METHODS OF PREPARING SUBSTITUTED PYRAZOLOPYRIMIDINES

1 . A compound of Formula I:

or a pharmaceutically acceptable salt thereof;

wherein

R 1 is selected from cyano, —CHO, —CH 2 NR 2 R 3 , and —CH 2 R 4 ;

R 2 is selected from hydrogen, optionally substituted aryl, and optionally substituted heteroaryl;

R 3 is selected from hydrogen, amino, and —NR 5 R 6 ;

R 4 is selected from Formula II and Formula III:

R 5 and R 6 are individually selected from hydrogen and an amine protecting group;

R 7 is selected from optionally substituted aryl and optionally substituted heteroaryl;

R 8 is selected from carbonyl, alkoxy, and sulfonate; and

R 9 is selected from hydroxy, alkoxy, sulfonate, and a leaving group.

2 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein one of R 5 and R 6 is hydrogen and the other of R 5 and R 6 is an amine protecting group selected from t-butyloxycarbonyl (Boc), fluorenylmethoxycarbonyl (Fmoc), benzyloxycarbonyl (Cbz), acetyl, trifluoroacetamide, phthalimide, benzyl, trityl, benzylideneamine, and toluenesulfonate.

3 . The compound of claim 2 , or a pharmaceutically acceptable salt thereof, wherein the amine protecting group is t-butyloxycarbonyl (Boc).

4 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 1 is —CH 2 NR 2 R 3 , R 2 is hydrogen, and R 3 is amino.

5 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 1 is —CH 2 NR 2 R 3 and R 2 is an optionally substituted pyrimidinyl.

6 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 7 has a Formula XIX:

wherein R 12 and R 13 are individually selected from hydrogen, hydroxy, alkyl, alkoxy, and cycloalkyl.

7 . The compound of claim 6 , or a pharmaceutically acceptable salt thereof, wherein R 12 is cyclopropyl and R 13 is methoxy.

8 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein the leaving group is selected from trifluoromethanesulfonate, toluenesulfonate, methanesulfonate, and halogen.

9 . The compound of claim 8 , or a pharmaceutically acceptable salt thereof, wherein the leaving group is trifluoromethanesulfonate.

10 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, selected from the group consisting of:

wherein R 9 is a leaving group, and

wherein R 14 is an amine protecting group.

11 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, selected from the group consisting of:

or a pharmaceutically acceptable salt thereof.

12 . A compound of Formula IV:

or a pharmaceutically acceptable salt thereof;

wherein

and

R 11 is hydrogen or alkyl.

13 . The compound of claim 12 , or a pharmaceutically acceptable salt thereof, selected from

14 . A process for preparing a compound of Formula VI:

comprising:

reducing a compound of Formula V:

15 . The process of claim 14 , wherein said reducing occurs in the presence of a palladium catalyst and a trialkylsilane.

16 . The process of claim 14 , wherein said reducing occurs in the presence of a palladium catalyst and triethylsilane.

17 . The process of claim 14 , further comprising:

mixing the compound of Formula VI with gentisic acid in a solvent to form a compound of Formula XVIII:

18 . The process of claim 17 , wherein the compound of Formula VI is mixed with gentisic acid in the presence of a solvent.

19 . The process of claim 18 , wherein the solvent is a mixture of isopropanol and heptane.

20 . A process for preparing a compound of Formula Va:

wherein R 9 is a leaving group selected from trifluoromethanesulfonate, toluenesulfonate, methanesulfonate;

comprising:

reacting a compound of Formula VII:

with toluenesulfonic anhydride, toluenesulfonyl chloride, methansulfonic anhydride, methansulfonyl chloride, trifluoromethanesulfonic anhydride, or trifluoromethanesulfonyl chloride to form a compound of Formula Va.

21 . The process of claim 20 , wherein the compound of Formula VII is reacted with trifluoromethanesulfonic anhydride or trifluoromethanesulfonyl chloride.

22 . A process of preparing a compound of Formula VII:

comprising:

reacting a compound of Formula VIII:

or a salt thereof,

with an acid to form a compound of Formula VII,

wherein R 14 is an amine protecting group.

23 . The process of claim 22 , wherein the acid is trifluoroacetic acid.

24 . The process of claim 22 , wherein said reacting occurs in the presence of toluene as a solvent.

25 . The process of claim 22 , wherein said reacting occurs at a temperature of from about 20° C. to about 55° C.

26 . A process of preparing a compound of Formula VIII:

or a salt thereof,

comprising:

coupling a compound of Formula IX:

or a salt thereof,

with (4-cyclopropyl-6-methoxypyrimidin-5-yl)boronic acid to form a compound of Formula VIII,

wherein R 14 is an amine protecting group.

27 . The process of claim 26 , wherein said coupling occurs in the presence of a palladium catalyst.

28 . The process of claim 26 , wherein said coupling occurs in the presence of a solvent selected from 1,4-dioxane, water, and mixtures thereof.

29 . The process of claim 26 , wherein said coupling occurs at a temperature of from about 20° C. to about 65° C.

30 . A process of preparing a compound of Formula IX:

or a salt thereof,

comprising:

reacting a compound of Formula X:

or a salt thereof,

with a 2,4-dichloropyrimidine-5-carboxylate ester to form a compound of Formula IX,

wherein R 14 is an amine protecting group.

31 . The process of claim 30 , wherein the 2,4-dichloropyrimidine-5-carboxylate ester is ethyl 2,4-dichloropyrimidine-5-carboxylate.

32 . The process of claim 30 , wherein the 2,4-dichloropyrimidine-5-carboxylate ester is isopropyl 2,4-dichloropyrimidine-5-carboxylate.

33 . The process of claim 30 , wherein the compound of Formula X is reacted with the 2,4-dichloropyrimidine-5-carboxylate ester in the presence of a base and a solvent.

