IP Library › Granted Patent US 9,518,026

Granted Patent B2

US 9,518,026 · App. 14/891,237 · Granted Dec 13, 2016

5-aminopyrazole-4-carboxamide inhibitors of CDPK1 from

Inventors: Erkang Fan (Seattle, WA); Wesley C. Van Voorhis (Seattle, WA); Zhongsheng Zhang (Seattle, WA); Wenlin Huang (Seattle, WA); Kayode K. Ojo (Seattle, WA)

Assignee: University of Washington Through its Center For Commercialization

C07D231/38 C07D231/14 C07D235/08 C07D235/12 C07D311/20 C07D401/04 C07D401/06 C07D403/04 C07D405/04 C07D405/14 C07D487/04

View Patent ↗

Loading inventors, assignments & file history…

Monitor This Case

Get email alerts when status or documents change.

Order Certified Copies

Most orders are placed with the USPTO same day — all within 24 business hours.

Order via The Patent Place →

Pre-filled with this patent's details

Quick Facts

Patent No.: US 9,518,026
App. No.: 14/891,237
Granted: Dec 13, 2016
Kind: B2

External Links

USPTO Patent Center↗ Full Patent PDF↗

Abstract

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

Claims (133)

1. A compound of the formula:

or a pharmaceutically acceptable salt thereof, wherein

R 1 is one of the formulas:

wherein

n is 0;

each R 7 is independently halogen, cyano, nitro, C 1-6 alkyl, C 1-6 haloalkyl, —OR 10 , —SR 10 , —N(R 10 ) 2 , —C(O)R 10 , —C(O)OR 10 , —C(O)N(R 10 ) 2 , —S(O) 2 R 10 , —OC(O)R 10 , —OC(O)OR 10 , —OC(O)N(R 10 ) 2 , —N(R 10 )C(O)R 10 , —N(R 10 )C(O)OR 10 , or —N(R 10 )C(O)N(R 10 ) 2 , wherein each R 10 is independently hydrogen or C 1-6 alkyl;

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

each R 9 is independently hydrogen or C 1-6 alkyl;

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. A compound according to claim 1 , wherein R is one of the formulas:

3. A compound according to claim 2 , 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)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.

4. A compound according to claim 2 , wherein R 8 is halogen, C 1-6 alkyl, or C 1-6 haloalkyl.

5. A compound according to claim 1 , wherein R 1 is one of the formulas:

6. A compound according to claim 1 , wherein each R 7 is independently halogen, cyano, nitro, C 1-6 alkyl, C 1-6 haloalkyl, —OR 10 , —SR 10 , —N(R 10 ) 2 , —C(O)R 10 , —C(O)OR 10 , or —C(O)N(R 10 ) 2 , wherein each R 10 is independently hydrogen or C 1-6 alkyl.

7. A compound according to claim 6 , wherein each R 7 is independently halogen, cyano, nitro, C 1-6 alkyl, or C 1-6 haloalkyl.

8. A compound according to claim 1 , wherein R 1 is one of the formulas:

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

10. A compound according to claim 9 , wherein each R 9 is independently hydrogen or methyl.

11. A compound 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 compound 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 compound according to claim 12 , where R 12 is —OR.

14. A compound 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 compound, which is:

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-((1-methylpiperidin-4-yl)methyl)-3-(naphthalen-2-yl)-1H-pyrazole-4-carboxamide;

5-amino-1-(2-hydroxyethyl)-3-(naphthalen-2-yl)-1H-pyrazole-4-carboxamide;

5-amino-1-(2-morpholinoethyl)-3-(naphthalen-2-yl)-1H-pyrazole-4-carboxamide;

5-amino-1-(tert-butyl)-3-(6-hydroxynaphthalen-2-yl)-1H-pyrazole-4-carboxamide;

5-amino-1-(tert-butyl)-3-(6-methoxynaphthalen-2-yl)-1H-pyrazole-4-carboxamide;

5-amino-1-(tert-butyl)-3-(6-propoxynaphthalen-2-yl)-1H-pyrazole-4-carboxamide;

5-amino-1-(tert-butyl)-3-(2-methylbenzofuran-3-yl)-1H-pyrazole-4-carboxamide;

3-(3-amino-1H-indazol-6-yl)-1-(tert-butyl)-1H-pyrazole-4-carboxamide;

3-(3-amino-1-methyl-1H-indazol-6-yl)-1-(tert-butyl)-1H-pyrazole-4-carboxamide;

5-amino-1-(tert-butyl)-3-(1-methyl-1H-indazol-5-yl)-1H-pyrazole-4-carboxamide;

5-amino-1-(tert-butyl)-3-(1-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)-1H-pyrazole-4-carboxamide;

5-amino-1-(tert-butyl)-3-(1,2-dimethyl-1H-benzo[d]imidazol-5-yl)-1H-pyrazole-4-carboxamide;

5-amino-3-(2-amino-1-methyl-1H-benzo[d]imidazol-5-yl)-1-(tert-butyl)-1H-pyrazole-4-carboxamide;

5-amino-1-(tert-butyl)-3-(2-oxo-2H-chromen-6-yl)-1H-pyrazole-4-carboxamide;

5-amino-1-(tert-butyl)-3-(quinolin-2-yl)-1H-pyrazole-4-carboxamide;

5-amino-1-(tert-butyl)-3-(6-ethoxyquinolin-2-yl)-1H-pyrazole-4-carboxamide;

5-amino-1-(tert-butyl)-3-(quinolin-6-yl)-1H-pyrazole-4-carboxamide;

5-amino-1-(tert-butyl)-3-(quinolin-3-yl)-1H-pyrazole-4-carboxamide;

5-amino-1-(tert-butyl)-3-(7-ethoxyquinolin-3-yl)-1H-pyrazole-4-carboxamide;

5-amino-3-(7-ethoxyquinolin-3-yl)-isopropyl-1H-pyrazole-4-carboxamide;

5-amino-3-(7-ethoxyquinolin-3-yl)-isobutyl-1H-pyrazole-4-carboxamide;

5-amino-3-(7-ethoxyquinolin-3-yl)-1-neopentyl-1H-pyrazole-4-carboxamide;

5-amino-3-(7-ethoxyquinolin-3-yl)-1-(2,2,2-trifluoroethyl)-1H-pyrazole-4-carboxamide;

5-amino-1-(cyclopropylmethyl)-3-(7-ethoxyquinolin-3-yl)-1H-pyrazole-4-carboxamide;

1-isobutyl-3-(2-(2,2,2-trifluoroethoxy)quinolin-6-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine;

5-amino-1-cyclopentyl-3-(7-ethoxyquinolin-3-yl)-1H-pyrazole-4-carboxamide;

5-amino-1-cyclohexyl-3-(7-ethoxyquinolin-3-yl)-1H-pyrazole-4-carboxamide;

5-amino-3-(7-ethoxyquinolin-3-yl)-1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazole-4-carboxamide;

5-amino-1-cycloheptyl-3-(7-ethoxyquinolin-3-yl)-1H-pyrazole-4-carboxamide;

5-amino-1-(cyclohexylmethyl)-3-(7-ethoxyquinolin-3-yl)-1H-pyrazole-4-carboxamide;

5-amino-3-(7-ethoxyquinolin-3-yl)-1-(1-hydroxypropan-2-yl)-1H-pyrazole-4-carboxamide;

5-amino-3-(7-ethoxyquinolin-3-yl)-1-(2-hydroxy-2-methylpropyl)-1H-pyrazole-4-carboxamide;

5-amino-3-(7-ethoxyquinolin-3-yl)-1-(4-hydroxybutan-2-yl)-1H-pyrazole-4-carboxamide;

5-amino-3-(7-ethoxyquinolin-3-yl)-1-(3-hydroxy-2,2-dimethylpropyl)-1H-pyrazole-4-carboxamide;

5-amino-1-(tert-butyl)-3-(2-ethoxyquinolin-6-yl)-1H-pyrazole-4-carboxamide;

