IRAK degraders and uses thereof

1. A compound of formula I-xxx-1:

or a pharmaceutically acceptable salt thereof, wherein:

(a)

X and X′ are each independently CR 8 , N or —N + —O − ; Y is independently N, —N + —O − or CR 8 ; provided that at least one of X, X′ or Y is neither N nor —N + —O − and that no more than one of X, X′ or Y is —N + —O − ;

R 1 is C 1 -C 6 alkyl; C 2 -C 6 alkenyl; C 2 -C 6 alkynyl; —(CR 3a R 3b ) m -(3-to 7-membered cycloalkyl); —(CR 3a R 3b ) m -(3 to 7-membered heterocycloalkyl) having one to three heteroatoms; —(CR 3a R 3b ) m -(5-to 10-membered heteroaryl), having one to three heteroatoms; or —(CR 3a R 3b ) m —C 6 -C 12 aryl; wherein said alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, heteroaryl or aryl is optionally substituted with one to five halogen, deuterium, —OR 5 , —SR 5 , —NR 11a R 11b , cyano, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl or —C 1 -C 6 alkoxy;

R 2 is —(CR 3a R 3b ) m -(3- to 10-membered cycloalkyl); —(CR 3a R 3b ) m -(3- to 10-membered heterocycloalkyl) having one to three heteroatoms; —(CR 3a R 3b ) m -(5- to 10 membered heteroaryl) having one to three heteroatoms; or —(CR 3a R 3b ) m —C 6 -C 12 aryl; wherein said cycloalkyl, heterocycloalkyl, heteroaryl or aryl is optionally substituted with one to five R 4 ; and wherein, if the heteroatom on said heterocycloalkyl and heteroaryl is N, said N is

optionally substituted with R 4′ ; or R 2 is C 1 -C 6 alkyl, wherein said alkyl is optionally substituted with NH 2 , OH or cyano;

R 3a and R 3b for each occurrence are independently hydrogen or C 1 -C 3 alkyl;

R 4 for each occurrence is independently a bond, deuterium halogen, cyano, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, oxo, —OR 5 , —SR 5 , —S(O)R 9 , —S(O) 2 R 9 , —NR 11a R 11b , —C(O)R 10 —(CR 3a R 3b ) n -(3- to 7-membered cycloalkyl), —(CR 3a R 3b ) n -(4- to 10-membered heterocycloalkyl), having one to three heteroatoms, —(CR 3a R 3b ) n -(5- to 10 membered heteroaryl), having one to three heteroatoms, or —(CR 3a R 3b ) n —C 6 -C 12 aryl wherein said alkyl, cycloalkyl, heterocycloalkyl, heteroaryl or aryl is each optionally and independently substituted with one to five deuterium, halogen, OR 5 , —SR 5 , —NR 11a R 11b , cyano, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl or —C 1 -C 6 alkoxy; or two R 4 taken together with the respective carbons to which each are bonded form a 3- to 6-membered cycloalkyl or 4- to 6-membered heterocycloalkyl, wherein said cycloalkyl or heterocycloalkyl is optionally substituted with one to three halogen, deuterium, —OR 5 , —SR 5 , —NR 11a R 11b , cyano or C 1 -C 6 alkyl or C 1 -C 6 alkoxy, wherein the alkyl or alkoxy is optionally substituted with halogen, deuterium, —OR 5 , —SR 5 , —NR 11a R 11b , or cyano; and wherein, if a heteroatom on said heterocycloalkyl is N, said N is optionally substituted with R 4′ ;

