# US 12,180,184 B2 · Pyrimidopyrazolone derivative as Wee1 inhibitor and use thereof

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- Number: US 12,180,184 B2
- Document ID: US12180184B2
- Status: Granted
- Kind: B2
- Application number: 17/288,707
- Filed: 2019-10-28
- Published: 2021-12-30
- Granted: 2024-12-31
- Earliest claimed: 2018-10-26
- Assignees: Wuxi Biocity Biopharmaceutics Co., Ltd.
- Applicants: Wuxi Biocity Biopharmaceutics Co., Ltd.
- Inventors: Wenyuan Qian; Chundao Yang; Zhengwei Li; Jian Li; Shuhui Chen
- Web page: https://patentgrep.com/patent/US12180184B2

## CPC

- C07D 401/14: containing three or more hetero rings
- C07D 487/22: in which the condensed system contains four or more hetero rings
- A61K 31/519: ortho- or peri-condensed with heterocyclic rings
- A61K 31/7068: having oxo groups directly attached to the pyrimidine ring, e.g. cytidine, cytidylic acid
- A61P 35/00: Antineoplastic agents
- 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

A pyrimidopyrazolone derivative as a Wee1 inhibitor and use thereof in preparation of a medicament for treating Wee1-related diseases are described. In particular, the present invention relates to a compound of formula (I), an isomer or a pharmaceutically acceptable salt thereof.

## Claims

### Claim 1

A compound of formula (I), or a stereoisomer or a pharmaceutically acceptable salt thereof,
wherein,
is a single bond or a double bond;
n is 1, 2 or 3;
ring A is selected from the group consisting of C6-10 aryl and 5-12 membered heteroaryl;
R1 is selected from the group consisting of H and C1-3 alkyl, wherein the C1-3 alkyl is optionally substituted by 1, 2 or 3 Ra;
R2 and R3 are each independently selected from the group consisting of H, F, Cl, Br, I, OH, NH2 and C1-3 alkyl, wherein the C1-3 alkyl is optionally substituted by 1, 2 or 3 Rb, and R2 and R3 are not H at the same time;
R4 is selected from the group consisting of C3-8 cycloalkyl and 4-10 membered heterocycloalkyl, wherein the C3-8 cycloalkyl and 4-10 membered heterocycloalkyl are optionally substituted by 1, 2 or 3 Rc;
R5 is selected from the group consisting of H, F, Cl, Br, I, OH, NH2, C1-3 alkyl and C1-3 alkoxy, wherein the C1-3 alkyl is optionally substituted by 1, 2 or 3 Rd;
Ra is each independently selected from the group consisting of F, Cl, Br, I, OH and NH2;
Rb is each independently selected from the group consisting of F, Cl, Br, I, OH and NH2;
Rc is each independently selected from the group consisting of H, F, Cl, Br, I, OH, NH2 and C1-3 alkyl, wherein the NH2 is optionally substituted by 1 or 2 R, and the C1-3 alkyl is optionally substituted by 1, 2 or 3 R;
Rd is each independently selected from the group consisting of F, Cl, Br, I, OH and NH2;
R is each independently selected from the group consisting of F, Cl, Br, I, OH and NH2;
the 5-12 membered heteroaryl and 4-10 membered heterocycloalkyl contain 1, 2, 3 or 4 heteroatoms or heteroradicals independently selected from the group consisting of —NH—, O, —S— and N.

### Claim 2 (depends on 1)

The compound according to claim 1, or a stereoisomer or a pharmaceutically acceptable salt thereof, wherein the ring A is selected from the group consisting of C6-8 aryl and 5-10 membered heteroaryl.

### Claim 3 (depends on 1)

The compound according to claim 1, or a stereoisomer or a pharmaceutically acceptable salt thereof, wherein the compound has the structure of formula (II) or (III)
wherein,
is a single bond or a double bond;
n is 1, 2 or 3;
R1 is each independently selected from the group consisting of H and C1-3 alkyl, wherein the C1-3 alkyl is optionally substituted by 1, 2 or 3 Ra;
R2 and R3 are each independently selected from the group consisting of H, F, Cl, Br, I, OH, NH2 and C1-3 alkyl, wherein the C1-3 alkyl is optionally substituted by 1, 2 or 3 Rb, and R2 and R3 are not H at the same time;
R4 is each independently selected from the group consisting of C3-8 cycloalkyl and 4-10 membered heterocycloalkyl, wherein the C3-8 cycloalkyl and 4-10 membered heterocycloalkyl are optionally substituted by 1, 2 or 3 Rc;
R5 is each independently selected from the group consisting of H, F, Cl, Br, I, OH, NH2, C1-3 alkyl and C1-3 alkoxy, wherein the C1-3 alkyl is optionally substituted by 1, 2 or 3 Rd;
Ra is each independently selected from the group consisting of F, Cl, Br, I, OH and NH2;
Rb is each independently selected from the group consisting of F, Cl, Br, I, OH and NH2;
Rc is each independently selected from the group consisting of H, F, Cl, Br, I, OH, NH2 and C1-3 alkyl, wherein the NH2 is optionally substituted by 1 or 2 R, and the C1-3 alkyl is optionally substituted by 1, 2 or 3 R;
Rd is each independently selected from the group consisting of F, Cl, Br, I, OH and NH2;
R is each independently selected from the group consisting of F, Cl, Br, I, OH and NH2;
the 4-10 membered heterocycloalkyl contains 1, 2, 3 or 4 heteroatoms or heteroradicals independently selected from the group consisting of —NH—, O, —S— and N;
the carbon atom with “*” is a chiral carbon atom, which is present in a form of a single enantiomer as (R) or (S) or in a form enriched with an enantiomer.

### Claim 4 (depends on 3)

The compound according to claim 3, or a stereoisomer or a pharmaceutically acceptable salt thereof, wherein the compound has the structure of formula (II-A) or (III-A):
wherein,
r is 1 or 2;
D is each independently selected from the group consisting of ×N(R6)— and —C(R7)(R8)—;
R6 is each independently selected from the group consisting of H and C1-3 alkyl, wherein the C1-3 alkyl is optionally substituted by 1, 2 or 3 Re;
R7 and R8 are each independently selected from the group consisting of H, F, Cl, Br, I, OH, NH2 and C1-3 alkyl, wherein the NH2 is optionally substituted by 1 or 2 Rf, and the C1-3 alkyl is optionally substituted by 1, 2 or 3 Rf;
Re is each independently selected from the group consisting of F, Cl, Br, I, OH and NH2;
Rf is each independently selected from the group consisting of F, Cl, Br, I, OH, NH2 and C1-3 alkyl;
the carbon atom with “*” is a chiral carbon atom, which is present in a form of a single enantiomer as (R) or (S) or in a form enriched with an enantiomer;
R1 is each independently selected from the group consisting of H and C1-3 alkyl, wherein the C1-3 alkyl is optionally substituted by 1, 2 or 3 Ra;
R2 and R3 are each independently selected from the group consisting of H, F, Cl, Br, I, OH, NH2 and C1-3 alkyl, wherein the C1-3 alkyl is optionally substituted by 1, 2 or 3 Rb, and R2 and R3 are not H at the same time;
Ra is each independently selected from the group consisting of F, Cl, Br, I, OH and NH2;
Rb is each independently selected from the group consisting of F, Cl, Br, I, OH and NH2.

### Claim 5 (depends on 1)

The compound according to claim 1, or a stereoisomer or a pharmaceutically acceptable salt thereof, wherein Rc is each independently selected from the group consisting of F, Cl, Br, I, OH, NH2, CH3 and Et.

### Claim 6 (depends on 4)

The compound according to claim 4, or a stereoisomer or a pharmaceutically acceptable salt thereof, wherein Rf is each independently selected from the group consisting of F, Cl, Br, I, OH, NH2, CH3 and Et.

### Claim 7 (depends on 1)

The compound according to claim 1, or a stereoisomer or a pharmaceutically acceptable salt thereof, wherein R1 is each independently selected from the group consisting of H, CH3 and Et.

### Claim 8 (depends on 1)

The compound according to claim 1, or a stereoisomer or a pharmaceutically acceptable salt thereof, wherein R2 and R3 are each independently selected from the group consisting of H, F, Cl, Br, I, OH, NH2, CH3 and Et, and R2 and R3 are not H at the same time.

### Claim 9 (depends on 1)

The compound according to claim 1, or a stereoisomer or a pharmaceutically acceptable salt thereof, wherein R5 is each independently selected from the group consisting of H, F, Cl, Br, I, OH, NH2, CH3, Et and OCH3.

### Claim 10 (depends on 4)

The compound according to claim 4, or a stereoisomer or a pharmaceutically acceptable salt thereof, wherein R6 is each independently selected from the group consisting of H, CH3 and Et.

### Claim 11 (depends on 4)

The compound according to claim 4, or a stereoisomer or a pharmaceutically acceptable salt thereof, wherein R7 and R8 are each independently selected from the group consisting of H, F, Cl, Br, I, OH, NH2, —NH(CH3), —N(CH3)2, CH3 and Et.

### Claim 12 (depends on 11)

The compound according to claim 11, or a stereoisomer or a pharmaceutically acceptable salt thereof, wherein R7 is each independently selected from the group consisting of H, F, Cl, Br, I, OH, NH2, —NH(CH3), —N(CH3)2, CH3 and Et.

