IP Library › Granted Patent US 6,969,720
Granted Patent B2
US 6,969,720 · App. 09/950,549 · Granted Nov 29, 2005

Biaryl substituted purine derivatives as potent antiproliferative agents

View Patent ↗
Loading inventors, assignments & file history…
Monitor This Case
Get email alerts when status or documents change.
Order Certified Copies
Most orders are placed with the USPTO same day — all within 24 business hours.
Order via The Patent Place →
Pre-filled with this patent's details
Quick Facts
Patent No.
US 6,969,720
App. No.
09/950,549
Granted
Nov 29, 2005
Kind
B2
Abstract

The compounds of the present invention are 2,6,9-trisubstituted purine derivatives which are inhibitors of cyclin/cdk complexes. The compounds of the current invention also are potent inhibitors of human cellular proliferation. As such, the compounds of the present invention constitute pharmaceutical compositions with a pharmaceutically acceptable carrier. Such compounds are useful in treating a disorder mediated by elevated levels of cell proliferation in a mammal compared to a healthy mammal by administering to such mammal an effective amount of the compound. Examples of the compounds of the present invention are represented by the following chemical structures: wherein: X=N; V=NH; O; S; or CH 2 ; A=CH 2 ; (CH 2 ) 2 ; (CH 2 ) 3 ; OCH 2 CH 2 ; or CHCH 3 ; and Y, R 1 , R 2 , R 3 , R 4 , and n 1 are defined herein.

Claims (948)

1. A compound of the following formula:

wherein:

R 1 are the same or different and independently selected from the group consisting of:

H;

C 1 -C 6 -straight chain alkyl;

C 2 -C 6 -straight alkenyl chain;

C 3 -C 6 -branched alkyl chain;

C 3 -C 6 -branched alkenyl chain;

C 3 -C 7 -cycloalkyl;

CH 2 —(C 3 -C 7 -cycloalkyl);

CH 2 CF 3 ;

CH 2 CH 2 CF 3 ; and

CH(CF 3 ) 2 ;

X=N;

V=NH;

O;

S; or

CH 2 ;

R 2 =phenyl;

substituted phenyl, wherein the substituents (1-2 in number) are in any position and are independently selected from the group consisting of R 1 , OR 1 , SR 1 , S(O)R 1 , S(O 2 )R 1 , NHR 1 , NO 2 , OC(O)CH 3 , NHC(O)CH 3 , F, Cl, Br, CF 3 , C(O)R 1 , C(O)NHR 1 , phenyl, and C(O)NHCHR 1 CH 2 OH;

1-naphthyl;

2-naphthyl;

heterocycles selected from the group consisting of:

2-pyridyl;

3-pyridyl;

4-pyridyl;

2-pyrimidyl;

4-pyrimidyl;

5-pyrimidyl;

thiophene-2-yl;

thiophene-3-yl;

2-furanyl;

3-furanyl;

oxazol-2-yl;

oxazol-4-yl;

oxazol-5-yl;

thiazol-2-yl;

thiazol-4-yl;

thiazol-5-yl;

imidazol-2-yl;

imidazol-4-yl;

pyrazol-3-yl;

pyrazol-4-yl;

isoxazol-3-yl;

isoxazol-4-yl;

isoxazol-5-yl;

isothiazol-3-yl;

isothiazol-4-yl;

isothiazol-5-yl;

1,3,4-thiadiazol-2-yl;

benzo[b]furan-2-yl;

benzo[b]thiophene-2-yl;

2-pyrrolyl;

3-pyrrolyl;

1,3,5-triazin-2-yl;

pyrazin-2-yl;

pyridazin-3-yl;

pyridazin-4-yl;

2-quinolinyl;

3-quinolinyl;

4-quinolinyl;

1-isoquinolinyl;

3-isoquinolinyl; and

4-isoquinolinyl; or

substituted heterocycle, wherein the heterocycle is as defined above and the substituents (1-2 in number) are in any position and are independently selected from the group consisting of Br, Cl, F, R 1 , and C(O)CH 3 ;

R 3 are the same or different and independently selected from the group consisting of:

H;

C 1 -C 4 -straight chain alkyl;

C 3 -C 4 -branched chain alkyl;

C 2 -C 4 -alkenyl chain;

(CH 2 ) n Ph; and

(CH 2 ) n -substituted phenyl, wherein the phenyl substituents are as defined above in R 2 ;

R 4 =H;

C 1 -C 4 -straight chain alkyl; or

C 3 -C 4 -branched chain alkyl;

R 3 and R 4 can be linked together by a carbon chain to form with intervening atoms a 5-8-membered saturated or unsaturated ring;

n 1 =0-3;

n=0-3;

A=CH 2 ;

(CH 2 ) 2 ;

(CH 2 ) 3 ;

OCH 2 CH 2 ; or

CHCH 3 ;

Y=H;

OR 1 ;

N(R 1 ) 2 ;

N(R 1 )C(O)R 3 ;

N(R 1 )C(O)R 5 ;

N(R 1 )C(O)CH(R 6 )NH 2 ;

N(R 1 )SO 2 R 3 ;

N(R 1 )C(O)NHR 3 ; or

N(R 1 )C(O)OR 6 ;

R 5 =C 3 -C 7 -cycloalkyl;

R 6 =C 1 -C 4 -straight chain alkyl;

C 3 -C 4 -branched chain alkyl;

C 2 -C 4 -alkenyl chain;

(CH 2 ) n Ph; or

(CH 2 ) n -substituted phenyl, wherein the phenyl substituents are as defined above in R 2 ;

or a pharmaceutically acceptable salt thereof;

with the proviso that the following conditions cannot all be true at the same time: R 3 =H, n=0, R 4 =H, and Y=OH.

