Compounds and compositions for the treatment of parasitic diseases

Patent metadata

Field	Value
Publication number	US-9296754-B2
Application number	US-201414209850-A
Country	US
Kind code	B2
Filing date	Mar 13, 2014
Priority date	Mar 15, 2013
Publication date	Mar 29, 2016
Grant date	Mar 29, 2016

Abstract

The present invention provides compounds of formula I:

or a pharmaceutically acceptable salt, tautomer, or stereoisomer, thereof, wherein the variables are as defined herein. The present invention further provides pharmaceutical compositions comprising such compounds and methods of using such compounds for treating, preventing, inhibiting, ameliorating, or eradicating the pathology and/or symptomology of a disease caused by a parasite, such as Leishmaniasis, Human African Trypanosomiasis and Chagas disease.

First claim

We claim:

1. A compound of Formula I:

or a pharmaceutically acceptable salt, or stereoisomer thereof; wherein
L 1 is —C(O)—or —S(O) 2 —;
R 1 is selected from nitro, C 1-4 alkyl, C 1-6 alkoxy, amino, C 5-9 heteroaryl, C 3-6 cycloalkyl and C 4-6 heterocycloalkyl, each of which is optionally substituted by 1-2substituents independently selected from halo, cyano, amino, C 1-4 alkyl, haloC 1-4 alkyl, C 1-6 alkoxy, and C 1-4 alkylcarbonyl;
R 3 is selected from hydrogen, halo, cyano, C 1-4 alkyl and haloC 1-4 alkyl;
R 4 is selected from hydrogen, C 1-4 alkyl, haloC 1-4 alkyl, and —C(O)R 10 , wherein R 10 is hydroxy, C 1-4 alkyl, C 1-4 alkoxy, amino, C 1-4 alkylamino, C 3-6 cycloalkyl and C 4-6 heterocycloalkyl, each of which is optionally substituted by 1-2substituents independently selected from hydroxyl, halo and C 1-4 alkyl;
L 3 is a bond, phenylene, or C 5-6 heteroarylene;
R 0 is selected from hydroxyl, halo, nitro, —N═CHN(CH 3 ) 2 , C 1-4 alkyl, C 1-4 alkoxy, —NR 2a R 2b , —NR 5 C(O) R 6 , —NR 5 S(O) 2 R 8 , C 3-6 cycloalkyl, C 4-6 heterocycloalkyl, C 4-6 heterocycloalkenyl, phenyl and C 5-6 heteroaryl; wherein
the C 1-4 alkyl or C 1-4 alkoxy is optionally substituted by 1-2 substituents independently selected from C 1-4 alkoxy, amino, phenyl and C 5-6 heteroaryl;

