# US 12,215,116 B2 · Arginase inhibitors and methods of use

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- Number: US 12,215,116 B2
- Document ID: US12215116B2
- Status: Granted
- Kind: B2
- Application number: 16/977,253
- Filed: 2019-03-08
- Published: 2021-02-11
- Granted: 2025-02-04
- Earliest claimed: 2018-03-13
- Assignees: Merck Sharp & Dohme Corp.
- Applicants: Merck Sharp & Dohme LLC
- Inventors: Abdelghani Abe Achab; Matthew L. Childers; Jared N. Cumming; Christian Fischer; Symon Gathiaka; Hakan Gunaydin; Charles A. Lesburg; Derun Li; Min Lu; Anandan Palani; Rachel L. Palte; Qinglin Pu; David L. Sloman; Sung-Sau So; Chunrui Sun; Hongjun Zhang
- Web page: https://patentgrep.com/patent/US12215116B2

## CPC

- C07F 5/025: {Boronic and borinic acid compounds}
- A61P 35/00: Antineoplastic agents
- C07K 16/2818: {against CD28 or CD152}
- C07F: ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM (metal-containing porphyrins C07D487/22)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- 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)

## Abstract

Described herein are compounds of Formula I or a pharmaceutically acceptable salt thereof. The compounds of Formula I act as arginase inhibitors and can be useful in preventing, treating or acting as a remedial agent for arginase-related diseases.

