Claims for Patent: 10,370,346

Summary for Patent: 10,370,346

Title:	KDM1A inhibitors for the treatment of disease
Abstract:	Disclosed herein are new compounds and compositions and their application as pharmaceuticals for the treatment of diseases. Methods of inhibition of KDM1A, methods of increasing gamma globin gene expression, and methods to induce differentiation of cancer cells in a human or animal subject are also provided for the treatment of diseases such as acute myelogenous leukemia.
Inventor(s):	McCall; John M. (Boca Grande, FL), Rienhoff, Jr.; Hugh Y. (San Carlos, CA), Clare; Michael (Skokie, IL)
Assignee:	Imago Biosciences, Inc. (San Carlos, CA)
Application Number:	15/667,166
Patent Claims:	1. A method of treatment of cancer comprising the administration of a therapeutically effective amount of a compound of Formula I: ##STR00093## or a salt thereof, wherein: Y is chosen from a bond, NR.sup.4a, O, C(O)NH, NHC(O), S, SO.sub.2, and CH.sub.2; Z is chosen from a bond, NR.sup.4b, O, C(O)NH, NHC(O), S, SO.sub.2, and CH.sub.2; m is an integer from 0 to 5; n is an integer from 0 to 3; R.sup.1 and R.sup.2 are each independently chosen from, alkyl, aminoalkyl, alkylsulfonylalkyl, alkoxyalkyl, aryl, arylalkyl, cycloalkyl, cycloalkylalkyl, phenyl, biphenyl, heteroaryl, heteroarylalkyl, heterocycloalkyl, and heterocycloalkylalkyl and R.sup.1 and R.sup.2, together with the nitrogen to which they attach, form a nitrogen-containing heterocycloalkyl or heteroaryl ring, which may be optionally substituted with between 0 and 3 R.sup.6 groups; or R.sup.1 and R.sup.2, together with the nitrogen to which they attach, form ##STR00094## R.sup.3 is chosen from alkylamino, cycloalkylamino, arylamino, heteroarylamino, heterocycloalkylamino, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl, and heterocycloalkylalkyl any of which may be optionally substituted with between 0 and 3 R.sup.6 groups; R.sup.4, R.sup.4a, and R.sup.4b are independently chosen from hydrogen, alkyl, alkenyl, alkynyl, and cycloalkyl; R.sup.5 is chosen from aryl and heteroaryl, any of which may be optionally substituted with between 0 and 3 R.sup.6 groups; each R.sup.6 is independently chosen from hydrogen, halogen, alkyl, alkenyl, alkynyl, cycloalkyl, haloalkyl, haloalkoxy, aryl, aralkyl, heterocycloalkyl, heteroaryl, heteroarylalkyl, cyano, alkoxy, amino, alkylamino, dialkylamino, COR.sup.7, SO.sub.2R.sup.7, NHSO.sub.2R.sup.7, NHSO.sub.2NHR.sup.7, NHCOR.sup.7, NHCONHR.sup.7, CONHR.sup.7, and CONR.sup.7R.sup.8; and R.sup.7 and R.sup.8 are independently chosen from hydrogen, and lower alkyl; or R.sup.7 and R.sup.8 may be taken together to form a nitrogen-containing heterocycloalkyl or heteroaryl ring, which may be optionally substituted with lower alkyl, to a patient in need thereof. 2. The method as recited in claim 1, wherein the cancer is a hematologic cancer. 3. The method as recited in claim 2, wherein the hematologic cancer is selected from multiple myeloma, Myelodysplastic Syndrome, Acute Myelogenous Leukemia (AML), Acute Lymphocytic Leukemia (ALL), Chronic Lymphocytic Leukemia (CLL), and Chronic Myelogenous Leukemia (CML), Hodgkin's lymphoma and non-Hodgkin's lymphoma. 4. The method as recited in claim 2, wherein the cancer is chosen from Myelodysplastic Syndrome (MDS), Acute Myelogenous Leukemia (AML), and Chronic Myelogenous Leukemia (CML). 5. The method as recited in claim 1, wherein the cancer is a non-hematologic cancer. 6. The method as recited in claim 5, wherein the non-hematologic cancer is a solid tumor. 7. The method as recited in claim 1, wherein Z is NR.sup.4b. 8. The method as recited in claim 7, wherein R.sup.4b is chosen from methyl and hydrogen. 9. The method as recited in claim 8, wherein the alkyl, whether by itself or as a named part of another non-cyclic substituent, is C.sub.1-C.sub.8 alkyl. 10. The method as recited in claim 9, wherein R.sup.3 is chosen from aryl, arylalkyl, heteroaryl, and heteroarylalkyl, any of which may be optionally substituted with between 0 and 3 R.sup.6 groups. 11. The method as recited in claim 10, wherein R.sup.3 is chosen from aryl and heteroaryl, any of which may be optionally substituted with between 0 and 3 R.sup.6 groups. 12. The method as recited in claim 11, wherein m is an integer from 0 to 1; Y is chosen from NR.sup.4a, O, S, SO.sub.2, and CH.sub.2; n is an integer from 1 to 3; and R.sup.4a is chosen from hydrogen and alkyl. 13. The method as recited in claim 12, wherein m is 0; Y is CH.sub.2; and n is an integer from 1 to 2. 14. The method as recited in claim 13, wherein R.sup.3 is 5-6 membered monocyclic or 8-12 membered bicyclic heteroaryl, in which between one and five ring members may be heteroatoms chosen from N, O, and S, and which may be optionally substituted with between 0 and 3 R.sup.6 groups. 15. The method as recited in claim 14, wherein R.sup.3 is 5-6 membered monocyclic heteroaryl, in which between one and four ring members may be heteroatoms chosen from N, O, and S, and which may be optionally substituted with between 0 and 3 R.sup.6 groups. 16. The method as recited in claim 15, wherein each R.sup.6 is chosen from lower alkyl, halogen, lower alkoxy, OCF.sub.3 and CF.sub.3. 17. The method as recited in claim 16, wherein R.sup.3 is chosen from ##STR00095## 18. The method as recited in claim 17, wherein R.sup.4 is hydrogen. 19. The method as recited in claim 18, wherein the nitrogen-containing heterocycloalkyl or heteroaryl ring formed by R.sup.1 and R.sup.2 together with the nitrogen to which they are attached contains 3 to eight atoms. 20. The method as recited in claim 19, wherein R.sup.1 and R.sup.2 are taken together to form a nitrogen-containing heterocycloalkyl, which may be optionally substituted with between 0 and 3 R.sup.6 groups. 21. The method as recited in claim 20, wherein the nitrogen-containing heterocycloalkyl is chosen from: ##STR00096## 22. The method as recited in claim 21, wherein the nitrogen-containing heterocycloalkyl is chosen from: ##STR00097## 23. The method as recited in claim 22, wherein n is 2. 24. The method as recited in claim 23, wherein R.sup.5 is aryl, which may be optionally substituted with between 0 and 3 R.sup.6 groups. 25. The method as recited in claim 24, wherein R.sup.5 is phenyl, which may be optionally substituted with between 0 and 3 R.sup.6 groups. 26. The method as recited in claim 12, wherein R.sup.3 is aryl, optionally substituted with between 0 and 3 R.sup.6 groups. 27. The method as recited in claim 26, wherein R.sup.3 is chosen from phenyl and biphenyl, either of which may be optionally substituted with between 0 and 3 R.sup.6 groups. 28. The method as recited in claim 27, wherein m is an integer from 0 to 1; Y is chosen from NR.sup.4a, O, S, SO.sub.2, and CH.sub.2; n is an integer from 1 to 3; and R.sup.4a is chosen from hydrogen and alkyl. 29. The method as recited in claim 28, wherein m is 0; Y is CH.sub.2; and n is an integer from 1 to 2. 30. The method as recited in claim 28, wherein each R.sup.6 is chosen from lower alkyl, halogen, lower alkoxy, OCF.sub.3 and CF.sub.3. 31. The method as recited in claim 30, wherein R.sup.4 is hydrogen. 32. The method as recited in claim 31, wherein n is 2. 33. The method as recited in claim 32, wherein the nitrogen-containing heterocycloalkyl or heteroaryl ring formed by R.sup.1 and R.sup.2 together with the nitrogen to which they are attached contains 3 to eight atoms. 34. The method as recited in claim 33, wherein R.sup.1 and R.sup.2 are taken together to form a nitrogen-containing heterocycloalkyl, which may be optionally substituted with between 0 and 3 R.sup.6 groups. 35. The method as recited in claim 34, wherein the nitrogen-containing heterocycloalkyl is chosen from: ##STR00098## 36. The method as recited in claim 35, wherein the nitrogen-containing heterocycloalkyl is chosen from: ##STR00099## 37. The method as recited in claim 36, wherein n is 2. 38. The method as recited in claim 37, wherein R.sup.5 is aryl, which may be optionally substituted with between 0 and 3 R.sup.6 groups, each of which is independently chosen from lower alkyl, halogen, lower alkoxy, OCF.sub.3 and CF.sub.3. 39. The method as recited in claim 38, wherein R.sup.5 is phenyl, which may be optionally substituted with between 0 and 3 R.sup.6 groups, each of which is independently chosen from lower alkyl, halogen, lower alkoxy, OCF.sub.3 and CF.sub.3. 40. The method as recited in claim 1, further comprising the administration of a second therapeutic agent. 41. The method as recited in claim 40, wherein the second therapeutic agent is selected from all-trans retinoic acid (ATRA), arsenic trioxide, an inhibitor of DNA methytransferases, an inhibitor of NF.kappa.B signaling, a conventional anti-neoplastic agent, a nucleoside analogue, and a checkpoint inhibitor. 42. The method as recited in claim 41, wherein the checkpoint inhibitor is a PD-1 inhibitor. 43. The method as recited in claim 42, wherein the PD-1 inhibitor is selected from pembrolizumab (KEYTRUDA.RTM.), nivolumab (OPDIVO.RTM.), pidilizumab, and BMS-936559. 44. The method as recited in claim 41, wherein the checkpoint inhibitor is a PD-L1 inhibitor. 45. The method as recited in claim 44, wherein the PD-L1 inhibitor is selected from atezolizumab (TECENTRIQ.RTM.), avelumab (BAVENCIO.RTM.), durvalumab (IMFINZI.RTM.), atezolizumab, and avelumab. 46. The method as recited in claim 41, wherein the second therapeutic agent is all-trans retinoic acid (ATRA). 47. A method of treatment of cancer comprising the administration of a therapeutically effective amount of a compound of Formula I: ##STR00100## or a salt thereof, wherein: Y is CH.sub.2; Z is NR.sup.4b; m is 0; n is 2; R.sup.1 and R.sup.2, together with the nitrogen to which they attach, form ##STR00101## R.sup.3 is chosen from phenyl and biphenyl, either of which may be optionally substituted with between 0 and 3 R.sup.6 groups; R.sup.4, R.sup.4a, and R.sup.4b are hydrogen; R.sup.5 is phenyl, which may be optionally substituted with between 0 and 3 groups each chosen from lower alkyl, halogen, lower alkoxy, OCF.sub.3 and CF.sub.3; each R.sup.6 is independently chosen from hydrogen, halogen, alkyl, alkenyl, alkynyl, cycloalkyl, haloalkyl, haloalkoxy, aryl, aralkyl, heterocycloalkyl, heteroaryl, heteroarylalkyl, cyano, alkoxy, amino, alkylamino, dialkylamino, COR.sup.7, SO.sub.2R.sup.7, NHSO.sub.2R.sup.7, NHSO.sub.2NHR.sup.7, NHCOR.sup.7, NHCONHR.sup.7, CONHR.sup.7, and CONR.sup.7R.sup.8; and R.sup.7 and R.sup.8 are independently chosen from hydrogen, and lower alkyl; or R.sup.7 and R.sup.8 may be taken together to form a nitrogen-containing heterocycloalkyl or heteroaryl ring, which may be optionally substituted with lower alkyl. 48. The method as recited in claim 47 further comprising the administration of all trans-retinoic acid (ATRA).

Details for Patent 10,370,346

Applicant	Tradename	Biologic Ingredient	Dosage Form	BLA	Approval Date	Patent No.	Expiredate
Merck Sharp & Dohme Corp.	KEYTRUDA	pembrolizumab	For Injection	125514	09/04/2014		2033-08-06
Merck Sharp & Dohme Corp.	KEYTRUDA	pembrolizumab	Injection	125514	01/15/2015		2033-08-06
Bristol-myers Squibb Company	OPDIVO	nivolumab	Injection	125554	12/22/2014		2033-08-06