IP Library › Granted Patent US 10,377,768

Granted Patent B2

US 10,377,768 · App. 15/587,934 · Granted Aug 13, 2019

Tetrahydronaphthyridine and related bicyclic compounds for inhibition of RORgamma activity and the treatment of disease

Inventors: Thomas D. Aicher (Ann Arbor, MI); Kenneth J. Barr (Boston, MA); Blair T. Lapointe (Brookline, MA); Vladimir Simov (Boston, MA); Karin A. Stein (Mountain View, CA); William D. Thomas (San Jose, CA); Peter L. Toogood (Ann Arbor, MI); Chad A. Van Huis (Hartland, MI); Catherine M. White (Boston, MA)

Assignees: Lycera Corporation; Merck Sharp & Dohme Corp.

C07D498/04 C07D413/06 C07D471/04

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Quick Facts

Patent No.: US 10,377,768
App. No.: 15/587,934
Granted: Aug 13, 2019
Kind: B2

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Abstract

The invention provides tetrahydronaphthyridine and related compounds, pharmaceutical compositions, methods of inhibiting RORγ activity, reducing the amount of IL-17 in a subject, and treating immune disorders and inflammatory disorders using such tetrahydronaphthyridine and related compounds.

Claims (145)

1. A compound represented by Formula I:

or a pharmaceutically acceptable salt or solvate thereof; wherein:

A is aryl, aralkyl, heteroaryl, cycloalkyl, or heterocycloalkyl; each of which is optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halogen, hydroxyl, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, —N(R 4 )(R 5 ), —CO 2 R 6 , —C(O)R 6 , —CN, —C 1-4 alkylene-C 1-4 alkoxy, —C 1-4 alkylene-N(R 4 )(R 5 ), —C 1-4 alkylene-CO 2 R 6 , —O—C 1-6 alkylene-N(R 4 )(R 5 ), —N(R 4 )C(O)—C 1-6 alkylene-N(R 4 )(R 5 ), —S(O) p C 1-6 alkyl, —SO 2 N(R 4 )(R 5 ), —N(R 4 )SO 2 (C 1-6 alkyl), —C(O)N(R 4 )(R 5 ), and —N(R 4 )C(O)N(R 4 )(R 5 );

X is —O—[C(R 6 )(R 7 )]—[C(R 6 ) 2 ] m -ψ, —O—C(R 6 ) 2 —C(R 6 )(R 7 )—C(R 6 ) 2 -ψ, —O—C(R 6 ) 2 —C(R 6 )(R 7 )—ψ, —C(R 6 ) 2 —[C(R 6 )(R 7 )]—[C(R 6 ) 2 ] m -ψ, —C(O)—[C(R 6 )(R 7 )]—[C(R 6 ) 2 ] m -ψ, —C(R 6 ) 2 —N(R 8 )—[C(R 6 )(R 7 )]—[C(R 6 ) 2 ] m -ψ, —C(R 6 )═N-ψ, —C(R 6 ) 2 C(R 6 )═N-ψ, —N═C(R 6 )—ψ, or —N═C(R 6 )C(R 6 ) 2 - ψ; wherein ψ is a bond to the sulfonamide ring nitrogen atom in Formula I;

Y 1 is C(R 3 ), and Y 2 is N;

R 1 is hydrogen or C 1-6 alkyl;

R 2 is hydrogen, —C(O)-aryl, —C(O)-aralkyl, —C(O)—[C(R 6 ) 2 ] m -cycloalkyl, —C(O)—[C(R 6 ) 2 ] m -heterocyclyl, —C(O)—C 1-8 alkyl, —C(O)—C 1-6 alkylene-C 1-6 alkoxyl, —C(O)—C 1-6 alkylene-cycloalkyl, or —C(O)—C 1-6 alkylene-heterocycloalkyl; each of which is optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halogen, hydroxyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 alkyl, C 1-6 haloalkyl, —N(R 4 )(R 5 ), —CN, —CO 2 —C 1-6 alkyl, —C(O)—C 1-6 alkyl, —C(O)N(R 4 )(R 5 ), —S(O) p C 1-6 alkyl, —SO 2 N(R 4 )(R 5 ), and —N(R 4 )SO 2 (C 1-6 alkyl);

R 3 represents independently for each occurrence hydrogen, halogen, or C 1-6 alkyl;

R 4 and R 5 each represent independently for each occurrence hydrogen or C 1-6 alkyl; or R 4 and R 5 taken together with the nitrogen atom to which they are attached form a 3-7 membered heterocyclic ring;

