SEQUENCE LISTING

The instant application contains a Sequence Listing which has been submitted electronically in ASCII format and is hereby incorporated by reference in its entirety. Said ASCII copy, created on May 27, 2021, is named 67LZ-000410US-332037_SL.txt and is 747 bytes in size.

FIELD

The present disclosure relates to p38α mitogen-activated protein kinase inhibitors, pharmaceutical compositions thereof, and the use of the p38α mitogen-activated protein kinase inhibitors and pharmaceutical compositions thereof for threating a disease.

BACKGROUND

MAPKs are serine/threonine protein kinases that process and regulate cellular properties in response to a wide range of extracellular stimuli. p38 MAPK comprises four isoforms (α, β, γ and δ). p38α MAPK was the first isoform of p38 MAPK to be identified and was first recognized as a stress-induced kinase that can be activated by lipopolysaccharide (LPS) and inflammatory cytokines. These enzymes phosphorylate the OH group of serine or threonine in proteins and play important roles in the regulation of cell proliferation, differentiation, survival and apoptosis. In mammalian cells, several distinct MAPKs have been identified, including p38 MAPK.

p38 MAPK is a class of MAPKs responsive to stress stimuli such as inflammatory cytokines and reactive oxygen species (ROS) and is involved in a wide range of signaling pathways that stimulate different biological functions. For example, p38 MAPK has been found to play an essential role in the regulation of pro-inflammatory signaling networks and in the biosynthesis of cytokines, including tumor necrosis factor-α (TNF-α) and interleukin-1β (IL-1β) in immune cells

Studies have shown that p38 MAPKs contribute to the pathogenesis of chronic inflammation, thereby motivating preclinical and clinical trials for the application of p38 MAPK inhibitors in inflammatory diseases such as rheumatoid arthritis and asthma.

Many p38 MAPK catalytic inhibitors are poorly effective and cause toxicity possibly due to activity against non-inflammatory p38 and loss of p38α-dependent counterregulatory responses. p38α MAPK inhibitors that can selectively inhibit certain p38α MAPK functions and preserve critical counterregulatory and homeostatic functions with application for the treatment of inflammatory and oncologic diseases are desired. Inhibition of p38 MAPKs has been shown to effectively alleviate inflammatory diseases such as rheumatoid arthritis, cardiovascular disease and inflammatory pain.

SUMMARY

According to the present invention, compounds have the structure of Formula (1):



or a pharmaceutically acceptable salt thereof, wherein,R1is selected from C1-4alkanediyl, C1-4heteroalkanediyl, substituted C1-4alkanediyl, and substituted C1-4heteroalkanediyl; andR2is selected from a moiety of Formula (2a), a moiety of Formula (2b), a moiety of Formula (2c), C8-16heterobicycloalkyl, and substituted C8-16heterobicycloalkyl:

wherein,each of B1, B2, B3, and B4is independently selected from —(CH(—R4))n—, wherein,each n is independently selected from, 0, 1, 2, 3, and 4;both B1and B2are not 0;both B3and B4are not 0; andeach R4is independently selected from hydrogen, —OH, —NH2, —NO2, C1-3alkyl, C1-3heteroalkyl, substituted C1-3alkyl, and substituted C1-3heteroalkyl;D is selected from methane-diyl and ethane-diyl; andX is selected from —O—, —CH(—OH)—, —NR3—, and —SO2—, wherein R3is selected from hydrogen, C1-6alkyl, C1-6cycloalkyl, C6aryl, C1-6heteroalkyl, C1-6heterocycloalkyl, C5-6heteroaryl, substituted C1-6alkyl, substituted C1-6cycloalkyl, substituted C6aryl, substituted C1-6heteroalkyl, substituted C1-6heterocycloalkyl, and substituted C5-6heteroaryl.

According to the present invention, compounds have the structure of Formula (1):



or a pharmaceutically acceptable salt thereof, wherein,R1is selected from C1-4alkanediyl, C1-4heteroalkanediyl, substituted C1-4alkanediyl, and substituted C1-4heteroalkanediyl; andR2is a moiety of Formula (2d):

wherein,each A1and A2is independently selected from —CH2—, —CH(—R5)—, and —C(═O)—, wherein, each R5is independently selected from —OH, —NH2, —NO2, C1-6alkyl, C1-6cycloalkyl, C6aryl, C1-6heteroalkyl, C1-6heterocycloalkyl, C5-6heteroaryl, substituted C1-6alkyl, substituted C1-6cycloalkyl, substituted C6aryl, substituted C1-6heteroalkyl, substituted C1-6heterocycloalkyl, and substituted C5-6heteroaryl;one or more of A1and A2is independently selected from —CH(—R5)— and —C(═O)—;each n is independently selected from, 1, 2, 3, and 4; andX is selected from —O—, —CH(—OH)—, —NR3—, and —SO2—, wherein R3is selected from hydrogen, C1-6alkyl, C5-8cycloalkyl, C6aryl, C6-12cycloalkylalkyl, C7-10arylalkyl, C1-6heteroalkyl, C5-8heterocycloalkyl, C5-6heteroaryl, C6-12heterocycloalkylalkyl, C7-10heteroarylalkyl, substituted C1-6alkyl, substituted C5-8cycloalkyl, substituted C6aryl, substituted C6-12cycloalkylalkyl, substituted C7-10arylalkyl, substituted C1-6heteroalkyl, substituted C5-8heterocycloalkyl, substituted C5-6heteroaryl, substituted C6-12heterocycloalkylalkyl, and substituted C7-10heteroarylalkyl.

According to the present invention, pharmaceutical compositions comprise a compound according to the present invention or a pharmaceutically acceptable salt thereof.

According to the present invention, methods of treating a disease in a patient comprise administering to a patient in need thereof a therapeutically effective amount of the compound of a compound according to the present invention or a pharmaceutically acceptable salt thereof, wherein the disease is cancer such as melanoma; an inflammatory disease such as acute respiratory distress syndrome, focal segmental glomerulonephritis, atherosclerosis/acute coronary syndrome, chronic obstructive pulmonary disease, asthma, inflammatory bowel disease, Crohn's disease, psoriasis, lupus, multiple sclerosis, inflammation in hypercholesteremia, pain, diabetes, rheumatoid arthritis, amyotrophic lateral sclerosis, cystic fibrosis; an autoimmune disease; an age-related disease such as hearing loss, muscle degeneration, Werner's syndrome, cellular aging, and Alzheimer's disease, or a viral disease such as a coronavirus infection, pneumonia associated with a coronavirus infection, and a Human Respiratory Syndical infection.

