# US 2024/0199701 A1 · Immunomodulators

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- Number: US 2024/0199701 A1
- Document ID: US20240199701A1
- Status: Published application
- Kind: A1
- Application number: 18/551,319
- Filed: 2022-03-24
- Published: 2024-06-20
- Earliest claimed: 2021-03-24
- Assignees: Bristol-Myers Squibb Company
- Applicants: Bristol-Myers Squibb Company
- Inventors: JENNIFER X. QIAO; MICHAEL A. POSS; YUNHUI ZHANG; MARTIN PATRICK ALLEN
- Web page: https://patentgrep.com/patent/US20240199701A1

## CPC

- C07K 7/08: having 12 to 20 amino acids (gastrins C07K14/595; somatostatins C07K14/655; melanotropins C07K14/68)
- C07K 7/54: with at least one abnormal peptide link in the ring
- A61K 47/54: the modifying agent being an organic compound
- A61K 47/542: {Carboxylic acids, e.g. a fatty acid or an amino acid}
- A61K 47/548: {Phosphates or phosphonates, e.g. bone-seeking (phospholipids A61K47/544)}
- A61P 35/00: Antineoplastic agents
- A61K 38/00: Medicinal preparations containing peptides (peptides containing beta-lactam rings A61K31/00; cyclic dipeptides not having in their molecule any other peptide link than those which form their ring, e.g. piperazine-2,5-diones, A61K31/00; ergot alkaloids of the cyclic peptide type A61K31/48; containing macromolecular compounds having statistically distributed amino acid units A61K31/74; medicinal preparations containing antigens or antibodies A61K39/00; medicinal preparations characterised by the non-active ingredients, e.g. peptides as drug carriers, A61K47/00)
- C07K: PEPTIDES (peptides in foodstuffs A23; obtaining protein compositions for foodstuffs, working-up proteins for foodstuffs A23J; preparations for medicinal purposes A61K; peptides containing beta-lactam rings C07D; cyclic dipeptides not having in their molecule any other peptide link than those which form their ring, e.g. piperazine-2,5-diones, C07D; ergot alkaloids of the cyclic peptide type C07D519/02; macromolecular compounds having statistically distributed amino acid units in their molecules, i.e. when the preparation does not provide for a specific; but for a random sequence of the amino acid units, homopolyamides and block copolyamides derived from amino acids C08G69/00; macromolecular products derived from proteins C08H1/00; preparation of glue or gelatine C09H; single cell proteins, enzymes C12N; genetic engineering processes for obtaining peptides C12N15/00; compositions for measuring or testing processes involving enzymes C12Q; investigation or analysis of biological material G01N33/00)
- A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS

## 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.

## Claims

### Claim 1

A compound of formula (I)
or a pharmaceutically acceptable salt thereof, wherein:
A is selected from
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;
m is 1 or 2;
u is 0 or 1;
w is 0, 1, or 2;
Rx is selected from hydrogen, amino, hydroxy, and methyl;
R14 and R11 are independently selected from hydrogen and methyl;
R16a is selected from hydrogen and C1-C6 alkyl;
R16 is selected from
—(C(R17a)2)2—X—R30, —(C(R17aR17))0-2—X′—R30, —(C(R17aR17)1-2C(O)NR16a)m′—X′—R30,
—C(R17a)2C(O)N(R16a)C(R17a)2—X′—R31, —(C(R17aR17))12C(O)N(R16a)C(R17a)2—X′—R31,
—C(R17a)2[C(O)N(R16a)C(R17a)2]w′—X—R31, —C(R17aR17)1-2[C(O)N(R16a)C(R17aR17)1-2]w′—X′—R31,
—(C(R17a)(R17)C(O)NR16a)n′—H; and
—(C(R17a)(R17)C(O)NR16a)m′—C(R17a)(R17)—CO2H;
wherein a PEGq′ spacer can be inserted in any part of the R16 (q′ is the number of —(CH2CH2O)— unit in a PEG spacer);
wherein w′ is 2 or 3;
n′ is 1-6;
m′ is 0-5;
q′ is 1-20
X is a chain of between 1 and 172 atoms wherein the atoms are selected from n:
carbon and oxygen and wherein the chain may contain one, two, three, or four groups selected from —NHC(O)—, —NHC(O)NH—, and —C(O)NH— embedded therein; and wherein the chain is optionally substituted with one to six groups independently selected from —CO2H, —C(O)NH2, —CH2C(O)NH2, and —(CH2)1-2CO2H;
X′ is a chain of between 1 and 172 atoms wherein the atoms are selected from carbon and oxygen and wherein the chain may contain one, two, three, or four groups selected from —NHC(O)—, —NHC(O)NH—, and —C(O)NH— embedded therein; and wherein the chain is optionally substituted with one to six groups independently selected from —CO2H, —C(O)NH2, and —(CH2)1-2CO2H, provided that X′ is other than unsubstituted PEG;
R30 is selected from —SO3H, —S(O)OH, and —P(O)(OH)2;
R31 is selected from —S(O)2OH, —S(O)OH, and —P(O)(OH)2;
each R17a is independently selected from hydrogen, C1-C6alkyl, —CH2OH, —CH2CO2H, —(CH2)2CO2H,
each R17 is independently selected from hydrogen, —CH3, (CH2)zN3,
—(CH2)zNH2, —X—R31, —(CH2)zCO2H, —CH2OH, CH2C≡CH, and —(CH2)z-triazolyl-X—R35, wherein z is 1-6 and R35 is selected from —SO3H, —S(O)OH, and —P(O)(OH)2; provided at least one R17 is other than hydrogen, —CH3, or —CH2OH;
provided at least one of R30, R31, or R35 is present;
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;
Rb is methyl or, Rb and R2, together with the atoms to which they are attached, form a ring selected from azetidine, pyrrolidine, 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, pyrrolidine, 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;
R9 is hydrogen or methyl or R9 and R7, together with the atoms to which they are attached, can form a ring selected from azetidine, pyrrolidine, 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
R1 is methyl or, R1 and R12, together with the atoms to which they are attached, form a ring selected from azetidine and pyrrolidine, wherein each ring is optionally substituted with one to four independently selected from amino, cyano, methyl, halo, and hydroxy.

