Process for making tetracyclic heterocycle compounds

Abstract

The present invention is directed to a process for making Tetracyclic Heterocycle Compounds of Formula (I) and pharmaceutically acceptable salts thereof, wherein X 1 , X 2 , R 1 , R 2 and R 3 are defined above herein. The present invention is also directed to compounds that are useful as synthetic intermediates in the process of the invention.

1 . A compound having the structure: 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof, 
       wherein:
 X 1  and X 2  are each independently selected from Cl, Br, I, OTf, OTs, OMs or OBs; 
 R 1  represents up to 3 optional ring substituent groups, which can be the same or different and are selected from —C 1 -C 6  alkyl, halo, —OR 5 , —C(O)R 5 , —C(O) 2 R 5 , —NHC(O)R 5 , —C(O)N(R 5 ) 2 , —SR 5 , —C 1 -C 6  hydroxyalkyl, —C 1 -C 6  haloalkyl, —N(R 5 ) 2 , —S(O)R 5 , —S(O) 2 R 5 , —CN and —NO 2;    
 R 2  represents up to 3 optional ring substituent groups, which can be the same or different and are selected from —C 1 -C 6  alkyl, halo, —OR 5 , —C(O)R 5 , —C(O) 2 R 5 , —NHC(O)R 5 , —C(O)N(R 5 ) 2 , —SR 5 , —C 1 -C 6  hydroxyalkyl, —C 1 -C 6  haloalkyl, —N(R 5 ) 2 , —S(O)R 5 , —S(O) 2 R 5 , —CN and —NO 2 ; 
 R 3  is C 1 -C 6  alkyl, C 6 -C 10  aryl, 5 or 6-membered monocyclic heteroaryl or 9 or 10-membered bicyclic heteroaryl, wherein said C 6 -C 10  aryl group, said 5 or 6-membered monocyclic heteroaryl group and said 9 or 10-membered bicyclic heteroaryl group can each be optionally and independently substituted with up to 3 groups, each independently selected from C 1 -C 6  alkyl, C 3 -C 7  cycloalkyl, halo, —OR 5 , —C(O)R 5 , —C(O) 2 R 5 , —NHC(O)R 5  , —C(O)N(R 5 ) 2 , —SR 5 , —C 1 -C 6  hydroxyalkyl, —C 1 -C 6  haloalkyl, —N(R 5 ) 2 , —S(O)R 5 , —S(O) 2 R 5 , —CN and —NO 2 ; and 
 R 4  is selected from Br, Cl, I, —OTf, —OMs, —OTs, —OBs, and —OS(O) 2 R 5 ; and 
 each occurrence of R 5  is independently selected from H, —C 1 -C 6  alkyl, C 3 -C 7  cycloalkyl, C 6 -C 1o  aryl, 5 or 6-membered monocyclic heteroaryl and 9 or 10-membered bicyclic heteroaryl. 
 
     
     
         2 . The compound of  claim 1 , having the structure: 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof, 
       wherein:
 R 2  represents an optional ring substituent group, which is —C 1 -C 6  alkyl or halo; and 
 R 3  is C 6 -C 10  aryl or 5 or 6-membered monocyclic heteroaryl wherein said C 6 -C 10  aryl group and said 5 or 6-membered monocyclic heteroaryl can each be optionally and independently substituted with C 1 -C 6  alkyl, halo or C 3 -C 7  cycloalkyl. 
 
     
     
         3 . The compound of  claim 1 , having the structure: 
       
         
           
           
               
               
           
         
       
     
     
