies. A method to inhibit C1 activity is used (Ramos, F., et al., Sci Transl Med., 4 (144): 144ra103 (2012);Bonne, G. & Quijano-Roy, S., Handb Clin Neurol. , 113: 1367-76 (2013). Accordingly, in some embodiments, the present invention A method for treating cardiomyopathy and skeletal muscular dystrophy in patients in need thereof administering to said patient a compound provided herein or a pharmaceutically acceptable salt thereof. The present invention provides a method including the steps of:

[0223] Leigh syndrome. Ndufs4 knockout (KO) mice are used as a model of Leigh syndrome. These results suggest that Ndufs4KO mice exhibit hyperactivation of mTORC1 and metabolic defects. Treatment with cephalosporin prolongs survival and reduces the metabolic and metabolic disorders associated with the disease. Improves economic deficiencies.

[0224] In some embodiments, the method comprises inhibiting mTORC1 activity to treat Leigh syndrome. is used (Johnson, SC, et al., Science, 342(6165): 1524-8 (2013) Accordingly, in some embodiments, the present invention provides a method for treating a patient in need thereof. a method of treating Leigh syndrome in a patient, said method comprising administering to said patient a compound provided herein or The present invention provides a method comprising administering a pharmaceutically acceptable salt thereof.

[0225] Oncology. Rapalog inhibition of mTOR has been shown to improve tumor growth in mouse cancer models and cancer patients. It has been shown to have anti-tumor activity in a variety of cancer types, including but not limited to: However, hepatocellular carcinoma, breast cancer, mantle cell lymphoma, lung cancer, tuberous sclerosis, and lymphoma Examples include angioleiomyomatosis.

[0226] In some embodiments, mTORC1 activity is inhibited to treat cancer and tumor disorders. The method used is (Ilagan, E. & Manning, B.D., Trends Cancer, 2(5): 2 41-51 (2016). Accordingly, in some embodiments, the present invention provides 1. A method of treating cancer and neoplastic disorders in a patient in need thereof, comprising administering to said patient The present invention provides a method for treating a rheumatoid arthritis, comprising administering a compound of the present invention or a pharmaceutically acceptable salt thereof to a patient. do.

[0227] Non-alcoholic steatohepatitis (NASH). The present invention is a drug that removes degraded cytoplasmic proteins. We provide an inhibitor of autophagy to remove NASH in the liver. It is characterized by lipid deposition, inflammation, and fibrosis. Inhibition of the mTORC1 pathway Induce ATP deficiency and downregulate SREBP-1, reducing lipid biosynthesis and lipid Reduces accumulation.

[0228] In some embodiments, mT is used to treat nonalcoholic steatohepatitis (NASH). A method to inhibit ORC1 activity is used (Puri, P. & Chandra, A., J Clin Ex p Hepatol, 4(1): 51-9 (2014). Accordingly, in some embodiments, The present invention provides a method for treating non-alcoholic steatohepatitis (NASH) in patients in need thereof. 1. A method of treating a patient, comprising administering to said patient a compound provided herein or a pharmaceutically acceptable salt thereof. The present invention provides a method comprising administering

[0229] Defects in mTOR regulation are associated with tuberous sclerosis complex (TSC) and lymphangioleiomyomatosis (LAM). , the genetic disorder tuberous sclerosis complex (TSC) and the related lung disease lymphangioleiomyoma Both diseases are caused by mutations in TSC1 or TSC2. This is caused by inappropriate activation of signaling downstream of mTORC1. Patients with TSC develop non-malignant tumors in many organs, including the brain, and most of these tumors are female. In patients with LAM, abnormalities occur in certain organs or tissues, particularly the lungs, lymph nodes, and kidneys. Muscle-like cells accumulate. For both TSC and LAM treatment, rapalogs are used. Everolimus and sirolimus are currently approved by the US FDA.

[0230] In some embodiments, mTO is used to treat tuberous sclerosis and lymphangioleiomyomatosis. A method to inhibit RC1 activity is used (Wander, SA, et al., J. Clin. Inves t., 121(4): 1231-41 (2011);Taveira-DaSilva, AM & Moss, J., J. Clin Epidemiol., 7: 249-57 (2015). Accordingly, in some embodiments, The present invention provides a method for treating tuberous sclerosis and lymphangioleiomyomatosis in patients in need thereof. a method of treating a patient comprising administering to said patient a compound provided herein or a pharmaceutically acceptable salt thereof. The method includes administering

[0231] Aging and diseases of aging. Rapamycin inhibits the mammalian TORC1 complex, which regulates translation. Rapamycin inhibits the inflammatory response of senescent cells and prolongs survival in various species, including mice. It has been shown to inhibit the progressive phenotype of senescent cells. Senescence-associated secretory phenomena (SASP) destroy tissues and contribute to age-related pathologies, including cancer. Inhibition of mTOR may suppress the secretion of inflammatory cytokines by senescent cells. Rapamycin reduced cytokine levels, including IL-6, and inhibited the proliferation of membrane-bound cytokines. The reduction of IL1A suppressed the transcriptional activity of NF-κB. Therefore, inhibition of mTORC1 may contribute to aging. By suppressing inflammation associated with aging, it is possible to prevent age-related pathologies, including cancer in later life. There is a possibility of improvement.

[0232] In some embodiments, mTORC1 activity is inhibited to treat aging and diseases of aging. A method that harms the cells is used (Laberge, RM, et al., Nature Cell Biology, 17(8) : 1049-61 (2015);Nacarelli, T., et al., Free Radic Biol Med., 95: 13 3-54 (2016)). Accordingly, in some embodiments, the present invention provides 1. A method of treating aging and diseases of aging in a patient in need thereof, comprising administering to said patient The present invention provides a method for treating a rheumatoid arthritis, comprising administering a compound of the present invention or a pharmaceutically acceptable salt thereof to a patient. do.

[0233] Diabetic nephropathy and kidney-related complications of type 1 and type 2 diabetes. Diabetic nephropathy is a kidney complication of type 1 and type 2 diabetes and affects up to approximately 40% of diabetic patients. High glucose levels cause the kidneys to work too hard to filter the blood. This forces the body to use more oxygen, resulting in kidney damage. Research has shown that the mTOR pathway is It is highly activated in the kidney and contributes to pathological changes and renal dysfunction caused by chronically high glucose. Furthermore, inhibition of mTOR may contribute to the development of hyper-inflammatory May attenuate insulinemia.

[0234] In some embodiments, diabetic nephropathy, or kidney-related disease in type 1 and type 2 diabetes, is Inhibiting mTORC1 activity is used to treat complications associated with glaucoma (Mori, H ., et al., Biochem. Res. Commun. 384(4): 471-5 (2009)). Accordingly, in some embodiments, the present invention provides a method for treating diabetic retinopathy in a patient in need thereof. A method for treating nephropathy, or kidney-related complications of type 1 and type 2 diabetes. administering to said patient a provided compound or a pharmaceutically acceptable salt thereof. The present invention provides a method comprising:

[0235] Polycystic kidney disease (PKD) is a destructive kidney disease that ultimately leads to kidney failure. PKD is characterized by the development and accumulation of cysts in the liver. It is an autosomal dominant disorder (ADPKD). ) or autosomal recessive (ARPKD). Dysfunction of the mTOR signaling pathway. has been observed in ADPKD and ARPKD. Normalization of the tract may ameliorate cyst development and disease progression.

[0236] In some embodiments, methods of inhibiting mTORC1 activity are used to treat PKD. (Torres, VE, et al., Clin. J. Am. Soc. Nephrol. 5(7): 1312- 29 (2010)). Accordingly, in some embodiments, the present invention provides A method of treating PKD in a patient in need thereof, comprising administering to said patient a compound or or a pharmaceutically acceptable salt thereof. In some embodiments, PKD is autosomal dominant. In some embodiments, PKD is autosomal recessive. do.

[0237] Focal segmental glomerulosclerosis (FSGS) and other diseases associated with kidney sclerosis. FS GS is the most common primary glomerular disorder causing end-stage renal disease (ESRD) in the United States. As the disease progresses, the podocytes of Bowman's capsule and the glomerular basement membrane they cover are destroyed. Surface area mismatch occurs. Research has shown that podocyte size control is regulated by mTOR. Activation of mTOR has been shown to contribute to disease progression. Constitutive activation of causes FSGS-like pathology in mouse knockdown experiments Therefore, inhibition of mTORC1 normalizes autophagy activity. or increase the risk of developing FSGS or other diseases associated with kidney stiffness. There is a possibility of improvement.

[0238] In some embodiments, the present invention provides a method for treating FSGS or other diseases associated with kidney stiffness. To achieve this, methods that inhibit mTORC1 activity are used (Zschiedrich, S. et al., J. (See Am. Soc. Nephrol. 28(7): 2144-57 (2017)). In some embodiments, the present invention provides a method for treating FSGS or nephrosclerosis in a patient in need thereof. a method for treating other diseases associated with the present invention, comprising administering to said patient a compound or and administering a pharmaceutically acceptable salt thereof.

[0239] Age-related macular degeneration. Age-related macular degeneration (AMD) is characterized by the death of photoreceptor cells in the macula. A possible mechanism of AMD progression is the oxidative stress-induced This leads to the deposition of proteins and dysfunctional organelles, leading to retinal pigment epithelial hypertrophy, dedifferentiation, and Finally, atrophy occurs. mTOR is involved in the dedifferentiation of the retinal pigment epithelium. Therefore, inhibition of mTORC1 may reduce AM proliferation by blocking hypertrophy and dedifferentiation. It may improve D.

[0240] In some embodiments, methods for inhibiting mTORC1 activity are used to treat age-related macular degeneration. The method is used (Kolosova, NG, et al., Am. J. Path. 181(2): 472-7 (201 2) and Zhen, C. & Vollrath, D., Aging 3(4): 346-47 (2011) Accordingly, in some embodiments, the present invention provides a method for treating aging in a patient in need thereof. A method of treating macular degeneration comprising administering to said patient a compound provided or a pharmaceutically acceptable salt thereof. The present invention provides a method comprising administering an acceptable salt thereof to a subject.

[0241] Diabetic Macular Edema. Diabetic macular edema (DME) is a leading cause of blindness in people with diabetes. It is the cause of diabetes and affects approximately 35% of people with diabetes. It has been suggested that the cause is an inflammatory disease involving various cytokines and chemokines. Chronic inflammation and oxidative stress may contribute to the progression of DME. Inhibition of mTORC1 may improve the symptoms and progression of DME by reducing the inflammatory response. There is a possibility of improving

[0242] In some embodiments, methods of inhibiting mTORC1 activity are used to treat DME. (Okamoto, T., et al., PLOS ONE, (11)(1): e0146517, https: / / doi. org / 10.1371 / journal.pone.0146517 (2016). In response, some In embodiments, the present invention provides a method of treating DME in a patient in need thereof, comprising: administering to said patient a provided compound or a pharmaceutically acceptable salt thereof. Provide a method for

[0243] Diabetic Retinopathy. Diabetic retinopathy (DR) is a common eye disease that accounts for approximately 5% of adult blindness. is a disorder associated with chronic hyperglycemia and defects in the insulin signaling pathway. DR patients experience vesicles caused by inflammation, reactive oxygen species, and chronic hyperglycemia. They suffer from persistent damage to retinal blood vessels and neurons due to physical stress. Rapamycin inhibits insulin-induced hypoxia-inducible factor 1 (HIF-1) activity and retinal Blocks cell senescence, induces autophagy, promotes apoptosis of newly formed blood vessels, and prevents blood It has been shown that inhibition of mTORC1 may be beneficial in preventing angiogenesis. , reducing inflammation and inhibiting pathogenic signaling pathways, thereby improving the symptoms and progression of DR. This may improve progression.

[0244] In some embodiments, methods of inhibiting mTORC1 activity are used to treat DR. (Di Rosa, M., et al., Curr. Neuropharmacol. 14(8): 810-25 (2016) (See, for example, US Pat. No. 6,299,499, filed on Dec. 1, 2003.) Accordingly, in some embodiments, the present invention provides a method for treating a patient in need thereof. 1. A method of treating DR in a patient, comprising administering to said patient a compound provided herein or a pharmaceutical The present invention provides a method comprising administering a physiologically acceptable salt thereof to a subject.

[0245] Glaucoma. Glaucoma is a common neuropathic eye disease associated with aging and increased intraocular pressure. It is a major cause of irreversible blindness. These findings suggest that mTOR-dependent dysregulation of may be a contributing factor in disease progression. Therefore, inhibiting mTORC1 may improve neuronal function by normalizing or increasing autophagy. , may slow or reverse the progression of glaucoma.

[0246] In some embodiments, the method of inhibiting mTORC1 activity is used to treat glaucoma. (Porter, K., et al., Biochim. Biophys. Acta. 1852(3): 379-85 ( 2014). Accordingly, in some embodiments, the present invention provides 10. A method of treating glaucoma in a patient, comprising administering to said patient a compound or and administering a pharmaceutically acceptable salt thereof.

[0247] Restoration of immune function. Inhibition of mTORC1 inhibits CD4 + and CD8 + T lymphocyte programming It reduces the expression of the PD-1 receptor and promotes T cell signaling. Therefore, inhibition of mTORC1 may enhance the adaptive immune response. This may restore immune function.

[0248] In some embodiments, the method of inhibiting mTORC1 activity to restore immune function is used (Mannick, JB, et al., Sci. Trans. Med. 6(268): ppra179 (20 14)). Accordingly, in some embodiments, the present invention provides 10. A method of restoring immune function in a patient having a leukemia, the method comprising administering to said patient a compound or and administering a pharmaceutically acceptable salt thereof.

[0249] Treatment of respiratory and / or urinary tract infections. Inhibition of mTORC1 has been shown to promote antiviral gene expression. Therefore, mTO may reduce infections by upregulating expression and response. Inhibition of RC1 enhances a patient's immune system's ability to defend against respiratory and / or urinary tract infections There is a possibility that this will happen.

[0250] In some embodiments, mTORC is used to treat respiratory and / or urinary tract infections. 1 activity is used (Mannick, JB, et al., Sci. Trans. Med. 10(449): eaaq1564 (2018)). Accordingly, in some embodiments, The present invention provides a method for restoring immune function in a patient in need thereof, comprising administering to said patient The present invention provides a method comprising administering a provided compound or a pharmaceutically acceptable salt thereof. Provide.

[0251] Heart failure. mTORC1 activity is essential for cardiac hypertrophy in response to stress but is not sufficient following infarction. Inhibition of mTORC1 can lead to cardiac dysfunction as a result of cardiac remodeling. Attenuates cardiac remodeling and heart failure in response to overload. Thus, mTOR Inhibition of C1 may reduce heart failure in patients who have suffered damage to the myocardium.

[0252] In some embodiments, methods of inhibiting mTORC1 activity are used to treat heart failure. (See Sciarretta, S. et al., Circ. Res. 122(3): 489-505 (2018) Accordingly, in some embodiments, the present invention provides a method for the treatment of a patient in need thereof. a method for treating heart failure in a patient, the method comprising administering to said patient a compound provided herein or a pharmaceutically acceptable salt thereof. The present invention provides a method comprising administering an acceptable salt thereof.

[0253] Osteoarthritis. Osteoarthritis (OA) is a chronic condition that results in cartilage loss and arthritis. mTOR regulates collagen homeostasis and turnover, as well as cartilage remodeling. Therefore, inhibition of mTORC1 may play an important role in the formation of cartilage. By normalizing metabolic turnover, it slows or reverses the progression of osteoarthritis symptoms. There is a possibility that it will improve.

[0254] In some embodiments, methods for inhibiting mTORC1 activity are used to treat osteoarthritis. The method is used (see Pal, B., et al., Drugs R&D, 15(1): 27-36 (2017)). Accordingly, in some embodiments, the present invention provides a method for the treatment of a patient in need thereof. a method for treating osteoarthritis by administering to said patient a compound provided herein or a pharmaceutical composition thereof; The present invention provides a method comprising administering a physiologically acceptable salt thereof to a subject.

[0255] Pulmonary arterial hypertension. Pulmonary arterial hypertension (PAH) is associated with increased pulmonary vascular resistance. Pulmonary artery smooth muscle cell proliferation and migration contribute to arterial wall thickening. Therefore, mTORC1 inhibition is associated with vascular remodeling. This may mitigate PAHs by reducing CO2 emissions.

[0256] In some embodiments, methods of inhibiting mTORC1 activity are used to treat PAH. (Ma, X., et al., Interact. Cardiovasc. Thorac. Surg. 25(2): 20 6-11 (2017)). Accordingly, in some embodiments, the present invention provides 1. A method of treating PAH in a patient in need thereof, comprising administering to said patient a compound provided herein. or a pharmaceutically acceptable salt thereof.

[0257] Chronic obstructive pulmonary disease. In patients with chronic obstructive pulmonary disease (COPD), autophagy The reduction in glucose leads to the accumulation of proteins and other cellular materials that accelerate cellular aging. Therefore, inhibition of mTORC1 normalizes or increases autophagy. This may slow or improve the progression of COPD symptoms.

[0258] In some embodiments, the method of inhibiting mTORC1 activity to treat COPD includes (See Fujii, S., et al., Oncoimmunology 1(5): 630-41 (2012) Accordingly, in some embodiments, the present invention provides a method for the treatment of a patient in need thereof. a method for treating COPD by administering to said patient a compound provided or a pharmaceutically acceptable salt thereof. The present invention provides a method comprising administering an acceptable salt thereof.

[0259] Additional therapeutic indications in which mTORC inhibition may be beneficial include cardiovascular disease (acute coronary syndromes) and ), coronary artery occlusion with eluting stents, polycystic kidney disease, and cyst formation or cyst development associated kidney disease, neurofibromatosis, and mutations in TSC1 and / or TSC2 Associated with epilepsy, polycystic liver, pachyonychia congenital, fragile X syndrome, Friedreich's ataxia, Peutz-Jeghers syndrome, age-related jaundice with neovascularization Eye diseases including macular degeneration, uveitis, diabetic macular edema, pulmonary fibrosis, renal failure / fibrosis, Fibroblast proliferation including metabolic syndrome, immunosenescence, lupus nephritis, chronic immune dyscrasia Related to thrombocytopenia, immune system disorders including multiple sclerosis, lymphoma, and TSC1 / 2 mutations Related tumors include angiomyolipoma, breast cancer, and liver cancer associated with TSC1 / 2 mutations. Cancer, including cell carcinoma, leukemia, glioma, adenoid cystic carcinoma, aging, autism, and vascular and articular carcinoma It is vascular rheumatoid arthritis.

[0260] In some embodiments, cardiovascular disease (acute coronary syndrome), coronary artery occlusion using eluting stents Associated with polycystic kidney disease, neurofibromatosis, and mutations in TSC1 and / or TSC2 Epilepsy, polycystic liver, pachyonychia congenita, fragile X syndrome, Friedreich's ataxia, Peutz-Jeghers syndrome, neovascular age-related macular degeneration, uveitis, diabetic macular edema eye diseases including pulmonary fibrosis, renal failure / fibrosis, fibroblasts including metabolic syndrome Immunological disorders including cell growth, immunosenescence, lupus nephritis, chronic immune thrombocytopenia, and multiple sclerosis Systemic diseases, lymphomas, tumors associated with TSC1 / 2 mutations, TSC1 / 2 apoptosis Angiomyolipoma, breast cancer, hepatocellular carcinoma, leukemia, glioma, and adenoid cysts associated with the mutation mTORC for the treatment of cancer, including cystic carcinoma, aging, autism, and rheumatoid arthritis 1 activity is inhibited.

[0261] Accordingly, in some embodiments, the present invention provides a method for the treatment of cardiovascular disease in a patient in need thereof. Vascular disease (acute coronary syndrome), coronary artery occlusion using eluting stents, polycystic kidney disease, neurofibroma syndrome, epilepsy associated with mutations in TSC1 and / or TSC2, polycystic liver disease, congenital pachyonychia, fragile X syndrome, Friedreich ataxia, Peutz-Jeghers syndrome, Eye diseases including neovascular age-related macular degeneration, uveitis, diabetic macular edema, and pulmonary fibrosis , renal failure / fibrosis, metabolic syndrome, including fibroblast growth, immunosenescence, loop Immune system disorders including leukemia, chronic immune thrombocytopenia, multiple sclerosis, lymphoma, and TSC Tumors associated with TSC1 / 2 mutations, blood vessels associated with TSC1 / 2 mutations Cancer including myolipoma, breast cancer, hepatocellular carcinoma, leukemia, glioma, adenoid cystic carcinoma, aging, autism and rheumatoid arthritis, comprising administering to said patient a compound or or a pharmaceutically acceptable salt thereof.

[0262] The pharmaceutically acceptable compositions of the present invention may be administered to humans and animals depending on the severity of the infection being treated. and other animals, orally, rectally, parenterally, intracisternally, intravaginally, intraperitoneally, topically (as powder, ointment or drop) It may also be administered as a buccal, oral or nasal spray, such as by drops. In certain embodiments, the compounds of the invention are administered in a dose of about 0.5 mg / day to achieve the desired therapeutic effect. 0.1 mg / kg to about 50 mg / kg, preferably about 1 mg / kg to about 25 mg / kg of the subject may be administered orally or parenterally, one or more times daily at a dosage level of .

[0263] Liquid dosage forms for oral administration include, but are not limited to, pharmaceutically acceptable emulsions. Examples of formulations include emulsions, microemulsions, solutions, suspensions, syrups and elixirs. In addition to the active compound, liquid dosage forms may contain, for example, water or other solvent, a solubilizing agent, and an ester. ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol Benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethyl Formamide, oils (especially cottonseed, peanut, corn, germ, olive, castor and Sesame oil), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycol and sorbitan fatty acid esters, and mixtures thereof. In addition to the inert diluents, oral Compositions may also contain adjuvants, such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents. The composition may further include a hydroxybenzoate.

[0264] Injectable preparations, for example, sterile injectable aqueous or oleaginous suspensions, may be prepared by dispersing in suitable agents or It may be formulated according to the known art using wetting agents and suspending agents. The preparation may also be prepared as a sterile injectable solution in a non-toxic parenterally acceptable diluent or solvent, It may be present as a suspension or emulsion, for example as a solution in 1,3-butanediol. Among the acceptable vehicles and solvents that may be employed are water, Ringer's solution, USP and isotonic sodium chloride solution. Any volatile oil is conventionally employed for this purpose, including synthetic mono- or diglycerides. Any bland fixed oil may be used, including but not limited to oleic acid, which may be used as an injectable. It is used in the preparation of drugs.

[0265] Injectable preparations can be readily prepared by, for example, filtration through a bacterial-retaining filter or by In the form of sterile solid compositions that can be dissolved or dispersed in sterile water or other sterile injectable medium. Sterilization can be achieved by incorporating a sterilizing agent.

[0266] To prolong the effect of the compounds of the present invention, they are often administered by subcutaneous or intramuscular injection. It is desirable to slow the absorption of the compound. This is because crystalline or amorphous compounds with poor water solubility This may be accomplished by using a liquid suspension of the material, in which case the rate of absorption of the compound may be increased. The degree of dissolution depends on its dissolution rate, which may depend on crystal size and crystalline morphology. Alternatively, delayed absorption of a parenterally administered compound form can be achieved by dissolving the compound in an oil vehicle. Injectable depot forms are prepared by dissolving or suspending the drug in a polylactide-polyglycerol solution. Forming a microencapsulated matrix of the compound in a biodegradable polymer such as lycolide The compound to polymer ratio and the particular polymer utilized Depending on the nature of the polymer, the release rate of the compound can be controlled. Examples include poly(orthoesters) and poly(anhydrides). Formulations may also be used to deliver the compounds to liposomes or microemulsions that are compatible with biological tissue. It is prepared by encapsulating it in a

[0267] Compositions for rectal or vaginal administration preferably comprise a compound of the invention in cocoa butter. , polyethylene glycol, or a compound that is solid at ambient temperature but liquid at body temperature, Therefore, suitable non-steroidal anti-inflammatory agents such as suppository waxes which melt in the rectum or vaginal cavity and release the active compound are suitable. Suppositories can be prepared by mixing with an irritating excipient or carrier.

[0268] Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In such solid dosage forms, the active compound is preferably soluble in sodium citrate or diphosphate. At least one inert pharmaceutically acceptable excipient or carrier, such as calcium and / or a) starch, lactose, sucrose, glucose, mannitol and b) fillers or extenders such as silicic acid, e.g., carboxymethylcellulose, alginate, binders such as phosphates, gelatin, polyvinylpyrrolidone, sucrose and acacia, ) humectants such as glycerol, d) agar, calcium carbonate, potato or tapioca disintegrating agents such as starch, alginic acid, certain silicates and sodium carbonate; e) paprika; f) dissolution retarders such as quaternary ammonium compounds; g) absorption enhancers such as e.g. h) humectants such as cetyl alcohol and glycerol monostearate; and absorbents such as bentonite clay, and i) talc, calcium stearate, Magnesium stearate, solid polyethylene glycol, sodium lauryl sulfate, etc. In the case of capsules, tablets and pills, The dosage form may also include a buffering agent.

[0269] Using excipients such as lactose or milk sugar and high molecular weight polyethylene glycols Solid compositions of a similar type are also employed as fillers in soft and hard-filled gelatin capsules. Solid dosage forms such as tablets, dragees, capsules, pills, and granules may be enterically coated. coatings and shells, such as encapsulants, encapsulants, and other coatings well known in the pharmaceutical arts These may optionally contain an opacifying agent, and The active substance may be delivered only or preferably in a specific part of the intestinal tract, optionally in a delayed manner. Examples of embedding compositions that can be used include: , polymeric substances and waxes. Lactose or milk sugar and high molecular weight polymers Filling in soft and hard-filled gelatin capsules using excipients such as ethylene glycol Similar types of solid compositions may also be utilized as fillers.

[0270] The active compounds can also be in microencapsulated form with one or more excipients as noted above. Solid dosage forms such as tablets, dragees, capsules, pills, and granules may be enteric coated. coatings, such as controlled release coatings, controlled release coatings and other coatings well known in the pharmaceutical arts. Such solid dosage forms can be prepared with an active ingredient, such as a coating and a shell. The mixture may contain at least one inert diluent, such as sucrose, lactose, or starch. Such dosage forms may also be admixed with, as is normal practice, other than inert diluents. Additional substances, such as tableting lubricants, and magnesium stearate and microcrystalline Other tableting aids such as cellulose may be included. For capsules, tablets and pills: Dosage forms may also contain buffering agents. They may also contain opacifying agents if necessary, and may also contain active ingredients. The active substance is then released into the intestinal tract, preferably in a specific part of the intestinal tract, optionally in a delayed manner. Examples of embedding compositions that can be used include: These include polymeric substances and waxes.

[0271] Dosage forms for topical or transdermal administration of the compounds of the present invention include ointments, pastes, and creams. The active ingredient may be a liquid, such as a lotion, gel, powder, solution, spray, inhalant, or patch. The components are prepared under sterile conditions in a pharmaceutically acceptable carrier and, as required, any other necessary Ophthalmic formulations, ear drops, and eye drops are also within the scope of this invention. Furthermore, the present invention provides for controlled delivery of compounds into the body. The use of transdermal patches is contemplated as an additional advantage. Such dosage forms allow the compound to be administered to the appropriate area. It can be prepared by dissolving or dispersing the compound in a vehicle. Absorption enhancers can be used to improve efficiencies. The rate can be controlled by providing a rate-controlling membrane. or by dispersing the compound in a polymer matrix or gel. This can be controlled.

[0272] The term "biological sample" as used herein includes, without limitation, cells Cultures or extracts thereof, biopsies or extracts thereof obtained from mammals, and blood, saliva, fluid, urine, feces, semen, tears, or other bodily fluids or extracts thereof.

[0273] In another embodiment, the present invention provides a method for treating mTORC1-mediated inflammatory bowel disease in a patient in need thereof. a method for treating a disorder mediated by steroids, comprising administering to said patient a compound according to the invention or The present invention provides a method for treating such disorders, comprising administering the pharmaceutically acceptable composition. The harms are detailed herein.

[0274] Depending on the particular condition or disease being treated, additional As used herein, a therapeutic agent for a particular disease or The additional therapeutic agent that is normally administered to treat the disease or condition being treated is referred to as the "disease or condition being treated." It is known as "suitable for

[0275] The compounds of the invention may be used to advantage in combination with other antiproliferative compounds. Such antiproliferative compounds include, but are not limited to, aromatase inhibitors agents, antiestrogens, topoisomerase I inhibitors, topoisomerase II inhibitors, duct-active compounds, alkylating compounds, histone deacetylase inhibitors, and cell differentiation processes Inducing compounds, cyclooxygenase inhibitors, MMP inhibitors, mTOR inhibitors, anti-cancer Antitumor antimetabolites, platin compounds, targeting protein or lipid kinase activity / and compounds that reduce the activity of proteins or lipid phosphatases, as well as additional anti-angiogenic compounds. compounds that target, decrease, or inhibit gonadorelin enzymes, gonadorelin agonists, anti- Androgens, methionine aminopeptidase inhibitors, matrix metalloproteinases enzyme inhibitors, bisphosphonates, biological response modifiers, antiproliferative antibodies, heparanase inhibitors , inhibitors of Ras oncogenic isoforms, telomerase inhibitors, proteasome inhibitors , a compound used in the treatment of hematological malignancies, targets and reduces the activity of Flt-3 , or an inhibitory compound, 17-AAG (17-allylaminogeldanamycin, NSC 330507), 17-DMAG (17-dimethylaminoethylamino-17-demethylamino) Shi-geldanamycin, NSC707545), IPI-504, Conforma T CNF1010, CNF2024, CNF1010 from herapeutics Hsp90 inhibitors, temozolomide (Temodal®), GlaxoSmit SB715992 or SB743921 from hKline, or Combina Kinesin spindle protein inhibitors such as pentamidine / chlorpromazine from toRx anti-inflammatory drug, ARRY142886 from Array BioPharma, AstraZeneca AZD6244 from ECA, PD181461 from Pfizer, and Leucovorin The term "aromatase inhibitor" as used herein includes MEK inhibitors such as riboflavin. When used, estrogen production, e.g., the substrate androstenedione and test Compounds that inhibit the conversion of steroids to estrone and estradiol, respectively The term refers to, but is not limited to, steroids, particularly atamestane, exemestane steroids, especially nonsteroidal, especially aminoglutethimide, log Retimide, pyridoglutethimide, trilostane, testolactone, ketoconazole, borohydrazide Includes aztrezole, fadrozole, anastrozole, and letrozole. is commercially available under the trade name Aromasin™. Formestane is commercially available under the trade name Len Fadrozole is sold under the trade name Afema™. Anastrozole is commercially available under the trade name Arimidex™. Letrozole is marketed under the trade names Femara™ or Femar™. Aminoglutethimide is commercially available under the trade name Orimeten™. The combinations of the present invention, which include chemotherapeutic agents that are thrombinase inhibitors, are useful in treating hormone-sensitive tumors, such as breast tumors. It is particularly useful in the treatment of receptor-positive tumors.

