Benzyl and pyridinyl derivatives as modulators of the hedgehog signaling pathway

• US 8,536,168 B2
• Filed: 03/13/2008
• Issued: 09/17/2013
• Est. Priority Date: 03/15/2007
• Status: Active Grant

• Current Assignee: Novartis Ag
• Original Assignee: Novartis Ag
• Inventors: Dai, Miao, He, Feng, Jain, Rishi Kumar, Karki, Rajesh, Lei, John, Llamas, Luis, Mcewan, Michael A., Miller-Moslin, Karen, Perez, Lawrence Bias, Peukert, Stefan, Yusuff, Naeem, Kelleher, Joseph III
• Primary Examiner(s): Wilson, James O
• Assistant Examiner(s): Jaisle, Cecilia M
• Application Number:
  US12/531,341
• Publication Number:
  US 20100069368A1
• Time in Patent Office: 2,014 Days
• Field of Search: 514/252.02, 514/218, 514/299.5, 514/248, 514/234.5, 514/229.5, 540/575, 540/234.5, 544/237, 544/121, 544/99, 544/235
• US Class Current: 514/229.5
• CPC Class Codes: A61P 29/00 Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 37/00 Drugs for immunological or allergic disorders
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: C07D 237/30 Phthalazines
• CPC Class Codes: C07D 401/04 directly linked by a ring-member-to-ring-member bond
• CPC Class Codes: C07D 401/06 linked by a carbon chain containing only aliphatic carbon atoms
• 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 405/14 containing three or more hetero rings
• CPC Class Codes: C07D 417/14 containing three or more hetero rings
• CPC Class Codes: C07D 487/04 Ortho-condensed systems
• CPC Class Codes: C07D 491/048 the oxygen-containing ring being five-membered
• CPC Class Codes: C07D 498/14 Ortho-condensed systems
• CPC Class Codes: C07F 9/65583 each of the hetero rings containing nitrogen as ring hetero atom

Abstract

The present disclosure relates to 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; specifically relating to compounds of formula I:

Claims

1. A compound of Formula I:

2. The compound according to claim 1 wherein:

R₃ is aryl or het; and

when R₃ is het, at least one heteroring atom is N;

U is C(H)_0-1;

R₄ is H, CH₃, halo or —

CN;

L is CH₂;

X is N;

Y is a single bond; and

Z is H or CH₃.

3. The compound according to claim 2 wherein:

R₂ is

4. A pharmaceutical composition comprising a therapeutically effective amount of a compound according to claim 1.

5. A compound selected from:

6-[4-(4-Benzyl-phthalazin-1-yl)-piperazin-1-yl]-nicotinonitrile;

1-Benzyl-4-[4-(5-trifluoromethyl-pyridin-2-yl)-piperazin-1-yl]-phthalazine;

1-Benzyl-4-[4-(5-trifluoromethyl-pyridin-2-yl)-[1,4]diazepan-1-yl]-phthalazine;

6-[4-(4-Pyridin-4-ylmethyl-phthalazin-1-yl)-piperazin-1-yl]-nicotinonitrile;

4-[4-(4-Benzyl-phthalazin-1-yl)-piperazin-1-yl]-benzoic acid ethyl ester;

1-(4-Phenyl-piperazin-1-yl)-4-pyridin-4-ylmethyl-phthalazine;

1-Benzyl-4-[4-(4-tert-butyl-phenyl)-piperazin-1-yl]-phthalazine;

1-[4-(4-tert-Butyl-phenyl)-piperazin-1-yl]-4-pyridin-4-ylmethyl-phthalazine;

1-[4-(4-tert-Butyl-phenyl)-piperazin-1-yl]-4-(3,5-dichloro-benzyl)-phthalazine;

4-[4-(4-tert-Butyl-phenyl)-piperazin-1-yl]-6-methyl-1-pyridin-4-ylmethyl-phthalazine;

1-(2-Methyl-pyridin-4-ylmethyl)-4-(4-phenyl-piperazin-1-yl)-phthalazine;

1-Benzyl-4-(4-phenyl-piperidin-1-yl)-phthalazine;

1-(4-Phenyl-piperidin-1-yl)-4-pyridin-4-ylmethyl-phthalazine;

