US 2022/0089593 A1Published application

Pde9 inhibitor and use thereof

AssigneeTransthera Sciences (Nanjing), Inc.

InventorFrank Wu

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Abstract

The present invention relates to the technical field of pharmaceuticals, and particularly to a PDE9 inhibitor compound of formula (I) or a pharmaceutically acceptable salt, an isomer, a deuterated compound, a metabolite or a prodrug thereof. The present invention also relates to pharmaceutical formulations, pharmaceutical compositions and use thereof. X1, X2, X3, X4, R1, R2, ring A, L and m are as defined in the specification. The compound of the present invention can be used in the manufacture of a medicament for treating or preventing a PDE9-mediated related disease.

Claims14

Dependent claims

A compound of general formula (I) or a pharmaceutically acceptable salt, an isomer, a deuterated compound, a metabolite or a prodrug thereof:

wherein X1, X2 and X4 are each independently selected from CR′ and N, X3 is selected from CR3 and N, and at least one of X1, X2, X3 and X4 is N, wherein the N heteroatom may be optionally oxidized to
R′ and R3, at each occurrence, are each independently selected from hydrogen, deuterium, hydroxy, amino, carboxyl, cyano, nitro, halogen, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, (C1-6 alkyl)2amino, halogenated C1-6 alkyl, halogenated C1-6 alkoxy, C2-8 alkenyl, C2-8 alkynyl, C1-6 alkylsulfonyl, C1-6 alkylthio, C3-6 cycloalkyl, 4-6 membered heterocyclyl, 5-6 membered heteroaryl, aryl, C1-6 alkylcarbonyl, aminocarbonyl, C1-6 alkylaminocarbonyl, (C1-6 alkyl)2aminocarbonyl, 4-6 membered heterocyclylcarbonyl and 5-6 membered heteroaryl-oxy, wherein the C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, (C1-6 alkyl)2amino, halogenated C1-6 alkoxy, C2-8 alkenyl, C2-8 alkynyl, C1-6 alkylsulfonyl, C1-6 alkylthio, C3-6 cycloalkyl, 4-6 membered heterocyclyl, 5-6 membered heteroaryl, aryl, C1-6 alkylcarbonyl, aminocarbonyl, C1-6 alkylaminocarbonyl, (C1-6 alkyl)2aminocarbonyl, 4-6 membered heterocyclylcarbonyl and 5-6 membered heteroaryl-oxy are unsubstituted or optionally substituted with one or more groups independently selected from hydroxy, amino, carboxyl, cyano, nitro, halogen, C1-6 alkyl, C1-6 alkoxy, C1-6 alkoxy C1-6 alkoxy, C1-6 alkylamino, (C1-6 alkyl)2amino, C1-6 alkylcarbonylamino, C1-6 alkylsulfonylamino, C1-6 alkylcarbonyloxy, C3-6 cycloalkyl, C3-6 cycloalkylcarbonyloxy, C2-8 alkynyl, halogenated C1-6 alkyl, C2-8 alkenyl, halogenated C1-6 alkoxy,
4-6 membered heterocyclyl unsubstituted or optionally substituted with one or more independent substituents, and heteroaryl unsubstituted or optionally substituted with one or more independent substituents;