R 6 represents independently for each occurrence hydrogen or C 1-6 alkyl;

R 7 is hydrogen, hydroxyl, C 1-6 hydroxyalkyl, C 1-6 alkyl, C 1-6 haloalkyl, —CO 2 R 6 , C 1-6 alkylene-CO 2 R 6 , C 1-4 hydroxyalkylene-CO 2 R 6 , —N(R 4 )(R 5 ), C 1-6 alkylene-N(R 4 )(R 5 ), C 1-6 hydroxyalkylene-N(R 4 )(R 5 ), —N(R 4 )C(O)R 9 , C 1-6 alkylene-N(R 4 )C(O)R 9 , C 1-6 alkylene-C(O)N(R 4 )(R 5 ), —N(R 4 )CO 2 —C 1-6 alkyl, or C 1-6 alkylene-N(R 4 )C(O)N(R 4 )(R 5 ); or R 7 is heterocycloalkyl or C 1-4 alkylene-heterocycloalkyl, wherein the heterocycloalkyl is optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of oxo, halogen, hydroxyl, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxy, and C 1-6 haloalkoxy;

R 8 is hydrogen, C 1-6 alkyl, or —C(O)—C 1-6 alkyl;

R 9 is hydrogen, C 1-6 alkyl, C 1-6 hydroxyalkyl, —N(R 4 )(R 5 ), C 1-6 alkylene-N(R 4 )(R 5 ), or C 1-6 alkylene-N(R 4 )C(O)—C 1-6 alkyl; each of which is optionally substituted with 1, 2, or 3 halogen, hydroxyl or amino, and

m and p each represent independently for each occurrence 0, 1, or 2.

2. The compound of claim 1 , wherein the compound is represented by Formula I:

or a pharmaceutically acceptable salt or solvate thereof; wherein:

A is aryl, aralkyl, heteroaryl, cycloalkyl, or heterocycloalkyl; each of which is optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halogen, hydroxyl, C 1-8 alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, —N(R 4 )(R 5 ), —CO 2 R 6 , —C(O)R 6 , —CN, —C 1-4 alkylene-C 1-4 alkoxy, —C 1-4 alkylene-N(R 4 )(R 5 ), —C 1-4 alkylene-CO 2 R 6 , —O—C 1-6 alkylene-N(R 4 )(R 5 ), —N(R 4 )C(O)—C 1-6 alkylene-N(R 4 )(R 5 ), —S(O) p C 1-6 alkyl, —SO 2 N(R 4 )(R 5 ), —N(R 4 )SO 2 (C 1-6 alkyl), —C(O)N(R 4 )(R 5 ), and —N(R 4 )C(O)N(R 4 )(R 5 );

X is —O—[C(R 6 )(R 7 )]—[C(R 6 ) 2 ] m -ψ, —O—C(R 6 ) 2 —C(R 6 )(R 7 )—C(R 6 ) 2 -ψ, —O—C(R 6 ) 2 —C(R 6 )(R 7 )—ψ, —C(R 6 ) 2 —[C(R 6 )(R 7 )]-[C(R 6 ) 2 ] m -ψ, —C(O)—[C(R 6 )(R 7 )]—[C(R 6 ) 2 ] m -ψ, —C(R 6 ) 2 —N(R 8 )—[C(R 6 )(R 7 )]—[C(R 6 ) 2 ] m -ψ, —C(R 6 )═N-ψ, —C(R 6 ) 2 C(R 6 )═N-ψ, —N═C(R 6 )—ψ, or —N═C(R 6 )C(R 6 ) 2 - ψ; wherein ψ is a bond to the sulfonamide ring nitrogen atom in Formula I;

Y 1 is C(R 3 ), and Y 2 is N;

R 1 is hydrogen or C 1-6 alkyl;

R 2 is —C(O)-aryl, —C(O)-aralkyl, —C(O)—[C(R 6 ) 2 ] m -cycloalkyl, —C(O)—[C(R 6 ) 2 ] m -heterocyclyl, —C(O)—C 1-8 alkyl, —C(O)—C 1-6 alkylene-C 1-6 alkoxyl, —C(O)—C 1-6 alkylene-cycloalkyl, or —C(O)—C 1-6 alkylene-heterocycloalkyl; each of which is optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halogen, hydroxyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 alkyl, C 1-6 haloalkyl, —N(R 4 )(R 5 ), —CN, —CO 2 —C 1-6 alkyl, —C(O)—C 1-6 alkyl, —C(O)N(R 4 )(R 5 ), —S(O) p C 1-6 alkyl, —SO 2 N(R 4 )(R 5 ), and —N(R 4 )SO 2 (C 1-6 alkyl);

