US 2004/0176390 A1Published application

Novel fused heteroaromatic compounds as transforming growth factor (TGF) inhibitors

AssigneePfizer Inc.

InventorsLaura C. Blumberg, Michael J. Munchhof, Andrei Shavnya

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Abstract

Novel fused heteroaromatic compounds, including derivatives thereof, to intermediates for their preparation, to pharmaceutical compositions containing them and to their medicinal use are described. The compounds of the present invention are potent inhibitors of transforming growth factor (“TGF”)-β signaling pathway. They are useful in the treatment of various TGF-related disease states including, for example, cancer and fibrotic diseases.

Claims15

Dependent claims

A compound of the formula (Ia) or (Ib):

91
or a pharmaceutically acceptable salt, tautomer, prodrug, hydrate, or solvate thereof, wherein:
R1 is an optionally substituted saturated, unsaturated, or aromatic C3-C20 mono-, bi- or polycyclic ring optionally containing at least one heteroatom selected from the group consisting of N, O and S;
each R3 is independently selected from the group consisting of:
hydrogen, halo, halo(C1-C6)alkyl, (C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, perhalo(C1-C6)alkyl, (C5-C10)heteroaryl, (C5-C10)heterocyclic, (C3-C10)cycloalkyl, hydroxy, (C1-C6)alkoxy, perhalo(C1-C6)alkoxy, phenoxy, (C5-C10)heteroaryl-O—, (C5-C10)heterocyclic-O—, (C3-C10)cycloalkyl-O—, (C1-C6)alkyl-S—, (C1-C6)alkyl-SO2—, (C1-C6)alkyl-NH—SO2—, nitro, cyano, amino, Ph(CH2)1-6NH—, (C1-C6)alkylamino, [(C1-C6)alkyl]2-amino, (C1-C6)alkyl-SO2—NH—, amino(C═O)—, aminoSO2—, (C1-C6)alkyl-(C═O)—NH—, (C1-C6)alkyl-(C═O)-[((C1-C6)alkyl)-N]-, phenyl-(C═O)—NH—, phenyl-(C═O)-[((C1-C6)alkyl)-N]-, (C1-C6)alkyl-(C═O)—, phenyl-(C═O)—, (C5-C10)heteroaryl-(C═O)—. (C5-C10)heterocyclic-(C═O)— (C, —C 10)cycloalkyl-(C═O)—, HO—(C═O)—, (C1-C6)alkyl-O—(C═O)—, H2N(C═O)—(C X—C6)alkyl-NH—(C═O)—, [(C1-C6)alkyl]2—N—(C═O)—, phenyl-NH—(C═O)—, phenyl-[((C1-C6)alkyl)-N]-(C═O)—, (C5-C10)heteroaryl-NH—(C═O)—, (C5-C10)heterocyclic-NH—(C═O)—, (C3-C10)cycloalkyl-NH—(C═O)— and (C1-C6)alkyl-(C═O)—O—, where R3 is optionally substituted by at least one substituent independently selected from (C1-C6)alkyl, (C1-C6)alkoxy, halo(C1-C6)alkyl, halo, H2N—, Ph(CH2)11NH—, and (C1-C6)alkylNH—;
s is an integer from one to five;
and
R4 and R6 taken together with the atoms to which they are attached form a core fused heteroaromatic.

5 more elements

A compound selected from the group consisting of:

