IP Library › Granted Patent US 11,117,889

Granted Patent B1

US 11,117,889 · App. 17/025,774 · Granted Sep 14, 2021

IRAK degraders and uses thereof

Inventors: Nello Mainolfi (Belmont, MA); Nan Ji (Arlington, MA); Arthur F. Kluge (Gainesville, FL); Matthew M. Weiss (Boston, MA); Yi Zhang (Belmont, MA); Xiaozhang Zheng (Lexington, MA)

Assignee: KYMERA THERAPEUTICS, INC.

C07D413/14 A61P29/00

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Quick Facts

Patent No.: US 11,117,889
App. No.: 17/025,774
Granted: Sep 14, 2021
Kind: B1

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Abstract

The present invention provides compounds, compositions thereof, and methods of using the same.

Claims (67)

1. A compound of formula II-f-5:

or a pharmaceutically acceptable salt thereof, wherein:

X 1 is a bivalent moiety selected from a covalent bond, —CH 2 —, —C(O)—, —C(S)—, and

R 1a is hydrogen, halogen, —CN, —OR, —SR, —S(O)R, —S(O) 2 R, —N(R) 2 , —Si(R) 3 , or an optionally substituted C 1-4 aliphatic;

each R 2a is independently hydrogen, R 6a , halogen, —CN, —NO 2 , —OR, —SR, —NR 2 , —S(O) 2 R, —S(O) 2 NR 2 , —S(O)R, —C(O)R, —C(O)OR, —C(O)NR 2 , —C(O)N(R)OR, —OC(O)R, —OC(O)NR 2 , —N(R)C(O)OR, —N(R)C(O)R, —N(R)C(O)NR 2 , or —N(R)S(O) 2 R;

Ring A a is a bicyclic or tricyclic ring selected from

Ring B a is a fused ring selected from 6-membered aryl containing 0-2 nitrogen atoms, 5 to 7-membered partially saturated carbocyclyl, 5 to 7-membered partially saturated heterocyclyl with 1-2 heteroatoms independently selected from nitrogen, oxygen or sulfur, or 5-membered heteroaryl with 1-3 heteroatoms independently selected from nitrogen, oxygen or sulfur;

R 3a is selected from hydrogen, halogen, —OR, —N(R) 2 , or —SR;

each R 4a is independently hydrogen, R 6a , halogen, —CN, —NO 2 , —OR, —SR, —NR 2 , —S(O) 2 R, —S(O) 2 NR 2 , —S(O)R, —C(O)R, —C(O)OR, —C(O)NR 2 , —C(O)N(R)OR, —OC(O)R, —OC(O)NR 2 , —N(R)C(O)OR, —N(R)C(O)R, —N(R)C(O)NR 2 , or —N(R)S(O) 2 R;

R 5a is hydrogen, C 1-4 aliphatic, or —CN;

each R 6a is independently an optionally substituted group selected from C 1-6 aliphatic, phenyl, a 4-7 membered saturated or partially unsaturated heterocyclic ring 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;

Ring A is a 4-10 membered saturated monocyclic or bicyclic carbocyclic or heterocyclic ring having 0-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur;

Ring C is phenyl or a 5-10 membered monocyclic or bicyclic heteroaryl ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur;

each of L 2 and L 3 is independently a covalent bond or a C 1-3 bivalent straight or branched saturated or unsaturated hydrocarbon chain wherein 1-3 methylene units of the chain are independently and optionally replaced with —O—, —C(O)—, —C(S)—, —C(R) 2 —, —CH(R)—, —C(F) 2 —, —N(R)—, —S—, —S(O) 2 — or —CR═CR—;

each R 1 is independently hydrogen, R 5 , halogen, —CN, —NO 2 , —OR, —SR, —NR 2 , —S(O) 2 R, —S(O) 2 NR 2 , —S(O)R, —S(O)(NR)R, —P(O)(OR) 2 , —P(O)(NR 2 ) 2 , —CFR 2 , —CF 2 (R), —CF 3 , —CR 2 (OR), —CR 2 (NR 2 ), —C(O)R, —C(O)OR, or —C(O)NR 2 ;