### Claim 2 (depends on 1)

The compound according to claim 1, or a pharmaceutically acceptable salt thereof,
wherein A is
m is 1 and w is 0; and
R14, R15, and R16a are each hydrogen.

### Claim 3 (depends on 1)

The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein
R16 is selected from —(C(R17a)2)2—X—R30, —(C(R17aR17))0-2—X′—R3 and —(C(R17aR17)1-2C(O)NR16a)m′X′—R30,
each R17a is selected from hydrogen, —CO2H, and —(CH2)1-2CO2H;
X is a chain of between 8 and 46 atoms wherein the atoms are selected from carbon and oxygen and wherein the chain may contain one, two, or three —NHC(O)—, C(O)NH groups embedded therein; and wherein the chain is optionally substituted with one or two groups independently selected from —CO2H, —C(O)NH2, —CH2C(O)NH2, and —CH2CO2H; and
R30 is selected from —SO3H and —P(O)(OH)2.

### Claim 4 (depends on 1)

The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein
A is
m is 1 and w is 0;
R14, R15, and R16a are each hydrogen;
R16 is selected from —C(R17a)2C(O)N(R16a)C(R17a)2—X′—R31 and —(C(R17aR17))1-2C(O)N(R16a)C(R17a)2—X′—R31,
each R17a is selected from hydrogen, —CO2H, and —CH2CO2H;
X′ is a chain of between 8 and 48 atoms wherein the atoms are selected from carbon and oxygen and wherein the chain may contain one, two, or three —NHC(O)— or —C(O)NH— groups embedded therein; and wherein the chain is optionally substituted with one or two groups independently selected from —CO2H, —C(O)NH2, —CH2C(O)NH2, and —CH2CO2H; provided that X′ is other than unsubstituted PEG; and
R31 is selected from —SO3H and —P(O)(OH)2.

### Claim 5 (depends on 1)

The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein A is
m is 1 and w is 0;
R14, R15, and R16a are each hydrogen;
R16 is selected from —C(R17a)2[C(O)N(R16a)C(R17a)z]w′—X—R31 and —C(R17aR17)1-2[C(O)N(R16a)C(R17aR17)1-2]w′—X′—R31,
each R17a is selected from hydrogen, —CO2H, and —CH2CO2H;
X is a chain of between 8 and 48 atoms wherein the atoms are selected from carbon and oxygen and wherein the chain may contain one, two, or three —NHC(O)— or —C(O)NH— groups embedded therein; and wherein the chain is optionally substituted with one or two groups independently selected from —CO2H, —C(O)NH2, —CH2C(O)NH2, and —CH2CO2H; and
R31 is selected from —SO3H and —P(O)(OH)2.

### Claim 6 (depends on 1)

The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein A is
m is 1 and w is 0;
R14, R15, and R16a are each hydrogen; and
R16 is —(C(R17a)(R17)C(O)NR16a)n′—H.
each R17a is hydrogen; and
each R17 is selected from hydrogen, —CH3, (CH2)zN3, —(CH2)zNH2, —X—R31,
—(CH2)zCO2H, —CH2OH, CH2C≡CH, and —(CH2)z-triazolyl-X—R35; provided at least one R17 is other than hydrogen, —CH3, or —CH2OH, and provided at least one R31 or R35 is present;
z is 1-4;
R31 is selected from —SO3H and —P(O)(OH)2;
X is a chain of between 7 and 155 atoms wherein the atoms are selected from carbon and oxygen and wherein the chain may contain one, two, or three —NHC(O)—, or —C(O)NH— groups embedded therein; and wherein the chain is optionally substituted with one or two groups independently selected from —CO2H, —C(O)NH2, —CH2C(O)NH2, and —CH2CO2H; and
R35 is selected from —SO3H and —P(O)(OH)2.

### Claim 7 (depends on 1)

The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein
A is
m is 1 and w is 0;
R14, R15, and R16a are each hydrogen;
R16 is —(CR17a)(R17)C(O)NR16a)m′—C(R17a)(R17)—CO2H;
m′ is 0-3;
each R17a is hydrogen;
each R17 is selected from hydrogen, —CH3, (CH2)zN3, —(CH2)zNH2, —X—R31,
—(CH2)zCO2H, —CH2OH, CH2C≡CH, —(CH2)z-triazolyl-X—R35; and
provided at least one R17 is other than hydrogen, —CH3, or —CH2OH, and provided at least one R31 or R35 is present;
z is 1-4;
R31 is selected from —SO3H and —P(O)(OH)2;
X is a chain of between 10 and 60 atoms wherein the atoms are selected from carbon and oxygen and wherein the chain may contain one, two, or three —NHC(O)—, —C(O)NH— groups embedded therein; and wherein the chain is optionally substituted with one or two groups independently selected from —CO2H, —C(O)NH2, —CH2C(O)NH2, and —CH2CO2H; and
R35 is selected from —SO3H and —P(O)(OH)2.

### Claim 8 (depends on 1)

The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein
R1 is phenylC1-C3alkyl wherein the phenyl part is optionally substituted with hydroxyl, halo, or methoxy;
R2 is C1-C7alkyl or, R2 and Rb, together with the atoms to which they are attached, form a piperidine ring;
R3 is NRxRy(C1-C7alkyl), NRuRvcarbonylC1-C3alkyl, or carboxyC1-C3alkyl;
R4 and Rd, together with the atoms to which they are attached, form a pyrrolidine ring;
R5 is hydroxyC1-C3alkyl, imidazolylC1-C3alkyl, or NRxRy(C1-C7alkyl);
R6 is carboxyC1-C3alkyl, NRuRvcarbonylC1-C3alkyl, NRxRy(C1-C7alkyl), or C1-C7alkyl;
R7 and R9, together with the atoms to which they are attached, form a pyrrolidine ring optionally substituted with hydroxy;
R8 and R10 are benzothienyl or indolylC1-C3alkyl optionally substituted with carboxyC1-C3alkyl;
R9 is hydroxyC1-C3alkyl, aminoC1-C4alkyl, or C1-C7alkyl, R11 is C1-C3alkoxyC1-C3alkyl or C1-C7alkyl;
R12 is C1-C7alkyl or hydroxyC1-C3alkyl; and
R13 is C1-C7 alkyl, carboxyC1-C3alkyl, or —(CH2)3NHC(NH)NH2.

### Claim 9 (depends on 1)

The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein
A is
m is 1 and w is 0;
R14 and R15, are each hydrogen;
R16a is hydrogen or methyl;
Rd is methyl or, Rd and R4, together with the atoms to which they are attached, form a ring selected from azetidine, pyrrolidine, morpholine, piperidine, piperazine, and tetrahydrothiazole; wherein each ring is optionally substituted with one or two groups independently selected from amino, cyano, methyl, halo, hydroxy, and phenyl;
R9 is methyl or, R9 and R7, together with the atoms to which they are attached,
form a ring selected from azetidine, pyrrolidine, morpholine, piperidine, piperazine, and tetrahydrothiazole; wherein each ring is optionally substituted with one or two 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 pyrrolidine.

### Claim 10

A compound or a pharmaceutically acceptable salt thereof which is

### Claim 11 (depends on 1)

A pharmaceutical composition comprising a compound of claim 1, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

### Claim 12 (depends on 10)

A pharmaceutical composition comprising a compound of claim 10 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

### Claim 13 (depends on 1)

A method of enhancing, stimulating, and/or increasing an immune response in a subject in need thereof, said method comprising administering to the subject a therapeutically effective amount of a compound of claim 1, or a pharmaceutically acceptable salt thereof.

### Claim 14 (depends on 1)

A method of inhibiting growth, proliferation, or metastasis of cancer cells in a subject in need thereof, said method comprising administering to the subject a therapeutically effective amount a compound of claim 1, or a pharmaceutically acceptable salt thereof.

### Claim 15 (depends on 14)

The method of claim 14 wherein the cancer is selected from melanoma, renal cell carcinoma, squamous non-small cell lung cancer (NSCLC), non-squamous NSCLC, colorectal cancer, castration-resistant prostate cancer, ovarian cancer, gastric cancer, hepatocellular carcinoma, pancreatic carcinoma, squamous cell carcinoma of the head and neck, carcinomas of the esophagus, gastrointestinal tract and breast, and hematological malignancies.

### Claim 16 (depends on 1)

A method of treating an infectious disease in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound of claim 1, or a pharmaceutically acceptable salt thereof.

### Claim 17 (depends on 16)

The method of claim 16 wherein the infectious disease is caused by a virus.

### Claim 18 (depends on 1)

A method of treating septic shock in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound of claim 1, or a pharmaceutically acceptable salt thereof.

### Claim 19 (depends on 1)

A method of blocking the interaction of PD-L1 with PD-1 and/or CD80 in a subject, said method comprising administering to the subject a therapeutically effective amount of a compound of claim 1, or a pharmaceutically acceptable salt thereof.