IP Library › Granted Patent US 12,371,433
Granted Patent B2
US 12,371,433 · App. 18/522,995 · Granted Jul 29, 2025

Heteroaryl-biphenyl amines for the treatment of PD-L1 diseases

Inventors: Pingchen Fan (Fremont, CA); Christopher W. Lange (Hayward, CA); Rebecca M. Lui (Mountain View, CA); Darren J. McMurtrie (Vancouver, CA); Ryan J. Scamp (Fremont, CA); Ju Yang (Palo Alto, CA); Yibin Zeng (Foster City, CA); Penglie Zhang (Foster City, CA)
Assignee: AMGEN INC.
C07D471/04A61K45/06
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Quick Facts
Patent No.
US 12,371,433
App. No.
18/522,995
Granted
Jul 29, 2025
Kind
B2
Abstract

Compounds are provided that are useful as immunomodulators. The compounds have the Formula (I) including stereoisomers and pharmaceutically acceptable salts thereof, wherein R 2a , R 2b , R 3 , R 3a , R 4 , R 6 , R 7 , R 8 , A, Z, X 1 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.

Claims (67)

1. A method of modulating an immune response mediated by PD-1 signaling in a subject, comprising administering to the subject a therapeutically effective amount of a compound of Formula (I),

or a pharmaceutically acceptable salt thereof, wherein:

A is a 5- or 6-membered heteroaryl group which is unsubstituted or substituted with from one to three members independently selected from the group consisting of halogen, C 1-3 alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, OH, and CN;

X 1 is a C 1-3 alkylene, which is unsubstituted or substituted with one or two members independently selected from the group consisting of C 1-2 alkyl and CO 2 H;

R 2a and R 2b are each independently selected from the group consisting of H, C 1-8 alkyl, C 1-8 haloalkyl, —Y, —X 2 —CO 2 R a , —X 2 —OR a , —X 2 —NR a R b , —X 2 —C(O)NR a R b , —X 2 —SO 2 R a , —X 2 —SO 2 NR a R b , —X 2 —SO 3 R a , and —X 2 —Y, wherein each X 2 is a C 1-6 alkylene, and any C 1-8 alkyl or C 1-6 alkylene is unsubstituted or substituted with one or two members independently selected from the group consisting of OH, SO 2 NH 2 , C(O)NH 2 , C(O)NHOH, PO 3 H 2 , CO 2 C 1-8 alkyl, and CO 2 H, and each Y is selected from the group consisting of C 3-6 cycloalkyl, C 4-8 heterocyclyl, and 5- to 6-membered heteroaryl, each of which is unsubstituted or substituted with one to four substituents independently selected from the group consisting of oxo, OH, C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 hydroxyalkyl, C 1-4 alkoxy, C 1-4 haloalkoxy, C 1-4 hydroxyalkoxy, SO 2 NH 2 , C(O)NH 2 , —C(O)NHOH, PO 3 H 2 , CO 2 C 1-8 alkyl, SO 3 H, and CO 2 H;

or R 2a and R 2b are combined to form a 4- to 9-membered ring or spirocyclic ring, having from zero to two additional heteroatom ring vertices selected from O, N, and S;

wherein the 4- to 9-membered ring or spirocyclic ring formed by combining R 2a and R 2b is unsubstituted or substituted with 1 to 4 substituents independently selected from the group consisting of oxo, C 1-8 alkyl, C 1-8 haloalkyl, C 1-8 hydroxyalkyl, —X 3 —CO 2 R a , —X 3 —OR a , —X 3 —NR a R b , —X 3 —C(O)NR a R b , —X 3 —SO 2 R a , —X 3 —SO 2 NR a R b , and —X 3 —SO 3 R a , wherein X 3 is a bond or C 1-6 alkylene;

R 3 and R 4 are each independently selected from the group consisting of H, F, Cl, CN, CH 3 , OCH 3 , CH 2 CH 3 , and CF 3 ;

the subscript n is 0, 1, 2, or 3;

each R 3a is independently selected from the group consisting of H, F, Cl, C 1-3 alkyl, C 1-3 alkoxy, C 1-3 haloalkyl, C 1-3 haloalkoxy, C 2-3 alkenyl, and CN;

