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

Patent metadata

Field	Value
Publication number	US-9657033-B2
Application number	US-201314398061-A
Country	US
Kind code	B2
Filing date	May 7, 2013
Priority date	May 8, 2012
Publication date	May 23, 2017
Grant date	May 23, 2017

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.

First claim

We claim:

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 )HC(R 6 ) 2 ] m -ψ, —C(O)—[C(R 6 )(R 7 )]—[C(R 6 ) 2 ] m -ψ, —C(R 6 ) 2 —NR 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 N, and Y 2 is C(R 3 );
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 )HC(R 6 ) 2 ]-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 N, and Y 2 is C(R 3 );
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 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, 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 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.

5. 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.

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

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

8. The compound of claim 1 , wherein X is —C(R 6 )═N-ψ.

9. The compound of claim 1 , wherein R 1 is hydrogen.

10

Assignees

• Merck Sharp & Dohme
• Lycera Corp

Inventors

• Aicher Thomas D
• Barr Kenneth J
• Lapointe Blair T
• Simov Vladimir
• Stein Karin A
• Thomas William D
• Toogood Peter L
• Van Huis Chad A
• White Catherine M

Classifications

• A61P35/00

  Antineoplastic agents · CPC title

• A61P37/08

  Antiallergic agents (antiasthmatic agents A61P11/06; ophthalmic antiallergics A61P27/14) · CPC title

• A61P37/00

  Drugs for immunological or allergic disorders · CPC title

• A61P43/00

  Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00 · CPC title

• A61P9/00

  Drugs for disorders of the cardiovascular system · CPC title