Pyridazinyl derivatives as SMO inhibitors

• US 9,409,871 B2
• Filed: 05/30/2013
• Issued: 08/09/2016
• Est. Priority Date: 07/18/2008
• Status: Active Grant

• Current Assignee: Novartis Ag
• Original Assignee: Novartis Ag
• Inventors: He, Feng, Peukert, Stefan, Miller-Moslin, Karen Marie, Yusuff, Naeem, Chen, Zhuoliang, Lagu, Bharat
• Primary Examiner(s): Balasubramanian, Venkataraman
• Application Number:
  US13/905,686
• Publication Number:
  US 20130261299A1
• Time in Patent Office: 1,167 Days
• Field of Search: 544/238, 514/252.02
• US Class Current: 1/1
• 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 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.

Claims

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: