Ketone inhibitors of lysine gingipain

A compound according to Formula I:

• or a pharmaceutically acceptable salt thereof, wherein:
• A is selected from the group consisting of —CH2— and —O—;
• R1a and R1b are each independently selected from the group consisting of hydrogen, C1-4 alkyl, and an amine protecting group;
• R2a and R2b are each independently selected from the group consisting of hydrogen, halogen, C1-4 haloalkyl, and C1-4 haloalkoxy;
• R3 is selected from the group consisting of C3-8 cycloalkyl, C3-8 alkyl, 3- to 12-membered heterocyclyl, C6-10 aryl, 5- to 12-membered heteroaryl, and a reporter moiety wherein R3 is optionally substituted with one or more R3a substituents;
• each R3a is independently selected from the group consisting of halogen, —CN, —NO2, —N3, —OH, C1-4 alkyl, C1-4 haloalkyl, C1-4 alkoxy, C1-4 haloalkoxy, —N(Rc)2, —N+(Rb)3, —(CH2)kC(O)Rb, —NRc(CH2)uC(O)Rb, —O(CH2)uC(O)Rb, —(CH2)kCONRcRc, —(CH2)kNRcC(O)Rb, —NRc(CH2)uCONRcRc, —NRc(CH2)uNRcC—(O)Rb, —O(CH2)uCONRcRc, and —O(CH2)uNRcC(O)Rb, and optionally substituted triazolyl;
• each Rb is independently selected from the group consisting of C1-4 alkyl, C1-4 haloalkyl, and C1-4 deuteroalkyl;
• each Rc is independently selected from the group consisting of hydrogen and C1-8 alkyl;
• each subscript k is independently selected from 0, 1, 2, 3, 4, 5, and 6;
• each subscript u is independently selected from 1, 2, 3, 4, 5, and 6;
• R4 is selected from the group consisting of hydrogen and C1-4 alkyl;
• R5 is selected from the group consisting of —CH2R5a, —CHS(O)(R5b)2, and C1-6 haloalkyl;
• R5a is selected from the group consisting of —O—R6, —S—R7, —SO—R7, —SO2—R7, —N(R8)2, 5- to 12-membered heteroaryl, and 3- to 12-membered heterocyclyl,
• wherein 5- to 12-membered heteroaryl is optionally substituted with one or more members independently selected from the group consisting of halogen, C1-3 alkyl, and C1-3 haloalkyl, and
• 3- to 12-membered heterocyclyl is optionally substituted with one or more members independently selected from the group consisting of oxo, halogen, C1-3 alkyl, and C1-3 haloalkyl;
• each R5b is independently selected C1-6 alkyl;
• R6 and R7 are selected from the group consisting of phenyl, C1-6 alkyl, C1-6 haloalkyl, and 5- to 12-membered heteroaryl,
• wherein phenyl is substituted with 1-5 halogens, and
• wherein 5- to 12-membered heteroaryl is optionally substituted with one or more halogen, C1-3 alkyl, or C1-3 haloalkyl;
• each R8 is independently selected C1-6 alkyl;
• and
• R5 optionally comprises a quenching moiety R9;
• provided that R5 is other than 2,3,5,6-tetrafluorophenoxymethyl.