Benzothiazole and benzooxazole derivatives and methods of use

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Quick Facts

Patent No.: US 8,580,968
App. No.: 13/410,206
Granted: Nov 12, 2013
Kind: B2

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Abstract

Compounds of formula (I) are useful in treating conditions or disorders prevented by or ameliorated by histamine-3 receptor ligands. Also disclosed are pharmaceutical compositions of compounds of formula (I), methods for using such compounds and compositions, and a process for preparing the compounds.

Claims (51)

1. A compound of formula:

or a pharmaceutically acceptable salt, ester, amide, or radiolabelled form thereof, wherein:

Z is sulfur;

n is an integer from 0 to 2;

p is an integer from 0 to 1;

one of R 1 and R 2 is (NR A R B )carbonyl- or a group of the formula -L—R 6 ;

the other of R 1 and R 2 is selected from hydrogen, chloro, cyano, alkoxy, alkoxyalkyl, alkyl, alkylthio, cycloalkyl, fluoro, fluoroalkyl, fluoroalkoxy, hydroxyalkoxy, —SO 2 N(R 14a ) and —N(R 14a )SO 2 (R 14b );

R 3a and R 3b are each independently selected from hydrogen, cyano, halogen, alkyl, cycloalkyl, fluoroalkyl, alkoxy, alkoxyalkyl, fluoroalkoxy, alkylthio, —SO 2 N(R 14a )(R 14b ), and —N(R 14a )SO 2 (R 14b ); N(R 14a )SO 2 (R 14b );

R 4 and R 5 taken together with the nitrogen atom to which each is attached form a non-aromatic ring of the formula:

R 7 , R 8 , R 9 , and R 10 at each occurrence are each independently selected from hydrogen, hydroxyalkyl, fluoroalkyl, cycloalkyl, and alkyl;

R 11 , R 12 , R 13 , and R 14 are each independently selected from hydrogen, hydroxyalkyl, alkyl, and fluoroalkyl;

R x and R y at each occurrence are independently selected from the group consisting of hydrogen, hydroxy, hydroxyalkyl, alkyl, alkoxy, alkylamino, fluoro, and dialkylamino;

Q is selected from O and S;

m is an integer from 1 to 5;

R 6 is a 4- to 12-membered heterocyclic ring;

L is selected from a bond, —O—, alkylene, —C(═O)—, —S—, —SO 2 N(R 14a )SO 2 —,—C(O)N(R 14a ), —N (R 14a )C(O)—, and —N (R 15 )—;

R 14a and R 14b each independently selected at each occurrence from hydrogen, alkyl, and cycloalkyl;

R 15 is selected from hydrogen, alkyl, acyl, alkoxycarbonyl and (R 14a )(R 14b )NC(O)—;

R 16a , R 16b , R 17a , R 17b , R 18a ,R 18b , R 19a , and R 19b are independently selected at each occurrence from hydrogen and lower alkyl; and

R A and R B are independently selected from hydrogen, alkyl, haloalkyl, hydroxyalkyl, alkoxycarbonyl, cycloalkyl, and formyl;

wherein, when substituted, heterocyclic rings are substituted with 0, 1, 2, 3, 4, 5, 6, 7, 8 or 9 substituents selected from acyl, acyloxy, alkenyl, alkoxy, alkoxyalkoxy, alkoxyalkyl, alkoxycarbonyl, alkoxyimino, alkoxysulfonyl, alkyl, alkylcarbonyl, alkylsulfonyl, alkynyl, amido, carboxy, cyano, cycloalkyl, fluoroalkoxy, formyl, haloalkoxy, haloalkyl, halogen, hydroxy, hydroxyalkyl, mercapto, nitro, oxo, alkylthio, —NR A R B , (NR A R B )carbonyl-, —SO 2 N(R 14a )(R 14b ), and —N(R 14a )SO 2 (R 14b ).

2. The compound of claim 1 , wherein R 3a and R 3b are hydrogen.

3. The compound of claim 1 , wherein R 4 and R 5 are taken together with the nitrogen atom to which each is attached to form a ring selected from azepanyl, azetidinyl, azocanyl, morpholinyl, piperidinyl and pyrrolidinyl, wherein each ring is substituted with 0, 1, or 2 substituents selected from alkyl, hydroxyalkyl, and fluoroalkyl.

4. The compound of claim 1 , wherein the compound has the formula (II):