# US 9,040,540 B2 · 5-(pyridin-2-yl-amino)-pyrazine-2-carbonitrile compounds and their therapeutic use

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- Number: US 9,040,540 B2
- Document ID: US9040540B2
- Status: Granted
- Kind: B2
- Application number: 14/356,626
- Filed: 2012-11-09
- Published: 2014-10-23
- Granted: 2015-05-26
- Earliest claimed: 2011-11-09
- Assignees: Cancer Research Technology Limited
- Applicants: Cancer Research Technology Limited
- Inventors: Ian Collins; Michael Lainchbury; Thomas Peter Matthews; John Charles Reader
- Web page: https://patentgrep.com/patent/US9040540B2

## CPC

- C07D 401/14: containing three or more hetero rings
- A61K 9/0053: {Mouth and digestive tract, i.e. intraoral and peroral administration}
- A61K 31/497: containing further heterocyclic rings
- A61K 45/06: Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
- A61N 5/10: X-ray therapy; Gamma-ray therapy; Particle-irradiation therapy (A61N5/01 takes precedence)
- A61P 35/00: Antineoplastic agents
- A61P 35/02: specific for leukemia
- A61P 43/00: Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
- C07D 401/12: linked by a chain containing hetero atoms as chain links
- A61N 2005/1098: {Enhancing the effect of the particle by an injected agent or implanted device}
- 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)
- A61N: ELECTROTHERAPY; MAGNETOTHERAPY; RADIATION THERAPY; ULTRASOUND THERAPY (measurement of bioelectric currents A61B; surgical instruments, devices or methods for transferring non-mechanical forms of energy to or from the body A61B18/00; anaesthetic apparatus in general A61M; incandescent lamps H01K; infrared radiators for heating H05B)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS

## Abstract

The present invention pertains generally to the field of therapeutic compounds. More specifically the present invention pertains to certain pyridyl-amino-pyrazine carbonitrile compounds that, inter alia, inhibit Checkpoint Kinase 1 (CHK1) kinase function. The present invention also pertains to pharmaceutical compositions comprising such compounds, and the use of such compounds and compositions, both in vitro and in vivo, to inhibit CHK1 kinase function, and in the treatment of diseases and conditions that are mediated by CHK1, that are ameliorated by the inhibition of CHK1 kinase function, etc., including proliferative conditions such as cancer, etc., optionally in combination with another agent, for example, (a) a DNA topoisomerase I or II inhibitor; (b) a DNA damaging agent; (c) an antimetabolite or thymidylate synthase (TS) inhibitor; (d) a microtubule targeted agent; and (e) ionizing radiation.

## Claims

### Claim 1

A compound of the following formula, or a pharmaceutically acceptable salt thereof:
wherein:
—RB3 is independently:
each —RB3A is independently —H or saturated aliphatic C1-3alkyl;
—RA4 is independently —NHRA4A, —NRA4A2, or —ORA4A;
each —RA4A is independently saturated aliphatic C1-3alkyl;
—RA5 is independently —RA5A, —RA5B, —RA5C, —RA5D, —RA5E, or —RA5F;
—RA5A is independently:
—RA5AA is saturated aliphatic C1-3alkyl;
—RA5B is —CF3;
—RA5C is independently —F, —Cl, —Br, or —I;
—RA5D is independently —C≡CH, —C≡C—RA5DA, or —C≡C—RA5DB—OH;
—RA5DA is saturated aliphatic C1-4alkyl;
—RA5DB is saturated aliphatic C1-4alkylene;
—RA5E is independently saturated C3-6cycloalkyl;
—RA5F is —C(═O)O—RA5FA; and
—RA5FA is saturated aliphatic C1-3alkyl.

### Claim 2 (depends on 1)

The compound according to claim 1, wherein —RB3 is:

### Claim 3 (depends on 1)

The compound according to claim 1, wherein —RB3 is:

### Claim 4 (depends on 1)

The compound according to claim 1, wherein —RB3A is —H or -Me.

### Claim 5 (depends on 2)

The compound according to claim 2, wherein —RB3A is -Me.

### Claim 6 (depends on 3)

The compound according to claim 3, wherein —RB3A is —H or -Me.

### Claim 7 (depends on 4)

The compound according to claim 4, wherein —RA4 is independently —NHRA4A or —NRA4A2; wherein each —RA4A is independently -Me or -Et.

### Claim 8 (depends on 5)

The compound according to claim 5, wherein —RA4 is independently —NHRA4A or —NRA4A2; wherein each —RA4A is independently -Me or -Et.

### Claim 9 (depends on 6)

The compound according to claim 6, wherein —RA4 is independently —NHRA4A or —NRA4A2; wherein each —RA4A is independently -Me or -Et.

### Claim 10 (depends on 4)

The compound according to claim 4, wherein —RA4 is —ORA4A; wherein each —RA4A is independently -Me or -Et.

### Claim 11 (depends on 5)

The compound according to claim 5, wherein —RA4 is —ORA4A; wherein each —RA4A is independently -Me or -Et.

### Claim 12 (depends on 6)

The compound according to claim 6, wherein —RA4 is —ORA4A; wherein each —RA4A is independently -Me or -Et.

### Claim 13 (depends on 1)

The compound according to claim 1, wherein —RA5 is —RA5A.

### Claim 14 (depends on 2)

The compound according to claim 2, wherein —RA5 is —RA5A.

### Claim 15 (depends on 3)

The compound according to claim 3, wherein —RA5 is —RA5A.

### Claim 16 (depends on 4)

The compound according to claim 4, wherein —RA5 is —RA5A.

### Claim 17 (depends on 5)

The compound according to claim 5, wherein —RA5 is —RA5A.

### Claim 18 (depends on 6)

The compound according to claim 6, wherein —RA5 is —RA5A.

### Claim 19 (depends on 7)

The compound according to claim 7 wherein —RA5 is —RA5A.

### Claim 20 (depends on 8)

The compound according to claim 8, wherein —RA5 is —RA5A.

### Claim 21 (depends on 9)

The compound according to claim 9, wherein —RA5 is —RA5A.

### Claim 22 (depends on 10)

The compound according to claim 10, wherein —RA5 is —RA5A.

### Claim 23 (depends on 11)

The compound according to claim 11, wherein —RA5 is —RA5A.

### Claim 24 (depends on 12)

The compound according to claim 12, wherein —RA5 is —RA5A.

### Claim 25 (depends on 1)

The compound according to claim 1, which is a compound of the following formula, or a pharmaceutically acceptable salt thereof:

### Claim 26 (depends on 1)

The compound according to claim 1, which is a compound of the following formula, or a pharmaceutically acceptable salt thereof:

### Claim 27 (depends on 1)

The compound according to claim 1, which is a compound of the following formula, or a pharmaceutically acceptable salt thereof:

### Claim 28 (depends on 1)

The compound according to claim 1, which is a compound of one of the following formulae, or a pharmaceutically acceptable salt thereof:

### Claim 29 (depends on 1)

The compound according to claim 1, which is a compound of the following formula, or a pharmaceutically acceptable salt thereof:

### Claim 30 (depends on 1)

The compound according to claim 1, which is a compound of the following formula, or a pharmaceutically acceptable salt thereof:

### Claim 31 (depends on 1)

The compound according to claim 1, which is a compound of one of the following formulae, or a pharmaceutically acceptable salt thereof:

### Claim 32 (depends on 1)

The compound according to claim 1, which is a compound of one of the following formulae, or a pharmaceutically acceptable salt thereof:

### Claim 33 (depends on 1)

The compound according to claim 1, which is a compound of one of the following formulae, or a pharmaceutically acceptable salt thereof:

### Claim 34 (depends on 1)

The compound according to claim 1, which is a compound of one of the following formulae, or a pharmaceutically acceptable salt, hydrate, or solvate thereof:

### Claim 35 (depends on 1)

The compound according to claim 1, which is a compound one of the following formulae, or a pharmaceutically acceptable salt thereof:

### Claim 36

A compound of the following formula, or a pharmaceutically acceptable salt thereof:

### Claim 37 (depends on 1)

A pharmaceutical composition comprising a compound according to claim 1, and a pharmaceutically acceptable carrier or diluent.

### Claim 38 (depends on 1)

A method of preparing a pharmaceutical composition comprising the step of admixing a compound according to claim 1, and a pharmaceutically acceptable carrier or diluent.

### Claim 39 (depends on 1)

A method of treatment of neuroblastoma and colon cancer comprising administering to a subject in need of treatment a therapeutically-effective amount of a compound according to claim 1.