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, or:

two R groups on the same atom are optionally taken together with their intervening atom to form an optionally substituted 4-11 membered saturated or partially unsaturated carbocyclic or heterocyclic monocyclic, bicyclic, bridged bicyclic, spirocyclic, or heteroaryl ring having 0-3 heteroatoms, in addition to the atom to which they are attached, independently selected from nitrogen, oxygen, and sulfur;

each R 2 is independently hydrogen, R 5 , halogen, —CN, —NO 2 , —OR, —SR, —NR 2 , —S(O) 2 R, —S(O) 2 NR 2 , —S(O)R, —S(O)(NR)R, —P(O)(OR) 2 , —P(O)(NR 2 ) 2 , —CF 2 (R), —CF 3 , —CR 2 (OR), —CR 2 (NR 2 ), —C(O)R, —C(O)OR, —C(O)NR 2 , —C(O)N(R)OR, —OC(O)R, —OC(O)NR 2 , —N(R)C(O)OR, —N(R)C(O)R, —N(R)C(O)NR 2 , or —N(R)S(O) 2 R;

R 4 is selected from

hydrogen, or an optionally substituted group selected from C 1-6 aliphatic or a 4-11 membered saturated or partially unsaturated monocyclic, bicyclic, bridged bicyclic or spirocyclic carbocyclic or heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur;

Ring D is phenyl, a 4-10 membered saturated or partially unsaturated monocyclic or bicyclic carbocyclic or heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or a 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;

each R 3 is independently hydrogen, R 5 , halogen, —CN, —NO 2 , —OR, —SR, —NR 2 , —S(O) 2 R, —S(O) 2 NR 2 , —S(O)R, —S(O)(NR)R, —P(O)(OR) 2 , —P(O)(NR 2 ) 2 , —CF 2 (R), —CF 3 , —CR 2 (OR), —CR 2 (NR 2 ), —C(O)R, —C(O)OR, —C(O)NR 2 , —C(O)N(R)OR, —OC(O)R, —OC(O)NR 2 , —N(R)C(O)OR, —N(R)C(O)R, —N(R)C(O)NR 2 , or —N(R)S(O) 2 R;

each R 5 is independently an optionally substituted group selected from C 1-6 aliphatic, phenyl, a 3-7 membered saturated or partially unsaturated carbocyclic or heterocyclic ring 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;

n is 0, 1, or 2;

each m is independently 0, 1, 2,3 or 4; and

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

2. The compound of claim 1 , wherein X 1 is —C(O)—, R 1a is hydrogen, m of (R 2a ) m is 0, Ring A a is

Ring B a is a fused 6-membered aryl, and R 4a is a C 1-6 aliphatic.

3. The compound of claim 1 , wherein

4. The compound of claim 1 , wherein Ring A is a 4-6 membered saturated monocyclic carbocyclic or heterocyclic ring having 0-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

5. The compound of claim 1 , wherein Ring A is cyclohexyl.

6. The compound of claim 1 , wherein Ring C is a 5-10 membered monocyclic or bicyclic heteroaryl ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

7. The compound of claim 1 , wherein Ring C is

8. The compound of claim 1 , wherein L 2 and L 3 are covalent bonds.

9. The compound of claim 1 , wherein n is 1 and R 1 is hydrogen, R 5 , halogen, —CN, —NO 2 , —OR, —SR, —NR 2 , —S(O) 2 R, —S(O) 2 NR 2 , —S(O)R, —CFR 2 , —CF 2 (R), —CF 3 , —CR 2 (OR), —CR 2 (NR 2 ), —C(O)R, —C(O)OR, or —C(O)NR 2 .

10. The compound of claim 1 , wherein n is 1 and R 1 is —CHF 2 .

11. The compound of claim 1 , wherein R 4 is an optionally substituted group selected from C 1-6 aliphatic or a 4-11 membered saturated or partially unsaturated monocyclic, bicyclic, bridged bicyclic, or spirocyclic carbocyclic or heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

12. The compound of claim 1 , wherein R 4 is

13. The compound of claim 1 , wherein said compound is