# US 8,772,279 B2 · 6,7-dihydroimidazo[1,5-a]pyrazin-8(5H)-one derivatives as protein kinase modulators

> Agents: this data is available as JSON from the patentgrep API and MCP server — see https://patentgrep.com/llms.txt

- Number: US 8,772,279 B2
- Document ID: US8772279B2
- Status: Granted
- Kind: B2
- Application number: 13/575,181
- Filed: 2011-01-21
- Published: 2013-01-31
- Granted: 2014-07-08
- Earliest claimed: 2010-01-29
- Assignees: Nerviano Medical Sciences S.R.L.
- Applicants: Danilo Mirizzi; Sten Christian Orrenius; Paolo Trifirò
- Inventors: Danilo Mirizzi; Sten Christian Orrenius; Paolo Trifirò
- Web page: https://patentgrep.com/patent/US8772279B2

## CPC

- C07D 487/04: Ortho-condensed systems
- A61P 9/00: Drugs for disorders of the cardiovascular system
- A61P 9/10: for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
- A61P 11/00: Drugs for disorders of the respiratory system
- A61P 13/08: of the prostate
- A61P 17/00: Drugs for dermatological disorders
- A61P 17/06: Antipsoriatics
- A61P 19/02: for joint disorders, e.g. arthritis, arthrosis
- A61P 25/00: Drugs for disorders of the nervous system
- A61P 31/00: Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P 31/12: Antivirals
- A61P 31/18: for HIV
- A61P 35/00: Antineoplastic agents
- A61P 35/02: specific for leukemia
- A61P 35/04: specific for metastasis
- A61P 37/06: Immunosuppressants, e.g. drugs for graft rejection
- A61P 43/00: Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS

## Abstract

There are provided 3,5-disubstituted derivatives of 6,7-dihydroimidazo[1,5-a]pyrazin-8(5H)-one compounds of formula (I) or a pharmaceutically acceptable salt thereof as defined in the present specification, which modulate the activity of protein kinases. The compounds are therefore useful in treating diseases caused by dysregulated protein kinase activity. In particular, such diseases to be treated with a compound of formula (I) of the present invention is one caused by and/or associated with disregulated protein kinase activity selected from the group consisting of cancer, viral infection, prevention of AIDS development in HIV-infected individuals, cell proliferative disorders, autoimmune and neurodegenerative disorders. The present invention also relates to processes for preparing the compounds of formula (I), combinatorial libraries thereof, pharmaceutical compositions comprising them, and methods of treating diseases utilizing pharmaceutical compositions comprising a compound of formula (I).

## Claims

### Claim 1

A compound of the formula (I):
wherein:
R1 is —NR3R4 or —OR3;
R2 is a hydrogen atom or an optionally substituted group selected from straight or branched C1-C6 alkyl, aryl, heteroaryl, aryl C1-C6 alkyl and heteroaryl C1-C6 alkyl;
R3 and R4, the same or different, are each independently hydrogen atom or an optionally substituted group selected from straight or branched C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, cycloalkyl C1-C6 alkyl, heterocyclyl, heterocyclyl C1-C6 alkyl, aryl, aryl C1-C6 alkyl, heteroaryl and heteroaryl C1-C6 alkyl, or R3 and R4, taken together with the nitrogen atom to which they are bonded, may form an optionally substituted 3 to 7 membered heterocyclyl or heteroaryl ring, optionally containing one additional heteroatom or heteroatomic group selected from S, O, N and NH; or a pharmaceutically acceptable salt thereof, wherein the optionally substituted group of R2, R3 and R4 is substituted in any of its free positions by 1 to 6 groups, selected from the groups consisting of: halogen, nitro, oxo groups (═O), carboxy, cyano, C1-C6 alkyl, polyfluorinated alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, heterocyclyl, aryl, heteroaryl; amino groups and derivatives thereof; carbonylamino groups and derivatives thereof; hydroxy groups and derivatives thereof; carbonyl groups and derivatives thereof; and sulfurated derivatives, wherein when R1 is —NR3R4, only one of R3 and R4 are hydrogen and when R1 is —OR3, R3 is not hydrogen.

### Claim 2 (depends on 1)

A compound of formula (I) according to claim 1 wherein R1 is —NH2 or NHR3 and R3 is a straight or branched C1-C6 alkyl or C2-C6 alkenyl group or it is an optionally substituted aryl or arylalkyl group, wherein the optionally substituted aryl or arlyalkyl of R3 is substituted in any of its free positions by 1 to 6 groups, selected from the groups consisting of: halogen, nitro, oxo groups (═O), carboxy, cyano, C1-C6 alkyl, polyfluorinated alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, heterocyclyl, aryl, heteroaryl; amino groups and derivatives thereof; carbonylamino groups and derivatives thereof; hydroxy groups and derivatives thereof; carbonyl groups and derivatives thereof; and sulfurated derivatives.

### Claim 3 (depends on 1)

A compound of formula (I) according to claim 1 wherein R2 is hydrogen or an optionally substituted aryl or heteroaryl group, wherein the optionally substituted aryl or heteroaryl of R2 is substituted in any of its free positions by 1 to 6 groups, selected from the groups consisting of: halogen, nitro, oxo groups (═O), carboxy, cyano, C1-C6 alkyl, polyfluorinated alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, heterocyclyl, aryl, heteroaryl; amino groups and derivatives thereof; carbonylamino groups and derivatives thereof; hydroxy groups and derivatives thereof; carbonyl groups and derivatives thereof; and sulfurated derivatives.

### Claim 4 (depends on 1)

A compound of formula (I) according to claim 1 wherein R2 is a fragment denoted by any of codes A1-A18 and R1 is a fragment denoted by any of codes B1-B32:
Fragment
CODE
Fragment
CODE
A1
A9
A2
A10
A3
A11
A4
A12
A5
A13
A6
A14
A7
H—M
A15
A8
A16
A17
A18
B1
B8
B2
B9
B3
B10
B4
B11
B5
HO—M
B12
B6
H2N—M
B13
B7
B14
B15
B24
B16
B25
B17
B26
B18
B27
B19
B28
B20
B29
B21
B30
B22
B31
B23
B32.

### Claim 5 (depends on 1)

A process for preparing a compound of the formula (I) or the pharmaceutically acceptable salts thereof, as defined in claim 1, which process comprises:
a) decarboxylating a compound of formula (II):
b) reacting the resultant compound of formula (III):
with a compound of formula (IV) or a salt thereof:
wherein R3 is a C1-C6 alkyl group, so as to obtain a compound of formula (I):
wherein R3 is a C1-C6 alkyl group and R2 is hydrogen, or a pharmaceutically acceptable salt thereof and, if necessary or desired, performing one or more of the following additional steps:
separating the compound of formula (I) into the single isomers;
converting a compound of formula (I) into a different compound of formula (I) by introduction on the imidazole moiety of a R2 group as defined in claim 1 but different from hydrogen;
converting a compound of formula (I) into a different compound of formula (I) by replacing the group —OR3 with a different group R1 as defined in claim 1;
converting a compound of formula (I) into a pharmaceutically acceptable salt or converting a salt into the free compound (I).

### Claim 6 (depends on 1)

A pharmaceutical composition comprising a therapeutically effective amount of a compound of formula (I), as defined in claim 1, and at least one pharmaceutically acceptable carrier and/or diluent.

### Claim 7 (depends on 6)

A pharmaceutical composition according to claim 6 further comprising one or more chemotherapeutic agents.

### Claim 8 (depends on 1)

A product comprising a compound of formula (I) as defined in claim 1 or a pharmaceutical composition thereof comprising said compound and at least one pharmaceutically acceptable carrier and/or diluent, and one or more chemotherapeutic agents, as a combined preparation for simultaneous, separate or sequential use in anticancer therapy.