Aryl-substituted dihydroquinolinones, their preparation and their use as pharmaceuticals

Abstract

This application relates to aryl-substituted dihydroquinolinones of formula (I), compositions comprising them and their uses in the treatment of diseases and conditions in which inhibition of a bromodomain is indicated. For example, the application relates to aryl-substituted dihydroquinolinones and to their use as bromodomain inhibitors. The present application is also related to the treatment or prevention of proliferative disorders, auto-immune disorders, inflammatory disorders, dermal disorders, and neoplasms, including tumors and/or cancers.

1 . A compound of formula (I): 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt, solvate, ester or prodrug thereof, 
       wherein:
 A is —CH 2 — or oxygen; 
 R 1  is hydrogen or methyl; 
 R 2  and R 5  independently represent hydrogen, halogen, —CH 3 , —C(R a )(R b )(R c ), —N(R d )(R e ) or —O(R f ); 
 wherein
 R a  is hydrogen or C 1 -C 6  alkyl; 
 R b  is hydrogen, hydroxyl or C 1 -C 6  alkyl; 
 R c  is C 3 -C 6  cycloalkyl, C 6 -C 10  aryl, 3-7 membered heterocycloalkyl, 5-10 membered heteroaryl, (C 3 -C 6  cycloalkyl)C 1 -C 6  alkyl, (3-7 membered heterocycloalkyl)C 1 -C 6  alkyl, (C 6 -C 10  aryl)C 1 -C 6  alkyl or (5-10 membered heteroaryl)C 1 -C 6  alkyl, —O(R g ) or —N(R g )(R h ); 
 R d  is hydrogen or C 1 -C 6  alkyl; 
 R e  is C 1 -C 6  alkyl, C 3 -C 6  cycloalkyl, C 6 -C 10  aryl, 3-7 membered heterocycloalkyl, 5-10 membered heteroaryl, (C 3 -C 6  cycloalkyl)C 1 -C 6  alkyl, (3-7 membered heterocycloalkyl)C 1 -C 6  alkyl, (C 6 -C 10  aryl)C 1 -C 6  alkyl, (5-10 membered heteroaryl)C 1 -C 6  alkyl, keto(C 6 -C 10  aryl) or keto(5-10 membered heteroaryl); 
 R f  is C 1 -C 6  alkyl, C 3 -C 6  cycloalkyl, 3-7 membered heterocycloalkyl, C 6 -C 10  aryl, 5-10 membered heteroaryl, (C 3 -C 6  cycloalkyl)C 1 -C 6  alkyl, (3-7 membered heterocycloalkyl)C 1 -C 6  alkyl, (C 6 -C 10  aryl)C 1 -C 6  alkyl or (5-10 membered heteroaryl)C 1 -C 6  alkyl; 
 R g  is C 1 -C 6  alkyl, C 3 -C 6  cycloalkyl, C 6 -C 10  aryl, 3-7 membered heterocycloalkyl, 5-10 membered heteroaryl, (C 3 -C 6  cycloalkyl)C 1 -C 6  alkyl, (3-7 membered heterocycloalkyl)C 1 -C 6  alkyl, (C 6 -C 10  aryl)C 1 -C 6  alkyl or (5-10 membered heteroaryl)C 1 -C 6  alkyl; 
 R h  is hydrogen, C 1 -C 4  alkyl, —C(O)(R 6 ); —C(O)NH 2 , —C(O) NH (R 6 ) or —C(O)N(R 6 ) (R 6 ′); 
 
 one of R 3  and R 4  represents a group of formula (II), provided that when R 3  is a group of formula (II), then R 4  has the same definition than R 2  and R 5 , and when R 4  is a group of formula (II), then R 3  has the same definition than R 2  and R 5 ; 
 the group of formula (II) has the following structure: 
 
       
         
           
           
               
               
           
         
         wherein:
 X 1 , X 2  and X 3  are each independently N or C, wherein when X 1 , X 2  or X 3  is N, then the R 7 , R 8  or R 10  attached thereto is absent, provided that at least two of X 1 , X 2  and X 3  are C; 
 R 7  and R 10  are each independently hydrogen, halogen, CN, linear or branched C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, OR 6 , SR 6 , NHR 6 , N(R 6 )(R 6 ′), NHC(O)R 6  or N(R 6 )C(O)R 6′ ; 
 R 8  is halogen (such as F, Cl), CN, linear or branched C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, OR 6 , SR 6 , NHR 6 , N(R 6 )(R 6 ′), NHC(O)R 6  or N(R 6 )C(O)R 6′ ; 
 R 6  and R 6 ′, which are the same or different, represent a C 1 -C 6  alkyl group; 
 R 9  is a C 1 -C 3 alkyl or C 3 -C 5 cycloalkyl group; 
 
         each alkyl group is linear or branched and optionally substituted with 1 to 3 groups being halogen, CN, alkoxy or haloalkoxy, and each of cycloalkyl, aryl, heterocycloalkyl and heteroaryl is optionally substituted by 1 to 3 groups being halogen, CN, alkyl, haloalkyl, alkoxy or haloalkoxy; 
         and 
         when R 3  is the group of formula (II), one of R 2 , R 4  and R 5  is —C(R a )(R b )(R c ), —N(R d )(R e ) or —O(R f ) and the other two of R 2 , R 4  and R 5  are independently hydrogen, halogen or —CH 3 ; or 
         when R 4  is the group of formula (II), one of R 2 , R 3  and R 5  is —C(R a )(R b )(R c ), —N(R d )(R e ) or —O(R f ) and the other two of R 2 , R 3  and R 5  are independently hydrogen, halogen or —CH 3 . 
       
     
     
         2 . The compound of  claim 1 , wherein A is —CH 2 —. 
     
     
         3 . (canceled) 
     
     
         4 . The compound of  claim 1 , wherein R 1  is hydrogen or methyl. 
     
     
         5 . The compound of  claim 1 , wherein R 2 , R 3 , R 4  or R 5  represent —C(R a )(R b )(R c ), —C(R a )(R b )O(R c ), —C(R a )(R b )N(R g )(R h ), —N(R d )(R e ) or —O(R f ), wherein:
 R a  is H; 
 R b  is H or methyl; 
 R c  is a group benzyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, thienyl, furanyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolizinyl, purinyl, naphthyridinyl, pteridinyl, [1,3]dioxolane, pyrrolidinyl, pyrazolinyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, piperidinyl, piperazinyl, oxazolidinyl, isoxazolidinyl, morpholinyl, thiazolidinyl, isothiazolidinyl, tetrahydrofuryl or tetrahydropyranyl, each group R being optionally substituted by 1 to 3 groups being halogen, CN, alkyl, haloalkyl, alkoxy or haloalkoxy; 
 R d  is hydrogen or methyl; 
 R e  is a group cyclobutyl, cyclopentyl, cyclohexyl, phenyl, thienyl, furanyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolizinyl, purinyl, naphthyridinyl, pteridinyl, [1,3]dioxolane, pyrrolidinyl, pyrazolinyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, piperidinyl, piperazinyl, oxazolidinyl, isoxazolidinyl, morpholinyl, thiazolidinyl, isothiazolidinyl, tetrahydrofuryl, or tetrahydropyranyl, each of these groups being optionally substituted by 1 to 3 groups being halogen, CN, alkyl, haloalkyl, alkoxy or haloalkoxy, or R e  is a group —CH(R h )(C 3- C 6  aryl) or —CH(R h )(5-10 membered heteroaryl); 
 R f  is C 3 -C 6  cycloalkyl, C 6 -C 10  aryl, 3-10 membered heterocycloalkyl, 5-10 membered heteroaryl, —CH(R h )(C 3 -C 6  cycloalkyl), —CH(R h )(C 3 -C 6  aryl), —CH(R h )(3-7 membered heterocycloalkyl) or —CH(R h )(5-10 membered heteroaryl); 
 R g  is a group methyl, ethyl, propyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, thienyl, furanyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolizinyl, purinyl, naphthyridinyl, pteridinyl, [1,3]dioxolane, pyrrolidinyl, pyrazolinyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, piperidinyl, piperazinyl, oxazolidinyl, isoxazolidinyl, morpholinyl, thiazolidinyl, isothiazolidinyl, tetrahydrofuryl or tetrahydropyranyl, each group R g  being optionally substituted by 1 to 3 groups being halogen, CN, alkyl, haloalkyl, alkoxy or haloalkoxy; 
 R h  is hydrogen, linear or branched C 1 -C 4  alkyl or —(CO)R 6  with R 6  being a C 1 -C 3  alkyl group; and 
 wherein each of cycloalkyl, heterocycloalkyl, aryl and heteroaryl is optionally substituted by 1 to 3 groups being halogen, CN, alkyl, haloalkyl, alkoxy or haloalkoxy. 
 
     
     