wherein the phenyl or C 5-6 heteroaryl is optionally further substituted by halo or C 1-4 alkyl;
the C 3-6 cycloalkyl, C 4-6 heterocycloalkyl, C 4-6 heterocycloalkenyl, phenyl and C 5-6 heteroaryl of R 0 is optionally substituted with halo, oxo, C 1-4 alkyl, hydroxyC 1-4 alkyl, haloC 1-4 alkyl, C 1-4 alkoxy, amino, C 1-4 alkylamino, and —(CH 2 ) 1-4 NR a R b , wherein R a and R b are each independently hydrogen, C 1-4 alkyl or C 3-6 cycloalkyl;
R 2a is hydrogen or C 1-4 alkyl;
R 2b is selected from hydrogen, C 1-4 alkyl, wherein the alkyl is optionally substituted by amino, C 4-6 heterocycloalkyl, phenyl or C 5-6 heteroaryl, wherein the C 4-6 heterocycloalkyl, phenyl or C 5-6 heteroaryl is further optionally substituted by hydroxyl, halo or C 1-4 alkyl;
R 5 is hydrogen or C 1-4 alkyl;
R 6 is selected from hydrogen, C l-6 alkyl, C 1-4 alkoxy, C 3-6 cycloalkoxy, amino, C 3-6 cycloalkyl, C 5-6 heterocycloalkyl, and C 5-6 heteroaryl, wherein
the C 1-6 alkyl, C 1-4 alkoxy, C 3-6 cycloalkoxy, and amino of R 6 are each optionally substituted by 1-2 substituents independently selected from halo, hydroxy, C 1-4 alkyl, haloC 1-4 alkyl, C 1-4 alkoxy, —NR 9a R 9b , C 3-6 cycloalkyl, C 5-6 heterocycloalkyl, and C 5-6 heteroaryl, wherein R 9a is hydrogen or C 1-4 alkyl and R 9b is selected from hydrogen, C 1-4 alkyl, C 1-4 alkylcarbonyl and the C 5-6 heterocycloalkyl and C 5-6 heteroaryl substituents are each further optionally substituted by 1-2 substituents independently selected from hydroxyl, C 1-4 alkyl and C 1-4 alkoxycarbonyl,
the C 5-6 heteroaryl of R 6 is optionally substituted with 1-2 substituents selected from hydroxy, C 1-4 alkyl, and C 1-4 alkoxycarbonyl,
the C 3-6 cycloalkyl or C 5-6 heterocycloalkyl of R 6 are each independently optionally substituted by 1-2 substituents independently selected from halo, cyano, hydroxy, C 1-4 alkyl, haloC 1-4 alkyl, C 1-4 alkoxylC 1-4 alkyl, aminocarbonyl, C 1-4 alkoxycarbonyl, and C 1-4 alkoxycarbonylaminoC 1-4 alkyl, and

R 8 is C 1-4 alkyl or C 1-4 alkylamino.

2. The compound according to claim 1 , wherein L 1 is —C(O)—.

3. The compound according to claim 1 , wherein R 1 is selected from C 1-4 alkyl, C 1-6 alkoxy, amino, C 5-9 heteroaryl, C 3-6 cycloalkyl and C 4-6 heterocycloalkyl, each is optionally substituted by 1-2 substituents independently selected from halo, cyano, amino, C 1-4 alkyl, haloC 1-4 alkyl, C 1-6 alkoxy, C 1-4 alkylcarbonyl.

4. The compound according to claim 1 , wherein R 1 is selected from C 5-9 heteroaryl, C 4-6 heterocycloalkyl, and C 3-6 cycloalkyl, each of which is independently optionally substituted by 1-2 substituents independently selected from halo, cyano, C 1-4 alkyl and C 1-4 alkoxy.

5. The compound according to claim 1 , wherein R 1 is selected from pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, furanyl, thiophenyl, thiazolyl, pyrazinyl, cyclopropyl, cyclopentyl, pyrrolidinyl, and indolyl, each of which is independently optionally substituted by 1-2 substituents independently selected from halo, cyano, C 1-4 alkyl, haloC 1-4 alkyl and C 1-4 alkylcarbonyl.

