IP Library Granted Patent US 10,611,768
Granted Patent B2
US 10,611,768 · App. 16/205,553 · Granted Apr 7, 2020

P2X

Inventors: Scott K. Thompson (Phoenixville, PA); Tony Priestley (West Chester, PA); Mrinalkanti Kundu (West Bengal, IN); Ashis Saha (Arlington, MA); Suvadeep Nath (Kolkata, IN)
Assignee: Asana BioSciences, LLC
C07D487/04C07D519/00
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Quick Facts
Patent No.
US 10,611,768
App. No.
16/205,553
Granted
Apr 7, 2020
Kind
B2
Abstract

The present disclosure provides novel compounds and methods for preparing and using these compounds. In one embodiment, the compounds are of the structure of formula (I), wherein R 1 -R 7 are defined herein. In a further embodiment, these compounds are useful in method for regulating one or both of the P2X 3 or P2X 2/3 receptors. In another embodiment, these compounds are useful for treating pain in patients by administering one or more of the compounds to a patient. In another embodiment, these compounds are useful for treating respiratory dysfunction in patients by administering one or more of the compounds to a patient.

Claims (183)

1. A compound of the structure of formula (I):

and prodrugs, enantiomers or pharmaceutically acceptable salts thereof, wherein:

R 1 is H, halogen, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, CN or CONH 2 ;

R 2 is none, optionally substituted C 1 -C 6 alkyl or aryl;

R 3 is substituted C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl or heterocycle;

R 4 is optionally substituted heteroaryl, optionally substituted C 1 -C 6 alkyl, optionally substituted C 3 -C 6 cycloalkyl or optionally substituted aryl;

R 5 , R 6 are independently H, C 1 -C 6 alkyl or C 3 -C 6 cycloalkyl; and

R 7 is optionally substituted piperazine, optionally substituted pyridine, optionally substituted pyridazine, optionally substituted pyrazole, optionally substituted triazole, optionally substituted tetrazole, optionally substituted pyrazole, substituted morpholine, or CONHR 8 , wherein R 8 is H, alkyl or cycloalkyl.

2. The compound according to claim 1 , wherein R 1 is H.

3. The compound according to claim 1 , wherein R 2 is optionally substituted C 1 -C 6 alkyl.

4. The compound according to claim 1 , wherein R 1 is halogen, C 1 -C 6 alkyl, or CN.

5. The compound according to claim 1 , wherein R 7 is selected from the group consisting of:

wherein: X is O or H 2 in a CH 2 group;

R 9 is H, optionally substituted C 1 -C 6 alkyl, CO(C 1 -C 6 alkyl), CONH 2 , C(NH)NH 2 , C(N—CN)NH 2 or SO 2 NH 2 ;

R 10 is H or alkyl optionally substituted with —OH;

R 11 is H, CH 2 —CONH 2 or alkyl optionally substituted with —OH or halogen; and

R 12 is H or CONH 2 .

6. The compound according to claim 1 , wherein R 4 is optionally substituted heteroaryl.

7. The compound according to claim 1 , wherein R 4 is optionally substituted aryl.

8. The compound according to claim 1 , wherein R 5 and R 6 are independently H or C 1 -C 6 alkyl or C 3 -C 6 cycloalkyl.

9. The compound according to claim 1 , wherein R 5 and R 6 are independently H or C 3 -C 6 cycloalkyl.

10. The compound according to claim 1 , wherein R 1 is H and R 2 is optionally substituted C 1 -C 6 alkyl.

11. The compound according to claim 1 , wherein R 1 is H, R 2 is optionally substituted C 1 -C 6 alkyl and R 4 is optionally substituted heteroaryl.

12. The compound according to claim 1 , wherein R 1 is H, R 2 is optionally substituted C 1 -C 6 alkyl, R 4 is optionally substituted heteroaryl, R 5 and R 6 are independently H or C 1 -C 6 alkyl or are independently H and C 3 -C 6 cycloalkyl, and R 7 is

wherein X is H 2 in a CH 2 group and R 9 is CONH 2 .

13. The compound according to claim 1 , wherein R 4 is an optionally substituted heteroaryl selected from the group consisting of quinoline, benzofuran, pyridine, benzothiophene, imidazopyridine and indazole.

14. A compound which is selected from the group consisting of:

1-{4-[2-Isopropyl-7-((R)-1-quinolin-3-yl-ethylamino)-2H-pyrazolo[4,3-d]pyrimidin-5-yl]-piperazin-1-yl}-ethanone;

1-{4-[2-Isopropyl-7-(1-quinolin-3-yl-ethylamino)-2H-pyrazolo[4,3-d]pyrimidin-5-yl]-piperazin-1-yl}-ethanone;

1-(4-{7-[2-(4-Chloro-phenyl)-1,1-dimethyl-ethylamino]-2-isopropyl-2H-pyrazolo[4,3-d]pyrimidin-5-yl}-piperazin-1-yl)-ethanone;

1-{4-[2-sec-Butyl-7-(1-quinolin-3-yl-ethylamino)-2H-pyrazolo[4,3-d]pyrimidin-5-yl]-piperazin-1-yl}-ethanone;

1-{4-[2-sec-Butyl-7-((R)-1-quinolin-3-yl-ethylamino)-2H-pyrazolo[4,3-d]pyrimidin-5-yl]-piperazin-1-yl}-ethanone;

1-(4-{2-sec-Butyl-7-[2-(4-chloro-phenyl)-1,1-dimethyl-ethylamino]-2H-pyrazolo[4,3-d]pyrimidin-5-yl}-piperazin-1-yl)-ethanone;

1-{4-[2-Isobutyl-7-((R)-1-quinolin-3-yl-ethylamino)-2H-pyrazolo[4,3-d]pyrimidin-5-yl]-piperazin-1-yl}-ethanone;

1-{4-[2-(1-Ethyl-propyl)-7-((R)-1-quinolin-3-yl-ethylamino)-2H-pyrazolo[4,3-d]pyrimidin-5-yl]-piperazin-1-yl}-ethanone;

1-{4-[2-Phenyl-7-((R)-1-quinolin-3-yl-ethylamino)-2H-pyrazolo[4,3-d]pyrimidin-5-yl]-piperazin-1-yl}-ethanone;

4-{1-sec-Butyl-7-[((R)-cyclopropyl-quinolin-3-yl-methyl)-amino]-1H-pyrazolo[4,3-d]pyrimidin-5-yl}-piperazine-1-carboxylic acid amide;

1-{4-[1-Isopropyl-4-(1-quinolin-3-yl-ethylamino)-1H-pyrazolo[3,4-d]pyrimidin-6-yl]-piperazin-1-yl}-ethanone;

1-{4-[1-Isopropyl-7-((R)-1-quinolin-3-yl-ethylamino)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-piperazin-1-yl}-ethanone;

1-(4-{7-[2-(4-Chloro-phenyl)-1,1-dimethyl-ethylamino]-1-isopropyl-1H-pyrazolo[4,3-d]pyrimidin-5-yl}-piperazin-1-yl)-ethanone;

1-(4-{1-Isopropyl-7-[(quinolin-3-ylmethyl)-amino]-1H-pyrazolo[4,3-d]pyrimidin-5-yl}-piperazin-1-yl)-ethanone;

4-[1-Isopropyl-7-((R)-1-quinolin-3-yl-ethylamino)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-1-methyl-piperazin-2-one;

1-{4-[1-Isobutyl-7-((R)-1-quinolin-3-yl-ethylamino)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-piperazin-1-yl}-ethanone;

1-{4-[1-Isopropyl-7-((S)-1-quinolin-3-yl-ethylamino)-2H-pyrazolo[4,3-d]pyrimidin-5-yl]-piperazin-1-yl}-ethanone;

1-{4-[1-sec-Butyl-7-((S)-1-quinolin-3-yl-ethylamino)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-piperazin-1-yl}-ethanone;

1-{4-[1-((S)-sec-Butyl)-7-((R)-1-quinolin-3-yl-ethylamino)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-piperazin-1-yl}-ethanone;

4-[1-sec-Butyl-7-((R)-1-quinolin-3-yl-ethylamino)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-1-methyl-piperazin-2-one;

1-{4-[1-((R)-sec-Butyl)-7-((R)-1-quinolin-3-yl-ethylamino)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-piperazin-1-yl}-ethanone;

1-{4-[1-(1-Ethyl-propyl)-7-((R)-1-quinolin-3-yl-ethylamino)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-piperazin-1-yl}-ethanone;

1-Ethyl-4-[1-isopropyl-7-((R)-1-quinolin-3-yl-ethylamino)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-piperazin-2-one;

1-{4-[1-(2-Methoxy-1-methyl-ethyl)-7-((R)-1-quinolin-3-yl-ethylamino)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-piperazin-1-yl}-ethanone;

1-{4-[1-Cyclopentyl-7-((R)-1-quinolin-3-yl-ethylamino)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-piperazin-1-yl}-ethanone;