6-[2-(6-Methyl-pyridin-2-yl)-imidazo[1,2-a]pyridin-3-yl]-quinoline;
6-[2-(6-Methyl-pyridin-2-yl)-imidazo[1,2-a]pyrazin-3-yl]-quinoline;
6-[2-(6-Methyl-pyridin-2-yl)-imidazo[1,2-a]pyrimidin-3-yl]-quinoline;
2-Benzo[1,3]dioxol-5-yl-3-(6-methyl-pyridin-2-yl)-1H-imidazo[1,2-a]imidazole;
2-Benzo[1,3]dioxol-5-yl-3-(6-methyl-pyridin-2-yl)-imidazo[1,2-a]pyrimidine;
6-[2-(6-Methyl-pyridin-2-yl)-imidazo[1,2-a]pyrazin-3-yl]-quinoline;
6-[3-(6-Methyl-pyridin-2-yl)-imidazo[1,2-a]pyridin-2-yl]-quinoline;
6-[3-(6-Methyl-pyridin-2-yl)-imidazo[1,2-a]pyrimidin-2-yl]-quinoline;
6-[6-(6-Methyl-pyridin-2-yl)-imidazo[2,1-b][1,3,4]thiadiazol-5-yl]-quinoline;
6-[6-(6-Methyl-pyridin-2-yl)-imidazo[2,1-b]thiazol-5-yl]-quinoline;
6-[8-Methyl-2-(6-methyl-pyridin-2-yl)-imidazo[1,2-a]pyridin-3-yl]-quinoline;
6-[7-Methyl-2-(6-methyl-pyridin-2-yl)-imidazo[1,2-a]pyridin-3-yl]-quinoline;
6-[6-Methyl-2-(6-methyl-pyridin-2-yl)-imidazo[1,2-a]pyridin-3-yl]-quinoline;
6-[3-(6-Methyl-pyridin-2-yl)-7H-imidazo[1,2-a]imidazol-2-yl]-quinoline;
1-Methyl-6-[3-(6-methyl-pyridin-2-yl)-imidazo[1,2-a]pyrimidin-2-yl]-1H-benzotriazole;
1-Methyl-6-[2-(6-methyl-pyridin-2-yl)-imidazo[1,2-a]pyridin-3-yl]-1H-benzotriazole;
6-[3-Methyl-6-(6-methyl-pyridin-2-yl)-imidazo[2,1-b]thiazol-5-yl]-quinoline;
6-[2-Methyl-6-(6-methyl-pyridin-2-yl)-imidazo[2,1-b]thiazol-5-yl]-quinoline;
6-[7-Methyl-2-(6-methyl-pyridin-2-yl)-imidazo[1,2-a]pyrimidin-3-yl]-15 quinoline;
2-(6-Methyl-pyridin-2-yl)-3-quinolin-6-yl-imidazo[1,2-a]pyrimidin-7-ylamine;
6-[7-Methyl-2-(6-methyl-pyridin-2-yl)-6-nitro-imidazo[1,2-a]pyridin-3-yl]-quinoline;
1-Methyl-6-[2-(6-methyl-pyridin-2-yl)-imidazo[1,2-a]pyrimidin-3-yl]-1H-benzotriazole;
1-Methyl-6-[6-(6-methyl-pyridin-2-yl)-imidazo[2,1-b]thiazol-5-yl]-1H-benzotriazole;
1-Methyl-6-[6-(6-methyl-pyridin-2-yl)-imidazo[2,1-b][1,3,4]thiadiazol-5-yl]-251H-benzotriazole;
2-Methyl-5-[2-(6-methyl-pyridin-2-yl)-imidazo[1,2-a]pyrimidin-3-yl]-2H-benzotriazole;
3-(2-Methyl-2H-benzotriazol-5-yl)-2-(6-methyl-pyridin-2-yl)-imidazo[1,2-a]pyrimidin-7-ylamine;
2-Methyl-5-[6-(6-methyl-pyridin-2-yl)-imidazo[2,1-b]thiazol-5-yl]-2H-benzotriazole.
2-Methyl-5-[6-(6-methyl-pyridin-2-yl)-imidazo[2,1-b][1,3,4]thiadiazol-5-yl]i 2H-benzotriazole;
2-(6-Methyl-pyridin-2-yl)-3-quinolin-6-yl-imidazo[1,2-a]pyrimidin-7-ol;
1-Methyl-6-[6-(6-methyl-pyridin-2-yl)-2-methylsulfanyl-imidazo[2,1-b][1,3,4]thiadiazol-5-yl]-1H-benzotriazole;
Dimethyl-[2-(6-methyl-pyridin-2-yl)-3-quinolin-6-yl-imidazo[1,2-a]pyrimidin-7-yl]-amine;
2-Methyl-5-[3-methyl-6-(6-methyl-pyridin-2-yl)-imidazo[2,1-b]thiazol-5-yl]-2H-benzotriazole;
2-Methyl-5-[2-methyl-6-(6-methyl-pyridin-2-yl)-imidazo[2,1-b]thiazol-5-yl]-2H-benzotriazole;
2-(6-Methyl-pyridin-2-yl)-3-pyridin-4-yl-imidazo[1,2-a]pyridine;
2-(6-Methyl-pyridin-2-yl)-3-pyridin-4-yl-imidazo[1,2-a]pyrimidine;
2-(6-Methyl-pyridin-2-yl)-3-pyridin-4-yl-imidazo[1,2-a]pyrimidin-7-ylamine;
3-Benzothiazol-6-yl-2-(6-methyl-pyridin-2-yl)-imidazo[1,2-a]pyrimidin-7-ylamine;
1-Methyl-6-[6-(6-cyclopropyl-pyridin-2-yl)-imidazo[2,1-b][1,3,4]thiadiazol-5-yl]-1H-benzotriazole;
3-Methyl-5-[6-(6-methyl-pyridin-2-yl)-imidazo[2,1-b]thiazol-5-yl]-3H-[1,2,3]triazolo[4,5-b]pyridine;
3-Methyl-5-[6-(6-methyl-pyridin-2-yl)-imidazo[2,1-b][1,3,4]thiadiazol-5-yl]-3H-[1,2,3]triazolo[4,5-b]pyridine;
2-Methyl-5-[6-(6-methyl-pyridin-2-yl)-imidazo[2,1-b]thiazol-5-yl]-2H-[1,2,3]triazolo[4,5-b]pyridine;
2-Methyl-5-[6-(6-methyl-pyridin-2-yl)-imidazo[2,1-b][1,3,4]thiadiazol-5-yl]-2H-[1,2,3]triazolo[4,5-b]pyridine;
and
2-Methyl-5-[2-(6-methyl-pyridin-2-yl)-7H-imidazo[1,2-a]imidazol-3-yl]-2H-benzotriazole.