[0276] The term "antiestrogen" as used herein refers to an agent that binds to an estrogen receptor. The term relates to compounds that antagonize the effects of estrogen at the steroid level. Tamoxifen, fulvestrant, raloxifene and raloxifene hydrochloride Tamoxifen is available commercially under the trade name Nolvadex™. Fulvestrant hydrochloride is commercially available under the trade name Evista™. It may be administered under the trade name Faslodex™. The combinations of the present invention comprising the agent are particularly useful in the treatment of estrogen receptor positive tumors, such as breast tumors. It is useful.

[0277] The term "antiandrogen" as used herein refers to an agent that inhibits the biological activity of male hormones. Any substance capable of inhibiting the biological action of, but not limited to, bicalcium The term "gonadorelin agonist" includes agonist, agonist, agonist-like substance ... As used herein, terms include, but are not limited to, abarelix, goserelin, and Contains goserelin acetate. Goserelin is also administered under the trade name Zoladex®. good.

[0278] The term "topoisomerase I inhibitor" as used herein includes, but is not limited to, Not specified, but includes topotecan, gimatecan, irinotecan, camptothecin n) and its analogs, 9-nitrocamptothecin and the macromolecular camptothecin conjugates Irinotecan is, for example, available in its commercially available form. Topotecan may be administered under the trade name Camptosar™. It is commercially available under the trademark Hycamptin.

[0279] The term "topoisomerase II inhibitors" as used herein refers to Without limitation, doxorubicin (including liposomal formulations such as Caelyx™) anthracyclines such as daunorubicin, epirubicin, idarubicin, and nemorubicin culin, the anthraquinones mitoxantrone and losoxantrone, and podoxantrone It contains the phyllotoxins etoposide and teniposide. Etoposide is sold under the trade name Eto Teniposide is commercially available under the trade name VM26-Bristo™. Doxorubicin is commercially available under the trade name Acriblastin™ or Epirubicin is marketed under the trademark Adriamycin. Idarubicin is commercially available under the trade name Zavedos®. Mitoxantrone is sold under the trade name Novantron.

[0280] The term "microtubule active agent" includes, but is not limited to, paclitaxel and docetaxel. Taxanes such as Taxel, vinblastine or vinblastine sulfate, and vincristine or vincristine sulfate, and vinca alkaloids such as vinorelbine, Disco Microcrystalline cellulose containing dermolide, colchicine, and epothilone and its derivatives Paclitaxel is a compound that inhibits microtubule polymerization and is a tubule-stabilizing, microtubule-destabilizing compound. It is marketed under the trade name Taxol™. Docetaxel is marketed under the trade name Taxotere Vinblastine sulfate is commercially available under the trade name Vinblastin®. Vincristine sulfate is commercially available under the trade name Farmistin. It is commercially available under the trademark.

[0281] The term "alkylating agent" as used herein includes, but is not limited to, , cyclophosphamide, ifosfamide, melphalan, or nitrosoureas (BCNU or Gliadel). Cyclophosphamide is sold under the trade name Cyclostin™ Ifosfamide is commercially available under the trade name Holoxan™ .

[0282] The term "histone deacetylase inhibitor" or "HDAC inhibitor" refers to a histone The present invention relates to compounds which inhibit deacetylase and have antiproliferative activity. Includes, but is not limited to, suberoylanilide hydroxamic acid (SAHA).

[0283] The term "antineoplastic antimetabolite" includes, but is not limited to, 5-fluorouracil. Rasil or 5-FU, capecitabine, gemcitabine, 5-azacytidine, and decitabine DNA demethylating compounds such as methotrexate and edatrexate, and Includes folate antagonists such as pemetrexed. Capecitabine is sold under the brand name Xeloda Gemcitabine is commercially available under the trade name Gemzar™. There are.

[0284] The term "platin compound" as used herein is not limited to include carboplatin, cisplatin, cisplatinum, and oxaliplatin. Ruboplatin may be used, for example, in the form as it is marketed, for example under the trademark Carboplat Oxaliplatin may be administered, for example, in the form as it is marketed, e.g. It may be administered under the trademark Eloxatin™.

[0285] "Protein or lipid kinase activity, or protein or lipid phosphatase activity The term "compounds that target / reduce enzyme activity, or further anti-angiogenic compounds" As used herein, refers to, but is not limited to, protein tyrosine kinases. and / or serine and / or threonine kinase inhibitors or lipid kinase inhibitors a) targeting and decreasing the activity of platelet-derived growth factor receptor (PDGFR); compounds that target, decrease, or inhibit the activity of PDGFR, e.g., or inhibiting compounds, particularly compounds that inhibit the PDGF receptor, such as N-phenyl- 2-pyrimidine-amine derivatives, such as imatinib, SU101, SU6668 and GFB-111, b) targets and reduces the activity of fibroblast growth factor receptors (FGFRs) c) compounds that inhibit or stimulate the activity of insulin-like growth factor receptor I (IGF-IR) Compounds that target, decrease, or inhibit the activity of IGF-IR, e.g. Compounds that target, decrease, or inhibit, in particular, the kinase activity of the IGF-1 receptor compounds that inhibit the activity of IGF-I receptors or the extracellular domain of the growth factor d) antibodies that target the activity of the Trk receptor tyrosine kinase family, e) compounds that reduce or inhibit AxI receptor tyrosine kinase activity or ephrin B4 inhibitors; f) compounds that target, decrease, or inhibit the activity of the synthase kinase family; Compounds that target, decrease, or inhibit the activity of the Ret receptor tyrosine kinase g) targeting or decreasing the activity of the Kit / SCFR receptor tyrosine kinase; h) compounds that inhibit Ck1, which is part of the PDGFR family, e.g., imatinib; compounds that target, decrease, or inhibit the activity of IT receptor tyrosine kinases; For example, targeting or decreasing the activity of the c-Kit receptor tyrosine kinase family or compounds that inhibit the c-Kit receptor, particularly compounds that inhibit the c-Kit receptor, e.g., imatinib i) members of the c-Abl family, their gene fusion products (e.g., BCR- Compounds that target, decrease, or inhibit the activity of Abl kinase and mutants compounds, such as members of the c-Abl family and their gene fusion products. Compounds that target, decrease, or inhibit, e.g., N-phenyl-2-pyrimidinyl amine derivatives, such as imatinib or nilotinib (AMN107), PD180 970, AG957, NSC680410, PD17395 from ParkeDavis 5, or dasatinib (BMS-354825), j) protein kinase C (PKC) and members of the Raf family of serine / threonine kinases, MEK, SRC, and J AK / pan-JAK, FAK, PDK1, PKB / Akt, Ras / MAPK, PI3K, S YK, TYK2, BTK and TEC family members, and / or midostasis The cyclin-dependent kinase family (C) Compounds that target, decrease, or inhibit the activity of members of the IL-16 receptor agonists (IL-16 receptor agonists); Examples of compounds include UCN-01, safingol, BAY43-9006, and Bryosta. Chin1, Perifosine, Irmofosine, RO318220 and RO320432, G O6976, Isis3521, LY333531 / LY379196, isoquinolination Compound, FTI, PD184352 or QAN697 (PI3K inhibitor) or AT75 19 (CDK inhibitors)) k) Protein tyrosine kinase inhibitors compounds that target, reduce, or inhibit the evec™), or tyrphostins, e.g., tyrphostin A23 / RG-508 10, AG99, Tyrphostin AG213, Tyrphostin AG1748, Tyrphostin A G490, Tyrphostin B44, Tyrphostin B44(+) enantiomer, Tyrphostin tyrphostins AG555, AG494, tyrphostins AG556, AG957, and adafoscin Adamantyl (4-{[2,5-dihydroxyphenyl)methyl]amino}benzoate Protein tyrosine kinases, including esters, NSC680410, and adafostin l) compounds that target, decrease or inhibit the activity of inhibitors of receptor tyrosine kinases; Enzymes (EGFR1, ErbB2, ErbB3, Erb as homo- or heterodimers) B4) and their mutants. compounds that stimulate or inhibit the activity of the epidermal growth factor receptor family, e.g. compounds that increase, decrease, or inhibit the activity of the EGF receptor tyrosine kinase family, in particular Inhibits members of the family, such as EGF receptor, ErbB2, ErbB3 and ErbB4 or a compound, protein or antibody that binds to EGF or an EGF-related ligand. CP358774, ZD1839, ZM105180, trastuzumab (Herce ptin(TM)), cetuximab (Erbitux(TM)), Iressa, Tar ceva, OSI-774, Cl-1033, EKB-569, GW-2016, E1. 1, E2.4, E2.5, E6.2, E6.4, E2.11, E6.3 or E7.6. 3 and 7H-pyrrolo-[2,3-d]pyrimidine derivatives, m) c-Met receptor activity Compounds that target, decrease, or inhibit the activity of c-Met, e.g., compounds that increase, decrease, or inhibit the kinase activity of the c-Met receptor, in particular Compounds that inhibit or target the extracellular domain of c-Met or bind to HGF Antibodies, including but not limited to PRT-062070, SB-1578, and Bali Citinib, pacritinib, momelotinib, VX-509, AZD-1480, TG-10 Antibody to one or more JAK-α pharmacokinetic (JAK) antibodies, including 1348, tofacitinib, and ruxolitinib Members of Milli (JAK1 / JAK2 / JAK3 / TYK2 and / or pan-JAK) o) compounds that target, decrease, or inhibit the kinase activity of However, ATU-027, SF-1126, DS-7423, PBI-05204, G SK-2126458, ZSTK-474, buparlisib, pictorelisib, PF-46 91502, BYL-719, Ductolisib, XL-147, XL-765 and Idera Targeting and decreasing the kinase activity of PI3 kinase (PI3K), including lisib or inhibiting compounds, and q) compounds including, but not limited to, cyclopamine, vismodena including gibb, itraconazole, erismodegib and IPI-926 (saridegib), Signal transduction via the Hedgehog protein (Hh) or Smoothened receptor (SMO) pathways These include compounds that target, decrease or inhibit the action of the receptor.

[0286] The term "PI3K inhibitor" as used herein is not limited to against one or more enzymes of the phosphatidylinositol-3-kinase family These include, but are not limited to, compounds that have inhibitory activity against PI3Kα, PI3Kγ, PI3Kδ, PI3Kβ, PI3K-C2α, PI3K-C2β, PI3K -C2γ, Vps34, p110-α, p110-β, p110-γ, p110-δ, p These include p85-α, p85-β, p55-γ, p150, p101 and p87. Examples of particularly useful PI3K inhibitors include, but are not limited to, ATU-027, SF -1126, DS-7423, PBI-05204, GSK-2126458, ZSTK -474, buparlisib, pictorelisib, PF-4691502, BYL-719, These include ixazomib, XL-147, XL-765 and idelalisib.

[0287] The term "Bcl-2 inhibitor" as used herein includes, but is not limited to, However, it contains compounds that have inhibitory activity against B-cell lymphoma 2 protein (Bcl-2). These include, but are not limited to, ABT-199, ABT-731, and ABT-7 37, apogossypol, Ascenta's pan-Bcl-2 inhibitor, curcumin (and its analogue), Bcl-2 / Bcl-xL dual inhibitor (Infinity Pharma uticals / Novartis Pharmaceuticals), Genase nse(G3139), HA14-1 (and its analogs, WO2008 / 118802 See U.S. Pat. No. 7,390,799, and U.S. Pat. No. 6,390,799. 9), NH-1 (Shenayng Pharmaceutical University), Obatoclax (and its analogues, WO2004 / 106 328), S-001 (Gloria Pharmaceuticals ), TW series compounds (University of Michigan), and venetoclax. In some embodiments, the Bcl-2 inhibitor is a small molecule therapeutic agent. The l-2 inhibitors are peptidomimetics.

[0288] The term "BTK inhibitor" as used herein includes, but is not limited to, and compounds having inhibitory activity against Bruton's tyrosine kinase (BTK), include, but are not limited to, AVL-292 and ibrutinib.

[0289] The term "SYK inhibitor" as used herein includes, but is not limited to, , including compounds having inhibitory activity against spleen tyrosine kinase (SYK), including: Including but not limited to PRT-062070, R-343, R-333, Excel lair, PRT-062607, and fostamatinib.

[0290] Further Examples of BTK Inhibitory Compounds and Such Compounds in Combination with Compounds of the Invention Conditions treatable by the method are described in WO 2007 / 022994, the entire contents of which are incorporated herein by reference. 08 / 039218 and WO2011 / 090760.

[0291] Further Examples of SYK Inhibitory Compounds and Such Compounds in Combination with Compounds of the Invention Conditions treatable by the method are described in WO 2007 / 022994, the entire contents of which are incorporated herein by reference. 03 / 063794, WO2005 / 007623 and WO2006 / 078846 can be found.

[0292] Further Examples of PI3K Inhibitory Compounds and Such Compounds in Combination with Compounds of the Invention Conditions treatable by the product are described in WO2 004 / 019973, WO2004 / 089925, WO2007 / 016176, US Patent No. 8,138,347, WO2002 / 088112, WO2007 / 0847 86, WO2007 / 129161, WO2006 / 122806, WO2005 / 11 3554 and WO2007 / 044729.

[0293] Further Examples of JAK Inhibitory Compounds and Such Compounds in Combination with Compounds of the Invention Conditions treatable by the method are described in WO 2007 / 022994, the entire contents of which are incorporated herein by reference. 09 / 114512, WO2008 / 109943, WO2007 / 053452, WO 2000 / 142246 and WO2007 / 070514.

[0294] Further anti-angiogenic compounds include, for example, compounds associated with protein or lipid kinase inhibition. compounds that have an alternative mechanism of their activity, such as thalidomide id™) and TNP-470.

[0295] Examples of proteasome inhibitors useful in combination with the compounds of the present invention include, but are not limited to, However, bortezomib, disulfiram, and epigallocatechin-3-gallate (EGCG) , salinosporamide A, carfilzomib, ONX-0912, CEP-18770 and and MLN9708.

[0296] Targeting, decreasing, or inhibiting the activity of protein or lipid phosphatases The compounds may be, for example, compounds that inhibit phosphatase 1, phosphatase 2, phosphatase 3, phosphatase 4, phosphatase 5, phosphatase 6, phosphatase 7, phosphatase 8, phosphatase 9, phosphatase 10, phosphatase 11, phosphatase 12, phosphat It is an inhibitor of CDC25 or CDC2A.

[0297] Compounds that induce cell differentiation processes include, but are not limited to, retinoic acid, α-, γ-, or δ-tocopherol or α-, γ-, or δ-tocotrienol Examples include:

[0298] The term cyclooxygenase inhibitor as used herein includes but is not limited to Cox-2 inhibitors, 5-alkyl-substituted 2-arylaminophenylacetic acids, and and derivatives such as celecoxib (Celebrex™), rofecoxib (Vi oxx™), etoricoxib, valdecoxib or 5-alkyl-2-aryl Aminophenylacetic acids, such as 5-methyl-2-(2'-chloro-6'-fluoroaniline) (n) Contains phenylacetic acid and lumiracoxib.

[0299] The term "bisphosphonate" as used herein includes, but is not limited to, However, etridonic acid, clodronic acid, tiludronic acid, pamidronic acid, allergy These include urandronate, ibandronate, risedronate, and zoledronic acid. Clodronic acid is commercially available under the trade name Bone fos™. Tiludronic acid is commercially available under the trade name Skelid™. Pamidronic acid is commercially available under the trade name Aredia™. Ibandronic acid is commercially available under the trade name Fosamax™. Risedronic acid is marketed under the trade name Actonel Zoledronic acid is commercially available under the trade name Zometa™. The term "mTOR inhibitor" refers to the inhibitory activity of mammalian target of rapamycin (mTOR). ) and have antiproliferative activity, such as sirolimus (Rapamune ( Registered Trademark), everolimus (Certican™), CCI-779 and AB Regarding T578.

[0300] The term "heparanase inhibitor" as used herein refers to an inhibitor of heparin sulfate. The term refers to compounds that target, decrease, or inhibit the action of certain compounds. The term "biological response modifier" as used herein refers to a compound that is not a steroid or steroid drug. When used, it refers to lymphokines or interferons.

[0301] Inhibition of oncogenic Ras isoforms such as H-Ras, K-Ras, or N-Ras The term "inhibitor" as used herein refers to an inhibitor that targets the oncogenic activity of Ras. compounds that reduce or inhibit the "Farnesyltransferase" such as 115777 (Zarnestra™) The term "telomerase inhibitor" as used herein refers to a telomerase inhibitor. refers to compounds that target, decrease or inhibit the activity of telomerase. Compounds that target, decrease, or inhibit the activity of enzymes, such as telomestatin, among others, are It is a compound that inhibits the telomerase receptor.

[0302] The term "methionine aminopeptidase inhibitor" as used herein means Compounds that target, decrease or inhibit the activity of methionine aminopeptidase refers to compounds that target, decrease, or inhibit the activity of methionine aminopeptidase. Compounds that may be used include, but are not limited to, bengamide or a derivative thereof.

[0303] The term "proteasome inhibitor" as used herein refers to a compound that inhibits the action of a proteasome. refers to compounds that target, decrease, or inhibit the activity of the proteasome. Compounds that target, decrease, or inhibit the These include lutezomib (Velcade™) and MLN341.

[0304] The term "matrix metalloproteinase inhibitors" or ("MMP" inhibitors) As used herein, refers to, but is not limited to, collagen peptidomimetics and and non-peptidomimetic inhibitors, tetracycline derivatives, e.g., hydroxamate peptidomimetics. The tidomimetic inhibitor batimastat and its orally bioavailable analogues Marimastat (BB-2516), Prinomastat (AG3340), Metastat (NSC683551), BMS-279251, BAY 12-9566, TAA21 1, including MMI270B or AAJ996.

[0305] The term "compounds used in the treatment of hematological malignancies" as used herein means , including, but not limited to, FMS-like tyrosine kinase receptor (Flt-3R) activity. FMS-like tyrosine kinase inhibitors are compounds that target, decrease, or inhibit , interferon, 1-β-D-arabinofuranosylcytosine ine)(ara-c) and bisulfan, and anaplastic lymphoma kinase-targeting These include ALK inhibitors, which are compounds that stimulate, decrease, or inhibit ALK expression.

[0306] Targeting and decreasing the activity of FMS-like tyrosine kinase receptor (Flt-3R) or inhibiting compounds, particularly PKC412, midostaurin, staurosporine-induced Flt-3R receptor kinase family, such as SU11248 and MLN518 The compound, protein, or antibody inhibits a member of the

[0307] The term "HSP90 inhibitor" as used herein includes, but is not limited to, However, targeting, decreasing, or inhibiting the intrinsic ATPase activity of HSP90 Degradation of HSP90 client proteins via the ubiquitin proteosome pathway These compounds include compounds that stimulate, target, decrease, or inhibit the endogenous A of HSP90. Compounds that target, decrease, or inhibit TPase activity are particularly useful for 17-antibiotics. 17-demethoxygeldanamycin (17AAG), geldanamycin derivatives , other geldanamycin-related compounds, radicicol, and HDAC inhibitors, such as HS A compound, protein, or antibody that inhibits the ATPase activity of P90.

[0308] The term "antiproliferative antibody" as used herein includes, but is not limited to, , trastuzumab (Herceptin™), trastuzumab-DM1, erbi tux, bevacizumab (Avastin™), rituximab (Rituxan™), (registered trademark), PRO64553 (anti-CD40) and 2C4 antibody. A clean monoclonal antibody, a polyclonal antibody, or at least two intact antibodies Multispecific antibodies formed from the antibody fragments may also be used, as long as they exhibit the desired biological activity. means.

[0309] For the treatment of acute myeloid leukemia (AML), the compounds of the present invention may be administered in combination with standard leukemia therapy. These compounds may be used in combination, particularly in combination with therapies used to treat AML. In particular, the compounds of the present invention are useful as, for example, farnesyltransferase inhibitors and / or Daunorubicin, Adriamycin, Ara-C, VP-16, Teniposide, Mitoxa For the treatment of AML, there are several drugs, such as thiazolidine, thiazolidine diphosphate (ATP), ... It can be administered in combination with other drugs that are useful.

[0310] Other anti-leukemic compounds include, for example, the 2'-alpha-hydroxybenzoates of deoxycytidine. Ara-C, a pyrimidine analogue that is a ribose (arabinoside) derivative, is also an example. In addition, the purine analogues of hydroxanthine, 6-mercaptopurine (6-MP) and fulvestib Darabine phosphate ester, sodium butyrate and suberoylanilide hydrochloride Targeting the activity of histone deacetylase (HDAC) inhibitors such as hydroxyapatite (SAHA) Compounds that increase, decrease, or inhibit the activity of enzymes known as histone deacetylases Specific HDAC inhibitors include MS275, SAHA, and FK228( (formerly FR901228), trichostatin A, and other compounds, including but not limited to N- Hydroxy-3-[4-[[[2-(2-methyl-1H-indol-3-yl)-ethyl phenyl]-amino]methyl]phenyl]-2E-2-propenamide, or a pharmaceutically acceptable salt thereof and N-hydroxy-3-[4-[(2-hydroxyethyl){2-(1 H-indol-3-yl)ethyl]amino]methyl]phenyl]-2E-2-propeno U.S. Patent No. 6,552, which is incorporated herein by reference. Somatostatin receptor antagonists include compounds disclosed in US Pat. No. 5,865,495. As used herein, somatostatins, such as octreotide and SOM230 refers to compounds that target, treat, or inhibit receptors. The term "ionizing radiation" referred to above and below refers to techniques such as ionizing radiation. The term refers to electromagnetic rays (such as X-rays and gamma rays) or particles (such as alpha and beta particles). Ionizing radiation is not limited to the above. Although not specified, it is produced by radiation therapy and is known in the art (Hellman, Principles es of Radiation Therapy, Cancer, in Principles and Practice of Oncology y, Devita et al., Eds., 4th Edition, Vol. 1, pp. 248-275 (1993). I want to be illuminated).

[0311] Additionally, EDG binders and ribonucleotide reductase inhibitors are included. The term "DG binder" as used herein refers to a lymphocyte-specific DG binder, such as FTY720. Refers to a class of immunosuppressants that modulate the recycling of ribonucleotide reductase (RIR) The term "enzyme inhibitor" includes, but is not limited to, fludarabine and / or cytosine ara-arabinoside (ara-C), 6-thioguanine, 5-fluorouracil, cladribine 6-mercaptopurine (especially in combination with ara-C for ALL) and / or refers to pyrimidine or purine nucleoside analogs, including ribonucleic acid or pentostatin. Nucleotide reductase inhibitors, in particular hydroxyurea or 2-hydroxy-1H -isoindole-1,3-dione derivative.

[0312] Furthermore, in particular, 1-(4-chloroanilino)-4-(4-pyridylmethyl)phthalazine or a pharmaceutically acceptable salt thereof, 1-(4-chloroanilino)-4-(4-pyridylmethyl)- (ethyl)phthalazine succinate, Angiostatin™, Endostatin (trademark), anthranilic acid amide, ZD4190, ZD6474, SU5416, SU6 668, VEGF compounds, proteins, or monoclonal antibodies such as bevacizumab antibodies, or VEGF aptamers such as rhuMAb and RHUFab, Macugon , FLT-4 inhibitors, FLT-3 inhibitors, VEGFR-2 IgGI antibodies, angiozymes anti-VEGF agents such as flucloxin (RPI4610) and bevacizumab (Avastin™) Antibodies and anti-VEGF receptor antibodies are examples of such antibodies.

[0313] Photodynamic therapy, as used herein, refers to the use of certain photosensitizing compounds known as photosensitizing compounds. It refers to the use of chemicals to treat or prevent cancer. Examples of photodynamic therapy include Treatment with compounds such as Visudyne™ and porfimer sodium has been reported. Examples include:

[0314] Antiangiogenic steroids, as used herein, include, for example, anecortave, trimethoprim-4000, Amcinolone, hydrocortisone, 11-alpha-epihydrocortisol, cortexolone , 17α-hydroxyprogesterone, corticosterone, desoxycorticosterone, Blocking or inhibiting angiogenesis, such as testosterone, estrone, and dexamethasone It refers to a compound that

[0315] Corticosteroid-containing implants include fluocinolone and dexamethasone. Refers to a compound.

[0316] Other chemotherapeutic compounds include, but are not limited to, plant alkaloids, hormones, Compounds and antagonists, biological response modifiers, preferably lymphokines or inhibitors Terferon, antisense oligonucleotide or oligonucleotide derivative, s hRNA or siRNA, or a wide variety of 1 with other or unknown mechanisms of action. The compound may be a species or a plurality of compounds.

[0317] The structures of active compounds identified by code number, generic name or trade name are listed in the standard list " The Merck Index, current edition or databases, e.g., Patent s International (e.g., IMS World Publicatio ns).

[0318] The compounds of the present invention may also be used in combination with known therapeutic methods, such as the administration of hormones or radiation. In certain embodiments, provided compounds are, among others, It is used as a radiosensitizer for the treatment of tumors that have shown low sensitivity to radiotherapy.

[0319] The compounds of the present invention may be administered alone or in combination with one or more other therapeutic compounds. The potential combination therapies may be administered in the form of fixed combinations or in combinations of the compounds of the invention. The administration of the compound and one or more other therapeutic compounds may be staggered or administered independently of each other. Administration of the given form or fixed combination in combination with one or more other therapeutic compounds The compounds of the present invention are useful in particular for chemotherapy, radiotherapy, immunotherapy, phototherapy, Regarding tumor therapy in combination with surgical intervention, or a combination thereof, separately and can be administered in addition to the above. Adjuvants in the context of other treatment strategies Other potential treatments include the use of steroids to treat patients after tumor regression. Treatment to maintain the patient's condition or even, for example, chemotherapy in at-risk patients. It is a preventative treatment.

[0320] These additional agents may contain the compounds of this invention as part of a multiple dose regimen. Alternatively, these agents may be administered separately from the compositions of the present invention in a single composition. as part of a single dosage form mixed with the compound of formula (I). When administered, the two active agents may be administered simultaneously, sequentially, or within a period of time from each other. They may usually be given within 5 hours of each other.

[0321] As used herein, the terms "combination," "combined," and related terms The term "sequential administration" refers to simultaneous or sequential administration of therapeutic agents according to the present invention. For example, a compound of the present invention may be administered simultaneously or sequentially with another therapeutic agent in separate unit dosage forms or together in a single unit dosage form. Thus, the present invention provides a method for administering a compound of the present invention, an additional therapeutic agent, and a pharmaceutical The pharmaceutical composition may be provided in a single unit dosage form containing a physiologically acceptable carrier, adjuvant, or vehicle.

[0322] The compounds of the present invention and additional compounds may be combined with carrier materials to produce a single dosage form. The amount of both additional therapeutic agents (in compositions containing such additional therapeutic agents) will depend on the host being treated and It depends on the particular mode of administration. Preferably, the composition of the present invention is 0.01 to 100 mg The compound of the present invention should be formulated so that it can be administered in a dosage of 1 / kg body weight / day. .

[0323] In those compositions that include an additional therapeutic agent, the additional therapeutic agent and the compound of this invention may be compatible. Thus, the amount of additional therapeutic agent in such compositions may be greater than or equal to that of that therapeutic agent. In such compositions, the amount of 0.01 to 100 mg of hydroxybenzoates is lower than that required for monotherapy using only hydroxybenzoates. A dosage of 1,000 μg / kg body weight / day of additional therapeutic agent may be administered.

[0324] The amount of additional therapeutic agent present in the compositions of this invention may vary depending on the individual agent used, including the therapeutic agent as the only active agent. Preferably, the amount of the additional The amount of therapeutic agent is about 50% of the amount normally present in a composition containing that agent as the only therapeutically active agent. The range is % to 100%.

[0325] In some embodiments, the additional therapeutic agent administered in combination with a compound of the invention is another m In some embodiments, the additional mTOR inhibitor inhibits the catalytic activity of mTOR. These additional mTOR inhibitors inhibit mTOR by binding to the active site. Examples include dactolisib, 8-(6-methoxy-pyridin-3-yl)-3-methyl-1 -(4-Piperazin-1-yl-3-trifluoromethyl-phenyl)-1,3-dihydriodide Imidazolo[4,5-c]quinolin-2-one (WO2006 / 122806), bis Tuseltib (AZD2014, WO2009 / 153597), AZD8055 (WO2 009 / 153597, XL388 (US Patent Application Publication 2010 / 0305093), Panisertib (MLN0128, INK128, WO2015 / 051043), DS3 078, apitolisib (GDC0980, WO2008 / 070740), omipalisib (GSK-2126458, WO2008 / 14446), NVP-BGT226(Chan g, KY, et al., Clin. Cancer Res. 17(22): 7116-26 (2011)), Boxtal Shiv (XL765, SAR245409, WO2007 / 044813), PF0469 1502 (WO2008 / 032162), gedatolisib (PF05212384, PK I-587, WO2009 / 143313), SF1126(WO2004 / 08992) 5), GSK1059615 (WO2007 / 136940), BI-860585, O SI 027(WO2007 / 061737), VS5584(WO2010 / 1144 84), CC-223 (WO2010 / 062571), DCBCI-0901 (Lee, YE, et al., Mol. Canc. Thera. 12(11 Suppl): Abstract nr C270 (2013 )):), LY3023414(WO2012 / 097039), P529(WO2007 / 133249), panulisib (P7170, WO2012 / 007926), DS-7 423 (Kashiyama, T., et al., PLoS One 9(2): e87220 (2014)), PWT3 3567 mesylate (VCD-597, WO2010 / 110685), ME-344( NV-128, Navarro, P., et al., Cell Rep. 15(12):2705-18 (2016)), A BTL0812(WO2010 / 106211), WYE-132, EXEL-3885 (Eur J Cancer Suppl. 6(12): Abst 322 (2008)), EXEL-4431(Eur J Cancer Suppl. 6(12): Abst 322 (2008)), AR-mTOR-26 (101st Ann u Meet Am Assoc Cancer Res (AACR) (April 17-21, Washington, DC) 201 0, Abst 4484), NV-128(AB Alvero et al., Mol Cancer Ther. 10(8 ): 1385-93 (2011)), salinomycin (VS-507, Gupta, PB, et al., Ce ll 138(4): 645-59 (2009)), BN-107, BN-108, WAY-600, WY E-687, WYE-354 (Yu, K., et al., Cancer Res. 69(15): 6232-40 (2009)), Ku-063794 (Garcia-Martinez, JM, et al., Biochem. J. 4 21(1): 29-42 (2009)), tolquinib (PP242, Apsel, B., et al., Nat. Ch em. Biol. 4(11): 691-99 (2008)), PP30, CZ415(REF), INK10 69, EXEL-2044, EXEL-7518, SB2158, SB2280, AR- mTOR-1(Wallace, EM, et al., Mol. Canc. Thera. 8(12 Suppl): Abs t. B267 (2009)).

