6 Phenyl or 6 Pyridin 3 YL Indazole Derivatives and Methods of Use

Patent metadata

Field	Value
Publication number	US-2016376240-A1
Application number	US-201515112870-A
Country	US
Kind code	A1
Filing date	Jan 16, 2015
Priority date	Jan 24, 2014
Publication date	Dec 29, 2016
Grant date	—

Abstract

Compounds of formula (I) and pharmaceutically acceptable salts, esters, amides, or radiolabelled forms thereof, wherein R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , and X are as defined in the specification, are useful in treating conditions or disorders prevented by or ameliorated by Tropomysin receptor kinases (Trk). Methods for making the compounds are disclosed. Also disclosed are pharmaceutical compositions of compounds of formula (I), and methods for using such compounds and compositions.

First claim

What is claimed is:

1 . A compound of formula (I):

or a pharmaceutically acceptable salt, ester, amide, or radiolabelled form thereof, wherein:
R 1 is hydrogen, C 1 -C 4 -alkyl, C 1 -C 4 -fluoroalkyl, C 3 -C 6 -cycloalkyl or H 2 N—;
R 2 is hydrogen or R 7 O—;
R 3 and R 6 are independently hydrogen or fluorine;
R 4 is hydrogen, G 1 -, G 2 -, or Y-L 1 -(CR a R b ) f -L 2 -;
R 5 is hydrogen, R 11 C(O)—, R 10 N(H)C(O)—, R 11 C(O)NH—, R 10 N(H)SO 2 —, R 11 SO 2 NH—, R 11 CH(OH)—, R 11 C(O)C(O)NH—, or NC—;
R 7 is C 1 -C 6 -alkyl, C 1 -C 6 -fluoroalkyl, C 3 -C 8 -cycloalkyl, C 3 -C 8 -cycloalkyl-C 1 -C 4 -alkyl, C 4 -C 8 -cycloalkenyl, C 4 -C 8 -cycloalkenyl-C 1 -C 4 -alkyl, M 4 -M 7 -heterocycle or M 4 -M 7 -heterocycle-C 1 -C 4 alkyl, wherein:
the C 1 -C 6 -alkyl and C 1 -C 6 -fluoroalkyl are optionally substituted with 1, 2, 3, 4, or 5 substituents selected from halogen, cyano, oxo, O 2 N—, R s O—, R s O—(CR a R b ) m —, R s C(O)O—, (R s )(R t )NC(O)O—, R s S—, R s S(O)—, R s S(O) 2 —, (R s )(R t )NS(O) 2 —, R s C(O)—, R s OC(O)—, (R s )(R t )NC(O)—, (R s )(R t )N—, R t C(O)N(R s )—, R t OC(O)N(R s )—, and (R t )S(O) 2 N(R s )—;
the C 3 -C 8 -cycloalkyl, C 3 -C 8 -cycloalkyl-C 1 -C 4 -alkyl, C 4 -C 8 -cycloalkenyl, C 4 -C 8 -cycloalkenyl-C 1 -C 4 -alkyl, M 4 -M 7 -heterocycle and M 4 -M 7 -heterocycle-C 1 -C 4 alkyl are optionally substituted with 1, 2, 3, 4, or 5 substituents selected from C 1 -C 4 -alkyl, C 2 -C 4 -alkenyl, C 2 -C 4 -alkynyl, halogen, cyano, oxo, O 2 N—, R u O—, R u O—(CR a R b ) m —, R u C(O)O—, (R u )(R v )NC(O)O—, R u S—, R u S(O)—, R u S(O) 2 —, (R u )(R v )NS(O) 2 —, R u C(O)—, R u OC(O)—, (R u )(R v )NC(O)—, (R u )(R v )N—, R v C(O)N(R u )—, (R v )OC(O)N(R u )—, (R v )S(O) 2 N(R u )—, and C 1 -C 4 -haloalkyl;

R 10 is hydrogen, C 1 -C 6 -alkyl, or C 3 -C 7 -cycloalkyl;
R 11 is C 1 -C 6 -alkyl or C 2 -C 6 -alkenyl;
R a and R b , at each occurrence, are each independently hydrogen, C 1 -C 4 -alkyl, or C 1 -C 4 -haloalkyl;
R c , at each occurrence, is independently hydrogen, C 1 -C 4 -alkyl, C 3 -C 6 -cycloalkyl or C 1 -C 4 -haloalkyl;
R s , R t , R u , and R v are, at each occurrence, independently hydrogen, C 1 -C 6 -alkyl, C 2 -C 6 -alkenyl, C 2 -C 6 -alkynyl or C 1 -C 6 -haloalkyl;
G 1 is monocyclic M 4 -M 7 -heterocycle unsubstituted or optionally substituted with 1, 2, 3, or 4 substituents selected from C 1 -C 8 -alkyl, C 2 -C 8 -alkenyl, C 2 -C 8 -alkynyl, halogen, cyano, oxo, O 2 N—, R u S(O)—, R u S(O) 2 —, G 1a S(O) 2 —, (R u )(R v )NS(O) 2 —, R u C(O)—, R u OC(O)—, (R u )(R v )NC(O)—, R u O—, R u O—(CR a R b ) h —, R u O—(CR a R b ) k —O—(CR a R b ) j —, R u O—(CR a R b ) k —OC(O)—, G 1a -, G 1a C(O)—, G 1a -(CR a R b ) p —, G 1a -(CR a R b ) p —C(O)—, G 1a -OC(O)—, G 1a -(CR a R b ) p —OC(O)—, G 1b -, G 1b C(O)—, G 1b -(CR a R b ) p —, G 1b C(O)—(CR a R b ) p , G 1b -(CR a R b ) p —OC(O)—, G 1b -(CR a R b ) p —C(O)—, G 1c -, G 1c C(O)—, G 1c -(CR a R b ) h —, G 1c C(O)—(CR a R b ) p —, G 1c -(CR a R b ) p —OC(O)—, G 1c -(CR a R b ) p —C(O)—, (R u )(R v )N—, R v C(O)N(R u )—, (R v )OC(O)N(R u )—, (R v )S(O) 2 N(R u )—, and C 1 -C 4 -haloalkyl;
G 1a is aryl or heteroaryl wherein the aryl or heteroaryl are optionally substituted with 1, 2, 3, 4, or 5 substituents selected from C 1 -C 4 -alkyl, C 2 -C 4 -alkenyl, C 2 -C 4 -alkynyl, halogen, cyano, O 2 N—, R u O—, R u O—(CR a R b ) m —, R u C(O)O—, (R u )(R v )NC(O)O—, R u S—, R u S(O)—, R u S(O) 2 —, (R u )(R v )NS(O) 2 —, R u C(O)—, R u OC(O)—, (R u )(R v )NC(O)—, (R u )(R v )N—, R v C(O)N(R u )—, (R v )OC(O)N(R u )—, (R v )S(O) 2 N(R u )—, and C 1 -C 4 -haloalkyl;
G 1b is C 3 -C 8 -cycloalkyl or C 4 -C 8 -cycloalkenyl, wherein the C 3 -C 8 -cycloalkyl or C 4 -C 8 -cycloalkenyl are optionally substituted with 1, 2, 3, 4, or 5 substituents selected from C 1 -C 4 -alkyl, C 2 -C 4 -alkenyl, C 2 -C 4 -alkynyl, halogen, cyano, O 2 N—, R u O—, R u O—(CR a R b ) m —, R u C(O)O—, (R u )(R v )NC(O)O—, R u S—, R u S(O)—, R u S(O) 2 —, (R u )(R v )NS(O) 2 —, R u C(O)—, R u OC(O)—, (R u )(R v )NC(O)—, (R u )(R v )N—, R v C(O)N(R u )—, (R v )OC(O)N(R u )—, (R v )S(O) 2 N(R u )—, and C 1 -C 4 -haloalkyl;
G 1c is M 4 -M 7 -heterocycle M 7 -heterocycle wherein the M 4 -M 7 -heterocycle is optionally substituted with 1, 2, 3, 4, or 5 substituents selected from C 1 -C 4 -alkyl, C 2 -C 4 -alkenyl, C 2 -C 4 -alkynyl, halogen, cyano, O 2 N—, R u O—, R u O—(CR a R b ) m —, R u C(O)O—, (R u )(R v )NC(O)O—, R u S—, R u S(O)—, R u S(O) 2 —, (R u )(R v )NS(O) 2 —, R u C(O)—, R u OC(O)—, (R u )(R v )NC(O)—, (R u )(R v )N—, R v C(O)N(R u )—, (R v )OC(O)N(R u )—, (R v )S(O) 2 N(R u )—, and C 1 -C 4 -haloalkyl;
