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US 2017/0283462 A1Published application
Immunomodulators
AssigneeBristol-Myers Squibb Company
InventorsMichael Matthew Miller, Martin Patrick Allen, Ling Li, Claudio Mapelli, Maude A. Poirier, Li-Qiang Sun, Qian Zhao, Eric Mull, Eric P. Gillis, Paul Michael Scola
Life of this patent
Estimating the term…
Abstract
The present disclosure provides novel macrocyclic peptides which inhibit the PD-1/PD-L1 and PD-L1/CD80 protein/protein interaction, and thus are useful for the amelioration of various diseases, including cancer and infectious diseases.
Claims23
A compound of formula (I)
- or a pharmaceutically acceptable salt thereof, wherein:
- A is selected from a bond,
- wherein:
- denotes the point of attachment to the carbonyl group and
- denotes the point of attachment to the nitrogen atom;
- z is 0, 1, or 2;
- w is 1 or 2;
- n is 0 or 1;
- m is 1 or 2;
- m′ is 0 or 1;
- p is 0, 1, or 2;
- Rx is selected from hydrogen, amino, hydroxy, and methyl;
- R14 and R15 are independently selected from hydrogen and methyl;
- and
- Rz is selected from hydrogen and —C(O)NHR16;
- wherein 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;
- Rv is hydrogen or a natural amino acid side chain;
- Q is selected from
- wherein Rb is defined below, and a five- or six-membered ring containing one, two, or three double bonds and optionally containing one, two, or three heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein the ring is optionally substituted with one, two, three, or four substituents independently selected from C1-C6alkoxycarbonyl, C1-C3alkyl, amino, C1-C3alkylamino, carboxy, C1-C3dialkylamino, halo, and haloC1-C3alkyl;
- U is selected from
- wherein Rk is defined below, and a five- or six-membered ring containing one, two, or three double bonds and optionally containing one, two, or three heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein the ring is optionally substituted with one, two, three, or four substituents independently selected from C1-C6alkoxycarbonyl, C1-C3alkyl, amino, C1-C3alkylamino, carboxy, C1-C3dialkylamino, halo, and haloC1-C3alkyl;
- provided that at least one of Q and U is a five- or six-membered ring containing one, two, or three double bonds and containing one, two, or three heteroatoms independently selected from nitrogen, oxygen, and sulfur;
- Rc, Rf, Rh, Ri, Rm, and Rn are hydrogen;
- Ra, Re, Rj, and Rk, 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;
- Re and Rk can each form a ring with the corresponding vicinal R group and the atoms to which they are attached selected from azetidine, pyrollidine, 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;
- Rb is methyl or, Rb and R2, together with the atoms to which they are attached, form a ring selected from azetidine, pyrollidine, 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 hydrogen or methyl, or, Rd and R4, together with the atoms to which they are attached, can form a ring selected from azetidine, pyrollidine, 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;
- Rg is hydrogen or methyl or Rg and R7, together with the atoms to which they are attached, can form a ring selected from azetidine, pyrollidine, 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;
- and
- Rl is methyl or, Rl and R12, together with the atoms to which they are attached, form a ring selected from azetidine and pyrollidine, wherein each ring is optionally substituted with one to four groups independently selected from amino, cyano, methyl, halo, and hydroxy.
