Dihydro-2H-benzo[b][1,4]oxazine sulfonamide and related compounds for use as agonists of RORγ and the treatment of disease
View Patent ↗The invention provides dihydro-2H-benzo[b] [1,4]oxazine sulfonamide and related compounds, pharmaceutical compositions, methods of promoting RORγ activity, methods of increasing the amount of IL-17 in a subject, and methods of treating cancer and other medical disorders using such compounds.
1. A compound represented by Formula I:
or a pharmaceutically acceptable salt thereof; wherein:
A 1 is phenylene, 5-6 membered heteroarylene, or C 3-6 heterocycloalkylene;
R 1 represents independently for each occurrence halogen, C 1-6 alkyl, C 1-6 haloalkyl, or C 3-6 cycloalkyl;
R 2A is —(C 1-6 alkylene)-A 2 , -(2-6 membered heteroalkylene)-A 2 , —(C 0-3 alkylene)-(C 3-6 cycloalkylene)-(C 0-3 alkylene)-A 2 , —O-A 2 , —N(R 8 )-A 2 , or -A 2 ; wherein A 2 is one of the following:
a 5-6 membered heterocyclic group containing at least one ring carbon atom substituted by oxo and the heterocyclic group being optionally substituted by 1 or 2 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 9 , —CO 2 R 8 , —N(R 4 )C(O)(R 9 ), and —N(R 4 )(R 5 ); or
a 5-6 membered heteroaromatic group comprising at least two ring nitrogen atoms, at least one unsaturated carbon atom in the ring, and the heteroaromatic group being optionally substituted by 1 or 2 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 9 , —CO 2 R 8 , —N(R 4 )C(O)(R 9 ), and —N(R 4 )(R 5 );
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;
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 and R 7 each represent independently for each occurrence hydrogen or C 1-6 alkyl, or R 6 and R 7 are taken together with the carbon atom to which they are attached to form a 3-6 membered carbocyclic ring; or R 6 and R 2A are taken together to form a bond;
R 8 represents independently for each occurrence hydrogen, C 1-6 alkyl, C 3-6 cycloalkyl, or aralkyl;
R 9 represents independently for each occurrence C 1-6 alkyl, C 3-6 cycloalkyl, or aralkyl;
X is one of the following:
(i) —(C 2-6 alkenylene)-phenyl, —(C 2-6 alkenylene)-heteroaryl, —(C 1-6 alkylene)-phenyl, —(C 1-6 alkylene)-heteroaryl, —(C 1-6 alkylene)-(partially unsaturated bicyclic heterocyclyl), —(C 1-6 alkylene)-(partially unsaturated bicyclic oxo-heterocyclyl), -(5-6 membered heterocycloalkylene)-phenyl, or —(C 3-6 cycloalkylene)-phenyl, each of which is optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halogen, C 1-6 haloalkyl, C 1-6 alkyl, C 3-6 cycloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, hydroxyl, and cyano;
(ii) —(C 2-6 alkenylene)-(C 3-6 cycloalkyl),
or an 8-10 membered, bicyclic partially saturated carbocyclyl, each of which is optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halogen, C 1-6 haloalkyl, C 1-6 alkyl, C 3-6 cycloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, hydroxyl, and cyano, wherein A* is a 5-8 membered, partially saturated carbocyclic or heterocyclic ring;
(iii) —(C 1-6 alkylene)-Z 1 or —(C 2-6 alkenylene)-Z 1 , wherein Z 1 is —O-aralkyl, —O-heteroaralkyl, —O-phenyl, —O-heteroaryl, —O-(partially unsaturated bicyclic carbocyclyl), —O—(C 1-6 alkylene)-(C 3-6 cycloalkyl), —O—(C 3-6 cycloalkyl), —N(R 4 )-aralkyl, —N(R 4 )-phenyl, —N(R 4 )-(partially unsaturated bicyclic carbocyclyl), or —N(R 4 )-(C 1-6 alkylene)-(C 3-6 cycloalkyl), each of which is optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halogen, C 1-6 haloalkyl, C 1-6 alkyl, C 3-6 cycloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, hydroxyl, and cyano; or
(iv) —O-aralkyl, —O-heteroaralkyl, —O-phenyl, —O-heteroaryl, —O-(partially unsaturated bicyclic carbocyclyl), —O—(C 1-6 alkylene)-(C 3-6 cycloalkyl), —O—(C 3-6 cycloalkyl), —N(R 4 )-aralkyl, —N(R 4 )-phenyl, —N(R 4 )-(partially unsaturated bicyclic carbocyclyl), or —N(R 4 )—(C 1-6 alkylene)-(C 3-6 cycloalkyl), each of which is optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halogen, C 1-6 haloalkyl, C 1-6 alkyl, C 3-6 cycloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, hydroxyl, and cyano;
