Granted Patent B2

US 12,565,496 · App. 18/018,221 · Granted Mar 3, 2026

Inventors: Volker Schulze (Hohen Neuendorf, DE); Anne Mengel (Berlin, DE); Adelaide Clara Faria Alvares De Lemos (Berlin, DE); Sven Christian (East Boston, MA); Ulf Bömer (Glienicke, DE); Roman Hillig (Berlin, DE); Christian Lechner (Berlin, DE); Jérémie Xavier Mortier (Berlin, DE); Stefan Kaulfuss (Berlin, DE); Steven Corsello (Boston, MA); Katarzyna Handing (Framingham, MA); Amael Madec (Boston, MA); Laura Furst (Somerville, MA); Mrinal Shekhar (Quincy, MA); Markus Berger (Berlin, DE); Rajesha Rupaimoole (North Billerica, MA); Philip Lienau (Leverkusen, DE); Douglas Orsi (Watertown, MA); David McKinney (Cambridge, MA); Krzysztof Brzezinka (Berlin, DE)

Assignees: Bayer Aktiengesellschaft; The Broad Institute, Inc.; Dana-Farber Cancer Institute, Inc.

C07D471/04C07D487/04

Abstract

Claims (138)

1 . A compound of formula (I)

wherein:

A represents a group selected from:

X represents N, C—H, C—F, C 1 -C 1 , or C-Me;

Y represents N or C—R 4a ;

Z represents N or C—R 4b ,

wherein none or one of X, Y, and Z represents N;

R 1b represents hydrogen or halogen;

R 1c represents hydrogen or fluoro;

R 1e represents hydrogen or fluoro;

R 1f represents hydrogen or fluoro;

R 1g represents hydrogen or fluoro;

R 2 represents hydrogen, halogen, methoxy, cyano, C 1 -C 2 -alkyl, or C 1 -C 3 -alkoxy-C 1 -C 3 -alkyl-;

R 3 represents phenyl, wherein said phenyl is independently optionally substituted, one or more times, with halogen, methyl, methoxy, C 1 -C 2 -haloalkyl, or C 1 -C 2 -haloalkoxy;

R 4a represents hydrogen, halogen, C 1 -C 3 -alkyl, C 2 -alkenyl, methoxy, difluoromethoxy, C 3 -cycloalkyl, 4-membered heterocycloalkyl, cyclopropyloxy, 4-membered heterocycloalkyl-O—, or R 5a R 6a N—;

R 4b represents hydrogen, halogen, C 1 -C 4 -alkyl, C 2 -C 4 -alkenyl, C 1 -C 3 -haloalkyl-CH 2 —, C 1 -C 3 -alkoxy, C 1 -C 3 -haloalkoxy, C 3 -C 5 -cycloalkyl, C 3 -C 5 -cycloalkyl-C 1 -C 2 -alkyl, C 3 -C 5 -cycloalkyl-O—, C 3 -C 5 -cycloalkyl-CH 2 —O—, piperazin-1-yl, morpholin-4-yl, 3- to 6-membered heterocycloalkyl connected via a carbon atom thereof, pyrrolidin-2-one, piperidin-2-one, morpholin-3-one, 4-methylpiperazin-2-one, 3- to 6-membered heterocycloalkyl-O—, 3- to 6-membered heterocycloalkyl-CH 2 —O—, C 1 -C 3 -alkoxy-C 1 -C 3 -alkyl-, C 1 -C 3 -alkoxy-C 2 -C 3 -alkoxy-, C 1 -C 4 -hydroxyalkyl, or C 1 -C 4 -hydroxyalkyl-O—, wherein said C 3 -C 5 -cycloalkyl, C 3 -C 5 -cycloalkyl C 1 -C 2 -alkyl, C 3 -C 5 -cycloalkyl-O—, C 3 -C 5 -cycloalkyl-CH 2 —O—, 3- to 6-membered heterocycloalkyl, pyrrolidin-2-one, piperidin-2-one, morpholin-3-one, 4-methylpiperazin-2-one, 3- to 6-membered heterocycloalkyl-O—, 3- to 6-membered heterocycloalkyl-CH 2 —O—, piperazin-1-yl, morpholin-4-yl, C 1 -C 3 -alkoxy-C 1 -C 3 -alkyl-, C 1 -C 3 -alkoxy-C 2 -C 3 -alkoxy-, C 1 -C 4 -hydroxyalkyl, and C 1 -C 4 -hydroxyalkyl-O— groups are optionally substituted, one, two or three times, with halogen, methyl, or methoxy;

R 5a represents hydrogen or methyl;

R 6a represents hydrogen or methyl, or

R 5a and R 6a , together with the nitrogen atom to which they are attached, represent a 4-membered heterocyclic ring, wherein said heterocyclic ring is optionally substituted with methyl;

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 . The compound of formula (I) according to claim 1 , wherein:

A represents a group selected from:

X represents N, C—H, C—F, or C—Cl;

Y represents N or C—R 4a ;

Z represents N or C—R 4b ,

wherein none or one of X, Y and Z represents N;

R 1b represents hydrogen or fluoro;

R 1c represents hydrogen;

R 1e represents hydrogen;

R 1f represents hydrogen or fluoro;

R 1g represents hydrogen or fluoro;

R 2 represents hydrogen, C 1 -C 2 -alkyl, or C 1 -C 2 -alkoxy-C 1 -C 2 -alkyl-;

R 3 represents phenyl, wherein said phenyl is independently optionally substituted, one or more times, with halogen, methyl, or C 1 -haloalkyl;

R 4a represents hydrogen, halogen, C 1 -alkyl, C 2 -alkenyl, C 3 -cycloalkyl, 4-membered heterocycloalkyl, or R 5a R 6a N—;

R 4b represents hydrogen, halogen, C 1 -C 4 -alkyl, C 2 -C 4 -alkenyl, C 1 -C 3 -haloalkyl-CH 2 —, C 1 -C 3 -alkoxy, C 1 -C 3 -haloalkoxy, C 3 -C 4 -cycloalkyl, C 3 -C 4 -cycloalkyl-C 1 -C 2 -alkyl, C 3 -C 4 -cycloalkyl-O—, C 3 -C 4 -cycloalkyl-CH 2 —O—, piperazin-1-yl, morpholin-4-yl, 3- to 6-membered heterocycloalkyl connected via a carbon atom thereof, pyrrolidin-2-one, piperidin-2-one, morpholin-3-one, 4-methylpiperazin-2-one, 3- to 6-membered heterocycloalkyl-O—, 3- to 6-membered heterocycloalkyl-CH 2 —O—, C 1 -C 3 -alkoxy-C 2 -C 3 -alkoxy-, C 1 -C 4 -hydroxyalkyl, or C 1 -C 4 -hydroxyalkyl-O—,

wherein said C 3 -C 4 -cycloalkyl, C 3 -C 4 -cycloalkyl-C 1 -C 2 -alkyl, C 3 -C 4 -cycloalkyl-O—, C 3 -C 4 -cycloalkyl-CH 2 —O—, 3- to 6-membered heterocycloalkyl, pyrrolidin-2-one, piperidin-2-one, morpholin-3-one, 4-methylpiperazin-2-one, 3- to 6-membered heterocycloalkyl-O—, 3- to 6-membered heterocycloalkyl-CH 2 —O—, piperazin-1-yl, morpholin-4-yl, C 1 -C 3 -alkoxy-C 2 -C 3 -alkoxy-, C 1 -C 4 -hydroxyalkyl and C 1 -C 4 -hydroxyalkyl-O— groups are optionally substituted, one or two times, with halogen or methyl;

R 5a represents hydrogen or methyl;

R 6a represents hydrogen or methyl, or

R 5a and R 6a , together with the nitrogen atom to which they are attached, represent a 4-membered heterocyclic ring;

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 . The compound of formula (I) according to claim 2 , wherein:

A represents:

X represents C—H, C—F;

Y represents N or C—R 4a ;

Z represents N or C—R 4b ;

wherein none or one of Y and Z represents N;

R 1b represents hydrogen or fluoro;

R 1e represents hydrogen;

R 1f represents hydrogen;

R 1g represents hydrogen or fluoro;

R 2 represents hydrogen, methyl, or C 1 -alkoxy-C 1 -C 2 -alkyl-;

R 3 represents phenyl, wherein said phenyl is independently optionally substituted, one or more times, with halogen or methyl;

R 4a represents hydrogen, halogen, or methyl;

R 4b represents hydrogen, halogen, C 1 -C 4 -alkyl, C 1 -C 3 -haloalkyl-CH 2 —, C 1 -C 3 -alkoxy, C 1 -C 3 -haloalkoxy, C 3 -cycloalkyl, C 3 -cycloalkyl-C 1 -C 2 -alkyl, C 3 -cycloalkyl-O—, C 3 -cycloalkyl-CH 2 —O—, piperazin-1-yl, morpholin-4-yl, 3- to 6-membered heterocycloalkyl connected via a carbon atom thereof, pyrrolidin-2-one, piperidin-2-one, morpholin-3-one, 4-methylpiperazin-2-one, 3- to 6-membered heterocycloalkyl-O—, 3- to 6-membered heterocycloalkyl-CH 2 —O—, C 1 -C 3 -alkoxy-C 2 -C 3 -alkoxy-, C 1 -C 4 -hydroxyalkyl, or C 1 -C 4 -hydroxyalkyl-O—;

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 selected from:

2-(4-fluorophenyl)-N-{4-[5-fluoro-3-(pyridin-2-yl)-1H-pyrrolo[3,2-b]pyridin-2-yl]pyridin-2-yl}propanamide;

(2R)-2-(4-fluorophenyl)-N-{4-[5-fluoro-3-(pyridin-2-yl)-1H-pyrrolo[3,2-b]pyridin-2-yl]pyridin-2-yl}propanamide;

(2S)-2-(4-fluorophenyl)-N-{4-[5-fluoro-3-(pyridin-2-yl)-1H-pyrrolo[3,2-b]pyridin-2-yl]pyridin-2-yl}propanamide;

2-(4-fluorophenyl)-N-{4-[5-fluoro-3-(pyridin-2-yl)-1H-pyrrolo[3,2-b]pyridin-2-yl]pyridin-2-yl}acetamide;

2-(4-fluorophenyl)-N-{4-[3-(pyridin-2-yl)-1H-pyrrolo[3,2-b]pyridin-2-yl]pyridin-2-yl}acetamide

2-(4-fluorophenyl)-N-{4-[3-(pyridin-2-yl)-1H-pyrrolo[3,2-b]pyridin-2-yl]pyridin-2-yl}propanamide;

(2R)-2-(4-fluorophenyl)-N-{4-[3-(pyridin-2-yl)-1H-pyrrolo[3,2-b]pyridin-2-yl]pyridin-2-yl}propanamide;

(2S)-2-(4-fluorophenyl)-N-{4-[3-(pyridin-2-yl)-1H-pyrrolo[3,2-b]pyridin-2-yl]pyridin-2-yl}propanamide;

2-(4-fluorophenyl)-N-{4-[6-fluoro-3-(pyridin-2-yl)-1H-pyrrolo[3,2-b]pyridin-2-yl]pyridin-2-yl}acetamide;

2-(4-fluorophenyl)-N-[4-(6-fluoro-3-phenyl-1H-pyrrolo[3,2-b]pyridin-2-yl)pyridin-2-yl]acetamide;

2-(4-fluorophenyl)-N-[4-(3-phenyl-1H-pyrrolo[3,2-b]pyridin-2-yl)pyridin-2-yl]propanamide;

(2R)-2-(4-fluorophenyl)-N-[4-(3-phenyl-1H-pyrrolo[3,2-b]pyridin-2-yl)pyridin-2-yl]propanamide;

(2S)-2-(4-fluorophenyl)-N-[4-(3-phenyl-1H-pyrrolo[3,2-b]pyridin-2-yl)pyridin-2-yl]propanamide;

2-(4-fluorophenyl)-N-[4-(3-phenyl-1H-pyrrolo[3,2-b]pyridin-2-yl)pyridin-2-yl]acetamide;

2-(4-fluorophenyl)-N-{4-[3-(3-fluorophenyl)-1H-pyrrolo[3,2-b]pyridin-2-yl]pyridin-2-yl}acetamide;

formic acid salt of 2-(4-fluorophenyl)-N-{4-[3-(pyrimidin-2-yl)-1H-pyrrolo[3,2-b]pyridin-2-yl]pyridin-2-yl}acetamide;

N-{4-[3-(5-chlorothiophen-2-yl)-1H-pyrrolo[3,2-b]pyridin-2-yl]pyridin-2-yl}-2-(4-fluorophenyl)acetamide;

2-(4-fluorophenyl)-N-[4-(7-phenyl-5H-pyrrolo[2,3-b]pyrazin-6-yl)pyridin-2-yl]acetamide;

2-(4-fluorophenyl)-N-{4-[7-(pyridin-2-yl)-5H-pyrrolo[2,3-b]pyrazin-6-yl]pyridin-2-yl}acetamide;

2-(4-fluorophenyl)-N-[4-(7-phenyl-5H-pyrrolo[3,2-c]pyridazin-6-yl)pyridin-2-yl]acetamide;

2-(4-fluorophenyl)-N-{4-[7-(pyridin-2-yl)-5H-pyrrolo[3,2-c]pyridazin-6-yl]pyridin-2-yl}acetamide;

N-{4-[7-chloro-3-(pyridin-2-yl)-1H-pyrrolo[3,2-b]pyridin-2-yl]pyridin-2-yl}-2-(4-fluorophenyl)acetamide;

N-{4-[5-chloro-3-(pyridin-2-yl)-1H-pyrrolo[3,2-b]pyridin-2-yl]pyridin-2-yl}-2-(4-fluorophenyl)acetamide;

(2RS)-2-(4-fluorophenyl)-N-{4-[5-fluoro-3-(pyridin-2-yl)-1H-pyrrolo[3,2-b]pyridin-2-yl]pyridin-2-yl}-3-methylbutanamide;

(2R)-2-(4-fluorophenyl)-N-{4-[5-fluoro-3-(pyridin-2-yl)-1H-pyrrolo[3,2-b]pyridin-2-yl]pyridin-2-yl}-3-methylbutanamide;

(2S)-2-(4-fluorophenyl)-N-{4-[5-fluoro-3-(pyridin-2-yl)-1H-pyrrolo[3,2-b]pyridin-2-yl]pyridin-2-yl}-3-methylbutanamide;

N-{4-[5-fluoro-6-methyl-3-(pyridin-2-yl)-1H-pyrrolo[3,2-b]pyridin-2-yl]pyridin-2-yl}-2-(4-fluorophenyl)acetamide;

(2RS)—N-{4-[5-fluoro-6-methyl-3-(pyridin-2-yl)-1H-pyrrolo[3,2-b]pyridin-2-yl]pyridin-2-yl}-2-(4-fluorophenyl)propanamide;

(2R)—N-{4-[5-fluoro-6-methyl-3-(pyridin-2-yl)-1H-pyrrolo[3,2-b]pyridin-2-yl]pyridin-2-yl}-2-(4-fluorophenyl)propanamide;

(2S)—N-{4-[5-fluoro-6-methyl-3-(pyridin-2-yl)-1H-pyrrolo[3,2-b]pyridin-2-yl]pyridin-2-yl}-2-(4-fluorophenyl)propanamide;

2-(4-fluorophenyl)-N-{4-[7-methoxy-3-(pyridin-2-yl)-1H-pyrrolo[3,2-b]pyridin-2-yl]pyridin-2-yl}acetamide;

2-(4-fluorophenyl)-N-{4-[5-methoxy-3-(pyridin-2-yl)-1H-pyrrolo[3,2-b]pyridin-2-yl]pyridin-2-yl}acetamide;