## Claims

### Claim 1

A compound of Formula I:
or a pharmaceutically acceptable salt thereof, wherein:
W is selected from the group consisting of straight or branched (C2-C5) alkylene, wherein one or more —CH2— groups in W are optionally and independently replaced with a moiety selected from the group consisting of —O—, —S— or —NH—;
V is selected from the group consisting of a bond, O, S, CR6R7 or NR8;
X is selected from the group consisting of a bond, O, S, CR9R10 or NR11;
Y is selected from the group consisting of a bond, O, S, CR12R13 or NR14,
is selected from the group consisting of a bond, O, S, CR15R16 or NR17, R1 is selected from the group consisting of hydrogen, —C3-C6cycloalkyl or —C1-C6alkyl or, taken with R2 forms a C3-C8cycloalkyl, wherein the C3-C8cycloalkyl is optionally substituted with one to four substituents selected from the group consisting of halogen, —C1-C6alkyl or —OH;
R2 is selected from the group consisting of hydrogen, —C3-C6cycloalkyl or —C1-C6alkyl or, taken with R1 forms a C3-C8cycloalkyl, wherein the C3-C8cycloalkyl is optionally substituted with one to four substituents selected from the group consisting of halogen, —C1-C6alkyl or —OH;
R3 is —COOH;
R4 is hydrogen, halogen, —C3-C6cycloalkyl, —C1-C6alkyl, —C1-C6alkylOH, —COOH, —C1-C6alkylN(R18)(R19), —C1-C6alkylheteroaryl, heteroaryl, —C1-C6alkoxy or —COOC1-C6alkyl;
R5 is selected from the group consisting of hydrogen, halogen, —CN, —OH, —C1-C6alkylCOOH, —COOH, —C3-C6cycloalkyl, —C1-C6alkyl, -haloC1-C6alkyl, —C1-C6alkylOH, —C1-C6alkylheteroaryl, —CON(R18)(R19), —N(R18)(R19) or —C1-C6alkylN(R18)(R19);
R6 is selected from the group consisting of hydrogen, halogen, —OH, C1-C6alkylOH, —C3-C6cycloalkyl, —C1-C6alkyl, -haloC1-C6alkyl, —COOH, —N(R18)(R19), —C1-C6alkylheteroaryl, —C1-C6alkylN(R18)(R19), —C1-C6alkoxy or —COOC1-C6alkyl;
R7 is selected from the group consisting of hydrogen, halogen, —OH, —C1-C6alkylOH, —C3-C6cycloalkyl, —C1-C6alkyl, —haloC1-C6alkyl, —COOH, —N(R18)(R19), —C1-C6alkylheteroaryl, —C1-C6alkylN(R18)(R19), —C1-C6alkoxy or —COOC1-C6alkyl;
R8 is selected from the group consisting of hydrogen, —C3-C6cycloalkyl, —C1-C6alkyl, —C1-C6alkylheteroaryl, or —C1-C6alkylN(R18)(R19);
R9 is selected from the group consisting of hydrogen, halogen, —OH, —C1-C6alkylOH, —C3-C6cycloalkyl, —C1-C6alkyl, -haloC1-C6alkyl, —COOH, —N(R18)(R19), —C1-C6alkylheteroaryl, —C1-C6alkylN(R18)(R19), —C1-C6alkoxy or —COOC1-C6alkyl;
R10 is selected from the group consisting of hydrogen, halogen, —OH, —C1-C6alkylOH, —C3-C6cycloalkyl, —C1-C6alkyl, —haloC1-C6alkyl, —COOH, —N(R18)(R19), —C1-C6alkylheteroaryl, —C1-C6alkylN(R18)(R19), —C1-C6alkoxy or —COOC1-C6alkyl;
R11 is selected from the group consisting of hydrogen, —C3-C6cycloalkyl, —C1-C6alkyl, —C1-C6alkylheteroaryl, or —C1-C6alkylN(R18)(R19);
R12 is selected from the group consisting of hydrogen, halogen, —OH, —C1-C6alkylOH, —C3-C6cycloalkyl, —C1-C6alkyl, —haloC1-C6alkyl, —COOH, —N(R18)(R19), —C1-C6alkylheteroaryl, —C1-C6alkylN(R18)(R19), —C1-C6alkoxy or —COOC1-C6alkyl;
R13 is selected from the group consisting of hydrogen, halogen, —OH, —C1-C6alkylOH, —C3-C6cycloalkyl, —C1-C6alkyl, —haloC1-C6alkyl, —COOH, —N(R18)(R19), —C1-C6alkylheteroaryl, —C1-C6alkylN(R18)(R19), —C1-C6alkoxy or —COOC1-C6alkyl;
R14 is selected from the group consisting of hydrogen, —C3-C6cycloalkyl, —C1-C6alkyl, —C1-C6alkylheteroaryl, or —C1-C6alkylN(R18)(R19);
R15 is selected from the group consisting of hydrogen, halogen, —OH, —C1-C6alkylOH, —C3-C6cycloalkyl, —C1-C6alkyl, —haloC1-C6alkyl, —COOH, —N(R18)(R19), —C1-C6alkylheteroaryl, —C1-C6alkylN(R18)(R19), —C1-C6alkoxy or —COOC1-C6alkyl;
R16 is selected from the group consisting of hydrogen, halogen, —OH, —C1-C6alkylOH, —C3-C6cycloalkyl, —C1-C6alkyl, —haloC1-C6alkyl, —COOH, —N(R18)(R19), —C1-C6alkylheteroaryl, —C1-C6alkylN(R18)(R19), —C1-C6alkoxy or —COOC1-C6alkyl;
R17 is selected from the group consisting of hydrogen, —C3-C6cycloalkyl, —C1-C6alkyl, —C1-C6alkylheteroaryl, and —C1-C6alkylN(R18)(R19);
R18 is independently selected from the group consisting of hydrogen, —C3-C6cycloalkyl, —haloC1-C6alkyl, —C1-C6alkyl, —C1-C6alkylNH2, —COheterocycle, and —COC1-C6alkyl, wherein the —COC1-C6alkyl can be optionally substituted with one or two substituents selected from the group consisting of —N(R19)(R19), —OH, cycloalkyl, or a 3-7 membered nitrogen containing ring or R18 taken with R19 forms a 3-7 membered nitrogen containing ring; and
R19 is independently selected from the group consisting of hydrogen, —C3-C6cycloalkyl, —haloC1-C6alkyl and —C1-C6alkyl, or R19 taken with R18 forms a 3-7 membered nitrogen containing ring;
wherein R6 and R7, R9 and R10, R12 and R13, and R15 and R16 cannot be: —COOH and —N (R18)(R19), or —N(R18)(R19) and —COOH.

### Claim 2 (depends on 1)

The compound of claim 1, or a pharmaceutically salt thereof, wherein R1 and R2 are both hydrogen.

### Claim 3 (depends on 1)

The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein W is propylenyl.

