Anti-wolbachia pyrido[2,3-d]pyrimidine compounds

Patent metadata

Field	Value
Publication number	US-12545675-B2
Application number	US-202217956435-A
Country	US
Kind code	B2
Filing date	Sep 29, 2022
Priority date	Jan 17, 2017
Publication date	Feb 10, 2026
Grant date	Feb 10, 2026

Abstract

The present invention relates to compounds of Formulae I and II as defined herein, and salts and solvates thereof.

The present invention also relates to pharmaceutical compositions comprising compounds of Formulae I and II, and to the use of compounds of Formulae I and II in the treatment or prevention of filarial worm infection, as well as other diseases or conditions in which filarial worm infection is implicated.

First claim

The invention claimed is:

1 . A compound of Formula I:

or a salt or solvate thereof, wherein,
Q is a group of Formula IIIa:

wherein
X 4 is selected from CH and N;
R 6 is selected from hydrogen and C 1-6 alkyl;
R 7 and R 7 ′ are independently selected from hydrogen, C 3-6 cycloalkyl, C 1-6 alkyl, where said C 3-6 cycloalkyl and C 1-6 alkyl are optionally substituted by one or more R a ; or
R 7 and R 7 ′, together with the carbon to which they are attached form a 3-7 membered cycloalkyl ring, optionally substituted with one or more R a , or R 7 and R 7 ′, together with the carbon to which they are attached form a carbonyl group; or
R 6 and R 7 , together with the atoms to which they are attached form a 3-7 membered heterocyclic ring, optionally substituted with one or more R a ;
n is a number selected from 1, 2 and 3;
R 2 is selected from —CN, —C(═O)R d , —C(═O)OR d , —C(═O)NR c R d , —C(O)C(═O)R d , —NR c R d , —NR c C(═O)R d , —NR c C(═O)OR d , —NR c C(═O)NR c R d , —NR c S(═O) 2 R d , —NR c S(═O) 2 NR c R d , —OR d , —SR d —OC(═O)R d , —OC(═O)NR c R d , —OC(═O)OR d , —S(═O)R d , —S(═O) 2 R d , —OS(═O)R d , —OS(═O) 2 R d , —OS(═O) 2 OR d , —S(═O)NR c R d , —OS(═O) 2 NR c R d , —S(═O) 2 NR c R d , C 1-10 haloalkyl, C 1-10 alkyl optionally substituted by one or more R e , C 2-6 alkenyl optionally substituted by one or more R e , C 2-6 alkynyl optionally substituted by one or more R e , C 6-11 aryl optionally substituted by one or more R c , (C 7-16 )alkylaryl optionally substituted by one or more R e , C 3-11 cycloalkyl optionally substituted by one or more R e , (C 4-17 )cycloalkylalkyl optionally substituted by one or more R e , 3-15 membered heterocycloalkyl optionally substituted by one or more R e , 4-21 membered alkylheterocycloalkyl optionally substituted by one or more R e , 5-15 membered heteroaryl optionally substituted by one or more R e , and 6-21 membered alkylheteroaryl optionally substituted by one or more R e ;
each R a is independently selected from hydroxyl, halogen, CN, C 1-6 haloalkyl, C 1-6 haloalkoxy, C 1-6 alkyl, C 3-6 cycloalkyl, 3-7 membered heterocycloalkyl, wherein said C 3-6 cycloalkyl and 3-7 membered heterocycloalkyl are optionally substituted with one or more groups selected from hydroxyl, halogen, CN, C 1-6 haloalkyl, C 3-6 cycloalkyl, C 1-6 alkyl and O—C 1-6 alkyl;
R b and each R e is independently selected from hydroxyl, ═O, halogen, CN, C 1-6 haloalkyl, C 1-6 haloalkoxy, C 1-6 alkyl, O—C 1-6 alkyl, C 3-6 cycloalkyl, 3-7 membered heterocycloalkyl, —C(═O)R d , —C(═O)OR d , —C(═O)NR c R d , —C(O)C(═O)R d , —NR c R d , —NR c C(═O)R d , —NR c C(═O)OR d , —NR c C(═O)NR c R d , —NR c S(═O) 2 R d , —NR'S(═O) 2 NR c R d , —OR d , —SR d , —OC(═O)R d , —OC(═O)NR c R d , —OC(═O)OR d , —S(═O) 2 R d , —S(═O)R d , —OS(═O)R d , —OS(═O) 2 R d , —OS(═O) 2 OR d , —S(═O)NR c R d , —OS(═O) 2 NR c R d , and —S(═O) 2 NR c R d , where said C 3-6 cycloalkyl, C 1-6 alkyl, and 3-7 membered heterocycloalkyl are optionally substituted with one or more groups selected from hydroxyl, halogen, ═O, CN, C 1-6 haloalkyl, C 1-6 haloalkoxy, C 3-6 cycloalkyl, C 1-6 alkyl and O—C 1-6 alkyl;
each R c is independently selected from hydrogen, hydroxyl, halogen, CN, C 1-6 haloalkyl, C 3-6 cycloalkyl, C 1-6 alkyl and O—C 1-6 alkyl;
each R d is independently selected from hydrogen, hydroxyl, halogen, CN, C 1-6 haloalkyl, 3-7 membered heterocycloalkyl, C 3-6 cycloalkyl, C 1-6 alkyl, O—C 1-6 alkyl and C 6-11 aryl, wherein said C 1-6 alkyl, C 6-11 aryl, 3-7 membered heterocycloalkyl and C 3-6 cycloalkyl are optionally substituted with one or more groups selected from hydroxyl, halogen, CN, amino, C 1-6 haloalkyl, C 3-6 cycloalkyl, C 6-11 aryl, 3-7 membered heterocycloalkyl, C 1-6 alkyl and O—C 1-6 alkyl; or
R c and R d , when attached to the same atom, together with the atom to which they are attached form a 3-7 membered ring, optionally containing one or more for heteroatoms selected from O, NH and S, and wherein said ring is optionally substituted with one or more R a ; and
R 4 and R 5 are independently selected from hydrogen, hydroxyl, halogen, CN, C 1-6 haloalkyl, C 1-6 haloalkoxy, C 1-6 alkyl, phenyl and cyclopropyl, wherein said C 1-6 alkyl, phenyl and cyclopropyl are optionally substituted by one or more R a .