Y is —C(R 6 )(R 7 )—, —O—, —C(O)—, or —S(O) p —;
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;
R 1 represents independently for each occurrence halogen, C 1-6 alkyl, or C 3-6 cycloalkyl;
R 2A is —(C 1-6 alkylene)-A 2 , -(2-6 membered heteroalkylene)-A 2 , or —O-A 2 ; wherein A 2 is one of the following:
a 5-6 membered heterocyclic group containing at least one ring carbon atom substituted by oxo and the heterocyclic group being optionally substituted by 1 or 2 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 9 , —CO 2 R 8 , —N(R 4 )C(O)(R 9 ), and —N(R 4 )(R 5 ); or
a 5-6 membered heteroaromatic group comprising at least two ring nitrogen atoms, at least one unsaturated carbon atom in the ring, and the heteroaromatic group being optionally substituted by 1 or 2 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 9 , —CO 2 R 8 , —N(R 4 )C(O)(R 9 ), and —N(R 4 )(R 5 );
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, or —O—(C 1-6 alkylene)-OH; or two vicinal occurrences of R 3 are taken together with intervening atoms to form a 4-6 membered ring;
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 and R 7 each represent independently for each occurrence hydrogen or C 1-6 alkyl, or R 6 and R 7 are taken together with the carbon atom to which they are attached to form a 3-6 membered carbocyclic ring;
R 8 represents independently for each occurrence hydrogen, C 1-6 alkyl, C 3-6 cycloalkyl, or aralkyl;
R 9 represents independently for each occurrence C 1-6 alkyl, C 3-6 cycloalkyl, or aralkyl;
X is one of the following:
(i) —(C 2-6 alkenylene)-phenyl, —(C 2-6 alkenylene)-heteroaryl, —(C 1-6 alkylene)-phenyl, —(C 1-6 alkylene)-heteroaryl, —(C 1-6 alkylene)-(partially unsaturated bicyclic heterocyclyl), —(C 1-6 alkylene)-(partially unsaturated bicyclic oxo-heterocyclyl), or -(5-6 membered heterocycloalkylene)-phenyl, each of which is optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halogen, C 1-6 haloalkyl, C 1-6 alkyl, C 3-6 cycloalkyl, C 1-6 alkoxy, and C 1-6 haloalkoxy;
(ii) —(C 1-6 alkylene)-Z 1 or —(C 2-6 alkenylene)-Z 1 , wherein Z 1 is —O-aralkyl, —O— heteroaralkyl, —O-phenyl, —O-heteroaryl, —O-(partially unsaturated bicyclic carbocyclyl), —O—(C 1-6 alkylene)-(C 3-6 cycloalkyl), —O—(C 3-6 cycloalkyl), —N(R 4 )-aralkyl, —N(R 4 )-phenyl, —N(R 4 )-(partially unsaturated bicyclic carbocyclyl), or —N(R 4 )—(C 1-6 alkylene)-(C 3-6 cycloalkyl), each of which is optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halogen, C 1-6 haloalkyl, C 1-6 alkyl, C 3-6 cycloalkyl, C 1-6 alkoxy, and C 1-6 haloalkoxy; or
(iii) —O-aralkyl, —O-heteroaralkyl, —O-phenyl, —O-heteroaryl, —O-(partially unsaturated bicyclic carbocyclyl), —O—(C 1-6 alkylene)-(C 3-6 cycloalkyl), —N(R 4 )-aralkyl, —N(R 4 )—phenyl, —N(R 4 )-(partially unsaturated bicyclic carbocyclyl), or —N(R 4 )—(C 1-6 alkylene)-(C 3-6 cycloalkyl), each of which is optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halogen, C 1-6 haloalkyl, C 1-6 alkyl, C 3-6 cycloalkyl, C 1-6 alkoxy, and C 1-6 haloalkoxy;
Y is —C(R 6 )(R 7 )—, —O—, or —C(O)—;
m and p are independently 0, 1, or 2; and
n is 1, 2, or 3.
3. The compound of claim 2 , wherein A 1 is phenylene.
4. The compound of claim 3 , wherein n is 1.
5. The compound of claim 4 , wherein R 3 is trifluoromethyl, fluoro, chloro, or methoxy.
6. The compound of claim 2 , wherein -A 1 -(R 3 ) n is
7. The compound of claim 2 , wherein R 2A is —(C 1-6 alkylene)-A 2 .
8. The compound of claim 2 , wherein R 2A is -(2-6 membered heteroalkylene)-A 2 .
9. The compound of claim 8 , wherein A 2 is a 5-6 membered heterocyclic group containing at least one ring carbon atom substituted by oxo and the heterocyclic group being optionally substituted by 1 or 2 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 9 , —CO 2 R 8 , —N(R 4 )C(O)(R 9 ), and —N(R 4 )(R 5 ).
