Selective Analogues of Rapamycin and Their Uses

Description

[001] This application claims priority for U.S. Provisional Application No. 63 / 494,839, filed April 7, 2023; U.S. Provisional Application No. 63 / 515,184, filed July 24, 2023; and U.S. Provisional Application No. 63 / 624,75, filed January 25, 2024, all of which are incorporated herein by reference in their entirety. TECHNICAL FIELD

[002] This descriptive report provides FKBP12-selective rapamycin analogues, pharmaceutical compositions comprising the analogues, and methods of treatment of diseases, disorders and conditions comprising the administration of the analogues or pharmaceutical compositions thereof. FUNDAMENTALS OF THE INVENTION

[003] Rapamycin is a known macrolide antibiotic produced by Streptomyces hygoscopius; see, for example, McAlpine, JB, et al., J. Antibiotics (1991) 44: 688; Schreiber, SL; et al., J. Am. Chem. Soc. (1991) 113: 7,433; and US Patent No. 3,929,992. The following numbering convention for rapamycin and its derivatives used in this descriptive report is shown below: HO, / oeV sL o Y923 Me Rapamycin Petition 870250090230, dated 03 / 10 / 2025, p. 25 / 341 2 / 217

[004] 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 the prevention or treatment of 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 carcinomas, inflammatory heart disease, anemia, and increased neuritic growth. Additionally, rapamycin analogs (so-called rapalogs) have been shown to be beneficial against hepatic fibrosis. See, for example, Liver Int. (2014) 34 (10): 1513-21.

[005] In eukaryotic cells, rapamycin and its analogs (rapalogs) inhibit TOR (Rapamycin Target) signaling. In mammalian cells, mTOR (mammalian target of rapamycin) exists in two distinct multiprotein complexes, described as the mTORC1 complex and the mTORC2 complex, both of which sense nutrient and energy availability and integrate growth factor inputs and stress signaling. mTORC1 integrates growth factor and nutrient signals and controls cell growth and metabolism. Laplante M. et al. Cell. (2012) 149 (2): 274-93. mTORC1 is a crucial regulator of protein translation and autophagy.

[006] 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 C. elegans systems) and, in mammals, the mTORC1 pathway. Modulation of TOR and mTORC1 signaling prolongs 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 by genetic mutation extended lifespan in yeast, C. Petition 870250090230, dated 03 / 10 / 2025, page 26 / 341 3 / 217 elegans and drosophila, and inhibition of the mTORC1 pathway extended lifespan in mice (Kaeberlein et al., Science (2005) 310: 1193-1196; Kapahi et al., Curr. Biol. (2004) 14: 885-890; Selman et al., Science (2009) 326: 140-144; Vellai et al., Nature (2003) 426: 620). Furthermore, the mTORC1 inhibitor rapamycin extended the lifespan of mice, even when administered late in life (Harrison et al., Nature (2009) 460 (7253): 392-395). These data raise the possibility that drugs targeting the mammalian TOR (mTOR) pathway will have therapeutic effects on age-related diseases in humans (M. Leslie, Science, 2013, 342). For example, J. Mannick et al. describe in Sci. Transl. Med. (2014) 6 (268): 268ra179 that mTOR inhibition improves immune function in older adults.

[007] Mitochondrial myopathy (MM) is the most common manifestation of adult-onset mitochondrial disease and shows a multifaceted tissue-specific stress response: (1) transcriptional response, including metabolic cytokines FGF21 and GDF15; (2) remodeling of one-carbon metabolism; and (3) the mitochondrial response to unfolded proteins (Khan et al., Cell Metabolism 26, 419-428, August 1, 2017). Inhibition of mTORC1 by rapamycin downregulated all components of ISRmt (the integrated mitochondrial stress response), improved all major features of MM, and reversed MM progression even at late stages, without inducing mitochondrial biogenesis. Thus, rapamycin and rapalogs are considered to be of potential value in addressing unmet needs in many clinical settings.

[008] Epilepsy, which is caused by mutations in the Tsc1 / Tsc2 complex, can be treated with rapamycin or rapalogs (Zeng et al., Ann. Neurology, April 2008; 63 (4) 444-453). It would be advantageous to have a rapalog that could inhibit epilepsy without disturbing other tissues where mTORC1 is expressed - in this way, Petition 870250090230, dated 03 / 10 / 2025, page 27 / 341 4 / 217 A more selective mTORCl inhibitor would be desirable in that scenario.

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

[010] It has also been reported that treatment with rapamycin selectively targets CD40-mediated B cell proliferation and differentiation (Atsuko Sakata et al., Immunology Letters. Volume 68, Numbers 2-3, June 1, 1999, pages 301-309). CD40 is a cell surface receptor that is part of the tumor necrosis factor (TNF) receptor superfamily. CD40 is expressed on antigen-presenting cells such as B cells, macrophages, and dendritic cells, as well as on some non-immune cells and tumors (Dakal et al., Immunobiology 2020, 225: 151899). Activation of resting B cells requires an initial triggering of the B cell antigen receptor (BCR) and secondary stimuli through various Petition 870250090230, dated 03 / 10 / 2025, page 28 / 341 5 / 217 cytokine receptors and B cell activating molecules, including CD40.

[011] The interaction of CD40 with its ligand CD40L provides a co-stimulatory signal that is essential for the survival of many cell types and is necessary for immune response functions such as, for example, germinal center formation, antibody responses to T-dependent antigens, and authorization for dendritic cells to mature and become potent to trigger T cell activation and differentiation (see, for example, Kawabe et al., Immunity 1994, 1: 167-178; Elgueta et al., Immunol. Rev. 2009, 229: 152-172).

[012] CD40-CD40L signaling is implicated in autoimmune conditions that are largely driven by autoantibodies, such as systemic rheumatic diseases in which autoantibodies play a significant role in disease progression (e.g., multiple sclerosis, autoimmune nephritis, rheumatoid arthritis, Sjögren's syndrome, and systemic lupus erythematosus), as well as non-rheumatic conditions that have an autoantibody component (e.g., myasthenia gravis, Graves' disease, and neuromyelitis optica) (see, Karnell et al., Adv. Drug Delivery Rev. 2019, 141: 92-103). Additionally, since CD40-CD40L signaling is essential for the activation of antigen-presenting cells, blocking antigen presentation by dendritic cells or B cells may impact CD8+ T cell responses in some diseases such as, for example, multiple sclerosis (see, for example, Denic et al., Expert Opin. Ther. Targets 2013, 17: 1053-1066).Altered CD40-CD40L signaling is also implicated in other diseases and conditions such as cardiovascular disease and transplantation (see, for example, Dakal et al., Immunobiology 2020, 225: 151899; Pamukcu et al., Ann. Med. 2011, 43: 331; 340; Pinelli et al., Immunotherapy 2015, 7: 399-410).

[013] For example, immunosuppression with blockade Petition 870250090230, dated 03 / 10 / 2025, p. 29 / 341 The 6 / 217 CD40 co-stimulatory regimen plus rapamycin provided long-term survival for islet and kidney allografts (90, 94, >120, >120, and >120 days), with only one recipient developing evidence of allograft rejection. The CD40 / rapamycin regimen was also tested in four kidney-only transplant recipients. All four recipients achieved long-term renal allograft survival (100% at day 120), which was superior to renal allograft survival (62.9% at day 120) with a triple immunosuppressive regimen (tacrolimus, mycophenolate mofetil, and steroids) (T. Oura 1, K. Hotta, et al., American Journal of Transplantation. Volume 17, Number 3, March 2017, pages 646-656).

[014] Because different FKBPs are differentially expressed in different tissues, and because there are some scenarios in which it is desirable to avoid mTORC1 inhibition in particular cell types, rapalogs that are selective for individual FKBPs would be needed to increase the ability to target specific tissues. For example, a rapalog that is selective for FKBP12 could target tissues with high FKBP12 expression but spare tissues that have low (or absent) levels of FKBP12. Selective FKBP analogs would provide unique and clinically advantageous benefits for patients, as they can avoid adverse events caused by widespread mTORC1 inhibition.

[015] Rapalogs that can be administered in combination with an anti-CD40 antibody are needed for the treatment of diseases in which autoantibodies play an important role in disease progression, to induce an immune response, and / or to prevent organ transplant rejection.

[016] Rapalogs are needed that can be administered in combination with immunotherapeutic agents that target T cells to specific tumors, so that the rapalogs do not inhibit or interfere with the immunotherapeutic approach. Petition 870250090230, dated 03 / 10 / 2025, page 30 / 341 7 / 217 SUMMARY OF THE INVENTION

[017] In one aspect, a compound of Formula I is provided in this descriptive report: r3'Txxi THE. HO. (I) or a pharmaceutically acceptable salt thereof; where R1 is hydrogen, C1-6 alkyl, heterocyclyl, aryl, heteroaryl, -CO-6 alkylene-SO2R4 or -CO-6 alkylene-SO2R5; in which C1-6 alkyl, heterocyclyl, aryl and heteroaryl are optionally substituted with one or two R1a groups; R2 is heterocyclyl, aryl, heteroaryl, -CO-6 alkylene-SO2R4 or -CO-6 alkylene-SO2R5; wherein heterocyclyl, aryl and heteroaryl are optionally substituted with one or two R2a groups; or R1 and R2 together with the attached nitrogen form an N-linked heteroaryl or N-linked heterocyclyl optionally substituted with one or two R1a groups; R3 is selected from the group consisting of -ORa, 3-6 membered heterocyclyls and 3-6 membered heteroaryls; Rae selected from the group consisting of H, -P(O)(Rb)2, C(O)Rc, -C(O)ORc, C1-6 alkyl and C1-6 hydroxyalkyl; each Rbé selected independently from the group consisting of H and C1-6 alkyl; Rcé selected from the group consisting of H, C1-6 alkyl and C1-6 hydroxyalkyl; R4 is C2-6 alkyl, C3-6 cycloalkyl, C1-6 hydroxyalkyl, Petition 870250090230, dated 03 / 10 / 2025, p. 31 / 341 8 / 217 heterocyclyl, aryl or heteroaryl; wherein heterocyclyl, aryl and heteroaryl are optionally substituted with one or two R4a groups; and R5 is heterocyclyl, aryl or heteroaryl; wherein heterocyclyl, aryl and heteroaryl are optionally substituted with one or two R5a groups; Each of one or two R1a, R2a, R4a and R5a groups, when present, are independently selected from C1-6 alkyl, C16 hydroxyalkyl, hydroxy, halo, C1-6 haloalkyl, C1-6 alkoxy, C1-6 haloalkoxy and cyano; or any two R1a, R2a, R4a and R5a groups, when present on the same carbon, are taken together to form an oxo group; where R1 is hydrogen, R2 is not -CO-6 alkyleneSO2R4.

[018] In one embodiment, the compound of Formula (I) is a compound of Formula (Ia): THE. HO. (Ia) or a pharmaceutically acceptable salt thereof; where R1 is hydrogen or C1-6 alkyl; R2 is a heterocyclyl, aryl, or heteroaryl group optionally substituted with one or two R2a groups; R3 is selected from the group consisting of -ORa, a 3-6 membered heterocyclyl and a 3-6 membered heteroaryl; Rae selected from the group consisting of H, -P(O)(Rb)2, Petition 870250090230, dated 03 / 10 / 2025, p. 32 / 341 9 / 217 C(O)Rc, -C(O)ORc, C1-6 alkyl and C1-6 hydroxyalkyl; Each Rb is selected independently from the group consisting of H and C1-6 alkyl; R is selected from the group consisting of H, C1-6 alkyl and C1-6 hydroxyalkyl; and each of one or two R2a groups, when present, are selected independently from C1-6 alkyl, C1-6 hydroxyalkyl, hydroxy, halo, C1-6 haloalkyl, C1-6 alkoxy, C1-6 haloalkoxy and cyano; or any two R2a groups, when present on the same carbon, are taken together to form an oxo group.

[019] In one embodiment, the compound of Formula (I) is a compound of Formula (Ib): or a pharmaceutically acceptable salt thereof; wherein R1 and R2 together with the attached nitrogen form a N-linked heteroaryl or N-linked heterocyclyl optionally substituted with one or two R1a groups; R3 is selected from the group consisting of -ORa, a 3-6 membered heterocyclyl and a 3-6 membered heteroaryl; Rae selected from the group consisting of H, -P(O)(Rb)2, C(O)Rc, -C(O)ORc, C1-6 alkyl and C1-6 hydroxyalkyl; each Rbé selected independently from the group consisting of H and C1-6 alkyl; Rcé selected from the group consisting of H, C1-6 alkyl and Petition 870250090230, dated 03 / 10 / 2025, pp. 33 / 341 10 / 217 C1-6 hydroxyalkyl; Each of one or two Ria groups, when present, are independently selected from C1-6 alkyl, C1-6 hydroxyalkyl, hydroxy, halo, C1-6 haloalkyl, C1-6 alkoxy, C1-6 haloalkoxy, and cyano; or two Ria groups, when present on the same carbon, are taken together to form an oxo group.

[020] In one embodiment, the compound of Formula (I) is a compound of Formula (Ic): THE. HO. (Ic) or a pharmaceutically acceptable salt thereof; in which Rie hydrogen or C1-6 alkyl; R2 is -C0-6 alkylene-SO2R4or -C0-6 alkylene-SO2R5; R3 is selected from the group consisting of -ORa, a 3-6 membered heterocyclyl and a 3-6 membered heteroaryl; Rae selected from the group consisting of H, -P(O)(Rb)2, C(O)Rc, -C(O)ORc, C1-6 alkyl and C1-6 hydroxyalkyl; each Rbé selected independently from the group consisting of H and C1-6 alkyl; Rcé selected from the group consisting of H, C1-6 alkyl and C1-6 hydroxyalkyl; R4 is C2-6 alkyl, C3-6 cycloalkyl, C1-6 hydroxyalkyl, heterocyclyl, aryl or heteroaryl; wherein heterocyclyl, aryl and heteroaryl are optionally substituted with one or two R4a groups; Petition 870250090230, dated 03 / 10 / 2025, pp. 34 / 341 11 / 217 R5 is heterocyclyl, aryl or heteroaryl; wherein heterocyclyl, aryl and heteroaryl are optionally replaced with one or two R5a groups; Each of one or two R4a and R5a groups, when present, are independently selected from C1-6 alkyl, C1-6 hydroxyalkyl, hydroxy, halo, C1-6 haloalkyl, C1-6 alkoxy, C1-6 haloalkoxy, and cyano; or any two R4a and R5a groups, when present on the same carbon, are taken together to form an oxo group; where R1 is hydrogen, R2 is not -CO-6 alkyleneSO2R4.

[021] The present disclosure provides at least the following modalities: a) A compound of Formula (PI), Formula (P-Ia), Formula (P-Ib), Formula (P-Ic), Formula (P-2), Formula (I), Formula (Ia), Formula (Ib), Formula (Ic), or a pharmaceutically acceptable salt thereof; (b) A compound selected from Compound 3-30, Compound 4365, or Compound 67-74 or a pharmaceutically acceptable salt thereof; c) The compound in (a) or (b), in which the compound binds to FKBP12 selectively with respect to other FK506-binding proteins, compared to Everolimus; (d) A pharmaceutical composition comprising a compound of Formula (PI), Formula (P-Ia), Formula (P-Ib), Formula (PIc), Formula (P-2), Formula (I), Formula (Ia), Formula (Ib), Formula (Ic), or a pharmaceutically acceptable salt thereof, in a pharmaceutically acceptable excipient, diluent or carrier; (e) A pharmaceutical composition comprising a compound of (b) or (c) in a pharmaceutically acceptable excipient, diluent or carrier; f) A pharmaceutical composition comprising a compound Petition 870250090230, dated 03 / 10 / 2025, pp. 35 / 341 12 / 217 of (a)-(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 compound of (a)-(c) or a pharmaceutical composition of (d)-(f), and an anti-CD40 antibody; h) A method of treating a disease or disorder mediated by the mTOR pathway in an individual in need comprising administering a therapeutically effective amount of a compound of (a)-(c), a pharmaceutical composition of (d)-(f) or a combination therapy of (g); i) The method in (h) where the target tissue, organ or cells associated with the disease or disorder pathology have sufficient levels of FKBP12 to inhibit mTORC1; j) The method in (h) or (i) wherein the therapeutically effective amount of a compound in (a)-(c) or pharmaceutical composition in (d)-(f) has a binding affinity high enough for FKBP12 to inhibit mTORC1; k) The (h)-(j) method wherein the disease or disorder is selected from sarcopenia, skin atrophy, cherry angiomas, seborrheic keratoses, cerebral atrophy, atherosclerosis, arteriosclerosis, pulmonary emphysema, osteoporosis, osteoarthritis, hypertension, erectile dysfunction, cataracts, macular degeneration, glaucoma, stroke, cerebrovascular disease (cerebrovascular accidents), chronic kidney disease, diabetic kidney disease, impaired liver function, hepatic fibrosis, autoimmune hepatitis, endometrial hyperplasia, metabolic dysfunction, renovascular disease, hearing loss, motor impairment, cognitive decline, tendon stiffness, cardiac dysfunction such as, for example, cardiac hypertrophy and / or systolic and / or diastolic dysfunction and / or hypertension, cardiac dysfunction resulting in a decline in ejection fraction, immune senescence, Parkinson's disease, disease Petition 870250090230, dated 03 / 10 / 2025, pp. 36 / 341 13 / 217 Alzheimer's disease, cancer, immune senescence leading to cancer due to decreased immune surveillance, infections resulting from a decline in immune function, chronic obstructive pulmonary disease (COPD), obesity, loss of taste, loss of smell, arthritis, cancer in which the tumor has elevated levels of mTORC1 signaling and / or sufficient levels of FKBP12 to allow mTORC1 inhibition, and type II diabetes; l) The (h)-(j) method wherein the disease or disorder is a selected age-related disease or disorder of sarcopenia; skin atrophy; cherry angiomas; seborrheic keratoses; cerebral atrophy; atherosclerosis; arteriosclerosis; pulmonary emphysema; osteoporosis; osteoarthritis; hypertension; erectile dysfunction; cataracts; macular degeneration; glaucoma; stroke; cerebrovascular disease (cerebrovascular accidents); chronic kidney disease; diabetic kidney disease; impaired liver function; hepatic fibrosis; autoimmune hepatitis; endometrial hyperplasia; metabolic dysfunction; renovascular disease; hearing loss; motor impairment; cognitive decline; tendon stiffness; cardiac dysfunction such as, for example, cardiac hypertrophy and / or systolic and / or diastolic dysfunction and / or hypertension; cardiac dysfunction resulting in a decline in ejection fraction; immune senescence; Parkinson's disease; Alzheimer's disease; cancer;Immune senescence leading to cancer due to decreased immune surveillance; infections resulting from a decline in immune function; chronic obstructive pulmonary disease (COPD); obesity; loss of taste; loss of smell; arthritis; cancer in which the tumor has elevated levels of mTORC1 signaling and / or sufficient levels of FKBP12 to allow mTORC1 inhibition; and type II diabetes. m) The (h)-(j) method where the disease or disorder is cancer; n) The method of (m) in which cancer is selected from cancer Petition 870250090230, dated 03 / 10 / 2025, pp. 37 / 341 14 / 217 renal, 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 neck cancer; o) Method (k) where the disease is Alzheimer's disease, p) Method (h) where the disease is graft-versus-host disease (GvHD). q) The method of (h) in which the disease is facial angiofibroma associated with tuberous sclerosis complex. r) The method of (h) in which the disease is unresectable or metastatic advanced perivascular malignant epithelioid cell tumors; s) A method of inducing immune tolerance and / or preventing organ transplant rejection in a needy individual comprising administering a therapeutically effective amount of a compound of (a)-(c), a pharmaceutical composition of (d)-(f) or a combination therapy of (g); t) Method of any of claims (h)-(s), wherein the compound is a compound selected from Compounds 16-19, 26-28, 45, 50, 63, 68-72 and 74. u) A compound of (a)-(c), a pharmaceutical composition of (d)-(f) or a combination therapy of (g) for use in the treatment of a disease or disorder; (v) A compound of (a)-(c), a pharmaceutical composition of (d)-(f) or a combination therapy of (g) for use in the treatment of a disease or disorder mediated by the mTOR pathway in an individual in need; w) The compound of (u)-(v), in which the compound is selected Petition 870250090230, dated 03 / 10 / 2025, pp. 38 / 341 15 / 217 of Compounds 16-19, 26-28, 45, 50, 63, 68-72 and 74; x) Use of a therapeutically effective amount of a compound of (a)-(c), of a pharmaceutical composition of (d)-(f) or of a combination therapy of (g) in the manufacture of a medicament for the treatment of a disease or disorder; y) Use of a therapeutically effective amount of a compound of (a)-(c), a pharmaceutical composition of (d)-(f) or a combination therapy of (g) in the manufacture of a medicament for the treatment of a disease or disorder mediated by the mTOR pathway in an individual in need; and z) The use of (x)-(y), where the compound is selected from Compounds 16-19, 26-28, 45, 50, 63, 68-72 and 74.

[022] In some embodiments, the pharmaceutical compounds and compositions disclosed in this descriptive report for use in the treatment of a disorder or disease mediated by the mTOR pathway are more selective in binding to FKBP12 than others in the FK506-binding protein (FKBP) group.

[023] In some other embodiments, the pharmaceutical compounds and compositions disclosed in this descriptive report for use in the treatment of a disorder or disease mediated by the mTOR pathway exhibit an unusual and surprising pharmacokinetic profile and enhanced pharmacodynamic selectivity among target FKBPs, these compounds, as well as the pharmaceutical compositions containing them, are useful for the treatment of age-related or aging-related diseases, diabetes-related complications, cancers, as well as disorders associated with inflammation.

[024] In some other embodiments, the pharmaceutical compounds and compositions disclosed in this descriptive report are for use in the treatment of a disorder or disease mediated by the mTOR pathway, wherein the compound inhibits S6K1 phosphorylation at least twice less efficiently than rapalog RAD001 in FKBP12 KO cells compared with cells that Petition 870250090230, dated 03 / 10 / 2025, pp. 39 / 341 16 / 217 express FKBP12.

[025] In some other embodiments, the pharmaceutical compounds and compositions disclosed in this descriptive report are for use in the treatment of a disorder or disease mediated by the mTOR pathway, wherein the compound inhibits S6K1 phosphorylation at least ten times less efficiently than rapalog RAD001 in FKBP12 KO cells compared to FKBP12 expressing cells.

[026] In some other embodiments, the pharmaceutical compounds and compositions disclosed in this descriptive report are for use in the treatment of a disorder or disease mediated by the mTOR pathway, wherein the compound inhibits S6K1 phosphorylation at least 100 times less efficiently than rapalog RAD001 in FKBP12 KO cells compared to FKBP12 expressing cells.

[027] In some other embodiments, the pharmaceutical compounds and compositions disclosed in this descriptive report for use in the treatment of a disorder or disease mediated by the mTOR pathway, wherein the compound requires a concentration approximately 10 times higher, compared to the rapalog RAD001, in cells with FKBP12 KO compared to cells expressing FKBP12, to obtain 20% inhibition of cell signaling by S6K1.

[028] In some other embodiments, the pharmaceutical compounds and compositions disclosed in this descriptive report for use in the treatment of a disorder or disease mediated by the mTOR pathway, wherein the compound requires a concentration approximately 100 times higher, compared to the rapalog RAD001, in cells with FKBP12 KO compared to cells expressing FKBP12, to obtain 20% inhibition of cell signaling by S6K1.

[029] In some other embodiments, the pharmaceutical compounds and compositions disclosed in this descriptive report are for use in the treatment of a disorder or disease mediated by the mTOR pathway, wherein the compound requires a concentration of approximately 500 Petition 870250090230, dated 03 / 10 / 2025, page 40 / 341 17 / 217 times greater, compared to the rapalog RAD001, in cells with FKBP12 KO compared to cells expressing FKBP12, to achieve 20% inhibition of cell signaling by S6K1.

[030] In some other embodiments, the pharmaceutical compounds and compositions disclosed in this descriptive report for use in the treatment of a disorder or disease mediated by the mTOR pathway, wherein the compound requires a concentration approximately 1,000 times higher, compared to rapalog RAD001, in cells with FKBP12 KO compared to cells expressing FKBP12, to obtain 20% inhibition of cell signaling by S6K1.

[031] In some other embodiments, the pharmaceutical compounds and compositions disclosed in this descriptive report for use in the treatment of a disorder or disease mediated by the mTOR pathway, wherein the compound requires a concentration approximately 10 times higher, compared to the rapalog RAD001, in cells with FKBP12 KO compared to cells expressing FKBP12, to obtain 30% inhibition of cell signaling by S6K1.

[032] In some other embodiments, the pharmaceutical compounds and compositions disclosed in this descriptive report for use in the treatment of a disorder or disease mediated by the mTOR pathway, wherein the compound requires a concentration approximately 100 times higher, compared to rapalog RAD001, in cells with FKBP12 KO compared to cells expressing FKBP12, to obtain 30% inhibition of cell signaling by S6K1.

[033] In some other embodiments, the pharmaceutical compounds and compositions disclosed in this descriptive report for use in the treatment of a disorder or disease mediated by the mTOR pathway, wherein the compound requires a concentration approximately 500 times higher, compared to rapalog RAD001, in cells with FKBP12 KO compared to cells expressing FKBP12, to obtain 30% inhibition of cell signaling by S6K1.

[034] In some other embodiments, the pharmaceutical compounds and compositions disclosed in this descriptive report Petition 870250090230, dated 03 / 10 / 2025, page 41 / 341 18 / 217 for use in the treatment of a disorder or disease mediated by the mTOR pathway, where the compound requires a concentration approximately 1,000 times higher, compared to rapalog RAD001, in FKBP12-KO cells compared to FKBP12-expressing cells, to achieve 30% inhibition of S6K1 cell signaling.

[035] In some other embodiments, a “FKBP12 selective rapalog” is a rapalog that is approximately 10 times to approximately 1,000 times less potent than RAD001 in a cell line that does not express FKBP12 (e.g., FKBP12 knockout cells compared with FKBP12 expressing cells). The term “potency,” as used in this context, can be expressed as the concentration of rapalog required to achieve a 20% inhibition of S6K1 (Thr389) phosphorylation in a cell-based assay such as, for example, that used in Example 3 and Figures 1–11 disclosed in this descriptive report. For example, a rapalog is considered selective for FKBP12 if the IC20 of the rapalog in an S6K1 phosphorylation inhibition assay (Thr389) using an FKBP12 knockout cell line is at least 20x higher (e.g., 30x, 50x, 100x, 200x, 500x, 1).000 x greater) than the IC20 of RAD001 in the same assay with the same cell line, which normally expresses FKBP12.

[036] In some other embodiments, a “FKBP12 selective rapalog” is a rapalog that is approximately 10 times to approximately 1,000 times less potent than RAD001 in a cell line that does not express FKBP12 (e.g., FKBP12 knockout cells compared to FKBP12 expressing cells). The term “potency,” as used in this context, can be expressed as the concentration of rapalog required to achieve a 30% inhibition of S6K1 (Thr389) phosphorylation in a cell-based assay such as, for example, that used in Example 3 and Figures 1–11 disclosed in this descriptive report. For example, a rapalog is considered selective for FKBP12 if the Petition 870250090230, dated 03 / 10 / 2025, page 42 / 341 19 / 217 The IC30 of rapálogo in an S6K1 phosphorylation inhibition assay (Thr389) using an FKBP12 knockout cell line is at least 20x higher (e.g., 30x, 50x, 100x, 200x, 500x, 1000x higher) than the IC30 of RAD001 in the same assay with the same cell line that normally expresses FKBP12.

[037] In one embodiment, the compound of Formula (I) or a pharmaceutically acceptable salt thereof has a higher binding affinity to FKBP12, sufficient to inhibit mTORC1, for example, when compared with rapamycin or RAD001.

[038] In one embodiment, a compound of (I), (P-1), (P-2), (Ia)-(Ic) or (P-Ia)-(P-Ic), or a pharmaceutically acceptable salt thereof, can form a complex with FKBP12 to bind and inhibit mTORC1 more potently when compared with rapamycin or RAD001.

[039] In one embodiment, the higher binding affinity to FKBP12 results in greater efficacy, for example, when compared with rapamycin or RAD001.

[040] In one modality, the effectiveness of the treatment is determined empirically, for example, when compared with rapamycin or RAD001.

[041] In yet another aspect, the disclosure provides a method of treating a disease or disorder in an individual who has, or has been previously determined to have, sufficient levels of FKBP12 to inhibit mTORc1, the method comprising administering to the individual in need a therapeutically effective amount of a compound of (I), (P-1), (P-2), (Ia)-(Ic) or (P-Ia)-(P-Ic), or of a pharmaceutically acceptable salt thereof, or of a pharmaceutical composition described in this descriptive report, or of a pharmaceutical combination described in this descriptive report.

[042] In another aspect, the revelation provides a method for treating an age-related disease or disorder in a Petition 870250090230, dated 03 / 10 / 2025, page 43 / 341 20 / 217 individual in need, the method comprising administering to the individual a therapeutically effective amount of a compound of (I), (P-1), (P-2), (Ia)-(Ic) or (P-Ia)-(P-Ic), or of a pharmaceutically acceptable salt thereof, or of a pharmaceutical composition described in this descriptive report, or of a pharmaceutical combination described in this descriptive report.

[043] In one embodiment, the disease or disorder is selected from sarcopenia, skin atrophy, cherry angiomas, seborrheic keratoses, cerebral atrophy (also referred to as dementia), atherosclerosis, arteriosclerosis, pulmonary emphysema, osteoporosis, osteoarthritis, hypertension, erectile dysfunction, cataracts, macular degeneration, glaucoma, stroke, cerebrovascular disease (cerebrovascular accidents), chronic kidney disease, diabetic kidney disease, impaired liver function, hepatic fibrosis, autoimmune hepatitis, endometrial hyperplasia, metabolic dysfunction, renovascular disease, hearing loss, motor impairment (e.g., frailty), cognitive decline, tendon stiffness, cardiac dysfunction such as, for example, cardiac hypertrophy and / or systolic and / or diastolic dysfunction and / or hypertension, cardiac dysfunction resulting in a decline in ejection fraction, immune senescence, Parkinson's disease, Alzheimer's disease, cancer,Immune senescence leading to cancer due to decreased immune surveillance, infections resulting from a decline in immune function, chronic obstructive pulmonary disease (COPD), obesity, loss of taste, loss of smell, arthritis, and type II diabetes (including complications arising from diabetes such as kidney failure, blindness, and neuropathy).

[044] In another aspect, the disclosure provides a method for the treatment of a disease or disorder in an individual in need, the method comprising administering to the individual a therapeutically effective amount of a compound of (I), (P-1), (P-2), (Ia)-(Ic) or (P-Ia)-(P-Ic), or of a salt Petition 870250090230, dated 03 / 10 / 2025, page 44 / 341 21 / 217 pharmaceutically acceptable of this, or of a pharmaceutical composition, or of a pharmaceutical combination thereof, wherein the disorder or disease is selected from: - Acute or chronic rejection of organ or tissue transplantation; - Transplant vasculopathies; - Proliferation and migration of smooth muscle cells leading to thickening of the intima of blood vessels, obstruction of blood vessels, obstructive coronary atherosclerosis, restenosis; Autoimmune diseases and inflammatory conditions; Asthma; Multidrug resistance (MDR); - Fungal infections; Inflammation; Infection; Age-related diseases; Neurodegenerative diseases; - Proliferative disorders, for example, cancer; - Seizures and seizure-related disorders; and Mitochondrial myopathy and mitochondrial stress.

[045] In another aspect, the disclosure provides a method for treating cancer in an individual in need, the method comprising administering to the individual a therapeutically effective amount of a compound of Formula (I) or of a pharmaceutically acceptable salt thereof, or of a pharmaceutical composition described in this descriptive report, or of a pharmaceutical combination described in this descriptive report.

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

[047] In one embodiment, the cancer is selected from renal cancer, renal cell carcinoma, colorectal cancer, uterine sarcoma, uterine endometrial cancer, endometrial cancer, breast cancer, ovarian cancer, cervical cancer, gastric cancer, Petition 870250090230, dated 03 / 10 / 2025, page 45 / 341 22 / 217 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 neck cancer.

[048] In one embodiment, the disorder is a liver disorder that includes the process of fibrosis and / or inflammation, for example, hepatic fibrosis that occurs in end-stage liver disease; hepatic cirrhosis; liver failure due to toxicity; non-alcohol-associated fatty liver disease or NASH; and alcohol-associated fatty liver disease.

[049] In one modality, the disorder is a kidney disorder that includes the process of fibrosis or inflammation in the kidney, for example, renal fibrosis, which occurs as a result of acute kidney injury, leading to chronic kidney disease and diabetic nephropathy.

[050] In one modality, the disorder is cardiac dysfunction, for example, myocardial infarction or cardiac hypertrophy. In one modality, the cardiac dysfunction is systolic and / or diastolic dysfunction. In one modality, the cardiac dysfunction is hypertension. In one modality, the cardiac dysfunction results in a decline in ejection fraction.

[051] In one form, the disorder is immune senescence that leads to cancer as a result of a decrease in immune surveillance.

[052] In one embodiment, the disorder is cancer, including tumors that are treated by immunotherapy, and those that have been previously treated with rapamycin, RAD001, or another rapalog. In one embodiment, cancer includes tumors in which the mTOR pathway is shown to be activated, including scenarios in which there is a mutation in the Tsc1 gene, or in which the tumor microenvironment is appropriately treated by a rapalog.

[053] Details of one or more disclosure methods are presented in this descriptive report. Other characteristics, Petition 870250090230, dated 03 / 10 / 2025, page 46 / 341 23 / 217 The objects and advantages of disclosure will become evident from the Figures, the detailed Description, the Examples, and the Claims. BRIEF DESCRIPTION OF THE DRAWINGS

[054] FIG. 1A is a line graph showing the inhibition of S6K1 (Thr389) in wild-type 293T cells. Cells were treated for 2 hours with the following compounds: RAD001 (everolimus; dashed line with circles) and Compound 44 (solid line with squares). All treatments were performed in duplicate. The Y-axis represents the percentage inhibition relative to the level of S6K1 (Thr389) in cells treated with media plus dimethyl sulfoxide (DMSO). The X-axis represents concentrations for the two compounds.

[055] FIG. 1B is a line graph showing the inhibition of S6K1 (Thr389) in FKBP12 knockout 293T cells. Cells were treated for 2 hours with the following compounds: RAD001 (everolimus; dashed line with circles) and Compound 44 (solid line with squares). All treatments were performed in duplicate. The Y-axis represents the percentage inhibition relative to the level of S6K1 (Thr389) in cells treated with media plus dimethyl sulfoxide (DMSO). The X-axis represents concentrations for the two compounds.

[056] FIG. 1C is a line graph showing the inhibition of S6K1 (Thr389) in wild-type 293T cells. Cells were treated for 2 hours with the following compounds: RAD001 (everolimus; dashed line with circles) and Compound 45 (solid line with squares). All treatments were performed in duplicate. The Y-axis represents the percentage inhibition relative to the level of S6K1 (Thr389) in cells treated with media plus dimethyl sulfoxide (DMSO). The X-axis represents concentrations for the two compounds.

[057] FIG. 1D is a line graph showing the inhibition of S6K1 (Thr389) in 293T cells with FKBP12 knockout. As Petition 870250090230, dated 03 / 10 / 2025, page 47 / 341 24 / 217 cells were treated for 2 hours with the following compounds: RAD001 (everolimus; dashed line with circles) and Compound 45 (solid line with squares). All treatments were performed in duplicate. The Y-axis represents the percentage inhibition relative to the S6K1 (Thr389) level in cells treated with media plus dimethyl sulfoxide (DMSO). The X-axis represents concentrations for the two compounds.

[058] FIG. 2A is a line graph showing the inhibition of S6K1 (Thr389) in wild-type 293T cells. Cells were treated for 2 hours with the following compounds: RAD001 (everolimus; dashed line with circles) and Compound 18 (solid line with squares). All treatments were performed in duplicate. The Y-axis represents the percentage inhibition relative to the level of S6K1 (Thr389) in cells treated with media plus dimethyl sulfoxide (DMSO). The X-axis represents concentrations for the two compounds.

[059] FIG. 2B is a line graph showing the inhibition of S6K1 (Thr389) in FKBP12 knockout 293T cells. Cells were treated for 2 hours with the following compounds: RAD001 (everolimus; dashed line with circles) and Compound 18 (solid line with squares). All treatments were performed in duplicate. The Y-axis represents the percentage inhibition relative to the level of S6K1 (Thr389) in cells treated with media plus dimethyl sulfoxide (DMSO). The X-axis represents concentrations for the two compounds.

[060] FIG. 3A is a line graph showing the inhibition of S6K1 (Thr389) in wild-type 293T cells. Cells were treated for 2 hours with the following compounds: RAD001 (everolimus; dashed line with circles) and Compound 16 (solid line with squares). All treatments were performed in duplicate. The Y-axis represents the percentage inhibition relative to the level of S6K1 (Thr389) in cells treated with media plus dimethyl sulfoxide (DMSO). The X-axis represents concentrations Petition 870250090230, dated 03 / 10 / 2025, page 48 / 341 25 / 217 for both compounds.

[061] FIG. 3B is a line graph showing the inhibition of S6K1 (Thr389) in FKBP12 knockout 293T cells. Cells were treated for 2 hours with the following compounds: RAD001 (everolimus; dashed line with circles) and Compound 16 (solid line with squares). All treatments were performed in duplicate. The Y-axis represents the percentage inhibition relative to the level of S6K1 (Thr389) in cells treated with media plus dimethyl sulfoxide (DMSO). The X-axis represents concentrations for the two compounds.

[062] FIG. 4A is a line graph showing the inhibition of S6K1 (Thr389) in wild-type 293T cells. Cells were treated for 2 hours with the following compounds: RAD001 (everolimus; dashed line with circles) and Compounds 26 (solid line with squares) and Compound 28 (solid line with crosses). All treatments were performed in duplicate. The Y-axis represents the percentage inhibition relative to the level of S6K1 (Thr389) in cells treated with media plus dimethyl sulfoxide (DMSO). The X-axis represents concentrations for the two compounds.

