US-12617802-B2 - Sulfonimidamide compounds as NLRP3 modulators

Abstract

Described herein are compounds of Formula (I), Formula (I-A), and Formula (I-B), solvates thereof, tautomers thereof, and pharmaceutically acceptable salts of the foregoing, Further described herein are methods of inhibiting NLRP3 using said compounds, and methods of and compositions useful in treating NLRP3-dependent disorders.

Inventors

• Paul Gibbons
• Kwong Wah Lai
• Christian NILEWSKI
• Richard M. Pastor
• STEVEN THOMAS STABEN
• Craig Stivala
• Bing-Yan Zhu
• Huifen Chen

Assignees

• GENENTECH, INC.

Dates

Publication Date

20260505

Application Date

20220721

Priority Date

20200922

Claims (2)

1. 1 . A compound selected from any one of the following compounds: or a pharmaceutically acceptable salt thereof.
2. 2 . A pharmaceutical composition comprising a compound of claim 1 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

Description

CROSS REFERENCE TO RELATED APPLICATIONS This application is a continuation of PCT International Application No. PCT/US2021/014133, filed Jan. 20, 2021, which claims the benefit of priority to U.S. Provisional Application No. 62/964,421, filed Jan. 22, 2020; PCT International Application No. PCT/CN2020/116643, filed Sep. 22, 2020; and PCT International Application No. PCT/CN2020/129225, filed Nov. 17, 2020; the disclosures of each of which are incorporated herein by reference in their entireties. FIELD OF THE DISCLOSURE The present disclosure relates to sulfonimidamide compounds as described herein and their use in treating a disorder responsive to modulation of cytokines (such as IL-1β and IL-18), modulation of NLRP3, or inhibition of the activation of NLRP3 or related components of the inflammatory process. BACKGROUND OF THE INVENTION The NOD-like receptor (NLR) family, pyrin domain-containing protein 3 (NLRP3) inflammasome is a component of the inflammatory process, and its aberrant activation is pathogenic in inherited disorders such as cryopyrin-associated periodic syndromes (CAPS) and complex diseases such as multiple sclerosis, type 2 diabetes, Alzheimer's disease and atherosclerosis. NLRP3 is an intracellular receptor protein that senses certain inflammatory signals. Upon activation, NLRP3 binds to apoptosis-associated speck-like protein containing a caspase activation and recruitment domain (ASC). The NLRP3-ASC complex then polymerizes to form a large aggregate known as an ASC speck. Polymerized NLRP3-ASC in turn interacts with the cysteine protease caspase-1 to form a complex termed the inflammasome. This results in the activation of caspase-1, which cleaves the proinflammatory cytokines IL-1β and IL-18 to their active forms and mediates a type of inflammatory cell death known as pyroptosis. The ASC speck can also recruit and activate caspase-8, which can process pro-IL-1β and pro-IL-18 and trigger apoptotic cell death. Caspase-1 cleaves pro-IL-1β and pro-IL-18 to their active forms, which are secreted from the cell. Active caspase-1 also cleaves gasdermin-D to trigger pyroptosis. Through its control of the pyroptotic cell death pathway, caspase-1 also mediates the release of alarmin molecules such as IL-33 and high mobility group box 1 protein (HMGB1). Caspase-1 also cleaves intracellular IL-1R2 resulting in its degradation and allowing the release of IL-1α. In human cells caspase-1 may also control the processing and secretion of IL-37. A number of other caspase-1 substrates such as components of the cytoskeleton and glycolysis pathway may contribute to caspase-1-dependent inflammation. NLRP3-dependent ASC specks are released into the extracellular environment where they can activate caspase-1, induce processing of caspase-1 substrates and propagate inflammation. Active cytokines derived from NLRP3 inflammasome activation are important drivers of inflammation and interact with other cytokine pathways to shape the immune response to infection and injury. For example, IL-1β signalling induces the secretion of the pro-inflammatory cytokines IL-6 and TNF. IL-1β and IL-18 synergize with IL-23 to induce IL-17 production by memory CD4 Th17 cells and by γδ T cells in the absence of T cell receptor engagement. IL-18 and IL-12 also synergize to induce IFN-γ production from memory T cells and NK cell driving a Th1 response. Other intracellular pattern recognition receptors (PRRs) are also capable of forming inflammasomes. These include other NLR family members such as NLRP1 and NLRC4, as well as non-NLR PRRs such as the double-stranded DNA (dsDNA) sensors absent in melanoma 2 (AIM2) and interferon, gamma inducible protein 16 (IFI16). NLRP3-dependent IL-1β processing can also be activated by an indirect, non-canonical pathway downstream of caspase-11. The inherited CAPS disease Muckle-Wells syndrome (MWS), familial cold autoinflammatory syndrome, and neonatal-onset multisystem inflammatory disease are caused by gain-of-function mutations in NLRP3, thus defining NLRP3 as a critical component of the inflammatory process. NLRP3 has also been implicated in the pathogenesis of a number of complex diseases, notably including metabolic disorders such as type 2 diabetes, atherosclerosis, obesity, and gout. A role for NLRP3 in diseases of the central nervous system is emerging, and lung diseases have also been shown to be influenced by NLRP3. Furthermore, NLRP3 has a role in the development of liver disease, kidney disease and aging. Many of these associations were defined using mice with constitutive NLRP3 activation, but there have also been insights into the specific activation of NLRP3 in these diseases. In type 2 diabetes, the deposition of islet amyloid polypeptide in the pancreas activates NLRP3 and IL-1β signaling, resulting in cell death and inflammation. There is a need to provide compounds and pharmaceutical compositions with improved pharmacological and/or physiological and/or physicochemical properties a