[0326] Reference herein to any specific additional mTOR inhibitor includes any pharmaceutically acceptable salt thereof. Acceptable salts, stereoisomers, tautomers, solvates, hydrates and polymorphs are also included.

[0327] The compounds of the present invention or pharmaceutically acceptable compositions thereof may also be used in the manufacture of prostheses, artificial valves, blood vessels, and the like. For coating implantable medical devices such as vascular grafts, stents and catheters For example, vascular stents may be incorporated into compositions for preventing restenosis (the retraction of the blood vessel wall after injury). However, stents or other implantable devices have been used to overcome the Patients using the device are at risk of clot formation or platelet activation. These can be pre-coated with a pharmaceutically acceptable composition containing a lipase inhibitor. The undesirable effects of coating with the compounds of the present invention can be prevented or reduced. The implantable device is another embodiment of the present invention. [Example]

[0328] As shown in the examples below, in certain exemplary embodiments, the following general procedure The compounds are prepared according to the following general methodology. However, the following general methods and other methods known to those skilled in the art are applicable to all of the methods described herein. This may apply to compounds, as well as to each subclass and species of these compounds. It is understood that (Luengo, JI et al., Chem. Biol., 2(7): 471-81 (1995); and Grinfeld, AA et al., Tet. Lett., 35(37): 6835-38 (1994). I want to be.

[0329] List of abbreviations used in the experimental section. CH3CN:Acetonitrile DCE: dichloroethane DCM: dichloromethane DIPEA: N,N-diisopropylethylamine DMF: N,N-dimethylformamide DMSO: dimethyl sulfoxide ESI: Electrospray ionization EtOAc: ethyl acetate EtOH: ethanol h: time HBr: Hydrogen bromide HF: Hydrogen fluoride HND-8: Acidic ion exchange resin (e.g., Amberlyst) H2O: Water HPLC: High-performance liquid chromatography MeOH: Methanol min:minutes mL: milliliter mM: millimolar concentration mmol: millimolar MS: Mass spectrometry N2: Nitrogen gas NaHCO3: Sodium bicarbonate NaI: sodium iodide NaN3: Sodium azide NaOH: Sodium hydroxide Na2SO4: Sodium sulfate NH4Cl: Ammonium chloride NMR: Nuclear magnetic resonance method ℃: Celsius prep-HPLC: preparative high-performance liquid chromatography PPh3: Triphenylphosphine p-TsOH: paratoluenesulfonic acid rt: room temperature TEA: Triethylamine TFA: Trifluoroacetic acid THF: tetrahydrofuran

[0330] Example 1 (21E,23E,25E,26E,34R,35S,36R,37R,39R,41 S,44S,45R,46R,55S)-45,55-dihydroxy-43-[2-[2 -(2-hydroxyethoxy)ethoxy]ethoxy]-44-[(1S)-2-[(1S ,3R,4R)-4-hydroxy-3-methoxy-cyclohexyl]-1-methyl-ethyl

[0046] -46-methoxy-34,35,36,37,47,48-hexamethyl-66,6 7-Dioxa-56-azatricyclohexatriaconta-21,23,25(47), 26(48)-tetraene-49,50,51,52,53-pentone (I-28, I- Synthesis of 29 and I-30: [ka] Synthesis scheme: [ka] Procedure and Characterization:

[0331] 2-[2-(2-hydroxyethoxy)ethoxy]ethanol (5 mL) was added to the rapamycin solution. Synthon (0.5 g, 0.547 mmol) and p-toluenesulfonic acid hydrate (0.52 g, 2.73 mmol) in THF (15 mL) was added at 25°C. The mixture was stirred for 2 hours, then added to ice-cold saturated aqueous NaHCO3 solution and extracted with EtOAc. The organic layers were combined, then dried over Na2SO4, filtered, and concentrated in vacuo. The crude material was purified by reverse phase chromatography (CH3CN / pure water: 7:3) to give 21E,23E,25E,26E,34R,35S,36R,37R,39R,41S, 44S,45R,46R,55S)-45,55-dihydroxy-43-[2-[2-( 2-hydroxyethoxy)ethoxy]ethoxy]-44-[(1S)-2-[(1S,3 R,4R)-4-hydroxy-3-methoxy-cyclohexyl]-1-methyl-ethyl] -46-Methoxy-34,35,36,37,47,48-hexamethyl-66,67- Dioxa-56-azatricyclohexatriaconta-21,23,25(47),26 (48)-Tetraene-49,50,51,52,53-pentone (I-28: 0.19 g, yield 33.7%) as a white solid. + , m / z):1054.4[ M + Na] + When 1.5 g of this material was subjected to chiral separation, I-29 (0.6 mg) and and I-30 (0.2 g) were obtained.

[0332] Chiral separation methods: Column: CHIRALPAK IC (IC00CD-TB016) Column size: 0.46cm inner diameter x 15cm length Mobile phase: hexane / EtOH = 60 / 40 (V / V) Flow rate: 1.0 ml / min Wavelength: UV254nm Temperature: 35℃ HPLC apparatus: Shimadzu Corporation LC-20AD CP-HPLC-05

[0333] I-29: 1 H NMR (500 MHz, CDCl3) δ 6.41 - 6.20 (m, 2H), 6.13 (dd, J = 15.0, 10.3 Hz, 1H), 5.92 (dd, J = 32.7, 11.0 Hz, 1H), 5.51 (dd, J = 15.1, 8.9 Hz, 1H), 5.41 (d, J = 9.9 Hz, 1H), 5.27 (d, J = 5.3 Hz, 1H), 5.13 (dd, J = 26.5, 20.5 Hz, 1H), 4.85 (s, 1H), 4.1 9 (t, J = 8.9 Hz, 1H), 3.92 (d, J = 36.4 Hz, 1H), 3.80 - 3.51 (m, 12H), 3.50 - 3.24 (m, 12H), 2.87-2.51 (m, 6H), 2.29 (t, J = 3 4.7 Hz, 2H), 2.12 - 1.87 (m, 5H), 1.84 - 1.66 (m, 13H), 1.53 - 1.15 (m, 9H), 1.15 - 0.77 (m, 18H), 0.65 (dt, J = 20.2, 10.1 Hz , 1H).

[0334] (Example 2) (21E,23E,25E,26E,34R,35S,36R,37R,39R,41 S,44S,45R,46R,55S)-43-[2-[2-(2-アミノエトキシ)エ トキシ]エトキシ]-45,55-ジヒドロキシ-44-[(1S)-2-[(1S,3 R,4R)-4-hydroxy-3-methoxy-cyclohexyl]-1-methyl-ethyl] -46-Methoxy-34,35,36,37,47,48-hexamethyl-66,67- Dioxa-57-azatricyclohexatriaconta-21,23,25(47),26 (48)-Tetraene-49,50,51,52,53-pentone trifluoroacetate ( Synthesis of I-39): [ka] Synthesis scheme: [ka] Procedure and Characterization: Step 1: 2-(2-(2-bromoethoxy)ethoxy)ethanol:

[0335] Hydrogen bromide (86.21 g, 1.07 mmol, 115 mL) was added to 2-[2-(2-hydroxybenzoyl) ((2-hydroxyethoxy)ethoxy]ethanol (100g, 665.90mmol) in toluene (1.15 L) of the solution, and the resulting mixture was stirred at reflux for 18 hours. The organic layer was washed with aqueous NaOH, concentrated in vacuo, and then purified by silica gel chromatography. The 2-[2-(2-bromoethoxy)methyl]- [Ci)ethoxy]ethanol (20 g, yield 14%) was obtained as a liquid. 1 H NMR (400 M Hz, CDCl3) δ 3.83 (t, J = 6.2 Hz, 2H), 3.77 - 3.72 (m, 2H), 3.6 9 (s, 4H), 3.64 - 3.61 (m, 2H), 3.49 (t, J = 6.1 Hz, 2H), 2.51 (t, J = 6.1 Hz, 1H). Step 2: (21E, 23E, 25E, 26E, 34R, 35S, 36R, 37R, 3 9R,41S,44S,45R,46R,55S)-43-[2-[2-(2-bromoethenyl) 45,55-dihydroxy-44-[(1S)-2-[ethoxy)ethoxy]ethoxy]-45,55-dihydroxy-44-[(1S)-2-[ (1S,3R,4R)-4-hydroxy-3-methoxy-cyclohexyl]-1-methyl -ethyl]-46-methoxy-34,35,36,37,47,48-hexamethyl-6 5,66-Dioxa-56-azatricyclohexatriaconta-21,23,25(4 7),26(48)-tetraene-49,50,51,52,53-pentone:

[0336] 2-[2-(2-bromoethoxy)ethoxy]ethanol (0.12 g, 0.547 m mol, 2 mL) was dissolved in rapamycin (0.5 g, 0.547 mmol) and p-toluenesulfonyl ether (PHE). A solution of benzoxazole sulfonic acid hydrate (0.5 g, 2.73 mmol) in THF (7 mL) was added at room temperature. The resulting mixture was stirred for 2 hours. Then, ice-cold aqueous NaHCO3 solution was added, The mixture was extracted with EtOAc (30 mL x 3), and the organic phase was then dried over Na2SO4. The resulting crude material was purified by reverse phase chromatography (CH3CN / pure Water = 7:3) and purified (21E, 23E, 25E, 26E, 34R, 35S, 36R ,37R,39R,41S,44S,45R,46R,55S)-43-[2-[2-( 2-Bromoethoxy)ethoxy]ethoxy]-45,55-dihydroxy-44-[(1 S)-2-[(1S,3R,4R)-4-hydroxy-3-methoxy-cyclohexyl] -1-methyl-ethyl]-46-methoxy-34,35,36,37,47,48-hex samethyl-65,66-dioxa-56-azatricyclohexatriaconta-21,2 3,25(47),26(48)-tetraene-49,50,51,52,53-pent (0.2g, yield 33.4%, 1 HNMR shows impurities of rapamycin) as a white solid MS(EI + , m / z): 1116.4 [M + Na] + . Step 3: (21E, 23E, 25E, 26E, 34R, 35S, 36R, 37R, 3 9R,41S,44S,45R,46R,55S)-43-[2-[2-(2-azidoe 45,55-dihydroxy-44-[(1S)-2-[ethoxy)ethoxy]ethoxy]-45,55-dihydroxy-44-[(1S)-2-[ (1S,3R,4R)-4-hydroxy-3-methoxy-cyclohexyl]-1-methyl -ethyl]-46-methoxy-34,35,36,37,47,48-hexamethyl-6 8,69-Dioxa-59-azatricyclohexatriaconta-21,23,25(4 7),26(48)-tetraene-49,50,51,52,53-pentone:

[0337] NaN3 (1.07g, 16.44mmol), NaI (0.33g, 2.19mmol) l) and (21E, 23E, 25E, 26E, 34R, 35S, 36R, 37R, 39 R,41S,44S,45R,46R,55S)-43-[2-[2-(2-bromoethoxy) 45,55-dihydroxy-44-[(1S)-2-[( 1S,3R,4R)-4-hydroxy-3-methoxy-cyclohexyl]-1-methyl- Ethyl]-46-methoxy-34,35,36,37,47,48-hexamethyl-65 ,66-Dioxa-56-azatricyclohexatriaconta-21,23,25(47 ), 26(48)-tetraene-49,50,51,52,53-pentone (0.6g, A solution of 0.548 mmol) in 10 mL of DMF was stirred at 60° C. for 1.5 hours. Then, the reaction was quenched with EtOAc (50 mL) and the mixture was diluted with aqueous NH4Cl (20 The crude material was washed with 1 mL of HCl, dried over Na2SO4, filtered, and concentrated in vacuo. The compounds were purified by chromatography (CH3CN / pure water = 4:1) to give (21E, 23E, 25 E,26E,34R,35S,36R,37R,39R,41S,44S,45R,46 R,55S)-43-[2-[2-(2-azidoethoxy)ethoxy]ethoxy]-45 ,55-dihydroxy-44-[(1S)-2-[(1S,3R,4R)-4-hydroxy 3-(3-methoxy-cyclohexyl)-1-methyl-ethyl)-46-methoxy-34, 35,36,37,47,48-Hexamethyl-68,69-dioxa-59-azatriamine Cyclohexatriaconta-21,23,25(47),26(48)-tetraene-4 9,50,51,52,53-pentone (0.3 g, 51.8% yield) was obtained as a pale yellow solid. MS(EI + , m / z): 1079.4 [M + Na] + . Step 4: (21E, 23E, 25E, 26E, 34R, 35S, 36R, 37R, 3 9R,41S,44S,45R,46R,55S)-43-[2-[2-(2-aminoethyl) 45,55-dihydroxy-44-[(1S)-2-[ethoxy)ethoxy]ethoxy]-45,55-dihydroxy-44-[(1S)-2-[ (1S,3R,4R)-4-hydroxy-3-methoxy-cyclohexyl]-1-methyl -ethyl]-46-methoxy-34,35,36,37,47,48-hexamethyl-6 6,67-Dioxa-57-azatricyclohexatriaconta-21,23,25(4 7),26(48)-tetraene-49,50,51,52,53-pentonetrifluoro Acetate:

[0338] Triphenylphosphine (0.186 g, 0.7 mmol) was added to (21E, 23E, 2 5E,26E,34R,35S,36R,37R,39R,41S,44S,45R,4 6R,55S)-43-[2-[2-(2-azidoethoxy)ethoxy]ethoxy]-4 5,55-dihydroxy-44-[(1S)-2-[(1S,3R,4R)-4-hydro 3-methoxy-cyclohexyl]-1-methyl-ethyl]-4,6-methoxy-34 ,35,36,37,47,48-Hexamethyl-68,69-dioxa-59-azato Lithium cyclohexatriaconta-21,23,25(47),26(48)-tetraene 49,50,51,52,53-pentone (0.25 g, 0.24 mmol) in THF( The resulting solution was heated at 60°C for 2 min. The mixture was stirred for 6 hours at room temperature, then 0.05 mL of water was added and the mixture was stirred for 6 hours at room temperature, then The resulting crude material was purified by reverse phase chromatography (0.02% T in CH3CN / water). FA (2:3)) and purified (21E, 23E, 25E, 26E, 34R, 35S, 3 6R,37R,39R,41S,44S,45R,46R,55S)-43-[2-[2 -(2-aminoethoxy)ethoxy]ethoxy]-45,55-dihydroxy-44-[ (1S)-2-[(1S,3R,4R)-4-hydroxy-3-methoxy-cyclohexyl 46-methoxy-34,35,36,37,47,48- Hexamethyl-66,67-dioxa-57-azatricyclohexatriaconta-21 ,23,25(47),26(48)-tetraene-49,50,51,52,53-pe To obtain thorontone (I-39: 0.035 g, 14% yield) as a white solid. MS (EI + , m / z ): 1031.4[M+H] + . 1 H NMR (500 MHz, DMSO-d6) δ 7.82 (s, 3H), 6.42 ( dd, J = 33.7, 19.3 Hz, 2H), 6.25 - 6.09 (m, 2H), 5.46 (dd, J = 14.7, 9.7 Hz, 1H), 5.28 (s, 1H), 5.08 (d, J = 10.1 Hz, 1H), 5.00 - 4.92 (m, 1H), 4.08 - 3.92 (m, 2H), 3.78 (d, J = 11.6 Hz, 1H), 3.63 - 3.38 (m, 16H), 3.36 - 3.08 (m, 12H), 2.99 (dd, J = 22.3 , 17.1 Hz, 2H), 2.87 - 2.73 (m, 2H), 2.37 (dd, J = 17.9, 8.4 Hz, 1H), 2.30-1.75(m, 4H), 1.7-1.49 (m, 15H), 1.51 - 1.01 (m, 6H), 1.0 1- 0.65 (m, 18H), 0.63 - 0.56 (m, 1H).

[0339] Example 3 (21E,23E,25E,26E,36R,37S,38R,39R,41R,43 S,46S,47R,48R,57S)-47,57-dihydroxy-45-[2-[2 -[2-(2-hydroxyethoxy)ethoxy]ethoxy]ethoxy]-46-[(1S )-2-[(1S,3R,4R)-4-hydroxy-3-methoxy-cyclohexyl]- 1-methyl-ethyl]-48-methoxy-36,37,38,39,49,50-hexa Methyl-68,69-dioxa-58-azatricyclohexatriaconta-21,23 ,25(49),26(50)-tetraene-51,52,53,54,55-pentone Synthesis of (I-36): [ka] Synthesis scheme: [ka] Procedure and Characterization:

[0340] 2-[2-[2-(2-hydroxyethoxy)ethoxy]ethoxy]ethanol (1. 0.6 g, 5.47 mmol, 5 mL) and rapamycin (0.5 g, 0.547 mmol) ) and p-toluenesulfonic acid hydrate (0.21 g, 1.09 mmol) in THF ( The reaction mixture was stirred at room temperature for 2 hours and then added to a solution of 100 ml of ice-cold saturated sodium hydroxide solution. The mixture was added to an aqueous solution of NaHCO3 and extracted with EtOAc (30 mL x 3). The crude material was purified by reverse phase chromatography (CH Purify with CN / pure water = 3:2 and add (21E, 23E, 25E, 26E, 36R, 37S ,38R,39R,41R,43S,46S,47R,48R,57S)-47,57- Dihydroxy-45-[2-[2-[2-(2-hydroxyethoxy)ethoxy]ethoxy]ethoxy 6-[(1S)-2-[(1S,3R,4R)-4-hydroxy-3-[(1S,3R,4R)-4-ethoxy]-4-hydroxy-3-[(1S)-2-[(1S,3R,4R)-4-hydroxy-3-[(1S)-2-[(1S)-3 ... -Methoxy-cyclohexyl]-1-methyl-ethyl]-48-methoxy-36,37, 38,39,49,50-Hexamethyl-68,69-dioxa-58-azatricyclo Hexatriaconta-21,23,25(49),26(50)-tetraene-51,5 2,53,54,55-pentone (I-36: 0.15 g, yield 25.5%) was obtained as a white solid MS (EI + , m / z): 1098.4[M+H] + . 1 H NMR (500 MHz, CDCl3) δ 6.40 - 5.92 (m, 4H), 5.73 - 5.35 (m, 3H), 5.25 - 5.05 (m, 2H), 4.31 - 4.12 (m, 1H), 3.97 (dd, J = 25.7, 6.3 Hz, 1H), 3.87 - 3.53 (m, 15H), 3.52 - 3.17 (m, 11H), 2.99 - 2.46 (m, 6H), 2.36 - 1.93 (m, 9H), 1.90 - 1.54 (m, 13H), 1.52 - 1.17 (m, 9H), 1.15 - 0.81 (m, 18H), 0.68 - 0.58 (m, 1H).

[0341] Example 4 (21E,23E,25E,26E,38R,39S,40R,41R,43R,45 S,47R,48S,49R,50R,59S)-49,59-dihydroxy-47-[ 2-[2-[2-[2-(2-hydroxyethoxy)ethoxy]ethoxy]ethoxy]ethoxy 48-[(1S)-2-[(1S,3R,4R)-4-hydroxy-3-meth 50-methoxy-38,39,40, 41,51,52-Hexamethyl-70,71-dioxa-60-azatricyclohexa Triaconta-21,23,25(51),26(52)-tetraene-53,54,5 Synthesis of 5,56,57-pentone (I-35): [ka] Synthesis scheme: [ka] Procedure and Characterization:

[0342] 2-[2-[2-[2-(2-hydroxyethoxy)ethoxy]ethoxy]ethoxy] Ethanol (0.08 g, 0.33 mmol, 2 mL) was dissolved in rapamycin (0.3 g, 0 0.328 mmol) and p-toluenesulfonic acid hydrate (0.31 g, 1.64 mmol) l) in THF (6 mL) was added at room temperature. The resulting mixture was stirred at room temperature for 2 hours. Then, it was added to ice-cold saturated aqueous NaHCO3 solution and extracted with EtOAc (20 mL x 3 The organic layers were combined, then dried over Na2SO4, filtered, and concentrated in vacuo. Purification by reverse phase chromatography (CH3CN / pure water: 3:2) gave (21E, 23E, 25E,26E,38R,39S,40R,41R,43R,45S,47R,48S, 49R,50R,59S)-49,59-dihydroxy-47-[2-[2-[2-[2 -(2-hydroxyethoxy)ethoxy]ethoxy]ethoxy]ethoxy]-48-[( 1S)-2-[(1S,3R,4R)-4-hydroxy-3-methoxy-cyclohexyl ]-1-methyl-ethyl]-50-methoxy-38,39,40,41,51,52- oxamethyl-70,71-dioxa-60-azatricyclohexatriaconta-21, 23,25(51),26(52)-tetraene-53,54,55,56,57-pene I-35 (0.06 g, 16.3% yield) was obtained as a white solid. MS (EI + , m / z ): 1042.4[M+Na] + . 1 H NMR (500 MHz, CDCl3) δ 6.42 - 5.81 (m, 4H ), 5.58 - 4.81 (m, 4H), 4.31 - 4.11 (m, 1H), 4.01 - 3.51 (m, 2 2H), 3.49 - 3.13 (m, 11H), 3.01 - 2.43 (m, 6H), 2.29 (t, J = 30 .6 Hz, 2H), 2.15 - 1.88 (m, 7H), 1.76 - 1.55 (m, 12H), 1.51 - 1.18 (m, 9H), 1.15 - 0.74 (m, 18H), 0.66 (dd, J = 23.9, 12.0 Hz, 1H).

[0343] Example 5 (21E,23E,25E,26E,30R,31S,32R,33R,35R,37 S,39S,40S,41R,42R,52S)-39-(2,3-dihydroxypropionyl) 40-[(1S)-2-[(1S,3R,4R)-(hydroxy)-41,52-dihydroxy-40-[(1S)-2-[(1S,3R,4R)- 4-Hydroxy-3-methoxy-cyclohexyl]-1-methyl-ethyl]-42-meth 30,31,32,33,43,44-hexamethyl-64,65-dioxa-5 3-Azatricyclohexatriaconta-21,23,25(43),26(44)-tetramethyl Synthesis of tolaene-45,46,47,48,49-pentone (I-25): [ka] Synthesis scheme: [ka] Procedure and Characterization: Step 1: (24E, 26E, 28E, 29E, 32R, 33S, 34R, 35R, 3 7R,39S,41S,42S,44R,45R,55S)-41-[(2,2-dimethy (1,3-dioxolan-4-yl)methoxy]-44,55-dihydroxy-42- [(1S)-2-[(1S,3R,4R)-4-hydroxy-3-methoxy-cyclohexane 4,5-methoxy-32,33,34,35,46,47-cyl-1-methyl-ethyl -Hexamethyl-66,67-dioxa-56-azatricyclohexatriaconta-2 4,26,28(46),29(47)-tetraene-48,49,50,51,52- Penton:

[0344] (2,2-dimethyl-1,3-dioxolan-4-yl)methanol (1 mL) was added to phamycin (0.2 g, 0.22 mmol) and p-toluenesulfonic acid hydrate (0. To a solution of 1 g (0.547 mmol) of HCl in 3 mL of THF was added at room temperature. The mixture was stirred at room temperature for 2 hours, then added to ice-cold saturated aqueous NaHCO3 solution and diluted with EtOAc. Extracted (20 mL x 2). The organic layers were combined, dried over Na2SO4, filtered and concentrated in vacuo. The crude product was purified by reverse phase chromatography (CH3CN / pure water: 7:3) to give (2 4E,26E,28E,29E,32R,33S,34R,35R,37R,39S,4 1S,42S,44R,45R,55S)-41-[(2,2-dimethyl-1,3-diol xolane-4-yl)methoxy]-44,55-dihydroxy-42-[(1S)-2- [(1S,3R,4R)-4-Hydroxy-3-methoxy-cyclohexyl]-1-methyl 45-Methoxy-32,33,34,35,46,47-hexamethyl- 66,67-Dioxa-56-azatricyclohexatriaconta-24,26,28( 46),29(47)-tetraene-48,49,50,51,52-pentone (0.0 7 g, 32% yield) was obtained as a white solid. MS (EI + , m / z): 1036.4 [M +Na] + . Step 2: (21E, 23E, 25E, 26E, 30R, 31S, 32R, 33R, 3 5R,37S,39S,40S,41R,42R,52S)-39-(2,3-dihydro 40-[(1S)-2-[(1S,3R)-41,52-dihydroxy-40-[(1S)-2-[(1S,3R)-4-hydroxypropoxy] ,4R)-4-hydroxy-3-methoxy-cyclohexyl]-1-methyl-ethyl]- 42-Methoxy-30,31,32,33,43,44-hexamethyl-64,65-di Oxa-53-azatricyclohexatriaconta-21,23,25(43),26( 44)-Tetraene-45,46,47,48,49-pentone (I-25):

[0345] 4-Methylbenzenesulfonic acid·pyridine (0.037 g, 0.148 mmol) (24E,26E,28E,29E,32R,33S,34R,35R,37R,39S ,41S,42S,44R,45R,55S)-41-[(2,2-dimethyl-1,3- Dioxolan-4-yl)methoxy]-44,55-dihydroxy-42-[(1S)- 2-[(1S,3R,4R)-4-hydroxy-3-methoxy-cyclohexyl]-1- Methyl-ethyl]-45-methoxy-32,33,34,35,46,47-hexamethionyl Ru-66,67-dioxa-56-azatricyclohexatriacin-24,26,2 8(46),29(47)-tetraene-48,49,50,51,52-pentone(0 To a solution of 1.0 ... The mixture was stirred for 18 hours. After evaporation of the methanol, the residue was neutralized with saturated aqueous NaHCO3 solution. The mixture was then extracted with EtOAc (10 mL × 3). The organic layers were combined and washed with Na2SO4 The crude material was purified by reverse phase chromatography (CHCN / pure water = 1: 1) and purified (21E, 23E, 25E, 26E, 30R, 31S, 32R, 33R ,35R,37S,39S,40S,41R,42R,52S)-39-(2,3-dihydro- hydroxypropoxy)-41,52-dihydroxy-40-[(1S)-2-[(1S, 3R,4R)-4-Hydroxy-3-methoxy-cyclohexyl]-1-methyl-ethyl ]-42-Methoxy-30,31,32,33,43,44-hexamethyl-64,65 -Dioxa-53-azatricyclohexatriaconta-21,23,25(43),2 6(44)-tetraene-45,46,47,48,49-pentone (I-25:0.0 0.5g, 10% yield) was obtained as a white solid. MS (EI + , m / z): 996.5[M+Na] + . 1 H NMR (500 MHz, CDCl3) δ 6.21-5.97 (m, 4H), 5.77 - 4.78 (m, 5H), 4.53 - 4.12 (m, 2H), 4.05 - 3.11 (m, 19H), 3.07 - 2.88 (m, 2H), 2.65-2.5 (m, 4H), 2.39 - 1.91 (m, 7H), 1.89 - 1.69 (m, 12H), 1. 52 - 1.20 (m, 9H), 1.17 - 0.76 (m, 18H), 0.73 - 0.61 (m, 1H).

[0346] Example 6 (21E,23E,25E,26E,42R,43S,44R,45R,47S,49 S,51S,52S,53R,54R,63R)-53,63-dihydroxy-51-[ 2-[2-[2-[2-[2-[2-[2-(2-hydroxyethoxy)ethoxy]eth ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]-52-[(1R)-2- [(1S,3R,4R)-4-Hydroxy-3-methoxy-cyclohexyl]-1-methyl 42,43,44,45,55,56-hexamethyl- 74,75-Dioxa-64-azatricyclohexatriaconta-21,23,25( 55),26(56)-tetraene-57,58,59,60,61-pentone (I-2 4) Synthesis of: [ka] Synthesis scheme: [ka] Procedure and Characterization:

[0347] Rapamycin (0.5 g, 547 mmol) and 2-[2-[2-[2-[2-[2 -[2-(2-hydroxyethoxy)ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy [Ci]ethoxy]ethanol (0.2 g, 0.547 mmol, 3 mL) and p-toluene A solution of benzoxazole sulfonic acid hydrate (0.52 g, 2.73 mmol) in THF (15 mL) was The mixture was stirred at room temperature for 3 hours and then quenched with EtOAc (30 mL x 3). The layer was washed with ice-cold saturated NaHCO3 solution and concentrated. The resulting crude material was purified by reverse phase chromatography. The mixture was purified using a 7:3 mixture of CHCN and purified water (21E, 23E, 25E, 26E). ,42R,43S,44R,45R,47S,49S,51S,52S,53R,54R ,63R)-53,63-dihydroxy-51-[2-[2-[2-[2-[2-[2- [2-(2-hydroxyethoxy)ethoxy]ethoxy]ethoxy]ethoxy]ethoxy ]ethoxy]ethoxy]-52-[(1R)-2-[(1S,3R,4R)-4-hydro 4-methoxy-3-methoxy-cyclohexyl]-1-methyl-ethyl]-5,4-methoxy-4,2 ,43,44,45,55,56-Hexamethyl-74,75-dioxa-64-azato Lithium cyclohexatriaconta-21,23,25(55),26(56)-tetraene 57,58,59,60,61-pentone (I-24: 0.13 g, 19%) was obtained as a white solid MS (EI + , m / z): 1275.6[M+Na] + . 1 H NMR (500 MHz, CDCl3) δ 6.45 - 5.80 (m, 4H), 5.57 - 5.05 (m, 4H), 4.85 - 4.08 (m, 2H) , 3.90 - 3.50 (m, 34H), 3.47 - 3.24 (m, 13H), 2.97 - 2.44 (m, 7H), 2.39 - 2.06 (m, 2H), 2.03 - 1.84 (m, 6H), 1.78 - 1.58 (m, 13H), 1.53 - 1.16 (m, 9H), 1.14 - 0.78 (m, 18H), 0.67-0.53 (m, 1H).

