Ketone inhibitors of lysine gingipain

A compound according to Formula I:

• or a pharmaceutically acceptable salt thereof, wherein:
• A is —CH2—
• R1a and R1b are each independently selected from the group consisting of hydrogen and an amine protecting group selected from the group consisting of benzyloxycarbonyl, 9-fluorenylmethyloxycarbonyl, tert-butyloxycarbonyl, allyloxycarbonyl, p-toluene sulfonyl, 2,2,5,7,8-pentamethylchroman-6-sulfonyl, 2,2,4,6,7-pentamethyl-2,3-dihydrobenzofuran-5-sulfonyl, mesityl-2-sulfonyl, 4-methoxy-2,3,6-trimethylphenylsulfonyl, acetamido, and phthalimido;
• 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, and 5- to 12-membered heteroaryl, 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, —NRcC(O)Rb, —NRc(CH2)uC(O)Rb, —O(CH2)uC(O)Rb, —(CH2)kCONRcRc, —(CH2)kNRcC(O)Rb, —NRc(CH2)uCON RcRc, —NRc(CH2)uNRcC—(O)Rb, —O(CH2)uCONRcRc, and —O(CH2)uNRcC(O)Rb;
• 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 a hydrogen;
• R5 is selected from the group consisting of —CH2R5a and —CHS(O)(R5b)2;
• R5a is selected from the group consisting of —O—R6, —S—R7, —SO—R7, —SO2—R7, —N(R8)2, imidazolyl, indolyl, isoindolyl, isoxazolyl, oxazinyl, oxazolyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridinyl, pyrimidinyl, pyrrolyl, quinolinyl, tetrazolyl, triazinyl, and triazolyl,
• wherein imidazolyl, indolyl, isoindolyl, isoxazolyl, oxazinyl, oxazolyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridinyl, pyrimidinyl, pyrrolyl, quinolinyl, tetrazolyl, triazinyl, and triazolyl are 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 C1-6 alkyl, C1-6 haloalkyl, isoxazolyl, oxazolyl, imidazolyl, pyrazolyl, pyridinyl, oxazinyl, pyrimidinyl, pyrazinyl, and pyridazinyl,
• wherein isoxazolyl, oxazolyl, imidazolyl, pyrazolyl, pyridinyl, oxazinyl, pyrimidinyl, pyrazinyl, and pyridazinyl are optionally substituted with one or more halogen, C1-3 alkyl, or C1-3;
• and
• each R8 is independently selected C1-6 alkyl.