Tetrahydroisoquinoline derivatives

Patent metadata

Field	Value
Publication number	US-9914741-B2
Application number	US-201715429738-A
Country	US
Kind code	B2
Filing date	Feb 10, 2017
Priority date	Feb 12, 2016
Publication date	Mar 13, 2018
Grant date	Mar 13, 2018

Abstract

Novel tetrahydroisoquinoline derivative compounds are disclosed herein that may be used as an active ingredient for a pharmaceutical composition, and in particular, for a pharmaceutical composition useful for preventing or treating a disease or condition responsive to modulation of the contractility of the skeletal sarcomere. This may be accomplished, for example, by modulation of the troponin complex of the fast skeletal muscle sarcomere through one or more of fast skeletal myosin, actin, tropomyosin, troponin C, troponin I, and troponin T, and fragments and isoforms thereof. The tetrahydroisoquinoline derivative compounds can thus be used as an agent for preventing or treating 1) neuromuscular disorders, 2) disorders of voluntary muscle, 3) CNS disorders in which muscle weakness, atrophy, and fatigue are prominent symptoms, 4) muscle symptoms stemming from systemic disorders, and 5) dysfunctions of pelvic floor and urethral/anal sphincter muscle.

First claim

We claim the following:

1. A compound of formula (I) or a salt thereof:

wherein,
X 1 is C—R 11 or N;
X 2 is C—R 12 or N;
R 11 is i) H, ii) halogen, iii) —CN, or iv) —O—C 1-6 alkyl;
R 12 is H or halogen;
R 1 is i) H, ii) C 1-6 alkyl which may be substituted with one or more substituent(s) selected from the group consisting of halogen(s), and pyrazolyl(s), iii) C 2-6 alkenyl, or iv) —OR 0 ;
R 2 is i) C 1-6 alkyl which may be substituted with one or more substituent(s) selected from the group consisting of —OR 0 (s), halogen(s), —COOR 0 (s), —CONR 21 R 22 (s), phenyl(s) which may be substituted with one or more substituent(s) selected from the G 1 group, and heteroaryl(s) which is selected from the group consisting of pyridyl, pyrazolyl, imidazolyl, thiazolyl, thiadiazolyl, thienyl, oxazolyl, isoxazolyl, and triazolyl, wherein, the heteroaryl may be substituted with one or more substituent(s) selected from the G 2 group, ii) C 2-6 alkenyl, iii) C 2-6 alkynyl, iv) —OR 0 , v) —NR 23 R 24 , vi) —COOR 0 , or vii) phenyl;
R 21 is H or C 1-6 alkyl;
R 22 is i) C 1-6 alkyl which may be substituted with one or more phenyl(s), or ii) phenyl;
R 23 is i) H, or ii) C 1-6 alkyl which may be substituted with one or more —OH(s);
R 24 is i) C 1-6 alkyl which may be substituted with one or more phenyl(s) which may be substituted with one or more halogen(s), ii) C 3-8 cycloalkyl which may be substituted with one or more C 1-6 alkyl(s), iii) phenyl which may be substituted with one or more halogen(s), or iv) tetrahydropyranyl; or
R 1 , R 2 , and a carbon atom bounded by R 1 and R 2 may interact to form a 4-piperidine ring or 4-tetrahydropyran ring, and the carbon atom bounded by R 1 and R 2 is a spiro atom and the 4-piperidine ring may be substituted with one or more substituent(s) selected from the group consisting of —SO 2 —(C 1-6 alkyl) and —COOR 0 ;
R 3 and R 4 are the same or different from each other, and are i) C 1-3 alkyl which may be substituted with one or more substituent(s) selected from the group consisting of halogen(s) and —OH(s) or ii) C 2-6 alkenyl which may be substituted with one or more substituent(s) selected from the group consisting of —OH(s) and heteroaryl(s) which is selected from the group consisting of pyrazolyl and thienyl, wherein the heteroaryl may be substituted with one or more C 1-6 alkyl(s), or,
R 3 , R 4 , and a carbon atom bounded by R 3 and R 4 may interact to form a 3-oxetane ring and the carbon atom bounded by R 3 and R 4 is a spiro atom;
R 5 is i) H, ii) C 1-6 alkyl which may be substituted with one or more —O—(C 1-6 alkyl)(s), iii) —O—C 1-6 alkyl, iv) halogen, v) —COO—(C 1-6 alkyl), or vi) C 3-8 cycloalkyl;
R 6 is i) H, ii) C 1-6 alkyl which may be substituted with one or more substituent(s) selected from the group consisting of —O—(C 1-6 alkyl(s) which may be substituted with one or more halogen(s)) and halogen(s), iii) —OH, iv) —O—(C 1-6 alkyl which may be substituted with one or more halogen(s)), v) halogen, vi) —CN, vii) —S—(C 1-6 alkyl), viii) C 3-8 cycloalkyl, ix) —NR 0 R 0 , or x) C 2-6 alkenyl;
G 1 group is i) halogen, ii) —COOR 0 , iii) —CONR 0 R 0 , iv) —OH, v) C 1-6 alkyl which may be substituted with one or more substituent(s) selected from the group consisting of —OH(s) and halogen, or vi) —O—(C 1-6 alkyl which may be substituted with one or more substituent(s) selected from the group consisting of —OH(s) and halogen(s));
G 2 group is i) halogen, ii) C 1-6 alkyl which may be substituted with one or more substituent(s) selected from the group consisting of —OH(s) and halogen(s) or iii) —CONR 0 R 0 ;
R 0 is the same or different from each other, and is H or C 1-6 alkyl, provided that said compound is not methyl 1,1-diallyl-3-oxo-2,4-dihydroisoquinoline-4-carboxylate or a salt thereof.

