Process for the preparation of tricyclic pi3k inhibitor compounds and methods for using the same for the treatment of cancer

Abstract

The present disclosure provides for methods for preparing tricyclic PI3K inhibitor compounds in high yield and purity in aqueous solvent systems.

What is claimed is: 
     
         1 . A process for preparing a compound of Formula III from a compound of Formula II in a reaction mixture according to the following reaction scheme: 
       
         
           
           
               
               
           
         
         the process comprising: 
         (i) forming a reaction mixture comprising the compound Formula II, organoboron-R 4 , the solvent system comprising at least 5 v/v % water, the base and the catalyst; 
         (ii) reacting the reaction mixture at a temperature of less than 100° C. to form a reaction product mixture comprising compound Formula III; and 
         (iii) isolating the compound Formula III, a stereoisomer, geometric isomer, tautomer, or a pharmaceutically acceptable salt thereof, from the reaction product mixture, 
         wherein 
         the catalyst comprises palladium and the reaction mixture comprises less than 0.05 equivalents of catalyst per equivalent of compound Formula II; 
         X 1  is S, O, N, NR 6 , CR 1 , C(R 1 ) 2 , or —C(R 1 ) 2 O—; 
         X 2  is C, CR 2  or N; 
         X 3  is C, CR 3  or N; 
         X 4  is halogen; 
         A is a 5, 6, or 7-membered carbocyclyl or heterocyclyl ring fused to X 2  and X 3 , optionally substituted with one or more R 5 , R 10  or R 15  groups; 
         R 6  is H, C 1 -C 12  alkyl, C 2 -C 8  alkenyl, C 2 -C 8  alkynyl, —(C 1 -C 12  alkylene)-(C 3 -C 12  carbocyclyl), —(C 1 -C 12  alkylene)(—C 2 -C 20  heterocyclyl), —(C 1 -C 12  alkylene)-C(═O)—(C 2 -C 20  heterocyclyl), (C 1 -C 12  alkylene)-(C 6 -C 20  aryl), and —(C 1 -C 12  alkylene)-(C 1 -C 20  heteroaryl), where alkyl, alkenyl, alkynyl, alkylene, carbocyclyl, heterocyclyl, aryl, and heteroaryl are optionally substituted with one or more groups independently selected from F, Cl, Br, I, —CH 3 , —CH 2 CH 3 , —C(CH 3 ) 3 , —CH 2 OH, —CH 2 CH 2 OH, —(CH 3 ) 2 OH, —CH 2 OCH 3 , —CN, —CO 2 H, —COCH 3 , —COC(CH 3 ) 3 , —CO 2 CH 3 , —CONH 2 , —CONHCH 3 , —CON(CH 3 ) 2 , —C(CH 3 ) 2 CONH 2 , —NO 2 , —NH 2 , —NHCH 3 , —N(CH 3 ) 2 , —NHCOCH 3 , —NHS(O) 2 CH 3 , —N(CH 3 )C(CH 3 ) 2 CONH 2 , —N(CH 3 )CH 2 CH 2 S(O) 2 CH 3 , ═O, —OH, —OCH 3 , —S(O) 2 N(CH 3 ) 2 , —SCH 3 , —S(O) 2 CH 3 , cyclopropyl, cyclobutyl, oxetanyl, morpholino, and 1,1-dioxo-thiopyran-4-yl; 
         R 1 , R 2 , and R 3  are independently selected from H, F, Cl, Br, I, —CH 3 , —CH 2 CH 3 , —C(CH 3 ) 3 , —CH 2 OH, —CH 2 CH 2 OH, —C(CH 3 ) 2 OH, —CH 2 OCH 3 , —CN, —CF 3 , —CO 2 H, —COCH 3 , —COC(CH 3 ) 3 , —CO 2 CH 3 , —CONH 2 , —CONHCH 3 , —CON(CH 3 ) 2 , —C(CH 3 ) 2 , —CONH 2 , —NO 2 , —NH 2 , —NHCH 3 , —N(CH 3 ) 2 , —NHCOCH 3 , —NHS(O) 2 CH 3 , —N(CH 3 )C(CH 3 ) 2 CONH 2 , —N(CH 3 )CH 2 CH 2 S(O) 2 CH 3 , ═O, —OH, —OCH 3 , —S(O) 2 N(CH 3 ) 2 , —SCH 3 , —S(O) 2 CH 3 , cyclopropyl, cyclobutyl, oxetanyl, morpholino, and 1,1-dioxo-thiopyran-4-yl; 
         R 4  is selected from C 6 -C 20  aryl, C 2 -C 20  heterocyclyl and C 1 -C 20  heteroaryl, each of which are optionally substituted with one or more groups independently selected from F, Cl, Br, I, —CH 3 , —CH 2 CH 3 , —CH(CH 3 ) 2 , —CH 2 CH(CH 3 ) 2 , —CH 2 CH 3 , —CH 2 CN, —CN, —CF 3 , —CH 2 OH, —CO 2 H, —CONH 2 , CONH(CH 3 ), —CON(CH 3 ) 2 , —NO 2 , —NH 2 , —NHCH 3 , —NHCOCH 3 , —OH, —OCH 3 , —OCH 2 CH 3 , —OCH(CH 3 ) 2 , —SH, —NHC(O)NHCH 3 , —NHC(O)NHCH 2 CH 3 , —NHS(O) 2 CH 3 , —N(CH 3 )C(O)OC(CH 3 ) 3 , —S(O) 2 CH 3 , benzyl, benzyloxy, morpholinyl, morpholinomethyl, and 4-methylpiperazin-1-yl; 
         Each R 5 , R 10  and R 15  is independently selected from C 1 -C 12  alkyl, C 2 -C 8  alkenyl, C 2 -C 8  alkynyl, —(C 1 -C 12  alkylene)-(C 3 -C 12  carbocyclyl), —(C 1 -C 12  alkylene)-(C 2 -C 20  heterocyclyl), —(C 1 -C 12  alkylene)-C(O)—(C 2 -C 20  heterocyclyl), —(C 1 -C 12  alkylene)-(C 6 -C 20  aryl), and —(C 1 -C 12  alkylene)-(C 1 -C 20  heteroaryl); or two geminal R 5 , R 10  and/or R 15  groups form a 3, 4, 5, or 6-membered carbocyclyl or heterocyclyl ring, where alkyl, alkenyl, alkynyl, alkylene, carbocyclyl, heterocyclyl, aryl, and heteroaryl are optionally substituted with one or more groups independently selected from F, Cl, Br, I, —CH 3 , —CH 2 CH 3 , —C(CH 3 ) 3 , —CH 2 OH, —CH 2 CH 2 OH, —C(CH 3 ) 2 OH, —CH 2 OCH 3 , —CN, —CH 2 F, —CHF 2 , —CF 3 , —CO 2 H, —COCH 3 , —COC(CH 3 ) 3 , —CO 2 CH 3 , —CONH 2 , —CONHCH 3 , —CON(CH 3 ) 2 , —C(CH 3 ) 2 CONH 2 , —NO 2 , —NH 2 , —NHCH 3 , —N(CH 3 ) 2 , —NH—COCH 3 , —NHS(O) 2 CH 3 , —N(CH 3 )C(CH 3 ) 2 CONH 2 , —N(CH 3 )CH 2 CH 2 S(O) 2 CH 3 , ═O, —OH, —OCH 3 , —S(O) 2 N(CH 3 ) 2 , —SCH 3 , —S(O) 2 CH 3 , cyclopropyl, cyclobutyl, oxetanyl, morpholino, and 1,1-dioxo-thiopyran-4-yl; and mor is selected from: 
       
       
         
           
           
               
               