1-(2-Methyl-pyridin-4-ylmethyl)-4-(4-phenyl-piperidin-1-yl)-phthalazine;

1-Pyridin-4-ylmethyl-4-[4-(3-trifluoromethyl-phenyl)-piperazin-1-yl]-phthalazine;

4-[4-(4-Benzyl-phthalazin-1-yl)-piperazin-1-yl]-benzoic acid;

1-Benzyl-4-[4-(3-chloro-5-trifluoromethyl-pyridin-2-yl)-[1,4]diazepan-1-yl]-phthalazine;

1-Benzyl-4-(4-quinolin-2-yl-piperazin-1-yl)-phthalazine;

6-[4-(4-Benzyl-phthalazin-1-yl)-[1,4]diazepan-1-yl]-nicotinonitrile;

4-(4-Pyridin-4-ylmethyl-phthalazin-1-yl)-3,4,5,6-tetrahydro-2H-[1,2′

]bipyrazinyl;

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

]bipyrazinyl;

1-(2-Methyl-pyridin-4-ylmethyl)-4-(4-pyridin-2-yl-piperazin-1-yl)-phthalazine;

1-Pyridin-4-ylmethyl-4-(4-pyridin-2-yl-piperazin-1-yl)-phthalazine;

1-Benzyl-4-(4-pyridin-2-yl-piperazin-1-yl)-phthalazine;

1-Benzyl-4-(4-pyrimidin-2-yl-piperazin-1-yl)-phthalazine;

1-Pyridin-4-ylmethyl-4-(4-pyridin-4-yl-piperazin-1-yl)-phthalazine;

1-Benzyl-4-(3-methyl-4-p-tolyl-piperazin-1-yl)-phthalazine;

1-(3-Methyl-4-p-tolyl-piperazin-1-yl)-4-pyridin-4-ylmethyl-phthalazine;

1-(2-Methyl-pyridin-4-ylmethyl)-4-(3-methyl-4-p-tolyl-piperazin-1-yl)-Phthalazine;

1-Benzyl-4-[4-(3,4-dichloro-phenyl)-piperazin-1-yl]-phthalazine;

1-Benzyl-4-(4-naphthalen-2-yl-piperazin-1-yl)-phthalazine;

1-(4-Naphthalen-2-yl-piperazin-1-yl)-4-pyridin-4-ylmethyl-phthalazine;

1-(2-Methyl-pyridin-4-ylmethyl)-4-(4-naphthalen-2-yl-piperazin-1-yl)-phthalazine;

1-Benzyl-4-(4-naphthalen-1-yl-piperazin-1-yl)-phthalazine;

1-(2-Methyl-pyridin-4-ylmethyl)-4-(4-naphthalen-1-yl-piperazin-1-yl)-phthalazine;

1-(4-Naphthalen-1-yl-piperazin-1-yl)-4-pyridin-4-ylmethyl-phthalazine;

1-Benzyl-4-(4-pyridin-4-yl-piperazin-1-yl)-phthalazine;

1-Benzyl-4-(4-o-tolyl-piperazin-1-yl)-phthalazine;

2-[4-(4-Benzyl-phthalazin-1-yl)-piperazin-1-yl]-pyrimidine-5-carbonitrile;

1-Benzyl-4-(4-pyrimidin-2-yl-[1,4]diazepan-1-yl)-phthalazine;

1-Benzyl-4-[4-(4-methyl-pyrimidin-2-yl)-[1,4]diazepan-1-yl]-phthalazine;

1-Benzyl-4-[4-(5-propyl-pyrimidin-2-yl)-piperazin-1-yl]-phthalazine;

1-Benzyl-4-[4-(5-ethyl-pyrimidin-2-yl)-piperazin-1-yl]-phthalazine;

1-Benzyl-4-[4-(5-propyl-pyrimidin-2-yl)-[1,4]diazepan-1-yl]-phthalazine;

1-Benzyl-4-[4-(5-ethyl-pyrimidin-2-yl)-[1,4]diazepan-1-yl]-phthalazine;

2-[4-(4-Benzyl-phthalazin-1-yl)-piperazin-1-yl]-6-methoxy-3H-pyrimidin-4-one;

1-Benzyl-4-[4-(4-methyl-pyrimidin-2-yl)-piperazin-1-yl]-phthalazine;

