Pyridazinyl derivatives as SMO inhibitors

Patent metadata

Field	Value
Publication number	US-9409871-B2
Application number	US-201313905686-A
Country	US
Kind code	B2
Filing date	May 30, 2013
Priority date	Jul 18, 2008
Publication date	Aug 9, 2016
Grant date	Aug 9, 2016

Abstract

The present invention relates to compounds of formula I:

in which L, W, X, Y, Z, m, p, R1, R2, R3, R4 and R7 are defined in the Summary of the Invention; capable of inhibiting the Hedgehog and Smo signaling pathway. The invention further provides a process for the preparation of compounds of the invention, pharmaceutical preparations comprising such compounds and methods of using such compounds and compositions in the diagnosis and treatment of pathologies relating to the Hedgehog and Smo signaling pathway, for example, tumor formation, cancer, neoplasia and non-malignant hyperproliferative disorders.

First claim

We claim:

1. A compound, or a pharmaceutically acceptable salt thereof, selected from: (R)-4-(4,5-Dimethyl-6-phenoxy-pyridazin-3-yl)-2-methyl-3,4,5,6-tetrahydro-2H-[1,2′]bipyrazinyl-5′-carboxylic methyl ester; (R)-4-(4,5-Dimethyl-6-phenylamino-pyridazin-3-yl)-2-methyl-3,4,5,6-tetra-hydro-2H-[1,2′]bipyrazinyl-5′-carboxylic acid methyl ester; (R)-4-(4,5-Dimethyl-6-phenylamino-pyridazin-3-yl)-2-methyl-3,4,5,6-tetra-hydro-2H-[1,2′]bipyrazinyl-5′-carboxylic acid phenylamide; 2-[(R)-4-(4,5-Dimethyl-6-phenylamino-pyridazin-3-yl)-2-methyl-3,4,5,6-tetrahydro-2H-[1,2′]bipyrazinyl-5′-yl]-propan-2-ol; (R)-4-[6-(4-fluoro-phenyl)-4,5-dimethyl-pyridazin-3-yl]-2-methyl-3,4,5,6-tetrahydro-2H-[1,2′]bipyrazinyl-5′-carboxylic acid methyl ester; (R)-4-[6-(4-trifluoromethyl-phenyl)-4,5-dimethyl-pyridazin-3-yl]-2-methyl-3,4,5,6-tetrahydro-2H-[1,2′]bipyrazinyl-5 ‘-carboxylic acid methyl ester; (R)-4-[6-(4-trifluoromethyl-phenyl)-4,5-dimethyl-pyridazin-3-yl]-2-methyl-3,4,5,6-tetrahydro-2H-[1,2’]bipyrazinyl-5′-carboxylic acid; (R)-4-[6-(4-fluoro-phenyl)-4,5-dimethyl-pyridazin-3-yl]-2-methyl-3,4,5,6-tetrahydro-2H-[1,2′]bipyrazinyl-5′-carboxylic acid; Methyl 5-(4-(6-benzyl-4,5-dimethylpyridazin-3-yl)piperidin-1-yl)pyrazine-2-carboxylate; 2-{5-[4-(6-Benzyl-4,5-dimethyl-pyridazin-3-yl)-piperidin-1-yl]-pyrazin-2-yl}-propan-2-ol; 3-Benzyl-6-{1-[5-(1-methoxy-1-methyl-ethyl)-pyrazin-2-yl]-piperidin-4-yl}-4,5-dimethyl-pyridazine; 3-Benzyl-6-{1-[5-(trifluoromethyl)pyridin-2-yl]-piperidin-4-yl}-4,5-dimethyl-pyridazine; (R)-4-(6-Benzoyl-4,5-dimethyl-pyridazin-3-yl)-2-methyl-3,4,5,6-tetrahydro-2H-[1,2′]bipyrazinyl-5′-carboxylic acid methyl ester; (6-{(R)-4-[4-(1-Hydroxy-1-methyl-ethyl)-phenyl]-3-methyl-piperazin-1-yl}-4,5-dimethyl-pyridazin-3-yl)-phenyl-methanone; (R)-4[6-(hydroxyl-phenyl-methyl)-4,5-dimethyl-pyridazin-3-yl]-2-methyl-3,4,5,6-tetrahydro-2H-[1,2]bipyrazinyl-5′-carboxylic acid methyl ester; (R)-4-(4,5-Dimethyl-6-pyridin-4-ylmethyl-pyridazin-3-yl)-2-methyl-3,4,5,6-tetrahydro-2H-[1,2′]bipyrazinyl-5′-carboxylic acid methyl ester; (R)-4-(4,5-Dimethyl-6-pyridin-3-ylmethyl-pyridazin-3-yl)-2-methyl-3,4,5,6-tetrahydro-2H-[1,2′]bipyrazinyl-5′-carboxylic acid methyl ester; 2-[(R)-4-(4,5-Dimethyl-6-pyridin-3-ylmethyl-pyridazin-3-yl)-2-methyl-3,4,5,6-tetrahydro-2H-[1,2′]bipyrazinyl-5′-yl]-propan-2-ol; (R)-4-(4,5-Dimethyl-6-pyridin-2-ylmethyl-pyridazin-3-yl)-2-methyl-3,4,5,6-tetrahydro-2H-[1,2′]bipyrazinyl-5′-carboxylic