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US-20260125417-A1 - GLUCOCORTICOID RECEPTOR AGONISTS

US20260125417A1US 20260125417 A1US20260125417 A1US 20260125417A1US-20260125417-A1

Abstract

The present invention provides a compound of Formula I: wherein R is H or R 1 is H, halogen, C1-C3 alkyl, C3-C6 cycloalkyl, C1-C3 alkoxy, C2-C3 alkenyl, OCF 3 , R 2 is H, halogen, C1-C3 alkyl, C1-C3 alkoxy, or C2-C4 alkenyl; R 3 is NH 2 , or CH 2 NH 2 ; and X is O, OCH 2 , OCH 2 CH 2 , OCH(CH 3 ), CH 2 O, SCH 2 , CH 2 S, CH 2 , NHCH 2 , CH 2 NH, N(CH 3 )CH 2 , CH 2 CH 2 , C≡C, or a bond, wherein X is connected to phenyl ring A at the ortho or the meta position, or a pharmaceutically acceptable salt thereof, wherein the compound of Formula I, or pharmaceutically acceptable salt thereof is useful for treating autoimmune and inflammatory diseases, such as atopic dermatitis and rheumatoid arthritis.

Inventors

  • Adel Ahmed Rashad Ahmed
  • Joshua Ryan Clayton
  • Jose Eduardo LOPEZ GARCIA
  • Jothirajah Marimuthu
  • William Thomas McMillen
  • Ryan Edward Stites
  • Takako WILSON
  • Jacqueline Mary WURST

Assignees

  • ELI LILLY AND COMPANY

Dates

Publication Date
20260507
Application Date
20230921

Claims (20)

  1. 1 . A compound of the formula: wherein R is H or R 1 is H, halogen, CN, C1-C3 alkyl, C3-C6 cycloalkyl, C1-C3 alkoxy, C2-C3 alkenyl, OCF 3 , R 2 is H, halogen, C1-C3 alkyl, C1-C3 alkoxy, or C2-C3 alkenyl; R 3 is NH 2 , or CH 2 NH 2 ; and X is O, OCH 2 , OCH 2 CH 2 , CH 2 O, SCH 2 , CH 2 S, CH 2 , NHCH 2 , CH 2 NH, N(CH 3 )CH 2 , CH 2 CH 2 , C≡C, or a bond, wherein X is connected to phenyl ring A at the ortho or the meta position, or a pharmaceutically acceptable salt thereof.
  2. 2 . The compound of claim 1 , wherein R 3 is NH 2 , or a pharmaceutically acceptable salt thereof.
  3. 3 . The compound of claim 1 , wherein R is H, or a pharmaceutically acceptable salt thereof.
  4. 4 . The compound of claim 1 , wherein the compound is of Formula or a pharmaceutically acceptable salt thereof.
  5. 5 . The compound of claim 1 , wherein R 1 is F, CH 2 CH 3 , OCH 3 , or OC( 2 H) 3 , or a pharmaceutically acceptable salt thereof.
  6. 6 . The compound of claim 1 , wherein R 1 is F, or a pharmaceutically acceptable salt thereof.
  7. 7 . The compound of claim 1 , wherein R 1 is CH 2 CH 3 , or a pharmaceutically acceptable salt thereof.
  8. 8 . The compound of claim 1 , wherein R 1 is OCH 3 , or a pharmaceutically acceptable salt thereof.
  9. 9 . The compound of claim 1 , wherein R 1 is OC( 2 H) 3 , or a pharmaceutically acceptable salt thereof.
  10. 10 . The compound of claim 1 , wherein R 2 is F, CH 2 CH 3 , OCH 3 , or OC( 2 H) 3 , or a pharmaceutically acceptable salt thereof.
  11. 11 . The compound of claim 1 , wherein R 2 is F, or a pharmaceutically acceptable salt thereof.
  12. 12 . The compound of claim 1 , wherein R 2 is CH 2 CH 3 , or a pharmaceutically acceptable salt thereof.
  13. 13 . The compound of claim 1 , wherein R 2 is OCH 3 , or a pharmaceutically acceptable salt thereof.
  14. 14 . The compound of claim 1 , wherein R 2 is OC( 2 H) 3 , or a pharmaceutically acceptable salt thereof.
  15. 15 . The compound of claim 1 , wherein X is CH 2 CH 2 , OCH 2 , or OCH 2 CH 2 , or a pharmaceutically acceptable salt thereof.
  16. 16 . The compound of claim 1 , wherein X is CH 2 CH 2 , or a pharmaceutically acceptable salt thereof.
  17. 17 . The compound of claim 1 , wherein X is OCH 2 , or a pharmaceutically acceptable salt thereof.
  18. 18 . The compound of claim 1 , wherein X is OCH 2 CH 2 , or a pharmaceutically acceptable salt thereof.
  19. 19 . The compound of claim 1 , wherein the compound is: or a pharmaceutically acceptable salt thereof.
  20. 20 . The compound of claim 19 , wherein the compound is:

