Methods of Making Modified BTK Inhibitors

1 . A compound of Formula (1):

or a pharmaceutically acceptable salt thereof, wherein:

X is chosen from —OH, —OY, —Y 2 , and -(halo) 2 , and Y is C 1 -C 4 alkyl optionally substituted with 1 to 3 halo.

2 . A compound of Formula (2):

or a pharmaceutically acceptable salt thereof, wherein:

X is chosen from —OH, —OY, —Y 2 , and -(halo) 2 , and Y is C 1 -C 4 alkyl optionally substituted with 1 to 3 halo.

3 . A compound of Formula (3):

or a pharmaceutically acceptable salt thereof, wherein:

X is chosen from —OH, —OY, —Y 2 , and -(halo) 2 , and Y is C 1 -C 4 alkyl optionally substituted with 1 to 3 halo.

4 . A compound of Formula (4):

or a pharmaceutically acceptable salt thereof, wherein:

X is chosen from —OH, —OY, —Y 2 , and -(halo) 2 , and Y is C 1 -C 4 alkyl optionally substituted with 1 to 3 halo.

5 . A compound of Formula (5):

or a pharmaceutically acceptable salt thereof, wherein:

X is chosen from —OH, —OY, —Y 2 , and -(halo) 2 , and Y is C 1 -C 4 alkyl optionally substituted with 1 to 3 halo.

6 . A compound of Formula (6):

or a pharmaceutically acceptable salt thereof, wherein:

X is chosen from —OH, —OY, —Y 2 , and -(halo) 2 , and Y is C 1 -C 4 alkyl optionally substituted with 1 to 3 halo.

7 . A compound of Formula (7):

or a pharmaceutically acceptable salt thereof, wherein:

X is chosen from —OH, —OY, —Y 2 , and -(halo) 2 , and Y is C 1 -C 4 alkyl optionally substituted with 1 to 3 halo.

8 . A compound of Formula (8):

or a pharmaceutically acceptable salt thereof, wherein:

X is chosen from —OH, —OY, —Y 2 , and -(halo) 2 , and Y is C 1 -C 4 alkyl optionally substituted with 1 to 3 halo.

9 . A compound of Formula (9):

or a pharmaceutically acceptable salt thereof, wherein:

X is chosen from —OH, —OY, —Y 2 , and -(halo) 2 , and Y is C 1 -C 4 alkyl optionally substituted with 1 to 3 halo.

10 . The compound of any one of claims 1 to 9 , wherein Y is chosen from methyl, ethyl, CH(halo) 2 , and C(halo) 3 .

11 . The compound of any one of claims 1 to 10 , wherein halo is F.

12 . The compound of any one of claims 1 to 11 chosen from:

Com-

pound

No.

Structure

1-A

1-B

1-C

1-D

2-A

2-B

2-C

2-D

3-A

3-B

3-C

3-D

4-A

4-B

4-C

4-D

5-A

5-B

5-C

5-D

6-A

6-B

6-C

6-D

7-A

7-B

7-C

7-D

8-A

8-B

8-C

8-D

9-A & 9-A′

9-B

9-C

or a pharmaceutically acceptable salt thereof.

13 . A composition comprising a pharmaceutically acceptable excipient and at least one compound chosen from any one of claims 1 to 12 .

14 . A method of treating a disease or disorder mediated by BTK comprising administering to a patient in need thereof an effective amount of a compound chosen from any one of claims 1 to 12 , or a composition according to claim 13 .

15 . A method of preparing a compound of Formula (3-A):

comprising:

(a) coupling a compound of Formula (2-a):

with a compound of Formula (2-b):

to provide a compound of Formula (2-c):

(b) coupling the compound of Formula (2-c) with the compound of Formula (2-d):

to provide a compound of Formula (2-e):

(c) undergoing a ring-formation reaction in the compound of Formula (2-e) to provide a compound of Formula (2-f):

(d) coupling the compound of Formula (2-f) with the compound of Formula (1-b):

to provide a compound of Formula (2-h):

(e) deprotecting the nitrogen substituted on the pyridine of the compound of Formula (2-h) to provide a compound of Formula (2-i):

(f) deprotecting the piperidine nitrogen of the compound of Formula (2-i) to provide a compound of Formula (2-j):

(g) coupling the compound of Formula (2-j) with the compound of Formula (1-g):

to provide a compound of Formula (3-b):

(h) deprotecting the oxygen of the compound of Formula (3-b) to provide a compound of Formula (3-A).