1-{4-[7-((R)-1-Quinolin-3-yl-ethylamino)-1-(tetrahydro-pyran-4-ylmethyl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-piperazin-1-yl}-ethanone;

1-{4-[7-((R)-1-Quinolin-3-yl-ethylamino)-1-(tetrahydro-pyran-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-piperazin-1-yl}-ethanone;

1-{4-[1-Hexyl-7-((R)-1-quinolin-3-yl-ethylamino)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-piperazin-1-yl}-ethanone;

1-{4-[7-{[1-(4-Chloro-phenyl)-cyclobutylmethyl]-amino}-1-(1-ethyl-propyl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-piperazin-1-yl}-ethanone;

1-{4-[7-[1-(4-Ethoxy-phenyl)-ethylamino]-1-(1-ethyl-propyl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-piperazin-1-yl}-ethanone;

1-[4-(1-sec-Butyl-7-{[1-(4-chloro-phenyl)-cyclobutylmethyl]-amino}-1H-pyrazolo[4,3-d]pyrimidin-5-yl)-piperazin-1-yl]-ethanone;

1-{4-[1-Cyclobutylmethyl-7-((R)-1-quinolin-3-yl-ethylamino)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-piperazin-1-yl}-ethanone;

1-{4-[7-[(S)-1-(4-Ethoxy-phenyl)-ethylamino]-1-(1-ethyl-propyl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-piperazin-1-yl}-ethanone;

1-{4-[1-Dicyclopropylmethyl-7-((R)-1-quinolin-3-yl-ethylamino)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-piperazin-1-yl}-ethanone;

1-{4-[1-(1-Ethyl-propyl)-7-((R)-1-quinolin-3-yl-propylamino)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-piperazin-1-yl}-ethanone;

1-{4-[1-(1-Ethyl-propyl)-7-((S)-1-quinolin-3-yl-propylamino)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-piperazin-1-yl}-ethanone;

1-{4-[1-Isopropyl-7-((R)-1-quinolin-3-yl-ethylamino)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-piperazin-1-yl}-propan-1-one;

1-{4-[1-sec-Butyl-7-((R)-1-quinolin-3-yl-ethylamino)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-piperazin-1-yl}-propan-1-one;

1-{4-[7-(1-Benzofuran-5-yl-ethylamino)-1-(1-ethyl-propyl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-piperazin-1-yl}-ethanone;

1-{4-[1-(1-Ethyl-propyl)-7-((R)-1-naphthalen-2-yl-ethylamino)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-piperazin-1-yl}-ethanone;

4-[1-Isopropyl-7-((R)-1-quinolin-3-yl-ethylamino)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-piperazin-2-one;

1-(4-{1-(1-Ethyl-propyl)-7-[1-(6-fluoro-quinolin-3-yl)-ethylamino]-1H-pyrazolo[4,3-d]pyrimidin-5-yl}-piperazin-1-yl)-ethanone;

1-{4-[1-sec-Butyl-7-((R)-1-quinolin-3-yl-propylamino)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-piperazin-1-yl}-ethanone;

1-{4-[7-[((R)-Cyclopropyl-quinolin-3-yl-methyl)-amino]-1-(1-ethyl-propyl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-piperazin-1-yl}-ethanone;

1-(4-{1-sec-Butyl-7-[1-(2-methyl-benzofuran-5-yl)-ethylamino]-1H-pyrazolo[4,3-d]pyrimidin-5-yl}-piperazin4.6-1-yl)-ethanone;

1-(4-{1-(1-Ethyl-propyl)-7-[1-(2-methyl-benzofuran-5-yl)-ethylamino]-1H-pyrazolo[4,3-d]pyrimidin-5-yl}-piperazin-1-yl)-ethanone;

1-(4-{1-(1-Ethyl-propyl)-7-[1-(4-isopropoxy-phenyl)-ethylamino]-1H-pyrazolo[4,3-d]pyrimidin-5-yl}-piperazin-1-yl)-ethanone;

1-{4-[1-Cyclobutyl-7-((R)-1-quinolin-3-yl-ethylamino)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-piperazin-1-yl}-ethanone;

4-[1-Cyclobutyl-7-((R)-1-quinolin-3-yl-ethylamino)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-1-methyl-piperazin-2-one;

1-{4-[1-Ethyl-7-((R)-1-quinolin-3-yl-ethylamino)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-piperazin-1-yl}-ethanone;

4-[1-(1-Ethyl-propyl)-7-((R)-1-quinolin-3-yl-ethylamino)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-piperazine-1-carboxylic acid amide;

1-(4-{1-sec-Butyl-7-[1-(6-phenyl-pyridin-3-yl)-ethylamino]-1H-pyrazolo[4,3-d]pyrimidin-5-yl}-piperazin-1-yl)-ethanone;

1-(4-{1-sec-Butyl-7-[1-(4-pyridin-2-yl-phenyl)-ethylamino]-1H-pyrazolo[4,3-d]pyrimidin-5-yl}-piperazin-1-yl)-ethanone;

1-(4-{1-(1-Ethyl-propyl)-7-[(R)-1-(6-fluoro-quinolin-3-yl)-ethylamino]-1H-pyrazolo[4,3-d]pyrimidin-5-yl}-piperazin-1-yl)-ethanone;

1-{4-[7-[1-(2-Cyclopropyl-benzofuran-5-yl)-ethylamino]-1-(1-ethyl-propyl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-piperazin-1-yl}-ethanone;

1-(4-{1-sec-Butyl-7-[((R)-cyclopropyl-quinolin-3-yl-methyl)-amino]-1H-pyrazolo[4,3-d]pyrimidin-5-yl}-piperazin-1-yl)-ethanone;

1-{4-[7-(1-Benzo[b]thiophen-5-yl-ethylamino)-1-(1-ethyl-propyl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-piperazin-1-yl}-ethanone;

1-[4-(1-sec-Butyl-7-{[cyclopropyl-(6-phenyl-pyridin-3-yl)-methyl]-amino}-1H-pyrazolo[4,3-d]pyrimidin-5-yl)-piperazin-1-yl]-ethanone;

4-{7-[((R)-Cyclopropyl-quinolin-3-yl-methyl)-amino]-1-isopropyl-1H-pyrazolo[4,3-d]pyrimidin-5-yl}-1-methyl-piperazin-2-one;

1-{4-[1-(1,2-Dimethyl-propyl)-7-((R)-1-quinolin-3-yl-ethylamino)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-piperazin-1-yl}-ethanone;

1-(4-{1-(1-Ethyl-propyl)-7-[(R)-1-(6-fluoro-quinolin-3-yl)-ethylamino]-1H-pyrazolo[4,3-d]pyrimidin-5-yl}-piperazin-1-yl)-ethanone

1-{4-[7-[((R)-Cyclopropyl-quinolin-3-yl-methyl)-amino]-1-(1,2-dimethyl-propyl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-piperazin-1-yl}-ethanone;

1-{4-[7-{[Cyclopropyl-(6-cyclopropylmethoxy-pyridin-3-yl)-methyl]-amino}-1-(1-ethyl-propyl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-piperazin-1-yl}-ethanone;

4-{1-(1-Ethyl-propyl)-7-[(quinolin-3-ylmethyl)-amino]-1H-pyrazolo[4,3-d]pyrimidin-5-yl}-piperazine-1-carboxylic acid amide;

1-{4-[7-{[Cyclopropyl-(6-fluoro-quinolin-3-yl)-methyl]-amino}-1-(1-ethyl-propyl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-piperazin-1-yl}-ethanone;

4-{7-[((R)-Cyclopropyl-quinolin-3-yl-methyl)-amino]-1-isopropyl-1H-pyrazolo[4,3-d]pyrimidin-5-yl}-piperazine-1-carboxylic acid amide;

4-{1-((S)-sec-Butyl)-7-[(cyclopropyl-imidazo[1,2-a]pyridin-6-yl-methyl)-amino]-1H-pyrazolo[4,3-d]pyrimidin-5-yl}-piperazine-1-carboxylic acid amide;

4-{1-((S)-sec-Butyl)-7-[1-(6,7-difluoro-quinolin-3-yl)-ethylamino]-1H-pyrazolo[4,3-d]pyrimidin-5-yl}-piperazine-1-carboxylic acid amide;

4-{1-((S)-sec-Butyl)-7-[((R)-cyclopropyl-quinolin-3-yl-methyl)-amino]-1H-pyrazolo[4,3-d]pyrimidin-5-yl}-piperazine-1-carboxylic acid amide;

4-{1-((R)-sec-Butyl)-7-[((R)-cyclopropyl-quinolin-3-yl-methyl)-amino]-1H-pyrazolo[4,3-d]pyrimidin-5-yl}-piperazine-1-carboxylic acid amide;

4-{1-((S)-sec-Butyl)-7-[1-(1H-indazol-3-yl)-ethylamino]-1H-pyrazolo[4,3-d]pyrimidin-5-yl}-piperazine-1-carboxylic acid amide;

4-[7-[((R)-Cyclopropyl-quinolin-3-yl-methyl)-amino]-1-(tetrahydro-pyran-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-piperazine-1-carboxylic acid amide;

4-[1-((S)-sec-Butyl)-7-(1-pyrazolo[1,5-a]pyridin-2-yl-ethylamino)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-piperazine-1-carboxylic acid amide;

((R)-Cyclopropyl-quinolin-3-yl-methyl)-[1-(1-ethyl-propyl)-5-[1,2,3]triazol-1-yl-1H-pyrazolo[4,3-d]pyrimidin-7-yl]-amine;

1-{1-sec-Butyl-7-[((R)-cyclopropyl-quinolin-3-yl-methyl)-amino]-1H-pyrazolo[4,3-d]pyrimidin-5-yl}-piperidine-4-carboxylic acid amide;

4-{1-sec-Butyl-7-[((R)-cyclopropyl-quinolin-3-yl-methyl)-amino]-1H-pyrazolo[4,3-d]pyrimidin-5-yl}-morpholine-2-carbonitrile;

1-{4-[1-sec-Butyl-3-methyl-7-((R)-1-quinolin-3-yl-ethylamino)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-piperazin-1-yl}-ethanone;

(1-sec-Butyl-5-[1,2,4]triazol-1-yl-1H-pyrazolo[4,3-d]pyrimidin-7-yl)-((R)-cyclopropyl-quinolin-3-yl-methyl)-amine;

(1-sec-Butyl-5-tetrazol-1-yl-1H-pyrazolo[4,3-d]pyrimidin-7-yl)-((R)-cyclopropyl-quinolin-3-yl-methyl)-amine;

(1-sec-Butyl-5-tetrazol-2-yl-1H-pyrazolo[4,3-d]pyrimidin-7-yl)-((R)-cyclopropyl-quinolin-3-yl-methyl)-amine;

4-(1-((S)-sec-Butyl)-7-{[cyclopropyl-(1-ethyl-1H-indazol-5-yl)-methyl]-amino}-1H-pyrazolo[4,3-d]pyrimidin-5-yl)-piperazine-1-carboxylic acidamide;

1-{4-[1-((S)-sec-Butyl)-7-(2-hydroxy-1-quinolin-3-yl-ethylamino)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-piperazin-1-yl}-ethanone;

1-{4-[1-((S)-sec-Butyl)-7-(2-methoxy-1-quinolin-3-yl-ethylamino)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-piperazin-1-yl}-ethanone;

4-{1-((S)-sec-Butyl)-7-[(cyclopropyl-quinoxalin-2-yl-methyl)-amino]-1H-pyrazolo[4,3-d]pyrimidin-5-yl}-piperazine-1-carboxylic acid amide;

4-{1-sec-Butyl-7-[(R)-1-(7-methyl-imidazo[1,2-a]pyridin-2-yl)-ethylamino]-1H-pyrazolo[4,3-d]pyrimidin-5-yl}-piperazine-1-carboxylic acid amide;

4-[1-sec-Butyl-7-((R)-1-quinolin-3-yl-ethylamino)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-piperazine-1-carboxylic acid amide;

4-{1-(1-Cyclopropyl-ethyl)-7-[((R)-cyclopropyl-quinolin-3-yl-methyl)-amino]-1H-pyrazolo[4,3-d]pyrimidin-5-yl}-piperazine-1-carboxylic acid amide;

1-sec-Butyl-7-[((R)-cyclopropyl-quinolin-3-yl-methyl)-amino]-1H-pyrazolo[4,3-d]pyrimidine-5-carboxylic acid amide;

1-{4-[1-sec-Butyl-7-((R)-1-quinolin-3-yl-ethylamino)-2H-pyrazolo[4,3-d]pyrimidin-5-yl]-piperazin-1-yl}-ethanone;

1-{4-[3-Bromo-1-sec-butyl-7-((R)-1-quinolin-3-yl-ethylamino)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-piperazin-1-yl}-ethanone;

5-(4-Acetyl-piperazin-1-yl)-1-sec-butyl-7-((R)-1-quinolin-3-yl-ethylamino)-1H-pyrazolo[4,3-d]pyrimidine-3-carbonitrile;

1-{4-[1-sec-Butyl-3-cyclopropyl-7-((R)-1-quinolin-3-yl-ethylamino)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-piperazin-1-yl}-ethanone;

1-{4-[3-Bromo-2-isopropyl-7-(1-quinolin-3-yl-ethylamino)-2H-pyrazolo[4,3-d]pyrimidin-5-yl]-piperazin-1-yl}-ethanone;

5-(4-Acetyl-piperazin-1-yl)-2-isopropyl-7-(1-quinolin-3-yl-ethylamino)-2H-pyrazolo[4,3-d]pyrimidine-3-carboxylic acid amide;

1-{4-[2-Isopropyl-3-methyl-7-(1-quinolin-3-yl-ethylamino)-2H-pyrazolo[4,3-d]pyrimidin-5-yl]-piperazin-1-yl}-ethanone;

1-(4-{3-Bromo-7-[2-(4-chloro-phenyl)-1,1-dimethyl-ethylamino]-2-isopropyl-2H-pyrazolo[4,3-d]pyrimidin-5-yl}-piperazin-1-yl)-ethanone;

1-{4-[3-Bromo-2-isopropyl-7-((R)-1-quinolin-3-yl-ethylamino)-2H-pyrazolo[4,3-d]pyrimidin-5-yl]-piperazin-1-yl}-ethanone;

1-{4-[3-Chloro-2-isopropyl-7-((R)-1-quinolin-3-yl-ethylamino)-2H-pyrazolo[4,3-d]pyrimidin-5-yl]-piperazin-1-yl}-ethanone;

1-{4-[3-Bromo-1-isopropyl-7-((R)-1-quinolin-3-yl-ethylamino)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-piperazin-1-yl}-ethanone;

1-(4-{7-[2-(4-Chloro-phenyl)-1,1-dimethyl-ethylamino]-2-isopropyl-3-methyl-2H-pyrazolo[4,3-d]pyrimidin-5-yl}-piperazin-1-yl)-ethanone;

1-{4-[2-Isopropyl-3-methyl-7-((R)-1-quinolin-3-yl-ethylamino)-2H-pyrazolo[4,3-d]pyrimidin-5-yl]-piperazin-1-yl}-ethanone;

5-(4-Acetyl-piperazin-1-yl)-2-isopropyl-7-((R)-1-quinolin-3-yl-ethylamino)-2H-pyrazolo[4,3-d]pyrimidine-3-carbonitrile;

5-(4-Acetyl-piperazin-1-yl)-1-isopropyl-7-((R)-1-quinolin-3-yl-ethylamino)-1H-pyrazolo[4,3-d]pyrimidine-3-carbonitrile;

1-{4-[3-Bromo-2-sec-butyl-7-((R)-1-quinolin-3-yl-ethylamino)-2H-pyrazolo[4,3-d]pyrimidin-5-yl]-piperazin-1-yl}-ethanone;

5-(4-Acetyl-piperazin-1-yl)-2-sec-butyl-7-((R)-1-quinolin-3-yl-ethylamino)-2H-pyrazolo[4,3-d]pyrimidine-3-carbonitrile;

1-{4-[3-Cyclopropyl-2-isopropyl-7-((R)-1-quinolin-3-yl-ethylamino)-2H-pyrazolo[4,3-d]pyrimidin-5-yl]-piperazin-1-yl}-ethanone;

4-{1-sec-Butyl-7-[((R)-cyclopropyl-quinolin-3-yl-methyl)-amino]-1H-pyrazolo[4,3-d]pyrimidin-5-yl}-piperazine-1-sulfonic acid amide;

2-(4-{1-sec-Butyl-7-[((R)-cyclopropyl-quinolin-3-yl-methyl)-amino]-1H-pyrazolo[4,3-d]pyrimidin-5-yl}-piperazin-1-yl)-acetamide;

4-{1-sec-Butyl-7-[((R)-cyclopropyl-quinolin-3-yl-methyl)-amino]-1H-pyrazolo[4,3-d]pyrimidin-5-yl}-N′-cyanopiperazine-1-carboximidamide;

4-(1-sec-butyl-7-{[(R)-methyl(quinolin-3-yl)methyl]amino}-1H-pyrazolo[4,3-d]pyrimidin-5-yl)-N′-cyanopiperazine-1-carboximidamide;

4-{1-sec-Butyl-7-[((R)-cyclopropyl-quinolin-3-yl-methyl)-amino]-1H-pyrazolo[4,3-d]pyrimidin-5-yl}-piperazine-1-carboxamidine;

2-{4-[1-sec-Butyl-7-((R)-1-quinolin-3-yl-ethylamino)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-pyrazol-1-yl}-ethanol;

