5-aminopyrazole-4-carboxamide inhibitors of CDPK1 from T. gondii and C. parvum

Patent metadata

Field	Value
Publication number	US-9956214-B2
Application number	US-201615351525-A
Country	US
Kind code	B2
Filing date	Nov 15, 2016
Priority date	May 20, 2013
Publication date	May 1, 2018
Grant date	May 1, 2018

Abstract

The present disclosure is generally directed to compositions and methods for treating apicomplexan protozoan related disease, such as toxoplasmosis and cryptosporidiosis.

First claim

We claim:

1. A method for treating an apicomplexan protozoan related disease, wherein the apicomplexan protozoan related disease is toxoplasmosis, cryptosporidiosis, malaria, neosporosis, eimeriosis, or coccidiosis, the method comprising providing to a patient in need of such treatment a therapeutically effective amount of either a compound of formula:

or a pharmaceutically acceptable salt thereof or a pharmaceutical composition thereof, wherein R 1 is one of the formulas:

wherein
R 8 is, halogen, cyano, nitro, C 1-6 alkyl, C 1-6 haloalkyl, or -Q-R 8′ ;
Q is —O—, —S—, —NH—, or —N(C 1-6 alkyl)-;
R 8′ is hydrogen, C 1-6 alkyl, C 2-6 alkenyl, C 1-6 haloalkyl, C 3-8 cycloalkyl, heterocyclyl, aryl, arylC 1-6 alkyl, heteroaryl, or heteroarylC 1-6 alkyl, wherein the alkyl, aryl, arylalkyl, heteroaryl, and heteroarylalkyl are optionally substituted with one, two, three, or four groups that are each independently halogen, cyano, nitro, C 1-6 alkyl, C 1-6 haloalkyl, —OR 14 , —SR 14 , —N(R 14 ) 2 , —C(O)R 14 , —C(O)OR 14 , —C(O)N(R 14 ) 2 , —S(O) 2 R 14 , —OC(O)R 14 , —OC(O)OR 14 , —OC(O)N(R 14 ) 2 , —N(R 14 )C(O)R 14 , —N(R 14 )C(O)OR 14 , or —N(R 14 )C(O)N(R 14 ) 2 , wherein each R 14 is independently hydrogen or C 1-6 alkyl; and

R 2 is hydrogen, C 1-6 alkyl, C 1-6 haloalkyl, —C 1-4 alkyl-R 12 , C 2-6 alkenyl, C 2-6 alkynyl, C 3-8 cycloalkyl, monocyclic heterocyclyl, monocyclic heteroaryl, or phenyl, wherein the alkyl, cycloalkyl, heterocyclyl, heteroaryl, and phenyl groups are each optionally substituted with one or two R 13 groups;
each R 13 is independently C 1-6 alkyl, C 1-6 haloalkyl, —OR, —SR, —NR 2 , —C(O)R, —C(O)OR, —C(O)NR 2 , —S(O) 2 NR 2 , or —S(O) 2 R; and
where R 12 is —OR, —SR, —NR 2 , —C(O)R, —C(O)OR, —C(O)NR 2 , —S(O) 2 R, —OC(O)R, —OC(O)OR, —OC(O)NR 2 , —N(R)C(O)R, —N(R)C(O)OR, —N(R)C(O)NR 2 , phenyl, monocyclic heteroaryl, C 3-8 cycloalkyl, or monocyclic heterocyclyl, wherein the aryl, heteroaryl, C 3-8 cycloalkyl, and heterocyclyl groups are each optionally substituted by one, two, or three groups that are each independently halogen, cyano, nitro, C 1-6 alkyl, C 1-6 haloalkyl, —OR, —SR, —NR 2 , —C(O)R, —C(O)OR, —C(O)NR 2 , —S(O) 2 R, —OC(O)R, —OC(O)OR, —OC(O)NR 2 , —N(R)C(O)R, —N(R)C(O)OR, or —N(R)C(O)NR 2 ;
and each R is independently hydrogen, C 1-6 alkyl, C 2-6 alkenyl, C 1-6 haloalkyl, C 3-8 cycloalkyl, heterocyclyl, aryl, arylC 1-6 alkyl, heteroaryl, or heteroarylC 1-6 alkyl, wherein the alkyl, aryl, arylalkyl, heteroaryl, and heteroarylalkyl are optionally substituted with one, two, three, or four groups that are each independently halogen, cyano, nitro, C 1-6 alkyl, C 1-6 haloalkyl, —OR 0 , —SR 0 ,) —N(R 0 ) 2 , —C(O)R 0 , —C(O)OR 0 , —C(O)N(R 0 ) 2 , —S(O) 2 R 0 , —OC(O)R 0 , —OC(O)OR 0 , —OC(O)N(R 0 ) 2 , —N(R 0 )C(O)R 0 , —N(R 0 )C(O)OR 0 , or —N(R 0 )C(O)N(R 0 ) 2 , wherein each R 0 is independently hydrogen or C 1-6 alkyl;
or R 2 and R 3 together with the atoms to which they are attached form 2-oxo-2,3-dihydro-imidazolyl ring;

