Claims for Patent: 10,239,912

Summary for Patent: 10,239,912

Title:	Modulators of 5\'-nucleotidase, ecto and the use thereof
Abstract:	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.
Inventor(s):	Debien; Laurent Pierre Paul (San Francisco, CA), Jaen; Juan Carlos (Burlingame, CA), Kalisiak; Jaroslaw (Mountain View, CA), Lawson; Kenneth V. (San Francisco, CA), Leleti; Manmohan Reddy (West San Jose, CA), Lindsey; Erick Allen (Fremont, CA), Miles; Dillon Harding (Berkeley, CA), Newcomb; Eric (Menlo Park, CA), Powers; Jay Patrick (Pacifica, CA), Rosen; Brandon Reid (San Mateo, CA), Sharif; Ehesan Ul (Menlo Park, CA)
Assignee:	ARCUS BIOSCIENCES, INC. (Hayward, CA)
Application Number:	15/400,748
Patent Claims:	1. A compound having the formula: ##STR00317## or a pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein, each R.sup.1 is independently selected from the group consisting of hydrogen, optionally substituted C.sub.1-C.sub.6 alkyl, optionally substituted aryl, and --C(R.sup.2R.sup.2)--O--C(O)--OR.sup.3, or two R.sup.1 groups are optionally combined to form a 5- to 7-membered ring; each R.sup.2 is independently selected from the group consisting of H and optionally substituted C.sub.1-C.sub.6 alkyl; each R.sup.3 is independently selected from the group consisting of H, C.sub.1-C.sub.6 alkyl, and optionally substituted aryl; R.sup.5 is selected from the group consisting of H and optionally substituted C.sub.1-C.sub.6 alkyl; X is selected from the group consisting of O, CH.sub.2, and S; A is ##STR00318## and Het is selected from the group consisting of: ##STR00319## ##STR00320## wherein the wavy line indicates the point of attachment to the remainder of the compound, and wherein: R.sup.a is selected from the group consisting of H, NH.sub.2, NHR.sup.7, NHC(O)R.sup.7, NR.sup.7R.sup.7, R.sup.7, OH, SR.sup.7 and OR.sup.7; R.sup.b is selected from the group consisting of H, halogen, NH.sub.2, NHR.sup.7, NR.sup.7R.sup.7, R.sup.7, OH, and OR.sup.7; R.sup.c and R.sup.d are independently selected from the group consisting of H, halogen, haloalkyl, NH.sub.2, NHR.sup.7, NR.sup.7R.sup.7, R.sup.7, OH, OR.sup.7, SR.sup.7, SO.sub.2R.sup.7, --X.sup.1--NH.sub.2, --X.sup.1--NHR.sup.7, --X.sup.1--NR'R.sup.7, --X.sup.1--OH, --X.sup.1--OR.sup.7, --X.sup.1--SR.sup.7 and --X.sup.1--SO.sub.2R.sup.7; R.sup.e and R.sup.f are independently selected from the group consisting of H, halogen, and optionally substituted C.sub.1-C.sub.6 alkyl; each X.sup.1 is C.sub.1-C.sub.4alkylene; and each R.sup.7 is independently selected from the group consisting of optionally substituted C.sub.1-C.sub.10 alkyl, optionally substituted C.sub.2-C.sub.10 alkenyl, optionally substituted C.sub.2-C.sub.10 alkynyl, optionally substituted C.sub.3-C.sub.7 cycloalkyl, optionally substituted C.sub.3-C.sub.7 cycloalkylC.sub.1-C.sub.4alkyl, optionally substituted 4-7 membered cycloheteroalkyl, optionally substituted 4-7 membered cycloheteroalkylC.sub.1-C.sub.4alkyl, optionally substituted aryl, optionally substituted arylC.sub.1-C.sub.4alkyl, optionally substituted arylC.sub.2-C.sub.4alkenyl, optionally substituted arylC.sub.2-C.sub.4alkynyl, optionally substituted heteroaryl, optionally substituted heteroarylC.sub.1-C.sub.4alkyl, optionally substituted heteroarylC.sub.1-C.sub.4alkenyl, optionally substituted heteroarylC.sub.2-C.sub.4alkynyl, and optionally, two R.sup.7 groups attached to a nitrogen atom are joined together to form a 4- to 7-membered heterocyclic ring, optionally fused to an aryl ring; with the proviso that the compounds are other than those compounds wherein the combination of X, A, and Het results in ##STR00321## wherein R.sup.g is H; and either (i) R.sup.c and R.sup.e are hydrogen and R.sup.a is --OEt, --OCH.sub.2Ph, --SCH.sub.2Ph, --NH.sub.2, methylamino, ethylamino, dimethylamino, diethylamino, N-methyl-N-ethylamino, phenylamino, benzylamino, 1-phenyl ethyl amino, 2-phenylethylamino, N-benzyl-N-ethylamino, N-benzyl-N-methylamino, dibenzylamino, 4-aminobenzylamino, 2-chlorobenzylamino, 3-chlorobenzylamino, 4-chlorobenzylamino, 4-hydroxybenzylamino, 4-methoxybenzylamino, 4-nitrobenzylamino, or 4-sulfamoylbenzylamino; or (ii) R.sup.c is hydrogen, R.sup.a is --NH.sub.2, and R.sup.e is bromo, chloro, aminomethyl, or thioethyl; or (iii) R.sup.c is hydrogen, R.sup.a is benzylamino, and R.sup.e is bromo; or (iv) R.sup.c is amino, R.sup.e is hydrogen, and R.sup.a is --NH.sub.2, dimethylamino, diethylamino, benzylamino or N-benzyl-N-methylamino; or (v) R.sup.c is chloro, R.sup.e is hydrogen, and R.sup.a is --NH.sub.2, benzylamino, 2-chlorobenzylamino, 1-phenylethylamino, (S)-1-phenylethylamino, (R)-1-phenylethylamino or N-benzyl-N-methylamino; or (vi) R.sup.c is iodo, R.sup.e is hydrogen, and R.sup.a is --NH.sub.2, benzylamino or N-benzyl-N-methylamino; or (vii) R.sup.a is amino, R.sup.e is hydrogen, and R is piperazinyl, thioallyl or cyclohexylethylthio. 2. A compound of claim 1, wherein Het is: ##STR00322## 3. A compound of claim 2, wherein R.sup.c is other than hydrogen. 4. A compound of claim 3, having a formula: ##STR00323## wherein each R.sup.g is H. 5. A compound of claim 4, wherein X is oxygen. 6. A compound of claim 5, wherein R.sup.c is hydrogen. 7. A compound of claim 1, wherein R.sup.5 is H. 8. A compound of claim 1, wherein R.sup.5 is H, and X is O. 9. A compound of claim 1, wherein R.sup.5 is H, X is O, and each R.sup.1 is H. 10. A compound of claim 1, wherein Het is selected from ##STR00324## 11. A compound of claim 2, wherein R.sup.5 is H, X is O, and each R.sup.1 is H. 12. A compound of claim 10, wherein R.sup.5 is H, X is O, each R.sup.1 is H, R.sup.e is H, and R.sup.a is selected from the group consisting of NH.sub.2, NHR.sup.7 and N(R.sup.7).sub.2. 13. A compound of claim 10, wherein R.sup.5 is H, X is O, each R.sup.1 is H, R.sup.e is H, R.sup.c is other than H, and R.sup.a is NHR.sup.7. 14. A compound of claim 4, having the formula: ##STR00325## 15. A compound of claim 14, having the formula: ##STR00326## 16. A compound of claim 1, selected from the compounds of Table 1. 17. A pharmaceutical composition comprising a compound of claim 1, and a pharmaceutically acceptable excipient. 18. 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. 19. A method of claim 18, wherein said compound is administered in an amount effective to reverse or stop the progression of CD73-mediated immunosuppression. 20. A method of claim 18, wherein said disease, disorder, or condition is cancer. 21. A method of claim 20, 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. 22. A method of claim 20, 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. 23. A method of claim 18, 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. 24. A combination comprising a compound of claim 1, and at least one additional therapeutic agent. 25. A combination of claim 24, 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. 26. A combination of claim 24, wherein the at least one additional therapeutic agent is an immune checkpoint inhibitor. 27. A kit comprising a compound of claim 1, and at least one additional therapeutic agent. 28. A kit of claim 27, 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. 29. A kit of claim 27, wherein the at least one additional therapeutic agent is an immune checkpoint inhibitor. 30. A method of treating cancer in a subject, said method comprising administering to said subject an effective amount of a compound of claim 1 and an immune checkpoint inhibitor. 31. A method in accordance with claim 30, wherein said administering is prior to, concurrent with, or subsequent to, radiation treatment. 32. A method in accordance with claim 30, wherein said compound and said immune checkpoint inhibitor are administered in combination. 33. A method in accordance with claim 30, wherein said compound and said immune checkpoint inhibitor are administered sequentially. 34. A method in accordance with claim 30, wherein said compound is administered after said immune checkpoint inhibitor. 35. A method in accordance with claim 30, wherein said compound is administered prior to said immune checkpoint inhibitor. 36. A combination, kit or method of any one of 26, 29, 30, wherein said immune checkpoint inhibitor is selected from the group consisting of ipulimumab, nivolumab and lambrolizumab. 37. A method of treating cancer in a subject, said method comprising administering to said subject an effective amount of a compound of claim 16 and an immune checkpoint inhibitor. 