# US 11,111,249 B2 · Heteroaryl-pyrazole derivative, and preparation method therefor and medical application thereof

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- Number: US 11,111,249 B2
- Document ID: US11111249B2
- Status: Granted
- Kind: B2
- Application number: 16/612,620
- Filed: 2018-05-17
- Published: 2020-04-30
- Granted: 2021-09-07
- Earliest claimed: 2017-05-18
- Assignees: Jiangsu Hengrui Medicine Co., Ltd.; Shanghai Hengrui Pharmaceutical Co., Ltd.
- Applicants: Jiangsu Hengrui Medicine Co., Ltd.; Shanghai Hengrui Pharmaceutical Co., Ltd.
- Inventors: Guobao Zhang; Dianqiang Ma; Huiqing Yuan; Feng He; Weikang Tao
- Web page: https://patentgrep.com/patent/US11111249B2

## CPC

- A61P 35/00: Antineoplastic agents
- C07D 487/04: Ortho-condensed systems
- A61K 31/519: ortho- or peri-condensed with heterocyclic rings
- A61K 31/5377: not condensed and containing further heterocyclic rings, e.g. timolol
- A61K 31/551: having two nitrogen atoms, e.g. dilazep
- A61P 31/12: Antivirals
- C07D 519/00: Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00
- A61P 31/14: for RNA viruses
- A61P 31/20: for DNA viruses
- A61P 31/22: for herpes viruses
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D)

## Abstract

A heteroaryl-pyrazole derivative, and a preparation method therefor and a medical application thereof are described. Specifically, a new heteroaryl-pyrazole derivative as shown in formula (I), a preparation method for the derivative, a pharmaceutical composition containing the derivative, and a use of the derivative as a therapeutic agent, in particular as a TLR7 agonist, are described. The substituents in formula (I) have the same definitions as in the description.

## Claims

### Claim 1

A compound of formula (I):
or a tautomer, a mesomer, a racemate, an enantiomer, a diastereomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof,
wherein,
ring A is selected from the group consisting of cycloalkyl, aryl and heteroaryl;
G is N or CR4;
L1 is selected from the group consisting of —NR5—, —O—, —C(O)—, —S(O)m—, —N(R5)C(O)—, —C(O)N(R5)—, —N(R5)S(O)2—, —S(O)2N(R5)— and a covalent bond;
R1 is selected from the group consisting of hydrogen atom, alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein each of the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl is independently and optionally substituted by one or more substituents selected from the group consisting of alkyl, alkoxy, halogen, haloalkyl, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl;
each R2 is identical or different, and each is independently selected from the group consisting of hydrogen atom, halogen, alkyl, alkoxy, haloalkyl, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl, heteroaryl, —C(O)R6, —C(O)OR6, —S(O)mR6, —NR7R8 and —C(O)NR7R8, wherein each of the alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl is independently and optionally substituted by one or more substituents selected from the group consisting of alkyl, alkoxy, halogen, haloalkyl, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl;
L2 is alkylene or a covalent bond, wherein the alkylene is optionally substituted by one or more substituents selected from the group consisting of halogen, alkyl, alkoxy, haloalkyl, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl and heterocyclyl;
R3 is selected from the group consisting of hydrogen atom, alkyl, alkoxy, halogen, haloalkyl, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl, heteroaryl, —C(O)R6, —C(O)OR6, —S(O)mR6, —NR7R8 and —C(O)NR7R8, wherein each of the cycloalkyl, heterocyclyl, aryl and heteroaryl is independently and optionally substituted by one or more substituents selected from the group consisting of alkyl, alkoxy, halogen, haloalkyl, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl, heteroaryl, —C(O)R6, —C(O)OR6, —S(O)mR6, —NR7R8 and —C(O)NR7R8;
Ra and Rb are identical or different, and each is independently selected from the group consisting of hydrogen atom, halogen, alkyl, alkoxy, haloalkyl, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl;
R4 is selected from the group consisting of hydrogen atom, halogen, alkyl, alkoxy, haloalkyl, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl;
R5 is selected from the group consisting of hydrogen atom, alkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;
R6 is selected from the group consisting of hydrogen atom, alkyl, haloalkyl, amino, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;
R7 and R8 are identical or different, and each is independently selected from the group consisting of hydrogen atom, alkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein each of the alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl is independently and optionally substituted by one or more substituents selected from the group consisting of alkyl, alkoxy, halogen, amino, cyano, nitro, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;
or, R7 and R8 are linked together with the attached nitrogen atom to form heterocyclyl, wherein, except the one nitrogen atom, the heterocyclyl contains one or two identical or different heteroatoms selected from the group consisting of N, O and S, and the heterocyclyl is optionally substituted by one or more substituents selected from the group consisting of alkyl, alkoxy, halogen, amino, cyano, nitro, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;
n is 0, 1, 2, 3 or 4; and
m is 0, 1 or 2.

### Claim 2 (depends on 1)

The compound according to claim 1, being a compound of formula (II):
or a tautomer, a mesomer, a racemate, an enantiomer, a diastereomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof,
wherein
the ring A, L1, L2, R1, R2, R3 and n are as defined in claim 1.

### Claim 3 (depends on 1)

The compound according to claim 1, wherein the ring A is phenyl or pyridyl.

### Claim 4 (depends on 1)

The compound according to claim 1, being a compound of formula (III):
or a tautomer, a mesomer, a racemate, an enantiomer, a diastereomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof,
wherein,
R7 and R8 are linked together with the attached nitrogen atom to form heterocyclyl, wherein, except the one nitrogen atom, the heterocyclyl contains one or two identical or different heteroatoms selected from the group consisting of N, O and S, and the heterocyclyl is optionally substituted by one or more substituents selected from the group consisting of alkyl, alkoxy, halogen, amino, cyano, nitro, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl; and
L1, L2, and R1 are as defined in claim 1.

