# US 2023/0056497 A1 · CD206 Modulators Their Use and Methods for Preparation

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- Number: US 2023/0056497 A1
- Document ID: US20230056497A1
- Status: Published application
- Kind: A1
- Application number: 17/787,313
- Filed: 2020-12-16
- Published: 2023-02-23
- Earliest claimed: 2019-12-19
- Applicants: The United States of America, As Represented by the Secretary, Dept. of Health and Human Services
- Inventors: Raul Rolando Calvo; Bolormaa Baljinnyam; Andres Eduardo Dulcey; Udo Rudloff; Mark James Henderson; Juan Jose Marugan; Xin Hu; Noel Terrence Southall; Rushikesh Vilas Sable
- Web page: https://patentgrep.com/patent/US20230056497A1

## CPC

- C07D 487/04: Ortho-condensed systems
- A61P 35/00: Antineoplastic agents
- C07D 307/80: Radicals substituted by oxygen atoms
- C07D 471/04: Ortho-condensed systems
- Y02A 50/30: Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- Y02A: TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE

## Abstract

Compounds of Formula I, Formula II, and Formula III and the pharmaceutically acceptable salts thereof are disclosed. The variables X, a, b, c, d, R1-4, R10-15 and R17-22 are disclosed herein. The compounds are useful for treating cancer disorders, especially those involving M2 phenotype of macrophages. Pharmaceutical compositions containing compounds of Formula I or Formula II or Formula III and methods of treatment comprising administering compounds of Formula I and Formula II and Formula III are also disclosed.

## Claims

### Claim 1

A compound of Formula I:
or a pharmaceutically acceptable salt thereof, wherein
each bond shown as a solid line and a dashed line together, , can be a single bond, double, or aromatic bond;
R1 is hydrogen, halogen, hydroxyl, cyano, —CO2H, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6alkoxy, —(C0-C6alkyl)cycloalkyl, C1-C6haloalkyl, —(C0-C6alkyl)phenyl, —(C0-C6alkyl)aryl, —(C0-C6alkyl)heteroaryl, —C(O)C1-C6alkyl, —C(O)NR8R9, —(C0-C6alkyl)NR5R6, —CO2R6, —C6H4—R7, and a monocyclic or bicyclic heterocycle of 4 to 10 ring atoms having 1, 2, or 3 ring atoms independently chosen from N, S and O;
R2, R3, and R4 are each independently chosen at each occurrence from hydrogen, halogen, hydroxyl, cyano, —CO2H, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6alkoxy, —(C0-C6alkyl)cycloalkyl, C1-C6haloalkyl, —(C0-C6alkyl)phenyl, —(C0-C6alkyl)aryl, —(C0-C6alkyl)heteroaryl, —C(O)C1-C6alkyl, —C(O)NR5R6, (C0-C6alkyl)NR8R9, —CO2R6, and —C6H4—R7;
a, b, c, d, and X are each independently chosen at each occurrence from N, C, and CH;
R5, and R6 are each independently chosen at each occurrence from hydrogen, halogen, hydroxy, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6alkoxy, a substituted or unsubstituted —(C0-C6alkyl)cycloalkyl, —(C0-C6alkyl)phenyl, —(C0-C6alkyl)aryl, —(C0-C6alkyl)heteroaryl, —C(O)C1-C6alkyl, —C(O)(C0-C6alkyl)phenyl, —(C0-C6alkyl)NR8R9, —C(O)(C0-C6alkyl)aryl, —C(O)(C0-C6alkyl)heteroaryl, and a 4- to 7-membered heterocycloalkyl ring having 1, 2, or 3 ring atoms independently chosen from N, O, and S;
any R5 and R6 bound to the same nitrogen atom may be taken together to form a 4- to 7-membered monocyclic heterocycloalkyl ring or 6- to 11-membered bridged bicyclic heterocycloalkyl ring, which heterocycloalkyl ring contains 0, 1, or 2 additional heteroatoms chosen from N, O, S, S(O), and SO2 which heterocycloalkyl ring is optionally substituted at any carbon or hetero ring atom with halogen, hydroxyl, cyano, oxo, dioxo, C1-C6alkyl, C1-C6alkoxy, C1-C6haloalkyl, —(C0-C6alkyl)cycloalkyl, —(C0-C6alkyl)phenyl, —(C0-C6alkyl)aryl, —(C0-C6alkyl)CO2R8, —(C0-C6alkyl)C(O)NR8R9, —(C1-C6alkyl)OR8, —C(O)C1-C6alkyl, —(C0-C6alkyl)NR8R9, or —C(O)(C0-C6alkyl)NR8R9;
R7 is hydrogen, halogen, hydroxyl, cyano, —CO2H, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6alkoxy, C1-C6haloalkyl, —(C0-C6alkyl)cycloalkyl, —(C0-C6alkyl)phenyl, —(C0-C6alkyl)aryl, —(C0-C6alkyl)heteroaryl, —CO2R8, —C(O)C1-C6alkyl, —C(O)C2-C6alkenyl, —C(O)C2-C6alkynyl, —C(O)C1-C6alkoxy, —C(O)C1-C6hydroxyalkyl, —C(O)—(C0-C6alkyl)cycloalkyl, —C(O)—(C0-C6alkyl)phenyl, —C(O)—(C0-C6alkyl)aryl, —C(O)—(C0-C6alkyl)heteroaryl, —C(O)NR8R9, —C(O)NR5R6, —C(O)—(C0-C6alkyl)NR5R6, —C(O)—NR8—(C0-C6alkyl)NR5R6, or (C0-C6alkyl)NR5R6;
R8 and R9 are each independently chosen at each occurrence from hydrogen, halogen, C1-C6 alkyl, C1-C6alkoxy, C1-C6haloalkyl, —(C0-C6alkyl)phenyl, —(C0-C6alkyl)aryl, —(C0-C6alkyl)NR5R6, —CO2R6, —C(O)C1-C6alkyl, and —(C0-C6alkyl)cycloalkyl.

### Claim 2 (depends on 1)

The compound or salt of claim 1 wherein
R1 is —C6H4—R7;
R2 and R4 are hydrogen;
R3 is —(C0-C6alkyl)phenyl, —(C0-C6alkyl)aryl, or —(C0-C6alkyl)heteroaryl;
a, c, and X are N;
b is C;
d is CH;
R7 is —C(O)NR5R6 or —C(O)—NR8—(C0-C6alkyl)NR5R6;
R5 and R6 are each independently chosen at each occurrence from hydrogen, a substituted or unsubstituted —(C0-C6alkyl)cycloalkyl, —(C0-C6alkyl)heteroaryl, C1-C6hydroxyalkyl, C1-C6alkoxy, —(C0-C6alkyl)NR8R9, and a 4- to 7-membered heterocycloalkyl ring having 1, 2, or 3 ring atoms independently chosen from N, O, and S;
any R5 and R6 bound to the same nitrogen atom may be taken together to form a 4- to 7-membered monocyclic heterocycloalkyl ring or 6- to 11-membered bridged bicyclic heterocycloalkyl ring, which heterocycloalkyl ring contains 0, 1, or 2 additional heteroatoms chosen from N, O, S, S(O), and SO2 which heterocycloalkyl ring is optionally substituted at any carbon or hetero ring atom with halogen, hydroxyl, cyano, oxo, dioxo, C1-C6alkyl, C1-C6alkoxy, C1-C6haloalkyl, —(C0-C6alkyl)cycloalkyl, —(C0-C6alkyl)phenyl, —(C0-C6alkyl)aryl, —(C0-C6alkyl)CO2R8, —(C0-C6alkyl)C(O)NR8R9, —(C1-C6alkyl)OR8, —CO2R8, —C(O)C1-C6alkyl, —(C0-C6alkyl)NR8R9, or —C(O)(C0-C6alkyl)NR8R9; and
R8 and R9 are each independently chosen at each occurrence from hydrogen, halogen, C1-C6 alkyl, C1-C6alkoxy, C1-C6haloalkyl, —(C0-C6alkyl)phenyl, —(C0-C6alkyl)aryl, —(C0-C6alkyl)NR5R6, —CO2R6, —C(O)C1-C6alkyl, and —(C0-C6alkyl)cycloalkyl.

