Selective rapamycin analogs and their use

Abstract

Compounds of formula (I) and their pharmaceutical compositions are disclosed for use in treating mTOR pathway-mediated disorders or diseases via more selective binding to FKBP12 among the FK506-binding proteins (FKBPs). Due to their abnormal pharmacokinetic profiles and enhanced pharmacodynamic selectivity at target FKBPs, these compounds are useful in treating age-related or senescence-related diseases, diabetes, cancer, and inflammation-related disorders. [Formula 1] JPEG2026512047000312.jpg8368

Description

Technical Field

[0001] Cross - Reference to Related Applications This application claims priority based on U.S. Provisional Patent Application No. 63 / 494,839 filed on April 7, 2023, U.S. Provisional Patent Application No. 63 / 515,184 filed on July 24, 2023, and U.S. Provisional Patent Application No. 63 / 624,875 filed on January 25, 2024, all of which are incorporated herein by reference in their entirety.

[0002] This specification provides a FKBP12 - selective rapamycin analog, a pharmaceutical composition containing the analog, and a method of treating diseases, disorders, and illnesses including the step of administering the analog and its pharmaceutical composition.

Background Art

[0003] Rapamycin is a known macrolide antibiotic produced by Streptomyces hygoscopius. See, for example, J. Antibiotics (1991) 44:688 by McAlpine, J.B. et al., J. Am. Chem. Soc. (1991) 113:7433 by Schreiber, S.L. et al., and U.S. Patent No. 3,929,992. The numbering rules for rapamycin and its derivatives used herein are shown below.

[0004]

Chemical Formula

[0005] Rapamycin is a potent immunosuppressant used to prevent organ transplant rejection and to treat certain types of cancer. It has also been shown to be useful in preventing or treating systemic lupus erythematosus, insulin-dependent diabetes mellitus, skin disorders such as psoriasis, smooth muscle cell proliferation and intimal thickening after vascular injury, adult T-cell leukemia / lymphoma, malignant carcinoma, inflammatory heart disease, anemia, and neurite outgrowth. Furthermore, rapamycin analogs (so-called "rapalogs") have been shown to be effective against hepatic fibrosis. See, for example, Liver Int. (2014) 34(10):15 pp. 13-21.

[0006] In eukaryotic cells, rapamycin and its analogues (rapalogs) inhibit TOR (Target of Rapamycin) signaling. In mammalian cells, mTOR (mammalian target of rapamycin) resides in two distinct multiprotein complexes, described as the mTORC1 and mTORC2 complexes, which together sense nutrient and energy availability and integrate inputs from growth factor and stress signaling. mTORC1 integrates signals from growth factors and nutrients to regulate cell growth and metabolism. (Laplante M. et al., Cell. (2012) 149(2):274-93). mTORC1 is an important regulator of protein translation and autophagy.

[0007] In animal models, rapalogs extend lifespan and delay the onset of age-related diseases. Aging, like other biological processes, is regulated by signaling pathways such as the TOR pathway (referred to as "TOR" in this case to include yeast and nematode (C elegans) systems) and, in mammals, the mTORC1 pathway. Regulation of TOR and mTORC1 signaling extends lifespan and delays the onset of age-related diseases in a wide range of organisms, from flies to mammals. For example, inhibition of the TOR pathway through gene mutations extended the lifespan of yeast, nematodes (C. elegans), and fruit flies (drosophila), and inhibition of the mTORC1 pathway extended the lifespan of mice (Science (2005) 310:1193-1196 by Kaeberlein et al., Curr Biol (2004) 14:885-890 by Kapahi et al., Science (2009) 326:140-144 by Selman et al., and Nature (2003) 426:620 by Vellai et al.). In addition, the mTORC1 inhibitor rapamycin extended the lifespan of mice even when administered in their later years (Nature (2009) 460(7253):392-395 by Harrison et al.). These data suggest that drugs targeting the mammalian TOR (mTOR) pathway may be effective in treating aging and age-related diseases in humans. For example, J. Mannick et al., in Sci Transl Med. (2014) 6(268):268ra179, described how mTOR inhibition improves immune function in elderly individuals.

[0008] Mitochondrial myopathy (MM) is the most common symptom manifestation of adult-onset mitochondrial disease and exhibits a multifaceted tissue-specific stress response: (1) transcriptional responses including metabolic cytokines FGF21 and GDF15, (2) monocarbon remodeling, and (3) mitochondrial endoplasmic reticulum stress response (Khan et al., Cell Metabolism 26, pp. 419-428, Aug. 1, 2017). Inhibition of mTORC1 with rapamycin downregulated all components of ISRmt (integrated mitochondrial stress response), improved all characteristics of MM, and even reversed the progression of end-stage MM, but did not induce mitochondrial neonatogenesis. Therefore, rapamycin and rapagnologs are considered to have potential value in addressing many unmet needs in clinical practice.

[0009] Epilepsy caused by mutations in the Tsc1 / Tsc2 complex can be treated with rapamycin or rapalogs (Ann. Neurology, 2008, April; 63(4) pp. 444-453, by Zeng et al.). It is advantageous to have rapalogs that can inhibit epilepsy without interfering with other tissues where mTORC1 is expressed, and therefore, more selective mTORC1 inhibitors are desirable in this environment.

[0010] mTORC1 is a key regulator of protein translation and autophagy. The mTORC1 complex is sensitive to allosteric mTOR inhibitors such as rapamycin and rapalog. The mode of action of rapamycin and previously produced rapalogs involves the formation of an intracellular complex with an FK506-binding protein, which may include FKBP12, FKBP12.6, FKBP13, FKBP25, FKBP51, or FKBP52 (these six FKBPs will be referred to herein as "FKBP" or "FKBPs"), followed by the binding of the FKBP-rapalog complex to the FRB (FK506-rapamycin-binding) domain of mTOR (Mol Cell Biol. (2013) 33(7):1357-1367 by Marz AM et al.). Such interaction between the FKBP-rapalog complex and mTORC1 results in allosteric inhibition of the complex. Rapalogs such as rapamycin and RAD001 (everolimus) have gained clinical importance by inhibiting mTORC1 activity, which is associated with both benign and malignant proliferative disorders (Breast Cancer (Auckl). (2015) 9:73-79, by Royce ME et al.; Kidney Int Rep. (2018) 3(1):155-159, by Pleniceanu O. et al.). Various FKBPs are expressed to varying degrees in various cell types and organs found in the body.

[0011] Furthermore, rapamycin treatment has been reported to selectively target CD40-mediated B cell proliferation and differentiation (Atsuko Sakata et al., Immunology Letters, Volume 68, Issues 2-3, 1 June 1999, pp. 301-309). CD40 is a cell surface receptor that is part of the tumor necrosis factor (TNF) receptor superfamily. CD40 is expressed in antigen-presenting cells such as B cells, macrophages, and dendritic cells, as well as in some non-immune cells and tumors (Dakal et al., Immunobiology 2020, 225:151899). Activation that quiescently stimulates B cells requires the initial induction of B cell antigen receptors (BCRs) and secondary stimuli by various cytokine receptors and B cell activating molecules, including CD40.

[0012] The interaction between CD40 and its ligand CD40L is essential for the survival of many cell types and provides costimulatory signals necessary for immune response functions such as germinal center formation, antibody response to T-dependent antigens, and dendritic cell "licensing," which enable T cells to mature and become powerful enough to induce activation and differentiation (see, for example, Immunity 1994, 1: pp. 167-178 by Kawabe et al., and Immunol. Rev. 2009, 229: pp. 152-172 by Elgueta et al.).

[0013] The signaling pathway from CD40 to CD40L is involved in autoimmune diseases, many of which are induced by autoantibodies, such as systemic rheumatic diseases in which autoantibodies play a crucial role in disease progression (multiple sclerosis, autoimmune nephritis, rheumatoid arthritis, Sjögren's syndrome, and systemic lupus erythematosus, etc.), as well as in non-rheumatic diseases with autoantibody components (myasthenia gravis, Graves' disease, and neuromyelitis, etc.) (see Adv Drug Delivery Rev. 2019, 141: pp. 92-103 by Karnell et al.). Furthermore, since the signaling pathway from CD40 to CD40L is essential for the activation of antigen-presenting cells, inhibiting antigen presentation by dendritic cells or B cells may affect the CD8+ T cell response in some diseases, such as multiple sclerosis (see, for example, Expert Opin Ther Targets 2013, 17: pp. 1053-1066 by Denic et al.). Modified CD40-to-CD40L signaling is also involved in other diseases and conditions such as heart disease and transplantation (see, for example, Immunobiology 2020,225:151899 by Dakal et al., Ann.Med.2011,43:331;340 by Pamukcu et al., and Immunotherapy 2015,7:399-410 by Pinelli et al.).

[0014] For example, CD40 co-stimulation inhibition and immunosuppression with rapamycin resulted in long-term islet and kidney transplant tissue survival (90, 94, over 120, over 120, and over 120 days), but only one recipient showed evidence of transplant tissue rejection. The CD40 / rapamycin regimen was also tested in four recipients of kidney transplants alone. All four recipients achieved long-term kidney transplant tissue survival (100% at day 120), which was superior to kidney transplant tissue survival with a triple immunosuppression regimen (tacrolimus, mycophenolate mofetil, and steroids) (62.9% at day 120) (T. Oura 1, K. Hotta et al., American Journal of Transplantation, Volume 17, Issue 3, March 2017, pp. 646-656).

[0015] Different FKBPs are expressed variably in different tissues, and there are some situations where it is desirable to avoid mTORC1 inhibition in specific cell types. Therefore, to improve the ability to target specific tissues, selective rapalogs for individual FKBPs are needed. For example, a rapalog selective for FKBP12 can target tissues with high FKBP12 expression but spare tissues with low (or zero) FKBP12 levels. Selective analogs for FKBPs can provide patient-specific and clinically advantageous benefits because they can avoid adverse events caused by broad inhibition of mTORC1.

[0016] There is also a need for rapalogs that can be administered in combination with anti-CD40 antibodies in the treatment of diseases where autoantibodies play an important role in disease progression, in order to induce an immune response and / or prevent organ transplant rejection.

[0017] Furthermore, there is a need for rapalogs that can be administered in combination with immunotherapeutic agents that target T cells against specific tumors, so as not to inhibit or interfere with the immunotherapeutic approach. SUMMARY OF THE INVENTION

[0018] In one aspect herein, a compound of formula (I)

[0019]

Chemical formula

[0020] In one embodiment, the compound of formula (I) is of formula (Ia)

[0021] [ka] A compound of or a pharmaceutically acceptable salt thereof, In the formula, R 1 is hydrogen or C 1-6 It is alkyl, R 2 is 1 or 2 R 2a A heterocyclyl, aryl, or heteroaryl that is optionally substituted with a base, R 3 is -OR a Selected from the group consisting of 3-6 member heterocyclyls and 3-6 member heteroaryls, R a H, -P(O)(R b )2, -C(O)R c , -C(O)OR c , C 1-6 Alkyl, and C1-6 selected from the group consisting of hydroxyalkyl, R b each independently is H and C 1-6 selected from the group consisting of alkyl, R c is H, C 1-6 alkyl, and C 1-6 selected from the group consisting of hydroxyalkyl, each of one or two R 2a groups, if present, independently is C 1-6 alkyl, C 1-6 hydroxyalkyl, hydroxy, halo, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, and cyano, or any two R 2a groups, if present on the same carbon, together form an oxo group.

[0022] In one embodiment, the compound of formula (I) is a compound of formula (Ib)

[0023]

Chemical formula

[0024] In one embodiment, the compound of formula (I) is a compound of formula (Ic)

[0025]

Chemical formula

[0026] This disclosure provides at least the following embodiments. a) Compounds of formula (PI), formula (P-Ia), formula (P-Ib), formula (P-Ic), formula (P-2), formula (I), formula (Ia), formula (Ib), formula (Ic), or pharmaceutically acceptable salts thereof. b) A compound selected from compounds 3-30, 43-65, or 67-74, or a pharmaceutically acceptable salt thereof. c) A compound of (a) or (b), or a pharmaceutically acceptable salt thereof, wherein the compound binds to FKBP12 more selectively than other FK506-binding proteins compared to everolimus. d) A pharmaceutical composition comprising a compound of formula (PI), formula (P-Ia), formula (P-Ib), formula (P-Ic), formula (P-2), formula (I), formula (Ia), formula (Ib), or formula (Ic), or a pharmaceutically acceptable salt thereof, in a pharmaceutically acceptable excipient, diluent, or carrier. e) A pharmaceutical composition comprising the compound of (b) or (c) in a pharmaceutically acceptable excipient, diluent, or carrier. f) A pharmaceutical composition comprising the compounds of (a) to (c) and at least one additional therapeutically active agent in a pharmaceutically acceptable excipient, diluent, or carrier. g) A combination therapy comprising a therapeutically effective amount of (a) to (c), or a pharmaceutical composition (d) to (f), and an anti-CD40 antibody. h) A method for treating a disease or disorder mediated by the mTOR pathway in a subject requiring treatment of such disease or disorder, comprising the step of administering a therapeutically effective dose of one of the compounds (a) to (c), one of the pharmaceutical compositions (d) to (f), or one of the combination therapy agents (g). i) The method of (h) wherein a target tissue, organ, or cell associated with the pathogenesis of the disease or disorder has sufficient FKBP12 levels to inhibit mTORC1. j) The method of (h) or (i), wherein a therapeutically effective amount of compound (a) to (c), or a pharmaceutical composition (d) to (f), has a binding affinity to FKBP12 that is sufficiently high to inhibit mTORC1. k) A disease or disorder is sarcopenia, skin atrophy, senile angioma, seborrheic keratosis, cerebral atrophy, atherosclerosis, arteriosclerosis, emphysema, osteoporosis, osteoarthritis, hypertension, erectile dysfunction, cataracts, macular degeneration, glaucoma, stroke, cerebrovascular disease (stroke), chronic kidney disease, diabetes-related kidney disease, hepatic insufficiency, hepatic fibrosis, autoimmune hepatitis, endometrial hyperplasia, metabolic dysfunction, renovascular disease, hearing loss, mobility impairment, cognitive decline, tendon stiffness, cardiac dysfunction, such as cardiac hypertrophy, and / or contraction and / or expansion. Methods (h) to (j) selected from cardiac dysfunction and / or hypertension, cardiac dysfunction that reduces ejection fraction, immunosenescence, Parkinson's disease, Alzheimer's disease, cancer, immunosenescence resulting in cancer due to reduced immune surveillance, infection due to decreased immune function, chronic obstructive pulmonary disease (COPD), obesity, loss of taste, loss of smell, arthritis, cancer in which the tumor has high mTORC1 signaling levels and / or sufficient FKBP12 levels to allow inhibition of mTORC1, and type 2 diabetes. l) Disease or disorder is sarcopenia, skin atrophy, senile angioma, seborrheic keratosis, cerebral atrophy, atherosclerosis, arteriosclerosis, emphysema, osteoporosis, osteoarthritis, hypertension, erectile dysfunction, cataracts, macular degeneration, glaucoma, stroke, cerebrovascular disease (stroke), chronic kidney disease, diabetes-related kidney disease, hepatic insufficiency, hepatic fibrosis, autoimmune hepatitis, endometrial hyperplasia, metabolic dysfunction, renovascular disease, hearing loss, mobility impairment, cognitive decline, tendon stiffness, cardiac dysfunction, such as cardiac hypertrophy, and / or contraction and / or expansion. Methods (h) to (j) selected from cardiac dysfunction and / or hypertension, cardiac dysfunction that reduces ejection fraction, immunosenescence, Parkinson's disease, Alzheimer's disease, cancer, immunosenescence resulting in cancer due to reduced immune surveillance, infection due to decreased immune function, chronic obstructive pulmonary disease (COPD), obesity, loss of taste, loss of smell, arthritis, cancer in which the tumor has high mTORC1 signaling levels and / or sufficient FKBP12 levels to allow inhibition of mTORC1, and type 2 diabetes. m) The disease or disorder is cancer, by the method of (h) to (j). n) The method of (m) wherein the cancer is selected from kidney cancer, renal cell carcinoma, colorectal cancer, uterine sarcoma, endometrial uterine cancer, endometrial cancer, breast cancer, ovarian cancer, cervical cancer, gastric cancer, fibrosarcoma, pancreatic cancer, liver cancer, melanoma, leukemia, multiple myeloma, nasopharyngeal cancer, prostate cancer, lung cancer, glioblastoma, bladder cancer, mesothelioma, head cancer, rhabdomyosarcoma, sarcoma, lymphoma, and cervical cancer. o) The disease is Alzheimer's disease, (k) the method, p) The disease is graft-versus-host disease (GvHD), by the method of (h). q) The disease is a facial angiofibroma associated with tuberous sclerosis, by the method of (h). r) The disease is a progressive, unresectable or metastatic malignant perivascular epithelioid cell tumor, by the method of (h). s) A method for inducing immune tolerance and / or preventing organ rejection in a subject requiring induction of immune tolerance and / or prevention of organ rejection, comprising the step of administering a therapeutically effective dose of one of the compounds (a) to (c), one of the pharmaceutical compositions (d) to (f), or one of the combination therapy agents (g). t) one of the methods (h) to (s), wherein the compound is selected from compounds 16-19, 26-28, 45, 50, 63, 68-72, and 74. u) Compounds of (a) to (c), pharmaceutical compositions of (d) to (f), or combination therapies of (g) for use in the treatment of a disease or disorder. v) Compounds of (a) to (c), pharmaceutical compositions of (d) to (f), or combination therapies of (g) for use in the treatment of a disease or disorder mediated by the mTOR pathway in a subject requiring treatment of such disease or disorder. w) one of the methods (u) to (v), wherein the compound is selected from compounds 16-19, 26-28, 45, 50, 63, 68-72, and 74. x) Use in therapeutically effective amounts of the compounds (a) to (c), the pharmaceutical compositions (d) to (f), or the combination therapy agent (g) in the manufacture of a pharmaceutical product for treating a disease or disorder. y) Use in therapeutically effective amounts of the compounds (a) to (c), the pharmaceutical compositions (d) to (f), or the combination therapy agent (g) in the manufacture of a pharmaceutical product for treating a disease or disorder mediated by the mTOR pathway in a subject requiring treatment of such disease or disorder. z) Use of any one of (x)-(y), wherein the compound is selected from compounds 16-19, 26-28, 45, 50, 63, 68-72, and 74.

[0027] In some embodiments, the compounds and pharmaceutical compositions disclosed herein, for use in treating disorders or diseases mediated by the mTOR pathway, are more selective than other FK506-binding proteins (FKBPs) in their binding to FKBP12.

[0028] In some other embodiments, the compounds and pharmaceutical compositions disclosed herein, for use in treating mTOR pathway-mediated disorders or diseases, exhibit unusual and remarkable pharmacokinetic profiles and enhanced pharmacodynamic selectivity at the target FKBP, and these compounds and pharmaceutical compositions are useful in treating age-related or aging-related diseases, diabetes-related complications, cancer, as well as inflammation-related disorders.

[0029] In other embodiments, the compounds and pharmaceutical compositions disclosed herein are for use in treating disorders or diseases mediated by the mTOR pathway, wherein the compounds inhibit S6K1 phosphorylation in FKBP12 KO cells with at least twice the efficiency of the rapalog RAD001 compared to FKBP12-expressing cells.

[0030] In some other embodiments, compounds and pharmaceutical compositions disclosed herein are for use in treating mTOR pathway-mediated disorders or diseases, wherein the compounds inhibit S6K1 phosphorylation in FKBP12 KO cells with at least 10 times lower efficiency than the rapalog RAD001 compared to FKBP12-expressing cells.

[0031] In some other embodiments, compounds and pharmaceutical compositions disclosed herein for use in treating mTOR pathway-mediated disorders or diseases, wherein the compounds inhibit S6K1 phosphorylation in FKBP12 KO cells with at least 100 times lower efficiency than the rapalog RAD001 compared to FKBP12-expressing cells.

[0032] In some other embodiments, compounds and pharmaceutical compositions disclosed herein for use in treating disorders or diseases mediated by the mTOR pathway, wherein the compounds require concentrations at least about 10 times higher in FKBP12 KO cells compared to the rapalog RAD001 compared to FKBP12-expressing cells to achieve a 20% inhibition of S6K1 cell signaling.

[0033] In some other embodiments, compounds and pharmaceutical compositions disclosed herein for use in treating mTOR pathway-mediated disorders or diseases, wherein the compounds require concentrations at least about 100 times higher in FKBP12 KO cells compared to the rapalog RAD001 compared to FKBP12-expressing cells to achieve a 20% inhibition of S6K1 cell signaling.

[0034] In some other embodiments, compounds and pharmaceutical compositions disclosed herein for use in treating mTOR pathway-mediated disorders or diseases, wherein the compounds require concentrations at least about 500 times higher in FKBP12 KO cells compared to the rapalog RAD001 compared to FKBP12-expressing cells to achieve a 20% inhibition of S6K1 cell signaling.

[0035] In some other embodiments, compounds and pharmaceutical compositions disclosed herein for use in treating mTOR pathway-mediated disorders or diseases, wherein the compounds require concentrations at least about 1000 times higher in FKBP12 KO cells compared to the rapalog RAD001 compared to FKBP12-expressing cells to achieve a 20% inhibition of S6K1 cell signaling.

[0036] In some other embodiments, compounds and pharmaceutical compositions disclosed herein for use in treating mTOR pathway-mediated disorders or diseases, wherein the compounds require concentrations at least about 10 times higher in FKBP12 KO cells compared to the rapalog RAD001 compared to FKBP12-expressing cells to achieve a 30% inhibition of S6K1 cell signaling.

[0037] In some other embodiments, compounds and pharmaceutical compositions disclosed herein for use in treating mTOR pathway-mediated disorders or diseases, wherein the compounds require concentrations at least about 100 times higher in FKBP12 KO cells compared to the rapalog RAD001 compared to FKBP12-expressing cells to achieve a 30% inhibition of S6K1 cell signaling.

[0038] In some other embodiments, compounds and pharmaceutical compositions disclosed herein for use in treating mTOR pathway-mediated disorders or diseases, wherein the compounds require concentrations at least about 500 times higher in FKBP12 KO cells compared to the rapalog RAD001 compared to FKBP12-expressing cells to achieve a 30% inhibition of S6K1 cell signaling.

[0039] In some other embodiments, compounds and pharmaceutical compositions disclosed herein for use in treating mTOR pathway-mediated disorders or diseases, wherein the compounds require concentrations at least about 1000 times higher in FKBP12 KO cells compared to the rapalog RAD001 compared to FKBP12-expressing cells to achieve a 30% inhibition of S6K1 cell signaling.

[0040] In other embodiments, the “FKBP12 selective rapalog” is a rapalog that is approximately 10 to 1000 times less potent than RAD001 in cell lines that do not express FKBP12 (e.g., FKBP12 knockout cells compared to FKBP12-expressing cells). “Potency,” as used in this context, can be expressed as the concentration of the rapalog required to achieve 20% inhibition of S6K1(Thr389) phosphorylation in a cell-based assay, such as those used in Example 3 and Figures 1 to 11 disclosed herein. For example, if the IC20 of a rapalog in an S6K1(Thr389) phosphorylation inhibition assay using an FKBP12 knockout cell line is at least 20 times higher (e.g., 30, 50, 100, 200, 500, or 1000 times higher) than the IC20 of RAD001 in the same assay using the same cell line, then the rapalog is considered FKBP12 selective and typically expresses FKBP12.

[0041] In some other embodiments, “FKBP12 selective rapalog” is a rapalog that is approximately 10 to 1000 times less potent than RAD001 in cell lines that do not express FKBP12 (e.g., FKBP12 knockout cells compared to FKBP12-expressing cells). “Potency” can be expressed in this context as the concentration of the rapalog required to achieve 30% inhibition of S6K1(Thr389) phosphorylation in a cell-based assay, such as those used in Example 3 and Figures 1 to 11 disclosed herein. For example, if the IC30 of a rapalog in an S6K1(Thr389) phosphorylation inhibition assay using an FKBP12 knockout cell line is at least 20 times higher (e.g., 30, 50, 100, 200, 500, or 1000 times higher) than the IC30 of RAD001 in the same assay using the same cell line, then the rapalog is considered FKBP12 selective and typically expresses FKBP12.

[0042] In one embodiment, the compound of formula (I) or a pharmaceutically acceptable salt thereof has a binding affinity to FKBP12 that is sufficiently high to inhibit mTORC1 compared to, for example, rapamycin or RAD001.

[0043] In one embodiment, compounds (I), (P-1), (P-2), (Ia) to (Ic), or (P-Ia) to (P-Ic), or pharmaceutically acceptable salts thereof, may form a complex with FKBP12 to bind to and inhibit mTORC1 more potently than rapamycin or RAD001.

[0044] In one embodiment, the high binding affinity to FKBP12 results in greater efficacy compared to, for example, rapamycin or RAD001.

[0045] In one embodiment, the effectiveness of the treatment is determined empirically, for example, compared to rapamycin or RAD001.

[0046] In another embodiment, the Disclosure provides a method for treating a disease or disorder of a subject having sufficient FKBP12 levels to inhibit mTORc1, or having been previously determined to do so, the method comprising administering to a subject in need of treatment for the disease or disorder a compound of (I), (P-1), (P-2), (Ia)~(Ic), or (P-Ia)~(P-Ic), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition or pharmaceutical combination described herein.

[0047] In another embodiment, the Disclosure provides a method for treating a disease or disorder in a subject requiring treatment for such disease or disorder, the method comprising administering to the subject a compound of (I), (P-1), (P-2), (Ia) to (Ic), or (P-Ia) to (P-Ic), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition or pharmaceutical combination described herein.

[0048] In one embodiment, the disease or disorder is sarcopenia, skin atrophy, senile angioma, seborrheic keratosis, cerebral atrophy (also called dementia), atherosclerosis, arteriosclerosis, emphysema, osteoporosis, osteoarthritis, hypertension, erectile dysfunction, cataracts, macular degeneration, glaucoma, stroke, cerebrovascular disease (stroke), chronic kidney disease, diabetes-related kidney disease, liver dysfunction, hepatic fibrosis, autoimmune hepatitis, endometrial hyperplasia, metabolic dysfunction, renovascular disease, hearing loss, mobility impairment (e.g., frailty), cognitive decline, tendon stiffness, heart Functional impairments, such as cardiac hypertrophy, and / or systolic and / or diastolic dysfunction, and / or hypertension, cardiac dysfunction that reduces ejection fraction, immunosenescence, Parkinson's disease, Alzheimer's disease, cancer, immunosenescence leading to cancer due to reduced immune surveillance, infections due to impaired immune function, chronic obstructive pulmonary disease (COPD), obesity, loss of taste, loss of smell, arthritis, and type 2 diabetes mellitus (including complications arising from diabetes such as renal failure, blindness, and neuropathy).

[0049] In another aspect, the Disclosure provides a method for treating a disease or disorder in a subject requiring treatment of the disease or disorder, the method comprising administering to the subject a compound of (I), (P-1), (P-2), (Ia) to (Ic), or (P-Ia) to (P-Ic), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition or pharmaceutical combination described herein, the disease or disorder being selected from: • Acute or chronic rejection of organ or tissue transplantation, ·Transplant vasculopathy, • Intimal thickening of vascular tissue, vascular occlusion, obstructive coronary artery atherosclerosis, restenosis, proliferation and migration of smooth muscle cells, • Autoimmune diseases and inflammatory diseases, ·asthma, • Multidrug resistance (MDR), ·Fungal infections, ·inflammation, ·Infectious diseases, • Diseases related to aging, • Neurodegenerative diseases, • Proliferative disorders, such as cancer, • Seizures and seizure-related disorders, and • Mitochondrial myopathy and mitochondrial stress.

[0050] In another embodiment, the Disclosure provides a method for treating cancer in a subject requiring treatment, the method comprising administering to the subject a therapeutically effective dose of a compound of formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition or pharmaceutical combination described herein.

[0051] In one embodiment, the method further comprises a PD-1 / PDL-1 inhibitor.

[0052] In one embodiment, the cancer is selected from kidney cancer, renal cell carcinoma, colorectal cancer, uterine sarcoma, endometrial uterine cancer, endometrial cancer, breast cancer, ovarian cancer, cervical cancer, gastric cancer, fibrosarcoma, pancreatic cancer, liver cancer, melanoma, leukemia, multiple myeloma, nasopharyngeal cancer, prostate cancer, lung cancer, glioblastoma, bladder cancer, mesothelioma, head cancer, rhabdomyosarcoma, sarcoma, lymphoma, and cervical cancer.

[0053] In one embodiment, the impairment is a liver impairment involving fibrotic and / or inflammatory processes, such as hepatic fibrosis occurring in end-stage liver disease, cirrhosis, toxic hepatic failure, non-alcoholic steatohepat

[0054] In one embodiment, the disorder is a renal disorder involving the process of renal fibrosis or inflammation, such as renal fibrosis resulting from acute kidney injury and leading to chronic kidney disease and diabetic nephropathy.

[0055] In one embodiment, the impairment is cardiac dysfunction, such as myocardial infarction or cardiac hypertrophy. In one embodiment, the cardiac dysfunction is systolic and / or diastolic dysfunction. In one embodiment, the cardiac dysfunction is hypertension. In one embodiment, the cardiac dysfunction results in a reduced ejection fraction.

[0056] In one embodiment, the impairment is immunosenescence, which leads to cancer due to a decrease in immune surveillance.

[0057] In one embodiment, the disorder is cancer, including tumors treated by immunotherapy and tumors previously treated with rapamycin, RAD001, or another rapagnolog. In one embodiment, the cancer includes tumors in which the mTOR pathway is shown to be activated, including environments in which mutations exist in the Tsc1 gene or in environments in which the tumor microenvironment is appropriately treated with a rapagnolog.

[0058] Details of one or more embodiments of the present disclosure are described herein. Other features, purposes, and advantages of the present disclosure will be evident from the drawings, detailed description, examples, and claims. [Brief explanation of the drawing]

