Process for the preparation of kinase inhibitors and intermediates thereof
Described are processes for the synthesis of certain compounds, useful for treating diseases, e.g. eye disease, such as glaucoma and ocular hypertension, in a subject.
1. A method for the synthesis of a compound of Formula (I):
or a pharmaceutically acceptable salt thereof; wherein A is cyclohexyl or phenyl, substituted with 0-3 substituents independently selected from alkyl, halogen, alkoxy, or cyano;
the method 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 alkyl, halogen, alkoxy, or cyano; and
(b) removing the nitrogen protecting group to form the compound of Formula (I);
further comprising:
(c) reacting a compound of Formula (IV),
wherein A is cyclohexyl or phenyl, substituted with 0-3 substituents independently selected from alkyl, halogen, alkoxy, or cyano; and T is a chiral auxiliary; with
wherein PG is a nitrogen protecting group;
to form a compound of Formula (V):
wherein A is cyclohexyl or phenyl, substituted with 0-3 substituents independently selected from alkyl, halogen, alkoxy, or cyano; and T is a chiral auxiliary; and
(d) removing the chiral auxiliary to form the compound of Formula (II).
2. The method of claim 1 , further comprising converting a compound of Formula (VIII):
wherein A is cyclohexyl or phenyl, substituted with 0-3 substituents independently selected from alkyl, halogen, alkoxy, or cyano; and R 1 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):
wherein A is cyclohexyl or phenyl, substituted with 0-3 substituents independently selected from alkyl, halogen, alkoxy, or cyano; and T is a chiral auxiliary.
3. The method of claim 2 , wherein the compound of Formula (II) is synthesized by a method comprising:
(a) reacting
with a compound of Formula (VI),
wherein A is cyclohexyl or phenyl, substituted with 0-3 substituents independently selected from alkyl, halogen, alkoxy, or cyano;
to form a compound of formula (VII-a),
wherein A is cyclohexyl or phenyl, substituted with 0-3 substituents independently selected from alkyl, halogen, alkoxy, or cyano; and
(b) converting the compound of Formula (VII) into the compound of Formula (VIII).
4. The method of claim 1 , 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.
5. The method of claim 4 , 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.
6. The method of claim 5 , wherein T is selected from:
7. The method of claim 6 , wherein T is