2. The compound or salt of claim 1 , wherein
R 1 is i) H, or ii) C 1-6 alkyl;
R 2 is i) C 1-6 alkyl which may be substituted with one or more substituent(s) selected from the group consisting of —OR 0 (s), halogen(s), —CONR 21 R 22 (s), phenyl(s) which may be substituted with one or more substituent(s) selected from the group consisting of halogen(s) and —COOR 0 (s), and heteroaryl(s) which is selected from the group consisting of pyrazolyl, and triazolyl, ii) C 2-6 alkenyl, iii) C 2-6 alkynyl, iv) —NR 23 R 24 , or v) —COOR 0 ;
R 21 is C 1-6 alkyl;
R 22 is C 1-6 alkyl;
R 23 is C 1-6 alkyl; and
R 24 is i) C 3-8 cycloalkyl, or ii) phenyl; or
R 1 , R 2 , and a carbon atom bounded by R 1 and R 2 may interact to form a 4-tetrahydropyran ring, and the carbon atom bounded by R 1 and R 2 is a spiro atom.

3. The compound or salt of claim 2 , wherein
R 3 and R 4 are the same or different each other, i) C 1-3 alkyl which may be substituted with one or more substituent(s) selected from the group consisting of halogen(s) and —OH(s) or ii) C 2-6 alkenyl which may be substituted with one or more substituent(s) selected from the group consisting of —OH(s) and pyrazolyl(s) which may be substituted with one or more C 1-6 alkyl(s), or,
R 3 , R 4 , and a carbon atom bounded by R 3 and R 4 may interact to form a 3-oxetane ring and the carbon atom bounded by R 3 and R 4 is a spiro atom.

4. The compound or salt of claim 3 , wherein
R 5 is i) H, ii) C 1-6 alkyl, iii) —O—C 1-6 alkyl, iv) halogen, or v) C 3-8 cycloalkyl; and
R 6 is i) H, ii) C 1-6 alkyl which may be substituted with one or more substituent(s) selected from the group consisting of —O—(C 1-6 alkyl)(s) and halogen(s), iii) —OH, iv) —O—(C 1-6 alkyl which may be substituted with one or more halogen(s)), v) halogen, vi) —CN, vii) —S—C 1-6 alkyl, viii) —NR 0 R 0 , or ix) C 2-6 alkenyl.

