TW202104214A - Chemical compounds - Google Patents

Abstract

Compounds that are useful as modulators of transmembrane protein 173 (TMEM173), also known as STING (Stimulator of Interferon Genes), and methods for treating Hepatitis B virus-related conditions in mammals by administering such a compound, are disclosed.

Description

Compound

The present invention relates to compounds that modulate the activity of transmembrane protein 173 (TMEM173), also known as STING (interferon gene stimulating protein), and methods for treating hepatitis B virus infection in mammals by administering these compounds.

Hepatitis B is a viral disease that is transmitted vertically and parenterally from contaminated substances (such as blood and blood products, contaminated needles), sexually, and from the mother of the infection or carrier to its offspring. In these areas where the disease is common in the world, vertical transmission at an early age causes a high proportion of infected individuals to become long-term carriers of hepatitis B. According to estimates by the World Health Organization, more than 2 billion people are infected worldwide, of which there are about 4 million acute cases each year, 1 million deaths each year, and 350-400 million long-term carriers. By. Approximately 25% of carriers die from chronic hepatitis, cirrhosis or liver cancer and almost 75% of long-term carriers are Asians. Hepatitis B virus (HBV) is the second most significant carcinogen after tobacco, causing 60% to 80% of all primary liver cancers. HBV is 100 times more infectious than HIV.

Hepatitis B virus infection is a continuing medical problem because, like any rapidly replicating infectious agent, there are persistent mutations that help some HBV subgroups to become resistant to current treatment regimens. There is currently no effective therapeutic agent for the treatment of humans infected with HBV infection that achieves the following results: In people with hepatitis B virus infection, compared with the baseline number before treatment, seroconversion against the virus is produced in the body Or reduce the antigen by 90%. Currently, the therapies recommended by the American Association for the Study of Liver Diseases (AASLD) and the European Association for the Study of the Liver (EASL) for chronic HBV infection include interferon alpha (INFα), pegylated interferon α-2a (Peg-IFN2α), entecavir (entecavir) and tenofovir (tenofovir). However, typical interferon therapy is 48 weeks and produces serious and unpleasant side effects, and the HBeAg seroconversion at 24 weeks after stopping the therapy is only in the range of 27% to 36%. The seroconversion of HBsAg was even lower, only 3% was observed just after treatment was stopped, and it increased to 12% after 5 years.

Nucleoside and nucleotide therapies Entecavir and Tenofovir successfully reduced the viral load, but the HBeAg seroconversion rate and HBsAg loss were even lower than those obtained with IFNa therapy. Other similar therapies (including lamivudine (3TC), telbivudine (LdT) and adefovir) are also used, but generally speaking, for nucleoside/nucleotide therapy , The emergence of resistance will limit the effectiveness of treatment.

Vertebrates have evolved immune defense mechanisms to eliminate infectious pathogens. In mammals, this immune system consists of two branches, namely innate immunity and adaptive immunity. The innate immune system is the first line of defense, which is initiated by pattern recognition receptors (PRR), which detect ligands from pathogens and damage-related molecular patterns (Takeuchi O. et al., Cell, 2010: 140, 805-820). An increasing number of these receptors have been identified, including toll-like receptors (TLR), C-type lectin receptors, retinoic acid inducible gene I (RIG-I)-like receptors, and NOD-like receptors ( NLR) and double-stranded DNA receptors. The activation of PRR leads to the up-regulation of genes involved in the inflammatory response, including type 1 interferons, pro-inflammatory cytokines and chemokines that inhibit pathogen replication and promote adaptive immunity.

Interferon was originally described as a substance that can protect cells from virus infection (Isaacs and Lindemann, J. Virus Interference. Proc. R. Soc. Lon. Ser. B. Biol. Sci. 1957: 147, 258-267). In humans, type I interferons are encoded by genes on chromosome 9 and encode at least 13 interferon alpha (IFN alpha) isoforms and one interferon beta (IFN beta) isoform related protein family. Recombinant IFNα is the first approved biotherapeutic agent and has become an important therapy for viral infections and cancer. In addition to the direct antiviral activity on cells, interferon-based powerful modulators of immune response are also known to act on cells of the immune system.

The transfer protein STING (interferon gene stimulating protein) is also known as TMEM 173, MPYS, MITA and ERIS. It has been identified as a central signal transduction molecule in the innate immune response to cytoplasmic nucleic acid (Ishikawa H and Barber GN, Nature, 2008: 455, 674-678; WO2013/1666000). The activation of STING up-regulates the IRF3 and NFκB pathways, leading to the induction of interferon-β and other cytokines. STING is essential for the response to cytoplasmic DNA of pathogen or host origin and unusual nucleic acid called cyclic dinucleotide (CDN).

CDN was originally identified as the bacterial second messenger responsible for controlling numerous reactions in prokaryotic cells. Bacterial CDN (e.g. c-bis-GMP) is a symmetric molecule characterized by two 3', 5'phosphodiester linkages.

It has recently been confirmed by X-ray crystallography that STING is directly activated by bacterial CDN (Burdette D L and Vance RE, Nature Immunology, 2013: 14, 19-26). Therefore, bacterial CDN and its analogues have attracted people's interest as potential vaccine adjuvants (Libanova R. et al., Microbial Biotechnology 2012: 5, 168-176; WO2007/054279, WO2005/087238).

Recently, the reaction to cytoplasmic DNA has been elucidated and it has been shown to involve the production of novel mammalian CDN signaling molecules (identified as cyclic GMP-AMP synthase (cGAS, previously known as C6orf150 or MB21D1)) by an enzyme cGAMP), this molecule then activates STING. Unlike bacterial CDN, cGAMP is an asymmetric molecule characterized by mixed 2', 5'and 3', 5'phosphodiester linkages. (Gao P et al., Cell, 2013: 153, 1094-1107). The interaction between cGAMP (II) and STING has also been demonstrated by X-ray crystallography (Cai X et al., Molecular Cell, 2014: 54, 289-296).

The administration of small molecule compounds that can regulate the innate immune response (including the activation or inhibition of type I interferon production and other cytokines) can be used to treat or prevent human diseases including viral infections and autoimmune diseases The important strategy. In particular, hepatitis B virus infection in animals can be advantageously treated by administering a first compound that modulates the activity of STING and a second compound that does not modulate the activity of STING.

STING is essential for antimicrobial host defense and has been associated with protection against a series of DNA and RNA viruses and bacteria (reviewed in Barber et al., Nat. Rev. Immunol. 2015: 15(2): 87-103, Ma and Damania, Cell Host & Microbe, 2016: 19(2) 150-158). Herpesviridae, Flaviviridae, Coronaviridae, Papillomaviridae, Adenoviridae, Hepadnaviridae, Orthomucus Orthomyxoviridae and paramyxoviridae and rhabdoviridae have evolved mechanisms to inhibit STING-mediated type I interferon production and evade host immune control (Holm et al., Nat Comm. 2016 : 7:10680; Ma et al., PNAS 2015: 112(31) E4306-E4315; Wu et al., Cell Host Microbe 2015: 18(3) 333-44; Liu et al., J Virol 2016: 90(20) 9406 -19; Chen et al., Protein Cell 2014: 5(5) 369-81; Lau et al., Science 2013: 350(6260) 568-71; Ding et al., J Hepatol 2013: 59(1) 52-8; Nitta et al., Hepatology 2013 57(1) 46-58; Sun et al., PloS One 2012: 7(2) e30802; Aguirre et al., PloS Pathog 2012: 8(10) e1002934; Ishikawa et al., Nature 2009: 461 (7265) 788-92). Therefore, activation of STING by small molecules can be beneficial to the treatment of these infectious diseases.

In contrast, increased and prolonged type I IFN production is associated with a variety of chronic infections, including Mycobacteria (Collins et al., Cell Host Microbe 2015: 17(6) 820-8); Wassermann et al., Cell Host Microbe 2015: 17(6) 799-810; Watson et al., Cell Host Microbe 2015: 17(6) 811-9), Franciscella (Storek et al., J Immunol. 2015: 194(7) ) 3236-45; Jin et al., J Immunol. 2011: 187(5) 2595-601), Chlamydia (Prantner et al., J Immunol 2010: 184(5) 2551-60), Plasmodium Plasmodium (Sharma et al., Immunity 2011: 35(2) 194-207) and HIV (Herzner et al., Nat Immunol 2015 16(10) 1025-33; Gao et al., Science 2013: 341(6148) 903-6). Similarly, excessive type I interferon production is found in patients with complex forms of autoimmune diseases. The genetic evidence in humans and the support from animal model studies support the following hypothesis: inhibiting STING reduces the type I interferon that drives autoimmune diseases (Crow YJ et al., Nat. Genet. 2006; 38(8) 38917-920 , Stetson DB et al., Cell 2008; 134 587-598). Therefore, STING inhibitors provide treatment for patients with long-term type I interferon and pro-inflammatory cytokine production associated with infection or complex autoimmune diseases. Allergic diseases are related to Th2 biased immune response to allergens. The Th2 reaction is related to the increase in the content of IgE. IgE promotes hypersensitivity to allergens through its effect on obese cells, leading to the symptoms seen in (for example) allergic rhinitis and asthma. In healthy individuals, allergic reactions to allergens are more balanced with mixed Th2/Th1 and regulatory T cell responses. It has been shown that induction of type 1 interferon reduces Th2 type cytokines in the local environment and promotes Th1/Treg response. In this context, the induction of type 1 interferon by, for example, activating STING can provide benefits in the treatment of allergic diseases such as asthma and allergic rhinitis (Huber JP et al., J Immunol 2010: 185, 813-817) .

It has been shown that compounds that bind to STING and act as agonists induce type 1 interferons and other cytokines when incubated with human PBMC. For example, international patent applications WO2014/093936, WO2014/189805, WO2013/185052, US2014/0341976, WO 2015/077354, PCT/EP2015/062281 and GB 1501462.4 disclose certain cyclic di-nucleotides and their The use of inducing immune response by activating STING. International patent application WO2017/106740 describes the use of cyclic di-nucleotides and related scaffolds that can measurably inhibit STING signaling, and methods for identifying potent inhibitors of STING signaling. International patent applications WO 2017/175147 and WO 2017/175156 describe the use of heterocyclic amides and their analogs as STING modifiers.

The international patent application PCT/IB2017/051945 filed on April 5, 2016 (which is incorporated herein by reference in its entirety) discloses that it can be used as a transmembrane protein 173 (TMEM173, also known as STING (interferon) Novel compounds of modulators of gene stimulating protein)), which are used to treat STING-mediated diseases or disorders, including inflammation, allergic and autoimmune diseases, cancer and precancerous syndromes, infectious diseases, and as immunogens Sexual composition or vaccine adjuvant. It is envisaged that the use of small molecules to target STING can be a promising method for the treatment of diseases and conditions, including infectious diseases, in which modulating type 1 IFN pathways is beneficial.

Viruses are becoming increasingly resistant to existing therapies, and the seroconversion rate in the serum of patients infected with certain viruses is found to be low when using existing antiviral therapies, which indicates the need to discover and develop new antiviral therapies. More specifically, the industry needs new anti-HBV therapies that can increase the seroconversion rate of HBeAg and HBsAg. HBV serum markers HBeAg (hepatitis B envelope antigen) and HBsAg (hepatitis B surface antigen) indicate immune control of HBV infection, and the reduction of serum antigen content produces an improved prognosis, that is, prevention of liver disease and progression to cirrhosis, Prevent liver failure, prevent hepatocellular carcinoma (HCC), prevent liver disease-related transplantation, and prevent death.

Clinical studies have found a correlation between seroconversion and HBeAg reduction (Fried et al. (2008) Hepatology 47:428) and HBsAg reduction (Moucari et al. (2009) Hepatology 49:1151). The reduction of antigen content can allow immune control of HBV infection, because it is believed that high content of antigen induces immune tolerance. The current nucleoside therapy for HBV can significantly reduce the serum content of HBV, but has a minimal effect on the content of HBeAg and HBsAg.

Targeting STING with small molecules can be a promising new method for the treatment of hepatitis B virus infection. In addition, the combination therapy of a compound targeting STING and other therapies for the treatment of HBV has the potential to effectively cure hepatitis B infection by combining multiple therapeutic agents with different modes of action in the combination therapy. For example, administration of a compound targeting STING and administration of small molecule inhibitors of HBV antigens HBsAg and HBeAg can directly target receptors involved in inflammation and HBV antigens that cause immunogenic reactions in mammals, so it is possible Reduce serum HBeAg and HBsAg levels.

The compounds of the present invention can be used as modulators of STING, and therefore can provide beneficial therapeutic effects in the treatment of diseases, disorders and/or conditions in which regulation of STING (interferon gene stimulating protein) is beneficial, such as for infectious diseases .

One embodiment of the present invention relates to a compound as described herein or a pharmaceutically acceptable salt or prodrug thereof.

(I) 其中A係C₂ -C₆ 烷基或C₂ -C₆ 烯基， 其中該C₂ -C₆ 烷基或該C₂ -C₆ 烯基各自獨立地視情況由1至2個選自-R^c 、-OH及-OR^c 之取代基取代； R¹ 及R² 獨立地不存在或係C₁ -C₃ 烷基； W¹ 、X¹ 、Y¹ 及Z¹ 各自獨立地係-CR³ 、-CR³ ′、-CR³ ″、-CR³ ′″或N，條件係W¹ 、X¹ 、Y¹ 及Z¹ 中不超過兩者可係N； W² 、X² 、Y² 及Z² 各自獨立地係-CR⁴ 、-CR⁴ ′、-CR⁴ ″、-CR⁴ ′″或N，條件係W² 、X² 、Y² 及Z² 中不超過兩者可係N； R³ 、R³ ′、R³ ″、R³ ′″、R⁴ 、R⁴ ′、R4″、R⁴ ′″、R⁹ 、R¹⁰ 、R¹¹ 及R¹² 各自獨立地選自H、C_1-4 烷氧基、C_1-4 烷基、-COO-C_1-4 烷基、-C_4-7 雜環烷基、-C_1-4 烷基C_4-7 雜環烷基及-OC_1-4 烷基C_4-7 雜環烷基，其中該-C_4-7 雜環烷基、該-C_1-4 烷基C_4-7 雜環烷基之-C_4-7 雜環烷基或該-OC_1-4 烷基C_4-7 雜環烷基之C_4-7 雜環烷基包含一或多個選自O及N之雜原子， 其中該C_1-4 烷基、C_1-4 烷氧基、該-C_1-4 烷基C_4-7 雜環烷基之C_1-4 烷基或該-OC_1-4 烷基C_4-7 雜環烷基之C_1-4 烷基視情況由1至4個獨立地選自-R^c 、-OH及-OR^c 之取代基取代，且 其中該C_4-7 雜環烷基、該-C_1-4 烷基C_4-7 雜環烷基之C_4-7 雜環烷基或該-OC_1-4 烷基C_4-7 雜環烷基之C_4-7 雜環烷基由1至4個取代基R’、R”、R”’及R””取代，其中R’、R”、R”’及R””各自獨立地選自-R^c 、-OH及-OR^c ，或R’、R”、R”’及R””中之任兩者可與其所連接之環原子組合以形成3員至7員環； R⁵ 及R⁶ 獨立地係C₁ -C₄ 烷基； R⁷ 及R⁸ 各自獨立地係H或C₁ -C₄ 烷基； 每一R^c 獨立地係C₁ -C₄ 烷基，其視情況由選自-OH或C_1-4 烷氧基之取代基取代； 或其鹽。An embodiment of the present invention relates to a compound of formula (I):

(I) wherein A is a C ₂ -C ₆ alkyl group or a C ₂ -C ₆ alkenyl group, wherein the C ₂ -C ₆ alkyl group or the C ₂ -C ₆ alkenyl group is independently from 1 to 2 as appropriate Substituents selected from -R ^c , -OH and -OR ^c ; R ¹ and R ^{2 are} independently absent or are C ₁ -C ₃ alkyl groups; W ¹ , X ¹ , Y ¹ and Z ¹ are each independently It is -CR ³ , -CR ³ ′, -CR ³ ″, -CR ³ ′″ or N, and the condition is that no more than two ^{of W 1} , X ¹ , Y ¹ and Z ^{1 can be N; W 2} , X ² , Y ² and Z ² are each independently -CR ⁴ , -CR ⁴ ′, -CR ⁴ ″, -CR ⁴ ′″ or N, and the condition is that no more than two ^{of W 2} , X ² , Y ² and Z ² Can be N; R ³ , R ³ ′, R ³ ″, R ³ ′″, R ⁴ , R ⁴ ′, R4 ″, R ⁴ ′″, R ⁹ , R ¹⁰ , R ¹¹ and R ¹² are each independently selected From H, C _1-4 alkoxy, C _1-4 alkyl, -COO-C _1-4 alkyl, -C _4-7 heterocycloalkyl, -C _1-4 alkyl C _4-7 hetero Cycloalkyl and -OC _1-4 alkyl C _4-7 heterocycloalkyl, wherein the -C _4-7 heterocycloalkyl, the -C _1-4 alkyl C _4-7 heterocycloalkyl- C _4-7 heterocycloalkyl, or the -OC _1-4 alkyl C _4-7 heterocycloalkyl, C _4-7 heterocycloalkyl comprising of one or more of the heteroatoms selected from O and N atoms, wherein the C _1-4 alkyl, C _1-4 alkoxy, -C _1-4 alkyl which C _4-7 heterocycloalkyl, C _1-4 alkyl or the -OC _1-4 alkyl which C _{4- 7 The C 1-4} alkyl group of the heterocycloalkyl group is optionally substituted by 1 to 4 substituents independently selected from -R ^c , -OH and -OR ^c , and wherein the C _4-7 heterocycloalkyl group, -C _1-4 alkyl which C _4-7 heterocycloalkyl, C _4-7 heterocycloalkyl, or the -OC _1-4 alkyl which C _4-7 heterocycloalkyl, C _4-7 heterocycloalkyl of The group is substituted by 1 to 4 substituents R', R", R"' and R"", wherein R', R", R"' and R"" are each independently selected from -R ^c , -OH and- OR ^c , or any two of R', R”, R”' and R”” can be combined with the ring atoms to which they are connected to form a 3- to 7-membered ring; R ⁵ and R ^{6 are} independently C _1- C ₄ alkyl; R ⁷ and R ⁸ are each independently H or C ₁ -C ₄ alkyl; each R ^{c is} independently C ₁ -C ₄ alkyl, which is optionally selected from -OH or C _{1 -4} Substituent substitution of alkoxy; or its salt.

In a specific embodiment, a compound selected from the group consisting of: N,N'-((2E,2'E)-((E)-but-2-ene-1,4-diyl)bis(3-methyl-1,3-dihydro-2H-benzo [d] Imidazol-1-yl-2-ylidene)) bis(1-ethyl-3-methyl-1H-pyrazole-5-carboxamide); (E)-2-((1-ethyl-3-methyl-1H-pyrazole-5-carbonyl)imino)-1-((E)-4-((E)-2-(( 1-Ethyl-3-methyl-1H-pyrazole-5-carbonyl)imino)-3-methyl-2,3-dihydro-1H-benzo(d)imidazol-1-yl)butyl -2-en-1-yl)-3-methyl-2,3-dihydro-1H-benzo[d]imidazole-5-carboxylic acid methyl ester; 1-Ethyl-N-((E)-3-((E)-4-((E)-2-((1-ethyl-3-methyl-1H-pyrazole-5-carbonyl) sub Amino)-3-methyl-2,3-dihydro-1H-benzo(d)imidazol-1-yl)but-2-en-1-yl)-4-methoxy-1-methyl -1,3-Dihydro-2H-benzo[d]imidazole-2-ylidene)-3-methyl-1H-pyrazole-5-carboxamide; 1-Ethyl-N-((E)-3-((E)-4-((E)-2-((1-ethyl-3-methyl-1H-pyrazole-5-carbonyl) sub Amino)-7-(3-hydroxypropoxy)-3-methyl-2,3-dihydro-1H-benzo(d)imidazol-1-yl)but-2-en-1-yl) -4-Methoxy-1-methyl-1,3-dihydro-2H-benzo[d]imidazole-2-ylidene)-3-methyl-1H-pyrazole-5-carboxamide; (E)-1-ethyl-N-(3-((E)-4-((E)-2-((1-ethyl-3-methyl-1H-pyrazole-5-carbonyl) sub Amino)-3-methyl-2,3-dihydro-1H-benzo(d)imidazol-1-yl)but-2-en-1-yl)-4-(hydroxymethyl)-1- Methyl-1H-benzo[d]imidazole-2(3H)-ylidene)-3-methyl-1H-pyrazole-5-carboxamide; 1-Ethyl-N-((E)-3-((E)-4-((E)-2-((1-ethyl-3-methyl-1H-pyrazole-5-carbonyl) sub Amino)-3-methyl-2,3-dihydro-1H-benzo(d)imidazol-1-yl)but-2-en-1-yl)-1-methyl-4-(morpholine Methyl)-1,3-dihydro-2H-benzo[d]imidazole-2-ylidene)-3-methyl-1H-pyrazole-5-carboxamide; 1-Ethyl-N-((E)-3-((E)-4-((E)-2-((1-ethyl-3-methyl-1H-pyrazole-5-carbonyl) sub Amino)-3-methyl-2,3-dihydro-1H-benzo(d)imidazol-1-yl)but-2-en-1-yl)-1-methyl-4-(hexahydro Pyridin-1-ylmethyl)-1,3-dihydro-2H-benzo[d]imidazole-2-ylidene)-3-methyl-1H-pyrazole-5-carboxamide; N-((E)-1-((E)-4-((E)-7-(azeppan-1-ylmethyl)-2-((1-ethyl-3-methyl) -1H-pyrazole-5-carbonyl)imino)-3-methyl-2,3-dihydro-1H-benzo(d)imidazol-1-yl)but-2-en-1-yl) -3-Methyl-1,3-dihydro-2H-benzo[d]imidazol-2-ylidene)-1-ethyl-3-methyl-1H-pyrazole-5-carboxamide; N-((E)-1-((E)-4-((E)-7-((3-oxa-6-azabicyclo[3.1.1]heptan-6-yl)methyl) -2-((1-ethyl-3-methyl-1H-pyrazole-5-carbonyl)imino)-3-methyl-2,3-dihydro-1H-benzo[d]imidazole- 1-yl)but-2-en-1-yl)-3-methyl-1,3-dihydro-2H-benzo(d)imidazol-2-ylidene)-1-ethyl-3-methyl Group-1H-pyrazole-5-carboxamide; 1-Ethyl-N-((E)-3-((E)-4-((E)-2-((1-ethyl-3-methyl-1H-pyrazole-5-carbonyl) sub Amino)-3-methyl-2,3-dihydro-1H-benzo(d)imidazol-1-yl)but-2-en-1-yl)-4-(methoxymethyl)- 1-Methyl-1,3-dihydro-2H-benzo[d]imidazole-2-ylidene)-3-methyl-1H-pyrazole-5-carboxamide; 1-Ethyl-N-((E)-3-((E)-4-((E)-2-((1-ethyl-3-methyl-1H-pyrazole-5-carbonyl) sub Amino)-3-methyl-2,3-dihydro-1H-benzo(d)imidazol-1-yl)but-2-en-1-yl)-4-(1-hydroxyethyl)- 1-Methyl-1,3-dihydro-2H-benzo[d]imidazole-2-ylidene)-3-methyl-1H-pyrazole-5-carboxamide; 1-Ethyl-N-((E)-1-((E)-4-((E)-2-((1-ethyl-3-methyl-1H-pyrazole-5-carbonyl) sub Amino)-3-methyl-2,3-dihydro-1H-benzo(d)imidazol-1-yl)but-2-en-1-yl)-4-(hydroxymethyl)-3- Methyl-1,3-dihydro-2H-benzo[d]imidazole-2-ylidene)-3-methyl-1H-pyrazole-5-carboxamide; 1-Ethyl-N-((E)-1-((E)-4-((E)-2-((1-ethyl-3-methyl-1H-pyrazole-5-carbonyl) sub Amino)-3-methyl-2,3-dihydro-1H-benzo(d)imidazol-1-yl)but-2-en-1-yl)-3-methyl-4-(morpholine Methyl)-1,3-dihydro-2H-benzo[d]imidazole-2-ylidene)-3-methyl-1H-pyrazole-5-carboxamide; 1-Ethyl-N-((E)-1-((E)-4-((E)-2-((1-ethyl-3-methyl-1H-pyrazole-5-carbonyl) sub Amino)-3-methyl-2,3-dihydro-1H-benzo(d)imidazol-1-yl)but-2-en-1-yl)-3-methyl-4-(hexahydro Pyridin-1-ylmethyl)-1,3-dihydro-2H-benzo[d]imidazole-2-ylidene)-3-methyl-1H-pyrazole-5-carboxamide; N-((E)-4-((3-oxa-6-azabicyclo[3.1.1]hept-6-yl)methyl)-1-((E)-4-((E) -2-((1-ethyl-3-methyl-1H-pyrazole-5-carbonyl)imino)-3-methyl-2,3-dihydro-1H-benzo[d]imidazole- 1-yl)but-2-en-1-yl)-3-methyl-1,3-dihydro-2H-benzo(d)imidazol-2-ylidene)-1-ethyl-3-methyl Group-1H-pyrazole-5-carboxamide; 1-Ethyl-N-((E)-1-((E)-4-((E)-2-((1-ethyl-3-methyl-1H-pyrazole-5-carbonyl) sub Amino)-3-methyl-2,3-dihydro-1H-benzo(d)imidazol-1-yl)but-2-en-1-yl)-4-(1-hydroxyethyl)- 3-Methyl-1,3-dihydro-2H-benzo[d]imidazol-2-ylidene)-3-methyl-1H-pyrazole-5-carboxamide; N,N'-((2E,2'E)-butane-1,4-diylbis(3-methyl-1,3-dihydro-2H-benzo[d]imidazol-1-yl- 2-subunit)) bis(1-ethyl-3-methyl-1H-pyrazole-5-carboxamide); 1-Ethyl-N-((E)-3-(4-((E)-2-((1-ethyl-3-methyl-1H-pyrazole-5-carbonyl)imino)- 3-methyl-2,3-dihydro-1H-benzo[d]imidazol-1-yl)butyl)-4-(hydroxymethyl)-1-methyl-1,3-dihydro-2H -Benzo[d]imidazole-2-ylidene)-3-methyl-1H-pyrazole-5-carboxamide; 1-Ethyl-N-((E)-3-(4-((E)-2-((1-ethyl-3-methyl-1H-pyrazole-5-carbonyl)imino)- 3-Methyl-2,3-dihydro-1H-benzo[d]imidazol-1-yl)butyl)-1-methyl-4-(morpholinylmethyl)-1,3-dihydro -2H-benzo[d]imidazole-2-ylidene)-3-methyl-1H-pyrazole-5-carboxamide; 1-Ethyl-N-((E)-3-(4-((E)-2-((1-ethyl-3-methyl-1H-pyrazole-5-carbonyl)imino)- 3-Methyl-2,3-dihydro-1H-benzo[d]imidazol-1-yl)butyl)-1-methyl-4-(hexahydropyridin-1-ylmethyl)-1, 3-Dihydro-2H-benzo[d]imidazole-2-ylidene)-3-methyl-1H-pyrazole-5-carboxamide; N-((E)-1-(4-((E)-7-((3-oxa-6-azabicyclo[3.1.1]hept-6-yl)methyl)-2-( (1-Ethyl-3-methyl-1H-pyrazole-5-carbonyl)imino)-3-methyl-2,3-dihydro-1H-benzo(d)imidazol-1-yl) Butyl)-3-methyl-1,3-dihydro-2H-benzo(d)imidazol-2-ylidene)-1-ethyl-3-methyl-1H-pyrazole-5-methyl amine; 1-Ethyl-N-((E)-1-(4-((E)-2-((1-ethyl-3-methyl-1H-pyrazole-5-carbonyl)imino)- 3-Methyl-2,3-dihydro-1H-benzo[d]imidazol-1-yl)butyl)-4-(hydroxymethyl)-3-methyl-1,3-dihydro-2H -Benzo[d]imidazole-2-ylidene)-3-methyl-1H-pyrazole-5-carboxamide; 1-Ethyl-N-((E)-1-(4-((E)-2-((1-ethyl-3-methyl-1H-pyrazole-5-carbonyl)imino)- 3-Methyl-2,3-dihydro-1H-benzo[d]imidazol-1-yl)butyl)-3-methyl-4-(morpholinylmethyl)-1,3-dihydro -2H-benzo[d]imidazole-2-ylidene)-3-methyl-1H-pyrazole-5-carboxamide; 1-Ethyl-N-((E)-3-((2R,5R)-5-((E)-2-((1-ethyl-3-methyl-1H-pyrazole-5-carbonyl )Imino)-3-methyl-2,3-dihydro-1H-benzo(d)imidazol-1-yl)hex-2-yl)-4-(hydroxymethyl)-1-methyl -1,3-Dihydro-2H-benzo[d]imidazole-2-ylidene)-3-methyl-1H-pyrazole-5-carboxamide; 1-Ethyl-N-((E)-3-((2R,5R)-5-((E)-2-((1-ethyl-3-methyl-1H-pyrazole-5-carbonyl )Imino)-3-methyl-2,3-dihydro-1H-benzo[d]imidazol-1-yl)hex-2-yl)-1-methyl-4-(morpholinylmethyl) Group)-1,3-dihydro-2H-benzo[d]imidazol-2-ylidene)-3-methyl-1H-pyrazole-5-carboxamide; 1-Ethyl-N-((E)-3-((2S,5S)-5-((E)-2-((1-ethyl-3-methyl-1H-pyrazole-5-carbonyl )Imino)-3-methyl-2,3-dihydro-1H-benzo(d)imidazol-1-yl)hex-2-yl)-4-(hydroxymethyl)-1-methyl -1,3-Dihydro-2H-benzo[d]imidazole-2-ylidene)-3-methyl-1H-pyrazole-5-carboxamide; 1-Ethyl-N-((E)-3-((2S,5S)-5-((E)-2-((1-ethyl-3-methyl-1H-pyrazole-5-carbonyl )Imino)-3-methyl-2,3-dihydro-1H-benzo[d]imidazol-1-yl)hex-2-yl)-1-methyl-4-(morpholinylmethyl) Group)-1,3-dihydro-2H-benzo[d]imidazol-2-ylidene)-3-methyl-1H-pyrazole-5-carboxamide; 1-Ethyl-N-((E)-3-((2S,5R)-5-((E)-2-((1-ethyl-3-methyl-1H-pyrazole-5-carbonyl )Imino)-3-methyl-2,3-dihydro-1H-benzo(d)imidazol-1-yl)hex-2-yl)-4-(hydroxymethyl)-1-methyl -1,3-Dihydro-2H-benzo[d]imidazole-2-ylidene)-3-methyl-1H-pyrazole-5-carboxamide; 1-Ethyl-N-((E)-3-((2S,5R)-5-((E)-2-((1-ethyl-3-methyl-1H-pyrazole-5-carbonyl )Imino)-3-methyl-2,3-dihydro-1H-benzo[d]imidazol-1-yl)hex-2-yl)-1-methyl-4-(morpholinylmethyl) Group)-1,3-dihydro-2H-benzo[d]imidazol-2-ylidene)-3-methyl-1H-pyrazole-5-carboxamide; 1-Ethyl-N-((E)-3-((2R,5S)-5-((E)-2-((1-ethyl-3-methyl-1H-pyrazole-5-carbonyl )Imino)-3-methyl-2,3-dihydro-1H-benzo(d)imidazol-1-yl)hex-2-yl)-4-(hydroxymethyl)-1-methyl -1,3-Dihydro-2H-benzo[d]imidazole-2-ylidene)-3-methyl-1H-pyrazole-5-carboxamide; 1-Ethyl-N-((E)-3-((2R,5S)-5-((E)-2-((1-ethyl-3-methyl-1H-pyrazole-5-carbonyl )Imino)-3-methyl-2,3-dihydro-1H-benzo[d]imidazol-1-yl)hex-2-yl)-1-methyl-4-(morpholinylmethyl) Group)-1,3-dihydro-2H-benzo[d]imidazol-2-ylidene)-3-methyl-1H-pyrazole-5-carboxamide; N-((E)-1-((E)-4-((E)-7-(1,2-dihydroxyethyl)-2-((1-ethyl-3-methyl-1H- Pyrazol-5-carbonyl)imino)-3-methyl-2,3-dihydro-1H-benzo(d)imidazol-1-yl)but-2-en-1-yl)-3- Methyl-1,3-dihydro-2H-benzo[d]imidazole-2-ylidene)-1-ethyl-3-methyl-1H-pyrazole-5-carboxamide; 1-Ethyl-N-((E)-3-((E)-4-((E)-2-((1-ethyl-3-methyl-1H-pyrazole-5-carbonyl) sub Amino)-3-methyl-2,3-dihydro-1H-benzo(d)imidazol-1-yl)but-2-en-1-yl)-4-(1-hydroxy-2-? (Hydroxyethyl)-1-methyl-1,3-dihydro-2H-benzo[d]imidazol-2-ylidene)-3-methyl-1H-pyrazole-5-carboxamide; 1-Ethyl-N-((E)-3-((E)-4-((E)-2-((1-ethyl-3-methyl-1H-pyrazole-5-carbonyl) sub Amino)-3-methyl-7-(morpholinylmethyl)-2,3-dihydro-1H-benzo(d)imidazol-1-yl)but-2-en-1-yl)- 4-(Hydroxymethyl)-1-methyl-1,3-dihydro-2H-benzo[d]imidazole-2-ylidene)-3-methyl-1H-pyrazole-5-carboxamide ； 1-Ethyl-N-((E)-3-((E)-4-((E)-2-((1-ethyl-3-methyl-1H-pyrazole-5-carbonyl) sub Amino)-1-methyl-1,2-dihydro-3H-imidazo[4,5-b]pyridin-3-yl)but-2-en-1-yl)-1-methyl-4 -(Morpholinylmethyl)-1,3-dihydro-2H-benzo[d]imidazole-2-ylidene)-3-methyl-1H-pyrazole-5-carboxamide; 1-Ethyl-N-((E)-3-((E)-4-((E)-2-((1-ethyl-3-methyl-1H-pyrazole-5-carbonyl) sub Amino)-1-methyl-1,2-dihydro-3H-imidazo[4,5-c]pyridin-3-yl)but-2-en-1-yl)-1-methyl-4 -(Morpholinylmethyl)-1,3-dihydro-2H-benzo[d]imidazole-2-ylidene)-3-methyl-1H-pyrazole-5-carboxamide; 1-Ethyl-N-((E)-3-((E)-4-((E)-2-((1-ethyl-3-methyl-1H-pyrazole-5-carbonyl) sub Amino)-3-methyl-2,3-dihydro-1H-imidazo[4,5-c]pyridin-1-yl)but-2-en-1-yl)-1-methyl-4 -(Morpholinylmethyl)-1,3-dihydro-2H-benzo[d]imidazole-2-ylidene)-3-methyl-1H-pyrazole-5-carboxamide; 1-Ethyl-N-((E)-3-((E)-4-((Z)-2-((1-ethyl-3-methyl-1H-pyrazole-5-carbonyl) sub Amino)-3-methyl-2,3-dihydro-1H-imidazo[4,5-b]pyridin-1-yl)but-2-en-1-yl)-1-methyl-4 -(Morpholinylmethyl)-1,3-dihydro-2H-benzo[d]imidazole-2-ylidene)-3-methyl-1H-pyrazole-5-carboxamide; 1-Ethyl-N-((E)-3-((E)-4-((E)-2-((1-ethyl-3-methyl-1H-pyrazole-5-carbonyl) sub Amino)-3-methyl-4-(morpholinylmethyl)-2,3-dihydro-1H-benzo(d)imidazol-1-yl)but-2-en-1-yl)- 1-Methyl-4-(morpholinylmethyl)-1,3-dihydro-2H-benzo[d]imidazol-2-ylidene)-3-methyl-1H-pyrazole-5-methyl Amide Or its salt.

The compound of formula (I) or a salt thereof, specifically a pharmaceutically acceptable salt, is a modulator of STING. Therefore, the present invention provides a compound of formula (I) or a salt thereof, particularly a pharmaceutically acceptable salt thereof, for use in therapy. The present invention specifically provides the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof as an active therapeutic substance for the treatment of diseases or disorders mediated by STING, in particular for the treatment of the agonist effect of STING Or diseases mediated by antagonism. The present invention also provides a compound of formula (I) or a salt thereof, specifically a pharmaceutically acceptable salt thereof, which is used in the manufacture of a medicament for treating STING-mediated diseases or disorders.

The present invention also relates to a method of regulating STING, which method comprises contacting a cell with a compound of formula (I) or a salt thereof, specifically a pharmaceutically acceptable salt. The present invention further relates to a method for treating STING-mediated diseases or disorders, which comprises administering a therapeutically effective amount of a compound of formula (I) or a salt thereof to a patient (human or other mammals, in particular human) in need, In particular, a pharmaceutically acceptable salt. These STING-mediated diseases or conditions include inflammation, allergic and autoimmune diseases, infectious diseases (including hepatitis B virus (HBV) infection and/or hepatitis D virus (HDV) infection), cancer, and precancerous syndrome , Metabolic diseases and cardiovascular diseases. In addition, modulators of STING can be used as immunogenic compositions or vaccine adjuvants.

The present invention further relates to a pharmaceutical composition, which comprises a compound of formula (I) or a salt thereof, a pharmaceutically acceptable salt in particular, and a pharmaceutically acceptable excipient. In particular, the present invention relates to a pharmaceutical composition for the treatment of STING-mediated diseases or conditions, wherein the composition comprises a compound of formula (I) or a salt thereof, a pharmaceutically acceptable salt, and a pharmaceutically acceptable salt. Accepted excipients.

definition .

Unless the context requires otherwise, as used in this specification and the appended patent scope, the following terms shall have the meanings indicated.

The alternative definitions for each group and substituent of formula (I) provided throughout this specification are intended to specifically describe each compound type disclosed herein, as well as the groups of one or more compound types. The scope of the present invention includes any combination of the definitions of these groups and substituents. Those familiar with the art should understand that the compounds of the present invention are only those compounds that are expected to be "chemically stable".

Those skilled in the art should understand that the compounds of the present invention may exist in other tautomeric forms (including zwitterionic forms) or isomeric forms. All tautomeric (including zwitterionic forms) and isomeric forms of the various formulae and compounds described herein are intended to be encompassed within the scope of the present invention.

Those familiar with the art should also understand that the compounds of the present invention can exist in the following forms: tautomeric (or isomeric) forms, including (but not limited to) formula (A), formula (B) and/or formula ( C); or zwitterionic form, including (but not limited to) formula (D) or formula (E). In formulas (B), (C), (D) or (E), each occurrence of R is independently any suitable substituent on H or nitrogen, such as an alkyl group.

The chemical names provided for the intermediate compounds described herein and/or the compounds of the present invention may refer to any of the tautomeric/isomeric manifestations of these compounds (in some cases, these alternatives The name is provided with the experiment). It should be understood that any reference to the named compound (intermediate compound or compound of the present invention) or structure drawing compound (intermediate compound or compound of the present invention) is intended to cover all tautomeric/isomeric forms of these compounds (Including zwitterionic forms) and any mixtures thereof.

As used herein, the term "alkyl" represents a saturated linear or branched hydrocarbon group having the specified number of carbon atoms. The term "C ₁ -C ₄ alkyl" refers to a linear or branched alkyl moiety containing 1 to 4 carbon atoms. Exemplary alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, pentyl, and hexyl.

When a substituent term such as "alkyl" is used in combination with another substituent term, for example, as in "hydroxy (C ₁ -C ₄ alkyl)", the linking substituent term (e.g., alkyl) is intended to cover the divalent Part, where the point of attachment is via the attachment substituent. Examples of "hydroxyl (C ₁ -C ₄ alkyl)" include, but are not limited to, hydroxymethyl, hydroxyethyl, and hydroxyisopropyl.

"Alkenyl" refers to a straight or branched chain hydrocarbon group having the specified number of carbon atoms and at least 1 and at most 3 carbon-carbon double bonds. Examples include vinyl and propenyl.

"Alkoxy-" or "(alkyl)oxy-" refers to "alkyl-oxy-", which contains an alkyl moiety, has a specified number of carbon atoms, and is connected via an oxygen linking atom. For example, the term "C ₁ -C ₄ alkoxy-" represents a saturated linear or branched hydrocarbon moiety having at least 1 and at most 4 carbon atoms connected via an oxygen linking atom. Exemplary "C ₁ -C ₄ alkoxy-" or "(C ₁ -C ₄ alkyl)oxy-" include (but are not limited to) methoxy, ethoxy, n-propoxy, isopropoxy Group, n-butoxy, second butoxy and tertiary butoxy.

A carbocyclic group or part is a cyclic group or part in which the ring members are carbon atoms, which may be saturated, partially unsaturated (non-aromatic) or fully unsaturated (aromatic).

"Cycloalkyl" refers to a non-aromatic saturated hydrocarbon ring group containing the specified number of carbon atoms in the ring. For example, the term "C ₃ -C ₆ cycloalkyl" refers to a cyclic group having 3 to 6 ring carbon atoms. Exemplary "C ₃ -C ₆ cycloalkyl" includes cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

A heterocyclic group or part is a cyclic group or part having atoms of at least two different elements as ring members. The cyclic group or part may be saturated, partially unsaturated (non-aromatic) or completely unsaturated Saturated (aromatic).

"Heteroatom" refers to a nitrogen, sulfur or oxygen atom, such as a nitrogen atom or an oxygen atom.

"Heterocycloalkyl" refers to a non-aromatic monocyclic or bicyclic ring containing 3 to 10 ring atoms and containing one or more (usually one or two) heteroatom ring members independently selected from oxygen, sulfur and nitrogen. Ring group. The point of attachment of the heterocycloalkyl group can be any suitable carbon or nitrogen atom.

Examples of "heterocycloalkyl" include (but are not limited to) aziridinyl, thiiridine, oxetanyl, azetidinyl, oxetanyl, thietane Alkyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothienyl, 1,3-dioxolane, hexahydropyridyl, hexahydropyrazinyl, tetrahydropyranyl, dihydropyranyl, Tetrahydrothiopyranyl, 1,3-dioxanyl, 1,4-dioxanyl, 1,3-oxathiolanyl, 1,3-oxathiolanyl, 1, 3-Dithianyl, 1,4-oxathiolanyl, 1,4-oxathiolanyl, 1,4-dithianyl, morpholinyl, thiomorpholinyl and hexa Hydrogen-1 H -1,4-diazepine.

Examples of "4-membered to 7-membered heterocycloalkyl" include oxetanyl, thietane and azetidinyl.

Examples of "4-membered to 7-membered heterocycloalkyl" include the compounds N-((E)-1-((E)-4-((E)-7-((3-oxo Hetero-6-azabicyclo[3.1.1]hepta-6-yl)methyl)-2-((1-ethyl-3-methyl-1H-pyrazole-5-carbonyl)imino) -3-Methyl-2,3-dihydro-1H-benzo[d]imidazol-1-yl)but-2-en-1-yl)-3-methyl-1,3-dihydro-2H -Benzo[d]imidazole-2-ylidene)-1-ethyl-3-methyl-1H-pyrazole-5-carboxamide and N-((E)-4-((3-oxa -6-Azabicyclo[3.1.1]hept-6-yl)methyl)-1-((E)-4-((E)-2-((1-ethyl-3-methyl- 1H-pyrazole-5-carbonyl)imino)-3-methyl-2,3-dihydro-1H-benzo(d)imidazol-1-yl)but-2-en-1-yl)- Found in 3-methyl-1,3-dihydro-2H-benzo[d]imidazole-2-ylidene)-1-ethyl-3-methyl-1H-pyrazole-5-carboxamide The other groups.

The term "5-membered to 6-membered heterocycloalkyl" represents a non-aromatic monocyclic group containing 5 or 6 ring atoms including one or two heteroatoms independently selected from oxygen, sulfur and nitrogen. Illustrative examples of 5-membered to 6-membered heterocycloalkyl include, but are not limited to, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothienyl, tetrahydropyranyl, tetrahydrothiopyranyl, hexahydropyridinyl, hexahydro Pyrazinyl, morpholinyl and thiomorpholinyl.

"Heteroaryl" refers to an aromatic monocyclic or bicyclic group containing 5 to 10 ring atoms, including 1 to 4 heteroatoms independently selected from nitrogen, oxygen and sulfur, wherein at least a part of the group It is aromatic. For example, this term encompasses bicyclic heterocyclic aryl groups containing a benzene ring fused to a heterocyclic moiety or a heteroaryl ring moiety fused to a carbocyclic moiety. The point of attachment of "heteroaryl" can be any suitable carbon or nitrogen atom.

The term "5-membered to 6-membered heteroaryl" represents an aromatic monocyclic group containing 5 or 6 ring atoms, including at least 1 carbon atom and 1 to 4 heteroatoms independently selected from nitrogen, oxygen and sulfur group. The selected 5-membered heteroaryl group contains 1 nitrogen, oxygen or sulfur ring heteroatom, and optionally 1, 2 or 3 additional nitrogen ring atoms. The selected 6-membered heteroaryl groups contain 1, 2 or 3 nitrogen ring heteroatoms. Examples of 5-membered heteroaryl groups include furyl (furyl, furanyl), thienyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, thiazolyl, isothiazolyl, thiadiazolyl, oxa Azolyl, isoxazolyl and oxadiazolyl. The selected 6-membered heteroaryl groups include pyridinyl (pyridyl), pyrazinyl, pyrimidinyl, tazinyl and triazinyl.

The term "9-membered to 10-membered heteroaryl group" refers to an aromatic bicyclic group containing 9 or 10 ring atoms, including 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. Examples of 9-membered heteroaryl groups (6,5 fused heteroaryl groups) include benzothienyl, benzofuranyl, indolyl, indolinyl (indolinyl), isoindolyl, iso Indolinyl, indazolyl, isobenzofuranyl, 2,3-dihydrobenzofuranyl, benzoxazolyl, benzisoxazolyl, benzothiazolyl, benzisothiazolyl, Benzimidazolyl, benzoxadiazolyl, benzothiadiazolyl, benzotriazolyl, purinyl, imidazopyridyl, pyrazolopyridyl, triazolopyridyl and 1,3-benzene And dioxolyl.

Examples of 10-membered heteroaryl (6,6-fused heteroaryl) include quinolinyl (quinolinyl, quinolyl), isoquinolyl, phthalazinyl, naphthyridinyl (1,5-naphthyridinyl, 1, 6-naphthyridinyl, 1,7-naphthyridinyl, 1,8-naphthyridinyl), quinazolinyl, quinolinyl, 4H-quinazinyl, 1,2,3,4-tetrahydroquine Linyl (tetrahydroquinolinyl), 1,2,3,4-tetrahydroisoquinolinyl (tetrahydroisoquinolinyl), prolinyl, pterridinyl and 2,3-dihydrobenzo[ b] [1,4] Dioxanyl.

"Pendant oxy" represents the oxygen moiety bonded by a double bond; for example, if it is directly connected to a carbon atom, it forms a carbonyl moiety (C=O).

"Hydroxy (hydroxyl)" is intended to mean the group -OH.

As used herein, the term "cyano" refers to the nitrile group -C≡N.

As used herein, the term "optionally substituted" indicates that a group (e.g., alkyl, cycloalkyl, alkoxy, heterocycloalkyl, aryl, or heteroaryl) or ring or part may be unsubstituted, or The group, ring or part may be substituted with one or more substituents as defined in the substituent definitions (A, R ^3, etc.) provided herein. In the case where a group can be selected from multiple alternative groups, the selected groups may be the same or different.

The term "independently" means that where more than one substituent is selected from multiple possible substituents, those substituents may be the same or different.

The term "pharmaceutically acceptable" refers to those compounds that are suitable for use in contact with human and animal tissues within the scope of reasonable medical judgment without excessive toxicity, irritation or other problems or complications and commensurate with a reasonable benefit/risk ratio, Materials, compositions and dosage forms.

As used herein, the term "compound(s) of the invention (compound(s) of the invention or compound(s) of this invention)" means a compound of formula (I) as defined herein, which is in any form, that is, any mutual Tautomeric/isomeric form, any salt or non-salt form (for example, in the form of free acid or base, or in the form of a salt, specifically its pharmaceutically acceptable salt form) and any physical form (for example, including non-solid Forms (such as liquid or semi-solid forms) and solid forms (such as amorphous or crystalline forms, specific polymorphic forms, solvate forms, including hydrate forms (such as monohydrate, dihydrate, and hemihydrate)) and Mixtures of various forms.

Therefore, the present invention includes compounds of formula (I) in any salt or non-salt form and any physical form and mixtures of various forms as defined herein. Although these forms are included in the present invention, it should be understood that the compound of formula (I) in any salt or non-salt form and in any physical form thereof as defined herein may have different degrees of activity, different Bioavailability and different disposal properties.