[1-sec-Butyl-5-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-7-yl]-((R)-cyclopropyl-quinolin-3-yl-methyl)-amine;

[1-sec-Butyl-5-(1-ethyl-1H-pyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-7-yl]-((R)-cyclopropyl-quinolin-3-yl-methyl)-amine;

{1-sec-Butyl-5-[1-(2-fluoro-ethyl)-1H-pyrazol-4-yl]-1H-pyrazolo[4,3-d]pyrimidin-7-yl}-((R)-cyclopropyl-quinolin-3-yl-methyl)-amine;

(R)-Cyclopropyl-quinolin-3-yl-methyl)-[5-(1-methyl-1H-pyrazol-4-yl)-1-(tetrahydro-pyran-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-7-yl]-amine;

4-{1-sec-Butyl-7-[((R)-cyclopropyl-quinolin-3-yl-methyl)-amino]-1H-pyrazolo[4,3-d]pyrimidin-5-yl}-piperidine-1-carboxylic acid amide;

[1-sec-Butyl-5-(1H-pyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-7-yl]-((R)-cyclopropyl-quinolin-3-yl-methyl)-amine;

2-(4-{1-sec-Butyl-7-[((R)-cyclopropyl-quinolin-3-yl-methyl)-amino]-1H-pyrazolo[4,3-d]pyrimidin-5-yl}-pyrazol-1-yl)-acetamide;

2-(4-{1-sec-Butyl-7-[((R)-cyclopropyl-quinolin-3-yl-methyl)-amino]-1H-pyrazolo[4,3-d]pyrimidin-5-yl}-pyrazol-1-yl)-ethanol;

2-{1-((S)-sec-Butyl)-5-[1-(2-fluoro-ethyl)-1H-pyrazol-4-yl]-1H-pyrazolo[4,3-d]pyrimidin-7-ylamino}-2-quinolin-3-yl-ethanol;

{1-sec-Butyl-5-[1-(2-fluoro-ethyl)-1H-pyrazol-4-yl]-1H-pyrazolo[4,3-d]pyrimidin-7-yl}-[(R)-1-(7-methyl-imidazo[1,2-a]pyridin-2-yl)-ethyl]-amine;

4-[1-((S)-sec-Butyl)-7-(2-hydroxy-1-quinolin-3-yl-ethylamino)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-piperazine-1-carboxylic acid amide;

1-sec-Butyl-7-[((R)-cyclopropyl-quinolin-3-yl-methyl)-amino]-1H-pyrazolo[4,3-d]pyrimidine-5-carboxylic acid cyclopropylamide;

[1-sec-Butyl-5-(5-methyl-[1,3,4]oxadiazol-2-yl)-1H-pyrazolo[4,3-d]pyrimidin-7-yl]-((R)-cyclopropyl-quinolin-3-yl-methyl)-amine;

1-{1-sec-Butyl-7-[((R)-cyclopropyl-quinolin-3-yl-methyl)-amino]-1H-pyrazolo[4,3-d]pyrimidin-5-yl}-1H-[1,2,3]triazole-4-carboxylic acid amide; and

(1-sec-Butyl-5-pyridazin-3-yl-1H-pyrazolo[4,3-d]pyrimidin-7-yl)-((R)-cyclopropyl-quinolin-3-yl-methyl)-amine.

15. A pharmaceutical composition comprising a compound of claim 1 and a pharmaceutically acceptable excipient.

16. A kit comprising a compound of claim 1 .

17. A kit comprising the pharmaceutical composition of claim 15 .

18. A method for regulating one or both of P2X 3 or P2X 2/3 receptors in a subject in need thereof, said method comprising administering a therapeutically effective amount of a compound of claim 1 to the subject.

19. The method according to claim 18 , wherein said regulating comprises inhibition of one or both of the P2X 3 or P2X 2/3 receptors.

20. A method for treating pain in a subject, comprising administering a therapeutically effective amount of a compound of claim 1 to said patient.

21. The method of claim 20 , wherein the pain is nociceptive, dysfunctional, idiopathic, neuropathic, somatic, central, visceral, inflammatory, or procedural pain.

22. The method of claim 20 , wherein the pain is caused by airway, bladder or visceral organ dysfunction.

23. The method of claim 20 , wherein the pain is a migraine, back pain, neck pain, gynecological pain, pre-labor pain, labor pain, orthopedic pain, post-stroke pain, post-surgical pain, post herpetic neuralgia, sickle cell crisis, interstitial cystitis, urological pain, dental pain, headache, wound pain, surgical pain, suturing, fracture setting pain, or pain incident to biopsy.