5. The compound or salt of claim 4 , wherein
X 1 is C—R 11 or N;
X 2 is C—R 12 or N;
R 11 is i) H, ii) halogen, iii) —CN, or iv) —O—C 1-6 alkyl; and
R 12 is H.

6. The compound or salt of claim 5 , wherein
R 1 is C 1-6 alkyl;
R 2 is C 1-6 alkyl which may be substituted with a —OR 0 ;
R 3 , R 4 , and a carbon atom bounded by R 3 and R 4 interact to form a 3-oxetane ring and the carbon atom bounded by R 3 and R 4 is a spiro atom as represented by formula (II) below:

R 5 is H; and
R 6 is i) C 1-6 alkyl, ii) —O—C 1-6 alkyl which is substituted with one to three halogen(s), iii) halogen, or iv) —CN.

7. The compound or salt of claim 6 , wherein
X 1 is C—R 11 ;
X 2 is C—R 12 ;
R 11 is i) H, ii) halogen, iii) —CN, or iv) —O—C 1-6 alkyl; and
R 12 is H.

8. The compound or salt of claim 1 , which is a compound selected from the group consisting of
(−)-2-(difluoromethyl)-8-ethyl-8-(2-hydroxyethyl)-6H-spiro[1,6-naphthyridine-5,3′-oxetan]-7(8H)-one,
4,4-diethyl-1,1-dimethyl-3-oxo-1,2,3,4-tetrahydroisoquinoline-6-carbonitrile,
8,8-diethyl-5,5-dimethyl-7-oxo-5,6,7,8-tetrahydro-1,6-naphthyridine-2-carbonitrile,
(−)-6-bromo-4-ethyl-4-(2-hydroxyethyl)-1,1-dimethyl-1,4-dihydroisoquinolin-3(2H)-one,
(+)-6-bromo-4-ethyl-4-(2-hydroxyethyl)-1,1-dimethyl-1,4-dihydroisoquinolin-3(2H)-one,
8,8-diethyl-7-oxo-7,8-dihydro-6H-spiro[1,6-naphthyridine-5,3′-oxetane]-2-carbonitrile,
8′,8′-diethyl-7′-oxo-7′,8′-dihydro-6′H-spiro[oxetane-3,5′-pyrido[3,4-b]pyrazine]-2′-carbonitrile,
4,4-diethyl-3-oxo-3,4-dihydro-2H-spiro[isoquinoline-1,3′-oxetane]-6-carbonitrile,
6-chloro-4,4-dimethyl-2H-spiro[isoquinoline-1,3′-oxetan]-3(4H)-one,
4,4-dimethyl-3-oxo-3,4-dihydro-2H-spiro[isoquinoline-1,3′-oxetane]-6-carbonitrile,
2-(difluoromethoxy)-8,8-dimethyl-6H-sp

Assignees

• Astellas Pharma Inc
• Cytokinetics Inc
• Cytokinectics Incorporated

Inventors

• Sato Ippei
• Kamikubo Takashi
• Miura Masanori
• Matsushima Yuji
• Tanaka Hiroaki
• Shiina Yasuhiro
• Yamaki Susumu
• Saito Tomoyuki
• Kiyohara Hiroshi
• OHE Munemichi
• Mihara Kayoko
• Morgan Bradley Paul
• Malik Fady
• Collibee Scott Emile
• Ashcraft Luke
• Lu Pu-Ping
• Warrington Jeffrey Michael
• Garard Marc

Classifications

• C07D471/04

  Ortho-condensed systems · CPC title

• C07D491/107 Primary

  with only one oxygen atom as ring hetero atom in the oxygen-containing ring · CPC title

• C07D491/20 Primary

  Spiro-condensed systems · CPC title

• C07D217/24 Primary

  Oxygen atoms · CPC title

• C07D471/10

  Spiro-condensed systems · CPC title