Claims for Patent: 10,689,346

Summary for Patent: 10,689,346

Title:	Human plasma kallikrein inhibitors
Abstract:	Disclosed are compounds of formula I as described herein, and pharmaceutically acceptable salts thereof. The compounds are inhibitors of plasma kallikrein. Also disclosed are pharmaceutical compositions comprising at least one such compound, and methods involving use of the compounds and compositions in the treatment and prevention of diseases and conditions characterized by unwanted plasma kallikrein activity.
Inventor(s):	Pravin L. Kotian, Yarlagadda S. Babu, Minwan Wu, Venkat R. Chintareddy, V. Satish Kumar, Weihe Zhang
Assignee:	Biocryst Pharmaceuticals Inc
Application Number:	US16/400,798
Patent Claims:	1. A method of treating a disease or condition characterized by unwanted plasma kallikrein activity, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of formula II, or a pharmaceutically acceptable salt thereof: wherein: X represents CH, C(OH), C(O(C1-C6)alkyl), —C(NH2), —C(NRaRb), —C(N3), —C(CN), —C(NO2), —C(S(O)nRa), —C[—C(═O)Rc], —C[—C(═O)NRcRd], —C[—C(═O)SRc], —C[—S(O)Rc], —C[—S(O)2Rc], —C[S(O)(ORc)], —C[—S(O)2(ORc)], —C[—SO2NRcRd], —C(halogen), —C[(C1-C5)alkyl], —C[(C4-C5)carbocyclyl], —C[(C1-C8)substituted alkyl], —C[(C2-C8)alkenyl], —C[(C2-C8)substituted alkenyl], —C[(C2-C8)alkynyl], —C[(C2-C8)substituted alkynyl], —C[aryl(C1-C5)alkyl] or N; —Y—R4 represents —((C1-C6)alkyl)-R4, —CH2C(O)—R4, —CH2NH-R4, —CH2N((C1-C6)alkyl)-R4, —CRaRb—R4, —NH—R4, —NHCH2—R4, —NHC(O)—R4, —N((C1-C6)alkyl)-R4, —N((C1-C6)alkyl)CH2—R4, —N((CH2)2OH)—R4, —N[(C3-C8)cycloalkyl(C1-C6)alkyl]R4, -heterocyclyl-R4, —OR4, —OCH2—R4, —OC(O)—R4, —SCH2R4, or —SR4, wherein the (C1-C6)alkyl moiety of —((C1-C6)alkyl)-R4 is optionally substituted; Z is absent or represents one or more substituents independently selected from the group consisting of halo, hydroxy, (C1-C6)alkyl, —CF3, —OCF3, (C1-C6)alkoxy, aryl, aryloxy, amino, amino(C1-C6)alkyl, —C(O)NH2, cyano, —NHC(O)(C1-C6)alkyl, —SO2(C1-C6)alkyl, —SO2NH2, (C3-C5)cycloalkyl, (CH2)rORa, N02, (CH2)rNRaRb, (CH2)rC(O)Ra, NRaC(O)Rb, C(O)NRcRd, NRaC(O)NRcRd, —C(═NRa)NRcRd, NHC(═NRa)NRcRd, NRaRb, SO2NRcRd, NRaSO2NRcRd, NRaSO2-(C1-C6)alkyl, NRaSO2Ra, S(O)pRa, (CF2)rCF3, NHCH2Ra, OCH2Ra, SCH2Ra, NH(CH2)2(CH2)rRa, O(CH2)2(CH2)rRa, and S(CH2)2(CH2)rRa; or alternatively Z is a 5- or 6-membered aromatic heterocycle containing from 1 to 4 heteroatoms selected from the group consisting of N, O, and S; R1c represents halo, amino(C1-C6)alkyl, (C1-C6)alkoxy, cyano, —C(═NH)NH2, —CONRaRb, —(C1-C6)alkylCONRaRb, —SO2CH3, formyl, acyl, —NH2, —C(═NH)NH(OH), —C(═NH)NH(C(O)O—(C1-C6)alkyl), —C(═NH)NH(C(O)O—(C1-C6)haloalkyl), —C(═NH)NH(C(O)S—(C1-C6)alkyl), —C(═NH)NH(C(O)(OCH(C1-C6)alkyl)OC(O)(C1-C6)alkyl), optionally substituted aryl, or optionally substituted heteroaryl; R2 represents halo, (C1-C6)alkyl, (C3-C8)cycloalkyl, (C1-C6)fluoroalkyl, —OCH3, —Si(CH3)3, —CONH2, —C(O)OH, cyano, or phenyl; R3 represents —NH—, —O—, optionally substituted aryl, heteroaryl, phenyl, carbocyclyl, or heterocyclyl; R3a is absent or represents one or more substituents independently selected from the group consisting of halo, hydroxy, (C1-C6)alkyl, —CF3, —OCF3, (C1-C6)alkoxy, aryl, aryloxy, amino, amino(C1-C6)alkyl, —C(O)NH2, cyano, —NHC(O)(C1-C6)alkyl, —SO2(C1-C6)alkyl, —SO2NH2, (C3-C8)cycloalkyl, (CH2)rORa, NO2, (CH2)rNRaRb, (CH2)rC(O)Ra, NRaC(O)Rb, C(O)NRcRd, NRaC(O)NRcRd, —C(═NRa)NRcRd, NHC(═NRa)NRcRd, NRaRb, SO2NRcRd, NRaSO2NRcRd, NRaSO2-(C1-C6)alkyl, NRaSO2Ra, S(O)pRa, (CF2)rCF3, NHCH2Ra, OCH2Ra, SCH2Ra, NH(CH2)2(CH2)rRa, O(CH2)2(CH2)rRa, or S(CH2)2(CH2)rRa; or alternatively R3a is a 5- or 6-membered aromatic heterocycle containing from 1 to 4 heteroatoms