[0348] Example 7 (21E,23E,25E,26E,34R,35S,36R,37R,38S,41 S,43S,45R,46R,55R)-45,55-dihydroxy-42-[2-(2 -hydroxyethoxy)ethoxy]-43-[(1R)-2-[(1S,2R,3R)- 3-(2-hydroxyethoxy)-2-methoxy-cyclohexyl]-1-methyl-ethoxy

[0046] -46-methoxy-34,35,36,37,47,48-hexamethyl-66,6 7-Dioxa-56-azatricyclohexatriaconta-21,23,25(47), Synthesis of 26(48)-tetraene-49,50,51,52,53-pentone (I-23) Form: [ka] Synthesis scheme: [ka] Procedure and Characterization: Step 1: 2-[tert-butyl(dimethyl)silyl]oxyethyl trifluoromethyl Tanesulfonates:

[0349] 2-[tert-butyl(dimethyl)silyl]oxyethanol (4 g, 22.69 m mol) and DIPEA (3.81 g, 29.49 mmol, 5.14 mL) in DCM The mixture was cooled to 0° C. under N2 and then treated with trifluoromethylsulfonyl Trifluoromethanesulfonate (7.04 g, 24.95 mmol) was added, and the resulting The resulting mixture was stirred at 0° C. for 1 h. The reaction was diluted with EtOAc (200 mL) and then , washed with saturated NaHCO3 (200 mL), water (200 mL), and brine (200 mL). The organic layer was then dried over Na2SO4, filtered, and concentrated in vacuo to give 2-[tert- butyl(dimethyl)silyl]oxyethyl trifluoromethanesulfonate (5.5 g, The compound was obtained in a 78.6% yield as a brown oil. 1 H NMR (500 MHz, CDCl3) δ 4.50 - 4.42 (t, 2H), 3.85 - 3.80 (t, 2H), 0.84 - 0.78 (s, 9H), 0.00 (s, 6H). Step 2: (27E, 29E, 31E, 32E, 36R, 37S, 38R, 39R, 4 0S,43S,44S,45S,47R,48R,57R)-45-[(1R)-2-[ (1S,2R,3R)-3-[2-[tert-butyl(dimethyl)silyl]oxyethoxy] [2-Methoxy-cyclohexyl]-1-methyl-ethyl]-47,57-dihydriodide 44,48-dimethoxy-36,37,38,39,49,50-hexamethyl -67,68-Dioxa-59-azatricyclohexatriaconta-27,29,31 (49),32(50)-tetraene-51,52,53,54,55-pentone:

[0350] Rapamycin (2 g, 2.19 mmol) and DIPEA (2.26 g, 17.50 (mmol, 3.05 mL) was dissolved in toluene (60 mL) and then heated to 60°C. Then, 2-[tert-butyl(dimethyl)silyl]oxyethyltrifluoromethyl Sulfonic acid salt (5.40 g, 17.50 mmol) was added under N2, and then the temperature was raised to 60 °C. The mixture was stirred at rt for 16 h. The mixture was poured into ice-cold saturated NaHCO3 (100 mL) and then The mixture was extracted with tOAc (150 mL x 3). The combined organic layers were washed with water and brine. The mixture was then concentrated in vacuo, and the residue was purified by reverse phase chromatography (CHCN / pure water = 4 :1) and purified (27E, 29E, 31E, 32E, 36R, 37S, 38R, 39 R,40S,43S,44S,45S,47R,48R,57R)-45-[(1R)- 2-[(1S,2R,3R)-3-[2-[tert-butyl(dimethyl)silyl]oxy] [Ethoxy]-2-methoxy-cyclohexyl]-1-methyl-ethyl]-47,57- Dihydroxy-44,48-dimethoxy-36,37,38,39,49,50-hexa Methyl-67,68-dioxa-59-azatricyclohexatriaconta-27,29 ,31(49),32(50)-tetraene-51,52,53,54,55-pentone (0.75 g, 32% yield) was obtained as a colorless oil. + , m / z) :1095.5[M+Na] + . Step 3: (22E, 24E, 26E, 27E, 31R, 32S, 33R, 34R, 3 5S,38S,39S,40S,42R,43R,52R)-42,52-dihydroxy -40-[(1R)-2-[(1S,2R,3R)-3-(2-hydroxyethoxy)- 2-Methoxy-cyclohexyl]-1-methyl-ethyl]-39,43-dimethoxy-3 1,32,33,34,44,45-Hexamethyl-62,63-dioxa-53-aza Tricyclohexatriaconta-22,24,26(44),27(45)-tetraene -46,47,48,49,50-Pentone:

[0351] TEA 3HF (4.65 g, 28.87 mmol) and (27E, 29E, 31E ,32E,36R,37S,38R,39R,40S,43S,44S,45S,47R ,48R,57R)-45-[(1R)-2-[(1S,2R,3R)-3-[2-[t ert-butyl(dimethyl)silyl]ethoxy]-2-methoxy-cyclohexyl]-1 -methyl-ethyl]-47,57-dihydroxy-44,48-dimethoxy-36,37 ,38,39,49,50-Hexamethyl-67,68-dioxa-59-azatricycl Rohexatriaconta-27,29,31(49),32(50)-tetraene-51, 52,53,54,55-Pentone (3.05 g, 2.89 mmol) in THF (50 m The solution in NaHCO3 (100 mL) was stirred at 20 °C for 2 h. The organic layers were combined and washed with water and ethyl acetate (150 mL x 3). The residue was purified by reverse phase chromatography (CH3CN / Purified with purified water (7:3) and (22E, 24E, 26E, 27E, 31R, 32S, 33 R,34R,35S,38S,39S,40S,42R,43R,52R)-42,52 -dihydroxy-40-[(1R)-2-[(1S,2R,3R)-3-(2-hydroxy (2-methoxy-cyclohexyl)-1-methyl-ethyl]-39,43- Dimethoxy-31,32,33,34,44,45-hexamethyl-62,63-dioxamethyl Sa-53-Azatricyclohexatriacin-22,24,26(44),27(45 )-tetraene-46,47,48,49,50-pentone (1.5 g, 54% yield) Obtained as a white solid. ESI-MS (EI +, m / z): 980.5 [M + Na] + . Step 4: (21E, 23E, 25E, 26E, 34R, 35S, 36R, 37R, 3 8S,41S,43S,45R,46R,55R)-45,55-dihydroxy-42- [2-(2-hydroxyethoxy)ethoxy]-43-[(1R)-2-[(1S,2R ,3R)-3-(2-hydroxyethoxy)-2-methoxy-cyclohexyl]-1-methyl ethyl-ethyl]-46-methoxy-34,35,36,37,47,48-hexamethyl -66,67-Dioxa-56-azatricyclohexatriaconta-21,23,25 (47),26(48)-tetraene-49,50,51,52,53-pentone(I- twenty three):

[0352] (22E,24E,26E,27E,31R,32S,33R,34R,35S,38 S,39S,40S,42R,43R,52R)-42,52-dihydroxy-40-[ (1R)-2-[(1S,2R,3R)-3-(2-hydroxyethoxy)-2-methoxy] cyclohexyl]-1-methyl-ethyl]-39,43-dimethoxy-31,32, 33,34,44,45-Hexamethyl-62,63-dioxa-53-azatricyclo Hexatriaconta-22,24,26(44),27(45)-tetraene-46,4 7,48,49,50-pentone (0.5 g, 0.52 mmol), 2-(2-hydroxybenzoyl) (ethoxy)ethanol (2.77 g, 26.09 mmol) and p-toluenesulfonyl A mixture of carboxylic acid hydrate (0.54 g, 3.13 mmol) in THF (6 mL) was heated at 20 °C. The mixture was stirred for 2 hours, poured into ice-cold saturated NaHCO3 (30 mL), and extracted with EtOAc. (50 mL x 3). The organic layers were combined, then washed with water and brine, and concentrated in vacuo. The residue was purified by reverse phase chromatography (CH3CN / pure water = 1:1) to give (21 E,23E,25E,26E,34R,35S,36R,37R,38S,41S,43 S,45R,46R,55R)-45,55-dihydroxy-42-[2-(2-hydroxy- 3-[(1R)-2-[(1S,2R,3R)-3-(2 -hydroxyethoxy)-2-methoxy-cyclohexyl]-1-methyl-ethyl]-4 6-Methoxy-34,35,36,37,47,48-hexamethyl-66,67-diol 56-Azatricyclohexatriacin-21,23,25(47),26(4 8)-Tetraene-49,50,51,52,53-pentone (I-23: 0.1 g, yield The product was obtained as a white solid (yield 19%). + , m / z): 1054.4 [M+Na] + . 1 HNM R (500 MHz, CDCl3) δ 6.63 - 5.86 (m, 4H), 5.70 - 5.00 (m, 4H), 4.87 - 4.15 (m, 2H), 4.02 - 3.54 (m, 14H), 3.50 - 3.26 (m, 11 H), 3.24 - 3.02 (m, 3H), 2.76 - 2.46 (m, 3H), 2.38 - 1.86 (m, 8H), 1.84 - 1.54 (m, 14H), 1.47 (m, 3H), 1.25 (m, 6H), 1.00 (m, 1 6H), 0.69 (dt, J = 34.1, 12.1 Hz, 1H).

[0353] Example 8 (21E,23E,25E,26E,36R,37S,38R,39R,40S,43 S,45S,47R,48R,57R)-47,57-dihydroxy-44-[2-[2 -(2-hydroxyethoxy)ethoxy]ethoxy]-45-[(1R)-2-[(1S ,2R,3R)-3-(2-hydroxyethoxy)-2-methoxy-cyclohexyl]- 1-methyl-ethyl]-48-methoxy-36,37,38,39,49,50-hexa Methyl-68,69-dioxa-58-azatricyclohexatriaconta-21,23 ,25(49),26(50)-tetraene-51,52,53,54,55-pentone Synthesis of (I-32): [ka] Synthesis scheme: [ka] Procedure and Characterization:

[0354] Everolimus (3.92 g, 26.09 mmol) and p-toluenesulfonic acid hydrate A mixture of the compound (0.45 g, 2.61 mmol) in THF (10 mL) was stirred at 20°C for 2 h. The mixture was poured into ice-cold saturated NaHCO3 (30 mL) and extracted with EtOAc (5 The organic layers were combined, then washed with water and brine, and concentrated in vacuo. The residue was purified by reverse phase chromatography (CH3CN / pure water = 1:1) to give (21E, 23 E,25E,26E,36R,37S,38R,39R,40S,43S,45S,47 R,48R,57R)-47,57-dihydroxy-44-[2-[2-(2-hydroxy 5-[(1R)-2-[(1S,2R,3R)-(ethoxy)ethoxy]ethoxy]-4 3-(2-hydroxyethoxy)-2-methoxy-cyclohexyl]-1-methyl-ethoxy

[0043] -48-methoxy-36,37,38,39,49,50-hexamethyl-68,6 9-Dioxa-58-azatricyclohexatriaconta-21,23,25(49), 26(50)-tetraene-51,52,53,54,55-pentone (I-32:0. 155 g (28% yield) was obtained as a white solid. ESI-MS (EI + , m / z): 1098.4 [M+Na] + . 1 H NMR (500 MHz, CDCl3) δ 6.49 - 5.83 (m, 4H), 5.67 - 5.35 (m, 2H), 5.33 - 5.01 (m, 2H), 4.92 - 4.08 (m, 2H), 4.05 - 3.5 1 (m, 17H), 3.52 - 3.23 (m, 11H), 3.23 - 3.01 (m, 3H), 2.66 (m, 4H), 2.40 - 1.95 (m, 5H), 1.95 - 1.55 (m, 17H), 1.52 - 1.13 ( m, 9H), 1.13 - 0.79 (m, 16H), 0.71 (dd, J = 23.8, 11.9 Hz, 1H).

[0355] Example 9 (21E,23E,25E,26E,38R,39S,40R,41R,42S,45 S,47S,49R,50R,59R)-49,59-dihydroxy-46-[2-[2 -[2-(2-hydroxyethoxy)ethoxy]ethoxy]ethoxy]-47-[(1R )-2-[(1S,2R,3R)-3-(2-hydroxyethoxy)-2-methoxy- cyclohexyl]-1-methyl-ethyl]-50-methoxy-38,39,40,41,5 1,52-Hexamethyl-70,71-dioxa-60-azatricyclohexatriako pentane-21,23,25(51),26(52)-tetraene-53,54,55,56 Synthesis of 57-pentone (I-22): [ka] Synthesis scheme: [ka] Procedure and Characterization:

[0356] Everolimus (0.5 g, 0.52 mmol), 2-[2-[2-(2-hydroxyethyl) [ethoxy]ethoxy]ethanol (2.03 g, 10.44 mmol) and p -Toluenesulfonic acid hydrate (0.54 g, 3.13 mmol) in THF (6 mL) The mixture was stirred at 20° C. for 2 h. The mixture was poured into ice-cold saturated NaHCO3 (30 mL) and The combined organic layer was washed with water, brine, and then The residue was purified by reversed phase chromatography (CH3CN / pure water = 1:1). (21E, 23E, 25E, 26E, 38R, 39S, 40R, 41R, 42S, 45S,47S,49R,50R,59R)-49,59-dihydroxy-46-[2- [2-[2-(2-hydroxyethoxy)ethoxy]ethoxy]ethoxy]-47-[( 1R)-2-[(1S,2R,3R)-3-(2-hydroxyethoxy)-2-methoxy -cyclohexyl]-1-methyl-ethyl]-50-methoxy-38,39,40,41 ,51,52-Hexamethyl-70,71-dioxa-60-azatricyclohexatri Aconta-21,23,25(51),26(52)-tetraene-53,54,55, 56,57-Pentone (I-22: 0.1 g, 17% yield) was obtained as a white solid. MS (EI + , m / z): 1043.4 [M+Na] + . 1 H NMR (500 MHz, CDCl3) δ 6.71 - 5.78 (m, 4H), 5.77 - 5.01 (m, 4H), 4.65 - 3.88 (m, 3H), 3.87 - 3.50 (m, 20H), 3.50 - 3.00 (m, 14H), 2.77 - 1.95 (m, 11H), 1. 89 - 1.53 (m, 13H), 1.53 - 0.79 (m, 27H), 0.76 - 0.62 (m, 1H).

[0357] Example 10 (22E,24E,26E,27E,35R,36S,37R,38R,39S,42 S,44S,46R,47R,56R)-46,56-dihydroxy-44-[(1R) -2-[(1S,2R,3R)-3-hydroxy-2-methoxy-cyclohexyl]-1 -methyl-ethyl]-47-methoxy-43-[2-[2-(2-methoxyethoxy)ethoxy] [ethoxy]ethoxy]-35,36,37,38,48,49-hexamethyl-66,67 -Dioxa-57-azatricyclohexatriaconta-22,24,26(48),2 Synthesis of 7(49)-tetraene-50,51,52,53,54-pentone (I-27) : [ka] Synthesis scheme: [ka] Procedure and Characterization:

[0358] Rapamycin (1 g, 1.09 mmol), 2-[2-(2-methoxyethoxy)ethoxy]ethoxy] [Hexyl]ethanol (8.98 g, 54.69 mmol) and aqueous p-toluenesulfonic acid A mixture of the solvate (0.94 g, 5.47 mmol) in THF (20 mL) was heated at 20°C for 2 h. The mixture was poured into ice-cold saturated NaHCO3 (50 mL) and extracted with EtOAc ( 100 mL x 3). The combined organic layers were washed with water, brine, and then concentrated in vacuo. The residue was purified by reverse phase chromatography (CH3CN / pure water = 4:1) to give (22E,2 4E,26E,27E,35R,36S,37R,38R,39S,42S,44S,4 6R,47R,56R)-46,56-dihydroxy-44-[(1R)-2-[(1S ,2R,3R)-3-hydroxy-2-methoxy-cyclohexyl]-1-methyl-ethyl -47-Methoxy-43-[2-[2-(2-methoxyethoxy)ethoxy]ethoxy ci]-35,36,37,38,48,49-hexamethyl-66,67-dioxa-5 7-Azatricyclohexatriaconta-22,24,26(48),27(49)-tetramethyl Tolaen-50,51,52,53,54-pentone (I-27: 0.16 g, yield 14 %) was obtained as a white solid. + , m / z): 1068.4 [M+Na] + . 1 H NMR (50 0 MHz, CDCl3) δ 6.50 - 5.81 (m, 4H), 5.73 - 5.05 (m, 4H), 4.85 - 3.98 (m, 3H), 3.90 - 3.10 (m, 27H), 3.02 - 2.24 (m, 7H), 1. 98 (m, 6H), 1.82 - 1.55 (m, 13H), 1.54 - 1.16 (m, 9H), 1.16 - 0.78 (m, 17H), 0.75 - 0.59 (m, 1H).

[0359] Example 11 (21E,23E,25E,26E,31R,32S,33R,34R,35S,38 S,40S,42R,43R,52R)-42,52-dihydroxy-40-[(1R) -2-[(1S,2R,3R)-3-hydroxy-2-methoxy-cyclohexyl]-1 -methyl-ethyl]-39-(3-hydroxypropoxy)-43-methoxy-31,3 2,33,34,44,45-Hexamethyl-63,64-dioxa-53-azatriazole Chlohexatriaconta-21,23,25(44),26(45)-tetraene-46 Synthesis of 47,48,49,50-pentone (I-34): [ka] Synthesis scheme: [ka] Procedure and Characterization:

[0360] Rapamycin (0.5 g, 0.55 mmol), propane-1,3-diol (13. 13 g, 172.48 mmol, 12.5 mL) and p-toluenesulfonic acid hydrate ( A mixture of 0.47 g (2.74 mmol) of HCl in THF (37.5 mL) was stirred at 20°C for 2 h. The mixture was poured into ice-cold saturated NaHCO3 (100 mL) and extracted with EtOAc ( (100 mL x 3). The organic layers were combined, washed with water and brine, and then concentrated in vacuo. The residue was purified by reverse phase chromatography (CH3CN / pure water = 7:3) to give (21E, 23E,25E,26E,31R,32S,33R,34R,35S,38S,40S, 42R,43R,52R)-42,52-dihydroxy-40-[(1R)-2-[(1 S,2R,3R)-3-hydroxy-2-methoxy-cyclohexyl]-1-methyl- 3-hydroxypropoxy-43-methoxy-31,32,33,3-ethyl 4,44,45-Hexamethyl-63,64-dioxa-53-azatricyclohexyl Rear Contour-21,23,25(44),26(45)-Tetraene-46,47,48 ,49,50-Pentone (0.15 g, 29% yield) was obtained as a white solid. I + , m / z): 980.3 [M+Na] + . 1 H NMR (500 MHz, CDCl3) δ 6.58 - 5.84 (m, 4H), 5.72 - 4.83 (m, 4H), 4.65 - 4.06 (m, 2H), 4.03 - 3.63 (m, 5H), 3.62 - 3.05 (m, 12H), 3.03 - 2.40 (m, 6H), 2.42 - 1. 91 (m, 7H), 1.89 - 1.56 (m, 17H), 1.53 - 1.27 (m, 6H), 1.25 - 0.76 (m, 19H), 0.62 (m, 1H). Example 12 (21E,23E,25E,26E,30R,31S,32R,33R,35R,37 S,40S,41R,42R,51S)-41,51-dihydroxy-39-(2-hydroxy (1S)-2-[(1S,3R,4R)-4-hydroxy- 3-Methoxy-cyclohexyl]-1-methyl-ethyl]-42-methoxy-30,31 ,32,33,43,44-Hexamethyl-62,63-dioxa-52-azatricycl Rohexatriaconta-21,23,25(43),26(44)-tetraene-45, Synthesis of 46,47,48,49-pentone (I-38): [ka] Synthesis scheme: [ka] Procedure and Characterization:

[0361] p-Toluenesulfonic acid hydrate (0.31 g, 1.64 mmol) was added to rapamycin ( 0.5 g, 0.547 mmol) and ethylene glycol (3 mL) in THF (10 m The resulting mixture was stirred at 10°C for 17 hours, then reacted. The reaction mixture was diluted with EtOAc (100 mL) and saturated aqueous NaHCO3 (approximately 50 mL) The pH was adjusted to 9 using HCl. The organic layer was concentrated in vacuo, and the residue was then purified by reverse phase chromatography. The mixture was purified with CH3CN / pure water = 5.5:4.5. The solvent was then removed by freeze-drying. (21E, 23E, 25E, 26E, 30R, 31S, 32R, 33R, 35R, 37S,40S,41R,42R,51S)-41,51-dihydroxy-39-(2- hydroxyethoxy)-40-[(1S)-2-[(1S,3R,4R)-4-hydroxy 3-(3-methoxy-cyclohexyl)-1-methyl-ethyl)-42-methoxy-30, 31,32,33,43,44-Hexamethyl-62,63-dioxa-52-azatriazole Cyclohexatriaconta-21,23,25(43),26(44)-tetraene-4 5,46,47,48,49-Pentone (0.05 g, 9% yield) was obtained as a white solid. MS (EI + , m / z): 966.3 [M+Na] + . 1 H NMR (500 MHz, CDCl3) δ 6.47-5.9 1 (m, 4H), 5.60-5.13 (m, 4H), 4.85-3.92 (m, 3H), 3.88-3.68 (m, 4H), 3.60-3.53 (m, 1H), 3.46-3.29 (m, 10H), 3.25-3.19 (m, 1H), 2.97-2.84 (m , 2H), 2.76-2.53 (m, 4H), 2.35-1.83 (m, 8H), 1.80-1.64 (m, 12H), 1.53 -1.16 (m, 9H), 1.14-0.82 (m, 18H), 0.67-0.57 (m, 1H).

[0362] Example 13 (21E,23E,25E,26E,40R,41S,42R,43R,45R,47 S,50S,51R,52R,61S)-51,61-dihydroxy-49-[2-[2 -[2-[2-[2-(2-hydroxyethoxy)ethoxy]ethoxy]ethoxy]ethoxy 50-[(1S)-2-[(1S,3R,4R)-4-hydroxy- 3-Methoxy-cyclohexyl]-1-methyl-ethyl]-52-methoxy-40,41 ,42,43,53,54-Hexamethyl-72,73-dioxa-62-azatricycl Rohexatriaconta-21,23,25(53),26(54)-tetraene-55, Synthesis of 56,57,58,59-pentone (I-33): [ka] Synthesis scheme: [ka] Procedure and Characterization:

[0363] p-Toluenesulfonic acid hydrate (0.19 g, 1.02 mmol) was added to rapamycin ( 0.31 g, 0.34 mmol) and hexaethylene glycol (2 mL) in THF ( The resulting mixture was stirred at 15°C for 17 hours, then The reaction mixture was diluted with EtOAc (200 mL) and saturated aqueous NaHCO3 (ca. 10 The pH was adjusted to 9 using 0.0 mL of ethanol. The organic layer was concentrated in vacuo. The residue was purified by reverse phase chromatography. The mixture was purified by filtration (CHCN / pure water = 3:2), and the solvent was then removed by freeze-drying. (21E,23E,25E,26E,40R,41S,42R,43R,45R,47S ,50S,51R,52R,61S)-51,61-dihydroxy-49-[2-[2- [2-[2-[2-(2-hydroxyethoxy)ethoxy]ethoxy]ethoxy]ethoxy 50-[(1S)-2-[(1S,3R,4R)-4-hydroxy-3-ethoxy]ethoxy]- -Methoxy-cyclohexyl]-1-methyl-ethyl]-52-methoxy-40,41, 42,43,53,54-Hexamethyl-72,73-dioxa-62-azatricyclo Hexatriaconta-21,23,25(53),26(54)-tetraene-55,5 6,57,58,59-Pentone (I-33: 0.21 g, 51% yield) was obtained as a white solid. MS (EI + , m / z): 1186.8 [M+Na] + . 1 H NMR (500 MHz, CDCl3) δ 6.39-5.94 (m, 4H), 5.55-5.14 (m, 4H), 4.93-3.75 (m, 2H), 3.73-3.71 (m, 2H), 3.67-3.55 (m, 22H), 3.48-3.44 (m, 1H), 3.41-3.16 (m, 12H), 2.98-2.86 (m, 2H), 2.75-2.69 (m, 2H), 2.59-2.44 (m, 1H), 2.34-2.21 ( m, 1H), 2.11-1.97 (m, 4H), 1.90 (s, 3H), 1.78-1.54 (m, 13H), 1.50-1.1 2 (m, 9H), 1.08-0.83 (m, 18H), 0.71-0.62 (m, 1H).

[0364] Example 14 (21E,23E,25E,26E,32R,33S,34R,35R,37R,39 S,42S,43R,44R,53S)-43,53-dihydroxy-41-[2-(2 -hydroxyethoxy)ethoxy]-42-[(1S)-2-[(1S,3R,4R)- 4-Hydroxy-3-methoxy-cyclohexyl]-1-methyl-ethyl]-44-meth 32,33,34,35,45,46-hexamethyl-64,65-dioxa-5 4-Azatricyclohexatriaconta-21,23,25(45),26(46)-tetrahydrofuran Synthesis of tolaene-47,48,49,50,51-pentone (I-18): [ka] Synthesis scheme: [ka] Procedure and Characterization:

[0365] p-Toluenesulfonic acid hydrate (0.187 g, 0.98 mmol) was added to rapamycin (0.3 g, 0.33 mmol) and diethylene glycol (2 mL) in THF (6 m The resulting mixture was stirred at 10°C for 17 hours, then reacted. The reaction mixture was diluted with EtOAc (100 mL) and saturated aqueous NaHCO3 (approximately 50 mL) The pH was adjusted to 9 using HCl. The organic layer was concentrated in vacuo. The residue was purified by reverse phase (CH3CN / pure The solvent was removed by lyophilization to give (21E, 23E, 25E, 26 E,32R,33S,34R,35R,37R,39S,42S,43R,44R,53 S)-43,53-dihydroxy-41-[2-(2-hydroxyethoxy)ethoxy] -42-[(1S)-2-[(1S,3R,4R)-4-hydroxy-3-methoxy- cyclohexyl]-1-methyl-ethyl]-44-methoxy-32,33,34,35,4 5,46-Hexamethyl-64,65-dioxa-54-azatricyclohexatriako pentane-21,23,25(45),26(46)-tetraene-47,48,49,50 ,51-Pentone (I-18: 0.126 g, 37% yield) was obtained as a white solid. (EI + , m / z): 1010.7 [M+Na] + . 1 H NMR (500 MHz, CDCl3) δ 6.40-5.95 (m , 4H), 5.55-5.14 (m, 4H), 4.85-4.17 (m, 2H), 4.05-3.57 (m, 10H), 3.53 -3.15 (m, 12H), 2.97-2.89 (m, 2H), 2.76-2.48 (m, 4H), 2.36-1.84 (m, 7 H), 1.79-1.56 (m, 14H), 1.49-1.14 (m, 9H), 1.10-0.81 (m, 18H), 0.70-0. 61 (m, 1H).

[0366] Example 15 (21E,23E,25E,26E,31R,32S,33R,34R,36R,38 S,41S,42R,43R,53S)-42,53-dihydroxy-40-[3-hydroxy 41-[(1S)-2-[(1S,3 R,4R)-4-hydroxy-3-methoxy-cyclohexyl]-1-methyl-ethyl] -43-Methoxy-31,32,33,34,44,45-hexamethyl-65,66- Dioxa-54-azatricyclohexatriaconta-21,23,25(44),26 Synthesis of (45)-tetraene-46,47,48,49,50-pentone (I-31): [ka] Synthesis scheme: [ka] Procedure and Characterization:

[0367] p-Toluenesulfonic acid hydrate (0.31 g, 1.64 mmol) was added to rapamycin ( 0.5g, 0.547mmol) and 2-(hydroxymethyl)propane-1,3-di To a mixture of 1,2-diol (0.58 g, 5.47 mmol) in THF (10 mL) was added at 15°C. The resulting mixture was stirred at 15°C for 17 h, and then the reaction mixture was diluted with EtOAc ( Dilute with 0.00 mL of saturated aqueous NaHCO3 (approximately 50 mL) and adjust to pH 9. The organic layer was concentrated under vacuum, and the residue was purified by reversed-phase chromatography (CH3CN / pure water = 3 The solvent was removed by lyophilization, and the resulting mixture was purified by the following procedure: (21E, 23E, 25E, 26E, 3 1R,32S,33R,34R,36R,38S,41S,42R,43R,53S)- 42,53-dihydroxy-40-[3-hydroxy-2-(hydroxymethyl)propionate 41-[(1S)-2-[(1S,3R,4R)-4-hydroxy-3-methoxy]-4 [Cyclohexyl]-1-methyl-ethyl]-43-methoxy-31,32,33,3 4,44,45-Hexamethyl-65,66-dioxa-54-azatricyclohexyl Rear Contour-21,23,25(44),26(45)-Tetraene-46,47,48 ,49,50-Pentone (I-31: 0.054 g, 9% yield) was obtained as a white solid. MS (EI + , m / z): 1010.4 [M+Na] + . 1 H NMR (500 MHz, CDCl3) δ 6.37-5.96 (m, 4H), 5.56-5.15 (m, 4H), 4.86-4.17 (m, 2H), 3.85-3.47 (m, 10H), 2.96-2.91 (m, 2H), 2.75-2.58 (m, 3H), 2.35-2.22 (m, 3H), 2.11-1.94 (m, 6H), 1.84-1.46 (m, 23H), 1.35-1.12 (m, 9H), 1.11-0.88 (m, 18H), 0.67 -0.65 (m, 1H).

[0368] Example 16 (21E,23E,25E,26E,34R,35S,36R,37R,39R,41 S,44S,45R,46R,55S)-45,55-dihydroxy-43-[2-[2 -[(2-Hydroxyethylsulfanyl)ethylsulfanyl]ethoxy]-44-[( (1S)-2-[(1S,3R,4R)-4-Hydroxy-3-methoxy-cyclohexyl -1-methyl-ethyl]-46-methoxy-34,35,36,37,47,48-he xamethyl-66,67-dioxa-56-azatricyclohexatriaconta-21, 23,25(47),26(48)-tetraene-49,50,51,52,53-pen tone (I-21) synthesis:

Chem.

Chem.