R 6 , R 7 , and R 8 are each independently selected from the group consisting of H, F, Cl, CN, CH 3 , OCH 3 , CH 2 CH 3 , and CF 3 ;

Z is selected from the group consisting of

 unsubstituted or substituted with one to three R c ;

each R a is independently selected from the group consisting of H, C 1-6 alkyl, C 3-6 cycloalkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 alkylene-CO 2 H, and C 1-6 alkylene-SO 3 H;

each R b is independently selected from the group consisting of H, C 1-6 alkyl, C 3-6 cycloalkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 alkylene-CO 2 H, and C 1-6 alkylene-SO 3 H, each of which is unsubstituted or substituted with one or two members independently selected from OH, SO 2 NH 2 , C(O)NH 2 , C(O)NHOH, PO 3 H 2 , CO 2 C 1-8 alkyl, and CO 2 H;

and R a and R b , when attached to the same nitrogen atom, are optionally combined to form a 4- to 8-membered ring or spirocyclic ring, which is unsubstituted or substituted with halogen, OH, SO 2 NH 2 , C(O)NH 2 , C(O)NHOH, PO 3 H 2 , CO 2 C 1-8 alkyl, or —CO 2 H; and

each R c is independently selected from the group consisting of H, halogen, CN, C 1-6 alkyl, C 1-6 haloalkyl, —Y 1 , —X 4 —CO 2 R a , —O—X 4 —CO 2 R a , —X 4 —OR a , —X 4 —NR a R b , —X 4 —C(O)NR a R b , —O—X 4 —C(O)NR a R b , —X 4 —SO 2 R a , —X 4 —SO 2 NR a R b , —X 4 —SO 3 R a , and —N(R a )—X 4 —CO 2 R a , wherein each X 4 is a bond or C 1-6 alkylene, and each Y 1 is independently selected from the group consisting of C 3-6 cycloalkyl and C 4-8 heterocyclyl; and optionally two R c on adjacent ring vertices are combined to form a fused 5- or 6-membered heterocyclic ring.

2. A method of inhibiting growth, proliferation, or metastasis of cancer cells in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of Formula (I),

or a pharmaceutically acceptable salt thereof, wherein:

A is a 5- or 6-membered heteroaryl group which is unsubstituted or substituted with from one to three members independently selected from the group consisting of halogen, C 1-3 alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, OH, and CN;

X 1 is a C 1-3 alkylene, which is unsubstituted or substituted with one or two members independently selected from the group consisting of C 1-2 alkyl and CO 2 H;

R 2a and R 2b are each independently selected from the group consisting of H, C 1-8 alkyl, C 1-8 haloalkyl, —Y, —X 2 —CO 2 R a , —X 2 —OR a , —X 2 —NR a R b , —X 2 —C(O)NR a R b , —X 2 —SO 2 R a , —X 2 —SO 2 NR a R b , —X 2 —SO 3 R a , and —X 2 —Y, wherein each X 2 is a C 1-6 alkylene, and any C 1-8 alkyl or C 1-6 alkylene is unsubstituted or substituted with one or two members independently selected from the group consisting of OH, SO 2 NH 2 , C(O)NH 2 , C(O)NHOH, PO 3 H 2 , CO 2 C 1-8 alkyl, and CO 2 H, and each Y is selected from the group consisting of C 3-6 cycloalkyl, C 4-8 heterocyclyl, and 5- to 6-membered heteroaryl, each of which is unsubstituted or substituted with one to four substituents independently selected from the group consisting of oxo, OH, C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 hydroxyalkyl, C 1-4 alkoxy, C 1-4 haloalkoxy, C 1-4 hydroxyalkoxy, SO 2 NH 2 , C(O)NH 2 , —C(O)NHOH, PO 3 H 2 , CO 2 C 1-8 alkyl, SO 3 H, and CO 2 H;

