Process for the preparation of kinase inhibitors and intermediates thereof

1. A method of synthesizing a compound of Formula (I-a):

or a pharmaceutically acceptable salt thereof; wherein each R is independently selected from the group consisting of C 1-4 alkyl, halogen, C 1 -C 4 alkoxy and cyano; and n is an integer from 0 to 3;

comprising:

(a) reacting a compound of Formula (II-a), wherein PG is a nitrogen protecting group,

with 6-aminoisoquinoline to form a compound of Formula (III-a)

wherein each R is independently selected from the group consisting of C 1-4 alkyl, halogen, C 1-4 alkoxy and cyano; and n is an integer from 0 to 3; and

(b) removing the nitrogen protecting group to form the compound of Formula (I-a).

2. The method of claim 1 , further comprising:

(a) reacting a compound of Formula (IV-a),

wherein each R is independently selected from the group consisting of C 1-4 alkyl, halogen, C 1-4 alkoxy and cyano; n is an integer from 0 to 3; and T is a chiral auxiliary; with

wherein PG is a nitrogen protecting group, in the presence of a base;

to form a compound of Formula (V-a):

wherein each R is independently selected from the group consisting of C 1-4 alkyl, halogen, C 1-4 alkoxy and cyano; n is an integer from 0 to 3; and T is a chiral auxiliary; and

(b) removing the chiral auxiliary to form the compound of Formula (II-a).

3. The method of claim 2 , further comprising converting a compound of Formula (VIII-a):

wherein each R is independently selected from the group consisting of C 1-4 alkyl, halogen, C 1-4 alkoxy and cyano; n is an integer from 0 to 3; and R1 is halogen, OR a , OC(O)R b , SR a , or SC(O)R b ; wherein R a is H, alkyl or aryl, and R b is alkyl or aryl;

to the compound of Formula (IV-a):

wherein each R is independently selected from the group consisting of C 1-4 alkyl, halogen, C 1-4 alkoxy and cyano; n is an integer from 0 to 3; and T is a chiral auxiliary.

4. The method of claim 3 , wherein the compound of Formula (II-a) is synthesized by a method comprising:

(a) reacting

with a compound of Formula (VI-a),

wherein each R is independently selected from the group consisting of C 1-4 alkyl, halogen, C 1-4 alkoxy and cyano; and n is an integer from 0 to 3;

to form a compound of formula (VII-a),

wherein each R is independently selected from the group consisting of C 1-4 alkyl, halogen, C 1-4 alkoxy and cyano; and n is an integer from 0 to 3; and

(b) converting the compound of Formula (VII-a) into the compound of Formula (VIII-a).

5. The method of claim 1 , wherein n is 2 and each R is methyl.

6. The method of claim 1 , wherein the compound of Formula (I-a) is

7. The method of claim 3 , wherein the compound of Formula (VIII-a) is

8. The method of claim 1 , wherein n is 0.

9. The method of claim 2 , wherein T is

wherein

Z is S or O;

B is S or O;

R c is hydrogen, C 1-4 alkyl, or aryl; and

R d is C 1-4 alkyl, C 3-7 branched alkyl; arylalkyl or aryl.

10. The method of claim 9 , wherein T is

wherein

Z is S or O;

B is S or O;

R c is hydrogen or aryl; and

R d is C 1-4 alkyl, arylalkyl or aryl.

11. The method of claim 10 , wherein T is selected from the group consisting of:

12. The method of claim 11 , wherein T is

13. A method of synthesizing a compound of the following formula

or pharmaceutically acceptable salt thereof; comprising:

(a) reacting

with a chlorinating agent, to form an acid chloride;

(b) crystallizing the acid chloride from n-heptane to form a purified acid chloride;

(c) reacting the purified acid chloride with

in the presence of a base, to form

(d) reacting the product of step (c) with

in the presence of a base at a temperature between −50° C. and −20° C. to form

(e) reacting the product of step (d) with LiOOH to form

(f) recrystallizing the product of step (e) to form a purified product of step (e);

(g) activating the carboxylic acid group of the purified product of step (f) and reacting the activated carboxylic acid with 6-aminoisoquinoline to form

(h) recrystallizing the product of step (g);

(i) reacting the product of step (h) with at least 2 equivalents of MeSO 3 H to form

14. The method of claim 13 , wherein the chlorinating agent of step (a) is oxalyl chloride or thionyl chloride.

15. The method of claim 13 , wherein the base of step (c) is NaH, LiH, KH, nBuLi, secBuLi, LiHMDS, NaHMDS, or KHMDS and step (b) is performed at a temperature between −90° C. and 50° C.

16. The method of claim 13 , wherein the base of step (d) is LiHMDS or NaH.

17. The method of claim 13 , wherein the LiOOH is formed in situ by lithium hydroxide and hydrogen peroxide.

18. The method of claim 13 , wherein the carboxylic acid group is activated in step (g) by addition of trichlorodimethyl ethyl chloroformate and collidine at a temperature of about 0° C.

19. The method of claim 18 , wherein the purified product of step (f), 6-aminoisoquinoline, and collidine are mixed followed by addition of trichlorodimethyl ethyl chloroformate.

20. The method of claim 18 , wherein the carboxylic acid group is activated by conversion to a mixed anhydride intermediate.

21. A method for the synthesis of the compound of formula (I):

or a pharmaceutically acceptable salt thereof; wherein A is cyclohexyl or phenyl, substituted with 0-3 substituents independently selected from the group consisting of alkyl, halogen, alkoxy, and cyano comprising

(a) reacting a compound of Formula (II), wherein PG is a nitrogen protecting group,

with 6-aminoisoquinoline to form a compound of Formula (III)

wherein A is cyclohexyl or phenyl, substituted with 0-3 substituents independently selected from the group consisting of alkyl, halogen, alkoxy, and cyano; and

(b) removing the nitrogen protecting group to form the compound of Formula (I).

22. A compound selected from the group consisting of