[0369] p-Toluenesulfonic acid hydrate (0.62 g, 3.28 mmol) was added to a mixture of rapamycin ( 1 g, 1.09 mmol) and 2-[2-(2-Hydroxyethylsulfanyl)ethyl sulfanyl]ethanol (1.99 g, 10.94 mmol) in THF (20 mL) at 15 °C. The resulting mixture was stirred at 15 °C for 17 h and then the reaction mixture was diluted with EtOAc (100 mL) and saturated aqueous NaHCO3 (ca. 50 mL) was used to adjust the pH to 9. The organic layer was concentrated under vacuum. The residue was purified by reverse-phase chromatography (CH3CN / pure water = 3:2). The solvent was removed by lyophilization to give (21E,23 E,25E,26E,34R,35S,36R,37R,39R,41S,44S,45 R,46R,55S)-45,55-Dihydroxy-43-[2-[2-(2-Hydroxy ethylsulfanyl)ethylsulfanyl]ethoxy]-44-[(1S)-2-[( 1S,3R,4R)-4-hydroxy-3-methoxy-cyclohexyl]-1-methyl- Ethyl]-46-methoxy-34,35,36,37,47,48-hexamethyl-66 ,67-Dioxa-56-azatricyclohexatriaconta-21,23,25(47 ), 26(48)-tetraene-49,50,51,52,53-pentone (I-21: 0.15 g, 0.133 mmol, 12% yield) was obtained as a yellow solid. MS (EI + , m / z ): 1086.4 [M+Na] + . 1 H NMR (500 MHz, CDCl3) δ 6.39-5.95 (m, 4H), 5.54-5.19 (m, 4H), 4.8 1-4.17 (m, 2H), 3.96-3.73 (m, 4H), 3.59-3.14 (m, 12H), 2.96-2.55 (m, 14H), 2.35-1.87 (m, 6H), 1.81-1.59 (m, 13H), 1.53-1.13 (m, 11H), 1.16- 0.84 (m, 18H), 0.71-0.63 (m, 1H).

[0370] Example 17 (21E,23E,25E,26E,42R,43S,44R,45R,47S,49 S,51S,52S,53R,54R,63R)-53,63-dihydroxy-51-[ 2-[2-[2-[2-[2-[2-(2-hydroxyethoxy)ethoxy]ethoxy] ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]-52-[(1R)-2-[(1S,3R, 4R)-4-Hydroxy-3-methoxy-cyclohexyl]-1-methyl-ethyl]-5 4-Methoxy-42,43,44,45,55,56-hexamethyl-74,75-diol 64-Azatricyclohexatriacin-21,23,25(55),26(5 Synthesis of 6)-tetraene-57,58,59,60,61-pentone (I-26): [ka] Synthesis scheme: [ka] Procedure and Characterization:

[0371] p-Toluenesulfonic acid hydrate (0.52 g, 2.73 mmol) was added to rapamycin ( 0.5g, 0.55mmol) and 2-[2-[2-[2-[2-[2-(2-hydrogen Ethoxy)ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethanol (3. The mixture was slowly added to a solution of 57 g (10.94 mmol) of methyl 2-hydroxybenzoate in 10 mL of THF. The resulting solution was stirred at 20°C for 17 hours and then concentrated. The residue was purified by reverse phase chromatography ( Purify with CH3CN / pure water = 7:3 (21E, 23E, 25E, 26E, 42R, 43S, 44R, 45R, 47S, 49S, 51S, 52S, 53R, 54R, 63R) -53,63-dihydroxy-51-[2-[2-[2-[2-[2-[2-(2-hydroxy Ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]-5 2-[(1R)-2-[(1S,3R,4R)-4-hydroxy-3-methoxy-cyclo hexyl]-1-methyl-ethyl]-54-methoxy-42,43,44,45,55, 56-Hexamethyl-74,75-dioxa-64-azatricyclohexatriacontane -21,23,25(55),26(56)-tetraene-57,58,59,60,6 1-Pentone (I-26: 0.16 g, 24% yield) was obtained as a white solid. MS (EI + , m / z): 1230.6[M+Na] + . 1 H NMR (500 MHz, CDCl3) δ 6.46 - 5.74 (m, 4H), 5.61 - 4.74 (m, 4H), 4.05-4.5 (m, 2H), 4.02 - 3.51 (m, 35H), 3.43 - 3.16 (m, 14 H), 2.99 - 2.42 (m, 8H), 2.4-1.6 (m, 7H), 1.61-1.1 (m, 12H), 1.13 - 0.79 (m, 18H), 0.74 - 0.61 (m, 1H).

[0372] Example 19 (22E,24E,26E,27E,33R,34S,35R,36R,38S,40 S,43S,44R,45R,54R)-44,54-dihydroxy-43-[(1R) -2-[(1S,3R,4R)-4-hydroxy-3-methoxy-cyclohexyl]-1 -methyl-ethyl]-45-methoxy-42-[R-2-(2-methoxyethoxy)ethoxy 33,34,35,36,46,47-hexamethyl-64,65-dioxa- 55-Azatricyclohexatriaconta-22,24,26(46),27(47)- Tetraene-48,49,50,51,52-pentone (I-119) and (22E, 24E,26E,27E,33R,34S,35R,36R,38S,40S,43S, 44R,45R,54R)-44,54-dihydroxy-43-[(1R)-2-[(1 S,3R,4R)-4-hydroxy-3-methoxy-cyclohexyl]-1-methyl- ethyl]-45-methoxy-42-[S-2-(2-methoxyethoxy)ethoxy]-33 ,34,35,36,46,47-Hexamethyl-64,65-dioxa-55-azato Lithium cyclohexatriaconta-22,24,26(46),27(47)-tetraene Synthesis of 48,49,50,51,52-pentone (I-120): [ka] Synthesis scheme: [ka] Procedure and Characterization: Step 1: (22E, 24E, 26E, 27E, 33R, 34S, 35R, 36R, 3 8S,40S,43S,44R,45R,54R)-44,54-dihydroxy-43- [(1R)-2-[(1S,3R,4R)-4-hydroxy-3-methoxy-cyclohexane 2-(2-methoxyethoxy)-4-(2-methyl-1-ethyl)-4 ...methyl-1-ethyl)-4-(2 )Ethoxy]-33,34,35,36,46,47-hexamethyl-64,65-di 55-Azatricyclohexatriacin-22,24,26(46),27(4 Synthesis of 7)-tetraene-48,49,50,51,52-pentone:

[0373] Rapamycin (2 g, 2.19 mmol), 2-(2-methoxyethoxy)ethanol To a mixture of HND-8 (240 mg, 2.19 mmol) (4 mL) in THF (30 mL) ) was added and the reaction was stirred at 50° C. under N for 4 hours, then filtered and concentrated. The obtained crude product was purified by reverse phase chromatography (C18, CH3CN:H2O = 3:1 ) and purified by (22E, 24E, 26E, 27E, 33R, 34S, 35R, 3 6R,38S,40S,43S,44R,45R,54R)-44,54-dihydroxy -43-[(1R)-2-[(1S,3R,4R)-4-hydroxy-3-methoxy- cyclohexyl]-1-methyl-ethyl]-45-methoxy-42-[2-(2-methoxy Ethoxy)ethoxy]-33,34,35,36,46,47-hexamethyl-64,6 5-Dioxa-55-azatricyclohexatriaconta-22,24,26(46), 27(47)-tetraene-48,49,50,51,52-pentone (0.6 g, yield 27%) as a pale yellow solid. + , m / z): 1024.3 [M+Na] + . 1 HNM R (400 MHz, CDCl3) δ 6.56 - 5.82 (m, 4H), 5.47 (ddd, J = 37.4, 17.7, 9.4 Hz, 2H), 5.31 - 5.06 (m, 2H), 4.82 - 4.50 (m, 1H), 4.3 2 - 3.94 (m, 2H), 3.92 - 3.71 (m, 2H), 3.70 - 3.44 (m, 8H), 3. 43 - 3.26 (m, 12H), 3.20 (dd, J = 27.0, 16.2 Hz, 1H), 3.00 - 2. 22 (m, 7H), 2.18 - 1.56 (m, 19H), 1.54 - 1.25 (m, 7H), 1.24 - 0.81 (m, 19H), 0.67 (dd, J = 23.8, 11.9 Hz, 1H). Step 2: (22E, 24E, 26E, 27E, 33R, 34S, 35R, 36R, 3 8S,40S,43S,44R,45R,54R)-44,54-dihydroxy-43- [(1R)-2-[(1S,3R,4R)-4-hydroxy-3-methoxy-cyclohexane 2-[R-2-(2-methoxyethyl)-4-(5-methoxy-4-methyl-1-methyl-ethyl]-4-(2-methoxyethyl) ... ethoxy]-33,34,35,36,46,47-hexamethyl-64,65- Dioxa-55-azatricyclohexatriaconta-22,24,26(46),27 (47)-tetraene-48,49,50,51,52-pentone (I-119) and (22E,24E,26E,27E,33R,34S,35R,36R,38S,40S ,43S,44R,45R,54R)-44,54-dihydroxy-43-[(1R)- 2-[(1S,3R,4R)-4-hydroxy-3-methoxy-cyclohexyl]-1- Methyl-ethyl]-45-methoxy-42-[S-2-(2-methoxyethoxy)ethoxy] CI]-33,34,35,36,46,47-hexamethyl-64,65-dioxa-5 5-Azatricyclohexatriaconta-22,24,26(46),27(47)-tetrahydrofuran Synthesis of tolaene-48,49,50,51,52-pentone (I-120):

[0374] (22E,24E,26E,27E,33R,34S,35R,36R,38S,40 S,43S,44R,45R,54R)-44,54-dihydroxy-43-[(1R) -2-[(1S,3R,4R)-4-hydroxy-3-methoxy-cyclohexyl]-1 -methyl-ethyl]-45-methoxy-42-[2-(2-methoxyethoxy)ethoxy ]-33,34,35,36,46,47-hexamethyl-64,65-dioxa-55 -Azatricyclohexatriaconta-22,24,26(46),27(47)-tet Laen-48,49,50,51,52-pentone (0.095 g, 0.095 mmol) ) was purified by preparative chiral HPLC to give (22E, 24E, 26E, 27E, 33R ,34S,35R,36R,38S,40S,43S,44R,45R,54R)-44 ,54-dihydroxy-43-[(1R)-2-[(1S,3R,4R)-4-hydroxy 4-(3-methoxy-cyclohexyl)-1-methyl-ethyl)-4-(5-methoxy-42- [R-2-(2-methoxyethoxy)ethoxy]-33,34,35,36,46,47 -Hexamethyl-64,65-dioxa-55-azatricyclohexatriaconta-2 2,24,26(46),27(47)-tetraene-48,49,50,51,52- Penton (I-119: 13.2 mg, yield 14%) and (22E, 24E, 26E, 27E,33R,34S,35R,36R,38S,40S,43S,44R,45R, 54R)-44,54-dihydroxy-43-[(1R)-2-[(1S,3R,4R) -4-hydroxy-3-methoxy-cyclohexyl]-1-methyl-ethyl]-45-methyl 42-[S-2-(2-methoxyethoxy)ethoxy]-33,34,35,3 6,46,47-Hexamethyl-64,65-dioxa-55-azatricyclohexyl Rear Contour-22,24,26(46),27(47)-Tetraene-48,49,50 , 51,52-pentone (I-120: 18.1 mg, yield 19%) was obtained as a white solid. Got it as a body.

[0375] Chiral separation methods are listed below: Equipment: Gilson-281 Column: CHIRALPAK IC 20 x 250 mm, 10 μm (Daicel) カラムTemperature:35℃ Moving phase:n-ヘキサン:エタノール=60:40 Flow rate: 50ml / min Wavelength detected: 214nm サイクル time: 18 minutes Sample solution: 7ml of のメタノールに95mgを dissolved Injection volume: 0.5 ml (load: 7.1 mg / injection)

[0376] I-119: ESI-MS (EI + , m / z): 1024.4 [M+Na] + . 1 H NMR (400 MHz, CDCl3) δ 6.42 - 5.92 (m, 4H), 5.75 - 5.05 (m, 4H), 4.49 (s, 1H), 4.2 8 (s, 1H), 4.15 (d, J = 10.9 Hz, 1H), 3.99 (t, J = 13.3 Hz, 1H), 3.88 - 3.73 (m, 1H), 3.69 - 3.46 (m, 8H), 3.45 - 3.29 (m, 11H ), 3.22 (dd, J = 10.1, 6.5 Hz, 2H), 2.99 - 2.77 (m, 3H), 2.68 (d t, J = 28.5, 11.1 Hz, 3H), 2.61 - 2.22 (m, 4H), 2.05 (ddd, J = 21.5, 15.3, 7.5 Hz, 5H), 1.88 - 1.65 (m, 12H), 1.53 - 1.30 (m, 7 H), 1.17 - 0.78 (m, 19H), 0.73 - 0.57 (m, 1H).

[0378] I-120: ESI-MS (EI + , m / z): 1024.3 [M+Na] + . 1 H NMR (400 MHz, CDCl3) δ 6.43 - 6.18 (m, 2H), 6.13 (dd, J = 15.0, 10 .0 Hz, 1H), 5.91 (dd, J = 31.6, 10.6 Hz, 1H), 5.56 - 5.36 (m, 2H ), 5.27 (d, J = 4.9 Hz, 1H), 5.16 (dt, J = 18.2, 9.1 Hz, 1H), 4. 78 (s, 1H), 4.20 (dd, J = 21.1, 11.1 Hz, 1H), 3.96 - 3.71 (m, 3H ), 3.70 - 3.43 (m, 9H), 3.42 - 3.26 (m, 14H), 2.98 - 2.87 (m, 1H), 2.77 - 2.62 (m, 3H), 2.58 (dd, J = 16.9, 6.3 Hz, 1H), 2.34 (d, J = 13.4 Hz, 2H), 2.15 - 1.84 (m, 5H), 1.83 - 1.64 (m, 7H), 1.34 (dddd, J = 22.7, 19.4, 18.1, 9.1 Hz, 12H), 1.16 - 0.80 (m, 19H), 0.66 (dt, J = 16.8, 8.4 Hz, 1H).

[0377] Example 20 (23E,25E,27E,28E,32R,33S,34R,35R,36S,39 S,41S,45R,46R,55R)-45,55-dihydroxy-41-[(1R) -2-[(1S,2R,3R)-3-hydroxy-2-methoxy-cyclohexyl]-1 -methyl-ethyl]-40-[[(2S,5S)-5-(hydroxymethyl)-1,4- Dioxan-2-yl]methoxy]-46-methoxy-32,33,34,35,47, 48-Hexamethyl-68,69-dioxa-56-azatricyclohexatriacontane -23,25,27(47),28(48)-tetraene-49,50,51,52,5 Synthesis of 3-pentone (I-118): [ka] Synthesis scheme: [ka] Procedure and Characterization: Step 1: Synthesis of (S)-1-(benzyloxy)-3-chloropropan-2-ol :

[0378] (2R)-2-(chloromethyl)oxirane (1 g, 10.81 mmol) and phenanthroline A solution of 2.34 g (21.62 mmol) of methylmethanol in 10 mL of DCE was stirred at room temperature. The mixture was stirred at rt for 1 h, then cooled to 0° C. and treated with boron trifluoride etherate (76.7 mg, 0 The reaction mixture was allowed to warm to room temperature and stirred overnight, then After cooling, the reaction mixture was diluted with 10% aqueous NaHCO3 and The combined organic layer was dried over anhydrous Na2SO4 and filtered. The resulting residue was purified by silica gel chromatography (PE: EtOAc = 1 0:1) to give the desired product (1.8 g, 86% yield) as a colorless oil Got it. ESI-MS (EI + , m / z): 218.1 [M+HO] + . 1 H NMR (500 MHz, CDCl3) δ 7.36-7.27 (m, 5H), 4.64 (s, 2H), 3.99-3.95 (m, 1H), 3.64-3.55 (m, 4 H), 2.75 (d, J = 6.0 Hz, 1H). Step 2: (S)-2-((S)-1-(benzyloxy)-3-chloropropane-2 Synthesis of (-yloxy)-3-hydroxypropyl 4-methylbenzenesulfonate:

[0379] (2S)-1-benzyloxy-3-chloro-propan-2-ol (6g, 29.9 mmol) and [(2S)-oxiran-2-yl]methyl 4-methylbenzenesulfonate A solution of phosphate (6.83 g, 29.9 mmol) in DCE (100 mL) was stirred at room temperature for 1 h. The mixture was stirred, then cooled to 0° C. and trifluoroborane etherate (254.6 mg, 1.79 The reaction was allowed to warm to room temperature, stirred at room temperature overnight, and refluxed for 2 hours. The mixture was then cooled to room temperature. EtOAc (100 mL) and water (50 mL) were added. The layers were separated and the aqueous layer was further extracted with EtOAc (100 mL x 2). The combined organic layer was washed with water (2 x 50 mL) and brine (50 mL) and diluted with anhydrous NaSO. The resulting residue was purified by silica gel chromatography. (8% EtOAc in PE) to purify [(2S)-2-[(1S)-1-(benzyloxy) (2-chloro-ethoxy)-3-hydroxy-propyl]4-methylbenzene The benzoxanthate (4.4 g, 34% yield) was obtained as a colorless oil. + , m / z): 429.1 [M+H] + . Step 3: ((2R,5R)-5-(benzyloxymethyl)-1,4-dioxane- Synthesis of (2-yl)methanol:

[0380] [(2S)-2-[(1S)-1-(benzyloxymethyl)-2-chloro-ethoxy ]-3-hydroxy-propyl]4-methylbenzenesulfonate (0.78 g, 1.8 2 mmol), a solution of NaOH (0.22 g, 5.46 mmol) in HO (10 mL) The mixture was stirred at room temperature for 2.5 hours, then heated at 90°C for 4 hours, cooled to room temperature, and stirred overnight. The reaction mixture was then heated at 90° C. for an additional 2 hours. The reaction mixture was acidified with 1N aqueous HCl solution. The combined organic layer was washed with aqueous NaHCO3 solution. , dried over anhydrous Na2SO4, filtered, and concentrated to give [(2R,5R)-5-(benzyloxy) [dimethyl]-1,4-dioxan-2-yl]methanol (4.4 g, 41% yield) was obtained This material was used without further purification. ESI-MS (EI + , m / z): 239.1 [M+H] + . Step 4: ((2R,5R)-1,4-dioxane-2,5-diyl)dimethanol Synthesis:

[0381] [(2R,5R)-5-(benzyloxymethyl)-1,4-dioxan-2-yl] A solution of methanol (2.4 g, 10 mmol) in MeOH (30 mL) was added to Pd / C (0 The mixture was stirred under a hydrogen balloon at room temperature overnight, then ethanol was added. The combined organic washes were filtered through a short plug of Celite, washing with ethyl acetate. Concentration gave (2R,5R)-1,4-dioxane-2,5-diyl)dimethanol (1. 2 g (74%) was obtained as an oil. ESI-MS (EI + , m / z):149.2 [M+H] + . Step 5: (23E, 25E, 27E, 28E, 32R, 33S, 34R, 35R, 3 6S,39S,41S,45R,46R,55R)-45,55-dihydroxy-41- [(1R)-2-[(1S,2R,3R)-3-hydroxy-2-methoxy-cyclohexane 40-[[(2S,5S)-5-(hydroxymethyl) -1,4-dioxan-2-yl]methoxy]-46-methoxy-32,33,34,3 5,47,48-Hexamethyl-68,69-dioxa-56-azatricyclohexyl Rear Contour-23,25,27(47),28(48)-Tetraene-49,50,51 Synthesis of ,52,53-pentone (I-118):

[0382] Rapamycin (0.5 g, 0.547 mmol) and 4-methylbenzenesulfonic acid To a solution of [(2R, 5R)-5-(hydroxymethyl)-1,4-dioxan-2-yl]methanol (0. After stirring at room temperature for 2 hours, the reaction mixture was added to cold NaCl. The mixture was quenched with aqueous HCO3 and extracted with EtOAc (50 mL x 2). The organic layer was dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified by reverse phase chromatography. - (C18, CH3CN:H2O = 65:35), followed by silica gel chromatography (hexane:DCM:EtOAc:MeOH=8:8:3:1) to give (2 3E,25E,27E,28E,32R,33S,34R,35R,36S,39S,4 1S,45R,46R,55R)-45,55-dihydroxy-41-[(1R)-2- [(1S,2R,3R)-3-Hydroxy-2-methoxy-cyclohexyl]-1-methyl 40-[[(2S,5S)-5-(hydroxymethyl)-1,4-dioxo- ... 32,33,34,35,47,48- Hexamethyl-68,69-dioxa-56-azatricyclohexatriaconta-23 ,25,27(47),28(48)-tetraene-49,50,51,52,53-pe The compound (I-118: 80 mg, 14% yield) was obtained as a white solid. + , m / z): 1052.9 [M+Na] + . 1 H NMR (500 MHz, CDCl3) δ 6.46 - 5.86 (m, 4H), 5.69 - 5.06 (m, 4H), 4.16 (ddd, J = 56.1, 52.0, 39.5 Hz, 3H) , 3.94 - 3.49 (m, 10H), 3.48 - 3.11 (m, 12H), 3.08 - 2.46 (m, 7H), 2.40 - 1.93 (m, 7H), 1.73 (dd, J = 16.9, 10.5 Hz, 13H), 1.52 - 1.17 (m, 8H), 1.16 - 0.79 (m, 18H), 0.65 (d, J = 17.5 Hz, 1 H).

[0383] Example 21 (21E,23E,25E,26E,34R,35S,36R,37R,39S,41 S,43R,44S,45R,46R,55R)-45,55-dihydroxy-43-[ 2-(2-hydroxyethoxy)ethoxy]-44-[(1R)-2-[(1S,3R, 4R)-4-(2-hydroxyethoxy)-3-methoxy-cyclohexyl]-1-methyl 46-Methoxy-34,35,36,37,47,48-Hexamethyl- 66,67-Dioxa-56-azatricyclohexatriaconta-21,23,25( 47),26(48)-tetraene-49,50,51,52,53-pentone (I-1 16) and (21E, 23E, 25E, 26E, 34R, 35S, 36R, 37R, 3 9S,41S,43S,44S,45R,46R,55R)-45,55-dihydroxy -43-[2-(2-hydroxyethoxy)ethoxy]-44-[(1R)-2-[(1 S,3R,4R)-4-(2-hydroxyethoxy)-3-methoxy-cyclohexyl] -1-methyl-ethyl]-46-methoxy-34,35,36,37,47,48-hex samethyl-66,67-dioxa-56-azatricyclohexatriaconta-21,2 3,25(47),26(48)-tetraene-49,50,51,52,53-pent Synthesis of I-117: [ka] Synthesis scheme: [ka] Procedure and Characterization: Step 1: (21E, 23E, 25E, 26E, 34R, 35S, 36R, 37R, 3 9S,41S,44S,45R,46R,55R)-45,55-dihydroxy-43- [2-(2-hydroxyethoxy)ethoxy]-44-[(1R)-2-[(1S,3R ,4R)-4-(2-hydroxyethoxy)-3-methoxy-cyclohexyl]-1-methyl ethyl-ethyl]-46-methoxy-34,35,36,37,47,48-hexamethyl -66,67-Dioxa-56-azatricyclohexatriaconta-21,23,25 Synthesis of (47),26(48)-tetraene-49,50,51,52,53-pentone :

[0384] A solution of everolimus (1 g, 1.04 mmol) in THF (15 mL) was degassed with N2. p-Toluenesulfonic acid (0.895 g, 5.20 mmol) was added at 0°C, followed by 2- (2-hydroxyethoxy)ethanol (2.8 mL) was added. The resulting mixture was The reaction was stirred at 0° C. for 0.5 h and then at 25° C. for 3 h. The reaction was diluted with saturated NaHCO (40 mL), extracted with EtOAc (30 mL), and then with water (30 mL × 2) and The extract was washed with ethanol (40 mL), then dried over anhydrous Na2SO4, filtered, and concentrated. The resulting residue was purified by normal phase silica gel chromatography (MeOH:DCM=1:15), Then, it was purified by reverse phase chromatography (C18, CH3CN:H2O=7:3) and (2 1E,23E,25E,26E,34R,35S,36R,37R,39S,41S,4 4S,45R,46R,55R)-45,55-dihydroxy-43-[2-(2-hydroxy- 4-[(1R)-2-[(1S,3R,4R)-4-( ... 2-hydroxyethoxy)-3-methoxy-cyclohexyl]-1-methyl-ethyl]- 46-Methoxy-34,35,36,37,47,48-hexamethyl-66,67-di Oxa-56-azatricyclohexatriaconta-21,23,25(47),26( 48)-Tetraene-49,50,51,52,53-pentone (0.43 g, yield 40 %) was obtained as a pale yellow solid. + , m / z):1053.9 [M+Na]+ . 1 H NMR (40 0 MHz, CDCl3) δ 6.47 - 5.85 (m, 4H), 5.40 (ddd, J = 99.7, 51.9, 29.1 Hz, 4H), 4.80 (d, J = 22.0 Hz, 1H), 4.23 (d, J = 42.5 Hz, 1H), 4.05 - 3.54 (m, 13H), 3.52 - 3.01 (m, 14H), 2.67 (ddd, J = 46.8, 27.3, 6.8 Hz, 4H), 2.17 (dd, J = 82.0, 45.9 Hz, 6H), 1.70 (dt, J = 21.0, 15.8 Hz, 12H), 1.34 (dd, J = 105.2, 26.3 Hz, 11H) , 1.15 - 0.79 (m, 18H), 0.76 - 0.64 (m, 1H). Step 2: (21E, 23E, 25E, 26E, 34R, 35S, 36R, 37R, 3 9S,41S,43R,44S,45R,46R,55R)-45,55-dihydroxy -43-[2-(2-hydroxyethoxy)ethoxy]-44-[(1R)-2-[(1 S,3R,4R)-4-(2-hydroxyethoxy)-3-methoxy-cyclohexyl] -1-methyl-ethyl]-46-methoxy-34,35,36,37,47,48-hex samethyl-66,67-dioxa-56-azatricyclohexatriaconta-21,2 3,25(47),26(48)-tetraene-49,50,51,52,53-pent (I-116) and (21E, 23E, 25E, 26E, 34R, 35S, 36R, 37R, 39S, 41S, 43S, 44S, 45R, 46R, 55R)-45, 55-di Hydroxy-43-[2-(2-hydroxyethoxy)ethoxy]-44-[(1R)- 2-[(1S,3R,4R)-4-(2-hydroxyethoxy)-3-methoxy-cyclo hexyl]-1-methyl-ethyl]-46-methoxy-34,35,36,37,47, 48-Hexamethyl-66,67-dioxa-56-azatricyclohexatriaconta -21,23,25(47),26(48)-tetraene-49,50,51,52,5 Synthesis of 3-pentone (I-117):

[0385] 90mg (21E, 23E, 25E, 26E, 34R, 35S, 36R, 37R, 3 9S,41S,44S,45R,46R,55R)-45,55-dihydroxy-43- [2-(2-hydroxyethoxy)ethoxy]-44-[(1R)-2-[(1S,3R ,4R)-4-(2-hydroxyethoxy)-3-methoxy-cyclohexyl]-1-methyl ethyl-ethyl]-46-methoxy-34,35,36,37,47,48-hexamethyl -66,67-Dioxa-56-azatricyclohexatriaconta-21,23,25 (47),26(48)-tetraene-49,50,51,52,53-pentone The epimers obtained by chiral HPLC purification were: (21E, 23E, 25E, 26E) ,34R,35S,36R,37R,39S,41S,43R,44S,45R,46R ,55R)-45,55-dihydroxy-43-[2-(2-hydroxyethoxy)ethoxy]ethoxy] 4-[(1R)-2-[(1S,3R,4R)-4-(2-hydroxyethoxy) 3-Methoxy-cyclohexyl]-1-methyl-ethyl]-46-methoxy-34 ,35,36,37,47,48-Hexamethyl-66,67-dioxa-56-azato Lithium cyclohexatriaconta-21,23,25(47),26(48)-tetraene 49,50,51,52,53-pentone (I-116: 14 mg, 16% yield) and (21E,23E,25E,26E,34R,35S,36R,37R,39S,41S ,43S,44S,45R,46R,55R)-45,55-dihydroxy-43-[2 -(2-hydroxyethoxy)ethoxy]-44-[(1R)-2-[(1S,3R,4 R)-4-(2-hydroxyethoxy)-3-methoxy-cyclohexyl]-1-methyl -ethyl]-46-methoxy-34,35,36,37,47,48-hexamethyl-6 6,67-Dioxa-56-azatricyclohexatriacin-21,23,25(4 7),26(48)-tetraene-49,50,51,52,53-pentone (I-11 7: 15 mg, 17% yield) were obtained as white solids.

[0386] Chiral separation methods are listed below: Column: CHIRALPAK IC Column size: 5.0cm inner diameter x 25cm length Solution concentration: 11.5mg / ml Injection: 10mL Mobile phase: Hexane / EtOH = 50 / 50 (V / V) Flow rate: 60ml / min Wavelength: UV254nm Temperature: 35℃

[0389] I-116: ESI-MS (EI + , m / z):1054.0 [M+Na] + . 1 H NMR (500 MHz, , CDCl3) δ 6.42 - 5.90 (m, 4H), 5.79 (ddd, J = 51.6, 30.9, 16.6 Hz, 1H), 5.54 - 5.08 (m, 4H), 5.03 - 4.88 (m, 1H), 4. 74 (d, J = 61.6 Hz, 1H), 4.28 (dd, J = 57.6, 29.0 Hz, 2H), 3.99 (dd, J = 26.5, 6.0 Hz, 1H), 3.89 - 3.55 (m, 12H), 3.54 - 2.96 ( m, 15H), 2.87 - 2.47 (m, 4H), 2.38 - 1.92 (m, 8H), 1.86 - 1.67 (m, 11H), 1.51 - 1.30 (m, 6 H), 1.14 - 0.80 (m, 18H), 0.76 - 0.64 (m, 1H).