         4 . A compound having the structure: 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof, 
       wherein:
 X 1  and X 2  are each independently selected from Cl, Br, I, —OTf, —OTs, —OMs or —OBs; 
 IV is selected from H, acyl, —C(O)O—(C 1 -C 6  alkyl), an alkali metal cation, and any phenol protecting group; 
 R 1  represents up to 3 optional ring substituent groups, which can be the same or different and are selected from —C 1 -C 6  alkyl, halo, —OR 6 , —C(O)R 6 , —C(O) 2 R 6 , —NHC(O)R 6  , —C(O)N(R 6 ) 2 , —SR 6 , —C 1 -C 6  hydroxyalkyl, —C 1 -C 6  haloalkyl, —N(R 6 ) 2 , —S(O)R 6 , —S(O) 2 R 6 , —CN and —NO 2 ; 
 R 2  represents up to 3 optional ring substituent groups, which can be the same or different and are selected from —C 1 -C 6  alkyl, halo, —OR 6 , —C(O)R 6 , —C(O) 2 R 6 , —NHC(O)R 6  , —C(O)N(R 6 ) 2 , —SR 6 , —C 1 -C 6  hydroxyalkyl, —C 1 -C 6  haloalkyl, —N(R 6 ) 2 , —S(O)R 6 , —S(O) 2 R 6 , —CN and —NO 2 ; 
 R 3  is C 1 -C 6  alkyl, C 6 -C 10  aryl, 5 or 6-membered monocyclic heteroaryl or 9 or 10-membered bicyclic heteroaryl, wherein said C 6 -C 10  aryl group, said 5 or 6-membered monocyclic heteroaryl group and said 9 or 10-membered bicyclic heteroaryl group can each be optionally and independently substituted with one or more R 5  groups; and 
 R 4  is selected from Br, Cl, I, —OTf, —OMs, —OTs, —OBs, and —OS(O) 2 R 6 ; 
 each occurrence of R 5  is independently selected from C 1 -C 6  alkyl, C 3 -C 7  cycloalkyl, halo, —OR 6 , —C(O)R 6 , —C(O) 2 R 6 , —NHC(O)R 6 , —C(O)N(R 6 ) 2 , —SR 6 , —C 1 -C 6  hydroxyalkyl, —C 1 -C 6  haloalkyl, —N(R 6 ) 2 , —S(O)R 6 , —S(O) 2 R 6 , —CN and —NO 2 ; and 
 each occurrence of R 6  is independently selected from H, —C 1 -C 6  alkyl, C 3 -C 7  cycloalkyl, C 6 -C 10  aryl, 5 or 6-membered monocyclic heteroaryl and 9 or 10-membered bicyclic heteroaryl. 
 
     
     
         5 . A compound having the structure: 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof. 
     
     
         6 . A process for preparing a compound having the formula (I): 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof, 
       wherein said process comprises the steps:
 (A) contacting a compound of Formula (II): 
 
       
         
           
           
               
               
           
         
       
       with a compound of formula (IIIa):
   R 3 —CHO    (IIIa)
 
 
       or a compound of formula (IIIb):
   R 3 —CH═NR 5     (IIIb)
 
 
       in the presence of an acid and an optional dehydrating agent, in an organic solvent A for a time and at a temperature sufficient to form a compound of formula (IV): 
       
         
           
           
               
               
           
         
       
       and
 (B) contacting the compound of formula (IV) with a transition metal catalyst in the presence of a base, in an organic solvent B, for a time and at a temperature sufficient to form a compound of formula (I), 
 
       wherein:
 X 1  and X 2  are each independently selected from Cl, Br, I, OTf, OTs, OMs or OBs; 
 R 1  represents up to 3 optional ring substituent groups, which can be the same or different and are selected from —C 1 -C 6  alkyl, halo, —OR 5 , —C(O)R 5 , —C(O) 2 R 5 , —NHC(O)R 5  , —C(O)N(R 5 ) 2 , —SR 5 , —C 1 -C 6  hydroxyalkyl, —C 1 -C 6  haloalkyl, —N(R 5 ) 2 , —S(O)R 5 , —S(O) 2 R 5 , —CN and —NO 2 ; 
 R 2  represents up to 3 optional ring substituent groups, which can be the same or different and are selected from —C 1 -C 6  alkyl, halo, —OR 5 , —C(O)R 5 , —C(O) 2 R 5 , —NHC(O)R 5  , —C(O)N(R 5 ) 2 , —SR 5 , —C 1 -C 6  hydroxyalkyl, —C 1 -C 6  haloalkyl, —N(R 5 ) 2 , —S(O)R 5 , —S(O) 2 R 5 , —CN and —NO 2 ; 
 R 3  is C 1 -C 6  alkyl , C 6 -C 10  aryl, 5 or 6-membered monocyclic heteroaryl or 9 or 10-membered bicyclic heteroaryl, wherein said C 6 -C 10  aryl group, said 5 or 6-membered monocyclic heteroaryl group and said 9 or 10-membered bicyclic heteroaryl group can each be optionally and independently substituted with up to three groups, each independently selected from C 1 -C 6  alkyl, C 3 -C 7  cycloalkyl, halo, —OR 5 , —C(O)R 5 , —C(O) 2 R 5 , —NHC(O)R 5  , —C(O)N(R 5 ) 2 , —SR 5 , —C 1 -C 6  hydroxyalkyl, —C 1 -C 6  haloalkyl, —N(R 5 ) 2 , —S(O)R 5 , —S(O) 2 R 5 , —CN and —NO 2 ; and 
 R 4  is selected from Br, Cl, I, —OTf, —OMs, —OTs, —OBs, and —OS(O) 2 R 5 ; and 
 each occurrence of R 5  is independently selected from H, —C 1 -C 6  alkyl, C 3 -C 7  cycloalkyl, C 6 -C 10  aryl, 5 or 6-membered monocyclic heteroaryl and 9 or 10-membered bicyclic heteroaryl. 
 
