US 12,503,468 B2 · Heterocyclic compound, intermediate, preparation method therefor and application thereof

Abstract

Disclosed by the invention is a heterocyclic compound, an intermediate, and a preparation method therefor and an application thereof. Provided by the invention are a heterocyclic compound as shown in formula I, and a stereoisomer, a geometric isomer, a tautomer, a nitrogen oxide, a hydrate, a solvate, a metabolite, an ester, a pharmaceutically acceptable salt or a prodrug thereof. The heterocyclic compound has a high P2X3 antagonistic activity, and has good selectivity, low toxicity, good metabolic stability and little taste influence.

Claims22

Dependent claims

A heterocyclic compound of formula I, a stereoisomer, or a pharmaceutically acceptable salt thereof,

wherein,
m is 1 or 2;
each R3 is independently H, halogen, or a C1-C6 alkyl;
W is a single bond;
is phenyl;
n is 1 or 2;
each R1 is independently H, halogen, an unsubstituted C1-C6 alkyl or C1-C6 alkyl substituted with one or more halogen;
Q is —S(═O)2—N(R1-9R1-10);
R1-9 and R1-10 are both H;
R2 is
wherein R2-1 and R2-2 are both H;
X and Y are each independently methylene, —O—, or
and
R2-4 is an unsubstituted C1-C6 alkyl or an unsubstituted C1-C6 alkyl-O.