[0390] I-117: ESI-MS (EI + , m / z):1053.9 [M+Na] + . 1 H NMR (500 MHz, , CDCl3) δ 6.41 - 6.22 (m, 2H), 6.13 (dd, J = 15.1, 1 0.1 Hz, 1H), 5.94 (dd, J = 22.3, 10.8 Hz, 1H), 5.52 (dt, J = 18.4 , 9.2 Hz, 1H), 5.41 (d, J = 9.9 Hz, 1H), 5.27 (d, J = 5.3 Hz, 1 H), 5.12 (dt, J = 46.3, 5.6 Hz, 1H), 4.83 (s, 1H), 4.23 - 4.14 ( m, 1H), 3.91 - 3.52 (m, 15H), 3.49 - 3.25 (m, 12H), 3.23 - 3.03 (m, 3H), 2.94 - 2.80 (m, 1H), 2.65 (ddd, J = 23.4, 16.9, 6.0 Hz , 3H), 2.39 - 2.15 (m, 2H), 2.16 - 1.85 (m, 5H), 1.82 - 1.64 ( m, 10H), 1.47 (dd, J = 26.8, 15.9 Hz, 5H), 1.38 - 1.16 (m, 6H), 1.10 (d, J = 6.8 Hz, 3H), 1.07 - 1.03 (m, 3H), 1.00 (t, J = 6.8 Hz, 3H), 0.94 (d, J = 6.6 Hz, 3H), 0.88 (ddd, J = 34.0, 16.9, 5 .0 Hz, 6H), 0.71 (dd, J = 23.9, 11.8 Hz, 1H).

[0387] Example 22 (21E,23E,25E,26E,38R,39S,40R,41R,43S,45 S,47R,48S,49R,50R,59R)-49,59-dihydroxy-47-[ 2-[2-[2-(2-hydroxyethoxy)ethoxy]ethoxy]ethoxy]-48- [(1R)-2-[(1S,3R,4R)-4-(2-hydroxyethoxy)-3-meth 50-methoxy-38,39,40, 41,51,52-Hexamethyl-70,71-dioxa-60-azatricyclohexa Triaconta-21,23,25(51),26(52)-tetraene-53,54,5 5,56,57-pentone (I-114) and (21E,23E,25E,26E,3 8R,39S,40R,41R,43S,45S,47S,48S,49R,50R,5 9R)-49,59-dihydroxy-47-[2-[2-[2-(2-hydroxyethoxy) 48-[(1R)-2-[(1S,3R,4R)ethoxy]ethoxy]ethoxy]-48-[(1R)-2-[(1S,3R,4R) -4-(2-hydroxyethoxy)-3-methoxy-cyclohexyl]-1-methyl- ethyl]-50-methoxy-38,39,40,41,51,52-hexamethyl-70, 71-Dioxa-60-azatricyclohexatriaconta-21,23,25(51) ,26(52)-tetraene-53,54,55,56,57-pentone (I-115) Synthesis of: [ka] Synthesis scheme: [ka] Procedure and Characterization: Step 1: (21E, 23E, 25E, 26E, 38R, 39S, 40R, 41R, 4 3S,45S,48S,49R,50R,59R)-49,59-dihydroxy-47- [2-[2-[2-(2-hydroxyethoxy)ethoxy]ethoxy]ethoxy]-48 -[(1R)-2-[(1S,3R,4R)-4-(2-hydroxyethoxy)-3-methyl [Cyclohexyl]-1-methyl-ethyl]-50-methoxy-38,39,40 ,41,51,52-Hexamethyl-70,71-dioxa-60-azatricyclohexyl Satriaconta-21,23,25(51),26(52)-tetraene-53,54, Synthesis of 55,56,57-pentone:

[0388] Everolimus (1 g, 1.04 mmol), 2-[2-[2-(2-hydroxyethoxy)- [C]ethoxy]ethoxy]ethanol (4.05 g, 20.87 mmol) and p-tolyl A mixture of benzenesulfonic acid (0.898 g, 5.22 mmol) in THF (20 mL) The mixture was stirred at 20° C. for 2 h. The mixture was then poured into cold saturated NaHCO (30 mL) and Extract with tOAc (50 mL x 3), wash the combined organic layers with water and brine, then The resulting residue was purified by reverse phase chromatography. The compounds were purified using a solvent (C18, CH3CN:H2O = 6:4) and purified as follows: (21E, 23E, 25E, 26E,38R,39S,40R,41R,43S,45S,48S,49R,50R, 59R)-49,59-dihydroxy-47-[2-[2-[2-(2-hydroxyethoxy) 48-[(1R)-2-[(1S,3R,4R )-4-(2-hydroxyethoxy)-3-methoxy-cyclohexyl]-1-methyl- Ethyl]-50-methoxy-38,39,40,41,51,52-hexamethyl-70 ,71-Dioxa-60-azatricyclohexatriaconta-21,23,25(51 ), 26(52)-tetraene-53,54,55,56,57-pentone (0.25g , yield 21%) was obtained as a white solid. + , m / z):1142.4 [M+Na] + . 1 HNM R (400 MHz, CDCl3) δ 6.41 - 5.85 (m, 4H), 5.78 (s, 1H), 5.60 - 4.98 (m, 4H), 4.22 (t, J = 27.1 Hz, 1H), 3.97 (dd, J = 17.7, 6. 4 Hz, 1H), 3.87 - 3.54 (m, 21H), 3.51 - 3.03 (m, 15H), 2.72 - 2.45 (m, 3H), 2.28 (s, 6H), 2.16 - 1.96 (m, 4H), 1.89 - 1.56 (m, 10H), 1.51 - 1.17 (m, 8H), 1.17 - 0.81 (m, 18H), 0.78 - 0.62 (m, 1H). Step 2: (21E, 23E, 25E, 26E, 38R, 39S, 40R, 41R, 4 3S,45S,47R,48S,49R,50R,59R)-49,59-dihydroxy -47-[2-[2-[2-(2-hydroxyethoxy)ethoxy]ethoxy]ethoxy ]-48-[(1R)-2-[(1S,3R,4R)-4-(2-hydroxyethoxy) -3-Methoxy-cyclohexyl]-1-methyl-ethyl]-50-methoxy-38,3 9,40,41,51,52-Hexamethyl-70,71-dioxa-60-azatriazole Chlohexatriaconta-21,23,25(51),26(52)-tetraene-53 ,54,55,56,57-Penton (I-114) and (21E,23E,25E, 26E,38R,39S,40R,41R,43S,45S,47S,48S,49R, 50R,59R)-49,59-dihydroxy-47-[2-[2-[2-(2-hydroxy) 48-[(1R)-2-[(1S,3 R,4R)-4-(2-hydroxyethoxy)-3-methoxy-cyclohexyl]-1- Methyl-ethyl]-50-methoxy-38,39,40,41,51,52-hexamethylenediamine Ru-70,71-dioxa-60-azatricyclohexatriacin-21,23,2 5(51),26(52)-tetraene-53,54,55,56,57-pentone (I -115) synthesis:

[0389] 1.5g (21E, 23E, 25E, 26E, 38R, 39S, 40R, 41R, 4 3S,45S,48S,49R,50R,59R)-49,59-dihydroxy-47- [2-[2-[2-(2-hydroxyethoxy)ethoxy]ethoxy]ethoxy]-48 -[(1R)-2-[(1S,3R,4R)-4-(2-hydroxyethoxy)-3-methyl [Cyclohexyl]-1-methyl-ethyl]-50-methoxy-38,39,40 ,41,51,52-Hexamethyl-70,71-dioxa-60-azatricyclohexyl Satriaconta-21,23,25(51),26(52)-tetraene-53,54, The 55,56,57-pentone was purified by preparative chiral HPLC, and the resulting epimers were Silica gel chromatography (hexane:DCM:EtOAc:MeOH=8:8:3 :1.2) and purified by (21E, 23E, 25E, 26E, 38R, 39S, 4 0R,41R,43S,45S,47R,48S,49R,50R,59R)-49,5 9-dihydroxy-47-[2-[2-[2-(2-hydroxyethoxy)ethoxy]ethoxy]ethoxy ethoxy]ethoxy]-48-[(1R)-2-[(1S,3R,4R)-4-(2-hydroxy (3-methoxy-cyclohexyl)-1-methyl-ethyl]-50-methyl Toxic-38,39,40,41,51,52-hexamethyl-70,71-dioxa- 60-Azatricyclohexatriaconta-21,23,25(51),26(52)- Tetraene-53,54,55,56,57-pentone (I-114: 300 mg, yield 20%) and (21E, 23E, 25E, 26E, 38R, 39S, 40R, 41R, 43S,45S,47S,48S,49R,50R,59R)-49,59-dihydroxy C-47-[2-[2-[2-(2-hydroxyethoxy)ethoxy]ethoxy]ethoxy 48-[(1R)-2-[(1S,3R,4R)-4-(2-hydroxyethoxy )-3-Methoxy-cyclohexyl]-1-methyl-ethyl]-50-methoxy-38, 39,40,41,51,52-Hexamethyl-70,71-dioxa-60-azatriamine Cyclohexatriaconta-21,23,25(51),26(52)-tetraene-5 3,54,55,56,57-pentone (I-115: 563 mg, yield 38%) was obtained as a white Obtained as a solid.

[0390] Chiral analysis conditions: Column: CHIRALPAK IC-3 (IC30CE-NJ008) Column size: 0.46cm inner diameter x 15cm length Injection: 20.0ul Mobile phase: hexane / EtOH = 60 / 40 (V / V) Flow rate: 1.0ml / min Wavelength: UV254nm Temperature: 35℃ HPLC equipment: Shimadzu LC-20AT

[0395] I-114: ESI-MS (EI + , m / z):1142.5 [M+Na] + . 1 H NMR (500 MHz, CDCl3) δ 6.42 - 5.91 (m, 4H), 5.60 - 5.08 (m, 4H), 4.19 (dd, J = 43.8, 32.6 Hz, 1H), 3.96 (dd, J = 27.1, 6.3 Hz, 1H) , 3.85 - 3.54 (m, 21H), 3.53 - 3.01 (m, 12H), 2.93 - 2.80 (m, 1H), 2.75 - 2.45 (m, 3H), 2.30 (d, J = 12.1 Hz, 1H), 2.03 (dd, J = 37.0, 32.8 Hz, 13H), 1.84 - 1.69 (m, 12H), 1.50 - 1.18 (m, 5 H), 1.16 - 0.82 (m, 18H), 0.71 (dt, J = 23.8, 12.1 Hz, 1H).

[0396] I-115: ESI-MS (EI + , m / z):1142.4 [M+Na] + . 1 H NMR (500 MHz, CDCl3) δ 6.36 (dd, J = 14.7, 10.9 Hz, 1H), 6.23 (dd, J = 14.7, 10.6 Hz, 1H), 6.10 (dd, J = 15.0, 10.5 Hz, 1H), 5.92 (d d, J = 45.2, 10.5 Hz, 1H), 5.61 (s, 1H), 5.43 (dd, J = 15.6, 9.6 Hz, 2H), 5.21 (d, J = 5.4 Hz, 1H), 5.10 (dd, J = 9.9, 5.9 Hz, 1H), 4.20 (d, J = 4.5 Hz, 1H), 4.10 - 3.95 (m, 1H), 3.84 (d, J = 5.0 Hz, 1H), 3.80 - 3.49 (m, 21H), 3.48 - 3.13 (m, 12H), 3.11 - 3.01 (m, 1H), 2.73 - 2.50 (m, 3H), 2.34 - 2.19 (m, 2H), 2.0 1 (ddd, J = 62.0, 34.6, 28.2 Hz, 12H), 1.80 - 1.54 (m, 10H), 1.51 - 1.37 (m, 5H), 1.35 - 1.12 (m, 6H), 1.05 (dd, J = 6.4, 5.0 H z, 6H), 0.97 (d, J = 6.5 Hz, 3H), 0.93 (d, J = 6.6 Hz, 3H), 0.91 - 0.82 (m, 6H), 0.74 - 0.67 (m, 1H).

[0391] Example 23 (21E,23E,25E,26E,33R,34S,35R,36R,38S,40 S,43S,44R,45R,54R)-44,54-dihydroxy-43-[(1R) -2-[(1S,3R,4R)-4-hydroxy-3-methoxy-cyclohexyl]-1 -methyl-ethyl]-42-(5-hydroxypentoxy)-45-methoxy-33,3 4,35,36,46,47-Hexamethyl-65,66-dioxa-55-azatrixine Chlohexatriaconta-21,23,25(46),26(47)-tetraene-48 Synthesis of 49,50,51,52-pentone (I-113): [ka] Synthesis scheme: [ka] Procedure and Characterization: Step 1: (21E, 23E, 25E, 26E, 33R, 34S, 35R, 36R, 3 8S,40S,43S,44R,45R,54R)-44,54-dihydroxy-43- [(1R)-2-[(1S,3R,4R)-4-hydroxy-3-methoxy-cyclohexane [Cycyl]-1-methyl-ethyl]-42-(5-hydroxypentoxy)-45-methoxy -33,34,35,36,46,47-Hexamethyl-65,66-dioxa-55- Azatricyclohexatriaconta-21,23,25(46),26(47)-tetra Synthesis of ene-48,49,50,51,52-pentone (I-113):

[0392] To a solution of rapamycin (0.5 g, 0.547 mmol) in THF (10 mL), 4- Methylbenzenesulfonic acid hydrate (0.52 g, 2.73 mmol) and pentane-1 ,5-diol (3 mL) was added. The resulting solution was stirred at room temperature for 2 hours, then cooled. The mixture was poured into aqueous NaHCO3 solution and extracted with EtOAc. The organic layer was concentrated and purified by reverse phase chromatography. The product was purified by a filter (C18, CH3CN:H2O ratio 10% to 72%) and then purified to give (21E,2 3E,25E,26E,33R,34S,35R,36R,38S,40S,43S,4 4R,45R,54R)-44,54-dihydroxy-43-[(1R)-2-[(1S ,3R,4R)-4-hydroxy-3-methoxy-cyclohexyl]-1-methyl-ethyl

[00100] -42-(5-hydroxypentoxy)-45-methoxy-33,34,35,36 ,46,47-Hexamethyl-65,66-dioxa-55-azatricyclohexatri Aconta-21,23,25(46),26(47)-tetraene-48,49,50, 51,52-Pentone (I-113: 150 mg, 28% yield) was obtained as a white solid. ESI-MS (EI + , m / z):1008.0 [M+Na] + . 1 HNMR (500 MHz, CDCl3) δ 6.42 - 5.82 (m, 4H), 5.58 - 5.37 (m, 2H), 5.32 - 5.02 (m, 2H), 4.78 ( t, J = 25.9 Hz, 1H), 4.31 - 4.08 (m, 1H), 4.00 - 3.53 (m, 5H), 3.53 - 3.05 (m, 12H), 2.99 - 2.80 (m, 2H), 2.77 - 2.51 (m, 3H ), 2.48 - 2.23 (m, 2H), 2.15 - 1.89 (m, 4H), 1.89 - 1.16 (m, 3 2H), 1.15 - 0.78 (m, 18H), 0.65 (dt, J = 24.1, 12.0 Hz, 1H).

[0393] Example 24 (28E,30E,32E,33E,36R,37S,38R,39R,41S,43 S,45R,46S,48R,49R,58R)-48,58-dihydroxy-46-[ (1R)-2-[(1S,3R,4R)-4-hydroxy-3-methoxy-cyclohexyl 49-Methoxy-36,37,38,39,50,51- Hexamethyl-45-(1,4,7,10-tetraoxacyclododec-2-ylmethacrylate) CI)-72,73-dioxa-59-azatricyclohexatriaconta-28,30, 32(50),33(51)-tetraene-52,53,54,55,56-pentone( I-111) and (28E, 30E, 32E, 33E, 36R, 37S, 38R, 39 R,41S,43S,45S,46S,48R,49R,58R)-48,58-dihyde 46-[(1R)-2-[(1S,3R,4R)-4-hydroxy-3-methoxy- [Cyclohexyl]-1-methyl-ethyl]-49-methoxy-36,37,38,3 9,50,51-Hexamethyl-45-(1,4,7,10-tetraoxacyclododeca) -2-ylmethoxy)-72,73-dioxa-59-azatricyclohexatriacon Ta-28,30,32(50),33(51)-tetraene-52,53,54,55, Synthesis of 56-pentone (I-112): [ka] Synthesis scheme: [ka] Procedure and Characterization: Step 1: (28E, 30E, 32E, 33E, 36R, 37S, 38R, 39R, 4 1S,43S,46S,48R,49R,58R)-48,58-dihydroxy-46- [(1R)-2-[(1S,3R,4R)-4-hydroxy-3-methoxy-cyclohexane 49-methoxy-36,37,38,39,50,51 -Hexamethyl-45-(1,4,7,10-tetraoxacyclododec-2-ylmethacrylate) Oxy)-72,73-dioxa-59-azatricyclohexatriaconta-28,30 ,32(50),33(51)-tetraene-52,53,54,55,56-pentone Synthesis of:

[0394] Rapamycin (0.5 g, 0.547 mmol) and 4-methylbenzenesulfonic acid To a solution of 1,4,7 hydrate (0.471 g, 2.73 mmol) in THF (15 mL), ,10-Tetraoxacyclododec-2-ylmethanol (2.25 g, 10.9 mmol) l) was added at 25° C. The resulting mixture was stirred at room temperature for 2 hours, and then ice-cold NaHC The organic layer was dried over anhydrous Na2SO4 and filtered. The resulting residue was purified by reversed-phase chromatography (C18, CHCN:H2O = 7 :3) and purified (28E, 30E, 32E, 33E, 36R, 37S, 38R, 39 R,41S,43S,46S,48R,49R,58R)-48,58-dihydroxy- 46-[(1R)-2-[(1S,3R,4R)-4-hydroxy-3-methoxy-cyclohexyl 49-Methoxy-36, 37, 38, 39, 50, 60-Hexyl]-1-methyl-ethyl]-49-methoxy-36, 37, 38, 39, 50 ,51-Hexamethyl-45-(1,4,7,10-tetraoxacyclododeca-2-yl) (methoxy)-72,73-dioxa-59-azatricyclohexatriaconta-28 ,30,32(50),33(51)-tetraene-52,53,54,55,56-pe The compound (70 mg, 11% yield) was obtained as a white solid. + , m / z):1110.5 [M+Na] + . 1 H NMR (500 MHz, CDCl3) δ 6.41 - 5.82 (m, 4H), 5.54 - 5.04 (m, 4H), 4.72 (d, J = 22.1 Hz, 1H), 4.35 - 4.09 (m, 1H), 3.92 - 3.51 (m, 18H), 3.48 - 3.03 (m, 14H), 2.99 - 2.51 (m, 5H) , 2.34 (d, J = 13.4 Hz, 1H), 2.04 (d, J = 62.6 Hz, 4H), 1.72 (dd d, J = 43.8, 30.6, 28.9 Hz, 12H), 1.53 - 1.17 (m, 10H), 1.14 - 0.81 (m, 18H), 0.70 - 0.62 (m, 1H). Step 2: (28E, 30E, 32E, 33E, 36R, 37S, 38R, 39R, 4 1S,43S,45S,46S,48R,49R,58R)-48,58-dihydroxy -46-[(1R)-2-[(1S,3R,4R)-4-hydroxy-3-methoxy- cyclohexyl]-1-methyl-ethyl]-49-methoxy-36,37,38,39,5 0,51-Hexamethyl-45-(1,4,7,10-tetraoxacyclododeca-2- (ylmethoxy)-72,73-dioxa-59-azatricyclohexatriaconta-2 8,30,32(50),33(51)-tetraene-52,53,54,55,56- Penton (I-112) and (28E, 30E, 32E, 33E, 36R, 37S, 3 8R,39R,41S,43S,45R,46S,48R,49R,58R)-48,5 8-dihydroxy-46-[(1R)-2-[(1S,3R,4R)-4-hydroxy- 3-Methoxy-cyclohexyl]-1-methyl-ethyl]-49-methoxy-36,37 ,38,39,50,51-Hexamethyl-45-(1,4,7,10-tetraoxamethyl) Chlododec-2-ylmethoxy)-72,73-dioxa-59-azatricyclohexa Triaconta-28,30,32(50),33(51)-tetraene-52,53,5 Synthesis of 4,55,56-pentone (I-111):

[0395] (28E,30E,32E,33E,36R,37S,38R,39R,41S,43 S,46S,48R,49R,58R)-48,58-dihydroxy-46-[(1R) -2-[(1S,3R,4R)-4-hydroxy-3-methoxy-cyclohexyl]-1 -methyl-ethyl]-49-methoxy-36,37,38,39,50,51-hexame 45-(1,4,7,10-tetraoxacyclododec-2-ylmethoxy)-7-yl 2,73-Dioxa-59-azatricyclohexatriaconta-28,30,32(5 0), 33(51)-tetraene-52,53,54,55,56-pentone (170m g) was purified by preparative chiral HPLC, and the resulting epimers were separated by silica gel chromatography. Purified by filtration (hexane:DCM:EtOAc:MeOH=3:3:1:0.5) (28E, 30E, 32E, 33E, 36R, 37S, 38R, 39R, 41S, 43S,45S,46S,48R,49R,58R)-48,58-dihydroxy-46 -[(1R)-2-[(1S,3R,4R)-4-hydroxy-3-methoxy-cyclohexane [xyl]-1-methyl-ethyl]-49-methoxy-36,37,38,39,50,5 1-Hexamethyl-45-(1,4,7,10-tetraoxacyclododec-2-ylmethyl) Toxo)-72,73-dioxa-59-azatricyclohexatriaconta-28,3 0,32(50),33(51)-tetraene-52,53,54,55,56-pent I-112 (55 mg, 32% yield) and (28E, 30E, 32E, 33E, 3 6R,37S,38R,39R,41S,43S,45R,46S,48R,49R,5 8R)-48,58-dihydroxy-46-[(1R)-2-[(1S,3R,4R)- 4-Hydroxy-3-methoxy-cyclohexyl]-1-methyl-ethyl]-49-meth Oxy-36,37,38,39,50,51-hexamethyl-45-(1,4,7,10 -tetraoxacyclododec-2-ylmethoxy)-72,73-dioxa-59-aza Tricyclohexatriaconta-28,30,32(50),33(51)-tetraene -52,53,54,55,56-pentone (I-111: 11 mg, yield 6%) Both were obtained as white solids.

[0396] Chiral analysis methods: Column: CHIRALPAK IC (IC00CE-OL002) Column size: 0.46cm inner diameter x 25cm length Injection: 100.0ul Shifting phase: Hekisan / EtOH = 60 / 40 (V / V) Flow rate: 1.0 ml / min Wavelength: UV254nm Temperature: 35℃ HPLC apparatus: Shimadzu Corporation LC-20AT CP-HPLC-06

[0403] I-112: ESI-MS (EI + , m / z):1109.9 [M+Na] + . 1 H NMR (500 MHz, CDCl3) δ 6.40 - 6.03 (m, 3H), 5.90 (dd, J = 37.1, 9.8 Hz, 1H), 5.54 - 5.06 (m, 4H), 4.71 (d, J = 22.4 Hz, 1H), 4.20 (t, J = 20.9 Hz, 1H), 3.93 - 3.52 (m, 17H), 3.50 - 3.24 (m, 11H ), 3.14 - 3.02 (m, 1H), 2.93 (dt, J = 31.2, 12.0 Hz, 1H), 2.63 ( tdd, J = 17.0, 14.2, 5.5 Hz, 3H), 2.37 - 2.18 (m, 2H), 1.94 (ddd, J = 31.3, 24.3, 22.1 Hz, 5H), 1.71 (dt, J = 22.5, 10.1 Hz, 11H), 1.51 - 1.17 (m, 13H), 1.15 - 0.81 (m, 18H), 0.67 (dd, J = 23.7 , 11.9 Hz, 1H).

[0404] I-111: 1 H NMR (500 MHz, CDCl3) δ 6.46 - 5.78 (m, 4H), 5.75 - 5.14 (m, 4H), 4.58 (d, J = 31.9 Hz, 1H), 4.21 (d, J = 66.8 Hz, 1H), 3.87 - 3.47 (m, 16H), 3.43 - 3.14 (m, 10H ), 2.94 (s, 1H), 2.80 - 2.54 (m, 3H), 2.26 (ddd, J = 110.3, 80.5, 42.6 Hz, 6H), 1.81 - 1.49 (m, 18H), 1.46 - 1.25 (m, 10H), 1.18 - 0.77 (m, 18H), 0.72 - 0.61 (m, 1H).

[0397] Example 25 (21E,23E,25E,26E,36R,37S,38R,39R,41S,43 S,45R,46S,47R,48R,57R)-47,57-dihydroxy-45-[ 2-[2-(2-hydroxyethoxy)ethoxy]ethoxy]-46-[(1R)-2- [(1S,3R,4R)-4-(2-hydroxyethoxy)-3-methoxy-cyclohexyl 48-methoxy-36,37,38,39,49,50 -Hexamethyl-68,69-dioxa-58-azatricyclohexatriaconta-2 1,23,25(49),26(50)-tetraene-51,52,53,54,55- Penton (I-109) and (21E, 23E, 25E, 26E, 36R, 37S, 3 8R,39R,41S,43S,45S,46S,47R,48R,57R)-47,5 7-Dihydroxy-45-[2-[2-(2-hydroxyethoxy)ethoxy]ethoxy ]-46-[(1R)-2-[(1S,3R,4R)-4-(2-hydroxyethoxy) -3-Methoxy-cyclohexyl]-1-methyl-ethyl]-48-methoxy-36,3 7,38,39,49,50-Hexamethyl-68,69-dioxa-58-azatrixine Chlohexatriaconta-21,23,25(49),26(50)-tetraene-51 Synthesis of 52,53,54,55-pentone (I-110): [ka] Synthesis scheme: [ka] Procedure and Characterization: Step 1: (21E, 23E, 25E, 26E, 36R, 37S, 38R, 39R, 4 1S,43S,46S,47R,48R,57R)-47,57-dihydroxy-45- [2-[2-(2-hydroxyethoxy)ethoxy]ethoxy]-46-[(1R)-2 -[(1S,3R,4R)-4-(2-hydroxyethoxy)-3-methoxy-cyclohexane [xyl]-1-methyl-ethyl]-48-methoxy-36,37,38,39,49,5 0-Hexamethyl-68,69-dioxa-58-azatricyclohexatriaconta 21,23,25(49),26(50)-tetraene-51,52,53,54,55 -Pentone synthesis:

[0398] Everolimus (0.5 g, 0.522 mmol), 2-[2-(2-hydroxyethoxy)- [(c)ethoxy]ethanol (3.92 g, 26.09 mmol) and p-toluenesulfonyl A mixture of 20% benzoic acid monohydrate (0.45 g, 2.61 mmol) in THF (10 mL) was The mixture was stirred at 0°C for 2 h. Then the mixture was poured into ice-cold saturated NaHCO3 (30 mL) and The combined organic layer was washed with water and brine, and then extracted with HCl (50 mL x 3). The resulting residue was purified by reverse phase chromatography. The product was purified by filtration (C18, CH3CN:H2O = 6.5:3.5) and then purified as follows: (21E,2 3E,25E,26E,36R,37S,38R,39R,41S,43S,46S,4 7R,48R,57R)-47,57-dihydroxy-45-[2-[2-(2-hydroxy) 6-[(1R)-2-[(1S,3R,4R)ethoxyethoxy]ethoxy]-46-[(1R)-2-[(1S,3R,4R) ... -4-(2-hydroxyethoxy)-3-methoxy-cyclohexyl]-1-methyl- ethyl]-48-methoxy-36,37,38,39,49,50-hexamethyl-68, 69-Dioxa-58-azatricyclohexatriaconta-21,23,25(49) ,26(50)-tetraene-51,52,53,54,55-pentone (0.155g , 28%) as a white solid. + , m / z):1098.4 [M+Na] + . 1 H NMR (500 MHz, CDCl3) δ 6.42 - 5.87 (m, 4H), 5.63 - 5.34 (m, 2H), 5.32 - 5.00 (m, 2H), 4.85 (s, 1H), 4.35 - 4.09 (m, 1H), 4.05 - 3.49 (m, 18H), 3.49 - 3.01 (m, 14H), 2.66 (dddd, J = 31.3, 24.8, 21.2, 13.0 Hz, 4H), 2.33 (d, J = 12.0 Hz, 2H), 2.06 (dd, J = 39 .9, 10.6 Hz, 3H), 1.77 - 1.53 (m, 13H), 1.51 - 1.14 (m, 10H), 1. 14 - 0.81 (m, 18H), 0.71 (dd, J = 23.8, 11.9 Hz, 1H). Step 2: (21E, 23E, 25E, 26E, 36R, 37S, 38R, 39R, 4 1S,43S,45S,46S,47R,48R,57R)-47,57-dihydroxy -45-[2-[2-(2-hydroxyethoxy)ethoxy]ethoxy]-46-[(1 R)-2-[(1S,3R,4R)-4-(2-hydroxyethoxy)-3-methoxy- Cyclohexyl]-1-methyl-ethyl]-48-methoxy-36,37,38,39, 49,50-Hexamethyl-68,69-dioxa-58-azatricyclohexatriazole Cont-21,23,25(49),26(50)-tetraene-51,52,53,5 4,55-pentone (I-110) and (21E, 23E, 25E, 26E, 36R, 37S, 38R, 39R, 41S, 43S, 45R, 46S, 47R, 48R, 57R) -47,57-dihydroxy-45-[2-[2-(2-hydroxyethoxy)ethoxy ]ethoxy]-46-[(1R)-2-[(1S,3R,4R)-4-(2-hydroxy Ethoxy)-3-methoxy-cyclohexyl]-1-methyl-ethyl]-48-methoxy -36,37,38,39,49,50-Hexamethyl-68,69-dioxa-58- Azatricyclohexatriaconta-21,23,25(49),26(50)-tetra Synthesis of ene-51,52,53,54,55-pentone (I-109):

[0399] 170mg(21E,23E,25E,26E,36R,37S,38R,39R, 41S,43S,46S,47R,48R,57R)-47,57-dihydroxy-45 -[2-[2-(2-hydroxyethoxy)ethoxy]ethoxy]-46-[(1R)- 2-[(1S,3R,4R)-4-(2-hydroxyethoxy)-3-methoxy-cyclo hexyl]-1-methyl-ethyl]-48-methoxy-36,37,38,39,49, 50-Hexamethyl-68,69-dioxa-58-azatricyclohexatriacont ... -21,23,25(49),26(50)-tetraene-51,52,53,54,5 The 5-pentone was purified by preparative chiral HPLC, and the resulting epimer was separated by silica gel chromatography. Chromatography (hexane:DCM:EtOAc:MeOH=3:3:1:0.8) Then, it is purified as follows: (21E, 23E, 25E, 26E, 36R, 37S, 38R, 39R, 41S,43S,45S,46S,47R,48R,57R)-47,57-dihydroxy C6-45-[2-[2-(2-hydroxyethoxy)ethoxy]ethoxy]-46-[( 1R)-2-[(1S,3R,4R)-4-(2-hydroxyethoxy)-3-methoxy -cyclohexyl]-1-methyl-ethyl]-48-methoxy-36,37,38,39 ,49,50-Hexamethyl-68,69-dioxa-58-azatricyclohexatri Aconta-21,23,25(49),26(50)-tetraene-51,52,53, 54,55-pentone (I-110: 37 mg, 21% yield) and (21E,23E, 25E,26E,36R,37S,38R,39R,41S,43S,45R,46S, 47R,48R,57R)-47,57-dihydroxy-45-[2-[2-(2-hydroxy) 6-[(1R)-2-[(1S,3R,4R )-4-(2-hydroxyethoxy)-3-methoxy-cyclohexyl]-1-methyl- Ethyl]-48-methoxy-36,37,38,39,49,50-hexamethyl-68 ,69-Dioxa-58-azatricyclohexatriaconta-21,23,25(49 ), 26(50)-tetraene-51,52,53,54,55-pentone (I-109 33 mg, 19% yield, all of which were obtained as white solids.

