Granted Patent B2

US 11,512,080 · App. 16/961,362 · Granted Nov 29, 2022

Inventors: Nello Mainolfi (Belmont, MA); Nan Ji (Arlington, MA); Arthur F. Kluge (Gainesville, FL)

Assignee: KYMERA THERAPEUTICS, INC.

C07D417/04C07D211/88C07D239/22C07D401/04C07D401/12C07D401/14C07D403/04C07D403/06C07D413/04C07D413/14C07D471/04C07D487/04

Abstract

Claims (110)

1. A compound of Formula I-b or I-k′:

or a pharmaceutically acceptable salt thereof, wherein:

X 3 is a bivalent moiety selected from a —C(R 1 )F—, —CF 2 —, and —C(R′) 2 —;

L is —S—;

each R 1 is independently hydrogen, deuterium, 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)R 2 , —Si(OH) 2 R, —SiR 3 , or an optionally substituted C 1-4 aliphatic; or

two R 1 groups on the same carbon are optionally taken together with their intervening atoms to form a 3-6 membered spiro fused ring or a 4-7 membered heterocyclic ring having 1-2 heteroatoms independently selected from boron, nitrogen, oxygen, silicon, or sulfur;

two R 1 groups on adjacent carbon atoms are optionally taken together with their intervening atoms to form a 3-7 membered saturated, partially unsaturated, carbocyclic ring or heterocyclic ring having 1-3 heteroatoms independently selected from boron, nitrogen, oxygen, silicon, or sulfur, or a 7-13 membered saturated, partially unsaturated, bridged heterocyclic ring, or a spiro heterocyclic ring having 1-3 heteroatoms, independently selected from boron, nitrogen, oxygen, silicon, or sulfur;

each R is independently hydrogen, deuterium, or 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 boron, nitrogen, oxygen, silicon, or sulfur, a 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from boron, nitrogen, oxygen, silicon, or sulfur, a 7-13 membered saturated, partially unsaturated, bridged heterocyclic ring, or a spiro heterocyclic ring having 1-3 heteroatoms, independently selected from boron, nitrogen, oxygen, silicon, or sulfur, and a 8-10 membered bicyclic heteroaryl ring having 1-4 heteroatoms, independently selected from boron, nitrogen, oxygen, silicon, or sulfur; or

two R groups on the same nitrogen are optionally taken together with their intervening atoms to form a 4-8 membered saturated, partially unsaturated, or heteroaryl monocyclic ring having 0-1 heteroatom, in addition to the nitrogen, independently selected from boron, nitrogen, oxygen, silicon, or sulfur, or a 7-13 membered saturated, partially unsaturated, bridged heterocyclic ring, or a spiro heterocyclic ring having 0-2 heteroatoms, in addition to the nitrogen, independently selected from boron, nitrogen, oxygen, silicon, or sulfur;

each R 2 is independently hydrogen, deuterium, halogen, —CN, —NO 2 , —OR, —SR, —NR 2 , —Si(OH) 2 R, —Si(OH)(R) 2 , —Si(R) 3 , —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 , —N(R)S(O) 2 R, —N(R)S(O) 2 NR 2 , —P(O)(OR) 2 , —P(O)(NR 2 )OR, —P(O)(NR 2 ) 2 , optionally substituted C 1-6 aliphatic, optionally substituted phenyl, optionally substituted 4-7 membered saturated or partially unsaturated heterocyclic ring having 1-3 heteroatoms independently selected from boron, nitrogen, oxygen, silicon, or sulfur, optionally substituted 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from boron, nitrogen, oxygen, silicon, or sulfur, optionally substituted 7-13 membered saturated, partially unsaturated, bridged heterocyclic ring, or a spiro heterocyclic ring having 1-3 heteroatoms, independently selected from boron, nitrogen, oxygen, silicon, or sulfur, or a 8-10 membered bicyclic heteroaryl ring having 1-4 heteroatoms, independently selected from boron, nitrogen, oxygen, silicon, or sulfur;

Ring B is selected from a 3 to 7-membered saturated or partially unsaturated carbocyclic ring, phenyl, 8-10 membered bicyclic carbocyclic aromatic ring, 4-7 membered saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from boron, nitrogen, oxygen, silicon, or sulfur, 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from boron, nitrogen, oxygen, silicon, or sulfur, 7-13 membered saturated, partially unsaturated, bridged heterocyclic ring, or a spiro heterocyclic ring having 1-3 heteroatoms, independently selected from boron, nitrogen, oxygen, silicon, or sulfur, or a 8-10 membered bicyclic heteroaryl ring having 1-4 heteroatoms, independently selected from boron, nitrogen, oxygen, silicon, or sulfur; wherein Ring B is optionally further substituted with 1-2 oxo groups;

