Mannose derivatives for treating bacterial infections

Patent metadata

Field	Value
Publication number	US-10407414-B2
Application number	US-201615735412-A
Country	US
Kind code	B2
Filing date	Jun 13, 2016
Priority date	Jun 12, 2015
Publication date	Sep 10, 2019
Grant date	Sep 10, 2019

Abstract

The compounds represented by Formula (I) or pharmaceutically acceptable salts thereof: with U, W, X, Y, Z, p and ring A as defined in claim 1 . Those compounds are useful for the treatment or prevention of bacteria infections. The variables of Formula (I) are as described herein. Pharmaceutically acceptable compositions comprise the compounds of Formula (I) or pharmaceutically acceptable salts thereof and pharmaceutically acceptable carriers, adjuvants, or vehicles. Methods of treating bacteria infections employ such compounds or pharmaceutically acceptable salts thereof.

First claim

What is claimed is:

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

or a pharmaceutically acceptable salt thereof, wherein:
X—Y—Z is —NR—N═CH—, ═N—NR—CH—, —CH═N—NR—, —NH—CH═CH—, —NH—CH═N—, —NH—N═N—, —NH—CH 2 —CH 2 —, —O—CH═N—, —NH—C(═O)—CH 2 —, or —NH—C(═O)—NH—;
R is —H, C 1-4 alkyl, C 1-4 haloalkyl or —(C 1-4 alkyl)-Ph, wherein Ph is phenyl optionally substituted with 1-3 occurrences of J Ph ;
U is —CH═CH—, —C≡C—, or phenylene;
p is 0 or 1;
W is —H; halogen; —CN; —C(═O)NR 1 R 2 ; —C(═O)OR 3 ; C 1-6 alkyl; a 3-8 membered partially unsaturated, or aromatic monocyclic ring having 0-4 heteroatoms selected from oxygen, nitrogen, or sulfur; or an 8-10 membered partially unsaturated, or aromatic bicyclic ring having 0-4 heteroatoms selected from oxygen, nitrogen, or sulfur; wherein said C 1-6 alkyl is optionally substituted with 1-4 occurrences of J W1 , and wherein each of said monocyclic and bicyclic rings independently and optionally is substituted with 1-4 occurrences of J W2 ;
J W1 is halogen, —CN, —OR 6 , —NR 4 R 5 , —NR 4 COR 5 , —C(═O)NR 4 R 5 , —C(═O)OR 6 , —S(O) 2 NR 4 R 5 —, S(O) 2 R 6 —, or Ph, wherein said Ph is phenyl optionally substituted with 1-3 occurrences of J Ph ;
J W2 is oxo, —NO 2 , halogen, —CN, —OR 6 , —O(CH 2 )O—, —O(CH 2 ) 2 O—, —NR 4 R 5 , —NR 4 COR 5 , —C(═O)NR 4 R 5 , —C(═O)OR 6 , —S(O) 2 NR 4 R 5 —, S(O) 2 R 6 —, —C 1-6 alkyl, Ph, —(C 1-4 alkyl)Ph, or —O(C 1-4 alkyl)Ph, wherein said —C 1-6 alkyl is optionally substituted with 1-3 occurrences of J A , and wherein said Ph is phenyl optionally substituted with 1-3 occurrences of J Ph ,
each of R 1 , R 3 , R 4 , R 5 , and R 6 independently is —H; C 1-6 alkyl optionally substituted with 1-3 occurrences of J A ; C 3-6 cycloalkyl optionally substituted with 1-3 occurrences of J B ; or —(C 1-4 alkyl)-Ph wherein Ph is phenyl optionally substituted with 1-3 occurrences of J Ph ;
R 2 is C 1-6 alkyl optionally substituted with 1-3 occurrences of J A ; C 3-6 cycloalkyl optionally substituted with 1-3 occurrences of J B ; or —(C 1-4 alkyl)-Ph wherein Ph is phenyl optionally substituted with 1-3 occurrences of J Ph ; or
optionally R 1 and R 2 together with the nitrogen atom to which they are attached form a 4-6 membered, non-aromatic, monocyclic ring wherein up to one methylene unit of the ring is optionally replaced with O, NH, N(C 1-4 alkyl), S, C(O), S(O), or S(O) 2 ; or
optionally R 4 and R 5 together with the nitrogen atom to which they are attached form a 4-6 membered, non-aromatic, monocyclic ring wherein up to one methylene unit of the ring is optionally replaced with O, NH, N(C 1-4 alkyl), S, C(O), S(O), or S(O) 2 ; and
each J A independently is halogen, CN, —OH, —O(C 1-4 alkyl), or —O(C 1-4 haloalkyl);
each J B independently is halogen, —CN, —OH, —O(C 1-4 haloalkyl), —O(C 1-4 haloalkyl), C 1-4 alkyl, or C 1-4 haloalkyl; and
each J Ph independently is halogen, —CN, —OH, —O(C 1-4 alkyl), —O(C 1-4 haloalkyl), C 1-4 alkyl, or C 1-4 haloalkyl.

2. The compound of claim 1 , wherein R is H, C 1-4 alkyl, or —(C 1-4 alkyl)-Ph, wherein Ph of —(C 1-4 alkyl)-Ph for R is phenyl optionally substituted with 1-2 occurrences of halogen, CN, —OH, —O(C 1-4 alkyl), —O(C 1-4 haloalkyl), C 1-4 alkyl, or C 1-4 haloalkyl.