[0059] [Figure 1A] This line graph shows the inhibition of S6K1 (Thr389) in wild-type 293T cells. Cells were treated over 2 hours with the following compounds: RAD001 (everolimus, dotted line and circle) and compound 44 (solid line and square). All treatments were performed in double rows. The Y-axis represents the inhibition rate of S6K1 (Thr389) levels in cells treated with dimethyl sulfoxide (DMSO) medium. The X-axis represents the concentrations of the two compounds. [Figure 1B] This line graph shows the inhibition of S6K1 (Thr389) in FKBP12 knockout 293T cells. Cells were treated over 2 hours with the following compounds: RAD001 (everolimus, dotted line and circle) and compound 44 (solid line and square). All treatments were performed in double rows. The Y-axis represents the inhibition rate of S6K1 (Thr389) levels in cells treated with medium supplemented with dimethyl sulfoxide (DMSO). The X-axis represents the concentrations of the two compounds. [Figure 1C] This line graph shows the inhibition of S6K1 (Thr389) in wild-type 293T cells. Cells were treated over 2 hours with the following compounds: RAD001 (everolimus, dotted line and circle) and compound 45 (solid line and square). All treatments were performed in double rows. The Y-axis represents the inhibition rate of S6K1 (Thr389) levels in cells treated with medium supplemented with dimethyl sulfoxide (DMSO). The X-axis represents the concentrations of the two compounds. [Figure 1D] This line graph shows the inhibition of S6K1 (Thr389) in FKBP12 knockout 293T cells. Cells were treated over 2 hours with the following compounds: RAD001 (everolimus, dotted line and circle) and compound 45 (solid line and square). All treatments were performed in double rows. The Y-axis represents the inhibition rate of S6K1 (Thr389) levels in cells treated with medium supplemented with dimethyl sulfoxide (DMSO). The X-axis represents the concentrations of the two compounds. [Figure 2A] This line graph shows the inhibition of S6K1(Thr389) in wild-type 293T cells. Cells were treated over 2 hours with the following compounds: RAD001 (everolimus, dotted line and circle) and compound 18 (solid line and square). All treatments were performed in double rows. The Y-axis represents the inhibition rate of S6K1(Thr389) levels in cells treated with dimethyl sulfoxide (DMSO) medium. The X-axis represents the concentrations of the two compounds. [Figure 2B] This line graph shows the inhibition of S6K1 (Thr389) in FKBP12 knockout 293T cells. Cells were treated over 2 hours with the following compounds: RAD001 (everolimus, dotted line and circle) and compound 18 (solid line and square). All treatments were performed in double rows. The Y-axis represents the inhibition rate of S6K1 (Thr389) levels in cells treated with medium supplemented with dimethyl sulfoxide (DMSO). The X-axis represents the concentrations of the two compounds. [Figure 3A] This line graph shows the inhibition of S6K1(Thr389) in wild-type 293T cells. Cells were treated over 2 hours with the following compounds: RAD001 (everolimus, dotted line and circle) and compound 16 (solid line and square). All treatments were performed in double rows. The Y-axis represents the inhibition rate of S6K1(Thr389) levels in cells treated with medium supplemented with dimethyl sulfoxide (DMSO). The X-axis represents the concentrations of the two compounds. [Figure 3B]This line graph shows the inhibition of S6K1 (Thr389) in FKBP12 knockout 293T cells. Cells were treated with the following compounds over 2 hours: RAD001 (everolimus, dotted line and circle) and compound 16 (solid line and square). All treatments were performed in double rows. The Y-axis represents the inhibition rate of S6K1 (Thr389) levels in cells treated with medium supplemented with dimethyl sulfoxide (DMSO). The X-axis represents the concentrations of the two compounds. [Figure 4A] This line graph shows the inhibition of S6K1(Thr389) in wild-type 293T cells. Cells were treated over 2 hours with the following compounds: RAD001 (everolimus, dotted line and circle), compound 26 (solid line and square), and compound 28 (solid line and cross). All treatments were performed in double rows. The Y-axis represents the inhibition rate of S6K1(Thr389) levels in cells treated with medium supplemented with dimethyl sulfoxide (DMSO). The X-axis represents the concentrations of the two compounds. [Figure 4B] This line graph shows the inhibition of S6K1(Thr389) in FKBP12 knockout 293T cells. Cells were treated over 2 hours with the following compounds: RAD001 (everolimus, dotted line and circle), compound 26 (solid line and square), and compound 28 (solid line and cross). All treatments were performed in double rows. The Y-axis represents the inhibition rate of S6K1(Thr389) levels in cells treated with medium supplemented with dimethyl sulfoxide (DMSO). The X-axis represents the concentrations of the two compounds. [Figure 5A] This line graph shows the inhibition of S6K1(Thr389) phosphorylation in wild-type (WT) 293T cells with increasing concentration of compound treatment. Cells were treated over 2 hours with the following compounds: RAD001 (everolimus, dotted line and circle) and compound 47 (solid line and square). All treatments were performed in double cycles. The Y-axis shows the S6K1(Thr389) phosphorylation value calculated as a percentage (%) for control cells treated in medium containing only dimethyl sulfoxide (DMSO). The S6K1(Thr389) phosphorylation value for control cells treated with DMSO is set to 100%. The X-axis represents the Log10 molar (M) concentration of the compound. [Figure 5B]This line graph shows the inhibition of S6K1(Thr389) phosphorylation in FKBP12 knockout (KO) 293T cells with increasing compound concentration. Cells were treated over 2 hours with the following compounds: RAD001 (everolimus, dotted line and circle) and compound 47 (solid line and square). All treatments were performed in double cycles. The Y-axis shows the S6K1(Thr389) phosphorylation value calculated as a percentage (%) for control cells treated in medium containing only dimethyl sulfoxide (DMSO). The S6K1(Thr389) phosphorylation value for control cells treated with DMSO is set to 100%. The X-axis represents the Log10 molar (M) concentration of the compound. [Figure 5C] This line graph shows the inhibition of S6K1(Thr389) phosphorylation in wild-type (WT) 293T cells with increasing concentration of compound treatment. Cells were treated over 2 hours with the following compounds: RAD001 (everolimus, dotted line and circle) and compound 48 (solid line and square). All treatments were performed in double cycles. The Y-axis shows the S6K1(Thr389) phosphorylation value calculated as a percentage (%) for control cells treated in medium with dimethyl sulfoxide (DMSO) alone. The S6K1(Thr389) phosphorylation value for control cells treated with DMSO is set to 100%. The X-axis represents the Log10 molar (M) concentration of the compound. [Figure 5D] This line graph shows the inhibition of S6K1(Thr389) phosphorylation in FKBP12 knockout (KO) 293T cells with increasing compound concentration. Cells were treated over 2 hours with the following compounds: RAD001 (everolimus, dotted line and circle) and compound 48 (solid line and square). All treatments were performed in double cycles. The Y-axis shows the S6K1(Thr389) phosphorylation value calculated as a percentage (%) for control cells treated in medium containing only dimethyl sulfoxide (DMSO). The S6K1(Thr389) phosphorylation value for control cells treated with DMSO is set to 100%. The X-axis represents the Log10 molar (M) concentration of the compound. [Figure 5E]This line graph shows the inhibition of S6K1(Thr389) phosphorylation in wild-type (WT) 293T cells with increasing compound concentrations. Cells were treated over 2 hours with the following compounds: RAD001 (everolimus, dotted line and circle) and compound 49 (solid line and square). All treatments were performed in double cycles. The Y-axis shows the S6K1(Thr389) phosphorylation value calculated as a percentage (%) for control cells treated in medium containing only dimethyl sulfoxide (DMSO). The S6K1(Thr389) phosphorylation value for control cells treated with DMSO is set to 100%. The X-axis represents the concentrations of the two compounds. [Figure 5F] This line graph shows the inhibition of S6K1(Thr389) phosphorylation in FKBP12 knockout (KO) 293T cells with increasing compound concentrations. Cells were treated over 2 hours with the following compounds: RAD001 (everolimus, dotted line and circle) and compound 49 (solid line and square). All treatments were performed in double cycles. The Y-axis shows the S6K1(Thr389) phosphorylation value calculated as a percentage (%) for control cells treated in medium containing only dimethyl sulfoxide (DMSO). The S6K1(Thr389) phosphorylation value for control cells treated with DMSO is set to 100%. The X-axis represents the Log10 molar (M) concentrations of the two compounds. [Figure 6A] This line graph shows the inhibition of S6K1(Thr389) phosphorylation in wild-type (WT) 293T cells with increasing compound concentration. Cells were treated over 2 hours with the following compounds: RAD001 (everolimus, dotted line and circle) and compound 50 (solid line and square). All treatments were performed in double cycles. The Y-axis shows the S6K1(Thr389) phosphorylation value calculated as a percentage (%) for control cells treated in medium containing only dimethyl sulfoxide (DMSO). The S6K1(Thr389) phosphorylation value for control cells treated with DMSO is set to 100%. The X-axis represents the concentrations of the two compounds. [Figure 6B]This line graph shows the inhibition of S6K1(Thr389) phosphorylation in FKBP12 knockout (KO) 293T cells with increasing compound concentrations. Cells were treated over 2 hours with the following compounds: RAD001 (everolimus, dotted line and circle) and compound 50 (solid line and square). All treatments were performed in double cycles. The Y-axis shows the S6K1(Thr389) phosphorylation value calculated as a percentage (%) for control cells treated in medium containing only dimethyl sulfoxide (DMSO). The S6K1(Thr389) phosphorylation value for control cells treated with DMSO is set to 100%. The X-axis represents the concentrations of the two compounds. [Figure 6C] This line graph shows the inhibition of S6K1(Thr389) phosphorylation in wild-type (WT) 293T cells with increasing compound concentration. Cells were treated over 2 hours with the following compounds: RAD001 (everolimus, dotted line and circle) and compound 51 (solid line and square). All treatments were performed in double cycles. The Y-axis shows the S6K1(Thr389) phosphorylation value calculated as a percentage (%) for control cells treated in medium containing only dimethyl sulfoxide (DMSO). The S6K1(Thr389) phosphorylation value for control cells treated with DMSO is set to 100%. The X-axis represents the concentrations of the two compounds. [Figure 6D] This line graph shows the inhibition of S6K1(Thr389) phosphorylation in FKBP12 knockout (KO) 293T cells with increasing compound concentrations. Cells were treated over 2 hours with the following compounds: RAD001 (everolimus, dotted line and circle) and compound 51 (solid line and square). All treatments were performed in double cycles. The Y-axis shows the S6K1(Thr389) phosphorylation value calculated as a percentage (%) for control cells treated in medium containing only dimethyl sulfoxide (DMSO). The S6K1(Thr389) phosphorylation value for control cells treated with DMSO is set to 100%. The X-axis represents the concentrations of the two compounds. [Figure 6E]This line graph shows the inhibition of S6K1(Thr389) phosphorylation in wild-type (WT) 293T cells with increasing compound concentration. Cells were treated over 2 hours with the following compounds: RAD001 (everolimus, dotted line and circle) and compound 52 (solid line and square). All treatments were performed in double cycles. The Y-axis shows the S6K1(Thr389) phosphorylation value calculated as a percentage (%) for control cells treated in medium containing only dimethyl sulfoxide (DMSO). The S6K1(Thr389) phosphorylation value for control cells treated with DMSO is set to 100%. The X-axis represents the concentrations of the two compounds. [Figure 6F] This line graph shows the inhibition of S6K1(Thr389) phosphorylation in FKBP12 knockout (KO) 293T cells with increasing compound concentrations. Cells were treated over 2 hours with the following compounds: RAD001 (everolimus, dotted line and circle) and compound 52 (solid line and square). All treatments were performed in double cycles. The Y-axis shows the S6K1(Thr389) phosphorylation value calculated as a percentage (%) for control cells treated in medium containing only dimethyl sulfoxide (DMSO). The S6K1(Thr389) phosphorylation value for control cells treated with DMSO is set to 100%. The X-axis represents the concentrations of the two compounds. [Figure 7A] This line graph shows the inhibition of S6K1(Thr389) phosphorylation in wild-type (WT) 293T cells with increasing compound concentrations. Cells were treated over 2 hours with the following compounds: RAD001 (everolimus, dotted line and circle) and compound 57 (solid line and square). All treatments were performed in double cycles. The Y-axis shows the S6K1(Thr389) phosphorylation value calculated as a percentage (%) for control cells treated in medium containing only dimethyl sulfoxide (DMSO). The S6K1(Thr389) phosphorylation value for control cells treated with DMSO is set to 100%. The X-axis represents the concentrations of the two compounds. [Figure 7B]This line graph shows the inhibition of S6K1(Thr389) phosphorylation in FKBP12 knockout (KO) 293T cells with increasing compound concentrations. Cells were treated over 2 hours with the following compounds: RAD001 (everolimus, dotted line and circle) and compound 57 (solid line and square). All treatments were performed in double cycles. The Y-axis shows the S6K1(Thr389) phosphorylation value calculated as a percentage (%) for control cells treated in medium containing only dimethyl sulfoxide (DMSO). The S6K1(Thr389) phosphorylation value for control cells treated with DMSO is set to 100%. The X-axis represents the concentrations of the two compounds. [Figure 7C] This line graph shows the inhibition of S6K1(Thr389) phosphorylation in wild-type (WT) 293T cells with increasing concentration of compound treatment. Cells were treated over 2 hours with the following compounds: RAD001 (everolimus, dotted line and circle) and compound 58 (solid line and square). All treatments were performed in double cycles. The Y-axis shows the S6K1(Thr389) phosphorylation value calculated as a percentage (%) for control cells treated in medium containing only dimethyl sulfoxide (DMSO). The S6K1(Thr389) phosphorylation value for control cells treated with DMSO is set to 100%. The X-axis represents the concentrations of the two compounds. [Figure 7D] This line graph shows the inhibition of S6K1(Thr389) phosphorylation in FKBP12 knockout (KO) 293T cells with increasing compound concentrations. Cells were treated over 2 hours with the following compounds: RAD001 (everolimus, dotted line and circle) and compound 58 (solid line and square). All treatments were performed in double cycles. The Y-axis shows the S6K1(Thr389) phosphorylation value calculated as a percentage (%) for control cells treated in medium containing only dimethyl sulfoxide (DMSO). The S6K1(Thr389) phosphorylation value for control cells treated with DMSO is set to 100%. The X-axis represents the concentrations of the two compounds. [Figure 7E]This line graph shows the inhibition of S6K1(Thr389) phosphorylation in wild-type (WT) 293T cells with increasing compound concentration. Cells were treated over 2 hours with the following compounds: RAD001 (everolimus, dotted line and circle) and compound 59 (solid line and square). All treatments were performed in double cycles. The Y-axis shows the S6K1(Thr389) phosphorylation value calculated as a percentage (%) for control cells treated in medium containing only dimethyl sulfoxide (DMSO). The S6K1(Thr389) phosphorylation value for control cells treated with DMSO is set to 100%. The X-axis represents the concentrations of the two compounds. [Figure 7F] This line graph shows the inhibition of S6K1(Thr389) phosphorylation in FKBP12 knockout (KO) 293T cells with increasing compound concentrations. Cells were treated over 2 hours with the following compounds: RAD001 (everolimus, dotted line and circle) and compound 59 (solid line and square). All treatments were performed in double cycles. The Y-axis shows the S6K1(Thr389) phosphorylation value calculated as a percentage (%) for control cells treated in medium containing only dimethyl sulfoxide (DMSO). The S6K1(Thr389) phosphorylation value for control cells treated with DMSO is set to 100%. The X-axis represents the concentrations of the two compounds. [Figure 8A] This line graph shows the inhibition of S6K1(Thr389) phosphorylation in wild-type (WT) 293T cells with increasing compound concentration. Cells were treated over 2 hours with the following compounds: RAD001 (everolimus, dotted line and circle) and compound 63 (solid line and square). All treatments were performed in double cycles. The Y-axis shows the S6K1(Thr389) phosphorylation value calculated as a percentage (%) for control cells treated in medium containing only dimethyl sulfoxide (DMSO). The S6K1(Thr389) phosphorylation value for control cells treated with DMSO is set to 100%. The X-axis represents the concentrations of the two compounds. [Figure 8B]This line graph shows the inhibition of S6K1(Thr389) phosphorylation in FKBP12 knockout (KO) 293T cells with increasing compound concentrations. Cells were treated over 2 hours with the following compounds: RAD001 (everolimus, dotted line and circle) and compound 63 (solid line and square). All treatments were performed in double cycles. The Y-axis shows the S6K1(Thr389) phosphorylation value calculated as a percentage (%) for control cells treated in medium containing only dimethyl sulfoxide (DMSO). The S6K1(Thr389) phosphorylation value for control cells treated with DMSO is set to 100%. The X-axis represents the concentrations of the two compounds. [Figure 9A] This line graph shows the inhibition of S6K1(Thr389) phosphorylation in wild-type (WT) 293T cells with increasing compound concentrations. Cells were treated over 2 hours with the following compounds: RAD001 (everolimus, dotted line and circle) and compound 69 (solid line and square). All treatments were performed in double cycles. The Y-axis shows the S6K1(Thr389) phosphorylation value calculated as a percentage (%) for control cells treated in medium containing only dimethyl sulfoxide (DMSO). The S6K1(Thr389) phosphorylation value for control cells treated with DMSO is set to 100%. The X-axis represents the concentrations of the two compounds. [Figure 9B] This line graph shows the inhibition of S6K1(Thr389) phosphorylation in FKBP12 knockout (KO) 293T cells with increasing compound concentrations. Cells were treated over 2 hours with the following compounds: RAD001 (everolimus, dotted line and circle) and compound 69 (solid line and square). All treatments were performed in double cycles. The Y-axis shows the S6K1(Thr389) phosphorylation value calculated as a percentage (%) for control cells treated in medium containing only dimethyl sulfoxide (DMSO). The S6K1(Thr389) phosphorylation value for control cells treated with DMSO is set to 100%. The X-axis represents the concentrations of the two compounds. [Figure 10A]This line graph shows the inhibition of S6K1(Thr389) phosphorylation in wild-type (WT) 293T cells with increasing compound concentration. Cells were treated over 2 hours with the following compounds: RAD001 (everolimus, dotted line and circle) and compound 72 (solid line and square). All treatments were performed in double cycles. The Y-axis shows the S6K1(Thr389) phosphorylation value calculated as a percentage (%) for control cells treated in medium containing only dimethyl sulfoxide (DMSO). The S6K1(Thr389) phosphorylation value for control cells treated with DMSO is set to 100%. The X-axis represents the concentrations of the two compounds. [Figure 10B] This line graph shows the inhibition of S6K1(Thr389) phosphorylation in FKBP12 knockout (KO) 293T cells with increasing compound concentrations. Cells were treated over 2 hours with the following compounds: RAD001 (everolimus, dotted line and circle) and compound 72 (solid line and square). All treatments were performed in double cycles. The Y-axis shows the S6K1(Thr389) phosphorylation value calculated as a percentage (%) for control cells treated in medium containing only dimethyl sulfoxide (DMSO). The S6K1(Thr389) phosphorylation value for control cells treated with DMSO is set to 100%. The X-axis represents the concentrations of the two compounds. [Figure 11A] This line graph shows the inhibition of S6K1(Thr389) phosphorylation in wild-type (WT) 293T cells with increasing concentration of compound treatment. Cells were treated over 2 hours with the following compounds: RAD001 (everolimus, dotted line and circle) and compound 73 (solid line and square). All treatments were performed in double cycles. The Y-axis shows the S6K1(Thr389) phosphorylation value calculated as a percentage (%) for control cells treated in medium with dimethyl sulfoxide (DMSO) alone. The S6K1(Thr389) phosphorylation value for control cells treated with DMSO is set to 100%. The X-axis represents the concentrations of the two compounds. [Figure 11B]This line graph shows the inhibition of S6K1(Thr389) phosphorylation in FKBP12 knockout (KO) 293T cells with increasing compound concentrations. Cells were treated over 2 hours with the following compounds: RAD001 (everolimus, dotted line and circle) and compound 73 (solid line and square). All treatments were performed in double cycles. The Y-axis shows the S6K1(Thr389) phosphorylation value calculated as a percentage (%) for control cells treated in medium containing only dimethyl sulfoxide (DMSO). The S6K1(Thr389) phosphorylation value for control cells treated with DMSO is set to 100%. The X-axis represents the concentrations of the two compounds. [Figure 12A] This graph shows the mouse plasma pharmacokinetic profiles of the control compound RAD001 after IV (2 mg / kg) and PO (10 mg / kg) administration. The Y-axis, set to a log10 scale, represents the plasma compound concentration (ng / ml). The X-axis represents the time (hour) at which plasma was collected after compound administration. [Figure 12B] This graph shows the mouse plasma pharmacokinetic profiles of compound 26 after IV (2 mg / kg) and PO (20 mg / kg) administration. The Y-axis, set to a log10 scale, represents the plasma compound concentration (ng / ml). The X-axis represents the time (hour) at which plasma was collected after compound administration. [Figure 12C] This graph shows the mouse plasma pharmacokinetic profiles of compound 45 after IV (2 mg / kg) and PO (20 mg / kg) administration. The Y-axis, set to a log10 scale, represents the plasma compound concentration (ng / ml). The X-axis represents the time (hour) at which plasma was collected after compound administration. [Figure 12D] This graph shows the mouse plasma pharmacokinetic profiles of compound 69 after IV (2 mg / kg) and PO (20 mg / kg) administration. The Y-axis, set to a log10 scale, represents the plasma compound concentration (ng / ml). The X-axis represents the time (hour) at which plasma was collected after compound administration.

[0060] The data shown in Figures 12A to 12D regarding the pharmacokinetic studies of selected compounds in mice are further summarized in Table 4, which is provided in the detailed explanation below. [Modes for carrying out the invention]

[0061] definition

[0062] When referring to the compounds provided herein, unless otherwise specified, the following terms have the following meanings. Unless otherwise specified, all technical and scientific terms used herein have the same meanings as those commonly understood by those skilled in the art. If there are multiple definitions for a term provided herein, unless otherwise specified, the definition herein shall prevail.

[0063] As used herein, “alkyl” refers to a monovalent and saturated hydrocarbon radical moiety. Alkyls are optionally substituted and may be linear, branched, or cyclic (i.e., cycloalkyl). Alkyls are radicals having 1 to 20 carbon atoms, for example, C 1-20 Alkyl radicals, radicals having 1 to 12 carbon atoms, for example, C 1-12 Alkyl radicals, radicals having 1 to 8 carbon atoms, for example, C 1-8 Alkyl radicals, radicals having 1 to 6 carbon atoms, for example, C 1-6 Alkyl and radicals having 1 to 3 carbon atoms, for example, C 1-3 Examples of alkyl moieties include, but are not limited to, alkyl. Examples of alkyl moieties include, but are not limited to, methyl, ethyl, n-propyl, i-propyl, n-butyl, s-butyl, t-butyl, i-butyl, pentyl moieties, hexyl moieties, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. Examples of pentyl moieties include, but are not limited to, n-pentyl and i-pentyl. Examples of hexyl moieties include, but are not limited to, n-hexyl.

[0064] As used herein, “haloalkyl” means an alkyl as defined herein, which comprises at least one substituent selected from halogens, e.g., F, Cl, Br, or I.

[0065] As used herein, “hydroxyalkyl” means an alkyl group as defined herein, which comprises at least one hydroxyl group.

[0066] As used herein, “alkylene” refers to a divalent alkyl group. Unless otherwise specified, alkylenes include, but are not limited to, 1 to 20 carbon atoms. The alkylene group is optionally substituted for alkyl groups as described herein. In some embodiments, the alkylene is not substituted. Examples of alkylene moieties include, but are not limited to, -CH2-, -CH2CH2-, -CH2CH2CH2-, -CH2CH2CH2CH2-, etc.

[0067] The designation of an amino acid or amino acid residue without stereochemical specification is intended to encompass the L-form of an amino acid or amino acid residue, the D-form of an amino acid or amino acid residue, or a racemic mixture thereof.

[0068] As used herein, “alkoxy” refers to a monovalent and saturated hydrocarbon radical moiety, where the hydrocarbon contains a single bond to an oxygen atom, and the radical is localized on an oxygen atom, e.g., CH3CH2-O- in the case of ethoxy. Alkoxy substituents are bonded to the compound they substitute by this oxygen atom of the alkoxy substituent. Alkoxys are optionally substituted and can be linear, branched, or cyclic, e.g., cycloalkoxys. Alkoxys can also be radicals having 1 to 20 carbon atoms, e.g., C 1-20 Alkoxy radicals, radicals having 1 to 12 carbon atoms, for example, C 1-12 Alkoxy radicals, radicals having 1 to 8 carbon atoms, for example, C 1-8 Alkoxy radicals, radicals having 1 to 6 carbon atoms, for example, C 1-6Alkoxy compounds, and radicals having 1 to 3 carbon atoms, for example, C 1-30 Examples of alkoxy moieties include, but are not limited to, methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, s-butoxy, t-butoxy, i-butoxy, pentoxy moieties, hexoxy moieties, cyclopropoxy, cyclobutoxy, cyclopentoxy, and cyclohexaoxy.

[0069] As used herein, “haloalkoxy” means an alkoxy as defined herein, in which the hydrocarbon is substituted with at least one halogen, e.g., F, Cl, Br, or I.

[0070] As used herein, “aryl” refers to a monovalent C5-C5 compound containing at least one aromatic ring. 15 This refers to a cyclic aryl system, which can be monocyclic, bicyclic, or tricyclic. The aryl can be attached to the main structure via its ring, i.e., any aromatic or non-aromatic ring. In some or any embodiment, the aryl group can be crosslinked (where chemically feasible) or uncrosslinked, spirocyclic (where chemically feasible) or non-spirocyclic, and / or condensed or uncondensed polycyclic groups. In some or any embodiment, the aryl can be phenyl, naphthyl, bicyclo[4.2.0]octa-1,3,5-trienyl, indanyl, fluorenyl, 6,7,8,9-tetrahydro-5H-benzo[7]anurenyl,

[0071] [ka] or tetrahydronaphthyl. If substituted, the aryl can be substituted on any ring, i.e., any aromatic or non-aromatic ring contained in the aryl. In some or any embodiment, the aryl is phenyl, naphthyl, tetrahydronaphthyl, fluorenyl, 6,7,8,9-tetrahydro-5H-benzo[7]anurenyl, or indanyl.

[0072] As used herein, "heteroaryl" refers to a monocyclic or polycyclic aromatic ring system in which one or more (in some or any embodiment, 1, 2, 3, or 4) ring atoms are independently O, S(O) 0-2 The heteroaryl group is a heteroatom selected from NH and N, the remaining ring atom is a carbon atom, and the ring may be optionally substituted as described herein. The heteroaryl group is bonded to the rest of the molecule by any atom in the ring system, where the rules of valence allow. In certain embodiments, each ring of the heteroaryl group may contain one or two O atoms, one or two S atoms, and / or one to four N atoms, or a combination thereof, provided that the total number of heteroatoms in each ring is four or less, and each ring contains at least one carbon atom. In certain embodiments, the heteroaryl has 5 to 20, 5 to 15, or 5 to 10 ring atoms. If the heteroaryl is substituted, substitution may occur on any of the rings. In some embodiments, heteroaryls include, but are not limited to, furanyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, thienyl, pyridinyl, pyrimidinyl, pyridadinyl, pyrazinyl, indolyl, quinolinyl, isoquinolinyl, oxazolyl, isoxazolyl, thienopyridinyl, thienopyridinyl, azaindolyl, etc. In some embodiments, heteroaryls are,

[0073] [ka] And in the formula,

[0074] [ka] The symbol indicates the binding site of the heteroaryl to the remainder of the molecule. In some embodiments, when a heteroaryl is substituted with one or more hydroxyls, it can be named or depicted as either a keto or enol tautomer. For example, 2,4(1H,3H)-dioxopyrimidinyl, 2,4-dihydroxypyrimidinyl, 2(1H)-oxo-4-hydroxypyrimidinyl, 4-hydroxy-2(3H)-oxopyrimidinyl, and 2-hydroxy-4(3H)-oxopyrimidinyl are within the range of heteroaryls when substituted with two hydroxyls. In some embodiments, the "heteroaryl" is N-linked.

[0075] In certain embodiments, monocyclic heteroaryl groups include, but are not limited to, furanyl, imidazolyl, isothiazolyl, isoxazolyl, oxadiazolyl, oxadiazolyl, oxazolyl, pyrazinyl, pyrazolyl, pyridyl, pyrimidinyl, pyrrolyl, thiadiazolyl, thiazolyl, thienyl, tetrazolyl, triazinyl, and triazolyl. In certain embodiments, bicyclic heteroaryl groups include, but are not limited to, benzofuranil, benzimidazolyl, benzoisoxazolyl, benzopyranil, benzothiadiazolyl, benzothiazolyl, benzothienyl, benzotriazolyl, benzoxazolyl, phlopyridyl, imidazopyridinyl, imidazothiazolyl, indolidinyl, indazolyl, isobenzofuranil, isobenzothienyl, isoindolyl, isoquinolinyl, isothiazolyl, naphthilidinyl, oxazolopyridinyl, phthalazinyl, pteridinyl, purinyl, pyridopyridyl, pyrrolopyridyl, quinolinyl, quinoxalinyl, quinazolinyl, thiadiazolopyrimidinyl, and thienopyridyl. In certain embodiments, the tricyclic heteroaryl group includes, but is not limited to, acridinyl, benzindolyl, carbazolyl, dibenzofuranyl, perimidinyl, phenanthrolinyl, phenanthridinel, and phenazinyl. In some or any of embodiments, the heteroaryl is indolyl, furanyl, pyridinyl, pyrimidinyl, imidazolyl, or pyrazolyl, each of which, in some embodiments, is independently C 1-6 Alkyl, hydroxy, halo, halo-C 1-6 Alkyl, C 1-6 The group is optionally substituted with one, two, three, or four groups as defined throughout this specification, including a group selected from alkoxy, cyano, or phenyl.

[0076] As used herein, “heterocycloalkyl” or “heterocyclyl” refers to a monovalent, monocyclic non-aromatic ring system, and / or a polycyclic ring system containing at least one non-aromatic ring, where one or more (in some or any embodiment, 1, 2, 3, or 4) non-aromatic monocyclic ring atoms are independently O, S(O) 0-2 A heteroatom selected from , and N, the remaining ring atoms are carbon atoms, and one or more (in some or any embodiment, 1, 2, 3, or 4) of the ring atoms in the polycyclic ring system are independently O, S(O) 0-2 The heteroatoms are selected from nitrogen and oxygen, and the remaining ring atoms are carbon. The term “heterocyclic” does not include fully aromatic rings, i.e., imidazoles, pyrimidines, pyridines, etc. In some or any embodiment, the heterocyclic ring contains one or two heteroatoms independently selected from nitrogen and oxygen. In some or any embodiment, the heterocyclic ring contains oxygen as one or two heteroatoms. In some or any embodiment, the heterocyclic ring contains nitrogen as one or two heteroatoms (the nitrogen is substituted as described in any aspect or embodiment described herein). In some or any embodiment, the heterocyclic is polycyclic and contains one heteroatom in the non-aromatic ring, one heteroatom in the aromatic ring, two heteroatoms in the aromatic ring, or two heteroatoms, one in the aromatic ring and the other in the non-aromatic ring. In some or any of the embodiments, the heterocyclic group has 3 to 20, 3 to 15, 3 to 10, 3 to 8, 4 to 7, or 5 to 6 ring atoms. In some or any of the embodiments, the heterocyclic group is a monocyclic, bicyclic, tricyclic, or tetracyclic ring system. In some or any of the embodiments, the heterocyclic group may be a bridged or unbridged, spirocyclic or non-spirocyclic, and / or fused or unfused polycyclic group. One or more of the nitrogen and sulfur atoms may be optionally oxidized, one or more of the nitrogen atoms may be optionally quaternized, and one or more of the carbon atoms may be

[0077] [ka] They may be optionally substituted. Some rings may be partially or completely saturated, or aromatic if the heterocycle is not completely aromatic. Monocyclic and polycyclic heterocyclic rings may be bonded to the main structure at any heteroatom or carbon atom that results in a stable compound. Polycyclic heterocycles may be bonded to the main structure via any ring, including any aromatic or non-aromatic ring, whether the ring contains a heteroatom or not. In some or any embodiment, the heterocycle is a "heterocycloalkyl" which is 1) a saturated or partially unsaturated (non-aromatic) monocyclic group containing at least one ring heteroatom as described herein, or 2) a saturated or partially unsaturated (non-aromatic) monocyclic or tricyclic group in which at least one ring contains at least one heteroatom as described herein. When heterocycles and heterocycloalkyls are substituted, they may be substituted on any ring, i.e., any aromatic or non-aromatic ring contained in heterocycles and heterocycloalkyls. In some or any embodiment, such heterocycles include azepinyl, benzodioxanyl, benzodioxolyl, 3,4-dihydro-2H-benzo[b][1,4]oxazinyl, 3,4-dihydro-2H-benzo[b][1,4]dioxepinyl, 1,3-dihydroisobenzofuranyl, benzofuranol, benzopyranonyl, benzopyranyl, dihydrobenzofuranyl,

[0078] [ka] Benzotetrahydrothienyl, 2,2-dioxo-1,3-dihydrobenzo[c]thienyl, benzothiopyranil, benzoxazinyl, β-carbonyl, chromanil, chromonil, sinnolinil, coumarinil, decahydroquinolinil, decahydroisoquinolinil, dihydrobenzisothiadinyl, dihydrobenzisoxazinyl, dihydrofuranil, dihydroisoindolyl, dihydropyranil, dihydropyrazolyl, dihydropyrazinyl, dihydropyridinyl, dihydro Dropyrimidinyl, dihydropyrrolyl, dioxolanil, 1,4-dithianil, furanol, imidazolidinyl, 2,4-dioxo-imidazolidinyl, imidazolinyl, indolinyl, 2-oxo-indolinyl, isobenzotetrahydrofuranil, isobenzotetrahydrothienyl, isochromanil, isocumalinil, isoindolinyl, 1-oxo-isoindolinyl, 1,3-dioxo-isoindolinyl, isothiazolidinyl, isoxazolidinyl, 3-oxo -Isoxazolidinyl, Morpholinyl, 3,5-Dioxo-morpholinyl, Octahydroindolyl, Octahydroisoindolyl, 1-Oxo-Octahydroisoindolyl, 1,3-Dioxo-Hexahydroisoindolyl, Oxazolidinyl, Oxazolidinyl, Oxiranil, Piperadinyl, 2,6-Dioxo-piperazinyl, Piperidinyl, 2,6-Dioxo-piperidinyl, 4-Piperidonyl, Pyrazolidinyl, Pyrazolinyl, Pyrrolidinyl, Pyrrolidinyl, Examples include, but are not limited to, 2-oxopyrrolidinyl, 2,5-dioxopyrrolidinyl, quinuclidinyl, tetrahydrofuryl, tetrahydroisoquinolinyl, tetrahydropyranil, tetrahydrothienyl, thiamorpholinyl, thiomorpholinyl, 3,5-dioxo-thiomorpholinyl, thiazolidinyl, 2,4-dioxo-thiazolidinyl, tetrahydroquinolinyl, phenothiazinyl, phenoxadinyl, xanthenyl, and 1,3,5-trithianyl.In some or any of the embodiments, the heterocycle is benzo-1,4-dioxanyl, benzodioxolyl, indolinyl, 2-oxo-indolinyl, pyrrolidinyl, piperidinyl, 2,3-dihydrobenzofuranyl, or decahydroquinolinyl, each of which is optionally substituted with one, two, three, or four groups as defined throughout this Spec, each independently comprising a group selected from halo, alkyl, and phenyl in some or any of the embodiments. In some embodiments, the heterocycloalkyl is pyrrolidinyl.

[0079] As used herein, "cyano" refers to -CN.

[0080] The term "oxo," as used herein and unless otherwise specified, refers to a keto group (C=O). An oxo group that is a substituent on a non-aromatic carbon results in a conversion from -CH2- to -C=O. An oxo group that is a substituent on an aromatic group results in a conversion from -CH- to -C=O. When the substituent is oxo, two hydrogen atoms on the atom are replaced. When the oxo group substitutes an aromatic moiety, the corresponding partially unsaturated ring replaces the aromatic ring. For example, a pyridyl group substituted by an oxo group is pyridone. Those skilled in the art will recognize that in one embodiment such groups, e.g., pyridone and 2,4(1H,3H)-dioxopyrimidinyl, may exist in tautomerized forms, e.g., hydroxypyridine and 2,4-dihydroxypyrimidinyl, respectively.

[0081] As used herein, “optionally substituted” means that, when used to describe a radical moiety, for example an optionally substituted alkyl, such moiety is optionally bonded to one or more substituents. Examples of such substituents include halo, cyano, nitro, amino, hydroxyl, optionally substituted haloalkyl, aminoalkyl, hydroxyalkyl, azide, epoxy, optionally substituted heteroaryl, optionally substituted heterocycloalkyl,

[0082] [ka] Examples include, but are not limited to, in the formula, R A , R B , and R C Independently, each instance of appearance is hydrogen, alkyl, alkenyl, alkynyl, aryl, alkylaryl, arylalkyl, heteroalkyl, heteroaryl, or heterocycloalkyl, or R A and R B These groups, together with the atoms to which they bond, form a saturated or unsaturated carbocyclic ring, which is optionally substituted, and one or more ring atoms are optionally replaced by heteroatoms. In certain embodiments, when the radical moiety is optionally substituted with an optionally substituted heteroaryl, optionally substituted heterocycloalkyl, or optionally substituted saturated or unsaturated carbocyclic ring, the substituents on the optionally substituted heteroaryl, optionally substituted heterocycloalkyl, or optionally substituted saturated or unsaturated carbocyclic ring are not substituted with substituents that, if substituted, are optionally substituted with additional substituents. In some embodiments, when the groups described herein are optionally substituted, substituents bonded to the groups are not substituted unless otherwise specified.

[0083] As used herein, the term “epimer” refers to one of a pair of diastereomers having opposite configurations in at least one of two stereocenters or chiral centers. For example, a compound of formula (I), (Ia), (Ib), or (Ic) having (R)-stereochemistry at the C-16 position is an epimer of the corresponding compound having (S)-stereochemistry.

[0084] As used herein, “diastereomer excess (de)” refers to a dimensionless molar ratio that describes the purity of a chiral substance with more than one stereocenter. For example, a diastereomer excess of 0 indicates an equimolar mixture of diastereoisomers. As a further example, a diastereomer excess of 99 indicates a nearly stereochemically pure diastereomer compound (i.e., one diastereomer is in greater excess than the other). Diastereomer excess can be calculated in a manner similar to that of ee. As those skilled in the art will understand, de is usually reported as de percent (%de). %de can be calculated in a manner similar to that of %ee.

[0085] As used herein, “therapeutic dose” means an amount (e.g., of a compound) sufficient to provide a therapeutic benefit to a patient in the treatment or management of a disease or disorder, or to slow or minimize one or more symptoms associated with the disease or disorder.

[0086] A particular group, subgroup, substituent, and atom is represented with one or more bonds and intersecting wavy lines to indicate the atoms that bond that group, subgroup, substituent, or atom. For example,

[0087] [ka] or

[0088] [ka] The phenyl group substituted with a propyl group, represented as follows:

[0089] [ka] It has. When used herein, examples of substituents attached to cyclic groups (e.g., aromatic, heteroaromatic, fused rings, and saturated or unsaturated cycloalkyl or heterocycloalkyl groups) by inter-ring atom bonds are intended, unless otherwise specified, to show that the cyclic group may be substituted with substituents at any ring position of the cyclic group or on any ring of a fused ring group, in accordance with techniques shown herein or known in the art to which this disclosure belongs. For example, the group

[0090] [ka] (In the formula, the subscript q is an integer between 0 and 2, and the position of substituent R2a is described generically, for example, not bonded to any vertices of the bond line structure, e.g., ring carbon atoms) is below, substituent R 2a This includes non-restrictive examples of groups that are bonded to specific ring carbon atoms.

[0091] [ka]

[0092] FKB12-selective rapamycin analog

[0093] As used herein, “FKBP12 selective” refers to the requirement of FKBP12 in the inhibition of mTORC1 phosphorylation of S6K1, as shown in Figure 1C. Compound 45 can inhibit S6K1 phosphorylation in the presence of FKBP12. However, when FKBP12 is knocked out, compound 45 inhibits S6K1 phosphorylation considerably less than RAD001, i.e., a rapalog that can function through other FKBPs.

[0094] Alternatively, “FKBP12 Selective Rapalog” is a rapalog, but it is potent in assays using wild-type cells, while its potency is approximately 10 to 1000 times lower than RAD001 in cell lines that do not express FKBP12 (e.g., FKBP12 knockout cells). In this context, “potency” can be expressed as the concentration of the rapalog required to achieve 20% inhibition of S6K1(Thr389) phosphorylation in cell-based assays, such as those used in Example 3 and Figures 1 to 11. For example, a rapalog is considered FKBP12 selective if it inhibits S6K1(Thr389) phosphorylation by approximately 20% in an assay using an FKBP12 knockout cell line that exhibits at least 20-fold (e.g., 20x, 30x, 50x, 100x, 200x, 500x, 1000x, etc.) lower potency compared to a similar level of inhibition achieved by RAD001 in the same assay using the same cell line that normally expresses FKBP12.