[0400] Chiral analysis methods: Column: CHIRALPAK IC (IC00CE-OL002) Column size: 0.46cm inner diameter x 25cm length Injection: 30.0ul Mobile phase: hexane / EtOH = 60 / 40 (V / V) Flow rate: 1.0ml / min Wavelength: UV254nm Temperature: 35℃ HPLC device: Shimadzu LC-20AT CP-HPLC-06

[0409] I-110: ESI-MS (EI + , m / z):1098.0 [M+Na] + . 1 H NMR (500 MHz, CDCl3) δ 6.41 - 6.18 (m, 2H), 6.12 (dd, J = 15.0, 10 .3 Hz, 1H), 5.93 (dd, J = 33.7, 10.6 Hz, 1H), 5.47 (ddd, J = 33.0 , 20.8, 9.5 Hz, 2H), 5.26 (d, J = 5.6 Hz, 1H), 5.13 (dt, J = 21. 8, 10.8 Hz, 1H), 4.88 (s, 1H), 4.19 (t, J = 9.3 Hz, 1H), 3.94 - 3.52 (m, 19H), 3.49 - 3.25 (m, 12H), 3.24 - 3.02 (m, 3H), 2.76 (ddd, J = 26.2, 16.6, 10.3 Hz, 3H), 2.57 (dd, J = 17.0, 6.3 Hz, 1H), 2.29 (t, J = 26.2 Hz, 2H), 2.16 - 1.85 (m, 6H), 1.74 - 1 .53 (m, 10H), 1.53 - 1.16 (m, 9H), 1.15 - 1.01 (m, 8H), 1.01 - 0.82 (m, 10H), 0.71 (dd, J = 23.9, 12.0 Hz, 1H).

[0410] I-109: ESI-MS (EI + , m / z):1098.0 [M+Na] + . 1 H NMR (500 MHz, CDCl3) δ 6.43 - 5.90 (m, 4H), 5.62 - 5.02 (m, 5H), 4.24 (d, J = 63.6 Hz, 1H), 3.97 (dd, J = 21.5, 6.8 Hz, 1H), 3.86 - 3.50 (m, 18H), 3.45 - 3.01 (m, 14H), 2.73 - 2.46 (m, 3H), 2 .39 - 1.94 (m, 6H), 1.91 - 1.69 (m, 10H), 1.50 - 1.31 (m, 12H), 1.16 - 0.85 (m, 18H), 0.69 (d, J = 11.7 Hz, 1H).

[0401] Example 26 (30E,32E,34E,35E,38R,39S,40R,41R,43S,45 S,47R,48S,50R,51R,60R)-50,60-dihydroxy-48-[ (1R)-2-[(1S,3R,4R)-4-hydroxy-3-methoxy-cyclohexyl 1-methyl-ethyl]-51-methoxy-38,39,40,41,52,53- Hexamethyl-47-(1,4,7,10,13-pentaoxacyclopentadeca-2- (ylmethoxy)-75,76-dioxa-61-azatricyclohexatriaconta-3 0,32,34(52),35(53)-tetraene-54,55,56,57,58- Penton (I-107): (30E, 32E, 34E, 35E, 38R, 39S, 40R ,41R,43S,45S,47S,48S,50R,51R,60R)-50,60- Dihydroxy-48-[(1R)-2-[(1S,3R,4R)-4-hydroxy-3- Methoxy-cyclohexyl]-1-methyl-ethyl]-51-methoxy-38,39,4 0,41,52,53-Hexamethyl-47-(1,4,7,10,13-pentaoxamethyl) Cyclopentadec-2-ylmethoxy)-75,76-dioxa-61-azatricyclo Hexatriaconta-30,32,34(52),35(53)-tetraene-54,5 Synthesis of 5,56,57,58-pentone (I-108): [ka] Synthesis scheme: [ka] Procedure and Characterization: Step 1: (30E, 32E, 34E, 35E, 38R, 39S, 40R, 41R, 4 3S,45S,48S,50R,51R,60R)-50,60-dihydroxy-48- [(1R)-2-[(1S,3R,4R)-4-hydroxy-3-methoxy-cyclohexane 51-methoxy-38,39,40,41,52,53 -Hexamethyl-47-(1,4,7,10,13-pentaoxacyclopentadeca-2 -ylmethoxy)-75,76-dioxa-61-azatricyclohexatriacin 30,32,34(52),35(53)-tetraene-54,55,56,57,58 -Pentone synthesis:

[0402] Rapamycin (2 g, 2.19 mmol), 1,4,7,10,13-pentaoxacin Chlopentadeca-2-ylmethanol (3.83 g, 15.31 mmol) and p-tolyl benzenesulfonic acid monohydrate (1.88 g, 10.94 mmol) in THF (10 mL) The solution was stirred at 20° C. for 2 h. The mixture was then added to ice-cold saturated NaHCO3 (50 mL). The mixture was poured into a filtrate and extracted with EtOAc (100 mL x 3). The combined organic layer was washed with water and brine. The residue was purified by reversed phase chromatography (C18, CH3 The resulting mixture was purified by CN:HO=8:2 to give (30E, 32E, 34E, 35E, 38R ,39S,40R,41R,43S,45S,48S,50R,51R,60R)-50 ,60-dihydroxy-48-[(1R)-2-[(1S,3R,4R)-4-hydroxy 3-(3-methoxy-cyclohexyl)-1-methyl-ethyl)-51-methoxy-38, 39,40,41,52,53-Hexamethyl-47-(1,4,7,10,13-pentamethyl) (2-methyl-2-oxacyclopentadecylmethoxy)-75,76-dioxa-61-azato Lithium cyclohexatriaconta-30,32,34(52),35(53)-tetraene- 54,55,56,57,58-pentone (80 mg, 2.6% yield) as a white solid Got it. ESI-MS (EI + , m / z):1154.0 [M+Na] + . 1 H NMR (500 MHz, CDCl3) δ 6 .16 (tdt, J = 40.0, 33.8, 20.7 Hz, 4H), 5.54 - 5.03 (m, 4H), 4.21 (t, J = 22.5 Hz, 1H), 3.90 - 3.46 (m, 22H), 3.44 - 3.04 (m, 1 2H), 2.74 (dddd, J = 27.8, 22.2, 13.7, 4.7 Hz, 5H), 2.37 - 1.56 ( m, 22H), 1.50 - 1.16 (m, 8H), 1.13 - 0.81 (m, 18H), 0.67 (dd, J = 23.8, 11.9 Hz, 1H). Step 2: (30E, 32E, 34E, 35E, 38R, 39S, 40R, 41R, 4 3S,45S,47S,48S,50R,51R,60R)-50,60-dihydroxy -48-[(1R)-2-[(1S,3R,4R)-4-hydroxy-3-methoxy- cyclohexyl]-1-methyl-ethyl]-51-methoxy-38,39,40,41,5 2,53-Hexamethyl-47-(1,4,7,10,13-pentaoxacyclopenta) Dec-2-ylmethoxy)-75,76-dioxa-61-azatricyclohexatriazole Conta-30,32,34(52),35(53)-tetraene-54,55,56,5 7,58-pentone (I-108) and (30E, 32E, 34E, 35E, 38R, 39S, 40R, 41R, 43S, 45S, 47R, 48S, 50R, 51R, 60R) -50,60-dihydroxy-48-[(1R)-2-[(1S,3R,4R)-4-hydroxy- hydroxy-3-methoxy-cyclohexyl]-1-methyl-ethyl]-51-methoxy- 38,39,40,41,52,53-Hexamethyl-47-(1,4,7,10,13 -pentaoxacyclopentadec-2-ylmethoxy)-75,76-dioxa-61- Azatricyclohexatriaconta-30,32,34(52),35(53)-tetra Synthesis of ene-54,55,56,57,58-pentone (I-107):

[0403] 130mg (30E, 32E, 34E, 35E, 38R, 39S, 40R, 41R, 43S,45S,48S,50R,51R,60R)-50,60-dihydroxy-48 -[(1R)-2-[(1S,3R,4R)-4-hydroxy-3-methoxy-cyclohexane 5-methoxy-38,39,40,41,52,5-xyl]-1-methyl-ethyl]-5 3-Hexamethyl-47-(1,4,7,10,13-pentaoxacyclopentadeca- 2-ylmethoxy)-75,76-dioxa-61-azatricyclohexatriaconta -30,32,34(52),35(53)-tetraene-54,55,56,57,5 The 8-pentone was purified by preparative chiral HPLC, and the resulting epimer was separated by silica gel chromatography. Chromatography (hexane:DCM:EtOAc:MeOH=3:3:1:0.5) Then, it is purified as follows: (30E, 32E, 34E, 35E, 38R, 39S, 40R, 41R, 43S,45S,47S,48S,50R,51R,60R)-50,60-dihydroxy 48-[(1R)-2-[(1S,3R,4R)-4-hydroxy-3-methoxy- Cyclohexyl]-1-methyl-ethyl]-51-methoxy-38,39,40,41, 52,53-Hexamethyl-47-(1,4,7,10,13-pentaoxacyclopentane) Tadec-2-ylmethoxy)-75,76-dioxa-61-azatricyclohexatri Aconta-30,32,34(52),35(53)-tetraene-54,55,56, 57,58-pentone (I-108: 18 mg, 13% yield) and (30E, 32E, 34E,35E,38R,39S,40R,41R,43S,45S,47R,48S, 50R,51R,60R)-50,60-dihydroxy-48-[(1R)-2-[(1 S,3R,4R)-4-hydroxy-3-methoxy-cyclohexyl]-1-methyl- ethyl]-51-methoxy-38,39,40,41,52,53-hexamethyl-47- (1,4,7,10,13-pentaoxacyclopentadec-2-ylmethoxy)-75 ,76-Dioxa-61-azatricyclohexatriaconta-30,32,34(52 ), 35(53)-tetraene-54,55,56,57,58-pentone (I-107 16 mg, 12% yield, all of which were obtained as white solids.

[0404] Chiral analysis methods: Column: CHIRALPAK IC (IC00CE-OL002) Column size: 0.46cm inner diameter x 25cm length Injection: 100.0ul Mobile phase: hexane / EtOH = 60 / 40 (V / V) Flow rate: 1.0ml / min Wavelength: UV254nm Temperature: 35℃ HPLC device: Shimadzu LC-20AT CP-HPLC-06

[0415] I-108: ESI-MS (EI + , m / z):1153.9 [M+Na] + . 1 H NMR (500 MHz, CDCl3) δ 6.31 (dt, J = 25.1, 14.5 Hz, 2H), 6.17 - 6. 08 (m, 1H), 5.95 (s, 1H), 5.55 - 5.37 (m, 2H), 5.26 (s, 1H), 5.16 (d, J = 4.4 Hz, 1H), 4.71 (d, J = 28.0 Hz, 1H), 4.19 (s, 1H), 3.93 - 3.48 (m, 25H), 3.44 - 3.26 (m, 12H), 3.20 - 3.03 (m, 1H) , 2.94 (dd, J = 16.5, 7.7 Hz, 1H), 2.70 (dd, J = 17.9, 12.1 Hz, 3H), 2.56 (d, J = 17.0 Hz, 1H), 2.33 (d, J = 12.0 Hz, 2H), 2.13 - 1.84 (m, 5H), 1.81 - 1.67 (m, 8H), 1.50 - 1.17 (m, 8H), 1.14 - 0.81 (m, 20H), 0.67 (dd, J = 23.6, 11.9 Hz, 1H).

[0416] I-107: ESI-MS (EI + , m / z):1153.9 [M+Na] + . 1 1H NMR (500 MHz, CDCl3) δ 6.40-5.95 (m, 4H), 5.58-5.11 (m, 4H), 4.30 - 4.12 (m, 1H), 3.88-3.51 (m, 25H), 3.42-3.12 (m, 上一页 12H), 2.99 - 2.53 ( m, 5H), 2.50 - 1.90 (m, 5H), 上一页 1.83 - 1.65 (m, 14H), 1.44 - 1.30 (m, 8H), 1.12 - 0.76 (m, 18H), 0.74 - 0.62 (m, 1H).

[0405] (Example 27) (21E,23E,25E,26E,31R,32S,33R,34R,36S,38 S,41S,42R,43R,52R)-40-[bis(hydroxymethyl)phosphoryl methoxy]-42,52-dihydroxy-41-[(1R)-2-[(1S,3R,4R )-4-hydroxy-3-methoxy-cyclohexyl]-1-methyl-ethyl]-43- Methoxy-31,32,33,34,44,45-hexamethyl-65,66-dioxa -53-Azatricyclohexatriaconta-21, 23, 25(44), 26(45) Synthesis of -tetraene-46,47,48,49,50-pentone (I-106): [ka] Synthesis scheme: [ka] Procedure and Characterization: Step 1: Synthesis of bis(hydroxymethyl)phosphorylmethanol:

[0406] Ba(OH)2 (8.43 g, 49.23 mmol) was dissolved in 50 mL of distilled water at 60 °C. Tetrakis(hydroxymethyl)phosphonium sulfate (20 g, 49.23 mm ol) was added dropwise to the solution, which was then stirred at 60°C for 4 hours. After removal by separation, hydrogen peroxide (30% solution, 98.45 mmol) was slowly added. The resulting reaction mixture was stirred at room temperature for 5 hours. The mixture was washed with chloroform and then The desired product was obtained as an oil by removing the water under reduced pressure (6.5 g, yield 94%). ESI-MS (EI + , m / z):141.1 [M+H] + . 1HNMR (500 MHz, DMSO-d): δ 5.35 (bs, 3H), 3.97 (s, 6H). Step 2: (21E, 23E, 25E, 26E, 31R, 32S, 33R, 34R, 3 6S,38S,41S,42R,43R,52R)-40-[bis(hydroxymethyl) phosphorylmethoxy]-42,52-dihydroxy-41-[(1R)-2-[(1S, 3R,4R)-4-Hydroxy-3-methoxy-cyclohexyl]-1-methyl-ethyl ]-43-Methoxy-31,32,33,34,44,45-hexamethyl-65,66 -Dioxa-53-azatricyclohexatriaconta-21,23,25(44),2 Synthesis of 6(45)-tetraene-46,47,48,49,50-pentone (I-106) Form:

[0407] Rapamycin (0.5 g, 0.547 mmol), bis(hydroxymethyl)phosphoryl Methanol (0.766 g, 5.47 mmol) and 4-methylbenzenesulfonic acid A mixture of the hydrate (0.52 g, 2.73 mmol) in THF (20 mL) was heated at 25 °C for 4 h. The mixture was stirred for 1 hour. EtOAc (100 mL) and water (50 mL) were added. The aqueous layer was diluted with EtO Extract with Ac (100 mL x 2), and the combined organic layer was washed with water (2 x 50 mL) and brine. (50 mL), then dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by reverse phase chromatography (C18, CH3CN:H2O=7:3). And (21E, 23E, 25E, 26E, 31R, 32S, 33R, 34R, 36S, 38S,41S,42R,43R,52R)-40-[bis(hydroxymethyl)phosphoric acid 42,52-dihydroxy-41-[(1R)-2-[(1S,3R, 4R)-4-Hydroxy-3-methoxy-cyclohexyl]-1-methyl-ethyl]-4 3-Methoxy-31,32,33,34,44,45-hexamethyl-65,66-diol 53-Azatricyclohexatriacin-21,23,25(44),26(4 5)-tetraene-46,47,48,49,50-pentone (I-106: 50 mg, The product was obtained as a white solid (9% yield). + , m / z):1043.9 [M+Na] + . 1 H NMR (500 MHz, CDCl3) δ 6.47 - 5.91 (m, 4H), 5.58 - 5.08 (m, 4H), 4.51 - 3.63 (m, 12H), 3.59 - 3.16 (m, 14H), 2.80 (d, J = 138.1 Hz, 6H), 2.38 - 1.91 (m, 8H), 1.50 - 0.77 (m, 35H), 0.67 (d, J = 9.0 Hz, 1H).

[0408] Example 28 (22E,24E,26E,27E,35R,36S,37R,38R,40S,42 S,44R,45S,46R,47R,56R)-46,56-dihydroxy-45-[ (1R)-2-[(1S,3R,4R)-4-(2-hydroxyethoxy)-3-methoxy] 4-[2-(2-methyl-4-cyclohexyl]-1-methyl-ethyl]-47-methoxy-44-[2-(2-methyl-4-cyclohexyl) ... (ethoxyethoxy)ethoxy]-35,36,37,38,48,49-hexamethyl-6 6,67-Dioxa-57-azatricyclohexatriaconta-22,24,26(4 8),27(49)-tetraene-50,51,52,53,54-pentone (I-10 4) and (22E, 24E, 26E, 27E, 35R, 36S, 37R, 38R, 40 S,42S,44S,45S,46R,47R,56R)-46,56-dihydroxy- 45-[(1R)-2-[(1S,3R,4R)-4-(2-hydroxyethoxy)-3 -Methoxy-cyclohexyl]-1-methyl-ethyl]-47-methoxy-44-[2- (2-Methoxyethoxy)ethoxy]-35,36,37,38,48,49-hexame Thiol-66,67-dioxa-57-azatricyclohexatriaconta-22,24, 26(48),27(49)-tetraene-50,51,52,53,54-pentone( Synthesis of I-105: [ka] Synthesis scheme: [ka] Procedure and Characterization: Step 1: (22E, 24E, 26E, 27E, 35R, 36S, 37R, 38R, 4 0S,42S,45S,46R,47R,56R)-46,56-dihydroxy-45- [(1R)-2-[(1S,3R,4R)-4-(2-hydroxyethoxy)-3-meth 4-[2-( ... Methoxyethoxy)ethoxy]-35,36,37,38,48,49-hexamethyl- 66,67-Dioxa-57-azatricyclohexatriaconta-22,24,26( Synthesis of 48),27(49)-tetraene-50,51,52,53,54-pentone:

[0409] Everolimus (5 g, 5.22 mmol) and 2-(2-methoxyethoxy)ethanoic acid A mixture of ethanol (15 mL) in THF (80 mL) was degassed with N2 and then heated to 50 °C. HND-8 (600 mg) was added, and the resulting mixture was heated at 50 °C for 4 hours under N2. The mixture was stirred for 1 hour, then filtered and diluted with EtOAc. After concentration, the residue was purified by reverse phase chromatography. The product was purified by a filtration method (C18, CH3CN:H2O ratio 0% to 100%) and then purified as follows: (22E, 24 E,26E,27E,35R,36S,37R,38R,40S,42S,45S,46 R,47R,56R)-46,56-dihydroxy-45-[(1R)-2-[(1S, 3R,4R)-4-(2-hydroxyethoxy)-3-methoxy-cyclohexyl]-1 -methyl-ethyl]-47-methoxy-44-[2-(2-methoxyethoxy)ethoxy ]-35,36,37,38,48,49-hexamethyl-66,67-dioxa-57 -Azatricyclohexatriaconta-22,24,26(48),27(49)-tet Laen-50,51,52,53,54-pentone (1.5 g, 27% yield) was obtained as a white solid ESI-MS (EI + , m / z):1068.4 [M+Na] + . 1 H NMR (400 MHz, CDCl3) δ 6.40 - 5.85 (m, 4H), 5.56 - 5.36 (m, 2H), 5.21 (ddd, J = 1 6.0, 11.7, 5.6 Hz, 2H), 4.21 (dd, J = 25.8, 15.5 Hz, 2H), 3.94 - 3.26 (m, 28H), 3.25 - 3.02 (m, 4H), 2.76 - 2.40 (m, 3H), 2.34 (d, J = 13.3 Hz, 2H), 2.19 - 2.06 (m, 2H), 2.01 - 1.67 (m, 13H) , 1.54 - 1.30 (m, 7H), 1.15 - 0.81 (m, 18H), 0.72 (dd, J = 23.1 , 11.7 Hz, 1H). Step 2: (22E, 24E, 26E, 27E, 35R, 36S, 37R, 38R, 4 0S,42S,44S,45S,46R,47R,56R)-46,56-dihydroxy -45-[(1R)-2-[(1S,3R,4R)-4-(2-hydroxyethoxy)- 3-Methoxy-cyclohexyl]-1-methyl-ethyl]-47-methoxy-44-[2 -(2-methoxyethoxy)ethoxy]-35,36,37,38,48,49-hexa Methyl-66,67-dioxa-57-azatricyclohexatriaconta-22,24 ,26(48),27(49)-tetraene-50,51,52,53,54-pentone (I-105) and (22E, 24E, 26E, 27E, 35R, 36S, 37R, 3 8R,40S,42S,44R,45S,46R,47R,56R)-46,56-Jihi hydroxy-45-[(1R)-2-[(1S,3R,4R)-4-(2-hydroxyethoxy) 7-methoxy-4-(2-methyl-2-methyl-1 ... 4-[2-(2-methoxyethoxy)ethoxy]-35,36,37,38,48,49 -Hexamethyl-66,67-dioxa-57-azatricyclohexatriaconta-2 2,24,26(48),27(49)-tetraene-50,51,52,53,54- Synthesis of pentone (I-104):

[0410] 120mg (22E, 24E, 26E, 27E, 35R, 36S, 37R, 38R, 40S,42S,45S,46R,47R,56R)-46,56-dihydroxy-45 -[(1R)-2-[(1S,3R,4R)-4-(2-hydroxyethoxy)-3-methyl 47-Methoxy-44-[2-(2-(2-Cyclohexyl)-1-methyl-ethyl]-47-methoxy ...(2-(2-(2-(2-(2-(2-(2-(2-(2-(2-(2-(2-(2-(2-(2- -Methoxyethoxy)ethoxy]-35,36,37,38,48,49-hexamethyl -66,67-Dioxa-57-azatricyclohexatriaconta-22,24,26 (48),27(49)-tetraene-50,51,52,53,54-pentone Purification by chiral HPLC gave (22E, 24E, 26E, 27E, 35R, 36S ,37R,38R,40S,42S,44S,45S,46R,47R,56R)-46 ,56-dihydroxy-45-[(1R)-2-[(1S,3R,4R)-4-(2-hydroxy hydroxyethoxy)-3-methoxy-cyclohexyl]-1-methyl-ethyl]-47- Methoxy-44-[2-(2-methoxyethoxy)ethoxy]-35,36,37,38 ,48,49-Hexamethyl-66,67-dioxa-57-azatricyclohexatri Aconta-22,24,26(48),27(49)-tetraene-50,51,52, 53,54-pentone (I-105: 17 mg, 20% yield) and (22E, 24E, 26E,27E,35R,36S,37R,38R,40S,42S,44R,45S, 46R,47R,56R)-46,56-dihydroxy-45-[(1R)-2-[(1 S,3R,4R)-4-(2-hydroxyethoxy)-3-methoxy-cyclohexyl] -1-methyl-ethyl]-47-methoxy-44-[2-(2-methoxyethoxy)ethoxy] 35,36,37,38,48,49-hexamethyl-66,67-dioxa- 57-Azatricyclohexatriaconta-22,24,26(48),27(49)- Tetraene-50,51,52,53,54-pentone (I-104: 15 mg, yield 1 6%), all as white solids.

[0411] Chiral separation methods: Column: CHIRALPAK IC Column size: 2.5cm inner diameter x 25cm length, 10μm Sample solution: 14mg / ml in mobile phase Injection: 15ml Mobile phase: Hexane / EtOH = 50 / 50 (V / V) Flow rate: 60ml / min Wavelength: UV254nm Temperature: 35℃

[0424] I-105: ESI-MS (EI + , m / z):1068.4 [M+Na] + . 1 H NMR (400 MHz, CDCl3) δ 6.42 - 6.19 (m, 2H), 6.13 (dd, J = 15.1, 10 .0 Hz, 1H), 5.91 (dd, J = 33.0, 10.5 Hz, 1H), 5.56 - 5.38 (m, 2H ), 5.27 (d, J = 5.0 Hz, 1H), 5.15 (dt, J = 15.2, 7.6 Hz, 1H), 4. 76 (s, 1H), 4.18 (d, J = 5.6 Hz, 1H), 3.93 - 3.25 (m, 30H), 3.24 - 3.03 (m, 3H), 2.72 (dd, J = 16.7, 5.6 Hz, 2H), 2.57 (dd, J = 16.8, 6.5 Hz, 1H), 2.34 (d, J = 13.9 Hz, 2H), 2.13 - 1.84 (m, 6H), 1.82 - 1.67 (m, 7H), 1.47 (dd, J = 24.1, 16.7 Hz, 4H), 1.25 (ddd, J = 24.1, 20.2, 10.0 Hz, 7H), 1.14 - 0.81 (m, 18H), 0.72 (dd, J = 23.9, 12.1 Hz, 1H).

[0425] I-104: ESI-MS (EI + , m / z):1068.4 [M+Na] + . 1 H NMR (400 MHz, CDCl3) δ 6.19 (m, 4H), 5.56 - 5.36 (m, 2H), 5.28 - 5.07 (m, 2H), 4.83 (d, J = 4.9 Hz, 4H), 4.28 (s, 1H), 4.21 - 4.0 9 (m, 1H), 4.04 - 3.51 (m, 15H), 3.46 - 3.29 (m, 11H), 3.27 - 2.91 (m, 5H), 2.76 - 2.42 (m, 3H), 2.31 (d, J = 11.3 Hz, 2H), 2. 18 - 1.70 (m, 13H), 1.53 - 1.19 (m, 8H), 1.16 - 0.84 (m, 18H), 0.76 - 0.60 (m, 1H).

