US 2023/0025880 A1 · FUSED TRICYCLIC COMPOUND AND MEDICINAL USE THEREOF

Abstract

The present invention provides a compound having a PDHK inhibitory activity and useful for the treatment or prophylaxis of diabetes (type 1 diabetes, type 2 diabetes etc.), insulin resistance syndrome, metabolic syndrome, hyperglycemia, hyperlactacidemia, diabetic complications (diabetic neuropathy, diabetic retinopathy, diabetic nephropathy, cataract etc.), cardiac failure (acute cardiac failure, chronic cardiac failure), cardiomyopathy, myocardial ischemia, myocardial infarction, angina pectoris, dyslipidemia, atherosclerosis, peripheral artery disease, intermittent claudication, chronic obstructive pulmonary disease s, brain ischemia, cerebral apoplexy, mitochondrial disease, mitochondrial encephalomyopathy, cancer, pulmonary hypertension, Alzheimer disease, vascular dementia, glaucoma, diabetic retinopathy, retinopathy of prematurity, retinal vein occlusion, ischemic optic neuropathy or chronic kidney disease. The present invention relates to a compound of the formula [I-a], or a pharmaceutically acceptable salt thereof: wherein each symbol is as defined in the DESCRIPTION.

A compound of formula [I-a], or a pharmaceutically acceptable salt thereof:

wherein:
a bond in a dotted line is a single bond or a double bond,
X1, X2, X3 and X4 are each independently C or N, Y1 and Y2 are each independently C, N or O, wherein a total number of N and O for X2, X3, X4, Y1 or Y2 is 0 to 3,
RA is C1-4 alkyl,
RB is:
(1) halogen,
(2) cyano,
(3) hydroxy,
(4) oxo,
(5) —COR1, wherein R1 is:
(A) hydrogen,
(B) —OH,
(C) —NR2R3, wherein R2 and R3 are each independently hydrogen or C1-4 alkyl, or
(D) a 4- to 6-membered saturated heterocyclyl having one nitrogen atom, wherein the saturated heterocyclyl is optionally substituted by 1 or 2 halogens,
(6) C1-8 alkyl, wherein the C1-8 alkyl is optionally substituted by 1 to 8 substituents independently selected from the group consisting of:
(A) halogen,
(B) hydroxy,
(C) phenyl optionally substituted by halogen,
(D) pyridyl optionally substituted by haloC1-4 alkyl, and
(E) —OR4, wherein R4 is:
(a) C1-4 alkyl,
(b) phenyl optionally substituted by halogen, or
(c) benzyl optionally substituted by C1-4 alkoxy,
(7) C1-8 alkoxy, wherein the C1-8 alkoxy is optionally substituted by 1 to 8 substituents independently selected from the group consisting of:
(A) halogen,
(B) cyano,
(C) hydroxy,
(D) C1-4 alkoxy optionally substituted by 1 to 3 halogens,
(E) C1-4 alkylsulfonyl,
(F) C3-6 cycloalkyl optionally substituted by one substituent selected from the group consisting of cyano and cyano C1-4 alkyl,
(G) phenyl optionally substituted by cyano,
(H)-COCy1, wherein Cy1 is a 4- to 6-membered saturated heterocyclyl having one nitrogen atom, and the saturated heterocyclyl is optionally substituted by 1 or 2 halogens, and
(I) a 4- to 6-membered saturated heterocyclyl having 1 or 2 hetero atoms independently selected from a nitrogen atom, an oxygen atom and a sulfur atom, wherein the saturated heterocyclyl is optionally substituted by 1 to 4 substituents independently selected from:
(a) C1-4 alkyl,
(b) oxo,
(c) C1-4 alkylcarbonyl,
(d) benzoyl optionally substituted by halogen, and
(e) C1-4 alkylsulfonyl,
when the saturated heterocyclyl is substituted by two C1-4 alkyls, the two C1-4 alkyls are optionally bonded to each other to form a bridged ring together with the atoms bonded thereto,
(8)-Cy2, wherein Cy2 is:
(A) C3-6 cycloalkyl, wherein the C3-6 cycloalkyl is optionally substituted by 1 or 2 substituents independently selected from:
(a) halogen,
(b) C1-4 alkyl,
(c) haloC1-4 alkyl, and
(d) phenyl optionally substituted by halogen,
(B) phenyl optionally substituted by 1 or 2 substituents independently selected from the group consisting of halogen, haloC1-4 alkyl, and C1-4 alkoxy, or
(C) a 4- to 6-membered saturated heterocyclyl having one nitrogen atom or oxygen atom (wherein the saturated heterocyclyl is optionally substituted by one substituent selected from the group consisting of (a) phenyl optionally substituted by halogen and (b) C1-4 alkylcarbonyl, or
(9) —OCy3, wherein Cy3 is:
(A) a 4- to 6-membered saturated heterocyclyl having one nitrogen atom or oxygen atom, wherein the saturated heterocyclyl is optionally substituted by one substituent selected from the group consisting of (a) benzoyl optionally substituted by halogen and (b) C1-4 alkylcarbonyl, or
(B) a 6-membered heteroaryl having 1 or 2 nitrogen atoms, wherein the heteroaryl is optionally substituted by 1 or 2 substituents independently selected from cyano, haloC1-4 alkyl, and C3-6 cycloalkyl,
m is 0 or 1, and
n is 0, 1 or 2, when n is 2, each RB may be the same or different.

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Fused tricyclic compound and medicinal use thereof

Life of this patent

Fused tricyclic compound and medicinal use thereof

Life of this patent

Abstract

Claims65