### Claim 3 (depends on 2)

The compound of claim 2 wherein the compound of Formula I is a compound represented by at least one of Compound 1, and Compound 4 to Compound 29:
or a pharmaceutically acceptable salt thereof.

### Claim 4 (depends on 1)

The compound or salt of claim 1 wherein
R1 is —C6H4—R7;
R2 and R4 are hydrogen;
R3 is —(C0-C6alkyl)phenyl, —(C0-C6alkyl)aryl, or —(C0-C6alkyl)heteroaryl;
a, c, d, and X are N;
b is C;
R7 is —C(O)—NR8—(C0-C6alkyl)NR5R6;
R5 and R6 bound to the same nitrogen atom may be taken together to form a 4- to 7-membered monocyclic heterocycloalkyl ring or 6- to 11-membered bridged bicyclic heterocycloalkyl ring, which heterocycloalkyl ring contains 0, 1, or 2 additional heteroatoms chosen from N, O, S, S(O), and SO2 which heterocycloalkyl ring is optionally substituted at any carbon or hetero ring atom with halogen, hydroxyl, cyano, oxo, dioxo, C1-C6alkyl, C1-C6alkoxy, C1-C6haloalkyl, —(C0-C6alkyl)cycloalkyl, —(C0-C6alkyl)phenyl, or —(C0-C6alkyl)aryl; and
R8 is hydrogen.

### Claim 5 (depends on 4)

The compound of claim 4 wherein the compound of Formula I is a compound represented by at least one of Compound 30 and Compound 31:
or a pharmaceutically acceptable salt thereof.

### Claim 6 (depends on 1)

The compound or salt of claim 1 wherein
R1 is —C6H4—R7;
R2 and R4 are hydrogen;
R3 is —(C0-C6alkyl)phenyl, —(C0-C6alkyl)aryl, or —(C0-C6alkyl)heteroaryl;
a is C;
b, d, and X are N;
c is CH;
R7 is —C(O)—NR8—(C0-C6alkyl)NR5R6;
R5 and R6 bound to the same nitrogen atom may be taken together to form a 4- to 7-membered monocyclic heterocycloalkyl ring or 6- to 11-membered bridged bicyclic heterocycloalkyl ring, which heterocycloalkyl ring contains 0, 1, or 2 additional heteroatoms chosen from N, O, S, S(O), and SO2 which heterocycloalkyl ring is optionally substituted at any carbon or hetero ring atom with halogen, hydroxyl, cyano, oxo, dioxo, C1-C6alkyl, C1-C6alkoxy, C1-C6haloalkyl, —(C0-C6alkyl)cycloalkyl, —(C0-C6alkyl)phenyl, or —(C0-C6alkyl)aryl; and
R8 is hydrogen.

### Claim 7 (depends on 6)

The compound of claim 6 wherein the compound of Formula I is a compound represented by Compound 32:
or a pharmaceutically acceptable salt thereof.

### Claim 8 (depends on 1)

The compound or salt of claim 1 wherein
R1 is —C6H4—R7;
R2 and R4 are hydrogen;
R3 is —(C0-C6alkyl)phenyl, —(C0-C6alkyl)aryl, or —(C0-C6alkyl)heteroaryl;
a is C;
b and X are N;
c and d are CH;
R7 is —C(O)—NR8—(C0-C6alkyl)NR5R6;
R5 and R6 bound to the same nitrogen atom may be taken together to form a 4- to 7-membered monocyclic heterocycloalkyl ring or 6- to 11-membered bridged bicyclic heterocycloalkyl ring, which heterocycloalkyl ring contains 0, 1, or 2 additional heteroatoms chosen from N, O, S, S(O), and SO2 which heterocycloalkyl ring is optionally substituted at any carbon or hetero ring atom with halogen, hydroxyl, cyano, oxo, dioxo, C1-C6alkyl, C1-C6alkoxy, C1-C6haloalkyl, —(C0-C6alkyl)cycloalkyl, —(C0-C6alkyl)phenyl, or —(C0-C6alkyl)aryl; and
R8 is hydrogen.

