Mannose derivatives for treating bacterial infections

Patent metadata

Field	Value
Publication number	US-9890176-B2
Application number	US-201414206303-A
Country	US
Kind code	B2
Filing date	Mar 12, 2014
Priority date	Mar 12, 2013
Publication date	Feb 13, 2018
Grant date	Feb 13, 2018

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 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.

First claim

The invention claimed is:

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

Assignees

• Vertex Pharma

Inventors

• Dietrich Evelyne
• Poisson Carl
• Gallant Michel
• Lessard Stephanie
• Liu Bingcan
• Das Sanjoy Kumar
• Ramtohul Yeeman
• Reddy Thumkunta Jagadeeswar
• Martel Julien
• Vallee Frederic
• Levesque Jean Francois

Classifications

• A61P31/04

  Antibacterial agents · CPC title

• A61P1/04

  for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants · CPC title

• C07H15/207

  Cyclohexane rings not substituted by nitrogen atoms, e.g. kasugamycins · CPC title

• C07H15/18

  Acyclic radicals, substituted by carbocyclic rings · CPC title

• C07H15/203

  Monocyclic carbocyclic rings other than cyclohexane rings; Bicyclic carbocyclic ring systems · CPC title