Inhibitors of lysine gingipain

1. A pharmaceutical composition comprising a compound according to Formula I:

or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient, wherein

Z is halogen-substituted aryloxymethyl-carbonyl;

A is selected from the group consisting of —CH 2 — and —O—;

B and D are independently selected from the group consisting of hydrogen, halogen, halomethyl, and halomethoxy;

R 1 is selected from the group consisting of hydrogen and an amine protecting group;

R 2 is hydrogen; and

R 3 is selected from the group consisting of C 6-10 aryl, 5-to-12 membered heteroaryl, C 3-8 cycloalkyl, 5-to-12 membered saturated heterocyclyl, and -L-R 5 , wherein

L is selected from the group consisting of —O—, —NR—, C 1-4 alkylene, and 2- to 4-membered heteroalkylene, wherein R is selected from the group consisting of hydrogen and C 1-8 alkyl,

R 5 is selected from the group consisting of C 6-10 aryl, 5-to-12 membered heteroaryl, C 3-8 cycloalkyl, and 5-to-12 membered saturated heterocyclyl,

and wherein R 3 is optionally substituted with one or more substituents selected from the group consisting of halo, —CN, —NO 2 , —N 3 , —OH, R a , R b , —OR a , —OR b , —(CH 2 ) k C(O)R c , —NR d (CH 2 ) u C(O)R c , —O(CH 2 ) u C(O)R c , —(CH 2 ) k CONR d R d , —(CH 2 ) k NR d C(O)R c , —NR d (CH 2 ) u CONR d R d , —NR d (CH 2 ) u NR d C(O)R c , —O(CH 2 ) u CONR d R d , —O(CH 2 ) u NR d C(O)R c , —(CH 2 ) k S(O) 2 NR d R d , —(CH 2 ) k NR d S(O) 2 R c , —(CH 2 ) k S(O) 2 R c , —(CH 2 ) k S(O)R c , —(CH 2 ) k SR d , —NR d (CH 2 ) u S(O) 2 NR d R d , —NR d (CH 2 ) u NR d S(O) 2 R c , —NR d (CH 2 ) u S(O) 2 R c , —NR d (CH 2 ) u S(O)R c , —NR d (CH 2 ) u SR d , —O(CH 2 ) u S(O) 2 NR d R d , —O(CH 2 ) u NR d S(O) 2 R c , —O(CH 2 ) u S(O) 2 R c , —(CH 2 ) u S(O)R c , and —O(CH 2 ) u SR c , wherein:

each R a is independently selected from the group consisting of C 1-4 alkyl and C 1-4 haloalkyl,

each R b is independently selected from the group consisting of C 3-6 cycloalkyl, C 3-6 halocycloalkyl, C 6-10 aryl, 5-to-12 membered heteroaryl, and 5-to-12 membered saturated heterocyclyl,

each R c is independently selected from the group consisting of —OH, C 1-8 alkyl, C 1-8 haloalkyl, C 3-8 cycloalkyl, C 3-8 halocycloalkyl, C 6-10 aryl, (C 6-10 aryl)-(C 1-8 alkyl), 5-to-12 membered heteroaryl, and 5-to-12 membered saturated heterocyclyl,

each R d is independently selected from the group consisting of hydrogen and C 1-8 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

R 4 is selected from the group consisting of hydrogen, halogen, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 haloalkyl, and C 1-4 haloalkoxy;

provided that when A is —CH 2 —, and B and D are hydrogen, then R 3 is other than (2-phenyl)ethyl or substituted (2-phenyl)ethyl.

2. The pharmaceutical composition of claim 1 , wherein Z is halogen-substituted phenoxymethyl carbonyl.

3. The pharmaceutical composition of claim 1 , wherein R 3 is selected from the group consisting of cyclohexyl, cyclopentyl, morpholino, phenyl, piperidinyl, pyridinyl, tetrahydrofuranyl, tetrahydropyranyl, 1,2,3,4-tetrahydronaphthyl, and thiazolyl, each of which is optionally substituted with 1-3 members selected from the group consisting of methyl, methoxy, trifluoromethyl, acetyl, and —N 3 .