### Claim 4 (depends on 1)

The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R4 and R5 are independently hydrogen or methyl.

### Claim 5 (depends on 1)

The compound of claim 1 having Formula II:
or a pharmaceutically acceptable salt thereof, wherein:
W is selected from the group consisting of straight or branched (C2-C5) alkylene, wherein one or more —CH2— groups in W are optionally and independently replaced with a moiety selected from the group consisting of —O—, —S— or —NH—;
V is selected from the group consisting of a bond, O, S, CR6R7 or NR8;
Y is selected from the group consisting of a bond, O, S, CR12R13 or NR14,
Z is selected from the group consisting of a bond, O, S, CR15R16 or NR17,
R1 is selected from the group consisting of hydrogen, —C3-C6cycloalkyl or —C1-C6alkyl or, taken with R2 forms a C3-C8cycloalkyl, wherein the C3-C8cycloalkyl is optionally substituted with one to four substituents selected from the group consisting of halogen, —C1-C6alkyl or —OH;
R2 is selected from the group consisting of hydrogen, —C3-C6cycloalkyl or —C1-C6alkyl or, taken with R1 forms a C3-C8cycloalkyl, wherein the C3-C6cycloalkyl is optionally substituted with one to four substituents selected from the group consisting of halogen, —C1-C6alkyl or —OH;
R3 is —COOH;
R4 is hydrogen, halogen, —C3-C6cycloalkyl, —C1-C6alkyl, —haloC1-C6alkyl, C1-C6alkylOH, —COOH, —C1-C6alkylN(R18)(R19), —C1-C6alkylheteroaryl, heteroaryl, —C1-C6alkoxy and —COOC1-C6alkyl;
R5 is selected from the group consisting of hydrogen, halogen —CN, —OH, —C1-C6alkylCOOH, —COOH, —C3-C6cycloalkyl, —C1-C6alkyl, —haloC1-C6alkyl, —C1-C6alkylOH, —C1-C6alkylheteroaryl, —CON (R18)(R19), —N(R18)(R19) or —C1-C6alkylN(R18)(R19);
R6 is selected from the group consisting of hydrogen, halogen, —OH, —C1-C6alkylOH, —C3-C6cycloalkyl, —C1-C6alkyl, —haloC1-C6alkyl, —COOH, —N(R18)(R19), —C1-C6alkylheteroaryl, —C1-C6alkylN(R18)(R19), —C1-C6alkoxy or —COOC1-C6alkyl;
R7 is selected from the group consisting of hydrogen, halogen, —OH, —C1-C6alkylOH, —C3-C6cycloalkyl, —C1-C6alkyl, —haloC1-C6alkyl, —COOH, —N(R18)(R19), —C1-C6alkylheteroaryl, —C1-C6alkylN(R18)(R19), —C1-C6alkoxy or —COOC1-C6alkyl;
R8 is selected from the group consisting of hydrogen, —C3-C6cycloalkyl, —C1-C6alkyl, —C1-C6alkylheteroaryl, or —C1-C6alkylN(R18)(R19);
R12 is selected from the group consisting of hydrogen, halogen, —OH, —C1-C6alkylOH, —C3-C6cycloalkyl, —C1-C6alkyl, —haloC1-C6alkyl, —COOH, —N(R18)(R19), —C1-C6alkylheteroaryl, —C1-C6alkylN(R18)(R19), —C1-C6alkoxy or —COOC1-C6alkyl;
R13 is selected from the group consisting of hydrogen, halogen, —OH, —C1-C6alkylOH, —C3-C6cycloalkyl, —C1-C6alkyl, —haloC1-C6alkyl, —COOH, —N(R18)(R19), —C1-C6alkylheteroaryl, —C1-C6alkylN(R18)(R19), —C1-C6alkoxy or —COOC1-C6alkyl;
R14 is selected from the group consisting of hydrogen, —C3-C6cycloalkyl, —C1-C6alkyl, —C1-C6alkylheteroaryl, or —C1-C6alkylN(R18)(R19);
R15 is selected from the group consisting of hydrogen, halogen, —OH, —C1-C6alkylOH, —C3-C6cycloalkyl, —C1-C6alkyl, —haloC1-C6alkyl, —COOH, —N(R18)(R19), —C1-C6alkylheteroaryl, —C1-C6alkylN(R18)(R19), —C1-C6alkoxy or —COOC1-C6alkyl;
R16 is selected from the group consisting of hydrogen, halogen, —OH, —C1-C6alkylOH, —C3-C6cycloalkyl, —C1-C6alkyl, —haloC1-C6alkyl, —COOH, —N(R18)(R19), —C1-C6alkylheteroaryl, —C1-C6alkylN(R18)(R19), —C1-C6alkoxy or —COOC1-C6alkyl;
R17 is selected from the group consisting of hydrogen, —C3-C6cycloalkyl, —C1-C6alkyl, —C1-C6alkylheteroaryl, and —C1-C6alkylN(R18)(R19);
R18 is selected from the group consisting of hydrogen, —C3-C6cycloalkyl, —haloC1-C6alkyl, —C1-C6alkyl, —C1-C6alkylNH2, —COheterocycle and —COC1-C6alkyl, wherein the —COC1-C6alkyl can be optionally substituted with one or two substituents selected from the group consisting of —N(R19)(R19), —OH, cycloalkyl, or a 3-7 membered nitrogen containing ring or R18 taken with R19 forms a 3-7 membered nitrogen containing ring; and
R19 is selected from the group consisting of hydrogen, —C3-C6cycloalkyl, —haloC1-C6alkyl and —C1-C6alkyl, or R19 taken with R18 forms a 3-7 membered nitrogen containing ring;
wherein R6 and R7, R12 and R13, and R15 and R16 cannot be —COOH and —N(R18)(R19) or —N(R18)(R19) and —COOH.

### Claim 6 (depends on 5)

The compound of claim 5, or a pharmaceutically salt thereof, wherein R1 and R2 are both hydrogen.

### Claim 7 (depends on 5)

The compound of claim 5, or a pharmaceutically acceptable salt thereof, wherein W is propylenyl.

### Claim 8 (depends on 1)

The compound of claim 1, having Formula III
or a pharmaceutically acceptable salt thereof, wherein:
W is selected from the group consisting of straight or branched (C2-C5) alkylene, wherein one or more —CH2— groups in W are optionally and independently replaced with a moiety selected from the group consisting of —O—, —S— or —NH—;
R1 is selected from the group consisting of hydrogen, —C3-C6cycloalkyl or —C1-C6alkyl or, taken with R2 forms a C3-C8cycloalkyl, wherein the C3-C8cycloalkyl is optionally substituted with one to four substituents selected from the group consisting of halogen, —C1-C6alkyl or —OH;
R2 is selected from the group consisting of hydrogen, —C3-C6cycloalkyl or —C1-C6alkyl or, taken with R1 forms a C3-C8cycloalkyl, wherein the C3-C8cycloalkyl is optionally substituted with one to four substituents selected from the group consisting of halogen, —C1-C6alkyl or —OH;
R3 is —COOH;
R4 is hydrogen, halogen, —C3-C6cycloalkyl, —C1-C6alkyl, —haloC1-C6alkyl, —C1-C6alkylOH, —COOH, —C1-C6alkylN(R18)(R19), —C1-C6alkylheteroaryl, heteroaryl, —C1-C6alkoxy and —COOC1-C6alkyl;
R5 is selected from the group consisting of hydrogen, halogen, —CN, —OH, —C1-C6alkylCOOH, —COOH, —C3-C6cycloalkyl, —C1-C6alkyl, —haloC1-C6alkyl, —C1-C6alkylOH, —C1-C6alkylheteroaryl, CON (R18)(R19), —N(R18)(R19) or —C1-C6alkylN(R18)(R19);
R18 is selected from the group consisting of hydrogen, —C3-C6cycloalkyl, —haloC1-C6alkyl, —C1-C6alkyl, —C1-C6alkylNH2, and —COC1-C6alkyl, wherein the —COC1-C6alkyl can be optionally substituted with one or two substituents selected from the group consisting of —N(R19)(R19), —OH, cycloalkyl, or a 3-7 membered nitrogen containing ring or R18 taken with R19 forms a 3-7 membered nitrogen containing ring; and
R19 is selected from the group consisting of hydrogen, —C3-C6cycloalkyl, —haloC1-C6alkyl and —C1-C6alkyl, or R19 taken with R18 forms a 3-7 membered nitrogen containing ring.

