Triazole derivatives as P2Y14 receptor antagonists

Patent metadata

Field	Value
Publication number	US-10683277-B2
Application number	US-201615762852-A
Country	US
Kind code	B2
Filing date	Sep 23, 2016
Priority date	Sep 25, 2015
Publication date	Jun 16, 2020
Grant date	Jun 16, 2020

Abstract

Described are compounds, which are antagonists of the P2Y 14 receptor, for example, a compound of formula (I) in which ring A, R 1 , R 2 , R 3 , and n are as described herein. Also provided are dendron conjugates comprising the compounds, and methods of using the compounds, including a method of treating a disorder, such as inflammation, diabetes, insulin resistance, hyperglycemia, a lipid disorder, obesity, a condition associated with metabolic syndrome, and asthma, and a method of antagonizing P2 14 receptor activity in a cell.

First claim

The invention claimed is:

1. A compound of formula (I), formula (II), formula (III), or formula (IV), wherein
(a) the compound of formula (I) is of the formula:

wherein
ring A is aryl, heteroaryl, or cycloalkyl;
R 1 is CO 2 H, —CO 2 (C 1 -C 8 alkyl), or a bioisostere of carboxylate;
R 2 is H, C 1 -C 8 alkyl, C 2 -C 8 alkenyl, C 2 -C 8 alkynyl, C 3 -C 6 cycloalkyl, C 3 -C 6 cycloalkylalkyl, hydroxyalkyl, C 1 -C 8 haloalkyl, cyanoalkyl, aryl, heteroaryl, heterocycloalkyl, —(CH 2 ) m aryl, —(CH 2 ) m heteroaryl, or —(CH 2 ) m heterocycloalkyl;
each R 3 is the same or different and each is C 1 -C 8 alkyl, C 2 -C 8 alkenyl, C 3 -C 6 cycloalkyl, hydroxy, hydroxyalkyl, C 1 -C 8 alkoxy, C 3 -C 6 cycloalkyloxy, aryloxy, halo, C 1 -C 8 haloalkyl, C 1 -C 8 haloalkoxy, —CN, —NO 2 , —NR 5 R 6 , —C(O)R 4 , —CO 2 R 4 , —C(O)NR 5 R 6 , —NR 5 C(O)R 4 , —(CH 2 ) m aryl, —(CH 2 ) m heteroaryl, or —(CH 2 ) m heterocycloalkyl;
R 4 , R 5 , and R 6 are the same or different and each is H or C 1 -C 8 alkyl; and
m and n are the same or different and each is 0 or an integer from 1-5;

or a pharmaceutically acceptable salt thereof;
(b) the compound of formula (II) is of the formula:

wherein
ring A′ is aryl, heteroaryl, or cycloalkyl;
R 1′ is CO 2 H, —CO 2 (C 1 -C 8 alkyl), or a bioisostere of carboxylate;
R 2′ is H, C 1 -C 8 alkyl, C 2 -C 8 alkenyl, C 2 -C 8 alkynyl, C 3 -C 6 cycloalkyl, C 3 -C 6 cycloalkylalkyl, hydroxyalkyl, C 1 -C 8 haloalkyl, cyanoalkyl, aryl, heteroaryl, heterocycloalkyl, —(CH 2 ) m′ aryl, —(CH 2 ) m′ heteroaryl, or —(CH 2 ) m′ heterocycloalkyl;
each R 3′ is the same or different and each is C 1 -C 8 alkyl, C 2 -C 8 alkenyl, C 3 -C 6 cycloalkyl, hydroxy, hydroxyalkyl, C 1 -C 8 alkoxy, C 3 -C 6 cycloalkyloxy, aryloxy, halo, C 1 -C 8 haloalkyl, C 1 -C 8 haloalkoxy, —CN, —NO 2 , —NR 5′ R 6′ , —C(O)R 4′ , —CO 2R 4′ , —C(O)NR 5′ R 6′ , —NR 5′ C(O)R 4′ , —(CH 2 ) m′ aryl, —(CH 2 ) m′ heteroaryl, or —(CH 2 ) m′ heterocycloalkyl;
R 4′ , R 5′ , and R 6′ are the same or different and each is H or C 1 -C 8 alkyl; and
m′ and n′ are the same or different and each is 0 or an integer from 1-5;

or a pharmaceutically acceptable salt thereof;
(c) the compound of formula (III) is a conjugate of the formula:

or a pharmaceutically acceptable salt thereof, wherein
ring A is aryl, heteroaryl, or cycloalkyl;
R 1 is —CO 2 H, —CO 2 (C 1 -C 8 alkyl), or a bioisostere of carboxylate;
each R 3 is the same or different and each is C 1 -C 8 alkyl, C 2 -C 8 alkenyl, C 3 -C 6 cycloalkyl, hydroxy, hydroxyalkyl, C 1 -C 8 alkoxy, C 3 -C 6 cycloalkyloxy, aryloxy, halo, C 1 -C 8 haloalkyl, C 1 -C 8 haloalkoxy, —CN, —NO 2 , —NR 5 R 6 , —C(O)R 4 , —CO 2 R 4 , —C(O)NR 5 R 6 , —NR 5 C(O)R 4 , —(CH 2 ) m aryl, —(CH 2 ) m heteroaryl, or —(CH 2 ) m heterocycloalkyl;
R 4 , R 5 , and R 6 are the same or different and each is H or C 1 -C 8 alkyl;
X 1 is selected from the group consisting of —(CH 2 ) o —, —C(O)—, —C(O)NH—, —OC(O)NH—, —OC(O)—, —C(O)O—, —C(S)NH—, and —SO 2 —;
X 2 is selected from the group consisting of