34 more elements
A compound of formula (II)
- or a pharmaceutically acceptable salt thereof, wherein:
- A is selected from a bond,
- 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;
- Q is a five- or six-membered ring containing one, two, or three double bonds and optionally containing one, two, or three heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein the ring is optionally substituted with one, two, three, or four substituents independently selected from C1-C6alkoxycarbonyl, C1-C3alkyl, amino, C1-C3alkylamino, carboxy, C1-C3dialkylamino, halo, and haloC1-C3alkyl;
- Ra, Rf, Rj, Rk, Rl, and Rm are hydrogen;
- Rb and Rc are methyl;
- Rg is selected from hydrogen and methyl;
- R1, R2, R3, R4, R5, R6, R7, R9, R10, R11, and R12 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;
- R20 is hydrogen;
- R8 is selected from a natural amino acid side chain, an unnatural amino acid chain, or can form a ring with the corresponding vicinal R group as described below, or, alternatively, R8 can form a three- to six-membered carbocyclic ring with R20;
- Rd is selected from hydrogen and methyl, or, Rd and R4, together with the atoms to which they are attached, form a ring selected from azetidine, pyrollidine, morpholine, piperidine, piperazine, and tetrahydrothiazole;
- wherein each ring is optionally substituted with one to four groups independently selected from amino, cyano, methyl, halo, halomethyl, and hydroxy;
- Re is selected from hydrogen and methyl, or, Re and R5, together with the atoms to which they are attached, form a ring selected from azetidine, pyrollidine, morpholine, piperidine, piperazine, and tetrahydrothiazole;
- wherein each ring is optionally substituted with one to four groups independently selected from amino, cyano, methyl, halo, halomethyl, and hydroxy;
- and
- Rh is selected from hydrogen and methyl, or, Rh and R8, together with the atoms to which they are attached, form a ring selected from azetidine, pyrollidine, morpholine, piperidine, piperazine, and tetrahydrothiazole;
- wherein each ring is optionally substituted with one to four groups independently selected from amino, cyano, methyl, halo, halomethyl, and hydroxy.
21 more elements
A compound selected from:
- Example 1001 (SEQ ID NO:
- 6);
- Example 1002 (SEQ ID NO:
- 7);
- Example 1003 (SEQ ID NO:
- 8);
- Example 1004 (SEQ ID NO:
- 9);
- Example 1005 (SEQ ID NO:
- 10);
- Example 1006 (SEQ ID NO:
- 11);
- Example 1007 (SEQ ID NO:
- 12);
- Example 1010 (SEQ ID NO:
- 13);
- Example 1012 (SEQ ID NO:
- 14);
- Example 1013 (SEQ ID NO:
- 15);
- Example 1014 (SEQ ID NO:
- 16);
- Example 1050 (SEQ ID NO:
- 17);
- Example 1051 (SEQ ID NO:
- 18);
- Example 1052 (SEQ ID NO:
- 19);
- Example 1053 (SEQ ID NO:
- 20);
- Example 1054 (SEQ ID NO:
- 21);
- Example 1055 (SEQ ID NO:
- 22);
- Example 1056 (SEQ ID NO:
- 23);
- Example 1057 (SEQ ID NO:
- 24);
- Example 1058 (SEQ ID NO:
- 25);
- Example 1059 (SEQ ID NO:
- 26);
- Example 1060 (SEQ ID NO:
- 27);
- Example 1061 (SEQ ID NO:
- 28);
- Example 1100 (SEQ ID NO:
- 29);
- Example 1101 (SEQ ID NO:
- 30);
- Example 1102 (SEQ ID NO:
- 31);
- Example 1103 (SEQ ID NO:
- 32);
- Example 1104 (SEQ ID NO:
- 33);
- Example 1105 (SEQ ID NO:
- 34);
- Example 1106 (SEQ ID NO:
- 35);
- Example 1107 (SEQ ID NO:
- 36);
- Example 1108 (SEQ ID NO:
- 37);
- Example 1109 (SEQ ID NO:
- 38);
- Example 1110 (SEQ ID NO:
- 39);
- Example 1111 (SEQ ID NO:
- 40);
- Example 1113 (SEQ ID NO:
- 41);
- Example 1114 (SEQ ID NO:
- 42);
- Example 3001 (SEQ ID NO:
- 44);
- Example 3002 (SEQ ID NO:
- 44);
- Example 3003 (SEQ ID NO:
- 45);
- or a pharmaceutically acceptable salt thereof.
78 more elements
A compound which is Example 1115 (SEQ ID NO:
- 43).
Dependencies are inferred from the claim text.