# US 10,870,681 B2 · CXCR4 antagonists and methods of use

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- Number: US 10,870,681 B2
- Document ID: US10870681B2
- Status: Granted
- Kind: B2
- Application number: 16/431,657
- Filed: 2019-06-04
- Published: 2019-10-10
- Granted: 2020-12-22
- Earliest claimed: 2016-09-06
- Assignees: Mainline Biosciences
- Applicants: Mainline Biosciences
- Inventors: Junge Zhang; Liang Zeng Yan
- Web page: https://patentgrep.com/patent/US10870681B2

## CPC

- C07K 7/64: Cyclic peptides containing only normal peptide links
- A61P 11/00: Drugs for disorders of the respiratory system
- A61P 19/02: for joint disorders, e.g. arthritis, arthrosis
- A61P 29/00: Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
- A61P 31/18: for HIV
- A61P 35/00: Antineoplastic agents
- A61P 35/02: specific for leukemia
- A61P 43/00: Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
- C07K 7/06: having 5 to 11 amino acids
- 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)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- 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)

## Abstract

The present invention provides method treating a subject suffering from a clinical condition associated with CXCR4 activity, said method comprising administering to a subject in need of such a treatment a therapeutically effective amount of a compound of the formula: or a pharmaceutically acceptable salt thereof, wherein a is 0 or 1; AA1 along with the sulfur atom that is attached thereto is 3-mercaptopropionic acid, optionally substituted cysteine, or optionally substituted homocysteine; AA2 along with the sulfur atom that is attached thereto is cysteine or homocysteine; Ar1 is an optionally substituted aryl; X1 is Arg, Dap, Dab, Orn, Lys, Dap(iPr), Dab(iPr), Orn(iPr), or Lys(iPr); X2 is Arg, Dap, Dab, Orn, Lys, Dap(iPr), Dab(iPr), Orn(iPr), Lys(iPr), a D-isomer thereof, or absent; X3 is Gly or absent; X4 is Phe, 2Nal, 1Nal, or absent; X5 is Gly or absent; R2 is —OR4 or —NHR5; R4 is H or alkyl; and R5 is H, alkyl, optionally substituted aryl, optionally substituted aralkyl. Methods of the invention can be used to treat a variety of clinical conditions, including but not limited to, cancers, pulmonary fibrosis, HIV infection, rheumatoid arthritis, and other immune disorders.

## Claims

### Claim 1

A method of treating a subject suffering from a clinical condition associated with overexpression, activation and/or upregulation of CXCR4, said method comprising administering to a subject in need of such a treatment a therapeutically effective amount of a compound of the formula:
or a pharmaceutically acceptable salt thereof, wherein
a is 0 or 1;
AA1 along with the sulfur atom that is attached thereto is 3-mercaptopropionic acid, optionally substituted cysteine, or optionally substituted homocysteine;
AA2 along with the sulfur atom that is attached thereto is cysteine or homocysteine;
Ar1 is an optionally substituted aryl;
X1 is Arg, Dap, Dab, Orn, Lys, Dap(iPr), Dab(iPr), Orn(iPr), or Lys(iPr);
X2 is Arg, Dap, Dab, Orn, Lys, Dap(iPr), Dab(iPr), Orn(iPr), Lys(iPr), D-Arg, D-Dap, D-Dab, D-Orn, D-Lys, D-Dap(iPr), D-Dab(iPr), D-Orn(iPr), D-Lys(iPr), or absent;
X3 is Gly or absent;
X4 is Phe, 2Nal, 1Nal, a D-isomer thereof, or absent;
X5 is Gly or absent;
R2 is —OR4 or —NHR5;
R4 is H or alkyl; and
R5 is H, alkyl, optionally substituted aryl, optionally substituted aralkyl.

### Claim 2 (depends on 1)

The method of claim 1, wherein said clinical condition comprises rheumatoid arthritis, pulmonary fibrosis, HIV infection, or a cancer.

### Claim 3 (depends on 2)

The method of claim 2, wherein said cancer is selected from the group consisting of breast cancer, pancreatic cancer, melanoma, prostate cancer, kidney cancer, neuroblastoma, non-Hodgkin's lymphoma, lung cancer, ovarian cancer, colorectal cancer, multiple myeloma, glioblastoma multiforme, and chronic lymphocytic leukemia.

### Claim 4 (depends on 1)

The method according to claim 1, wherein said compound is of the formula:
or a pharmaceutically acceptable salt thereof, wherein:
a is an integer 0 or 1;
m and n are independently 1 or 2;
R1 is H or NHR3, wherein R3 is H, alkyl, acyl, optionally substituted aryl, optionally substituted aralkyl, —C(═O)—Ara, wherein Ara is optionally substituted aryl; and
Ar1, X1, X2, X3, X4, X5 and R2 are those defined in claim 1.

### Claim 5 (depends on 1)

The method according to claim 1, wherein a=1 and Ar1 is an optionally substituted phenyl.

### Claim 6 (depends on 4)

The method according to claim 4, wherein m=1 and n=1.

### Claim 7 (depends on 4)

The method according to claim 4, wherein m=1 and n=2.

### Claim 8 (depends on 4)

The method according to claim 4, wherein m=2 and n=1.

### Claim 9 (depends on 1)

The method according to claim 1, wherein X2 is a (D)-isomer or absent.

### Claim 10 (depends on 1)

The method according to claim 1, wherein X4 absent.

### Claim 11 (depends on 4)

The method according to claim 4, wherein R1 is H and m=1.

### Claim 12 (depends on 4)

The method according to claim 4, wherein R1 is Ac—NH and m=2.

### Claim 13 (depends on 4)

The method according to claim 4, wherein R2 is —NH(Et), and X4 and X5 are absent.

### Claim 14 (depends on 1)

The method according to claim 1 selected from the group consisting of from SEQ ID NO:4 to SEQ ID NO:28.

### Claim 15 (depends on 4)

The method according to claim 4, wherein m=1, n=1 and R1 is NHR3.

### Claim 16 (depends on 4)

The method according to claim 4, wherein m=1, n=2, and R1 is NHR3.

### Claim 17 (depends on 4)

The method according to claim 4, wherein m=2, n=1, and R1 is NHR3.

### Claim 18

A method of treating a patient suffering from rheumatoid arthritis, pulmonary fibrosis, HIV infection, or a cancer, said method comprising administering to said patient a therapeutically effective amount of a compound of the formula:
or a pharmaceutically acceptable salt thereof, wherein
a is 0 or 1;
AA1 along with the sulfur atom that is attached thereto is 3-mercaptopropionic acid, optionally substituted cysteine, or optionally substituted homocysteine;
AA2 along with the sulfur atom that is attached thereto is cysteine or homocysteine;
Ar1 is an optionally substituted aryl;
X1 is Arg, Dap, Dab, Orn, Lys, Dap(iPr), Dab(iPr), Orn(iPr), or Lys(iPr);
X2 is Arg, Dap, Dab, Orn, Lys, Dap(iPr), Dab(iPr), Orn(iPr), Lys(iPr), D-Arg, D-Dap, D-Dab, D-Orn, D-Lys, D-Dap(iPr), D-Dab(iPr), D-Orn(iPr), D-Lys(iPr), or absent;
X3 is Gly or absent;
X4 is Phe, 2Nal, 1Nal, a D-isomer thereof, or absent;
X5 is Gly or absent;
R2 is —OR4 or —NHR5;
R4 is H or alkyl; and
R5 is H, alkyl, optionally substituted aryl, optionally substituted aralkyl.

### Claim 19 (depends on 18)

The method according to claim 18, wherein said patient suffers from a cancer selected from the group consisting of breast cancer, pancreatic cancer, melanoma, prostate cancer, kidney cancer, neuroblastoma, non-Hodgkin's lymphoma, lung cancer, ovarian cancer, colorectal cancer, multiple myeloma, glioblastoma multiforme, and chronic lymphocytic leukemia.

### Claim 20 (depends on 18)

The method according to claim 18, wherein said compound is of the formula:
or a pharmaceutically acceptable salt thereof, wherein:
a is an integer 0 or 1;
m and n are independently 1 or 2;
R1 is H or NHR3, wherein R3 is H, alkyl, acyl, optionally substituted aryl, optionally substituted aralkyl, —C(═O)—Ara, wherein Ara is optionally substituted aryl; and
Ar1, X1, X2, X3, X4, X5 and R2 are those defined in claim 18.