Pyrazolo [3,4-D] pyrimidine derivatives as anti-cancer agents

1. A compound of formula-I,

or a pharmaceutically acceptable salt thereof,

where in m is 1, 2, or 3;

W is single bond;

R 1 is C 2 -C 6 alkyl, when n=1; C 1 -C 6 alkyl, when n=2 or 3; or C 1 -C 6 alkenyl, alkynyl, NH, S, SO, SO2, O, C═O or an amide group, when n=1, 2 and 3;

or each R 1 is independently selected from halo, hydroxy, amino, hydroxyamino, carboxy, nitro, guanidino, ureido, carbamoyl, cyano, trifluoromethyl;

or each R 1 is independently selected from the group consisting of C 2 -C 6 alkyl, when n=1; C 1 -C 6 alkyl, when n=2 or 3; and C 3 -C 6 cycloalkyl, C 1 -C 6 alkoxy, C 3 -C 6 cycloalkoxy; (C 1 -C 6 ) alkoxycarbonyl, aryloxy, heteroaryloxy, C 1 -C 6 thioalkoxy, C 3 -C 6 thiocycloalkoxy, thioaryloxy, thioheteroaryloxy, nitro, amino, N-mono(C 1 -C 6 ) alkylamino, N,N-di(C 1 -C 6 ) alkylamino, formamido, amido, acetamido, hydroxylamino, C 1 -C 6 alkoxyamino, hydrazino, trifluoromethyl, trifluoromethoxy, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, aryl, heterocyclyl, fused aryl, fused heteroaryl and fused heterocyclyl, when n=1, 2 and 3;

or each R 1 is independently selected from R 3 -sulfonylamino, phthalimido-(C 1 -C 4 )-alkylsulfonylamino, benzamido, benzenesulfonylamino, 3-phenylureido, 2-oxopyrrolidin-1-yl, 2,5-dioxopyrrolidin-1-yl, and C 2 -C 4 alkanoylamino and wherein said benzenesulfonylamino or phenyl or phenoxy or anilino or phenylsulfanyl substituent in R 1 may optionally bear one or two halogens, (C 1 -C 4 ) alkyl, cyano, methansulfonyl or (C 1 -C 4 ) alkoxy substituents; or any two R 1 taken together with the carbons to which they are attached comprise a 5-8 membered ring comprising at least one or two heteroatoms selected from oxygen, sulfur or nitrogen; and wherein the alkyl groups and alkyl portions of the alkoxy or alkylamino groups may be straight chained or if comprising at least three carbons may be branched or cyclic; where R 3 is selected from C 1 -C 6 -alkyl, C 3 -C 6 cycloalkyl when n=1, 2 and 3;

R 2 is selected from the group consisting of hydrogen, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, C 1 -C 6 alkoxycarbonyl, aryl, heteroaryl, C 1 -C 6 thioalkyl, trifluoromethyl, trifluoromethoxy, heterocyclyl, fused aryl, fused heteroaryl and fused heterocyclyl; or

R 2 is selected from the group consisting of phenyl or benzyl and substituted with 1, 2, 3 or 4 groups and the substituents are independently selected from R4,

where R4 is selected from hydrogen, halo, hydroxy, amino, hydroxyamino, carboxy, nitro, guanidino, ureido, carbamoyl, cyano, trifluoromethyl, C 1 -C 6 -alkyl, C 3 -C 6 cycloalkyl, hydroxy, C 1 -C 6 alkoxy, C 3 -C 6 cycloalkoxy, C 1 -C 6 alkoxycarbonyl, aryloxy, heteroaryloxy, C 1 -C 6 thioalkoxy, C 3 -C 6 thiocycloalkoxy, thioaryloxy, thioheteroaryloxy, nitro, amino, N-mono (C 1 -C 6 ) alkylamino, N,N-di(C 1 -C 6 ) alkylamino, formamido, amido, acetamido, hydroxylamino, C 1 -C 6 alkoxyamino, hydrazino, trifluoromethyl, trifluoromethoxy, alkenyl, alkynyl, aryl, heterocyclyl, fused aryl, fused heteroaryl and fused heterocyclyl.

2. The compound of claim 1 , wherein the compound is:

N-((2,3-dihydrobenzo[b][1,4]dioxin-6-yl)methyl)-[1-(3-ethynyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl-amine,

[2-(2 methoxy-ethoxy)-ethyl]-[1-(3-ethynyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)-amine,

[2-(2 methoxy-ethoxy)-ethyl]-[1-(3-ethynyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)-amine,

(3,4-Dimethoxy-benzyl)-[1-(3-ethynyl-phenyl)1H-pyrazolo[3,4-d]pyrimidine-4yl)-amine,

[3,4-Bis-(2-methoxy-ethoxy)-benzyl[1-(3-ethynyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidine-4-yl)-amine,

Benzo[1,3]dioxol-5-yl methyl-[1-(3-ethynyl-phenyl)-1-H-pyrazolo[3,4-d]pyrimidine-4-yl]-amine,

[1-(3-ethynyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidine-4ylamino)-acetic acid

3,4-Diethoxy-benzyl-[1-(3-ethynyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidine-4yl)-amine,

[1-(3 ethynyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidine-4yl)-(3,4,5-trimethoxy-benzyl)-amine,

[4-(2 methoxy-ethoxy)-benzyl)-[1-(3-ethynyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidine-4yl)-amine,

(4-methoxy-benzyl-[1-(3-ethynyl-phenyl) 1H-pyrazolo[3,4-d]pyrimidine-4yl)-amine,

[4 (3-morpholin-4-yl-propoxy)-benzyl]-[1-(3-ethynyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidine-4yl)-amine;

N-((2,3-dihydrobenzo[b][1,4]dioxin-6-yl)methyl)-[1-(3-trimethylsilanyl ethynyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4yl-amine,

[2-(2 methoxy-ethoxy)-ethyl]-[1-(3-trimethylsilanyl ethynyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4yl)-amine,

[4-Methoxy-3-(3-morpholine-4-yl-propoxy)-benzyl)-[1-(3-trimethylsilanyl ethynyl-phenyl)1H-pyrazolo[3,4-d]pyrimidine-4yl)-amine,

(3,4-Dimethoxy-benzyl)-[1-(3-trimethylsilanyl ethynyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidine-4yl)-amine,

[3,4-Bis-(2-methoxy-ethoxy)-benzyl[1-(3-trimethylsilanyl ethynyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidine-4yl)-amine,

Benzo[1,3]dioxol-5-yl methyl-[1-(3-trimethylsilany ethynyl-phenyl)-1-H-pyrazolo[3,4-d]pyrimidine-4-yl]-amine,

[1-(3 trimethylsilanyl ethynyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidine-4ylamino)-acetic acid,

3,4-Diethoxy-benzyl-[1-(3-trimethylsilanyl ethynyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidine-4yl)-amine,

[1-(3 trimethylsilanyl ethynyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidine-4yl)-(3,4,5-trimethoxy-benzyl)-amine,

[4-(2 methoxy-ethoxy)-benzyl)-[1-(3-trimethylsilanyl ethynyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidine-4yl)-amine,

(4-methoxy-benzyl-[1-(3-trimethylsilanyl ethynyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidine-4yl)-amine, or

[4-(3 morpholin-4-yl-propoxy)-benzyl]-[1-(3-trimethylsilanyl ethynyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidine-4yl)-amine;

N-((2,3-dihydrobenzo[b][1,4]dioxin-6-yl)methyl)-[1-(3-iodo-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4yl-amine,

[2-(2 methoxy-ethoxy)-ethyl]-[1-(3-iodo-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4yl)-amine,

[4-Methoxy-3-(3-morpholine-4-yl-propoxy)-benzyl)-[1-(3-iodo-phenyl)-1H-pyrazolo[3,4-d]pyrimidine-4yl)-amine,