or R 2a and R 2b are combined to form a 4- to 9-membered ring or spirocyclic ring, having from zero to two additional heteroatom ring vertices selected from O, N, and S;

wherein the 4- to 9-membered ring or spirocyclic ring formed by combining R 2a and R 2b is unsubstituted or substituted with 1 to 4 substituents independently selected from the group consisting of oxo, C 1-8 alkyl, C 1-8 haloalkyl, C 1-8 hydroxyalkyl, —X 3 —CO 2 R a , —X 3 —OR a , —X 3 —NR a R b , —X 3 —C(O)NR a R b , —X 3 —SO 2 R a , —X 3 —SO 2 NR a R b , and —X 3 —SO 3 R a , wherein X 3 is a bond or C 1-6 alkylene;

R 3 and R 4 are each independently selected from the group consisting of H, F, Cl, CN, CH 3 , OCH 3 , CH 2 CH 3 , and CF 3 ;

the subscript n is 0, 1, 2, or 3;

each R 3a is independently selected from the group consisting of H, F, Cl, C 1-3 alkyl, C 1-3 alkoxy, C 1-3 haloalkyl, C 1-3 haloalkoxy, C 2-3 alkenyl, and CN;

R 6 , R 7 , and R 8 are each independently selected from the group consisting of H, F, Cl, CN, CH 3 , OCH 3 , CH 2 CH 3 , and CF 3 ;

Z is selected from the group consisting of

 unsubstituted or substituted with one to three R c ;

each R a is independently selected from the group consisting of H, C 1-6 alkyl, C 3-6 cycloalkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 alkylene-CO 2 H, and C 1-6 alkylene-SO 3 H;

each R b is independently selected from the group consisting of H, C 1-6 alkyl, C 3-6 cycloalkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 alkylene-CO 2 H, and C 1-6 alkylene-SO 3 H, each of which is unsubstituted or substituted with one or two members independently selected from OH, SO 2 NH 2 , C(O)NH 2 , C(O)NHOH, PO 3 H 2 , CO 2 C 1-8 alkyl, and CO 2 H;

and R a and R b , when attached to the same nitrogen atom, are optionally combined to form a 4- to 8-membered ring or spirocyclic ring, which is unsubstituted or substituted with halogen, OH, SO 2 NH 2 , C(O)NH 2 , C(O)NHOH, PO 3 H 2 , CO 2 C 1-8 alkyl, or —CO 2 H; and

each R c is independently selected from the group consisting of H, halogen, CN, C 1-6 alkyl, C 1-6 haloalkyl, —Y 1 , —X 4 —CO 2 R a , —O—X 4 —CO 2 R a , —X 4 —OR a , —X 4 —NR a R b , —X 4 —C(O)NR a R b , —O—X 4 —C(O)NR a R b , —X 4 —SO 2 R a , —X 4 —SO 2 NR a R b , —X 4 —SO 3 R a , and —N(R a )—X 4 —CO 2 R a , wherein each X 4 is a bond or C 1-6 alkylene, and each Y 1 is independently selected from the group consisting of C 3-6 cycloalkyl and C 4-8 heterocyclyl; and optionally two R c on adjacent ring vertices are combined to form a fused 5- or 6-membered heterocyclic ring.

3. A method of treating a subject suffering from a disease or disorder mediated by PD-1 signaling, comprising administering to the subject a therapeutically effective amount of a compound of Formula (I),

or a pharmaceutically acceptable salt thereof, wherein:

A is a 5- or 6-membered heteroaryl group which is unsubstituted or substituted with from one to three members independently selected from the group consisting of halogen, C 1-3 alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, OH, and CN;

X 1 is a C 1-3 alkylene, which is unsubstituted or substituted with one or two members independently selected from the group consisting of C 1-2 alkyl and CO 2 H;