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

n is 0, 1, 2, 3, or 4; provided that the compound is other than the following, or a pharmaceutically acceptable salt thereof:

2. The compound of claim 1 , wherein R 1 is selected from hydrogen, halogen, —CN, —OR, —N(R) 2 , or C 1-4 alkyl.

3. The compound of claim 1 , wherein R 2 is selected from hydrogen, halogen, —CN, —NO 2 , —OR, —SR, —N(R) 2 , —C(O)R, —N(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)NR 2 , —N(R)S(O) 2 R, optionally substituted C 1-6 aliphatic, optionally substituted phenyl, an optionally substituted 4-7 membered saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or an optionally substituted 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

4. The compound of claim 1 , wherein

is selected from

5. The compound of claim 1 , wherein R 1 is selected from hydrogen, halogen, —OR, or C 1-4 alkyl.

6. The compound of claim 1 , wherein R 2 is selected from hydrogen, halogen, —CN, —NO 2 , —OR, —SR, —N(R) 2 , —C(O)R, —N(R)C(O)R, —C(O)OR, —C(O)NR 2 , optionally substituted C 1-6 aliphatic, optionally substituted phenyl, an optionally substituted 4-7 membered saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or an optionally substituted 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

7. The compound of claim 1 , wherein

is selected from

8. A compound selected from the following:

I-4

I-5

I-6

I-9

I-10

I-11

I-12

I-13

I-14

I-15

I-16

I-17

I-58

I-60

I-61

I-62

I-63

I-66

I-67

I-68

I-69

I-70

I-72

I-73

I-74

I-75

I-79

I-80

I-83

I-84

I-85

I-86

I-87

I-89

I-90

I-92

I-93

I-95

I-96

I-97

I-98

I-99

I-100

I-101

I-102

I-104

I-105

I-108

I-109

I-110

I-111

I-112

I-113

I-114

I-116

I-117

I-120

I-121

I-122

I-123

I-126

I-127

I-130

I-131

I-132

I-133

I-134

I-135

I-136

I-137

I-138

I-139

I-140

I-141

I-142

or a pharmaceutically acceptable salt thereof.

9. A pharmaceutical composition comprising the compound according to claim 8 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, adjuvant, or vehicle.

10. A pharmaceutical composition comprising the compound according to claim 1 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, adjuvant, or vehicle.

11. The compound of claim 1 , wherein R 2 is an optionally substituted C 1-6 aliphatic.

12. The compound of claim 1 , wherein R 2 is a C 1-6 aliphatic.

13. The compound of claim 1 , wherein R 2 is an optionally substituted phenyl.

14. The compound of claim 1 , wherein R 2 is an optionally substituted 4-7 membered saturated or partially unsaturated heterocyclic ring having 1-3 heteroatoms independently selected from boron, nitrogen, oxygen, silicon, or sulfur.

15. The compound of claim 1 , wherein R 2 is an optionally substituted 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from boron, nitrogen, oxygen, silicon, or sulfur.

16. The compound of claim 1 , wherein Ring B is a 8-10 membered bicyclic carbocyclic aromatic ring.

17. The compound of claim 1 , wherein Ring B is a 4-7 membered saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from boron, nitrogen, oxygen, silicon, or sulfur.

18. The compound of claim 1 , wherein Ring B is a 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from boron, nitrogen, oxygen, silicon, or sulfur.

19. The compound of claim 1 , wherein Ring B is a 7-13 membered saturated, partially unsaturated, bridged heterocyclic ring, or a spiro heterocyclic ring having 1-3 heteroatoms, independently selected from boron, nitrogen, oxygen, silicon, or sulfur.

20. The compound of claim 1 , wherein Ring B is a 8-10 membered bicyclic heteroaryl ring having 1-4 heteroatoms, independently selected from boron, nitrogen, oxygen, silicon, or sulfur.

Assignments (1)

Continuity (2)

Cited By (10)

US 12,258,341 US 12,521,438 US 12,528,785 US 12,539,295 US 12,540,127 US 12,545,659 US 12,551,564 US 12,558,427 US 12,606,568 US 12,624,044