ORGANIC COMPOUNDS AS SMO INHIBITORS

• US 20120289507A1
• Filed: 07/20/2012
• Published: 11/15/2012
• Est. Priority Date: 07/18/2008
• Status: Active Grant

• Current Assignee: Novartis Ag
• Original Assignee: Novartis Ag
• Inventors: HE, Feng, PEUKERT, Stefan, CHEN, Zhuoliang, MILLER-MOSLIN, Karen, YUSUFF, Naeem, LAGU, Bharat
• Granted Patent: US 8,481,542 B2
• Time in Patent Office: Days
• US Class Current: 514/236.5
• CPC Class Codes: A61K 31/4427 containing further heterocyclic ring systems
• CPC Class Codes: A61K 31/4523 containing further heterocyclic ring systems
• CPC Class Codes: A61K 31/501 not condensed and containing further heterocyclic rings
• CPC Class Codes: A61P 13/08 of the prostate
• CPC Class Codes: A61P 17/06 Antipsoriatics
• CPC Class Codes: A61P 17/14 for baldness or alopecia
• CPC Class Codes: A61P 19/08 for bone diseases, e.g. rachitism, Paget's disease
• CPC Class Codes: A61P 27/02 Ophthalmic agents
• CPC Class Codes: A61P 3/10 for hyperglycaemia, e.g. antidiabetics
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: C07D 237/20 Nitrogen atoms nitro radicals C07D237/12
• CPC Class Codes: C07D 237/26 condensed with carbocyclic rings or ring systems
• CPC Class Codes: C07D 401/12 linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 401/14 containing three or more hetero rings
• CPC Class Codes: C07D 403/12 linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 403/14 containing three or more hetero rings
• CPC Class Codes: C07D 413/14 containing three or more hetero rings
• CPC Class Codes: C07D 471/04 Ortho-condensed systems

Abstract

The present invention relates generally to novel compounds relating to the diagnosis and treatment of pathologies relating to the Hedgehog pathway, including but not limited to tumor formation, cancer, neoplasia, and non-malignant hyperproliferative disorders. The present invention includes novel compounds, novel compositions, methods of their use and methods of their manufacture, where such compounds are generally pharmacologically useful as agents in therapies whose mechanism of action involve methods of inhibiting tumorigenesis, tumor growth and tumor survival using agents that inhibit the Hedgehog and Smo signaling pathway.

Claims

1. A compound of formula (Ia):

2. The compound of claim 1 selected from:

2-[(R)-4-(4,5-Dimethyl-6-phenoxy-pyridazin-3-yl)-2-methyl-3,4,5,6-tetra-hydro-2H-[1,2′

]bipyrazinyl-5′

-yl]-propan-2-ol;

2-[(R)-4-(6-(Hydroxyl-phenyl-methyl)-4,5-dimethyl-pyridazin-3-yl)-2-methyl-3,4,5,6-tetrahydro-2H-[1,2′

]bipyrazinyl-5′

-yl]-propan-2-ol;

2-[(R)-4-(4,5-Dimethyl-6-pyridin-4-ylmethyl-pyridazin-3-yl)-2-methyl-3,4,5,6-tetrahydro-2H-[1,2′

]bipyrazinyl-5′

-yl]-propan-2-ol;

2-[(R)-4-(4,5-Dimethyl-6-pyridin-2-ylmethyl-pyridazin-3-yl)-2-methyl-3,4,5,6-tetrahydro-2H-[1,2′

]bipyrazinyl-5′

-yl]-propan-2-ol;

2-[(R)-4-(6-Benzyl-4,5-dimethyl-pyridazin-3-yl)-2-methyl-3,4,5,6-tetrahydro-2H-[1,2′

]bipyrazinyl-5′

-yl]-propan-2-ol;

2-[4-(6-Benzyl-4,5-dimethyl-pyridazin-3-yl)-3,4,5,6-tetrahydro-2H-[1,2′

]bipyrazinyl-5′

yl]-propan-2-ol;

2-[(S)-4-(6-Benzyl-4,5-dimethyl-pyridazin-3-yl)-2-methyl-3,4,5,6-tetrahydro-2H-[1,2′

]bipyrazinyl-5′

-yl]-propan-2-ol;

2-[(R)-4-(6-Benzyl-4,5-dimethyl-pyridazin-3-yl)-2-ethyl-3,4,5,6-tetrahydro-2H-[1,2′

]bipyrazinyl-5′

-yl]-propan-2-ol;

1-[(R)-4-(6-Benzyl-4,5-dimethyl-pyridazin-3-yl)-2-methyl-3,4,5,6-tetrahydro-2H-[1,2′

]bipyrazinyl-5′

-yl]-ethanone; and

2-[(R)-4-(6-Benzyl-4,5-dimethyl-pyridazin-3-yl)-2-methyl-3,4,5,6-tetrahydro-2H-[1,2′

]bipyrazinyl-5′

-yl]-propane-1,2-diol.

3. A pharmaceutical composition comprising a therapeutically effective amount of a compound of claim 1.

4. A pharmaceutical composition comprising a compound according to claim 1 and a pharmaceutically acceptable carrier.

5. A pharmaceutical composition comprising a compound according to claim 1 and a pharmaceutically acceptable carrier in a form suitable for oral administration.

6. A compound of formula: