GDF-8 inhibitors

Patent metadata

Field	Value
Publication number	US-9981944-B2
Application number	US-201615043729-A
Country	US
Kind code	B2
Filing date	Feb 15, 2016
Priority date	Feb 20, 2015
Publication date	May 29, 2018
Grant date	May 29, 2018

Abstract

Disclosed are 2,2′-bipyridyl compounds, as well as pharmaceutical compositions and methods of use thereof. One embodiment is a compound having the structure

and pharmaceutically acceptable salts, prodrugs and N-oxides thereof (and solvates and hydrates thereof), wherein R 1 , Z and n are as described herein. In certain embodiments, a compound disclosed herein inhibits GDF8, and can be used to treat disease by blocking GDF8 signaling.

First claim

What is claimed:

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

or a pharmaceutically acceptable salt, prodrug, or N-oxide thereof, or a solvate or hydrate thereof,
wherein
n is 1, 2, 3 or 4;
R 1 is hydrogen, halogen, cyano, nitro, C 1-6 alkyl, C 1-6 haloalkyl, C 3-8 cycloalkyl, C 3-8 cycloalkenyl, heterocyclyl, aryl, heteroaryl, —R a , or —C 1-6 alkyl-R a , wherein R a is —OR S1 , —SR S1 , —NR S1 R S1 , —C(O)R S1 , —C(O)OR S1 , —C(O)NR S1 R S1 , —S(O) 2 NR S1 R S1 , —OC(O)R S1 , —N(R S1 )C(O)R S1 , —OC(O)OR S1 , —O(CH 2 ) m C(O)NR S1 R S1 , —N(R S1 )C(O)OR S1 , —N(R)C(O)NR S1 R S1 , —N(R S1 )S(O) 2 NR S1 R S1 , or —N(R S1 )S(O) 2 R S1 ;
wherein m is 0, 1, 2 or 3; and
wherein each R S1 is independently hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, —(C 0 -C 6 alkyl)-Ar, —(C 0 -C 6 alkyl)-Het, —(C 0 -C 6 alkyl)-Cak, or —(C 0 -C 6 alkyl)-Hca, wherein Ar, Het, Cak, Hca, alkyl, and haloalkyl are optionally substituted with C 1 -C 6 alkyl, halogen, C 1 -C 6 haloalkyl or cyano;

p is 1, 2, 3 or 4;
R 2 is hydrogen, halogen, cyano, nitro, C 1-6 alkyl, C 1-6 haloalkyl, C 3-8 cycloalkyl, C 3-8 cycloalkenyl, heterocyclyl, aryl, heteroaryl, —R b , or —C 1-6 alkyl-R b , wherein R b is —OR S4 , —SR S4 ; —NR S4 R S4 , —C(O)R S4 , —C(O)OR S4 , —C(O)NR S4 R S4 , —S(O) 2 NR S4 R S4 , —OC(O)R S4 , —N(R S4 )C(O)R S4 , —OC(O)OR S4 , —O(CH 2 ) q C(O)NR S4 R S4 , —N(R S4 )C(O)OR S4 , —N(R)C(O)NR S4 R S4 , —N(R S4 )S(O) 2 NR S4 R S4 or —N(R S4 )S(O) 2 R S4 ;
wherein q is 0, 1, 2 or 3; and
wherein each R S4 is independently hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, —(C 0 -C 6 alkyl)-Ar, —(C 0 -C 6 alkyl)-Het, —(C 0 -C 6 alkyl)-Cak, or —(C 0 -C 6 alkyl)-Hca, wherein Ar, Het, Cak, Hca, alkyl, and haloalkyl are optionally substituted with C 1 -C 6 alkyl, halogen, C 1 -C 6 haloalkyl or cyano;