38. A compound having the formula: ##STR00327## or a pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein, each R.sup.1 is independently selected from the group consisting of hydrogen, optionally substituted C.sub.1-C.sub.6 alkyl, optionally substituted aryl, and --C(R.sup.2R.sup.2)--O--C(O)--OR.sup.3, or two R.sup.1 groups are optionally combined to form a 5- to 7-membered ring; each R.sup.2 is independently selected from the group consisting of H and optionally substituted C.sub.1-C.sub.6 alkyl; each R.sup.3 is independently selected from the group consisting of H, C.sub.1-C.sub.6 alkyl, and optionally substituted aryl; R.sup.5 is selected from the group consisting of H and optionally substituted C.sub.1-C.sub.6 alkyl; X is selected from the group consisting of O, CH.sub.2, and S; A is selected from the group consisting of: ##STR00328## each of which is optionally substituted with from 1 to 5 R.sup.6 substituents, and wherein the subscript n is an integer from 0 to 3; Z is selected from the group consisting of CH.sub.2, CHR.sup.6, NR.sup.6, and 0; each R.sup.6 is independently selected from the group consisting of H, CH.sub.3, OH, CN, F, optionally substituted C.sub.1-C.sub.6 alkyl, and OC(O)--C.sub.1-C.sub.6 alkyl; and optionally two R.sup.6 groups on adjacent ring vertices are joined together to form a 5- to 6-membered ring having at least one heteroatom as a ring vertex; and Het is selected from the group consisting of: ##STR00329## wherein the wavy line indicates the point of attachment to the remainder of the compound, and wherein: R.sup.a is selected from the group consisting of H, NH.sub.2, NHR.sup.7, NHC(O)R.sup.7, NR.sup.7R.sup.7, R.sup.7, OH, SR.sup.7 and OR.sup.7; R.sup.b is selected from the group consisting of H, halogen, NH.sub.2, NHR.sup.7, NR.sup.7R.sup.7, R.sup.7, OH, and OR.sup.7; R.sup.c is selected from the group consisting of H, halogen, haloalkyl, NH.sub.2, NHR.sup.7, NR.sup.7R.sup.7, R.sup.7, OH, OR.sup.7, SR.sup.7, SO.sub.2R.sup.7, --X.sup.1--NH.sub.2, --X.sup.1--NHR.sup.7, --X.sup.1--NR.sup.7R.sup.7, --X.sup.1--OH, --X.sup.1--OR.sup.7, --X.sup.1--SR.sup.7 and --X.sup.1--SO.sub.2R.sup.7; R.sup.e and R.sup.f are independently selected from the group consisting of H, halogen, and optionally substituted C.sub.1-C.sub.6 alkyl; each X.sup.1 is C.sub.1-C.sub.4alkylene; and each R.sup.7 is independently selected from the group consisting of optionally substituted C.sub.1-C.sub.10 alkyl, optionally substituted C.sub.2-C.sub.10 alkenyl, optionally substituted C.sub.2-C.sub.10 alkynyl, optionally substituted C.sub.3-C.sub.7 cycloalkyl, optionally substituted C.sub.3-C.sub.7 cycloalkylC.sub.1-C.sub.4alkyl, optionally substituted 4-7 membered cycloheteroalkyl, optionally substituted 4-7 membered cycloheteroalkylC.sub.1-C.sub.4alkyl, optionally substituted aryl, optionally substituted arylC.sub.1-C.sub.4alkyl, optionally substituted arylC.sub.2-C.sub.4alkenyl, optionally substituted arylC.sub.2-C.sub.4alkynyl, optionally substituted heteroaryl, optionally substituted heteroarylC.sub.1-C.sub.4alkyl, optionally substituted heteroarylC.sub.1-C.sub.4alkenyl, optionally substituted heteroarylC.sub.2-C.sub.4alkynyl, and optionally, two R.sup.7 groups attached to a nitrogen atom are joined together to form a 4- to 7-membered heterocyclic ring, optionally fused to an aryl ring. 39. A compound of claim 38, wherein A is: ##STR00330## which is optionally substituted with from 1 to 5 R.sup.6. 40. A compound of claim 39, wherein A is selected from the group consisting of: ##STR00331## 41. A compound of claim 38, wherein Het is ##STR00332## 42. A compound of claim 41, wherein R.sup.5 is H, X is O, each R.sup.1 is H, R.sup.e is H, R.sup.c is other than H, and R.sup.a is NHR.sup.7. 43. A compound of claim 38, wherein Het is ##STR00333## 44. A compound of claim 43, wherein R.sup.5 is H, X is O, each R.sup.1 is H, R.sup.e and R.sup.f is H, R.sup.c is other than H, and R.sup.a is NHR.sup.7. 45. A compound of claim 38, wherein Het is ##STR00334## 46. A compound of claim 45, wherein R.sup.5 is H, X is O, each R.sup.1 is H, R.sup.e and R.sup.b is H, R.sup.c is other than H, and R.sup.a is NHR.sup.7. 47. A compound of claim 39, selected from the group consisting of ##STR00335##

Details for Patent 10,239,912

Applicant	Tradename	Biologic Ingredient	Dosage Form	BLA	Approval Date	Patent No.	Expiredate
Bristol-myers Squibb Company	OPDIVO	nivolumab	Injection	125554	12/22/2014		2036-01-08
Bristol-myers Squibb Company	OPDIVO	nivolumab	Injection	125554	10/04/2017		2036-01-08
Bristol-myers Squibb Company	OPDIVO	nivolumab	Injection	125554	08/27/2021		2036-01-08