Aryl dihydro-2H-benzo[b][1,4]oxazine sulfonamide and related compounds for use as agonists of RORγ and the treatment of disease

Patent metadata

Field	Value
Publication number	US-10611740-B2
Application number	US-201615580414-A
Country	US
Kind code	B2
Filing date	Jun 10, 2016
Priority date	Jun 11, 2015
Publication date	Apr 7, 2020
Grant date	Apr 7, 2020

Abstract

The invention provides aryl dihydro-2H-benzo[b] [1,4]oxazine sulfonamide and related compounds, pharmaceutical compositions, methods of promoting RORy activity, methods of increasing the amount of IL-17 in a subject, and methods of treating cancer and other medical disorders using such compounds.

First claim

What is claimed is:

1. A compound represented by Formula I:

or a pharmaceutically acceptable salt thereof; wherein:
A 1 is phenylene, 5-6 membered heteroarylene, or 3-6 membered heterocycloalkylene;
X is phenyl or 5-10 membered heteroaryl, each of which is optionally substituted by 1, 2, 3, or 4 substituents independently selected from the group consisting of C 1-6 alkyl, C 3-6 cycloalkyl, halogen, C 1-6 haloalkyl, hydroxyl, C 1-6 alkoxy, C 1-6 haloalkoxy, —O—C 3-6 cycloalkyl, —O—(C 1-6 alkylene)-OH, cyano, —N(R 4 )(R 5 ), —S(O) 2 —R 6 , acetyl, and C 6-10 aryl;
R 1 represents independently for each occurrence halogen, C 1-6 alkyl, C 1-6 haloalkyl, or C 3-6 cycloalkyl;
R 2A is one of the following:
(i) —(C 1-6 alkylene)-A 2 , —(C 3-6 cycloalkylene)-A 2 , -(2-6 membered heteroalkylene)-A 2 , —(C 1-3 alkylene)-(C 3-6 cycloalkylene)-(C 0-3 alkylene)-A 2 , —(C 1-3 alkylene)-(3-6 membered heterocycloalkylene)-(C 0-3 alkylene)-A 2 , C 2-6 hydroxyalkyl, or —CO 2 R 4 ;
where
A 2 is —CO 2 R 4 , —C(O)-A 3 , —C(O)R 6 , —C(O)N(R 4 )(R 5 ), —C(O)N(R 4 )—(C 1-4 alkylene)-CO 2 R 4 , —C(O)N(R 4 )SO 2 R 4 , —C(O)N(R 4 )SO 2 A 3 , —C(O)N(R 4 )—(C 1-6 alkylene)-N(R 7 )C(O)R 6 , —C(O)N(R 4 )—(C 1-6 alkylene)-SO 2 N(R 7 ) 2 , —C(O)N(R 4 )—(C 1-6 alkylene)-CN, —C(O)N(R 4 )—(C 1-6 alkylene)-OC(O)R 6 , —N(R 4 )C(O)R 7 , —N(R 4 )C(O)A 3 , —N(R 4 )C(O)—(C 1-6 alkylene)-CO 2 R 4 , —N(R 4 )C(O)—(C 1-6 alkylene)-N(R 7 )C(O)R 6 , —N(R 4 )C(O)—(C 1-6 alkylene)-SO 2 N(R 7 ) 2 , —N(R 4 )C(O)—(C 1-6 alkylene)-CN, —N(R 4 )C(O)—(C 1-6 alkylene)-OC(O)R 6 , —N(R 4 )C(O)N(R 4 )—(C 1-6 alkylene)-CO 2 R 4 , —N(R 4 )C(O)N(R 7 ) 2 , —N(R 4 )CO 2 R 6 , —N(R 4 )S(O) 2 R 7 , —N(R 4 )S(O) 2 N(R 4 )(R 5 ), —N(R 4 )(R 5 ), hydroxyl, or -A 3 ;
A 3 is aryl, C 3-6 cycloalkyl, or a 5-8 membered heterocyclic group, each of which is optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of C 1-6 alkyl, C 1-6 haloalkyl, C 3-6 cycloalkyl, halogen, C 1-6 alkoxy, C 1-6 haloalkoxy, oxo, —C(O)R 6 , —CO 2 R 7 , —N(R 4 )C(O)(R 6 ), and —N(R 4 )(R 5 ); and
any alkylene, cycloalkylene, or heteroalkylene within the definition of R 2A is optionally substituted by 1, 2, or 3 substitutents independently selected from the group consisting of hydroxyl and C 1-6 alkoxy; or

