IRAK degraders and uses thereof

1. A compound of formula I:

or a pharmaceutically acceptable salt thereof, wherein:

(a)

IRAK is an IRAK binding moiety capable of binding to IRAK4, said compound of formula I is a compound of formula I-pp-1:

or a pharmaceutically acceptable salt thereof, wherein:

Ring A is a 3-7 membered saturated or partially unsaturated carbocyclic ring or a 4-7 membered saturated or partially unsaturated heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur;

Ring B is

wherein represents the portion of the ring fused to the pyrimidine ring and # is -L 2 (R 4 ) P —R X ;

each R 1 and R 1′ is independently —R 2 , halogen, —CN, —NO 2 , —OR, —SR, —N(R) 2 , —S(O) 2 R, —S(O) 2 N(R) 2 , —S(O)R, —C(O)R, —C(O)OR, —C(O)N(R) 2 , —C(O)N(R)OR, —N(R)C(O)OR, —N(R)C(O)N(R) 2 , Cy, or —N(R)S(O) 2 R; or R 1 is selected from one of the following formulae:

two R 1 groups are taken together with their intervening atoms to form an optionally substituted 4-7 membered fused, spiro-fused, or bridged bicyclic ring having 0-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur;

each Cy is independently an optionally substituted ring selected from a 3-7 membered saturated or partially unsaturated carbocyclic ring or a 4-10 membered saturated or partially unsaturated heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur;

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

two R groups on the same nitrogen are taken together with their intervening atoms to form a 4-7 membered saturated, partially unsaturated, or heteroaryl ring having 0-3 heteroatoms, in addition to the nitrogen, independently selected from nitrogen, oxygen, or sulfur;

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

each R 4 is independently halogen, —CN, —NO 2 , —OR, —SR, —N(R) 2 , —S(O) 2 R, —S(O) 2 N(R) 2 , —S(O)R, —C(O)R, —C(O)OR, —C(O)N(R) 2 , —N(R)C(O)R, —N(R)C(O)N(R) 2 , —C(O)N(R)OR, —N(R)C(O)OR, —N(R)S(O) 2 N(R) 2 , —N(R)S(O) 2 R, or an optionally substituted group selected from C 1-6 aliphatic, phenyl, 4-7 membered saturated or partially unsaturated heterocyclic having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur;

R x is hydrogen, —R 2 , —CN, —NO 2 , halogen, —C(O)N(R) 2 , —C(O)OR, —C(O)R, —N(R) 2 , —NH[Ar], —OR, or —S(O) 2 N(R) 2 ;

R z is hydrogen, —R 2 , —CN, —NO 2 , halogen, —C(O)N(R) 2 , —C(O)OR, —C(O)R, —N(R) 2 , —NH[Ar], —OR, or —S(O) 2 N(R) 2 ;

[Ar] is phenyl or a 5-6 membered heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein [Ar] is substituted by m instances of R1;

L 1 is a covalent bond or a C 1-6 bivalent hydrocarbon chain wherein one or two methylene units of the chain are optionally and independently replaced by —N(R)—, —N(R)C(O)—, —C(O)N(R)—, —N(R)S(O) 2 —, —S(O) 2 N(R)—, —O—, —C(O)—, —OC(O)—, —C(O)O—, —S—, —S(O)— or —S(O) 2 —;

L 2 is a covalent bond or a C 1-6 bivalent hydrocarbon chain wherein one or two methylene units of the chain are optionally and independently replaced by —N(R)—, —N(R)C(O)—, —C(O)N(R)—, —N(R)S(O) 2 —, —S(O) 2 N(R)—, —O—, —C(O)—, —OC(O)—, —C(O)O—, —S—, —S(O)— or —S(O) 2 —;

m is 0-4;

n is 0-4; and

p is 0-2;

(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 according to 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 —, —or

S(O) 2 NR—, —NRC(O)—, —C(O)NR—, —OC(O)NR—, —NRC(O)O—.

3. The compound according to claim 1 , wherein the IRAK4 binding moiety is

wherein

is attached to a modifiable carbon or nitrogen atom.

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

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

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

I-691

I-692

.

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

8. The pharmaceutical composition according to claim 7 , further comprising an additional therapeutic agent.

9. 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.

10. 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.

11. The method according to claim 10 , further comprising administration of an additional therapeutic agent.

12. The method according to claim 10 , 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.

13. The method of claim 10 , wherein the IRAK4-mediated disorder, disease or condition is selected from a MyD88 driven disorder.

14. The method of claim 13 , wherein the MyD88 driven disorder is selected from ABC DLBCL, Waldenström's macroglobulinemia, Hodgkin's lymphoma, primary cutaneous T-cell lymphoma, and chronic lymphocytic leukemia.