Substituted triazolopyridines and methods of use thereof

Patent metadata

Field	Value
Publication number	US-9550775-B2
Application number	US-201414772735-A
Country	US
Kind code	B2
Filing date	Mar 14, 2014
Priority date	Mar 14, 2013
Publication date	Jan 24, 2017
Grant date	Jan 24, 2017

Abstract

The invention provides compounds having the general formula: [insert formula (I)] (I) and pharmaceutically acceptable salts thereof, wherein the variables R A , subscript n, ring A, X 2 , L, subscript m, X 1 , R 1 , R 2 , R 3 , R 4 , and R N have the meaning as described herein, and compositions containing such compounds and methods for using such compounds and compositions.

First claim

We claim:

1. A compound of Formula I:

or a pharmaceutically acceptable salt thereof, wherein:
R 1 is C 1-8 alkyl, C 2-8 alkenyl, C 1-8 haloalkyl, C 1-8 alkoxy, C 3-12 carbocycle, C-linked C 2-11 heterocycle, or —NR 1A R 1B , wherein R 1A and R 1B are each independently selected from the group consisting of hydrogen, C 1-8 alkyl, C 1-8 alkoxy, (6-10 membered aryl)-(X R1 ) 0-1 —, (5-10 membered heteroaryl)-(X R1 ) 0-1 —, and wherein R 1A and R 1B are optionally combined to form a 3 to 8 membered heterocyclic ring optionally comprising 1 additional heteroatom selected from N, O and S as ring vertex and optionally fused thereto is a benzene or pyridine ring; X R1 is selected from the group consisting of C 1-4 alkylene, C 1-4 heteroalkylene, C 2-4 alkenylene, C 2-4 alkynylene; and wherein the aliphatic and aromatic portions of R 1 are optionally substituted with from 1 to 5 R R1 substituents selected from the group consisting of C 1-8 alkyl, C 1-8 haloalkyl, oxo (═O), F, Cl, Br, I, —OH, —CN, —NO 2 , —(X 1R ) 0-1 NR R1a R R1b , —(X 1R ) 0-1 OR R1a , —(X 1R ) 0-1 SR R1a , —(X 1R ) 0-1 N(R R1a )C(═O)OR R1c , —(X 1R ) 0-1 OC(═O)N(R R1a )(R R1b ), —(X 1R ) 0-1 N(R R1a )C(═O)N(R R1a )(R R1b ), —(X 1R ) 0-1 C(═O)N(R R1a )(R R1b ), —(X 1R ) 0-1 N(R R1a )C(═O)R R1b , —(X 1R ) 0-1 C(═O)OR R1a , —(X 1R ) 0-1 OC(═O)R R1a , —(X 1R ) 0-1 —P(═O)(OR R1a )(OR R1b ), —(X 1R ) 0-1 S(O) 1-2 R R1c , —(X 1R ) 0-1 S(O) 1-2 N(R R1a )(R R1b ), —(X 1R ) 0-1 N(R R1a )S(O) 1-2 N(R R1a )(R R1b ) and —(X 1R ) 0-1 N(R R1a )S(O) 1-2 (R R1c ), wherein X 1R is selected from the group consisting of C 1-4 alkylene, C 1-4 heteroalkylene, C 2-4 alkenylene and C 2-4 alkynylene; wherein R R1a and R R1b are independently selected from the group consisting of hydrogen, C 1-8 alkyl, C 1-8 haloalkyl, C 3-8 carbocycle, phenyl, benzyl, C 5-6 heteroaryl and C 2-7 heterocycle; R R1c is selected from the group consisting of C 1-8 alkyl, C 1-8 haloalkyl, C 3-8 carbocycle, phenyl, benzyl, C 5-6 heteroaryl and C 2-7 heterocycle;
R N is hydrogen, C 1-4 alkyl or C 1-4 haloalkyl;
R 2 and R 3 are each independently selected from the group consisting of H, F, Cl, Br, I, —CN, C 1-8 alkyl, C 1-8 haloalkyl and C 1-8 alkoxy;