(ii) —OH, —N(R 4 )C(O)R 6 , —N(R 4 )CO 2 R 6 , or —N(R 4 )C(O)N(R 7 ) 2 ;
R 2B represents independently for each occurrence C 1-6 alkyl or C 1-3 haloalkyl;
R 3 represents independently for each occurrence hydrogen, C 1-6 haloalkyl, halogen, hydroxyl, C 1-6 alkyl, C 3-6 cycloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, —O—(C 1-6 alkylene)-OH, or —O—(C 1-6 alkylene)-CO 2 R 4 ; or two vicinal occurrences of R 3 are taken together with intervening atoms to form a 4-6 membered ring optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of C 1-6 alkyl, C 1-6 haloalkyl, C 3-6 cycloalkyl, halogen, C 1-6 alkoxy, C 1-6 haloalkoxy, —C(O)R 6 , and —CO 2 R 7 ;
R 4 and R 5 each represent independently for each occurrence hydrogen, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 hydroxylalkyl, or C 3-6 cycloalkyl; or an occurrence of R 4 and R 5 attached to the same nitrogen atom are taken together with the nitrogen atom to which they are attached to form a 3-7 membered heterocyclic ring;
R 6 represents independently for each occurrence C 1-6 alkyl, C 3-6 cycloalkyl, or aralkyl;
R 7 represents independently for each occurrence hydrogen, C 1-6 alkyl, C 1-6 hydroxyalkyl, C 1-6 haloalkyl, C 1-6 hydroxyhaloalkyl, C 3-6 cycloalkyl, C 3-6 hydroxycycloalkyl, —(C 1-6 alkylene)-(C 3-6 cycloalkyl), —(C 1-6 alkylene)-(C 2-4 alkenyl), or aralkyl;
R 8 and R 9 each represent independently for each occurrence hydrogen, halogen, or C 1-6 alkyl, or R 8 and R 9 are taken together with the carbon atom to which they are attached to form a 3-6 membered carbocyclic ring; or R 8 and R 2B may taken together to form a bond when R 2B is attached to the same carbon atom as R 2A ;
Y is —O—, —C(O)—, —S(O) p —, or —C(R 8 )(R 9 )—;
m and p each represent independently for each occurrence 0, 1, or 2; and
n is 1, 2, or 3.

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

or a pharmaceutically acceptable salt thereof; wherein:
A 1 is phenylene or a 5-6 membered heteroarylene;
X is phenyl or 5-6 membered heteroaryl, each of which is optionally substituted by 1, 2, or 3 substituents independently selected from the group consisting of C 1-6 alkyl, C 3-6 cycloalkyl, halogen, C 1-6 haloalkyl, hydroxyl, C 1-6 alkoxy, C 1-6 haloalkoxy, —O—C 3-6 cycloalkyl, —O—(C 1-6 alkylene)-OH, cyano, —N(R 4 )(R 5 ), and C 6-10 aryl;
R 1 represents independently for each occurrence halogen, C 1-6 alkyl, or C 1-6 haloalkyl;
R 2A is —(C 1-6 alkylene)-A 2 , —(C 3-6 cycloalkylene)-A 2 , -(2-6 membered heteroalkylene)-A 2 , or —CO 2 R 4 ; wherein A 2 is —CO 2 R 4 , —C(O)-A 3 , —C(O)N(R 4 )(R 5 ), —C(O)N(R 4 )—(C 1-4 alkylene)-CO 2 R 4 , —N(R 4 )C(O)R 7 , —N(R 4 )C(O)A 3 , —N(R 4 )C(O)—(C 1-6 alkylene)-CO 2 R 4 , —N(R 4 )C(O)N(R 4 )—(C 1-6 alkylene)-CO 2 R 4 , —N(R 4 )CO 2 R 6 , or A 3 ; and A 3 is a 5-8 membered heterocyclic group optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of C 1-6 alkyl, C 1-6 haloalkyl, C 3-6 cycloalkyl, halogen, C 1-6 alkoxy, C 1-6 haloalkoxy, oxo, —C(O)R 6 , and —CO 2 R 7 ;
R 2B represents independently for each occurrence C 1-6 alkyl or C 1-3 haloalkyl;
R 3 represents independently for each occurrence hydrogen, C 1-6 haloalkyl, halogen, hydroxyl, C 1-6 alkyl, C 3-6 cycloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, —O—(C 1-6 alkylene)-OH, or —O—(C 1-6 alkylene)-CO 2 R 4 ;
R 4 and R 5 each represent independently for each occurrence hydrogen, C 1-6 alkyl, or C 3-6 cycloalkyl; or an occurrence of R 4 and R 5 attached to the same nitrogen atom are taken together with the nitrogen atom to which they are attached to form a 3-7 membered heterocyclic ring;
R 6 represents independently for each occurrence C 1-6 alkyl, C 3-6 cycloalkyl, or aralkyl;
R 7 represents independently for each occurrence hydrogen, C 1-6 alkyl, C 1-6 hydroxyalkyl, C 3-6 cycloalkyl, C 3-6 hydroxycycloalkyl, or aralkyl;
m and p are independently 0, 1, or 2; and
n is 1, 2, or 3.

3. The compound of claim 2 , wherein the compound is represented by Formula I-A.

4. The compound of claim 2 , wherein A 1 is phenylene.

5. The compound of claim 4 , wherein n is 1.

6. The compound of claim 2 , wherein A 1 is

7. The compound of claim 5 , wherein m is 0.

8. The compound of claim 7 , wherein R 2A is —(C 1-6 alkylene)-A 2 .

9. The compound of claim 8 , wherein A 2 is —CO 2 R 4 .

10. The compound of claim 8 , wherein A 2 is —CO 2 H.

11. The compound of claim 8 , wherein A 2 is A 3 .

12. The compound of claim 11 , wherein A 3 is a 5-6 membered saturated heterocyclic group optionally substituted by 1 or 2 substituents independently selected from the group consisting of methyl, ethyl, isopropyl, trifluoromethyl, cyclopropyl, C 1

Assignees

• Lycera Corp

Inventors

• Aicher Thomas Daniel
• Taylor Clarke B
• Vanhuis Chad A

Classifications

• C07D417/06

  linked by a carbon chain containing only aliphatic carbon atoms · CPC title

• C07D413/06

  linked by a carbon chain containing only aliphatic carbon atoms · CPC title

• C07D417/12

  linked by a chain containing hetero atoms as chain links · CPC title

• C07D413/04

  directly linked by a ring-member-to-ring-member bond · CPC title

• C07D471/04

  Ortho-condensed systems · CPC title