### Claim 13 (depends on 11)

The compound according to claim 11, or a stereoisomer or a pharmaceutically acceptable salt thereof, wherein R8 is each independently selected from the group consisting of H, F, Cl, Br, I, OH, CH3 and Et.

### Claim 14 (depends on 4)

The compound according to claim 4, or a stereoisomer or a pharmaceutically acceptable salt thereof, wherein the structural unit
is selected from the group consisting of

### Claim 15 (depends on 14)

The compound according to claim 14, or a stereoisomer or a pharmaceutically acceptable salt thereof, wherein the structural unit
is selected from the group consisting of

### Claim 16 (depends on 1)

The compound according to claim 1, or a stereoisomer or a pharmaceutically acceptable salt thereof, wherein the structural unit
is selected from the group consisting of

### Claim 17 (depends on 1)

The compound according to claim 1, or a stereoisomer or a pharmaceutically acceptable salt thereof, wherein the compound has the structure of formula (II-A1), (II-A2) or (III-AA1)
wherein, R1 is selected from the group consisting of H and C1-3 alkyl, wherein the C1-3 alkyl is optionally substituted by 1, 2 or 3 Ra;
R2 and R3 are each independently selected from the group consisting of H, F, Cl, Br, I, OH, NH2 and C1-3 alkyl, wherein the C1-3 alkyl is optionally substituted by 1, 2 or 3 Rb, and R2 and R3 are not H at the same time;
Ra is each independently selected from the group consisting of F, Cl, Br, I, OH and NH2;
Rb is each independently selected from the group consisting of F, Cl, Br, I, OH and NH2;
R6 is each independently selected from the group consisting of H and C1-3 alkyl, wherein the C1-3 alkyl is optionally substituted by 1, 2 or 3 Re;
Re is each independently selected from the group consisting of F, Cl, Br, I, OH and NH2;
R7 and R8 are each independently selected from the group consisting of H, F, Cl, Br, I, OH, NH2 and C1-3 alkyl, wherein the NH2 is optionally substituted by 1 or 2 Rf, and the C1-3 alkyl is optionally substituted by 1, 2 or 3 Rf;
Rf is each independently selected from the group consisting of F, Cl, Br, I, OH, NH2 and C1-3 alkyl;
the carbon atom with “*” is a chiral carbon atom, which is present in a form of a single enantiomer as (R) or (S) or in a form enriched with an enantiomer;
the “” refers to (Z) stereoisomer, (E) stereoisomer or a mixture of two stereoisomers of the compound.

### Claim 18 (depends on 17)

The compound according to claim 17, or a stereoisomer or a pharmaceutically acceptable salt thereof, wherein the compound has the structure of formula (II-1), (II-2) or (III-A1)
wherein
R1 is selected from the group consisting of H and C1-3 alkyl, wherein the C1-3 alkyl is optionally substituted by 1, 2 or 3 Ra;
R2 and R3 are each independently selected from the group consisting of H, F, Cl, Br, I, OH, NH2 and C1-3 alkyl, wherein the C1-3 alkyl is optionally substituted by 1, 2 or 3 Rb, and R2 and R3 are not H at the same time;
Ra is each independently selected from the group consisting of F, Cl, Br, I, OH and NH2;
Rb is each independently selected from the group consisting of F, Cl, Br, I, OH and NH2;
R6 is each independently selected from the group consisting of H and C1-3 alkyl, wherein the C1-3 alkyl is optionally substituted by 1, 2 or 3 Re;
Re is each independently selected from the group consisting of F, Cl, Br, I, OH and NH2;
R7 and R8 are each independently selected from the group consisting of H, F, Cl, Br, I, OH, NH2 and C1-3 alkyl, wherein the NH2 is optionally substituted by 1 or 2 Rf, and the C1-3 alkyl is optionally substituted by 1, 2 or 3 Rf;
Rf is each independently selected from the group consisting of F, Cl, Br, I, OH, NH2 and C1-3 alkyl;
the carbon atom with “*” is a chiral carbon atom, which is present in a form of a single enantiomer as (R) or (S) or in a form enriched with an enantiomer.

### Claim 19 (depends on 1)

The compound according to claim 1, or a stereoisomer or a pharmaceutically acceptable salt thereof, wherein the compound is selected from the group consisting of

### Claim 20 (depends on 19)

The compound according to claim 19, or a stereoisomer or a pharmaceutically acceptable salt thereof, wherein the compound is selected from the group consisting of

### Claim 21 (depends on 1)

A method for treating pancreatic cancer, comprising administering the compound according to claim 1, or a stereoisomer or a pharmaceutically acceptable salt thereof to a subject in need thereof.

### Claim 22 (depends on 1)

A pharmaceutical composition, comprising the compound according to claim 1, or a stereoisomer or a pharmaceutically acceptable salt thereof.