US 2023/0147833 A1Published application

Optically pure oxaspiro-substituted pyrrolopyrazole derivative, preparation method therefor and pharmaceutical use thereof

AssigneesShanghai Haiyan Pharmaceutical Technology Co., Ltd., Yangtze River Pharmaceutical Group Co., Ltd.

InventorsBin HU, Kai ZHANG, Huiping GUAN

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Abstract

Disclosed are an optically pure oxaspiro-substituted pyrrolopyrazole derivative, a preparation method therefor and the pharmaceutical use thereof. The compounds are compounds as shown in formula (I) and formula (II) or a pharmaceutically acceptable salt thereof, or a solvate thereof, or a prodrug thereof. Also disclosed are a preparation method therefor and the use thereof

Claims31

Dependent claims

A compound as shown in Formula (I) or Formula (II), or a pharmaceutically acceptable salt, solvate, or prodrug thereof:

wherein in the Formula (I),
Ra and Rb are each independently hydrogen, halogen, C1-6 alkyl, halogenated C1-6 alkyl, or halogenated C1-6 alkoxyl;
or Ra and Rb together with the carbon atom linked thereto form a four- to six-membered saturated monoheterocyclic ring or a three- to six-membered saturated monocyclic ring, wherein the four- to six-membered saturated monoheterocyclic ring and the three- to six-membered saturated monocyclic ring are each unsubstituted or substituted with one, two or three substituent groups selected from the group consisting of cyano, hydroxyl, hydroxymethyl, cyanomethyl, halogen, C1-3 alkoxyl, C1-3 alkyl, —CO(C1-3 alkyl), —CONRa1Rb1, NRa1Rb1, —NHCO(C1-3 alkyl), —NHCONRa1Rb1, —NHSO2(C1-3 alkyl), —NHSO2NRa1Rb1, and —NHSO2(C3-6 cycloalkyl);
Rc is hydrogen, halogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 alkoxyl, halogenated C1-6 alkyl, halogenated C1-6 alkoxyl, —CO(C1-6 alkyl), —CONRa1Rb1, NRa1Rb1, —NHCO(C1-6 alkyl), —NHCONRa1Rb1, —NHSO2(C1-3 alkyl), —NHSO2NRa1Rb1, —NHSO2(C3-6 cycloalkyl), —SO2(C1-3 alkyl), —SO2NRa1Rb1, a four- to six-membered saturated monoheterocyclic ring, C6-10 aryl, or five- or six-membered monocyclic heteroaryl, wherein the four- to six-membered saturated monoheterocyclic ring, the C6-10 aryl, and the five- or six-membered monocyclic heteroaryl are each unsubstituted or substituted with one, two or three substituent groups selected from the group consisting of cyano, hydroxyl, hydroxymethyl, cyanomethyl, halogen, C1-3 alkoxyl, C1-3 alkyl, —CO(C1-3 alkyl), —CONRa1Rb1, NRa1Rb1, —NHCO(C1-3 alkyl), —NHCONRa1Rb1, —NHSO2(C1-3 alkyl), —NHSO2NRa1Rb1, and —NHSO2(C3-6 cycloalkyl),
wherein Ra1 and Rb1 are each independently hydrogen, C1-6 alkyl, halogenated C1-6 alkyl, C3-6 cycloalkyl, or a four- to six-membered saturated monoheterocyclic ring;
or Ra1 and Rb1 together with the nitrogen atom linked thereto form a four- to six-membered saturated monoheterocyclic ring, wherein the four- to six-membered saturated monoheterocyclic ring is unsubstituted or substituted with one, two, or three C1-3 alkyl groups;
and
* indicates an R or S configuration;
and
wherein in the Formula (II),
R1 and R2 are each independently hydrogen, halogen, C1-6 alkyl, halogenated C1-6 alkyl, or halogenated C1-6 alkoxyl;
or R1 and R2 together with the carbon atom linked thereto form a four- to six-membered saturated monoheterocyclic ring or a three- to six-membered saturated monocyclic ring, wherein the four- to six-membered saturated monoheterocyclic ring and the three- to six-membered saturated monocyclic ring are each unsubstituted or substituted with one, two or three substituent groups selected from the group consisting of cyano, hydroxyl, hydroxymethyl, cyanomethyl, halogen, C1-3 alkoxyl, C1-3 alkyl, —CO(C1-3 alkyl), —CONR11R12, NR11R12, —NHCO(C1-3 alkyl), —NHCONR11R12, —NHSO2(C1-3 alkyl), —NHSO2NR11R12, and —NHSO2(C3-6 cycloalkyl);
R3 is hydrogen, halogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkenyl, C1-6 alkoxyl, halogenated C1-6 alkyl, halogenated C1-6 alkoxyl, —CO(C1-6 alkyl), —CONR11R12, —NHCO(C1-6 alkyl), —NHCONR11R12, —NHSO2(C1-3 alkyl), —NHSO2NR11R12, —NHSO2(C3-6 cycloalkyl), —SO2(C1-3 alkyl), —SO2NR11R12, a four- to six-membered saturated monoheterocyclic ring, C6-10 aryl, or a five- or six-membered monocyclic heteroaryl, wherein the four- to six-membered saturated monoheterocyclic ring, the C6-10 aryl, and the five- or six-membered monocyclic heteroaryl are each unsubstituted or substituted with one, two or three substituent groups selected from the group consisting of cyano, hydroxyl, hydroxymethyl, cyanomethyl, halogen, C1-3 alkoxyl, C1-3 alkyl, —CO(C1-3 alkyl), —CONR11R12, NR11R12, —NHCO(C1-3 alkyl), —NHCONR11R12, —NHSO2(C1-3 alkyl), —NHSO2NR11R12, and —NHSO2(C3-6 cycloalkyl),
wherein R11 and R12 are each independently hydrogen, C1-6 alkyl, halogenated C1-6 alkyl, C3-6 cycloalkyl, or a four- to six-membered saturated monoheterocyclic ring;
or R11 and R12 together with the nitrogen atom linked thereto form a four- to six-membered saturated monoheterocyclic ring, wherein the four- to six-membered saturated monoheterocyclic ring is unsubstituted or substituted with one, two, or three C1-3 alkyl groups;
and
* indicates an R or S configuration.

14 more elements

A compound as shown in Formula (III), or a salt, enantiomer, diastereomer, racemate, or mixture of diastereomers thereof:

wherein,
R1a and R1b are each independently hydrogen, halogen, C1-6 alkyl, halogenated C1-6 alkyl, or halogenated C1-6 alkoxyl;
or R1a and R1b together with the carbon atom linked thereto form a four- to six-membered saturated monoheterocyclic ring or a three- to six-membered saturated monocyclic ring, wherein the four- to six-membered saturated monoheterocyclic ring and the three- to six-membered saturated monocyclic ring are each unsubstituted or substituted with one, two or three substituent groups selected from the group consisting of cyano, hydroxyl, hydroxymethyl, cyanomethyl, halogen, C1-3 alkoxyl, C1-3 alkyl, —CO(C1-3 alkyl), —CONRa1Rb1, NRa1Rb1, —NHCO(C1-3 alkyl), —NHCONRa1Rb1, —NHSO2(C1-3 alkyl), —NHSO2NRa1Rb1, and —NHSO2(C3-6 cycloalkyl);
R1c is hydrogen, halogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 alkoxyl, halogenated C1-6 alkyl, halogenated C1-6 alkoxyl, —CO(C1-6 alkyl), —CONRa1Rb1, NRa1Rb1, —NHCO(C1-6 alkyl), —NHCONRa1Rb1, —NHSO2(C1-3 alkyl), —NHSO2NRa1Rb1, —NHSO2(C3-6 cycloalkyl), —SO2(C1-3 alkyl), —SO2NRa1Rb1, a four- to six-membered saturated monoheterocyclic ring, C6-10 aryl, or a five- or six-membered monocyclic heteroaryl, wherein the four- to six-membered saturated monoheterocyclic ring, the C6-10 aryl, and the five- or six-membered monocyclic heteroaryl are each unsubstituted or substituted with one, two or three substituent groups selected from the group consisting of cyano, hydroxyl, hydroxymethyl, cyanomethyl, halogen, C1-3 alkoxyl, C1-3 alkyl, —CO(C1-3 alkyl), —CONRa1Rb1, NRa1Rb1, —NHCO(C1-3 alkyl), —NHCONRa1Rb1, —NHSO2(C1-3 alkyl), —NHSO2NRa1Rb1, and —NHSO2(C3-6 cycloalkyl),
wherein Ra1 and Rb1 are each independently hydrogen, C1-6 alkyl, halogenated C1-6 alkyl, C3-6 cycloalkyl, or a four- to six-membered saturated monoheterocyclic ring;
or Ra1 and Rb1 together with the nitrogen atom linked thereto form a four- to six-membered saturated monoheterocyclic ring, wherein the four- to six-membered saturated monoheterocyclic ring is unsubstituted or substituted with one, two, or three C1-3 alkyl groups.

3 more elements

Dependencies are inferred from the claim text.

