Compounds and compositions for the treatment of parasitic diseases

Patent metadata

Field	Value
Publication number	US-9556169-B2
Application number	US-201314443609-A
Country	US
Kind code	B2
Filing date	Nov 18, 2013
Priority date	Nov 19, 2012
Publication date	Jan 31, 2017
Grant date	Jan 31, 2017

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 Plasmodium parasite, such as malaria.

First claim

We claim:

1. A compound of Formula I,

or a pharmaceutical acceptable salt, tautomer or stereoisomer thereof, wherein
n is 0, 1, 2 or 3;
p is 0, 1, 2 or 3;
L is selected from the group consisting of *—(CHR 3 ) 1-3 —, *—CHR 3 N(R 2 )—, *—CHR 3 O—, *—CHR 3 S—, *—CHR 3 S(O)—, *—CHR 3 N(R 2 )CHR 3 —, *—C(O)—, *—C(O)N(R 2 )—, *—C(O)N(R 2 )CHR 3 —, *—N(R 2 )—, *—N(R 2 )CHR 3 —, *—N(R 2 )C(O)—, *—N(R 2 )C(O)N(R 2 )—, *—N(R 2 )S(O) 2 —, wherein
* represents the point of attachment of L to the pyrazolo[1,5-a]pyridine fused ring depicted in Formula I;
each R 2 is independently selected from the group consisting of hydrogen, C 1-6 alkyl, haloC 1-6 alkyl, R—C 0-4 alkylene, and R—C 0-4 alkylene-C(O)—, wherein R is selected from the group consisting of hydroxyl, C 1-4 alkoxy, amino, C 1-4 alkylamino, C 3-6 cycloalkyl, C 4-6 heterocycloalkyl, and C 5-6 heteroaryl, wherein the C 3-6 cycloalkyl, C 4-6 heterocycloalkyl, and C 5-6 heteroaryl of R are each unsubstituted or substituted with 1-2 substituents independently selected from the group consisting of halo, amino, hydroxyl, C 1-4 alkyl, C 1-4 alkoxy, oxo, and C 5-6 heteroaryl; and
each R 3 is independently selected from the group consisting of hydrogen and C 1-4 alkyl;

Ring A is selected from the group consisting of C 6-10 aryl and C 5-10 heteroaryl;
Ring C is selected from the group consisting of C 6-10 aryl, C 6-10 heteroaryl, C 5-7 cycloalkyl, C 5-7 heterocycloalkyl, and fused bicyclyl comprising a C 5-6 heterocycloalky fused to a phenyl;
each R 1 is independently selected from the group consisting of halo, cyano, amino, C 1-4 alkyl, C 1-4 alkoxyl, halo-C 1-4 alkyl, —C(O)NR 7 R 8 , —NHC(O)R 11 , phenyl, and C 5-6 heteroaryl; wherein
the phenyl and C 5-6 heteroaryl of R 1 are each unsubstituted or substituted with 1-2 substituents independently selected from the group consisting of C 1-4 alkyl, amino, halo, and C 1-4 alkylamino;
R 7 and R 8 are each independently selected from hydrogen, C 1-4 alkyl and haloC 1-4 alkyl;
R 11 is C 1-6 alkyl, unsubstituted or substituted with 1-2 substituents independently selected from the group consisting of amino, C 3-6 cycloalkyl and C 4-6 heterocycloalkyl;

R 17 is selected from the group consisting of cyano, halo, C 1-4 alkyl, halo-C 1-4 alkyl, oxo, C 3-6 cycloalkyl, and —SO 2 —C 1-4 alkyl.

2. The compound of claim 1 , wherein L is selected from the group consisting of *—C(O)N(R 2 )— and *—N(R 2 )C(O)—, wherein each R 2 is independently selected from hydrogen, C 1-4 alkyl, and R—C 0-4 alkylene, and wherein R is selected from the group consisting of C 1-4 alkylamino, C 3-6 cycloalkyl, C 4-6 heterocycloalkyl and C 5-6 heteroaryl, each of which is unsubstituted or substituted with 1-2 substituents independently selected from the group consisting of halo, amino, hydroxyl, C 1-4 alkyl, C 1-4 alkoxy, oxo, and C 5-6 heteroaryl.

