IP Library › Granted Patent US 8,987,273

Granted Patent B2

US 8,987,273 · App. 13/812,555 · Granted Mar 24, 2015

Substituted imidazo[1,2-B]pyridazines

Inventors: Hartmut Rehwinkel (Berlin, DE); Andrea Hägebarth (Berlin, DE); Oliver Politz (Panketal OT Zepernick, DE); Roland Neuhaus (Berlin, DE); Ulf Bömer (Glienicke, DE)

Assignee: Bayer Intellectual Property GmbH

C07D487/04

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Quick Facts

Patent No.: US 8,987,273
App. No.: 13/812,555
Granted: Mar 24, 2015
Kind: B2

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Abstract

The invention relates to imidazo[1,2-b]pyridazines of general formula (I) a process for their manufacture and their use for the treatment of benign and malignant neoplasia.

Claims (215)

1. A compound of formula (I)

wherein

R1 is hydrogen, halogen, 2-6C-alkenylen-C(O)NH2, 2-6C-alkenylen-C(O)OR10, or a group selected from 1-6C-alkyl, 2-6C-alkenyl, 3-7C-cycloalkyl, aryl, heteroaryl, wherein said group being optionally substituted, one or more times, identically or differently, with a substituent selected from:

hydroxy, halogen, 1-6C-alkyl, 1-4C-haloalkyl, 1-4C-hydroxyalkyl, 1-6C-alkoxy, —NR8R9, cyano, —C(O)NR8R9, —C(O)OR10, —NHC(O)R11, —NHS(O) 2 R11, —S(O) 2 R11, —S(O) 2 NR8R9,

R2 is hydrogen, halogen, cyano, or a group selected from 1-6C-alkyl, 3-7C-cycloalkyl,

wherein said 1-6C-alkyl being optionally substituted, one or more times, identically or differently, with a substituent selected from: hydroxy, halogen, 1-6C-alkoxy,

R3 is hydrogen, 1-6C-alkyl, 3-7C-cycloalkyl,

R4 is phenyl optionally substituted, one or more times, identically or differently, with a substituent selected from: 1-6C-alkyl, halogen, cyano,

R5 is hydrogen, halogen,

R6 is hydrogen, 1-6C-alkyl,

R8, R9 which can be the same or different, is hydrogen, 1-4C-alkyl or 3-7C-cycloalkyl, wherein said 1-4C-alkyl and 3-7C-cycloalkyl is optionally substituted in the same way of differently one or more times with halogen, hydroxy, mono- or di-1-4C-alkylamino, 1-4C-alkoxy,

or,

in the case of —NR8R9, R8 and R9 together with the nitrogen to which they are attached may also form a 3-6C-heterocyclic ring,

R10 is hydrogen, 1-6C-alkyl,

R11 is 1-4C-alkyl (optionally substituted in the same way of differently one or more times with halogen, hydroxy) or 3-7C-cycloalkyl,

X is —(CH 2 ) n —,

n is 0, 1, 2, or 3,

Y is —CH 2 —, —CH(OH)—,

or an N-oxide, a salt, a tautomer or a stereoisomer of said compound, or a salt of said N-oxide, tautomer or stereoisomer.

2. A compound according to claim 1 ,

wherein

hydroxy, halogen, 1-6C-alkyl, 1-4C-haloalkyl, 1-4C-hydroxyalkyl, 1-6C-alkoxy, —NR8R9, cyano, —C(O)NR8R9, —C(O)OR10, —NHC(O)R11, —NHS(O) 2 R11, —S(O) 2 R11, —S(O) 2 NR8R9,

R2 is hydrogen, halogen, cyano, or a group selected from 1-6C-alkyl, 3-7C-cycloalkyl,

wherein said 1-6C-alkyl being optionally substituted, one or more times, identically or differently, with a substituent selected from:

hydroxy, halogen, 1-6C-alkoxy,

R3 is hydrogen, 1-6C-alkyl, 3-7C-cycloalkyl,

R4 is phenyl optionally substituted, one or more times, identically or differently, with a substituent selected from: 1-6C-alkyl, halogen, cyano,

R5 is hydrogen, halogen,

R6 is hydrogen,

or,

in the case of —NR8R9, R8 and R9 together with the nitrogen to which they are attached may also form a 3-6C-heterocyclic ring,

R10 is hydrogen, 1-6C-alkyl,

R11 is 1-4C-alkyl (optionally substituted in the same way of differently one or more times with halogen, hydroxy) or 3-7C-cycloalkyl,

X is —(CH 2 ) n —,

n is 0, 1, 2, or 3,

Y is —CH 2 —, —CH(OH)—,

or an N-oxide, a salt, a tautomer or a stereoisomer of said compound, or a salt of said N-oxide, tautomer or stereoisomer.