[0095] Alternatively, “FKBP12 Selective Rapalog” is a rapalog, but it is potent in assays using wild-type cells, while its potency is approximately 10 to 1000 times lower than RAD001 in cell lines that do not express FKBP12 (e.g., FKBP12 knockout cells). In this context, “potency” can be expressed as the concentration of the rapalog required to achieve 30% inhibition of S6K1(Thr389) phosphorylation in cell-based assays, such as those used in Example 3 and Figures 1 to 11. For example, a rapalog is considered FKBP12 selective if it inhibits S6K1(Thr389) phosphorylation by approximately 30% in an assay using an FKBP12 knockout cell line that exhibits at least 20-fold (e.g., 20-fold, 30-fold, 50-fold, 100-fold, 200-fold, 500-fold, 1000-fold, etc.) lower potency compared to a similar level of inhibition achieved by RAD001 in the same assay using the same cell line that normally expresses FKBP12.

[0096] In one embodiment, the compound of formula (I) is of formula (PI)

[0097] [ka] A compound of or a pharmaceutically acceptable salt thereof, In the formula, R 1 is hydrogen, C 1-6 Alkyl, heterocyclyl, aryl, heteroaryl, -C 0-6 Alkylene-SO2R 4 , or -C 0-6 Alkylene-SO2R 5 Heterocyclyl, aryl, and heteroaryl compounds have 1 or 2 R 1a It is optionally substituted in the base, R 2 These are heterocyclyl, aryl, heteroaryl, -C 0-6 Alkylene-SO2R 4 , or -C 0-6 Alkylene-SO2R 5 Heterocyclyl, aryl, and heteroaryl compounds have 1 or 2 R 2a It is optionally substituted in the base, Or R 1 and R 2 It forms an N-linked heteroaryl molecule by integrating with the bonded nitrogen atom. R 3 is -OR a Selected from the group consisting of 3-6 member heterocyclyls and 3-6 member heteroaryls, R a H, -P(O)(R b )2, -C(O)R c , -C(O)OR c , C 1-6 Alkyl, and C 1-6 Selected from the group consisting of hydroxyalkyl groups, R b These are H and C, respectively, independently. 1-6 Selected from the group consisting of alkyl groups, R c H, C 1-6 Alkyl, and C 1-6 Selected from the group consisting of hydroxyalkyl groups, R 4 C 2-6 Alkyl, C3-6 Cycloalkyl, C 1-6 A hydroxyalkyl, heterocyclyl, aryl, or heteroaryl, where heterocyclyl, aryl, and heteroaryl have 1 or 2 R 4a It is optionally substituted in the base, R 5 A heterocyclyl, aryl, or heteroaryl is a heterocyclyl, aryl, and heteroaryl, which have one or two R 5a It is optionally substituted in the base, 1 or 2 R 1a Group, R 2a Group, R 4a base, and R 5a Each of the elements, if present, independently of C 1-6 Alkyl, C 1-6 Hydroxyalkyl, hydroxy, halo, C 1-6 Haloalkyl and C 1-6 Selected from alkoxys, or any two R 1a Group, R 2a Group, R 4a base, and R 5a When the groups are located on the same carbon, they combine to form an oxo group. R 1 When R is hydrogen, 2 is -C 0-6 Alkylene-SO2R 4 isn't it.

[0098] In one embodiment, the compound of formula (Ia) is formula (P-Ia)

[0099] [ka] A compound of or a pharmaceutically acceptable salt thereof, In the formula, R 1 is hydrogen or C 1-6 It is alkyl, R 2 is 1 or 2 R 2a A heterocyclyl, aryl, or heteroaryl that is optionally substituted with a base, R3 is -OR a Selected from the group consisting of 3-6 member heterocyclyls and 3-6 member heteroaryls, R a H, -P(O)(R b )2, -C(O)R c , -C(O)OR c , C 1-6 Alkyl, and C 1-6 Selected from the group consisting of hydroxyalkyl groups, R b These are H and C, respectively, independently. 1-6 Selected from the group consisting of alkyl groups, R c H, C 1-6 Alkyl, and C 1-6 Selected from the group consisting of hydroxyalkyl groups, 1 or 2 R 2a Each of the elements, if present, independently of C 1-6 Alkyl, C 1-6 Hydroxyalkyl, hydroxy, halo, C 1-6 Haloalkyl and C 1-6 Selected from alkoxys, or any two R 2a When the groups are located on the same carbon atom, they combine to form an oxo group.

[0100] In one embodiment, the compound of formula (Ib) is (P-Ib)

[0101] [ka] A compound of or a pharmaceutically acceptable salt thereof, In the formula, R 1 and R 2 It, together with the bonded nitrogen, forms one or two R 1a Forms an N-linked heteroaryl with optional substitution of the base, R 3 is -OR a Selected from the group consisting of 3-6 member heterocyclyls and 3-6 member heteroaryls, Ra H, -P(O)(R b )2, -C(O)R c , -C(O)OR c , C 1-6 Alkyl, and C 1-6 Selected from the group consisting of hydroxyalkyl groups, R b These are H and C, respectively, independently. 1-6 Selected from the group consisting of alkyl groups, R c H, C 1-6 Alkyl, and C 1-6 Selected from the group consisting of hydroxyalkyl groups, 1 or 2 R 1a Each of the elements, if present, independently of C 1-6 Alkyl, C 1-6 Hydroxyalkyl, hydroxy, halo, C 1-6 Haloalkyl and C 1-6 Selected from alkoxys, or two R 1a When the groups are located on the same carbon atom, they combine to form an oxo group.

[0102] In one embodiment, the compound of formula (Ic) is of formula (P-Ic)

[0103] [ka] A compound of or a pharmaceutically acceptable salt thereof, In the formula, R 1 is hydrogen or C 1-6 It is alkyl, R 2 is -C 0-6 Alkylene-SO2R 4 or -C 0-6 Alkylene-SO2R 5 And, R 3 is -OR a Selected from the group consisting of 3-6 member heterocyclyls and 3-6 member heteroaryls, R a H, -P(O)(R b)2, -C(O)R c , -C(O)OR c , C 1-6 Alkyl, and C 1-6 Selected from the group consisting of hydroxyalkyl groups, R b These are H and C, respectively, independently. 1-6 Selected from the group consisting of alkyl groups, R c H, C 1-6 Alkyl, and C 1-6 Selected from the group consisting of hydroxyalkyl groups, R 4 C 2-6 Alkyl, C 3-6 Cycloalkyl, C 1-6 A hydroxyalkyl, heterocyclyl, aryl, or heteroaryl, where heterocyclyl, aryl, and heteroaryl have 1 or 2 R 4a It is optionally substituted in the base, R 5 A heterocyclyl, aryl, or heteroaryl is a heterocyclyl, aryl, and heteroaryl, which have one or two R 5a It is optionally substituted in the base, 1 or 2 R 4a base and R 5a Each of the elements, if present, independently of C 1-6 Alkyl, C 1-6 Hydroxyalkyl, hydroxy, halo, C 1-6 Haloalkyl and C 1-6 Selected from alkoxys, or any two R 4a base and R 5a When the groups are located on the same carbon, they combine to form an oxo group. R 1 When R is hydrogen, 2 is -C 0-6 Alkylene-SO2R 4 isn't it.

[0104] In one embodiment, the compound of formula (I) is of formula (P-2)

[0105] [ka] A compound of or a pharmaceutically acceptable salt thereof, In the formula, R 1 is hydrogen, C 1-6 Alkyl, heterocyclyl, aryl, heteroaryl, -C 0-6 Alkylene-SO2R 4 , or -C 0-6 Alkylene-SO2R 5 Heterocyclyl, aryl, and heteroaryl compounds have 1 or 2 R 1a It is optionally substituted in the base, R 2 These are heterocyclyl, aryl, heteroaryl, -C 0-6 Alkylene-SO2R 4 , or -C 0-6 Alkylene-SO2R 5 Heterocyclyl, aryl, and heteroaryl compounds have 1 or 2 R 2a It is optionally substituted in the base, Or R 1 and R 2 It, together with the bonded nitrogen, forms one or two R 1a Forms an N-linked heteroaryl or N-linked heterocycline which is optionally substituted with a group, R 3 is -OR a Selected from the group consisting of 3-6 member heterocyclyls and 3-6 member heteroaryls, R a H, -P(O)(R b )2, -C(O)R c , -C(O)OR c , C 1-6 Alkyl, and C 1-6 Selected from the group consisting of hydroxyalkyl groups, R b These are H and C, respectively, independently. 1-6 Selected from the group consisting of alkyl groups, R c H, C 1-6 Alkyl, and C 1-6Selected from the group consisting of hydroxyalkyl groups, R 4 C 2-6 Alkyl, C 3-6 Cycloalkyl, C 1-6 A hydroxyalkyl, heterocyclyl, aryl, or heteroaryl, where heterocyclyl, aryl, and heteroaryl have 1 or 2 R 4a It is optionally substituted in the base, R 5 A heterocyclyl, aryl, or heteroaryl is a heterocyclyl, aryl, and heteroaryl, which have one or two R 5a It is optionally substituted in the base, 1 or 2 R 1a Group, R 2a Group, R 4a base, and R 5a Each of the elements, if present, independently of C 1-6 Alkyl, C 1-6 Hydroxyalkyl, hydroxy, halo, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Selected from haloalkoxys and cyanos, or any two Rs 1a Group, R 2a Group, R 4a base, and R 5a When the groups are located on the same carbon, they combine to form an oxo group. R 1 When R is hydrogen, 2 is -C 0-6 Alkylene-SO2R 4 isn't it.

[0106] In one embodiment of formula (I), (Ia)~(Ic), (P-1), (P-2), or (P-Ia)~(P-Ic), R 3 は-OR a In one embodiment of equation (I), (Ia)~(Ic), (P-1), (P-2), or (P-Ia)~(P-Ic), R 3is -OH. In one embodiment of formula (I), (Ia)~(Ic), (P-1), (P-2), or (P-Ia)~(P-Ic), R 3 is -OP(O)(R b )2. In one embodiment of equation (I), (Ia)~(Ic), (P-1), (P-2), or (P-Ia)~(P-Ic), R 3 is -OP(O)H2. In one embodiment of formula (I), (Ia)~(Ic), (P-1), (P-2), or (P-Ia)~(P-Ic), R 3 is -OP(O)(C 1-6 Alkyl)2. In one embodiment of formula (I), (Ia)~(Ic), (P-1), (P-2), or (P-Ia)~(P-Ic), R 3 is -OP(O)(Me)2. In one embodiment of equation (I), (Ia)~(Ic), (P-1), (P-2), or (P-Ia)~(P-Ic), R 3 is -OP(O)(C 1-6 Alkyl)(H). In one embodiment of formula (I), (Ia)~(Ic), (P-1), (P-2), or (P-Ia)~(P-Ic), R 3 is -OP(O)(Me)(H). In one embodiment of equation (I), (Ia)~(Ic), (P-1), (P-2), or (P-Ia)~(P-Ic), R 3 -C(O)R c In one embodiment of equation (I), (Ia)~(Ic), (P-1), (P-2), or (P-Ia)~(P-Ic), R 3 is -C(O)H. In one embodiment of formula (I), (Ia)~(Ic), (P-1), (P-2), or (P-Ia)~(P-Ic), R 3 is -C(O)C 1-6 It is alkyl. In one embodiment of formula (I), (Ia)~(Ic), (P-1), (P-2), or (P-Ia)~(P-Ic), R 3 is -C(O)C 1-6 It is a hydroxyalkyl compound. In one embodiment of formula (I), (Ia) to (Ic), (P-1), (P-2), or (P-Ia) to (P-Ic), R 3 is -C(O)OR cIn one embodiment of equation (I), (Ia)~(Ic), (P-1), (P-2), or (P-Ia)~(P-Ic), R 3 is -COOH. In one embodiment of formula (I), (Ia)~(Ic), (P-1), (P-2), or (P-Ia)~(P-Ic), R 3 -C(O)OC 1-6 It is alkyl. In one embodiment of formula (I), (Ia)~(Ic), (P-1), (P-2), or (P-Ia)~(P-Ic), R 3 -C(O)OC 1-6 It is a hydroxyalkyl compound. In one embodiment of formula (I), (Ia) to (Ic), (P-1), (P-2), or (P-Ia) to (P-Ic), R 3 ha-OC 1-6 It is alkyl. In one embodiment of formula (I), (Ia)~(Ic), (P-1), (P-2), or (P-Ia)~(P-Ic), R 3 ha-OC 1-6 It is a hydroxyalkyl group.

[0107] In one embodiment of formula (I), (Ia)~(Ic), (P-1), (P-2), or (P-Ia)~(P-Ic), R 3 is a 3-6 member heterocyclyl. In one embodiment of formula (I), (Ia)~(Ic), (P-1), (P-2), or (P-Ia)~(P-Ic), R 3 R is a 3- to 6-membered heterocycline containing 1, 2, or 3 atoms selected from nitrogen, oxygen, and sulfur. In one embodiment of formula (I), (Ia) to (Ic), (P-1), (P-2), or (P-Ia) to (P-Ic), R 3 R is a 3-6 member heterocycline containing one nitrogen atom. In one embodiment of formula (I), (Ia)-(Ic), (P-1), (P-2), or (P-Ia)-(P-Ic), R 3 It is a 3- to 6-membered heterocycline containing 2 or 3 nitrogen atoms.

[0108] In one embodiment of formula (I), (Ia)~(Ic), (P-1), (P-2), or (P-Ia)~(P-Ic), R3 R is a 3-6 member heteroaryl. In one embodiment of formula (I), (Ia)-(Ic), (P-1), (P-2), or (P-Ia)-(P-Ic), R 3 R is a 3- to 6-membered heteroaryl containing 1, 2, 3, or 4 atoms selected from nitrogen, oxygen, and sulfur atoms. In one embodiment of formula (I), (Ia) to (Ic), (P-1), (P-2), or (P-Ia) to (P-Ic), R 3 R is a 3-6 member heteroaryl containing one nitrogen atom. In one embodiment of formula (I), (Ia)-(Ic), (P-1), (P-2), or (P-Ia)-(P-Ic), R 3 R is a 3- to 6-membered heteroaryl containing 2 or 3 nitrogen atoms. In one embodiment of formula (I), (Ia) to (Ic), (P-1), (P-2), or (P-Ia) to (P-Ic), R 3 R is a 3- to 6-membered heteroaryl containing 4 nitrogen atoms. In one embodiment of formula (I), (Ia) to (Ic), (P-1), (P-2), or (P-Ia) to (P-Ic), R 3 is a tetrazole or triazole. In one embodiment of formula (I), (Ia) to (Ic), (P-1), (P-2), or (P-Ia) to (P-Ic), R 3 teeth,

[0109] [ka] And in the formula,

[0110] [ka] This is a bonding site to the remainder of the compound.

[0111] In one embodiment of formulas (I), (Ia)~(Ic), (P-1), (P-2), or (P-Ia)~(P-Ic), including any of the above, R 1is hydrogen. In one embodiment of formula (I), (Ia)~(Ic), (P-1), (P-2), or (P-Ia)~(P-Ic), including any of the above, R 1 is C 1-6 It is alkyl. In one embodiment of formula (I), (P-1), or (P-2), including any of the above, R 1 is a heterocyclyl, aryl, or heteroaryl. In one embodiment of formula (I), (P-1), or (P-2), including any of the above, R 1 is a heterocyclyl, aryl, or heteroaryl. In one embodiment of formula (I), (P-1), or (P-2), including any of the above, R 1 is -C 0-6 Alkylene-SO2R 4 or -C 0-6 Alkylene-SO2R 5 That is the case.

[0112] In one embodiment of formulas (I), (Ia)~(Ic), (P-1), (P-2), or (P-Ia)~(P-Ic), including any of the above, R 1 is C 1-6 It is alkyl, C 1-6 Alkyl is not substituted. In one embodiment of formula (I), (Ia)~(Ic), (P-1), (P-2), or (P-Ia)~(P-Ic), including any of the above, R 1 is C 1-6 It is alkyl, C 1-6 Alkyl is composed of 1 or 2 R 2a It is substituted with a base. In one embodiment of formula (I), (Ia)~(Ic), (P-1), (P-2), or (P-Ia)~(P-Ic), including any of the above, R 1 is C 1-6 It is alkyl, C 1-6 Alkyl is C 1-6 Substituted with a hydroxyalkyl group. In one embodiment of formula (I), (Ia)~(Ic), (P-1), (P-2), or (P-Ia)~(P-Ic), including any of the above, R 1 teeth,

[0113] [ka] And in the formula,

[0114] [ka] is a bonding site to the remainder of the compound. In one embodiment of formula (I), (Ia)~(Ic), (P-1), (P-2), or (P-Ia)~(P-Ic), including any of the above, R 1 is C 1-6 It is alkyl, C 1-6 Alkyl is C 1-6 Substituted with an alkoxy. In one embodiment of formula (I), (Ia)~(Ic), (P-1), (P-2), or (P-Ia)~(P-Ic), including any of the above, R 1 teeth,

[0115] [ka] And in the formula,

[0116] [ka] This is a bonding site to the remainder of the compound.

[0117] In one embodiment of formula (I), (PI), (Ia), (P-Ia), or (P-2), including any of the above, R 2 is a heterocyclyl, and heterocyclyls are not substituted. In one embodiment of formula (I), (PI), (Ia), (P-Ia), or (P-2), including any of the above, R 2 A heterocycline is a heterocycline, and a heterocycline has 1 or 2 R 2a It is substituted with a base. In one embodiment of formula (I), (PI), (Ia), (P-Ia), or (P-2), including any of the above, R 2It is a 5-12 member monocyclic or bicyclic heterocycline containing 1, 2, or 3 atoms selected from nitrogen, oxygen, and sulfur, where nitrogen is C 1-6 Alkyl or C 3-6 Optionally substituted with cycloalkyl groups, heterocyclyl groups have 1 or 2 R groups. 2a It is optionally substituted in the base.

[0118] In one embodiment of formula (I), (PI), (Ia), (P-Ia), or (P-2), including any of the above, R 2 is an aryl, and the aryl is not substituted. In one embodiment of formula (I), (PI), (Ia), (P-Ia), or (P-2), including any of the above, R 2 A 5-12 member monocyclic or bicyclic aryl is formed, and the aryl has 1 or 2 R 2a It is optionally substituted at the base. In one embodiment of formula (I), (PI), (Ia), (P-Ia), or (P-2), including any of the above, R 2 is an unsubstituted phenyl. In one embodiment of formula (I), (PI), (Ia), (P-Ia), or (P-2), including any of the above, R 2 is 1 or 2 R 2a It is a phenyl substituted with a group. In one embodiment of formula (I), (PI), (Ia), (P-Ia), or (P-2), including any of the above, R 2 Hello, C 1-6 Alkoxy, C 1-6 Alkyl, and C 1-6 One R selected from haloalkyl 2a It is a phenyl compound substituted with a group.

[0119] In one embodiment of formula (I), (PI), (Ia), (P-Ia), or (P-2), including any of the above, R 2 is a heteroaryl compound, and the heteroaryl compound is not substituted. In one embodiment of formula (I), (PI), (Ia), (P-Ia), or (P-2), including any of the above, R 2It is a heteroaryl, and a heteroaryl is one or two R 2a It is optionally substituted at the base. In one embodiment of formula (I), (PI), (Ia), (P-Ia), or (P-2), including any of the above, R 2 It is a 5-12 member monocyclic or bicyclic heteroaryl containing 1, 2, 3, or 4 atoms selected from nitrogen, oxygen, and sulfur, where nitrogen is C 1-6 Alkyl or C 3-6 Optionally substituted with cycloalkyl groups, heteroaryl groups have 1 or 2 R groups. 2a It is optionally substituted in the base.

[0120] In one embodiment of formula (I), (PI), (Ia), (P-Ia), or (P-2), including any of the above, R 2 C 1-6 Alkyl or C 3-6 A 5-12 member monocyclic heteroaryl containing one nitrogen atom optionally substituted with a cycloalkyl group, wherein the heteroaryl has two R groups on the same carbon that together form an oxo group. 2a It is optionally substituted in the base.

[0121] In one embodiment of formula (I), (PI), (Ia), (P-Ia), or (P-2), including any of the above, R 2 teeth,

[0122] [ka] Selected from, in the formula,

[0123] [ka] This is a bonding site to the remainder of the compound.

[0124] In one embodiment of formula (I), (PI), (Ia), (P-Ia), or (P-2), including any of the above, R 2 teeth,

[0125] [ka] Selected from, in the formula,

[0126] [ka] R is a bonding site to the remainder of the compound. 2a This is defined herein.

[0127] In one embodiment of formula (I), (PI), (Ia), (P-Ia), or (P-2), including any of the above, R 2a C 1-6 Alkyl, C 1-6 Haloalkyl, halogen, C 1-6 Alkoxy, cyano, and C 1-6 Selected from haloalkoxys. In one embodiment of formula (I), (PI), (Ia), (P-Ia), or (P-2), including any of the above, R 2a C 1-6 Hydroxyalkyl or C 1-6 It is an alkoxy.

[0128] In one embodiment of formula (I), (PI), (Ia), (P-Ia), or (P-2), including any of the above, R 2 teeth,

[0129] [ka] Selected from.

[0130] In one embodiment of formula (I), (PI), (Ia), (P-Ia), or (P-2), including any of the above, R 2 teeth,

[0131] [ka] Selected from.

[0132] In one embodiment of formula (I), (PI), (Ia), (P-Ia), or (P-2), including any of the above, R 2 teeth,

[0133] [ka] Selected from, in the formula,

[0134] [ka] This is a bonding site to the remainder of the compound.

[0135] In one embodiment of formula (I), (PI), (Ia), (P-Ia), or (P-2), including any of the above, R 2 teeth,

[0136] [ka] Selected from, in the formula,

[0137] [ka] This is a bonding site to the remainder of the compound.

[0138] In one embodiment of formula (I), (PI), (Ia), (P-Ia), or (P-2), including any of the above, R 1 is hydrogen, R 2 teeth,

[0139] [ka] Selected from, in the formula,

[0140] [ka] This is a bonding site to the remainder of the compound.

[0141] In one embodiment of formula (I), (PI), (Ia), (P-Ia), or (P-2), including any of the above, R 1 is methyl, and R 2 teeth,

[0142] [ka] Selected from, in the formula,

[0143] [ka] This is a bonding site to the remainder of the compound.

[0144] In one embodiment of formula (I), (PI), (Ia), (P-Ia), or (P-2), including any of the above, R 1 is hydrogen, R 2 teeth,

[0145] [ka] Selected from, in the formula,

[0146] [ka] This is a bonding site to the remainder of the compound.

[0147] In one embodiment of formula (I), (PI), (Ia), (P-Ia), or (P-2), including any of the above, R 1 is methyl, and R 2 teeth,

[0148] [ka] Selected from, in the formula,

[0149] [ka] This is a bonding site to the remainder of the compound.

[0150] In one embodiment of formula (I), (PI), (Ia), (P-Ia), or (P-2), including any of the above, R 1 is hydrogen, R 2 teeth,

[0151] [ka] Selected from, in the formula,

[0152] [ka] This is a bonding site to the remainder of the compound.

[0153] In one embodiment of formula (I), (PI), (Ia), (P-Ia), or (P-2), including any of the above, R 1 is C 1-6 It is alkyl, C 1-6 Alkyl is either not substituted or C 1-6 Hydroxyalkyl or C 1-6 It is an alkoxy hydrogen, R 2 teeth,

[0154] [ka] And in the formula,

[0155] [ka] This is a bonding site to the remainder of the compound.

[0156] In one embodiment of formula (I), (PI), (Ia), (P-Ia), or (P-2), including any of the above, R 1 is hydrogen, R 2 teeth,

[0157] [ka] Selected from, R 3 OH is OH, and in the formula,

[0158] [ka] This is a bonding site to the remainder of the compound.

[0159] In one embodiment of formula (I), (PI), (Ia), (P-Ia), or (P-2), including any of the above, R 1 is methyl, and R 2 teeth,

[0160] [ka] Selected from, R 3 OH is OH, and in the formula,

[0161] [ka] This is a bonding site to the remainder of the compound.

[0162] In one embodiment of formula (I), (PI), (Ia), (P-Ia), or (P-2), including any of the above, R 1 is hydrogen, R 2 teeth,

[0163] [ka] Selected from, R 3 OH is OH, and in the formula,

[0164] [ka] This is a bonding site to the remainder of the compound.

[0165] In one embodiment of formula (I), (PI), (Ia), (P-Ia), or (P-2), including any of the above, R 1 is methyl, and R 2 teeth,

[0166] [ka] Selected from, R 3 OH is OH, and in the formula,

[0167] [ka] This is a bonding site to the remainder of the compound.

[0168] In one embodiment of formula (I), (PI), (Ia), (P-Ia), or (P-2), including any of the above, R 1 is hydrogen, R 2 teeth,

[0169] [ka] Selected from, R 3 -OH, -OP(O)(R) contains 1, 2, 3, or 4 atoms selected from nitrogen, oxygen, and sulfur atoms. b ) A heteroaryl with 2 or 3-6 members, in the formula,

[0170] [ka] This is a bonding site to the remainder of the compound.

[0171] In one embodiment of formula (I), (PI), (Ia), (P-Ia), or (P-2), including any of the above, R 1 is hydrogen, R 2 teeth,

[0172] [ka] Selected from, R 3 is -OH, -OP(O)(Me)2, or

[0173] [ka] And in the formula,

[0174] [ka] This is a bonding site to the remainder of the compound.

[0175] In one embodiment of formula (I), (PI), (Ia), (P-Ia), or (P-2), including any of the above, R 1 is methyl, and R 2 teeth,

[0176] [ka] Selected from, R 3 -OH, -OP(O)(R) contains 1, 2, 3, or 4 atoms selected from nitrogen, oxygen, and sulfur atoms. b ) A heteroaryl with 2 or 3-6 members, in the formula,

[0177] [ka] This is a bonding site to the remainder of the compound.

[0178] In one embodiment of formula (I), (PI), (Ia), (P-Ia), or (P-2), including any of the above, R 1 is methyl, and R 2 teeth,

[0179] [ka] Selected from, R 3 is -OH, -OP(O)(Me)2, or

[0180] [ka] And in the formula,

[0181] [ka] This is a bonding site to the remainder of the compound.

[0182] In one embodiment of formula (I), (PI), (Ia), (P-Ia), or (P-2), including any of the above, R 1 is hydrogen, R 2 teeth,

[0183] [ka] Selected from, R 3 -OH, -OP(O)(R) contains 1, 2, 3, or 4 atoms selected from nitrogen, oxygen, and sulfur atoms. b )2 or 3-6 member heteroaryl, in the formula,

[0184] [ka] This is a bonding site to the remainder of the compound.

[0185] In one embodiment of formula (I), (PI), (Ia), (P-Ia), or (P-2), including any of the above, R 1 is hydrogen, R 2 teeth,

[0186] [ka] Selected from, R 3 is -OH, -OP(O)(Me)2, or

[0187] [ka] And in the formula,

[0188] [ka] This is a bonding site to the remainder of the compound.

[0189] In one embodiment of formula (I), (PI), (Ia), (P-Ia), or (P-2), including any of the above, R 1 is methyl, and R 2 teeth,

[0190] [ka] Selected from, R 3 -OH, -OP(O)(R) contains 1, 2, 3, or 4 atoms selected from nitrogen, oxygen, and sulfur atoms. b ) A heteroaryl with 2 or 3-6 members, in the formula,

[0191] [ka] This is a bonding site to the remainder of the compound.

[0192] In one embodiment of formula (I), (PI), (Ia), (P-Ia), or (P-2), including any of the above, R 1 is methyl, and R 2 teeth,

[0193] [ka] Selected from, R 3 is -OH, -OP(O)(Me)2, or

[0194] [ka] And in the formula,

[0195] [ka] This is a bonding site to the remainder of the compound.

[0196] In one embodiment of formula (I), (PI), (Ia), (P-Ia), or (P-2), including any of the above, R 1 is hydrogen, R 2 teeth,

[0197] [ka] Selected from, R 3 is -OH, and in the formula,

[0198] [ka] This is a bonding site to the remainder of the compound.

[0199] In one embodiment of formula (I), (PI), (Ia), (P-Ia), or (P-2), including any of the above, R 1 is C 1-6 It is alkyl, C 1-6 Alkyl is either not substituted or C 1-6 Hydroxyalkyl or C 1-6 It is an alkoxy hydrogen, R 2 teeth,

[0200] [ka] And in the formula,

[0201] [ka] This is a bonding site to the remainder of the compound.

[0202] In one embodiment of formula (I), (PI), (Ia), (P-Ia), or (P-2), including any of the above, R 1 and R2 These together form a 5-12 member monocyclic or bicyclic heteroaryl with N-linking containing 1, 2, 3, or 4 atoms selected from nitrogen, oxygen, and sulfur, and the heteroaryl is not substituted. In one embodiment of formula (I), (PI), (Ia), (P-Ia), or (P-2), including any of the above, R 1 and R 2 They become one, R 1 and R 2 The N-linked 5-12 member monocyclic or bicyclic heteroaryls contain 1, 2, 3, or 4 atoms selected from nitrogen, oxygen, and sulfur, including the nitrogen to which they are bonded, and the heteroaryls contain 1 or 2 R 1a It is optionally substituted at the base. In one embodiment of formula (I), (PI), (Ia), (P-Ia), or (P-2), including any of the above, R 1 and R 2 They become one, R 1 and R 2 The heteroaryl is a 5-12 member monocyclic or bicyclic heteroaryl with N-linking, containing 1, 2, 3, or 4 atoms selected from nitrogen, oxygen, and sulfur, including the nitrogen to which it is bonded, and the heteroaryl has 1 R 1a It is optionally substituted at the base. In one embodiment of formula (I), (PI), (Ia), (P-Ia), or (P-2), including any of the above, R 1 and R 2 They become one, R 1 and R 2 The N-linked heteroaryls have 5 to 12 members and contain 1, 2, 3, or 4 nitrogen atoms, including the nitrogen to which they are bonded, and the heteroaryls have 1 or 2 R 1a It is optionally substituted in the base.

[0203] In one embodiment of formula (I), (PI), (Ia), (P-Ia), or (P-2), including any of the above, R 1 and R 2These together form a 5-12 member monocyclic or bicyclic heterocycline with N-linking containing 1, 2, 3, or 4 atoms selected from nitrogen, oxygen, and sulfur, and the heterocycline is not substituted. In one embodiment of formula (I), (PI), (Ia), (P-Ia), or (P-2), including any of the above, R 1 and R 2 They become one, R 1 and R 2 The heterocycline is a 5-12 member monocyclic or bicyclic heterocycline with N-linking, containing 1, 2, 3, or 4 atoms selected from nitrogen, oxygen, and sulfur, including the nitrogen to which it is bonded, and the heterocycline contains 1 or 2 R 1a It is optionally substituted at the base. In one embodiment of formula (I), (PI), (Ia), (P-Ia), or (P-2), including any of the above, R 1 and R 2 They become one, R 1 and R 2 The heterocycline is a 5-12 member monocyclic or bicyclic heterocycline with N-linking, containing 1, 2, 3, or 4 atoms selected from nitrogen, oxygen, and sulfur, including the nitrogen to which it is bonded, and the heterocycline has 1 R 1a It is optionally substituted at the base. In one embodiment of formula (I), (PI), (Ia), (P-Ia), or (P-2), including any of the above, R 1 and R 2 They become one, R 1 and R 2 The heterocyclils are 5-12 member monocyclic or bicyclic with N-linking containing 1, 2, 3, or 4 nitrogen atoms, including the nitrogen to which they are bonded, and the heterocyclils contain 1 or 2 R 1a It is optionally substituted at the base. In one embodiment of formula (I), (PI), (Ia), (P-Ia), or (P-2), including any of the above, R 1 and R 2 They become one, R 1 and R 2 The nitrogen atom bonded to it is one nitrogen atom and S(O) 0-2It contains N-linked, 5-12 member monocyclic or bicyclic heterocyclines, and the heterocycline has 1 or 2 R 1a It is optionally substituted at the base. In one embodiment of formula (I), (PI), (Ia), (P-Ia), or (P-2), including any of the above, R 1 and R 2 They become one, R 1 and R 2 It forms an N-linked, 5-12 member monocyclic or bicyclic heterocycline containing one nitrogen atom and S(O)2, to which the heterocycline has 1 or 2 R 1a It is optionally substituted in the base.

[0204] In one embodiment of formula (I), (PI), (Ib), (P-Ib), or (P-2), including any of the above, R 1 and R 2 They became one,

[0205] [ka] Forms, and in the formula,

[0206] [ka] This is a bonding site to the remainder of the compound.

[0207] In one embodiment of formula (I), (PI), (Ib), (P-Ib), or (P-2), including any of the above, R 1 and R 2 They became one,

[0208] [ka] Forms, and in the formula,

[0209] [ka] This is a bonding site to the remainder of the compound.

[0210] In one embodiment of formula (I), (PI), (Ib), (P-Ib), or (P-2), including any of the above, R 1 and R 2 They became one,

[0211] [ka] Forms, and in the formula,

[0212] [ka] This is a bonding site to the remainder of the compound.

[0213] In one embodiment of formula (I), (PI), (Ib), (P-Ib), or (P-2), including any of the above, R 1 and R 2 They became one,

[0214] [ka] Forms R 3 OH is OH, and in the formula,

[0215] [ka] This is a bonding site to the remainder of the compound.

[0216] In one embodiment of formula (I), (PI), (Ib), (P-Ib), or (P-2), including any of the above, R 1 and R 2 They became one,

[0217] [ka] Forms R 3-OH, -OP(O)(R) contains 1, 2, 3, or 4 atoms selected from nitrogen, oxygen, and sulfur atoms. b ) A heteroaryl with 2 or 3-6 members, in the formula,

[0218] [ka] This is a bonding site to the remainder of the compound.

[0219] In one embodiment of formula (I), (PI), (Ib), (P-Ib), or (P-2), including any of the above, R 1 and R 2 They became one,

[0220] [ka] Forms R 3 is -OH, -OP(O)(Me)2, or

[0221] [ka] And in the formula,

[0222] [ka] This is a bonding site to the remainder of the compound.

[0223] In one embodiment of formulas (I), (PI), (Ic), (P-Ic), or (P-2), including any of the above, R 2 is -C 0-6 Alkylene-SO2R 4 In one embodiment of formulas (I), (PI), (Ic), (P-Ic), or (P-2), R 2 is -C 0-6 Alkylene-SO2R 5 That is the case.

[0224] In one embodiment of formulas (I), (PI), (Ic), (P-Ic), or (P-2), including any of the above, R 2 is -C 0-6 Alkylene-SO2R 4 And R 4 is C 2-6 It is alkyl. In one embodiment of formula (I), (PI), (Ic), (P-Ic), or (P-2), including any of the above, R 2 is -C 0-6 Alkylene-SO2R 4 And R 4 is C 3-6 It is a cycloalkyl compound. In one embodiment of formula (I), (PI), (Ic), (P-Ic), or (P-2), including any of the above, R 2 is -C 0-6 Alkylene-SO2R 4 And R 4 is C 1-6 It is a hydroxyalkyl compound. In one embodiment of formula (I), (PI), (Ic), (P-Ic), or (P-2), including any of the above, R 2 is -C 0-6 Alkylene-SO2R 4 And R 4 A heterocycline is a heterocycline, and a heterocycline has 1 or 2 R 4a It is optionally substituted at the base. In one embodiment of formula (I), (PI), (Ic), (P-Ic), or (P-2), including any of the above, R 2 is -C 0-6 Alkylene-SO2R 4 And R 4 It is an aryl, and the aryl has 1 or 2 R 4a It is optionally substituted at the base. In one embodiment of formula (I), (PI), (Ic), (P-Ic), or (P-2), including any of the above, R 2 is -C 0-6 Alkylene-SO2R 4 And R 4 It is a heteroaryl, and a heteroaryl is one or two R 4a It is optionally substituted in the base.