3. The compound of claim 1 , wherein L is selected from *—C(O)N(CH 3 )—*—C(O)N(CH 2 CH 3 )—, *—C(O)N(CH(CH 3 ) 2 )—, *—C(O)N(NH(CH 3 ))—, and *—N(CH 3 )C(O)—.

4. The compound according to claim 1 , wherein Ring A is selected from the group consisting of phenyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrrolopyridinyl, and indazolyl, each of which is unsubstituted or substituted by (R 1 ) n .

5. The compound according to claim 1 , wherein Ring C is selected from the group consisting of

each of which is unsubstituted or substituted by (R 17 ) p .

6. The compound according to claim 1 , wherein Ring C is selected from the group consisting of phenyl and pyridinyl, each of which is unsubstituted or substituted by (R 17 ) p .

7. The compound according to claim 1 , wherein each R 1 is independently selected from the group consisting of trifluoromethyl, cyano, —NH 2 —, —C(O)NH 2 , —C(O)NHCH 3 , —C(O)N(CH 3 ) 2 , and —NHC(O)CH(NH 2 )(CH 3 ).

8. The compound according to claim 1 , wherein each R 17 is independently selected from the group consisting of cyano, halo, C 1-4 alkyl, haloC 1-4 alkyl, —SO 2 —C 1-4 alkyl, and C 3-6 cycloalkyl.

9. The compound of claim 1 , wherein the compound is of Formula Ia:

or a pharmaceutical acceptable salt, tautomer or stereoisomer thereof,
wherein
n is 1 or 2;
n is 1 or 2;
Ring A is phenyl, pyridinyl, or pyrimidinyl;
Ring C is phenyl or pyridinyl;
L is *—C(O)NR 2 — or *—NR 2 C(O)—, wherein R 2 is selected from hydrogen, C 1-4 alkyl, C 1-4 alkylamino-(C 0-4 )alkylene, C 3-6 cycloalkyl-(C 0-4 )alkylene, C 4-6 heterocycloalkyl-(C 0-4 )alkylene, wherein the C 4-6 heterocycloalkyl is selected from the group consisting of piperazinyl, morpholinyl, thiomorpholinyl, tetrahydropyranyl, and oxetanyl, and wherein the C 3-6 cycloalkyl is selected from cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl;
each R 1 is independently *—C(O)NR 7 R 8 or —NH 2 —, wherein R 7 and R 8 are each independently hydrogen or C 1-4 alkyl; and
R 17 is selected from the group consisting of cyano, halo, —NH 2 —, —C(O)NH 2 , —C(O)NH(CH 3 ), and —C(O)N(CH 3 ) 2 .

10. The compound of claim 9 , wherein L is selected from *—C(O)N(CH 3 )—*—C(O)N(CH 2 CH 3 )—, *—C(O)N(CH(CH 3 ) 2 )—, *—C(O)N(NH(CH 3 ))—, and *—N(CH 3 )C(O)—.