(3,4-Dimethoxy-benzyl)-[1-(3-iodo-phenyl) 1H-pyrazolo[3,4-d]pyrimidine-4yl)-amine,

[3,4-Bis-(2-methoxy-ethoxy)-benzyl]-[1-(3-iodo-phenyl)-1H-pyrazolo[3,4-d]pyrimidine-4yl)-amine,

Benzo[1,3]dioxol-5-yl methyl-[1-(3-iodo-phenyl)-1-H-pyrazolo[3,4-d]pyrimidine-4-yl]-amine,

[1-(3-iodo-phenyl)-1H-pyrazolo[3,4-d]pyrimidine-4ylamino)-acetic acid,

3,4-Diethoxy-benzyl)-)-[1-(3-iodo-phenyl)-1H-pyrazolo[3,4-d]pyrimidine-4yl)-amine,

[1-(3 iodo-phenyl)-1H-pyrazolo[3,4-d]pyrimidine-4yl)-(3,4,5-trimethoxy-benzyl)-amine,

[4-(2 methoxy-ethoxy)-benzyl)-[1-(3-iodo-phenyl)-1H-pyrazolo[3,4-d]pyrimidine-4yl)-amine,

(4-methoxy-benzyl-[1-(3-iodo-phenyl) 1H-pyrazolo[3,4-d]pyrimidine-4yl)-amine, or

[4-(3-morpholin-4-yl-propoxy)-benzyl]-[1-(3-iodo-phenyl)-1H-pyrazolo[3,4-d]pyrimidine-4yl)-amine.

3. The compound of claim 1 , wherein the compound is:

a) 3-{4-[(2,3-Dihydro-benzo[1,4]dioxin-6-ylmethyl)-amino]-pyrazolo[3,4-d]pyrimidin-1-yl}-benzonitrile,

b) 3-{4-[2-(2-methoxy-ethoxy)-ethylamino]-pyrazolo[3,4-d]-1-yl}-benzonitrile,

c) 3-{4-[4-methoxy-3-(3-morpholin-4-yl-propoxy)-benzyl amino]-pyrazolo[3,4-d]pyrimidin-1yl-}-benzonitrile,

d) 3-[4-(3,4-dimethoxy-benzyl amino]-pyrazolo[3,4-d]pyrimidin-1yl-}-benzonitrile,

e) 3-{4-[3,4-bis-(2-methoxy-ethoxy)-benzyl amino]-pyrazolo[3,4-d]pyrimidin-1yl-}-benzonitrile,

f) 3-{4-[(Benzo[1,3]dioxol-5-yl methyl)-amino-pyrazolo[3,4-d]pyrimidin-1yl-}-benzonitrile,

g) [1-(3-cyano-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-ylamino]-acetic acid,

h) 3-[4-(3,4-Diethoxy-benzyl amino)-pyrazolo[3,4-d]pyrimidin-1-yl]-benzonitrile,

i) 3-[4-(3,4,5-trimethoxy-benzylamino)-pyrazolo[3,4-d]pyrimidin-1-yl]-benzonitrile,

j) 3-{4-[4-(2-mehoxy-ethoxy)-benzyl amino]-pyrazolo[3,4-d]pyrimidin-1-yl}-benzonitrile,

k) 3-[4-(4-methoxy-benzylamino)-pyrazolo[3,4-d]pyrimidin-1yl]-benzonitrile, or

l) 3-{4-[4-(3-morpholin-4-yl-propoxy)benzyl amino]-pyrazolo[3,4-d]pyrimidin-1-yl}-benzonitrle.