10. The compound of claim 2 , wherein A 2 is imidazolyl; pyrazolyl; 1,2,3-triazolyl; tetrazolyl; 1,2,4-oxadiazol-5(4H)-onyl; 1,3,4-oxadiazol-2(3H)-onyl; 1,3-dihydro-2H-imidazol-2-onyl; or 2,4-dihydro-3H-1,2,4-triazol-3-onyl; each of which is optionally substituted by 1 or 2 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 9 , —CO 2 R 8 , —N(R 4 )C(O)(R 9 ), and —N(R 4 )(R 5 ).
11. The compound of claim 8 , wherein A 2 is one of the following:
each of which is optionally substituted by 1 or 2 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 9 , and —CO 2 R 8 .
12. The compound of claim 2 , wherein X is —(C 2-6 alkenylene)-phenyl, —(C 2-6 alkenylene)-heteroaryl, —(C 1-6 alkylene)-phenyl, —(C 1-6 alkylene)-heteroaryl, —(C 1-6 alkylene)-(partially unsaturated bicyclic heterocyclyl), —(C 1-6 alkylene)-(partially unsaturated bicyclic oxo-heterocyclyl), or -(5-6 membered heterocycloalkylene)-phenyl, each of which is optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halogen, C 1-6 haloalkyl, C 1-6 alkyl, C 3-6 cycloalkyl, C 1-6 alkoxy, and C 1-6 haloalkoxy.
13. The compound of claim 2 , wherein X is —(C 2-6 alkenylene)-phenyl optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halogen, C 1-6 haloalkyl, C 1-6 alkyl, C 3-6 cycloalkyl, C 1-6 alkoxy, and C 1-6 haloalkoxy.
14. The compound of claim 2 , wherein Y is —C(R 6 )(R 7 )—, R 6 and R 7 are independently hydrogen or methyl, and X is attached at the 7-position of the 1,2,3,4-tetrahydroquinolinyl ring.
15. The compound of claim 2 , wherein Y is —O—, and X is attached at the 6-position of the 3,4-dihydro-2H-benzo[b][1,4]oxazinyl ring.
16. The compound of claim 9 , wherein p is 0, and m is 0.
17. A compound represented by Formula II:
or a pharmaceutically acceptable salt thereof; wherein:
A 1 is phenyl, 5-6 membered heteroaryl, or C 3-6 heterocycloalkyl;
R 1 represents independently for each occurrence halogen, C 1-6 alkyl, C 1-6 haloalkyl, or C 3-6 cycloalkyl;
R 2A is —(C 1-6 alkylene)-A 2 , -(2-6 membered heteroalkylene)-A 2 , —(C 0-3 alkylene)-(C 3-6 cycloalkylene)-(C 0-3 alkylene)-A 2 , —O-A 2 , —N(R 8 )-A 2 , or -A 2 ; wherein A 2 is one of the following:
a 5-6 membered heterocyclic group containing at least one ring carbon atom substituted by oxo and the heterocyclic group being optionally substituted by 1 or 2 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 9 , —CO 2 R 8 , —N(R 4 )C(O)(R 9 ), and —N(R 4 )(R 5 ); or
a 5-6 membered heteroaromatic group comprising at least two ring nitrogen atoms, at least one unsaturated carbon atom in the ring, and the heteroaromatic group being optionally substituted by 1 or 2 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 9 , —CO 2 R 8 , —N(R 4 )C(O)(R 9 ), and —N(R 4 )(R 5 );
R 2B represents independently for each occurrence C 1-6 alkyl or C 1-3 haloalkyl;
R 2C is hydrogen or C 1-6 alkyl;
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;
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 and R each represent independently for each occurrence hydrogen or C 1-6 alkyl, or R 6 and R 7 are taken together with the carbon atom to which they are attached to form a 3-6 membered carbocyclic ring; or R 6 and R 2A are taken together to form a bond;
R 8 represents independently for each occurrence hydrogen, C 1-6 alkyl, C 3-6 cycloalkyl, or aralkyl;
R 9 represents independently for each occurrence C 1-6 alkyl, C 3-6 cycloalkyl, or aralkyl;
X is one of the following:
(i) —(C 2-6 alkenylene)-phenyl, —(C 2-6 alkenylene)-heteroaryl, —(C 1-6 alkylene)-phenyl, —(C 1-6 alkylene)-heteroaryl, —(C 1-6 alkylene)-(partially unsaturated bicyclic heterocyclyl), —(C 1-6 alkylene)-(partially unsaturated bicyclic oxo-heterocyclyl), -(5-6 membered heterocycloalkylene)-phenyl, or —(C 3-6 cycloalkylene)-phenyl, each of which is optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halogen, C 1-6 haloalkyl, C 1-6 alkyl, C 3-6 cycloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, hydroxyl, and cyano;