### Claim 9 (depends on 8)

The compound of claim 8, or a pharmaceutically salt thereof, wherein R1 and R2 are both hydrogen.

### Claim 10 (depends on 8)

The compound of claim 8, or a pharmaceutically acceptable salt thereof, wherein W is propylenyl.

### Claim 11 (depends on 1)

The compound of claim 1, having Formula IV:
or a pharmaceutically acceptable salt thereof, wherein:
W is selected from the group consisting of straight or branched (C2-C5) alkylene, wherein one or more —CH2— groups in W are optionally and independently replaced with a moiety selected from the group consisting of —O—, —S— or —NH—;
Y is selected from the group consisting of a bond, O, S, CR12R13 or NR14,
X is selected from the group consisting of a bond, O, S, CR9R10 or NR11,
Z is selected from the group consisting of a bond, O, S, CR15R16 or NR17;
R1 is selected from the group consisting of hydrogen, —C3-C6cycloalkyl or —C1-C6alkyl or, taken with R2 forms a C3-C8cycloalkyl, wherein the C3-C6cycloalkyl is optionally substituted with one to four substituents selected from the group consisting of halogen, —C1-C6alkyl or —OH;
R2 is selected from the group consisting of hydrogen, —C3-C6cycloalkyl or —C1-C6alkyl or, taken with R1 forms a C3-C8cycloalkyl, wherein the C3-C8cycloalkyl is optionally substituted with one to four substituents selected from the group consisting of halogen, —C1-C6alkyl or —OH;
R3 is —COOH;
R4 is hydrogen, halogen, —C3-C6cycloalkyl, —C1-C6alkyl, —C1-C6alkylOH, —COOH, —C1-C6alkylN(R18)(R19), —C1-C6alkylheteroaryl, heteroaryl, —C1-C6alkoxy or —COOC1-C6alkyl;
R5 is selected from the group consisting of hydrogen, halogen, —CN, —OH, —C1-C6alkylCOOH, —COOH, —C3-C6cycloalkyl, —C1-C6alkyl, —haloC1-C6alkyl, —C1-C6alkylOH, —C1-C6alkylheteroaryl, —CON(R18)(R19), —N(R18)(R19) or —C1-C6alkylN(R18)(R19);
R9 is selected from the group consisting of hydrogen, halogen, —OH, —C1-C6alkylOH, —C3-C6cycloalkyl, —C1-C6alkyl, —haloC1-C6alkyl, —COOH, —N(R18)(R19), —C1-C6alkylheteroaryl, —C1-C6alkylN(R18)(R19), —C1-C6alkoxy or —COOC1-C6alkyl;
R10 is selected from the group consisting of hydrogen, halogen, —OH, —C1-C6alkylOH, —C3-C6cycloalkyl, —C1-C6alkyl, —haloC1-C6alkyl, —COOH, —N(R18)(R19), —C1-C6alkylheteroaryl, —C1-C6alkylN(R18)(R19), —C1-C6alkoxy or —COOC1-C6alkyl;
R11 is selected from the group consisting of hydrogen, —C3-C6cycloalkyl, —C1-C6alkyl, —C1-C6alkylheteroaryl, or —C1-C6alkylN(R18)(R19);
R12 is selected from the group consisting of hydrogen, halogen, —OH, —C1-C6alkylOH, —C3-C6cycloalkyl, —C1-C6alkyl, —haloC1-C6alkyl, —COOH, —N(R18)(R19), —C1-C6alkylheteroaryl, —C1-C6alkylN(R18)(R19), —C1-C6alkoxy or —COOC1-C6alkyl;
R13 is selected from the group consisting of hydrogen, halogen, —OH, —C1-C6alkylOH, —C3-C6cycloalkyl, —C1-C6alkyl, —haloC1-C6alkyl, —COOH, —N(R18)(R19), —C1-C6alkylheteroaryl, —C1-C6alkylN(R18)(R19), —C1-C6alkoxy or —COOC1-C6alkyl;
R14 is selected from the group consisting of hydrogen, —C3-C6cycloalkyl, —C1-C6alkyl, —C1-C6alkylheteroaryl, or —C1-C6alkylN(R18)(R19);
R15 is selected from the group consisting of hydrogen, halogen, —OH, —C1-C6alkylOH, —C3-C6cycloalkyl, —C1-C6alkyl, —haloC1-C6alkyl, —COOH, —N(R18)(R19), —C1-C6alkylheteroaryl, —C1-C6alkylN(R18)(R19), —C1-C6alkoxy or —COOC1-C6alkyl;
R16 is selected from the group consisting of hydrogen, halogen, —OH, —C6alkylOH, —C3-C6cycloalkyl, —C1-C6alkyl, —haloC1-C6alkyl, —COOH, —N(R18)(R19), —C1-C6alkylheteroaryl, —C1-C6alkylN(R18)(R19), —C1-C6alkoxy or —COOC1-C6alkyl;
R17 is selected from the group consisting of hydrogen, —C3-C6cycloalkyl, —C1-C6alkyl, —C1-C6alkylheteroaryl, and —C1-C6alkylN(R18)(R19);
R18 is selected from the group consisting of hydrogen, —C3-C6cycloalkyl, —haloC1-C6alkyl, —C1-C6alkyl, —C1-C6alkylNH2, —COheterocycle and —COC1-C6alkyl, wherein the COC1-C6alkyl can be optionally substituted with one or two substituents selected from the group consisting of —N(R19)(R19), —OH, cycloalkyl, or a 3-7 membered nitrogen containing ring or R18 taken with R19 forms a 3-7 membered nitrogen containing ring; and
R19 is selected from the group consisting of hydrogen, —C3-C6cycloalkyl, —haloC1-C6alkyl and —C1-C6alkyl, or R19 taken with R18 forms a 3-7 membered nitrogen containing ring;
wherein R9 and R10, R12 and R13 and R15 and R16 cannot be —COOH and —N(R18)(R19) or —N(R18)(R19) and —COOH.

