MTORC1 regulators and uses thereof

Abstract

The present disclosure provides compounds and salts showing high selectivity and inhibitory activity against mTORC1 and their use in treating diseases.

Description

[0001] Cross-references

[0002] This application claims the benefit of U.S. Provisional Patent Application No. 63 / 054,767, filed on July 21, 2020, which is incorporated herein by reference in its entirety. Background Art

[0003] The therapeutic potential of rapamycin has been demonstrated in many chronic diseases ranging from Alzheimer's disease and Parkinson's disease to diabetes and cardiovascular disease. However, the prohibitive safety profile of rapamycin for long-term treatment has limited its use in treating various diseases. As an FDA-approved compound, rapamycin inhibits mTOR signaling, thereby leading to an increase in the lifespan of many species, but it can induce adverse effects such as peripheral edema, hypercholesterolemia, mucosal ulceration, abdominal pain, headache, nausea, diarrhea, pain, constipation, hypertriglyceridemia, hypertension, increased creatinine, fever, urinary tract infection, anemia, arthralgia and thrombocytopenia. In view of the complications associated with rapamycin, therapeutic alternatives are needed. Summary of the Invention

[0004] In one aspect, the present disclosure provides a compound represented by formula (IA) or (IIA):

[0005]

[0006] or a salt thereof, wherein:

[0007] R 1 Selected from and -OCH3;

[0008] R 2 is selected from hydrogen, hydroxy and optionally substituted C1-C6 alkoxy, wherein the substituents on the C1-C6 alkoxy are independently selected at each occurrence from hydroxy, halogen, cyano, nitro, C2-C6 alkoxy, optionally substituted carbocycle and optionally substituted heterocycle, wherein the substituents on the carbocycle or heterocycle are independently selected from hydroxy, halogen, cyano, nitro, C1-C6 alkyl, haloalkyl, hydroxyC1-C6 alkyl, alkoxy and alkoxyC1-C6 alkyl;

[0009] R 3is selected from hydrogen, hydroxy and optionally substituted C1-C6 alkoxy, wherein the substituents on the C1-C6 alkoxy are independently selected at each occurrence from hydroxy, halogen, cyano, nitro, C2-C6 alkoxy, optionally substituted carbocycle and optionally substituted heterocycle, wherein the substituents on the carbocycle or heterocycle are independently selected from hydroxy, halogen, cyano, nitro, C1-C6 alkyl, haloalkyl, hydroxyC1-C6 alkyl, alkoxy and alkoxyC1-C6 alkyl;

[0010] R 4 Selected from -O-(CH2) 0-1 T and -O-CH(CH3)2;

[0011] T is an optionally substituted 3-6 membered heterocycloalkyl group, wherein the substituents are independently selected from hydroxy, halogen, cyano, nitro, C1-C6 alkyl, haloalkyl, hydroxyC1-C6 alkyl, alkoxy and alkoxyC1-C6 alkyl;

[0012] Q 1 and Q 3 Independently selected from -O-, -OC(=O)NR 41 -, -S-, and -NR 40 -;

[0013] Q 2 Selected from optionally substituted C 3-6 Carbocycle, optionally substituted 3-8 membered heterocycle, -OR 34 、-(O-CH2-(CH2) p ) n -W and -N(R 39 )2, where C 3-6 The substituents on the carbocyclic ring and the 3-8 membered heterocyclic ring are independently selected from hydroxy, halogen, cyano, nitro, C1-C6 alkyl, haloalkyl, hydroxy C1-C6 alkyl, alkoxy and alkoxy C1-C6 alkyl;

[0014] Q 4 Selected from optionally substituted C 3-6 Carbocycle, optionally substituted 3-8 membered heterocycle and -OR 42 , where C 3-6 The substituents on the carbocyclic ring and the 3-8 membered heterocyclic ring are independently selected from hydroxy, halogen, cyano, nitro, C1-C6 alkyl, haloalkyl, hydroxy C1-C6 alkyl, alkoxy and alkoxy C1-C6 alkyl;

[0015] R 30 、R 31 、R 35 and R 36independently selected from hydrogen, hydroxy, halogen, cyano, nitro, C1-C6 alkyl, haloalkyl, hydroxy C1-C6 alkyl, alkoxy and alkoxy C1-C6 alkyl;

[0016] Each R 32 、R 33 、R 37 and R 38 independently selected from hydrogen, hydroxy, halogen, cyano, nitro, C1-C6 alkyl, haloalkyl, hydroxy C1-C6 alkyl, alkoxy and alkoxy C1-C6 alkyl;

[0017] Each R 34 is selected from hydrogen, optionally substituted C1-C6 alkyl, optionally substituted carbocycle and optionally substituted heterocycle, wherein the substituents on C1-C6 alkyl, carbocycle and heterocycle are independently selected at each occurrence from hydroxy, halogen, cyano, nitro, C1-C6 alkoxy, carbocycle and heterocycle;

[0018] Each R 39 Selected from hydrogen, C1-C6 alkyl, haloalkyl and alkoxy C1-C6 alkyl;

[0019] Each R 40 is selected from hydrogen and optionally substituted C1-C6 alkyl, wherein the substituents are independently selected at each occurrence from hydroxy, halogen, cyano, nitro, C2-C6 alkoxy, carbocycle, and heterocycle; and

[0020] Each R 41 is selected from hydrogen and optionally substituted C1-C6 alkyl, wherein the substituents are independently selected at each occurrence from hydroxy, halogen, cyano, nitro, C2-C6 alkoxy, carbocycle and heterocycle;

[0021] Each R 42 is selected from hydrogen, optionally substituted C1-C6 alkyl, optionally substituted carbocycle and optionally substituted heterocycle, wherein the substituents on C1-C6 alkyl, carbocycle and heterocycle are independently selected at each occurrence from hydroxy, halogen, cyano, nitro, C1-C6 alkoxy, carbocycle and heterocycle;

[0022] Each p is selected from 1 or 2;

[0023] n is selected from 2 to 4; and

[0024] W is selected from -OH and -OCH3.

[0025] In certain aspects, the present disclosure provides a compound represented by formula (III-A) or (III-C):

[0026]

[0027] or a salt thereof, wherein:

[0028] R 1’ Selected from -OH, and -OCH3;

[0029] R 4 Selected from -O-(CH2) 0-1 T and -O-CH(CH3)2;

[0030] T is an optionally substituted 3-6 membered heterocycloalkyl group, wherein the substituents are independently selected from hydroxy, halogen, cyano, nitro, C1-C6 alkyl, haloalkyl, hydroxyC1-C6 alkyl, alkoxy and alkoxyC1-C6 alkyl;

[0031] Q 1 and Q 3 Independently selected from -O-, -OC(=O)NR 41 -, -S-, and -NR 40 -;

[0032] Q 2 Selected from optionally substituted C 3-6 Carbocycle, optionally substituted 3-8 membered heterocycle, -OR 34 、-(O-CH2-(CH2) p ) n -W and -N(R 39 )2, where C 3-6 The substituents on the carbocyclic ring and the 3-8 membered heterocyclic ring are independently selected from hydroxy, halogen, cyano, nitro, C1-C6 alkyl, haloalkyl, hydroxy C1-C6 alkyl, alkoxy and alkoxy C1-C6 alkyl;

[0033] Q 4 Selected from optionally substituted C 3-6 Carbocycle, optionally substituted 3-8 membered heterocycle and -OR 42 , where C 3-6 The substituents on the carbocyclic ring and the 3-8 membered heterocyclic ring are independently selected from hydroxy, halogen, cyano, nitro, C1-C6 alkyl, haloalkyl, hydroxy C1-C6 alkyl, alkoxy and alkoxy C1-C6 alkyl;

[0034] R 30 、R 31 、R 35 and R 36 independently selected from hydrogen, hydroxy, halogen, cyano, nitro, C1-C6 alkyl, haloalkyl, hydroxy C1-C6 alkyl, alkoxy and alkoxy C1-C6 alkyl;

[0035] Each R 32 、R 33 、R 37 and R 38independently selected from hydrogen, hydroxy, halogen, cyano, nitro, C1-C6 alkyl, haloalkyl, hydroxy C1-C6 alkyl, alkoxy and alkoxy C1-C6 alkyl;

[0036] Each R 34 is selected from hydrogen, optionally substituted C1-C6 alkyl, optionally substituted carbocycle and optionally substituted heterocycle, wherein the substituents on C1-C6 alkyl, carbocycle and heterocycle are independently selected at each occurrence from hydroxy, halogen, cyano, nitro, C1-C6 alkoxy, carbocycle and heterocycle;

[0037] Each R 39 Selected from hydrogen, C1-C6 alkyl, haloalkyl and alkoxy C1-C6 alkyl;

[0038] Each R 40 is selected from hydrogen and optionally substituted C1-C6 alkyl, wherein the substituents are independently selected at each occurrence from hydroxy, halogen, cyano, nitro, C2-C6 alkoxy, carbocycle, and heterocycle; and

[0039] Each R 41 is selected from hydrogen and optionally substituted C1-C6 alkyl, wherein the substituents are independently selected at each occurrence from hydroxy, halogen, cyano, nitro, C2-C6 alkoxy, carbocycle and heterocycle;

[0040] Each R 42 is selected from hydrogen, optionally substituted C1-C6 alkyl, optionally substituted carbocycle and optionally substituted heterocycle, wherein the substituents on C1-C6 alkyl, carbocycle and heterocycle are independently selected at each occurrence from hydroxy, halogen, cyano, nitro, C1-C6 alkoxy, carbocycle and heterocycle;

[0041] Each p is selected from 1 or 2;

[0042] n is selected from 2 to 4; and

[0043] W is selected from -OH and -OCH3.

[0044] In certain aspects, the present disclosure provides a compound of Formula (IB), (IC), (ID), (IE), (IIB), (IIC), (III-A), (III-B), (III-C), (III-D), (III-E), (III-F), (III-G), or (III-H), or a salt of any one thereof.

[0045] In certain aspects, the present disclosure provides a pharmaceutical formulation comprising a compound of Formula (IA), (IB), (IC), (ID), (IE), (IIA), (IIB), (IIC), (III-A), (III-B), (III-C), (III-D), (III-E), (III-F), (III-G), or (III-H), or a salt of any one thereof, and a pharmaceutically acceptable excipient.

[0046] In certain aspects, the present disclosure provides methods for treating mTOR disorders using pharmaceutical formulations of a compound of Formula (IA), (IB), (IC), (ID), (IE), (IIA), (IIB), (IIC), (III-A), (III-B), (III-C), (III-D), (III-E), (III-F), (III-G), or (III-H).

[0047] Incorporation by reference

[0048] All publications, patents, and patent applications mentioned in this specification are incorporated herein by reference to the same extent as if each individual publication, patent, or patent application was specifically and individually indicated to be incorporated by reference. If a publication, patent, or patent application incorporated herein by reference conflicts with the disclosure contained in the specification, the specification is intended to supersede and / or take precedence over any such conflicting material. DETAILED DESCRIPTION

[0049] Although preferred embodiments of the present invention have been shown and described herein, it will be apparent to those skilled in the art that such embodiments are provided by way of example only. Numerous changes, variations, and substitutions will now occur to those skilled in the art without departing from the present invention. It should be understood that various alternatives to the embodiments of the present invention described herein can be used to practice the present invention. It is intended that the following claims define the scope of the invention, and methods and structures within the scope of these claims and their equivalents are covered by the claims.

[0050] definition

[0051] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. All patents and publications mentioned herein are incorporated herein by reference.

[0052] As used in the specification and claims, the singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise.

[0053] A pharmaceutically acceptable salt also refers to any salt that can be formed in vivo as a result of administration of an acid, another salt, or a prodrug that is converted into an acid or salt. A salt comprises the association of one or more ionic forms of a compound, such as a conjugate acid or base, with one or more corresponding counterions. A salt can be formed from or contain one or more deprotonated acidic groups (e.g., carboxylic acids), one or more protonated basic groups (e.g., amines), or both (e.g., zwitterions).

[0054] The term "C x-y " when used in conjunction with a chemical moiety such as alkyl, alkenyl, or alkynyl is intended to include groups containing x to y carbons in the chain. For example, the term "C 1-6 "Alkyl" refers to a saturated hydrocarbon group containing 1 to 6 carbon atoms, including straight-chain and branched-chain alkyl groups. The term -C x-y Alkylene- refers to a substituted or unsubstituted alkylene chain having from x to y carbons in the alkylene chain. For example, –C 1-6 Alkylene- may be selected from methylene, ethylene, propylene, butylene, pentylene, and hexylene, any of which are optionally substituted.

[0055] The term "C x-y Alkenyl" and "C x-y "Alkynyl" refers to an unsaturated aliphatic group analogous to the alkyl groups described above in length and possible substitution, but containing at least one double or triple bond, respectively. The term -C x-y Alkenylene- refers to a substituted or unsubstituted alkenylene chain having from x to y carbons in the alkenylene chain. For example, –C 2-6 Alkenylene - may be selected from ethenylene, propenylene, butenylene, pentenylene and hexenylene, any of which are optionally substituted. The alkenylene chain may have one double bond or more than one double bond in the alkenylene chain. Term - C x-y Alkyne- refers to a substituted or unsubstituted alkynylene chain having from x to y carbon atoms in the chain. For example, -C 2-6 Alkynylene-can be selected from ethynylene, propynylene, butynylene, pentynylene and hexynylene, any of which are optionally substituted. The alkynylene chain can have one triple bond or more than one triple bond in the alkynylene chain.

[0056] "Alkylene" refers to a linear divalent hydrocarbon chain that is attached to the rest of the molecule and consists solely of carbon and hydrogen, contains no unsaturation, and preferably has from one to twelve carbon atoms, such as methylene, ethylene, propylene, butylene, and the like. The alkylene chain is attached to the rest of the molecule and to the radical group via a single bond. The points of attachment of the alkylene chain to the rest of the molecule and to the radical group are respectively through a terminal carbon. The alkylene chain may be optionally substituted with one or more substituents such as those described herein.

[0057] "Alkenylene" refers to a straight, divalent hydrocarbon chain that is attached to the rest of the molecule and consists solely of carbon and hydrogen, contains at least one carbon-carbon double bond, and preferably has from two to twelve carbon atoms. The alkenylene chain is attached to the rest of the molecule by a single bond and to the radical group by a single bond. The points of attachment of the alkenylene chain to the rest of the molecule and to the radical group are each through a terminal carbon. The alkenylene chain may be optionally substituted with one or more substituents such as those described herein.

[0058] "Alkynylene" refers to a straight, divalent hydrocarbon chain consisting solely of carbon and hydrogen, containing at least one carbon-carbon triple bond, and preferably having from two to twelve carbon atoms, which connects the rest of the molecule to a radical. The alkynylene chain is attached to the rest of the molecule by a single bond and to the radical by a single bond. The points of attachment of the alkynylene chain to the rest of the molecule and to the radical are respectively through a terminal carbon. The alkynylene chain may be optionally substituted with one or more substituents such as those described herein.

[0059] As used herein, the term "carbocycle" refers to a saturated, unsaturated, or aromatic ring in which each atom of the ring is carbon. Carbocycles can include 3-10 membered monocycles, 6-12 membered bicyclic rings, and 6-12 membered bridged rings. Each ring of a bicyclic carbocycle can be selected from saturated, unsaturated, and aromatic rings. In some embodiments, the carbocycle is an aryl group. In some embodiments, the carbocycle is a cycloalkyl group. In some embodiments, the carbocycle is a cycloalkenyl group. In an exemplary embodiment, an aromatic ring such as a phenyl group can be fused to a saturated or unsaturated ring such as cyclohexane, cyclopentane, or cyclohexene. When valence permits, any combination of saturated, unsaturated, and aromatic bicyclic rings is included in the definition of carbocycle. Exemplary carbocycles include cyclopentyl, cyclohexyl, cyclohexenyl, adamantyl, phenyl, indanyl, and naphthyl. The carbocycle can optionally be substituted with one or more substituents such as those described herein. The bicyclic carbocycle can be a fused, bridged, or spirocyclic ring system.

[0060] As used herein, the term "heterocycle" refers to a saturated, unsaturated, or aromatic ring containing one or more heteroatoms. Exemplary heteroatoms include N, O, Si, P, B, and S atoms. Heterocycles include 3-10 membered monocyclic rings, 6-12 membered bicyclic rings, and 6-12 membered bridged rings. Each ring of a bicyclic heterocycle can be selected from saturated, unsaturated, and aromatic rings. Where valence permits, the heterocycle can be attached to the rest of the molecule via any atom of the heterocycle, such as a carbon or nitrogen atom of the heterocycle. In some embodiments, the heterocycle is a heteroaryl. In some embodiments, the heterocycle is a heterocycloalkyl. In an exemplary embodiment, a heterocycle such as a pyridyl group can be fused to a saturated or unsaturated ring such as cyclohexane, cyclopentane, or cyclohexene. Exemplary heterocycles include pyrrolidinyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, piperidinyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, thienyl, oxazolyl, thiazolyl, morpholinyl, indazolyl, indolyl, and quinolinyl. The heterocycle may be optionally substituted with one or more substituents such as those described herein.The bicyclic heterocycle may be a fused, bridged or spiro ring system.

[0061] The term "heteroaryl" includes aromatic monocyclic ring structures whose ring structures include at least one heteroatom, preferably one to four heteroatoms, more preferably one or two heteroatoms, preferably 5- to 7-membered rings, more preferably 5- to 6-membered rings. The term "heteroaryl" also includes polycyclic ring systems having two or more rings, wherein two or more atoms are shared by two adjacent rings, and wherein at least one ring is heteroaromatic, e.g., the other rings may be aromatic or non-aromatic carbocyclic or heterocyclic rings. Heteroaryl groups include, for example, pyrrole, furan, thiophene, imidazole, oxazole, thiazole, pyrazole, pyridine, pyrazine, pyridazine, and pyrimidine.

[0062] The term "substituted" refers to a substituent that replaces one or more carbon atoms of a compound or a substitutable heteroatom, such as NH or NH2. It should be understood that "substituted" or "substituted by..." includes implicit conditions, i.e., such substitutions conform to the permissible valences of the substituted atom and the substituent, and that the substitution produces a stable compound, i.e., a compound that does not spontaneously undergo a transformation such as by rearrangement, cyclization, elimination, etc. In certain embodiments, substituted refers to a substituent that replaces two hydrogen atoms on the same carbon atom, such as replacing two hydrogen atoms on a single carbon with an oxo group, an imino group, or a thio group. As used herein, the term "substituted" is considered to include all permissible substituents of an organic compound. In a broad aspect, permissible substituents include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, aromatic and non-aromatic substituents of an organic compound. For appropriate organic compounds, permissible substituents may be one or more and may be the same or different.

[0063] In some embodiments, the substituents may include any of the substituents described herein, for example, halogen, hydroxy, oxo (=O), thio (=S), cyano (-CN), nitro (-NO2), imino (=NH), oxime (=N-OH), hydrazine (=N-NH2), -R b -OR a 、-R b -OC(O)-R a 、-R b -OC(O)-OR a 、-R b -OC(O)-N(R a )2. -R b -N(R a )2. -R b -C(O)R a 、-R b -C(O)OR a 、-R b -C(O)N(R a )2. -R b -OR c -C(O)N(R a )2. -R b -N(R a )C(O)OR a 、-R b -N(R a )C(O)R a 、-R b -N(R a )S(O) t R a (where t is 1 or 2), -R b -S(O) t R a (where t is 1 or 2), -R b -S(O) t OR a (where t is 1 or 2) and -R b -S(O) t N(R a )2 (wherein t is 1 or 2); and alkyl, alkenyl, alkynyl, aryl, aralkyl, aralkenyl, aralkynyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl, and heteroarylalkyl, any of which may be optionally substituted with alkyl, alkenyl, alkynyl, halogen, haloalkyl, haloalkenyl, haloalkynyl, oxo (=O), thioxo (=S), cyano (-CN), nitro (-NO2), imino (=NH), oxime (=N-OH), hydrazine (=N-NH2), -R b -OR a、-R b -OC(O)-R a 、-R b -OC(O)-OR a 、-R b -OC(O)-N(R a )2. -R b -N(R a )2. -R b -C(O)R a 、-R b -C(O)OR a 、-R b -C(O)N(R a )2. -R b -OR c -C(O)N(R a )2. -R b -N(R a )C(O)OR a 、-R b -N(R a )C(O)R a 、-R b -N(R a )S(O) t R a (where t is 1 or 2), -R b -S(O) t R a (where t is 1 or 2), -R b -S(O) t OR a (where t is 1 or 2) and -R b -S(O) t N(R a )2 (where t is 1 or 2); where each R a are independently selected from hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl or heteroarylalkyl, wherein each R a Where valence permits, it may be optionally substituted by: alkyl, alkenyl, alkynyl, halogen, haloalkyl, haloalkenyl, haloalkynyl, oxo (=O), thio (=S), cyano (-CN), nitro (-NO2), imino (=NH), oxime (=N-OH), hydrazine (=N-NH2), -R b -OR a 、-R b -OC(O)-R a 、-R b -OC(O)-OR a 、-R b -OC(O)-N(Ra )2. -R b -N(R a )2. -R b -C(O)R a 、-R b -C(O)OR a 、-R b -C(O)N(R a )2. -R b -OR c -C(O)N(R a )2. -R b -N(R a )C(O)OR a 、-R b -N(R a )C(O)R a 、-R b -N(R a )S(O) t R a (where t is 1 or 2), -R b -S(O) t R a (where t is 1 or 2), -R b -S(O) t OR a (where t is 1 or 2) and -R b -S(O) t N(R a )2 (where t is 1 or 2); and wherein each R b are independently selected from a direct bond or a straight or branched alkylene, alkenylene or alkynylene chain, and each R c is a straight or branched alkylene, alkenylene or alkynylene chain. It will be understood by those skilled in the art that substituents may themselves be substituted, if appropriate.

[0064] As used herein, the phrases "parenteral administration" and "administered parenterally" mean modes of administration other than enteral and topical administration, usually by injection, and include, but are not limited to, intravenous, intramuscular, intraarterial, intrathecal, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, transtracheal, subcutaneous, subcutaneous, intraarticular, subcapsular, subarachnoid, intraspinal, and intrasternal injection and infusion.

[0065] The phrase "pharmaceutically acceptable" is used herein to refer to those compounds, materials, compositions, and / or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit / risk ratio.

[0066] As used herein, the phrase "pharmaceutically acceptable excipient" or "pharmaceutically acceptable carrier" means a pharmaceutically acceptable material, composition, or vehicle, such as a liquid or solid filler, diluent, excipient, solvent, or encapsulating material. Each carrier must be "acceptable" in the sense of being compatible with the other ingredients of the formulation and not injurious to the patient. Some examples of materials that can serve as pharmaceutically acceptable carriers include: (1) sugars such as lactose, glucose, and sucrose; (2) starches such as corn starch and potato starch; (3) cellulose and its derivatives such as sodium carboxymethylcellulose, ethylcellulose, and cellulose acetate; (4) powdered tragacanth; (5) malt; (6) gelatin; (7) talc; (8) excipients such as cocoa butter and suppository waxes; (9) oils such as peanut oil, cottonseed oil, , safflower oil, sesame oil, olive oil, corn oil and soybean oil; (10) glycols such as propylene glycol; (11) polyols such as glycerol, sorbitol, mannitol and polyethylene glycol; (12) esters such as ethyl oleate and ethyl laurate; (13) agar; (14) buffers such as magnesium hydroxide and aluminum hydroxide; (15) alginic acid; (16) pyrogen-free water; (17) isotonic saline; (18) Ringer's solution; (19) ethanol; (20) phosphate buffer solution; and (21) other nontoxic compatible substances used in pharmaceutical preparations.

[0067] The terms "subject," "individual," and "patient" are used interchangeably and refer to humans as well as non-human mammals (e.g., non-human primates, canines, equines, felines, porcines, bovines, ungulates, lagomorphs, etc.). In various embodiments, a subject may be a human (e.g., an adult male, an adult female, an adolescent male, an adolescent female, a male child, a female child) who is hospitalized under the care of a physician or other health care provider, as an outpatient, or in other clinical settings. In certain embodiments, a subject may not be under the care or prescription of a physician or other health care provider.

[0068] As used herein, the phrase "a subject in need thereof" refers to a subject as described below who suffers from, or is at risk of, a condition to be treated prophylactically or therapeutically with a compound or salt described herein.

[0069] The term "administer" or "administered" or "administers" or "administering" is defined as providing a composition to a subject by any route known in the art, including but not limited to intravenous, intraarterial, oral, parenteral, buccal, topical, transdermal, rectal, intramuscular, subcutaneous, intraosseous, transmucosal, or intraperitoneal administration. In certain embodiments, an oral route of administration of the composition may be used. The term "administering" a compound should be understood to mean providing a compound of the present invention or a prodrug of a compound of the present invention to an individual in need thereof.

[0070] The term "effective amount" or "therapeutically effective amount" refers to that amount of a compound or salt described herein that is sufficient to achieve the intended application, including but not limited to disease treatment, as defined below. The therapeutically effective amount may vary depending on the intended application (in vitro or in vivo); or the subject and disease condition being treated, such as the weight and age of the subject, the severity of the disease condition; the mode of administration, etc., which can be readily determined by one of ordinary skill in the art. The term can also apply to a dose that can induce a specific response in the target cell, such as a decrease in proliferation or downregulation of the activity of a target protein. The specific dose may vary depending on the specific compound selected, the dosing regimen to be followed, whether it is administered in combination with other compounds, the timing of administration, the tissue to which it is administered, and the physical delivery system in which it is carried.

[0071] As used herein, "treatment" or "treating" refers to a method for obtaining a beneficial or desired result with respect to a disease, disorder, or medical condition, including, but not limited to, a therapeutic benefit and / or a preventive benefit. In certain embodiments, treatment involves administering a compound or composition disclosed herein to a subject. The therapeutic benefit may include the eradication or improvement of the underlying condition being treated. In addition, the therapeutic benefit may be achieved by eradicating or improving one or more physiological symptoms associated with the underlying condition, such as by observing an improvement in the subject, even though the subject may still be suffering from the underlying condition. In certain embodiments, for preventive benefit, the composition is administered to a subject at risk of developing a particular disease, or to a subject reporting one or more physiological symptoms of a disease, although a diagnosis of the disease may not yet have been made. Treatment may include, for example, reducing, delaying, or alleviating the severity of one or more symptoms of a disease or illness, or it may include reducing the frequency of symptoms experienced by a patient of a disease, defect, disorder, or adverse condition. Treatment may be used herein to refer to a method that results in a certain level of treatment or improvement of a disease or illness, and a range of results directed toward the goal may be considered, including, but not limited to, preventing the disease completely.

[0072] In certain embodiments, the terms "prevent" or "preventing" as used in connection with a disease or condition may refer to a compound reducing the occurrence of the condition or disorder in a treated sample relative to an untreated control sample, or delaying the onset of or reducing the severity of one or more symptoms of the condition or disorder relative to an untreated control sample.

[0073] "Therapeutic effect," as the term is used herein, encompasses therapeutic benefit and / or prophylactic benefit as described above. A prophylactic effect includes delaying or eliminating the appearance of a disease or disorder, delaying or eliminating the onset of symptoms of a disease or disorder, slowing, stopping, or reversing the progression of a disease or disorder, or any combination thereof.

[0074] As used in relation to a biologically active agent, the term "selective inhibition" or "selectively inhibit" means that the agent is able to preferentially reduce target signaling activity over off-target signaling activity by interacting directly or indirectly with the target.

[0075] introduction

[0076] The mechanistic target of rapamycin (mTOR) signaling pathway integrates both intracellular and extracellular signals and acts as a master regulator of cell metabolism, growth, proliferation, and survival. Specifically, mTOR complex 1 (mTORC1) positively regulates cell growth and proliferation by promoting many anabolic processes including the biosynthesis of proteins, lipids, and organelles, and by limiting catabolic processes such as autophagy. Much of the knowledge about mTORC1 function comes from the use of the bacterial macrolide rapamycin.

[0077] Rapamycin is thought to directly inhibit mTORC1 and indirectly inhibit mTORC2 after long-term treatment. Recent evidence has revealed that inhibition of mTORC1 leads to effects associated with lifespan extension, whereas inhibition of mTORC2 is unrelated to longevity and leads to several adverse effects of rapamycin, such as impaired insulin sensitivity, impaired glucose homeostasis, and dysregulation of lipids.

[0078] Studies on rapamycin and related compounds have revealed that these compounds form binary complexes with FKB binding proteins such as FKBP12 and FKBP51. This binary complex can allosterically inhibit the functionality of mTORC1 by binding to the FRB domain of mTOR. FKBP12 and FKBP51 direct binding assays provide a method for assessing the relative binding affinity of rapamycin and related compounds for a given FKBP. Without wishing to be bound by any particular mechanistic theory, it is preferred that the binding of rapamycin and related compounds to FKB proteins, such as FKBP12 or FKBP51, is similar, equivalent, or stronger than the binding of rapamycin to the FKB protein.

[0079] The ternary complex formation assay provides a method to assess the relative binding affinity of the rapamycin / FKB binary complex to the FRB domain of mTOR. The different binding affinities exhibited by rapamycin and related compound / FKB complexes to mTOR relative to rapamycin, everolimus, and related compounds may result in different pharmacological and safety profiles.

[0080] In certain aspects, the present disclosure provides compounds and salts thereof and methods of use for treating diseases. In certain aspects, the compounds described herein exhibit similar direct binding properties, such as similar or improved FKB binding, relative to known compounds such as rapamycin and everolimus. In certain aspects, the compounds described herein exhibit altered ternary binding affinity, such as reduced binding affinity to the FRB domain of mTOR, relative to known compounds such as rapamycin or everolimus.

[0081] In certain embodiments, the compounds or salts of the present disclosure are evaluated for direct binding to FKBP12 and / or FKBP51. In certain embodiments, the compounds or salts of the present disclosure are evaluated for ternary complex formation with MTORC1 and FKBP12. In certain embodiments, the compounds or salts thereof have strong binding to FKBP12 and / or FKBP51.

[0082] Compound

[0083] In some aspects, the present disclosure provides a compound represented by Formula (IA) or (IIA):

[0084]

[0085] or a salt thereof, wherein:

[0086] R 1 Selected from and -OCH3;

[0087] R 2 is selected from hydrogen, hydroxy and optionally substituted C1-C6 alkoxy, wherein the substituents on the C1-C6 alkoxy are independently selected at each occurrence from hydroxy, halogen, cyano, nitro, C2-C6 alkoxy, optionally substituted carbocycle and optionally substituted heterocycle, wherein the substituents on the carbocycle or heterocycle are independently selected from hydroxy, halogen, cyano, nitro, C1-C6 alkyl, haloalkyl, hydroxyC1-C6 alkyl, alkoxy and alkoxyC1-C6 alkyl;

[0088] R 3 is selected from hydrogen, hydroxy and optionally substituted C1-C6 alkoxy, wherein the substituents on the C1-C6 alkoxy are independently selected at each occurrence from hydroxy, halogen, cyano, nitro, C2-C6 alkoxy, optionally substituted carbocycle and optionally substituted heterocycle, wherein the substituents on the carbocycle or heterocycle are independently selected from hydroxy, halogen, cyano, nitro, C1-C6 alkyl, haloalkyl, hydroxyC1-C6 alkyl, alkoxy and alkoxyC1-C6 alkyl;

[0089] R 4 Selected from -O-(CH2) 0-1 T and -O-CH(CH3)2;

[0090] T is an optionally substituted 3-6 membered heterocycloalkyl group, wherein the substituents are independently selected from hydroxy, halogen, cyano, nitro, C1-C6 alkyl, haloalkyl, hydroxyC1-C6 alkyl, alkoxy and alkoxyC1-C6 alkyl;

[0091] Q 1 and Q 3 Independently selected from -O-, -OC(=O)NR 41 -, -S-, and -NR 40 -;

[0092] Q 2 Selected from optionally substituted C 3-6 Carbocycle, optionally substituted 3-8 membered heterocycle, -OR 34 、-(O-CH2-(CH2) p ) n -W and -N(R 39 )2, where C 3-6 The substituents on the carbocyclic ring and the 3-8 membered heterocyclic ring are independently selected from hydroxy, halogen, cyano, nitro, C1-C6 alkyl, haloalkyl, hydroxy C1-C6 alkyl, alkoxy and alkoxy C1-C6 alkyl;

[0093] Q 4 Selected from optionally substituted C 3-6 Carbocycle, optionally substituted 3-8 membered heterocycle and -OR 42, where C 3-6 The substituents on the carbocyclic ring and the 3-8 membered heterocyclic ring are independently selected from hydroxy, halogen, cyano, nitro, C1-C6 alkyl, haloalkyl, hydroxy C1-C6 alkyl, alkoxy and alkoxy C1-C6 alkyl;

[0094] R 30 、R 31 、R 35 and R 36 independently selected from hydrogen, hydroxy, halogen, cyano, nitro, C1-C6 alkyl, haloalkyl, hydroxy C1-C6 alkyl, alkoxy and alkoxy C1-C6 alkyl;

[0095] Each R 32 、R 33 、R 37 and R 38 independently selected from hydrogen, hydroxy, halogen, cyano, nitro, C1-C6 alkyl, haloalkyl, hydroxy C1-C6 alkyl, alkoxy and alkoxy C1-C6 alkyl;

[0096] Each R 34 is selected from hydrogen, optionally substituted C1-C6 alkyl, optionally substituted carbocycle and optionally substituted heterocycle, wherein the substituents on C1-C6 alkyl, carbocycle and heterocycle are independently selected at each occurrence from hydroxy, halogen, cyano, nitro, C1-C6 alkoxy, carbocycle and heterocycle;

[0097] Each R 39 Selected from hydrogen, C1-C6 alkyl, haloalkyl and alkoxy C1-C6 alkyl;

[0098] Each R 40 is selected from hydrogen and optionally substituted C1-C6 alkyl, wherein the substituents are independently selected at each occurrence from hydroxy, halogen, cyano, nitro, C2-C6 alkoxy, carbocycle, and heterocycle; and

[0099] Each R 41 is selected from hydrogen and optionally substituted C1-C6 alkyl, wherein the substituents are independently selected at each occurrence from hydroxy, halogen, cyano, nitro, C2-C6 alkoxy, carbocycle and heterocycle;

[0100] Each R 42 is selected from hydrogen, optionally substituted C1-C6 alkyl, optionally substituted carbocycle and optionally substituted heterocycle, wherein the substituents on C1-C6 alkyl, carbocycle and heterocycle are independently selected at each occurrence from hydroxy, halogen, cyano, nitro, C1-C6 alkoxy, carbocycle and heterocycle;

[0101] Each p is selected from 1 or 2;

[0102] n is selected from 2 to 4; and

[0103] W is selected from -OH and -OCH3.