3. A compound according to claim 1 ,

wherein

hydroxy, halogen, 1-6C-alkyl, 1-4C-haloalkyl, 1-4C-hydroxyalkyl, 1-6C-alkoxy, —NR8R9, cyano, —C(O)NR8R9, —C(O)OR10, —NHC(O)R11, —NHS(O) 2 R11, —S(O) 2 R11, —S(O) 2 NR8R9,

R2 is hydrogen, halogen, cyano, or a group selected from 1-6C-alkyl, 3-7C-cycloalkyl,

R3 is hydrogen, 1-6C-alkyl, 3-7C-cycloalkyl,

R4 is phenyl,

R5 is hydrogen,

R6 is hydrogen,

or,

in the case of —NR8R9, R8 and R9 together with the nitrogen to which they are attached may also form a 3-6C-heterocyclic ring,

R10 is hydrogen, 1-6C-alkyl,

R11 is 1-4C-alkyl (optionally substituted in the same way of differently one or more times with halogen, hydroxy) or 3-7C-cycloalkyl,

X is —(CH 2 ) n —,

n is 0, 1, 2, or 3,

Y is —CH 2 —, —CH(OH)—,

or an N-oxide, a salt, a tautomer or a stereoisomer of said compound, or a salt of said N-oxide, tautomer or stereoisomer.

4. A compound according to claim 1 ,

wherein

R1 is hydrogen, halogen, 2-6C-alkenylen-C(O)NH2, 2-6C-alkenylen-C(O)OR10, or a group selected from 1-6C-alkyl, 2-6C-alkenyl, aryl, heteroaryl,

wherein said group being optionally substituted, one or more times, identically or differently, with a substituent selected from:

hydroxy, halogen, 1-6C-alkyl, 1-4C-hydroxyalkyl, cyano, —C(O)NR8R9, —C(O)OR10, —NHC(O)R11, —NHS(O) 2 R11, —S(O) 2 R11, —S(O) 2 NR8R9,

R2 is hydrogen, halogen, cyano, or 1-6C-alkyl,

R3 is hydrogen,

R4 is phenyl,

R5 is hydrogen,

R6 is hydrogen,

or,

in the case of —NR8R9, R8 and R9 together with the nitrogen to which they are attached may also form a 3-6C-heterocyclic ring,

R10 is hydrogen, 1-6C-alkyl,

R11 is 1-4C-alkyl,

X is —(CH 2 ) n —,

n is 1,

Y is —CH 2 —,

or an N-oxide, a salt, a tautomer or a stereoisomer of said compound, or a salt of said N-oxide, tautomer or stereoisomer.

5. A compound according to claim 1 ,

wherein,

R1 is hydrogen, halogen, 1-3C-alkyl, 2-3C-alkenyl, —(CH═CH)C(O)NH2, —(CH═CH)C(O)OR10,

pyrazolyl (optionally substituted with methyl),

pyridyl (optionally substituted with hydroxy, methoxy, —C(O)OR10), indazolyl,

phenyl, wherein the phenyl group can optionally be substituted with a substituent selected from the group consisting of

halogen, methyl, hydroxymethyl, cyano, C(O)NH 2 , —C(O)OR10, —S(O) 2 R11, SO 2 —NH 2 ,

R2 is hydrogen, methyl, halogen,

R3 is hydrogen,

R4 is phenyl,

R5 is hydrogen,

R6 is hydrogen,

R10 is 1-3C-alkyl,

R11 is 1-3C-alkyl,

X is —CH 2 —,

Y is —CH 2 —,

or an N-oxide, a salt, a tautomer or a stereoisomer of said compound, or a salt of said N-oxide, tautomer or stereoisomer.