4. The pharmaceutical composition of claim 1 , wherein the compound is a compound, or pharmaceutically acceptable salt thereof, according to Formula Id:

wherein R 3 is selected from the group consisting of C 6-10 aryl, 5-to-12 membered heteroaryl, C 3-8 cycloalkyl, 5-to-12 membered saturated heterocyclyl, and -L-R 5 ,

wherein L is C 1-4 alkylene.

5. The pharmaceutical composition of claim 4 , wherein

R 3 is selected from the group consisting of cyclohexyl, cyclopentyl, morpholino, phenyl, piperidinyl, pyridinyl, tetrahydrofuranyl, tetrahydropyranyl, 1,2,3,4-tetrahydronaphthyl, and thiazolyl,

each of which is optionally substituted with 1-3 members selected from the group consisting of methyl, methoxy, trifluoromethyl, acetyl, and —N 3 .

6. The pharmaceutical composition of claim 1 , wherein the compound is selected from the group consisting of:

and pharmaceutically acceptable salts thereof.

7. The pharmaceutical composition of claim 1 , wherein the compound is selected from the group consisting of:

and pharmaceutically acceptable salts thereof.

8. The pharmaceutical composition of claim 1 , wherein the compound is selected from the group consisting of:

and pharmaceutically acceptable salts thereof.

9. The pharmaceutical composition of claim 1 , wherein the compound is selected from the group consisting of:

and pharmaceutically acceptable salts thereof.

10. The pharmaceutical composition of claim 1 , wherein R 4 is selected from the group consisting of C 1-4 alkyl and C 1-4 haloalkyl.

11. The pharmaceutical composition of claim 10 , wherein the compound is

or a pharmaceutically acceptable salt thereof.

12. A pharmaceutical composition comprising a compound according to the formula:

or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient, wherein

Z is selected from the group consisting of benzothiazol-2-yl-carbonyl, pyridin-2-yl-carbonyl, and thiazol-2-yl-carbonyl; and

R 3 is selected from the group consisting of cyclohexyl; 1-methylcyclohexyl; 1-methoxycyclohexyl; cyclopentyl; morpholin-2-yl; 4-acetylmorpholin-2-yl; phenyl; 2-trifluoromethylphenyl; 3-azidophenyl; piperidine-3-yl; 1-acetyl-piperidine-3-yl; pyridin-2-yl; pyridin-3-yl; pyridin-4-yl; 6-oxo-1,6-dihydropyridin-2-yl; tetrahydrofuran-2-yl; tetrahydro-2H-pyran-2-yl; tetrahydro-2H-pyran-3-yl; tetrahydro-2H-pyran-4-yl; 1,2,3,4-tetrahydronaphth-1-yl; 1,2,3,4-tetrahydronaphth-2-yl; thiazol-5-yl; and thiazol-2-yl.

13. The pharmaceutical composition of claim 12 , wherein the compound is a compound, or pharmaceutically acceptable salt thereof, according to the formula:

14. The pharmaceutical composition of claim 12 , wherein the compound is selected from the group consisting of:

and pharmaceutically acceptable salts thereof.

15. The pharmaceutical composition of claim 12 , wherein the compound is selected from the group consisting of:

and pharmaceutically acceptable salts thereof.

16. The pharmaceutical composition of claim 12 , wherein Z is selected from the group consisting of pyridin-2-yl-carbonyl and thiazol-2-yl-carbonyl.

17. The pharmaceutical composition of claim 16 , wherein the compound is selected from the group consisting of:

and pharmaceutically acceptable salts thereof.

18. The pharmaceutical composition of claim 16 , wherein the compound is selected from the group consisting of:

and pharmaceutically acceptable salts thereof.