11 more elements

A preparation method of a heterocyclic compound of formula I

wherein,
m is 1, 2, 3 or 4;
R3 is H, halogen, —OH, a C1-C6 haloalkyl, —CN or a C1-C6 alkyl;
when m is not 1, R3 is independently the same or different;
W is a single bond;
is phenyl;
n is 1, 2, 3 or 4;
R1 is independently H, halogen, —OH, —CN, an unsubstituted or substituted C1-C6 alkyl, or an unsubstituted or substituted C1-C6 alkyl-O—;
wherein the substituted C1-C6 alkyl or the substituted C1-C6 alkyl-O— is substituted with one or more substituents independently selected from halogen, —OH, —CF3, —CN, —COOH, —C(═O)NH2, a C1-C6 alkyl, a C1-C6 alkyl-O—, and ═O;
when a plurality of substituents are present, they are the same or different;
and when n is not 1, R1 is independently the same or different;
Q is —NH—C(═O)—R1-1, —O—C(═O)—N(R1-3R1-4), —S(═O)2—N(R1-9R1-10), —N(R1-14R1-15), —NH—S(═O)2—R1-16, an unsubstituted or substituted C3-C10 cycloalkyl, an unsubstituted or substituted C3-C9 heterocycloalkyl, an unsubstituted or substituted C3-C9 heterocycloalkenyl, or an unsubstituted or substituted 5-10 membered heteroaryl;
wherein the C3-C9 heterocycloalkyl contains 1-3 heteroatoms selected from one or more of O, S, and N;
the C3-C9 heterocycloalkenyl contains 1-3 heteroatoms selected from one or more of O, S, and N;
and the 5-10 membered heteroaryl contains 1-3 heteroatoms selected from one or more of O, S, and N;
and the substituted C3-C10 cycloalkyl, the substituted C3-C9 heterocycloalkyl, the substituted C3-C9 heterocycloalkenyl or the substituted 5-10 membered heteroaryl is substituted with one or more substituents independently selected from halogen, —OH, —CF3, —CN, —COOH, —C(═O)NH2, ═O, —N(R1-21R1-22), —C(═O)—N(R1-23R1-24), —S(═O)2—N(R1-25R1-26), —C(═O)—O—R1-27, a C1-C6 alkyl, a C1-C6 alkyl-O—, and a C3-C6 cycloalkyl that is unsubstituted or substituted with one or more Ra, wherein when a plurality of Ra are present, they are the same or different, and each Ra is halogen, —OH, ═O, —CF3, —CN, —COOH or —C(═O)NH2;
and when a plurality of substituents are present, they are the same or different;
wherein the —O—C(═O)—N(R1-3R1-4) is —O—C(═O)—NH—CH3;
—N(R1-14R1-15) is
—NH—S(═O)2—R1-16 is —NH—S(═O)2—CH3;
R1-1, R1-9, R1-10, R1-21, R1-22, R1-23, R1-24, R1-25, R1-26 and R1-27 are each independently H, an unsubstituted or substituted C1-C6 alkyl, an unsubstituted or substituted C1-C6 alkyl-O—, an unsubstituted or substituted C2-C6 alkenyl, an unsubstituted or substituted C2-C6 alkenyl-O—, an unsubstituted or substituted C2-C6 alkynyl, an unsubstituted or substituted C3-C10 cycloalkyl, an unsubstituted or substituted C3-C9 heterocycloalkyl, an unsubstituted or substituted C3-C9 heterocycloalkenyl, an unsubstituted or substituted phenyl, or an unsubstituted or substituted 5-10 membered heteroaryl;
wherein the C3-C9 heterocycloalkyl contains 1-3 heteroatoms selected from one or more of O, S, and N;
the C3-C9 heterocycloalkenyl contains 1-3 heteroatoms selected from one or more of O, S, and N;
and the 5-10 membered heteroaryl contains 1-3 heteroatoms selected from one or more of N, O, and S;
and the substituted C1-C6 alkyl, the substituted C1-C6 alkyl-O—, the substituted C2-C6 alkenyl, the substituted C2-C6 alkenyl-O—, the substituted C2-C6 alkynyl, the substituted C3-C10 cycloalkyl, the substituted C3-C9 heterocycloalkyl, the substituted C3-C9 heterocycloalkenyl, the substituted phenyl or the substituted 5-10 membered heteroaryl is substituted with one or more substituents independently selected from halogen, —OH, —CF3, —CN, —COOH, —COOCH3, —NH2, ═O, a C1-C6 alkyl, a C1-C6 alkyl-O—, and a C3-C6 cycloalkyl that is unsubstituted or substituted with one or more Rd, wherein when a plurality of Rd are present, they are the same or different, and each Rd is independently H, halogen, —OH, ═O, —CF3, —CN, —COOH or —C(═O)NH2;
and when a plurality of substituents are present, they are the same or different;
or
R2 is independently
or an unsubstituted or substituted 5-6 membered heteroaryl;
wherein the 5-6 membered heteroaryl contains 1-3 heteroatoms selected from one or more of N, O, and S;