R 4′ is independently C 1 -C 6 alkyl, C 2 -C 6 alkenyl, —C(O)R 10 , —S(O) 2 R 9 , —(CR 3a R 3b ) n -(3- to 7-membered cycloalkyl), —(CR 3a R 3b ) n -(4- to 10-membered heterocycloalkyl) or C(O)(CH 2 ) t CN; wherein said alkyl, alkenyl, cycloalkyl, or heterocycloalkyl is each optionally and independently substituted with one to five deuterium, halogen, OH, cyano or C 1 -C 6 alkoxy; or R 4 and R 4′ taken together with the respective atoms to which each are bonded form a 3- to 6-membered cycloalkyl or 4- to 6-membered heterocycloalkyl, wherein said cycloalkyl or heterocycloalkyl is optionally substituted with one to three halogen, deuterium, —OR 5 , —SR 5 , —NR 11a R 11b , cyano, C 1 -C 6 alkyl or C 1 -C 6 alkoxy, wherein the alkyl or alkoxy is optionally substituted with halogen, deuterium, —OR 5 , —SR 5 , —NR 11a R 11b , or cyano;

R 5 is independently hydrogen or C 1 -C 6 alkyl, wherein said alkyl is optionally substituted with halogen, deuterium, C 1 -C 6 alkoxy, C 1 -C 6 alkylthiolyl, —NR 11a R 11b , cyano, C 1 -C 6 alkyl or C 3 -C 6 cycloalkyl; or two R taken together with the oxygen atoms to which they are bonded form a 5- or 6-membered heterocycloalkyl;

R 6 is —C(O)NHR 7 , CO 2 R 7 or cyano;

R 7 is hydrogen or C 1 -C 6 alkyl;

each R 8 is independently hydrogen, halogen, cyano, —OR 5 , —SR 5 , —NR 11a R 11b , C 6 alkyl, C 3 -C 6 cycloalkyl, 3 to 10-membered heterocycloalkyl or 5- to 6-membered heteroaryl or aryl, wherein said alkyl, cycloalkyl, heterocycloalkyl, heteroaryl or aryl is optionally substituted with one to three halogen, —NR 11a R 11b OR 5 , —SR 5 , cyano, C 1 -C 3 alkyl, —C(O)R 10 or oxo;

R 8′ is hydrogen, deuterium, halogen, cyano, —OR 5 , —SR 5 or NR 11a R 11b ;

R 9 is —(CR 3a R 3b ) p —(C 1 -C 3 alkyl), —(CR 3a R 3b ) p -(4- to 6-membered cycloalkyl), —(CR 3a R 3b ) p -(4- to 6-membered heterocycloalkyl) or —(CR 3a R 3b ) p —(C 5 -C 9 aryl), wherein said alkyl, cycloalkyl, heterocycloalkyl or aryl are each optionally substituted with fluoro or C 1 -C 3 alkyl;

R 10 is C 1 -C 6 alkyl, wherein said alkyl is optionally substituted with deuterium, halogen, OH, C 1 -C 6 alkoxy or cyano;

R 11a and R 11b are each independently hydrogen or C 1 -C 6 alkyl, wherein said alkyl is optionally substituted with deuterium, C 1 -C 6 alkoxy or cyano; and if C 2 -C 6 alkyl, said alkyl is optionally substituted with deuterium, C 1 -C 6 alkoxy, cyano, halogen or OH;

m is independently 0, 1, 2 or 3;

n is independently 0, 1, 2 or 3;

p is independently 0 or 1; and

t is 1,2 or 3;

(b)

L is a covalent bond or a bivalent, saturated or unsaturated, straight or branched C 1-50 hydrocarbon chain, wherein 0-6 methylene units of L are independently replaced by -Cy-, —O—, —NR—, —S—, —OC(O)—, —C(O)O—, —C(O)—, —S(O)—, —S(O) 2 —, —NRS(O) 2 —, —S(O) 2 NR—, —NRC(O)—, —C(O)NR—, —OC(O)NR—, —NRC(O)O—,

wherein:

each -Cy- is independently an optionally substituted bivalent ring selected from phenylenyl, an 8-10 membered bicyclic arylenyl, a 4-7 membered saturated or partially unsaturated carbocyclylenyl, a 4-7 membered saturated or partially unsaturated spiro carbocyclylenyl, an 8-10 membered bicyclic saturated or partially unsaturated carbocyclylenyl, a 4-7 membered saturated or partially unsaturated heterocyclylenyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 4-7 membered saturated or partially unsaturated spiro heterocyclylenyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, an 8-10 membered bicyclic saturated or partially unsaturated heterocyclylenyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 5-6 membered heteroarylenyl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and an 8-10 membered bicyclic heteroarylenyl having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur;

each of n is independently 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; and

each R is independently hydrogen, or an optionally substituted group selected from C 1-6 aliphatic, phenyl, a 4-7 membered saturated or partially unsaturated heterocyclic having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; and

(c)

LBM is

wherein:

X 1 is —C(O)—;

X 2 is —C(O)—;

X 3 is —CH 2 — or —C(O)—;

R 1 is hydrogen or C 1-4 aliphatic;

each of R 2 is independently hydrogen, halogen, C 1-4 aliphatic or —OC 1-4 aliphatic;

Ring A is a fused ring selected from 6-membered aryl containing 0-1 nitrogen atoms; and

m is 0, 1, 2, 3 or 4.

2. The compound of claim 1 , wherein X is N, X′ is CR 8 and Y is CR 8′ ; X is N, X′ is N and Y is CR 8′ ; X is N, X′ is CR 8 and Y is N; X is CR 8 , X′ and Y are N; X and X′ are CR 8 and Y is N; X is CR 8 and Y is CR 8 ′ and X′ is N; or X and X′ are CR 8 and Y is CR 8′ .

3. The compound of claim 1 , wherein R 1 is C 1 -C 6 alkyl.

4. The compound of claim 1 , wherein R 2 is —(CR 3a R 3b ) m -(3- to 10-membered heterocycloalkyl) having one to three heteroatoms; wherein said heterocycloalkyl is optionally substituted with one to five R 4 .

5. The compound of claim 1 , wherein R 6 is —C(O)NHR 7 or cyano.

6. The compound according to claim 1 , wherein

wherein

is attached to a modifiable carbon or nitrogen atom.

7. The compound according to claim 1 , wherein R 8 is

8. The compound according to claim 1 , wherein the LBM is selected from:

9. The compound of claim 1 , wherein L is a covalent bond or a bivalent, saturated or unsaturated, straight or branched C 1-20 hydrocarbon chain, wherein 0-6 methylene units of L are independently replaced by -Cy-, —O—, —NR—, —S—, —OC(O)—, —C(O)O—, —C(O)—, —S(O)—, —S(O) 2 —, —NRS(O) 2 —, —S(O) 2 NR—, —NRC(O)—, —C(O)NR—, —OC(O)NR—, or —NRC(O)O—.

10. The compound according to claim 1 , wherein L is selected from:

11. The compound according to claim 1 , wherein said compound is selected from any one of the following compounds, or a pharmaceutically acceptable salt thereof,

12. A pharmaceutical composition comprising a compound according to claim 1 , and a pharmaceutically acceptable carrier, adjuvant, or vehicle.

13. A method of degrading IRAK4 protein kinase in a patient or biological sample comprising administering to said patient, or contacting said biological sample with a compound according to claim 1 , or a pharmaceutical composition thereof.

14. A method of treating an IRAK4-mediated disorder, disease, or condition in a patient comprising administering to said patient a compound according to claim 1 , or a pharmaceutical composition thereof.

15. The method according to claim 14 , wherein the IRAK4-mediated disorder, disease or condition is selected from a cancer, a neurodegenerative disease, a viral disease, an autoimmune disease, an inflammatory disorder, a hereditary disorder, a hormone-related disease, a metabolic disorder, a condition associated with organ transplantation, an immunodeficiency disorder, a destructive bone disorder, a proliferative disorder, an infectious disease, a condition associated with cell death, thrombin-induced platelet aggregation, liver disease, a pathologic immune condition involving T cell activation, a cardiovascular disorder, and a CNS disorder.

16. The method of claim 14 , wherein the IRAK4-mediated disorder, disease or condition is selected from a MyD88 driven disorder.

17. The method of claim 16 , wherein the MyD88 driven disorder is selected from ABC DLBCL, Waldenstrom's macroglobulinemia, Hodgkin's lymphoma, primary cutaneous T-cell lymphoma, and chronic lymphocytic leukemia.