### Claim 9 (depends on 8)

The compound of claim 8 wherein the compound of Formula I is a compound represented by Compound 33:
or a pharmaceutically acceptable salt thereof.

### Claim 10

A compound of Formula II:
or a pharmaceutically acceptable salt thereof,
each bond shown as a solid line and a dashed line together, , can be a single bond, double, or aromatic bond;
R10, R11, and R13 are each independently chosen at each occurrence from hydrogen, hydroxyl, —CO2H, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6alkoxy, —(C0-C6alkyl)cycloalkyl, C1-C6haloalkyl, —(C0-C6alkyl)phenyl, —(C0-C6alkyl)aryl, —(C0-C6alkyl)heteroaryl, —C(O)C1-C6alkyl, —C(O)heteroaryl, and —CO2R16;
R12, R14, and R15 are each independently chosen at each occurrence from hydrogen, halogen, hydroxyl, and cyano;
X is O or S; and
R16 is hydrogen, halogen, hydroxy, an amino group, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6alkoxy, —(C0-C6alkyl)cycloalkyl, —C(O)C1-C6alkyl, —(C0-C6alkyl)aryl, —(C0-C6alkyl)heteroaryl, —(C0-C6alkyl)phenyl, or a monocyclic or bicyclic heterocycle of 4 to 10 ring atoms having 1, 2, or 3 ring atoms independently chosen from N, S and O.

### Claim 11 (depends on 10)

The compound or salt of claim 10 of Formula IIA

### Claim 12 (depends on 11)

The compound or salt of claim 11 wherein
R10 and R11 are each independently chosen at each occurrence from —(C0-C6alkyl)phenyl, —(C0-C6alkyl)aryl, and —(C0-C6alkyl)heteroaryl;
R12, R14 and R15 are hydrogen;
R13 is —C(O)heteroaryl.

### Claim 13 (depends on 12)

The compound or salt of claim 12 wherein
R10 is —(C0-C6alkyl)phenyl;
R11 is —(C0-C6alkyl)heteroaryl;
R12, R14 and R15 are hydrogen;
R13 is —C(O)heteroaryl.

### Claim 14 (depends on 13)

The compound or salt of claim 13 wherein the compound of Formula IIA is Compound 2:
or a pharmaceutically acceptable salt thereof.

### Claim 15

A compound of Formula III:
or a pharmaceutically acceptable salt thereof,
R17, R18, and R21 are each independently chosen at each occurrence from hydrogen, halogen, hydroxyl, cyano, an amidino group, —NR23R24, a sulfonic acid group or a salt thereof, a phosphoric acid group or a salt thereof, —CO2H, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6alkoxy, —(C0-C6alkyl)cycloalkyl, C1-C6haloalkyl, —(C0-C6alkyl)phenyl, —(C0-C6alkyl)aryl, —(C0-C6alkyl)heteroaryl, —C(O)C1-C6alkyl, —C(O)(C0-C6alkyl)phenyl, —C(O)(C0-C6alkyl)aryl, —C(O)(C0-C6alkyl)heteroaryl, —C(O)NR23R24, —(C0-C6alkyl)NR23R24, —CO2R23, and a monocyclic or bicyclic heterocycle of 4 to 10 ring atoms having 1, 2, or 3 ring atoms independently chosen from N, S and O;
X is chosen at each occurrence from 0 and S;
R19, R20, and R22 are each independently chosen at each occurrence from hydrogen, halogen, hydroxy, cyano, and an amino group;
R23 and R24 are each independently chosen at each occurrence from hydrogen, halogen, C1-C6 alkyl, C1-C6alkoxy, C1-C6haloalkyl, C1-C6haloalkoxy, C1-C6alkoxy, —(C0-C6alkyl)phenyl, —(C0-C6alkyl)aryl, —(C0-C6alkyl)heteroaryl, —C(O)(C0-C6alkyl)phenyl, —C(O)(C0-C6alkyl)aryl, —C(O)(C0-C6alkyl)heteroaryl, —S(O)phenyl, —S(O)aryl, —S(O)heteroaryl, —SO2phenyl, —SO2aryl, —SO2heteroaryl, —(C0-C6alkyl)cycloalkyl, and —CO2R25; and
R25 is hydrogen, halogen, hydroxy, an amino group, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6alkoxy, —(C0-C6alkyl)cycloalkyl, —C(O)C1-C6alkyl, —(C0-C6alkyl)aryl, —(C0-C6alkyl)heteroaryl, —(C0-C6alkyl)phenyl, or a monocyclic or bicyclic heterocycle of 4 to 10 ring atoms having 1, 2, or 3 ring atoms independently chosen from N, S and O.