2. A compound according to claim 1 , wherein

R 3 are the same or different and independently selected from the group consisting of:

H;

C 1 -C 4 -straight chain alkyl; and

C 3 -C 4 -branched chain alkyl;

Y=H;

OR 1 ;

N(R 1 ) 2 ;

N(R 1 )C(O)R 3 ;

N(R 1 )SOR 3 ; or

N(R 1 )C(O)NHR 3 .

3. A compound of the following formula:

wherein:

R 1 are the same or different and independently selected from the group consisting of:

H;

C 1 -C 6 -straight chain alkyl;

C 2 -C 6 -straight alkenyl chain;

C 3 -C 6 -branched alkyl chain;

C 3 -C 6 -branched alkenyl chain;

C 3 -C 7 -cycloalkyl;

CH 2 —(C 3 -C 7 -cycloalkyl);

CH 2 CF 3 ;

CH 2 CH 2 CF 3 ; and

CH(CF 3 ) 2 ;

X=N;

V=NH;

O;

S; or

CH 2 ;

R 2 =phenyl;

substituted phenyl, wherein the substituents (1-2 in number) are in any position and are independently selected from the group consisting of R 1 , OR 1 , SR 1 , S(O)R 1 , S(O 2 )R 1 , NHR 1 , NO 2 , OC(O)CH 3 , NHC(O)CH 3 , F, Cl, Br, CF 3 , C(O)R 1 , C(O)NHR 1 , phenyl, and C(O)NHCHR 1 CH 2 OH;

1-naphthyl;

2-naphthyl;

heterocycles selected from the group consisting of:

2-pyridyl;

3-pyridyl;

4-pyridyl;

2-pyrimidyl;

4-pyrimidyl;

5-pyrimidyl;

thiophene-2-yl;

thiophene-3-yl;

2-furanyl;

3-furanyl;

oxazol-2-yl;

oxazol-4-yl;

oxazol-5-yl;

thiazol-2-yl;

thiazol-4-yl;

thiazol-5-yl;

imidazol-2-yl;

imidazol-4-yl;

pyrazol-3-yl;

pyrazol-4-yl;

isoxazol-3-yl;

isoxazol-4-yl;

isoxazol-5-yl;

isothiazol-3-yl;

isothiazol-4-yl;

isothiazol-5-yl;

1,3,4-thiadiazol-2-yl;

benzo[b]furan-2-yl;

benzo[b]thiophene-2-yl;

2-pyrrolyl;

3-pyrrolyl;

1,3,5-triazin-2-yl;

pyrazin-2-yl;

pyridazin-3-yl;

pyridazin-4-yl;

2-quinolinyl;

3-quinolinyl;

4-quinolinyl;

1-isoquinolinyl;

3-isoquinolinyl; and

4-isoquinolinyl; or

substituted heterocycle, wherein the heterocycle is as defined above and the substituents (1-2 in number) are in any position and are independently selected from the group consisting of Br, Cl, F, R 1 , and C(O)CH 3 ;

A=CH 2 ;

(CH 2 ) 2 ;

(CH 2 ) 3 ;

OCH 2 CH 2 ; or

CHCH 3 ;

Y=H;

OR 1 ;

N(R 1 ) 2 ;

N(R 1 )C(O)R 3 ;

N(R 1 )C(O)R 5 ;

N(R 1 )C(O)CH(R 6 )NH 2 ;

N(R 1 )SO 2 R 3 ;

N(R 1 )C(O)NHR 3 ; or

N(R 1 )C(O)OR 6 ;

R 3 are the same or different and independently selected from the group consisting of:

H;

C 1 -C 4 -straight chain alkyl;

C 3 -C 4 -branched chain alkyl;

C 2 -C 4 -alkenyl chain;

(CH 2 ) n Ph; and

(CH 2 ) n -substituted phenyl, wherein the phenyl substituents are as defined above in R 2 ;

R 5 =C 3 -C 7 -cycloalkyl;

R 6 =C 1 -C 4 -straight chain alkyl;

C 3 -C 4 -branched chain alkyl; or

C 2 -C 4 -alkenyl chain;

n=0-3;

or a pharmaceutically acceptable salt thereof.

4. A pharmaceutical composition of matter comprising the compound of claim 1 and one or more pharmaceutical excipients.

5. A pharmaceutical composition of matter comprising the compound of claim 3 and one or more pharmaceutical excipients.

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

wherein:

R 1 are the same or different and independently selected from the group consisting of:

H;

C 1 -C 6 -straight chain alkyl;

C 2 -C 6 -straight alkenyl chain;

C 3 -C 6 -branched alkyl chain;

C 3 -C 6 -branched alkenyl chain;

C 3 -C 7 -cycloalkyl;

CH 2 —(C 3 -C 7 -cycloalkyl);

CH 2 CF 3 ;

CH 2 CH 2 CF 3 ; and

CH(CF 3 ) 2 ;

X=N;or

CH;

V=NH;

O;

S; or

CH 2 ;

R 2 =phenyl;

substituted phenyl, wherein the substituents (1-2 in number) are in any position and are independently selected from the group consisting of R 1 , OR 1 , SR 1 , S(O)R 1 , S(O 2 )R 1 , NHR 1 , NO 2 , OC(O)CH 3 , NHC(O)CH 3 , F, Cl, Br, CF 3 , C(O)R 1 , C(O)NHR 1 , phenyl, and C(O)NHCHR 1 CH 2 OH;

