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 processes for making the compounds described herein. Furthermore, the present invention provides a composition comprising the compounds described herein, and a pharmaceutically acceptable carrier, adjuvant, or vehicle. The present invention also provides methods of treating or preventing bacteria infection in a subject, comprising administering to the subject an effective amount of the compound or the composition described herein.
1. A compound of Formula I
or a pharmaceutically acceptable salt thereof, wherein
each M and M 2 is independently
wherein:
Y 1 is —O—, —O(C 1 -C 4 aliphatic)-, —O(haloC 1 -C 4 aliphatic)-, —S—, —S(C 1 -C 4 aliphatic)-, —S(O) p —, —S(O) p (C 1 -C 4 aliphatic)-, or —(C 1 -C 6 )aliphatic;
Y 2 is —O(C 1 -C 4 aliphatic)-, —O(haloC 1 -C 4 aliphatic)-, —S(C 1 -C 4 aliphatic)-, —SO 2 (C 1 -C 4 aliphatic)-, or —(C 1 -C 6 ) aliphatic;
X 1 is methyl or —U 1 —V 1 ; X 1 is optionally substituted with 1-4 occurrences of halo;
U 1 is —(CH 2 ) q — or —C(O)—;
V 1 is a C 1 -C 10 aliphatic wherein up to four methylene units can be optionally replaced with —O—, —NR 2 —, —S—, —C(O)—, —S(O)—, —S(O) 2 —, or P(O);
X 2 is H, C 1 -C 10 aliphatic, —U 2 —V 2 , or —U 2 —V 2 -Q;
U 2 is —(CH 2 ) q — or —C(O)—;
V 2 is a C 1 -C 10 aliphatic wherein up to four methylene units can be optionally replaced with —O—, —NR 2 —, —S—, —C(O)—, —S(O)—, —S(O) 2 —, or P(O);
Q is a 3-8 membered saturated, partially unsaturated, or aromatic ring having 0-4 heteratoms selected from oxygen, nitrogen, or sulfur;
wherein X 2 is optionally substituted with 1-4 occurrences of halo, CN, NO 2 , or C 1 -C 10 aliphatic wherein up to three methylene units of the C 1 -C 10 aliphatic can be optionally replaced with —NR—, —O—, —S—, —C(O)—, or —S(O)—, or —S(O) 2 —;
each X 3 , X 4 , X 5 , and X 6 is independently H or C 1-3 alkyl;
provided that only one of X 2 , X 3 , X 4 , X 5 , and X 6 is not H;
Ring A is C 3 -C 10 cycloalkyl, 3-12 membered heterocyclyl, C 6-10 aryl, or 5-14 membered heteroaryl; wherein the heterocyclyl or heteroaryl independently has 1-6 heteroatoms selected from oxygen, nitrogen, or sulfur;
Ring A 2 is optionally absent, C 3 -C 10 cycloalkyl, 3-12 membered heterocyclyl, C 6-10 aryl, or 5-14 membered heteroaryl;
Z is —CH═CH—, —C≡C—, or Ring B substituted by (J B ) n ;
Ring B is C 3 -C 10 cycloalkyl, 3-12 membered heterocyclyl, C 6-10 aryl, or 5-14 membered heteroaryl; wherein said heterocyclyl or heterocyclyl independently has 1-6 heteroatoms selected from oxygen, nitrogen, or sulfur;
each J A , J A2 , and J B is independently halogen, CN, NO 2 , oxo, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl, 5-10 membered heteroaryl, (C 6-10 aryl)-(C 1 -C 6 alkyl)-, (5-10 membered heteroaryl)-(C 1 -C 6 alkyl)-, (C 3-8 cycloalkyl)-(C 1 -C 6 alkyl)-, (3-8 membered heterocyclyl)-(C 1 -C 6 alkyl)-, or a C 1 -C 12 aliphatic; wherein up to four methylene units of the C 1 -C 12 aliphatic or up to three methylene units of the C 1 -C 6 alkyl can be optionally replaced with —NR, —O, —S—, —C(O)—, —S(O)—, —S(O) 2 —, or P(O); each J A , J A2 , and J B is independently and optionally substituted with 1-5 occurrences of halo, CN, NO 2 , or C 1 -C 10 aliphatic wherein up to three methylene units of the C 1 -C 10 aliphatic can be optionally replaced with —NR—, —O—, —S—, —C(O)—, or —S(O)—, or —S(O) 2 —;
R and R 2 are each independently H, C 1 -C 6 aliphatic, or C 3-6 cycloalkyl;
each m, n, and u is independently 0, 1, 2, 3, or 4;
each t and r is independently 0 or 1; and
each p and q is independently 1 or 2.