[0104] In some embodiments, the compound or salt of Formula (IA) is represented by the structure of Formula (IB), (IC), (ID), or (IE), or a salt of any of them. In some embodiments, the structure of Formula (IB) is represented by or a salt thereof. In some embodiments, the structure of formula (IC) is represented by or a salt thereof. In some embodiments, the structure of Formula (ID) is represented by or a salt thereof. In some embodiments, the structure of Formula (IE) is represented by or a salt thereof.

[0105] In some embodiments, the compound or salt of Formula (IIA) is represented by the structure of Formula (IIB) or Formula (IIC). In some embodiments, the structure of Formula (IIB) is represented by or its salts. In some embodiments, the structure of formula (IIC) can be represented by or a salt thereof.

[0106] In certain embodiments, the compounds of the present disclosure may be selected from Formula (III-A), (III-B), (III-C), (III-D), (III-E), (III-F), (III-G), and (III-H):

[0107]

[0108]

[0109]

[0110] or a salt thereof, wherein:

[0111] R 1 Selected from and -OCH3;

[0112] R 4 Selected from -O-(CH2) 0-1 T and -O-CH(CH3)2;

[0113] T is an optionally substituted 3-6 membered heterocycloalkyl group, wherein the substituents are independently selected from hydroxy, halogen, cyano, nitro, C1-C6 alkyl, haloalkyl, hydroxyC1-C6 alkyl, alkoxy and alkoxyC1-C6 alkyl;

[0114] Q 1 and Q3 Independently selected from -O-, -OC(=O)NR 41 -, -S-, and -NR 40 -;

[0115] Q 2 Selected from optionally substituted C 3-6 Carbocycle, optionally substituted 3-8 membered heterocycle, -OR 34 、-(O-CH2-(CH2) p ) n -W and -N(R 39 )2, where C 3-6 The substituents on the carbocyclic ring and the 3-8 membered heterocyclic ring are independently selected from hydroxy, halogen, cyano, nitro, C1-C6 alkyl, haloalkyl, hydroxy C1-C6 alkyl, alkoxy and alkoxy C1-C6 alkyl;

[0116] Q 4 Selected from optionally substituted C 3-6 Carbocycle, optionally substituted 3-8 membered heterocycle and -OR 42 , where C 3-6 The substituents on the carbocyclic ring and the 3-8 membered heterocyclic ring are independently selected from hydroxy, halogen, cyano, nitro, C1-C6 alkyl, haloalkyl, hydroxy C1-C6 alkyl, alkoxy and alkoxy C1-C6 alkyl;

[0117] R 30 、R 31 、R 35 and R 36 independently selected from hydrogen, hydroxy, halogen, cyano, nitro, C1-C6 alkyl, haloalkyl, hydroxy C1-C6 alkyl, alkoxy and alkoxy C1-C6 alkyl;

[0118] Each R 32 、R 33 、R 37 and R 38 independently selected from hydrogen, hydroxy, halogen, cyano, nitro, C1-C6 alkyl, haloalkyl, hydroxy C1-C6 alkyl, alkoxy and alkoxy C1-C6 alkyl;

[0119] Each R 34 is selected from hydrogen, optionally substituted C1-C6 alkyl, optionally substituted carbocycle and optionally substituted heterocycle, wherein the substituents on C1-C6 alkyl, carbocycle and heterocycle are independently selected at each occurrence from hydroxy, halogen, cyano, nitro, C1-C6 alkoxy, carbocycle and heterocycle;

[0120] Each R 39 Selected from hydrogen, C1-C6 alkyl, haloalkyl and alkoxy C1-C6 alkyl;

[0121] Each R 40 is selected from hydrogen and optionally substituted C1-C6 alkyl, wherein the substituents are independently selected at each occurrence from hydroxy, halogen, cyano, nitro, C2-C6 alkoxy, carbocycle, and heterocycle; and

[0122] Each R 41 is selected from hydrogen and optionally substituted C1-C6 alkyl, wherein the substituents are independently selected at each occurrence from hydroxy, halogen, cyano, nitro, C2-C6 alkoxy, carbocycle and heterocycle;

[0123] Each R 42 is selected from hydrogen, optionally substituted C1-C6 alkyl, optionally substituted carbocycle and optionally substituted heterocycle, wherein the substituents on C1-C6 alkyl, carbocycle and heterocycle are independently selected at each occurrence from hydroxy, halogen, cyano, nitro, C1-C6 alkoxy, carbocycle and heterocycle;

[0124] Each p is selected from 1 or 2;

[0125] n is selected from 2 to 4; and

[0126] W is selected from -OH and -OCH3.

[0127] In certain embodiments, the compounds of the present disclosure may be selected from compounds represented by formula (III-A) or (III-C):

[0128]

[0129] or a salt thereof, wherein:

[0130] R 1’ Selected from -OH, and -OCH3;

[0131] R 4 Selected from -O-(CH2) 0-1 T and -O-CH(CH3)2;

[0132] T is an optionally substituted 3-6 membered heterocycloalkyl group, wherein the substituents are independently selected from hydroxy, halogen, cyano, nitro, C1-C6 alkyl, haloalkyl, hydroxyC1-C6 alkyl, alkoxy and alkoxyC1-C6 alkyl;

[0133] Q 1 and Q 3 Independently selected from -O-, -OC(=O)NR 41 -, -S-, and -NR 40 -;

[0134] Q 2 Selected from optionally substituted C 3-6Carbocycle, optionally substituted 3-8 membered heterocycle, -OR 34 、-(O-CH2-(CH2) p ) n -W and -N(R 39 )2, where C 3-6 The substituents on the carbocyclic ring and the 3-8 membered heterocyclic ring are independently selected from hydroxy, halogen, cyano, nitro, C1-C6 alkyl, haloalkyl, hydroxy C1-C6 alkyl, alkoxy and alkoxy C1-C6 alkyl;

[0135] Q 4 Selected from optionally substituted C 3-6 Carbocycle, optionally substituted 3-8 membered heterocycle and -OR 42 , where C 3-6 The substituents on the carbocyclic ring and the 3-8 membered heterocyclic ring are independently selected from hydroxy, halogen, cyano, nitro, C1-C6 alkyl, haloalkyl, hydroxy C1-C6 alkyl, alkoxy and alkoxy C1-C6 alkyl;

[0136] R 30 、R 31 、R 35 and R 36 independently selected from hydrogen, hydroxy, halogen, cyano, nitro, C1-C6 alkyl, haloalkyl, hydroxy C1-C6 alkyl, alkoxy and alkoxy C1-C6 alkyl;

[0137] Each R 32 、R 33 、R 37 and R 38 independently selected from hydrogen, hydroxy, halogen, cyano, nitro, C1-C6 alkyl, haloalkyl, hydroxy C1-C6 alkyl, alkoxy and alkoxy C1-C6 alkyl;

[0138] Each R 34 is selected from hydrogen, optionally substituted C1-C6 alkyl, optionally substituted carbocycle and optionally substituted heterocycle, wherein the substituents on C1-C6 alkyl, carbocycle and heterocycle are independently selected at each occurrence from hydroxy, halogen, cyano, nitro, C1-C6 alkoxy, carbocycle and heterocycle;

[0139] Each R 39 Selected from hydrogen, C1-C6 alkyl, haloalkyl and alkoxy C1-C6 alkyl;

[0140] Each R 40 is selected from hydrogen and optionally substituted C1-C6 alkyl, wherein the substituents are independently selected at each occurrence from hydroxy, halogen, cyano, nitro, C2-C6 alkoxy, carbocycle, and heterocycle; and

[0141] Each R 41is selected from hydrogen and optionally substituted C1-C6 alkyl, wherein the substituents are independently selected at each occurrence from hydroxy, halogen, cyano, nitro, C2-C6 alkoxy, carbocycle and heterocycle;

[0142] Each R 42 is selected from hydrogen, optionally substituted C1-C6 alkyl, optionally substituted carbocycle and optionally substituted heterocycle, wherein the substituents on C1-C6 alkyl, carbocycle and heterocycle are independently selected at each occurrence from hydroxy, halogen, cyano, nitro, C1-C6 alkoxy, carbocycle and heterocycle;

[0143] Each p is selected from 1 or 2;

[0144] n is selected from 2 to 4; and

[0145] W is selected from -OH and -OCH3.

[0146] In certain embodiments, the compounds of the present disclosure may be selected from compounds represented by formula (III-C).

[0147] In certain embodiments, the compounds of the present disclosure may be selected from compounds represented by formula (III-A).

[0148] In some embodiments, for the compound or salt of Formula (III-A) or (III-C), R 1’ Selected from: and -OCH3.

[0149] In some embodiments, for the compound or salt of Formula (III-A) or (III-C), R 1’ It is -OH.

[0150] In some embodiments, for the compound or salt of Formula (III-A) or (III-C), R 1’ Selected from: where Q 1 It's O.

[0151] In some embodiments, for the compound or salt of Formula (III-A) or (III-C), R 1’ Selected from: where Q 2 is selected from an optionally substituted 5-7 membered heterocycle, -OH or C1-C6 alkoxy.

[0152] In some embodiments, for the compound or salt of Formula (III-A) or (III-C), R 1’ Selected from: where Q 2 is selected from an optionally substituted 5-6 membered heterocycle, -OH or C1-C6 alkoxy.

[0153] In some embodiments, for the compound or salt of Formula (III-A) or (III-C), R 1’ Selected from:

[0154] where Q 2 The optional substituents of the 5-6 membered heterocyclic ring may be selected from hydroxy, hydroxy C1-C6 alkyl, C1-C6 alkyl and alkoxy.

[0155] In some embodiments, for the compound or salt of Formula (III-A) or (III-C), R 30 、R 31 、R 32 and R 33 is independently selected from hydrogen and hydroxy at each occurrence. In some embodiments, for compounds or salts of Formula (III-A) or (III-C), R 30 、R 31 、R 32 and R 33 Each is hydrogen.

[0156] In some embodiments, for the compound or salt of Formula (III-A) or (III-C), R 4 Selected from In some embodiments, R 4 Selected from where Q 3 Yes -O-.

[0157] In some embodiments, for the compound or salt of Formula (III-A) or (III-C), R 35 、R 36 、R 37 and R 38 is independently selected at each occurrence from hydrogen, hydroxy, hydroxyC1-C6 alkyl, and C1-C6 alkyl.

[0158] In some embodiments, for the compound or salt of Formula (III-A) or (III-C), R 35 、R 36 、R 37 and R 38 is independently selected at each occurrence from hydrogen.

[0159] In some embodiments, for the compound or salt of Formula (III-A) or (III-C), Q 4 Selected from optionally substituted C 3-6 Carbocycle, optionally substituted 3-7 membered heterocycle and -OR 42 .

[0160] In some embodiments, for the compound or salt of Formula (III-A) or (III-C), R 42 is selected from hydrogen, optionally substituted C1-C6 alkyl, wherein the optional substituent is selected from hydroxy and C1-C6 alkoxy.

[0161] In some embodiments, for the compound or salt of Formula (III-A) or (III-C), R 4 Selected from:

[0162]

[0163] In some embodiments, for the compound or salt of Formula (III-A) or (III-C), R 4 Selected from:

[0164] In some embodiments, for the compound or salt of Formula (III-A) or (III-C), R 4 Selected from

[0165] In some embodiments, for a compound or salt of Formula (IA), (IB), (IC), (ID), (IE), (IIA), (IIB), (IIC), (III-A), (III-B), (III-C), (III-D), (III-E), (III-F), (III-G), or (III-H), R 1 yes

[0166] R 4 no

[0167] In some embodiments, for a compound or salt of Formula (IA), (IB), (IC), (ID), (IE), (IIA), (IIB), (IIC), (III-A), (III-B), (III-C), (III-D), (III-E), (III-F), (III-G), or (III-H), R 1 no

[0168] In some embodiments, for a compound or salt of Formula (IA), (IB), (IC), (ID), (IE), (IIA), (IIB), (IIC), (III-A), (III-B), (III-C), (III-D), (III-E), (III-F), (III-G), or (III-H), R 1 In some embodiments, for a compound or salt of Formula (IA), (IB), (IC), (ID), (IE), (IIA), (IIB), (IIC), (III-A), (III-B), (III-C), (III-D), (III-E), (III-F), (III-G), or (III-H), R 1 Not hydroxyl.

[0169] In some embodiments, for a compound or salt of Formula (IA), (IB), (IC), (ID), (IE), (IIA), (IIB), or (IIC), R 2 is selected from optionally substituted C1-C6 alkoxy. 2 In some embodiments, R 2 It is -OCH3.

[0170] In some embodiments, for a compound or salt of Formula (IA), (IB), (IC), (ID), (IE), (IIA), (IIB), or (IIC), R 3 In some embodiments, R 3 is C1-C3 alkoxy. In some embodiments, R 3 In some embodiments, R 3 It is -OCH3.

[0171] In some embodiments, for a compound or salt of Formula (IA), (IB), (IC), (ID), (IE), (IIA), (IIB), (IIC), (III-A), (III-B), (III-C), (III-D), (III-E), (III-F), (III-G), or (III-H), R 1 Selected from: In some embodiments, R 1 Selected from: wherein n is 0, 1, 2, 3, 4, or 5. In some embodiments, n is 0, 1, 2 or 3. In some embodiments, n is 0, 1 or 2. In some embodiments, n is 0. In some embodiments, Where n is 1. In some embodiments, The n is 2.

[0172] In some embodiments, for a compound or salt of Formula (IA), (IB), (IC), (ID), (IE), (IIA), (IIB), (IIC), (III-A), (III-B), (III-C), (III-D), (III-E), (III-F), (III-G), or (III-H), Q 2 is selected from optionally substituted phenyl, optionally substituted 5-7 membered heterocycle and -N(R 39 )2, wherein the substituents on the phenyl group and the 5-7 membered heterocyclic ring are independently selected from hydroxy, halogen, cyano, nitro, C1-C6 alkyl, haloalkyl, hydroxy C1-C6 alkyl, alkoxy and alkoxy C1-C6 alkyl.

[0173] In some embodiments, for compounds of Formula (IA), (IB), (IC), (ID), (IE), (IIA), (IIB), (IIC), (III-A), (III-B), (III-C), (III-D), (III-E), (III-F), (III-G), or (III-H), when Q 1 When it is -O-, Q 2 is selected from optionally substituted phenyl, optionally substituted 5-7 membered heterocycle and -N(R 39 )2, wherein the substituents on the phenyl group and the 5-7 membered heterocyclic ring are independently selected from hydroxy, halogen, cyano, nitro, C1-C6 alkyl, haloalkyl, hydroxy C1-C6 alkyl, alkoxy and alkoxy C1-C6 alkyl.

[0174] In some embodiments, for compounds of Formula (IA), (IB), (IC), (ID), (IE), (IIA), (IIB), (IIC), (III-A), (III-B), (III-C), (III-D), (III-E), (III-F), (III-G), or (III-H), Q 2 Selected from optionally substituted phenyl and optionally substituted 5- or 6-membered heterocyclic ring, wherein the substituents on the phenyl and 5- or 6-membered heterocyclic ring are independently selected from hydroxy, halogen, cyano, nitro, C1-C6 alkyl, haloalkyl, hydroxyC1-C6 alkyl, alkoxy and alkoxyC1-C6 alkyl.

[0175] In some embodiments, for compounds of Formula (IA), (IB), (IC), (ID), (IE), (IIA), (IIB), (IIC), (III-A), (III-B), (III-C), (III-D), (III-E), (III-F), (III-G), or (III-H), Q 2 is selected from optionally substituted phenyl and optionally substituted 5- or 6-membered saturated heterocyclic ring, wherein the substituents on the phenyl and 5- or 6-membered saturated heterocyclic ring are independently selected from hydroxy, halogen, cyano, nitro, C1-C6 alkyl, haloalkyl, hydroxyC1-C6 alkyl, C1-C6 alkoxy and C1-C6 alkoxyC1-C6 alkyl.

[0176] In some embodiments, for compounds of Formula (IA), (IB), (IC), (ID), (IE), (IIA), (IIB), (IIC), (III-A), (III-B), (III-C), (III-D), (III-E), (III-F), (III-G), or (III-H), Q 2 is selected from optionally substituted phenyl, optionally substituted piperidine, optionally substituted morpholine, optionally substituted piperazine, optionally substituted pyrrolidine, optionally substituted pyrazolidine, optionally substituted oxazolidine and optionally substituted isoxazolidine, wherein the substituents on phenyl, morpholine, piperidine, pyrrolidine, pyrazolidine, oxazolidine, isoxazolidine and piperazine are independently selected from hydroxy, halogen, cyano, nitro, C1-C6 alkyl, haloalkyl, hydroxyC1-C6 alkyl, alkoxy and alkoxyC1-C6 alkyl.

[0177] In some embodiments, for compounds of Formula (IA), (IB), (IC), (ID), (IE), (IIA), (IIB), (IIC), (III-A), (III-B), (III-C), (III-D), (III-E), (III-F), (III-G), or (III-H), Q 2 is selected from optionally substituted phenyl, optionally substituted piperidine, optionally substituted morpholine and optionally substituted piperazine, wherein the substituents on phenyl, morpholine, piperidine and piperazine are independently selected from hydroxy, halogen, cyano, nitro, C1-C6 alkyl, haloalkyl, hydroxyC1-C6 alkyl, alkoxy and alkoxyC1-C6 alkyl.

[0178] In some embodiments, for compounds of Formula (IA), (IB), (IC), (ID), (IE), (IIA), (IIB), (IIC), (III-A), (III-B), (III-C), (III-D), (III-E), (III-F), (III-G), or (III-H), R 1Q 1 Selected from -O- and -OC(=O)NR 41 -. In some embodiments, R 1 Q 1 Selected from -O- and -OC(=O)NR 41 -, and R 41 is selected from hydrogen and C1-C3 alkyl, wherein the substituents are independently selected at each occurrence from halogen, hydroxy, carbocycle and heterocycle. In some embodiments, R 41 The carbocyclic ring of the optionally substituted C1-C3 alkyl group is C 3-6 In some embodiments, R 41 The heterocyclic ring of the optionally substituted C1-C3 alkyl is a 3- to 6-membered heterocyclic ring, such as a 5- or 6-membered heteroaryl ring. 1 Q 1 Selected from -O- and -OC(=O)NR 41 -, and R 41 is selected from hydrogen and C1-C3 alkyl, wherein the substituent is independently selected at each occurrence from halogen or hydroxy. In some embodiments, R 1 Q 1 Selected from -O- and -OC(=O)NR 41 -, and R 41 is selected from hydrogen and C1-C3 alkyl. 1 Q 1 Selected from -O- and -OC(=O)NR 41 -, and R 41 is selected from hydrogen and C1 alkyl. In some embodiments, R 1 Q 1 Yes-OC(=O)NR 41 -, and R 41 Selected from hydrogen and C 1-3 alkyl.

[0179] In some embodiments, for compounds of Formula (IA), (IB), (IC), (ID), (IE), (IIA), (IIB), (IIC), (III-A), (III-B), (III-C), (III-D), (III-E), (III-F), (III-G), or (III-H), R 1 Q 1 In some embodiments, R 1 Q 1 In some embodiments, R 1 Q 1is -OC(=O)NH-. In some embodiments, R 1 Q 1 In some embodiments, R 1 Q 1 In some embodiments, R 1 Q 1 In some embodiments, R 1 Q 1 It is -OC(=O)N(CH2CH2CH2CH3)-.

[0180] In some embodiments, for compounds of Formula (IA), (IB), (IC), (ID), (IE), (IIA), (IIB), (IIC), (III-A), (III-B), (III-C), (III-D), (III-E), (III-F), (III-G), or (III-H), R 1 R 30 、R 31 、R 32 and R 33 Each of R is independently selected from hydrogen, hydroxy, halogen, cyano, nitro, and C1-C6 alkyl. 1 R 30 、R 31 、R 32 and R 33 Each of R is independently selected from hydrogen, hydroxy, halogen, cyano, nitro, and C1-C3 alkyl. 1 R 30 、R 31 、R 32 and R 33 Each of which is independently selected from hydrogen, hydroxyl and C1-C3 alkyl.

[0181] In some embodiments, for compounds of Formula (IA), (IB), (IC), (ID), (IE), (IIA), (IIB), (IIC), (III-A), (III-B), (III-C), (III-D), (III-E), (III-F), (III-G), or (III-H), R 1 R 30 、R 31 、R 32 and R 33 Each of R is independently selected from hydrogen, hydroxyl and methyl. 1 R30 、R 31 、R 32 and R 33 One of them is hydroxy or methyl, and R 30 、R 31 、R 32 and R 33 The remainder of R is each hydrogen. 1 R 30 、R 31 、R 32 and R 33 One of them is hydroxyl, and R 30 、R 31 、R 32 and R 33 The remainder of R is each hydrogen. 1 Each R 30 、R 31 、R 32 and R 33 It's hydrogen.

[0182] In some embodiments, for compounds of Formula (IA), (IB), (IC), (ID), (IE), (IIA), (IIB), (IIC), (III-A), (III-B), (III-C), (III-D), (III-E), (III-F), (III-G), or (III-H), R 1 Q 2 Selected from optionally substituted C 3-6 Carbocycle, optionally substituted 5-7 membered heterocycle, -OR 34 、-(O-CH2-(CH2) p ) n -W and -N(R 39 )2, where C 3-6 The substituents on the carbocyclic ring and the 5-7 membered heterocyclic ring are independently selected from hydroxy, halogen, cyano, nitro, C1-C6 alkyl, haloalkyl, hydroxy C1-C6 alkyl, alkoxy and alkoxy C1-C6 alkyl. 1 Q 2 is selected from optionally substituted phenyl, optionally substituted 5-7 membered heterocycle, -OR 34 、-(O-CH2-(CH2) p ) n -W and -N(R 39 )2, wherein the substituents on the phenyl group and the 5-7 membered heterocyclic ring are independently selected from hydroxy, halogen, cyano, nitro, C1-C6 alkyl, haloalkyl, hydroxy C1-C6 alkyl, alkoxy and alkoxy C1-C6 alkyl.

[0183] In some embodiments, for compounds of Formula (IA), (IB), (IC), (ID), (IE), (IIA), (IIB), (IIC), (III-A), (III-B), (III-C), (III-D), (III-E), (III-F), (III-G), or (III-H), R 1 Q 2 Selected from optionally substituted 5-7 membered heterocycle and -OR 34 In some embodiments, R 1 Q 2 Select from -OR 34 , and R 34 is selected from hydrogen and optionally substituted C1-C6 alkyl. 1 Q 2 Select from -OR 34 , and R 34 is selected from hydrogen and C1-C6 alkyl. 1 Q 2 Select from -OR 34 , and R 34 is selected from hydrogen, methyl, ethyl and propyl.

[0184] In some embodiments, for compounds of Formula (IA), (IB), (IC), (ID), (IE), (IIA), (IIB), (IIC), (III-A), (III-B), (III-C), (III-D), (III-E), (III-F), (III-G), or (III-H), R 1 Q 2 In some embodiments, R 1 Q 2 The carbon ring can be selected from: Any of which is optionally substituted. In some embodiments, R 1 Q 2 The heterocyclic ring can be selected from:

[0185] Any of them is optionally substituted.

[0186] In some embodiments, for compounds of Formula (IA), (IB), (IC), (ID), (IE), (IIA), (IIB), (IIC), (III-A), (III-B), (III-C), (III-D), (III-E), (III-F), (III-G), or (III-H), R 1 Q 2 is an optionally substituted carbocyclic ring. In some embodiments, the substituents on the carbocyclic ring are independently selected from hydroxy, halogen, cyano, nitro, C1-C6 alkyl, haloalkyl, hydroxy C1-C6 alkyl, alkoxy and alkoxy C1-C6 alkyl. In some embodiments, R 1 Q 2 is an optionally substituted C 3-6 In some embodiments, C 3-6 The substituents on the carbocyclic ring are independently selected from hydroxy, halogen, cyano, nitro, C1-C6 alkyl, haloalkyl, hydroxy C1-C6 alkyl, alkoxy and alkoxy C1-C6 alkyl. 3-6 The carbocyclic ring is substituted with a substituent selected from the group consisting of hydroxy, halogen, cyano, nitro, C1-C6 alkyl, haloalkyl, hydroxy C1-C6 alkyl, alkoxy, and alkoxy C1-C6 alkyl. 3-6 The carbocyclic ring is substituted with a substituent selected from the group consisting of hydroxy, C1-C6 alkyl, hydroxy C1-C6 alkyl, alkoxy, and alkoxy C1-C6 alkyl. 1 Q 2 is an optionally substituted phenyl. In some embodiments, R 1 Q 2 The substituents on the phenyl group are independently selected from hydroxy, halogen, cyano, nitro, C1-C6 alkyl, haloalkyl, hydroxy C1-C6 alkyl, alkoxy and alkoxy C1-C6 alkyl. 1 Q 2 The phenyl group is substituted with a substituent selected from the group consisting of hydroxy, halogen, cyano, nitro, C1-C6 alkyl, haloalkyl, hydroxy C1-C6 alkyl, alkoxy and alkoxy C1-C6 alkyl.

[0187] In some embodiments, for a compound or salt of Formula (IA), (IB), (IC), (ID), (IE), (IIA), (IIB), (IIC), (III-A), (III-B), (III-C), (III-D), (III-E), (III-F), (III-G), or (III-H), R 1 Q 2 is an optionally substituted 5-7 membered heterocyclic ring.1 Q 2 The substituents on the 5-7 membered heterocyclic ring of are independently selected from hydroxy, halogen, cyano, nitro, C1-C6 alkyl, haloalkyl, hydroxy C1-C6 alkyl, alkoxy and alkoxy C1-C6 alkyl. 1 Q 2 The substituents on the 5-7 membered heterocyclic ring are independently selected from hydroxy, C1-C6 alkyl, hydroxy C1-C6 alkyl, alkoxy and alkoxy C1-C6 alkyl. 1 Q 2 The 5-7 membered heterocyclic ring is substituted with a substituent selected from the group consisting of hydroxy, halogen, cyano, nitro, C1-C6 alkyl, haloalkyl, hydroxy C1-C6 alkyl, alkoxy and alkoxy C1-C6 alkyl. 1 Q 2 The 5-7 membered heterocyclic ring is substituted with two substituents independently selected at each occurrence from the group consisting of hydroxy, halogen, cyano, nitro, C1-C6 alkyl, haloalkyl, hydroxy C1-C6 alkyl, alkoxy, and alkoxy C1-C6 alkyl. 1 Q 2 The 5-7 membered heterocyclic ring is substituted with one, two or three substituents independently selected at each occurrence from the group consisting of hydroxy, halogen, cyano, nitro, C1-C6 alkyl, haloalkyl, hydroxy C1-C6 alkyl, alkoxy and alkoxy C1-C6 alkyl. 1 Q 2 The 5-7 membered heterocyclic ring is substituted with one or two substituents independently selected at each occurrence from the group consisting of hydroxy, halogen, cyano, nitro, C1-C6 alkyl, haloalkyl, hydroxyC1-C6 alkyl, alkoxy, and alkoxyC1-C6 alkyl. 1 Q 2 The C1-C6 alkyl group of the 5-7 membered heterocyclic ring, which is independently selected at each occurrence, may be substituted with substituents independently selected at each occurrence from the group consisting of hydroxy, C1-C6 alkyl, and alkoxy.

[0188] In some embodiments, for a compound or salt of Formula (IA), (IB), (IC), (ID), (IE), (IIA), (IIB), (IIC), (III-A), (III-B), (III-C), (III-D), (III-E), (III-F), (III-G), or (III-H), R 1 Q 2 Yes-OR 34 In some embodiments, R 1 Q 2 Yes-OR34 , and R 34 is selected from hydrogen, optionally substituted C1-C6 alkyl, optionally substituted carbocycle and optionally substituted heterocycle, wherein the substituents on C1-C6 alkyl, carbocycle and heterocycle are independently selected from hydroxy, C1-C6 alkoxy, carbocycle and heterocycle at each occurrence. In some embodiments, -OR 34 R 34 The optionally substituted carbocyclic ring is C 3-6 In some embodiments, -OR 34 R 34 The optionally substituted heterocycle is a 3-7 membered heterocycle.

[0189] In some embodiments, for compounds of Formula (IA), (IB), (IC), (ID), (IE), (IIA), (IIB), (IIC), (III-A), (III-B), (III-C), (III-D), (III-E), (III-F), (III-G), or (III-H), R 1 Selected from

[0190]

[0191] In some embodiments, for compounds of Formula (IA), (IB), (IC), (ID), (IE), (IIA), (IIB), (IIC), (III-A), (III-B), (III-C), (III-D), (III-E), (III-F), (III-G), or (III-H), R 1 Selected from:

[0192] In some embodiments, for compounds of Formula (IA), (IB), (IC), (ID), (IE), (IIA), (IIB), (IIC), (III-A), (III-B), (III-C), (III-D), (III-E), (III-F), (III-G), or (III-H), R 1 yes

[0193] In some embodiments, for compounds of Formula (IA), (IB), (IC), (ID), (IE), (IIA), (IIB), (IIC), (III-A), (III-B), (III-C), (III-D), (III-E), (III-F), (III-G), or (III-H), R 1 yes

[0194] In some embodiments, for compounds of Formula (IA), (IB), (IC), (ID), (IE), (IIA), (IIB), (IIC), (III-A), (III-B), (III-C), (III-D), (III-E), (III-F), (III-G), or (III-H), -OR 34 R 34 The carbon ring can be selected from: Any of them is optionally substituted.

[0195] In some embodiments, for compounds of Formula (IA), (IB), (IC), (ID), (IE), (IIA), (IIB), (IIC), (III-A), (III-B), (III-C), (III-D), (III-E), (III-F), (III-G), or (III-H), -OR 34 R 34 The heterocyclic ring can be selected from: Any of them is optionally substituted.

[0196] In some embodiments, for compounds of Formula (IA), (IB), (IC), (ID), (IE), (IIA), (IIB), (IIC), (III-A), (III-B), (III-C), (III-D), (III-E), (III-F), (III-G), or (III-H), R 1 Q 2 Yes-OR 34 , and R 34 is selected from hydrogen, C1-C6 alkyl, carbocycle and heterocycle. In some embodiments, -OR 34 R 34 The carbon ring is C 3-6 In some embodiments, R 1 Q 2 Select from -OR34 , and R 34 is selected from hydrogen and optionally substituted C1-C6 alkyl. 1 Q 2 Select from -OR 34 , and R 34 is selected from hydrogen and C1-C6 alkyl. 1 Q 2 Select from -OR 34 , and R 34 is selected from hydrogen, methyl, ethyl and propyl.

[0197] In some embodiments, for compounds of Formula (IA), (IB), (IC), (ID), (IE), (IIA), (IIB), (IIC), (III-A), (III-B), (III-C), (III-D), (III-E), (III-F), (III-G), or (III-H), R 1 Selected from

[0198]

[0199] In some embodiments, for compounds of Formula (IA), (IB), (IC), (ID), (IE), (IIA), (IIB), (IIC), (III-A), (III-B), (III-C), (III-D), (III-E), (III-F), (III-G), or (III-H), R 1 Selected from:

[0200] In some embodiments, for compounds of Formula (IA), (IB), (IC), (ID), (IE), (IIA), (IIB), (IIC), (III-A), (III-B), (III-C), (III-D), (III-E), (III-F), (III-G), or (III-H), R 4 Selected from and -O-(CH2) 0-1 T.

[0201] In some embodiments, for compounds of Formula (IA), (IB), (IC), (ID), (IE), (IIA), (IIB), (IIC), (III-A), (III-B), (III-C), (III-D), (III-E), (III-F), (III-G), or (III-H), R 4 is -O-(CH2) 0-1 T. In some embodiments, -O-(CH2) 0-1 T of T is an optionally substituted 3-6 membered heterocycloalkyl group, wherein the substituents are independently selected from hydroxy, C1-C6 alkyl, hydroxyC1-C6 alkyl, alkoxy and alkoxyC1-C6 alkyl.

[0202] In some embodiments, for compounds of Formula (IA), (IB), (IC), (ID), (IE), (IIA), (IIB), (IIC), (III-A), (III-B), (III-C), (III-D), (III-E), (III-F), (III-G), or (III-H), R 4 Selected from In some embodiments, R 4 Q 3 Yes -O-.

[0203] In some embodiments, for compounds of Formula (IA), (IB), (IC), (ID), (IE), (IIA), (IIB), (IIC), (III-A), (III-B), (III-C), (III-D), (III-E), (III-F), (III-G), or (III-H), R 4 R 35 、R 36 、R 37 and R 38 Each of R is independently selected from hydrogen, hydroxy, halogen, cyano, nitro, and C1-C3 alkyl. 4 R 35 、R 36 、R 37 and R 38 Each of is independently selected from hydrogen, hydroxyl and methyl.

[0204] In some embodiments, for compounds of Formula (IA), (IB), (IC), (ID), (IE), (IIA), (IIB), (IIC), (III-A), (III-B), (III-C), (III-D), (III-E), (III-F), (III-G), or (III-H), R 4 R35 、R 36 、R 37 and R 38 One or both of them are selected from hydroxyl and methyl, and R 35 、R 36 、R 37 and R 38 The remainder of each is hydrogen.

[0205] In some embodiments, for compounds of Formula (IA), (IB), (IC), (ID), (IE), (IIA), (IIB), (IIC), (III-A), (III-B), (III-C), (III-D), (III-E), (III-F), (III-G), or (III-H), R 35 、R 36 、R 37 and R 38 Each of the following is independently selected from hydrogen, hydroxy, halogen, cyano, nitro, C1-C6 alkyl, haloalkyl, hydroxyl C 1-6 Alkyl, alkoxy and alkoxy C1-C6 alkyl, where R 35 、R 36 、R 37 and R 38 At most three of them are hydroxy, halogen, cyano, nitro, C1-C6 alkyl, haloalkyl, hydroxyl C 1-6 Alkyl, alkoxy and alkoxy C1-C6 alkyl, and the others are hydrogen.

