# US 11,028,076 B2 · Inhibiting ataxia telangiectasia and Rad3-related protein (ATR)

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- Number: US 11,028,076 B2
- Document ID: US11028076B2
- Status: Granted
- Kind: B2
- Application number: 16/745,709
- Filed: 2020-01-17
- Published: 2020-12-24
- Granted: 2021-06-08
- Earliest claimed: 2016-01-11
- Assignees: Celator Pharmaceuticals, Inc.
- Applicants: Celator Pharmaceuticals, Inc.
- Inventors: Daryl C. Drummond; Bolin Geng; Dmitri B. Kirpotin; Suresh K. Tipparaju; Alexander Koshkaryev; Ozan Alkan
- Web page: https://patentgrep.com/patent/US11028076B2

## CPC

- C07D 403/12: linked by a chain containing hetero atoms as chain links
- A61K 9/1271: Non-conventional liposomes, e.g. PEGylated liposomes or liposomes coated or grafted with polymers (liposomes as conjugates {A61K47/6911})
- A61K 31/4745: condensed with ring systems having nitrogen as a ring hetero atom, e.g. phenantrolines (yohimbine derivatives, vinblastine A61K31/475; ergoline derivatives A61K31/48)
- A61K 31/496: Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
- A61K 31/4965: Non-condensed pyrazines
- A61K 31/497: containing further heterocyclic rings
- A61K 31/555: containing heavy metals, e.g. hemin, hematin, melarsoprol
- A61K 31/7068: having oxo groups directly attached to the pyrimidine ring, e.g. cytidine, cytidylic acid
- A61K 47/14: Esters of carboxylic acids, e.g. fatty acid monoglycerides, medium-chain triglycerides, parabens or PEG fatty acid esters
- 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

Novel compounds inhibiting ATR protein kinase include compounds of formula (I) disclosed herein, as well as liposome formulations comprising ATR protein kinase inhibitor compounds. The compositions are useful for the treatment of cancer.

## Claims

### Claim 1

A liposome composition comprising an ATR protein kinase inhibitor, or a pharmaceutically acceptable salt thereof, encapsulated in a liposome and having a plasma half-life of at least about 5 hours in mice, wherein the ATR protein kinase inhibitor is a compound of formula (I):
wherein R is a moiety comprising an amine with a pKa of greater than 7.0;
and the liposome comprises cholesterol.

### Claim 2 (depends on 1)

The liposome composition of claim 1, wherein R is a moiety comprising an amine with a pKa of at least about 9.5.

### Claim 3 (depends on 1)

The liposome composition of claim 1, wherein the ATR protein kinase inhibitor is a compound of formula (I), or a pharmaceutically acceptable salt thereof:
wherein R is:
i)
,wherein A1 is either absent or C1-C4 alkyl, and R1 is C1-C4alkylamino;
ii) —N(H)(C1-C4 alkyl)—NRaRb, wherein Ra and Rb are each independently C1-C4 alkyl;
iii) -(G)- NRaRb; wherein Ra and Rb are each independently C1-C4 alkyl; and
G is C1-C4 alkyl, wherein G can be optionally substituted with C1-C4 alkyl; or
iv)
,wherein Rc and Rd are each independently C1-C4 alkyl.

### Claim 4 (depends on 1)

The liposome composition of claim 1, wherein the liposome further comprises PEG(2000)-distearoylglycerol (PEG-DSG).

### Claim 5 (depends on 4)

The liposome composition of claim 4, wherein the liposome comprises cholesterol and PEG-DSG in a molar ratio of about 2:0.15.

### Claim 6 (depends on 1)

The liposome composition of claim 1, wherein the ATR protein kinase inhibitor is selected from the group consisting of:

### Claim 7 (depends on 1)

The liposome composition of claim 1, wherein the ATR protein kinase inhibitor is selected from the group consisting of:

### Claim 8 (depends on 1)

The liposome composition of claim 1, wherein the ATR protein kinase inhibitor is Compound 1:

### Claim 9 (depends on 6)

The liposome composition of claim 6, wherein the liposome further comprises PEG(2000)-distearoylglycerol (PEG-DSG).

### Claim 10 (depends on 6)

The liposome composition of claim 6, wherein the liposome comprises cholesterol and PEG-DSG in a molar ratio of about 2:0.15.

### Claim 11

An ataxia-telangiectasia and Rad3-related (ATR) protein kinase inhibitor of formula (Ia), or a pharmaceutically acceptable salt thereof:
wherein R′ is NRaRb, wherein Ra and Rb are each independently C1-C4alkyl.

### Claim 12 (depends on 1)

The liposome composition of claim 1, wherein the liposome comprises one or more phospholipids.

### Claim 13 (depends on 6)

The liposome composition of claim 6, wherein the liposome comprises one or more phospholipids.

### Claim 14 (depends on 12)

The liposome composition of claim 12, wherein the phospholipid is 1,2-distearoyl-sn-glycero-3-phosphocholine (DSPC).

### Claim 15 (depends on 13)

The liposome composition of claim 13, wherein the phospholipid is 1,2-distearoyl-sn-glycero-3-phosphocholine (DSPC).

### Claim 16 (depends on 11)

A liposome composition comprising an ATR protein kinase inhibitor of claim 11, or a pharmaceutically acceptable salt thereof.

### Claim 17 (depends on 16)

The liposome composition of claim 16, wherein the liposome comprises cholesterol.

### Claim 18 (depends on 16)

The liposome composition of claim 16, wherein the liposome comprises one or more phospholipids.

### Claim 19 (depends on 18)

The liposome composition of claim 18, wherein the phospholipid is 1,2-distearoyl-sn-glycero-3-phosphocholine (DSPC).

### Claim 20 (depends on 16)

The liposome composition of claim 16, wherein the liposome comprises PEG(2000)-distearoylglycerol (PEG-DSG).