6. A compound according to claim 1 , which is selected from the group consisting of:

1-[4-(7-Phenyl-imidazo[1,2-b]pyridazin-6-yl)-phenyl]-cyclobutylamine,

1-[4-(3-Methyl-7-phenyl-imidazo[1,2-b]pyridazin-6-yl)-phenyl]-cyclobutylamine,

3-{6-[4-(1-Amino-cyclobutyl)-phenyl]-7-phenyl-imidazo[1,2-b]pyridazin-3-yl}-benzonitrile,

1-{4-[3-(4-Methanesulfonylphenyl)-7-phenyl-imidazo[1,2-b]pyridazin-6-yl]-phenyl}-cyclobutylamine,

4-{6-[4-(1-Amino-cyclobutyl)-phenyl]-7-phenyl-imidazo[1,2-b]pyridazin-3-yl}-benzonitrile,

3-{6-[4-(1-Amino-cyclobutyl)-phenyl]-7-phenyl-imidazo[1,2-b]pyridazin-3-yl}-benzoic acid methyl ester,

1-{4-[3-(4-Fluorophenyl)-7-phenyl-imidazo[1,2-b]pyridazin-6-yl]-phenyl}-cyclobutylamine,

1-[4-(7-Phenyl-3-p-tolyl-imidazo[1,2-b]pyridazin-6-yl)-phenyl]-cyclobutylamine,

(3-{6-[4-(1-Amino-cyclobutyl)-phenyl]-7-phenyl-imidazo[1,2-b]pyridazin-3-yl}-phenyl)-methanol,

(4-{6-[4-(1-Amino-cyclobutyl)-phenyl]-7-phenyl-imidazo[1,2-b]pyridazin-3-yl}-phenyl)-methanol formiate,

4-{6-[4-(1-Amino-cyclobutyl)-phenyl]-7-phenyl-imidazo[1,2-b]pyridazin-3-yl}-benzenesulfonamide hydrochloride,

1-[4-(3-Bromo-7-phenyl-imidazo[1,2-b]pyridazin-6-yl)-phenyl]-cyclobutylamine hydrochloride,

(5-{6-[4-(1-Amino-cyclobutyl)-phenyl]-7-phenyl-imidazo[1,2-b]pyridazin-3-yl}-2-fluorophenyl)-methanol hydrochloride,

4-{6-[4-(1-Amino-cyclobutyl)-phenyl]-7-phenyl-imidazo[1,2-b]pyridazin-3-yl}-benzamide hydrochloride,

3-{6-[4-(1-Amino-cyclobutyl)-phenyl]-7-phenyl-imidazo[1,2-b]pyridazin-3-yl}-benzamide hydrochloride,

1-{4-[7-Phenyl-3-(1H-pyrazol-4-yl)-imidazo[1,2-b]pyridazin-6-yl]-phenyl}-cyclobutylamine,

1-[4-(2-Methyl-7-phenyl-imidazo[1,2-b]pyridazin-6-yl)-phenyl]-cyclobutylamine hydrochloride,

5-{6-[4-(1-Amino-cyclobutyl)-phenyl]-7-phenyl-imidazo[1,2-b]pyridazin-3-yl}-pyridin-2-ol,

5-{6-[4-(1-Amino-cyclobutyl)-phenyl]-7-phenyl-imidazo[1,2-b]pyridazin-3-yl}-pyridine-2-carboxylic acid methyl ester,

1-{4-[7-Phenyl-3-(2H-pyrazol-3-yl)-imidazo[1,2-b]pyridazin-6-yl]-phenyl}-cyclobutylamine,

1-{4-[3-(1H-Indazol-6-yl)-7-phenyl-imidazo[1,2-b]pyridazin-6-yl]-phenyl}-cyclobutylamine,

5-{6-[4-(1-Amino-cyclobutyl)-phenyl]-7-phenyl-imidazo[1,2-b]pyridazin-3-yl}-nicotinic acid ethyl ester,

1-{4-[3-(5-Methoxypyridin-3-yl)-7-phenyl-imidazo[1,2-b]pyridazin-6-yl]-phenyl}-cyclobutylamine,

3-{6-[4-(1-Amino-cyclobutyl)-phenyl]-2-methyl-7-phenyl-imidazo[1,2-b]pyridazin-3-yl}-benzamide,

(5-{6-[4-(1-Amino-cyclobutyl)-phenyl]-2-methyl-7-phenyl-imidazo[1,2-b]pyridazin-3-yl}-2-fluorophenyl)-methanol,

1-{4-[2-Methyl-7-phenyl-3-(1H-pyrazol-4-yl)-imidazo[1,2-b]pyridazin-6-yl]-phenyl}-cyclobutylamine,

1-{4-[3-(4-Fluorophenyl)-2-methyl-7-phenyl-imidazo[1,2-b]pyridazin-6-yl]-phenyl}-cyclobutylamine,

4-{6-[4-(1-Amino-cyclobutyl)-phenyl]-2-methyl-7-phenyl-imidazo[1,2-b]pyridazin-3-yl}-benzamide,

1-{4-[2-Methyl-7-phenyl-3-(2H-pyrazol-3-yl)-imidazo[1,2-b]pyridazin-6-yl]-phenyl}-cyclobutylamine,

1-{4-[2-Methyl-7-phenyl-3-(5-methyl-2H-pyrazol-3-yl)-imidazo[1,2-b]pyridazin-6-yl]-phenyl}-cyclobutylamine,

1-{4-[2-Bromo-3-(4-fluorophenyl)-7-phenyl-imidazo[1,2-b]pyridazin-6-yl]-phenyl}-cyclobutylamine,

1-{4-[2-Chloro-3-(4-fluorophenyl)-7-phenyl-imidazo[1,2-b]pyridazin-6-yl]-phenyl}-cyclobutylamine,

(E)-3-{6-[4-(1-Amino-cyclobutyl)-phenyl]-7-phenyl-imidazo[1,2-b]pyridazin-3-yl}-acrylamide,

1-[4-(7-Phenyl-3-vinyl-imidazo[1,2-b]pyridazin-6-yl)-phenyl]-cyclobutylamine,

(E)-3-{6-[4-(1-Amino-cyclobutyl)-phenyl]-2-methyl-7-phenyl-imidazo[1,2-b]pyridazin-3-yl}-acrylamide,

(E)-3-{6-[4-(1-Amino-cyclobutyl)-phenyl]-2-methyl-7-phenyl-imidazo[1,2-b]pyridazin-3-yl}-acrylic acid methyl ester,

1-[4-(2-Methyl-7-phenyl-3-vinyl-imidazo[1,2-b]pyridazin-6-yl)-phenyl]-cyclobutylamine,

1-[4-(3-Ethyl-2-methyl-7-phenyl-imidazo[1,2-b]pyridazin-6-yl)-phenyl]-cyclobutylamine.

7. A compound of formula (II),

wherein

Rx is R6 or a protecting group,

Ry is hydrogen or a protecting group,

whereby Rx and Ry together, or Y and Rx together, may form a cyclic protecting group,

hydroxy, halogen, 1-6C-alkyl, 1-4C-haloalkyl, 1-4C-hydroxyalkyl, 1-6C-alkoxy, —NR8R9, cyano, —C(O)NR8R9, —C(O)OR10, —NHC(O)R11, —NHS(O) 2 R11, —S(O) 2 R11, —S(O) 2 NR8R9,

R2 is hydrogen, halogen, cyano, or a group selected from 1-6C-alkyl, 3-7C-cycloalkyl,

wherein said 1-6C-alkyl being optionally substituted, one or more times, identically or differently, with a substituent selected from: hydroxy, halogen, 1-6C-alkoxy,

R3 is hydrogen, 1-6C-alkyl, 3-7C-cycloalkyl,

R4 is phenyl optionally substituted, one or more times, identically or differently, with a substituent selected from: 1-6C-alkyl, halogen, cyano,

R5 is hydrogen, halogen,

R6 is hydrogen, 1-6C-alkyl,

or,

in the case of —NR8R9, R8 and R9 together with the nitrogen to which they are attached may also form a 3-6C-heterocyclic ring,

R10 is hydrogen, 1-6C-alkyl,

R11 is 1-4C-alkyl (optionally substituted in the same way of differently one or more times with halogen, hydroxy) or 3-7C-cycloalkyl,

X is —(CH 2 ) n —,

n is 0, 1, 2, or 3, and

Y is —CH 2 —, —CH(OH)—.

8. A compound according to claim 2 ,

wherein

hydroxy, halogen, 1-6C-alkyl, 1-4C-haloalkyl, 1-4C-hydroxyalkyl, 1-6C-alkoxy, —NR8R9, cyano, —C(O)NR8R9, —C(O)OR10, —NHC(O)R11, —NHS(O) 2 R11, —S(O) 2 R11, —S(O) 2 NR8R9,

R2 is hydrogen, halogen, cyano, or a group selected from 1-6C-alkyl, 3-7C-cycloalkyl,

R3 is hydrogen, 1-6C-alkyl, 3-7C-cycloalkyl,

R4 is phenyl,

R5 is hydrogen,

R6 is hydrogen,

or,

in the case of —NR8R9, R8 and R9 together with the nitrogen to which they are attached may also form a 3-6C-heterocyclic ring,

R10 is hydrogen, 1-6C-alkyl,

R11 is 1-4C-alkyl (optionally substituted in the same way of differently one or more times with halogen, hydroxy) or 3-7C-cycloalkyl,

X is —(CH 2 ) n —,

n is 0, 1, 2, or 3,

Y is —CH 2 —, —CH(OH)—,

or an N-oxide, a salt, a tautomer or a stereoisomer of said compound, or a salt of said N-oxide, tautomer or stereoisomer.

