# US 8,541,429 B2 · Pyrazolo quinazoline derivatives, process for their preparation and their use as kinase inhibitors

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- Number: US 8,541,429 B2
- Document ID: US8541429B2
- Status: Granted
- Kind: B2
- Application number: 12/262,933
- Filed: 2008-10-31
- Published: 2009-05-14
- Granted: 2013-09-24
- Earliest claimed: 2003-05-22
- Assignees: Nerviano Medical Sciences S.R.L.
- Applicants: Gabriella Traquandi; Maria Gabriella Brasca; Roberto D'Alessio; Paolo Polucci; Fulvia Roletto; Anna Vulpetti; Paolo Pevarello; Achille Panzeri; Francesca Quartieri; Ron Ferguson; Paola Vianello; Daniele Fancelli
- Inventors: Gabriella Traquandi; Maria Gabriella Brasca; Roberto D'Alessio; Paolo Polucci; Fulvia Roletto; Anna Vulpetti; Paolo Pevarello; Achille Panzeri; Francesca Quartieri; Ron Ferguson; Paola Vianello; Daniele Fancelli
- Web page: https://patentgrep.com/patent/US8541429B2

## CPC

- C07D 487/14: Ortho-condensed systems
- A61K 31/519: ortho- or peri-condensed with heterocyclic rings
- A61K 31/5377: not condensed and containing further heterocyclic rings, e.g. timolol
- A61K 31/551: having two nitrogen atoms, e.g. dilazep
- A61P 9/00: Drugs for disorders of the cardiovascular system
- A61P 11/00: Drugs for disorders of the respiratory system
- A61P 13/08: of the prostate
- A61P 13/12: of the kidneys
- A61P 17/06: Antipsoriatics
- A61P 17/14: for baldness or alopecia
- A61P 19/02: for joint disorders, e.g. arthritis, arthrosis
- A61P 25/00: Drugs for disorders of the nervous system
- A61P 25/28: for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
- A61P 29/00: Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
- 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 37/00: Drugs for immunological or allergic disorders
- A61P 37/02: Immunomodulators
- 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 231/56: Benzopyrazoles; Hydrogenated benzopyrazoles
- C07D 239/72: Quinazolines; Hydrogenated quinazolines
- C07D 401/10: linked by a carbon chain containing aromatic rings
- C07D 403/14: containing three or more hetero rings
- C07D 413/14: containing three or more hetero rings
- C07D 487/04: Ortho-condensed systems
- 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

Pyrazolo-quinazoline derivatives of formula (Ia) or (Ib) as defined in the specification, and pharmaceutically acceptable salts thereof, process for their preparation and pharmaceutical compositions comprising them are disclosed; the compounds of the invention may be useful, in therapy, in the treatment of diseases associated with a disregulated protein kinase activity, like cancer.

## Claims

### Claim 1

A method for treating a disease, the disease selected from the group consisting of ovarian cancer, acute myeloid leukemia, prostate cancer, breast cancer, melanoma, colon cancer, non-small cell lung cancer, pancreatic cancer and pancreatic adenocarcinoma, by administering to a mammal in need thereof an effective amount of a pyrazolo-quinazoline derivative represented by formula (Ia) or (Ib)
wherein
R is hydrogen or an optionally substituted group selected from amino, straight or branched C1-C6 alkyl, C3-C10 cycloalkyl, aryl, arylalkyl, heterocyclyl or heterocyclylalkyl;
X is a single bond or a divalent radical selected from —NR′—, —CONR′—, —NH—CO—NH—, —O—, —S— or —SO2—, wherein R′ is hydrogen or an optionally substituted group selected from straight or branched C1-C6 alkyl, C3-C6 cycloalkyl, aryl, arylalkyl, heterocyclyl, heterocyclylalkyl or, together with the nitrogen atom to which they are bonded, R and R′ may form a 5 to 6 membered heteroaryl or heterocyclyl group optionally containing one additional heteroatom selected among N, O or S;
R1, bonded to any one of the nitrogen atoms of the pyrazole ring as per formulae (Ia) or (Ib), represents a hydrogen atom or an optionally substituted group selected from straight or branched C1-C6 alkyl, C3-C6 cycloalkyl, aryl, arylalkyl, heterocyclyl or heterocyclylalkyl or, in formula (Ib), R1 is a divalent —(CH2)n—NH— group being linked to R2, wherein n is 2 or 3;
wherein R1 is optionally substituted in any of its free positions by one or more groups independently selected from: halogen, nitro, oxo groups (═O), cyano, azido, alkyl, polyfluorinated alkyl, hydroxyalkyl, aryl, arylalkyl, heterocyclyl, heterocyclylalkyl, cycloalkyl, alkylaryl, alkylheterocyclyl, hydroxy, alkoxy, polyfluorinated alkoxy, aryloxy, arylalkyloxy, heterocyclyloxy, heterocyclylalkyloxy, methylenedioxy, alkylcarbonyloxy, arylcarbonyloxy, carboxy, alkoxycarbonyl, alkoxycarbonylalkyl, aryloxycarbonyl, cycloalkyloxycarbonyl, amino, aminoalkyl, alkylaminoalkyl, alkylaminoalkyloxy, ureido, alkylamino, dialkylamino, arylamino, diarylamino, formylamino, alkylcarbonylamino, arylcarbonylamino, heterocyclylcarbonylamino, alkoxycarbonylamino, alkoxyimino, alkylsulfonylamino, arylsulfonylamino, formyl, alkylcarbonyl, arylcarbonyl, heterocyclylcarbonyl, cycloalkylcarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, arylaminocarbonyl, alkylsulfonyl, arylsulfonyl, alkylaminosulfonyl, arylthio and alkylthio;
R2 is a group selected from —NR″R′″, —N(OH)R″, —OR″ or —R″, wherein R″ and R′″ are, each independently, hydrogen or an optionally substituted group selected from straight or branched C1-C6 alkyl, C3-C6 cycloalkyl or cycloalkyl-alkyl, aryl, arylalkyl, heterocyclyl or heterocyclylalkyl or, together with the nitrogen atom to which they are bonded, R″ and R′″ may form a 5 to 6 membered heteroaryl or heterocyclyl group, optionally containing one additional heteroatom selected among N, O or S;
A is a divalent group selected from —CH2—, —(CH2)2—, —CH2—C(CH3)2—, —C(CH3)2—CH2— or —CH═CH—;
or a pharmaceutically acceptable salt thereof.

### Claim 2 (depends on 1)

The method according to claim 1, wherein the treatment of the disease also provides tumor angiogenesis and metastasis inhibition as well as treatment of organ transplant rejection and host versus graft disease.

### Claim 3 (depends on 1)

The method according to claim 1, wherein the treatment of the disease also provides treatment of radiotherapy-induced or chemotherapy-induced alopecia.

### Claim 4 (depends on 1)

The method according to claim 1 further comprising subjecting the mammal in need thereof to a radiation therapy or chemotherapy regimen in combination with at least one cytostatic or cytotoxic agent.

### Claim 5 (depends on 1)

The method according to claim 1 wherein the mammal in need thereof is a human.

### Claim 6 (depends on 1)

The method according to claim 1 wherein the disease is prostate cancer.

### Claim 7

A method of inhibiting Aurora 2 activity of a mammal, the method comprising:
administering to the mammal an effective amount of a pyrazolo-quinazoline derivative represented by formula (Ia) or (Ib)
wherein
R is hydrogen or an optionally substituted group selected from amino, straight or branched C1-C6 alkyl, C3-C10 cycloalkyl, aryl, arylalkyl, heterocyclyl or heterocyclylalkyl;
X is a single bond or a divalent radical selected from —NR′—, —CONR′—, —NH—CO—NH—, —O—, —S— or —SO2—, wherein R′ is hydrogen or an optionally substituted group selected from straight or branched C1-C6 alkyl, C3-C6 cycloalkyl, aryl, arylalkyl, heterocyclyl, heterocyclylalkyl or, together with the nitrogen atom to which they are bonded, R and R′ may form a 5 to 6 membered heteroaryl or heterocyclyl group optionally containing one additional heteroatom selected among N, O or S;
R1, bonded to any one of the nitrogen atoms of the pyrazole ring as per formulae (Ia) or (Ib), represents a hydrogen atom or an optionally substituted group selected from straight or branched C1-C6 alkyl, C3-C6 cycloalkyl, aryl, arylalkyl, heterocyclyl or heterocyclylalkyl or, in formula (Ib), R1 is a divalent —(CH2)n—NH— group being linked to R2, wherein n is 2 or 3;
wherein R1 is optionally substituted in any of its free positions by one or more groups independently selected from: halogen, nitro, oxo groups (═O), cyano, azido, alkyl, polyfluorinated alkyl, hydroxyalkyl, aryl, arylalkyl, heterocyclyl, heterocyclylalkyl, cycloalkyl, alkylaryl, alkylheterocyclyl, hydroxy, alkoxy, polyfluorinated alkoxy, aryloxy, arylalkyloxy, heterocyclyloxy, heterocyclylalkyloxy, methylenedioxy, alkylcarbonyloxy, arylcarbonyloxy, carboxy, alkoxycarbonyl, alkoxycarbonylalkyl, aryloxycarbonyl, cycloalkyloxycarbonyl, amino, aminoalkyl, alkylaminoalkyl, alkylaminoalkyloxy, ureido, alkylamino, dialkylamino, arylamino, diarylamino, formylamino, alkylcarbonylamino, arylcarbonylamino, heterocyclylcarbonylamino, alkoxycarbonylamino, alkoxyimino, alkylsulfonylamino, arylsulfonylamino, formyl, alkylcarbonyl, arylcarbonyl, heterocyclylcarbonyl, cycloalkylcarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, arylaminocarbonyl, alkylsulfonyl, arylsulfonyl, alkylaminosulfonyl, arylthio and alkylthio;
R2 is a group selected from —NR″R′″, —N(OH)R″, —OR″ or —R″, wherein R″ and R′″ are, each independently, hydrogen or an optionally substituted group selected from straight or branched C1-C6 alkyl, C3-C6 cycloalkyl or cycloalkyl-alkyl, aryl, arylalkyl, heterocyclyl or heterocyclylalkyl or, together with the nitrogen atom to which they are bonded, R″ and R′″ may form a 5 to 6 membered heteroaryl or heterocyclyl group, optionally containing one additional heteroatom selected among N, O or S;
A is a divalent group selected from —CH2—, —(CH2)2—, —CH2—C(CH3)2—, —C(CH3)2—CH2— or —CH═CH—;
or a pharmaceutically acceptable salt thereof.

### Claim 8

A method of inhibiting cell cycle dependent kinase activity of a mammal, the method comprising: administering to the mammal an effective amount of a pyrazolo-quinazoline derivative represented by formula (Ia) or (Ib)
wherein
R is hydrogen or an optionally substituted group selected from amino, straight or branched C1-C6 alkyl, C3-C10 cycloalkyl, aryl, arylalkyl, heterocyclyl or heterocyclylalkyl;
X is a single bond or a divalent radical selected from —NR′—, —CONR′—, —NH—CO—NH—, —O—, —S— or —SO2—, wherein R′ is hydrogen or an optionally substituted group selected from straight or branched C1-C6 alkyl, C3-C6 cycloalkyl, aryl, arylalkyl, heterocyclyl, heterocyclylalkyl or, together with the nitrogen atom to which they are bonded, R and R′ may form a 5 to 6 membered heteroaryl or heterocyclyl group optionally containing one additional heteroatom selected among N, O or S;
R1, bonded to any one of the nitrogen atoms of the pyrazole ring as per formulae (Ia) or (Ib), represents a hydrogen atom or an optionally substituted group selected from straight or branched C1-C6 alkyl, C3-C6 cycloalkyl, aryl, arylalkyl, heterocyclyl or heterocyclylalkyl or, in formula (Ib), R1 is a divalent —(CH2)n—NH— group being linked to R2, wherein n is 2 or 3;
wherein R1 is optionally substituted in any of its free positions by one or more groups independently selected from: halogen, nitro, oxo groups (═O), cyano, azido, alkyl, polyfluorinated alkyl, hydroxyalkyl, aryl, arylalkyl, heterocyclyl, heterocyclylalkyl, cycloalkyl, alkylaryl, alkylheterocyclyl, hydroxy, alkoxy, polyfluorinated alkoxy, aryloxy, arylalkyloxy, heterocyclyloxy, heterocyclylalkyloxy, methylenedioxy, alkylcarbonyloxy, arylcarbonyloxy, carboxy, alkoxycarbonyl, alkoxycarbonylalkyl, aryloxycarbonyl, cycloalkyloxycarbonyl, amino, aminoalkyl, alkylaminoalkyl, alkylaminoalkyloxy, ureido, alkylamino, dialkylamino, arylamino, diarylamino, formylamino, alkylcarbonylamino, arylcarbonylamino, heterocyclylcarbonylamino, alkoxycarbonylamino, alkoxyimino, alkylsulfonylamino, arylsulfonylamino, formyl, alkylcarbonyl, arylcarbonyl, heterocyclylcarbonyl, cycloalkylcarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, arylaminocarbonyl, alkylsulfonyl, arylsulfonyl, alkylaminosulfonyl, arylthio and alkylthio;
R2 is a group selected from —NR″R′″, —N(OH)R″, —OR″ or —R″, wherein R″ and R′″ are, each independently, hydrogen or an optionally substituted group selected from straight or branched C1-C6 alkyl, C3-C6 cycloalkyl or cycloalkyl-alkyl, aryl, arylalkyl, heterocyclyl or heterocyclylalkyl or, together with the nitrogen atom to which they are bonded, R″ and R′″ may form a 5 to 6 membered heteroaryl or heterocyclyl group, optionally containing one additional heteroatom selected among N, O or S;
A is a divalent group selected from —CH2—, —(CH2)2—, —CH2—C(CH3)2—, —C(CH3)2—CH2— or —CH═CH—;
or a pharmaceutically acceptable salt thereof.