R 4 is selected from the group consisting of H, F, Cl, Br, I, —CN, C 1-8 alkyl, C 2-8 alkenyl, C 1-8 haloalkyl, C 1-8 alkoxy, C 3-8 carbocycle, C 2-7 heterocycle, phenyl and 5-6 membered heteroaryl comprising 1 to 3 heteroatoms selected from N, O and S, wherein said 5-6 membered heteroaryl is further optionally substituted with from 1 to 3 R 5 substituents selected from F, Cl, Br, I, —CN, C 1-4 alkyl, C 1-4 haloalkyl and C 1-4 alkoxy;
L is a linker selected from the group consisting of C 1-4 alkylene, C 2-4 alkenylene, C 2-4 alkynylene, and C 1-4 heteroalkylene, wherein L is optionally substituted with from 1 to 3 R L substituents selected from the group consisting of ═O, C 1-4 alkyl, C 1-4 haloalkyl and C 1-4 acyl;
the subscript m represents the integer 0 or 1;
X 1 and X 2 are each independently selected from the group consisting of absent, —O—, —S(O)—, —S(O) 2 — and —N(R X )— wherein R x is H, C 1-8 alkyl, C 1-8 acyl or —S(O) 2 (C 1-8 alkyl), and wherein if the subscript m is 0 then one of X 1 or X 2 is absent;
the subscript n is an integer from 0 to 5;
A is selected from the group consisting of C 3 -C 20 carbocycle, C 2 -C 20 heterocycle, aryl, and heteroaryl; and
R A is selected from the group consisting of C 1-8 alkyl, C 1-8 haloalkyl, F, Cl, Br, I, —OH, —CN, —NO 2 , carbocycle, heterocycle, heteroaryl, —(X RA ) 0-1 NR A1 R A2 , —(X RA ) 0-1 OR A1 , —(X RA ) 0-1 SR A1 , —(X RA ) 0-1 N(R A1 )C(═O)OR A3 , —(X RA ) 0-1 OC(═O)N(R A1 )(R A2 ), —(X RA ) 0-1 N(R A1 )C(═O)N(R A1 )(R A2 ), —(X RA ) 0-1 C(═O)N(R A1 )(R A2 ), —(X RA ) 0-1 N(R A1 )C(═O)R A2 , —(X RA ) 0-1 C(═O)OR A1 , —(X RA ) 0-1 OC(═O)R A1 , —P(═O)(OR A1 )(OR A2 ), —(X RA ) 0-1 S(O) 1-2 R A3 , —(X RA ) 0-1 S(O) 1-2 N(R A1 )(R A2 ), —(X RA ) 0-1 N(R A1 )S(O) 1-2 N(R A1 )(R A2 ) and —(X RA ) 0-1 N(R A1 )S(O) 1-2 (R A3 ), wherein X RA is selected from the group consisting of C 1-4 alkylene, C 1-4 heteroalkylene, C 2-4 alkenylene and C 2-4 alkynylene; wherein R A1 and R A2 are independently selected from the group consisting of hydrogen, C 1-8 alkyl, C 1-8 haloalkyl, C 3-8 carbocycle, tetrahydronapthalene, phenyl, benzyl, C 5-6 heteroaryl and C 2-7 heterocycle; R A3 is selected from the group consisting of C 1-8 alkyl, C 1-8 haloalkyl, C 3-8 carbocycle, tetrahydronapthalene, phenyl, benzyl, C 5-6 heteroaryl and C 2-7 heterocycle; and wherein the aliphatic and aromatic portions of a R A substitutent is optionally substituted with from 1 to 5 R RA substitutents selected from, R A4 , F, Cl, Br, I, —NH 2 , —OH, —CN, —NO 2 , ═O, C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 alkoxy, C 1-4 (halo)alkyl-C(═O)—, C 1-4 (halo)alkyl-S(O) 0-2 —, C 1-4 (halo)alkyl-C(═O)N(H)—, C 1-4 (halo)alkyl-N(H)—C(═O)—, ((halo)alkyl) 2 N—C(═O)—, C 1-4 (halo)alkyl-OC(═O)N(H)—, C 1-4 (halo)alkyl-OC(═O)N(H)—, (halo)alkyl-N(H)—C(═O)O—, ((halo)alkyl) 2 N—C(═O)O—, C 1-4 alkylamino, and C 1-4 dialkylamino; each R A4 is independently selected from C 3-6 carbocycle, C 3-6 carbocycleoxy, C 2-5 heterocycleoxy, and aryl, wherein C 3-6 carbocycle, C 3-6 carbocycleoxy, C 2-5 heterocycleoxy, and aryl is optionally substituted with one or more substituents independently selected from F, Cl, Br, I, —NH 2 , —OH, —CN, —NO 2 , ═O, C 1-4 alkyl, C 1-4 haloalkyl, and C 1-4 alkoxy.