### Claim 12 (depends on 1)

The compound of claim 1, having Formula V:
or a pharmaceutically acceptable salt thereof, wherein:
W is selected from the group consisting of straight or branched (C2-C5) alkylene, wherein one or more —CH2— groups in W are optionally and independently replaced with a moiety selected from the group consisting of —O—, —S— or —NH—;
R1 is selected from the group consisting of hydrogen, —C3-C6cycloalkyl or —C1-C6alkyl or, taken with R2 forms a C3-C8cycloalkyl, wherein the C3-C8cycloalkyl is optionally substituted with one to four substituents selected from the group consisting of halogen, C1-C6alkyl-C1-C6alkyl or —OH;
R2 is selected from the group consisting of hydrogen, —C3-C6cycloalkyl or —C1-C6alkyl or, taken with R1 forms a C3-C8cycloalkyl, wherein the C3-C6cycloalkyl is optionally substituted with one to four substituents selected from the group consisting of halogen, —C1-C6alkyl or —OH;
R3 is —COOH;
R4 is hydrogen, halogen, —C3-C6cycloalkyl, —C1-C6alkyl, —C1-C6alkylOH, —COOH, —C1-C6alkylN(R18)(R19), —C1-C6alkylheteroaryl, heteroaryl, —C1-C6alkoxy and —COOC1-C6alkyl;
R5 is selected from the group consisting of hydrogen, halogen, —CN, —OH, —C1-C6alkylCOOH, COOH, —C3-C6cycloalkyl, —C1-C6alkyl, —haloC1-C6alkyl, —C1-C6alkylOH, —C1-C6alkylheteroaryl, —CON (R18)(R19), —N(R18)(R19) or —C1-C6alkylN(R18)(R19);
R18 is selected from the group consisting of hydrogen, —C3-C6cycloalkyl, —haloC1-C6alkyl, —C1-C6alkyl, —C1-C6alkylNH2, —COheterocycle and —COC1-C6alkyl, wherein the —COC1-C6alkyl can be optionally substituted with one or two substituents selected from the group consisting of —N(R19)(R19), —OH, cycloalkyl, or a 3-7 membered nitrogen containing ring or R18 taken with R19 forms a 3-7 membered nitrogen containing ring; and
R19 is selected from the group consisting of hydrogen, —C3-C6cycloalkyl, —haloC1-C6alkyl and —C1-C6alkyl, or R19 taken with R18 forms a 3-7 membered nitrogen containing ring.

### Claim 13 (depends on 1)

The compound of claim 1, having Formula VI:
or a pharmaceutically acceptable salt thereof, wherein:
W is selected from the group consisting of straight or branched (C2-C5) alkylene, wherein one or more —CH2— groups in W are optionally and independently replaced with a moiety selected from the group consisting of —O—, —S— or —NH—;
R1 is selected from the group consisting of hydrogen, —C3-C6cycloalkyl or —C1-C6alkyl or, taken with R2 forms a C3-C8cycloalkyl, wherein the C3-C8cycloalkyl is optionally substituted with one to four substituents selected from the group consisting of halogen, or —OH;
R2 is selected from the group consisting of hydrogen, —C3-C6cycloalkyl or —C1-C6alkyl or, taken with R1 forms a C3-C8cycloalkyl, wherein the C3-C6cycloalkyl is optionally substituted with one to four substituents selected from the group consisting of halogen, —C1-C6alkyl or —OH;
R3 is —COOH;
R4 is hydrogen, halogen, —C3-C6cycloalkyl, —C1-C6alkyl, —C1-C6alkylOH, —COOH, —C1-C6alkylN(R18)(R19), —C1-C6alkylheteroaryl, heteroaryl, —C1-C6alkoxy or —COOC1-C6alkyl;
R5 is selected from the group consisting of hydrogen, halogen, —CN, —OH, —C1-C6alkylCOOH, —COOH, —C3-C6cycloalkyl, —C1-C6alkyl, —haloC1-C6alkyl, —C1-C6alkylOH, —C1-C6alkylheteroaryl, CON (R18)(R19),>—N(R18)(R19) or —C1-C6alkylN(R18)(R19);
R18 is selected from the group consisting of hydrogen, —C3-C6cycloalkyl, —haloC1-C6alkyl, —C1-C6alkyl, —C1-C6alkylNH2, —COheterocycle and —COC1-C6alkyl, wherein the —COC1-C6alkyl can be optionally substituted with one or two substituents selected from the group consisting of —N(R19)(R19), —OH, cycloalkyl, or a 3-7 membered nitrogen containing ring or R18 taken with R19 forms a 3-7 membered nitrogen containing ring; and
R19 is selected from the group consisting of hydrogen, —C3-C6cycloalkyl, —haloC1-C6alkyl and —C1-C6alkyl, or R19 taken with R18 forms a 3-7 membered nitrogen containing ring.

### Claim 14 (depends on 1)

The compound of claim 1, having Formula VII:
or a pharmaceutically acceptable salt thereof, wherein:
W is selected from the group consisting of straight or branched (C2-C5) alkylene, wherein one or more —CH2— groups in W are optionally and independently replaced with a moiety selected from the group consisting of —O—, —S— or —NH—;
R1 is selected from the group consisting of hydrogen, —C3-C6cycloalkyl or —C1-C6alkyl or, taken with R2 forms a C3-C8cycloalkyl, wherein the C3-C8cycloalkyl is optionally substituted with one to four substituents selected from the group consisting of halogen, —C1-C6alkyl or —OH;
R2 is selected from the group consisting of hydrogen, —C3-C6cycloalkyl or —C1-C6alkyl or, taken with R1 forms a C3-C8cycloalkyl, wherein the C3-C8cycloalkyl is optionally substituted with one to four substituents selected from the group consisting of halogen, —C1-C6alkyl or —OH;
R3 is —COOH;
R4 is hydrogen, halogen, —C3-C6cycloalkyl, —C1-C6alkyl, —C1-C6alkylOH, —COOH, N (R18)(R19), —C1-C6alkylN(R18)(R19), —C1-C6alkylheteroaryl, heteroaryl, —C1-C6alkoxy or —COOC1-C6alkyl;
R5 is selected from the group consisting of hydrogen, halogen, —CN, —OH, —C1-C6alkylCOOH, —COOH, —C3-C6cycloalkyl, —C1-C6alkyl, —haloC1-C6alkyl, —C1-C6alkylOH, —C1-C6alkylheteroaryl, —CON(R18)(R19), —N(R18)(R19) or —C1-C6alkylN(R18)(R19);
R18 is selected from the group consisting of hydrogen, —haloC1-C6alkyl, —C1-C6alkyl, —C1-C6alkylNH2, —COheterocycle and —COC1-C6alkyl, wherein the —COC1-C6alkyl can be optionally substituted with one or two substituents selected from the group consisting of —N(R19)(R19), —OH, cycloalkyl, or a 3-7 membered nitrogen containing ring or R18 taken with R19 forms a 3-7 membered nitrogen containing ring; and
R19 is selected from the group consisting of hydrogen, —C3-C6cycloalkyl, —haloC1-C6alkyl and —C1-C6alkyl, or R19 taken with R18 forms a 3-7 membered nitrogen containing ring.