G 2 is a fused-bicyclic heterocycle or spirocyclic heterocycle unsubstituted or optionally substituted with 1, 2, 3, or 4 substituents selected from C 1 -C 8 -alkyl, C 2 -C 8 -alkenyl, C 2 -C 8 -alkynyl, halogen, cyano, oxo, O 2 N—, R u S(O)—, R u S(O) 2 —, (R u )(R v )NS(O) 2 —, R u C(O)—, R u OC(O)—, (R u )(R v )NC(O)—, R u O—, R u O—(CR a R b ) m —, R u O—(CR a R b ) n —O—(CR a R b ) m —, G 1a -, G 1a C(O)—, G 1a -(CR a R b ) q —, G 1b -, G 1b C(O)—, G 1b -(CR a R b ) q —, G 1b C(O)—(CR a R b ) q —, (R u )(R v )N—, R v C(O)N(R u )—, (R v )OC(O)N(R u )—, (R v )S(O) 2 N(R a )—, and C 1 -C 4 -haloalkyl;
L 1 and L 2 are independently selected from a bond, —O—, —NR c —, —C(O)—, —R c NC(O)—, —C(O)NR c —, —R c NC(O)O—, —OC(O)NR c —, —NR c C(O)NR c —, —S(O)—, —S(O) 2 —, —R c NS(O) 2 —, and —S(O) 2 NR c —;
X is N, CH, or CF;
Y is monocyclic C 3 -C 8 -cycloalkyl, monocyclic C 3 -C 8 -cycloalkenyl, or monocyclic M 4 -M 7 -heterocycle unsubstituted or optionally substituted with 1, 2, 3, or 4 substituents selected from C 1 -C 8 -alkyl, C 2 -C 8 -alkenyl, C 2 -C 8 -alkynyl, halogen, cyano, oxo, O 2 N—, R u S(O)—, R u S(O) 2 —, (R u )(R v )NS(O) 2 —, R u C(O)—, R u OC(O)—, (R u )(R v )NC(O)—, R u O—, R u O—(CR a R b ) p —, (R u )(R v )N—, R v C(O)N(R u )—, (R v )OC(O)N(R u )—, (R v )S(O) 2 N(R a )—, and C 1 -C 4 -haloalkyl; or
Y is aryl or heteroaryl unsubstituted or optionally substituted with 1, 2, 3, or 4 substituents selected from C 1 -C 8 -alkyl, C 2 -C 8 -alkenyl, C 2 -C 8 -alkynyl, halogen, cyano, O 2 N—, R u S(O)—, R u S(O) 2 —, (R u )(R v )NS(O) 2 —, R u C(O)—, R u OC(O)—, (R u )(R v )NC(O)—, R u O—, R u O—(CR a R b ) m —, (R u )(R v )N—, R v C(O)N(R u )—, (R v )OC(O)N(R u )—, (R v )S(O) 2 N(R u )—, and C 1 -C 4 -haloalkyl; or
Y is C 1 -C 6 -alkyl or C 1 -C 6 -fluoroalkyl optionally substituted with 1, 2, 3, 4, or 5 substituents selected from halogen, cyano, oxo, O 2 N—, R s O—, R s C(O)O—, (R s )(R t )NC(O)O—, R s S—, R s S(O)—, R s S(O) 2 —, (R s )(R t )NS(O) 2 —, R s C(O)—, R s OC(O)—, (R s )(R t )NC(O)—, (R s )(R t )N—, R t C(O)N(R s )—, (R t )OC(O)N(R s )—, and (R t )S(O) 2 N(R s )—;
f is 1, 2, 3, or 4; or
f is 2, 3, or 4 when the moieties attaching to each side of —(CR a R b ) f — are selected from O, NR c , or a ring nitrogen atom of a monocyclic M 4 -M 7 -heterocycle when L 1 is a bond;
h, j, k and n are independently 2, 3, or 4; and
m, p and q are independently 1, 2, 3, or 4.

2 . The compound of claim 1 , wherein R 1 is H 2 N—.

3 . The compound of claim 2 , wherein, R 2 is R 7 O—.

4 . The compound of claim 3 , wherein R 4 is G 1 - or G 2 -.

5 . The compound of claim 4 , wherein
R 4 is G 1 -; R 5 is hydrogen, R 11 C(O)—, R 10 N(H)C(O)—, R 11 C(O)NH—, R 11 SO 2 NH—, R 10 N(H)SO 2 —, R 11 CH(OH)—, or NC—; R 7 is C 1 -C 6 -alkyl, C 1 -C 6 -fluoroalkyl, C 3 -C 8 -cycloalkyl, or M 4 -M 7 -heterocy

Assignees

• Abbvie Inc

Inventors

• BUNNELLE William
• Cowart Marlon
• Drizin Irene
• Koenig John Robert
• Pliushchev Marina
• Scanio Marc

Classifications

• A61P43/00

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

• C07D401/10

  linked by a carbon chain containing aromatic rings · CPC title

• C07D487/10

  Spiro-condensed systems · CPC title

• C07D403/12

  linked by a chain containing hetero atoms as chain links · CPC title

• C07D413/10

  linked by a carbon chain containing aromatic rings · CPC title