Description

The present disclosure provides compounds that are glucocorticoid receptor agonists and are useful for the treatment of autoimmune and inflammatory diseases, such as atopic dermatitis, inflammatory bowel disease, systemic lupus erythematosus, lupus nephritis, and rheumatoid arthritis, processes for preparing these compounds, pharmaceutical compositions comprising these compounds, and methods of using these compounds and compositions are also provided. Atopic dermatitis is a chronic, pruritic relapsing and remitting inflammatory skin disease that occurs frequently in children, but also affects many adults. Current treatments of atopic dermatitis include light therapy, topical creams containing corticosteroids or calcineurin inhibitors, or a subcutaneous injectable biologic known as dupilumab. In spite of progress made in treating atopic dermatitis, there remains a significant need for new compounds to treat atopic dermatitis and other inflammatory and autoimmune diseases. WO2017/210471 discloses certain glucocorticoid receptor agonists and immunoconjugates thereof useful for treating autoimmune or inflammatory diseases. WO2018/089373 discloses novel steroids, protein conjugates thereof, and methods for treating diseases, disorders, and conditions comprising administering the steroids and conjugates. The present invention provides certain novel compounds which are glucocorticoid receptor agonists. The present invention further provides certain novel compounds which are prodrugs of glucocorticoid receptor agonists. In addition, the present invention provides certain novel compounds which are glucocorticoid receptor agonists useful in the treatment of autoimmune and inflammatory diseases such as atopic dermatitis, inflammatory bowel disease, rheumatoid arthritis, systemic lupus erythematosus, and lupus nephritis. Accordingly, in one embodiment, the invention provides a compound of Formula I: wherein R is H or R1 is H, halogen, CN, C1-C3 alkyl, C3-C6 cycloalkyl, C1-C3 alkoxy, C2-C3 alkenyl, OCF3, R2 is H, halogen, C1-C3 alkyl, C1-C3 alkoxy, or C2-C3 alkenyl;R3 is NH2, or CH2NH2; andX is O, OCH2, OCH2CH2, CH2O, SCH2, CH2S, CH2, NHCH2, CH2NH, N(CH3)CH2, CH2CH2, C≡C, or a bond, wherein X is connected to phenyl ring A at the ortho or the meta position, or a pharmaceutically acceptable salt thereof. In one embodiment, the invention provides a compound of Formula Ia: wherein R is H or R1 is H, halogen, C1-C3 alkyl, C3-C6 cycloalkyl, C1-C3 alkoxy, C2-C3 alkenyl, OCF3, R2 is H, halogen, C1-C3 alkyl, C1-C3 alkoxy, or C2-C4 alkenyl;R3 is NH2, or CH2NH2; andX is O, OCH2, OCH2CH2, OCH2C≡C, OCH(CH3), CH2O, SCH2, CH2S, CH2, NHCH2, CH2NH, N(CH3)CH2, CH2CH2, C≡C, or a bond, wherein X is connected to phenyl ring A at the ortho or the meta position, or a pharmaceutically acceptable salt thereof. In one embodiment, the invention provides a compound of Formula Ib: wherein R is H or R1 is H, halogen, C1-C3 alkyl, C3-C6 cycloalkyl, C1-C3 alkoxy, C2-C3 alkenyl, OCF3, R2 is H, halogen, C1-C3 alkyl, C1-C3 alkoxy, or C2-C4 alkenyl;R3 is NH2, or CH2NH2; andX is O, OCH2, OCH2CH2, OCH(CH3), CH2O, SCH2, CH2S, CH2, NHCH2, CH2NH, N(CH3)CH2, CH2CH2, C≡C, or a bond, wherein X is connected to phenyl ring A at the ortho or the meta position, or a pharmaceutically acceptable salt thereof. In one embodiment, the invention provides a compound of Formula Ic: wherein R is H or R1 is H, halogen, C1-C3 alkyl, C3-C6 cycloalkyl, C1-C3 alkoxy, C2-C3 alkenyl, OCF3, R2 is H, halogen, C1-C3 alkyl, C1-C3 alkoxy, or C2-C4 alkenyl;R3 is NH2, or CH2NH2; andX is O, OCH2, OCH2CH2, OCH(CH3), CH2O, SCH2, CH2S, CH2, NHCH2, CH2NH, N(CH3)CH2, CH2CH2, C≡C, or a bond, wherein X is connected to phenyl ring A at the ortho or the meta position, or a pharmaceutically acceptable salt thereof. In an embodiment, the invention provides a compound of Formula Ib(i): or a pharmaceutically acceptable salt thereof. In an embodiment, the invention provides a compound of Formula Ic(i): or a pharmaceutically acceptable salt thereof. In an embodiment, the invention provides a compound of Formula Ib(ii): or a pharmaceutically acceptable salt thereof. In an embodiment, the invention provides a compound of Formula Ic(ii): or a pharmaceutically acceptable salt thereof. In an embodiment, the invention provides a compound of Formula Ib(iii): or a pharmaceutically acceptable salt thereof. In an embodiment, the invention provides a compound of Formula Ic(iii): or a pharmaceutically acceptable salt thereof. In one embodiment, the invention provides a compound of Formula II: wherein R is H or and R1 is —CH3 or —OCH3,or a pharmaceutically acceptable salt thereof. In a particular embodiment, the invention provides a compound of Formula IIa: wherein R is H or and R1 is —CH3 or —OCH3,or a pharmaceutically acceptable salt thereof. In a particular embodiment, the invention provides a compound of Formula IIb: wherein R is H or and R1 is —CH3 or —OCH3, or a pharmaceutically acceptable salt thereof. In a par