selected from the group consisting of N, O, and S; R4 represents hydrogen, hydroxy, optionally substituted (C1-C6)alkyl, optionally substituted (C3-C8)cycloalkyl, heterocyclyl(C1-C6)alkyl, (C3-C8)cycloalkyl(C1-C6)alkyl, —CH2OH, —CH((C1-C6)alkyl)OH, —CH(NH2)CH((C1-C6)alkyl)2, optionally substituted aryl, optionally substituted aryl(C1-C6)alkyl, heteroaryl, optionally substituted heteroaryl(C1-C6)alkyl, —CH2S(C1-C6)alkyl, amino, or cyano; each Ra and Rb is independently H, (C1-C8)alkyl, (C2-C8)alkenyl, (C2-C8)alkynyl, aryl(C1-C8)alkyl, (C3-C8)carbocyclyl, —C(═O)Rc, —C(═O)ORc, —C(═O)NRcRd, —C(═O)SRc, —S(O)Rc, —S(O)2Rc, —S(O)(ORc), or —SO2NRcRd; each Rc and Rd is independently H, (C1-C8)alkyl, (C2-C8)alkenyl, (C2-C8)alkynyl, (C4-C8) carbocyclyl, optionally substituted aryl, optionally substituted heteroaryl, —C(═O)(C1-C8)alkyl, —S(O)n(C1-C8)alkyl, or aryl(C1-C8)alkyl; or when R and Rd are bonded to a common nitrogen atom, then they may form a 3- to 7-membered heterocyclic ring wherein optionally a carbon atom of said heterocyclic ring may be replaced with —O—, —S— or —NRa—; n is 2 or 3; r is independently for each occurrence 0, 1, 2, or 3; p is independently for each occurrence 0, 1, or 2; and the stereochemical configuration at any chiral center is R, S, or a mixture of R and S. 2. The method of claim 1, wherein X represents CH, C(OH), C(O(C1-C6)alkyl), —C(NH2), —C(NRaRb), —C(halogen), —C[(C2-C8)alkenyl], —C[(C2-C8)substituted alkenyl], or N. 3. The method of claim 1, wherein X represents CH. 4. The method of claim 1, wherein —X—Y— represents —CHNHCH2—, —C(OH)CH2CH2—, or —CHOCH2—. 5. The method of claim 1, wherein R3 represents phenylene-R3a. 6. The method of claim 1, wherein —R3—Ra represents 7. The method of claim 1, wherein R4 is cyclopropyl. 8. The method of claim 1, wherein R3 is phenyl, and R3a is ortho, meta, or para —OH. 9. The method of claim 1, wherein R3 is phenyl, and R3a is meta or para —NH2. 10. The method of claim 1, wherein R3 is phenyl, and R3a is meta or para —CN. 11. The method of claim 1, wherein Z is absent, or represents fluoro or chloro. 12. The method of claim 1, wherein Z represents 2-F, 4-F, 5-F, 6-F, 6-Cl, or 5-(C3-C8)cycloalkyl. 13. The method of claim 1, wherein R1c represents aminomethyl. 14. The method of claim 1, wherein R1c represents cyano. 15. The method of claim 1, wherein R1c represents —SO2CH3. 16. The method of claim 1, wherein R2 is —CH3, —CF3, tert-butyl, cyclopropyl, —OCH3, —Si(CH3)3, —CONH2, cyano, or phenyl. 17. The method of claim 1, wherein the compound of formula (II) is selected from the group consisting of: 18. The method of claim 1, wherein the compound of formula (II) has the structure: 19. The method of claim 1, wherein the compound of formula (II) is the (+)-enantiomer. 20. The method of claim 18, wherein the compound of formula (II) is the (−)-enantiomer. 21. The method of claim 18, wherein the compound of formula (II) is a hydrochloride salt. 22. The method of claim 18, wherein the compound of formula (II) is a bis(hydrochloride) salt. 23. The method of claim 19, wherein the compound of formula (II) is a hydrochloride salt. 24. The method of claim 19, wherein the compound of formula (II) is a bis(hydrochloride) salt. 25. The method of claim 20, wherein the compound of formula (II) is a hydrochloride salt. 26. The method of claim 20, wherein the compound of formula (II) is a bis(hydrochloride) salt. 27. The method of claim 1, wherein the disease or condition characterized by unwanted plasma kallikrein activity is selected from the group consisting of stroke, inflammation, reperfusion injury, acute myocardial infarction, deep vein thrombosis, post fibrinolytic treatment condition, angina, edema, angioedema, hereditary angioedema, sepsis, arthritis, hemorrhage, blood loss during cardiopulmonary bypass, inflammatory bowel disease, diabetes mellitus, retinopathy, diabetic retinopathy, diabetic macular edema, diabetic macular degeneration, age-related macular edema, age-related macular degeneration, proliferative retinopathy, neuropathy, hypertension, brain edema, increased albumin excretion, macroalbuminuria, and nephropathy. 28. The method of claim 1, wherein the disease or condition characterized by unwanted plasma kallikrein activity is angioedema. 29. The method of claim 1, wherein the disease or condition characterized by unwanted plasma kallikrein activity is hereditary angioedema. 30. The method of claim 18, wherein the disease or condition characterized by unwanted plasma kallikrein activity is selected from the group consisting of stroke, inflammation, reperfusion injury, acute myocardial infarction, deep vein thrombosis, post fibrinolytic treatment condition, angina, edema, angioedema, hereditary angioedema, sepsis, arthritis, hemorrhage, blood loss during cardiopulmonary bypass, inflammatory bowel disease, diabetes mellitus, retinopathy, diabetic retinopathy, diabetic macular edema, diabetic macular degeneration, age-related macular edema, age-related macular degeneration, proliferative retinopathy, neuropathy, hypertension, brain edema, increased albumin excretion, macroalbuminuria, and nephropathy. 31. The method of claim 18, wherein the disease or condition characterized by unwanted plasma kallikrein activity is angioedema. 32. The method of claim 18, wherein the disease or condition characterized by unwanted plasma kallikrein activity is hereditary angioedema. 33. The method of claim 19, wherein the disease or condition characterized by unwanted plasma kallikrein activity is selected from the group consisting of stroke, inflammation, reperfusion injury, acute myocardial infarction, deep vein thrombosis, post fibrinolytic treatment condition, angina, edema, angioedema, hereditary angioedema, sepsis, arthritis, hemorrhage, blood loss during cardiopulmonary bypass, inflammatory bowel disease, diabetes mellitus, retinopathy, diabetic retinopathy, diabetic macular edema, diabetic macular degeneration, age-related macular edema, age-related macular degeneration, proliferative retinopathy, neuropathy, hypertension, brain edema, increased albumin excretion, macroalbuminuria, and nephropathy. 34. The method of claim 19, wherein the disease or condition characterized by unwanted plasma kallikrein activity is angioedema. 35. The method of claim 19, wherein the disease or condition characterized by unwanted plasma kallikrein activity is hereditary angioedema. 36. The method of claim 24, wherein the disease or condition characterized by unwanted plasma kallikrein activity is selected from the group consisting of stroke, inflammation, reperfusion injury, acute myocardial infarction, deep vein thrombosis, post fibrinolytic treatment condition, angina, edema, angioedema, hereditary angioedema, sepsis, arthritis, hemorrhage, blood loss during cardiopulmonary bypass, inflammatory bowel disease, diabetes mellitus, retinopathy, diabetic retinopathy, diabetic macular edema, diabetic macular degeneration, age-related macular edema, age-related macular degeneration, proliferative retinopathy, neuropathy, hypertension, brain edema, increased albumin excretion, macroalbuminuria, and nephropathy. 37. The method of claim 24, wherein the disease or condition characterized by unwanted plasma kallikrein activity is angioedema. 38. The method of claim 24, wherein the disease or condition characterized by unwanted plasma kallikrein activity is hereditary angioedema.