[063] FIG. 4B is a line graph showing the inhibition of S6K1 (Thr389) in FKBP12 knockout 293T cells. Cells were treated for 2 hours with the following compounds: RAD001 (everolimus; dashed line with circles) and Compounds 26 (solid line with squares) and Compound 28 (solid line with crosses). All treatments were performed in duplicate. The Y-axis represents the percentage inhibition relative to the level of S6K1 (Thr389) in cells treated with media plus dimethyl sulfoxide (DMSO). The X-axis represents concentrations for the two compounds.

[064] FIG. 5A is a line graph showing the inhibition of S6K1 (Thr389) phosphorylation in wild-type (WT) 293T cells with treatment with increasing concentrations of the compound. As Petition 870250090230, dated 03 / 10 / 2025, page 49 / 341 26 / 217 cells were treated for 2 hours with the following compounds: RAD001 (everolimus; dashed line with circles); Compound 47 (solid line with squares). All treatments were performed in duplicate. The Y-axis shows the phosphorylation values ​​of S6K1 (Thr389) calculated as a percentage (%) of the value in control cells treated only with media plus dimethyl sulfoxide (DMSO). The phosphorylation value of S6K1 (Thr389) in control cells treated with DMSO is set to 100%. The X-axis represents Log10 molar (M) concentrations for the compounds.

[065] FIG. 5B is a line graph showing the inhibition of S6K1 (Thr389) phosphorylation in FKBP12 knockout (KO) 293T cells with treatment with increasing compound concentrations. Cells were treated for 2 hours with the following compounds: RAD001 (everolimus; dashed line with circles); Compound 47 (solid line with squares). All treatments were performed in duplicate. The Y-axis shows the S6K1 (Thr389) phosphorylation values ​​calculated as a percentage (%) of the value in control cells treated only with media plus dimethyl sulfoxide (DMSO). The S6K1 (Thr389) phosphorylation value in control cells treated with DMSO is set to 100%. The X-axis represents Log10 molar (M) concentrations for the compounds.

[066] FIG. 5C is a line graph showing the inhibition of S6K1 (Thr389) phosphorylation in wild-type (WT) 293T cells with treatment with increasing compound concentrations. Cells were treated for 2 hours with the following compounds: RAD001 (everolimus; dashed line with circles); Compound 48 (solid line with squares). All treatments were performed in duplicate. The Y-axis shows the S6K1 (Thr389) phosphorylation values ​​calculated as a percentage (%) of the value in control cells treated only with media plus dimethyl sulfoxide (DMSO). The value of S6K1 phosphorylation Petition 870250090230, dated 03 / 10 / 2025, page 50 / 341 27 / 217 (Thr389) in control cells treated with DMSO is set to 100%. The X-axis represents Log10 molar (M) concentrations for the compounds.

[067] FIG. 5D is a line graph showing the inhibition of S6K1 (Thr389) phosphorylation in FKBP12 knockout (KO) 293T cells with treatment with increasing compound concentrations. Cells were treated for 2 hours with the following compounds: RAD001 (everolimus; dashed line with circles); Compound 48 (solid line with squares). All treatments were performed in duplicate. The Y-axis shows the calculated S6K1 (Thr389) phosphorylation values ​​as a percentage (%) of the value in control cells treated only with media plus dimethyl sulfoxide (DMSO). The S6K1 (Thr389) phosphorylation value in control cells treated with DMSO is set to 100%. The X-axis represents Log10 molar (M) concentrations for the compounds.

[068] FIG. 5E is a line graph showing the inhibition of S6K1 (Thr389) phosphorylation in wild-type (WT) 293T cells with treatment with increasing compound concentrations. Cells were treated for 2 hours with the following compounds: RAD001 (everolimus; dashed line with circles); Compound 49 (solid line with squares). All treatments were performed in duplicate. The Y-axis shows the S6K1 (Thr389) phosphorylation values ​​calculated as a percentage (%) of the value in control cells treated only with media plus dimethyl sulfoxide (DMSO). The S6K1 (Thr389) phosphorylation value in control cells treated with DMSO is set to 100%. The X-axis represents concentrations for both compounds.

[069] FIG. 5F is a line graph showing the inhibition of S6K1 (Thr389) phosphorylation in FKBP12 knockout (KO) 293T cells with treatment with increasing concentrations of the compound. The cells were treated for 2 hours with the following Petition 870250090230, dated 03 / 10 / 2025, page 51 / 341 28 / 217 compounds: RAD001 (everolimus; dashed line with circles); Compound 49 (solid line with squares). All treatments were performed in duplicate. The Y-axis shows the phosphorylation values ​​of S6K1 (Thr389) calculated as a percentage (%) of the value in control cells treated only with media plus dimethyl sulfoxide (DMSO). The phosphorylation value of S6K1 (Thr389) in control cells treated with DMSO is set to 100%. The X-axis represents Log10 molar (M) concentrations for the two compounds.

[070] FIG. 6A is a line graph showing the inhibition of S6K1 (Thr389) phosphorylation in wild-type (WT) 293T cells with treatment with increasing compound concentrations. Cells were treated for 2 hours with the following compounds: RAD001 (everolimus; dashed line with circles); Compound 50 (solid line with squares). All treatments were performed in duplicate. The Y-axis shows the S6K1 (Thr389) phosphorylation values ​​calculated as a percentage (%) of the value in control cells treated only with media plus dimethyl sulfoxide (DMSO). The S6K1 (Thr389) phosphorylation value in control cells treated with DMSO is set to 100%. The X-axis represents concentrations for both compounds.

[071] FIG. 6B is a line graph showing the inhibition of S6K1 (Thr389) phosphorylation in FKBP12 knockout (KO) 293T cells with treatment with increasing compound concentrations. Cells were treated for 2 hours with the following compounds: RAD001 (everolimus; dashed line with circles); Compound 50 (solid line with squares). All treatments were performed in duplicate. The Y-axis shows the calculated S6K1 (Thr389) phosphorylation values ​​as a percentage (%) of the value in control cells treated only with media plus dimethyl sulfoxide (DMSO). The S6K1 (Thr389) phosphorylation value in control cells treated with DMSO is set Petition 870250090230, dated 03 / 10 / 2025, page 52 / 341 29 / 217 to 100%. The X-axis represents concentrations for the two compounds.

[072] FIG. 6C is a line graph showing the inhibition of S6K1 (Thr389) phosphorylation in wild-type (WT) 293T cells with treatment with increasing compound concentrations. Cells were treated for 2 hours with the following compounds: RAD001 (everolimus; dashed line with circles); Compound 51 (solid line with squares). All treatments were performed in duplicate. The Y-axis shows the S6K1 (Thr389) phosphorylation values ​​calculated as a percentage (%) of the value in control cells treated only with media plus dimethyl sulfoxide (DMSO). The S6K1 (Thr389) phosphorylation value in control cells treated with DMSO is set to 100%. The X-axis represents concentrations for both compounds.

[073] FIG. 6D is a line graph showing the inhibition of S6K1 (Thr389) phosphorylation in FKBP12 knockout (KO) 293T cells with treatment with increasing compound concentrations. Cells were treated for 2 hours with the following compounds: RAD001 (everolimus; dashed line with circles); Compound 51 (solid line with squares). All treatments were performed in duplicate. The Y-axis shows the S6K1 (Thr389) phosphorylation values ​​calculated as a percentage (%) of the value in control cells treated only with media plus dimethyl sulfoxide (DMSO). The S6K1 (Thr389) phosphorylation value in control cells treated with DMSO is set to 100%. The X-axis represents concentrations for both compounds.

[074] FIG. 6E is a line graph showing the inhibition of S6K1 (Thr389) phosphorylation in wild-type (WT) 293T cells with treatment with increasing concentrations of compound. The cells were treated for 2 hours with the following compounds: RAD001 (everolimus; dotted line with circles); Compound 52 Petition 870250090230, dated 03 / 10 / 2025, page 53 / 341 30 / 217 (solid line with squares). All treatments were performed in duplicate. The Y-axis shows the phosphorylation values ​​of S6K1 (Thr389) calculated as a percentage (%) of the value in control cells treated only with media plus dimethyl sulfoxide (DMSO). The phosphorylation value of S6K1 (Thr389) in control cells treated with DMSO is set to 100%. The X-axis represents concentrations for the two compounds.

[075] FIG. 6F is a line graph showing the inhibition of S6K1 (Thr389) phosphorylation in FKBP12 knockout (KO) 293T cells with increasing compound concentrations. Cells were treated for 2 hours with the following compounds: RAD001 (everolimus; dashed line with circles); Compound 52 (solid line with squares). All treatments were performed in duplicate. The Y-axis shows the S6K1 (Thr389) phosphorylation values ​​calculated as a percentage (%) of the value in control cells treated only with media plus dimethyl sulfoxide (DMSO). The S6K1 (Thr389) phosphorylation value in control cells treated with DMSO is set to 100%. The X-axis represents concentrations for both compounds.

[076] FIG. 7A is a line graph showing the inhibition of S6K1 (Thr389) phosphorylation in wild-type (WT) 293T cells with treatment with increasing compound concentrations. Cells were treated for 2 hours with the following compounds: RAD001 (everolimus; dashed line with circles); Compound 57 (solid line with squares). All treatments were performed in duplicate. The Y-axis shows the S6K1 (Thr389) phosphorylation values ​​calculated as a percentage (%) of the value in control cells treated only with media plus dimethyl sulfoxide (DMSO). The S6K1 (Thr389) phosphorylation value in control cells treated with DMSO is set to 100%. The X-axis represents concentrations for the two Petition 870250090230, dated 03 / 10 / 2025, page 54 / 341 31 / 217 compounds.

[077] FIG. 7B is a line graph showing the inhibition of S6K1 (Thr389) phosphorylation in FKBP12 knockout (KO) 293T cells with treatment with increasing compound concentrations. Cells were treated for 2 hours with the following compounds: RAD001 (everolimus; dashed line with circles); Compound 57 (solid line with squares). All treatments were performed in duplicate. The Y-axis shows the S6K1 (Thr389) phosphorylation values ​​calculated as a percentage (%) of the value in control cells treated only with media plus dimethyl sulfoxide (DMSO). The S6K1 (Thr389) phosphorylation value in control cells treated with DMSO is set to 100%. The X-axis represents concentrations for both compounds.

[078] FIG. 7C is a line graph showing the inhibition of S6K1 (Thr389) phosphorylation in wild-type (WT) 293T cells with treatment with increasing compound concentrations. Cells were treated for 2 hours with the following compounds: RAD001 (everolimus; dashed line with circles); Compound 58 (solid line with squares). All treatments were performed in duplicate. The Y-axis shows the S6K1 (Thr389) phosphorylation values ​​calculated as a percentage (%) of the value in control cells treated only with media plus dimethyl sulfoxide (DMSO). The S6K1 (Thr389) phosphorylation value in control cells treated with DMSO is set to 100%. The X-axis represents concentrations for both compounds.

[079] FIG. 7D is a line graph showing the inhibition of S6K1 (Thr389) phosphorylation in FKBP12 knockout (KO) 293T cells with treatment with increasing compound concentrations. Cells were treated for 2 hours with the following compounds: RAD001 (everolimus; dashed line with circles); Compound 58 (solid line with squares). All treatments Petition 870250090230, dated 03 / 10 / 2025, page 55 / 341 32 / 217 were performed in duplicate. The Y-axis shows the phosphorylation values ​​of S6K1 (Thr389) calculated as a percentage (%) of the value in control cells treated only with media plus dimethyl sulfoxide (DMSO). The phosphorylation value of S6K1 (Thr389) in control cells treated with DMSO is set to 100%. The X-axis represents concentrations for the two compounds.

[080] FIG. 7E is a line graph showing the inhibition of S6K1 (Thr389) phosphorylation in wild-type (WT) 293T cells with treatment with increasing compound concentrations. Cells were treated for 2 hours with the following compounds: RAD001 (everolimus; dashed line with circles); Compound 59 (solid line with squares). All treatments were performed in duplicate. The Y-axis shows the S6K1 (Thr389) phosphorylation values ​​calculated as a percentage (%) of the value in control cells treated only with media plus dimethyl sulfoxide (DMSO). The S6K1 (Thr389) phosphorylation value in control cells treated with DMSO is set to 100%. The X-axis represents concentrations for both compounds.

[081] FIG. 7F is a line graph showing the inhibition of S6K1 (Thr389) phosphorylation in FKBP12 knockout (KO) 293T cells with treatment with increasing compound concentrations. Cells were treated for 2 hours with the following compounds: RAD001 (everolimus; dashed line with circles); Compound 59 (solid line with squares). All treatments were performed in duplicate. The Y-axis shows the S6K1 (Thr389) phosphorylation values ​​calculated as a percentage (%) of the value in control cells treated only with media plus dimethyl sulfoxide (DMSO). The S6K1 (Thr389) phosphorylation value in control cells treated with DMSO is set to 100%. The X-axis represents concentrations for both compounds. Petition 870250090230, dated 03 / 10 / 2025, page 56 / 341 33 / 217

[082] FIG. 8A is a line graph showing the inhibition of S6K1 (Thr389) phosphorylation in wild-type (WT) 293T cells with treatment with increasing compound concentrations. Cells were treated for 2 hours with the following compounds: RAD001 (everolimus; dashed line with circles); Compound 63 (solid line with squares). All treatments were performed in duplicate. The Y-axis shows the S6K1 (Thr389) phosphorylation values ​​calculated as a percentage (%) of the value in control cells treated only with media plus dimethyl sulfoxide (DMSO). The S6K1 (Thr389) phosphorylation value in control cells treated with DMSO is set to 100%. The X-axis represents concentrations for both compounds.

[083] FIG. 8B is a line graph showing the inhibition of S6K1 (Thr389) phosphorylation in FKBP12 knockout (KO) 293T cells with treatment with increasing compound concentrations. Cells were treated for 2 hours with the following compounds: RAD001 (everolimus; dashed line with circles); Compound 63 (solid line with squares). All treatments were performed in duplicate. The Y-axis shows the S6K1 (Thr389) phosphorylation values ​​calculated as a percentage (%) of the value in control cells treated only with media plus dimethyl sulfoxide (DMSO). The S6K1 (Thr389) phosphorylation value in control cells treated with DMSO is set to 100%. The X-axis represents concentrations for both compounds.

[084] FIG. 9A is a line graph showing the inhibition of S6K1 (Thr389) phosphorylation in wild-type (WT) 293T cells with treatment with increasing concentrations of compound. Cells were treated for 2 hours with the following compounds: RAD001 (everolimus; dashed line with circles); Compound 69 (solid line with squares). All treatments were performed in duplicate. The Y-axis shows the values ​​of Petition 870250090230, dated 03 / 10 / 2025, page 57 / 341 34 / 217 S6K1 (Thr389) phosphorylation calculated as a percentage (%) of the value in control cells treated only with media plus dimethyl sulfoxide (DMSO). The S6K1 (Thr389) phosphorylation value in control cells treated with DMSO is set to 100%. The X-axis represents concentrations for the two compounds.

[085] FIG. 9B is a line graph showing the inhibition of S6K1 (Thr389) phosphorylation in FKBP12 knockout (KO) 293T cells with increasing compound concentrations. Cells were treated for 2 hours with the following compounds: RAD001 (everolimus; dashed line with circles); Compound 69 (solid line with squares). All treatments were performed in duplicate. The Y-axis shows the S6K1 (Thr389) phosphorylation values ​​calculated as a percentage (%) of the value in control cells treated only with media plus dimethyl sulfoxide (DMSO). The S6K1 (Thr389) phosphorylation value in control cells treated with DMSO is set to 100%. The X-axis represents concentrations for both compounds.

[086] FIG. 10A is a line graph showing the inhibition of S6K1 (Thr389) phosphorylation in wild-type (WT) 293T cells with treatment with increasing compound concentrations. Cells were treated for 2 hours with the following compounds: RAD001 (everolimus; dashed line with circles); Compound 72 (solid line with squares). All treatments were performed in duplicate. The Y-axis shows the S6K1 (Thr389) phosphorylation values ​​calculated as a percentage (%) of the value in control cells treated only with media plus dimethyl sulfoxide (DMSO). The S6K1 (Thr389) phosphorylation value in control cells treated with DMSO is set to 100%. The X-axis represents concentrations for both compounds.

[087] FIG. 10B is a line graph showing the inhibition Petition 870250090230, dated 03 / 10 / 2025, page 58 / 341 35 / 217 of S6K1 (Thr389) phosphorylation in FKBP12 knockout (KO) 293T cells treated with increasing compound concentrations. Cells were treated for 2 hours with the following compounds: RAD001 (everolimus; dashed line with circles); Compound 72 (solid line with squares). All treatments were performed in duplicate. The Y-axis shows the calculated S6K1 (Thr389) phosphorylation values ​​as a percentage (%) of the value in control cells treated only with media plus dimethyl sulfoxide (DMSO). The S6K1 (Thr389) phosphorylation value in control cells treated with DMSO is set to 100%. The X-axis represents concentrations for both compounds.

[088] FIG. 11A is a line graph showing the inhibition of S6K1 (Thr389) phosphorylation in wild-type (WT) 293T cells with treatment with increasing compound concentrations. Cells were treated for 2 hours with the following compounds: RAD001 (everolimus; dashed line with circles); Compound 73 (solid line with squares). All treatments were performed in duplicate. The Y-axis shows the S6K1 (Thr389) phosphorylation values ​​calculated as a percentage (%) of the value in control cells treated only with media plus dimethyl sulfoxide (DMSO). The S6K1 (Thr389) phosphorylation value in control cells treated with DMSO is set to 100%. The X-axis represents concentrations for both compounds.

[089] FIG. 11B is a line graph showing the inhibition of S6K1 (Thr389) phosphorylation in FKBP12 knockout (KO) 293T cells with treatment with increasing compound concentrations. Cells were treated for 2 hours with the following compounds: RAD001 (everolimus; dashed line with circles); Compound 73 (solid line with squares). All treatments were performed in duplicate. The Y-axis shows the calculated S6K1 (Thr389) phosphorylation values ​​as a percentage (%). Petition 870250090230, dated 03 / 10 / 2025, page 59 / 341 36 / 217 of the value in control cells treated only with media plus dimethyl sulfoxide (DMSO). The phosphorylation value of S6K1 (Thr389) in control cells treated with DMSO is set to 100%. The X-axis represents concentrations for both compounds.

[090] FIG. 12A is a graph showing the pharmacokinetic profile in mouse plasma of the comparator compound RAD001 after IV (2 mg / kg) and PO (10 mg / kg) administration. The Y-axis, set to Log 10 scale, shows the compound concentration (ng / ml) in plasma. The X-axis shows the time points (hours) for plasma collection after compound administration.

[091] FIG. 12B is a graph showing the pharmacokinetic profile in mouse plasma of Compound 26 after IV (2 mg / kg) and PO (20 mg / kg) administration. The Y-axis, set to Log 10 scale, shows compound concentration (ng / ml) in plasma. The X-axis shows the time points (hours) for plasma collection after compound administration.

[092] FIG. 12C is a graph showing the pharmacokinetic profile in mouse plasma of Compound 45 after IV (2 mg / kg) and PO (20 mg / kg) administration. The Y-axis, set to Log 10 scale, shows the compound concentration, ng / ml, in plasma. The X-axis shows the time points (hours) for plasma collection after compound administration.

[093] FIG. 12D is a graph showing the pharmacokinetic profile in mouse plasma of Compound 69 after IV (2 mg / kg) and PO (10 mg / kg) administration. The Y-axis, set to a Log 10 scale, shows the compound concentration, ng / ml, in plasma. The X-axis shows the time points (hours) for plasma collection after compound administration.

[094] The data depicted in FIG. 12A - Fig. 12D from pharmacokinetic studies of selected compounds in mice are further summarized in Table 4 shown in the Detailed Description below. Petition 870250090230, dated 03 / 10 / 2025, page 60 / 341 37 / 217 DETAILED DESCRIPTION OF THE INVENTION Definitions

[095] When referring to the compounds provided in this descriptive report, the following terms have the following meanings, unless otherwise indicated. Unless otherwise defined, all technical and scientific terms used in this descriptive report have the same meanings as commonly understood by those skilled in the art. If there are multiple definitions for a term provided in this descriptive report, those definitions prevail, unless stated otherwise.

[096] As used in this descriptive report, the term alkyl refers to a monovalent, saturated hydrocarbon radical moiety. Alkyl is optionally substituted and may be linear, branched, or cyclic (i.e., cycloalkyl). Alkyl includes, without limitation, those radicals having from one to twenty carbon atoms, for example, C1-20 alkyl; one to twelve carbon atoms, for example, C1-12 alkyl; one to eight carbon atoms, for example, C1-8 alkyl; one to six carbon atoms, for example, C1-6 alkyl; and one to three carbon atoms, for example, C1-3 alkyl. Examples of alkyl moieties include, without limitation, methyl, ethyl, n-propyl, i-propyl, n-butyl, s-butyl, t-butyl, butyl, a pentyl moiety, a hexyl moiety, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. A pentyl moiety includes, without limitation, n-pentyl and i-pentyl. A hexyl moiety includes, without limitation, n-hexyl.

[097] As used in this descriptive report, the term haloalkyl refers to alkyl, as defined in this descriptive report, wherein the alkyl includes at least one substituent selected from a halogen, for example, F, Cl, Br or I.

[098] As used in this descriptive report, the term hydroxyalkyl refers to alkyl, as defined in this descriptive report, wherein the alkyl includes at least one group Petition 870250090230, dated 03 / 10 / 2025, page 61 / 341 38 / 217 hydroxy.

[099] As used in this descriptive report, the term alkylene refers to a divalent alkyl group. Unless otherwise specified, alkylene includes, without limitation, one to twenty carbon atoms. The alkylene group is optionally substituted as described in this descriptive report for alkyl. In some embodiments, alkylene is unsubstituted. Examples of alkylene moieties include -CH2-, -CH2CH2-, -CH2CH2CH2, -CH2CH2CH2CH2- and the like.

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

[101] As used in this descriptive report, the term alkoxy refers to a monovalent and saturated hydrocarbon radical moiety in which the hydrocarbon includes a single bond to an oxygen atom and in which the radical is located on the oxygen atom, for example, CH3CH2-O- for ethoxy. Alkoxy substituents attach to the compound they replace through this oxygen atom of the alkoxy substituent. Alkoxy is optionally substituted and may be linear, branched, or cyclic, for example, cycloalkoxy. Alkoxy includes, without limitation, those radicals having from one to twenty carbon atoms, for example, C1-20 alkoxy; one to twelve carbon atoms, for example, C1-12 alkoxy; one to eight carbon atoms, for example, C1-8 alkoxy; one to six carbon atoms, for example, C1-6 alkoxy; and one to three carbon atoms, for example, C1-3 alkoxy.Examples of alkoxy moieties include, without limitation, methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, s-butoxy, t-butoxy, i-butoxy, a pentoxy moiety, a hexoxy moiety, cyclopropoxy, cyclobutoxy, cyclopentoxy, and cyclohexoxy.

[102] As used in this descriptive report, the term Petition 870250090230, dated 03 / 10 / 2025, page 62 / 341 39 / 217 haloalkoxy refers to an alkoxy, as defined in this descriptive report, in which the hydrocarbon is substituted with at least one halogen, for example, F, Cl, Br or I.

[103] As used in this descriptive report, the term aryl refers to a monovalent C5-C15 carbocyclic ring system comprising at least one aromatic ring, wherein the aryl ring system is mono-, di-, or tricyclic. The aryl may be attached to the main structure via any of its rings, i.e., any aromatic or non-aromatic ring. In some or any embodiment, the aryl group may be bridging (when chemically feasible) or non-bridging, spirocyclic (when chemically feasible) or non-spirocyclic, and / or fused or non-fused. In some or any embodiment, aryl is phenyl, naphthyl, bicyclo[4.2.0]octa-1,3,5trienyl, indanyl, fluorenyl, 6,7,8,9-tetrahydro-5H benzo[7]anulenyl, or tetrahydronaphthyl. When aryl is substituted, it can be substituted on any ring, that is, on any aromatic or non-aromatic ring composed of aryl. In some or any of the embodiments, aryl is phenyl, naphthyl, tetrahydronaphthyl, fluorenyl, 6,7,8,9-tetrahydro-5H benzo[7]anulenyl or indanyl;

[104] As used in this descriptive report, the term heteroaryl refers to a monocyclic aromatic ring system or multicyclic aromatic ring system in which one or more (in some or any of the embodiments, 1, 2, 3 or 4) of the ring atoms is a heteroatom selected independently from O, S(O)o-2, NH and N, and the remaining ring atoms are carbon atoms, and when the ring can be optionally substituted as Petition 870250090230, dated 03 / 10 / 2025, p. 63 / 341 40 / 217 described in this descriptive report. The heteroaryl group is attached to the rest of the molecule through any atom in the ring system, if the valence rules allow. In certain embodiments, each ring of a 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 that 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. When heteroaryl is substituted, it may be substituted in any ring. In some embodiments, heteroaryl includes, without limitation, furanil, pyrrolil, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, tienyl, pyridinil, pyrimidinil, pyridazinil, pyrazinyl, indolyl, quinolinil, isoquinolinil, oxazolyl, isoxazolyl, thienopyridinil, thienopyrimidinil, azaindolinil and the like. In some embodiments, a to the rest of the molecule. In some embodiments, the heteroaryl, when one or more hydroxyl groups are substituted, may be referred to or drawn as the keto or enol tautomer. For example, 2,4(1H,3H)dioxo-pyrimidinyl, 2,4-dihydroxy-pyrimidinyl; 2(1H)-oxo-4-hydroxypyrimidinyl, 4-hydroxy-2(3H)-oxo-pyrimidinyl and 2-hydroxy-4(3H)-oxo-pyrimidinyl are within the scope of heteroaryl when substituted with two hydroxyl groups. In some embodiments, the heteroaryl is linked to the N-group.

[105] In certain embodiments, monocyclic heteroaryl groups include, without limitation, furanil, imidazolyl, isothiazolyl, Petition 870250090230, dated 03 / 10 / 2025, p. 64 / 341 41 / 217 isoxazolil, oxadiazolil, oxadiazolil, oxazolil, pirazinil, pirazolil, piridazinil, piridil, pirimidinil, pirrolil, tiadiazolil, tiazolil, tienil, tetrazolil, triazinil e triazolil. Em certas modalidades, grupos heteroaril bicíclicos incluem, sem limitação, benzofuranil, benzimidazolil, benzoisoxazolil, benzopiranil, benzotiadiazolil, benzotiazolil, benzotienil, benzotriazolil, benzoxazolil, fluorpiridil, imidazopiridinil, imidazotiazolil, indolizinil, indolil, indazolil, isobenzofuranil, isobenzotienil, isoindolil, isoquinolinil, isotiazolil, naftiridinil, oxazolopiridinil, ftalazinil, pteridinil, purinil, piridopiridil, pirrolopiridil, quinolinil, quinoxalinil, quinazolinil, tiadiazolopirimidil e tienopiridil. Em certas modalidades, grupos heteroaril tricíclicos incluem, sem limitação, acridinil, benzindolil, carbazolil, dibenzofuranil, perimidinil, fenantrolinil, fenantridinil e fenazinil.In some or any of the embodiments, heteroaryl is indol, furanil, pyridinyl, pyrimidinyl, imidazolyl, or pyrazolyl; each of which is optionally replaced with 1, 2, 3, or 4 groups as defined throughout the descriptive report, including, in some embodiments, with group(s) selected independently from C1-6 alkyl, hydroxy, halo, halo-C1-6 alkyl, C1-6 alkoxy, cyano, or phenyl.

[106] As used in this descriptive report, the term heterocycloalkyl or heterocyclyl refers to a monovalent monocyclic non-aromatic ring system and / or a multicyclic ring system containing at least one non-aromatic ring; wherein one or more (in some or any embodiment, 1, 2, 3 or 4) of the atoms of the monocyclic non-aromatic ring is a heteroatom selected independently from O, S(O)0-2 and N, and the remaining ring atoms are carbon atoms; and wherein one or more (in some or any embodiment, 1, 2, 3 or 4) of any of the ring atoms in the multicyclic ring system Petition 870250090230, dated 03 / 10 / 2025, p. 65 / 341 42 / 217 is a heteroatom selected independently of O, S(O)o-2 and N, and the remaining ring atoms are carbon. The term heterocyclic does not include fully aromatic ring(s), i.e., it does not include imidazole, pyrimidine, pyridine and the like. In some or any of the embodiments, the heterocyclic ring comprises one or two heteroatoms that are selected independently of nitrogen and oxygen. In some or any of the embodiments, the heterocyclic ring comprises one or two heteroatoms that are oxygen. In some or any of the embodiments, the heterocyclic ring comprises one or two heteroatoms that are nitrogen (where the nitrogen is substituted as described in any aspect or embodiment described in this descriptive report).In some or any of the embodiments, heterocyclic is multicyclic and comprises a heteroatom in a non-aromatic ring, or comprises a heteroatom in an aromatic ring, or comprises two heteroatoms in an aromatic ring, or comprises two heteroatoms, wherein one is in an aromatic ring and the other is in a non-aromatic ring. In some or any of the embodiments, the heterocyclic group has from 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 is a monocyclic, bicyclic, tricyclic, or tetracyclic ring system. In some or any of the embodiments, the heterocyclic group may be a bridging or non-bridging multicyclic group, spirocyclic or non-spirocyclic, and / or fused or non-fused. One or more of the nitrogen and sulfur atoms may optionally be oxidized, one or more of the nitrogen atoms may optionally be quaternized, one or more of the carbon atoms. They can optionally be replaced with 0. Some rings may be partially or fully saturated, or aromatic, provided the heterocycle is not entirely aromatic. Monocyclic and multicyclic heterocyclic rings may be attached. Petition 870250090230, dated 03 / 10 / 2025, page 66 / 341 43 / 217 to the main structure at any heteroatom or carbon atom that results in a stable compound. The multicyclic heterocycle may be attached to the main structure via any of its rings, including any aromatic or non-aromatic ring, regardless of whether the ring contains a heteroatom. In some or any of the embodiments, heterocycle is heterocycloalkyl, which is: 1) a saturated or partially unsaturated (but not aromatic) monocyclic group containing at least one heteroatom ring, as described in this descriptive report, or 2) a saturated or partially unsaturated (but not aromatic) bi- or tricyclic monovalent group in which at least one ring contains at least one heteroatom as described in this descriptive report. When heterocyclic and heterocycloalkyl groups are substituted, they can be substituted onto any ring, that is, onto any aromatic or non-aromatic ring composed of heterocyclic and heterocycloalkyl groups.In some or any embodiment, this heterocycle includes, without limitation, azepinil, benzodioxanil, benzodioxolyl, 3,4-dihydro-2H-benzo[b][1,4]oxazinyl, 3,4-dihydro-2H-benzo[b][1,4]dioxepinil, 1,3-dihydroisobenzofuranil, benzofuranonyl, benzopyranyl. benzopyranil, dihydrobenzofuranil, benzotetrahydrothienyl, 2,2-dioxo-1,3-dihydrobenzo[c]thienyl, benzothiopyranyl, benzoxazinyl, β-carbolinyl, cromanyl, chromonyl, cinolinyl, coumarinyl, decahydroquinolinyl, decahydroisoquinolinyl, dihydrobenzisothiazinyl, dihydrobenzisoxazinyl, dihydrofuryl, dihydroisoindolyl, dihydropyranyl, dihydropyrazolyl, dihydropyrazinyl, Petition 870250090230, dated 03 / 10 / 2025, page 67 / 341 44 / 217 diidropiridinil, diidropirimidinil, diidropirrolil, dioxolanil, 1,4-ditianil, furanonil, imidazolidinil, 2,4-dioxoimidazolidinil, imidazolinil, indolinil, 2-oxo-indolinil, isobenzotetrahidrofuranil, isobenzotetrahidrotienil, isocromanil, isocumarinil, isoindolinil, 1-oxo-isoindolinil, 1,3-dioxo-isoindolinil, isotiazolidinil, isoxazolidinil, 3-oxoisoxazolidinil, morfolinil, 3,5-dioxo-morfolinil, octahidroindolil, octahidroisoindolil, 1-oxooctahidroisoindolil, 1,3-dioxo-hexahidroisoindolil, oxazolidinonil, oxazolidinil, oxiranil, piperazinil, 2,6-dioxopiperazinil, piperidinil, 2,6-dioxo-piperidinil, 4-piperidonil, pirazolidinil, pirazolinil, pirrolidinil, pirrolinil, 2-oxopirrolidinil, 2,5-dioxopirrolidinil, quinuclidinil, tetrahidrofuril, tetrahidroisoquinolinil, tetrahidropiranil, tetrahidrotienil, tiamorfolinil, tiomorfolinil, 3,5-dioxotiomorfolinil, tiazolidinil, 2,4-dioxo-tiazolidinil, tetrahidroquinolinil, fenotiazinil, fenoxazinil, xantenil e 1,3,5-tritianil.In some or any of the embodiments, heterocyclic is benzo-1,4-dioxanyl, benzodioxolyl, indolinyl, 2-oxo-indolinyl, pyrrolidinyl, piperidinyl, 2,3-dihydrobenzofuranyl, or decahydroquinolinyl; each of which is optionally substituted with 1, 2, 3, or 4 groups as defined throughout the descriptive report, including, in some or any of the embodiments, with group(s) selected independently from halo, alkyl, and phenyl. In some embodiments, heterocycloalkyl is pyrrolidinyl.

[107] As used in this descriptive report, the term cyan refers to -CN.

[108] The term oxo, as used in this descriptive report, 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 of -CH2- to -C=O. An oxo group that is a substituent on an aromatic carbon results in a Petition 870250090230, dated 03 / 10 / 2025, p. 68 / 341 45 / 217 conversion of -CH- to -C=O. When a substituent is oxo, then two hydrogens on the atom are substituted. When an oxo group substitutes aromatic moieties, the corresponding partially unsaturated ring substitutes the aromatic ring. For example, a pyridyl group substituted by an oxo group is a pyridone. Those skilled in the art will observe that, in some embodiments, such a group, for example, pyridone and 2,4(1H,3H)-dioxopyrimidinyl, may exist in its tautomeric form, for example, hydroxypyridine and 2,4-dihydroxypyrimidinyl, respectively.

[109] As used in this descriptive report, the term optionally substituted, when used to describe a radical moiety, for example, optionally substituted alkyl, means that this moiety is optionally attached to one or more substituents. Examples of such substituents include, without limitation, halo, cyano, nitro, amino, hydroxyl, optionally substituted haloalkyl, aminoalkyl, hydroxyalkyl, azido, epoxy, optionally substituted heteroaryl, optionally substituted heterocycloalkyl, -|-sra -|-nrarb 11—oa -W-ORao 1L nrArB THE -U_rA NH |1Lnrarb NH W—NRaRb-|-S(O)-Ra-é>-S(O)2-RaR\ In which ra, rbe, and RC are, independently in each occurrence, hydrogen, alkyl, alkenyl, alkynyl, aryl, alkylaryl, arylalkyl, heteroalkyl, heteroaryl, or heterocycloalkyl, or RA and RB together with the atoms to which they are attached, form a saturated or unsaturated carbocyclic ring, in which the ring is optionally substituted, and in which one or more atoms of the ring are optionally substituted with a heteroatom. In certain embodiments, when a portion of the radical is optionally substituted with an optionally substituted heteroaryl, optionally substituted heterocycloalkyl, or optionally substituted saturated or unsaturated carbocyclic ring, the Petition 870250090230, dated 03 / 10 / 2025, p. 69 / 341 46 / 217 Substituents on the optionally substituted heteroaryl, optionally substituted heterocycloalkyl, or optionally substituted saturated or unsaturated carbocyclic ring, if they are substituted, are not substituted with substituents that are additionally optionally substituted with additional substituents. In some embodiments, when a group described in this descriptive report is optionally substituted, the substituent attached to the group is unsubstituted, unless otherwise specified.

[110] As used in this descriptive report, the term epimer is one of a pair of diastereomers that have the opposite configuration only at one stereogenic center, or chiral center, of at least two. For example, a compound of Formula (I), (Ia), (Ib) or (Ic) with stereochemistry-(R) at the C-16 position is an epimer of the corresponding compound with stereochemistry(S).

[111] As used in this descriptive report, the term diastereomeric excess (de) refers to a dimensionless molar ratio describing various chiral substances containing more than one stereogenic center. For example, a diastereomeric excess of zero would indicate an equimolar mixture of diastereomers. By way of further example, a diastereomeric excess of ninety-nine would indicate a nearly sterically pure diastereomeric compound (i.e., a large excess of one diastereomer over the other). Diastereomeric excess can be calculated using a method similar to ee. As would be appreciated by those skilled in the art, de is normally reported as a percent (% of). % of can be calculated in a similar way to % ee.

[112] As used in this descriptive report, the term therapeutically effective amount refers to an amount (e.g., of a compound) that is sufficient to provide a therapeutic benefit to a patient in the treatment or management of Petition 870250090230, dated 03 / 10 / 2025, p. 70 / 341 47 / 217 a disease or disorder, or to delay or minimize one or more symptoms associated with the disease or disorder.

[113] Certain groups, moieties, substituents, and atoms are depicted with a wavy line crossing a bond or bonds to indicate the atom through which the groups, moieties, substituents, or atoms are attached. For example, a phenyl group that is substituted with a propyl group is depicted as: ch3ch3ou It has the following structure: As used in this descriptive report, linked substituents, illustrations showing a cyclic group (e.g., cycloalkyl or heterocycloalkyl aromatic, fused ring heteroaromatic, and saturated or unsaturated) via a linkage between ring atoms, are intended to indicate, unless otherwise specified, that the cyclic group can be substituted with that substituent at any ring position on the cyclic group or on any ring in the fused ring group, according to techniques presented in this descriptive report or that are known in the field to which the present disclosure pertains. For example, the group, or in which the subscript q is an integer from zero to two and in which the positions of the substituent R2a are described generically, for example, not directly attached to any vertex of the bond-line structure, for example, a specific atom of the carbon ring includes the following non-limiting examples of groups in which the substituent R2a is attached to a specific atom of the carbon ring: Petition 870250090230, dated 03 / 10 / 2025, p. 71 / 341 48 / 217 Rapamycin analogs selective for FKB12

[114] As used in this descriptive report, the term “selective for FKB12” refers to the requirement of FKBP12 for the inhibition of mTORC1 phosphorylation of S6K1, as shown in Figure 1C; compound 45 is able to inhibit S6K1 phosphorylation in the presence of FKBP12; however, when FKBP12 is knocked out, there is much less inhibition of S6K1 phosphorylation with compound 45 compared to RAD001, a rapalog that can act through other FKBPs.