R 2a and R 2b are each independently selected from the group consisting of H, C 1-8 alkyl, C 1-8 haloalkyl, —Y, —X 2 —CO 2 R a , —X 2 —OR a , —X 2 —NR a R b , —X 2 —C(O)NR a R b , —X 2 —SO 2 R a , —X 2 —SO 2 NR a R b , —X 2 —SO 3 R a , and —X 2 —Y, wherein each X 2 is a C 1-6 alkylene, and any C 1-8 alkyl or C 1-6 alkylene is unsubstituted or substituted with one or two members independently selected from the group consisting of OH, SO 2 NH 2 , C(O)NH 2 , C(O)NHOH, PO 3 H 2 , CO 2 C 1-8 alkyl, and CO 2 H, and each Y is selected from the group consisting of C 3-6 cycloalkyl, C 4-8 heterocyclyl, and 5- to 6-membered heteroaryl, each of which is unsubstituted or substituted with one to four substituents independently selected from the group consisting of oxo, OH, C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 hydroxyalkyl, C 1-4 alkoxy, C 1-4 haloalkoxy, C 1-4 hydroxyalkoxy, SO 2 NH 2 , C(O)NH 2 , —C(O)NHOH, PO 3 H 2 , CO 2 C 1-8 alkyl, SO 3 H, and CO 2 H;

or R 2a and R 2b are combined to form a 4- to 9-membered ring or spirocyclic ring, having from zero to two additional heteroatom ring vertices selected from O, N, and S;

wherein the 4- to 9-membered ring or spirocyclic ring formed by combining R 2a and R 2b is unsubstituted or substituted with 1 to 4 substituents independently selected from the group consisting of oxo, C 1-8 alkyl, C 1-8 haloalkyl, C 1-8 hydroxyalkyl, —X 3 —CO 2 R a , —X 3 —OR a , —X 3 —NR a R b , —X 3 —C(O)NR a R b , —X 3 —SO 2 R a , —X 3 —SO 2 NR a R b , and —X 3 —SO 3 R a , wherein X 3 is a bond or C 1-6 alkylene;

R 3 and R 4 are each independently selected from the group consisting of H, F, Cl, CN, CH 3 , OCH 3 , CH 2 CH 3 , and CF 3 ;

the subscript n is 0, 1, 2, or 3;

each R 3a is independently selected from the group consisting of H, F, Cl, C 1-3 alkyl, C 1-3 alkoxy, C 1-3 haloalkyl, C 1-3 haloalkoxy, C 2-3 alkenyl, and CN;

R 6 , R 7 , and R 8 are each independently selected from the group consisting of H, F, Cl, CN, CH 3 , OCH 3 , CH 2 CH 3 , and CF 3 ;

Z is selected from the group consisting of

 unsubstituted or substituted with one to three R c ;

each R a is independently selected from the group consisting of H, C 1-6 alkyl, C 3-6 cycloalkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 alkylene-CO 2 H, and C 1-6 alkylene-SO 3 H;

each R b is independently selected from the group consisting of H, C 1-6 alkyl, C 3-6 cycloalkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 alkylene-CO 2 H, and C 1-6 alkylene-SO 3 H, each of which is unsubstituted or substituted with one or two members independently selected from OH, SO 2 NH 2 , C(O)NH 2 , C(O)NHOH, PO 3 H 2 , CO 2 C 1-8 alkyl, and CO 2 H;

and R a and R b , when attached to the same nitrogen atom, are optionally combined to form a 4- to 8-membered ring or spirocyclic ring, which is unsubstituted or substituted with halogen, OH, SO 2 NH 2 , C(O)NH 2 , C(O)NHOH, PO 3 H 2 , CO 2 C 1-8 alkyl, or —CO 2 H; and

each R c is independently selected from the group consisting of H, halogen, CN, C 1-6 alkyl, C 1-6 haloalkyl, —Y 1 , —X 4 —CO 2 R a , —O—X 4 —CO 2 R a , —X 4 —OR a , —X 4 —NR a R b , —X 4 —C(O)NR a R b , —O—X 4 —C(O)NR a R b , —X 4 —SO 2 R a , —X 4 —SO 2 NR a R b , —X 4 —SO 3 R a , and —N(R a )—X 4 —CO 2 R a , wherein each X 4 is a bond or C 1-6 alkylene, and each Y 1 is independently selected from the group consisting of C 3-6 cycloalkyl and C 4-8 heterocyclyl; and optionally two R c on adjacent ring vertices are combined to form a fused 5- or 6-membered heterocyclic ring.