4. The compound of claim 1 , wherein the compound is:

N-((2,3-dihydrobenzo[b][1,4]dioxin-6-yl)methyl)-1-(3,5-dimethylphenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine,

N-(benzo[d][1,3]dioxol-5-ylmethyl)-1-(3,5-dimethylphenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine,

1-(3,5-dimethylphenyl)-N-(2-(2-methoxyethoxy)ethyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine,

[1(3,5-dimethyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidine-4-yl]-[4-methoxy-3-(3-morpholin-4-yl-propoxy)-benzyl]-amine,

(3,4-dimethoxy-benzyl)-[1-(3,5-dimethyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidine-4-yl]-amine,

[3,4-bis-(2-methoxy-ethoxy)-benzyl]-[1-(3,5-dimethyl-phenyl)-1H-pyazolo[3,4-d]pyrimidin-4-yl]-amine,

[1(3,5-dimethyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-ylamino]acetic acid,

3,4-diethoxy-benzyl)-[1-(3,5-dimethyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidine-4-yl]-amine,

[1(3,5-dimethyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl]-(3,4,5-trimethoxy-benzyl)-amine,

[1(3,5-dimethyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl]-[4-(2-methoxy-ethoxy)benzyl amine,

[1(3,5-dimethyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl]-[4-(methoxy)benzyl amine, or

[1(3,5-dimethyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl]-[4-(3-morpholine-4-yl-propoxy)benzyl amine.

5. The compound of claim 1 , wherein the compound is:

a) N-((2,3-dihydrobenzo[b][1,4]dioxin-6-yl)methyl)-1-m-tolyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine,

b) [2-(2-methoxy-ethoxy)-ethyl]-(1-m-tolyl-1H-pyrazolo[3,4-d]pyrimidine-4yl)-amine,

c) [4-Methoxy-3-(3-morpholine-4-yl-propoxy)-benzyl]-(1-m-tolyl-1H-pyrazolo[3,4-d]pyrimidine-4yl)-amine,

d) (3,4-Dimethoxy-benzyl)-(1-m-tolyl-1H-pyrazolo[3,4-d]pyrimidine-4yl)-amine,

e) [3,4-Bis-(2-methoxy-ethoxy)-benzyl]-(1-m-tolyl-1H-pyrazolo[3,4-d]pyrimidine-4yl)-amine,

f) (1-m-tolyl-1H-pyrazolo[3,4-d]pyrimidine-4ylamino)-acetic acid,

g) 3,4-Diethoxy-benzyl)-(1-m-tolyl-1H-pyrazolo[3,4-d]pyrimidine-4yl)-amine,

h) (1-m-tolyl-1H-pyrazolo[3,4-d]pyrimidine-4yl)-(3,4,5-trimethoxy-benzyl)-amine,

i) [4-(2-methoxy-ethoxy)-benzyl]-(1-m-tolyl-1H-pyrazolo[3,4-d]pyrimidine-4yl)-amine,

j) (4-methoxy-benzyl)-(1-m-tolyl-1H-pyrazolo[3,4-d]pyrimidine-4yl)-amine, or

k) [4-(3-morpholin-4-yl-propoxy)-benzyl]-(1-m-tolyl-1H-pyrazolo[3,4-d]pyrimidine-4yl)-amine.

6. A process for the preparation of a compound of Formula-I with an ethynyl substitution on the N-phenyl ring or a pharmaceutically acceptable salt thereof,

the process comprising:

diazotising a compound of formula i with mineral acid and sodium nitrite at −10° C. to 5° C. to obtain iodo substituted phenyl hydrazine hydrochloride solid of formula-J;

neutralizing the compound of formula-J with a base to get an iodo substituted phenyl hydrazine of formula-K;

reacting the compound of formula K with ethoxymethelenemalononitrile in a protic solvent to obtain an N-(iodo substituted) phenyl-5-amino-1H-pyrazole-4-carbonitrile of formula-L;

hydrolyzing the nitrile group of the compound of formula L with a mineral acid in aqueous medium; followed by basification with a base at 10° C. to 40° C. to obtain an N-(iodo substituted) phenyl-5-amino-1H-pyrazole-4-carboxamides of formula-M;