[0225] In one embodiment of formulas (I), (PI), (Ic), (P-Ic), or (P-2), including any of the above, R 2 is -C 0-6 Alkylene-SO2R 5 And R 5 A heterocycline is a heterocycline, and a heterocycline has 1 or 2 R 5a It is optionally substituted at the base. In one embodiment of formula (I), (PI), (Ic), (P-Ic), or (P-2), including any of the above, R 2 is -C 0-6 Alkylene-SO2R 5 And R 5 It is an aryl, and the aryl has 1 or 2 R 5a It is optionally substituted at the base. In one embodiment of formula (I), (PI), (Ic), (P-Ic), or (P-2), including any of the above, R 2 is -C 0-6 Alkylene-SO2R 5 And R 5 It is a heteroaryl, and a heteroaryl is one or two R 5a It is optionally substituted in the base.

[0226] In one embodiment of formulas (I), (PI), (Ic), (P-Ic), or (P-2), including any of the above, R 2 is -C 0-6 Alkylene-SO2R 5 And R 5 R is a 5-12 member monocyclic heteroaryl containing two atoms selected from nitrogen and oxygen, 5 is 1 or 2 R 5a It is optionally substituted at the base. In one embodiment of formula (I), (PI), (Ic), (P-Ic), or (P-2), including any of the above, R 5 teeth,

[0227] [ka] Selected from.

[0228] In one embodiment of formulas (I), (PI), (Ic), (P-Ic), or (P-2), including any of the above, R 1 is methyl, and R 2 is -C 0-6 Alkylene-SO2R 4 In one embodiment of formulas (I), (PI), (Ic), (P-Ic), or (P-2), including any of the above, R 1 is hydrogen, R 2 is -C 0-6 Alkylene-SO2R 5 In one embodiment of formulas (I), (PI), (Ic), (P-Ic), or (P-2), including any of the above, R 1 is methyl, and R 2 is -C 0-6 Alkylene-SO2R 5 That is the case.

[0229] In one embodiment of formulas (I), (PI), (Ic), (P-Ic), or (P-2), including any of the above, R 2 teeth,

[0230] [ka] Selected from, in the formula,

[0231] [ka] This is a bonding site to the remainder of the compound.

[0232] In one embodiment of formulas (I), (PI), (Ic), (P-Ic), or (P-2), including any of the above, R 1 is hydrogen, R 2 teeth,

[0233] [ka] Selected from, R 3 is -OH, and in the formula,

[0234] [ka] This is a bonding site to the remainder of the compound.

[0235] In one embodiment of formulas (I), (PI), (Ic), (P-Ic), or (P-2), including any of the above, R 1 is methyl, and R 2 teeth,

[0236] [ka] Selected from, R 3 is -OH, and in the formula,

[0237] [ka] This is a bonding site to the remainder of the compound.

[0238] In one embodiment of formulas (I), (PI), (Ic), (P-Ic), or (P-2), including any of the above, R 2 teeth,

[0239] [ka] Selected from, R 3 is -OH, and in the formula,

[0240] [ka] This is a bonding site to the remainder of the compound.

[0241] In one embodiment of formulas (I), (PI), (Ic), (P-Ic), or (P-2), including any of the above, R 1 is methyl, and R 2 is -C 0-6 Alkylene-SO2R 4 And R3 -OH, -OP(O)(R) contains 1, 2, 3, or 4 atoms selected from nitrogen, oxygen, and sulfur atoms. b ) is a heteroaryl with 2, or 3 to 6 members. In one embodiment of formula (I), (PI), (Ic), (P-Ic), or (P-2), including any of the above, R 1 is hydrogen, R 2 is -C 0-6 Alkylene-SO2R 5 And R 3 -OH, -OP(O)(R) contains 1, 2, 3, or 4 atoms selected from nitrogen, oxygen, and sulfur atoms. b ) is a heteroaryl with 2, or 3 to 6 members. In one embodiment of formula (I), (Ic), or (P-2), including any of the above, R 1 is methyl, and R 2 is -C 0-6 Alkylene-SO2R 5 And R 3 -OH, -OP(O)(R) contains 1, 2, 3, or 4 atoms selected from nitrogen, oxygen, and sulfur atoms. b ) A heteroaryl with 2, or 3-6 members.

[0242] In one embodiment of formulas (I), (PI), (Ic), (P-Ic), or (P-2), including any of the above, R 1 is methyl, and R 2 is -C 0-6 Alkylene-SO2R 4 And R 3 is -OH, -OP(O)(Me)2, or

[0243] [ka] And in the formula,

[0244] [ka] R is a bonding site to the remainder of the compound. In one embodiment of formula (I), (Ic), or (P-2), including any of the above, R 1 is hydrogen, R 2 is -C 0-6 Alkylene-SO2R 5 And R 3 is -OH, -OP(O)(Me)2, or

[0245] [ka] And in the formula,

[0246] [ka] R is a bonding site to the remainder of the compound. In one embodiment of formula (I), (PI), (Ic), (P-Ic), or (P-2), including any of the above, R 1 is methyl, and R 2 is -C 0-6 Alkylene-SO2R 5 And R 3 is -OH, -OP(O)(Me)2, or

[0247] [ka] And in the formula,

[0248] [ka] This is a bonding site to the remainder of the compound.

[0249] In one embodiment of formulas (I), (PI), (Ic), (P-Ic), or (P-2), including any of the above, R 1 is hydrogen, R 2 teeth,

[0250] [ka] Selected from, R3 -OH, -OP(O)(R) contains 1, 2, 3, or 4 atoms selected from nitrogen, oxygen, and sulfur atoms. b ) A heteroaryl with 2 or 3-6 members, in the formula,

[0251] [ka] This is a bonding site to the remainder of the compound.

[0252] In one embodiment of formulas (I), (PI), (Ic), (P-Ic), or (P-2), including any of the above, R 1 is methyl, and R 2 teeth,

[0253] [ka] Selected from, R 3 -OH, -OP(O)(R) contains 1, 2, 3, or 4 atoms selected from nitrogen, oxygen, and sulfur atoms. b ) A heteroaryl with 2 or 3-6 members, in the formula,

[0254] [ka] This is a bonding site to the remainder of the compound.

[0255] In one embodiment of formulas (I), (PI), (Ic), (P-Ic), or (P-2), including any of the above, R 1 is hydrogen, R 2 teeth,

[0256] [ka] Selected from, R 3 is -OH, -OP(O)(Me)2, or

[0257] [ka] And in the formula,

[0258] [ka] This is a bonding site to the remainder of the compound.

[0259] In one embodiment of formulas (I), (PI), (Ic), (P-Ic), or (P-2), including any of the above, R 1 is methyl, and R 2 teeth,

[0260] [ka] Selected from, R 3 is -OH, -OP(O)(Me)2, or

[0261] [ka] And in the formula,

[0262] [ka] This is a bonding site to the remainder of the compound.

[0263] In one embodiment of formulas (I), (PI), (Ic), (P-Ic), or (P-2), including any of the above, R 4 teeth,

[0264] [ka] Selected from, in the formula,

[0265] [ka] This is a bonding site to the remainder of the compound.

[0266] In one embodiment of formulas (I), (PI), (Ic), (P-Ic), or (P-2), including any of the above, R 4 teeth,

[0267] [ka] Selected from, in the formula,

[0268] [ka] R is a bonding site to the remainder of the compound. 4a This is defined herein.

[0269] In one embodiment of formulas (I), (PI), (Ic), (P-Ic), or (P-2), including any of the above, R 4 teeth,

[0270] [ka] Selected from, in the formula,

[0271] [ka] This is a bonding site to the remainder of the compound.

[0272] In one embodiment of formulas (I), (PI), (Ic), (P-Ic), or (P-2), including any of the above, R 5 teeth,

[0273] [ka] Selected from, in the formula,

[0274] [ka] This is a bonding site to the remainder of the compound.

[0275] In one embodiment of formulas (I), (PI), (Ic), (P-Ic), or (P-2), including any of the above, R 5 teeth,

[0276] [ka] Selected from, in the formula,

[0277] [ka] R is a bonding site to the remainder of the compound. 5a This is defined herein.

[0278] In one embodiment of formulas (I), (PI), (Ic), (P-Ic), or (P-2), including any of the above, R 4 teeth,

[0279] [ka] Selected from, in the formula,

[0280] [ka] This is a bonding site to the remainder of the compound.

[0281] In one embodiment, the compound of formula (I) is the following formula

[0282] [ka] A compound of or a pharmaceutically acceptable salt thereof, in which R 1 , R 2 , and R 3 This is as described in any of the embodiments relating to formula (I) described herein.

[0283] Non-restrictive examples of compounds of formula (Ia) are:

[0284] [ka] or comprising a pharmaceutically acceptable salt thereof, where R 2 and R b This is as described in any of the embodiments relating to formula (Ia) described herein.

[0285] Non-limiting examples of compounds of formula (Ib) are:

[0286] [ka] or comprising a pharmaceutically acceptable salt thereof, where R 1 , R 2 , and R b This is as described in any of the embodiments relating to formula (Ib) described herein.

[0287] Non-limiting examples of compounds of formula (Ic) are:

[0288] [ka] or comprising a pharmaceutically acceptable salt thereof, where R 2 and R b This is as described in any of the embodiments relating to formula (Ic) described herein.

[0289] In certain embodiments, the compounds of formula (P-2), formula (PI), formula (P-Ia), formula (P-Ib), formula (P-Ic), formula (I), formula (Ia), formula (Ib), or formula (Ic) have a de or %de of zero. In certain embodiments, the compounds of formula (P-2), formula (PI), formula (P-Ia), formula (P-Ib), formula (P-Ic), formula (I), formula (Ia), formula (Ib), or formula (Ic) have a de or %de greater than zero. For example, in certain embodiments, the compounds of formula (P-2), formula (PI), formula (P-Ia), formula (P-Ib), formula (P-Ic), formula (I), formula (Ia), formula (Ib), or formula (Ic) have a de or %de of about 10. In certain embodiments, the compounds of formula (P-2), formula (PI), formula (P-Ia), formula (P-Ib), formula (P-Ic), formula (I), formula (Ia), formula (Ib), or formula (Ic) have a de or %de of about 25. In certain embodiments, the compounds of formula (P-2), formula (PI), formula (P-Ia), formula (P-Ib), formula (P-Ic), formula (I), formula (Ia), formula (Ib), or formula (Ic) have a de or %de of about 50. In certain embodiments, the compounds of formula (P-2), formula (PI), formula (P-Ia), formula (P-Ib), formula (P-Ic), formula (I), formula (Ia), formula (Ib), or formula (Ic) have a de or %de of about 75. In certain embodiments, the compounds of formula (P-2), formula (PI), formula (P-Ia), formula (P-Ib), formula (P-Ic), formula (I), formula (Ia), formula (Ib), or formula (Ic) have a de or %de of about 80. In certain embodiments, the compounds of formula (P-2), formula (PI), formula (P-Ia), formula (P-Ib), formula (P-Ic), formula (I), formula (Ia), formula (Ib), or formula (Ic) have a de or %de of about 85. In certain embodiments, the compounds of formula (P-2), formula (PI), formula (P-Ia), formula (P-Ib), formula (P-Ic), formula (I), formula (Ia), formula (Ib), or formula (Ic) have a de or %de of about 90. In certain embodiments, the compounds of formula (P-2), formula (PI), formula (P-Ia), formula (P-Ib), formula (P-Ic), formula (I), formula (Ia), formula (Ib), or formula (Ic) have a de or %de of about 95.In certain embodiments, the compounds of formula (P-2), formula (PI), formula (P-Ia), formula (P-Ib), formula (P-Ic), formula (I), formula (Ia), formula (Ib), or formula (Ic) have a de or %de of about 97. In certain embodiments, the compounds of formula (P-2), formula (PI), formula (P-Ia), formula (P-Ib), formula (P-Ic), formula (I), formula (Ia), formula (Ib), or formula (Ic) have a de or %de of about 98. In certain embodiments, the compounds of formula (P-2), formula (PI), formula (P-Ia), formula (P-Ib), formula (P-Ic), formula (P-2), formula (I), formula (Ia), formula (Ib), or formula (Ic) have a de or %de of about 99. In certain embodiments, the compounds described herein have a de or %de of 100.

[0290] In one embodiment, a compound of formula (P-2), formula (PI), formula (P-Ia), formula (P-Ib), formula (P-Ic), formula (I), formula (Ia), formula (Ib), or formula (Ic), or a pharmaceutically acceptable salt thereof, is a C-16(R)-epimer of formula (P-2), formula (PI), formula (P-Ia), formula (P-Ib), formula (P-Ic), formula (I), formula (Ia), formula (Ib), or formula (Ic), based solely on the weight of the compound of formula (P-2), formula (PI), formula (P-Ia), formula (P-Ib), formula (P-Ic), formula (I), formula (Ia), formula (Ib), or formula (Ic), in amounts of at least about 50%, at least about 60%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 97%, at least about 99%, or even 100% by weight. In one embodiment, compounds of formula (P-2), formula (PI), formula (P-Ia), formula (P-Ib), formula (P-Ic), formula (I), formula (Ia), formula (Ib), or formula (Ic), or pharmaceutically acceptable salts thereof, are approximately 85% to 95% (R)-C-16 epimers. In another embodiment, compounds of formula (P-2), formula (PI), formula (P-Ia), formula (P-Ib), formula (P-Ic), formula (I), formula (Ia), formula (Ib), or formula (Ic), or pharmaceutically acceptable salts thereof, are approximately 90% to 95% (R)-C-16 epimers.

[0291] In one embodiment, the compound of formula (P-2), formula (PI), formula (P-Ia), formula (P-Ib), formula (P-Ic), formula (I), formula (Ia), formula (Ib), or formula (Ic), or a pharmaceutically acceptable salt thereof, is 50 wt% C-16(S)-epimer and 50 wt% C-16(R)-epimer, based solely on the weight of the compound of formula (P-2), formula (PI), formula (P-Ia), formula (P-Ib), formula (P-Ic), formula (I), formula (Ia), formula (Ib), or formula (Ic) (i.e., excluding the weight of the pharmaceutically acceptable salt if the compound exists as a pharmaceutically acceptable salt).

[0292] In one embodiment, a compound of formula (P-2), formula (PI), formula (P-Ia), formula (P-Ib), formula (P-Ic), formula (I), formula (Ia), formula (Ib), or formula (Ic), or a pharmaceutically acceptable salt thereof, is a C-16(S)-epimer of formula (P-2), formula (PI), formula (P-Ia), formula (P-Ib), formula (P-Ic), formula (I), formula (Ia), formula (Ib), or formula (Ic), based solely on the weight of the compound of formula (P-2), formula (PI), formula (P-Ia), formula (P-Ib), formula (P-Ic), formula (I), formula (Ia), formula (Ib), or formula (Ic), in amounts of at least about 50%, at least about 60%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 97%, at least about 99%, or even 100% by weight. In one embodiment, compounds of formula (P-2), formula (PI), formula (P-Ia), formula (P-Ib), formula (P-Ic), formula (I), formula (Ia), formula (Ib), or formula (Ic), or pharmaceutically acceptable salts thereof, are approximately 85% to 95% (S)-C-16 epimer. In another embodiment, compounds of formula (P-2), formula (PI), formula (P-Ia), formula (P-Ib), formula (P-Ic), formula (I), formula (Ia), formula (Ib), or formula (Ic), or pharmaceutically acceptable salts thereof, are approximately 90% to 95% (S)-C-16 epimer.

[0293] In some embodiments, the compounds and pharmaceutical compositions disclosed herein, for use in treating disorders or diseases mediated by the mTOR pathway, are more selective than other FK506-binding proteins (FKBPs) in their binding to FKBP12.

[0294] In some other embodiments, the compounds and pharmaceutical compositions disclosed herein, for use in treating mTOR pathway-mediated disorders or diseases, exhibit unusual and remarkable pharmacokinetic profiles and enhanced pharmacodynamic selectivity at the target FKBP, and these compounds and pharmaceutical compositions are useful in treating age-related or senescence-related diseases, complications of diabetes, cancer, as well as inflammation-related disorders.

[0295] In other embodiments, the compounds and pharmaceutical compositions disclosed herein are for use in treating disorders or diseases mediated by the mTOR pathway, wherein the compounds inhibit S6K1 phosphorylation in FKBP12 KO cells with at least twice the efficiency of the rapalog RAD001 compared to FKBP12-expressing cells.

[0296] In some other embodiments, compounds and pharmaceutical compositions disclosed herein are for use in treating mTOR pathway-mediated disorders or diseases, wherein the compounds inhibit S6K1 phosphorylation in FKBP12 KO cells with at least 10 times lower efficiency than the rapalog RAD001 compared to FKBP12-expressing cells.

[0297] In some other embodiments, compounds and pharmaceutical compositions disclosed herein for use in treating mTOR pathway-mediated disorders or diseases, wherein the compounds inhibit S6K1 phosphorylation in FKBP12 KO cells with at least 100 times lower efficiency than the rapalog RAD001 compared to FKBP12-expressing cells.

[0298] In some other embodiments, compounds and pharmaceutical compositions disclosed herein for use in treating disorders or diseases mediated by the mTOR pathway, wherein the compounds require concentrations at least about 10 times higher in FKBP12 KO cells compared to the rapalog RAD001 compared to FKBP12-expressing cells to achieve a 20% inhibition of S6K1 cell signaling.

[0299] In some other embodiments, compounds and pharmaceutical compositions disclosed herein for use in treating mTOR pathway-mediated disorders or diseases, wherein the compounds require concentrations at least about 20 times higher in FKBP12 KO cells compared to the rapalog RAD001 compared to FKBP12-expressing cells to achieve a 20% inhibition of S6K1 cell signaling.

[0300] In some other embodiments, compounds and pharmaceutical compositions disclosed herein for use in treating mTOR pathway-mediated disorders or diseases, wherein the compounds require concentrations at least about 100 times higher in FKBP12 KO cells compared to the rapalog RAD001 compared to FKBP12-expressing cells to achieve a 20% inhibition of S6K1 cell signaling.

[0301] In some other embodiments, compounds and pharmaceutical compositions disclosed herein for use in treating mTOR pathway-mediated disorders or diseases, wherein the compounds require concentrations at least about 500 times higher in FKBP12 KO cells compared to the rapalog RAD001 compared to FKBP12-expressing cells to achieve a 20% inhibition of S6K1 cell signaling.

[0302] In some other embodiments, compounds and pharmaceutical compositions disclosed herein for use in treating mTOR pathway-mediated disorders or diseases, wherein the compounds require concentrations at least about 1000 times higher in FKBP12 KO cells compared to the rapalog RAD001 compared to FKBP12-expressing cells to achieve a 20% inhibition of S6K1 cell signaling.

[0303] In some other embodiments, the “FKBP12 selective rapalog” is a rapalog that is potent in assays using wild-type cells, but is approximately 10 to 1000 times less potent than RAD001 in cell lines that do not express FKBP12 (e.g., FKBP12 knockout cells). “Potential,” as used in this context, can be expressed as the concentration of the rapalog required to achieve 20% inhibition of S6K1(Thr389) phosphorylation in cell-based assays, such as those used in Example 3 and Figures 1 to 11. For example, a rapalog is considered FKBP12 selective if it inhibits S6K1(Thr389) phosphorylation by approximately 20% in an assay using an FKBP12 knockout cell line that exhibits at least 20 times (e.g., 25x, 30x, 50x, 100x, 200x, 500x, 1000x, etc.) lower potency compared to a similar level of inhibition achieved by RAD001 in the same assay using the same cell line that normally expresses FKBP12.

[0304] In some other embodiments, compounds and pharmaceutical compositions disclosed herein for use in treating disorders or diseases mediated by the mTOR pathway, wherein the compounds require concentrations at least about 20 times higher in FKBP12 KO cells compared to the rapalog RAD001 compared to FKBP12-expressing cells to achieve a 30% inhibition of S6K1 cell signaling.

[0305] In some other embodiments, compounds and pharmaceutical compositions disclosed herein for use in treating mTOR pathway-mediated disorders or diseases, wherein the compounds require concentrations at least about 100 times higher in FKBP12 KO cells compared to the rapalog RAD001 compared to FKBP12-expressing cells to achieve a 30% inhibition of S6K1 cell signaling.

[0306] In some other embodiments, compounds and pharmaceutical compositions disclosed herein for use in treating mTOR pathway-mediated disorders or diseases, wherein the compounds require concentrations at least about 500 times higher in FKBP12 KO cells compared to the rapalog RAD001 compared to FKBP12-expressing cells to achieve a 30% inhibition of S6K1 cell signaling.

[0307] In some other embodiments, compounds and pharmaceutical compositions disclosed herein for use in treating mTOR pathway-mediated disorders or diseases, wherein the compounds require concentrations at least about 1000 times higher in FKBP12 KO cells compared to the rapalog RAD001 compared to FKBP12-expressing cells to achieve a 30% inhibition of S6K1 cell signaling.

[0308] In some other embodiments, the “FKBP12 selective rapalog” is a rapalog that is potent in assays using wild-type cells, but is approximately 20 to 1000 times less potent than RAD001 in cell lines that do not express FKBP12 (e.g., FKBP12 knockout cells). “Potential,” as used in this context, can be expressed as the concentration of the rapalog required to achieve 30% inhibition of S6K1(Thr389) phosphorylation in cell-based assays, such as those used in Example 3 and Figures 1 to 11. For example, a rapalog is considered FKBP12 selective if it inhibits S6K1(Thr389) phosphorylation by approximately 30% in an assay using an FKBP12 knockout cell line that exhibits at least 20-fold (e.g., 25-fold, 30-fold, 50-fold, 100-fold, 200-fold, 500-fold, 1000-fold, etc.) lower potency compared to a similar level of inhibition achieved by RAD001 in the same assay using the same cell line that normally expresses FKBP12.

[0309] Examples of non-limiting compounds of the present invention include:

[0310] [ka]

[0311] [ka]

[0312] [ka]

[0313] [ka]

[0314] [ka]

[0315]

change

[0316]

change

[0317]

change

[0318]

change

[0319]

change

[0320]

change

[0321]

change

[0322]

change

[0323]

change

[0324]

change

[0325]

change

[0326]

change

[0327]

change

[0328]

change

[0329]

change

[0330]

change

[0331]

change

[0332]

change

[0333]

change

[0334]

change

[0335]

change

[0336]

change

[0337] [ka]

[0338] Pharmaceutical composition and treatment method

[0339] This specification provides methods for treating and preventing diseases, disorders, or disabilities, comprising the step of administering one or more of the compounds disclosed herein, for example, one or more of the compounds of the formulas provided herein, in a therapeutic or prophylactic effective dose. Diseases, disorders, and / or disabilities include, but are not limited to, those mediated by the mTOR pathway.

[0340] In some embodiments of the methods described herein, multiple doses of the compounds described herein (or pharmaceutical compositions comprising a combination of the compounds described herein and any additional therapeutic agents referred herein) may be administered to a subject over a predetermined period of time. Methods according to this embodiment of the Disclosure include the step of administering multiple doses of the compounds described herein to a subject in succession. As used herein, “succession” means that each dose of the compound is administered to a subject on different days separated by a predetermined interval, for example, several hours, several days, several weeks, or several months. The Disclosure includes methods that include the step of administering to a patient in succession a first dose of the compound described herein alone, followed by one or more secondary doses of the compound, and then optionally one or more tertiary doses of the compound.

[0341] The terms “initial dose,” “secondary dose,” and “tertiary dose” refer to the temporary sequence of administration of the compounds described herein. Thus, the “initial dose” is the dose administered at the start of the treatment regimen (also referred to as the “baseline dose”), the “secondary dose” is the dose administered after the initial dose, and the “tertiary dose” is the dose administered after the secondary dose. While the initial, secondary, and tertiary doses may all contain the same amount of the compounds described herein, they may generally differ from one another in terms of administration frequency. In certain embodiments, the amounts of the compounds in the initial, secondary, and / or tertiary doses may vary from one another during the course of treatment (e.g., adjusted upward or downward as appropriate). In certain embodiments, two or more doses (e.g., two, three, four, or five) may be administered as “loading doses” at the start of the treatment regimen, followed by doses administered at a lower frequency (e.g., “maintenance doses”).

[0342] In certain exemplary embodiments of this disclosure, the secondary dose and / or tertiary dose are each 1 to 26 weeks after the immediately preceding dose (e.g., 1, 1 1 / 2 , 2, 2 1 / 2 ,3,3 1 / 2 ,4,4 1 / 2 , 5, 5 1 / 2 , 6, 6 1 / 2 , 7, 7 1 / 2 , 8, 8 1 / 2 ,9,9 1 / 2 , 10, 10 1 / 2 , 11, 11 1 / 2 , 12, 12 1 / 2 , 13, 13 1 / 2 , 14, 14 1 / 2 , 15, 15 1 / 2 , 16, 16 1 / 2 , 17, 17 1 / 2 , 18, 18 1 / 2 , 19, 19 1 / 2 , 20, 20 1 / 2 , 21, 21 1 / 2 , 22, 22 1 / 2 , 23, 23 1 / 2 , 24, 24 1 / 2 , 25, 25 1 / 2 , 26, 26 1 / 2It is administered over a period of weeks or more. The phrase "the immediately preceding dose," as used herein, means the dose of the compound administered to the patient in a multi-dose sequence before the next dose, without requiring an intervening dose.

[0343] The methods according to this embodiment of the Disclosure may include the step of administering secondary and / or tertiary doses of the compound to a patient in any number of times. For example, in one particular embodiment, only one secondary dose is administered to the patient. In another embodiment, two or more (e.g., two, three, four, five, six, seven, eight or more) secondary doses are administered to the patient. Similarly, in one particular embodiment, only one tertiary dose is administered to the patient. In another embodiment, two or more (e.g., two, three, four, five, six, seven, eight or more) tertiary doses are administered to the patient. The administration regimen may be carried out indefinitely until the life of a particular subject or until such treatment is no longer therapeutically necessary or advantageous.

[0344] In embodiments including multiple secondary doses, each secondary dose may be administered at the same frequency as the other secondary doses. For example, each secondary dose may be administered to the patient 1 to 2 weeks or 1 to 2 months after the previous dose. Similarly, in embodiments including multiple tertiary doses, each tertiary dose may be administered at the same frequency as the other tertiary doses. For example, each tertiary dose may be administered to the patient 1 to 12 weeks after the previous dose. In certain embodiments of this disclosure, the frequency at which secondary and / or tertiary doses are administered to the patient may vary during the course of the treatment regimen. The administration frequency may also be adjusted by the physician during the course of treatment according to the individual patient's needs after clinical examinations.

[0345] This disclosure includes a dosing regimen in which two to six loading doses are administered to a patient at a first frequency (e.g., once a week, once every two weeks, once every three weeks, once a month, once every two months, etc.), followed by two or more maintenance doses administered to the patient at an even less frequent frequency. For example, according to this embodiment of the disclosure, if the loading dose is administered at a frequency of once a month, the maintenance dose may then be administered to the patient at a frequency of once every six weeks, once every two months, once every three months, etc.

[0346] This disclosure includes pharmaceutical compositions comprising compounds described herein, e.g., compounds of formula (I), (P-1), (P-2), (Ia) to (Ic), or (P-Ia) to (P-Ic), or compounds 3 to 74, or salts, and pharmaceutically acceptable carriers, diluents, and / or excipients. Examples of suitable carriers, diluents, and excipients include, but are not limited to, buffers for maintaining a suitable composition pH (e.g., citrate buffer, succinate buffer, acetate buffer, phosphate buffer, lactate buffer, oxalate buffer, etc.), carrier proteins (e.g., human serum albumin), physiological saline, polyols (e.g., trehalose, sucrose, xylitol, sorbitol, etc.), surfactants (e.g., polysorbate 20, polysorbate 80, polyoxolate, etc.), antimicrobial agents, and antioxidants.

[0347] The disclosure also includes a combination therapy agent comprising 1) a compound of formula (I), (P-1), (P-2), (Ia)-(Ic), or (P-Ia)-(P-Ic), or a pharmaceutical composition thereof, and 2) an anti-CD40 antibody. In some embodiments, the compound of formula (I), (P-1), (P-2), (Ia)-(Ic), or (P-Ia)-(P-Ic), or a pharmaceutical composition thereof, and the anti-CD40 antibody are administered in separate dosage forms. In some embodiments, the compound of formula (I), (P-1), (P-2), (Ia)-(Ic), or (P-Ia)-(P-Ic), or a pharmaceutical composition thereof, and the anti-CD40 antibody are administered in a combined dosage form.

[0348] In some embodiments, a method for treating a disorder or disorder in a person requiring treatment of such disorder or disorder is described, comprising the step of administering a compound of formula (I), (P-1), (P-2), (Ia) to (Ic), or (P-Ia) to (P-Ic), or a pharmaceutically acceptable salt thereof.

[0349] In some embodiments, a method for treating a disorder or disorder in a subject requiring treatment of said disorder or disorder is described, comprising the step of administering a combination therapy agent comprising 1) a compound of formula (I), (P-1), (P-2), (Ia) to (Ic), or (P-Ia) to (P-Ic), or a pharmaceutical composition thereof, and 2) an anti-CD40 antibody.

[0350] In some embodiments, this specification describes a method for treating a disorder or disorder mediated by the mTOR pathway in a subject requiring treatment of such disorder or disorder, comprising the step of administering a compound of formula (I), (P-1), (P-2), (Ia) to (Ic), or (P-Ia) to (P-Ic), or a pharmaceutically acceptable salt thereof. In one embodiment, a target tissue, organ, or cell associated with the pathogenesis of the disorder or disorder has FKBP12 levels sufficient to inhibit mTORC1.

[0351] In one embodiment, the disease or disorder is sarcopenia, skin atrophy, senile angioma, seborrheic keratosis, cerebral atrophy, atherosclerosis, arteriosclerosis, emphysema, osteoporosis, osteoarthritis, hypertension, erectile dysfunction, cataracts, macular degeneration, glaucoma, stroke, cerebrovascular disease (stroke), chronic kidney disease, diabetes-related kidney disease, liver dysfunction, liver fibrosis, autoimmune hepatitis, endometrial hyperplasia, metabolic dysfunction, renovascular disease, hearing loss, mobility impairment, cognitive decline, tendon stiffness, cardiac dysfunction, For example, age-related disorders or diseases selected from cardiac hypertrophy, and / or systolic and / or diastolic dysfunction, and / or hypertension, cardiac dysfunction that reduces ejection fraction, immunosenescence, Parkinson's disease, Alzheimer's disease or its syndromes, cancer, immunosenescence leading to cancer due to reduced immune surveillance, infections due to impaired immune function, chronic obstructive pulmonary disease (COPD), obesity, loss of taste, loss of smell, arthritis, and type 2 diabetes.

[0352] In one embodiment, the disease or disorder is cancer. In one embodiment, cancer is selected from kidney cancer, renal cell carcinoma, colorectal cancer, uterine sarcoma, endometrial uterine cancer, endometrial cancer, breast cancer, ovarian cancer, cervical cancer, gastric cancer, fibrosarcoma, pancreatic cancer, liver cancer, melanoma, leukemia, multiple myeloma, nasopharyngeal cancer, prostate cancer, lung cancer, glioblastoma, bladder cancer, mesothelioma, head cancer, rhabdomyosarcoma, sarcoma, lymphoma, and cervical cancer.

[0353] In one embodiment, the disease or disorder is graft-versus-host disease (GvHD) or a syndrome thereof.

[0354] In one embodiment, the disease or disorder is a facial angiofibroma associated with tuberous sclerosis.

[0355] In one embodiment, the disease or disorder is a progressive, unresectable or metastatic, malignant perivascular epithelioid cell tumor.

[0356] In some embodiments, this specification also describes a method for inducing immune tolerance and / or preventing organ rejection in subjects requiring induction of immune tolerance and / or prevention of organ rejection, comprising the step of administering a compound of formula (I), (P-1), (P-2), (Ia) to (Ic), or (P-Ia) to (P-Ic), or a pharmaceutically acceptable salt thereof.

[0357] This disclosure provides compounds of formula (I), (P-1), (P-2), (Ia) to (Ic), or (P-Ia) to (P-Ic), or pharmaceutically acceptable salts thereof, for the treatment of diseases and disorders described herein, such as age-related disorders, or diseases and disorders for which treatment with rapalogs such as RAD001 is currently approved.

[0358] In one embodiment, the present disclosure provides a method for treating a disorder or disorder mediated by the mTOR pathway in a subject requiring treatment of such disorder or disorder, the method comprising administering to the subject a therapeutically effective dose of a compound of formula (I), (P-1), (P-2), (Ia) to (Ic), or (P-Ia) to (P-Ic), or a pharmaceutically acceptable salt thereof.

[0359] In one embodiment, the effectiveness of the treatment is determined empirically, for example, compared to rapamycin or RAD001.

[0360] In another aspect, the Disclosure provides a method for treating a disease or disorder of a subject having sufficient FKBP12 levels to inhibit mTORC1, or having been previously determined to do so, the method comprising administering to a subject in need of treatment for the disease or disorder a compound of formula (I), (P-1), (P-2), (Ia) to (Ic), or (P-Ia) to (P-Ic), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition or pharmaceutical combination described herein.

[0361] In one embodiment, the disease or disorder is sarcopenia, skin atrophy, senile angioma, seborrheic keratosis, cerebral atrophy, atherosclerosis, arteriosclerosis, emphysema, osteoporosis, osteoarthritis, hypertension, erectile dysfunction, cataracts, macular degeneration, glaucoma, stroke, cerebrovascular disease (stroke), chronic kidney disease, diabetes-related kidney disease, liver dysfunction, hepatic fibrosis, autoimmune hepatitis, endometrial hyperplasia, metabolic dysfunction, renovascular disease, hearing loss, mobility impairment, cognitive decline, tendon stiffness, cardiac dysfunction, for example, heart The following conditions are selected: hypertrophy, and / or systolic and / or diastolic dysfunction, and / or hypertension, cardiac dysfunction that reduces ejection fraction, immunosenescence, Parkinson's disease, Alzheimer's disease, cancer, immunosenescence leading to cancer due to reduced immune surveillance, infections due to impaired immune function, chronic obstructive pulmonary disease (COPD), obesity, loss of taste, loss of smell, arthritis, and type 2 diabetes mellitus (including complications arising from diabetes such as renal failure, blindness, and neuropathy).

[0362] In one embodiment, the disorder is hepatic fibrosis.

[0363] In another aspect, the Disclosure provides a method for treating a disease or disorder in a subject requiring treatment of the disease or disorder, the method comprising administering to the subject a compound of formula (I), (P-1), (P-2), (Ia)-(Ic), or (P-Ia)-(P-Ic), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a compound of formula (I), (P-1), (P-2), (Ia)-(Ic), or (P-Ia)-(P-Ic), or a pharmaceutically acceptable salt thereof, the disease or disorder being selected from: • Acute or chronic rejection of organ or tissue transplantation, ·Transplant vasculopathy, • Intimal thickening of vascular tissue, vascular occlusion, obstructive coronary artery atherosclerosis, restenosis, proliferation and migration of smooth muscle cells, • Autoimmune diseases and inflammatory diseases, ·asthma, • Multidrug resistance (MDR), ·Fungal infections, ·inflammation, ·Infectious diseases, • Diseases related to aging, • Neurodegenerative diseases, • Proliferative disorders, specifically cancer, • Seizures and seizure-related disorders, and • Mitochondrial myopathy and mitochondrial stress.

[0364] In one embodiment, the disorder is a disorder that includes processes of fibrosis and / or inflammation.

[0365] In one embodiment, the impairment is selected from liver and kidney impairment.

[0366] In one embodiment, the liver disorder is selected from hepatic fibrosis, cirrhosis, non-alcoholic steatohepatopathy (NASH), and alcoholic steatohepatopathy, which occur in end-stage liver disease.

[0367] In one embodiment, the disorder is hepatic fibrosis.

[0368] In one embodiment, renal fibrosis results from acute kidney injury.

