Modulators of 5′-nucleotidase, ecto and the use thereof
Compounds that modulate the conversion of AMP to adenosine by 5′-nucleotidase, ecto, and compositions containing the compounds and methods for synthesizing the compounds, are described herein. The use of such compounds and compositions for the treatment and/or prevention of a diverse array of diseases, disorders and conditions, including cancer- and immune-related disorders, that are mediated by 5′-nucleotidase, ecto is also provided.
1. A compound having the formula:
or a pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein,
each R 1 is independently selected from the group consisting of hydrogen, optionally substituted C 1 -C 6 alkyl, optionally substituted aryl, and —C(R 2 R 2 )—O—C(O)—OR 3 , or two R 1 groups are optionally combined to form a 5- to 7-membered ring;
each R 2 is independently selected from the group consisting of H and optionally substituted C 1 -C 6 alkyl;
each R 3 is independently selected from the group consisting of H, C 1 -C 6 alkyl, and optionally substituted aryl;
R 5 is selected from the group consisting of H and optionally substituted C 1 -C 6 alkyl;
X is O;
A is selected from the group consisting of:
and
Het is:
wherein the wavy line indicates the point of attachment to the remainder of the compound, and wherein:
R a is selected from the group consisting of NHR 7 , and NR 7 R 7 ;
R c is selected from the group consisting of H, halogen, haloalkyl, NH 2 , optionally substituted C 1 -C 10 alkyl, optionally substituted 4-7 membered cycloheteroalkyl, optionally substituted 4-7 membered cycloheteroalkylC 1 -C 4 alkyl, —X 1 —O—C 1 -C 10 alkyl;
R e is selected from the group consisting of H, halogen, and optionally substituted C 1 -C 6 alkyl;
each X 1 is C 1 -C 4 alkylene; and
each R 7 is independently selected from the group consisting of optionally substituted C 3 -C 7 cycloalkyl, optionally substituted C 3 -C 7 cycloalkylC 1 -C 4 alkyl, optionally substituted 4-7 membered cycloheteroalkyl, optionally substituted 4-7 membered cycloheteroalkylC 1 -C 4 alkyl, and optionally, two R 7 groups attached to a nitrogen atom are joined together to form a 4- to 7-membered heterocyclic ring.
2. A compound of claim 1 , or a pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein A is
3. A compound of claim 1 , having the formula:
or a pharmaceutically acceptable salt, hydrate, or solvate thereof.
4. A compound of claim 3 , or a pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein R a is NR 7 R 7 .
5. A compound of claim 3 , or a pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein R c is halogen.
6. A compound of claim 3 , or a pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein R e is H.
7. A compound of claim 1 , having the formula:
8. A compound of claim 1 , having the formula:
9. A compound of claim 1 , selected from the group consisting of
10. A pharmaceutical composition comprising a compound of claim 1 , and a pharmaceutically acceptable excipient.
11. A method of treating a disease, disorder, or condition, mediated at least in part by CD73, said method comprising administering an effective amount of a compound of claim 1 , to a subject in need thereof.
12. A method of claim 11 , wherein said compound is administered in an amount effective to reverse or stop the progression of CD73-mediated immunosuppression.
13. A method of claim 11 , wherein said disease, disorder, or condition is cancer.
14. A method of claim 13 , wherein said cancer is a cancer of the prostate, colon, rectum, pancreas, cervix, stomach, endometrium, brain, liver, bladder, ovary, testis, head, neck, skin, mesothelial lining, white blood cell, esophagus, breast, muscle, connective tissue, lung, adrenal gland, thyroid, kidney, or bone; or is glioblastoma, mesothelioma, renal cell carcinoma, gastric carcinoma, sarcoma, choriocarcinoma, cutaneous basocellular carcinoma, or testicular seminoma.
15. A method of claim 13 , wherein said cancer is selected from the group consisting of melanoma, colon cancer, pancreatic cancer, breast cancer, prostate cancer, lung cancer, leukemia, a brain tumor, lymphoma, ovarian cancer, and Kaposi's sarcoma.
16. A method of claim 11 , wherein said disease, disorder, or condition is an immune-related disease, disorder or condition selected from the group consisting of rheumatoid arthritis, kidney failure, lupus, asthma, psoriasis, colitis, pancreatitis, allergies, fibrosis, anemia fibromyalgia, Alzheimer's disease, congestive heart failure, stroke, aortic valve stenosis, arteriosclerosis, osteoporosis, Parkinson's disease, infections, Crohn's disease, ulcerative colitis, allergic contact dermatitis and other eczemas, systemic sclerosis and multiple sclerosis.
17. A combination comprising a compound of claim 1 , and at least one additional therapeutic agent.
18. A combination of claim 17 , wherein the at least one additional therapeutic agent is a chemotherapeutic agent, an immune- and/or inflammation-modulating agent, an anti-hypercholesterolemia agent, or an anti-infective agent.
19. A combination of claim 17 , wherein the at least one additional therapeutic agent is an immune checkpoint inhibitor.
20. A kit comprising a compound of claim 1 , and at least one additional therapeutic agent.