The compounds of the present invention may contain one or more asymmetric centers (also called chiral centers), such as chiral carbons or chiral -SO- moieties. The compounds of the present invention containing one or more chiral centers can exist in the following forms: racemic mixtures, diastereoisomeric mixtures, enantiomerically enriched mixtures, diastereomeric enriched mixtures, or enantiomers or non The individual stereoisomers of the mirror image isomers are pure.

The stereochemistry of the chiral center present in the compound of the present invention is usually indicated in the compound name and/or in the chemical structure illustrated herein. Where the stereochemistry of the chiral centers present in the compounds of the invention or in any chemical structure illustrated herein is not specified, the structure is intended to encompass any stereoisomers and all mixtures thereof. Therefore, the present invention covers all isomers of the compounds described herein or compounds of formula (I) and their salts, whether as individual isomers separated to be substantially free of other isomers (ie pure) or as individual isomers. Mixtures (ie racemates and racemic mixtures). Individual isomers that are separated to be substantially free of other isomers (i.e., pure) can be separated so that less than 10%, specifically less than about 1%, for example, less than about 0.1% of other isomers are present Things.

Individual stereoisomers (or mixtures of stereoisomers that can be enriched) of the compounds of the present invention can be resolved using methods known to those skilled in the art. For example, this resolution can be implemented by: (1) by forming diastereomer salts, complexes or other derivatives; (2) by selectively reacting with stereoisomer-specific reagents , For example, by enzymatic oxidation or reduction; or (3) by performing gas in a chiral environment (for example, on a chiral carrier such as silica with a bound chiral ligand or in the presence of a chiral solvent) Phase-liquid phase or liquid chromatography. It should be understood that when the desired enantiomer is converted into another chemical entity by one of the aforementioned separation procedures, another step is required to release the desired form. Alternatively, specific enantiomers can be synthesized by asymmetric synthesis using optically active reagents, substrates, catalysts, or solvents, or by converting one enantiomer into another enantiomer by asymmetric transformation.

As used herein, "cleavable bond" means any chemical bond that can be broken. In certain embodiments, the cleavable bond system is selected from the following: amide bond, polyamide bond, ester bond, ether bond, phosphodiester bond, phosphate bond, urethane bond, disulfide bond or Peptide bond.

As used herein, "modulation" means a change in the amount or quality of a molecule, function, or activity when compared with the amount or quality of the molecule, function, or activity before the adjustment.

As used herein, "pharmaceutically acceptable carrier or diluent" means any substance suitable for administration to animals. In certain embodiments, the pharmaceutically acceptable carrier or diluent is sterile saline. In some embodiments, the sterile saline is pharmaceutical grade saline.

酸酯鍵或一些其他可裂解鍵。As used herein, "prodrug" refers to an inactive or less active form of a compound that undergoes some biological transformations in vivo through chemical or enzymatic cleavage when administered to an individual, thereby enabling the delivery of more active or more active forms The compound (such as drugs). The prodrug may include a cleavable moiety, where the cleavable moiety is removed or metabolized to form a more active or more active compound. The cleavable moiety can be linked to the active form of the compound by a cleavable bond. The cleavable bond includes, but is not limited to, an ester bond, an amide bond, a sulfonamide bond, an amine bond, an imine bond, an ether bond, and a sulfur bond. Ether bond, disulfide bond, glycosidic bond, phosphate bond, urethane bond, carbonate bond or

An acid ester bond or some other cleavable bond.

As used herein, the term "effective amount" means the amount of a drug or drug substance or pharmaceutical agent that will elicit a biological or medical response in a tissue, system, animal, or human, for example, as sought by a researcher or clinician. In addition, the term "therapeutically effective amount" means any of the following amounts: this amount causes improved treatment, cure, prevention or amelioration of the disease, disorder, or side effect, or the rate of progression of the disease or disorder, compared to the corresponding individual who did not receive the amount. It is lowered. The term also includes within its scope the amount effective to enhance normal physiological functions.

As used herein, the term "HBV" means mammalian hepatitis B virus, including human hepatitis B virus. The term encompasses hepatitis B virus, in particular the geographic genotype of human hepatitis B virus, and variant strains of the geographic genotype of hepatitis B virus.

As used herein, "hepatitis B-related conditions" or "HBV-related conditions" means any aggravated by, caused by, related to, related to, or traceable to hepatitis B infection, exposure, or disease Disease, biological condition, medical condition or event. When combined with a positive test for the presence of hepatitis B virus, hepatitis B virus antigen, or a positive test for the presence of antibodies specific to hepatitis B virus antigen, the term hepatitis B-related conditions includes jaundice, Liver cancer, liver inflammation, liver fibrosis, liver cirrhosis, liver failure, diffuse hepatocellular inflammatory disease, phagocytosis syndrome, serum hepatitis, HBV viremia, and symptoms that may include any or all of the following Symptoms: flu-like illness, weakness, pain, headache, fever, loss of appetite, diarrhea, jaundice, nausea and vomiting, pain in the liver area, clay-colored or gray stools, itchy whole body, and dark urine.

(I) 其中A係C₂ -C₆ 烷基或C₂ -C₆ 烯基， 其中該C₂ -C₆ 烷基或該C₂ -C₆ 烯基各自獨立地視情況由1至2個選自-R^c 、-OH及-OR^c 之取代基取代； R¹ 及R² 獨立地不存在或係C₁ -C₃ 烷基； W¹ 、X¹ 、Y¹ 及Z¹ 各自獨立地係-CR³ 、-CR³ ′、-CR³ ″、-CR³ ′″或N，條件係W¹ 、X¹ 、Y¹ 及Z¹ 中不超過兩者可係N； W² 、X² 、Y² 及Z² 各自獨立地係-CR⁴ 、-CR⁴ ′、-CR⁴ ″、-CR⁴ ′″或N，條件係W² 、X² 、Y² 及Z² 中不超過兩者可係N； R³ 、R³ ′、R³ ″、R³ ′″、R⁴ 、R⁴ ′、R4″、R⁴ ′″、R⁹ 、R¹⁰ 、R¹¹ 及R¹² 各自獨立地選自H、C_1-4 烷氧基、C_1-4 烷基、-COO-C_1-4 烷基、-C_4-7 雜環烷基、-C_1-4 烷基C_4-7 雜環烷基及-OC_1-4 烷基C_4-7 雜環烷基，其中該-C_4-7 雜環烷基、該-C_1-4 烷基C_4-7 雜環烷基之-C_4-7 雜環烷基或該-OC_1-4 烷基C_4-7 雜環烷基之C_4-7 雜環烷基包含一或多個選自O及N之雜原子， 其中該C_1-4 烷基、C_1-4 烷氧基、該-C_1-4 烷基C_4-7 雜環烷基之C_1-4 烷基或該-OC_1-4 烷基C_4-7 雜環烷基之C_1-4 烷基視情況由1至4個獨立地選自-R^c 、-OH及-OR^c 之取代基取代，且 其中該C_4-7 雜環烷基、該-C_1-4 烷基C_4-7 雜環烷基之C_4-7 雜環烷基或該-OC_1-4 烷基C_4-7 雜環烷基之C_4-7 雜環烷基由1至4個取代基R’、R”、R”’及R””取代，其中R’、R”、R’’’及R””各自獨立地選自-R^c 、-OH及-OR^c ，或R’、R”、R”’及R””中之任兩者可與其所連接之環原子組合以形成3員至7員環； R⁵ 及R⁶ 獨立地係C₁ -C₄ 烷基； R⁷ 及R⁸ 各自獨立地係H或C₁ -C₄ 烷基； 每一R^c 獨立地係C₁ -C₄ 烷基，其視情況由選自-OH或C_1-4 烷氧基之取代基取代； 或其鹽。An embodiment of the present invention relates to a compound of formula (I):

(I) wherein A is a C ₂ -C ₆ alkyl group or a C ₂ -C ₆ alkenyl group, wherein the C ₂ -C ₆ alkyl group or the C ₂ -C ₆ alkenyl group is independently from 1 to 2 as appropriate Substituents selected from -R ^c , -OH and -OR ^c ; R ¹ and R ^{2 are} independently absent or are C ₁ -C ₃ alkyl groups; W ¹ , X ¹ , Y ¹ and Z ¹ are each independently It is -CR ³ , -CR ³ ′, -CR ³ ″, -CR ³ ′″ or N, and the condition is that no more than two ^{of W 1} , X ¹ , Y ¹ and Z ^{1 can be N; W 2} , X ² , Y ² and Z ² are each independently -CR ⁴ , -CR ⁴ ′, -CR ⁴ ″, -CR ⁴ ′″ or N, and the condition is that no more than two ^{of W 2} , X ² , Y ² and Z ² Can be N; R ³ , R ³ ′, R ³ ″, R ³ ′″, R ⁴ , R ⁴ ′, R4 ″, R ⁴ ′″, R ⁹ , R ¹⁰ , R ¹¹ and R ¹² are each independently selected From H, C _1-4 alkoxy, C _1-4 alkyl, -COO-C _1-4 alkyl, -C _4-7 heterocycloalkyl, -C _1-4 alkyl C _4-7 hetero Cycloalkyl and -OC _1-4 alkyl C _4-7 heterocycloalkyl, wherein the -C _4-7 heterocycloalkyl, the -C _1-4 alkyl C _4-7 heterocycloalkyl- C _4-7 heterocycloalkyl, or the -OC _1-4 alkyl C _4-7 heterocycloalkyl, C _4-7 heterocycloalkyl comprising of one or more of the heteroatoms selected from O and N atoms, wherein the C _1-4 alkyl, C _1-4 alkoxy, -C _1-4 alkyl which C _4-7 heterocycloalkyl, C _1-4 alkyl or the -OC _1-4 alkyl which C _{4- 7 The C 1-4} alkyl group of the heterocycloalkyl group is optionally substituted by 1 to 4 substituents independently selected from -R ^c , -OH and -OR ^c , and wherein the C _4-7 heterocycloalkyl group, -C _1-4 alkyl which C _4-7 heterocycloalkyl, C _4-7 heterocycloalkyl, or the -OC _1-4 alkyl which C _4-7 heterocycloalkyl, C _4-7 heterocycloalkyl of The group is substituted by 1 to 4 substituents R', R", R"' and R"", wherein R', R", R"' and R"" are each independently selected from -R ^c , -OH and -OR ^c , or any two of R', R”, R”' and R”” can be combined with the ring atoms to which they are connected to form a 3- to 7-membered ring; R ⁵ and R ^{6 are} independently C ₁ -C ₄ alkyl; R ⁷ and R ⁸ are each independently H or C ₁ -C ₄ alkyl; each R ^{c is} independently C ₁ -C ₄ alkyl, which is optionally selected from -OH or C _{Substituent substitution of 1-4} alkoxy; or a salt thereof.

An embodiment of the present invention relates to a compound of formula (I), wherein: wherein A is C ₂ alkenylene; R ¹ and R ² are -CH ₂ -; Y ¹ , Y ² , X ¹ and X ² are -CH -; W ¹ , W ² , Z ¹ and Z ² are each independently selected from: -CH-, -C(aza-methyl)-, -C(3-oxa-6-azabicyclo[3.1 .1]Heptane-methyl)-, -C(methoxymethyl)-, -C(1-hydroxyethyl)-, -C(C(O)OCH ₃ )-, -C(methoxy Group)-, -C(3-hydroxypropoxy)-, -C(hydroxymethyl)-, -C(morpholinylmethyl)-, -C(1,2-dihydroxyethyl)- and -C(1-hydroxy-2-morpholinoethyl)-; R ⁵ and R ⁶ are -CH ₃ ; R ⁷ and R ⁸ are C ₂ alkyl groups; R ⁹ , R ¹⁰ , R ¹¹ and R ¹² are each Independently selected from: H and CH ₃ ; or a salt thereof, suitably a pharmaceutically acceptable salt thereof.

One embodiment provides a compound of formula (I) ^{wherein R 1} and R ² are -CH ₂ -and R ⁵ and R ⁶ are -CH _3.

One embodiment provides wherein W ¹ , X ¹ , Y ¹ and Z ¹ are each independently -CR ³ , -CR ³ ′, -CR ³ ″ or -CR ³ ′″ and W ² , X ² , Y ² and Z ² each independently is a compound of formula (I) ^{of -CR 4} , -CR ⁴ ′, -CR ⁴ ”or -CR ^{4 ′”.}

One embodiment provides a compound of formula (I) ^{wherein W 1} is CR ³ and W ² is CR ^{4 , wherein CR 3} and CR ⁴ are each independently selected from -C _4-7 heterocycloalkyl, -C _1-4 alkane Group C _4-7 heterocycloalkyl and -OC _1-4 alkyl C _4-7 heterocycloalkyl.

One embodiment provides a compound of formula (I) ^{wherein W 1} is CR ³ and W ² is CR ^{4 , wherein R 3} and CR ⁴ are each independently selected from C _1-4 alkoxy or C _1-4 alkyl, wherein The C _1-4 alkyl group or C _1-4 alkoxy group is optionally substituted with 1 to 4 substituents independently selected from -R ^c , -OH and -OR ^c .

One embodiment provides a compound of formula (I) _{wherein A is C 2} -C _{6 alkenyl.}

One example provides a compound of formula (I) _{wherein A is C 2} -C _{6 alkenylene.}

One embodiment provides a compound of formula (I) ^{wherein R 1} and R ² are each -CH ₂ -and A is C _{2 -alkenylene.}

One embodiment provides compounds of formula (I) ^{wherein R 7} and R ⁸ are each independently H or C _{2 alkyl.}

One embodiment provides a compound of formula (I) ^{wherein R 7} and R ⁸ are each a C _{2 alkyl group.}

One embodiment provides a compound of formula (I) ^{wherein R 9} , R ¹⁰ , R ¹¹ and R ¹² are each independently H or -CH _3.

One embodiment provides a compound of formula (I) ^{wherein Y 1} , Y ² , X ¹ and X ^{2 are -CH.}

One embodiment provides a ^{compound of formula (I) wherein W 1} , W ² , Z ¹ and Z ² are each independently selected from the following: H, aza-methyl, 3-oxa-6-azabicyclo [3.1.1] Heptane-methyl, methoxymethyl, 1-hydroxyethyl, -C(O)OCH ₃ , methoxy, 3-hydroxypropoxy, hydroxymethyl, morpholinomethyl Group, 1,2-dihydroxyethyl and 1-hydroxy-2-morpholinoethyl.

In a specific embodiment, a compound selected from the group consisting of: N,N'-((2E,2'E)-((E)-but-2-ene-1,4-diyl)bis(3-methyl-1,3-dihydro-2H-benzo [d] Imidazol-1-yl-2-ylidene)) bis(1-ethyl-3-methyl-1H-pyrazole-5-carboxamide); (E)-2-((1-ethyl-3-methyl-1H-pyrazole-5-carbonyl)imino)-1-((E)-4-((E)-2-(( 1-Ethyl-3-methyl-1H-pyrazole-5-carbonyl)imino)-3-methyl-2,3-dihydro-1H-benzo(d)imidazol-1-yl)butyl -2-en-1-yl)-3-methyl-2,3-dihydro-1H-benzo[d]imidazole-5-carboxylic acid methyl ester; 1-Ethyl-N-((E)-3-((E)-4-((E)-2-((1-ethyl-3-methyl-1H-pyrazole-5-carbonyl) sub Amino)-3-methyl-2,3-dihydro-1H-benzo(d)imidazol-1-yl)but-2-en-1-yl)-4-methoxy-1-methyl -1,3-Dihydro-2H-benzo[d]imidazole-2-ylidene)-3-methyl-1H-pyrazole-5-carboxamide; 1-Ethyl-N-((E)-3-((E)-4-((E)-2-((1-ethyl-3-methyl-1H-pyrazole-5-carbonyl) sub Amino)-7-(3-hydroxypropoxy)-3-methyl-2,3-dihydro-1H-benzo(d)imidazol-1-yl)but-2-en-1-yl) -4-Methoxy-1-methyl-1,3-dihydro-2H-benzo[d]imidazole-2-ylidene)-3-methyl-1H-pyrazole-5-carboxamide; (E)-1-ethyl-N-(3-((E)-4-((E)-2-((1-ethyl-3-methyl-1H-pyrazole-5-carbonyl) sub Amino)-3-methyl-2,3-dihydro-1H-benzo(d)imidazol-1-yl)but-2-en-1-yl)-4-(hydroxymethyl)-1- Methyl-1H-benzo[d]imidazole-2(3H)-ylidene)-3-methyl-1H-pyrazole-5-carboxamide; 1-Ethyl-N-((E)-3-((E)-4-((E)-2-((1-ethyl-3-methyl-1H-pyrazole-5-carbonyl) sub Amino)-3-methyl-2,3-dihydro-1H-benzo(d)imidazol-1-yl)but-2-en-1-yl)-1-methyl-4-(morpholine Methyl)-1,3-dihydro-2H-benzo[d]imidazole-2-ylidene)-3-methyl-1H-pyrazole-5-carboxamide; 1-Ethyl-N-((E)-3-((E)-4-((E)-2-((1-ethyl-3-methyl-1H-pyrazole-5-carbonyl) sub Amino)-3-methyl-2,3-dihydro-1H-benzo(d)imidazol-1-yl)but-2-en-1-yl)-1-methyl-4-(hexahydro Pyridin-1-ylmethyl)-1,3-dihydro-2H-benzo[d]imidazole-2-ylidene)-3-methyl-1H-pyrazole-5-carboxamide; N-((E)-1-((E)-4-((E)-7-(azeppan-1-ylmethyl)-2-((1-ethyl-3-methyl) -1H-pyrazole-5-carbonyl)imino)-3-methyl-2,3-dihydro-1H-benzo(d)imidazol-1-yl)but-2-en-1-yl) -3-Methyl-1,3-dihydro-2H-benzo[d]imidazol-2-ylidene)-1-ethyl-3-methyl-1H-pyrazole-5-carboxamide; N-((E)-1-((E)-4-((E)-7-((3-oxa-6-azabicyclo[3.1.1]heptan-6-yl)methyl) -2-((1-ethyl-3-methyl-1H-pyrazole-5-carbonyl)imino)-3-methyl-2,3-dihydro-1H-benzo[d]imidazole- 1-yl)but-2-en-1-yl)-3-methyl-1,3-dihydro-2H-benzo(d)imidazol-2-ylidene)-1-ethyl-3-methyl Group-1H-pyrazole-5-carboxamide; 1-Ethyl-N-((E)-3-((E)-4-((E)-2-((1-ethyl-3-methyl-1H-pyrazole-5-carbonyl) sub Amino)-3-methyl-2,3-dihydro-1H-benzo(d)imidazol-1-yl)but-2-en-1-yl)-4-(methoxymethyl)- 1-Methyl-1,3-dihydro-2H-benzo[d]imidazole-2-ylidene)-3-methyl-1H-pyrazole-5-carboxamide; 1-Ethyl-N-((E)-3-((E)-4-((E)-2-((1-ethyl-3-methyl-1H-pyrazole-5-carbonyl) sub Amino)-3-methyl-2,3-dihydro-1H-benzo(d)imidazol-1-yl)but-2-en-1-yl)-4-(1-hydroxyethyl)- 1-Methyl-1,3-dihydro-2H-benzo[d]imidazole-2-ylidene)-3-methyl-1H-pyrazole-5-carboxamide; 1-Ethyl-N-((E)-1-((E)-4-((E)-2-((1-ethyl-3-methyl-1H-pyrazole-5-carbonyl) sub Amino)-3-methyl-2,3-dihydro-1H-benzo(d)imidazol-1-yl)but-2-en-1-yl)-4-(hydroxymethyl)-3- Methyl-1,3-dihydro-2H-benzo[d]imidazole-2-ylidene)-3-methyl-1H-pyrazole-5-carboxamide; 1-Ethyl-N-((E)-1-((E)-4-((E)-2-((1-ethyl-3-methyl-1H-pyrazole-5-carbonyl) sub Amino)-3-methyl-2,3-dihydro-1H-benzo(d)imidazol-1-yl)but-2-en-1-yl)-3-methyl-4-(morpholine Methyl)-1,3-dihydro-2H-benzo[d]imidazole-2-ylidene)-3-methyl-1H-pyrazole-5-carboxamide; 1-Ethyl-N-((E)-1-((E)-4-((E)-2-((1-ethyl-3-methyl-1H-pyrazole-5-carbonyl) sub Amino)-3-methyl-2,3-dihydro-1H-benzo(d)imidazol-1-yl)but-2-en-1-yl)-3-methyl-4-(hexahydro Pyridin-1-ylmethyl)-1,3-dihydro-2H-benzo[d]imidazole-2-ylidene)-3-methyl-1H-pyrazole-5-carboxamide; N-((E)-4-((3-oxa-6-azabicyclo[3.1.1]hept-6-yl)methyl)-1-((E)-4-((E) -2-((1-ethyl-3-methyl-1H-pyrazole-5-carbonyl)imino)-3-methyl-2,3-dihydro-1H-benzo[d]imidazole- 1-yl)but-2-en-1-yl)-3-methyl-1,3-dihydro-2H-benzo(d)imidazol-2-ylidene)-1-ethyl-3-methyl Group-1H-pyrazole-5-carboxamide; 1-Ethyl-N-((E)-1-((E)-4-((E)-2-((1-ethyl-3-methyl-1H-pyrazole-5-carbonyl) sub Amino)-3-methyl-2,3-dihydro-1H-benzo(d)imidazol-1-yl)but-2-en-1-yl)-4-(1-hydroxyethyl)- 3-Methyl-1,3-dihydro-2H-benzo[d]imidazol-2-ylidene)-3-methyl-1H-pyrazole-5-carboxamide; N,N'-((2E,2'E)-butane-1,4-diylbis(3-methyl-1,3-dihydro-2H-benzo[d]imidazol-1-yl- 2-subunit)) bis(1-ethyl-3-methyl-1H-pyrazole-5-carboxamide); 1-Ethyl-N-((E)-3-(4-((E)-2-((1-ethyl-3-methyl-1H-pyrazole-5-carbonyl)imino)- 3-methyl-2,3-dihydro-1H-benzo[d]imidazol-1-yl)butyl)-4-(hydroxymethyl)-1-methyl-1,3-dihydro-2H -Benzo[d]imidazole-2-ylidene)-3-methyl-1H-pyrazole-5-carboxamide; 1-Ethyl-N-((E)-3-(4-((E)-2-((1-ethyl-3-methyl-1H-pyrazole-5-carbonyl)imino)- 3-Methyl-2,3-dihydro-1H-benzo[d]imidazol-1-yl)butyl)-1-methyl-4-(morpholinylmethyl)-1,3-dihydro -2H-benzo[d]imidazole-2-ylidene)-3-methyl-1H-pyrazole-5-carboxamide; 1-Ethyl-N-((E)-3-(4-((E)-2-((1-ethyl-3-methyl-1H-pyrazole-5-carbonyl)imino)- 3-Methyl-2,3-dihydro-1H-benzo[d]imidazol-1-yl)butyl)-1-methyl-4-(hexahydropyridin-1-ylmethyl)-1, 3-Dihydro-2H-benzo[d]imidazole-2-ylidene)-3-methyl-1H-pyrazole-5-carboxamide; N-((E)-1-(4-((E)-7-((3-oxa-6-azabicyclo[3.1.1]hept-6-yl)methyl)-2-( (1-Ethyl-3-methyl-1H-pyrazole-5-carbonyl)imino)-3-methyl-2,3-dihydro-1H-benzo(d)imidazol-1-yl) Butyl)-3-methyl-1,3-dihydro-2H-benzo(d)imidazol-2-ylidene)-1-ethyl-3-methyl-1H-pyrazole-5-methyl amine; 1-Ethyl-N-((E)-1-(4-((E)-2-((1-ethyl-3-methyl-1H-pyrazole-5-carbonyl)imino)- 3-Methyl-2,3-dihydro-1H-benzo[d]imidazol-1-yl)butyl)-4-(hydroxymethyl)-3-methyl-1,3-dihydro-2H -Benzo[d]imidazole-2-ylidene)-3-methyl-1H-pyrazole-5-carboxamide; 1-Ethyl-N-((E)-1-(4-((E)-2-((1-ethyl-3-methyl-1H-pyrazole-5-carbonyl)imino)- 3-Methyl-2,3-dihydro-1H-benzo[d]imidazol-1-yl)butyl)-3-methyl-4-(morpholinylmethyl)-1,3-dihydro -2H-benzo[d]imidazole-2-ylidene)-3-methyl-1H-pyrazole-5-carboxamide; 1-Ethyl-N-((E)-3-((2R,5R)-5-((E)-2-((1-ethyl-3-methyl-1H-pyrazole-5-carbonyl )Imino)-3-methyl-2,3-dihydro-1H-benzo(d)imidazol-1-yl)hex-2-yl)-4-(hydroxymethyl)-1-methyl -1,3-Dihydro-2H-benzo[d]imidazole-2-ylidene)-3-methyl-1H-pyrazole-5-carboxamide; 1-Ethyl-N-((E)-3-((2R,5R)-5-((E)-2-((1-ethyl-3-methyl-1H-pyrazole-5-carbonyl )Imino)-3-methyl-2,3-dihydro-1H-benzo[d]imidazol-1-yl)hex-2-yl)-1-methyl-4-(morpholinylmethyl) Group)-1,3-dihydro-2H-benzo[d]imidazol-2-ylidene)-3-methyl-1H-pyrazole-5-carboxamide; 1-Ethyl-N-((E)-3-((2S,5S)-5-((E)-2-((1-ethyl-3-methyl-1H-pyrazole-5-carbonyl )Imino)-3-methyl-2,3-dihydro-1H-benzo(d)imidazol-1-yl)hex-2-yl)-4-(hydroxymethyl)-1-methyl -1,3-Dihydro-2H-benzo[d]imidazole-2-ylidene)-3-methyl-1H-pyrazole-5-carboxamide; 1-Ethyl-N-((E)-3-((2S,5S)-5-((E)-2-((1-ethyl-3-methyl-1H-pyrazole-5-carbonyl )Imino)-3-methyl-2,3-dihydro-1H-benzo[d]imidazol-1-yl)hex-2-yl)-1-methyl-4-(morpholinylmethyl) Group)-1,3-dihydro-2H-benzo[d]imidazol-2-ylidene)-3-methyl-1H-pyrazole-5-carboxamide; 1-Ethyl-N-((E)-3-((2S,5R)-5-((E)-2-((1-ethyl-3-methyl-1H-pyrazole-5-carbonyl )Imino)-3-methyl-2,3-dihydro-1H-benzo(d)imidazol-1-yl)hex-2-yl)-4-(hydroxymethyl)-1-methyl -1,3-Dihydro-2H-benzo[d]imidazole-2-ylidene)-3-methyl-1H-pyrazole-5-carboxamide; 1-Ethyl-N-((E)-3-((2S,5R)-5-((E)-2-((1-ethyl-3-methyl-1H-pyrazole-5-carbonyl )Imino)-3-methyl-2,3-dihydro-1H-benzo[d]imidazol-1-yl)hex-2-yl)-1-methyl-4-(morpholinylmethyl) Group)-1,3-dihydro-2H-benzo[d]imidazol-2-ylidene)-3-methyl-1H-pyrazole-5-carboxamide; 1-Ethyl-N-((E)-3-((2R,5S)-5-((E)-2-((1-ethyl-3-methyl-1H-pyrazole-5-carbonyl )Imino)-3-methyl-2,3-dihydro-1H-benzo(d)imidazol-1-yl)hex-2-yl)-4-(hydroxymethyl)-1-methyl -1,3-Dihydro-2H-benzo[d]imidazole-2-ylidene)-3-methyl-1H-pyrazole-5-carboxamide; 1-Ethyl-N-((E)-3-((2R,5S)-5-((E)-2-((1-ethyl-3-methyl-1H-pyrazole-5-carbonyl )Imino)-3-methyl-2,3-dihydro-1H-benzo[d]imidazol-1-yl)hex-2-yl)-1-methyl-4-(morpholinylmethyl) Group)-1,3-dihydro-2H-benzo[d]imidazol-2-ylidene)-3-methyl-1H-pyrazole-5-carboxamide; N-((E)-1-((E)-4-((E)-7-(1,2-dihydroxyethyl)-2-((1-ethyl-3-methyl-1H- Pyrazol-5-carbonyl)imino)-3-methyl-2,3-dihydro-1H-benzo(d)imidazol-1-yl)but-2-en-1-yl)-3- Methyl-1,3-dihydro-2H-benzo[d]imidazole-2-ylidene)-1-ethyl-3-methyl-1H-pyrazole-5-carboxamide; 1-Ethyl-N-((E)-3-((E)-4-((E)-2-((1-ethyl-3-methyl-1H-pyrazole-5-carbonyl) sub Amino)-3-methyl-2,3-dihydro-1H-benzo(d)imidazol-1-yl)but-2-en-1-yl)-4-(1-hydroxy-2-? (Hydroxyethyl)-1-methyl-1,3-dihydro-2H-benzo[d]imidazol-2-ylidene)-3-methyl-1H-pyrazole-5-carboxamide; 1-Ethyl-N-((E)-3-((E)-4-((E)-2-((1-ethyl-3-methyl-1H-pyrazole-5-carbonyl) sub Amino)-3-methyl-7-(morpholinylmethyl)-2,3-dihydro-1H-benzo(d)imidazol-1-yl)but-2-en-1-yl)- 4-(Hydroxymethyl)-1-methyl-1,3-dihydro-2H-benzo[d]imidazole-2-ylidene)-3-methyl-1H-pyrazole-5-carboxamide ； 1-Ethyl-N-((E)-3-((E)-4-((E)-2-((1-ethyl-3-methyl-1H-pyrazole-5-carbonyl) sub Amino)-1-methyl-1,2-dihydro-3H-imidazo[4,5-b]pyridin-3-yl)but-2-en-1-yl)-1-methyl-4 -(Morpholinylmethyl)-1,3-dihydro-2H-benzo[d]imidazole-2-ylidene)-3-methyl-1H-pyrazole-5-carboxamide; 1-Ethyl-N-((E)-3-((E)-4-((E)-2-((1-ethyl-3-methyl-1H-pyrazole-5-carbonyl) sub Amino)-1-methyl-1,2-dihydro-3H-imidazo[4,5-c]pyridin-3-yl)but-2-en-1-yl)-1-methyl-4 -(Morpholinylmethyl)-1,3-dihydro-2H-benzo[d]imidazole-2-ylidene)-3-methyl-1H-pyrazole-5-carboxamide; 1-Ethyl-N-((E)-3-((E)-4-((E)-2-((1-ethyl-3-methyl-1H-pyrazole-5-carbonyl) sub Amino)-3-methyl-2,3-dihydro-1H-imidazo[4,5-c]pyridin-1-yl)but-2-en-1-yl)-1-methyl-4 -(Morpholinylmethyl)-1,3-dihydro-2H-benzo[d]imidazole-2-ylidene)-3-methyl-1H-pyrazole-5-carboxamide; 1-Ethyl-N-((E)-3-((E)-4-((Z)-2-((1-ethyl-3-methyl-1H-pyrazole-5-carbonyl) sub Amino)-3-methyl-2,3-dihydro-1H-imidazo[4,5-b]pyridin-1-yl)but-2-en-1-yl)-1-methyl-4 -(Morpholinylmethyl)-1,3-dihydro-2H-benzo[d]imidazole-2-ylidene)-3-methyl-1H-pyrazole-5-carboxamide; 1-Ethyl-N-((E)-3-((E)-4-((E)-2-((1-ethyl-3-methyl-1H-pyrazole-5-carbonyl) sub Amino)-3-methyl-4-(morpholinylmethyl)-2,3-dihydro-1H-benzo(d)imidazol-1-yl)but-2-en-1-yl)- 1-Methyl-4-(morpholinylmethyl)-1,3-dihydro-2H-benzo[d]imidazol-2-ylidene)-3-methyl-1H-pyrazole-5-methyl Amide Or its salt.

In a specific embodiment, provided are selected from Examples 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13-1, 13-2, 14, 15, 16, 17 , 19, 32 and 33 compounds or their salts.

In a specific embodiment, a compound selected from the group consisting of: (E)-1-ethyl-N-(3-((E)-4-((E)-2-((1-ethyl-3-methyl-1H-pyrazole-5-carbonyl) sub Amino)-3-methyl-2,3-dihydro-1H-benzo(d)imidazol-1-yl)but-2-en-1-yl)-4-(hydroxymethyl)-1- Methyl-1H-benzo[d]imidazole-2(3H)-ylidene)-3-methyl-1H-pyrazole-5-carboxamide; 1-Ethyl-N-((E)-1-((E)-4-((E)-2-((1-ethyl-3-methyl-1H-pyrazole-5-carbonyl) sub Amino)-3-methyl-2,3-dihydro-1H-benzo(d)imidazol-1-yl)but-2-en-1-yl)-4-(hydroxymethyl)-3- Methyl-1,3-dihydro-2H-benzo[d]imidazole-2-ylidene)-3-methyl-1H-pyrazole-5-carboxamide; N-((E)-4-((3-oxa-6-azabicyclo[3.1.1]hept-6-yl)methyl)-1-((E)-4-((E) -2-((1-ethyl-3-methyl-1H-pyrazole-5-carbonyl)imino)-3-methyl-2,3-dihydro-1H-benzo[d]imidazole- 1-yl)but-2-en-1-yl)-3-methyl-1,3-dihydro-2H-benzo(d)imidazol-2-ylidene)-1-ethyl-3-methyl Group-1H-pyrazole-5-carboxamide; N-((E)-1-((E)-4-((E)-7-(1,2-dihydroxyethyl)-2-((1-ethyl-3-methyl-1H- Pyrazol-5-carbonyl)imino)-3-methyl-2,3-dihydro-1H-benzo(d)imidazol-1-yl)but-2-en-1-yl)-3- Methyl-1,3-dihydro-2H-benzo[d]imidazol-2-ylidene)-1-ethyl-3-methyl-1H-pyrazole-5-carboxamide; and 1-Ethyl-N-((E)-3-((E)-4-((E)-2-((1-ethyl-3-methyl-1H-pyrazole-5-carbonyl) sub Amino)-3-methyl-2,3-dihydro-1H-benzo(d)imidazol-1-yl)but-2-en-1-yl)-4-(1-hydroxy-2-? (Hydroxyethyl)-1-methyl-1,3-dihydro-2H-benzo[d]imidazol-2-ylidene)-3-methyl-1H-pyrazole-5-carboxamide; Or its pharmaceutically acceptable salt.

The compounds of the present invention can exist in both unsolvated and solvated forms. The term "solvate" is used herein to describe a molecular complex comprising a compound of the invention and one or more pharmaceutically acceptable solvent molecules (such as ethanol). When the solvent is water, the term "hydrate" is used. Pharmaceutically acceptable solvates include hydrates and other solvates, in which the solvent for crystallization can be replaced by isotope, such as D ₂ O, d ₆ -acetone, and d ₆ -DMSO.

Suitable pharmaceutically acceptable salts of the compounds described herein may include acid addition salts or base addition salts. For a review of pharmaceutically acceptable suitable salts, see Berge et al., J. Pharm. Sci., 66:1-19, (1977) and PH Stahl and CG Wermuth editors, Handbook of Pharmaceutical Salts: Properties, Selection and Use , Weinheim/Zürich:Wiley-VCH/VHCA (2002).

The salts of compounds containing basic amines or other basic functional groups described herein can be prepared by any suitable method known in the art, such as treating the free base with a suitable inorganic or organic acid. Examples of pharmaceutically acceptable salts so formed include acetate, adipate, ascorbate, aspartate, besylate, benzoate, camphorate, camphor-sulfonate (camphor- sulfonate, camsylate), caprate (caprate, decanoate), caproate (caproate, hexanoate), caprylate (caprylate, octanoate), carbonate, bicarbonate, cinnamate, citrate, cyclohexamide Acid salt, dodecyl sulfate (estolate), ethane-1,2-disulfonate (ethanedisulfonate), ethanesulfonate (ethanesulfonate, esylate), formate , Fumarate (hemifumarate, etc.), galactose (mucate), gentisate (2,5-dihydroxybenzoate), glucoheptonate (glucoheptonate, gluceptate), gluconate, glucuronate, glutamate, glutarate, glycerophosphate, glycolate, hippurate, hydrobromide, hydrochloride (dihydrochloride, etc.), Hydroiodide, isobutyrate, lactate, lactobionate, laurate, maleate, malate, malonate, mandelic acid, methanesulfonate (methanesulfonate), Naphthalene-1,5-disulfonate (naphthalene-sulfonate, napsylate), nicotinate, nitrate, oleate, oxalate, palmitate, Pamoate, phosphate (diphosphate, etc.), propionate, pyroglutamate, salicylate, sebacate, stearate, succinate, sulfate, tartrate, sulfur Cyanate, p-toluenesulfonate (toluenesulfonate), undecylenate, 1-hydroxy-2-naphthoate, 2,2-dichloroacetate, 2-hydroxyethanesulfonic acid Salt (isethionate), 2-side oxoglutarate, 4-acetamidobenzoate and 4-aminosalicylate.

Salts of the disclosed compounds containing carboxylic acid or other acidic functional groups can be prepared by reacting with a suitable base. This pharmaceutically acceptable salt can be prepared using a base that provides pharmaceutically acceptable cations, including alkali metal salts (especially sodium and potassium), alkaline earth metal salts (especially calcium and magnesium), aluminum salts and ammonium salts And from physiologically acceptable organic bases (e.g. trimethylamine, triethylamine, morpholine, pyridine, hexahydropyridine, picoline, dicyclohexylamine, N,N'-dibenzylethylenediamine, 2-hydroxyl Ethylamine, bis-(2-hydroxyethyl)amine, tris-(2-hydroxyethyl)amine, procaine, dibenzylhexahydropyridine, dehydrorosinamine, N,N'- Didehydrorosinamine, glucosamine, N-methylglucamine, collidine, choline, quinine, quinoline and basic amino acids such as lysine and arginine) salt.

The present invention includes within its scope all possible stoichiometric and non-stoichiometric salts of the compounds described herein (for example, hydrobromide, dihydrobromide, fumarate, hemifumarate, etc.).

酸酯鍵、醣苷鍵或一些其他可裂解鍵。可裂解鍵通常將位於可裂解部分與連結至如本文所闡述化合物之連接體之間。The compounds described herein can be prepared and administered as prodrugs, wherein the compounds as described herein include a cleavable moiety linked to the compound by a cleavable bond. In certain embodiments, the cleavable moiety is only cleaved after the compound is internalized by the target cell after administration to the animal. The cleavable moiety is cleaved inside the cell, thereby releasing the active compound. Although not wishing to be bound by theory, it is believed that the cleavable moiety is cleaved by the presence of one or more enzymes or chemical transformations within the cell. In certain embodiments, the one or more enzymes or chemical transformations cleave cleavable bonds, which may be ester bonds, amide bonds, sulfonamide bonds, ether bonds, thioether bonds, disulfide bonds, amine bonds, Imine bond, phosphate bond, urethane bond, carbonate bond,

Ester bond, glycosidic bond or some other cleavable bond. The cleavable bond will generally be located between the cleavable moiety and the linker that connects to the compound as described herein.

The scope of the claimed compounds of the present invention includes all the stereoisomers, geometric isomers and tautomeric forms of compounds as described herein and compounds of formula (I), including compounds exhibiting more than one type of isomerism, and A mixture of one or more.

In a specific embodiment of the present invention, the use of the compound as described herein is provided for the prevention, amelioration or treatment of liver disease or its symptoms in animals.

A specific embodiment of the present invention provides the use of a combination of the first compound and the second compound as described herein for the prevention, amelioration or treatment of liver disease or its symptoms in animals. In these embodiments, the first compound is a compound of formula (I), and the second compound is a compound described herein or a pharmaceutically acceptable salt thereof.

A specific embodiment of the present invention provides the use of a compound as described herein or a pharmaceutically acceptable salt thereof for the prevention, amelioration or treatment of liver disease or its symptoms in animals.

One embodiment of the present invention provides a compound as disclosed herein or a pharmaceutically acceptable salt thereof for use in therapy. The present invention provides a compound as described herein or a pharmaceutically acceptable salt thereof for use in therapy, specifically for the treatment of hepatitis B virus-related diseases, conditions or disorders (for example, hepatitis B virus Related diseases, conditions or disorders may be hepatitis D virus, jaundice, liver cancer, liver inflammation, liver fibrosis, liver cirrhosis, liver failure, diffuse hepatocyte inflammatory disease, hemophagocytic syndrome, or serum hepatitis). Specifically, the present invention provides a compound as described in formula (I) or a pharmaceutically acceptable salt thereof for use in therapy.

In another embodiment, the present invention provides a compound of the present invention as described herein for use in the treatment of hepatitis B virus-related diseases, conditions, or disorders, specifically the diseases, conditions, or disorders listed herein. The present invention provides a compound of formula (I) (including a compound of Table 1) or a pharmaceutically acceptable salt thereof as described herein, for use in the treatment of hepatitis B virus-related diseases, conditions or disorders. The present invention provides a compound of formula (I) (including a compound in Table 1) or a pharmaceutically acceptable salt thereof as described herein, for use in the treatment of hepatitis B virus-related diseases, conditions or disorders, wherein the hepatitis B virus The related disease, condition or condition may be hepatitis D virus, jaundice, liver cancer, liver inflammation, liver fibrosis, liver cirrhosis, liver failure, diffuse hepatocyte inflammatory disease, phagocytic syndrome, or serum hepatitis.

The present invention provides a compound of formula (I) (including the compound of Table 1) or a pharmaceutically acceptable salt thereof as described herein, which is used for the functional cure of hepatitis B virus infection in humans, such as by stopping limited After anti-HBV treatment, with or without anti-HBs seroconversion, HBV DNA content and continuous HBsAg serum clearance cannot be determined.

The present invention specifically provides the use of the compound of formula (I) (including the compound of Table 1) or a pharmaceutically acceptable salt thereof as described herein. More specifically, the present invention provides the use of the compounds described herein for the treatment of hepatitis B virus-related diseases, conditions, or disorders, specifically the diseases, conditions, or disorders listed herein. Therefore, the present invention provides the use of the compound of formula (I) as described (including the compound of Table 1) or a pharmaceutically acceptable salt thereof as an active therapeutic agent for treating or suffering from the following diseases Humans in need at risk: Hepatitis B virus-related diseases, conditions, or disorders, specifically the diseases, conditions, or disorders listed herein.

The present invention further provides the use of the compound of formula (I) (including the compound of Table 1) or a pharmaceutically acceptable salt thereof as described herein, for the manufacture of the compound for the treatment of hepatitis B virus-related diseases, conditions or disorders ( For example, the drugs for the diseases and disorders listed in this article. Specifically, the present invention also provides the use of the compound of formula (I) as described herein, which is used in the manufacture for the treatment of hepatitis B virus-related diseases, conditions or disorders (such as the diseases, conditions and conditions listed herein). Disease) medicine.

In a specific embodiment of the present invention, the use of a compound (which is a compound of formula (I)) or a salt, specifically a pharmaceutically acceptable salt, as described herein is provided for the prevention, amelioration or treatment of animals The liver disease or its symptoms.

In a specific embodiment of the present invention, there is provided the use of a compound (which is a compound of formula (I) as described herein) or a pharmaceutically acceptable salt thereof for the prevention, amelioration or treatment of liver diseases in animals or Its symptoms. In these embodiments, the compound of formula (I) may be a compound from Table 1.

Certain embodiments provide the use of a compound of formula (I), suitably a compound of Table 1 or a pharmaceutically acceptable salt thereof as described herein, for use in manufacturing for the treatment, amelioration, delay or prevention of HBV-related diseases in animals, Medicaments for illnesses or conditions.

Certain embodiments provide the use of a compound of formula (I), suitably a compound of Table 1 or a pharmaceutically acceptable salt thereof as described herein, for the manufacture of a medicament for the treatment, amelioration, delay or prevention of liver diseases in animals .

Another embodiment of the present invention provides a method for treating hepatitis B virus infection in mammals, treating hepatitis B virus-related conditions, or treating hepatitis B/hepatitis D virus co-infection, the method comprising administering a therapeutically effective method The amount of the STING compound as described herein is to treat the hepatitis B virus infection, the hepatitis B virus-related condition, and/or the hepatitis B/hepatitis D virus co-infection. In related embodiments, the mammal is a human and the hepatitis B virus infection, the hepatitis B virus-related condition, and/or the hepatitis B/hepatitis D virus co-infection is derived from human hepatitis B virus B Hepatitis B virus infection. Human hepatitis B virus can be any of the following human geographic genotypes: A (Northwest Europe, North America, Central America); B (Indonesia, China, Vietnam); C (Eastern Asia, Korea, China, Japan) , Polynesia, Vietnam); D (Mediterranean, Middle East, India); E (Africa); F (Native American, Polynesia); G (United States, France); or H (Central America).

Related embodiments provide a method for treating hepatitis B virus infection or hepatitis B virus-related conditions in a mammal, the method comprising administering a therapeutically effective amount of any pharmaceutical composition as described herein to a mammal in need Among them, human hepatitis B virus-related symptoms can be jaundice, liver cancer, liver inflammation, liver fibrosis, liver cirrhosis, liver failure, diffuse hepatocyte inflammatory disease, phagocytic syndrome, or serum hepatitis.

In a specific embodiment, a method for treating hepatitis B virus infection, hepatitis B virus-related conditions, or hepatitis B/hepatitis D virus co-infection in a mammal in need of treatment is provided, the method comprising administering to the mammal The compound of formula (I) of the present invention or a pharmaceutically acceptable salt thereof as described herein.

In certain embodiments, the method of treating HBV infection comprises administering a first therapeutic agent, which is a compound of formula (I) or a pharmaceutically acceptable salt thereof as described herein. In certain embodiments, the methods include administering a first therapeutic agent (which is a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof as described herein, or a prodrug or pharmaceutically acceptable The salt), and the administration of one or more second therapeutic agents. In certain embodiments, the first therapeutic agent is co-administered with one or more second therapeutic agents. In certain embodiments, the first therapeutic agent and one or more second therapeutic agents are administered separately in any order.

酸酯鍵或醣苷鍵鍵或一些其他可裂解鍵。通常，可裂解鍵可位於可裂解部分與連結至式(I)化合物之連接體之間。Certain embodiments provide the use of a compound as described herein, wherein the compound of formula (I) as described herein is a conjugate or prodrug, which has a cleavable moiety linked to the compound by a cleavable bond. In certain embodiments, the cleavable moiety is only cleaved after the compound is internalized by the target cell after administration to the animal. The cleavable moiety is cleaved inside the cell, thereby releasing the active compound of formula (I). Although not wishing to be bound by theory, it is believed that the cleavable moiety is cleaved by one or more enzymes or chemical transformations within the cell. In certain embodiments, the prodrug may comprise a cleavable bond. Examples of cleavable bonds include, but are not limited to, ester bonds, amide bonds, amine bonds, imine bonds, ether bonds, thioether bonds, disulfide bonds, urethane bonds, carbonate bonds, and phosphate bonds , Sulfonamide bond,

Ester bond or glycosidic bond or some other cleavable bond. Generally, the cleavable bond can be located between the cleavable moiety and the linker that is linked to the compound of formula (I).

In certain embodiments, a first therapeutic agent (which is a compound of formula (I) or a pharmaceutically acceptable salt thereof as described herein), and a second therapeutic agent are provided. In certain embodiments, the compound of formula (I) is a compound of Table 1. In certain embodiments, the first therapeutic agent, which is a compound of formula (I), and the second therapeutic agent are co-administered sequentially or simultaneously. In certain embodiments, the second therapeutic agent is selected from an anti-inflammatory agent, a chemotherapeutic agent, or an anti-infective agent. In certain embodiments, the second therapeutic agent is an HBV agent, HCV agent, chemotherapeutic agent, antibiotic, analgesic, non-steroidal anti-inflammatory (NSAID) agent, antifungal agent, antiparasitic agent, antinausea agent, anti Diarrhea agents, immunomodulators or immunosuppressive agents.

In certain embodiments, the second therapeutic agent is an HBV agent. In certain embodiments, the HBV agent is any one of the following: the compounds described in WO2019/069293, interferon alpha-2b, interferon alpha-2a, and interferon alphacon-1 (pegylated and non- PEGylation), ribavirin (ribavirin); HBV RNA replication inhibitor; HBV antigen production inhibitor; HBV therapeutic vaccine; HBV preventive vaccine; Lamivudine (3TC); Entecavir (ETV); Fu Tenofovir disoproxil marate (TDF); Telbivudine (LdT); Adefovir; or HBV antibody therapy (single strain or multiple strains).

In certain embodiments, the second therapeutic agent is an HCV agent. In certain embodiments, the HCV agent is any of the following: interferon alpha-2b, interferon alpha-2a, and interferon alphacon-1 (pegylated and non-pegylated); ribavir Lin; HCV RNA replication inhibitors (for example, ViroPharma's VP50406 series); HCV antisense agents; HCV therapeutic vaccines; HCV protease inhibitors; HCV helicase inhibitors; or HCV single or multiple strain antibody therapy.

In certain embodiments, the second therapeutic agent is an anti-inflammatory agent (ie, inflammation reduction therapy). In certain embodiments, the inflammation-reducing therapy is any of the following: therapeutic lifestyle changes, steroids, NSAIDs, or DMARDs. Steroids can be corticosteroids. NSAID can be aspirin, acetaminophen, ibuprofen, naproxen, COX inhibitor, indomethacin and the like. DMARD can be TNF inhibitors, purine synthesis inhibitors, calcineurin inhibitors, pyrimidine synthesis inhibitors, sulfasalazine, methotrexate and the like.

In certain embodiments, the second therapeutic agent is a chemotherapeutic agent (ie, a cancer therapeutic agent). Chemotherapeutic agents may include (but are not limited to) daunorubicin (daunorubicin), daunomycin (daunomycin), actinomycin D (dactinomycin), doxorubicin (doxorubicin), epirubicin (epirubicin), Idarubicin, esorubicin, bleomycin, mafosfamide, ifosfamide, cytosine arabinoside, bis-chloroethyl nitroso Urea, busulfan, mitomycin C, actinomycin D, mithramycin, prednisone, hydroxyprogesterone, testosterone, other Tamoxifen, dacarbazine, procarbazine, hexamethylmelamine, pentamethylmelamine, mitoxantrone, amsacrine, nitroxide Mustard, methylcyclohexylnitrosourea, nitrogen mustard, melphalan, cyclophosphamide, 6-mercaptopurine, 6-thioguanine, cytarabine (CA), 5-nitrogen Cytidine, hydroxyurea, deoxycoformycin, 4-hydroxyperoxycyclophosphamide, 5-fluorouracil (5-FU), 5-fluorodeoxyuridine (5-FUdR), Methotrexate (MTX), colchicine, paclitaxel, vincristine (vincristine), vinblastine (vinblastine), etoposide, trimetrexate, teniposide, cis Platinum (cisplatin), gemcitabine (gemcitabine) and diethylstilbestrol (DES).

In certain embodiments, the second therapeutic agent is an immunomodulator called an innate immune activator, a checkpoint inhibitor, a T cell stimulator, or an agent that restores an adaptive immune response against HBV. Immunomodulators include (but are not limited to) antibodies or small molecules that antagonize the following: CTLA-4, such as ipilimumab (YERVOY); PD-1, such as Opdivo/nivolumab And Keytruda/pembrolizumab); PDL1, such as TECENTRIQ™ (atezolizumab); LAG3; TIM3; or IDO. Immunomodulators include, but are not limited to, antibodies or small molecules that stimulate ICOS, OX-40, TLR, IL7R or IL12R.

In certain embodiments, the second therapeutic agent is an anti-infective agent. Examples of anti-infective agents include, but are not limited to, antibiotics, antifungal drugs, and antiviral drugs.

In specific embodiments, HBV agents may include (but are not limited to) the compounds described in WO2019/069293, thymosin α1, interferon β-1a, interferon β-1b, interferon γ-1b, interferon γ1, Interferon γ2, interferon γ3, interferon α-2a, interferon α-2b, pegylated interferon β-2a, pegylated interferon β-2b, pegylated interferon γ1, polyethylene Glycolated interferon γ2, GS-9620 (4-amino-2-butoxy-8-[[3-(pyrrolidin-1-ylmethyl)phenyl]methyl]-5,7-dihydro Pteridine-6-one), dehydroepiandrosterone, androstendiol or androsteniol; interferon alphacon-1 (pegylated and non-pegylated), ribavirin; HBV RNA replication Inhibitor; HBV therapeutic vaccine; HBV preventive vaccine; Lamivudine (3TC); Entecavir (ETV); Tenofovir disoproxil fumarate (TDF); Telbivudine (LdT); Defovir dipivoxil (adefovir dipivoxil); and HBV antibody therapy (single strain or multiple strains).

In one embodiment, a method for treating HBV infection in a human is provided, which is implemented by administering to the human a therapeutically effective amount of a compound of formula (I) as described herein or a pharmaceutically acceptable salt thereof. In one embodiment, there is provided a method for treating HBV infection in a human being suffering from HBV infection or at risk of suffering from HBV infection by administering to the human a therapeutically effective amount of a compound of formula (I) described herein (Such as a compound in Table 1) or a pharmaceutically acceptable salt or prodrug thereof, and optionally a therapeutically effective amount of a second therapeutically active compound is administered, wherein the second therapeutically active agent is selected from: HBV agents, HCV Medicaments, chemotherapeutics, antibiotics, analgesics, non-steroidal anti-inflammatory (NSAID) agents, antifungal agents, antiparasitic agents, antinausea agents, antidiarrheal agents, or immunosuppressive agents.

In one embodiment, a method for treating HBV infection in a human is provided, which is implemented by administering to the human a therapeutically effective amount of a compound of formula (I) as described herein or a pharmaceutically acceptable salt thereof. In one embodiment, the present invention relates to a method for treating HBV infection in a human being suffering from HBV infection or at risk of suffering from HBV infection, which comprises administering to the human a therapeutically effective amount of the formula (I ) The compound or its pharmaceutically acceptable salt.

Another embodiment provides a method for reducing the amount of HBV DNA and the amount of HBV antigen in a mammal infected with hepatitis B virus, the method comprising administering to the mammal a therapeutically effective amount comprising the formula as described herein ( I) The pharmaceutical composition of the compound or its pharmaceutically acceptable salt can reduce hepatitis B virus infection and hepatitis B antigen compared with the amount of HBV DNA and the amount of HBV antigen in the mammal before treatment. In some embodiments, the mammal can be a human, and the hepatitis B virus can be a human hepatitis B virus. More specifically, the human hepatitis B virus can be any of the following human geographic genotypes: A (Northwest Europe, North America, Central America); B (Indonesia, China, Vietnam); C (Eastern Asia, South Korea, China, Japan, Polynesia, Vietnam); D (Mediterranean, Middle East, India); E (Africa); F (Native American, Polynesia); G (U.S., France); or H (Central America).

In a specific embodiment, a method for reducing the amount of HBV DNA and the amount of HBV antigen in a mammal infected with hepatitis B virus is provided, the method comprising administering a therapeutically effective amount of a therapeutic agent, wherein the therapeutic agent is as herein described The described compound of formula (I) or a pharmaceutically acceptable salt thereof reduces hepatitis B virus infection and hepatitis B antigen compared with the amount of hepatitis B virus and the amount of HBV antigen in the mammal before treatment, and The amount of hepatitis B virus was reduced by 90% compared to the amount before administration of the therapeutic agent. In related methods, HBV antigen can be HBsAg or can be HBeAg, and more specifically, the amount of HBV antigen can be sufficiently reduced to cause seroconversion. In the case of monitoring HBeAg as the determinant of seroconversion, seroconversion is defined as In the absence of serum HBeAg plus the presence of serum HBeAb, or in the case of monitoring HBsAg as a determinant of seroconversion, seroconversion is defined as the absence of serum HBsAg, as determined by the currently available detection limit of a commercially available ELISA system.

In certain embodiments, a method for reducing the amount of HBV DNA and the amount of HBV antigen in a mammal infected with hepatitis B virus is provided by administering a therapeutically active amount of a first therapeutic agent (such as The compound of formula (I) described) is administered with a second therapeutic agent, wherein the first therapeutic agent and the second therapeutic agent are administered together in a single formulation or separately administered in different formulations, and wherein The first therapeutic agent and the second therapeutic agent are administered simultaneously or continuously. In certain related embodiments, the method as described further comprises administering a therapeutically effective amount of an optional third therapeutic agent, wherein the optional third therapeutic agent is selected from HBV agents, HCV agents, chemotherapeutic agents, antibiotics, Analgesics, non-steroidal anti-inflammatory (NSAID) agents, antifungal agents, antiparasitic agents, antinausea agents, antidiarrheal agents, and immunosuppressive agents. In a more specific related embodiment, the optional third therapeutic agent is selected from interferon alpha-2b; interferon alpha-2a; and interferon alphacon-1 (pegylated and non-pegylated); Bavirin; HBV RNA replication inhibitor; HBV antigen production inhibitor; HBV therapeutic vaccine; HBV preventive vaccine; Lamivudine (3TC); Entecavir (ETV); Tenofovir disoproxil fumarate (TDF); Telbivudine (LdT); Adefovir; or HBV antibody therapy (single strain or multiple strains); HCV agent, which is selected from HCV RNA replication inhibitors (for example, ViroPharma's VP50406 series), HCV therapy Sex vaccines, HCV protease inhibitors, HCV helicase inhibitors or HCV antibody therapy (single strain or multiple strains).

Another embodiment provides a method for promoting seroconversion of hepatitis B virus in a mammal infected with HBV, the method comprising administering a therapeutically effective amount of a compound of formula (I) as described herein to a mammal infected with hepatitis B; The method includes monitoring the presence of HBeAg plus HBeAb in a serum sample of mammals, or monitoring the presence of HBsAg in a serum sample of mammals, so that if HBeAg is monitored as a determinant of seroconversion, there is no HBeAg plus presence in the serum sample HBeAb, or if HBsAg is monitored as the determinant of seroconversion, there is no HBsAg in the serum sample (as determined by the current detection limit of the commercially available ELISA system), which is an indicator of seroconversion in mammals.

In the specific embodiment described herein for the treatment of hepatitis B virus, hepatitis B virus infection, hepatitis B virus-related conditions, or hepatitis B/hepatitis D virus co-infection in a mammal in need of treatment, the method Comprises the administration of a first therapeutic agent (which is a compound of formula (I) as described herein or a pharmaceutically acceptable salt or prodrug thereof) and a second therapeutic agent, wherein the second therapeutic agent may be an anti-inflammatory agent; chemical Therapeutic or anti-infective agent; HBV agent; HCV agent; antibiotic; analgesic; non-steroidal anti-inflammatory (NSAID) agent; antifungal agent; antiparasitic agent; antinausea agent; antidiarrheal agent; immunomodulator; or immunity Inhibitor.

Certain embodiments provide the use of a compound of formula (I) as described herein, suitably a compound of Table 1 or a pharmaceutically acceptable salt or prodrug thereof, in combination with a second therapeutic agent or composition as described herein , Which is used to manufacture medicaments for treating, ameliorating, delaying or preventing HBV related diseases, disorders or conditions in animals.

Certain embodiments provide the use of a combination of a first therapeutic agent (which is a compound of formula (I) as described herein or a pharmaceutically acceptable salt or prodrug thereof) and a second therapeutic agent or composition as described herein , Which is used to manufacture drugs for treating, improving, delaying or preventing liver diseases in animals.

For any of the embodiments described herein, these embodiments provide methods for treating hepatitis B virus infection or hepatitis B virus-related conditions, and reducing the amount of HBV DNA and HBV antigen in mammals infected with hepatitis B virus A method or a method for promoting seroconversion of hepatitis B virus in a mammal infected with HBV, wherein the method comprises administering a therapeutically effective amount of a compound of formula (I) as described herein or a pharmaceutically acceptable salt thereof or Prodrugs, including therapeutically effective amounts of the compounds from Table 1 or pharmaceutically acceptable salts thereof, whether alone or in combination, and whether present in a pharmaceutical formulation or simply in a diluent, can be administered as Oral, buccal, rectal, parenteral, intraperitoneal, intradermal, transdermal or intratracheal administration.

In the pharmaceutical dosage form, the administration of the compound of formula (I) (including the compound of Table 1) as described herein can be carried out alone or in appropriate combination, as well as in combination with other pharmaceutically active agents (for example, other HBV agents known in the art) get on. The following methods and excipients are only exemplary and in no way restrictive. The STING compound of formula (I) or its pharmaceutically acceptable salt as described herein and in Table 1 can be combined with conventional pharmaceutical carriers, excipients or the like (e.g., mannitol, lactose, starch, magnesium stearate, Sodium saccharin, talc, cellulose, croscarmellose sodium, glucose, gelatin, sucrose, magnesium carbonate and the like) are administered in combination. If desired, the pharmaceutical composition may also contain a very small amount of non-toxic auxiliary substances, such as wetting agents, emulsifiers, solubilizers, pH buffers and the like (for example, sodium acetate, sodium citrate, cyclodextrin derivatives, dehydration Sorbitol monolaurate, triethanolamine acetate, triethanolamine oleate and the like).

For oral preparations, the compounds described herein can be used alone or in combination with appropriate additives to prepare lozenges, powders, granules or capsules, for example in combination with conventional additives, such as lactose, mannitol, corn starch or potato starch; and Used in combination with binders, such as crystalline cellulose, cellulose derivatives, gum arabic, corn starch or gelatin; used in combination with disintegrants, such as corn starch, potato starch or sodium carboxymethyl cellulose; used in combination with lubricants, For example, talc or magnesium stearate; and if desired, used in combination with diluents, buffers, wetting agents, preservatives, and flavoring agents.

In addition, the compounds described herein can be mixed with various bases (for example, emulsifying bases or water-soluble bases) to prepare suppositories, and can be administered rectally via suppositories. Suppositories may include vehicles such as cocoa butter, carbowax and polyethylene glycol, which melt at body temperature but solidify at room temperature.

Generally speaking, the compound of formula (I) as described herein (including the compound of Table 1) or a pharmaceutically acceptable salt or prodrug thereof used in combination with the therapeutic agent and HBV agent described herein will be used by Any accepted therapeutic agent administration mode for similar purposes is administered in a therapeutically effective amount.

Depending on the properties of the specific composition of the STING compound or its pharmaceutically acceptable salt or prodrug combined with the second therapeutic agent as described herein, it can be used to desirably reduce the target viral transcript, viral gene volume or target Any convenient way of loading the cells to administer the composition to the host. Therefore, the compound as described herein or a pharmaceutically acceptable salt or prodrug thereof can be incorporated into a variety of formulations for therapeutic administration. More specifically, by combining with a pharmaceutically acceptable suitable carrier or diluent, the compound as described herein or a pharmaceutically acceptable salt or prodrug thereof and the combination described herein can be formulated into a medicine combination. In certain embodiments, the compound described herein, or a pharmaceutically acceptable salt or prodrug thereof, and the combination described herein can be formulated into a solid, semi-solid, liquid or gaseous preparation, such as a lozenge , Capsules, powders, granules, ointments, solutions, suppositories, injections, inhalants and aerosols. In certain embodiments, the administration of a compound as described herein, or a pharmaceutically acceptable salt or prodrug thereof, and a combination thereof as described herein can be achieved in various ways, including (but not limited to) oral, oral Buccal, rectal, parenteral, intraperitoneal, intravenous, intradermal, transdermal or intratracheal administration, and the administration can also be delivered via microneedle patches or topical formulations.

For oral preparations, the compounds described herein or their pharmaceutically acceptable salts or prodrugs described herein can be used alone or in combination with appropriate additives to prepare tablets, powders, granules or capsules, for example, with conventional additives Used in combination, such as lactose, mannitol, corn starch or potato starch; used in combination with binders, such as crystalline cellulose, cellulose derivatives, gum arabic, corn starch or gelatin; used in combination with disintegrants, such as corn starch, Potato starch or sodium carboxymethyl cellulose; used in combination with lubricants, such as talc or magnesium stearate; and, if desired, used in combination with diluents, buffers, wetting agents, preservatives, and flavoring agents.

It can be achieved by dissolving, suspending or emulsifying the compound of formula (I) as described herein (including the compound of Table 1) or its pharmaceutically acceptable salt or prodrug as described herein in an aqueous or non-aqueous solvent (e.g., vegetable oil). Or other similar oils, synthetic fatty acid glycerides, high carbon number fatty acids or esters of propylene glycol) and formulated into injection preparations; and if desired, conventional additives such as solubilizers, isotonic agents, suspending agents, Emulsifier, stabilizer and preservative. The pharmaceutically administrable liquid composition of the STING compound as described herein can be, for example, by combining at least the compound as described herein and an optional pharmaceutical adjuvant in a carrier (e.g., water, saline, aqueous dextrose solution) , Glycerol, ethylene glycol, ethanol or the like) dissolved in, dispersed, etc. to form a solution or suspension. Injectables can be prepared in conventional forms: in the form of a liquid solution or suspension, in the form of an emulsion, or in a solid form suitable for dissolution or suspension in a liquid prior to injection. The percentage of the compound contained in these parenteral compositions is highly dependent on their specific properties and the activity of the compound and the needs of the individual. However, 0.01% to 10% of the active ingredient percentage in the solution can be used, and if the composition is solid, the percentage will be higher, and then it will be diluted to the above percentage. In certain embodiments, the composition will contain about 0.2% to 2% active agent in solution.

The actual amount of the therapeutic compound (ie, therapeutic ingredient) will depend on many factors, such as the severity of the disease to be treated, the age and relative health of the individual, the efficacy of the compound used, the route and form of administration, and other factors. The pharmaceutical composition can be administered more than once a day, for example, once or twice a day. In a specific embodiment, the HBV pharmaceutical formulation will be administered once or twice a week as necessary for a period of 24 weeks, 36 weeks, or 48 weeks or longer, to effectively treat HBV infection, including reducing viral load , Reduce viral antigens, produce seroconversion, enhance individual immune response and/or reduce HBV DNA content and normalize alanine transferase (ALT) content.

Unit dosage forms, such as syrups, elixirs and suspensions, for oral or rectal administration of a compound as described herein, or a pharmaceutically acceptable salt thereof, or a combination thereof as described herein, can be provided, wherein each dosage unit (For example, one teaspoon, one tablespoon, lozenge or suppository) contains a predetermined amount of a composition containing one or more inhibitors. Similarly, a unit dosage form for injection or intravenous administration of a compound as described herein or a pharmaceutically acceptable salt thereof or a combination thereof as described herein can be included in the composition as sterile water, physiological saline or another An inhibitor of solution in a pharmaceutically acceptable carrier.

As used herein, the term "unit dosage form" refers to a physically discrete unit suitable as a unit dosage for human and animal individuals. Each unit contains a predetermined amount of the compound of the present invention and a pharmaceutical in a calculated amount sufficient to produce the desired effect. Acceptable diluent, carrier or vehicle. The specifications of the novel unit dosage form of the present invention depend on the specific compound used and the effect to be achieved, and the pharmacodynamics in the host associated with each compound.

Pharmaceutically acceptable excipients (such as vehicles, adjuvants, carriers or diluents) are readily available to the public. In addition, the public can easily obtain pharmaceutically acceptable auxiliary substances, such as pH adjusters and buffers, tonicity adjusters, stabilizers, wetting agents, and the like.

Those skilled in the art will readily understand that the dosage amount can vary with the specific therapeutic agent, the nature of the delivery vehicle, and the like. Those skilled in the art can easily determine the preferred dosage of a given therapeutic agent, including a specific compound as described herein, included in the combination with a second therapeutic agent in a variety of ways.

Examples of delivery methods for administering the therapeutic agents described herein and details of pharmaceutical formulations, solvates, hydrates, salts, and prodrugs (such as esters) are well known to those skilled in the art and are described in the literature.

Ultimately, the choice of formulation and dosage depends on various factors, such as the mode of drug administration and the bioavailability of the drug substance.

The method of the present invention will work in any mammalian cell. Representative mammalian cells of interest include (but are not limited to) cells of the following animals: ungulate or hooved animals, such as cattle, goats, Pigs, sheep, etc.; rodents, such as hamsters, mice, rats, etc.; lagomorphs, such as rabbits; primates, such as monkeys, baboons, humans, etc.; and the like.

The pharmaceutical formulation of the compound described herein for the prevention, amelioration or treatment of liver disease or its symptoms in animals may comprise at least one STING compound of formula (I) as described herein or a pharmaceutically acceptable salt or prodrug thereof, The compound from Table 1 or a pharmaceutically acceptable salt thereof and the second therapeutic agent as described herein are included as active ingredients. It should be understood that the pharmaceutical composition may include a diluent, and optionally a pharmaceutical carrier; and the pharmaceutical composition may optionally include other compounds, such as chemotherapeutic compounds, anti-inflammatory compounds, antiviral compounds, analgesics, NSAIDs, Anesthetics, antibiotics, antifungal compounds, antiparasitic compounds and/or immunomodulatory compounds.

The compounds described herein used to prevent, ameliorate, or treat liver disease or its symptoms in animals can be used "as is" or in the form of various pharmaceutically acceptable salts or prodrugs. As used herein, the term "pharmaceutically acceptable salt" refers to a salt that retains the desired biological activity of the compounds identified herein and exhibits minimal undesired toxicological effects. Non-limiting examples of these salts can be acid addition salts formed with organic acids and metal cations (e.g., zinc, calcium, bismuth, barium, magnesium, aluminum, copper, cobalt, nickel, cadmium, sodium, potassium and the like ) Or a base addition salt formed with cations formed from ammonia, N,N-dibenzylethylenediamine, D-glucamine, tetraethylammonium or ethylenediamine.

In certain embodiments of the invention, the compounds as described herein may be in the form of prodrugs. A prodrug may include a cleavable moiety linked to the compound by a cleavable bond. The cleavable portion may be the portion that directs the compound as described herein to the liver. Examples of such cleavable moieties targeted to the liver include carbohydrate moieties, including mannose or galactose moieties, or N-acetylmannosamine or more specifically N-acetylgalactosamine (GalNAc) section. In certain embodiments, there may be carbohydrate clusters or GalNac clusters as cleavable moieties, which are linked by a cleavable bond to the compound of formula (I) as described herein, suitably a compound of Table 1. The GalNAc cluster may include 2 GalNAc parts, 3 GalNac parts, or 4 GalNac parts.

Other parts and techniques that can be used for carrier-mediated delivery of target compounds to the liver as described herein include the use of cholesterol, polyethylene glycol (PEG), polyethylene glycol (PEG), Polydextrose, lipid nanoparticles, masked endosomal compounds, for example by coupling poly(vinyl ether) to GalNAc and PEG and then connecting GalNAc-PEG to the desired via cleavable bonds (e.g. disulfide bonds) Delivery of the compound to implement. For a discussion of the technique of targeting siRNA to the liver (those familiar with this technique should understand that it is suitable for targeting compounds as described herein to the liver), see Nature Reviews Genetics 16 , 543-553 (2015) (A. Wittrup and J. Lieberma), the entire contents of which are incorporated herein by reference. As described herein, the delivery of the STING agonist of formula (I), suitably the compound of Table 1 to the tissue can also be enhanced by carrier-mediated delivery, which includes (but is not limited to) cationic liposomes, cyclodextrins, Porphyrin derivatives, branched dendrimers, polyethyleneimine polymers, nanoparticles and microspheres (Dass, CR. J Pharm Pharmacol 2002; 54(1):3-27), which are based on The way of reference is incorporated into this article. For other discussion of targeted drug delivery to the liver, please refer to N. Mishra et al., "Efficient Hepatic Delivery of Drugs: Novel Strategies and Their Significance" BioMed Research International, 2013 (2013), article ID 328184, page 20, all of which The content is incorporated into this article by reference.

The pharmaceutical compositions of the compounds described herein for the prevention, amelioration or treatment of liver disease or its symptoms in animals include, but are not limited to, solutions, emulsions, and liposome-containing formulations. The compositions can be produced from a variety of components, including but not limited to pre-formed liquids, self-emulsifying solids, and self-emulsifying semi-solids. The pharmaceutical formulations of the compounds described herein for preventing, ameliorating, or treating liver diseases or their symptoms in animals can be prepared according to conventional techniques well known in the pharmaceutical industry, which can be conveniently presented in unit dosage forms. These techniques include the step of associating the active ingredient with a pharmaceutical carrier or excipient. Generally speaking, formulations are prepared by uniformly and fully associating the active ingredient with a liquid carrier or a fine solid carrier or both, and then (if necessary) shaping the product. The compounds described herein for the prevention, amelioration or treatment of liver disease or its symptoms in animals can be formulated into any of a variety of possible dosage forms, such as (but not limited to) tablets, capsules, gel capsules, liquid syrups, Soft gels and suppositories.

The compounds described herein, which are used to prevent, ameliorate or treat liver diseases in animals or their symptoms, can also be formulated as suspensions in aqueous, non-aqueous or mixed media. The aqueous suspension may further contain substances that increase the viscosity of the suspension, including, for example, sodium carboxymethyl cellulose, sorbitol, and/or polydextrose. The suspension may also contain stabilizers. The compounds described herein, which are used to prevent, ameliorate or treat liver diseases or their symptoms in animals, can also be coupled to active APIs, such as aspirin, ibuprofen, sulfa drugs, antidiabetics, antibacterial agents, or Antibiotics and anti-cancer raw materials. In addition, the compounds described herein for the prevention, amelioration or treatment of liver disease or its symptoms in animals can be administered as a combination therapy together with or separately with the following: can be used to treat cancer, inflammation, pain, bacteria, fungi, and/or APIs for parasitic infections, alcoholism, drug abuse, diabetes, and APIs that can be used to treat other viral infections (such as HIV, HCV and the like).

There are two general forms of hepatitis B virus infection: acute and chronic. Individuals who have experienced HBV infection can also recover and become asymptomatic carriers. Acute hepatitis B occurs when people exposed to hepatitis B virus begin to show signs and symptoms of viral hepatitis. This period of time is called the incubation period, which is 90 days on average, but can be as short as 45 days or as long as 6 months. For most people, this infection will cause mild to moderate discomfort, but will disappear on its own, because the body's immune response successfully fights the virus. However, some people, specifically those with compromised immune systems (for example, people with AIDS, undergoing chemotherapy, taking immunosuppressive drugs, or taking steroids) will have serious problems due to acute HBV infection and continue to occur More serious conditions, such as fulminant liver failure.

Chronic hepatitis B occurs when a person initially has an acute infection, but is unable to fight the infection later. Whether the disease becomes chronic or disappears completely depends on the age of the infected person. About 90% of babies infected at birth will progress to chronic diseases. However, as people age, the risk of chronic infection decreases, so that between 20%-50% of children and less than 10% of older children or adults will progress from acute infection to chronic infection. Chronic HBV infection is the main treatment target of the embodiments of the present invention, but the compounds of the present invention can also treat HBV-related conditions, such as inflammation, fibrosis, cirrhosis, liver cancer, serum hepatitis and more.

There is a 95% chance that children will develop immune tolerance and the condition will progress to chronic hepatitis; and if the patient is infected with HBV in adulthood, the chance that the condition will become chronic will only be 5%.

There are four stages of chronic HBV infection. The first stage is the immune tolerance stage, during which the liver exhibits minimal fibrosis and inflammation, accompanied by high HBV DNA and normal alanine transaminase (ALT) content. The second stage is the immune clearance stage, during which active inflammation of the liver can be observed histologically, which can also include fluctuating ALT activity and fluctuating HBV DNA content. Next can be the third stage of inactive carrier state, in which infected individuals can exhibit mild hepatitis and minimal fibrosis histologically. The fourth stage, called the reactivation of HBV, is also reported. As observed by the biopsy laboratory, this last stage is characterized by active inflammation of the liver, even though hepatitis B e antigen (HBeAg) is negative and anti-HBeAg is positive.

There are several types of chronic HBV disease. The first is called HBeAg-positive or "wild type" HBV infection, characterized by anti-HBeAg-negative and show the amount of HBV DNA> 20,000 IU / mL (> 10 5 copies / mL). The second is called HBeAg-negative or "mutant core" HBV infection, characterized by anti-HBeAg positive and show HBV DNA> 2,000 IU / mL ( > 10 4 copies / mL). Historically, these two types of chronic HBV infection evaded therapeutic methods.

Patients with acute HBV infection have a strong multi-strain and multispecific cytotoxic T lymphocyte (CTL) response to viral antigens, while patients with chronic infection have weak or undetectable CTL responses. Hepatitis occurs when the activation intensity is sufficient to destroy the weak HBV-specific immune response of liver cells infected with HBV. Little is known about the mechanism leading to T cell hyporesponsiveness or tolerance, but it is believed that it may involve the following mechanisms: negative selection (newborns); immune neglect; peripheral unresponsiveness or lack of costimulatory molecules (such as regulatory T cells) (Treg)); depletion (upgrade of PD-1). The common factor for all these proposed mechanisms is the persistent high levels of antigen in the patient's body.

The HBV antigen HBeAg is a secreted non-particulate form of HBV core protein. The HBV antigens HBeAg and HBcAg share a primary amino acid sequence, so they show cross-reactivity at the T cell level. HBeAg is not required for virus assembly or replication, but studies have shown that it may be necessary for the establishment of chronic infection.

Newborn infections with HBeAg-negative mutants usually lead to fulminant acute rather than chronic HBV infection (Terezawa et al. (1991) Pediatr. Res. 29:5), while the use of WHeAg-negative mutants to infect juvenile woodchucks results in much lower chronic WHV Infection rate (Cote et al. (2000) Hepatology 31:190). HBeAg may act as a tolerogen by inactivating core-specific T cells through deletion or colonization anergy (Milich et al. (1998) J. Immunol. 160: 8102). During antiviral therapy and HBeAg seroconversion, the reduction of HBV viral load and antigen and the programmed death of T cells to inhibitory receptors-1 (PD-1; also known as PDCD1) are the negative effects of activated T cells. There is a positive correlation between the reduction in performance of modulators (Evans et al. (2008) Hepatology 48:759).

HBV surface antigen or HBsAg is the envelope protein of infectious HBV virus particles, but it is also secreted in the form of non-infectious particles, and its serum content is 1000 times higher than that of HBV virus particles. The serum level of HBsAg in infected humans or animals can be as high as 1000 μg/mL (Kann and Gehrlich (1998) Topley &Wilson's Microbiology and Microbial Infections, 9th edition, 745). In acute HBV infection, the HBsAg serum or serum half-life t _½ was 8.3 days (Chulanov et al. (2003) J. Med Virol 69: .. 313). Bone marrow-like dendritic cells upregulate the internalization of HBsAg inhibiting costimulatory molecules (ie B7) and inhibit T cell stimulating ability (den Brouw et al. (2008) Immunology 126:280), and dendritic cells from chronically infected patients also It has been shown that in the presence of HBsAg, the performance of costimulatory molecules, the secretion of IL-12 and the stimulation of T cells are insufficient (Zheng et al. (2004) J. Viral Hepatitis 11:217).

HBsAg-specific CD8 cells from CHB patients showed altered tetramer binding. These CD8 cells are not anergic, but may have a TCR topology, which confers partial tolerance or negligence (Reignat et al. (2002) J. Exp. Med. 195:1089). In addition, during Peg-IFNα2a therapy, a decrease in serum HBsAg> 1 log at week 24 has a higher prediction for sustained virological response (SVR, which is defined as undetectable HBV DNA by PCR 1 year after treatment) Value (92%) (Moucari et al. (2009) Hepatology 49:1151).

Due to overlapping transmission routes, many people have been exposed to hepatitis B virus (HBV) and hepatitis C virus (HCV) at the same time, and a small number of people have been infected with the two viruses for a long time, especially in areas where HBV is endemic such as Asia. It is estimated that up to 10% of people with HCV may also have HBV, and about 20% of people with HBV are co-infected with HCV. However, the treatment of hepatitis B or hepatitis B in HBV-HCV co-infected individuals has not been thoroughly studied.

HCV and HBV seem to inhibit each other's replication (but not all studies have observed this interaction), a fact that complicates the treatment. Therefore, treatments that completely inhibit HBV can potentially allow HCV to reappear, or vice versa.

Therefore, use a compound of formula (I) as described herein, a compound of Table 1 or a pharmaceutically acceptable salt or prodrug thereof, and a second therapeutic agent (which may be a therapeutic agent as described herein, including as described herein). The combination of the described HVC agents) is used to prevent, ameliorate or treat liver disease or its symptoms can be advantageously used to treat humans infected with both HBV and HCV. Exemplary treatment options for hepatitis C (HCV) include interferons, such as interferon alpha-2b, interferon alpha-2a, and interferon alphacon-1. The use of pegylated interferon (interferon is linked to the polyethylene glycol moiety, which significantly improves its pharmacokinetic characteristics) can reduce the frequency of administration of interferon. For some patient populations, the combination therapy of interferon alpha-2b (pegylated and non-pegylated) and ribavirin has also been shown to be effective. Other agents currently under development include HCV RNA replication inhibitors (such as ViroPharma's VP50406 series), HCV antisense agents, HCV therapeutic vaccines, HCV protease inhibitors, HCV helicase inhibitors, and HCV antibody therapy (single or multiple strains). Strain).

In another embodiment, the STING compound of formula (I) as described herein, suitably a compound of Table 1 or its pharmaceutically acceptable as described herein is used to prevent, ameliorate or treat liver disease or its symptoms in animals. The salt or prodrug can be administered to a human subject infected with HBV in combination with a second therapeutic agent, where the second therapeutic agent can be administered in the same pharmaceutical formulation as the STING compound, or can be administered in a separate formulation. The second therapeutic agent can also be administered simultaneously with the optional third therapeutic agent, or can be administered separately, so that the STING compound of formula (I), the compound of Table 1 or a pharmaceutically acceptable salt thereof, as described herein, The respective doses of the second therapeutic agent and the optional third therapeutic agent overlap in time in the individual's body. In related embodiments, the second and optional third therapeutic agents may be therapeutic agents as described herein, including HBV agents selected from the group consisting of the compounds described in WO2019/069293, thymosin α1, interferon β -1a, interferon beta-1b, interferon gamma-1b, interferon gamma1, interferon gamma2, interferon gamma3, interferon alpha-2a, interferon alpha-2b, pegylated interferon beta-2a, poly Glycylated interferon β-2b, pegylated interferon γ1, pegylated interferon γ2, GS-9620 (4-amino-2-butoxy-8-[[3-(pyrrolidine- 1-ylmethyl)phenyl)methyl)-5,7-dihydropteridine-6-one), dehydroepiandrosterone, androstendiol or androsteniol; interferon alphacon-1 (poly Glycolated and non-pegylated), ribavirin; HBV RNA replication inhibitor; HBV therapeutic vaccine; HBV preventive vaccine; Lamivudine (3TC); Entecavir (ETV); Tenol fumarate Fovir disoproxil (TDF); Telbivudine (LdT); Adefovir disoproxil; and HBV antibody therapy (single or multiple strains).

Use encompasses the combination of a compound as described herein or a pharmaceutically acceptable salt or prodrug thereof and a second therapeutic agent as described herein (wherein the optional second therapeutic agent may be an HBV agent as described herein), and The third therapeutic agent (which may be the HBV agent described herein) is used together and the pharmaceutical composition of the present invention combined with the optional fourth therapeutic agent (which may be the HBV agent described herein) will thus be a patient with chronic Patients with HBV infection are provided with improved therapeutic treatments, which can produce complete seroconversion, which will eventually lead to a complete cure of chronic HBV infection. The use of compounds as described herein or their pharmaceutically acceptable salts or prodrugs and second therapeutic agents and optionally third therapeutic agents and optionally fourth therapeutic agents are also expected to reduce HBV-related liver conditions (such as cirrhosis). , Hepatocellular carcinoma (HCC) and fibrosis and inflammation), which reduces the need for liver transplantation and helps prevent deaths caused by liver diseases.

In addition, in addition to the improved viral load reduction, the use of compounds as described herein will also provide other benefits. It is believed that HBeAg has an immunosuppressive effect, and HBsAg is believed to promote T cell depletion. Therefore, treatment with a compound as described herein or a pharmaceutically acceptable salt or prodrug thereof in combination with a second therapeutic agent, in combination with an optional third therapeutic agent, and in combination with an optional fourth therapeutic agent will be reduced by The content of HBeAg and HBsAg enhances the patient's immune response, thereby allowing the immune system to better control the infection. The second, third and fourth therapeutic agents may be selected from the following HBV agents: compounds described in WO2019/069293, thymosin α1, interferon β-1a, interferon β-1b, interferon γ-1b, Interferon gamma1, interferon gamma2, interferon gamma3, interferon alpha-2a, interferon alpha-2b, pegylated interferon beta-2a, pegylated interferon beta-2b, pegylated interferon γ1, Pegylated interferon γ2, GS-9620 (4-amino-2-butoxy-8-[[3-(pyrrolidin-1-ylmethyl)phenyl]methyl]-5, 7-dihydropteridine-6-one), dehydroepiandrosterone, androstendiol or androsteniol; interferon alphacon-1 (pegylated and non-pegylated), ribavirin ; HBV RNA replication inhibitor; HBV therapeutic vaccine; HBV preventive vaccine; Lamivudine (3TC); Entecavir (ETV); Tenofovir disoproxil fumarate (TDF); Telbivudine ( LdT); Adefovir disoproxil; and HBV antibody therapy (single strain or multiple strains). It is also expected that reducing HBV antigen presentation in the liver will help minimize the extent of HBV infection outbreaks caused by the recovery of the immune system, all of which will increase the chance of a complete cure for chronic HBV infection.

An additional list of therapeutic agents that can be useful when used in combination with the compounds described herein or their pharmaceutically acceptable salts or prodrugs is indicated in Table 3.

The embodiment of the present invention provides a method for treating hepatitis B virus infection and reducing hepatitis B virus gene bodies in mammalian target cells, which comprises administering a therapeutically effective amount of the STING compound as described herein or its pharmaceutically An acceptable salt or prodrug, a therapeutically effective amount of a second therapeutic agent, and a therapeutically effective amount of an optional third therapeutic agent and an optional fourth therapeutic agent (which may each be an HBV agent) are administered, thereby treating Hepatitis B virus infection. Pharmaceutical compositions for practicing the methods of the invention are also provided. The embodiments of the present invention include the use of a compound as described herein, or a pharmaceutically acceptable salt or prodrug thereof, and a second therapeutic agent, an optional third therapeutic agent, and an optional fourth therapeutic agent as described herein, It can be used in a variety of applications, including the treatment of individuals with virus-mediated disease conditions, such as HBV-mediated disease conditions. These conditions include, but are not limited to, fibrosis and inflammation of the liver, cirrhosis and hepatocellular carcinoma (liver cancer).

In one embodiment, a combination of a first therapeutic agent (which is a STING compound of formula (I), suitably a compound of Table 1 or a pharmaceutically acceptable salt thereof as described herein) and a second therapeutic agent (which is an HBV agent) is provided The use in combination with an optional third agent (which is an HBV agent), and an optional fourth therapeutic agent (which is an HBV agent), which is used in combination to prevent, ameliorate or treat liver disease or its symptoms in animals.

In another embodiment, a method for treating HBV infection in mammals, including humans, is provided, wherein the treatment comprises administering a therapeutically effective dose of a first therapeutic agent (which is a compound as described herein or a pharmaceutically acceptable salt thereof) Or prodrug), a therapeutically effective amount of the second therapeutic agent (which is an HBV agent), and a therapeutically effective amount of an optional third therapeutic agent (which is an HBV agent) and an optional third agent that is administered in a therapeutically effective amount Four therapeutic agents (which are HBV agents) to treat HBV infections in the mammals, including humans, and to promote seroconversion. The effective dose or each therapeutic agent may be in the range of 0.01 mg/kg body weight to about 100 mg/kg body weight, and administered once or twice a week for 24 weeks, 36 weeks, or 48 weeks or longer, as prescribed by a physician determine. Quantification of viral load or other evidence of infection can be used to determine therapeutic efficacy, for example, by measuring HBeAg, HBsAg, HBV DNA content, ALT activity level, serum HBV content and the like, thereby allowing adjustment of therapeutic dose, frequency of treatment, and length of treatment time .

Instance

General synthesis method

The compounds of the present invention can be prepared using the synthetic procedures illustrated in the following reaction schemes. By learning from the knowledge of skilled organic chemists, these synthetic procedures can be easily modified to prepare other compounds of the present invention. The synthesis provided in these schemes is suitable for using appropriate precursors to produce compounds of the present invention with multiple R groups. If necessary, these precursors are suitably protected to achieve compatibility with the reactions outlined herein Sex. If necessary, subsequent deprotection provides compounds with generally revealed properties. The intermediate can also exist in the form of a salt.

The naming program used for the compound is ChemDraw ^® Professional 16.0.

General Synthesis Scheme Scheme 1

The compounds exemplified herein can be prepared by the general sequence outlined in Scheme 1. Treatment of amine A with 1-fluoro-2-nitrobenzene B under basic conditions provides intermediate C. It is worth noting that inorganic bases (K ₂ CO ₃ ), organic bases (DIPEA), aprotic solvents (DMF) and protic solvents (MeOH, iPrOH) have all proved effective for this transformation. The intermediate C is subjected to acidic conditions (HCl, TEA) to expose part of the side chain amine (Note: In the synthesis of various examples, without prior formation of the amine functional group D as the corresponding carbamic acid tert-butyl ester (Boc ) For protection). After obtaining amine D , it is treated with 1-fluoro-2-nitrobenzene E under basic conditions to generate intermediate F. Palladium-catalyzed hydrogenation (10% Pd/C, H ₂ ), sodium bisulfite (sodium dithiosulfinate) in the presence of ammonium hydroxide or acidic conditions (acetic acid) in the presence of zinc can make The nitro functional group of F is reduced to the corresponding aniline. Using 1-ethyl-3-methyl-1 H -pyrazole-5-carbonyl isothiocyanate (i), then EDC/DIPEA treatment of bis-aniline G to assemble bis-benzimidazole H. In the final step, methylation is performed under standard conditions (MeI, Cs ₂ CO ₃ ) to provide the target compound of general structure J.

Intermediate

Intermediate i. 1- Ethyl- 3 -methyl- 1 H - pyrazole- 5- carbonyl isothiocyanate

1- Ethyl- 3 -methyl- 1 H - pyrazole- 5- carbonyl chloride

In dichloromethane (DCM) (300 mL) was added a solution of the N-pyrazole-5-carboxylic acid (14.7 g, 95 mmol), - the 1-ethyl-3-methyl -1 H under an atmosphere of N ₂ N -Dimethylformamide (0.185 mL, 2.38 mmol), and then oxalic chloride (9.18 mL, 105 mmol) was added dropwise. The mixture was stirred at room temperature for 2 h. After this duration, the mixture was concentrated to dryness, and the crude title compound (17.18 g) was used without any further purification.

1- Ethyl- 3 -methyl- 1 H - pyrazole- 5- carbonyl isothiocyanate (i)

Add sulfur to a solution of 1-ethyl-3-methyl-1 H -pyrazole-5-carbonyl chloride (17.2 g, 96 mmol) in acetone (300 mL) at 0°C under N _{2 atmosphere.} Potassium cyanate (11.2 g, 115 mmol). The mixture was stirred at room temperature for 4 h. After this duration, the mixture was concentrated to dryness, and the crude product was taken up in hexane (100 mL) and filtered through celite. The solid was washed with hexane (2x) and filtered. The combined filtrates were concentrated under vacuum to give the title compound (16.1 g, 82 mmol, 86% yield) as an orange oil. ¹ H NMR (400 MHz, chloroform- d ) δ ppm 1.38-1.47 (m, 3 H) 2.29-2.35 (m, 3 H) 4.52 (q, J =7.25 Hz, 2 H) 6.75 (s, 1 H) .

Compound example

Example 1. N, N '- (( 2 E, 2' E) - ((E) - but-2-en-1,4-diyl) bis (3-methyl-1,3-dihydro - 2 H -Benzo [d] imidazol- 1 -yl -2- ylidene )) bis (1- ethyl- 3 -methyl- 1 H - pyrazole- 5- carboxamide )

( E )-(4-((2- Nitrophenyl ) amino ) but -2- en- 1 -yl ) aminocarboxylate tertiary butyl ester

To a solution of (E)-(4-aminobut-2-en-1-yl)carbamic acid tert-butyl ester (1 g, 5.4 mmol) in isopropanol (10.7 ml) was added 1-fluoro -2-nitrobenzene (0.57 ml, 5.4 mmol) and DIPEA (2.0 ml, 11.3 mmol). The reaction vessel was capped and heated to 70°C. After stirring for about 1 hour, add ( E )-(4-aminobut-2-en-1-yl) tertiary butyl carbamate (500 mg, 2.68 mmol) and DIPEA (0.938 ml, 5.37 mmol), and the reaction temperature was raised to 80°C. After 3 h, anhydrous sodium bicarbonate (1 g, 11.9 mmol) was added and the mixture was stirred at 80°C. After 5 h, the mixture was allowed to cool to room temperature, resulting in a precipitate. The solids were filtered off and the filtrate was concentrated through a nitrogen purge unit to obtain the title compound as an orange solid. The material will continue to be used without purification. LC-MS m / z 330.1 (M+Na)+, 1.14 min (retention time); ¹ H NMR (400 MHz, CDCl ₃ ) δ ppm 8.22 (dd, J =8.62, 1.52 Hz, 1 H) 8.18 (br . s., 1 H) 7.42-7.51 (m, 1 H) 6.85 (d, J =8.62 Hz, 1 H) 6.71 (ddd, J =8.49, 7.10, 1.14 Hz, 1 H) 5.70-5.88 (m, 3 H) 4.64 (br. s., 1 H) 3.95-4.05 (m, 2 H) 3.69-3.87 (m, 3 H) 1.37-1.60 (m, 9 H).

( E ) -N1 -(2- nitrophenyl ) but -2- ene -1,4- diamine

( E )-(4-((2-nitrophenyl)amino)but-2-en-1-yl)aminocarboxylate (430 mg, 1.4 mmol) was dissolved in dichloromethane (DCM) (7.0 mL). To this clear orange solution was added a 4 M solution of HCl in dioxane (1.8 mL, 7.0 mmol). The mixture was stirred at room temperature. After 18 h, the volatile substances were removed by a nitrogen blow-down unit to obtain a yellow solid. This yellow solid was dried under vacuum to obtain the title compound (400 mg, 1.4 mmol, 97% yield). LC-MS m / z 208.1 (M+H)+, 0.53 min (retention time); ¹ H NMR (400 MHz, DMSO- d ₆ ) δ ppm 8.28 (br. s., 2 H) 8.08 (dd, J =8.62, 1.52 Hz, 2 H) 7.53 (ddd, J =8.68, 6.91, 1.65 Hz, 1 H) 6.98 (dd, J =8.74, 0.89 Hz, 1 H) 6.71 (ddd, J =8.43, 7.03, 1.27 Hz, 1 H) 5.82-6.03 (m, 1 H) 5.63-5.82 (m, 1 H) 4.07 (d, J = 3.80 Hz, 1 H) 3.34-3.54 (m, 2 H).

( E )- N1 , N4 -bis (2- nitrophenyl ) but -2- ene -1,4- diamine

Dissolve ( E ) -N1 -(2-nitrophenyl)but-2-ene-1,4-diamine dihydrochloride (395 mg, 1.410 mmol) in isopropanol (4.7 mL), and Then anhydrous sodium bicarbonate (415 mg, 4.9 mmol) was added. To this heterogeneous yellow solution was added 1-fluoro-2-nitrobenzene (0.15 mL, 1.4 mmol). The reaction vessel was capped, and the mixture was heated to 80°C. After 4 h, additional 1-fluoro-2-nitrobenzene (37 µL, 0.352 mmol) was added, and the mixture was stirred at 80°C for about 14 h. After this duration, the reaction mixture was cooled to room temperature to obtain a precipitate, which was then filtered. The yellow solid was washed with isopropanol, followed by water washing and drying in a vacuum oven at 50°C for 4 hours to obtain the title compound (517 mg, 1.50 mmol, 106% yield) as a yellow/orange solid. LC-MS m / z 329.1 (M+H)+, 1.27 min (retention time); ¹ H NMR (400 MHz, DMSO- d ₆ ) δ ppm 8.28 (t, J =5.58 Hz, 2 H) 8.05 (dd , J =8.62, 1.52 Hz, 2 H) 7.47 (td, J =7.73, 1.27 Hz, 2 H) 6.86-7.06 (m, 2 H) 6.68 (ddd, J =8.43, 7.03, 1.01 Hz, 2 H) 5.77 (t, J =2.41 Hz, 2 H) 3.90-4.16 (m, 4 H).

( E ) -N1,N1' -(But - 2- ene -1,4 -diyl ) bis ( benzene -1,2- diamine )

Dissolve ( E ) -N 1 ,N 4-bis(2-nitrophenyl)but-2-ene-1,4-diamine (517 mg, 1.6 mmol) in methanol (5 mL) and acetic acid (1 mL). Add zinc (721 mg, 11.02 mmol) in equal portions to this yellow heterogeneous solution. The heterogeneous mixture was stirred at room temperature. After stirring at room temperature for 15 minutes, the reaction was filtered through Celite and the filtrate was concentrated. The crude material was purified by silica gel chromatography (2%-10% MeOH:DCM, with NH ₃ as the modifier). The fractions containing the product were combined and concentrated to give the title compound (92 mg, 0.336 mmol, 21% yield) as an off-white solid. LC-MS m / z 269.3 (M+H)+, 0.47 min (retention time); ¹ H NMR (400 MHz, DMSO- d ₆ ) δ ppm 6.66-6.80 (m, 4 H) 6.52-6.66 (m, 4 H) 5.91 (dt, J =2.66, 1.46 Hz, 2 H) 3.69-3.89 (m, 4 H).

(E) - N, N ' - ( but-2-ene-1,4-diyl bis (1 H - benzo [d] imidazole-1,2-diyl)) bis (1-ethyl-3 - methyl - -1 H - pyrazole-5-amine XI)

Dissolve ( E ) -N1,N1' -(but-2-ene-1,4-diyl)bis(benzene-1,2-diamine) (92 mg, 0.343 mmol) in N,N -dimethyl Methamide (DMF) (3.4 mL). The resulting pale orange homogeneous solution was cooled to 0°C. After stirring for 5 minutes at 0°C, a 1 M solution of 1-ethyl-3-methyl-1H-pyrazole-5-carbonyl isothiocyanate in 1,4-dioxane (0.50 mL, 0.50 mmol). The mixture was stirred at 0°C. After 15 minutes, EDC (164 mg, 0.857 mmol) was added, followed by DIPEA (0.30 mL, 1.71 mmol). The reaction mixture was heated to 45°C. After 30 minutes, the reaction was allowed to cool to room temperature. A 4:1 water/saturated _{aqueous NH 4} Cl solution (20 mL) was added, and a light brown solid precipitated. The solid was filtered off and rinsed with water (2×10 mL). The solid was dried in a vacuum oven (50°C) for 4 hours to obtain the title compound (130 mg, 0.216 mmol, 63% yield) as a light brown solid. LC-MS m / z 591.3 (M+H)+, 1.04 min (retention time); ¹ H NMR (400 MHz, DMSO- d ₆ ) δ ppm 12.68 (br. s., 2 H) 7.50 (d, J =7.35 Hz, 2 H) 7.39 (d, J =7.86 Hz, 2 H) 6.93-7.30 (m, 4 H) 6.55 (s, 2 H) 5.90 (br. s., 2 H) 4.83 (br. s ., 4 H) 4.54 (q, J =7.10 Hz, 4 H) 2.13 (s, 6 H) 1.28 (t, J =7.10 Hz, 6 H).

N,N' -((2 E ,2' E )-(( E ) -but -2- ene -1,4 -diyl ) bis (3- methyl- 1,3 -dihydro- 2 H- Benzo [d] imidazol- 1 -yl -2- ylidene )) bis (1- ethyl- 3 -methyl - 1H - pyrazole- 5- carboxamide )

( E ) -N,N' -(But-2-ene-1,4-diylbis( 1H -benzo[d]imidazole-1,2-diyl))bis(1-ethyl- 3-Methyl- 1H -pyrazole-5-formamide) (110 mg, 0.186 mmol) was dissolved in N , N -dimethylformamide (DMF) (2 mL). To the resulting brown solution was added cesium carbonate (203 mg, 0.623 mmol), followed by iodomethane (29.1 μL, 0.466 mmol). The reaction vessel was capped, and the mixture was stirred at room temperature. After stirring at room temperature for 16 hours, cesium carbonate (203 mg, 0.623 mmol) and methyl iodide (29.1 μL, 0.466 mmol) were added, and the mixture was heated to 45°C. After 1 h, the mixture was diluted with a 3:1 chloroform/EtOH solution (15 mL) and water (15 mL). The layers were separated, and the aqueous layer was back-extracted twice with a 3:1 chloroform/EtOH solution (10 mL each time). The combined organic phase was dried over anhydrous MgSO ₄ , filtered and concentrated. The crude material was purified by silica gel chromatography (35%-100% (3:1 EtOAc/EtOH)/heptane as the eluent; the compound appeared at approximately 90% (3:1 EtOAc/EtOH)/heptane). The product-containing fractions were combined and concentrated to give a light brown solid, which was then triturated to provide the title compound (42.2 mg, 0.067 mmol, 35.9% yield) as an off-white solid. LC-MS m / z 619.4 (M+H)+, 0.77 min (retention time); ¹ H NMR (400 MHz, DMSO- d ₆ ) δ ppm 7.56 (d, J =7.86 Hz, 2 H) 7.42 (d , J = 8.11 Hz, 2 H) 7.26-7.36 (m, 2 H) 7.16-7.26 (m, 2 H) 6.43 (s, 2 H) 5.82 (br. s., 2 H) 4.74 (br. s. , 4 H) 4.45 (q, J =7.10 Hz, 4 H) 3.53 (s, 6 H) 2.13 (s, 6 H) 1.22 (t, J =7.10 Hz, 6 H).

Example 2. ( E )-2-((1- ethyl- 3 -methyl - 1H - pyrazole- 5- carbonyl ) imino )-1-(( E )-4-(( E )- 2-((1- ethyl- 3 -methyl- 1 H - pyrazole- 5- carbonyl ) imino )-3 -methyl -2,3 -dihydro- 1 H - benzo [d] imidazole -1 -yl ) but -2- en- 1 -yl )-3 -methyl -2,3 -dihydro - 1H - benzo [d] imidazole -5- carboxylic acid methyl ester

2,2,2- Trifluoro - N -(2- nitrophenyl ) acetamide

To a stirred solution of 2-nitroaniline (50 g, 362 mmol) in dichloromethane (DCM) (700 mL) at 0°C was added DIPEA (190 mL, 1086 mmol), and then TFAA (112 mL , 796 mmol). The resulting reaction mixture was stirred at 28°C for 3 h. After 3 h, water (500 mL) was added to the reaction mixture. The aqueous layer was extracted with DCM (3×500 mL). The combined organic layer was washed with cold water (2×300 mL), followed by brine (500 mL) and dried over anhydrous sodium sulfate. After filtration, the organic layer was concentrated under reduced pressure to obtain a crude material. Water (600 mL) was added to the crude material and the mixture was stirred at room temperature for 1 h. The obtained yellow solid was filtered and dried under vacuum to give the title compound (70 g, 294 mmol, 81% yield) as a yellow solid. LC-MS m / z 233 (MH)+, 2.05 min (retention time).

( E ) -N -(4- Bromobut- 2- en- 1 -yl )-2,2,2- trifluoro - N -(2- nitrophenyl ) acetamide

To a stirred solution of 2,2,2-trifluoro-N -(2-nitrophenyl)acetamide (70 g, 299 mmol) in acetonitrile (1400 mL) at 0°C was added potassium carbonate (45.5 g , 329 mmol), followed by ( E )-1,4-dibromobut-2-ene (160 g, 747 mmol). The reaction mixture was stirred at 28°C for 3 h. After 3 h, the reaction mixture was filtered and washed with DCM (1000 ml). The filtrate was concentrated under reduced pressure to obtain a brown oil (250 g). The brown oil was absorbed onto silica gel (500 g) and purified by silica gel chromatography (10%-15% EtOAc in petroleum ether) to give the title compound (75 g, 202 mmol) as a yellow semi-solid , 68% yield). LC-MS m / z 287 (M-Br)+, 2.38 min (retention time).

Methyl 3- nitro- 4-(2,2,2- trifluoroacetamido ) benzoate

To a stirred solution of 4-amino-3-nitrobenzoic acid methyl ester (20 g, 102 mmol) in dichloromethane (DCM) (300 mL) at 0°C was added DIPEA (53.4 mL, 306 mmol) , Then add TFAA (31.7 mL, 224 mmol) dropwise. The resulting reaction mixture was stirred at 28°C for 3 h. After 3 h, water (500 mL) was added to the reaction mixture, and it was extracted with DCM (3×200 mL). The combined organic layer was washed with cold water (2×200 mL), followed by brine (200 mL) and dried over sodium sulfate. After filtration, the organic layer was concentrated under reduced pressure to obtain the crude title compound (30 g) as a brown liquid. The brown liquid was then absorbed onto silica gel (60 g) and purified by silica gel chromatography (10%-15% EtOAc in petroleum ether) to provide the title compound as a yellow solid (18 g, 59 mmol, 58 %Yield). LC-MS m / z 290.9 (M+H)+, 2.22 min (retention time).

( E )-3 -nitro- 4-((4-(2,2,2- trifluoro - N -(2- nitrophenyl ) acetamido ) but -2- en- 1 -yl ) Amino ) benzoic acid methyl ester

Add carbonic acid to a stirred solution of 3-nitro-4-(2,2,2-trifluoroacetamido)benzoic acid methyl ester (15 g, 51.3 mmol) in acetonitrile (250 mL) at room temperature Potassium (15.6 g, 113 mmol), then add ( E ) -N -(4-bromobut-2-en-1-yl)-2,2,2-trifluoro- N -(2-nitrophenyl) Acetamide (22.6 g, 61.6 mmol). The reaction was stirred at 70°C for 16 h. After this duration, the reaction mixture was filtered and washed with DCM (300 ml). The filtrate was concentrated under reduced pressure to obtain the crude title compound (40 g) as a brown oil. The brown oil was adsorbed onto silica gel (80 g) and purified by silica gel chromatography (20%-25% EtOAc in petroleum ether) to obtain the title compound (20 g, 34.9 mmol, 68% yield). LC-MS m / z 482.9 (M+H)+, 2.62 min (retention time).

( E )-3 -nitro- 4-((4-((2- nitrophenyl ) amino ) but -2- en- 1 -yl ) amino ) benzoic acid methyl ester

To (E )-3-nitro-4-((4-(2,2,2-trifluoro- N -(2-nitrophenyl)acetamido)but-2-ene at 28℃ -1-yl) amino) benzoic acid methyl ester (20 g, 41.5 mmol) in methanol (150 mL) and dichloromethane (DCM) (300 mL) in a stirred solution of potassium carbonate (14.3 g, 104 mmol) ). The reaction was stirred at 28°C for 16 h. After 16 h, the reaction mixture was filtered and washed with DCM (300 ml). The filtrate was concentrated under reduced pressure to obtain a residue. Water (200 mL) was added to the residue, and the mixture was stirred at room temperature for 1 h. The yellow solid obtained was filtered and dried under vacuum to give the title compound (13 g, 32.9 mmol, 79% yield) as a yellow solid. LC-MS m / z 387 (M+H)+, 2.54 min (retention time).

( E )-3 -amino- 4-((4-((2 -aminophenyl ) amino ) but -2- en- 1 -yl ) amino ) benzoic acid methyl ester

To (E )-3-nitro-4-((4-((2-nitrophenyl)amino)but-2-en-1-yl)amino)benzoic acid methyl ester at 0℃ A stirred solution of (13 g, 33.6 mmol) in methanol (300 mL) was added dropwise with ammonium hydroxide (114 mL, 673 mmol). Then a solution of sodium dithiosulfinate (58.6 g, 336 mmol) in water (150 mL) was added dropwise at 0°C. The reaction was stirred at 28°C for 32 h. After 32 h, the reaction mixture was filtered through celite and washed with ethyl acetate (500 ml). The filtrate was evaporated under reduced pressure to obtain a residue. Water was added to the residue and the resulting mixture was stirred at room temperature for 1 h. The obtained solid was filtered and dried under vacuum to give the title compound (7.5 g, 22.4 mmol, 66.7% yield) as a brown solid. LC-MS m / z 327 (M+H)+, 1.28 min (retention time).

(E) -2- (1- ethyl-3-methyl -1 H - pyrazole-5-acyl amino) -1- (4- (2- (1-ethyl-3-methyl - 1 H -pyrazole- 5- carboxamido )-1 H -benzo [d] imidazol- 1 -yl ) but -2- en- 1 -yl )-1 H -benzo [d] imidazole- 5 - carboxylic acid methyl ester

To (E )-3-amino-4-((4-((2-aminophenyl)amino)but-2-en-1-yl)amino)benzoic acid methyl ester at 28℃ (4 g, 12.25 mmol) in a stirred solution of N,N -dimethylformamide (DMF) (80 mL) add 1-ethyl-3-methyl-1 H -pyrazole-5 carbonyl isosulfide Cyanate ester (7.2 g, 36.8 mmol) and stir for 5 h. After 5 h, EDC (14.1 g, 73.5 mmol) was added to the reaction mixture at 0°C, followed by triethylamine (27.3 mL, 196 mmol), and the resulting reaction mixture was stirred at 28°C for 16 h. After 16 h, water (500 ml) was added to the reaction mixture and stirred at room temperature for 1 h. The obtained solid was filtered, washed with diethyl ether (200 ml) and dried under vacuum to give the title compound (4.5 g, 6.7 mmol, 55% yield) as an off-white solid. LC-MS m / z 648.9 (M+H)+, 2.43 min (retention time).

( E )-2-((1- ethyl- 3 -methyl- 1 H - pyrazole- 5- carbonyl ) imino )-1-(( E )-4-(( E )-2-( (1- Ethyl- 3 -methyl - 1H - pyrazole- 5- carbonyl ) imino )-3 -methyl -2,3 -dihydro - 1H - benzo (d) imidazole- 1- (Yl ) but -2- en- 1 -yl )-3 -methyl -2,3 -dihydro - 1H - benzo [d] imidazole -5- carboxylic acid methyl ester

To ( E )-2-((1-ethyl-3-methyl-1 H -pyrazole-5-carbonyl)imino)-1-(( E )-4-((E )-2-((1-ethyl-3-methyl-1H-pyrazole-5-carbonyl)imino)-2,3-dihydro-1H benzo(d)imidazol-1-yl)butane -2-en-1-yl)-2,3-dihydro-1H-benzo[d]imidazole-5-carboxylic acid methyl ester (3.5 g, 5.4 mmol) in N,N -dimethylformamide (DMF) Add cesium carbonate (7.0 g, 21.6 mmol) to the stirred solution in (50 mL), followed by methyl iodide (1.3 mL, 21.6 mmol). The reaction was stirred at 28°C for 3 h in a sealed tube. After 3 h, water (500 ml) was added to the reaction mixture and stirred at room temperature for 1 h. The obtained solid was filtered, washed with diethyl ether (200 ml) and dried under vacuum to give the title compound (2.2 g, 3.0 mmol, 56% yield) as an off-white solid. LC-MS m / z 677.2 (M+H)+, 1.95 min (retention time); ¹ H NMR (400 MHz, DMSO- d ₆ ) δ ppm 8.07 (d, J = 1.2 Hz, 1H), 7.82 (dd , J = 1.60, 8.4 Hz, 1H), 7.55 (d, J = 8.0 Hz, 1H), 7.50 (d, J = 8.4 Hz, 1H), 7.42 (d, J = 8.0 Hz, 1H), 7.29-7.29 (m, 1H), 7.19-7.20 (m, 1H), 6.44 (s, 1H), 6.40 (d, J = 0.4 Hz, 1H), 5.81 (q, J = 4.4 Hz, 2H), 4.75 (t, J = 4.0 Hz, 4H), 4.42-4.42 (m, 4H), 3.90 (s, 3H), 3.57 (s, 3H), 3.53 (s, 3H), 2.13 (s, 3H), 2.12 (s, 3H) ), 1.23 (t, J = 2.8 Hz, 3H), 1.21 (t, J = 4.8 Hz, 3H).

Example 3. 1- Ethyl - N -(( E )-3-(( E )-4-(( E )-2-((1- ethyl- 3 -methyl- 1 H - pyrazole- 5 - carbonyl) imino) -3-methyl-2,3-dihydro -1 H - benzo [d] imidazol-1-yl) but-2-en-1-yl) -4-methoxy -1 -Methyl- 1,3 -dihydro- 2 H -benzo [d] imidazol -2- ylidene )-3 -methyl- 1 H -pyrazole- 5- carboxamide

2,2,2- Trifluoro - N -(2 -methoxy- 6- nitrophenyl ) acetamide

To a stirred solution of 2-methoxy-6-nitroaniline (1.5 g, 8.9 mmol) in dichloromethane (DCM) (18 mL) at 0°C, DIPEA (4.7 mL, 26.8 mmol) was added, followed by TFAA (2.77 mL, 19.63 mmol) was added dropwise. The resulting reaction mixture was stirred at 28°C for 3 h. After this duration, the volatile substances are removed under reduced pressure to obtain a brown viscous material. Water (15 mL) was added and the resulting mixture was stirred at room temperature for 1 h. The obtained pale yellow precipitate was filtered and dried under vacuum to obtain the title compound (2 g, 7.46 mmol, 84% yield) as a pale yellow solid. LC-MS m / z 263 (M+H)+, 1.84 min (retention time).

( E )-2,2,2- Trifluoro - N -(2 -Methoxy- 6- nitrophenyl ) -N -(4-(2,2,2- Trifluoro - N -(2- Nitrophenyl ) acetamido ) but -2- en- 1 -yl ) acetamide

Add 2,2,2-trifluoro-N- (2-methoxy-6-nitrophenyl)acetamide (1.0 g, 3.8 mmol) in acetonitrile (15 mL) at room temperature under a nitrogen atmosphere Add ( E ) -N -(4-bromobut-2-en-1-yl)-2,2,2-trifluoro- N -(2-nitrophenyl)acetamide (see above Text, 1.7 g, 4.5 mmol) and potassium carbonate (1.2 g, 8.3 mmol). The resulting reaction mixture was stirred at 70°C for 16 h. After this duration, the reaction mixture was filtered through celite and the filtrate was concentrated under reduced pressure. The obtained residue was dissolved in ethyl acetate (20 mL) and washed with water (20 mL). The aqueous layer was extracted with EtOAc (2×20 mL), and the combined organic layer was washed with brine (20 mL) and dried over anhydrous sodium sulfate. After filtration, the organic layer was concentrated under reduced pressure to obtain a brown liquid. The brown liquid was then absorbed onto silica gel (5 g) and purified by silica gel chromatography (5%-20% EtOAc in petroleum ether) to obtain the title compound (700 mg, 1.2 mmol, 31% yield). LC-MS m / z 551 (M+H)+, 2.60 min (retention time).

( E ) -N1 -(2 -Methoxy- 6- nitrophenyl ) -N4 -(2- nitrophenyl ) but -2- ene -1,4- diamine

To (E )-2,2,2-trifluoro- N -(2-methoxy-6-nitrophenyl) -N -(4-(2,2,2) under nitrogen atmosphere at room temperature -Trifluoro- N -(2-nitrophenyl)acetamido)but-2-en-1-yl)acetamide (1.1 g, 2.0 mmol) in methanol:DCM 1:2 mixture (30 Add potassium carbonate (0.691 g, 5.0 mmol) to the suspension in mL). The reaction mixture was stirred at 27°C for 16 h. After this duration, the reaction mixture was filtered through Celite. The filtrate was evaporated under reduced pressure, and the resulting residue was dissolved in EtOAc (100 mL) and washed with water (50 mL) and brine (50 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated to obtain a brown residue. The brown residue was then adsorbed onto silica gel (1.2 g) and purified by silica gel chromatography (15% EtOAc in petroleum ether) to give the title compound (0.45 g, 1.22 mmol, 61 %Yield). LC-MS m / z 359 (M+H)+, 2.60 min (retention time).

( E ) -N1 -(4-((2 -aminophenyl ) amino ) but -2- en- 1 -yl )-6 -methoxybenzene -1,2- diamine

To ( E ) -N1 -(2-methoxy-6-nitrophenyl) -N4- (2-nitrophenyl)but-2-ene-1,4- A stirred suspension of diamine (0.4 g, 1.1 mmol) in methanol (16 mL) was added with a solution of ammonium hydroxide (0.78 g, 22.3 mmol) and sodium dithiosulfinate in water (8 mL) (1.9 g , 11.2 mmol). The reaction mixture was stirred at room temperature for 8 h. After this duration, the reaction mixture was filtered through celite and washed with MeOH (2×10 mL). The filtrate was evaporated, and the resulting material was dissolved in water (30 mL), then extracted with EtOAc (2×50 mL). The combined organic layer was washed with brine (30 mL) and dried over sodium sulfate. After filtration, the organic layer was concentrated under reduced pressure to obtain a brown residue. The brown residue was then adsorbed onto silica gel and purified by silica gel chromatography (80% EtOAc in petroleum ether) to obtain the title compound (300 mg, 0.95 mmol, 85% yield) as a brown gum . LC-MS m / z 299 (M+H)+, 0.96 min (retention time).

( E )-1 -ethyl - N -(1-(4-(2-(1- ethyl- 3 -methyl- 1 H - pyrazole- 5- carboxamido )-1 H - benzo [d] imidazol-1-yl) but-2-en-1-yl) -7-methoxy -1 H - benzo [d] imidazol-2-yl) -3-methyl -1 H - pyrazol Azol - 5-carboxamide

Add ( E ) -N1 -(4-((2-aminophenyl)amino)but-2-en-1-yl)-6-methoxybenzene-1,2-diamine (0.25 g, 0.84 mmol) and 1-ethyl-3-methyl-1 H -pyrazole-5-carbonyl isothiocyanate (0.82 g, 4.2 mmol) in N,N -dimethylformamide (DMF) ( The solution in 12 mL) was stirred for 4 h at room temperature under nitrogen. After this duration, triethylamine (1.4 g, 13.4 mmol) and 3-(((ethylimino)methylene)amino) -N,N -dimethylpropane- 1-amine-hydrochloride (1.1 g, 5.9 mmol), and the resulting reaction mixture was stirred at room temperature for 16 h. After this duration, water (30 ml) was added and the resulting reaction mixture was stirred at room temperature for 1 h. The mixture was filtered, and the collected solid was washed with pentane (30 ml) and dried under vacuum to give the title compound (300 mg, 0.42 mmol, 58% yield) as a white solid. LC-MS m / z 621 (M+H)+, 2.40 min (retention time).

1- Ethyl - N -(( E )-3-(( E )-4-(( E )-2-((1- ethyl- 3 -methyl- 1 H -pyrazole- 5- carbonyl ) Imino )-3 -methyl -2,3 -dihydro - 1H - benzo (d) imidazol- 1 -yl ) but -2- en- 1 -yl )-4 -methoxy- 1- Methyl- 1,3 -dihydro- 2 H -benzo [d] imidazol -2- ylidene )-3 -methyl- 1 H -pyrazole- 5- carboxamide

To 1-ethyl- N -(( E )-1-(( E )-4-(( E )-2-((1-ethyl-3-methyl-1 H -pyrazole) at 0℃ -5-carbonyl)imino)-2,3-dihydro- 1H -benzo(d)imidazol-1-yl)but-2-en-1-yl)-7-methoxy-1, 3-Dihydro- 2H -benzo[d]imidazole-2-ylidene)-3-methyl- 1H -pyrazole-5-carboxamide (0.3 g, 0.48 mmol) and cesium carbonate (0.787 g , 2.42 mmol) in a stirred suspension of N , N -dimethylformamide (DMF) (12 mL) was added methyl iodide (0.343 g, 2.42 mmol). The resulting reaction mixture was stirred at room temperature for 18 h. After this duration, the reaction was warmed to 45°C and stirred for 1 h. After this duration, the reaction mixture was filtered through Celite and washed with EtOAc (2×20 mL). The filtrate was concentrated under reduced pressure. This concentrated filtrate was dissolved in 20 mL 3:1 DCME:EtOH and washed with water (10 mL), brine (20 mL) and dried over anhydrous sodium sulfate. After filtration, the organic layer was concentrated under reduced pressure to obtain a crude compound. Then the crude compound was purified by reversed-phase HPLC (Sunfire C18 (19*150) mm 5 micron column, eluent is 0.1% TFA in water:acetonitrile, 10 mL/min flow rate) to obtain TFA contaminants The title compound. The material was then stirred in aqueous ammonia (1 mL), separated and filtered, and the collected solids were washed with water and pentane and then dried under vacuum to give the title compound (25 mg, 0.038 mmol, 8%) as an off-white solid Yield). LC-MS m / z 649 (M+H)+, 2.29 min (retention time); ¹ H NMR (400 MHz, DMSO- d ₆ ) δ ppm 7.56 (d, J =7.6 Hz, 1H), 7.39 (d , J = 8.0 Hz, 1H), 7.31 (dd, J = 8.0, 7.6 Hz, 1H), 7.27-7.15 (m, 3H), 6.89 (d, J = 8.0 Hz, 1H), 6.41 (s, 3H) , 6.40 (s, 1H), 5.89-5.83 (m, 1H), 5.67-5.62 (m, 1H), 4.83 (q, J = 5.6 Hz, 2H), 4.73 (q, J = 5.6 Hz, 2H), 4.48-4.42 (m, 4H), 3.71(s, 1H), 3.53 (s, 3H), 3.49(s, 3H).

Example 4. 1- Ethyl - N -(( E )-3-(( E )-4-(( E )-2-((1- ethyl- 3 -methyl- 1 H - pyrazole- 5 - carbonyl) imino) -7- (3-hydroxypropoxy) -3-methyl-2,3-dihydro -1 H - benzo [d] imidazol-1-yl) but-2-ene -1 -yl )-4 -methoxy- 1 -methyl- 1,3 -dihydro- 2 H -benzo [d] imidazole -2- ylidene )-3 -methyl- 1 H - pyrazole -5- methylamide

( E )-(4-((2 -Methoxy- 6- nitrophenyl ) amino ) but -2- en- 1 -yl ) carbamic acid tertiary butyl ester

To ( E )-(4-aminobut-2-en-1-yl) tertiary butyl carbamate (1.2 g, 6.4 mmol; Friedman Ohana, R. et al., ACS Chem. Biol. 2016 , 2608-2617) and DIPEA (1.5 mL, 8.8 mmol) in isopropanol (25 mL) was added 2-fluoro-1-methoxy-3-nitrobenzene (1 g, 5.8 mmol). The mixture was stirred at 60°C for 66 h, then concentrated. The residue was dissolved in ethyl acetate and washed with water and brine. The organic layer was dried (anhydrous sodium sulfate), filtered, and concentrated. The residue was purified by silica gel chromatography (RediSep Gold 40g 10%-30% ethyl acetate/heptane) to provide the title compound as an orange solid. LC-MS m / z 369,1 (M+Na)+, 1.09 min (retention time).

( E )-(4-((2- Amino -6 -methoxyphenyl ) amino ) but -2- en- 1 -yl ) aminocarboxylate tertiary butyl ester

To ( E )-(4-((2-methoxy-6-nitrophenyl)amino)but-2-en-1-yl)carbamic acid tert-butyl ester (450 mg, 1.3 mmol ) Solution in methanol (10 mL) Add sodium bisulfite (1.4 g, 6.7 mmol) in water (4 mL). The mixture was stirred at room temperature for 1 h, and then concentrated. The residue was partitioned between water and dichloromethane. The layers were separated and the aqueous layer was extracted with dichloromethane. The combined organic layer was washed with brine, dried (anhydrous sodium sulfate), filtered and concentrated to provide the title compound as a yellow oil. LC-MS m / z 308.3 (M+H)+, 0.58 min (retention time).

( E )-(4-(2-(1- ethyl- 3 -methyl- 1 H - pyrazole- 5- carboxamido )-7- methoxy- 1 H - benzo [d] imidazole -1 -yl ) but -2- en- 1 -yl ) tertiary butyl carbamate

(E )-(4-((2-Amino-6-methoxyphenyl)amino)but-2-en-1-yl)carbamic acid tertiary butyl ester cooled in an ice bath (6.1 g, 19.8 mmol) in N,N -dimethylformamide (DMF) (60 mL), add 1-ethyl-3-methyl-1 H -pyrazole-5-carbonyl dropwise Isothiocyanate (21.8 mL, 21.8 mmol). After stirring for 60 min, TEA (5.5 mL, 39.7 mmol) and EDC (4.57 g, 23.81 mmol) were added, and the ice bath was removed. The mixture was stirred at room temperature for 18 h, and then diluted with water. The mixture was extracted with dichloromethane. The combined organic layer was washed with water and brine, dried (anhydrous sodium sulfate), filtered and concentrated to provide the crude product (11.9 g, 25.4 mmol, 128%) as a yellow solid. LC-MS m / z 469.5 (M+H)+, 1.02 min (retention time).

(( E )-4-(( E )-2-((1- ethyl- 3 -methyl- 1 H - pyrazole- 5- carbonyl ) imino )-7- methoxy- 3 -methyl Tertiary butyl - 2,3 -dihydro- 1 H - benzo [d] imidazol- 1 -yl ) but -2- en- 1 -yl )carbamate

To (( E )-4-(( E )-2-((1-ethyl-3-methyl- 1H -pyrazole-5-carbonyl)imino)-7- cooled in an ice bath Tertiary butyl methoxy-2,3-dihydro-1 H -benzo[d]imidazol-1-yl)but-2-en-1-yl)carbamate (3 g, 5.3 mmol) To a solution in N,N -dimethylformamide (DMF) (20 mL), cesium carbonate (2.60 g, 7.97 mmol) and methyl iodide (0.4 mL, 6.4 mmol) were added sequentially. The ice bath was removed, and the mixture was stirred at room temperature for 3 days. Add cesium carbonate (1.7 g, 5.3 mmol) and methyl iodide (0.4 mL, 6.4 mmol) and continue stirring for 4 h. After diluting with water and dichloromethane, the layers were separated and the aqueous layer was extracted with dichloromethane. The combined organic layer was washed with water and brine, dried (anhydrous sodium sulfate), filtered and concentrated. The crude material was purified by silica gel chromatography [RediSep Gold 80g, 10%-60% (3:1 ethyl acetate:ethanol)/dichloromethane] to provide the title compound as a white foamy solid (1.6 g, 63 %Yield). LC-MS m / z 483.5 (M+H)+, 0.83 min (retention time).

Tert-butyl (3- (2-fluoro-3-nitrophenyl) propoxy) dimethyl Silane

To the mixture of 2-fluoro-3-nitrophenol (1 g, 6.4 mmol) and potassium carbonate (1.9 g, 14.0 mmol) in N,N -dimethylformamide (DMF) (15 mL), add the first Tributyl(3-(2-fluoro-3-nitrophenoxy)-propoxy)dimethylsilane (2.0 g, 6.1 mmol). The mixture was stirred at 80°C for 2 h, then diluted with water and extracted with diethyl ether (3×). The organic layer was washed sequentially with water, 10% lithium chloride aqueous solution and water. The organic layer was dried (anhydrous sodium sulfate), filtered, and concentrated. The residue was purified by silica gel chromatography (Redisep Rf Gold column 40 g, 0%-30% ethyl acetate/heptane) to provide the title compound as an amber liquid (2.1 g, 6.1 mmol, 96% yield) . ¹ H NMR (400 MHz, DMSO- d ₆ ) δ ppm 0.02 (s, 6 H) 0.84-0.88 (m, 9 H) 1.85-2.04 (m, 2 H) 3.72-3.81 (m, 2 H) 4.13- 4.30 (m, 2 H) 7.27-7.42 (m, 1 H) 7.54-7.71 (m, 2 H).

N -(( E )-3-(( E )-4 -aminobut -2- en- 1 -yl )-4 -methoxy- 1 -methyl- 1,3 -dihydro- 2 H- Benzo [d] imidazole -2- ylidene )-1 -ethyl- 3 -methyl- 1 H - pyrazole- 5- carboxamide hydrochloride

To (( E )-4-(( E )-2-((1-ethyl-3-methyl- 1H -pyrazole-5-carbonyl)imino)-7-methoxy-3- Tertiary butyl methyl-2,3-dihydro-1 H -benzo[d]imidazol-1-yl)but-2-en-1-yl)carbamate (1.5 g, 3.0 mmol) in Add HCl (4 M dioxane solution) (3.0 mL, 12.0 mmol) to the suspension in methanol (15 mL). The mixture was allowed to warm to room temperature and stirred for 16 h, then concentrated to provide the title compound, which was used without further purification (1.3 g). LC-MS m / z 383.3 (M+H)+, 0.50 min (retention time).

N -(( E )-3-(( E )-4-((2-(3-(( tertiary butyldimethylsilyl ) oxy ) propoxy )-6- nitrophenyl ) Amino ) but -2- en- 1 -yl )-4 -methoxy- 1 -methyl- 1,3 -dihydro - 2H - benzo (d) imidazole -2- ylidene )-1- Ethyl- 3 -methyl- 1 H - pyrazole- 5- carboxamide

To N -(( E )-3-(( E )-4-aminobut-2-en-1-yl)-4-methoxy-1-methyl-1,3-dihydro-2 H -Benzo[d]imidazole-2-ylidene)-1-ethyl-3-methyl-1 H -pyrazole-5-carboxamide hydrochloride (1.3g, 3 mmol), DIPEA (1.6 mL , 9.0 mmol) and isopropanol (25 mL) add tertiary butyl (3-(2-fluoro-3-nitrophenoxy)propoxy) dimethyl silane (0.946 g, 2.87 mmol) . The mixture was stirred at 60°C for 3 days, then cooled to room temperature and concentrated. The crude was dissolved in dichloromethane and washed with water and brine. The organic layer was dried (anhydrous sodium sulfate), filtered and concentrated to provide a mixture of silylation and desilylation products (2 g). To a solution of this product mixture (2 g) in N,N -dimethylformamide (DMF) (12 mL) was added imidazole (0.354 g, 5.19 mmol) and TBDMS-Cl (0.783 g, 5.19 mmol). The mixture was stirred at room temperature for 2 h, and then diluted with ethyl acetate and water. The organic layer was washed with water and brine, then dried (anhydrous sodium sulfate), filtered and concentrated to provide the title compound, which was used without further purification (2.5 g). LC-MS m / z 692.4 (M+H)+, 1.34 min (retention time).

N -(( E )-3-(( E )-4-((2- amino -6-(3-(( tertiary butyldimethylsilyl ) oxy ) propoxy ) phenyl ) Amino ) but -2- en- 1 -yl )-4 -methoxy- 1 -methyl- 1,3 -dihydro - 2H - benzo (d) imidazole -2- ylidene )-1- Ethyl- 3 -methyl- 1 H - pyrazole- 5- carboxamide

To the N -(( E )-3-(( E )-4-((2-(3-((tertiary butyldimethylsilyl)oxy)propoxy)- 6-nitrophenyl)amino)but-2-en-1-yl)-4-methoxy-1-methyl-1,3-dihydro-2H-benzo[d]imidazole-2- Subunit)-1-ethyl-3-methyl-1 H -pyrazole-5-carboxamide (2.4 g, 3.5 mmol) in methanol (20 mL) is added to water (8.4 mL) Sodium bisulfite (2.8 g, 13.9 mmol). The ice bath was removed and the mixture was stirred at room temperature for 30 min, and then concentrated. The residue was partitioned between water and 3:1 chloroform/ethanol. The layers were separated, and the aqueous layer was extracted with 3:1 chloroform/ethanol. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated to provide the title compound (2.3 g, 3.4 mmol, 98%) as an amber oil. LC-MS m / z 662.4 (M+H)+, 1.03 min (retention time).

N -(( E )-7-(3-(( tertiary butyldimethylsilyl ) oxy ) propoxy )-1-(( E )-4-(( E )-2-(( 1- Ethyl- 3 -methyl- 1 H - pyrazole- 5- carbonyl ) imino )-7- methoxy- 3 -methyl -2,3 -dihydro- 1 H - benzo (d ] Imidazol- 1 -yl ) but -2- en- 1 -yl )-1,3 -dihydro - 2H - benzo [d] imidazol -2- ylidene )-1 -ethyl- 3 -methyl -1 H -pyrazole- 5- carboxamide

To N -(( E )-3-(( E )-4-((2-amino-6-(3-((tertiary butyldimethylsilyl)oxy) cooled in an ice bath Propoxy)-phenyl)amino)but-2-en-1-yl)-4-methoxy-1-methyl-1,3-dihydro-2H-benzo(d)imidazole-2 -Subunit)-1-ethyl-3-methyl-1H-pyrazole-5-carboxamide (2.2 g, 3.3 mmol) in N,N -dimethylformamide (DMF) (20 mL) Add 1-ethyl-3-methyl-1 H -pyrazole-5-carbonyl isothiocyanate (3.7 mL, 3.7 mmol) dropwise to the solution in the solution. After stirring for 90 min, TEA (0.927 mL, 6.65 mmol) and EDC (0.765 g, 3.99 mmol) were added, and the ice bath was removed. The mixture was stirred at room temperature for 18 h, and then diluted with water. The mixture was extracted with dichloromethane. The combined organic layer was washed with water and brine, dried over anhydrous sodium sulfate, filtered and concentrated. The crude material was purified by silica gel chromatography [RediSep Gold 80g, 0-50% (3:1 ethyl acetate:ethanol)/heptane] to provide the title compound (1.5 g, 1.8 mmol, 55 %Yield). LC-MS m / z 823.3 (M+H)+, 1.28 min (retention time).

N -(( E )-3-(( E )-4-(( E )-7-(3-(( tertiary butyldimethylsilyl ) oxy ) propoxy )-2-(( 1- Ethyl- 3 -methyl - 1H - pyrazole- 5- carbonyl ) imino )-3 -methyl -2,3 -dihydro - 1H - benzo [d] imidazol- 1 -yl )But - 2- en- 1 -yl )-4 -methoxy- 1 -methyl- 1,3 -dihydro - 2H - benzo [d] imidazol -2- ylidene )-1 -ethyl -3 -methyl- 1 H - pyrazole- 5- carboxamide

To the N -(( E )-7-(3-((tertiary butyldimethylsilyl)oxy)propoxy)-1-(( E )-4-(( E )-2-((1-ethyl-3-methyl- 1H -pyrazole-5-carbonyl)imino)-7-methoxy-3-methyl-2,3-dihydro- 1 H -Benzo[d]imidazol-1-yl)but-2-en-1-yl)-1,3-dihydro-2 H -benzo[d]imidazol-2-ylidene)-1- Ethyl-3-methyl-1 H -pyrazole-5-carboxamide (1.5 g, 1.8 mmol) in N , N -dimethylformamide (DMF) (12 mL) was added sequentially Cesium carbonate (0.891 g, 2.73 mmol) and methyl iodide (0.137 mL, 2.2 mmol). The ice bath was removed, and the mixture was stirred at room temperature for 64 h. After diluting with water, the precipitate was filtered and rinsed with water. The collected solid was dried in vacuum to provide the title compound, which was used without further purification (1.4 g, 92% yield). LC-MS m / z 837.4 (M+H)+, 1.17 min (retention time).

1- Ethyl - N -(( E )-3-(( E )-4-(( E )-2-((1- ethyl- 3 -methyl- 1 H -pyrazole- 5- carbonyl ) Imino )-7-(3 -hydroxypropoxy )-3 -methyl -2,3 -dihydro- 1 H - benzo (d) imidazol- 1 -yl ) but -2- ene- 1- Yl )-4 -methoxy- 1 -methyl- 1,3 -dihydro - 2H - benzo [d] imidazole -2- ylidene )-3 -methyl - 1H - pyrazole- 5- Formamide

To N -(( E )-3-(( E )-4-(( E )-7-(3-((tertiary butyldimethylsilyl)oxy)propoxy)-2-( (1-Ethyl-3-methyl- 1H -pyrazole-5-carbonyl)imino)-3-methyl-2,3-dihydro- 1H -benzo(d)imidazole-1- (Yl)but-2-en-1-yl)-4-methoxy-1-methyl-1,3-dihydro- 2H -benzo(d)imidazol-2-ylidene)-1-ethyl A solution of phenyl-3-methyl- 1H -pyrazole-5-carboxamide (150 mg, 0.179 mmol) in methanol (2 mL) was added with HCl methanol solution (0.29 mL, 0.36 mmol). The mixture was stirred at room temperature for 2 h, then HCl methanol solution (0.72 mL, 0.90 mmol) was added and stirring was continued for 16 h. After concentration, the residue was purified by reversed-phase HPLC/MS [Waters XSelect 5 μm C18, 150 × 30 mm, 15%-55% CH ₃ CN: H ₂ O, 0.1% TFA as modifier]. The fraction containing the desired product is passed through a PL-HCO3 MP SPE column. The eluate was concentrated to provide the title compound (64 mg, 49% yield). LC-MS m / z 723.3 (M+H)+, 0.72 min (retention time). ¹ H NMR (400 MHz, DMSO- d ₆ ) δ ppm 1.21 (td, J =7.15, 3.01 Hz, 6 H) 1.69 (quin, J =6.21 Hz, 2 H) 2.12 (s, 3 H) 2.12 ( s, 3 H) 3.43 (t, J =6.15 Hz, 2 H) 3.49 (s, 3 H) 3.50 (s, 3 H) 3.64 (s, 3 H) 3.96 (t, J =6.40 Hz, 2 H) 4.40-4.49 (m, 4 H) 4.77-4.87 (m, 4 H) 5.64-5.78 (m, 2 H) 6.39 (s, 1 H) 6.40 (s, 1 H) 6.85 (dd, J =7.78, 2.76 Hz, 2 H) 7.13-7.18 (m, 2 H) 7.20-7.27 (m, 2 H).

Example 5. ( E )-1 -Ethyl - N -(3-(( E )-4-(( E )-2-((1- Ethyl- 3 -methyl- 1 H - pyrazole- 5 - carbonyl) imino) -3-methyl-2,3-dihydro -1 H - benzo [d] imidazol-1-yl) but-2-en-1-yl) -4- (hydroxy carboxylic Yl )-1 -methyl- 1 H - benzo [d] imidazole -2(3 H ) -ylidene )-3 -methyl- 1 H - pyrazole- 5- carboxamide

( E )-(4-((2- Nitrophenyl ) amino ) but -2- en- 1 -yl ) aminocarboxylate tertiary butyl ester

Combine 1-fluoro-2-nitrobenzene (0.749 mL, 7.09 mmol), ( E )-(4-aminobut-2-en-1-yl) amino acid tert-butyl ester (1.6 g, 8.5 A mixture of DIPEA (2.476 mL, 14.17 mmol) and isopropanol (20 mL) was stirred at room temperature for 3 days. The mixture was stirred at 50°C for another 20 hours. The mixture was concentrated and the residue was redissolved in ethyl acetate and washed with water. The organic layer was dried over anhydrous MgSO ₄ . The organic layer was filtered and the filtrate was concentrated. The crude product was purified by silica gel chromatography using a gradient of 0% to 40% ethyl acetate in heptane. The title compound (1.9 g, 6.2 mmol, 87% yield) was obtained as an orange oil. LC-MS m / z 308.1 (M+H) ⁺ , 1.10 min (retention time).

2- fluoro -1-(( methoxymethoxy ) methyl )-3 -nitrobenzene

To a solution of (2-fluoro-3-nitrophenyl)methanol (1.0 g, 5.84 mmol) in dichloromethane (DCM) (20 mL) was added DIPEA (2.041 mL, 11.69 mmol), followed by MOM-Cl (0.577 mL, 7.60 mmol). The reaction mixture was stirred at room temperature for 3 days. The mixture was diluted with water and extracted with dichloromethane. The organic extract was dried over anhydrous MgSO ₄ . The organic extract was filtered and the filtrate was concentrated. The crude product was purified by silica gel chromatography using a gradient of 0% to 30% ethyl acetate in heptane. The title compound (1.1 g, 5.1 mmol, 87% yield) was obtained as a pale yellow oil. ¹ H NMR (400 MHz, chloroform- d ) d ppm 3.44 (s, 3 H) 4.75 (s, 2 H) 4.78 (s, 2 H) 7.29-7.35 (m, 1 H) 7.75-7.83 (m, 1 H) 7.97-8.06 (m, 1 H).

( E ) -N1 -(2-(( methoxymethoxy ) methyl )-6- nitrophenyl ) -N4 -(2- nitrophenyl ) but -2- ene -1,4- Diamine

2-Fluoro-1 - ((methoxymethoxy) methyl) -3-nitrobenzene (500 mg, 2.3 mmol), (E) - N1 - (2- nitrophenyl) -2-butoxy A mixture of ene-1,4-diamine dihydrochloride (716 mg, 2.6 mmol) and DIPEA (2.0 mL, 11.6 mmol) in isopropanol (20 mL) was stirred at 70°C for 20 hours. After cooling to room temperature, the mixture was concentrated and the residue was diluted with water and extracted with ethyl acetate. The organic extract was washed with water and dried over anhydrous MgSO ₄ . The organic extract was filtered and the filtrate was concentrated. The crude product was purified by silica gel chromatography using a gradient of 0% to 40% ethyl acetate in heptane. The title compound (920 mg, 2.3 mmol, 98% yield) was obtained as a red oil. LC-MS m / z 403.3 (M+H) ⁺ , 1.25 min (retention time).

( E ) -N1 -(4-((2 -aminophenyl ) amino ) but -2- en- 1 -yl )-6-(( methoxymethoxy ) methyl ) benzene- 1, 2- diamine

To ( E ) -N1 -(2-((methoxymethoxy)methyl)-6-nitrophenyl) -N4 -(2-nitrophenyl)but-2-ene-1,4 -Suspension of diamine (0.9 g, 2.2 mmol) and ammonium hydroxide (12.4 mL, 89 mmol) in methanol (30 mL) and sodium bisulfite (3.89 g, 22.37 mmol) in water (10 mL) ). The reaction mixture was stirred at room temperature for 18 h. The methanol was evaporated, and the residue was extracted with ethyl acetate. The organic extract was washed with water and dried over anhydrous MgSO ₄ . The organic extract was filtered and the filtrate was concentrated. The crude product was purified by silica gel chromatography using a gradient of 0% to 100% ethyl acetate in heptane. The title compound (495 mg, 1.4 mmol, 65% yield) was obtained as a colorless oil. LC-MS m / z 343.3 (M+H) ⁺ , 0.46 min (retention time).

1- Ethyl - N -(( E )-1-(( E )-4-(( E )-2-((1- ethyl- 3 -methyl- 1 H -pyrazole- 5- carbonyl ) Imino )-2,3 -dihydro- 1 H - benzo (d) imidazol- 1 -yl ) but -2- en- 1 -yl )-7-(( methoxymethoxy ) methyl )-1,3 -Dihydro -2H- benzo [d] imidazol -2- ylidene )-3 -methyl - 1H - pyrazole- 5- carboxamide

To ( E ) -N1 -(4-((2-aminophenyl)amino)but-2-en-1-yl)-6-((methoxymethoxy)methyl)benzene-1 A solution of ,2-diamine (490 mg, 1.4 mmol) in N,N -dimethylformamide (DMF) (6.0 mL) was added to 1.0 M in dioxane (3.15 mL, 3.15 mmol) 1 -Ethyl-3-methyl-1H-pyrazole-5-carbonyl isothiocyanate. The reaction mixture was stirred at room temperature for 3 hours. EDC (823 mg, 4.29 mmol) and TEA (1.197 mL, 8.59 mmol) were added, and the mixture was stirred at room temperature for 18 hours. The mixture was diluted with water (10 mL) and extracted with ethyl acetate (15 mL). The organic extract was washed with water and dried over anhydrous MgSO ₄ . The organic extract was filtered and the filtrate was concentrated. The obtained solid was triturated with ethyl acetate/hexane (1:1) and filtered to obtain the title compound (654 mg, 0.984 mmol, 69% yield) as a white solid. LC-MS m / z 665.4 (M+H) ⁺ , 1.15 min (retention time).

1- Ethyl - N -(( E )-3-(( E )-4-(( E )-2-((1- ethyl- 3 -methyl- 1 H -pyrazole- 5- carbonyl ) Imino )-3 -methyl -2,3 -dihydro - 1H - benzo (d) imidazol- 1 -yl ) but -2- en- 1 -yl )-4-(( methoxymethyl (Oxy ) methyl )-1 -methyl- 1,3 -dihydro - 2H - benzo (d) imidazol -2- ylidene )-3 -methyl - 1H - pyrazole- 5 -methan amine

To 1-ethyl- N -(( E )-1-(( E )-4-(( E )-2-((1-ethyl-3-methyl-1 H -pyrazole) at 0℃ -5-carbonyl)imino)-2,3-dihydro- 1H -benzo[d]imidazol-1-yl)but-2-en-1-yl)-7-((methoxymethyl (Oxy)methyl)-1,3-dihydro- 2H -benzo(d)imidazol-2-ylidene)-3-methyl- 1H -pyrazole-5-carboxamide (650 mg, 0.978 mmol) and cesium carbonate (1274 mg, 3.91 mmol) in N,N -dimethylformamide (DMF) (4.0 mL) were added with methyl iodide (0.183 mL, 2.93 mmol) and stirred for 30 min. The mixture was filtered and the filtrate was concentrated and purified by reverse phase HPLC [Waters XSelect 5 μm C18, 150×30 mm, 30%-85% CH ₃ CN: H ₂ O, 0.1% TFA as modifier]. The title compound (452 mg, 0.65 mmol, 67% yield) was obtained as a white powder. LC-MS m / z 693.5 (M+H) ⁺ , 0.91 min (retention time).

