# US 11,897,863 B2 · Indazole amine derivative, preparation method therefor and medical use thereof

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- Number: US 11,897,863 B2
- Document ID: US11897863B2
- Status: Granted
- Kind: B2
- Application number: 17/267,771
- Filed: 2019-08-15
- Published: 2021-10-07
- Granted: 2024-02-13
- Earliest claimed: 2018-08-17
- Assignees: Zhejiang Hisun Pharmaceutical Co., Ltd.
- Applicants: Zhejiang Hisun Pharmaceutical Co., Ltd.
- Inventors: Yongping Lu; Cheng Ye; Wenjian Qian; Taishan Hu; Lei Chen
- Web page: https://patentgrep.com/patent/US11897863B2

## CPC

- C07D 401/12: linked by a chain containing hetero atoms as chain links
- A61K 31/4439: containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole (nicotine A61K31/465)
- A61P 15/00: Drugs for genital or sexual disorders (for disorders of sex hormones A61P5/24); Contraceptives
- A61P 17/00: Drugs for dermatological disorders
- A61P 19/02: for joint disorders, e.g. arthritis, arthrosis
- A61P 29/00: Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
- A61P 35/00: Antineoplastic agents
- A61P 37/02: Immunomodulators
- C07D 401/14: containing three or more hetero rings
- 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)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS

## Abstract

Indazole derivatives represented by formula (I) or stereoisomers, tautomers, and pharmaceutically acceptable salts thereof are provided. A preparation method of indazole derivatives represented by formula (I) and a method of use of the indazole derivatives as therapeutic agents is also provided. The indazole derivatives of formula (I) are especially useful as interleukin-1 receptor-associated kinase 4 (IRAK4) inhibitors

## Claims

### Claim 1

A compound of formula (I), or stereoisomers, tautomers or pharmaceutically acceptable salts thereof:
wherein:
R1 and R2 are independently selected from hydrogen or C 1-C6 alkyl;
R3 is selected from halogen, cyano, carboxyl, —CONRARB, haloalkyl or heteroaryl; wherein the heteroaryl is optionally further substituted by one or more substituents selected from halogen, hydroxyl, cyano, carboxyl, —CONRARB or haloalkyl;
W is azetidinyl, nitrogen-containing aromatic heterocyclic ring group or nitrogen-containing aromatic heterocyclic ring group bonded via a single methylene group; wherein the azetidinyl is optionally further substituted by one or more substituents selected from —CORC, —SO2RD, C1-C6 alkyl or C 3-C6 cycloalkyl; wherein the nitrogen-containing aromatic heterocyclic ring group is optionally further substituted by one or more substituents selected from halogen, cyano, carboxyl, —CONRARB and haloalkyl;
or, W has a structure of formula (II):
* represents bonding site of the group to rest of the molecule;
Ra is selected from hydrogen, C 1-C6 alkyl or C 3-C6 cycloalkyl; wherein the C 1-C6 alkyl or C 3-C6 cycloalkyl is optionally further substituted by one or more substituents selected from halogen, hydroxyl, carboxyl and —SO2NRERF;
Rb and Rc are independently selected from hydrogen, —CORC, —SO2RD, C1-C6 alkyl or C3-C6 cycloalkyl; or, any two of R a, R b and Rc together with the atoms to which they are attached form a 4-8 membered nitrogen-containing heterocyclic ring, wherein the nitrogen-containing heterocyclic ring may be further substituted by one or more oxo groups (O═);
RA, R B, R E and R F are independently selected from hydrogen, C1-C6 alkyl or C3-C6 cycloalkyl; wherein the alkyl or cycloalkyl is optionally further substituted by one or more substituents selected from halogen, hydroxyl, cyano or haloalkyl;
RC and R D are independently selected from C1-C6 alkyl or C 3-C6 cycloalkyl; wherein the alkyl or cycloalkyl is optionally further substituted by one or more substituents selected from halogen, hydroxyl, cyano or haloalkyl.

### Claim 2 (depends on 1)

The compound, or stereoisomers, tautomers or pharmaceutically acceptable salts thereof of claim 1, having the structure of formula (III):
wherein R3 and W are defined as in claim 1.

### Claim 3 (depends on 1)

The compound, or stereoisomers, tautomers or pharmaceutically acceptable salts thereof of claim 1, having the structure of formula (IV):
wherein, W is defined as in claim 1.

