Arginase inhibitors

Patent metadata

Field	Value
Publication number	US-2021002306-A1
Application number	US-201916978335-A
Country	US
Kind code	A1
Filing date	Mar 4, 2019
Priority date	Mar 5, 2018
Publication date	Jan 7, 2021
Grant date	—

Abstract

Compounds that are inhibitors of at least one of the ARG1 and ARG2, and compositions containing the compounds and methods for synthesizing the compounds, are described herein. The use of such compounds and compositions for the treatment of a diverse array of diseases, disorders, and conditions, including cancer- and immune-related disorders that are mediated, at least in part, by ARG1 and ARG2 are also described herein.

First claim

What is claimed is:

1 . A compound having the Formula (I)

or a pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein,
X is CH 2 , NH or O;
R 1 is a member selected from the group consisting of H, —X a —NH 2 , —C(O)—X a —NH 2 and —R c , wherein
X a is a C 1-4 alkylene which is unsubstituted or substituted with one or two R a ;
each R a is independently selected from the group consisting of C 1-6 alkyl and aryl(C 1-4 alkyl); wherein the C 1-6 alkyl is unsubstituted or substituted with hydroxyl, methoxy, amino, thiol, —CO 2 H, —CONH 2 , and —NHCONH 2 ; and aryl is selected from the group consisting phenyl, hydroxyphenyl, methoxyphenyl, and indole; and
R c is a four to six membered saturated heterocyclic ring having a ring vertex selected from the group consisting of O and NH; or is C 1-6 alkyl which is unsubstituted or substituted with one to three substituents independently selected from the group consisting of halogen, hydroxyl and amino; or

R 1 is a naturally-occurring amino acid;
each R 2 is independently selected from the group consisting of H and C 1-6 alkyl; or two R 2 groups are combined with the atoms to which each is attached to form a five to eight-membered mono- or bicyclic ring, which is unsubstituted or substituted with one to four substituents independently selected from the group consisting of halogen, hydroxyl, and methyl.

2 . The compound of claim 1 , or a pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein,
X is CH 2 , NH or O; R 1 is a member selected from the group consisting of H, —X a —NH 2 and —C(O)—X a —NH 2 ; wherein X a is a C 1-4 alkylene which is unsubstituted or substituted with one or two R a ; each R a is independently selected from the group consisting of C 1-6 alkyl and aryl(C 1-4 alkyl); wherein the C 1-6 alkyl is unsubstituted or substituted with hydroxyl, methoxy, amino, thiol, —CO 2 H, —CONH 2 , and —NHCONH 2 ; and aryl is selected from the group consisting phenyl, hydroxyphenyl, methoxyphenyl, and indole; or R 1 is a naturally-occurring amino acid; each R 2 is independently selected from the group consisting of H and C 1-6 alkyl; or two R 2 groups are combined with the atoms to which each is attached to form a five or six-membered ring.

3 . The compound of claim 2 , having the formula:

4 . The compound of claim 3 , having the formula:

5 . The compound of claim 4 , having the formula:

6 . The compound of claim 5 , having the formula:

7 . The compound of claim 5 , having the formula:

wherein m is 1, 2, or 3.

8 . The compound of claim 1 , having the formula:

wherein R 1 is a naturally occurring amino acid.

9 . The compound of claim 8 , having the formula:

10 . The compound of claim 5 , having the formula:

11 . The compound of claim 1 , selected from those compounds of Table 1.

12 . A pharmaceutical composition, comprising a compound of any one of claims 1 - 11 , and a pharmaceutically acceptable excipient.

13 . A method of treating a disease, disorder, or condition, mediated at least in part by ARG1, ARG2 or both ARG1 and ARG2, said method comprising administering a therapeutically effective amount of a compound of any one of claims 1 to 11 to a subject in need thereof.

14 . The method of claim 13 , wherein said disease, disorder, or condition is mediated at least in part by ARG1.

15 . The method of claim 13 , wherein said disease, disorder, or condition is mediated at least in part by ARG2.

16 . The method of claim 13 , wherein said disease, disorder, or condition is mediated at least in part by ARG1 and ARG2.

17 . The method of any one of claims 14 to 16 , wherein said compound is administered in an amount effective to slow, stop or reverse the progression of arginase-mediated immunosuppression.

18 . The method of any one of claims 14 to 16 , wherein said disease, disorder, or condition is cancer.

19 . The method of claim 18 , wherein said cancer is a cancer of the prostate, colon, rectum, pancreas, cervix, stomach, endometrium, brain, liver, bladder, ovary, testis, head, neck, skin (including melanoma and basal carcinoma), mesothelial lining, white blood cell (including lymphoma and leukemia), esophagus, breast, muscle, connective tissue, lung (including small-cell lung carcinoma and non-small-cell lung carcinoma), adrenal gland, thyroid, kidney, or bone; or is colorectal cancer, head and neck cancer, glioblastoma, mesothelioma, renal cell carcinoma, gastric carcinoma, sarcoma (including Kaposi's sarcoma), choriocarcinoma, cutaneous basocellular carcinoma, or testicular seminoma.

20 . The method of claim 19 , wherein said cancer is selected from the group consisting of melanoma, colorectal cancer, pancreatic cancer, breast cancer, prostate cancer, lung cancer, leukemia, a brain tumor, lymphoma, ovarian cancer, Kaposi's sarcoma, renal cell carcinoma, head and neck cancer, and esophageal cancer.

21 . The method of any one of claims 14 to 16 , wherein said disease, disorder, or condition is an immune-related disease, disorder or condition.

22 . The method of claim 21 , wherein said immune-related disease, disorder, or condition is selected from the group consisting of rheumatoid arthritis, kidney failure, lupus, asthma, psoriasis, colitis, pancreatitis, allergies, fibrosis, anemia fibromyalgia, Alzheimer's disease, congestive heart failure, stroke, aortic valve stenosis, arteriosclerosis, osteoporosis, Parkinson's disease, infections, Crohn's disease, ulcerative colitis, allergic contact dermatitis and other eczemas, systemic sclerosis and multiple sclerosis.

23 . A combination comprising a compound of any one of claims 1 to 11 , and at least one additional therapeutic agent.

24 . The combination of claim 23 , wherein said at least one additional therapeutic agent is a chemotherapeutic agent, an immune- and/or inflammation-modulating agent, or radiation.

25 . The combination of claim 23 , wherein said at least one additional therapeutic agent is an immune checkpoint inhibitor.

26 . The combination of claim 25 , wherein said immune checkpoint inhibitor blocks the activity of at least one of PD1, PDL1, BTLA, LAG3, a B7 family member, TIM3, TIGIT or CTLA4.

27 . The combination of claim 26 , wherein said immune checkpoint inhibitor blocks the activity of PD1 or PDL1.

28 . The combination of claim 27 , wherein said immune checkpoint inhibitor is selected f

Assignees

• Arcus Biosciences Inc

Inventors

• Foley Corinne Nicole
• Grange Rebecca Louise
• Guney Tezcan
• Kalisiak Jaroslaw
• Newcomb Eric Thomas
• Tran Anh Thu

Classifications

• C07F5/025 Primary

  Boronic and borinic acid compounds · CPC title

• A61K31/69 Primary

  Boron compounds · CPC title

• A61P35/00

  Antineoplastic agents · CPC title

• A61K33/243

  Platinum; Compounds thereof · CPC title

• C07F5/02

  Boron compounds · CPC title