R 3 represents independently for each occurrence hydrogen, halogen, or C 1-6 alkyl;

R 6 represents independently for each occurrence hydrogen or C 1-6 alkyl;

R 8 is hydrogen, C 1-6 alkyl, or —C(O)—C 1-6 alkyl;

R 9 is hydrogen, C 1-6 alkyl, C 1-6 hydroxyalkyl, C 1-6 alkylene-N(R 4 )(R 5 ), or C 1-6 alkylene-N(R 4 )C(O)—C 1-6 alkyl; and

m and p each represent independently for each occurrence 0, 1, or 2.

3. The compound of claim 1 , wherein A is aryl optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, and C 1-6 haloalkoxy.

4. The compound of claim 1 , wherein A is heteroaryl optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, and C 1-6 haloalkoxy.

5. The compound of claim 1 , wherein X is —O—[C(R 6 )(R 7 )]—[C(R 6 ) 2 ] m -ψ.

6. The compound of claim 1 , wherein X is —C(R 6 ) 2 —[C(R 6 )(R 7 )]—[C(R 6 ) 2 ] m -ψ.

7. The compound of claim 1 , wherein R 2 is —C(O)-aryl or —C(O)— aralkyl; each of which is optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halogen, hydroxyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 alkyl, and C 1-6 haloalkyl.

8. The compound of claim 1 , wherein R 2 is —C(O)-phenyl or —C(O)-benzyl; each of which is optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halogen, C 1-6 alkyl, and C 1-6 haloalkyl.

9. The compound of claim 1 , wherein R 2 is represented by:

wherein each R′ is independently halogen, C 1-6 alkyl, or C 1-6 haloalkyl.

10. The compound of claim 1 , wherein R 2 is represented by:

wherein R″ is C 1-6 alkyl, aryl, or heterocyclyl, each of which is optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halogen, hydroxyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 alkyl, C 1-6 haloalkyl, —N(R 4 )(R 5 ), —CN, —CO 2 —C 1-6 alkyl, —C(O)—C 1-6 alkyl, —C(O)N(R 4 )(R 5 ), —S(O) p C 1-6 alkyl, —SO 2 N(R 4 )(R 5 ), and —N(R 4 )SO 2 (C 1-6 alkyl).

11. The compound of claim 1 , wherein R 7 is hydroxyl, C 1-6 hydroxyalkyl, C 1-6 alkyl, C 1-6 haloalkyl, —CO 2 R 6 , C 1-6 alkylene-CO 2 R 6 , C 1-4 hydroxyalkylene-CO 2 R 6 , —N(R 4 )(R 5 ), C 1-6 alkylene-N(R 4 )(R 5 ), C 1-6 hydroxyalkylene-N(R 4 )(R 5 ), —N(R 4 )C(O)R 9 , C 1-6 alkylene-N(R 4 )C(O)R 9 , C 1-6 alkylene-C(O)N(R 4 )(R 5 ), —N(R 4 )CO 2 —C 1-6 alkyl, or —N(R 4 )C(O)R 9 .

12. The compound of claim 1 , wherein R 7 is C 1-3 hydroxyalkyl, methyl, ethyl, or C 1-3 alkylene-N(H)C(O)—C 1-4 alkyl.

13. The compound of claim 1 , wherein the compound is represented by Formula II:

or a pharmaceutically acceptable salt or solvate thereof; wherein:

Y 1 is C(R 3 ), and Y 2 is N;

R 1 is hydrogen or C 1-6 alkyl;

R 3 represents independently for each occurrence hydrogen, halogen, or C 1-6 alkyl;

R 4 and R 5 each represent independently for each occurrence hydrogen or C 1-6 alkyl; or

R 4 and R 5 taken together with the nitrogen atom to which they are attached form a 3-7 membered heterocyclic ring;

R 6 represents independently for each occurrence hydrogen or C 1-6 alkyl;

m and p each represent independently for each occurrence 0, 1, or 2.

14. The compound of claim 13 , wherein A is phenyl optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, and C 1-6 haloalkoxy.

15. The compound of claim 13 , wherein R 2 is —C(O)-phenyl or —C(O)-benzyl; each of which is optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halogen, C 1-6 alkyl, and C 1-6 haloalkyl.