3. The compound of claim 1 , wherein:
each of R 1 , R 3 , R 4 , R 5 , and R 6 independently is —H, C 1-4 alkyl, C 1-4 haloalkyl, or C 3-6 cycloalkyl;
R 2 is C 1-4 alkyl, C 1-4 haloalkyl, or C 3-6 cycloalkyl; or
optionally R 1 and R 2 together with the nitrogen atom to which they are attached form a 4-6 membered, non-aromatic, monocyclic ring wherein up to one methylene unit of the ring is optionally replaced with O, NH, N(C 1-4 alkyl), S, C(O), S(O), or S(O) 2 ; or
optionally R 4 and R 5 together with the nitrogen atom to which they are attached form a 4-6 membered, non-aromatic, monocyclic ring wherein up to one methylene unit of the ring is optionally replaced with O, NH, N(C 1-4 alkyl), S, C(O), S(O), or S(O) 2 .

4. The compound of claim 1 , wherein p is 0.

5. The compound of claim 1 , represented by any one of the following structural formulae or a pharmaceutically acceptable salt thereof:

wherein Het of Formula (III) is a 3-8 membered partially unsaturated, or aromatic monocyclic ring having 1-4 heteroatoms selected from oxygen, nitrogen, or sulfur; or an 8-10 membered partially unsaturated, or aromatic bicyclic ring having 1-4 heteroatoms selected from oxygen, nitrogen, or sulfur; wherein each of said monocyclic and bicyclic rings independently and optionally is substituted with 1-4 occurrences of J W2 .

6. The compound of claim 1 , represented by the following structural formula or a pharmaceutically acceptable salt thereof:

wherein R is —H or —CH 3 .

7. The compound of claim 6 , wherein W is —C(═O)NR 1 R 2 ; C 1-6 alkyl optionally substituted with 1-4 occurrences of J W1 ; a 3-8 membered partially unsaturated, or aromatic monocyclic ring having 0-4 heteroatoms selected from oxygen, nitrogen, or sulfur; or an 8-10 membered partially unsaturated, or aromatic bicyclic ring having 0-4 heteroatoms selected from oxygen, nitrogen, or sulfur; wherein each of said monocyclic and bicyclic rings independently and optionally is substituted with 1-4 occurrences of J W2 .

8. The compound of claim 6 , wherein:
J W1 is selected from the group consisting of halogen, CN, —OH, —O(C 1-4 alkyl), —O(C 1-4 haloalkyl), —O(C 1-4 alkyl)-Ph, —NH 2 , —NH(C 1-4 alkyl), and —N(C 1-4 alkyl) 2 ; and
J W2 is selected from the group consisting of halogen, CN, oxo, NO 2 , C 1-4 alkyl, C 1-4 haloalkyl, —NH 2 , —NH(C 1-4 alkyl), —N(C 1-4 alkyl) 2 , —C(═O)OH, —C(═O)O(C 1-4 alkyl), —OH, —O(C 1-4 alkyl), —O(C 1-4 haloalkyl), —O(C 1-4 alkyl)-Ph, —O(CH 2 )O—, —O(CH 2 ) 2 O—, —C(═O)NH 2 , —C(═O)NH(C 1-4 alkyl), —C(═O)N(C 1-4 alkyl) 2 , —SO 2 (C 1-4 alkyl), —NHCO(C 1-4 alkyl), —SO 2 NH 2 , —SO 2 NH(C 1-4 alkyl), and —SO 2 N(C 1-4 alkyl) 2 .

9. The compound of claim 6 , wherein W is

wherein each W is independently and optionally substituted, and each R′ independently —H or —C 1-4 alkyl.

10. The compound of claim 6 , wherein W is optionally substituted C 1-6 alkyl, or a benzene, pyridine, pyridine-2-one, imidazo[1,2-a]pyridine, benzoimidazole, benzo[d][1,3]dioxole, indole, 1,3,4-oxadiazole, pyrrole, or triazole, each of which independently and optionally is substituted.

11. The compound of claim 1 , represented by anyone of the following structural formulae or a pharmaceutically acceptable salt thereof:

wherein each of rings A-Q independently and optionally is substituted, and each R′ is —H or methyl.

12. The compound of claim 11 , wherein each of rings A-Q is independently and optionally substituted with 1-3 occurrences of J W2 selected from —F, —Cl, —CN, NO 2 , C 1-2 alkyl, C 1-2 haloalkyl, —NH 2 , —NH(C 1-2 alkyl), —N(C 1-2 alkyl) 2 , —C(═O)O(C

Assignees

• Vertex Pharma

Inventors

• Gallant Michel
• Truchon Jean-Francois
• Reddy Thumkunta Jagadeeswar
• Dietrich Evelyne
• Vaillancourt Louis
• Vallee Frederic

Classifications

• C07D405/14

  containing three or more hetero rings · CPC title

• C07D405/06 Primary

  linked by a carbon chain containing only aliphatic carbon atoms · CPC title

• A61P29/00

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

• C07D413/06

  linked by a carbon chain containing only aliphatic carbon atoms · CPC title

• A61P31/04

  Antibacterial agents · CPC title