           
         
         wherein mor is optionally substituted with one or more R 7  groups independently selected from F, Cl, Br, I, —CH 3 , —CH 2 CH 3 , —CH 2 CH 2 CH 3 , —CH(CH 3 ) 2 , —C(CH 3 ) 3 , —CH 2 OCH 3 , —CHF 2 , —CN, —CF 3 , —CH 2 OH, —CH 2 OCH 3 , —CH 2 CH 2 OH, —CH 2 C(CH 3 ) 2 OH, —CH(CH 3 )OH, —CH(CH 2 CH 3 )OH, —CH 2 CH(OH)CH 3 , —C(CH 3 ) 2 OH, —C(CH 3 ) 2 OCH 3 , —CH(CH 3 )F, —C(CH 3 )F 2 , —CH(CH 2 CH 3 )F, —C(CH 2 CH 3 ) 2 F, —CO 2 H, —CONH 2 , —CON(CH 2 CH 3 ) 2 , —COCH 3 , —CON(CH 3 ) 2 , —NO 2 , —NH 2 , —NHCH 3 , —N(CH 3 ) 2 , —NHCH 2 CH 3 , —NHCH(CH 3 ) 2 , —NHCH 2 CH 2 OH, —NHCH 2 CH 2 OCH 3 , —NHCOCH 3 , —NHCOCH 2 CH 3 , —NHCOCH 2 OH, —NHS(O) 2 CH 3 , —N(CH 3 )S(O) 2 CH 3 , ═O, —OH, —OCH 3 , —OCH 2 CH 3 , —OCH(CH 3 ) 2 , —SH, —NHC(O)NHCH 3 , —NHC(O)NHCH 2 CH 3 , —S(O)CH 3 , —S(O)CH 2 CH 3 , —S(O) 2 CH 3 , —S(O) 2 NH 2 , —S(O) 2 NHCH 3 , —S(O) 2 N(CH 3 ) 2 , and —CH 2 S(O) 2 CH 3 . 
       
     
     
         2 . The process of  claim 1 , wherein the solvent system further comprises at least one polar aprotic solvent selected from N-methylpyrrolidone, methyl isobutyl ketone, methyl ethyl ketone, tetrahydrofuran, dichloromethane, ethyl acetate, acetone, N,N-dimethylformamide, acetonitrile and dimethyl sulfoxide. 
     
     
         3 . The process of  claim 2 , wherein the ratio of water to the at least one polar aprotic solvent is from about 1:10 v/v to about 5:1 v/v, from about 1:1 v/v to about 1:10 v/v, or from about 1:3 v/v to about 1:7 v/v. 
     
     
         4 . The process of  claim 1 , wherein the solvent system comprises water and tetrahydrofuran. 
     
     
         5 . The process of  claim 2 , wherein the solvent system consists essentially of water and the at least one polar aprotic solvent. 
     
     
         6 . The process of  claim 1 , wherein the organoboron-R 4  is 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2 yl)-R 4 . 
     
     
         7 . The process of  claim 1 , wherein the base is selected from K 3 PO 4 , Cs 2 CO 3 , and KOH. 
     
     
         8 . The process of  claim 1 , wherein the base is K3PO 4 . 
     
     
         9 . The process of  claim 1 , wherein the equivalent ratio of base to compound Formula II is at least 1:1, from about 1:1 to about 3:1, or about 2:1. 
     
     
         10 . The process of  claim 1 , wherein the catalyst comprising palladium is selected from chloro(2-dicyclohexylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)[2-(2-aminoethyl) phenyl)]palladium(II) (“Pd Xphos”); 1,1′-bis(diphenylphosphino)ferrocene] dichloropalladium(II) complex with dichloromethane (“PdCl 2  dppf CH 2 Cl 2 ”); Bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II) (“Pd(amphos)Cl 2 ”); dichlorobis(di-tert-butylphenylphosphine)palladium(II) (“Pd 122”); PdCl 2 (PPh 3 ) 2 ; Pd(t-Bu) 3 ; Pd(PPh 3 ) 4 ; Pd(Oac)/PPh 3 ; Cl 2 Pd[(Pet 3 )]2; Pd(DIPHOS) 2 ; Cl 2 Pd(Bipy); [PdCl(Ph 2 PCH 2 PPh 2 )] 2 ; Cl 2 Pd[P(o-tol) 3 ] 2 ; Pd 2 (dba) 3 /P(o-tol) 3 ; Pd 2 (dba)/P(furyl) 3 ; Cl 2 Pd[P(furyl) 3 ] 2 ; Cl 2 Pd(PmePh 2 ) 2 ; Cl 2 Pd[P(4-F-Ph) 3 ] 2 ; Cl 2 Pd[P(C 6 F 6 ) 3 ] 2 ; Cl 2 Pd[P(2-COOH-Ph)(Ph) 2 ] 2 ; Cl 2 Pd[P(4-COOH-Ph)(Ph) 2 ] 2 ; palladium acetate, microencapsulated in a polyuria matrix, comprising 0.4 mmol/g Pd; palladium acetate and triphenylphosphine, microencapsulated in a polyuria matrix, comprising 0.4 mmol/g Pd and 0.3 mmol/g phosphorous; and palladium acetate and BINAP, microencapsulated in a polyuria matrix, comprising 0.4 mmol/g Pd. 
     
     
         11 . The process of  claim 10  wherein the catalyst comprising palladium is selected from chloro(2-dicyclohexylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)[2-(2-aminoethyl) phenyl)]palladium(II) and 1,1′-bis(diphenylphosphino)ferrocene] dichloropalladium(II) complex with dichloromethane, or is chloro(2-dicyclohexylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)[2-(2-aminoethyl) phenyl)]palladium(II). 
     
     
         12 . The process of  claim 1 , wherein the equivalent ratio of the catalyst comprising palladium to compound Formula II is between about 0.003:1 and 0.05:1, from about 0.003:1 to about 0.03:1 or from about 0.004:1 to about 0.02:1. 
     
     
         13 . The process of  claim 1 , wherein the catalyst is chloro(2-dicyclohexylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)[2-(2-aminoethyl) phenyl)]palladium(II) and the equivalent ratio of the catalyst comprising palladium to compound Formula II is from about 0.004:1 to about 0.015:1, from about 0.004:1 to about 0.01:1, from about 0.004:1 to about 0.007:1, or about 0.005:1. 
     
     
         14 . The process of  claim 1 , wherein the catalyst is chloro(2-dicyclohexylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)[2-(2-aminoethyl) phenyl)]palladium(II) or 1,1′-bis(diphenylphosphino)ferrocene] dichloropalladium(II) complex with dichloromethane and the equivalent ratio of the catalyst comprising palladium to compound Formula II is from about 0.005:1 to about 0.04:1, from about 0.005:1 to about 0.03:1, from about 0.01:1 to about 0.03:1, or about 0.02:1. 
     
     
         15 . The process of  claim 1 , wherein the reaction temperature is between about 40° C. and 100° C., from about 40° C. to about 90° C., from about 40° C. to about 80° C., from about 50° C. to about 80° C. or from about 55° C. to about 75° C. 
     
     
         16 . The process of  claim 1 , further comprising adding a polar protic solvent to the reaction product mixture to form an admixture comprising greater than 25 v/v % water and separating compound Formula III from the reaction product mixture by solid liquid separation. 
     
     
         17 . The process of  claim 16  wherein the polar protic solvent is selected from water, methanol, ethanol, isopropanol, n-propanol, and acetic acid. 
     
     
         18 . The process of  claim 17  wherein the polar protic solvent is water. 
     
     
         19 . The process of  claim 18  wherein the volume ratio of the solvent system to water added to the reaction product mixture is from about 1:5 v/v to about 5:1 v/v, from about 1:3 v/v to about 3:1 v/v, from about 1:2 v/v to about 2:1 v/v, from about 1:1.5 v/v to about 1.5:1 v/v, or about 1:1 v/v. 
     
     
         20 . The process of  claim 18 , further comprising adding compound Formula III seed crystals to admixture of the reaction product mixture and water.