Granted Patent B2

US 12,071,442 · App. 17/656,924 · Granted Aug 27, 2024

Inventors: Neelu Kaila (Lexington, MA); Ian Linney (Saffron Walden, GB); Stuart Ward (Saffron Walden, GB); Grant Wishart (Saffron Walden, GB); Benjamin Whittaker (Saffron Walden, GB); Alexandre Cote (West New York, NJ); Jeremy Robert Greenwood (Brooklyn, NY); Abba Leffler (Bronx, NY)

Assignee: Nimbus Saturn, Inc.

C07D519/00C07D487/04

Abstract

Claims (95)

1. A compound of formula I:

or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof,

wherein:

X is —NR—;

R 1 is a 3- to 7-membered carbocyclyl, 3- to 7-membered heterocyclyl, 8- to 10-membered heterocyclyl, phenyl, or 5- or 6-membered heteroaryl;

wherein the 3- to 7-membered carbocyclyl or 3- to 7-membered heterocyclyl is monocyclic and saturated or partially unsaturated;

wherein the 8- to 10-membered heterocyclyl is bicyclic and saturated or partially unsaturated;

wherein the 5- or 6-membered heteroaryl is monocyclic;

wherein the 3- to 7-membered heterocyclyl contains 1 or 2 heteroatoms independently selected from the group consisting of N, O, and S;

wherein the 8- to 10-membered heterocyclyl or 5- or 6-membered heteroaryl contains 1, 2, 3, or 4 heteroatoms independently selected from the group consisting of N, O, and S; and

wherein the 3- to 7-membered carbocyclyl, 3- to 7-membered heterocyclyl, 8- to 10-membered heterocyclyl, phenyl, or 5- or 6-membered heteroaryl is substituted with q independently selected R C substituents;

R 2 is a 3- to 7-membered carbocyclyl, 3- to 7-membered heterocyclyl, 6- to 11-membered cyclyl, phenyl, or 5- or 6-membered heteroaryl;

wherein the 3- to 7-membered carbocyclyl or 3- to 7-membered heterocyclyl is monocyclic and saturated or partially unsaturated;

wherein the 6- to 11-membered cyclyl is (a) bicyclic, (b) fused, bridged, or spirocyclic, and (c) saturated, partially unsaturated, or fully unsaturated;

wherein the 5- or 6-membered heteroaryl is monocyclic;

wherein the 3- to 7-membered heterocyclyl contains 1 or 2 heteroatoms independently selected from the group consisting of N, O, and S;

wherein the 6- to 11-membered cyclyl contains 0, 1, 2, or 3 heteroatoms independently selected from the group consisting of N, O, and S;

wherein the 5- or 6-membered heteroaryl contains 1, 2, 3, or 4 heteroatoms independently selected from the group consisting of N, O, and S; and

wherein the 3- to 7-membered carbocyclyl, 3- to 7-membered heterocyclyl, 6- to 11-membered cyclyl, phenyl, or 5- or 6-membered heteroaryl is substituted with q independently selected R C substituents;

each R 3 is independently H or C 1-6 aliphatic, wherein the C 1-6 aliphatic is substituted with s independently selected R D substituents;

each R C is independently halogen, CN, NO 2 , C 1-6 aliphatic, C(O)R, C(O)NR 2 , C(O)NROR, C(O)OR, NR 2 , NRC(NR)NR 2 , NRCN, NRC(O)R, NRC(O)NR 2 , NRC(O)OR, NRNR 2 , NRS(O)R, NRS(O) 2 R, NRS(O) 2 NR 2 , N═S(O)R 2 , OR, OC(O)R, OC(O)NR 2 , ═O, P(O)R 2 , P(O)RNR 2 , P(O)ROR, SR, S(O)R, S(O)NR 2 , S(NR)(O)R, S(O) 2 R, S(O) 2 NR 2 , 3- to 7-membered carbocyclyl, 3- to 7-membered heterocyclyl, 5- to 8-membered cyclyl, 6- to 11-membered cyclyl, 6- to 11-membered heterocyclyl, phenyl, naphthalenyl, 5- or 6-membered heteroaryl, or 8- to 10-membered heteroaryl;

wherein each 3- to 7-membered carbocyclyl or 3- to 7-membered heterocyclyl is independently monocyclic and saturated or partially unsaturated;

wherein each 5- to 8-membered cyclyl is independently (a) bicyclic, (b) bridged, and (c) saturated or partially unsaturated;

wherein each 6- to 11-membered cyclyl is independently spirocyclic and saturated or partially unsaturated;

wherein each 6- to 11-membered heterocyclyl is independently bicyclic and saturated or partially unsaturated;

wherein each 5- or 6-membered heteroaryl is independently monocyclic;

wherein each 8- to 10-membered heteroaryl is independently bicyclic;

wherein each 3- to 7-membered heterocyclyl independently contains 1 or 2 heteroatoms independently selected from the group consisting of N, O, P, Si, and S;