[0206] In some embodiments, for compounds of Formula (IA), (IB), (IC), (ID), (IE), (IIA), (IIB), (IIC), (III-A), (III-B), (III-C), (III-D), (III-E), (III-F), (III-G), or (III-H), R 35 、R 36 、R 37 and R 38 Each of the following is independently selected from hydrogen, hydroxy, halogen, cyano, nitro, C1-C6 alkyl, haloalkyl, hydroxyl C 1-6 Alkyl, alkoxy and alkoxy C1-C6 alkyl, where R 35 、R 36 、R 37 and R 38 At most three of them are hydroxyl groups.

[0207] In some embodiments, for compounds of Formula (IA), (IB), (IC), (ID), (IE), (IIA), (IIB), (IIC), (III-A), (III-B), (III-C), (III-D), (III-E), (III-F), (III-G), or (III-H), R 35 、R 36 、R 37 and R 38 Each of the following is independently selected from hydrogen, hydroxy, halogen, cyano, nitro, C1-C6 alkyl, haloalkyl, hydroxyl C 1-6 Alkyl, alkoxy and alkoxy C1-C6 alkyl, where R 35 、R 36 、R 37 and R 38 At most two of the groups are hydroxyl groups.

[0208] In some embodiments, for compounds of Formula (IA), (IB), (IC), (ID), (IE), (IIA), (IIB), (IIC), (III-A), (III-B), (III-C), (III-D), (III-E), (III-F), (III-G), or (III-H), R 4 Q 4 Selected from optionally substituted phenyl and -OR 42 , wherein the substituents on the phenyl group are independently selected from hydroxy, halogen, cyano, nitro, C1-C6 alkyl, haloalkyl, hydroxy C1-C6 alkyl, alkoxy and alkoxy C1-C6 alkyl.

[0209] In some embodiments, for compounds of Formula (IA), (IB), (IC), (ID), (IE), (IIA), (IIB), (IIC), (III-A), (III-B), (III-C), (III-D), (III-E), (III-F), (III-G), or (III-H), R 4 Q 4 Selected from phenyl and -OR 42 , and R 42 is selected from hydrogen and optionally substituted C1-C6 alkyl.

[0210] In some embodiments, for compounds of Formula (IA), (IB), (IC), (ID), (IE), (IIA), (IIB), (IIC), (III-A), (III-B), (III-C), (III-D), (III-E), (III-F), (III-G), or (III-H), R 4 Q4 Selected from phenyl and -OR 42 , and R 42 is selected from hydrogen, methyl, hydroxyethyl and methoxyethyl.

[0211] In some embodiments, for compounds of Formula (IA), (IB), (IC), (ID), (IE), (IIA), (IIB), (IIC), (III-A), (III-B), (III-C), (III-D), (III-E), (III-F), (III-G), or (III-H), R 4 Selected from:

[0212] In some embodiments, for compounds of Formula (IA), (IB), (IC), (ID), (IE), (IIA), (IIB), (IIC), (III-A), (III-B), (III-C), (III-D), (III-E), (III-F), (III-G), or (III-H), R 4 Selected from:

[0213] In certain embodiments, for compounds of Formula (IA), (IB), (IC), (ID), (IE), (IIA), (IIB), (IIC), (III-A), (III-B), (III-C), (III-D), (III-E), (III-F), (III-G), or (III-H):

[0214] R 1 Selected from and -OCH3;

[0215] R 2 Selected from optionally substituted C1-C6 alkoxy groups, such as R 2 is a C1-C6 alkoxy group, and preferably, R 2 is -OCH3;

[0216] R 3 Selected from optionally substituted C1-C6 alkoxy groups, such as R 2 is a C1-C6 alkoxy group, and preferably, R 2 is -OCH3;

[0217] R 4 Selected from and -O-(CH2) 0-1 T;

[0218] T is an optionally substituted 4-6 membered heterocycloalkyl, wherein the substituents are independently selected from hydroxy, halogen, cyano, nitro, C1-C6 alkyl, haloalkyl, hydroxyC1-C6 alkyl, alkoxy and alkoxyC1-C6 alkyl, such as T is selected from optionally substituted oxetane and optionally substituted pyran;

[0219] Q 1 and Q 3 Independently selected from -O-, -OC(=O)NR 41 -, -S-, and -NR 40 -, preferably, Q 1 and Q 3 Each is -O-;

[0220] Q 2 Selected from optionally substituted C 3-6 Carbocycle, optionally substituted 3-8 membered heterocycle, -OR 34 and -N(R 39 )2, where C 3-6 The substituents on the carbocyclic ring and the 3-8 membered heterocyclic ring are independently selected from hydroxy, halogen, cyano, nitro, C1-C6 alkyl, haloalkyl, hydroxy C1-C6 alkyl, alkoxy and alkoxy C1-C6 alkyl. Preferably, Q 2 Yes-OR 34 ;

[0221] Q 4 Selected from optionally substituted C 3-6 Carbocycle, optionally substituted 3-8 membered heterocycle and -OR 42 , where C 3-6 The substituents on the carbocyclic ring and the 3-8 membered heterocyclic ring are independently selected from hydroxy, halogen, cyano, nitro, C1-C6 alkyl, haloalkyl, hydroxy C1-C6 alkyl, alkoxy and alkoxy C1-C6 alkyl. Preferably, Q 4 Yes-OR 42 ;

[0222] R 30 、R 31 、R 35 and R 36 are independently selected from hydrogen, hydroxy, halogen, cyano, nitro, C1-C6 alkyl, haloalkyl, hydroxy C1-C6 alkyl, alkoxy and alkoxy C1-C6 alkyl, and preferably, R 30 、R 31 、R 35 and R 36 Each of is hydrogen;

[0223] Each R 32 、R 33 、R 37 and R38 are independently selected from hydrogen, hydroxy, halogen, cyano, nitro, C1-C6 alkyl, haloalkyl, hydroxy C1-C6 alkyl, alkoxy and alkoxy C1-C6 alkyl, wherein R 35 、R 36 、R 37 and R 38 At most two of them are hydroxyl groups, such as preferably, R 32 、R 33 、R 37 and R 38 Each of is hydrogen;

[0224] R 34 is selected from hydrogen and optionally substituted C1-C6 alkyl, hydrogen, optionally substituted C1-C6 alkyl, optionally substituted carbocycle and optionally substituted heterocycle, wherein the substituents on C1-C6 alkyl, carbocycle and heterocycle are independently selected from hydroxy, halogen, cyano, nitro, C1-C6 alkoxy, carbocycle and heterocycle at each occurrence, preferably, R 34 It is hydrogen or CH3;

[0225] Each R 39 Selected from hydrogen, C1-C6 alkyl, haloalkyl and alkoxy C1-C6 alkyl;

[0226] Each R 40 is selected from hydrogen and optionally substituted C1-C6 alkyl, wherein the substituents are independently selected at each occurrence from hydroxy, halogen, cyano, nitro, C2-C6 alkoxy, carbocycle and heterocycle;

[0227] Each R 41 is selected from hydrogen and optionally substituted C1-C6 alkyl, wherein the substituents are independently selected at each occurrence from hydroxy, halogen, cyano, nitro, C2-C6 alkoxy, carbocycle, and heterocycle; and

[0228] Each R 42 is selected from hydrogen, optionally substituted C1-C2 alkyl, optionally substituted carbocycle and optionally substituted heterocycle, wherein the substituents on C1-C2 alkyl, carbocycle and heterocycle are independently selected at each occurrence from hydroxy, halogen, cyano, nitro, C1-C2 alkoxy, carbocycle and heterocycle.

[0229] In certain embodiments, for compounds of Formula (IA), (IB), (IC), (ID), (IE), (IIA), (IIB), (IIC), (III-A), (III-B), (III-C), (III-D), (III-E), (III-F), (III-G), or (III-H):

[0230] R 1 Selected from

[0231] R 2 Selected from optionally substituted C1-C6 alkoxy groups, such as R 2 is a C1-C6 alkoxy group, and preferably, R 2 is -OCH3;

[0232] R 3 Selected from optionally substituted C1-C6 alkoxy groups, such as R 2 is a C1-C6 alkoxy group, and preferably, R 2 is -OCH3;

[0233] R 4 Selected from -O-(CH2) 0-1 T and -O-CH(CH3)2;

[0234] T is an optionally substituted 3-6 membered heterocycloalkyl group, wherein the substituents are independently selected from hydroxy, halogen, cyano, nitro, C1-C6 alkyl, haloalkyl, hydroxyC1-C6 alkyl, alkoxy and alkoxyC1-C6 alkyl;

[0235] Q 1 Selected from -OC(=O)NR 41 -, -S-, and -NR 40 -, preferably, Q 1 Yes-OC(=O)NR 41 -;

[0236] Q 3 Selected from -O-, -OC(=O)NR 41 -, -S-, and -NR 40 -, preferably, Q 3 is -O-;

[0237] Q 2 is selected from optionally substituted phenyl, optionally substituted 3-6 membered saturated heterocycle, -OR 34 and -N(R 39 ) 2, wherein the substituents on the phenyl group and the 3-6 membered saturated heterocyclic ring are independently selected from hydroxy, halogen, cyano, nitro, C1-C6 alkyl, haloalkyl, hydroxy C1-C6 alkyl, alkoxy and alkoxy C1-C6 alkyl;

[0238] Q 4 Selected from optionally substituted C 3-6 Carbocycle, optionally substituted 3-8 membered heterocycle and -OR 42 , where C 3-6The substituents on the carbocyclic ring and the 3-8 membered heterocyclic ring are independently selected from hydroxy, halogen, cyano, nitro, C1-C6 alkyl, haloalkyl, hydroxy C1-C6 alkyl, alkoxy and alkoxy C1-C6 alkyl. Preferably, Q 4 Yes-OR 42 ;

[0239] R 30 、R 31 、R 35 and R 36 are independently selected from hydrogen, hydroxy, halogen, cyano, nitro, C1-C6 alkyl, haloalkyl, hydroxy C1-C6 alkyl, alkoxy and alkoxy C1-C6 alkyl, and preferably, R 30 、R 31 、R 35 and R 36 Each of is hydrogen;

[0240] Each R 32 、R 33 、R 37 and R 38 are independently selected from hydrogen, hydroxy, halogen, cyano, nitro, C1-C6 alkyl, haloalkyl, hydroxy C1-C6 alkyl, alkoxy and alkoxy C1-C6 alkyl, wherein R 35 、R 36 、R 37 and R 38 At most two of them are hydroxyl groups, such as preferably, R 32 、R 33 、R 37 and R 38 Each of is hydrogen;

[0241] Each R 34 is selected from hydrogen, optionally substituted C1-C6 alkyl, optionally substituted carbocycle and optionally substituted heterocycle, wherein the substituents on C1-C6 alkyl, carbocycle and heterocycle are independently selected from hydroxy, halogen, cyano, nitro, C1-C6 alkoxy, carbocycle and heterocycle at each occurrence, preferably, R 34 It is hydrogen or CH3;

[0242] Each R 39 Selected from hydrogen, C1-C6 alkyl, haloalkyl and alkoxy C1-C6 alkyl;

[0243] Each R 40 is selected from hydrogen and optionally substituted C1-C6 alkyl, wherein the substituents are independently selected at each occurrence from hydroxy, halogen, cyano, nitro, C2-C6 alkoxy, carbocycle and heterocycle;

[0244] Each R 41is selected from hydrogen and optionally substituted C1-C6 alkyl, wherein the substituents are independently selected at each occurrence from hydroxy, halogen, cyano, nitro, C2-C6 alkoxy, carbocycle, and heterocycle; and

[0245] Each R 42 is selected from hydrogen, optionally substituted C1-C2 alkyl, optionally substituted carbocycle and optionally substituted heterocycle, wherein the substituents on C1-C2 alkyl, carbocycle and heterocycle are independently selected at each occurrence from hydroxy, halogen, cyano, nitro, C1-C2 alkoxy, carbocycle and heterocycle.

[0246] In certain embodiments, for a compound or salt of Formula (IA), (IB), (IC), (ID), (IE), (IIA), (IIB), (IIC), (III-A), (III-B), (III-C), (III-D), (III-E), (III-F), (III-G), or (III-H),

[0247] R 1 Selected from

[0248] R 2 Selected from optionally substituted C1-C6 alkoxy groups, such as R 2 is a C1-C6 alkoxy group, and preferably, R 2 is -OCH3;

[0249] R 3 Selected from optionally substituted C1-C6 alkoxy groups, such as R 2 is a C1-C6 alkoxy group, and preferably, R 2 is -OCH3;

[0250] R 4 Selected from -O-(CH2) 0-1 T and -O-CH(CH3)2;

[0251] T is an optionally substituted 3-6 membered heterocycloalkyl group, wherein the substituents are independently selected from hydroxy, halogen, cyano, nitro, C1-C6 alkyl, haloalkyl, hydroxyC1-C6 alkyl, alkoxy and alkoxyC1-C6 alkyl;

[0252] Q 1 Selected from -O-, -OC(=O)NR 41 -and-NR 40 -, preferably, Q 1 is -O-;

[0253] Q 3 Selected from -O-, -OC(=O)NR 41 -, -S-, and -NR40 -, preferably, Q 3 is -O-;

[0254] Q 2 is selected from the group consisting of optionally substituted phenyl, optionally substituted 3-8 membered saturated heterocyclic ring and -N(R 39 ) 2, wherein the substituents on the phenyl group and the 3-8 membered saturated heterocyclic ring are independently selected from hydroxy, halogen, cyano, nitro, C1-C6 alkyl, haloalkyl, hydroxy C1-C6 alkyl, alkoxy and alkoxy C1-C6 alkyl;

[0255] Q 4 Selected from optionally substituted C 3-6 Carbocycle, optionally substituted 3-8 membered heterocycle and -OR 42 , where C 3-6 The substituents on the carbocyclic ring and the 3-8 membered heterocyclic ring are independently selected from hydroxy, halogen, cyano, nitro, C1-C6 alkyl, haloalkyl, hydroxy C1-C6 alkyl, alkoxy and alkoxy C1-C6 alkyl. Preferably, Q 4 Yes-OR 42 ;

[0256] R 30 、R 31 、R 35 and R 36 are independently selected from hydrogen, hydroxy, halogen, cyano, nitro, C1-C6 alkyl, haloalkyl, hydroxy C1-C6 alkyl, alkoxy and alkoxy C1-C6 alkyl, and preferably, R 30 、R 31 、R 35 and R 36 Each of is hydrogen;

[0257] Each R 32 、R 33 、R 37 and R 38 are independently selected from hydrogen, hydroxy, halogen, cyano, nitro, C1-C6 alkyl, haloalkyl, hydroxy C1-C6 alkyl, alkoxy and alkoxy C1-C6 alkyl, wherein R 35 、R 36 、R 37 and R 38 At most two of them are hydroxyl groups, such as preferably, R 32 、R 33 、R 37 and R 38 Each of is hydrogen;

[0258] Each R 34is selected from hydrogen, optionally substituted C1-C6 alkyl, optionally substituted carbocycle and optionally substituted heterocycle, wherein the substituents on C1-C6 alkyl, carbocycle and heterocycle are independently selected from hydroxy, halogen, cyano, nitro, C1-C6 alkoxy, carbocycle and heterocycle at each occurrence, preferably, R 34 It is hydrogen or CH3;

[0259] Each R 39 Selected from hydrogen, C1-C6 alkyl, haloalkyl and alkoxy C1-C6 alkyl;

[0260] Each R 40 is selected from hydrogen and optionally substituted C1-C6 alkyl, wherein the substituents are independently selected at each occurrence from hydroxy, halogen, cyano, nitro, C2-C6 alkoxy, carbocycle, and heterocycle; and

[0261] Each R 41 is selected from hydrogen and optionally substituted C1-C6 alkyl, wherein the substituents are independently selected at each occurrence from hydroxy, halogen, cyano, nitro, C2-C6 alkoxy, carbocycle, and heterocycle; and

[0262] Each R 42 is selected from hydrogen, optionally substituted C1-C2 alkyl, optionally substituted carbocycle and optionally substituted heterocycle, wherein the substituents on C1-C2 alkyl, carbocycle and heterocycle are independently selected at each occurrence from hydroxy, halogen, cyano, nitro, C1-C2 alkoxy, carbocycle and heterocycle.

[0263] In certain embodiments, for the compound or salt of Formula (III-A), R 1 and R 4 can be selected from Table 1. In some cases, R 1 can be selected from Table 1. In some cases, R 4 Can be selected from Table 1.

[0264] In certain embodiments, for the compound or salt of Formula (III-B), R 1 and R 4 can be selected from Table 2. In some cases, R 1 can be selected from Table 2. In some cases, R 4 Can be selected from Table 2.

[0265] In certain embodiments, for the compound or salt of Formula (III-C), R 1 and R 4 can be selected from Table 3. In some cases, R 1 can be selected from Table 3. In some cases, R 4 Can be selected from Table 3.

[0266] In certain embodiments, for the compound or salt of Formula (III-D), R 1 and R 4 can be selected from Table 4. In some cases, R 1 can be selected from Table 4. In some cases, R 4 Can be selected from Table 4.

[0267] In certain embodiments, for the compound or salt of Formula (III-E), R 1 and R 4 Can be selected from Table 5. In some cases, R 1 Can be selected from Table 5. In some cases, R 4 Can be selected from Table 5.

[0268] In certain embodiments, for the compound or salt of Formula (III-F), R 1 and R 4 Can be selected from Table 6. In some cases, R 1 Can be selected from Table 6. In some cases, R 4 Can be selected from Table 6.

[0269] In certain embodiments, for the compound or salt of Formula (III-G), R 1 and R 4 Can be selected from Table 7. In some cases, R 1 Can be selected from Table 7. In some cases, R 4 Can be selected from Table 7.

[0270] In certain embodiments, for the compound or salt of Formula (III-H), R 1 and R 4 Can be selected from Table 8. In some cases, R 1 Can be selected from Table 8. In some cases, R 4 Can be selected from Table 8.

[0271] Chemical entities with carbon-carbon double bonds or carbon-nitrogen double bonds can exist in Z or E form (or cis or trans form). In addition, some chemical entities can exist in various tautomeric forms. Unless otherwise specified, the compounds described herein are also intended to include all Z, E and tautomeric forms.

[0272] "Isomers" are different compounds with the same molecular formula. "Stereoisomers" are isomers that differ only in the way their atoms are arranged in space. "Enantiomers" are a pair of stereoisomers that are non-superimposable mirror images of each other. A 1:1 mixture of a pair of enantiomers is a "racemic" mixture. Where appropriate, the term "(±)" is used to designate a racemic mixture. "Diastereomers" or "diastereomers" are stereoisomers that have at least two asymmetric atoms but are not mirror images of each other. Absolute stereochemistry is specified according to the Cahn-Ingold-Prelog RS system. When a compound is a pure enantiomer, the stereochemistry at each chiral carbon can be specified as R or S. Resolved compounds whose absolute configuration is unknown can be designated as (+) or (-) depending on the direction (right-handed or left-handed) in which they rotate plane polarized light at the wavelength of the sodium D line. Certain compounds described herein contain one or more asymmetric centers and can therefore give rise to enantiomers, diastereomers, and other stereoisomeric forms, whose asymmetric centers can be defined in terms of absolute stereochemistry as (R)- or (S)-. The chemical entities, pharmaceutical compositions, and methods of the present invention are intended to include all such possible stereoisomers, including racemic mixtures, optically pure forms, mixtures of diastereomers, and intermediate mixtures. Optically active (R)- and (S)-isomers can be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques. The optical activity of a compound can be analyzed by any suitable method, including but not limited to chiral chromatography and polarimetry, and the degree of dominance of one stereoisomer over another can be determined.

[0273] When stereochemistry is not specified, the molecules with stereo centers described herein include isomers, such as enantiomers and diastereomers; mixtures of enantiomers, including racemates; mixtures of diastereomers; and other mixtures thereof, as long as they can be prepared by those of ordinary skill in the art by routine experiments. In certain embodiments, a single enantiomer or diastereomer, i.e., an optically active form, can be obtained by asymmetric synthesis or by splitting a mixture of a racemate or diastereomers. If possible, the splitting of a mixture of a racemate or diastereomer can be achieved, for example, by conventional methods, such as crystallization in the presence of a resolving agent, or chromatography using, for example, a chiral high pressure liquid chromatography (HPLC) column. In addition, a mixture of two enantiomers enriched in one of the two enantiomers can be purified by recrystallization and / or wet grinding to provide a further optically enriched form of the main enantiomer.

[0274] For any formula described herein having a stereochemistry depicted at a particular position, the intended stereochemistry of the substituent is the stereochemistry depicted in the formula. For example, where R 4 yes The compound of formula (III-A) is4 will have the following stereochemistry:

[0275] Methods for producing substantially pure enantiomers are well known to those skilled in the art. For example, a single stereoisomer, such as an enantiomer, substantially free of its stereoisomers can be obtained by resolving a racemic mixture using methods such as the formation of diastereomers using optically active resolving agents (Stereochemistry of Carbon Compounds, (1962), E.L. Eliel, McGraw Hill; Lochmuller (1975) J. Chromatogr., 113(3): 283-302). Racemic mixtures of chiral compounds can be separated and isolated by any suitable method, including but not limited to: (1) forming ionic diastereomeric salts with chiral compounds and separating by fractional crystallization or other methods, (2) forming diastereomeric compounds with chiral derivatizing agents, separating diastereomers, and converting to pure stereoisomers, and (3) separating substantially pure or enriched stereoisomers directly under chiral conditions. Another method for separation of enantiomers is to use a Diacel chiral column and elute with an organic mobile phase, such as is available on a fee-for-service basis from Chiral Technologies (www.chiraltech.com).

[0276] "Tautomers" refer to molecules in which a proton can potentially shift from one atom of a molecule to another atom of the same molecule. In certain embodiments, the compounds provided herein exist as tautomers. In cases in which tautomerism is possible, a chemical equilibrium of the tautomers will exist. The exact ratio of the tautomers depends on several factors, including physical state, temperature, solvent, and pH. Some examples of tautomeric equilibrium include:

[0277]

[0278] In some embodiments, the compounds disclosed herein are used in different isotopically enriched forms, for example, 2 H. 3 H. 11 C. 13 C and / or 14 In one embodiment, the compound is enriched in C content. In a specific embodiment, the compound is deuterated in at least one position. Such deuterated forms can be prepared by the procedures described in U.S. Patents 5,846,514 and 6,334,997. As described in U.S. Patents 5,846,514 and 6,334,997, deuteration can improve metabolic stability and / or efficacy, thereby increasing the duration of action of the drug.

[0279] Unless otherwise stated, the compounds described herein are intended to include compounds that differ only in the presence of one or more isotopically enriched atoms. For example, a structure having the present invention except that a hydrogen is replaced by a deuterium or tritium, or a carbon is replaced by a 13 C or 14 C-enriched carbon-substituted compounds are within the scope of the present disclosure.

[0280] The compounds of the present disclosure optionally contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute such compounds. For example, the compounds may be labeled with isotopes such as deuterium ( 2 H), tritium ( 3 H), iodine-125 ( 125 I) or carbon-14 ( 14 C). Use 2 H. 11 C. 13 C. 14 C. 15 C. 12 N. 13 N. 15 N. 16 N. 16 O. 17 O. 14 F. 15 F. 16 F. 17 F. 18 F. 33 S. 34 S. 35 S. 36 S. 35 Cl, 37 Cl, 79 Br, 81 Br and 125 All isotopic variations of the compounds of the present invention, whether radioactive or not, are encompassed within the scope of the present invention.

[0281] In certain embodiments, some or all of the compounds disclosed herein 1 H atoms are 2 H atom replacement. Methods for synthesizing deuterium-containing compounds are known in the art and include, by way of non-limiting example only, the following synthetic methods.

[0282] Deuterium-substituted compounds are synthesized using various methods such as those described in Dean, Dennis C., ed. Recent Advances in the Synthesis and Applications of Radiolabeled Compounds for Drug Discovery and Development. [Curr., Pharm. Des., 2000; 6(10)] 2000, p. 110; George W.; Varma, Rajender S. The Synthesis of Radiolabeled Compounds via Organometallic Intermediates, Tetrahedron, 1989, 45(21), 6601-21; and Evans, E. Anthony. Synthesis of radiolabeled compounds, J. Radioanal. Chem., 1981, 64(1-2), 9-32.

[0283] Deuterated starting materials are readily available and are amenable to the synthetic methods described herein to provide the synthesis of deuterium-containing compounds. A large number of deuterium-containing reagents and building blocks are commercially available from chemical suppliers such as Aldrich Chemical Co.

[0284] The compounds of the present invention also include crystalline and amorphous forms of these compounds, pharmaceutically acceptable salts, and active metabolites of these compounds having the same type of activity, including, for example, polymorphs, pseudopolymorphs, solvates, hydrates, unsolvated polymorphs (including anhydrates), conformational polymorphs and amorphous forms of the compounds, and mixtures thereof.

[0285] The present disclosure includes salts of the compounds described herein, particularly pharmaceutically acceptable salts. Compounds of the present disclosure having sufficiently acidic functional groups, sufficiently basic functional groups, or both functional groups can react with any of a number of inorganic bases and inorganic and organic acids to form salts. Alternatively, inherently charged compounds, such as those having quaternary nitrogen, can form salts with appropriate counterions, for example, halides such as bromide, chloride, or fluoride, particularly bromide.

[0286] The methods and compositions described herein include the use of amorphous forms as well as crystalline forms (also known as polymorphs). The compounds described herein may be in the form of pharmaceutically acceptable salts. Likewise, in some embodiments, active metabolites of these compounds having the same type of activity are included within the scope of this disclosure. In addition, the compounds described herein may exist in unsolvated form as well as in solvated form with pharmaceutically acceptable solvents such as water, ethanol, etc. The solvated forms of the compounds provided herein are also considered to be disclosed herein.

[0287] In certain embodiments, the compound or the salt of the compound may be a prodrug, for example, wherein the hydroxyl group in the parent compound is presented as an ester or carbonate, or the carboxylic acid present in the parent compound is presented as an ester. The term "prodrug" is intended to encompass compounds that are converted to the disclosed medicament under physiological conditions. A method for preparing a prodrug is to include one or more selected portions that are hydrolyzed under physiological conditions to reveal the desired molecule. In other embodiments, the prodrug is converted by the enzymatic activity of specific target cells in a host animal such as a host animal. For example, esters or carbonates (e.g., esters or carbonates of alcohols or carboxylic acids, and esters of phosphonic acids) are preferred prodrugs of the present disclosure.

[0288] Prodrugs are often useful because, in some cases, they can be easier to administer than the parent drug. They can, for example, be made bioavailable by oral administration, whereas the parent drug is not. Prodrugs can help enhance the cell permeability of a compound relative to the parent drug. Prodrugs can also have improved solubility in pharmaceutical compositions compared to the parent drug. Prodrugs can be designed as reversible drug derivatives to act as modulators to enhance drug transport to site-specific tissues or to increase drug retention within cells.

[0289] In some embodiments, the design of the prodrug increases the lipophilicity of the agent. In some embodiments, the design of the prodrug increases the effective water solubility. See, e.g., Fedorak et al., Am. J. Physiol., 269:G210-218 (1995); McLoed et al., Gastroenterol, 106:405-413 (1994); Hochhaus et al., Biomed. Chrom., 6:283-286 (1992); J. Larsen and H. Bundgaard, Int. J. Pharmaceutics, 37, 87 (1987); J. Larsen et al., Int. J. Pharmaceutics, 47, 103 (1988); Sinkula et al., J. Pharm. Sci., 64:181-210 (1975); T. Higuchi and V. Stella, Pro-drugs as Novel Delivery Systems, Volume 14 of the ACS Symposium Series; and Edward B. Roche, Bioreversible Carriers in Drug Design, American Pharmaceutical Association and Pergamon Press, 1987, all incorporated herein for such disclosure). According to another embodiment, the present disclosure provides methods for producing the compounds defined above. The compounds can be synthesized using conventional techniques. Advantageously, these compounds are conveniently synthesized from readily available starting materials.

[0290] Synthetic chemistry transformations and methods useful for synthesizing the compounds described herein are known in the art and include, for example, those described in R. Larock, Comprehensive Organic Transformations (1989); T. W. Greene and P. G. Wuts, Protective Groups in Organic Synthesis, 2nd ed. (1991); L. Fieser and M. Fieser, Fieser and Fieser's Reagents for Organic Synthesis (1994); and L. Paquette, ed., Encyclopedia of Reagents for Organic Synthesis (1995).

[0291] pharmaceutical preparations

[0292] The compound or salt of any one of Formula (IA), (IB), (IC), (ID), (IE), (IIA), (IIB), (IIC), (III-A), (III-B), (III-C), (III-D), (III-E), (III-F), (III-G), or (III-H) can be formulated into any suitable pharmaceutical formulation. The pharmaceutical formulations of the present disclosure generally contain an active ingredient (e.g., a compound or salt of any one of Formula (IA), (IB), (IC), (ID), (IE), (IIA), (IIB), (IIC), (III-A), (III-B), (III-C), (III-D), (III-E), (III-F), (III-G), or (III-H)) and one or more pharmaceutically acceptable excipients or carriers, including but not limited to: inert solid diluents and fillers, diluents, sterile aqueous solutions and various organic solvents, penetration enhancers, antioxidants, solubilizers, and excipients.

[0293] In certain embodiments, the pharmaceutical preparation of the present disclosure comprises a diastereomeric mixture. The pharmaceutical preparation may include a major diastereomeric mixture of 50wt% or more and one or more minor diastereomeric mixtures of less than 50wt% individually or in combination. The pharmaceutical preparation may include 51wt% or more of the major diastereomeric mixture, such as about 60wt% to 95wt%, such as 70wt% to 95wt%, such as 80wt% to 95wt% of the major diastereomeric mixture, and one or more minor diastereomeric mixtures that make up a percentage of 100wt%. For example, the pharmaceutical preparation includes 80wt% of Table 3 compound 525 and 20wt% of Table 1 compound 126. As another example, the pharmaceutical preparation includes a diastereomeric mixture having 80wt% of Table 4 compound 601, 10wt% of Table 2 compound 201, 8wt% of Table 3 compound 401, and 2wt% of Table 1 compound 2.

[0294] In certain embodiments, the pharmaceutical preparation comprises a compound or salt of the present disclosure in the form of a diastereomeric mixture having a major diastereomer and one or more minor diastereomers, wherein the one or more minor diastereomers comprise from about 0.5 wt % to about 20 wt % of the diastereomeric mixture in the pharmaceutical preparation. For example, the pharmaceutical preparation comprises from about 1 wt % to about 40 wt %, such as from about 1 wt % to about 30 wt %, such as from about 1 wt % to about 20 wt %, such as from about 2 wt % to about 10 wt %, such as from about 5 wt % to about 10 wt % of the minor diastereomer or a combination of minor diastereomers.

[0295] In certain embodiments, a pharmaceutical formulation comprises a compound or salt of the present disclosure as a diastereomeric mixture, wherein the major diastereomer comprises 90% or more, 95% or more, or even 98% or more by weight of the diastereomeric mixture.

[0296] In certain embodiments, the compound or salt of Formula (IA), (IB), (IC), (ID), (IE), (IIA), (IIB), (IIC), (III-A), (III-B), (III-C), (III-D), (III-E), (III-F), (III-G), or (III-H) is formulated with an agent that inhibits degradation of the compound or salt. In certain embodiments, the compound or salt is formulated with one or more antioxidants. Acceptable antioxidants include, but are not limited to, citric acid, d, 1-α-tocopherol, BHA, BHT, monothioglycerol, ascorbyl palmitate, ascorbic acid, and propyl gallate. In certain embodiments, the formulation contains 0.1 to 30%, 0.5 to 25%, 1 to 20%, 5 to 15% or 7 to 12% (wt / wt) CCI-779, 0.5 to 50%, 1 to 40%, 5 to 35%, 10 to 25% or 15 to 20% (wt / wt) water-soluble polymer, 0.5 to 10%, 1 to 8% or 3 to 5% (wt / wt) surfactant, and 0.001% to 1%, 0.01% to 1% or 0.1% to 0.5% (wt / wt) antioxidant. In certain embodiments, the antioxidant of the formulation of the present invention will be used at a concentration within the range of 0.001% to 3% wt / wt.

[0297] In certain embodiments, the compound or salt of Formula (IA), (IB), (IC), (ID), (IE), (IIA), (IIB), (IIC), (III-A), (III-B), (III-C), (III-D), (III-E), (III-F), (III-G), or (III-H) is formulated with a pH adjuster to maintain a pH of about 4 to about 6. Acceptable pH adjusters include, but are not limited to, citric acid, sodium citrate, dilute HCl, and other weak acids or bases capable of buffering solutions containing the compounds or salts of the present disclosure to a pH in the range of about 4 to about 6.

[0298] In certain embodiments, the compound or salt of Formula (IA), (IB), (IC), (ID), (IE), (IIA), (IIB), (IIC), (III-A), (III-B), (III-C), (III-D), (III-E), (III-F), (III-G), or (III-H) is formulated with a chelating agent or other material capable of binding metal ions, such as ethylenediaminetetraacetic acid (EDTA) and its salts, which can enhance the stability of the compound or salt of Formula (IA), (IB), (IC), (ID), (IE), (IIA), (IIB), (IIC), (III-A), (III-B), (III-C), (III-D), (III-E), (III-F), (III-G), or (III-H).

[0299] Pharmaceutical preparations can be provided in any suitable form, which may depend on the route of administration. In some embodiments, pharmaceutical compositions disclosed herein may be formulated into dosage forms to be administered to a subject. In some embodiments, pharmaceutical compositions are formulated for oral, intravenous, intra-arterial, aerosol, parenteral, buccal, surface, transdermal, rectal, intramuscular, subcutaneous, intraosseous, intranasal, intrapulmonary, mucosal, inhalation and / or intraperitoneal administration. In some embodiments, dosage forms are formulated for oral administration. For example, pharmaceutical compositions may be formulated in the form of pills, tablets, capsules, inhalants, liquid suspensions, liquid emulsions, gels or powders. In some embodiments, pharmaceutical compositions may be formulated into unit doses in liquid, gel, semi-liquid, semi-solid or solid forms.

[0300] The amount of the compound or salt of any of Formula (IA), (IB), (IC), (ID), (IE), (IIA), (IIB), (IIC), (III-A), (III-B), (III-C), (III-D), (III-E), (III-F), (III-G), or (III-H) will depend on the mammal being treated, the severity of the disorder or condition, the rate of administration, the disposition of the compound or salt of any of Formula (IA), (IB), (IC), (ID), (IE), (IIA), (IIB), (IIC), (III-A), (III-B), (III-C), (III-D), (III-E), (III-F), (III-G), or (III-H), and the judgment of the prescribing physician.

[0301] In some embodiments, a pharmaceutically acceptable carrier of Formula (IA), (IB), (IC), (ID), (IE), (IIA), (IIB), (IIC), (III-A), (III-B), (III-C), (III-D), (III-E), (III-F), (III-G), or (III-H) may include a physiologically acceptable compound that is an antioxidant.

[0302] In some embodiments, the present disclosure provides a pharmaceutical composition for oral administration, comprising at least one compound or salt of any one of Formula (IA), (IB), (IC), (ID), (IE), (IIA), (IIB), (IIC), (III-A), (III-B), (III-C), (III-D), (III-E), (III-F), (III-G), or (III-H) and a pharmaceutical excipient suitable for oral administration. The composition can be in the form of a solid, liquid, gel, semi-liquid, or semi-solid. In some embodiments, the composition further comprises a second dose.

[0303] Pharmaceutical compositions of the present disclosure suitable for oral administration can be presented as discrete dosage forms such as hard or soft capsules, cachets, lozenges, troches or tablets, or liquids or aerosol sprays (each containing a predetermined amount of active ingredient in powdered or granular form), solutions, or suspensions in aqueous or non-aqueous liquids, oil-in-water emulsions, or water-in-oil liquid emulsions, or dispersible powders or granules, or syrups or elixirs. Such dosage forms can be prepared by any of the pharmaceutical methods that generally include the step of bringing one or more active ingredients into association with a carrier. In general, the compositions are prepared by uniformly and intimately admixing one or more active ingredients with a liquid carrier or a finely divided solid carrier, or both, and then, if necessary, shaping the product into the desired appearance. For example, tablets can be prepared by compression or molding, optionally with one or more auxiliary ingredients. Compressed tablets can be prepared by compressing one or more active ingredients in a free-flowing form (such as a powder or granules), optionally mixed with an excipient such as, but not limited to, a binder, a lubricant, an inert diluent, and / or a surfactant or dispersant, in a suitable machine. Molded tablets can be prepared by molding a mixture of a compound or salt of any one of Formula (IA), (IB), (IC), (ID), (IE), (IIA), (IIB), (IIC), (III-A), (III-B), (III-C), (III-D), (III-E), (III-F), (III-G), or (III-H), moistened with an inert liquid diluent, in a suitable machine.

[0304] In some embodiments, the present disclosure provides a pharmaceutical composition for injection, comprising a compound or salt of any one of Formula (IA), (IB), (IC), (ID), (IE), (IIA), (IIB), (IIC), (III-A), (III-B), (III-C), (III-D), (III-E), (III-F), (III-G), or (III-H) disclosed herein and a pharmaceutical excipient suitable for injection. The components of the composition and the amounts of the agent are as described herein.

[0305] In certain embodiments, the compound or salt of any of Formula (IA), (IB), (IC), (ID), (IE), (IIA), (IIB), (IIC), (III-A), (III-B), (III-C), (III-D), (III-E), (III-F), (III-G), or (III-H) can be formulated for injection as an aqueous or oily suspension; emulsions containing sesame oil, corn oil, cottonseed oil, or peanut oil; as well as elixirs, mannitol, dextrose, or sterile aqueous solutions and similar pharmaceutical vehicles.

[0306] Aqueous solutions in saline are also conventionally used for injection. Ethanol, glycerol, propylene glycol, liquid polyethylene glycols, etc. (and suitable mixtures thereof), cyclodextrin derivatives, and vegetable oils can also be used. Suitable fluidity can be maintained, for example, by using a coating such as lecithin, by maintaining the desired particle size in the case of a dispersion, and by using a surfactant. Preventing the effects of microorganisms can be achieved by various antibacterial and antifungal agents such as parabens, chlorobutanol, phenol, sorbic acid, thimerosal, etc.

[0307] Pharmaceutical compositions can also be prepared from a compound or salt of any of Formula (IA), (IB), (IC), (ID), (IE), (IIA), (IIB), (IIC), (III-A), (III-B), (III-C), (III-D), (III-E), (III-F), (III-G), or (III-H) and one or more pharmaceutically acceptable excipients suitable for transdermal, inhalation, sublingual, buccal, rectal, intraosseous, intraocular, intranasal, epidural, or intraspinal administration. The preparation of such pharmaceutical compositions is well known in the art. See, e.g., Anderson, Philip O.; Knoben, James E.; Troutman, William G, eds., Handbook of Clinical Drug Data, 10th ed., McGraw-Hill, 2002; Pratt and Taylor, eds., Principles of Drug Action, 3rd ed., Churchill Livingston, New York, 1990; Katzung, ed., Basic and Clinical Pharmacology, 9th ed., McGraw Hill, 2003; Goodman and Gilman, eds., The Pharmacological Basis of Therapeutics, 10th ed., McGraw Hill, 2001; Remingtons Pharmaceutical Sciences, 20th ed., Lippincott Williams & Wilkins., 2000; Martindale, The Extra Pharmacopoeia, 32nd ed. (The Pharmaceutical Press, London, 1999).

[0308] The present disclosure also provides kits. The kits can include a compound or salt of any one of Formula (IA), (IB), (IC), (ID), (IE), (IIA), (IIB), (IIC), (III-A), (III-B), (III-C), (III-D), (III-E), (III-F), (III-G), or (III-H) and one or more additional agents in suitable packaging, as well as written materials that may include instructions for use, discussions of clinical studies, lists of side effects, and the like. Such kits can also include information indicating or confirming the activity and / or advantages of the composition, and / or describing dosing, application, side effects, drug interactions, such as scientific references, package inserts, clinical trial results, and / or summaries of such information, or other information useful to health care providers. Such information can be based on the results of various studies, such as studies using experimental animals, studies involving in vivo models, and studies based on human clinical trials. The kit can also contain another agent. In some embodiments, the compound or salt of any one of Formula (IA), (IB), (IC), (ID), (IE), (IIA), (IIB), (IIC), (III-A), (III-B), (III-C), (III-D), (III-E), (III-F), (III-G), or (III-H) and the agent are provided as separate compositions in separate containers within the kit. In some embodiments, the compound or salt of any one of Formula (IA), (IB), (IC), (ID), (IE), (IIA), (IIB), (IIC), (III-A), (III-B), (III-C), (III-D), (III-E), (III-F), (III-G), or (III-H) and the agent are provided as a single composition within a container within the kit. Suitable packaging and additional supplies (e.g., measuring cups for liquid formulations, foil packaging to minimize air exposure, etc.) are known in the art and can be included in the kit. The kits described herein can be provided, sold, and / or promoted to health providers, including physicians, nurses, pharmacists, prescribing officials, etc. In some embodiments, the kits can also be sold directly to consumers.

[0309] application

[0310] In one aspect, the present disclosure provides a method of inhibiting mTORC1, comprising administering a compound or salt of any one of Formula (IA), (IB), (IC), (ID), (IE), (IIA), (IIB), (IIC), (III-A), (III-B), (III-C), (III-D), (III-E), (III-F), (III-G), or (III-H). In one aspect, the present disclosure provides a method of inhibiting mTORC1 without significantly modulating mTORC2, comprising administering a compound or salt of any one of Formula (IA), (IB), (IC), (ID), (IE), (IIA), (IIB), (IIC), (III-A), (III-B), (III-C), (III-D), (III-E), (III-F), (III-G), or (III-H). In certain embodiments, the compounds and salts of the present disclosure do not significantly inhibit mTORC2.

[0311] Without being bound by any particular mechanism, the compounds or salts of any of Formula (IA), (IB), (IC), (ID), (IE), (IIA), (IIB), (IIC), (III-A), (III-B), (III-C), (III-D), (III-E), (III-F), (III-G), or (III-H) may exhibit reduced side effects relative to rapamycin. In particular, the compounds or salts of the present disclosure may not significantly affect the gastrointestinal and / or cardiac systems. In certain embodiments, the compounds of the present disclosure may be administered in larger doses or over longer periods of time than prescribed for rapamycin. For example, in terms of a predetermined time frame, a compound or salt of any of Formula (IA), (IB), (IC), (ID), (IE), (IIA), (IIB), (IIC), (III-A), (III-B), (III-C), (III-D), (III-E), (III-F), (III-G), or (III-H) can be administered daily, every other day, once a week, once every two weeks, over a period of time such as 2 months or more, 4 months or more, 6 months or more, 1 year or more, or even 2 years or more. For example, with respect to intended dosing, a compound or salt of any of Formula (IA), (IB), (IC), (ID), (IE), (IIA), (IIB), (IIC), (III-A), (III-B), (III-C), (III-D), (III-E), (III-F), (III-G), or (III-H) may be administered at a dose that is 30% or greater, 50% or greater, or 80% or greater than the indicated dosing of rapamycin for the same indication.

[0312] In certain embodiments, a compound or salt of any one of Formula (IA), (IB), (IC), (ID), (IE), (IIA), (IIB), (IIC), (III-A), (III-B), (III-C), (III-D), (III-E), (III-F), (III-G), or (III-H) is administered to a subject in need thereof to treat and / or prevent tauopathies (including but not limited to Alzheimer's disease, Parkinson's disease, progressive supranuclear palsy (PSP), corticobasal degeneration, corticobasal syndrome, frontotemporal dementia, frontotemporal lobar degeneration (FTLD) (including but not limited to FTLD-17), behavioral variant FTD, primary progressive aphasia (semantic, agrammatic, or oligoword variant), argyrophilic grain disease, Pick's disease ( disease), globular glial tauopathies, primary age-related tauopathies (including neurofibrillary tangle dementia), chronic traumatic encephalopathy (CTE) - traumatic brain injury and aging-related tau astrogliopathy), mTOR diseases (including but not limited to tuberous sclerosis complex (TSC)), mTOR diseases associated with seizures, focal cortical dysplasia (FCD), ganglioglioma, hemimegalencephaly, neurofibromatosis 1, Sturge-Weber syndrome, Cowden syndrome syndrome), PMSE (polyhydramnios, megalencephaly, symptomatic epilepsy), familial multiple discoid fibrosis (FMDF), epilepsy / seizures (both inherited and acquired forms of the disease, such as familial focal epilepsy, epileptic spasms, infantile spasms (IS), status epilepticus (SE), temporal lobe epilepsy (PLE), and absence epilepsy), rare diseases associated with dysfunction of mTORC1 activity (e.g., lymphangioleiomyomatosis (LAM), Leigh's syndrome, Friedrich's ataxia, Diamond-Blackfan anemia, and leukemia). anemia, etc.), metabolic diseases (e.g., obesity, type II diabetes, etc.), autoimmune and inflammatory diseases (e.g., systemic lupus erythematosus (SLE), multiple sclerosis (MS), psoriasis, etc.), cancer, fungal infections, proliferative diseases, maintenance of immunosuppression, transplant rejection, traumatic brain injury, autism, lysosomal storage diseases and neurodegenerative diseases associated with excessive mTORC1 activity (e.g., Parkinson's disease, Huntington's disease, etc.), accumulation of abnormal compounds, dysfunction of the autophagy mechanism, and generally include but are not limited to conditions that can be regulated by selective inhibition of the mTORC1 pathway.

[0313] In certain embodiments, a compound or salt of any one of Formula (IA), (IB), (IC), (ID), (IE), (IIA), (IIB), (IIC), (III-A), (III-B), (III-C), (III-D), (III-E), (III-F), (III-G), or (III-H) is administered to a subject in need thereof to treat and / or prevent a tauopathy selected from progressive supranuclear palsy, dementia pugilistica (chronic traumatic encephalopathy), Frontotemporal dementia, Lyto-Bodig disease (Guam Parkinson-dementia complex), tangle-dominant dementia (with NFTs similar to AD but without the plaques), gangliogliomas and gangliocytomas, meningioangiomatosis, subacute sclerosing panencephalitis, lead encephalopathy, tuberous sclerosis, Pick's disease, corticobasal degeneration (tau protein is deposited as inclusions within swollen or "ballooned" neurons), Alzheimer's disease, Parkinson's disease, Huntington's disease, frontotemporal dementia, and frontotemporal lobar degeneration.

[0314] In certain embodiments, a compound or salt of any one of Formula (IA), (IB), (IC), (ID), (IE), (IIA), (IIB), (IIC), (III-A), (III-B), (III-C), (III-D), (III-E), (III-F), (III-G), or (III-H) is administered to a subject in need thereof to treat and / or prevent a tauopathy selected from Alzheimer's disease, Parkinson's disease, progressive supranuclear palsy (PSP), corticobasal degeneration, corticobasal syndrome, frontotemporal dementia, frontotemporal lobar degeneration (FTLD) (including but not limited to FTLD-17), behavioral variant of FTD, primary progressive aphasia (semantic, agrammatic, or oligomorphic variant), argyrophilic grain disease, Pick's disease, globular glial tauopathies, primary age-related tauopathies (including neurofibrillary tangle dementia), chronic traumatic encephalopathy (CTE) - traumatic brain injury, and aging-associated tau astrocytopathy.

[0315] In certain embodiments, a compound or salt of any one of Formula (IA), (IB), (IC), (ID), (IE), (IIA), (IIB), (IIC), (III-A), (III-B), (III-C), (III-D), (III-E), (III-F), (III-G), or (III-H) is administered to a subject in need thereof to treat and / or prevent an mTOR disease. An mTOR disease can be, for example, tuberous sclerosis, focal cortical dysplasia, or PTEN (phosphatase and tensin homolog) disease. An mTOR disease can be a disease or disorder described elsewhere herein.

[0316] In certain embodiments, a compound or salt of any one of Formula (IA), (IB), (IC), (ID), (IE), (IIA), (IIB), (IIC), (III-A), (III-B), (III-C), (III-D), (III-E), (III-F), (III-G), or (III-H) is administered to a subject in need thereof to treat and / or prevent cancer.Non-limiting examples of cancer may include acute lymphoblastic leukemia (ALL); acute myeloid leukemia; adrenocortical carcinoma; childhood cerebellar or cerebral astrocytoma; basal cell carcinoma; bladder cancer; bone tumors, osteosarcoma / malignant fibrous histiocytoma; brain cancer; brain tumors such as cerebellar astrocytoma, malignant glioma, ependymoma, medulloblastoma, optic pathway and hypothalamic glioma; brain stem glioma; breast cancer; bronchial adenoma / carcinoid; Burkitt's lymphoma lymphoma; cerebellar astrocytoma; cervical cancer; bile duct cancer; chondrosarcoma; chronic lymphocytic leukemia; chronic myeloid leukemia; chronic myeloproliferative disorders; colon cancer; cutaneous T-cell lymphoma; endometrial cancer; ependymoma; esophageal cancer; eye cancers, such as intraocular melanoma and retinoblastoma; gallbladder cancer; glioma; hairy cell leukemia; head and neck cancer; heart cancer; hepatocellular (liver) cancer; Hodgkin lymphoma; hypopharyngeal cancer; islet cell carcinoma (endocrine pancreas); Kaposi sarcoma sarcoma); kidney cancer (renal cell carcinoma); laryngeal cancer; leukemias, such as acute lymphoblastic leukemia, acute myeloid leukemia, chronic lymphocytic leukemia, chronic myeloid leukemia, and hairy cell leukemia; cancers of the lip and oral cavity; liposarcoma; lung cancers, such as non-small cell lung cancer and small cell lung cancer; lymphomas, such as AIDS-related Burkitt lymphoma; cutaneous T-cell Hodgkin and non-Hodgkin lymphomas, macroglobulinemia, malignant fibrous histiocytoma of bone / osteosarcoma; melanoma; Merkel cell carcinoma; mesothelioma; multiple myeloma / plasma cell neoplasms; mycosis fungoides; myeloproliferative disorders myeloproliferative disorders; myelosuppressive syndromes; myeloproliferative disorders; chronic myeloproliferative disorders; nasal and paranasal sinus cancer; nasopharyngeal cancer; neuroblastoma; oligodendroglioma; oropharyngeal cancer; osteosarcoma / malignant fibrous histiocytoma of bone; ovarian cancer; pancreatic cancer; parathyroid cancer; pharyngeal cancer; pheochromocytoma; pituitary adenoma; plasmacytoma; pleuropulmonary blastoma; prostate cancer; rectal cancer; renal cell carcinoma (kidney cancer); transitional cell carcinoma of the renal pelvis and ureter; rhabdomyosarcoma; salivary gland cancer; Ewing family of tumor sarcomas; Kaposi's sarcoma; soft tissue sarcoma; uterine sarcoma; Sézary syndrome syndrome); skin cancer (non-melanoma); skin cancer; small bowel cancer; soft tissue sarcoma; squamous cell carcinoma; metastatic squamous neck cancer with occult primary; stomach cancer; testicular cancer; pharyngeal cancer; thymoma and thymic carcinoma; thymoma; thyroid cancer; childhood thyroid cancer; uterine cancer; vaginal cancer; Waldenstrom's macroglobulinemia. macroglobulinemia); Wilms tumor; and any combination thereof.

[0317] In certain embodiments, a compound or salt of any one of Formula (IA), (IB), (IC), (ID), (IE), (IIA), (IIB), (IIC), (III-A), (III-B), (III-C), (III-D), (III-E), (III-F), (III-G), or (III-H) is administered to a subject in need thereof to treat and / or prevent seizures and / or seizure-related disorders. Seizure-related disorders may include, but are not limited to, West syndrome, focal cortical dysplasia (FCD), tuberous sclerosis complex (TSC), childhood absence epilepsy, benign focal epilepsy of childhood, juvenile myoclonic epilepsy (JME), temporal lobe epilepsy, frontal lobe epilepsy, refractory epilepsy, Lennox-Gastaut syndrome, occipital lobe epilepsy, Proteus syndrome, hemimegalencephaly syndrome (HMEG), megalencephaly syndrome (MEG), megalencephaly-capillary malformation (MCAP), megalencephaly-polymicrogyria-polydactyly-hydrocephalus syndrome (MPPH), and PTEN disorders.

[0318] Compounds according to any of the therapeutic compounds disclosed herein are useful for treating and / or preventing conditions that include fibrotic and / or inflammatory processes (e.g., liver and kidney conditions). Conditions may include, but are not limited to, liver fibrosis (which may occur in end-stage liver disease); cirrhosis; liver failure due to toxicity; non-alcoholic hepatic steatosis or NASH; and alcohol-related steatosis. Another example may be renal fibrosis, which may occur due to acute kidney injury, or diabetic nephropathy may induce renal fibrosis and inflammation.

[0319] Compounds according to any of the therapeutic compounds disclosed herein are used to treat and / or prevent conditions (e.g., liver and kidney conditions) that include fibrotic and / or inflammatory processes. Conditions may include, but are not limited to, liver fibrosis (which may occur in end-stage liver disease); cirrhosis; liver failure due to toxicity; non-alcohol-related hepatic steatosis or NASH; and alcohol-related steatosis. Another example may be renal fibrosis, which may occur due to acute kidney injury, chronic kidney disease, or diabetic nephropathy may induce renal fibrosis and inflammation. Conditions may include polycystic kidney disease, ischemia / reperfusion injury, transplantation, adriamycin nephropathy, unilateral ureteral obstruction (UUO), glomerulopathy, IgA nephropathy, focal segmental glomerulosclerosis (FSGS), lupus mesangial proliferative nephritis.

[0320] Compounds according to any of the therapeutic compounds disclosed herein are useful for treating and / or preventing acute or chronic organ or tissue transplant rejection, e.g., heart, lung, combined heart-lung, liver, kidney, pancreas, skin or corneal transplants, preventing graft-versus-host disease, such as after bone marrow transplantation, etc.

[0321] Compounds according to any of the therapeutic compounds disclosed herein are useful in the treatment and / or prevention of autoimmune diseases and / or inflammatory disorders, particularly including inflammatory disorders whose etiology may include an autoimmune component, such as arthritis (e.g., rheumatoid arthritis, chronic progressive arthritis, and arthritis deformans) and rheumatic diseases. Examples may include autoimmune blood disorders (including, for example, hemolytic anemia, aplastic anemia, pure red cell anemia, and idiopathic thrombocytopenia), systemic lupus erythematosus, polychondritis, scleroderma, Wegener granulomatosis, dermatomyositis, chronic active hepatitis, myasthenia gravis, psoriasis, Steven-Johnson syndrome, and inflammatory bowel disease. syndrome), idiopathic sprue, autoimmune inflammatory bowel disease (including, for example, ulcerative colitis and Crohn's disease), endocrine eye diseases, Graves' disease, sarcoidosis, multiple sclerosis, primary biliary cirrhosis, juvenile diabetes mellitus (type 1 diabetes), uveitis (anterior and posterior), keratoconjunctivitis sicca and vernal keratoconjunctivitis, interstitial pulmonary fibrosis, psoriatic arthritis, glomerulonephritis (with and without nephrotic syndrome, including, for example, idiopathic nephrotic syndrome or minimal change disease), and juvenile dermatomyositis.

[0322] The compound according to any of the therapeutic compounds disclosed herein is used to treat and / or prevent a mitochondrial disease or disorder.

[0323] The compounds according to any of the therapeutic compounds disclosed herein are useful for treating and / or preventing smooth muscle cell proliferation and migration leading to vascular intimal thickening, vascular occlusion, obstructive coronary atherosclerosis, or restenosis.

[0324] In certain embodiments, a compound or salt of Formula (IA), (IB), (IC), (ID), (IE), (IIA), (IIB), (IIC), (III-A), (III-B), (III-C), (III-D), (III-E), (III-F), (III-G), or (III-H), or a compound of any one of Tables 1, 2, 3, 4, 5, 6, 7, or 8, is administered to a subject in need thereof to treat and / or prevent diabetic nephropathy, kidney-related complications of type 1 diabetes and type 2 diabetes, autosomal dominant polycystic kidney disease (ADK), or other autosomal dominant polycystic kidney disease (ADK). PKD), autosomal recessive polycystic kidney disease (ARPKD), kidney diseases associated with cyst formation or cystogenesis, focal segmental glomerulosclerosis (FSGS), and other diseases associated with nephrosclerosis (glomerulopathies, IgA nephropathy, lupus mesangial proliferative nephritis), laminopathies, age-related macular degeneration (AMD), diabetic macular edema, diabetic retinopathy, glaucoma, age-related retinal diseases, weakened immune system, respiratory tract infections, urinary tract infections, heart failure, osteoarthritis, pulmonary arterial hypertension (PAH), and / or chronic obstructive pulmonary disease (COPD).

[0325] In certain embodiments, a compound or salt of Formula (IA), (IB), (IC), (ID), (IE), (IIA), (IIB), (IIC), (III-A), (III-B), (III-C), (III-D), (III-E), (III-F), (III-G), or (III-H), or a compound of any one of Tables 1, 2, 3, 4, 5, 6, 7, or 8, is administered to a subject in need thereof to treat and / or prevent lymphangioleiomyomatosis (LAM) and / or polycystic kidney disease.

[0326] In certain embodiments, the present disclosure provides a method for treating a disease characterized by overactivation of mTORC1. The following references include methods for assessing mTORC (e.g., mTORC1) activity: T. O'Reilly et al., Translational Oncology, v3, i2, pp. 65-79, (2010); J. Peralba, Clinical Cancer Research, v9, i8, pp. 2887-2892 (2003); DR Moore et al., Acta Physiologica, v201, i3, pp. 365-372 (2010); M. Dieterlen., Clinical Cytometry, v82B, i3, pp. 151-157, (2012); the contents of each of the references are incorporated herein by reference.

[0327] In certain embodiments, the present disclosure provides a method for treating age-related diseases. It has been determined that regulating mTORC1 signaling can extend lifespan and delay the onset of age-related diseases in a wide range of organisms, from flies to mammals, thereby potentially providing therapeutic options for preventing or treating age-related diseases in humans. In a recent clinical study, Mannick et al. (mTOR inhibition improves immune function in the elderly, Sci Transl Med. 2014 Dec 24; 6(268):268ra179. doi:10.1126 / scitranslmed.3009892) may have shown that mTOR inhibition improves immune function in the elderly.

[0328] In certain embodiments, the present disclosure provides a method for treating mitochondrial diseases. Mitochondrial myopathy and mitochondrial stress can be mitochondrial disorders as described in Chinnery, PF (2015); EMBO Mol. Med. 7, 1503-1512; Koopman, WJ et al., 10 (2016); EMBO Mol. Med. 8, 311-327 and Young, MJ and Yound and Copeland, WC (2016); Curr. Opin. Genet. Dev. 38, 52-62.

[0329] In certain embodiments, the present disclosure provides a method for treating a disease in which autophagy is impaired. In some cases, these may include impaired autophagy leading to mitochondrial damage, lysosomal storage diseases, cancer, Crohn's disease, and the like. In some cases, impaired autophagy may be as described in Jiang P. and Mizushima, N., Autophagy and human diseases, Cell Research, Vol. 24, pp. 69-79 (2014).

[0330] In certain embodiments, the present disclosure provides a method for treating edge-dominant age-related tar DNA binding protein 43 (TDP-43) encephalopathy. In some cases, the compound herein can be used to treat the illness or disease related to misfolded TDP-43. In some cases, the compound herein can be used to treat the neurodegenerative disease related to TDP-43.

[0331] In certain embodiments, the compounds or salts of the present disclosure are used to induce heterodimerization of the FRB domains of FKBP12 and mTOR. Chemical induction of dimerization (CID) can be used as a biological tool to manipulate specific molecules, such as peptides and polypeptides, in cells at precise times and spatially. The uses of CID include experimental studies to illustrate cell systems and therapeutic uses for regulating cell-based therapies. Exemplary uses include activating cells for promoting implantation, treating diseases or disorders, or controlling or regulating the activity of therapeutic cells expressing chimeric antigen receptors or recombinant T cell receptors. The compounds of the present disclosure can be used to develop inducible systems or molecular switches to control cell signaling.

[0332] The use of rapamycin as a dimerizing agent is limited by side effects associated with mTOR inhibition. mTOR inhibition can lead to reduced cell growth and proliferation and possible immunosuppression. In contrast, the compounds of the present disclosure may offer advantages over rapamycin due to their high selectivity for mTOR1 over mTOR2. mTOR2 inhibition is associated with the negative side effects associated with rapamycin. The currently described compounds are selective for mTOR1 and have minimal effects on mTOR2.

[0333] In certain embodiments, the present disclosure provides a method of bringing two or more polypeptides into proximity or multimerization in a cell, the method comprising administering a compound having a pIC50 for mTOR1 of 8.0 or greater, 8.5 or greater, or even 9.0 or greater, and a pIC50 for mTOR2 of 7.0 or less, 6.5 or less, or even 6 or less. In certain embodiments, the present disclosure provides a method of inducing heterodimerization of the FRB domain of FKBP12 and mTOR in a cell, the method comprising contacting the cell with a compound having a pIC50 for mTOR1 of 8.0 or greater, 8.5 or greater, or even 9.0 or greater, and a pIC50 for mTOR2 of 7.0 or less, 6.5 or less, or even 6 or less. In certain embodiments, the compound is any one of the compounds described herein, e.g., a compound of Formula (IA), (IB), (IC), (ID), (IE), (IIA), (IIB), (IIC), (III-A), (III-B), (III-C), (III-D), (III-E), (III-F), (III-G), or (III-H), or a compound of any one of Tables 1, 2, 3, 4, 5, 6, 7, or 8. In certain embodiments, the cell is in vitro. In certain embodiments, the cell is in vivo.

[0334] The term "multimerize" or multimerization refers to the dimerization of two peptides or polypeptides, or the multimerization of more than two peptides or polypeptides, such as the dimerization of FKBP12 and the FRB domain of mTOR.

[0335] The inducible multimerization system based on FKBP12 / FRB can also be incorporated into chimeric antigen receptor (CAR) T cells that can be used, for example, in immunotherapy applications. One type of immunotherapy is adoptive cell transfer, in which the immune cells of the subject are collected and modified in vitro, such as CAR-modified T cells, to provide specificity and targeted tumor cell killing when the modified cells are returned to the body. T cells from the patient's blood can be extracted and genetically engineered to express CAR on the cell surface. The components of CAR generally include an extracellular antibody-derived single-chain variable fragment (scFv) that specifically recognizes a target tumor cell antigen, and one or more multicellular T cell-derived signaling sequences fused with the scFv. The combination of scFv region and antigen results in activation of T cells by the signaling domain of CAR. In certain embodiments, the compound of the present disclosure can be administered to cells to activate CAR-T cells with a multimerization system based on FKBP12 / FRB. In certain embodiments, the present disclosure provides a method of activating the growth of cells, such as CAR-T cells, containing an FKBP protein fusion and a FRB fusion protein, by contacting the cells with a compound of Formula (IA), (IB), (IC), (ID), (IE), (IIA), (IIB), (IIC), (III-A), (III-B), (III-C), (III-D), (III-E), (III-F), (III-G) or (III-H), or a compound of any one of Tables 1, 2, 3, 4, 5, 6, 7 or 8.

[0336] In some cases, it is beneficial to increase the activity of therapeutic cells. For example, co-stimulatory polypeptides can be used to enhance the activation of T cells and CAR-expressing T cells for antigens, which will increase the effectiveness of adoptive immunotherapy. These treatments are, for example, used to treat tumors to achieve elimination, and for treating cancer and blood disorders, but these therapies may have negative side effects. Too active on-target effects, such as those for large tumor masses, can lead to cytokine storms with tumor lysis syndrome (TLS), cytokine release syndrome (CRS) or macrophage activation syndrome (MAS). In some cases of adverse events induced by therapeutic cells, there is a need to quickly and nearly completely eliminate therapeutic cells. If there is a need to reduce the number of transferred CAR-T cells, then inducible ligands can be administered to the treated object, thereby specifically inducing the apoptosis of modified T cells. For example, multimeric forms of the ligand binding domains FRB and / or FKBP12 or variants thereof, such as those described in WO 2020 / 076738, fused to caspase proteins and expressed in modified therapeutic cells, can serve as scaffolds that allow spontaneous dimerization and activation of caspase units upon recruitment by FRB and / or FKBP12 using chemical inducers such as compounds of Formula (IA), (IB), (IC), (ID), (IE), (IIA), (IIB), (IIC), (III-A), (III-B), (III-C), (III-D), (III-E), (III-F), (III-G) or (III-H), or compounds of any one of Tables 1, 2, 3, 4, 5, 6, 7 or 8. In certain embodiments, the disclosure provides a method of inhibiting the growth of a cell containing an FKBP protein fusion and a FRB fusion protein by contacting the cell with a compound of Formula (IA), (IB), (IC), (ID), (IE), (IIA), (IIB), (IIC), (III-A), (III-B), (III-C), (III-D), (III-E), (III-F), (III-G), or (III-H), or a compound of any one of Tables 1, 2, 3, 4, 5, 6, 7, or 8.

[0337] The following examples are provided to illustrate, but not to limit, the claimed invention. It will be appreciated that these methods of preparation are illustrative and not limiting. Numerous other methods of producing the rapamycin analogs described herein will be readily available to those skilled in the art using the teachings provided herein.

[0338] Example

[0339] Illustrative synthetic schemes

[0340] The illustrative synthetic routes shown and described herein for preparing compounds of Formula (IA), (IB), (IC), (ID), (IE), (IIA), (IIB), (IIC), (III-A), (III-B), (III-C), (III-D), (III-E), (III-F), (III-G), or (III-H), or any of the compounds in Tables 1, 2, 3, 4, 5, 6, 7, or 8, are exemplary only, and are not intended, and should not be construed, to limit the scope of the present disclosure in any way. One skilled in the art will be able to recognize modifications of the disclosed synthetic schemes and devise alternative routes based on the disclosed examples provided herein; all such modifications and alternative routes are within the scope of the claims.

[0341] Chemical entities described herein can be synthesized according to one or more illustrative schemes herein and / or techniques known in the art. Materials used herein are commercially available or prepared by synthetic methods generally known in the art. These schemes are not limited to the compounds listed in the examples or by any specific substituents, which are adopted for illustrative purposes. Although various steps are described and depicted in schemes 1-32, in some cases, the steps can be performed in an order different from the order shown in schemes 1-32. The numbering or R groups in each scheme may not correspond to the numbering or R groups of the claims or other schemes or tables herein. In some embodiments, C16 modification can be performed before C40 modification. In some embodiments, C40 modification can be performed before C16 modification. In some embodiments, C28 modification can be performed before / after C16 and / or C40 modification.

[0342] Compounds of the present disclosure having C40 and / or C28 modifications, including inversion of stereochemistry at these positions, can be prepared as previously described, for example, in PCT Publication Nos. WO 95 / 14023 and WO 01 / 14387.

[0343] In certain embodiments, compounds of the present disclosure are prepared from one of the following compounds as a starting material: rapamycin, everolimus, and / or 27-o-desmethylrapamycin.

[0344] In some embodiments, the compounds of Tables 1 to 8 can be prepared according to Schemes 1 to 32. The compounds of Tables 1 to 8 can have a core structure of Formula (III-A), Formula (III-B), Formula (III-C), Formula (III-D), Formula (III-E), Formula (III-F), Formula (III-G), or Formula (III-H) as shown below, wherein R 1 and R 4 These are described in Tables 1 to 8.

[0345] The following compound names were generated using Dotmatics ELN.

[0346] Solution 1

[0347]

[0348] Oxetane-3-ol (5.8 mL, 87.5 mmol) was added to a solution of rapamycin (2.00 g, 2.19 mmol) in anhydrous DCM (87 mL). The mixture was cooled to -40 ° C and 4-methylbenzenesulfonic acid (1.88 g, 10.9 mmol) was added. The mixture was stirred at room temperature for 90 minutes. The mixture was diluted with DCM and neutralized with saturated NaHCO solution. The phases were separated. The organic phase was washed with water (40 mL), dried, filtered and concentrated to dryness. The resulting crude mixture was purified by reverse phase chromatography (Uptisphere Strategy C18-Hq 10 um 250 × 30.0 mm, CH3CN:H2O gradient 70:30 to 100:0, 277 nm). The main fraction (872 mg) was purified by SFC separation to afford (1R,9S,12S,15R,16E,18R,19R,21R,23S,24E,26E,28E,30S,32S,35R)-1,18-dihydroxy-12-[(2R)-1-[(1S,3R,4R)-4-hydroxy-3-methoxycyclohexyl]propan-2-yl]-19-methoxy-15,17,21,23,29,35-hexamethyl-30-(oxetan-3-yloxy)-11,36-dioxa-4-azatricyclo[30.3.1.04,9]hexatriacontac-16,24,26,28-tetraene-2,3,10,14,20-pentaone (169 mg, 9%, white amorphous solid, compound 523) and (1R,9S,12S,15R,16E,18R,19R,21R,23S,24E,26E,28E,30R,32S,35R)-1,18-dihydroxy-12-[(2R)-1-[(1S,3R,4R)-4-hydroxy-3-methoxycyclohexyl]propan-2-yl]-19-methoxy-15,17,21,23,29,35-hexamethyl-30-(oxetan-3-yloxy)-11,36-dioxa-4-azatricyclo[30.3.1.04,9]hexatriacontitanate-16,24,26,28-tetraene-2,3,10,14,20-pentaone (56 mg, 3%, white amorphous solid, compound 124).