reacting the compound of formula-N with formamide to obtain an N-(iodo substituted) phenyl-5-amino-1H-pyrazole-4-carboxamide of formula-O;

reacting the compound of formula O with phosphorus oxychloride, thionyl chloride, phosphorous trichloride or phosphorous pentachloride to obtain an N-(iodo substituted) 4-chloro-pyrazolo[3,4-d]pyrimidine of formula-P;

refluxing the compound of formula Q with substituted alkyl amine of formula-H in protic solvent to obtain an 1-(iodo substituted) substituted 4-amino substituted-pyrazolo[3,4-d]pyrimidine of formula-S;

refluxing the compound of formula S with substituted trimethyl silyl acetylene in protic solvent to obtain an N-(trimethyl silyl protected ethynyl substituted) phenyl-4-amino substituted-pyrazolo[3,4-d]pyrimidine of formula-T;

deprotecting the compound of formula T with a base to get the acetylene substituted compounds of formula-I.

7. A process for the preparation of N-((2,3-dihydrobenzo[b][1,4]dioxin-6-yl)methyl)-1-(3,5-dimethylphenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine

or salt thereof, the process comprising:

diazotising a compound of formula A with mineral acid and sodium nitrite at −10° C. to 5° C. to obtain a substituted phenyl hydrazine hydrochloride of formula-B;

neutralizing the compound of formula-B with a base to get a novel substituted phenylhydrazine of formula-C;

reacting the compound of formula C ethoxymethelenemalononitrile in protic solvent to obtain an N-substituted phenyl-5-amino-1H-pyrazole-4-carbonitrile of formula-D;

hydrolyzing the nitrile group of compound of formula D with a mineral acid in aqueous medium; followed by basification with a base at 10° C. to 40° C. to obtain an N-substituted phenyl-5-amino-1H-pyrazole-4-carboxamides of formula-E;

reacting the compound of formula E with formamide to obtain an N-substituted phenyl-5-amino-1H-pyrazole-4-carboxamide of formula F;

reacting the compound of formula F with phosphorus oxychloride, thionyl chloride, phosphorous trichloride or phosphorous pentachloride to obtain an N-substituted 4-chloro-pyrazolo[3,4-d]pyrimidine of formula-G;

refluxing the compound of formula G with 2,3-dihydro-benzo[1,4]dioxin-6-yl-methylamine hydrochloride in a protic solvent to obtain the N-((2,3-dihydrobenzo[b][1,4]dioxin-6-yl)methyl)-1-(3,5-dimethylphenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine.

8. The process of claim 7 , further comprising treating the N-((2,3-dihydrobenzo[b][1,4]dioxin-6-yl)methyl)-1-(3,5-dimethylphenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine with hydrochloric acid in a solvent to produce

9. A process for the preparation of a compound of Formula-I with a cyano substitution on the N-phenyl ring or a pharmaceutically acceptable salt thereof, the process comprising:

heating a compound of formula S with copper cyanide and copper iodide in dimethyl formamide or dimethyl sulfoxide at temperatures ranging from 120° C. to 145° C. to obtain an N-(cyano substituted) phenyl-4-amino substituted-pyrazolo[3,4-d]pyrimidine.

10. A pharmaceutical composition comprising, a pharmaceutically acceptable excipient and a therapeutically effective amount of a compound of claim 2 .

11. The process of claim 8 , wherein the solvent comprises water, methanol, ethanol, isopropyl alcohol, ethyl acetate, acetonitrile, methylene chloride, acetone, or a mixture thereof.

12. The method of claim 6 , wherein the acid:

for diazotising a compound of formula i comprises hydrochloric acid or sulfuric acid;

for hydrolyzing the nitrile group of the compound of formula L comprises sulphuric acid in aqueous medium;

or combination thereof.

13. The method of claim 6 , wherein the mineral acid for diazotising a compound of formula i comprises hydrochloric acid.