1-naphthyl;

2-naphthyl;

heterocycles selected from the group consisting of:

2-pyridyl;

3-pyridyl;

4-pyridyl;

2-pyrimidyl;

4-pyrimidyl;

5-pyrimidyl;

thiophene-2-yl;

thiophene-3-yl;

2-furanyl;

3-furanyl;

oxazol-2-yl;

oxazol-4-yl;

oxazol-5-yl;

thiazol-2-yl;

thiazol-4-yl;

thiazol-5-yl;

imidazol-2-yl;

imidazol-4-yl;

pyrazol-3-yl;

pyrazol-4-yl;

isoxazol-3-yl;

isoxazol-4-yl;

isoxazol-5-yl;

isothiazol-3-yl;

isothiazol-4-yl;

isothiazol-5-yl;

1,3,4-thiadiazol-2-yl;

benzo[b]furan-2-yl;

benzo[b]thiophene-2-yl;

2-pyrrolyl;

3-pyrrolyl;

1,3,5-triazin-2-yl;

pyrazin-2-yl;

pyridazin-3-yl;

pyridazin-4-yl;

2-quinolinyl;

3-quinolinyl;

4-quinolinyl;

1-isoquinolinyl;

3-isoquinolinyl; and

4-isoquinolinyl; or

substituted heterocycle, wherein the heterocycle is as defined above and the substituents (1-2 in number) are in any position and are independently selected from the group consisting of Br, Cl, F, R 1 , and C(O)CH 3 ;

R 3 are the same or different and independently selected from the group consisting of:

H;

C 1 -C 4 -straight chain alkyl;

C 3 -C 4 -branched chain alkyl;

C 2 -C 4 -alkenyl chain;

(CH 2 ) n Ph; and

(CH 2 ) n -substituted phenyl, wherein the phenyl substituents are as defined above in R 2 ;

R 4 =H;

C 1 -C 4 -straight chain alkyl; or

C 3 -C 4 -branched chain alkyl;

R 3 and R 4 can be linked together by a carbon chain to form with intervening atoms a 5-8-membered saturated or unsaturated ring;

n 1 =0-3;

n=0-3;

A=CH 2 ;

(CH 2 ) 2 ;

(CH 2 ) 2 ;

OCH 2 CH 3 ; or

CHCH 3 ;

Y=H;

OR 1 ;

N(R 1 ) 2 ;

N(R 1 )C(O)R 3 ;

N(R 1 )C(O)R 5 ;

N(R 1 )C(O)CH(R 6 )NH 2 ;

N(R 1 )SO 2 R 3 ;

N(R 1 )C(O)NHR 3 ; or

N(R 1 )C(O)OR 6 ;

R 5 =C 3 -C 7 -cycloalkyl;

R 6 =C 1 -C 4 -straight chain alkyl;

C 3 -C 4 -branched chain alkyl;

C 2 -C 4 -alkenyl chain;

(CH 2 ) n Ph; or

(CH 2 ) n -substituted phenyl, wherein the phenyl substituents are as defined above in R 2 ;

or a pharmaceutically acceptable salt thereof,

with the proviso that the following conditions cannot all be true at the same time: R 3 =H, n=0, R 4 =H, and Y=OH, said process comprising:

reacting a first intermediate compound of the formula:

where Z=Br or I

with a compound of the formula: R 2 —B(OH) 2 , R 2 —Sn(n-Bu) 3 , or R 2 —Sn(Me) 3 , or mixtures thereof, under conditions effective to form the purine derivative compound.

7. A process according to claim 6 , wherein if Y is NHR 1 , said process further comprises:

reacting the purine derivative compound with R 3 C(O)Cl or R 5 C(O)Cl or R 3 SO 2 Cl or R 3 NCO or R 6 OC(O)Cl under conditions effective to form a final product having the same formula as the purine derivative compound except that Y is NR 1 C(O)R 3 or Y is NR 1 C(O)R 5 or NR 1 SO 2 R 3 or NR 1 C(O)NHR 3 or NR 1 C(O)OR 6 .

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

wherein:

R 1 are the same or different and independently selected from the group consisting of:

H;

C 1 -C 6 -straight chain alkyl;

C 2 -C 6 -straight alkenyl chain;

C 3 -C 6 -branched alkyl chain;

C 3 -C 6 -branched alkenyl chain;

C 3 -C 7 -cycloalkyl;

CH 2 —(C 3 -C 7 -cycloalkyl);

CH 2 CF 3 ;

CH 2 CH 2 CF 3 ; and

CH(CF 3 ) 2 ;

X=N;or

CH;

V=NH;

O; or

S;

R 2 =phenyl;

substituted phenyl, wherein the substituents (1-2 in number) are in any position and are independently selected from the group consisting of R 1 , OR 1 , SR 1 , S(O)R 1 , S(O 2 )R 1 , NHR 1 , NO 2 , OC(O)CH 3 , NHC(O)CH 3 , F, Cl, Br, CF 3 , C(O)R 1 , C(O)NHR 1 , phenyl, and C(O)NHCHR 1 CH 2 OH;

1-naphthyl;

2-naphthyl;

heterocycles selected from the group consisting of:

2-pyridyl;

3-pyridyl;

4-pyridyl;

2-pyrimidyl;

4-pyrimidyl;

5-pyrimidyl;

thiophene-2-yl;

thiophene-3-yl;

2-furanyl;

3-furanyl;

oxazol-2-yl;

oxazol-4-yl;

oxazol-5-yl;

thiazol-2-yl;

thiazol-4-yl;

thiazol-5-yl;

imidazol-2-yl;

imidazol-4-yl;

pyrazol-3-yl;

pyrazol-4-yl;

isoxazol-3-yl;

isoxazol-4-yl;

isoxazol-5-yl;

isothiazol-3-yl;

isothiazol-4-yl;

isothiazol-5-yl;

1,3,4-thiadiazol-2-yl;

benzo[b]furan-2-yl;

benzo[b]thiophene-2-yl;

2-pyrrolyl;

3-pyrrolyl;

1,3,5-triazin-2-yl;

pyrazin-2-yl;

pyridazin-3-yl;

pyridazin-4-yl;

2-quinolinyl;

3-quinolinyl;

4-quinolinyl;

1-isoquinolinyl;

3-isoquinolinyl; and

4-isoquinolinyl; or

substituted heterocycle, wherein the heterocycle is as defined above and the substituents (1-2 in number) are in any position and are independently selected from the group consisting of Br, Cl, F, R 1 , and C(O)CH 3 ;

R 3 are the same or different and independently selected from the group consisting of:

H;

C 1 -C 4 -straight chain alkyl;

C 3 -C 4 -branched chain alkyl;

C 2 -C 4 -alkenyl chain;

(CH 2 ) n Ph; and

(CH 2 ) n -substituted phenyl, wherein the phenyl substituents are as defined above in R 2 ;

R=H;

C 1 -C 4 -straight chain alkyl; or

C 3 -C 4 -branched chain alkyl;

R 3 and R 4 can be linked together by a carbon chain to form with intervening atoms a 5-8-membered saturated or unsaturated ring;

n 1 =0-3;

n=0-3;

A=CH 2 ;

(CH 2 ) 2 ;

(CH 2 ) 3 ;

OCH 2 CH 2 ; or

CHCH 3 ;

Y=H;

OR 1 ;

N(R 1 ) 2 ;

N(R 1 )C(O)R 3 ;

N(R 1 )C(O)R 5 ;

N(R 1 )C(O)CH(R 6 )NH 2 ;

N(R 1 )SO 2 R 3 ;

N(R 1 )C(O)NHR 3 ; or

N(R 1 )C(O)OR 6 ;

R 5 =C 3 -C 7 -cycloalkyl;

R 6 =C 1 -C 4 -straight chain alkyl;

C 3 -C 4 -branched chain alkyl;

C 2 -C 4 -alkenyl chain;

(CH 2 ) n Ph; or

(CH 2 ) n -substituted phenyl, wherein the phenyl substituents are as defined above in R 2 ;

or a pharmaceutically acceptable salt thereof;

with the proviso that the following conditions cannot all be true at the same time: R 3 =H, n=O, R 4 =H, and Y=OH, said process comprising:

reacting a second intermediate compound of the formula:

with a second compound of the formula:

wherein: V 1 =NH 2 ;

OH; or

SH;

under conditions effective to form a first intermediate compound of the formula:

where Z=Br or I; and

reacting the first intermediate compound with a compound of the formula: R 2 —B(OH) 2 , R 2 —Sn(n-Bu) 3 , or R 2 —Sn(Me) 3 , or mixtures thereof, under conditions effective to form the purine derivative compound.

9. A process according to claim 8 further comprising:

reacting a third intermediate compound of the formula:

with a compound of the formula R 1 —Z under conditions effective to form the second intermediate compound.

10. A process according to claim 6 , wherein the purine derivative compound has the formula:

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

wherein:

R 1 are the same or different and independently selected from the group consisting of:

H;

C 1 -C 6 -straight chain alkyl;

C 2 -C 6 -straight alkenyl chain;

C 3 -C 6 -branched alkyl chain;

C 3 -C 6 -branched alkenyl chain;

C 3 -C 7 -cycloalkyl;

CH 2 —(C 3 -C 7 -cycloalkyl);

CH 2 CF 3 ;

CH 2 CH 2 CF 3 ; and

CH(CF 3 ) 2 ;

X=N; or

CH;

V=CH 2 ;

R 2 =phenyl;

substituted phenyl, wherein the substituents (1-2 in number) are in any position and are independently selected from the group consisting of R 1 , OR 1 , SR 1 , S(O)R 1 , S(O 2 )R 1 , NHR 1 , NO 2 , OC(O)CH 3 , NHC(O)CH 3 , F, Cl, Br, CF 3 , C(O)R 1 , C(O)NHR 1 , phenyl, and C(O)NHCHR 1 CH 2 OH;

1-naphthyl;

2-naphthyl;

heterocycles selected from the group consisting of:

2-pyridyl;

3-pyridyl;

4-pyridyl;

2-pyrimidyl;

4-pyrimidyl;

5-pyrimidyl;

thiophene-2-yl;

thiophene-3-yl;

2-furanyl;

3-furanyl;

oxazol-2-yl;

oxazol-4-yl;

oxazol-5-yl;

thiazol-2-yl;

thiazol-4-yl;

thiazol-5-yl;

imidazol-2-yl;

imidazol-4-yl;

pyrazol-3-yl;

pyrazol-4-yl;

isoxazol-3-yl;

isoxazol-4-yl;

isoxazol-5-yl;

isothiazol-3-yl;

isothiazol-4-yl;

isothiazol-5-yl;

1,3,4-thiadiazol-2-yl;

benzo[b]furan-2-yl;

benzo[b]thiophene-2-yl;

2-pyrrolyl;

3-pyrrolyl;

