Flt3 receptor antagonists

Patent metadata

Field	Value
Publication number	US-2017233354-A1
Application number	US-201515500174-A
Country	US
Kind code	A1
Filing date	Jul 30, 2015
Priority date	Jul 31, 2014
Publication date	Aug 17, 2017
Grant date	—

Abstract

The invention pertains to novel FLT3 receptor antagonists of general formula (1). The compounds are useful for the treatment or the prevention of pain disorders, cancer and autoimmune diseases.

First claim

1 - 15 . (canceled)

16 . A method of treating chronic pain or neuropathic pain in a patient in need thereof comprising
administering to the patient a therapeutically effective amount of a compound of general formula (2)

wherein
X is selected from a bond, CO, NH, CONH, NHCO and a 5- or 6-member heteroaromatic group comprising 2 or 3 N atoms;
Y represents SO 2 ,
Q is selected from a group of formula:

R 1 is selected from halo, OR 11 , COO R 11 , 1H-tetrazolyl; PO 4 H 2 , amidino and N-hydroxyamidino
R 2 is selected from H, alkyl, halo, OR 11 and COR 11 ;
R 3 is selected from H, OR 11 , halo and O—(CH 2 ) p —O-alkyl;
R 4 is selected from H, alkyl, halo, CN, trifluoromethyl, CO-alkyl, phenyl and benzyl;
R 5 is H;
or R 1 is as defined above and two from R 2 and R 3 or R 3 and R 4 or R 4 and R 5 together with the carbon atoms to which they are attached form an aromatic ring comprising 5 to 6 members, and the others from R 2 to R 5 represent H;
R 6 is selected from H, OH, halo, alkyl, hydroxyalkyl and alkoxy,
or R 1 together with R 6 form a O or a NH chain;
R 7 is selected from H, alkyl, cycloalkyl, phenyl, benzyl, (CH 2 ) q —R 12 ,
R 8 is selected from H, alkyl, cycloalkyl, adamantyl, pyridyl, (CH 2 ) r —R 13 ,
or R 7 and R 8 together with the N atom to which they are attached form a group of formula:

wherein Z is a bond or Z is selected from CHR 14 , CH 2 CHR 14 , NR 14 , CH 2 NR 14 , and O,
R 10 is selected from H, alkyl, halo, trifluoromethyl, aryl and hydroxyalkyl,
or two adjacent R 10 groups together with the cyclic atoms to which they are attached form an aryl group; and

R 11 is H or alkyl;
R 12 is selected from OH, COOH, CO-alkyl, phenyl, morpholino, NH 2 , NH-alkyl, N-(alkyl) 2 NH(NH) NH 2 , CH 2 COO-alkyl,
R 13 is selected from OH, and phenyl;
R 14 is selected from H, alkyl, cycloalkyl, aryl, and arylalkyl, wherein the cycloalkyl or aryl ring may comprise one or two heteroatoms in the cyclic structure selected from N and O and may be substituted with one or more substituent selected from alkyl,
halo, cyano, amino, alkyl amino, dialkyamino, nitro, trifluoromethyl, aryl, alkyl-aryl, acyl, alkyloxy or aryloxy,
R 15 represents a group selected from H, halo, OH and alkoxy;
one of Q 1 and Q 2 is CH and the other NH;
Q 3 is selected from O, S, N and NH;
Q 4 is selected from C and N, and CO;
Q 5 is selected from C and N;
n is 0, 1 or 2;
p is 1, 2, 3 or 4;
g is 0, 1, 2, 3 or 4;
r is 0, 1, 2, 3 or 4;
s is 0, 1, 2 or 3;
or a pharmaceutically acceptable salt thereof.

17 . The method of claim 16 , wherein the compound is selected from the group consisting of:
N-(5-chloro-2-hydroxy-phenyl)-3-(1-piperidylsulfonyl)benzamide; N-(5-fluoro-2-hydroxy-phenyl)-3-(1-piperidylsulfonyl)benzamide; N-(5-bromo-2-hydroxy-phenyl)-3-(1-piperidylsulfonyl)benzamide; N-(2-hydroxy-5-phenyl-phenyl)-3-(1-piperidylsulfonyl)benzamide; N-(5-benzyl-2-hydroxy-phenyl)-3-(1-piperidylsulfonyl)benzamide; N-[2-hydroxy-5-(trifluoromethyl)phenyl]-3-(1-piperidylsulfonyl)benzamide; N-(5-cyano-2-hydroxy-phenyl)-3-(1-piperidylsulfonyl)benzamide; N-(5-acetyl-2-hydroxy-phenyl)-3-(1-piperidylsulfonyl)benzamide; N-[5-(1,1-dimethylpropyl)-2-hydroxy-phenyl]-3-(1-piperidylsulfonyl)benzamide; N-(2-hydroxy-4-methoxy-phenyl)-3-(1-piperidylsulfonyl)benzamide; N-(3-hydroxy-2-naphthyl)-3-(1-piperidylsulfonyl)benzamide; N-(2-hydroxy-1-naphthyl)-3-(1-piperidylsulfonyl)benzamide; 5-chloro-2-hydroxy-N-[3-(1-piperidylsulfonyl)phenyl]benzamide; N-(5-chloro-2-hydroxy-phenyl)-4-methyl-3-(1-piperidylsulfonyl)benzamide; N-(5-chloro-2-hydroxy-phenyl)-3-(dimethylsulfamoyl)benzamide; N-(5-chloro-2-hydroxy-phenyl)-3-(cyclohexylsulfamoyl)benzamide; 3-(azepan-1-ylsulfonyl)-N-(5-chloro-2-hydroxy-phenyl)benzamide; N-(5-chloro-2-hydroxy-phenyl)-3-[(2-methyl-1-piperidyl)sulfonyl]benzamide; N-(5-chloro-2-hydroxy-phenyl)-3-[(3-methyl-1-piperidyl)sulfonyl]benzamide; N-(5-chloro-2-hydroxy-phenyl)-3-[(4-methyl-1-piperidyl)sulfonyl]benzamide; 3-[(4-benzyl-1-piperidyl)sulfonyl]-N-(5-chloro-2-hydroxy-phenyl)benzamide; N-(5-chloro-2-hydroxy-phenyl)-3-[[4-(1-piperidyl)-1-piperidyl]sulfonyl]benzamide; N-(5-chloro-2-hydroxy-phenyl)-3-(4-methylpiperazin-1-yl)sulfonyl-benzamide; N-(5-chloro-2-hydroxy-phenyl)-3-(4-phenylpiperazin-1-yl)sulfonyl-benzamide; 3-(4-benzylpiperazin-1-yl)sulfonyl-N-(5-chloro-2-hydroxy-phenyl)benzamide; N-(5-chloro-1H-indol-7-yl)-3-(1-piperidylsulfonyl)benzamide; 5-chloro-3-[3-(1-piperidylsulfonyl)benzoyl]-1H-benzimidazol-2-one; 3-(1-adamantylsulfamoyl)-N-(5-chloro-2-hydroxy-phenyl)benzamide; N-(5-chloro-2-hydroxy-phenyl)-3-[cyclohexyl(methyl)sulfamoyl]benzamide; N-(5-chloro-2-hydroxy-phenyl)-3-[[2-(hydroxymethyl)-1-piperidyl]sulfonyl]benzamide; N-(5-chloro-2-hydroxy-phenyl)-3-(4-pyrimidin-2-ylpiperazin-1-yl)sulfonyl-benzamide; N-(5-chloro-2-hydroxy-phenyl)-3-[(3-phenyl-1-piperidyl)sulfonyl]benzamide; N-(5-chloro-2-hydroxy-phenyl)-3-[[3-(hydroxymethyl)-1-piperidyl]sulfonyl]benzamide; N-(5-chloro-2-hydroxy-phenyl)-3-pyrrolidin-1-ylsulfonyl-benzamide; N-(5-chloro-2-hydroxy-phenyl)-3-morpholinosulfonyl-benzamide; N-(5-chloro-2-hydroxy-phenyl)-3-indolin-1-ylsulfonyl-benzamide; N-(2-chlorophenyl)-3-(1-piperidylsulfonyl)benzamide; N-(2,5-dichlorophenyl)-3-(1-piperidylsulfonyl)benzamide; N-(5-chloro-2-fluoro-phenyl)-3-(1-piperidylsulfonyl)benzamide; N-(4-chloro-2-hydroxy-phenyl)-3-(1-piperidylsulfonyl)benzamide; 