[0369] In one embodiment, the kidney damage is chronic kidney disease.

[0370] In one embodiment, the kidney damage is diabetic nephropathy.

[0371] In another aspect, the Disclosure provides a method for treating age-related disorders or disorders in subjects requiring treatment of such disorders or disorders, the method comprising administering to a subject a compound of formula (I), (P-1), (P-2), (Ia)-(Ic), or (P-Ia)-(P-Ic), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a compound of formula (I), (P-1), (P-2), (Ia)-(Ic), or (P-Ia)-(P-Ic), or a pharmaceutically acceptable salt thereof, or a pharmaceutical combination comprising a compound of formula (I), (P-1), (P-2), (Ia)-(Ic), or (P-Ia)-(P-Ic), or a pharmaceutically acceptable salt thereof, wherein the disorders or disorders include sarcopenia, cutaneous atrophy, senile angioma, seborrheic keratosis, cerebral atrophy, and atherosclerotic artery disease. The following conditions are selected: sclerosis, arteriosclerosis, emphysema, osteoporosis, osteoarthritis, hypertension, erectile dysfunction, cataracts, macular degeneration, glaucoma, stroke, cerebrovascular disease (stroke), chronic kidney disease, diabetes-related kidney disease, hepatic insufficiency, hepatic fibrosis, autoimmune hepatitis, endometrial hyperplasia, metabolic dysfunction, renovascular disease, hearing loss, mobility impairment, cognitive decline, tendon rigidity, cardiac dysfunction, such as cardiac hypertrophy and / or systolic and / or diastolic dysfunction and / or hypertension, cardiac dysfunction that reduces ejection fraction, immunosenescence, Parkinson's disease, Alzheimer's disease, cancer, immunosenescence leading to cancer due to reduced immune surveillance, infections due to impaired immune function, chronic obstructive pulmonary disease (COPD), obesity, loss of taste, loss of smell, arthritis, and type 2 diabetes mellitus (including complications arising from diabetes such as renal failure, blindness, and neuropathy).

[0372] In another embodiment, the Disclosure provides a method for treating cancer in a subject requiring treatment, the method comprising administering to the subject a compound of formula (I), (P-1), (P-2), (Ia)-(Ic), or (P-Ia)-(P-Ic), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a compound of formula (I), (P-1), (P-2), (Ia)-(Ic), or (P-Ia)-(P-Ic), or a pharmaceutically acceptable salt thereof, or a pharmaceutical combination comprising a compound of formula (I), (P-1), (P-2), (Ia)-(Ic), or (P-Ia)-(P-Ic), or a pharmaceutically acceptable salt thereof.

[0373] In one embodiment, the method further comprises a PD-1 / PDL-1 inhibitor.

[0374] In one embodiment, the cancer is selected from kidney cancer, renal cell carcinoma, colorectal cancer, uterine sarcoma, endometrial uterine cancer, endometrial cancer, breast cancer, ovarian cancer, cervical cancer, gastric cancer, fibrosarcoma, pancreatic cancer, liver cancer, melanoma, leukemia, multiple myeloma, nasopharyngeal cancer, prostate cancer, lung cancer, glioblastoma, bladder cancer, mesothelioma, head cancer, rhabdomyosarcoma, sarcoma, lymphoma, and cervical cancer.

[0375] In another aspect, the disclosure provides a compound of formula (I), (P-1), (P-2), (Ia)~(Ic), or (P-Ia)~(P-Ic), or a pharmaceutically acceptable salt thereof, for use as a pharmaceutical, or a pharmaceutical composition comprising a compound of formula (I), (P-1), (P-2), (Ia)~(Ic), or (P-Ia)~(P-Ic), or a pharmaceutically acceptable salt thereof, or a pharmaceutical combination comprising a compound of formula (I), (P-1), (P-2), (Ia)~(Ic), or (P-Ia)~(P-Ic), or a pharmaceutically acceptable salt thereof.

[0376] In another aspect, the Disclosure provides a pharmaceutical composition comprising a compound of formula (I), (P-1), (P-2), (Ia)-(Ic), or (P-Ia)-(P-Ic), or a pharmaceutically acceptable salt thereof, for use in the prevention or treatment of a disorder or disease mediated by the mTOR pathway, or a pharmaceutical combination comprising a compound of formula (I), (P-1), (P-2), (Ia)-(Ic), or (P-Ia)-(P-Ic), or a pharmaceutically acceptable salt thereof, or a pharmaceutical combination comprising a compound of formula (I), (P-1), (P-2), (Ia)-(Ic), or (P-Ia)-(P-Ic), or a pharmaceutically acceptable salt thereof.

[0377] In another aspect, this disclosure is as follows: • Acute or chronic rejection of organ or tissue transplantation, ·Transplant vasculopathy, • Intimal thickening of vascular tissue, vascular occlusion, obstructive coronary artery atherosclerosis, restenosis, proliferation and migration of smooth muscle cells, • Autoimmune diseases and inflammatory diseases, ·asthma, • Multidrug resistance (MDR), ·Fungal infections, ·inflammation, ·Infectious diseases, • Diseases related to aging, • Neurodegenerative diseases, • Proliferative disorders, specifically cancer, • Seizures and seizure-related disorders, and • Mitochondrial myopathy and mitochondrial stress The present invention provides pharmaceutical compositions containing compounds of formula (I), (P-1), (P-2), (Ia)-(Ic), or (P-Ia)-(P-Ic), or pharmaceutically acceptable salts thereof, for use in the prevention or treatment of disorders or diseases selected from the above.

[0378] In another aspect, the Disclosure provides a compound of formula (I), (P-1), (P-2), (Ia)-(Ic), or (P-Ia)-(P-Ic), or a pharmaceutically acceptable salt thereof, for use in the prevention or treatment of disorders or diseases including fibrotic and / or inflammatory processes, a pharmaceutical composition comprising a compound of formula (I), (P-1), (P-2), (Ia)-(Ic), or (P-Ia)-(P-Ic), or a pharmaceutically acceptable salt thereof, or a pharmaceutical combination comprising a compound of formula (I), (P-1), (P-2), (Ia)-(Ic), or (P-Ia)-(P-Ic), or a pharmaceutically acceptable salt thereof.

[0379] In one embodiment, the impairment is selected from liver and kidney impairment.

[0380] In one embodiment, the liver disorder is selected from hepatic fibrosis, cirrhosis, non-alcoholic steatohepatopathy (NASH), and alcoholic steatohepatopathy, which occur in end-stage liver disease.

[0381] In one embodiment, the kidney injury is renal fibrosis resulting from acute kidney injury.

[0382] In one embodiment, the kidney damage is chronic kidney disease.

[0383] In one embodiment, the kidney damage is diabetic nephropathy.

[0384] In another aspect, this disclosure relates to sarcopenia, skin atrophy, senile angioma, seborrheic keratosis, cerebral atrophy (also known as dementia), atherosclerosis, arteriosclerosis, emphysema, osteoporosis, osteoarthritis, hypertension, erectile dysfunction, cataracts, macular degeneration, glaucoma, stroke, cerebrovascular disease (stroke), chronic kidney disease, diabetes-related kidney disease, hepatic insufficiency, hepatic fibrosis, autoimmune hepatitis, endometrial hyperplasia, metabolic dysfunction, renovascular disease, hearing loss, mobility impairment (e.g., frailty), cognitive decline, tendon rigidity, cardiac dysfunction (e.g., cardiac hypertrophy), and / or systolic and / or diastolic dysfunction, and / or hypertension, cardiac dysfunction that reduces ejection fraction, immunosenescence, Parkinson's disease, Alzheimer's disease, cancer, immunosenescence resulting in cancer due to reduced immune surveillance, infections due to decreased immune function, chronic occlusion The present invention provides pharmaceutical compositions containing compounds of formula (I), (P-1), (P-2), (Ia)-(Ic), or (P-Ia)-(P-Ic), or pharmaceutically acceptable salts thereof, or pharmaceutical combinations containing compounds of formula (I), (P-1), (P-2), (Ia)-(Ic), or (P-Ia)-(P-Ic), or pharmaceutically acceptable salts thereof, for use in the prevention or treatment of age-related disorders or diseases selected from among cerebrospinal fluid disease (COPD), obesity, loss of taste, loss of smell, arthritis, and type II diabetes mellitus (including complications arising from diabetes such as renal failure, blindness, and neuropathy).

[0385] In another embodiment, the Disclosure provides a pharmaceutical composition comprising a compound of formula (I), (P-1), (P-2), (Ia)-(Ic), or (P-Ia)-(P-Ic), or a pharmaceutically acceptable salt thereof, for use in the treatment of cancer, or a pharmaceutical combination comprising a compound of formula (I), (P-1), (P-2), (Ia)-(Ic), or (P-Ia)-(P-Ic), or a pharmaceutically acceptable salt thereof, or a pharmaceutical combination comprising a compound of formula (I), (P-1), (P-2), (Ia)-(Ic), or (P-Ia)-(P-Ic), or a pharmaceutically acceptable salt thereof.

[0386] In another aspect, the Disclosure relates to formulas (I), (P-1), (P-2), (Ia)-(Ic), or (P-I) for use in the treatment of kidney cancer, renal cell carcinoma, colorectal cancer, uterine sarcoma, endometrial uterine cancer, endometrial cancer, breast cancer, ovarian cancer, cervical cancer, gastric cancer, fibrosarcoma, pancreatic cancer, liver cancer, melanoma, leukemia, multiple myeloma, nasopharyngeal cancer, prostate cancer, lung cancer, glioblastoma, bladder cancer, mesothelioma, head cancer, rhabdomyosarcoma, sarcoma, lymphoma, or cervical cancer. a) A pharmaceutical composition containing a compound of formula (I), (P-1), (P-2), (Ia)-(Ic), or (P-Ia)-(P-Ic), or a pharmaceutically acceptable salt thereof, or a pharmaceutical combination containing a compound of formula (I), (P-1), (P-2), (Ia)-(Ic), or (P-Ia)-(P-Ic), or a pharmaceutically acceptable salt thereof.

[0387] In another aspect, the disclosure provides the use of compounds of formula (I), (P-1), (P-2), (Ia) to (Ic), or (P-Ia) to (P-Ic), or pharmaceutically acceptable salts thereof, in the manufacture of pharmaceuticals.

[0388] In another aspect, the disclosure provides the use of compounds of formula (I), (P-1), (P-2), (Ia) to (Ic), or (P-Ia) to (P-Ic), or pharmaceutically acceptable salts thereof, in the manufacture of a pharmaceutical product for treating a disorder or disease mediated by the mTOR pathway.

[0389] In another aspect, this disclosure is: • Acute or chronic rejection of organ or tissue transplantation, ·Transplant vasculopathy, • Intimal thickening of vascular tissue, vascular occlusion, obstructive coronary artery atherosclerosis, restenosis, proliferation and migration of smooth muscle cells, • Autoimmune diseases and inflammatory diseases, ·asthma, • Multidrug resistance (MDR), ·Fungal infections, ·inflammation, ·Infectious diseases, • Diseases related to aging, • Neurodegenerative diseases, • Proliferative disorders, such as cancer, • Seizures and seizure-related disorders, and • Mitochondrial myopathy and mitochondrial stress The present invention provides the use of compounds of formula (I), (P-1), (P-2), (Ia) to (Ic), or (P-Ia) to (P-Ic), or pharmaceutically acceptable salts thereof, in the manufacture of pharmaceuticals for treating disorders or diseases selected from the above.

[0390] In another aspect, the disclosure provides the use of compounds of formula (I), (P-1), (P-2), (Ia) to (Ic), or (P-Ia) to (P-Ic), or pharmaceutically acceptable salts thereof, in the manufacture of a pharmaceutical product for treating a disorder or disease including the processes of fibrosis and / or inflammation.

[0391] In one embodiment, the impairment is selected from liver and kidney impairment.

[0392] In one embodiment, the liver disorder is selected from hepatic fibrosis, cirrhosis, non-alcoholic steatohepatopathy (NASH), and alcoholic steatohepatopathy, which occur in end-stage liver disease.

[0393] In one embodiment, the kidney injury is renal fibrosis resulting from acute kidney injury.

[0394] In one embodiment, the kidney damage is chronic kidney disease.

[0395] In one embodiment, the kidney damage is diabetic nephropathy.

[0396] In another aspect, the disclosure relates to sarcopenia, skin atrophy, senile angioma, seborrheic keratosis, cerebral atrophy (also known as dementia), atherosclerosis, arteriosclerosis, emphysema, osteoporosis, osteoarthritis, hypertension, erectile dysfunction, cataracts, macular degeneration, glaucoma, stroke, cerebrovascular disease (stroke), chronic kidney disease, diabetes-related kidney disease, hepatic insufficiency, hepatic fibrosis, autoimmune hepatitis, endometrial hyperplasia, metabolic dysfunction, renovascular disease, hearing loss, mobility impairment, cognitive decline, tendon rigidity, cardiac dysfunction, such as cardiac hypertrophy, and / or systolic and / or diastolic dysfunction, and / or hypertension, cardiac mechanisms that reduce ejection fraction The present invention provides the use of compounds of formula (I), (P-1), (P-2), (Ia) to (Ic), or (P-Ia) to (P-Ic), or pharmaceutically acceptable salts thereof, in the manufacture of pharmaceuticals for preventing or treating age-related disorders or diseases selected from among cognitive impairment, immunosenescence, Parkinson's disease, Alzheimer's disease, cancer, immunosenescence leading to cancer due to reduced immune surveillance, infections due to decreased immune function, chronic obstructive pulmonary disease (COPD), obesity, loss of taste, loss of smell, arthritis, and type II diabetes mellitus (including complications arising from diabetes such as renal failure, blindness, and neuropathy).

[0397] In another aspect, the disclosure provides the use of compounds of formula (I), (P-1), (P-2), (Ia) to (Ic), or (P-Ia) to (P-Ic), or pharmaceutically acceptable salts thereof, in the manufacture of pharmaceuticals for the prevention or treatment of cancer.

[0398] In another aspect, the Disclosure provides the use of compounds of formula (I), (P-1), (P-2), (Ia) to (Ic), or (P-Ia) to (P-Ic), or pharmaceutically acceptable salts thereof, in the manufacture of pharmaceuticals for treating kidney cancer, renal cell carcinoma, colorectal cancer, uterine sarcoma, endometrial uterine cancer, endometrial cancer, breast cancer, ovarian cancer, cervical cancer, gastric cancer, fibrosarcoma, pancreatic cancer, liver cancer, melanoma, leukemia, multiple myeloma, nasopharyngeal cancer, prostate cancer, lung cancer, glioblastoma, bladder cancer, mesothelioma, head cancer, rhabdomyosarcoma, sarcoma, lymphoma, or cervical cancer.

[0399] Details of one or more embodiments of the present disclosure are described herein. Other features, purposes, and advantages of the present disclosure will be evident from the examples, figures / drawings, and claims. [Examples]

[0400] Certain embodiments of this disclosure are illustrated by the following non-limiting examples. Where used herein, the symbols and rules used in these processes, schemes, and examples are consistent with those used in modern scientific literature, such as the Journal of the American Chemical Society or the Journal of Biological Chemistry, regardless of whether specific abbreviations are specifically defined. Specifically, but not limited to, the following abbreviations may be used in the examples and throughout this specification.

[0401] [Table 1-1]

[0402] [Table 1-2]

[0403] Example 1.32 - Synthesis of deoxorapamycin:

[0404] [ka]

[0405] Step 1: To a solution of rapamycin (20 g, 21.88 mmol) in DCM (280 mL), 2,6-lutidine (15.29 mL, 131.26 mmol) and TESOTf (14.84 mL, 65.63 mmol) were added at -40°C and stirred for 1.5 hours. The resulting mixture was diluted with Et2O and quenched with saturated NaHCO3 aqueous solution. The organic phase was separated and washed with saturated NaHCO3 aqueous solution, saturated CuSO4 aqueous solution, and saturated NH4Cl aqueous solution. The combined aqueous phase was re-extracted with Et2O. The combined organic phase was washed with saturated CuSO4 aqueous solution, dried with MgSO4, filtered, and concentrated under vacuum. The residue was dissolved in DCM and subjected to an ISCO silica column, and eluted with ethylacetate / hexane at a gradient of 0-25%, yielding 95% of the intermediate product 1((3S,6R,7E,9R,10R,12R,14S,15E,17E,19E,21S,23S,26R,27R,34aS)-27-hydroxy-10,21-dimethoxy-3-((R)-1-((1S,3R,4R)-3-methoxy-4-((triethylsilyl)oxy)cyclohexyl) Ropan-2-yl)-6,8,12,14,20,26-hexamethyl-9-((triethylsilyl)oxy)-9,10,12,13,14,21,22,23,24,25,26,27,32,33,34,34a-hexadecahydro-3H-23,27-epoxypyrido[2,1-c][1]oxa[4]azacyclohenthriacontin-1,5,11,28,29(4H,6H,31H)-pentaone) was obtained as a white solid. 1 The 1H-NMR data were consistent with the reference (i.e., Tetrahedron Letters, 1994, 35(41), pp. 7557-7560).

[0406] Step 2: Intermediate Product 2((3S,5R,6R,7E,9R,10R,12R,14S,15E,17E,19E,21S,23S,26R,27R,34aS)-5,27-dihydroxy-10,21-dimethoxy-3-((R)-1-((1S,3R,4R)-3-methoxy-4-((triethylsilyl)oxy)cyclohexyl)propan-2-yl)-6,8,12,14,20,26-hexa Methyl-9-((triethylsilyl)oxy)-5,6,9,10,12,13,14,21,22,23,24,25,26,27,32,33,34,34a-octadecahydro-3H-23,27-epoxypyrido[2,1-c][1]oxa[4]azacyclohenthriacontin-1,11,28,29(4H,31H)-tetraone) was prepared according to the procedure in International Publication WO96 / 41807. 1 The H-NMR data was matched.

[0407] Step 3: Intermediate Product 3((3S,5R,6R,7E,9R,10R,12R,14S,15E,17E,19E,21S,23S,26R,27R,34aS)-27-hydroxy-10,21-dimethoxy-3-((R)-1-((1S,3R,4R)-3-methoxy-4-((triethylsilyl)oxy)cyclohexyl)propan-2-yl)-6,8,12,14,20,26-hexamethyl-1,11,28,2 9-Tetraoxo-9-((triethylsilyl)oxy)-1,4,5,6,9,10,11,12,13,14,21,22,23,24,25,26,27,28,29,31,32,33,34,34a-Tetracosahydro-3H-23,27-Epoxypyrido[2,1-c][1]oxa[4]azacyclohenthriacontin-5-ylmethanesulfonate) was prepared according to the procedure in International Publication WO96 / 41807. 1 The H-NMR data was matched.

[0408] Step 4: Intermediate product 4((3S,5S,6R,7E,9R,10R,12R,14S,15E,17E,19E,21S,23S,26R,27R,34aS)-27-hydroxy-5-iodo-10,21-dimethoxy-3-((R)-1-((1S,3R,4R)-3-methoxy-4-((triethylsilyl)oxy)cyclohexyl)propan-2-yl)-6,8,12,14,20,26-hex Samethyl-9-((triethylsilyl)oxy)-5,6,9,10,12,13,14,21,22,23,24,25,26,27,32,33,34,34a-Octadecahydro-3H-23,27-Epoxypyrido[2,1-c][1]oxa[4]azacyclohenthriacontin-1,11,28,29(4H,31H)-tetraone) was prepared according to the procedure in International Publication WO96 / 41807. 1 The H-NMR data was matched.

[0409] Step 5: Intermediate Product 5((3S,6R,7E,9R,10R,12R,14S,15E,17E,19E,21S,23S,26R,27R,34aS)-27-hydroxy-10,21-dimethoxy-3-((R)-1-((1S,3R,4R)-3-methoxy-4-((triethylsilyl)oxy)cyclohexyl)propan-2-yl)-6,8,12,14,20,26-hexamethyl -9-((triethylsilyl)oxy)-5,6,9,10,12,13,14,21,22,23,24,25,26,27,32,33,34,34a-octadecahydro-3H-23,27-epoxypyrido[2,1-c][1]oxa[4]azacyclohenthriacontin-1,11,28,29(4H,31H)-tetraone was prepared according to the procedure in International Publication WO96 / 41807. 1 The H-NMR data was matched.

[0410] Step 6: 32-deoxorapamycin was prepared according to the procedure in International Publication WO96 / 41807. Purification was performed using an ISO silica column, and elution with siRNA / hexane at a gradient of 40-60% yielded 95% of the product as a white solid. 1 The H-NMR data and mass were consistent with the baseline.

[0411] Example 2. Synthesis of representative 32-deoxorapamycin analogs

[0412] Basic condition A1: To a solution of 32-deoxorapamycin (30.0 mg, 0.0333 mmol) and a suitable amine nucleophile (5 equivalents) in DCM (0.67 mL), ZnCl2 (3 equivalents, 1.0 M solution in Et2O) was added at 0°C. The reaction mixture was heated to room temperature and stirred until the 32-deoxorapamycin was consumed. The resulting mixture was diluted with siRNA and quenched with saturated NaHCO3 aqueous solution. The organic phase was separated, and the aqueous phase was extracted three times with siRNA. The combined organic phase was dried over Na2SO4, filtered, and concentrated under vacuum. The residue was dissolved in DMF and eluted on an ISCO C18 RP column with an ACN / water gradient of 60-85% (0.05% AcOH added as a modifier) ​​to obtain the product.

[0413] Basic Condition B1: To a solution of 32-deoxorapamycin (30.0 mg, 0.0333 mmol) and a suitable amine nucleophile (20 equivalents) in DCM (0.67 mL), pTSA·H2O (5 equivalents) was added at room temperature. The reaction mixture was stirred at room temperature until 32-deoxorapamycin was consumed. The resulting mixture was diluted with siRNA and quenched with saturated NaHCO3 aqueous solution. The organic phase was separated, and the aqueous phase was extracted three times with siRNA. The combined organic phase was dried over Na2SO4, filtered, and concentrated under vacuum. The residue was dissolved in DMF and eluted on an ISCO C18 RP column with an ACN / water gradient of 60–85% (0.05% AcOH added as a modifier) ​​to obtain the product.

[0414] Compound 3:

[0415] [ka]

[0416] Basic condition A1 was applied. This procedure was modified using 20 equivalents of triazole and 15 equivalents of ZnCl2. Furthermore, 1.0 mL of ACN was added as a co-solvent. The reaction was completed by stirring the mixture at 39°C for 5 days. Compound 3 was isolated as a 6.1% white solid. Mass calculated 936.58, found 935.93 (MH). - .

[0417] Compound 4:

[0418] [ka]

[0419] Basic condition A1 was applied. This procedure was modified using 10 equivalents of pyrazole and 10 equivalents of ZnCl2. The reaction was completed by stirring the mixture at room temperature for 2 days. Compound 4 was isolated as a 13% white solid. Mass calculated 935.59, found 934.93 (MH) - .

[0420] Compound 5:

[0421] [ka]

[0422] Basic condition A1 was applied. The reaction was completed by stirring the mixture at room temperature for 2 hours. Compound 5 was isolated as a white solid at 32%. Mass calculated 1002.59, found 1001.99 (MH). - .

[0423] Compound 6:

[0424] [ka]

[0425] Basic condition A1 was applied. This procedure was modified using 30 equivalents of triazole and 10 equivalents of ZnCl2. Additionally, 2.0 mL of THF was added as a co-solvent. The reaction was completed by stirring the mixture at 39°C for 2 days. Compound 6 was isolated as a 10% white solid. Mass calculated 936.58, found 938.06 (M+H). + .

[0426] Compound 8:

[0427] [ka]

[0428] Basic condition A1 was applied. This procedure was modified using 20 equivalents of tetrazole and 15 equivalents of ZnCl2. The reaction was completed by stirring the mixture at room temperature for 1 hour. Compound 8 was isolated as a white solid at 11%. Mass calculated 937.58, found 939.05 (M+H) + .

[0429] Compound 9:

[0430] [ka]

[0431] Basic condition A1 was applied. The reaction was completed by stirring the mixture at room temperature for 2 hours. Compound 9 was isolated as a white solid at 25%. Mass calculated 1004.60, found 1004.04 (MH). - .

[0432] Compound 10:

[0433] [ka]

[0434] Basic condition A1 was applied. The reaction was completed by stirring the mixture at room temperature for 2 hours. Compound 10 was isolated as a white solid at 18%. Mass calculated 990.5g, found 989.68mg (MH). - .

[0435] Compound 11:

[0436] [ka]

[0437] Basic condition A1 was applied. Additionally, 0.6 mL of ACN was added as a co-solvent. The reaction was completed by stirring the mixture at room temperature for 6 hours. Compound 11 was isolated as a 9.5% white solid. Mass calculated 1006.58, found 1006.06 (MH). - .

[0438] Compound 12:

[0439] [ka]

[0440] Basic condition A1 was applied. Additionally, 0.6 mL of ACN was added as a co-solvent. The reaction was completed by stirring the mixture at room temperature for 2 hours. Compound 12 was isolated as a white solid at 8.3%. Mass calculated 1005.63, found 1006.73 (M+H). + .

[0441] Compound 13:

[0442] [ka]

[0443] Basic condition A1 was applied. Additionally, 0.6 mL of ACN was added as a co-solvent. The reaction was completed by stirring the mixture at room temperature for 16 hours. Compound 14 was isolated as a 22% white solid. Mass calculated 991.61, found 991.01 (MH). - .

[0444] Compound 14:

[0445] [ka]

[0446] Basic condition A1 was applied. This procedure was modified using 10 equivalents of sulfonamide and 6 equivalents of ZnCl2. The reaction was completed by stirring the mixture at room temperature for 5 days. Compound 14 was isolated as a yellow solid at 11%. Mass calculated 951.58, found 950.89 (MH) - .

[0447] Compound 15:

[0448] [ka]

[0449] Basic condition A1 was applied. The reaction was completed by stirring the reactants at room temperature for 16 hours. Compound 15 was isolated as a white solid at 5.7%. Mass calculated 978.63, found 979.92 (M+H) + .

[0450] The following compounds were prepared under basic conditions A2, B2, C2, D2, or E2.

[0451] Basic condition A2: To a solution of 32-deoxorapamycin (30.0 mg, 0.0333 mmol) and a suitable amine nucleophile (10 equivalents) in DCM (0.67 mL), ZnCl2 (10 equivalents, 1.0 M solution in Et2O) was added at room temperature. The reaction mixture was stirred until 32-deoxorapamycin was consumed. The resulting mixture was diluted with siRNA and quenched with saturated NaHCO3 aqueous solution. The organic phase was separated, and the aqueous phase was extracted three times with siRNA. The combined organic phase was dried over Na2SO4, filtered, and concentrated under vacuum. The residue was dissolved in DMF and eluted on an ISCO C18 RP column with a gradient of (30-60)-(80-90)% ACN / water (with 0.05% TFA added as a modifier) ​​to obtain the product.

[0452] Basic Condition B2: To a solution of 32-deoxorapamycin (30.0 mg, 0.0333 mmol) and a suitable amine nucleophile (20 equivalents) in DCM (0.67 mL), pTSA·H2O (5 equivalents) was added at room temperature. The reaction mixture was stirred at room temperature until 32-deoxorapamycin was consumed. The resulting mixture was diluted with siRNA and quenched with saturated NaHCO3 aqueous solution. The organic phase was separated, and the aqueous phase was extracted three times with siRNA. The combined organic phase was dried over Na2SO4, filtered, and concentrated under vacuum. The residue was dissolved in DMF and eluted on an ISCO C18 RP column with an ACN / water gradient of 60–85% (0.05% AcOH added as a modifier) ​​to obtain the product.

[0453] Basic Condition C2: To a solution of 32-deoxorapamycin (30.0 mg, 0.0333 mmol) and a suitable amine nucleophile (10 equivalents) in THF (0.67 mL), BF3·Et2O (15 equivalents) was added at room temperature. The reaction was stirred at room temperature until 32-deoxorapamycin was consumed. The resulting mixture was diluted with siRNA and quenched with saturated NaHCO3 aqueous solution. The organic phase was separated, and the aqueous phase was extracted three times with siRNA. The combined organic phase was dried over Na2SO4, filtered, and concentrated under vacuum. The residue was dissolved in DMF and eluted on an ISCO C18 RP column with a gradient of (30-60)-(80-90)% ACN / water (with 0.05% AcOH added as a modifier) ​​to obtain the product.

[0454] Basic condition D2: 32-deoxorapamycin (60.0 mg, 0.0667 mmol) and a suitable amine nucleophile (10 equivalents) in DCM / ACN (1:1) (2.7 mL) were mixed, and Zn(OTf)2 (6 equivalents) was added at room temperature. The reaction mixture was stirred at room temperature until all 32-deoxorapamycin was consumed. The resulting mixture was diluted with ethyl acetate and quenched with saturated aqueous NaHCO3. The organic phase was separated, and the aqueous phase was extracted three times with ethyl acetate. The combined organic phase was dried over Na2SO4, filtered, and concentrated under vacuum. The residue was dissolved in DMF and eluted on an ISCO C18 RP column with an ACN / water gradient of 50–95% (with 0.05% AcOH added as a modifier) ​​to obtain the product.

[0455] Basic conditions E2: To a solution of 32-deoxorapamycin (60.0 mg, 0.0667 mmol) and a suitable amine nucleophile (10 equivalents) in DCM (3 mL) at -40°C, TFA (20 equivalents) was added, and the reaction mixture was warmed to room temperature. The reaction mixture was stirred at room temperature until 32-deoxorapamycin was consumed. The resulting mixture was diluted with siRNA and quenched with saturated NaHCO3 aqueous solution. The organic phase was separated, and the aqueous phase was extracted three times with siRNA. The combined organic phase was dried over Na2SO4, filtered, and concentrated under vacuum. The residue was dissolved in DMF and eluted on an ISCO C18 RP column with an ACN / water gradient of 30-80% (0.05% AcOH added as a modifier) ​​to obtain the product.

[0456] Compound 16:

[0457] [ka]

[0458] Basic condition A2 was applied. ZnCl2 (10 equivalents, 1.0 M solution in Et2O) was added at room temperature to a solution of 32-deoxorapamycin (30.0 mg, 0.0333 mmol) and a sulfonamide nucleophile (10 equivalents) in DCM (0.67 mL). The reaction mixture was stirred until 32-deoxorapamycin was consumed. The resulting mixture was diluted with siRNA and quenched with saturated NaHCO3 aqueous solution. The organic phase was separated, and the aqueous phase was extracted three times with siRNA. The combined organic phase was dried over Na2SO4, filtered, and concentrated under vacuum. The residue was dissolved in DMF and eluted on an ISCO C18 RP column with a gradient of (30-60)-(80-90)% ACN / water (with 0.05% TFA added as a modifier) ​​to obtain the product. The reaction mixture was stirred for 1 hour to complete the reaction. Compound 16 was isolated and re-purified using a 150 × 30 Phenomenex Gemini reversed-phase column, eluting at 40–80% to obtain the product as a white solid with a purity of 15.5%, and the mixture was obtained in a yield of 30.2%. Mass calculated 1023.56, found 1024.56 (MH) - .

[0459] Compound 17:

[0460] [ka]

[0461] Basic condition A2 was applied. ZnCl2 (10 equivalents, 1.0 M solution in Et2O) was added at room temperature to a solution of 32-deoxorapamycin (30.0 mg, 0.0333 mmol) and a sulfonamide nucleophile (10 equivalents) in DCM (0.67 mL). The reaction mixture was stirred until 32-deoxorapamycin was consumed. The resulting mixture was diluted with siRNA and quenched with saturated NaHCO3 aqueous solution. The organic phase was separated, and the aqueous phase was extracted three times with siRNA. The combined organic phase was dried over Na2SO4, filtered, and concentrated under vacuum. The residue was dissolved in DMF and eluted on an ISCO C18 RP column with a gradient of (30-60)-(80-90)% ACN / water (with 0.05% TFA added as a modifier) ​​to obtain the product. The reaction mixture was stirred for 4 days to complete the reaction. Compound 17 was isolated and re-purified using a 150 × 30 Phenomenex Gemini reversed-phase column. The product was eluted at 35–75% purity to obtain a white solid with a purity of 1.4%, and the mixture was obtained in 5% yield. Mass calculated 10²⁶.57, found 10²⁷.30 (M+H) + .

[0462] Compound 18:

[0463] [ka]

[0464] Basic condition C2 was applied. BF3·Et2O (15 equivalents) was added at room temperature to a solution of 32-deoxorapamycin (30.0 mg, 0.0333 mmol) and a sulfonamide nucleophile (10 equivalents) in THF (0.67 mL). The reaction mixture was stirred at room temperature until 32-deoxorapamycin was consumed. The resulting mixture was diluted with siRNA and quenched with saturated NaHCO3 aqueous solution. The organic phase was separated, and the aqueous phase was extracted three times with siRNA. The combined organic phase was dried over Na2SO4, filtered, and concentrated under vacuum. The residue was dissolved in DMF and eluted on an ISCO C18 RP column with a gradient of (30-60)-(80-90)% ACN / water (with 0.05% AcOH added as a modifier) ​​to obtain the product. The reaction mixture was stirred for 5 hours to complete the process. Compound 18 was isolated and re-purified using a 150 × 30 Phenomenex Gemini reversed-phase column, eluting at 30–80% to obtain the product as a pale yellow solid in 12.4% yield. Mass calculated 10²⁴.56, found 10²⁵.13 (MH). - .

[0465] Compound 19:

[0466] [ka]

[0467] Basic condition C2 was applied. BF3·Et2O (15 equivalents) was added at room temperature to a solution of 32-deoxorapamycin (30.0 mg, 0.0333 mmol) and a sulfonamide nucleophile (10 equivalents) in THF (0.67 mL). The reaction mixture was stirred at room temperature until 32-deoxorapamycin was consumed. The resulting mixture was diluted with siRNA and quenched with saturated NaHCO3 aqueous solution. The organic phase was separated, and the aqueous phase was extracted three times with siRNA. The combined organic phase was dried over Na2SO4, filtered, and concentrated under vacuum. The residue was dissolved in DMF and eluted on an ISCO C18 RP column with a gradient of (30-60)-(80-90)% ACN / water (with 0.05% AcOH added as a modifier) ​​to obtain the product. The reaction mixture was stirred for 5 hours to complete the process. Compound 19 was isolated and re-purified using a 150 × 30 Phenomenex Gemini reversed-phase column. The product was obtained as a pale yellow solid in 7% yield by elution at 30–80%. Mass calculated 1024.56, found 1026.46 (MH). - .

[0468] Compound 20:

[0469] [ka]

[0470] Basic condition A was applied. ZnCl2 (15 equivalents) and ACN (0.67 mL) were added to the reactant, and the reaction was stirred for 3 days to complete. Compound 20 was isolated and re-purified using a 150 × 30 Phenomenex Gemini reversed-phase column. The product was obtained as a yellow solid in 7.3% yield by elution at 40–80%. Mass calculated 962.61, found 963.31 (M+H) + .

[0471] Compound 21:

[0472] [ka]

[0473] Basic condition C2 was applied. BF3·Et2O (15 equivalents) was added at room temperature to a solution of 32-deoxorapamycin (30.0 mg, 0.0333 mmol) and an amine nucleophile (10 equivalents) in THF (0.67 mL). The reaction mixture was stirred at room temperature until 32-deoxorapamycin was consumed. The resulting mixture was diluted with siRNA and quenched with saturated NaHCO3 aqueous solution. The organic phase was separated, and the aqueous phase was extracted three times with siRNA. The combined organic phase was dried over Na2SO4, filtered, and concentrated under vacuum. The residue was dissolved in DMF and eluted on an ISCO C18 RP column with a gradient of (30-60)-(80-90)% ACN / water (with 0.05% AcOH added as a modifier) ​​to obtain the product. The reaction mixture was stirred for 3 hours to complete the process. Compound 21 was isolated and re-purified using a 150 × 30 Phenomenex Gemini reversed-phase column. The product was obtained as a white solid in 9% yield by elution at 30–80%, and the mixture in 10.2% yield. Mass calculated 962.61, found 963.31 (M+H). + .

