IP Library › Granted Patent US 8,198,298

Granted Patent B2

US 8,198,298 · App. 13/026,789 · Granted Jun 12, 2012

Pyrrolo[2,3-b]pyridine derivatives active as kinase inhibitors

Assignee: Pfizer Italia S.r.l.

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Quick Facts

Patent No.: US 8,198,298
App. No.: 13/026,789
Granted: Jun 12, 2012
Kind: B2

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Abstract

Compounds which are pyrrolo[2,3-b]pyridine derivatives or pharmaceutically acceptable salts thereof, their preparation process and pharmaceutical compositions comprising them are disclosed; these compounds are useful in the treatment of diseases caused by and/or associated with an altered protein kinase activity such as cancer, cell proliferative disorders, Alzheimer's disease, viral infections, auto-immune diseases and neurodegenerative disorders; also disclosed is a process under SPS conditions for preparing the compounds of the invention and chemical libraries comprising a plurality of them.

Claims (237)

1. A method for inhibiting one or more protein kinases selected from the group consisting of ACK1, AKT, JAK2, MET, MST4, NEK6, RET and IGF-1R which comprises contacting said kinase with an effective amount of a pyrrolo[2,3-b]pyridine represented by formula (I)

wherein

R is —R a , —COR a , —CONR a R b , —SO 2 R a or —COOR a ;

R 1 is —NR c R d or —OR c ;

wherein R a , R b , R c and R d , are the same or different, and are each independently hydrogen or a group optionally further substituted, selected from straight or branched C 1 -C 6 alkyl, straight or branched C 2 -C 6 alkenyl, straight or branched C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl or cycloalkyl C 1 -C 6 alkyl, aryl or aryl C 1 -C 6 alkyl, or heterocycle or heterocycle C 1 -C 6 alkyl or, taken together with the nitrogen atom to which they are bonded, R a and R b as well as R C and R d , may form a 1,3-dioxolane, pyran, pyrrolidine, pyrroline, imidazoline, imidazolidine, pyrazolidine, pyrazoline, piperidine, piperazine, morpholine, tetrahydrofuran, hexamethylenediamine, 1,4-hexahydrodiazepine or azetidine group;

R 2 is a group, optionally further substituted, selected from straight or branched C 1 -C 6 alkyl, straight or branched C 2 -C 6 alkenyl, straight or branched C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl or cycloalkyl C 1 -C 6 alkyl, aryl or aryl C 1 -C 6 alkyl, or heterocycle or heterocycle C 1 -C 6 alkyl;

or isomers, tautomers, and pharmaceutically acceptable salts thereof.

2. A method for inhibiting protein kinase activity which comprises contacting the said kinase with an effective amount of a compound of formula (I) having the formula

wherein

R is —R a , —COR a , —CONR a R b , —SO 2 R a or —COOR a ;

R 1 is —NR c R d or —OR c ;

or isomers, tautomers, and pharmaceutically acceptable salts thereof.

3. A library comprised of two or more compounds of formula (I)

wherein

R is selected from the group consisting of —R a , —COR a , —CONR a R b , —SO 2 R a or —COOR a ;

R 1 is a group —NR c R d or —OR c ;

wherein R a , R b , R c and R d , are the same or different, and are each independently hydrogen or a group optionally further substituted, selected from straight or branched C 1 -C 6 alkyl, straight or branched C 2 -C 6 alkenyl, straight or branched C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl or cycloalkyl C 1 -C 6 alkyl, aryl, aryl C 1 -C 6 alkyl, or heterocycle or heterocycle C 1 -C 6 — alkyl or, taken together with the nitrogen atom to which they are bonded, R a and R b as well as R C and R d , may form a 1,3-dioxolane, pyran, pyrrolidine, pyrroline, imidazoline, imidazolidine, pyrazolidine, pyrazoline, piperidine, piperazine, morpholine, tetrahydrofuran, hexamethylenediamine, 1,4-hexahydrodiazepine or azetidine group;

or isomers, tautomers, and pharmaceutically acceptable salts thereof.

4. The library according to claim 3 wherein R 1 is a group —NR c R d and R c and R d are both hydrogen atoms or one of them is a hydrogen atom and the remaining one of R c or R d is alkyl or alkenyl group, or an optionally substituted aryl or arylalkyl group.

5. The library according to claim 3 wherein R is hydrogen or a group —SO 2 R a wherein R a is a straight or branched alkyl or optionally substituted aryl or arylalkyl group.

6. The library according to claim 3 wherein R is a group —COR a wherein R a is a straight or branched alkyl, cycloalkyl or optionally substituted aryl or arylalkyl group.

7. The library according to claim 3 wherein R is —CONR a R b wherein one of R a and R b is hydrogen and the other of R a and R b is a straight or branched alkyl or optionally substituted aryl or arylalkyl group.

8. The library according to claim 3 wherein R is —CONR a R b , R a and R b form, together with the nitrogen atom to which they are bonded, an optionally substituted 6 membered heterocyclic ring.

9. The library according to claim 3 wherein R 2 is alkyl, alkenyl group, cycloalkyl, cycloalkyl-alkyl or an optionally substituted aryl or arylalkyl group.

10. The library according to claim 3 wherein the compound in the library is a compound listed in Table IV, V, VI, VII, VIII or IX:

A3-M-B5-C2

A3-M-B6-C2

A4-M-B5-C2

A4-M-B6-C2

A7-M-B5-C2

A7-M-B6-C2

A6-M-B5-C2

A6-M-B6-C2

A1-M-B5-C2

A1-M-B6-C2

A5-M-B5-C2

A5-M-B6-C2

A8-M-B5-C2

A8-M-B6-C2

A2-M-B5-C2

A2-M-B6-C2

A3-M-B5-C5

A3-M-B6-C5

A4-M-B5-C5

A4-M-B6-C5

A7-M-B5-C5

A7-M-B6-C5

A6-M-B5-C5

A6-M-B6-C5

A1-M-B5-C5

A1-M-B6-C5

A5-M-B5-C5

A5-M-B6-C5

A8-M-B5-C5

A8-M-B6-C5

A2-M-B5-C5

A2-M-B6-C5

A3-M-B1-C2

A3-M-B4-C2

A4-M-B1-C2

A4-M-B4-C2

A7-M-B1-C2

A7-M-B4-C2

A6-M-B1-C2

A6-M-B4-C2

A1-M-B1-C2

A1-M-B4-C2

A5-M-B1-C2

A5-M-B4-C2

A8-M-B1-C2

A8-M-B4-C2

A2-M-B1-C2

A3-M-B1-C5

A3-M-B4-C5

A4-M-B1-C5

A4-M-B4-C5

A7-M-B1-C5

A7-M-B4-C5

A6-M-B1-C5

A6-M-B4-C5

A1-M-B1-C5

A1-M-B4-C5

A5-M-B1-C5

A5-M-B4-C5

A8-M-B1-C5

A8-M-B4-C5

A2-M-B1-C5

A2-M-B4-C5

A3-M-B9-C2

A3-M-B10-C2

A4-M-B10-C2

A1-M-B10-C2

A5-M-B10-C2

A3-M-B9-C5

A7-M-B9-C5

A1-M-B9-C5

A1-M-B10-C5

A9-M-B5-C1

A9-M-B7-C1

A9-M-B5-C2

A9-M-B7-C2

A9-M-B5-C3

A9-M-B7-C3

A9-M-B8-C3

A9-M-B5-C4

A9-M-B5-C5

A9-M-B5-C6

A9-M-B7-C6

A9-M-B8-C6

A9-M-B5-C7

A9-M-B6-C7

A9-M-B8-C7

A9-M-B5-C8

A9-M-B7-C8

A9-M-B8-C8

A9-M-B13-C2

A9-M-B13-C5

A9-M-B13-C6

A9-M-B13-C8

A9-M-B1-C1

A9-M-B4-C2

A9-M-B3-C3

A9-M-B1-C4

A9-M-B3-C4

A9-M-B1-C5

A9-M-B3-C5

A9-M-B4-C5

A9-M-B2-C6

A9-M-B3-C6

A9-M-B4-C6

A9-M-B3-C7

A9-M-B1-C8

A9-M-B2-C8

A9-M-B3-C8

A9-M-B4-C8

A9-M-B9-C1

A9-M-B9-C2

A9-M-B10-C2

A9-M-B11-C2

A9-M-B9-C3

A9-M-B10-C3

A9-M-B11-C3

A9-M-B9-C4

A9-M-B10-C4

A9-M-B11-C4

A9-M-B9-C5

A9-M-B12-C5

A9-M-B10-C5

A9-M-B11-C5

A9-M-B9-C6

A9-M-B12-C6

A9-M-B10-C6

A9-M-B11-C6

A9-M-B9-C7

A9-M-B12-C7

A9-M-B10-C7

A9-M-B11-C7

A9-M-B9-C8

A9-M-B12-C8

A9-M-B10-C8

TABLE I

A groups

Fragment

Code

TABLE II

B groups

Fragment

Code

B10

B11

B12

B13

B14

B15

TABLE III

C groups

Fragment

Code

C9.

