Toll-like receptor 8 (TLR8) specific antagonists and methods of making and uses thereof

1. A compound comprising the chemical formula:

or a pharmaceutically acceptable salt thereof, wherein:

X is independently N or C, wherein when one X position is N, the other X positions are C;

X′ is N;

R1 is H, —OH, —OMe, —C(O)CH 3 , —CO 2 CH 3 , —CO 2 (CH 2 ) 2 CH 3 , —CO 2 (CH 2 ) 4 OH, —CO 2 (CH 2 ) 3 CH 3 , —O(CH 2 ) 3 CH 3 , —O(CH 2 ) 4 CH 2 (CH 2 ) 2 , or —Cl;

R2 is H, or NH 2 ;

R3 is absent, H or —CH 3 ;

R4 is —OH, —O(CH 2 ) 3 CH 3 , —O(CH 2 ) 4 OH, —OMe, or —OCH 2 —C 6 H 5 , wherein when R1-R3, and R5 are H, R4 is not —OH; and

R5 is absent or H; or

R1 and R5 together form a 5- or 6-membered unsubstituted, aromatic, heterocyclic ring comprising one or two heterocyclic atoms selected from nitrogen, oxygen or carbon; and

wherein said dashed lines represents possible double bond positions according to the configuration of X and/or R1-R5.

2. A pharmaceutical composition comprising a compound of claim 1 , and a pharmaceutically acceptable excipient.

3. A method of inhibiting TLR8 in an individual, the method comprising: administering to the individual the pharmaceutical composition of claim 2 in an amount effective to inhibit the TLR8 activity in the individual.

4. A method of treating inflammation in an individual, the method comprising: administering to the individual the pharmaceutical composition of claim 2 in an amount effective to inhibit TLR8 activity in the individual.

5. The method of claim 4 , wherein said inflammation comprises inflammation caused by an autoimmune disease.

6. The method of claim 5 , wherein said inflammation caused by an autoimmune disease comprises inflammation caused by an autoimmune disease selected from the group consisting of: arthritis, rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), systemic scleroderma (SSc), multiple sclerosis (MS), Sjögren's syndrome, autoimmune hepatitis, systemic onset arthritis, Still's Disease (ASOD), Osteoarthritis (OA), Crohn's disease, irritable bowel disease (IBD), ulcerative colitis, polymyositis, type I diabetes mellitus, glomerulonephritis, pyelitis, autoimmune pancreatitis (AIP), sclerosing cholangitis, autoimmune skin disease, uveitis, psoriasis, antiphospholipid syndrome (APS), pernicious anemia, hypoparathyroidism, polyangiitis overlap syndrome, kawasaki's disease, sarcoidosis, vitiligo, pemphigus vulgaris, pemphigus foliaceus, hypopituitarism, and cryopathies.

7. A compound comprising the chemical formula selected from the group consisting of:

or a pharmaceutically acceptable salt thereof.

8. A pharmaceutical composition comprising one or more compounds of claim 7 , and a pharmaceutically acceptable excipient.

9. A method of inhibiting TLR8 in an individual, the method comprising: administering to the individual the pharmaceutical composition of claim 8 in an amount effective to inhibit the TLR8 activity in the individual.

10. A method of treating inflammation in an individual, the method comprising: administering to the individual the pharmaceutical composition of claim 8 in an amount effective to inhibit TLR8 activity in the individual.

11. The method of claim 10 , wherein said inflammation comprises inflammation caused by disease or condition selected from the group consisting of: arthritis, rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), systemic scleroderma (SSc), multiple sclerosis (MS), Sjögren's syndrome, autoimmune hepatitis, systemic onset arthritis, Still's Disease (ASOD), Osteoarthritis (OA), Crohn's disease, irritable bowel disease (IBD), ulcerative colitis, polymyositis, type I diabetes mellitus, glomerulonephritis, pyelitis, autoimmune pancreatitis (AIP), sclerosing cholangitis, autoimmune skin disease, uveitis, psoriasis, antiphospholipid syndrome (APS), pernicious anemia, hypoparathyroidism, polyangiitis overlap syndrome, kawasaki's disease, sarcoidosis, vitiligo, pemphigus vulgaris, pemphigus foliaceus, hypopituitarism, and cryopathies.

12. A compound comprising the chemical formula:

or a pharmaceutically acceptable salt thereof, wherein:

X is independently N or C, wherein when one X position is N, the other X positions are C;

X′ is N; and

R1-R5 are selected from H, alkyl, —OCH 2 C 6 H 5 , —OH, Cl, NH 2 , and alkoxy; and

wherein R4 is not H, and when R1-R3, and R5 are H, R4 is not —OH.

13. A pharmaceutical composition comprising one or more compounds of claim 12 , and a pharmaceutically acceptable excipient.

14. A method of inhibiting TLR8 in an individual, the method comprising: administering to the individual the pharmaceutical composition of claim 13 in an amount effective to inhibit the TLR8 activity in the individual.

15. A method of treating inflammation in an individual, the method comprising: administering to the individual the pharmaceutical composition of claim 12 in an amount effective to inhibit TLR8 activity in the individual.

16. The method of claim 15 , wherein said inflammation comprises inflammation caused by disease or condition selected from the group consisting of: arthritis, rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), systemic scleroderma (SSc), multiple sclerosis (MS), Sjögren's syndrome, autoimmune hepatitis, systemic onset arthritis, Still's Disease (ASOD), Osteoarthritis (OA), Crohn's disease, irritable bowel disease (IBD), ulcerative colitis, polymyositis, type I diabetes mellitus, glomerulonephritis, pyelitis, autoimmune pancreatitis (AIP), sclerosing cholangitis, autoimmune skin disease, uveitis, psoriasis, antiphospholipid syndrome (APS), pernicious anemia, hypoparathyroidism, polyangiitis overlap syndrome, kawasaki's disease, sarcoidosis, vitiligo, pemphigus vulgaris, pemphigus foliaceus, hypopituitarism, and cryopathies.