Z is
a fused bicyclic ring of the formula,

 wherein
ring A is Ar or 6-membered Het,
ring B is 5- or 6-membered Het,

wherein
Z is optionally substituted by one or two —R Z groups that are each independently halogen, cyano, C 1-6 alkyl, C 1-6 haloalkyl, —C 1 -C 6 alkoxy, —OR S2 , —SR S2 , —NR S2 2 , —C(O)R S2 , —C(O)OR S2 , —C(O)NR S2 2 , —S(O) 2 NR S2 2 , —S(O) 2 R S2 , —OC(O)R S2 , —N(R S2 )C(O)R S2 , —OC(O)OR S2 , —OC(O)NR S2 2 , —N(R S2 )C(O)OR S2 , —N(R S2 )C(O)NR S2 2 , —N(R S2 )S(O) 2 R S2 , —OP(O)(OR S2 ) 2 or —CH 2 —OP(O)(OR S2 ), wherein each alkyl, haloalkyl and alkoxy is optionally substituted by one or two —R Z2 groups;
wherein each R S2 is independently hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkyl-O—C 1 -C 6 alkyl, —(C 0 -C 6 alkyl)-Ar, —(C 0 -C 6 alkyl)-Het, —(C 0 -C 6 alkyl)-Cak, or —(C 0 -C 6 alkyl)-Hca, wherein Ar, Het, Cak, Hca, alkyl, and haloalkyl are optionally substituted with C 1 -C 6 alkyl, halogen, C 1 -C 6 haloalkyl or cyano; and
each —R Z2 is independently halogen, cyano, C 1-6 alkyl, C 1-6 haloalkyl, —C 1 -C 6 alkoxy, —OR S3 , —SR S3 , —NR S3 2 , —C(O)R S3 , —C(O)OR S3 , —C(O)NR S3 2 , —S(O) 2 NR S3 2 , —S(O) 2 R S3 , —OC(O)R S3 , —N(R S3 )C(O)R S3 , —OC(O)OR S3 , —OC(O)NR S3 2 , —N(R S3 )C(O)OR S3 , —N(R S3 )C(O)NR S3 2 , —N(R S3 )S(O) 2 R S3 , —OP(O)(OR S3 ) 2 or —CH 2 —OP(O)(OR S3 ); and
 wherein each R S3 is independently hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, —(C 0 -C 6 alkyl)-Ar, —(C 0 -C 6 alkyl)-Het, —(C 0 -C 6 alkyl)-Cak, or —(C 0 -C 6 alkyl)-Hca, wherein Ar, Het, Cak, Hca, alkyl, and haloalkyl are optionally substituted with C 1 -C 6 alkyl, halogen, C 1 -C 6 haloalkyl or cyano.

2. The compound of claim 1 , wherein
Z is

wherein Z is optionally substituted by one or two —R Z groups.

3. The compound of claim 1 , wherein
Z is

4. The compound of claim 1 , wherein n is 1 or 2 and each R 1 is independently halogen, C 1-6 alkyl, C 1-6 haloalkyl, or C 3-8 cycloalkyl.

5. The compound of claim 1 , wherein the compound has the structure of one of Formulae (Ia)-(Ih):

6. A compound according to claim 1 that is:
6-(6′-methyl-[2,2′-bipyridin]-3-yl)quinazolin-4-amine;
6-(6′-methyl-[2,2′-bipyridin]-3-yl)quinazolin-4-aminium 2,2,2-trifluoroacetate;
6-(6′-methyl-[2,2′-bipyridin]-3-yl)quinazolin-4-aminium formate;
6-(6′-Methyl-[2,2′-bipyridin]-3-yl)imidazo[1,2-a]pyridine-3-carbonitrile;
6-(6′-Methyl-[2,2′-bipyridin]-3-yl)-[1,2,4]triazolo[1,5-a]pyridine;
7-(6′-Methyl-[2,2′-bipyridin]-3-yl)-[1,2,4]triazolo[1,5-a]pyridine;
6-(6′-Methyl-[2,2′-bipyridin]-3-yl)imidazo[1,2-a]pyridine-3-carboxamide;
6-([2,2′-Bipyridin]-3-yl)imidazo[1,2-a]pyridine-3-carbonitrile;
6-([2,2′-Bipyridin]-3-yl)-[1,2,4]triazolo[1,5-a]pyridine;
6-([2,2′-Bipyridin]-3-yl)imidazo[1,2-a]pyridine-3-carboxamide;
6-(6′-methyl-[2,2′-bipyridin]-3-yl)pyrido[3,2-d]pyrimidin-4-amine;
6-(6′-fluoro-[2,2′-bipyridin]-3-yl)quinazolin-4-amine;
6-(6′-fluoro-[2,2′-bipyridin]-3-yl)quinazolin-4-aminium 2,2,2-trifluoroacetate;
6-([2,2′-bipyridin]-3-yl)quinazolin-4-amine;
6-([2,2′-bipyridin]-3-yl)quinazolin-4-aminium formate;
or a pharmaceutically acceptable salt, prodrug, or N-oxide thereof, or a solvate or hydrate thereof.

7. A compound according to claim 1 having the structure of formula (II):

or a pharmaceutically acceptable salt, prodrug or N-oxide thereof, or solvate or hydrate thereof,
wherein
R 1 is hydrogen, halogen, cyano, nitro, C 1-6 alkyl or C 1-6 haloalkyl;
Z is
a fused bicyclic ring of the formula,

 wherein
ring A is Ar or 6-membered Het,
ring B is 5- or 6-membered Het,

wherein
Z is optionally substituted by one or two —R Z groups that are each independently halogen, cyano, C 1-6 alkyl, C 1-6 haloalkyl, —C 1 -C 6 alkoxy, —OR S2 , —SR S2 , —NR S2 2 , —C(O)R S2 , —C(O)OR S2 , —C(O)NR S2 2 , —S(O) 2 NR S2 2 , —S(O) 2 R S2 , —OC(O)R S2 , —N(R S2 )C(O)R S2 , —OC(O)OR S2 , —OC(O)NR S2 2 , —N(R S2 )C(O)OR S2 , —N(R S2 )C(O)NR S2 2 , —NR S2 )S(O) 2 R S2 , —OP(O)(OR S2 ) 2 or —CH 2 —OP(O)(OR S2 );
wherein each R S2 is independently hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, —(C 0 -C 6 alkyl)-Ar, —(C 0 -C 6 alkyl)-Het, —(C 0 -C 6 alkyl)-Cak, or —(C 0 -C 6 alkyl)-Hca, wherein Ar, Het, Cak, Hca, alkyl, and haloalkyl are optionally substituted with C 1 -C 6 alkyl, halogen, C 1 -C 6 haloalkyl or cyano;

provided that the compound is not 5-(6′-methyl-[2,2′-bipyridin]-3-yl)-1H-indazole.

8. The compound of claim 7 , wherein
Z is

wherein Z is optionally substituted by one or two —R Z groups.

9. The compound of claim 7 , wherein
Z is

wherein Z is optionally substituted by one or two —R Z groups.

10. The compound of claim 7 , wherein R 1 is hydrogen or methyl.

11. The compound of claim 7 , wherein the compound has the structure of Formulae (IIa)-

Assignees

• Rigel Pharmaceuticals Inc
• Bristol Myers Squibb Co
• Rigel Pharmaceuticals Inc

Inventors

• Ding Pingyu
• Gelman Marina
• Kinsella Todd
• Singh Rajinder
• Bhamidipati Somasekhar
• Velaparthi Upender
• Borzilleri Robert M
• Rahaman Hasibur
• Warrier Jayakumar Sankara

Classifications

• A61P37/02

  Immunomodulators · CPC title

• A61P43/00

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

• A61P5/24

  of the sex hormones · CPC title

• A61P5/14

  of the thyroid hormones, e.g. T3, T4 · CPC title

• A61P3/06

  Antihyperlipidemics · CPC title