2-chloro-N-(5-chloro-2-hydroxy-phenyl)-5-(1-piperidylsulfonyl)benzamide; N-(5-chloro-2-hydroxy-phenyl)-2-fluoro-5-(1-piperidylsulfonyl)benzamide; N-(5-chloro-2-hydroxy-phenyl)-3-(cyclohexylsulfamoyl)-4-methyl-benzamide; N-(5-chloro-2-hydroxy-phenyl)-3-(2-pyridylsulfamoyl)benzamide; N-(5-chloro-2-hydroxy-phenyl)-2-methyl-5-(1-piperidylsulfonyl)benzamide; N-(4-hydroxy-3-pyridyl)-3-(1-piperidylsulfonyl)benzamide; 2-hydroxy-N-(2-hydroxyphenyl)-5-(1-piperidylsulfonyl)benzamide; N-(5-chloro-2-hydroxy-phenyl)-3-(2-phenylethylsulfamoyl)benzamide; N-(5-chloro-2-hydroxy-phenyl)-3-(4-phenylbutylsulfamoyl)benzamide; N-(5-chloro-2-hydroxy-phenyl)-3-(2-hydroxyethylsulfamoyl)benzamide; N-[3-(1-piperidylsulfonyl)phenyl]-1H-indazol-3-amine; 4-chloro-2-[2-[3-(1-piperidylsulfonyl)phenyl]-1H-imidazol-5-yl]phenol; 3-[benzyl(cyclohexyl)sulfamoyl]-N-(5-chloro-2-hydroxy-phenyl)benzamide; tert-butyl 2-[[3-[(5-chloro-2-hydroxy-phenyl)carbamoyl]phenyl]sulfonyl-cyclohexyl-amino]acetate; N-(5-chloro-2-hydroxy-phenyl)-3-[cyclohexyl(3-phenylpropyl)sulfamoyl]benzamide; N-(5-chloro-2-hydroxy-phenyl)-3-(4-hydroxybutylsulfamoyl)benzamide; 2-[[3-[(5-chloro-2-hydroxy-phenyl)carbamoyl]phenyl]sulfonyl-cyclohexyl-amino]acetic acid; 2-[3-(1-piperidylsulfonyl)phenyl]-3H-benzimidazol-4-ol; 3-[3-aminopropyl(cyclohexyl)sulfamoyl]-N-(5-chloro-2-hydroxy-phenyl)benzamide; N-(3-aminopropyl)-3-(5-chloro-1,3-benzoxazol-2-yl)-N-cyclohexyl-benzenesulfonamide; N-(5-chloro-2-hydroxy-phenyl)-3-[cyclohexyl(3-guanidinopropyl)sulfamoyl]benzamide; N-(4,5-dichloro-2-hydroxy-phenyl)-3-(1-piperidylsulfonyl)benzamide; 5-chloro-N-[3-(1-piperidylsulfonyl)phenyl]-1H-indazol-3-amine; N-(3-chloro-2-hydroxy-phenyl)-3-(1-piperidylsulfonyl)benzamide; 3-chloro-8-(1-piperidylsulfonyl)-5H-benzo[b][1,4]benzoxazepin-6-one; 3-chloro-8-(1-piperidylsulfonyl)-5,11-dihydrobenzo[b][1,4]benzodiazepin-6-one; 5-ch

Assignees

• Inserm (Institut Nat De Santé Et De La Rech Médicale)
• Univ Montpellier
• Centre Nat De La Rech Scient (Cnrs)
• Univ Strasbourg

Inventors

• Valmier Jean
• Leyris Jean-Philippe
• Rognan Didier
• Schmitt Martine

Classifications

• A61P35/00

  Antineoplastic agents · CPC title

• A61P37/02

  Immunomodulators · CPC title

• A61P3/10

  for hyperglycaemia, e.g. antidiabetics · CPC title

• A61P37/06

  Immunosuppressants, e.g. drugs for graft rejection · CPC title

• A61P29/00

  Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID] · CPC title