# US 8,785,448 B2 · Substituted pyrrolo-pyrazole derivatives as kinase inhibitors

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- Number: US 8,785,448 B2
- Document ID: US8785448B2
- Status: Granted
- Kind: B2
- Application number: 14/010,819
- Filed: 2013-08-27
- Published: 2013-12-26
- Granted: 2014-07-22
- Earliest claimed: 2002-12-19
- Assignees: Nerviano Medical Sciences S.R.L.
- Applicants: Maria Gabriella Brasca; Raffaella Amici; Daniele Fancelli; Marcella Nesi; Paolo Orsini; Fabrizio Orzi; Patrick Roussel; Anna Vulpetti; Paolo Pevarello
- Inventors: Maria Gabriella Brasca; Raffaella Amici; Daniele Fancelli; Marcella Nesi; Paolo Orsini; Fabrizio Orzi; Patrick Roussel; Anna Vulpetti; Paolo Pevarello
- Web page: https://patentgrep.com/patent/US8785448B2

## CPC

- C07D 487/04: Ortho-condensed systems
- A61K 31/4162: condensed with heterocyclic ring systems
- A61K 31/454: containing a five-membered ring with nitrogen as a ring hetero atom, e.g. pimozide, domperidone
- A61K 31/496: Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
- A61K 31/5377: not condensed and containing further heterocyclic rings, e.g. timolol
- 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 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 17/00: Drugs for dermatological disorders
- 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 31/00: Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P 31/12: Antivirals
- A61P 31/14: for RNA viruses
- A61P 35/00: Antineoplastic agents
- 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: 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

Compounds represented by formula (Ia) or (Ib) and wherein R and R1 are as defined in the description, and pharmaceutically acceptable salts thereof, are disclosed; the said compounds are useful in the treatment of cell cycle proliferative disorders, e.g. cancer, associated with an altered cell cycle dependent kinase activity.

## Claims

### Claim 1

A method for treating cell proliferative disorders caused by and/or associated with an altered cell cycle dependent kinase activity, the cell proliferative disorder selected from the group consisting of ovarian cancer, breast cancer, colon cancer, non-small cell lung cancer, small cell lung cancer and mesothelioma, the method comprising administering to a mammal in need thereof an effective amount of a compound represented by formula (Ib)
wherein
R is a group —CORa, —CONHRa or —CONRaRb wherein Ra and Rb are, each independently, hydrogen or an optionally substituted group selected from straight or branched C1-C6 alkyl, C3-C6 cycloalkyl, aryl, arylalkyl, heterocyclyl or heterocyclylalkyl or; together with the nitrogen atom to which they are bonded, Ra and Rb may form an optionally substituted 5 or 6 membered heterocycle optionally containing one additional heteroatom or heteroatomic group selected among N, NH, O or S;
R1 is selected from the group consisting of:
a) straight or branched C3-C4 alkyl;
b) cycloalkyl, cycloalkyl-alkyl or alkyl-cycloalkyl wherein the cycloalkyl moiety comprises any C3-C6 cycloalkyl group and wherein the alkyl moiety comprises any straight or branched C1-C4 alkyl group:
c) 3-methylthienyl-2-yl; 2-thienyl; phenyl; 2,6-difluorophenyl; 4-(aminosulfonyl)phenyl; 4-(dimethylaminomethyl)phenyl; 4-(4-methylpiperazinyl)methyl-phenyl;
d) a group of formula (IIa) or (IIb):
wherein, in formula (IIa), the cycle represents a 5 to 7 membered heterocyclic ring wherein X, directly linked to the rest of the molecule, represents a carbon or nitrogen atom; Y is a carbon, nitrogen, oxygen or sulfur atom or it is an NH group, provided that at least one of X and Y is other than a carbon atom; Rc is, independently from each other and in any one of the free positions of the heterocyclic ring of formula (IIa), a halogen atom or hydroxy group or it is an optionally substituted group selected from straight or branched C1-C6 alkyl, C3-C6 cycloalkyl, aryl, arylalkyl, heterocyclyl, heterocyclylalkyl, amino, aminocarbonyl, carboxy, xox (═O), alkoxycarbonyl, alkylcarbonyl or arylcarbonyl; and n is 0 or an integer from 1 to 4;
e) a group of formula (IIc) or (IId):
wherein Rd, R′d and Re represent, the same or different and independently from each other, a hydrogen atom or a straight or branched C1-C6 alkyl optionally substituted by one or more groups selected from hydroxy (—OH), aminocarbonyl (—CONH2) or methylaminocarbonyl (—CONHCH3);
or a pharmaceutically acceptable salt thereof.