2. The compound of formula I as described in claim 1 , or a pharmaceutically acceptable salt thereof, wherein:
R 1 is C 1-8 alkyl, C 2-8 alkenyl, C 1-8 haloalkyl, C 1-8 alkoxy, C 3-12 carbocycle, C-linked C 2-11 heterocycle, or —NR 1A R 1B , wherein R 1A and R 1B are each independently selected from the group consisting of hydrogen, C 1-8 alkyl, C 1-8 alkoxy, (6-10 membered aryl)-(X R1 ) 0-1 —, (5-10 membered heteroaryl)-(X R1 ) 0-1 —, and wherein R 1A and R 1B are optionally combined to form a 3 to 8 membered heterocyclic ring optionally comprising 1 additional heteroatom selected from N, O and S as ring vertex and optionally fused thereto is a benzene or pyridine ring; X R1 is selected from the group consisting of C 1-4 alkylene, C 1-4 heteroalkylene, C 2-4 alkenylene, C 2-4 alkynylene; and wherein the aliphatic and aromatic portions of R 1 are optionally substituted with from 1 to 5 R R1 substituents selected from the group consisting of C 1-8 alkyl, C 1-8 haloalkyl, oxo (═O), F, Cl, Br, I, —OH, —CN, —NO 2 , —(X 1R ) 0-1 NR R1a R R1b , —(X 1R ) 0-1 OR R1a , —(X 1R ) 0-1 SR R1a , —(X 1R ) 0-1 N(R R1a )C(═O)OR R1c , —(X 1R ) 0-1 OC(═O)N(R R1a )(R R1b ), —(X 1R ) 0-1 N(R R1a )C(═O)N(R R1a )(R R1b ), —(X 1R ) 0-1 C(═O)N(R R1a )(R R1b ), —(X 1R ) 0-1 N(R R1a )C(═O)R R1b , —(X 1R ) 0-1 C(═O)OR R1a , —(X 1R ) 0-1 OC(═O)R R1a , —(X 1R ) 0-1 —P(═O)(OR R1a )(OR R1b ), —(X 1R ) 0-1 S(O) 1-2 R R1c , —(X 1R ) 0-1 S(O) 1-2 N(R R1a )(R R1b ), —(X 1R ) 0-1 N(R R1a )S(O) 1-2 N(R R1a )(R R1b ) and —(X 1R ) 0-1 N(R R1a )S(O) 1-2 (R R1c ), wherein X 1R is selected from the group consisting of C 1-4 alkylene, C 1-4 heteroalkylene, C 2-4 alkenylene and C 2-4 alkynylene; wherein R R1a and R R1b are independently selected from the group consisting of hydrogen, C 1-8 alkyl, C 1-8 haloalkyl, C 3-8 carbocycle, phenyl, benzyl, C 5-6 heteroaryl and C 2-7 heterocycle; R R1c is selected from the group consisting of C 1-8 alkyl, C 1-8 haloalkyl, C 3-8 carbocycle, phenyl, benzyl, C 5-6 heteroaryl and C 2-7 heterocycle;
R N is hydrogen, C 1-4 alkyl or C 1-4 haloalkyl;
R 2 and R 3 are each independently selected from the group consisting of

Assignees

• Genentech Inc
• Xenon Pharmaceuticals Inc

Inventors

• Bichler Paul Robert
• Chowdhury Sultan
• Decker Shannon Marie
• Dehnhardt Christoph Martin
• Focken Thilo
• Grimwood Michael Edward
• Hemeon Ivan William
• Safina Brian
• Sheng Tao
• Sun Shaoyi
• Wilson Michael Scott
• Zenova Alla Yurevna

Classifications

• A61P43/00

  Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00 · CPC title

• A61P9/10

  for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis · CPC title

• A61P35/00

  Antineoplastic agents · CPC title

• A61P9/00

  Drugs for disorders of the cardiovascular system · CPC title

• A61P9/06

  Antiarrhythmics · CPC title