the substituents for the aforementioned 4-6 membered heterocyclyl optionally substituted with one or more independent substituents and heteroaryl optionally substituted with one or more independent substituents are selected from hydroxy, amino, carboxyl, cyano, nitro, halogen, C1-6 alkyl and C1-6 alkoxy;
Y is selected from metal ions and organic ammonium ions, and is preferably Na+, K+ or NH4+;
L is a bond or —NH—(CH2)t-, wherein t is 0, 1, 2 or 3;
ring A is 3-12 membered heterocyclyl, 5-10 membered heteroaryl, 3-12 membered cycloalkyl or 3-12 membered cycloalkenyl, wherein the 3-12 membered heterocyclyl has heteroatoms selected from one of or any combinations of O, S and N, the S atom may be optionally oxidized to S(O) or S(O)2, the C atom may be optionally oxidized to C(O), the N heteroatom may be optionally oxidized to
and the 5-10 membered heteroaryl has heteroatoms selected from one of or any combinations of O, S and N;
each R1 is independently selected from hydrogen, deuterium, hydroxy, amino, carboxyl, cyano, nitro, halogen, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, (C1-6 alkyl)2amino, halogenated C1-6 alkyl, halogenated C1-6 alkoxy, C2-8 alkenyl, C2-8 alkynyl, C1-6 alkylsulfonyl, C1-6 alkylthio, 3-12 membered cycloalkyl, 3-12 membered cycloalkenyl, 3-12 membered heterocyclyl, aryl and 5-10 membered heteroaryl, wherein the C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, (C1-6 alkyl)2amino, halogenated C1-6 alkyl, halogenated C1-6 alkoxy, C2-8 alkenyl, C2-8 alkynyl, C1-6 alkylsulfonyl, C1-6 alkylthio, 3-12 membered cycloalkyl, 3-12 membered cycloalkenyl, 3-12 membered heterocyclyl, aryl and 5-10 membered heteroaryl are unsubstituted or optionally substituted with a group selected from hydroxy, amino, carboxyl, cyano, nitro, halogen, C1-6 alkyl, C1-6 alkoxy, C1-6 alkoxy C1-6 alkoxy, C1-6 alkylamino, (C1-6 alkyl)2amino, C1-6 alkylcarbonylamino and C1-6 alkylsulfonylamino;
m is 0, 1, 2 or 3;
and
R2 is selected from hydrogen, C1-6 alkyl, C2-8 alkenyl, C2-8 alkynyl and halogenated C1-6 alkyl;
with the proviso that
(1) when X2 is N, X1 is CH, X3 is CR3, and X4 is CH, ring A is
(i) when
R3 is not H;
(ii) when
R3 is not Cl;
and
(iii) when
R3 is not H,
(2) when X2 and X4 are each N, X1 is CH, X3 is CR3, ring A is
and m is 0, R3 is not methylthio;
(3) when X4 is N, X1 and X2 are each CH, X3 is CR3, ring A is
and m is 0, R3 is not hydrogen;
and
(4) when X1 is N, X2 and X4 are CR′, X3 is CR3, ring a is pyrrolidinyl or
and m is 0, R2 is not H or C1-6 alkyl;
preferably, when X2 is N, X1 is CH, X3 is CR3, X4 is CH, and
R3 is selected from isopropyl, cyclopropyl, hydroxymethyl,
C1-6 alkylcarbonyl, C1-6 alkylcarbonyloxy C1-6 alkyl, C1-6 alkyl substituted with
C3-6 cycloalkylcarbonyloxy C1-6 alkyl and deuterated C1-6 alkyl;
and
preferably, when X2 is N, X1 is CH, X3 is CR3, and X4 is CH, ring A is

