C26-linked rapamycin analogs as mTOR inhibitors

1. A method of treating a disease or disorder in in a subject suffering from or susceptible to developing a disease or disorder mediated by mTOR,

wherein the disease or disorder is cancer; and wherein the cancer is selected from brain and neurovascular tumors, head and neck cancers, breast cancer, lung cancer, mesothelioma, lymphoid cancer, stomach cancer, kidney cancer, renal carcinoma, liver cancer, ovarian cancer, ovary endometriosis, testicular cancer, gastrointestinal cancer, prostate cancer, glioblastoma, skin cancer, melanoma, neuro cancers, spleen cancers, pancreatic cancers, blood proliferative disorders, lymphoma, leukemia, endometrial cancer, cervical cancer, vulva cancer, prostate cancer, penile cancer, bone cancers, muscle cancers, soft tissue cancers, intestinal or rectal cancer, anal cancer, bladder cancer, bile duct cancer, ocular cancer, gastrointestinal stromal tumors, and neuro-endocrine tumors; or

wherein the disease or disorder is an immune-mediated disease; and wherein the immune-mediated disease is selected from resistance by transplantation of heart, kidney, liver, medulla ossium, skin, cornea, lung, pancreas, intestinum tenue, limb, muscle, nerves, duodenum, small-bowel, or pancreatic-islet-cell; graft-versus-host diseases brought about by medulla ossium transplantation; rheumatoid arthritis, systemic lupus erythematosus, Hashimoto's thyroiditis, multiple sclerosis, myasthenia gravis, type I diabetes, uveitis, allergic encephalomyelitis, and glomerulonephritis; or

wherein the disease or disorder is selected from sarcopenia, skin atrophy, muscle wasting, brain atrophy, atherosclerosis, arteriosclerosis, pulmonary emphysema, osteoporosis, osteoarthritis, high blood pressure, erectile dysfunction, dementia, Huntington's disease, Alzheimer's disease, cataracts, age-related macular degeneration, prostate cancer, stroke, diminished life expectancy, impaired kidney function, and age-related hearing loss, aging-related mobility disability, cognitive decline, age-related dementia, memory impairment, tendon stiffness, heart dysfunction, immunosenescence, cancer, obesity, and diabetes;

the method comprising administering to the subject a therapeutically effective amount of a compound of Formula Ia:

or a pharmaceutically acceptable salt, stereoisomer, tautomer, or oxepane isomer thereof, wherein:

R 32 is H, ═O, —OR 3 , or —N 3 ;

A 3 is —[C(R 3 ) 2 ] n —, (C 6 -C 10 ) arylene, cycloalkylene, heteroarylene, or heterocyclylene;

R 26 is -A 1 -L 1 -A 2 -B; -A 1 -A 2 -B; or -L 2 -A 1 -L 1 -A 2 -L 3 -B;

A 1 and A 2 are independently absent or are independently selected from

wherein the bond on the left side of A 1 , as drawn, is bound to —C(═O)— or L 2 ; and wherein the bond on the right side of the A 2 moiety, as drawn, is bound to B or L 3 ;

each Q is independently 1 to 3 rings selected from arylene, cycloalkylene, heteroarylene, and heterocyclylene;

each X is independently absent or 1 to 2 rings selected from arylene, cycloalkylene, heteroarylene, and heterocyclylene;

each X 1 is independently a heteroarylene or heterocyclylene ring;

each W is independently absent or 1 to 2 rings selected from arylene, cycloalkylene, heteroarylene, and heterocyclylene;

each W 1 is independently a heteroarylene or heterocyclylene ring;

each G is independently absent or a ring selected from arylene, cycloalkylene, heteroarylene, and heterocyclylene;

each G 1 and G 2 are independently heteroarylene or heterocyclylene ring;

each L 1 is independently selected from

L 2 and L 3 are independently absent or are independently selected from

each B is independently selected from

each B 1 is independently selected from

wherein the

bond on the left side of B 1 , as drawn, is bound to A 2 or L 1 ; and wherein the heteroarylene, heterocyclylene, and arylene are each independently optionally substituted with alkyl, hydroxyalkyl, haloalkyl, alkoxy, halogen, or hydroxyl;

each R 3 is independently H or (C 1 -C 6 )alkyl;

each R 4 is independently H, (C 1 -C 6 )alkyl, halogen, 5-12 membered heteroaryl, 5-12 membered heterocyclyl, (C 6 -C 10 ) aryl, wherein the heteroaryl, heterocyclyl, and aryl are each independently optionally substituted with —N(R 3 ) 2 , —OR 3 , halogen, (C 1 -C 6 )alkyl, —(C 1 -C 6 )alkylene-heteroaryl, —(C 1 -C 6 )alkylene-CN, —C(O) NR 3 -heteroaryl, or —C(O) NR 3 -heterocyclyl;

each R 5 is independently H, (C 1 -C 6 )alkyl, —C(O) OR 3 , or —N(R 3 ) 2 , wherein the alkyl of (C 1 -C 6 )alkyl is optionally substituted with —N(R 3 ) 2 or —OR 3 ;

each R 6 is independently H, (C 1 -C 6 )alkyl, —C(O) OR 3 , or —N(R 3 ) 2 , wherein the alkyl of (C 1 -C 6 )alkyl is optionally substituted with —N(R 3 ) 2 or —OR 3 ;

each R 7 is independently H, (C 1 -C 6 )alkyl, —C(O) OR 3 , or —N(R 3 ) 2 , wherein the alkyl of (C 1 -C 6 )alkyl is optionally substituted with —N(R 3 ) 2 or —OR 3 ;

each R 8 is independently H, (C 1 -C 6 )alkyl, —C(O) OR 3 , or —N(R 3 ) 2 , wherein the alkyl of (C 1 -C 6 )alkyl is optionally substituted with —N(R 3 ) 2 or —OR 3 ;

each Y is independently C(R 3 ) 2 or a bond;

each n is independently an integer from one to 12;

each o is independently an integer from zero to 30;

each p is independently an integer from zero to 12;

each q is independently an integer from zero to 30; and

each r is independently an integer from one to 6.

2. The method of claim 1 , wherein R 32 is ═O or —OR 3 .

3. The method of claim 1 , wherein A 3 is —[C(R 3 ) 2 ] n — or —(C 6 -C 10 )arylene-.

4. The method of claim 1 , wherein R 26 is

-A 1 -L 1 -A 2 -B, wherein A 1 and A 2 are absent;

-A 1 -L 1 -A 2 -B, wherein A 2 is absent;

-A 1 -L 1 -A 2 -B, wherein A 1 is absent;

-A 1 -L 1 -A 2 -B;

-A 1 -A 2 -B; or

-L 2 -A 1 -L 1 -A 2 -L 3 -B.

5. The method of claim 1 , wherein the compound is selected from the group consisting of:

or a pharmaceutically acceptable salt, stereoisomer, tautomer, or oxepane isomer thereof.

6. The method of claim 1 , wherein the compound is selected from the group consisting of:

or a pharmaceutically acceptable salt, stereoisomer, tautomer, or oxepane isomer thereof.

7. The method of claim 1 , wherein the compound is selected from the group consisting of:

or a pharmaceutically acceptable salt, stereoisomer, tautomer, or oxepane isomer thereof.

8. The method of claim 1 , wherein the aging-related mobility disability is frailty.

9. The method of claim 1 , wherein the heart dysfunction is cardiac hypertrophy or systolic and diastolic dysfunction.