[0412] (Example 29) (21E,23E,25E,26E,34R,35S,36R,37R,39S,41 S,43S,44S,45R,46R,55R)-45,55-ジヒドロキシ-43-[ 2-[2-(2-ヒドロキシエチルスルホニル)エチルスルホニル]エトキシ]-44- [(1R)-2-[(1S,3R,4R)-4-hydroxy-3-methoxy-cyclohexane 4,6-methoxy-34,35,36,37,47,48-cyl-1-methyl-ethyl -Hexamethyl-70,71-dioxa-56-azatricyclohexatriaconta-2 1,23,25(47),26(48)-tetraene-49,50,51,52,53- Penton (I-95) and (21E, 23E, 25E, 26E, 34R, 35S, 36 R,37R,39R,41S,44S,45R,46R,55S)-45,55-dihydro 43-[2-[2-(2-hydroxyethylsulfonyl)ethylsulfonyl]ethoxy] 4-[(1S)-2-[(1S,3R,4R)-4-hydroxy-3-meth 34,35,36-Oxy-cyclohexyl]-1-methyl-ethyl]-46-methoxy- 37,47,48-Hexamethyl-70,71-dioxa-56-azatricyclohexa Triaconta-21,23,25(47),26(48)-tetraene-49,50,5 Synthesis of 1,52,53-pentone (I-102): [ka] Synthesis scheme: [ka] Procedure and Characterization: Step 1: (21E, 23E, 25E, 26E, 34R, 35S, 36R, 37R, 3 9R,41S,44S,45R,46R,55S)-45,55-dihydroxy-43- [2-[2-(2-hydroxyethylsulfanyl)ethylsulfanyl]ethoxy]- 44-[(1S)-2-[(1S,3R,4R)-4-hydroxy-3-methoxy-cyclohexyl 4,6-Methoxy-34,35,36,37,47-Hexyl]-1-methyl-ethyl]-4,6-Methoxy-34,35,36,37,47 ,48-Hexamethyl-66,67-dioxa-56-azatricyclohexatriacon Ta-21,23,25(47),26(48)-tetraene-49,50,51,52, Synthesis of 53-pentone:

[0413] Rapamycin (1 g, 1.09 mmol), 2-[2-(2-hydroxyethylsulfonyl)sulfonyl] [(2g, 10.94mmol) ethylsulfanyl]ethanol in THF (20 To the mixture, 4-methylbenzenesulfonic acid monohydrate (0.62 g, 3.28 mm ol) was added at 15° C. The resulting mixture was stirred at 15° C. for 17 h, and then EtO Dilute with HCl (100 mL) and adjust to pH 9 using saturated aqueous NaHCO3 (approximately 50 mL). The organic layer was then concentrated, and the residue was purified by reverse phase chromatography (C18, CH3 Purify with CN:HO=6:4 to obtain (21E, 23E, 25E, 26E, 34R, 35 S,36R,37R,39R,41S,44S,45R,46R,55S)-45,55 -dihydroxy-43-[2-[2-(2-hydroxyethylsulfanyl)ethylsulfanyl] 4-[(1S)-2-[(1S,3R,4R)-4-hydroxyphenyl]ethoxy]-4 3-(3-methoxy-cyclohexyl)-1-methyl-ethyl)-46-methoxy-34, 35,36,37,47,48-Hexamethyl-66,67-dioxa-56-azatriazole Cyclohexatriaconta-21,23,25(47),26(48)-tetraene-4 9,50,51,52,53-pentone (150 mg, 12% yield) was obtained as a yellow solid. ESI-MS (EI + , m / z):1086.4 [M+Na]+ . 1 H NMR (500 MHz, CDCl3) δ 6 .39-5.95 (m, 4H), 5.54-5.19 (m, 4H), 4.81-4.17 (m, 2H), 3.96-3.73 (m, 4H), 3.59-3.14 (m, 12H), 2.96-2.55 (m, 14H), 2.35-1.87 (m, 6H), 1.81 -1.59 (m, 13H), 1.53-1.13 (m, 11H), 1.16-0.84 (m, 18H), 0.71-0.63 (m, 1H). Step 2: (21E, 23E, 25E, 26E, 34R, 35S, 36R, 37R, 3 9R,41S,44S,45R,46R,55S)-45,55-dihydroxy-43- [2-[2-(2-hydroxyethylsulfonyl)ethylsulfonyl]ethoxy]-44 -[(1S)-2-[(1S,3R,4R)-4-hydroxy-3-methoxy-cyclohexane xyl]-1-methyl-ethyl]-46-methoxy-34,35,36,37,47,4 8-Hexamethyl-70,71-dioxa-56-azatricyclohexatriaconta 21,23,25(47),26(48)-tetraene-49,50,51,52,53 -Synthesis of pentone (I-102):

[0414] (21E,23E,25E,26E,34R,35S,36R,37R,39R,41 S,44S,45R,46R,55S)-45,55-dihydroxy-43-[2-[2 -(2-hydroxyethylsulfanyl)ethylsulfanyl]ethoxy]-44-[( 1S)-2-[(1S,3R,4R)-4-hydroxy-3-methoxy-cyclohexyl ]-1-methyl-ethyl]-46-methoxy-34,35,36,37,47,48- oxamethyl-66,67-dioxa-56-azatricyclohexatriaconta-21, 23,25(47),26(48)-tetraene-49,50,51,52,53-pene A solution of oxone (3) (170 mg, 0.16 mmol) in methanol (8 mL) was added to the The resulting mixture was warmed to 10°C and 5 The reaction mixture was filtered and then purified by reverse phase chromatography (C18, 5-60%). acetonitrile-water) to give (21E, 23E, 25E, 26 E,34R,35S,36R,37R,39R,41S,44S,45R,46R,55 S)-45,55-dihydroxy-43-[2-[2-(2-hydroxyethyl)sulfonyl 4-[(1S)-2-[(1S,3R,4R)- 4-Hydroxy-3-methoxy-cyclohexyl]-1-methyl-ethyl]-46-meth 34,35,36,37,47,48-hexamethyl-70,71-dioxa-5 6-Azatricyclohexatriaconta-21,23,25(47),26(48)-tetramethyl Tolaen-49,50,51,52,53-pentone (I-102, 30 mg, yield 17 %) was obtained as a white solid. + , m / z):1150.8 [M+Na] + . 1 H NMR (500 MHz, CDCl3) δ 6.40 - 5.90 (m, 4H), 5.57 - 5.08 (m, 5H), 4.14 (s, 4H), 3.68 (tdd, J = 37.6, 33.2, 11.6 Hz, 11H), 3.48 - 3.13 (m , 20H), 2.95 (s, 2H), 2.68 (dd, J = 36.4, 30.5 Hz, 5H), 2.37 - 1 .70 (m, 12H), 1.31 (dd, J = 78.6, 46.8 Hz, 7H), 1.13 - 0.81 (m, 18H), 0.67 (d, J = 11.9 Hz, 1H). Step 3: (21E, 23E, 25E, 26E, 34R, 35S, 36R, 37R, 3 9S,41S,43S,44S,45R,46R,55R)-45,55-dihydroxy -43-[2-[2-(2-hydroxyethylsulfonyl)ethylsulfonyl]ethoxy ]-44-[(1R)-2-[(1S,3R,4R)-4-hydroxy-3-methoxy- Cyclohexyl]-1-methyl-ethyl]-46-methoxy-34,35,36,37, 47,48-Hexamethyl-70,71-dioxa-56-azatricyclohexatriazole Conta-21,23,25(47),26(48)-tetraene-49,50,51,5 Synthesis of 2,53-pentone (I-95):

[0415] 90mg (21E, 23E, 25E, 26E, 34R, 35S, 36R, 37R, 3 9R,41S,44S,45R,46R,55S)-45,55-dihydroxy-43- [2-[2-(2-hydroxyethylsulfonyl)ethylsulfonyl]ethoxy]-44 -[(1S)-2-[(1S,3R,4R)-4-hydroxy-3-methoxy-cyclohexane xyl]-1-methyl-ethyl]-46-methoxy-34,35,36,37,47,4 8-Hexamethyl-70,71-dioxa-56-azatricyclohexatriaconta 21,23,25(47),26(48)-tetraene-49,50,51,52,53 The pentones were purified by preparative chiral HPLC to give (21E, 23E, 25E, 26E ,34R,35S,36R,37R,39S,41S,43S,44S,45R,46R ,55R)-45,55-dihydroxy-43-[2-[2-(2-hydroxyethyl) 4-[(1R)-2-[(1S,3R,4 R)-4-hydroxy-3-methoxy-cyclohexyl]-1-methyl-ethyl]-46 -Methoxy-34,35,36,37,47,48-hexamethyl-70,71-diox Sa-56-Azatricyclohexatriacin-21,23,25(47),26(48 )-tetraene-49,50,51,52,53-pentone (I-95: 15 mg, yield 16%) as a white solid.

[0416] Chiral analysis methods: Column: CHIRALPAK IC (IC00CD-NA012) Column size: 0.46cm inner diameter x 15cm length Injection: 10.0ul Mobile phase: EtOH=100% Flow rate: 0.5ml / min Wavelength: UV254nm Temperature: 35℃ HPLC equipment: Shimadzu LC-20AD CP-HPLC-06

[0431] I-95: ESI-MS (EI + , m / z):1150.3 [M+Na] + . 1 H NMR ( 400 MHz, CDCl3) δ 6.32 (td, J = 24.8, 14.8 Hz, 2H), 6.13 (dd, J = 14.9, 9.9 Hz, 1H), 5.98 (dd, J = 22.1, 10.3 Hz, 1H), 5.56 - 5. 31 (m, 2H), 5.26 (d, J = 5.4 Hz, 1H), 5.14 (d, J = 4.1 Hz, 1H), 4.86 (s, 1H), 4.16 (dd, J = 11.9, 5.5 Hz, 3H), 3.92 - 3.49 (m, 11H), 3.44 - 3.17 (m, 15H), 2.93 (dd, J = 14.1, 5.5 Hz, 1H), 2. 78 - 2.50 (m, 5H), 2.36 - 2.17 (m, 2H), 2.01 (ddd, J = 21.5, 18 .0, 9.0 Hz, 5H), 1.84 - 1.65 (m, 11H), 1.49 - 1.16 (m, 12H), 1.1 4 - 0.82 (m, 14H), 0.66 (dd, J = 23.8, 12.0 Hz, 1H).

[0417] Example 29 3-[2,2-bis(2-cyanoethoxymethyl)-3-[[(21E,23E,25 E,26E,41R,42S,43R,44R,46S,48S,51S,52R,53 R,62R)-52,62-dihydroxy-51-[(1R)-2-[(1S,3R,4 R)-4-hydroxy-3-methoxy-cyclohexyl]-1-methyl-ethyl]-53 -Methoxy-41,42,43,44,54,55-Hexamethyl-56,57,58, 59,60-Pentaoxo-76,77-dioxa-67-azatricyclohexatriazole Conta-21,23,25(54),26(55)-tetraen-50-yl]oxy] Synthesis of propoxy]propanenitrile (I-101): [ka] Synthesis scheme: [ka] Procedure and Characterization: Step 1: (1-methyl-2,6,7-trioxabicyclo[2.2.2]octane- Synthesis of (4-yl)methanol:

[0418] 2,2-bis(hydroxymethyl)propane-1,3-diol (20g, 146.9 of 4-methylbenzenesulfonic acid (0.25 g, 1.47 mmol) and To a solution in toluene (200 mL) was added 1,1,1-triethoxyethane (27 mL, 146. 9 mmol) was added under reflux. The reaction was then heated to 130°C until the solution became clear. The mixture was stirred at RT, a few drops of TEA were added, and the reaction mixture was filtered while hot. The filtrate was cooled and then , concentrated, and (1-methyl-2,6,7-trioxabicyclo[2.2.2]octane- 4-yl)methanol (20 g, yield 85%) was obtained as colorless crystals. 1 HNMR (500 MHz , DMSO-d6): δ 4.79 (t, J = 5.3 Hz, 1H), 3.85 (s, 6H), 3.22 (d, J = 5.3 Hz, 2H), 1.29 (s, 3H). Step 2: 4-(benzyloxymethyl)-1-methyl-2,6,7-trioxavirin Synthesis of chloro[2.2.2]octane:

[0419] Solid (1-methyl-2,6,7-trioxabicyclo[2.2.2]octane-4- Methanol (1.5 g, 9.37 mmol) was dissolved in finely powdered KOH (2.47 g, 44 (1.86 g, 10.86 mmol) and BnBr (1.86 g, 10.86 mmol) in DMSO (5 mL) The resulting solution was stirred at room temperature for 1 hour, then poured into ice water and diluted with Et The mixture was extracted with OAc, dried, filtered, and concentrated. The residue was purified by silica gel chromatography (E 4-(benzyloxymethyl)-1-methylpropional 1.5 g (64% yield) of 2,6,7-trioxabicyclo[2.2.2]octane was obtained as a pale yellow solid. + , m / z):251.1 [M+H] + . 1 H NMR (500 MHz , CDCl3) δ 7.36-7.25 (m, 5H), 4.45 (s, 2H), 4.01 (s, 6H), 3.19 (s, 2H), 1.45 (s, 3H). Step 3: 2-(benzyloxymethyl)-2-(hydroxymethyl)propane-1, Synthesis of 3-diol:

[0420] 4-(benzyloxymethyl)-1-methyl-2,6,7-trioxabicyclo[2. 2.2]Octane (2 g, 8 mmol) and hydrogen chloride (2 mL, 2 M in water) in THF ( The solution was stirred at room temperature overnight, then concentrated and purified by reverse phase chromatography (C1 8, CH3CN:H2O=1:3) and purified to give 2-(benzyloxymethyl)-2-( Hydroxymethyl)propane-1,3-diol (1.3 g, 72% yield) was obtained as a dark yellow oil. The compound was obtained as ESI-MS (EI + , m / z): 227.1 [M+H] + . 1 H NMR (500 MHz, CDCl ) δ 7.36-7.26 (m, 5H), 4.48 (s, 2H), 3.68 (s, 6H), 3.46 (s, 2H), 3.40 (bs, 3H). Step 4: 3-[2-(benzyloxymethyl)-3-(2-cyanoethoxy)-2- Synthesis of (2-cyanoethoxymethyl)propoxy]propanenitrile:

[0421] 2-(benzyloxymethyl)-2-(hydroxymethyl)propane-1,3-diol A mixture of ethanol (4.9 g, 21.66 mmol) and KOH (98 mg, 1.75 mmol) was Add acrylonitrile (11%) to the mixture, ensuring that the internal reaction temperature does not exceed 30°C. The mixture was then stirred overnight at room temperature. The mixture was stirred, neutralized with 1N aqueous HCl, and extracted with EtOAc (200 mL). The organic layer was washed twice with water, dried over anhydrous Na2SO4, filtered, and concentrated to give 3-[2-(benzyl methyl)- 3-(2-cyanoethoxy)-2-(2-cyanoethoxymethyl)-3-(2-cyanoethoxymethyl) )propoxy]propanenitrile (7 g, 84% yield) was obtained as a yellow solid. MS(EI + , m / z): 386.3 [M+H] + . Step 5: 3-[2,2-bis(2-cyanoethoxymethyl)-3-hydroxy-propyl] Synthesis of [epoxy]propanenitrile:

[0422] 3-[2-(benzyloxymethyl)-3-(2-cyanoethoxy)-2-(2-cyano (5g, 12.97mmol) Me To a solution in OH (50 mL) was added Pd / C (1.59 g). The mixture was heated under a hydrogen balloon. The mixture was stirred overnight at room temperature under reduced pressure, and then filtered through a pad of Celite and washed with ethanol. The resulting solution was concentrated to give 3-[2,2-bis(2-cyanoethoxymethyl)-3-hydroxybenzoyl] Di-propoxy]propanenitrile (2.6 g, 68% yield) was obtained as a colorless oil. ESI-MS(EI+ , m / z): 296.2 [M+H] + . Step 6: 3-[2,2-bis(2-cyanoethoxymethyl)-3-[[(21E,2 3E,25E,26E,41R,42S,43R,44R,46S,48S,51S,5 2R,53R,62R)-52,62-dihydroxy-51-[(1R)-2-[(1S ,3R,4R)-4-hydroxy-3-methoxy-cyclohexyl]-1-methyl-ethyl 53-Methoxy-41,42,43,44,54,55-hexamethyl-56,5 7,58,59,60-Pentaoxo-76,77-dioxa-67-azatricyclohexyl Xatriaconta-21,23,25(54),26(55)-tetraen-50-yl Synthesis of ]oxy]propoxy]propanenitrile (I-101):

[0423] To a solution of rapamycin (0.5 g, 0.547 mmol) in DCM (30 mL), 2, 2,2-Trifluoroacetic acid (2.4 mL) was added at −40° C. The reaction was stirred at −40° C. for 1 Stir for 10 minutes, then add 3-[2,2-bis(2-cyanoethoxymethyl)-3-hydroxybenzoate] [Oxy-propoxy]propanenitrile (0.48 g, 1.64 mmol) was added. After stirring for an additional hour, the reaction was diluted with DCM (3 ml) and poured into cold aqueous NaHCO3. The organic layer was washed with water and brine, dried over Na2SO4, filtered, and concentrated. The residue was purified by reverse phase chromatography (C18, CH3CN:H2O=8:2) to give 3 -[2,2-bis(2-cyanoethoxymethyl)-3-[[(21E, 23E, 25E, 26E,41R,42S,43R,44R,46S,48S,51S,52R,53R, 62R)-52,62-dihydroxy-51-[(1R)-2-[(1S,3R,4R) -4-hydroxy-3-methoxy-cyclohexyl]-1-methyl-ethyl]-53-methyl Toxo-41,42,43,44,54,55-hexamethyl-56,57,58,59 ,60-Pentaoxo-76,77-dioxa-67-azatricyclohexatriacon ter-21,23,25(54),26(55)-tetraen-50-yl]oxy]pro [epoxy]propanenitrile (I-101: 80 mg, 12% yield) was obtained as a white solid. ESI-MS (EI + , m / z): 1198.8 [M+Na] + . 1 H NMR (500 MHz, CDCl) δ 6.4 2 - 5.87 (m, 4H), 5.35 (ddd, J = 120.9, 41.2, 32.5 Hz, 4H), 4.24 (dd, J = 29.5, 16.4 Hz, 2H), 3.98 (d, J = 4.2 Hz, 1H), 3.87 - 3.60 (m, 7H), 3.56 - 3.01 (m, 18H), 2.88 (d, J = 59.1 Hz, 2H), 2.74 - 2.42 (m, 9H), 2.34 (s, 2H), 2.23 - 1.84 (m, 5H), 1.82 - 1.65 (m, 13H), 1.53 - 1.22 (m, 10H), 1.16 - 0.84 (m, 18H), 0. 72 - 0.61 (m, 1H).

[0424] Example 30 (21E,23E,25E,26E,37R,38S,39R,40R,42S,44 S,47S,48R,49R,59R)-48,59-dihydroxy-46-[2-[3 -(2-hydroxyethoxy)-2-(2-hydroxyethoxymethyl)propoxy] 47-[(1R)-2-[(1S,3R,4R)-4-hydroxy-3-meth 49-methoxy-37,38,39, 40,50,51-Hexamethyl-71,72-dioxa-60-azatricyclohexa Triaconta-21,23,25(50),26(51)-tetraene-52,53,5 4,55,56-pentone (I-100) and (21E,23E,25E,26E,3 7R,38S,39R,40R,42S,44S,46R,47S,48R,49R,5 9R)-48,59-dihydroxy-46-[2-[3-(2-hydroxyethoxy)- 2-(2-hydroxyethoxymethyl)propoxy]ethoxy]-47-[(1R)-2 -[(1S,3R,4R)-4-hydroxy-3-methoxy-cyclohexyl]-1-methyl ethyl-ethyl]-49-methoxy-37,38,39,40,50,51-hexamethyl -71,72-Dioxa-60-azatricyclohexatriaconta-21,23,25 (50),26(51)-tetraene-52,53,54,55,56-pentone(I- 64) and (21E, 23E, 25E, 26E, 37R, 38S, 39R, 40R, 4 2S,44S,46S,47S,48R,49R,59R)-48,59-dihydroxy -46-[2-[3-(2-hydroxyethoxy)-2-(2-hydroxyethoxymethyl 7-[(1R)-2-[(1S,3R,4R)-4-hydroxypropyl]propoxy]ethoxy]-4 hydroxy-3-methoxy-cyclohexyl]-1-methyl-ethyl]-49-methoxy- 37,38,39,40,50,51-Hexamethyl-71,72-dioxa-60-a Zatricyclohexatriaconta-21,23,25(50),26(51)-tetraethoxy Synthesis of pentone-52,53,54,55,56-pentone (I-65): [ka] Synthesis scheme: [ka] Procedure and Characterization: Step 1: 7-((2-(benzyloxy)ethoxy)methyl)-1,13-diphenyl Synthesis of thiazolinone-2,5,9,12-tetraoxatridecane:

[0425] 2-(hydroxymethyl)propane-1,3-diol (2 g, 18.85 mmHg) at 0 °C To a solution of 100 ml of HCl in THF (30 mL) was added sodium hydride (9.05 g, 376.93 m mol) was added and the reaction was heated to 50° C. for 1 hour and then cooled to room temperature. 2-Bromoethoxymethylbenzene (40.54 g, 188.47 mmol) was added, The mixture was heated to 65° C. for 17 h. The reaction was quenched with ice water (50 mL) and then This was extracted with EtOAc (50 mL x 2). The combined organic layers were washed with brine (100 mL ), dried, filtered, concentrated, and then purified by silica gel chromatography (PE: EtOAc = 20:1) to give 2-[3-(2-benzyloxyethoxy)-2- (2-benzyloxyethoxymethyl)propoxy]ethoxymethylbenzene (5g, yield The product was obtained as a colorless liquid with a yield of 52%. + , m / z): 509.0 [M+ H] + . Step 2: 2,2'-(2-((2-hydroxyethoxy)methyl)propane-1,3 Synthesis of (-diyl)bis(oxy)diethanol:

[0426] 2-[3-(2-benzyloxyethoxy)-2-(2-benzyloxyethoxymethyl [20(2-methyl-1,2-propoxy)ethoxymethylbenzene (2 g, 3.93 mmol) in MeOH ( To the solution in 1 mL of ethanol was added Pd / C (2.41 g). The mixture was heated under a hydrogen balloon at room temperature. The reaction mixture was then filtered through a pad of Celite, which was then diluted with ethanol. The resulting solution was concentrated under reduced pressure to give 2,2'-((2-((2-hydroxy Ethoxy)methyl)propane-1,3-diyl)bis(oxy))bis(ethane-1-ol The compound (0.92 g, 98% yield) was obtained. 1 HNMR (500 MHz, CDCl3) δ 3.65 (dd , J = 5.7, 3.4 Hz, 6H), 3.53 - 3.48 (m, 12H), 2.22-2.14 (m, 1H). Step 3: (21E, 23E, 25E, 26E, 37R, 38S, 39R, 40R, 4 2S,44S,47S,48R,49R,59R)-48,59-dihydroxy-46- [2-[3-(2-hydroxyethoxy)-2-(2-hydroxyethoxymethyl)propanol] 7-[(1R)-2-[(1S,3R,4R)-4-hydroxy]ethoxy]-4 -3-Methoxy-cyclohexyl]-1-methyl-ethyl]-49-methoxy-37,3 8,39,40,50,51-Hexamethyl-71,72-dioxa-60-azatriazole Chlohexatriaconta-21,23,25(50),26(51)-tetraene-52 Synthesis of 53,54,55,56-pentone (I-100):

[0427] Rapamycin (0.5 g, 0.547 mmol) and 4-methylbenzenesulfonic acid To a solution of (0.47 g, 2.73 mmol) in THF (10 mL), 2-[3-(2-hydroxybenzoyl)- hydroxyethoxy)-2-(2-hydroxyethoxymethyl)propoxy]ethanol ( The mixture was stirred at 25°C for 2 hours and then cooled to 100°C. Poured into cold aqueous NaHCO3 and extracted with EtOAc. The organic layer was dried, filtered and concentrated. The residue was purified by reversed phase chromatography (C18, CH3CN:H2O:7:3), followed by column chromatography. The compound was purified by silica gel chromatography (DCM:MeOH=15:1) to give (21E,2 3E,25E,26E,37R,38S,39R,40R,42S,44S,47S,4 8R,49R,59R)-48,59-dihydroxy-46-[2-[3-(2-hydroxy (2-hydroxyethoxymethyl)propoxy]ethoxy]-47 -[(1R)-2-[(1S,3R,4R)-4-hydroxy-3-methoxy-cyclohexane [xyl]-1-methyl-ethyl]-49-methoxy-37,38,39,40,50,5 1-Hexamethyl-71,72-dioxa-60-azatricyclohexatriacont- 21,23,25(50),26(51)-tetraene-52,53,54,55,56 -pentone (I-100, 150 mg, 25% yield) was obtained as a white solid. S(EI + , m / z): 1142.0 [M + Na] + . 1 H NMR (500 MHz, CDCl3) δ 6.21 (dddd, J = 32.0, 27.8, 21.3, 10.2 Hz, 3H), 6.05 - 5.84 (m , 1H), 5.57 - 5.36 (m, 2H), 5.29 - 4.97 (m, 2H), 4.83 (s, 1H), 4.20 (dd, J = 36.3, 30.2 Hz, 1H), 4.01 - 3.66 (m, 6H), 3.62 - 3 .22 (m, 29H), 3.00 - 2.43 (m, 9H), 2.36 - 1.85 (m, 9H), 1.77 - 1.51 (m, 6H), 1.52 - 1.17 (m, 9H), 1.16 - 0.79 (m, 18H), 0.65 (dt, J = 21.9, 11.0 Hz, 1H). Step 4: (21E, 23E, 25E, 26E, 37R, 38S, 39R, 40R, 4 2S,44S,46S,47S,48R,49R,59R)-48,59-dihydroxy -46-[2-[3-(2-hydroxyethoxy)-2-(2-hydroxyethoxymethyl 7-[(1R)-2-[(1S,3R,4R)-4-hydroxypropyl]propoxy]ethoxy]-4 hydroxy-3-methoxy-cyclohexyl]-1-methyl-ethyl]-49-methoxy- 37,38,39,40,50,51-Hexamethyl-71,72-dioxa-60-a Zatricyclohexatriaconta-21,23,25(50),26(51)-tetraethoxy 52,53,54,55,56-pentone (I-65) and (21E,23E,2 5E,26E,37R,38S,39R,40R,42S,44S,46R,47S,4 8R,49R,59R)-48,59-dihydroxy-46-[2-[3-(2-hydroxy (2-hydroxyethoxymethyl)propoxy]ethoxy]-47 -[(1R)-2-[(1S,3R,4R)-4-hydroxy-3-methoxy-cyclohexane [xyl]-1-methyl-ethyl]-49-methoxy-37,38,39,40,50,5 1-Hexamethyl-71,72-dioxa-60-azatricyclohexatriacont- 21,23,25(50),26(51)-tetraene-52,53,54,55,56 -Synthesis of pentone (I-64):

[0428] 140mg(21E,23E,25E,26E,37R,38S,39R,40R, 42S,44S,47S,48R,49R,59R)-48,59-dihydroxy-46 -[2-[3-(2-hydroxyethoxy)-2-(2-hydroxyethoxymethyl)prop 7-[(1R)-2-[(1S,3R,4R)-4-hydroxypropyl]ethoxy]-4 ... 3-(3-methoxy-cyclohexyl)-1-methyl-ethyl)-49-methoxy-37, 38,39,40,50,51-Hexamethyl-71,72-dioxa-60-azatriazole Cyclohexatriaconta-21,23,25(50),26(51)-tetraene-5 The 2,53,54,55,56-pentone was purified by preparative chiral HPLC. Epimers were purified by silica gel chromatography (hexane:DCM:EtOAc:MeOH = P...

Claims

1. Formula I: 【Chemistry 273】 or a pharmaceutically acceptable salt thereof, Ring A is a monovalent derivative of rapamycin or an analog thereof; R １ is attached to said rapamycin or analog thereof at the C7 hydroxyl position; R １ is an optionally substituted, linear or branched, saturated or unsaturated monovalent C ３～３０ is a hydrocarbon chain, and R １ One or more methylene units of and independently —N(R)—, —N(R)C(O)—, —C(O)N(R)—, —N(R) S(O) ２ -、-S(O) ２ N(R)-、-O-、-C(O)-、-OC(O)-、-C (O)O-, -S-, -S(O)-, -S(O) ２ - or -P(O)(R) ２ ,Ma or 1 to 6 heteroatoms independently selected from nitrogen, oxygen, or sulfur; replaced by a 6- to 18-membered saturated or partially unsaturated heterocyclic ring; or R １ is the formula P-0: 【Chemistry 274】 (In the formula, 【Chemistry 275】 indicates the point of attachment to ring A, Each Z is independently —O—, —S—, —NR—, or —SO ２ - and n is from about 2 to about 300; Each R is independently hydrogen or an optionally substituted C １～６ aliphatic groups) Selected from wherein the compound is 【Chemistry 276】 or a pharmaceutically acceptable salt thereof, provided that:

2. 2. The compound of claim 1, wherein Ring A is selected from rapamycin and everolimus.

3. R １ optionally substituted, linear or branched, saturated or unsaturated monovalent C ３～３０ is a hydrocarbon chain, and R １ One or more methylene units of and independently —N(R)—, —N(R)C(O)—, —C(O)N(R)—, —N(R) S(O) ２ -、-S(O) ２ N(R)-、-O-、-C(O)-、-OC(O)-、-C (O)O-, -S-, -S(O)-, -S(O) ２ - or -P(O)(R) ２ By 3. The compound of claim 1 or 2, wherein:

4. R １ optionally substituted, linear or branched, saturated or unsaturated monovalent C ３～３０ is a hydrocarbon chain, and R １ One or more methylene units of and independently replaced by -O- or -S-. The compounds listed above.

5. R １ but 【Chemistry 277】 The compound according to any one of claims 1 to 4, selected from:

6. R １ has 1 to 6 heteroatoms independently selected from nitrogen, oxygen, or sulfur; 1 or 2, wherein the heterocyclic ring is a 6- to 18-membered saturated or partially unsaturated heterocyclic ring.

2. The compound according to any one of claims 1 to 11.

7. Formula II: 【Chemistry 278】 or a pharmaceutically acceptable salt thereof, R １ is an optionally substituted, linear or branched, saturated or unsaturated monovalent C ３～３０ is a hydrocarbon chain, and R １ One or more methylene units of and independently —N(R)—, —N(R)C(O)—, —C(O)N(R)—, —N(R) S(O) ２ -、-S(O) ２ N(R)-、-O-、-C(O)-、-OC(O)-、-C (O)O-, -S-, -S(O)-, -S(O) ２ - or -P(O)(R) ２ ,Ma or 1 to 6 heteroatoms independently selected from nitrogen, oxygen, or sulfur; replaced by a 6- to 18-membered saturated or partially unsaturated heterocyclic ring; or R １ is the formula P-0: 【Chemistry 279】 (In the formula, 【Chemistry 280】 indicates the point of attachment to the C-7 hydroxyl position, Each Z is independently —O—, —S—, —NR—, or —SO ２ - and n is from about 2 to about 300; Each R is independently hydrogen or an optionally substituted C １～６ aliphatic groups) Selected from].

8. R １ optionally substituted, linear or branched, saturated or unsaturated monovalent C ３～３０ is a hydrocarbon chain, and R １ One or more methylene units of and independently —N(R)—, —N(R)C(O)—, —C(O)N(R)—, —N(R) S(O) ２ -、-S(O) ２ N(R)-、-O-、-C(O)-、-OC(O)-、-C (O)O-, -S-, -S(O)-, -S(O) ２ - or -P(O)(R) ２ By 8. The compound of claim 7, wherein

9. R １ optionally substituted, linear or branched, saturated or unsaturated monovalent C ３～３０ is a hydrocarbon chain, and R １ One or more methylene units of 9. Any of claims 7 and 8, wherein each of the groups is independently replaced by -O- or -S-. The compound described above.

10. R １ but 【Chemistry 281】 The compound according to any one of claims 7 to 9, selected from:

11. R １ has 1 to 6 heteroatoms independently selected from nitrogen, oxygen, or sulfur; The compound according to claim 7, which is a 6- to 18-membered saturated or partially unsaturated heterocyclic ring. thing.

12. Formulas II, III, IV, V, VI, VII and VIII: 【Chemistry 282】 【Chemistry 283】 【Chemistry 284】 or a pharmaceutically acceptable salt thereof 2. The compound of claim 1, wherein the compound is selected from any one of:

13. Formulas II-a, II-b, III-a and III-b: 【Chemical 285】 【Chemistry 286】 or a pharmaceutically acceptable salt thereof 13. The compound of claim 1 or claim 12, selected from any one of:

14. R １ but, 【Chemistry 287】 【Chemical 288】 14. The compound of any one of claims 1, 7, 12 or 13, selected from:

15. Formulas XII-a, XII-b, XIII-a and XIII-b: 【Chemistry 289】 【Chemistry 290】 or a pharmaceutically acceptable salt thereof 13. The compound of claim 1 or claim 12, selected from either:

16. 2. The compound of claim 1 selected from those shown in Table 1.

17. A compound according to any one of claims 1 to 16, a pharmaceutically acceptable carrier, and ajuba A pharmaceutically acceptable composition comprising a compound or vehicle.

18. Methods of treating mTORC-mediated diseases, disorders or conditions in a patient in need thereof The compound according to any one of claims 1 to 16 or a pharmaceutical composition thereof is administered to the patient. The method of claim 1, further comprising administering

19. The mTORC-mediated disease, disorder or condition is diabetic nephropathy, type 1 diabetes and type 2 diabetes. Kidney-related complications of diabetes, autosomal dominant polycystic kidney disease (ADPKD), autosomal recessive ARPKD, a kidney disease associated with cyst formation or cystogenesis, focal Segmental glomerulosclerosis (FSGS) and other diseases associated with kidney stiffness, including laminopathies - Age-related macular degeneration (AMD), diabetic macular edema, diabetic retinopathy, glaucoma, age-related retinal disease, aging of the immune system, respiratory infections, urinary tract infections, heart failure, osteoarthritis, pulmonary arthritis pulmonary arterial hypertension (PAH) and chronic obstructive pulmonary disease (COPD).

18. The method according to claim 18.

20. 19. The method of claim 18 further comprising administering an additional therapeutic agent in combination with said compound.

20. The method of any one of claims 19 to 20.

21. For the manufacture of a medicament for treating an mTORC-mediated disorder in a patient in need thereof.

17. Use of a compound or composition according to any one of claims 1 to 16 for the treatment of rheumatoid arthritis.

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