[0349] SFC separation: Column: Princeton 2-ethylpyridine 5 μm 60A. Column dimensions: 3 cm ID × 15 cm L. Mobile phase: carbon dioxide / isopropanol (CO2 / IpOH) 80 / 20. Flow rate: 100 ml / min. Pressure: 100 bar. Wavelength: UV 277 nm. SFC equipment: Waters SFC200.

[0350] Compound 523: 1 H NMR (DMSO-d6, 600MHz): δ (ppm) 5.84-6.54 (m, 5H), 5.47 (dd, J = 14.9, 9.8Hz, 1H), 5.23 (d, J = 4.5Hz, 1H), 5.08 (br d,J=10.1Hz,1H),4.90-5.02(m,2H),4.47-4.72(m,3H),4.28-4.45(m,3H),3.9 7-4.08(m,2H),3.88(d,J=5.0Hz,1H),3.69-3.79(m,1H),3.41-3.49(m,1H),3. 00-3.36(m,9H),2.66-2.89(m,2H),2.34-2.47(m,2H),2.13-2.33(m,1H),1.46 -2.11(m,19H),1.10-1.46(m,7H),0.65-1.09(m,19H),0.59(q,J=12.0Hz,1H). LCMS: MNa+ (ionic form), 978.3 (ion m / z).

[0351] Compound 124: 1H NMR (DMSO-d6, 600MHz): δ (ppm) 5.84-6.54 (m, 5H), 5.47 (dd, J = 14.9, 9.8Hz, 1H), 5.23 (d, J = 4.5Hz, 1H), 5.08 (br d,J=10.1Hz,1H),4.90-5.02(m,2H),4.47-4.72(m,3H),4.28-4.45(m,3H),3.9 7-4.08(m,2H),3.88(d,J=5.0Hz,1H),3.69-3.79(m,1H),3.41-3.49(m,1H),3. 00-3.36(m,9H),2.66-2.89(m,2H),2.34-2.47(m,2H),2.13-2.33(m,1H),1.46 -2.11(m,19H),1.10-1.46(m,7H),0.65-1.09(m,19H),0.59(q,J=12.0Hz,1H). LCMS: MNa+ (ionic form), 978.3 (ion m / z).

[0352] Option 2

[0353]

[0354] Oxetanes-3-ylmethanol (8.03 g, 86.6 mmol) was added to a solution of rapamycin (2.00 g, 2.19 mmol) in anhydrous DCM (87 mL). The mixture was cooled to 0 ° C and 4-methylbenzenesulfonic acid (1.88 g, 10.9 mmol) was added. The mixture was stirred at 0 ° C for 5 hours. The mixture was diluted with DCM and neutralized with saturated NaHCO solution. The phases were separated. The organic phase was washed with water (40 mL), dried, filtered and concentrated to dryness. The resulting crude mixture was purified by reverse phase chromatography (Uptisphere Strategy C18-Hq 10 um 250 × 30.0 mm, CH3CN:H2O gradient 50: 50 to 100: 0, 277 nm). The main fraction (900 mg) was purified by SFC separation to afford (1R,9S,12S,15R,16E,18R,19R,21R,23S,24E,26E,28E,30S,32S,35R)-1,18-dihydroxy-12-[(2R)-1-[(1S,3R,4R)-4-hydroxy-3-methoxycyclohexyl]propane -2-yl]-19-methoxy-15,17,21,23,29,35-hexamethyl-30-[(oxetan-3-yl)methoxy]-11,36-dioxa-4-azatricyclo[30.3.1.04,9]hexatriacontahedral-16,24,26,28-tetraene-2,3,10,14,20-pentaone (102.9 mg, 5%, white Amorphous solid, compound 521) and (1R,9S,12S,15R,16E,18R,19R,21R,23S,24E,26E,28E,30R,32S,35R)-1,18-dihydroxy-12-[(2R)-1-[(1S,3R,4R)-4-hydroxy-3-methoxycyclohexyl]propan-2-yl]-19-methoxy -15,17,21,23,29,35-Hexamethyl-30-[(oxetan-3-yl)methoxy]-11,36-dioxa-4-azatricyclo[30.3.1.04,9]hexatriacontaria-16,24,26,28-tetraene-2,3,10,14,20-pentaone (22.9 mg, 1%, white amorphous solid, compound 122).

[0355] SFC separation method: Column: Princeton 2-ethylpyridine 5 μm 60. Column dimensions: 3 cm ID × 15 cm L. Mobile phase: CO2 / IpOH 78:22. Flow rate: 100 ml / min. Pressure: 100 bar. Wavelength: UV 277 nm. SFC instrument: Waters SFC200.

[0356] Compound 521: 1H NMR (DMSO-d6, 600MHz): δ (ppm) 6.32-6.50 (m, 2H), 6.05-6.28 (m, 3H), 5.47 (dd, J=14.9, 9.6Hz, 1H), 5.24 (br d, J=2.3Hz, 1H), 5.09 (br d,J=10.1Hz,1H),4.96-5.02(m,1H),4.91-4.95(m,1H),4.47-4.66(m,3H),4.18-4 .33(m,2H),3.97-4.08(m,2H),3.92(d,J=4.7Hz,1H),3.78(dd,J=11.7,2.1Hz,1H) , 3.01-3.48 (m, 13H), 2.83 (ddd, J = 11.1, 8.7, 4.5 Hz, 1H), 2.74 (dd, J = 17.7, 2.6 Hz, 1H), 2.35-2.46 (m, 2H), 2.17-2.26 (m, 1H), 1.46-2.13 (m, 19H), 0.55-1.44 (m, 27H). LCMS: MNa+ (ionic form), 992.4 (ion m / z).

[0357] Compound 124: 1 H NMR (DMSO-d6, 600 MHz): δ ppm 6.31-6.71 (m, 2H), 5.85-6.28 (m, 3H), 4.75-5.70 (m, 5H), 4.45-4.69 (m, 3H), 4.15-4.40 (m, 2H), 3.67-4.12 (m, 4H), 3.50-3.64 (m, 1H), 3.36-3.49 (m, 2H), 3.00-3.24 (m, 6H), 2.52-2.90 (m, 4H), 1.82-2.47 (m, 6H), 0.67-1.80 (m, 44H), 0.51-0.63 (m, 1H). LCMS: MNa+ (ionic), 992.4 (ion m / z).

[0358] Option 3

[0359]

[0360] (Oxan-4-yl)methanol (10.06 g, 86.6 mmol) was added to a solution of rapamycin (2.00 g, 2.19 mmol) in anhydrous DCM (87 mL). The mixture was cooled to -40 ° C and 4-methylbenzenesulfonic acid (1.88 g, 10.9 mmol) was added. The mixture was allowed to reach -10 ° C and stirred at -10 ° C for 1 hour. The mixture was diluted with DCM and neutralized with saturated NaHCO solution. The phases were separated. The organic phase was washed with water (40 mL), dried, filtered and concentrated to dryness. The resulting crude mixture was purified by reverse phase chromatography (Uptisphere Strategy C18-Hq 10 um 250 × 30.0 mm, CH3CN:H2O gradient 60:40 to 100:0 in 40 min, 277 nm). The main fraction (450 mg) was purified by SFC separation to afford (1R,9S,12S,15R,16E,18R,19R,21R,23S,24E,26E,28E,30S,32S,35R)-1,18-dihydroxy-12-[(2R)-1-[(1S,3R,4R)-4-hydroxy-3-methoxycyclohexyl] Propan-2-yl]-19-methoxy-15,17,21,23,29,35-hexamethyl-30-[(oxan-4-yl)methoxy]-11,36-dioxa-4-azatricyclo[30.3.1.04,9]hexatriacontahedral-16,24,26,28-tetraene-2,3,10,14,20-pentaone (109 mg, 5%, amorphous White solid, compound 525) and (1R,9S,12S,15R,16E,18R,19R,21R,23S,24E,26E,28E,30R,32S,35R)-1,18-dihydroxy-12-[(2R)-1-[(1S,3R,4R)-4-hydroxy-3-methoxycyclohexyl]propan-2-yl]-19-methoxy -15,17,21,23,29,35-Hexamethyl-30-[(oxan-4-yl)methoxy]-11,36-dioxa-4-azatricyclo[30.3.1.04,9]hexatriacontaria-16,24,26,28-tetraene-2,3,10,14,20-pentaone (6 mg, 0.5%, amorphous white solid, compound 126).

[0361] SFC separation: Column: Princeton 2-ethylpyridine 5 μm 60A, column dimensions: 3 cm ID × 15 cm L. Mobile phase: CO2 / IpOH 83 / 17. Flow rate: 100 ml / min. Pressure: 100 bar. Wavelength: UV 277 nm. SFC instrument: Waters SFC200

[0362] Compound 525: 1 H NMR (DMSO-d6, 600MHz): δppm 6.27-6.52(m,2H),6.04-6.25(m,3H),5.46(dd,J=14.9,9.8Hz,1H),5.23(s,1H),5.13-5.39(m,1H),5.09(br d,J=10.1Hz,1H),4.96-5.00(m,1H),4.91-4.95(m,1H),4.34-4.64(m,1H),3.99-4.08(m,2H),3.94(d,J=4.5Hz,1H),3.79-3.8 6(m,2H),3.65-3.75(m,1H),3.23-3.37(m,6H),3.12-3.21(m,6H),3.07(dd,J=9.1,6.3Hz,1H),2.94(dd,J=9.1,6.2Hz,1H),2.8 3 (ddd, J = 11.1, 8.6, 4.3 Hz, 1H), 2.73 (dd, J = 17.7, 2.6 Hz, 1H), 2.34-2.45 (m, 2H), 2.17-2.26 (m, 1H), 1.93-2.14 (m, 3H), 1.11-1.92 (m, 28H), 0.89-1.08 (m, 6H), 0.87 (d, J = 6.6 Hz, 3H), 0.80-0.85 (m, 3H), 0.78 (d, J = 6.7 Hz, 3H), 0.70-0.76 (m, 3H), 0.60 (m, 1H). LCMS: MNa+ (ionic), 1020.5 (ion m / z).

[0363] Compound 126: LCMS: MNa+ (ionic form), 1020.5 (ion m / z).

[0364] Option 4

[0365]

[0366] Cyclopropanol (5.47 mL, 86.64 mmol) was added to a solution of rapamycin (2.00 g, 2.19 mmol) in anhydrous DCM (87 mL). The mixture was cooled to -20 ° C and 4-methylbenzenesulfonic acid (1.88 g, 10.9 mmol) was added. The mixture was stirred at -20 ° C for 2 hours. The mixture was allowed to reach room temperature within 1 hour. The mixture was diluted with DCM and neutralized with saturated NaHCO solution. The phases were separated. The organic phase was washed with water (40 mL), dried, filtered and concentrated to dryness. The resulting crude mixture was purified by reverse phase chromatography (Uptisphere Strategy C18-Hq 10 um 250 × 30.0 mm, CH3CN:H2O gradient 70:30 to 100:0 in 33 min, 277 nm). The main fraction (940 mg) was purified by SFC separation to afford (1R,9S,12S,15R,16E,18R,19R,21R,23S,24E,26E,28E,30R,32S,35R)-30-(cyclopropyloxy)-1,18-dihydroxy-12-[(1R)-2-[(1S,3R,4R)-4-hydroxy-3-methoxy-cyclohexyl]-1-methyl-ethyl]-19-methoxy-15,17,21,23,29,35-hexamethyl-11,36-dioxa-4-azatricyclo[30.3.1.04,9]hexatriacontita-16,24,26,28-tetraene-2,3,10,14,20-pentaone (132 mg, 6.5%, amorphous) White solid, compound 519) and (1R,9S,12S,15R,16E,18R,19R,21R,23S,24E,26E,28E,30S,32S,35R)-30-(cyclopropyloxy)-1,18-dihydroxy-12-[(1R)-2-[(1S,3R,4R)-4-hydroxy-3-methoxy-cyclohexyl]-1-methyl-ethyl]-19-methoxy-15,17,21,23,29,35-hexamethyl-11,36-dioxa-4-azatricyclo[30.3.1.04,9]hexatriacontitania-16,24,26,28-tetraene-2,3,10,14,20-pentaone (14 mg, 0.6%, amorphous white solid, compound 120).

[0367] SFC separation: Column: Princeton 2-ethylpyridine 5 μm 60A. Column dimensions: 3 cm ID × 15 cm L. Mobile phase: CO2 / IpOH 80 / 20. Flow rate: 70 ml / min. Pressure: 100 bar. Wavelength: UV 277 nm. SFC equipment: Waters SFC200

[0368] Compound 519: 1H NMR (DMSO-d6, 600MHz): δ (ppm) 6.35-6.49 (m, 2H), 6.19-6.29 (m, 1H), 6.09-6.18 (m, 2H), 5.46 (dd, J = 15.0, 9.5Hz, 1H), 5.17-5.32 (m, 1H), 5.09 (br d,J=10.1Hz,1H),4.95-5.02(m,1H),4.93(br d,J=5.3Hz,1H),4.56(br s,1H),3.98-4.06(m,1H),3.92(d,J=4.7Hz,1H),3.84-3.90(m,1H),3.82(dd,J=11.8,2.0Hz,1H),3.39-3.45(m,1H),3.30(s,3H),3 .25-3.29(m,2H),3.16-3.22(m,1H),3.16(s,3H),3.04(tt,J=6.0,3.1Hz,1H),2.79-2.91(m,1H),2.73(dd,J=17.6,2.5Hz,1H),2.3 4-2.46 (m, 2H), 1.78-2.34 (m, 6H), 1.63-1.77 (m, 10H), 1.01-1.62 (m, 13H), 0.98 (d, J = 6.6 Hz, 2H), 0.92-1.01 (m, 2H), 0.87 (d, J = 6.5 Hz, 3H), 0.83 (d, J = 6.5 Hz, 3H), 0.81-0.86 (m, 1H), 0.75-0.81 (m, 3H), 0.69-0.75 (m, 3H), 0.60 (q, J = 11.9 Hz, 1H), 0.27-0.52 (m, 4H). LCMS: MNa+ (ionic), 962.3 (ion m / z).

[0369] Compound 120: 1 H NMR (DMSO-d6, 600 MHz): δ (ppm) 5.91-6.72 (m, 5H), 5.61-5.73 (m, 1H), 4.86-5.45 (m, 4H), 4.35-4.75 (m, 1H), 4.05 (br d, J=1.6 Hz, 1H), 3.69-3.99 (m, 3H), 3.51-3.63 (m, 1H), 2.98-3.42 (m, 10H), 2.63-2.93 (m, 2H), 2.51-2.59 (m, 2H), 2.21-2.34 (m, 1H), 1.85-2.19 (m, 3H), -0.05-1.83 (m, 47H). LCMS: MNa+ (ionic), 962.3 (ion m / z).

[0370] Option 5

[0371]

[0372] 2-Phenylethanol (10 mL, 86.6 mmol) was added to a solution of rapamycin (2.00 g, 2.19 mmol) in anhydrous DCM (87 mL). The mixture was cooled to -20 ° C and 4-methylbenzenesulfonic acid (1.88 g, 10.9 mmol) was added. The mixture was stirred at 0 ° C for 1 hour. The mixture was allowed to reach room temperature within 1 hour. The mixture was diluted with DCM and neutralized with saturated NaHCO solution. The phases were separated. The organic phase was washed with water (40 mL), dried, filtered and concentrated to dryness. The resulting crude mixture was purified by reverse phase chromatography (Uptisphere Strategy C18-Hq 10um 250×30.0 mm, CH3CN:H2O gradient 60:40 to 100:0 in 25 min, 277 nm). The main fraction (1.76 g) was purified by SFC separation to afford (1R,9S,12S,15R,16E,18R,19R,21R,23S,24E,26E,28E,30S,32S,35R)-1,18-dihydroxy-12-[(1R)-2-[(1S,3R,4R)-4-hydroxy-3-methoxy-cyclohexyl]-1-methyl-ethyl]-19-methoxy-15,17,21,23,29,35-hexamethyl-30-(2-phenylethoxy)-11,36-dioxa-4-azatricyclo[30.3.1.04,9]hexatriacontita-16,24,26,28-tetraene-2,3,10,14,20-pentaone (95.2 mg, 4.2%, amorphous) White solid, compound 520) and ((1R,9S,12S,15R,16E,18R,19R,21R,23S,24E,26E,28E,30R,32S,35R)-1,18-dihydroxy-12-[(1R)-2-[(1S,3R,4R)-4-hydroxy-3-methoxy-cyclohexyl]-1-methyl-ethyl]-19-methoxy-15,17,21,23,29,35-hexamethyl-30-(2-phenylethoxy)-11,36-dioxa-4-azatricyclo[30.3.1.04,9]hexatriacontitania-16,24,26,28-tetraene-2,3,10,14,20-pentaone) (42 mg, 1.9%, amorphous white solid, compound 121).

[0373] SFC separation: Column: Princeton 2-ethylpyridine 5 μm 60A. Column dimensions: 3 cm ID × 15 cm L. Mobile phase: CO2 / IpOH 80 / 20. Flow rate: 100 ml / min. Pressure: 100 bar. Wavelength: UV 277 nm. SFC equipment: Waters SFC200.

[0374] Compound 520: 1 H NMR (DMSO-d6, 600MHz): δ (ppm) 7.13-7.31 (m, 5H), 6.30-6.42 (m, 2H), 6.05-6.24 (m, 3H), 5.45 (dd, J = 14.8, 9.7Hz, 1H), 5.17-5.28 (m, 1H), 5.08 (br d,J=10.1Hz,1H),4.94-5.05(m,1H),4.93(br d,J=5.4Hz,1H),4.57(d,J=4.5Hz,1H),3.89-4.06(m,3H),3.68-3.75(m,1H),3.40-3.48(m,2H),3.31-3.33(m,4H),3.25(br dd,J=10.1,6.6Hz,1H),3.16-3.21(m,2H),3.15(s,3H),2.71-2.85(m,4H),2.33-2.44(m,2H ),2.16-2.33(m,1H),2.05-2.12(m,1H),1.96-2.05(m,1H),1.80-1.91(m,2H),1.74-1.78(m, 1H), 1.73 (s, 3H), 1.59-1.70 (m, 5H), 1.57-1.59 (m, 3H), 0.91-1.56 (m, 16H), 0.85 (d, J = 6.6 Hz, 3H), 0.82 (d, J = 6.5 Hz, 4H), 0.76 (d, J = 6.7 Hz, 3H), 0.72 (d, J = 6.7 Hz, 3H), 0.55-0.62 (m, 1H). LCMS: MNa+ (ionic form), 1026.5 (ion m / z).

[0375] Compound 121: 1H NMR (600 MHz, DMSO-d6) shift 7.16-7.28 (m, 5H), 6.55 (s, 1H), 5.88-6.50 (m, 4H), 5.53-5.71 (m, 1H), 5.21-5.26 (m, 1H), 5.08-5.13 (m, 1H), 4.96-5.00 (m, 1H), 4.52-4.58 (m, 1H), 3.77-4.11 (m, 4H), 3.54 (br d, J = 13.06 Hz, 1H), 3.35-3.48 (m, 2H), 3.20-3.29 (m, 4H), 3.10-3.20 (m, 4H), 2.93-3.08 (m, 1H), 2.70-2.84 (m, 4H), 2.51-2.55 (m, 1H), 2.31-2.47 (m, 1H), 2.20-2.30 (m, 1H), 2.15 (brd, J = 13.79 Hz, 1H), 1.87-2.05 (m, 2H), 1.07-1.83 (m, 26H), 0.53-0.99 (m, 18H). LCMS: MNa+ (ionic), 1026.4 (ion m / z).

[0376] Option 6

[0377]

[0378] Oxetan-3-ylmethanol (3.83 g, 41 mmol) was added to (1R,9S,12S,15R,16E,18R,19R,21R,23S,24E,26E,28E,30S,32S,35R)-1,18-dihydroxy-12-{(2R)-1-[(1S,3R,4R)-4-(2-hydroxyethoxy)- To a solution of 1,3-dimethoxy-1,5,17,21,23,29,35-hexamethyl-11,36-dioxa-4-azatricyclo[30.3.1.0-4,9-]hexatriacontahedral-16,24,26,28-tetraene-2,3,10,14,20-pentaone (1 g, 1.04 mmol) in anhydrous DCM (41.7 mL) was added 4-methylbenzenesulfonic acid (0.88 g, 5.11 mmol). The mixture was stirred at 0° C. for 6 hours, diluted with DCM, and neutralized with saturated NaHCO solution. The phases were separated. The organic phase was washed with water (60 mL), dried, filtered, and concentrated to dryness. The crude mixture was purified by reverse phase chromatography (Uptisp here Strategy C18-Hq 10 um 250×30.0 mm, CH 3 CN:H 2 O gradient 60:40 to 100:0 in 25 min, 277 nm).The main fraction (395 mg) was purified by SFC separation to afford (1R,9S,12S,15R,16E,18R,19R,21R,23S,24E,26E,28E,30S,32S,35R)-1,18-dihydroxy-12-[(1R)-2-[(1S,3R,4R)-4-(2-hydroxyethoxy)-3-methoxy-cyclohexane] [1-methyl-ethyl]-19-methoxy-15,17,21,23,29,35-hexamethyl-30-(oxetane-3-ylmethoxy)-11,36-dioxa-4-azatricyclo[30.3.1.04,9]triacontria-16,24,26,28-tetraene-2,3,10,14,20-pentaone (75.5 mg, 7.1%, non- White solid, compound 474) and (1R,9S,12S,15R,16E,18R,19R,21R,23S,24E,26E,28E,30R,32S,35R)-1,18-dihydroxy-12-[(1R)-2-[(1S,3R,4R)-4-(2-hydroxyethoxy)-3-methoxy-cyclohexyl]-1-methyl-ethyl] -19-methoxy-15,17,21,23,29,35-hexamethyl-30-(oxetan-3-ylmethoxy)-11,36-dioxa-4-azatricyclo[30.3.1.04,9]hexatriacontaria-16,24,26,28-tetraene-2,3,10,14,20-pentaone (48 mg, 3.7%, amorphous white solid, compound 75).

[0379] SFC separation: Column: Princeton 2-ethylpyridine 5 μm 60A. Column dimensions: 3 cm ID × 15 cm L. Mobile phase: CO2 / IpOH 80 / 20. Flow rate: 50 ml / min. Pressure: 100 bar. Wavelength: UV 277 nm. SFC equipment: Waters SFC200.

[0380] Compound 474: 11H NMR (DMSO-d6, 600 MHz): δ (ppm) 6.45 (s, 1H), 6.40 (dd, J = 14.7, 11.2 Hz, 1H), 6.18 - 6.26 (m, 1H), 6.10 - 6.17 (m, 2H), 5.47 (dd, J = 15.0, 9.5 Hz, 1H), 5.25 (d, J = 4.5 Hz, 1H), 5.09 (br d, J = 10.1 Hz, 1H), 4.95 - 5.00 (m, 1H), 4.93 (br d, J = 5.7 Hz, 1H), 4.61 (dd, J = 7.8, 5.9 Hz, 2H), 4.44 (t, J = 5.4 Hz, 1H), 4.25 (td, J = 6.0, 2.0 Hz, 2H), 3.96 - 4.06 (m, 2H), 3.92 (d, J = 4.7 Hz, 1H), 3.78 (br d, J = 13.5 Hz, 1H), 3.39 - 3.55 (m, 6H), 3.32 - 3.34 (m, 1H), 3.33 (s, 3H), 3.24 - 3.29 (m, 1H), 3.16 - 3.23 (m, 1H), 3.15 (s, 3H), 3.02 - 3.12 (m, 2H), 2.97 (ddd, J = 11.1, 8.8, 4.5 Hz, 1H), 2.73 (br d, J = 15.1 Hz, 1H), 2.30 - 2.48 (m, 2H), 2.19 - 2.34 (m, 1H), 2.09 (br d, J = 13.5 Hz, 1H), 1.79 - 2.06 (m, 5H), 1.74 (s, 3H), 1.62 - 1.70 (m, 5H), 0.00 (d, J = 6.9 Hz, 3H), 0.90 - 1.60 (m, 15H), 0.87 (d, J = 6.6 Hz, 3H), 0.83 (d, J = 6.5 Hz, 3H), 0.79 - 0.82 (m, 1H), 0.78 (d, J = 6.7 Hz, 3H), 0.73 (d, J = 6.7 Hz, 3H), 0.65 (q, J = 11.8 Hz, 1H). LCMS: MNa+ (ionic form), 1036.5 (ionic m / z).

[0381] Compound 75: 11H NMR (DMSO-d6, 600 MHz): δ (ppm) 6.58 (s, 1H), 6.38 - 6.50 (m, 1H), 6.11 - 6.25 (m, 3H), 6.06 (br d, J = 11.0 Hz, 1H), 5.64 (dd, J = 14.5, 8.4 Hz, 1H), 5.25 (br d, J = 4.5 Hz, 2H), 5.09 - 5.14 (m, 1H), 4.99 (br d, J = 6.0 Hz, 1H), 4.60 (dt, J = 7.8, 6.3 Hz, 2H), 4.41 - 4.45 (m, 1H), 4.32 (t, J = 5.8 Hz, 1H), 4.26 (t, J = 5.9 Hz, 1H), 4.05 (t, J = 4.4 Hz, 1H), 3.91 - 4.02 (m, 1H), 3.88 (d, J = 4.8 Hz, 1H), 3.85 (dd, J = 10.1, 1.9 Hz, 1H), 3.57 (br d, J = 13.8 Hz, 1H), 3.38 - 3.54 (m, 6H), 3.32 - 3.34 (m, 1H), 3.31 (s, 3H), 3.18 (s, 3H), 3.05 - 3.13 (m, 2H), 2.99 - 3.05 (m, 1H), 2.92 - 2.99 (m, 1H), 2.78 (br dd, J = 17.5, 2.6 Hz, 1H), 2.52 - 2.73 (m, 2H), 2.23 - 2.38 (m, 1H), 2.06 - 2.19 (m, 1H), 1.86 - 2.05 (m, 3H), 1.71 - 1.76 (m, 1H), 1.69 (s, 3H), 1.66 (s, 3H), 1.21 - 1.65 (m, 12H), 1.03 - 1.14 (m, 3H), 0.99 (d, J = 6.6 Hz, 3H), 0.98 - 1.02 (m, 1H), 0.94 (br d, J = 6.7 Hz, 3H), 0.86 - 0.92 (m, 2H), 0.85 (d, J = 6.6 Hz, 3H), 0.80 (d, J = 6.7 Hz, 3H), 0.74 (d, J = 6.6 Hz, 3H), 0.62 (q, J = 11.8 Hz, 1H). LCMS: MNa+ (ionic form), 1036.5 (ionic m / z).

[0382] Scheme 7

[0383]

[0384] Under argon, (1R,9S,12S,15R,16E,18R,19R,21R,23S,24E,26E,28E,30S,32S,35R)-1,18-dihydroxy-12-[(1R)-2-[(1S,3R,4R)-4-(3-hydroxypropyloxy)-3-methoxy-cyclohexyl]-1-methyl-ethyl]-19- A solution of methoxy-30-(2-methoxyethoxy)-15,17,21,23,29,35-hexamethyl-11,36-dioxa-4-azatricyclo[30.3.1.0^4,9]triacontahedral-16,24,26,28-tetraene-2,3,10,14,20-pentaketone (compound 427, 350 mg, 0.344 mmol) in anhydrous DCM (2.87 mL) was cooled to -78 ° C. Then, 2,6-lutidine (171 uL, 1.48 mmol) was added. The solution was stirred for several minutes and trifluoromethanesulfonic anhydride (116 uL, 0.689 mmol) was added. The mixture was stirred for 10 min at -78 ° C. The bath was removed and 1-methylpiperazine (191 uL, 1.72 mmol) was added. The reaction mixture was stirred while it reached room temperature within 20 minutes. The mixture was diluted with DCM, concentrated, and purified by silica gel flash column chromatography (0 to 10% (MeOH:triethylamine 1:1) / ethyl acetate). The isolated target fraction was purified again by silica gel flash column chromatography (0 to 20% MeOH / DCM) to provide the target compound (1R,9S,12S,15R,16E,18R,19R,21R,23S,24E,26E,28E,30S*,32S,35R)-1,18-dihydroxy-19-methoxy-30-(2-methoxyethoxy)-12-[(1R)-2-[(1S,3R,4R)-3-methoxy- 4-[3-(4-Methylpiperazin-1-yl)propoxy]cyclohexyl]-1-methyl-ethyl]-15,17,21,23,29,35-hexamethyl-11,36-dioxa-4-azatricyclo[30.3.1.0^4,9]hexatriacontaria-16,24,26,28-tetraene-2,3,10,14,20-pentaone (368 mg, 77%, compound 431).

[0385] Compound 431: 11H NMR (DMSO-d6, 600 MHz): δ (ppm) 5.87 - 6.57 (m, 5H), 5.46 (dd, J = 14.9, 9.6 Hz, 1H), 5.25 (d, J = 4.5 Hz, 1H), 5.09 (br d, J = 10.1 Hz, 1H), 4.98 (dt, J = 7.8, 4.0 Hz, 1H), 4.93 (br d, J = 5.6 Hz, 1H), 4.01 (br t, J = 4.1 Hz, 2H), 3.94 (d, J = 4.5 Hz, 1H), 3.78 (dd, J = 11.8, 1.7 Hz, 1H), 3.07 - 3.62 (m, 19H), 2.87 - 3.04 (m, 2H), 2.73 (br dd, J = 17.7, 2.6 Hz, 1H), 2.13 - 2.66 (m, 11H), 2.06 - 2.11 (m, 1H), 1.81 - 2.05 (m, 5H), 1.47 - 1.78 (m, 17H), 1.34 - 1.44 (m, 2H), 0.98 (br d, J = 6.5 Hz, 13H), 0.80 - 0.88 (m, 7H), 0.77 (d, J = 6.7 Hz, 3H), 0.73 (d, J = 6.6 Hz, 3H), 0.65 (q, J = 11.8 Hz, 1H). LCMS: MH+ (ionic form), 1098.5 (ionic m / z).

[0386] Scheme 8

[0387]

[0388] (1R,9S,12S,15R,16E,18R,19R,21R,23S,24E,26E,28E,30S,32S,35R)-12-[(1R)-2-[(1S,3R,4R)-4-[3-[tert-butyl(dimethyl)silyl]oxypropoxy]-3-methoxy-cyclohexyl]-1-methyl-ethyl]-1, 18-dihydroxy-19-methoxy-30-(2-methoxyethoxy)-15,17,21,23,29,35-hexamethyl-11,36-dioxa-4-azatricyclo[30.3.1.04,9]hexatriacontahedral-16,24,26,28-tetraene-2,3,10,14,20-pentaone (Compound A, 600 mg, 0.531 mmol) was dissolved in anhydrous THF (6 mL) and stirred at room temperature. 1 M aqueous hydrochloric acid (53 uL, 0.0531 mmol) was added. After 2 hours at room temperature, water and DCM were added, the layers were separated, and the aqueous phase was extracted twice with DCM. The combined organic layers were concentrated and purified by flash column chromatography on silica gel (AcOEt / cyclohexane 0 / 100 to 100 / 0) to afford (1R,9S,12S,15R,16E,18R,19R,21R,23S,24E,26E,28E,30S,32S,35R)-1,18-dihydroxy-12-[(1R)-2-[(1S,3R,4R)-4-(3-hydroxypropyl)-1-[[[[[[[[[[[[[[[[[[[[[[[[[[[ [3-methoxy-cyclohexyl]-1-methyl-ethyl]-19-methoxy-30-(2-methoxyethoxy)-15,17,21,23,29,35-hexamethyl-11,36-dioxa-4-azatricyclo[30.3.1.04,9]hexatriacontahedral-16,24,26,28-tetraene-2,3,10,14,20-pentaone (250 mg, 57%, compound 427, white amorphous solid)

[0389] Compound 427: 1H NMR (600 MHz, chloroform-d, 300 K) δ ppm 5.79-6.44 (m, 4H), 5.02-5.60 (m, 4H), 4.78 (br s, 1H), 4.17 (d, J=5.9 Hz, 1H), 2.95-3.97 (m, 26H), 2.54-2.91 (m, 4H), 2.05-2.39 (m, 5H), 0.78-2.01 (m, 43H), 0.62-0.76 (m, 1H). LCMS: MNa+ (ionic), 1038.5 (ion m / z).

[0390] Option 9

[0391]

[0392] Under argon, (1R,9S,12S,15R,16E,18R,19R,21R,23S,24E,26E,28E,30S,32S,35R)-1,18-dihydroxy-12-[(1R)-2-[(1S,3R,4R)-4-hydroxy-3-methoxy-cyclohexyl]-1-methyl-ethyl]-19-methoxy-30-(2-methoxyethoxy)-15,17,21,23,29,35-hexamethyl-11,36-diol Oxa-4-azatricyclo[30.3.1.04,9]hexatriacontria-16,24,26,28-tetraene-2,3,10,14,20-pentaone (compound 529, 1.00 g, 1.04 mmol) was dissolved in chlorobenzene (10 mL) along with N-ethyl-N-isopropyl-propan-2-amine (0.58 mL, 3.34 mmol) and 3-[tert-butyl(dimethyl)silyl]oxypropyl trifluoromethanesulfonate (1009 mg, 3.13 mmol). The reaction mixture was heated at 50° C. for 2 hours. Additional N-ethyl-N-isopropyl-propan-2-amine (0.58 mL, 3.34 mmol) and 3-[tert-butyl(dimethyl)silyl]oxypropyl trifluoromethanesulfonate (1009 mg, 3.13 mmol) were added after 2 and 4 hours of reaction. At 50 ℃ after 6 hours, make the mixture reach room temperature.Then it is diluted with DCM and water.Separate each layer, and organic phase is washed with saturated NaCl aqueous solution.The organic layer of collection is concentrated, and by silica gel flash column chromatography (AcOEt / hexamethylene 0 / 100 to 30 / 70) purifying to provide (1R, 9S, 12S, 15R, 16E, 18R, 19R, 21R, 23S, 24E, 26E, 28E, 30S, 32S, 35R)-12-[(1R)-2-[(1S, 3R, 4R)-4-[3-[tert-butyl (dimethyl) silyl] oxypropoxy]- [3-methoxy-cyclohexyl]-1-methyl-ethyl]-1,18-dihydroxy-19-methoxy-30-(2-methoxyethoxy)-15,17,21,23,29,35-hexamethyl-11,36-dioxa-4-azatricyclo[30.3.1.04,9]hexatriacontaria-16,24,26,28-tetraene-2,3,10,14,20-pentaone (545 mg, 44% Compound A, white amorphous solid).