wherein each 5- to 8-membered cyclyl and 6- to 11-membered cyclyl independently contains 0, 1, 2, or 3 heteroatoms independently selected from the group consisting of N, O, and S;

wherein each 6- to 11-membered heterocyclyl independently contains 1, 2, or 3 heteroatoms independently selected from the group consisting of N, O, and S;

wherein each 5- or 6-membered heteroaryl independently contains 1, 2, 3, or 4 heteroatoms independently selected from the group consisting of N, O, and S;

wherein each 8- to 10-membered heteroaryl independently contains 1, 2, 3, 4, or 5 heteroatoms independently selected from the group consisting of N, O, and S; and

wherein each C 1-6 aliphatic, 3- to 7-membered carbocyclyl, 3- to 7-membered heterocyclyl, 5- to 8-membered cyclyl, 6- to 11-membered cyclyl, 6- to 11-membered heterocyclyl, phenyl, naphthalenyl, 5- or 6-membered heteroaryl, or 8- to 10-membered heteroaryl is independently substituted with r independently selected R substituents and s independently selected R D substituents;

each R is independently H, halogen, CN, C 1 0.6 aliphatic, 3- to 7-membered carbocyclyl, 3- to 7-membered heterocyclyl, 5- to 8-membered cyclyl, 6- to 10-membered cyclyl, 6- to 11-membered heterocyclyl, 7- to 12-membered heterocyclyl, phenyl, naphthalenyl, 5- or 6-membered heteroaryl, or 8- to 10-membered heteroaryl;

wherein each 3- to 7-membered carbocyclyl or 3- to 7-membered heterocyclyl is independently monocyclic and saturated or partially unsaturated;

wherein each 5- to 8-membered cyclyl is independently (a) bicyclic, (b) bridged, and (c) saturated or partially unsaturated;

wherein each 6- to 10-membered cyclyl is independently spirocyclic and saturated or partially unsaturated;

wherein each 6- to 11-membered heterocyclyl and 7- to 12-membered heterocyclyl is independently bicyclic and saturated or partially unsaturated;

wherein each 5- or 6-membered heteroaryl is independently monocyclic;

wherein each 8- to 10-membered heteroaryl is independently bicyclic;

wherein each 3- to 7-membered heterocyclyl independently contains 1 or 2 heteroatoms independently selected from the group consisting of N, O, and S;

wherein each 5- to 8-membered cyclyl and 6- to 10-membered cyclyl independently contains 0, 1, 2, or 3 heteroatoms independently selected from the group consisting of N, O, and S;

wherein each 6- to 11-membered heterocyclyl independently contains 1 or 2 heteroatoms independently selected from the group consisting of N, O, and S; and

wherein each 7- to 12-membered heterocyclyl, 5- or 6-membered heteroaryl, and 8- to 10-membered heteroaryl independently contains 1, 2, 3, or 4 heteroatoms independently selected from the group consisting of N, O, and S; and

wherein each C 1-6 aliphatic, 3- to 7-membered carbocyclyl, 3- to 7-membered heterocyclyl, 5- to 8-membered cyclyl, 6- to 10-membered cyclyl, 6- to 11-membered heterocyclyl, 7- to 12-membered heterocyclyl, phenyl, naphthalenyl, 5- or 6-membered heteroaryl, or 8- to 10-membered heteroaryl is independently substituted with s independently selected R D substituents; or

any two R substituents, together with the nitrogen heteroatom to which they are attached, independently forms a 4- to 7-membered heterocyclyl, 7- to 12-membered heterocyclyl, or 8- to 10-membered heteroaryl;

wherein each 4- to 7-membered heterocyclyl is independently monocyclic and saturated, partially unsaturated, or fully saturated;

wherein each 7- to 12-membered heterocyclyl is independently bicyclic and saturated or partially unsaturated;

wherein each 8- to 10-membered heteroaryl is independently bicyclic;

wherein each 4- to 7-membered heterocyclyl, 7- to 12-membered heterocyclyl, and 8- to 10-membered heteroaryl optionally and independently contains 1, 2, or 3 additional heteroatoms independently selected from the group consisting of N, O, and S; and

wherein each 4- to 7-membered heterocyclyl, 7- to 12-membered heterocyclyl, and 8- to 10-membered heteroaryl is independently substituted with s independently selected R D substituents;

each R D is independently halogen, CN, NO 2 , C(O)R, C(O)NR 2 , C(O)NROR, C(O)OR, NR 2 , NRC(NR)NR 2 , NRCN, NRC(O)R, NRC(O)NR 2 , NRC(O)OR, NRNR 2 , NRS(O)R, NRS(O) 2 R, NRS(O) 2 NR 2 , N═S(O)R 2 , OR, OC(O)R, OC(O)NR 2 , ═O, P(O)R 2 , P(O)RNR 2 , P(O)ROR, SR, S(O)R, S(O)NR 2 , S(NR)(O)R, S(O) 2 R, or S(O) 2 NR 2 ;

each q is independently 0, 1, 2, 3, or 4;