R 3 and R 4 are independently hydrogen; and
R 5 and R 6 are independently hydrogen.

2. The method of claim 1 , wherein the apicomplexan protozoan related disease is toxoplasmosis, or cryptosporidiosis.

3. A method according to claim 1 , wherein R 1 is of the formula:

4. A method according to claim 1 , wherein R 1 is of the formula:

5. A method according to claim 1 , wherein R 8 is -Q-R 8′ ; wherein
Q is —O—, —S—, —NH—, or —N(C 1-6 alkyl)-;
R 8′ is hydrogen, C 1-6 alkyl, C 2-6 alkenyl, C 1-6 haloalkyl, C 3-8 cycloalkyl, heterocyclyl, aryl, arylC 1-6 alkyl, heteroaryl, or heteroarylC 1-6 alkyl wherein the alkyl, aryl, arylalkyl, heteroaryl, and heteroarylalkyl are optionally substituted with one, two, three, or four groups that are each independently halogen, cyano, nitro, C 1-6 alkyl, C 1-6 haloalkyl, —OR 14 , —SR 14 , —N(R 14 ) 2 , —C(O)R 14 , —C(O)OR 14 , —C(O)N(R 14 ) 2 , —S(O) 2 R 14 , —OC(O)R 14 , —OC(O)OR 14 , —OC(O)N(R 14 ) 2, —N(R 14 )C(O)R 14 , —N(R 14 )C(O)OR 14 , or —N(R 14 )C(O)N(R 14 ) 2 , wherein each R 14 is independently hydrogen or C 1-6 alkyl.

6. A method according to claim 5 , wherein R 8′ is C 1-6 alkyl optionally substituted with one, two, three, or four groups that are each independently halogen, —OR 14 , —SR 14 , —N(R 14 ) 2 , —C(O)R 14 , —C(O)OR 14 , —C(O)N(R 14 ) 2 , or —S(O) 2 R 14 , wherein each R 14 is independently hydrogen or C 1-6 alkyl.

7. A method according to claim 6 , wherein R 8′ is C 1-6 alkyl.

8. A method according to claim 6 , wherein R 8′ is ethyl.

9. A method according to claim 1 , wherein R 8 is hydrogen, halogen, C 1-6 alkyl, or C 1-6 haloalkyl.

10. A method according to claim 1 , wherein each R 9 is independently hydrogen or C 1-4 alkyl.

11. A method according to claim 1 , wherein R 2 is C 1-6 alkyl, C 1-6 haloalkyl, —C 1-4 alkyl-R 12 , C 2-6 alkenyl, C 2-6 alkynyl, C 3-8 cycloalkyl, monocyclic heterocyclyl, monocyclic heteroaryl, or phenyl, wherein the alkyl, cycloalkyl, heterocyclyl, heteroaryl, and phenyl groups are each optionally substituted with one or two R 13 groups.