[115] Alternatively, a “rapalog selective for FKBP12” is a rapalog that, although potent in an assay using a wild-type cell, is approximately 10 times to approximately 1,000 times less potent than RAD001 in a cell line that does not express FKBP12 (e.g., FKBP12 knockout cells). The term “potency,” as used in this context, can be expressed as the concentration of rapalog required to obtain a 20% inhibition of S6K1 (Thr389) phosphorylation in a cell-based assay such as, for example, that used in Example 3 and Figures 1-11. For example, a rapalog is considered selective for FKBP12 if the rapalog inhibits approximately 20% of S6K1 (Thr389) phosphorylation inhibition in an assay using an FKBP12 knockout cell line with at least 20x potency (e.g., 20x, 30x, 50x, 100x, 200x, 500x, 1000x, etc.).) lower, compared to a similar level of inhibition obtained by RAD001 in the same assay with the same cell line, which normally expresses FKBP12.

[116] Alternatively, a “selective rapálogo for FKBP12 is Petition 870250090230, dated 03 / 10 / 2025, page 72 / 341 49 / 217 a rapalog that, although potent in an assay using a wild-type cell, is approximately 10 times to approximately 1,000 times less potent than RAD001 in a cell line that does not express FKBP12 (e.g., FKBP12 knockout cells). The term potency, as used in this context, can be expressed as the concentration of rapalog required to achieve a 30% inhibition of S6K1 (Thr389) phosphorylation in a cell-based assay such as, for example, that used in Example 3 and Figures 1-11. For example, a rapalog is considered selective for FKBP12 if the rapalog inhibits approximately 30% of S6K1 (Thr389) phosphorylation inhibition in an assay using an FKBP12 knockout cell line with at least 20x potency (e.g., 20x, 30x, 50x, 100x, 200x, 500x, 1000x, etc.).) lower, compared to a similar level of inhibition obtained by RAD001 in the same assay with the same cell line, which normally expresses FKBP12.

[117] In one embodiment, the compound of Formula (I) is a compound of Formula (PI): THE. HO. (PI) or a pharmaceutically acceptable salt thereof; where R1 is hydrogen, C1-6 alkyl, heterocyclyl, aryl, heteroaryl, -CO-6 alkylene-SO2R4 or -CO-6 alkylene-SO2R5; wherein heterocyclyl, aryl, heteroaryl are optionally substituted with one or two R1a groups; Petition 870250090230, dated 03 / 10 / 2025, p. 73 / 341 50 / 217 R2 is heterocyclyl, aryl, heteroaryl, -CO-6 alkylene-SO2R4 or -CO-6 alkylene-SO2R5; wherein heterocyclyl, aryl and heteroaryl are optionally substituted with one or two R2a groups; or R1 and R2 together with the attached nitrogen form a N-linked heteroaryl; R3 is selected from the group consisting of -ORa, 3-6 membered heterocyclyls, and 3-6 membered heteroaryls; Rae selected from the group consisting of H, -P(O)(Rb)2, C(O)Rc, -C(O)ORc, C1-6 alkyl and C1-6 hydroxyalkyl; each Rbé selected independently from the group consisting of H and C1-6 alkyl; Rcé selected from the group consisting of H, C1-6 alkyl and C1-6 hydroxyalkyl; R4 is C2-6 alkyl, C3-6 cycloalkyl, C1-6 hydroxyalkyl, heterocyclyl, aryl or heteroaryl; wherein heterocyclyl, aryl and heteroaryl are optionally substituted with one or two R4a groups; and R5 is heterocyclyl, aryl or heteroaryl; wherein heterocyclyl, aryl and heteroaryl are optionally replaced with one or two R5a groups; Each of one or two R1a, R2a, R4a and R5a groups, when present, are independently selected from C1-6 alkyl, C16 hydroxyalkyl, hydroxy, halo, C1-6 haloalkyl and C1-6 alkoxy; or any two R1a, R2a, R4a and R5a groups, when present on the same carbon, are taken together to form an oxo group; where R1 is hydrogen, R2 is not -CO-6 alkyleneSO2R4.

[118] In one embodiment, the compound of Formula (Ia) is a compound of Formula (P-Ia): Petition 870250090230, dated 03 / 10 / 2025, p. 74 / 341 51 / 217 O. HO. (P-Ia) or a pharmaceutically acceptable salt thereof; where R1 is hydrogen or C1-6 alkyl; R2 is a heterocyclyl, aryl, or heteroaryl group optionally substituted with one or two R2a groups; R3 is selected from the group consisting of -ORa, a 3-6 membered heterocyclyl and a 3-6 membered heteroaryl; Rae selected from the group consisting of H, -P(O)(Rb)2, C(O)Rc, -C(O)ORc, C1-6 alkyl and C1-6 hydroxyalkyl; each Rbé selected independently from the group consisting of H and C1-6 alkyl; R is selected from the group consisting of H, C1-6 alkyl and C1-6 hydroxyalkyl; and each of one or two R2a groups, when present, are selected independently from C1-6 alkyl, C1-6 hydroxyalkyl, hydroxy, halo, C1-6 haloalkyl and C1-6 alkoxy; or any two R2a groups, when present on the same carbon, are taken together to form an oxo group.

[119] In one embodiment, the compound of Formula (Ib) is a compound of Formula (P-Ib): Petition 870250090230, dated 03 / 10 / 2025, p. 75 / 341 52 / 217 (P-Ib) O. HO. or a pharmaceutically acceptable salt thereof; where R1 and R2 together with the attached nitrogen form an N-linked heteroaryl optionally substituted with one or two R1a groups; R3 is selected from the group consisting of -ORa, a 3-6 membered heterocyclyl and a 3-6 membered heteroaryl; Rae selected from the group consisting of H, -P(O)(Rb)2, C(O)Rc, -C(O)ORc, C1-6 alkyl and C1-6 hydroxyalkyl; each Rbé selected independently from the group consisting of H and C1-6 alkyl; Rcé selected from the group consisting of H, C1-6 alkyl and C1-6 hydroxyalkyl; Each of one or two R1a groups, when present, are independently selected from C1-6 alkyl, C1-6 hydroxyalkyl, hydroxy, halo, C1-6 haloalkyl, and C1-6 alkoxy; or two R1a groups, when present on the same carbon, are taken together to form an oxo group.

[120] In one embodiment, the compound of Formula (Ic) is a compound of Formula (P-Ic): Petition 870250090230, dated 03 / 10 / 2025, p. 76 / 341 53 / 217 O. HO. (P-Ic) or a pharmaceutically acceptable salt thereof; where R1 is hydrogen or C1-6 alkyl; R2 is -C0-6 alkylene-SO2R4 or -C0-6 alkylene-SO2R5; R3 is selected from the group consisting of -ORa, a 3-6 membered heterocyclyl and a 3-6 membered heteroaryl; Rae selected from the group consisting of H, -P(O)(Rb)2, C(O)Rc, -C(O)ORc, C1-6 alkyl and C1-6 hydroxyalkyl; each Rbé selected independently from the group consisting of H and C1-6 alkyl; Rcé selected from the group consisting of H, C1-6 alkyl and C1-6 hydroxyalkyl; R4 is C2-6 alkyl, C3-6 cycloalkyl, C1-6 hydroxyalkyl, heterocyclyl, aryl or heteroaryl; wherein heterocyclyl, aryl and heteroaryl are optionally substituted with one or two R4a groups; R5 is heterocyclyl, aryl or heteroaryl; wherein heterocyclyl, aryl and heteroaryl are optionally replaced with one or two R5a groups; Each of one or two R4a and R5a groups, when present, are independently selected from C1-6 alkyl, C1-6 hydroxyalkyl, hydroxy, halo, C1-6 haloalkyl, and C1-6 alkoxy; or any two R4a and R5a groups, when present on the same carbon, are taken together to form an oxo group; Petition 870250090230, dated 03 / 10 / 2025, p. 77 / 341 54 / 217 where, when R1 is hydrogen, R2 is not -CO-6 alkyleneSO2R4.

[121] In one embodiment, the compound of Formula (I) is a compound of Formula (P-2): or a pharmaceutically acceptable salt thereof; where R1 is hydrogen, C1-6 alkyl, heterocyclyl, aryl, heteroaryl, -CO-6 alkylene-SO2R4 or -CO-6 alkylene-SO2R5; wherein heterocyclyl, aryl and heteroaryl are optionally substituted with one or two R1a groups; R2 is heterocyclyl, aryl, heteroaryl, -CO-6 alkylene-SO2R4 or -CO-6 alkylene-SO2R5; wherein heterocyclyl, aryl and heteroaryl are optionally substituted with one or two R2a groups; or R1 and R2 together with the attached nitrogen form an N-linked heteroaryl or N-linked heterocyclyl optionally substituted with one or two R1a groups; R3 is selected from the group consisting of -ORa, 3-6 membered heterocyclyls, and 3-6 membered heteroaryls; Rae selected from the group consisting of H, -P(O)(Rb)2, C(O)Rc, -C(O)ORc, C1-6 alkyl and C1-6 hydroxyalkyl; each Rbé selected independently from the group consisting of H and C1-6 alkyl; Rcé selected from the group consisting of H, C1-6 alkyl and C1-6 hydroxyalkyl; Petition 870250090230, dated 03 / 10 / 2025, p. 78 / 341 55 / 217 R4 is C2-6 alkyl, C3-6 cycloalkyl, C1-6 hydroxyalkyl, heterocyclyl, aryl or heteroaryl; wherein heterocyclyl, aryl and heteroaryl are optionally substituted with one or two R4a groups; and R5 is heterocyclyl, aryl or heteroaryl; wherein heterocyclyl, aryl and heteroaryl are optionally replaced with one or two R5a groups; Each of one or two R1a, R2a, R4a and R5a groups, when present, are independently selected from C1-6 alkyl, C16 hydroxyalkyl, hydroxy, halo, C1-6 haloalkyl, C1-6 alkoxy, C1-6 haloalkoxy and cyano; or any two R1a, R2a, R4a and R5a groups, when present on the same carbon, are taken together to form an oxo group; where R1 is hydrogen, R2 is not -CO-6 alkyleneSO2R4.

[122] In a Formula (I) (Ia)-(Ic), (P-1), (P-2) or (P-Ia)-(P-Ic) configuration, R3 is -ORa. In a Formula (I) (Ia)-(Ic), (P-1), (P-2) or (P-Ia)-(P-Ic) configuration, R3 is -OH. In a Formula (I) (Ia)-(Ic), (P-1), (P-2) or (P-Ia)(P-Ic) configuration, R3 is -OP(O)(Rb)2. In an embodiment of Formula ((I), (Ia)(Ic), (P-1), (P-2) or (P-Ia)-(P-Ic), R3 is -OP(O)H2. In an embodiment of Formula (I), (Ia)-(Ic), (P-1), (P-2) or (P-Ia)(P-Ic), R3 is -OP(O)(C1-6 alkyl)2. In an embodiment of Formula (I), (Ia)-(Ic), (P-1), (P-2) or (P-Ia)-(P-Ic), R3 is -OP(O)(Me)2. In an embodiment of Formula (I), (Ia)-(Ic), (P-1), (P-2), or (P-Ia)-(P-Ic), R3 is -OP(O)(C1-6 alkyl)(H). In an embodiment of Formula (I), (Ia)-(Ic), (P-1), (P-2) or (P-Ia)-(P-Ic), R3 is OP(O)(Me)(H). In a Formula (I) modality, (Ia)-(Ic), (P1), (P-2) or (P-Ia)-(P-Ic), R3 is -C(O)Rc. In a Formula (I) modality, (Ia)-(Ic), (P-1), (P-2) or (P-Ia)-(P-Ic), R3 is C(O)H.In an embodiment of Formula (I), (Ia)-(Ic), (P-1), (P-2) or (P-Ia)-(P-Ic), R3 is -C(O)C1-6 alkyl. In an embodiment of Formula (I), (Ia)-(Ic), (P-1), (P-2) or (P-Ia)-(P-Ic), R3 is Petition 870250090230, dated 03 / 10 / 2025, page 79 / 341. 56 / 217 C(O)C1-6 hydroxyalkyl. In an embodiment of Formula (I), (Ia)(Ic), (P-1), (P-2) or (P-Ia)-(P-Ic), R3 is -C(O)ORc. In an embodiment of Formula (I), (Ia)-(Ic), (P-1), (P-2) or (P-Ia)(P-Ic), R3 is -COOH. In an embodiment of Formula (I), (Ia)-(Ic), (P-1), (P-2) or (P-Ia)-(P-Ic), R3 is -C(O)OC1-6 alkyl. In an embodiment of Formula (I), (Ia)-(Ic), (P-1), (P-2) or (P-Ia)(P-Ic), R3 is -C(O)OC1-6 hydroxyalkyl. In one embodiment of Formula (I), (Ia)-(Ic), (P-1), (P-2) or (P-Ia)-(P-Ic), R3 is -OC16 alkyl. In one embodiment of Formula (I), (Ia)-(Ic), (P-1), (P-2) or (P-Ia)-(P-Ic), R3 is -OC1-6 hydroxyalkyl.

[123] In an embodiment of Formula (I), (Ia)-(Ic), (P-1), (P2) or (P-Ia)-(P-Ic), R3 is a 3-6 membered heterocycle. In an embodiment of Formula (I), (Ia)-(Ic), (P-1), (P-2) or (P-Ia)-(P-Ic), R3 is a 3-6 membered heterocycle containing one, two or three atoms selected from nitrogen, oxygen and sulfur. In an embodiment of Formula (I), (Ia)-(Ic), (P-1), (P-2) or (PIa)-(P-Ic), R3 is a 3-6 membered heterocycle containing one nitrogen atom. In one embodiment of Formula (I), (Ia)-(Ic), (P1), (P-2) or (P-Ia)-(P-Ic), R3 is a 3-6 membered heterocycle containing two or three nitrogen atoms.

[124] In an embodiment of Formula (I), (Ia)-(Ic), (P-1), (P2) or (P-Ia)-(P-Ic), R3 is a 3-6 membered heteroaryl. In an embodiment of Formula (I), (Ia)-(Ic), (P-1), (P-2) or (P-Ia)-(P-Ic), R3 is a 3-6 membered heteroaryl containing one, two, three or four atoms selected from nitrogen, oxygen and sulfur atoms. In an embodiment of Formula (I), (Ia)-(Ic), (P-1), (P-2) or (P-Ia)-(P-Ic), R3 is a 3-6 membered heteroaryl containing one nitrogen atom. In one embodiment of Formula (I), (Ia)(Ic), (P-1), (P-2) or (P-Ia)-(P-Ic), R3 is a 3-6 membered heteroaryl group containing two or three nitrogen atoms. In one embodiment of Formula (I), (Ia)-(Ic), (P-1), (P-2) or (P-Ia)(P-Ic), R3 is a 3-6 membered heteroaryl group containing four nitrogen atoms. In one embodiment of Formula (I), (Ia)-(Ic), (P Petition 870250090230, dated 03 / 10 / 2025, p. 80 / 341 57 / 217 1), (P-2) or (P-Ia)-(P-Ic), R3 is a tetrazole or a triazole. In one embodiment of Formula (I), (Ia)-(Ic), (P-1), (P-2) or (Pi Ia)-(P-Ic), R3 is where » is the point of adhesion to the rest of the compound.

[125] In a Formula (I) mode, (Ia)-(Ic), (P-1), (P- 2) or (P-Ia)-(P-Ic), including any of the above, R1 is hydrogen. In an embodiment of Formula (I), (Ia)-(Ic), (P-1), (P-2) or (P-Ia)-(P-Ic), including any of the above, R1 is C1-6 alkyl. In an embodiment of Formula (I), (PI) or (P-2), including any of the above, R1 is heterocyclyl, aryl or heteroaryl. In an embodiment of Formula (I), (PI) or (P-2), including any of the above, R1 is heterocyclyl, aryl or heteroaryl. In an embodiment of Formula (I), (PI) or (P-2), including any of the above, R1 is -CO-6 alkylene-SO2R4 or -CO-6 alkylene-SO2R5.

[126] In an embodiment of Formula (I), (Ia)-(Ic), (P-1), (P2) or (P-Ia)-(P-Ic), including any of the foregoing, R1 is C1-6 alkyl in which the C1-6 alkyl is unsubstituted. In an embodiment of Formula (I), (Ia)-(Ic), (P-1), (P-2) or (PIa)-(P-Ic), including any of the foregoing, R1 is C1-6 alkyl in which the C1-6 alkyl is substituted with one or two R2a groups. In an embodiment of Formula (I), (Ia)-(Ic), (P-1), (P-2) or (P-Ia)-(P-Ic), including any of the foregoing, R1 is C1-6 alkyl in which the C1-6 alkyl is substituted with C1-6 hydroxyalkyl. In an embodiment of Formula (I), (Ia)(Ic), (P-1), (P-2) or (P-Ia)-(P-Ic), including any of the aforementioned —I, R1 is । where ' is the point of adhesion to the rest of the compound. In an embodiment of Formula (I), (Ia)-(Ic), (P-1), (P-2) or (P-Ia)-(P-Ic), including any of the Petition 870250090230, dated 03 / 10 / 2025, p. 81 / 341 58 / 217 cited above, R1 is C1-6 alkyl wherein the C1-6 alkyl is replaced with C1-6 alkoxy. In an embodiment of Formula (I), (Ia)-(Ic), (P-1), (P-2) or (P-Ia)-(P-Ic), including any of the above, R1 is HO where is the point of attachment to the rest of the compound.

[127] In an embodiment of Formula (I), (PI), (Ia), (P-Ia) or (P-2), including any of the foregoing, R2 is a heterocyclyl, wherein the heterocyclyl is unsubstituted. In an embodiment of Formula (I), (PI), (Ia), (P-Ia) or (P-2), including any of the foregoing, R2 is a heterocyclyl, wherein the heterocyclyl is substituted with one or two R2a groups. In an embodiment of Formula (I), (PI), (Ia), (P-Ia) or (P-2), including any of the foregoing, R2 is a 5-12 membered monocyclic or bicyclic heterocyclyl containing one, two or three atoms selected from nitrogen, oxygen and sulfur wherein, when a nitrogen is present, the nitrogen is optionally substituted with C1-6 alkyl or C3-6 cycloalkyl and wherein the heterocyclyl is optionally substituted with one or two R2a groups.

[128] In an embodiment of Formula (I), (PI), (Ia), (P-Ia) or (P-2), including any of the foregoing, R2 is an aryl group, in which the aryl group is unsubstituted. In an embodiment of Formula (I), (PI), (Ia), (P-Ia) or (P-2), including any of the foregoing, R2 is a 5-12 membered monocyclic or bicyclic aryl group, in which the aryl group is optionally substituted with one or two R2a groups. In an embodiment of Formula (I), (PI), (Ia), (P-Ia) or (P-2), including any of the foregoing, R2 is an unsubstituted phenyl group. In an embodiment of Formula (I), (PI), (Ia), (P-Ia) or (P-2), including any of the foregoing, R2 is a phenyl group substituted with one or two R2a groups. In a Formula (I), (PI), (Ia), (PIa) or (P-2) category, including any of the aforementioned, R2 Petition 870250090230, dated 03 / 10 / 2025, p. 82 / 341 59 / 217 is phenyl substituted with an R2 group selected from halo, C1-6 alkoxy, C1-6 alkyl and C1-6 haloalkyl.

[129] In an embodiment of Formula (I), (PI), (Ia), (P-Ia) or (P-2), including any of the foregoing, R2 is a heteroaryl, wherein the heteroaryl is unsubstituted. In an embodiment of Formula (I), (PI), (Ia), (P-Ia) or (P-2), including any of the foregoing, R2 is a heteroaryl, wherein the heteroaryl is optionally substituted with one or two R2a groups. In an embodiment of Formula (I), (PI), (Ia), (PIa) or (P-2), including any of the foregoing, R2 is a 5-12 membered monocyclic or bicyclic heteroaryl containing one, two, three or four atoms selected from nitrogen, oxygen and sulfur wherein, when a nitrogen is present, the nitrogen is optionally substituted with C1-6 alkyl or C3-6 cycloalkyl and wherein the heteroaryl is optionally substituted with one or two R2a groups.

[130] In an embodiment of Formula (I), (PI), (Ia), (P-Ia) or (P-2), including any of the foregoing, R2 is a 5-12 membered monocyclic heteroaryl containing a nitrogen atom optionally substituted with C1-6 alkyl or C3-6 cycloalkyl and wherein the heteroaryl is optionally substituted with two R2 groups on the same carbon that are joined together to form an oxo group.

[131] In a Formula (I), (PI), (Ia), (P-Ia) or (P-2) modality, including any of the above, R2 is selected from Petition 870250090230, dated 03 / 10 / 2025, p. 83 / 341 60 / 217 and Formula

[132] In an embodiment of (I), (PI), (Ia), (P-Ia) or (P-2) including any of the above, R2 is selected from Petition 870250090230, dated 03 / 10 / 2025, p. 84 / 341 61 / 217 which is the point of adhesion to the rest of the compound; and R2a is as defined in this descriptive report.

[133] In an embodiment of Formula (I), (PI), (Ia), (P-Ia) or (P-2), including any of the foregoing, R2a is selected from C1-6 alkyl, C1-6 haloalkyl, halogen, C1-6 alkoxy, cyano, and C1-6 haloalkoxy. In an embodiment of Formula (I), (PI), (Ia), (P-Ia) or (P-2), including any of the foregoing, R2a is C1-6 hydroxyalkyl or C1-6 alkoxy.

[134] In a Formula (I), (PI), (Ia), (P-Ia) or (P-2) modality, including any of the above, R2 is selected from

[135] In a Formula (I), (PI), (Ia), (P-Ia) or (P-2) modality, including any of the above, R2 is

[136] In a Formula (I), (PI), (Ia), (P-Ia) or (P-2) mode, including any of the above, R2 is selected from Petition 870250090230, dated 03 / 10 / 2025, p. 85 / 341 62 / 217 ; where < is the point of adhesion to the rest of the compound.

[137] In a Formula (I), (PI), (Ia), (P-Ia) or (P-2) modality, including any of the above, R2 is selected from 0'1 Nl 0'N O-N N / 7 ON H ; where the point of adhesion to the rest of the compound. or

[138] In a type of Formula (I), (PI), (Ia), (P-Ia) (P-2) including any of the above, R1 is hydrogen and R2 is selected from ; where < is the point of adhesion to the rest of the compound.

[139] In an embodiment of Formula (I), (PI), (Ia), (P-Ia) or (P-2), including any of the above, R1 is methyl and R2 is selected from and ; where is the point of adhesion to the rest of the compound.

[140] In a Formula (I), (PI), (Ia), (P-Ia) or (P-2) modality, including any of the above, R1é Petition 870250090230, dated 03 / 10 / 2025, p. 86 / 341 63 / 217 hydrogen and R2 is selected from ON O-N ON and ; where the point of adhesion to the rest of the compound. or

[141] In a type of Formula (I), (PI), (Ia), (P-Ia) (P-2) including any of the above, R1 is methyl and R2 is selected from and ; in the point of adhesion to the rest of the compound.

[142] In a Formula (I), (PI), (Ia), (P-Ia) or (P-2) modality, including any of the above, R1 is to the rest of the compound.

[143] In an embodiment of Formula (I), (PI), (Ia), (P-Ia) or (P-2), including any of the foregoing, R1 is C16 alkyl in which the C1-6 alkyl is unsubstituted or substituted Petition 870250090230, dated 03 / 10 / 2025, p. 87 / 341 64 / 217 with C1-6 hydroxyalkyl or C1-6 alkoxy and R2 is H. which is the point of adhesion to the rest of the compound.

[144] In an embodiment of Formula (I), (PI), (Ia), (P-Ia) or (P-2), including any of the above, R1 is hydrogen; R2 is selected from hey N bN and R3 OH; where is the point of adhesion to the rest of the compound.

[145] In a type of Formula (I), (PI), (Ia), (P-Ia) or (P-2) including any of the above, R1 is methyl; R2 0-1 N bN is selected from O1 R3 is OH; which is the point of adhesion to the rest of the compound.

[146] In an embodiment of Formula (I) (PI), (Ia), (P-Ia) or (P-2) including any of the aforementioned, R1 is hydrogen; R2 is selected from nn 0-N 0-N 0-N R3 is OH; at what point does it adhere to the rest of the compound?

[147] In an embodiment of Formula (I), (PI), (Ia), (P-Ia) or (P-2) including any of the foregoing, R1 is methyl; R2 is selected from Petition 870250090230, dated 03 / 10 / 2025, p. 88 / 341 65 / 217 and, R3é OH; in what It is the point of adhesion to the rest of the compound.

[148] In an embodiment of Formula (I), or (P-2), (PI), (Ia), (P-Ia) including any of the aforementioned, R1 is hydrogen; R2 is selected from O'l O'l N b'N and, R3 is -OH, -OP(O)(Rb)2, or a 3-6 membered heteroaryl containing one, two, three, or four atoms selected from nitrogen, oxygen, and sulfur atoms; where I is the point of attachment to the rest of the compound.

[149] In an embodiment of Formula (I), (PI), (Ia) or (P-Ia) (P-2), including any of the above, R1 is hydrogen; R2 is selected from 0'1 0'1 N b'N ; and, R3 is -OH, -OP(O)(Me)2, or N'\._| IN—I N^ / ; where is the point of adhesion to the rest of the compound.

[150] In a type of Formula (I), (PI), (Ia), (P-Ia) or (P-2) including any of the above, R1 is methyl; R2 is selected from 0'1 0'1 N b'N Petition 870250090230, dated 03 / 10 / 2025, p. 89 / 341 66 / 217 ; and, R3 is -OH, -OP(O)(Rb)2, or a 3-6 membered heteroaryl containing one, two, three, or four atoms selected from nitrogen, oxygen, and sulfur atoms; where I is the point of attachment to the rest of the compound.

[151] In a type of Formula (I), (PI), (Ia) (P-Ia) or (P-2) including any of the above, R1 is methyl; R2 is selected from 0'1 N ON ; and, R3 is -OH, -OP(O)(Me)2, or IN—I ; where is the point of adhesion to the rest of the compound.

[152] In an embodiment of Formula (I), (PI), (Ia), (P-Ia) or (P-2) including any of the aforementioned, R1 is hydrogen; R2 is selected from 0'N 0-N and R3 is -OH, -OP(O)(Rb)2, or a 3-6 membered heteroaryl; and containing one, two, three, or four selected atoms of nitrogen, oxygen, and sulfur; where is the point of attachment to the rest of the compound.

[153] In an embodiment of Formula (I), (PI), (Ia), (P-Ia) or (P-2), including any of the above, R1 is hydrogen; R2 is selected from N ON Petition 870250090230, dated 03 / 10 / 2025, p. 90 / 341 67 / 217 ON 0'1 R3é -OH -OP (O) (Me)2 or j,NH N^ / ; where is the point of adhesion to the rest of the compound. or

[154] In a type of Formula (I), (PI), (Ia), (P-Ia) (P-2) including any of the above, R1 is methyl; R2 is selected from ON 0-N and and R3 is -OH, -OP(O)(Rb)2, or a 3-6 membered heteroaryl containing one, two, three, or four selected atoms of nitrogen, oxygen, and sulfur; where is the point of attachment to the rest of the compound.

[155] In an embodiment of Formula (I), (PI), (Ia), (P-Ia) or (P-2) including any of the foregoing, R1 is methyl; R2 is selected from 0-N R3; N-Ni is -OH, -OP(O)(Me)2, or where is the point of adhesion to the rest of the compound. or [15 6] In a (P-2) modality, including any Formula (I), (PI), (Ia), (P-Ia) one of the aforementioned, R1 is Petition 870250090230, dated 03 / 10 / 2025, p. 91 / 341 68 / 217 R2 is selected from hydrogen; and, R3 is -OH, in which point of adhesion to the rest of the compound.

[157] In an embodiment of Formula (I), (PI), (Ia), (P-Ia) or (P-2), including any of the foregoing, R1 is C16 alkyl in which the C1-6 alkyl is unsubstituted or substituted vi with C1-6 hydroxyalkyl or C1-6 alkoxy; R2 is ; and, R3 is -OH, where I is the point of attachment to the remainder of the compound.

[158] In an embodiment of Formula (I), (PI), (Ib), (P-Ib) or (P-2), including any of the foregoing, R1 and R2 are joined together to form a 5-12 membered monocyclic or bicyclic heteroaryl group linked to N containing one, two, three or four selected nitrogen, oxygen and sulfur atoms, wherein the heteroaryl group is unsubstituted. In an embodiment of Formula (I), (PI), (Ib), (P-Ib) or (P-2), including any of the foregoing, R1 and R2 are joined together to form a 5-12 membered monocyclic or bicyclic heteroaryl group linked to N containing one, two, three or four selected nitrogen, oxygen and sulfur atoms, including the nitrogen to which R1 and R2 are attached, wherein the heteroaryl group is optionally substituted with one or two R1a groups. In an embodiment of Formula (I), (PI), (Ib), (P-Ib) or (P-2), including any of the aforementioned, R1 and R2 are joined together to form a monocyclic or bicyclic heteroaryl. Petition 870250090230, dated 03 / 10 / 2025, p. 92 / 341 69 / 217 of 5-12 N-linked members containing one, two, three or four atoms selected from nitrogen, oxygen and sulfur, including the nitrogen to which R1 and R2 are attached, wherein the heteroaryl is optionally substituted with an R1a group. In an embodiment of Formula (I), (PI), (Ib), (P-Ib) or (P-2), including any of the foregoing, R1 and R2 are joined together to form a 5-12 N-linked monocyclic or bicyclic heteroaryl containing one, two, three or four nitrogen atoms, including the nitrogen to which R1 and R2 are attached, wherein the heteroaryl is optionally substituted with one or two R1a groups.

[159] In an embodiment of Formula (I), (PI), (Ib), (P-Ib) or (P-2), including any of the foregoing, R1 and R2 are joined together to form a 5-12 membered monocyclic or bicyclic heterocyclyl linked to N containing one, two, three or four selected nitrogen, oxygen and sulfur atoms, wherein the heterocyclyl is unsubstituted. In an embodiment of Formula (I), (PI), (Ib), (P-Ib) or (P-2), including any of the foregoing, R1 and R2 are joined together to form a 5-12 membered monocyclic or bicyclic heterocyclyl linked to N containing one, two, three or four selected nitrogen, oxygen and sulfur atoms, including the nitrogen to which R1 and R2 are attached, wherein the heterocyclyl is optionally substituted with one or two R1a groups.In an embodiment of Formula (I), (PI), (Ib), (P-Ib) or (P-2), including any of the foregoing, R1 and R2 are joined together to form a 5-12 membered monocyclic or bicyclic heterocycline linked to N containing one, two, three or four atoms selected from nitrogen, oxygen and sulfur, including the nitrogen to which R1 and R2 are attached, wherein the heterocycline is optionally substituted with an R1a group. In an embodiment of Formula (I), (PI), (Ib), (P-Ib) or (P-2), including any of the foregoing, R1 and R2 are... Petition 870250090230, dated 03 / 10 / 2025, p. 93 / 341 70 / 217 joined together to form a 5-12 membered N-linked monocyclic or bicyclic heterocycle containing one, two, three, or four nitrogen atoms, including the nitrogen to which R1 and R2 are attached, where the heterocyclyl is optionally substituted with one or two R1a groups. In an embodiment of Formula (I), (PI), (Ib), (P-Ib) or (P-2), including any of the above, R1 and R2 are joined together to form a 5-12 membered monocyclic or bicyclic heterocyclyl linked to N containing a nitrogen atom, which is the nitrogen to which R1 and R2 are attached, and S(O)0-2, wherein the heterocyclyl is optionally substituted with one or two R1a groups. In an embodiment of Formula (I), (PI), (Ib), (P-Ib) or (P-2), including any of the foregoing, R1 and R2 are joined together to form a 5-12 membered monocyclic or bicyclic heterocyclyl group linked to N containing a nitrogen atom, which is the nitrogen to which R1 and R2 are attached, and S(O)2, wherein the heterocyclyl group is optionally substituted with one or two R1a groups.

[160] In an embodiment of Formula (I), (PI), (Ib), (P-Ib) or (P-2), including any of the above, R1e R2N-Λ * .Nn,N l N—| I Nd IN—| IN—í are joined together to form , , , and ; where I is the point of attachment to the remainder of the compound.

[161] In a Formula (I), (PI), (Ib), (P-Ib) or (P-2) mode, including any of the above, R1 and R2 are joined together to form which is the point of adhesion to the rest of the compound.

[162] In a Formula (I), (PI), (Ib), (P-Ib) or (P-2) modality, including any of the above, R1 and R2 Petition 870250090230, dated 03 / 10 / 2025, p. 94 / 341 71 / 217 are joined together to form where » is the point of adhesion to the rest of the compound.

[163] In a Formula (I), (PI), (Ib), (P-Ib) or (P-2) configuration, including any of the above, R1e R2νΛ| ρΛ In,N IN—IIN—IIN—| IN—| are joined together to form , , N-^ / , and ; and R3 is OH; where is the point of adhesion to the rest of the compound.

[164] In a Formula (I), (PI), (Ib), (P-Ib) or (P-2) configuration, including any of the above, R1e R2N-Λ J .Nn,N I NH I Nd IN—| IN—Í are joined together to form , , , and ; and, R3 is -OH, -OP(O) (Rb)2, or a 3-6 membered heteroaryl containing one, two, three, or four atoms selected from nitrogen, oxygen, and sulfur atoms; where is the point of attachment to the rest of the compound.

[165] In a Formula (I), (PI), (Ib), (P-Ib) or (P-2) configuration, including any of the above, R1e R2N-Λ J .Nn,N I Nd I Nd IN—| IN—í are joined together to form , , , and ; and, R3 is -OH, -OP(O) (Me)2, or ; where » is the point of adhesion to the rest of the compound.

[166] In an embodiment of Formula (I), (PI), (Ic), (P-Ic) or (P-2), including any of the foregoing, R2 is CO-6 alkylene-SO2R4. In an embodiment of Formula (I), (PI), (Ic), (P-Ic) or (P-2), R2 is CO-6 alkylene-SO2R5.

[167] In an embodiment of Formula (I), (PI), (Ic), (P-Ic) or (P-2), including any of the foregoing, R2 is C0-6 alkylene-SO2R4 and R4 is C2-6 alkyl. In an embodiment of Formula (I), (PI), (Ic), (P-Ic) or (P-2), including any Petition 870250090230, dated 03 / 10 / 2025, p. 95 / 341 72 / 217 one of those mentioned above, R2 is -CO-6 alkylene-SO2R4 and R4 is C3-6 cycloalkyl. In an embodiment of Formula (I), (PI), (Ic), (PIc) or (P-2), including any of the above, R2 is -CO-6 alkylene-SO2R4 and R4 is C1-6 hydroxyalkyl. In an embodiment of Formula (I), (PI), (Ic), (P-Ic) or (P-2), including any of the above, R2 is -CO-6 alkylene-SO2R4 and R4 is heterocyclyl and the heterocyclyl is optionally substituted with one or two R4a groups. In an embodiment of Formula (I), (PI), (Ic), (P-Ic) or (P-2), including any of the foregoing, R2 is -CO-6 alkylene-SO2R4 and R4 is aryl and the aryl is optionally substituted with one or two R4a groups. In an embodiment of Formula (I), (PI), (Ic), (P-Ic) or (P-2), including any of the foregoing, R2 is -CO-6 alkylene-SO2R4 and R4 is heteroaryl and the heteroaryl is optionally substituted with one or two R4a groups.

[168] In an embodiment of Formula (I), (PI), (Ic), (P-Ic) or (P-2), including any of the foregoing, R2 is CO-6 alkylene-SO2R5 and R5 is heterocyclyl and the heterocyclyl is optionally substituted with one or two R5a groups. In an embodiment of Formula (I), (PI), (Ic), (P-Ic) or (P-2), including any of the foregoing, R2 is CO-6 alkylene-SO2R5 and R5 is aryl and the aryl is optionally substituted with one or two R5a groups. In an embodiment of Formula (I), (PI), (Ic), (P-Ic) or (P-2), including any of the foregoing, R2 is CO-6 alkylene-SO2R5 and R5 is heteroaryl and the heteroaryl is optionally substituted with one or two R5a groups.

[169] In an embodiment of Formula (I), (PI), (Ic), (P-Ic) or (P-2), including any of the foregoing, R2 is C0-6 alkylene-SO2R5 and R5 is a 5-12 membered monocyclic heteroaryl containing two selected nitrogen and oxygen atoms and in which R5 is optionally substituted with one or two R5a groups. In an embodiment of Formula (I), (PI), (Ic), (PIc) or (P-2), including any of the foregoing, R5 Petition 870250090230, dated 03 / 10 / 2025, p. 96 / 341 73 / 217 selected from

[170] In a Formula (I) mode, or (P-2), including any of the above, R1 is methyl and R2 is -CO-6 alkylene-SO2R4. In an embodiment of Formula (I), (PI), (Ic), (P-Ic) or (P-2), including any of the above, R1 is hydrogen and R2 is -CO-6 alkylene-SO2R5. In an embodiment of Formula (I), (PI), (Ic), (P-Ic) or (P-2), including any of the above, R1 is methyl and R2 is -CO-6 alkylene-SO2R5.

[171] In a Formula (I), (PI), (Ic), (P-Ic) or (P-2) modality, including any of the above, R2 is in which

[172] Selected from =0 the point of adhesion to the remainder of a Formula (I) modality composite. (PI), (Ic) (P-Ic) R2 is selected from hydrogen |— NH * \ H3 NH ' \ s=o mentioned above, R1é or (P-2), including any of the S=O and R3 is Petition 870250090230, dated 03 / 10 / 2025, p. 97 / 341 74 / 217 -OH; where is the point of adhesion to the rest of the compound.

