Ketone inhibitors of lysine gingipain
The present invention provides compounds according to Formula I as described herein, and their use for inhibiting the lysine gingipain protease (Kgp) from the bacterium Porphyromonas gingivalis . Also described are gingipain activity probe compounds and methods for assaying gingipain activity are also described, as well as methods for the treatment of disorders associated with P. gingivalis infection, including brain disorders such as Alzheimer's disease.
1. A compound according to Formula I:
or a pharmaceutically acceptable salt thereof, wherein:
A is —CH 2 —
R 1a and R 1b 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;
R 2a and R 2b are each independently selected from the group consisting of hydrogen, halogen, C 1-4 haloalkyl, and C 1-4 haloalkoxy;
R 3 is selected from the group consisting of C 3-8 cycloalkyl, C 3-8 alkyl, 3- to 12-membered heterocyclyl, C 6-10 aryl, and 5- to 12-membered heteroaryl, wherein R 3 is optionally substituted with one or more R 3a substituents;
each R 3a is independently selected from the group consisting of halogen, —CN, —NO 2 , —N 3 , —OH, C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 alkoxy, C 1-4 haloalkoxy, —N(R c ) 2 , —N + (R b ) 3 , —(CH 2 ) k C(O)R b , —NR c C(O)R b , —NR c (CH 2 ) u C(O)R b , —O(CH 2 ) u C(O)R b , —(CH 2 ) k CONR c R c , —(CH 2 ) k NR c C(O)R b , —NR c (CH 2 ) u CON R c R c , —NR c (CH 2 ) u NR c C—(O)R b , —O(CH 2 ) u CONR c R c , and —O(CH 2 ) u NR c C(O)R b ;
each R b is independently selected from the group consisting of C 1-4 alkyl, C 1-4 haloalkyl, and C 1-4 deuteroalkyl;
each R c 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;
each subscript u is independently selected from 1, 2, 3, 4, 5, and 6;
R 4 is a hydrogen;
R 5 is selected from the group consisting of —CH 2 R 5a and —CHS(O)(R 5b ) 2 ;
R 5a is selected from the group consisting of —O—R 6 , —S—R 7 , —SO—R 7 , —SO 2 —R 7 , —N(R 8 ) 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, C 1-3 alkyl, and C 1-3 haloalkyl;
each R 5b is independently selected C 1-6 alkyl;
R 6 and R 7 are selected from the group consisting of C 1-6 alkyl, C 1-6 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, C 1-3 alkyl, or C 1-3 ; and
each R 8 is independently selected C 1-6 alkyl.
2. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 3 is selected from the group consisting of C 3-8 cycloalkyl, C 3-8 alkyl, C 6-10 aryl, pyridin-2-yl, pyridin-3-yl, and pyridin-4-yl, each of which is optionally substituted with one or more R 3a substituents.
3. The compound of claim 2 , or a pharmaceutically acceptable salt thereof, wherein R 3 is selected from the group consisting of cyclopentyl and phenyl, each of which is optionally substituted with one or more R 3a substituents.
4. The compound of claim 3 , or a pharmaceutically acceptable salt thereof, wherein each R 3a is independently selected from the group consisting of halogen, —N 3 , C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 alkoxy, C 1-4 haloalkoxy, —N(R c ) 2 , —N + (R b ) 3 , and —NR c C(O)R b .
5. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, having a structure according to Formula Ia:
6. The compound of claim 5 , or a pharmaceutically acceptable salt thereof, wherein R 5a is —O—R 6 , and R 6 is C 1-6 haloalkyl.
7. The compound of claim 6 , or a pharmaceutically acceptable salt thereof, wherein R 6 is selected from the group consisting of trifluoroethyl and hexafluoropropyl.
8. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 5 is —CH 2 R 5a , R 5a is —O—R 6 , and R 6 is isoxazolyl, oxazolyl, imidazolyl, pyrazolyl, pyridinyl, oxazinyl, pyrimidinyl, pyrazinyl, and pyridazinyl.
9. The compound of claim 5 , or a pharmaceutically acceptable salt thereof, wherein R 5a is selected from the group consisting of —N(R 8 ) 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, C 1-3 alkyl, and C 1-3 haloalkyl.
10. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein:
R 5 is selected from the group consisting of —CH 2 R 5a and —CHS(O)(R 5b ) 2 ,
R 5a is selected from the group consisting of —S—R 7 and —S—(O) 2 R 7 , and
R 7 is selected from the group consisting of C 1-6 alkyl, C 1-6 haloalkyl, isoxazolyl, oxazolyl, imidazolyl, pyrazolyl, pyridinyl, oxazinyl, pyrimidinyl, pyrazinyl, and pyridazinyl.
11. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, which is selected from the group consisting of:
12. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, which is
13. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, which is selected from the group consisting of:
14. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, which is
15. A pharmaceutical composition comprising a compound claim 1 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.
16. A method of treating a disease or condition associated with P. gingivalis infection, the method comprising administering to a subject in need thereof an effective amount of a compound according to claim 1 , or a pharmaceutically acceptable salt thereof.
17. The method of claim 16 , wherein the disease or condition is selected from the group consisting of a brain disorder, periodontal disease, diabetes, a cardiovascular disease, arthritis, elevated risk of preterm birth, pneumonia, cancer, a kidney disease, a liver disease, a retinal disorder, and glaucoma.
18. The method of claim 17 , wherein the arthritis is selected from the group consisting of rheumatoid arthritis, osteoarthritis, infectious arthritis, and psoriatic arthritis.
19. The method of claim 16 , wherein the disease or condition is a brain disorder.
20. The method of claim 17 , wherein the cancer is selected from the group consisting of oral cancer, breast cancer, pancreatic cancer, and glioblastoma multiforme.
21. The method of claim 19 , wherein the brain disorder is selected from the group consisting of Alzheimer's disease, dementia, Down's syndrome, epilepsy, autism, Parkinson's disease, essential tremor, fronto-temporal dementia, progressive supranuclear palsy, amyotrophic lateral sclerosis, Huntington's disease, multiple sclerosis, mild cognitive impairment, age associated memory impairment, chronic traumatic encephalopathy, stroke, cerebrovascular disease, Lewy Body disease, multiple system atrophy, schizophrenia, and depression.