[0474] Compound 22:

[0475] [ka]

[0476] Basic condition C2 was applied. BF3·Et2O (15 equivalents) was added at room temperature to a solution of 32-deoxorapamycin (30.0 mg, 0.0333 mmol) and the corresponding amine nucleophile (10 equivalents) in THF (0.67 mL). The reaction mixture was stirred at room temperature until 32-deoxorapamycin was consumed. The resulting mixture was diluted with ELISA and quenched with saturated NaHCO3 aqueous solution. The organic phase was separated, and the aqueous phase was extracted three times with ELISA. The combined organic phase was dried over Na2SO4, filtered, and concentrated under vacuum. The residue was dissolved in DMF and eluted on an ISCO C18 RP column with a gradient of (30-60)-(80-90)% ACN / water (with 0.05% AcOH added as a modifier) ​​to obtain the product. The reaction mixture was stirred for 3 hours to complete the process. Compound 22 was isolated and re-purified using a 150 × 30 Phenomenex Gemini reversed-phase column, eluting at 30–80% to obtain the product as a white solid in 1.54% yield, and the mixture in 2.89% yield. Mass calculated 962.61, found 963.28 (M+H) + .

[0477] Compound 23:

[0478] [ka]

[0479] Basic condition E2 was applied. To a solution of 32-deoxorapamycin (60.0 mg, 0.0667 mmol) and an amine nucleophile (10 equivalents) in DCM (3 mL) at -40°C, TFA (20 equivalents) at room temperature was added. The reaction mixture was stirred at room temperature until 32-deoxorapamycin was consumed. The resulting mixture was diluted with siRNA and quenched with saturated NaHCO3 aqueous solution. The organic phase was separated, and the aqueous phase was extracted three times with siRNA. The combined organic phase was dried over Na2SO4, filtered, and concentrated under vacuum. The residue was dissolved in DMF and eluted through an ISCO C18 RP column with an ACN / water gradient of 30-80% (0.05% AcOH added as a modifier) ​​to obtain the product. The reaction mixture was stirred for 19 hours to complete the process. Compound 23 was isolated and re-purified using a 150 × 30 Phenomenex Gemini reversed-phase column, eluting at 30–80% to obtain the product as a yellowish-brown solid in 7.6% yield, and the mixture in 5.6% yield. Mass calculated 965.62, found 966.35 (M+H) + .

[0480] Compound 24:

[0481] [ka]

[0482] Basic condition E2 was applied. To a solution of 32-deoxorapamycin (60.0 mg, 0.0667 mmol) and an amine nucleophile (10 equivalents) in DCM (3 mL) at -40°C, TFA (20 equivalents) at room temperature was added. The reaction mixture was stirred at room temperature until 32-deoxorapamycin was consumed. The resulting mixture was diluted with siRNA and quenched with saturated NaHCO3 aqueous solution. The organic phase was separated, and the aqueous phase was extracted three times with siRNA. The combined organic phase was dried over Na2SO4, filtered, and concentrated under vacuum. The residue was dissolved in DMF and eluted through an ISCO C18 RP column with an ACN / water gradient of 30-80% (0.05% AcOH added as a modifier) ​​to obtain the product. The reaction mixture was stirred for 2 hours to complete the process. Compound 24 was isolated and re-purified using a 150 × 30 Phenomenex Gemini reversed-phase column, eluting at 30–80% to obtain the product as a yellowish-brown solid in 14.9% yield, and the mixture in 21.6% yield. Mass calculated 950.57, found 951.08 (MH). - .

[0483] Compound 26(3S,6S,7E,9R,10R,12R,14S,15E,17E,19E,23S,26R,27R,34aS)-9,27-dihydroxy-3-((R)-1-((1S,3R,4R)-4-hydroxy-3-methoxycyclohexyl)propan-2-yl)-10-methoxy-6,8,12,14,20,26-hexamethyl-21-( Phenylamino)-5,6,9,10,12,13,14,21,22,23,24,25,26,27,32,33,34,34a-Octadecahydro-3H-23,27-Epoxypyrido[2,1-c][1]oxa[4]azacyclohenthriacontin-1,11,28,29(4H,31H)-tetraone;16-Aniline-32-Deoxolapamycin:

[0484] [ka]

[0485] To a stirred solution of 32-deoxorapamycin (80 mg, 0.088 mmol) in DCM (2 mL), aniline (0.080 mL, 0.888 mmol) and TFA (0.136 mL, 1.776 mmol) were added at -20°C and stirred for 2 hours. The resulting mixture was diluted with siRNA and quenched with saturated NaHCO3 aqueous solution. The aqueous layer was extracted with siRNA, and the combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude product was dissolved in DMF and eluted from 60-80% ACN / H2O on an ISCO C18 column. The pure product fraction was freeze-dried to obtain compound 26 as a 7.3 mg (9%) white solid. MS(ESI)calc'd for C 56 H 84 N2O 11 +H=960.61, found 960.08.

[0486] Compound 27(3S,6S,7E,9R,10R,12R,14S,15E,17E,19E,23S,26R,27R,34aS)-9,27-dihydroxy-3-((R)-1-((1S,3R,4R)-4-hydroxy-3-methoxycyclohexyl)propan-2-yl)-10-methoxy-6,8,12,14,20,26-hexamethyl-21-((5-methylisoxazole-3-yl) (Lu)amino)-5,6,9,10,12,13,14,21,22,23,24,25,26,27,32,33,34,34a-octadecahydro-3H-23,27-epoxypyrido[2,1-c][1]oxa[4]azacyclohentriacontin-1,11,28,29(4H,31H)-tetraone;16-(3-amino-5-methylisoxazole)-32-deoxolapamycin:

[0487] [ka]

[0488] To a stirred solution of 32-deoxorapamycin (80 mg, 0.088 mmol) in DCM (2 mL), 3-amino-5-methylisoxazole (87 mg, 0.888 mmol) and TFA (0.136 mL, 1.779 mmol) were added at -20°C and stirred for 2 hours. The resulting mixture was diluted with siRNA and quenched with saturated NaHCO3 aqueous solution. The aqueous layer was extracted with siRNA, and the combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude product was dissolved in DMF and eluted from 60-80% ACN / H2O on an ISCO C18 column. The pure product fraction was freeze-dried to obtain compound 27 as a 5.8 mg (7%) white solid. MS(ESI)calc'd for C 54 H 83 N3O 12 +H=965.61, found 965.10.

[0489] Compound 28(3S,6S,7E,9R,10R,12R,14S,15E,17E,19E,23S,26R,27R,34aS)-9,27-dihydroxy-3-((R)-1-((1S,3R,4R)-4-hydroxy-3-methoxycyclohexyl)propan-2-yl)-10-methoxy-6,8,12,14,20,26-hexamethyl-21-((6-methylpyrazine-2-yl) (Lu)amino)-5,6,9,10,12,13,14,21,22,23,24,25,26,27,32,33,34,34a-octadecahydro-3H-23,27-epoxypyrido[2,1-c][1]oxa[4]azacyclohentriacontin-1,11,28,29(4H,31H)-tetraone;16-(2-amino-6-methylpyrazine)-32-deoxolapamycin:

[0490] [ka]

[0491] To a stirred solution of 32-deoxorapamycin (50 mg, 0.055 mmol) in DCM (2 mL), 2-amino-6-methylpyrazine (61 mg, 0.555 mmol) and TFA (0.085 mL, 1.112 mmol) were added at -20°C and stirred for 2 hours. The resulting mixture was diluted with ethyl acetate and quenched with saturated aqueous NaHCO3 solution. The aqueous layer was extracted with ethyl acetate, and the combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude product was dissolved in DMF and eluted from 60-80% ACN / H2O on an ISCO C18 column. The pure product fraction was freeze-dried to obtain compound 28 as a 7.2 mg (13%) white solid. MS(ESI)calc'd for C 55 H 84 N4O 11 +H=976.61, found 976.31.

[0492] Compound 29,(3S,6S,7E,9R,10R,12R,14S,15E,17E,19E,23S,26R,27R,34aS)-9,27-dihydroxy-3-((R)-1-((1S,3R,4R)-4-hydroxy-3-methoxycyclohexyl)propan-2-yl)-10-methoxy-6,8,12,14,20,26-hexamethyl-21 -((1-methyl-1H-pyrazole-5-yl)amino)-5,6,9,10,12,13,14,21,22,23,24,25,26,27,32,33,34,34a-octadecahydro-3H-23,27-epoxypyrido[2,1-c][1]oxa[4]azacyclohenthriacontin-1,11,28,29(4H,31H)-tetraone

[0493] [ka]

[0494] To a stirred solution of 32-deoxorapamycin (60 mg, 0.066 mmol) in DCM (2 mL), 1,2,5-oxazole-3-amine (66 mg, 0.666 mmol) and TFA (0.102 mL, 1.322 mmol) were added at -20°C and stirred for 2 hours. The resulting mixture was diluted with siRNA and quenched with saturated NaHCO3 aqueous solution. The aqueous layer was extracted with siRNA, and the combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude product was dissolved in DMF and eluted from 60-80% ACN / H2O on an ISCO C18 column. The pure product fraction was freeze-dried to obtain 1.3 mg (2%) of white solid. MS(ESI-)calc'd for C 52 H 80 N4O 12 -H=964.61, found 964.11.

[0495] Compound 30(3S,6S,7E,9R,10R,12R,14S,15E,17E,19E,23S,26R,27R,34aS)-21-((1,2,4-oxazol-3-yl)amino)-9,27-dihydroxy-3-((R)-1-((1S,3R,4R)-4-hydroxy-3-methoxycyclohexyl)propan-2-yl)-10-methoxy-6,8,12,14,20,26- Hexamethyl-5,6,9,10,12,13,14,21,22,23,24,25,26,27,32,33,34,34a-Octadecahydro-3H-23,27-Epoxypyrido[2,1-c][1]oxa[4]azacyclohenthriacontin-1,11,28,29(4H,31H)-tetraone;(16-(1,2,4-oxazole-3-amine)-32-deoxolapamycin:

[0496] [ka]

[0497] To a stirred solution of 32-deoxorapamycin (50 mg, 0.055 mmol) in DCM (2 mL), 1,2,4-oxazole-3-amine (55 mg, 0.555 mmol) and TFA (0.085 mL, 1.112 mmol) were added at -20°C and stirred for 2 hours. The resulting mixture was diluted with Âlyde and quenched with saturated NaHCO3 aqueous solution. The aqueous layer was extracted with Âlyde 52 H 80 N4O 12 +H=952.58, found 952.17.

[0498] Additional compounds were synthesized as described below.

[0499] Compound 31:

[0500] [ka]

[0501] Dimethylphosphinate chloride (12.5 mg, 0.111 mmol) was added at 0°C to a solution of 32-deoxorapamycin (20.0 mg, 0.0222 mmol) and 2,6-di-tert-butyl-4-methylpyridine (36.5 mg, 0.178 mmol) in DCM (0.22 mL) and stirred for 2 hours. The resulting mixture was diluted with siRNA and quenched with saturated NaHCO3 aqueous solution. The organic phase was separated, and the aqueous phase was extracted three times with siRNA. The combined organic phase was dried over Na2SO4, filtered, and concentrated under vacuum. The residue was dissolved in DCM and eluted on an ISCO silica column with an acetone / hexane gradient of 0-100% to obtain 65% compound 31 as a white solid. Mass calculated 975.58, found 974.69 (MH) - .

[0502] Compound 32:

[0503] [ka]

[0504] Basic condition A1 was applied. The reaction was completed by stirring the mixture for 2 hours. Compound 32 was isolated as a white solid at 21%. Mass calculated 974.55, found 973.25 (MH). - .

[0505] Compound 33:

[0506] [ka]

[0507] Basic condition B1 was applied. The reaction was completed by stirring the reactants for 0.5 hours. Compound 33 was isolated as a white solid at 53%. Mass calculated 988.57, found 987.19 (MH). - .

[0508] Compound 34:

[0509] [ka]

[0510] To a solution of 32-deoxorapamycin (20.0 mg, 0.0222 mmol) and 2,6-lutidine (6.4 μL, 0.0556 mmol) in DCM (0.28 mL), Tf2O (6.0 μL, 0.0333 mmol) was added at -30°C and the mixture was stirred for 30 minutes. The reaction mixture was warmed to 0°C and stirred for another 30 minutes. Next, 1-H-tetrazole (5.4 mg, 0.0778 mmol) and DIPEA (0.019 mL, 0.111 mmol) were added to the solution and the mixture was stirred at room temperature for 16 hours. The resulting mixture was diluted with ethyl acetate and quenched with saturated aqueous NaHCO3. The organic phase was separated, and the aqueous phase was extracted three times with ethyl acetate. The combined organic phase was dried over Na2SO4, filtered, and concentrated under vacuum. The residue was dissolved in DFM and eluted through an ISCO C18 RP column with an ACN / water gradient of 50-100% (with 0.5% AcOH added as a modifier) ​​to obtain 69% of compound 34 as a yellow solid. Mass calculated 951.59, found 951.26 (MH). - .

[0511] Compound 35:

[0512] [ka]

[0513] Basic condition B1 was applied. The reaction was completed by stirring the mixture for 2 days. Compound 35 was isolated as a white solid at 39%. Mass calculated 967.61, found 966.88 (MH). - .

[0514] Compound 36:

[0515] [ka]

[0516] To a solution of 40-phosphinate-32-deoxorapamycin (19.0 mg, 0.0195 mmol) and ethane sultam (10.4 mg, 0.0974 mmol) in DCM (0.39 mL), ZnCl2 (0.0584 mL, 0.0584 mmol, 1.0 M solution in Et2O) was added at room temperature. The reaction mixture was stirred at room temperature for 30 minutes. The resulting mixture was diluted with ethyl acetate and quenched with saturated aqueous NaHCO3 solution. The organic phase was separated, and the aqueous phase was extracted three times with ethyl acetate. The combined organic phase was dried over Na2SO4, filtered, and concentrated under vacuum. The residue was dissolved in DMF and eluted on an ISCO C18 RP column with an ACN / water gradient of 50-90% (0.5% AcOH added as a modifier) ​​to isolate compound 36 as a 29% white solid. Mass calculated 1050.56,found 1049.67(MH) - .

[0517] Compound 37:

[0518] [ka]

[0519] To a solution of 40-dimethylphosphinate-32-deoxorapamycin (compound 31, 20.0 mg, 0.0205 mmol) and propylsultam (24.8 mg, 0.205 mmol) in ACN (0.21 mL), pTSA·H2O (0.4 mg, 0.0021 mmol) was added at room temperature. The reaction mixture was stirred at room temperature for 2 hours. The resulting mixture was diluted with ethyl acetate and quenched with saturated aqueous NaHCO3 solution. The organic phase was separated, and the aqueous phase was extracted three times with ethyl acetate. The combined organic phase was dried over Na2SO4, filtered, and concentrated under vacuum. The residue was dissolved in DMF and eluted on an ISCO C18 RP column with an ACN / water gradient of 50–90% (0.5% AcOH added as a modifier) ​​to isolate compound 37 as a 49% white solid. Mass calculated 1064.58,found 1063.76(MH) - .

[0520] Compound 38:

[0521] [ka]

[0522] Basic condition A1 was applied. The reaction was completed by stirring the reactants for 2 hours. Compound 38 was isolated as a white solid at 20%. Mass calculated 1026.57, found 1025.51 (MH).

[0523] Compound 39:

[0524] [ka]

[0525] Basic condition B1 was applied. ACN was used as the solvent instead of DCM. The reaction was completed by stirring the mixture for 1 hour. Compound 39 was isolated as a white solid at 32%. Mass calculated 1040.59, found 1063.85 (M+Na). + .

[0526] Compound 40:

[0527] [ka]

[0528] Basic condition A1 was applied. The reaction was completed by stirring the mixture at room temperature for 1 hour. Compound 40 was isolated as a white solid at 19%. Mass calculated 976.57, found 975.70 (MH). - .

[0529] Compound 41:

[0530] [ka]

[0531] Basic condition A1 was applied. This procedure was modified using 10 equivalents of sulfonamide and 8 equivalents of ZnCl2. Additionally, 2.0 mL of ACN was added as a co-solvent. The reaction was completed by stirring the mixture at 39°C for 2 days. Compound 41 was isolated as a 4.9% white solid. Mass calculated 962.55, found 962.26 (MH). - .

[0532] Compound 42:

[0533] [ka]

[0534] Basic condition A1 was applied. This procedure was modified using 20 equivalents of sulfonamide and 15 equivalents of ZnCl2. THF was used as the solvent instead of DCM. The reaction was completed by stirring the mixture at 39°C for 5 days. Compound 42 was isolated as a 5.5% white solid. Mass calculated 988.57, found 987.94 (MH). - .

[0535] Compound 43(3S,6S,7E,9R,10R,12R,14S,15E,17E,19E,23S,26R,27R,34aS)-21-((3-chlorophenyl)amino)-9,27-dihydroxy-3-((R)-1-((1S,3R,4R)-4-hydroxy-3-methoxycyclohexyl)propan-2-yl)-10-methoxy- 6,8,12,14,20,26-Hexamethyl-5,6,9,10,12,13,14,21,22,23,24,25,26,27,32,33,34,34a-Octadecahydro-3H-23,27-Epoxypyrido[2,1-c][1]oxa[4]azacyclohenthriacontin-1,11,28,29(4H,31H)-Tetraone

[0536] [ka]

[0537] To a stirred solution of 32-deoxorapamycin (50 mg, 0.055 mmol) in DCM (2 mL), 3-chloroaniline (0.049 mL, 0.555 mmol) and TFA (0.085 mL, 1.112 mmol) were added at -20°C and stirred for 2 hours. The resulting mixture was diluted with ethyl acetate and quenched with saturated aqueous NaHCO3 solution. The aqueous layer was extracted with ethyl acetate, and the combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude product was dissolved in DMF and eluted from 60-80% ACN / H2O on an ISCO C18 column. The pure product fraction was freeze-dried to obtain compound 43 as an 8.1 mg (15%) white solid. MS(ESI-)calc'd for C 56 H 83 ClN2O 11 -H=994.57, found 994.05.

[0538] Compound 44(3S,6S,7E,9R,10R,12R,14S,15E,17E,19E,23S,26R,27R,34aS)-9,27-dihydroxy-3-((R)-1-((1S,3R,4R)-4-hydroxy-3-methoxycyclohexyl)propan-2-yl)-10-methoxy-21-((3-methoxyphenyl)amino)- 6,8,12,14,20,26-Hexamethyl-5,6,9,10,12,13,14,21,22,23,24,25,26,27,32,33,34,34a-Octadecahydro-3H-23,27-Epoxypyrido[2,1-c][1]oxa[4]azacyclohenthriacontin-1,11,28,29(4H,31H)-Tetraone

[0539] [ka]

[0540] To a stirred solution of 32-deoxorapamycin (50 mg, 0.055 mmol) in DCM (2 mL), meta-anisidine (0.062 mL, 0.555 mmol) and TFA (0.085 mL, 1.112 mmol) were added at -20°C and stirred for 2 hours. The resulting mixture was diluted with ethyl acetate and quenched with saturated aqueous NaHCO3 solution. The aqueous layer was extracted with ethyl acetate, and the combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude product was dissolved in DMF and eluted from 60-80% ACN / H2O on an ISCO C18 column. The pure product fraction was freeze-dried to obtain compound 44 as a 3.0 mg (5%) white solid. MS(ESI-)calc'd for C 57 H 86 N2O 12 -H=990.62, found 990.14.

[0541] Compound 45(3S,6S,7E,9R,10R,12R,14S,15E,17E,19E,23S,26R,27R,34aS)-21-((1,2,5-oxazol-3-yl)amino)-9,27-dihydroxy-3-((R)-1-((1S,3R,4R)-4-hydroxy-3-methoxycyclohexyl)propan-2-yl)-10-meth Xy-6,8,12,14,20,26-Hexamethyl-5,6,9,10,12,13,14,21,22,23,24,25,26,27,32,33,34,34a-Octadecahydro-3H-23,27-Epoxypyrido[2,1-c][1]oxa[4]azacyclohenthriacontin-1,11,28,29(4H,31H)-tetraone.

[0542] [ka]

[0543] To a stirred solution of 32-deoxorapamycin (30 mg, 0.033 mmol) in DCM (2 mL), 1,2,5-oxazole-3-amine (30 mg, 0.333 mmol) and TFA (0.051 mL, 3.32 mmol) were added at -20°C and stirred for 2 hours. The resulting mixture was diluted with Âlyde and quenched with saturated NaHCO3 aqueous solution. The aqueous layer was extracted with Âlyde, and the combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude product was dissolved in DMF and eluted from 60-80% ACN / H2O on an ISCO C18 column. The pure product fraction was freeze-dried to obtain compound 45 as a 9.5 mg (30%) white solid. MS(ESI-)calc'd for C 57 H 86 N2O 12 -H=952.58, found 952.03.

[0544] Compound 46.N-((3S,6S,7E,9R,10R,12R,14S,15E,17E,19E,23S,26R,27R,34aS)-9,27-dihydroxy-3-((R)-1-((1S,3R,4R)-4-hydroxy-3-methoxycyclohexyl)propan-2-yl)-10-methoxy-6,8,12,14,20,26-hexamethyl-1,11,28 ,29-Tetraoxo-1,4,5,6,9,10,11,12,13,14,21,22,23,24,25,26,27,28,29,31,32,33,34,34a-Tetracosahydro-3H-23,27-Epoxypyrido[2,1-c][1]oxa[4]azacyclohentricontin-21-yl)-3,5-dimethylisoxazole-4-sulfonamide.

[0545] [ka]

[0546] To a stirred solution of 32-deoxorapamycin (80 mg, 0.089 mmol) in DCM (2 mL), dimethyl-1,2-oxazole-4-sulfonamide (157 mg, 0.899 mmol) and ZnCl2 (0.889 mL, 0.889 mmol) were added at -20°C and stirred for 2 hours. The resulting mixture was diluted with siRNA and quenched with saturated NaHCO3 aqueous solution. The aqueous layer was extracted with siRNA, and the combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude product was dissolved in DMF and eluted from 60-80% ACN / H2O on an ISCO C18 column. The pure product fraction was freeze-dried to obtain compound 46 as an 8.3 mg (9%) white solid. MS(ESI-)calc'd for C 55 H 85 N3O 14 SH=1043.58, found 1042.87.

[0547] Compound 47(3S,6S,7E,9R,10R,12R,14S,15E,17E,19E,23S,26R,27R,34aS)-9,27-dihydroxy-3-((R)-1-((1S,3R,4R)-4-hydroxy-3-methoxycyclohexyl)propan-2-yl)-10-methoxy-21-((4-methoxyphenyl)amino)- 6,8,12,14,20,26-Hexamethyl-5,6,9,10,12,13,14,21,22,23,24,25,26,27,32,33,34,34a-Octadecahydro-3H-23,27-Epoxypyrido[2,1-c][1]oxa[4]azacyclohenthriacontin-1,11,28,29(4H,31H)-tetraone.

[0548] [ka]

[0549] To a stirred solution of 32-deoxorapamycin (50 mg, 0.055 mmol) in DCM (2 mL), para-anisidine (0.064 mL, 0.556 mmol) and TFA (0.085 mL, 1.112 mmol) were added at -20°C and stirred for 4 hours. The resulting mixture was diluted with ethyl acetate and quenched with saturated NaHCO3 aqueous solution. The aqueous layer was extracted with ethyl acetate, and the combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude product was dissolved in DMF and eluted from 60-80% ACN / H2O on an ISCO C18 column. The pure product fraction was freeze-dried to obtain 2.0 mg (4%) of white solid. MS(ESI-)calc'd for C 57 H 86 N2O 12 -H=991.32, found 990.67.

[0550] Compound 48.(3S,6S,7E,9R,10R,12R,14S,15E,17E,19E,23S,26R,27R,34aS)-21-((4-chlorophenyl)amino)-9,27-dihydroxy-3-((R)-1-((1S,3R,4R)-4-hydroxy-3-methoxycyclohexyl)propan-2-yl)-10-methoxy- 6,8,12,14,20,26-Hexamethyl-5,6,9,10,12,13,14,21,22,23,24,25,26,27,32,33,34,34a-Octadecahydro-3H-23,27-Epoxypyrido[2,1-c][1]oxa[4]azacyclohenthriacontin-1,11,28,29(4H,31H)-tetraone.

[0551] [ka]

[0552] To a stirred solution of 32-deoxorapamycin (50 mg, 0.055 mmol) in DCM (2 mL), 4-chloroaniline (0.050 mL, 0.556 mmol) and TFA (0.085 mL, 1.112 mmol) were added at -20°C and stirred for 2 hours. The resulting mixture was diluted with ethyl acetate and quenched with saturated NaHCO3 aqueous solution. The aqueous layer was extracted with ethyl acetate, and the combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude product was dissolved in DMF and eluted from 60-80% ACN / H2O on an ISCO C18 column. The pure product fraction was freeze-dried to obtain 5.2 mg (9%) of white solid. MS(ESI-)calc'd for C 56 H 83 ClN2O 11 -H=994.57, found 993.86.

[0553] Compound 49(3S,6S,7E,9R,10R,12R,14S,15E,17E,19E,23S,26R,27R,34aS)-9,27-dihydroxy-3-((R)-1-((1S,3R,4R)-4-hydroxy-3-methoxycyclohexyl)propan-2-yl)-10-methoxy-6,8,12,14,20,26-hex Samethyl-21-(p-tolylamino)-5,6,9,10,12,13,14,21,22,23,24,25,26,27,32,33,34,34a-Octadecahydro-3H-23,27-Epoxypyrido[2,1-c][1]oxa[4]azacyclohenthriacontin-1,11,28,29(4H,31H)-tetraone.

[0554] [ka]

[0555] To a stirred solution of 32-deoxorapamycin (50 mg, 0.055 mmol) in DCM (2 mL), para-toluidine (0.060 mL, 0.556 mmol) and TFA (0.085 mL, 1.112 mmol) were added at -20°C and stirred for 2 hours. The resulting mixture was diluted with ethyl acetate and quenched with saturated NaHCO3 aqueous solution. The aqueous layer was extracted with ethyl acetate, and the combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude product was dissolved in DMF and eluted from 60-80% ACN / H2O on an ISCO C18 column. The pure product fraction was freeze-dried to obtain 1.6 mg (3%) of white solid. MS(ESI-)calc'd for C 57 H 86 N2O 11 -H=974.62, found 973.76.

[0556] Compound 50(3S,6S,7E,9R,10R,12R,14S,15E,17E,19E,23S,26R,27R,34aS)-9,27-dihydroxy-3-((R)-1-((1S,3R,4R)-4-hydroxy-3-methoxycyclohexyl)propan-2-yl)-10-methoxy-6,8,12,14,20,26-hex Samethyl-21-(m-tolylamino)-5,6,9,10,12,13,14,21,22,23,24,25,26,27,32,33,34,34a-Octadecahydro-3H-23,27-Epoxypyrido[2,1-c][1]oxa[4]azacyclohenthriacontin-1,11,28,29(4H,31H)-tetraone.

[0557] [ka]

[0558] To a stirred solution of 32-deoxorapamycin (50 mg, 0.055 mmol) in DCM (2 mL), meta-toluidine (0.060 mL, 0.556 mmol) and TFA (0.085 mL, 1.112 mmol) were added at -20°C and stirred for 2 hours. The resulting mixture was diluted with ethyl acetate and quenched with saturated NaHCO3 aqueous solution. The aqueous layer was extracted with ethyl acetate, and the combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude product was dissolved in DMF and eluted from 60-80% ACN / H2O on an ISCO C18 column. The pure product fraction was freeze-dried to obtain 2.5 mg (5%) of white solid. MS(ESI-)calc'd for C 57 H 86 N2O 11 -H=974.62, found 973.95.

[0559] compound 51

[0560] N-((3S,6S,7E,9R,10R,12R,14S,15E,17E,19E,23S,26R,27R,34aS)-9,27-dihydroxy-3-((R)-1-((1S,3R,4R)-4-hydroxy-3-methoxycyclohexyl)propan-2-yl)-10-methoxy-6,8,12,14,20,26-hexamethyl-1,11,28, 29-Tetraoxo-1,4,5,6,9,10,11,12,13,14,21,22,23,24,25,26,27,28,29,31,32,33,34,34a-Tetracosahydro-3H-23,27-Epoxypyrido[2,1-c][1]oxa[4]azacyclohentriacontin-21-yl)-5-methylisoxazole-4-sulfonamide.

[0561] [ka]

[0562] To a stirred solution of 32-deoxorapamycin (80 mg, 0.089 mmol) in DCM (2 mL), 5-methyl-1,2-oxazole-4-sulfonamide (144 mg, 0.889 mmol) and ZnCl2 (0.889 mL, 0.889 mmol) were added at room temperature and stirred for 3 hours. The resulting mixture was diluted with siRNA and quenched with saturated NaHCO3 aqueous solution. The aqueous layer was extracted with siRNA, and the combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude product was dissolved in DMF and eluted from 60-80% ACN / H2O on an ISCO C18 column. The pure product fraction was freeze-dried to obtain 4.1 mg (9%) of a white solid. MS(ESI-)calc'd for C 54 H 83 N3O 14 SH=1030.33, found 1029.16.

[0563] Compound 52(3S,6S,7E,9R,10R,12R,14S,15E,17E,19E,23S,26R,27R,34aS)-9,27-dihydroxy-3-((R)-1-((1S,3R,4R)-4-hydroxy-3-methoxycyclohexyl)propan-2-yl)-10-methoxy-6,8,12,14,20,26-hex Samethyl-21-(p-tolylamino)-5,6,9,10,12,13,14,21,22,23,24,25,26,27,32,33,34,34a-Octadecahydro-3H-23,27-Epoxypyrido[2,1-c][1]oxa[4]azacyclohenthriacontin-1,11,28,29(4H,31H)-tetraone.

[0564] [ka]

[0565] To a stirred solution of 32-deoxorapamycin (50 mg, 0.055 mmol) in DCM (2 mL), aminopyrazine (53 mg, 0.556 mmol) and TFA (0.085 mL, 1.112 mmol) were added at -20°C and stirred for 2 hours. The resulting mixture was diluted with ethyl acetate and quenched with saturated NaHCO3 aqueous solution. The aqueous layer was extracted with ethyl acetate, and the combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude product was dissolved in DMF and eluted from 60-80% ACN / H2O on an ISCO C18 column. The pure product fraction was freeze-dried to obtain 4.2 mg (8%) of white solid. MS(ESI-)calc'd for C 54 H 82 N4O 11 -H=962.60, found 961.91.

[0566] compound 53

[0567] N-((3S,6S,7E,9R,10R,12R,14S,15E,17E,19E,23S,26R,27R,34aS)-9,27-dihydroxy-3-((R)-1-((1S,3R,4R)-4-hydroxy-3-methoxycyclohexyl)propan-2-yl)-10-methoxy-6,8,12,14,20,26-hexamethyl-1,11,28, 29-Tetraoxo-1,4,5,6,9,10,11,12,13,14,21,22,23,24,25,26,27,28,29,31,32,33,34,34a-Tetracosahydro-3H-23,27-Epoxypyrido[2,1-c][1]oxa[4]azacyclohentriacontin-21-yl)-3-methylisoxazole-4-sulfonamide.

[0568] [ka]

[0569] To a stirred solution of 32-deoxorapamycin (80 mg, 0.089 mmol) in DCM (2 mL), 3-methyl-1,2-oxazole-4-sulfonamide (144 mg, 0.889 mmol) and ZnCl2 (0.889 mL, 0.889 mmol) were added at room temperature and stirred for 3 hours. The resulting mixture was diluted with siRNA and quenched with saturated NaHCO3 aqueous solution. The aqueous layer was extracted with siRNA, and the combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude product was dissolved in DMF and eluted from 60-80% ACN / H2O on an ISCO C18 column. The pure product fraction was freeze-dried to obtain 1.7 mg (2%) of white solid. MS(ESI-)calc'd for C 54 H 83 N3O 14 SH=1030.33, found 1029.27.

[0570] Compound 54(3S,6S,7E,9R,10R,12R,14S,15E,17E,19E,23S,26R,27R,34aS)-9,27-dihydroxy-3-((R)-1-((1S,3R,4R)-4-hydroxy-3-methoxycyclohexyl)propan-2-yl)-10-methoxy-6,8,12,14,20,26-hexamethyl-21 -((3-(trifluoromethyl)phenyl)amino)-5,6,9,10,12,13,14,21,22,23,24,25,26,27,32,33,34,34a-octadecahydro-3H-23,27-epoxypyrido[2,1-c][1]oxa[4]azacyclohenthriacontin-1,11,28,29(4H,31H)-tetraone.

[0571] [ka]

[0572] To a stirred solution of 32-deoxorapamycin (50 mg, 0.055 mmol) in DCM (2 mL), 3-trifluoromethylaniline (0.065 mL, 0.556 mmol) and TFA (0.085 mL, 1.112 mmol) were added at -20°C and stirred for 2 hours. The resulting mixture was diluted with ethyl acetate and quenched with saturated aqueous NaHCO3 solution. The aqueous layer was extracted with ethyl acetate, and the combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude product was dissolved in DMF and eluted from 60-80% ACN / H2O on an ISCO C18 column. The pure product fraction was freeze-dried to obtain 6.5 mg (11%) of white solid. MS(ESI-)calc'd for C 57 H 83 F3N2O 11 -H=1028.57, found 1027.90.

[0573] Compound 55(3S,6S,7E,9R,10R,12R,14S,15E,17E,19E,23S,26R,27R,34aS)-9,27-dihydroxy-3-((R)-1-((1S,3R,4R)-4-hydroxy-3-methoxycyclohexyl)propan-2-yl)-10-methoxy-6,8,12,14,20,26-hexamethyl-21 -((4-(trifluoromethyl)phenyl)amino)-5,6,9,10,12,13,14,21,22,23,24,25,26,27,32,33,34,34a-octadecahydro-3H-23,27-epoxypyrido[2,1-c][1]oxa[4]azacyclohenthriacontin-1,11,28,29(4H,31H)-tetraone.

[0574] [ka]

[0575] To a stirred solution of 32-deoxorapamycin (50 mg, 0.055 mmol) in DCM (2 mL), 4-trifluoromethylaniline (0.065 mL, 0.556 mmol) and TFA (0.085 mL, 1.112 mmol) were added at -20°C and stirred for 2 hours. The resulting mixture was diluted with ethyl acetate and quenched with saturated aqueous NaHCO3 solution. The aqueous layer was extracted with ethyl acetate, and the combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude product was dissolved in DMF and eluted from 60-80% ACN / H2O on an ISCO C18 column. The pure product fraction was freeze-dried to obtain 2.3 mg (4%) of white solid. MS(ESI-)calc'd for C 57 H 83 F3N2O 11 -H=1028.57, found 1028.05.