1-Benzyl-4-[4-(4,6-dimethyl-pyrimidin-2-yl)-piperazin-1-yl]-phthalazine;

1-Benzyl-4-[4-(5-chloro-3-fluoro-pyridin-2-yl)-piperazin-1-yl]-phthalazine;

1-Benzyl-4-[4-(4-trifluoromethyl-pyrimidin-2-yl)-piperazin-1-yl]-phthalazine;

1-Benzyl-4-[4-(2,5-difluoro-pyridin-3-yl)-piperazin-1-yl]-phthalazine;

1-Benzyl-4-[4-(3,5-difluoro-pyridin-2-yl)-piperazin-1-yl]-phthalazine;

6-[4-(4-Benzyl-phthalazin-1-yl)-piperazin-1-yl]-nicotinamide;

6-[4-(4-Benzyl-phthalazin-1-yl)-piperazin-1-yl]-nicotinic acid ethyl ester;

2-{6-[4-(4-Benzyl-phthalazin-1-yl)-piperazin-1-yl]-pyridin-3-yl}-propan-2-ol;

6-[4-(4-Benzyl-phthalazin-1-yl)-piperazin-1-yl]-nicotinic acid;

6-[4-(4-Benzyl-phthalazin-1-yl)-piperazin-1-yl]-N-(2-hydroxy-ethyl)-N-methyl-nicotinamide;

6-[4-(4-Benzyl-phthalazin-1-yl)-piperazin-1-yl]-N-ethyl-N-(2-hydroxy-ethyl)-nicotinamide;

6-[4-(4-Benzyl-phthalazin-1-yl)-piperazin-1-yl]-N-(2-hydroxy-ethyl)-nicotinamide;

6-[4-(4-Benzyl-phthalazin-1-yl)-piperazin-1-yl]-N-(2-methoxy-ethyl)-nicotinamide;

6-[4-(4-Benzyl-phthalazin-1-yl)-piperazin-1-yl]-N-(2-methoxy-ethyl)-N-methyl-nicotinamide;

6-[4-(4-Benzyl-phthalazin-1-yl)-piperazin-1-yl]-N-(2-dimethylamino-ethyl)-nicotinamide;

{6-[4-(4-Benzyl-phthalazin-1-yl)-piperazin-1-yl]-pyridin-3-yl}-(4-methyl-piperazin-1-yl)-methanone;

{6-[4-(4-Benzyl-phthalazin-1-yl)-piperazin-1-yl]-pyridin-3-yl}-piperazin-1-yl-methanone;

{6-[4-(4-Benzyl-phthalazin-1-yl)-piperazin-1-yl]-pyridin-3-yl}-morpholin-4-yl-methanone;

N-Benzyl-6-[4-(4-benzyl-phthalazin-1-yl)-piperazin-1-yl]-nicotinamide;

6-[4-(4-Benzyl-phthalazin-1-yl)-piperazin-1-yl]-N-cyclohexylmethyl-nicotinamide;

6-[4-(4-Benzyl-phthalazin-1-yl)-piperazin-1-yl]-N-propyl-nicotinamide;

{6-[4-(4-Benzyl-phthalazin-1-yl)-piperazin-1-yl]-pyridin-3-yl}-(3-hydroxy-pyrrolidin-1-yl)-methanone;

{6-[4-(4-Benzyl-phthalazin-1-yl)-piperazin-1-yl]-pyridin-3-yl}-thiazolidin-3-yl-methanone;

{6-[4-(4-Benzyl-phthalazin-1-yl)-piperazin-1-yl]-pyridin-3-yl}-(1-oxo-1lambda*4*-thiazolidin-3-yl)-methanone;

({6-[4-(4-Benzyl-phthalazin-1-yl)-piperazin-1-yl]-pyridine-3-carbonyl}-amino)-acetic acid methyl ester;

1-Benzyl-4-[4-(4-trifluoromethyl-phenyl)-piperazin-1-yl]-phthalazine;

6-{4-[4-(3-Trifluoromethyl-benzyl)-phthalazin-1-yl]-piperazin-1-yl}-nicotinonitrile;