### Claim 2 (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 3 (depends on 1)

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

### Claim 4 (depends on 1)

A method for inhibiting a kinase selected from the group consisting of CDK/cyclin A and Aurora-A, comprising contacting said kinase with an effective amount of a compound as defined in claim 1.

### Claim 5

A compound represented by formula (Ib)
wherein
R is a group —CORa, —CONHRa or —CONRaRb wherein Ra and Rb are, each independently, hydrogen or an optionally substituted group selected from straight or branched C1-C6 alkyl, C3-C6 cycloalkyl, aryl, arylalkyl, heterocyclyl or heterocyclylalkyl or; together with the nitrogen atom to which they are bonded, Ra and Rb may form an optionally substituted 5 or 6 membered heterocycle optionally containing one additional heteroatom or heteroatomic group selected among N, NH, O or S;
R1 is selected from the group consisting of:
straight or branched C3-C4 alkyl;
cycloalkyl, cycloalkyl-alkyl or alkyl-cycloalkyl wherein the cycloalkyl moiety comprises any C3-C6 cycloalkyl group and wherein the alkyl moiety comprises any straight or branched C1-C4 alkyl group:
3-methylthienyl-2-yl; 2-thienyl; phenyl; 2,6-difluorophenyl; 4-(aminosulfonyl)phenyl; 4-(dimethylaminomethyl)phenyl; 4-(4-methylpiperazinyl)methyl-phenyl;
a group of formula (IIa) or (IIb):
wherein, the formula (IIa), the cycle represents a 5 to 7 membered heterocyclic ring wherein X, directly linked to the rest of the molecule, represents a carbon or nitrogen atom; Y is a carbon, nitrogen, oxygen or sulfur atom or it is an NH group, provided that at least one of X and Y is other than a carbon atom; Rc is, independently from each other and in any one of the free positions of the heterocyclic ring of formula (IIa), a halogen atom or hydroxy group or it is an optionally substituted group selected from straight or branched C1-C6 alkyl, C3-C6 cycloalkyl, aryl, arylalkyl, heterocyclyl, heterocyclylalkyl, amino, aminocarbonyl, carboxy, oxo (═O), alkoxycarbonyl, alkylcarbonyl or arylcarbonyl; and n is 0 or an integer from 1 to 4;
a group of formula (IIc) or (IId):
wherein Rd, R′d and Re represent, the same or different and independently from each other, a hydrogen atom or a straight or branched C1-C6 alkyl optionally substituted by one or more groups selected from hydroxy (—OH), aminocarbonyl (—CONH2) or methylaminocarbonyl (—CONHCH3);
or a pharmaceutically acceptable salt thereof.

### Claim 6 (depends on 5)

A compound of formula (Ib) according to claim 5 wherein R is a group —CORa, Ra is as defined in claim 5 and R1 is tert-butyl.

### Claim 7 (depends on 5)

A compound of formula (Ib) according to claim 5 wherein R is a group —CONHRa, Ra is as defined in claim 5 and R1 is tert-butyl.

### Claim 8 (depends on 5)

A compound of formula (Ib) according to claim 5 wherein R is a group —CONRaRb, Ra and Rb are as defined in claim 5 and R1 is tert-butyl.

### Claim 9 (depends on 5)

A compound of formula (Ib) according to claim 5 wherein R is as defined in claim 5 and R1 is a group of formula (IIa) selected from:
wherein n and Rc are as defined in claim 5.

### Claim 10 (depends on 5)

A compound of formula (Ib) according to claim 5 wherein R is as defined in claim 5 and R1 is a group of formula (IIa) selected from:
wherein Rc is as defined in claim 5.

### Claim 11 (depends on 5)

A compound of claim 5, wherein any of Ra, Rb and Rc is a group, as defined in claim 5, optionally further substituted in one or more of their free positions, by groups independently selected from halogen, nitro, oxo groups (═O), cyano, alkyl, perfluorinated alkyl, perfluorinated alkoxy, alkenyl, alkynyl, hydroxyalkyl, aryl, arylalkyl, heterocyclyl, cycloalkyl, hydroxy, alkoxy, aryloxy, heterocyclyloxy, methylenedioxy, alkylcarbonyloxy, arylcarbonyloxy, cycloalkenyloxy, alkylideneaminooxy, carboxy, alkoxycarbonyl, aryloxycarbonyl, cycloalkyloxycarbonyl, amino, ureido, alkylamino, dialkylamino, arylamino, diarylamino, formylamino, alkylcarbonylamino, arylcarbonylamino, heterocyclylcarbonylamino, alkoxycarbonylamino, alkoxyimino, alkylsulfonylamino, arylsulfonylamino, formyl, alkylcarbonyl, arylcarbonyl, cycloalkylcarbonyl, heterocyclylcarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylsulfonyl, arylsulfonyl, aminosulfonyl, alkylaminosulfonyl, dialkylaminosulfonyl, arylthio and alkylthio.