4. The method of claim 1 , wherein the subject suffers from a disease or disorder selected from the group consisting of an infectious disease, a bacterial infectious disease, a viral infectious disease, a fungal infectious disease, a solid tumor, a hematological malignancy, an immune disorder, an inflammatory disease, and cancer.

5. The method of claim 3 , wherein the disease or disorder 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, sepsis, biliary tumor, basal cell carcinoma, thymus neoplasm, thyroid gland cancer, parathyroid gland cancer, uterine cancer, adrenal gland cancer, liver infection, Merkel cell carcinoma, nerve tumor, follicle center lymphoma, colon cancer, Hodgkin's disease, non-Hodgkin's lymphoma, leukemia, chronic or acute leukemias, 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 (NSCLC), non-squamous NSCLC, colorectal cancer, ovarian cancer, gastric cancer, hepatocellular carcinoma, pancreatic carcinoma, pancreatic cancer, pancreatic ductal adenocarcinoma, head and neck squamous cell carcinoma, head or neck cancer, gastrointestinal tract cancer, stomach cancer, HIV, Hepatitis A, Hepatitis B, Hepatitis C, Hepatitis D, influenza, bone cancer, skin cancer, rectal cancer, anal region cancer, testicular cancer, fallopian tube carcinoma, endometrium carcinoma, cervix carcinoma, vagina carcinoma, vulva carcinoma, esophagus cancer, small intestine cancer, endocrine system cancer, urethra cancer, penis cancer, bladder cancer, kidney cancer, ureter cancer, renal pelvis carcinoma, central nervous system (CNS) neoplasm, tumor angiogenesis, spinal axis tumor, brain stem glioma, pituitary adenoma, epidermoid cancer, abestosis, 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.

6. The method of claim 1 , further comprising administering to the subject a therapeutically effective amount of one or more additional therapeutic agents.

7. The method of claim 6 , 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.

8. The method of claim 1 , wherein the compound or pharmaceutically acceptable salt thereof is selected from the group consisting of:

and pharmaceutically acceptable salts thereof.

9. The method of claim 1 , wherein the compound or pharmaceutically acceptable salt thereof is selected from the group consisting of:

and pharmaceutically acceptable salts thereof.

10. The method of claim 2 , wherein the compound or pharmaceutically acceptable salt thereof is selected from the group consisting of:

and pharmaceutically acceptable salts thereof.

11. The method of claim 2 , wherein the compound or pharmaceutically acceptable salt thereof is selected from the group consisting of:

and pharmaceutically acceptable salts thereof.

12. The method of claim 3 , wherein the compound or pharmaceutically acceptable salt thereof is selected from the group consisting of:

and pharmaceutically acceptable salts thereof.

13. The method of claim 3 , wherein the compound or pharmaceutically acceptable salt thereof is selected from the group consisting of:

and pharmaceutically acceptable salts thereof.

Assignments (2)
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded May 1, 2025
From: FAN, PINGCHEN; LANGE, CHRISTOPHER; LUI, REBECCA M.; MCMURTRIE, DARREN J.; SCAMP, RYAN J.; YANG, JU; ZENG, YIBIN; ZHANG, PENGLIE
To: CHEMOCENTRYX, INC.
Reel/Frame 070998/0460 →
ASSIGNEE CHANGE OF ADDRESS Recorded May 1, 2025
From: CHEMOCENTRYX, INC.
To: CHEMOCENTRYX, INC.
Reel/Frame 071149/0468 →
Continuity (3)
Division 17071056 · Oct 15, 2020
Provisional Application 62915771 · Oct 16, 2019
Related Publication 20240132495A1 · Apr 25, 2024
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