### Claim 4 (depends on 1)

The compound or stereoisomers, tautomers or pharmaceutically acceptable salts thereof of claim 1, having the structure of formula (Va), (Vb) or (Vc):
wherein:
Rb and R c are defined as in claim 1;
Rd and R e are independently selected from hydrogen, —CORC, —SO2RD, C1-C6 alkyl or C3-C6 cycloalkyl; wherein, RC and RD are as defined in claim 1;
G is selected from —CH2—, —CO— or —SO2—;
n is an integer from 0 to 2.

### Claim 5 (depends on 1)

The compound, or stereoisomers, tautomers or pharmaceutically acceptable salts thereof of claim 1, being
N-(2-(2-(dimethylamino)ethyl)-6-(2-hydroxypropan-2-yl)-2H-indazol-5-yl)-6-(trifluoromethyl)pyridin-2-carboxamide.

### Claim 6 (depends on 1)

A pharmaceutical composition comprising a therapeutically effective amount of the compound, or stereoisomers, tautomers or pharmaceutically acceptable salts thereof of claim 1, and optional pharmaceutically acceptable carriers, excipients or combinations thereof.

### Claim 7 (depends on 1)

A method for inhibiting IRAK4 kinase activity, comprising administering the compound, or stereoisomers, tautomers or pharmaceutically acceptable salts thereof of claim 1 to a subject in need thereof.

### Claim 8 (depends on 1)

A method for preventing or treating autoimmune diseases, inflammatory diseases or cancers by inhibiting IRAK4 kinase activity, comprising administering the compound, or stereoisomers, tautomers or pharmaceutically acceptable salts thereof of claim 1 to a subject in need thereof.

### Claim 9 (depends on 1, 2)

The compound or stereoisomers, tautomers or pharmaceutically acceptable salts thereof of claim 2, having the structure of formula (Va), (Vb) or (Vc):
wherein:
Rb and R c are defined as in claim 1;
Rd and Re are independently selected from hydrogen, —CORC, —SO2RD, C1-C6 alkyl or C3-C6 cycloalkyl; wherein, RC and RD are as defined in claim 1;
G is selected from —CH2—, —CO— or —SO2—;
n is an integer from 0 to 2.

### Claim 10 (depends on 1, 3)

The compound or stereoisomers, tautomers or pharmaceutically acceptable salts thereof of claim 3, having the structure of formula (Va), (Vb) or (Vc):
wherein:
Rb and Rc are defined as in claim 1;
Rd and Re are independently selected from hydrogen, —CORC, —SO2RD, C1-C6 alkyl or C3-C6 cycloalkyl; wherein, RC and RD are as defined in claim 1;
G is selected from —CH2—, —CO— or —SO2—;
n is an integer from 0 to 2.

### Claim 11 (depends on 1)

The compound, or stereoisomers, tautomers or pharmaceutically acceptable salts thereof of claim 1, being
(S)—N-(6-(2-hydroxypropan-2-yl)-2-(5-oxopyrrolidin-2-yl)methyl)-2H-indazol-5-yl)-6-(trifluoromethyl)pyridin-2-carboxamide.

### Claim 12 (depends on 1)

The compound, or stereoisomers, tautomers or pharmaceutically acceptable salts thereof of claim 1, being
N-(2-(azetidin-3-yl)-6-(2-hydroxypropan-2-yl)-2H-indazol-5-yl)-6-(trifluoromethyl)pyridin-2-carboxamide.

### Claim 13 (depends on 6)

A method for inhibiting IRAK4 kinase activity, comprising administering the pharmaceutical composition of claim 6 to a subject in need thereof.

### Claim 14 (depends on 6)

A method for preventing or treating autoimmune diseases, inflammatory diseases or cancers by inhibiting IRAK4 kinase activity, comprising administering the pharmaceutical composition of claim 6 to a subject in need thereof.

### Claim 15 (depends on 8)

The method of claim 8, wherein the autoimmune diseases, inflammatory diseases or cancers are selected from lymphoma, endometriosis, psoriasis, lupus erythematosus, multiple sclerosis or rheumatoid arthritis.

### Claim 16 (depends on 15)

The method of claim 15, wherein the lymphoma is primary central nervous system lymphoma or diffuse large B-cell lymphoma with MYD88 L265P mutation.

### Claim 17 (depends on 14)

The method of claim 14, wherein the autoimmune diseases, inflammatory diseases or cancers are selected from lymphoma, endometriosis, psoriasis, lupus erythematosus, multiple sclerosis or rheumatoid arthritis.

### Claim 18 (depends on 17)

The method of claim 17, wherein the lymphoma is primary central nervous system lymphoma or diffuse large B-cell lymphoma with MYD88 L265P mutation.