N-{4-[7-ethenyl-3-(pyridin-2-yl)-1H-pyrrolo[3,2-b]pyridin-2-yl]pyridin-2-yl}-2-(4-fluorophenyl)acetamide;

N-{4-[7-ethyl-3-(pyridin-2-yl)-1H-pyrrolo[3,2-b]pyridin-2-yl]pyridin-2-yl}-2-(4-fluorophenyl)acetamide;

N-{4-[7-cyclopropyl-3-(pyridin-2-yl)-1H-pyrrolo[3,2-b]pyridin-2-yl]pyridin-2-yl}-2-(4-fluorophenyl)acetamide;

2-(4-fluorophenyl)-N-{4-[7-(2-methoxyethyl)-3-(pyridin-2-yl)-1H-pyrrolo[3,2-b]pyridin-2-yl]pyridin-2-yl}acetamide;

N-{4-[7-(cyclopropylmethyl)-5-fluoro-3-(pyridin-2-yl)-1H-pyrrolo[3,2-b]pyridin-2-yl]pyridin-2-yl}-2-(4-fluorophenyl)acetamide;

2-(4-fluorophenyl)-N-{4-[7-(4-methylpiperazin-1-yl)-3-(pyridin-2-yl)-1H-pyrrolo[3,2-b]pyridin-2-yl]pyridin-2-yl}acetamide;

2-(4-fluorophenyl)-N-(4-{7-[methyl(1-methylpiperidin-4-yl)amino]-3-(pyridin-2-yl)-1H-pyrrolo[3,2-b]pyridin-2-yl}pyridin-2-yl)acetamide;

2-(4-fluorophenyl)-N-{4-[7-(2-oxopyrrolidin-1-yl)-3-(pyridin-2-yl)-1H-pyrrolo[3,2-b]pyridin-2-yl]pyridin-2-yl}acetamide;

2-(4-fluoro-3-methylphenyl)-N-{4-[3-(pyridin-2-yl)-1H-pyrrolo[3,2-b]pyridin-2-yl]pyridin-2-yl}acetamide;

2-(4-chlorophenyl)-N-{4-[3-(pyridin-2-yl)-1H-pyrrolo[3,2-b]pyridin-2-yl]pyridin-2-yl}acetamide;

(2RS)-2-(4-fluorophenyl)-3-methoxy-N-(4-(3-(pyridin-2-yl)-1H-pyrrolo[3,2-b]pyridin-2-yl)pyridin-2-yl)propanamide;

(2RS)-4-methoxy-2-phenyl-N-(4-(3-(pyridin-2-yl)-1H-pyrrolo[3,2-b]pyridin-2-yl)pyridin-2-yl)butanamide;

(2RS)-2-(4-fluorophenyl)-N-[4-[6-fluoro-3-(2-pyridyl)-1H-pyrrolo[3,2-b]pyridin-2-yl]-2-pyridyl]-3-methoxy-propanamide;

2-phenyl-N-(4-(3-(pyridin-2-yl)-1H-pyrrolo[3,2-b]pyridin-2-yl)pyridin-2-yl)acetamide;

(2RS)-4,4-difluoro-N-{4-[5-fluoro-3-(5-fluoropyridin-2-yl)-1H-pyrrolo[3,2-b]pyridin-2-yl]pyridin-2-yl}-2-(4-fluorophenyl)butanamide;

(2R)—N-{4-[5-fluoro-3-(5-fluoropyridin-2-yl)-1H-pyrrolo[3,2-b]pyridin-2-yl]pyridin-2-yl}-2-(4-fluorophenyl)propanamide;

(2S)—N-{4-[5-fluoro-3-(5-fluoropyridin-2-yl)-1H-pyrrolo[3,2-b]pyridin-2-yl]pyridin-2-yl}-2-(4-fluorophenyl)propanamide;

N-{4-[5-fluoro-3-(5-fluoropyridin-2-yl)-1H-pyrrolo[3,2-b]pyridin-2-yl]pyridin-2-yl}-2-(4-fluorophenyl)acetamide;