2. The compound of claim 1 , wherein Ring A 2 is absent; r and q are 0; t is 1; and Z is Ring B as shown in Formula Ia:
3. The compound of claim 2 , as represented in Formula II:
4. The compound of claim 1 , wherein M is
5. The compound of claim 1 , as represented by formula A:
wherein
Y 1 is —O—, —O(C 1 -C 4 alkyl)-, —S—, —S(C 1 -C 4 alkyl)-, —S(O) p —, —SO p (C 1 -C 4 alkyl)-, or —(C 1 -C 6 )aliphatic;
X 2 is H, C 1 -C 10 aliphatic, —U 2 —V 2 , or —U 2 —V 2 -Q;
U 2 is —(CH 2 ) q — or —C(O)—;
V 2 is a C 1 -C 10 aliphatic wherein up to four methylene units can be optionally replaced with —O—, —NR 2 —, —S—, —C(O)—, —S(O)—, —S(O) 2 —, or P(O);
Q is a 3-8 membered saturated, partially unsaturated, or aromatic ring having 0-4 heteratoms selected from oxygen, nitrogen, or sulfur;
wherein X 2 is optionally substituted with 1-4 occurrences of halo, CN, NO 2 , or C 1 -C 10 aliphatic wherein up to three methylene units of the C 1 -C 10 aliphatic can be optionally replaced with —NR—, —O—, —S—, —C(O)—, or —S(O)—, or —S(O) 2 —;
R 2 is H, C 1 -C 6 aliphatic, or C 3-6 cycloalkyl;
each X 3 , X 4 , and X 6 is independently H or C 1-3 alkyl;
X 5 is H;
provided that only one of X 2 , X 3 , X 4 , and X 6 is not H;
Ring A is C 3 -C 10 cycloalkyl, 3-12 membered heterocyclyl, C 6-10 aryl, or 5-14 membered heteroaryl; wherein the heterocyclyl or heteroaryl independently has 1-6 heteroatoms selected from oxygen, nitrogen, or sulfur; Ring A is optionally bonded to Ring B;
Ring B is absent, C 3 -C 10 cycloalkyl, 3-12 membered heterocyclyl, C 6-10 aryl, or 5-14 membered heteroaryl; wherein said heterocyclyl or heterocyclyl independently has 1-6 heteroatoms selected from oxygen, nitrogen, or sulfur;
each J A and J B is independently halogen, CN, NO 2 , C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl, 5-10 membered heteroaryl, (C 6-10 aryl)-(C 1 -C 6 alkyl)-, (5-10 membered heteroaryl)-(C 1 -C 6 alkyl)-, or a C 1 -C 12 aliphatic wherein up to four methylene units of the C 1 -C 10 aliphatic can be optionally replaced with —NR, —O—, —S—, —C(O)—, —S(O)—, —SO 2 —, or P(O); each J A and J B is independently and optionally substituted with 1-5 occurrences of halo, CN, or NO 2 ;
R is H, C 1 -C 6 aliphatic, C 3-6 cycloalkyl, C(O)OH, C(O)O(C 1-4 alkyl), or C(O)(C 1-4 alkyl);
each m and n is independently 0, 1, 2, 3, or 4;
each p and q is independently 1 or 2.
