Mannose derivatives for treating bacterial infections

Patent metadata

Field	Value
Publication number	US-10669298-B2
Application number	US-201815945221-A
Country	US
Kind code	B2
Filing date	Apr 4, 2018
Priority date	Dec 18, 2012
Publication date	Jun 2, 2020
Grant date	Jun 2, 2020

Abstract

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 of Formula I, or a pharmaceutically acceptable salt thereof:

wherein
Z is

Ring H is an optionally substituted 5-6 membered aromatic monocyclic ring optionally having 1-4 heteroatoms selected from nitrogen, or sulfur; an 8-12 membered aromatic bicyclic ring optionally having 1-6 heteroatoms selected from oxygen, nitrogen, or sulfur; or a 10-14 membered aromatic tricyclic ring optionally having 1-6 heteroatoms selected from oxygen, nitrogen, or sulfur;
L 2 is —X 2 Y 2 —wherein X 2 is a C 1 aliphatic or —C(O)— and Y 2 is C 1 -C 10 aliphatic wherein up to two methylene units of the C 1 -C 10 aliphatic are optionally replaced with —C(O)—, NH, or N(C 1 -C 6 aliphatic); L 2 is optionally substituted with 1-3 halo;
L 3 is C 1 -C 12 aliphatic wherein up to three methylene units of the C 1 -C 12 aliphatic are optionally replaced with —C(O)—, NH, or N(C 1 -C 6 aliphatic); L 3 is optionally substituted with 1-3 halo;
each J H is independently halogen, —CN, —NO 2 , X J , Q J , or X J -Q J ; or two J H groups bound to the same carbon atom, together with the carbon atom to which they are bound, optionally form —C═N—OH, —C(O)—, or Ring HH;
Ring HH is a 3-8 membered saturated monocyclic ring having 0-2 heteroatoms selected from oxygen, nitrogen, or sulfur; optionally substituted with 1-4 occurrences of J HH ;
J HH is halo, CN, oxo, 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)—, —C(═NOH)—,—S(O)—, —S(O) 2 —, P, or P(O); X J is optionally substituted with 0-6 occurrences of halo, OH, or C 1-4 alkyl; or optionally substituted with 0-1 occurrences of CN and;
Q J is a 3-7 membered monocyclic saturated, fully unsaturated, partially unsaturated, or aromatic ring optionally having 1-4 heteroatoms selected from oxygen, nitrogen, or sulfur; or an 8-12 membered saturated, fully unsaturated, partially unsaturated, or aromatic ring optionally having 1-6 heteroatoms selected from oxygen, nitrogen, or sulfur; wherein each Q J is optionally substituted with 1-6 occurrences of halo, oxo, CN, or C 1-6 alkyl, wherein up to 2 methylene units of said C 1-6 alkyl are optionally replaced with —O—, —NH, N(C 1 -C 6 aliphatic), —S—, —C(O)—, —S(O)—, or —S(O) 2 —.

2. The compound of claim 1 , wherein Ring H, is phenyl, napthyl, or a 5-6 membered heteroaryl having 1-4 heteroatoms selected from oxygen, nitrogen, or sulfur.

3. The compound of claim 1 , wherein Z is

and
J H is halo, CN, NO 2 , phenyl, or C 1-10 aliphatic wherein up to 3 methylene units are optionally replaced with O, NH, N(C 1-4 alkyl), S, C(O), SO, or SO 2 ; wherein said J H is optionally substituted with 1-3 occurrences of CN, halo or phenyl.

4. The compound of claim 3 wherein
L 2 is C 1-6 aliphatic or (C 1-4 aliphatic)-C(O)NH—;
L 3 is C 1-6 aliphatic or —NHC(O)—(C 1-4 aliphatic)-;
Ring H is phenyl or naphthyl; and
J H is halo, CN, NO 2 , C 1-6 aliphatic, —OC 1-6 aliphatic, or C(O)O(C 1-6 aliphatic); wherein
said J H is optionally substituted with 1-3 occurrences of halo.

5. The compound of claim 1 , wherein L 2 and L 3 are each independently C 1 -C 4 alkenyl or C 1 -C 4 alkynyl.

6. The compound of claim 1 , having formula IB:

7. The compound of claim 6 , wherein L 2 and L 3 are bonded to the mannose ring via a carbon atom.

8. The compound of claim 7 , wherein L 2 and L 3 are each independently C 1 -C 6 alkenyl or C 1 -C 6 alkynyl.

9. The compound of claim 8 , wherein at least one of L 2 and L 3 is —C≡C—.

10. The compound of claim 1 , having formula ID:

11. The compound of claim 10 , wherein Ring H is an optionally substituted 5-6 membered monocyclic aromatic ring optionally having 1-4 heteroatoms selected from nitrogen, or sulfur; or an 8-12 membered bicyclic aromatic ring optionally having 1-6 heteroatoms selected from oxygen, nitrogen, or sulfur; or a 10-14 tricyclic aromatic ring optionally having 1-6 heteroatoms selected from oxygen, nitrogen, or sulfur.

12. The compound of claim 11 , wherein Ring H is optionally substituted phenyl, naphthyl, thienyl, isoxazolyl, pyridinyl, pyrazinyl, indolyl, indazolyl, thienylthiophenyl, quinolinyl, quinazolinyl, benzothiadiazolyl, or fluorenyl.

13. The compound of claim 10 , wherein Ring H, together with J H and J HH , is selected from the following:

14. The compound of claim 10 , wherein J H is halogen, oxo, CN,
Q J , or X J -Q J ; wherein
X J is 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)—, —S(O) 2 —;
Q J is phenyl; and
J H is optionally substituted with 0-3 occurrences of halo or 0-1 occurrences of CN.

15. The compound of claim 14 , wherein J H is halogen, CN, —C(CH 3 ) 2 CN, C 3-6 cycloalkyl, phenyl, —O—CH 2 phenyl, or C 1-6 alkyl wherein up to one methylene unit is optionally replaced with —O—, —S—, —NH—, —N(C 1-6 alkyl)-, or —C(O)—; wherein said J H is substituted with 0-3 halo or 0-1 CN.

16. The compound of claim 10 , wherein Ring H is optionally substituted phenyl or naphthyl.

17. The compound of claim 16 , wherein Ring H is phenyl and J H is halo, CN, —C(CH 3 ) 2 CN, C 3-6 cycloalkyl, phenyl, CH 2 phenyl, —O—CH 2 phenyl, or C 1-6 alkyl wherein up to one methylene unit is optionally replaced with —O—, —S—, —NH—, —N(C 1-6 alkyl)-, or —C(O)—; wherein said J H is substituted with 0-3 halo or 0-1 CN.

18. The compound of claim 1 , represented by a structural formula selected from the group consisting of:

#
Structure

 69

 70

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

• A61K31/7042

  Compounds having saccharide radicals and heterocyclic rings · CPC title

• C07D309/10

  Oxygen atoms · CPC title

• C07H7/04

  Carbocyclic radicals · CPC title

• C07D409/14

  containing three or more hetero rings · CPC title

• A61K31/7064

  containing condensed or non-condensed pyrimidines · CPC title