1,3,5-triazin-2-yl;

pyrazin-2-yl;

pyridazin-3-yl;

pyridazin-4-yl;

2-quinolinyl;

3-quinolinyl;

4-quinolinyl;

1-isoquinolinyl;

3-isoquinolinyl; and

4-isoquinolinyl; or

substituted heterocycle, wherein the heterocycle is as defined above and the substituents (1-2 in number) are in any position and are independently selected from the group consisting of Br, Cl, F, R 1 , and C(O)CH 3 ;

R 3 are the same or different and independently selected from the group consisting of:

H;

C 1 -C 4 -straight chain alkyl;

C 3 -C 4 -branched chain alkyl;

C 2 -C 4 -alkenyl chain;

(CH 2 ) n Ph; and

(CH 2 ) n -substituted phenyl, wherein the phenyl substituents are as defined above in R 2 ;

R 4 =H;

C 1 -C 4 -straight chain alkyl; or

C 3 -C 4 -branched chain alkyl;

R 3 and R 4 can be linked together by a carbon chain to form with intervening atoms a 5-8-membered saturated or unsaturated ring;

n 1 =0-3;

n=0-3;

A=CH 2 ;

(CH 2 ) 2 ;

(CH 2 ) 3 ;

OCH 2 CH 2 ; or

CHCH 3 ;

Y=H;

OR 1 ;

N(R 1 ) 2 ;

N(R 1 )C(O)R 3 ;

N(R 1 )C(O)R 5 ;

N(R 1 )C(O)CH(R 6 )NH 2 ;

N(R 1 )SO 2 R 3 ;

N(R 1 )C(O)NHR 3 ; or

N(R 1 )C(O)OR 6 ;

R 5 =C 3 -C 7 -cycloalkyl;

R 6 =C 1 -C 4 -straight chain alkyl;

C 3 -C 4 -branched chain alkyl;

C 2 -C 4 -alkenyl chain;

(CH 2 ) n Ph; or

(CH 2 ) n -substituted phenyl, wherein the phenyl substituents are as defined above in R 2 ;

or a pharmaceutically acceptable salt thereof;

with the proviso that the following conditions cannot all be true at the same time: R 3 =H, n=0, R 4 =H, and Y=OH, said process comprising:

reacting a first intermediate compound of the formula:

under reductive or hydrogenation conditions effective to form the purine derivative compound.

12. A process according to claim 11 further comprising:

reacting a second intermediate compound of the formula:

with a second compound of the formula:

under conditions effective to form the first intermediate compound.

13. A process according to claim 12 further comprising:

reacting a third intermediate compound of the formula:

with a compound of the formula: R 2 —B(OH) 2 , R 2 —Sn(n-Bu) 3 , or R 2 —Sn(Me) 3 , or mixtures thereof, under conditions effective to form the second intermediate compound.

14. A process according to claim 10 further comprising:

reacting a fourth intermediate compound of the formula:

with a compound of the formula: R 2 —B(OH) 2 , R 2 —Sn(n-Bu) 3 , or R 2 —Sn(Me) 3 , or mixtures thereof, under conditions effective to form the first intermediate compound.

15. A process according to claim 14 further comprising:

reacting a fifth intermediate compound of the formula:

with a compound of the formula:

under conditions effective to form the fourth intermediate compound.

16. A process according to claim 11 , wherein the purine derivative compound has the formula:

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

wherein:

R 1 are the same or different and independently selected from the group consisting of:

H;

C 1 -C 6 -straight chain alkyl;

C 2 -C 6 -straight alkenyl chain;

C 3 -C 6 -branched alkyl chain;

C 3 -C 6 -branched alkenyl chain;

C 3 -C 7 -cycloalkyl;

CH 2 —(C 3 -C 7 cycloalkyl);

CH 2 CF 3 ;

CH 2 CH 2 CF 3 ; and

CH(CF 3 ) 2 ;

X=N;

V=NH;

O; or

S;

R 2 =phenyl;

substituted phenyl, wherein the substituents (1-2 in number) are in any position and are independently selected from the group consisting of R 1 , OR 3 , SR 1 , S(O)R 1 , S(O 2 )R 1 , NHR 1 , NO 2 , OC(O)CH 3 , NHC(O)CH 3 , F, Cl, Br, CF 3 , C(O)R 1 , C(O)NHR 1 , phenyl, and C(O)NHCHR 1 CH 2 OH;

1-naphthyl;

2-naphthyl;

heterocycles selected from the group consisting of:

2-pyridyl;

3-pyridyl;

4-pyridyl;

2-pyrimidyl;

4-pyrimidyl;

5-pyrimidyl;

thiophene-2-yl

thiophene-3-yl

2-furanyl;

3-furanyl;

oxazol-2-yl;

oxazol-4-yl;

oxazol-5-yl;

thiazol-2-yl;

thiazol-4-yl;

thiazol-5-yl;

imidazol-2-yl;

imidazol-4-yl;

pyrazol-3-yl;

pyrazol-4-yl;

isoxazol-3-yl;

isoxazol-4-yl;

isoxazol-5-yl;

isothiazol-3-yl;

isothiazol-4-yl;

isothiazol-5-yl;

1,3,4-thiadiazol-2-yl;

benzo[b]furan-2-yl;

benzo[b]thiophene-2-yl;

2-pyrrolyl;

3-pyrrolyl;

1,3,5-triazin-2-yl;

pyrazin-2-yl;

pyridazin-3-yl;

pyridazin-4-yl;

2-quinolinyl;

3-quinolinyl;

