Substituted pyridazines as skeletal muscle modulators

Patent metadata

Field	Value
Publication number	US-10076519-B2
Application number	US-201715463288-A
Country	US
Kind code	B2
Filing date	Mar 20, 2017
Priority date	Apr 23, 2010
Publication date	Sep 18, 2018
Grant date	Sep 18, 2018

Abstract

Also provided are methods of using a compound of Formula I, or a pharmaceutically acceptable salt thereof.

First claim

What is claimed is:

1. A compound of Formula I:

or a pharmaceutically acceptable salt thereof, wherein:
R 1 is selected from the group consisting of hydrogen, halogen, CN, C 1-6 alkyl, and C 1-6 haloalkyl;
R 2 is 3-8 membered heterocycloalkyl optionally substituted with 1, 2, 3, 4 or 5 substituents selected from the group consisting of halogen, CN, oxo, (CH 2 ) n OR a , (CH 2 ) n OC(O)R a , (CH 2 ) n OC(O)OR a , (CH 2 ) n OC(O)NR b R c , (CH 2 ) n NR b R c , (CH 2 ) n NR d C(O)R a , (CH 2 ) n NR d C(O)OR a , (CH 2 ) n NR d C(O)NR b R c , (CH 2 ) n NR d C(O)C(O)NR b R c , (CH 2 ) n NR d C(S)R a , (CH 2 ) n NR d C(S)OR a , (CH 2 ) n NR d C(S)NR b R c , (CH 2 ) n NR d C(NR e )NR b R c , (CH 2 ) n NR d S(O)R a , (CH 2 ) n NR d SO 2 R a , (CH 2 ) n NR d SO 2 NR b R c , (CH 2 ) n C(O)R a , (CH 2 ) n C(O)NR b R c , (CH 2 ) n C(S)R a , (CH 2 ) n C(S)OR a , (CH 2 ) n C(S)NR b R c , (CH 2 ) n C(NR e )NR b R c , (CH 2 ) n SR a , (CH 2 ) n S(O)R a , (CH 2 ) n SO 2 R a , (CH 2 ) n SO 2 NR b R c , C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, (CH 2 ) n C 3-8 cycloalkyl, (CH 2 ) n 3-8 membered heterocycloalkyl, and (CH 2 ) n C 6-10 aryl, wherein each of the C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, (CH 2 ) n C 3-8 cycloalkyl, (CH 2 ) n 3-8 membered heterocycloalkyl, and (CH 2 ) n C 6-10 aryl groups is optionally substituted with 1, 2, 3, 4 or 5 R f substituents;
or R 2 is selected from the group consisting of 5-10 membered heteroaryl and C 6-10 aryl, wherein each of the 5-10 membered heteroaryl and C 6-10 aryl is substituted with 1, 2, 3, 4 or 5 substituents selected from the group consisting of halogen, CN, (CH 2 ) n OR a , (CH 2 ) n OC(O)R a , (CH 2 ) n OC(O)OR a , (CH 2 ) n OC(O)NR b R c , (CH 2 ) n NR b R c , (CH 2 ) n NR d C(O)R a , (CH 2 ) n NR d C(O)OR a , (CH 2 ) n NR d C(O)NR b R c , (CH 2 ) n NR d C(O)C(O)NR b R c , (CH 2 ) n NR d C(S)R a , (CH 2 ) n NR d C(S)OR a , (CH 2 ) n NR d C(S)NR b R c , (CH 2 ) n NR d C(NR e )NR b R c , (CH 2 ) n NR d S(O)R a , (CH 2 ) n NR d SO 2 R a , (CH 2 ) n NR d SO 2 NR b R c , (CH 2 ) n C(O)R a , (CH 2 ) n C(O)NR b R c , (CH 2 ) n C(S)R a , (CH 2 ) n C(S)OR a , (CH 2 ) n C(S)NR b R c , (CH 2 ) n C(NR e )NR b R c , (CH 2 ) n SR a , (CH 2 ) n S(O)R a , (CH 2 ) n SO 2 R a , (CH 2 ) n SO 2 NR b R c , C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, (CH 2 ) n C 3-8 cycloalkyl, (CH 2 ) n 3-8 membered heterocycloalkyl, and (CH 2 ) n C 6-10 aryl, wherein each of the C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, (CH 2 ) n C 3-8 cycloalkyl, (CH 2 ) n 3-8 membered heterocycloalkyl, and (CH 2 ) n C 6-10 aryl groups is optionally substituted with 1, 2, 3, 4 or 5 R f substituents;
R 3 is selected from the group consisting of hydrogen, halogen, CN, C 1-6 alkyl, and C 1-6 haloalkyl;
R 4 is hydrogen;
R 5 is selected from the group consisting of hydrogen, halogen, and C 1-6 haloalkyl;
R 6 is selected from the group consisting of halogen, C 1-6 alkyl, C 1-6 haloalkyl;
R 7 is selected from the group consisting of C 6-10 aryl and 5-10 membered heteroaryl, each optionally substituted with 1, 2, 3, 4 or 5 substituents selected from the group consisting of halogen, CN, oxo, OR a , OC(O)R a , OC(O)OR a , OC(O)NR b R c , NR b R c , NR d C(O)R a , NR d C(O)OR a , NR d C(O)NR b R c , NR d C(O)C(O)NR b R c , NR d C(S)R a , NR d C(S)OR a , NR d C(S)NR b R c , NR d C(NR e )NR b R c , NR d S(O)R a , NR d SO 2 R a , NR d SO 2 NR b R c , C(O)R a , C(O)OR a , C(O)NR b R c , C(S)R a , C(S)OR a , C(S)NR b R c , C(NR e )NR b R c , SR a , S(O)R a , SO 2 R a , SO 2 NR b R c , C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-8 cycloalkyl, C 3-8 cycloalkenyl, 3-8 membered heterocycloalkyl, 3-8 membered heterocycloalkenyl, C 6-10 aryl, C 7-11 aralkyl, and 5-10 membered heteroaryl, wherein each of the C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-8 cycloalkyl, C 3-8 cycloalkenyl, 3-8 membered heterocycloalkyl, 3-8 membered heterocycloalkenyl, C 6-10 aryl, C 7-11 aralkyl and 5-10 membered heteroaryl groups is optionally substituted with 1, 2, 3, 4 or 5 R f substituents;