11. The compound of claim 1 , wherein the compound, or a pharmaceutical acceptable salt, tautomer or stereoisomer thereof, is selected from the group consisting of:
N-(4-cyanophenyl)-N-methyl-3-(4-(trifluoromethyl)phenyl)pyrazolo[1,5-a]pyridine-5-carboxamide;
4-fluoro-N-methyl-N-((3-(4-(trifluoromethyl)phenyl)pyrazolo[1,5-a]yridine-5-yl)methyl)aniline;
N-(4-chlorophenyl)-N-methyl-3-(4-(trifluoromethyl)phenyl)pyrazolo[1,5-a]pyridine-5-carboxamide;
N-(4-fluorophenyl)-N-methyl-3-(4-(trifluoromethyl)phenyl)pyrazolo[1,5-a]pyridine-5-carboxamide;
N-methyl-N-(5-methylpyridin-2-yl)-3-(4-(trifluoromethyl)phenyl)pyrazolo[1,5-a]pyridine-5-carboxamide;
4-chloro-N-methyl-N-((3-(4-(trifluoromethyl)phenyl)pyrazolo[1,5-a]yridine-5-yl)methyl)aniline;
N,5-dimethyl-N-((3-(4-(trifluoromethyl)phenyl)pyrazolo[1,5-a]yridine-5-yl)methyl)yridine-2-amine;
5-((4-fluorophenoxy)methyl)-3-(4-(trifluoromethyl)phenyl)pyrazolo[1,5-a]pyridine;
N-(4-cyanophenyl)-N-(2-methoxyethyl)-3-(4-(trifluoromethyl)phenyl)pyrazolo[1,5-a]pyridine-5-carboxamide;
N-(4-cyanophenyl)-N-(2-(dimethylamino)ethyl)-3-(4-(trifluoromethyl)phenyl)pyrazolo[1,5-a]pyridine-5-carboxamide;
N-(4-cyanophenyl)-N-((tetrahydro-2H-pyran-4-yl)methyl)-3-(4-(trifluoromethyl)phenyl)pyrazolo[1,5-a]pyridine-5-carboxamide;
N-(4-(methylsulfonyl)phenyl)-N-((tetrahydro-2H-pyran-4-yl)methyl)-3-(4-(trifluoromethyl)phenyl)pyrazolo[1,5-a]pyridine-5-carboxamide;
N-(5-cyanopyridin-2-yl)-N-methyl-3-(4-(trifluoromethyl)phenyl)pyrazolo[1,5-a]pyridine-5-carboxamide;
N-methyl-N-(5-methylpyridin-3-yl)-3-(4-(trifluoromethyl)phenyl)pyrazolo[1,5-a]pyridine-5-carboxamide;
5-(((5-methylpyridin-2-yl)oxy)methyl)-3-(4-(trifluoromethyl)phenyl)pyrazolo[1,5-a]pyridine;
5-(4-fluorophenethyl)-3-(4-(trifluoromethyl)phenyl)pyrazolo[1,5-a]pyridine;
N-(4-cyanophenyl)-N-methyl-3-(1-methyl-1H-indazol-5-yl)pyrazolo[1,5-a]pyridine-5-carboxamide;
3-(6-acetamidopyridin-3-yl)-N-(4-cyanophenyl)-N-methylpyrazolo[1,5-a]pyridine-5-carboxamide;
3-(4-carbamoylphenyl)-N-(4-cyanophenyl)-N-methylpyrazolo[1,5-a]pyridine-5-carboxamide;
3-(4-carbamoylphenyl)-N-(4-fluorophenyl)-N-methylpyrazolo[1,5-a]pyridine-5-carboxamide;
5-(((4-fluorophenyl)thio)methyl)-3-(4-(trifluoromethyl)phenyl)pyrazolo[1,5-a]pyridine;
5-(((4-fl

Assignees

• Novartis Ag

Inventors

• Chatterjee Arnab Kumar
• Nagle Advait Suresh
• Paraselli Prasuna
• Kondreddi Ravinder Reddy
• Leong Seh Yong
• Mishra Pranab Kumar
• Moreau Robert Joseph
• Roland Jason Thomas
• Sim Wei Lin Sandra
• Simon Oliver
• Tan Jocelyn Liying
• Yeung Bryan K S
• Zou Bin
• Bollu Venkatataiah

Classifications

• A61K31/538

  ortho- or peri-condensed with carbocyclic ring systems · CPC title

• C07D519/00

  Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00 · CPC title

• A61K31/437

  the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline · CPC title

• A61P33/00

  Antiparasitic agents · CPC title

• A61K31/506

  not condensed and containing further heterocyclic rings · CPC title