US 11,732,005 B2
Peptidomimetic proteasome inhibitors
Gang Lin, Forest Hills, NY (US); Carl Nathan, Larchmont, NY (US); Wenhu Zhan, Elmhurst, NY (US); Trevor Morgan, Royston (GB); Ryoma Hara, Tokyo (JP); Toshihiro Imaeda, Kanagawa (JP); Rei Okamoto, Kanagawa (JP); Kenjiro Sato, Kanagawa (JP); Kazuyoshi Aso, Kanagawa (JP); Tzu-Tshin Wong, Acton, MA (US); and Michael A. Foley, New York, NY (US)
Assigned to CORNELL UNIVERSITY, Ithaca, NY (US); and TRI-INSTITUTIONAL THERAPEUTICS DISCOVERY INSTITUTE, New York, NY (US)
Filed by CORNELL UNIVERSITY, Ithaca, NY (US); and TRI-INSTITUTIONAL THERAPEUTICS DISCOVERY INSTITUTE, New York, NY (US)
Filed on Nov. 8, 2021, as Appl. No. 17/521,328.
Application 17/521,328 is a division of application No. 16/755,427, granted, now 11,203,613, previously published as PCT/US2018/055482, filed on Oct. 11, 2018.
Claims priority of provisional application 62/571,146, filed on Oct. 11, 2017.
Prior Publication US 2022/0056073 A1, Feb. 24, 2022
Int. Cl. C07K 5/062 (2006.01); C07K 5/02 (2006.01); C07D 235/14 (2006.01); C07D 235/10 (2006.01); A61K 38/00 (2006.01)
CPC C07K 5/06026 (2013.01) [C07D 235/10 (2013.01); C07D 235/14 (2013.01); C07K 5/02 (2013.01); A61K 38/00 (2013.01)] 15 Claims
 
1. A method of treating bacterial infections, parasite infections, fungal infections, cancer, autoimmune disorders, neurodegenerative diseases and disorders, inflammatory disorders, or muscular dystrophy, in a subject or for achieving immunosuppression in transplanted organs or tissues in a subject, said method comprising:
administering to the subject in need thereof a compound of Formula (I):

OG Complex Work Unit Chemistry
wherein
R is H or C1-6 alkyl;
R′ is H or C1-6 alkyl;
R1 is H or C1-6 alkyl;
or R and R1 are taken together with the carbon to which they are attached to form a C3-8 cycloalkyl ring;
R2 is independently selected at each occurrence thereof from

OG Complex Work Unit Chemistry
 or —(CH2)nC(O)NR6R7;
R3 is independently selected at each occurrence thereof from the group consisting of H, C1-12 alkyl, -Boc, —C(O)(CH2)nR5, —(CH2)nC(O)R5, —C(O)OR5, —C(O)(CH2)nNR6R7, —S(O)2R5, monocyclic and bicyclic heteroaryl, monocyclic and bicyclic heterocyclyl, and monocyclic and bicyclic non-aromatic heterocycle, wherein monocyclic and bicyclic heteroaryl, monocyclic and bicyclic heterocyclyl, and monocyclic and bicyclic non-aromatic heterocycle can be optionally substituted from 1 to 3 times with R8;
R4 is H, halogen, NH2, NHCOOC1-12 alkyl, or C1-12 alkyl;
R5 is selected from the group consisting of C1-12 alkyl, monocyclic or bicyclic C3-10 cycloalkyl, C3-12 cycloalkylalkyl, C1-12 alkoxy, monocyclic and bicyclic aryl, monocyclic and bicyclic heteroaryl, monocyclic and bicyclic heterocyclyl, and monocyclic and bicyclic non-aromatic heterocycle, wherein C1-12 alkyl, monocyclic or bicyclic C3-10 cycloalkyl, C3-12 cycloalkylalkyl, C1-12 alkoxy, monocyclic and bicyclic aryl, monocyclic and bicyclic heteroaryl, monocyclic and bicyclic heterocyclyl, and monocyclic and bicyclic non-aromatic heterocycle can be optionally substituted from 1 to 3 times with R8;
R6 and R7 are each independently selected from the group consisting of H, C1-6 alkyl, and arylalkyl;
or R6 and R7 are taken together with the nitrogen to which they are attached to form a piperidine, pyrrolidine, azepane, or morpholine ring, wherein piperidine, pyrrolidine, azepane, or morpholine ring can be optionally substituted 1 to 3 times with R9;
R8 is selected independently at each occurrence thereof from the group consisting of halogen, C1-6 alkyl, C3-8 cycloalkyl, aryl, and arylalkyl, wherein C1-6 alkyl, C3-8 cycloalkyl, aryl, and arylalkyl can be optionally substituted 1 to 3 times with R9;
R9 is selected from the group consisting of H, halogen, C1-6 alkyl, C3-8 cycloalkyl, and aryl, wherein C1-6 alkyl can be optionally substituted 1 to 3 times with halogen;
W is CHR2, NR2, or

OG Complex Work Unit Chemistry
X is selected from the group consisting of —C(O)—NH—, monocyclic and bicyclic heteroaryl, monocyclic and bicyclic heterocyclyl, and monocyclic and bicyclic non-aromatic heterocycle;
Y is optional and, if present, is —(CH2)m—;
Z is optional and, if present, is aryl or bicyclic heteroaryl;

OG Complex Work Unit Chemistry
 is the point of attachment to NHR3 moiety;

OG Complex Work Unit Chemistry
 is the point of attachment to C(O) moiety;
k is 1 or 2;
m is 0, 1, or 2; and
n is 0, 1, 2, 3, or 4,
with the proviso that R2 is not —CH2C(O)NH2, —CH2C(O)NHCH2C(CH3)3, or —(CH2)2C(O)NH2,
a pharmaceutically acceptable salt thereof or a solvate thereof,
wherein the autoimmune disorder is selected from the group consisting of arthritis, colitis, multiple sclerosis, lupus, Sjogren Syndrome, Systemic Lupus Erythematosus, lupus nephritis, glomerulonephritis, Rheumatoid Arthritis, Inflammatory bowel disease (IBD), ulcerative colitis, Crohn's diseases, Psoriasis, and asthma;
the inflammatory disorder is Crohn's disease;
the cancer is selected from the group consisting of neoplastic disorders, hematologic malignances, lymphocytic malignancies, mantel cell lymphoma, leukemia, Waldenstrom Macroglobulinemia, pancreatic cancer, bladder cancer, colorectal cancer, breast cancer, metastatic breast cancer, prostate cancer, androgen-dependent and androgen-independent prostate cancer, renal cancer, metastatic renal cell carcinoma, hepatocellular cancer, lung cancer, non-small cell lung cancer (NSCLC), bronchioloalveolar carcinoma (BAC), adenocarcinoma of the lung, ovarian cancer, progressive epithelial or primary peritoneal cancer, cervical cancer, gastric cancer, esophageal cancer, head and neck cancer, squamous cell carcinoma of the head and neck, melanoma, neuroendocrine cancer, metastatic neuroendocrine tumors, brain tumors, glioma, anaplastic oligodendroglioma, adult glioblastoma multiforme, and adult anaplastic astrocytoma, bone cancer, and soft tissue sarcoma; and
the neurodegenerative disease or disorder is Amyotrophic Lateral Sclerosis (ALS) or Multiple Sclerosis (MS).