R 8 and R 9 , at each occurrence, are each independently selected from the group consisting of hydrogen, halogen, and C 1-6 alkyl;
X is a bond;
R a , at each occurrence, is independently selected from the group consisting of hydrogen, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-8 cycloalkyl, C 3-8 cycloalkenyl, 3-8 membered heterocycloalkyl, 3-8 membered heterocycloalkenyl, C 6-10 aryl, C 7-11 aralkyl, and 5-10 membered heteroaryl, wherein each of the C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-8 cycloalkyl, C 3-8 cycloalkenyl, 3-8 membered heterocycloalkyl, 3-8 membered heterocycloalkenyl, C 6-10 aryl, C 7-11 aralkyl, and 5-10 membered heteroaryl groups is optionally substituted with 1, 2, 3, 4 or 5 R f substituents;
R b and R e , at each occurrence, are each independently selected from the group consisting of hydrogen, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-8 cycloalkyl, C 3-8 cycloalkenyl, 3-8 membered heterocycloalkyl, 3-8 membered heterocycloalkenyl, C 6-10 aryl, C 7-11 aralkyl, 5-10 membered heteroaryl, C(O)R g , C(O)OR g , C(O)NR i R j , and SO 2 R g , wherein each of the C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-8 cycloalkyl, C 3-8 cycloalkenyl, 3-8 membered heterocycloalkyl, 3-8 membered heterocycloalkenyl, C 6-10 aryl, C 7-11 aralkyl, and 5-10 membered heteroaryl groups is optionally substituted with 1, 2, 3, 4 or 5 R f substituents;
R d , at each occurrence, is independently selected from the group consisting of hydrogen and C 1-6 alkyl;
R e , at each occurrence, is independently selected from the group consisting of hydrogen, CN, OH, C 1-6 alkoxy, C 1-6 alkyl, and C 1-6 haloalkyl;
R f , at each occurrence, is independently selected from the group consisting of halogen, CN, OR h , OC(O)R h , OC(O)OR h , OC(O)NR i R j , NR i R j , NR d C(O)R h , NR d C(O)OR h , NR d C(O)NR i R j , NR d C(O)C(O)NR i R j , NR d C(S)R h , NR d C(S)OR h , NR d C(S)NR i R j , NR d C(NR e )NR i R j , NR d S(O)R h , NR d SO 2 R h , NR d SO 2 NR i R j , C(O)R h , C(O)OR h , C(O)NR i R j , C(S)R h , C(S)OR h , C(S)NR i R j , C(NR e )NR i R j , SR h , S(O)R h , SO 2 R h , SO 2 NR i R j , C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-8 cycloalkyl, C 3-8 cycloalkenyl, 3-8 membered heterocycloalkyl, 3-8 membered heterocycloalkenyl, C 6-10 aryl, C 7-11 aralkyl, and 5-10 membered heteroaryl, wherein each of the C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-8 cycloalkyl, C 3-8 cycloalkenyl, 3-8 membered heterocycloalkyl, 3-8 membered heterocycloalkenyl, C 6-10 aryl, C 7-11 aralkyl, and 5-10 membered heteroaryl groups is optionally substituted with 1, 2, 3, 4 or 5 R k substituents;
or two R f substituents bound to a single carbon atom, together with the carbon atom to which they are both bound, form a group selected from the group consisting of carbonyl, C 3-8 cycloalkyl, and 3-8 membered heterocycloalkyl;
R g , at each occurrence, is independently selected from the group consisting of C 1-6 alkyl, C 1-6 haloalkyl, phenyl, naphthyl, and C 7-11 aralkyl, each optionally substituted with 1, 2, 3, 4 or 5 substituents selected from the group consisting of halogen, CN, OH, C 1-6 alkoxy, C 1-6 alkyl and C 1-6 haloalkyl;
R h , at each occurrence, is independently selected from the group consisting of hydrogen, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-8 cycloalkyl, C 3-8 cycloalkenyl, 3-8 membered heterocycloalkyl, 3-8 membered heterocycloalkenyl, C 6-10 aryl, C 7-11 aralkyl, and 5-10 membered heteroaryl, wherein each of the C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-8 cycloalkyl, C 3-8 cycloalkenyl, 3-8 me

Assignees

• Cytokinetics Inc

Inventors

• Ashcraft Luke W
• Bergnes Gustave
• Collibee Scott
• Chuang Chihyuan
• Gardina Jeff
• Morgan Bradley P
• Muci Alex R
• Qian Xiangping
• Warrington Jeffrey
• Yang Zhe
• Lu Pu-Ping
• Romero Antonio

Classifications

• A61P9/00

  Drugs for disorders of the cardiovascular system · CPC title

• A61P9/04

  Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure · CPC title

• A61P25/28

  for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia · CPC title

• A61P3/00

  Drugs for disorders of the metabolism (of the blood or the extracellular fluid A61P7/00) · CPC title

• A61P25/02

  for peripheral neuropathies · CPC title