# US 2023/0263784 A1 · Combination therapy using a chemokine receptor 2 (ccr2) antagonist and a pd-1/pd-l1 inhibitor

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- Number: US 2023/0263784 A1
- Document ID: US20230263784A1
- Status: Published application
- Kind: A1
- Application number: 18/165,262
- Filed: 2023-02-06
- Published: 2023-08-24
- Earliest claimed: 2017-09-25
- Assignees: ChemoCentryx, Inc.
- Applicants: Chemocentryx, Inc.
- Inventors: James J. CAMPBELL; Zhenhua MIAO
- Web page: https://patentgrep.com/patent/US20230263784A1

## CPC

- A61K 31/4375: the heterocyclic ring system containing a six-membered ring having nitrogen as a ring heteroatom, e.g. quinolizines, naphthyridines, berberine, vincamine
- A61P 35/00: Antineoplastic agents
- C07K 16/2818: {against CD28 or CD152}
- C07K 16/2827: {against B7 molecules, e.g. CD80, CD86}
- C07K 16/2866: {against receptors for cytokines, lymphokines, interferons}
- A61K 2039/507: {Comprising a combination of two or more separate antibodies}
- 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
- 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

The present disclosure is drawn to the combination therapy of a Chemokine Receptor 2 (CCR2) antagonist and a PD-1 and/or PD-L1 inhibitor in the treatment of cancer.

## Claims

### Claim 1

A method of treating colorectal cancer in a subject in need thereof, comprising administering a therapeutically effective amount of a CCR2 chemokine receptor antagonist and a therapeutically effective amount of a PD-1 and/or PD-L1 inhibitor to the subject, wherein the CCR2 chemokine receptor antagonist has the formula:
or a pharmaceutically acceptable salt thereof, wherein:
X3 and X4 are each independently selected from the group consisting of hydrogen, halogen, substituted or unsubstituted C1-8 alkyl, substituted or unsubstituted C2-8 alkenyl, substituted or unsubstituted C2-8 alkynyl, —CN, —NO2, —C(O)R18, —CO2R18, —C(O)NR18R19, —OR18, —OC(O)R19, —OC(O)NR18R19, —NO2, —NR18C(O)R19, —NR18C(O)NR19R20, —NR18R19, —NR18CO2R19, —NR18S(O)2R19, —SR18, —S(O)R18, —S(O)2R18, —S(O)2NR18R19, substituted or unsubstituted C6-10 aryl, substituted 5- to 10-membered heteroaryl, and substituted or unsubstituted 3- to 10-membered heterocyclyl;
R18, R19, and R20 are each independently selected from the group consisting of hydrogen, substituted or unsubstituted C1-8 alkyl, substituted or unsubstituted C2-8 alkenyl, substituted or unsubstituted C2-8 alkynyl, substituted or unsubstituted C6-10 aryl, substituted or unsubstituted 5- to 10-membered heteroaryl, and substituted or unsubstituted 3- to 10-membered heterocyclyl; or
R18 and R19, R19 and R20, or R18 and R20 may, together with the atoms to which they are attached, form a substituted or unsubstituted 5-, 6-, or 7-membered ring;
Y9 is selected from the group consisting of hydrogen, halogen, —CN, —NO2, —OR21, —CO2R21, —OC(O)R21, —OC(O)NR21R22, —C(O)NR21R22, —C(O)R21, —SR21, —S(O)R21, —S(O)2R21, —NR21R22, —NR21C(O)R22, —NR21C(O)2R22, —NR21S(O)2R22, —NR21C(O)NR22R23, substituted or unsubstituted C1-8 alkyl, and substituted or unsubstituted 3- to 10-membered heterocyclyl;
R21, R22, and R23 are each independently selected from the group consisting of hydrogen, substituted or unsubstituted C1-8 alkyl, substituted or unsubstituted C2-8 alkenyl, substituted or unsubstituted C2-8 alkynyl, substituted or unsubstituted C6-10 aryl, substituted or unsubstituted 5- to 10-membered heteroaryl, and substituted or unsubstituted 3- to 10-membered heterocyclyl; or
R21 and R22, R22 and R23, or R21 and R23 may, together with the atoms to which they are attached, form a substituted or unsubstituted 5-, 6-, or 7-membered ring; and
Y11 is —CH—, —N—, and —N+(O)−—.

### Claim 2 (depends on 1)

The method of claim 1, wherein:
X4 and X3 are each independently selected from the group consisting of hydrogen, halogen, C1-8 alkyl, and C1-8 haloalkyl; and
Y9 is selected from the group consisting of hydrogen, halogen, and substituted or unsubstituted C1-8 alkyl.

### Claim 3 (depends on 1)

The method of claim 1, wherein:
X3 is selected from the group consisting of halogen, C1-8 alkyl, and C1-8 haloalkyl;
X4 is selected from the group consisting of halogen and C1-8 alkyl;
Y9 is selected from the group consisting of halogen and C1-8 alkyl; and
Y11 is —CH— or —N—.

### Claim 4 (depends on 1)

The method of claim 1, wherein:
X3 is C1-8 haloalkyl;
X4 is selected from the group consisting of halogen and C1-8 alkyl;
Y9 is selected from the group consisting of halogen and C1-8 alkyl; and
Y11 is —CH— or —N—.

