GDF-8 inhibitors

Patent metadata

Field	Value
Publication number	US-9518040-B2
Application number	US-201514833689-A
Country	US
Kind code	B2
Filing date	Aug 24, 2015
Priority date	Oct 5, 2012
Publication date	Dec 13, 2016
Grant date	Dec 13, 2016

Abstract

Described are GCF-8 inhibitors of the formula (I),

and pharmaceutically acceptable salts thereof, wherein n, R 1 , R 2 , R 5 , R 6 , X and Z are defined herein. Also provided are pharmaceutical compositions comprising the same. Such compounds and compositions are useful in methods for inhibiting GDF-8 in a cell and methods for treating a patient suffering from a disease or disorder, wherein the patient would therapeutically benefit from an increase in mass or strength of muscle tissue.

First claim

We claim:

1. A compound of the formula

or a pharmaceutically acceptable salt thereof, wherein
X is N;
R 1 is halogen, cyano, nitro, C 1-6 alkyl, C 1-6 haloalkyl, C 3-8 cycloalkyl, C 3-8 cycloalkenyl, heterocyclyl, aryl, heteroaryl, —R 10 , or —C 1-6 alkyl-R 10 , wherein
R 10 is —OR, —SR, —NR a R a , —C(O)R, —C(O)OR, —C(O)NR a R a , —S(O) 2 NR a R a , —OC(O)R, —N(R)C(O)R, —OC(O)OR, —O(CH 2 ) m C(O)NR a R a , —N(R)C(O)OR, —N(R)C(O)NR a R a , —N(R)S(O) 2 NR a R a or —N(R)S(O) 2 R;

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 10 , or —C 1-6 alkyl-R 10 , wherein R 10 is —OR, —SR, —NR a R a , —C(O)R, —C(O)OR, —C(O)NR a R a , —S(O) 2 NR a R a , —OC(O)R, —N(R)C(O)R, —OC(O)OR, —O(CH 2 ) m C(O)NR a R a , —N(R)C(O)OR, —N(R)C(O)NR a R a , —N(R)S(O) 2 NR a R a or —N(R)S(O) 2 R;
or when R 1 and R 2 are attached to adjacent carbon atoms they are optionally taken together with the atoms to which they are attached to form a 5- or 6-membered ring optionally substituted with one or two groups that are each independently halogen, oxo, oxime, imino, C 1-6 alkyl, C 1-6 haloalkyl, or R 10 ;
each R a is independently R or, two R a together with the nitrogen atom to which they are attached form a 3-8 membered heterocyclyl group, optionally including 1-4 additional heteroatoms selected from O, N and S and optionally substituted with 1-4 R groups;
each R b is independently halogen, cyano, oxo, C 1-6 alkyl, C 1-6 haloalkyl, or —OR;
m is 0, 1 or 2;
n is 1, 2, 3 or 4;
R 5 and R 6 are each independently hydrogen, halogen, C 1-6 alkyl optionally substituted with 1-3 R b , C 1-6 haloalkyl, C 3-8 cycloalkyl optionally substituted with one or two R b , heteroaryl optionally substituted with one or two R b , aryl optionally substituted with one or two R b , heterocyclyl(C 1-6 alkyl) optionally substituted with one or two Rb, —OR, —SR, —NR a R a , —OC(O)R, —C(O)NR a R a , —OC(O)NR a R a , —C(O)OR, —N(R)C(O)R, —N(R)S(O) 2 R, or R 5 and R 6 are optionally taken together with the atoms to which they are attached to form a 5- or 6-membered ring optionally including 1-3 additional heteroatoms selected from O, N and S and optionally substituted with 1-4 Rb;
Z is (a) a fused bicyclic ring of the formula,

wherein
ring A is a phenyl or 5- or 6-membered heteroaryl,
ring B is a 5- or 6-membered heterocyclyl or 5- or 6-membered heteroaryl;
or (b) pyridinyl or pyrimidinyl,
wherein
Z is optionally substituted by one or two groups that are each independently halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 3-8 cycloalkyl, heterocyclyl, aryl, heteroaryl, C 3-8 cycloalkyl(C 1-6 alkyl), heterocyclyl(C 1-6 alkyl), aryl(C 1-6 alkyl), heteroaryl(C 1-6 alkyl), —R Z , or —C 1-6 alkyl-R Z , wherein the C 3-8 cycloalkyl, heterocyclyl, aryl, heteroaryl, C 3-8 cycloalkyl(C 1-6 alkyl), heterocyclyl(C 1-6 alkyl), aryl(C 1-6 alkyl), and heteroaryl(C 1-6 alkyl) are each optionally substituted by one or two groups that are each independently halogen, C 1-6 alkyl, or R Z ;

and R Z is cyano, —CF 3 , —OR, —SR, —NR a R a , —C(O)R, —C(O)OR, —C(O)NR a R a , —S(O) 2 NR a R a , —S(O) 2 R 0 , —OC(O)R, —N(R)C(O)R, —OC(O)OR, —OC(O)NR a R a , —N(R)C(O)OR, —N(R)C(O)NR a R a , —N(R)S(O) 2 R, or —OP(O)(OR) 2 ;
or Z is (c) phenyl substituted with 1, 2, 3, 4, or 5 groups that are each independently a halogen;

wherein each R is independently hydrogen, C 1-6 alkyl, C 1-6 haloalkyl, C 3-8 cycloalkyl, heterocyclyl, aryl, heteroaryl, heteroaryl(heteroaryl)-, heterocyclyl(aryl)-, heteroaryl(heterocyclyl)-, C 3-8 cycloalkyl(C 1-6 alkyl), heterocyclyl(C 1-6 alkyl), aryl(C 1-6 alkyl), or heteroaryl(C 1-6 alkyl), each optionally substituted by 1-5 groups that are each independently R b , —OR 0 , —SR 0 , —N(R 0 ) 2 , —C(O)R 0 , —C(O)OR 0 , —C(O)N(R 0 ) 2 , —S(O) 2 N(R 0 ) 2 , —OC(O)R 0 , —N(R 0 )C(O)R 0 , —OC(O)OR 0 , —O(CH 2 ) m C(O)N(R 0 ) 2 , —N(R 0 )C(O)OR 0 , —N(R 0 )C(O)N(R 0 ) 2 , or —N(R 0 )S(O) 2 R 0
and each R 0 is independently hydrogen, C 1-6 haloalkyl, C 1-6 alkyl optionally substituted with 1-3 R b , C 3-8 cycloalkyl optionally substituted with one or two R b or, alternatively two R 0 together with a nitrogen atom to which they are bound form a 3-8 membered heterocyclyl group, optionally including 1-4 additional heteroatoms selected from O, N and S and optionally substituted with 0-3 R b and R groups.

2. The compound or pharmaceutically acceptable salt of claim 1 of the formula,

3. The compound or pharmaceutically acceptable salt of claim 1 , wherein R 1 is halogen, cyano, nitro, C 1-6 alkyl, C 1-6 haloalkyl, C 3-8 cycloalkyl, C 3-8 cycloalkenyl, heterocyclyl, aryl, heteroaryl, —R 10 , or —C 1-6 alkyl-R 10 , wherein R 10 is —OR, —SR, —NR 2 , —C(O)R, —C(O)OR, —C(O)NR 2 , —S(O) 2 NR 2 , —OC(O)R, —N(R)C(O)R, —OC(O)OR, —OC(O)NR 2 , —N(R)C(O)OR, —N(R)C(O)NR 2 , or —N(R)S(O) 2 R, and
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 10 , or —C 1-6 alkyl-R 10 , wherein R 10 is —OR, —SR, —NR 2 , —C(O)R, —C(O)OR, —C(O)NR 2 , —S(O) 2 NR 2 , —OC(O)R, —N(R)C(O)R, —OC(O)OR, —OC(O)NR 2 , —N(R)C(O)OR, —N(R)C(O)NR 2 , or —N(R)S(O) 2 R.

4. The compound or pharmaceutically acceptable salt of claim 1 , wherein R 1 is halogen, or C 1-6 alkyl, and R 2 is hydrogen, halogen, or C 1-6 alkyl.

5. The compound or pharmaceutically acceptable salt of claim 1 , wherein R 1 is fluoro and R 2 is methyl.

6. The compound or pharmaceutically acceptable salt of claim 1 , wherein ring A is a phenyl or pyridyl ring.

7. The compound or pharmaceutically acceptable salt of claim 1 , wherein Z is of the formula,

wherein each is optionally substituted by one or two groups that are each independently halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 3-8 cycloalkyl, heterocyclyl, aryl, heteroaryl, C 3-8 cycloalkyl(C 1-6 alkyl), heterocyclyl(C 1-6 alkyl), aryl(C 1-6 alkyl), heteroaryl(C 1-6 alkyl), —R Z , or —C 1-6 alkyl-R Z , wherein the C 3-8 cycloalkyl, heterocyclyl, aryl, heteroaryl, C 3-8 cycloalkyl(C 1-6 alkyl), heterocyclyl(C 1-6 alkyl), aryl(C 1-6 alkyl), and heteroaryl(C 1-6 alkyl) are each optionally substituted by one to four groups that are each independently C 1-6 alkyl or —R Z .

8. The compound or pharmaceutically acceptable salt of claim 1 , wherein Z is of the formula,

wherein each is optionally substituted by one or two groups that are each independently halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 3-8 cycloalkyl, heterocyclyl, aryl, heteroaryl, C 3-8 cycloalkyl(C 1-6 alkyl), heterocyclyl(C 1-6 alkyl), aryl(C 1-6 alkyl), heteroaryl(C 1-6 alkyl), —R Z , or —C 1-6 alkyl-R Z , wherein the C 3-8 cycloalkyl, heterocyclyl, aryl, heteroaryl, C 3-8 cycloalkyl(C 1-6 alkyl), heterocyclyl(C 1-6 alkyl), aryl(C 1-6 alkyl), and heteroaryl(C 1-6 alkyl) are each optionally substituted by one to four groups that are each independently C 1-6 alkyl or —R Z .

9. The compound or pharmaceutically acceptable salt of claim 1 , wherein Z is

Assignees

• Rigel Pharmaceuticals Inc

Inventors

• Bhamidipati Somasekhar
• Gelman Marina
• Ding Pingyu
• Singh Rajinder
• Clough Jeffrey
• Kinsella Todd
• Payan Donald

Classifications

• A61P5/24

  of the sex hormones · CPC title

• A61P5/18

  of the parathyroid hormones · CPC title

• A61P43/00

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

• A61P5/44

  Glucocorticosteroids; Drugs increasing or potentiating the activity of glucocorticosteroids · CPC title

• A61P5/26

  Androgens · CPC title