acid methyl ester; 2-{(R)-4-[6-(Difluoro-phenyl-methyl)-4,5-dimethyl-pyridazin-3-yl]-2-methyl-3,4,5,6-tetrahydro-2H-[1,2′]bipyrazinyl-5′-yl}-propan-2-ol; 3-Benzyl-6-[4-(5-chloro-1H-imidazol-2-yl)-piperidin-1-yl]-4,5-dimethyl-pyridazine; 1′-(6-Benzyl-4,5-dimethyl-pyridazin-3-yl)-5-(1-hydroxy-1-methyl-ethyl)-2′,3′,5′,6′-tetrahydro-1′H-[2,4′]bipyridinyl-4′-carbonitrile; 3-Benzyl-4,5-dimethyl-6-[4-(4-trifluoromethyl-1H-imidazol-2-yl)-piperidin-1-yl]-pyridazine; 1′-(6-Benzyl-4,5-dimethyl-pyridazin-3-yl)-5-(1-hydroxy-1-methyl-ethyl)-2′,3′,5′,6′-tetrahydro-1′H-[2,4′]bipyridinyl-4′-ol; 2-[1′-(6-Benzyl-4,5-dimethyl-pyridazin-3-yl)-4′-fluoro-1′,2′,3′,4′,5′,6′-hexahydro-[2,4′]bipyridinyl-5-yl]-propan-2-ol; 2-(6-{(S)-4-[4-(2-Chloro-benzyl)-6,7-dihydro-5H-cyclopenta[d]pyridazin-1-yl]-3-methyl-piperazin-1-yl}-pyridin-3-yl)-propan-2-ol; (R)-4-(6-Benzyl-4,5-dimethyl-pyridazin-3-yl)-2-methyl-3,4,5,6-tetrahydro-2H-[1,2′]bipyrazinyl-5′-carboxylic acid methyl ester; 3-Benzyl-4,5-dimethyl-6-[(R)-3-methyl-4-(4-trifluoro-methanesulfonylphenyl)-piperazin-1-yl]-pyridazine; 2-[(R)-4-(6-Benzyl-4,5-dimethyl-pyridazin-3-yl)-2-methyl-3,4,5,6-tetrahydro-2H-[1,2′]bipyrazinyl-5′-yl]-2,2-dimethoxy-ethanol; 1-[(R)-4-(6-Benzyl-4,5-dimethyl-pyridazin-3-yl)-2-methyl-3,4,5,6-tetrahydro-2H-[1,2′]bipyrazinyl-5′-yl]-ethanol; 1-[(R)-4-(6-Benzyl-4,5-dimethyl-pyridazin-3-yl)-2methyl-3,4,5,6-tetrahydro-2H-[1,2′]bipyrazinyl-5′-yl)-2-hydroxy-ethanone; 1-[(R)-4-(6-Benzyl-4,5-dimethyl-pyridazin-3-yl)-2methyl-3,4,5,6-tetrahydro-2H-[1,2′]bipyrazinyl-5′-yl)-ethane-1,2-diol; (R)-4-(6-Benzyl-4,5-dimethyl-pyridazin-3-yl)-2-methyl-3,4,5,6-tetrahydro-2H-[1,2′]bipyrazinyl-5′-carboxylic acid; (R)-4-(6-Benzyl-4,5-dimethyl-pyridazin-3-yl)-2-methyl-3,4,5,6-tetrahydro-2H-[1,2′]bipyrazinyl-5′-carboxylic acid methoxy-methyl-amide; (R)-4-(6-Benzyl-4,5-dimethyl-pyridazin-3-yl)-5′-isopropenyl-2-methyl-3,4,5,6-tetrahydro-2H-[1,2′]bipyrazinyl; 4,5-Dimethyl-3-(5-methyl-[1,2,4]oxadiazol-3-yl-methyl)-6-[4-(5-trifluoro-methyl-pyridin-2-yl)-piperazin-1-yl]-pyridazine; 4,5-Dimethyl-3-(1-methyl-1H-tetrazol-5-ylmethyl)-6-[4-(5-trifluoromethyl-pyridin-2-yl)-piperazin-1-yl]-pyridazine; 4,5-Dimethyl-3-(2-methyl-2H-tetrazol-5-ylmethyl)-6-[4-(5-trifluoromethyl-pyridin-2-yl)-piperazin-1-yl]-pyridazine; 4,5-Dimethyl-3-(5-methyl-[1,3,4]oxadiazol-2-ylmethyl)-6-[4-(5-trifluoromethyl-pyridin-2-yl)-piperazin-1-yl]-pyridazine; 2-[(R)-4-(6-Benzyl-5-hydroxymethyl-4-methyl-pyridazin-3-yl)-2-methyl-3,4,5,6-tetrahydro-2H-[1,2′]bipyrazinyl-5′-yl]-propan-2-ol; and 2-[(R)-4-(6-Benzyl-4-hydroxymethyl-5-methyl-pyridazin-3-yl)-2-methyl-3,4,5,6-tetrahydro-2H-[1,2′]bipyrazinyl-5′-yl]-propan-2-ol.

2. A compound, or a pharmaceutically acceptable salt thereof, selected from:

Assignees

• Novartis Ag

Inventors

• He Feng
• Peukert Stefan
• Miller-Moslin Karen Marie
• Yusuff Naeem
• Chen Zhuoliang
• Lagu Bharat

Classifications

• A61P35/00

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• A61P3/10

  for hyperglycaemia, e.g. antidiabetics · CPC title

• A61P27/02

  Ophthalmic agents · CPC title

• A61P19/08

  for bone diseases, e.g. rachitism, Paget's disease · CPC title

• A61P13/08

  of the prostate · CPC title