N-sulfonylated tetrahydroquinolines and related bicyclic compounds for inhibition of RORγ activity and the treatment of disease

Patent metadata

Field	Value
Publication number	US-9512111-B2
Application number	US-201113883419-A
Country	US
Kind code	B2
Filing date	Nov 8, 2011
Priority date	Nov 8, 2010
Publication date	Dec 6, 2016
Grant date	Dec 6, 2016

Abstract

The invention provides tetrahydroquinoline 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 tetrahydroquinoline and related compounds are provided.

First claim

What is claimed is:

1. A compound represented by Formula III:

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, —N(R 3 )(R 4 ), —CO 2 R 6 , —C 1-6 alkylene-N(R 3 )(R 4 ), —C 1-6 alkylene-C 1-6 alkoxy, —C 1-6 alkylene-CO 2 R 6 , —O-aryl, —O—C 1-6 alkylene-N(R 3 )(R 4 ), —N(R 6 )C(O)—C 1-6 alkylene-N(R 3 )(R 4 ), —CN, —S(O) p C 1-6 alkyl, —SO 2 N(R 3 )(R 4 ), —N(R 3 )SO 2 (C 1-6 alkyl), heterocyclyl, C(O)R 11 , —C(R 11 )(R 12 )OH, —C(O)N(R 3 )(R 4 ), and —N(R 3 )C(O)N(R 3 )(R 4 );
X is —O—[C(R 6 ) 2 ] m -ψ, —O—[C(R 6 )(R 9 )C(R 6 ) 2 ]-ψ, —O—[C(R 6 )(R 9 )]-ψ, —O—[C(R 6 ) 2 —C(hydroxyC 1-6 alkyl)(R 6 )]-ψ, —N(R 6 )—[C(R 6 ) 2 ] m -ψ, —N═C(R 6 )-ψ, —N═C(R 6 )C(R 6 ) 2 -ψ, —C(R 6 ) 2 C(O)C(R 6 ) 2 -ψ, —[C(R 6 ) 2 ] m —C(O)-ψ, —C(R 6 )═C(R 6 )C(O)-ψ, —C(O)C(R 6 )═C(R 6 )-ψ, or —N(R 6 )—C(O)-ψ; wherein ψ is a bond to the sulfonamide ring nitrogen atom in Formula III;
R 1 represents independently for each occurrence hydrogen, halogen, or C 1-6 alkyl;
R 2 is —N(R 7 )C(O)R 8 , —(C 1-2 alkylene)-N(R 7 )C(O)R 8 , —N(R 7 )C(O)N(R 7 )(R 8 ), or heteroaryl, wherein said heteroaryl group is optionally substituted with 1 or 2 substituents independently selected from the group consisting of halogen, hydroxyl, C 1-6 alkoxy, C 1-6 alkyl, C 1-6 haloalkyl, aryl, and heteroaryl;
R 3 and R 4 each represent independently hydrogen or C 1-6 alkyl; or R 3 and R 4 taken together with the nitrogen atom to which they are attached form a 3-7 membered heterocyclic ring;
R 5 represents independently for each occurrence hydrogen, halogen, or C 1-6 alkyl;
R 6 and R 7 each represent independently for each occurrence hydrogen or C 1-6 alkyl;
R 8 is aryl, aralkyl, cycloalkyl, cycloalkenyl, heterocyclyl, —C(R 6 ) 2 -cycloalkyl, —C(R 6 ) 2 -cycloalkenyl, —C(R 6 ) 2 -heterocyclyl, or C 1-6 alkyl; 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 3 )(R 4 ), —CN, —CO 2 —C 1-6 alkyl, —C(O)—C 1-6 alkyl, —C(O)N(R 3 )(R 4 ), —S(O) p C 1-6 alkyl, —SO 2 N(R 3 )(R 4 ), and —N(R 3 )SO 2 (C 1-6 alkyl);
R 9 is C 1-6 haloalkyl, C 1-6 hydroxyalkyl, —C 1-6 alkylene-N(R 3 )(R 4 ), —C 1-6 alkylene-N(R 3 )C(O)—C 1-6 alkyl, —C 1-6 alkylene-CO 2 R 3 , —C 1-6 alkylene-CN, —C 1-6 alkylene-C 1-6 alkoxy, —C 1-6 alkylene-C(O)N(R 3 )(R 4 ), —C(O)N(R 3 )(R 4 ), —C 1-6 alkylene-N(R 3 )C(O)N(R 3 )(R 4 ), —C 1-6 alkylene-N(R 3 )C(O)—[C(OH)(R 3 )(R 4 )], —C 1-6 alkylene-O—C(O)N(R 3 )(R 4 ), —C 1-6 alkylene-SO 2 N(R 3 )(R 4 ), —C 1-6 alkylene-N(R 3 )SO 2 N(R 3 )(R 4 ), C 2-4 alkenyl, -arylene-CO 2 R 6 , or —CN;
R 11 is C 1-6 alkyl, C 1-6 haloalkyl, aryl, aralkyl, heteroaryl, or heterocycloalkyl; each of which is optionally substituted with 1 or 2 substituents independently selected from the group consisting of halogen, C 1-6 alkyl, C 1-6 haloalkyl, hydroxyl, C 1-6 alkoxy, C 1-6 haloalkoxy, —CO 2 R 3 , and, —N(R 3 )(R 4 );
R 12 is hydrogen, C 1-6 alkyl, C 1-6 haloalkyl, aryl, aralkyl, heteroaryl, or heterocycloalkyl;
each of which is optionally substituted with 1 or 2 substituents independently selected from the group consisting of halogen, C 1-6 alkyl, C 1-6 haloalkyl, hydroxyl, C 1-6 alkoxy, C 1-6 haloalkoxy, —CO 2 R 3 , and, —N(R 3 )(R 4 );
m is 1 or 2;
p represents independently for each occurrence 0, 1, or 2;
y is 1 or 2; and
wherein the stereochemical configuration at a stereocenter in a compound represented by Formula III is R, S, or a mixture thereof.