and the substituted 5-6 membered heteroaryl is substituted with one or more substituents independently selected from halogen, —OH, —CN, an unsubstituted or halogen-substituted C1-C6 alkyl, an unsubstituted or halogen-substituted C1-C6 alkyl-O—, —C(═O) R2-7, and —C(═O)N(R2-8R2-9), wherein when a plurality of substituents are present, they are the same or different;
wherein R2-1 and R2-2 are each independently H, halogen, —OH, —CN, an unsubstituted or substituted C1-C6 alkyl, an unsubstituted or substituted C1-C6 alkyl-O—, or ═O;
wherein the substituted C1-C6 alkyl or the substituted C1-C6 alkyl-O— is substituted with one or more substituents independently selected from halogen, —OH, —CF3, —CN, a C1-C6 alkyl, a C1-C6 alkyl-O—, and ═O, and when a plurality of substituents are present, they are the same or different;
X and Y are each independently a single bond, methylene, —O—, —N(R2-3)— or
R2-3 and R2-4 are each independently H, an unsubstituted or substituted C1-C6 alkyl, an unsubstituted or substituted C3-C8 cycloalkyl, an unsubstituted or substituted C3-C8 cycloalkyl-O—or an unsubstituted or substituted C1-C6 alkyl-O—;
wherein the substituted C1-C6 alkyl, the substituted C3-C8 cycloalkyl, the substituted C3-C8 cycloalkyl-O— or the substituted C1-C6 alkyl-O— is substituted with one or more substituents independently selected from halogen, —OH, —CF3, —CN, a C1-C6 alkyl, a C1-C6 alkyl-O—, and ═O, and when a plurality of substituents are present, they are the same or different;
R2-7 is independently H, halogen, —OH, —CN, an unsubstituted or halogen-substituted C1-C6 alkyl, or an unsubstituted or halogen-substituted C1-C6 alkyl-O—;
and
R2-8 and R2-9 are each independently H, or an unsubstituted or halogen-substituted C1-C6 alkyl,
wherein the preparation method is Scheme I, Scheme II, Scheme III, Scheme IV, Scheme V, Scheme VI, Scheme VII, or Scheme VIII, wherein
Scheme I comprises the following step:
performing Stille coupling reaction as shown below on a compound of formula II-1 and an organic tin reagent of formula III-1 in an organic solvent in the presence of a catalyst to give the heterocyclic compound of formula I:
wherein X1 is Br or Cl;
Scheme II comprises the following step:
performing Suzuki coupling reaction as shown below on a compound of formula II-2 and a compound of formula III-2 in a solvent in the presence of a catalyst and a basic reagent to give the heterocyclic compound of formula I:
wherein X2 is Br or Cl;
Scheme III comprises the following step:
performing the reaction as shown below on a compound of formula II-3, a compound of formula III-3 and formaldehyde in an organic solvent to give the heterocyclic compound of formula I:
Scheme IV comprises the following step:
performing the reaction as shown below on a compound of formula II-3 and a compound of formula III-4 in an organic solvent to give the heterocyclic compound of formula I:
wherein X3 is a leaving group;
Scheme V comprises the following step:
performing amidation reaction as shown below on a compound of formula I, wherein R2 is
and Y is —NH—, and a compound of formula III-5 in an organic solvent in the presence of a basic reagent to give the heterocyclic compound of formula I, wherein Y is
wherein X4 is halogen;
Scheme VI comprises the following step:
performing deprotection reaction as shown below on a compound of formula II-4 and a compound of formula III-5 in an organic solvent in the presence of an acid to give the heterocyclic compound of formula I:
Scheme VII comprises the following step:
performing substitution reaction as shown below on a compound of formula II-5 and NH(R1-9R1-10) in an organic solvent to give the heterocyclic compound of formula I, wherein Q is —S(═O)2—N(R1-9R1-10):
wherein X5 is Br or Cl;
and
Scheme VIII comprises the following step:
performing deprotection reaction as shown below on a compound of formula II-6 or formula II-6′ in an organic solvent in the presence of an acid to give the heterocyclic compound of formula I:
wherein X6, X6 and X6″ are N protecting groups.

61 more elements

A compound selected from the group consisting of compounds of formulae II-1, II-2, II-3, II-4, II-5, II-6, and II-6′:

wherein,
m is 1, 2, 3 or 4;
R3 is H, halogen, —OH, a C1-C6 haloalkyl, —CN or a C1-C6 alkyl;
when m is not 1, R3 is independently the same or different;
W is a single bond;
is phenyl;
n is 1, 2, 3 or 4;
R1 is independently H, halogen, —OH, —CN, an unsubstituted or substituted C1-C6 alkyl, or an unsubstituted or substituted C1-C6 alkyl-O—;
wherein the substituted C1-C6 alkyl or the substituted C1-C6 alkyl-O— is substituted with one or more substituents independently selected from halogen, —OH, —CF3, —CN, —COOH, —C(═O)NH2, a C1-C6 alkyl, a C1-C6 alkyl-O—, and ═O;
when a plurality of substituents are present, they are the same or different;
and when n is not 1, R1 is independently the same or different;
Q is —NH—C(═O)—R1-1, —O—C(═O)—N(R1-3R1-4), —S(═O)2—N(R1-9R1-10), —N(R1-14R1-15), —NH—S(═O)2—R1-16, an unsubstituted or substituted C3-C10 cycloalkyl, an unsubstituted or substituted C3-C9 heterocycloalkyl, an unsubstituted or substituted C3-C9 heterocycloalkenyl, or an unsubstituted or substituted 5-10 membered heteroaryl;
wherein the C3-C9 heterocycloalkyl contains 1-3 heteroatoms selected from one or more of O, S, and N;
the C3-C9 heterocycloalkenyl contains 1-3 heteroatoms selected from one or more of O, S, and N;
and the 5-10 membered heteroaryl contains 1-3 heteroatoms selected from one or more of O, S, and N;
and the substituted C3-C10 cycloalkyl, the substituted C3-C9 heterocycloalkyl, the substituted C3-C9 heterocycloalkenyl or the substituted 5-10 membered heteroaryl is substituted with one or more substituents independently selected from halogen, —OH, —CF3, —CN, —COOH, —C(═O)NH2, ═O, —N(R1-21R1-22), —C(═O)—N(R1-23R1-24), —S(═O)2—N(R1-25R1-26), —C(═O)—O—R1-27, a C1-C6 alkyl, a C1-C6 alkyl-O—, and a C3-C6 cycloalkyl that is unsubstituted or substituted with one or more Ra, wherein when a plurality of Ra are present, they are the same or different, and each Ra is halogen, —OH, ═O, —CF3, —CN, —COOH or —C(═O)NH2;
and when a plurality of substituents are present, they are the same or different;
wherein the —O—C(═O)—N(R1-3R1-4) is —O—C(═O)—NH—CH3;
—N(R1-14R1-15) is
—NH—S(═O)2—R1-16 is —NH—S(═O)2—CH3;
R1-1, R1-9, R1-10, R1-21, R1-22, R1-23, R1-24, R1-25, R1-26 and R1-27 are each independently H, an unsubstituted or substituted C1-C6 alkyl, an unsubstituted or substituted C1-C6 alkyl-O—, an unsubstituted or substituted C2-C6 alkenyl, an unsubstituted or substituted C2-C6 alkenyl-O—, an unsubstituted or substituted C2-C6 alkynyl, an unsubstituted or substituted C3-C10 cycloalkyl, an unsubstituted or substituted C3-C9 heterocycloalkyl, an unsubstituted or substituted C3-C9 heterocycloalkenyl, an unsubstituted or substituted phenyl, or an unsubstituted or substituted 5-10 membered heteroaryl;
wherein the C3-C9 heterocycloalkyl contains 1-3 heteroatoms selected from one or more of O, S, and N;
the C3-C9 heterocycloalkenyl contains 1-3 heteroatoms selected from one or more of O, S, and N;
and the 5-10 membered heteroaryl contains 1-3 heteroatoms selected from one or more of N, O, and S;
and the substituted C1-C6 alkyl, the substituted C1-C6 alkyl-O—, the substituted C2-C6 alkenyl, the substituted C2-C6 alkenyl-O—, the substituted C2-C6 alkynyl, the substituted C3-C10 cycloalkyl, the substituted C3-C9 heterocycloalkyl, the substituted C3-C9 heterocycloalkenyl, the substituted phenyl or the substituted 5-10 membered heteroaryl is substituted with one or more substituents independently selected from halogen, —OH, —CF3, —CN, —COOH, —COOCH3, —NH2, ═O, a C1-C6 alkyl, a C1-C6 alkyl-O—, and a C3-C6 cycloalkyl that is unsubstituted or substituted with one or more Rd, wherein when a plurality of Rd are present, they are the same or different, and each Rd is independently H, halogen, —OH, ═O, —CF3, —CN, —COOH or —C(═O)NH2;
and when a plurality of substituents are present, they are the same or different;
or
R2 is independently or an unsubstituted or substituted 5-6 membered heteroaryl;
wherein the 5-6 membered heteroaryl contains 1-3 heteroatoms selected from one or more of N, O, and S;
and the substituted 5-6 membered heteroaryl is substituted with one or more substituents independently selected from halogen, —OH, —CN, an unsubstituted or halogen-substituted C1-C6 alkyl, an unsubstituted or halogen-substituted C1-C6 alkyl-O—, —C(═O) R2-7, and —C(═O)N(R2-8R2-9), wherein when a plurality of substituents are present, they are the same or different;
wherein R2-1 and R2-2 are each independently H, halogen, —OH, —CN, an unsubstituted or substituted C1-C6 alkyl, an unsubstituted or substituted C1-C6 alkyl-O—, or ═O;
wherein the substituted C1-C6 alkyl or the substituted C1-C6 alkyl-O— is substituted with one or more substituents independently selected from halogen, —OH, —CF3, —CN, a C1-C6 alkyl, a C1-C6 alkyl-O—, and ═O, and when a plurality of substituents are present, they are the same or different;
X and Y are each independently a single bond, methylene, —O—, —N(R2-3)— or
R2-3 and R2-4 are each independently H, an unsubstituted or substituted C1-C6 alkyl, an unsubstituted or substituted C3-C8 cycloalkyl, an unsubstituted or substituted C3-C8 cycloalkyl-O—, or an unsubstituted or substituted C1-C6 alkyl-O—;
wherein the substituted C1-C6 alkyl, the substituted C3-C8 cycloalkyl, the substituted C3-C8 cycloalkyl-O— or the substituted C1-C6 alkyl-O— is substituted with one or more substituents independently selected from halogen, —OH, —CF3, —CN, a C1-C6 alkyl, a C1-C6 alkyl-O—, and ═O, and when a plurality of substituents are present, they are the same or different;
R2-7 is independently H, halogen, —OH, —CN, an unsubstituted or halogen-substituted C1-C6 alkyl, or an unsubstituted or halogen-substituted C1-C6 alkyl-O—;
and
R2-8 and R2-9 are each independently H, or an unsubstituted or halogen-substituted C1-C6 alkyl, and
X1 is Br or Cl, X5 is Br or Cl, X6, X6′ and X6″ are N protecting groups.

36 more elements

Dependencies are inferred from the claim text.

Facts

Application

17/417,304Filed 27 Dec 2019

Priority

CN 201811642319.929 Dec 2018

Published

US 2023/0068538 A12 Mar 2023

Granted

23 Dec 2025

Term ends

Not estimatedThe source records don’t support an estimate.

Classification20 codes

A61P 11/00
Drugs for disorders of the respiratory system
C07D 471/04
In which the condensed system contains two hetero rings: ortho-condensed systems
A61P 11/06
Drugs for disorders of the respiratory system: antiasthmatics
A61P 11/14
Drugs for disorders of the respiratory system: antitussive agents

Heterocyclic compound, intermediate, preparation method therefor and application thereof

Life of this patent

Heterocyclic compound, intermediate, preparation method therefor and application thereof

Life of this patent

Abstract

Claims22