### Claim 5 (depends on 1)

The method of claim 1, wherein:
X3 is CF3;
X4 is Cl or CH3;
Y9 is Cl or CH3; and
Y11 is —CH— or —N—.

### Claim 6 (depends on 1)

The method of claim 1, wherein the CCR2 chemokine receptor antagonist is selected from the group consisting of
or a pharmaceutically acceptable salt thereof.

### Claim 7 (depends on 1)

The method of claim 1, wherein the CCR2 chemokine receptor antagonist is
or a pharmaceutically acceptable salt thereof.

### Claim 8 (depends on 1)

The method of claim 1, wherein the CCR2 chemokine receptor antagonist is
or a pharmaceutically acceptable salt thereof.

### Claim 9 (depends on 1)

The method of claim 1, wherein the CCR2 chemokine receptor antagonist is
or a pharmaceutically acceptable salt thereof.

### Claim 10 (depends on 1)

The method of claim 1, wherein the PD-1 and/or PD-L1 inhibitor is a PD-1 inhibitor.

### Claim 11 (depends on 10)

The method of claim 10, wherein the PD-1 inhibitor is pembrolizumab, nivolumab, or pidilizumab.

### Claim 12 (depends on 1)

The method of claim 1, wherein the PD-1 and/or PD-L1 inhibitor is a PD-L1 inhibitor.

### Claim 13 (depends on 12)

The method of claim 12, wherein the PD-L1 inhibitor is durvalumab, atezolizumab, or avelumab.

### Claim 14 (depends on 6)

The method of claim 6, wherein the PD-1 and/or PD-L1 inhibitor is pembrolizumab, nivolumab, durvalumab, atezolizumab, or avelumab.

### Claim 15 (depends on 1)

The method of claim 1, wherein the administration reduces tumor size.

### Claim 16 (depends on 1)

The method of claim 1, wherein the administration increases a ratio of CD8 T cells to M-MDSCs in a tumor microenvironment.

### Claim 17 (depends on 1)

The method of claim 1, wherein the subject is a human subject.

### Claim 18

A kit comprising a therapeutically effective amount of a CCR2 chemokine receptor antagonist and a therapeutically effective amount of a PD-1 and/or PD-L1 inhibitor, with instruction for effective administration to a subject having a colorectal cancer, wherein the CCR2 chemokine receptor antagonist has the formula:
or a pharmaceutically acceptable salt thereof, wherein:
X3 and X4 are each independently selected from the group consisting of hydrogen, halogen, substituted or unsubstituted C1-8 alkyl, substituted or unsubstituted C2-8 alkenyl, substituted or unsubstituted C2-8 alkynyl, —CN, —NO2, —C(O)R18, —CO2R18, —C(O)NR18R19, —OR18, —OC(O)R19, —OC(O)NR18R19, —NO2, —NR18C(O)R19, —NR18C(O)NR19R20, —NR18R19, —NR18CO2R19, —NR18S(O)2R19, —SR18, —S(O)R18, —S(O)2R18, —S(O)2NR18R19, substituted or unsubstituted C6-10 aryl, substituted 5- to 10-membered heteroaryl, and substituted or unsubstituted 3- to 10-membered heterocyclyl;
R18, R19, and R20 are each independently selected from the group consisting of hydrogen, substituted or unsubstituted C1-8 alkyl, substituted or unsubstituted C2-8 alkenyl, substituted or unsubstituted C2-8 alkynyl, substituted or unsubstituted C6-10 aryl, substituted or unsubstituted 5- to 10-membered heteroaryl, and substituted or unsubstituted 3- to 10-membered heterocyclyl; or
R18 and R19, R19 and R20, or R18 and R20 may, together with the atoms to which they are attached, form a substituted or unsubstituted 5-, 6-, or 7-membered ring;
Y9 is selected from the group consisting of hydrogen, halogen, —CN, —NO2, —OR21, —CO2R21, —OC(O)R21, —OC(O)NR21R22, —C(O)NR21R22, —C(O)R21, —SR21, —S(O)R21, —S(O)2R21, —NR21R22, —NR21C(O)R22, —NR21C(O)2R22, —NR21S(O)2R22, —NR21C(O)NR22R23, substituted or unsubstituted C1-8 alkyl, and substituted or unsubstituted 3- to 10-membered heterocyclyl;
R21, R22, and R23 are each independently selected from the group consisting of hydrogen, substituted or unsubstituted C1-8 alkyl, substituted or unsubstituted C2-8 alkenyl, substituted or unsubstituted C2-8 alkynyl, substituted or unsubstituted C6-10 aryl, substituted or unsubstituted 5- to 10-membered heteroaryl, and substituted or unsubstituted 3- to 10-membered heterocyclyl; or
R21 and R22, R22 and R23, or R21 and R23 may, together with the atoms to which they are attached, form a substituted or unsubstituted 5-, 6-, or 7-membered ring; and
Y11 is —CH—, —N—, and —N+(O)−—.

### Claim 19 (depends on 18)

The kit of claim 18, wherein the CCR2 chemokine receptor antagonist is selected from the group consisting of
or a pharmaceutically acceptable salt thereof.

### Claim 20 (depends on 18)

The kit of claim 18, wherein the PD-1 and/or PD-L1 inhibitor is pembrolizumab, nivolumab, or pidilizumab.