[0576] Compound 56(4-(((3S,6S,7E,9R,10R,12R,14S,15E,17E,19E,23S,26R,27R,34aS)-9,27-dihydroxy-3-((R)-1-((1S,3R,4R)-4-hydroxy-3-methoxycyclohexyl)propan-2-yl)-10-methoxy-6,8,12,14,20,26-hexamethyl -1,11,28,29-Tetraoxo-1,4,5,6,9,10,11,12,13,14,21,22,23,24,25,26,27,28,29,31,32,33,34,34a-Tetracosahydro-3H-23,27-Epoxypyrido[2,1-c][1]oxa[4]azacyclohentriacontin-21-yl)amino)benzonitrile)

[0577] [ka]

[0578] To a stirred solution of 32-deoxorapamycin (50 mg, 0.055 mmol) in DCM (8 mL), 4-aminobenzonitrile (0.065 mL, 0.556 mmol) and TFA (0.085 mL, 1.112 mmol) were added at -20°C, and the reaction mixture was stirred for 3 hours. The resulting mixture was diluted with ethyl acetate and quenched with saturated aqueous NaHCO3 solution. The aqueous layer was extracted with ethyl acetate, and the combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude product was dissolved in DMF and eluted from 60-80% ACN / H2O on an ISCO C18 column. The pure product fraction was freeze-dried to obtain 2.4 mg (4%) of white solid. MS(ESI-)calc'd for C 57 H 83 N3O 11 -H=985.60, found 985.08.

[0579] Compound 57(3-(((3S,6S,7E,9R,10R,12R,14S,15E,17E,19E,23S,26R,27R,34aS)-9,27-dihydroxy-3-((R)-1-((1S,3R,4R)-4-hydroxy-3-methoxycyclohexyl)propan-2-yl)-10-methoxy-6,8,12,14,20,26-hexameth Ru-1,11,28,29-tetraoxo-1,4,5,6,9,10,11,12,13,14,21,22,23,24,25,26,27,28,29,31,32,33,34,34a-tetracosahydro-3H-23,27-epoxypyrido[2,1-c][1]oxa[4]azacyclohentriacontin-21-yl)amino)benzonitrile

[0580] [ka]

[0581] To a stirred solution of 32-deoxorapamycin (75 mg, 0.083 mmol) in DCM (10 mL), 3-aminobenzonitrile (0.065 mL, 0.556 mmol) and TFA (0.085 mL, 1.112 mmol) were added at -20°C and stirred for 3 hours. The resulting mixture was diluted with siRNA and quenched with saturated NaHCO3 aqueous solution. The aqueous layer was extracted with siRNA, and the combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude product was dissolved in DMF and eluted from 60-80% ACN / H2O on an ISCO C18 column. The pure product fraction was freeze-dried to obtain 3.1 mg (6%) of white solid. MS(ESI-)calc'd for C 57 H 83 N3O 11 -H=984.60, found 985.01.

[0582] Compound 58((3S,6S,7E,9R,10R,12R,14S,15E,17E,19E,23S,26R,27R,34aS)-9,27-dihydroxy-3-((R)-1-((1S,3R,4R)-4-hydroxy-3-methoxycyclohexyl)propan-2-yl)-10-methoxy-6,8,12,14,20,26-hexamethyl-21 -((3-(trifluoromethoxy)phenyl)amino)-5,6,9,10,12,13,14,21,22,23,24,25,26,27,32,33,34,34a-octadecahydro-3H-23,27-epoxypyrido[2,1-c][1]oxa[4]azacyclohentriacontin-1,11,28,29(4H,31H)-tetraone)

[0583] [ka]

[0584] To a stirred solution of 32-deoxorapamycin (50 mg, 0.055 mmol) in DCM (10 mL), 3-trifluoromethoxyaniline (0.076 mL, 0.834 mmol) and TFA (0.128 mL, 1.667 mmol) were added at -20°C and stirred for 3 hours. The resulting mixture was diluted with siRNA and quenched with saturated NaHCO3 aqueous solution. The aqueous layer was extracted with siRNA, and the combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude product was dissolved in DMF and eluted from 60-80% ACN / H2O on an ISCO C18 column. The pure product fraction was freeze-dried to obtain 10.9 mg (13%) of white solid. MS(ESI-)calc'd for C 57 H 83 F3N2O 12 -H=1043.59, found 1044.09.

[0585] Compound 59((3S,6S,7E,9R,10R,12R,14S,15E,17E,19E,23S,26R,27R,34aS)-21-((3-ethoxyphenyl)amino)-9,27-dihydroxy-3-((R)-1-((1S,3R,4R)-4-hydroxy-3-methoxycyclohexyl)propan-2-yl)-10-methoxy- 6,8,12,14,20,26-Hexamethyl-5,6,9,10,12,13,14,21,22,23,24,25,26,27,32,33,34,34a-Octadecahydro-3H-23,27-Epoxypyrido[2,1-c][1]oxa[4]azacyclohenthriacontin-1,11,28,29(4H,31H)-Tetraone)

[0586] [ka]

[0587] To a stirred solution of 32-deoxorapamycin (75 mg, 0.083 mmol) in DCM (10 mL), 3-ethoxyaniline (0.095 mL, 0.834 mmol) and TFA (0.128 mL, 1.667 mmol) were added at -20°C and stirred for 3 hours. The resulting mixture was diluted with siRNA and quenched with saturated NaHCO3 aqueous solution. The aqueous layer was extracted with siRNA, and the combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude product was dissolved in DMF and eluted from 60-80% ACN / H2O on an ISCO C18 column. The pure product fraction was freeze-dried to obtain 6.5 mg (8%) of white solid. MS(ESI-)calc'd for C 58 H 88 N2O 12 -H=1003.63, found 1003.97

[0588] Compound 60((3S,6S,7E,9R,10R,12R,14S,15E,17E,19E,23S,26R,27R,34aS)-9,27-dihydroxy-3-((R)-1-((1S,3R,4R)-4-hydroxy-3-methoxycyclohexyl)propan-2-yl)-10-methoxy-6,8,12,14,20,26-hexamyl Chil-21-(thiophene-3-ylamino)-5,6,9,10,12,13,14,21,22,23,24,25,26,27,32,33,34,34a-octadecahydro-3H-23,27-epoxypyrido[2,1-c][1]oxa[4]azacyclohenthriacontin-1,11,28,29(4H,31H)-tetraone)

[0589] [ka]

[0590] To a stirred solution of 32-deoxorapamycin (75 mg, 0.083 mmol) in DCM (10 mL), thiophene-3-amine hydrochloride (113 mg, 0.834 mmol) and TFA (0.128 mL, 1.667 mmol) were added at -20°C and stirred for 3 hours. The resulting mixture was diluted with siRNA and quenched with saturated NaHCO3 aqueous solution. The aqueous layer was extracted with siRNA, and the combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude product was dissolved in DMF and eluted from 60-80% ACN / H2O on an ISCO C18 column. The pure product fraction was freeze-dried to obtain 2.0 mg (2%) of white solid. MS(ESI-)calc'd for C 54 H 82 N2O 11 SH=965.56, found 965.86

[0591] Compound 61(N-((3S,6S,7E,9R,10R,12R,14S,15E,17E,19E,23S,26R,27R,34aS)-9,27-dihydroxy-3-((R)-1-((1S,3R,4R)-4-hydroxy-3-methoxycyclohexyl)propan-2-yl)-10-methoxy-6,8,12,14,20,26-hexamethyl-1, 11,28,29-Tetraoxo-1,4,5,6,9,10,11,12,13,14,21,22,23,24,25,26,27,28,29,31,32,33,34,34a-Tetracosahydro-3H-23,27-Epoxypyrido[2,1-c][1]oxa[4]azacyclohentricontin-21-yl)isoxazole-4-sulfonamide)

[0592] [ka]

[0593] To a stirred solution of 32-deoxorapamycin (75 mg, 0.083 mmol) in DCM (10 mL), 1,2-oxazole-4-sulfonamide (124 mg, 0.834 mmol) and ZnCl2 (0.834 mL, 0.834 mmol) were added at room temperature and stirred for 16 hours. The resulting mixture was diluted with siRNA and quenched with saturated NaHCO3 aqueous solution. The aqueous layer was extracted with siRNA, and the combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude product was dissolved in DMF and eluted from 60-80% ACN / H2O on an ISCO C18 column. The pure product fraction was freeze-dried to obtain 1.0 mg (1%) of white solid. MS(ESI-)calc'd for C 53 H 81 N3O 14 SH=1015.54, found 1015.14.

[0594] Compound 62((3S,6S,7E,9R,10R,12R,14S,15E,17E,19E,23S,26R,27R,34aS)-9,27-dihydroxy-3-((R)-1-((1S,3R,4R)-4-hydroxy-3-methoxycyclohexyl)propan-2-yl)-10-methoxy-21-((3-methoxyphenyl)(methyl)amine (n)-6,8,12,14,20,26-Hexamethyl-5,6,9,10,12,13,14,21,22,23,24,25,26,27,32,33,34,34a-Octadecahydro-3H-23,27-Epoxypyrido[2,1-c][1]oxa[4]azacyclohenthriacontin-1,11,28,29(4H,31H)-Tetraone)

[0595] [ka]

[0596] To a stirred solution of 32-deoxorapamycin (75 mg, 0.083 mmol) in DCM (10 mL), 3-methoxy-N-methylaniline (0.094 mL, 0.834 mmol) and TFA (0.128 mL, 1.667 mmol) were added at -20°C and stirred for 6 hours. The resulting mixture was diluted with siRNA and quenched with saturated NaHCO3 aqueous solution. The aqueous layer was extracted with siRNA, and the combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude product was dissolved in DMF and eluted from 60-80% ACN / H2O on an ISCO C18 column. The pure product fraction was freeze-dried to obtain 5.8 mg (7%) of white solid. MS(ESI-)calc'd for C 58 H 88 N2O 12 -H=1004.63, found 1004.39

[0597] Compound 63((3S,6S,7E,9R,10R,12R,14S,15E,17E,19E,23S,26R,27R,34aS)-9,27-dihydroxy-3-((R)-1-((1S,3R,4R)-4-hydroxy-3-methoxycyclohexyl)propan-2-yl)-10-methoxy-6,8,12,14,20,26-hexa Methyl-21-(methyl(phenyl)amino)-5,6,9,10,12,13,14,21,22,23,24,25,26,27,32,33,34,34a-Octadecahydro-3H-23,27-Epoxypyrido[2,1-c][1]oxa[4]azacyclohentriacontin-1,11,28,29(4H,31H)-tetraone)

[0598] [ka]

[0599] To a stirred solution of 32-deoxorapamycin (100 mg, 0.111 mmol) in DCM (10 mL), N-methylaniline (0.120 mL, 1.112 mmol) and TFA (0.170 mL, 2.223 mmol) were added at -20°C and stirred for 6 hours. The resulting mixture was diluted with siRNA and quenched with saturated NaHCO3 aqueous solution. The aqueous layer was extracted with siRNA, and the combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude product was dissolved in DMF and eluted from 60-80% ACN / H2O on an ISCO C18 column. The pure product fraction was freeze-dried to obtain 2.6 mg (3%) of white solid. MS(ESI-)calc'd for C 57 H 86 N2O 11 -H=974.62, found 974.07.

[0600] Compound 64(3S,6S,7E,9R,10R,12R,14S,15E,17E,19E,21S,23S,26R,27R,34aS)-9,27-dihydroxy-3-((R)-1-((1S,3R,4R)-4-hydroxy-3-methoxycyclohexyl)propan-2-yl)-10-methoxy-6,8,12,14,20,26-hex Samethyl-21-(methyl(phenyl)amino)-5,6,9,10,12,13,14,21,22,23,24,25,26,27,32,33,34,34a-Octadecahydro-3H-23,27-Epoxypyrido[2,1-c][1]oxa[4]azacyclohenthriacontin-1,11,28,29(4H,31H)-tetraone:

[0601] [ka]

[0602] To a stirred solution of 32-deoxorapamycin (200 mg, 0.222 mmol) in DCM (10 mL), N-methylaniline (0.240 mL, 2.223 mmol) and TFA (0.340 mL, 4.445 mmol) were added at -20°C and stirred for 16 hours to reach room temperature. The resulting mixture was diluted with siRNA and quenched with saturated NaHCO3 aqueous solution. The aqueous layer was extracted with siRNA, and the combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude product was dissolved in DMF and eluted from 60-80% ACN / H2O on an ISCO C18 column. The pure product fraction was freeze-dried to obtain 4.1 mg (2%) of white solid. MS(ESI-)calc'd for C 57 H 86 N2O 11 -H=974.62, found 974.33

[0603] Compound 65(3S,6S,7E,9R,10R,12R,14S,15E,17E,19E,23S,26R,27R,34aS)-21-(3,4-dihydroquinoline-1(2H)-yl)-9,27-dihydroxy-3-((R)-1-((1S,3R,4R)-4-hydroxy-3-methoxycyclohexyl)propan-2-yl)-10-meth Xy-6,8,12,14,20,26-Hexamethyl-5,6,9,10,12,13,14,21,22,23,24,25,26,27,32,33,34,34a-Octadecahydro-3H-23,27-Epoxypyrido[2,1-c][1]oxa[4]azacyclohenthriacontin-1,11,28,29(4H,31H)-Tetraone:

[0604] [ka]

[0605] To a stirred solution of 32-deoxorapamycin (200 mg, 0.222 mmol) in DCM (10 mL), 1,2,3,4-tetrahydroisoquinoline (0.278 mL, 2.223 mmol) and TFA (0.340 mL, 4.445 mmol) were added at -20°C and stirred for 16 hours to reach room temperature. The resulting mixture was diluted with siRNA and quenched with saturated NaHCO3 aqueous solution. The aqueous layer was extracted with siRNA, and the combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude product was dissolved in DMF and eluted from 60-80% ACN / H2O on an ISCO C18 column. The pure product fraction was freeze-dried to obtain 4.8 mg (2%) of white solid. MS(ESI-)calc'd for C 57 H 86 N2O 11 -H=1000.64, found 1000.17.

[0606] Compound 66(3S,6S,7E,9R,10R,12R,14S,15E,17E,19E,21R,23S,26R,27R,34S)-21-(1,1-dioxideisothiazolidine-2-yl)-9,27-dihydroxy-3-((R)-1-((1S,3R,4R)-4-hydroxy-3-methoxycyclohexyl)propan-2-yl)-10- Methoxy-6,8,12,14,20,26-Hexamethyl-5,6,9,10,12,13,14,21,22,23,24,25,26,27,32,33,34,34a-Octadecahydro-3H-23,27-Epoxypyrido[2,1-c][1]oxa[4]azacyclohenthriacontin-1,11,28,29(4H,31H)-Tetraone:

[0607] [ka]

[0608] To a stirred solution of 32-deoxorapamycin (100 mg, 0.111 mmol) in DCM (10 mL), 1,3-propanesultam (0.136 mL, 1.112 mmol) and ZnCl2 (1.112 mL, 1.112 mmol) were added at room temperature and stirred for 16 hours. The resulting mixture was diluted with siRNA and quenched with saturated NaHCO3 aqueous solution. The aqueous layer was extracted with siRNA, and the combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude product was dissolved in DMF and eluted from 60-80% ACN / H2O on an ISCO C18 column. The pure product fraction was freeze-dried to obtain 14.4 mg (13%) of white solid. MS(ESI-)calc'd for C 53 H 84 N2O 13 SH=988.57, found 988.16.

[0609] Compound 67: (3S,6S,7E,9R,10R,12R,14S,15E,17E,19E,21R,23S,26R,27R,34S)-21-(1,1-dioxideisothiazolidine-2-yl)-9,27-dihydroxy-3-((R)-1-((1S,3R,4R)-4-hydroxy-3-methoxycyclohexyl)propan-2-yl)-10 -Methoxy-6,8,12,14,20,26-Hexamethyl-5,6,9,10,12,13,14,21,22,23,24,25,26,27,32,33,34,34a-Octadecahydro-3H-23,27-Epoxypyrido[2,1-c][1]oxa[4]azacyclohenthriacontin-1,11,28,29(4H,31H)-Tetraone

[0610] [ka]

[0611] To a stirred solution of 32-deoxorapamycin (100 mg, 0.111 mmol) in DCM (10 mL), 1,3-propanesultam (0.136 mL, 1.112 mmol) and ZnCl2 (1.112 mL, 1.112 mmol) were added at room temperature and stirred for 16 hours. The resulting mixture was diluted with siRNA and quenched with saturated NaHCO3 aqueous solution. The aqueous layer was extracted with siRNA, and the combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude product was dissolved in DMF and eluted from 60-80% ACN / H2O on an ISCO C18 column. The pure product fraction was freeze-dried to obtain 8.5 mg (8%) of white solid. MS(ESI-)calc'd for C 53 H 84 N2O 13 SH=988.57, found 988.01.

[0612] Compound 68: (3S,6S,7E,9R,10R,12R,14S,15E,17E,19E,23S,26R,27R,34aS)-9,27-dihydroxy-3-((R)-1-((1S,3R,4R)-4-hydroxy-3-methoxycyclohexyl)propan-2-yl)-21-((2-hydroxyethyl)(phenyl)amino)-10-meth Xy-6,8,12,14,20,26-Hexamethyl-5,6,9,10,12,13,14,21,22,23,24,25,26,27,32,33,34,34a-Octadecahydro-3H-23,27-Epoxypyrido[2,1-c][1]oxa[4]azacyclohenthriacontin-1,11,28,29(4H,31H)-Tetraone:

[0613] [ka]

[0614] To a stirred solution of 32-deoxorapamycin (75 mg, 0.083 mmol) in DCM (10 mL), 2-(phenylamino)ethanol (0.122 mL, 0.834 mmol) and TFA (0.128 mL, 1.667 mmol) were added at -20°C and stirred for 16 hours to reach room temperature. The resulting mixture was diluted with siRNA and quenched with saturated NaHCO3 aqueous solution. The aqueous layer was extracted with siRNA, and the combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude product was dissolved in DMF and eluted from 60-80% ACN / H2O on an ISCO C18 column. The pure product fraction was freeze-dried to obtain 15.5 mg (19%) of white solid. MS(ESI-)calc'd for C58H88N2O12-H=1004.63,found 1004.08.

[0615] Compound 69: (3S,6S,7E,9R,10R,12R,14S,15E,17E,19E,23S,26R,27R,34aS)-9,27-dihydroxy-3-((R)-1-((1S,3R,4R)-4-hydroxy-3-methoxycyclohexyl)propan-2-yl)-10-methoxy-21-((2-methoxyethyl)(phenyl)amine (no)-6,8,12,14,20,26-Hexamethyl-5,6,9,10,12,13,14,21,22,23,24,25,26,27,32,33,34,34a-Octadecahydro-3H-23,27-Epoxypyrido[2,1-c][1]oxa[4]azacyclohenthriacontin-1,11,28,29(4H,31H)-tetraone:

[0616] [ka]

[0617] To a stirred solution of 32-deoxorapamycin (75 mg, 0.083 mmol) in DCM (10 mL), N-(2-methoxyethyl)aniline (0.125 mL, 0.834 mmol) and TFA (0.128 mL, 1.667 mmol) were added at -20°C and stirred for 16 hours to reach room temperature. The resulting mixture was diluted with siRNA and quenched with saturated NaHCO3 aqueous solution. The aqueous layer was extracted with siRNA, and the combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude product was dissolved in DMF and eluted from 60-80% ACN / H2O on an ISCO C18 column. The pure product fraction was freeze-dried to obtain 2.7 mg (3%) of white solid. MS(ESI-)calc'd for C59H90N2O12-H=10¹⁸.65, found 10¹⁸.21.

[0618] Compound 70: (3S,6S,7E,9R,10R,12R,14S,15E,17E,19E,23S,26R,27R,34aS)-21-((3-(difluoromethoxy)phenyl)amino)-9,27-dihydroxy-3-((R)-1-((1S,3R,4R)-4-hydroxy-3-methoxycyclohexyl)propan-2-yl)-10-methyl Toxy-6,8,12,14,20,26-Hexamethyl-5,6,9,10,12,13,14,21,22,23,24,25,26,27,32,33,34,34a-Octadecahydro-3H-23,27-Epoxypyrido[2,1-c][1]oxa[4]azacyclohenthriacontin-1,11,28,29(4H,31H)-Tetraone:

[0619] [ka]

[0620] To a stirred solution of 32-deoxorapamycin (100 mg, 0.111 mmol) in DCM (10 mL), 3-difluoromethoxyaniline (0.139 mL, 1.112 mmol) and TFA (0.170 mL, 2.223 mmol) were added at -20°C and stirred at room temperature for 16 hours. The resulting mixture was diluted with siRNA and quenched with saturated NaHCO3 aqueous solution. The aqueous layer was extracted with siRNA, and the combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude product was dissolved in DMF and eluted from 60-80% ACN / H2O on an ISCO C18 column. The pure product fraction was freeze-dried to obtain 7.7 mg (7%) of white solid. MS(ESI-)calc'd for C57H84F2N2O12-H=1026.60, found 1026.16.

[0621] compound 71

[0622] [ka]

[0623] (1R,2R,4S)-4-((2R)-2-((3S,6S,7E,9R,10R,12R,14S,15E,17E,19E,23S,26R,27R,34aS)-9,27-dihydroxy-10-methoxy-21-((2-methoxyethyl)(phenyl)amino)-6,8,12,14,20,26-hexamethyl-1,11,28,29-tetraoxy So-1,4,5,6,9,10,11,12,13,14,21,22,23,24,25,26,27,28,29,31,32,33,34,34a-Tetracosahydro-3H-23,27-Epoxypyrido[2,1-c][1]oxa[4]azacyclohentriacontin-3-yl)propyl)-2-methoxycyclohexyldimethylphosphinate.

[0624] Compound 71 was prepared in the same manner as compound 69, using compound 31 as the starting material.

[0625] compound 72

[0626] N-((3S,6S,7E,9R,10R,12R,14S,15E,17E,19E,23S,26R,27R,34aS)-9,27-dihydroxy-3-((R)-1-((1S,3R,4R)-4-hydroxy-3-methoxycyclohexyl)propan-2-yl)-10-methoxy-6,8,12,14,20,26-hexamethyl-1,11, 28,29-Tetraoxo-1,4,5,6,9,10,11,12,13,14,21,22,23,24,25,26,27,28,29,31,32,33,34,34a-Tetracosahydro-3H-23,27-Epoxypyrido[2,1-c][1]oxa[4]azacyclohentriacontin-21-yl)-3-methylbenzenesulfonamide.

[0627] [ka]

[0628] To a stirred solution of 32-deoxorapamycin (50 mg, 0.055 mmol) in DCM (6 mL), 3-methylbenzene-1-sulfonamide (95 mg, 0.555 mmol) and ZnCl2 (0.56 mL, 0.555 mmol) were added at room temperature and stirred for 16 hours. The resulting mixture was diluted with Âlyde and quenched with saturated NaHCO3 aqueous solution. The aqueous layer was extracted with Âlyde, and the combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude product was dissolved in DMF and eluted from an ISCO C18 column using 60-80% ACN / H2O. The pure product fraction was freeze-dried to obtain 4.2 mg (7%) of yellow solid RGN-3768. MS(ESI-)calc'd for C57H86N2O13S-H=1038.59, found 1038.62.

[0629] compound 73

[0630] N-((3S,6S,7E,9R,10R,12R,14S,15E,17E,19E,23S,26R,27R,34aS)-9,27-dihydroxy-3-((R)-1-((1S,3R,4R)-4-hydroxy-3-methoxycyclohexyl)propan-2-yl)-10-methoxy-6,8,12,14,20,26-hexamethyl-1,11, 28,29-Tetraoxo-1,4,5,6,9,10,11,12,13,14,21,22,23,24,25,26,27,28,29,31,32,33,34,34a-Tetracosahydro-3H-23,27-Epoxypyrido[2,1-c][1]oxa[4]azacyclohentriacontin-21-yl)-N-methylbenzenesulfonamide.

[0631] To a stirred solution of 32-deoxorapamycin (50 mg, 0.055 mmol) in DCM (6 mL), N-methylbenzenesulfonamide (0.080 mL, 0.555 mmol) and ZnCl2 (0.56 mL, 0.555 mmol) were added at room temperature, and the mixture was stirred for 16 hours. The resulting mixture was diluted with Âlyde and quenched with saturated NaHCO3 aqueous solution. The aqueous layer was extracted with Âlyde, and the combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude product was dissolved in DMF and eluted from an ISCO C18 column using 60-80% ACN / H2O. The pure product fraction was freeze-dried to obtain 26.9 mg (52%) of yellow solid RGN-3769. MS(ESI-)calc'd for C57H86N2O13S-H=1038.59, found 1038.24.

[0632] [ka]

[0633] Compound 74.(3S,6S,7E,9R,10R,12R,14S,15E,17E,19E,23S,26R,27R,34aS)-21-((3-fluorophenyl)amino)-9,27-dihydroxy-3-((R)-1-((1S,3R,4R)-4-hydroxy-3-methoxycyclohexyl)propan-2-yl)-10-methoxy- 6,8,12,14,20,26-Hexamethyl-5,6,9,10,12,13,14,21,22,23,24,25,26,27,32,33,34,34a-Octadecahydro-3H-23,27-Epoxypyrido[2,1-c][1]oxa[4]azacyclohenthriacontin-1,11,28,29(4H,31H)-tetraone.

[0634] [ka]

[0635] To a stirred solution of 32-deoxorapamycin (300 mg, 0.333 mmol) in DCM (10 mL), 3-fluoroaniline (0.322 mL, 3.335 mmol) and TFA (0.510 mL, 6.670 mmol) were added at -20°C and stirred for 16 hours to reach room temperature. The resulting mixture was diluted with siRNA and quenched with saturated NaHCO3 aqueous solution. The aqueous layer was extracted with siRNA, and the combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude product was dissolved in DMF and eluted from 60-80% ACN / H2O on an ISCO C18 column. The pure product fraction was freeze-dried to obtain 2.9 mg (1%) of white solid 74. MS(ESI-)calc'd for C56H83FN2O11-H=978.60, found 978.85.

[0636] Example 3. Inhibition of representative compounds against wild-type (WT) and FKBP12 knockout 293T cells.

[0637] Examples of FKBP 12 knockout cell generation. Using a CRISPR / Cas9 system, a ribonucleoprotein complex containing a guide RNA sequence targeting FKBP12 (acCGGTGTAGTGCACCACGC, position 1369062; ccactactcacCGTCTCCTG, position 1369181) was delivered to HEK293T cells using the Lipofectamine CRISPRMAX transfection reagent (Invitrogen CMAX00008). Cell clones were screened by immunoblotting with an anti-FKBP-specific antibody (Novus, NB300-508). Single cells with insufficient FKBP12 protein were selected and cloned.

[0638] Treatment of wild-type (WT) and FKBP12 knockout 293T cells with RAD001 (everolimus) and test compounds. WT and FKBP12 knockout 293T cells were cultured in Dulbecco's modified Eagle medium (Gibco #11971-025) supplemented with 10% fetal bovine serum (Gibco #26140-079). Cells were seeded at a cell density of 15,000 cells per well in poly-D-lysine-coated 96-well plates (Corning, #354461) and incubated at 37°C and 5% CO2 for 24 hours until approximately 80% concentration was reached. Cells were treated with RAD001 or test compounds reconstituted in dimethyl sulfoxide (DMSO) at a dose range of 0.001 pM to 10 μM using 8 to 11 dose points. All treatments were performed in double cycles at 37°C for 2 hours. A blank cell culture medium supplemented with dimethyl sulfoxide (DMSO) was used as a negative control for all compounds. The phosphorylation level of S6K1 (Thr389) was measured using an ELISA kit (Invitrogen 85-86052-11) according to the manufacturer's protocol.

[0639] Since S6K1 is a target immediately downstream of mTORC1, mTORC1 activity (PMID: 16968213) was measured using phosphorylation of S6K1 in Thr389 residue. The amount of phosphorylated S6K1 (Thr389) was measured in WT and FKBP12 knockout 293T cells treated with either RAD001 or compound 44 (Figures 1A and 1B), and compound 45 (Figures 1C and 1D).

[0640] In WT cells, both RAD001 and compound 44 completely inhibit S6K1 phosphorylation depending on the dose (Figure 1A). In WT cells, RAD001 inhibited S6K1 phosphorylation by 50% (IC50) at 0.66 nM, while compound 44 inhibited S6K1 phosphorylation by 50% (IC50) at 11 nM. Therefore, in WT cells, compound 44 was approximately 17 times less potent than RAD001 (Figure 1A).

[0641] In FKBP12 knockout cells (i.e., cells lacking FKBP12), RAD001 achieved approximately 30% inhibition of S6K1 phosphorylation at 100 nM, while compound 44 achieved approximately 30% inhibition at 10 μM. Therefore, in FKBP12 KO cells, compound 44 was approximately 100 times less potent than RAD001 at the highest test concentration of 10 μM (Figure 1B). In FKBP12 knockout cells, compound 44 did not inhibit S6K1 phosphorylation at concentrations below 10 μM (Figure 1B). These data suggest that compound 44 is more selective for FKBP12 than RAD001, and that FKBP12 is required for mTORC1 signaling inhibition when used at concentrations below 1 μM in this cell line.

[0642] In WT cells, both RAD001 and compound 45 completely inhibit S6K1 phosphorylation depending on the dose (Figure 1C). In WT cells, RAD001 inhibited S6K1 phosphorylation by 50% (IC50) at 0.47 nM, while compound 45 inhibited S6K1 phosphorylation by 50% (IC50) at 8.4 nM. Therefore, in WT cells, compound 45 was approximately 18 times less potent than RAD001 (Figure 1C).

[0643] In FKBP12 knockout cells (i.e., cells lacking FKBP12), RAD001 achieved approximately 35% inhibition of S6K1 phosphorylation at concentrations of 100 nM and a maximum test concentration of 10 μM, while RAD001 inhibited S6K1 phosphorylation by approximately 80%. In FKBP12 knockout cells, compound 45 inhibited S6K1 phosphorylation by approximately 25% at a concentration of 10 μM (Figure 1D). A similar level of S6K1 inhibition was achieved with approximately 100 nM of RAD001. Therefore, in FKBP12 knockout cells, compound 45 was approximately 100 times less potent than RAD001 when tested at a concentration of 10 μM (Figure 1D).

[0644] These data demonstrate that compound 45 is more selective for FKBP12 than RAD001.

[0645] In WT HEK293T cells expressing FKBP12, both RAD001 and compound 18 achieved complete inhibition of S6K1(Thr389) phosphorylation (Figure 2A). In WT cells, the potency of compound 18 was approximately 9 times lower than that of RAD001. However, in the absence of FKBP12 (in FKBP12 knockout cells), RAD001 achieved approximately 40% S6K1(Thr389) inhibition at 447 nM, while compound 18 achieved a similar level of S6K1(Thr389) inhibition at 9.5 μM (Figure 2B). This indicates that in FKBP12 knockout cells, compound 18 is approximately 20 times less potent than RAD001. These data demonstrate that compound 18 is more selective for FKBP12 than RAD001, but still achieves approximately 40% inhibition of S6K1 in the absence of FKBP12 at the highest test concentration.

[0646] In WT HEK293T cells expressing FKBP12, both RAD001 and compound 16 achieved complete inhibition of S6K1(Thr389) phosphorylation (Figure 3A). In WT cells, the potency of compound 16 was approximately 28 times lower than that of RAD001. However, in the absence of FKBP12 (in FKBP12 knockout cells), the potency of compound 16 was equivalent to that of RAD001 (Figure 3B). At the highest test concentration (10 μM), both rapalogs achieved approximately 70% inhibition of S6K1(Thr389) phosphorylation. These data suggest that compound 16 may have lower affinity for FKBP12 than RAD001, but maintains affinity for other FKBPs expressed in HEK293T cells.

[0647] In WT HEK293T cells expressing FKBP12, RAD001, compound 26, and compound 28 achieved complete inhibition of S6K1(Thr389) phosphorylation (Figure 4A). Cells were treated for 2 hours with the following compounds: RAD001 (everolimus; dotted line and circle, IC50 0.017 nM), compound 26 (solid line and square, IC50 0.55 nM), and compound 28 (solid line and cross, IC50 3.0 nM). In FKBP12 knockout 293T cells, RAD001 (everolimus; dotted line and circle, IC50 31.3 nM) achieved approximately 50% S6K1 inhibition, while compound 26 (solid line and square, IC50 unmeasurable / undetectable) did not inhibit S6K1 at any test concentration, indicating that compound 26 is more selective for FKBP12 than RAD001. In FKBP12 KO cells, compound 28 (solid line and cross, IC50 unmeasurable / undetectable) exhibited similar behavior to RAD001, indicating that compound 28's selectivity for FKBP12 is not as high as that of RAD001.

[0648] In wild-type HEK293T cells expressing FKBP12, compounds 47 (IC50=69nM), 48 (IC50=9.8nM), and 49 (IC50=9.5nM), in addition to RAD001 (IC50=0.319nM), also inhibited mTORC1 signaling in a dose-dependent manner, achieving near-complete inhibition of S6K1 (Thr389) phosphorylation as the concentration increased (Figures 5A, 5C, and 5E). The potency of these novel compounds was 219-fold (47), 30-fold (48), and 29-fold (49), respectively, compared to RAD001, as indicated by their corresponding IC50 values.

[0649] In FKBP12 knockout cells, RAD001 inhibited S6K1(Thr389) phosphorylation in the absence of FKBP12, achieving a 42% inhibition at a concentration of 10 μM. Novel compounds 47, 48, and 49, tested in parallel with RAD001, did not inhibit S6K1(Thr389) phosphorylation at any of the test concentrations (Figures 5B, 5D, and 5F). These results suggest that, unlike RAD001, the activity of compounds 47, 48, and 49 is FKBP12-dependent, and in the absence of FKBP12, these compounds do not inhibit mTORC1 signaling; that is, compounds 47, 48, and 49 are more selective for FKBP12 than RAD001.

[0650] In wild-type HEK293T cells expressing FKBP12, compounds 50 (IC50=5.72nM), 51 (IC50=4.53nM), and 52 (IC50=9.15nM), in addition to RAD001 (IC50=0.365nM), also inhibited mTORC1 signaling in a dose-dependent manner, achieving near-complete inhibition of S6K1 (Thr389) phosphorylation as the concentration increased (Figures 6A, 6C, and 6E). The potency of these novel compounds was 15-fold (50), 12-fold (51), and 25-fold (52), respectively, compared to RAD001, as indicated by their corresponding IC50 values.

[0651] In FKBP12 knockout cells, where FKBP12 was absent, RAD001 inhibited S6K1(Thr389) phosphorylation in a dose-dependent manner, achieving 45% inhibition at 10 μM. Novel compounds 50 and 52, tested in parallel with RAD001, either inhibited S6K1(Thr389) phosphorylation only at the highest test concentration (12% inhibition for 50), or did not inhibit S6K1(Thr389) phosphorylation at any test concentration (confirmed for 52) (Figures 6B and 6F). These results indicate that, unlike RAD001, the activity of compounds 50 and 52 is FKBP12-dependent, and in the absence of FKBP12, these compounds do not inhibit mTORC1 signaling; that is, compounds 50 and 52 are selective for FKBP12.

[0652] In FKBP12 knockout cells, compound 51 retained some efficacy, inhibiting S6K1(Thr389) phosphorylation by 18% at a concentration of 1 μM, with no further inhibition observed at 10 μM (Figure 6D). In the same assay, RAD001 achieved 20% inhibition of S6K1(Thr389) phosphorylation at a concentration of 115 nM. These results suggest that compound 51 is not completely selective for FKBP12, and that the inhibitory effect of compound 51 on mTORC1 signaling may be mediated by FKBPs other than FKBP12.

[0653] In wild-type HEK293T cells expressing FKBP12, RAD001 (IC50=0.084nM) and compounds 57 (IC50=3.68nM), 58 (IC50=2.94nM), and 59 (IC50=0.17nM) inhibited mTORC1 signaling depending on the dose, achieving near-complete inhibition of S6K1 (Thr389) phosphorylation at the highest test concentration (Figures 7A, 7C, and 7E). In this assay, the potency of the novel compounds was 44-fold (57), 35-fold (58), and 2-fold (59), respectively, lower than that of RAD001, as indicated by their corresponding IC50 values.