12. A method according to claim 11 , where R 12 is —OR, —NR 2 , —C(O)R, —C(O)OR, —C(O)NR 2 , —S(O) 2 R, phenyl, monocyclic heteroaryl, C 3-8 cycloalkyl, or monocyclic heterocyclyl, wherein the aryl, heteroaryl, C 3-8 cycloalkyl, and heterocyclyl groups are each optionally substituted by one, two, or three groups that are each independently halogen, cyano, nitro, C 1-6 alkyl, C 1-6 haloalkyl, —OR, —SR, —NR 2 , —C(O)R, —C(O)OR, —C(O)NR 2 , —S(O) 2 R, —OC(O)R, —OC(O)OR, —OC(O)NR 2 , —N(R)C(O)R, —N(R)C(O)OR, or —N(R)C(O)NR 2 .

13. A method according to claim 12 , where R 12 is —OR.

14. A method according to claim 1 , wherein R 2 is C 3-8 cycloalkyl or monocyclic heterocyclyl, each optionally substituted with one or two R 13 groups.

15. A method according to claim 1 , wherein the compound is selected from:
5-amino-1-tert-butyl-3-(naphthalen-2-yl)-1H-pyrazole-4-carboxamide;
5-amino-1-tert-butyl-3-(6-ethoxynaphthalen-2-yl)-1H-pyrazole-4-carboxamide;
1-tert-butyl-3-(6-ethoxynaphthalen-2-yl)-1H-pyrazole-4-carboxamide;
5-amino-3-(naphthalen-2-yl)-1-(piperidin-4-ylmethyl)-1H-pyrazole-4-carboxamide;
5-amino-3-(6-ethoxynaphthalen-2-yl)-1-((1-methylpiperidin-4-yl)methyl)-1H-pyrazole-4-carboxamide;
5-amino-3-(6-methoxynaphthalen-2-yl)-1-((1-methylpiperidin-4-yl)methyl)-1H-pyrazole-4-carboxamide;
5-amino-3-(6-methoxynaphthalen-2-yl)-1H-pyrazole-4-carboxamide;
5-amino-1-ethyl-3-(naphthalen-2-yl)-1H-pyrazole-4-carboxamide;
5-amino-1-isopropyl-3-(naphthalen-2-yl)-1H-pyrazole-4-carboxamide;
5-amino-1-isobutyl-3-(naphthalen-2-yl)-1H-pyrazole-4-carboxamide;
5-amino-1-(cyclopropylmethyl)-3-(naphthalen-2-yl)-1H-pyrazole-4-carboxamide;
5-amino-1-(cyclohexylmethyl)-3-(naphthalen-2-yl)-1H-pyrazole-4-carboxamide;
5-amino-1-cyclohexyl-3-(naphthalen-2-yl)-1H-pyrazole-4-carboxamide;
5-amino-3-(naphthalen-2-yl)-1-(2,2,2-trifluoroethyl)-1H-pyrazole-4-carboxamide;
5-amino-3-(naphthalen-2-yl)-1-neopentyl-1H-pyrazole-4-carboxamide;
5-amino-1-(1-methylpiperidin-4-yl)-3-(naphthalen-2-yl)-1H-pyrazole-4-carboxamide;
5-amino-1-(

Assignees

• Univ Washington Through Its Center For Commercialization

Inventors

• Fan Erkang
• Van Voorhis Wesley C
• Zhang Zhongsheng
• Huang Wenlin
• Ojo Kayode K

Classifications

• A61P33/06

  Antimalarials · CPC title

• A61P33/02

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

• C07D235/08

  Radicals containing only hydrogen and carbon atoms · CPC title

• A61K31/454

  containing a five-membered ring with nitrogen as a ring hetero atom, e.g. pimozide, domperidone · CPC title

• A61K31/416

  condensed with carbocyclic ring systems, e.g. indazole · CPC title