### Claim 15

A compound which is:
or a pharmaceutically acceptable salt thereof.

### Claim 16

A compound which is:
or a pharmaceutically acceptable salt thereof.

### Claim 17 (depends on 1)

A method of treating cancer comprising administering to a patient in need thereof a compound, or pharmaceutically acceptable salt thereof, of claim 1.

### Claim 18 (depends on 1)

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

### Claim 19 (depends on 1)

A pharmaceutical composition comprising a compound of claim 1 and a pharmaceutically acceptable carrier.

### Claim 20 (depends on 1)

A method of treating cancer comprising administering to a patient in need thereof a compound, or pharmaceutically acceptable salt thereof, of claim 1 and pembrolizumab.

### Claim 21 (depends on 15)

The compound of claim 15 which is:
or a pharmaceutically acceptable salt thereof.

### Claim 22 (depends on 15)

The compound of claim 15 which is:

### Claim 23 (depends on 15)

The compound of claim 15 which is:
or a pharmaceutically acceptable salt thereof.

### Claim 24 (depends on 15)

The compound of claim 15 which is:

### Claim 25 (depends on 15)

The compound of claim 15 which is:
or a pharmaceutically acceptable salt thereof.

### Claim 26 (depends on 15)

The compound of claim 15 which is:

### Claim 27 (depends on 15)

The compound of claim 15 which is:
or a pharmaceutically acceptable salt thereof.

### Claim 28 (depends on 15)

The compound of claim 15 which is:

### Claim 29 (depends on 15)

The compound of claim 15 which is:
or a pharmaceutically acceptable salt thereof.

### Claim 30 (depends on 15)

The compound of claim 15 which is:

### Claim 31 (depends on 16)

The compound of claim 16 which is:
or a pharmaceutically acceptable salt thereof.

### Claim 32 (depends on 16)

The compound of claim 16 which is:

### Claim 33 (depends on 16)

The compound of claim 16 which is:
or a pharmaceutically acceptable salt thereof.

### Claim 34 (depends on 16)

The compound of claim 16 which is:

### Claim 35 (depends on 16)

The compound of claim 16 which is:
or a pharmaceutically acceptable salt thereof.

### Claim 36 (depends on 16)

The compound of claim 16 which is:

### Claim 37 (depends on 16)

The compound of claim 16 which is:
or a pharmaceutically acceptable salt thereof.

### Claim 38 (depends on 16)

The compound of claim 16 which is:

### Claim 39 (depends on 19)

The compound of claim 19 which is:
or a pharmaceutically acceptable salt thereof.

### Claim 40 (depends on 16)

The compound of claim 16 which is:

### Claim 41 (depends on 16)

The compound of claim 16 which is:
or a pharmaceutically acceptable salt thereof.

### Claim 42 (depends on 16)

The compound of claim 16 which is:

### Claim 43 (depends on 16)

A method of treating cancer comprising administering to a patient in need thereof a compound, or pharmaceutically acceptable salt thereof, of claim 16.

### Claim 44 (depends on 16)

A pharmaceutical composition comprising a compound, or a pharmaceutically acceptable salt thereof, of claim 16 and a pharmaceutically acceptable carrier.

### Claim 45 (depends on 19)

A pharmaceutical composition comprising a compound of claim 19 and a pharmaceutically acceptable carrier.

### Claim 46 (depends on 16)

A method of treating cancer comprising administering to a patient in need thereof a compound, or pharmaceutically acceptable salt thereof, of claim 16 and pembrolizumab.