Macrocyclic immunomodulators

Patent metadata

Field	Value
Publication number	US-11059834-B2
Application number	US-201916504536-A
Country	US
Kind code	B2
Filing date	Jul 8, 2019
Priority date	Aug 8, 2017
Publication date	Jul 13, 2021
Grant date	Jul 13, 2021

Abstract

Compounds are provided that are useful as immunomodulators. The compounds have the following Formula (I) or (II):

including stereoisomers and pharmaceutically acceptable salts thereof, wherein R, R 1 , R 2a , R 2b , R 2c , R 3 , R 4 , R 5 , R 6a , R 6b , R 6c , m and n are as defined herein. Methods associated with preparation and use of such compounds, as well as pharmaceutical compositions comprising such compounds, are also disclosed.

First claim

What is claimed is:

1. A method of treating a cancer mediated by the PD-1 signaling pathway, comprising administering to the subject a therapeutically effective amount of a compound of Formula IIa1 or Formula IIb1:

or a pharmaceutically acceptable salt thereof; wherein:
W is N or C(R 9 );
R is selected from the group consisting of H, halogen, CN, C 1-3 haloalkyl, C 1-3 alkyl and C 1-3 alkoxy;
R 1 is phenyl, optionally substituted with 1 to 3 R 1a substituents;
each R 1a is independently selected from halogen, C 1-8 alkyl, O—C 1-8 alkyl, O—C 1-8 haloalkyl, —NR a R b , and CN, and optionally when two R 1a substituents are on adjacent atoms, they are combined to form a fused six-membered heterocyclic ring optionally substituted with from 1 to 3 substituents independently selected from oxo, C 1-8 haloalkyl and C 1-8 alkyl;
each R a and R b is independently selected from hydrogen, C 1-8 alkyl, and C 1-8 haloalkyl, or when attached to the same nitrogen atom can be combined with the nitrogen atom to form a five or six-membered ring having from 0 to 2 additional heteroatoms as ring members selected from N, O or S, wherein the five or six-membered ring is optionally substituted with oxo;
each of R 1b , R 1c , R 1d and R 1e is independently selected from the group consisting of H, halogen, CF 3 , CN, C 1-4 alkyl and —O—C 1-4 alkyl, wherein the C 1-4 alkyl and —O—C 1-4 alkyl are optionally further substituted with halogen, hydroxyl, methoxy or ethoxy;
wherein Z—L— is a member selected from the group consisting of:

R 2b and R 2c are both H and R 2a is selected from the group consisting of halogen, C 1-4 alkyl, C 2-4 alkenyl, C 1-3 haloalkyl, —CN, —OMe and OEt;
R 6a is H;
R 6c is selected from the group consisting of H, C 1-4 alkyl and C 1-4 haloalkyl;
each R 7a and R 7b is independently selected from the group consisting of H, CO 2 H, and CH 2 OH; and
R 9 is CN.

2. The method of claim 1 , comprising administering to the subject a therapeutically effective amount of a compound of Formula (IIa1).

3. The method of claim 1 , comprising administering to the subject a therapeutically effective amount of a compound of Formula (IIb1).

4. The method of claim 1 , wherein R 1 is selected from the group consisting of:

5. The method of claim 1 , wherein Z-L- is a member selected from the group consisting of:

6. The method of claim 1 , wherein R 2b and R 2c are both H and R 2a is halogen.

7. The method of claim 1 , wherein R 2b and R 2c are both H and R 2a is Cl.

8. A compound or a pharmaceutically acceptable salt thereof, selected from the group consisting of

9. A pharmaceutical composition comprising a compound of claim 8 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

10. The pharmaceutical composition of claim 9 , further comprising one or more additional therapeutic agents.

11. The pharmaceutical composition of claim 10 , wherein the one or more additional therapeutic agents is selected from the group consisting of an antimicrobial agent, an antiviral agent, a cytotoxic agent, a gene expression modulatory agent, a chemotherapeutic agent, an anti-cancer agent, an anti-angiogenic agent, an immunotherapeutic agent, an anti-hormonal agent, an anti-fibrotic agent, radiotherapy, a radiotherapeutic agent, an anti-neoplastic agent, and an anti-proliferation agent.