2-(4-fluorophenyl)-N-{4-[3-(pyrimidin-2-yl)-1H-pyrrolo[3,2-b]pyridin-2-yl]pyridin-2-yl}acetamide;

N-{4-[6-chloro-3-(pyridin-2-yl)-1H-pyrrolo[3,2-b]pyridin-2-yl]pyridin-2-yl}-2-(4-fluorophenyl)propanamide;

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 method of preparing a compound of general formula (I) according to claim 1 , said method comprising reacting an intermediate compound of general formula (VII-A):

in which A, X, Y and Z are as defined for the compound of general formula (I) according to claim 1 ,

with an acylating reagent selected from:

a) a carboxylic acid of formula

b) an acyl halide of formula

wherein Hal represents F, Cl, or Br, or

c) an anhydride of formula

in which R 2 and R 3 are as defined for the compound of general formula (I) according to claim 1 ,

to give a compound of general formula (I):

in which R 2 , R 3 , A, X, Y and Z are as defined for the compound of general formula (I) according to claim 1 .

6 . A method of treating or preventing a hyperproliferative disease and/or a disorder responsive to induction of cell death in a subject, comprising administering a compound of general formula (I) according to claim 1 to the subject.

7 . The method according to claim 6 , wherein the hyperproliferative disease and/or disorder responsive to induction of cell death are haematological tumours, solid tumours and/or metastases thereof.

8 . The method according to claim 7 , wherein the haematological tumour is a lymphoma and/or metastases thereof.

9 . The method according to claim 8 , wherein the lymphoma is diffuse large B-cell lymphoma and/or metastases thereof.

10 . The method according to claim 7 , wherein the solid tumour is a cervical tumour, a lung tumour, a colon tumour and/or metastases thereof.

11 . The method according to claim 10 , wherein the lung tumour is a lung carcinoma and/or metastases thereof.

12 . The method according to claim 10 , wherein the colon tumour is a colorectal carcinoma and/or metastases thereof.

13 . A pharmaceutical composition comprising at least one compound of general formula (I) according to claim 1 , together with at least one pharmaceutically acceptable auxiliary.

14 . A combination comprising one or more first active ingredients selected from a compound of general formula (I) according to claim 1 , and one or more second active ingredients selected from chemotherapeutic anti-cancer agents and target-specific anti-cancer agents.

15 . An intermediate compound of general formula (IX-Q), (IX-A), (XIV-Q) or (XVII), or a salt thereof:

wherein R 2 , R 3 , X, Y and Z are as defined for the compound of general formula (I) according to claim 1 Q represents a chloro, a bromo or an iodo, PG represents a protecting group and T represents CF 3 —C(O)—, mesylate, tosylate or Ph-SO 2 —, wherein Ph can be substituted one, two or three times with halogen or a methyl-group or a nitro-group.

16 . A method of preparing a compound of general formula (I) according to claim 1 , said method comprising reacting an intermediate compound of general formula (XIV-Q):

wherein R 2 , R 3 , X, Y and Z are as defined for the compound of general formula (I) according to claim 1 , and Q represents a chloro, a bromo or an iodo,

with a stannane or a boronic acid A-B(OH) 2 or a boronic acid ester thereof, in which A is as defined for the compound of general formula (I), in the presence of a palladium catalyst,

to prepare compounds of general formula (I).

17 . A method of preparing a compound of general formula (I) according to claim 1 , said method comprising reacting an intermediate compound of general formula (XVII):

wherein R 2 , R 3 , X, Y and Z are as defined for the compound of general formula (I) according to claim 1 , and T represents CF 3 —C(O)—, mesylate, tosylate or Ph-SO 2 —, wherein Ph can be substituted one, two or three times with halogen, methyl, or nitro,

with A-Br or A-I, in which A is as defined for the compound of general formula (I), in the presence of a palladium catalyst, in a Cacchi reaction,

to directly provide compounds of general formula (I) or to provide compounds of general formula (I) after removal of the group T.

Assignments (8)

Continuity (2)

References Cited (44)