14. The method of claim 6 , wherein the base:

for neutralizing the compound of formula-J comprises sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, ammonium carbonate, or a bicarbonate of an alkali metal;

for basification comprises ammonia, a bicarbonate of an alkali metal, a carbonate of an alkali metal, or a hydroxide of an alkali metal;

for deprotecting the compound of formula T comprises ammonia, a monoalkylamine, a dialkylamine, a trialkylamine, sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, ammonium carbonate, or a bicarbonate of an alkali metal;

or combination thereof.

15. The method of claim 6 , wherein the protic solvent:

for reacting the compound of formula K comprises methanol, ethanol, isopropanol, n-butanol, dimethyl formamide, or a mixture thereof;

for refluxing the compound of formula Q comprises methanol, ethanol, isopropyl alcohol, or a mixture thereof;

for refluxing the compound of formula S comprises methanol, ethanol, isopropyl alcohol, or a mixture thereof;

or combination thereof.

16. The method of claim 6 , further comprising preparing ethoxymethylenemalononitrile in situ by reacting triethyl orthoformate and malononitrile; optionally, at 40° C. to 100° C.

17. The method of claim 6 , wherein reacting with formamide is conducted in solvent, and the solvent comprises sulfolane, optionally, at 150° C. to 220° C.

18. The method of claim 6 , comprising reacting the compound of formula O with phosphorus oxychloride.

19. The method of claim 18 , wherein reacting is at reflux in solvent comprising methylene chloride, ethylene chloride, chloroform, or a mixture thereof.

20. The method of claim 6 , comprising reacting the compound of formula O with thionyl chloride, phosphorous trichloride, or phosphorous pentachloride.

21. The method of claim 20 , wherein reacting is at 25° C. in solvent comprising methylene chloride, ethylene chloride, chloroform, or a mixture thereof.

22. The method of claim 7 , wherein the acid:

for diazotising a compound of formula A comprises hydrochloric acid or sulfuric acid;

for hydrolyzing the nitrile group of the compound of formula D comprises sulphuric acid in aqueous medium;

or combination thereof.

23. The method of claim 7 , wherein the mineral acid for diazotising a compound of formula A comprises hydrochloric acid.

24. The method of claim 6 , wherein the base:

for neutralizing the compound of formula B comprises ammonia, a monoalkylamine, a dialkylamine, a trialkylamine, sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, ammonium carbonate, or a bicarbonate of an alkali metal;

for basification comprises ammonia, a bicarbonate of an alkali metal, a carbonate of an alkali metal, or a hydroxide of an alkali metal; or

combination thereof.

25. The method of claim 6 , wherein the protic solvent:

for reacting the compound of formula C comprises methanol, ethanol, isopropanol, n-butanol, dimethyl formamide, or a mixture thereof;

for refluxing the compound of formula G comprises methanol, ethanol, isopropyl alcohol, or a mixture thereof; or

combination thereof.

26. The method of claim 7 , further comprising preparing ethoxymethylenemalononitrile in situ by reacting triethyl orthoformate and malononitrile; optionally, at 40° C. to 100° C.

27. The method of claim 6 , wherein reacting with formamide is conducted in solvent, and the solvent comprises sulfolane, optionally, at 150° C. to 220° C.

28. The method of claim 7 , comprising reacting the compound of formula F with phosphorus oxychloride.

29. The method of claim 28 , wherein reacting is at reflux in solvent comprising methylene chloride, ethylene chloride, chloroform, or a mixture thereof.

30. The method of claim 7 , comprising reacting the compound of formula F with thionyl chloride, phosphorous trichloride, or phosphorous pentachloride.

31. The method of claim 30 , wherein reacting is at 25° C. in solvent comprising methylene chloride, ethylene chloride, chloroform, or a mixture thereof.

32. The compound of claim 1 , wherein R 2 is 1,3-benzodioxol or 1,4-benzodioxin.

33. The compound of claim 1 , wherein R 1 is alkyl, alkynyl, halogen, or cyano when n=1 and R 1 is alkyl when n=2.