Dual inhibitors of tim-3 and pd-1 pathways
AssigneeAurigene Oncology Limited
InventorsPottayil Govindan Nair Sasikumar, Muralidhara Ramachandra, Seetharamaiah Setty Sudarshan Naremaddepalli, Nagaraj Gowda
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Abstract
The present disclosure relates to 3-substituted 1,2,4-oxadiazole compounds and their derivatives, which are useful as T-cell immunoglobulin and mucin-domain containing-3 (TIM-3) inhibitors or as dual inhibitors of TIM-3 and the programmed cell death 1 (PD-1) signaling pathway. The disclosure also relates to treatment of disorders by inhibiting an immunosuppressive signal induced by TIM-3, PD-1, PD-L1, and/or PD-L2.
Claims85
A method of modulating an immune response mediated by T-cell immunoglobulin and mucin-domain containing-3 (TIM-3) activity in a cell, comprising contacting the cell with a compound of Formula (I), or a pharmaceutically acceptable salt thereof:
- wherein:
- Z represents —OH or —NH-G;
- G represents hydrogen or (C1-C6)alkyl;
- Y represents hydrogen or a group represented by the following structural formula
- Ra represents (C1-C6)alkyl substituted with —OH, —NRxRy, —SRx, carboxylic acid, guanidino, or aryl, wherein the aryl group is optionally further substituted with hydroxyl;
- or Ra and G taken together with the atom to which they are attached form a 5- to 6-membered ring containing 1 to 3 heteroatoms selected from O, N or S;
- Ra′ represents hydrogen;
- or Ra and Ra′ taken together with the atom to which they are attached form a 5- to 6-membered ring, optionally containing 1 to 3 heteroatoms selected from O, N or S;
- Rb represents (C1-C6)alkyl, optionally substituted with —C(O)NRxRy, —NRxRy, or carboxylic acid;
- Rc represents hydrogen;
- or Rb and Rc taken together with the atoms to which they are attached form a 5- to 6-membered ring containing 1 to 3 heteroatoms selected from O, N or S, wherein the 5- to 6-membered ring is optionally further substituted with hydroxyl;
- Rd represents (C1-C6)alkyl, optionally substituted with —ORx, carboxylic acid, or aryl-OH;
- Re represents hydrogen;
- or Rd and Re taken together with the atoms to which they are attached form a 5- to 6-membered ring containing 1 to 3 heteroatoms selected from O, N or S;
- and
- Rx and Ry independently represent hydrogen, (C1-C6)alkyl or (C2-C6)acyl.
A pharmaceutical composition comprising a pharmaceutically acceptable carrier or excipient and at least one compound of Formula (I), or a pharmaceutically acceptable salt thereof:
- wherein:
- Z represents —OH or —NH-G;
- G represents hydrogen or (C1-C6)alkyl;
- Y represents hydrogen or a group represented by the following structural formula
- Ra represents (C1-C6)alkyl substituted with —OH, —NRxRy, —SRx, carboxylic acid, guanidino, or aryl, wherein the aryl group is optionally further substituted with hydroxyl;
- or Ra and G taken together with the atom to which they are attached form a 5- to 6-membered ring containing 1 to 3 heteroatoms selected from O, N or S;
- Ra′ represents hydrogen;
- or Ra and Ra′ taken together with the atom to which they are attached form a 5- to 6-membered ring, optionally containing 1 to 3 heteroatoms selected from O, N or S;
- Rb represents (C1-C6)alkyl, optionally substituted with —C(O)NRxRy, —NRxRy, or carboxylic acid;
- Rc represents hydrogen;
- or Rb and Rc taken together with the atoms to which they are attached form a 5- to 6-membered ring containing 1 to 3 heteroatoms selected from O, N or S, wherein the 5- to 6-membered ring is optionally further substituted with hydroxyl;
- Rd represents (C1-C6)alkyl, optionally substituted with —ORx, carboxylic acid, or aryl-OH;
- Re represents hydrogen;
- or Rd and Re taken together with the atoms to which they are attached form a 5- to 6-membered ring containing 1 to 3 heteroatoms selected from O, N or S;
- and
- Rx and Ry independently represent hydrogen, (C1-C6)alkyl or (C2-C6)acyl.
Dependencies are inferred from the claim text.