Mannose derivatives for treating bacterial infections

Patent metadata

Field	Value
Publication number	US-9598454-B2
Application number	US-201314132662-A
Country	US
Kind code	B2
Filing date	Dec 18, 2013
Priority date	Dec 18, 2012
Publication date	Mar 21, 2017
Grant date	Mar 21, 2017

Abstract

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.

First claim

What is claimed is:

1. A compound represented by Structural Formula ID or a pharmaceutically acceptable salt thereof:

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 compound 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 compound of claim 1 , wherein the Ring HH is selected from cyclopentyl, cyclohexyl, piperidinyl, piperazinyl, 1,3-dithianyl, or tetrahydropyranyl.

4. The compound 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 compound of claim 1 , wherein Ring H, together with Ring HH, is selected from one of the following formulae:

6. The compound 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 compound of claim 6 , wherein Ring HH is cyclopentyl, cyclohexyl, tetrahydropyranyl, 1,3 dithianyl, piperazinyl, piperidinyl, or oxepanyl.

8. The compound of claim 7 , wherein Ring HH is piperidinyl or tetrahydropyranyl.

9. The compound 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 compound 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 compound 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. A compound represented by the following structural formula or a pharmaceutically acceptable salt thereof:

13. A compound represented by the following structural formula or a pharmaceutically acceptable salt thereof:

Assignees

• Vertex Pharma

Inventors

• Ramtohul Yeeman K
• Das Sanjoy Kumar
• Cadilhac Caroline
• Reddy Thumkunta Jagadeeswar
• Vaillancourt Louis
• Gallant Michel
• Liu Bingcan
• Dietrich Evelyne
• Vallee Frederic
• Martel Julien
• Poisson Carl

Classifications

• A61P43/00

  Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00 · CPC title

• A61P31/04

  Antibacterial agents · CPC title

• A61P29/00

  Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID] · CPC title

• A61P13/02

  of urine or of the urinary tract, e.g. urine acidifiers · CPC title

• A61P1/00

  Drugs for disorders of the alimentary tract or the digestive system · CPC title