JPWO2021032643A5

JPWO2021032643A5 -

Info

Publication number: JPWO2021032643A5
Application number: JP2022510087A
Authority: JP
Publication date: 2023-08-17

Claims

A compound of general formula I below or a pharmaceutically acceptable salt thereof.

[In the formula,
R ¹ is hydrogen or the group —CH ₂ R ^1a , where R ^1a is hydrogen, C ₁ -C ₃ -alkyl, phenyl (phenyl is unsubstituted or independently halogen, cyano, C ₁ -C ₃ -alkyl, C ₁ -C ₃ -haloalkyl and C ₁ -C ₃ -alkoxy), and independently N, NR as ring members a 5- to 10-membered heteroaromatic ring containing 1 to 4 heteroatoms or heterogroups selected from the group consisting of ^c , O and S, wherein said 5- to 10-membered heteroaromatic ring is unsubstituted or 1, may have 2 or 3 groups R ⁷ );
R ² is selected from the group consisting of hydrogen, methyl and fluorinated methyl;
^R3 is selected from the group consisting of hydrogen, methyl and fluorinated methyl;
R ⁴ is selected from the group consisting of hydrogen and C ₁ -C ₄ -alkyl;
each R ⁵ is independently selected from the group consisting of halogen, cyano, C ₁ -C ₃ -alkyl, C ₁ -C ₃ -haloalkyl, C ₁ -C ₃ -alkoxy and C ₁ -C ₃ -haloalkoxy;
each R ⁶ is independently selected from the group consisting of halogen, cyano, C ₁ -C ₃ -alkyl, C ₁ -C ₃ -haloalkyl, C ₁ -C ₃ -alkoxy and C ₁ -C ₃ -haloalkoxy;
each R ⁷ is independently selected from the group consisting of halogen, cyano, C ₁ -C ₃ -alkyl, C ₁ -C ₃ -haloalkyl, C ₁ -C ₃ -alkoxy and C ₁ -C ₃ -haloalkoxy;
X ¹ is NR ^a or O;
X ² is NR ^b , O or S;
Y represents an oxygen atom or two hydrogen atoms;
R ^a , R ^b , R ^c are each independently selected from the group consisting of hydrogen and C ₁ -C ₄ -alkyl;
a is 0, 1, 2, 3 or 4;
b is 0, 1, 2 or 3; ]

R ¹ is selected from the group consisting of hydrogen and the group —CH ₂ R ^1a and R ^1a is hydrogen, methyl and 1 to 3 heteroatoms independently selected from the group consisting of N, O and S as ring members is selected from the group consisting of a 5- to 6-membered monocyclic ^{heteroaromatic} ring comprising A compound according to claim 1, wherein R ⁷ is selected from the group consisting of halogen, C ₁ -C ₃ -alkyl and C ₁ -C ₂ -alkoxy.

R ¹ is selected from the group consisting of hydrogen and the group —CH ₂ R ^1a , wherein R ^1a contains hydrogen and 1 to 3 heteroatoms independently selected from the group consisting of N, O and S as ring members is selected from the group consisting of 5- to 6-membered monocyclic heteroaromatic rings; R ¹ is in particular the group —CH ₂ R ^1a , R ^1a being independently selected as ring members from the group consisting of N, O and S A compound according to claim 2, which is an unsubstituted 5-6 membered monocyclic heteroaromatic ring containing 1-3 heteroatoms, in particular 1 heteroatom.

R ² is hydrogen or methyl;
R ³ is hydrogen;
R ⁴ is methyl;
each R ⁵ is independently selected from the group consisting of halogen, C ₁ -C ₃ -alkyl and C ₁ -C ₂ -alkoxy;
each R ⁶ is independently selected from the group consisting of halogen, C ₁ -C ₃ -alkyl and C ₁ -C ₂ -alkoxy;
X ¹ is NH or O;
X ² is O;
a is 0, 1 or 2;
A compound according to any one of claims 1 to 3, wherein b is 0 or 1.

A compound according to claim 1, wherein R ¹ is selected from the groups CH ₂ -I' or CH ₂ -II'.

[In the formula,
* indicates the point of attachment to the urea nitrogen atom;
each R ⁷ is independently selected from the group consisting of halogen, cyano, C ₁ -C ₃ -alkyl, C ₁ -C ₃ -haloalkyl, C ₁ -C ₃ -alkoxy and C ₁ -C ₃ -haloalkoxy;
X ³ is NR ^c , O or S;
R ^c is selected from the group consisting of hydrogen and C ₁ -C ₄ -alkyl;
c is 0, 1, 2 or 3; ]

R ² is hydrogen or methyl;
R ³ is hydrogen;
R ⁴ is methyl;
each R ⁵ is independently selected from the group consisting of halogen, C ₁ -C ₃ -alkyl and C ₁ -C ₂ -alkoxy;
each R ⁶ is independently selected from the group consisting of halogen, C ₁ -C ₃ -alkyl and C ₁ -C ₂ -alkoxy;
each R ⁷ is independently selected from the group consisting of halogen, C ₁ -C ₃ -alkyl and C ₁ -C ₂ -alkoxy;
X ¹ is NH or O;
X ² is O;
X ³ is O or S;
a is 0, 1 or 2;
b is 0 or 1;
6. The compound of claim 5, wherein c is 0 or 1.