2 . The compound according to claim 1 , or a salt or solvate thereof, wherein R b is selected from fluoro, chloro, and CF 3 .

3 . The compound according to claim 1 , wherein R 6 , R 7 and R 7 ′ are each hydrogen.

4 . The compound according to claim 1 , or a salt or solvate thereof, wherein n is 1.

5 . The compound according to claim 1 , or a salt or solvate thereof, wherein R 2 is selected from

each of which may optionally be substituted with one or more R e .

6 . The compound according to claim 1 , or a salt or solvate thereof, wherein each R e is independently selected from fluoro, chloro, CN, CF 3 , OCF 3 , and methyl.

7 . The compound according to claim 1 , or a salt or solvate thereof, which is a sub-Formula Ia:

wherein,
R 6 is selected from hydrogen and C 1-6 alkyl;
R 7 is selected from hydrogen, ═O, C 3-6 cycloalkyl, C 1-6 alkyl, where said C 3-6 cycloalkyl, C 1-6 alkyl are optionally substituted by one or more R a ; or
R 6 and R 7 , together with the atoms to which they are attached form a 3-7 membered heterocyclic ring, optionally substituted with one or more R a ;
X 4 is selected from CH and N;
R 2 is selected from —CN, —C(═O)R d , —C(═O)OR d , —C(═O)NR c R d , —C(O)C(═O)R d , —NR c R d , —NR c C(═O)R d , —NR c C(═O)OR d , —NR c C(═O)NR c R d , —NR c S(═O) 2 R d , —NR c S(═O) 2 NR c R d , —OR d , —SR d —OC(═O)R d , —OC(═O)NR c R d , —OC(═O)OR d , —S(═O)R d , —S(═O) 2 R d , —OS(═O)R d , —OS(═O) 2 R d , —OS(═O) 2 OR d , —S(═O)NR c R d , —OS(═O) 2 NR c R d , —S(═O) 2 NR c R d , C 1-10 haloalkyl, C 1-10 alkyl optionally substituted by 1-13 R e , C 2-6 alkenyl optionally substituted by 1-11 R e , C 2-6 alkynyl optionally substituted by 1-9 R e , C 6-11 aryl optionally substituted by 1-11 R e , (C 7-16 )alkylaryl optionally substituted by 1-9 R e , C 3-11 cycloalkyl optionally substituted by 1-21 R e , (C 4-17 )cycloalkylalkyl optionally substituted by 1-32 R e , 3-15 membered heterocycloalkyl optionally substituted by 1-28 R e , 4-21 membered alkylheterocycloalkyl optionally substituted by 1-40 R e , 5-15 membered heteroaryl optionally substituted by 1-15 R e , and 6-21 membered alkylheteroaryl optionally substituted by 1-27 R e ;
each R a is independently selected from hydroxyl, halogen, CN, C 1-6 haloalkyl, C 1-6 haloalkoxy, C 1-6 alkyl, C 3-6 cycloalkyl, 3-7 membered heterocycloalkyl, wherein said C 3-6 cycloalkyl, 3-7 membered heterocycloalkyl are optionally substituted with one or more groups selected from hydroxyl, halogen, CN, C 1-6 haloalkyl, C 3-6 cycloalkyl, C 1-6 alkyl and O—C 1-6 alkyl;
R b and each R e is independently selected from hydroxyl, ═O, halogen, CN, C 1-6 haloalkyl, C 1-6 haloalkoxy, C 3-6 cycloalkyl, C 1-6 alkyl, O—C 1-6 alkyl, C 3-6 cycloalkyl, 3-7 membered heterocycloalkyl, —C(═O)R d , —C(═O)OR d , —C(═O)NR c R d , —C(O)C(═O)R d , —NR c R d , —NR c C(═O)R d , —NR c C(═O)OR d , —NR c C(═O)NR c R d , —NR c S(═O) 2 R d , —NR'S(═O) 2 NR c R d , —OR d , —SR d , —OC(═O)R d , —OC(═O)NR c R d , —OC(═O

Assignees

• Liverpool School Tropical Medicine
• Univ Liverpool
• Eisai R&D Man Co Ltd

Inventors

• Ward Stephen A
• Taylor Mark J
• O'Neill Paul M
• Hong Weiqian David
• Benayoud Farid

Classifications

• C07D495/04

  Ortho-condensed systems · CPC title

• C07D239/86

  with hetero atoms directly attached in position 4 · CPC title

• Y02A50/30

  Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change · CPC title

• A61P33/00

  Antiparasitic agents · CPC title

• A61P31/04

  Antibacterial agents · CPC title