[173] In a Formula (I), (PI), (Ic), (P-Ic) modality including any of the selected from or (P-2) mentioned above, R1 is methyl, R2 S=O ; and R3 is -OH; It is the point of adhesion to which the rest of the compound adheres.

[174] In a type of Formula (I), (PI), (Ic), (P-Ic) mentioned above, R2 is one of S=O NH selected from or (P-2), including any CH3e R3 is -OH; the point of adhesion to the rest of where; compound.

[175] In a Formula (I), (PI), (Ic), (P-Ic) or (P-2) modality, including any of the above, R1 is Petition 870250090230, dated 03 / 10 / 2025, p. 98 / 341 75 / 217 methyl; R2 is -CO-6 alkylene-SO2R4; and R3 is -OH, -OP(O)(Rb)2, or a 3-6 membered heteroaryl containing one, two, three, or four atoms selected from nitrogen, oxygen, and sulfur atoms. In an embodiment of Formula (I), (PI), (Ic), (P-Ic), or (P-2), including any of the foregoing, R1 is hydrogen; R2 is -CO-6 alkylene-SO2R5; and R3 is -OH, -OP(O)(Rb)2, or a 3-6 membered heteroaryl containing one, two, three, or four atoms selected from nitrogen, oxygen, and sulfur atoms. In an embodiment of Formula (I), (Ic), or (P-2), including any of the foregoing, R1 is methyl; R2 is -CO-6 alkylene-SO2R5; and, R3 is -OH, -OP(O)(Rb)2, or a 36-membered heteroaryl containing one, two, three, or four atoms selected from nitrogen, oxygen, and sulfur atoms.

[176] In an embodiment of Formula (I), (PI), (Ic), (P-Ic) or (P-2), including any of the foregoing, R1 is methyl; R2 is -CO-6 alkylene-SO2R4; and, R3 is -OH, -OP(O)(Me)2, or IN—I ; where * is the point of attachment to the rest of the compound. In an embodiment of Formula (I), (Ic) or (P-2), including any of the above, R1 is hydrogen; R2 is -CO-6 alkyleneSO2R5; and R3 is -OH, -OP(O)(Me)2, or ; where * is the point of attachment to the rest of the compound. In an embodiment of Formula (I), (PI), (Ic), (P-Ic) or (P-2), including any of the above, R1 is methyl; R2 is -CO-6 alkylene-SO2R5; and R3n-n. It is -OH, -OP(O)(Me)2, or where I is the point of adhesion to the rest of the compound.

[177] In a Formula (I), (PI), (Ic), (P-Ic) or (P-2) modality, including any of the above, R1 is Petition 870250090230, dated 03 / 10 / 2025, p. 99 / 341 76 / 217 R2 is selected from hydrogen S=O which contains a heteroaryl of 3-6 members N; and R3 is -OH, -OP(O)(Rb)2, or two, three, or four atoms selected from nitrogen, oxygen, and sulfur atoms; in what I is the point of adhesion to the rest of the compound.

[178] In a Formula (I), (PI), (Ic), (P-Ic) modality including any of the selected from or (P-2) mentioned above, R1 is methyl, R2 S=O (Rb)2 or a three- or four-membered heteroaryl; and R3 is -OH, -OP (O) containing one, two 3-6 member atoms selected from nitrogen, oxygen, and sulfur atoms; which is the point of adhesion to the rest of the compound.

[179] In a Formula (I), (PI), (Ic), (P-Ic) or (P-2) modality, including any of the above, R1 is Petition 870250090230, dated 03 / 10 / 2025, p. 100 / 341 77 / 217 R2 is selected from hydrogen S=O is the point of adhesion to the rest of the compound. N; and R3 is; in -OH, -OP(O)(Me)2

[180] In a Formula (I) (PI), (Ic), (P-Ic) or (P-2) modality including any of the selected from those previously mentioned, R1 is methyl, R2 S=O where or ; ; and R3 is -OH, -OP(O)(Me)2 is the point of adhesion to the rest of the compound.

[181] In a Formula (I), (PI), (Ic) (P-Ic) or (P-2) mode, including any of the above, R4 is selected from Petition 870250090230, dated 03 / 10 / 2025, p. 101 / 341 78 / 217 in what It is the point of adhesion to the rest of the compound.

[182] In a Formula (I), (PI), (Ic), (P-Ic) or (P-2) mode, including any of the above, R4 is selected from Petition 870250090230, dated 03 / 10 / 2025, p. 102 / 341 79 / 217 in what It is the point of adhesion to the rest of the compound; and R4a is as defined in this descriptive report.

[183] ​​In a Formula (I), (PI), (Ic), (P-Ic) or (P-2) modality, including any of the above, R4 is selected from CH3 It is the point of adhesion to the rest of the compound.

[184] In a Formula (I), (PI) (Ic), (P-Ic) or (P-2) mode, including any of the above, R5 is selected from It is the point of adhesion to the rest of the compound. in what Petition 870250090230, dated 03 / 10 / 2025, p. 103 / 341 80 / 217

[185] In a Formula (I), (PI), (Ic), (P-Ic) or (P-2) modality, including any of the above, R5 is selected from R5a is as defined in this descriptive report.

[186] In a Formula (I), (PI), (Ic), (P-Ic) or (P-2) mode, including any of the above, R4 is selected from where is the point of adhesion? Petition 870250090230, dated 03 / 10 / 2025, p. 104 / 341 81 / 217 to the rest of the compound.

[187] In one embodiment, the compound of Formula (I) is of the formula: and R3 are as described in any of the embodiments for Formula (I) described in that descriptive report.

[188] Non-limiting examples of compounds of Formula (Ia) include: Petition 870250090230, dated 03 / 10 / 2025, p. 105 / 341 82 / 217 Rbsão as described in any of the modalities for Formula (Ia) described in that descriptive report.

[189] Non-limiting examples of compounds of Formula (Ib) include: Petition 870250090230, dated 03 / 10 / 2025, p. 106 / 341 83 / 217 and or a pharmaceutically acceptable salt thereof; where R1, R2 and Rb are as described in any of the embodiments for Formula (Ib) described in that descriptive report.

[190] Non-limiting examples of compounds with Formula (Ic) include: Petition 870250090230, dated 03 / 10 / 2025, p. 107 / 341 84 / 217 are as described in any of the modalities for Formula (Ic) described in that descriptive report. Petition 870250090230, dated 03 / 10 / 2025, p. 108 / 341 85 / 217

[191] In certain embodiments, 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) has a of or “% of zero. In certain embodiments, 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) has a of or % of greater than zero. For example, in certain embodiments, 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) has a of or “% of about ten. In certain forms, 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) has one of or “% of about twenty-five.In certain embodiments, 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) has a percentage of about fifty. In certain embodiments, 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) has a percentage of about seventy-five. In certain embodiments, 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) has a percentage of about eighty. In certain embodiments, 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) has a percentage of about eighty-five.In certain embodiments, 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) has a percentage of approximately ninety percent. In certain embodiments, the compound of Formula (P-2), Formula (PI), Formula (P-Ia), Formula (P-Ib), Formula. Petition 870250090230, dated 03 / 10 / 2025, p. 109 / 341 86 / 217 (P-Ic), Formula (I), Formula (Ia), Formula (Ib) or Formula (Ic) has a of or “% of about ninety-five. In certain embodiments, 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) has a of or “% of about ninety-seven. In certain embodiments, 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) has a percentage of about ninety-eight. In certain embodiments, the compound of Formula (P-2), Formula (PI), Formula (P-Ia), Formula (P-Ib), Formula (P-Ic), Formula (P2), Formula (I), Formula (Ia), Formula (Ib) or Formula (Ic) has a percentage of about ninety-nine. In certain embodiments, the compounds described in this descriptive report have a percentage of one hundred.

[192] 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 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 of the C-16 epimer-(R) 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 a pharmaceutically acceptable salt, if the compound exists as a pharmaceutically acceptable salt).In one embodiment, the compound of Formula (P-2), Formula (PI), Formula (P-Ia), Formula (P-Ib), Formula (P-Ic), Formula (I), (Ia), (Ib) or (Ic) or a pharmaceutically acceptable salt thereof, is about 85% - 95% of the (R)-C-16 epimer. In one embodiment, the compound of Formula. Petition 870250090230, dated 03 / 10 / 2025, p. 110 / 341 87 / 217 (P-2), Formula (PI), Formula (P-Ia), Formula (P-Ib), Formula (P-Ic), Formula (I), (Ia), (Ib) or (Ic) or a pharmaceutically acceptable salt thereof, is about 90% - 95% of the epimer of (R) -C-16.

[193] 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% by weight of the C-16 epimer-(S) and 50% by weight of the C-16 epimer-(R) 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 a pharmaceutically acceptable salt, if the compound exists as a pharmaceutically acceptable salt).

[194] 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 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 of the C-16 epimer-(S) 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 a pharmaceutically acceptable salt, if the compound exists as a pharmaceutically acceptable salt).In one embodiment, the compound of Formula (P-2), Formula (PI), Formula (P-Ia), Formula (P-Ib), Formula (P-Ic), Formula (I), (Ia), (Ib) or (Ic) or a pharmaceutically acceptable salt thereof, is about 85% - 95% of the (S)-C-16 epimer. In one embodiment, the compound of Formula (P-2), Formula (PI), Formula (P-Ia), Formula (P-Ib), Formula. Petition 870250090230, dated 03 / 10 / 2025, p. 111 / 341 88 / 217 (P-Ic), Formula (I), (Ia), (Ib) or (Ic) or a pharmaceutically acceptable salt thereof, is about 90% - 95% of the (S)-C-16 epimer.

[195] In some embodiments, the pharmaceutical compounds and compositions disclosed in this descriptive report for use in the treatment of a disorder or disease mediated by the mTOR pathway are more selective in binding to FKBP12 than others in the FK506-binding protein (FKBP) group.

[196] In some other embodiments, the compounds and pharmaceutical compositions disclosed in this descriptive report for use in the treatment of a disorder or disease mediated by the mTOR pathway exhibit an unusual and surprising pharmacokinetic profile and enhanced pharmacodynamic selectivity among target FKBPs, these compounds, as well as the pharmaceutical compositions containing them, are useful for the treatment of age-related or aging-related diseases, diabetes complications, cancers, as well as disorders associated with inflammation.

[197] In some other embodiments, the pharmaceutical compounds and compositions disclosed in this descriptive report are for use in the treatment of a disorder or disease mediated by the mTOR pathway, wherein the compound inhibits S6K1 phosphorylation at least twice less efficiently than rapalog RAD001 in FKBP12 KO cells compared with FKBP12 expressing cells.

[198] In some other embodiments, the pharmaceutical compounds and compositions disclosed in this descriptive report are for use in the treatment of a disorder or disease mediated by the mTOR pathway, wherein the compound inhibits S6K1 phosphorylation at least 10 times less efficiently than rapalog RAD001 in FKBP12 KO cells compared to FKBP12 expressing cells.

[199] In some other forms, the compounds and Petition 870250090230, dated 03 / 10 / 2025, page 112 / 341 89 / 217 pharmaceutical compositions disclosed in this descriptive report for use in the treatment of a disorder or disease mediated by the mTOR pathway, in which the compound inhibits S6K1 phosphorylation at least 100 times less efficiently than rapalog RAD001 in FKBP12 KO cells compared to FKBP12 expressing cells.

[200] In some other embodiments, the pharmaceutical compounds and compositions disclosed in this descriptive report for use in the treatment of a disorder or disease mediated by the mTOR pathway, wherein the compound requires a concentration approximately 10 times higher, compared to the rapalog RAD001, in cells with FKBP12 KO compared to cells expressing FKBP12, to obtain 20% inhibition of cell signaling by S6K1.

[201] In some other embodiments, the pharmaceutical compounds and compositions disclosed in this descriptive report for use in the treatment of a disorder or disease mediated by the mTOR pathway, where the compound requires a concentration approximately 20 times higher, compared to the rapalog RAD001, in cells with FKBP12 KO compared to cells expressing FKBP12, to obtain 20% inhibition of cell signaling by S6K1.

[202] In some other embodiments, the pharmaceutical compounds and compositions disclosed in this descriptive report for use in the treatment of a disorder or disease mediated by the mTOR pathway, wherein the compound requires a concentration approximately 100 times higher, compared to the rapalog RAD001, in cells with FKBP12 KO compared to cells expressing FKBP12, to obtain 20% inhibition of cell signaling by S6K1.

[203] In some other embodiments, the pharmaceutical compounds and compositions disclosed in this descriptive report for use in the treatment of a disorder or disease mediated by the mTOR pathway, where the compound requires a concentration approximately 500 times higher, compared with rapalog RAD001, in cells with FKBP12 KO compared with cells expressing FKBP12, Petition 870250090230, dated 03 / 10 / 2025, page 113 / 341 90 / 217 to achieve 20% inhibition of cell signaling by S6K1.

[204] In some other embodiments, the pharmaceutical compounds and compositions disclosed in this descriptive report for use in the treatment of a disorder or disease mediated by the mTOR pathway, wherein the compound requires a concentration approximately 1,000 times higher, compared to the rapalog RAD001, in cells with FKBP12 KO compared to cells expressing FKBP12, to obtain 20% inhibition of cell signaling by S6K1.

[205] In some other embodiments, a “FKBP12 selective rapalog” is a rapalog that, while potent in an assay using a wild-type cell, is approximately 10 times to approximately 1,000 times less potent than RAD001 in a cell line that does not express FKBP12 (e.g., FKBP12 knockout cells). The term “potency,” as used in this context, can be expressed as the concentration of rapalog required to achieve a 20% inhibition of S6K1 (Thr389) phosphorylation in a cell-based assay such as, for example, that used in Example 3 and Figures 1-11. For example, a rapalog is considered selective for FKBP12 if the rapalog inhibits approximately 20% inhibition of S6K1 (Thr389) phosphorylation in an assay using a knockout cell line. FKBP12 with a power of at least 20x (e.g., 25x, 30x, 50x, 100x, 200x, 500x, 1000x, etc.).) lower, compared to a similar level of inhibition obtained by RAD001 in the same assay with the same cell line, which normally expresses FKBP12.

[206] In some other embodiments, the pharmaceutical compounds and compositions disclosed in this descriptive report for use in the treatment of a disorder or disease mediated by the mTOR pathway, wherein the compound requires a concentration approximately 20 times higher, compared to the rapalog RAD001, in cells with FKBP12 KO compared to cells expressing FKBP12, to obtain 30% inhibition of cell signaling by S6K1. Petition 870250090230, dated 03 / 10 / 2025, page 114 / 341 91 / 217

[207] In some other embodiments, the pharmaceutical compounds and compositions disclosed in this descriptive report for use in the treatment of a disorder or disease mediated by the mTOR pathway, wherein the compound requires a concentration approximately 100 times higher, compared to the rapalog RAD001, in cells with FKBP12 KO compared to cells expressing FKBP12, to obtain 30% inhibition of cell signaling by S6K1.

[208] In some other embodiments, the pharmaceutical compounds and compositions disclosed in this descriptive report for use in the treatment of a disorder or disease mediated by the mTOR pathway, wherein the compound requires a concentration approximately 500 times higher, compared to the rapalog RAD001, in cells with FKBP12 KO compared to cells expressing FKBP12, to obtain 30% inhibition of cell signaling by S6K1.

[209] In some other embodiments, the pharmaceutical compounds and compositions disclosed in this descriptive report for use in the treatment of a disorder or disease mediated by the mTOR pathway, wherein the compound requires a concentration approximately 1,000 times higher, compared to the rapalog RAD001, in cells with FKBP12 KO compared to cells expressing FKBP12, to obtain 30% inhibition of cell signaling by S6K1.

[210] In some other embodiments, a “FKBP12 selective rapalog” is a rapalog that, while potent in an assay using a wild-type cell, is approximately 20 times to approximately 1,000 times less potent than RAD001 in a cell line that does not express FKBP12 (e.g., FKBP12 knockout cells). The term “potency,” as used in this context, can be expressed as the concentration of rapalog required to achieve a 30% inhibition of S6K1 (Thr389) phosphorylation in a cell-based assay such as, for example, that used in Example 3 and Figures 1-11. For example, a rapalog is considered selective for FKBP12 if the rapalog inhibits approximately 30% inhibition of Petition 870250090230, dated 03 / 10 / 2025, page 115 / 341 92 / 217 S6K1 (Thr389) phosphorylation in an assay using an FKBP12 knockout cell line with a potency at least 20x (e.g., 25x, 30x, 50x, 100x, 200x, 500x, 1000x, etc.) lower compared to a similar level of inhibition obtained by RAD001 in the same assay with the same cell line that normally expresses FKBP12.

[211] Non-limiting components of the present invention include: Petition 870250090230, dated 03 / 10 / 2025, p. 116 / 341 93 / 217 Petition 870250090230, dated 03 / 10 / 2025, p. 117 / 341 94 / 217 Compound 13 Compound 16 Petition 870250090230, dated 03 / 10 / 2025, p. 118 / 341 95 / 217 Compound 17 Compound 18 Petition 870250090230, dated 03 / 10 / 2025, p. 119 / 341 96 / 217 HO, MeO**^ Me J^le--, A-°h ° MeO''' .. H0J J Me^X „ O Me \ N^NH Me Μθ VN\ Compound 23 HO,40^ ΜβΟ^^^η Me JCoH °V^O ° MeO' m HCM J 0 Me XI j 16 2±> ' Mp Me z^s^NH Me 9 ^=7 Compound 24 HO,^ MeO^Aii Me Me,, 1 Ξ L / O Jkz0H NJ| Me JO\ A. o A ^o ,,ΛΆ MeO' A^ HOJ 1 MeAy Me^X, NH Μθ Me F3c Compound 55 Η°,ήθ / \ MeO***^ Me 9^γδ ΗΗΛγ°Η θν^Ο ° MeO''' m HCM J MGkX^ ., ^^.NH Me Me Compound 26 φ Ξ 1 >—(ο ο δ o =c~A o °=( / —* O'< CD 'Λ \ / / ω \ A\w Z \ / ÇD \__ / 0 4 9. / I 0 / —\ / N> \--JO ^'\ωΖ ¥ CD O ΗΟ,ήθ^^ MeO^^ Me L. / L / Ó HH JL^OH O\ As O ck^o Xy^O MeO' A^ m HCM 1 Me«. Petition 870250090230, dated 03 / 10 / 2025, pp. 120 / 341 97 / 217 Petition 870250090230, dated 03 / 10 / 2025, pp. 121 / 341 98 / 217 Compound 49 Compound 50 Petition 870250090230, dated 03 / 10 / 2025, pp. 122 / 341 99 / 217 Petition 870250090230, dated 03 / 10 / 2025, pp. 123 / 341 100 / 217 Petition 870250090230, dated 03 / 10 / 2025, pp. 124 / 341 101 / 217 Petition 870250090230, dated 03 / 10 / 2025, p. 125 / 341 102 / 217 Compound 68 Compound 69 thecf2h Compound 70 Compound 72 Compound 71 Compound 73 Petition 870250090230, dated 03 / 10 / 2025, pp. 126 / 341 103 / 217 Compound 12-A Compound 12-B Petition 870250090230, dated 03 / 10 / 2025, pp. 127 / 341 104 / 217 Petition 870250090230, dated 03 / 10 / 2025, pp. 128 / 341 105 / 217 Petition 870250090230, dated 03 / 10 / 2025, pp. 129 / 341 106 / 217 Petition 870250090230, de 03 / 10 / 2025, pág. 130 / 341 107 / 217 Petition 870250090230, de 03 / 10 / 2025, pág. 131 / 341 108 / 217 HO,- MeO'^X'Y Me °Á ° MeO'-V . - H0J J £ Me Mθ xt^NH QT Compound 2 6-A H°,ΐ°χ\ Metj^ Me L , xL / Õ H Η JL^OH (X xk ο Â / O MeO' ΓΛ H0^ 1 Me^ / Me Me [Χ^|ΧΝΗ Compound 26-B HO,—xx. ΜβΟΙ^'^η Me Υγ'''\χ-Υγ^\ hhÀz>h °Y^O ° MeO' .. HOJ 1 Me*. .. <S\ ' mo Me NH Me —< T O'N Composto 27-A η°4°χ\ MeO / > Sx / j Me χΜθ'-'Ι^χΧΧ^^ CNJyõ ηηΛ^οη °Y^O ° MeO' γ·° .. HO.J 1 Me^^k Β< X^° xT^v-^Xx^Xx^ / ' i\ / io Me NH Me —< Y O'N Composto 27-B φ S , (DT _ / >—< oo op 2 Z \ / C / \ \° ss / / )—Ο λ-Ζ v < ) \ \ d \—' —' \ % Λ z ? z -1- / 05 O Ç / * O'< φ 'X \ / ΞΕ_ / ω Ά T \Μ / 5. \__ / φ ά 9. / ' / φ 7—ν / Μ \- / ο 2'\<ίΥ Ss ¥ ω ο T- O Φ SX / A'2 oy—< cxi / 7----~ Φ \( / =< & Ξ 7 Φ / \ Φ / S'< xs \< cm y co / I. / \ V. Φ )'O / —S / : ν'*3· / —\ õ* / —\ Z\_ < > Ύ zY os' ο\_γ vj y / \ \ 'o' o oo\—' ) τ 1 Τω Petition 870250090230, de 03 / 10 / 2025, pág. 132 / 341 109 / 217 Compound 28-A Compound 28-B HO^ Me 1^-,,1^^^32^ l.zLó HH JL X)H Οχ X. O 0'k / O ^Υ Ο MeO . . Η0^ 1 ~ Me Me / yyNH N'N\ Compound 2 9-AH°4°x\ ΜθΟ^^'^'^^η Me Ι>Υδ ηηΛχ°η θΥ^Ο ° MeO''' γ^0 »ΛH0>J 1 Μβχ>χ_ • Μα Μ® ζ^ / νηΜ ΝΝ\ Compound 29-B HO,- Me Lil HH JLuDH CK Y. O / y MeO . . H0*J 1 Me.>x „„ >A. * r / io Mθ |\L ^NHMe o' YV=N Composto 30-A ΗΟο,Υ^ MeO^^^^A Me >Αγδ ΗΗΛγ°Η θν^Ο 0 MeO''' η^0 Μ HOJ ] Mθχ>*\_ ,, χ*\ N^ / NHMe Mθ Ο' Υ V=N Composto 30-B HO-. / X MeCrY / n Me Me,, 1 ξ L.ÁY Asxoh NJ| Me y CK X. OY / O ,,ΑΤ'Ο MeO' H°J 1 Me-^ / ^Q íe Me Cl Η0„ζ ΜεΟ^Υ / η Me Me,, 1 ξ J\xoh N η Me y O\ / U o c'k^o , .^Y^o MeO' H°J 1 Me <«^ / ^0 Me^\^ ^^NH Me Me Cl Petition 870250090230, de 03 / 10 / 2025, pág. 133 / 341 110 / 217 Petition 870250090230, de 03 / 10 / 2025, pág. 134 / 341 111 / 217 Compound 4 6-A Compound 46-B HO„ / \ MeO^Ai Me Me-, 1 Ξ kiA^OJ\^OH N η Me [ OX O 0'k^O , ,^Χ^ Ο MeO HOJ 1 Me-y^O Me^X / ^NHΜθ Me ^O Compound 47-A HO- / X MeO^^A^fi Me Me-, 1 Ξ kiA^O / \x-OH N II Me y Os A o cA^O ,, Ay O MeO' HOJ 1 Me-yA^o Me^X ,^ / NH ye. Me A> ^O Compound 47-B HOzXX MeOZXl Me Me-,1 E LXO JL^OH NT| Me [ Ox As. ci'^^ Compound 48-A HO',. / X MeO'XT Me Me-,,1 Ξ ki^S <O JkzOH N Π Me | o^A^. o A„<o X MeO' HOJ 1 Me-y^O Me^X -s-NHMe Me £3 Cl7^^ Composto 48-B MeO^^Ajfn Me Me-, 1 Ξ Jkx0H N J Me [ Os As. Ο .Ά / Ο AX MeO' H°J 1 Me-^A^Q Me Me A> Compound 49-AH°-„^\ MeO^^Afíl Me Me-, 1 Ξ J£z0H N f[ Me [ O\ As. o .sA / O MeO' H°J 1 Me-^A^Q NH Me Me A? Compound 49-B Petition 870250090230, dated 03 / 10 / 2025, pp. 135 / 341 112 / 217 Petition 870250090230, dated 03 / 10 / 2025, pp. 136 / 341 113 / 217 Petition 870250090230, dated 03 / 10 / 2025, pp. 137 / 341 114 / 217 Petition 870250090230, dated 03 / 10 / 2025, pp. 138 / 341 115 / 217 Petition 870250090230, dated 03 / 10 / 2025, pp. 139 / 341 116 / 217 Petition 870250090230, dated 03 / 10 / 2025, pp. 140 / 341 117 / 217 Compound 64-A Compound 64-B Compound 68-A Compound 68-B Petition 870250090230, dated 03 / 10 / 2025, pp. 141 / 341 118 / 217 Petition 870250090230, dated 03 / 10 / 2025, pp. 142 / 341 119 / 217 Pharmaceutical compositions and treatment methods

[212] Methods of treatment and prevention of diseases, conditions or disorders comprising the administration of a therapeutically or prophylactically effective amount of one or more of the compounds disclosed are provided in this descriptive report. Petition 870250090230, dated 03 / 10 / 2025, pp. 143 / 341 120 / 217 in this descriptive report, for example, one or more of the compounds of a formula disclosed in this descriptive report. Diseases, disorders and / or conditions include, without limitation, those that are mediated by the mTOR pathway.

[213] In some embodiments of the methods disclosed in this descriptive report, multiple doses of a compound described in this descriptive report (or of a pharmaceutical composition comprising a combination of a compound described in this descriptive report and any of the additional therapeutic agents mentioned in this descriptive report) may be administered to an individual over a defined time interval. The methods according to this embodiment of the disclosure comprise sequentially administering to an individual multiple doses of a compound described in this descriptive report. As used in this descriptive report, the term "administer sequentially" means that each dose of the compound is administered to the individual at a different point in time, for example, on different days separated by a predetermined interval (e.g., hours, days, weeks, or months).This disclosure includes methods comprising the sequential administration to the patient of a single initial dose of a compound described in this descriptive report, followed by one or more secondary doses of the compound and, optionally, followed by one or more tertiary doses of the compound.

[214] The terms "initial dose," "secondary doses," and "tertiary doses" refer to the temporal sequence of administration of the compounds described in this descriptive report. Thus, the "initial dose" is the dose administered at the beginning of the treatment regimen (also referred to as the "baseline dose"); the "secondary doses" are the doses administered after the initial dose; and the "tertiary doses" are the doses administered after the secondary doses. The initial, secondary, and tertiary doses may all include the same Petition 870250090230, dated 03 / 10 / 2025, pp. 144 / 341 121 / 217 The amount of the compound described in this descriptive report, but they may generally differ from one another in terms of frequency of administration. In certain embodiments, the amount of the compound included in the initial, secondary and / or tertiary doses varies from one another (e.g., adjusted up or reduced as appropriate) during the course of treatment. In certain embodiments, two or more (e.g., two, three, four or five) doses are administered at the beginning of the treatment regimen as loading doses, followed by subsequent doses that are administered less frequently (e.g., maintenance doses).

[215] In certain exemplary embodiments of this revelation, each secondary and / or tertiary dose is administered one to twenty-six (for example, 1, 1^, 2, 2^, 3, 3^, 4, 4^, 5, 5^, 6, 6½ 7, 7^, 8, 8½ 9, 9½ 10, 10½ 11, 11½ 12, 12½ 13, 13½ 14, 14½ 15, 15½ 16, 16½ 17, 17½ ​​18, 18½ 19, 19½ 20, 20½ 21, 21½ 22, 22½ 23, 23½ 24, 24½ 25, 25½ 26, 26½ or more) weeks after the immediately preceding dose. The phrase "the immediately preceding dose," as used in this descriptive report, means, in a sequence of multiple administrations, the dose of the compound that is administered to a patient before the administration of the next dose in the sequence without intervening doses.

[216] The methods according to this embodiment of the disclosure may comprise administering to a patient any number of secondary and / or tertiary doses of the compound. For example, in certain embodiments, only a single secondary dose is administered to the patient. In other embodiments, two or more (e.g., two, three, four, five, six, seven, eight or more) secondary doses are administered to the patient. Similarly, in certain embodiments, only a single tertiary dose is administered to the patient. In other embodiments, two or more (e.g., two, three, four, five, six, seven, eight or more) tertiary doses are administered to the patient. The Petition 870250090230, dated 03 / 10 / 2025, pp. 145 / 341 122 / 217 administration regimen may be carried out indefinitely throughout the life of a particular individual, or until such treatment is no longer therapeutically necessary or advantageous.

[217] In modalities involving multiple secondary doses, each secondary dose may be administered at the same frequency as other secondary doses. For example, each secondary dose may be administered to the patient one to two weeks or one to two months after the immediately preceding dose. Similarly, in modalities involving multiple tertiary doses, each tertiary dose may be administered at the same frequency as other tertiary doses. For example, each tertiary dose may be administered to the patient two to twelve weeks after the immediately preceding dose. In certain modalities of development, the frequency at which secondary and / or tertiary doses are administered to a patient may vary throughout the course of the treatment regimen. The frequency of administration may also be adjusted during the course of treatment by a physician depending on the individual patient's needs after clinical examination.

[218] This disclosure includes administration regimens in which two to six loading doses are administered to a patient at an initial frequency (e.g., once weekly, once every two weeks, once every three weeks, once monthly, once every two months, etc.), followed by administration of two or more maintenance doses to the patient less frequently. For example, according to this disclosure modality, if loading doses are administered at a frequency of once a month, then maintenance doses may be administered to the patient once every six weeks, once every two months, once every three months, etc.

[219] This disclosure includes pharmaceutical compositions of the compounds described in this descriptive report, for example, Petition 870250090230, dated 03 / 10 / 2025, pp. 146 / 341 123 / 217 compounds of Formula (I), (P-1), (P-2), (Ia)-(Ic) or (P-Ia)-(PIc) or Compounds 3-74, or a salt, and a pharmaceutically acceptable carrier, diluent and / or excipient. Examples of suitable carriers, diluents and excipients include, without limitation, buffers for maintaining the proper pH of the composition (e.g., citrate buffers, succinate buffers, acetate buffers, phosphate buffers, lactate buffers, oxalate buffers and the like), carrier proteins (e.g., human serum albumin), saline solution, polyols (e.g., trehalose, sucrose, xylitol, sorbitol and the like), surfactants (e.g., polysorbate 20, polysorbate 80, polyoxolate and the like), antimicrobials and antioxidants.

[220] This disclosure also includes a combination therapy 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 combination dosage form.

[221] In some embodiments, this descriptive report presents a method of treating a disorder or disease in a needy individual comprising administering a compound of Formula (I), (P-1), (P-2), (Ia)-(Ic) or (P-Ia)-(PIc), or a pharmaceutically acceptable salt thereof.

[222] In some embodiments, this descriptive report presents a method of treating a disorder or disease in an individual in need comprising administering a combination therapy 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. Petition 870250090230, dated 03 / 10 / 2025, pp. 147 / 341 124 / 217

[223] In some embodiments, this descriptive report presents a method of treating a disorder or disease mediated by the mTOR pathway in a needy individual comprising administering a compound of Formula (I), (P-1), (P-2), (Ia)-(Ic) or (P-Ia)-(P-Ic), or a pharmaceutically acceptable salt thereof. In one embodiment, the target tissue, organ or cells associated with the pathology of the disease or disorder have sufficient levels of FKBP12 to inhibit mTORC1.

[224] In one embodiment, the disease or disorder is a selected age-related disorder or disease of sarcopenia; skin atrophy; cherry angiomas; seborrheic keratoses; cerebral atrophy; atherosclerosis; arteriosclerosis; pulmonary emphysema; osteoporosis; osteoarthritis; arterial hypertension; erectile dysfunction; cataracts; macular degeneration; glaucoma; stroke; cerebrovascular disease (cerebrovascular accidents); chronic kidney disease; kidney disease associated with diabetes; impaired liver function; hepatic fibrosis; autoimmune hepatitis; endometrial hyperplasia; metabolic dysfunction; renovascular disease; hearing loss; motor impairment; cognitive decline; tendon stiffness; cardiac dysfunction such as, for example, cardiac hypertrophy and / or systolic and / or diastolic dysfunction and / or hypertension; cardiac dysfunction resulting in a decline in ejection fraction; immune senescence; Parkinson's disease; Alzheimer's disease or a syndrome thereof; cancer;Immune senescence leading to cancer due to decreased immune surveillance; infections resulting from a decline in immune function; chronic obstructive pulmonary disease (COPD); obesity; loss of taste; loss of smell; arthritis; and type II diabetes.

[225] In one embodiment, the disease or disorder is cancer. In one embodiment, the cancer is selected from renal cancer, renal cell carcinoma, colorectal cancer, uterine sarcoma, endometrial uterine cancer, endometrial cancer, breast cancer, cancer Petition 870250090230, dated 03 / 10 / 2025, pp. 148 / 341 125 / 217 ovarian, 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 neck cancer.

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

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

[228] In one embodiment, the disease or disorder consists of advanced unresectable or metastatic perivascular malignant epithelioid cell tumors.

[229] In some embodiments, this descriptive report also presents a method for inducing immune tolerance and / or preventing organ transplant rejection in a needy individual comprising administering a compound of Formula (I), (P-1),(Ia)-(Ic) or (P-Ia)-(P-Ic), or a pharmaceutically acceptable salt thereof.

[230] 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 the treatment of diseases and disorders described in this descriptive report, for example, age-related disorders or diseases and disorders currently approved for treatment with the use of rapalogs such as, for example, RAD001.

[231] In one aspect, the disclosure provides a method for treating a disorder or disease mediated by the mTOR pathway in an individual in need, the method comprising administering to the individual a therapeutically effective amount of a compound of Formula (I), (P-1), (P-2), (Ia)-(Ic) or (P-Ia)-(P-Ic), or of a pharmaceutically acceptable salt thereof.

[232] In one modality, the effectiveness of the treatment is Petition 870250090230, dated 03 / 10 / 2025, pp. 149 / 341 126 / 217 determined empirically, for example, when compared with rapamycin or RAD001.

[233] In another aspect, the disclosure provides a method of treating a disease or disorder in an individual who has, or has been previously determined to have, sufficient levels of FKBP12 to inhibit mTORC1, the method comprising administering to the individual in need a therapeutically effective amount of a compound of Formula (I), (P-1), (P-2), (Ia)-(Ic) or (P-Ia)-(P-Ic), or of a pharmaceutically acceptable salt thereof, or of a pharmaceutical composition described in this descriptive report, or of a pharmaceutical combination described in this descriptive report.

[234] In one modality, the disease or disorder is selected from sarcopenia, skin atrophy, cherry angiomas, seborrheic keratoses, cerebral atrophy, atherosclerosis, arteriosclerosis, pulmonary emphysema, osteoporosis, osteoarthritis, arterial hypertension, erectile dysfunction, cataract, macular degeneration, glaucoma, stroke, cerebrovascular disease (cerebrovascular accidents), chronic kidney disease, kidney disease associated with diabetes, impaired liver function, hepatic fibrosis, autoimmune hepatitis, endometrial hyperplasia, metabolic dysfunction, renovascular disease, hearing loss, motor impairment, cognitive decline, tendon stiffness, cardiac dysfunction such as, for example, cardiac hypertrophy and / or systolic and / or diastolic dysfunction and / or hypertension, cardiac dysfunction resulting in a decline in ejection fraction, immune senescence, Parkinson's disease, Alzheimer's disease, cancer,Immune senescence leading to cancer due to decreased immune surveillance, infections resulting from a decline in immune function, chronic obstructive pulmonary disease (COPD), obesity, loss of taste, loss of smell, arthritis, and type II diabetes, including complications arising from diabetes such as kidney failure, blindness, and neuropathy. Petition 870250090230, dated 03 / 10 / 2025, pp. 150 / 341 127 / 217

[235] In one form, the disorder is hepatic fibrosis.

[236] In another aspect, the disclosure provides a method of treating a disease or disorder in an individual in need, the method comprising administering to the individual a therapeutically effective amount of a compound of Formula (I), (P-1), (P-2), (Ia)-(Ic) or (P-Ia)-(P-Ic), or of a pharmaceutically acceptable salt thereof, of a pharmaceutical composition comprising a compound of Formula (I), (P-1), (P-2), (Ia)-(Ic) or (P-Ia)-(P-Ic), or of 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 of a pharmaceutically acceptable salt thereof, wherein the disorder or disease is selected from: - Acute or chronic rejection of organ or tissue transplantation; - Transplant vasculopathies; - Proliferation and migration of smooth muscle cells leading to thickening of the intima of blood vessels, obstruction of blood vessels, obstructive coronary atherosclerosis, restenosis; Autoimmune diseases and inflammatory conditions; Asthma; Multidrug resistance (MDR); - Fungal infections; Inflammation; Infection; Age-related diseases; Neurodegenerative diseases; - Proliferative disorders, particularly cancer; - Seizures and seizure-related disorders; and Mitochondrial myopathy and mitochondrial stress.

[237] In one modality, the disorder is a disorder that includes the process of fibrosis and / or inflammation.

[238] In one modality, the disorder is selected from Petition 870250090230, dated 03 / 10 / 2025, pp. 151 / 341 128 / 217 liver and kidney disorders.

[239] In one embodiment, the liver disorder is selected from: hepatic fibrosis, which occurs in end-stage liver disease; hepatic cirrhosis; liver failure due to toxicity; non-alcohol-associated or NASH hepatic steatosis; and alcohol-associated steatosis.

[240] In one form, the kidney disorder is renal fibrosis.

[241] In one form, renal fibrosis occurs as a result of acute kidney injury.

[242] In one form, the kidney disorder is a chronic kidney disorder.

[243] In one form, the kidney disorder is diabetic nephropathy.

[244] In another aspect, the disclosure provides a method of treating an age-related disorder or disease in an individual in need, the method comprising administering to the individual a therapeutically effective amount of a compound of Formula (I), (P-1), (P-2), (Ia)-(Ic) or (P-Ia)-(P-Ic), or of a pharmaceutically acceptable salt thereof, of a pharmaceutical composition comprising a compound of Formula (I), (P-1), (P-2), (Ia)-(Ic) or (P-Ia)-(P-Ic), or of 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 of a pharmaceutically acceptable salt thereof, wherein the disorder or disease is selected from: sarcopenia, skin atrophy, cherry angiomas, seborrheic keratoses, cerebral atrophy, Atherosclerosis, arteriosclerosis, pulmonary emphysema, osteoporosis, osteoarthritis, hypertension, erectile dysfunction, cataracts, macular degeneration, glaucoma.stroke, cerebrovascular disease (cerebrovascular accidents), chronic kidney disease, diabetic kidney disease, impaired liver function, liver fibrosis, autoimmune hepatitis, endometrial hyperplasia, Petition 870250090230, dated 03 / 10 / 2025, pp. 152 / 341 129 / 217 metabolic dysfunction, renovascular disease, hearing loss, motor impairment, cognitive decline, tendon stiffness, cardiac dysfunction such as cardiac hypertrophy and / or systolic and / or diastolic dysfunction and / or hypertension, cardiac dysfunction resulting in a decline in ejection fraction, immune senescence, Parkinson's disease, Alzheimer's disease, cancer, immune senescence leading to cancer due to decreased immune surveillance, infections due to a decline in immune function, chronic obstructive pulmonary disease (COPD), obesity, loss of taste, loss of smell, arthritis and type II diabetes, including complications arising from diabetes such as renal failure, blindness and neuropathy.

[245] In another aspect, the disclosure provides a method of treating cancer in an individual, the method comprising administering to the individual a therapeutically effective amount of a compound of Formula (I), (P-1), (P-2), (Ia)-(Ic) or (P-Ia)-(P-Ic), or of a pharmaceutically acceptable salt thereof, of a pharmaceutical composition comprising a compound of Formula (I), (P-1), (P-2), (Ia)-(Ic) or (P-Ia)-(P-Ic), or of 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 of a pharmaceutically acceptable salt thereof.

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

[247] In one embodiment, the cancer is selected from renal cancer, renal cell carcinoma, colorectal cancer, uterine sarcoma, uterine endometrial 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, Petition 870250090230, dated 03 / 10 / 2025, pp. 153 / 341 130 / 217 lymphoma and neck cancer.

[248] 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, 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, for use as a medicament.

[249] 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, 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, for use in the prevention or treatment of a disorder or disease mediated by the mTOR pathway.

[250] 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, 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, for use in the prevention or treatment of a selected disorder or disease of: - Acute or chronic rejection of organ or tissue transplantation; - Transplant vasculopathies; - Proliferation and migration of smooth muscle cells leading to thickening of the intima of blood vessels, causing vessel obstruction. Petition 870250090230, dated 03 / 10 / 2025, pp. 154 / 341 131 / 217 blood cells, obstructive coronary atherosclerosis, restenosis; Autoimmune diseases and inflammatory conditions; Asthma; Multidrug resistance (MDR); - Fungal infections; Inflammation; Infection; Age-related diseases; Neurodegenerative diseases; - Proliferative disorders, particularly cancer; - Seizures and seizure-related disorders; and Mitochondrial myopathy and mitochondrial stress.

[251] 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, 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, for use in the prevention or treatment of a disorder or disease that includes the process of fibrosis and / or inflammation.

[252] In one form, the disorder is selected from liver and kidney disorders.

[253] In one embodiment, the liver disorder is selected from: hepatic fibrosis, which occurs in end-stage liver disease; hepatic cirrhosis; liver failure due to toxicity; non-alcohol-associated or NASH hepatic steatosis; and alcohol-associated steatosis.

[254] In one form, the kidney disorder is renal fibrosis, which occurs as a result of acute kidney injury.

[255] In one form, the kidney disorder is a chronic kidney disorder. Petition 870250090230, dated 03 / 10 / 2025, pp. 155 / 341 132 / 217

[256] In one form, the kidney disorder is diabetic nephropathy.

[257] 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, 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, for use in the treatment of a selected age-related disorder or disease of sarcopenia, skin atrophy, cherry angiomas, seborrheic keratoses, cerebral atrophy (also referred to as dementia), atherosclerosis, arteriosclerosis, pulmonary emphysema, osteoporosis, Osteoarthritis, high blood pressure, erectile dysfunction, cataracts, macular degeneration, glaucoma, stroke, cerebrovascular disease (strokes), chronic kidney disease, diabetic kidney disease.Impaired liver function, hepatic fibrosis, autoimmune hepatitis, endometrial hyperplasia, metabolic dysfunction, renovascular disease, hearing loss, motor impairment (e.g., frailty), cognitive decline, tendon stiffness, cardiac dysfunction such as cardiac hypertrophy and / or systolic and / or diastolic dysfunction and / or hypertension, cardiac dysfunction resulting in a decline in ejection fraction, immune senescence, Parkinson's disease, Alzheimer's disease, cancer, immune senescence leading to cancer due to decreased immune surveillance, infections due to a decline in immune function, chronic obstructive pulmonary disease (COPD), obesity, loss of taste, loss of smell, arthritis, and type II diabetes (including complications arising from diabetes such as renal failure, blindness, and neuropathy).

[258] In another aspect, the revelation provides a compound of Petition 870250090230, dated 03 / 10 / 2025, pp. 156 / 341 133 / 217 Formula (I), (P-1), (P-2), (Ia)-(Ic) or (P-Ia)-(P-Ic), or a pharmaceutically acceptable salt thereof, 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, for use in the treatment of cancer.

[259] 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, 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, for use in the treatment of renal cancer, renal cell carcinoma, colorectal cancer, uterine sarcoma, uterine endometrial 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 neck cancer.

[260] In another aspect, the disclosure provides a use of a compound of Formula (I), (P-1), (P-2), (Ia)-(Ic) or (P-Ia)-(PIc), or of a pharmaceutically acceptable salt thereof for the manufacture of a medicament.

[261] In another aspect, the disclosure provides a use of a compound of Formula (I), (P-1), (P-2), (Ia)-(Ic) or (P-Ia)-(PIc), or of a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment of a disorder or disease mediated by the mTOR pathway. Petition 870250090230, dated 03 / 10 / 2025, pp. 157 / 341 134 / 217

[262] In another aspect, the disclosure provides a use of a compound of Formula (I), (P-1), (P-2), (Ia)-(Ic) or (P-Ia)-(PIc), or of a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment of a selected disorder or disease of: - Acute or chronic rejection of organ or tissue transplantation; - Transplant vasculopathies; - Proliferation and migration of smooth muscle cells leading to thickening of the intima of blood vessels, obstruction of blood vessels, obstructive coronary atherosclerosis, restenosis; Autoimmune diseases and inflammatory conditions; Asthma; Multidrug resistance (MDR); - Fungal infections; Inflammation; Infection; Age-related diseases; Neurodegenerative diseases; - Proliferative disorders, for example, cancer; - Seizures and seizure-related disorders; and Mitochondrial myopathy and mitochondrial stress.

[263] In another aspect, the disclosure provides a use of a compound of Formula (I), (P-1), (P-2), (Ia)-(Ic) or (P-Ia)-(PIc), or of a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the treatment of a disorder or disease which includes the process of fibrosis or inflammation.

[264] In one form, the disorder is selected from liver and kidney disorders.

[265] In one embodiment, the liver disorder is selected from: hepatic fibrosis, which occurs in end-stage liver disease; hepatic cirrhosis; liver failure due to toxicity; non-alcohol-associated fatty liver disease or NASH; Petition 870250090230, dated 03 / 10 / 2025, pp. 158 / 341 135 / 217 and steatosis associated with alcohol.

[266] In one form, the kidney disorder is renal fibrosis, which occurs as a result of acute kidney injury.

[267] In one form, the kidney disorder is a chronic kidney disorder.

[268] In one form, the kidney disorder is diabetic nephropathy.

[269] In another aspect, the disclosure provides a use of a compound of Formula (I), (P-1), (P-2), (Ia)-(Ic) or (P-Ia)-(PIc), or of a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the prevention or treatment of a selected age-related disorder or disease of sarcopenia, skin atrophy, cherry angiomas, seborrheic keratoses, cerebral atrophy (also referred to as dementia), atherosclerosis, arteriosclerosis, pulmonary emphysema, osteoporosis, osteoarthritis, hypertension, erectile dysfunction, cataracts, macular degeneration, glaucoma, stroke, cerebrovascular disease (cerebrovascular accidents), chronic kidney disease, diabetic kidney disease, impaired liver function, hepatic fibrosis, autoimmune hepatitis, endometrial hyperplasia, metabolic dysfunction, renovascular disease, hearing loss, motor impairment, cognitive decline, tendon stiffness, cardiac dysfunction such as, for example,Cardiac hypertrophy and / or systolic and / or diastolic dysfunction and / or hypertension, cardiac dysfunction resulting in a decline in ejection fraction, immune senescence, Parkinson's disease, Alzheimer's disease, cancer, immune senescence leading to cancer due to decreased immune surveillance, infections resulting from a decline in immune function, chronic obstructive pulmonary disease (COPD), obesity, loss of taste, loss of smell, arthritis, and type II diabetes (including complications arising from diabetes such as renal failure, blindness, and neuropathy). Petition 870250090230, dated 03 / 10 / 2025, pp. 159 / 341 136 / 217

[270] In another aspect, the disclosure provides a use of a compound of Formula (I), (P-1), (P-2), (Ia)-(Ic) or (P-Ia)-(PIc), or of a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the prevention or treatment of cancer.

[271] In another aspect, the disclosure provides a use of a compound of Formula (I), (P-1), (P-2), (Ia)-(Ic) or (P-Ia)-(PIc), or of a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the treatment of renal cancer, renal cell carcinoma, colorectal cancer, uterine sarcoma, uterine endometrial 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 neck cancer.

[272] The details of one or more forms of disclosure are presented in this descriptive report. Other features, objects and advantages of disclosure will become apparent from the Examples, Figures / Drawings and Claims. EXAMPLES

[273] Certain modalities of this disclosure are illustrated by the following non-limiting examples. As used in this descriptive report, the symbols and conventions used in these processes, schemes, and examples, regardless of whether a particular abbreviation is specifically defined, are consistent with those used in contemporary scientific literature, for example, in the "Journal of the American Chemical Society" or the "Journal of Biological Chemistry." Specifically, but without limitation, the following abbreviations may be used in the Examples, and throughout the descriptive report. Petition 870250090230, dated 03 / 10 / 2025, pp. 160 / 341 137 / 217 Abbreviation Term or phrase AcOH Acetic acid ACN Acetonitrile ADC Antibody-drug conjugate Aq. Aqueous DCM Dichloromethane DMF N,N-dimethylformamide DMSO Dimethyl sulfoxide Et2O Ethyl ether EtOAc Ethyl acetate g Gram HC Immunoglobulin heavy chain HPLC High-performance liquid chromatography hr, h Hours IC50 The concentration that provides 50% inhibition of target activity / signaling IC30 The concentration that provides 30% inhibition of target activity / signaling LC Immunoglobulin light chain mg milligrams min minutes ml milliliters μL microliters mM millimolar μM micromolar MW Molecular weight nM nanomolar NMR Nuclear magnetic resonance PABC Para-aminobenzyloxy(carbonyl) PEG Polyethylene glycol p TSA p-Toluenesulfonic acid ppm Parts per million (chemical shift, δ) RP Reversed phase rt Room temperature Sat. Saturated TEA Triethylamine TESOTf Triethylsilyl trifluoromethanesulfonate TMS Tetramethylsilane TFA Trifluoroacetic acid TG Transglutaminase THF Tetrahydrofuran. Petition 870250090230, dated 03 / 10 / 2025, pp. 161 / 341 138 / 217 Example 1. Synthesis of 32-desoxorrapaiaicin: Intermediate 1 1)LTBA, THF -78--15 °C, 2 hours later 0 °C, 1 hour 2) Cu(OAc)2MeOH 0 °C, 1 h Step 2 Intermediate 2 Intermediate 3 Intermediate 4 32-deoxorrapimycin Petition 870250090230, dated 03 / 10 / 2025, pp. 162 / 341 139 / 217

[274] Step 1: To a solution of rapamycin (20 g, 21.88 mmol) in DCM (280 ml) were added 2,6-lutidine (15.29 ml, 131.26 mmol) and TESOTf (14.84 ml, 65.63 mmol) at -40°C and stirred for 1.5 h. The resulting mixture was diluted with Et2O and quenched with saturated aqueous NaHCO3. The organic phase was separated and washed with saturated aqueous NaHCO3, saturated aqueous CuSO4, and saturated aqueous NH4Cl. The combined aqueous phase was extracted again with Et2O. The combined organic phase was washed with saturated aqueous CuSO4 and then dried with MgSO4, filtered, and concentrated under vacuum.The residue was dissolved in DCM and subjected to an ISCO silica column and eluted with a gradient of 0 to 25% EtOAc / hexane to obtain 95% 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)propan-2-yl)-6,8,12,14,20,26hexamethyl-9-((tr ietilsilil)óxi)9,10,12,13,14,21,22,23,24,25,26,27,32,33,34,34a-hexadecahydro3H-23,27-epoxypyrido[2,1-c][1]oxa[4]azacyclohentriacontina1,5,11,28,29(4H,6H,31H)-pentaone) as a white solid. The 1H-NMR data were matched with the reference (i.e., Tetrahedron Letters, 1994, 35(41), 7557-7560).

[275] 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)-6,8,12,14,20,26hexamethyl-9-((triethylsilyl)oxy)5,6,9,10,12,13,14,21,22,23,24,25,26,27,32,33,34,34aoctadecahydro-3H-23,27-epoxypyrido[2,1c][1]oxa[4]azacyclohentriacontina-1,11,28,29(4H,31H)-tetraone) was made following the procedure in Patent WO 96 / 41807 and the data de1H-MRN were matched.

[276] Step 3: Intermediate product 3 ((3S,5R,6R,7E,9R,10R,12R,14S,15E,17E,19E,21S,23S,26R,27R,34aS) Petition 870250090230, dated 03 / 10 / 2025, pp. 163 / 341 140 / 217 -27-hydroxy-10,21-dimethoxy-3-((R)-1-((1S, 3R, 4R)-3-methoxy-4((triethylsilyl)oxy)cyclohexyl)propan-2-yl)-6, 8, 12, 14,20,26hexamethyl-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, 32,33,3 4,34a-tetracosahydro-3H-23, 27-epoxypyrido[2, 1c][1]oxa[4]azacyclohentriacontin-5-yl The methanesulfonate assay was performed following the procedure in Patent WO 96 / 41807, and the 1H-NMR data matched.

[277] 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)-3methoxy-4-((triethylsilyl)oxy)cyclohexyl)propan-2-yl)6,8,12,14,20,26-hexamethyl-9-((triethylsilyl)oxy)5,6,9,10,12,13,14,21,22,23,24,25,26,27,32,33,34,34aoctadecahydro-3H-23, 27-epoxypyrido[2,1c][1]oxa[4]azacyclohentriacontina-1,11,28,29(4H,31H)-tetraone) was prepared following the procedure in Patent WO 96 / 41807 and the 1H-NMR data were matched.

[278] 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)-6,8,12,14,20,26hex ametil-9-((triethylsilyl)oxy)5,6,9,10,12,13,14,21,22,23,24,25,26,27,32,33,34,34aoctadecahydro-3H-23,27-epoxypyrido[2,1c][1]oxa[4]azacyclohentriacontina-1,11,28,29(4H,31H)-tetraone was made following the procedure in Patent WO 96 / 41807 and the 1H-NMR data were matched.

[279] Step 6: 32-deoxorrapamycin was made following the procedure in Patent WO 96 / 41807. Purification was performed by ISO silica column eluting with a gradient of 40 to 60% EtOAc / Hexane to generate 95% product as a white solid. 1H-NMR and mass data were matched with the reference. Petition 870250090230, dated 03 / 10 / 2025, pp. 164 / 341 141 / 217 Example 2. Synthesis of representative 32-desoxorrapamycin analogs

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

[281] General Condition B1: To a solution of 32-deoxorrapamycin (30.0 mg, 0.0333 mmol) and the appropriate amine nucleophile (20 equivalents) in DCM (0.67 ml) was added pTSA^H2O (5 equivalents) at room temperature. The reaction was stirred at room temperature until 32-deoxorrapamycin was consumed. The resulting mixture was diluted with EtOAc and quenched with saturated aqueous NaHCO3. The organic phase was separated and the aqueous phase was extracted with EtOAc three times. The combined organic phase was dried with Na2SO4, filtered, and concentrated under vacuum. The residue was dissolved in DMF and subjected to a C18 RP ISCO column and eluted with a 60 to 85% ACN / water gradient (+ 0.05% AcOH as the modifier) ​​to obtain the product. Compound 3: Petition 870250090230, dated 03 / 10 / 2025, pp. 165 / 341 142 / 217

[282] General condition A1 was applied. The procedure was modified with 20 triazole equivalents and 15 ZnCl2 equivalents. An additional 1.0 ml of ACN was added as the cosolvent. The reaction was stirred at 39°C for 5 days to complete. Compound 3 was isolated at 6.1% as a white solid. Calculated mass 936.58, found 935.93 (MH)-.

[283] General condition A1 was applied. The procedure was modified with 10 equivalents of pyrazole and 10 equivalents of ZnCl2. The reaction was stirred at room temperature for 2 days to complete. Compound 4 was isolated at 13% as a white solid. Calculated mass 935.59, found 934.93 (MH)-. Compound 5: Petition 870250090230, dated 03 / 10 / 2025, pp. 166 / 341 143 / 217

[284] General condition A1 was applied. The reaction was stirred at room temperature for 2 h to complete. Compound 5 was isolated at 32% as a white solid. Calculated mass 1002.5g, found 1001.9g (MH)-. Compound 6:

[285] General condition A1 was applied. The procedure was modified with 30 equivalents of triazole and 10 equivalents of ZnCl2. A further 2.0 ml of THF was added as the cosolvent. The reaction was stirred at 39°C for 2 days to complete. Compound 6 was isolated at 10% as a white solid. Calculated mass 936.58, found 938.06 (M+H)+. Compound 8: Petition 870250090230, dated 03 / 10 / 2025, pp. 167 / 341 144 / 217

[286] General condition A1 was applied. The procedure was modified with 20 equivalents of tetrazole and 15 equivalents of ZnCl2. The reaction was stirred at room temperature for 1 h to complete. Compound 8 was isolated at 11% as a white solid. Calculated mass 937.58, found 939.05 (M+H)+. Compound 9:

[287] General condition A1 was applied. The reaction was stirred at room temperature for 2 h to complete. Compound 9 was isolated at 25% as a white solid. Calculated mass 1004.60, found 1004.04 (MH)-. Compound 10: Petition 870250090230, dated 03 / 10 / 2025, pp. 168 / 341 145 / 217

[288] General condition A1 was applied. The reaction was stirred at room temperature for 2 h to complete. Compound 10 was isolated at 18% as a white solid. Calculated mass 990.59, found 989.68 (MH)-. Compound 11:

[289] General condition A1 was applied. A further 0.6 ml ACN was added as the cosolvent. The reaction was stirred at room temperature for 6 h to complete. Compound 11 was isolated at 9.5% as a white solid. Calculated mass 1006.58, found 1006.06 (MH)-. Compound 12: Petition 870250090230, dated 03 / 10 / 2025, pp. 169 / 341 146 / 217

[290] General condition A1 was applied. An additional 0.6 ml ACN was added as the cosolvent. The reaction was stirred at room temperature for 2 h to complete. Compound 12 was isolated at 8.3% as a white solid. Calculated mass 1005.63, found 1006.73 (M+H)+. Compound 13:

[291] General condition A1 was applied. An additional 0.6 ml ACN was added as the cosolvent. The reaction was stirred at room temperature for 16 h to complete. Compound 14 was isolated at 22% as a white solid. Calculated mass 991.61, found 991.01 (MH)-. Petition 870250090230, dated 03 / 10 / 2025, pp. 170 / 341 147 / 217

[292] General condition A1 was applied. The procedure was modified with 10 equivalents of sulfonamide and 6 equivalents of ZnCl2. The reaction was stirred at room temperature for 5 days to complete. Compound 14 was isolated at 11% as a yellow solid. Calculated mass 951.58, found 950.89 (MH)-. Compound 15:

[293] General condition A1 was applied. The reaction was stirred at room temperature for 16 h to complete. Compound 15 was isolated at 5.7% as a white solid. Calculated mass 978.63, found 979.92 (M+H)+.

[294] The following compounds were prepared by means of Petition 870250090230, dated 03 / 10 / 2025, pp. 171 / 341 148 / 217 General condition A2, B2, C2, D2 or E2.

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

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

[297] General condition C2: To a solution of 32-desoxorrapamycin (30.0 mg, 0.0333 mmol) and the appropriate amine nucleophile (10 equivalents) in THF (0.67 ml) was added BF3^Et2O (15 equivalents) at room temperature. The reaction was stirred at room temperature until 32-desoxorrapamycin was consumed. The resulting mixture was diluted with EtOAc and quenched with saturated aqueous NaHCO3. The organic phase was separated and the aqueous phase was extracted with EtOAc three times. The phase Petition 870250090230, dated 03 / 10 / 2025, page 172 / 341 149 / 217 combined organic material was dried with Na2SO4, filtered, and concentrated under vacuum. The residue was dissolved in DMF and subjected to a C18 RP ISCO column and eluted with a gradient of (30-60) to (80-90)% ACN / water (+ 0.05% AcOH as the modifier) ​​to obtain the product.

[298] General Condition D2: To a solution of 32-deoxorrapamycin (60.0 mg, 0.0667 mmol) and the appropriate amine nucleophile (10 equivalents) in DCM / ACN(1:1) (2.7 ml) Zn(OTf)2 (6 equivalents) was added at room temperature. The reaction was stirred at room temperature until all 32-deoxorrapamycin was consumed. The resulting mixture was diluted with EtOAc and quenched with saturated aqueous NaHCO3. The organic phase was separated and the aqueous phase was extracted with EtOAc three times. The combined organic phase was dried with Na2SO4, filtered, and concentrated under vacuum. The residue was dissolved in DMF and subjected to a C18 RP ISCO column and eluted with a 50 to 95% ACN / water gradient (+ 0.05% AcOH as the modifier) ​​to obtain the product.

[299] General Condition E2: To a solution of 32-desoxorrapamycin (60.0 mg, 0.0667 mmol) and the appropriate amine nucleophile (10 equivalents) in DCM (3 ml) at -40°C, TFA (20 equivalents) was added and the reaction was allowed to warm to room temperature. The reaction was stirred at room temperature until 32-desoxorrapamycin was consumed. The resulting mixture was diluted with EtOAc and quenched with saturated aqueous NaHCO3. The organic phase was separated and the aqueous phase was extracted with EtOAc three times. The combined organic phase was dried with Na2SO4, filtered, and concentrated under vacuum. The residue was dissolved in DMF and subjected to a C18 RP ISCO column and eluted with a 30 to 80% ACN / water gradient (+ 0.05% AcOH as the modifier) ​​to obtain the product. Compound 16: Petition 870250090230, dated 03 / 10 / 2025, page 173 / 341 150 / 217

[300] General condition A2 was applied. To a solution of 32-deoxorrapamycin (30.0 mg, 0.0333 mmol) and sulfonamide nucleophile (10 equivalents) in DCM (0.67 ml) was added ZnCl2 (10 equivalents, 1.0 M solution in Et2O) at room temperature. The reaction was stirred until 32-deoxorrapamycin was consumed. The resulting mixture was diluted with EtOAc and quenched with saturated aqueous NaHCO3. The organic phase was separated and the aqueous phase was extracted with EtOAc three times. The combined organic phase was dried with Na2SO4, filtered, and concentrated under vacuum. The residue was dissolved in DMF and subjected to a C18 RP ISCO column and eluted with a gradient of (30-60) to (80-90)% ACN / water (+ 0.05% TFA as the modifier) ​​to obtain the product. The reaction was stirred for 1 h to complete. Compound 16 was isolated and repurified by a 150 x 30 Phenomenex Gemini reversed-phase column eluted with 40 to 80% to yield a product as a pure white solid in 15.5% and a mixture in 30.2% yield.Calculated mass 1023.56, found 1024.56 (MH)-. Petition 870250090230, dated 03 / 10 / 2025, pp. 174 / 341 151 / 217

[301] General condition A2 was applied. To a solution of 32-desoxorrapamycin (30.0 mg, 0.0333 mmol) and sulfonamide nucleophile (10 equivalents) in DCM (0.67 ml) was added ZnCl2 (10 equivalents, 1.0 M solution in Et2O) at room temperature. The reaction was stirred until 32-desoxorrapamycin was consumed. The resulting mixture was diluted with EtOAc and quenched with saturated aqueous NaHCO3. The organic phase was separated and the aqueous phase was extracted with EtOAc three times. The combined organic phase was dried with Na2SO4, filtered and concentrated under vacuum. The residue was dissolved in DMF and subjected to a C18 RP ISCO column and eluted with a gradient of (30-60) to (80-90)% ACN / water (+ 0.05% TFA as the modifier) ​​to obtain the product. The reaction was stirred for 4 days to complete. Compound 17 was isolated and repurified by a 150 x 30 Phenomenex Gemini reversed-phase column eluted with 35 to 75% to yield product as a pure white solid in 1.4% and a mixture in 5% yield.Calculated mass 1026.57, found 1027.30 (M+H)+. Compound 18: HO,,40. Me 32

[302] General condition C2 was applied. To a solution of 32-deoxorrapamycin (30.0 mg, 0.0333 mmol) and sulfonamide nucleophile (10 equivalents) in THF (0.67 ml) was added BF3^Et2O (15 equivalents) at room temperature. The reaction was Petition 870250090230, dated 03 / 10 / 2025, page 175 / 341 152 / 217 was stirred at room temperature until 32-deoxorrapamycin was consumed. The resulting mixture was diluted with EtOAc and quenched with saturated aqueous NaHCO3. The organic phase was separated and the aqueous phase was extracted with EtOAc three times. The combined organic phase was dried with Na2SO4, filtered, and concentrated under vacuum. The residue was dissolved in DMF and subjected to a C18 RP ISCO column and eluted with a gradient of (30-60) to (80-90)% ACN / water (+ 0.05% AcOH as the modifier) ​​to obtain the product. The reaction was stirred for 5 hours to complete. Compound 18 was isolated and repurified by a 150 x 30 Phenomenex Gemini reversed-phase column eluted with 30 to 80% to yield a product as a light yellow solid in 12.4% yield. Calculated mass 1024.56, found 1025.13 (MH)-.

[303] General condition C2 was applied. To a solution of 32-desoxorrapamycin (30.0 mg, 0.0333 mmol) and sulfonamide nucleophile (10 equivalents) in THF (0.67 ml) was added BF3^Et2O (15 equivalents) at room temperature. The reaction was stirred at room temperature until 32-desoxorrapamycin was consumed. The resulting mixture was diluted with EtOAc and Petition 870250090230, dated 03 / 10 / 2025, page 176 / 341 153 / 217 quenched with saturated aqueous NaHCO3. The organic phase was separated and the aqueous phase was extracted with EtOAc three times. The combined organic phase was dried with Na2SO4, filtered, and concentrated under vacuum. The residue was dissolved in DMF and subjected to a C18 RP ISCO column and eluted with a gradient of (30-60) to (80-90)% ACN / water (+ 0.05% AcOH as the modifier) ​​to obtain the product. The reaction was stirred for 5 hours to complete. Compound 19 was isolated and repurified by a 150 x 30 Phenomenex Gemini reversed-phase column eluted with 30 to 80% to yield a product as a light yellow solid in 7% yield. Calculated mass 1024.56, found 1026.46 (MH)-. Compound 20:

[304] General condition A was applied. ZnCl2 (15 equivalents) and ACN (0.67 ml) were added to the reaction and the reaction was stirred for 3 days to complete. Compound 20 was isolated and repurified by a 150 x 30 Phenomenex Gemini reversed-phase column eluted with 40 to 80% to yield a product as a yellow solid in 7.3% yield. Calculated mass 962.61, found 963.31 (M+H)+. Compound 21: Petition 870250090230, dated 03 / 10 / 2025, page 177 / 341 154 / 217 BF3^Et2O (15 equivalents) was added to 10 equivalents in THF (0.67 ml) at room temperature. The reaction was stirred at room temperature until 32-deoxorrapamycin was consumed. The resulting mixture was diluted with EtOAc and quenched with saturated aqueous NaHCO3. The organic phase was separated, and the aqueous phase was extracted three times with EtOAc. The combined organic phase was dried with Na2SO4, filtered, and concentrated under vacuum. The residue was dissolved in DMF and subjected to a C18 RP ISCO column and eluted with a gradient of (30-60) to (80-90)% ACN / water (+ 0.05% AcOH as the modifier) ​​to obtain the product. The reaction was stirred for 3 hours to complete. Compound 21 was isolated and repurified by a 150 x 30 Phenomenex Gemini reversed-phase column eluted with 30 to 80% to yield product as a white solid in 9% yield and a mixture in 10.2% yield. Calculated mass 962.61, found 963.31 (M+H)+. Compound 22: Petition 870250090230, dated 03 / 10 / 2025, pp. 178 / 341 155 / 217

[306] General condition C2 was applied. To a solution of 32-deoxorrapamycin (30.0 mg, 0.0333 mmol) and the corresponding amine nucleophile (10 equivalents) in THF (0.67 ml) was added BF3^Et2O (15 equivalents) at room temperature. The reaction was stirred at room temperature until 32-deoxorrapamycin was consumed. The resulting mixture was diluted with EtOAc and quenched with saturated aqueous NaHCO3. The organic phase was separated and the aqueous phase was extracted with EtOAc three times. The combined organic phase was dried with Na2SO4, filtered and concentrated under vacuum. The residue was dissolved in DMF and subjected to a C18 RP ISCO column and eluted with a gradient of (30-60) to (80-90)% ACN / water (+ 0.05% AcOH as the modifier) ​​to obtain the product. The reaction was stirred for 3 hours to complete.Compound 22 was isolated and repurified by a 150 x 30 Phenomenex Gemini reversed-phase column eluted with 30 to 80% to yield product as a white solid in 1.54% yield and a mixture in 2.89% yield. Calculated mass 962.61, found 963.28 (M+H)+. Compound 23: Me THE

[307] General condition E2 was applied. To a solution of 32-deoxorrapamycin (60.0 mg, 0.0667 mmol) and amine nucleophile (10 equivalents) in DCM (3 ml) at -40°C, TFA (20 equivalents) was added and allowed to warm to room temperature. The reaction was stirred at room temperature until Petition 870250090230, dated 03 / 10 / 2025, page 179 / 341 156 / 217 32-deoxorrapamycin was consumed. The resulting mixture was diluted with EtOAc and quenched with saturated aqueous NaHCO3. The organic phase was separated and the aqueous phase was extracted with EtOAc three times. The combined organic phase was dried with Na2SO4, filtered, and concentrated under vacuum. The residue was dissolved in DMF and subjected to a C18 RP ISCO column and eluted with a 30 to 80% ACN / water gradient (+ 0.05% AcOH as the modifier) ​​to obtain the product. The reaction was stirred for 19 hours to complete. Compound 23 was isolated and repurified by a 150 x 30 Phenomenex Gemini reversed-phase column eluted with 30 to 80% to yield product as a brown solid in 7.6% yield and a mixture in 5.6% yield. Calculated mass 965.62, found 966.35 (M+H)+. Compound 24: Me THE

[308] General condition E2 was applied. To a solution of 32-desoxorrapamycin (60.0 mg, 0.0667 mmol) and amine nucleophile (10 equivalents) in DCM (3 ml) at -40°C, TFA (20 equivalents) was added and allowed to warm to room temperature. The reaction was stirred at room temperature until 32-desoxorrapamycin was consumed. The resulting mixture was diluted with EtOAc and quenched with saturated aqueous NaHCO3. The organic phase was separated and the aqueous phase was extracted with EtOAc three times. The combined organic phase was dried with Na2SO4, filtered, and concentrated under vacuum. The residue was dissolved in DMF. Petition 870250090230, dated 03 / 10 / 2025, pp. 180 / 341 157 / 217 and submitted to a C18 RP ISCO column and eluted with a gradient of 30 to 80% ACN / water (+ 0.05% AcOH as the modifier) ​​to obtain the product. The reaction was stirred for 2 hours to complete. Compound 24 was isolated and repurified by a 150 x 30 Phenomenex Gemini reversed-phase column eluted with 30 to 80% to yield product as a brown solid in 14.9% yield and a mixture in 21.6% yield. Calculated mass 950.57, found 951.08(MH)-. Compound 26

[309] (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-3methoxycyclohexyl)propan-2-yl)-10-methoxy-6,8,12,14,20,26hexamethyl-21-(phenylamino)5,6,9,10,12 ,13,14,21,22,23,24,25,26,27,32,33,34,34aoctadecahydro-3H-23,27-epoxypyrido[2,1c][1]oxa[4]azacyclohentriacontine-1,11,28,29(4H,31H)-tetraone; 16-Aniline-32-desoxorrapamycin: Me 32 1

[310] Aniline (0.080 ml, 0.888 mmol) and TFA (0.136 ml, 1.776 mmol) were added to a stirred solution of 32-deoxorrapamycin (80 mg, 0.088 mmol) in DCM (2 ml) at -20°C and stirred for 2 h. The resulting mixture was diluted with EtOAc and quenched with saturated aqueous NaHCO3. The aqueous layer was extracted with EtOAc and the combined organic layers were dried with Na2SO4, filtered and concentrated under reduced pressure. The crude product was Petition 870250090230, dated 03 / 10 / 2025, pp. 181 / 341 158 / 217 dissolved in DMF and subjected to a C18 ISCO column and eluted with 60-80% ACN / H2O. The pure product fractions were lyophilized to yield 7.3 mg (9%) of the white solid Compound 26. MS (ESI) calculated for C56H84N2O11 + H = 960.61, found to be 960.08. Compound 27

[311] (3S,6S,7E,9R,10R, 12R, 14S,15E,17E,19E,23S,26R,27R, 34aS )-9,27-diidróxi-3-((R)-1-((1S,3R,4R)-4-hidróxi-3methoxyciclohexyl)propan-2-yl)-10-metóxi-6,8,12,14,20,26hexametil-21-((5-methylisoxazol-3-yl)amino)5,6 ,9,10,12,13,14,21,22,23,24,25,26,27,32,33,34,34aoctadecahidro-3H-23,27-epoxipirido[2,1c][1]oxa[4]azaciclohentriacontina-1,11,28,29(4H,31H)-tetraone; 16-(3-Amino-5-Methylisoxazol)-32-desoxorrapamycin:

[312] To a stirred solution of 32-deoxorrapamycin (80 mg, 0.088 mmol) in DCM (2 ml) were added 3-amino-5-methylisoxazole (87 mg, 0.888 mmol) and TFA (0.136 ml, 1.779 mmol) at -20°C and stirred for 2 h. The resulting mixture was diluted with EtOAc and quenched with saturated aqueous NaHCO3. The aqueous layer was extracted with EtOAc and the combined organic layers were dried with Na2SO4, filtered and concentrated under reduced pressure. The crude product was dissolved in DMF and subjected to a C18 ISCO column and eluted with 60-80% ACN / H2O. The pure product fractions were lyophilized to yield 5.8 mg (7%) of the white solid. Petition 870250090230, dated 03 / 10 / 2025, pp. 182 / 341 159 / 217 Compound 27. MS (ESI) calculated for C54H83N3O12 + H = 965.61, found to be 965.10. Compound 28

[313] (3S,6S,7E,9R,10R, 12R, 14S,15E,17E,19E,23S,26R,27R, 34aS )-9,27-diidróxi-3-((R)-1-((1S,3R,4R)-4-hidróxi-3methoxyciclohexyl)propan-2-yl)-10-metóxi-6,8,12,14,20,26hexametil-21-((6-methylpyrazin-2-yl)amino)5,6 ,9,10,12,13,14,21,22,23,24,25,26,27,32,33,34,34aoctadecahidro-3H-23,27-epoxipirido[2,1c][1]oxa[4]azaciclohentriacontina-1,11,28,29(4H,31H)-tetraone; 16-(2-Amino-6-methylpyrazine)-32-desoxorrapamycin:

[314] To a stirred solution of 32-deoxorrapamycin (50 mg, 0.055 mmol) in DCM (2 ml) were added 2-amino-6-methylpyrazine (61 mg, 0.555 mmol) and TFA (0.085 ml, 1.112 mmol) at -20°C and stirred for 2 h. The resulting mixture was diluted with EtOAc and quenched with saturated aqueous NaHCO3. The aqueous layer was extracted with EtOAc and the combined organic layers were dried with Na2SO4, filtered and concentrated under reduced pressure. The crude product was dissolved in DMF and subjected to a C18 ISCO column and eluted with 60-80% ACN / H2O. The pure product fractions were lyophilized to yield 7.2 mg (13%) of the white solid Compound 28. MS (ESI) calculated for C55H84N4O11 + H = 976.61, found to be 976.31. Petition 870250090230, dated 03 / 10 / 2025, pp. 183 / 341 160 / 217 Compound 29

[315] (3S,6S,7E,9R,10R, 12R, 14S,15E,17E,19E,23S,26R,27R, 34aS )-9,27-diidróxi-3-((R)-1-((1S,3R,4R)-4-hidróxi-3methoxyciclohexyl)propan-2-yl)-10-metóxi-6,8,12,14,20,2 6hexametil-21-((1-metil-1H-pyrazol-5-yl)amino)5,6,9,10,12,13,14,21,22,23,24,25,26,27,32,33,34,34aoctadecahydro-3H-23,27-epoxypyrido[2,1- c][1]oxa[4]azaciclohentriacontina-1,11,28,29(4H,31H)-tetraone

[316] To a stirred solution of 32-deoxorrapamycin (60 mg, 0.066 mmol) in DCM (2 ml) were added 1,2,5-oxadiazol-3-amine (66 mg, 0.666 mmol) and TFA (0.102 ml, 1.322 mmol) at -20°C and stirred for 2 h. The resulting mixture was diluted with EtOAc and quenched with saturated aqueous NaHCO3. The aqueous layer was extracted with EtOAc and the combined organic layers were dried with Na2SO4, filtered and concentrated under reduced pressure. The crude product was dissolved in DMF and subjected to a C18 ISCO column and eluted with 60-80% ACN / H2O. The pure product fractions were lyophilized to yield 1.3 mg (2%) of the white solid. MS (ESI-) calculated for C52H80N4O12 - H = 964.61, found to be 964.11. Compound 30

[317] (3S,6S,7E,9R,10R,12R,14S,15E,17E,19E,23S,26R,27R,34aS )-21-((1,2,4-oxadiazol-3-yl)amino)-9,27-dihydroxy-3-((R)-1((1S,3R,4R)-4-hydroxy-3-methoxycyclohexyl)propan-2-yl)-10- Petition 870250090230, dated 03 / 10 / 2025, pp. 184 / 341 161 / 217 methoxy-6,8,12,14,20,26-hexamethyl5,6,9,10, 12, 13,14,21,22,23,24,25,26,27,32,33, 34,34aoctadecahydro-3H-23, 27-epoxypyrido[2, Ιο] [1]oxa[4]azacyclohentriacontin-1,11,28,29(4H,31H)-tetraone; (16-(1,2,4-Oxadiazol-3-amine)-32-deoxorrapamycin:

[318] To a stirred solution of 32-deoxorrapamycin (50 mg, 0.055 mmol) in DCM (2 ml) were added 1,2,4-oxadiazol-3-amine (55 mg, 0.555 mmol) and TFA (0.085 ml, 1.112 mmol) at -20°C and stirred for 2 h. The resulting mixture was diluted with EtOAc and quenched with saturated aqueous NaHCO3. The aqueous layer was extracted with EtOAc and the combined organic layers were dried with Na2SO4, filtered and concentrated under reduced pressure. The crude product was dissolved in DMF and subjected to a C18 ISCO column and eluted with 60-80% ACN / H2O. The pure product fractions were lyophilized to yield 5.3 mg (10%) of the white solid Compound 30. MS (ESI) calculated for C52H80N4O12 + H = 952.58, found to be 952.17. Additional compounds are synthesized as described below. Compound 31: Petition 870250090230, dated 03 / 10 / 2025, pp. 185 / 341 162 / 217

[319] To a solution of 32-deoxorrapamycin (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) was added dimethylphosphinic chloride (12.5 mg, 0.111 mmol) at 0°C and stirred for 2 h. The resulting mixture was diluted with EtOAc and quenched with saturated aqueous NaHCO3. The organic phase was separated and the aqueous phase was extracted with EtOAc three times. The combined organic phase was dried with Na2SO4, filtered and concentrated under vacuum. The residue was dissolved in DCM and subjected to an ISCO silica column and eluted with a 0 to 100% acetone / hexane gradient to obtain 65% of Compound 31 as a white solid. Calculated mass 975.58, found 974.69(MH)-.

