Macrocyclic inhibitors of the PD-1/PD-L1 and CD80(B7-1)/PD-L1 protein/protein interactions

A method of treating septic shock in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of one or more macrocyclic peptides of formula (I)

• or a pharmaceutically acceptable salt thereof, wherein:
• A is
• wherein:
• denotes the point of attachment to the carbonyl group and denotes the point of attachment to the nitrogen atom;
• n is 0 or 1;
• R14 and R15 are independently selected from hydrogen and methyl;
• and
• R16 is selected from hydrogen, —CHR17C(O)NH2,
• —CHR17C(O)NHCHR18C(O)NH2, and
• —CHR17C(O)NHCHR18C(O)NHCH2C(O)NH2;
• wherein R17 is selected from hydrogen and CH2OH and wherein R18 is selected from hydrogen and methyl;
• Rc, Rf, Rh, Ri, Rm, and Rn are hydrogen;
• Ra and Rj are each independently selected from hydrogen and methyl;
• R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R11, R12, and R13 are independently selected from a natural amino acid side chain and an unnatural amino acid side chain or form a ring with the corresponding vicinal R group as described below;
• Rb is methyl or, Rb and R2, together with the atoms to which they are attached, form a ring selected from azetidine, pyrolidine, morpholine, piperidine, piperazine, and tetrahydrothiazole;
• wherein each ring is optionally substituted with one to four groups independently selected from amino, cyano, methyl, halo, and hydroxy;
• Rd is methyl or Rd and R4, together with the atoms to which they are attached, can form a ring selected from azetidine, pyrolidine, morpholine, piperidine, piperazine, and tetrahydrothiazole;
• wherein each ring is optionally substituted with one to four groups independently selected from amino, cyano, methyl, halo, hydroxy, and phenyl;
• Re is hydrogen or methyl, or Re and R5, together with the atoms to which they are attached, form a ring selected from azetidine, pyrolidine, morpholine, piperidine, piperazine, and tetrahydrothiazole;
• wherein each ring is optionally substituted with one to four groups independently selected from amino, cyano, methyl, halo, and hydroxy;
• Rg is methyl or Rg and R7, together with the atoms to which they are attached, can form a ring selected from azetidine, pyrolidine, morpholine, piperidine, piperazine, and tetrahydrothiazole;
• wherein each ring is optionally substituted with one to four groups independently selected from amino, benzyl optionally substituted with a halo group, benzyloxy, cyano, cyclohexyl, methyl, halo, hydroxy, isoquinolinyloxy optionally substituted with a methoxy group, quinolinyloxy optionally substituted with a halo group, and tetrazolyl;
• and wherein the pyrrolidine and the piperidine ring are optionally fused to a cyclohexyl, phenyl, or indole group;
• Rk is methyl or Rk and R11, together with the atoms to which they are attached, selected from azetidine, pyrolidine, morpholine, piperidine, piperazine, and tetrahydrothiazole;
• wherein each ring is optionally substituted with one to four groups independently selected from amino, cyano, methyl, halo, and hydroxy;
• and
• R1 is methyl or, R1 and R12, together with the atoms to which they are attached, form a ring selected from azetidine and pyrolidine, wherein each ring is optionally substituted with one to four groups independently selected from amino, cyano, methyl, halo, and hydroxy.