11. A pharmaceutical composition comprising a therapeutically effective amount of a compound of formula (I)

wherein

R is selected from the group consisting of —R a , —COR a , —CONR a R b , —SO 2 R a and —COOR a ;

R 1 is —NR c R d or —OR c ;

wherein R a , R b , R c and R d are the same or different and are each independently hydrogen or a group, optionally further substituted, which is straight or branched C 1 -C 6 alkyl, straight or branched C 2 -C 6 alkenyl, straight or branched C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, C 3 -C 6 cycloalkyl C 1 -C 6 alkyl, an aryl, aryl C 1 -C 6 alkyl, a heterocycle and heterocycle C 1 -C 6 alkyl or, taken together with the nitrogen atom to which they are bonded, R a and R b as well as R c and R d form a 1,3-dioxolane, pyran, pyrrolidine, pyrroline, imidazoline, imidazolidine, pyrazolidine, pyrazoline, piperidine, piperazine, morpholine, tetrahydrofuran, hexamethyleneimine, 1,4-hexahydrodiazepine or azetidine group;

R 2 is a group, optionally further substituted, selected from the group consisting of straight or branched C 1 -C 6 alkyl, straight or branched C 2 -C 6 alkenyl, straight or branched C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, C 3 -C 6 cycloalkyl C 1 -C 6 alkyl, aryl, aryl C 1 -C 6 alkyl, heterocycle and heterocycle C 1 -C 6 alkyl;

wherein any of R a , R b , R c , R d or R 2 is independently optionally substituted by halogen, nitro, oxo groups, carboxy, cyano, alkyl, perfluoroalkyl, alkenyl, cycloalkyl, cycloalkenyl, aryl, heterocyclyl, amino groups, carbonylamino groups, hydroxy groups, carbonyl groups or sulfurated groups;

wherein said aryl is selected from the group consisting of phenyl, indanyl, biphenyl, α- or β-naphthyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, indolyl, imidazolyl, imidazopyridyl, 1,2-methylenedioxyphenyl, thiazolyl, isothiazolyl, pyrrolyl, pyrrolyl-phenyl, furyl, phenyl-furyl, benzotetrahydrofuranyl, oxazolyl, isoxazolyl, pyrazolyl, chromenyl, thienyl, benzothienyl, isoindolinyl, benzoimidazolyl, quinolinyl, isoquinolinyl, quinoxalinyl, benzofurazanyl, 1,2,3-triazolyl and 1-phenyl-1,2,3-triazolyl;

wherein said heterocycle is selected from the group consisting of 1,3-dioxolane, pyran, pyrrolidine, pyrroline, imadazoline, imidazolidine, pyrazolidine, pyrazoline, piperidine, piperazine, morpholine, tetrahydrofuran, hexamethyleneimine, 1,4-hexahydrodiazepine and azetidine;

or isomers, tautomers, and pharmaceutically acceptable salts thereof and, at least, one pharmaceutically acceptable excipient, carrier and/or diluent.

12. The pharmaceutical composition according to claim 11 further comprising one or more chemotherapeutic agents.

13. A kit comprising a compound of formula (I)

wherein

R is selected from the group consisting of —R a , —COR a , —CONR a R b , —SO 2 R a and —COOR a ;

R 1 is —NR c R d or —OR c ;

or isomers, tautomers, and pharmaceutically acceptable salts thereof and, at least optionally associated with a pharmaceutical excipient or carrier and/or diluent, and one or more chemotherapeutic agents.

14. A method for inhibiting one or more protein kinases selected from the group consisting of cdk2, cdk5, protein kinase C, PAK-4, PAK-5, ZC-1, STLK-2, DDR-2, Aurora 1, Aurora 2, Bub 1, PLK, Chk1, Chk2, HER2, raf1, MEK1, MAPK, EGF-R, PDGF-R, FGF-R, PI3K, week kinase, Src, Abl, ILK, MK-2, IKK-2, Cdc7 which comprises contacting said kinase with an effective amount of a pyrrolo[2,3-b]pyridine represented by formula (I)

wherein

R is —R a , —COR a , —CONR a R b , —SO 2 R a or —COOR a ;

R 1 is —NR c R d or —OR c ;

wherein R a , R b , R c and R d , are the same or different, and are each independently hydrogen or a group optionally further substituted, selected from straight or branched C 1 -C 6 alkyl, straight or branched C 2 -C 6 alkenyl, straight or branched C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl or cycloalkyl C 1 -C 6 alkyl, aryl or aryl C 1 -C 6 alkyl, or heterocycle or heterocycle C 1 -C 6 alkyl or, taken together with the nitrogen atom to which they are bonded, R a and R b as well as R c and R d , may form a 1,3-dioxolane, pyran, pyrrolidine, pyrroline, imidazoline, imidazolidine, pyrazolidine, pyrazoline, piperidine, piperazine, morpholine, tetrahydrofuran, hexamethylenediamine, 1,4-hexahydrodiazepine or azetidine group;

or isomers, tautomers, and pharmaceutically acceptable salts thereof.

Assignments (1)

ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Feb 2, 2017

From: PFIZER ITALIA S.R.L.

To: NERVIANO MEDICAL SCIENCES S.R.L

Reel/Frame 041154/0945 →

Priority Claims (1)

GB 0330042.3 · Dec 24, 2003 · national

Continuity (2)

Division 11020794 · Dec 23, 2004

Related Publication 20110136857A1 · Jun 9, 2011