# US 2023/0416237 A1 · Amide compound, pharmaceutical composition and use thereof

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- Number: US 2023/0416237 A1
- Document ID: US20230416237A1
- Status: Published application
- Kind: A1
- Application number: 18/254,089
- Filed: 2021-11-24
- Published: 2023-12-28
- Earliest claimed: 2020-11-26
- Assignees: Artivila (Shenzhen) Innovation Center, Ltd.
- Applicants: Shenzhen Bo Li Jian Medicine Co., Ltd.
- Inventors: Liye HUANG; Hua LI; Huabin LIU; Xinmiao ZHANG
- Web page: https://patentgrep.com/patent/US20230416237A1

## CPC

- A61P 11/06: Antiasthmatics
- C07D 403/14: containing three or more hetero rings
- A61K 31/506: not condensed and containing further heterocyclic rings
- 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 37/00: Drugs for immunological or allergic disorders
- C07D 401/14: containing three or more hetero rings
- C07D 405/14: containing three or more hetero rings
- 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

Provided in the present application are an amide compound, and an isomer, a pharmaceutically acceptable salt, and a pharmaceutical composition thereof, and the use thereof. The amide compound has a structure as represented by formula I. The amide compound of the present application has a significant JAK kinase inhibitory activity, especially a JAKI kinase inhibitory activity, has a higher inhibitory activity on JAK1 kinase than on JAK2 kinase, and can be used as a highly selective JAK1 kinase inhibitor. Therefore, the amide compound of the present application can be used for preparing drugs for treating JAK1 kinase-mediated diseases.

## Claims

### Claim 1

An amide compound having a structure represented by Formula I:
wherein R1 is selected from H, halogen, C1 to C6 linear or branched alkyl, C3 to C6 cycloalkyl or ORa; wherein the linear or branched alkyl or the cycloalkyl is unsubstituted or substituted with 1 to 3 R1a;
R1a is selected from D or halogen;
R2 is selected from H, C1 to C6 linear or branched alkyl, C3 to C10 cycloalkyl or C2 to C10 heterocycloalkyl; wherein the linear or branched alkyl, the cycloalkyl or the heterocycloalkyl is unsubstituted or substituted with 1 to 3 R2a;
R2a is selected from D, halogen, cyano, unsubstituted or halogenated C1 to C6 linear or branched alkyl, C3 to C6 cycloalkyl, C2 to C6 heterocycloalkyl, ORa1, SRa1, NRb1Rc1, CORa1, CONRb1Rc1, COORa1, SO2Ra1, SO2NRb1Rc1, NRb1CORa1, NRd1CONRb1Rc1, NRb1SO2Ra1, NRd1SO2NRb1Rc1 or SORa1;
R3 is selected from H, halogen, cyano, unsubstituted or halogenated C1 to C6 linear or branched alkyl, C2 to C6 alkenyl, C2 to C6 alkynyl or C3 to C6 cycloalkyl;
R4 is selected from SO2Ra2, CORa2, COORa2, C3 to C10 cycloalkyl or C2 to C10 heterocycloalkyl; wherein the cycloalkyl or the heterocycloalkyl is unsubstituted or substituted with 1 to 5 R4a;
R4a is selected from D, halogen, cyano, C1 to C6 linear or branched alkyl, C3 to C6 cycloalkyl, C2 to C6 heterocycloalkyl, ORa3, SRa3, NRb3Rc3, CORa3, CONRb3Rc3, COORa3, SO2Ra3 or SO2NRb3Rc3; wherein the linear or branched alkyl, the cycloalkyl or the heterocycloalkyl is unsubstituted or substituted with 1 to 5 R4b;
R4b is selected from D, halogen, cyano, ORa4 or NRb4Rc4;
R5 is selected from F, cyano, C1 to C6 linear or branched alkyl, C3 to C6 cycloalkyl or ORa5;
Ra, Ra1, Rb1, Rc1, Rd1, Ra2, Ra3, Rb3, Rc3, Ra4, Rb4, Rc4 and Ra5 are each independently selected from H, C1 to C10 linear or branched alkyl, C2 to C10 alkenyl, C2 to C10 alkynyl, C3 to C10 cycloalkyl or C2 to C10 heterocycloalkyl; wherein the linear or branched alkyl, the alkenyl, the alkynyl, the cycloalkyl or the heterocycloalkyl is unsubstituted or substituted with 1 to 4 R6;
R6 is selected from D, halogen, cyano, hydroxyl, unsubstituted or halogenated C1 to C6 linear or branched alkyl, C2 to C6 alkenyl, C2 to C6 alkynyl, C3 to C6 cycloalkyl, C2 to C6 heterocycloalkyl, ORa6, SRa6, NRb6Rc6, CORa6, CONRb6Rc6, COORd6, SO2Ra6, SO2NRb6Rc6, NRb6CORa6, NRd6CONRb6Rc6, NRb6SO2Ra6, NRd6SO2NRb6Rc6 or SORa6;
Ra6, Rb6, Rc6 and Rd6 are each independently selected from H, C1 to C10 linear or branched alkyl, C2 to C10 alkenyl, C2 to C10 alkynyl, C3 to C10 cycloalkyl or C2 to C10 heterocycloalkyl; and
n is an integer selected from 0 to 3, and when n≥2, R5 are not joined to each other or are joined by a chemical bond to form a 3- to 6-membered carbocycle or carboheterocycle.