41 more elements

Dependencies are inferred from the claim text.

Facts

Application: 10/783,251Filed 20 Feb 2004
Priority: 4 Mar 2003
Published: 9 Sep 2004
Term ends: Not estimatedThe source records don’t support an estimate.

Classification15 codes

C07D 471/04
In which the condensed system contains two hetero rings: ortho-condensed systems
A61P 1/16
Drugs for disorders of the alimentary tract or the digestive system: for liver or gallbladder disorders, e.g. hepatoprotective agents,…
A61P 3/10
For glucose homeostasis: for hyperglycaemia, e.g. antidiabetics
A61P 9/08
Drugs for disorders of the cardiovascular system: vasodilators for multiple indications

Family

Application60/451,683Us provisional application · filed 4 Mar 2003
US 7,417,041 B2Related patent
US 2004/0176390 A1This patent

From the US filing history. Foreign family members aren’t listed.

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Abstract

Facts

Application

10/783,251Filed 20 Feb 2004

Priority

4 Mar 2003

Published

9 Sep 2004

Term ends

Not estimatedThe source records don’t support an estimate.

Classification15 codes

C07D 471/04
In which the condensed system contains two hetero rings: ortho-condensed systems
A61P 1/16
Drugs for disorders of the alimentary tract or the digestive system: for liver or gallbladder disorders, e.g. hepatoprotective agents,…
A61P 3/10
For glucose homeostasis: for hyperglycaemia, e.g. antidiabetics
A61P 9/08
Drugs for disorders of the cardiovascular system: vasodilators for multiple indications