### Claim 5 (depends on 1)

The compound according to claim 1, wherein L1 is —O—.

### Claim 6 (depends on 1)

The compound according to claim 1, wherein R1 is alkyl.

### Claim 7 (depends on 1)

The compound according to claim 1, wherein L2 is alkylene.

### Claim 8

A compound of formula:

### Claim 9

A compound of formula (IA):
or a tautomer, a mesomer, a racemate, an enantiomer, a diastereomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof,
wherein,
W is amino protecting group;
ring A is selected from the group consisting of cycloalkyl, aryl and heteroaryl;
G is N or CR4;
L1 is selected from the group consisting of —NR5—, —O—, —C(O)—, —S(O)m—, —N(R5)C(O)—, —C(O)N(R5)—, —N(R5)S(O)2—, —S(O)2N(R5)— and a covalent bond;
R1 is selected from the group consisting of hydrogen atom, alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein each of the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl is independently and optionally substituted by one or more substituents selected from the group consisting of alkyl, alkoxy, halogen, haloalkyl, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl;
each R2 is identical or different, and each is independently selected from the group consisting of hydrogen atom, halogen, alkyl, alkoxy, haloalkyl, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl, heteroaryl, —C(O)R6, —C(O)OR6, —S(O)mR6, —NR7R8 and —C(O)NR7R8, wherein each of the alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl is independently and optionally substituted by one or more substituents selected from the group consisting of alkyl, alkoxy, halogen, haloalkyl, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl;
L2 is alkylene or a covalent bond, wherein the alkylene is optionally substituted by one or more substituents selected from the group consisting of halogen, alkyl, alkoxy, haloalkyl, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl and heterocyclyl;
R3 is selected from the group consisting of hydrogen atom, alkyl, alkoxy, halogen, haloalkyl, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl, heteroaryl, —C(O)R6, —C(O)OR6, —S(O)mR6, —NR7R8 and —C(O)NR7R8, wherein each of the cycloalkyl, heterocyclyl, aryl and heteroaryl is independently and optionally substituted by one or more substituents selected from the group consisting of alkyl, alkoxy, halogen, haloalkyl, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl, heteroaryl, —C(O)R6, —C(O)OR6, —S(O)mR6, —NR7R8 and —C(O)NR7R8;
Ra and Rb are identical or different, and each is independently selected from the group consisting of hydrogen atom, halogen, alkyl, alkoxy, haloalkyl, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl;
R4 is selected from the group consisting of hydrogen atom, halogen, alkyl, alkoxy, haloalkyl, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl;
R5 is selected from the group consisting of hydrogen atom, alkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;
R6 is selected from the group consisting of hydrogen atom, alkyl, haloalkyl, amino, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;
R7 and R8 are identical or different, and each is independently selected from the group consisting of hydrogen atom, alkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein each of the alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl is independently and optionally substituted by one or more substituents selected from the group consisting of alkyl, alkoxy, halogen, amino, cyano, nitro, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;
or, R7 and R8 are linked together with the attached nitrogen atom to form heterocyclyl, wherein, except the one nitrogen atom, the heterocyclyl contains one or two identical or different heteroatoms selected from the group consisting of N, O and S, and the heterocyclyl is optionally substituted by one or more substituents selected from the group consisting of alkyl, alkoxy, halogen, amino, cyano, nitro, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;
n is 0, 1, 2, 3 or 4; and
m is 0, 1 or 2.

### Claim 10 (depends on 9)

The compound according to claim 9, being a compound of

### Claim 11 (depends on 9)

A method for preparing the compound of formula (IA) according to claim 9, comprising:
reacting a compound of formula (TB) with a nitrite salt to obtain the compound of formula (IA);
wherein,
W is amino protecting group; and
the ring A, G, L1, L2, R1, R2, R3, Ra, Rb and n are as defined in claim 9.

### Claim 12 (depends on 1)

A method for preparing the compound of formula (I) according to claim 1, comprising:
carrying out a de-protecting group reaction on a compound of formula (IA) to obtain the compound of formula (I);
wherein,
W is amino protecting group; and
the ring A, G, L1, L2, R1, R2, R3, Ra, Rb and n are as defined in claim 1.

### Claim 13 (depends on 1)

A pharmaceutical composition, comprising a therapeutically effective amount of the compound according to claim 1, and one or more pharmaceutically acceptable carriers, diluents or excipients.

### Claim 14 (depends on 13)

A method of treating an infection caused by viruses in a patient in need thereof, the method comprising administering to the patient a therapeutically effective amount of the pharmaceutical composition according to claim 13, wherein the virus is selected from the group consisting of dengue virus, yellow fever virus, West Nile virus, Japanese encephalitis virus, tick-borne encephalitis virus, Kunjin virus, Murray Valley encephalitis virus, St. Louis encephalitis virus, Omsk hemorrhagic fever virus, bovine viral diarrhea virus, Zika virus, HIV, HBV, HCV, HPV, RSV, SARS and influenza virus.

### Claim 15 (depends on 13)

A method of treating a cancer in a patient in need thereof, the method comprising administering to the patient a therapeutically effective amount of the pharmaceutical composition according to claim 13, wherein the cancer is selected from the group consisting of melanoma, non-small cell lung cancer, hepatocellular carcinoma, basal cell carcinoma, renal cell carcinoma and myeloma.