# US 11,028,074 B2 · CD73 inhibitors

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- Number: US 11,028,074 B2
- Document ID: US11028074B2
- Status: Granted
- Kind: B2
- Application number: 16/481,146
- Filed: 2019-02-22
- Published: 2021-01-07
- Granted: 2021-06-08
- Earliest claimed: 2018-03-01
- Assignees: Eli Lilly and Company
- Applicants: Eli Lilly and Company
- Inventors: Robert Dean Dally; Maria Cristina Garcia Paredes; Lawrence Joseph Heinz, II; Jennifer Marie Howell; Frank George Njoroge; Yan Wang; Genshi Zhao
- Web page: https://patentgrep.com/patent/US11028074B2

## CPC

- C07D 403/04: directly linked by a ring-member-to-ring-member bond
- A61P 35/00: Antineoplastic agents
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS

## Abstract

The present invention provides 5-[5]-[2-cycloalkyl]-6-pyridazin-3-yl]-1H-pyrimidine-2,4-dione compounds, or pharmaceutically acceptable salts thereof, that inhibit the activity of CD73 and are useful in treating cancer.

## Claims

### Claim 1

A compound of the formula:
wherein n is 0-3;
R1 is —H, —F, -gem-difluoro, -gem-dimethyl,
—C1-4 alkyl, —CHF2, —CF2CH3 or —CH2CH2F; and
R2 is selected from —H, —CH3, —F, —Cl, —CN, or —OCH3;
or a pharmaceutically acceptable salt thereof.

### Claim 2 (depends on 1)

The compound according to claim 1, which is:
or a pharmaceutically acceptable salt thereof.

### Claim 3 (depends on 2)

The compound according to claim 2, which is:
or a pharmaceutically acceptable salt thereof.

### Claim 4 (depends on 2)

The compound according to claim 2, which is:
or a pharmaceutically acceptable salt thereof.

### Claim 5 (depends on 4)

The compound according to claim 4, which is:
or a pharmaceutically acceptable salt thereof.

### Claim 6 (depends on 1)

The compound according to claim 1,
wherein n is 0, R1 is —C1-4 alkyl, and R2 is —CH3,
or a pharmaceutically acceptable salt thereof.

### Claim 7 (depends on 6)

The compound according to claim 6, wherein R1 is isopropyl, or a pharmaceutically acceptable salt thereof.

### Claim 8 (depends on 1)

The compound according to claim 1, which is
or a pharmaceutically acceptable salt thereof.

### Claim 9 (depends on 2)

The compound according to claim 2, which is:
or a pharmaceutically acceptable salt thereof.

### Claim 10 (depends on 9)

The compound according to claim 9, which is 5-[5-[(1S,2R)-2-isopropylcyclopropyl]-6-methyl-pyridazin-3-yl]-1H-pyrimidine-2,4-dione, or a pharmaceutically acceptable salt thereof.

### Claim 11 (depends on 2)

The compound according to claim 2, which is:
or a pharmaceutically acceptable salt thereof.

### Claim 12 (depends on 11)

The compound according to claim 11, which is 5-[5-[(1S,2S)-2-ethylcyclopropyl]-6-methyl-pyridazin-3-yl]-1H-pyrimidine-2,4-dione, or a pharmaceutically acceptable salt thereof.

### Claim 13

A pharmaceutical composition comprising a compound of the formula:
wherein n is 0-3;
R1 is —H, —F, -gem-difluoro, -gem-dimethyl, —C1-4 alkyl, —CHF2, —CF2CH3 or —CH2CH2F; and
R2 is selected from —H, —CH3, —F, —Cl, —CN, or —OCH3;
or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers, diluents, or excipients.

### Claim 14

A method of treating cancer, comprising administering to a patient in need thereof, an effective amount of a compound of the formula:
wherein n is 0-3;
R1 is —H, —F, -gem-difluoro, -gem-dimethyl, —C1-4 alkyl, —CHF2, —CF2CH3 or —CH2CH2F; and
R2 is selected from —H, —CH3, —F, —Cl, —CN, or —OCH3;
or a pharmaceutically acceptable salt thereof,
wherein the cancer is bladder cancer, breast cancer, cholangiocarcinoma, colorectal cancer, colon cancer, gastric cancer, gallbladder cancer, glioblastoma, head and neck cancer, liver cancer, lung cancer, lymphoma, medulloblastoma, melanoma, ovarian cancer, pancreatic cancer, prostate cancer or renal cancer.

### Claim 15 (depends on 14)

The method of claim 14, wherein the patient is one in whom serum CD73 activity has been determined.

### Claim 16 (depends on 14)

The method of claim 14, wherein the patient is one in whom tissue CD73 expression has been determined.

### Claim 17

A method, comprising determining CD73 activity in the serum of a patient to whom a compound of the formula:
wherein n is 0-3;
R1 is —H, —F, -gem-difluoro, -gem-dimethyl, —C1-4 alkyl, —CHF2, —CF2CH3 or —CH2CH2F; and
R2 is selected from —H, —CH3, —F, —Cl, —CN, or —OCH3;
or a pharmaceutically acceptable salt thereof, has been administered.

### Claim 18

A method, comprising determining CD73 expression in tissue from a patient to whom a compound of the formula:
wherein n is 0-3;
R1 is —H, —F, -gem-difluoro, -gem-dimethyl, —C1-4 alkyl, —CHF2, —CF2CH3 or —CH2CH2F; and
R2 is selected from —H, —CH3, —F, —Cl, —CN, or —OCH3;
or a pharmaceutically acceptable salt thereof, has been administered.

### Claim 19 (depends on 13)

The pharmaceutical composition according to claim 13, wherein the compound is:
or a pharmaceutically acceptable salt thereof.

### Claim 20 (depends on 19)

The pharmaceutical composition according to claim 19, wherein the compound is 5-[5-[(1S,2R)-2-isopropylcyclopropyl]-6-methyl-pyridazin-3-yl]-1H-pyrimidine-2,4-dione, or a pharmaceutically acceptable salt thereof.

### Claim 21 (depends on 14)

The method according to claim 14, wherein the compound is:
or a pharmaceutically acceptable salt thereof.

### Claim 22 (depends on 21)

The method according to claim 21, wherein the compound is 5-[5-[(1S,2R)-2-isopropylcyclopropyl]-6-methyl-pyridazin-3-yl]-1H-pyrimidine-2,4-dione, or a pharmaceutically acceptable salt thereof.