### Claim 2 (depends on 1)

The amide compound according to claim 1, wherein the amide compound has a structure represented by Formula IA:
wherein R3 and R4 are each independently defined within the same ranges as in Formula I;
R5a and R5b are each independently selected from H, F, cyano, C1 to C6 linear or branched alkyl, C3 to C6 cycloalkyl or ORa5; and R5a and R5b are not joined to each other or are joined by a chemical bond to form a 3- to 6-membered carbocycle or heterocarbocycle.

### Claim 3 (depends on 2)

The amide compound according to claim 2, wherein R3 is selected from H, halogen or C1 to C6 linear or branched alkyl.

### Claim 4 (depends on 2)

The amide compound according to claim 2, wherein R4 is selected from SO2Ra2 or unsubstituted or R4a-substituted C2 to C10 heterocycloalkyl;
optionally, Ra2 is selected from C1 to C6 linear or branched alkyl;
optionally, R4a is selected from C1 to C6 linear or branched alkyl; and
optionally, Ra5 is selected from C1 to C6 linear or branched alkyl.

### Claim 5 (depends on 2)

The amide compound according to claim 2, wherein the amide compound has a structure represented by Formula IB:
wherein R3, R5a and R5b are each independently defined within the same ranges as in Formula IA;
Y is NR7 or O;
R7 is selected from H, C1 to C6 linear or branched alkyl, C3 to C6 cycloalkyl or C2 to C6 heterocycloalkyl; wherein the linear or branched alkyl, the cycloalkyl or the heterocycloalkyl is unsubstituted or substituted with 1 to 5 R7a;
R7a is selected from D, halogen, cyano, C1 to C6 linear or branched alkyl, C3 to C6 cycloalkyl, C2 to C6 heterocycloalkyl, hydroxyl or C1 to C6 linear or branched alkoxy; wherein the linear or branched alkyl, the cycloalkyl or the heterocycloalkyl is unsubstituted or substituted with 1 to 5 R7b;
R7b is selected from D, halogen, cyano, hydroxyl or C1 to C6 linear or branched alkoxy; and
m is 1 or 2, and p is an integer selected from 1 to 3.

### Claim 6 (depends on 5)

The amide compound according to claim 5, wherein R3 is selected from H, halogen or methyl;
optionally, R5a and R5b are each independently selected from H, F, methoxy or ethoxy.

### Claim 7 (depends on 5)

The amide compound according to claim 5, wherein R7 is H or methyl;
optionally, p is 2.

### Claim 8 (depends on 1)

The amide compound according to claim 1, wherein the amide compound comprises the following compounds:

### Claim 9 (depends on 1)

A stereoisomer, geometric isomer, tautomer or pharmaceutically acceptable salt of the amide compound according to claim 1.

### Claim 10 (depends on 1)

A pharmaceutical composition, comprising an active ingredient and at least one pharmaceutical carrier or excipient; wherein the active ingredient comprises any one or a combination of at least two of the amide compound according to claim 1.

### Claim at position 11

-12. (canceled)

### Claim 13 (depends on 1)

A method of preparing a medicament for inhibiting JAK using the amide compound according to claim 1.

### Claim 14 (depends on 1)

A method for treating a disease mediated by JAK, comprising administering an effective amount of the amide compound according to claim 1 to subject in need thereof.

### Claim 15 (depends on 14)

The method of claim 14 wherein the disease comprises an inflammatory disease, an autoimmune disease or cancer.

### Claim 16 (depends on 15)

The method of claim 15, wherein the inflammatory disease or the autoimmune disease is selected from systemic lupus erythematosus, lupus nephritis, arthritis, psoriasis, Crohn's disease, ulcerative colitis, atopic dermatitis, gout, alopecia totalis, vitiligo, hidradenitis suppurativa, type I diabetes, chronic kidney disease, acute kidney injury, chronic obstructive pulmonary disease, asthma, bronchitis and graft-versus-host disease.

### Claim 17 (depends on 15)

The method of claim 15, wherein the cancer is selected from breast cancer, lung cancer, prostate cancer, cholangiocarcinoma, bone cancer, bladder cancer, head and neck cancer, kidney cancer, liver cancer, gastrointestinal tissue cancer, esophageal cancer, ovarian cancer, pancreatic cancer, skin cancer, testicular cancer, thyroid cancer, uterine cancer, cervical cancer, vaginal cancer, leukemia, myelofibrosis, multiple myeloma and lymphoma.

### Claim 18 (depends on 1)

A method of preparing a medicament for inhibiting JAK1 using the amide compound according to claim 1.