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

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

2. The compound of claim 1 , or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, wherein X is —NH—.

3. The compound of claim 1 , or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, wherein R 1 is 3- to 7-membered heterocyclyl, 8- to 10-membered heterocyclyl, phenyl, or 5- or 6-membered heteroaryl;

wherein the 3- to 7-membered heterocyclyl is monocyclic and saturated or partially unsaturated;

wherein the 8- to 10-membered heterocyclyl is bicyclic and saturated or partially unsaturated;

wherein the 5- or 6-membered heteroaryl is monocyclic;

wherein the 3- to 7-membered heterocyclyl contains 1 or 2 heteroatoms independently selected from the group consisting of N, O, and S;

wherein the 8- to 10-membered heterocyclyl or 5- or 6-membered heteroaryl contains 1, 2, 3, or 4 heteroatoms independently selected from the group consisting of N, O, and S; and

wherein the 3- to 7-membered heterocyclyl, 8- to 10-membered heterocyclyl, phenyl, or 5- or 6-membered heteroaryl is substituted with q independently selected R C substituents.

4. The compound of claim 3 , or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, wherein R 1 is phenyl or 5- or 6-membered heteroaryl;

wherein the 5- or 6-membered heteroaryl is monocyclic;

wherein the 5- or 6-membered heteroaryl contains 1, 2, 3, or 4 heteroatoms independently selected from the group consisting of N, O, and S; and

wherein the phenyl or 5- or 6-membered heteroaryl is substituted with q independently selected R C substituents.

5. The compound of claim 3 , or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, wherein R 1 is phenyl, pyrazolyl, pyridinyl, pyrimidinyl, or pyrazinyl, wherein the phenyl, pyrazolyl, pyridinyl, pyrimidinyl, or pyrazinyl is substituted with q independently selected R C substituents.

6. The compound of claim 5 , or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, wherein R 1 is:

7. The compound of claim 1 , or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, wherein R 1 is:

8. The compound of claim 1 , or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, wherein R 2 is 3- to 7-membered carbocyclyl, 3- to 7-membered heterocyclyl, phenyl, or 5- or 6-membered heteroaryl;

wherein the 3- to 7-membered carbocyclyl or 3- to 7-membered heterocyclyl is monocyclic and saturated or partially unsaturated;

wherein the 5- or 6-membered heteroaryl is monocyclic;

wherein the 3- to 7-membered heterocyclyl contains 1 or 2 heteroatoms independently selected from the group consisting of N, O, and S;

wherein the 5- or 6-membered heteroaryl contains 1, 2, 3, or 4 heteroatoms independently selected from the group consisting of N, O, and S; and

wherein the 3- to 7-membered carbocyclyl, 3- to 7-membered heterocyclyl, phenyl, or 5- or 6-membered heteroaryl is substituted with q independently selected R C substituents.

9. The compound of claim 8 , or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, wherein R 2 is cyclopropyl, tetrahydropyranyl, morpholinyl, phenyl, pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, pyridinyl, pyridazinyl, or pyrimidinyl, wherein the cyclopropyl, tetrahydropyranyl, morpholinyl, phenyl, pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, pyridinyl, pyridazinyl, or pyrimidinyl is substituted with q independently selected R C substituents.

10. The compound of claim 8 , or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, wherein R 2 is:

11. The compound of claim 8 , or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, wherein R 2 is:

12. The compound of claim 1 , or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, wherein R 2 is a 6- to 11-membered cyclyl;

wherein the 6- to 11-membered cyclyl is (a) bicyclic, (b) fused, bridged, or spirocyclic, and (c) saturated, partially unsaturated, or fully unsaturated;

wherein the 6- to 11-membered cyclyl contains 0, 1, 2, or 3 heteroatoms independently selected from the group consisting of N, O, and S; and

wherein the 6- to 11-membered cyclyl is substituted with q independently selected R C substituents.

13. The compound of claim 12 , or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, wherein R 2 is a 9-membered heterocyclyl;

wherein the 9-membered heterocyclyl is (a) bicyclic, (b) fused, and (c) saturated, partially unsaturated, or fully unsaturated;

wherein the 9-membered heterocyclyl contains 1, 2, or 3 N heteroatoms; and

wherein the 9-membered heterocyclyl is substituted with q independently selected R C substituents.

14. The compound of claim 13 , or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, wherein R 2 is:

15. The compound of claim 13 , or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, wherein R 2 is:

16. The compound of claim 1 , or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, wherein each R 3 is independently H or C 1-4 aliphatic, wherein the C 1-4 aliphatic is substituted with s independently selected R D substituents.

17. The compound of claim 1 , or a stereoisomer thereof, wherein the compound, or stereoisomer thereof, is selected from the group consisting of:

or a pharmaceutically acceptable salt or tautomer thereof.

18. A pharmaceutical composition comprising a pharmaceutically acceptable carrier, adjuvant, or vehicle and a compound of claim 1 , or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof.

19. A compound:

or a pharmaceutically acceptable salt or tautomer thereof.

Assignments (8)

Continuity (3)