Inhibitors of lysine gingipain

A compound according to Formula I:

• or a pharmaceutically acceptable salt thereof, wherein
• Z is a thiol-reactive group or a masked thiol-reactive group;
• A is selected from the group consisting of —CH2— and —O—;
• B and D are independently selected from the group consisting of hydrogen, halogen, C1-4 haloalkyl, and C1-4 haloalkoxy;
• R1 is selected from the group consisting of hydrogen and an amine protecting group;
• R2 is hydrogen;
• and
• R3 is selected from the group consisting of C6-10 aryl, 5-to-12 membered heteroaryl, C1-8 alkyl, C3-8 cycloalkyl, 5-to-12 membered saturated heterocyclyl, -L-R5, and —OR6, wherein
• L is selected from the group consisting of —O—, —NR—, C1-4 alkylene, and 2- to 4-membered heteroalkylene, wherein R is selected from the group consisting of hydrogen and C1-8 alkyl,
• R5 is selected from the group consisting of C6-10 aryl, 5-to-12 membered heteroaryl, C3-8 cycloalkyl, and 5-to-12 membered saturated heterocyclyl, and
• —OR6 and the carbonyl to which it is bonded form an amine protecting group,
• and wherein R3 is optionally substituted with one or more substituents selected from the group consisting of halo, —CN, —NO2, —N3, —OH, Ra, Rb, —ORa, —ORb, —(CH2)kC(O)Rc, —NRd(CH2)uC(O)Rc, —O(CH2)uC(O)Rc, —(CH2)kCONRdRd, —(CH2)kNRdC(O)Rc, —NRd(CH2)uCONRdRd, —NRd(CH2)uNRdC(O)Rc, —O(CH2)uCONRdRd, —O(CH2)uNRdC(O)Rc, —(CH2)kS(O)2NRdRd, —(CH2)kNRdS(O)2Rc, —(CH2)kS(O)2Rc, —(CH2)kS(O)Rc, —(CH2)kSRd, —NRd(CH2)uS(O)2NRdRd, —NRd(CH2)uNRdS(O)2Rc, —NRd(CH2)uS(O)2Rc, —NRd(CH2)uS(O)Rc, —NRd(CH2)uSRd, —O(CH2)uS(O)2NRdRd, —O(CH2)uNRdS(O)2Rc, —O(CH2)uS(O)2Rc, —O(CH2)uS(O)Rc, and —O(CH2)uSRc, wherein:
• each Ra is independently selected from the group consisting of C1-4 alkyl and C1-4 haloalkyl,
• each Rb is independently selected from the group consisting of C3-6 cycloalkyl, C3-6 halocycloalkyl, C6-10 aryl, 5-to-12 membered heteroaryl, and 5-to-12 membered saturated heterocyclyl,
• each Rc is independently selected from the group consisting of —OH, C1-8 alkyl, C1-8 haloalkyl, C3-8 cycloalkyl, C3-8 halocycloalkyl, C6-10 aryl, (C6-10 aryl)-(C1-8 alkyl), 5-to-12 membered heteroaryl, and 5-to-12 membered saturated heterocyclyl,
• each Rd 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, and
• each subscript u is independently selected from 1, 2, 3, 4, 5, and 6;
• and
• R4 is selected from the group consisting of hydrogen, halogen, C1-4 alkyl, C1-4 alkoxy, C1-4 haloalkyl, and C1-4 haloalkoxy;
• provided that when Z is benzothiazol-2-yl-carbonyl, A is —CH2—, and B, D, and R1 are hydrogen, then R3 is other than benzyloxy, substituted benzyloxy, or 1-(3-phenylpropanoyl)piperidin-3-yl, and
• provided that when Z is phenoxymethyl-carbonyl or substituted phenoxymethyl-carbonyl, A is —CH2—, and B and D are hydrogen, then R3 is other than (2-phenyl)ethyl or substituted (2-phenyl)ethyl.