R 7 is CH 2 , NH, or O;
X 3 is a dendron;
X 4 is selected from the group consisting of —(CH 2 ) o —, —C(O)—, —C(O)NH—, —OC(O)NH—, —OC(O)—, —C(O)O—, —C(S)NH—, —SO 2 —, —NHC(O)—, and

X 5 is a reactive sulfur-containing moiety;
m, n, and q are the same or different and each is 0 or an integer from 1-5;
o is an integer from 1-5; and
p is 0 or an integer from 1-36;

wherein X 5 is optionally linked to a particle; and
(d) the compound of formula (IV) is a dendron conjugate of the formula:

or a pharmaceutically acceptable salt thereof, wherein
ring A′ is aryl, heteroaryl, or cycloalkyl;
R 1′ is —CO 2 H, —CO 2 (C 1 -C 8 alkyl), or a bioisostere of carboxylate;
each R 3′ is the same or different and each is C 1 -C 8 alkyl, C 2 -C 8 alkenyl, C 3 -C 6 cycloalkyl, hydroxy, hydroxyalkyl, C 1 -C 8 alkoxy, C 3 -C 6 cycloalkyloxy, aryloxy, halo, C 1 -C 8 haloalkyl, C 1 -C 8 haloalkoxy, —CN, —NO 2 , —NR 5′ R 6′ , —C(O)R 4′ , —CO 2R 4′ , —C(O)NR 5′ R 6′ , —NR 5′ C(O)R 4′ , —(CH 2 ) m′ aryl, —(CH 2 ) m′ heteroaryl, or —(CH 2 ) m′ heterocycloalkyl;
R 4′ , R 5′ , and R 6′ are the same or different and each is H or C 1 -C 8 alkyl;
X 1′ is selected from the group consisting of —(CH 2 )O—, —C(O)—, —C(O)NH—, —OC(O)NH—, —OC(O)—, —C(O)O—, —C(S)NH—, and —SO 2 —;
X 2′ is selected from the group consisting of;

R 7′ is CH 2 , NH, or O;
X 3′ is a dendron;
X 4′ is selected from the group consisting of —(CH 2 ) o′ —, —C(O)—,
—C(O)NH—, —OC(O)NH—, —OC(O)—, —C(O)O—, —C(S)NH—, —SO 2 —, —NHC(O)—, and

m′, n′, and q′ are the same or different and each is 0 or an integer from 1-5;
o′ is an integer from 1-5; and
p′ is 0 or an integer from 1-36;

wherein X 5′ is optionally linked to a particle.

2. The compound of claim 1 , wherein in formula (I), ring A is phenyl, furanyl, thiazolyl, thienyl, pyrazolyl, pyridazinyl, pyridinyl, pyrazinyl, benzofuranyl, cyclopropyl, or cyclohexyl, or a pharmaceutically acceptable salt thereof.

3. The compound of claim 2 , wherein in formula (I), ring A is phenyl, or a pharmaceutically acceptable salt thereof.

4. The compound of claim 1 , wherein in formula (I), R 1 is —CO 2 H, or a pharmaceutically acceptable salt thereof.

5. The compound of claim 1 , wherein in formula (I), R 1 is a bioisostere of carboxylate selected from the group consisting of

or a pharmaceutically acceptable salt thereof.

6. The compound of claim 1 , wherein in formula (I), R 2 is H or C 2 -C 8 alkynyl, or a pharmaceutically acceptable salt thereof.

7. The compound of claim 1 , wherein in formula (I), R 3 is C 1 -C 8 alkyl, hydroxy, hydroxyalkyl, C 1 -C 8 alkoxy, halo, C 1 -C 8 haloalkyl, C 1 -C 8 haloalkoxy, —CN, —NH 2 , —CO 2 R 4 , or a pharmaceutically acceptable salt thereof.

8. The compound of claim 1 , wherein in formula (I), n is 0, 1, or 2.

9. The compound of claim 1 , wherein in formula (I),
R 1 is —CO 2 H;
R 2 is H; and

is selected from the group consisting of

or a pharmaceutically acceptable salt thereof.

10. The compound of claim 1 , wherein the compound is a compound of formula (II):

wherein
ring A′ is aryl, heteroaryl, or c

Assignees

• Us Health

Inventors

• Jacobson Kenneth A
• Junker Anna
• Uliassi Elisa
• Kiselev Evgeny

Classifications

• C07D211/18

  with substituted hydrocarbon radicals attached to ring carbon atoms · CPC title

• C07D401/06

  linked by a carbon chain containing only aliphatic carbon atoms · CPC title

• C07D401/10 Primary

  linked by a carbon chain containing aromatic rings · CPC title

• C07D401/14

  containing three or more hetero rings · CPC title

• C07D409/14

  containing three or more hetero rings · CPC title