### Claim 12 (depends on 5)

A compound of claim 5 selected from the group consisting of:
N-[5-[(1-methylpiperidin-4-yl)carbonyl]-2,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-6-spirocyclopropan-3-yl]-4-fluorobenzamide; and
N-[5-[(4-methylpiperazin-1-yl)carbonyl]-2,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-6-spirocyclopropan-3-yl]-4-fluorobenzamide;
or a pharmaceutically acceptable salt thereof.

### Claim 13 (depends on 5)

A process for preparing a compound of formula (Ib) as defined in claim 5, or the pharmaceutically acceptable salts thereof, which process comprises:
a) reacting a compound of formula (IIIb)
with acrylonitrile so as to obtain the corresponding derivative of formula (IVb)
b) protecting the amino group of the compound of formula (IVb) so as to obtain the corresponding derivative of formula (Vb)
wherein Q is a suitable amino protecting group;
c) reacting the compound of formula (Vb) with a suitable alkylating agent so as to obtain the corresponding ester derivative of formula (VIb)
wherein Alk stands for a suitable C1-C4 alkyl group;
d) reacting the compound of formula (VIb) with sodium hydride (NaH) so as to obtain the corresponding derivative of formula (VIIb)
e) reacting the compound of formula (VIIb) with hydrazine hydrate so as to obtain the compound of formula (VIIIb)
f) reacting the compound of formula (VIIIb) with ethyl chloroformate so as to obtain the derivative of formula (IXb), each one in any of the two regioisomeric forms
and reacting the compounds of formula (IXb) according to any one of the alternative steps (g.1), (g.2) or (g.3)
g.1) with a compound of formula (X)
RaCO—Z (X)
wherein Ra is as defined in claim 5 and Z is a halogen atom, so as to obtain the compound of formula (XIb)
wherein R is a group —CORa;
g.2) with a compound of formula (XII)
Ra—NCO (XII)
wherein Ra is as defined in claim 5, so as to obtain the compound of the formula (XIb) wherein R is a group —CONHRa; or
g.3) with a suitable amine of formula (XIII) in the presence of triphosgene or of a suitable chloroformate
HNRaRb (XIII)
wherein Ra and Rb are as defined in claim 5, so as to obtain the compound of formula (XIb) wherein R is a group —CONRaRb;
h) deprotecting the amino group of the compound of formula (XIb) prepared according to any one of steps from (g.1) to (g.3), so as to obtain the corresponding derivative of formula (XIVb)
wherein R has the above reported meanings; and reacting the compound of formula (XIVb) according to any one of the alternative steps (i.1), (i.2), (i.3) or (i.4)
i.1) with an acyl halide derivative of formula (XV)
R1—COZ (XV)
wherein R1 is as set forth in claim 5 under groups (a), (b), (c), (IIa) with X as a carbon atom and (IIb), and Z is a halogen atom, so as to obtain a compound of formula (XVIb)
wherein R and R1 are as above defined;
i.2) with a 5 to 7 membered heterocyclic compound of formula (XVII) or a suitable amine of formula (XVIII), in the presence of triphosgene
wherein X is NH and Y, Rc, n, Rd and R′d are defined in claim 5, so as to obtain the corresponding compounds of formula (XVIb) wherein R is as above defined and R1 is either a group of formula (IIa) with X as a nitrogen atom and R, Y, Rc and n as above defined, or of formula (IIc) wherein Rd and R′d are as above defined;
i.3) with a carboxylic acid of formula (XIX) in the presence of a suitable condensing agent
R1—COOH (XIX)
so as to obtain a compound of formula (XVIb) wherein R1 is as set forth in formula (Ib) under groups (a), (b), (c) or it is a group of formual (IIa) with X as a carbon atom or of formula (IIb), and R, Y, Rc and n are as above defined;
i.4) with a compound of formula (XX)
R1—COZ (XX)
wherein R1 is a group of formula (IId) and Z is a chlorine or bromine atom, so as to obtain the a compound of formula (XVIb) wherein R is defined above and R1 is a group of formula (IId); and
j) reacting the compound of formula (XVIb) prepared according to any one of steps from (i.1) to (i.4) under basic conditions, so as to obtain the corresponding derivative of formula (Ib) wherein R and R1 are as above defined; and, optionally,
k) converting them into other compounds of formula (Ib), respectively, and/or into pharmaceutically acceptable salts thereof.

### Claim 14 (depends on 13)

The process of claim 13 wherein, in step (b), Q is tert-butoxycarbonyl (boc).

### Claim 15 (depends on 13)

The process of claim 13 wherein, in step (c), Alk is methyl.

### Claim 16

A library of two or more compounds of formula (Ib)
wherein
R is a group —CORa, —CONHRa or —CONRaRb wherein Ra and Rb are, each independently, hydrogen or an optionally substituted group selected from straight or branched C1-C6 alkyl, C3-C6 cycloalkyl, aryl, arylalkyl, heterocyclyl or heterocyclylalkyl or; together with the nitrogen atom to which they are bonded, Ra and Rb may form an optionally substituted 5 or 6 membered heterocycle optionally containing one additional heteroatom or heteroatomic group selected among N, NH, O or S;
R1 is selected from the group consisting of:
straight or branched C3-C4 alkyl;
cycloalkyl, cycloalkyl-alkyl or alkyl-cycloalkyl wherein the cycloalkyl moiety comprises any C3-C6 cycloalkyl group and wherein the alkyl moiety comprises any straight or branched C1-C4 alkyl group:
3-methylthienyl-2-yl; 2-thienyl; phenyl; 2,6-difluorophenyl; 4-(aminosulfonyl)phenyl; 4-(dimethylaminomethyl)phenyl; 4-(4-methylpiperazinyl)methyl-phenyl;
a group of formula (IIa) or (IIb):
wherein, in formula (IIa), the cycle represents a 5 to 7 membered heterocyclic ring wherein X, directly linked to the rest of the molecule, represents a carbon or nitrogen atom; Y is a carbon, nitrogen, oxygen or sulfur atom or it is an NH group, provided that at least one of X and Y is other than a carbon atom; Rc is, independently from each other and in any one of the free positions of the heterocyclic ring of formula (IIa), a halogen atom or hydroxy group or it is an optionally substituted group selected from straight or branched C1-C6 alkyl, C3-C6 cycloalkyl, aryl, arylalkyl, heterocyclyl, heterocyclylalkyl, amino, aminocarbonyl, carboxy, xoxo (═O), alkoxycarbonyl, alkylcarbonyl or arylcarbonyl; and n is 0 or an integer from 1 to 4;
a group of formula (IIc) or (IId):
wherein Rd, R′d and Re represent, the same or different and independently from each other, a hydrogen atom or a straight or branched C1-C6 alkyl optionally substituted by one or more groups selected from hydroxy (—OH), aminocarbonyl (—CONH2) or methylaminocarbonyl (—CONHCH3);
or a pharmaceutically acceptable salt thereof.

### Claim 17 (depends on 5)

A pharmaceutical composition comprising a therapeutically effective amount of a compound of formula (Ib), as defined in claim 5, and at least one pharmaceutically acceptable excipient, carrier and/or diluents.

### Claim 18 (depends on 17)

A pharmaceutical composition according to claim 17 further comprising one or more chemotherapeutic agents.

### Claim 19 (depends on 5, 17)

A product or kit comprising a compound of formula (Ib) as defined in claim 5 or a pharmaceutical composition thereof as defined in claim 17, and one or more chemotherapeutic agents, as a combined preparation for simultaneous, separate or sequential use in anticancer therapy.

### Claim 20 (depends on 5)

A pharmaceutical composition comprising a therapeutically effective amount of a compound, as defined in claim 5, and a chemotherapeutic agent selected from the group consisting of cytostatic or cytotoxic agents, antibiotic-type agents, alkylating agents, antimetabolite agents, hormonal agents, immunological agents, interferon-type agents, cyclooxygenase inhibitors, matrixmetalloprotease inhibitors, telomerase inhibitors, tyrosine kinase inhibitors, anti-grow factor receptor agents, anti-HER agents, anti-EGFR agents, anti-angiogenesis agents, farnesyl transferase inhibitors, ras-raf signal transduction pathway inhibitors, cell cycle inhibitors, cdks inhibitors, tubulin binding agents, topoisomerase I inhibitors, typoisomerase II inhibitors and mixtures thereof.

### Claim 21 (depends on 5)

A product or kit comprising a compound of claim 5, and a chemotherapeutic agent selected from the group consisting of cytostatic or cytotoxic agents, antibiotic-type agents, alkylating agents, antimetabolite agents, hormonal agents, immunological agents, interferon-type agents, cyclooxygenase inhibitors, matrixmetalloprotease inhibitors, telomerase inhibitors, tyrosine kinase inhibitors, anti-grow factor receptor agents, anti-HER agents, anti-EGFR agents, anti-angiogenesis agents, farnesyl transferase inhibitors, ras-raf signal transduction pathway inhibitors, cell cycle inhibitors, cdks inhibitors, tubulin binding agents, topoisomerase I inhibitors, typoisomerase II inhibitors and mixtures thereof, as a combined preparation for simultaneous, separate or sequential use in anticancer therapy.