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Abstract

A compound as shown in Formula (I) or Formula (II), or a pharmaceutically acceptable salt, solvate, or prodrug thereof:

wherein in the Formula (I),
Ra and Rb are each independently hydrogen, halogen, C1-6 alkyl, halogenated C1-6 alkyl, or halogenated C1-6 alkoxyl;
or Ra and Rb together with the carbon atom linked thereto form a four- to six-membered saturated monoheterocyclic ring or a three- to six-membered saturated monocyclic ring, wherein the four- to six-membered saturated monoheterocyclic ring and the three- to six-membered saturated monocyclic ring are each unsubstituted or substituted with one, two or three substituent groups selected from the group consisting of cyano, hydroxyl, hydroxymethyl, cyanomethyl, halogen, C1-3 alkoxyl, C1-3 alkyl, —CO(C1-3 alkyl), —CONRa1Rb1, NRa1Rb1, —NHCO(C1-3 alkyl), —NHCONRa1Rb1, —NHSO2(C1-3 alkyl), —NHSO2NRa1Rb1, and —NHSO2(C3-6 cycloalkyl);
Rc is hydrogen, halogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 alkoxyl, halogenated C1-6 alkyl, halogenated C1-6 alkoxyl, —CO(C1-6 alkyl), —CONRa1Rb1, NRa1Rb1, —NHCO(C1-6 alkyl), —NHCONRa1Rb1, —NHSO2(C1-3 alkyl), —NHSO2NRa1Rb1, —NHSO2(C3-6 cycloalkyl), —SO2(C1-3 alkyl), —SO2NRa1Rb1, a four- to six-membered saturated monoheterocyclic ring, C6-10 aryl, or five- or six-membered monocyclic heteroaryl, wherein the four- to six-membered saturated monoheterocyclic ring, the C6-10 aryl, and the five- or six-membered monocyclic heteroaryl are each unsubstituted or substituted with one, two or three substituent groups selected from the group consisting of cyano, hydroxyl, hydroxymethyl, cyanomethyl, halogen, C1-3 alkoxyl, C1-3 alkyl, —CO(C1-3 alkyl), —CONRa1Rb1, NRa1Rb1, —NHCO(C1-3 alkyl), —NHCONRa1Rb1, —NHSO2(C1-3 alkyl), —NHSO2NRa1Rb1, and —NHSO2(C3-6 cycloalkyl),
wherein Ra1 and Rb1 are each independently hydrogen, C1-6 alkyl, halogenated C1-6 alkyl, C3-6 cycloalkyl, or a four- to six-membered saturated monoheterocyclic ring;
or Ra1 and Rb1 together with the nitrogen atom linked thereto form a four- to six-membered saturated monoheterocyclic ring, wherein the four- to six-membered saturated monoheterocyclic ring is unsubstituted or substituted with one, two, or three C1-3 alkyl groups;
and
* indicates an R or S configuration;
and
wherein in the Formula (II),
R1 and R2 are each independently hydrogen, halogen, C1-6 alkyl, halogenated C1-6 alkyl, or halogenated C1-6 alkoxyl;
or R1 and R2 together with the carbon atom linked thereto form a four- to six-membered saturated monoheterocyclic ring or a three- to six-membered saturated monocyclic ring, wherein the four- to six-membered saturated monoheterocyclic ring and the three- to six-membered saturated monocyclic ring are each unsubstituted or substituted with one, two or three substituent groups selected from the group consisting of cyano, hydroxyl, hydroxymethyl, cyanomethyl, halogen, C1-3 alkoxyl, C1-3 alkyl, —CO(C1-3 alkyl), —CONR11R12, NR11R12, —NHCO(C1-3 alkyl), —NHCONR11R12, —NHSO2(C1-3 alkyl), —NHSO2NR11R12, and —NHSO2(C3-6 cycloalkyl);
R3 is hydrogen, halogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkenyl, C1-6 alkoxyl, halogenated C1-6 alkyl, halogenated C1-6 alkoxyl, —CO(C1-6 alkyl), —CONR11R12, —NHCO(C1-6 alkyl), —NHCONR11R12, —NHSO2(C1-3 alkyl), —NHSO2NR11R12, —NHSO2(C3-6 cycloalkyl), —SO2(C1-3 alkyl), —SO2NR11R12, a four- to six-membered saturated monoheterocyclic ring, C6-10 aryl, or a five- or six-membered monocyclic heteroaryl, wherein the four- to six-membered saturated monoheterocyclic ring, the C6-10 aryl, and the five- or six-membered monocyclic heteroaryl are each unsubstituted or substituted with one, two or three substituent groups selected from the group consisting of cyano, hydroxyl, hydroxymethyl, cyanomethyl, halogen, C1-3 alkoxyl, C1-3 alkyl, —CO(C1-3 alkyl), —CONR11R12, NR11R12, —NHCO(C1-3 alkyl), —NHCONR11R12, —NHSO2(C1-3 alkyl), —NHSO2NR11R12, and —NHSO2(C3-6 cycloalkyl),
wherein R11 and R12 are each independently hydrogen, C1-6 alkyl, halogenated C1-6 alkyl, C3-6 cycloalkyl, or a four- to six-membered saturated monoheterocyclic ring;
or R11 and R12 together with the nitrogen atom linked thereto form a four- to six-membered saturated monoheterocyclic ring, wherein the four- to six-membered saturated monoheterocyclic ring is unsubstituted or substituted with one, two, or three C1-3 alkyl groups;
and
* indicates an R or S configuration.

14 more elements