2. The compound of claim 1 , wherein A is phenyl substituted with 1, 2, or 3 substituents independently selected from the group consisting of halogen, hydroxyl, C 1-6 alkyl, C 1-6 haloalkyl, —N(R 3 )(R 4 ), —CN, —CO 2 R 6 , —C(O)—C 1-6 alkyl, —C 1-6 alkylene-N(R 3 )(R 4 ), —C 1-6 alkylene-C 1-6 alkoxy, —C 1-6 alkylene-CO 2 R 6 , —O—C 1-6 alkylene-N(R 3 )(R 4 ), and —N(R 6 )C(O)—C 1-6 alkylene-N(R 3 )(R 4 ).

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

4. The compound of claim 1 , wherein X is —O—[C(R 6 ) 2 ] m -ψ or —O—[C(R 6 )(R 9 )C(R 6 ) 2 ]-ψ.

5. The compound of claim 1 , wherein R 2 is —N(R 7 )C(O)R 8 .

6. The compound of claim 1 , wherein R 8 is aryl or aralkyl, each of which is substituted with 1, 2, or 3 substituents independently selected from the group consisting of halogen, C 1-6 alkyl, and C 1-6 haloalkyl.

7. The compound of claim 6 , wherein R 8 is phenyl substituted with 1, 2, or 3 substituents independently selected from the group consisting of halogen, C 1-6 alkyl, and C 1-6 haloalkyl.

8. The compound of claim 1 , wherein said compound is represented by Formula III-C:

or a pharmaceutically acceptable salt or solvate thereof; wherein:
A is aryl or heteroaryl; each of which is substituted with 1, 2, or 3 substituents independently selected from the group consisting of halogen, hydroxyl, C 1-6 alkyl, C 1-6 haloalkyl, —CN, and —C(O)—C 1-6 alkyl;
R 1 represents independently for each occurrence hydrogen, halogen, or C 1-6 alkyl;
R 2 is —N(R 7 )C(O)R 8 ;
R 3 and R 4 each represent independently hydrogen or C 1-6 alkyl; or R 3 and R 4 taken together with the nitrogen atom to which they are attached form a 3-7 membered heterocyclic ring;
R 6 and R 7 each represent independently for each occurrence hydrogen or C 1-6 alkyl;
R 8 is aryl substituted with 1, 2, or 3 substituents independently selected from the group consisting of halogen, C 1-6 alkyl, and C 1-6 haloalkyl;
R 9 is C 1-6 haloalkyl, C 1-6 hydroxyalkyl, —C 1-6 alkylene-N(R 3 )(R 4 ), —C 1-6 alkylene-N(R 3 )C(O)—C 1-6 alkyl, —C 1-6 alkylene-CN, or —C 1-6 alkylene-C 1-6 alkoxy; and
wherein the stereochemical configuration at a stereocenter in a compound represented by Formula III-C is R, S, or a mixture thereof.

9. The compound of claim 8 , wherein A is phenyl substituted with 1, 2, or 3 substituents independently selected from the group consisting of halogen, hydroxyl, C 1-6 alkyl, C 1-6 haloalkyl, and —CN.

10. The compound of claim 8 , wherein R 8 is phenyl substituted with 1, 2, or 3 substituents independently selected from the group consisting of halogen, C 1-6 alkyl, and C 1-6 haloalkyl.

11. The compound of claim 8 , wherein R 9 is C 1-6 haloalkyl, C 1 -6hydroxyalkyl, —C 1-6 alkylene-N(R 3 )C(O)—C 1-6 alkyl, or —C 1-6 alkylene-C 1-6 alkoxy.

12. The compound of claim 8 , wherein R 2 is attached to the 6-position of the benzoxazine ring.

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

14. A pharmaceutical composition comprising the compound of claim 4 and a pharmaceutically acceptable carrier.

15. A pharmaceutical composition comprising the compound of claim 8 and a pharmaceutically acceptable carrier.

Assignees

• Glick Gary D
• Toogood Peter L
• Romero Arthur G
• Van Huis Chad A
• Aicher Thomas D
• Kaub Carl
• Mattson Matthew N
• Thomas William D
• Stein Karin A
• Krogh-Jespersen Erik
• Wang Zhan
• Lycera Corp

Inventors

• Glick Gary D
• Toogood Peter L
• Romero Arthur G
• Van Huis Chad A
• Aicher Thomas D
• Kaub Carl
• Mattson Matthew N
• Thomas William D
• Stein Karin A
• Krogh-Jespersen Erik
• Wang Zhan

Classifications

• A61P37/08

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

• A61P43/00

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

• A61P3/10

  for hyperglycaemia, e.g. antidiabetics · CPC title

• A61P7/02

  Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors · CPC title

• A61P9/10

  for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis · CPC title