(ii) —(C 2-6 alkenylene)-(C 3-6 cycloalkyl),
or an 8-10 membered, bicyclic partially saturated carbocyclyl, each of which is optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halogen, C 1-6 haloalkyl, C 1-6 alkyl, C 3-6 cycloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, hydroxyl, and cyano, wherein A* is a 5-8 membered, partially saturated carbocyclic or heterocyclic ring;
(iii) —(C 1-6 alkylene)-Z 1 or —(C 2-6 alkenylene)-Z 1 , wherein Z 1 is —O-aralkyl, —O— heteroaralkyl, —O-phenyl, —O-heteroaryl, —O-(partially unsaturated bicyclic carbocyclyl), —O—(C 1-6 alkylene)-(C 3-6 cycloalkyl), —O—(C 3-6 cycloalkyl), —N(R 4 )-aralkyl, —N(R 4 )-phenyl, —N(R 4 )-(partially unsaturated bicyclic carbocyclyl), or —N(R 4 )—(C 1-6 alkylene)-(C 3-6 cycloalkyl), each of which is optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halogen, C 1-6 haloalkyl, C 1-6 alkyl, C 3-6 cycloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, hydroxyl, and cyano; or
(iv) —O-aralkyl, —O-heteroaralkyl, —O-phenyl, —O-heteroaryl, —O-(partially unsaturated bicyclic carbocyclyl), —O—(C 1-6 alkylene)-(C 3-6 cycloalkyl), —O—(C 3-6 cycloalkyl), —N(R 4 )-aralkyl, —N(R 4 )-phenyl, —N(R 4 )-(partially unsaturated bicyclic carbocyclyl), or —N(R 4 )—(C 1-6 alkylene)-(C 3-6 cycloalkyl), each of which is optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halogen, C 1-6 haloalkyl, C 1-6 alkyl, C 3-6 cycloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, hydroxyl, and cyano;
Y is —C(R 6 )(R 7 )—, —O—, —C(O)—, or —S(O) p —;
m and p each represent independently for each occurrence 0, 1, or 2; and
n is 0, 1, 2, or 3.
18. A compound represented by Formula I-C:
or a pharmaceutically acceptable salt thereof; wherein:
A 1 is phenylene or pyrazolylene;
R 2A is -(2-6 membered heteroalkylene)-A 2 ; wherein A 2 is a 5-6 membered heterocyclic group containing at least one unsaturated carbon atom and the heterocyclic group being optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of C 1-3 alkyl, C 1-3 fluoroalkyl, chloro, fluoro, and oxo;
R 3 represents independently for each occurrence C 1-2 fluoroalkyl, chloro, fluoro, cyclopropyl, C 1-3 alkyl, C 1-2 alkoxy, or C 1-2 fluoroalkoxy;
X is —(C 2-6 alkenylene)-phenyl wherein the phenyl is substituted with 1, 2, or 3 substituents independently selected from the group consisting of chloro, fluoro, C 1 -2 fluoroalkyl, C 1-2 alkoxy, and C 1-2 fluoroalkoxy;
n is 1 or 2.
19. The compound of claim 18 , wherein A 1 is phenylene; and R 3 represents independently for each occurrence C 1-2 fluoroalkyl, chloro, fluoro, C 1-2 alkoxy, or C 1-2 fluoroalkoxy.
20. The compound of claim 19 , wherein A 2 is
21. The compound of claim 18 , wherein X is —(C(H)═C(CH 3 ))-phenyl substituted with 1 or 2 substituents independently selected from the group consisting of chloro, fluoro, and trifluoromethyl, and said substituents are located at the ortho positions of the phenyl group.
22. A compound in any one of Tables 1-8 herein or a pharmaceutically acceptable salt thereof.
23. A pharmaceutical composition comprising a compound of claim 1 and a pharmaceutically acceptable carrier.
24. A method of treating cancer by promoting the activity of RORγ, comprising administering a therapeutically effective amount of a compound of claim 1 to a subject in need thereof to treat the cancer, wherein the cancer is colon cancer, pancreatic, cancer, breast cancer, ovarian cancer, prostate cancer, squamous cell carcinoma, lung cancer leukemia bladder cancer, stomach cancer, skin cancer, or esophagus cancer.
25. The method of claim 4 , wherein the subject is a human.
26. A method of promoting the activity of RORγ, comprising exposing a RORγ to an effective amount of a compound of claim 1 to promote the activity of said RORγ.