Potent and selective irreversible inhibitors of IRAK1

1 . A compound of Formula I:

or a pharmaceutically acceptable salt thereof;

wherein

A is piperidinyl;

B is CH or CR 5 ;

C is CH;

D is N;

L is selected from the group consisting of

R 1 is pyrazole or isoxazole optionally substituted one or two times with R 8 ;

R 3 is selected from the group consisting of halogen, C 1 -C 6 alkyl, C(O)C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, 3-8 membered cycloalkyl, 3-8 membered heterocycloalkyl, 6-10 membered aryl, 5-10 membered heteroaryl, OR 9 , N(R 9 ) 2 , and SR 9 , wherein alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are optionally substituted with one, two, or three R 9 ;

R 4 is independently, at each occurrence, selected from the group consisting of hydrogen, halogen, and C 1 -C 2 alkyl, wherein alkyl is optionally substituted with one, two, or three fluorine atoms;

R 5 is selected from the group consisting of halogen, C 1 -C 6 alkyl, C(O)C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, OR 9 , N(R 9 ) 2 , and SR 9 , wherein alkyl is optionally substituted with one, two, or three halogen;

R 8 is selected from the group consisting of C 1 -C 6 alkyl, OH, CN, NO 2 , halogen, C 1 -C 6 alkoxy, and C 1 -C 6 alkylamine, wherein alkyl is optionally substituted one, two, or three times with halogen, OH, and NH 2 ;

R 9 is independently, at each occurrence, selected from the group consisting of hydrogen, halogen, C 1 -C 6 alkyl, C(O)C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, 3-8 membered cycloalkyl, 3-8 membered heterocycloalkyl, 6-10 membered aryl, and 5-10 membered heteroaryl;

alternatively, two R 9 , together with the atoms to which they are attached form a 3-8 membered heterocycloalkyl;

R 2 is

n is 0 or 1; and

p is 0, 1, or 2.

2 . The compound of claim 1 , wherein the compound of Formula I is a compound of Formula IV:

or a pharmaceutically acceptable salt thereof.

3 . The compound of claim 1 , wherein the compound of Formula I is a compound of Formula IVa:

or a pharmaceutically acceptable salt thereof.

4 . The compound of claim 1 , wherein B is CH.

5 . The compound of claim 1 , wherein B is CR 5 .

6 . The compound of claim 1 , wherein the compound of Formula I is selected from the group consisting of

or a pharmaceutically acceptable salt thereof.

7 . A pharmaceutical composition comprising a compound of claim 1 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

8 . A method of inhibiting interleukin-1 receptor-associated kinase 1 (IRAK1) in a subject in need thereof comprising administering to the subject a therapeutically effective amount of a compound of claim 1 .

9 . A method of treating a proliferative disease associated with overexpression, aberrant activity, or increased activity of interleukin-1 receptor-associated kinase (IRAK) in a subject in need thereof comprising administering to the subject a therapeutically effective amount of a compound of claim 1 .

10 . The method of claim 9 , wherein the proliferative disease is associated with overexpression of interleukin-1 receptor-associated kinase 1 (IRAK1) or interleukin-1 receptor-associated kinase 4 (IRAK4).

11 . The method of claim 10 , wherein the proliferative disease is cancer, an inflammatory disease, or an autoimmune disease.

12 . The method of claim 11 , wherein the proliferative disease is cancer.

13 . The method of claim 12 , wherein the cancer is selected from the group consisting of breast cancer, Waldenström macroglobulinemia, myelodysplastic syndrome (MDS), leukemia, and lymphoma.

14 . The method of claim 12 , wherein the cancer is triple-negative breast cancer (TNBC) or acute myeloid leukemia (AML).

15 . The method of claim 12 , wherein the cancer is acute myeloid leukemia (AML).

16 . The method of claim 9 , wherein the method further comprises administering a second pharmaceutical agent.

17 . The method of claim 16 , wherein the second pharmaceutical agent is a Bruton's tyrosine kinase (BTK) inhibitor.