Mannose derivatives for treating bacterial infections
The present invention relates to compounds useful for the treatment or prevention of bacteria infections. These compounds have formula I: The invention also provides pharmaceutically acceptable compositions containing the compounds and methods of using the compositions in the treatment of bacteria infections. Finally, the invention provides processes for making compounds of the invention.
1. A method of treating or preventing a bacteria infection in a subject, comprising administering a therapeutically effective amount of a compound represented by Structural Formula ID or a pharmaceutically acceptable salt thereof or a composition comprising same and a pharmaceutically acceptable carrier, adjuvant, or vehicle:
wherein Ring H is
wherein G is O, S, S(O), S(O) 2 , CF 2 , C(J H1 )(J H2 ), C(J H3 ) 2 -C(J H4 ) 2 -, or N(J H5 );
J H1 is H, OH, or C 1-6 alkyl wherein up to 2 methylene units are optionally replaced with —O—, —NH—, —NH(C 1 -C 6 aliphatic)-, —S—, —C(O)—, —S(O)—, or —S(O) 2 —; J H1 is optionally and independently substituted with 1-3 occurrences of OH;
J H2 is H, X JH , Q JH , or X JH -Q JH ; J H2 is optionally substituted with 1-3 occurrences of OH;
X JH is C 1-6 alkyl wherein up to 3 methylene units of C 1-6 alkyl is optionally replaced with —O—, —NH, N(C 1 -C 6 aliphatic), —S—, —C(O)—, —S(O)—, or —S(O) 2 —;
Q JH is C 3-6 cycloalkyl, phenyl, or a 5-7 membered monocyclic heterocyclyl having 1-3 heteroatoms selected from oxygen, nitrogen, or sulfur;
or J H1 and J H2 , together with the carbon atom to which they are attached, form C═N—OH, C═O, or Ring HH;
Ring HH is a 5-7 membered saturated monocyclic ring having 0-2 heteroatoms selected from oxygen, nitrogen, or sulfur; wherein said ring is optionally substituted with 1-4 occurrences of J HH ;
J HH is H, halo, CN, X J , Q J , or X J -Q J , and J HH is optionally substituted with OH, O(C 1 -C 6 alkyl), oxo, C 1 -C 6 alkyl, CN or halo;
J H5 is X J , Q J , or X J -Q J ;
X J is a C 1 -C 10 aliphatic, wherein up to 4 methylene units of the C 1 -C 10 aliphatic are optionally replaced with —O—, —NH, N(C 1 -C 6 aliphatic), —S—, —C(O)—, —S(O)—, or —S(O) 2 —; X J is optionally substituted with 0-6 occurrences of halo or 0-1 occurrences of CN;
Q J is a 3-6 membered saturated, partially unsaturated, or aromatic monocyclic ring optionally having 1-4 heteroatoms selected from oxygen, nitrogen, or sulfur; or an 8-12 membered saturated, partially unsaturated, or aromatic bicyclic ring optionally having 1-6 heteroatoms selected from oxygen, nitrogen, or sulfur; wherein each Q J is optionally substituted with 1-6 occurrences of halogen, oxo, CN, NO 2 or a C 1 -C 6 aliphatic wherein up to 3 methylene units of the C 1 -C 6 aliphatic are optionally replaced with O, NR, S, or CO;
each J H , J H3 , and J H4 is independently H, halo, CN, or C 1 -C 10 aliphatic, wherein up to 3 methylene units of the C 1 -C 10 aliphatic are optionally replaced with —O—, —NH, N(C 1 -C 6 aliphatic), S, —C(O)—, —S(O)—, or SO 2 —; each J H , J H3 , and J H4 is independently and optionally substituted with 0-2 occurrences of halo, OH, or C 1-4 alkyl or with 1 occurrence of CN; and
R is H or C 1-4 alkyl.
2. The method of claim 1 , wherein
G is C(J H1 )(J H2 );
J H1 is OH, F, or —CH 2 CH 2 OH;
J H2 is OH, CH 3 , cyclopropyl, F, CH 2 CH 3 , —CH 2 CH 2 OH, —CH 2 CH(OH)CH 2 OH, or phenyl optionally substituted with OCH 3 ;
or J H1 and J H2 , together with the carbon atom to which they are attached, form ═N—OH or a 6-membered saturated monocyclic ring having 0-2 heteroatoms selected from oxygen, nitrogen, or sulfur; wherein said ring is optionally substituted with C 1-6 alkyl, OH,
NH 2 , —C(O)OCH 3 , —C(O)OC(CH 3 ) 3 , —C(O)C(CH 3 ) 2 OH, or —S(O) 2 CH 3 .
3. The method of claim 1 , wherein the Ring HH is selected from cyclopentyl, cyclohexyl, piperidinyl, piperazinyl, 1,3-dithianyl, or tetrahydropyranyl.
4. The method of claim 1 , wherein X JH is C 1-6 alkyl and Q JH is C 3-6 cycloaliphatic, oxetanyl, tetrahydropyrrolidinyl, piperidinyl, piperazinyl, or morpholinyl.
5. The method of claim 1 , wherein Ring H, together with Ring HH, is selected from one of the following formulae:
6. The method of claim 5 , wherein the compound has formula ID-a:
wherein
Ring HH is a 5-7 membered saturated monocyclic ring having 0-2 heteroatoms selected from oxygen, nitrogen, or sulfur;
J HH is H, X J , Q J , or X J -Q J and J HH is optionally substituted with OH, O(C 1 -C 6 alkyl), oxo, C 1 -C 6 alkyl, CN or halo;
X J is a C 1 -C 10 aliphatic, wherein up to 4 methylene units of the C 1 -C 10 aliphatic are optionally replaced with —O—, —NH, N(C 1 -C 6 aliphatic), —S—, —C(O)—, —S(O)—, or —S(O) 2 —; X J is optionally substituted with 0-6 occurrences of halo or 0-1 occurrences of CN;
Q J is a 3-7 membered monocyclic saturated, partially unsaturated, or aromatic ring optionally having 1-4 heteroatoms selected from oxygen, nitrogen, or sulfur; wherein each Q J is optionally substituted with 1-6 occurrences of halogen, CN, NO 2 , or C 1 -C 6 aliphatic wherein up to three methylene units are optionally replaced with O, NH, NH(C 1 -C 6 aliphatic), S, C(O), S(O), or S(O)— 2 ; and
J H is halogen, CN, NO 2 , or C 1 -C 6 aliphatic wherein up to three methylene units are optionally replaced with O, NH, NH(C 1 -C 6 aliphatic), S, C(O), S(O), or S(O) 2 .
7. The method of claim 6 , wherein Ring HH is cyclopentyl, cyclohexyl, tetrahydropyranyl, 1,3 dithianyl, piperazinyl, piperidinyl, or oxepanyl.
8. The method of claim 7 , wherein Ring HH is piperidinyl or tetrahydropyranyl.
9. The method of claim 8 , wherein the compound has formula ID-b:
wherein
J HH is H, X J , Q J , or X J -Q J and J HH is optionally substituted with OH, O(C 1 -C 6 alkyl), oxo, C 1 -C 6 alkyl, CN or halo;
X J is a C 1 -C 4 aliphatic, wherein up to two methylene units of the C 1 -C 4 aliphatic are optionally replaced with —O—, —NH, N(C 1 -C 6 aliphatic), —S—, —C(O)—, —S(O)—, or —S(O) 2 —;
Q J is a 3-6 membered monocyclic saturated, partially unsaturated, or aromatic ring optionally having 1-4 heteroatoms selected from oxygen, nitrogen, or sulfur; wherein each Q J is optionally substituted with 1-3 occurrences of halogen, CN, or C 1 -C 6 aliphatic wherein up to two methylene units of said C 1 -C 6 aliphatic are optionally replaced with O, NH, NH(C 1 -C 6 aliphatic), S, C(O), S(O), or S(O) 2 ; and
J H is halogen or C 1-4 alkyl.
10. The method of claim 9 , wherein J HH is H, C(O)(C 1-6 alkyl), C(O)O(C 1-6 alkyl), S(O) 2 (C 1-6 alkyl), C(O)(C 3-6 cycloalkyl), C(O)(3-6 membered heterocyclyl), C(O)(5-6 membered heteroaryl), C(O)—(C 1-4 alkyl)-(5-6 membered heteroaryl), C(O)—(C 1-4 alkyl)-(heterocyclyl); wherein said heteroaryl or heterocyclyl has 1-3 heteroatoms selected from oxygen, nitrogen, or sulfur; J HH is optionally substituted with OH, O(C 1-6 alkyl), oxo, C 1-6 alkyl, CN, or halo.
11. The method of claim 9 , wherein J HH is H, C(O)CH 3 , C(O)OC(CH 3 ) 3 , C(O)OCH(CH 3 ) 2 , C(O)OCH 2 CH 3 , C(O)OC(OH)(CH 3 ) 2 , S(O) 2 CH 3 , C(O)CH(CH 3 ) 2 , C(O)C(CH 3 ) 3 , C(O)CH(CH 3 )OCH 3 ,
12. The method of claim 1 , wherein the compound of formula (ID) is represented by the following structural formula or a pharmaceutically acceptable salt thereof:
13. The method of claim 1 , wherein the compound of formula (ID) is represented by the following structural formula or a pharmaceutically acceptable salt thereof:
14. The method of claim 1 , wherein the compound is represented by any of the following structural formulae or a pharmaceutically acceptable salt thereof:
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15. The method of claim 1 , wherein the bacteria infection is urinary tract infection.
16. A method of treating or preventing inflammatory bowel disease caused by a bacteria infection, comprising the method of claim 1 .
17. The method of claim 16 , wherein the inflammatory bowel disease is Crohn's disease or ulcerative colitis.
18. A method of treating or preventing inflammatory bowel disease caused by a bacteria infection, comprising the method of claim 12 .
19. The method of claim 18 , wherein the inflammatory bowel disease is Crohn's disease or ulcerative colitis.
20. The method of claim 12 , wherein the bacteria infection is urinary tract infection.
21. A method of treating or preventing inflammatory bowel disease caused by a bacteria infection, comprising the method of claim 13 .
22. The method of claim 21 , wherein the inflammatory bowel disease is Crohn's disease or ulcerative colitis.
23. The method of claim 13 , wherein the bacteria infection is urinary tract infection.
24. A method of inhibiting FimH in a subject, comprising administering a therapeutically effective amount of a compound represented by Structural Formula ID as defined in claim 1 or a pharmaceutically acceptable salt thereof or a composition comprising same and a pharmaceutically acceptable carrier, adjuvant, or vehicle.
25. A method of inhibiting adhesion of E. coli in a subject, comprising administering a therapeutically effective amount of a compound represented by Structural Formula ID as defined in claim 1 or a pharmaceutically acceptable salt thereof or a composition comprising same and a pharmaceutically acceptable carrier, adjuvant, or vehicle.
26. A method of blocking the interaction between type 1 pili and CEACAM6 in a subject, comprising administering a therapeutically effective amount of a compound represented by Structural Formula ID as defined in claim 1 or a pharmaceutically acceptable salt thereof or a composition comprising same and a pharmaceutically acceptable carrier, adjuvant, or vehicle.
27. The method of claim 24 , wherein the compound represented by Structural Formula ID is represented by the following structural formula or a pharmaceutically acceptable salt thereof:
28. The method of claim 24 , wherein the compound represented by Structural Formula ID is represented by the following structural formula or a pharmaceutically acceptable salt thereof:
29. The method of claim 25 , wherein the compound represented by Structural Formula ID is represented by the following structural formula or a pharmaceutically acceptable salt thereof:
30. The method of claim 25 , wherein the compound represented by Structural Formula ID is represented by the following structural formula or a pharmaceutically acceptable salt thereof:
31. The method of claim 26 , wherein the compound represented by Structural Formula ID is represented by the following structural formula or a pharmaceutically acceptable salt thereof:
32. The method of claim 26 , wherein the compound represented by Structural Formula ID is represented by the following structural formula or a pharmaceutically acceptable salt thereof: