Invented by James Jeffry Howbert, Robert Hershberg, Laurence E. Burgess, Hong Woon Yang, Array Biopharma Inc, VentiRx Pharmaceuticals Inc

The market for substituted benzoazepines as toll-like receptor modulators is experiencing significant growth in recent years. Toll-like receptors (TLRs) are a class of proteins that play a crucial role in the innate immune system by recognizing various pathogen-associated molecular patterns (PAMPs) and initiating an immune response. Modulating TLR activity has emerged as a promising therapeutic strategy for a wide range of diseases, including cancer, autoimmune disorders, and infectious diseases. Substituted benzoazepines are a class of small molecules that have shown great potential as TLR modulators. These compounds possess a unique chemical structure that allows them to interact with TLRs and modulate their activity. By selectively targeting specific TLRs, substituted benzoazepines can either enhance or suppress the immune response, depending on the desired therapeutic outcome. One of the key drivers behind the market growth of substituted benzoazepines as TLR modulators is the increasing prevalence of chronic diseases and the need for more effective treatment options. Autoimmune disorders, such as rheumatoid arthritis and multiple sclerosis, affect millions of people worldwide and often require long-term management. Substituted benzoazepines offer a potential solution by targeting TLRs involved in the pathogenesis of these diseases, thereby reducing inflammation and disease progression. Furthermore, the rising incidence of cancer has also fueled the demand for TLR modulators. TLRs play a critical role in recognizing tumor-associated antigens and initiating an anti-tumor immune response. Substituted benzoazepines can be used to enhance TLR activity and promote the immune system’s ability to recognize and eliminate cancer cells. This approach, known as immunotherapy, has shown promising results in various types of cancer, including melanoma and lung cancer. Infectious diseases, such as viral and bacterial infections, also represent a significant market opportunity for substituted benzoazepines as TLR modulators. TLRs are involved in recognizing and responding to pathogens, and modulating their activity can enhance the immune response against infections. Substituted benzoazepines can be used to boost the immune system’s ability to fight off pathogens, potentially reducing the severity and duration of infections. The market for substituted benzoazepines as TLR modulators is highly competitive, with several pharmaceutical companies actively engaged in research and development in this field. Companies are investing in the discovery and development of novel substituted benzoazepines with improved efficacy and safety profiles. Additionally, collaborations between pharmaceutical companies and academic institutions are driving innovation and advancing the understanding of TLR biology. However, there are still challenges to overcome in the market for substituted benzoazepines as TLR modulators. One of the main challenges is the complex nature of TLR signaling pathways and the need for a deeper understanding of their role in various diseases. Additionally, the development of substituted benzoazepines as therapeutics requires rigorous preclinical and clinical testing to ensure safety and efficacy. In conclusion, the market for substituted benzoazepines as toll-like receptor modulators is witnessing significant growth due to the increasing prevalence of chronic diseases, the rising incidence of cancer, and the need for more effective treatment options. These compounds have the potential to revolutionize the field of immunotherapy and provide new avenues for the treatment of various diseases. However, further research and development are needed to fully exploit the therapeutic potential of substituted benzoazepines as TLR modulators.

The Array Biopharma Inc, VentiRx Pharmaceuticals Inc invention works as follows

The compositions and methods are useful in modulating signaling via the Toll-like TLR7 or TLR8 receptors. These compositions and methods are useful in treating or preventing diseases, such as cancer, autoimmune diseases, cardiovascular disease infections, inflammatory disorders, graft rejecting or graft versus host disease.

Background for Substituted Benzoazepines As Toll-Like Receptor Modulators

Stimulation” of the immune system (which includes both innate and adaptive immunity) is a complex process that can have either a protective or adverse physiological outcome for the host. Recent years, there has been an increased interest in mechanisms that underlie innate immunity. It is believed that innate immunity initiates and supports adaptive immunity. This interest was fueled by the discovery of Toll-like Receptors (TLRs), a highly conserved family of pattern recognition receptors that are believed to play a role in innate immune responses as receptors for PAMPs. The compositions and methods that modulate innate immunity may have a therapeutic impact on conditions such as autoimmunity and inflammation, allergies, asthma, graft reject, graft against host disease (GvHD), cancer, infection, and immunodeficiency.

Toll like receptors (TLRs), are type I transmembrane protein that allows organisms, including mammals, to detect microbes, and initiate an immune response. (Beutler B., Nature 2004 430:257-263). They have homologous extracellular and cytoplasmic regions and form homodimers to sense external (or internalized signals) and initiate a signal-transduction cascade through adaptor molecules like MyD88 (myeloid difference factor 88). The cytoplasmic regions of TLRs are so homologous that it was initially thought that all TLRs share the same signaling pathways (Re, F. and Strominger, J. L. Immunobiology 2004:209:191-198). All TLRs are able to activate NFKB and MAP Kinases. However, each TLR has a unique profile of cytokine/chemokine releases resulting from TLR activation. TLRs also stimulate a signaling pathway very similar to that of the cytokine receptor IL-1R. It may be because these receptors have a homology, i.e. TIR (Toll/IL-1R) domains. After the TIR domain in TLRs is activated and MyD88 recruited, activation occurs of the IRAK serine/threonine kinases, which promotes degradation of IkB and activation NF-kB. (Means T. K. et al. Life Sci. 2000, 68:241-258). It appears that the cascade is intended to promote intracellular activities by allowing extracellular stimuli, but there is evidence to suggest that some TLRs can migrate to endosomes to initiate signaling. This process allows for close contact with microbes that are engulfed and is consistent with the role these receptors play during the innate immunity response (Underhill D. M. et al. Nature 1999, 401: 811-815). This process could also trigger a response by releasing host nucleic acid from damaged tissues, such as in inflammatory diseases or apoptosis. There are 11 TLRs in mammals that coordinate the rapid response. A hypothesis that was put forward many years ago (Janeway C. A. Jr., Cold Spring Harb. Syrup. Quant. Biol. Biol. The pathogen-associated molecular patterns (PAMPs), presented by diverse infectious organisms, result in an innate immune reaction involving cytokines, growth factors, and chemokines. This is followed by an adaptive immune response that is tailored to the infectious pathogen through antigen presentation, leading to antibody production and T cell generation.

The Gram-negative bacterial Lipopolysaccharide, or LPS, has been used for many years as an adjuvant to stimulate the immune system and induce an inflammatory response in mammals that is similar to septica shock. TLR4 has been identified using a genetic method as the receptor of LPS. The discovery that LPS was an agonist for TLR4 shows the value of TLR modulation in vaccines and disease treatment (Aderem A.; Ulevitch R. J. Nature 2000, 406:782-787). “It is now understood that TLR agonists activate B cells as well as neutrophils and mast cells. They also regulate proliferation and apoptosis in certain cell types.

TLR7 and TLR8, both of which are similar, were characterized by researchers as receptors for single stranded RNA in endosomal cells and thought to be crucial for the immune response against viral infection. Imiquimod, an approved topical antiviral/anti-cancer drug, has recently been described as a TLR7 agonist that has demonstrated clinical efficacy in certain skin disorders (Miller R. L., et al., Int. J. Immunopharm. 1999, 21:1-14). This small molecule has been described by scientists as a structural mimic of ssRNA. TLR8 was described for the first time in 2000 by Du, X. et. al. European Cytokine Network, September 2000, 11(3):362-371. It was quickly attributed to be involved with the innate immunity response to viral infections (Miettinen M. et. al. Genes and Immunity, October 2001, 2(6):349-355).

Recently it was reported that certain imidazoquinoline compounds having antiviral activity are ligands of TLR7 and TLR8 (Hemmi H., et al. (2002) Nat. Immunol. 3:196-200; Jurk M., et al. (2002) Nat. Immunol. 3:499). Imidazoquinolines are potent synthetic activators of immune cells with antiviral and antitumor properties. Using macrophages from wildtype and MyD88-deficient mice, Hemmi et al. recently reported that two imidazoquinolines, imiquimod and resiquimod (R848), induce tumor necrosis factor (TNF) and interleukin-12 (IL-12) and activate NF-icB only in wildtype cells, consistent with activation through a TLR (Hemmi H., et al. (2002) Nat. Immunol. 3:196-200). Macrophages from mice deficient in TLR7 but not other TLRs produced no detectable cytokines in response to these imidazoquinolines. In addition, the imidazoquinolines induced dose-dependent proliferation of splenic B cells and the activation of intracellular signaling cascades in cells from wildtype but not TLR7?/? mice. Luciferase analysis established that expression of human TLR7, but not TLR2 or TLR4, in human embryonic kidney cells results in NF-KB activation in response to resiquimod. The findings of Hemmi et al. thus suggest that these imidazoquinoline compounds are non-natural ligands of TLR7 that can induce signaling through TLR7. Recently it was reported that R848 is also a ligand for human TLR8 (Jurk M., et al. (2002) Nat. Immunol. 3:499).

The use of these compounds and their therapeutic benefits must be expanded, despite all the previous work.

The compositions described in this application are useful in modulating immune response in vitro and invivo. These compositions can be used in many clinical applications. For example, they could be used to treat or prevent conditions that involve unwanted immune activity.

Specifically, the invention is a compound with the formula I:”.

Or a salt thereof

whereinnis either a double or single bond

R2 & R3 independently select from H & unsubstituted / substituted C1 -C6 alkyls, or together R2 & R3 with the carbon to which they’re attached form a carbocycle with 3-7 members, or together R3 et one Ra / Rb atom with the atoms they’re attached form a heterocyclic ring with 5-7 members;

R7 has been selected from a group consisting:

n” can be 0, 1, 2, or 3.

each R8 independently is selected from unsubstituted, or substituted, C1 to C6 alkyls, unsubstituted, or substituted, C1 to C6 alkoxycarbonyls, nitro, carbonylaminos, unsubstituted, or substituted, sulfonamides, unsubstituted, or substituted heterocycles comprising 1, 2, 5, or 6-member rings, and 1-4 heteroatoms from N, S, O,

R9 can be unsubstituted, substituted, C1-C6 aryl, unsubstituted, substituted, C1C6 aloxy, or


Rf and RG are independently H, unsubstituted, or substituted C1 to C6 alkyl, or Rf and RG, together with the Nitrogen atom they are attached to, form a heterocycle consisting of 1 or 2, 5-or 6-member rings, and optionally, 1-3 additional heteroatoms chosen from N, S, and O;

Rh and rj are independently H, unsubstituted, or substituted, C1-C6 aryl, or unsubstituted, or substituted, C6-C10 alkyl. Rh and rj together with the nitrogen to which they’re attached form a heterocycle consisting of 1 or 2, 5, or 6-member rings, and optionally, 1-3 additional heteroatoms chosen from N, O, and S.

R11″ is “H, unsubstituted, substituted, C1-C6 Alkylcarbonyl or C1C6 Alkoxycarbonyl or 3-7 member carbocycle substituted carbonyl or 5-7 member heterocyclyl substituted carbonyl.

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