[0654] In the absence of FKBP12, RAD001 and all other test compounds (57, 58, and 59) inhibited mTORC1 signaling in FKBP12 knockout cells, depending on the dose (Figures 7B, 7D, and 7F). These results indicate that, like RAD001, compounds (57, 58, and 59) retain their potency in the absence of FKBP12, suggesting that their inhibitory effects on mTORC1 signaling may be mediated by FKBPs other than FKBP12, i.e., compounds 57, 58, and 59 are relatively indifferent to FKBP12.

[0655] In wild-type HEK293T cells expressing FKBP12, both RAD001 (IC50 = 0.235 nM) and compound 63 (IC50 = 2.43 nM) inhibited mTORC1 signaling in a dose-dependent manner, achieving near-complete inhibition of S6K1 (Thr389) phosphorylation as the concentration increased (Figure 8A). In this assay, the potency of 63 was 10-fold lower than that of RAD001, as indicated by the corresponding IC50 values.

[0656] In FKBP12 knockout cells, compound 63 retained some potency, inhibiting S6K1(Thr389) phosphorylation by 17% at the highest test concentration of 10 μM (Figure 8B). In the same assay, RAD001 achieved 20% inhibition of S6K1(Thr389) phosphorylation at a concentration of 1.3 nM, and further inhibition of 58% at 10 μM. These results indicate that compound 63 is still more selective than RAD001 for FKBP12, even if not exclusively selective. In wild-type cells expressing FKBP12, 63 is 10 times less potent than RAD001, but in FKBP12 knockout cells, 63 does not achieve S6K1(Thr389) inhibition of more than 17%, while RAD001 inhibits S6K1(Thr389) by as much as 58% depending on the dose.

[0657] In wild-type HEK293T cells expressing FKBP12, both RAD001 (IC50=0.389nM) and compound 69 (IC50=1.53nM) inhibited mTORC1 signaling, achieving near-complete inhibition of S6K1(Thr389) phosphorylation as the concentration increased (Figure 9A). The potency of 69 was four times lower than that of RAD001, as indicated by the corresponding IC50 values.

[0658] In the absence of FKBP12, FKBP12 knockout cells achieved dose-dependent inhibition of S6K1(Thr389) phosphorylation up to 73.5% at the highest test concentration (10 μM) as the concentration of RAD001 increased. In the absence of FKBP12, compound 69 maintained very low potency, achieving approximately 30% inhibition of S6K1(Thr389) phosphorylation at the highest test concentration (10 μM). In the same FKBP12 knockout cell assay, RAD001 achieved 30% inhibition of S6K1(Thr389) phosphorylation at a concentration of approximately 3.0 nM. These results suggest that compound 69 is still more selective than RAD001 for FKBP12, even if not exclusively selective. In wild-type cells expressing FKBP12, compound 69 was only four times less potent than RAD001. However, in FKBP12 knockout cells, compound 69 inhibited phosphorylated S6K1 by 30% at approximately 3000 times higher concentrations than RAD001.

[0659] In wild-type HEK293T cells expressing FKBP12, both RAD001 (IC50 = 0.174 nM) and compound 72 (IC50 = 0.914 nM) inhibited mTORC1 signaling, achieving near-complete inhibition of S6K1 (Thr389) phosphorylation as the concentration increased (Figure 10A). In this assay, the potency of compound 72 was 5.2 times lower than that of RAD001, as indicated by the corresponding IC50 values.

[0660] In FKBP12 knockout cells, RAD001 inhibited S6K1(Thr389) phosphorylation in a dose-dependent manner as the concentration increased, achieving a maximum inhibition of 62% at the highest test concentration (10 μM) (Figure 10B). In the absence of FKBP12, compound 72 retained some potency, further inhibiting S6K1(Thr389) phosphorylation in a dose-dependent manner, achieving a 40% inhibition at the highest test concentration (10 μM) (Figure 10B). These results indicate that 72 is less potent than RAD001 in FKBP12 knockout cells, but these two rapalogs exhibit similar behavior. That is, they can induce mTORC1 inhibition when complexed with FKBP other than FKBP12.

[0661] In wild-type HEK293T cells expressing FKBP12, both RAD001 (IC50=0.174nM) and compound 73 (IC50=2.22nM) inhibited mTORC1 signaling, achieving near-complete inhibition of S6K1(Thr389) phosphorylation as the concentration increased (Figure 11A). In this assay, the potency of compound 73 was 13-fold lower than that of RAD001, as indicated by the corresponding IC50 values.

[0662] In the absence of FKBP12, for example in FKBP12 knockout cells, RAD001 and 73 achieved dose-dependent inhibition of S6K1(Thr389) phosphorylation as their concentrations increased, achieving up to approximately 60% inhibition at the highest test concentration (10 μM) (Figure 11B). Furthermore, while 73 was 13 times less potent than RAD001 in wild-type cells expressing FKBP12, 73 exhibited superior potency to RAD001 in the absence of FKBP12 (in FKBP12 knockout cells). Specifically, in FKBP12 knockout cells, 73 inhibited S6K1(Thr389) phosphorylation by 20% at a concentration of 2.7 nM, while RAD001 achieved 20% inhibition at 7.4 nM (Figure 11B). However, at the highest test concentration of 10 mM, both RAD001 and compound 73 inhibited S6K1 phosphorylation by approximately 60% (Figure 11B).

[0663] These results indicate that 73 can induce mTORC1 inhibition when it forms a complex with FKBP other than FKBP12, meaning that 73 is not selective for FKBP12. Furthermore, the higher potency of 73 compared to RAD001 in FKBP12 knockout cells (in the dose range of less than 1 mM) suggests that 73 can acquire a higher affinity for FKBP other than FKBP12 than RAD001.

[0664] Example 4. Microsome Stability

[0665] Materials and methods

[0666] Buffer solution: PBK buffer: Contains 50 mM potassium phosphate buffer (PPB), pH 7.2, and 3.3 mM magnesium chloride.

[0667] Dilution of the compound:

[0668] TA intermediate solution: Dilute the compound or control (3 μL) from a stock solution (10 mM) containing 297 μL of 90.0% methanol / water (concentration: 100 μM, 1.0% DMSO, 89.1% MeOH).

[0669] Control cocktail intermediate solution: Each control (3 μL) was diluted with 291 μL of 90.0% methanol / water.

[0670] Diluted TA intermediate stock solutions and PC control stocks were prepared by transferring 80 μL of 100 μM TA stock solution to a new tube and adding 720 μL of 1.0% DMSO to 50 mM potassium phosphate buffer (concentration 10 μM, 1.0% DMSO, 8.91% MeOH).

[0671] Synthesis of liver mixture and NADPH cofactor (listed in Table 1)

[0672] Preparation of a liver microsome dilution standard solution (1.25 times) (final concentration: 0.5 mg / mL).

[0673] [Table 2]

[0674] Stock solution:

[0675] Acetonitrile:methanol (9:1, v / v) (containing 200 ng / mL tolbutamide and 200 ng / mL labetalol hydrochloride as internal standards).

[0676] Diluted standard solution: The intermediate solution (80 μL) was diluted with 720 μL of 1.0% DMSO in 50 mM potassium phosphate buffer (concentration: 10 μM, 1.0% DMSO, 8.91% MeOH).

[0677] Procedure: Stock solutions were added to plates at each time point. Microsome solution (360 μL / well), TA / PC (45 μL / well), and NADPH (45 μL / well) min. (concentration: 1.0 μM, 0.10% DMSO, 0.891% MeOH) were added to incubation plates. TA (15 ul / well) and microsomes (120 ul) were added to T60 and NCF60 plates. Microsomes (50 ul / well) containing stop solution (150 ul / well) were added to blank plates. At the end of each time point, 50 ul / well was equally divided from the incubation plate. The sampling plates were shaken on a shaker for approximately 10 minutes, and the samples were centrifuged at 4000 rpm for 15 minutes. The supernatant (120 μL) was transferred for LC / MS / MS. The compounds listed in Table 3 were incubated at 37°C using 1 μM liver microsomes (pooled from multiple donors) in the presence of a 0.5 mg / ml microsomal protein NADPH regeneration system. Positive controls included testosterone (3A4 substrate), propaferone (2D6), and diclofenac (2C9), which were incubated with microsomes in the presence of the NADPH regeneration system. At multiple time points (0, 5, 10, 20, 30, and 60 minutes), the samples were removed and immediately mixed with cold acetonitrile containing an internal standard (IS). Test compounds incubated with microsomes for 60 minutes without the NADPH regeneration system were also included. One point (n=1) was obtained for each test condition, and the samples were analyzed by LC / MS / MS. The disappearance of the test compounds was evaluated based on the analyte / IS peak area ratio (no standard curve). As shown in Table 1, several compounds showed good stability to human and mouse liver microsomes. 1 / 2 The time was over 2 hours, and microsomal clearance was low.

[0678] [Table 3]

[0679] Example 5. Pharmacokinetic study of the test substance in male CD-1 mice

[0680] Test design

[0681] [Table 4]

[0682] Animal experiments were conducted at Wuxi AppTec. Male CD1 mice aged 6-8 weeks were obtained from Hilltop Labs. Upon arrival at Wuxi AppTec, the mice were placed in an environment-controlled animal room (temperature: 20-26°C, lighting: 12-hour light / dark cycle). The mice were fed a certified pellet diet (LabDiet's Certified Rodent Diet #5002). Water was freely available to the animals. The mice were allowed to acclimate to the facility for at least 3 days before the experiments began.

[0683] Administration formulation

[0684] Appropriate amounts of the test substance were formulated in 5% ethanol, 5% Tween-80, 5% PEG-400, and 85% water. The formulations were prepared on the day of administration and administered within 2 hours of preparation. Dose accuracy was determined by LC-MS / MS.

[0685] Administration

[0686] The administered drug was given according to standard operating procedures (facility SOPs). After individually determining the dosage volume, the dosage was administered based on the animal's body weight.

[0687] Sample collection and plasma isolation

[0688] Approximately 40 μL of blood samples were collected from peripheral veins (e.g., saphenous veins) at each predetermined time point. The collected blood samples were placed in tubes containing K2EDTA as an anticoagulant and kept on ice until centrifugation.

[0689] Within 30 minutes of collection, blood samples were centrifuged at 4°C and 3000g for 5 minutes. Plasma was transferred to polypropylene tubes or 96-well plates, immediately frozen on dry ice, and stored at -70±10°C until LC-MS / MS analysis.

[0690] Biological analytical methods and sample analysis

[0691] The concentrations of the test compounds in mouse plasma were determined by LC-MS / MS using a calibration curve with at least six non-zero calibration standards.

[0692] Data Analysis

[0693] The pharmacokinetics (PK) of the test compound were analyzed using Phoenix WinNonlin software (version 8.3) and a non-compartmental analysis model. The derived PK parameters included C0 and CL. p , Vdss, C max , T max , T 1 / 2 AUC (0-t) AUC (0-inf) , MRT (0-t) , MRT (0-inf) This includes, but is not limited to, , and %F (bioavailability).

[0694] Results The pharmacokinetic test results for the selected compounds are shown in Figure 12A (everolimus, RAD001), Figure 12B (compound 26), Figure 12C (compound 45), and Figure 12D (compound 63), respectively.

[0695] Figure 12A is a graph showing the pharmacokinetic profiles of RAD001 in mouse plasma after IV (2 mg / kg) and PO (10 mg / kg) administration. The Y-axis, set to a Log 10 scale, shows the compound concentration in plasma (ng / ml). The X-axis shows the time (hour) at which plasma was collected after compound administration.

[0696] Figure 12B is a graph showing the pharmacokinetic profiles of the drug in the plasma of 26 mice after IV (2 mg / kg) and PO (20 mg / kg) administrations. The Y-axis set on a Log 10 scale indicates the compound concentration (ng / ml) in the plasma. The X-axis indicates the time point (time) of plasma collection after compound administration.

[0697] Figure 12C is a graph showing the pharmacokinetic profiles of compound 45 in the plasma of mice after IV (2 mg / kg) and PO (20 mg / kg) administrations. The Y-axis set on a Log 10 scale indicates the compound concentration in the plasma in units of ng / ml. The X-axis indicates the time point (time) of plasma collection after compound administration.

[0698] Figure 12D is a graph showing the pharmacokinetic profiles of the drug in the plasma of 69 mice after IV (2 mg / kg) and PO (10 mg / kg) administrations. The Y-axis set on a Log 10 scale indicates the compound concentration in the plasma in units of ng / ml. The X-axis indicates the time point (time) of plasma collection after compound administration.

[0699] Compound 69 has an improved pharmacokinetic profile compared to RAD001. For example, the oral bioavailability is increased (30.7% for 69 compared to 26% for RAD001), the Cmax in plasma after oral administration is increased (12,933 ng / ml for 69 compared to 7,224 ng / ml for RAD001), and the plasma clearance rate is decreased (15.5 hours for 69 compared to 5.85 hours for RAD001) (compare Figure 12A and Figure 12D). See also Table 4 below.

[0700]

Table 5

[0701] * IV T 1 / 2 - The amount of time required for the compound concentration in the plasma to decrease by 50% after IV administration. ** Cl (ml / min / kg) - Compound clearance after IV administration. *** Vdss (L / kg) - Volume of distribution after IV administration. ****PO C max - The maximum (peak) plasma concentration of the compound achieved after PO administration.

[0702] The embodiments and examples described above are merely illustrative and not intended to be limiting. Those skilled in the art will be able to identify or confirm numerous equivalents of certain compounds, materials, and procedures using only conventional experiments. All such equivalents are considered to be within and encompassed by the appended claims.

Claims

1. Equation I 【Chemistry 1】 A compound thereof, or a pharmaceutically acceptable salt thereof, In the formula, R １ is hydrogen, C １－６ alkyl, heterocyclyl, aryl, heteroaryl, -C ０－６ alkylene-SO ２ R ４ or -C ０－６ alkylene-SO ２ R ５ wherein the C １－６ alkyl, the heterocyclyl, the aryl, and the heteroaryl are optionally substituted with one or two R １ａ groups, R ２ These are heterocyclyl, aryl, heteroaryl, and -C. ０－６ Alkylene-SO ２ R ４ , or -C ０－６ Alkylene-SO ２ R ５ The heterocyclyl, the aryl, and the heteroaryl each contain one or two R ２ａ It is optionally substituted in the base, Or R １ and R ２ It, together with the bonded nitrogen, forms one or two R １ａ Forms an N-linked heteroaryl or N-linked heterocycline which is optionally substituted with a group, R ３ is, -OR ａ Selected from the group consisting of 3-6 membered heterocyclyls and 3-6 membered heteroaryls, R ａ H, -P(O)(R ｂ ) ２ , -C(O)R ｃ , -C(O)OR ｃ , C １－６ Alkyl and C １－６ Selected from the group consisting of hydroxyalkyl groups, R ｂ These are H and C, respectively, independently. １－６ Selected from the group consisting of alkyl groups, R ｃ H, C １－６ Alkyl and C １－６ Selected from the group consisting of hydroxyalkyl groups, R ４ C ２－６ Alkyl, C ３－６ Cycloalkyl, C １－６ A hydroxyalkyl, heterocyclyl, aryl, or heteroaryl, wherein the heterocyclyl, the aryl, and the heteroaryl each have one or two R ４ａ It is optionally substituted in the base, R ５ is a heterocyclyl, aryl, or heteroaryl, wherein the heterocyclyl, the aryl, and the heteroaryl have one or two R ５ａ It is optionally substituted in the base, One or two R １ａ group, R ２ａ group, R ４ａ base, and R ５ａ Each of the elements, if present, independently of C １－６ Alkyl, C １－６ Hydroxyalkyl, hydroxy, halo, C １－６ Haloalkyl and C １－６ Selected from alkoxys, or any two R １ａ group, R ２ａ group, R ４ａ base, and R ５ａ When the groups are located on the same carbon, they combine to form an oxo group. R １ When R is hydrogen, ２ is, -C ０－６ Alkylene-SO ２ R ４ Not a compound, or a pharmaceutically acceptable salt thereof.

2. Equation Ia 【Chemistry 2】 A compound of or a pharmaceutically acceptable salt thereof, In the formula, R １ is hydrogen or C １－６ It is alkyl, R ２ is one or two R ２ａ A heterocyclyl, aryl, or heteroaryl that is optionally substituted with a base, R ３ is, -OR ａ Selected from the group consisting of 3-6 membered heterocyclyls and 3-6 membered heteroaryls, R ａ H, -P(O)(R ｂ ) ２ , -C(O)R ｃ , -C(O)OR ｃ , C １－６ Alkyl and C １－６ Selected from the group consisting of hydroxyalkyl groups, R ｂ These are H and C, respectively, independently. １－６ Selected from the group consisting of alkyl groups, R ｃ H, C １－６ Alkyl and C １－６ Selected from the group consisting of hydroxyalkyl groups, The one or two R ２ａ Each of the elements, if present, independently of C １－６ Alkyl, C １－６ Hydroxyalkyl, hydroxy, halo, C １－６ Haloalkyl and C １－６ Selected from alkoxys, or any two R ２ａ The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein the groups, when present on the same carbon, form an oxo group together.

3. Formula Ib 【Transformation 3】 A compound of or a pharmaceutically acceptable salt thereof, In the formula, R １ and R ２ It, together with the bonded nitrogen, forms one or two R １ａ Forms an N-linked heteroaryl or N-linked heterocycline which is optionally substituted with a group, R ３ is, -OR ａ Selected from the group consisting of 3-6 membered heterocyclyls and 3-6 membered heteroaryls, R ａ is selected from the group consisting of H, -P(O)(R ｂ ), ２ , -C(O)R ｃ , -C(O)OR ｃ , C １－６ alkyl, and C １－６ hydroxyalkyl, R ｂ is independently selected from the group consisting of H and C １－６ alkyl R ｃ H, C １－６ Alkyl and C １－６ Selected from the group consisting of hydroxyalkyl groups, The one or two R １ａ Each of the elements, if present, independently of C １－６ Alkyl, C １－６ Hydroxyalkyl, hydroxy, halo, C １－６ Haloalkyl and C １－６ Selected from alkoxys, or two R １ａ The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein the groups, when present on the same carbon, form an oxo group together.

4. Formula Ic 【Chemistry 4】 A compound of or a pharmaceutically acceptable salt thereof, In the formula, R １ is hydrogen or C １－６ It is alkyl, R ２ is, -C ０－６ Alkylene-SO ２ R ４ or -C ０－６ Alkylene-SO ２ R ５ And, R ３ is, -OR ａ Selected from the group consisting of 3-6 membered heterocyclyls and 3-6 membered heteroaryls, R ａ H, -P(O)(R ｂ ) ２ , -C(O)R ｃ , -C(O)OR ｃ , C １－６ Alkyl and C １－６ Selected from the group consisting of hydroxyalkyl groups, R ｂ These are H and C, respectively, independently. １－６ Selected from the group consisting of alkyl groups, R ｃ H, C １－６ Alkyl and C １－６ Selected from the group consisting of hydroxyalkyl groups, R ４ C ２－６ Alkyl, C ３－６ Cycloalkyl, C １－６ A hydroxyalkyl, heterocyclyl, aryl, or heteroaryl, wherein the heterocyclyl, the aryl, and the heteroaryl each have one or two R ４ａ It is optionally substituted in the base, R ５ is a heterocyclyl, aryl, or heteroaryl, wherein the heterocyclyl, the aryl, and the heteroaryl have one or two R ５ａ It is optionally substituted in the base, The one or two R ４ａ base and R ５ａ Each of the elements, if present, independently of C １－６ Alkyl, C １－６ Hydroxyalkyl, hydroxy, halo, C １－６ Haloalkyl and C １－６ Selected from alkoxys, or any two R ４ａ base and R ５ａ When the groups are located on the same carbon, they combine to form an oxo group. R １ When R is hydrogen, ２ is, -C ０－６ Alkylene-SO ２ R ４ Not the compound described in claim 1, or a pharmaceutically acceptable salt thereof.

5. R １ is hydrogen, R ２ However, aryl, heteroaryl, or C ５－１２ It is a heterocyclyl, and the aryl, the heteroaryl, and C ５－１２ Heterocyclines have one or two R ２ａ The compound according to claim 1, or a pharmaceutically acceptable salt thereof, which is optionally substituted with a group.

6. R １ However, hydrogen or C １－６ It is alkyl, R ２ However, aryl, heteroaryl, or C ５－１２ It is a heterocyclyl, and the aryl, the heteroaryl, and C ５－１２ Heterocyclines have one or two R ２ａ The compound according to claim 1, or a pharmaceutically acceptable salt thereof, which is optionally substituted with a group.

7. R １ is hydrogen, R ２ However, C ５－２０ Members: Ariel, C ５－２０ A heteroaryl group, or C ５－２０ It is a heterocyclyl, and the aryl, the heteroaryl, and C ５－１２ Heterocyclines have one or two R ２ａ The compound according to claim 1, or a pharmaceutically acceptable salt thereof, which is optionally substituted with a group.

8. R １ However, hydrogen or C １－６ It is alkyl, R ２ However, C ５－２０ Members: Ariel, C ５－２０ A heteroaryl group, or C ５－２０ It is a heterocyclyl, and the aryl, the heteroaryl, and C ５－１２ Heterocyclines have one or two R ２ａ The compound according to claim 1, or a pharmaceutically acceptable salt thereof, which is optionally substituted with a group.

9. R ２ but, 【Transformation 5】 Selected from, in the formula, 【Transformation 6】 The compound according to any one of claims 5 to 8, or a pharmaceutically acceptable salt thereof, wherein is a bonding site to the remainder of the compound.

10. R ４ However, the heterocyclyl, the aryl, and the heteroaryl are one or two R ４ａ It is optionally substituted by the base, or R ５ However, the heterocyclyl, aryl, or heteroaryl is a heterocyclyl, and the heterocyclyl, aryl, or heteroaryl is a heterocyclyl, with 1 or 2 R ５ａ A compound according to claim 1 or 4, or a pharmaceutically acceptable salt thereof, which is optionally substituted with a group.

11. R ４ but, 【Transformation 7】 And in the formula, 【Transformation 8】 The compound according to claim 10, or a pharmaceutically acceptable salt thereof, wherein is a bonding site to the remainder of the compound.

12. R ５ but, 【Chemistry 9】 And in the formula, 【Chemistry 10】 The compound according to claim 10, or a pharmaceutically acceptable salt thereof, wherein is a bonding site to the remainder of the compound.

13. R ３ ga- OR ａ And R ａ C １－６ A compound according to any one of claims 1 to 12, which is alkyl, or a pharmaceutically acceptable salt thereof. 【Request Item 14】 【Chemistry 11】 【Chemistry 12】 【Chemistry 13】 【Chemistry 14】 【Chemistry 15】 【Chemistry 16】 【Chemistry 17】 [Chemistry 18] 【Chemistry 19】 【Chemistry 20】 【Chemistry 21】 【Chemistry 22】 【Chemistry 23】 【Chemistry 24】 【Chemistry 25】 【Chemistry 26】 【Chemistry 27】 【Chemistry 28】 【Chemistry 29】 【Transformation 30】 【Chemistry 31】 【Chemistry 32】 【Transformation 33】 【Transformation 34】 【Chemistry 35】 【Transformation 36】 【Chemistry 37】 The compound according to claim 1, or a pharmaceutically acceptable salt thereof, selected from among the pharmaceutically acceptable salts thereof. 【Request Item 15】 【Chemistry 38】 【Chemistry 39】 The compound according to claim 14, or a pharmaceutically acceptable salt thereof. 【Request Item 16】 【Chemistry 40】 【Chemistry 41】 A compound selected from the group consisting of a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt thereof.

17. The compound according to any one of claims 1 to 16, or a pharmaceutically acceptable salt thereof, wherein the compound selectively binds to FKBP12.

18. The compound according to claim 17, or a pharmaceutically acceptable salt thereof, wherein the compound inhibits S6K1 phosphorylation in FKBP12 KO cells with at least twice the efficiency of the rapalog RAD001 compared to wild-type FKBP12-expressing cells.

19. The compound according to claim 17, or a pharmaceutically acceptable salt thereof, wherein the compound requires at least 10 times higher concentrations in FKBP12 KO cells compared to the rapalog RAD001 compared to wild-type FKBP12-expressing cells to achieve a 20% inhibition of S6K1 cell signaling.

20. The compound according to claim 17, or a pharmaceutically acceptable salt thereof, wherein the compound inhibits S6K1 phosphorylation in FKBP12 KO cells with at least 10 times lower efficiency than the rapalog RAD001 compared to wild-type FKBP12-expressing cells.

21. The compound according to claim 17, or a pharmaceutically acceptable salt thereof, wherein the compound requires at least 100 times higher concentrations in FKBP12 KO cells compared to the rapalog RAD001 compared to wild-type FKBP12-expressing cells to achieve a 20% inhibition of S6K1 cell signaling.

22. The compound according to claim 17, or a pharmaceutically acceptable salt thereof, wherein the compound requires at least 10 times higher concentrations in FKBP12 KO cells compared to the rapalog RAD001 compared to wild-type FKBP12-expressing cells in order to achieve a 30% inhibition of S6K1 cell signaling.

23. The compound according to claim 17, or a pharmaceutically acceptable salt thereof, wherein the compound requires at least 100 times higher concentrations in FKBP12 KO cells compared to the rapalog RAD001 compared to wild-type FKBP12-expressing cells in order to achieve a 30% inhibition of S6K1 cell signaling.

24. The compound according to claim 17, or a pharmaceutically acceptable salt thereof, wherein the relative loss of potency of FKBP12 KO cells compared to wild-type cells is at least twice as great compared to the loss of RAD001.

25. The compound according to claim 17, or a pharmaceutically acceptable salt thereof, wherein the relative loss of potency of FKBP12 KO cells compared to wild-type cells is at least 10 times greater than the loss of RAD001.

26. The compound according to claim 17, or a pharmaceutically acceptable salt thereof, wherein the relative loss of potency of FKBP12 KO cells compared to wild-type cells is at least 100 times greater than the loss of RAD001.

27. A pharmaceutical composition comprising a therapeutically effective amount of the compound according to any one of claims 1 to 26 or a pharmaceutically acceptable salt thereof in one or more pharmaceutically acceptable carriers.

28. A pharmaceutical combination comprising one or more pharmaceutically acceptable carriers containing a therapeutically effective amount of a compound according to any one of claims 1 to 26 or a pharmaceutically acceptable salt thereof, and one or more therapeutically active agents.

29. A method for treating a disorder or disorder mediated by the mTOR pathway in a subject requiring treatment of such disorder or disorder, comprising the step of administering to the subject a therapeutically effective amount of a compound according to any one of claims 1 to 26 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 27 or 28.

30. A method for treating a disease or disorder, wherein a target tissue, organ, or cell associated with the pathogenesis of the disease or disorder has an FKBP12 level sufficient to inhibit mTORC1, and the method comprises administering to the subject requiring treatment of the disease or disorder a therapeutically effective amount of a compound according to any one of claims 1 to 26 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 27 or 28.

31. The method according to claim 29 or 30, wherein the compound or a pharmaceutically acceptable salt thereof has a binding affinity to FKBP12 that is sufficiently high to inhibit mTORC1.

32. If the aforementioned disease or disorder is sarcopenia, skin atrophy, senile angioma, seborrheic keratosis, cerebral atrophy, atherosclerosis, arteriosclerosis, emphysema, osteoporosis, osteoarthritis, hypertension, erectile dysfunction, cataracts, macular degeneration, glaucoma, stroke, cerebrovascular disease (stroke), chronic kidney disease, diabetes-related kidney disease, hepatic insufficiency, hepatic fibrosis, autoimmune hepatitis, endometrial hyperplasia, metabolic dysfunction, renovascular disease, hearing loss, mobility impairment, cognitive decline, tendon stiffness, cardiac dysfunction, such as cardiac hypertrophy, and / or systolic and / or diastolic dysfunction, The method according to any one of claims 29 to 31, selected from: diabetes and / or hypertension, cardiac dysfunction that reduces ejection fraction, immunosenescence, Parkinson's disease, Alzheimer's disease, cancer, immunosenescence resulting in cancer due to reduced immune surveillance, infection due to impaired immune function, chronic obstructive pulmonary disease (COPD), obesity, loss of taste, loss of smell, arthritis, epilepsy, cancer in which the tumor has high mTORC1 signaling levels and / or FKBP12 levels sufficient to allow inhibition of mTORC1, and type II diabetes.

33. A method for treating age-related disorders or diseases in a subject requiring treatment of such disorders or diseases, comprising the step of administering a therapeutically effective amount of a compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 26, or a pharmaceutical composition according to claim 27 or 28, wherein the disorder or disease is sarcopenia, skin atrophy, senile angioma, seborrheic keratosis, cerebral atrophy, atherosclerosis, arteriosclerosis, pulmonary emphysema, osteoporosis, osteoarthritis, hypertension, erectile dysfunction, cataract, macular degeneration, glaucoma, stroke, cerebrovascular disease (stroke), chronic kidney disease, diabetes-related kidney disease, hepatic insufficiency, hepatic fibrosis, autoimmune hepatitis, endometrial hyperplasia, metabolic A method selected from functional impairment, renovascular disease, hearing loss, mobility impairment, cognitive decline, tendon stiffness, cardiac dysfunction, e.g., cardiac hypertrophy, and / or systolic and / or diastolic dysfunction, and / or hypertension, cardiac dysfunction that reduces ejection fraction, immunosenescence, Parkinson's disease, Alzheimer's disease, cancer, immunosenescence resulting in cancer due to reduced immune surveillance, infection due to decreased immune function, chronic obstructive pulmonary disease (COPD), obesity, loss of taste, loss of smell, arthritis, epilepsy, cancer in which the tumor has high mTORC1 signaling levels and / or sufficient FKBP12 levels to allow inhibition of mTORC1, and type II diabetes.

34. A method for treating cancer in a subject requiring treatment, comprising the step of administering to the subject a therapeutically effective amount of a compound according to any one of claims 1 to 26 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 27 or 28.

35. The method according to claim 34, wherein the cancer is selected from kidney cancer, renal cell carcinoma, colorectal cancer, uterine sarcoma, endometrial uterine cancer, endometrial cancer, breast cancer, ovarian cancer, cervical cancer, gastric cancer, fibrosarcoma, pancreatic cancer, liver cancer, melanoma, leukemia, multiple myeloma, nasopharyngeal cancer, prostate cancer, lung cancer, glioblastoma, bladder cancer, mesothelioma, head cancer, rhabdomyosarcoma, sarcoma, lymphoma, and cervical cancer.

36. A method for treating Alzheimer's disease or a syndrome in a subject requiring treatment for Alzheimer's disease or a syndrome therefor, comprising the step of administering to the subject a therapeutically effective amount of a compound according to any one of claims 1 to 26 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 27 or 28.

37. A method for inducing immune tolerance and preventing organ rejection in a subject requiring induction of immune tolerance, comprising the step of administering to the subject a therapeutically effective amount of a compound according to any one of claims 1 to 26 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 27 or 28.

38. A method for treating graft-versus-host disease (GvHD) or a syndrome in a subject requiring treatment for said GvHD or a syndrome therefor, comprising the step of administering to the subject a therapeutically effective amount of a compound according to any one of claims 1 to 26 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 27 or 28.

39. A method for treating facial angiofibromas in a subject requiring treatment for such facial angiofibromas associated with tuberous sclerosis, comprising the step of administering to the subject a therapeutically effective amount of a compound according to any one of claims 1 to 26 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 27 or 28.

40. A method for treating a perivascular epithelioid tumor in a subject requiring treatment for the progressive, unresectable, or metastatic and malignant perivascular epithelioid tumor, comprising the step of administering to the subject a therapeutically effective amount of a compound according to any one of claims 1 to 26 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 27 or 28.

41. A compound according to any one of claims 1 to 26 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 27 or 28, for use as a pharmaceutical.

42. A compound according to any one of claims 1 to 26 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 27 or 28, for use in treating disorders or diseases mediated by the mTOR pathway.

43. Sarcopenia, skin atrophy, senile angioma, seborrheic keratosis, cerebral atrophy, atherosclerosis, arteriosclerosis, emphysema, osteoporosis, osteoarthritis, hypertension, erectile dysfunction, cataracts, macular degeneration, glaucoma, stroke, cerebrovascular disease (stroke), chronic kidney disease, diabetes-related kidney disease, hepatic insufficiency, hepatic fibrosis, autoimmune hepatitis, endometrial hyperplasia, metabolic dysfunction, renovascular disease, hearing loss, mobility impairment, cognitive decline, tendon stiffness, cardiac dysfunction, e.g., cardiac hypertrophy, and / or systolic and / or diastolic dysfunction, and / or hypertension, cardiac dysfunction that reduces ejection fraction, immunosenescence, parky A compound according to any one of claims 1 to 26 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 27 or 28, for use in the treatment of disorders or diseases selected from among: Sonnson's disease, Alzheimer's disease, cancer, immunosenescence resulting in cancer due to reduced immune surveillance, infections due to decreased immune function, chronic obstructive pulmonary disease (COPD), obesity, loss of taste, loss of smell, arthritis, epilepsy, cancer in which the tumor has high mTORC1 signaling levels and / or FKBP12 levels sufficient to allow inhibition of mTORC1, and type II diabetes.

44. The aforementioned compound, 【Chemistry 42】 【Chemistry 43】 【Chemistry 44】 【Chemistry 45】 【Chemistry 46】 【Chemistry 47】 【Chemistry 48】 【Chemistry 49】 [Transformation 50] 【Chemistry 51】 【Chemistry 52】 【Chemistry 53】 【Chemistry 54】 【Transformation 55】 【Transformation 56】 【Chemistry 57】 【Transformation 58】 【Chemistry 59】 【Transformation 60】 【Chemistry 61】 【Transformation 62】 【Transformation 63】 【Chemistry 64】 【Transformation 65】 【Chemical Formula 66】 【Transformation 67】 【Transformation 68】 A compound according to any one of claims 41 to 43, selected from or from pharmaceutically acceptable salts.

45. The aforementioned compound, 【Transformation 69】 【Transformation 70】 A compound according to any one of claims 41 to 44, selected from a pharmaceutically acceptable salt thereof.

46. A combination therapy agent comprising a therapeutically effective amount of a compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 26, or the pharmaceutical composition according to claim 27 or 28, and an anti-CD40 antibody.

47. The combination therapy agent according to claim 46 for use in the treatment and / or prevention of Alzheimer's disease, GvHD, facial angiofibromas associated with tuberous sclerosis, progressive unresectable or metastatic malignant perivascular epithelioid cell tumors, and transplant organ rejection.

48. The combination therapy agent according to claim 46, for use in the treatment of a human disease selected from the group consisting of cancer, diabetes, obesity, neurological disorders, genetic diseases, and other age-related or aging-related diseases.

49. A method for treating Alzheimer's disease or syndrome in a subject requiring treatment for Alzheimer's disease or syndrome, comprising the step of administering to the subject a therapeutically effective dose of the combination therapy agent according to claim 46.

50. A method for inducing immune tolerance and preventing organ rejection in a subject requiring induction of immune tolerance, the method comprising the step of administering the combination therapy agent described in claim 46 to the subject in a therapeutically effective amount.

51. A method for treating graft-versus-host disease (GvHD) or a syndrome in a subject requiring treatment for said GvHD or syndrome, the method comprising the step of administering to the subject a therapeutically effective dose of the combination therapy agent according to claim 46.

52. A method for treating facial angiofibromas in a subject requiring treatment for such facial angiofibromas associated with tuberous sclerosis, comprising the step of administering to the subject a therapeutically effective dose of the combination therapy agent described in claim 46.

53. A method for treating a perivascular epithelioid tumor in a subject requiring treatment for a progressive, unresectable or metastatic malignant perivascular epithelioid tumor, comprising the step of administering to the subject a therapeutically effective dose of the combination therapy agent according to claim 46.

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