16. The compound of claim 13 , wherein R 2 is represented by:

wherein each R′ is independently halogen, C 1-6 alkyl, or C 1-6 haloalkyl.

17. The compound of claim 13 , wherein R 7 is C 1-6 hydroxyalkyl, C 1-6 alkyl, C 1-6 alkylene-CO 2 R 6 , C 1-6 alkylene-N(R 4 )(R 5 ), or C 1-6 alkylene-N(R 4 )C(O)R 9 .

18. The compound of claim 1 , wherein the compound is represented by Formula III:

or a pharmaceutically acceptable salt or solvate thereof; wherein:

Y 1 is C(R 3 ), and Y 2 is N;

R 1 is hydrogen or C 1-6 alkyl;

R 3 represents independently for each occurrence hydrogen, halogen, or C 1-6 alkyl;

R 4 and R 5 each represent independently for each occurrence hydrogen or C 1-6 alkyl; or

R 4 and R 5 taken together with the nitrogen atom to which they are attached form a 3-7 membered heterocyclic ring;

R 6 represents independently for each occurrence hydrogen or C 1-6 alkyl;

R 9 is hydrogen, C 1-6 alkyl, C 1-6 hydroxyalkyl, ═N(R 4 )(R 5 ), C 1-6 alkylene-N(R 4 )(R 5 ), or C 1-6 alkylene-N(R 4 )C(O)—C 1-6 alkyl; each of which is optionally substituted with 1, 2, or 3 halogen, hydroxyl or amino; and

m and p each represent independently for each occurrence 0, 1, or 2.

19. The compound of claim 18 , wherein A is phenyl optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, and C 1-6 haloalkoxy.

20. The compound of claim 18 , wherein R 2 is —C(O)-phenyl or —C(O)-benzyl; each of which is optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halogen, C 1-6 alkyl, and C 1-6 haloalkyl.

21. The compound of claim 18 , wherein R 2 is represented by:

wherein each R′ is independently halogen, C 1-6 alkyl, or C 1-6 haloalkyl.

22. The compound of claim 18 , wherein R 7 is C 1-6 hydroxyalkyl, C 1-6 alkyl, C 1-6 alkylene-CO 2 R 6 , —N(R 4 )(R 5 ), C 1-6 alkylene-N(R 4 )(R 5 ), or C 1-6 alkylene-N(R 4 )C(O)R 9 .

23. A compound in any one of Tables 2A, 3A, or 4A or a pharmaceutically acceptable salt thereof:

TABLE 2A

No.

II-11

II-12

II-13

II-14

II-15

II-16

II-17

II-18

II-19

II-20

II-21

II-22

II-23

II-24

II-25

II-26

II-27

II-28

II-29

II-30

II-31

II-32

II-33

II-34

II-35

II-36

II-37

II-38

II-39

II-40

II-41

II-42

II-43

II-44

II-47

II-48

II-49

II-50

II-57

II-58

II-59

II-60

TABLE 3A

No.

Compound

III-59

III-60

TABLE 4A

Compound

No.

Chemical Structure

24. A pharmaceutical composition comprising a compound of claim 1 and a pharmaceutically acceptable carrier.

25. A method of reducing the amount of interleukin 17 (IL-17) in a subject, comprising administering to a subject an effective amount of a compound of claim 1 to reduce the amount of IL-17 in the subject.

26. A method of inhibiting the activity of RORγ, comprising exposing a retinoid-related orphan receptor γ (RORγ) to an effective amount of a compound of claim 1 to inhibit the activity of said RORγ.

27. The compound of claim 7 , wherein X is —C(R 6 )═N-ψ.

28. The compound of claim 27 , wherein A is aryl or heteroaryl, each of which is optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, and C 1-6 haloalkoxy.

Assignments (6)

MERGER Recorded Aug 8, 2022

From: MERCK SHARP & DOHME CORP.

To: MERCK SHARP & DOHME LLC

Reel/Frame 061102/0145 →

SECURITY INTEREST Recorded Jan 3, 2019

From: LYCERA CORP.

To: WILMINGTON TRUST, NATIONAL ASSOCIATION

Reel/Frame 048002/0201 →

ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Oct 25, 2018

From: BARR, KENNETH JAY; LAPOINTE, BLAIR T.; SIMOV, VLADIMIR; WHITE, CATHERINE M.

To: MERCK SHARP & DOHME CORP.