R ² is hydrogen;
R ³ is hydrogen;
R ⁴ is methyl;
X ¹ is NH or O;
X ² is O;
X ³ is O or S;
a is 0;
b is 0;
7. The compound of claim 6, wherein c is 0.

Formula IA below:

[In the formula,
X ¹ is NH or O;
^X3 is O or S; ]
or Formula IB below:

[In the formula,
X ¹ is NH or O; ]
or Formula IC below:

[In the formula,
X ¹ is NH or O;
^X3 is O or S; ]
or Formula I-D below:

[In the formula,
R ¹ is hydrogen or methyl;
X ¹ is NH or O; ]
The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 7 , represented by

below:
[2-(2-furylmethylcarbamoylamino)-2-oxo-ethyl] 4-[(4-methyl-2-oxo-chromen-7-yl)oxymethyl]benzoate ;
4-[(4-methyl-2-oxo-chromen-7-yl)oxymethyl]-N-[2-(2-thienylmethylcarbamoylamino)ethyl]benzamide ;
[2-oxo-2-(2-pyridylmethylcarbamoylamino)ethyl]4-[(4-methyl-2-oxo-chromen-7-yl)oxymethyl]benzoate ;
N-[2-(2-furylmethylcarbamoylamino)-2-oxo-ethyl]-4-[(4-methyl-2-oxo-chromen-7-yl)oxymethyl]benzamide ;
[2-oxo-2-(2-thienylmethylcarbamoylamino)ethyl] 4-[(4-methyl-2-oxo-chromen-7-yl)oxymethyl]-benzoate ;
4-[(4-methyl-2-oxo-chromen-7-yl)oxymethyl]-N-[2-oxo-2-(2-thienylmethylcarbamoylamino)ethyl]-benzamide ;
(1-methyl-2-oxo-2-ureido-ethyl) 4-[(4-methyl-2-oxo-chromen-7-yl)oxymethyl]benzoate ; and [1-methyl-2-(methylcarbamoylamino )-2-oxo-ethyl]4-[(4-methyl-2-oxo-chromen-7-yl)oxymethyl]benzoate ;
A compound selected from the group consisting of or a pharmaceutically acceptable salt thereof.

A pharmaceutical composition comprising at least one compound according to any one of claims 1 to 9 or at least one pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable carrier.

A compound according to any one of claims 1 to 9 , or a pharmaceutically acceptable salt thereof, for use as a pharmaceutical.

A compound according to any one of claims 1 to 9 , or a pharmaceutically acceptable salt thereof, for use in treating or preventing a muscle wasting condition.

The following diseases or conditions:
Congestive Heart Failure, Chronic Heart Failure, Cancer, Cancer Treatment with Myotoxic and/or Cardiotoxic Agents such as Doxorubicin, Congenital Myopathy, AIDS, Chronic Obstructive Pulmonary Disease (COPD), Chronic Kidney Disease, Renal Failure, Diabetes , severe burns, age-related sarcopenia, reduced blood supply, temporary or long-term immobilization, long-term mechanical ventilation, denervation, long-term weightlessness and malnutrition of skeletal or myocardial atrophy. for therapeutic or prophylactic use, or
for use in the treatment or prevention of conditions associated with increased muscle ring finger 1 (MuRF1) expression, or
for use in the treatment or prevention of cardiac conditions associated with systolic or diastolic dysfunction; or
for use in the treatment or prevention of diabetes,
A compound according to any one of claims 1 to 9 or a pharmaceutically acceptable salt thereof.

the condition associated with increased muscle ring finger 1 (MuRF1) expression is myopathy associated with increased muscle ring finger 1 (MuRF1) expression;
said myopathy is selected from critical illness myopathy, nemarin myopathy, inflammatory myopathy, myopathy from diabetes, myopathy from pulmonary hypertension, myopathy from chronic heart failure, myopathy from renal failure and myopathy from neoplastic cachexia , a compound according to claim 13 or a pharmaceutically acceptable salt thereof .

- atrophy of skeletal or myocardial muscle due to or associated with heart failure with reduced ejection fraction (HF-rEF), heart failure with preserved ejection fraction (HF-pEF), hypertension or tumor cachexia;
- doxorubicin-induced muscle atrophy and/or cardiotoxicity;
- age-related sarcopenia and/or cardiomyopathy;
- muscle atrophy due to chronic kidney disease;
- diaphragmatic weakness due to mechanical ventilation or congestive heart failure;
- congenital myopathy, especially congenetic muscle atrophy;
- diabetes-induced muscle atrophy; and/or - a compound according to any one of claims 1 to 9 , or a pharmaceutically acceptable salt thereof, for use in the treatment or prevention of diabetes.