         6 . The compound of  claim 1 , wherein R 2 , R 3 , R 4  or R 5  represent —C(R a )(R b )(R c ), —C(R a )(R b )O(R g ), —C(R a )(R b )N(R g )(R h ), —N(R d )(R e ) or —O(R f ), wherein:
 R a  is H; 
 R b  is H or methyl; 
 R c  is a group phenyl, benzyl, piperidinyl, tetrahydropyranyl or pyridyl; 
 R d  is hydrogen or methyl; 
 R e  is cyclohexyl, phenyl, benzyl, pyridyl, tetrahydropyranyl, —CH 2 (pyridyl) or —CH(CH 3 )(pyridyl); 
 R f  is phenyl, cyclobutyl, cyclopentyl, cyclohexyl, benzyl, —CH 2 (pyridyl), —CH(CH 3 )(pyridyl), —CH 2 (pyrazinyl), —CH 2 (pyrimidinyl), —CH 2 (tetrahydropyranyl), —CH 2 (cyclopentyl), —CH 2 (cyclohexyl), —CH 2 (oxazolyl) or —CH 2 (thiazolyl); 
 R g  is ethyl, phenyl, cyclobutyl, cyclopentyl, cyclohexyl or tetrahydropyranyl; 
 R h  is hydrogen, methyl or acetyl; 
 wherein each of R c , R e , R f  and R g  is optionally substituted by a 1 to 3 groups being halogen, CN, C 1 -C 6  alkyl or C 1 -C 6  alkoxy. 
 
     
     
         7 . The compound of  claim 1 , wherein R 2 , R 3 , R 4  or R 5  represent a group: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         8 . The compound of  claim 1 , wherein R 2 , R 3 , R 4  or R 5  represent a group: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         9 . The compound of  claim 1 , wherein X 1 , X 2  and X 3  are all carbon atoms. 
     
     
         10 .- 11 . (canceled) 
     
     
         12 . The compound of  claim 1 , wherein R 9  is methyl, ethyl, n-propyl, isopropyl or cyclopropyl. 
     
     
         13 . The compound of  claim 9 , wherein R 7  and R 10  are each hydrogen atoms and R 8  is Cl, CN, NHR 6  or a substituted or unsubstituted C 1 -C 6 alkyl or C 3 -C 6 cycloalkyl group. 
     
     
         14 . (canceled) 
     
     
         15 . The compound of  claim 1 , having the following formula (IIIa), (IIIb) or (IIIc): 
       
         
           
           
               
               
           
         
         wherein A, R 1 , R 2 , R 3 , R 5 , R 7 , R 8 , R 9  and R 10  are as defined in  claim 1 , or a pharmaceutically acceptable salt, solvate, ester or prodrug thereof. 
       
     
     
         16 .- 18 . (canceled) 
     
     
         19 . The compound of  claim 1 , having the following formula (IVa), (IVb) or (IVc): 
       
         
           
           
               
               
           
         
         wherein A, R 1 , R 2 , R 4 , R 5 , R 7 , R 8 , R 9 , R 10  are as defined in  claim 1 , or a pharmaceutically acceptable salt, solvate, ester or prodrug thereof. 
       
     
     
         20 .- 25 . (canceled) 
     
     
         26 . The compound of  claim 1 , having the following formula (IIId), (IIIe) or (IIIf): 
       
         
           
           
               
               
           
         
         wherein A, R 1 , R 2 , R 3  and R 5  are as defined in  claim 1 , 
       
       or a pharmaceutically acceptable salt, solvate, ester or prodrug thereof. 
     
     
         27 . The compound of  claim 1 , having the following formula (IVd), (IVe) or (IVf): 
       
         
           
           
               
               
           
         
         wherein A, R 1 , R 2 , R 4  and R 5  are as defined in  claim 1 , 
       
       or a pharmaceutically acceptable salt, solvate, ester or prodrug thereof. 
     
     
         28 .- 31 . (canceled) 
     
     
         32 . The compound of  claim 1 , wherein the compound is selected from the following compounds: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         33 . The compound of  claim 32 , wherein the compound is selected from Compounds 1-29, 30-32, 34, 38, 39, 44, 46, 47, 48a, 48b, 52, 53, 54a, 54b, 55a, 55b, 57, 58, 61, 62, 67-73, 74a, 74b, 75-91, 92a, 92b and 93-101. 
     
     
         34 . A pharmaceutical composition, comprising a compound of  claim 1 , together with a pharmaceutically acceptable carrier, diluent or excipient. 
     
     
         35 .- 61 . (canceled) 
     
     
         62 . A method for treating a disease or condition for which a bromodomain inhibitor is indicated, which comprises administering to a subject in need thereof, a therapeutically effective amount of a compound according to  claim 1 . 
     
     
         63 .- 72 . (canceled) 
     
     
         73 . A method for the treatment of a disease or condition selected from auto-immune disorders, inflammatory disorders, dermal disorders, and neoplasms, which comprises administering to a subject in need thereof, a therapeutically effective amount of a compound according to  claim 1 . 
     
     
         74 .- 76 . (canceled) 
     
     
         77 . The method of  claim 73 , wherein the disease or condition is a neoplasm selected from bladder cancer, leukemia, lymphoma, brain cancer, central nervous system cancer, breast cancer, cervix cancer, colorectal cancer, colon cancer, kidney cancer, liver cancer, lung cancer, mesothelioma, ovarian cancer, pancreatic cancer, prostate cancer, skin cancer or gastric cancer. 
     
     
         78 .- 80 . (canceled)