[320] General condition A1 was applied. The reaction was stirred for 2 h to complete. Compound 32 was isolated at 21% as a Petition 870250090230, dated 03 / 10 / 2025, pp. 186 / 341 163 / 217 white solid. Calculated mass 974.55, found 973.25(MH)-.

[321] General condition B1 was applied. The reaction was stirred for 0.5 h to complete. Compound 33 was isolated in 53% as a white solid. Calculated mass 988.57, found 987.19(MH)-.

[322] To a solution of 32-deoxorrapamycin (20.0 mg, 0.0222 mmol) and 2,6-lutidine (6.4 pl, 0.0556 mmol) in DCM (0.28 ml) Tf2O (6.0 pl, 0.0333 mmol) was added at -30°C and stirred for 30 min. The reaction was heated to 0°C and stirred for a further 30 min. Then, 1-H-tetrazole (5.4 mg, 0.0778 mmol) and DIPEA (0.019 ml, 0.111 mmol) were added to the solution and stirred at room temperature for 16 hours. The resulting mixture was diluted with EtOAc and quenched with saturated aqueous NaHCO3. The phase Petition 870250090230, dated 03 / 10 / 2025, pp. 187 / 341 164 / 217 organic matter was separated and the aqueous phase was extracted with EtOAc three times. The combined organic phase was dried with Na2SO4, filtered, and concentrated under vacuum. The residue was dissolved in DFM and subjected to a C18 RP ISCO column and eluted with a gradient of 50 to 100% ACN / water (+ 0.5% AcOH as a modifier) ​​to obtain 69% of Compound 34 as a yellow solid. Calculated mass 951.5g, found 951.26 (MH)-.

[323] General condition B1 was applied. The reaction was stirred for 2 days to complete. Compound 35 was isolated at 39% as a white solid. Calculated mass 967.61, found 966.88 (MH)-. Petition 870250090230, dated 03 / 10 / 2025, pp. 188 / 341 165 / 217

[324] To a solution of 40-phosphinate-32-deoxorrapamycin (19.0 mg, 0.0195 mmol) and sultama ethane (10.4 mg, 0.0974 mmol) in DCM (0.39 ml) was added ZnCl2 (0.0584 ml, 0.0584 mmol, 1.0 M solution in Et2O) at room temperature. The reaction was stirred at room temperature for 30 min. The resulting mixture was diluted with EtOAc and quenched with saturated aqueous NaHCO3. The organic phase was separated and the aqueous phase was extracted with EtOAc three times. The combined organic phase was dried with Na2SO4, filtered and concentrated under vacuum. The residue was dissolved in DMF and subjected to a C18 RP ISCO column and eluted with a gradient of 50 to 90% ACN / water (+ 0.5% AcOH as a modifier) ​​to obtain Compound 36 at 29% as a white solid. Calculated mass 1050.56, found 1049.67 (MH)-.

[325] To a solution of 40-dimethylphosphinate-32-deoxorrapamycin (Compound 31, 20.0 mg, 0.0205 mmol) and propyl sultama (24.8 mg, 0.205 mmol) in ACN (0.21 ml) was added pTSA^H2O (0.4 mg, 0.0021 mmol) at room temperature. The reaction was stirred at room temperature for 2 h. The resulting mixture was diluted with EtOAc and quenched with saturated aqueous NaHCO3. The organic phase was separated, and the aqueous phase was extracted with EtOAc three times. The combined organic phase was dried with Na2SO4, filtered, and concentrated under vacuum. The residue was dissolved in DMF and subjected to a C18 RP ISCO column and eluted with a gradient of 50 to Petition 870250090230, dated 03 / 10 / 2025, pp. 189 / 341 166 / 217 90% ACN / water (+ 0.5% AcOH as modifier) ​​to obtain Compound 37 at 49% as a white solid. Calculated mass 1064.58, found 1063.76 (MH)-.

[326] General condition A1 was applied. The reaction was stirred for 2 h to complete. Compound 38 was isolated at 20% as a white solid. Calculated mass 1026.57, found 1025.51 (MH).

[327] General condition B1 was applied. ACN was used as the solvent instead of DCM. The reaction was stirred for 1 h to complete. Compound 39 was isolated at 32% as a white solid. Calculated mass 1040.59, found 1063.85 (M+Na)+. Petition 870250090230, dated 03 / 10 / 2025, pp. 190 / 341 167 / 217

[328] General condition A1 was applied. The reaction was stirred at room temperature for 1 h to complete. Compound 40 was isolated at 19% as a white solid. Calculated mass 976.57, found 975.70 (MH)-. Compound 41:

[329] General condition A1 was applied. The procedure was modified with 10 equivalents of sulfonamide and 8 equivalents of ZnCl2. A further 2.0 ml of ACN were added as the cosolvent. The reaction was stirred at 39°C for 2 days to complete. Compound 41 was isolated at 4.9% as a white solid. Calculated mass 962.55, found 962.26 (MH)-. Compound 42: Petition 870250090230, dated 03 / 10 / 2025, pp. 191 / 341 168 / 217

[330] General condition A1 was applied. The procedure was modified with 20 equivalents of sulfonamide and 15 equivalents of ZnCl2. THF was used as the solvent instead of DCM. The reaction was stirred at 39°C for 5 days to complete. Compound 42 was isolated at 5.5% as a white solid. Calculated mass 988.57, found 987.94 (MH)-. Compound 43

[331] (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-methoxy6, 8, 12, 14,20,26-hexamethyl5,6,9,10,12,13,14,21,22,23,24,25,26,27,32,33,34,34aoctadecahydro-3 H-23,27-epoxypyrido[2,1c][1]oxa[4]azacyclohentriacontine-1,11,28,29(4H,31H)-tetraone Petition 870250090230, dated 03 / 10 / 2025, pp. 192 / 341 169 / 217

[332] To a stirred solution of 32-deoxorrapamycin (50 mg, 0.055 mmol) in DCM (2 ml) were added 3-chloroaniline (0.049 ml, 0.555 mmol) and TFA (0.085 ml, 1.112 mmol) at -20°C and stirred for 2 h. The resulting mixture was diluted with EtOAc and quenched with saturated aqueous NaHCO3. The aqueous layer was extracted with EtOAc and the combined organic layers were dried with Na2SO4, filtered and concentrated under reduced pressure. The crude product was dissolved in DMF and subjected to a C18 ISCO column and eluted with 60-80% ACN / H2O. The pure product fractions were lyophilized to yield 8.1 mg (15%) of the white solid Compound 43. MS (ESI-) calculated for C56H83CIN2O11 - H = 994.57, found to be 994.05. Compound 44

[333] (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-3methoxycyclohexyl)propan-2-yl)-10-methoxy-21-((3methoxyphenyl)amino)-6 ,8,12,14,20,26-hexamethyl5,6,9,10,12,13,14,21,22,23,24,25,26,27,32,33,34,34aoctadecahydro-3H-23,27-epoxypyrido[2,1- c][1]oxa[4]azacyclohentriacontin-1,11,28,29(4H,31H)-tetraone THE. HO.

[334] To a stirred solution of 32-desoxorrapamycin (50 mg, Petition 870250090230, dated 03 / 10 / 2025, pp. 193 / 341 170 / 217 Meta-anisidine (0.055 mmol) in DCM (2 ml) was added at -20°C and stirred for 2 h. The resulting mixture was diluted with EtOAc and quenched with saturated aqueous NaHCO3. The aqueous layer was extracted with EtOAc and the combined organic layers were dried with Na2SO4, filtered, and concentrated under reduced pressure. The crude product was dissolved in DMF and subjected to a C18 ISCO column and eluted with 60-80% ACN / H2O. The pure product fractions were lyophilized to yield 3.0 mg (5%) of the white solid Compound 44. MS (ESI-) calculated for C57H86N2O12 - H = 990.62, found to be 990.14. Compound 45

[335] (3S,6S,7E,9R,10R,12R,14S,15E,17E,19E,23S,26R,27R,34aS )-21-((1,2,5-oxadiazol-3-yl)amino)-9,27-dihydroxy-3-((R)-1((1S,3R,4R)-4-hydroxy-3-methoxycyclohexyl)propan-2-yl)-10methoxy-6,8,12,14,20,26-hexamethyl5,6 ,9,10,12,13,14,21,22,23,24,25,26,27,32,33,34,34aoctadecahydro-3H-23,27-epoxypyrido[2,1c][1]oxa[4]azacyclohentriacontine-1,11,28,29(4H,31H)-tetraone.

[336] To a stirred solution of 32-desoxorrapamycin (30 mg, 0.033 mmol) in DCM (2 ml) were added 1,2,5-oxadiazol-3-amine (30 mg, 0.333 mmol) and TFA (0.051 ml, 3.32 mmol) at -20°C and stirred for 2 h. The resulting mixture was diluted with EtOAc and Petition 870250090230, dated 03 / 10 / 2025, pp. 194 / 341 171 / 217 quenched with saturated aqueous NaHCO3. The aqueous layer was extracted with EtOAc and the combined organic layers were dried with Na2SO4, filtered and concentrated under reduced pressure. The crude product was dissolved in DMF and subjected to a C18 ISCO column and eluted with 60-80% ACN / H2O. The pure product fractions were lyophilized to yield 9.5 mg (30%) of the white solid Compound 45. MS (ESI-) calculated for C57H86N2O12 - H = 952.58, found to be 952.03. Compound 46.

[337] 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-3methoxycyclohexyl)propan-2-yl)-10-methoxy-6,8, 12, 14,20,2 6hexamethyl-1,11,28,29-tetraoxo1,4,5,6,9,10,11,12,13,14,21,22,23,24,25,26,27,28,29,31,32,33,3 4,34a-tetracosahydro-3H-23, 27-epoxypyrido[2, 1c][1]oxa[4]azacyclohentriacontin-21-yl)-3,5-dimethylisoxazol-4sulfonamide.

[338] To a stirred solution of 32-desoxorrapamycin (80 mg, 0.089 mmol) in DCM (2 ml) were added dimethyl-1,2-oxazol-4-sulfonamide (157 mg, 0.899 mmol) and ZnCl2 (0.889 ml, 0.889 mmol) at -20°C and stirred for 2 h. The resulting mixture was diluted with EtOAc and quenched with saturated aqueous NaHCO3. The aqueous layer was Petition 870250090230, dated 03 / 10 / 2025, pp. 195 / 341 172 / 217 extracted with EtOAc and the combined organic layers were dried with Na2SC>4, filtered and concentrated under reduced pressure. The crude product was dissolved in DMF and subjected to a C18 ISCO column and eluted with 60-80% ACN / H2O. The pure product fractions were lyophilized to yield 8.3 mg (9%) of the white solid Compound 46. MS (ESI-) calculated for C55H85N3O14S - H = 1043.58, found to be 1042.87. Compound 47

[339] (3S,6S,7E,9R,10R,12R,14S,15E,17E,19E,23S,26R,27R,34aS )-9,27-dihydroxy-3-((R)-1-((IS,3R,4R)-4-hydroxy-3methoxycyclohexyl)propan-2-yl)-10-methoxy-21-((4methoxyphenyl)amino)-6, 8, 12, 14,20, 26-hexamethyl- 5,6,9,10, 12, 13,14,21,22,23,24,25,26,27,32,33, 34,34aoctadecahydro-3H-23, 27-epoxypyrido[2, Ιο] [1] oxa[4]azacyclohentriacontin-1, 11,28,29(4H,31H)-tetraone.

[340] To a stirred solution of 32-deoxorrapamycin (50 mg, 0.055 mmol) in DCM (2 ml) were added para-anisidine (0.064 ml, 0.556 mmol) and TFA (0.085 ml, 1.112 mmol) at -20°C and stirred for 4 h. The resulting mixture was diluted with EtOAc and quenched with saturated aqueous NaHCO3. The aqueous layer was extracted with EtOAc and the combined organic layers were dried with Na2SO4, filtered and concentrated under reduced pressure. The crude product Petition 870250090230, dated 03 / 10 / 2025, pp. 196 / 341 173 / 217 was dissolved in DMF and subjected to a C18 ISCO column and eluted with 60-80% ACN / H2O. The pure product fractions were lyophilized to yield 2.0 mg (4%) of the white solid. MS (ESI-) calculated for C57H86N2O12 - H = 991.32, found to be 990.67. Compound 48.

[341] (3S,6S,7E,9R,10R,12R,14S,15E,17E,19E,23S,26R,27R,34aS )-21-((4-chlorophenyl) amino)-9,27-dihydroxy-3-((R)-1-((IS, 3R, 4R) 4-hydroxy-3-methoxycyclohexyl)propan-2-yl)-10-methoxy6,8,12,14,20,26-hexamethyl- 5,6,9,10, 12, 13,14,21,22,23,24,25,26,27,32,33, 34,34aoctadecahydro-3H-23, 27-epoxypyrido[2, Ιο] [1]oxa[4]azacyclohentriacontine-1,11,28,29(4H,31H)-tetraone. THE. HO,

[342] To a stirred solution of 32-deoxorrapamycin (50 mg, 0.055 mmol) in DCM (2 ml) were added 4-chloroaniline (0.050 ml, 0.556 mmol) and TFA (0.085 ml, 1.112 mmol) at -20°C and stirred for 2 h. The resulting mixture was diluted with EtOAc and quenched with saturated aqueous NaHCO3. The aqueous layer was extracted with EtOAc and the combined organic layers were dried with Na2SO4, filtered and concentrated under reduced pressure. The crude product was dissolved in DMF and subjected to a C18 ISCO column and eluted with 60-80% ACN / H2O. The pure product fractions were lyophilized to yield 5.2 mg (9%) of the white solid. MS (ESI-) calculated for C56H83CIN2O11 - H = 994.57, found to be 993.86. Petition 870250090230, dated 03 / 10 / 2025, pp. 197 / 341 174 / 217 Compound 49

[343] (3S,6S,7E,9R,10R,12R,14S,15E,17E,19E,23S,26R,27R,34aS )-9,27-dihydroxy-3-((R)-1-((IS,3R,4R)-4-hydroxy-3methoxycyclohexyl)propan-2-yl)-10-methoxy-6,8,12,14,20,26hexamethyl-21-(p-tolylamino)- 5,6,9,10, 12, 13,14,21,22,23,24,25,26,27,32,33, 34,34aoctadecahydro-3H-23, 27-epoxypyrido[2, Ιο] [1]oxa[4]azacyclohentriacontine-1,11,28,29(4H,31H)-tetraone.

[344] To a stirred solution of 32-deoxorrapamycin (50 mg, 0.055 mmol) in DCM (2 ml) were added para-toluidine (0.060 ml, 0.556 mmol) and TFA (0.085 ml, 1.112 mmol) at -20°C and stirred for 2 h. The resulting mixture was diluted with EtOAc and quenched with saturated aqueous NaHCO3. The aqueous layer was extracted with EtOAc and the combined organic layers were dried with Na2SO4, filtered and concentrated under reduced pressure. The crude product was dissolved in DMF and subjected to a C18 ISCO column and eluted with 60-80% ACN / H2O. The pure product fractions were lyophilized to yield 1.6 mg (3%) of the white solid. MS (ESI-) calculated for C57H86N2O11 - H = 974.62, found to be 973.76. Compound 50

[345] (3S,6S,7E,9R,10R,12R,14S,15E,17E,19E,23S,26R,27R,34aS )-9,27-dihydróxi-3-((R)-1-((IS,3R,4R)-4-hidróxi-3- Petition 870250090230, 03 / 10 / 2025, pág. 198 / 341 175 / 217 methoxycyclohexyl)propan-2-yl)-1O-metόχι-6, ​​8, 12, 14,20,26hexamethyl-21-(m-tolylamino)5,6,9,10, 12, 13,14,21,22,23,24,25,26,27,32,33, 34,34aoctadecahidro-3H-23, 27-epoxypirido[2, Ιο] [1]oxa[4]azacyclohentriacontine-1,11,28,29(4H,31H)-tetraona. OR. I HAVE,

[346] Meta-toluidine (0.060 ml, 0.556 mmol) and TFA (0.085 ml, 1.112 mmol) were added to a stirred solution of 32-deoxorrapamycin (50 mg, 0.055 mmol) in DCM (2 ml) at -20°C and stirred for 2 h. The resulting mixture was diluted with EtOAc and quenched with saturated aqueous NaHCO3. The aqueous layer was extracted with EtOAc and the combined organic layers were dried with Na2SO4, filtered, and concentrated under reduced pressure. The crude product was dissolved in DMF and subjected to a C18 ISCO column and eluted with 60-80% ACN / H2O. The pure product fractions were lyophilized to yield 2.5 mg (5%) of the white solid. MS (ESI-) calculated for C57H86N2O11 - H = 974.62, found to be 973.95. Compound 51

[347] N- ((3S,6S,7E,9R,10R,12R,14S,15E,17E,19E,23S,26R,27R,34aS)-9,27dihydroxy-3-((R)-1-((IS,3R,4R)-4-hydroxy-3methoxycyclohexyl)propan-2-yl)-10-methoxy-6, 8, 12, 14,20,26hexamethyl-1, 11, 28, 29-tetraoxoPetition 870250090230, of 10 / 03 / 2025, p. 176 / 217 1,4,5,6,9,10,11,12,13,14,21,22,23,24,25,26,27,28,29,31,32,33,3 4,34a-tetracosahydro-3H-23,27-epoxypyrido[2,1— c][1]oxa[4]azacyclohentriacontin-21-yl)-5-methylisoxazol-4sulfonamide.

[348] To a stirred solution of 32-deoxorrapamycin (80 mg, 0.089 mmol) in DCM (2 ml) were added 5-methyl-1,2-oxazol-4-sulfonamide (144 mg, 0.889 mmol) and ZnCl2 (0.889 ml, 0.889 mmol) at room temperature and stirred for 3 h. The resulting mixture was diluted with EtOAc and quenched with saturated aqueous NaHCO3. The aqueous layer was extracted with EtOAc and the combined organic layers were dried with Na2SO4, filtered and concentrated under reduced pressure. The crude product was dissolved in DMF and subjected to a C18 ISCO column and eluted with 60-80% ACN / H2O. The pure product fractions were lyophilized to yield 4.1 mg (9%) of the white solid. MS (ESI-) calculated for C54H83N3O14S - H = 1030.33, found to be 1029.16. Compound 52

[349] (3S,6S,7E,9R,10R,12R,14S,15E,17E,19E,23S,26R,27R,34aS )-9,27-dihydróxi-3-((R)-1-((IS,3R, 4R)-4-hidróxi-3methoxiciclohexil)propan-2-yl)-10-methóxi-6,8,12,14,20,26hexamethyl-21-(p-tolylamino)- 5,6,9,10, 12, 13,14,21,22,23,24,25,26,27,32,33, 34,34aPetição 870250090230, de 03 / 10 / 2025, pág. 200 / 341 177 / 217 octadecahidro-3H-23, 27-epoxypirido[2, Ιο] [1]oxa[4]azacyclohentriacontine-1,11,28,29(4H,31H)-tetraona.

[350] To a stirred solution of 32-deoxorrapamycin (50 mg, 0.055 mmol) in DCM (2 ml) were added aminopyrazine (53 mg, 0.556 mmol) and TFA (0.085 ml, 1.112 mmol) at -20°C and stirred for 2 h. The resulting mixture was diluted with EtOAc and quenched with saturated aqueous NaHCO3. The aqueous layer was extracted with EtOAc and the combined organic layers were dried with Na2SÜ4, filtered and concentrated under reduced pressure. The crude product was dissolved in DMF and subjected to a C18 ISCO column and eluted with 60-80% ACN / H2O. The pure product fractions were lyophilized to yield 4.2 mg (8%) of the white solid. MS (ESI-) calculated for C54H82N4O11 - H = 962.60, found to be 961.91. Compound 53

[351] N- ((3S,6S,7E,9R,10R,12R,14S,15E,17E,19E,23S,2 6R,2 7R,34aS)-9, 2 7dihydroxy-3-((R)-1-((IS,3R,4R)-4-hydroxy-3methoxycyclohexy1)propan-2-yl)-10-methoxy-6, 8, 12, 14,20,26hexamethyl-1, 11, 28, 29-tetraoxo1,4,5,6,9,10,11,12,13,14,21,22,23,24,25,26,27,28,29,31,32,33,3 4,34a-tetracosahydro-3H-23,27-epoxypyrido[2,ο] [1]oxa[4]azacyclohentriacontín-21-yl)-3-methylisoxazol-4Petition 870250090230, of 03 / 10 / 2025, p. 201 / 341 178 / 217 sulfonamide. KILL,

[352] To a stirred solution of 32-deoxorrapamycin (80 mg, 0.089 mmol) in DCM (2 ml) were added 3-methyl-1,2-oxazol-4-sulfonamide (144 mg, 0.889 mmol) and ZnCl2 (0.889 ml, 0.889 mmol) at room temperature and stirred for 3 h. The resulting mixture was diluted with EtOAc and quenched with saturated aqueous NaHCO3. The aqueous layer was extracted with EtOAc and the combined organic layers were dried with Na2SO4, filtered and concentrated under reduced pressure. The crude product was dissolved in DMF and subjected to a C18 ISCO column and eluted with 60-80% ACN / H2O. The pure product fractions were lyophilized to yield 1.7 mg (2%) of the white solid. MS (ESI-) calculated for C54H83N3O14S - H = 1030.33, found to be 1029.27. Compound 54

[353] (3S,6S,7E,9R,10R,12R,14S,15E,17E,19E,23S,26R,27R,34aS )-9,27-dihydroxy-3-((R)-1-((IS,3R, 4R)-4-hydroxy-3methoxycyclohexyl)propan-2-yl)-10-methoxy-6,8,12,14,20,26hexamethyl-21-((3-(trifluoromethyl)phenyl)amino)- 5,6,9,10, 12, 13,14,21,22,23,24,25,26,27,32,33, 34,34aoctadecahydro-3H-23, 27-epoxypyrido[2, Ιο] [1]oxa[4]azacyclohentriacontine-1,11,28,29(4H,31H)-tetraone. Petition 870250090230, dated 03 / 10 / 2025, pp. 202 / 341 179 / 217

[354] To a stirred solution of 32-deoxorrapamycin (50 mg, 0.055 mmol) in DCM (2 ml) was added 3-trifluoromethylaniline (0.065 ml, 0.556 mmol) and TFA (0.085 ml, 1.112 mmol) at -20°C and stirred for 2 h. The resulting mixture was diluted with EtOAc and quenched with saturated aqueous NaHCO3. The aqueous layer was extracted with EtOAc and the combined organic layers were dried with Na2SO4, filtered and concentrated under reduced pressure. The crude product was dissolved in DMF and subjected to a C18 ISCO column and eluted with 60-80% ACN / H2O. The pure product fractions were lyophilized to yield 6.5 mg (11%) of the white solid. MS (ESI) calculated for C57H83F3N2O11 - H = 1028.57, found to be 1027.90. Compound 55

[355] (3S, 6S,7E,9R,10R,12R,14S,15E,17E,19E,23S,26R,27R,34aS )-9,27-dihydroxy-3-((R)-1-((IS,3R, 4R)-4-hydroxy-3methoxycyclohexyl)propan-2-yl)-10-methoxy-6,8, 12, 14,20,26hexamethyl-21-((4-(trifluoromethyl)phenyl)amino)5,6,9,10, 12, 13,14,21,22,23,24,25,26,27,32,33, 34,34aoctadecahydro-3H-23,27-epoxypyrido[2,Ιο] [1] oxa[4]azacyclohentriacontin-1,11,28,29(4H,31H)-tetraone. Petition 870250090230, dated 03 / 10 / 2025, pp. 203 / 341 180 / 217

[356] To a stirred solution of 32-deoxorrapamycin (50 mg, 0.055 mmol) in DCM (2 ml) were added 4-trifluoromethylaniline (0.065 ml, 0.556 mmol) and TFA (0.085 ml, 1.112 mmol) at -20°C and stirred for 2 h. The resulting mixture was diluted with EtOAc and quenched with saturated aqueous NaHCO3. The aqueous layer was extracted with EtOAc and the combined organic layers were dried with Na2SO4, filtered and concentrated under reduced pressure. The crude product was dissolved in DMF and subjected to a C18 ISCO column and eluted with 60-80% ACN / H2O. The pure product fractions were lyophilized to yield 2.3 mg (4%) of the white solid. MS (ESI-) calculated for C57H83F3N2O11 - H = 1028.57, found to be 1028.05. Compound 56

[357] (4- (((3S, 6S,7E,9R,10R,12R,14S,15E,17E,19E,23S,26R,27R,34aS)-9,27dihydróxi-3-((R)-1-((IS,3R, 4R)-4-hidróxi-3methoxiciclohexil)propan-2-yl)-10-methóxi-6,8,12,14,20,26hexamethyl- 1,11,28,29-tetraoxo1,4,5,6,9,10,11,12,13,14,21,22,23,24,25,26,27,28,29,31,32,33,3 4,34a-tetracosahidro-3H-23,27-epoxypyrido[2,Ιο] [1]oxa[4]azacyclohentriacontin-21-yl) amino)benzonitrila) Petition 870250090230, 03 / 10 / 2025, pág. 204 / 341 181 / 217 O. HO.

[358] To a stirred solution of 32-deoxorrapamycin (50 mg, 0.055 mmol) in DCM (8 ml) were added 4-aminobenzonitrile (0.065 ml, 0.556 mmol) and TFA (0.085 ml, 1.112 mmol) at -20°C and the reaction was stirred for 3 h. The resulting mixture was diluted with EtOAc and quenched with saturated aqueous NaHCO3. The aqueous layer was extracted with EtOAc and the combined organic layers were dried with Na2SO4, filtered and concentrated under reduced pressure. The crude product was dissolved in DMF and subjected to a C18 ISCO column and eluted with 60-80% ACN / H2O. The pure product fractions were lyophilized to yield 2.4 mg (4%) of the white solid. MS (ESI-) calculated for C57H83N3O11 - H = 985.60, found to be 985.08. Compound 57

[359] (3- (((3S,6S,7E,9R,10R,12R,14S,15E,17E,19E,23S,26R,27R,34aS)-9,27dihydroxy-3-((R)-1-((1S,3R,4R)-4-hydroxy- 3methoxycyclohexyl)propan-2-yl)-10-methoxy-6,8,12,14,20,26hexamethyl-1,11,28,29-tetraoxo1,4,5,6,9,10,11, 12, 13,14,21,22,23,24,25,26,27,28,29,31, 32,33,3 4,34a-tetracosahydro-3H-23,27-epoxypyrido[2,1c][1]oxa[4]azacyclohentriacontin-21-yl)amino)benzonitrile Petition 870250090230, dated 03 / 10 / 2025, pp. 205 / 341 182 / 217

[360] To a stirred solution of 32-deoxorrapamycin (75 mg, 0.083 mmol) in DCM (10 ml) were added 3-aminobenzonitrile (0.065 ml, 0.556 mmol) and TFA (0.085 ml, 1.112 mmol) at -20°C and stirred for 3 h. The resulting mixture was diluted with EtOAc and quenched with saturated aqueous NaHCO3. The aqueous layer was extracted with EtOAc and the combined organic layers were dried with Na2SO4, filtered and concentrated under reduced pressure. The crude product was dissolved in DMF and subjected to a C18 ISCO column and eluted with 60-80% ACN / H2O. The pure product fractions were lyophilized to yield 3.1 mg (6%) of the white solid. MS (ESI-) calculated for C57H83N3O11 - H = 984.60, found to be 985.01. Compound 58

[361] ((3S,6S,7E,9R,10R,12R,14S,15E,17E,19E,23S,26R,27R,34a S)-9,27-dihydroxy-3-((R)-1-((1S,3R,4R)-4-hydroxy-3methoxycyclohexyl)propan-2-yl)-10-methoxy-6,8,12,14,20,26hexamethyl-21-((3-(trifluoromethoxy)phenyl)amino)5 ,6,9,10,12,13,14,21,22,23,24,25,26,27,32,33,34,34aoctadecahydro-3H-23,27-epoxypyrido[2,1c][1]oxa[4]azacyclohentriacontin-1,11,28,29(4H,31H)-tetraone) Petition 870250090230, dated 03 / 10 / 2025, pp. 206 / 341 183 / 217

[362] To a stirred solution of 32-deoxorrapamycin (50 mg, 0.055 mmol) in DCM (10 ml) were added 3-trifluoromethoxyaniline (0.076 ml, 0.834 mmol) and TFA (0.128 ml, 1.667 mmol) at -20°C and stirred for 3 h. The resulting mixture was diluted with EtOAc and quenched with saturated aqueous NaHCO3. The aqueous layer was extracted with EtOAc and the combined organic layers were dried with Na2SO4, filtered and concentrated under reduced pressure. The crude product was dissolved in DMF and subjected to a C18 ISCO column and eluted with 60-80% ACN / H2O. The pure product fractions were lyophilized to yield 10.9 mg (13%) of the white solid. MS (ESI-) calculated for C57H83F3N2O12 - H = 1043.59, found to be 1044.09. Compound 59

[363] ((3S,6S,7E,9R,10R,12R,14S,15E,17E,19E,23S,26R,27R,34a S)-21-((3-ethoxyphenyl)amino)-9,27-dihydroxy-3-((R)-1((1S,3R,4R)-4-hydroxy-3-methoxycyclohexyl)propan-2-yl)-10methoxy-6,8,12,14,20,26-hexamethyl5,6,9, 10,12,13,14,21,22,23,24,25,26,27,32,33,34,34aoctadecahydro-3H-23,27-epoxypyrido[2,1c][1]oxa[4]azacyclohentriacontine-1,11,28,29(4H,31H)-tetraone) Petition 870250090230, dated 03 / 10 / 2025, pp. 207 / 341 184 / 217

[364] To a stirred solution of 32-deoxorrapamycin (75 mg, 0.083 mmol) in DCM (10 ml) were added 3-ethoxyaniline (0.095 ml, 0.834 mmol) and TFA (0.128 ml, 1.667 mmol) at -20°C and stirred for 3 h. The resulting mixture was diluted with EtOAc and quenched with saturated aqueous NaHCO3. The aqueous layer was extracted with EtOAc and the combined organic layers were dried with Na2SO4, filtered and concentrated under reduced pressure. The crude product was dissolved in DMF and subjected to a C18 ISCO column and eluted with 60-80% ACN / H2O. The pure product fractions were lyophilized to yield 6.5 mg (8%) of the white solid. MS (ESI-) calculated for C58H88N2O12 - H = 1003.63, found to be 1003.97. Compound 60

[365] ((3S,6S,7E,9R, 10R, 12R, 14S,15E,17E,19E,23S,26R,27R,34a S)-9,27-dihydroxy-3-((R)-1-((1S,3R,4R)-4-hydroxy-3methoxycyclohexyl)propan-2-yl)-10-methoxy-6,8,12,14,20,26hexamethyl-21-(thiophen-3-ylamino)5,6,9,10 ,12,13,14,21,22,23,24,25,26,27,32,33,34,34aoctadecahydro-3H-23,27-epoxypyrido[2,1c][1]oxa[4]azacyclohentriacontine-1,11,28,29(4H,31H)-tetraone) Petition 870250090230, dated 03 / 10 / 2025, pp. 208 / 341 185 / 217

[366] Thiophene-3-amine hydrochloride (113 mg, 0.834 mmol) and TFA (0.128 ml, 1.667 mmol) were added to a stirred solution of 32-deoxorrapamycin (75 mg, 0.083 mmol) in DCM (10 ml) at -20°C and stirred for 3 h. The resulting mixture was diluted with EtOAc and quenched with saturated aqueous NaHCO3. The aqueous layer was extracted with EtOAc and the combined organic layers were dried with Na2SO4, filtered, and concentrated under reduced pressure. The crude product was dissolved in DMF and subjected to a C18 ISCO column and eluted with 60-80% ACN / H2O. The pure product fractions were lyophilized to yield 2.0 mg (2%) of the white solid. MS (ESI-) calculated for C54H82N2O11S - H = 965.56, found to be 965.86. Compound 61

[367] (N- ((3S,6S,7E,9R,10R,12R,14S,15E,17E,19E,23S,26R,27R,34aS)-9,27dihydróxi-3-((R)-1-((1S,3R,4R)-4-hidróxi-3methoxiciclohexil)propa n-2-yl)-10-methoxy-6,8,12,14,20,26hexamethyl-1,11,28,29-tetraoxo1,4,5,6,9,10,11,12,13,14,21,22,23,24,25,26,27,28,29,31,32,33,3 4,34a-tetracosahidro-3H-23,27-epoxypirido[2,1c][1]oxa[4]azacyclohentriacontin-21-yl)isoxazol-4-sulfonamida) Petition 870250090230, 03 / 10 / 2025, pág. 209 / 341 186 / 217

[368] To a stirred solution of 32-deoxorrapamycin (75 mg, 0.083 mmol) in DCM (10 ml) were added 1,2-oxazol-4-sulfonamide (124 mg, 0.834 mmol) and ZnCl2 (0.834 ml, 0.834 mmol) at room temperature and stirred for 16 h. The resulting mixture was diluted with EtOAc and quenched with saturated aqueous NaHCO3. The aqueous layer was extracted with EtOAc and the combined organic layers were dried with Na2SO4, filtered and concentrated under reduced pressure. The crude product was dissolved in DMF and subjected to a C18 ISCO column and eluted with 60-80% ACN / H2O. The pure product fractions were lyophilized to yield 1.0 mg (1%) of the white solid. MS (ESI-) calculated for C53H81N3O14S - H = 1015.54, found to be 1015.14. Compound 62

[369] ((3S,6S,7E,9R,10R, 12R, 14S,15E,17E,19E,23S,26R,27R, 34a S)-9,27-dihydroxy-3-((R)-1-((1S,3R,4R)-4-hydroxy-3methoxycyclohexyl)propan-2-yl)-10-methoxy-21-((3methoxyphenyl)(methyl)amino)-6,8,12,14,20,26-hexamethyl5, 6,9,10,12,13,14,21,22,23,24,25,26,27,32,33,34,34aoctadecahydro-3H-23,27-epoxypyrido[2,1c][1]oxa[4]azacyclohentriacontine-1,11,28,29(4H,31H)-tetraone) Petition 870250090230, dated 03 / 10 / 2025, pp. 210 / 341 187 / 217

[370] To a stirred solution of 32-deoxorrapamycin (75 mg, 0.083 mmol) in DCM (10 ml) were added 3-methoxy-N-methylaniline (0.094 ml, 0.834 mmol) and TFA (0.128 ml, 1.667 mmol) at -20°C and stirred for 6 h. The resulting mixture was diluted with EtOAc and quenched with saturated aqueous NaHCO3. The aqueous layer was extracted with EtOAc and the combined organic layers were dried with Na2SO4, filtered and concentrated under reduced pressure. The crude product was dissolved in DMF and subjected to a C18 ISCO column and eluted with 60-80% ACN / H2O. The pure product fractions were lyophilized to yield 5.8 mg (7%) of the white solid. MS (ESI-) calculated for C58H88N2O12 - H = 1004.63, found to be 1004.39. Compound 63

