JPWO2020257161A5

JPWO2020257161A5 -

Info

Publication number: JPWO2020257161A5
Application number: JP2021575327A
Authority: JP
Publication date: 2023-06-21
Anticipated expiration: 2040-06-16

Claims

Formula (I):

[In the formula,
Ar ¹ is phenyl substituted with 1-2 R ^1a and 1-2 R ^1b or 1-3 substituted with 1-2 R ^1a and 1-2 R ^1b is a 6-membered ring heteroaryl containing a nitrogen atom of;
Ar ² is phenyl substituted with 1-4 R ² or 6-membered heteroaryl containing 1-3 nitrogen atoms substituted with 1-4 R ² ;
Ar ³ is phenyl substituted with 0-4 R ³ or pyridinyl substituted with 0-4 R ³ ;
R ^1a is hydrogen or halogen;
R ^1b is halogen, haloalkyl, alkoxy, or haloalkoxy;
^R2 is hydrogen, cyano, halogen, alkyl, hydroxyalkyl, haloalkyl, cycloalkyl, alkoxy, or haloalkoxy;
^R3 is cyano, halogen, alkyl, alkoxy, hydroxyalkyl, alkoxyalkyl, or haloalkyl; and
^R4 is alkyl or alkoxy]
or a pharmaceutically acceptable salt thereof.

Formula (II):

[In the formula,
Ar ¹ is phenyl substituted with 1 R ^1a and 1-2 R ^1b or 1-2 nitrogen atoms substituted with 1 R ^1a and 1-2 R ^1b is a 6-membered heteroaryl containing;
Ar ² is phenyl substituted with 1-3 R ² or pyridinyl substituted with 1-3 R ² ;
R ^1a is hydrogen or halogen;
R ^1b is halogen, C _1-4 haloalkyl, C _1-4 alkoxy, or C _1-4 haloalkoxy;
^R2 is hydrogen, halogen, _C1-4 alkyl, _C1-4 hydroxyalkyl, _C1-4 haloalkyl, _C3-6 cycloalkyl, _C1-4 alkoxy, or _C1-4 haloalkoxy; and
R ⁴ is C _1-3 alkyl]
or a pharmaceutically acceptable salt thereof , according to claim 1, having the structure

Formula (III):

[In the formula,
Ar ¹ is phenyl substituted with 1 R ^1a and 1-2 R ^1b , pyridinyl substituted with 1 R ^1a and 1-2 R ^1b , or 1 R ^1a and 1 pyrazinyl substituted with ~2 R ^1b ;
R ^1a is hydrogen or halogen;
R ^1b is halogen, C _1-4 haloalkyl, C _1-4 alkoxy, or C _1-4 haloalkoxy;
^R2 is hydrogen, halogen, _C1-4 alkyl, _C1-4 hydroxyalkyl, _C1-4 haloalkyl, _C3-6 cycloalkyl, _C1-4 alkoxy, or _C1-4 haloalkoxy; and
R ⁴ is C _1-2 alkyl]
3. The compound of claim 1 or 2 having the structure or a pharmaceutically acceptable salt thereof.

Formula (IV):

[In the formula,
R ^1a is hydrogen or F;
R ^1b is halogen, C _1-2 haloalkyl, or C _1-2 alkoxy;
^R2 is hydrogen, halogen, _C1-3 alkyl, _C1-3 haloalkyl, or _C3-6 cycloalkyl; and
^R4 is methyl or ethyl]
4. The compound of claim 3 having the structure or a pharmaceutically acceptable salt thereof.

Formula (VI):

[In the formula,
R ^1a is hydrogen or F;
R ^1b is halogen, C _1-2 haloalkyl, or C _1-2 alkoxy;
^R2 is halogen, _C1-3 alkyl, _C1-3 haloalkyl, or _C3-6 cycloalkyl; and
^R4 is methyl or ethyl]
5. The compound of claim 4 having the structure or a pharmaceutically acceptable salt thereof.

During the ceremony,
R ^1a is hydrogen or F;
^R1b is F, Cl, or _CF3 ;
^R2 is hydrogen, F, Cl, isopropyl, CF3 _, or cyclopropyl; and
^R4 is methyl;
6. A compound according to claim 4 or 5, or a pharmaceutically acceptable salt thereof.

Formula (V):

[In the formula,
R ^1a is hydrogen or F;
R ^1b is halogen, C _1-2 haloalkyl, or C _1-2 alkoxy;
^R2 is halogen; and
^R4 is methyl or ethyl]
4. The compound of claim 3 having the structure or a pharmaceutically acceptable salt thereof.

Formula (VII):

[In the formula,
R ^1a is hydrogen or halogen;
R ^1b is halogen, C _1-2 haloalkyl, or C _1-2 alkoxy;
^R2 is hydrogen, halogen, _C1-3 alkyl, or _C3-6 cycloalkyl; and
R ⁴ is C _1-2 alkyl]
4. The compound of claim 3 having the structure or a pharmaceutically acceptable salt thereof.

Formula (VIII):

[In the formula,
R ^1b is halogen, C _1-2 haloalkyl, or C _1-2 alkoxy;
^R2 is hydrogen, halogen, _C1-3 alkyl, or _C3-6 cycloalkyl; and
R ⁴ is C _1-2 alkyl]
4. The compound of claim 3 having the structure or a pharmaceutically acceptable salt thereof.

Formula (IX):

[In the formula,
Ar ¹ is phenyl substituted with 1 R ^1a and 1-2 R ^1b , pyridinyl substituted with 1 R ^1a and 1-2 R ^1b , or 1 R ^1a and 1 pyrazinyl substituted with ~2 R ^1b ;
R ^1a is hydrogen or halogen;
R ^1b is halogen, C _1-4 haloalkyl, C _1-4 alkoxy, or C _1-4 haloalkoxy; and
R ⁴ is C _1-2 alkyl]
3. The compound of claim 1 or 2 having the structure or a pharmaceutically acceptable salt thereof.

the following:

2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, selected from the group consisting of:

A composition comprising a compound according to any one of claims 1-11, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, diluent, or excipient.

A pharmaceutical composition comprising a compound according to any one of claims 1 to 11, or a pharmaceutically acceptable salt thereof, for use in therapy.

14. A pharmaceutical composition according to claim 13 for treating heart disease .

15. The pharmaceutical composition according to claim 14, wherein the heart disease is selected from the group consisting of angina pectoris, unstable angina, myocardial infarction, heart failure, acute coronary disease, and iatrogenic heart injury.

Heart failure includes congestive heart failure, systolic heart failure, diastolic heart failure, heart failure with reduced ejection fraction (HF _R EF), heart failure with preserved ejection fraction (HF _P EF), acute heart failure, ischemic and non-ischemic heart failure. 16. The pharmaceutical composition according to claim 15, selected from the group consisting of hematogenous chronic heart failure.