### Claim 16 (depends on 15)

The compound or salt of claim 15 wherein
R17 is —C(O)C1-C6alkyl, —C(O)(C0-C6alkyl)phenyl, —C(O)(C0-C6alkyl)aryl, or —C(O)(C0-C6alkyl)heteroaryl;
R18 is C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6alkoxy, —(C0-C6alkyl)cycloalkyl, C1-C6haloalkyl, —(C0-C6alkyl)phenyl, —(C0-C6alkyl)aryl, or —(C0-C6alkyl)heteroaryl;
R19, R20 and R22 are hydrogen;
R21 is —NR23R24;
X is chosen at each occurrence from 0 and S;
R23 and R24 are each independently chosen at each occurrence from —S(O)phenyl, —S(O)aryl, —S(O)heteroaryl, —SO2phenyl, —SO2aryl, —SO2heteroaryl, —(C0-C6alkyl)cycloalkyl, and —CO2R25; and
R25 is C1-C6alkyl, —(C0-C6alkyl)cycloalkyl, —(C0-C6alkyl)aryl, or —(C0-C6alkyl)phenyl.

### Claim 17 (depends on 16)

The compound or salt of claim 16 wherein
R17 is —C(O)C1-C6alkyl;
R18 is C1-C6alkyl;
R19, R20 and R22 are hydrogen;
R21 is —NR23R24;
X is oxygen;
R23 and R24 are each independently chosen at each occurrence from a substituted or unsubstituted aryl sulfonyl, —CO2R25, —SO2phenyl, —SO2aryl, and —SO2R25; and
R25 is phenyl.

### Claim 18 (depends on 17)

The compound or salt of claim 17 wherein the compound of Formula III is Compound 3:
or a pharmaceutically acceptable salt thereof.

### Claim 19 (depends on 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18)

A pharmaceutical composition comprising a compound or salt of any one of claims 1 to 18, together with a pharmaceutically acceptable carrier.

### Claim 20 (depends on 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18)

A method of treating a cancer characterized by selective targeting M2 macrophages and the reprogramming of M2 macrophages towards a M1 phenotype in a patient, comprising the step of providing to a patient in need thereof a therapeutic agent, wherein the therapeutic agent is a compound or salt thereof of any one of claims 1 to 18.

### Claim 21 (depends on 20)

The method of claim 20, wherein CD206, a large C-type lectin receptor, targets and modulates the M2 macrophages and induces cell death.

### Claim 22 (depends on 20)

The method of claim 20, wherein the cancer is selected from glioma (glioblastoma), acute myelogenous leukemia, acute myeloid leukemia, myelodysplastic/myeloproliferative neoplasms, sarcoma, chronic myelomonocytic leukemia, non-Hodgkin lymphoma, astrocytoma, melanoma, non-small cell lung cancer, cholangiocarcinomas, chondrosarcoma, colon cancer or pancreatic cancer.

### Claim 23 (depends on 20, 21, 22)

The method of any one of claims 20 to 22, further comprising administering to the patient in need thereof at least one additional therapeutic agent.