[0393] Compound A: 1H NMR (DMSO-d6, 600MHz): δ (ppm) 5.86-6.55 (m, 5H), 5.46 (dd, J = 15.0, 9.7Hz, 1H), 5.25 (d, J = 4.5Hz, 1H), 5.09 (br d,J=10.1Hz,1H),4.90-5.00(m,2H),3.70-4.36(m,4H),3.60-3.68(m,2H),3.28-3.59(m,11H),3.03-3.28(m,9H),2.89-3.03(m,2H),2.73(br dd, J=17.5, 2.4 Hz, 1H), 1.79-2.46 (m, 9H), 0.48-1.78 (m, 49H), -0.11-0.16 (m, 6H). LCMS: MNa+ (ionic form), 1152.6 (ion m / z).

[0394] Plan 10

[0395]

[0396] Rapamycin (2.0 g, 2.19 mmol), pTSA monohydrate (1.88 g, 10 mmol), DCM (27 mL) and 2-methoxyethanol (63 mL) were placed in a 100 mL flask and stirred at room temperature for 1 h. The mixture was diluted with EtOAc and aqueous NaHCO3. The layers were separated and the aqueous layer was extracted with EtOAc. The combined organic phases were washed with water, concentrated, and purified by SFC purification to provide two fractions. FC purification conditions: Instrument: Waters SFC80; Stationary phase: Princeton 2-ethylpyridine 20×150 mm 5 μm;

[0397] Mobile phase: CO2 / IpOH 83 / 17; Flow rate: 100 mL / min; Detection: 277 nm; Pressure: 50 bar

[0398] 1185 mg of sample was dissolved in 65 mL of IpOH.

[0399] Compound 529: (1R,9S,12S,15R,16E,18R,19R,21R,23S,24E,26E,28E,30S,32S,35R)-1,18-dihydroxy-12-[(1R)-2-[(1S,3R,4R)-4-hydroxy-3-methoxy-cyclohexyl]-1-methyl-ethyl]-19-methoxy-30-(2-methoxyethoxy)-15,17,21,23,29,35-hexamethyl-11,36-dioxa-4-azatricyclo[30.3.1.04,9]triacontria-16,24,26,28-tetraene-2,3,10,14,20-pentaone (12.6 g, 45%, compound 529, white amorphous solid).

[0400] Compound 529: 1 H NMR (DMSO-d6, 600MHz): δ (ppm) 6.44 (s, 1H), 6.39 (dd, J = 14.7, 11.3Hz, 1H), 6.18-6. 25(m,1H),6.07-6.16(m,2H),5.46(dd,J=15.0,9.7Hz,1H),5.24(brs,1H),5.09(br d,J=10.1Hz,1H),4.98(ddd,J=8.5,4.6,2.9Hz,1H),4.93(br d,J=5.4Hz,1H),4.43-4.71(m,1H),3.98-4.09(m,2H),3.94(d,J=4.7Hz,1H),3.76-3.81 (m,1H),3.09-3.48(m,17H),2.83(ddd,J=11.1,8.7,4.4Hz,1H),2.73(dd,J=17.5,2.6Hz, 1H), 2.34-2.45 (m, 2H), 2.16-2.27 (m, 1H), 1.80-2.14 (m, 6H), 1.46-1.78 (m, 14H), 1.35-1.45 (m, 2H), 1.11-1.33 (m, 4H), 0.91-1.09 (m, 6H), 0.67-0.89 (m, 13H), 0.55-0.64 (m, 1H). LCMS: MNH4+ (ionic form), 975.5 (ion m / z).

[0401] Compound 130: (1R,9S,12S,15R,16E,18R,19R,21R,23S,24E,26E,28E,30R,32S,35R)-1,18-dihydroxy-12-[(1R)-2-[(1S,3R,4R)-4-hydroxy-3-methoxy-cyclohexyl]-1-methyl-ethyl]-19-methoxy-30-(2-methoxyethoxy)-15,17,21,23,29,35-hexamethyl-11,36-dioxa-4-azatricyclo[30.3.1.04,9]triacontria-16,24,26,28-tetraene-2,3,10,14,20-pentaone (350 mg, 17%, compound 130, white amorphous solid).

[0402] Compound 130: 1 H NMR(DMSO-d6,600MHz)δ5.9-6.6(m,5H),5.61(dd,1H,J=8.4,14.6Hz),5.2-5.3 (m,2H),5.11(ddd,1H,J=2.8,4.8,9.0Hz),4.99(dd,1H,J=1.0,6.1Hz),4.57(br dd,1H,J=1.2,1.9Hz),4.04(br d,1H,J=3.8Hz),3.9-4.0(m,1H),3.90(d,1H,J=4.5Hz),3.82(dd,1H,J=1.9,9.7Hz),3.55(br d, 1H, J = 13.6 Hz), 3.0-3.5 (m, 12H), 2.5-2.9 (m, 4H), 2.2-2.3 (m, 1H), 1.8-2.2 (m, 4H), 0.5-1.8 (m, 46H); LCMS: MNa+ (ionic form), 980.6 (ion m / z).

[0403] Plan 11

[0404]

[0405] (1R,9S,12S,15R,16E,18R,19R,21R,23S,24E,26E,28E,30S,32S,35R)-1,18-dihydroxy-12-[(1R)-2-[(1S,3R,4R)-4-(3-hydroxypropyloxy)-3-methoxy-cyclohexyl]-1-methyl-ethyl]-19-methoxy-30-(2

[00145] 1,2-Dimethyl-1,2-dioxa-4-azatricyclo[30.3.1.0^4,9]hexatriacontahedral-16,24,26,28-tetraene-2,3,10,14,20-pentaone (compound 14, 237 mg, 0.233 mmol) was dissolved in anhydrous DCM (1.94 mL). 2,6-Lutidine (116 uL, 1.00 mmol) was then added and the mixture was cooled to -78°C, followed by the addition of trifluoromethanesulfonic anhydride (78 uL, 0.466 mmol). The reaction was stirred at -78°C for 1 hour. The ice bath was removed and morpholine (102 uL, 1.17 mmol) was added. The reaction mixture was stirred while allowing it to reach room temperature over 20 minutes. The mixture was diluted with DCM, concentrated, and purified by silica gel flash column chromatography (0 to 10% (MeOH:triethylamine 1:1) / ethyl acetate). The isolated target fraction was purified again by silica gel flash column chromatography (0 to 20% MeOH / DCM) to afford (1R,9S,12S,15R,16E,18R,19R,21R,23S,24E,26E,28E,30S,32S,35R)-1,18-dihydroxy-19-methoxy-30-(2-methoxyethoxy)-12-[(1R)-2-[(1S,3R, 4R)-3-methoxy-4-(3-morpholinopropoxy)cyclohexyl]-1-methyl-ethyl]-15,17,21,23,29,35-hexamethyl-11,36-dioxa-4-azatricyclo[30.3.1.04,9]hexatriacontaria-16,24,26,28-tetraene-2,3,10,14,20-pentaone (118.2 mg, 41%, compound 447, white amorphous solid).

[0406] Compound 447: 1H NMR (DMSO-d6, 600MHz): δ (ppm) 6.45 (d, J = 1.5Hz, 1H), 6.39 (dd, J = 14.7, 11.2Hz, 1H ),6.08-6.25(m,3H),5.46(dd,J=14.8,9.7Hz,1H),5.25(d,J=4.5Hz,1H),5.09(br d,J=10.1Hz,1H),4.95-5.05(m,1H),4.91-4.95(m,1H),3.97-4.08(m,2H),3.86-3.95(m,1H),3.76-3.82(m,1H),3.51-3. 59(m,6H),3.33-3.50(m,5H),3.32(s,3H),3.25-3.28(m,1H),3.23(s,3H),3.11-3.16(m,3H),2.92-3.04(m,2H),2.73(br dd, J = 17.8, 2.5 Hz, 1H), 2.34-2.45 (m, 2H), 2.27-2.34 (m, 6H), 1.83-2.23 (m, 7H), 1.71-1.77 (m, 3H), 0.89-1.70 (m, 26H), 0.85-0.88 (m, 3H), 0.83 (d, J = 6.5 Hz, 3H), 0.81-0.84 (m, 1H), 0.77 (d, J = 6.7 Hz, 3H), 0.73 (d, J = 6.6 Hz, 3H), 0.60-0.69 (m, 1H). LCMS: MH+ (ionic), 1085.6 (ion m / z).

[0407] Plan 12

[0408]

[0409] To (1R,9S,12S,15R,16E,18R,19R,21R,23S,24E,26E,28E,30S,32S,35R)-1,18-dihydroxy-12-[(1R)-2-[(1S,3R,4R)-4-(3-iodopropoxy)-3-methoxy-cyclohexyl]-1-methyl-ethyl]-19-methoxy-30-(2-methoxyethoxy)-15,17,21,23,29,35-hexamethoxy To a solution of 1,3-dioxa-4-azatricyclo[30.3.1.0^4,9]triacontahedral-16,24,26,28-tetraene-2,3,10,14,20-pentaketone (Compound C1) (326 mg, 0.289 mmol) in anhydrous DCM (1.8 mL) was added N-ethyl-N-isopropyl-propan-2-amine (152 uL, 0.868 mmol) and piperidine (34 uL, 0.347 mmol) in sequence. At room temperature, under argon, the reaction mixture was stirred for 4.5 hours. The reaction mixture was diluted with DCM and quenched with a saturated NH4Cl aqueous solution (pH = 6). The organic phase was washed with water and dried. The crude product was then purified by flash column chromatography on silica gel (100 / 0 to 70 / 30 EtOAc / MeOH:Et3N (50:50)). The target fraction was then purified by silica gel flash column chromatography (100 / 0 to 80 / 20 DCM / MeOH) to provide the desired product (1R,9S,12S,15R,16E,18R,19R,21R,23S,24E,26E,28E,30S,32S,35R)-1,18-dihydroxy-19-methoxy-30-(2-methoxyethoxy)-12-[(1R)-2-[(1 S,3R,4R)-3-methoxy-4-[3-(1-piperidinyl)propoxy]cyclohexyl]-1-methyl-ethyl]-15,17,21,23,29,35-hexamethyl-11,36-dioxa-4-azatricyclo[30.3.1.0^4,9]hexatriacontaria-16,24,26,28-tetraene-2,3,10,14,20-pentaone (115.5 mg, 36%, compound 434).

[0410] Compound 434: MS (ES+, m / z): 1083.7 [M+Na]+. 1H NMR (600 MHz, DMSO-d6) shift 5.87-6.57 (m, 5H), 5.42-5.68 (m, 1H), 5.24 (d, J = 4.40 Hz, 1H), 4.89-5.16 (m, 3H), 3.86-4.08 (m, 3H), 3.67-3.81 (m, 1H), 3.33-3.61 (m, 7H), 3.31-3.33 (m, 3H), 3.12-3.27 ( m, 9H), 2.63-3.08 (m, 7H), 2.22-2.43 (m, 3H), 2.07-2.12 (m, 1H), 1.83-2.01 (m, 5H), 1.51-1.76 (m, 18H), 1.36-1.44 (m, 3H), 1.20-1.20 (m, 1H), 1.10-1.33 (m, 7H), 0.94-1.05 (m, 6H), 0.87 (s, 14H). LCMS: MH+ (ionic), 1083.6 (ion m / z).

[0411] Plan 13

[0412]

[0413] To (1R,9S,12SR,15R,16E,18R,19R,21R,23S,24E,26E,28E,30S,32S,35R)-1,18-dihydroxy-12-[(1R)-2-[(1S,3R,4R)-4-(3-iodopropoxy)-3-methoxy-cyclohexyl]-1-methyl-ethyl]-19,30-dimethoxy-15,17,21,23,29,3 5-hexamethyl-11,36-dioxa-4-azatricyclo[30.3.1.04,9]triacontahedral-16,24,26,28-tetraene-2,3,10,14,20-pentaketone (6.83 g, 6.31 mmol) was added 2-methoxyethanol (161 mL, 2.31 mol) and 4-methylbenzenesulfonic acid (5.43 g, 31.5 mmol) in DCM (77 mL) in sequence. The reaction mixture was stirred at room temperature for 1 h and then neutralized with a saturated NaHCO aqueous solution. The two phases were separated. The organic phase was washed with NaCl, dried and concentrated to dryness. The crude mixture was purified by reverse phase chromatography (Uptisphere Strategy C18-Hq 10 um 250 × 30.0 mm, CH3CN:HO gradient 75:25 to 100:0, 277 nm). The main fraction (2.88 g) was purified by SFC separation to afford (1R,9S,12S,15R,16E,18R,19R,21R,23S,24E,26E,28E,30S,32S,35R)-1,18-dihydroxy-12-[(1R)-2-[(1S,3R,4R)-4-(3-iodopropoxy)-3-methoxy-cyclohexyl]-1-methyl-ethyl]-19-methoxy-30-(2-methoxyethoxy)-15,17,21,23,29,35-hexamethyl-11,36-dioxa-4-azatricyclo[30.3.1.0^4,9]hexatriacontita-16,24,26,28-tetraene-2,3,10,14,20-pentaone (2.11 g). g, 29%, compound C1) and (1R,9S,12S,15R,16E,18R,19R,21R,23S,24E,26E,28E,30R,32S,35R)-1,18-dihydroxy-12-[(1R)-2-[(1S,3R,4R)-4-(3-iodopropoxy)-3-methoxy-cyclohexyl]-1-methyl-ethyl]-19-methoxy-30-(2-methoxyethoxy)-15,17,21,23,29,35-hexamethyl-11,36-dioxa-4-azatricyclo[30.3.1.04,9]hexatriacontita-16,24,26,28-tetraene-2,3,10,14,20-pentaone (850 mg, 12%, compound C2).SFC separation: column: Princeton 2-ethylpyridine 5 μm 60A; column size: 3 cm ID×15 cm L; mobile phase: CO2 / IpOH 80 / 20; flow rate: 100 ml / min; pressure: 100 bar; wavelength: UV 277 nm; SFC equipment: Waters SFC200.

[0414] Compound C1: 1 H NMR (600MHz, DMSO-d6) δ5.87-6.54(m,5H),5.40-5.70(m,1H),4.86-5.35(m,4H),3.99-4.06(m,2H),3.92-3.99(m,1H),3.71-3.82( m,2H),3.47-3.57(m,3H),3.31-3.32(m,3H),3.09-3.27(m,10H),2.94-3.06(m,3H),2.66-2.85(m,2H),2.35-2.48(m,2H),2.22(br d, J = 7.34 Hz, 1H), 2.07-2.12 (m, 1H), 2.01-2.05 (m, 1H), 1.84-1.99 (m, 6H), 1.74 (s, 2H), 1.52-1.70 (m, 11H), 1.33-1.45 (m, 2H), 1.21-1.33 (m, 3H), 1.10-1.20 (m, 2H), 0.94-1.09 (m, 8H), 0.76-0.88 (m, 9H), 0.71-0.75 (m, 3H), 0.64-0.68 (m, 1H). LCMS: MNa+ (ionic form), 1148.6 (ion m / z).

[0415] Compound C2: 1 H NMR (DMSO-d6, 600 MHz) δ 5.8-6.6 (m, 5H), 5.61 (dd, 1H, J = 8.3, 14.5 Hz), 5.2-5.3 (m, 2H), 5.1-5.2 (m, 1H), 4.99 (br d, 1H, J = 5.1 Hz), 3.8-4.1 (m, 4H), 2.9-3.6 (m, 22H), 2.5-2.8 (m, 3H), 2.2-2.4 (m, 1H), 2.1-2.2 (m, 1H), 1.8-2.1 (m, 5H), 0.5-1.8 (m, 42H), LCMS: MNa+ (ionic), 1148.4 (ion m / z).

[0416] Plan 14

[0417]

[0418] Under Ar, rapamycin (3.00 g, 3.28 mmol) was dissolved in anhydrous toluene (20.25 mL) and then N-ethyl-N-isopropyl-propan-2-amine (5.3 mL, 30.1 mmol) and 3-iodopropyl trifluoromethanesulfonate (5.41 g, 16.4 mmol) were added. The mixture was then heated at 60 ° C for 2.5 hours. The crude mixture was then concentrated in vacuo and purified by flash column chromatography on silica gel (cyclohexane / EtOAc, from 100 / 0 to 50 / 50) to produce (1R, 9S, 12S, 15R, 16E, 18R, 19R, 21R, 23S, 24E, 26E, 28E, 30S, 32S, 35R)-1,18-dihydroxy-12-[(1R)-2-[(1S, 3R, 4R)- [4-(3-iodopropoxy)-3-methoxy-cyclohexyl]-1-methyl-ethyl]-19,30-dimethoxy-15,17,21,23,29,35-hexamethyl-11,36-dioxa-4-azatricyclo[30.3.1.0^4,9]hexatriacontahedral-16,24,26,28-tetraene-2,3,10,14,20-pentaone (3.07 g, 47%, compound D).

[0419] Compound D: MS (ES+, m / z): 1104.5 [M+Na]+. 1H NMR(DMS O, 600MHz): δ (ppm) 6.43 (d, 1H), 6.41–6.38 (m, 1H), 6.25–6.09 (m, 3H), 5.46 (dd, J = 14.9, 9.6Hz, 1H), 5.25 (d, J = 4.5Hz ,1H),5.10(d,J=10.2Hz,1H),5.00–4.92(m,2H),4.28(d,1H),4.03–3.98(m,2H),3.94(d,J=4.6Hz,1H),3.64–3.60(m, 1H), 3.53 (dtt, J = 19.7, 9.9, 5.5 Hz, 2H), 3.44 (d, J = 13.5 Hz, 1H), 3.33–3.28 (m, 5H), 3.10 (d, J = 63.6 Hz, 9H), 2.73 (dd, J = 17.7, 2.6 Hz, 1H), 2.43–2.36 (m, 2H), 2.25–1.80 (m, 7H), 1.75–0.89 (m, 31H), 0.89–0.71 (m, 10H), 0.69–0.60 (m, 1H). LCMS: MNa+ (ionic), 1104.5 (ion m / z).

[0420] Plan 15

[0421]

[0422] (1R,9S,12S,15R,16E,18R,19R,21R,23S,24E,26E,28E,30S,32S,35R)-1,18-dihydroxy-12-[(1R)-2-[(1S,3R,4R)-4-(3-iodopropoxy)-3-methoxy-cyclohexyl]-1-methyl-ethyl]-19-methoxy-30- (2-methoxyethoxy) -15,17,21,23,29,35- hexamethyl -11,36- dioxa -4- azatricyclo [30.3.1.0^4,9] trihexahexadecan -16,24,26,28- tetraene -2,3,10,14,20- pentaketone (350 mg, 0.311 mmol, compound C1) is dissolved in anhydrous DCM (1.5 mL). A solution of (2R) -2- methylmorpholine hydrochloride (51 mg, 0.373 mmol) and N- ethyl -N- isopropyl -propan- 2- amine (228 uL, 1.31 mmol) in anhydrous DCM (0.6 mL) is added and the solution is stirred at room temperature for 20 hours. The reaction mixture is diluted with DCM and quenched with saturated NH4Cl. The resulting mixture was washed with water, dried, concentrated, and purified by flash column chromatography on silica gel (100 / 0 to 70 / 30 EtOAc / MeOH:Et3N (50:50)). The target fraction was purified by flash column chromatography on silica gel (DCM / MeOH, 100 / 0 to 90 / 10) to yield (1R,9S,12S,15R,16E,18R,19R,21R,23S,24E,26E,28E,30S,32S,35R)-1,18-dihydroxy-19-methoxy-30-(2-methoxyethoxy)-12-[(1R)-2-[(1S,3R,4R) -3-methoxy-4-[3-[(2R)-2-methylmorpholin-4-yl]propoxy]cyclohexyl]-1-methyl-ethyl]-15,17,21,23,29,35-hexamethyl-11,36-dioxa-4-azatricyclo[30.3.1.04,9]hexatriacontaria-16,24,26,28-tetraene-2,3,10,14,20-pentaone (72.3 mg, 21%, compound 435).

[0423] Compound 435: MS (ES+, m / z): 1099.7 [M+Na]+. 11H NMR (DMSO-d6, 600 MHz): δ (ppm) 6.45 (d, J = 1.3 Hz, 1H), 6.39 (dd, J = 14.6, 11.2 Hz, 1H), 6.18 - 6.25 (m, 1H), 6.08 - 6.16 (m, 2H), 5.46 (dd, J = 14.9, 9.6 Hz, 1H), 5.25 (d, J = 4.5 Hz, 1H), 5.09 (br d, J = 10.1 Hz, 1H), 4.96 - 5.00 (m, 1H), 4.91 - 4.95 (m, 1H), 3.98 - 4.06 (m, 2H), 3.93 (d, J = 4.7 Hz, 1H), 3.76 - 3.81 (m, 1H), 3.70 (dd, J = 11.2, 1.6 Hz, 1H), 3.34 - 3.56 (m, 7H), 3.32 (s, 3H), 3.24 - 3.29 (m, 2H), 3.23 (s, 3H), 3.17 - 3.21 (m, 1H), 3.15 (s, 3H), 2.90 - 3.05 (m, 2H), 2.55 - 2.76 (m, 3H), 2.33 - 2.45 (m, 2H), 2.30 (br t, J = 7.2 Hz, 2H), 2.16 - 2.25 (m, 1H), 2.09 (br d, J = 13.2 Hz, 1H), 1.98 - 2.06 (m, 1H), 1.77 - 1.97 (m, 5H), 1.73 (s, 3H), 1.65 - 1.68 (m, 2H), 1.64 (s, 3H), 1.45 - 1.62 (m, 8H), 1.35 - 1.45 (m, 2H), 1.24 - 1.33 (m, 3H), 1.08 - 1.20 (m, 3H), 1.04 - 1.08 (m, 2H), 1.02 (d, J = 6.3 Hz, 3H), 0.98 (d, J = 6.6 Hz, 3H), 0.88 - 0.96 (m, 2H), 0.87 (d, J = 6.6 Hz, 3H), 0.83 (d, J = 6.5 Hz, 3H), 0.77 (d, J = 6.7 Hz, 3H), 0.73 (d, J = 6.6 Hz, 3H), 0.65 (q, J = 11.9 Hz, 1H). LCMS: MH+ (ionic form), 1099.6 (ionic m / z).

[0424] Scheme 16

[0425]

[0426] (1R,9S,12S,15R,16E,18R,19R,21R,23S,24E,26E,28E,30S,32S,35R)-1,18-dihydroxy-12-[(1R)-2-[(1S,3R,4R)-4-(3-iodopropoxy)-3-methoxy-cyclohexyl]-1-methyl-ethyl]-19-methoxy-30-(2- (2S)-2-methylmorpholine hydrochloride (21.99 mg, 0.159 mmol) and N-ethyl-N-isopropyl-propan-2-amine (97.7 uL 0.559 mmol) in anhydrous DCM (0.4 mL) were added and the solution was stirred at room temperature for 20 hours. The reaction mixture was diluted with DCM and quenched with saturated NH4Cl. The resulting mixture was washed with water, dried, concentrated, and purified by flash column chromatography on silica gel (100 / 0 to 70 / 30 EtOAc / MeOH:Et3N (50:50)). The target fraction was purified by flash column chromatography on silica gel (DCM / MeOH, 100 / 0 to 90 / 10) to yield (1R,9S,12S,15R,16E,18R,19R,21R,23S,24E,26E,28E,30S,32S,35R)-1,18-dihydroxy-19-methoxy-30-(2-methoxyethoxy)-12-[(1R)-2-[(1S,3R,4R )-3-methoxy-4-[3-[(2S)-2-methylmorpholin-4-yl]propoxy]cyclohexyl]-1-methyl-ethyl]-15,17,21,23,29,35-hexamethyl-11,36-dioxa-4-azatricyclo[30.3.1.04,9]hexatriacontaria-16,24,26,28-tetraene-2,3,10,14,20-pentaone (80 mg, 54%, compound 517).

[0427] Compound 517: MS (ES+, m / z): 1099.7 [M+Na]+. Rt = 2.29 min. 1H NMR (600 MHz, DMSO-d6) shifts 6.04-6.50 (m, 1H), 5.40-5.70 (m, 1H), 5.20-5.28 (m, 1H), 4.86-5.16 (m, 1H), 3.62-4.08 (m, 5H), 3.32-3.56 (m, 11H), 3.11-3.28 (m, 9H), 2.92-3 0.04 (m, 2H), 2.58-2.74 (m, 3H), 2.35-2.45 (m, 2H), 2.18-2.33 (m, 3H), 1.79-2.12 (m, 8H), 1.73 (s, 2H), 1.52-1.70 (m, 14H), 1.31-1.44 (m, 3H), 1.21-1.31 (m, 5H), 1.18 (br dd, J=4.84, 11.59 Hz, 1H), 0.94-1.11 (m, 11H), 0.72-0.88 (m, 13H), 0.53-0.71 (m, 2H). LCMS: MH+ (ionic), 1099.7 (ion m / z).

[0428] Plan 17

[0429]

[0430] To a solution of (1R,9S,12SR,15R,16E,18R,19R,21R,23S,24E,26E,28E,30S,32SR,35R)-1,18-dihydroxy-12-[(1R)-2-[(1S,3R,4R)-4-(3-iodopropoxy)-3-methoxy-cyclohexyl]-1-methyl-ethyl]-19,30-dimethoxy- Ethylene glycol (34 mL, 0.61 mol) and 4-methylbenzenesulfonic acid (1.59 g, 9.24 mmol) were added to 1,3-dioxa-4-azatricyclo[30.3.1.0^4,9]triacontahedral-16,24,26,28-tetraene-2,3,10,14,20-pentaketone (2.00 g, 1.85 mmol). The reaction mixture was stirred at room temperature for 3 hours and then neutralized with a saturated aqueous NaHCO solution. The two phases were separated. The organic phase was washed with NaCl, dried and concentrated to dryness. The crude mixture was purified by reverse phase chromatography (Uptisphere Strategy C18-Hq 10 um 250 × 30.0 mm, CH3CN:HO gradient 70:30 to 100:0, 277 nm). The two separated fractions were purified by SFC to provide (1R,9S,12S,15R,16E,18R,19R,21R,23S,24E,26E,28E,30S,32S,35R)-1,18-dihydroxy-30-(2-hydroxyethoxy)-12-[(1R)-2-[(1S,3R,4R)-4-(3-iodopropoxy)-3-methoxy-cyclohexyl]-1-methyl-ethyl]-19-methoxy-15,17,21,23,29,35-hexamethyl-11,36-dioxa-4-azatricyclo[30.3.1.0^4,9]hexatriacontita-16,24,26,28-tetraene-2,3,10,14,20-pentaone (400 mg) , 19%, compound L) and (1R,9S,12S,15R,16E,18R,19R,21R,23S,24E,26E,28E,30R,32S,35R)-1,18-dihydroxy-30-(2-hydroxyethoxy)-12-[(1R)-2-[(1S,3R,4R)-4-(3-iodopropoxy)-3-methoxy-cyclohexyl]-1-methyl-ethyl]-19-methoxy-15,17,21,23,29,35-hexamethyl-11,36-dioxa-4-azatricyclo[30.3.1.04,9]hexatriacontita-16,24,26,28-tetraene-2,3,10,14,20-pentaone (500 mg, 19%, compound M).

[0431] SFC separation: Column: Princeton 2-ethylpyridine 5 μm 60A. Column dimensions: 3 cm ID × 15 cm L. Mobile phase: CO2 / IpOH 80 / 20. Flow rate: 50 ml / min. Pressure: 100 bar. Wavelength: UV 277 nm. SFC equipment: Waters SFC200.

[0432] Compound L: 1H NMR (DMSO-d6, 600 MHz): δ (ppm) 6.43 (d, J = 1.0 Hz, 1H), 6.40 (dd, J = 14.6, 11.2 Hz, 1H), 6.07-6.25 (m, 3H), 5.46 (dd, J = 14.9, 9.6 Hz, 1H), 5.25 (br d, J = 4.1 Hz, 1H), 5.09 (br d,J=10.1Hz,1H),4.95-5.00(m,1H),4.92-4.94(m,1H),4.44-4.53(m,1H),3.99 -4.09(m,2H),3.94(d,J=4.5Hz,1H),3.75-3.81(m,1H),3.49-3.57(m,2H),3.40 -3.48(m,3H),3.32(s,3H),3.30-3.30(m,2H),3.19-3.28(m,3H),3.15(s,3H),3 .12-3.16(m,1H),3.02-3.07(m,1H),2.97(ddd,J=11.0,8.8,4.5Hz,1H),2.73(br dd,J=17.5,2.6Hz,1H),2.34-2.44(m,2H),2.18-2.33(m,1H),1.78-2.15(m,8H ),1.74(s,3H),1.67-1.72(m,2H),1.65(s,3H),1.48-1.64(m,5H),1.01-1.43(m ,10H),0.98(d,J=6.6Hz,3H),0.87(d,J=6.5Hz,3H),0.84-0.85(m,1H),0.83(d ,J=6.5Hz,3H),0.78(d,J=6.7Hz,3H),0.73(d,J=6.7Hz,3H),0.62-0.69(m,1H). LCMS: MN a+ (ionic form), 1134.3 (ion m / z).

[0433] Compound M: MS (ES+, m / z): 1134.3 [M+Na]+. Rt=5.34 min. 11H NMR (DMSO-d6, 600 MHz): δ (ppm) 6.51 (s, 1H), 6.40 - 6.48 (m, 1H), 6.13 - 6.22 (m, 2H), 6.04 (br d, J = 11.2 Hz, 1H), 5.63 (br dd, J = 14.2, 8.2 Hz, 1H), 5.05 - 5.45 (m, 8H), 4.99 (br d, J = 5.9 Hz, 1H), 4.51 (br t, J = 5.4 Hz, 1H), 4.04 (br t, J = 4.2 Hz, 1H), 3.99 - 4.03 (m, 1H), 3.89 (d, J = 4.7 Hz, 1H), 3.83 (br dd, J = 9.6, 1.2 Hz, 1H), 3.41 - 3.59 (m, 5H), 3.31 - 3.32 (m, 1H), 3.31 (br s, 3H), 3.29 - 3.29 (m, 2H), 3.21 - 3.25 (m, 2H), 3.18 (s, 3H), 3.05 - 3.10 (m, 1H), 2.93 - 3.05 (m, 2H), 2.75 - 2.80 (m, 1H), 2.67 - 2.74 (m, 1H), 2.52 - 2.59 (m, 1H), 2.21 - 2.32 (m, 1H), 1.87 - 2.18 (m, 7H), 1.46 - 1.78 (m, 13H), 1.08 - 1.45 (m, 6H), 0.99 (br d, J = 6.6 Hz, 3H), 0.95 - 0.98 (m, 1H), 0.93 (br d, J = 6.7 Hz, 3H), 0.85 (br d, J = 6.6 Hz, 3H), 0.80 (br d, J = 6.7 Hz, 3H), 0.75 (br d, J = 6.6 Hz, 3H), 0.59 - 0.67 (m, 1H). LCMS: MNa+ (ionic form), 1134.3 (ionic m / z).

[0434] Scheme 18

[0435]

[0436] (1R,9S,12S,15R,16E,18R,19R,21R,23S,24E,26E,28E,30S,32S,35R)-1,18-dihydroxy-30-(2-hydroxyethoxy)-12-[(1R)-2-[(1S,3R,4R)-4-(3-iodopropoxy)-3-methoxy-cyclohexyl]-1-methyl-ethyl]-19-methoxy-15,17,21,23,29,35-hexamethyl-1 1,36-dioxa-4-azatricyclo[30.3.1.0^4,9]triacontahedral-16,24,26,28-tetraene-2,3,10,14,20-pentaketone (350 mg, 0.315 mmol) was dissolved in anhydrous DCM (1.1444 mL) along with N-ethyl-N-isopropyl-propan-2-amine (220 uL, 1.26 mmol) and (3R)-3-methylmorpholine (97%, 43 uL, 0.378 mmol). The reaction mixture was stirred at room temperature for 24 hours. The mixture was diluted with DCM. Saturated aqueous NH4Cl solution was added to adjust the pH to 7. The resulting mixture was washed with water, dried, concentrated, and purified by silica gel flash column chromatography (100 / 0 to 90 / 10 EtOAc / MeOH:Et3N (50:50)). The target fraction was purified by silica gel flash column chromatography (D CM / MeOH, 100 / 0 to 90 / 10) to yield (1R,9S,12S,15R,16E,18R,19R,21R,23S,24E,26E,28E,30S,32S,35R)-1,18-dihydroxy-30-(2-hydroxyethoxy)-19-methoxy-12-[(1R)-2-[(1S,3R,4R)-3-methoxy-4- [3-[(3R)-3-Methylmorpholin-4-yl]propoxy]cyclohexyl]-1-methyl-ethyl]-15,17,21,23,29,35-hexamethyl-11,36-dioxa-4-azatricyclo[30.3.1.04,9]hexatriacontaria-16,24,26,28-tetraene-2,3,10,14,20-pentaone (101.3 mg, 29%, compound 404).

