Granted Patent B2

US 12,077,555 · App. 17/736,669 · Granted Sep 3, 2024

Inventors: Nello Mainolfi (Belmont, MA); Nan Ji (Arlington, MA); Bin Yang (Lexington, MA); Yi Zhang (Belmont, MA)

Assignee: Kymera Therapeutics, Inc.

C07F9/6561C07F9/65068A61K45/06

Abstract

Claims (88)

1. A method of degrading STAT3 protein in a patient or biological sample comprising administering to said patient, or contacting said biological sample with a compound of formula I:

or a pharmaceutically acceptable salt thereof, wherein:

LBM is a cereblon E3 ubiquitin ligase binding moiety;

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—, —N(R)—, —Si(R) 2 —, —Si(OH)(R)—, —Si(OH) 2 —, —P(O)(OR)—, —P(O)(R)—, —P(O)(NR 2 )—, —S—, —OC(O)—, —C(O)O—, —C(O)—, —S(O)—, —S(O) 2 —, —N(R)S(O) 2 —, —S(O) 2 N(R)—, —N(R)C(O)—, —C(O)N(R)—, —OC(O)N(R)—, —N(R)C(O)O—,

 wherein

each-Cy- is independently an optionally substituted bivalent ring selected from phenylenyl, 8-10 membered bicyclic arylenyl, 4-7 membered saturated or partially unsaturated carbocyclylenyl, 4-11 membered saturated or partially unsaturated spiro carbocyclylenyl, an 8-10 membered bicyclic saturated or partially unsaturated carbocyclylenyl, 4-7 membered saturated or partially unsaturated heterocyclylenyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 4-11 membered saturated or partially unsaturated spiro heterocyclylenyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 8-10 membered bicyclic saturated or partially unsaturated heterocyclylenyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 5-6 membered heteroarylenyl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 8-10 membered bicyclic heteroarylenyl having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur, and

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, and sulfur, and 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or:

two R groups on the same nitrogen are optionally 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, and sulfur;

r is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; and

STAT is a STAT3 protein binding moiety selected from

2. The method of claim 1 , wherein LBM is a cereblon E3 ubiquitin ligase binding moiety of formula I-aa-1:

or a pharmaceutically acceptable salt thereof, wherein:

each of X 1 , X 2a , and X 3a is independently a bivalent moiety selected from covalent bond, —CH 2 —, —C(O)—, —C(S)—, and

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

each of R 2 is independently hydrogen, R 6 , 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;

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

Ring A 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 and sulfur, and 5-membered heteroaryl with 1-3 heteroatoms independently selected from nitrogen, oxygen and sulfur; and

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

3. The method of claim 2 , wherein Ring A a is a fused ring selected from 6-membered aryl containing 0-2 nitrogen atoms and 5-membered heteroaryl with 1-3 heteroatoms independently selected from nitrogen, oxygen and sulfur.

4. The method of claim 1 , wherein LBM is a cereblon E3 ubiquitin ligase binding moiety selected from

5. The method of claim 1 , wherein LBM is a cereblon E3 ubiquitin ligase binding moiety of formula I-c:

or a pharmaceutically acceptable salt thereof, wherein:

X 1 is a bivalent moiety selected from covalent bond, —CH 2 —, —CHCF 3 —, —SO 2 —, —S(O)—, —P(O)R—, —P(O)OR—, —P(O)NR 2 —, —C(O)—, —C(S)—, and

X 2 is a carbon atom or silicon atom;

X 3 is a bivalent moiety selected from —CR 2 —, —NR—, —O—, —S—, and —Si(R 2 )—;

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

each R 2 is independently hydrogen, —R 6 , halogen, —CN, —NO 2 , —OR, —SR, —N(R) 2 , —Si(R) 3 , —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, —C(R) 2 N(R)C(O)R, —C(R) 2 N(R)C(O)N(R) 2 ,—OC(O)R, —OC(O)N(R) 2 , —OP(O)R 2 , —OP(O)(OR) 2 , —OP(O)(OR)(NR 2 ), —OP(O)(NR 2 ) 2 —, —N(R)C(O)OR, —N(R)C(O)R, —N(R)C(O)N(R) 2 , —N(R)S(O) 2 R, —NP(O)R 2 , —N(R)P(O)(OR) 2 , —N(R)P(O)(OR)(NR 2 ), —N(R)P(O)(NR 2 ) 2 , or —N(R)S(O) 2 R;

Ring A is a bicyclic or tricyclic ring selected from

Ring B is a fused ring selected from 6-membered aryl, 6-membered heteroaryl containing 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 5 to 7-membered saturated or partially unsaturated carbocyclyl, 5 to 7-membered saturated or partially unsaturated heterocyclyl ring with 1-3 heteroatoms independently selected from boron, nitrogen, oxygen, silicon, and sulfur, and 5-membered heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur;

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

each R 4 is independently hydrogen, —R 6 , 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 5 is hydrogen, C 1-4 aliphatic, or —CN;

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

L 1 is a covalent bond or a C 1-3 bivalent straight or branched saturated or unsaturated hydrocarbon chain wherein 1-2 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(O) 2 — or —(C)═CH—; and

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

6. The method of claim 5 , wherein X 1 is a bivalent moiety selected from covalent bond, —CH 2 —, —C(O)—, —C(S)—, and

7. The method of claim 5 , wherein R 1 is hydrogen or an optionally substituted C 1-4 aliphatic.

8. The method of claim 5 , wherein each R 2 is independently hydrogen, —R 6 , halogen, —CN, —NO 2 , —OR, —SR, —N(R) 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)NROR, —CR 2 NRC(O)R, —CR 2 NRC(O)NR 2 , —OC(O)R, —OC(O)NR 2 , —NRC(O)OR, —NRC(O)R, —NRC(O)NR 2 , —NRS(O) 2 R, or —NRS(O) 2 R.

9. The method of claim 5 , wherein Ring A is a bicyclic ring selected from

10. The method of claim 5 , wherein Ring B is a fused ring selected from 6-membered aryl or 5- to 6-membered heteroaryl containing 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

11. The method according to claim 1 , wherein LBM is a cereblon E3 ubiquitin ligase binding moiety selected from

12. The method of claim 1 , wherein L is 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—, —C(O)—, —S(O)—, or —S(O) 2 —.

13. The method of claim 1 , wherein L is selected from a covalent bond,

14. The method of claim 1 , wherein said compound is selected from:

I-3

I-5

I-6

I-9

I-10

I-24

I-25

I-29

I-36

I-38

I-39

I-40

I-41

I-42

I-43

I-44

I-45

I-46

I-47

I-48

I-49

I-50

I-51

I-52

I-53

I-54

I-55

I-56

I-57

I-58

I-59

I-60

I-61

I-62

I-63

I-64

I-65

I-66

I-67

I-68

I-69

I-70

I-110

or a pharmaceutically acceptable salt thereof.

Assignments (1)

Continuity (15)

Cited By (1)

US 12,570,679