[371] ((3S,6S,7E,9R,10R, 12R, 14S,15E,17E,19E,23S,26R,27R,34a S)-9,27-dihydroxy-3-((R)-1-((1S,3R,4R)-4-hydroxy-3methoxycyclohexyl)propan-2-yl)-10-methoxy-6,8, 12, 14,20,2 6hexamethyl-21-(methyl(phenyl)amino)5,6,9,10,12,13,14,21,22,23,24,25,26,27,32,33,34,34aoctadecahydro-3H-23, 27-epoxypyrido[2, 1c][1]oxa[4]azacyclohentriacontin-1,11,28,29(4H,31H)-tetraone) Petition 870250090230, dated 03 / 10 / 2025, pp. 211 / 341 188 / 217

[372] To a stirred solution of 32-deoxorrapamycin (100 mg, 0.111 mmol) in DCM (10 ml) were added N-methylaniline (0.120 ml, 1.112 mmol) and TFA (0.170 ml, 2.223 mmol) at -20°C and stirred for 6 h. The resulting mixture was diluted with EtOAc and quenched with saturated aqueous NaHCO3. The aqueous layer was extracted with EtOAc and the combined organic layers were dried with Na2SO4, filtered and concentrated under reduced pressure. The crude product was dissolved in DMF and subjected to a C18 ISCO column and eluted with 60-80% ACN / H2O. The pure product fractions were lyophilized to yield 2.6 mg (3%) of the white solid. MS (ESI-) calculated for C57H86N2O11 - H = 974.62, found to be 974.07. Compound 64

[373] (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-3methoxycyclohexyl)propan-2-yl)-10-methoxy-6,8,12,14,20,26hexamethyl-21-(methyl(phenyl)amino)5,6,9, 10,12,13,14,21,22,23,24,25,26,27,32,33,34,34aoctadecahydro-3H-23,27-epoxypyrido[2,1c][1]oxa[4]azacyclohentriacontine-1,11,28,29(4H,31H)-tetraone: Petition 870250090230, dated 03 / 10 / 2025, pp. 212 / 341 189 / 217

[374] To a stirred solution of 32-deoxorrapamycin (200 mg, 0.222 mmol) in DCM (10 ml) were added N-methylaniline (0.240 ml, 2.223 mmol) and TFA (0.340 ml, 4.445 mmol) at -20°C and stirred for 16 h to room temperature. The resulting mixture was diluted with EtOAc and quenched with saturated aqueous NaHCO3. The aqueous layer was extracted with EtOAc and the combined organic layers were dried with Na2SO4, filtered and concentrated under reduced pressure. The crude product was dissolved in DMF and subjected to a C18 ISCO column and eluted with 60-80% ACN / H2O. The pure product fractions were lyophilized to yield 4.1 mg (2%) of the white solid. MS (ESI-) calculated for C57H86N2O11 - H = 974.62, found to be 974.33. Compound 65

[375] (3S,6S,7E,9R,10R,12R,14S,15E,17E,19E,23S,26R,27R,34aS )-21-(3,4-dihydroquinolin-1(2H)-yl)-9,27-diidróxi-3-((R)-1((1S,3R,4R)-4-hidróxi-3-metoxiciclohexyl)propan-2-yl)-10metóxi-6,8,12,14,20,26-hexametil5,6,9,10,12,13,14,21,22,23,24,25,26,27,32,33,34,34aoctadecahidro-3H-23,27-epoxipirido[2,1c][1]oxa[4]azaciclohentriacontina-1,11,28,29(4H,31H)-tetraona: Petition 870250090230, 03 / 10 / 2025, pág. 213 / 341 190 / 217

[376] To a stirred solution of 32-deoxorrapamycin (200 mg, 0.222 mmol) in DCM (10 ml) were added 1,2,3,4-tetrahydroquinoline (0.278 ml, 2.223 mmol) and TFA (0.340 ml, 4.445 mmol) at -20°C and stirred for 16 h to room temperature. The resulting mixture was diluted with EtOAc and quenched with saturated aqueous NaHCO3. The aqueous layer was extracted with EtOAc and the combined organic layers were dried with Na2SO4, filtered and concentrated under reduced pressure. The crude product was dissolved in DMF and subjected to a C18 ISCO column and eluted with 60-80% ACN / H2O. The pure product fractions were lyophilized to yield 4.8 mg (2%) of the white solid. MS (ESI-) calculated for C57H86N2O11 - H = 1.000, 64, found 1.000, 17. Compound 66

[377] (3S,6S,7E,9R,10R, 12R, 14S,15E,17E,19E,21R,23S,26R,27R, 34S)-21-(1,1-dioxidoisothiazolidin-2-yl)-9,27-dihydroxy-3-((R)1-((1S,3R,4R)-4-hydroxy-3-methoxycyclohexyl)propan-2-yl)-10methoxy-6,8,12,14,20,26-hexamethyl 5,6,9,10,12,13,14,21,22,23,24,25,26,27,32,33,34,34aoctadecahydro-3H-23,27-epoxypyrido[2,1c][1]oxa[4]azacyclohentriacontine-1,11,28,29(4H,31H)-tetraone: Petition 870250090230, dated 03 / 10 / 2025, pp. 214 / 341 191 / 217

[378] To a stirred solution of 32-deoxorrapamycin (100 mg, 0.111 mmol) in DCM (10 ml) were added 1,3-propanosultam (0.136 ml, 1.112 mmol) and ZnCl2 (1.112 ml, 1.112 mmol) at room temperature and stirred for 16 h. The resulting mixture was diluted with EtOAc and quenched with saturated aqueous NaHCO3. The aqueous layer was extracted with EtOAc and the combined organic layers were dried with Na2SO4, filtered and concentrated under reduced pressure. The crude product was dissolved in DMF and subjected to a C18 ISCO column and eluted with 60-80% ACN / H2O. The pure product fractions were lyophilized to yield 14.4 mg (13%) of the white solid. MS (ESI-) calculated for C53H84N2O13S - H = 988.57, found to be 988.16. Compound 67:

[379] (3S,6S,7E,9R,10R, 12R, 14S,15E,17E,19E,21R,23S,26R,27R, 34S)-21-(1,1-dioxidoisothiazolidin-2-yl)-9,27-dihydroxy-3-((R)1-((1S,3R,4R)-4-hydroxy-3-methoxycyclohexyl)propan-2-yl) -10methoxy-6,8,12,14,20,26-hexamethyl5,6,9,10,12,13,14,21,22,23,24,25,26,27,32,33,34,34aoctadecahydro-3H-23, 27-epoxypyrido[2, 1c][1]oxa[4]azacyclohentriacontin-1,11,28,29(4H,31H)-tetraone Petition 870250090230, dated 03 / 10 / 2025, pp. 215 / 341 192 / 217

[380] To a stirred solution of 32-deoxorrapamycin (100 mg, 0.111 mmol) in DCM (10 ml) were added 1,3-propanosultam (0.136 ml, 1.112 mmol) and ZnCl2 (1.112 ml, 1.112 mmol) at room temperature and stirred for 16 h. The resulting mixture was diluted with EtOAc and quenched with saturated aqueous NaHCO3. The aqueous layer was extracted with EtOAc and the combined organic layers were dried with Na2SO4, filtered and concentrated under reduced pressure. The crude product was dissolved in DMF and subjected to a C18 ISCO column and eluted with 60-80% ACN / H2O. The pure product fractions were lyophilized to yield 8.5 mg (8%) of the white solid. MS (ESI-) calculated for C53H84N2O13S - H = 988.57, found to be 988.01. Compound 68:

[381] (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-3methoxycyclohexyl)propan-2-yl)-21-((2hydroxyethyl)(phenyl)amino )-10-methoxy-6,8,12,14,20,26-hexamethyl5,6,9,10,12,13,14,21,22,23,24,25,26,27,32,33,34,34aoctadecahydro-3H-23, 27-epoxypyrido[2, 1c][1]oxa[4]azacyclohentriacontin-1,11,28,29(4H,31H)-tetraone: Petition 870250090230, dated 03 / 10 / 2025, pp. 216 / 341 193 / 217 O. HO.

[382] To a stirred solution of 32-deoxorrapamycin (75 mg, 0.083 mmol) in DCM (10 ml) were added 2(phenylamino)ethanol (0.122 ml, 0.834 mmol) and TFA (0.128 ml, 1.667 mmol) at -20°C and stirred for 16 h to room temperature. The resulting mixture was diluted with EtOAc and quenched with saturated aqueous NaHCO3. The aqueous layer was extracted with EtOAc and the combined organic layers were dried with Na2SO4, filtered and concentrated under reduced pressure. The crude product was dissolved in DMF and subjected to a C18 ISCO column and eluted with 60-80% ACN / H2O. The pure product fractions were lyophilized to yield 15.5 mg (19%) of the white solid. MS (ESI-) calculated for C58H88N2O12 - H = 1004.63, found to be 1004.08. Compound 69:

[383] (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-3methoxycyclohexyl)propan-2-yl)-10-methoxy-21-((2methoxyethyl)(phenyl)amino)-6,8,12,14,20,26-hexamethyl5,6 ,9,10,12,13,14,21,22,23,24,25,26,27,32,33,34,34aoctadecahydro-3H-23,27-epoxypyrido[2,1c][1]oxa[4]azacyclohentriacontine-1,11,28,29(4H,31H)-tetraone: Petition 870250090230, dated 03 / 10 / 2025, pp. 217 / 341 194 / 217 O. HO.

[384] To a stirred solution of 32-deoxorrapamycin (75 mg, 0.083 mmol) in DCM (10 ml) were added N-(2-methoxyethyl)aniline (0.125 ml, 0.834 mmol) and TFA (0.128 ml, 1.667 mmol) at -20°C and stirred for 16 h to room temperature. The resulting mixture was diluted with EtOAc and quenched with saturated aqueous NaHCO3. The aqueous layer was extracted with EtOAc and the combined organic layers were dried with Na2SO4, filtered and concentrated under reduced pressure. The crude product was dissolved in DMF and subjected to a C18 ISCO column and eluted with 60-80% ACN / H2O. The pure product fractions were lyophilized to yield 2.7 mg (3%) of the white solid. MS (ESI-) calculated for C59H90N2O12 - H = 1018.65, found to be 1018.21. Compound 70:

[385] (3S,6S,7E,9R,10R, 12R, 14S,15E,17E,19E,23S,2 6R,2 7R, 34aS )-21-((3-(difluoromethoxy)phenyl)amino)-9,27-dihydroxy-3-((R)-1((1S,3R,4R)-4-hydroxy-3-methoxycyclohexyl)propan-2-yl)-10methoxy-6,8,12,14,20,26-hexamethyl5, 6,9,10,12,13,14,21,22,23,24,25,26,27,32,33,34,34aoctadecahydro-3H-23,27-epoxypyrido[2,1c][1]oxa[4]azacyclohentriacontine-1,11,28,29(4H,31H)-tetraone: Petition 870250090230, dated 03 / 10 / 2025, pp. 218 / 341 195 / 217 mg were added to DCM (10 ml) 0.111 mmol) 3difluoromethoxyaniline (0.139 ml, 1.112 mmol) and TFA (0.170 ml 2.223 mmol) at -20°C and stirred for 16 h at room temperature. The resulting mixture was diluted with EtOAc and quenched with saturated aqueous NaHCO3. The aqueous layer was extracted with... EtOAc and the combined organic layers were dried with Na2SO4, filtered, and concentrated under reduced pressure. The crude product was dissolved in DMF and subjected to a C18 ISCO column and eluted from 60-80% ACN / H2O. Pure product fractions were lyophilized to yield 7.7 mg (7%) of the white solid. MS (ESI-) calculated for C57H84F2N2O12 H = 1026.60, found to be 1026.16. Petition 870250090230, dated 03 / 10 / 2025, pp. 219 / 341 196 / 217

[387] (1R,2R,4S)-4-((2R)-2((3S,6S,7E,9R,10R, 12R, 14S,15E,17E,19E,23S ,26R,27R,34aS)-9,27dihydroxy-10-methoxy-21-((2-methoxyethyl)(phenyl)amino)6,8,12,14,20,26-hexamethyl-1,11,28,29-tetraoxo1,4,5,6,9,10,11, 12, 13,14,21,22,23,24,25,26,27,28,2 9, 31, 32,33,3 4,34a-tetracosahydro-3H-23, 27-epoxypyrido[2, 1c][1]oxa[4]azacyclohentriacontin-3-yl)propyl)-2methoxycyclohexyl dimethylphosphinate.

[388] Compound 71 is prepared in the same way as compound 69 using Compound 31 as the starting material. Compound 72

[389] 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-3methoxycyclohexyl)propan-2-i l)-10-methoxy-6,8,12,14,20,26hexamethyl-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-3H23,27-epoxypyrido[2,1-c][1]oxa[4]azacyclohentriacontin-21-yl)3-methylbenzenesulfonamide.

[390] To a stirred solution of 32-deoxorrapamycin (50 mg, 0.055 mmol) in DCM (6 ml) were added 3-methylbenzene-1-sulfonamide (95 mg, 0.555 mmol) and ZnCl2 (0.56 ml, 0.555 mmol) at room temperature and stirred for 16 h. The resulting mixture was diluted with EtOAc and quenched with saturated aqueous NaHCO3. The aqueous layer was extracted with EtOAc and the organic layers Petition 870250090230, dated 03 / 10 / 2025, pp. 220 / 341 Combined 197 / 217 samples were dried with Na2SO4, filtered, and concentrated under reduced pressure. The crude product was dissolved in DMF and subjected to a C18 ISCO column and eluted with 60-80% ACN / H2O. The pure product fractions were lyophilized to yield 4.2 mg (7%) of the yellow solid RGN-3768. MS (ESI-) calculated for C57H86N2O13S - H = 1038.59, found to be 1038.62. Compound 73

[391] N- ((3S,6S,7E,9R,10R,12R,14S,15E,17E,19E,23S,26R,27R,34aS)-9,27dihydroxy-3-((R)-1-((1S,3R,4R)-4-hydroxy-3methoxycyclohexyl)propa n-2-yl)-10-methoxy-6,8,12,14,20,26hexamethyl-1,11,28,29-tetraoxo1,4,5,6,9,10,11,12,13,14,21,22,23,24,25,26,27,28,29,31,32,33,3 4,34a-tetracosahydro-3H-23,27-epoxypyrido[2,1c][1]oxa[4]azacyclohentriacontin-21-yl)-Nmethylbenzenesulfonamide.

[392] To a stirred solution of 32-deoxorrapamycin (50 mg, 0.055 mmol) in DCM (6 ml) were added N-methylbenzenesulfonamide (0.080 ml, 0.555 mmol) and ZnCl2 (0.56 ml, 0.555 mmol) at room temperature and stirred for 16 h. The resulting mixture was diluted with EtOAc and quenched with saturated aqueous NaHCO3. The aqueous layer was extracted with EtOAc and the combined organic layers were dried with Na2SO4, filtered and concentrated under reduced pressure. The crude product was dissolved in DMF and subjected to a C18 ISCO column and eluted with 60-80% ACN / H2O. The pure product fractions were lyophilized to yield 26.9 mg (52%) of the yellow solid RGN-3769. MS (ESI-) calculated for C57H86N2O13S - H = 1038.59, found to be 1038.24. Petition 870250090230, dated 03 / 10 / 2025, pp. 221 / 341 198 / 217

[393] (3S,6S,7E,9R,10R,12R,14S,15E,17E,19E,23S,26R,27R, 34aS )-21-((3-fluorophenyl)amino)-9,27-diidróxi-3-((R)-1((1S,3R,4R)-4-hidróxi-3-methoxyciclohexyl)propan-2-yl)-10metóxi-6,8,12,14,20,26-hexamethyl5,6,9,10,12, 13,14,21,22,23,24,25,26,27,32,33,34,34aoctadecahydro-3H-23,27-epoxypyrido[2, 1c][1]oxa[4]azacyclohentriacontina-1,11,28,29(4H,31H)-tetraone.

[394] To a stirred solution of 32-deoxorrapamycin (300 mg, 0.333 mmol) in DCM (10 ml) were added 3-fluoraniline (0.322 ml, 3.335 mmol) and TFA (0.510 ml, 6.670 mmol) at -20°C and stirred for 16 h to room temperature. The resulting mixture was diluted with EtOAc and quenched with saturated aqueous NaHCO3. The aqueous layer was extracted with EtOAc and the combined organic layers were dried with Na2SO4, filtered and concentrated under reduced pressure. The crude product was dissolved in DMF and subjected to a C18 ISCO column and eluted with 60-80% ACN / H2O. Pure product fractions were lyophilized to yield 2.9 mg (1%) of the white solid 74. MS (ESI-) calculated for C56H83FN2O11 Petition 870250090230, dated 03 / 10 / 2025, pp. 222 / 341 199 / 217 - H = 978.60, found 978.85. Example 3. Inhibition of representative compounds against wild-type (WT) and FKBP12 knockout 293T cells

[395] Example Generation of FKBP12 knockout cells. A CRISPR / Cas9 system was used to deliver ribonucleoprotein complexes containing guide RNA sequences targeting FKBP12 (acCGGTGTAGTGCACCACGC, locality 1369062; ccactactcacCGTCTCCTG, locality 1369181) into HEK293T cells using Lipofectamine CRISPRMAX transfection reagent (Invitrogen CMAX00008). Cell clones were evaluated by immunoblotting with anti-FKBP-specific antibody (Novus, NB300508). Single cells that were deficient for FKBP12 protein were selected and cloned. Treatment of wild-type (WT) and FKBP12 knockout 2 93T cells with RAD001 (everolimus) and test compounds.

[396] 293T WT cells with FKBP12 knockout were cultured in Dulbecco's modified Eagle medium (Gibco #11971-025) supplemented with 10% fetal bovine serum (Gibco #26140-079). Cells were plated at a density of 15,000 cells per well in 96-well poly-D-Lysine-coated plates (Corning, #354461) and incubated at 37°C, 5% CO2, for 24 hours until they reached approximately 80% confluence. Cells were treated with RAD001 or test compounds reconstituted in dimethyl sulfoxide (DMSO) using a dose range of 8-11 points, from 0.001 pM to 10 μM. All treatments were performed in duplicate for 2 hours at 37°C. Cell culture medium supplemented with dimethyl sulfoxide (DMSO) alone was used as a negative control for all compounds. Phosphorylated amounts of S6K1 (Thr389) were measured using an ELISA kit (Invitrogen 85-86052-11), following the manufacturer's protocol.

[397] S6K1 is an immediate downstream target of mTORCl and therefore phosphorylation of S6K1 at residue Thr389 is used to Petition 870250090230, dated 03 / 10 / 2025, pp. 223 / 341 200 / 217 measure mTORCl activity (PMID: 16968213). Quantities of phosphorylated S6K1 (Thr389) were measured in 293T WT and FKBP12 knockout cells treated with RAD001 or Compound 44 (Figures 1A and 1B), and Compound 45 (Figures 1C and 1D).

[398] In WT cells, both RAD001 and Compound 44 completely inhibit S6K1 phosphorylation in a dose-dependent manner (Figure 1A). In WT cells, RAD001 inhibited 50% (IC50) of S6K1 phosphorylation at 0.66 nM, while Compound 44 inhibited 50% (IC50) of S6K1 phosphorylation at 11 nM. Thus, in WT cells, Compound 44 is approximately 17 times less potent compared to RAD001 (Figure 1A).

[399] 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 of S6K1 phosphorylation at 10 μM. Thus, in FKBP12 knockout cells, Compound 44 is approximately 100 times less potent compared to RAD001 at the highest tested concentration of 10 μM (Figure 1B). In FKBP12 knockout cells, Compound 44 did not inhibit S6K1 phosphorylation at any tested concentration lower than 10 μM (Figure 1B). These data demonstrate that Compound 44 is relatively more selective for FKBP12 compared to RAD001 and requires FKBP12 to inhibit mTORC1 signaling when used at 1 μM or lower concentration in this cell system.

[400] In WT cells, both RAD001 and Compound 45 completely inhibit S6K1 phosphorylation in a dose-dependent manner (Figure 1C). In WT cells, RAD001 inhibited 50% (IC50) of S6K1 phosphorylation at 0.47 nM, while Compound 45 inhibited 50% (IC50) of S6K1 phosphorylation at 8.4 nM. Thus, in WT cells, Compound 45 is approximately 18 times less potent compared to RAD001 (Figure 1C).

[401] In FKBP12 knockout cells (i.e., cells that lack FKBP12), RAD001 achieved approximately 35% of Petition 870250090230, dated 03 / 10 / 2025, pp. 224 / 341 201 / 217 inhibition of S6K1 phosphorylation at a concentration of 100 nM and at the highest concentration tested of 10 μM, RAD001 inhibited S6K1 phosphorylation by approximately 80%. In FKBP12 knockout cells, Compound 45 at a concentration of 10 mM inhibited S6K1 phosphorylation by approximately 25% (Figure 1D). A similar level of S6K1 inhibition was obtained by RAD001 at approximately 100 nM. Thus, in FKBP12 knockout cells, when tested at a concentration of 10 mM, Compound 45 is approximately 100 times less potent compared to RAD001 (Figure 1D).

[402] These data demonstrate that Compound 45 is relatively more selective for FKBP12, compared with RAD001.

[403] In HEK293T WT 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 compared to that of RAD001. However, in the absence of FKBP12 (in FKBP12 knockout cells), RAD001 achieved approximately 40% inhibition of S6K1 (Thr389) at 447 nM, while Compound 18 achieved similar levels 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 compared to RAD001. These data demonstrate that Compound 18 is relatively more selective for FKBP12 compared to RAD001; however, it still achieves approximately 40% inhibition of S6K1 in the absence of FKBP12 at the highest concentration tested.

[404] In HEK293T WT 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 compared to that of RAD001. However, in the absence of FKBP12 (in FKBP12 knockout cells), the potency of Compound 16 was comparable to that of RAD001 (Figure 3B). In the larger Petition 870250090230, dated 03 / 10 / 2025, pp. 225 / 341 At the 202 / 217 concentration tested (10 μM), both rapalogs achieved approximately 70% inhibition of S6K1 phosphorylation (Thr389). These data suggest that Compound 16 may have the lowest affinity for FKBP12 compared to RAD001; however, it maintains affinity for other FKBPs that are expressed in HEK293T cells.

[405] In HEK293T WT cells, which express FKBP12, RAD001, Compound 26 and Compound 28 achieved complete inhibition of S6K1 (Thr389) phosphorylation (Figure 4A). The cells were treated for 2 hours with the following compounds: RAD001 (everolimus; dashed line with circles, IC50 0.017 nM) and Compound 26 (solid line with squares, IC50 0.55 nM) and Compound 28 (solid line with crosses, IC50 3.0 nM). In 293T cells with FKBP12 knockout, while RAD001 (everolimus; dashed line with circles, IC50 31.3 nM) achieves approximately 50% inhibition of S6K1, Compound 26 (solid line with squares, IC50 not measurable / detectable) does not inhibit S6K1 at any of the concentrations tested, indicating that Compound 26 is more selective for FKBP12 compared to RAD001.In cells with FKBP12 KO, Compound 28 (solid line with crosses, IC50 not measurable / detectable) behaved similarly to RAD001, indicating that the selectivity of Compound 28 for FKBP12 is not greater compared to RAD001.

[406] In wild-type HEK293T cells expressing FKBP12, RAD001 (IC50 = 0.319 nM), as well as Compounds 47 (IC50 = 69 nM), 48 (IC50 = 9.8 nM) and 49 (IC50 = 9.5 nM) inhibited mTORC1 signaling in a dose-dependent manner and achieved near-complete inhibition of S6K1 (Thr389) phosphorylation with increasing concentrations (FIG. 5A, 5C and 5E). The potency of the new compounds was lower relative to RAD001 by x 219 times (47), x 30 times (48) and x 29 times (49), respectively, as indicated by their respective IC50 values.

[407] In the absence of FKBP12, in cells with knockout of Petition 870250090230, dated 03 / 10 / 2025, pp. 226 / 341 203 / 217 FKBP12, RAD001 inhibited the phosphorylation of S6K1 (Thr389), achieving 42% inhibition at a concentration of 10 μM. The new compounds 47, 48, and 49, tested side-by-side with RAD001, did not inhibit the phosphorylation of S6K1 (Thr389) at any of the concentrations tested (FIG. 5B, 5D, and 5F). These results indicate that, unlike RAD001, the activity of Compounds 47, 48, and 49 is dependent on FKBP12 and, in the absence of FKBP12, these compounds did not inhibit mTORC1 signaling; that is, Compounds 47, 48, and 49 are relatively more selective for FKBP12 compared to RAD001.

[408] In wild-type HEK293T cells expressing FKBP12, RAD001 (IC50 = 0.365 nM), as well as Compounds 50 (IC50 = 5.72 nM), 51 (IC50 = 4.53 nM) and 52 (IC50 = 9.15 nM) inhibited mTORC1 signaling in a dose-dependent manner and achieved near-complete inhibition of S6K1 (Thr389) phosphorylation with increasing concentrations (FIG. 6A, 6C and 6E). The potency of these new compounds was lower relative to RAD001 by x 15 times (50), x 12 times (51) and 25 times (52) respectively, as indicated by their respective IC50 values.

[409] In the absence of FKBP12, in FKBP12 knockout cells, RAD001 inhibited S6K1 (Thr389) phosphorylation in a dose-dependent manner, achieving 45% inhibition at 10 μM. The new compounds 50 and 52 tested side-by-side with RAD001 slightly inhibited S6K1 (Thr389) phosphorylation only at the highest concentration tested (12% inhibition in the case of 50), or did not inhibit S6K1 (Thr389) phosphorylation at any of the concentrations tested (observed for 52) (FIG. 6B, 6F). These results indicate that, unlike RAD001, the activity of Compounds 50 and 52 is dependent on FKBP12 and, in the absence of FKBP12, these compounds did not inhibit mTORC1 signaling, that is, Compounds 50 and 52 are selective for FKBP12.

[410] In FKBP12 knockout cells, Compound 51 retained some potency and inhibited S6K1 (Thr389) phosphorylation by 18% Petition 870250090230, dated 03 / 10 / 2025, pp. 227 / 341 204 / 217 at a concentration of 1 mM, with no inhibition at 10 mM (FIG. 6D). In the same assay, RAD001 achieved 20% inhibition of S6K1 (Thr389) phosphorylation at a concentration of 115 nM. These results indicate that Compound 51 is not completely selective for FKBP12 and the inhibitory effect of Compound 51 on mTORC1 signaling may be mediated by FKBPs other than FKBP12.

[411] In wild-type HEK293T cells expressing FKBP12, RAD001 (IC50 = 0.084 nM) and Compounds 57 (IC50 = 3.68 nM), 58 (IC50 = 2.94 nM) and 59 (IC50 = 0.17 nM) inhibited mTORC1 signaling in a dose-dependent manner and achieved near-complete inhibition of S6K1 (Thr389) phosphorylation at the highest concentrations tested (FIG. 7A, 7C and 7E). In this assay, the potencies of the new compounds were lower than RAD001 by x 44 times (57), x 35 times (58) and 2 times (59), respectively, as indicated by their respective IC50 values.

[412] In the absence of FKBP12, in FKBP12 knockout cells, RAD001 and all compounds tested (57, 58 and 59) inhibited mTORC1 signaling in a dose-dependent manner (FIG. 7B, 7D and 7F). These results indicate that, similar to RAD001, compounds (57, 58 and 59) retain potency in the absence of FKBP12, meaning that their inhibitory effect on mTORC1 signaling may be mediated by FKBPs other than FKBP12, i.e., compounds 57, 58 and 59 are relatively non-selective for FKB12.

[413] 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 and achieved near-complete inhibition of S6K1 (Thr389) phosphorylation with increasing concentrations (FIG. 8A). In this assay, the potency of 63 was 10 times lower compared to RAD001, as indicated by their respective IC50 values.

[414] In FKBP12 knockout cells, Compound 63 retained Petition 870250090230, dated 03 / 10 / 2025, pp. 228 / 341 205 / 217 showed some potency and inhibited S6K1 (Thr389) phosphorylation by 17% at the maximum concentration tested, 10 mM (FIG. 8B). In the same assay, RAD001 achieved 20% inhibition of S6K1 (Thr389) phosphorylation at a concentration of 1.3 nM and a further 58% inhibition at 10 mM. These results indicate that, although Compound 63 is not exclusively selective for FKBP12, it is still more selective than RAD001. In wild-type cells expressing FKBP12, 63 is 10 times less potent compared to RAD001; however, in FKBP12 knockout cells, 63 achieves no more than 17% inhibition of S6K1 (Thr389), while RAD001 inhibits S6K1 (Thr389) in a dose-dependent manner by up to 58%.

[415] In wild-type HEK293T cells expressing FKBP12, both RAD001 (IC50 = 0.389 nM) and Compound 69 (IC50 = 1.53 nM) inhibited mTORC1 signaling and achieved near-complete inhibition of S6K1 phosphorylation (Thr389) with increasing concentrations (FIG. 9A), with the potency of 69 being x 4 times lower compared to RAD001, as indicated by their respective IC50 values.

[416] In the absence of FKBP12, in FKBP12 knockout cells, increasing concentrations of RAD001 achieved dose-dependent inhibition of S6K1 (Thr389) phosphorylation up to 73.5% at the highest concentration tested (10 pM). In the absence of FKBP12, Compound 69 retained very low potency and achieved approximately 30% inhibition of S6K1 (Thr389) phosphorylation at the highest concentration tested (10 pM). In the same assay with FKBP12 knockout cells, RAD001 achieved 30% inhibition of S6K1 (Thr389) phosphorylation at a concentration of approximately 3.0 nM. These results indicate that, although Compound 69 is not exclusively selective for FKBP12, it is still more selective than RAD001. In wild-type cells expressing FKBP12, Compound 69 is only 4 times less potent compared to RAD001. However, in FKBP12 knockout cells, Compound 69 inhibits 30% of phosphorylated S6K1 at a concentration approximately 3,000 times higher compared to RAD001. Petition 870250090230, dated 03 / 10 / 2025, pp. 229 / 341 206 / 217 with RAD001.

[417] In wild-type HEK293T cells expressing FKBP12, both RAD001 (IC50 = 0.174 nM) and Compound 72 (IC50 = 0.914 nM) inhibited mTORC1 signaling and achieved near-complete inhibition of S6K1 (Thr389) phosphorylation with increasing concentrations (FIG. 10A). In this assay, the potency of 72 was 5.2 times lower compared to RAD001, as indicated by their respective IC50 values.

[418] In the absence of FKBP12, in FKBP12 knockout cells, increasing concentrations of RAD001 achieved dose-dependent inhibition of S6K1 (Thr389) phosphorylation with up to 62% inhibition at the highest concentration tested (10 μM) (FIG. 10B). In the absence of FKBP12, Compound 72 also retained some of its potency and inhibited S6K1 (Thr389) phosphorylation in a dose-dependent manner, with 40% inhibition at the highest concentration tested (10 μM) (FIG. 10B). These results indicate that, although 72 is less potent than RAD001 in FKBP12 knockout cells, these two rapalogs behave similarly. In other words, they can induce mTORC1 inhibition when in complex with FKBPs, unlike FKBP12.

[419] In wild-type HEK293T cells expressing FKBP12, both RAD001 (IC50 = 0.174 nM) and Compound 73 (IC50 = 2.22 nM) inhibited mTORC1 signaling and achieved near-complete inhibition of S6K1 (Thr389) phosphorylation with increasing concentrations (FIG. 11A). In this assay, the potency of 73 was 13 times lower compared to RAD001, as indicated by their respective IC50 values.

[420] In the absence of FKBP12, for example, in FKBP12 knockout cells, increasing concentrations of RAD001 and 73 achieved dose-dependent inhibition of S6K1 phosphorylation (Thr389), with up to approximately 60% inhibition at the highest concentration tested (10 μH) (FIG. 11B). Furthermore, although 73 was 13 times less potent compared to RAD001 in cells Petition 870250090230, dated 03 / 10 / 2025, pages 230 / 341 In wild-type 207 / 217 cells expressing FKBP12, in the absence of FKBP12 (in FKBP12 knockout cells), 73 gained potency compared to RAD001. 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 (FIG. 11B). However, at the highest concentration tested of 10 mM, both RAD001 and Compound 73 inhibited S6K1 phosphorylation by approximately 60% (FIG. 11B).

[421] These results indicate that 73 can induce mTORC1 inhibition when in complex with FKBPs, unlike FKBP12, i.e., 73 is not selective for FKB12. Furthermore, greater potency (in the dose range less than 1 mM) of 73 vs. RAD001 in FKBP12 knockout cells indicates that 73 may have gained affinity for FKBP(s) other than FKBP12, compared to RAD001. Example 4. Stability in microsomes. Materials and methods.

[422] Buffers: PBK buffer: 50 mM potassium phosphate buffer (PPB), pH 7.2, with 3.3 mM magnesium chloride.

[423] Dilution of the compound: Intermediate solution TA: Compound or control (3 pl) diluted from the stock solution (10 mM) with 297 pl of methanol / water 90.0% (concentration: 100 pM; DMSO 1.0%, MeOH 89.1%); Intermediate control cocktail solution: each control (3 pl) was diluted with 291 pl of 90.0% methanol / water; Diluted intermediate stock solution TA and control stock PC were made by transferring 80 µl of 100 pM stock solution TA into new tubes and then adding 720 µl of 1.0% DMSO in 50 mM potassium phosphate buffer (concentration of 10 pM; 1.0% DMSO, 8.91% MeOH). Preparation of liver and NADPH cofactor mixture (described in Table 1)

[424] Preparation of working solution of liver microsomes (1.25x) (final concentration: 0.5 mg / ml). Petition 870250090230, dated 03 / 10 / 2025, pages 231 / 341 208 / 217 Table 1. Preparation of liver and NADPH cofactor mixture. Species Seller Description Vol. of x LM (20 mg protein / ml) Vol. of 50 mM PBK Buffer with 3.3 mM MgCl2 Total volume (ml) Working conc. Final conc. Mouse liver microsome Xenotech 2 0 mg protein / ml, n = 1,400, Male pool 0.100 ml 3,100 ml 3,200 ml 0.625 mg / ml 0.5 mg / ml Human liver microsome Xenotech 2 0 mg protein / ml, n=200, Mixed sexes 0.100 ml 3,100 ml 3,200 ml 0.625 mg / ml 0.5 mg / ml Information Vol. of NADPH Concentration Source NADPH (mg) of the product PBK Buffer working solution Conc. final NADPH Catalog No. N1630 Sigma 10.6 1.18 ml 10 mM Lot No. SLCK6270 1 mM Petition 870250090230, dated 03 / 10 / 2025, pages 232 / 341 209 / 217 Inventory solution:

[425] Acetonitrile:methanol (9:1, v / v) (including 200 ng / ml tolbutamide and 200 ng / ml labetalol hydrochloride as internal standards).

[426] Working solution: 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)

[427] Procedure: Stock solution was added to each of the time-point plates. Microsome solution (360 μl / well), TA / PC (45 μl / well) and NADPH (45 μl / well) min. (concentration: 1.0 μM, DMSO 0.10%, MeOH 0.891%) were added to the incubation plates. To the T60 and NCF60 plates, TA (15 μl / well) and Microsomes (120 μL) were added. To the blank plate, microsome (50 μl / well) with stop solution (150 μl / well) were added. At the end of each time point, 50 μl / well were divided into aliquots of the incubation plate. The sampling plates were shaken for approximately 10 min in a shaker and the samples were centrifuged at 4,000 rpm for 15 min. The supernatant (120 μM) was transferred to LC / MS / MS. Compounds from Table 3 were incubated at 37°C with liver microsomes (pooled from multiple donors) at 1 μM in the presence of a NADPH regeneration system at 0.5 mg / ml microsomal protein.Positive controls included testosterone (substrate 3A4), propafenone (2D6), and diclofenac (2C9), which were incubated with microsomes in the presence of an NADPH regeneration system. At time points (0, 5, 10, 20, 30, and 60 minutes), samples were removed and immediately mixed with ice-cold acetonitrile containing the internal standard (IS). Test compounds incubated with microsomes without the NADPH regeneration system for 60 min were also included. A single point for each test condition (n = 1) was obtained, and samples were analyzed by LC / MS / MS. The disappearance of the test compound was evaluated based on area ratios. Petition 870250090230, dated 03 / 10 / 2025, pp. 233 / 341 210 / 217 peak analyte / IS (without standard curve). As shown in Table 1, several compounds showed good stability in human and mouse liver microsomes, with a T1 / 2 above 2 hours and low microsome clearance. Petition 870250090230, dated 03 / 10 / 2025, pages 234 / 341 211 / 217 Table 2. In vitro microsomal metabolic stability assay of selected compounds in CD-1 mouse and human liver microsomes. ID No. Compound Species T1 / 2 (min) CL CLint Remaining Remaining (μL / min / mg) (ml / min / kg) (T = 60 min) (T = NCF60 min) 26 Mouse 131 10.6 41.9 69.80% 92.30% Human 15.4 89.9 80.9 6.60% 92.80% 28 Mouse 83.5 16.6 65.7 59.40% 106% Human 26.3 52.8 47.5 19.40% 84.00% 44 Mouse 33.8 41 162 31% 96% Human 17.4 79.6 71.7 7.50% 99% 45 Mouse 84.6 16.4 64.8 64.30% 81.40% Human 7.13 194 0.00% 71.30% 48 Mouse > 145 < 9.6 101% 150% Human 33 42.1 37.8 32% 107% 49 Mouse 130 10.7 42.3 67% 139% Human 20.9 66.2 59.6 15% 102% 50 Mouse > 145 < 9.6 89% 112% Human 22.8 60.8 54.7 18% 99% 51 Mouse 21.5 64.3 255 15% 85% Human 6, 86 202 182 0.20% 89% 58 Mouse 217 6, 4 25.3 83% 96% Petition 870250090230, dated 03 / 10 / 2025, pages 235 / 341 212 / 217 Human 69.5 20.0 18.0 55% 93% 59 Mouse 135 10.3 40.8 76% 112% Human 56.2 24.7 22.2 47% 102% 60 Mouse 14.8 93.5 370 5.6% 75% Human 16.0 89.3 80.4 6.6% 99% 69 Mouse 492 2.81 11.1 113% 99.6% Human 49.0 28.3 25.5 63.3% 115% 32-Deoxo Rapamycin Mouse 39.5 35.1 139 36% 110% Human 3.4 405 364 0.00% 96% Rapamycin Mouse 32.1 43.1 171 27% 102% Human 10.7 130 117 1.40% 116% RAD001 Mouse 71.3 19.4 76.9 56% 126% Human 11.1 124 112 2.10% 120% Petition 870250090230, dated 03 / 10 / 2025, pp. 236 / 341 213 / 217 Example 5. Pharmacokinetic studies of test articles in male CD-1 mice. Study design Table 3. Pharmacokinetic study design * Group Number of animals (Sex) Treatment Test article* ** Dose (mg / kg) Dose volume (ml / kg) Conc. (mg / ml) Vehicle Route 1 3 (Males) 69 2 5 0.4 Ethanol 5%, Tween-80 5% and PEG-400 5%, water 85% IV 2 3 (Males) 69 10 10 1.0 Ethanol 5%, Tween-80 5% and PEG-400 5%, water 85% PO Feeding status: □ Fed K Fasting *For both groups (IV and PO), plasma samples are collected at the following times: 0.083, 0.25, 0.5, 1.0, 2.0, 4.0, 8.0 and 24 h post-dosage. Terminal (24 h) plasma collection is performed via cardiac puncture. **For Compounds RAD001, 26, and 45, the studies were conducted in the same way as for Compound 69, with one difference: Compounds 26 and 45 were dosed orally (PO) at 20 mg / kg of Compound 69, and RAD001 was dosed PO at 10 mg / kg.**

[428] Animal experiments were performed on Wuxi AppTec CD1 male mice aged 6–8 weeks were obtained from Hilltop Labs. Upon arrival at Wuxi AppTec, the mice were housed in environmentally controlled animal rooms (temperature: 20–26°C; lighting: 12-hour light / dark cycles). The mice were fed a certified pelleted diet. Petition 870250090230, dated 03 / 10 / 2025, pp. 237 / 341 214 / 217 (Certified Rodent Diet No. 5002 by LabDiet). Water was provided to the animals ad libitum. The mice were acclimated to the facilities for at least 3 days before the start of the experiments. Dose formulation

[429] An appropriate amount of test article was formulated in 5% ethanol, 5% Tween-80 and 5% PEG-400, 85% water. The formulation was prepared on the day of dosing and dosed within 2 hours of preparation of the formulations. Dosing accuracy was determined by LC-MS / MS. Dose administration

[430] The dose formulation (or formulations) was administered after SOPs of the facilities. Dose volumes were determined individually prior to dosing based on the animals’ body weights. Sample collection and plasma isolation

[431] Approximately 40 pl of blood samples were collected via peripheral veins (e.g., saphenous veins) at each predefined time point. Blood samples were collected in tubes containing K2EDTA as an anticoagulant and kept on ice until centrifugation.

[432] Blood samples were centrifuged at 4°C, 3,000 g for 5 min within half an hour to one hour of collection. Plasma was transferred to 96-well polypropylene tubes or plates, promptly frozen on dry ice and stored at -70 ± 10°C until analysis by LC-MS / MS. Bioanalytical method and sample analysis

[433] The test compound concentration in mouse plasma was determined using the LC-MS / MS method with a calibration curve containing at least 6 non-zero calibration standards. Data analysis

[434] The pharmacokinetics (PK) of the test article was analyzed Petition 870250090230, dated 03 / 10 / 2025, pages 238 / 341 215 / 217 using Phoenix WinNonlin software (version 8.3) and a non-compartmental analysis model. The derived PK parameters include, but are not limited to, Co, CLp, Vdss, Cmax, Tmax, Th, AUC(ot), AUC(o-inf), MRT(ot), MRT(o-inf), and %F (bioavailability).

[435] Results: The results of the pharmacokinetic study of selected compounds are shown in Figs. 12A (Everolimus, RAD001), 12B (Compound 26), 12C (Compound 45) and 12D (Compound 63), respectively.

[436] FIG. 12A is a graph showing the pharmacokinetic profile in mouse plasma of RAD001 after IV (2 mg / kg) and PO (10 mg / kg) administration. The Y-axis, set to Log 1o scale, shows compound concentration (ng / ml) in plasma. The X-axis shows the time points (hours) for plasma collection after compound administration.

[437] FIG. 12B is a graph showing the pharmacokinetic profile in mouse plasma after IV (2 mg / kg) and PO (20 mg / kg) administration. The Y-axis, set to Log 10 scale, shows the compound concentration (ng / ml) in plasma. The X-axis shows the time points (hours) for plasma collection after compound administration.

[438] FIG. 12C is a graph showing the pharmacokinetic profile in mouse plasma of Compound 45 after IV (2 mg / kg) and PO (20 mg / kg) administration. The Y-axis, set to Log 10 scale, shows the compound concentration, ng / ml, in plasma. The X-axis shows the time points (hours) for plasma collection after compound administration.

[439] FIG. 12D is a graph showing the pharmacokinetic profile in mouse plasma after IV (2 mg / kg) and PO (10 mg / kg) administration. The Y-axis, set to Log 10 scale, shows the compound concentration, ng / ml, in plasma. The X-axis shows the time points (hours) for plasma collection after compound administration.

[440] Compound 69 has a pharmacokinetic profile Petition 870250090230, dated 03 / 10 / 2025, pp. 239 / 341 216 / 217 improved, when compared with RAD001, for example, higher oral bioavailability (30.7% for 69 vs. 26% for RAD001), higher Cmax in plasma after oral administration (12,933 ng / ml for 69 vs. 7,224 ng / ml for RAD001) and slower plasma clearance rate (15.5 hours for 69 vs. 5.85 hours for RAD001) (compare FIG. 12A with FIG. 12D), see also Table 4 below. Table 4. Summary table of pharmacokinetic studies of selected Compounds in mice. Note that Compounds 26 and 45 were dosed orally (PO) at 20 mg / kg (FIG. 12B and 12C), while Compound 69 and RAD001 were dosed PO at 10 mg / kg (FIG. 12A and 12D). Everolimus / RAD001 Compound #26 Compound #45 Compound #69 IV T1 / 2 * 5.85 h 5.25 h 5.63 h 15.5 h CI (ml / min / kg)** 0.934 2.31 1.13 0.176 Vdss (l / kg)*** 0.433 0.828 0.475 0.228 PO Cmax **** 7224 ng / ml 4118 ng / ml 9183 ng / ml 12933 ng / ml Compound concentration at 8 hours, PO administration 1959 ng / ml 1325 ng / ml 1517 ng / ml 10010 ng / ml Compound concentration at 24 hours, PO administration 273 ng / ml 184 ng / ml 239 ng / ml 4670 ng / ml Oral bioavailability 26% 28.5% 17% 30.7% * IV T1 / 2 - the amount of time required for the plasma concentration of the compound to decline by 50% after IV administration. **Cl (ml / min / kg) - clearance of compounds after IV administration. ***Vdss (l / kg) - volume of distribution after IV administration. Petition 870250090230, dated 03 / 10 / 2025, pages 240 / 341 217 / 217 IV administration. **** PO Cmax — maximum (peak) plasma concentration of the compound obtained after PO administration.

[441] The embodiments and examples described above are intended to be merely illustrative and not limiting. Those skilled in the art will recognize, or be able to verify using only routine experimentation, numerous equivalents of specific compounds, materials and procedures. All such equivalents are considered to be within the scope of, and are encompassed by, the appended claims.

Claims

1. Compound characterized by having Formula I: O. HO. (I) or a pharmaceutically acceptable salt thereof; wherein R1 is hydrogen, C1-6 alkyl, heterocyclyl, aryl, heteroaryl, -CO-6 alkylene-SO2R4 or -CO-6 alkylene-SO2R5; wherein C1-6 alkyl, heterocyclyl, aryl, heteroaryl are optionally substituted with one or two R1a groups; R2 is heterocyclyl, aryl, heteroaryl, -CO-6 alkylene-SO2R4 or -CO-6 alkylene-SO2R5; wherein heterocyclyl, aryl, heteroaryl are optionally substituted with one or two R2a groups; or R1 and R2 together with the attached nitrogen form an N-linked heteroaryl or N-linked heterocyclyl optionally substituted with one or two R1a groups; R3 is selected from the group consisting of -ORa, 3-6 membered heterocyclyl and 3-6 membered heteroaryl; Ra is selected from the group consisting of H, -P(O)(Rb)2, C(O)Rc, -C(O)ORc, C1-6 alkyl and C1-6 hydroxyalkyl; each Rb is selected independently from the group consisting of H and C1-6 alkyl;Rc is selected from the group consisting of H, C1-6 alkyl and C1-6 hydroxyalkyl; R4 is C2-6 alkyl, C3-6 cycloalkyl, C1-6 hydroxyalkyl, heterocyclyl, aryl or heteroaryl; wherein heterocyclyl, aryl and heteroaryl are optionally substituted with one or two R4a groups; and R5 is heterocyclyl, aryl or heteroaryl; wherein heterocyclyl, aryl and heteroaryl are optionally substituted with one or two R5a groups; each of one or two R1a, R2a, R4a and R5a groups, when present, are selected independently from C1-6 alkyl, C16 hydroxyalkyl, hydroxy, halo, C1-6 haloalkyl and C1-6 alkoxy; or any two groups R1a, R2a, R4a and R5a, when present on the same carbon, are taken together to form an oxo group; where, when R1 is hydrogen, R2 is not -CO-6 alkyleneSO2R4.; 2. Compound according to claim 1, characterized in that the compound is Formula Ia: O. HO. (Ia) or a pharmaceutically acceptable salt thereof; where R1 is hydrogen or C1-6 alkyl; R2 is heterocyclyl, aryl or heteroaryl optionally substituted with one or two R2a groups; R3 is selected from the group consisting of -ORa, a 3-6 membered heterocyclyl and a 3-6 membered heteroaryl; Ra is selected from the group consisting of H, -P(O)(Rb)2, C(O)Rc, -C(O)ORc, C1-6 alkyl and C1-6 hydroxyalkyl; each Rb is independently selected from the group consisting of H and C1-6 alkyl; Rc is selected from the group consisting of H, C1-6 alkyl and Petition 870250090230, dated 03 / 10 / 2025, p.243 / 341 3 / 77 C1-6 hydroxyalkyl; and each of one or two R2a groups, when present, are selected independently from C1-6 alkyl, C1-6 hydroxyalkyl, hydroxy, halo, C1-6 haloalkyl and C1-6 alkoxy; or any two R2a groups, when present on the same carbon, are taken together to form an oxo group.

3. Compound according to claim i, characterized in that the compound is of Formula Ib: O. HO. (Ib) or a pharmaceutically acceptable salt thereof; wherein R1 and R2 together with the attached nitrogen form an N-linked heteroaryl or N-linked heterocyclyl optionally substituted with one or two Ria groups; R3 is selected from the group consisting of -ORa, a 3-6 membered heterocyclyl and a 3-6 membered heteroaryl; Ra is selected from the group consisting of H, -P(O)(Rb)2, C(O)Rc, -C(O)ORc, C1-6 alkyl and C1-6 hydroxyalkyl; each Rb is independently selected from the group consisting of H and C1-6 alkyl; Rc is selected from the group consisting of H, C1-6 alkyl and C1-6 hydroxyalkyl; Each of one or two Ria groups, when present, are selected independently from C1-6 alkyl, C1-6 hydroxyalkyl, hydroxy, halo, C1-6 haloalkyl and C1-6 alkoxy; or two Ria groups, when present on the same carbon, are taken together for Petition 870250090230, dated 03 / 10 / 2025, page.244 / 341 4 / ΊΊ form an oxo group.

4. Compound according to claim 1, characterized in that the compound is Formula Ic: O.HO.(Ic) or a pharmaceutically acceptable salt thereof; wherein R1 is hydrogen or C1-6 alkyl; R2 is -CO-6 alkylene-SO2R4 or -CO-6 alkylene-SO2R5; R3 is selected from the group consisting of -ORa, a 3-6 membered heterocyclyl and a 3-6 membered heteroaryl; Ra is selected from the group consisting of H, -P(O)(Rb)2, C(O)Rc, -C(O)ORc, C1-6 alkyl and C1-6 hydroxyalkyl; each Rb is independently selected from the group consisting of H and C1-6 alkyl; Rc is selected from the group consisting of H, C1-6 alkyl and C1-6 hydroxyalkyl; R4 is C2-6 alkyl, C3-6 cycloalkyl, C1-6 hydroxyalkyl, heterocyclyl, aryl or heteroaryl; wherein heterocyclyl, aryl and heteroaryl are optionally substituted with one or two R4a groups; R5 is heterocyclyl, aryl or heteroaryl; wherein heterocyclyl, aryl and heteroaryl are optionally substituted with one or two R5a groups;Each of one or two R4a and R5a groups, when present, are independently selected from C1-6 alkyl, C1-6 hydroxyalkyl, hydroxy, halo, C1-6 haloalkyl and C1-6 alkoxy; or Petition 870250090230, dated 10 / 03 / 2025, p. 245 / 341 5 / 77 any two R4a and R5a groups, when present on the same carbon, are taken together to form an oxo group; wherein, when R1 is hydrogen, R2 is not -CO-6 alkyleneSO2R4.

5. Compound according to claim 1, characterized in that R1 is hydrogen and R2 is an aryl, heteroaryl or a C5-12 heterocyclyl wherein the aryl, heteroaryl and C5-12 heterocyclyl are optionally substituted with one or two R2a groups.

6. Compound according to claim 1, characterized in that R1 is hydrogen or C1-6 alkyl and R2 is aryl, heteroaryl or a C5-12 heterocyclyl wherein the aryl, heteroaryl and C5-12 heterocyclyl are optionally substituted with one or two R2a groups.

7. Compound according to claim 1, characterized in that R1 is hydrogen and R2 is a C5-20 membered aryl, C5-20 membered heteroaryl or a C5-20 heterocyclyl wherein the aryl, heteroaryl and a C5-12 heterocyclyl are optionally substituted with one or two R2a groups.

8. Compound according to claim 1, characterized in that R1 is hydrogen or C1-6 alkyl and R2 is a C5-20 membered aryl, C5-20 membered heteroaryl or a C5-20 heterocyclyl wherein the aryl, heteroaryl and a C5-12 heterocyclyl are optionally substituted with one or two R2a groups.

9. Compound according to any one of claims 5-8, characterized in that R2 is selected from: Petition 870250090230, dated 03 / 10 / 2025, p. 246 / 341 6 / 77 and is the remaining attachment point of the compound. wherein to; 10. Compound according to claim 1 or characterized in that R4 is heterocyclyl, aryl or heteroaryl; wherein heterocyclyl, aryl, heteroaryl are optionally substituted with one or two R4a groups; or R5 is heterocyclyl, aryl or heteroaryl; wherein heterocyclyl, aryl, heteroaryl are optionally substituted with one or two R5a groups.

11. Compound, according to claim 10, characterized in that R4 is Petition 870250090230, dated 03 / 10 / 2025, p. 247 / 341 7 / 77 where it is the point of adhesion to the rest of the compound.

12. Compound, according to claim 10, characterized in that R5 is Petition 870250090230, dated 03 / 10 / 2025, p. 248 / 341 8 / 77 which is the point of adhesion to 1-12 13. Compound, according to any one of the claims, characterized by the fact that R3 is the remainder of the compound. -ORa and Ra is C1-6 alkyl.

14. Compound according to claim 1, characterized in that the compound is selected from: Petition 870250090230, dated 10 / 03 / 2025, p. 249 / 341 9 / 77 Petition 870250090230, dated 10 / 03 / 2025, p. 250 / 341 10 / 77 Petition 870250090230, dated 10 / 03 / 2025, p. 251 / 341 11 / 77 Compound 17, Compound 19, Compound 20, Compound 21, Petition 870250090230, dated 10 / 03 / 2025, p. 252 / 341 12 / 77 Petition 870250090230, dated 03 / 10 / 2025, p. 253 / 341 13 / 77 Petition 870250090230, dated 03 / 10 / 2025, p. 254 / 341 14 / 77 Petition 870250090230, dated 03 / 10 / 2025, p. 255 / 341 15 / 77 Petition 870250090230, dated 03 / 10 / 2025, p. 256 / 341 16 / 77 Petition 870250090230, dated 03 / 10 / 2025, p. 257 / 341 17 / 77 Compound 59 Compound 62 Compound 63 Compound 64 Petition 870250090230, dated 03 / 10 / 2025, p. 258 / 341 18 / 77 Petition 870250090230, dated 03 / 10 / 2025, p. 259 / 341 19 / 77 Petition 870250090230, dated 03 / 10 / 2025, p. 260 / 341 20 / 77 Petition 870250090230, dated 03 / 10 / 2025, p. 261 / 341 21 / 77 Petition 870250090230, dated 03 / 10 / 2025, p.262 / 341 22 / 77 Petition 870250090230, of 03 / 10 / 2025, p. 263 / 341 23 / 77 Petition 870250090230, of 03 / 10 / 2025, p. 264 / 341 24 / 77 HO4jY. Me / Ν / γέ HHáy°H ÇÀo 0 MeO-'A0 / X / VVZZ £ Me Μθ V^NH QT Compound 2 6-A HO,- MeO*'*^ Me Y\'\vYY\ áYõ hhY Ao 0 Meo-' V .. HOJ zTV / MeO^T Composite Q^T2 26-B H0,í°x\ MeC)^ Me °Y^O ° MeO''' Y-0 .. H0J 1 zV / xvv^ * Me Me NH Me —< Y O'N Compound 27-A Η0,ί°χ\ MeC)^ Me ^Yé hh JAoh °Y^O ° MeO'CM Q'M q> Y^χ χ ., * Mio Me / x.NH Me —< Y O'N Compound 27-B hoMeC)^ Me / nYó hhÀx°h unY^° ° MeO''' γ5·0 IK Λ H0^ J Μθ,. .. \ / ^0 z^yV / \V^ \,N NH Me Μθ V Compound 28-A ΗΟ'ΐ^Υη MeO / *Xs / j Me / nY6 hhY°h unY^° 0 MeO''' jY IK Λ H(YJ \,N NH Me Compound Μθ-B 870250090230, of 03 / 10 / 2025, p. 265 / 341 25 / 77 TODAY MeO*Zx Me 1 lú HH JL>3H CK Y. ΗΟ-ήΥχ ΜβΟ^^^η Me Υ\'^Υ£Ϋχ L.^L^Õ Η Η JL^OH Οχ Υ Ο Υ^ο Yr^O MeO' Υ^ ΓΛ Η0^ J ίΛι^Μ|ΜΜ. ν-νχ Compound 29-B ΗΟ,^Υχ MeC / x''''^q Me jyie,l^^32^ LA^Õ HH JLzDH Y.O , ,Υό MeO' . . H0«j 1 MeZZ .. Y = h / io Me N .NHMe 0' YV=N Compound 30-A Η°4°χ\ ΜβΟ^^^η Me ΐνΐβ,γ^32Ξ LA^Õ HH JLzDH Ο^Υ. Ο e'L / O ,, Υ ο MeO' ΛΛHCY 1 MexYY .. Υ ^χΧ^ r / ίο Me ν .NHMe οζ Υ Ζ=Ν Compound 30-B ΗΟ,,,^χ MeO^Yfq Me Me,, 1 ξ LAY Λυη NJ Me Y ο. Υ. ο Υ^ο YfO MeO' Υ H°J 1 Me^Y^Q MeY^ Ç^NH^Íe Me Cl Compound 43-A ΗΟ,,,^χ MeO^Yfi Me Me,, 1 ξ Λύη Ν J Μθ Υ ο^Υ ο ,Υ^ο Υτ~Ό MeO' Υ H°J 1 MeYY) Ç^NH^Íe Me Cl Composto 43-B Petition 870250090230, of 10 / 03 / 2025, p. 266 / 341 26 / 77 Petition 870250090230, of 10 / 03 / 2025, p. 267 / 341 27 / 77 Petition 870250090230, dated 03 / 10 / 2025, p. 268 / 341 28 / 77 Petition 870250090230, dated 03 / 10 / 2025, p. 269 / 341 29 / 77 Petition 870250090230, dated 03 / 10 / 2025, p. 270 / 341 30 / 77 Petition 870250090230, dated 03 / 10 / 2025, p. 271 / 341 31 / 77 Petition 870250090230, dated 03 / 10 / 2025, p. 272 / 341 32 / 77 Petition 870250090230, dated 03 / 10 / 2025, p. 273 / 341 33 / 77 Petition 870250090230, dated 03 / 10 / 2025, p. 274 / 341 34 / 77 Petition 870250090230, dated 03 / 10 / 2025, p.275 / 341 35 / 77 Petition 870250090230, dated 03 / 10 / 2025, p. 276 / 341 36 / 77 or a pharmaceutically acceptable salt thereof.

15. Compound, according to claim 14, characterized in that the compound is: Petition 870250090230, dated 03 / 10 / 2025, p. 277 / 341 37 / 77 HO,„ MeO^Adi Me Me,, 1 Ξ LU / U0H NJ Me y OxÁ 0 ,,Αο AAo Meo' A^ H°J 1 Me-η / Χο N ,NH Jie Me óx JN Compound 45; MeO^Aríi Me Me,, I Ξ A^0H NJ Me J Os As O ..ΑτΌ MeO' HOJ I Me^AX0 / s-NH Me Me O Compound 50 MeO^ATÍi Me Me,, - S . NY Me [ Os As o c'k / 0 Αχ^Ο MeO' A^ H°J 1 Μθ-AAq Me**\ 1 1 16 Ax\_Me Me OMe Compound 69 H0 / / | J£zOH NY Me Y Os As o ,_x^o MeO' A^ HOÃ^ I Me^A^Q Me^\ 16 XXs / N\ Me Μθ Compound 63 H0,, / s MeO^AXX Me Me,, I Ξ Ín-Jsà Axxoh NJ Me [ Os As OA / O MeO' A HOJ I Me^^A^o MeXX* nA Me sZo2 Compound 72 HO,, / Ss MeO'^AffA Me Me,, I Ξ AsX0H NY Mex J Os A- ß A / O Η0ΥΑ> MeO' A- Me«*A^Q MeA\^ NH' Me £j^-so2 F Compound 74 Petition 870250090230, of 10 / 03 / 2025, p. 38 / 77 consists of: Compound 26; Compound 28; Compound 50;279 / 341 39 / 77 or a pharmaceutically acceptable salt thereof.

17. Compound according to any one of claims 1-16, characterized in that the compound selectively binds to FKBP12.

18. Compound according to claim 17, characterized in that the compound inhibits S6K1 phosphorylation at least twice less efficiently than rapalog RAD001 in FKBP12 KO cells compared to wild-type cells expressing FKBP12.

19. Compound, according to claim 17, characterized in that the compound requires a concentration at least 10 times higher, compared to rapalog RAD001, in FKBP12 KO cells compared to wild-type cells expressing FKBP12, to obtain 20% inhibition of S6K1 cell signaling.

20. Compound according to claim 1, characterized in that the compound inhibits S6K1 phosphorylation at least ten times less efficiently than rapalog RAD001 in FKBP12 KO cells compared to wild-type cells expressing FKBP12.

21. Compound, according to claim 1, characterized in that the compound requires a concentration at least 100 times higher, compared to rapalog RAD001, in FKBP12 KO cells compared to wild-type cells expressing FKBP12, to achieve 20% inhibition of S6K1 cell signaling.

22. Compound, according to claim 1, characterized in that the compound requires a concentration at least 10 times higher, compared to rapalog RAD001, in FKBP12 KO cells compared to wild-type cells expressing FKBP12, to achieve 30% inhibition of S6K1 cell signaling.

23. Compound, according to claim 1, characterized in that the compound requires a concentration at least 100 times higher, compared to rapalog RAD001, in FKBP12 KO cells compared to wild-type cells expressing FKBP12, to achieve 30% inhibition of S6K1 cell signaling.

24. Compound according to claim 1, characterized in that, for this compound, the relative potency loss in cells with FKBP12 KO versus wild-type cells is at least twice as large compared to that of RAD001.

25. Compound, according to claim 1, characterized in that, for this compound, the relative power loss in cells with KO of FKBP12 versus wild-type cells is at least ten times greater, compared with that of RAD001.

26. Compound according to claim 17, characterized in that, for this compound, the relative potency loss in cells with FKBP12 KO versus wild-type cells is at least 100 times greater compared with that of RAD001.

27. Pharmaceutical composition characterized by comprising a therapeutically effective amount of a compound, as defined in any one of claims 1-26, or of a pharmaceutically acceptable salt thereof in one or more pharmaceutically acceptable carriers.

28. Pharmaceutical combination characterized by comprising a therapeutically effective amount of a compound, as defined in any of claims 1-26, or of a pharmaceutically acceptable salt thereof, and one or more therapeutically active agents in one or more pharmaceutically acceptable carriers.

29. A method for treating a disorder or disease mediated by the mTOR pathway in an individual in need, characterized by comprising administering to the individual a therapeutically effective amount of a compound, as defined in any one of claims 1-26, or of a pharmaceutically acceptable salt thereof or of a pharmaceutical composition, as defined in claim 27 or 28.

30. Method for treating a disease or disorder in an individual, characterized in that the tissue, organ or target cells associated with the pathology of the disease or disorder have sufficient levels of FKBP12 to inhibit mTORC1, comprising administering to the individual in need a therapeutically effective amount of a compound, as defined in any one of claims 1-26, or of a pharmaceutically acceptable salt thereof, or of a pharmaceutical composition, as defined in claim 2 or 28.

31. Method according to claim 29 or 30, characterized in that the compound or a pharmaceutically acceptable salt thereof has a binding affinity high enough for FKBP12 to inhibit mTORCl.

32. A method, according to any one of claims 29-31, characterized in that the disease or disorder is selected from sarcopenia; skin atrophy; cherry angiomas; seborrheic keratoses; cerebral atrophy; atherosclerosis; arteriosclerosis; pulmonary emphysema; osteoporosis; osteoarthritis; arterial hypertension; erectile dysfunction; cataracts; macular degeneration; glaucoma; stroke; cerebrovascular disease (cerebrovascular accidents); chronic kidney disease; kidney disease associated with diabetes; impaired liver function; hepatic fibrosis; autoimmune hepatitis; endometrial hyperplasia; metabolic dysfunction; renovascular disease; hearing loss; motor impairment; cognitive decline; tendon stiffness; cardiac dysfunction such as, for example, cardiac hypertrophy and / or systolic and / or diastolic dysfunction and / or hypertension; cardiac dysfunction resulting in a decline in ejection fraction; immune senescence; Parkinson's disease; Alzheimer's disease; cancer;Immune senescence leading to cancer due to decreased immune surveillance, infections resulting from a decline in immune function, chronic obstructive pulmonary disease (COPD), obesity, loss of taste, loss of smell, arthritis, epilepsy, cancer in which the tumor has elevated levels of mTORC1 signaling and / or sufficient levels of FKBP12 to allow mTORC1 inhibition, and type II diabetes.

33. A method for treating an age-related disorder or disease in a needy individual, characterized by comprising administering to the individual a therapeutically effective amount of a compound, as defined in Petition 870250090230, dated 10 / 03 / 2025, pp. 283 / 341 43 / 77, or any of claims 1-2 or a pharmaceutically acceptable salt thereof or of a pharmaceutical composition, as defined in claim 27 or 28, wherein the disorder or disease is selected from sarcopenia; skin atrophy; cherry angiomas; seborrheic keratoses; cerebral atrophy; atherosclerosis; arteriosclerosis; pulmonary emphysema; osteoporosis; osteoarthritis; hypertension; erectile dysfunction; cataracts; macular degeneration; glaucoma; stroke; cerebrovascular disease (cerebrovascular accidents); chronic kidney disease; diabetic kidney disease; impaired liver function; hepatic fibrosis; autoimmune hepatitis; endometrial hyperplasia;Metabolic dysfunction; renovascular disease; hearing loss; motor impairment; cognitive decline; tendon stiffness; cardiac dysfunction such as cardiac hypertrophy and / or systolic and / or diastolic dysfunction and / or hypertension; cardiac dysfunction resulting in a decline in ejection fraction; immune senescence; Parkinson's disease; Alzheimer's disease; cancer; immune senescence leading to cancer due to decreased immune surveillance; infections resulting from a decline in immune function; chronic obstructive pulmonary disease (COPD); obesity; loss of taste; loss of smell; arthritis; epilepsy; cancer in which the tumor has elevated levels of mTORC1 signaling and / or sufficient levels of FKBP12 to allow mTORC1 inhibition; and type II diabetes.

34. A method for treating cancer in a needy individual, characterized by comprising administering to the individual a therapeutically effective amount of a compound, as defined in any one of claims 1-26, or of a pharmaceutically acceptable salt thereof or of a pharmaceutical composition, as defined in claim 27 or 28.

35. Method, according to claim 34, characterized in Petition 870250090230, dated 10 / 03 / 2025, pp. 284 / 341 44 / 77 by the fact that the cancer is selected from renal 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 neck cancer.

36. A method for treating Alzheimer's disease or Alzheimer's syndrome in a needy individual, characterized by comprising administering to the individual a therapeutically effective amount of a compound, as defined in any one of claims 1-26, or of a pharmaceutically acceptable salt thereof, or of a pharmaceutical composition, as defined in claim 27 or 28.

37. A method for inducing immune tolerance and preventing organ transplant rejection in a needy individual, characterized by comprising administering to the individual a therapeutically effective amount of a compound, as defined in any one of claims 1-26, or of a pharmaceutically acceptable salt thereof or of a pharmaceutical composition, as defined in claim 27 or 28.

38. A method for treating graft-versus-host disease (GvHD) or its syndrome in a needy individual, characterized by comprising administering to the individual a therapeutically effective amount of a compound, as defined in any one of claims 1-26, or of a pharmaceutically acceptable salt thereof, or of a pharmaceutical composition, as defined in claim 27 or 28.

39. Method of treating facial angiofibroma associated with tuberous sclerosis complex in a needy individual, characterized by comprising administering to the individual a therapeutically effective amount of a compound, as defined in any one of claims 1-2 or of a pharmaceutically acceptable salt thereof or of a pharmaceutical composition, as defined in claim 27 or 28.

40. A method for treating advanced, unresectable, or metastatic perivascular malignant epithelioid cell tumors in a needy individual, characterized by comprising administering to the individual a therapeutically effective amount of a compound, as defined in any one of claims 1-26, or of a pharmaceutically acceptable salt thereof or of a pharmaceutical composition, as defined in claim 27 or 28.

41. A compound according to any one of claims 1-26 or a pharmaceutically acceptable salt thereof or a pharmaceutical composition according to claim 27 or 28, characterized in that it is used as a medicament.

42. A compound according to any one of claims 1-26 or a pharmaceutically acceptable salt thereof or a pharmaceutical composition according to claim 27 or 28, characterized in that it is used in the treatment of a disorder or disease mediated by the mTOR pathway.

43. Compound, according to any one of claims 1-26 or a pharmaceutically acceptable salt thereof or a pharmaceutical composition, according to claim 27 or 28, characterized by being used in the treatment of a selected disorder or disease of sarcopenia; skin atrophy; cherry angiomas; seborrheic keratoses; cerebral atrophy; atherosclerosis; arteriosclerosis; pulmonary emphysema; osteoporosis; osteoarthritis; arterial hypertension; erectile dysfunction; cataracts; macular degeneration; glaucoma; stroke; cerebrovascular disease (cerebrovascular accidents); chronic kidney disease; kidney disease associated with diabetes; impaired liver function; hepatic fibrosis; autoimmune hepatitis; hyperplasia. Petition 870250090230, dated 03 / 10 / 2025, p.286 / 341 46 / 77 endometrial; metabolic dysfunction; renovascular disease; hearing loss; motor impairment; cognitive decline; tendon stiffness; cardiac dysfunction such as, for example, cardiac hypertrophy and / or systolic and / or diastolic dysfunction and / or hypertension; cardiac dysfunction resulting in a decline in ejection fraction; immune senescence; Parkinson's disease; Alzheimer's disease; cancer; immune senescence leading to cancer due to decreased immune surveillance; infections resulting from a decline in immune function; chronic obstructive pulmonary disease (COPD); obesity; loss of taste; loss of smell; arthritis; epilepsy; cancer in which the tumor has elevated levels of mTORC1 signaling and / or sufficient levels of FKBP12 to allow mTORC1 inhibition; and type II diabetes.

44. Compound, according to any one of claims 41-43, characterized in that the compound is selected Petition 870250090230, dated 10 / 03 / 2025, p. 287 / 341 47 / 77 Petition 870250090230, dated 10 / 03 / 2025, p. 288 / 341 48 / 77 Petition 870250090230, dated 10 / 03 / 2025, p. 289 / 341 49 / 77 Compound 17, Compound 19, Compound 20, Compound 21, Petition 870250090230, dated 10 / 03 / 2025, p. 290 / 341 50 / 77 Compound 26, Petition 870250090230, dated 03 / 10 / 2025, p. 291 / 341 51 / 77 Petition 870250090230, dated 03 / 10 / 2025, p. 292 / 341 52 / 77 Petition 870250090230, dated 03 / 10 / 2025, p. 293 / 341 53 / 77 Petition 870250090230, dated 03 / 10 / 2025, p. 294 / 341 54 / 77 Petition 870250090230, dated 03 / 10 / 2025, p. 295 / 341 55 / 77 Petition 870250090230, dated 03 / 10 / 2025, p. 296 / 341 56 / 77 Petition 870250090230, dated 03 / 10 / 2025, p. 297 / 341 57 / 77 Petition 870250090230, dated 03 / 10 / 2025, p. 298 / 341 58 / 77 Petition 870250090230, dated 03 / 10 / 2025, p. 299 / 341 59 / 77 Petition 870250090230, dated 03 / 10 / 2025, p.300 / 341 60 / 77 Petition 870250090230, dated 03 / 10 / 2025, p. 301 / 341 61 / 77 Petition 870250090230, dated 03 / 10 / 2025, p. 302 / 341 62 / 77 ΗΟ,ήγχ Me ^Ν^γέ ΗΗΥ°Η / Λ 0 MeO'Y° , „ HOJ £ Me ^e ^<χ.ΝΗ QT Compound 2 6-A H0%Y\ MeC>''x' / Xq Me 1, / Ló HH JL^OH Ox Y. O x'Y^O VX MeO' ΓΛ HO>1 J / Me Μθ Compound 26-B ΗθΥ / -χ MeC)^ Me 1^,,,^^32^ ^n\-6 HHY°H ° MeO'''X .. H0J 1 * Md Me / x^ / NH Me —< Y O'N Compound 27-A Η°,ίθ / χ MeO^^j Me jyie-oL^^SZ^ ^Υδ hhAz°h θΥ^Ο ° MeO''' Y-0H0*JJ ^^^x^^xJJXíz - i\ / io Me zx / NH Me Ύ Y ON Compound 27-B hoMeC)^ Me ^nYó HHJy°n unY^° ° MeO''' γ5·0 . I,. 870250090230, of 10 / 03 / 2025, p. 303 / 341 63 / 77 Compound 2 9-A Compound 29-B Compound 43-A Compound 43-B Petition 870250090230, dated 10 / 03 / 2025, p. 870250090230, dated 03 / 10 / 2025, page.306 / 341 66 / 77 Petition 870250090230, dated 03 / 10 / 2025, p. 307 / 341 67 / 77 Petition 870250090230, dated 03 / 10 / 2025, p. 308 / 341 68 / 77 Petition 870250090230, dated 03 / 10 / 2025, p. 309 / 341 69 / 77 Petition 870250090230, dated 03 / 10 / 2025, p. 310 / 341 70 / 77 Petition 870250090230, dated 03 / 10 / 2025, p. 311 / 341 71 / 77 Petition 870250090230, dated 03 / 10 / 2025, p. 312 / 341 72 / 77 Petition 870250090230, dated 03 / 10 / 2025, p. 313 / 341 73 / 77 Petition 870250090230, dated 03 / 10 / 2025, p. 314 / 341 7 4 / 77.

45. Compound, according to any of claims 41-44, characterized in that the compound is selected Petition 870250090230, dated 10 / 03 / 2025, pp. 315 / 341 75 / 77 or a pharmaceutically acceptable salt thereof.

46. ​​Combination therapy characterized by comprising a therapeutically effective amount of a compound, as defined in any of claims 1-2 or of a pharmaceutically acceptable salt thereof or of a pharmaceutical composition, as defined in claim 27 or 28, and an anti-CD40 antibody.

47. Combination therapy, according to claim 46, characterized by being used in the treatment and / or prevention of Alzheimer's disease, GvHD, facial angiofibroma associated with tuberous sclerosis complex, advanced unresectable or metastatic perivascular malignant epithelioid cell tumors, and organ transplant rejection.

48. Combination therapy, according to claim 46, characterized by being used in the treatment of selected human diseases from the group consisting of cancer, diabetes, obesity, neurological diseases, genetic disorders, and other age- or aging-related diseases.

49. A method for treating Alzheimer's disease or syndrome in a needy individual, characterized by comprising administering to the individual a therapeutically effective amount of the combination therapy, as defined in claim 46.

50. A method for inducing immune tolerance and preventing organ transplant rejection in a needy individual, characterized by comprising administering to the individual a therapeutically effective amount of the combination therapy, as defined in claim 46.

51. A method for treating graft-versus-host disease or syndrome (GvHD) in a needy individual, characterized by comprising administering to the individual a therapeutically effective amount of the combination therapy, as defined in claim 46.

52. Method of treating facial angiofibroma associated with tuberous sclerosis complex in a needy individual, Petition 870250090230, dated 10 / 03 / 2025, pp. 317 / 341 77 / 77 characterized by comprising administering to the individual a therapeutically effective amount of the combined therapy, as defined in claim 46.

53. A method for treating advanced, unresectable, or metastatic perivascular malignant epithelioid cell tumors in a needy individual, characterized by comprising administering to the individual a therapeutically effective amount of the combination therapy, as defined in claim 46.

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