[0437] Compound 404: MS (ES+, m / z): 1085.6 [M+Na]+. 1H NMR (600 MHz, DMSO-d6) shifts 5.89-6.62 (m, 5H), 5.43-5.67 (m, 1H), 5.19-5.28 (m, 1H), 4.91-5.14 (m, 3H), 4.43-4.57 (m, 1H), 3.43-4.07 (m, 12H), 3.31-3.34 (m, 3H), 3.11-3.28 (m, 7H), 2.93-3.10 (m, 4H), 2.64-2.81 (m, 3H) , 1.84-2.44 (m, 12H), 1.73 (s, 3H), 1.51-1.70 (m, 12H), 1.36-1.44 (m, 2H), 1.22-1.35 (m, 4H), 1.13-1.19 (m, 1H), 0.94-1.11 (m, 8H), 0.81-0.92 (m, 9H), 0.77 (d, J = 6.75 Hz, 2H), 0.73 (d, J = 6.60 Hz, 2H), 0.63-0.70 (m, 1H). LCMS: MH+ (ionic), 1085.6 (ion m / z).

[0438] Plan 18B

[0439]

[0440] (1R,9S,12S,15R,16E,18R,19R,21R,23S,24E,26E,28E,30R,32S,35R)-1,18-dihydroxy-30-(2-hydroxyethoxy)-12-[(1R)-2-[(1S,3R,4R)-4-(3-iodopropoxy)-3-methoxy-cyclohexyl]-1-methyl-ethyl]-19-methoxy-15,17,21,23,29,35-hexamethyl-1 1,36-dioxa-4-azatricyclo[30.3.1.04,9]triacontahedral-16,24,26,28-tetraene-2,3,10,14,20-pentaketone (350 mg, 0.315 mmol) was dissolved in anhydrous DCM (1.1444 mL) along with N-ethyl-N-isopropyl-propan-2-amine (220 uL, 1.26 mmol) and (3R)-3-methylmorpholine (97%, 43 uL, 0.378 mmol). The reaction mixture was stirred at room temperature for 72 hours. The mixture was diluted with DCM. Saturated aqueous NH4Cl solution was added to adjust the pH to 7. The resulting mixture was washed with water, dried, concentrated, and purified by silica gel flash column chromatography (100 / 0 to 90 / 10 EtOAc / MeOH:Et3N (50:50)). The target fraction was purified by silica gel flash column chromatography (DC M / MeOH, 100 / 0 to 90 / 10) to yield (1R,9S,12S,15R,16E,18R,19R,21R,23S,24E,26E,28E,30R,32S,35R)-1,18-dihydroxy-30-(2-hydroxyethoxy)-19-methoxy-12-[(1R)-2-[(1S,3R,4R)-3-methoxy-4 -[3-[(3R)-3-methylmorpholin-4-yl]propoxy]cyclohexyl]-1-methyl-ethyl]-15,17,21,23,29,35-hexamethyl-11,36-dioxa-4-azatricyclo[30.3.1.04,9]hexatriacontaria-16,24,26,28-tetraene-2,3,10,14,20-pentaone (52 mg, 15%, compound 404).

[0441] Compound 5: MS (ES+, m / z): 1085.6 [M+Na]+. 6.63-5.85 (m, 5H), 5.74-5.51 (m, 1H), 5.45-5.05 (m, 3H), 5.04-4.72 (m, 2H), 4.58-4.41 (m, 1H), 4.18-3.39 (m, 9H), 3.33-3.30 (m, 3H), 3.26-3.09 (m, 4H), 3.09-2.89 (m, 3H), 2.82-2.62 (m, 3H), 2.33-1.85 (m, 7H), 1.80-1.44 (m, 11H), 1.42-1.21 (m, 5H), 1.19-0.60 (m, 17H) LCMS: MH+ (ionic), 1085.6 (ion m / z).

[0442] Plan 19

[0443]

[0444] (1R,9S,12S,15R,16E,18R,19R,21R,23S,24E,26E,28E,30S,32S,35R)-1,18-dihydroxy-30-(2-hydroxyethoxy)-12-[(1R)-2-[(1S,3R,4R)-4-(3-iodopropoxy)-3-methoxy-cyclohexyl]-1-methyl-ethyl]-19-methoxy-15,17,21,23,29 ,35-Hexamethyl-11,36-dioxa-4-azatricyclo[30.3.1.0^4,9]triacontahedral-16,24,26,28-tetraene-2,3,10,14,20-pentaketone (143 mg, 0.129 mmol) was dissolved in anhydrous DCM (1.1444 mL) along with N-ethyl-N-isopropyl-propan-2-amine (90 uL, 0.514 mmol) and (3S)-3-methylmorpholine (18 uL, 0.154 mmol). The reaction mixture was stirred at room temperature for 48 hours. The mixture was diluted with DCM. Saturated aqueous NH4Cl solution was added to adjust the pH to 7. The resulting mixture was washed with water, dried, concentrated, and purified by flash column chromatography on silica gel (100 / 0 to 90 / 10 EtOAc / MeOH:Et3N (50:50)). The target fraction was purified by silica gel flash column chromatography (DCM / MeOH, 100 / 0 to 90 / 10) to give (1R,9S,12S,15R,16E,18R,19R,21R,23S,24E,26E,28E,30S,32S,35R)-1,18-dihydroxy-30-(2-hydroxyethoxy)-19-methoxy-12-[(1R)-2-[(1S,3R,4R)-3-methoxy-4-[3- [(3S)-3-Methylmorpholin-4-yl]propoxy]cyclohexyl]-1-methyl-ethyl]-15,17,21,23,29,35-hexamethyl-11,36-dioxa-4-azatricyclo[30.3.1.04,9]hexatriacontaria-16,24,26,28-tetraene-2,3,10,14,20-pentaone (118.4 mg, 85%, compound 401).

[0445] Compound 401: MS (ES+, m / z): 1085.6 [M+Na]+. Rt=1.34 min. 1H NMR (600MHz, DMSO-d6) displacement 5.90-6.58(m,5H),5.39-5.67(m,1H),5.20-5.27 (m,1H),4.84-5.15(m,3H),4.43-4.57(m,1H),3.40-4.11(m,12H),3.31-3 .34(m,3H),3.12-3.29(m,7H),2.93-3.08(m,3H),2.63-2.77(m,3H),1.85 -2.41(m,12H),1.46-1.79(m,16H),1.22-1.42(m,6H),0.65-1.05(m,23H). LCMS: MH+ (ionic form), 1085.6 (ion m / z).

[0446] Plan 20

[0447]

[0448] (1R,9S,12SR,15R,16E,18R,19R,21R,23S,24E,26E,28E,30S,32S (R,35R)-1,18-dihydroxy-12-[(1R)-2-[(1S,3R,4R)-4-(3-iodopropoxy)-3-methoxy-cyclohexyl]-1-methyl-ethyl]-19,30-dimethoxy-15,17,21,23,29,35-hexamethyl-11,36-dioxa-4-azatricyclo[30.3.1.0^4,9]hexatriacontaria-16,24,26,28-tetraene-2,3,10,14,20-pentaone (5.00 g, 4.62 mmol) was dissolved in anhydrous DCM (184 mL) and butane-1,4-diol (16 mL, 182 mmol). 4-Methylbenzenesulfonic acid (3.97 g, 23 mmol) was added and the reaction mixture was stirred at room temperature for 4 hours. Then it was neutralized with saturated NaHCO3 aqueous solution and the two phases were separated. The organic phase was washed with brine, dried and concentrated to dryness. The crude product obtained by purification by reverse phase chromatography (Uptisphere Strategy C18-Hq10um 250×30.0mm, CH3CN:H2O gradient 70:30 to 100:0, 277nm) provided a major fraction (2.2g), which was purified by SFC to provide two fractions.

[0449] SFC separation: Column: Princeton 2-ethylpyridine 5 μm 60A. Column dimensions: 3 cm ID × 15 cm L. Mobile phase: CO2 / IpOH 83 / 17. Flow rate: 50 ml / min. Pressure: 100 bar. Wavelength: UV 277 nm. SFC instrument: Waters SFC200.

[0450] Compound O1: (1R,9S,12S,15R,16E,18R,19R,21R,23S,24E,26E,28E,30S,32S,35R)-1,18-dihydroxy-30-(4-hydroxybutoxy)-12-[(1R)-2-[(1S,3R,4R)-4-(3-iodopropoxy)-3-methoxy-cyclohexyl]-1-methyl-ethyl]-19-methoxy-15,17,21,23,29,35-hexamethyl-11,36-dioxa-4-azatricyclo[30.3.1.04,9]triacontahedral-16,24,26,28-tetraene-2,3,10,14,20-pentaone (969 mg, 16%, compound O1).

[0451] Compound O1: 11H NMR (DMSO-d6, 600 MHz): δ (ppm) 6.44 (s, 1H), 6.37 - 6.42 (m, 1H), 6.17 - 6.24 (m, 1H), 6.07 - 6.16 (m, 2H), 5.45 (dd, J = 14.9, 9.8 Hz, 1H), 5.25 (d, J = 4.5 Hz, 1H), 5.09 (br d, J = 10.3 Hz, 1H), 4.98 (br s, 1H), 4.93 (br s, 1H), 4.30 - 4.40 (m, 1H), 4.02 (br d, J = 12.0 Hz, 2H), 3.94 (d, J = 4.5 Hz, 1H), 3.72 (br d, J = 13.5 Hz, 1H), 3.48 - 3.57 (m, 2H), 3.41 - 3.47 (m, 1H), 3.35 - 3.40 (m, 2H), 3.32 (s, 3H), 3.30 - 3.30 (m, 2H), 3.16 - 3.28 (m, 3H), 3.15 (s, 3H), 3.07 - 3.11 (m, 1H), 3.01 - 3.06 (m, 1H), 2.93 - 3.00 (m, 1H), 2.73 (br d, J = 15.3 Hz, 1H), 2.36 - 2.48 (m, 2H), 2.18 - 2.33 (m, 1H), 2.07 - 2.14 (m, 1H), 1.99 - 2.06 (m, 1H), 1.88 - 1.98 (m, 4H), 1.83 (br s, 1H), 1.74 (s, 3H), 1.52 - 1.68 (m, 9H), 1.35 - 1.52 (m, 7H), 1.24 (br s,​​Compound O2: (1R,9S,12S,15R,16E,18R,19R,21R,23S,24E,26E,28E,30R,32S,35R)-1,18-dihydroxy-30-(4-hydroxybutoxy)-12-[(1R)-2-[(1S,3R,4R)-4-(3-iodopropoxy)-3-methoxy-cyclohexyl]-1-methyl-ethyl]-19-methoxy-15,17,21,23,29,35-hexamethyl-11,36-dioxa-4-azatricyclo[30.3.1.04,9]triacontahedral-16,24,26,28-tetraene-2,3,10,14,20-pentaone (341 mg, 4%, compound O2).

[0453] Compound O2: 1 H NMR(600MHz,DMSO-d6)δ5.87-6.64(m,5H),5.42-5.68(m,1H),5.20-5.35(m,2H),5.05-5.16(m, 1H),4.99(brd,J=4.84Hz,1H),4.26-4.45(m,1H),3.76-4.09(m,4H),3.44-3.58(m,3H),3.35-3. 41 (m, 2H), 3.32-3.33 (m, 1H), 3.12-3.23 (m, 5H), 3.3 (m, 6H) 2.95-3.05 (m, 2H), 2.73-2.83 (m, 1H), 2.5-2.5 (m, 2H), 2.25-2.32 (m, 1H), 1.78-2.19 (m, 6H), 1.21-1.76 (m, 25H), 0.55-1.19 (m, 21H). LCMS: MNa+ (ionic form), 1162.5 (ion m / z).

[0454] Plan 21

[0455]

[0456] To a solution of (1R,9S,12SR,15R,16E,18R,19R,21R,23S,24E,26E,28E,30S,32S,35R)-1,18-dihydroxy-30-(4-hydroxybutyloxy)-12-[(1R)-2-[(1S,3R,4R)-4-(3-iodopropoxy)-3-methoxy-cyclohexyl]-1-methyl-ethyl]-19-methoxy To 1,5,17,21,23,29,35-hexamethyl-11,36-dioxa-4-azatricyclo[30.3.1.0^4,9]triacontria-16,24,26,28-tetraene-2,3,10,14,20-pentaone (240 mg, 0.210 mmol) were added N-ethyl-N-isopropyl-propan-2-amine (110 uL, 0.631 mmol) and morpholine (22 uL, 0.253 mmol). The reaction mixture was stirred at room temperature for 24 hours. The mixture was then diluted with DCM and 1N aqueous HCl was added until pH = 5. The organic phase was washed with water, dried, concentrated to dryness, and purified by flash column chromatography on silica gel (100 / 0 to 85 / 15 EtOAc / MeOH:Et3N (50:50)). The target fraction was purified by silica gel flash column chromatography (DCM / MeOH, 100 / 0 to 90 / 10) to give (1R,9S,12S,15R,16E,18R,19R,21R,23S,24E,26E,28E,30S,32S,35R)-1,18-dihydroxy-30-(4-hydroxybutoxy)-19-methoxy-12-[(1R)-2-[(1S ,3R,4R)-3-methoxy-4-(3-morpholinopropoxy)cyclohexyl]-1-methyl-ethyl]-15,17,21,23,29,35-hexamethyl-11,36-dioxa-4-azatricyclo[30.3.1.0^4,9]triacontahedral-16,24,26,28-tetraene-2,3,10,14,20-pentaone (107 mg, 46%, compound 426).

[0457] Compound 426: MS (ES+, m / z): 1099.6 [M+H]+, Rt=1.62 min. 11H NMR (DMSO-d6, 600 MHz): δ (ppm) 6.43 - 6.46 (m, 1H), 6.39 (dd, J = 14.5, 11.2 Hz, 1H), 6.07 - 6.24 (m, 3H), 5.42 - 5.49 (m, 1H), 5.25 (d, J = 4.7 Hz, 1H), 5.09 (br d, J = 10.1 Hz, 1H), 4.98 (dt, J = 7.7, 4.1 Hz, 1H), 4.93 (br d, J = 5.3 Hz, 1H), 4.35 (t, J = 5.1 Hz, 1H), 3.97 - 4.07 (m, 2H), 3.94 (d, J = 4.7 Hz, 1H), 3.72 (dd, J = 11.8, 1.8 Hz, 1H), 3.42 - 3.57 (m, 7H), 3.34 - 3.40 (m, 2H), 3.32 (s, 3H), 3.24 - 3.29 (m, 1H), 3.17 - 3.23 (m, 2H), 3.15 (s, 3H), 3.09 (dt, J = 9.4, 6.1 Hz, 1H), 2.92 - 3.04 (m, 2H), 2.73 (br dd, J = 17.5, 2.4 Hz, 1H), 2.35 - 2.45 (m, 2H), 2.31 (br t, J = 7.2 Hz, 6H), 2.16 - 2.25 (m, 1H), 1.78 - 2.14 (m, 6H), 1.74 (s, 3H), 0.89 - 1.69 (m, 29H), 0.87 (d, J = 6.5 Hz, 3H), 0.81 - 0.84 (m, 1H), 0.83 (d, J = 6.3 Hz, 3H), 0.77 (d, J = 6.7 Hz, 3H), 0.73 (d, J = 6.7 Hz, 3H), 0.61 - 0.69 (m, 1H). LCMS: MH+ (ionic form), 1099.6 (ionic m / z).

[0458] Scheme 22

[0459]

[0460] To a solution of everolimus (1.50 g, 1.57 mmol) in anhydrous DCM (19.568 mL) was added 2-methoxyethanol (45 mL, 0.573 mol) and 4-methylbenzenesulfonic acid (1.35 g, 7.83 mmol) in sequence. The reaction mixture was stirred at room temperature for 1 h. The reaction mixture was neutralized with a saturated aqueous NaHCO solution and extracted with DCM. The organic phase was washed with water (60 mL), dried, filtered and concentrated to dryness. The resulting crude mixture was purified by reverse phase chromatography (Uptisp here Strategy C18-Hq10um 250 × 30.0 mm, CH3CN:H2O gradient 60:40 to 100:0, 277 nm in 25 min). The main fraction (768 mg) was purified by SFC separation to afford (1R,9S,12S,15R,16E,18R,19R,21R,23S,24E,26E,28E,30S,32S,35R)-1,18-dihydroxy-12-[(1R)-2-[(1S,3R,4R)-4-(2-hydroxyethoxy)-3-methoxy-cyclohexyl]-1 -methyl-ethyl]-19-methoxy-30-(2-methoxyethoxy)-15,17,21,23,29,35-hexamethyl-11,36-dioxa-4-azatricyclo[30.3.1.0^4,9]hexatriacontahedral-16,24,26,28-tetraene-2,3,10,14,20-pentaone (compound 439, 231 mg, 15%, white amorphous solid).

[0461] SFC separation: Column: Princeton 2-ethylpyridine 5 μm 60A. Column dimensions: 3 cm ID × 15 cm L. Mobile phase: CO2 / IpOH 85 / 15. Flow rate: 50 ml / min. Pressure: 100 bar. Wavelength: UV 277 nm. SFC instrument: Waters SFC200.

[0462] Compound 439: 1H NMR (DMSO-d6, 600MHz): δ (ppm) 5.90-6.49 (m, 5H), 5.42-5.5 (m, 1H), 5.25 (d, J = 4.5Hz, 1H), 5.09 (d, J = 10.1Hz, 1H), 5.00– 4.95(m,1H),4.93(d,J=5.5Hz,1H),4.44(t,J=5.4Hz,1H),4.08–3.98(m,2H),3.94(d,J=4.5Hz,1H),3.78(d,J=13.7Hz,1 H), 3.56–3.35 (m, 6H), 3.35–3.31 (m, 3H), 3.28–3.11 (m, 7H), 3.08–2.93 (m, 2H), 2.77–2.70 (m, 1H), 2.45–2.34 (m, 2H), 2.21 (s, 1H), 2.14–1.81 (m, 6H), 1.74 (s, 2H), 1.72–1.47 (m, 8H), 1.47–1.21 (m, 5H), 1.20–0.91 (m, 8H), 0.89–0.60 (m, 10H). LCMS: M Na+ (ionic), 1024.7 (ion m / z).

[0463] Plan 23

[0464]

[0465] (1R,9S,12S,15R,16E,18R,19R,21R,23S,24E,26E,28E,30S,32S,35R)-1,18-dihydroxy-12-[(1R)-2-[(1S,3R,4R)-4-(2-hydroxyethoxy)-3-methoxy-cyclohexyl]-1-methyl-ethyl]-19-methoxy-30-(2 1,3-dioxa-4-azatricyclo[30.3.1.04,9]hexatriacontac-16,24,26,28-tetraene-2,3,10,14,20-pentaone (compound 29, 250 mg, 0.249 mmol) was diluted in anhydrous DCM (2.079 mL). The mixture was then cooled to -78°C before the addition of 2,6-lutidine (0.12 mL, 1.07 mmol) and stirred for 10 min. A subsequent addition of trifluoromethanesulfonic anhydride (84 uL, 0.499 mmol) was performed. The reaction was stirred at -78°C for 1 hour. The ice bath was removed after the addition of 2-oxa-6-azaspiro[3.3]heptane (98%, 0.11 mL, 1.25 mmol). The mixture was allowed to reach room temperature, diluted with DCM, concentrated, and purified by flash column chromatography on silica gel (100 / 0 to 90 / 10 EtOAc / MeOH:Et3N (50:50)). The isolated target fraction was purified again by flash column chromatography on silica gel (0 to 20% MeOH / DCM) to provide (1R,9S,12S,15R,16E,18R,19R,21R,23S,24E,26E,28E,30S,32S,35R)-1,18-dihydroxy-19-methoxy-30-(2-methoxyethoxy)-12-[(1R)-2-[(1S,3R,4R)-3-methoxy-4-[2-(2-oxa-

[0369] Methyl-6-(6-azaspiro[3.3]heptan-6-yl)ethoxy]cyclohexyl]-1-methyl-ethyl]-15,17,21,23,29,35-hexamethyl-11,36-dioxa-4-azatricyclo[30.3.1.04,9]hexatriacontaria-16,24,26,28-tetraene-2,3,10,14,20-pentaone (compound 443, 21.2 mg, 8%, white amorphous solid).

[0466] Compound 443: 1H NMR (DMSO-d6, 600MHz): δ (ppm) 6.45 (d, J = 1.3Hz, 1H), 6.39 (dd, J = 14.6, 11.2Hz, 1H), 6.19-6 .25(m,1H),6.07-6.17(m,2H),5.46(dd,J=14.8,9.5Hz,1H),5.25(d,J=4.4Hz,1H),5.09(br d,J=10.0Hz,1H),4.95-5.01(m,1H),4.90-4.96(m,1H),4.57(s,4H),3.96-4.07(m,2H),3.94(d,J=4.5Hz,1H),3.78(dd,J=11.8,2.0 Hz,1H),3.33-3.76(m,11H),3.31(s,3H),3.24-3.27(m,2H),3.24(s,3H),3.19-3.23(m,2H),3.15(s,3H),2.92-3.02(m,2H),2.73(br dd,J=17.8,2.7Hz,1H),2.36-2.44(m,3H),2.18-2.26(m,1H),2.07-2.13(m,1H),1. 82-2.04(m,5H),1.73(s,3H),1.67-1.72(m,2H),1.64(s,3H),1.37-1.58(m,7H),1. 25-1.35 (m, 3H), 0.99-1.21 (m, 5H), 0.98 (d, J = 6.6 Hz, 3H), 0.87 (d, J = 6.5 Hz, 3H), 0.83 (d, J = 6.5 Hz, 3H), 0.77 (d, J = 6.7 Hz, 3H), 0.73 (d, J = 6.6 Hz, 3H), 0.58-0.69 (m, 1H). LCMS: MH+ (ionic), 1083.7 (ion m / z).

[0467] Plan 24

[0468]

[0469] 2,2'-Oxydiethanol (8.7 mL, 86.6 mmol) was added to (1R,9S,12S,15R,16E,18R,19R,21R,23S,24E,26E,28E,30S,32S,35R)-1,18-dihydroxy-12-[(1R)-2-[(1S,3R,4R)-4-hydroxy-3-methoxy-cyclohexyl]-1 -methyl-ethyl] -19,30-dimethoxy-15,17,21,23,29,35-hexamethyl-11,36-dioxa-4-azatricyclo [30.3.1.0^4,9] thirty-six carbon -16,24,26,28-tetraene-2,3,10,14,20-pentaketone (2.00g, 2.19mmol) in anhydrous DCM (87mL). The mixture was cooled to -15 ° C and 4-methylbenzenesulfonic acid (1.88g, 10.9mmol) was added. The mixture was stirred at -15 ° C for 60 minutes and at room temperature for 120 minutes. The mixture was diluted with DCM and neutralized with saturated NaHCO solution. Separate the phases. The organic phase was washed with water (40mL), dried, filtered and concentrated to dryness. The crude mixture was purified by reverse phase chromatography (Uptisphere Strategy C18-Hq10um 250×30.0 mm, CH 3 CN:H 2 O gradient 70:30 to 100:0, 277 nm). The main fraction (1.1 g) was purified by SFC separation to provide two fractions.

[0470] (1R,9S,12S,15R,16E,18R,19R,21R,23S,24E,26E,28E,30S,32S,35R)-1,18-dihydroxy-30-[2-(2-hydroxyethoxy)ethoxy]-12-[(1R)-2-[(1S,3R,4R)-4-hydroxy-3-methoxy-cyclohexyl]-1-methyl-ethyl]-19-methoxy-15,17,21,23,29,35-hexamethyl-11,36-dioxa-4-azatricyclo[30.3.1.04,9]hexatriacontitanate-16,24,26,28-tetraene-2,3,10,14,20-pentaone (138 mg, 6%, white amorphous solid, Compound 524) and (1R,9S,12S,15R,16E,18R,19R,21R,23S,24E,26E,28E,30R,32S,35R)-1,18-dihydroxy-30-[2-(2-hydroxyethoxy)ethoxy]-12-[(1R)-2-[(1S,3R,4R)-4-hydroxy-3-methoxy-cyclohexyl]-1-methyl-ethyl]-19-methoxy-15,17,21,23,29,35-hexamethyl-11,36-dioxa-4-azatricyclo[30.3.1.04,9]hexatriacontitania-16,24,26,28-tetraene-2,3,10,14,20-pentaone (58 mg, 3%, white amorphous solid, compound 125).

[0471] SFC separation: Column: Princeton 2-ethylpyridine 5 μm 60A. Column dimensions: 3 cm ID × 15 cm L. Mobile phase: CO2 / IpOH 82 / 18. Flow rate: 100 ml / min. Pressure: 100 bar. Wavelength: UV 277 nm. SFC instrument: Waters SFC200.

[0472] Compound 524: 1H NMR (DMSO-d6, 600MHz): δ (ppm) 6.44 (d, J = 1.5Hz, 1H), 6.40 (dd, J = 14.5, 11.2Hz, 1H), 6.18-6 .25(m,1H),6.07-6.16(m,2H),5.46(dd,J=14.8,9.7Hz,1H),5.24(d,J=4.5Hz,1H),5.09(br d,J=10.1Hz,1H),4.96-5.01(m,1H),4.93(br d,J=4.8Hz,1H),4.47-4.63(m,2H),3.97-4.08(m,2H),3.94(d,J=4.7Hz,1H),3.79(dd,J=11.7,1.9Hz,1 H),3.38-3.58(m,7H),3.22-3.37(m,6H),3.11-3.21(m,5H),2.83(ddd,J=11.2,8.6,4.5Hz,1H),2.73(br dd, J = 17.7, 2.6 Hz, 1H), 2.34-2.46 (m, 2H), 2.17-2.27 (m, 1H), 1.83-2.12 (m, 5H), 1.46-1.79 (m, 14H), 0.90-1.44 (m, 13H), 0.68-0.90 (m, 13H), 0.60 (q, J = 11.8 Hz, 1H) LCMS: MNa+ (ionic type), 1010.4 (ion m / z).

[0473] Compound 125: 1 H NMR (DMSO-d6, 600 MHz): δ (ppm) 5.93-6.63 (m, 5H), 5.61 (dd, J = 14.4, 8.5 Hz, 1H), 5.24 (br d, J = 4.5 Hz, 1H), 5.07-5.13 (m, 1H), 4.98 (br d, J = 4.8 Hz, 1H), 4.46-4.63 (m, 3H), 3.67-4.14 (m, 4H), 2.99-3.60 (m, 18H), 2.79 (br s, 4H), 0.35-2.42 (m, 47H). LCMS: MNa+ (ionic), 1010.4 (ion m / z).

[0474] Plan 25

[0475]

[0476] 2,2'-[Ethane-1,2-diylbis(oxy)]diethanol (18.37 mL, 129 mmol) was added to (1R,9S,12S,15R,16E,18R,19R,21R,23S,24E,26E,28E,30S,32S,35R)-1,18-dihydroxy-12-{(2R)-1-[(1S,3R,4R To a solution of 1,3-dimethoxy-4-(2-[(2-[(2-[(2-[(2-hydroxy-3-methoxycyclohexyl]propane-2-yl)-19,30-dimethoxy-15,17,21,23,29,35-hexamethyl-11,36-dioxa-4-azatricyclo[30.3.1.0-4,9-]triacontahedral-16,24,26,28-tetraene-2,3,10,14,20-pentaone) (3.00 g, 3.28 mmol) in anhydrous DCM (131 mL) was added 4-methylbenzenesulfonic acid (2.82 g, 16.4 mmol). The mixture was stirred at room temperature for 60 minutes. The mixture was diluted with DCM and neutralized with saturated NaHCO solution. The phases were separated. The organic phase was washed with water, dried, filtered and concentrated to dryness. The crude mixture was purified by reverse phase chromatography (Uptisphere Strategy C18-Hq 10 um 250×30.0 mm, CH 3 CN:H 2 O gradient 70:30 to 100:0, 277 nm). The main fraction (1.8 g) was purified by SFC separation to provide two fractions.

[0477] (1R,9S,12S,15R,16E,18R,19R,21R,23S,24E,26E,28E,30R,32S,35R)-1,18-dihydroxy-30-[2-[2-(2-hydroxyethoxy)ethoxy]ethoxy]-12-[(1R)-2-[(1S,3R,4R)-4-hydroxy-3-methoxy-cyclohexyl]-1-methyl-ethyl]-19-methoxy-15,17,21,23,29,35-hexamethyl-11,36-dioxa-4-azatricyclo[30.3.1.04,9]hexatriacontitanate-16,24,26,28-tetraene-2,3,10,14,20-pentaone (444 mg, 13%, white amorphous solid, Compound 526) and (1R,9S,12S,15R,16E,18R,19R,21R,23S,24E,26E,28E,30S,32S,35R)-1,18-dihydroxy-30-[2-[2-(2-hydroxyethoxy)ethoxy]ethoxy]-12-[(1R)-2-[(1S,3R,4R)-4-hydroxy-3-methoxy-cyclohexyl]-1-methyl-ethyl]-19-methoxy-15,17,21,23,29,35-hexamethyl-11,36-dioxa-4-azatricyclo[30.3.1.04,9]hexatriacontitania-16,24,26,28-tetraene-2,3,10,14,20-pentaone (288 mg, 3%, white amorphous solid, compound 127).

[0478] SFC separation: Column: Princeton 2-ethylpyridine 5 μm 60A. Column dimensions: 3 cm ID × 15 cm L. Mobile phase: CO2 / IpOH 60 / 40. Flow rate: 100 ml / min. Pressure: 100 bar. Wavelength: UV 277 nm. SFC instrument: Waters SFC200.

[0479] Compound 526: 1H NMR(DMSO-d6,600MHz)δ5.9-6.6(m,5H),5.46(dd,1H,J=9.6,14.9Hz),5.2-5.3(m,1H),5.09(br d,1H,J=10.1Hz),5.0-5.1(m,1H),4.93(br d,1H,J=6.2Hz),4.5-4.6(m,2H),4.0-4.1(m,2H),3.94(d,1H,J=4.5Hz),3.8-3.8( m,1H),3.4-3.6(m,12H),3.1-3.3(m,7H),2.82(ddd,2H,J=4.3,8.5,11.2Hz),2.73( dd, 1H, J = 2.4, 17.5 Hz), 2.3-2.4 (m, 2H), 2.2-2.3 (m, 1H), 1.8-2.2 (m, 5H), 1.5-1.8 (m, 14H), 0.7-1.5 (m, 28H), 0.59 (q, 1H, J = 12.0 Hz) LCMS: MNa+ (ionic form), 1054.8 (ion m / z).

[0480] Compound 127: 11H NMR (DMSO-d6, 600 MHz): δ (ppm) 6.53 (d, J = 0.9 Hz, 1H), 6.43 (dd, J = 14.0, 11.7 Hz, 1H), 6.13 - 6.22 (m, 2H), 6.05 (br d, J = 10.3 Hz, 1H), 5.60 (dd, J = 14.5, 8.4 Hz, 1H), 5.25 (d, J = 4.5 Hz, 1H), 5.19 - 5.24 (m, 1H), 5.10 (ddd, J = 8.9, 4.8, 2.7 Hz, 1H), 4.98 (br d, J = 5.1 Hz, 1H), 4.57 (d, J = 4.3 Hz, 1H), 4.55 (t, J = 5.4 Hz, 1H), 4.04 (br d, J = 4.1 Hz, 1H), 3.95 - 4.00 (m, 1H), 3.91 (d, J = 4.5 Hz, 1H), 3.80 - 3.83 (m, 1H), 3.53 - 3.57 (m, 1H), 3.44 - 3.52 (m, 8H), 3.40 - 3.43 (m, 2H), 3.32 - 3.40 (m, 2H), 3.30 - 3.31 (m, 1H), 3.30 (s, 3H), 3.18 (s, 3H), 3.12 - 3.15 (m, 1H), 3.01 - 3.09 (m, 1H), 2.79 - 2.86 (m, 1H), 2.75 - 2.79 (m, 1H), 2.50 (br s, 2H), 2.22 - 2.31 (m, 1H), 2.15 (br d, J = 12.9 Hz, 1H), 1.97 - 2.04 (m, 1H), 1.87 - 1.96 (m, 1H), 1.70 - 1.78 (m, 3H), 1.70 (s, 3H), 1.65 (s, 3H), 1.47 - 1.63 (m, 7H), 1.32 - 1.46 (m, 3H), 1.22 - 1.32 (m, 3H), 1.05 - 1.21 (m, 4H), 0.98 (br d, J = 6.7 Hz, 3H), 0.94 - 0.97 (m, 1H), 0.92 (d, J = 6.6 Hz, 3H), 0.85 - 0.88 (m, 1H), 0.83 (d, J = 6.5 Hz, 3H), 0.79 (br d, J = 6.7 Hz, 2H), 0.73 (s, 3H), 0.52 - 0.60 (m, 1H) LCMS: MNa+ (ionic form), 1054.8 (ionic m / z). <{

[0481] Scheme 26

[0482]

[0483] Cyclopropanol (2.6 mL, 41.3 mmol) was added to (1R,9S,12S,15R,16E,18R,19R,21R,23S,24E,26E,28E,30S,32S,35R)-1,18-dihydroxy-12-{(2R)-1-[(1S,3R,4R)-4-(2-hydroxyethoxy)-3-methoxycyclohexyl]propane A solution of 1,2-dimethyl-2-yl}-19,30-dimethoxy-15,17,21,23,29,35-hexamethyl-11,36-dioxa-4-azatricyclo[30.3.1.0~4,9~]triacontahedral-16,24,26,28-tetraene-2,3,10,14,20-pentaketone (1.00 g, 1.04 mmol) in anhydrous DCM (42 mL) was added. The mixture was cooled to -20 ° C and 4-methylbenzenesulfonic acid (881 mg, 5.11 mmol) was added. The mixture was stirred at room temperature for 30 minutes. The mixture was diluted with DCM and neutralized with saturated NaHCO3 solution. The phases were separated. The organic phase was washed with water (40 mL), dried, filtered and concentrated to dryness. The resulting crude mixture was purified by reverse phase chromatography (Upsphere Strategy C18-Hq 10 um 250×30.0 mm, CH 3 CN:H 2 O gradient 70:30 to 100:0, 277 nm). The main fraction was purified by SFC separation to provide two fractions.