12. The method of claim 1 , wherein the cancer mediated by the PD-1 signaling pathway is selected from the group consisting of melanoma, glioblastoma, esophagus tumor, nasopharyngeal carcinoma, uveal melanoma, lymphoma, lymphocytic lymphoma, primary CNS lymphoma, T-cell lymphoma, diffuse large B-cell lymphoma, primary mediastinal large B-cell lymphoma, prostate cancer, castration-resistant prostate cancer, chronic myelocytic leukemia, Kaposi's sarcoma, fibrosarcoma, liposarcoma, chondrosarcoma, osteogenic sarcoma, angiosarcoma, lymphangiosarcoma, synovioma, meningioma, leiomyosarcoma, rhabdomyosarcoma, sarcoma of soft tissue, sarcoma, biliary tumor, basal cell carcinoma, thymus neoplasm, cancer of the thyroid gland, cancer of the parathyroid gland, uterine cancer, cancer of the adrenal gland, Merkel cell carcinoma, nerve tumor, follicle center lymphoma, colon cancer, Hodgkin's disease, non-Hodgkin's lymphoma, leukemia, chronic or acute leukemias including acute myeloid leukemia, chronic myeloid leukemia, acute lymphoblastic leukemia, chronic lymphocytic leukemia, multiple myeloma, ovary tumor, myelodysplastic syndrome, cutaneous or intraocular malignant melanoma, renal cell carcinoma, small-cell lung cancer, lung cancer, mesothelioma, breast cancer, squamous non-small cell lung cancer (SCLC), non-squamous NSCLC, colorectal cancer, ovarian cancer, gastric cancer, hepatocellular carcinoma, pancreatic carcinoma, pancreatic cancer, Pancreatic ductal adenocarcinoma, squamous cell carcinoma of the head and neck, cancer of the head or neck, cancer of the gastrointestinal tract, stomach cancer, bone cancer, skin cancer, rectal cancer, cancer of the anal region, testicular cancer, carcinoma of the fallopian tubes, carcinoma of the endometrium, carcinoma of the cervix, carcinoma of the vagina, carcinoma of the vulva, cancer of the esophagus, cancer of the small intestine, cancer of the endocrine system, cancer of the urethra, cancer of the penis, cancer of the bladder, cancer of the kidney, cancer of the ureter, carcinoma of the renal pelvis, neoplasm of the central nervous system (CNS), tumor angiogenesis, spinal axis tumor, brain stem glioma, pituitary adenoma, epidermoid cancer, carcinoma, adenocarcinoma, papillary carcinoma, cystadenocarcinoma, bronchogenic carcinoma, renal cell carcinoma, transitional cell carcinoma, choriocarcinoma, seminoma, embryonal carcinoma, wilm's tumor, pleomorphic adenoma, liver cell papilloma, renal tubular adenoma, cystadenoma, papilloma, adenoma, leiomyoma, rhabdomyoma, hemangioma, lymphangioma, osteoma, chondroma, lipoma and fibroma.

13. The method of claim 12 , further comprising administering to the subject a therapeutically effective amount of one or more additional therapeutic agents.

14. The method of claim 13 , wherein the one or more additional therapeutic agents is selected from the group consisting of a cytotoxic agent, a gene expression modulatory agent, a chemotherapeutic agent, an anti-

Assignees

• Chemocentryx Inc

Inventors

• Malathong Viengkham
• Mcmahon Jeffrey
• Mcmurtrie Darren J
• Punna Sreenivas
• Roth Howard S
• Singh Rajinder
• Zhang Penglie

Classifications

• C07D498/08 Primary

  Bridged systems · CPC title

• C07D471/18

  Bridged systems · CPC title

• C07D273/02 Primary

  having two nitrogen atoms and only one oxygen atom · CPC title

• A61P37/02

  Immunomodulators · CPC title

• A61P31/12

  Antivirals · CPC title