4-quinolinyl;

1-isoquinolinyl;

3-isoquinolinyl; and

4-isoquinolinyl; or

substituted heterocycle, wherein the heterocycle is as defined above and the substituents (1-2 in number) are in any position and are independently selected from the group consisting of Br, Cl, F, R 1 , and C(O)CH 3 ;

R 3 are the same or different and independently selected from the group consisting of:

H;

C 1 -C 4 -straight chain alkyl;

C 3 -C 4 -branched chain alkyl;

C 2 C 4 -alkenyl chain;

(CH 2 ) n Ph; and

(CH 2 ) n -substituted phenyl, wherein the phenyl substituents are as defined above in R 2 ;

R 4 =H;

C 1 -C 4 -straight chain alkyl; or

C 3 -C 4 -branched chain alkyl;

R 3 and R 4 can be linked together by a carbon chain to form with intervening atoms a 5-8-membered saturated or unsaturated ring;

n 1 =0-3;

n=0-3;

A=CH 2 ;

(CH 2 ) 2 ;

(CH 2 ) 3 ;

OCH 2 CH 2 ; or

CHCH 3 ;

Y=H;

OR 1 ;

N(R 1 )C(O)R 3 ;

N(R 1 )C(O)R 5 ;

N(R 1 )C(O)CH(R 6 )NH 2 ;

N(R 1 )SO 2 R 3 ;

N(R 1 )C(O)NHR 3 ; or

N(R 1 )C(O)OR 6 ;

R 5 =C 3 -C 7 -cycloalkyl;

R 6 =C 1 -C 4 -straight chain alkyl;

C 3 -C 4 -branched chain alkyl;

C 2 -C 4 -alkenyl chain;

(CH 2 ) n Ph; or

(CH 2 ) n -substituted phenyl, wherein the phenyl substituents are as defined above in R 2 ;

or a pharmaceutically acceptable salt thereof;

with the proviso that the following conditions cannot all be true at the same time: R 3 =H, n=0, R 4 =H, and Y=OH, said process comprising:

reacting a first intermediate compound of the formula:

with a compound of the formula:

where V 1 =H 2 ;

OH; or

SH;

under conditions effective to form the purine derivative compound, wherein if Y is NHR 1 , said process further comprises:

reacting the purine derivative compound with R 3 C(O)Cl or R 5 C(O)Cl or R 3 SO 2 Cl or R 3 NCO or R 6 OC(O)Cl under conditions effective to form a final product having the same formula as the purine derivative compound except that Y is NR 1 C(O)R 3 or NR 1 C(O)R 5 or NR 1 SO 2 R 3 or NR 1 C(O)NHR 3 or NR 1 C(O)OR 6 .

18. A process according to claim 17 further comprising:

reacting a second intermediate compound of the formula:

with a compound of the formula R 1 —Z where Z=Br or I, under conditions effective to form the first intermediate compound.

19. A process according to claim 18 further comprising:

reacting a third intermediate compound of the formula:

with a compound of the formula 2,6-dichioropurine (Formula IV) under conditions effective to form the second intermediate compound.

20. A process according to claim 19 further comprising:

reacting a fourth intermediate compound of the formula:

with a compound of the formula: R 2 —B(OH) 2 , R 2 —Sn(n-Bu) 3 , or R 2 —Sn(Me) 3 , or mixtures thereof, under conditions effective to form the third intermediate compound.

21. A process according to claim 17 , wherein the purine derivative compound has the formula:

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

wherein:

R 1 are the same or different and independently selected from the group consisting of:

H;

C 1 -C 6 -straight chain alkyl;

C 2 -C 6 -straight alkenyl chain;

C 3 -C 6 -branched alkyl chain;

C 3 -C 6 -branched alkenyl chain;

C 3 -C 7 -cycloalkyl;

CH 2 —(C 3 -C 7 -cycloalkyl);

CH 2 CF 3 ;

CH 2 CH 2 CF 3 ; and

CH(CF 3 ) 2 ;

X=N; or

CH;

V=NH;

O;

S; or

CH 2 ;

R 2 =phenyl;

substituted phenyl, wherein the substituents (1-2 in number) are in any position and are independently selected from the group consisting of R 1 , OR 1 , SR 1 , S(O)R 1 , S(O 2 )R 1 , NHR 1 , NO 2 , OC(O)CH 3 , NHC(O)CH 3 , F, Cl, Br, CF 3 , C(O)R 1 , C(O)NHR 1 , phenyl, and C(O)NHCHR 1 CH 2 OH;

1-naphthyl;

2-naphthyl;

heterocycles selected from the group consisting of:

2-pyridyl;

3-pyridyl;

4-pyridyl;

2-pyrimidyl;

4-pyrimidyl;

5-pyrimidyl;

thiophene-2-yl;

thiophene-3-yl;

2-furanyl;

3-furanyl;

oxazol-2-yl;

oxazol-4-yl;

oxazol-5-yl;

thiazol-2-yl;

thiazol-4-yl;

thiazol-5-yl;

imidazol-2-yl;

imidazol-4-yl;

pyrazol-3-yl;

pyrazol-4-yl;

isoxazol-3-yl;

isoxazol-4-yl;

isoxazol-5-yl;

isothiazol-3-yl;

isothiazol-4-yl;

isothiazol-5-yl;

1,3,4-thiadiazol-2-yl;

benzo[b]furan-2-yl;

benzo[b]thiophene-2-yl;

2-pyrrolyl;

3-pyrrolyl;

1,3,5-triazin-2-yl;

pyrazin-2-yl;

pyridazin-3-yl;

pyridazin-4-yl;

2-quinolinyl;

3-quinolinyl;

4-quinolinyl;

1-isoquinolinyl;

3-isoquinolinyl; and

4-isoquinolinyl; or

substituted heterocycle, wherein the heterocycle is as defined above and the substituents (1-2 in number) are in any position and are independently selected from the group consisting of Br, Cl, F, R 1 , and C(O)CH 3 ;

R 3 are the same or different and independently selected from the group consisting of:

H;

C 1 -C 4 -straight chain alkyl;

C 3 -C 4 -branched chain alkyl;

C 2 -C 4 -alkenyl chain;

(CH 2 ) n Ph; and

(CH 2 ) n -substituted phenyl, wherein the phenyl substituents are as defined above in R 2 ;

R 4 =H;

C 1 -C 4 -straight chain alkyl; or

C 3 -C 4 -branched chain alkyl;

R 3 and R 4 can be linked together by a carbon chain to form with intervening atoms a 5-8-membered saturated or unsaturated ring;

n 1 =0-3;

n=0-3;

A=CH 2 ;

(CH 2 ) 2 ;

(CH 2 ) 3 ;

OCH 2 CH 2 ; or

CHCH 3 ;

Y=NR 1 C(O)R 3 ;

NR 1 SO 2 R 3 ;

NR 1 C(O)NHR 3 ; or

NR 1 C(O)OR 6 ;

NR 1 C(O)R 5 ;

R 5 =C 3 -C 7 -cycloalkyl;

R 6 =C 1 -C 4 -straight chain alkyl;

C 3 -C 4 -branched chain alkyl;

C 2 -C 4 -alkenyl chain;

(CH 2 ) n Ph; or

(CH 2 ) n -substituted phenyl, wherein the phenyl substituents are as defined above in R 2 ;

or a pharmaceutically acceptable salt thereof;

said process comprising:

reacting a first intermediate compound having the same formula as the purine derivative compound except that Y=NHR 1 , with R 3 COCl or R 5 COCl or R 3 SO 2 Cl or R 3 NCO or R 6 OC(O)Cl under conditions effective to form the purine derivative compound.

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

wherein:

R 1 are the same or different and independently selected from the group consisting of:

C 2 -C 6 -straight chain alkyl;

C 3 -C 6 -straight alkenyl chain;

CH 2 CH(CH 3 ) 2 ;

C 5 -C 6 -branched alkyl chain;

C 4 -C 6 -branched alkenyl chain;

CH 2 —(C 3 -C 7 -cycloalkyl);

CH 2 CF 3 ; and

CH 2 CH 2 CF 3 ;

X=N; or

CH;

V=NH;

O;

S; or

CH 2 ;

R 2 =phenyl;

substituted phenyl, wherein the substituents (1-2 in number) are in any position and are independently selected from the group consisting of R 1 , OR 1 , SR 1 , S(O)R 1 , S(O 2 )R 1 , NHR 1 , NO 2 , OC(O)CH 3 , NHC(O)CH 3 , F, Cl, Br, CF 3 , C(O)R 1 , C(O)NHR 1 , phenyl, and C(O)NHCHR 1 CH 2 OH;

1-naphthyl;

2-naphthyl;

heterocycles selected from the group consisting of:

2-pyridyl;

3-pyridyl;

4-pyridyl;

2-pyrimidyl;

4-pyrimidyl;

5-pyrimidyl;

thiophene-2-yl;

thiophene-3-yl;

2-furanyl;

3-furanyl;

oxazol-2-yl;

oxazol-4-yl;

oxazol-5-yl;

thiazol-2-yl;

thiazol-4-yl;

thiazol-5-yl;

imidazol-2-yl;

imidazol-4-yl;

pyrazol-3-yl;

pyrazol-4-yl;

isoxazol-3-yl;

isoxazol-4-yl;

isoxazol-5-yl;

isothiazol-3-yl;

isothiazol-4-yl;

isothiazol-5-yl;

1,3,4-thiadiazol-2-yl;

benzo[b]furan-2-yl;

benzo[b]thiophene-2-yl;

2-pyrrolyl;

3-pyrrolyl;

1,3,5-triazin-2-yl;

pyrazin-2-yl;

pyridazin-3-yl;

pyridazin-4-yl;

2-quinolinyl;

3-quinolinyl;

4-quinolinyl;

1-isoquinolinyl;

3-isoquinolinyl; and

4-isoquinolinyl; or

substituted heterocycle, wherein the heterocycle is as defined above and the substituents (1-2 in number) are in any position and are independently selected from the group consisting of Br, Cl, F, R 1 , and C(O)CH 3 ;

R 3 are the same or different and independently selected from the group consisting of:

H;

C 1 -C 4 -straight chain alkyl;

C 3 -C 4 -branched chain alkyl;

C 2 -C 4 -alkenyl chain;

(CH 2 ) n Ph; and

(CH 2 ) n -substituted phenyl, wherein the phenyl substituents are as defined above in R 2 ;

R 4 =H;

C 1 -C 4 -straight chain alkyl; or

C 3 -C 4 -branched chain alkyl;

R 3 and R 4 can be linked together by a carbon chain to form with intervening atoms a 5-8-membered saturated or unsaturated ring;

n 1 =0-3;

n=0-3;

A=CH 2 ;

(CH 2 ) 2 ;

(CH 2 ) 3 ;

OCH 2 CH 2 ; or

CHCH 3 ;

Y=NR 1 C(O)R 3 ;

