# US 12,595,263 B2 · Pyrazolopyrimidine compound used as ATR kinase inhibitor

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- Number: US 12,595,263 B2
- Document ID: US12595263B2
- Status: Granted
- Kind: B2
- Application number: 18/016,164
- Filed: 2021-07-13
- Published: 2023-08-31
- Granted: 2026-04-07
- Earliest claimed: 2020-07-13
- Assignees: Beijing Tide Pharmaceutical Co., Ltd.
- Applicants: Beijing Tide Pharmaceutical Co., Ltd.
- Inventors: Cheung Ling Cheng; Yanping Zhao; Hongjun Wang; Bin Liu; Weiting Zhong; Huifen Xu; Chuangchuang Huang; Jing Li; Weina Liu
- Web page: https://patentgrep.com/patent/US12595263B2

## CPC

- C07D 487/04: Ortho-condensed systems
- A61P 35/00: Antineoplastic agents
- A61P 35/02: specific for leukemia
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS

## Abstract

Disclosed is a compound of a general formula (I), which may be used for the treatment of ATR kinase-mediated diseases, for example, proliferative diseases such as cancer. Further disclosed are a preparation method for the compound of the general formula (I), a pharmaceutical composition, and use of the pharmaceutical composition for the treatment of ATR kinase-mediated diseases.

## Claims

### Claim 1

A compound of general formula (I), or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, polymorph, prodrug, or isotopic variant thereof, or a mixture thereof:
wherein
X is CRX or N;
Y is CRY or N;
R1, R2, R3, R4 and RY are independently selected from H, D, halogen, C1-6 alkyl, C2-6 alkenyl and C2-6 alkynyl, or R1 and R2, R3 and R4 are connected to form bond, C1-6 alkylene, C2-6 alkenylene or C2-6 alkynylene; wherein the groups may be substituted by one or more D or halogens up to fully substituted;
wherein RX is H, D, halogen, —CN, —NRR′, —OR, —SR or C1-6 alkyl, wherein the groups may be substituted by one or more D or halogens up to fully substituted;
when Y is CRY, RY and R1 are taken together with the atoms to which they are attached to form C3-5 cycloalkyl or 3- to 5-membered heterocyclyl, wherein the groups may be substituted by one or more D or halogens up to fully substituted;
ring A is C3-7 cycloalkyl, 4- to 7-membered heterocyclyl, C6-10 aryl or 5- to 10-membered heteroaryl;
Ra is independently selected from H, D, halogen, —CN, —NRR′, —OR, —SR, —C(O)R, —C(O)OR, —C(O)NRR′, —OC(O)R′, —NRC(O)R′, —OC(O)NRR′, —NRC(O)NRR′, —S(O)pR, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-7 cycloalkyl and 3- to 8-membered heterocyclyl, each of which is optionally substituted with R*, wherein the groups may be substituted by one or more D or halogens up to fully substituted;
m is 0, 1, 2, 3, 4 or 5;
ring B is 5- to 6-membered heteroaryl;
Rb is independently selected from H, D, halogen, —CN, —NRR′, —OR, —SR, —C(O)R, —C(O)OR, —C(O)NRR′, —OC(O)R′, —NRC(O)R′, —OC(O)NRR′, —NRC(O)NRR′, —S(O)pR, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-7 cycloalkyl and 3- to 8-membered heterocyclyl, each of which is optionally substituted with R*, wherein the groups may be substituted by one or more D or halogens up to fully substituted;
n is 0, 1, 2, 3, 4 or 5;
ring C is C3-7 cycloalkyl, 4- to 7-membered heterocyclyl, C6-10 aryl or 5- to 10-membered heteroaryl;
L is a bond, —O—, —S—, —N(R)—, —C(O)—, C1-6 alkylene, C2-6 alkenylene or C2-6 alkynylene;
R5 is H, D, halogen, —CN, —NRR′, —OR, —SR, C1-6 alkyl, C2-6 alkenyl or C2-6 alkynyl, wherein the groups may be substituted by one or more D or halogens up to fully substituted;
R6 is H, D, halogen, —CN, —NRR′, —OR, —SR, C1-6 alkyl, C2-6 alkenyl or C2-6 alkynyl, wherein the groups may be substituted by one or more D or halogens up to fully substituted;
R* is H, halogen, —CN, —NRR′, —OR, —SR, —C(O)R, —C(O) OR, —C(O)NRR′, —OC(O)R′, —NRC(O)R′, —OC(O)NRR′, —NRC(O)NRR′, —S(O)pR, C3-7 cycloalkyl, 3- to 8-membered heterocyclyl, C6-10 aryl or 5- to 10-membered heteroaryl, wherein the groups may be substituted by one or more D or halogens up to fully substituted;
R and R′ are independently selected from H, C1-6 alkyl, C2-6 alkenyl and C2-6 alkynyl, or R and R′ are taken together with the nitrogen atom to which they are attached to form 4- to 8-membered heterocyclyl; wherein the groups may be substituted by one or more D or halogens up to fully substituted;
p is 1 or 2.