31 more elements

Dependencies are inferred from the claim text.

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Abstract

A compound of general formula (I) or a pharmaceutically acceptable salt, an isomer, a deuterated compound, a metabolite or a prodrug thereof:

wherein X1, X2 and X4 are each independently selected from CR′ and N, X3 is selected from CR3 and N, and at least one of X1, X2, X3 and X4 is N, wherein the N heteroatom may be optionally oxidized to
R′ and R3, at each occurrence, are each independently selected from hydrogen, deuterium, hydroxy, amino, carboxyl, cyano, nitro, halogen, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, (C1-6 alkyl)2amino, halogenated C1-6 alkyl, halogenated C1-6 alkoxy, C2-8 alkenyl, C2-8 alkynyl, C1-6 alkylsulfonyl, C1-6 alkylthio, C3-6 cycloalkyl, 4-6 membered heterocyclyl, 5-6 membered heteroaryl, aryl, C1-6 alkylcarbonyl, aminocarbonyl, C1-6 alkylaminocarbonyl, (C1-6 alkyl)2aminocarbonyl, 4-6 membered heterocyclylcarbonyl and 5-6 membered heteroaryl-oxy, wherein the C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, (C1-6 alkyl)2amino, halogenated C1-6 alkoxy, C2-8 alkenyl, C2-8 alkynyl, C1-6 alkylsulfonyl, C1-6 alkylthio, C3-6 cycloalkyl, 4-6 membered heterocyclyl, 5-6 membered heteroaryl, aryl, C1-6 alkylcarbonyl, aminocarbonyl, C1-6 alkylaminocarbonyl, (C1-6 alkyl)2aminocarbonyl, 4-6 membered heterocyclylcarbonyl and 5-6 membered heteroaryl-oxy are unsubstituted or optionally substituted with one or more groups independently selected from hydroxy, amino, carboxyl, cyano, nitro, halogen, C1-6 alkyl, C1-6 alkoxy, C1-6 alkoxy C1-6 alkoxy, C1-6 alkylamino, (C1-6 alkyl)2amino, C1-6 alkylcarbonylamino, C1-6 alkylsulfonylamino, C1-6 alkylcarbonyloxy, C3-6 cycloalkyl, C3-6 cycloalkylcarbonyloxy, C2-8 alkynyl, halogenated C1-6 alkyl, C2-8 alkenyl, halogenated C1-6 alkoxy,
4-6 membered heterocyclyl unsubstituted or optionally substituted with one or more independent substituents, and heteroaryl unsubstituted or optionally substituted with one or more independent substituents;
the substituents for the aforementioned 4-6 membered heterocyclyl optionally substituted with one or more independent substituents and heteroaryl optionally substituted with one or more independent substituents are selected from hydroxy, amino, carboxyl, cyano, nitro, halogen, C1-6 alkyl and C1-6 alkoxy;
Y is selected from metal ions and organic ammonium ions, and is preferably Na+, K+ or NH4+;
L is a bond or —NH—(CH2)t-, wherein t is 0, 1, 2 or 3;
ring A is 3-12 membered heterocyclyl, 5-10 membered heteroaryl, 3-12 membered cycloalkyl or 3-12 membered cycloalkenyl, wherein the 3-12 membered heterocyclyl has heteroatoms selected from one of or any combinations of O, S and N, the S atom may be optionally oxidized to S(O) or S(O)2, the C atom may be optionally oxidized to C(O), the N heteroatom may be optionally oxidized to
and the 5-10 membered heteroaryl has heteroatoms selected from one of or any combinations of O, S and N;
each R1 is independently selected from hydrogen, deuterium, hydroxy, amino, carboxyl, cyano, nitro, halogen, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, (C1-6 alkyl)2amino, halogenated C1-6 alkyl, halogenated C1-6 alkoxy, C2-8 alkenyl, C2-8 alkynyl, C1-6 alkylsulfonyl, C1-6 alkylthio, 3-12 membered cycloalkyl, 3-12 membered cycloalkenyl, 3-12 membered heterocyclyl, aryl and 5-10 membered heteroaryl, wherein the C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, (C1-6 alkyl)2amino, halogenated C1-6 alkyl, halogenated C1-6 alkoxy, C2-8 alkenyl, C2-8 alkynyl, C1-6 alkylsulfonyl, C1-6 alkylthio, 3-12 membered cycloalkyl, 3-12 membered cycloalkenyl, 3-12 membered heterocyclyl, aryl and 5-10 membered heteroaryl are unsubstituted or optionally substituted with a group selected from hydroxy, amino, carboxyl, cyano, nitro, halogen, C1-6 alkyl, C1-6 alkoxy, C1-6 alkoxy C1-6 alkoxy, C1-6 alkylamino, (C1-6 alkyl)2amino, C1-6 alkylcarbonylamino and C1-6 alkylsulfonylamino;
m is 0, 1, 2 or 3;
and
R2 is selected from hydrogen, C1-6 alkyl, C2-8 alkenyl, C2-8 alkynyl and halogenated C1-6 alkyl;
with the proviso that
(1) when X2 is N, X1 is CH, X3 is CR3, and X4 is CH, ring A is
(i) when
R3 is not H;
(ii) when
R3 is not Cl;
and
(iii) when
R3 is not H,
(2) when X2 and X4 are each N, X1 is CH, X3 is CR3, ring A is
and m is 0, R3 is not methylthio;
(3) when X4 is N, X1 and X2 are each CH, X3 is CR3, ring A is
and m is 0, R3 is not hydrogen;
and
(4) when X1 is N, X2 and X4 are CR′, X3 is CR3, ring a is pyrrolidinyl or
and m is 0, R2 is not H or C1-6 alkyl;
preferably, when X2 is N, X1 is CH, X3 is CR3, X4 is CH, and
R3 is selected from isopropyl, cyclopropyl, hydroxymethyl,
C1-6 alkylcarbonyl, C1-6 alkylcarbonyloxy C1-6 alkyl, C1-6 alkyl substituted with
C3-6 cycloalkylcarbonyloxy C1-6 alkyl and deuterated C1-6 alkyl;
and
preferably, when X2 is N, X1 is CH, X3 is CR3, and X4 is CH, ring A is

31 more elements