6-substituted biaryl purine derivatives as potent cyclin/CDK inhibitors and antiproliferative agents

A compound of the following formula:

• 84
• R1 are the same or different and independently selected from:
• H;
• C1-C4-straight chain alkyl;
• C3-C4-branched chain alkyl;
• X=N;
• CH;
• R2=phenyl;
• substituted phenyl, wherein the substituents (1-2 in number) are in any position and independently selected from R1, OR1, SR1, S(O)R1, S(O2)R1, NHR1, NO2, OC(O)CH3, NHC(O)CH3, F, Cl, Br, CF3, C(O)R1, C(O)NHR1, phenyl, C(O)NHCHR1CH2OH;
• heterocycles including:
• 2-pyridyl;
• 3-pyridyl;
• 4-pyridyl;
• 5-pyrimidyl;
• thiophene-2-yl;
• thiophene-3-yl;
• 2-furanyl;
• 3-furanyl;
• 2-benzofuranyl;
• benzothiophene-2-yl;
• 2-pyrrolyl;
• 3-pyrrolyl;
• 2-quinolinyl;
• 3-quinolinyl;
• 4-quinolinyl;
• 1-isoquinolinyl;
• 3-isoquinolinyl;
• 4-isoquinolinyl;
• substituted heterocycle, wherein the substituents (1-2 in number) are in any position and are independently selected from Br, Cl, F, R1, C(O)CH3;
• Y=OR1;
• NHR1;
• NHC(O)R1;
• NHSO2R1;
• NHC(O)NHR1;
• NHC(O)OR6;
• or a pharmaceutically acceptable salt thereof,
• R6=C1-C4-straight chain alkyl;
• C3-C4-branched chain alkyl;
• C2-C4-alkenyl chain;
• or a pharmaceutically acceptable salt thereof.

A process for preparation of a purine derivative compound of the formula:

• 124
• R1 are the same or different and independently selected from:
• H;
• C1-C4-straight chain alkyl;
• C3-C4-branched chain alkyl;
• X=N;
• CH;
• R2=phenyl;
• substituted phenyl, wherein the substituents (1-2 in number) are in any position and are independently selected from R1, OR1, SR1, S(O)R1, S(O2)R1, NHR1, NO2, OC(O)CH3, NHC(O)CH3, F, Cl, Br, CF3, C(O)R1, C(O)NHR1, phenyl, C(O)NHCHRICH2OH;
• 1-naphthyl;
• 2-naphthyl;
• heterocycles including:
• 2-pyridyl;
• 3-pyridyl;
• 4-pyridyl;
• 5-pyrimidyl;
• thiophene-2-yl;
• thiophene-3-yl;
• 2-furanyl;
• 3-furanyl;
• 2-benzofuranyl;
• benzothiophene-2-yl;
• 2-pyrrolyl;
• 3-pyrrolyl;
• 2-quinolinyl;
• 3-quinolinyl;
• 4-quinolinyl;
• 1-isoquinolinyl;
• 3-isoquinolinyl;
• 4-isoquinolinyl;
• substituted heterocycle, wherein the substituents (1-2 in number) are in any position and are independently selected from Br, Cl, F, R1, C(O)CH3;
• R3 are the same or different and independently selected from:
• H;
• C1-C4-straight chain alkyl;
• C3-C4-branched chain alkyl;
• C2-C4-alkenyl chain;
• (CH2)nPh;
• (CH2)n-substituted phenyl, wherein the phenyl substituents are as defined above in R2;
• R4=H;
• C1-C4-straight chain alkyl;
• C3-C4-branched chain alkyl;
• R3 and R4 can be linked together by a carbon chain to form a 5-8-membered ring;
• n=0-3;
• Y=H;
• OR1;
• NHR1;
• NHC(O)R3;
• NHSO2R3;
• NHC(O)NHR3;
• NHC(O)R5;
• NHC(O)OR6;
• R5=C3-C7-cycloalkyl;
• R6=C1-C4-straight chain alkyl;
• C3-C4-branched chain alkyl;
• C2-C4-alkenyl chain;
• (CH2)nPh;
• (CH2)n-substituted phenyl, wherein the phenyl substituents are as defined above in R2;
• or a pharmaceutically acceptable salt thereof;
• with the proviso that when R1=CH(CH3)2, and R2=Ph, and X=CH, then R3≠H, and n≠0, and R4≠H, and Y≠OH, said process comprising:
• reacting a first intermediate compound of the formula:
• 125
• Z=Br or I
• with a compound of the formula:
• R2—B(OH)2, R2—Sn(n-Bu)3, R2—Sn(Me)3, or mixtures thereof, under conditions effective to form the purine derivative compound.

A process for preparation of a purine derivative compound of the formula

• 132
• R1 are the same or different and independently selected from:
• H;
• C1-C4-straight chain alkyl;
• C3-C4-branched chain alkyl;
• X—N;
• CH;
• R2=phenyl;
• substituted phenyl, wherein the substituents (1-2 in number) are in any position and are independently selected from R1, OR1, SR1, S(O)R1, S(O2)R1, NHR1, NO2, OC(O)CH3, NHC(O)CH3, F, Cl, Br, CF3, C(O)R1, C(O)NHR1, phenyl, C(O)NHCHR1CH2OH;
• 1-naphthyl;
• 2-naphthyl;
• heterocycles including:
• 2-pyridyl;
• 3-pyridyl;
• 4-pyridyl;
• 5-pyrimidyl;
• thiophene-2-yl;
• thiophene-3-yl;
• 2-furanyl;
• 3-furanyl;
• 2-benzofuranyl;
• benzothiophene-2-yl;
• 2-pyrrolyl;
• 3-pyrrolyl;
• 2-quinolinyl;
• 3-quinolinyl;
• 4-quinolinyl;
• 1-isoquinolinyl;
• 3-isoquinolinyl;
• 4-isoquinolinyl;
• substituted heterocycle, wherein the substituents (1-2 in number) are in any position and are independently selected from Br, Cl, F, R1, C(O)CH3;
• R3 are the same or different and independently selected from:
• H;
• C1-C4-straight chain alkyl;
• C3-C4-branched chain alkyl;
• C2-C4-alkenyl chain;
• (CH2)nPh;
• (CH2)n-substituted phenyl, wherein the phenyl substituents are as defined above in R2;
• R4=H;
• C1-C4-straight chain alkyl;
• C3-C4-branched chain alkyl;
• R3 and R4 can be linked together by a carbon chain to form a 5-8-membered ring;
• n=0-3;
• Y=H;
• OR1;
• NHR1;
• NHC(O)R3;
• NHSO2R3;
• NHC(O)NHR3;
• NHC(O)R5;
• NHC(O)OR6;
• R5=C3-C7-cycloalkyl;
• R6=C1-C4-straight chain alkyl;
• C3-C4-branched chain alkyl;
• C2-C4-alkenyl chain;
• (CH2)nPh;
• (CH2)n-substituted phenyl, wherein the phenyl substituents are as defined above in R2;
• or a pharmaceutically acceptable salt thereof;
• with the proviso that when R1=CH(CH3)2, and R2=Ph, and X=CH, then R3≠H, and n≠0, and R4≠H, and Y≠OH, said process comprising:
• reacting a first intermediate compound of the formula:
• 133
• with a compound of the formula:
• 134
• under conditions effective to form the purine derivative compound.