Benzothiazole and benzooxazole derivatives and methods of use

View Patent ↗

Loading inventors, assignments & file history…

Monitor This Case

Get email alerts when status or documents change.

Order Certified Copies

Most orders are placed with the USPTO same day — all within 24 business hours.

Order via The Patent Place →

Pre-filled with this patent's details

Quick Facts

Patent No.: US 8,153,813
App. No.: 12/337,433
Granted: Apr 10, 2012
Kind: B2

External Links

USPTO Patent Center↗ Full Patent PDF↗

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 (107)

1. A compound of formula:

or a pharmaceutically acceptable salt, ester, or amide-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 a group of the formula -L-R 6 or a group of -L 2a -R 6a -L 2b -R 6b ;

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 )(R 14b ), 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 );

R 4 and R 5 are each independently selected from alkyl, fluoroalkyl, hydroxyalkyl, alkoxyalkyl, and cycloalkyl; or 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 an unsubstituted or substituted group selected from aryl, a 5- to 6-membered heteroaryl ring, an 8- to 12-membered bicyclic heteroaryl ring, and a 4- to 12-membered heterocyclic ring containing two, three, four, or five heteroatoms;

R 6a is an unsubstituted or substituted group selected from a divalent 5- to 6-membered heteroaryl ring, a divalent cyanophenyl, a divalent 8- to 12-membered bicyclic heteroaryl ring, and a divalent 4- to 12-membered heterocyclic ring containing two, three, four, or five heteroatoms:

R 6b is hydrogen or an unsubstituted or substituted group selected from a 5- to 6-membered heteroaryl ring, an aryl ring, an 8- to 12-membered bicyclic heteroaryl ring, and a 4- to 12-membered heterocyclic ring;

L, L 2a , L 2b are each independently selected from a bond, —O—, alkylene, —C(═O )—, —S—, —SO 2 N(R 14a )—, —N(R 14a )SO 2 —, and —C(O)N(R 14a );

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

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, alkoxycarbonyl, cycloalkyl, and formyl:

wherein, when substituted, aryl and heteroaryl rings are substituted with one or more 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, 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 )and;

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 1 is -L-R 6 , wherein L is a bond and R 6 is as defined in claim 1 .

3. The compound of claim 1 wherein R 6 is an unsubstituted or substituted group selected from furyl, imidazolyl, imidazolidin-2-onyl, isoxazolyl, isothiazolyl, oxazolyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridinyl, pyrimidinyl, pyrrolyl, tetrazolyl, thiadiazolyl, thiadiazolonyl, thiadiazinonyl, oxadiazolyl, oxadiazolonyl, oxadiazinonyl, oxazolidin-2-onyl, thiazolyl, thienyl, triazinyl, triazolyl, pyridazinonyl, pyridonyl, pyrimidinonyl, indolyl, benzothienyl, benzofuranyl, indazolyl, benzimidazolyl, benzothiazolyl, benzoxazolyl, benzoisothiazolyl, benzoisoxazolyl, quinolinyl, isoquinolinyl, quinazolinyl, quinoxalinyl, phthalazinyl, pteridinyl, purinyl, naphthyridinyl, cinnolinyl, thieno[2,3-d]imidazole, pyrrolopyrimidinyl, morpholinyl, piperazinyl, dihydrothiazolyl, thiomorpholinyl, dioxanyl, dithianyl, [1,3]dioxolanyl, quinazolin-4-onyl, and phenyl.

4. The compound of claim 3 , wherein R 6 is a group selected from cyanophenyl, pyrazolyl, pyrimidinyl, pyrimidinonyl, pyridinyl, pyridazinonyl, imidazolidin-2-onyl, oxazolidin-2-onyl, pyridazinyl, thiazolyl, morpholinyl, and quinazolin-4-onyl, wherein each group is substituted with 0, 1, or 2 substituents selected from hydroxy, methoxy, oxo, amido, alkoxycarbonyl, carboxy, haloalkyl, and methyl.

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

6. The compound of claim 1 , wherein R 4 and R 5 taken together with the nitrogen atom to which each is attached form a non-aromatic ring of formula (a) or formula (b) that is a 4- to 9-membered non-aromatic ring.

7. 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, and wherein each ring is substituted with 0, 1, or 2 substituents selected from alkyl, hydroxyalkyl, and fluoroalkyl.

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