NR 1 SO 2 R 3 ;

NR 1 C(O)NHR 3 ; or

NR 1 C(O)OR 6 ;

NR 1 C(O)R 5 ;

R 5 =C 3 -C 7 -cycloalkyl;

R 6 =C 1 -C 4 -straight chain alkyl;

C 3 -C 4 -branched chain alkyl;

C 2 -C 4 -alkenyl chain;

(CH 2 ) n Ph; or

(CH 2 ) n -substituted phenyl, wherein the phenyl substituents are as defined above in R 2 ;

or a pharmaceutically acceptable salt thereof;

said process comprising:

reacting a second intermediate compound having the same formula as the purine derivative compound except that Y is NH 2 , with R 8 CH 2 Z or R 8 CHO under conditions effective to form a first intermediate compound where Y=NHCH 2 R 8 , wherein Z is Br or I, and R 8 is C 1 -C 5 -straight chain alkyl, C 2 -C 5 -straight alkenyl chain, C 3 -C 5 -branched alkyl chain, C 3 -C 5 -branched alkenyl chain, C 3 -C 7 -cycloalkyl, CF 3 , or CH 2 CF 3 ; and

reacting the first intermediate compound with R 3 COCl or R 5 COCl or R 3 SO 2 Cl or R 3 NCO or R 6 OC(O)Cl under conditions effective to form the purine derivative compound.

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

wherein:

R 1 are the same or different and independently selected from the group consisting of:

H;

C 1 -C 6 -straight chain alkyl;

C 2 -C 6 -straight alkenyl chain;

C 3 -C 6 -branched alkyl chain;

C 3 -C 6 -branched alkenyl chain;

C 3 -C 7 -cycloalkyl;

CH 2 —(C 3 -C 7 -cycloalkyl);

CH 2 CF 3 ;

CH 2 CH 2 CF 3 ; and

CH(CF 3 ) 2 ;

X=N; or

CH;

V=NH;

O;

S; or

CH 2 ;

R 2 =phenyl;

substituted phenyl, wherein the substituents (1-2 in number) are in any position and are independently selected from the group consisting of R 1 , OR 1 , SR 1 , S(O)R 1 , S(O 2 )R 1 , NHR 1 , NO 2 , OC(O)CH 3 , NHC(O)CH 3 , F, Cl, Br, CF 3 , C(O)R 1 , C(O)NHR 1 , phenyl, and C(O)NHCHR 1 CH 2 OH;

1-naphthyl;

2-naphthyl;

heterocycles selected from the group consisting of:

2-pyridyl;

3-pyridyl;

4-pyridyl;

2-pyrimidyl;

4-pyrimidyl;

5-pyrimidyl;

thiophene-2-yl;

thiophene-3-yl;

2-furanyl;

3-furanyl;

oxazol-2-yl;

oxazol-4-yl;

oxazol-5-yl;

thiazol-2-yl;

thiazol-4-yl;

thiazol-5-yl;

imidazol-2-yl;

imidazol-4-yl;

pyrazol-3-yl;

pyrazol-4-yl;

isoxazol-3-yl;

isoxazol-4-yl;

isoxazol-5-yl;

isothiazol-3-yl;

isothiazol-4-yl;

isothiazol-5-yl;

1,3,4-thiadiazol-2-yl;

benzo[b]furan-2-yl;

benzo[b]thiophene-2-yl;

2-pyrrolyl;

3-pyrrolyl;

1,3,5-triazin-2-yl;

pyrazin-2-yl;

pyridazin-3-yl;

pyridazin-4-yl;

2-quinolinyl;

3-quinolinyl;

4-quinolinyl;

1-isoquinolinyl;

3-isoquinolinyl; and

4-isoquinolinyl; or

substituted heterocycle, wherein the heterocycle is as defined above and the substituents (1-2 in number) are in any position and are independently selected from the group consisting of Br, Cl, F, R 1 , and C(O)CH 3 ;

R 3 are the same or different and independently selected from the group consisting of:

H;

C 1 -C 4 -straight chain alkyl;

C 3 -C 4 -branched chain alkyl;

C 2 -C 4 -alkenyl chain;

(CH 2 ) n Ph; and

(CH 2 ) n -substituted phenyl, wherein the phenyl substituents are as defined above in R 2 ;

R 4 =H;

C 1 -C 4 -straight chain alkyl; or

C 3 -C 4 -branched chain alkyl;

R 3 and R 4 can be linked together by a carbon chain to form with intervening atoms a 5-8-membered saturated or unsaturated ring;

n 1 =0-3;

n=0-3;

A=CH 2 ;

(CH 2 ) 2 ;

(CH 2 ) 3 ;

OCH 2 CH 2 ; or

CHCH 3 ;

Y=NHC(O)CH(R 6 )NH 2

R 5 =C 3 -C 7 -cycloalkyl;

R 6 =C 1 -C 4 -straight chain alkyl;

C 3 -C 4 -branched chain alkyl;

C 2 -C 4 -alkenyl chain;

(CH 2 ) n Ph; or

(CH 2 ) n -substituted phenyl, wherein the phenyl substituents are as defined above in R 2 ;

or a pharmaceutically acceptable salt thereof; said process comprising:

reacting a first intermediate compound having the same formula as the purine derivative compound except that Y is NH 2 , with a compound of the formula:

PNHCH(R 6 )CO 2 H under conditions effective to form the purine derivative compound after a suitable deprotection strategy,

wherein

P=C(O)OtBu;

C(O)OCH 2 Ph;

Fmoc;

Benzyl; or

Alloc.