6. The compound of claim 1 , as represented by formula B:
wherein
Y 2 is —O(C 1 -C 4 alkyl)-, —S(C 1 -C 4 alkyl)-, —S(O)—, —SO 2 (C 1 -C 4 alkyl)-, or —(C 1 -C 6 )alkyl;
X 1 is methyl or —U 1 —V 1 ; X 1 is optionally substituted with 1-4 occurrences of halo;
U 1 is —(CH 2 ) q — or —C(O)—;
V 1 is a C 1 -C 10 aliphatic wherein up to four methylene units can be optionally replaced with —O—, —NR 2 —, —S—, —C(O)—, —S(O)—, —S(O) 2 —, or P(O);
Ring A is C 3 -C 10 cycloalkyl, 3-12 membered heterocyclyl, C 6-10 aryl, or 5-14 membered heteroaryl; wherein the heterocyclyl or heteroaryl independently has 1-6 heteroatoms selected from oxygen, nitrogen, or sulfur; Ring A is optionally bonded to Ring B;
Ring B is absent, C 3 -C 10 cycloalkyl, 3-12 membered heterocyclyl, C 6-10 aryl, or 5-14 membered heteroaryl; wherein said heterocyclyl or heterocyclyl independently has 1-6 heteroatoms selected from oxygen, nitrogen, or sulfur;
each J A and J B is independently halogen, CN, NO 2 , C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl, 5-10 membered heteroaryl, (C 6-10 aryl)-(C 1 -C 6 alkyl)-, (5-10 membered heteroaryl)-(C 1 -C 6 alkyl)-, or a C 1 -C 12 aliphatic wherein up to four methylene units of the C 1 -C 10 aliphatic can be optionally replaced with —NR, —O—, —S—, —C(O)—, —S(O)—, —SO 2 —, or P(O); each J A and J B is independently and optionally substituted with 1-5 occurrences of halo, CN, or NO 2 ;
R is H, C 1 -C 6 aliphatic, C 3-6 cycloalkyl, C(O)OH, C(O)O(C 1-4 alkyl), or C(O)(C 1-4 alkyl);
each m and n is independently 0, 1, 2, 3, or 4;
each p and q is independently 1 or 2.
7. The compound of claim 1 , as represented by formula III:
8. The compound of claim 1 , as represented by formula E:
9. The compound of claim 1 , as represented by formula F:
10. The compound of claim 1 , as represented by formula G:
11. The compound of claim 1 , wherein the compound is selected from one of the following:
Compound No.
Structure
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.
12. The compound of claim 1 having the formula
13. A composition comprising the compound of claim 1 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, adjuvant, or vehicle.
14. The composition of claim 13 comprising the compound of formula
or a pharmaceutically acceptable salt thereof.
15. A method of treating a bacterial infection in a subject, comprising administering to the subject an effective amount of the compound of claim 1 or a pharmaceutically acceptable salt thereof.
16. The method of claim 15 comprising administering to the subject an effective amount of the compound of formula
or a pharmaceutically acceptable salt thereof.
17. A method of inhibiting FimH in a subject, comprising administering to the subject an effective amount of the compound of claim 1 or a pharmaceutically acceptable salt thereof.
18. The method of claim 17 , comprising administering to the subject an effective amount of the compound of formula
or a pharmaceutically acceptable salt thereof.
19. A method of inhibiting adhesion of e. coli in a subject, comprising administering to the subject an effective amount of the compound of claim 1 or a pharmaceutically acceptable salt thereof.
20. The method of claim 19 , comprising administering to the subject an effective amount of the compound of formula
or a pharmaceutically acceptable salt thereof.
21. A method of blocking the interaction between type 1 pili and CEACAM6 in a subject, comprising administering to the subject an effective amount of the compound of claim 1 or a pharmaceutically acceptable salt thereof.
22. The method of claim 21 , comprising administering to the subject an effective amount of the compound of formula
or a pharmaceutically acceptable salt thereof.