# US 11,028,089 B2 · Pyrimido-diazepinone kinase scaffold compounds and methods of treating DCLK1/2-mediated disorders

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- Number: US 11,028,089 B2
- Document ID: US11028089B2
- Status: Granted
- Kind: B2
- Application number: 16/343,102
- Filed: 2017-10-18
- Published: 2019-10-17
- Granted: 2021-06-08
- Earliest claimed: 2016-10-18
- Assignees: Dana-Farber Cancer Institute, Inc.
- Applicants: Dana-Farber Cancer Institute, Inc.
- Inventors: Fleur M. Ferguson; Nathanael S. Gray
- Web page: https://patentgrep.com/patent/US11028089B2

## CPC

- C07D 487/04: Ortho-condensed systems
- A61K 31/551: having two nitrogen atoms, e.g. dilazep
- A61K 45/06: Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
- A61P 1/16: for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
- A61P 3/04: Anorexiants; Antiobesity agents
- A61P 3/06: Antihyperlipidemics
- A61P 3/10: for hyperglycaemia, e.g. antidiabetics
- A61P 29/00: Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
- A61P 35/00: Antineoplastic agents
- A61P 43/00: Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
- 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

The present invention relates to use of pyrimido-diazepinone compounds that are able to modulate protein kinases such as doublecortin-like kinase (DCLK1) and doublecortin-like kinase 2 (DCLK2), which are members of serine/threonine-protein kinase family and Ca2+/calmodulin-dependent protein kinase class of enzymes, and the use of such compounds in the treatment of various diseases, disorders or conditions.

## Claims

### Claim 1

A method of treating pancreatic cancer in a subject, the method comprising administering to the subject a compound of formula F-1:
or a pharmaceutically acceptable salt thereof,
wherein,
R1 is
R2 is —CH2—CH2F, —CH2—CHF2, or —CH2—CF3;
R5 is hydrogen or methyl; and
R6 is hydrogen or optionally substituted alkyl;
each R7 is independently alkyl, alkenyl, aryl, arylalkyl, heteroaryl, heterocyclic, carbocyclic, alkoxy, NH(alkyl), NH(aryl), N(alkyl)(alkyl), or N(alkyl)(aryl), each of which may be optionally substituted; halo, nitro, or cyano; and
p is 0-4.

### Claim 2 (depends on 1)

The method of claim 1, wherein the compound is of formula F-1-a:
or a pharmaceutically acceptable salt thereof.

### Claim 3 (depends on 1)

The method of claim 1, wherein the subject is administered simultaneously or sequentially an additional therapeutic agent, wherein the additional therapeutic agent comprises an anti-inflammatory agent, which is azathioprine, cyclophosphamide, or sulfasalazine, or a chemotherapeutic agent, which is imatinib mesylate, adriamycin, dexamethasone, vincristine, cyclophosphamide, fluorouracil, topotecan, taxol, an interferon, or a platinum derivative.

### Claim 4 (depends on 1)

The method of claim 1, wherein the subject is a human.

### Claim 5

A compound of formula F-1:
or a pharmaceutically acceptable salt thereof,
wherein,
R1 is
R2 is —CH2—CH2F, —CH2—CHF2, or —CH2—CF3;
R5 is hydrogen or methyl; and
R6 is hydrogen or optionally substituted alkyl;
each R7 is independently alkyl, alkenyl, aryl, arylalkyl, heteroaryl, heterocyclic, carbocyclic, alkoxy, NH(alkyl), NH(aryl), N(alkyl)(alkyl), or N(alkyl)(aryl), each of which may be optionally substituted; halo, nitro, or cyano; and
p is 0-4.

### Claim 6 (depends on 5)

The compound of claim 5, wherein the compound is of formula F-1-a:
or a pharmaceutically acceptable salt thereof.

### Claim 7 (depends on 5)

A pharmaceutical composition comprising the compound of claim 5, or a pharmaceutically acceptable salt thereof.

### Claim 8 (depends on 1)

The method of claim 1, wherein the compound is
or a pharmaceutically acceptable salt thereof.

### Claim 9 (depends on 5)

The compound of claim 5, wherein the compound is
or a pharmaceutically acceptable salt thereof.

### Claim 10

A compound which is:
or a pharmaceutically acceptable salt thereof.

### Claim 11 (depends on 10)

A method of treating pancreatic cancer in a subject, the method comprising administering to the subject a compound of claim 10, or a pharmaceutically acceptable salt thereof.