34 . The process of claim 33 , wherein the base is an amine base, and the solvent is an alcohol solvent.

35 . The process of claim 34 , wherein the amine base is 2,6-lutidine.

36 . The process of claim 34 , wherein the solvent is isopropanol.

37 . The process of any of claims 22-36 , wherein the amine protecting group is t-butyloxycarbonyl (Boc).

38 . A process of preparing a compound of Formula X:

or a salt thereof,

comprising:

reacting a compound of Formula XI:

with tert-butyl carbazate and a reducing agent to form a compound of Formula X.

39 . The process of claim 38 , wherein the compound of Formula XI is reacted with tert-butyl carbazate in the presence of sodium cyanoborohydride.

40 . The process of claim 38 , wherein the compound of Formula XI is reacted with tert-butyl carbazate in the presence of hydrogen and a transition metal catalyst.

41 . A process of preparing a compound of Formula XI:

comprising:

reacting a compound of Formula XII:

with a reducing agent to form a compound of Formula XI.

42 . The process of claim 41 , wherein the reducing agent is diisobutylaluminum hydride.

43 . A process of preparing a compound of Formula XII:

comprising:

reacting a compound of Formula XIII:

with an alkylating agent to form a compound of Formula XII.

44 . The process of claim 43 , wherein the alkylating agent is selected from 2-iodopropane, 2-bromopropane, 2-isopropyl mesylate, and 2-isopropyl tosylate.

45 . The process of claim 43 , wherein the alkylating agent is 2-iodopropane.

46 . A process of preparing a compound of Formula XIV:

comprising:

reacting a compound of Formula XV:

or a salt thereof,

with a compound of Formula XVI:

to form a compound of Formula XIV.

47 . The process of claim 46 , wherein the compound of Formula XV is reacted with the compound of Formula XVI in the presence of a solvent and a base.

48 . The process of claim 47 , wherein the solvent is selected from ethanol, isopropanol, and tetrahydrofuran.

49 . The process of claim 47 , wherein the base is an amine base.

50 . The process of claim 49 , wherein the base is selected from triethylamine and diisopropylethylamine.

51 . The process of claim 46 , wherein the compound of Formula XV is reacted with the compound of Formula XVI at a temperature of from −20° C. to 25° C.

52 . The process of claim 46 , wherein the reaction of the compound of Formula XV with the compound of Formula XVI also forms a compound of Formula XVII.

53 . The process of claim 52 , wherein the compound of Formula XVII forms in an amount of less than 5% AUC as compared to the area of the compound of Formula XIV.

54 . The process of claim 52 , wherein the compound of Formula XIV is isolated containing less than 1%, less than 0.5%, less than 0.25%, or less than 0.15% AUC of the compound of Formula XVII.

55 . The process of claim 46 , further comprising reacting the compound of Formula XIV with a compound of Formula XXI

to obtain a compound of Formula VI

56 . The process of claim 55 , further comprising mixing the compound of Formula VI with gentisic acid in a solvent to form a compound of Formula XVIII:

57 . A compound of Formula XIV

or a salt thereof, prepared by the process of claim 47 .

58 . A compound of Formula XVII:

or a salt thereof.

59 . A compound of Formula XX:

or a salt thereof.

60 . A compound of Formula XXVIII:

or a salt thereof.

61 . A compound of Formula XXVIV:

or a salt thereof.

62 . A compound of Formula XXX:

or a salt thereof.

63 . A process of preparing a compound of Formula XIV:

comprising:

reacting a compound of Formula X:

or a salt thereof,

with a compound of Formula XVI:

to form a compound of Formula XIV;

wherein R 14 is an amine protecting group.

64 . A process of preparing a compound of Formula XXX:

comprising:

reacting a compound of Formula XXVIV

or a salt thereof,

with a compound of Formula XVI:

to form a compound of Formula XXX.

65 . The process of claim 64 , wherein the compound of Formula XXVIV is reacted with the compound of Formula XVI in the presence of a solvent and a base.

66 . The process of claim 65 , wherein the solvent is selected from ethanol, isopropanol, or THF.

67 . The process of claim 65 , wherein the base is an amine base.

68 . The process of claim 67 , wherein the base is selected from triethylamine and diisopropylethylamine.

69 . The process of claim 64 , wherein the reaction is conducted at a temperature of between −20° C. and 25° C.

70 . A process of preparing a compound of Formula XXVIV:

or a salt thereof,

comprising:

reacting a compound of Formula XXVIII

with acid to form a compound of Formula XXVIV or a salt thereof.

71 . The process of claim 70 , wherein the acid is selected from hydrochloric acid (HCl), hydrobromic acid (HBr), methanesulfonic acid, toluenesulfonic acid, trifluoroacetic acid, and trifluoromethanesulfonic acid.

72 . The process of claim 70 , wherein the reaction is conducted at a temperature of between between 0 and 75° C.

73 . A process of preparing a compound of Formula XXVIII:

or a salt thereof,

comprising:

reacting a compound of Formula XXVII:

with tert-butyl carbazate and a reducing agent to form a compound of Formula XXVIII.

74 . The process of claim 73 , wherein the compound of Formula XXVII is reacted with tert-butyl carbazate in the presence of hydrogen and a transition metal catalyst.

75 . The process of claim 64 , further comprising reacting the compound of Formula XXX with a compound of Formula XXI:

to form a compound of Formula XXXI:

76 . The process of claim 75 , further comprising reacting the compound of Formula XXXI with

wherein X is a leaving group and R 15 is an alkyl group;

to form a compound of Formula XXXII:

or a salt thereof.

77 . The process of claim 76 , wherein R 15 is an isopropyl group.

78 . The process of claim 76 , wherein R 15 is a methyl group.