# US 12,600,714 B2 · Substituted pyrazinecarboxamide compounds for treating diseases related to EGFR mutation

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- Number: US 12,600,714 B2
- Document ID: US12600714B2
- Status: Granted
- Kind: B2
- Application number: 17/917,435
- Filed: 2021-06-01
- Published: 2023-06-01
- Granted: 2026-04-14
- Earliest claimed: 2020-06-01
- Assignees: Wigen Biomedicine Technology (Shanghai) Co., Ltd.
- Applicants: Wigen Biomedicine Technology (Shanghai) Co., Ltd.
- Inventors: Yuli Xie; Yingming Wu; Houxing Fan; Lihui Qian
- Web page: https://patentgrep.com/patent/US12600714B2

## CPC

- A61P 35/00: Antineoplastic agents
- C07D 405/14: containing three or more hetero rings
- C07D 401/12: linked by a chain containing hetero atoms as chain links
- C07D 401/14: containing three or more hetero rings
- C07D 405/12: linked by a chain containing hetero atoms as chain links
- C07D 409/14: containing three or more hetero rings
- C07D 413/14: containing three or more hetero rings
- C07D 417/14: containing three or more hetero rings
- C07D 471/04: Ortho-condensed systems
- C07D 471/10: Spiro-condensed systems
- C07D 487/04: Ortho-condensed systems
- C07D 491/107: with only one oxygen atom as ring hetero atom in the oxygen-containing ring
- 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
- C07B 2200/05: Isotopically modified compounds, e.g. labelled
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- C07B: GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR (preparation of carboxylic acid esters by telomerisation C07C67/47; telomerisation C08F)

## Abstract

The present invention relates to a compound as represented by general formula (1), and a preparation method therefor, and the use of the compound as represented by general formula (1) and an isomer, a crystal form, a pharmaceutically acceptable salt, a hydrate or a solvate thereof as an EGFR inhibitor in the preparation of a drug against EGFR-related diseases, such as tumors.

## Claims

### Claim 1

A compound having a structure of general formula (1), or an isomer, a crystalline form, a pharmaceutically acceptable salt, a hydrate or a solvate thereof:
wherein, in general formula (1):
Y is
L1 is —O— or —NH—;
X is a C6-C14 arylene or a 5-11 membered heteroarylene, wherein the arylene and the heteroarylene may be optionally substituted with one or more of the following groups: —H, a halogen, a C1-C6 alkyl, a C3-C6 cycloalkyl, a C1-C6 alkoxy and a C1-C6 haloalkoxy;
R1 is —H, a halogen, —(CH2)nNR6R7, —NR6R7, —O(CH2)mNR6R7, —N(R5)(CH2)mNR6R7, a C1-C6 alkoxy, a —CH2-3-15 membered heterocycloalkyl or a 3-15 membered heterocycloalkyl, wherein the alkoxy and the heterocycloalkyl may be optionally substituted with one or more of the following groups: —H, —R4, —(CH2)nNR6R7, —NR6R7, —O(CH2)mNR6R7, —N(R5)(CH2)mNR6R7 and —R3;
L2 is —O—, —NH— or a chemical bond;
R2 is a C1-C6 alkyl, a C3-C14 cycloalkyl, a C6-C14 aryl, a 3-4 membered heterocycloalkyl,
or a 6-11 membered heterocycloalkyl; wherein the alkyl, the cycloalkyl, the aryl, the heterocycloalkyl,
may be optionally substituted with one or more of the following groups: —H, a halogen, —R4, —(CH2)nOR4—, —(CH2)nNR4R5—, —OR4, —NR4R5, —CN, —C(O)NR4R5, —NR5C(O)R4, —NR5S(O)2R4, —S(O)pR4 and —S(O)2NR4R5;
R3 is a 3-11 membered heterocycloalkyl, wherein the heterocycloalkyl may be optionally substituted with one or more of the following groups: —H, —CD3, —R4, —OR4 and —NR4R5;
R4 and R5 are each independently —H, a C1-C6 alkyl or a C3-C14 cycloalkyl;
R6 and R7 are each independently —H, a C1-C6 alkyl or a C3-C14 cycloalkyl, or R6 and R7 form a 3-11 membered heterocycloalkyl along with N atoms connected thereto, wherein the heterocycloalkyl may be optionally substituted with one or more of the following groups: —H, —CD3, a halogen, —R4 and —OR4;
R0 is a C1-C6 alkyl or a C3-C14 cycloalkyl; and
p is an integer of 0, 1 or 2, n is an integer of 0, 1, 2 or 3, and m is an integer of 1, 2 or 3;
or
Y is
L1 is —O— or —NH—;
X is a C6-C14 arylene or a 5-11 membered heteroarylene, wherein the arylene and the heteroarylene may be optionally substituted with one or more of the following groups: —H, a halogen, a C1-C6 alkyl, a C3-C6 cycloalkyl, a C1-C6 alkoxy and a C1-C6 haloalkoxy;
R1 is —H, a halogen, —(CH2)nNR6R7, —NR6R7, —O(CH2)mNR6R7, —N(R5)(CH2)mNR6R7, a C1-C6 alkoxy, a —CH2-3-15 membered heterocycloalkyl or a 3-15 membered heterocycloalkyl, wherein the alkoxy and the heterocycloalkyl may be optionally substituted with one or more of the following groups: —H, —R4, —(CH2)nNR6R7, —NR6R7, —O(CH2)mNR6R7, —N(R5)(CH2)mNR6R7 and —R3;
L2 is —O—, —NH— or a chemical bond;
R2 is a C1-C6 alkyl, a C3-C14 cycloalkyl, a C6-C14 aryl, a 3-4 membered heterocycloalkyl,
or a 6-11 membered heterocycloalkyl; wherein the alkyl, the cycloalkyl, the aryl, the heterocycloalkyl,
may be optionally substituted with one or more of the following groups: —H, a halogen, —R4, —(CH2)nOR4—, —(CH2)nNR4R5—, —OR4, —NR4R5, —CN, —C(O)NR4R5, —NR5C(O)R4, —NR5S(O)2R4, —S(O)pR4 and —S(O)2NR4R5;
R3 is a 3-11 membered heterocycloalkyl, wherein the heterocycloalkyl may be optionally substituted with one or more of the following groups: —H, —CD3, —R4, —OR4 and —NR4R5;
R4 and R5 are each independently —H, a C1-C6 alkyl or a C3-C14 cycloalkyl;
R6 and R7 are each independently —H, a C1-C6 alkyl or a C3-C14 cycloalkyl, or R6 and R7 form a 3-11 membered heterocycloalkyl along with N atoms connected thereto, wherein the heterocycloalkyl may be optionally substituted with one or more of the following groups: —H, —CD3, a halogen, —R4 and —OR4; and
p is an integer of 0, 1 or 2, n is an integer of 0, 1, 2 or 3, and m is an integer of 1, 2 or 3.

### Claim 2 (depends on 1)

The compound, or the isomer, the crystalline form, the pharmaceutically acceptable salt, the hydrate or the solvate thereof according to claim 1, wherein, in general formula (1), X is phenylene or a 6-membered heteroarylene, wherein the phenylene and the heteroarylene may be optionally substituted with one or more of the following groups: —H, —F, —CH3, —CH2CH3, —CH(CH3)2,
—OCH3, —OCF2H and —OCF3.

### Claim 3 (depends on 2)

The compound, or the isomer, the crystalline form, the pharmaceutically acceptable salt, the hydrate or the solvate thereof according to claim 2, wherein, in general formula (1), X is:

### Claim 4 (depends on 1)

The compound, or the isomer, the crystalline form, the pharmaceutically acceptable salt, the hydrate or the solvate thereof according to claim 1, wherein, in general formula (1), R1 is: —H, —N(CH3)2, —CH2-6-11 membered heterocycloalkyl or a 6-11 membered heterocycloalkyl, wherein the heterocycloalkyl is
and may be optionally substituted with one or more of the following groups:

### Claim 5 (depends on 4)

The compound, or the isomer, the crystalline form, the pharmaceutically acceptable salt, the hydrate or the solvate thereof according to claim 4, wherein, in general formula (1), R1 is:
—H, —N(CH3)2.

### Claim 6 (depends on 1)

The compound, or the isomer, the crystalline form, the pharmaceutically acceptable salt, the hydrate or the solvate thereof according to claim 1, wherein, in general formula (1),
when L2 is —NH— and Y is
R2 is:
or
when L2 is —NH— and Y is
R2 is:

### Claim 7 (depends on 1)

The compound, or the isomer, the crystalline form, the pharmaceutically acceptable salt, the hydrate or the solvate thereof according to claim 1, wherein, in general formula (1), when L2 is —O—, R2 is:

### Claim 8 (depends on 1)

The compound, or the isomer, the crystalline form, the pharmaceutically acceptable salt, the hydrate or the solvate thereof according to claim 1, wherein, in general formula (1), when L2 is a chemical bond, R2 is:

### Claim 9 (depends on 1)

The compound, or the isomer, the crystalline form, the pharmaceutically acceptable salt, the hydrate or the solvate thereof according to claim 1, wherein the compound has one of the following structures:

### Claim 10 (depends on 1)

A pharmaceutical composition, comprising a pharmaceutically acceptable excipient or carrier, and the compound, or the isomer, the crystalline form, the pharmaceutically acceptable salt, the hydrate or the solvate thereof according to claim 1 as an active ingredient.

### Claim 11 (depends on 1)

A method for treating, regulating and/or preventing a disease related to an EGFR mutant protein, comprising administering to a subject a therapeutically effective amount of the compound, or the isomer, the crystalline form, the pharmaceutically acceptable salt, the hydrate or the solvate thereof according to claim 1, wherein the disease is selected from lung cancer, brain cancer, breast cancer, and ovarian cancer.