[0484] (1R,9S,12S,15R,16E,18R,19R,21R,23S,24E,26E,28E,30S,32S,35R)-30-(cyclopropyloxy)-1,18-dihydroxy-12-[(1R)-2-[(1S,3R,4R)-4-(2-hydroxyethoxy)-3-methoxy-cyclohexyl]-1-methyl-ethyl]-19-methoxy-15,17,21,23,29,35-hexamethyl-11,36-dioxa-4-azatricyclo[30.3.1.04,9]hexatriacontitania-16,24,26,28-tetraene-2,3,10,14,20-pentaone (381 mg, 36%, white amorphous solid, compound 527) and (1R,9S,12S,15R,16E,18R,19R,21R,23S,24E,26E,28E,30R,32S,35R)-30-(cyclopropyloxy)-1,18-dihydroxy-12-[(1R)-2-[(1S,3R,4R)-4-(2-hydroxyethoxy)-3-methoxy-cyclohexyl]-1-methyl-ethyl]-19-methoxy-15,17,21,23,29,35-hexamethyl-11,36-dioxa-4-azatricyclo[30.3.1.04,9]hexatriacontaria-16,24,26,28-tetraene-2,3,10,14,20-pentaone (168 mg, 15%, white amorphous solid, compound 128).

[0485] SFC separation: Column: Waters Viridis Ethylpyridine 5 μm 60A. Column dimensions: 19 × 250 mm. Mobile phase: CO₂ / IpOH 80 / 20. Flow rate: 50 ml / min. Pressure: 100 bar. Wavelength: UV 277 nm. SFC instrument: Waters SFC200.

[0486] Compound 527: 1H NMR(600MHz,DMSO-d6)δ5.91-6.52(m,5H),5.44-5.59(m,1H),5.19-5.32(m,1H),5.03-5.17(m,1H),4.91-5.00(m,2H),4.41-4.46(m,1H), 3.99-4.03(m,1H),3.66-3.96(m,3H),3.38-3.55(m,5H),3.31-3.35( m,3H),3.24-3.29(m,1H),3.12-3.21(m,3H),2.95-3.10(m,3H),2.65 -2.78(m,1H),2.34-2.48(m,2H),2.18-2.26(m,1H),2.06-2.15(m,1H),1.65-2.04(m,13H),1.50-1.62(m,5H),1.36-1.44(m,2H),1.22-1.33(m,4H),1.10-1.19(m,2H),0.93-1.06(m,7H),0.81-0.91(m,6H),0.62-0.79(m,7H),0.22-0.54(m,4H)LCMS:MNa+(ionic form),1006.6(ion m / z).

[0487] Compound 128: 1 H NMR(600MHz,DMSO-d6)δ5.91-6.70(m,5H),5.61-5.74(m,1H),5.18-5.34(m,2H),5.05-5.18(m,1H),4.98 (brd,J=5.43Hz,1H),4.40-4.46(m,1H),4.01-4.09(m,1H),3.80-3.99(m,3H),3.42-3.59(m,5H),3.30-3 .39(m,4H),3.13-3.28(m,4H),2.92-3.10(m,3H),2.53-2.86(m,3H),2.25-2.32(m,1H),2.06-2.19(m,1H ),1.87-2.03(m,3H),1.65-1.71(m,6H),1.49-1.61(m,6H),1.40-1.45(m,1H),1.20-1.37(m,5H),1.17(br s, 1H), 1.06-1.15 (m, 4H), 0.93-1.05 (m, 7H), 0.70-0.90 (m, 11H), 0.61-0.66 (m, 1H), 0.22-0.53 (m, 4H) LCMS: MNa+ (ionic form), 1006.7 (ion m / z).

[0488] Plan 27

[0489]

[0490] Preparation of (1R,9S,12S,15R,16E,18R,19R,21R,23S,24E,26E,28E,30S,32S,35R)-12-[(1R)-2-[(1S,3R,4R)-4-[3-[tert-butyl(dimethyl)silyl]oxypropoxy]-3-methoxy-cyclohexyl]-1-methyl-ethyl]-1,18-dihydroxy-19,30-dimethoxy-15,17,21,23,29,35-hexamethyl-11,36-dioxa-4-azatricyclo[30.3.1.0A4,9]triacontahedral-16,24,26,28-tetraene-2,3,10,14,20-pentaone (Compound V). Under argon, 3-[tert-butyl(dimethyl)silyl]oxypropyl trifluoromethanesulfonate (1799 mg, 5.58 mmol) was added to a mixture of sirolimus (1.7 g, 1.86 mmol) and N-ethyl-N-isopropyl-propan-2-amine (1.8 mL, 10.2 mmol) previously dissolved in anhydrous toluene (6.9 mL). After stirring at 60 ° C for 3 hours, the crude mixture was concentrated and purified on silica gel by flash column chromatography (cyclohexane / ethyl acetate 100: 0 to 70: 30) to provide the desired product (799 mg) as an amorphous white solid. Yield 39%. LCMS: MNa + (ionic), 1108.7 (ion m / z).

[0491] Plan 28

[0492]

[0493] 2-Methoxyethanol (81 mL, 1.02 mmol) was added to (1R,9S,12SR,15R,16E,18R,19R,21R,23S,24E,26E,28E,30S,32S,35R)-12-[(1R)-2-[(1S,3R,4R)-4-[3-[tert-butyl(dimethyl)silyl]oxypropoxy]-3-methoxy-cyclohexyl]-1 [-methyl-ethyl]-1,18-dihydroxy-19,30-dimethoxy-15,17,21,23,29,35-hexamethyl-11,36-dioxa-4-azatricyclo[30.3.1.0^4,9]triacontahedral-16,24,26,28-tetraene-2,3,10,14,20-pentaketone (3.03 g, 2.79 mmol) in anhydrous DCM (30 mL). 4-Methylbenzenesulfonic acid (2.40 g, 13.9 mmol) was added. The mixture was stirred at room temperature for 60 minutes. The mixture was diluted with DCM and neutralized with saturated NaHCO solution. The phases were separated. The organic phase was washed with water (40 mL), dried, filtered and concentrated to dryness. The resulting crude mixture was purified by reverse phase chromatography (Uptisphere Strategy C18-Hq 10 um 250×30.0 mm, CH 3 CN:H 2 O gradient 60:40 to 100:0, 277 nm). The main fraction was purified by SFC separation to provide two fractions.

[0494] (1R,9S,12S,15R,16E,18R,19R,21R,23S,24E,26E,28E,30S,32S,35R)-1,18-dihydroxy-12-[(1R)-2-[(1S,3R,4R)-4-(3-hydroxypropyloxy)-3-methoxy-cyclohexyl]-1-methyl-ethyl]-19-methoxy-30-(2-methoxyethoxy)-15,17,21,23,29,35-hexamethyl-11,36-dioxa-4-azatricyclo[30.3.1.04,9]hexatriacontitanate-16,24,26,28-tetraene-2,3,10,14,20-pentaone (66 mg, 3%, white amorphous solid, compound 427) and (1R,9S,12S,15R,16E,18R,19R,21R,23S,24E,26E,28E,30R,32S,35R)-1,18-dihydroxy-12-[(1R)-2-[(1S,3R,4R)-4-(3-hydroxypropyloxy)-3-methoxy-cyclohexyl]-1-methyl-ethyl]-19-methoxy-30-(2-methoxyethoxy)-15,17,21,23,29,35-hexamethyl-11,36-dioxa-4-azatricyclo[30.3.1.04,9]hexatriacontitanate-16,24,26,28-tetraene-2,3,10,14,20-pentaone (19.7 mg, 1%, white amorphous solid, compound 28).

[0495] SFC separation: Column: Waters Viridis Ethylpyridine 5 μm 60A. Column dimensions: 19 × 250 mm. Mobile phase: CO₂ / IpOH 80 / 20. Flow rate: 50 ml / min. Pressure: 100 bar. Wavelength: UV 277 nm. SFC instrument: Waters SFC200.

[0496] Compound 427: 1 H NMR(600MHz,DMSO-d6,300K)δppm 11H NMR (DMSO-d6, 500 MHz): δ (ppm) 6.45 (d, J = 1.7 Hz, 1H), 6.32 - 6.43 (m, 1H), 6.08 - 6.26 (m, 3H), 5.46 (dd, J = 14.8, 9.7 Hz, 1H), 5.26 (d, J = 4.4 Hz, 1H), 5.09 (br d, J = 10.0 Hz, 1H), 4.98 (dt, J = 7.6, 4.0 Hz, 1H), 4.94 (br d, J = 5.4 Hz, 1H), 4.30 (br t, J = 5.1 Hz, 1H), 3.97 - 4.08 (m, 2H), 3.94 (d, J = 4.6 Hz, 1H), 3.79 (br d, J = 11.5 Hz, 1H), 3.53 - 3.60 (m, 1H), 3.34 - 3.52 (m, 6H), 3.33 (s, 3H), 3.25 - 3.30 (m, 2H), 3.24 (s, 3H), 3.16 (s, 3H), 2.89 - 3.05 (m, 2H), 2.73 (br d, J = 15.4 Hz, 1H), 2.30 - 2.44 (m, 2H), 2.17 - 2.28 (m, 1H), 2.10 (br d, J = 13.0 Hz, 1H), 1.99 - 2.06 (m, 1H), 1.81 - 1.98 (m, 4H), 1.74 (s, 3H), 1.66 - 1.70 (m, 2H), 1.64 (s, 3H), 1.50 - 1.63 (m, 6H), 1.35 - 1.47 (m, 2H), 1.21 - 1.33 (m, 3H), 1.09 - 1.20 (m, 2H), 1.04 (d, J = 5.9 Hz, 3H), 1.00 - 1.08 (m, 2H), 0.98 (br d, J = 6.6 Hz, 3H), 0.91 - 0.96 (m, 1H), 0.87 (d, J = 6.6 Hz, 3H), 0.83 (d, J = 6.4 Hz, 3H), 0.79 - 0.81 (m, 1H), 0.78 (d, J = 6.8 Hz, 3H), 0.73 (d, J = 6.8 Hz, 3H), 0.65 (q, J = 12.0 Hz, 1H)

[0497] Compound 28: 1H NMR (600 MHz, DMSO-d6, 300 K) δ ppm 5.49-6.45 (m, 5H), 4.98-5.57 (m, 5H), 4.10-4.51 (m, 3H), 3.57-3.94 (m, 8H), 3.18-3.57 (m, 16H), 2.97-3.17 (m, 2H), 2.51-2.76 (m, 3H), 1.89-2.42 (m, 8H), 1.24-1.88 (m, 18H), 0.65-1.18 (m, 14H). LCMS: MNa+ (ionic), 1038.7 (ion m / z).

[0498] Plan 29

[0499]

[0500] To (1R,9S,12S,15R,16E,18R,19R,21R,23S,24E,26E,28E,30S,32S,35R)-1,18-dihydroxy-12-[(1R)-2-[(1S,3R,4R)-4-(3-iodopropoxy)-3-methoxy-cyclohexyl]-1-methyl-ethyl]-19-methoxy-30-(2-methoxyethoxy)-15,17,21,23,29,35-hexamethyl- 11,36-dioxa-4-azatricyclo[30.3.1.0^4,9]triacontahedral-16,24,26,28-tetraene-2,3,10,14,20-pentaketone (Compound C1) (300mg, 0.266mmol) was added to a solution of anhydrous DCM (1.66mL) with N-ethyl-N-isopropyl-propan-2-amine (139uL, 0.799mmol) and methylpiperazine (36uL, 0.319mmol). At room temperature, under argon, the reaction mixture was stirred for 6 hours. The reaction mixture was diluted with DCM and quenched with a saturated NH4Cl aqueous solution (pH=6). The organic phase was washed with water and dried. The crude product was then purified by flash column chromatography on silica gel (100 / 0 to 70 / 30 EtOAc / MeOH:Et3N (50:50)). The target fraction was then purified by silica gel flash column chromatography (100 / 0 to 80 / 20 DCM / MeOH) to provide the desired product (1R,9S,12S,15R,16E,18R,19R,21R,23S,24E,26E,28E,30S,32S,35R)-1,18-dihydroxy-19-methoxy-30-(2-methoxyethoxy)-12-[(1R)-2-[(1S, 3R,4R)-3-methoxy-4-[3-(4-methylpiperazin-1-yl)propoxy]cyclohexyl]-1-methyl-ethyl]-15,17,21,23,29,35-hexamethyl-11,36-dioxa-4-azatricyclo[30.3.1.0^4,9]hexatriacontaria-16,24,26,28-tetraene-2,3,10,14,20-pentaone (137 mg, 47%, compound 431).

[0501] Compound 431: MS (ES+, m / z): 1098.7 [M+H]+. 1H NMR (600MHz, DMSO-d6) δ5.88-6.53(m,5H),5.42-5.70(m,1H),5.20-5.29(m,1H),5.06-5.15(m,1H),4.92-5.05(m,2H),3.98-4.08( m,2H),3.83-3.96(m,1H),3.67-3.81(m,1H),3.32-3.57(m,9H),3.10-3.28(m,9H),2.91-3.05(m,2H),2.70-2.76(m,1H),2.16-2.4 8(m,13H),2.16(brs,3H),1.97-2.13(m,3H),1.83-1.96(m,4H),1.73(s,2H),1.52-1.70(m,12H),1.35-1.45(m,2H),1.21-1.33(m, 4H), 1.14-1.20 (m, 1H), 0.93-1.11 (m, 8H), 0.80-0.89 (m, 6H), 0.72-0.79 (m, 5H), 0.63-0.69 (m, 1H) LCMS: MH+ (ES+), 1098.7 (ion m / z).

[0502] Plan 30

[0503]

[0504] To ((1R,9S,12S,15R,16E,18R,19R,21R,23S,24E,26E,28E,30R,32S,35R)-1,18-dihydroxy-12-[(1R)-2-[(1S,3R,4R)-4-(3-iodopropoxy)-3-methoxy-cyclohexyl]-1-methyl-ethyl]-19-methoxy-30- (2-Methoxyethoxy)-15,17,21,23,29,35-hexamethyl-11,36-dioxa-4-azatricyclo[30.3.1.04,9]hexatriacontahedral-16,24,26,28-tetraene-2,3,10,14,20-pentaone (Compound C1) (502.9 mg, 0.446 mmol) was dissolved in anhydrous DCM (2.79 ml) L) in the solution in the reaction mixture was added N- ethyl -N- isopropyl - propan- 2- amine (233uL, 1.34mmol) and 1- methylpiperazine (60uL, 0.535mmol) in sequence. At room temperature, under argon, the reaction mixture was stirred for 3 hours. The reaction mixture was diluted with DCM and quenched with saturated NH4Cl aqueous solution (pH = 6). The organic phase was washed with water and dried. The crude product was then purified by silica gel flash column chromatography (100 / 0 to 70 / 30 EtOAc / MeOH: Et3N (50: 50)). The target fraction was then purified by silica gel flash column chromatography (100 / 0 to 80 / 20 DCM / MeOH) to provide the desired product (1R, 9S, 12S ,15R,16E,18R,19R,21R,23S,24E,26E,28E,30R,32S,35R)-1,18-dihydroxy-19-methoxy-30-(2-methoxyethoxy)-12-[(1R)-2-[(1S,3R,4R)-3-methoxy-4-[3-(4-methylpiperazin-1-yl)propoxy]cyclohexyl]-1-methyl-ethyl]-15,17,21,23,29,35-hexamethyl-11,36-dioxa-4-azatricyclo[30.3.1.04,9]triacontahedral-16,24,26,28-tetraene-2,3,10,14,20-pentaone (78.9 mg, 15%, compound 32).

[0505] Compound 32: MS (ES+, m / z): 1098.7 [M+H]+. 1 H NMR (600 MHz,

[0506] DMSO-d6)δ5.89-6.61(m,5H),5.39-5.67(m,1H),5.04-5.38(m,4H),4.89-5.02(m,1H),3.89-4.07(m,2H),3.77 -3.87(m,1H),3.65-3.75(m,1H),3.32-3.51(m,7H),2.91-3.07(m,4H),2.64-2.83(m,3H),2.51-2.63(m,2H),2. 26-2.44(m,9H),2.07-2.23(m,6H),1.86-2.03(m,4H),1.54-1.72(m,18H),1.47-1.52(m,2H),1.22-1.41(m,7H) ,1.04-1.11(m,5H),0.90-1.02(m,10H),0.72-0.88(m,10H),0.61-0.68(m,1H)LCMS:MH+(ES+),1098.7(ion m / z).

[0507] Plan 31

[0508]

[0509] To a solution of (1R,9S,12SR,15R,16E,18R,19R,21R,23S,24E,26E,28E,30R,32S,35R)-1,18-dihydroxy-30-(4-hydroxybutyloxy)-12-[(1R)-2-[(1S,3R,4R)-4-(3-iodopropoxy)-3-methoxy-cyclohexyl]-1-methyl-ethyl]-19-methoxy- To 1,3-dioxa-15,17,21,23,29,35-hexamethyl-11,36-dioxa-4-azatricyclo[30.3.1.04,9]hexatriacontac-16,24,26,28-tetraene-2,3,10,14,20-pentaone (334 mg, 0.29 mmol) were added N-ethyl-N-isopropyl-propan-2-amine (113 uL, 0.88 mmol) and morpholine (22 uL, 0.25 mmol). The reaction mixture was stirred at room temperature for 24 hours. The mixture was then diluted with DCM and 1N aqueous HCl was added until pH = 5. The organic phase was washed with water, dried, concentrated to dryness, and purified by flash column chromatography on silica gel (100 / 0 to 85 / 15 EtOAc / MeOH:Et3N (50:50)). The target fraction was purified by silica gel flash column chromatography (DCM / MeOH, 100 / 0 to 90 / 10) to give (1R,9S,12S,15R,16E,18R,19R,21R,23S,24E,26E,28E,30R,32S,35R)-1,18-dihydroxy-30-(4-hydroxybutoxy)-19-methoxy-12-[(1R)-2-[(1 [S,3R,4R)-3-methoxy-4-(3-morpholinopropoxy)cyclohexyl]-1-methyl-ethyl]-15,17,21,23,29,35-hexamethyl-11,36-dioxa-4-azatricyclo[30.3.1.04,9]hexatriacontaria-16,24,26,28-tetraene-2,3,10,14,20-pentaone (110 mg, 34%, compound 27).

[0510] Compound 27: 1H NMR (600 MHz, DMSO-d6) δ 5.86-6.59 (m, 5H), 5.43-5.64 (m, 1H), 4.89-5.27 (m, 4H), 4.29-4.43 (m, 1H), 3.60-4.09 (m, 4H), 3.45-3.58 (m, 7H), 3.34-3.41 (m, 2H), 3.32 (br d, J = 5.28 Hz, 4H), 3.10-3.20 (m, 5H), 2.93-3.01 (m, 2H), 2.61-2.83 (m, 3H), 2.26-2.35 (m, 7H), 0.64-2.20 (m, 53H) LCMS: MH+ (ionic), 1099.6 (ion m / z).

[0511] Plan 32

[0512]

[0513] To a solution of everolimus (1.50 g, 1.57 mmol) in anhydrous DCM (19.568 mL) was added 2-methoxyethanol (45 mL, 0.573 mol) and 4-methylbenzenesulfonic acid (1.35 g, 7.83 mmol) in sequence. The reaction mixture was stirred at room temperature for 1 h. The reaction mixture was neutralized with a saturated aqueous NaHCO solution and extracted with DCM. The organic phase was washed with water (60 mL), dried, filtered and concentrated to dryness. The resulting crude mixture was purified by reverse phase chromatography (Uptisp here Strategy C18-Hq10um 250 × 30.0 mm, CH3CN:H2O gradient 60:40 to 100:0, 277 nm in 25 min). The main fraction (540 mg) was purified by SFC separation to afford (1R,9S,12S,15R,16E,18R,19R,21R,23S,24E,26E,28E,30R,32S,35R)-1,18-dihydroxy-12-[(1R)-2-[(1S,3R,4R)-4-(2-hydroxyethoxy)-3-methoxy-cyclohexyl]-1 -methyl-ethyl]-19-methoxy-30-(2-methoxyethoxy)-15,17,21,23,29,35-hexamethyl-11,36-dioxa-4-azatricyclo[30.3.1.0^4,9]hexatriacontahedral-16,24,26,28-tetraene-2,3,10,14,20-pentaone (compound 439, 231 mg, 15%, white amorphous solid).

[0514] SFC separation: Column: Princeton 2-ethylpyridine 5 μm 60A. Column dimensions: 3 cm ID × 15 cm L. Mobile phase: CO2 / IpOH 85 / 15. Flow rate: 50 ml / min. Pressure: 100 bar. Wavelength: UV 277 nm. SFC instrument: Waters SFC200.

[0515] Compound 439: 1 H NMR (DMSO-d6, 600MHz): δ (ppm) 5.87-6.60 (m, 5H), 5.61 (dd, J=14.3, 8.5Hz, 1H), 5.04-5.53 (m, 3), 4.99 (d, J=5.8Hz, 1H), 4.95 -4.89(m,1H),4.43(t,J=5.5Hz,1H),3.91-4.15(2H,m),3.78-3.92(m,1H),3.62-3.78(m,1H),3.35-3.59(m,3H),3.26-3.34(m 7H), 3.10-3.26(m,3H),2.89-3.09(m,4H),2.59-2.85(m,2H),2.34-2.43(m,1H),2.20-2.33(m,1H),1.81-2.19(m,4H),1.45-1.81(m,6H),1.19-1.45(m,3H),0.89-1.19(m,5H),0.59-0.89(5H,m).LCMS: MNa+(ionic form), 1024.6(ion m / z).

[0516]

[0517] Table 1, having a core of formula (III-A):

[0518]

[0519]

[0520]

[0521]

[0522]

[0523]

[0524]

[0525]

[0526]

[0527]

[0528] Table 2, core having formula (III-B):

[0529]

[0530]

[0531]

[0532]

[0533]

[0534]

[0535]

[0536]

[0537]

[0538]

[0539] Table 3, core having formula (III-C):

[0540]

[0541]

[0542]

[0543]

[0544]

[0545]

[0546]

[0547]

[0548]

[0549]

[0550] Table 4, having a core of formula (III-D):

[0551]

[0552]

[0553]

[0554]

[0555]

[0556]

[0557]

[0558]

[0559]

[0560]

[0561] Table 5, having a core of formula (III-E):

[0562]

[0563]

[0564]

[0565]

[0566]

[0567]

[0568]

[0569]

[0570]

[0571]

[0572] Table 6, having a core of formula (III-F):

[0573]

[0574]

[0575]

[0576]

[0577]

[0578]

[0579]

[0580]

[0581]

[0582] Table 7, core having formula (III-G):

[0583]

[0584]

[0585]

[0586]

[0587]

[0588]

[0589]

[0590]

[0591]

[0592]

[0593] Table 8, core having formula (III-H):

[0594]

[0595]

[0596]

[0597]

[0598]

[0599]

[0600]

[0601]

[0602]

[0603] Example 1: Supercritical Fluid Chromatography (SFC) Analytical Method for Separating Various Diastereomers

[0604] Table 9: SFC analysis method

[0605]

[0606]

[0607] Table 10: Structure and retention time

[0608]

[0609]

[0610]

[0611]

[0612]

[0613]

[0614] Differential pharmacology of the compounds described herein can be observed in different cell or tissue types in the following assays, depending on (1) the relative abundance of FKBP homologs in these cells / tissues and (2) the specificity of binding to these different FKBP homologs (Mol. Cell Biol. (2013) 33: 1357-1367). Various FKBP homologs were used in the following examples.

[0615] Example 2:

[0616] SPR assay to determine binding affinity to FKBP12.

[0617] Biotinylated avi-FKBP12 was immobilized on a streptavidin chip (Cytiva S Series SA) using Biacore 8K or 8K+ (Cytiva). To achieve an immobilization level of 1000 RU, 2 μg / ml of biotinylated avi-FKBP12 was injected over 100 seconds at a flow rate of 10 μl / min. The test compounds described in Table 11 were diluted to a 100× working concentration in DMSO. Each test compound was diluted 100-fold in 50 mM HEPES (pH 7.5), 150 mM NaCl, 2 mM MgCl2, 1 mM DTT, and 0.05% Tween-20, and serial dilutions were prepared (9 concentrations, 3-fold dilutions, 0.08–500 nM). Rapamycin was used as a reference sample (9 concentrations, 3-fold dilutions, 0.02–100 nM). Compound dilutions were then injected sequentially at increasing concentrations at 100 uL / min over a 120-second contact time. Dissociation was monitored for 3600 seconds. 50 mM HEPES (pH 7.5), 150 mM NaCl, 2 mM MgCl2, 1 mM DTT, 0.05% Tween-20, 1% DMSO were used as the running buffer. Single-cycle kinetic data were fit to a 1:1 binding model to determine the association rate ka (1 / Ms), dissociation rate kd (1 / s), and affinity Kd (M).

[0618] Table 11 includes the FKBP12 direct binding K values ​​of selected compounds d (nM) values; wherein the FKBP12 direct binding K d The compound is represented by A and has a FKBP12 direct binding K of 0.3 nM to 1.0 nM. d Compounds are designated as B and have a direct FKBP12 binding K greater than 1.0 nM. d The compound is represented by C.

[0619] Table 11: Direct FKBP12 binding of various compounds represented by the following formula:

[0620]

[0621]

[0622]

[0623]

[0624] Compound <![CDATA[FKBP12 K d (nM)]]> Rapamycin A

[0625] Example 3: SPR assay to determine binding affinity to FKBP51.

[0626] Biotinylated avi-FKBP51 was immobilized on a streptavidin chip (Cytiva S Series SA) using Biacore 8K or 8K+ (Cytiva). To achieve an immobilization level of 2000 RU, 3 μg / mL of biotinylated avi-FKBP51 was injected over 360 seconds at a flow rate of 10 μl / min. Test compounds were diluted to a 100× working concentration in DMSO. Each test compound was diluted 100-fold in 50 mM HEPES (pH 7.5), 150 mM NaCl, 2 mM MgCl2, 1 mM DTT, and 0.05% Tween-20, and serial dilutions were prepared (8 concentrations, 3-fold dilutions, 0.5–1000 nM). Rapamycin was used as a reference sample (8 concentrations, 3-fold dilutions, 0.5–1000 nM). Compound dilutions were then injected at increasing concentrations at 100 uL / min over a 120-second contact time, with a dissociation time of 3600 seconds. 50 mM HEPES (pH 7.5), 150 mM NaCl, 2 mM MgCl2, 1 mM DTT, 0.05% Tween-20, 1% DMSO were used as the running buffer. Multi-cycle kinetic data were fitted to a 1:1 binding model to determine the association rate ka (1 / Ms), dissociation rate kd (1 / s), and affinity Kd (M).

[0627] Example 4: SPR assay to characterize ternary complex formation with FKBP12.

[0628] Biotinylated avi-FKBP12 was immobilized on a streptavidin chip (Cytiva S Series SA) using Biacore 8K or 8k+ (Cytiva). To achieve an immobilization level of 100 RU, 0.3 μg / ml of biotinylated avi-FKBP12 was injected over 80 seconds at a flow rate of 10 μl / min. Serial dilutions of FRB were prepared (12 concentrations, 3-fold dilutions, 0.00011–20 μM) and supplemented with 100 nM of the test compound. ABA injection mode was used to ensure saturation of immobilized FKBP12 with the corresponding test compound. A 100 nM solution of the corresponding test compound was injected over 120 seconds before the FRB injection and over 420 seconds during the dissociation period. The FRB dilutions were then injected at increasing concentrations over a 120-second contact time. Rapamycin was used as a reference sample. 50 mM HEPES (pH 7.5), 150 mM NaCl, 2 mM MgCl2, 1 mM DTT, 0.05% Tween-20, 1% DMSO was used as the running buffer at a flow rate of 30 μl / min. Multi-cycle kinetic data were fitted to a 1:1 binding model to measure the association rate ka (1 / M s), the dissociation rate kd (1 / s), and the affinity Kd (M). In the case of rapid association and dissociation, steady-state affinity analysis following the law of mass action was used to determine the affinity Kd (M).

[0629] Table 12 includes the FKBP12 ternary complex K values ​​of selected compounds d (nM) values; wherein the FKBP12 ternary complex K is less than 500 nM d The compound is represented by A and has a FKBP12 ternary complex K of 500nM to 1100nM. d The compound is designated as B and has a FKBP12 ternary complex K greater than 1100 nM. d The compound is represented by C.

[0630] Table 12: FKBP12 ternary complexes of various compounds represented by the following formula:

[0631]

[0632]

[0633]

[0634]

[0635] Example 5: SPR assay to characterize ternary complex formation with FKBP51.

[0636] Biotinylated avi-FKBP51 was immobilized on a streptavidin chip (Cytiva S Series SA) using Biacore 8K or 8k+ (Cytiva). To achieve an immobilization level of 200 RU, 0.6 μg / ml of biotinylated avi-FKBP51 was injected over 150 seconds at a flow rate of 10 μl / min. Serial dilutions of FRB were prepared (12 concentrations, 3-fold dilutions, 0.00011–20 μM) and supplemented with 100 nM of the test compound. ABA injection mode was used to ensure saturation of immobilized FKBP12 with the corresponding test compound. A 100 nM solution of the corresponding test compound was injected over 120 seconds before the FRB injection and over 420 seconds during the dissociation period. The FRB dilutions were then injected at increasing concentrations over a 120-second contact time. Rapamycin was used as a reference sample. 50 mM HEPES (pH 7.5), 150 mM NaCl, 2 mM MgCl2, 1 mM DTT, 0.05% Tween-20, 1% DMSO was used as running buffer at a flow rate of 30 μl / min. Multi-cycle kinetic data were fitted to a 1:1 binding model to measure the association rate ka (1 / M s), dissociation rate kd (1 / s) and affinity K d (M). Steady-state affinity analysis following the law of mass action in the case of rapid association and dissociation is used to determine the affinity Kd (M).

[0637] Example 6: mTORC1 inhibition, mTORC2 inhibition, cell lysis, AlphaLISA assay and data analysis

[0638] The corresponding AlphaLISA kit (PerkinElmer Alpha SF Ultra TM Multiplex Phosphorylated (Thr389) / Total p70 S6K Assay Kit (Eu / Tb) and AlphaLISA SF Ultra TMmTORC1 inhibition was determined by analyzing the phosphorylation levels of phosphorylated p70 S6 kinase (p70S6K pT389) and phosphorylated S6 ribosomal protein (pRPS6pS240 / pS244). Therefore, PC-3 cells were plated at 1.20E+06 cells / ml in 96-well Corning clear bottom plates (Cat. No. 3997) in growth medium (DMEM: Ham's F12 basal medium (CLS CellLines Service GmbH, Cat. No. 820400a) supplemented with an additional 5% fetal bovine serum (FBS; Gibco, Cat. No. 10500064) and incubated overnight at 37° C., 5% CO . The following day, cells were treated with growth medium containing increasing compound concentrations (12 points of 3-fold dilutions) and incubated for an additional 24 hours at 37° C., 5% CO before cell lysis.

[0639] The corresponding AlphaLISA kit (PerkinElmer, Alpha SF Ultra TM mTORC2 inhibition was determined by analyzing the phosphorylation levels of phosphorylated AKT (pAKT pS473) (multiplex p-AKT1 / 2 / 3 (Ser473) / total AKT1). PC3 cells were plated at 1.20E+06 cells / mL in 96-well plates in assay medium (DMEM: Ham's F12 basal medium (CLS CellLines Service GmbH, catalog number 820400a)) supplemented with an additional 10% FBS and incubated overnight at 37°C, 5% CO2. The next day, cells were treated with assay medium (10% FBS) containing increasing compound concentrations (12 points of 3-fold dilutions) and incubated at 37°C, 5% CO2 for 6 hours. Afterwards, the medium was aspirated and the cells were rinsed with PBS. The cells were then treated with compound dilutions in starvation medium (DMEM: Ham's F12 basal medium; no FBS) for a further 18 h at 37° C., 5% CO 2 . The cells were then treated with 12% FBS for 15 min just before cell lysis.

[0640] Following experiments with mTORC1 and mTORC2 protocols, cells were harvested and enriched in Roche Omplete TMThe cells were lysed in 50 μL of lysis buffer supplied with the AlphaLISA kit containing a protease inhibitor cocktail (Cat. No. CO-RO). 50 μL of lysis buffer was then used to lyse the cells and incubated at 4°C for 60 min under shaking. After centrifugation at 4000 rpm for 5 min, the experiment was performed according to the AlphaLISA manufacturer's protocol. Ten microliters of cell lysate were mixed with the acceptor mixture. After incubation at room temperature for 2 h, the donor mixture was added. After an additional 2 h of incubation at room temperature, the cells were incubated on a P-type ELISA with an AlphaPLEX module. AlphaLISA signals were read on an FSX (BMG Labtech). Percent inhibition was calculated using the ExcelFit standard algorithm based on high controls (cells incubated with vehicle / DMSO) and low controls (mTORC1: cells incubated with 0.1 μM rapamycin; mTORC2: cells incubated with 1 μM rapamycin). All IC50 experiments were performed in triplicate using rapamycin and vehicle controls.

[0641] Data Analysis

[0642] The activity / inhibition percentage was calculated by applying the following equation:

[0643] %-Activity = 100*((Sample - Low Control) / (High Control - Low Control))

[0644] %-Inhibition = 100*(1-((Sample - Low Control) / (High Control - Low Control)))

[0645] Sample = Assay signal at corresponding compound concentration (phosphoprotein normalized to total protein)

[0646] High control = assay signal in the presence of vehicle / DMSO

[0647] Low control = assay signal in the presence of 0.1 μM (mTORC1) or 1 μM rapamycin (mTORC2)

[0648] EC50 values ​​were calculated by ExcelFit standard algorithm.All IC50 experiments were performed in triplicate (six high / low controls per plate) using rapamycin and vehicle controls.

[0649] Table 13 includes IC values ​​for mTORC1 as measured by inhibition of p70S6K pT389 levels by selected compounds. 50 (nM) values; with an IC<0.8 nM for mTOR C1 50 The compound is represented by A and has an IC against mTORC1 of 0.8 nM to 1.5 nM 50The compound is denoted as B and has an IC greater than 1.5 against mTORC1 50 The compound is represented by C.

[0650] When tested by the mTORC2 assay of Example 6, compounds of the present disclosure generally exhibited IC50 > 1.0 uM, while everolimus and rapamycin generally exhibited IC50 less than 10 nM

[0651] Table 13: mTORC 1 IC of compounds represented by 50 :

[0652]

[0653]

[0654]

[0655]

Claims

1. A compound represented by formula (III-C): or a pharmaceutically acceptable salt thereof, wherein the compound is selected from:

2. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound is selected from:

3. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound is selected from:

4. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound is:

5. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound is:

6. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound is:

7. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound is selected from:

8. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound is selected from:

9. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound is:

10. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound is:

11. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound is:

12. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound is: 13 . A pharmaceutical composition comprising the compound according to claim 1 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient.

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