TYK2 INHIBITOR SYNTHESIS AND INTERMEDIATES THEREOF

1 . A method for preparing Compound 1:

or a pharmaceutically acceptable salt or solvate thereof, the method comprising deprotecting a compound of formula I:

or a pharmaceutically acceptable salt thereof, wherein PG is a suitable amino protecting group.

2 . The method of claim 1 , further comprising the steps of:

a) cross-coupling a compound of formula II:

 or a pharmaceutically acceptable salt thereof, wherein PG is a suitable amino protecting group; with Compound 4:

 or a pharmaceutically acceptable salt thereof, to produce a compound of formula I; and

b) deprotecting the compound of formula I:

 or a pharmaceutically acceptable salt thereof.

3 . The method of claim 2 , further comprising the steps of:

a) amidating a compound of formula III:

 or a pharmaceutically acceptable salt thereof, wherein PG is a suitable amino protecting group; with Compound 5:

 or a pharmaceutically acceptable salt thereof,

to produce the compound of formula II;

b) cross-coupling the compound of formula II:

 or a pharmaceutically acceptable salt thereof, wherein PG is a suitable amino protecting group; with Compound 4:

 to produce the compound of formula I; and

c) deprotecting the compound of formula I:

 or a pharmaceutically acceptable salt thereof, to produce Compound 1.

4 . The method of any one of claims 1-3 , wherein PG is t-butyloxycarbonyl (BOC), ethyloxycarbonyl, methyloxycarbonyl, trichloroethyloxycarbonyl, allyloxycarbonyl (Alloc), benzyloxocarbonyl (CBZ), allyl, benzyl (Bn), fluorenylmethylcarbonyl (Fmoc), acetyl, chloroacetyl, dichloroacetyl, trichloroacetyl, trifluoroacetyl, phenylacetyl, or benzoyl.

5 . The method of any one of claims 1-4 , wherein PG is t-butyloxycarbonyl (BOC).

6 . The method of any one of claims 1-5 , wherein the compound of formula I is Compound 2:

or a pharmaceutically acceptable salt thereof.

7 . The method of any one of claims 2-6 , wherein the compound of formula II is Compound 6:

or a pharmaceutically acceptable salt thereof.

8 . The method of any one of claims 3-7 , wherein the compound of formula III is Compound 7:

or a pharmaceutically acceptable salt thereof.

9 . A method of preparing a compound of formula I:

or a pharmaceutically acceptable salt thereof, wherein PG is a suitable amino protecting group, the method comprising cross-coupling a compound of formula III:

or a pharmaceutically acceptable salt thereof, with Compound 4:

or a pharmaceutically acceptable salt thereof.

10 . The method of claim 9 , further comprising:

a) amidating a compound of formula III:

 or a pharmaceutically acceptable salt thereof, with Compound 5:

 or a pharmaceutically acceptable salt thereof;

to produce the compound of formula II; and

b) cross-coupling the compound of formula II:

 or a pharmaceutically acceptable salt thereof, with Compound 4:

 or a pharmaceutically acceptable salt thereof,

to produce the compound of formula I.

11 . A method of preparing a compound of formula II:

or a pharmaceutically acceptable salt thereof, wherein PG is a suitable amino protecting group; the method comprising amidating a compound of formula III:

or a pharmaceutically acceptable salt thereof, with Compound 5:

or a pharmaceutically acceptable salt thereof; to produce the compound of formula II.

12 . The method of any one of claims 9-11 , wherein PG is t-butyloxycarbonyl (BOC), ethyloxycarbonyl, methyloxycarbonyl, trichloroethyloxycarbonyl, allyloxycarbonyl (Alloc), benzyloxocarbonyl (CBZ), allyl, benzyl (Bn), fluorenylmethylcarbonyl (Fmoc), acetyl, chloroacetyl, dichloroacetyl, trichloroacetyl, trifluoroacetyl, phenylacetyl, or benzoyl.

13 . The method of any one of claims 9-12 , wherein PG is t-butyloxycarbonyl (BOC).

14 . The method of claim 9 or 10 , wherein the compound of formula I is Compound 2:

or a pharmaceutically acceptable salt thereof.

15 . The method of any one of claims 9-14 , wherein the compound of formula II is Compound 6:

or a pharmaceutically acceptable salt thereof.

16 . The method of any one of claims 10-15 , wherein the compound of formula III is Compound 7:

or a pharmaceutically acceptable salt thereof.

17 . Compound 1, or a pharmaceutically acceptable salt or solvate thereof, produced by the method of any one of claims 1-8 :

18 . A compound of Formula I:

or a pharmaceutically acceptable salt or solvate thereof, wherein:

PG is a suitable amino protecting group.

19 . The compound of claim 18 , wherein the compound of formula I is Compound 2:

or a pharmaceutically acceptable salt thereof.

20 . A compound of formula II:

or a pharmaceutically acceptable salt or solvate thereof, wherein:

PG is a suitable amino protecting group.

21 . The compound of claim 20 , wherein the compound of formula II is Compound 6:

or a pharmaceutically acceptable salt or solvate thereof.

22 . The compound of claim 18 or 20 , wherein PG is t-butyloxycarbonyl (BOC), ethyloxycarbonyl, methyloxycarbonyl, trichloroethyloxycarbonyl, allyloxycarbonyl (Alloc), benzyloxocarbonyl (CBZ), allyl, benzyl (Bn), fluorenylmethylcarbonyl (Fmoc), acetyl, chloroacetyl, dichloroacetyl, trichloroacetyl, trifluoroacetyl, phenylacetyl, or benzoyl.

23 . The compound of any one of claims 18, 20, or 22 , wherein PG is t-butyloxycarbonyl (BOC).

24 . A method of inhibiting a TYK2 protein kinase, or a mutant thereof, in a patient comprising administering to the patient a therapeutically effective amount of Compound 1:

or a pharmaceutically acceptable salt or solvate thereof, wherein Compound 1 is produced by the method of any one of claims 1-8 .