24. The method of claim 20 , wherein the pain is due to inflammation, nerve compression, or a mechanical force resulting from tissue distension as a consequence of invasion by a tumor into a tissue.

25. The method of claim 20 , wherein the pain is caused by esophageal cancer, colitis, cystitis, irritable bowel syndrome or idiopathic neuropathy.

26. The method of claim 21 , wherein the somatic pain comprises pain from bone, joint, muscle, skin or connective tissue.

27. The method of claim 21 , wherein the central pain comprises pain from brain trauma, stroke or spinal cord injury.

28. The method of claim 21 , wherein the visceral pain comprises pain from the respiratory tract, gastrointestinal tract, pancreas, urinary tract or reproductive organs.

29. The method of claim 21 , wherein the dysfunctional pain comprises pain from a rheumatologic condition, tension type headache, irritable bowel disorder or erythermalgia.

30. The method of claim 21 , wherein the nociceptive pain comprises pain from a cut, bruise, bone fracture, crush injury, burn, trauma, surgery, labor, sprain, bump, injection, dental procedure, skin biopsy or obstruction.

31. The method of claim 21 , wherein the neuropathic pain comprises pain due to trauma, surgery, herniation of an intervertebral disk, spinal cord injury, diabetes, infection with herpes zoster, HIV/AIDS, late-stage cancer, amputation, carpal tunnel syndrome, chronic alcohol use, exposure to radiation, or an unintended side-effect of a neurotoxic treatment agent.

32. The method of claim 21 , wherein the inflammatory pain comprises pain due to joint injury, muscle injury, tendon injury, surgical procedures, infection or arthritis.

33. The method of claim 21 , wherein the procedural pain comprises pain from a medical, dental or surgical procedure.

34. The method of claim 33 , wherein the procedural pain is postoperative pain, associated with an injection, draining an abscess, surgery, dermatological, dental procedure, ophthalmic procedure, arthroscopy or cosmetic surgery.

35. The method of claim 20 , wherein the pain is caused by cancer.

36. The method of claim 35 , wherein the cancer is bone cancer.

37. The method of claim 20 , wherein the administration is oral, intramuscular, rectal, cutaneous, subcutaneous, topical, transdermal, sublingual, nasal, vaginal, epidural, intrathecal, intravesical or ocular.

38. A method for treating a respiratory dysfunction in a subject in need thereof, said method comprising administering a therapeutically effective amount of a compound of claim 1 to the subject.

39. The method of claim 38 , wherein the respiratory dysfunction is one or more of bronchial hyperactivity, bronchoconstriction, bronchospasm, hypersecretion, cough, cough hypersensitivity syndrome, wheezing, dyspnea, breathlessness and chest tightness.

40. The method of claim 38 , wherein the respiratory dysfunction is caused by idiopathic pulmonary fibrosis (IPF), chronic obstructive pulmonary disease (COPD), asthma, upper respiratory infection, interstitial lung disease (ILD), post-nasal drip, bronchitis, gastroesophageal reflux disease (GERD), treatment with an ACE (Angiotensin Converting Enzyme) inhibitor or smoking.

41. The method of claim 39 , wherein the cough is acute cough, sub-acute cough, chronic cough, pathologic cough, or the urge to cough.

42. The method of claim 39 , wherein the cough is caused by idiopathic pulmonary fibrosis (IPF), chronic obstructive pulmonary disease (COPD), asthma, upper respiratory infection, interstitial lung disease (ILD), post-nasal drip, bronchitis, gastroesophageal reflux disease (GERD), treatment with an ACE (Angiotensin Converting Enzyme) inhibitor or smoking.

43. The method of claim 38 , wherein the administration is oral, intramuscular, rectal, cutaneous, subcutaneous, topical, transdermal, sublingual, nasal, vaginal, epidural, intrathecal, intravesical, ocular or inhalation.

Assignments (3)
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Mar 22, 2024
From: ABS DEVELOPMENT 1, INC.
To: ASANA BIOSCIENCES, LLC
Reel/Frame 066867/0051 →
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded May 20, 2022
From: ASANA BIOSCIENCES, LLC
To: ABS DEVELOPMENT 1, INC.
Reel/Frame 059968/0937 →
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Nov 30, 2018
From: THOMPSON, SCOTT K.; PRIESTLEY, TONY; KUNDU, MRINALKANTI; SAHA, ASHIS; NATH, SUVADEEP
To: ASANA BIOSCIENCES, LLC
Reel/Frame 047634/0321 →