### Claim 2 (depends on 1)

The compound of claim 1, or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, polymorph, or isotopic variant thereof, or a mixture thereof, wherein the compound has one or more of the following definitions:
i) wherein R1 is C1-6 alkyl, alternatively (R)—C1-6 alkyl, yet alternatively (R)-methyl;
ii) wherein X is CRX, and R2, R3, R4 and RX are hydrogen or D;
iii) wherein Y is N;
iv) wherein ring A is selected from the following groups:
wherein A1 is CRa1 or N; A2 is CRa2 or N; A3 is CRa3 or N; A4 is CRa4 or N; A5 is CRa5 or N;
Ra1, Ra2, Ra3, Ra4 and Ras have the same definition as Ra in claim 1;
alternatively, (Ra)m-ring A-L- is selected from the following groups:
v) wherein ring A is selected from piperazinyl and piperidinyl;
vi) wherein Ra is independently selected from H, D, halogen, —CN, —NRR′, —OR, —SR, —C(O)R, —C(O)OR, —C(O)NRR′, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl and C2-6 alkynyl, wherein the groups may be substituted by one or more D up to fully deuterated;
vii) wherein ring B is pyrrolyl, furanyl, thienyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, triazolyl, pyridyl, pyrimidinyl or pyrazinyl; alternatively pyrrolyl, furanyl, thienyl, pyrazolyl or pyridyl; alternatively pyrazolyl;
viii) wherein Rb is independently selected from H, D, halogen, —CN, —NRR′, —OR, —SR, C1-6 alkyl and C1-6 haloalkyl, each of which is optionally substituted with R*; alternatively H or D;
ix) wherein ring C is 5- to 6-membered heteroaryl or phenyl; alternatively pyrrolyl, furanyl, thienyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, triazolyl, pyridyl, pyrimidinyl or pyrazinyl; alternatively pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl or triazolyl; alternatively pyrazolyl;
x) wherein ring C is C3-7 cycloalkyl or 4- to 7-membered heterocyclyl;
xi) wherein L is a bond, —C(O)— or C1-6 alkylene;
xii) wherein R5 and R6 are independently H, D, C1-6 alkyl, C2-6 alkenyl or C2-6 alkynyl, wherein the groups may be substituted by one or more D or halogens up to fully substituted.

### Claim 3 (depends on 1)

The compound of claim 1, or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, polymorph, or isotopic variant thereof, or a mixture thereof, which has the following general structure:
wherein each group has the same definition as in claim 1.

### Claim 4 (depends on 3)

The compound of claim 3, or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, polymorph, or isotopic variant thereof, or a mixture thereof, which is a compound of general formula (I-1) or (I-2):
wherein
ring C is C3-7 cycloalkyl or 4- to 7-membered heterocyclyl; alternatively cyclopentyl or tetrahydropyranyl;
ring B is pyrrolyl, furanyl, thienyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, triazolyl, pyridyl, pyrimidinyl or pyrazinyl; alternatively pyrrolyl, furanyl, thienyl, pyrazolyl or pyridyl;
R5 is alternatively H, D, halogen, —CN, —NRR′, —OR, or —SR, wherein the groups may be substituted by one or more D or halogens up to fully substituted; alternatively, R5 is located on the C atom where the ring C is attached to the parent nucleus;
other groups have the same definition as in claim 3.

### Claim 5 (depends on 3)

The compound of claim 3, or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, polymorph, or isotopic variant thereof, or a mixture thereof, which is a compound of general formula (I-1):
wherein
ring C is 5- to 6-membered heteroaryl or phenyl; alternatively pyrrolyl, furanyl, thienyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, triazolyl, pyridyl, pyrimidinyl or pyrazinyl; alternatively pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl or triazolyl; alternatively pyrazolyl;
other groups have the same definition as in claim 3.

### Claim 6 (depends on 5)

The compound of general formula (I-1) of claim 5, or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, polymorph, or isotopic variant thereof, or a mixture thereof, wherein
ring B is pyrrolyl, furanyl, thienyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, triazolyl, pyridyl, pyrimidinyl or pyrazinyl; alternatively pyrrolyl, furanyl, thienyl, pyrazolyl or pyridyl;
other groups have the same definition as in claim 5.

### Claim 7 (depends on 3)

The compound of claim 3, or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, polymorph, or isotopic variant thereof, or a mixture thereof, which is a compound of general formula (II) or (II-1):
wherein
ring A is C3-7 cycloalkyl or 4- to 7-membered heterocyclyl;
other groups have the same definition as in claim 3;
alternatively, ring A is 4- to 7-membered heterocyclyl; alternatively piperidyl or piperazinyl;
ring B is pyrrolyl, furanyl, thienyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, triazolyl, pyridyl, pyrimidinyl or pyrazinyl; alternatively pyrrolyl, furanyl, thienyl, pyrazolyl or pyridyl;
L is a bond, —O—, —S—, —N(R)—, —C(O)— or C1-6 alkylene;
R5 and R6 are independently C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl or C2-6 alkynyl, wherein the groups may be substituted by one or more D up to fully deuterated;
other groups have the same definition as in claim 3.

### Claim 8 (depends on 3)

The compound of claim 3, or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, polymorph, or isotopic variant thereof, or a mixture thereof, which is a compound of general formula (III) or (III-1):
wherein
ring C is 5- to 6-membered heteroaryl or phenyl; alternatively pyrrolyl, furanyl, thienyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, triazolyl, pyridyl, pyrimidinyl or pyrazinyl; alternatively pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl or triazolyl; alternatively pyrazolyl;
other groups have the same definition as in claim 3.

### Claim 9 (depends on 8)

The compound of general formula (III) or (III-1) of claim 8, or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, polymorph, or isotopic variant thereof, or a mixture thereof, wherein
ring B is pyrrolyl, furanyl, thienyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, triazolyl, pyridyl, pyrimidinyl or pyrazinyl; alternatively pyrrolyl, furanyl, thienyl, pyrazolyl or pyridyl;
other groups have the same definition as in claim 8.

### Claim 10 (depends on 3)

The compound of claim 3, or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, polymorph, or isotopic variant thereof, or a mixture thereof, which is a compound of general formula (III-2) or (III-3):
wherein
A1 is CRa1 or N; A2 is CRa2 or N; A5 is CRa5 or N;
other groups have the same definition as in claim 3.

### Claim 11 (depends on 10)

The compound of general formula (III-3) of claim 10, or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, polymorph, or isotopic variant thereof, or a mixture thereof, wherein
A3 is CRa3 or N;
Ra1, Ra2, Ra3, Ra5, R5 and R6 are independently H, D, halogen, —CN, —OR, —SR, —NRR′, —C(O)R, —C(O)OR, —C(O)NRR′ or C1-6 alkyl, wherein the groups may be substituted by one or more D or halogens up to fully substituted;
other groups have the same definition as in claim 10;
alternatively, A3 is CRa3 or N;
Ra1, Ra2, Ra3 and Ras are independently selected from H, D, halogen, —CN, —OH, —C(O)NH2, C1-6 alkyl and C1-6 haloalkyl, wherein the groups may be substituted by one or more D up to fully deuterated;
R5 and R6 are independently C1-6 alkyl or C1-6 haloalkyl, wherein the groups may be substituted by one or more D up to fully deuterated;
alternatively, A3 is CRa3 or N;
Ra1 is H or D;
Ra2 is H, D, halogen, —CN, —OH, —C(O)NH2, C1-6 alkyl or C1-6 haloalkyl;
Ra3 is H, D or —OH;
Ra5 is H or D;
R5 is C1-6 alkyl or C1-6 haloalkyl; alternatively methyl;
R6 is C1-6 alkyl or C1-6 haloalkyl; alternatively methyl.

### Claim 12 (depends on 3)

The compound of claim 3, or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, polymorph, or isotopic variant thereof, or a mixture thereof, which is a compound of general formula (III-3):
wherein
A3 is CRa3 or N;
Ra1, Ra2, Ra3, Ra5, R5 and R6 are independently H, D, halogen, —OR, —SR, —NRR′, C1-6 alkyl or C1-6 haloalkyl, wherein the groups may be substituted by one or more D up to fully deuterated;
R and R′ are independently selected from H, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl and C2-6 alkynyl, or R and R′ are taken together with the nitrogen atom to which they are attached to form 4- to 8-membered heterocyclyl; wherein the groups may be substituted by one or more D up to fully deuterated.

### Claim 13 (depends on 12)

The compound of general formula (III-3) of claim 12, or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, polymorph, or isotopic variant thereof, or a mixture thereof, wherein
A3 is CRa3 or N;
Ra1, Ra2, Ra3 and Ras are independently selected from H, D, halogen, —OH, C1-6 alkyl and C1-6 haloalkyl, wherein the groups may be substituted by one or more D up to fully deuterated;
R5 and R6 are independently C1-6 alkyl or C1-6 haloalkyl, wherein the groups may be substituted by one or more D up to fully deuterated;
alternatively, A3 is CRa3 or N;
Ra1 is H or D;
Ra2 is H, D, halogen, C1-6 alkyl or C1-6 haloalkyl;
Ra3 is H, D or —OH;
Ra5 is H or D;
R5 is C1-6 alkyl or C1-6 haloalkyl; alternatively methyl;
R6 is C1-6 alkyl or C1-6 haloalkyl; alternatively methyl.

### Claim 14 (depends on 3)

The compound of claim 3, or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, polymorph, or isotopic variant thereof, or a mixture thereof, which is a compound of general formula (III-4):
wherein
A4 is CRa4 or N;
Ra1, Ra2, Ra4, Ra5, R5 and R6 are independently H, D, halogen, —CN, —OR, —SR, —NRR′, —C(O)R, —C(O)OR, —C(O)NRR′ or C1-6 alkyl, wherein the groups may be substituted by one or more D or halogens up to fully substituted;
other groups have the same definition as in claim 3.

### Claim 15 (depends on 14)

The compound of general formula (III-4) of claim 14, or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, polymorph, or isotopic variant thereof, or a mixture thereof, wherein
A4 is CRa4 or N;
Ra1, Ra2, Ra4 and Ras are independently selected from H, D, halogen, —CN, —OH, —C(O)NH2, C1-6 alkyl and C1-6 haloalkyl, wherein the groups may be substituted by one or more D up to fully deuterated;
R5 and R6 are independently C1-6 alkyl or C1-6 haloalkyl, wherein the groups may be substituted by one or more D up to fully deuterated;
alternatively, A4 is CRa4 or N;
Ra1 is H, D or halogen;
Ra2 is H, D, halogen, —CN, —OH, —C(O)NH2, C1-6 alkyl or C1-6 haloalkyl;
Ra4 is H, D or —OH;
Ra5 is H or D;
R5 is C1-6 alkyl or C1-6 haloalkyl; alternatively methyl;
R6 is C1-6 alkyl or C1-6 haloalkyl; alternatively methyl.

### Claim 16 (depends on 1)

The compound of claim 1, which is selected from:

### Claim 17 (depends on 1)

A pharmaceutical composition comprising the compound of claim 1, or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, polymorph, or isotopic variant thereof, and a pharmaceutically acceptable excipient; alternatively, further comprising other therapeutic agent(s).

### Claim 18 (depends on 1)

A method of treating and/or preventing a disease mediated by ATR kinase in a subject, comprising administering to the subject the compound of claim 1 or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, polymorph, or isotopic variant thereof.

### Claim 19 (depends on 18)

The method of claim 18, wherein the disease mediated by ATR kinase comprises a proliferative disease, leukemia or lymphoma.

### Claim 20 (depends on 3)

The compound of claim 3, or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, polymorph, or isotopic variant thereof, or a mixture thereof, which is a compound of general formula (III-3) or (III-4):
wherein
A3 is CRa3 or N;
A4 is CRa3 or N;
R5 and R6 are independently C1-6 alkyl, wherein the groups may be substituted by one or more D up to fully deuterated;
Ra1, Ra2, Ra3, Ra4 and Ras are independently selected from H, D, halogen, C1-6 alkyl and C1-6 haloalkyl, wherein the groups may be substituted by one or more D up to fully deuterated.

### Claim 21 (depends on 20)

The compound of claim 20, or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, polymorph, or isotopic variant thereof, or a mixture thereof, which is a compound of general formula (III-3):
wherein
A3 is CRa3;
R5 and R6 are independently C1-6 alkyl; alternatively methyl;
Ra1 is H or D;
Ra2 is H, D, halogen, C1-6 alkyl or C1-6 haloalkyl;
Ra3 is H or D;
Ra5 is H or D.

### Claim 22 (depends on 1)

A compound of claim 1 having the following structure:
or a pharmaceutically acceptable salt thereof.

### Claim 23 (depends on 1)

A compound of claim 1 having the following structure:
or a pharmaceutically acceptable salt thereof.

### Claim 24 (depends on 1)

A compound of claim 1 having the following structure:
or a pharmaceutically acceptable salt thereof.

### Claim 25 (depends on 1)

A compound of claim 1 having the following structure:
or a pharmaceutically acceptable salt thereof.

### Claim 26 (depends on 1)

A compound of claim 1 having the following structure:
or a pharmaceutically acceptable salt thereof.

### Claim 27 (depends on 1)

A compound of claim 1 having the following structure:
or a pharmaceutically acceptable salt thereof.

### Claim 28 (depends on 1)

A compound of claim 1 having the following structure:
or a pharmaceutically acceptable salt thereof.

### Claim 29 (depends on 18)

The method of claim 18, wherein the disease mediated by ATR kinase comprises cancer, solid tumors, carcinoma, or sarcoma.

### Claim 30 (depends on 18)

The method of claim 18, wherein the disease mediated by ATR kinase comprises breast cancer, colorectal cancer, lung cancer, prostate cancer and bile duct cancer, bone cancer, bladder cancer, head and neck cancer, kidney cancer, liver cancer, gastrointestinal cancer, esophageal cancer, ovarian cancer, pancreatic cancer, skin cancer, testicular cancer, thyroid cancer, uterine cancer, cervical cancer and vulvar cancer, and leukemia, multiple myeloma, or lymphoma.

### Claim 31 (depends on 18)

The method of claim 18, wherein the disease mediated by ATR kinase comprises small cell lung cancer, non-small cell lung cancer and bronchioloalveolar carcinom, acute lymphoblastic leukemia (ALL), chronic myeloid leukemia (CML), or acute myeloid leukemia (AML).