6-{4-[4-(4-Cyano-benzyl)-phthalazin-1-yl]-piperazin-1-yl}-nicotinonitrile;

6-{4-[4-(3,4-Dimethoxy-benzyl)-phthalazin-1-yl]-piperazin-1-yl}-nicotino-nitrile;

6-{4-[4-(4-Chloro-benzyl)-phthalazin-1-yl]-piperazin-1-yl}-nicotinonitrile;

6-{4-[4-(3-Chloro-benzyl)-phthalazin-1-yl]-piperazin-1-yl}-nicotinonitrile;

6-[4-(4-Phenethyl-phthalazin-1-yl)-piperazin-1-yl]-nicotinonitrile;

6-[4-(4-Naphthalen-2-ylmethyl-phthalazin-1-yl)-piperazin-1-yl]-nicotino-nitrile;

6-{4-[4-(4-Trifluoromethyl-benzyl)-phthalazin-1-yl]-piperazin-1-yl}-nicotinonitrile;

6-{4-[4-(4-Methoxy-benzyl)-phthalazin-1-yl]-piperazin-1-yl}-nicotinonitrile;

6-{4-[4-(3-Cyano-benzyl)-phthalazin-1-yl]-piperazin-1-yl}-nicotinonitrile;

6-{4-[4-(4-Bromo-benzyl)-phthalazin-1-yl]-piperazin-1-yl}-nicotinonitrile;

6-{4-[4-(3-Bromo-benzyl)-phthalazin-1-yl]-piperazin-1-yl}-nicotinonitrile;

6-{4-[4-(1-Phenyl-ethyl)-phthalazin-1-yl]-piperazin-1-yl}-nicotinonitrile;

6-{4-[4-(4-Methyl-benzyl)-phthalazin-1-yl]-piperazin-1-yl}-nicotinonitrile;

N-{6-[4-(4-Benzyl-phthalazin-1-yl)-piperazin-1-yl]-pyridin-3-ylmethyl}-acetamide;

C-{6-[4-(4-Benzyl-phthalazin-1-yl)-piperazin-1-yl]-pyridin-3-yl}-methyl-amine;

4-[4-(4-Pyridin-4-ylmethyl-phthalazin-1-yl)-piperazin-1-yl]-benzylamine;

4-[4-(4-Benzyl-phthalazin-1-yl)-piperazin-1-yl]-benzylamine;

4-[5-({6-[4-(4-Benzyl-phthalazin-1-yl)-piperazin-1-yl]-pyridin-3-ylmethyl}-carbamoyl)-pentyl]-8-ethyl-3,8,9,10-tetrahydro-2H-1,6,11-trioxa-8,13-diaza-4-azonia-pentacene;

N-{4-[4-(4-Benzyl-phthalazin-1-yl)-piperazin-1-yl]-benzyl}-acetamide;

N-{4-[4-(4-Pyridin-4-ylmethyl-phthalazin-1-yl)-piperazin-1-yl]-benzyl}-acetamide;

{4-[4-(4-Benzyl-phthalazin-1-yl)-piperazin-1-yl]-benzyl}-carbamic acid benzyl ester;

{4-[4-(4-Pyridin-4-ylmethyl-phthalazin-1-yl)-piperazin-1-yl]-benzyl}-carbamic acid benzyl ester;

N-{4-[4-(4-Benzyl-phthalazin-1-yl)-piperazin-1-yl]-benzyl}-propionamide;

N-{4-[4-(4-Benzyl-phthalazin-1-yl)-piperazin-1-yl]-benzyl}-2-methoxy-acetamide;

N-{4-[4-(4-Benzyl-phthalazin-1-yl)-piperazin-1-yl]-benzyl}-3-methyl-butyramide;

6-[4-(1-Benzyl-isoquinolin-4-yl)-piperazin-1-yl]-nicotinonitrile;

6-{4-[1-(3-Cyano-benzyl)-isoquinolin-4-yl]-piperazin-1-yl}-nicotinonitrile;

6-{4-[1-(3-Chloro-benzyl)-isoquinolin-4-yl]-piperazin-1-yl}-nicotinonitrile;

6-{4-[1-(3-Trifluormethyl-benzyl)-isoquinolin-4-yl]-piperazin-1-yl}-nicotinonitrile;

6-[4-(4-Benzyl-isoquinolin-1-yl)-piperazin-1-yl]-nicotinonitrile;

4-{4-[6-(4-Fluoro-benzyl)-4-methyl-pyridazin-3-yl]-piperazin-1-yl}-benzo-nitrile;

4-{4-[6-(4-Fluoro-benzyl)-5-methyl-pyridazin-3-yl]-piperazin-1-yl}-benzo-nitrile;

4-{4-[6-(4-Benzyl)-4-methyl-pyridazin-3-yl]-piperazin-1-yl}-nicotinonitrile;

4-{4-[6-(4-Benzyl)-5-methyl-pyridazin-3-yl]-piperazin-1-yl}-nicotinonitrile;

6-Benzyl-4-methyl-3-[4-(5-trifluoromethyl-pyridin-2-yl)-piperazin-1-yl]-pyridazine;

6-Benzyl-5-methyl-3-[4-(5-trifluoromethyl-pyridin-2-yl)-piperazin-1-yl]-pyridazine;

6-(4-Fluoro-benzyl)-4-methyl-3-[4-(5-trifluoromethyl-pyridin-2-yl)-piperazin-1-yl]-pyridazine;

6-(4-Fluoro-benzyl)-5-methyl-3-[4-(5-trifluoromethyl-pyridin-2-yl)-piperazin-1-yl]-pyridazine;

4-{4-[6-(4-chloro-benzyl)-4-methyl-pyridazin-3-yl]-piperazin-1-yl}-nicotinonitrile;

4-{4-[6-(4-chloro-benzyl)-5-methyl-pyridazin-3-yl]-piperazin-1-yl}-nicotinonitrile;

4-{4-[6-(4-Fluoro-benzyl)-4,5-dimethyl-pyridazin-3-yl]-piperazin-1-yl}-nicotinonitrile;

4-{4-[4-(4-fluoro-benzyl)-5,6,7,8-tetrahydro-phthalzin-1-yl]-piperazin-1-yl}-nicotinonitrile;

6-{4-[4-(4-Fluoro-benzyl)-6,7-dihydro-5H-cyclopenta[d]pyridazin-1-yl]-piperazin-1-yl}-nicotinonitrile;

3-{4-[1-(4-Fluoro-benzyl)-1H-indol-3-yl]-piperidine-1-carbonyl}-benzo-nitrile;

4-[1-(4-Fluoro-benzyl)-1H-indol-3-yl)-5′

-trifluoromethyl-3,4,5,6-tetra-hydro-2H-[1,2]-bipyridinyl;

4-[3-(5′

-Trifluoromethyl-3,4,5,6-tetrahydro-2H-[1,2]bipyridinyl-4-yl)-indol-1-ylmethyl]-benzonitrile;

4-[1-Benzyl-1H-indol-3-yl)-5′

-trifluoromethyl-3,4,5,6-tetra-hydro-2H-[1,2]-bipyridinyl;

4-[1-(4-Fluoro-benzyl)-1H-indol-3-yl]-3,4,5,6-tetrahydro-2H-[1,2]bipyridinyl-5′

-carbonitrile;

4-[1-(4-Bromo-benzyl)-1H-indol-3-yl)-5′

-trifluoromethyl-3,4,5,6-tetra-hydro-2H-[1,2]-bipyridinyl;

4-(1-Benzyl-1H-indol-3-yl)-3,4,5,6-tetrahydro-2H-[1,2]bipyridinyl-5′

-carbonitrile;

{4-[1-(4-Fluoro-benzyl)-1H-indol-3-yl]-piperidin-1-yl}-(3-fluoro-phenyl)-methanone;

4-{4-[1-(4-Fluoro-benzyl)-1H-indol-3-yl]-piperidine-1-carbonyl}-benzonitrile;

3-{4-[1-(4-Fluoro-benzyl)-1H-indol-3-yl]-piperidine-1-carbonyl}-benzonitrile;

{4-[1-(4-Fluoro-benzyl)-1H-indol-3-yl]-piperidin-1-yl}-(4-trifluoromethyl-phenyl)-methanone;

or {4-[1-Benzyl-1H-indol-3-yl]-piperidin-1-yl}-(4-trifluoromethyl-phenyl)-methanone.