( E )-1 -ethyl - N -(3-(( E )-4-(( E )-2-((1- ethyl- 3 -methyl- 1 H - pyrazole- 5- carbonyl ) Imino )-3 -methyl -2,3 -dihydro- 1 H -benzo (d) imidazol- 1 -yl ) but -2- en- 1 -yl )-4-( hydroxymethyl )- 1 -Methyl- 1 H -benzo [d] imidazole -2(3 H ) -ylidene )-3 -methyl- 1 H -pyrazole- 5- carboxamide

Add 1-ethyl- N -(( E )-3-(( E )-4-(( E )-2-((1-ethyl-3-methyl-1 H -pyrazole-5-carbonyl )Imino)-3-methyl-2,3-dihydro-1 H -benzo[d]imidazol-1-yl)but-2-en-1-yl)-4-((methoxy Methoxy)methyl)-1-methyl-1,3-dihydro- 2H -benzo(d)imidazole-2-ylidene)-3-methyl- 1H -pyrazole-5-methyl A mixture of amide (450 mg, 0.650 mmol) and 4.0 M HCl in methanol (4 mL) in dioxane (1.6 mL, 6.5 mmol) was stirred at 70°C for 20 hours. After cooling to room temperature, the mixture was concentrated and purified by reverse phase HPLC [Waters XSelect 5 μm C18, 150 × 30 mm, 15%-55% CH ₃ CN:H ₂ O, 0.1% formic acid as modifier] Crude product, the title compound (420 mg, 0.647 mmol, 100% yield) was obtained as a white solid. LC-MS m / z 649.4 (M+H) ⁺ , 0.79 min (retention time). ¹ H NMR (400 MHz, DMSO- d ₆ ) δ ppm 1.16-1.23 (m, 6 H) 2.13 (s, 6 H) 3.53 (d, J =1.47 Hz, 6 H) 4.43 (q, J =7.01 Hz , 4 H) 4.59 (d, J = 5.14 Hz, 2 H) 4.72 (d, J = 5.14 Hz, 2 H) 4.98 (d, J = 3.18 Hz, 2 H) 5.43-5.51 (m, 1 H) 5.53 (t, J = 5.26 Hz, 1 H) 5.88-5.96 (m, 1 H) 6.39 (s, 1 H) 6.40 (s, 1 H) 7.19-7.25 (m, 2 H) 7.26-7.35 (m, 2 H) 7.41 (d, J =8.07 Hz, 1 H) 7.54 (dd, J =11.49, 8.07 Hz, 2 H).

Example 6. 1- Ethyl - N -(( E )-3-(( E )-4-(( E )-2-((1- ethyl- 3 -methyl- 1 H - pyrazole- 5 - carbonyl) imino) -3-methyl-2,3-dihydro -1 H - benzo [d] imidazol-1-yl) but-2-en-1-yl) -1-methyl - 4-( morpholinylmethyl )-1,3 -dihydro - 2H - benzo [d] imidazol -2- ylidene )-3 -methyl - 1H - pyrazole- 5- carboxamide

N -(( E )-1-(( E )-4-(( E )-7-( chloromethyl )-2-((1- ethyl- 3 -methyl- 1 H -pyrazole- 5 - carbonyl) imino) -3-methyl-2,3-dihydro -1 H - benzo [d] imidazol-1-yl) but-2-en-1-yl) -3-methyl - 1,3 -Dihydro- 2 H -benzo [d] imidazole -2- ylidene )-1 -ethyl- 3 -methyl- 1 H -pyrazole- 5- carboxamide

To 1-ethyl- N -(( E )-3-(( E )-4-(( E )-2-((1-ethyl-3-methyl-1 H -pyrazole-5-carbonyl )Imino)-3-methyl-2,3-dihydro-1 H -benzo[d]imidazol-1-yl)but-2-en-1-yl)-4-(hydroxymethyl) -1-Methyl-1,3-dihydro-2 H -benzo[d]imidazol-2-ylidene)-3-methyl-1 H -pyrazole-5-carboxamide (200 mg, 0.308 mmol) Suspension in 1,2-Dichloroethane (DCE) (15 mL) Add Thionyl Chloride (0.135 mL, 1.85 mmol). The reaction mixture was stirred at 90°C for 20 hours. After cooling to room temperature, the reaction mixture was filtered to obtain the title compound (200 mg, 0.3 mmol, 97% yield) as a white solid. LC-MS m / z 667.4 (M+H) ⁺ , 0.98 min (retention time).

1- Ethyl - N -(( E )-3-(( E )-4-(( E )-2-((1- ethyl- 3 -methyl- 1 H -pyrazole- 5- carbonyl ) Imino )-3 -methyl -2,3 -dihydro - 1H - benzo (d) imidazol- 1 -yl ) but -2- en- 1 -yl )-1 -methyl- 4-( Morpholinylmethyl )-1,3 -dihydro - 2H - benzo [d] imidazol -2- ylidene )-3 -methyl - 1H - pyrazole- 5- carboxamide

Add N -(( E )-1-(( E )-4-(( E )-7-(chloromethyl)-2-((1-ethyl-3-methyl-1 H -pyrazole- 5-carbonyl)imino)-3-methyl-2,3-dihydro- 1H -benzo(d)imidazol-1-yl)but-2-en-1-yl)-3-methyl -1,3-Dihydro-2 H -benzo[d]imidazol-2-ylidene)-1-ethyl-3-methyl-1 H -pyrazole-5-carboxamide (30 mg, 0.045 A mixture of morpholine (0.020 mL, 0.225 mmol) and DIPEA (0.024 mL, 0.135 mmol) in ethanol (1.5 mL) was stirred at 70°C for 3 hours. The mixture was concentrated and the residue was purified by reverse phase HPLC [Waters XSelect 5 μm C18, 150 × 30 mm, 15%-55% CH ₃ CN: H ₂ O, 0.1% formic acid as a modifier] to obtain a white The title compound as a solid (26 mg, 0.036 mmol, 81% yield). LC-MS m / z 718.5 (M+H) ⁺ , 0.73 min (retention time). ¹ H NMR (400 MHz, DMSO- d ₆ ) δ ppm 1.21 (td, J =7.09, 3.18 Hz, 6 H) 2.13 (s, 6 H) 2.22 (br. s., 4 H) 3.45 (br. s ., 6 H) 3.52 (s, 3 H) 3.54 (s, 3 H) 4.40-4.50 (m, 4 H) 4.73 (d, J = 4.89 Hz, 2 H) 5.10 (br. s., 2 H) 5.35-5.45 (m, 1 H) 5.88-5.98 (m, 1 H) 6.40 (s, 1 H) 6.41 (s, 1 H) 7.11 (d, J =7.58 Hz, 1 H) 7.20-7.28 (m, 2 H) 7.32 (t, J =7.70 Hz, 1 H) 7.44 (d, J =7.82 Hz, 1 H) 7.55 (t, J =7.34 Hz, 2 H).

The example compounds 7 to 9 in Table 1 were prepared in a similar manner to the synthetic sequence set forth for Example 6:

Example 10. 1- Ethyl- N-((E)-3-((E)-4-((E)-2-((1- ethyl- 3 -methyl -1H- pyrazole- 5- Carbonyl ) imino )-3 -methyl -2,3 -dihydro- 1H- benzo (d) imidazol- 1 -yl ) but -2- en- 1 -yl )-4-( methoxymethyl Yl )-1 -methyl- 1,3 -dihydro -2H- benzo [d] imidazol -2- ylidene )-3 -methyl -1H- pyrazole- 5- carboxamide

Add N -(( E )-1-(( E )-4-(( E )-7-(chloromethyl)-2-((1-ethyl-3-methyl-1 H -pyrazole- 5-carbonyl)imino)-3-methyl-2,3-dihydro- 1H -benzo(d)imidazol-1-yl)but-2-en-1-yl)-3-methyl -1,3-Dihydro-2 H -benzo[d]imidazol-2-ylidene)-1-ethyl-3-methyl-1 H -pyrazole-5-carboxamide (30 mg, 0.045 A mixture of sodium methoxide (25 mg, 0.463 mmol) in methanol (1.5 mL) was stirred at 70°C for 20 hours. After cooling to room temperature, the mixture was concentrated and purified by reverse phase HPLC [Waters XSelect 5 μm C18, 150 × 30 mm, 30%-85% CH ₃ CN: H ₂ O, 0.1% formic acid as modifier] Crude product, the title compound (14 mg, 0.021 mmol, 47% yield) was obtained as a white solid. LC-MS m / z 663.5 (M+H) ⁺ , 0.92 min (retention time). ¹ H NMR (400 MHz, DMSO- d ₆ ) δ ppm 1.21 (t, J =7.09 Hz, 6 H) 2.13 (s, 6 H) 3.17 (s, 3 H) 3.53 (d, J =1.96 Hz, 6 H) 4.44 (q, J =7.09 Hz, 4 H) 4.49 (s, 2 H) 4.73 (d, J =5.14 Hz, 2 H) 4.87 (br. s., 2 H) 5.42-5.51 (m, 1 H) 5.85-5.94 (m, 1 H) 6.40 (s, 1 H) 6.41 (s, 1 H) 7.20-7.26 (m, 2 H) 7.27-7.35 (m, 2 H) 7.43 (d, J =8.07 Hz, 1 H) 7.57 (t, J =8.68 Hz, 2 H).

Example 11. ( racemic )-1 -ethyl - N -(( E )-3-(( E )-4-(( E )-2-((1- ethyl- 3 -methyl- 1) H - pyrazole- 5- carbonyl ) imino )-3 -methyl -2,3 -dihydro- 1 H - benzo [d] imidazol- 1 -yl ) but -2- en- 1 -yl ) 4- (1-hydroxyethyl) -1-methyl-1,3-dihydro -2 H - benzo [d] imidazol-2-ylidene) -3-methyl -1 H - pyrazol - 5 -methanamide

1- Ethyl - N -(( E )-3-(( E )-4-(( E )-2-((1- ethyl- 3 -methyl- 1 H -pyrazole- 5- carbonyl ) Imino )-3 -methyl -2,3 -dihydro- 1 H - benzo (d) imidazol- 1 -yl ) but -2- en- 1 -yl )-4 -methan- 1-yl Methyl- 1,3 -dihydro- 2 H -benzo [d] imidazol -2- ylidene )-3 -methyl- 1 H -pyrazole- 5- carboxamide

To 1-ethyl- N -(( E )-3-(( E )-4-(( E )-2-((1-ethyl-3-methyl-1 H -pyrazole-5-carbonyl )Imino)-3-methyl-2,3-dihydro-1 H -benzo[d]imidazol-1-yl)but-2-en-1-yl)-4-(hydroxymethyl) -1-Methyl-1,3-dihydro-2 H -benzo[d]imidazol-2-ylidene)-3-methyl-1 H -pyrazole-5-carboxamide (80 mg, 0.123 mmol) a suspension in dichloromethane (DCM) (20 mL) with active manganese dioxide (214 mg, 2.466 mmol). The mixture was stirred at 40°C for 2.0 hours. The mixture was then filtered and the filtrate was concentrated to give the title compound (80 mg, 0.124 mmol, 100% yield) as a pale yellow solid. LC-MS m / z 647.4 (M+H) ⁺ , 0.88 min (retention time).

1- Ethyl - N -(( E )-3-(( E )-4-(( E )-2-((1- ethyl- 3 -methyl- 1 H -pyrazole- 5- carbonyl ) Imino )-3 -methyl -2,3 -dihydro- 1 H - benzo (d) imidazol- 1 -yl ) but -2- en- 1 -yl )-4-(1- hydroxyethyl )-1 -Methyl- 1,3 -dihydro - 2H - benzo [d] imidazol -2- ylidene )-3 -methyl - 1H - pyrazole- 5- carboxamide

To 1-ethyl- N -(( E )-3-(( E )-4-(( E )-2-((1-ethyl-3-methyl-1 H -pyrazole-5-carbonyl )Imino)-3-methyl-2,3-dihydro-1 H -benzo[d]imidazol-1-yl)but-2-en-1-yl)-4-methanyl-1 -Methyl-1,3-dihydro-2 H -benzo[d]imidazol-2-ylidene)-3-methyl-1 H -pyrazole-5-carboxamide (80 mg, 0.124 mmol) A suspension in tetrahydrofuran (THF) (2.0 mL) was added 3.4 M methylmagnesium bromide (0.109 mL, 0.371 mmol) in 2-THF. The mixture was stirred at room temperature for 2.0 hours. To this mixture was further added 3.4 M methylmagnesium bromide (0.109 mL, 0.371 mmol) in 2-THF, and the reaction mixture was stirred for 30 min. The mixture was diluted with saturated NH ₄ Cl (aq) and extracted with ethyl acetate. The organic extract was concentrated and the crude product was purified by reverse phase HPLC [Waters XSelect 5 μm C18, 150 × 30 mm, 15%-55% CH ₃ CN: H ₂ O, 0.1% formic acid as a modifier] to obtain a The title compound is a white solid. LC-MS m / z 663.4 (M+H) ⁺ , 0.83 min (retention time). ¹ H NMR (400 MHz, DMSO- d ₆ ) δ ppm 1.21 (t, J =7.09 Hz, 6 H) 1.31 (d, J =6.36 Hz, 3 H) 2.12 (s, 3 H) 2.13 (s, 3 H) 3.52 (s, 3 H) 3.53 (s, 3 H) 4.44 (q, J =7.09 Hz, 4 H) 4.73 (d, J =5.14 Hz, 2 H) 4.85-4.94 (m, 1 H) 5.02 -5.11 (m, 2 H) 5.40 (d, J =5.38 Hz, 1 H) 5.42-5.51 (m, 1 H) 5.88-5.96 (m, 1 H) 6.40 (s, 2 H) 7.19-7.25 (m , 1 H) 7.28-7.35 (m, 2 H) 7.36-7.40 (m, 1 H) 7.42 (d, J =7.82 Hz, 1 H) 7.50 (d, J =6.85 Hz, 1 H) 7.56 (d, J =7.82 Hz, 1 H).

Example 12. 1- Ethyl - N -(( E )-1-(( E )-4-(( E )-2-((1- ethyl- 3 -methyl- 1 H - pyrazole- 5 - carbonyl) imino) -3-methyl-2,3-dihydro -1 H - benzo [d] imidazol-1-yl) but-2-en-1-yl) -4- (hydroxy carboxylic Yl )-3 -methyl- 1,3 -dihydro - 2H - benzo [d] imidazol -2- ylidene )-3 -methyl - 1H - pyrazole- 5- carboxamide

( E )-(2- nitro- 3-((4-((2- nitrophenyl ) amino ) but -2- en- 1 -yl ) amino ) phenyl ) methanol

To a solution of ( E ) -N1 -(2-nitrophenyl)but-2-ene-1,4-diamine (630 mg, 3.04 mmol) in isopropanol (12 mL) was added DIPEA (2.65 mL , 15.20 mmol), followed by (3-fluoro-2-nitrophenyl)methanol (520 mg, 3.04 mmol). The reaction mixture was stirred at 100°C for 2 days. After cooling to room temperature, the mixture was concentrated and the residue was diluted with water and extracted with ethyl acetate. The organic extract was dried over anhydrous MgSO ₄ . The organic extract was filtered and the filtrate was concentrated. The crude product was purified by silica gel chromatography with a gradient of 0% to 60% ethyl acetate in heptane to obtain the title compound (570 mg, 1.6 mmol, 52% yield) as an orange solid. LC-MS m / z 359.3 (M+H) ⁺ , 1.06 min (retention time).

( E )-(2- amino- 3-((4-((2 -aminophenyl ) amino ) but -2- en- 1 -yl ) amino ) phenyl ) methanol

To ( E )-(2-nitro-3-((4-((2-nitrophenyl)amino)but-2-en-1-yl)amino)phenyl)methanol (560 mg, 1.6 mmol) suspension in methanol (30 mL) with ammonium hydroxide (28% in water) (8.69 mL, 62.5 mmol), followed by sodium bisulfite (2721 mg, 15.6 mmol) in water (10 mL) In the solution. The reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was filtered and washed with methanol and water. The filtrate was concentrated and extracted with ethyl acetate. The organic extract was washed with water and dried over anhydrous MgSO ₄ . The organic extract was filtered and the filtrate was concentrated to give the title compound (350 mg, 1.2 mmol, 75% yield) as an off-white solid. LC-MS m / z 299.4 (M+H) ⁺ , 0.36 min (retention time).

( E )-1 -ethyl - N -(1-(4-(2-(1- ethyl- 3 -methyl- 1 H - pyrazole- 5- carboxamido )-1 H - benzo [d] imidazol- 1 -yl ) but -2- en- 1 -yl )-4-( hydroxymethyl )-1 H -benzo [d] imidazol -2- yl )-3 -methyl- 1 H - pyrazole-5-Amides

To ( E )-(2-amino-3-((4-((2-aminophenyl)amino)but-2-en-1-yl)amino)phenyl)methanol (350 mg, 1.2 mmol) in N,N -dimethylformamide (DMF) (10 mL), 1.0 M 1-ethyl-3-methyl-1 H -pyrazole-5 in dioxane -Carbonyl isothiocyanate (2.3 mL, 2.3 mmol). The mixture was stirred for 3 hours, EDC (675 mg, 3.52 mmol) was added, followed by TEA (0.981 mL, 7.04 mmol). The reaction mixture was stirred at room temperature for 3 days. The mixture was added dropwise to vigorously stirred water. The resulting precipitate was filtered, washed with water and dried to obtain the title compound (652 mg, 1.05 mmol, 90% yield) as a white solid. LC-MS m / z 621.4 (M+H) ⁺ , 1.06 min (retention time).

1- Ethyl - N -(( E )-1-(( E )-4-(( E )-2-((1- ethyl- 3 -methyl- 1 H -pyrazole- 5- carbonyl ) Imino )-3 -methyl -2,3 -dihydro- 1 H -benzo (d) imidazol- 1 -yl ) but -2- en- 1 -yl )-4-( hydroxymethyl )- 3- methyl- 1,3 -dihydro- 2 H -benzo [d] imidazol -2- ylidene )-3 -methyl- 1 H -pyrazole- 5- carboxamide

To ( E )-1-ethyl- N -(1-(4-(2-(1-ethyl-3-methyl-1 H -pyrazole-5-methamido)- 1 H -Benzo[d]imidazol-1-yl)but-2-en-1-yl)-4-(hydroxymethyl)-1 H -benzo[d]imidazol-2-yl)-3- Methyl-1 H -pyrazole-5-formamide (650 mg, 1.5 mmol) and cesium carbonate (1365 mg, 4.19 mmol) in N,N -dimethylformamide (DMF) (12 mL) Add iodomethane (0.196 mL, 3.14 mmol) to the solution. The ice bath was removed and the reaction mixture was stirred for 1 hour. The mixture is added to the water with stirring. The resulting precipitate was filtered and washed with water. The solid was purified by reverse phase [Waters XSelect 5 μm C18, 150 × 30 mm, 15%-55% CH ₃ CN:H ₂ O, 0.1% formic acid as modifier] to obtain the title compound as a white solid (280 mg , 0.432 mmol, 41% yield). LC-MS m / z 649.5 (M+H) ⁺ , 0.80 min (retention time). ¹ H NMR (400 MHz, DMSO- d ₆ ) δ ppm 1.23 (q, J =7.09 Hz, 6 H) 2.14 (d, J =1.22 Hz, 6 H) 3.53 (s, 3 H) 3.77 (s, 3 H) 4.46 (quin, J =7.09 Hz, 4 H) 4.74 (br. s., 4 H) 4.84 (d, J =5.14 Hz, 2 H) 5.54 (t, J =5.38 Hz, 1 H) 5.80 ( s, 2 H) 6.43 (s, 1 H) 6.45 (s, 1 H) 7.13-7.27 (m, 3 H) 7.29-7.34 (m, 1 H) 7.39 (t, J =8.44 Hz, 2 H) 7.56 (d, J =8.07 Hz, 1 H).

N -((E )-4-( 氯甲基 )-1-((E )-4-((E )-2-((1- 乙基 -3- 甲基 -1H - 吡唑 -5- 羰基 ) 亞胺基 )-3- 甲基 -2,3- 二氫 -1H - 苯并 [d] 咪唑 -1- 基 ) 丁 -2- 烯 -1- 基 )-3- 甲基 -1,3- 二氫 -2H - 苯并 [d] 咪唑 -2- 亞基 )-1- 乙基 -3- 甲基 -1H - 吡唑 -5- 甲醯胺

Example 13-1. 1- Ethyl - N -(( E )-1-(( E )-4-(( E )-2-((1- Ethyl- 3 -methyl- 1 H - pyrazole -5- carbonyl ) imino )-3 -methyl -2,3 -dihydro- 1H- benzo [d] imidazol- 1 -yl ) but -2- en- 1 -yl )-3 -methyl -4-( Morpholinylmethyl )-1,3 -dihydro- 2 H -benzo [d] imidazol -2- ylidene )-3 -methyl- 1 H -pyrazole- 5- carboxamide

N -(( E )-4-( chloromethyl )-1-(( E )-4-(( E )-2-((1- ethyl- 3 -methyl- 1 H -pyrazole- 5 - carbonyl) imino) -3-methyl-2,3-dihydro -1 H - benzo [d] imidazol-1-yl) but-2-en-1-yl) -3-methyl - 1,3 -Dihydro- 2 H -benzo [d] imidazole -2- ylidene )-1 -ethyl- 3 -methyl- 1 H -pyrazole- 5- carboxamide

To 1-ethyl- N -(( E )-1-(( E )-4-(( E )-2-((1-ethyl-3-methyl-1 H -pyrazole-5-carbonyl )Imino)-3-methyl-2,3-dihydro-1 H -benzo[d]imidazol-1-yl)but-2-en-1-yl)-4-(hydroxymethyl) -3-Methyl-1,3-dihydro- 2H -benzo[d]imidazol-2-ylidene)-3-methyl- 1H -pyrazole-5-carboxamide (155 mg, 0.239 mmol) a solution in dichloromethane (DCM) (2.0 mL) was added sulfite chloride (0.105 mL, 1.433 mmol). The reaction mixture was stirred at room temperature for 2 hours. The mixture was concentrated to give the title compound (160 mg, 0.24 mmol, 100% yield) as a white solid. LC-MS m / z 667.4 (M+H) ⁺ , 0.97 min (retention time).

1- Ethyl - N -(( E )-1-(( E )-4-(( E )-2-((1- ethyl- 3 -methyl- 1 H -pyrazole- 5- carbonyl ) Imino )-3 -methyl -2,3 -dihydro- 1H- benzo (d) imidazol- 1 -yl ) but -2- en- 1 -yl )-3 -methyl- 4-( ? (Hydroxymethyl )-1,3 -dihydro - 2H - benzo [d] imidazol -2- ylidene )-3 -methyl - 1H - pyrazole- 5- carboxamide

Add N -(( E )-4-(chloromethyl)-1-(( E )-4-(( E )-2-((1-ethyl-3-methyl-1 H -pyrazole- 5-carbonyl)imino)-3-methyl-2,3-dihydro- 1H -benzo(d)imidazol-1-yl)but-2-en-1-yl)-3-methyl -1,3-Dihydro-2 H -benzo[d]imidazol-2-ylidene)-1-ethyl-3-methyl-1 H -pyrazole-5-carboxamide (35 mg, 0.052 A mixture of morpholine (0.023 mL, 0.262 mmol) and DIPEA (0.027 mL, 0.157 mmol) in ethanol (1.5 mL) was stirred at 70°C for 2 hours. The mixture was concentrated and the residue was purified by reverse phase HPLC [Waters XSelect 5 μm C18, 150 × 30 mm, 15%-55% CH ₃ CN: H ₂ O, 0.1% formic acid as a modifier] to obtain a white The title compound as a solid (28 mg, 0.039 mmol, 74% yield). LC-MS m / z 718.5 (M+H) ⁺ , 0.68 min (retention time). ¹ H NMR (400 MHz, DMSO- d ₆ ) δ ppm 1.22 (td, J =7.09, 3.67 Hz, 6 H) 2.13 (s, 6 H) 2.40 (br. s., 4 H) 3.53 (s, 3 H) 3.54 (br. s., 4 H) 3.76 (s, 2 H) 3.86 (s, 3 H) 4.44 (qd, J =7.01, 2.69 Hz, 4 H) 4.73 (br. s., 4 H) 5.80-5.86 (m, 2 H) 6.42 (s, 1 H) 6.44 (s, 1 H) 7.11-7.16 (m, 2 H) 7.18-7.23 (m, 1 H) 7.31 (t, J =7.83 Hz, 1 H) 7.37-7.42 (m, 2 H) 7.56 (d, J = 8.07 Hz, 1 H).

1- 乙基 -N -((E )-1-((E )-4-((E )-2-((1- 乙基 -3- 甲基 -1H - 吡唑 -5- 羰基 ) 亞胺基 )-3- 甲基 -2,3- 二氫 -1H - 苯并 [d] 咪唑 -1- 基 ) 丁 -2- 烯 -1- 基 )-4- 甲醯基 -3- 甲基 -1,3- 二氫 -2H - 苯并 [d] 咪唑 -2- 亞基 )-3- 甲基 -1H - 吡唑 -5- 甲醯胺

The example compounds 13-2, 14 and 15 in Table 1 were prepared in a similar manner to the synthetic sequence set forth for Example 13-1. Example 16. ( racemic )-1 -ethyl - N -(( E )-1-(( E )-4-(( E )-2-((1- ethyl- 3 -methyl- 1) H - pyrazole- 5- carbonyl ) imino )-3 -methyl -2,3 -dihydro- 1 H - benzo [d] imidazol- 1 -yl ) but -2- en- 1 -yl ) -4-(1- hydroxyethyl )-3 -methyl- 1,3 -dihydro -2H- benzo [d] imidazole -2- ylidene )-3 -methyl- 1 H - pyrazole- 5 - A Amides

1- Ethyl - N -(( E )-1-(( E )-4-(( E )-2-((1- ethyl- 3 -methyl- 1 H -pyrazole- 5- carbonyl ) Imino )-3 -methyl -2,3 -dihydro - 1H - benzo (d) imidazol- 1 -yl ) but -2- en- 1 -yl )-4 -methanyl- 3- Methyl- 1,3 -dihydro- 2 H -benzo [d] imidazol -2- ylidene )-3 -methyl- 1 H -pyrazole- 5- carboxamide

To 1-ethyl- N -(( E )-1-(( E )-4-(( E )-2-((1-ethyl-3-methyl-1 H -pyrazole-5-carbonyl )Imino)-3-methyl-2,3-dihydro-1 H -benzo[d]imidazol-1-yl)but-2-en-1-yl)-4-(hydroxymethyl) -3-Methyl-1,3-dihydro- 2H -benzo[d]imidazol-2-ylidene)-3-methyl- 1H -pyrazole-5-carboxamide (60 mg, 0.092 mmol) in dichloromethane (DCM) (2 mL) was added active manganese dioxide (161 mg, 1.850 mmol). The mixture was stirred at room temperature for 20 hours. The mixture was filtered and the filtrate was concentrated to give the title compound as a pale yellow solid. LC-MS m / z 647.4 (M+H) ⁺ , 0.90 min (retention time). 1- Ethyl - N -(( E )-1-(( E )-4-(( E )-2-((1- ethyl- 3 -methyl- 1 H -pyrazole- 5- carbonyl ) Imino )-3 -methyl -2,3 -dihydro- 1 H - benzo (d) imidazol- 1 -yl ) but -2- en- 1 -yl )-4-(1- hydroxyethyl )-3 -methyl- 1,3 -dihydro - 2H - benzo [d] imidazol -2- ylidene )-3 -methyl - 1H - pyrazole- 5- carboxamide

To 1-ethyl- N -(( E )-1-(( E )-4-(( E )-2-((1-ethyl-3-methyl-1 H -pyrazole-5-carbonyl )Imino)-3-methyl-2,3-dihydro-1 H -benzo[d]imidazol-1-yl)but-2-en-1-yl)-4-methanyl-3 -Methyl-1,3-dihydro-2 H -benzo[d]imidazole-2-ylidene)-3-methyl-1 H -pyrazole-5-carboxamide (50 mg, 0.077 mmol) A suspension in tetrahydrofuran (THF) (2.0 mL) was added 3.4 M methylmagnesium bromide (0.114 mL, 0.387 mmol) in 2-THF. The mixture was stirred at room temperature for 30 min. The mixture was diluted with saturated NH ₄ Cl (aq) and extracted with ethyl acetate. The organic extract was concentrated and the crude product was purified by reverse phase HPLC [Waters XSelect 5 μm C18, 150 × 30 mm, 15%-55% CH ₃ CN: H ₂ O, 0.1% formic acid as a modifier] to obtain a The title compound (32 mg, 0.048 mmol, 63% yield) as a white solid. LC-MS m / z 663.5 (M+H) ⁺ , 0.84 min (retention time). ¹ H NMR (400 MHz, DMSO- d ₆ ) δ ppm 1.23 (td, J =7.09, 5.14 Hz, 6 H) 1.50 (d, J =6.36 Hz, 3 H) 2.14 (d, J =0.98 Hz, 6 H) 3.53 (s, 3 H) 3.76 (s, 3 H) 4.46 (quin, J =6.72 Hz, 4 H) 4.73 (br. s., 4 H) 5.36-5.44 (m, 1 H) 5.47 (d , J = 4.89 Hz, 1 H) 5.80 (br. s., 2 H) 6.43 (s, 1 H) 6.45 (s, 1 H) 7.21 (q, J =7.50 Hz, 2 H) 7.29-7.36 (m , 2 H) 7.40 (dd, J =7.70, 3.79 Hz, 2 H) 7.56 (d, J =7.82 Hz, 1 H). Example 17. N, N '- (( 2 E, 2' E) - butane-1,4-bis (3-methyl-1,3-dihydro -2 H - benzo [d] imidazole -1 -yl -2- ylidene )) bis (1- ethyl- 3 -methyl- 1 H - pyrazole- 5- carboxamide )

N1, N4 - bis (2-nitrophenyl) butane-1,4-diamine

A solution of 1-fluoro-2-nitrobenzene (2.6 g, 18.2 mmol) and butane-1,4-diamine (800 mg, 9.1 mmol) in isopropanol (50 mL) was stirred at room temperature 18 h to form an orange suspension. The suspension was filtered and the filtrate was washed with isopropanol (3×50 mL), and then dried under vacuum for 18 h to obtain the title compound (2.0 g, 6.1 mmol, 67% yield), which was continued without further purification use. LC-MS m / z 353.1 (M+Na) ⁺ , 1.29 min (retention time). ¹ H NMR (400 MHz, DMSO- d ₆ ) δ ppm 8.16 (t, J=5.5 Hz, 2H), 8.06 (dd, J=8.7, 1.6 Hz, 2H), 7.48-7.58 (m, 2H), 7.08 (d, J=8.0 Hz, 2H), 6.68 (ddd, J=8.4, 7.0, 1.1 Hz, 2H), 3.43 (d, J=5.8 Hz, 4H), 1.66-1.80 (m, 4H).

N1,N1' -( butane -1,4 -diyl ) bis ( benzene -1,2- diamine )

Combine N1,N4 -bis-(2-nitrophenyl)butane-1,4-diamine (1.9 g, 6.0 mmol) and zinc (0.4 g, 6.0 mmol) in methanol (60 mL) and acetic acid (6 The suspension in mL) was stirred at 40°C for 3 hours. After this duration, the reaction mixture was filtered and washed with DCM/MeOH (approximately 5:1, 3×100 mL) to give a solid residue and filtrate. The filtrate was concentrated, then dissolved in DCM (200 mL) and washed with saturated aqueous sodium bicarbonate (150 mL). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated. Then the solid residue was sequentially triturated with saturated aqueous sodium bicarbonate (50 mL) and DCM/MeOH (approximately 5:1, 3×50 mL), and this procedure was repeated three times. The resulting biphasic mixture was separated and the aqueous phase was extracted with additional DCM (100 mL). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated. The two samples were combined to obtain the title compound (1.2 g, 4.4 mmol, 74% yield) as a dark brown residue. LC-MS m / z 271.2 (M+H) ⁺ , 0.46 min (retention time). ¹ H NMR (400 MHz, DMSO- d ₆ ) δ ppm 6.47-6.57 (m, 4H), 6.32-6.46 (m, 4H), 4.47 (br. s., 4H), 4.34 (t, J=4.9 Hz , 2H), 3.06 (d, J=5.0 Hz, 4H), 1.61-1.81 (m, 4H).

N, N '- (butane-1,4-diyl bis (1 H - benzo [d] imidazole-1,2-diyl)) bis (1-ethyl-3-methyl -1 H - Pyrazol- 5- carboxamide )

To N1,N1' -(butane-1,4-diyl)bis(phenyl-1,2-diamine) (1.2 g, 4.4 mmol) in N,N -dimethylformamide at room temperature (DMF) (10 mL) add 1-ethyl-3-methyl-1 H -pyrazole-5-carbonyl isothiocyanate (1 M in dioxane) (9.8 mL, 9.8 mmol ). The reaction was stirred at room temperature for 3 hours. After this duration, EDC (2.6 g, 13.3 mmol) and Et ₃ N (3.7 mL, 26.6 mmol) were added, and the reaction was stirred at room temperature for 18 h. The reaction mixture was then diluted with water (300 mL) and stirred for 30 minutes. The resulting precipitate was filtered and washed with water and dried under vacuum to give a brown residue. The residue was purified by silica gel chromatography (0%-100% EtOAc in hexane, 80 g column, eluted with 100% EtOAc) to give an off-white residue (1.2 g, 2.0 mmol, 45% yield) rate). LC-MS m / z 593.2 (M+H) ⁺ , 1.03 min (retention time). ¹ H NMR (400 MHz, DMSO- d ₆ ) δ ppm 12.68 (s, 2H), 7.39-7.58 (m, 4H), 7.08-7.30 (m, 4H), 6.59 (s, 2H), 4.57 (q, J=7.0 Hz, 4H), 4.27 (br. s., 4H), 2.11 (s, 6H), 1.87 (br. s., 4H), 1.30 (t, J=7.0 Hz, 6H).

N, N '- ((2 E, 2' E) - butane-1,4-bis (3-methyl-1,3-dihydro -2 H - benzo [d] imidazol-1 yl-2-ylidene)) bis (1-ethyl-3-methyl -1 H - pyrazole-5-amine XI)

N,N' -(butane-1,4-diylbis(1 H -benzo[d]imidazole-1,2-diyl))bis(1-ethyl-3-methyl-1 H -Pyrazole-5-methylamide) (200 mg, 0.44 mmol), MeI (0.04 mL, 0.68 mmol), Cs ₂ CO ₃ (440 mg, 1.4 mmol) in N,N -dimethylformamide ( The solution in DMF) (2 mL) was stirred at room temperature for 18 h. After this duration, the reaction was filtered and concentrated. The resulting residue was purified by reverse phase HPLC (15%-55% acetonitrile in water, 0.1% formic acid) to give the title compound (122 mg, 0.20 mmol, 58% yield) as an off-white solid. LC-MS m / z 621.3 (M+H) ⁺ , 0.75 min (retention time). ¹ H NMR (400 MHz, DMSO- d ₆ ) δ ppm 7.47-7.58 (m, 4H), 7.21-7.37 (m, 4H), 6.44 (s, 2H), 4.47 (q, J=7.1 Hz, 4H) , 4.15 (br. s., 4H), 3.51 (s, 6H), 2.13 (s, 6H), 1.75 (br. s., 4H), 1.23 (t, J=7.0 Hz, 6H).

(4-((2-( 羥基甲基 )-6- 硝基苯基 ) 胺基 ) 丁基 ) 胺基甲酸第三丁基酯

將市售(2-氟-3-硝基苯基)甲醇(1.05 g, 6.14 mmol)、市售(4-胺基丁基)胺基甲酸第三丁基酯(1.271 g, 6.75 mmol)及DIPEA (3.21 mL, 18.41 mmol)於異丙醇(10 mL)中之混合物在70℃下攪拌20小時。使該混合物冷卻至室溫且濃縮。用水稀釋殘餘物且用乙酸乙酯萃取。將有機萃取物用水洗滌，經無水MgSO₄ 乾燥，過濾且將濾液濃縮。在Combiflash上利用於庚烷中之0%至40%乙酸乙酯/乙醇(3:1)梯度進行溶析來純化提供呈紅色油狀物之標題化合物(2.05 g，6.04 mmol，98%產率)。LC-MSm /z 340.3 (M+H)⁺ 。¹ H NMR (400 MHz，氯仿-d ) δ ppm 1.45 (s, 9 H) 1.54 - 1.60 (m, 2 H) 1.62 - 1.71 (m, 2 H) 2.78 (br s, 1 H) 3.16 (q,J =6.6 Hz, 2 H) 3.32 (q,J =6.6 Hz, 2 H) 4.58 (br s, 1 H) 4.79 (d,J =5.4 Hz, 2 H) 6.87 (dd,J =8.5, 7.3 Hz, 1 H) 6.94 (br s, 1 H) 7.55 (dd,J =7.3, 1.6 Hz, 1 H) 8.03 (dd,J =8.5, 1.6 Hz, 1 H)。(2-((4- 胺基丁基 ) 胺基 )-3- 硝基苯基 ) 甲醇二鹽酸鹽

向(4-((2-(羥基甲基)-6-硝基苯基)胺基)丁基)胺基甲酸酯第三丁基(2.04 g, 6.01 mmol)於甲醇(15 mL)中之溶液添加於二噁烷中之4.0 M HCl (15.03 mL, 60.1 mmol)。將反應混合物在室溫下攪拌2.0小時且濃縮。將殘餘物與二氯甲烷一起研磨並過濾，以提供呈白色固體之標題化合物(1.88 g，6.02 mmol，100%產率)。LC-MSm /z 240.2 (M+H)⁺ 。¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 1.53 - 1.62 (m, 4 H) 2.75 (br d,J =5.4 Hz, 2 H) 3.05 - 3.12 (m, 2 H) 3.17 (s, 1 H) 4.56 (s, 2 H) 6.83 (dd,J =8.3, 7.2 Hz, 1 H) 7.56 (dd,J =7.2, 1.6 Hz, 1 H) 7.79 (dd,J =8.3, 1.6 Hz, 1 H) 8.01 (br s, 3 H)。(3- 硝基 -2-((4-((2- 硝基苯基 ) 胺基 ) 丁基 ) 胺基 ) 苯基 ) 甲醇

將(2-((4-胺基丁基)胺基)-3-硝基苯基)甲醇二鹽酸鹽(651 mg, 2.086 mmol)、市售1-氟-2-硝基苯(0.20 mL, 1.897 mmol)及DIPEA (1.656 mL, 9.48 mmol)於異丙醇(10 mL)中之混合物在80℃下攪拌20小時。使該混合物冷卻至室溫且濃縮。用水稀釋殘餘物，用乙酸乙酯萃取。將有機萃取物用水洗滌，經無水MgSO₄ 乾燥，過濾且將濾液濃縮。在Combiflash上利用於庚烷中之0%至50%乙酸乙酯梯度進行溶析來純化提供呈橙色固體之標題化合物(485 mg，1.346 mmol，71%產率)。LC-MSm /z 361.3 (M+H)⁺ 。¹ H NMR (400 MHz，氯仿-d ) δ ppm 1.83 (m, 4 H) 2.27 (t,J =5.9 Hz, 1 H) 3.38 (q,J =6.4 Hz, 4 H) 4.80 (d,J =597 Hz, 2 H) 6.68 (td,J =7.7, 1.2 Hz, 1 H) 6.78 - 6.93 (m, 2 H) 6.93 - 6.98 (m, 1 H) 7.46 (t,J =6.9 Hz, 1 H) 7.55 (d,J =5.9 Hz, 1 H) 8.03 (dd,J =8.3, 1.4 Hz, 1 H) 8.06 (br s, 1 H) 8.19 (dd,J =8.8, 1.5 Hz, 1 H)。(3- 胺基 -2-((4-((2- 胺基苯基 ) 胺基 ) 丁基 ) 胺基 ) 苯基 ) 甲醇

向(3-硝基-2-((4-((2-硝基苯基)胺基)丁基)胺基)苯基)甲醇(0.48 g, 1.332 mmol)於甲醇(40 mL)中之溶液添加氫氧化銨(7.41 mL, 53.3mmol)，之後添加於水(10 mL)中之亞硫酸氫鈉(2.319 g, 13.32 mmol)。將所得混合物在室溫下攪拌1小時且濃縮。用水稀釋殘餘物且用乙酸乙酯萃取。將有機萃取物用水洗滌，經無水MgSO₄ 乾燥，過濾且將濾液濃縮，得到呈澄清無色油狀物之標題化合物(0.345 g，1.148 mmol，86%產率)。LC-MSm /z 301.3 (M+H)⁺ 。¹ H NMR (400 MHz，氯仿-d ) δ ppm 1.74 - 1.86 (m, 4 H) 3.05 (t,J =6.6 Hz, 2 H) 3.19 (t,J =6.6 Hz, 3 H) 3.26 - 3.57 (m, 2 H) 3.88 (br s, 2 H) 4.67 (s, 2 H) 6.64 (d,J =1.5 Hz, 1 H) 6.66 (d,J =1.5 Hz, 1 H) 6.67 - 6.69 (m, 1 H) 6.69 - 6.72 (m, 2 H) 6.74 (d,J =1.5 Hz, 1 H) 6.76 (d,J =1.5 Hz, 1 H) 6.82 - 6.92 (m, 2 H)。1- 乙基 -N-(1-(4-(2-(1- 乙基 -3- 甲基 -1H- 吡唑 -5- 甲醯胺基 )-1H- 苯并 [d] 咪唑 -1- 基 ) 丁基 )-7-( 羥基甲基 )-1H- 苯并 [d] 咪唑 -2- 基 )-3- 甲基 -1H- 吡唑 -5- 甲醯胺

向(3-胺基-2-((4-((2-胺基苯基)胺基)丁基)胺基)苯基)甲醇(0.34 g, 1.132 mmol)於N,N-二甲基甲醯胺(DMF) (6.0 mL)中之溶液添加於二噁烷中之1.0 M 1-乙基-3-甲基-1H-吡唑-5-羰基異硫氰酸酯(2.377 mL, 2.377 mmol)。將混合物在室溫下攪拌18小時，添加EDC•HCl (0.651 g, 3.40 mmol)，之後添加TEA (0.947 mL, 6.79 mmol)。將反應混合物在室溫下再攪拌18小時且用水稀釋。將所得沈澱物過濾，用乙酸乙酯洗滌並乾燥，得到呈白色固體之標題化合物(447 mg，0.718 mmol，63.4%產率)。LC-MSm /z 623.4 (M+H)⁺ 。¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 1.27 - 1.33 (m, 6 H) 1.90 (br s, 3 H) 2.09 (s, 3 H) 2.10 (s, 3 H) 2.52 - 2.55 (m, 1 H) 4.18 - 4.38 (m, 2 H) 4.45 - 4.51 (m, 2 H) 4.57 (dq,J =11, 7.1 Hz, 4 H) 4.75 (d,J =5.4 Hz, 2 H) 5.53 (t,J =5.4 Hz, 1 H) 6.56 (s, 1 H) 6.59 (s, 1 H) 7.13 - 7.30 (m, 4 H) 7.48 - 7.57 (m, 3 H) 12.70 (br s, 1 H) 12.77 (br d,J =7.8 Hz, 1 H)。1- 乙基 -N-((E)-3-(4-((E)-2-((1- 乙基 -3- 甲基 -1H- 吡唑 -5- 羰基 ) 亞胺基 )-3- 甲基 -2,3- 二氫 -1H- 苯并 [d] 咪唑 -1- 基 ) 丁基 )-4-( 羥基甲基 )-1- 甲基 -1,3- 二氫 -2H- 苯并 [d] 咪唑 -2- 亞基 )-3- 甲基 -1H- 吡唑 -5- 甲醯胺

向1-乙基-N-(1-(4-(2-(1-乙基-3-甲基-1H-吡唑-5-甲醯胺基)-1H-苯并[d]咪唑-1-基)丁基)-7-(羥基甲基)-1H-苯并[d]咪唑-2-基)-3-甲基-1H吡唑-5-甲醯胺(400 mg, 0.642 mmol)及碳酸銫(837 mg, 2.57 mmol)於N,N-二甲基甲醯胺(DMF) (8.0 mL)中之混合物添加碘甲烷(0.120 mL, 1.927 mmol)，且將混合物在室溫下攪拌30 min。將混合物過濾，用水稀釋，且用乙酸乙酯萃取。將有機萃取物用水洗滌，經無水MgSO₄ 乾燥，過濾且將濾液濃縮。在Combiflash上利用於二氯甲烷中之0%至40%甲醇/二氯甲烷(1:4)梯度進行溶析來純化提供呈白色固體之標題化合物(250 mg，0.384 mmol，59.8%產率)。LC-MSm /z 651.4 (M+H)⁺ 。¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 1.23 (t,J =7.1 Hz, 6 H) 1.67 - 1.85 (m, 4 H) 2.13 (d,J =1.2 Hz, 6 H) 3.50 (s, 3 H) 3.51 (s, 3 H) 4.16 (t,J =6.4 Hz, 2 H) 4.36 (t,J =6.7 Hz, 2 H) 4.47(q,J =7.1 Hz, 4 H) 4.71 (d,J =5.1 Hz, 2 H) 5.53 (t,J =5.3 Hz, 1 H) 6.44 (s, 1 H) 6.45 (s, 1 H) 7.24 - 7.35 (m, 4 H) 7.48 - 7.56 (m, 3 H)。N-((E)-1-(4-((E)-7-( 氯甲基 )-2-((1- 乙基 -3- 甲基 -1H- 吡唑 -5- 羰基 ) 亞胺基 )-3- 甲基 -2,3- 二氫 -1H- 苯并 [d] 咪唑 -1- 基 ) 丁基 )-3- 甲基 -1,3- 二氫 -2H- 苯并 [d] 咪唑 -2- 亞基 )-1- 乙基 -3- 甲基 -1H- 吡唑 -5- 甲醯胺

向1-乙基-N-((E)-3-(4-((E)-2-((1-乙基-3-甲基-1H-吡唑-5-羰基)亞胺基)-3-甲基-2,3-二氫-1H-苯并[d]咪唑-1-基)丁基)-4-(羥基甲基)-1-甲基-1,3-二氫-2H-苯并[d]咪唑-2-亞基)-3-甲基-1H-吡唑-5-甲醯胺(35 mg, 0.054 mmol)於二氯甲烷(DCM) (1.0 mL)中之溶液添加亞硫醯氯(0.020 mL, 0.269 mmol)。將反應混合物在室溫下攪拌1.0小時並濃縮，以提供呈白色固體之標題化合物(35 mg，0.052 mmol，97%產率)。LC-MSm /z 669.3 (M+H)⁺ 。1- 乙基 -N-((E)-3-(4-((E)-2-((1- 乙基 -3- 甲基 -1H- 吡唑 -5- 羰基 ) 亞胺基 )-3- 甲基 -2,3- 二氫 -1H- 苯并 [d] 咪唑 -1- 基 ) 丁基 )-1- 甲基 -4-( 嗎啉基甲基 )-1,3- 二氫 -2H- 苯并 [d] 咪唑 -2- 亞基 )-3- 甲基 -1H- 吡唑 -5- 甲醯胺甲酸鹽

向N,N-((E)-1-(4-((E)-7-(氯甲基)-2-((1-乙基-3-甲基-1H-吡唑-5-羰基)亞胺基)-3-甲基-2,3-二氫-1H-苯并[d]咪唑-1-基)丁基)-3-甲基-1,3-二氫-2H-苯并[d]咪唑-2-亞基)-1-乙基-3-甲基-1H-吡唑-5-甲醯胺(35 mg, 0.052 mmol)於乙醇(1.5 mL)中之溶液添加嗎啉(0.023 mL, 0.261 mmol)，之後添加DIPEA (0.027 mL, 0.157 mmol)。將混合物在70℃下攪拌2.0小時，冷卻至室溫且濃縮。在MDAP上利用於含有0.1%甲酸之水中的15%至55%乙腈梯度進行溶析來純化提供呈白色固體之標題化合物(31 mg，0.043 mmol，82%產率)。LC-MSm /z 720.4 (M+H)⁺ 。¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 1.23 (dt,J =11, 7.1 Hz, 6 H) 1.78 (br s, 4 H) 2.13 (s, 3 H) 2.14 (s, 3 H) 2.20 - 2.28 (m, 4 H) 3.43 (br s, 4 H) 3.49 (s, 3 H) 3.52 (s, 3 H) 3.57 (s, 2 H) 4.15 - 4.22 (m, 2 H) 4.36 - 4.44 (m, 2 H) 4.44 - 4.52 (m, 4 H) 6.44 (s, 1 H) 6.45 (s, 1 H) 7.15 (d,J =7.1 Hz, 1 H) 7.22 - 7.35 (m, 3 H) 7.48 - 7.57 (m, 3 H)。 The compound of Example 18 is usually prepared according to the process described in the above scheme and examples. Example 19. 1- Ethyl- N-((E)-3-(4-((E)-2-((1- ethyl- 3 -methyl -1H- pyrazole- 5- carbonyl ) imine (Yl )-3 -methyl -2,3 -dihydro- 1H- benzo (d) imidazol- 1 -yl ) butyl )-1 -methyl- 4-( morpholinylmethyl )-1,3 - dihydro -2H- benzo [d] imidazol-2-ylidene) -3-methyl -1H- pyrazole-5-carboxylic acid Amides

(4-((2-( Hydroxymethyl )-6- nitrophenyl ) amino ) butyl ) tertiary butyl carbamate

The commercially available (2-fluoro-3-nitrophenyl) methanol (1.05 g, 6.14 mmol), the commercially available (4-aminobutyl) carbamate tert-butyl ester (1.271 g, 6.75 mmol) and A mixture of DIPEA (3.21 mL, 18.41 mmol) in isopropanol (10 mL) was stirred at 70°C for 20 hours. The mixture was cooled to room temperature and concentrated. The residue was diluted with water and extracted with ethyl acetate. The organic extracts were washed with water, dried over anhydrous MgSO _4, filtered and the filtrate was concentrated. Elute on Combiflash using a gradient of 0% to 40% ethyl acetate/ethanol (3:1) in heptane to purify the title compound (2.05 g, 6.04 mmol, 98% yield) as a red oil ). LC-MS m / z 340.3 (M+H) ⁺ . ¹ H NMR (400 MHz, chloroform- d ) δ ppm 1.45 (s, 9 H) 1.54-1.60 (m, 2 H) 1.62-1.71 (m, 2 H) 2.78 (br s, 1 H) 3.16 (q, J =6.6 Hz, 2 H) 3.32 (q, J =6.6 Hz, 2 H) 4.58 (br s, 1 H) 4.79 (d, J =5.4 Hz, 2 H) 6.87 (dd, J =8.5, 7.3 Hz , 1 H) 6.94 (br s, 1 H) 7.55 (dd, J =7.3, 1.6 Hz, 1 H) 8.03 (dd, J =8.5, 1.6 Hz, 1 H). (2-((4- Aminobutyl ) amino )-3 -nitrophenyl ) methanol dihydrochloride

To (4-((2-(hydroxymethyl)-6-nitrophenyl)amino)butyl)carbamate tert-butyl (2.04 g, 6.01 mmol) in methanol (15 mL) The solution was added 4.0 M HCl (15.03 mL, 60.1 mmol) in dioxane. The reaction mixture was stirred at room temperature for 2.0 hours and concentrated. The residue was triturated with dichloromethane and filtered to provide the title compound (1.88 g, 6.02 mmol, 100% yield) as a white solid. LC-MS m / z 240.2 (M+H) ⁺ . ¹ H NMR (400 MHz, DMSO- d ₆ ) δ ppm 1.53-1.62 (m, 4 H) 2.75 (br d, J = 5.4 Hz, 2 H) 3.05-3.12 (m, 2 H) 3.17 (s, 1 H) 4.56 (s, 2 H) 6.83 (dd, J =8.3, 7.2 Hz, 1 H) 7.56 (dd, J =7.2, 1.6 Hz, 1 H) 7.79 (dd, J =8.3, 1.6 Hz, 1 H ) 8.01 (br s, 3 H). (3- nitro- 2-((4-((2- nitrophenyl ) amino ) butyl ) amino ) phenyl ) methanol

(2-((4-Aminobutyl)amino)-3-nitrophenyl)methanol dihydrochloride (651 mg, 2.086 mmol), commercially available 1-fluoro-2-nitrobenzene (0.20 mL, 1.897 mmol) and DIPEA (1.656 mL, 9.48 mmol) in isopropanol (10 mL) was stirred at 80°C for 20 hours. The mixture was cooled to room temperature and concentrated. The residue was diluted with water and extracted with ethyl acetate. The organic extracts were washed with water, dried over anhydrous MgSO _4, filtered and the filtrate was concentrated. Elute on Combiflash using a gradient of 0% to 50% ethyl acetate in heptane to purify the title compound (485 mg, 1.346 mmol, 71% yield) as an orange solid. LC-MS m / z 361.3 (M+H) ⁺ . ¹ H NMR (400 MHz, chloroform- d ) δ ppm 1.83 (m, 4 H) 2.27 (t, J =5.9 Hz, 1 H) 3.38 (q, J =6.4 Hz, 4 H) 4.80 (d, J = 597 Hz, 2 H) 6.68 (td, J =7.7, 1.2 Hz, 1 H) 6.78-6.93 (m, 2 H) 6.93-6.98 (m, 1 H) 7.46 (t, J =6.9 Hz, 1 H) 7.55 (d, J =5.9 Hz, 1 H) 8.03 (dd, J =8.3, 1.4 Hz, 1 H) 8.06 (br s, 1 H) 8.19 (dd, J =8.8, 1.5 Hz, 1 H). (3- Amino- 2-((4-((2 -aminophenyl ) amino ) butyl ) amino ) phenyl ) methanol

To (3-nitro-2-((4-((2-nitrophenyl)amino)butyl)amino)phenyl)methanol (0.48 g, 1.332 mmol) in methanol (40 mL) Ammonium hydroxide (7.41 mL, 53.3 mmol) was added to the solution, followed by sodium bisulfite (2.319 g, 13.32 mmol) in water (10 mL). The resulting mixture was stirred at room temperature for 1 hour and concentrated. The residue was diluted with water and extracted with ethyl acetate. The organic extract was washed with water, dried over anhydrous MgSO ₄ , filtered and the filtrate was concentrated to give the title compound (0.345 g, 1.148 mmol, 86% yield) as a clear colorless oil. LC-MS m / z 301.3 (M+H) ⁺ . ¹ H NMR (400 MHz, chloroform- d ) δ ppm 1.74-1.86 (m, 4 H) 3.05 (t, J =6.6 Hz, 2 H) 3.19 (t, J =6.6 Hz, 3 H) 3.26-3.57 ( m, 2 H) 3.88 (br s, 2 H) 4.67 (s, 2 H) 6.64 (d, J =1.5 Hz, 1 H) 6.66 (d, J =1.5 Hz, 1 H) 6.67-6.69 (m, 1 H) 6.69-6.72 (m, 2 H) 6.74 (d, J =1.5 Hz, 1 H) 6.76 (d, J =1.5 Hz, 1 H) 6.82-6.92 (m, 2 H). 1- Ethyl -N-(1-(4-(2-(1- ethyl- 3 -methyl -1H- pyrazole- 5- carboxamido )-1H- benzo [d] imidazole -1 - yl) butyl) -7- (hydroxymethyl) lH-benzo [d] imidazol-2-yl) -3-methyl-lH-pyrazole-5-Amides

To (3-amino-2-((4-((2-aminophenyl)amino)butyl)amino)phenyl)methanol (0.34 g, 1.132 mmol) in N,N-dimethyl A solution of methylamide (DMF) (6.0 mL) was added to 1.0 M 1-ethyl-3-methyl-1H-pyrazole-5-carbonyl isothiocyanate in dioxane (2.377 mL, 2.377 mmol). The mixture was stirred at room temperature for 18 hours, EDC•HCl (0.651 g, 3.40 mmol) was added, followed by TEA (0.947 mL, 6.79 mmol). The reaction mixture was stirred at room temperature for another 18 hours and diluted with water. The resulting precipitate was filtered, washed with ethyl acetate and dried to obtain the title compound (447 mg, 0.718 mmol, 63.4% yield) as a white solid. LC-MS m / z 623.4 (M+H) ⁺ . ¹ H NMR (400 MHz, DMSO- d ₆ ) δ ppm 1.27-1.33 (m, 6 H) 1.90 (br s, 3 H) 2.09 (s, 3 H) 2.10 (s, 3 H) 2.52-2.55 (m , 1 H) 4.18-4.38 (m, 2 H) 4.45-4.51 (m, 2 H) 4.57 (dq, J =11, 7.1 Hz, 4 H) 4.75 (d, J =5.4 Hz, 2 H) 5.53 ( t, J =5.4 Hz, 1 H) 6.56 (s, 1 H) 6.59 (s, 1 H) 7.13-7.30 (m, 4 H) 7.48-7.57 (m, 3 H) 12.70 (br s, 1 H) 12.77 (br d, J =7.8 Hz, 1 H). 1- Ethyl- N-((E)-3-(4-((E)-2-((1- ethyl- 3 -methyl -1H- pyrazole- 5- carbonyl ) imino )- 3- methyl -2,3 -dihydro- 1H- benzo [d] imidazol- 1 -yl ) butyl )-4-( hydroxymethyl )-1 -methyl- 1,3 -dihydro- 2H - benzo [d] imidazol-2-ylidene) -3-methyl -1H- pyrazole-5-Amides

To 1-ethyl-N-(1-(4-(2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-1H-benzo[d]imidazole- 1-yl)butyl)-7-(hydroxymethyl)-1H-benzo(d)imidazol-2-yl)-3-methyl-1Hpyrazole-5-carboxamide (400 mg, 0.642 mmol ) And a mixture of cesium carbonate (837 mg, 2.57 mmol) in N,N-dimethylformamide (DMF) (8.0 mL) was added methyl iodide (0.120 mL, 1.927 mmol), and the mixture was kept at room temperature Stir for 30 min. The mixture was filtered, diluted with water, and extracted with ethyl acetate. The organic extracts were washed with water, dried over anhydrous MgSO _4, filtered and the filtrate was concentrated. Elute on Combiflash with a gradient of 0% to 40% methanol/dichloromethane (1:4) in dichloromethane to purify the title compound as a white solid (250 mg, 0.384 mmol, 59.8% yield) . LC-MS m / z 651.4 (M+H) ⁺ . ¹ H NMR (400 MHz, DMSO- d ₆ ) δ ppm 1.23 (t, J =7.1 Hz, 6 H) 1.67-1.85 (m, 4 H) 2.13 (d, J =1.2 Hz, 6 H) 3.50 (s , 3 H) 3.51 (s, 3 H) 4.16 (t, J =6.4 Hz, 2 H) 4.36 (t, J =6.7 Hz, 2 H) 4.47(q, J =7.1 Hz, 4 H) 4.71 (d , J = 5.1 Hz, 2 H) 5.53 (t, J = 5.3 Hz, 1 H) 6.44 (s, 1 H) 6.45 (s, 1 H) 7.24-7.35 (m, 4 H) 7.48-7.56 (m, 3 H). N-((E)-1-(4-((E)-7-( chloromethyl )-2-((1- ethyl- 3 -methyl -1H- pyrazole- 5- carbonyl ) imine Yl )-3 -methyl -2,3 -dihydro- 1H- benzo (d] imidazol- 1 -yl ) butyl )-3 -methyl- 1,3 -dihydro -2H- benzo (d ] Imidazole -2- ylidene )-1 -ethyl- 3 -methyl -1H- pyrazole- 5- carboxamide

To 1-ethyl-N-((E)-3-(4-((E)-2-((1-ethyl-3-methyl-1H-pyrazole-5-carbonyl)imino) -3-Methyl-2,3-dihydro-1H-benzo(d]imidazol-1-yl)butyl)-4-(hydroxymethyl)-1-methyl-1,3-dihydro- 2H-benzo[d]imidazole-2-ylidene)-3-methyl-1H-pyrazole-5-carboxamide (35 mg, 0.054 mmol) in dichloromethane (DCM) (1.0 mL) Thionyl chloride (0.020 mL, 0.269 mmol) was added to the solution. The reaction mixture was stirred at room temperature for 1.0 hour and concentrated to provide the title compound (35 mg, 0.052 mmol, 97% yield) as a white solid. LC-MS m / z 669.3 (M+H) ⁺ . 1- Ethyl- N-((E)-3-(4-((E)-2-((1- ethyl- 3 -methyl -1H- pyrazole- 5- carbonyl ) imino )- 3- Methyl -2,3 -dihydro- 1H- benzo [d] imidazol- 1 -yl ) butyl )-1 -methyl- 4-( morpholinylmethyl )-1,3 -dihydro -2H- benzo [d] imidazole -2- ylidene )-3 -methyl -1H- pyrazole- 5- carboxamide

To N,N-((E)-1-(4-((E)-7-(chloromethyl)-2-((1-ethyl-3-methyl-1H-pyrazole-5-carbonyl )Imino)-3-methyl-2,3-dihydro-1H-benzo(d]imidazol-1-yl)butyl)-3-methyl-1,3-dihydro-2H-benzene Add [d]imidazole-2-ylidene)-1-ethyl-3-methyl-1H-pyrazole-5-carboxamide (35 mg, 0.052 mmol) in ethanol (1.5 mL) Morpholine (0.023 mL, 0.261 mmol), followed by DIPEA (0.027 mL, 0.157 mmol). The mixture was stirred at 70°C for 2.0 hours, cooled to room temperature and concentrated. Purification on MDAP using a gradient of 15% to 55% acetonitrile in water containing 0.1% formic acid to provide the title compound (31 mg, 0.043 mmol, 82% yield) as a white solid. LC-MS m / z 720.4 (M+H) ⁺ . ¹ H NMR (400 MHz, DMSO- d ₆ ) δ ppm 1.23 (dt, J =11, 7.1 Hz, 6 H) 1.78 (br s, 4 H) 2.13 (s, 3 H) 2.14 (s, 3 H) 2.20-2.28 (m, 4 H) 3.43 (br s, 4 H) 3.49 (s, 3 H) 3.52 (s, 3 H) 3.57 (s, 2 H) 4.15-4.22 (m, 2 H) 4.36-4.44 (m, 2 H) 4.44-4.52 (m, 4 H) 6.44 (s, 1 H) 6.45 (s, 1 H) 7.15 (d, J =7.1 Hz, 1 H) 7.22-7.35 (m, 3 H) 7.48-7.57 (m, 3 H).

Instance 20 to 31 The compound is usually prepared according to the process described in the above scheme and examples.

2- 氟 -1- 硝基 -3- 乙烯基苯

將市售3-溴-2-氟硝基苯(2.0 g, 9.09 mmol)、三丁基(乙烯基)錫烷(3.99 mL, 13.64 mmol)及四(三苯基膦)鈀(0) (0.525 g, 0.455 mmol)於甲苯(12 mL)中之混合物在100℃下攪拌20小時。使混合物冷卻至室溫，用水稀釋且用乙醚萃取。將有機萃取物用鹽水洗滌，經無水MgSO₄ 乾燥，過濾且將濾液濃縮。在Combiflash上利用於庚烷中之0%至5%乙酸乙酯梯度進行溶析來純化提供呈澄清淺黃色液體之標題化合物(1.15 g，6.88 mmol，76%產率)。¹ H NMR (400 MHz，氯仿-d ) δ ppm 5.58 (d,J =11 Hz, 1 H) 5.94 (d,J =18 Hz, 1 H) 6.90 - 6.98 (m, 1 H) 7.25 - 7.31 (m, 2 H) 7.80 (ddd,J =7.7, 6.2, 1.7 Hz,1 H) 7.94 (ddd,J =8.3, 6.9, 1.5 Hz, 1 H)。1-(2- 氟 -3- 硝基苯基 ) 乙 烷 -1,2- 二醇

向2-氟-1-硝基-3-乙烯基苯(1.12 g, 6.70 mmol)於四氫呋喃(THF) (10 mL)中之溶液添加氧化鋨(VIII) (2.5 wt.%於第三丁醇中) (4.21 mL, 0.335 mmol)，之後添加NMO (1.178 g, 10.05 mmol)。將混合物在室溫下攪拌18小時，用飽和Na₂ S₂ O₃ (aq)稀釋且用乙酸乙酯萃取。將有機萃取物用水洗滌，經無水MgSO₄ 乾燥，過濾且將濾液濃縮，以提供呈黃色油狀物之標題化合物(1.3 g，6.46 mmol，96%產率)。¹ H NMR (400 MHz，氯仿-d ) δ ppm 2.15 (br s, 1 H) 2.93 (br s, 1 H) 3.66 (br dd,J =11, 7.8 Hz, 1 H) 3.97 (br d,J =10 Hz, 1 H) 5.26 (dd,J =7.3, 2.5 Hz, 1 H) 7.35 (td,J =8.0, 1.2 Hz, 1 H) 7.92 (ddd,J =7.8, 5.6, 2.0 Hz, 1 H) 8.01 (td,J =7.7, 1.1 Hz, 1 H)。4-(2- 氟 -3- 硝基苯基 )-2,2- 二甲基 -1,3- 二氧雜環戊烷

將1-(2-氟-3-硝基苯基)乙烷-1,2-二醇(1.25 g, 6.21 mmol)、2,2-二甲氧基丙烷(2.292 mL, 18.64 mmol)及對甲苯磺酸一水合物(0.118 g, 0.621 mmol)於N ,N -二甲基甲醯胺(DMF) (10 mL)中之混合物在室溫下攪拌2天，用飽和NaHCO₃ (aq)稀釋且用乙酸乙酯萃取。將有機萃取物用水洗滌，經無水MgSO₄ 乾燥，過濾且將濾液濃縮。在Combiflash上利用於庚烷中之0%至20%乙酸乙酯梯度進行溶析來純化提供呈澄清淺黃色油狀物之標題化合物(1.13 g，4.68 mmol，75%產率)。¹ H NMR (400 MHz，氯仿-d ) δ ppm 1.54 (s, 3 H) 1.57 (s, 3 H) 3.75 -3.79 (m, 1 H) 4.53 (ddd,J =8.3, 6.0, 1.7 Hz, 1 H) 5.42 (t,J =6.9 Hz, 1 H) 7.34 (td,J =8.1, 1.0 Hz, 1 H) 7.87 - 7.94 (m, 1 H) 8.00 (t,J =7.6 Hz, 1 H)。(E )-N1 -(2-(2,2- 二甲基 -1,3- 二氧雜環戊烷 -4- 基 )-6- 硝基苯基 )-N4 -(2- 硝基苯基 ) 丁 -2- 烯 -1,4- 二胺

將(E )-N1 -(2-硝基苯基)丁-2-烯-1,4-二胺二鹽酸鹽(607 mg, 2.166 mmol)、4-(2-氟-3-硝基苯基)-2,2-二甲基-1,3-二氧雜環戊烷(475 mg, 1.969 mmol)及DIPEA (1.720 mL, 9.85 mmol)於異丙醇(5.0 mL)中之混合物在80℃下攪拌20小時。使混合物冷卻至室溫且濃縮。用水稀釋殘餘物且用乙酸乙酯萃取。使有機萃取物經無水MgSO₄ 乾燥，過濾且將濾液濃縮。在Combiflash上利用於庚烷中之0%至30%乙酸乙酯梯度進行溶析來純化提供呈橙色油狀物之標題化合物(730 mg，1.704 mmol，87%產率)。LC-MSm /z 429.2 (M+H)⁺ 。(E )-N1 -(4-((2- 胺基苯基 ) 胺基 ) 丁 -2- 烯 -1- 基 )-6-(2,2- 二甲基 -1,3- 二氧雜環戊烷 -4- 基 ) 苯 -1,2- 二胺

向(E )-N 1-(2-(2,2-二甲基-1,3-二氧雜環戊烷-4-基)-6-硝基苯基)-N 4-(2-硝基苯基)丁-2-烯-1,4-二胺(0.73 g, 1.704 mmol)於甲醇(45 mL)中之溶液添加氫氧化銨(9.48 mL, 68.2 mmol)，之後添加於水(15 mL)中之二硫亞磺酸鈉(2.97 g, 17.04 mmol)。將反應混合物在室溫下攪拌1.0小時且濃縮。用鹽水稀釋殘餘物且用乙酸乙酯萃取。使有機萃取物經無水MgSO₄ 乾燥，過濾且將濾液濃縮。在Combiflash上利用於庚烷中之0%至40%乙酸乙酯/乙醇(3:1)梯度進行溶析來純化提供呈無色油狀物之標題化合物(380 mg，1.031 mmol，60.5%產率)。LC-MSm /z 369.3 (M+H)⁺ 。 N -((E )-7-(2,2- 二甲基 -1,3- 二氧雜環戊烷 -4- 基 )-1-((E )-4-((E )-2-((1- 乙基 -3- 甲基 -1H- 吡唑 -5- 羰基 ) 亞胺基 )-2,3- 二氫 -1H- 苯并 [d] 咪唑 -1- 基 ) 丁 -2- 烯 -1- 基 )-1,3- 二氫 -2H- 苯并 [d] 咪唑 -2- 亞基 )-1- 乙基 -3- 甲基 -1H- 吡唑 -5- 甲醯胺

向(E )-N 1-(4-((2-胺基苯基)胺基)丁-2-烯-1-基)-6-(2,2-二甲基-1,3-二氧雜環戊烷-4-基)苯-1,2-二胺(380 mg, 1.031 mmol)於N ,N -二甲基甲醯胺(DMF) (6.0 mL)中之溶液添加於二噁烷中之1.0 M 1-乙基-3-甲基-1H-吡唑-5-羰基異硫氰酸酯(2.269 mL, 2.269 mmol)。將混合物在室溫下攪拌3小時，添加EDC•HCl (593 mg, 3.09 mmol)，之後添加TEA (0.862 mL, 6.19 mmol)。將反應混合物在室溫下攪拌3天，用水稀釋且用乙酸乙酯萃取。將有機萃取物用水洗滌，經無水MgSO₄ 乾燥，過濾且將濾液濃縮。在Combiflash上利用於庚烷中之0%至40%乙酸乙酯/乙醇(3:1)梯度進行溶析來純化提供呈白色固體之標題化合物(560 mg，0.811 mmol，79%產率)。LC-MSm /z 691.6 (M+H)⁺ 。¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 1.23 - 1.32 (m, 6 H) 1.40 (s, 2 H) 2.13 (d,J =7.34 Hz, 4 H) 2.74 (s, 2 H) 2.90 (s, 2 H) 3.77 (dd,J =8.1, 7.09 Hz, 2 H) 4.18 (dd,J =8.3, 6.4 Hz, 1 H) 4.44 - 4.61 (m, 4 H) 4.82 (br d,J =4.9 Hz, 3 H) 4.88 (br s, 1 H) 5.10 (br d,J =16 Hz, 1 H) 5.41 (t,J =6.4 Hz, 1 H) 5.50 - 5.60 (m, 1 H) 5.94 - 6.03 (m, 1 H) 6.53 (d,J =8.3 Hz, 1 H) 7.11 - 7.25 (m, 3 H) 7.28 - 7.32 (m, 1 H) 7.38 (d,J =7.8 Hz, 1 H) 7.45 - 7.59 (m, 2 H) 7.96 (s, 1 H) 12.67 (br s, 1 H) 12.83 (br s, 1 H)。 N -((E )-1-((E )-4-((E )-7-(2,2- 二甲基 -1,3- 二氧雜環戊烷 -4- 基 )-2-((1- 乙基 -3- 甲基 -1H- 吡唑 -5- 羰基 ) 亞胺基 )-3- 甲基 -2,3- 二氫 -1H- 苯并 [d] 咪唑 -1- 基 ) 丁 -2- 烯 -1- 基 )-3- 甲基 -1,3- 二氫 -2H- 苯并 [d] 咪唑 -2- 亞基 )-1- 乙基 -3- 甲基 -1H- 吡唑 -5- 甲醯胺

向N -((E )-7-(2,2-二甲基-1,3-二氧雜環戊烷-4-基)-1-((E )-4-((E )-2-((1-乙基-3-甲基-1H-吡唑-5-羰基)亞胺基)-2,3-二氫-1H-苯并[d]咪唑-1-基)丁-2-烯-1-基)-1,3-二氫-2H-苯并[d]咪唑-2-亞基)-1-乙基-3-甲基-1H-吡唑-5-甲醯胺(560 mg, 0.811 mmol)於N ,N -二甲基甲醯胺(DMF) (6.0 mL)中之溶液添加碳酸銫(1056 mg, 3.24 mmol)，之後添加碘甲烷(0.152 mL, 2.432 mmol)。將反應混合物在室溫下攪拌1.0小時，用水稀釋且用乙酸乙酯萃取。將有機萃取物用水洗滌，經無水MgSO₄ 乾燥，過濾且將濾液濃縮。在Combiflash上利用於庚烷中之20%至80%乙酸乙酯/乙醇(3:1)梯度進行溶析來純化提供呈白色固體之標題化合物(400 mg，0.556 mmol，68.6%產率)。LC-MSm /z 719.4 (M+H)⁺ 。¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 1.18 - 1.24 (m, 6 H) 1.26 (s, 3 H) 1.40 (s, 3 H) 2.12 (s, 3 H) 2.14 (s, 3 H) 3.53 (s, 3 H) 3.53 (s, 3 H) 3.80 (dd,J =8.6, 6.6 Hz, 1 H) 4.20 (dd,J =8.3, 6.4 Hz, 1 H) 4.44 (qd,J =7.0, 3.9 Hz, 4 H) 4.72 - 4.81 (m, 3 H) 4.97 (br s, 1 H) 5.40 (t,J =6.4 Hz, 1 H) 5.52 (br d,J =16 Hz, 1 H) 5.94 (br d,J =16 Hz, 1 H) 6.39 (s, 1 H) 6.41 (s, 1 H) 7.19 - 7.24 (m, 1 H) 7.29 - 7.38 (m, 2 H) 7.38 - 7.41 (m, 1 H) 7.43 (d,J =7.8 Hz, 1 H) 7.56 (d,J =7.3 Hz, 2 H)。 N -((E )-1-((E )-4-((E )-7-(1,2- 二羥基乙基 )-2-((1- 乙基 -3- 甲基 -1H- 吡唑 -5- 羰基 ) 亞胺基 )-3- 甲基 -2,3- 二氫 -1H- 苯并 [d] 咪唑 -1- 基 ) 丁 -2- 烯 -1- 基 )-3- 甲基 -1,3- 二氫 -2H- 苯并 [d] 咪唑 -2- 亞基 )-1- 乙基 -3- 甲基 -1H- 吡唑 -5- 甲醯胺

向N -((E )-1-((E )-4-((E )-7-(2,2-二甲基-1,3-二氧雜環戊烷-4-基)-2-((1-乙基-3-甲基-1H-吡唑-5-羰基)亞胺基)-3-甲基-2,3-二氫-1H-苯并[d]咪唑-1-基)丁-2-烯-1-基)-3-甲基-1,3-二氫-2H-苯并[d]咪唑-2-亞基)-1-乙基-3-甲基-1H-吡唑-5-甲醯胺(380 mg, 0.529 mmol)於甲醇(8.0 mL)中之溶液添加於二噁烷中之4.0 M HCl (2.0 mL, 8.00 mmol)。將反應混合物在室溫下攪拌2.0小時，且將混合物濃縮以提供呈白色固體之標題化合物(350 mg，0.516 mmol，98%產率)。LC-MSm /z 679.5 (M+H)⁺ 。 Example 32 N - ((E) -1 - ((E) -4 - ((E) -7- (1,2- dihydroxy-ethyl) -2 - ((1-ethyl-3-methyl - 1H- pyrazole- 5- carbonyl ) imino )-3 -methyl -2,3 -dihydro- 1H- benzo (d) imidazol- 1 -yl ) but -2- en- 1 -yl )- 3- methyl- 1,3 -dihydro -2H- benzo [d] imidazol -2- ylidene )-1 -ethyl- 3 -methyl -1H- pyrazole- 5- carboxamide

2- fluoro- 1 -nitro- 3- vinylbenzene

Combine commercially available 3-bromo-2-fluoronitrobenzene (2.0 g, 9.09 mmol), tributyl(vinyl)stannane (3.99 mL, 13.64 mmol) and tetrakis(triphenylphosphine)palladium(0) ( A mixture of 0.525 g, 0.455 mmol) in toluene (12 mL) was stirred at 100°C for 20 hours. The mixture was cooled to room temperature, diluted with water and extracted with ether. The organic extract was washed with brine, dried over anhydrous MgSO ₄ , filtered and the filtrate was concentrated. Elute on Combiflash using a gradient of 0% to 5% ethyl acetate in heptane to purify the title compound (1.15 g, 6.88 mmol, 76% yield) as a clear light yellow liquid. ¹ H NMR (400 MHz, chloroform- d ) δ ppm 5.58 (d, J =11 Hz, 1 H) 5.94 (d, J =18 Hz, 1 H) 6.90-6.98 (m, 1 H) 7.25-7.31 ( m, 2 H) 7.80 (ddd, J =7.7, 6.2, 1.7 Hz, 1 H) 7.94 (ddd, J =8.3, 6.9, 1.5 Hz, 1 H). 1- (2-fluoro-3-nitrophenyl) ethane-1,2-diol

To a solution of 2-fluoro-1-nitro-3-vinylbenzene (1.12 g, 6.70 mmol) in tetrahydrofuran (THF) (10 mL) was added osmium oxide (VIII) (2.5 wt.% in tertiary butanol) Medium) (4.21 mL, 0.335 mmol), then add NMO (1.178 g, 10.05 mmol). The mixture was stirred at room temperature for 18 hours, diluted with saturated Na ₂ S ₂ O ₃ (aq) and extracted with ethyl acetate. The organic extract was washed with water, dried over anhydrous MgSO ₄ , filtered and the filtrate was concentrated to provide the title compound (1.3 g, 6.46 mmol, 96% yield) as a yellow oil. ¹ H NMR (400 MHz, chloroform- d ) δ ppm 2.15 (br s, 1 H) 2.93 (br s, 1 H) 3.66 (br dd, J =11, 7.8 Hz, 1 H) 3.97 (br d, J =10 Hz, 1 H) 5.26 (dd, J =7.3, 2.5 Hz, 1 H) 7.35 (td, J =8.0, 1.2 Hz, 1 H) 7.92 (ddd, J =7.8, 5.6, 2.0 Hz, 1 H ) 8.01 (td, J =7.7, 1.1 Hz, 1 H). 4-(2- Fluoro- 3 -nitrophenyl )-2,2 -dimethyl- 1,3- dioxolane

Combine 1-(2-fluoro-3-nitrophenyl)ethane-1,2-diol (1.25 g, 6.21 mmol), 2,2-dimethoxypropane (2.292 mL, 18.64 mmol), and A mixture of toluenesulfonic acid monohydrate (0.118 g, 0.621 mmol) in N , N -dimethylformamide (DMF) (10 mL) was stirred at room temperature for 2 days and diluted with saturated NaHCO ₃ (aq) And extracted with ethyl acetate. The organic extracts were washed with water, dried over anhydrous MgSO _4, filtered and the filtrate was concentrated. Elute on Combiflash using a gradient of 0% to 20% ethyl acetate in heptane to purify the title compound (1.13 g, 4.68 mmol, 75% yield) as a clear light yellow oil. ¹ H NMR (400 MHz, chloroform- d ) δ ppm 1.54 (s, 3 H) 1.57 (s, 3 H) 3.75 -3.79 (m, 1 H) 4.53 (ddd, J =8.3, 6.0, 1.7 Hz, 1 H) 5.42 (t, J =6.9 Hz, 1 H) 7.34 (td, J =8.1, 1.0 Hz, 1 H) 7.87-7.94 (m, 1 H) 8.00 (t, J =7.6 Hz, 1 H). ( E )- N1 -(2-(2,2 -Dimethyl- 1,3- dioxolane- 4 -yl )-6- nitrophenyl ) -N4 -(2 -nitrobenzene Yl ) but -2- ene -1,4- diamine

The (E) - N1 - (2- nitrophenyl) but-2-ene-1,4-diamine dihydrochloride (607 mg, 2.166 mmol), 4- (2- fluoro-3-nitro A mixture of phenyl)-2,2-dimethyl-1,3-dioxolane (475 mg, 1.969 mmol) and DIPEA (1.720 mL, 9.85 mmol) in isopropanol (5.0 mL) Stir at 80°C for 20 hours. The mixture was cooled to room temperature and concentrated. The residue was diluted with water and extracted with ethyl acetate. The organic extract was dried over anhydrous MgSO _4, filtered and the filtrate was concentrated. Elute on Combiflash using a gradient of 0% to 30% ethyl acetate in heptane to purify the title compound (730 mg, 1.704 mmol, 87% yield) as an orange oil. LC-MS m / z 429.2 (M+H) ⁺ . ( E ) -N1 -(4-((2 -aminophenyl ) amino ) but -2- en- 1 -yl )-6-(2,2 -dimethyl- 1,3- dioxa Cyclopentane- 4 -yl ) benzene -1,2- diamine

To ( E )- N 1-(2-(2,2-dimethyl-1,3-dioxolane-4-yl)-6-nitrophenyl) -N 4-(2- Nitrophenyl) but-2-ene-1,4-diamine (0.73 g, 1.704 mmol) in methanol (45 mL) was added with ammonium hydroxide (9.48 mL, 68.2 mmol), and then added to water ( 15 mL) sodium dithiosulfinate (2.97 g, 17.04 mmol). The reaction mixture was stirred at room temperature for 1.0 hour and concentrated. The residue was diluted with brine and extracted with ethyl acetate. The organic extract was dried over anhydrous MgSO _4, filtered and the filtrate was concentrated. Elute on Combiflash using a gradient of 0% to 40% ethyl acetate/ethanol (3:1) in heptane to purify the title compound (380 mg, 1.031 mmol, 60.5% yield) as a colorless oil ). LC-MS m / z 369.3 (M+H) ⁺ . N -(( E )-7-(2,2 -Dimethyl- 1,3- dioxolane- 4 -yl )-1-(( E )-4-(( E )-2- ((1- Ethyl- 3 -methyl -1H- pyrazole- 5- carbonyl ) imino )-2,3 -dihydro- 1H- benzo (d) imidazol- 1 -yl ) butan -2- (En- 1 -yl )-1,3 -dihydro -2H- benzo [d] imidazol -2- ylidene )-1 -ethyl- 3 -methyl -1H- pyrazole- 5- carboxamide

To ( E ) -N 1-(4-((2-aminophenyl)amino)but-2-en-1-yl)-6-(2,2-dimethyl-1,3-di A solution of oxolol-4-yl)benzene-1,2-diamine (380 mg, 1.031 mmol) in N , N -dimethylformamide (DMF) (6.0 mL) was added to the dioxins 1.0 M 1-ethyl-3-methyl-1H-pyrazole-5-carbonyl isothiocyanate (2.269 mL, 2.269 mmol) in the alkane. The mixture was stirred at room temperature for 3 hours, EDC•HCl (593 mg, 3.09 mmol) was added, followed by TEA (0.862 mL, 6.19 mmol). The reaction mixture was stirred at room temperature for 3 days, diluted with water and extracted with ethyl acetate. The organic extracts were washed with water, dried over anhydrous MgSO _4, filtered and the filtrate was concentrated. Elute on Combiflash using a gradient of 0% to 40% ethyl acetate/ethanol (3:1) in heptane to purify the title compound (560 mg, 0.811 mmol, 79% yield) as a white solid. LC-MS m / z 691.6 (M+H) ⁺ . ¹ H NMR (400 MHz, DMSO- d ₆ ) δ ppm 1.23-1.32 (m, 6 H) 1.40 (s, 2 H) 2.13 (d, J =7.34 Hz, 4 H) 2.74 (s, 2 H) 2.90 (s, 2 H) 3.77 (dd, J =8.1, 7.09 Hz, 2 H) 4.18 (dd, J =8.3, 6.4 Hz, 1 H) 4.44-4.61 (m, 4 H) 4.82 (br d, J = 4.9 Hz, 3 H) 4.88 (br s, 1 H) 5.10 (br d, J =16 Hz, 1 H) 5.41 (t, J =6.4 Hz, 1 H) 5.50-5.60 (m, 1 H) 5.94- 6.03 (m, 1 H) 6.53 (d, J =8.3 Hz, 1 H) 7.11-7.25 (m, 3 H) 7.28-7.32 (m, 1 H) 7.38 (d, J =7.8 Hz, 1 H) 7.45 -7.59 (m, 2 H) 7.96 (s, 1 H) 12.67 (br s, 1 H) 12.83 (br s, 1 H). N -(( E )-1-(( E )-4-(( E )-7-(2,2 -dimethyl- 1,3- dioxolane- 4 -yl )-2- ((1- Ethyl- 3 -methyl -1H- pyrazole- 5- carbonyl ) imino )-3 -methyl -2,3 -dihydro- 1H- benzo (d) imidazol- 1 -yl )But - 2- en- 1 -yl )-3 -methyl- 1,3 -dihydro -2H- benzo [d] imidazol -2- ylidene )-1 -ethyl- 3 -methyl- 1H - pyrazole-5-Amides

To N -(( E )-7-(2,2-dimethyl-1,3-dioxolane-4-yl)-1-(( E )-4-(( E )-2 -((1-Ethyl-3-methyl-1H-pyrazole-5-carbonyl)imino)-2,3-dihydro-1H-benzo[d]imidazol-1-yl)butan-2 -En-1-yl)-1,3-dihydro-2H-benzo[d]imidazol-2-ylidene)-1-ethyl-3-methyl-1H-pyrazole-5-carboxamide (560 mg, 0.811 mmol) in N , N -Dimethylformamide (DMF) (6.0 mL) with cesium carbonate (1056 mg, 3.24 mmol), followed by methyl iodide (0.152 mL, 2.432 mmol) . The reaction mixture was stirred at room temperature for 1.0 hour, diluted with water and extracted with ethyl acetate. The organic extracts were washed with water, dried over anhydrous MgSO _4, filtered and the filtrate was concentrated. Elute on Combiflash using a gradient of 20% to 80% ethyl acetate/ethanol (3:1) in heptane to purify the title compound (400 mg, 0.556 mmol, 68.6% yield) as a white solid. LC-MS m / z 719.4 (M+H) ⁺ . ¹ H NMR (400 MHz, DMSO- d ₆ ) δ ppm 1.18-1.24 (m, 6 H) 1.26 (s, 3 H) 1.40 (s, 3 H) 2.12 (s, 3 H) 2.14 (s, 3 H) ) 3.53 (s, 3 H) 3.53 (s, 3 H) 3.80 (dd, J =8.6, 6.6 Hz, 1 H) 4.20 (dd, J =8.3, 6.4 Hz, 1 H) 4.44 (qd, J =7.0 , 3.9 Hz, 4 H) 4.72-4.81 (m, 3 H) 4.97 (br s, 1 H) 5.40 (t, J =6.4 Hz, 1 H) 5.52 (br d, J =16 Hz, 1 H) 5.94 (br d, J =16 Hz, 1 H) 6.39 (s, 1 H) 6.41 (s, 1 H) 7.19-7.24 (m, 1 H) 7.29-7.38 (m, 2 H) 7.38-7.41 (m, 1 H) 7.43 (d, J =7.8 Hz, 1 H) 7.56 (d, J =7.3 Hz, 2 H). N -(( E )-1-(( E )-4-(( E )-7-(1,2 -dihydroxyethyl )-2-((1- ethyl- 3 -methyl -1H- Pyrazol- 5- carbonyl ) imino )-3 -methyl -2,3 -dihydro- 1H- benzo (d) imidazol- 1 -yl ) but -2- en- 1 -yl )-3- Methyl- 1,3 -dihydro -2H- benzo [d] imidazole -2- ylidene )-1 -ethyl- 3 -methyl -1H- pyrazole- 5- carboxamide

To N -(( E )-1-(( E )-4-(( E )-7-(2,2-dimethyl-1,3-dioxolane-4-yl)-2 -((1-Ethyl-3-methyl-1H-pyrazole-5-carbonyl)imino)-3-methyl-2,3-dihydro-1H-benzo[d]imidazole-1- (Yl)but-2-en-1-yl)-3-methyl-1,3-dihydro-2H-benzo(d)imidazol-2-ylidene)-1-ethyl-3-methyl- A solution of 1H-pyrazole-5-carboxamide (380 mg, 0.529 mmol) in methanol (8.0 mL) was added to 4.0 M HCl (2.0 mL, 8.00 mmol) in dioxane. The reaction mixture was stirred at room temperature for 2.0 hours, and the mixture was concentrated to provide the title compound (350 mg, 0.516 mmol, 98% yield) as a white solid. LC-MS m / z 679.5 (M+H) ⁺ .

甲烷磺酸 2-((E )-2-((1- 乙基 -3- 甲基 -1H- 吡唑 -5- 羰基 ) 亞胺基 )-3-((E )-4-((E )-2-((1- 乙基 -3- 甲基 -1H- 吡唑 -5- 羰基 ) 亞胺基 )-3- 甲基 -2,3- 二氫 -1H- 苯并 [d] 咪唑 -1- 基 ) 丁 -2- 烯 -1- 基 )-1- 甲基 -2,3- 二氫 -1H- 苯并 [d] 咪唑 -4- 基 )-2- 羥基乙基酯

向N-((E)-1-((E)-4-((E)-7-(1,2-二羥基乙基)-2-((1-乙基-3-甲基-1H-吡唑-5-羰基)亞胺基)-3-甲基-2,3-二氫-1H-苯并[d]咪唑-1-基)丁-2-烯-1-基)-3-甲基-1,3-二氫-2H-苯并[d]咪唑-2-亞基)-1-乙基-3-甲基-1H-吡唑-5-甲醯胺(0.9 g, 1.326 mmol)於二氯甲烷(DCM) (25 mL)中之懸浮液添加TEA (1.109 mL, 7.96 mmol)，之後添加甲磺醯氯(0.207 mL, 2.65 mmol)。將反應混合物在室溫下攪拌10 min。藉由LC-MS監測反應。向混合物添加0.2 mL TEA且將反應攪拌5 min。再次藉由LC-MS監測反應。再向混合物添加0.2 mL TEA及0.05 mL甲磺醯氯，且將其攪拌5 min。確定反應完全。用水稀釋反應混合物且用乙酸乙酯萃取。將有機萃取物用水洗滌且經無水MgSO₄ 乾燥。過濾該有機萃取物且將濾液濃縮，得到用作中間體之呈白色固體之標題化合物(1.0 g，1.189 mmol，90%純度，90%產率)，其不經進一步純化。LC-MSm /z 757.6 (M+H)+，0.82 min (滯留時間)。1- 乙基 -N -((E )-3-((E )-4-((E )-2-((1- 乙基 -3- 甲基 -1H- 吡唑 -5- 羰基 ) 亞胺基 )-3- 甲基 -2,3- 二氫 -1H- 苯并 [d] 咪唑 -1- 基 ) 丁 -2- 烯 -1- 基 )-1- 甲基 -4-( 氧雜環丙烷 -2- 基 )-1,3- 二氫 -2H- 苯并 [d] 咪唑 -2- 亞基 )-3- 甲基 -1H- 吡唑 -5- 甲醯胺

向甲烷磺酸2-((E)-2-((1-乙基-3-甲基-1H-吡唑-5-羰基)亞胺基)-3-((E)-4-((E)-2-((1-乙基-3-甲基-1H-吡唑-5-羰基)亞胺基)-3-甲基-2,3-二氫-1H苯并[d]咪唑-1-基)丁-2-烯-1-基)-1-甲基-2,3-二氫-1H-苯并[d]咪唑-4-基)-2-羥基乙基酯(1.0 g, 1.321 mmol)於甲醇(25 mL)中之溶液添加碳酸鉀(0.548 g, 3.96 mmol)。將反應混合物在室溫下攪拌2小時。使其經由矽藻土過濾且將濾液濃縮。用水稀釋殘餘物且用乙酸乙酯萃取。用水洗滌有機萃取物且經無水MgSO₄ 乾燥並過濾漿液。將濾液濃縮，得到用作中間體之標題化合物(0.9 g，1.308 mmol，99%產率)，其不經進一步純化。LC-MSm /z 661.7 (M+H)+，0.88 min (滯留時間)。¹ H NMR (400 MHz，氯仿-d) δ ppm 1.41 (td, J=7.09, 3.42 Hz, 6 H) 2.29 (s, 3 H) 2.30 (s, 3 H) 2.83 (dd, J=5.38, 2.45 Hz, 1 H) 3.01 - 3.12 (m, 2 H) 3.62 (s, 3 H)3.63 (s, 3 H) 4.60 - 4.67 (m, 4 H) 4.71 - 4.77 (m, 2 H) 5.04 (br dd, J=12.47, 3.18 Hz, 2 H) 5.68 (br d, J=15.65 Hz, 1 H) 5.90 (br d, J=15.65 Hz, 1 H) 6.57 (s, 1 H) 6.58 (s, 1 H) 7.15 - 7.20 (m, 3 H) 7.25 - 7.31 (m, 4 H)。 Example 33. 1- Ethyl - N -(( E )-3-(( E )-4-(( E )-2-((1- ethyl- 3 -methyl -1H- pyrazole- 5- carbonyl) imino) -3-methyl-2,3-dihydro -1H- benzo [d] imidazol-1-yl) but-2-en-1-yl) -4- (1-hydroxy - 2- morpholinoethyl )-1 -methyl- 1,3 -dihydro -2H- benzo [d] imidazol -2- ylidene )-3 -methyl -1H- pyrazole- 5 -methan amine

Methanesulfonic acid 2-(( E )-2-((1- ethyl- 3 -methyl -1H- pyrazole- 5- carbonyl ) imino )-3-(( E )-4-(( E )-2-((1- ethyl- 3 -methyl -1H- pyrazole- 5- carbonyl ) imino )-3 -methyl -2,3 -dihydro- 1H- benzo [d] imidazole -1 -yl ) but -2- en- 1 -yl )-1 -methyl -2,3 -dihydro- 1H- benzo (d) imidazol- 4 -yl )-2- hydroxyethyl ester

To N-((E)-1-((E)-4-((E)-7-(1,2-dihydroxyethyl)-2-((1-ethyl-3-methyl-1H -Pyrazol-5-carbonyl)imino)-3-methyl-2,3-dihydro-1H-benzo[d]imidazol-1-yl)but-2-en-1-yl)-3 -Methyl-1,3-dihydro-2H-benzo[d]imidazole-2-ylidene)-1-ethyl-3-methyl-1H-pyrazole-5-carboxamide (0.9 g, A suspension of 1.326 mmol) in dichloromethane (DCM) (25 mL) was added TEA (1.109 mL, 7.96 mmol), followed by methanesulfonyl chloride (0.207 mL, 2.65 mmol). The reaction mixture was stirred at room temperature for 10 min. The reaction was monitored by LC-MS. 0.2 mL TEA was added to the mixture and the reaction was stirred for 5 min. The reaction was monitored by LC-MS again. 0.2 mL TEA and 0.05 mL methanesulfonyl chloride were added to the mixture, and it was stirred for 5 min. Make sure the reaction is complete. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic extract was washed with water and dried over anhydrous MgSO ₄ . The organic extract was filtered and the filtrate was concentrated to obtain the title compound (1.0 g, 1.189 mmol, 90% purity, 90% yield) used as an intermediate as a white solid, which was not further purified. LC-MS m / z 757.6 (M+H)+, 0.82 min (retention time). 1-ethyl - N - ((E) -3 - ((E) -4 - ((E) -2 - ((1- ethyl-3-methyl -1H- pyrazol-5-yl-carbonyl) alkylene Amino )-3 -methyl -2,3 -dihydro- 1H- benzo (d) imidazol- 1 -yl ) but -2- en- 1 -yl )-1 -methyl- 4-( oxa Cyclopropan- 2- yl )-1,3 -dihydro -2H- benzo [d] imidazole -2- ylidene )-3 -methyl -1H- pyrazole- 5- carboxamide

To methanesulfonic acid 2-((E)-2-((1-ethyl-3-methyl-1H-pyrazole-5-carbonyl)imino)-3-((E)-4-(( E)-2-((1-ethyl-3-methyl-1H-pyrazole-5-carbonyl)imino)-3-methyl-2,3-dihydro-1H benzo(d)imidazole -1-yl)but-2-en-1-yl)-1-methyl-2,3-dihydro-1H-benzo(d)imidazol-4-yl)-2-hydroxyethyl ester (1.0 g, 1.321 mmol) in methanol (25 mL) was added potassium carbonate (0.548 g, 3.96 mmol). The reaction mixture was stirred at room temperature for 2 hours. It was filtered through celite and the filtrate was concentrated. The residue was diluted with water and extracted with ethyl acetate. The organic extract was washed with water and dried over anhydrous MgSO ₄ and the slurry was filtered. The filtrate was concentrated to give the title compound (0.9 g, 1.308 mmol, 99% yield) used as an intermediate without further purification. LC-MS m / z 661.7 (M+H)+, 0.88 min (retention time). ¹ H NMR (400 MHz, chloroform-d) δ ppm 1.41 (td, J=7.09, 3.42 Hz, 6 H) 2.29 (s, 3 H) 2.30 (s, 3 H) 2.83 (dd, J=5.38, 2.45 Hz, 1 H) 3.01-3.12 (m, 2 H) 3.62 (s, 3 H) 3.63 (s, 3 H) 4.60-4.67 (m, 4 H) 4.71-4.77 (m, 2 H) 5.04 (br dd , J=12.47, 3.18 Hz, 2 H) 5.68 (br d, J=15.65 Hz, 1 H) 5.90 (br d, J=15.65 Hz, 1 H) 6.57 (s, 1 H) 6.58 (s, 1 H ) 7.15-7.20 (m, 3 H) 7.25-7.31 (m, 4 H).

向1-乙基-N-((E)-3-((E)-4-((E)-2-((1-乙基-3-甲基-1H-吡唑-5-羰基)亞胺基)-3-甲基-2,3-二氫-1H-苯并[d]咪唑-1-基)丁-2-烯-1-基)-1-甲基-4-(氧雜環丙烷-2-基)-1,3-二氫-2H-苯并[d]咪唑-2-亞基)-3-甲基-1H-吡唑-5-甲醯胺(0.9 g, 1.362 mmol)於乙醇(6.0 mL)中之溶液添加嗎啉(1.187 mL, 13.62 mmol)。將反應混合物在75℃下攪拌20小時。將混合物濃縮且在質量定向自動純化(MDAP)系統(甲酸，補充方法B，8次注射)上純化殘餘物，得到呈白色固體之標題化合物(612 mg，0.771 mmol，56.6%產率)。LC-MSm /z 748.5 (M+H)+，0.59 min (滯留時間)。¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 1.20 (t,J =6.85 Hz, 6 H) 2.12 (s, 3 H) 2.13 (s, 3 H) 2.19 - 2.26 (m, 2 H) 2.27 - 2.34 (m, 2 H) 2.47 - 2.55 (m, 1 H) 2.56 - 2.64 (m, 1 H) 3.39 (t,J =4.28 Hz, 4 H) 3.52 (s, 3 H) 3.54 (s, 3 H) 4.42 (quin,J =7.09 Hz, 4 H) 4.68 - 4.78 (m, 2 H) 4.87 - 4.96 (m, 1 H) 5.07 (d,J =19.56 Hz, 2 H) 5.36 (d,J =4.16 Hz, 1 H) 5.48 - 5.58 (m, 1 H) 5.94 (d,J =15.65 Hz, 1 H) 6.38 (s, 1 H) 6.39 (s, 1 H) 7.19 - 7.24 (m, 1 H) 7.33 (t,J =7.83 Hz, 2 H) 7.44 (dd,J =12.47, 7.58 Hz, 2 H) 7.50 (d,J =8.07 Hz, 1 H) 7.57 (d,J =8.07 Hz, 1 H)。 1-ethyl - N - ((E) -3 - ((E) -4 - ((E) -2 - ((1- ethyl-3-methyl -1H- pyrazol-5-yl-carbonyl) alkylene Amino )-3 -methyl -2,3 -dihydro- 1H- benzo (d) imidazol- 1 -yl ) but -2- en- 1 -yl )-4-(1- hydroxy -2- ? (Hydroxyethyl )-1 -methyl- 1,3 -dihydro -2H- benzo [d] imidazol -2- ylidene )-3 -methyl -1H- pyrazole- 5- carboxamide

To 1-ethyl-N-((E)-3-((E)-4-((E)-2-((1-ethyl-3-methyl-1H-pyrazole-5-carbonyl) Imino)-3-methyl-2,3-dihydro-1H-benzo(d)imidazol-1-yl)but-2-en-1-yl)-1-methyl-4-(oxy Cyclopropan-2-yl)-1,3-dihydro-2H-benzo[d]imidazol-2-ylidene)-3-methyl-1H-pyrazole-5-carboxamide (0.9 g, Add morpholine (1.187 mL, 13.62 mmol) to a solution of 1.362 mmol) in ethanol (6.0 mL). The reaction mixture was stirred at 75°C for 20 hours. The mixture was concentrated and the residue was purified on a mass-directed automated purification (MDAP) system (formic acid, supplementary method B, 8 injections) to give the title compound (612 mg, 0.771 mmol, 56.6% yield) as a white solid. LC-MS m / z 748.5 (M+H)+, 0.59 min (retention time). ¹ H NMR (400 MHz, DMSO- d ₆ ) δ ppm 1.20 (t, J =6.85 Hz, 6 H) 2.12 (s, 3 H) 2.13 (s, 3 H) 2.19-2.26 (m, 2 H) 2.27 -2.34 (m, 2 H) 2.47-2.55 (m, 1 H) 2.56-2.64 (m, 1 H) 3.39 (t, J = 4.28 Hz, 4 H) 3.52 (s, 3 H) 3.54 (s, 3 H) 4.42 (quin, J =7.09 Hz, 4 H) 4.68-4.78 (m, 2 H) 4.87-4.96 (m, 1 H) 5.07 (d, J =19.56 Hz, 2 H) 5.36 (d, J = 4.16 Hz, 1 H) 5.48-5.58 (m, 1 H) 5.94 (d, J =15.65 Hz, 1 H) 6.38 (s, 1 H) 6.39 (s, 1 H) 7.19-7.24 (m, 1 H) 7.33 (t, J =7.83 Hz, 2 H) 7.44 (dd, J =12.47, 7.58 Hz, 2 H) 7.50 (d, J =8.07 Hz, 1 H) 7.57 (d, J =8.07 Hz, 1 H) .

Instance 34 to 38 The compound is usually prepared according to the process described in the above scheme and examples.

Biological analysis

Cell culture

Maintain human and mouse macrophage cell lines and Kupffer cells in Dulbecco's modified Eagle medium (DMEM) supplemented with 10% fetal bovine serum (FBS) in. As described in Ladner et al., AAC 1997, it maintains an immortalized human hepatocyte-derived cell line that supports a high degree of HBV replication in a tetracycline (tet)-inducible manner. Cryopreserved primary human hepatocytes (PHH) from Lonza were used in these experiments. Place the frozen PHH vial in a 37°C water bath for approximately 70 seconds until it thaws. The cells were combined, gently resuspended in differentiation medium (Williams medium containing differentiation supplement GlutaMax-1™ and penicillin/streptomycin), and counted using a hemocytometer. The cells were pelleted by centrifugation at 100 × g for 10 min and resuspended in differentiation medium to ^{a density of 5.5 × 10 5} cells/mL. Spread 100 μL of cell suspension in each well of a 96-well plate coated with collagen. The plates are incubated at 37°C and 5% CO ₂ for 2 to 4 days before infection.

Reagent

The STING compound can be as described herein and as an international patent application PCT/IB2017/051945 entitled "HETEROCYCLIC AMIDES USEFUL AS PROTEIN MODULATORS" filed on April 5, 2016 (the entire contents of which are incorporated by reference In this article).

Recombinant murine IFN-α, IL-1, IL-6 and TNF-α can be purchased from PBL InterferonSource. As previously described in Xu C et al., Interferons accelerate decay of replication-competent nucleocapsids of hepatitis B virus. J Virol 2010; 84 : 9332-40, antibodies against the 14 amino acids at the carboxy terminal of the HBV core protein can be prepared. Anti-β-actin and mouse IFNAR-1 antibodies were obtained from Sigma-Aldrich and Santa Cruz Biotechnology, respectively. Antibodies against human and mouse STING, TBK1, S ¹⁷² -phosphorylated TBK1, IkBα p38, phosphorylated p38, JNK, phosphorylated JNK, ERK, and phosphorylated ERK can be purchased from Cell Signaling Technology.

Instance 39

HEK WT Agonist analysis:

Luciferase reporter gene analysis can be used in human embryonic kidney cells co-transfected with plastids (Agilent Technologies) expressing STING and firefly luciferase driven by the interferon-stimulated response element promoter (pISRE-Luc) (HEK293T) measures the activation of STING in cells. Full-length human STING (gene ID 340061) and full-length human cyclic guanine adenine synthase (cGAS) (reference sequence NM_138441.2) can be cloned into mammalian cell expression vectors containing cytomegalovirus promoters. Use Fugene ^® 6 to follow the manufacturer's instructions (3:1 Fugene ^® :DNA) to prepare transfection solution using cell suspension. Dispense 50 microliters of transfection suspension into wells of a 384-well plate containing 250 nL of the compound of formula (I) as described herein, suitably a compound of Table 1, or a pharmaceutically acceptable salt thereof. The final well composition contains about 20,000 cells/well, 1 ng STING, 20 ng pISRE-Luc and empty vector pcDNA3.1 (Invitrogen) to achieve a total DNA concentration of 125 ng. Co-transfection with cGAS expression plastids is expected to produce control wells with maximum STING activation. The plate was sealed and incubated at 37°C for 24 hours. The Steady-Glo ^® Luciferase Analysis System (Promega) is used to process the performance of firefly luciferase and can be analyzed using a standard laboratory luminescence plate reader. Normalized emission data for the reaction in the presence of cGAS, plotted as compound concentration with the change, and may use a standard fitting receptor activation model to derive pEC _50.

Instance 40

Correct HBV DNA , RNA , HBsAg and HBeAg Analysis

The Abazyme HBV s Ag kit, catalog number EL10018, can be used to measure the HBsAg content according to the manufacturer's instructions. The BioChain HBV e Ag kit, catalog number KO31006096, can be used to measure the HBeAg content according to the manufacturer's instructions. For the analysis of HBV DNA in the supernatant, the QiaAmp 96 DNA Blood Set (Qiagen) was used, and DNA was extracted from 50 µL of the supernatant according to the manufacturer's instructions. Using primers and conditions as described in [Thimme R et al. (2003) J. Virol. 77, 68-76], 5 µL of DNA was used for TaqMan analysis. A standard curve based on a known quantity of HBV DNA plastid pure lines can be used to calculate the equivalent of HBV gene bodies secreted in the culture medium. Values from cells that underwent the transfection procedure in the absence of oligonucleotides were used to normalize cell viability, inhibition of HBV DNA and secreted antigens. The data was analyzed by nonlinear regression, and GraphPad Prism5 was used to fit the log (inhibitor) response curve.

Real-time PCR and RT-PCR analysis For cytokines gene expression analysis, use TRIzol reagent or RNeasy kit to extract total RNA. CDNA was synthesized using SuperScript III (Invitrogen). Quantitative real-time PCR analysis was performed using LightCycler 480 II (Roche).

Isolation of non-parenchymal cells from mouse liver

As described in Mohar et al., Methods in Molecular Biology, 2015, non-parenchymal cells (NPC), such as sinusoidal endothelial cells (LSEC), Kuffern cells (KC), natural killer cells (NK), and NK are isolated from the liver. -T cells, dendritic cells, CD4+ and CD8+ T cells and hepatic stellate cells (HSC). In addition to NPC, this protocol also allows the collection of peripheral blood, intact liver tissue and hepatocytes. In situ perfusion via the portal vein allows efficient digestion by the liver. NPC was enriched from the obtained single cell suspension by differential and gradient centrifugation. NPCs can be analyzed by flow cytometry or sorted into highly enriched populations. The isolated cells are suitable for flow cytometry, protein and mRNA analysis, and primary culture. For analysis based on flow cytometry, the epitopes of CD8a, CD4, CD11b, NK1.1, Tie2, F4/80, GR1 can be used for the main liver NPC and white blood cells.

Instance 41

Intracellular cytokine staining (ICS) analysis

ICS analysis can be performed on both spleen cells and liver monocytes. The cells were seeded in a U-shaped bottom 96-well plate. The plate with cells was incubated in complete medium alone as a negative control or with HLA-A2/DR1 restricted HBV epitope peptide at a concentration of 2 pg/ml at 37°C overnight. The list of HBV-specific epitopes is described in Bertoletti et al., Gastroenterology 1997, Pajot et al., Microbes Infect 2006, Sette et al., J Immuno 1994, Rehermann et al., J Exp Med 1995, Nayersina et al., J Immunol 1993, Loirat et al. Et al., J Immunol 2000 and Mizukoshi et al., J Immunol 2004. After one hour of incubation, 2 pg/mL of Brefeldin A (Sigma, B6542) was added. After overnight culture, the cells were washed with PBS FAGS and incubated with 5 pL of PBS FAGS containing rat anti-mouse CD16/CD32 antibody and the yellow survival marker LD (Thermofisher, L34959) in the dark at 4°C 10 min. Then, the cells were stained in the dark with 25 pL of PBS FAGS containing Mab at 4°C for 20 min. The mixture is composed of CD3 (hamster Mab anti-mouse CD3-PerCP, BD Biosciences, 553067), CD8 (rat Mab anti-mouse CD8-APC-H7, BD Biosciences, 560182), CD4 (rat Mab anti-mouse CD4 -PE-Cy7, BD Biosciences, 552775) and NK cell (rat Mab anti-mouse NK P46 BV421, Biolegend, 137612) monoclonal antibody composition. After washing several times, the cells were fixed and permeabilized with Cytofix/Cytoperm at room temperature in the dark for 20 min, and washed with Perm/Wash solution (BD Biosciences, 554714) at 4°C. Use for IFNγ (rat Mab anti-mouse IFNγ-APC, pure line XMG1.2, BD Biosciences, 554413) and tumor necrosis factor α (TNFα) (rat Mab anti-mouse TNFα-FITC, pure line MP6-XT22; 1/ 250 (BD Biosciences 554418) antibody stains 20 types of intracellular interleukins for 30 min at 4°C in the dark. Before analysis by flow cytometry using the MACSQuant analyzer, wash the cells with Perm/Wash And resuspend it in PBS FACS containing 1% formaldehyde. Live CD3+CD8+CD4- and CD3+CD8-CD4+ cells are gated and displayed on a dot map. Two areas can be defined to match each A cytokine-positive cell is gated. The number of events found in these gates can be divided by the total number of events in the parental population to get the percentage of reactive T cells. For each mouse, The percentage obtained in medium only is regarded as background and subtracted from the percentage obtained by peptide stimulation. The positive threshold is defined according to the experimental background, that is, the average of the stained cells obtained in each group of medium only conditions Percentage plus two standard deviations. Only the percentage of cytokines representing at least 5 events is considered positive.

Instance 42

STING Agonists in AAV-HBV Antiviral efficacy in mouse models

Male C57BL/6 mice (4-6 weeks old) without specific pathogens were purchased from SLAG (Shanghai Laboratory Animal Center of Chinese Academy of Sciences), and they were housed in individual ventilated cages in animal care centers. As instructed by WuXi IACUC (Institutional Animal Care and Use Committee, WUXI IACUC program number R20131126-mouse), follow the guidelines for animal care and use. The mice were adapted to the new environment for 3 days and grouped according to the experimental design. The recombinant AAV-HBV was diluted in PBS, 200 pL/injection. This recombinant virus carries 1.3 copies of the HBV gene body (genotype D, serotype ayw). On day 0, all mice were injected with 200 pL of AAV-HBV via the tail vein. On day 6, day 13 and day 20 after AAV injection, all mice were subjected to submandibular bleeding (0.1 ml blood/mouse) to collect serum. On the 22nd day after injection, mice with stable viremia were ready for treatment.

Animals were tested for the efficacy of STING agonists in vivo by intravenous bolus injection of 30 ug every 3-4 days for a week. Then a group of mice were sacrificed 24 hours after treatment to detect cytokines (IFN-I, II, IL6, TNF, IL12, CXCL10) and interferon-stimulating genes ( OAS1, IFH1) are up-regulated in the liver. The body weight of individual mice was monitored before treatment and 24 hours after treatment. Liver tissues were collected from mice and fixed in 3.7% formaldehyde. Each liver was divided into six parts, individually embedded in paraffin and sectioned. Liver sections were stained with hematoxylin and eosin or immunostained with rabbit anti-HBcAg primary antibody (Dako, France). HBcAg positive hepatocytes were analyzed by using ImageJ software (version 1.43; W. S. Rasband, U.S. NIH, Bethesda, MD). A commercially available enzyme-linked immunosorbent assay (ELISA) kit was used to analyze HBsAg and HBeAg in mouse serum. Calculate the HBsAg concentration (in ng/ml) by referring to a standard curve established with a known concentration of HBsAg. The serum HBeAg content was determined in 10-fold diluted serum. As previously described in Mancini et al., J. Med. Virol 1993, antibodies were quantified by ELISA. Measure the alanine aminotransferase (ALAT) and aspartate aminotransferase (ASAT) activities in the serum of mice injected with AAV8-HBV- and PBS.

Instance 43

Establish a cell culture system for evaluation PRR Agonist-induced targeting HBV Antiviral response

Unlike RIG-I-like receptors that are ubiquitously expressed in many types of somatic cells, the expression of other PRRs (such as TLR, cGAS STING) is usually limited to macrophages, dendritic cells, and some other cell types. Due to the lack of PRR (such as STING and TLR) or its low level of expression, treatment of hepatocytes usually does not induce a strong cytokine response. For example, the cytokine response induced by the direct treatment of liver cells with TLR agonists is negligible. However, liver-resident dendritic cells, macrophages (Kouffer's cells), and other liver non-parenchymal cells (NPC) exhibit high levels of TLR, and therefore respond to TLR agonists and produce inflammatory cytokines.

To screen small molecule PRR agonists for the treatment of chronic hepatitis B, cell-based analysis that mimics the liver environment can be used. Treat HBV-infected primary human hepatocytes (PHH) with the test compound, and then apply the conditioned medium of the treated macrophages to the HBV-infected PHH to test the compound-induced antiviral cytokine response in the macrophages .

Instance 44

STING The agonist induces an antiviral response in non-parenchymal cells in the liver to inhibit the HBV copy

Using the analysis system described above, the indirect (indirect) antiviral activity of the STING compound of formula (I), the compound of Table 1 or a pharmaceutically acceptable salt thereof, was tested against HBV. In short, different concentrations of STING compounds can be used to treat HBV-infected PHH for 2 days (direct treatment), and can be obtained from isolated human sinusoidal endothelial cells (LSEC), Kuffer’s cells (KC) or NK cells or The isolated human macrophages (treated with each STING compound for 12 h) were harvested with 50% conditioned medium (indirect treatment). STING compounds of 0.5 μM to 125 μM or LPS of 1 μg/ml can be used to simulate HBV-infected PHH, RAW264.7 or macrophages for 30 and 60 minutes. The performance and activation of STING were determined by Western blot analysis. Phosphorylation of STING can cause changes in gel mobility. β-actin can be used as a loading control. Detect intracellular HBV RNA by qRT-PCR. By Western blot analysis, the HBV core protein was determined using an antibody against the 14 amino acids at the carboxy terminal of the HBV core protein (β-actin was used as a loading control). The HBV nucleocapsid was examined by granular gel analysis to detect both the intact nucleocapsid and the HBV DNA associated with the capsid. The encapsidated HBV (core DNA) replication intermediates (RC, DSL and SS) were determined by Southern blot analysis.

Any antiviral response induced by STING compounds in non-parenchymal cell types (such as LSEC, NK, KC) is expected to reduce the amount of HBV capsid protein and assembled capsids after transcription. Therefore, the amount of HBV DNA replication intermediates is also expected to decrease.

Instance 45

expected STING Compounds induce different cytokines response profiles

In order to determine the antiviral mechanism of the conditioned medium harvested from LSEC, NK, KC cells treated with STING compounds, the activation of signal transduction pathways and cytokine profiles in treated cells induced by STING compounds can be analyzed.

The cells were treated with a dose-response STING compound at different times. The total cell protein can be separated by SDS-PAGE and transferred to PVDF membrane. Western blot analysis can use its specific antibodies to detect total and phosphorylated STING, TBK1, p38, JNK, Erk, and IκBα. β-actin was used as a loading control.

The STING compound is expected to induce phosphorylation of STING, which should be detectable in cells treated with the STING compound for more than 30 min. The STING compound is expected to induce phosphorylation of TBK1, which is a kinase necessary for phosphorylation of IRF3 and the induction of IFN-β in the STING pathway. In addition, the STING compound is expected to induce degradation of IKBα.

The cytokine profile induced by STING compounds can be determined by qRT-PCR analysis. The cells were treated with a dose-response STING compound at different times. Then, real-time RT-PCR analysis can be used to quantify the amount of mRNA for the specified specific cytokines and chemokines. The data (mean +-standard deviation, N=3) can be expressed as the induction fold of gene expression relative to the untreated control.

The qRT-PCR analysis is expected to show whether the STING compound induces an IFN response and/or an inflammatory cytokine response.

Instance 46

Type I IFN was tested as a mediator of the antiviral response against HBV induced by STING compounds.

In order to determine the role of type I IFN and other cytokines in the antiviral response induced by STING compounds, it can be studied whether blocking type I IFN response with monoclonal antibodies that specifically recognize type I IFN receptors can attenuate the type I IFN response can be induced by STING compounds Any antiviral activity in the macrophages.

Incubate the HBV-infected PHH with or without 10 μg/ml monoclonal antibody against type I interferon receptor IFNAR1 (Ab INFAR) at 37°C for 1 h, and then use different concentrations of IFN-α or self-preservation Phage cells (treated with the same different concentration of STING compound for 12 h) were harvested and treated with 50% conditioned medium for 2 days. The cytoplasmic HBV DNA can be quantified by real-time PCR analysis, and the data (average value +-standard deviation, N=4) can be expressed as a percentage of the simulated treatment control. Different concentrations of IL-1, IL-6 or TNF-α can be used to treat HBV-infected PHH for 4 days. Then the cytoplasmic HBV core DNA can be analyzed by qPCR or Southern blot hybridization.

It is expected that blocking the type I IFN receptor in PHH infected by HBV significantly reduces the antiviral response caused by IFN-α. Treatment of HBV-infected PHH with type I IFN receptor antibody can also attenuate the antiviral response caused by the conditioned medium of macrophages treated with STING compound. Therefore, this may indicate that type I IFN may be induced by STING compound against HBV. The medium of antiviral response.

In order to determine the role of other cytokines in the antiviral response induced by STING compounds, the antiviral effects of IL-1, IL-6 and TNF-α can be tested to observe which inhibit HBV DNA replication and which may be observed It plays a role in the antiviral response induced by any STING compound against HBV.

Instance 47

STING Agonist in vivo in mice PK/PD

In order to determine the target participation after STING agonist treatment in vivo, the pharmacokinetics and pharmacodynamic relationship after intravenous or oral administration of STING agonist were examined in C57BL/6 mice. Different doses of STING agonist and vehicle arm only were administered in 3 mice/group. At the time points of 0 h, 1 h, 3 h, 4 h, 6 h and 24 h, the mice were euthanized and blood, serum, liver, spleen and draining lymph nodes were collected to measure the drug concentration in the liver and serum And the response of type I and type II IFN and various cytokines (including IL6, TNFα, IL12, IL7, CXCL10) in the collected tissues.

To further understand which cell types are responsible for the induction of cytokines in the liver, non-parenchymal cells (NPC) were collected for qRT-PCR and flow cytometry as described previously. Using cell markers specific to each cell type, cell types that induce type I IFN can be identified.

It is expected that the activation of STING induces a strong up-regulation of type I response at an early time point after administration of the compound, and it decreases over time within 24 hours. This reaction tends to occur in NPC rather than in hepatocytes, which are the parenchymal cells in the liver.

Instance 48

STING The compound inhibits in mice HBV copy

To further verify the antiviral effect of the STING compound in vivo, C57BL/6 mice can be infected with AAV8-HBV to establish HBV replication in the mice. One month after infection, mice can be treated intravenously with 3 doses of 30 ug or 100 ug of STING compound every 3 days for one week or with vehicle only. 24 hours after the last dose, liver and serum were collected and analyzed for HBsAg, HBV DNA, and cytokine responses. Each of the control group and the STING compound treatment group may include four mice. After subtracting the copies from the input plastid, the number of HBV DNA copies/ml from each animal can be plotted. Total RNA is extracted from the liver and the mRNA content of cytokines can be analyzed by real-time RT-PCR analysis. Draw a graph representing the mRNA content of each animal. All data are presented as box plots to indicate the median, quartile, and range (minimum, maximum), and can be statistically analyzed by t-test.

Compared with the vehicle-treated control group, STING compound treatment in mice is expected to reduce systemic and intrahepatic HBV DNA by 1-log to 2-log after the course of treatment. Consistent with the predicted antiviral mechanism, it is expected to induce the expression of representative IFN-stimulating genes (ISG) and cytokines in the liver of animals treated with STING compounds.

Instance 49

STING Compound and HBV In vivo effects of a combination of inhibitors in mice

In order to understand the effect of STING agonist as an immunomodulator to break the immune tolerance against HBV, the AAV8-HBV mouse model was used to examine the STING agonist together with HBV antiviral therapy. C57BL/6 mice were infected with AAV8-HBV for 30 days. Mice suffering from persistent HBV infection were divided into groups and treated with the compound of formula (I) as described herein, a compound of Table 1 or a pharmaceutically acceptable salt or vehicle thereof at 10 mg/kg BID per day for 8 weeks . At 8 weeks after treatment, the treatment was combined with 30 ug intravenous STING agonist or vehicle within 3 days for another week. The mice were maintained for another 4 weeks without further treatment. Serum was collected at a scheduled time, and a part of the mice in the group was euthanized at the scheduled time and tissues were collected. At the end of the study, all mice were euthanized and treated for HBV endpoints (e.g. HBsAg, HBeAg, HBV DNA, intrahepatic HBV mRNA), and cell responses (e.g. cytokines) were measured by RT-PCR, ELISA or qPCR reaction). Isolate NPC and analyze the activation of its STING pathway. The content of HBV-specific CD4 and CD8 T cells was determined by tetramer staining using known HBV epitopes. Anti-HBs was determined from the collected serum.

It is expected that treatment with HBV antiviral inhibitors known to inhibit the content of HBsAg reduces the viral barrier, so that the host immune response can be rejuvenated after immunomodulator treatment. After 8 weeks of antiviral therapy and subsequent co-treatment with STING agonists, the sustained response of serum clearance and seroconversion indicated that the immune tolerance against HBV was broken. The increase in the frequency of IFNγ-producing CD4+ and CD8+ T cells specific to HBV epitopes in the liver and spleen can be confirmed.

Instance 50

FRET analysis: The competitive binding analysis as described in WO2017/175156 was used to determine the binding efficacy of the molecule to the C-terminal domain (CTD) of human STING. In this analysis, STING recombinant protein with C-terminal biotinylated Avi tag was used. When bound to STING, the Alexa488 labeled orthosteric site probe received 490 nm emission from Tb-streptavidin-Avi-STING and the increase in fluorescence was measured at 520 nm. Molecules that compete for the probe binding site produce a lower 520 nm signal. The analysis was performed in a Greiner black 384-well plate (catalog number 784076) containing 125 nL of compound in pure DMSO. Use Combi Liquid Disposer (ThermoFisher) to mix 500 pM STING, 500 pM Streptavidin-Lumi4-Tb and 100 nM Alexa488 probes with 0.02% (w/v) pluronic F127 and 0.02% (w/v) A solution of bovine serum albumin in phosphate buffered saline is added to the plate. The plate was centrifuged at 500 rpm for 1 min, incubated at room temperature for 15 min, and then the fluorescence emission at 520 nm after laser excitation at 337 nm was measured on a PheraSTAR plate reader (BMG Labtech).

將該比率表示為抑制%，其中U係未知值，C1係不含截短之STING (對應於人類STING酶之胺基酸149-379)重組蛋白之混合物的平均低對照反應，且C2係最大反應之平均值。在ABASE XE中使用方程式

來實施曲線擬合，其中A係最小反應，B係最大反應，C係log₁₀ EC₅₀ ，D係斜率因子，且x係log₁₀ 化合物濃度[M]。Use the raw counts of fluorescence at 490 nm and 520 nm to calculate the HTRF ratio (fluorescence at 520 nm/490 nm), and then use the formula

Express this ratio as% inhibition, where U is an unknown value, C1 is the average low control response of a mixture of recombinant proteins without truncated STING (corresponding to the amino acid 149-379 of human STING enzyme), and C2 is the largest The average value of the response. Use equations in ABASE XE

To implement curve fitting, where A is the smallest response, B is the largest response, C is the log ₁₀ EC ₅₀ , D is the slope factor, and x is the log ₁₀ compound concentration [M].

Instance 51

PBMC agonist analysis: The activation of STING by the compound was determined by measuring the amount of IFNβ secreted from human peripheral blood mononuclear cells (PBMC, homozygous WT-STING) treated with different doses of the compound. Thaw frozen PBMC cells and resuspend in medium (containing L-glutamic acid, 1.5 g/L NaHCO ₃ , 4.5 g/L glucose, 10 mM Hepes and 1 mM sodium pyruvate + 10% FBS + 1% Glutamax supplement RPMI-1640) to the final concentration of 3×10 ⁵ cells/mL, and the density of 15,000 cells/well (containing 250 nL of the compound diluted in DMSO) was distributed to a 384-well tissue culture plate (Griener 781073 )in. After incubating at 37°C for four hours, the human IFNβ electrochemiluminescence kit (Meso Scale Diagnostics) was used to measure the amount of IFNβ protein secreted into the growth medium following the manufacturer's instructions. For dose response, use the following normalized equation to express the results of each test hole as activation%: N = 100-100*(CMPD-CTRL2)/(CTRL1-CTRL2), where CMPD is an unknown value and CTRL1 is 100% activation The average value of control wells (using 750 nM or a known complete agonist), and C2 is the average value of 0% activated control wells (DMSO). Use the following equation to implement curve fitting: y = A+((BA)/(1+(10^x/10^C)^D)), where A is the smallest response, B is the largest response, and C is log ₁₀ EC ₅₀ , And D is the Hill slope. The results of each compound are recorded as pEC ₅₀ values (-C in the above equation). _{Table 2 records the results (pEC 50} ) of each of the example compounds 1 to 17 and the values of PBMC agonist maximum %, STING FRET IC ₅₀ and STING FRET maximum %.

The embodiments of the present invention described above are intended to be illustrative only; various variations and modifications will be obvious to those familiar with the art. All such changes and modifications are intended to be within the scope of the present invention, as defined in any appended patent scope. Those familiar with the art should understand that various changes and modifications can be made to the preferred embodiments of the disclosed methods, and these changes and modifications can be made without departing from the spirit of the methods. Therefore, the scope of the attached patent application intends to cover all these equivalent variations within the true spirit and scope of these methods.

N,N'-((2E,2'E)-((E)-丁-2-烯-1,4-二基)雙(3-甲基-1,3-二氫-2H-苯并[d]咪唑-1-基-2-亞基))雙(1-乙基-3-甲基-1H-吡唑-5-甲醯胺) 2

(E)-2-((1-乙基-3-甲基-1H-吡唑-5-羰基)亞胺基)-1-((E)-4-((E)-2-((1-乙基-3-甲基-1H-吡唑-5-羰基)亞胺基)-3-甲基-2,3-二氫-1H-苯并[d]咪唑-1-基)丁-2-烯-1-基)-3-甲基-2,3-二氫-1H-苯并[d]咪唑-5-甲酸甲基酯 3

1-乙基-N-((E)-3-((E)-4-((E)-2-((1-乙基-3-甲基-1H-吡唑-5-羰基)亞胺基)-3-甲基-2,3-二氫-1H-苯并[d]咪唑-1-基)丁-2-烯-1-基)-4-甲氧基-1-甲基-1,3-二氫-2H-苯并[d]咪唑-2-亞基)-3-甲基-1H-吡唑-5-甲醯胺 4

1-乙基-N-((E)-3-((E)-4-((E)-2-((1-乙基-3-甲基-1H-吡唑-5-羰基)亞胺基)-7-(3-羥基丙氧基)-3-甲基-2,3-二氫-1H-苯并[d]咪唑-1-基)丁-2-烯-1-基)-4-甲氧基-1-甲基-1,3-二氫-2H-苯并[d]咪唑-2-亞基)-3-甲基-1H-吡唑-5-甲醯胺 5

(E)-1-乙基-N-(3-((E)-4-((E)-2-((1-乙基-3-甲基-1H-吡唑-5-羰基)亞胺基)-3-甲基-2,3-二氫-1H-苯并[d]咪唑-1-基)丁-2-烯-1-基)-4-(羥基甲基)-1-甲基-1H-苯并[d]咪唑-2(3H)-亞基)-3-甲基-1H-吡唑-5-甲醯胺 6

1-乙基-N-((E)-3-((E)-4-((E)-2-((1-乙基-3-甲基-1H-吡唑-5-羰基)亞胺基)-3-甲基-2,3-二氫-1H-苯并[d]咪唑-1-基)丁-2-烯-1-基)-1-甲基-4-(嗎啉基甲基)-1,3-二氫-2H-苯并[d]咪唑-2-亞基)-3-甲基-1H-吡唑-5-甲醯胺 7

1-乙基-N-((E)-3-((E)-4-((E)-2-((1-乙基-3-甲基-1H-吡唑-5-羰基)亞胺基)-3-甲基-2,3-二氫-1H-苯并[d]咪唑-1-基)丁-2-烯-1-基)-1-甲基-4-(六氫吡啶-1-基甲基)-1,3-二氫-2H-苯并[d]咪唑-2-亞基)-3-甲基-1H-吡唑-5-甲醯胺 8

N-((E)-1-((E)-4-((E)-7-(氮雜環庚烷-1-基甲基)-2-((1-乙基-3-甲基-1H-吡唑-5-羰基)亞胺基)-3-甲基-2,3-二氫-1H-苯并[d]咪唑-1-基)丁-2-烯-1-基)-3-甲基-1,3-二氫-2H-苯并[d]咪唑-2-亞基)-1-乙基-3-甲基-1H-吡唑-5-甲醯胺 9

N-((E)-1-((E)-4-((E)-7-((3-氧雜-6-氮雜二環[3.1.1]庚-6-基)甲基)-2-((1-乙基-3-甲基-1H-吡唑-5-羰基)亞胺基)-3-甲基-2,3-二氫-1H-苯并[d]咪唑-1-基)丁-2-烯-1-基)-3-甲基-1,3-二氫-2H-苯并[d]咪唑-2-亞基)-1-乙基-3-甲基-1H-吡唑-5-甲醯胺 10

1-乙基-N-((E)-3-((E)-4-((E)-2-((1-乙基-3-甲基-1H-吡唑-5-羰基)亞胺基)-3-甲基-2,3-二氫-1H-苯并[d]咪唑-1-基)丁-2-烯-1-基)-4-(甲氧基甲基)-1-甲基-1,3-二氫-2H-苯并[d]咪唑-2-亞基)-3-甲基-1H-吡唑-5-甲醯胺 11

(外消旋)-1-乙基-N-((E)-3-((E)-4-((E)-2-((1-乙基-3-甲基-1H-吡唑-5-羰基)亞胺基)-3-甲基-2,3-二氫-1H-苯并[d]咪唑-1-基)丁-2-烯-1-基)-4-(1-羥基乙基)-1-甲基-1,3-二氫-2H-苯并[d]咪唑-2-亞基)-3-甲基-1H-吡唑-5-甲醯胺 12

1-乙基-N-((E)-1-((E)-4-((E)-2-((1-乙基-3-甲基-1H-吡唑-5-羰基)亞胺基)-3-甲基-2,3-二氫-1H-苯并[d]咪唑-1-基)丁-2-烯-1-基)-4-(羥基甲基)-3-甲基-1,3-二氫-2H-苯并[d]咪唑-2-亞基)-3-甲基-1H-吡唑-5-甲醯胺 13-1

1-乙基-N-((E)-1-((E)-4-((E)-2-((1-乙基-3-甲基-1H-吡唑-5-羰基)亞胺基)-3-甲基-2,3-二氫-1H-苯并[d]咪唑-1-基)丁-2-烯-1-基)-3-甲基-4-(嗎啉基甲基)-1,3-二氫-2H-苯并[d]咪唑-2-亞基)-3-甲基-1H-吡唑-5-甲醯胺 13-2

1-乙基-N-((E)-3-((E)-4-((E)-2-((1-乙基-3-甲基-1H-吡唑-5-羰基)亞胺基)-3-甲基-4-(嗎啉基甲基)-2,3-二氫-1H-苯并[d]咪唑-1-基)丁-2-烯-1-基)-1-甲基-4-(嗎啉基甲基)-1,3-二氫-2H-苯并[d]咪唑-2-亞基)-3-甲基-1H-吡唑-5-甲醯胺 14

1-乙基-N-((E)-1-((E)-4-((E)-2-((1-乙基-3-甲基-1H-吡唑-5-羰基)亞胺基)-3-甲基-2,3-二氫-1H-苯并[d]咪唑-1-基)丁-2-烯-1-基)-3-甲基-4-(六氫吡啶-1-基甲基)-1,3-二氫-2H-苯并[d]咪唑-2-亞基)-3-甲基-1H-吡唑-5-甲醯胺 15

N-((E)-4-((3-氧雜-6-氮雜二環[3.1.1]庚-6-基)甲基)-1-((E)-4-((E)-2-((1-乙基-3-甲基-1H-吡唑-5-羰基)亞胺基)-3-甲基-2,3-二氫-1H-苯并[d]咪唑-1-基)丁-2-烯-1-基)-3-甲基-1,3-二氫-2H-苯并[d]咪唑-2-亞基)-1-乙基-3-甲基-1H-吡唑-5-甲醯胺 16

(外消旋)-1-乙基-N-((E)-1-((E)-4-((E)-2-((1-乙基-3-甲基-1H-吡唑-5-羰基)亞胺基)-3-甲基-2,3-二氫-1H-苯并[d]咪唑-1-基)丁-2-烯-1-基)-4-(1-羥基乙基)-3-甲基-1,3-二氫-2H-苯并[d]咪唑-2-亞基)-3-甲基-1H-吡唑-5-甲醯胺 17

N,N'-((2E,2'E)-丁烷-1,4-二基雙(3-甲基-1,3-二氫-2H-苯并[d]咪唑-1-基-2-亞基))雙(1-乙基-3-甲基-1H-吡唑-5-甲醯胺) 18

1-乙基-N-((E)-3-(4-((E)-2-((1-乙基-3-甲基-1H-吡唑-5-羰基)亞胺基)-3-甲基-2,3-二氫-1H-苯并[d]咪唑-1-基)丁基)-4-(羥基甲基)-1-甲基-1,3-二氫-2H-苯并[d]咪唑-2-亞基)-3-甲基-1H-吡唑-5-甲醯胺 19

1-乙基-N-((E)-3-(4-((E)-2-((1-乙基-3-甲基-1H-吡唑-5-羰基)亞胺基)-3-甲基-2,3-二氫-1H-苯并[d]咪唑-1-基)丁基)-1-甲基-4-(嗎啉基甲基)-1,3-二氫-2H-苯并[d]咪唑-2-亞基)-3-甲基-1H-吡唑-5-甲醯胺 20

1-乙基-N-((E)-3-(4-((E)-2-((1-乙基-3-甲基-1H-吡唑-5-羰基)亞胺基)-3-甲基-2,3-二氫-1H-苯并[d]咪唑-1-基)丁基)-1-甲基-4-(六氫吡啶-1-基甲基)-1,3-二氫-2H-苯并[d]咪唑-2-亞基)-3-甲基-1H-吡唑-5-甲醯胺 21

N-((E)-1-(4-((E)-7-((3-氧雜-6-氮雜二環[3.1.1]庚-6-基)甲基)-2-((1-乙基-3-甲基-1H-吡唑-5-羰基)亞胺基)-3-甲基-2,3-二氫-1H-苯并[d]咪唑-1-基)丁基)-3-甲基-1,3-二氫-2H-苯并[d]咪唑-2-亞基)-1-乙基-3-甲基-1H-吡唑-5-甲醯胺 22

1-乙基-N-((E)-1-(4-((E)-2-((1-乙基-3-甲基-1H-吡唑-5-羰基)亞胺基)-3-甲基-2,3-二氫-1H-苯并[d]咪唑-1-基)丁基)-4-(羥基甲基)-3-甲基-1,3-二氫-2H-苯并[d]咪唑-2-亞基)-3-甲基-1H-吡唑-5-甲醯胺 23

1-乙基-N-((E)-1-(4-((E)-2-((1-乙基-3-甲基-1H-吡唑-5-羰基)亞胺基)-3-甲基-2,3-二氫-1H-苯并[d]咪唑-1-基)丁基)-3-甲基-4-(嗎啉基甲基)-1,3-二氫-2H-苯并[d]咪唑-2-亞基)-3-甲基-1H-吡唑-5-甲醯胺 24

1-乙基-N-((E)-3-((2R,5R)-5-((E)-2-((1-乙基-3-甲基-1H-吡唑-5-羰基)亞胺基)-3-甲基-2,3-二氫-1H-苯并[d]咪唑-1-基)己-2-基)-4-(羥基甲基)-1-甲基-1,3-二氫-2H-苯并[d]咪唑-2-亞基)-3-甲基-1H-吡唑-5-甲醯胺 25

1-乙基-N-((E)-3-((2R,5R)-5-((E)-2-((1-乙基-3-甲基-1H-吡唑-5-羰基)亞胺基)-3-甲基-2,3-二氫-1H-苯并[d]咪唑-1-基)己-2-基)-1-甲基-4-(嗎啉基甲基)-1,3-二氫-2H-苯并[d]咪唑-2-亞基)-3-甲基-1H-吡唑-5-甲醯胺 26   

1-乙基-N-((E)-3-((2S,5S)-5-((E)-2-((1-乙基-3-甲基-1H-吡唑-5-羰基)亞胺基)-3-甲基-2,3-二氫-1H-苯并[d]咪唑-1-基)己-2-基)-4-(羥基甲基)-1-甲基-1,3-二氫-2H-苯并[d]咪唑-2-亞基)-3-甲基-1H-吡唑-5-甲醯胺 27

1-乙基-N-((E)-3-((2S,5S)-5-((E)-2-((1-乙基-3-甲基-1H-吡唑-5-羰基)亞胺基)-3-甲基-2,3-二氫-1H-苯并[d]咪唑-1-基)己-2-基)-1-甲基-4-(嗎啉基甲基)-1,3-二氫-2H-苯并[d]咪唑-2-亞基)-3-甲基-1H-吡唑-5-甲醯胺 28

1-乙基-N-((E)-3-((2S,5R)-5-((E)-2-((1-乙基-3-甲基-1H-吡唑-5-羰基)亞胺基)-3-甲基-2,3-二氫-1H-苯并[d]咪唑-1-基)己-2-基)-4-(羥基甲基)-1-甲基-1,3-二氫-2H-苯并[d]咪唑-2-亞基)-3-甲基-1H-吡唑-5-甲醯胺 29

1-乙基-N-((E)-3-((2S,5R)-5-((E)-2-((1-乙基-3-甲基-1H-吡唑-5-羰基)亞胺基)-3-甲基-2,3-二氫-1H-苯并[d]咪唑-1-基)己-2-基)-1-甲基-4-(嗎啉基甲基)-1,3-二氫-2H-苯并[d]咪唑-2-亞基)-3-甲基-1H-吡唑-5-甲醯胺 30

1-乙基-N-((E)-3-((2R,5S)-5-((E)-2-((1-乙基-3-甲基-1H-吡唑-5-羰基)亞胺基)-3-甲基-2,3-二氫-1H-苯并[d]咪唑-1-基)己-2-基)-4-(羥基甲基)-1-甲基-1,3-二氫-2H-苯并[d]咪唑-2-亞基)-3-甲基-1H-吡唑-5-甲醯胺 31

1-乙基-N-((E)-3-((2R,5S)-5-((E)-2-((1-乙基-3-甲基-1H-吡唑-5-羰基)亞胺基)-3-甲基-2,3-二氫-1H-苯并[d]咪唑-1-基)己-2-基)-1-甲基-4-(嗎啉基甲基)-1,3-二氫-2H-苯并[d]咪唑-2-亞基)-3-甲基-1H-吡唑-5-甲醯胺 32

N-((E)-1-((E)-4-((E)-7-(1,2-二羥基乙基)-2-((1-乙基-3-甲基-1H-吡唑-5-羰基)亞胺基)-3-甲基-2,3-二氫-1H-苯并[d]咪唑-1-基)丁-2-烯-1-基)-3-甲基-1,3-二氫-2H-苯并[d]咪唑-2-亞基)-1-乙基-3-甲基-1H-吡唑-5-甲醯胺 33

1-乙基-N-((E)-3-((E)-4-((E)-2-((1-乙基-3-甲基-1H-吡唑-5-羰基)亞胺基)-3-甲基-2,3-二氫-1H-苯并[d]咪唑-1-基)丁-2-烯-1-基)-4-(1-羥基-2-嗎啉基乙基)-1-甲基-1,3-二氫-2H-苯并[d]咪唑-2-亞基)-3-甲基-1H-吡唑-5-甲醯胺 34

1-乙基-N-((E)-3-((E)-4-((E)-2-((1-乙基-3-甲基-1H-吡唑-5-羰基)亞胺基)-3-甲基-7-(嗎啉基甲基)-2,3-二氫-1H-苯并[d]咪唑-1-基)丁-2-烯-1-基)-4-(羥基甲基)-1-甲基-1,3-二氫-2H-苯并[d]咪唑-2-亞基)-3-甲基-1H-吡唑-5-甲醯胺 35

1-乙基-N-((E)-3-((E)-4-((E)-2-((1-乙基-3-甲基-1H-吡唑-5-羰基)亞胺基)-1-甲基-1,2-二氫-3H-咪唑并[4,5-b]吡啶-3-基)丁-2-烯-1-基)-1-甲基-4-(嗎啉基甲基)-1,3-二氫-2H-苯并[d]咪唑-2-亞基)-3-甲基-1H-吡唑-5-甲醯胺 36

1-乙基-N-((E)-3-((E)-4-((E)-2-((1-乙基-3-甲基-1H-吡唑-5-羰基)亞胺基)-1-甲基-1,2-二氫-3H-咪唑并[4,5-c]吡啶-3-基)丁-2-烯-1-基)-1-甲基-4-(嗎啉基甲基)-1,3-二氫-2H-苯并[d]咪唑-2-亞基)-3-甲基-1H-吡唑-5-甲醯胺 37

1-乙基-N-((E)-3-((E)-4-((E)-2-((1-乙基-3-甲基-1H-吡唑-5-羰基)亞胺基)-3-甲基-2,3-二氫-1H-咪唑并[4,5-c]吡啶-1-基)丁-2-烯-1-基)-1-甲基-4-(嗎啉基甲基)-1,3-二氫-2H-苯并[d]咪唑-2-亞基)-3-甲基-1H-吡唑-5-甲醯胺 38

1-乙基-N-((E)-3-((E)-4-((Z)-2-((1-乙基-3-甲基-1H-吡唑-5-羰基)亞胺基)-3-甲基-2,3-二氫-1H-咪唑并[4,5-b]吡啶-1-基)丁-2-烯-1-基)-1-甲基-4-(嗎啉基甲基)-1,3-二氫-2H-苯并[d]咪唑-2-亞基)-3-甲基-1H-吡唑-5-甲醯胺 表 2 ： 生物數據 PBMC促效劑分析：EC₅₀ ＜ 1 nM = +++++；1 nM ≤ EC₅₀ ＜ 10 nM = ++++；10 nM ≤ EC₅₀ ＜ 100 nM = +++；100 nM ≤ EC₅₀ ＜ 500 nM = ++；EC₅₀ ≥ 500 nM STING FRET分析：IC₅₀ ＜ 1 nM = +++++；1 nM ≤ IC₅₀ ＜ 10 nM = ++++；10 nM ≤ IC₅₀ ＜ 100 nM = +++；100 nM ≤ IC₅₀ ＜ 500 nM = ++；IC₅₀ ≥ 500 nM 實例編號 PBMC 促效劑 EC₅₀ STING FRET IC₅₀ 1 +++ +++ 2 ++++ +++ 3 +++++ ++++ 4 +++++ +++++ 5 +++++ ++++ 6 +++++ +++++ 7 +++++ +++++ 8 +++++ +++++ 9 +++++ ++++ 10 +++++ ++++ 11 ++++ ++++ 12 +++++ +++++ 13-1 ++++ ++++ 14 +++ ++++ 15 +++++ ++++ 16 ++++ +++ 17 ++++ +++ 19 ++++ ++++ 32 ++++ +++++ 33 ++++ ++++ 在上文分析中測試實例32之化合物，且發現其在上文PBMC促效劑分析中活性(EC₅₀ )為5 nM，且在上文STING FRET分析中活性(IC₅₀ )為1 nM。表 3 ： 一般治療劑 類型 類別 免疫治療劑 一般類 免疫療法 免疫調節劑 一般類 免疫療法 治療性抗體 一般類 免疫療法 治療性疫苗 一般類 免疫療法 雙特異性抗體 一般類 免疫療法 雙特異性或三特異性治療性肽/蛋白質 一般類 免疫療法 抗體-藥物偶聯物 一般類 免疫療法 基因修飾劑/編輯劑 一般類 遺傳療法 細胞療法 一般類 T細胞及/或工程改造T細胞受體          具體治療劑 縮寫 / 其他名稱 類別 干擾素 IFN 免疫療法 聚乙二醇化干擾素 peg-IFN 免疫療法 干擾素-α IFN-α 免疫療法 聚乙二醇化干擾素-α peg-IFN-α 免疫療法 干擾素-α-2b IFN-α-2b (Intron-A^TM ) 免疫療法 聚乙二醇化干擾素-α-2a peg-IFN-α-2a (Pegasys^TM ) 免疫療法 聚乙二醇化干擾素-α-2b 聚乙二醇化IFN-α-2b (Pegintron®) 免疫療法 胸腺素 (Zadaxin^TM) 免疫療法 干擾素λ1       干擾素λ1       干擾素γ       腫瘤壞死因子α       聚乙二醇化干擾素λ1       GS-9620    類鐸受體促效劑 ANA-773    類鐸受體促效劑          IMO-2055    免疫刺激性寡核苷酸 IMO-2125    免疫刺激性寡核苷酸                   富馬酸替諾福韋二吡呋酯 TDF 核苷/核苷酸類似物 富馬酸替諾福韋二吡呋酯    核苷/核苷酸類似物 替諾福韋艾拉酚胺(tenofovir alafenamide) TAF 核苷/核苷酸類似物 替比夫定       治療劑名稱 縮寫 / 其他名稱 類別 干擾素 IFN 免疫療法 聚乙二醇化干擾素 peg-IFN 免疫療法 干擾素-α IFN-α 免疫療法 聚乙二醇化干擾素-α peg-IFN-α 免疫療法 干擾素-α-2b IFN-α-2b (Intron-A^TM ) 免疫療法 聚乙二醇化干擾素-α-2a peg-IFN-α-2a (Pegasys^TM ) 免疫療法 聚乙二醇化干擾素-α-2b 聚乙二醇化IFN-α-2b (Pegintron®) 免疫療法 胸腺素 (Zadaxin^TM) 免疫療法 干擾素λ1       干擾素λ1       干擾素λ1       干擾素γ       腫瘤壞死因子α       聚乙二醇化干擾素λ1       GS-9620    類鐸受體促效劑 ANA-773    類鐸受體促效劑          IMO-2055    免疫刺激性寡核苷酸 IMO-2125    免疫刺激性寡核苷酸                   富馬酸替諾福韋二吡呋酯 TDF 核苷/核苷酸類似物 富馬酸替諾福韋二吡呋酯    核苷/核苷酸類似物 替諾福韋艾拉酚胺 TAF 核苷/核苷酸類似物 替比夫定       The disclosure content of each patent, patent application and publication cited or described in this document is incorporated herein by reference in its entirety. Table 1 Instance structure name 1

N,N'-((2E,2'E)-((E)-but-2-ene-1,4-diyl)bis(3-methyl-1,3-dihydro-2H-benzo (d]imidazol-1-yl-2-ylidene)) bis(1-ethyl-3-methyl-1H-pyrazole-5-carboxamide) 2

(E)-2-((1-ethyl-3-methyl-1H-pyrazole-5-carbonyl)imino)-1-((E)-4-((E)-2-(( 1-Ethyl-3-methyl-1H-pyrazole-5-carbonyl)imino)-3-methyl-2,3-dihydro-1H-benzo(d)imidazol-1-yl)butyl -2-en-1-yl)-3-methyl-2,3-dihydro-1H-benzo[d]imidazole-5-carboxylic acid methyl ester 3

1-Ethyl-N-((E)-3-((E)-4-((E)-2-((1-ethyl-3-methyl-1H-pyrazole-5-carbonyl) sub Amino)-3-methyl-2,3-dihydro-1H-benzo(d)imidazol-1-yl)but-2-en-1-yl)-4-methoxy-1-methyl -1,3-Dihydro-2H-benzo[d]imidazol-2-ylidene)-3-methyl-1H-pyrazole-5-carboxamide 4

1-Ethyl-N-((E)-3-((E)-4-((E)-2-((1-ethyl-3-methyl-1H-pyrazole-5-carbonyl) sub Amino)-7-(3-hydroxypropoxy)-3-methyl-2,3-dihydro-1H-benzo(d)imidazol-1-yl)but-2-en-1-yl) -4-Methoxy-1-methyl-1,3-dihydro-2H-benzo[d]imidazole-2-ylidene)-3-methyl-1H-pyrazole-5-carboxamide 5

(E)-1-ethyl-N-(3-((E)-4-((E)-2-((1-ethyl-3-methyl-1H-pyrazole-5-carbonyl) sub Amino)-3-methyl-2,3-dihydro-1H-benzo(d)imidazol-1-yl)but-2-en-1-yl)-4-(hydroxymethyl)-1- Methyl-1H-benzo[d]imidazole-2(3H)-subunit)-3-methyl-1H-pyrazole-5-carboxamide 6

1-Ethyl-N-((E)-3-((E)-4-((E)-2-((1-ethyl-3-methyl-1H-pyrazole-5-carbonyl) sub Amino)-3-methyl-2,3-dihydro-1H-benzo(d)imidazol-1-yl)but-2-en-1-yl)-1-methyl-4-(morpholine Methyl)-1,3-dihydro-2H-benzo[d]imidazol-2-ylidene)-3-methyl-1H-pyrazole-5-carboxamide 7

1-Ethyl-N-((E)-3-((E)-4-((E)-2-((1-ethyl-3-methyl-1H-pyrazole-5-carbonyl) sub Amino)-3-methyl-2,3-dihydro-1H-benzo(d)imidazol-1-yl)but-2-en-1-yl)-1-methyl-4-(hexahydro (Pyridin-1-ylmethyl)-1,3-dihydro-2H-benzo[d]imidazole-2-ylidene)-3-methyl-1H-pyrazole-5-carboxamide 8

N-((E)-1-((E)-4-((E)-7-(azeppan-1-ylmethyl)-2-((1-ethyl-3-methyl) -1H-pyrazole-5-carbonyl)imino)-3-methyl-2,3-dihydro-1H-benzo(d)imidazol-1-yl)but-2-en-1-yl) -3-methyl-1,3-dihydro-2H-benzo[d]imidazol-2-ylidene)-1-ethyl-3-methyl-1H-pyrazole-5-carboxamide 9

N-((E)-1-((E)-4-((E)-7-((3-oxa-6-azabicyclo[3.1.1]heptan-6-yl)methyl) -2-((1-ethyl-3-methyl-1H-pyrazole-5-carbonyl)imino)-3-methyl-2,3-dihydro-1H-benzo[d]imidazole- 1-yl)but-2-en-1-yl)-3-methyl-1,3-dihydro-2H-benzo(d)imidazol-2-ylidene)-1-ethyl-3-methyl Yl-1H-pyrazole-5-carboxamide 10

1-Ethyl-N-((E)-3-((E)-4-((E)-2-((1-ethyl-3-methyl-1H-pyrazole-5-carbonyl) sub Amino)-3-methyl-2,3-dihydro-1H-benzo(d)imidazol-1-yl)but-2-en-1-yl)-4-(methoxymethyl)- 1-Methyl-1,3-dihydro-2H-benzo[d]imidazol-2-ylidene)-3-methyl-1H-pyrazole-5-carboxamide 11

(Racemic)-1-ethyl-N-((E)-3-((E)-4-((E)-2-((1-ethyl-3-methyl-1H-pyrazole -5-carbonyl)imino)-3-methyl-2,3-dihydro-1H-benzo[d]imidazol-1-yl)but-2-en-1-yl)-4-(1 -Hydroxyethyl)-1-methyl-1,3-dihydro-2H-benzo[d]imidazole-2-ylidene)-3-methyl-1H-pyrazole-5-carboxamide 12

1-Ethyl-N-((E)-1-((E)-4-((E)-2-((1-ethyl-3-methyl-1H-pyrazole-5-carbonyl) sub Amino)-3-methyl-2,3-dihydro-1H-benzo(d)imidazol-1-yl)but-2-en-1-yl)-4-(hydroxymethyl)-3- Methyl-1,3-dihydro-2H-benzo[d]imidazol-2-ylidene)-3-methyl-1H-pyrazole-5-carboxamide 13-1

1-Ethyl-N-((E)-1-((E)-4-((E)-2-((1-ethyl-3-methyl-1H-pyrazole-5-carbonyl) sub Amino)-3-methyl-2,3-dihydro-1H-benzo(d)imidazol-1-yl)but-2-en-1-yl)-3-methyl-4-(morpholine Methyl)-1,3-dihydro-2H-benzo[d]imidazol-2-ylidene)-3-methyl-1H-pyrazole-5-carboxamide 13-2

1-Ethyl-N-((E)-3-((E)-4-((E)-2-((1-ethyl-3-methyl-1H-pyrazole-5-carbonyl) sub Amino)-3-methyl-4-(morpholinylmethyl)-2,3-dihydro-1H-benzo(d)imidazol-1-yl)but-2-en-1-yl)- 1-Methyl-4-(morpholinylmethyl)-1,3-dihydro-2H-benzo[d]imidazol-2-ylidene)-3-methyl-1H-pyrazole-5-methyl Amide 14

1-Ethyl-N-((E)-1-((E)-4-((E)-2-((1-ethyl-3-methyl-1H-pyrazole-5-carbonyl) sub Amino)-3-methyl-2,3-dihydro-1H-benzo(d)imidazol-1-yl)but-2-en-1-yl)-3-methyl-4-(hexahydro (Pyridin-1-ylmethyl)-1,3-dihydro-2H-benzo[d]imidazole-2-ylidene)-3-methyl-1H-pyrazole-5-carboxamide 15

N-((E)-4-((3-oxa-6-azabicyclo[3.1.1]hept-6-yl)methyl)-1-((E)-4-((E) -2-((1-ethyl-3-methyl-1H-pyrazole-5-carbonyl)imino)-3-methyl-2,3-dihydro-1H-benzo[d]imidazole- 1-yl)but-2-en-1-yl)-3-methyl-1,3-dihydro-2H-benzo(d)imidazol-2-ylidene)-1-ethyl-3-methyl Yl-1H-pyrazole-5-carboxamide 16

(Racemic)-1-ethyl-N-((E)-1-((E)-4-((E)-2-((1-ethyl-3-methyl-1H-pyrazole -5-carbonyl)imino)-3-methyl-2,3-dihydro-1H-benzo[d]imidazol-1-yl)but-2-en-1-yl)-4-(1 -Hydroxyethyl)-3-methyl-1,3-dihydro-2H-benzo[d]imidazole-2-ylidene)-3-methyl-1H-pyrazole-5-carboxamide 17

N,N'-((2E,2'E)-butane-1,4-diylbis(3-methyl-1,3-dihydro-2H-benzo[d]imidazol-1-yl- 2-subunit)) bis(1-ethyl-3-methyl-1H-pyrazole-5-carboxamide) 18

1-Ethyl-N-((E)-3-(4-((E)-2-((1-ethyl-3-methyl-1H-pyrazole-5-carbonyl)imino)- 3-methyl-2,3-dihydro-1H-benzo[d]imidazol-1-yl)butyl)-4-(hydroxymethyl)-1-methyl-1,3-dihydro-2H -Benzo[d]imidazole-2-ylidene)-3-methyl-1H-pyrazole-5-carboxamide 19

1-Ethyl-N-((E)-3-(4-((E)-2-((1-ethyl-3-methyl-1H-pyrazole-5-carbonyl)imino)- 3-Methyl-2,3-dihydro-1H-benzo[d]imidazol-1-yl)butyl)-1-methyl-4-(morpholinylmethyl)-1,3-dihydro -2H-Benzo[d]imidazole-2-ylidene)-3-methyl-1H-pyrazole-5-carboxamide 20

1-Ethyl-N-((E)-3-(4-((E)-2-((1-ethyl-3-methyl-1H-pyrazole-5-carbonyl)imino)- 3-Methyl-2,3-dihydro-1H-benzo[d]imidazol-1-yl)butyl)-1-methyl-4-(hexahydropyridin-1-ylmethyl)-1, 3-Dihydro-2H-benzo[d]imidazole-2-ylidene)-3-methyl-1H-pyrazole-5-carboxamide twenty one

N-((E)-1-(4-((E)-7-((3-oxa-6-azabicyclo[3.1.1]hept-6-yl)methyl)-2-( (1-Ethyl-3-methyl-1H-pyrazole-5-carbonyl)imino)-3-methyl-2,3-dihydro-1H-benzo(d)imidazol-1-yl) Butyl)-3-methyl-1,3-dihydro-2H-benzo(d)imidazol-2-ylidene)-1-ethyl-3-methyl-1H-pyrazole-5-methyl amine twenty two

1-Ethyl-N-((E)-1-(4-((E)-2-((1-ethyl-3-methyl-1H-pyrazole-5-carbonyl)imino)- 3-Methyl-2,3-dihydro-1H-benzo[d]imidazol-1-yl)butyl)-4-(hydroxymethyl)-3-methyl-1,3-dihydro-2H -Benzo[d]imidazole-2-ylidene)-3-methyl-1H-pyrazole-5-carboxamide twenty three

1-Ethyl-N-((E)-1-(4-((E)-2-((1-ethyl-3-methyl-1H-pyrazole-5-carbonyl)imino)- 3-Methyl-2,3-dihydro-1H-benzo[d]imidazol-1-yl)butyl)-3-methyl-4-(morpholinylmethyl)-1,3-dihydro -2H-Benzo[d]imidazole-2-ylidene)-3-methyl-1H-pyrazole-5-carboxamide twenty four

1-Ethyl-N-((E)-3-((2R,5R)-5-((E)-2-((1-ethyl-3-methyl-1H-pyrazole-5-carbonyl )Imino)-3-methyl-2,3-dihydro-1H-benzo(d)imidazol-1-yl)hex-2-yl)-4-(hydroxymethyl)-1-methyl -1,3-Dihydro-2H-benzo[d]imidazol-2-ylidene)-3-methyl-1H-pyrazole-5-carboxamide 25

1-Ethyl-N-((E)-3-((2R,5R)-5-((E)-2-((1-ethyl-3-methyl-1H-pyrazole-5-carbonyl )Imino)-3-methyl-2,3-dihydro-1H-benzo[d]imidazol-1-yl)hex-2-yl)-1-methyl-4-(morpholinylmethyl) Yl)-1,3-dihydro-2H-benzo[d]imidazol-2-ylidene)-3-methyl-1H-pyrazole-5-carboxamide 26

1-Ethyl-N-((E)-3-((2S,5S)-5-((E)-2-((1-ethyl-3-methyl-1H-pyrazole-5-carbonyl )Imino)-3-methyl-2,3-dihydro-1H-benzo(d)imidazol-1-yl)hex-2-yl)-4-(hydroxymethyl)-1-methyl -1,3-Dihydro-2H-benzo[d]imidazol-2-ylidene)-3-methyl-1H-pyrazole-5-carboxamide 27

1-Ethyl-N-((E)-3-((2S,5S)-5-((E)-2-((1-ethyl-3-methyl-1H-pyrazole-5-carbonyl )Imino)-3-methyl-2,3-dihydro-1H-benzo[d]imidazol-1-yl)hex-2-yl)-1-methyl-4-(morpholinylmethyl) Yl)-1,3-dihydro-2H-benzo[d]imidazol-2-ylidene)-3-methyl-1H-pyrazole-5-carboxamide 28

1-Ethyl-N-((E)-3-((2S,5R)-5-((E)-2-((1-ethyl-3-methyl-1H-pyrazole-5-carbonyl )Imino)-3-methyl-2,3-dihydro-1H-benzo(d)imidazol-1-yl)hex-2-yl)-4-(hydroxymethyl)-1-methyl -1,3-Dihydro-2H-benzo[d]imidazol-2-ylidene)-3-methyl-1H-pyrazole-5-carboxamide 29

1-Ethyl-N-((E)-3-((2S,5R)-5-((E)-2-((1-ethyl-3-methyl-1H-pyrazole-5-carbonyl )Imino)-3-methyl-2,3-dihydro-1H-benzo[d]imidazol-1-yl)hex-2-yl)-1-methyl-4-(morpholinylmethyl) Yl)-1,3-dihydro-2H-benzo[d]imidazol-2-ylidene)-3-methyl-1H-pyrazole-5-carboxamide 30

1-Ethyl-N-((E)-3-((2R,5S)-5-((E)-2-((1-ethyl-3-methyl-1H-pyrazole-5-carbonyl )Imino)-3-methyl-2,3-dihydro-1H-benzo(d)imidazol-1-yl)hex-2-yl)-4-(hydroxymethyl)-1-methyl -1,3-Dihydro-2H-benzo[d]imidazol-2-ylidene)-3-methyl-1H-pyrazole-5-carboxamide 31

1-Ethyl-N-((E)-3-((2R,5S)-5-((E)-2-((1-ethyl-3-methyl-1H-pyrazole-5-carbonyl )Imino)-3-methyl-2,3-dihydro-1H-benzo[d]imidazol-1-yl)hex-2-yl)-1-methyl-4-(morpholinylmethyl) Yl)-1,3-dihydro-2H-benzo[d]imidazol-2-ylidene)-3-methyl-1H-pyrazole-5-carboxamide 32

N-((E)-1-((E)-4-((E)-7-(1,2-dihydroxyethyl)-2-((1-ethyl-3-methyl-1H- Pyrazol-5-carbonyl)imino)-3-methyl-2,3-dihydro-1H-benzo(d)imidazol-1-yl)but-2-en-1-yl)-3- Methyl-1,3-dihydro-2H-benzo[d]imidazole-2-ylidene)-1-ethyl-3-methyl-1H-pyrazole-5-carboxamide 33

1-Ethyl-N-((E)-3-((E)-4-((E)-2-((1-ethyl-3-methyl-1H-pyrazole-5-carbonyl) sub Amino)-3-methyl-2,3-dihydro-1H-benzo(d)imidazol-1-yl)but-2-en-1-yl)-4-(1-hydroxy-2-? (Hydroxyethyl)-1-methyl-1,3-dihydro-2H-benzo[d]imidazol-2-ylidene)-3-methyl-1H-pyrazole-5-carboxamide 34

1-Ethyl-N-((E)-3-((E)-4-((E)-2-((1-ethyl-3-methyl-1H-pyrazole-5-carbonyl) sub Amino)-3-methyl-7-(morpholinylmethyl)-2,3-dihydro-1H-benzo(d)imidazol-1-yl)but-2-en-1-yl)- 4-(Hydroxymethyl)-1-methyl-1,3-dihydro-2H-benzo[d]imidazole-2-ylidene)-3-methyl-1H-pyrazole-5-carboxamide 35

1-Ethyl-N-((E)-3-((E)-4-((E)-2-((1-ethyl-3-methyl-1H-pyrazole-5-carbonyl) sub Amino)-1-methyl-1,2-dihydro-3H-imidazo[4,5-b]pyridin-3-yl)but-2-en-1-yl)-1-methyl-4 -(Morpholinylmethyl)-1,3-dihydro-2H-benzo[d]imidazole-2-ylidene)-3-methyl-1H-pyrazole-5-carboxamide 36

1-Ethyl-N-((E)-3-((E)-4-((E)-2-((1-ethyl-3-methyl-1H-pyrazole-5-carbonyl) sub Amino)-1-methyl-1,2-dihydro-3H-imidazo[4,5-c]pyridin-3-yl)but-2-en-1-yl)-1-methyl-4 -(Morpholinylmethyl)-1,3-dihydro-2H-benzo[d]imidazole-2-ylidene)-3-methyl-1H-pyrazole-5-carboxamide 37

1-Ethyl-N-((E)-3-((E)-4-((E)-2-((1-ethyl-3-methyl-1H-pyrazole-5-carbonyl) sub Amino)-3-methyl-2,3-dihydro-1H-imidazo[4,5-c]pyridin-1-yl)but-2-en-1-yl)-1-methyl-4 -(Morpholinylmethyl)-1,3-dihydro-2H-benzo[d]imidazole-2-ylidene)-3-methyl-1H-pyrazole-5-carboxamide 38

1-Ethyl-N-((E)-3-((E)-4-((Z)-2-((1-ethyl-3-methyl-1H-pyrazole-5-carbonyl) sub Amino)-3-methyl-2,3-dihydro-1H-imidazo[4,5-b]pyridin-1-yl)but-2-en-1-yl)-1-methyl-4 -(Morpholinylmethyl)-1,3-dihydro-2H-benzo[d]imidazole-2-ylidene)-3-methyl-1H-pyrazole-5-carboxamide Table 2 : Biological data PBMC agonist analysis: EC ₅₀ ＜ 1 nM = +++++; 1 nM ≤ EC ₅₀ ＜ 10 nM = ++++; 10 nM ≤ EC ₅₀ ＜ 100 nM = +++; 100 nM ≤ EC ₅₀ ＜ 500 nM = ++; EC ₅₀ ≥ 500 nM STING FRET analysis: IC ₅₀ ＜ 1 nM = +++++; 1 nM ≤ IC ₅₀ ＜ 10 nM = ++++; 10 nM ≤ IC ₅₀ ＜ 100 nM = +++; 100 nM ≤ IC ₅₀ ＜ 500 nM = ++; IC ₅₀ ≥ 500 nM Instance number PBMC agonist EC ₅₀ STING FRET IC ₅₀ 1 +++ +++ 2 ++++ +++ 3 +++++ ++++ 4 +++++ +++++ 5 +++++ ++++ 6 +++++ +++++ 7 +++++ +++++ 8 +++++ +++++ 9 +++++ ++++ 10 +++++ ++++ 11 ++++ ++++ 12 +++++ +++++ 13-1 ++++ ++++ 14 +++ ++++ 15 +++++ ++++ 16 ++++ +++ 17 ++++ +++ 19 ++++ ++++ 32 ++++ +++++ 33 ++++ ++++ In the above analysis of Test Example 32 of the compounds, and pro-found active in the PBMC above analysis agonist (EC ₅₀₎ of 5 nM, and the above STING FRET activity assay (IC ₅₀₎ was 1 nM. Table 3 : General therapeutic agent Types of category Immunotherapeutics General category Immunotherapy Immunomodulator General category Immunotherapy Therapeutic antibody General category Immunotherapy Therapeutic vaccine General category Immunotherapy Bispecific antibody General category Immunotherapy Bispecific or trispecific therapeutic peptide/protein General category Immunotherapy Antibody-drug conjugate General category Immunotherapy Gene modifier/editing agent General category Genetic therapy Cell therapy General category T cell and/or engineered T cell receptor Specific therapeutic agent Abbreviations / other names category Interferon IFN Immunotherapy Pegylated interferon peg-IFN Immunotherapy Interferon-α IFN-α Immunotherapy Pegylated interferon-α peg-IFN-α Immunotherapy Interferon-α-2b IFN-α-2b (Intron-A ^TM ) Immunotherapy Pegylated interferon-α-2a peg-IFN-α-2a (Pegasys ^TM ) Immunotherapy Pegylated interferon-α-2b Pegylated IFN-α-2b (Pegintron®) Immunotherapy Thymosin (Zadaxin ^TM) Immunotherapy Interferon λ1 Interferon λ1 Interferon gamma Tumor Necrosis Factor Alpha Pegylated interferon λ1 GS-9620 Toll-like receptor agonist ANA-773 Toll-like receptor agonist IMO-2055 Immunostimulatory oligonucleotide IMO-2125 Immunostimulatory oligonucleotide Tenofovir disoproxil fumarate TDF Nucleoside/Nucleotide Analog Tenofovir disoproxil fumarate Nucleoside/Nucleotide Analog Tenofovir alafenamide TAF Nucleoside/Nucleotide Analog Telbivudine Name of therapeutic agent Abbreviations / other names category Interferon IFN Immunotherapy Pegylated interferon peg-IFN Immunotherapy Interferon-α IFN-α Immunotherapy Pegylated interferon-α peg-IFN-α Immunotherapy Interferon-α-2b IFN-α-2b (Intron-A ^TM ) Immunotherapy Pegylated interferon-α-2a peg-IFN-α-2a (Pegasys ^TM ) Immunotherapy Pegylated interferon-α-2b Pegylated IFN-α-2b (Pegintron®) Immunotherapy Thymosin (Zadaxin ^TM) Immunotherapy Interferon λ1 Interferon λ1 Interferon λ1 Interferon gamma Tumor Necrosis Factor Alpha Pegylated interferon λ1 GS-9620 Toll-like receptor agonist ANA-773 Toll-like receptor agonist IMO-2055 Immunostimulatory oligonucleotide IMO-2125 Immunostimulatory oligonucleotide Tenofovir disoproxil fumarate TDF Nucleoside/Nucleotide Analog Tenofovir disoproxil fumarate Nucleoside/Nucleotide Analog Tenofovir alafenamide TAF Nucleoside/Nucleotide Analog Telbivudine

Claims (18)

A compound of formula (I),

(I) or a salt thereof, wherein A is a C ₂ -C ₆ alkyl group or a C ₂ -C ₆ alkenyl group, wherein the C ₂ -C ₆ alkyl group or the C ₂ -C ₆ alkenyl group is each independently as appropriate 1 to 2 substituents selected from -R ^c , -OH and -OR ^c ; R ¹ and R ^{2 are} independently absent or are C ₁ -C ₃ alkyl groups; W ¹ , X ¹ , Y ¹ and Z ¹ Each independently is -CR ³ , -CR ³ ′, -CR ³ ″, -CR ³ ′″ or N, and the condition is that no more than two ^{of W 1} , X ¹ , Y ¹ and Z ^{1 can be N; W 2.} X ² , Y ² and Z ² are each independently -CR ⁴ , -CR ⁴ ′, -CR ⁴ ”, -CR ⁴ ”or N, and the conditions are W ² , X ² , Y ² and Z ² No more than two can be N; R ³ , R ³ ′, R ³ ″, R ³ ′″, R ⁴ , R ⁴ ′, R ⁴ ″, R ⁴ ′″, R ⁹ , R ¹⁰ , R ¹¹ and R ¹² are each independently selected from H, C _1-4 alkoxy, C _1-4 alkyl, -COO-C _1-4 alkyl, -C _4-7 heterocycloalkyl, -C _1-4 alkyl C _4-7 heterocycloalkyl and -OC _1-4 alkyl C _4-7 heterocycloalkyl, wherein the -C _4-7 heterocycloalkyl, the -C _1-4 alkyl C _4-7 hetero the cycloalkyl -C _4-7 heterocycloalkyl, or the -OC _1-4 alkyl of C _4-7 heterocycloalkyl C _4-7 heterocycloalkyl comprising one or more heteroatoms selected from O and N the hetero atoms, wherein the C _1-4 alkyl, C _1-4 alkoxy, -C _1-4 alkyl which C _4-7 heterocycloalkyl group of the C _1-4 alkyl or -OC _{1- The C 1-4} alkyl group of the _4- alkyl C _4-7 heterocycloalkyl group is optionally substituted with 1 to 4 substituents independently selected from -R ^c , -OH and -OR ^c , and wherein the C _{4- 7} heterocycloalkyl, -C _1-4 alkyl which C _4-7 heterocycloalkyl group of C _4-7 heterocycloalkyl, or -OC _1-4 alkyl which C _4-7 heterocycloalkyl of The C _4-7 heterocycloalkyl group is substituted by 1 to 4 substituents R', R", R"' and R"", wherein R', R", R"' and R"" are each independently selected from- R ^c , -OH and -OR ^c , or any two of R', R", R"' and R"" can be combined with the ring atoms to which they are connected to form a 3- to 7-membered ring; R ⁵ and R ^{6 is} independently C ₁ -C ₄ alkyl; R ⁷ and R ⁸ are each independently H or C ₁ -C ₄ alkyl; and each R ^{c is} independently C ₁ -C ₄ alkyl, as the case may be It is substituted by a substituent selected from -OH or C _1-4 alkoxy. The compound of formula (I) according to claim 1, or a salt thereof, wherein R ¹ and R ² are -CH ₂ -and R ⁵ and R ⁶ are -CH ₃ . The compound of formula (I) or its salt according to claim 1 or 2, wherein W ¹ , X ¹ , Y ¹ and Z ¹ are each independently -CR ³ , -CR ³ ′, -CR ³ ″ or -CR ³ ′ "And W ² , X ² , Y ² and Z ² are each independently -CR ⁴ , -CR ⁴ ′, -CR ⁴ ”or -CR ⁴ ′”. The compound of formula (I) or a salt thereof according to any one of claims 1 to 3, wherein W ¹ is CR ³ and W ² is CR ⁴ , wherein R ³ and R ⁴ are each independently selected from H, -C _{4- 7} heterocycloalkyl, -C _1-4 alkyl C _4-7 heterocycloalkyl, and -OC _1-4 alkyl C _4-7 heterocycloalkyl. The compound of formula (I) or its salt according to claim 1 or 2, wherein W ¹ is CR ³ and W ² is CR ⁴ , wherein R ³ and R ⁴ are each independently selected from H, C _1-4 alkoxy or A C _1-4 alkyl group, wherein the C _1-4 alkyl group or C _1-4 alkoxy group is optionally substituted with 1 to 4 substituents independently selected from -R ^c , -OH and -OR ^c . The compound of formula (I) according to claim 1 or 2, or a salt thereof, wherein A is a C ₂ -C ₆ alkylene group. The compound of formula (I) according to claim 1 or 2, or a salt thereof, wherein A is a C ₂ alkenylene group. The compound of formula (I) according to claim 1 or 2, or a salt thereof, wherein R ¹ and R ² are each -CH ₂ -and A is C ₂ -alkenylene. The compound of formula (I) according to claim 1 or 2, or a salt thereof, wherein R ⁶ and R ⁷ are each independently H or C ₂ alkyl. A compound selected from the group consisting of: N,N'-((2E,2'E)-((E)-but-2-ene-1,4-diyl)bis(3-methyl-1,3-dihydro-2H-benzo [d] Imidazol-1-yl-2-ylidene)) bis(1-ethyl-3-methyl-1H-pyrazole-5-carboxamide); (E)-2-((1-ethyl-3-methyl-1H-pyrazole-5-carbonyl)imino)-1-((E)-4-((E)-2-(( 1-Ethyl-3-methyl-1H-pyrazole-5-carbonyl)imino)-3-methyl-2,3-dihydro-1H-benzo(d)imidazol-1-yl)butyl -2-en-1-yl)-3-methyl-2,3-dihydro-1H-benzo[d]imidazole-5-carboxylic acid methyl ester; 1-Ethyl-N-((E)-3-((E)-4-((E)-2-((1-ethyl-3-methyl-1H-pyrazole-5-carbonyl) sub Amino)-3-methyl-2,3-dihydro-1H-benzo(d)imidazol-1-yl)but-2-en-1-yl)-4-methoxy-1-methyl -1,3-Dihydro-2H-benzo[d]imidazole-2-ylidene)-3-methyl-1H-pyrazole-5-carboxamide; 1-Ethyl-N-((E)-3-((E)-4-((E)-2-((1-ethyl-3-methyl-1H-pyrazole-5-carbonyl) sub Amino)-7-(3-hydroxypropoxy)-3-methyl-2,3-dihydro-1H-benzo(d)imidazol-1-yl)but-2-en-1-yl) -4-Methoxy-1-methyl-1,3-dihydro-2H-benzo[d]imidazole-2-ylidene)-3-methyl-1H-pyrazole-5-carboxamide; (E)-1-ethyl-N-(3-((E)-4-((E)-2-((1-ethyl-3-methyl-1H-pyrazole-5-carbonyl) sub Amino)-3-methyl-2,3-dihydro-1H-benzo(d)imidazol-1-yl)but-2-en-1-yl)-4-(hydroxymethyl)-1- Methyl-1H-benzo[d]imidazole-2(3H)-ylidene)-3-methyl-1H-pyrazole-5-carboxamide; 1-Ethyl-N-((E)-3-((E)-4-((E)-2-((1-ethyl-3-methyl-1H-pyrazole-5-carbonyl) sub Amino)-3-methyl-2,3-dihydro-1H-benzo(d)imidazol-1-yl)but-2-en-1-yl)-1-methyl-4-(morpholine Methyl)-1,3-dihydro-2H-benzo[d]imidazole-2-ylidene)-3-methyl-1H-pyrazole-5-carboxamide; 1-Ethyl-N-((E)-3-((E)-4-((E)-2-((1-ethyl-3-methyl-1H-pyrazole-5-carbonyl) sub Amino)-3-methyl-2,3-dihydro-1H-benzo(d)imidazol-1-yl)but-2-en-1-yl)-1-methyl-4-(hexahydro Pyridin-1-ylmethyl)-1,3-dihydro-2H-benzo[d]imidazole-2-ylidene)-3-methyl-1H-pyrazole-5-carboxamide; N-((E)-1-((E)-4-((E)-7-(azeppan-1-ylmethyl)-2-((1-ethyl-3-methyl) -1H-pyrazole-5-carbonyl)imino)-3-methyl-2,3-dihydro-1H-benzo(d)imidazol-1-yl)but-2-en-1-yl) -3-Methyl-1,3-dihydro-2H-benzo[d]imidazol-2-ylidene)-1-ethyl-3-methyl-1H-pyrazole-5-carboxamide; N-((E)-1-((E)-4-((E)-7-((3-oxa-6-azabicyclo[3.1.1]heptan-6-yl)methyl) -2-((1-ethyl-3-methyl-1H-pyrazole-5-carbonyl)imino)-3-methyl-2,3-dihydro-1H-benzo[d]imidazole- 1-yl)but-2-en-1-yl)-3-methyl-1,3-dihydro-2H-benzo(d)imidazol-2-ylidene)-1-ethyl-3-methyl Group-1H-pyrazole-5-carboxamide; 1-Ethyl-N-((E)-3-((E)-4-((E)-2-((1-ethyl-3-methyl-1H-pyrazole-5-carbonyl) sub Amino)-3-methyl-2,3-dihydro-1H-benzo(d)imidazol-1-yl)but-2-en-1-yl)-4-(methoxymethyl)- 1-Methyl-1,3-dihydro-2H-benzo[d]imidazole-2-ylidene)-3-methyl-1H-pyrazole-5-carboxamide; 1-Ethyl-N-((E)-3-((E)-4-((E)-2-((1-ethyl-3-methyl-1H-pyrazole-5-carbonyl) sub Amino)-3-methyl-2,3-dihydro-1H-benzo(d)imidazol-1-yl)but-2-en-1-yl)-4-(1-hydroxyethyl)- 1-Methyl-1,3-dihydro-2H-benzo[d]imidazole-2-ylidene)-3-methyl-1H-pyrazole-5-carboxamide; 1-Ethyl-N-((E)-1-((E)-4-((E)-2-((1-ethyl-3-methyl-1H-pyrazole-5-carbonyl) sub Amino)-3-methyl-2,3-dihydro-1H-benzo(d)imidazol-1-yl)but-2-en-1-yl)-4-(hydroxymethyl)-3- Methyl-1,3-dihydro-2H-benzo[d]imidazole-2-ylidene)-3-methyl-1H-pyrazole-5-carboxamide; 1-Ethyl-N-((E)-1-((E)-4-((E)-2-((1-ethyl-3-methyl-1H-pyrazole-5-carbonyl) sub Amino)-3-methyl-2,3-dihydro-1H-benzo(d)imidazol-1-yl)but-2-en-1-yl)-3-methyl-4-(morpholine Methyl)-1,3-dihydro-2H-benzo[d]imidazole-2-ylidene)-3-methyl-1H-pyrazole-5-carboxamide; 1-Ethyl-N-((E)-1-((E)-4-((E)-2-((1-ethyl-3-methyl-1H-pyrazole-5-carbonyl) sub Amino)-3-methyl-2,3-dihydro-1H-benzo(d)imidazol-1-yl)but-2-en-1-yl)-3-methyl-4-(hexahydro Pyridin-1-ylmethyl)-1,3-dihydro-2H-benzo[d]imidazole-2-ylidene)-3-methyl-1H-pyrazole-5-carboxamide; N-((E)-4-((3-oxa-6-azabicyclo[3.1.1]hept-6-yl)methyl)-1-((E)-4-((E) -2-((1-ethyl-3-methyl-1H-pyrazole-5-carbonyl)imino)-3-methyl-2,3-dihydro-1H-benzo[d]imidazole- 1-yl)but-2-en-1-yl)-3-methyl-1,3-dihydro-2H-benzo(d)imidazol-2-ylidene)-1-ethyl-3-methyl Group-1H-pyrazole-5-carboxamide; 1-Ethyl-N-((E)-1-((E)-4-((E)-2-((1-ethyl-3-methyl-1H-pyrazole-5-carbonyl) sub Amino)-3-methyl-2,3-dihydro-1H-benzo(d)imidazol-1-yl)but-2-en-1-yl)-4-(1-hydroxyethyl)- 3-Methyl-1,3-dihydro-2H-benzo[d]imidazol-2-ylidene)-3-methyl-1H-pyrazole-5-carboxamide; N,N'-((2E,2'E)-butane-1,4-diylbis(3-methyl-1,3-dihydro-2H-benzo[d]imidazol-1-yl- 2-subunit)) bis(1-ethyl-3-methyl-1H-pyrazole-5-carboxamide); 1-Ethyl-N-((E)-3-(4-((E)-2-((1-ethyl-3-methyl-1H-pyrazole-5-carbonyl)imino)- 3-methyl-2,3-dihydro-1H-benzo[d]imidazol-1-yl)butyl)-4-(hydroxymethyl)-1-methyl-1,3-dihydro-2H -Benzo[d]imidazole-2-ylidene)-3-methyl-1H-pyrazole-5-carboxamide; 1-Ethyl-N-((E)-3-(4-((E)-2-((1-ethyl-3-methyl-1H-pyrazole-5-carbonyl)imino)- 3-Methyl-2,3-dihydro-1H-benzo[d]imidazol-1-yl)butyl)-1-methyl-4-(morpholinylmethyl)-1,3-dihydro -2H-benzo[d]imidazole-2-ylidene)-3-methyl-1H-pyrazole-5-carboxamide; 1-Ethyl-N-((E)-3-(4-((E)-2-((1-ethyl-3-methyl-1H-pyrazole-5-carbonyl)imino)- 3-Methyl-2,3-dihydro-1H-benzo[d]imidazol-1-yl)butyl)-1-methyl-4-(hexahydropyridin-1-ylmethyl)-1, 3-Dihydro-2H-benzo[d]imidazole-2-ylidene)-3-methyl-1H-pyrazole-5-carboxamide; N-((E)-1-(4-((E)-7-((3-oxa-6-azabicyclo[3.1.1]hept-6-yl)methyl)-2-( (1-Ethyl-3-methyl-1H-pyrazole-5-carbonyl)imino)-3-methyl-2,3-dihydro-1H-benzo(d)imidazol-1-yl) Butyl)-3-methyl-1,3-dihydro-2H-benzo(d)imidazol-2-ylidene)-1-ethyl-3-methyl-1H-pyrazole-5-methyl amine; 1-Ethyl-N-((E)-1-(4-((E)-2-((1-ethyl-3-methyl-1H-pyrazole-5-carbonyl)imino)- 3-Methyl-2,3-dihydro-1H-benzo[d]imidazol-1-yl)butyl)-4-(hydroxymethyl)-3-methyl-1,3-dihydro-2H -Benzo[d]imidazole-2-ylidene)-3-methyl-1H-pyrazole-5-carboxamide; 1-Ethyl-N-((E)-1-(4-((E)-2-((1-ethyl-3-methyl-1H-pyrazole-5-carbonyl)imino)- 3-Methyl-2,3-dihydro-1H-benzo[d]imidazol-1-yl)butyl)-3-methyl-4-(morpholinylmethyl)-1,3-dihydro -2H-benzo[d]imidazole-2-ylidene)-3-methyl-1H-pyrazole-5-carboxamide; 1-Ethyl-N-((E)-3-((2R,5R)-5-((E)-2-((1-ethyl-3-methyl-1H-pyrazole-5-carbonyl )Imino)-3-methyl-2,3-dihydro-1H-benzo(d)imidazol-1-yl)hex-2-yl)-4-(hydroxymethyl)-1-methyl -1,3-Dihydro-2H-benzo[d]imidazole-2-ylidene)-3-methyl-1H-pyrazole-5-carboxamide; 1-Ethyl-N-((E)-3-((2R,5R)-5-((E)-2-((1-ethyl-3-methyl-1H-pyrazole-5-carbonyl )Imino)-3-methyl-2,3-dihydro-1H-benzo[d]imidazol-1-yl)hex-2-yl)-1-methyl-4-(morpholinylmethyl) Group)-1,3-dihydro-2H-benzo[d]imidazol-2-ylidene)-3-methyl-1H-pyrazole-5-carboxamide; 1-Ethyl-N-((E)-3-((2S,5S)-5-((E)-2-((1-ethyl-3-methyl-1H-pyrazole-5-carbonyl )Imino)-3-methyl-2,3-dihydro-1H-benzo(d)imidazol-1-yl)hex-2-yl)-4-(hydroxymethyl)-1-methyl -1,3-Dihydro-2H-benzo[d]imidazole-2-ylidene)-3-methyl-1H-pyrazole-5-carboxamide; 1-Ethyl-N-((E)-3-((2S,5S)-5-((E)-2-((1-ethyl-3-methyl-1H-pyrazole-5-carbonyl )Imino)-3-methyl-2,3-dihydro-1H-benzo[d]imidazol-1-yl)hex-2-yl)-1-methyl-4-(morpholinylmethyl) Group)-1,3-dihydro-2H-benzo[d]imidazol-2-ylidene)-3-methyl-1H-pyrazole-5-carboxamide; 1-Ethyl-N-((E)-3-((2S,5R)-5-((E)-2-((1-ethyl-3-methyl-1H-pyrazole-5-carbonyl )Imino)-3-methyl-2,3-dihydro-1H-benzo(d)imidazol-1-yl)hex-2-yl)-4-(hydroxymethyl)-1-methyl -1,3-Dihydro-2H-benzo[d]imidazole-2-ylidene)-3-methyl-1H-pyrazole-5-carboxamide; 1-Ethyl-N-((E)-3-((2S,5R)-5-((E)-2-((1-ethyl-3-methyl-1H-pyrazole-5-carbonyl )Imino)-3-methyl-2,3-dihydro-1H-benzo[d]imidazol-1-yl)hex-2-yl)-1-methyl-4-(morpholinylmethyl) Group)-1,3-dihydro-2H-benzo[d]imidazol-2-ylidene)-3-methyl-1H-pyrazole-5-carboxamide; 1-Ethyl-N-((E)-3-((2R,5S)-5-((E)-2-((1-ethyl-3-methyl-1H-pyrazole-5-carbonyl )Imino)-3-methyl-2,3-dihydro-1H-benzo(d)imidazol-1-yl)hex-2-yl)-4-(hydroxymethyl)-1-methyl -1,3-Dihydro-2H-benzo[d]imidazole-2-ylidene)-3-methyl-1H-pyrazole-5-carboxamide; 1-Ethyl-N-((E)-3-((2R,5S)-5-((E)-2-((1-ethyl-3-methyl-1H-pyrazole-5-carbonyl )Imino)-3-methyl-2,3-dihydro-1H-benzo[d]imidazol-1-yl)hex-2-yl)-1-methyl-4-(morpholinylmethyl) Group)-1,3-dihydro-2H-benzo[d]imidazol-2-ylidene)-3-methyl-1H-pyrazole-5-carboxamide; N-((E)-1-((E)-4-((E)-7-(1,2-dihydroxyethyl)-2-((1-ethyl-3-methyl-1H- Pyrazol-5-carbonyl)imino)-3-methyl-2,3-dihydro-1H-benzo(d)imidazol-1-yl)but-2-en-1-yl)-3- Methyl-1,3-dihydro-2H-benzo[d]imidazole-2-ylidene)-1-ethyl-3-methyl-1H-pyrazole-5-carboxamide; 1-Ethyl-N-((E)-3-((E)-4-((E)-2-((1-ethyl-3-methyl-1H-pyrazole-5-carbonyl) sub Amino)-3-methyl-2,3-dihydro-1H-benzo(d)imidazol-1-yl)but-2-en-1-yl)-4-(1-hydroxy-2-? (Hydroxyethyl)-1-methyl-1,3-dihydro-2H-benzo[d]imidazol-2-ylidene)-3-methyl-1H-pyrazole-5-carboxamide; 1-Ethyl-N-((E)-3-((E)-4-((E)-2-((1-ethyl-3-methyl-1H-pyrazole-5-carbonyl) sub Amino)-3-methyl-7-(morpholinylmethyl)-2,3-dihydro-1H-benzo(d)imidazol-1-yl)but-2-en-1-yl)- 4-(Hydroxymethyl)-1-methyl-1,3-dihydro-2H-benzo[d]imidazole-2-ylidene)-3-methyl-1H-pyrazole-5-carboxamide ； 1-Ethyl-N-((E)-3-((E)-4-((E)-2-((1-ethyl-3-methyl-1H-pyrazole-5-carbonyl) sub Amino)-1-methyl-1,2-dihydro-3H-imidazo[4,5-b]pyridin-3-yl)but-2-en-1-yl)-1-methyl-4 -(Morpholinylmethyl)-1,3-dihydro-2H-benzo[d]imidazole-2-ylidene)-3-methyl-1H-pyrazole-5-carboxamide; 1-Ethyl-N-((E)-3-((E)-4-((E)-2-((1-ethyl-3-methyl-1H-pyrazole-5-carbonyl) sub Amino)-1-methyl-1,2-dihydro-3H-imidazo[4,5-c]pyridin-3-yl)but-2-en-1-yl)-1-methyl-4 -(Morpholinylmethyl)-1,3-dihydro-2H-benzo[d]imidazole-2-ylidene)-3-methyl-1H-pyrazole-5-carboxamide; 1-Ethyl-N-((E)-3-((E)-4-((E)-2-((1-ethyl-3-methyl-1H-pyrazole-5-carbonyl) sub Amino)-3-methyl-2,3-dihydro-1H-imidazo[4,5-c]pyridin-1-yl)but-2-en-1-yl)-1-methyl-4 -(Morpholinylmethyl)-1,3-dihydro-2H-benzo[d]imidazole-2-ylidene)-3-methyl-1H-pyrazole-5-carboxamide; 1-Ethyl-N-((E)-3-((E)-4-((Z)-2-((1-ethyl-3-methyl-1H-pyrazole-5-carbonyl) sub Amino)-3-methyl-2,3-dihydro-1H-imidazo[4,5-b]pyridin-1-yl)but-2-en-1-yl)-1-methyl-4 -(Morpholinylmethyl)-1,3-dihydro-2H-benzo[d]imidazole-2-ylidene)-3-methyl-1H-pyrazole-5-carboxamide; 1-Ethyl-N-((E)-3-((E)-4-((E)-2-((1-ethyl-3-methyl-1H-pyrazole-5-carbonyl) sub Amino)-3-methyl-4-(morpholinylmethyl)-2,3-dihydro-1H-benzo(d)imidazol-1-yl)but-2-en-1-yl)- 1-Methyl-4-(morpholinylmethyl)-1,3-dihydro-2H-benzo[d]imidazol-2-ylidene)-3-methyl-1H-pyrazole-5-methyl Amide Or its salt. A compound selected from the group consisting of: (E)-1-ethyl-N-(3-((E)-4-((E)-2-((1-ethyl-3-methyl-1H-pyrazole-5-carbonyl) sub Amino)-3-methyl-2,3-dihydro-1H-benzo(d)imidazol-1-yl)but-2-en-1-yl)-4-(hydroxymethyl)-1- Methyl-1H-benzo[d]imidazole-2(3H)-ylidene)-3-methyl-1H-pyrazole-5-carboxamide; 1-Ethyl-N-((E)-1-((E)-4-((E)-2-((1-ethyl-3-methyl-1H-pyrazole-5-carbonyl) sub Amino)-3-methyl-2,3-dihydro-1H-benzo(d)imidazol-1-yl)but-2-en-1-yl)-4-(hydroxymethyl)-3- Methyl-1,3-dihydro-2H-benzo[d]imidazole-2-ylidene)-3-methyl-1H-pyrazole-5-carboxamide; N-((E)-4-((3-oxa-6-azabicyclo[3.1.1]hept-6-yl)methyl)-1-((E)-4-((E) -2-((1-ethyl-3-methyl-1H-pyrazole-5-carbonyl)imino)-3-methyl-2,3-dihydro-1H-benzo[d]imidazole- 1-yl)but-2-en-1-yl)-3-methyl-1,3-dihydro-2H-benzo(d)imidazol-2-ylidene)-1-ethyl-3-methyl Group-1H-pyrazole-5-carboxamide; N-((E)-1-((E)-4-((E)-7-(1,2-dihydroxyethyl)-2-((1-ethyl-3-methyl-1H- Pyrazol-5-carbonyl)imino)-3-methyl-2,3-dihydro-1H-benzo(d)imidazol-1-yl)but-2-en-1-yl)-3- Methyl-1,3-dihydro-2H-benzo[d]imidazol-2-ylidene)-1-ethyl-3-methyl-1H-pyrazole-5-carboxamide; and 1-Ethyl-N-((E)-3-((E)-4-((E)-2-((1-ethyl-3-methyl-1H-pyrazole-5-carbonyl) sub Amino)-3-methyl-2,3-dihydro-1H-benzo(d)imidazol-1-yl)but-2-en-1-yl)-4-(1-hydroxy-2-? (Hydroxyethyl)-1-methyl-1,3-dihydro-2H-benzo[d]imidazol-2-ylidene)-3-methyl-1H-pyrazole-5-carboxamide; Or its pharmaceutically acceptable salt. The compound of claim 1 or 2, or a salt thereof, wherein the compound is a compound of Table 1. A pharmaceutical composition comprising a compound according to any one of claims 1 to 10 or 12 or a salt thereof, wherein the salt is a pharmaceutically acceptable salt, or a compound according to claim 11 or a pharmaceutically acceptable salt thereof salt. A use of the pharmaceutical composition according to claim 13, which is used to manufacture an agent for inhibiting hepatitis B virus in animals. A use of the pharmaceutical composition according to claim 13 for the manufacture of a medicament for the treatment of hepatitis B infection in humans infected with or at risk of infection with hepatitis B virus. A use of the pharmaceutical composition according to claim 13 for manufacturing a medicament for reducing the amount of hepatitis B DNA and the amount of hepatitis B antigen in a mammal infected with hepatitis B virus, wherein the hepatitis B The reduction of DNA and the reduction of the hepatitis B antigen are calculated by comparing the amount of hepatitis B DNA and the amount of HBV antigen in the mammal before the administration of the agent. The use of claim 16, wherein the amount of the hepatitis B DNA and the amount of the hepatitis B antigen are reduced by at least 90% compared with the amount before the administration of the agent. A use of the pharmaceutical composition according to claim 13 for the manufacture of a medicament for promoting the seroconversion of hepatitis B virus in mammals, After administering the agent, monitor the mammal's serum sample for the presence of HBeAg plus HBeAb; or The presence of HBsAg in the mammal’s serum sample, If HBeAg is monitored as the determinant of seroconversion, the absence of HBeAg plus the presence of HBeAb in the serum sample, or If HBsAg is monitored as the determinant of seroconversion, the absence of HBsAg in the serum sample plus the presence of serum HBsAb is evidence of seroconversion in the mammal, which is determined by the current detection limit of the commercially available ELISA system.