5-amino-1-(cyclopropylmethyl)-3-(2-ethoxyquinolin-6-yl)-1H-pyrazole-4-carboxamide;

5-amino-1-cyclohexyl-3-(2-ethoxyquinolin-6-yl)-1H-pyrazole-4-carboxamide;

5-amino-1-cycloheptyl-3-(2-ethoxyquinolin-6-yl)-1H-pyrazole-4-carboxamide;

5-amino-3-(2-ethoxyquinolin-6-yl)-1-(3-hydroxy-2,2-dimethylpropyl)-1H-pyrazole-4-carboxamide;

5-amino-1-tert-butyl-3-(7-fluoroquinolin-3-yl)-1H-pyrazole-4-carboxamide;

5-amino-1-tert-butyl-3-(7-chloroquinolin-3-yl)-1H-pyrazole-4-carboxamide;

5-amino-1-tert-butyl-3-(7-(trifluoromethyl)quinolin-3-yl)-1H-pyrazole-4-carboxamide;

5-amino-1-tert-butyl-3-(7-methylquinolin-3-yl)-1H-pyrazole-4-carboxamide;

5-amino-1-(tert-butyl)-3-(7-ethylquinolin-3-yl)-1H-pyrazole-4-carboxamide;

5-amino-1-tert-butyl-3-(7-methoxyquinolin-3-yl)-1H-pyrazole-4-carboxamide;

5-amino-1-tert-butyl-3-(7-(trifluoromethoxy)quinolin-3-yl)-1H-pyrazole-4-carboxamide;

5-amino-1-(tert-butyl)-3-(7-isopropoxyquinolin-3-yl)-1H-pyrazole-4-carboxamide;

5-amino-1-tert-butyl-3-(7-propoxyquinolin-3-yl)-1H-pyrazole-4-carboxamide;

5-amino-1-(tert-butyl)-3-(7-(cyclopropylmethoxy)quinolin-3-yl)-1H-pyrazole-4-carboxamide;

5-amino-1-(tert-butyl)-3-(7-cyclopropoxyquinolin-3-yl)-1H-pyrazole-4-carboxamide;

5-amino-1-(tert-butyl)-3-(2-cyclopropoxyquinolin-6-yl)-1H-pyrazole-4-carboxamide;

5-amino-1-(tert-butyl)-3-(7-cyclobutoxyquinolin-3-yl)-1H-pyrazole-4-carboxamide;

5-amino-1-(tert-butyl)-3-(2-cyclobutoxyquinolin-6-yl)-1H-pyrazole-4-carboxamide;

5-amino-3-(7-cyclobutoxyquinolin-3-yl)-1-cyclobutyl-1H-pyrazole-4-carboxamide;

5-amino-3-(2-cyclobutoxyquinolin-6-yl)-1-cyclobutyl-1H-pyrazole-4-carboxamide;

5-amino-3-(7-cyclobutoxyquinolin-3-yl)-1-cyclopentyl-1H-pyrazole-4-carboxamide;

5-amino-3-(2-cyclobutoxyquinolin-6-yl)-1-cyclopentyl-1H-pyrazole-4-carboxamide;

5-amino-3-(7-cyclobutoxyquinolin-3-yl)-1-cyclohexyl-1H-pyrazole-4-carboxamide;

5-amino-3-(2-cyclobutoxyquinolin-6-yl)-1-cyclohexyl-1H-pyrazole-4-carboxamide;

5-amino-3-(7-cyclobutoxyquinolin-3-yl)-1-(3-hydroxy-2,2-dimethylpropyl)-1H-pyrazole-4-carboxamide;

5-amino-3-(2-cyclobutoxyquinolin-6-yl)-1-(3-hydroxy-2,2-dimethylpropyl)-1H-pyrazole-4-carboxamide;

5-amino-1-(tert-butyl)-3-(7-(2-methoxyethoxy)quinolin-3-yl)-1H-pyrazole-4-carboxamide;

5-amino-3-(7-ethoxyquinolin-3-yl)-1-(2-hydroxyethyl)-1H-pyrazole-4-carboxamide;

5-amino-1-(tert-butyl)-3-(7-(neopentyloxy)quinolin-3-yl)-1H-pyrazole-4-carboxamide;

5-amino-1-(tert-butyl)-3-(7-isobutoxyquinolin-3-yl)-1H-pyrazole-4-carboxamide;

5-amino-3-(7-ethoxyquinolin-3-yl)-1H-pyrazole-4-carboxamide;

5-amino-3-(7-ethoxyquinolin-3-yl)-1-(2-methoxyethyl)-1H-pyrazole-4-carboxamide;

5-amino-3-(7-ethoxyquinolin-3-yl)-N, 1-bis(2-methoxyethyl)-1H-pyrazole-4-carboxamide;

5-amino-1-(2,4-dimethylpentan-3-yl)-3-(7-ethoxyquinolin-3-yl)-1H-pyrazole-4-carboxamide;

6-(7-ethoxyquinolin-3-yl)-2-oxo-2,3-dihydro-1H-imidazo[1,2-b]pyrazole-7-carboxamide;

5-amino-3-(7-ethoxyquinolin-3-yl)-1-(3-hydroxybutan-2-yl)-1H-pyrazole-4-carboxamide;

5-amino-3-(7-ethoxyquinolin-3-yl)-1-(tetrahydrofuran-3-yl)-1H-pyrazole-4-carboxamide;

5-amino-3-(7-ethoxyquinolin-3-yl)-1-(3-hydroxy-3-methylbutan-2-yl)-1H-pyrazole-4-carboxamide;

5-amino-3-(7-ethoxyquinolin-3-yl)-1-(3-methylbutan-2-yl)-1H-pyrazole-4-carboxamide;

5-amino-1-(1,3-dihydroxypropan-2-yl)-3-(7-ethoxyquinolin-3-yl)-1H-pyrazole-4-carboxamide;

5-amino-1-(1-cyclopropylethyl)-3-(7-ethoxyquinolin-3-yl)-1H-pyrazole-4-carboxamide;

5-amino-3-(2-ethoxyquinolin-6-yl)-1-(tetrahydrofuran-3-yl)-1H-pyrazole-4-carboxamide;

5-amino-3-(2-ethoxyquinolin-6-yl)-1-(3-hydroxy-3-methylbutan-2-yl)-1H-pyrazole-4-carboxamide;

5-amino-3-(7-ethoxyquinolin-3-yl)-1-(4-hydroxy-3,3-dimethylbutan-2-yl)-1H-pyrazole-4-carboxamide;

5-amino-3-(7-ethoxyquinolin-3-yl)-1-(1-methylcyclohexyl)-1H-pyrazole-4-carboxamide;

5-amino-1-(tert-butyl)-3-(6-ethoxyquinolin-3-yl)-1H-pyrazole-4-carboxamide;

5-amino-1-cyclohexyl-3-(6-ethoxyquinolin-3-yl)-1H-pyrazole-4-carboxamide;

5-amino-3-(2-ethoxyquinolin-6-yl)-isopropyl-1H-pyrazole-4-carboxamide;

or pharmaceutically acceptable salt thereof.

16. A pharmaceutical composition comprising one or more of compounds according to claim 1 .

Assignments (2)

CONFIRMATORY LICENSE Recorded Oct 7, 2016

From: UNIVERSITY OF WASHINGTON

To: NATIONAL INSTITUTES OF HEALTH (NIH), U.S. DEPT. OF HEALTH AND HUMAN SERVICES (DHHS), U.S. GOVERNMENT

Reel/Frame 040289/0494 →

ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Nov 17, 2015

From: FAN, ERKANG; VAN VOORHIS, WESLEY C.; HUANG, WENLIN; ZHANG, ZHONGSHENG; OJO, KAYODE K.

To: UNIVERSITY OF WASHINGTON THROUGH ITS CENTER FOR COMMERCIALIZATION

Reel/Frame 037059/0295 →

Continuity (3)

Provisional Application 61825364 · May 20, 2013

Provisional Application 61889451 · Oct 10, 2013

Related Publication 20160090362A1 · Mar 31, 2016