6. The compound according to claim 1 , wherein L 1 -R 1 is selected from

7. The compound according to claim 1 , wherein L 1 -R 1 is selected from

8. The compound according to claim 1 , wherein R 3 is selected from hydrogen, halo, methyl, or trifluoromethyl.

9. The compound according to claim 1 , wherein R 3 is chloro or fluoro.

10. The compound according to claim 1 , wherein R 4 is hydrogen.

11. The compound according to claim 1 , wherein R 0 is selected from halo, nitro, C 1-4 alkyl, —N═CHN(CH 3 ) 2 , —NHR 2b , —NR 5 C(O)R 6 , —NR 5 S(O) 2 R 8 , C 4-6 heterocycloalkyl, C 4-6 heterocycloalkenyl, phenyl and C 5-6 heteroaryl; wherein
the C 4-6 heterocycloalkyl, C 4-6 heterocycloalkenyl, phenyl and C 5-6 heteroaryl of R 0 is optionally substituted with oxo, C 1-4 alkyl, —(CH 2 ) 1-4 OH, and —(CH 2 ) 1-4 NR a R b , wherein R a and R b are each independently hydrogen, C 1-4 alkyl or C 3-6 cycloalkyl;
R 2b is selected from hydrogen, C 1-4 alkyl, wherein the alkyl is optionally substituted by amino, C 4-6 heterocycloalkyl, phenyl or C 5-6 heteroaryl, wherein the C 4-6 heterocycloalkyl, phenyl or C 5-6 heteroaryl is further optionally substituted by hydroxy or halo;
R 5 is hydrogen or C 1-4 alkyl;
R 6 is selected from hydrogen, C 1-6 alkyl, C 1-4 alkoxy, C 3-6 cycloalkoxy, amino, C 3-6 cycloalkyl, C 5-6 heterocycloalkyl, and C 5-6 heteroaryl, wherein
the C 1-6 alkyl, C 1-4 alkoxy, C 3-6 cycloalkoxy, and amino of R 6 are each optionally substituted by 1-2 substituents independently selected from halo, hydroxy, C 1-4 alkyl, haloC 1-4 alkyl, C 1-4 alkoxy, —NR 9a R 9b , C 5-6 heterocycloalkyl, and C 5-6 heteroaryl, wherein R 9a is hydrogen or C 1-4 alkyl, and R 9b is selected from hydrogen, C 1-4 alkyl, and C 1-4 alkoxycarbonyl; and the C 5-6 heterocycloalkyl and C 5-6 heteroaryl are each further optionally substituted by 1-2 substituents independently selected from hydroxyl, C, 1-4 alkyl and C 1-4 alkoxycarbonyl;
the C 5-6 heteroaryl of R 6 is optionally substituted with 1 to 2 C 1-4 alkyl;
the C 3-6 cycloalkyl or C 5-6 heterocycloalkyl of R 6 are each independently optionally substituted by 1-2 substituents independently selected from halo, cyano, hydroxy, C 1-4 alkyl, haloC 1-4 alkyl, —CH 2 OCH 3 , —C(O)NH 2 , C 1-4 alkoxycarbonyl and C 1-4 alkoxycarbonylaminoC 1-4 alkyl; and
R 8 is C 1-4 alkyl or C 1-4 alkylamino.

12. The compound according to claim 1 , wherein R 0 is selected from halo, nitro, hydroxyl, C 1-4 alkoxy, amino, C 1-4 alkylamino, —NH(CH 2 ) 1 - 2 -phenyl, —NR 5 C(O)R 6 , —NR 5 S(O) 2 R 8 , oxazolidin-2-one, 1,2,4-triazol-5(4H)-one, pyrrolidin-2-one, phenyl and C 5-6 heteroaryl; wherein
the oxazolidin-2-one, 1,2,4-triazol-5(4H)-one, pyrrolidin-2-one, phenyl or C 5-6 heteroaryl is optionally substituted with halo, C 1-4 alkyl, C 1-4 alkoxy, amino, C 1-4 alkylamino, —(CH 2 ) 1-4 (OH, and —(CH 2 ) 1-4 NR a R b , wherein R a and R b

Assignees

• Liang Fang
• Mishra Pranab Kumar
• Molteni Valentina
• Nagle Advait Suresh
• Supek Frantisek
• Tan Liying Jocelyn
• Vidal Agnes
• Novartis Ag

Inventors

• Liang Fang
• Mishra Pranab Kumar
• Molteni Valentina
• Nagle Advait Suresh
• Supek Frantisek
• Tan Liying Jocelyn
• Vidal Agnes

Classifications

• A61K31/519

  ortho- or peri-condensed with heterocyclic rings · CPC title

• A61P33/02

  Antiprotozoals, e.g. for leishmaniasis, trichomoniasis, toxoplasmosis · CPC title

• C07D487/04 Primary

  Ortho-condensed systems · CPC title

• A61K45/06

  Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca · CPC title

• A61K2300/00

  Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00 · CPC title