Aryl methyl benzoquinazolinone m1 receptor positive allosteric modulators

Abstract

The present invention is directed to benzoquinazilinone compounds of formula (I) which are M1 receptor positive allosteric modulators and that are useful in the treatment of diseases in which the M1 receptor is involved, such as Alzheimer's disease, schizophrenia, pain or sleep disorders. The invention is also directed to pharmaceutical compositions comprising the compounds, and to the use of the compounds and compositions in the treatment of diseases mediated by the M1 receptor.

What is claimed is: 
     
         1 - 62 . (canceled) 
     
     
         63 . A pharmaceutically acceptable salt of rac-3-[trans-2-hydroxycyclohexyl]-6-[(6-methylpyridin-3-yl)methyl]benzo[h]quinazolin-4(3H)-one, wherein the salt is selected from the group consisting of acetate, trifluoroacetate, benzenesulfonate, benzoate, camphorsulfonate, citrate, ethanesulfonate, fumarate, gluconate, glutamate, hydrobromide, hydrochloride, isethionate, lactate, maleate, malate, mandelate, methanesulfonate, mucate, nitrate, pamoate, pantothenate, phosphate, succinate, sulfate, tartrate, and para-toluenesolfonate. 
     
     
         64 . The salt according to  claim 63  which is selected from the group consisting of acetate, trifluoroacetate, fumarate, and hydrochloride. 
     
     
         65 . The salt according to  claim 63  which is selected from the group consisting of fumarate, and hydrochloride. 
     
     
         66 . A pharmaceutically acceptable salt of 3-[(1S,2S)-2-hydroxycyclohexyl]-6-[(6-methylpyridin-3-yl)methyl]benzo[h]quinazolin-4(3H)-one wherein the salt is selected from the group consisting of acetate, trifluoroacetate, benzenesulfonate, benzoate, camphorsulfonate, citrate, ethanesulfonate, fumarate, gluconate, glutamate, hydrobromide, hydrochloride, isethionate, lactate, maleate, malate, mandelate, methanesulfonate, mucate, nitrate, pamoate, pantothenate, phosphate, succinate, sulfate, tartrate, para-toluenesolfonate. 
     
     
         67 . The salt according to  claim 66  which is selected from the group consisting of acetate, trifluoroacetate, fumarate, and hydrochloride. 
     
     
         68 . The salt according to  claim 66  which is selected from the group consisting of fumarate, and hydrochloride. 
     
     
         69 . A pharmaceutically acceptable salt of rac-3-[trans-2-hydroxycyclohexyl]-6-[(6-methoxypyridin-3-yl)methyl]benzo[h]quinazolin-4(3H)-one wherein the salt is selected from the group consisting of acetate, trifluoroacetate, benzenesulfonate, benzoate, camphorsulfonate, citrate, ethanesulfonate, fumarate, gluconate, glutamate, hydrobromide, hydrochloride, isethionate, lactate, maleate, malate, mandelate, methanesulfonate, mucate, nitrate, pamoate, pantothenate, phosphate, succinate, sulfate, tartrate, and para-toluenesolfonate. 
     
     
         70 . The salt according to  claim 69  which is selected from the group consisting of acetate, trifluoroacetate, fumarate, and hydrochloride. 
     
     
         71 . The salt according to  claim 69  which is selected from the group consisting of fumarate, and hydrochloride. 
     
     
         72 . A pharmaceutically acceptable salt of 3-[(1S,2S)-2-hydroxycyclohexyl]-6-[(6-isopropylpyridin-3-yl)methylbenzo[h]quinazolin-4(3H)-one wherein the salt is selected from the group consisting of acetate, trifluoroacetate, benzenesulfonate, benzoate, camphorsulfonate, citrate, ethanesulfonate, fumarate, gluconate, glutamate, hydrobromide, hydrochloride, isethionate, lactate, maleate, malate, mandelate, methanesulfonate, mucate, nitrate, pamoate, pantothenate, phosphate, succinate, sulfate, tartrate, and para-toluenesolfonate. 
     
     
         73 . The salt according to  claim 72  which is selected from the group consisting of acetate, trifluoroacetate, fumarate, and hydrochloride. 
     
     
         74 . The salt according to  claim 72  which is selected from the group consisting of fumarate, and hydrochloride. 
     
     
         75 . A pharmaceutically acceptable salt of rac-3-[trans-2-hydroxycyclohexyl]-6-{[6-(hydroxymethyl)pyridine-3-yl]methyl}benzo[h]-quinazolin-4(3H)-one wherein the salt is selected from the group consisting of acetate, trifluoroacetate, benzenesulfonate, benzoate, camphorsulfonate, citrate, ethanesulfonate, fumarate, gluconate, glutamate, hydrobromide, hydrochloride, isethionate, lactate, maleate, malate, mandelate, methanesulfonate, mucate, nitrate, pamoate, pantothenate, phosphate, succinate, sulfate, tartrate, and para-toluenesolfonate. 
     
     
         76 . The salt according to  claim 75  which is selected from the group consisting of acetate, trifluoroacetate, fumarate, and hydrochloride. 
     
     
         77 . The salt according to  claim 75  which is selected from the group consisting of fumarate, and hydrochloride. 
     
     
         78 . A pharmaceutical composition which comprises a pharmaceutically acceptable carrier and pharmaceutically acceptable salt of rac-3-[trans-2-hydroxycyclohexyl]-6-[(6-methylpyridin-3-yl)methyl]benzo[h]quinazolin-4(3H)-one wherein the salt is selected from the group consisting of acetate, trifluoroacetate, benzenesulfonate, benzoate, camphorsulfonate, citrate, ethanesulfonate, fumarate, gluconate, glutamate, hydrobromide, hydrochloride, isethionate, lactate, maleate, malate, mandelate, methanesulfonate, mucate, nitrate, pamoate, pantothenate, phosphate, succinate, sulfate, tartrate, and para-toluenesolfonate. 
     
     
         79 . The composition according to  claim 78  wherein the salt is selected from the group consisting of acetate, trifluoroacetate, fumarate, and hydrochloride. 
     
     
         80 . The composition according to  claim 78  wherein the salt is selected from the group consisting of fumarate, and hydrochloride. 
     
     
         81 . A pharmaceutical composition which comprises a pharmaceutically acceptable carrier and pharmaceutically acceptable salt of 3-[(1S,2S)-2-hydroxycyclohexyl]-6-[(6-methylpyridin-3-yl)methyl]benzo[h]quinazolin-4(3H)-one wherein the salt is selected from the group consisting of acetate, trifluoroacetate, benzenesulfonate, benzoate, camphorsulfonate, citrate, ethanesulfonate, fumarate, gluconate, glutamate, hydrobromide, hydrochloride, isethionate, lactate, maleate, malate, mandelate, methanesulfonate, mucate, nitrate, pamoate, pantothenate, phosphate, succinate, sulfate, tartrate, and para-toluenesolfonate. 
     
     
         82 . The composition according to  claim 81  wherein the salt is selected from the group consisting of acetate, trifluoroacetate, fumarate, and hydrochloride. 
     
     
         83 . The composition according to  claim 81  wherein the salt is selected from the group consisting of fumarate, and hydrochloride. 
     
     
         84 . A pharmaceutical composition which comprises a pharmaceutically acceptable carrier and pharmaceutically acceptable salt of rac-3-[trans-2-hydroxycyclohexyl]-6-[(6-methoxypyridin-3-yl)methyl]benzo[h]quinazolin-4(3H)-one wherein the salt is selected from the group consisting of acetate, trifluoroacetate, benzenesulfonate, benzoate, camphorsulfonate, citrate, ethanesulfonate, fumarate, gluconate, glutamate, hydrobromide, hydrochloride, isethionate, lactate, maleate, malate, mandelate, methanesulfonate, mucate, nitrate, pamoate, pantothenate, phosphate, succinate, sulfate, tartrate, and para-toluenesolfonate. 
     
     
         85 . The composition according to  claim 84  wherein the salt is selected from the group consisting of acetate, trifluoroacetate, fumarate, and hydrochloride. 
     
     
         86 . The composition according to  claim 84  wherein the salt is selected from the group consisting of fumarate, and hydrochloride. 
     
     
         87 . A pharmaceutical composition which comprises a pharmaceutically acceptable carrier and pharmaceutically acceptable salt of 3-[(1S,2S)-2-hydroxycyclohexyl]-6-[(6-isopropylpyridin-3-yl)methylbenzo[h]quinazolin-4(3H)-one wherein the salt is selected from the group consisting of acetate, trifluoroacetate, benzenesulfonate, benzoate, camphorsulfonate, citrate, ethanesulfonate, fumarate, gluconate, glutamate, hydrobromide, hydrochloride, isethionate, lactate, maleate, malate, mandelate, methanesulfonate, mucate, nitrate, pamoate, pantothenate, phosphate, succinate, sulfate, tartrate, and para-toluenesolfonate. 
     
     
         88 . The composition according to  claim 87  wherein the salt is selected from the group consisting of acetate, trifluoroacetate, fumarate, and hydrochloride. 
     
     
         89 . The composition according to  claim 87  wherein the salt is selected from the group consisting of fumarate, and hydrochloride. 
     
     
         90 . A pharmaceutical composition which comprises a pharmaceutically acceptable carrier and pharmaceutically acceptable salt of rac-3-[trans-2-hydroxycyclohexyl]-6-{[6-(hydroxymethyl)pyridine-3-yl]methyl}benzo[h]-quinazolin-4(3H)-one wherein the salt is selected from the group consisting of acetate, trifluoroacetate, benzenesulfonate, benzoate, camphorsulfonate, citrate, ethanesulfonate, fumarate, gluconate, glutamate, hydrobromide, hydrochloride, isethionate, lactate, maleate, malate, mandelate, methanesulfonate, mucate, nitrate, pamoate, pantothenate, phosphate, succinate, sulfate, tartrate, and para-toluenesolfonate. 
     
     
         91 . The composition according to  claim 90  wherein the salt is selected from the group consisting of acetate, trifluoroacetate, fumarate, and hydrochloride.