9. A compound according to claim 2 ,

wherein

R1 is hydrogen, halogen, 2-6C-alkenylen-C(O)NH2, 2-6C-alkenylen-C(O)OR10, or a group selected from 1-6C-alkyl, 2-6C-alkenyl, aryl, heteroaryl,

wherein said group being optionally substituted, one or more times, identically or differently, with a substituent selected from:

hydroxy, halogen, 1-6C-alkyl, 1-4C-hydroxyalkyl, cyano, —C(O)NR8R9, —C(O)OR10, —NHC(O)R11, —NHS(O) 2 R11, —S(O) 2 R11, —S(O) 2 NR8R9,

R2 is hydrogen, halogen, cyano, or 1-6C-alkyl,

R3 is hydrogen,

R4 is phenyl,

R5 is hydrogen,

R6 is hydrogen,

or,

in the case of —NR8R9, R8 and R9 together with the nitrogen to which they are attached may also form a 3-6C-heterocyclic ring,

R10 is hydrogen, 1-6C-alkyl,

R11 is 1-4C-alkyl,

X is —(CH 2 ) n —,

n is 1,

Y is —CH 2 —,

or an N-oxide, a salt, a tautomer or a stereoisomer of said compound, or a salt of said N-oxide, tautomer or stereoisomer.

10. A compound according to claim 2 ,

wherein,

R1 is hydrogen, halogen, 1-3C-alkyl, 2-3C-alkenyl, —(CH═CH)C(O)NH2, —(CH═CH)C(O)OR10,

pyrazolyl (optionally substituted with methyl),

pyridyl (optionally substituted with hydroxy, methoxy, —C(O)OR10), indazolyl,

phenyl, wherein the phenyl group can optionally be substituted with a substituent selected from the group consisting of

halogen, methyl, hydroxymethyl, cyano, C(O)NH 2 , —C(O)OR10, —S(O) 2 R11, SO 2 —NH 2 ,

R2 is hydrogen, methyl, halogen,

R3 is hydrogen,

R4 is phenyl,

R5 is hydrogen,

R6 is hydrogen,

R10 is 1-3C-alkyl,

R11 is 1-3C-alkyl,

X is —CH 2 —,

Y is —CH 2 —,

or an N-oxide, a salt, a tautomer or a stereoisomer of said compound, or a salt of said N-oxide, tautomer or stereoisomer.

11. A pharmaceutical composition comprising at least one compound according to claim 1 , together with at least one pharmaceutically acceptable auxiliary.

12. A pharmaceutical combination comprising at least one compound according to claim 1 , and one or more second active ingredients selected from chemotherapeutic anti-cancer agents and target-specific anti-cancer agents.

13. A method for the treatment of a tumor of the breast comprising administering to a human in need thereof a therapeutically effective amount of a compound according to claim 1 .

14. A method for the treatment of a tumor of the breast comprising administering to a human in need thereof a therapeutically effective amount of a compound according to claim 2 .

15. A method for the treatment of a tumor of the breast comprising administering to a human in need thereof a therapeutically effective amount of a compound according to claim 3 .

16. A method for the treatment of a tumor of the breast comprising administering to a human in need thereof a therapeutically effective amount of a compound according to claim 4 .

17. A method for the treatment of a tumor of the breast comprising administering to a human in need thereof a therapeutically effective amount of a compound according to claim 5 .

18. A method for the treatment of a tumor of the breast comprising administering to a human in need thereof a therapeutically effective amount of a compound according to claim 6 .

Assignments (1)

ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Jun 13, 2013

From: REHWINKEL, HARTMUT, DR.; HAGEBARTH, ANDREA, DR.; POLITZ, OLIVER, DR.; NEUHAUS, ROLAND, DR.; BOMER, ULF, DR.

To: BAYER INTELLECTUAL PROPERTY GMBH

Reel/Frame 030607/0391 →

Priority Claims (1)

EP 10171006 · Jul 28, 2010 · regional

Continuity (1)

Related Publication 20130210825A1 · Aug 15, 2013