     
     
         7 . The process according to  claim 6 , wherein in step A, the compound of formula (II) is reacted with a compound of formula (IIIa). 
     
     
         8 . The process according to  claim 6 , wherein in step A, the compound of formula (II) is reacted with a compound of formula (IIIb). 
     
     
         9 . The process according to  claim 6 , wherein X 1  and X 2  are each —Cl. 
     
     
         10 . The process according to  claim 6 , wherein R 4  is —Br. 
     
     
         11 . The process according to  claim 6 , wherein
 the organic solvent A is selected from toluene, dichloromethane, benzene, tetrahydrofuran, ethyl acetate and acetonitrile;   the acid employed in Step A is trifluoroacetic acid or camphorsulfonic acid;   Step A is conducted at a temperature in a range of from about 0° C. to about 100° C.;   the organic solvent B is selected from toluene, dimethylacetamide, dioxane, acetonitrile, tetrahydrofuran, t-amyl alcohol, benzene, xylenes, N,N-dimethylformamide, dichlororomethane, water, dimethoxyethane, and mixtures thereof;   the transition metal catalyst employed in Step B, is selected from an organopalladium, organocopper, organonickel or organoiron compound that is bound to a chiral ligand;   the base employed in step B is selected from a carbonate base, a phosphate base, a fluoride base, an acetate base, a bicarbonate base and a hydroxide base; and   Step B is conducted at a temperature in a range of from about 0° C. to about 120° C.   
     
     
         12 . The process according to  claim 6 , wherein:
 the organic solvent A is toluene or dichloromethane;   the acid employed in Step A is trifluoroacetic acid or camphorsulfonic acid;   Step A is conducted at a temperature in a range of from about 25° C. to about 65° C.;   the organic solvent B is a mixture of water and either toluene or dimethoxyethane;   the transition metal catalyst employed in Step B, is an organopalladium compound that is bound to a chiral ligand;   the base employed in step B is a phosphate base and   Step B is conducted at a temperature in a range of from about 30° C. to about 70° C.   
     
     
         13 . The process according to  claim 6 , wherein:
 the organic solvent A is toluene or dichloromethane;   the acid employed in Step A is trifluoroacetic acid;   Step A is conducted at a temperature in a range of from about 0° C. to about 65° C.;   the organic solvent B is N,N-dimethylacetamide, toluene, or acetonitrile;   the transition metal catalyst employed in Step B, is an organocopper compound;   the base employed in step B is a carbonate base or a phosphate base; and   Step B is conducted at a temperature in a range of from about 25° C. to about 100° C.   
     
     
         14 . The process according to  claim 6 , wherein the base employed in step B is potassium phosphate and the ligand for the transition metal catalyst employed in Step B is: 
       
         
           
           
               
               
           
         
       
     
     
         15 . The process according to  claim 6 , wherein each occurrence of R 1  and R 2  is optionally and independently halo and R 3  is 5 or 6-membered heteroaryl or C 6 -C 1o  aryl, wherein R 3  can be optionally substituted with a group selected from C 1 -C 6  alkyl and C 3 -C 7  cycloalkyl. 
     
     
         16 . The process according to  claim 6 , wherein each occurrence of R 1  and R 2  is optionally and independently F, and R 3  is phenyl, thiophenyl or thiazolyl, wherein R 3  can be optionally substituted with a group selected from C 1 -C 6  alkyl and C 3 -C 7  cycloalkyl. 
     
     
         17 . The process according to  claim 6 , wherein the compound of formula (I) that is made is: