modulators of the interferon gene stimulator (sting)

专利摘要:
Compounds of formula (I) are disclosed:where q, r, s, A, B, C, RA1, RA2, RB1, RB2, RC1, RC2, R3, R4, R5, R6, R14, R15, R16, R17, Rx and Ry are as defined in this document ; or a tautomer thereof, or a salt, in particular a pharmaceutically acceptable salt, thereof.
公开号:BR112020006780A2
申请号:R112020006780-6
申请日:2018-10-04
公开日:2020-10-06
发明作者:David T. FOSBENNER；George Scott PESIRIDIS；Joshi M. Ramanjulu；Joseph J. Romano；Stuart Paul Romeril；Mark J. Schulz；Huiqiang Zhou；Junya Qu；Todd L. Graybill；Jianxing Kang；Bryan W. King；Yunfeng LAN；Lara Kathryn Leister；Mukesh K Mahajan；John F. Mehlmann；Angel I. MORALES-RAMOS
申请人:Glaxosmithkline Intellectual Property Development Limited；
IPC主号:

专利说明:

[001] [001] This application claims the priority of US Provisional Application No. 62 / 568,420, filed on October 5, 2017, the content of which is incorporated into this document by reference in its entirety. FIELD OF THE INVENTION
[002] [002] The present invention relates to heterocyclic amides that are useful as modulators of transmembrane protein 173 (TMEM173), also known as STING (Interferon Gene Stimulant), and methods for producing and using them. BACKGROUND OF THE INVENTION
[003] [003] Vertebrates are constantly threatened by the invasion of microorganisms and have evolved immune defense mechanisms to eliminate infectious pathogens. In mammals, this immune system comprises two branches; innate immunity and adaptive immunity. The innate immune system is the first line of defense, which is initiated by Pattern Recognition Receptors (PRRs), which detect pathogen ligands as well as damage-associated molecular patterns (Takeuchi O. et a /., Cell, 2010: 140, 805-820). An increasing number of these receptors have been identified, including Toll-like receptors (TLRs), type C lectin receptors, receptors similar to the retinoic acid-inducible gene | (RIG-I) and NOD-like receptors (NLRs), as well as double-stranded DNA sensors. The activation of PRRs leads to the overloading of genes involved in the inflammatory response, including type 1 interferons, proinflammatory cytokines and chemokines that suppress pathogen replication and facilitate adaptive immunity.
[004] [004] The adapter protein STING (Interferon Gene Stimulator), also called TMEM 173, MPYS, MITA and ERIS, has been identified as a central signaling molecule in the innate immune response to cytosolic nucleic acids (Ishikawa H and Barber GN, Nature , 2008: 455, 674-678; WO2013 / 1666000). The activation of STING results in the over-regulation of the IRF3 and NFKB pathways, leading to the induction of Interferon-B and other cytokines. STING is crucial in responding to cytosolic DNA from pathogens or the host, and from atypical nucleic acids called Cyclic Dinucleotides (CDNs)
[005] [005]) CDNs were first identified as secondary bacterial messengers responsible for controlling various responses in the prokaryotic cell. Bacterial CDNs, such as c-di-GMP, are symmetrical molecules characterized by two 3 '5 phosphodiester bonds.
[007] [007] More recently, the response to cytosolic DNA has been elucidated and proved to involve the generation, by an enzyme called cyclic GMP-AMP synthase (cCGAS, previously known as C6orf150 or MB21D1), of a new mammalian CDN signaling molecule identified as cGAMP, which then activates STING. Unlike bacterial CDNs, cCGAMP is an asymmetric molecule characterized by its mixed 2 ', 5-phosphodiester and 3', 5'-phosphodiester bonds (Gao P et al., Cell, 2013: 153, 1094-1107). The interaction of CGAMP (II) with STING was also demonstrated via X-ray crystallography (Cai X et al., Molecular Cell, 2014: 54, 289-296).
[008] [008] Interferon was first described as a substance that could protect cells against viral infection (ISsaacs & Lindemann, J., Virus Interference. Proc. R. Soc. Lon. Ser. B. Biol. Sci. 1957: 147 , 258-267). In men, type | are a family of related proteins encoded by genes on chromosome 9 and encoding at least 13 isoforms of interferon-alpha (IFNa) and one isoform of interferon-beta (IFNB). Recombinant IFNa was the first approved biological drug and became an important therapy in viral infections and cancer. In addition to direct antiviral activity in cells, interferons are known to be strong modulators of the immune response, acting on cells of the immune system.
[009] [009] The administration of a small molecular compound capable of modulating the immune response, including the activation or inhibition of the production of interferons of the type | and other cytokines, could become an important strategy in the treatment or prevention of human diseases, including viral infections and autoimmune diseases. This type of immunomodulatory strategy has the potential to identify compounds that could be useful not only in innate immunity against infectious diseases, but also against cancer (Zitvogel, L., et al., Nature Reviews Immunology, 2015 15 (7), p405- 414), against allergic diseases (Moisan J. et al., Am. J. Physiol. Lung Cell Mol. Physiol., 2006: 290, L987-995), against neurodegenerative diseases, such as amyotrophic lateral sclerosis and multiple sclerosis (Lemos , H. et al., J. Immunol., 2014: 192 (12), 5571-8; Cirulli, E. et al., Science, 2015: 347 (6229), 1436-41; Freischmidt, A., et al., Nat. Neurosci., 18 (5), 631-6), against other inflammatory conditions, such as irritable bowel disease (Rakoff-Nahoum S ,, Cell., 2004, 23, 118 (2): 229- 41), and as vaccine adjuvants (Persing et al., Trends Microbiol., 2002: 10 (10 Suppl), S32-7 and Dubensky et al., Therapeutic Advances in Vaccines, published online on September 5, 2013 ).
[010] [010] STING is essential for host antimicrobial defense, including protection against a variety of DNA and RNA viruses and bacteria (investigated in Barber et a / l., Nat. Rev. Immunol.). The families Herpesviridae, Flaviviridae, Coronaviridae, Papillomaviridae, Adenoviridae, Hepadnaviridae, ortomyxoviridae, paramyxoviridae and rhabdoviridae have evolved mechanisms to inhibit the production of interferons of the type | mediated by STING and evade host immune control (Holm et a /., 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 ). Thus, activation in small molecules of STING could be beneficial for the treatment of these infectious diseases.
[011] [011] On the other hand, larger and prolonged production of type IFN | it is associated with a variety of chronic infections, including mycobacteria (Collins et a /., Cell Host Microbe, 2015: 17 (6) 820-8); Wassermann et al., Cell Host Microbe, 2015: 17 (6) 799-810; Watson et a / l., Cell Host Microbe, 2015: 17 (6) 811-9), Francisella (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 (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). Excessive interferon-type | is found among patients with complex forms of autoimmune disease.Genetic evidence in humans and the support of studies in animal models support the hypothesis that STING inhibition results in less | type interferons that cause 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 offer a treatment to patients with chronic production of type | interferons and proinflammatory cytokines associated with infections or autoimmune diseases complex bonds. Allergic diseases are associated with an immune response influenced by Th2 against allergens. Th2 responses are associated with high levels of IgE, which, through its effect on mast cells, promotes hypersensitivity against allergens, resulting in the symptoms observed, for example, allergic rhinitis and asthma. In healthy people, the immune response against allergens is more balanced with a mixed Th2 / Th1 response and regulatory T cells. Induction of type 1 interferons has also been shown to result in the reduction of Th2 type cytokines in the local environment and to promote Th1i / Treg responses. In this context, the induction of type 1 interferons, for example, by activating STING, can bring benefits to the treatment of allergic diseases, such as asthma and allergic rhinitis (Huber JP et al, J. Immunol., 2010: 185, 813- 817).
[012] [012] Compounds that bind to STING and act as agonists have been proven to induce type 1 interferons and other cytokines upon incubation with human PBMCs. Compounds that induce human interferons can be useful in the treatment of various disorders, for example, in the treatment of allergic diseases and other inflammatory conditions, for example, allergic rhinitis and asthma, in the treatment of infectious diseases, neurodegenerative diseases, precancerous syndromes and cancer , and may also be useful as an immunogenic composition or as a vaccine adjuvant. Compounds that bind to STING can act as antagonists and could be useful in the treatment of inflammation, for example, autoimmune diseases, metabolic diseases, neuroinflammation and inflammation in the heart that would lead to heart disease (such as myocardial infarction), as suggested recent studies. (Ridker et al., N. ENG. J. Med., 2017, 377 (12), 1119-1131; King et al., Nat Med., December 2017; 23 (12): 1481-1487.)
[013] [013] Based on recent studies, it is believed that inhibiting cGas or STING may be useful in the treatment or prevention of metabolic diseases (such as insulin resistance, non-alcoholic fatty liver disease (NAFLD) / non-alcoholic steatohepatitis (NASH), obesity, diabetes, high blood pressure, fatty liver and cardiovascular diseases) (Qiao. Et al, Metabolism Clinical and Experimental (2007), 81, 13 - 24; Bai et al, PNAS (2017), 114, nº 46, 12196-12201; Iracheta et al., Journal of Biological Chemistry (2016) 52, 26794-26805; Cruz.et al., Molecular Metabolism (2018) 1-11, Patrasek et al., Proc Natl Acad Sci (2013 ), 110 (41): 16544-9, Mao et al., Arterioscler. Thromb. Vasc. Biol. (2017) 37 (5): 920-929).
[014] [014] It is contemplated that targeting STING with activating or inhibiting agents can be a promising approach to treating diseases and conditions in which modulation of the type 1 IFN pathway is beneficial, including inflammatory, allergic and autoimmune diseases, infectious diseases, cancer, precancerous syndromes, tumor metastasis, metabolic disease, cardiovascular disease and as an immunogenic composition or vaccine adjuvants.
[015] [015] Skin cancers and various viral skin infections involve a privileged immune environment, and the activation of the local immune response against injuries can be a topical therapeutic approach. STING agonists can be used to treat viral warts, superficial skin cancers and pre-malignant actinic keratoses. By means of a double mechanism of action, the activation of STING (for example, via adhesive distribution with microneedles or topical formula) can serve to control HPV directly through the production of interferons of the type | antivirals and indirectly by enhancing the immune response downstream of innate immune activation. The STING agonist can activate the innate immune response in the lesion and lead to the anti-HPV T cell response.
[016] [016] Recent evidence indicates that spontaneous activation of the STING pathway within tumor-resident dendritic cells leads to the production of type IFN | and adaptive immune responses against tumor. In addition, the activation of this pathway in antigen presenting cells (APCs) within the tumor microenvironment causes the subsequent initiation of T cells against tumor-associated antigens (Corrales and Gajewski, Clin. Cancer Res .; 21 (21); 4774- 9, 2015).
[017] [017] International Patent Applications WO2014 / 093936, WO 2014/189805, WO 2013/185052, U.8.2014 / 0341976, - WO2015 / 077354, WOZ2015 / 185565, —PCT / IB2017 / 051945 and GB 15014624 reveal certain cyclic dinucleotides and their use in inducing an immune response via STING activation. International Patent Application WO2017 / 106740 describes the use of cyclic dinucleotides and related frameworks that measurably inhibit STING signaling, as well as methods to identify possible STING signaling inhibitors. International Patent Applications WO 2017/175147 and WO2017 / 175156 describe the use of heterocyclic amides and their analogs as modulators of STING.
[018] [018] The compounds of the present invention modulate STING activity and, therefore, can produce a beneficial therapeutic impact in the treatment of diseases, disorders and / or conditions in which modulation of STING (Interferon Gene Stimulator) is beneficial, for example, inflammation, allergic and autoimmune diseases, metabolic disease, cardiovascular disease, infectious diseases, cancer, precancerous syndromes, and as vaccine adjuvants. SUMMARY OF THE INVENTION
[019] [019] The invention relates to a compound according to Formula (|):
[020] [020] It should be remembered that references in this document to compounds of Formula (1) and salts thereof include compounds of Formula (Il) as free bases or as salts thereof, for example, as pharmaceutically acceptable salts of themselves. Thus, in one embodiment, the invention relates to compounds of Formula (|) as a free base. In another embodiment, the invention relates to compounds of Formula (1), and salts thereof. In another embodiment, the invention relates to compounds of Formula (I), and pharmaceutically acceptable salts thereof.
[021] [021] The compounds according to Formula (I), or salts, in particular pharmaceutically acceptable salts thereof, are modulators of STING. Therefore, the present invention also proposes a compound of Formula (1) or salt thereof, in particular a pharmaceutically acceptable salt thereof, for use in a therapy. More specifically, the present invention proposes the use of a compound of Formula (Il), or a pharmaceutically acceptable salt thereof, as an active therapeutic substance in the treatment of a STING-mediated disease or disorder, more specifically for use in the treatment against a disease mediated by agonism or antagonism to STING. The invention also proposes a compound of Formula (1)) or a salt thereof, in particular a pharmaceutically acceptable salt thereof, for use in the manufacture of a medicament for the treatment against a STING-mediated disease or disorder.
[022] [022] The invention also relates to a method for modulating STING, which method comprises putting a cell in contact with a compound according to Formula (Il), or with a salt thereof, in particular a pharmaceutically salt acceptable value. The invention further relates to a method for treating a STING-mediated disease or disorder which comprises administering a therapeutically effective amount of a compound according to Formula (Il), or a salt thereof, in particular a pharmaceutically acceptable salt of the same, to a patient (a human being or another mammal, in particular a human being) who needs it. These STING-mediated diseases or disorders include inflammation, allergic and autoimmune diseases, infectious diseases, cancer, precancerous syndromes, metabolic diseases and cardiovascular diseases. In addition, STING modulators can be useful as immunogenic compositions or vaccine adjuvants.
[023] [023] The present invention further relates to a pharmaceutical composition comprising a compound according to Formula (1), or a salt thereof, in particular a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient. In particular, the present invention relates to a pharmaceutical composition for the treatment of a disease or disorder mediated by STING, where the composition comprises a compound according to Formula (1), or a salt thereof, in particular a salt pharmaceutically acceptable thereof, and a pharmaceutically acceptable excipient. DETAILED DESCRIPTION OF ORDER
[024] [024] According to one aspect of the present invention, it relates to compounds of Formula (1):
[025] [025] The alternative definitions for the various groups and substituting groups of Formula (Il) given throughout this specification aim to describe in particular each species of compound disclosed in this document individually, as well as groups of one or more species of compound. The scope of the present invention includes any combination of these definitions of groups and substituting groups. The compounds of the invention are only those contemplated as "chemically stable", as those skilled in the art will appreciate.
[026] [026] Those skilled in the art will appreciate that the compounds of the present invention can exist in other tautomeric forms, including zwitterionic forms, or isomeric forms. All tautomeric forms (including zwitterionic forms) and isomeric forms of the formulas and compounds described in this document are intended to be encompassed within the scope of the present invention.
[027] [027] Those skilled in the art will also appreciate that the compounds of the present invention may exist in tautomeric (or isomeric) forms, including, but not limited to, Formula (A), Formula (B) and / or Formula (C), or in zwitterionic forms, including but not limited to Formula (D) or Formula (E). In Formula (B), (C), (D) or (E), each occurrence of R is independently H or any appropriate substituent group on nitrogen, for example, alkyl.
[028] [028] The chemical names given for the intermediate compounds and / or for the compounds of the present invention described in this document can refer to any of the tautomeric / isomeric representations of these compounds (in some cases, these alternative names are given along with the experimental). It should be borne in mind that any reference to a named compound (an intermediate compound or a compound of the invention) or a structurally represented compound (an intermediate compound or a compound of the invention) is intended to cover all tautomeric / isomeric forms, including zwitterionic forms of these compounds, and any mixture of these.
[029] [029] As used herein, the term "alkyl" represents a saturated, linear or branched hydrocarbon group with the specified number of carbon atoms. The term "C1-C4 alkyl" refers to a linear or branched alkyl group containing 1 to 4 carbon atoms. Examples of alkyl include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, s-butyl, t-butyl, pentyl and hexyl.
[030] [030] When a substituting term such as 'alkyl' is used in combination with another substituting term, for example, as in
[031] [031] As used in this document, the term "halo (alkyl)" represents a saturated, linear or branched hydrocarbon group with the specified number (n) of carbon atoms and one or more (up to 2n + 1) halogen atoms. For example, the term "halo (C1-C4 alkyl)" represents a group with one or more halogen atoms, which can be the same or different, in one or more carbon atoms in an alkyl group containing from 1 to 4 carbon atoms . Examples of "halo (C1-C4aalkyl)" groups include, but are not limited to, -CF3 (trifluoromethyl), -CCIs (trichloromethyl), 1,1-difluorethyl, 2,2,2-trifluorethyl and hexafluorisopropyl.
[032] [032] "Alkenyl" refers to a linear or branched group with the specified number of carbon atoms and at least 1 and up to 3 carbon-carbon double bonds. Examples include ethylene and propylene.
[033] [033] "Alquinyl" refers to a straight or branched hydrocarbon group with the specified number of carbon atoms and at least 1 and up to 3 carbon-carbon triple bonds. Examples include ethinyl and propynyl.
[034] [034] "Alkoxy-" or "(alkyl) oxy-" refer to an "alkyl-oxy" group containing an alkyl group with the specified number of carbon atoms attached through an oxygen-binding atom. For example, the term "C1-C-alkoxy" represents a saturated, linear or branched hydrocarbon group with at least 1 and up to 4 carbon atoms linked through an oxygen-binding atom. Examples of "C1-Ca-" alkoxy or "(C1-Ca) -oxy" groups include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, s-butoxy and t-butoxy.
[035] [035] As used herein, the term "halo (alkoxy) -" represents a saturated, linear or branched hydrocarbon group with the specified number
[036] [036] A carbocyclic group or group is a cyclic group or group in which the ring members are carbon atoms and can be saturated, partially unsaturated (non-aromatic) or totally unsaturated (aromatic).
[037] [037] "Cycloalkyl" refers to a saturated non-aromatic hydrocarbon ring group that contains the specified number of carbon atoms in the ring. For example, the term "C3-Ce cycloalkyl" refers to a cyclic group with three to six ring carbon atoms. Examples of "C3-Ce cycloalkyl" groups include cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.
[038] [038] A heterocyclic group or group is a cyclic group or group with, as ring members, atoms of at least two different elements, which group may be saturated, partially unsaturated (non-aromatic) or totally unsaturated.
[039] [039] "Heteroatom" refers to a nitrogen, sulfur or oxygen atom, for example, a nitrogen atom or an oxygen atom.
[040] [040] "Heterocycloalkyl" refers to a non-aromatic, monocyclic or bicyclic group that contains 3 to 10 ring atoms and that contains one or more (usually one or two) heteroatoms ring members selected independently from oxygen, sulfur and nitrogen. The point of attachment of a heterocycloalkyl group can be through any suitable carbon or nitrogen atom.
[041] [041] Examples of "heterocycloalkyl" groups include, but are not limited to, aziridinyl, thiiranyl, —oxyranil, azetidinyl, oxetanyl, tietanyl, pyrrolidinyl, tetrahydrofuranyl, = tetrahydrothienyl, - 1,3-dioxolanyl, - piperidinyl, - piperidinyl, - piperidinyl, - piperidinyl, - piperidinyl, - piperidinyl, - piperidinyl, - piperidinyl, - piperidine, , tetrahydrothiopyranil, 1,3-dioxanyl, 1,4-dioxanyl, 1,3-oxathiolanil, 1,3-oxathianyl, 1,3-dithianyl, 1,4-oxathiolanyl, 1,4-oxathianyl, 1,4-dithianyl , morpholinyl, thiomorpholinyl and hexahydro-1H-1,4-diazepinyl.
[042] [042] Examples of "4-membered heterocycloalkyl" groups include oxetanil, tietanyl and azetidinyl.
[043] [043] The term "5- to 6-membered heterocycloalkyl" represents a saturated and monocyclic group containing 5 or 6 ring atoms, which includes one or two hetero atoms "independently selected from oxygen, sulfur and nitrogen. Illustrative examples of 5- to 6-membered heterocycloalkyl groups include, but are not limited to, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothienyl, tetrahydropyranyl, tetrahydrothiopyranyl, piperidinyl, piperazinyl, morpholinyl and thiomorpholinyl.
[044] [044] "Heteroaryl" refers to an aromatic monocyclic or bicyclic group that contains 5 to 10 ring atoms, including 1 to 4 heteroatoms independently selected from nitrogen, oxygen and sulfur, in which at least a portion of the group is aromatic. For example, this term encompasses bicyclic heterocyclic aryl groups containing either a phenyl ring fused to a heterocyclic group or a heteroaryl ring group fused to a carbocyclic group. The point of attachment of a heteroaryl group can be through any suitable carbon or nitrogen atom.
[045] [045] The term "5- to 6-membered heteroaryl" represents an aromatic monocyclic group containing 5 or 6 ring atoms, including at least one carbon atom and 1 to 4 hetero atoms independently selected from nitrogen, oxygen and sulfur. The selected 5-membered heteroaryl groups contain a nitrogen, oxygen or sulfur ring heteroatom and optionally contain 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 (furanyl), thienyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, thiazolyl, isothiazolyl, thiadiazolyl, oxazolyl, isoxazolyl and oxadiazolyl. The selected 6-membered heteroaria groups include pyridinyl (pyridyl), pyrazinyl, pyrimidinyl, pyridazinyl and triazinyl.
[046] [046] The term "9 to 10 membered heteroaryl" refers to an aromatic bicyclic group that contains 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) include benzothienyl, - benzofuranyl, indolyl, indolinyl - (dihydroindolyl), isoindolyl, isoindolinyl, = indazolyl, isobenzofuryl, = 2,3-dihydrobenzofuryl, - benzoxazolol, benzooxazolyl, benzooxazolol, benzooxazole benzothiazolyl, benzoisothiazolyl, benzimidazolyl, benzoxadiazolyl, benzothiadiazolyl, “benzotriazolyl, purinyl, imidazopyridinyl, = pyrazolopyridinyl, triazolopyridinyl and 1,3-benzodioxolyl.
[047] [047] Examples of 10-membered heteroaryl groups (heteroaryl fused at 6.6) include quinolinyl (quinolyl), isoquinolyl, phthalazinyl, naphtridinyl (1,5-naphthyridinyl, - 1,6-naphthyridinyl, - 1,7-naphthyridinyl, - 1,8-naphthyridinyl) - quinazolinyl, quinoxalinyl, 4H-quinolizinyl, 1,2,3,4-tetrahydroquinolinyl (tetrahydroquinolinyl), 1,2,3 4-tetrahydroisoquinolinyl (tetrahydroisoquinolinyl), cinolinyl, pteridinyl and 2,3-dihydrobenzo [b] [1, 4] dioxinyl.
[048] [048] The terms "halogen" and "halo" refer to a halogen radical, for example, a fluorine, chlorine, bromine or iodine substituent.
[049] [049] "Ox0o" represents a group of double-bonded oxygen; for example, if attached directly to a carbon atom, it forms a carbonyl group (C = O).
[050] [050] "Hydroxy" or "hydroxyl" is intended to mean the radical -OH.
[051] [051] As used in this document, the term "cyan" refers to a nitrile group, -C = N,
[052] [052] As used herein, the term "optionally substituted (a)" indicates that a group (such as an alkyl, cycloalkyl, alkoxy, heterocycloalkyl, aryl or heteroaryl group) or ring or group may be unsubstituted, or the group , ring or group may be replaced with one or more substituents as defined in the substituent definitions (A, Rº etc.) given in this document. If groups can be selected from a number of alternative groups, the selected groups can be the same or different.
[053] [053] The term "independently" means that when more than one substituent is selected from among a number of possible substituents, those substituents may be the same or different.
[054] [054] The term "pharmaceutically acceptable" refers to compounds, materials, compositions and / or dosage forms that are, within the scope of correct medical advice, suitable for use in contact with the tissues of humans and animals without causing toxicity, irritation or other problems or complications in excess, combined with a sensible risk-benefit ratio.
[055] [055] As used herein, the terms "compound (s) of the invention" or "compound (s) of the present invention" mean a compound of Formula (1) as defined herein, in any form, that is, in any form tautomeric / isomeric, any salt or non-salt form (for example, as a form of acid or free base, or as a salt, in particular a pharmaceutically acceptable salt thereof) and any physical form of it (for example, including forms non-solid (for example, liquid or semi-solid forms), and solid forms (for example, amorphous or crystalline forms, specific polymorphic forms, solvate forms, including hydrate forms (for example, mono-, di- and semi-hydrates) ), and mixtures in various ways.
[056] [056] Therefore, compounds of Formula (1), as defined in this document, in any form in salt or non-salt form and any physical form thereof, and mixtures of various forms are included in the present invention. Although all of these are included in the present invention, it should be borne in mind that the compounds of Formula (Il), as defined herein, in either salt or non-salt form, and in any physical form thereof, may have levels varied activity levels, different bioavailability and different handling properties for formulation purposes.
[057] [057] In one embodiment of the compounds of the present invention, each of R and Rº is independently -CON (Rº) (R '), or one of R and Rº is -CON (Rº) (R) and the other for Rº and Rº is H or -CO2X (Rº). In one modality, each of Rº and Rº is independently -CON (Rº) (R '). In another modality, one of Rº and Rº is -CON (Rº) (R ') and the other of Rº and Rº is H. In a specific modality, each of R and Rº is -CONH>.
[058] [058] It must be kept in mind that when q is 0, A is absent and Rº * and Rºº are not connected. Likewise, it must be kept in mind that when r is O, B is absent and RE and R & are not connected. Likewise, it must be kept in mind that when s is O, C is absent and Rº and Rº are not connected.
[059] [059] In an embodiment of the compounds of the present invention, q is 1, aft O es is O (q + r + s = 1), and the compound has the Formula (I-A) or (| -a):
[060] [060] In an embodiment of the compounds of the present invention, q is 0, aft 1 es is O (q + r + s = 1), and the compound has the Formula (I-B) or (I-b): Rº r o; We N RV RA N RU
[061] [061] In an embodiment of the compounds of the present invention, q is 0, aft O es is 1 (q + r + s = 1), and the compound has the Formula (| -C) or (l-c):
[062] [062] In an embodiment of the compounds of the present invention, q is 1, aft 1 es is O (qr + r + s = 2), and the compound has the Formula (I-AB) or (I-ab): Rº -. 7 ú Ré Í T a SS N À SS. N Ré RAT P O "d =" No | DN Nx | Ro Re O J Rº RM des Õ y Rs Rºº e RE
[063] [063] In an embodiment of the compounds of the present invention, q is 1, aft O es is 1 (q + r + s = 2), and the compound has the Formula (I-AC) or (I | -ac):
[064] [064] In an embodiment of the compounds of the present invention, q is 0, aft 1 es is 1 (q + r + s = 2), and the compound has the Formula (I-BC) or (I-bc): Rº Rx | 9 R WN RÉ 4 | 'red = "de, Sv N RV GIVE> N | L, = N Ny soda É NAN º Y À R né Ro Re O Ro |) ã RA É qe Lo Lo Lo - Ne RA À LO Va VA Va» | XY R | XY R $ ROO RU o Re mo o R7 RR * (I-BC) (I-bc) [065JEM a modality of the compounds of the present invention, q is O and each of RA! And R * Is independently H, halogen, hydroxy, -OP (O) (OH) 2, -O- P (OXRIR!) a, -N (RNR), -CO2R, -N (R) CORP, -N (R9) SOz2 ( C1-Ca alkyl) -N (Rº) (R),
[066] [066] In M an embodiment of the compounds of the present invention, q is O and each of Rº and RM is independently H, hydroxy, -OP (O) (OH) 2, -O- P (O) (R'R! ) 2, amino, (C1-Ca alkyl) amino-, (C1-Ca alkyl) (C1-C4 alkyl) amino-, (C1-C4 alkyl), hydroxy (C1-Ca alkyl) -, amino (C1-Ca alkyl) -, (C1 alkyl) -Ca) amino (C1-Ca alkyl) -, (C1-Ca alkyl) (C1-Ca alkyl)> amino (C1-Ca alkyl) -, C-Ca alkoxy-, hydroxy (Ca-alkoxy) -, - (alkoxy-Ca) - - OP (O) (OH) 2, - (alkoxyCa-Ca) -O- P (OX (RIR!) 2, amino (alkoxyC2-Ca) -, (alkylC1-Ca) amino (alkoxyCa-Ca) -, (alkylC1 -Ca) (C1-Ca alkyl)> amino (C-Ca-Ca4a alkoxy) -, 6-membered heterocycloalkyl- (C1-Ca alkyl) -, phenyl (C1-Ca alkoxy) -, (C1-Ca alkyl) OCONH (C1-C4 alkyl) -,
[067] [067] In one modality, q is O and each of RN and Rº is independently H, (C1-alkyl-Ce) 9oxy or hydroxy (C2-alkyl-Ces) oxic. In one embodiment, q is O and each of Rºº and Rº is independently H, (C1-alkyl) Ce-, hydroxy (C2-alkyl) Oxy-, - (alkoxy-Ca) -OP (O) (OH) 2 , - (Ca-alkoxy) -OP (O) (RIR!) 2. In a modality, q is O and each of Rº and Rº is H. In selected modalities, q is O and each of Rºº and Rºº is independently selected from H, -OCH2CH2CH2O0H and -OCHs.
[068] [068] In M a modality q is O and each of Rº and Rº is independently H, (C1-Cs alkyl) optionally substituted or optionally substituted (C1-Cs alkyl), in which the C-Cs alkyl of said (C1-alkyl) ) optionally - substituted or optionally substituted (CC-alkyl + -Ce) is optionally substituted with 1 to 4 substituents, each independently selected from the group consisting of hydroxyl, -OP (O) (OH) 2, -O-
[069] [069] In M a modality, q is O and each of Rº and Rº is independently H, (optionally substituted C1-Cs alkyl) or (C1-Ces alkyl) optionally substituted, and the C1-Cs alkyl of said (C1 alkyl) ) optionally substituted or (optionally substituted C: + - Cs alkyl) is optionally substituted with 1 to 4 substituents, each independently selected from the group consisting of hydroxyl, -OP (O) (OH) ', -OP (O) (RIR! ') 2e, -N (RºKR), C1-Ca alkoxy, phenyl and 5- to 6-membered heterocycloalkyl optionally substituted containing at least one nitrogen or oxygen as a ring member, and each R is independently selected from H, C1- alkyl Ca, - (C1-Ca alkyl) NH2 or - (C1-Ca alkyl) C1-alkoxy.
[070] [070] In one embodiment, q is O and at least one of Rº or RU is independently H, (optionally substituted C1-Cs alkyl) or (optionally substituted C1-Cs alkyl), and said C1-Cs alkyl (C1- alkyl) Optionally substituted Cs or optionally substituted (C: -Cs alkyl) is optionally substituted with 1 to 4 substituents, each independently selected from -N (Rº) (R), tetrahydropyran, pyrrolidinyl, piperazinyl, piperidyl and morpholinyl and each Rº is independently selected from H, C1-Ca alkyl, - (C1-Ca alkyl) NH2 or - (C1-Ca alkyl) C-C alkoxy.
[071] [071] In one embodiment, q is 0 and at least one of Rº or Rº is independently H, (C1-Cs alkyl) optionally substituted or (optionally substituted C1-Cs alkyl), and the C1-Cs alkyl of said (C1- alkyl) Optionally substituted Cs or optionally substituted (C: + - Cs alkyl) is optionally substituted with 1 to 4 substituents, each independently selected from tetrahydropyran, pyrrolidinyl, piperazinyl, piperidyl and morpholinyl, and each R is independently selected from H or C1 alkyl -Here.
[072] [072] In a modality, q is O and each of R% and Rº is independently selected from H, hydroxy or (optionally substituted C1-Ce6) alkyl and C - Cs of said (C + alkyl + Ces) oxy - optionally substituted is optionally substituted with hydroxy, phenyl or morpholinyl, where each of phenyl or morpholinyl is optionally substituted with methyl or methoxy.
[073] [073] In one embodiment, q is 0, Rº and R * are independently H or (C1-C1-alkyl) optionally substituted Oxy, where the optionally substituted (C1-Cs) alkyl is optionally substituted with 1 selected substituent among the group consisting of hydroxy, optionally substituted phenyl and optionally substituted 5- to 6-membered heterocycloalkyl, in which the phenyl and 5- to 6-membered heterocycloalkyl are optionally substituted with a substituent selected from the group consisting of C1-C3 alkyl and C1-Cs3 alkoxy .
[074] [074] In one embodiment, q is O, each of Rº and Rº is independently H or (C1 alkyl + -Ce6) optionally substituted oxy, where the optionally substituted oxy (C1-Cs) alkyl is optionally substituted with 1 substituent selected from the group consisting of hydroxy, optionally substituted phenyl and optionally substituted morpholine, in which phenyl and morpholinyl are optionally substituted with a substituent selected from the group consisting of C1-C3 alkyl and C1-C3 alkoxy.
[076] [076] In one embodiment, q is 0, one for RN and Rº is H and the other for Rºº and RM is hydroxy or (optionally substituted C1-Ca) alkyl, in which the alkyl of (alkylC: + - Ca) Optionally substituted oxide is optionally substituted with 1 to 2 substituents, each independently selected from the group consisting of hydroxy and optionally substituted phenyl, wherein said optionally substituted phenyl is optionally substituted with 1 to 2 substituents, each independently selected from ( C1-Ca alkyl) OX-.
[077] [077] In a modality, q is O and Rºº and Rº are both H.
[078] [078] In one mode, r is O and each of Rº and RIP is H.
[079] [079] In another embodiment, r is O and each of Rº 'and Rº is independently H, optionally substituted C1-Cs alkyl, halo (C1-Cs alkyl), optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, C3-Cs cycloalkyl optionally substituted, optionally substituted 4- to 6-membered heterocycloalkyl, optionally substituted 5- to 6-membered heteroaryl or optionally substituted 9-membered heteroaryl.
[080] [080] In an embodiment of the compounds of the present invention, s is 0 and Rº is H, halogen or C1-Ca alkyl and Rº is optionally substituted C1-Ca alkyl, wherein said optionally substituted C: -C4 alkyl group is optionally substituted with a substituent selected from -ORº, -NRºR9 $, -CO> 2Rº, -CONRºR $, -SO2NRºRº and -OCONRºRº.
[081] [081] In an embodiment of the compounds of the present invention, when s is 0, Rº is H and Rº is C1-Ca alkyl. In another embodiment, when s is 0, Rº * is C1- C3alkyl, more specifically methyl. In another embodiment, when s is 0, Rº is C1-C3 alkyl, more specifically methyl or ethyl. In a selected mode, when s is O, Rº it's ethyl.
[082] [082] In one modality, q is 1 and A, together with Rºº and RM, forms a linking group of 4 to 8 members. In another modality, q is 1 and A, together with Rºº and RM, forms a linking group of 4 to 6 members. In yet another modality, qé 1e A, together with RA! and Rº , form a 5-member linking group.
[083] [083] In another modality, q is 1, each of Rº and Rº is independently -CH2> -, -NRº- or -O-, and A is an optionally substituted -C2 -C1-1 alkyl group or is a -C2 alkyl group -Cio-, -C2-C10- alkenyl, -C2-C10-, -alkylC1-Ca-O-C1-alkyl-Ca- or -C1-Ca-NR -C1 -C4-Ca4- alkyl, unsubstituted, said -C2-C10-alkyl group - substituted being substituted with 1 to 4 substituents independently selected from halogen, hydroxy, -O- P (O) (OH)>, -OP (O) (RIR !!) 2, amino, (C1-Ca) alkyl-, (C 1 -C alkyl) (C 1 -C alkyl) amino-, halo (C 1 -C alkyl), halo (C 1 -C alkoxy) - and C 1 -C- alkoxy.
[084] [084] IN another modality, q is 1, each of RN and Rº is independently -CH2-, -NRº- or -O-, and A is a substituted -C2-Csg- alkyl group or is a -C2-Ca alkyl group -, -C2-C2- substituted -C2- Cs-, -C2-Cs-, -C2-C2-O-C1-C2- or -Calkyl-alkyl: -Cao-NRº-alkylC1-C2- unsubstituted, said -C2-Cs- substituted group being substituted with 1 to 2 substituents, each independently selected from halogen, hydroxy, -OP (O) (OH) 2, -OP (O) (RIR "')), - amino, - (someone C + -Ca) amino- , - (C 1 -C alkyl) (C 1 -C alkyl) amino-, halo (C 1 -C 4 alkyl), halo (C 1 -C alkoxy) - and C 1 -C- alkoxy.
[086] [086] In another modality, q is 1, each of Rº and Rº is independently -CH> 2- or -O-, and A is a group -C2 alkyl- Ca-, -C2 alkenyl or -AlquinylC2-Ca -.
[087] [087] In selected modalities, q is 1, each of RN and RE is -O-, and À is -CH2CH2CH> 2-, where A, together with Rº! and RM, forms a -OCH2CH2C0H20- group.
[088] [088] In another modality, q is 1, each of RN and Rº is -O-, and A is -CH2- feni-CH2-, where A, together with Rº * and RM , Forms a -OCH2 group -phenyl-CH20-. In a specific modality, q is 1, and A, together with RA! and RM, forms a -OCH2- phenyl-CH20- group, in which the -OCH> - groups are located at 1, 4 in the phenyl ring group.
[089] [089] The length of the linking groups defined in this document represents the smallest number of atoms in a direct chain composed of -RA! - A-RM- and / or -R8! -B-R82- and / or -R $! - CR 2-, For example, when B is an optionally substituted phenyl, the linker group -RB! -B-R82- can be represented by - (CH2) -phenyl- (CH2) -. This linker group is characterized as a 4-membered linker group when groups 2 - (CH> 2) - are located on adjacent carbon atoms of the phenyl ring (phenyl substituted in 1,2). In another embodiment, this linking group is characterized as a 6-member linking group when the 2 groups - (CH2) - are substituted in positions for in the phenyl ring (phenyl substituted in 1,4). It should be borne in mind that any alkyl, alkenyl or alkynyl group or group of A, B or C is a linear or branched alkyl, alkenyl or alkynyl group or group. For example, a linker group -R81-B-R8 - where B is -C1-C10alkyl- may contain an 8-membered linker group with a branched group (C1-Caalkyl) or 2 to 4 branched groups (C1-C3alkyl) ), for example, 4 branched methyl groups (2 gem-dimethyl groups) or 2 branched methyl groups.
[090] [090] In an embodiment of the compounds of the present invention, r is 1 and each of R8º and R8 is independently -CH2-, and B, together with R8º and RE , forms a linker group, where B is a bond or B is -halo (C1-C10 alkyl) -, -C1-C10- optionally - substituted, -alkenylC2 -Ci1o- - optionally - substituted, -C2-C10 -alkynyl optionally substituted, -C1-C6-O-C1-alkyl-Ce- optionally substituted, -C1-Ce-NRº-alkylC1-Ce- optionally substituted, C3-Cs-cycloalkyl - optionally substituted , optionally substituted phenyl, optionally substituted 4- to 6-membered heterocycloalkyl, optionally substituted 5-6 membered heteroaryl, -C1-C1-alkyl- (cycloalkylC3-Cs) -C1-alkyl-Ca- optionally substituted, -C1-Ca-phenyl-C1-C4-alkyl - optionally substituted, optionally substituted -C1-Ca- (4- to 6-membered heterocycloalkyl) -C1-C4- -alkyl or -C1- (5-6 membered heteroarill) -C1-Ca- optionally substituted, where the alkyl group of said optionally substituted -C1-Cio- alkyl-, -C2-Cio- alkenyl - o optionally substituted, optionally substituted -C2-C10- alkynyl, -C1-Cs-O-C1-Cs-alkyl- optionally substituted, -C1-Ce-NRº-C1-Ce- optionally substituted, -C1-alkyl- Ca- (cycloalkylC3-Ce- ) -C1-C4- alkyl - optionally - substituted, - optionally substituted -C1-Ca-phenyl-C1-C4-alkyl, -C1-Ca- (4- to 6-membered heterocycloalkyl) -C1-C4-alkyl- optionally substituted or -C1- alkyl Ca- (5- to 6-membered heteroaryl-C1-C4-alkyl) - optionally substituted is optionally substituted with 1 to 4 substituents, each selected from -C1-Ca-alkyl, halogen, halo (C1-Ca-alkyl), -OH, -OP ( O) (OH) ', -OP (O) (RIR!') 2e, -ORº, -NH2, -NRºRº, -OCORº, -CO2H, -COXRº, -SORº, -SO2Rº, -CONH2 -CONRºRi, -SO2NH, -SO2NH >, -SO2NRºRi, -OCONH2, -OCONRºRi, -NRÍCORº, -NRISORº, -NRÍCOXRº and -NR $ SO> 2Rº, and the cycloalkyl group C3-Cs, phenyl, heterocycloalkyl of 4 to 6 members or heteroaryl of 5 to 6 members of 5 to 6 members said optionally substituted C3-Cs cycloalkyl, pheni optionally substituted, optionally substituted 4- to 6-membered heterocycloalkyl, optionally substituted 5- to 6-membered heteroaryl, -C1-Cse-alkyl- (C3-Cse-cycloalkyl) -C1-Ca4-alkyl-optionally substituted, -C1-Ca-phenyl-alkyl-C1- C4- optionally substituted, optionally substituted -C1-Ca- (4- to 6-membered heterocycloalkyl) -C1-C4-alkyl- or -C1-Ca- (5-6 membered heteroaryl) -C1-C4- alkyl optionally substituted is optionally substituted with 1 to 4 substituents, each independently selected from halogen, hydroxy, -OP (O) (OH)>, -OP (O) (RIR! ') 2, amino, (C 1 -C alkyl) amino-, (C 1 -C alkyl) ) (C1-Ca alkyl) amino-, C1-Ca alkyl, halo (C1-Ca 4 alkyl), halo (C 1 -C alkoxy) -, C 1 -C alkoxy, hydroxy- (C 1 -C alkoxy) - and C 1 -C alkoxy (Ca-alkoxy) ) -.
[091] [091] In one embodiment of the compounds of the present invention, r is 1, each of R8 ' and R & is it independently -CH2-, and B, along with R $ and R8 , form a 2- to 6-membered linking group. In another modality, r is 1, each of R8º and R & is it independently -CH> 2-, and B, along with R $ and R8 , form a 3- to 6-membered linking group. In yet another modality, r is 1, each of Rºº and Rº is independently -CH2-, and B, together with R * And RP , Forms a linking group of 4 to 5 members.
[092] [092] In one embodiment of the compounds of the present invention, r is 1, each of R8 'and R8 it is independently -CRºR: -, and B, together with R8 'and R8 , forms a linking group of 2 to 6 members. In another modality, r is 1, each of Rºº and R $
[093] [093] In one mode, B is a link
[094] [094] IN another modality, r is 1, each of Rºº and Rºº is independently -CH> 2-, and B is a substituted -C1-C10- alkyl group or is a -C1-C10-, -C2-C10 alkyl group - unsubstituted, -C2-C10-, -C1-Ce6-O-alkyl-C1-Ces-or -C1-Ce-NRº-C1-Cs-alkyl-substituted, said substituted -C1-C1-alkyl group being substituted with 1 to 4 substituents , each independently selected “from -C-alkyl-Ca, halogen, hydroxy, -OP (O) (OH)>, -OP (O) (RIR" '), - amino, - (someone C + -Cs) amino-, - (C1-Ce alkyl) (C1-Ce alkyl) amino-, halo (C1-Cs alkyl), halo (C 1 -C alkoxy) -, C 1 -C alkoxy, hydroxy- (C 1 -C alkoxy) -, C 1-Ca- alkoxy (C 1 -C alkoxy) ) -, -NHCO (C1-Ca4 alkyl), optionally substituted phenyl, optionally substituted 5 to 6 membered heterocycloalkyl and optionally substituted 5 to 6 membered heteroaryl, wherein said phenyl, 5 to 6 membered heterocycloalkyl or 5 to 6 heteroaryl optionally substituted member is optionally substituted with 1 to 4 substituents, each to one independently selected from -C1-Caalkyl, halogen, hydroxy, -OP (O) (OH) 2, -O- P (OX (R'R!) 2, amino, (C1-Ces) alkyl) amino-, (C1-alkyl) -Cs) (C1-Ces alkyl) amino-, halo (C1-Cs alkyl), - halo (C1-alkoxy) -, —aloxy-Ca-, hydroxy- (alkoxy-Ca) - and C1-Ca- (alkoxyCi-Ca) ) -.
[095] [095] JEM another modality, r is 1, each of Rºº and Rº is independently -CH> 2-, and B is a substituted -C1-C10- alkyl group or is a -C1-C10-, -alkenylC2-C10 group - unsubstituted, -C2-C10-, -C1-alkyl-Ce-O-C1-alkyl- or -C1-Ce-NRº-C1-Cs- alkyl substituted, said substituted -C1-C1-alkyl group being replaced with 1 to 4 substituted , each independently selected from -C1alkyl: -Ca, halogen, hydroxy, -OP (O) (OH) 2, -O- P (OX (R'R!) 2, amino, (C1-Ca) alkyl- amino-, (C 1 -C alkyl) (C 1 -C alkyl) amino-, halo (C 1 -C 4 alkyl), halo (C 1 -C alkoxy) - and C 1 -C- alkoxy.
[096] [096] In another modality, r is 1, each of Rº and Rº is independently -CH2-, and B is a substituted -C1-Cs- alkyl group or is a -C1-Cg-, -C2-Cg-, alkyl group, - unsubstituted -C2-Cg-, -C1-Ca-O-alkylC1-Ca- or -C1-alkyl-Ca-NR -C1 -Calkyl-substituted, said substituted -C1-Cs-alkyl group is substituted with 1 to 4 substituents, each independently selected “from -C-alkyl-Ca, halogen, hydroxy, -OP (O) (OH)>, -OP (O) (RIR" ')., - amino, - (someone C + -Ca) amino-, - (C 1 -C alkyl) (C 1 -C alkyl) amino-, halo (C 1 -C 4 alkyl), halo (C 1 -C alkoxy) - and C 1 -C- alkoxy.
[097] [097] IN another modality, r is 1, each of Rº and Rº is independently -CH72-, and B is a substituted -C1-Cs- alkyl group or is a -C1-Ce-, -AlkenylC2-Cs- group, -C2-Ce-, -C1-C2-O-C1-C2-alkyl-or -C1-C2-NRº -C1-C2-alkyl-unsubstituted, said substituted -C1-Ce-alkyl group is substituted with 1 to 4 substituents, each independently selected from -C1-Caalkyl, halogen, hydroxy, -OP (O) (OH) 2, -O- P (OX (RIR!) 2, amino, (C1-Ca) alkyl) amino-, (C1-alkyl) ) (C1-Ca alkyl) amino-, halo (C1-Ca 4 alkyl), halo (C 1 -C alkoxy) - and C 1 -C-alkoxy.
[098] [098] In another modality, r is 1, and each of Rº and Rº is independently -CH2-, and B is a substituted -C2-C4- alkyl group or is a -C2 alkyl- Ca-, - -alkenylC2-Ca group -, - -C2 -Ca-alkyl-, - -C1-O-alkylC1 + alkyl - or - unsubstituted -C1-NRº-C1- alkyl alkyl, the said substituted -C2 -Calkyl group is substituted with 1 to 4 substituents, each independently selected among -C1-Caalkyl, - halogen, - hydroxy, —-OP (O) (OH), - -OP (O) (RIR!), - amino, (C1-Ca alkyl) amino-, (C1-Ca alkyl) ( C1-Ca alkyl) amino-, halo (C1-Ca4 alkyl), halo (C1-Ca alkoxy) - and C-Ca-alkoxy.
[099] [099] In a modality, r is 1, each of Rº and R & is independently -CRIR ', D and R is H or methyl, and B is -CH = CH-, -CH (CH3) = CH (CH3) -, -CH2CH> -, -CH (OH) CH (OH) - , -CH (CH3) CH (CH3) -, -CF2-CF2- or -CH2CH2CH2. In one mode, r is 1, each of R8º and R & is independently -CRºR ', Rº and R' are H or methyl, and B is -CH = CH-, -CH2CH2-, -CH (OH) CH (OH) -. In these modalities, r is 1, B, together with R8º and R8 , Forms a group -CH2CH = CHCH2-, -CH2CH2CH2CH> -, -CH2CH (OH) CH (OH) CH2- or -CH2CH2N (CH3) CH2CH2-. In these modalities, r is 1, and B, together with RE and RE , form -CH2CH = CHCH2-. In a modality, D 1, and B, together with Rº 'and R8 , It forms -CH2CH2CH2CH> -.
[0100] [0100] In an embodiment of the compounds of the present invention, see 1 and each of Rº * and Rº is it independently -CH2-, and C, along with RC and Rº, forms a linker group, where C is -halo (C1-C12 alkyl) -, -C1-C12- alkyl optionally substituted, - -C2-C12-alkenyl - optionally - substituted, - -C2-C12- optionally substituted, - optionally substituted C1-C6-O-C1-Cs-alkyl, -C1-Ce-NRº-optionally substituted-C1-Ce-alkyl, -C1-Ce- (C3-cycloalkyl-Cs) -C1-Cs- alkyl - optionally - substituted, - -alkylC1 -Cs-phenyl-C1-Cs-alkyl- optionally substituted, -C1-alkyl- (4- to 6-membered heterocycloalkyl) -C1-Cs-alkyl- optionally substituted or -C1-Cs- alkyl (5- to 6-membered heteroaryl) -C1-Cs-alkyl - optionally substituted, in which the alkyl group of said optionally substituted -C1-C12- alkyl, - -C2-C12- alkenyl - optionally - substituted, - optionally substituted -C2-C12- alkynyl, -C1-C6-O-alkylC1-Cs- optionally substituted, -C1-Ce-NRº-C1-Ce- alkyl optionally substituted, -C1-alkyl- (C3-Cs-cycloalkyl) -C1-Cs-alkyl- - optionally - s substituted, - optionally substituted -C1-Cs-phenyl-C1-Cs-alkyl, -Ce- (4- to 6-membered heterocycloalkyl) -C1-Cs-alkyl- optionally substituted or -C1-Cs- (heteroaryl from 5 to 6 members) -C1-Cs- optionally substituted alkyl is optionally substituted with 1 or 2 substituents, each independently selected from halogen, halo (C1-Csalkyl), -OH, -OP (O) (OH) 2, -OP (OX ( RIR!) A, -ORº, -NH>, -NRºR%, -OCORº, -CO2H, -CO2Rº, -SORº, -SO2Rº, -CONH2, -CONRºRº, -SO2NH>, -SO2NRºRi, -OCONHº, -OCONRºRi, -NRÍCORº, -NRISORº, -NRÍCOXRº and -NR $ SO> 2Rº, and the C3-Cs cycloalkyl group, phenyl, 4- to 6-membered heterocycloalkyl or 5- to 6-membered heteroaryl of said -C1-Cse6-cycloalkyl ) -C1-Ce- optionally substituted, -C1-Ce-phenyl-C1-Ce- optionally substituted, -C1-Cse-alkyl- (4- to 6-membered heterocycloalkyl) -C1-Ceg-optionally substituted or -C1-Ce- (heteroaryl 5 to 6 members) -C1-Cs-alkyl- optionally substituted is optionally substituted with 1 to 4 substituents, each independently selected from halogen, hydroxy, -OP (O) (OH)>, -OP (O) (RIR! ') 2, amino, (C1-Ca) alkyl- , (C1-Ca alkyl) (C1-Ca alkyl) amino-, C1-Ca alkyl, halo (C1-Ca alkyl), halo (C-alkoxy) -, C-alkoxy-, hydroxy- (alkoxy-Ca-Ca) -, - (alkoxyCa -Ca) -OP (O) (OH) 2, - (alkoxyCa-Ca) -O- P (OXRIR!) 2 and alkoxyC1-Ca- (alkoxyCi-Ca) -.
[0101] [0101] In an embodiment of the compounds of the present invention, s is 1, each of Rº ' and Rº it is independently -CH2-, and C, together with Rº * and Rº , forms a linking group of 4 to 8 members. In another modality, s is 1, and C, together with Rº * 'and Rº , Forms a linking group of 4 to 6 members. In yet another modality, s is 1, and C, together with Rº * and Rº , Forms a 5-member linking group.
[0102] [0102] JEmM another modality, s is 1, each of Rº and Rº is independently -CH72-, and C is a -C2-C1- substituted alkyl group or is a -C2-C10- alkyl group, -C2-C10- alkyl group, - unsubstituted -C2-C10-, -C1-Ca4-O-C1-alkyl-Ca- or -Cyl-C1-Ca-NRº-C1-C4- alkyl, said substituted -C2-C1- alkyl group being replaced with 1 to 4 substituents, each one independently selected from halogen, hydroxy, -OP (O) (OH) 2, -OP (O) (RIR!) 2, amino,
[0103] [0103] In another modality, s is 1, each of Rº and Rº is independently -CH2-, and C is a substituted -C2-Csg- alkyl group or is a -C2-Cg-, -C2-Cg-, alkyl group, -C2-Cg-, -C1-C2-O-alkylC1-C2- or -C1-C2-NRº -C1-C2- alkyl-unsubstituted, said substituted -C2-Cs-alkyl group being replaced with 1 to 2 substituents, each one independently selected from halogen, hydroxy, -OP (O) (OH) 2, -OP (O) (RIR! ") 2, amino, (C1-Ca alkyl) amino-, (C1-Ca alkyl) (C1-Ca alkyl) ) amino-, halo (C1-C4 alkyl), halo (C1-C4 alkoxy) - and C1-Ca- alkoxy.
[0104] [0104] In another modality, s is 1, each of Rº and Rº is independently -CH> -, and C is a substituted -C2alkyl-Ce- group or is a -C2alkyl-Cs-, -alkenylC2-Cs- group , unsubstituted -C2-Ce-, -C1-C2-O-alkylC1-C2 - or -C1-C2-NRº -C1-C2-alkyl, the said -C2-Ce- substituted group being substituted with 1 to 2 substituents , each independently selected from halogen, hydroxy, -OP (O) (OH) 2, -OP (O) (RIR! ") 2, amino, (C1-Ca alkyl) amino-, (C1-Ca alkyl) (C1 alkyl) -Ca) amino-, halo (C1-Ca alkyl), halo (C1-Ca4 alkoxy) - and alkoxy-Ca-.
[0106] [0106] In selected modalities, s is 1, each of Rºº and Rº is independently -CH2-, and C is -CH2CH2CH2-, where C, together with Rº and Rº , forms a group -CH2CH2CH2CH2CH> 2-.
[0107] [0107] In a modality of the compounds of the present invention, each of Rº and Rº is independently selected from H, halogen, halo (C1-Cs alkyl), halo (C1-Cs alkoxy) -, hydroxy, -OP (O) (OH ) 2, -OP (O) (RIR!) 2, -NH>,
[0108] [0108] In one modality, each of Rº and R $ is H.
[0109] [0109] In a modality, each of Rº and Rº is independently selected from the group consisting of -CO-N (Ri) (R5), and each of Rº and R 'is independently H or C1-C3 alkyl.
[0110] [0110] In one mode, R and Rº are CONH>.
[0111] [0111] In an embodiment of the compounds of the present invention, R'º is optionally substituted C1-Caalkyl, wherein said optionally substituted C1-Caalkyl is optionally substituted with a substituent selected from -ORº, -NRºRº, -CO2Rº, -CONRºR $ º, -SO2NRºRº and -OCONRºRº,
[0112] [0112] In an embodiment of the compounds of the present invention, R'º is H, halogen, or C1-Ca alkyl.
[0113] [0113] In one embodiment of the compounds of the present invention, each of R'º and R '' is independently H, cyclopropyl or C1-Ca alkyl.
[0114] [0114] In an embodiment of the compounds of the present invention, R '%, R'5, R'6 and R'7 are independently H or C1-Ca alkyl.
[0115] [0115] In an embodiment of the present invention, R'º is H.
[0117] [0117] In another modality, each of R'1º, Rº and RU is independently C1-C3 alkyl, more specifically methyl or ethyl. In a selected modality, R "º is ethyl.
[0118] [0118] In another modality, each of R '* and R'7 is methyl.
[0119] [0119] In a modality of the compounds of the present invention, Rº is H, -Rº, -CORº, -CO2H, -CO2Rº, -SORº, -SO2Rº, -CONH2, -CONRºRº, -SO2NRºRº, -SO2NRºRº,
[0120] [0120] In another embodiment, Rº is H, C1-alkyl, -CO (C1-alkyl), -CO (C1-alkyl) -OH, - -CO (C1-alkyl) -O- (C1-alkyl), - -CO (C1-Ca) alkyl -NH>, -CO (C1-Ca alkyl) -NH (C1-Ca alkyl) or -CO (C1-Ca alkyl) -N (C1-Ca alkyl) (C1-Ca alkyl).
[0121] [0121] In one embodiment of the compounds of the present invention, each of RX and RJ is independently methyl or ethyl. In an embodiment of the compounds of the present invention, R * and Ry are both methyl. In one embodiment of the compounds of the present invention, in the compounds of Formula (1), one of Re RU is methyl and the other is H.
[0122] [0122] One embodiment of the present invention relates to a compound of Formula (1), in which: q + r + s = 10u2; q is 0, and Rº and Rº are independently selected from H, -OCH2CH2CH20H and -OCH3; or q is 1, each of Rºº and RM is -O-, and A is -CH2CH2CH> 2-; D O, and each of Rº and R8 is H; or r is 1, each of Rº and RP is independently -CH2-, and B is -CH = CH-, -CH2CH2-, -CH (OH) CH (OH) - or -CH2aN (CH3) CH> 2-; s is 0, Rºº is methyl, and Rº it is ethyl; or s is 1, each of Rº and Rº is independently -CH2-, and C is -CH2CH2CH2-; each of R and Rº is -CONH;>; each of Rº and Rº is H; D ethyl; R'º is methyl; Rs is H; R "'is methyl, or a salt thereof, in particular a pharmaceutically acceptable salt thereof.
[0123] [0123] In an embodiment of the compounds of the present invention: R14, R15, Rº and R'7 are independently methyl or ethyl; one for Rº 'and Rº is H and the other for Rº * and RM is (optionally substituted C1-Ca) Oxy-,
[0124] [0124] In one embodiment of the present invention, the compound of the invention is of Formula (I-B '):
[0125] [0125] In one embodiment of the present invention, the compound of the invention is of Formula (I-b '): o R o Rs ú OZ Ro [e] Re' N Re 1007 bh "| JA Ô RR O Ri Formula (1 -b ”) where B is -halo (C1-Cs5alkyl), unsubstituted -C1-Csalkyl or unsubstituted -C2-C5- alkenyl;
[0126] [0126] In one embodiment, the compound is of Formula (I-B '), or (I-D'), where each of R and R is independently H, halogen, (C1-Cs alkyl) optionally substituted or ( optionally substituted C + -Cs alkyl), and the optionally substituted C1-Cs alkyl (optionally substituted C1-Cs alkyl) or optionally substituted (C1-Ce) alkyl is optionally substituted with 1 to 4 substituents, each independently selected from the compound group with hydroxyl, -O- P (O) (OH) 2, -OP (OX (RIR ") 2, -N (RºUR)), C1-Ca alvoxy, phenyl and 5- to 6-membered optionally substituted heterocycloalkyl containing at least one nitrogen or oxygen as a ring member, each Rº is independently selected from H, (C1-alkylCa), - (C1-alkyl) -NH2 or - (CC-alkyl) alkoxy-Ca and each RÍ is independently H or (C1alkyl) -C4).
[0127] [0127] In one embodiment, the compound is of Formula (1I-B ') or (I-b'), where each of Rº and Rº is independently H, halogen, (C1-Cs alkyl) optionally substituted or (C + alkyl) -Ces) 9oxy optionally substituted, and the C1-Cs alkyl of said (optionally substituted C1-Cs alkyl) or (optionally substituted C1-C6 alkyl) is optionally substituted with 1 to 4 substituents, each independently selected from the group consisting of hydroxyl, - N (RºUR)), C1-Ca alkoxy, phenyl and 5- to 6-membered optionally substituted heterocycloalkyl containing at least one nitrogen or oxygen as a ring member, and each of Rº and R 'is independently H or (C1alkyl) -Here).
[0128] [0128] In one embodiment, is the compound of Formula (1I-B ') or (I-b'), in which at least one of RM or Rº is independently H, halogen, optionally substituted (C1-Cs alkyl) or (optionally substituted C: -Ce alkyl) 9O, and optionally substituted C1-Cs (C1-Cs alkyl) or optionally (C1-Ce) alkyl substituted is optionally substituted with 1 to 4 substituents, each independently selected from -N (Rº) (R ”), tetrahydropyran, pyrrolidinyl, piperazinyl, piperidyl and morpholinyl, each Rº is independently selected from H, (C1-C4 alkyl), - (C 1 -C alkyl) -NH> 2 or - (C 1 -C alkyl) C 1 -C alkoxy and each R 'is independently H or (C 1 -C 4 alkyl).
[0129] [0129] In one embodiment, is the compound of Formula (1I-B ') or (I-b'), in which at least one of RM or Rº 'is independently H, halogen, optionally substituted (C1-Cs alkyl) or optionally substituted (C + -Cs alkyl), and the optionally substituted C1-Cs (C1-Cs alkyl) or optionally (C1-Ce) alkyl substituted is optionally substituted with 1 to 4 substituents, each independently selected from -N (Rº) (R '), tetrahydropyran, pyrrolidinyl, piperazinyl, piperidyl or morpholinyl, and each of Rº and R' is independently H or (C1-alkyl) C4).
[0130] [0130] In one embodiment, the compounds are of Formula (I-B ') or (I-b'), where each of R * and RY is independently methyl or ethyl. In another embodiment, the compounds are of Formula (I-B ') or (I-b'), where R * and Ry are both methyl In another embodiment, the compounds are of Formula (I-B ') or (I -b '), where one of Re RY is methyl and the other is H.
[0131] [0131] In one embodiment, the compound is of Formula (1I-B ') or (I-b'), where B is unsubstituted -C 1 -Cs alkyl or unsubstituted -C 2 -Cs 5 alkenyl; each of Rº and RM is independently H, halogen, optionally substituted (C1-Cs alkyl) or (optionally substituted C1-C) alkyl, in which the C1-Cs alkyl of said (C1-Cs alkyl) optionally substituted or (C1-Ce alkyl) ) Optionally unsubstituted oxide is optionally substituted with 1 to 2 substituents, each independently selected from the group consisting of hydroxyl, C1-Ca alkoxy, -N (Rº) (R), -COX (R5), unsubstituted phenyl and heterocycloalkyl 5-6 members not replaced,
[0132] [0132] In one embodiment, the compound is of Formula (I-b '), where B is unsubstituted -C2-C5- alkenyl; each of R * was! is independently H, (optionally substituted C1-Cs) or (optionally substituted C1-C1-alkyl), wherein the optionally substituted C1-Cs (C1-Cs) alkyl, or optionally substituted (C1-Cs) Oxy is optionally substituted substituted with 1 substituent, each independently selected from the group consisting of hydroxyl, C1-Ca alkoxy, 5- to 6-membered heterocycloalkyl unsubstituted, R * º is C1-Ca alkyl; Rº is C1-Ca alkyl; R '* is C1-Ca alkyl; and R * 7 is C1-Ca alkyl; at least one of R * or RY is independently C1-C> 2 alkyl and the other is H, or both R * and RY are independently C1-C2 alkyl; or a tautomer of it,
[0133] [0133] In one embodiment, the compound is of Formula (I-b '), in which B is unsubstituted ethylene; each of Rº and Rº 'is independently optionally substituted H or (C: -Cs) alkyl, wherein the optionally substituted C1-Cs of said (C1-C6 alkyl) is optionally substituted with a substituent selected from hydroxyl or morpholinyl not replaced; R * º * is methyl or ethyl; RO it is methyl or ethyl; R '* is methyl or ethyl; and R * 7 is methyl or ethyl; at least one of R * or RY is independently C1-C> 2 alkyl and the other is H, or both R * and RY are independently C1-C2 alkyl; or a tautomer thereof, or a salt thereof.
[0134] [0134] In one embodiment, the compound is of Formula (1-1), re by À
[0136] [0136] In one embodiment, the compound of the invention has the Formula (I-bc),
[0137] [0137] In M an embodiment, the compound is of Formula (I-bc), where each of R * and Rº is independently H, halogen, optionally substituted (C1-Csalkyl) or (C: alkyl-Ce) optionally substituted, and the C: + - Cs alkyl of said optionally substituted (C1-Cs alkyl) or optionally substituted (C1-Ce alkyl) is optionally substituted with 1 to 4 substituents, each independently selected from the group consisting of hydroxyl, -O - Optionally substituted P (O) (OH) 2, -OP (OX (RIR! ") 2, -N (Rº) (R5), C1-Ca alkoxy, phenyl and heterocycloalkyl containing at least one nitrogen or oxygen as a ring member, each R ° is independently selected from H, C1-Ca alkyl, - (C1-alkyl) Ca -NH2 or - (C1-Ca alkyl) C1-Ca alkoxy, and each R1 is independently H or (C1-C4 alkyl) .
[0138] [0138] In one embodiment, the compound is of Formula (I-bc), in which at least one of Rº or Rº 'is independently H, halogen, optionally substituted (C1-Cs alkyl), or (C: -Ce alkyl) oxy - optionally substituted, and the optionally substituted C1-Cs alkyl of said (C1-Cs alkyl) or optionally substituted (C1-Ce) alkyl is optionally substituted with 1 to 4 substituents, each independently selected from -N (Rº) (R5) , tetrahydropyran, pyrrolidinyl, piperazinyl, piperidyl and morpholinyl, each Rº is independently selected from H, C1-Ca alkyl, - (C1-Ca alkyl) -NH2 or - (C1-Ca) alkoxyC1I-Ca and each R is independently H or C1- alkyl Here.
[0139] [0139] In one embodiment, the compound is of Formula | -2:
[0140] [0140] In an embodiment of the compounds of Formula (1-2), R1º, R1º, R2 and R'7 are independently methyl or ethyl.
[0141] [0141] In an embodiment of the compounds of Formula (1-2), R1º and Rº are ethyl, and R'º and R'7 are methyl.
[0142] [0142] In an embodiment of the compounds of Formula (1-2), R14, R1, R2 and R'7 are methyl.
[0143] [0143] In an embodiment of the compounds of Formula (1-2), Rºº and Rº are independently H, hydroxy or (C1-C6 alkyl) optionally substituted Oxy, where the optionally substituted C (alkyl: + - Cs) Oxy is optionally substituted with 1 to 4 substituents, each independently selected from the group consisting of hydroxy COOH and optionally substituted phenyl, wherein said optionally substituted phenyl is optionally substituted with 1 to 4 substituents, each independently selected from the group consisting of (C 1 -C 1 -alkyl) Oxy-.
[0144] [0144] In an embodiment of the compounds of Formula (1-2), one of Rºº and RM is He the other of Rºº and RM is hydroxy or optionally substituted oxy (C1-Cs) alkyl, in which the optionally substituted oxy (C: + - Cs) alkyl is optionally substituted with 1 to 4 substituents, each independently selected from the group consisting of hydroxy COOH and optionally substituted phenyl, wherein said optionally substituted phenyl is optionally substituted with 1 to 4 substituents, each independently selected from the group consisting of (C 1 -C 1 -alkyl) OXi-.
[0145] [0145] In a modality of the compounds of Formula (1-2), one of Rºº and RM is He the other of Rºº and Rº is hydroxy or (optionally substituted C1-Ca) alkyl, in which the optionally substituted (CC-alkyl) Oxy alkyl is optionally substituted with 1 to 2 substituents, each independently selected from among the group consisting of hydroxy and optionally substituted phenyl,
[0146] [0146] In an embodiment of the compounds of Formula (1-2), RYº and Rºº are both H.
[0147] [0147] In a modality, the compounds are of Formula (| -2), where at least one of R ** and Rº is not H.
[0148] [0148] In an embodiment of the compounds of Formula (1-2), each of Rº and R * is independently optionally substituted (C1-Ca) alkyl, where the optionally substituted (C1-Ca) alkyl is optionally substituted with 1 to 2 hydroxy substituents.
[0149] [0149] In an embodiment of the compounds of Formula (1-2), each of R and Ró is independently selected from the group consisting of -CO-N (Rº) (R), and each of Rº and R * is independently H or C1-C3 alkyl.
[0150] [0150] In an embodiment of the compounds of Formula (| -2), Rº and Rº are - CO-NH>.
[0152] [0152] In an embodiment of the compounds of Formula (1-2), B is -CH2-CH2- substituted or -CH = CH- substituted, where -CH2-CH> 2- substituted or -CH = CH- substituted is substituted with 1 to 4 substituents, each independently selected from the group consisting of halogen and C1 + 4 alkyl.
[0153] [0153] In an embodiment of the compounds of Formula (1-2), B is -CH2-CH2- substituted or -CH = CH- substituted, where -CH2-CH2- substituted or -CH = CH- substituted with 1 to 4 substituents, each independently selected from the group consisting of fluorine and C1-2alkyl.
[0154] [0154] In an embodiment of the compounds of Formula (1-2), B is -CH2-CH2- substituted or -CH = CH- substituted, where -CH2-CH> 2- substituted or -CH = CH- substituted is replaced with 1 to 4 fluorine substituents.
[0155] [0155] In an embodiment of the compounds of Formula (1-2), B is -CH2-CH> 2- substituted or -CH = CH- substituted, where -CH2-CH> 2- substituted or -CH = CH - substituted is substituted with 1 to 4 substituents, each independently of C1-2 alkyl.
[0156] [0156] In an embodiment of the compounds of Formula (1-2), B is -CH2-CH2- substituted or -CH = CH- substituted, where -CH2-CH2- substituted or -CH = CH- substituted is substituted with 1 to 4 hydroxy substituents.
[0157] [0157] In an embodiment of the compounds of Formula (1-2), B is -CH2-CH2- substituted with 1 to 2 hydroxy substituents.
[0158] [0158] In one embodiment, the compounds are of Formula (1-2), where each of R * and RY is independently methyl or ethyl. In another embodiment, the compounds are of Formula (1-2), in which RX and RY are both methyl. In another embodiment, the compounds are of Formula (1-2), where one of Re RU is methyl and the other is H.
[0159] [0159] In one embodiment, the compounds are of Formula (1-2), where R14, R'5, Rº and R'7 are independently methyl or ethyl;
[0160] [0160] In one embodiment, the compounds are of Formula (1-2), in which R14, R15, R and R17 are independently methyl or ethyl; one of Rºº and Rºº is H and the other of Rº * and RM is optionally substituted (C1-Ca) -oxy, wherein the optionally substituted (C-alkyl: + - Ca) -oxy is optionally substituted with 1 to 2 hydroxy substituents; R and Rº are both -CO-NH ;; and B is -CH2-CH2- substituted or -CH = CH- substituted, where -CH2-CH> 2- substituted or -CH = CH- substituted is substituted with 1 to 4 substituents, each independently selected from the group composed of hydroxy and C1-2alkyl; and at least one of R * or RY is independently C1-Ca alkyl and the other is H, or both R * and RY are independently C1-Ca alkyl.
[0161] [0161] In one embodiment, the compound is Formula 1-3: And what R & PIÁIO Ç RA B AND LO SFA IA
[0162] [0162] In an embodiment of the compounds of Formula (1-3), R1º, R1º, R2 and R'7 are independently methyl or ethyl.
[0163] [0163] In an embodiment of the compounds of Formula (1-3), R'º and Rº are ethyl, and R'º and R'7 are methyl.
[0164] [0164] In an embodiment of the compounds of Formula (1-3), RYº and Rº are independently H, hydroxy or optionally substituted (C1-C6) alkyl, where the optionally substituted (C: alkyl: + - Cs) alkyl is optionally substituted with 1 to 4 substituents, each independently selected from the group consisting of hydroxy COOH and optionally substituted phenyl, wherein said optionally substituted phenyl is optionally substituted with 1 to 4 substituents, each independently selected from the group consisting of (C1-Ca) -oxy-alkyl.
[0165] [0165] In an embodiment of the compounds of Formula (1-3), one of Rºº and RM is He the other of Rºº and RM is hydroxy or (optionally substituted C1-Cs alkyl),
[0166] [0166] In an embodiment of the compounds of Formula (1-3), one of Rº! was is He the other of Rºº and Rº is hydroxy or (optionally substituted C1-Ca) alkyl, in which the optionally substituted (CC-alkyl) Oxy alkyl is optionally substituted with 1 to 2 substituents, each independently selected from among the group consisting of hydroxy and optionally substituted phenyl, wherein said optionally substituted phenyl is optionally substituted with 1 to 2 substituents, each independently selected from the group consisting of (C1-Ca) -oxy-alkyl.
[0167] [0167] In an embodiment of the compounds of Formula (1-3), each of RM! and Rº is independently optionally substituted (C1-Ca) alkyloxy, in which the optionally substituted (C1-Ca) alkyloxy is optionally substituted with 1 to 2 hydroxy substituents.
[0168] [0168] In an embodiment of the compounds of Formula (1-3), Rº and Rº are - CO-NH>.
[0169] [0169] In an embodiment of the compounds of Formula (1-3), B is -CH2-CH2- substituted or -CH = CH- substituted, where -CH2-CH> 2- substituted or -CH = CH- substituted is substituted with 1 to 4 substituents, each independently selected from the group consisting of halogen and C1 + 4 alkyl.
[0170] [0170] In an embodiment of the compounds of Formula (1-3), B is -CH2-CH2- substituted or -CH = CH- substituted, where -CH2-CH2- substituted or -CH = CH- substituted with 1 to 4 substituents, each independently selected from the group consisting of fluorine and C1-2alkyl.
[0171] [0171] In an embodiment of the compounds of Formula (1-3), B is -CH2-CH2- substituted or -CH = CH- substituted, where -CH2-CH> 2- substituted or -CH = CH- substituted is replaced with 1 to 4 fluorine substituents.
[0172] [0172] In an embodiment of the compounds of Formula (1-3), B is -CH2-CH> 2- substituted or -CH = CH- substituted, where -CH2-CH> 2- substituted or -CH = CH - substituted is substituted with 1 to 4 substituents, each independently of C1-2 alkyl.
[0173] [0173] In an embodiment of the compounds of Formula (1-3), B is -CH2-CH2- substituted or -CH = CH- substituted, where -CH2-CH2- substituted or -CH = CH- substituted with 1 to 4 hydroxy substituents.
[0174] [0174] In an embodiment of the compounds of Formula (1-3), B is -CH2-CH2- substituted with 1 to 2 hydroxy substituents.
[0175] [0175] JEM a modality, the compounds are of Formula (1-3), in which each of R * and RY is independently methyl or ethyl. In another embodiment, the compounds are of Formula (1-3), in which RX and RY are both methyl. In another embodiment, the compounds are of Formula (1-3), where one of Re RU is methyl and the other is H.
[0176] [0176] In one embodiment, the compounds are of Formula (1-3), in which R14, R'5, Rº and R'7 are independently methyl or ethyl;
[0177] [0177] In one embodiment, the compounds are of Formula (1-3), in which R14, R15, R and R17 are independently methyl or ethyl; one of Rºº and Rºº is H and the other of Rº * and RM is optionally substituted (C1-Ca) -oxy, wherein the optionally substituted (C-alkyl: + - Ca) -oxy is optionally substituted with 1 to 2 hydroxy substituents; R and Rº are both -CO-NH ;; and B is -CH2-CH2- substituted or -CH = CH- substituted, where -CH2-CH> 2- substituted or -CH = CH- substituted is substituted with 1 to 4 substituents, each independently selected from the group composed of hydroxy and C1-2alkyl; and at least one of RX or RY is independently C1-C4 alkyl and the other is H, or both R * and RY are independently C1-Ca alkyl.
[0178] [0178] Representative compounds of the present invention include the compounds of the Examples. It will be appreciated that the present invention encompasses compounds of Formula (1) as a free base and as salts thereof, for example, as a pharmaceutically acceptable salt thereof. In one embodiment, the invention relates to compounds of Formula (1) in the form of a free base. In another embodiment, the invention relates to compounds of Formula (II) in the form of a salt, in particular a pharmaceutically acceptable salt. It will also be appreciated that, in one embodiment, the invention relates to compounds of the Examples in the form of a free base. In another embodiment, the invention relates to compounds of the Examples in the form of a salt, in particular a pharmaceutically acceptable salt.
[0179] [0179] Specific embodiments of the compounds of the present invention include: (E) -1 - ((E) -4 - ((E) -5-carbamoyl-2 - ((1-ethyl-3-methyl-1 H-pyrazole -5-carbonyl) imino) -3-methyl-2,3-dihydro-1H-benzo [d] imidazo | -1-i1) -2,3-dimethylbut-2-en-1-i1) -2- ( (1-ethyl-3-methyl-1H-pyrazol-S-carbonyl) imino) -7-hydroxy-3-methyl-2,3-dihydro-1H-benzo [d] imidazo! -5-carboxamide, (E) -1 - (((E) -4 - ((E) -5-carbamoyl-2 - (((1-ethyl-3-methyl-1 H-pyrazol-5-carbonyl) imino) -3-methyl-2,3 -dihydro-1H-benzo [d] imidazo | -1-i1) -2,3-dimethylbut-2-en-1-i1) -2 - ((1-ethyl-3-methyl-1H-pyrazole-5- carbonyl) imino) -7- (3-hydroxypropoxy) -3-methyl-2,3-dihydro-1H-benzo [d] imidazole-5-carboxamide, (2E, 2'E) -1,1 '- (pentane -1,5-diyl) bis (2 - ((1-ethyl-3-methyl-1H-pyrazol-5-carbonyl) imino) -3-methyl-2,3-dihydro-1H-benzo [d] imidazole- 5-carboxamide, (E) -1 - ((E) -4 - ((E) -5-carbamoyl-2 - ((1-ethyl-3-methyl-1 H-pyrazol-5-carbonyl) imino) - 3-methyl-2,3-dihydro-1H-benzo [d] imidazo | -1-i1) -2,3-dimethylbut-2-en-1-11) -2 - ((1-ethyl-3-methyl -
[0180] [0180] In one embodiment, the compounds of the formulas described above, for example, the compounds of Formula (1), Formula (1-2) or Formula (1-3), are (E) -1- ((2R, 3R) -4 - ((E) -5-carbamoyl-2 - ((1-ethyl-3-methyl-1H-pyrazol-S-carbonyl) imino) -7- (3-hydroxypropoxy) -3-methyl-2 , 3-dihydro-1H-benzo [d] imidazo | -1-i1) -2,3-dihydroxybutyl) -2 - ((1-ethyl-3-methyl-1H-pyrazol-S-carbonyl) imino) -7 -methoxy-3-methyl-2,3-dihydro-1H-benzo [d] imidazole-5-carboxamide with the structure: À DR Do “oo
[0181] [0181] In one embodiment, the compounds of the formulas described above, for example, the compounds of Formula (1), Formula (1I-2) or Formula (1-3), are (E) -1- ((28, 3S) -4 - ((E) -5-carbamoyl-2 - ((1-ethyl-3-methyl-1 H-pyrazol-5-carbonyl) imino) -7- (3-hydroxypropoxy) -3-methyl- 2,3-dihydro-1H-benzo [d] imidazole | -1-i1) -2,3-dihydroxybutyl) -2 - ((1-ethyl-3-methyl-1H-pyrazol-5-carbonyl) imino) - 7-methoxy-3-methyl-2,3-dihydro-1H-benzo [d] imidazole-5-carboxamide with the structure: To DR bm oo S ro ”ko A, NH to W / T or a tautomer thereof ; or a salt thereof, in particular a pharmaceutically acceptable salt thereof.
[0182] [0182] In one embodiment, the compounds of the formulas described above, for example, the compounds of Formula (1), Formula (1-2) or Formula (1-3), are not the following compounds: (E) - 1 - (((2R, 3R) -4 - ((E) -5-carbamoyl-2 - (((1-ethyl-3-methyl-1H-pyrazol-5-carbonyl) imino) -7- (3-hydroxypropoxy) -3-methyl-2,3-dihydro-1H-benzo [d] imidazo | -1-11) -2,3-dihydroxybutyl) -2 - ((1-ethyl-3-methyl-1H-pyrazole-5- carbonyl) imino) -7-methoxy-3-methyl-2,3-dihydro-1H-benzo [d] imidazole-5-carboxamide with the structure:
[0183] [0183] In one embodiment, the compounds of the formulas described above, for example, the compounds of Formula (1), Formula (1-2) or Formula (1I-3), are not the following compounds: (E) - 1 - (((2S, 3S) -4 - ((E) -5-carbamoyl-2 - (((1-ethyl-3-methyl-1H-pyrazol-5-carbonylN) imino) -7- (3-hydroxypropoxy) -3-methyl-2,3-dihydro-1H-benzo [d] imidazo | -1-11) -2,3-dihydroxybutyl) -2 - ((1-ethyl-3-methyl-1H-pyrazole-5- carbonyl) imino) -7-methoxy-3-methyl-2,3-dihydro-1H-benzo [d] imidazole | -5-carboxamide with the structure: Í DR Ds o Ss ro ”kt O o or a tautomer thereof ; or a salt thereof, in particular a pharmaceutically acceptable salt thereof.
[0184] [0184] The compounds of the present invention may contain one or more asymmetric centers (also called chiral centers), such as a chiral carbon, or an -SO-chiral group. The compounds of the present invention the present invention containing one or more chiral centers can be present as racemic mixtures, as diastereomeric mixtures, as enantiomerically enriched mixtures, = as - diastereomerically enriched mixtures = or as individual enantiomeric or diastereomerically pure stereoisomers.
[0185] [0185] The stereochemistry of the chiral center present in compounds of the present invention is represented in general in the names of the compounds and / or in the chemical structures illustrated in this document. When the stereochemistry of a chiral center present in a compound of the present invention, or in any chemical structure illustrated in this document, is not specified, the structure is intended to encompass any stereoisomer and all mixtures thereof. Therefore, the present invention encompasses all isomers of the compounds of Formula (Il), and salts thereof, either as isolated individual isomers, as substantially free from the other isomer (i.e., pure), or in the form of mixtures (i.e. , racemates and racemic mixtures). An isolated individual isomer, such as substantially free of the other isomer (i.e., pure), can be isolated in such a way that less than 10%, in particular less than about 1%, for example, less than about 0.1 % of the other isomer, if present.
[0186] [0186] Individual stereoisomers of a compound of the present invention can be resolved (or mixtures of stereoisomers can be enriched) using methods known to those skilled in the art. For example, this resolution can be achieved (1) by the formation of salts, complexes or other diastereoisomeric derivatives; (2) by the selective reaction with a specific reagent to the stereoisomer, for example, by oxidation or enzymatic reduction; or (3) by gas-liquid chromatography or liquid chromatography in a chiral environment, for example, on a chiral support such as silica with a bound chiral binder or in the presence of a chiral solvent. It will be appreciated that, when the desired stereoisomer is converted into another chemical entity by one of the separation procedures described above, a new step will be necessary to release the desired shape. Alternatively, specific stereoisomers can be synthesized by asymmetric synthesis using optically active reagents, substrates, catalysts or solvents, or by converting one enantiomer into another by asymmetric transformation.
[0187] [0187] The present invention also includes several deuterated forms of the compounds thereof. Each available hydrogen atom attached to a carbon atom can be replaced independently by a deuterium atom. Those skilled in the art will also know how to synthesize deuterated forms of the compounds of the present invention. For example, a-deuterated α-amino acids are available in the marketplace or can be prepared by conventional techniques (see, for example: Elemes, Y. and Ragnarsson, UJ Chem. Soc., Perkin Trans. 1, 1996, 6, 537-40). The use of these compounds can allow the preparation of compounds in which the hydrogen atom in a chiral center is replaced by a deuterium atom. Other deuterated starting materials available in the marketplace can be used in the preparation of deuterated analogs of the compounds of the present invention (see, for example: amine methyl available from Aldrich Chemical Co., Milwaukee, WI), or can be synthesized using conventional techniques employing deuterated reagents (for example, reducing the use of lithium and aluminum deuteride or sodium borodeuteride or by metal-halogen exchange followed by tempering with D2O or methanol-d3).
[0188] [0188] Pharmaceutically suitable salts of the compounds of Formula (1) can include acid addition salts or base addition salts. For examinations of pharmaceutically suitable salts, see Berge et al., J. Pharm. Sci., 66: 1-19, (1977) and P. H. Stahl and C. G. Wermuth, Eds., Handbook of Pharmaceutical Salts: Properties, Selection and Use, Weinheim / Zürich: Wiley-VCH / VHCA (2002).
[0189] [0189] Salts of the compounds of Formula (1) containing a basic amine or other basic functional group can be prepared by any suitable method known in the art, such as treatment of the free base with a suitable inorganic or organic acid. Examples of pharmaceutically acceptable salts formed in this way include acetate, adipate, ascorbate, aspartate, benzenesulfonate, benzoate, camphorate, camphor-sulfonate (cansilate), caprate (decanoate), caproate (hexanoate), caprylate (octanoate), carbonate, bicarbonate, cinamate , citrate, cyclamate, dodecyl sulfate (stolate), ethane-1,2-disulfonate (edisylate), ethanesulfonate (esilate), format, fumarate (hemifumarate etc.), galactarate (mucate), gentisate (2,5-dihydroxybenzoate), glycoheptonate (glyceptate), gluconate, glucuronate, glutamate, glutarate, glycerophosphorate, glycolate, hypurate, hydrobromide, hydrochloride (dihydrochloride etc.), iodrate, isobutyrate, lactate, lactobionate, laurate, maleate, malate, malonate, methanate, mandelate, mandelate, mandelaate naphthalene-1,5-disulfonate (napadisylate), naphthalene-sulfonate (napsylate), nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, phosphate (diphosphate etc.), propionate, pyroglutamate, salicylate, sebacate, stearate, succate inate, sulfate, tartrate, thiocyanate, p-toluenesulfonate (tosylate), undecylenate, 1-hydroxy-2-naphthoate, 2,2-dichloroacetate, 2-hydroxyethanesulfonate (isethionate), 2-oxoglutarate, 4-acetamidobenzoate and 4-aminosalicate.
[0190] [0190] Salts of the disclosed compounds containing a carboxylic acid or other acid functional group can be prepared by reaction with a suitable base. This pharmaceutically acceptable salt can be obtained with a base that produces a pharmaceutically acceptable cation, which includes alkali metal salts (especially sodium and potassium), alkaline earth metal salts (especially calcium and magnesium),
[0191] [0191] The invention includes within that scope all possible stoichiometric and non-stoichiometric forms of the salts (e.g., hydrobromide, dibromhydrate, fumarate, hemifumarate etc.) of the compounds of Formula (1).
[0192] [0192] When a disclosed compound or its salt is named or represented by its structure, it must be borne in mind that the compound or salt, including solvates (in particular, hydrates) of it, may exist in crystalline forms, in non-crystalline forms crystalline or a mixture of these. The compound or salt, or solvates (in particular, hydrates) thereof, may also exhibit polymorphism (that is, the ability to occur in different crystalline forms). These different crystalline forms are typically known as "polymorphs". It should be borne in mind that the present invention includes all polymorphs of any compound thereof, for example, all polymorphic forms of any compound named or represented by its structure in this document, including any salts and / or solvates (in particular, hydrates).
[0193] [0193] Polymorphs have the same chemical composition but differ in terms of coating, geometric arrangement and other descriptive properties of the crystalline solid state. Polymorphs, therefore, can have different physical properties, such as shape, density, hardness, deformability, stability and dissolution properties. Polymorphs typically exhibit different melting points, IR spectra and powder X-ray diffraction patterns, which can be used for identification. It will be appreciated that different polymorphs can be produced, for example, by changing or adjusting the conditions used in the crystallization / recrystallization of the compound. Polymorphic forms can be characterized and differentiated using several conventional analytical techniques, including, among others, powder X-ray diffraction patterns (XRPD), infrared (IR) spectra, Raman spectra, differential scanning calorimetry (DSC), thermogravimetric analysis ( TGA) and nuclear magnetic resonance in the solid state (sSSNMR).
[0194] [0194] Those skilled in the art will appreciate that pharmaceutically acceptable solvates (in particular, hydrates) of a compound of Formula (1), including pharmaceutically acceptable solvates of a pharmaceutically acceptable salt of a compound of Formula (1), may form when solvent molecules are incorporated into the crystalline lattice during crystallization. Solvates can involve non-aqueous solvents, such as ethanol, or they can involve water as the solvent that is incorporated into the crystalline lattice. Solvates in which water is the solvent that is incorporated into the crystalline lattice are typically called "hydrates".
[0195] [0195] The present invention includes within its scope all possible stoichiometric and non-stoichiometric salt and / or hydrate forms.
[0196] [0196] Salts and solvates (e.g., hydrates and hydrates of salts) of the compounds of the invention that are suitable for use in medicine are those in which the counterion or associated solvent is pharmaceutically acceptable. Salts with non-pharmaceutically acceptable counterions are within the scope of the present invention, for example, for use as intermediates in the preparation of other compounds of the invention.
[0197] [0197] Typically, a pharmaceutically acceptable salt! can be readily prepared using a desired acid or base, as appropriate. The resulting salt can crystallize or precipitate from the solution, or be formed by grinding, and can be recovered by filtration or by evaporation of the solvent.
[0198] [0198] As the compounds of the present invention are intended for use in pharmaceutical compositions, it will readily be understood that each of them is preferably supplied in substantially pure form, for example at least 60% pure, more suitably at least 75 % pure and preferably at least 85%, in particular at least 98% pure (percentages are given on a weight by weight basis). Impure preparations of the compounds can be used to prepare the purest forms used in pharmaceutical compositions.
[0199] [0199] The invention encompasses all prodrugs of the compounds of the present invention, which, upon administration to the patient, are capable of providing (directly or indirectly) a compound of the present invention, or a metabolite or active residue thereof. These derivatives are identifiable by those skilled in the art, without undue experimentation. However, reference is made to the teachings of Burger's Medicinal Chemistry and Drug Discovery, 5th Edition, Vol. 1: Principles and Practice, which is incorporated into this document by reference with respect to the teaching of these derivatives.
[0200] [0200] It should also be borne in mind that the present invention includes within its scope all tautomeric or isomeric forms of any free base form of the compounds of the present invention, as well as possible stoichiometric and non-stoichiometric salt forms. The compounds of the invention are useful in the treatment or prevention of diseases and disorders in which STING modulation is beneficial. These STING-mediated diseases or disorders include inflammation, allergic and autoimmune diseases, infectious diseases, cancer, precancerous syndromes, metabolic diseases and cardiovascular diseases. The compounds of the invention are also useful as an immunogenic composition or vaccine adjuvant. Therefore, the present invention relates to a method for modulating the STING which comprises placing a cell in contact with a compound of the invention.
[0201] [0201] One aspect of the invention proposes methods for the treatment or prevention of STING-mediated diseases and disorders in which agonizing STING is beneficial. Examples of diseases / disorders include, but are not limited to, cancer, infectious disease (for example, HIV, HBV, HCV, HPV and influenza), vaccine adjuvant.
[0202] [0202] One aspect of the invention proposes methods for the treatment or prevention of STING-mediated diseases and disorders in which inhibiting STING is beneficial. Examples of diseases / disorders include, but are not limited to, systemic lupus erythematosus (SLE), cutaneous lupus, lupus nephritis, psoriasis, diabetes mellitus, including insulin-dependent diabetes mellitus (IDDM), obesity-related insulin resistance and non-alcoholic fatty liver disease (NAFLD), dermatomyositis, systemic sclerosis (scleroderma), and Sjogren's syndrome (SS), rheumatoid arthritis, psoriasis arthritis, STING-associated childhood vasculitis (SAVI), Aicardi-Goutiêres syndrome (AGS), perioperous lupus, mixed connective tissue disease, Alzheimer's disease-related neuroinflammation, amyotrophic lateral sclerosis (ALS), Parkison's syndrome, Huntington's disease, and multiple sclerosis, as well as heart inflammation associated with myocardial infarction.
[0203] [0203] In one embodiment, the present invention proposes a compound of the invention for use in a therapy. The present invention also proposes a compound of Formula, or a pharmaceutically acceptable salt thereof for use in a therapy. The present invention particularly proposes a compound of Formula (1) or a pharmaceutically acceptable salt thereof, for use in the treatment against a STING-mediated disease or disorder.
[0204] [0204] The present invention also proposes a compound of Formula (1), or a pharmaceutically acceptable salt thereof, for use as a vaccine adjuvant. Therefore, an immunogenic or adjuvant vaccine composition comprising a compound of Formula (II), or a pharmaceutically acceptable salt thereof is also proposed.
[0205] [0205] In another embodiment of the invention, a composition is proposed comprising a compound of Formula (Il)) or a pharmaceutically acceptable salt thereof, and one or more immunostimulating agents.
[0206] [0206] In another embodiment, the present invention proposes a compound of the invention for use in the treatment of a STING-mediated disease or disorder and / or for use as an immunogenic or adjuvant vaccine composition. In another embodiment, the present invention proposes a compound of Formula (1), or a pharmaceutically acceptable salt thereof, for use in ameliorating injury or damage to sustained organs as a result of a STING-mediated disease or disorder.
[0207] [0207] The invention also proposes the use of a compound of the invention in the manufacture of a medicament for treatment against a disease or disorder mediated by STING. The invention also proposes the use of a compound of Formula (1), or a salt thereof, in particular a pharmaceutically acceptable salt thereof, in the manufacture of a medicine for the treatment against a disease or disorder mediated by STING, for example , the diseases and disorders mentioned in this document.
[0208] [0208] The invention also proposes the use of a compound of Formula (1), or a salt thereof, in particular a pharmaceutically acceptable salt thereof, in the manufacture of a vaccine. It is also proposed to use a compound of Formula (1), or a pharmaceutically acceptable salt thereof, in the manufacture of an immunogenic composition comprising an antigen or antigenic composition for the treatment or prevention of a disease. It is further proposed to use a compound of Formula (1), or a pharmaceutically acceptable salt thereof, in the manufacture of a vaccine composition comprising an antigen or antigenic composition for the treatment or prevention of a disease.
[0209] [0209] In another embodiment, the invention relates to a method for treating a STING-mediated disease or disorder which comprises administering a therapeutically effective amount of a compound of the present invention to a human in need. In another embodiment, the invention relates to a method for treating a STING-mediated disease or disorder which comprises administering a therapeutically effective amount of a compound of Formula (1) or a salt, in particular a pharmaceutically acceptable salt thereof, to a human being who needs it.
[0210] [0210] In another embodiment, the invention relates to a method for treating or preventing a disease, the method comprising administering to a human patient suffering from, or susceptible to, a disease, an immunogenic composition comprising a antigen or antigenic composition and a compound of Formula (|), or a pharmaceutically acceptable salt thereof. In another embodiment, the invention relates to a method for treating or preventing a disease, the method comprising administering to a human patient suffering from, or susceptible to, a disease, a vaccine composition comprising an antigen or antigenic composition and a compound of Formula (1), or a pharmaceutically acceptable salt thereof.
[0211] [0211] In one embodiment, the present invention relates to a compound of Formula (|), or a pharmaceutically acceptable salt thereof, for use in the treatment of an inflammation. In another aspect, a method for treating inflammation is proposed which comprises administering to a human being in need of a therapeutically effective amount of a compound of Formula (1), or a pharmaceutically acceptable salt thereof. In another aspect, a compound of Formula (II), or a pharmaceutically acceptable salt thereof, is proposed for use in the manufacture of a medicament for the treatment of an inflammation.
[0212] [0212] In one embodiment, the present invention relates to a compound of Formula (1), or a pharmaceutically acceptable salt thereof, for use in the treatment of an allergic disease. In another aspect, a method for treating an allergic disease is proposed which comprises administering to a human being in need of a therapeutically effective amount of a compound of Formula (1), or a pharmaceutically acceptable salt thereof. In another aspect, a compound of Formula (|), or a pharmaceutically acceptable salt thereof, is proposed for use in the manufacture of a medicament for the treatment of an allergic disease. Examples of allergic diseases include allergic rhinitis, hay fever, atopic dermatitis, urticaria.
[0213] [0213] In one embodiment, the present invention relates to a compound of Formula (|), or a pharmaceutically acceptable salt thereof, for use in the treatment of an autoimmune disease. In another aspect, a method for treating an autoimmune disease is proposed which comprises administering to a human being in need of a therapeutically effective amount of a compound of Formula (1), or a pharmaceutically acceptable salt thereof. In another aspect, a compound of Formula (1), or a pharmaceutically acceptable salt thereof, is proposed for use in the manufacture of a medicament for the treatment of an autoimmune disease.
[0214] [0214] In one embodiment, the present invention relates to a compound of Formula (|), or a pharmaceutically acceptable salt thereof, for use in the treatment of an infectious disease. In another aspect, a method for treating an infectious disease is proposed which comprises administering to a human being in need of a therapeutically effective amount of a compound of Formula (1), or a pharmaceutically acceptable salt thereof. In another aspect,
[0215] [0215] In one embodiment, the present invention relates to a method for treating an HIV infection in a human by administering to him a therapeutically effective amount of a compound of Formula (l)) or a pharmaceutically acceptable salt thereof . In one embodiment, the present invention relates to a method for treating an HIV infection, in a human with the infection or at risk of contracting it, by administering to him a therapeutically effective amount of a compound of Formula (| I )) or a pharmaceutically acceptable salt thereof. In another embodiment, the present invention relates to a method for treating an AIDS infection in a human with the infection by administering to him a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof. .
[0216] [0216] In one embodiment, the present invention relates to a method for treating an HBV infection in a human by administering to him a therapeutically effective amount of a compound of Formula (|), or a pharmaceutically acceptable salt thereof . In one embodiment, the present invention relates to a method for treating an HBV infection, in a human being with the infection or at risk of contracting it, by administering to him a therapeutically effective amount of a compound of Formula (l) ) or a pharmaceutically acceptable salt thereof.
[0217] [0217] In one embodiment, the method for treating an HBV infection comprises administering a first therapeutic agent. In one embodiment, the methods comprise administering a first therapeutic agent, that is, a therapeutically effective amount of a compound of Formula (|), or a pharmaceutically acceptable salt thereof, and administering one or more second therapeutic agents. In one embodiment, the first therapeutic agent and one or more second therapeutic agents are co-administered.
[0218] [0218] In one embodiment, the first therapeutic agent and one or more second therapeutic agents are co-administered in sequence or concurrently. In one embodiment, the one or more second therapeutic agents are also a compound of Formula (1). In one embodiment, the one or more second therapeutic agents are different from a compound or composition described in this document. Examples of the one or more second therapeutic agents include, but are not limited to, an anti-inflammatory agent, a chemotherapeutic agent or an anti-infection agent. In other related embodiments, the additional therapeutic agent may be an HBV agent, an HVC agent, a chemotherapeutic agent, an antibiotic, an analgesic, a non-steroidal anti-inflammatory agent (NSAID), an antifungal agent, an antiparasitic agent, an anti-nausea agent, an anti-diarrhea agent, an immunomodulator or an immunosuppressive agent.
[0219] [0219] In one embodiment, the one or more second analgesic agents are an HBV agent. In one embodiment, the HBV agent may include, but is not limited to, interferon alfa-2b, interferon 5 alpha-2a and interferon alfacon-1 (pegylated and non-pegylated), ribavirin; an inhibitor of HBV RNA replication; an inhibitor of HBV antigen production; a therapeutic vaccine against HBV; a prophylactic vaccine against HBV; lamivudine (3TC); entecavir (ETV); tenofovir diisoproxil fumarate (TDF); telbivudine (LdT); adefovir; or a therapy with antibodies against HBV (monoclonal or polyclonal).
[0220] [0220] In one embodiment, the one or more second analgesic agents are an agent against HCV. In one embodiment, the HCV agent may include, inter alia, interferon alfa-2b, interferon alfa-2a, and interferon alfacon-1 (pegylated and non-pegylated); ribavirin; an inhibitor of HCV RNA replication
[0221] [0221] In one embodiment, the one or more second therapeutic agents are an anti-inflammatory agent (ie, a therapy for reducing inflammation). In one embodiment, therapy for reducing inflammation may include, among others, a therapeutic change in lifestyle, a steroid, an NSAID or a DMARD. The steroid can be a corticosteroid. The NSAID can be an aspirin, acetaminophen, ibuprofen, naproxen, COX inhibitors, indomethacin, and the like. DMARD can be an inhibitor of TNF, an inhibitor of purine synthesis, an inhibitor of calcineurin, an inhibitor of pyrimidine synthesis, a sulfasalazine, methotrexate and the like.
[0222] [0222] In one embodiment, the one or more second therapeutic agents are a chemotherapeutic agent (ie, an agent to treat cancer). Chemotherapeutic agents may include, among others, daunorubicinay daunomycin, dactinomycin, doxorubicin, epirubicin, idarubicin, esorubicin, bleomycin, mafosfamide, ifosfamide, cytosine-arabinoside, bis-chloroethylnitrosurein, prednisone, hydroxy, mitone, actin, hydroxy, mitone, actin, hydroxy, mitone, hydroxy, mitone , - tamoxifen, - dacarbazine, —procarbazine, hexamethylmelamine, pentamethylmelamine, mitoxantrone, amsacrine, chlorambucil, methylcyclohexylnitrosureia, nitrogen mustards, melphalan, cyclophosphamide, 6-mercaptopurine, g-tacanidine, hydroxy- 4-hydroxiperoxycyclophosphoramide, - 5-fluorouracil (5-FU), 5-fluordesoxyuridine (5-FUdR), methotrexate (MTX), colchicine, taxol, vincristine, vinblastine, etoposide, trimetrexate, teniposide, cisplatinay gencitestine and gencitestine! (DES).
[0223] [0223] In one embodiment, the one or more second therapeutic agents are immunomodulatory agents known as innate immunological agents, control point inhibitors, T cell stimulating agents or other agents that restore adaptive immune responses against HBV. Immunomodulators include, but are not limited to, antibodies or small molecules that antagonize CTLA-, such as ipilimumab (YERVOY), PD-1, such as Opdivo / nivolumab and Keytruda / pembrolizumab),) PDL1, such as TECENTRIQ'Y (atezolizumab), LAG3, TIM3 or IDO. Immunomodulators include, but are not limited to, antibodies or small molecules that stimulate ICOS, OX-40, TLRs, IL7R or ILI2R.
[0224] [0224] In one embodiment, the one or more second analgesic agents are an anti-infection agent. Examples of anti-infection agents include, but are not limited to, antibiotics, antifungal drugs and antiviral drugs.
[0225] [0225] In one embodiment, the present invention relates to a method for treating an HCV infection in a human by administering to him a therapeutically effective amount of a compound of Formula (|), or a pharmaceutically acceptable salt thereof . In one embodiment, the present invention relates to a method for treating an HCV infection, in a human with the infection or at risk of contracting it, by administering to him a therapeutically effective amount of a compound of Formula (l) ) or a pharmaceutically acceptable salt thereof.
[0226] [0226] In one embodiment, the present invention relates to a method for treating influenza in a human by administering to him a therapeutically effective amount of a compound of Formula (I)) or a pharmaceutically acceptable salt thereof. In one embodiment, the present invention relates to a method for treating influenza, in a human being with the infection or at risk of contracting it, by administering to him a therapeutically effective amount of a compound of Formula (Il), or of a pharmaceutically acceptable salt thereof.
[0227] [0227] In one embodiment, the present invention relates to a method for treating a papillomavirus (HPV) infection in a human by administering to him a therapeutically effective amount of a compound of Formula (1), or a pharmaceutically salt. acceptable value. In one embodiment, the present invention relates to a method for treating an HPV infection, in a human with the infection or at risk of contracting it, by administering to it a therapeutically effective amount of a compound of Formula (|) , or a pharmaceutically acceptable salt thereof.
[0228] [0228] As used in this document, the terms "cancer", "neoplasm" and "tumor" are interchangeable and, whether used in the singular or plural, refer to cells that have undergone a malignant transformation making them pathological to the host organism . Primary cancer cells can be readily differentiated from non-cancer cells by established techniques, in particular by histological examination. The definition of a cancer cell, as used in this document, includes not only a primary cancer cell, but any cell derived from an ancestor cancer cell. This includes metastasized cancer cells, and in vitro cultures and cell lines derived from cancer cells. When alluding to a type of cancer that normally manifests itself as a solid tumor, a "clinically detectable" tumor is such that it is detectable based on its mass; for example, by procedures such as computed tomography (CT) scanning, magnetic resonance imaging (MRI), X-ray, ultrasound or physical examination by touch, and / or such that it is detectable thanks to the expression of one or more antigens specific to the cancer in a sample obtained from the patient. Tumors can be hematopoietic (or hematological or blood-related) cancer, for example, cancers derived from blood cells or immune cells, which can be called "liquid tumors". Specific examples of clinical conditions based on hematological tumors include leukemias, such as chronic myeloid leukemia, acute myeloid leukemia, chronic lymphocytic leukemia and acute lymphocytic leukemia; plasma cell malignancies, such as multiple myeloma, MGUS and Waldenstrom's macroglobulinemia; lymphomas, such as non-Hodgkin's lymphoma, Hodgkin's lymphoma; and their peers.
[0229] [0229] Cancer can be any cancer in which an abnormal number of blast cells or the proliferation of unwanted cells is present or which is diagnosed as a hematological cancer, including both lymphoid and myeloid malignancies. Myeloid malignancies include, but are not limited to, acute myeloid leukemia (or myelocytic or myelogenous or myeloblastic) (undifferentiated or differentiated), acute promieloid leukemia (or promyelocytic or promyelogenous or promyeloblastic), “acute myelomonocytic (or myelomonoblastic) leukemia (or myelomonoblastic), leukemia (leukemia) or leukemia monoblastic), erythroleukemia and megakaryocytic (or megakaryoblastic) leukemia. These leukemias can be called jointly acute myeloid leukemia (or myelocytic or myelogenous) (AML). Myeloid malignancies also include myeloproliferative diseases (MPD) that include, among others, chronic myelogenous (or myeloid) leukemia (CML), myelomonocytic leukemia (CMML), essential thrombocythemia (or thrombocytosis), and polycythemia vera (PCV). Myeloid malignancies also include myelodysplasia (or myelodysplastic syndrome or MDS), which can be called refractory anemia (RA), refractory anemia with excess blasts (RAEB) and refractory anemia with excess blasts in transformation (RAEBT); as well as myelofibrosis (MFS) with or without agnogenic myeloid metaplasia.
[0230] [0230] Hematopoietic cancers also include lymphoid malignancies, which can affect lymph nodes, spleens, bone marrow, peripheral blood and / or extranodal sites. Lymphoid cancers include B-cell malignancies, which include,
[0231] [0231] Hematopoietic cancers also include Hodgkin's lymphoma (or disease), including classic Hodgkin's lymphoma, sclerosing nodular Hodgkin's lymphoma, mixed-cell Hodgkin's lymphoma, lymphocyte-dominant (LP) Hodgkin's lymphoma, and nodular LP Hodgkin's lymphoma Hodgkin's lymphoma with lymphocyte depletion. Hematopoietic cancers also include diseases or cancers of plasma cells, such as multiple myeloma (MM), including smoldering MM, monoclonal gammopathy of undetermined (or unknown or uncertain) significance (MGUS), plasmacytoma (bone, extramedullary), lymphplasmocytic lymphoma (LPL) , Waldenstrom's macroglobulinemia, plasma cell leukemia and primary amyloidosis (LA). Hematopoietic cancers may also include other cancers of additional hematopoietic cells, including polymorphonuclear (or neutrophil) leukocytes, basophils, eosinophils, dendritic cells, platelets, erythrocytes and natural killer cells. Tissues that include hematopoietic cells — referred to in this document as "hematopoietic cell tissues" include the bone marrow; peripheral blood; thymus; and peripheral lymphoid tissues, such as spleen, lymph nodes, lymphoid tissues associated with the mucosa (such as lymphoid tissues associated with the intestine), tonsils, Peyer plaques and appendix, and lymphoid tissues associated with other mucosa, for example, bronchial mucosa.
[0232] [0232] In one embodiment, the present invention relates to a compound of Formula (! 1), or a pharmaceutically acceptable salt thereof, for use in the treatment of cancer and precancerous syndromes. In another aspect, a method for treating cancer and precancerous syndromes is proposed which comprises administering to a human being in need of a therapeutically effective amount of a compound of Formula (|), or a pharmaceutically acceptable salt thereof. In another aspect, a compound of Formula (1), or a pharmaceutically acceptable salt thereof, is proposed for use in the manufacture of a medicament for the treatment of cancer and precancerous syndromes.
[0233] [0233] Associated autoimmune diseases include, among others, childhood-onset vasculitis associated with STING (SAVI), Aicardi-Goutiêres syndrome (AGS),
[0234] [0234] Inflammation represents a group of vascular, cellular and neurological responses to trauma. Inflammation can be characterized as the displacement of inflammatory cells, such as monocytes, neutrophils and granulocytes, to tissues. This is typically associated with reduced endothelial barrier function and tissue edema. The inflammation can be classified as either acute or chronic. Acute inflammation is the body's initial response against harmful stimuli and is achieved by a greater displacement of plasma and leukocytes from the blood to the injured tissues. A cascade of biochemical events propagates and matures the inflammatory response, involving the local vascular system, the immune system, and several cells within the injured tissue. Prolonged inflammation, known as chronic inflammation, leads to a progressive change in the type of cells that are present at the site of the inflammation and is characterized by the simultaneous destruction and healing of the tissue in relation to the inflammatory process.
[0235] [0235] When it occurs as part of an immune response against infection or as an acute response to trauma, inflammation can be beneficial and is usually self-limiting. However, inflammation can be harmful in several conditions. These include the production of excessive inflammation in response to infectious agents, which can cause significant damage and death (for example, in the sepsis scenario). In addition, chronic inflammation is usually harmful and is at the root of numerous chronic diseases, causing severe and irreversible tissue damage. In these settings, the immune response is often directed against self-tissues (autoimmunity), although chronic responses to foreign entities can also lead to collateral damage to self-tissues.
[0236] [0236] The goal of anti-inflammatory therapy is, therefore, to reduce this inflammation, to inhibit autoimmunity, when present, and to allow the physiological process or tissue healing and repair to proceed.
[0237] [0237] The compounds of the present invention can be used to treat inflammation of any tissue and organs in the body, including musculoskeletal inflammation, vascular inflammation, neural inflammation, inflammation of the digestive system, eye inflammation, cardiac inflammation, inflammation of adipose tissue, inflammation reproductive system and other inflammation, as exemplified below.
[0238] [0238] Musculoskeletal inflammation refers to any inflammatory condition of the musculoskeletal system, in particular conditions that affect skeletal joints, including joints of the hands, wrists, elbows, shoulders, jaw, spine, neck, hips, knees, heels and feet, and conditions that affect tissues that connect muscles to bones, such as tendons. Examples of musculoskeletal inflammation that can be treated with compounds of the invention include arthritis (including, for example, osteoarthritis, rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis, acute and chronic infectious arthritis, gout and pseudogout arthritis, and juvenile idiopathic arthritis), tendinitis, synovitis, tenosynovitis, bursitis, fibrositis (fibromyalgia), epicondylitis, myositis and osteitis (including, for example, Paget's disease, osteitis, pubis and cystic fibrous osteitis).
[0239] [0239] Eye inflammation refers to the inflammation of any structure in the eye, including the eyelids. Examples of eye inflammation that can be treated with the compounds of the invention include blepharitis, blepharocalase, conjunctivitis, dacrioadenitis, keratitis, dry keratoconjunctivitis (dry eye), scleritis, trichiasis and uveitis.
[0240] [0240] Examples of inflammation of the nervous system that can be treated with the compounds of the invention include encephalitis, Guillain-Barré syndrome, meningitis, neuromyotonia, narcolepsy, multiple sclerosis, myelitis, CNS vasculitis and schizophrenia.
[0241] [0241] Examples of inflammation associated with neurodegenerative diseases that can be treated with compounds of the invention include Alzheimer's disease and related dementias, amyotrophic lateral sclerosis (ALS) and Frontotemporal Lobar Degeneration (FTD), Parkinson's disease, and Huntington's disease.
[0242] [0242] Examples of inflammation of the vasculature or lymphatic system that can be treated with the compounds of the invention include arthrosclerosis, arthritis, phlebitis, vasculitis and lymphangitis.
[0243] [0243] Examples of inflammation of the cardiovascular system that can be treated with the compounds of the invention include, among others, myocardial infarction, heart failure, congenital heart disease, arterial disease! coronary artery disease, hypertension, cardiomyopathy, and other related cardiovascular conditions.
[0244] [0244] EXamples of liver inflammation that can be treated with the compounds of the invention include, but are not limited to, liver fibrosis, alcoholic liver disease (ALD), non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis, and liver disease biliary.
[0245] [0245] Examples of adipose tissue inflammation that can be treated with the compounds of the invention include, but are not limited to, obesity and obesity-induced insulin resistance.
[0246] [0246] Examples of liver inflammation that can be treated with the compounds of the invention include, but are not limited to, liver fibrosis, and fibrosis-carcinoma, alcoholic liver disease (ALD), non-alcoholic fatty liver disease (NAFLD) and non-steatohepatitis alcohol (NASH), and biliary liver disease.
[0247] [0247] Examples of inflammation of the pancreas that can be treated with the compounds of the invention include, but are not limited to, pancreatitis and pancreatic beta cell dysfunction induced by metabolic syndrome.
[0248] [0248] Examples of inflammation of the kidney that can be treated with the compounds of the invention include, but are not limited to, renal nephritis.
[0249] [0249] Examples of inflammation in the lung that can be treated with the compound of the invention include pulmonary fibrosis, COPD and asthma.
[0250] [0250] Examples of inflammation in the eye that can be treated with the compound of the invention include dry eye syndromes and age-related macular degeneration.
[0251] [0251] Examples of inflammatory conditions of the digestive system that can be treated with the compounds of the invention include cholangitis, cholecystitis, enteritis, enterocolitis, gastritis, gastroenteritis, inflammatory bowel disease (such as Crohn's disease and ulcerative colitis), ileitis and proctitis.
[0252] [0252] Examples of inflammatory conditions of the reproductive system that can be treated with the compounds of the invention include cervicitis, chorioamnionitis, endometritis, epididymitis, omphalitis, oophoritis, orchitis, salpingitis, ovarian tube abscess, urethritis, vaginitis, vulvitis and vulvodynia.
[0253] [0253] In one embodiment, the compounds of the present invention can be used to treat systemic lupus erythematosus, rheumatoid arthritis, osteoarthritis,
[0254] [0254] The compounds of the present invention can be used to treat autoimmune conditions with an inflammatory component. These conditions include acute disseminated universal alopecia, Behçet's disease, Chagas' disease, STING-associated childhood vasculitis (SAVI), Aicardi- Goutiêres syndrome (AGS), lupus pernio, ataxia-telangiectasia (also known as Louis syndrome -Bar), retinal vasculopathy with cerebral leukodystrophy (RCVL), ANCA associated vasculitis, chronic fatigue syndrome, dysautonomia, encephalomyelitis, ankylosing spondylitis, aplastic anemia, suppurative hidradenitis, autoimmune hepatitis, autoimmune oophoritis, celiac disease, Crohn's disease, Crohn's disease type 1 melito, giant cell arthritis, Goodpasture syndrome, Grave's disease, Guillain-Barré syndrome, Hashimoto's disease, Henoch-Schônlein purpura, Kawasaki's disease, lupus erythematosus, microscopic colitis, microscopic polyarteritis, mixed tissue disease connective tissue, multiple sclerosis, myasthenia gravis, opsoclonus-myoclonus syndrome, optic neuritis, Ord thyroiditis, pemphigus, polyarteritis nodosa, pol imialgia, rheumatoid arthritis, Reiter's syndrome, Sjogren's syndrome, temporal arteritis, Wegener's granulomatosis, hot autoimmune hemolytic anemia, interstitial cystitis, Lyme disease, morphia, psoriasis, sarcoidosis, scleroderma, ulcerative colitis, chronic obstructive pulmonary disease, chronic obstructive pulmonary disease adult respiratory distress, and vitiligo.
[0255] [0255] The compounds of the present invention can be used to treat T-cell-mediated hypersensitivity diseases with an inflammatory component. These conditions include contact hypersensitivity, contact dermatitis (including due to poison ivy), hives, skin allergies, respiratory allergies (hay fever, allergic rhinitis) and gluten-sensitive enteropathy (celiac disease).
[0256] [0256] Other inflammatory conditions that can be treated with the compounds of the present invention include, for example, appendicitis, dermatitis, dermatomyositis, endocarditis, fibrositis, gingivitis, glossitis, hepatitis, suppurative hidradenitis, iritis, laryngitis, mastitis, myocarditis, nephritis, otitis, pancreatitis, parotitis, percarditis, peritonitis, pharyngitis, pleuritis, pneumonitis, prostatitis, pyelonephritis, and stomatitis, transplant rejection (involving organs such as kidney, liver, heart, lung, pancreas (eg islets), bone marrow, cornea, small intestine, skin allografts, skin homografts, and heart valve xenografts, serum disease, and graft versus host disease), acute pancreatitis, chronic pancreatitis, acute respiratory distress syndrome, Sézary syndrome, congenital adrenal hyperplasia , non-suppurative thyroiditis, cancer-associated hypercalcemia, pemphigus, bullous dermatitis, herpetiformis, severe erythema multiforme, exfoliative dermatitis, dermatitis seborrheic, seasonal or perennial allergic rhinitis, bronchial asthma, contact dermatitis, atopic dermatitis, and drug hypersensitivity reactions, allergic conjunctivitis, keratitis, ophthalmic herpes zoster, iritis and iridocyclitis, chorioretinitis, optic neuritis, chemotherapy against symptomatic chemotherapy fulminant or disseminated pulmonary tuberculosis, idiopathic thrombocytopenic purpura in adults, secondary thrombocytopenia in adults, acquired hemolytic anemia (autoimmune), leukemia and lymphomas in adults, acute childhood leukemia, regional enteritis, autoimmune vasculitis, multiple sclerosis, chronic obstructive pulmonary disease, rejection of solid organ transplantation, sepsis.
[0257] [0257] Examples of cancerous diseases and conditions in which compounds of the present invention may have potentially beneficial antitumor effects include, but are not limited to, lung, bone, pancreas, skin, head, neck, uterus, ovaries, stomach, colon, breast, cancers, esophagus, small intestine, intestine, endocrine system, thyroid gland, parathyroid gland, adrenal gland, urethra, prostate, penis, testicles, ureter, bladder, kidney or liver; rectal cancer; cancer of the anal region; carcinomas of the fallopian tubes, endometrium, cervix, vagina, vulva, renal pelvis, renal cells; soft tissue sarcoma; myxoma; rhabdomyoma; fibroma; lipoma; teratoma; cholangiocarcinoma; hepatoblastoma; angiosarcoma; hemangioma; hepatoma; fibrosarcoma; chondrosarcoma; myeloma; chronic or acute leukemia; lymphocytic lymphomas; primary CNS lymphoma; CNS neoplasms; tumors of the spinal axis; squamous cell carcinomas; synovial sarcoma; malignant pleural mesotheliomas; brain stem glioma; pituitary adenoma; bronchial adenoma; chondromatous hamartoma; mesothelioma; Hodgkin's disease or a combination of one or more of the aforementioned cancers.
[0258] [0258] Suitably, the present invention relates to a method for treating or reducing the severity of cancers selected from the group consisting of brain cancer (gliomas), glioblastomas, astrocytomas, glioblastoma multiforme, Bannayan-Zonana syndrome, Cowden, Lhermitte-Duclos disease, Wilms' tumor, Ewing's sarcoma, Rhabdomyosarcoma, ependymoma, medulloblastoma, head and neck cancer, kidney cancer, liver cancer, melanoma, ovarian cancer, pancreatic cancer, adenocarcinoma, ductal adenocarcinoma, adenosquamous carcinoma, acinar cell carcinoma, glucagonoma, insulinoma, prostate, sarcoma, osteosarcoma, giant cell bone tumor, thyroid, T-cell lymphoblastic leukemia, chronic myeloid leukemia, chronic lymphoid leukemia, hairy cell leukemia, acute lymphoblastic leukemia, acute lymphoblastic leukemia acute myeloid, chronic neutrophilic leukemia, T-cell lymphoblastic leukemia,
[0259] [0259] In one aspect, the human being suffers from a solid tumor. In one aspect, the tumor is selected from head and neck cancer, gastric cancer, melanoma, renal cell carcinoma (RCC), esophageal cancer, non-small cell lung carcinoma, prostate cancer, colorectal cancer, ovarian cancer and pancreatic cancer. In one aspect, the human being suffers from one or more of the following: colorectal cancer (CRC), esophageal cancer, cervical cancer, bladder cancer, breast cancer, head and neck cancer, ovarian cancer, melanoma , renal cell carcinoma (RCC), squamous cell cancer EC, non-small cell lung carcinoma, mesothelioma, and prostate cancer. In another aspect, the human being suffers from a liquid tumor, such as diffuse large B cell lymphoma (DLBCL), multiple myeloma, chronic lymphoblastic leukemia (CLL), follicular lymphoma, acute myeloid leukemia and chronic myelogenous leukemia.
[0260] [0260] In one embodiment, the compounds of the present invention may be useful in the treatment of skin cancer (e.g., non-melanoma skin cancer, squamous cell carcinoma, basal cell carcinoma) or actinic keratosis. In addition to a field effect to eliminate superficial skin cancers, the compounds of the present invention can prevent the development of subsequent skin cancers and pre-malignant actinic keratosis in treated patients.
[0261] [0261] The compounds of the present invention may also be useful in the treatment of one or more diseases afflicting mammals characterized by cell proliferation in the area of disorders associated with neo-vascularization and / or vascular permeability, including proliferative disorders in blood vessels, including arthritis (rheumatoid arthritis) and restenosis; fibrotic disorders including liver cirrhosis and atherosclerosis; proliferative disorders of mesangial cells including glomerulonetphritis, diabetic nephropathy, malignant nephrosclerosis, thrombotic microangiopathy syndromes, proliferative retinopathies, organ transplant rejection and glomerulopathies; and metabolic disorders including psoriasis, diabetes mellitus, healing of chronic wounds, inflammation and neurodegenerative diseases.
[0262] [0262] The compounds of the present invention can be used to treat neurodegenerative diseases. Examples of neurodegenerative diseases include,
[0263] [0263] The compounds of the present invention can be used to treat or prevent metabolic disorders (such as insulin resistance, non-alcoholic fatty liver disease (NAFLD) / non-alcoholic steatohepatitis (NASH), obesity, diabetes, high blood pressure, fatty liver and cardiovascular disease).
[0264] [0264] The compounds of the present invention can be used to treat an infectious disease, which is any disease instigated by or coinciding with an infection by a pathogen. Pathogens are widely defined as any species of organism that is foreign to an environment of human tissue. Common disease-causing pathogens include bacteria (many, such as TB), viruses (many, such as HBV, HIV, influenza) and parasitic protozoa (such as falciparum P, which causes malaria). The compounds of the present invention can be used to treat infectious diseases derived from bacteria, such as TB infection (Mycobacterium tuberculosis), chlamydiae, Tularemia infection (Francisella tularensis), plasmodium infection or infections by DNA or RNA virus. The compounds of the present invention can be used to treat infectious diseases derived from the DNA virus families: Herpesviridae (herpes simplex virus-1, virus associated with Kaposi's sarcoma and Epstein-Barr virus), Papillomaviridae (human papilloma virus) , Adenovirus and Hepadnaviridae (Hepatitis B virus). Examples of RNA virus families include Retroviridae (human immunodeficiency virus), Flaviviridae (dengue virus, hepatitis C virus), Orthomyxoviridae (influenza), and Coronaviridae (human coronavirus and SARS coronavirus).
[0265] [0265] The compounds of the present invention can be used alone or in combination with other therapeutic agents. As modulators of the immune response, the compounds of the present invention can also be used in monotherapy or used in combination with another therapeutic agent in the treatment of diseases and conditions in which STING modulation is beneficial. Combined therapies according to the present invention therefore comprise the administration of a compound of Formula (1), or a pharmaceutically acceptable salt thereof, and at least one other therapeutically active agent. In one embodiment, combined therapies in accordance with the present invention comprise the administration of at least one compound of Formula (II), or a pharmaceutically acceptable salt thereof, and at least one other therapeutic agent. The compound (s) of Formula (1), and pharmaceutically acceptable salts thereof, and other therapeutic agent (s) can be administered together in the same pharmaceutical composition or separately and, when administered separately, this can be done simultaneously or sequentially in any order. The amounts of the compound (s) of Formula (I), and pharmaceutically acceptable salts thereof, and the other therapeutic agent (s) and the relative administration times will be selected with a view to to achieve the desired combined therapeutic effect. Therefore, in another aspect, a combination is proposed which comprises a compound of Formula (1), or a pharmaceutically acceptable salt thereof, together with one or more other therapeutic agents.
[0266] [0266] The compounds of Formula (1), and pharmaceutically acceptable salts thereof, can be used in combination with one or more other therapeutic agents that may be useful in the prevention or treatment of allergic diseases, inflammatory diseases or autoimmune diseases, for example ; immunotherapy with antigens, antihistamines, steroids, NSAIDs, bronchodilators (e.g., beta-2 agonists, adrenergic agonists, anticholinergic agents, theophylline), methotrexate, leukotriene modulators and similar agents; therapy with monoclonal antibodies such as anti-IgE, anti-TNF, anti-IL-5, anti-IL-6, anti-IL-12,
[0267] [0267] The compounds of Formula (1), and pharmaceutically acceptable salts thereof, can be used in combination with radiation therapy and / or surgery and / or at least one other therapeutic agent that may be useful in the treatment of cancer and syndromes precancerous. Any antineoplastic agent that has activity against a susceptible tumor being treated can be used in combination. Typical useful antineoplastic agents include, but are not limited to, antimicrotubule agents, such as diterpenoids and vinca alkaloids; platinum coordination complexes; alkylating agents such as nitrogen mustards, oxazaphosphorins, alkyl sulfonates, nitrosoureas and triazenes; antibiotic agents such as anthracyclines, actinomycins and bleomycins; topoisomerase inhibitors | such as epipodophyllotoxins; antimetabolites such as purine and pyrimidine analogs and antifolate compounds; topoisomerase inhibitors | such as camptothecins; hormones and hormonal analogues; inhibitors of signal transduction pathways; inhibitors of non-receptor tyrosine angiogenesis; immunotherapeutic agents; pro-apoptotic agents; cell cycle signaling inhibitors; immunological agents and immunostimulatory agents.
[0268] [0268] Anti-microtubule or antimitotic agents are specific-phase agents active against tumor cell microtubules during M phase or cell cycle mitosis. Examples of antimicrotubule agents include, but are not limited to, diterpenoids and vinca alkaloids.
[0269] [0269] Diterpenoids, which are derived from natural sources, are phase-specific anticancer agents that operate in the G2 / M phases of the cell cycle. We believe
[0270] [0270] Paclitaxel, 58,20-epoxy-1,20,4,7B, 10B, 13a-hexahydroxytax-11-en-9-one 4,10-diacetate 2-benzoate 13-ester with (2R, 3S) -N-benzoyl-3-phenylisoserine, is a natural diterpene product isolated from the Pacific yew Taxus brevifolia and is commercially available as an injectable TAXOL solution. He is a member of the taxane family of terpenes. Paclitaxel has been approved for clinical use in the treatment of refractory ovarian cancer in the United States (Markman et al., Yale Journal of Biology and Medicine, 64: 583, 1991; McGuire et al., Ann. Intem. Med., 111: 273, 1989) and for the treatment of breast cancer (Holmes et a / l., J. Nat. Cancer Inst., 83: 1797, 1991). He is a potential candidate for the treatment of skin neoplasms (Einzig et al, Proc. Am. Soc. Clin, Oncol., 20:46) and head and neck carcinomas (Forastire et al., Sem. Oncol. , 20:56, 1990). The compound also exhibits potential for the treatment of polycystic kidney disease (Woo et al., Nature, 368: 750. 1994), lung cancer and malaria. Treatment of patients with paclitaxel results in bone marrow suppression (several cell lines, Ignoff, RJ et al., Cancer Chemotherapy Pocket Guide, 1998) associated with the duration of a certain dosage above a limit concentration (50 nM) (Kearns, CM et al., Seminars in Oncology, 3 (6) p. 16-23, 1995).
[0271] [0271] Docetaxel, (2R, 3S) -N-carboxy-3-phenylisoserine, N-tert-butyl ester, 13-ester “with 538-20-epoxy-1,20,4 4-acetate 2-benzoate , 78B, 108,130-hexahydroxytax-11-en-9-one, trihydrate, is commercially available as an injectable solution under the name TAXOTERES. Docetaxel is indicated for the treatment against breast cancer. Docetaxel is a semi-synthetic derivative of paclitaxel q.v., prepared using a natural precursor, 10-deacetyl-baccatine II, extracted from the acicular leaf of the European yew.
[0272] [0272] Vinca alkaloids are specific phase antineoplastic agents derived from vinca. Vinca alkaloids act in the M phase (mitosis) of the cell cycle, specifically binding to tubulin. Therefore, the bound tubulin molecule is unable to polymerize into microtubules. Mitosis is believed to be stopped in metaphase with cell death ensuing. Examples of vinca alkaloids include, but are not limited to, vinblastine, vincristine and vinorelbine.
[0273] [0273] Vinblastine, vincaleucoblastinay sulfate is commercially available under the name VELBANº as an injectable solution. Although it may be indicated as a second-line therapy against various solid tumors, it is primarily indicated for the treatment of testicular cancer and various lymphomas, including Hodgkin's disease; and lymphocytic and histiocytic lymphomas. Myelosuppression is the dose-limiting side effect of vinblastine.
[0274] [0274] Vincristine, vincaleucoblastine, 22-0x0-, sulfate, is commercially available under the name ONCOVINº as an injectable solution. Vincristine is indicated for the treatment against acute leukemias and is also used in treatment regimes against malignant Hodgkin's and non-Hodgkin's lymphomas. Alopecia and neurological effects are the most common side effect of vincristine and, to a lesser extent, effects of myelosuppression and gastrointestinal mucositis occur.
[0275] [0275] Vinorelbine, 3 ', 4'-dideshydro-4'-deoxy-C'-norvincaleucoblastine [R- (R *, R *) - 2,3-dihydroxybutanedioate (1: 2) (salt)], made available commercially as an injectable solution of vinorelbine tartrate (NAVELBINES), it is a semi-synthetic vinca alkaloid. Vinorelbine is indicated for use as a separate agent or in combination with other chemotherapeutic agents, such as cisplatin, in the treatment of various solid tumors, in particular against non-small cell lung cancer, breast cancer and hormone prostate cancer. -refractory. Myelosuppression is the most common dose-limiting side effect of vinorelbine.
[0276] [0276] Platinum coordination complexes are anticancer agents with no specific phase that interact with DNA. The platinum complexes enter the tumor cells, undergo heating and cross-link within strands and between strands with DNA, causing adverse biological effects to the tumor. Examples of platinum coordination complexes include, but are not limited to, oxaliplatin, cisplatin and carboplatin.
[0277] [0277] Cisplatin, cis-diaminodichloroplatin, is commercially available under the name PLATINOLº as a solution for injection. Cisplatin is primarily indicated for the treatment of metastatic testicular cancer and advanced bladder cancer.
[0278] [0278] Carboplatin, platinum, diamine [1,1-cyclobutane-dicarboxylate (2 -) - O, O '], is commercially available under the name PARAPLATINº as a solution for injection. Carboplatin is indicated mainly in the first and second line treatments against advanced ovarian carcinoma.
[0279] [0279] Alkylating agents are anti-cancer agents with no specific phase and strong electrophiles. Typically, alkylating agents form covalent bonds, by alkylation, with DNA through nucleophilic groups of the DNA molecule, such as phosphate, amino, sulfhydryl, hydroxy, carboxyl and imidazole groups. This alkylation undermines the function of the nucleic acid, leading to cell death. Examples of alkylating agents include, but are not limited to, nitrogen mustards such as cyclophosphamide, melphalan and chlorambucil; alkyl sulfonates such as busulfan; nitrosoureas such as carmustine; and triazenes such as dacarbazine.
[0280] [0280] Cyclophosphamide, —2-bis (2-chloroethyl) amino 2-oxide monohydrate] tetrahydro-2H-1,3,2-oxazaphosphorine, is commercially available as an injectable solution or tablets under the name CYTOXANº. Cyclophosphamide is indicated for use as a separate agent or in combination with other chemotherapeutic agents in the treatment of malignant lymphomas, multiple myeloma and leukemias.
[0281] [0281] Melphalan, 4- [bis (2-chloroethyl) amino] -L-phenylalanine, is commercially available as a solution for injection or tablets with the name ALKERANº. Melphalan is indicated for palliative treatment against multiple myeloma and non-extirpable epithelial carcinoma of the ovary. Bone marrow suppression is the most common dose-limiting side effect of melphalan.
[0282] [0282] Chlorambucil, 4- [bis (2-chloroethyl) amino] benzenobutanoic acid, is commercially available as LEUKERANº tablets. Chlorambucil is indicated for palliative treatment against chronic lymphatic leukemia and malignant lymphomas, such as lymphosarcoma, giant follicular lymphoma and Hodgkin's disease.
[0283] [0283] Busulfan, 1,4-butanediol dimethanesulfonate, is commercially available as MYLERANº tablets. Busulfan is indicated for palliative treatment against chronic myelogenous leukemia.
[0284] [0284] Carmustine, 1,3- [bis (2-chloroethyl) -I-nitrosourea, is commercially available in simple bottles of lyophilized material under the name BICNUº. Carmustine is indicated for palliative treatment as a separate agent or in combination with other agents against brain tumors, multiple myeloma, Hodgkin's disease and non-Hodgkin's lymphomas.
[0285] [0285] Dacarbazine, 5- (3,3-dimethyl-1-triazene) -imidazole-4-carboxamide, is commercially available in simple bottles of material with the name DTIC-Domeº. Dacarbazine is indicated for the treatment against metastatic malignant melanoma and for use in combination with other agents for the second-line treatment against Hodgkin's disease.
[0286] [0286] Antibiotic antineoplastic agents are agents with no specific phase that bind to or intercalate with DNA. Typically, this action results in stable DNA complexes or strand rupture, which undermines the usual function of nucleic acids, leading to cell death. Examples of antibiotic antineoplastic agents include, but are not limited to, actinomycins such as dactinomycins, anthracyclines such as daunorubicin and doxorubicin; and bleomycins.
[0287] [0287] Dactinomycin, also known as Actinomycin D, is commercially available in an injectable form under the name COSMEGENº. Dactinomycin is indicated for the treatment against Wilms' tumor and rhabdomyosarcoma.
[0288] [0288] Daunorubicin, (8S-cis -) - 8-acetyl-10 - [(3-amino-2,3,6-tridesoxy-aL-waste-hexopyranosyl) oxy] l-7,8,9 hydrochloride , 10-tetrahydro-6,8,11-trihydroxy-1-methoxy-5,12 naphtacenedione, is commercially available in a liposomal injectable form with the name of DAUNOXOMESº or in injectable form with the name of CERUBIDINES. Daunorubicin is indicated for inducing remission in the treatment of acute non-lymphocytic leukemia and Kaposi's sarcoma associated with advanced HIV.
[0289] [0289] Doxorubicin, (8S, 108S) -10 - [(3-amino-2,3,6-tridesoxy-a-L-trash-hexopyranosyl) oxyl-8-glycolol hydrochloride, 7,8,9, 10-tetrahydro-6,8,11-trihydroxy-1I-methoxy-5,12 naphthopenedione, is commercially available in injectable form with the names RUBEXº or ADRIAMYCIN RDFº. Doxorubicin is mainly indicated for the treatment against acute lymphoblastic leukemia and acute myeloblastic leukemia, but it is also a useful component in the treatment of some solid tumors and lymphomas.
[0290] [0290] Bleomycin, a mixture of cytotoxic glycopeptide antibiotics isolated from a strain of Streptomyces verticilus, is commercially available under the name BLENOXANEº. Bleomycin is indicated for palliative treatment, either as a separate agent or in combination with other agents, against squamous cell carcinoma, lymphomas and testicular carcinomas.
[0291] [0291] topoisomerase inhibitors | include, among others, epipodophyllotoxins. Epipodophyllotoxins are specific phase antineoplastic agents derived from mandrake. Epipodophyllotoxins typically affect cells in the S and G2 phases of the cell cycle by forming a ternary complex with topoisomerase | 1 and DNA causing DNA strand breaks. Tape breaks accumulate and cell death follows. Examples of epipodophyllotoxins include, but are not limited to, etoposide and teniposide.
[0292] [0292] Ethoposide, 4'-demethyl-epipodophyllotoxin 9 [4,6-0- (R) -ethylidene-BD-glycopyranoside], is commercially available in a solution for injection or in capsules with the name VePESIDº and is commonly known like VP-16. Ethoposide is indicated as a separate agent or in combination with other chemotherapeutic agents in the treatment against testicular cancer and non-small cell lung cancer.
[0293] [0293] Teniposide, 4'-demethyl-epipodophyllotoxin 9 [4,6-0- (R) -tenylidene-BD-glycopyranoside], is commercially available as an injectable solution with the name VUMONº and is commonly known as VM- 26. Teniposide is indicated as a separate agent or in combination with other chemotherapeutic agents in the treatment against acute leukemia in children.
[0294] [0294] Antimetabolite antineoplastic agents are specific phase antineoplastic agents that act on the S phase (DNA synthesis) of the cell cycle by inhibiting DNA synthesis or by inhibiting purine or pyrimidine synthesis and thereby limit the synthesis of DNA. Consequently, the S phase does not progress and cell death follows. Examples of antimetabolite antineoplastic agents include, but are not limited to, fluorouracil, methotrexate, cytarabine, mecaptopurine, thioguanine and gemcitabine.
[0295] [0295] 5-fluorouracil, 5-fluorine-2,4- (1H, 3H) pyrimidinedione, is commercially available as fluoracil. Administration of 5-fluoracil leads to inhibition of thymidylate synthesis and is also incorporated into both RNA and DNA. The result is typically cell death. 5-fluorouracil is indicated as a separate agent or in combination with other chemotherapeutic agents in the treatment of breast, colon, rectum, stomach and pancreas carcinomas. Other analogs of fluorpirimidine include S5-fluordesoxyuridine (floxuridine) and 5-fluordesoxyuridine monophosphate.
[0296] [0296] Cytarabine, y 4-amino-1-B-D-arabinofuranosyl-2 (1H) -pyrimidinone, is commercially available under the name CYTOSAR-Uº and is commonly known as Ara-C. Cytarabine is believed to exhibit cell phase specificity in the S phase, inhibiting the elongation of DNA strands by terminal incorporation of cytarabine into the growing DNA strand. Cytarabine is indicated as a separate agent or in combination with other chemotherapeutic agents in the treatment against acute leukemia. Other analogs of cytidine include 5-azacytidine and 2 ', 2'-difluordesoxycytidine (gemcitabine)
[0297] [0297] Mercaptopurine, 1,7-dihydro-6H-purine-6-thione monohydrate, is commercially available under the name PURINETHOLS. Mercaptopurine exhibits cell phase specificity in the S phase by inhibiting DNA synthesis by a mechanism that has not yet been elucidated. Mercaptopurine is indicated as a separate agent or in combination with other chemotherapeutic agents in the treatment against acute leukemia. A useful analog of mecaptopurine is azathioprine.
[0298] [0298] Thioguanine, 2-amino-1,7-dihydro-6H-purine-6-thione, is commercially available under the name TABLOIDº. Thioguanine exhibits cell phase specificity in the S phase by inhibiting DNA synthesis by a mechanism that has not yet been elucidated. Thioguanine is indicated as a separate agent or in combination with other chemotherapeutic agents in the treatment against acute leukemia. Other purine analogs include pentostatin, erythrohydroxynonyladenine (EHNA), fludarabine phosphate and cadribine.
[0299] [0299] Gemcitabine, 2'-deoxy-2 ', 2'-difluorcitidine (B-isomer) monocliorhydrate, is commercially available under the name GEMZARº. Gemcitabine exhibits cell phase specificity in the S phase and blocks the progression of cells across the G1 / S limit. Gemcitabine is indicated in combination with cisplatin in the treatment against locally advanced non-small cell lung cancer and separately in the treatment against locally advanced pancreatic cancer.
[0300] [0300] Methotrexate, N- [4 [[(2,4-diamino-6-pteridinyl)] methyl | methylamino] benzoyl] - L-glutamic acid, is commercially available as sodium methotrexate. Methotrexate exhibits effects in the cell phase specifically in the S phase by inhibiting DNA synthesis, repair and / or replication through the inhibition of dihydrofolic acid reductase, which is necessary for the synthesis of purine and thymidylate nucleotides. Methotrexate is indicated as an agent separately or in combination with other chemotherapeutic agents in the treatment of choriocarcinoma, meningeal leukemia, non-Hodgkin's lymphoma and carcinomas of the breast, head, neck, ovary and bladder.
[0301] [0301] JAs camptothecins, including camptothecin and camptothecin derivatives, are available and under development as topoisomerase inhibitors | The cytotoxic activity of camptothecins is believed to be associated with their topoisomerase | inhibitory activity. Examples of camptothecins include, but are not limited to, irinotecan, topotecan and the various optical forms of 7- (4-methylpiperazine-methylene) -10,11-ethylenedioxy-20-camptothecin described below.
[0302] [0302] The HCI of irinotecan, (4S) -4,11-diethyl-4-hydroxy-9 - [(4-piperidinopiperidine) carbonyloxy] -1H-pyran [3 ', 4', 6,7] hydrochloride [1,2-b] quinoline-3.14 (4H, 12H) -dione, is commercially available as the CAMPTOSARS solution for injection. Irinotecan is a derivative of camptothecin that binds, together with its active metabolite SN-38, to the topoisomerase | - DNA. Cytotoxicity is believed to occur as a result of irreparable double-strand breaks caused by the interaction of the topoisomerase complex | : DNA: irintecan or SN-38 ternary complex with replication enzymes. Irinotecan is indicated for the treatment against metastatic colon or rectal cancer.
[0303] [0303] Topotecan HCI, (S) -10 - [(dimethylamino) methyl] -4-ethyl-4,9-dihydroxy-1H-pyran [3 ', 4', 6,7] indolizine [1 , 2-b] quinoline-3,14- (4H, 12H) -dione, is available for sale as the HYCAMTINE solution for injection. Topotecan is a camptothecin derivative that binds the topoisomerase complex | - DNA and prevents rewiring of single strand breaks caused by topoisomerase | in response to the torsional deformation of the DNA molecule. Topotecan is indicated for second-line treatment against metastatic ovarian carcinoma and small cell lung cancer.
[0304] [0304] Hormones and hormone analogues are useful compounds to treat cancers in which there is a relationship between the hormone (s) and the growth and / or lack of growth of the cancer. Examples of hormones and hormonal analogs useful in cancer treatment include, but are not limited to, adrenocorticoids, such as prednisone and prednisolone, which are useful in the treatment of malignant lymphoma and acute leukemia in children; aminoglutetimide and other aromatase inhibitors, such as anastrozole, letrazole, vorazole and exemestane, useful in the treatment against adrenocortical carcinoma and hormone-dependent breast carcinoma containing estrogen receptors; progestrins, such as medgestrol | acetate, useful in the treatment of hormone-dependent breast cancer and endometrial carcinoma; estrogens and antiestrogens, such as fulvestranto, flutamide, nilutamide, bicalutamide, cyproterone acetate and 5a-reductases, such as finasteride and dutasteride, useful in the treatment against prostate carcinoma and benign prostatic hypertrophy; antiestrogens, such as tamoxifen, toremifene, raloxifene, droloxifene, iodoxifene, as well as selective estrogen receptor modulators (SERMS), such as those described in U.S. Patents 5,681,835,
[0305] [0305] Inhibitors of signal transduction pathways are those that block or inhibit a chemical process that evokes an intracellular change. As used in this document, that change is cell proliferation or differentiation. Signal transduction inhibitors useful in the present invention include receptor tyrosine kinase inhibitors, non-receptor tyrosine kinases, SH2 / SH3 domain blockers, serine / threonine kinases, phosphotidylinositol-3 kinases, myo-inositol signaling, and Ras oncogenes.
[0306] [0306] Several protein tyrosine kinases catalyze the phosphorylation of specific tyrosyl residues in various proteins involved in the regulation of cell growth. These protein tyrosine kinases can be broadly classified as receptor or non-receptor kinases.
[0307] [0307] Receptor tyrosine kinases are transmembrane proteins with an extracellular ligand binding domain, a transmembrane domain and a tyrosine kinase domain. Receptor tyrosine kinases are involved in the regulation of cell growth and are generally called growth factor receptors. The inappropriate or uncontrolled activation of many of these kinases, that is, aberrant activity of the growth factor kinase receptor, for example, by overexpression or mutation, has proven to result in uncontrolled cell growth. Therefore, the aberrant activity of these kinases is associated with the growth of malignant tissues. Therefore, inhibitors of these kinases could provide methods of treatment against cancer. Growth factor receptors include, for example, epidermal growth factor receptor (EGFr), platelet-derived growth factor receptor (PDGFr), erbB2, erbBA4, ret, vascular endothelial growth factor receptor (VEGFTr), tyrosine kinase with homology domains with immunoglobulin and epidermal growth factor (TIE-2), insulin growth factor-1 receptor (IGFI), macrophage colony stimulating factor (cfms), BTK, ckit, cmet, fibroblast growth factor (FGF) receptors, Trk receptors (TrkA, TrkB and TrkC), ephrin receptors (eph), and the RET proto-oncogene. Several growth receptor inhibitors are under development and include ligand antagonists, antibodies, tyrosine kinase inhibitors and antisense oligonucleotides. Growth factor receptors and agents that inhibit the function of growth factor receptors are described, for example, in Kath, John C., Exp. Opin. The R. Patents (2000) 10 (6): 803-818; Shawver et al., DDT Vol. 2, No. 2, February 1997; and Lofts, F. J. et al., "Growth factor receptors as targets", New Molecular Targets for Cancer Chemotherapy, ed. Workman, Paul and Kerr, David, CRC press 1994, London.
[0308] [0308] Tyrosine kinases that are not growth factor receptor kinases are called non-receptor tyrosine kinases. Non-receptor tyrosine kinases useful in the present invention, which are potential targets or targets for anticancer drugs, include cSrc, Lck, Fyn, Yes, Jak, cAbl, FAK (focal adhesion kinase), Bruton tyrosine kinase and Bcr-Abl. These non-receptor kinases and agents that inhibit the function of non-receptor tyrosine kinases are described in Sinh, S. and Corey, S.J., (1999) Journal of Hematotherapy and Stem Cell Research 8 (5): 465 - 480; and Bolen, J.B., Brugge, J.S., (1997) Annual review of Immunology, 15: 371-404.
[0309] [0309] SH2 / SH3 domain blockers are agents that disrupt the binding of the SH2 or SH3 domain in a variety of enzymes and adapter proteins including the PI8-K p8ê5 subunit, Src family kinases, adapter molecules (Shc, Crk, Nck , Grb2) and Ras-GAP. The SH2 / SH3 domains as a target for anticancer drugs are discussed in Smithgall, T.E. (1995), Journal of Pharmacological and Toxicological Methods, 34 (3) 125-132.
[0310] [0310] Serine / Threonine Kinase inhibitors, including MAP kinase blockers that include Raf kinase (rafk) blockers, Mitogen Regulated or Extracellular Kinase (MEKs), and Extracellular Regulated Kinases (ERKs); and blockers members of the protein kinase C family including PKC blockers (alpha, beta, gamma, epsilon, mu, lambda, iota, zeta). The IkB family of kinases (IKKa, IKKb), PKB family kinases, members of the akt kinase family and TGF receptor beta kinases. Such Serine / Threonine kinases and inhibitors thereof are described in Yamamoto, T., Taya, S., Kaibuchi, K., (1999), Journal of Biochemistry, 126 (5) 799-803; Brodt, P, Samani, A., and Navab, R. (2000), Biochemical Pharmacology, 60, 1101-1107; Massague, J., Weis-Garcia, F. (1996) Cancer Surveys, 27: 41-64; Philip, P.A., and Harris, AL. (1995), Cancer Treatment and Research, 78: 3-27, Lackey, K. et al., Bioorganic and Medicinal Chemistry Letters (10), 2000, 223-226; U.S. Patent No. 6,268,391; and Martinez-lacaci, L., et al., Int. J. Cancer (2000), 88 (1), 44-52.
[0312] [0312] Inhibitors of myo-inositol signaling, such as phospholipase C blockers and Myo-inositol analogs, are also useful in the present invention. Such signal inhibitors are described in Powis, G., and Kozikowski A., (1994) New Molecular Targets for Cancer Chemotherapy ed., Paul Workman and David Kerr, CRC press 1994, London.
[0313] [0313] Another group of inhibitors of signal transduction pathways includes inhibitors of the Ras oncogene. These inhibitors include farnesyl transferase, geranylgeranyl transferase and CAAX proteases, in addition to antisense oligonucleotides, ribozymes and immunotherapy. These inhibitors have been proven to block the activation of ras in cells containing wild-type mutant ras, thus acting as antiproliferation agents. The inhibition of the Ras oncogene is discussed in Scharovsky, O.G., Rozados, V.R., Gervasoni, S.l. Matar, P. (2000), Journal of Biomedical Science 7 (4) 292-8; Ashby, M.N. (1998), Current Opinion in Lipidology 9 (2) 99 - 102; and BioChim. Biophys. Acta, (1989) 1423 (3): 19-30.
[0314] [0314] As mentioned above, antibody antagonists for binding to the receptor kinase ligand may also act as signal transduction inhibitors. This group of inhibitors of signal transduction pathways includes the use of humanized antibodies to the binding domain of the extracellular tyrosine kinase receptor receptor. For example, the EGFR-specific antibody C225 (see Green, M.C. et al., Monoclonal Antibody Therapy for Solid Tumors, Cancer Treat. Rev., (2000), 26 (4), 269-286); erbB2 Herceptin® antibody (see Tyrosine Kinase Signalling in Breast cancer: erbB Family Receptor Tyrosine Kniases, Breast cancer Res., 2000, 2 (3), 176-183); and VEGFR2 2CB specific antibody (see Brekken, R.A. et al., Selective Inhibition of VEGFR2 Activity by a monoclonal Anti-VEGF antibody blocks tumor growth in mice, Cancer Res. (2000) 60, 5117-5124).
[0315] [0315] Antiangiogenic therapeutic agents including non-receptor MEK angiogenesis inhibitors may also be useful. Antiangiogenic agents, such as those that inhibit the effects of vascular endothelial growth factor (for example, the antivascular endothelial cell growth factor antibody bevacizumab [Avastin'Y], and compounds that act by other mechanisms (for example linomide, inhibitors integrin function avB3, endostatin and angiostatin).
[0316] [0316] Agents used in immunotherapeutic regimens may also be useful in combination with compounds of Formula (1). Immunotherapy approaches, including, for example, ex vivo and in vivo approaches to increase the immunogenicity of tumor cells in patients, such as transfection with cytokines such as interleukin 2, interleukin 4 or granulocyte-macrophage colony stimulating factor, approaches to decrease T cell energy, approaches using transfected immune cells such as cytokine-transfected dendritic cells, approaches using cytokine-transfected tumor cell lines and approaches using anti-idiotypic antibodies.
[0317] [0317] Therapeutic agents used in pro-apoptotic regimens (e.g., antisense bcl-2 oligonucleotides) can also be used in the combination of the present invention.
[0318] [0318] Cell cycle signaling inhibitors inhibit molecules involved in cell cycle control. A family of protein kinases called cyclin-dependent kinases (CDKs) and their interaction with a family of proteins called cyclins governs progression through the eukaryotic cell cycle. The coordinated activation and inactivation of different cyclin / CDK complexes is necessary for normal progression through the cell cycle. Several cell cycle signaling inhibitors are under development. For example, examples of cyclin-dependent kinases, including CDK2, CDK4 and CDKG6, and inhibitors thereof, are described, for example, in Rosania et al., Exp. Opin. The R. Patents (2000) 10 (2): 215-230.
[0319] [0319] In one embodiment, the combination of the present invention comprises a compound of Formula (I), or a salt thereof, in particular a pharmaceutically acceptable salt thereof, and at least one antineoplastic agent selected from antimicrotubule agents, coordination complexes platinum, agents —alkylating agents, antibiotic agents, topoisomerase inhibitors |, antimetabolites, topoisomerase | inhibitors, hormones and hormonal analogs, inhibitors of signal transduction pathways, inhibitors of non-receptive MEK tyrosine angiogenesis, immunotherapeutic agents, pro-agents -apoptotics and cell cycle signaling inhibitors.
[0320] [0320] IN one embodiment, the combination of the present invention comprises a compound of Formula (|), or a salt thereof, in particular a pharmaceutically acceptable salt thereof, and at least one antineoplastic agent, which is an antimicrotubule agent selected from among diterpenoids and vinca alkaloids.
[0321] [0321] In another embodiment, at least one antineoplastic agent is a diterpenoid. In another embodiment, at least one antineoplastic agent is a vinca alkaloid.
[0322] [0322] IN one embodiment, the combination of the present invention comprises a compound of Formula (! I), or a salt thereof, in particular a pharmaceutically acceptable salt thereof, and at least one antineoplastic agent, which is a coordination complex platinum.
[0323] [0323] In another modality, at least one antineoplastic agent is paclitaxel, carboplatin or vinorelbine. In another modality, at least one antineoplastic agent is carboplatin. In another embodiment, at least one antineoplastic agent is vinorelbine. In another embodiment, at least one antineoplastic agent is paclitaxel. In one embodiment, the combination of the present invention comprises a compound of Formula (|), or a salt thereof, in particular a pharmaceutically acceptable salt thereof, and at least one antineoplastic agent, which is an inhibitor of signal transduction pathways .
[0324] [0324] In another embodiment, the inhibitor of signal transduction pathways is an inhibitor of a growth factor receptor kinase VEGFR 2, TIE2, PDGFR, BTK, erbB2, EGFr, IGFR-1, TrkA, TrkB, TrkC or c-fms. In another embodiment, the inhibitor of signal transduction pathways is an inhibitor of a serine / threonine kinase rafk, akt or PKC-zeta. In another embodiment, the inhibitor of signal transduction pathways is an inhibitor of a non-receptor tyrosine kinase selected from the src family of kinases. In another embodiment, the inhibitor of signal transduction pathways is an inhibitor of c-src. In another embodiment, the inhibitor of signal transduction pathways is an inhibitor of the Ras oncogene selected from inhibitors of farnesyl transferase and geranylgeranyl transferase. In another embodiment, the inhibitor of signal transduction pathways is an inhibitor of a serine / threonine kinase selected from the group consisting of PI3K.
[0325] [0325] In another embodiment, the inhibitor of the signal transduction pathways is a double inhibitor of EGFr / erbB2, for example, N- (3-chloro-4 - [(3-fluorbenzyl) oxylphenyl) -6- [5- (([2- (methanesulfonyl) ethyl) methyl) -2-furyl] -4-quinazolinamine.
[0326] [0326] In one embodiment, the combination of the present invention comprises a compound of Formula (!), Or a salt thereof, in particular a pharmaceutically acceptable salt thereof, and at least one antineoplastic agent, which is an inhibitor of the signaling of cell cycle. In another embodiment, the cell cycle signaling inhibitor is an inhibitor of CDK2, CDK4 or CDK6.
[0327] [0327] Additional EXAMPLES of other therapeutic agents (for example, antineoplastic agent) for use in combination or co-administration with the compound of Formula (|) are immunomodulators.
[0328] [0328] As used in this document, "immunomodulators" refers to any substance, including monoclonal antibodies, that affects the immune system. Immunomodulators can be used as antineoplastic agents for cancer treatment. For example, immunomodulators include, among others, anti-CTLA-H antibodies, such as ipilimumab (YERVOY) and anti-PD-1 antibodies (Opdivo / nivolumab and Keytruda / pembrolizumab). Other immunomodulators include, but are not limited to, ICOS antibodies, OXA40 antibodies, PD-L1 antibodies, LAG3 antibodies, TIM-3 antibodies, 41BB antibodies and GITR antibodies.
[0329] [0329] Additional examples of other therapeutic agents (antineoplastic agent) for use in combination or co-administration with a compound of the present invention are anti-PD-L1 agents. Anti-PD-L1 antibodies and methods of producing them are known in the art. These antibodies against PD-L1 can be polyclonal or monoclonal, and / or recombinant, and / or humanized. Examples of PD-L1 antibodies are disclosed in U.S. Patent No. 8,217,149, 8,383,796,
[0330] [0330] In one embodiment, the antibody against PD-L1 is an antibody disclosed in U.S. Patent No. 8,217,149. In another embodiment, the anti-PD-L1 antibody comprises the CDRs of an antibody disclosed in U.S. Patent No.
[0331] [0331] Other examples of mAbs that bind to human PD-L1 and useful in the method of treatment, drugs and uses of the present invention are described in WOZ2013 / 019906, WO2010 / 077634 A1 and US8383796. Specific human anti-PD-L1 mAbs useful as PD-1 antagonists in the treatment method, medicaments and uses of the present invention include MPDL3280A, BMS-936559, MEDI4736, MSBOO010718C.
[0332] [0332] Additional examples of other therapeutic agents (antineoplastic agent) for use in combination or co-administration with a compound of the present invention are PD-1 antagonists.
[0333] [0333] "PD-1 antagonist" means any chemical compound or biological molecule that blocks the binding of PD-L1 expressed in a cancer cell with PD-1 expressed in an immune cell (T cell, B cell or NKT cell) and that preferably also blocks the binding of the PD-L2 expressed in a cancer cell with the PD-1 expressed in an immune cell. Alternative or synonymous names for PD-1 and its ligands include: PDCD1, PD1, CD279 and SLEB2 for PD-1; PDCD1L1, PDL1, B7H1, B7-4, CD274 and B7-H for PD-L1; and PDCD1L2, PDL2, B7-DC, Btde and CD273 for PD-L2. In any embodiment of the aspects or embodiments of the present invention in which a human individual will be treated, the PD-1 antagonist blocks the binding of human PD-L1 to human PD-1 and preferably blocks the binding of both PD- L1 as well as human PD-L2 with human PD-1. Amino acid sequences of human PD-1 can be found in NCBI locus No. NP 005009. Amino acid sequences of human PD-L1 and PD-L2 can be found in NCBI locus No. NP 054862 and NP 079515, respectively.
[0334] [0334] PD-1 antagonists useful in any aspect of the present invention include a monoclonal antibody (mAb), or antigen-binding fragment thereof, which specifically binds to PD-1 or PD-L1 and, preferably, it specifically binds to human PD-1 or human PD-L1. The mAb can be a human antibody, a humanized antibody or a chimeric antibody, and can include a human constant region. In some modalities, the human constant region is selected from the group composed of the IgG1, IgG2, IgG3 and IgG4 constant regions, and, in preferred modalities, the human constant region is an IgG1 or IgG4 constant region. In some embodiments, the antigen-binding fragment is selected from the group consisting of Fab, Fab'-SH, F (ab ') 2, scFv and Fv fragments.
[0335] [0335] Examples of mAbs that bind to human PD-1 and useful in the various aspects and modalities of the present invention are described in the documents
[0336] [0336] specific human anti-PD-1 mAbs useful as a PD-1 antagonist in any of the aspects and modalities of the present invention include: MK-3475, a humanized IgG4 mMAb with the structure described in WHO Drug Information, Vol. 27, nº 2, pages 161-162 (2013), and with the heavy and light chain amino acid sequences illustrated in Figure 6; nivolumab, a human IgG4 mAb with the structure described in WHO Drug Information, Vol. 27, no. 1, pages 68-69 (2013), and with the heavy and light chain amino acid sequences illustrated in Figure 7; the humanized antibodies h409A11, h409A16 and h409A17, which are described in WOZ2008 / 156712, and AMP-514, which is being developed by Medimmune.
[0337] [0337] Other PD-1 antagonists useful in any of the aspects and modalities of the present invention include an immunoadhesin that specifically binds to PD-1 and preferably specifically binds to human PD-1, for example, a fusion protein containing the PD-1 or extracellular binding portion of PD-L1 or PD-L2 fused to a constant region, such as an Fc region of an immunoglobulin molecule. Examples of immunoadhesive molecules that specifically bind PD-1 are described in WO 2010/027827 and WOZ2011 / 066342. Fusion-specific proteins useful as PD-1 antagonists in the method of treatment, medications and uses of the present invention include AMP-224 (also known as B7-DClIg), which is a PD-L2-FC fusion protein and human PD-1.
[0338] [0338] 0 —KEYTRUDA / pembrolizumab is an anti-PD-1 antibody marketed for the treatment of lung cancer by Merck. The amino acid sequence of pembrolizumab and methods for using it are disclosed in U.S. Patent No. 8,168,757.
[0339] [0339] Opdivo / nivolumab is a fully human monoclonal antibody marketed by Bristol Myers Squibb directed against the PD-1 negative immunoregulatory cell surface receptor (programmed death-1 or programmed cell death-1 / PCD-1) with immunopotentialization activity . Nivolumab binds and blocks the activation of PD-1, a transmembrane protein of the Ig superfamily, by its ligands PD-L1 and PD-L2, resulting in the activation of T cells and cell-mediated immune responses against tumor cells and pathogens. Activated PD-1 negatively regulates T cell activation and effector function by suppressing activation of the PISK / Akt pathway. Other names for nivolumab include: BMS-936558, MDX-1106 and ONO-4538. The amino acid sequence of nivolumab and methods for using and producing it are disclosed in U.S. Patent No. 8,008,449.
[0340] [0340] Additional examples of other therapeutic agents (antineoplastic agent) for use in combination or co-administration with the compound of Formula (1) are antibodies against ICOS.
[0341] [0341] ICOS is a co-stimulator T cell receptor with structural and functional relationship to the CD28 / CTLA-4-Ig superfamily (Hutloff, et al., "/ ICOS is an inducible T-cell co-stimulator structurally and functionally related to CD28 ", Nature, 397: 263-266 (1999)). The activation of ICOS occurs through connection by ICOS-L (B7RP-1 / B7-H2). Neither B7-1 nor B7-2 (ligands for CD28 and CTLA4) bind or activate ICOS. However, ICOS-L proved to bind weakly to both CD28 and CTLA-4 (Yao S et al., "B7-H2 is a costimulatory ligand for CD28 in human", Immunity, 34 (5); 40 (2011)). ICOS expression appears to be restricted to T cells. ICOS expression levels vary between different subsets of T cells and on the activation status of T cells. ICOS expression was displayed on latent TH17, follicular auxiliary T ( TFH) and regulatory T cells (Treg); however, unlike CD28, it is not highly expressed over populations of virgin ThW1 and effector Tr2 T cells (Paulos CM et al., "The inducible costimulator (ICOS) is critical for the development of human Th17 cells", Sci. Transl Med., 2 (55); 55ra78 (2010)). ICOS expression is highly induced in CD4 + and CD8 + effector T cells after activation by coupling with the TCR (Wakamatsu E, et a /., "Convergent and divergent effects of costimulatory molecules in conventional and regulatory CD4 + T cells", Proc. Natal Acad. Sci. USA, 110 (3); 1023-8 (2013)).
[0342] [0342] CDRs for murine antibodies against human ICOS with agonist activity are disclosed in PCT / EP2012 / 055735 (WOZ2012 / 131004). Antibodies against ICOS are also disclosed in WOZ2008 / 137915, WOZ2010 / 056804, EP1374902, EP1374901 and EP1125585.
[0343] [0343] Antibody agonists against ICOS or binding proteins with ICOS are disclosed in WOZ2012 / 13004, WO2014 / 033327, WO2016 / 120789, US20160215059 and US20160304610. In one embodiment, agonist antibodies against ICOS include ICOS binding proteins or antigen binding portions thereof comprising one or more of: CDRH1 as defined in SEQ ID NO: 1; CDRH2 as defined in SEQ ID NO: 2; CDRH3 as defined in SEQ ID NO: 3; CDRL1 as defined in SEQ ID NO: 4; CDRL2 as defined in SEQ ID NO: 5 and / or CDRL3 as defined in SEQ ID NO: 6 or a direct equivalent of each CDR, wherein a direct equivalent has no more than two amino acid substitutions in said CDR as disclosed in WO 2016/120789, which is incorporated into this document by reference in its entirety. In one embodiment, the ICOS binding protein or the antigen binding portion thereof is an agonist antibody against ICOS comprising a Vr domain with an amino acid sequence at least 90% identical to the amino acid sequence defined in SEQ ID No. 7 and / or a V. domain with an amino acid sequence at least 90% identical to the amino acid sequence as defined in SEQ ID NO: 8 as set out in WO2016 / 120789, in which said ICOS binding protein binds specifically to human ICOS. In one embodiment, the ICOS-binding protein is an agonist antibody against ICOS that comprises a Vx domain with the amino acid sequence defined in SEQ ID NO: 7 and a VL domain with the amino acid sequence defined in SEQ ID NO: 8 as set out in WO 2016/120789.
[0344] [0344] Yervoy (ipiimumab) is a human CTLA4 antibody marketed by Bristol Myers Squibb. The protein structure of ipilimumab and methods for using it are described in U.S. Patent Nos. 6,984,720 and 7,605,238.
[0345] [0345] CD134, also known as OX40, is a member of the TNFR receptor superfamily that is not constitutively expressed in latent virgin T cells, unlike CD28. OX40 is a secondary co-stimulating molecule, expressed 24 to 72 hours after activation; its ligand, OX40L, is also not expressed in cells with latent antigens, but follows its activation. The expression of OX40 depends on the total activation of the T cell; without CD28, OX40 expression is delayed and four times less. Antibodies against OX-40, OX-40 fusion proteins and methods for using them are disclosed in U.S. Patent Nos. US 7,504,101, US 7,758,852, US 7,858,765, US 7,550,140, US
[0346] [0346] In one embodiment, the binding protein with the OX40 antigen is one disclosed in WOZ2012 / 027328 (PCT / US2011 / 048752), international filing date on August 23, 2011. In another embodiment, the binding protein with antigen comprises the CDRs of an antibody disclosed in WO2012 / 027328 (PCT / US2011 / 048752), international filing date 23 August 2011, or CDRs with 90% identity to the revealed CDR sequences. In another embodiment, the antigen binding protein comprises a VH, a VL, or both of an antibody disclosed in WO2012 / 027328 (PCT / US2011 / 048752), international filing date 23 August 2011, or a VH or a VL with 90% identity to the revealed VH or VL sequences.
[0347] [0347] In another embodiment, the binding protein with the OX40 antigen is disclosed in WO2013 / 028231 (PCT / US2012 / 024570), international filing date 9 February 2012, which is incorporated by reference in its entirety by reference. . In another embodiment, the antigen-binding protein comprises the CDRs of an antibody disclosed in WO2013 / 028231 (PCT / US2012 / 024570), international filing date 9 February 2012, or CDRs with 90% identity to the sequences of CDRs revealed. In another embodiment, the antigen-binding protein comprises a VH, a VL or both of an antibody disclosed in WO2013 / 028231 (PCT / US2012 / 024570), international filing date 9 February 2012, or a VH or a VL with 90% identity to the revealed VH or VL sequences. In one embodiment, the OX40 antigen binding protein is an agonist antibody isolated against OX40 that comprises a light chain variable region with a sequence at least 90% identical to the amino acid sequence SEQ ID NO: 10 as defined in WO2013 / 028231 and a heavy chain variable region with a sequence at least 90% identical to the amino acid sequence of SEQ ID NO: 4 as defined in WO2013 / 028231. In one embodiment, the OX40 antigen-binding protein is an isolated antibody comprising a light chain variable region with the amino acid sequence of SEQ ID NO: 10 as defined in WO2013 / 028231 and a heavy chain variable region with the amino acid sequence of SEQ ID NO: 4 as defined in WO2013 / 028231.
[0348] [0348] Therefore, in one embodiment, methods are proposed to treat a human being who needs them, which include administering a compound of Formula (Il), or a salt thereof, and at least an immunomodulator. In one embodiment, the immunomodulator is selected from an agonist antibody against ICOS, an antibody against OX-40 or an antibody against PD-1. In one embodiment, the human being suffers from cancer. It is also proposed in this document to use a compound of Formula (1), or a salt thereof, in combination with at least one immunomodulator for the treatment of a human being who needs it.
[0349] [0349] Additional examples of other therapeutic agents for use in combination or co-administration with a compound of Formula (1), or with a salt thereof, are immunostimulating agents.
[0350] [0350] As used in this document, "immunostimulating agent" refers to any agent that is capable of stimulating the immune system. As used herein, immunostimulatory agents include, but are not limited to, vaccine adjuvants, such as Toll-like receptor agonists, T cell control point blockers, such as mAbs against PD-1 and CTLA, and control of T cells, such as mAbs agonists against OX40 and ICOS.
[0351] [0351] The term "Toll-like receptor" (or "TLR"), as used in this document, refers to a member of the Toll-like receptor protein family, or a fragment thereof, that detects a product microbial and / or initiate an adaptive immune response. In one embodiment, a TLR activates a dendritic cell (DC). Toll-like receptors (TLRs) are a family of pattern recognition receptors that were initially identified as innate immune system detectors that recognize microbial pathogens. TLRs recognize distinct structures in microbes, often called "PAMPs" (molecular patterns associated with pathogens). The binding of a ligand with TLRs invokes a cascade of intracellular signaling pathways that induce the production of factors involved in inflammation and immunity. In humans, ten TLRs have been identified. The
[0352] [0352] TLR agonists known in the art and which find use in the present invention include, among others, the following: Pam3Cys, a TLR1 / 2 agonist; CFA, a TLR2 agonist; MALP2, a TLR2 agonist; Pam2Cys, a TLR2 agonist; FSL-I, a TLR2 agonist; Hib-OMPC, a TLR2 agonist; polyinosinic acid: polycytidyl (Poli EC), a TLR3 agonist; polyadenosine-polyuridyl acid (poly AU), a TLR3 agonist; polyinosinic-polycytidyl acid stabilized with poly-L-lysine and carboxymethylcellulose (Hiltonol), a TLR3 agonist; bacterial flagellin, a TLR5 agonist; imiquimod, a TLR7 agonist; resiquimod, a TLR7 / 8 agonist; ioxoribine, a TLR7 / 8 agonist; and unmethylated CpG dinucleotide (CPG-ODN), a TLR9 agonist.
[0353] [0353] Other TLR agonists known in the art that find use in the present invention further include, but are not limited to, aminoalkyl glycosaminide phosphates (AGPs) that bind to the TLR4 receptor are known to be useful as vaccine adjuvants and immunostimulatory agents to stimulate cytokine production, activate macrophages, promote innate immune response and increase antibody production in immunized animals. An example of a naturally occurring TLRA4 agonist is the bacterial lipopolysaccharide. Suitably, a TLR4 agonist is a non-toxic derivative of lipid A. An example of a non-toxic semi-synthetic derivative of the TLRA4 agonist of lipid A is monophosphoryl lipid A, and in particular monophosphoryl lipid A 3-des-O-acylated (3D -MPL). 3D-MPL is marketed under the name of MPL by GlaxoSmithKline Biologicals SA AGPs and its immunomodulatory effects via TLR4 are revealed in patent publications such as WO2006 / 016997, WO2001 / 090129 and / or US Patent No. 6,113,918 and have been disclosed in literature. Other AGP derivatives are disclosed in U.S. Patent No. 7,129,219, U.S. Patent No. 6,525,028 and U.S. Patent No.
[0354] [0354] In one embodiment, the immunostimulating agent for use in combination with the compounds of the present invention is a TLR4 agonist. In one embodiment, the TLR4 agonist is called CRX-601 and CRX-527. Their structures are defined according to the following:
[0355] [0355] In addition, another preferred modality makes use of the TLRA4 CRX 547 agonist with the illustrated structure.
[0356] [0356] Still other modalities include AGP's, such as CRX 602 or CRX 526, providing greater stability to AGPs with minor secondary acyl or alkyl chains. oH Ho | no ”and o o Ce O: NK o Oo: o! CRX 602 the pH
[0357] [0357] Therefore, in one embodiment, methods are proposed to treat a human being who needs them, which include administering a compound of Formula (1), or a salt thereof, and at least an immunostimulator. In one embodiment, the immunostimulating agent is a TLR4 agonist. In one embodiment, the immunostimulating agent is an AGP. In yet another modality, the TLRA4 agonist is selected from a compound with the formula CRX-601, CRX-527, CRX-547, CRX-602 or CRX-526. In one embodiment, the human being suffers from cancer. It is also proposed in this document to use a compound of Formula (|), or a salt thereof, in combination with at least one immunostimulator for the treatment of a human being who needs it.
[0358] [0358] In addition to the immunostimulatory agents described above, the compositions of the present invention can also comprise other therapeutic agents which, thanks to their adjuvant nature, can act to stimulate the immune system to respond to cancer antigens present in inactivated tumor cells. Such adjuvants include, but are not limited to, lipids, liposomes, inactivated bacteria that induce innate immunity (for example, inactivated or attenuated Listeriamonocytogenes), compositions that mediate innate immune activation via receptors similar to (NOD) (NLRs), receptors similar to (RIG) ) - | (RLRs) based on inducible retinoic acid genes, and / or type C lectin receptors (CLRs). Examples of PAMPs include lipoproteins, lipopolypeptides, peptidoglycans, zymosan, liposaccharide, neisserial porins, flagellin, profilinay galactoceramiday muramil dipeptide. Peptidoglycans, lipoproteins and lipoteic acids are components of Gram-positive cell walls. Lipopolysaccharides are expressed by most bacteria, MPL being an example. Flagellin refers to the structural component of the bacterial flagellum that is secreted by pathogenic and commensal bacteria. Rt.- Galactosylceramide (rt.-GalCer) is a natural killer T cell activator (NKT). Muramyl dipeptide is a bioactive peptidoglycan motif common to all bacteria.
[0359] [0359] Thanks to their adjuvant qualities, TLR agonists are preferably used in combinations with other vaccines, adjuvants and / or immunological modulators and can be combined in various combinations. Thus, in certain embodiments, the compounds of Formula (1) described in this document that bind to STING and induce the activation of STING-dependent TBKIs and an inactivated tumor cell that expresses and secretes one or more cytokines that stimulate induction , recruitment and / or maturation of DCs, as described in this document, may be administered together with one or more TLR agonists for therapeutic purposes.
[0360] [0360] Indoleamine 2,3-dioxigenase 1 (IDOI) is a key immunosuppressive enzyme that modulates the anti-tumor immune response by promoting the generation of regulatory T cells and blocking the activation of effector T cells, thus facilitating tumor growth by allowing cancer cells avoid immune surveillance (Lemos H, et al, Cancer Res., April 15, 2016; 76 (8): 2076-81), (Munn DH, et al., Trends Immunol., March 2016; 37 (3): 193-207). Other active ingredients (antineoplastic agents) for use in combination or co-administered with the compounds of Formula (I) of the present invention are IDO inhibitors. Epacadostat, ((Z) -N- (3-bromo-4-fluorophenyl) -N'-hydroxy-4- [2- (sulfamoylamino) ethylamino] -1,2,5-oxadiazole-3-carboxamidine), is a highly potent and selective oral inhibitor of the IDO1 enzyme that reverses tumor-associated immune suppression and restores effective anti-tumor immune responses. Epacadostat is disclosed in U.S. Patent No. 8,034,953.
[0361] [0361] Additional examples of other therapeutic agents (antineoplastic agent) for use in combination or co-administration with a compound of Formula (1) are inhibitors of CD73 and antagonists of A2a and A2b adenosine.
[0362] [0362] In one embodiment, the compound of the invention can be used in conjunction with other therapeutic methods to treat an infectious disease. In particular, antiviral and antibacterial agents are contemplated.
[0363] [0363] The compounds of Formula (I), and pharmaceutically acceptable salts thereof, can be used in combination with at least one other therapeutic agent useful in the prevention or treatment of bacterial and viral infections. Examples of such agents include, but are not limited to: polymerase inhibitors such as those disclosed in WO2004 / 037818-A1, as well as those disclosed in WO2004 / 037818 and WO2006 / 045613; JTK-003, JTK-019, NM-283, HCV-796, R-803, R1728, R1626, as well as those disclosed in WOZ2006 / 018725, WOZ2004 / 074270, WO2003 / 095441, US2005 / 0176701, WO2006 / 020082, WOZ2005 / 080388, WO2004 / 064925, WO2004 / 065367, WO2003 / 007945, WO02 / 04425, WO 2005/014543, WOZ2003 / 000254, EP1065213, WO 01/47883, WO2002 / 057287, WO2002 / 057245 and similar agents; replication inhibitors, such as acyclovir, famciclovir, ganciclovir, cidofovir, lamivudine and similar agents; protease inhibitors, such as the HIV protease inhibitors saquinavir, ritonavir, indinavir, nelfinavir, amprenavir, fosamprenavir, brecanavir, atazanavir, tipranavir, palinavir, lasinavir, and the HCV protease inhibitors BILN2061, VX-950; and similar agent; nucleoside and nucleotide reverse transcriptase inhibitors, such as zidovudine, didanosine, lamivudine, zalcitabine, abacavir, stavudine, adefovir, adefovir dipivoxil, fozivudine, todoxili emtricitabine, alovudinay amdoxovir, tenvofitate, elvucitamine, tenvofitamine, , and similar agents; non-nucleoside reverse transcriptase inhibitors (including an agent with antioxidant activity such as immunocal, oltipraz, etc.), such as nevirapine, delavirdine, efavirenz, loviride, immunocal, oltipraz, capravirine, TMC-278, TMC-125, etravirine, rilpivirine and similar agents; entry inhibitors, such as enfuvirtide (T-20), T-1249, PRO-542, PRO-140, TNX-355, BMS-806, 5-Helix and similar agents; integrase inhibitors, such as dolutegravir, elvitegravir, raltegravir L-870,180 and similar agents; germination inhibitors, such as PA-344 and PA-457, and similar agents; chemokine receptor inhibitors, such as vicriviroc (Sch-C), Sch-D, TAK779, maraviroc (UK-427.857), TAK449, as well as those disclosed in WO 02/74769, WO2004 / 054974, WO2004 / 055012, WO2004 / 055010, WO2004 / 055016, WOZ2004 / 055011 and WO2004 / 054581, and the like; pharmacokinetic enhancers, such as cobicistat; neuraminidase inhibitors, such as CS-8958, zanamivir, oseltamivir, peramivir and similar agents; ion channel blockers, such as amantadine or rimantadine and similar agents; and interfering RNA and antisense oligonucleotides, such as ISIS-14803 and similar agents; antiviral agents with indeterminate mechanism of action, for example, those disclosed in WOZ2005 / 105761, WO2003 / 085375, WO2006 / 122011, ribavirin, and similar agents.
[0364] [0364] The compounds of Formula (I), and pharmaceutically acceptable salts thereof, may also be used in combination with other therapeutic agents that may be useful in the treatment of Kaposi's sarcoma-associated herpesvirus (KSHV and KSHV-related) infections , including, but not limited to, chemotherapeutic agents such as bleomycin, vinblastine, vincristine, cyclophosphamide, prednisone, alitretinoin and liposomal anthracyclines, such as doxorubicin, - daunorubicin, - immunotherapeutics such as Rituximab, Tocilizumab, Siltuximaita and others such as Rapid and Rapid.
[0365] [0365] In one embodiment of the present invention, the at least one other therapeutic agent is an antimycobacterial agent of a bactericidal antibiotic. The compounds of Formula (1), and pharmaceutically acceptable salts thereof, can also be used in combination with at least one other therapeutic agent that may be useful in the treatment against an infection by TB (Mycobacterium tuberculosis) and Tularemia (Francisella tularensis), including, but not limited to, first-line oral agents isoniazid, Rifampicin, pyrazinamide, ethambutol, streptomycin, rifabutin; injectable agents including kanamycin, amikacin, capreomycin, streptomycin; fluoroquinolones including levofloxacin, moxifloxacin, ofloxacin; oral bacteriostatic agents para-aminosalicylic acid, cycloserine, terizidone, thionamide, protionamide; SQ-109 PNU-100480, Rifapentine, Linezolid, PA-824 AZD5847, Gatifloxacin, Moxifloxacin, Sirturo (bedaquiline), Delamanide (OPC-67683), and agents with an undetermined mechanism of action in the treatment of drug-resistant TB, including clofazine, linezolid, amoxicillin / clavulanate, thioacetazone, imipenem / cilastatin, high dose isoniazid, clarithromycin, ciprofloxacin. The compounds of Formula (1), and pharmaceutically acceptable salts thereof, can also be used in combination with an antimycobacterial agent (such as isoniazid (INH), ethambutol (Myambutolº), rifampin (Rifadinº) and pyrazinamide (PZA)), one bactericidal antibiotic (such as rifabutin (Mycobutinº) or rifapentin (Priftinº)), an aminoglycoside (Capreomycinº), a fluoroquinolone (levofloxacin, moxifloxicin, ofloxacin), thioamide (etionamide), cyclosporine (Eosiline), cycloserine (Seromycinº), kanamycin (Kantrexº), streptomycin, viomycin, capreomycin
[0366] [0366] The compounds of Formula (|), and pharmaceutically acceptable salts thereof, may also be used in combination with at least one other therapeutic agent that may be useful in the treatment of Chlamydia, including, but not limited to, Azithromycin, Doxycycline, Erythromycin , Levofloxacin, Ofloxacin.
[0367] [0367] The compounds of the present invention may also be useful in combination with at least one other therapeutic agent that may be useful in the treatment of a plasmodium infection, including, but not limited to, chloroquine, atovaquone-proguanil, artemether-lumefantrine, mefloquine, quinine, quinidine, doxocycline, cindamycin, artesunate, primaquine.
[0368] [0368] In the treatment of amyotrophic lateral sclerosis (ALS), a compound of Formula (Il), or a pharmaceutically acceptable salt thereof, can be used in combination with a glutamate blocker (Riluzole (Rilutek &)), quinidine (Nuedexta & ), anticholinergics (amitriptylineG, Artane &, scopolamine adhesive (Transderm Scop6)), sympathomimetic agents (pseudoephedrine), mucolytic agents (guaifenesin) or analgesic agents (tramadol (Ultrtam &G); ketorolac (Toradol &);morphine; )).
[0369] [0369] In the treatment of multiple sclerosis, a compound of Formula (1), or pharmaceutically acceptable salts thereof, can be used in combination with corticosteroids (prednisone, methylprednisolone), Interferon Beta-1A (Avonex &, Extavia &, Rebifo, Betaseron & G) , peginterferon beta-1A (Plegridy & S), glatiramer acetate (CopaxoneG &); glatiramer acetate (the generic equivalent of Copaxona Glatopa &); dimethyl fumarate (Tecfidera &); Fingolimod (Gilenya &)); teriflunomide (Aubagio &); dalfampridine (Ampyra &); daclizumab (Zinbryta); alemtuzumab (Lemtrada &); natalizumab (Tysabrio); or mitoxantrone chloriddate (Novantrone &).
[0370] [0370] The compounds of the present invention can also be used as adjuvants to enhance the elevated immune response against any given antigen and / or reduce the reactogenicity / toxicity in a patient, particularly a human, who needs them. As such, a compound of the present invention can be used in combination with vaccine compositions to modify, in particular to enhance, the immune response, for example, by increasing the level or duration of protection and / or allowing a reduction in the antigenic dose.
[0371] [0371] The compounds of Formula (I), and pharmaceutically acceptable salts thereof, can be used in combination with at least one or more vaccines or immunogenic antigens useful in the prevention or treatment of viral infections. Such vaccines or immunogenic antigens include, but are not limited to, proteins or particles derived from pathogens, such as attenuated viruses, virus particles and viral proteins, typically used as immunogenic substances. Examples of viruses and viral antigen sources include, but are not limited to, poliovirus, Chloronaviridae and coronavirus, rhinovirus (all subtypes), adenovirus (all subtypes), Hepatitis A, Hepatitis B, Hepatitis C, Hepatitis D, human papillomavirus (including all subtypes), rabies virus, human T-cell lipotropic virus (all subtypes), rubella virus, mumps virus, Coxsackie A virus (all subtypes), Coxsackie B virus (all subtypes), human enteroviruses, herpesvirus including cytomegalovirus, Epstein-Barr virus, human herpesvirus (all subtypes), herpes simplex virus, varicella-zoster virus, human immunodeficiency virus (HIV) (all subtypes), Epstein-Barr virus, reovirus (all subtypes) , phyloviruses including Marburg virus and Ebola virus (all strains), arenavirus including lymphocytic choriomeningitis virus, Lassa virus, Junin virus, and Machupo virus, arbovirus including West Nile virus, dengue virus (all serotypes os), Zika virus, Colorado tick fever virus, Syndis virus, Togaviridae, Flaviviridae, Bunyaviridae, Reoviridae, Rhabdoviridae, Orthomyxoviridae, smallpox virus including orthopoxvirus (smallpox virus, monkey pox virus, Vaccinia virus cowpox), yatapoxvirus (tanapox virus, Yaba monkey tumor virus), parapoxvirus, molluscipoxvirus, yellow fever, hantavirus including Hantaan, Seoul, Dobrava, Sin Nombre, Puumala, and Dobrava-like Saaremaa, human para-influenza virus ( all types), influenza virus HIN1 and swine influenza, respiratory syncytial virus (all subgroups), rotavirus including human rotavirus A to E, bovine rotavirus, monkey rhesus rotavirus, polyomavirus including simian virus 40, JC virus, BK virus , Coltivirus, Eyach virus, calcivirus, and Parvoviridae including dependovirus, parvovirus and erythrovirus.
[0372] [0372] In another aspect, the invention proposes methods for curing HIV comprising administering to a patient a compound of the invention. "Healing" a patient or "curing" a patient are used to indicate the eradication, interruption, paralysis or end of the human immunodeficiency virus or its symptoms, or the progression of the virus or its symptoms, over a defined period. As an example, in one embodiment, "cure" or "cure" refers to therapeutic administration or a combination of administration that alone or in combination with one or more agents causes and maintains sustained viral control (undetectable levels of viremia in plasma, for example, according to a polymerase chain reaction test (PCR), bDNA test (branched chain DNA) or NASBA test (amplification based on nucleic acid sequence) of the human immunodeficiency virus after a minimum of, for example, a year or two without any other therapeutic intervention. The PCR, bDNA and NASBA tests above are performed using techniques known and familiar to those skilled in the industry. As an example, the eradication, interruption, paralysis or end of the human immunodeficiency virus or its symptoms, or the progression of the virus or its symptoms, can be sustained for a minimum of two years.
[0373] [0373] In another embodiment of the present invention, a compound of the invention is proposed for use in curing an HIV infection.
[0374] [0374] In another embodiment of the present invention, it is proposed to use a compound of the invention in the manufacture of a medicament to cure an HIV infection.
[0375] [0375] In another aspect, a combination is proposed which comprises a compound of the invention and one or more additional pharmaceutical agents active against HIV. These compounds and agents can be present in a pharmaceutical formula or composition. Thus, the invention also encompasses methods for treating, curing and / or preventing HIV infection in a patient by administering to him a combination (or pharmaceutical formula or composition) comprising a compound of the invention and one or more additional active pharmaceutical agents against HIV.
[0376] [0376] In these modalities, one or more additional active agents against HIV are selected from the group consisting of zidovudine, didanosine, lamivudine, zalcitabine, abacavir, stavudine, adefovir, adefovir dipivoxil, fozivudine, todoxil, emtricitabine, alovudine, amdoxovovine, amdoxovovine elvucitabine, nevirapine, delavirdine, efavirenz, loviride, immunocal, oltipraz, capravirin, lersivirine, GSK2248761, TMC- 278, TMC-125, etravirine, saquinavir, ritonavir, indinavir, nelfinavir, amprenavir, tipravir, tarnavir, ataprenavir, levam palinavir, lasinavir, enfuvirtide, T-20, T-1249, PRO-542, PRO-140, TNX-355, BMS-806, BMS-663068 and BMS-626529, 5-Helix, raltegravir, elvitegravir, dolutegravir, cabotegravir, vicriviroc (Sch-C), Sch-D, TAK779, maraviroc, TAK449, didanosine, tenofovir, lopinavir and darunavir.
[0377] [0377] As such, the compounds of the present invention, and any other pharmaceutically active agents, can be administered together or separately and, when administered separately, administration can occur simultaneously or in sequence, in any order. The amounts of the compounds of the present invention and the other pharmaceutically active agent (s) and the relative times of administration will be selected in order to obtain the desired combined therapeutic effect. Administration in combination of compounds of the present invention together with other treatment agents can be in combination by concomitant administration in: (1) a unitary pharmaceutical composition that includes both compounds; or (2) separate pharmaceutical compositions, each including one of the compounds. Alternatively, the combination can be administered separately in a sequence, with one treatment agent being administered first and the other second or vice versa. This sequential administration can be closed in time or remote in time. The amounts of the compounds of the present invention and the other pharmaceutically active agent (s) against HIV and the relative times of administration will be selected in order to obtain the desired combined therapeutic effect.
[0378] [0378] In addition, the compounds of the present invention can be used in combination with one or more other agents that may be useful in preventing, treating or curing HIV. Examples of such agents include: nucleotide reverse transcriptase inhibitors, such as zidovudine, didanosine, lamivudine, zalcitabine, abacavir, stavudine, adefovir, adefovir dipivoxil, fozivudine, todoxil, emitricitabine, alovudine, amdoxovir, TD and similar; non-nucleotide reverse transcriptase inhibitors (including an agent with antioxidant activity, such as immunocal, oltipraz, etc.), such as nevirapine, delavirdine, —efavirenz, loviride, immunocal, oltipraz, capravirine, lersivirine, GSK2248761, TMC-278, TMC- 125, etravirine, and similar agents; protease inhibitors, such as saquinavir, ritonavir, indinavir, nelfinavir, amprenavir, fosamprenavir, brecanavir, darunavir, atazanavir, tipranavir, palinavir, lasinavir, and the like; integrase inhibitors, such as raltegravir, elvitegravir, bictegravir, dolutegravir, cabotegravir, and similar agents; maturation inhibitors, such as PA-344 and PA-457, and similar agents; and inhibitors of GSK2838232.CXCR4 and / or CCR5, such as vicriviroc (Sch-C), Sch-D, TAK779, maraviroc (UK 427.857), TAK449, as well as those disclosed in WO 02/74769, PCT / US03 / 39644, —PCT / US03 / 39975, PCT / US03 / 389619, PCT / US03 / 39618, PCT / US03 / 39740, and PCT / US03 / 39732, and similar agents.
[0379] [0379] The scope of combinations of compounds of the present invention with agents against HIV is not limited to those mentioned above, but includes, in principle, any combination with any pharmaceutical composition useful for the cure, treatment and / or prevention of HIV. As mentioned, in these combinations, the compounds of the present invention and other agents against HIV can be administered separately or together. In addition, an agent can be administered before, simultaneously, or after administration of another agent (s).
[0380] [0380] The present invention can be used in combination with one or more agents useful as pharmacological enhancers, as well as with or without additional compounds for the prevention or treatment of HIV. Examples of such pharmacological enhancers (or pharmacokinetic boosters) include, but are not limited to, ritonavir, GS-9350 and SPI-452.
[0381] [0381] Ritonavir is 10-hydroxy-2-methyl-5- (1-methylethyl) -1-1 [2- (1-methylethyl) -4-thiazolyl] -3,6-dioxo-8.11 -bis (phenylmethyl) -2,4,7,12-tetraazatridecan-13-oico, 5-thiazolylmethyl ester [58- (58 *, 8R *, 10R *, 11R *)] and is available from Abbott Laboratories of Abbott park , Illinois, under the name of Norvir. Ritonavir is an HIV protease inhibitor indicated together with other antiretroviral agents for the treatment against HIV infection. Ritonavir also inhibits the metabolism of P450-mediated drugs, as well as the P-glycoprotein (Pgp) cell transport system, thus resulting in higher concentrations of the active compound within the body.
[0382] [0382] GS-9350 is a compound developed by Gilead Sciences of Foster City California as a pharmacological intensifier.
[0383] [0383] SPI-452 is a compound under development by Sequoia Pharmaceuticals of Gaithersburg, Maryland, as a pharmacological intensifier.
[0384] [0384] The other therapeutic agents above, when used in combination with the compound of the invention, can be used, for example, in the amounts indicated in Physicians' Desk Reference (PDR) or as otherwise determined by those skilled in the art.
[0385] [0385] In another embodiment of the invention, a method for treating HIV infection in a patient is proposed which comprises administering to him a combination as set forth in this document.
[0386] [0386] In another embodiment of the invention, a method for curing an HIV infection in a patient is proposed which comprises administering to him a combination as set forth in this document.
[0387] [0387] In another embodiment of the invention, a method for preventing HIV infection in a patient is proposed which comprises administering to him a combination as set forth in this document.
[0388] [0388] In another embodiment of the invention, a combination as set out in this document for use as a medicine to treat HIV is proposed.
[0389] [0389] In another embodiment of the invention, a combination as set out in this document for use as a medicine to prevent HIV is proposed.
[0390] [0390] In another embodiment of the invention, a combination as set out in this document for use as a medicine to cure HIV is proposed.
[0391] [0391] In another embodiment of the invention, a combination as set forth in this document for use in the treatment of an HIV infection is proposed.
[0392] [0392] In another embodiment of the invention, a combination as set out in this document for use in preventing an HIV infection is proposed.
[0393] [0393] In another embodiment of the invention, a combination as proposed in this document is proposed for use in curing an HIV infection.
[0394] [0394] In another embodiment of the present invention, it is proposed to use a combination as set out in this document in the manufacture of a drug to treat an HIV infection.
[0395] [0395] In another embodiment of the present invention, it is proposed to use a combination as set out in this document in the manufacture of a medicament to prevent HIV infection.
[0396] [0396] In another embodiment of the present invention, it is proposed to use a combination as set out in this document in the manufacture of a drug to cure an HIV infection.
[0397] [0397] Therefore, the present invention proposes an immunogenic composition that comprises an antigen or antigenic composition and a compound of Formula (I), or a pharmaceutically acceptable salt thereof. A vaccine composition is also proposed which comprises an antigen or antigenic composition and a compound of Formula (1), or a pharmaceutically acceptable salt thereof.
[0398] [0398] The compounds of Formula (1), and pharmaceutically acceptable salts thereof, can also be used in combination with at least one other therapeutic agent that may be useful in the prevention or treatment of viral infections, for example, immunological therapies (for example, example, interferon or other cytokines / chemokines, cytokine / chemokine receptor modulators, cytokine agonists or antagonists, and the like); and therapeutic vaccines, anti-fibrotic agents, anti-inflammatory agents, such as corticosteroids or NSAIDs (non-steroidal anti-inflammatory agents) and similar agents.
[0399] [0399] A compound that modulates STING, in particular a compound of Formula (1)) or a pharmaceutically acceptable salt thereof, can be administered in combination with other anti-inflammatory agents, including oral or topical corticosteroids, anti-TNF agents , preparations of 5-aminosalicylic acid and mesalamine, hydroxychloroquine, thiopurines, methotrexate, cyclophosphamide, cyclosporine, calcineurin inhibitors, mycophenolic acid, mTOR inhibitors, JAK inhibitors, Syk inhibitors, RIPK1 inhibitors and RIPK2, biological agents , including biological anti-IL6, anti-IL1 agents, biological anti-IL17, anti-CD22, anti-integrin agents, anti-| FNa, biological anti-CD20 or anti-CD4 agents and other cytokine inhibitors or biological agents against receptors of T cells or B cells or interleukins.
[0400] [0400] For example, in the treatment of systemic lupus erythematosus and lupus-related disorders, a compound that modulates STING, in particular a compound of Formula (|), or a pharmaceutically acceptable salt thereof, may be administered in combination with at least one therapeutic agent, including a corticosteroid (such as prednisolone (Delatsoneº, Orapred, Millipred, Omnipred, Econopred, Flo-Pred), an immunosuppressive agent (such as methotrexate
[0401] [0401] In the treatment of Sjogren's syndrome, a compound that modulates STING, in particular a compound of Formula (1), or a pharmaceutically acceptable salt! it can be administered in combination with antirheumatic agents (hydroxychloroquine and Plaquenilº, Ridauraº, Kineretº), cholinergic agonists (Salagenº, Evoxacº), a JAK inhibitor (Xelijanzº, and anti-TNFa treatments (Remicadeº, Humiraº, Enbrºº, Enbrelº, Simponiº).
[0402] [0402] In the treatment of vasculitis and a disease with inflammation of small or medium-sized blood vessels, a compound that modulates STING, in particular a compound of Formula (|), or a pharmaceutically acceptable salt thereof, can be administered in combination with alkylating agents (cyclophosphamide, “Cytoxanº), anti-CD20 anti-rheumatic antibodies (Rituxanº, Rituximabº) and anti-TNFa inhibitors (Etanrceptº).
[0403] [0403] In the treatment of psoriasis, a compound that modulates STING, in particular a compound of Formula (1I), or a pharmaceutically acceptable salt thereof, can be administered in combination with ixekizumab, tildrakizumab, secukinumab, alefacept, calcipotriene and dipropionate betamethasone, prednisone, topical tazorac gel, methotrexate, cyclosporine, fumaric acid, acitretin, phototherapy (UVA, UVB), psoralen, coal tar, TNF inhibitors (etanercept, inflivimab, adalimumab, certolizumab pegol-, PDolE inhibitors) 4 (apremilast), JAK inhibitors (tofacitinib), IL 12/23 (ustekinumab), IL17 (secukinumabe, ixekizumab, brodalumab with AMG-827), 1123 (tildrakizumab with MK-3222, guselkumabe, itolizumabe, infl (Inflectra &), Sandoz GP 11111), rituximab biosimilars (CT-P10 (Mabthera &), PF-05280586 (MabTheraO)), etanercept biosimilars (CHS-2014), adalimumab biosimilars (GP-2017), topical vitamin D M -518101; Maruho GK-664, or C T-327 (topical tropomyosin kinase A receptor), CF-101, secukinumab (AIN457), or dimethyl fumarate LAS-41008.
[0404] [0404] In the treatment of rheumatoid arthritis, a compound that modulates STING, in particular a compound of Formula (1), or a pharmaceutically acceptable salt thereof, can be administered in combination with tocilizumab, DMARDs (methotrexate, hydroxychloroquine, sulfasalazine, leflunomide), disease delayed by sulfasalazine, certolizumab pegol, ibuprofen, naproxen sodium, adalimumab, Kineret; etodolac, naproxen sodium, abatacept, prednisone, inflimimab, golimuma, rofecoxib, tofacitinib, methotrexate, selective inhibitors of JAK1 & JAK2 (baracitinib), antisense oligonucleotide (alicafosene) (inflima) (inflima) Aprogen), infliimab SB2, infliimab PF-06438179, GP11111, rituximab biosimilars (CT-P10 rituximab —Celltrion),) BI-695500, GP-2013, PF-05280586, etanercept biosimilars (etanercept SB4 (Brenzys' ") , Benepali6; etanercept CHS-0214, GP-2015, adalimumab biosimilars (ABP-501 adalimumab, BI-695501, Samsung SB5, GP-2017. PF-06410293, Momenta M923, or abatacept biosimilar (M834).
[0405] [0405] In another embodiment, a compound that modulates STING, in particular a compound of Formula (I), or a pharmaceutically acceptable salt thereof, can be administered to a patient who needs it in combination with at least one other therapy and / or at least one other active therapeutic agent that is considered a standard of care (US Department of Health and Human Services, US Agency for Research and Quality in Health, National Guideline Clearinghouse, https://www.guideline.gov/ and World Health Organization, http://www.who.int/management/quality/standards/en/) for any of the diseases and / or disorders mentioned in this document.
[0406] [0406] In another embodiment, a compound that modulates STING, in particular a compound of Formula (I), or a pharmaceutically acceptable salt thereof, can be administered to a patient who needs it in combination with at least one other therapy, for example, in combination with UVA and / or UVB phototherapy, as indicated for the treatment of psoriasis.
[0407] [0407] In another embodiment, a compound that modulates STING, in particular a compound of Formula (I), or a pharmaceutically acceptable salt thereof, can be administered to a patient who needs it in combination with at least one other therapeutic agent active for an indication mentioned in this document, where the at least one other active therapeutic agent is: a corticosteroid [administered orally, topically, by injection or as a suppository; prednisone, methylprednisolone, prednisolone, budesonide, betamethasone, dexamethasone, hydrocortisone, triamcinolone, fluticasone (fluticasone furoate, fluticasone propionate), fludroxychloride (flurandrenolide, flurandrenolone), fluocinone -TNF (etanecerpt, adalimumab, infliimab, certolizumab or golimumab), a PDE4 inhibitor (apremilast), 5-aminosalicyclic acid (mesalazine / mesalamine; sulfasalazine, balsalazide)) a DMARD (hydroxy-rheumatic drug, hydroxy-rheumatic agent, modifier , leflunomide), a thiopurine (azathioprine, mercaptopurine), a JAK inhibitor (tofacitinib), an NSAID (aspirin, acetaminophen, ibuprofen, naproxen (naproxen sodium), etodolac, celecoxib, diclofenac, IL-agent (meloxicam) tocilizumab)) an anti-IL1 biological agent (anakinra, canakinumab, rilonacept), an anti-IL12 or I1L23 biological agent (ustekinumab, risankizumab and, guselkumabe, tildrakizumab), an anti-CD6 biological agent (itolizumab), an anti-integrin agent (natalizumab (Tysabri &), etrolizumab), an anti-IL17 biological agent (secukinumab, ixekizumab, brodalumab), an anti-biological agent CD22 (epratuzumab), an anti-CD20 biological agent (rituximab, ofatumumab), an anti-CD20 or anti-CD4 biological agent and another cytokine inhibitor or biological agent against T-cell or B-cell receptors or interleukins, a calcineurin inhibitor (cyclosporine, pimecrolimus, tacrolimus), acitretin, fumaric acid, dimethyl fumarate, cyclophosphamide, cyclosporine (or cyclosporine), methotrexate, mycophenolic acid (or mycophenolate mofetil), topical vitamin D (calcipotriol or calcipotriol) (temsirolimus, everolimus), a Syk inhibitor (fostamatinib), an anti-IFNa biological agent (sifalimumab), or a retinoid (tazarotene). Examples of other suitable biological agents include abatacept, belimumab and alicafossene.
[0408] [0408] In one embodiment of the present invention, at least one other therapeutic agent is selected from an inhaled corticosteroid, a long-acting beta agonist, a combination of an inhaled corticosteroid and a long-acting beta agonist, a short-acting beta agonist duration, a leukotriene modifier, an anti-IgE, a methylxanthine bronchodilator, a mast cell inhibitor, and a long-acting muscarinic antagonist. For example, in the treatment of asthma, a compound that inhibits STING, in particular a compound of Formula (|), or a pharmaceutically acceptable salt thereof, can be administered in combination with an inhaled corticosteroid ((ICS), such as propionate fluticasone (Floventº), beclomethasone dipropionate (QVARSº), budesonide (Pulmicort), trincinolone acetonide (Azmacortº), flunisolide (Aerobidº), mometasone furoate (Asmanexº Twisthalerº), or Ciclesonida (beta) for a long time ((LABA) such as formoterol fumarate (Foradilº), salmeterol xinafoate (Sereventº)), a combination of ICS and LABA (such as fluticasone and vilanterol furoate (Breo Elliptaº), formoteric! L / budesonide (Symbicortº) inhalation) , beclomethasone dipropionate / formoterol (Inuvairº), and fluticasone propionate / salmetero | (Advairº), a short-acting beta agonist ((SABA) such as albuterol sulfate (ProAirº, Proventil HFAº, Ventolin HFAº, AccuNebº inhalation solution) , tartrate of levalbuterol (Xopenexº HFA), ipratropium bromide / albuterol (Combiventº Respimatº), ipratropium bromide (Atroventº HFA), a leukotriene modifier (such as sodium montelukast (Singulairº), zafirlucaste (Accolateº), and anti-IgE (such as omalizumab (Xolairº)), a methylxanthine bronchodilator (such as theophylline (Accurbronº, Aerolateº, Aquaphyllinº, Asbronº, Bronkodylº, Duraphylº, Elixiconº, Elixominº, Elixophyllinº, , Slo-Phyllinº, Somophyllinº, Sustaireº, Synophylateº, T-Phyllº, Theo-24º, Theo-Durº, Theobidº, Theochronº, Theoclearº, Theolairº, Theolixirº, Theophylº, Theoventº, Uni-durº, Uniphylº), a mastiff inhibitor such as sodium chromoline (Nasalchrom) and nedocromil sodium (Tilade)), a long-acting muscarinic antagonist ((LAMA) such as mometasone furoate / formotero fumarate dihydride! | (Duleraº)).
[0409] [0409] Other agents that may be suitable for use in a combination therapy in the treatment of asthma include a protein tyrosine kinase inhibitor (masitinib), CRTH2 / D-prostanoid receptor antagonist (AMG 853), indacaterol (ArcaptaºNeohalerº), an epinephrine inhalation aerosol (EOO4), fluticasone furoate / fluticasone propionate, vilanterol / fluticasone furoate powder (Relovair "”), fluticasone propionate / dehydrated formoterol fumarate (Flutiformº), reslizumab, salbutam inhalation! dry powder, tiotropium bromide (Spirivaº HandiHalerº), formoterol / budesonide (SymbicortºSMARTº), fluticasone furoate (Veramystº), Vectura VR506, lebrikizumab (RG3637), a combined phosphoriesterase (PDE) -3 e inhibitor (PDE) -3 and -4 (RPL554).
[0410] [0410] In one embodiment of the present invention, at least one other therapeutic agent is selected from a long-acting beta agonist, a long-acting inhaled anticholinergic or muscarinic antagonist, a phosphodiesterase inhibitor, an inhaled corticosteroid-beta agonist combination long-acting, a short-acting beta agonist, and an inhaled corcitosteroid. For example, in the treatment of COPD, a compound that modulates STING, in particular a compound of Formula (|), or a pharmaceutically acceptable salt thereof, can be administered in combination with a LABA (such as salmeterol xinafoate (Serevent) , umeclidinium / vilanterol (Anuro Elliptaº), umeclidinium (Incruse Elliptaº), aformoterol tartrate (Brovanaº), inhaled powder formoterol fumarate (Foradilº), indacaterol maleate (Arcaptaº Neohalerº), or fluticasol dehydrate propionate / (Flutiformº)), a long-acting inhaled anticholinergic (or a muscarinic antagonist, such as tiotropium bromide (Spirivaº), and aclidinium bromide (Tudorzaº Pressairº), a phosphodiesterase inhibitor (PDE-r) (such as roflumilast, Dalires ), an ICS / LABA combination (such as fluticasone fluorate and vilanterol (Breo Elliptaº), fluticasone propionate / salmetero | (Advairº), budesonide / formoterol (Symbicortº), mometasone / formoterol (Duleraº), ipratropium bromide / albuterol sulfate (Duonebº, Atroventº), albuterol / ipratropium (Combivent Respimatº)), a SABA (such as ipratropium bromide (Atroventº), and albuterol sulfate (ProAirº, Proventilº)), and an ICS (such as budesonide (Pulmicortº) ) and fluticasone propionate (Floventº), beclomethasone dipropionate (QVARº).
[0411] [0411] Other agents that may be suitable for use in combination therapy in the treatment of COPD include SCH527123 (a CXCR2 antagonist), glycopyrronium bromide ((NVA237) Seebriº Breezhalerº), glycopyrronium bromide and indacaterol maleate ((QVA149) Ultibroº Breezhalerº), glycopyrrolate and formoterol fumarate (PTOO03), indacaterol maleate (QVA149), olodaterol (Striverdiº Respimatº), tiotropium (Spirivaº) / olodaterol (Striverdi Respimatº), and aclidinium inhalation / formoterol.
[0412] [0412] JEM a modality of the present invention, the at least one other therapeutic agent is selected from an oral corticosteroid, an antithymocyte globulin, thalidomide, chlorambucil, a calcium channel blocker, a topical emollient, an ACE inhibitor, an inhibitor reabsorption of serotonin, an endothelin-1 receptor inhibitor, an anti-fibrotic agent, a proton pump inhibitor or imatinib, ARG201, and tocilizumab. For example, in the treatment of systemic scleroderma, a compound that modulates STING, in particular a compound of Formula (1), or a pharmaceutically acceptable salt thereof, can be administered in combination with an oral corticosteroid (such as prednisolone (Delatsoneº, Orapred, Millipred, Omnipred, Econopred, Flo-Pred), an immunosuppressive agent (such as methotrexate (Rhuematrexº, Trexallº), cyclosporine (Sandimmuneº), antithymocyte globulin (Atgamº), mofetil mycophtol (CyCeptam), Cytophtam, (tacrolimus), thalidomide (Thalomidº), chlorambucil (Leukeranº), azathioprine (Imuranº, Azasanº)), a calcium channel blocker (such as nifedipine (Procardiaº, Adalatº) or nicardipine (Cardeneº), a topical emollient (nitrate ointment) ), an ACE inhibitor (such as lisinopril (Zestrilº, Prinivilº), dilitazem (Cardizemº, Cardizem SRº, Cardizem CDº, Cardiaº, Dilacorº, Tiazacº)), a serotonin reuptake inhibitor (such as fluoxetine (Prozacº)), one inhib endothelin-1 receptor idor (such as bosentan (Tracleerº) or epoprostene! (Flolanº, Veletriº, Prostacyclinº)), an anti-fibrotic agent (such as colchicines (Colcrysº), para-aminobenzoic acid (PABA), dimethyl sulfoxide (DMSO), and D-penicillamine (Cuprimineº, Depenº), alpha interferon and gamma interferon (INF-g)), a proton pump inhibitor (such as omeprazole (Prilosecº), metoclopramide (Reglanº), lansoprazole (Prevacidº), esomeprazole (Nexiumº), pantoprazole (Protonixº), rabeprazole (Aciphexibe)) or imatmat (Gleevecº) ARG201 (arGentis Pharmaceutical), belimumab (Benlystaº), tocilizumab (Actemaº).
[0413] [0413] In one embodiment of the present invention, the at least one other therapeutic agent is a ciliary neurotrophic growth factor or a gene transfer agent. For example, in the treatment of retinitis pigmentosa, a compound that modulates STING, in particular a compound of Formula (1), or a pharmaceutically acceptable salt thereof, can be administered in combination with a ciliary neurotrophic growth factor (NT-501 -CNTF) or UshStatº gene transfer agent.
[0414] [0414] In one embodiment of the present invention, at least one other therapeutic agent is selected from a trivalent inactivated influenza vaccine (IIV3), a quadrivalent inactivated influenza vaccine (IIV4), a trivalent recombinant influenza vaccine, a quadrivalent attenuated live influenza, an antiviral agent, or an inactivated influenza vaccine. For example, in the treatment of influenza, a compound that modulates STING, in particular a compound of Formula (1), or a pharmaceutically acceptable salt thereof, can be administered in combination with a trivalent inactivated influenza vaccine (IIV3) (such as such as Afluriaº, Fluarixº, Flucelvaxº, FluLavalº, Fluvirinº, Fluzoneº), a quadrivalent inactivated influenza vaccine (IIV4) (such as Flivalix Quadrivalent, Flulavalº Quadrivalent, Fluzoneº Quadrivalent), a trivalent recombinant influenza vaccine (such as a FluBl of quadrivalent attenuated live influenza (such as FluMistº Quadrivalent), an antiviral agent (such as oseltamivir (Tamiífluº), zanamivir (Relenzaº), rimantadine (Flumadineº), or amantadine (Symmetrelº)), or Fluadº, Fludase, FluNhanceº, Pre VaxiGripº
[0415] [0415] In the treatment of a staph infection, a compound that modulates STING, in particular a compound of Formula (1) or a pharmaceutically acceptable salt thereof, can be administered in combination with an antibiotic (such as a B- They lactate cephalosporin (Duricefº, Kefzolº, Ancefº, Biocefº etc.), nafcilina (Unipenº), a sulfonamide (sulfamethoxazole and trimethoprim (Bacrimº, Septraº,) sulfasalazine (Azulfidineº), acetyl sulfisoxazoline (Gantrisinº)) or Vantrisinin). ).
[0416] [0416] In one embodiment of the present invention, at least one other therapeutic agent is selected from a topical immunomodulator or calcineurin inhibitor, a topical corticosteroid, an oral corticosteroid, a gamma interferon, an antihistamine, or an antibiotic. For example, in the treatment of atopic dermatitis, a compound that modulates STING, in particular a compound of Formula (Il), or a pharmaceutically acceptable salt thereof, can be administered in combination with a topical immunomodulator or calcineurin inhibitor (such as pimecrolimus (Elidelº) or tacrolimus ointment (Protopicº)), a topical corticosteroid (such as hydrocortizone (Synacortº, Westcortº), betamethasone (Diproleneº), flurandrenolide (Cordanº), fluticasone (Cutivateº), triamcinolone (Kenocinide), , and clobetasol (Temovateº)), an oral corticosteroid (such as hydrocortisone (Cortefº), methylprednisolone (Medrolº), or prednisolone (Pediapredº, Preloneº), an immunosuppressant (such as cyclosporine (Neoralº) or interferon gamma (Alferon Nº, Infer, Intron A, Roferon-Aº), an antihistamine (against itching such as Ataraxº, Vistarilº, Benadrylº), an antibiotic (such as penicillin derivatives flucloxacillin (Floxapenº) or dicloxacillin (Dynapenº), erit romicin (Erycº, T-Statº, Erythra-Dermº etc.)), non-steroidal immunosuppressive agent (such as azathioprine (Imuranº, Azasanº), methotrexate (Rhuematrexº, Trexallº), cyclosporine (Sandimmuneº), or mycophenolate mofetila) .
[0417] [0417] In the treatment of Parkinson's disease, the compounds of the invention can be administered in combination with therapies based on L-dopamine (Carbidopa (Lodosyn) -levodopa), dopamine agonists such as pramipexole (Mrapex), ropinirole (Requip), rotigotine (Neupro), and Apomorphine (Apokyn), monoamine oxidase (MAO), B inhibitors such as selegiline (Eldepryl, Zelapar), rasagiline (Azilect), and Safinamide (Xadago)), cetcol, O-methyltransferase (COMT) inhibitors, entacapone (Comtan) and Tolcapone (Tasmar), anticholinergics such as beztropine (Cogentin) or trihexiphenidyl, and amantadine. A compound of Formula (|), or a pharmaceutically acceptable salt thereof, can be administered in combination with devices implanted in patients that discharge electrical pulses in the brain and reduce known symptoms of Parkinson's disease such as deep brain stimulation (DBS).
[0418] [0418] In the treatment of myocardial infarction, the compounds of the invention can be administered in combination with therapies with anti-IL1beta antibodies (e.g., canakinumab).
[0419] [0419] The compounds of the invention can also be formulated with vaccines as adjuvants to modulate their activity. Such compositions may contain one or more antibodies or antibody fragments or an antigenic component including, but not limited to, protein, DNA, live or dead bacteria and / or viruses or virus-like particles, together with one or more other components with adjuvant activity including , among others, aluminum salts, oil and water emulsions, heat shock proteins, lipid A preparations and derivatives, glycolipids, other TLR agonists such as CpG DNA or similar agents, cytokines such as GM-CSF or IL-12 or similar agents.
[0420] [0420] In another aspect of the invention, a vaccine adjuvant is proposed which comprises a compound of Formula (II), or a pharmaceutically acceptable salt thereof. A vaccine composition is also proposed which comprises a compound of Formula (1), or a pharmaceutically acceptable salt thereof, and an antigen or antigenic composition.
[0421] [0421] "Therapeutically effective amount" means an amount of a compound that, when administered to a patient in need of such treatment, is sufficient for effective treatment or prevention, as defined in this document. Thus, for example, a therapeutically effective amount of a compound of Formula (1) or a pharmaceutically acceptable salt thereof, is an amount of an agent of the invention which, when administered to a human being in need, is sufficient to modulate the STING activity in such a way that a diseased condition that is mediated by that activity is reduced, mitigated or prevented. The amount of compound data that will correspond to that amount will vary depending on factors such as the specific compound (for example, the potency (plCso), the effectiveness (ECs0), and the biological half-life of the specific compound), the diseased condition and their severity, the identity (for example, age, height and weight) of the patient who needs treatment, but, nevertheless, can be routinely determined by those skilled in the art. Furthermore, the duration of treatment and the period of time of administration (time between dosages and dosing times, for example, before / along with / after meals) of the compound will vary according to the identity of the mammal that needs the treatment (eg weight), the compound and its specific properties (eg pharmacokinetic properties), the disease or disorder and its severity and the specific composition and method being used, but can nevertheless be determined by those skilled in the art. technical.
[0422] [0422] "Treat" or "treatment" means at least the mitigation of a disease or disorder in a patient. Treatment methods for mitigating a disease or disorder include using the compounds of this invention in any conventionally acceptable manner, for example, for the delay, therapy or cure of a STING-mediated disease or disorder, as described above. In one embodiment, "treating" or "treatment", with respect to cancer, refers to mitigating cancer, eliminating or reducing one or more symptoms of cancer, delaying or eliminating the progression of cancer, and delaying the recurrence of cancer. condition in a previously afflicted or diagnosed patient.
[0423] [0423] "Prevent" or "prevention" refers to the prophylactic administration of a drug to decrease the likelihood of onset or to delay the onset of a disease or its biological manifestation. Prophylactic therapy is appropriate, for example, when the patient is considered to be at high risk of developing cancer, such as when the patient has a strong family history of cancer or when the patient has been exposed to a carcinogen.
[0424] [0424] The compounds of the invention can be administered by any suitable route of administration, including both systemic and topical administration. Systemic administration includes oral administration, parenteral administration, transdermal administration, rectal administration and administration by inhalation. Parenteral administration refers to routes of administration other than enteral, transdermal or by inhalation and is typically by injection or infusion. Parenteral administration includes intravenous, intramuscular and subcutaneous injection or infusion. Inhalation refers to the administration to the patient's lungs inhaled, either through the mouth or through the nasal passages. Topical administration includes application to the skin.
[0425] [0425] In addition to the administration routes suitable for the treatment of an oncology described above, the pharmaceutical compositions can be adapted for administration by intratumoral or peritumoral injection. Intratumoral or peritumoral injection of a compound of the present invention is expected directly or adjacent to a single solid tumor to elicit an immune response capable of attacking and destroying cancer cells throughout the body, thereby substantially reducing the tumor and, in some cases, permanently eliminating the sick patient's tumor. Activation of the immune system in this way to exterminate tumors at a remote site is commonly known as the abscopal effect and has been demonstrated in animals with multiple therapeutic modalities (van der Jeught, et a /., Oncotarget, 2015, 6 (3), 1359- 1381). Another advantage of local or intratumoral or peritumoral administration is the ability to obtain efficacy equivalent to much lower doses, thus minimizing or eliminating adverse events that can be seen with much higher systemic doses (Marabelle, A., et a /., Clinical Cancer Research, 2014, 20 (7), pp. 1747-1756).
[0426] [0426] The compounds of the invention can be administered using eye drops to treat Sjogren's syndrome.
[0427] [0427] The compounds of the invention can be administered only once or according to a dosage regimen in which a number of doses are administered at varying time intervals over a given period of time. For example, doses can be administered once, twice, three or four times a day. Doses can be administered until the desired therapeutic effect is obtained or indefinitely to maintain the desired therapeutic effect. Suitable dosage regimens for a compound of the invention depend on the pharmacokinetic properties of the compound in question, such as absorption, distribution and half-life, which can be determined by those skilled in the art. In addition, suitable dosage regimens, including the duration for which these regimens are administered, for a compound of the invention depend on the disease or disorder being treated, the severity of the disease or disorder being treated, the age and physical condition of the patient being treated , the medical history of the patient to be treated, the nature of concomitant therapies, the desired therapeutic effect and similar factors within the knowledge and experience of those skilled in the art. Those skilled in the art will also realize that adequate dosing regimens may require adjustments given a specific patient's response to the dosing regimen or over time as the specific patient needs changes. Total daily dosages range from 1 mg to 2,000 mg.
[0428] [0428] For use in therapy, the compounds of the invention will normally, but not necessarily, be formulated in pharmaceutical compositions prior to administration to a patient. Therefore, the invention also relates to pharmaceutical compositions that comprise a compound of the invention and at least one pharmaceutically acceptable excipient.
[0429] [0429] The pharmaceutical compositions of the invention can be prepared and packaged in bulk form, in which an effective amount of a compound of the invention can be extracted and then given to the patient, such as powders, syrups and solutions for injection. Alternatively, the pharmaceutical compositions of the invention can be prepared and packaged in a unit dosage form. In case of oral application, for example, one or more tablets or capsules can be administered. A dose of the pharmaceutical composition contains at least a therapeutically effective amount of a compound of the present invention (i.e., a compound of Formula (1), or a salt thereof, in particular a pharmaceutically acceptable salt thereof).
[0430] [0430] As provided in this document, unit dosage forms (pharmaceutical compositions) containing from 1 mg to 1,000 mg of a compound of the invention can be administered once, twice, three or four times a day to effect the treatment of a disease or disorder mediated by STING.
[0431] [0431] The pharmaceutical compositions of the invention typically contain a compound of the invention. However, in certain embodiments, the pharmaceutical compositions of the invention contain more than one compound of the invention. Besides that,
[0432] [0432] As used herein, "pharmaceutically acceptable excipient" refers to a pharmaceutically acceptable material, composition or vehicle involved in shaping or forming the pharmaceutical composition. Each excipient must be compatible with the other ingredients of the pharmaceutical composition when combined to avoid interactions that reduce the effectiveness of the compound of the invention when administered to a patient and interactions that result in pharmaceutical compositions that are not pharmaceutically acceptable. In addition, as expected, each excipient must be of sufficiently high purity to make it pharmaceutically acceptable.
[0433] [0433] The compounds of the invention and the one or more pharmaceutically acceptable excipients will typically be formulated in a dosage form adapted for administration to the patient by the desired route of administration. Conventional dosage forms include those adapted for (1) oral administration, such as tablets, capsules, caplets, pills, lozenges, powders, syrups, elixirs, suspensions, solutions, emulsions, sachets and cachets; (2) parenteral administration, such as sterile solutions, suspensions and powders for reconstitution; (3) transdermal administration, such as transdermal patches; (4) rectal administration, such as suppositories; (5) inhalation, such as aerosols and solutions; and (6) topical administration, such as creams, ointments, lotions, solutions, pastes, sprays, foams and gels.
[0434] [0434] Suitable pharmaceutically acceptable excipients will vary depending on the specific dosage form chosen. In addition, suitable pharmaceutically acceptable excipients can be chosen for a specific function which they can serve in the composition. For example, certain pharmaceutically acceptable excipients can be chosen for their ability to facilitate the production of uniform dosage forms. Certain pharmaceutically acceptable excipients can be chosen for their ability to facilitate the production of stable dosage forms. Certain pharmaceutically acceptable excipients can be chosen for their ability to facilitate the transport or distribution of one or more compounds of the invention, once administered to the patient, from one organ or body part to another organ or body part. Certain pharmaceutically acceptable excipients can be chosen for their ability to improve patient compliance.
[0435] [0435] Suitable pharmaceutically acceptable excipients include the following types of excipients: diluents, fillers, binders, disintegrants, lubricants, glissants, granulants, coating agents, wetting agents, solvents, - cosolvents, suspending agents, emulsifiers, sweeteners, flavorings, flavor masking agents, dyes, anti-caking agents, wetting agents, chelating agents, plasticizers, viscosity-increasing agents, antioxidants, preservatives, stabilizers, surfactants and buffering agents. Those skilled in the art will realize that certain pharmaceutically acceptable excipients may serve more than one function and may serve alternative functions depending on the amount of excipient present in the formula and which other ingredients are present in the formula.
[0436] [0436] Those skilled in the art have the knowledge and skill necessary to select suitable pharmaceutically acceptable excipients in amounts appropriate for use in the invention. In addition, there are a number of sources available to those skilled in the art that describe pharmaceutically acceptable excipients and which may be useful in selecting suitable pharmaceutically acceptable excipients. Examples include Remington's Pharmaceutical Sciences (Mack Publishing Company), The Handbook of Pharmaceutical Additives (Gower
[0437] [0437] The pharmaceutical compositions of the invention are prepared using techniques and methods known to those skilled in the art. Some of the methods commonly used in the art are described in Remington's Pharmaceutical Sciences (Mack Publishing Company).
[0438] [0438] In one aspect, the present invention relates to a solid oral dosage form, such as a tablet or capsule, which comprises an effective amount of a compound of the invention and a diluent or filler. Suitable diluents and fillers include lactose, sucrose, dextrose, mannitol, sorbitol, starch (eg corn starch, potato starch and pregelatinized starch), cellulose and its derivatives (eg microcrystalline cellulose), calcium sulfate and dibasic calcium phosphate. The solid oral dosage form may further comprise a binder. Suitable binders include starch (eg corn starch and pregelatinized starch), gelatin, acacia, sodium alginate, alginic acid, tragacanth, guar gum, povidone and cellulose and its derivatives (eg microcrystalline cellulose)) A solid oral dosage form may further comprise a disintegrant. Suitable disintegrants include crospovidone, sodium starch glycolate, croscarmellose, alginic acid and sodium carboxymethylcellulose. The solid oral dosage form may further comprise a lubricant. Suitable lubricants include stearic acid, magnesium stearate, calcium stearate and talc.
[0439] [0439] It should be kept in mind that the compounds of the present invention can also be formulated with vaccines as adjuvants to modulate their activity. Such compositions may contain one or more antibodies or antibody fragments or an antigenic component including, but not limited to, protein, DNA, live or dead bacteria and / or whole, inactivated or fractionated viruses or virus-like particles, recombinant proteins or antigenic fragments of optionally together with one or more other components with adjuvant activity including, but not limited to, aluminum salts, oil and water emulsions, heat shock proteins, saponins, lipid A preparations and derivatives, glycolipids, liposomes, TLR agonists such as CpG DNA or similar agents, cytokines such as GM-CSF or IL-12, or similar agents.
[0440] [0440] Certain - compounds of the present invention can be potent immunomodulators and therefore care must be taken when handling them. EXAMPLES
[0441] [0441] The following examples illustrate the present invention. These examples are not intended to exhaust the scope of the present invention, but instead serve as a guide for those skilled in the art to prepare and use the compounds, compositions and methods thereof. Although specific embodiments of the present invention are described, it will be apparent to those skilled in the art the possibility of making various changes and modifications without departing from the scope or essence of the invention.
[0442] [0442] It should be borne in mind that certain compounds of the invention can be potent immunomodulators and therefore care must be taken when handling them.
[0443] [0443] The reactions described in this document apply to the production of compounds of the invention with a variety of different substituent groups (for example, R ', R' etc.) as defined in this document. Those skilled in the art will realize that if a specific substituent is not compatible with the synthesis methods described in this document, that substituent may be protected by a suitable protecting group that is stable under the conditions of the reaction. Suitable protecting groups and methods for protecting and deprotecting different substituents using such suitable protecting groups are well known to those skilled in the art; examples of which can be found in T. W. Greene 'Protective Groups in Organic Synthesis' (4th edition, J. Wiley and Sons, 2006). Unless otherwise noted, all starting materials were obtained from commercial suppliers and used without further purification.
[0444] [0444] Certain intermediate compounds described in this document form yet another aspect of the invention. GENERAL SYNTHESIS METHODS
[0445] [0445] The compounds of the present invention can be prepared using synthetic procedures illustrated in the reaction schemes below, which can be readily adapted to prepare other compounds of the invention based on the knowledge of an experienced organic chemist. The syntheses proposed in these schemes apply to the production of compounds of the invention with a variety of different R groups employing appropriate precursors, which are suitably protected if necessary, to achieve compatibility with the reactions set out in this document. Subsequent deprotection, when necessary, produces compounds of the nature generally disclosed. Although the schemes are illustrated only with compounds of Formula (1), they are illustrative of processes that can be used to produce the compounds of the present invention. Intermediates (compounds used in the preparation of the compounds of the invention) can also be present as salts.
[0446] [0446] All variables are as defined in Formula (1). A suitably substituted halo-nitrophenyl compound (1A) is reacted with a monoprotected diamine such as (1B) to obtain N-protected nitro-aniline. Removing the amine protecting group produces amine (1D). Alternatively, the amine (1D) can be obtained directly by reacting the halo-nitrophenyl compound (1A) with a symmetric diamine (1C). The amine (1D) can be reacted with a halo-nitrophenyl compound (1E) to obtain a bis-nitro compound (1F). In cases where (1A) is identical to (1E), the bis-nitro compound (1F) can be obtained directly by the reaction of diamine (1C) with an excess halo-nitrophenyl compound.
[0447] [0447] All variables are as defined in Formula (1). A suitably substituted halo-nitrophenyl compound (2A) is reacted with a monoprotected diamine such as (2B) to obtain nitroaniline (2C). The reduction of the nitro group under appropriate conditions will produce dianiline (2D). Dianiline (2D) can be converted to amidobenzimidazole (2E) by one of two methods: 1) Treatment with cyanogen bromide, followed by coupling amide with a pyrazolic acid such as (2M); or 2) Treatment with isothiocyanate (2N) until thiourea formation is complete, followed by the addition of EDC (or another suitable desulfurization reagent) and triethylamine (or another suitable base) and stirring until the cyclodulfurization is complete. Removing the amine protecting group produces amine
[0448] [0448] All variables are as defined in Formula (1). A suitably substituted halo-nitrophenyl compound (3A) is reacted with a suitable dielectrophile such as dibromide (3B) to obtain nitro-annyl monobromide (3C). Treatment of (3C) with another suitably substituted halo-nitrophenyl compound (3D) produces the bound bis-halo-nitrophenyl compound (3E). The reaction of the bis-halo-nitrophenyl compound (3E) with a diamine containing a linker group (3F) produces a dinitro macrocycle (3G). The reduction of both nitro groups will produce a tetraaniline (3H). Tetraaniline (3H) can be converted to macrocycles (31) by one of two methods: 1) Treatment with cyanogen bromide to obtain a bis-aminobenzimidazole, followed by coupling amide with a pyrazolic acid such as (3L) or a linked pyrazolic diacid (3M); or 2) Treatment with isothiocyanate (3N) until the formation of dithiourea is complete, followed by the addition of EDC (or another desulfurizing reagent) and triethylamine (or another suitable base) and stirring until the cyclodulfurization is complete.
[2] [2] and EE [5] BJ »or are Ã2 Rº the NH and NH Ng N = c = s Ri Ri ke NAN pi NX NH | Ro Rs
[0449] [0449] All variables are as defined in Formula (1). A suitably substituted halo-nitrophenyl compound (4A) is reacted with a monoprotected diamine such as (4B) to obtain nitroaniline (4C). The reduction of the nitro group under appropriate conditions will produce dianiline (4D). Dianiline (4D) can be converted to amidobenzimidazole (4E) by one of two methods: 1) Treatment with cyanogen bromide, followed by coupling amide with a pyrazolic acid such as (4N); or 2) Treatment with isothiocyanate (40) until thiourea formation is complete, followed by the addition of EDC (or another suitable desulfurization reagent) and triethylamine (or another suitable base) and stirring until the cyclodulfurization is complete.
[0450] [0450] All variables are as defined in Formula (1). A suitably substituted halo-nitrophenyl compound (5A) is reacted with a monoprotected diamine such as (5B) to obtain N-protected nitro-aniline. Removing the amine protecting group produces amine (5D). Alternatively, the amine (5D) can be obtained directly by reacting the halo-nitrophenyl compound (5A) with a symmetric diamine (5C). The amine (5D) can be reacted with a halo-nitrophenyl compound (SE) to obtain a bis-nitro compound (5F). In cases where (5A) is identical to (5E), the bis-nitro compound (5F) can be obtained directly by the reaction of diamine (5C) with an excess halo-nitrophenyl compound. If necessary, deprotect / functionalize R groups (ie formation of CC bonds when the Rº * group is halide). The reduction of nitro groups will produce a tetraaniline (5H). If present, and depending on the conditions employed, other groups present in (5F) can also be reduced (ie, alkene, aryl halides). Tetra-aniline (5H) can be converted to (51)) a macrocycle or amidobenzimidazo | dimer, by one of two methods: 1) Cyanogen bromide treatment to obtain a bis-aminobenzimidazole, followed by amide coupling with a pyrazolic acid such as (5L) or a linked pyrazolic diacid (SM); or 2) Treatment with isothiocyanate (5N) until the formation of dithiourea is complete, followed by the addition of EDC (or another desulfurizing reagent) and triethylamine (or another suitable base) and stirring until the cyclodulfurization is complete.
[0451] [0451] The names for the intermediate and final compounds described in this document were generated using the nomenclature software programs ChembDraw Pro 12.0.2.1076 Plug-lh in Perkin Elmer E-Notebook or MarvinSketch
[0452] [0452] Those skilled in the art will appreciate that, in certain circumstances, these programs may name a compound structurally represented as a tautomer or isomer of that compound. It should be borne in mind that any reference to a named compound or to a structurally represented compound is intended to cover all tautomers or isomers of that compound and any mixtures of tautomers and / or isomers thereof.
[0453] [0453] The following abbreviations can be used in this specification:
[0454] [0454] To 1H-imidazole (13.4 g, 197 mmol) in DCM (100 mL), 3-bromopropan-1-ol (13.7 g, 99 mmol) was added, followed by tert-butylchlorodimethylsilane (17 , 8.9, 118 mmol) in DCM (20 ml). After 3 h at room temperature, the reaction was concentrated to -100 ml and poured into EtOAc (800 ml), washed with aq. 5% (2 x 200 mL) and brine. The organic layer was dried over MgSO4, filtered and concentrated to obtain the title compound (10.0 g, 39.5 mmol, 40% yield). 1H NMR (400 MHz, chloroform-d) at ppm 3.78 (t, J = 5.70 Hz, 2 H), 3.56 (t, J = 6.46 Hz, 2 H), 2.07 (t, J = 5.83 Hz, 2 H), 0.94 (s, 9 H), 0.11 (s, 6 H). Intermediate 2 4-chloro-3-methoxy-S-nitrobenzamide À cl Oo 5
[0455] [0455] Methyl 4-chloro-3-methoxy-5-nitrobenzoate (1000 mg, 4.07 mmol) was stirred in NH.OH (10 mL, 77 mmol) at room temperature for 24 h. Then, the reaction temperature was raised to 50º C for 2 h. An additional 2 mL (- 3.7 eq.) Of NH.OH was added to the container. After another 2 h of stirring at 50º C (4 h in all), the reaction mixture was cooled to room temperature. The solid was filtered and rinsed with cold water. The solid was dried in a central vacuum and lyophilized to obtain 4-chloro-3-methoxy-5-nitrobenzamide (710 mg, 2.99 mmol, 73% yield) as a brown solid. * H NMR (400 MHz, DMSO-ds) 5 ppm 8.31 (br. S., 1 H), 8.06 (d, J = 1.77 Hz, 1 H), 7.88 (d, J = 1.77 Hz, 1 H), 7.81 (br. S., 1 H), 4.02 (s, 3 H). LCMS [M + H] * = 230.9. Intermediate 3 4-chloro-3-hydroxy-o-nitrobenzamide OH to E.
[0456] [0456] 4-chloro-3-methoxy-5-nitrobenzamide (1 g, 4.34 mmol) was suspended in dry DCM (15 mL) and stirred at room temperature. To the reaction, BBr3 (17.4 mL, 1 M in DCM) was added dropwise. A paste formed quickly, which was stirred overnight at room temperature under nitrogen. The reaction was poured into ice water (300 mL) and stirred vigorously for 30 min. The resulting suspension was filtered, and the solids were dried to obtain the title compound (610 mg, 2.82 mmol, 65% yield). * H NMR (400 MHz, DMSO-ds) δ ppm 11.53 (br. S., 1 H), 8.17 (br. S., 1 H), 7.92 (s, 1 H), 7.72 (s, 1 H), 7.66 (br. S., 1 H). LCMS [M + HJ * = 217. Intermediate 4 $ - (3 - ((fero-butyldimethylsil) oxy) propoxy) -4-chloro-S-nitrobenzamide 8 Ke AMX o
[0457] [0457] (3-bromopropoxy) (tert-butyl) dimethylsilane (7.3 g, 28.8 mmol) was dissolved in dry DMF (75 mL), 4-chloro-3-hydroxy-S5-nitrobenzamide was added (4.8 g, 22.16 mmol), followed by K2COs; (6.13 g, 44.3 mmol), and stirred for 2 h at 100º C under nitrogen. The reaction was cooled to room temperature, poured into EtOAc (600 ml), washed with water (600 ml) and brine, dried over MgSO:, filtered and concentrated in vacuo. The residue was purified by chromatography on silica gel eluting with 20% to 80% hexanes / EtOAc to obtain the title compound (7.43 g, 19.1 mmol, 86% yield). 1H NMR (400 MHz, DMSO-ds) 5 ppm 8.29 (br. S., 1 H), 8.05 (d, J = 1.71 Hz, 1 H), 7.89 (d, J = 1.71 Hz, 1 H), 7.77 (br. S, 1 H), 4.30 (t, J = 5.99 Hz, 2 H), 3.80 (t, J = 5, 99 Hz, 2 H), 1.98 (quin, J = 5.99 Hz, 2 H), 0.80 - 0.90 (m, 9 H), 0.02 (s, 6 H). LCMS [M + H] * = 389. Intermediate 5 4-chloro-3- (3-morpholinopropoxy) -S-nitrobenzamide el. x
[0458] [0458] A mixture of 4-chloro-3-hydroxy-5-nitrobenzamide (5,000 mg, 23.09 mmol), 4- (3-chloropropyl) morpholine (4,534 mg, 27.7 mmol), K2CO3 (4,148 mg, 30.0 mmol) in DMF (30 mL) was stirred at 70 ° C overnight. The solvent was removed in vacuo to obtain a crude solid product, which was purified by chromatography on silica gel (12 gq column, MEOH: DCM = 1:10). The pure fractions were concentrated and the solvents were removed in vacuo to obtain 4-chloro-3- (3-morpholinopropoxy) -S-nitrobenzamide (3,200 mg, 9.31 mmol, 40.3% yield) as a solid yellow. * H NMR (400 MHz, DMSO-ds) 5 ppm 8.29 (s, 1 H), 8.04 (s, 1 H), 7.88 (d, J = 1.2 Hz, 1 H) , 7.77 (s, 1 H), 4.28 (t, J = 6.2 Hz, 2 H), 3.62 - 3.52 (m, 4 H), 246 - 2.44 (m, 2 H), 2.37 (br. S., 4 H), 2.02 - 1.90 (m, 2 H). LCMS (m / z): 343.8 [M + HJ *. Intermediate 6 - - (E) -1- (4-aminobut-2-en-1-i1) -2- (1-ethyl-3-methyl-1H-pyrazol-5-carboxamido) -1H-benzo hydrochloride [ d] imidazole-5-carboxamide o N IT IS HAN
[0459] [0459] A mixture of 4-fluor-3-nitrobenzamide (10.0 g, 54.3 mmol), (E) -tert-butyl (4, aminobut-2-en-1-yl) carbamate (10, 62 g, 57.0 mmol) and K2COs (15.01 g, 109 mmol) in DMSO (200 mL) were stirred at room temperature overnight. The reaction was poured into water (2,000 ml) and stirred for 30 min. The resulting solid was collected by filtration to obtain the title compound (18.3 g, 52.2 mmol, 96% yield). LCMS [2M + H] * = 700.5 Step 2: (E) - tert-butyl carbamate (4 - ((2-amino-4-carbamoylphenyl) amino) but-2-en-1-yl) e HN
[0460] [0460] A (4 - ((4-carbamoyl-2-nitrophenyl) amino) but-2-en-1-yl) (E) - tert-butyl carbamate (18.3 g, 52.2 mmol) in DMF (300 ml), stannous chloride dihydrate (58.9 g, 261 mmol) was added. After stirring it at room temperature overnight, the reaction was added dropwise to NaHCO; aq. saturated (2,000 ml) and extracted with EtOAc (5 X 500 ml). The combined organic layers were washed with brine (200 ml), dried over Na2SO3, filtered and concentrated to obtain the title compound (16.5 g, 51.5 mmol, 99% yield) as a yellow oil. LCMS [M-BOC + H] * = 221.1
[0461] [0461] A “mixture of (E) -tert-butyl (4 - ((2-amino-4-carbamoylphenyl) amino) but-2-en-1-yl) carbamate (16.5 g, 51.5 mmol) and cyanogen bromide (8.18 9, 77 mmol) in THF (200 mL) was heated to reflux overnight. The reaction was cooled to room temperature, diluted with NaHCO; aq. saturated (500 ml) and extracted with EtOAc (5 x 300 ml). The combined organic matter was washed with brine, dried over Na2SOs, filtered and concentrated. The residue was purified on silica gel, eluting with 50: 1 to 20: 1 DOM in MeOH (+ 3% NH4OH) to obtain the title compound (13.7 g, 39.7 mmol, 77% yield ) as an off-white solid. LCMS [M + H] * = 346.1 Step 4: (4- (5-carbamoyl-2- (1-ethyl-3-methyl-1H-pyrazol-5-carboxamido) -1H-benzo [d] imidazole | -1-yl) but-2-en-1-yl) (E) -tert-butyl carbamate NA ia À NA OS " N 1 soc
[0462] [0462] To 1-ethyl-3-methyl-1H-pyrazol-5-carboxylic acid (9.17 g, 59.5 mmol) in DCM (500 mL) at 0 ° C, EDC (20.53 9 , 107 mmol) and HOBt (18.22 9, 119 mmol). After 15 min, a mixture of (E) (4- (2-amino-5-carbamoyl-1H-benzo [d] imidazo | -1-yl) but-2-en-1-yl) carbamate -tert-butyl (13.7 g, 39.7 mmol) in DMF (50 mL), followed by TEA (27.6 mL, 198 mmol). The reaction was warmed to room temperature, stirred overnight and concentrated. The residue was diluted with water (500 ml) and extracted with EtOAc (3 x 300 ml), and the combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated. The residue was purified on silica gel, eluting with 50: 1 to 20: 1 DCM: MeOH to obtain the crude product, which was washed with DCM (300 mL) and collected by filtration to obtain the title compound (14, 0 g, 29.1 mmol, 73% yield) as an off-white solid. * H NMR (400 MHz, DMSO-ds) δ ppm 12.84 (s, 1 H), 8.00 - 7.97 (m, 2 H), 7.80 - 7.78 (m, 1 H ), 7.49 (d, J = 8.4 Hz, 1 H), 7.34 (s, 1 H), 6.95 (t, J = 5.5 Hz, 1 H), 6.66 ( s, 1 H), 5.73 - 5.65 (m, 2 H), 4.83 (d, J = 4.3 Hz, 2 H), 4.62 (q, J = 7.0 Hz, 2 H), 3.52 (s, 2 H), 2.18 (s, 3 H), 1.38 - 1.33 (m, 12 H); LCMS [M + H] * = 482.0 Step 5: (E) -1- (4-aminobut-2-en-1-i1) -2- (1-ethyl-3-methyl-1H-pyrazole hydrochloride -5-carboxamido) -1 H-benzoldlimidazole-5-carboxamide
[0463] [0463] To a suspension of (4- (5-carbamoyl-2- (1-ethyl-3-methyl-1H-pyrazol-5-carboxamido) -1H-benzo [d] imidazol-1-yl) but-2 -en-1-yl) carbamate = - (E) -tert-butyl (3.00 g, 6.23 mmol) in dioxane (60 mL), 4 N HCI in dioxane (15.6 mL) was added , 62.3 mmol), followed by MeOH (15 mL) to dissolve any remaining solid. After 30 min at room temperature, the reaction mixture became stiff and allowed to stir for about 3 days. The resulting solid was collected by filtration and washed with DCM to obtain the title compound (2.0 g, 4.8 mmol, 77% yield) as a white solid. * H NMR (400 MHz, DMSO-ds) 5 ppm 7.97 - 8.09 (br. S., 1 H), 7.82 (d, J = 8.11 Hz, 1 H), 7, 50 (d, J = 8.11 Hz, 1 H), 7.38 (br. S, 1 H), 6.70 (s, 1 H), 5.97 - 6.08 (m, 1 H ), 5.68 - 5.80 (m, 1 H),
[0464] [0464] A microwave tube containing (E) -1- (4-aminobut-2-en-1-i1) -2- (1-ethyl-3-methyl-1 H-pyrazole-5- hydrochloride carboxamido) -1H-benzo [d] imidazo carboxamide (517 mg, 1.24 mmol) in DMSO (10 mL) was treated with TEA (0.28 mL, 2.0 mmol), followed by K2CO3; (274 mg, 1.98 mmol) and 3- (3 - ((tert-butyldimethylsilyl) oxy) propoxy) -4-chloro-5-nitrobenzamide (385 mg, 0.990 mmol). The reaction was heated to 75º C. After 7 h, the mixture was concentrated, and the residue was purified on silica gel, eluting with 10% to 90% EtOAc, to remove impurities, then by 0% to 10% MeOH in DCM to obtain the title compound (200 mg, 0.273 mmol, 28% yield) as an orange solid. * H NMR (400 MHz, DMSO-ds) 5 ppm 8.16 (d, J = 1.52 Hz, 1 H), 7.94 - 8.08 (m, 3 H), 7.74 (d , J = 8.11 Hz, 2 H), 7.50 (s, 1 H), 7.31 - 7.43 (m, 3 H), 6.62 (s, 1 H), 5.74 - 5.81 (m, 2 H), 4.80 (br. S, 2 H), 4.59 (d, J = 6.84 Hz, 2 H), 4.13 (br. S., 2 H), 4.01 (t, J = 6.08 Hz, 2 H), 3.63 (t, J = 5.96 Hz, 2 H), 2.16 (s, 3 H), 1.76 - 1.88 (m, 2 H), 1.33 (t, J = 7.10 Hz, 3 H), 0.74 - 0.82 (m, 9 H), -0.06 (s, 6 H); LCMS [M + H] * = 734.6 Step 2: (E) -1- (4 - ((2-amino-6- (3 - ((tert-butyldimethylsilyl) oxy) propoxy) -4-carbamoylphenyl) amino ) but-2-en-1-yl) -2- (1-ethyl-3-methyl-1 Hpirazol-5-carboxamido) -1H-benzo [d] imidazol-5-carboxamide o] DÁS ") N | TBDMSO WMO
[0465] [0465] (E) -1- (4 - ((2- (3 - ((tert-butyldimethylsilyl) oxy) propoxy) -4-carbamoyl-6-nitrophenyl) amino) but-2-en-1 -i1) -2- (1-ethyl-3-methyl-1H-pyrazol-5-carboxamido) -1H-benzo [d] imidazole-5-carboxamide (1 g, 1.363 mmol) in MeOH (20 mL), added ammonium hydroxide (4.62 mL, 34.1 mmol), and the mixture was stirred for 5 min at room temperature. After that, sodium hydrosulfite (1.675 g, 8.18 mmol) in water (5 ml) was added. After 60 min, EtOAc (300 ml) was added, and the mixture was extracted with water (50 ml x 3). The organic phase was separated, dried with NazSO3. and concentrated in vacuo to obtain the title compound (710 mg, 1.009 mmol, 74.0% yield) as a light yellow solid, which was used without further purification. 1H NMR (400 MHz, DMSO-ds) 5 ppm 12.80 (br. S., 1 H),
[0466] [0466] To a solution of (E) -1- (4 - ((2-amino-6- (3 - ((tert-butyldimethylsilyl) oxy) propoxy) -4-carbamoylphenyl) amino) but-2-en- 1-11) -2- (1-ethyl-3-methyl-1H-pyrazol-5-carboxamido) -1H-benzo [d] imidazole-5-carboxamide (120 mg, 0.170 mmol) in MeOH (5 mL), cyanogen bromide (36 mg, 0.34 mmol) was added at room temperature. After 2 h, the reaction was concentrated, and EtOAc (10 ml) was added. After stirring for 30 min, the solid was isolated by filtration and washed with EtOAc to obtain the title compound (120 mg, 0.165 mmol, 97% yield) as a light brown solid, which was used without further purification. * H NMR (400 MHz, MeOH-da) 5 ppm 8.00 (d, J = 1.27 Hz, 1 H), 7.81 (dd, J = 8.36, 1.77 Hz, 1 H ), 7.49 (d, J = 1.27 Hz, 1 H), 7.39 - 7.45 (m, 1 H), 7.36 (d, J = 1.27 Hz, 1 H), 6.61 (s, 1 H), 5.82 - 5.99 (m, 2 H), 4.96 - 5.01 (m, 2 H), 4.56 - 4.65 (m, 2 H ), 4.12 (t, J = 6.21 Hz,
[0467] [0467] To a solution of 1-ethyl-3-methyl-1 H-pyrazol-S-carboxylic acid (33 mg, 0.21 mmol) in DMF (3 mL), HATU (75 mg, 0, 20 mmol) and HOBt (12.6 mg, 0.082 mmol). After stirring at room temperature for 10 min, trietlamine (0.09 mL, 0.668 mmol) was added, followed by (E) -2-amino-7- (3 - ((tert-butyldimethylsilyl) oxy) propoxy) - 1- (4- (5-carbamoyl-2- (1-ethyl-3-methyl-1 H-pyrazol-5-carboxamido) -1H-benzo [d] imidazol-1-yl) but-2-en-1 -i1) - 1H-benzo [d] imidazole-5-carboxamide (120 mg, 0.165 mmol), and the reaction was continued at room temperature. After 3 days, a solid was precipitated from the reaction by the dropwise addition of water. The solid was isolated by filtration and washed with water. After that, the solid was purified on silica gel (12 g HP Gold column), eluting with 0% to 20% MeOH in DCM. The desired fractions were combined and concentrated to obtain the title compound (29 mg, 0.034 mmol, 20% yield) as an off-white solid. * H NMR (400 MHz, THF-da) 5 ppm 12.53 (br. S., 2 H), 8.00 (d, J = 1.01 Hz, 1 H), 7.61 (d, J = 1.01 Hz, 1 H), 7.53 (dd, J = 8.36, 1.52 Hz, 1 H), 7.36 (d, J = 6.84 Hz, 2 H), 7 , 29 (d, J = 1.01 Hz, 1 H), 7.12 (d, J = 8.36 Hz, 1 H), 6.83 (br., 2 H), 6.66 ( d, J = 2.28 Hz, 2 H), 6.06 (dt, J = 15.46, 5.58 Hz, 1 H), 5.87 (dt, J = 15.46, 5.83 Hz , 1 H), 5.09 (d, J = 5.32 Hz, 2 H), 4.89 (d, J = 5.58 Hz, 2 H), 4.59 - 4.72
[0468] [0468] To a 1 L round bottom flask, 1-ethyl-3-methyl-1H-pyrazole-5-carboxylic acid (25 g, 162 mmol) and DCM (500 ml) were added. To this heterogeneous solution, DMF (0.1 mL, 1.291 mmol) was added, followed by the slow addition of oxalyl chloride (15.61 mL, 178 mmol). After stirring for 1 h at room temperature, the volatile substances were removed in vacuo, and the crude product was coevaporated twice by dichloromethane (100 ml each). 100% yield was assumed, and the crude product (1-ethyl-3-methyl-1H-pyrazol-5-carbonyl chloride (28.0 9, 162 mmol, 100% yield)) was used directly.
[0469] [0469] To a dry 1 L round-bottom flask, KSCN (18.92 g, 195 mmol) and acetone (463 mL) were added. This clear homogeneous solution was cooled to 0 ° C. After stirring for 5 min at 0 ° C, 1-ethyl-3-methyl-1H-pyrazol-5-carbonyl chloride (28 g, 162 mmol) was added as a solution in acetone (25 ml). Once the addition was complete, the reaction was allowed to stir at 0º C. After 1 min, more KSCN (-2 g) was added, and the reaction was stirred for another 20 min. This time, hexanes (200 mL) were added to the reaction mixture, and the crude heterogeneous solution was concentrated in vacuo to one third of the volume. The process of adding hexanes and concentration was repeated twice (300 ml of hexanes each time). After the last concentration, hexanes (200 ml) were added, and the solid was removed by filtration, rinsing with hexanes (100 ml). The resulting light yellow filtered clear was concentrated and purified by chromatography (330 g Gold silica column; eluting with 0% to 20% EtOAc / hexanes). The desired product elutes at -7% EtOAc / hexanes. The desired fractions were combined and concentrated, thus producing 1-ethyl-3-methyl-1H-pyrazol-5-carbonyl isothiocyanate (27.5 g, 139 mmol, 86% yield) as a clear colorless liquid. * H NMR (400 MHz, chloroform-d) 5 ppm 6.77 (s, 1 H), 4.54 (q, J = 7.10 Hz, 2H), 2.34 (s, 3 H), 1.44 (t, J = 7.22 Hz, 3 H); LCMS [M + H] * = 196.1. The acylisothiocyanate product degrades over time, and for this reason, a solution of 1,4-dioxane at -0.4 M was prepared and frozen to prevent / delay decomposition. This solution was thawed and used directly in subsequent reactions.
[0470] [0470] To a suspension of 4-chloro-3-methoxy-5-nitrobenzamide (1.50 g, 6.50 mmol) in EtoOH (25 mL), were added (4-aminobut-2-en-1- il) (E) - tert-butyl carbamate (1.454 g, 7.81 mmol) and DIEA (3.4 mL, 20 mmol). The reaction was stirred at 120º C in a sealed tube overnight and allowed to cool to room temperature. The resulting orange solid was collected by filtration and washed with EtoH to obtain the title compound (2.10 g, 5.52 mmol, 85% yield). * H NMR (400 MHz, DMSO-ds) 5 ppm 8.19 (d, J = 1.77 Hz, 1 H) 8.03 (br. S., 1 H) 7.76 (t, J = 6.08 Hz, 1 H) 7.55 (d, J = 1.52 Hz, 1 H) 7.34 (br. S, 1 H) 6.95 (t, J = 5.45 Hz, 1 H) 5.53 (br., 2 H) 4.09 (br., 2 H) 3.88 (s, 3 H) 3.48 (br., 2 H) 1.35 (s, 9 H). LCMS (m / z): 325.1 [M-t-Bu + HJ *.
[0471] [0471] An alternative way to prepare the compound described in this document: To a 5 liter bottle and 3 bottlenecks, 4-chloro-3-methoxy-5- was added
[0472] [0472] To a suspension of tert-butyl (E) - (4 - ((4-carbamoyl-2-methoxy-6-nitrophenyl) amino) but-2-en-1-yl) carbamate (20 9, 47 , 3 mmol) in MeOH (50 mL), 4 M HCl in dioxane (100 mL, 400 mmol) was added slowly. The reaction mixture was stirred at room temperature for 1 h, then the resulting solid was isolated by filtration, washed with diethyl ether (3 x 100mL) and dried under high vacuum to obtain the title compound (13.90 g, 43 , 9 mmol, 93% yield). * H NMR (400 MHz, DMSO-ds) 5 ppm 8.22 (d, J = 2.03 Hz, 1 H), 7.76 - 8.16 (br., 5 H), 7, 60 (d, J = 2.03 Hz, 1 H), 7.37 (br. S., 1 H), 5.87 (dt, J = 15.52, 5.80 Hz, 1 H), 5 , 62 (dt, J = 15.65, 6.37 Hz, 1 H), 4.18 (d, J = 5.32 Hz, 2 H), 3.90 (s, 3 H), 3.40 (t, J = 5.70 Hz, 2 H). LCMS (m / z): 281.1 [M + HJ ". Intermediate 11 (E) -1 - ((E) -4-aminobut-2-en-1-i1) -2 - ((1-ethyl- 3-methyl-1 H-pyrazol-5-carbonyl) imino) -7-methoxy-3-methyl-2,3-dihydro-1H-benzo [d] imidazole-5-carboxamide, 3 NH hydrochloride> ”(the QN Ny í x FU = N HAN N
[0473] [0473] JA (E) - (4- (5-carbamoyl-2- (1-ethyl-3-methyl-1H-pyrazol-5-carboxamido) -7-methoxy-1H-benzo [d] imidazo | -1 -yl) but-2-en-1-yl) tert-butyl carbamate (530 mg, 1.036 mmol) in DMF (5 mL) at room temperature, cesium carbonate (675 mg, 2.072 mmol) and iodide were added methyl (0.097 mL, 1.554 mmol). The reaction was stirred at room temperature. After 2 h, the reaction was diluted with 100 mL of
[0474] [0474] A ((E) -4 - ((E) -5-carbamoyl-2 - (((1-ethyl-3-methyl-1H-pyrazol-5-carbonyl) imino) - 7-methoxy-3- methyl-2,3-dihydro-1H-benzo [d] imidazo | -1-yl) but-2-en-1-yl) tert-butyl carbamate (600 mg, 1.142 mmol) in MeOH (5 mL), 4 M hydrochloric acid in dioxane (2.85 ml, 11.42 mmol) was added, and the reaction was stirred at room temperature. After 3 h, the volatile substances were removed in vacuo to obtain the title compound as an orange solid (650 mg, 1.04 mmol, 92% yield). * H NMR (400 MHz, DMSO-ds) 5 ppm 1.33 (t, J = 7.10 Hz, 3 H) 2.20 (s, 3 H) 3.32 - 3.42 (m, 3 H) 3.66 (br. S., 3 H) 4.03 (s, 3 H) 4.54 (q, J = 7.10 Hz, 2 H) 5.03 (br. S., 2H) 5.60 - 5.71 (m, 1 H) 5.97 (dt, J = 15.59, 5.89 Hz, 1 H) 6.79 (br., 1 H) 7.52 - 7 , 61 (m, 2H) 7.90 (br., 1 H) 8.05 (br., 3 H) 8.22 (br., 1 H). LCMS m / z = 426 [M + H] J *.
[0475] [0475] (E) -4 - ((4-aminobut-2-en-1-yl) amino) -3-methoxy-S-nitrobenzamide, hydrochloride (1.7 g, 5.37 mmol), 4-chlorine -3- (3-morpholinopropoxy) -5-nitrobenzamide (1.65 g, 4.81 mmol), isopropanol (15 mL) and DIPEA (2.94 mL, 16.85 mmol) were divided into two 24 mL ampoules . The ampoules were capped and heated to 120º C for 42 h. The resulting solid was isolated by filtration and rinsed with isopropanol (2 x 3 mL) to obtain (E) - 4 - ((4 - ((4-carbamoyl-2- (3-morpholinopropoxy) -6-nitrophenyl) amino) but -2-en-1-yl) amino) -3-methoxy-5-nitrobenzamide (1.95 g, 2.79 mmol, 51.9% yield) as a brick red solid. LCMS (m / z): 588.2 [M + HJ ". Step 2: (E) -3-amino-4 - ((4 - ((2-amino-4-carbamoyl-6- (3-morpholinopropoxy)) phenyl)> amino) but-2-en-1-yl) amino) -5-methoxybenzamide o “o
[0476] [0476] A (E) -4 - ((4 - ((4-carbamoyl-2- (3-morpholinopropoxy) -6-nitrophenyl) amino) but- 2-en-1-yl) amino) -3-methoxy -5-nitrobenzamide (4.6 g, 6.65 mmol) in MeOH (83.0 mL) at room temperature, sodium hydrosulfite (19.08 9, 93.0 mmol) in water (70 mL) was added . After 15 min, solid sodium bicarbonate (24 grams) was added. After 10 min, the reaction was filtered, and the solid was rinsed with MeOH (4 x mL). The combined filtrates were concentrated on diatomaceous earth, and the mixture was purified by dry loading on silica gel (809 Gold column), eluting with 2% to 40% (10: 1 MeOH: NH.OH aq.) in DCM, to obtain the title compound (1.81 g, 3.26 mmol, 49% yield) as a dark yellow film. * H NMR (400 MHz, DMSO-ds) 5 ppm 7.64 (br. S., 2 H), 6.99 (br., 2 H), 6.85 (dd, J = 5, 07, 1.77 Hz, 2 H), 6.78 (dd, J = 4.31, 1.77 Hz, 2 H), 5.63 - 5.72 (m, 2 H), 4.66 ( d, J = 8.11 Hz, 4 H), 3.96 (t, J = 6.21 Hz, 2 H), 3.74 (s, 3 H), 3.51 - 3.60 (m, 6 H), 3.17 (br. S, 4 H), 2.43 (t, J = 7.10 Hz, 2 H), 2.35 (br. 4 h), 1.87 (t, J = 6.72 Hz, 2 H); LCMS (m / z): 528.4 [M + H]) *. Step 3: (E) -1- (4- (5-carbamoyl-2- (1-ethyl-3-methyl-1H-pyrazol-5-carboxamido) -7- (3-morpholinopropoxy) -1H-benzo [d ] imidazo | -1-yl) but-2-en-1-i1) -2- (1-ethyl-3-methyl-1H-pyrazol-5-carboxamido) -7-methoxy-1H-benzo [d] imidazole -5-carboxamide
[0477] [0477] A (E) -3-amino-4 - (((4 - ((2-amino-4-carbamoyl-6- (3-morpholinopropoxy) phenyl) amino) -but-2-en-1-yl) amino) -5-methoxybenzamide - (368 mg, 0.697 mmol) in DMF (6.97 mL) at 0 ° C, 1-ethyl-3-methyl-1H-pyrazol-5-carbonyl isothiocyanate in dioxane (2, 0 mL, 0.80 mmol). After -10 min, another portion of 0.4 M 1-ethyl-3-methyl-1H-pyrazol-S-carbonyl isothiocyanate in dioxane (0.5 mL, 0.20 mmol) was added, followed by -15 min later by a final portion (0.5 mL, 0.20 mmol). After a total reaction time of 35 min, EDC (334 mg, 1.74 mmol) was added, followed by triethylamine (0.486 ml, 3.49 mmol). The mixture was allowed to warm to room temperature and stirred overnight (-14 hours). The reaction was quenched with 3: 1 water: saturated aqueous NHaCl (40 mL) and extracted with 3: 1 chloroform: EtOH (2x40 mL). The combined organic phase was washed with water (20 ml), dried over magnesium sulfate and concentrated. The resulting residue was purified by chromatography on silica gel (40 9 column, 2% to 40% gradient of [10: 1 MeOH: aq. NHaOH] / DCM) to obtain the title compound (361 mg, 0.425 mmol, 60.9% yield) as a pear-colored solid. 1H NMR (400 MHz, DMSO-ds) 5 ppm 1.20-1.35 (m, 6 H), 1.55 - 1.73 (m, 2 H), 2.02 - 2.31 (m , 12 H), 3.46 (t, J = 4.44 Hz, 4 H), 3.70 (s, 3 H), 3.93 (t, J = 5.96 Hz, 2H), 4, 40 - 4.68 (m, 4 H), 4.80 - 5.00 (m, 4 H), 5.69 - 6.00 (m, 2 H), 6.41 - 6.74 (m, 2H), 7.13 -7.51 (m, 4 H), 7.56 - 7.76 (m, 2 H), 7.99 (d, J = 3.55 Hz, 2 H), 12, 85 (br., 2H). LCMS (m / z): 851.5 [M + HJ *.
[0478] [0478] To 2,2,3,3-tetrafluorbutane-1,4-diol (10.0 g, 61.7 mmol) in pyridine (150 mL) at 0 ° C, 4-methylbenzene-1 chloride was added -sulfonyl (29.4 g, 154 mmol) for 5 min, and then the reaction was heated to 55º C. After 1 day, the reaction was quenched with cold water, and the resulting solid was collected by filtration, dissolved in DCM (200 mL) and washed with H2SO. aq. 5% (100 mL x 3). The organic layer was dried over Na2SO. and concentrated to obtain the title compound (27.3 g, 58.0 mmol, 94% yield) as a white solid. LCMS [M + H] * = 470.9 Step 2: 1,4-diazide-2,2,3,3-tetrafluorbutane FF
[0479] [0479] Bis (4-methylbenzenesulfonate) of 2,2,3,3-tetrafluorbutane-1,4-diyl (10.0 g, 21.3 mmol) and sodium azide (5.53 g, 85.0 mmol ) in DMF (40 mL) were stirred at 110 ° C overnight. The reaction was quenched with NaCIO (aq.) And extracted with DCM (5 ml x 3). The combined organic layers were washed with water (10 ml), dried over Na2SO4 and concentrated to obtain the title compound (3.5 g, 16.5 mmol, 78% yield). LCMS [M + H] * = 213.1 Step 3: 2,2,3,3-tetrafluorbutane-1 4-diamine ENS a, FF
[0480] [0480] To a solution of 1,4-diazido-2,2,3,3-tetrafluorbutane (36.0 g, 170 mmol) in MeOH (350 mL), Pd on 10% carbon (18, 1 g, 17.0 mmol). The reaction mixture was stirred at 40º C under hydrogen (4 atm) for 16h. The mixture was filtered through a layer of diatomaceous earth and washed with MeOH, and the filtrate was concentrated in vacuo to obtain the title compound (22.0 g, 124 mmol, 73% yield). 1H NMR (400 MHz, chloroform-d) 5 ppm 3.12 - 3.37 (m, 4 H), 1.43 (br. S., 4H). Intermediates 14A and 14B 7- (3 - ((tert-butyldimethylsilyl) oxy) propoxy) -1- (5- (5-carbamoyl-2- (1-ethyl-3-methyl-1 H-pyrazole-5-carboxamide) -1H-benzo [d] imidazol-1-yl) hexan-2-i1) -2- (1-ethyl-3-methyl-1H-pyrazol-5-carboxamido) -1H-benzo [d] imidazole-5- carboxamide Intermediate 14A Intermediate 14B O o + P '. + O O ”O Si. N Si: N“ o o “o o Oo Cp VA sr Ô A TN TN TN N N
[0481] [0481] To a 500 ml round bottom flask, 2,5-dibromohexane (10 g, 41.0 mmol) and DMF (100 ml) were added. To this homogeneous solution, sodium azide (10.66 g, 164 mmol) was added. The heterogeneous reaction mixture was stirred at 80º C for 1 h. The mixture was cooled to room temperature, and water (100 ml) was added. The aqueous phase was extracted with ethyl ether (3 x 100 ml). The combined organic phase was washed with brine (100 ml), dried over sodium sulfate, filtered and concentrated in vacuo. 2,5-diazidohexane (8.54 g, 33.5 mmol, 83% yield, 66% purity) was obtained as a yellow oil.
[0482] [0482] 2,5-diazidohexane (8.54 g, 50.8 mmol) was dissolved in MeOH (300 ml). This solution was hydrogenated in a single pass through a ThalesNano H-Cubeº system (35º C, 25 bars of hydrogen pressure, flow rate of 2 mL / min). Then, the solution was concentrated, and the crude product was used in subsequent reactions. Hexane-2,5-diamine (6.04 g, 49.4 mmol, 97% yield) was obtained as a colorless oil. * H NMR (400 MHz, D-CHLOROPHORM) δ ppm 1.09 (dd, J = 6.21, 1.65 Hz, 6 H), 1.21 - 1.62 (m, 8 H), 2 , 78 - 3.02 (m, 2H).
[0483] [0483] In a 40 ml ampoule, 3- (3 - ((tert-butyldimethylsilyl) oxy) propoxy) -4-chloro-5-nitrobenzamide (the compound of intermediate 4) (1.255 g, 3.23 mmol), isopropanol (8 mL) and DIPEA (1.879 mL, 10.76 mmol). To this heterogeneous mixture, hexane-2,5-diamine (500 mg, 4.380 mmol) was added as a solution in isopropanol (2 mL). The ampoule was capped and heated to 110º C overnight (-14 h). The solution was cooled to room temperature. 4-Fluorine-3-nitrobenzamide (0.594 g, 3.23 mmol) was added, followed by DIPEA (1.879 mL, 10.76 mmol). The reaction was heated again at 110º C for 2 h. The solid formed when cooling to room temperature. The solid was collected on a filter and rinsed twice with isopropanol (2 ml each). This crude solid was purified by chromatography on silica gel (ISCO unit, 80 g SiO27 cartridge, 2% to 20% MeOH / DCM gradient). The corresponding fractions were combined and concentrated. 3- (3 - ((tert-butyldimethylsilyl) oxy) propoxy) -4 - ((5 - ((4-carbamoyl-2-nitrophenyl) amino) hexan-2-yl) amino) -5-nitrobenzamide ( 300 mg, 0.450 mmol, 10.47% yield) as an orange glassy film (mixture of diastereomers). LCMS (m / z): 633.5 [M + HJ *.
[0484] [0484] To a 125 mL Erlenmeyer flask, 3- (3 - ((tert-butyldimethylsilyl) oxy) propoxy) -4 - ((5 - (((4-carbamoyl-2-nitrophenyl) amino) hexan were added -2-yl) amino) -5-nitrobenzamide (386 mg, 0.610 mmol) and MeOH (40 ml). This solution was hydrogenated using a ThalesNano H-Cubeº system (5% Pd / C cartridge, 30º C, 10 bars of hydrogen pressure, flow rate of 1.5 mL / min). After two cycles, the reduction was completed. The solution was concentrated to obtain 3-amino-4 - ((5- ((2-amino-4-carbamoylphenyl) amino) hexan-2-yl) amino) -5- (3 - ((tert-butyldimethylsilyl) oxy) propoxy) benzamide (352 mg, 0.602 mmol, 99% yield). LCMS (m / z): 573.5 [M + HJ *.
[0485] [0485] To a 100 ml round bottom flask, 3-amino-4- ((5 - (((2-amino-4-carbamoylphenyl) amino) hexan-2-yl) amino) -5- ( 3 - ((tert-butyldimethylsilyl) oxy) propoxy) benzamide (352 mg, 0.614 mmol) and DMF (6.1 mL). A solution of 1-ethyl-3-methyl-1H-pyrazol-5-carbonyl isothiocyanate (the compound of intermediate 8) (- 0.4 M in dioxane, 2.75 mL, 1,100 mmol) was added at 0 ° C , and the mixture was stirred for 15 min. After that, EDC (295 mg, 1.536 mmol) was added, followed by the addition of triethylamine (0.428 mL, 3.07 mmol). The reaction was stirred overnight (-14 h) at room temperature. The reaction was divided between 50 ml of ethyl acetate and 50 ml of a 1: 1 mixture of saturated aqueous ammonium chloride solution and water. The layers were separated. The aqueous layer was extracted with ethyl acetate (2 x 25 ml). The combined organic phase was washed with brine, dried over sodium sulfate and concentrated in vacuo. Purification by preparative reverse phase chromatography (biphasic ISCO system, Gemini C18 column, 5 um, 50 x 30 mm; 40% to 70% MeCN / water gradient with NHOH modifier) allowed the separation and characterization of a first eluting diastereomer and a second diastereomer eluting. Each diastereomer (i.e., pair of enantiomers) is expected to be racemic. Fractions containing the first eluting diastereomer and the second eluting diastereomer were pooled separately and dried to obtain Intermediates XA and XB, respectively, as white solids.
[0486] [0486] To 4-chloro-3-hydroxy-S-nitrobenzamide (942 mg, 4.35 mmol) dissolved in DMF (7 mL), Cs2COs (1.599 g, 4.78 mmol) were added, followed by chloride 4-methoxybenzyl (0.622 mL, 4.57 mmol). The reaction mixture was stirred for 24 h at room temperature. With vigorous stirring, water (15 mL) was added dropwise, and the resulting solid was stirred for 5 minutes, collected by filtration and rinsed with water to obtain the title compound (1.26 g, 3.74 mmol, 82% yield) as a light orange solid. * H NMR (400 MHz, CDCl3) 5 ppm 7.80 (d, J = 1.8 Hz, 1 H), 7.76 (d, J = 1.8 Hz, 1 H), 7.43 ( d, J = 8.6 Hz, 2 H), 6.98 (d, J = 8.6 Hz, 2 H), 6.13 (br. s., 1 H), 5.82 (br. s ., 1 H), 5.25 (s, 2 H), 3.87 (s, 3 H); LCMS (m / z): 337.1 [M + HJ *.
[0487] [0487] To a solution of (E) -1,4-dibromo-2,3-dimethylbut-2-ene (29.5 g, 122 mmol) in DMF (244 mL), potassium salt of phthalimide was added (45.2 g, 244 mmol). The white suspension was stirred at room temperature overnight. The reaction was poured into water (2 L), and the resulting white suspension was filtered. The filter cake was air-dried (48 h) to obtain (E) -2.2 '- (2,3-dimethylbut-2-eno- 1,4-diyl) bis (isoindoline-1,3-dione) (37 g, 99 mmol, 81% yield) as a white solid. The solid was used without further purification. * H NMR (400 MHz, D-CHLOROPHORM) 5 ppm 7.84 - 7.93 (m, 4 H), 7.72 - 7.81 (m, 4 H), 4.39 (s, 4 H ), 1.95 (s, 6 H).
[0488] [0488] To a mixture of (E) -2,2 '- (2,3-dimethylbut-2-ene-1,4-diyl) bis (isoindoline-1,3-dione) (15.3 g, 40 , 9 mmol) in EtoH (332 mL), hydrazine monohydrate (6.01 mL, 123 mmol) was added. The reaction was heated to 80º C. After 3 h, the reaction was cooled to room temperature. The thick white mixture was filtered, the filter cake was washed with ethanol, and the filtrate was concentrated to dryness. The white solid resulting from the filtrate was divided between water (150 ml) and EtOAc (150 ml). The aqueous layer was concentrated to dryness to obtain a yellow viscous oil. The viscous oil was treated with 1 N HCI (250 ml) and EtOAc (250 ml). The resulting white precipitate (by-product) was removed by filtration. The filtrate was transferred to a separating funnel. The aqueous layer was separated; filtered to remove remaining white solids and concentrated to dryness to obtain (E) -2,3-dimethylbut-2-eno- 1,4-diamine, 2 hydrochloride (4.2 g, 22.45 mmol, 54.9% yield) in the form of a grayish pink solid. The material was used without further purification. * H NMR (400 MHz, DMSO-ds) 5 ppm 8.23 (br. S., 6 H), 3.45 (q, J = 5.75 Hz, 4 H), 1.83 (s, 6 H).
[0489] [0489] To a 2 L round bottom flask, (E) - (4 - (((4-carbamoyl-2-methoxy-6-nitrophenyl) amino) but-2-en-1-yl) carbamate tert-butyl (25.8 9, 67.8 mmol) and methanol (484 mL). This homogeneous orange solution was cooled to 0ºC. After 20 minutes of stirring at 0ºC, ammonium hydroxide solution (29% by weight, 91 mL, 678 mmol) was added, followed by sodium hydrosulfite (85% by weight) , 70.0 g, 342 mmol) as a solution in water (194 mL). The flask was removed from the ice bath and stirred at room temperature. The heterogeneous mixture slowly changes from orange to whitish. After 3 h of stirring at room temperature, water (-800 ml) was added until a clear solution was obtained. Methanol was evaporated using reduced pressure. The white solid that formed during evaporation was filtered and washed with water twice (300 ml each). The solid was air-dried for 16 h and then for 5 h in a 50 ° C vacuum oven. (E) - (4 - ((2-amino-4-carbamoyl-6-methoxyphenyl) amino) but -2-en- 1-yl) tert-butyl carbamate (19.34 g, 54.1 mmol, 80% yield) as an off-white solid. The purity of this solid was evaluated at 98% by HPLC, LCMS and * H NMR. * H NMR (400 MHz, DMSO-ds) 5 ppm 7.62 (br. S., 1 H) 6.98 (br., 1 H) 6.92 (t, J = 5.45 Hz , 1 H) 6.87 (d, J = 1.77 Hz, 1 H) 6.79 (d, J = 1.77 Hz, 1 H) 5.57 (qt, J = 15.27, 5, 23 Hz, 2 H) 4.67 (br., 2 H) 3.82 (br., 1 H) 3.76 (s, 3 H) 3.51 (dd, J = 12.29 , 5.70 Hz, 4 H) 1.37 (s, 9 H). LCMS (m / z): 351.1 (M + H) *.
[0490] [0490] To a 2 liter round bottom flask, (E) - (4 - (((2-amino-4-carbamoyl-6-methoxyphenyl) amino) but-2-en-1-yl) carbamate tert-butyl (19.34 g, 55.2 mmol) and DMF (184 mL). This solution was cooled to 0 ° C. After 20 minutes of stirring at 0 ° C, 1-ethyl-3-methyl-1H-pyrazol-5-carbonyl isothiocyanate (44.2 mL, 44.2 mmol) was added as of a -1.0 M solution in dioxane. After 10 minutes of stirring at 0º C, the formation of the thiourea intermediate was completed. EDC (15.87 g, 83 mmol) and DIEA (28.9 mL, 166 mmol) were added. The reaction was warmed to room temperature and stirred overnight (-14 h). To the heterogeneous reaction mixture, a mixture of 250 ml of saturated aqueous ammonium chloride and 750 ml of water was added. This heterogeneous mixture was stirred for 1 h at room temperature. The solid was filtered and rinsed twice with water (200 ml each). The whitish solid was dried in a vacuum oven at 50º C for 3 days. (E) - (4- (5-carbamoyl-2- (1-ethyl-3-methyl-1H-pyrazol-5-carboxamido) -7-methoxy-1H-benzo [d] imidazol-1-yl was obtained ) but-2-en-1-yl) carbamate = tert-
[0491] [0491] To a 1 liter round bottom flask, (E) - (4- (5- carbamoyl-2- (1-ethyl-3-methyl-1H-pyrazol-5-carboxamido) -7- methoxy-1H-benzo [d] imidazol-1-yl) but-2-en-1-yl) tert-butyl carbamate (21.23 g, 41.5 mmol), ethanol (234 mL) and t- ether butylmethyl (96 mL). To this heterogeneous solution, HCI (114 mL, 456 mmol) was added as a 4 M solution in dioxane. During the addition of HCl, the solution went from heterogeneous to homogeneous with a canary yellow color. The reaction was stirred at room temperature overnight. The following morning, a white solid had precipitated. More 4 M HCl solution (15.56 mL, 62.2 mmol) was added, and the mixture was stirred for an additional 9 m until the reaction was complete. The white solid was filtered and rinsed with a 1: 4 mixture of ethanol (200 ml) / TBME (800 ml). The solid obtained was dried in the vacuum oven overnight (50º C). (E) -1- (4-aminobut-2-en-1-i1) -2- (1-ethyl-3-methyl-1 H-pyrazol-5-carboxamido) -7-methoxy-1H- benzo [d] imidazole-5-carboxamide, 2 Hydrochloride (22.56 9, 44.2 mmol, 107% yield) as a white solid with a purity of
[0492] [0492] To a solution of (E) -1,4-dibromo-2,3-dimethylbut-2-ene (13.59 g, 50.6 mmol) in DCM (200 mL), 1.3 , 5,7-tetraazaadamantane (7.09 g, 50.6 mmol) in portions for more than 2 min. The reaction was stirred for 25 min, and the resulting solid was filtered, washed with DCM and dried to obtain (3r, 5r, 7r) -1 - ((E) -4-bromo-2,3-dimethylbut-2-en -1-i1) -1,3,5,7-tetraazaadamantan-1-ium, bromide (16.7 g, 43.7 mmol, 86% yield) as a white solid. LCMS (m / z): 301.1 [M] *.
[0493] [0493] To a suspension of (3r, 5r, 7r) -1 - ((E) -4-bromo-2,3-dimethylbut-2-en-1- i1) -1,3,5,7-tetraazaadamantan -1-ium, bromide (16.7 g, 43.7 mmol) in acetone (200 mL), potassium 1,3-dioxoisoindolin-2-acid (8.09 g, 43.7 mmol) was added. The reaction mixture was heated to 55º C for 1.5 h. Over the next 2.5 h, the reaction was treated with more potassium phthalimide until the starting material was consumed. The reaction mixture was removed from the heat, stirred for 10 min and then filtered while still warm. The solid was rinsed with acetone and dried to obtain 20.4 g of crude product. The crude product was stirred in cold water (ice bath) for 5 min. The solid was collected on a filter, rinsed with cold water and dried to obtain (3r, 5r, 7r) -1 - ((E) -4- (1,3-dioxoisoindolin-2-yl) -2,3-dimethylbut -2-en-1-yl) - 1,3,5,7-tetraazaadamantan-1-lum, bromide (10.3 g, 229 mmol, 52.6% yield) as a light yellow solid. LCMS (m / z): 368.2 [M] *.
[0494] [0494] To a suspension of (3r, 5r, 7r) -1 - ((E) -4- (1,3-dioxoisoindolin-2-i1) -2,3-dimethylbut-2-en-1-i1) -1,3,5,7-tetraazaadamantan-1-ium, bromide (10.3 g, 22.97 mmol) in EtoH (100 mL) at room temperature, concentrated hydrogen chloride (7.55 mL, 92 mmol). The reaction mixture changed from light yellow to light orange. The reaction was heated to 80 ° C for 55 min. The color became darker orange over time. The reaction mixture was cooled to room temperature, and NaHCO solution was added; saturated to raise the pH of the solution (-20 mL). The mixture was stirred for 5 min, diluted with 20 ml of water and extracted with 3: 1 chloroform: EtOH (3 x 75 ml). The organic extracts were dried over sodium sulfate, concentrated and dried to obtain (E) -2- (4-amino-2,3-dimethylbut-2-en-1-iN) isoindoline-1,3-dione (5, 77 g, 22.4 mmol, 98% yield) as a light brown solid. 1H NMR (400 MHz, DMSO-ds) 5 ppm 7.71 - 8.09 (m, 6 H), 4.25 (s, 2 H), 3.45 (s, 2 H), 1.95 (d, J = 1.27 Hz, 3 H), 1.65 (d, J = 1.27 Hz, 3 H). LCMS (m / z): 245.2 [M + HJ *.
[0495] [0495] To a solution of tert-butyl carbamate (20.1 g, 172 mmol) in DCM (400 mL) at 0 ° C, calcium hypochlorite (technical grade, available chlorine 65%) (75 g, 343 mmol) and then 6 M hydrochloric acid (143 mL, 858 mmol) dropwise over 35 min (internal temperature from 5 ° to 10 ° C during the addition). After that, the resulting yellow suspension was stirred for 20 min. The layers were separated, and the organic layer was washed with water and brine and dried over sodium sulfate. The solution was cautiously concentrated under reduced pressure (23 ° C, 80 mbars) to obtain tert-butyl dichlorocarbamate (33.4 9, 172 mmol, 100%) as a light yellow liquid. * H NMR (400 MHz, CDCl3) 5 ppm 1.56 (s, 9 H).
[0496] [0496] Nitrogen was bubbled through 300 mL of chloroform for 10 min. After that, 2,3-dimethylbut-1,3-diene (24.79 mL, 219 mmol) was added and the solution was cooled to 0 ° C under a nitrogen atmosphere. A solution of tert-butyl dichlorocarbamate (41 g, 220 mmol) in chloroform (150 mL) was stirred over 80 min to generate a mixture of chlorine (4-chloro-2,3-dimethylbut-2-en-1 - (E) (E) -tert-butyl carbamate and (E) - (3-chloro-2,3-dimethylbut-2-en-1-yl) tert-butyl carbamate. After 15 min of further stirring in an ice bath, a freshly prepared aqueous solution of sodium sulfite (SM, 219 mL, 657 mmol) was added
[0497] [0497] To a solution of tert-butyl (E) - (4-chloro-2,3-dimethylbut-2-en-1-yl) carbamate (40.4 g, 164 mmol) in DMF (300 mL) , 1,3-dioxoisoindolin-2-acid (30.4 g, 164 mmol) was added, and the reaction mixture was stirred at room temperature for 3 h. The mixture was cooled in an ice / water bath, and water (450 ml) was added to obtain a thick precipitate. After stirring at room temperature for min, the solids were filtered, rinsed with water and dried to obtain (E) - (4- (1,3-dioxoisoindolin-2-i1) -2,3-dimethylbut-2-en-1 -yl) tert-butyl carbamate (50.08 9, 137 mmol, 84% yield) as a white solid. 1H NMR (400 MHz, CHLOROPHORM-d) 5 ppm 7.87 (dd, J = 5.40, 3.14 Hz, 2 H), 7.74 (dd, J = 5.27, 3.01 Hz , 2 H), 4.41 - 4.48 (m, 1 H), 4.35 (s, 2 H), 3.78 (br. S., 2 H), 1.97 (s, 3 H ), 1.70 (d, J = 1.25 Hz, 3 H), 1.47 (s, 9H).
[0498] [0498] Two identical reactions were organized in parallel. To a mixture of tert-butyl (E) - (4- (1,3-dioxoisoindolin-2-yl) -2,3-dimethylbut-2-en-1-yl) carbamate (25 g, 69.0 mmol ) in ethanol (400 ml), hydrazine monohydrate (6.69 ml, 138 mmol) was added. The mixture was stirred at 80 ° C for 4.5 h. After heating for 30 min, a thick precipitate started to form, which made it difficult to stir. The two reactions were combined and concentrated to remove ethanol and produced a white solid. This material was stirred in water (450 mL). Solutions of 1 M HCl (50 ml) and 6 M HCl (14 ml) were added to adjust the pH to -5, and the suspension was stirred for 10 min. The solid was filtered and rinsed with water. The aqueous filtrate was extracted with DCM (100 ml) to remove any impurities / color. After that, the aqueous phase was pH adjusted to 13 with 1 M sodium hydroxide and was extracted with 3: 1 CHCl3z: EtoH (3 x 300 ml). The combined organic layer was dried over sodium sulfate, filtered and concentrated to obtain a pale orange oil, which solidified quickly. The solids were crushed with 5% diethyl ether / heptane (200 mL) for 5 min, then filtered and rinsed with hepane (harvest 1). The filtrate was concentrated and stirred in 5 ml of diethyl ether. The solids were rinsed with a minimum of diethyl ether and filtered to obtain a second crop. Combination and vacuum drying produced tert-butyl (E) - (4-amino-2,3-dimethylbut-2-en-1-yl) carbamate (23.9 g, 111 mmol, 80% yield) at form of an off-white solid. 1 H NMR (400 MHz, METANOL-da4) 5 ppm 3.70 (s, 2 H), 3.24 (s, 2 H), 1.81 (d, J = 1.00 Hz, 3 H) , 1.73 (s, 3 H), 1.46 (s, 9 H). LCMS (m / z): 215.3 [M + HI *.
[0499] [0499] To a solution of tert-butyl (E) - (4-amino-2,3-dimethylbut-2-en-1-yl) carbamate (1.92 g, 8.96 mmol) and 4-fluorine -3-nitrobenzamide (1.650 g, 8.96 mmol) in DMSO (25 mL), potassium carbonate (1.486 g, 10.75 mmol) was added. The bright orange mixture was stirred at room temperature for 2 h. The mixture was added dropwise to ice water with rapid stirring (200 ml) and stirred for 1 h. The resulting precipitate was filtered, rinsed with water and dried to obtain tert (E) - (4- ((4-carbamoyl-2-nitrophenyl) amino) -2,3-dimethylbut-2-en-1-yl) carbamate -butyl (2.9 g, 7.5 mmol, 84% yield) as a bright yellow solid. 1H NMR (400 MHz, DMSO-ds) 5 ppm 8.66 (d, J = 2.28 Hz, 1 H), 8.36 (t, J = 5.32 Hz, 1 H), 7.99 (dd, J = 8.87, 2.03 Hz, 2 H), 7.31 (br. s., 1 H), 7.02 (t, J = 5.70 Hz, 1 H), 6, 92 (d, J = 9.12 Hz, 1 H), 4.02 (d, J = 5.07 Hz, 2 H), 3.60 (d, J = 5.58 Hz, 2 H), 1 , 75 (s, 3 H), 1.68 (s, 3 H), 1.38 (s, 9 H). Step 2: (E) 4 - (((4-amino-2,3-dimethylbut-2-en-1-yl) amino) -3-nitrobenzamide, Hydrochloride o "
[0501] [0501] To a solution of bis (4-methylbenzenesulfonate) of ((4S, 58) -2,2-dimethyl-1,3-dioxolane-4,5-diyl) bis (methylene) (5.23 g, 11 , 11 mmol) in DMF (20 mL), sodium azide (2.89 g, 44.5 mmol) was added. The mixture was stirred at 80 ° C for 18 h. The mixture was diluted with water (100 ml) and extracted with EtOAc (2 x 100 ml). The organic phase was washed with water (2 x 100 ml) and brine (100 ml), dried with magnesium sulfate and concentrated to obtain (4S, 5S) -4,5-bis (azidomethyl) -2,2-dimethyl- 1,3-dioxolane (2.3 g, 10.8 mmol, 98% yield) as a clear oil. 1H NMR (400 MHz, CHLOROPHORMUM-d) 5 ppm 1.51 (s, 6 H), 3.30 - 3.43 (m, 2 H), 3.54 - 3.66 (m, 2 H) , 4.10 (td, J = 2.8, 1.3 Hz, 2 H). LCMS (m / z): not prominent [M + H] *. Step 2: (28.3S) -1 A-diazidobutane-2,3-diol O OH
[0502] [0502] To the solution of (48,58S) -4,5-bis (azidomethyl) -2,2-dimethyl-1,3-dioxolane (2,39, 10,84 mmol) in THF (50 mL), para-toluenesulfonic acid (0.103 g, 0.542 mmol) was added. The reaction mixture was heated at 60 ° C for 18 h. The reaction mixture was cooled to room temperature and partitioned between EtOAc (50 ml) and water (30 ml). The aqueous phase was extracted with EtOAc (2 x 50 ml). The combined organic phase was washed with brine (30 ml), dried over magnesium sulfate and concentrated. NMR analysis does not indicate the occurrence of any reaction. To the mixture, 1.25 M HCl in methanol (34.7 mL, 43.4 mmol) was added. The reaction was heated to 60º C for 18 h. The reaction mixture was concentrated to obtain (2S, 3S) - 1,4-diazidobutane-2,3-diol (2.01 g, 10.5 mmol, 97% yield) as a clear, light yellow oil . 1H NMR (400 MHz, CHLOROPHORMUM-d) 5 ppm 3.35 - 3.59 (m, 4 H), 3.71 - 3.90 (m, 2H).
[0503] [0503] To the mixture of (28.3S) -1.4-diazidobutane-2,3-diol (2.01 g, 11.68 mmol) in DMF (50 mL), sodium hydride (1.167 g , 29.2 mmol) at 0 ° C. The mixture was stirred at room temperature for 5 min, then iodoethane (2.36 mL, 29.2 mmol) was added. The mixture was stirred at room temperature for 18 h. The mixture was partitioned between EtOAc (100 ml) and water (100 ml). The organic phase was washed with brine (3 x 30 ml), dried over magnesium sulfate and concentrated to obtain crude (28.3S) -1.4-diazido-2,3-dimethoxybutane (2.47 g) as a clear oil * H NMR (400 MHz, CHLOROPHORM-d) 5 ppm 1.27 (t, J = 7.0 Hz, 6 H), 3.31 - 3.47 (m, 4 H), 3, 56 - 3.82 (m, 6 H). A mixture of crude (2S, 3S) -1,4-diazide-2,3-dimethoxybutane (2.47 g) and palladium on carbon (0.3 g, 2.8 mmol) in methanol (30 mL) with nitrogen and replaced with a hydrogen atmosphere (balloon). The mixture was stirred at room temperature for 18 h. The hydrogen was replaced with nitrogen, and the mixture was filtered through diatomaceous earth and concentrated to obtain (2S, 3S) -2,3-dimethoxybutane-1,4-diamine (1.86 g, 90% yield) as of a clear oil. * H NMR (400 MHz, DMSOdes) δ ppm 1.07 - 1.43 (m, 6 H), 2.31 - 2.49 (m, 2 H), 2.57 - 2.68 ( m, 2 H), 3.20 - 3.27 (m, 2 H), 3.50 - 3.60 (m, 4 H). Intermediate 23 4-chloro-S-nitro-5- (trifluormethyl) benzamide F. F NH;
[0504] [0504] To a solution of 4-chloro-3-nitro-S- (trifluormethyl) benzoic acid (3.94 g, 14.62 mmol) in DCM (97 mL), oxalyl chloride (2.047 mL, 23.39 mmol) and 4 drops of DMF at room temperature. After stirring for 1 h, 30% ammonium hydroxide solution (9.49 mL, 73.1 mmol) was added and stirred for 18 h. The resulting white precipitate was filtered, washed first with water, then with DCM and dried to obtain 4-chloro-3-nitro-5- (trifluoromethyl) benzamide (3.32 g, 12.36 mmol, 85% yield ) as a white solid. * H NMR (400 MHz, DMSO-ds) 5 ppm 8.77 (d, J = 2.0 Hz, 1 H), 8.57 (d, J = 1.8 Hz, 1 H), 7, 97 (br., 2H). LCMS (m / z): 269.1 [M + HJ *. Intermediate 24 ethyl 3- (5-carbamoyl-2-fluor-3-nitrophenyl) propanoate oO -o-Nso
[0505] [0505] To 3-bromo-4-fluoro-S-nitrobenzamide (5 g, 18.25 mmol) in DMF (60.8 mL), tetra-n-butylammonium chloride (5.18 g, 18 , 25 mmol) and Pd (OAc) 2
[0506] [0506] To a brown solution of 2-fluorine-3-nitrophenol (4.75 g, 30.2 mmol) in DMF (40 mL) at room temperature, cesium carbonate (10.84 g, 33, 3 mmol) and 4-methoxybenzyl chloride (4.32 mL, 31.7 mmol). The mixture was stirred at room temperature for 16 h. Water (150 ml) was added to the vigorously stirred reaction mixture, and stirred for 10 min to produce a precipitate. The solids were filtered, rinsed with water and dried to obtain 2-fluorine-1 - ((4-methoxybenzyl) oxy) -3-nitrobenzene (8.1 g, 28.1 mmol, 93% yield). * H NMR (400 MHz, DMSO-ds) 5 ppm 7.63 - 7.75 (m, 2 H), 7.42 (d, J = 8.62 Hz, 2 H), 7.36 (d , J = 1.77 Hz, 1 H), 6.92 - 7.02 (m, 2 H), 5.21 (s, 2 H), 3.77 (s, 3 H). LCMS (m / z): none [M + H] J * observed.
[0507] [0507] To the mixture of dimethyl (2R, 3S) -2,3-dihydroxysucinate (5.86 g, 32.9 mmol) and silver oxide (22.87 g, 99 mmol), iodomethane (41 , 1 mL, 658 mmol). The mixture was heated to 45º C for 6 h and at room temperature for 18 h. The mixture was filtered, washed with DCM and concentrated to obtain the title compound (5.8 g, 28.3 mmol, 86% yield) as a clear oil, which solidified upon storage. H NMR (400 MHz, METANOL-da) 5 ppm 4.26 (s, 2 H) 3.76 (s, 6 H) 3.46 (s, 6 H). Step 2: (2R, 3S) -2,3-dimethoxybutane-1,4-diol o BoA or ô
[0508] [0508] A solution of dimethyl (2R, 3S) -2,3-dimethoxysuccinate (5.19, 24.73 mmol) in THF (30 mL) was added to the LAH mixture (2.065 g, 54.4 mmol ) in THF (150 mL) at 0º C. The mixture was warmed to room temperature for 2 hours. The reaction was quenched with saturated sodium sulfate solution (9.1 ml). The mixture was filtered, dried over magnesium sulfate and concentrated to obtain the title compound (3.6 g, 24.0 mmol, 97% yield) as a clear oil. 1H NMR (400 MHz, DMSO-ds) 5 ppm 4.51 (t, J = 5.58 Hz, 2 H) 3.51 - 3.59 (m, 2 H) 3.38 - 3.45 ( m, 2 H) 3.32 (s, 6 H) 3.19 - 3.26 (m, 2 H). Step 3: (2R, 38) -2,3-dimethoxybutane-1,4-diyl bis (4-methylbenzenesulfonate)
[0509] [0509] To a solution of (2R, 3S) -2,3-dimethoxybutane-1,4-diol (3.3 g, 21.97 mmol) in pyridine (40 mL) at -78 ° C, was added TsCI (12.57 g, 65.9 mmol). The mixture was allowed to warm to room temperature and stirred for 18 h. Water (150 mL) was added, and the mixture was cooled to 0 ° C for 2 h. The resulting precipitate was filtered, rinsed with water and dried to obtain the title compound (7.52 9, 16.4 mmol, 74.6% yield) as a white solid. * H NMR (400 MHz, CHLOROPHORMUM-d) 5 ppm 7.69 - 7.86 (m, 4 H) 7.35 - 7.44 (m, 4 H) 4.08 - 4.33 (m, 4 H) 3.33 - 3.45 (m, 2 H) 3.25 (s, 6 H) 2.49 (s, 6 H). Step 4: (2R, 3S) -1 A-diazido-2,3-dimethoxybutane
[0510] [0510] To a solution of bis (4-methylbenzenesulfonate) of (2R, 38) -2,3-dimethoxybutane-1,4-diyl (7.52 g, 16.40 mmol) in DMF (40 mL), added sodium azide (4.26 g, 65.6 mmol). The mixture was stirred at 80 ° C for 18 h. The mixture was diluted with water (200 ml) and extracted with EtOAc (2 x 200 ml). The organic phase was washed with water (2 x 200 ml) and brine (100 ml), dried with magnesium sulfate and concentrated to obtain the title compound (3.16 g, 15.8 mmol, 96% yield) in the form of a clear oil. * H NMR (400 MHz, CHLOROPHORMOMOD) d ppm 3.60 - 3.68 (m, 2 H) 3.48 (s, 6 H) 3.37 - 3.45 (m, 4 H). Step 5: (2R, 3S) -2,3-dimethoxybutane-1,4-diamine en A and —º
[0511] [0511] JA a mixture of (2R, 3S) -1,4-diazido-2,3-dimethoxybutane (3.16 g, 15.8 mmol) and palladium on carbon (0.672 g, 6.81 mmol) in methanol (30 mL), hydrogen (flask) was added. The mixture was stirred at room temperature for 60 h. After removing the hydrogen, the mixture was filtered through diatomaceous earth and concentrated to obtain the title compound (2.33 g, 15.7 mmol, 100% yield) as a clear oil. '* H NMR (400 MHz, CHLOROPHORMUM-d) 5 ppm 3.49 (s, 6 H) 3.25 - 3.35 (m, 2 H) 2.83 - 2.96 (m, 4 H) . Intermediate 27 ((18,2S) -cyclopropane-1,2-diyl) dimethanamine, 2 AAA hydrochloride, Nos. Step 1: (18,2S) -cyclopropane-1,2-dicarboxamide as NH> TT
[0512] [0512] To a 250 mL round-bottom flask, diethyl cyclopropane-1,2-dicarboxylate (38 g, 204 mmol) and ammonium hydroxide solution (28% by weight) were added (1S, 2S) aqueous solution; 380 mL, 3.035 mmol). The mixture was stirred at 25 ° C for 48 h. The mixture was filtered, and the filter cake was subsequently washed with EtOAc (100 ml). The solid was vacuum dried to obtain (1S, 2S) -cyclopropane-1,2-dicarboxamide (14.5 g, 108 mmol, 53% yield) as a white solid. 1H NMR (300 MHz, DMSO-ds) 5 ppm 7.65 (s, 2 H), 6.90 (s, 2 H), 1.86 (m, 2 H), 0.97 (m, 2H ). Step 2: (((18,2S) -cyclopropane-1,2-diyl) bis (methylene)) di-tert-butyl dicarbamate AV N A. K Yº Oo O x
[0513] [0513] To a mixture of (18.2S) -cyclopropane-1,2-dicarboxamide (14.5 9, 113 mmol) and THF (300 mL) at 0 ° C, LiAlHa (17.18 g, 453 mmol) in batches. The mixture was then stirred at 25 ° C for 48 h. The mixture was quenched by the addition of crushed ice (200 g) at 0º C. The mixture was filtered, and the filtrate was used directly in the next step. To the filtrate, LiOH (10.52 g, 4.39 mmol) and water (200 mL) were added. Boc anhydride (56.1 ml, 242 mmol) was added, and the mixture was stirred overnight at room temperature. Then, the reaction mixture was extracted three times with DCM (100 ml x 3). The combined organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by chromatography on normal phase silica gel (80 g silica, 1: 4 EtOAc / petroleum ether) to obtain (((1S, 2S) -cyclopropane-1,2-diyl) bis (methylene) )) di-tert-butyl dicarbamate (10 g, 31.6 mmol, 29% yield after two steps) as a colorless oil. * H NMR (300 MHz, Methanol-da) 5 pom 3.03 (m, 2 H), 2.85 (m, 2 H), 0.83 (m, 2 H), 0.41 (m , 2H).
[0514] [0514] To a 500 mL round-bottom flask, (((1S, 2S) - cyclopropane-1,2-diyl) bis (methylene)) di-tert-butyl dicarbamate (10 g, 33, 3 mmol) and HC! (4 M in 1,4-dioxane, 100 mL, 400 mmol). After stirring at 25 ° C for 30 min, the mixture was concentrated under reduced pressure. Then, the residue was dissolved in water (100 ml) and freeze dried. ((18S, 2S) -cyclopropane-1,2-diyl) dimethanamine, 2 hydrochloride (5.3 g, 29.1 mmol, 87% yield) was obtained as an off-white solid. * H NMR (400 MHz, Methanol-da) δ ppm 3.05 (m, 2 H), 2.81 (m, 2H), 1.27 - 1.18 (m, 2 H), 0, 87 - 0.79 (m, 2 H). LCMS (m / z): 101.2 [M + HJ ”, no UV peak observed.
[0515] [0515] To a (E) -1- (4-aminobut-2-en-1-11) -2- (1-ethyl-3-methyl-1H-pyrazol-5-carboxamido) -1H hydrochloride suspension -benzo [d] imidazole | -5-carboxamide (535 mg, 1.280 mmol) in EtOH (5 mL), triethylamine (471 mg, 4.65 mmol) and 4-chloro-3- (3-morpholinopropoxy) were added -5-nitrobenzamide (400 mg, 1.164 mmol). The reaction vessel was sealed and heated to 120º C for 20 h. Upon cooling, an orange solid precipitated out of the dark solution. The solid was washed with EtOAc and dried to obtain (E) -1- (4 - ((4-carbamoyl-2- (3-morpholinopropoxy) -6-nitrophenyl) amino) but- 2-en-1-i1) - 2- (1-ethyl-3-methyl-1 H-pyrazol-5-carboxamido) -1H-benzo [d] imidazole! -5-
[0516] [0516] (E) -1- (4 - ((4-carbamoyl-2- (3-morpholinopropoxy) -6-nitrophenyl) amino) but-2-en-1-i1) -2- (1 -ethyl-3-methyl-1 H-pyrazol-5-carboxamido) -1H-benzol [d] imidazole-5-carboxamide (1.05 g, 1.525 mmol) in MeOH (16 mL) and 28% ammonium hydroxide (5.17 mL, 38.1 mmol). After 5 min of stirring, a solution of sodium hydrosulfite (1.593 g, 9.15 mmol) in water (4.00 mL) was added and subsequently stirred at room temperature for 2 h.
[0517] [0517] EtOAc was added, and the organic layer was washed with water and brine. After that, the organic phase was dried and concentrated to obtain (E) -1- (4- ((2-amino-4-carbamoyl-6- (3-morpholinopropoxy) phenyl) amino) but-2-en-1- 11) -2- (1-ethyl-3-methyl-1H-pyrazol-5-carboxamido) -1H-benzo [d] imidazole | -5-crude carboxamide (330 mg, 0.501 mmol, 32.9% yield) in the form of an off-white solid. The crude material was used without further purification. LCMS m / z = 659 [M + H] *.
[0518] [0518] To a solution of (E) -1- (4 - ((2-amino-4-carbamoyl-6- (3-morpholinopropoxy) phenyl) amino) but-2-en-1-i1) -2- (1-ethyl-3-methyl-1H-pyrazol-5-carboxamido) -1H-benzo [d] imidazole-5-carboxamide (330 mg, 0.501 mmol) in MeOH (15 mL), cyanogen bromide ( 159 mg, 1.503 mmol), and the reaction mixture was stirred at room temperature for 3 h. The precipitation of the product was obtained by the addition of EtOAc and subsequent stirring for 1 h. The solid was filtered, washed with EtOAc and dried to obtain (E) -2-amino-1- (4- (5-carbamoyl-2- (1-ethyl-3-methyl-1H-pyrazol-5-carboxamido) - 1H-benzo [d] imidazol | -1-yl) but-2-en-1-11) -7- (3-morpholinopropoxy) -1H-benzo [d] imidazole-5-carboxamide (284 mg, 0.416 mmol, 83% yield) as a light brown solid. The material was used without further purification. LCMS m / z = 684 [M + HJ *.
[0519] [0519] To a suspension of (E) -2-amino-1- (4- (5-carbamoyl-2- (1-ethyl-3-methyl-1H-pyrazol-5-carboxamido) -1H-benzo [d ] imidazol-1-yl) but-2-en-1-11) -7- (3-morpholinopropoxy) -1H-benzo [d] imidazole | -5-carboxamide (260 mg, 0.380 mmol) in DMF (4 mL ), a solution of 1-ethyl-3-methyl-1H-pyrazol-5-carboxylic acid (117 mg, 0.7 / 60 mmol) and 1H-benzol hydrate [dl] [1, 2.3] triazole-1-0l (58.2 mg, 0.380 mmol) and 2- (3H- [1,2,3] triazolo [4,5-b] pyridin-3-yl) -1 hexafluorophosphate, 1,3,3-tetramethylisouronium (V) (289 mg, 0.760 mmol) and triethylamine (0.212 mL, 1.521 mmol) in DMF (4 mL). The mixture was stirred at room temperature overnight. After that, water (10 mL) was added, and the resulting cloudy solution was left in the refrigerator for 3 h. The resulting precipitate was filtered (180 mg) and combined with an additional 80 mg of crude solid from a previous reaction. The crude product was further purified by chromatography on silica gel (ISCO column 24 g, gradient 0% to 35% MeOH in DCM) to obtain, after removing the solvents, (E) -1- (4- ( 5-carbamoyl-2- (1-ethyl-3-methyl-1H-pyrazol-5-carboxamido) -1H-benzo [d] imidazol-1-yl) but-2-en-1-i1) -2- ( 1-ethyl-3-methyl-1H-pyrazol-5-carboxamido) -7- (3-morpholinopropoxy) -1H-benzo [d] imidazole-5-carboxamide (140 mg, 0.171 mmol). * H NMR (METANOL-da, 600 MHz): 5 ppm 7.96 (s, 1 H), 7.71 (dd, J = 8.3, 1.6 Hz, 1 H), 7.56 ( s, 1 H), 7.35 (d, J = 8.4 Hz, 1 H), 7.27 (s, 1 H), 6.62 (s, 1 H), 6.55 (s, 1 H), 5.95 (dt, J = 15.5, 5.1 Hz, 1 H), 5.76-5.83 (m, 1 H), 5.06 (br d, J = 4.6 Hz, 2 H), 4.86 (br d, J = 5.3 Hz, 2 H), 4.63 (s, 2 H), 4.56 (q, J = 7.0 Hz, 2H), 3.99 (t, J = 6.1 Hz, 2 H), 3.64 (br t, J = 4.2 Hz, 4 H), 2.43-2.48 (m, 2 H), 240 (brs, 4 H), 2.21 (s, 3 H), 2.19 (s, 3 H), 1.75-1.81 (m, 2 H), 1.37 (t, J = 7 , 1 Hz, 3 H), 1.32 (t, J = 7.2 Hz, 3 H). LCMS m / z = 820.9 [M + HJ ".
[0520] [0520] To a suspension of (E) -1- (4- (5-carbamoyl-2- (1-ethyl-3-methyl-1H-pyrazol-B5-carboxamido) -1H-benzo [d] imidazo | - 1-yl) but-2-en-1-i1) -2- (1-ethyl-3-methyl-1H-pyrazol-5-carboxamido) -7- (3-morpholinopropoxy) -1H-benzo [d] imidazole -5-carboxamide (52 mg, 0.063 mmol) in DMF (2 mL), cesium carbonate (62.0 mg, 0.190 mmol) and methyl iodide (9.91 µl, 0.159 mmol) were added. The reaction mixture was stirred at room temperature for 12 h. The solvent was evaporated, and the residue was purified by chromatography on silica gel (gradient 0% to 25% MeOH / DCM, silica gel column 12 g) to obtain the clear product in the form of (E) - 1 - ((E) -4 - ((E) -5-carbamoyl-2 - (((1-ethyl-3-methyl-1H-pyrazol-S5-carbonyl) imino) -3-methyl-2,3-dihydro -1H- benzol [d] imidazo | -1-yl) but-2-en-1-i1) -2 - ((1-ethyl-3-methyl-1 H-pyrazol-5-carbonyl) imino) -3 - methyl-7- (3-morpholinopropoxy) -2,3-dihydro-1H-benzo [d] imidazole-5-carboxamide (44 mg, 0.052 mmol, 82% yield). * H NMR (DMSO-ds, 600 MHz): 5 ppm 8.07 (br s, 1 H), 7.80 (br d, J = 8.3 Hz, 1 H), 7.74 (br s , 1 H), 7.48 (br d, J = 8.4 Hz, 1 H), 7.41 (s, 1 H), 6.29-6.44 (m, 2 H), 5.83 -5.99 (m, 1 H), 5.60-5.76 (m, 1 H), 4.81 - 4.94 (m, 2 H), 4.75 (br d, J = 5, 1 Hz, 2 H), 4.38-4.55 (m, 4 H), 4.06 (br s, 2 H), 3.54 (br s, 3 H), 3.45- 3.59 (m, 7 H), 2.25-2.30 (m, 2 H), 2.15-2.37 (m, 4 H), 2.11 (br d, J = 7.0 Hz, 6 H), 1.72 (br s, 2 H), 1.19-1.24 (m, 3 H), 1.14-1.26 (m, 3 H). LCMS m / z = 848 [M + HJ *.
[0521] [0521] The compound prepared by the above process can exist in a tautomer / isomer, for example, (E) -1 - ((E) -4 - ((E) -5-carbamoyl-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-i1) -2- ((1-ethyl-3-methyl-1H-pyrazol-5-carbonyl) imino) -3-methyl-7- (3-morpholinopropoxy) -2,3-dihydro-1H-benzo [d] imidazole-5-carboxamide í DR Ds “eos
[0522] [0522] A mixture of tert-butyl (4-aminobutyl) carbamate (5.00 g, 26.6 mmol), 4-fluoro-3-nitrobenzamide (4.89 g, 26.6 mmol) and K2CO; 3 (4.04 g, 29.2 mmol) in DMSO (25 mL) was stirred at 70 ° C for 2 h. The reaction was cooled to room temperature and slowly diluted with 125 ml of water through an addition funnel. The resulting solid was isolated by filtration, dried and introduced into a vacuum oven at
[0523] [0523] A 500 mL round bottom flask was loaded with tert-butyl (4 - ((4-carbamoyl-2-nitrophenyl) amino) butyl) carbamate (9.2 g, 26.1 mmol), Pd / 10% C (0.920 g, 8.684 mmol) (wet type Degussa), EtOH (100 ml) and MeOH (100 ml). The flask was evacuated and placed under a stirred hydrogen balloon. A condenser was positioned at the top of the flask, and the hydrogen balloon was positioned over the condenser. The mixture was stirred at room temperature for 20 h, then the flask was evacuated and the suspension was filtered through a layer of diatomaceous earth using EtOH to aid in the rinse. The filtrate was concentrated in vacuo and placed under high vacuum to obtain the title compound (8.4 g, 26.1 mmol, 100% yield) as a black solid. * H NMR (400 MHz, DMSO-ds) 5 ppm 7.44 (br. S., 1 H) 7.04 - 7.15 (m, 2 H) 6.85 (t, J = 5.43 Hz, 1 H) 6.74 (br., 1 H) 6.37 (d, J = 8.08 Hz, 1 H) 4.89 (t, J = 5.18 Hz, 1 H) 4 , 60 (br. S., 2 H) 3.07 (q, J = 6.48 Hz, 2 H) 2.97 (q, J = 6.40 Hz, 2 H) 1.45 - 1.64 (m, 4 H) 1.39 (s, 9 H). LCMS [M + HJ] * = 323.1
[0524] [0524] tert-Butyl (4 - ((2-amino-4-carbamoylphenyl) amino) butyl) carbamate (8.40 g, 26.1 mmol) was dissolved in MeOH (110 mL) and a 5 M cyanogen bromide solution in CH3CN (5.73 mL, 28.7 mmol) using a syringe. The dark reaction was capped and stirred for 15 h at room temperature. The reaction was concentrated in vacuo and placed under high vacuum to obtain the title compound (11.17 g, 26.1 mmol, 100% yield) as a black solid. * H NMR (400 MHz, DMSO-ds) 5 ppm 12.85 (br. S, 1 H) 8.74 (br., 2 H) 8.08 (br. S., 1 H) 7.80 - 7.90 (m, 2 H) 7.64 (d, J = 8.34 Hz, 1 H) 7.44 (br. S., 1 H) 6.89 (t, J = 5 , 56 Hz, 1 H) 4.15 (t, J = 7.20 Hz, 2 H) 2.96 (q, J = 6.32 Hz, 2 H) 1.66 (d, J = 7.07 Hz, 2 H) 1.42 - 1.50 (m, 2 H) 1.38 (s, 9 H). LCMS [M + H] * = 348.1 Step 4: (4- (5-carbamoyl-2- (1-ethyl-3-methyl-1H-pyrazol-5-carboxamido) -1H-benzo [d] imidazole- 1-yl) butyl) tert-butyl carbamate o m Ke Ke e to O o
[0525] [0525] A mixture of tert-butyl (4- (2-amino-5-carbamoyl-1H-benzo [d] imidazo | -1- iN) butyl) carbamate, hydrobromide (11.17 g, 26.1 mmol ), 1-ethyl-3-methyl-1H-pyrazole-S5-carboxylic acid (4.82 g, 31.3 mmol), HATU (11.90 g, 31.3 mmol), DIPEA (18.22 mL, 104 mmol) and HOBt (1.997 g, 13.04 mmol) in DMF (100 mL) was stirred at room temperature for 21 h. The reaction was diluted with 300 ml of water and 300 ml of EtOAc, transferred to a separating funnel, the layers were separated and the aqueous layer was extracted with EtOAc (2 x 150 ml). The combined EtOAc layers were washed with saturated NH.aCl (2 x 200 ml), water (1 x 200 ml) and brine (2 x 200 ml). The organic layer was dried over Na2SO4: filtered, concentrated in vacuo and placed under high vacuum. The solid was purified via silica gel chromatography (ISCOº Combiflash, 0% to 20% MeOH: DCM, 330 g column, loaded in 50 ml of DCM). The desired fractions were combined, concentrated in vacuo and placed under high vacuum to obtain the title compound as a purple solid (9.53 g, 19.71 mmol, 76% yield). 1H NMR (400 MHz, DMSO-ds) 5 ppm 12.85 (s, 1 H) 8.01 (br. S., 2 H) 7.81 (d, J = 8.34 Hz, 1 H) 7.59 (d, J = 8.34 Hz, 1 H) 7.36 (br. S., 1 H) 6.80 - 6.86 (m, 1 H) 6.68 (s, 1 H) 4.64 (q, J = 6.82 Hz, 2 H) 4.23 (t, J = 6.44 Hz, 2 H) 2.98 (d, J = 5.81 Hz, 2 H) 2, 19 (s, 3 H) 1.76 (d, J = 6.57 Hz, 2 H) 1.40 - 1.48 (m, 2 H) 1.30 - 1.40 (m, 13 H). LCMS [M + HI * = 484.3 Step 5: 1- (4-aminobutyl) -2- (1-ethyl-3-methyl-1H-pyrazol-S-carboxamido) -1H-benzo [d] imidazole-5 -carboxamide, 2 hydrochloride b See
[0526] [0526] An ice-cooled 500 mL round-bottom flask containing (4- (5-carbamoyl-2- (1-ethyl-3-methyl-1 H-pyrazol-5-carboxamido) -1H-benzo [d] tert-butyl imidazo -1- iN) butyl) carbamate (9.53 g, 19.71 mmol) was treated with 4 M HCl in 1,4-dioxane (42.0 mL, 168 mmol). The ice bath was removed, and the purple mud was stirred at room temperature for 2.5 h. After that, the reaction was concentrated in vacuo and placed under high vacuum, and the resulting solid was introduced into a vacuum oven at 50º C for 15 h and cooled under high vacuum to obtain the impure title compound as a gray solid, which also contained 1,4-dioxane (11.89 grams, assumed 19.7 mmol, 100% yield). This material was used as obtained without further purification. * H NMR (400 MHz, DMSO-ds) 5 ppm 12.91 (br. S, 1 H) 8.03 (d, J = 1.26 Hz, 2 H) 7.77 - 7.87 (m , 4 H) 7.62 (d, J = 8.34 Hz, 1 H) 7.38 (br. S., 1 H) 6.70 (s, 1 H) 6-5 (br. S, 1 H), 4.63 (q, J = 7.07 Hz, 2 H) 4.28 (t, J = 6.57 Hz, 2H) 2.77 - 2.87 (m, 2 H) 2.20 (s, 3 H) 1.81 - 1.91 (m, 2 H) 1.52 - 1.60 (m, 2 H) 1.38 (t, J = 7.07 Hz, 3 H). LCMS [M + H] * = 384.2 Step 6: 4 - ((4- (5-carbamoyl-2- (1-ethyl-3-methyl-1H-pyrazol-5-carboxamido) -1H-benzo [d ] imidazole | -1-yl) butyl) amino) -3-methoxy-S-nitrobenzoate methyl No À NO;
[0527] [0527] A 250 ml 3-neck round-bottom flask equipped with a condenser, a long stir bar and an internal thermometer was loaded with 1- (4-aminobutyl) -2- (1-ethyl-3-methyl- 1 H-pyrazol-5-carboxamido) -1H-benzo [d] imidazole-5-carboxamide, 2 hydrochloride (9.38 g, 20.55 mmol) and methyl 4-chloro-3-methoxy-5-nitrobenzoate ( 5.048 g, 20.55 mmol). DMSO (50 ml) was added, followed by DIPEA (17.95 ml, 103 mmol), and the dark suspension was heated to 100 ° C for about 24 h, cooled and 500 ml of stirred water was added to it. After the addition was complete, the resulting orange suspension was stirred for min and filtered. The isolated orange-red paste was washed with water and hexanes, dried in the Búchner funnel and then in a vacuum oven at 56º C for 20 h. After that, the reddish solid was triturated with Et2O0 (60mL) and isolated by filtration. Grinding and filtering were repeated. The resulting solid was introduced into a vacuum oven at 56 ° C for 3 days to obtain the title compound (11.17 g, 18.85 mmol, 92% yield) as a reddish solid. * H NMR (400 MHz, DMSO-ds) 5 ppm 12.78 (br. S., 1 H) 8.12 (s, 1 H) 7.99 (s, 1 H) 7.93 (d, J = 7.53 Hz, 2 H) 7.79 (d, J = 8.28 Hz, 1 H) 7.53 (d, J = 7.78 Hz, 1 H) 7.36 (s, 1 H ) 7.31 (br. S., 1 H) 6.60 (s, 1 H) 4.60 (d, J = 7.03 Hz, 2 H) 4.23 (br. S., 2 H) 3.84 (s, 3 H) 3.80 (s, 3 H) 3.53 (d, J = 5.77 Hz, 2 H) 2.15 (s, 3 H) 1.82 (br. S ., 2 H) 1.62 (br. S., 2 H) 1.35 (t, J = 7.03 Hz, 3 H). LCMS [M + H] * = 711.6 Step r 3-amino-4 - ((4- (5-carbamoyl-2- (1-ethyl-3-methyl-1 H-pyrazol-5-carboxamido) -1H -benzo [d] imidazol-1-yl) butyl) amino) -5-methyl methoxybenzoate No NH
[0528] [0528] 4 - ((4- (5-carbamoyl-2- (1-ethyl-3-methyl-1H-pyrazol-5-carboxamido) -1H-benzo [d] imidazol-1-yl) butyl dissolved ) amino) -3-methoxy-5-nitrobenzoate - methyl (5.0 g, 8.44 mmol) mostly in DMF (50 mL) with stirring at room temperature in a 250 mL round-bottom flask. Raney nickel (Raney nickel 2800 in water, about 10 ml of mud, Aldrich) was added, and a condenser was added to the top of the flask. A three-way regulating valve adapter with a connected hydrogen balloon was positioned on top of the condenser and the configuration was evacuated, filled with hydrogen, evacuated and, finally, filled with hydrogen. The reaction was heated to 70º C for 7 h. An additional 8 ml of Raney nickel was added, and the reaction was heated to 70º C for 14 h. The reaction was cooled and filtered through diatomaceous earth while being washed with DMF. The filtrate, a solution of about 100 ml of DMF and 20 ml of Raney nickel sludge water, containing the desired product was used as a solution directly in the next reaction. Quantitative yield assumed. LCMS [M + HJ * = 563.4 Step 8: 2-amino-1- (4- (5-carbamoyl-2- (1-ethyl-3-methyl-1H-pyrazol-5-carboxamido) -1H-benzo [d] imidazol-1-yl) butyl) -7-methoxy-1H-benzo [d] imidazole-5-methyl carboxylate, hydrobromide or Ao. N Y * Y SS
[0529] [0529] 3-Amino-4 - ((4- (5-carbamoyl-2- (1-ethyl-3-methyl-1 H-pyrazol-5-carboxamido) -1H-benzo [d] imidazole- Methyl 1-yl) butyl) amino) -S5-methoxybenzoate (DMF / water solution from the previous step) with 5 M cyanogen bromide in CH3CN (1.875 mL, 9.37 mmol), and the resulting solution was stirred in room temperature for 22 h. The reaction was concentrated in vacuo and placed under high vacuum to obtain a brown semi-solid. The semisolid was triturated with EtOAc and vigorously stirred for 30 min, and the resulting solid was isolated by filtration and dried on a Buchner funnel to obtain the crude title product as a brown solid (5.08 g). This impure material was used without further purification. LCMS [M + H] * = 588.5.
[0530] [0530] A mixture of 2-amino-1- (4- (5-carbamoyl-2- (1-ethyl-3-methyl-1H-pyrazol-5-carboxamido) -1H-benzo [d] imidazole | -1 -yl) butyl) -7-methoxy-1H-benzo [d] imidazole-5-methyl carboxylate, hydrobromide (5.073 g, 7.59 mmol), 1-ethyl-3-methyl-1H-pyrazole-5- acid carboxylic (1.287 g, 8.385 mmol), HATU (3.46 g, 9.11 mmol) and DIPEA (3.98 mL, 22.76 mmol) in DMF (30 mL) was stirred at room temperature for 17 h. The reaction was concentrated in vacuo and then the resulting residue was triturated with water (100 ml) and stirred for 30 min. The resulting suspension was filtered and partially dried on a Búchner funnel to obtain a dark brown solid. The solid was mostly dissolved in 150 mL of 10% IPA: chloroform, diluted with water and filtered. After that, the filtrate layers were separated, and the organic layer was dried over Na2SO4, filtered, concentrated and placed under high vacuum to obtain a brown solid. The solid was triturated with 10% warm IPA: chloroform (100 mL) and filtered. The filtrate layers were separated, and the organic layer was dried over Na2SO2, filtered, added to the original brown solid, concentrated in vacuo and placed under high vacuum. The solid was purified by silica gel chromatography (Biotageº Isolera, 120 gm Gold column, 0% to 10% MeOH: DCM over 30 min, loaded as a solution in DCM / MeOH). Fractions of the desired product were combined, concentrated and placed under high vacuum to obtain a light brown solid. The solid was triturated with DCM (50 mL), isolated by filtration and introduced in a vacuum oven at 56º C for 30 h to obtain 1- (4- (5-carbamoyl-2- (1-ethyl-3-methyl- 1 H-pyrazol-5-carboxamido) -1H-benzol [d] imidazo | -1-yl) butyl) -2- (1-ethyl-3-methyl-1 H-pyrazol-5-carboxamido) -7-methoxy -1H-
[0531] [0531] To a suspension of 1- (4- (5-carbamoyl-2- (1-ethyl-3-methyl-1H-pyrazol-5-carboxamido) -1H-benzo [d] imidazole | -1-yl) butyl) -2- (1-ethyl-3-methyl-1H-pyrazol-5-carboxamido) -7-methoxy-1H-benzo [d] imidazole-5-methyl carboxylate (550 mg, 0.760 mmol) in MeOH ( 11 ml) and water (11 ml), NaOH (304 mg, 7.60 mmol) was added. The reaction was stirred at room temperature overnight. The MeOH was removed in vacuo, and the resulting solution was treated with 1 N HCI until the pH became —3. The resulting sludge was filtered, and the filter cake was dried in a vacuum oven to obtain 1- (4- (5-carbamoyl-2- (1-ethyl-3-methyl-1H-pyrazole-5-carboxamido) acid) - 1H-benzo [d] imidazo | -1-yl) butyl) -2- (1-ethyl-3-methyl-1H-pyrazol-S5-carboxamido) -7-methoxy- 1H-benzo [d] imidazole-5 -carboxylic (650 mg, 0.687 mmol, 90% yield) as a white solid. The compound was used in the next step without further purification. LCMS m / z = 710 [M + HJ *.
[0532] [0532] To a solution of 1- (4- (5-carbamoyl-2- (1-ethyl-3-methyl-1H-pyrazol-5-carboxamido) -1H-benzo [d] imidazole | -1-yl ) butyl) -2- (1-ethyl-3-methyl-1H-pyrazol-5-carboxamido) -7-methoxy-1H-benzo [d] imidazole-5-carboxylic (320 mg, 0.338 mmol) and HATU (154 mg, 0.406 mmol) in DMF (3.381 mL), DIEA (295 µL, 1.691 mmol) was added. After 20 min, ammonium chloride (54.3 mg, 1.014 mmol) was added to the reaction mixture, and the reaction was stirred at room temperature for 3 days. More HATU (50 mg, 0.132 mmol) and DIEA (58.9 µl, 0.338 mmol) were added. The reaction was stirred for 10 min at room temperature and ammonium chloride (18.26 mg, 0.338 mmol) was added. To drive the reaction to completion, HOBt hydrate (51.7 mg, 0.338 mmol) was added, and the reaction was stirred at room temperature for 90 min. The reaction was dry loaded on silica gel and purified by silica gel chromatography (12 g ISCO-Rf column, 0% to 30% gradient MeOH / DCM) to obtain 1- (4- (5-carbamoyl) -2- (1-ethyl-3-methyl-1 H-pyrazol-5-carboxamido) -1H-benzo [d] imidazol-1-yl) butyl) -2- (1-ethyl-3-methyl-1 H -pyrazol-5-carboxamido) -7-methoxy-1H-benzo [d] imidazole-5-carboxamide (175 mg, 0.244 mmol, 72.3% yield) as a white solid. LCMS m / z = 709 [M + HJ *. Step 12: (E) -1- (4 - ((E) -5-carbamoyl-2 - (((1-ethyl-3-methyl-1H-pyrazol-5-carbonyl) imino) -3-methyl-2, 3-dihydro-1H-benzo [d] imidazo | -1-yl) butyl) -2 - ((1-ethyl-3-methyl-
[0533] [0533] To a suspension of 1- (4- (5-carbamoyl-2- (1-ethyl-3-methyl-1H-pyrazol-5-carboxamido) -1H-benzo [d] imidazol-1-yl) butyl ) -2- (1-ethyl-3-methyl-1H-pyrazol-5-carboxamido) -7-methoxy-1H-benzo [d] imidazole-5-carboxamide (100 mg, 0.141 mmol) in DMF (4 ml) , cesium carbonate (138 mg, 0.423 mmol) and methyl iodide (50.1 mg, 0.353 mmol, 100 µl of a stock solution (220 µL of methyl iodide in 780 µl of DMF) were added. it was stirred at room temperature for 2 h, dry loaded on silica gel and purified by silica gel chromatography (ISCO-Rf, 12 g column, 0% to 30% MeOH / DCM gradient) to obtain 100 mg of solid (-93% pure by LCMS). The resulting residue (100 mg) was dissolved in MeOH, loaded dry on silica gel and repurified (ISCO-Rf, column 12 9, gradient 0% to 20% MeOH / DCM). The pure fractions were combined and concentrated to dryness to obtain (E) -1- (4 - ((E) -5-carbamoyl-2 - ((1-ethyl-3-methyl-1H-pyrazole- 5-carbonyl) imino) -3-methyl-2,3-dihydro-1H-benzo [d] imidaz ol-1-yl) butyl) -2 - ((1-ethyl-3-methyl-1H-pyrazol-5-carbonyl) imino) -7-methoxy-3-methyl-2,3-dihydro-1H-benzo [ d] imidazole-5-carboxamide (33 mg, 0.044 mmol, 31.4% yield). 1H NMR (400 MHz, DMSO-ds) 5 ppm 7.98 - 8.13 (m, 3 H) 7.84 (dd, J = 8.36, 1.52 Hz, 1 H) 7.69 ( d, J = 1.01 Hz, 1 H) 7.58 (d, J = 8.62 Hz, 1 H) 7.47 (d, J = 14.19 Hz, 2 H) 7.42 (s, 1 H) 6.46 (d, J = 6.84 Hz, 2 H) 4.42 - 4.55 (m, 4 H) 4.11 - 4.28 (m, 4 H) 3.83 (s , 3
[0534] [0534] A mixture of ethyl 3-methyl-1H-pyrazol-5-carboxylate (22 g, 143 mmol), (S-chloropent-1-in-1-iD) trimethylsilane (24.94 g, 143 mmol) , K2CO; 3 (39.4 g, 285 mmol) and DMF (4 mL) was stirred at 60º C overnight under nitrogen gas. After that, the mixture was dissolved in DCM and washed with water. The organic phase was dried over anhydrous Na2SO3, filtered, concentrated under reduced pressure and purified by silica gel column chromatography (petroleum ether / EtOAc = 10: 1) to obtain 3-methyl-1- (5- (trimethylsilyl)) ) ethyl pent-4-in-1-yl) -1 H-pyrazol-S-carboxylate (12.5 g, 42.7 mmol, 30% yield) as a colorless oil. LCMS [M + H] * = 293. Step 2: Ethyl 3-methyl-1- (pent-4-in-1-yl) -1H-pyrazol-5-carboxylate AO Eto 'N and Me
[0535] [0535] A mixture of ethyl 3-methyl-1- (5- (trimethylsilyl) Dent-4-in-1-i1) -1H-pyrazol-5-carboxylate (37.7 g, 129 mmol), K2CO; 3 (44.5 g, 322 mmol) and EtoH (800 mL) was stirred at room temperature overnight. Then, the mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was dissolved in DCM, washed with water, dried over anhydrous Na2SOa, filtered and concentrated under reduced pressure to obtain 3-methyl-1- (pent-4-in-1-yl) -1H-pyrazol-5-carboxylate ethyl (20 g, 91 mmol, 70.4% yield) as a colorless oil. LCMS [M + HJ * = 221. Step 3: Benzyl 1-ethyl-3-methyl-1H-pyrazol-5-carboxylate or Me
[0536] [0536] A mixture of 1-ethyl-3-methyl-1H-pyrazol-5-carboxylic acid (20 g, 130 mmol), (bromomethyl) benzene (22.2 g, 130 mmol), K2CO; (26.9 g, 195 mmol) and DMF (200 mL) was stirred at 60 ° C overnight. After that, the mixture was dissolved in DCM, washed with water, dried over Na2SO. anhydrous, filtered, concentrated under reduced pressure and purified by silica gel column chromatography (petroleum ether / EtOAc = 10: 1) to obtain benzyl 1-ethyl-3-methyl-pyrazol-5-carboxylate (31.4 g, 129 mmol, 99% yield) as a colorless oil. LCMS [M + H] * = 245. Step 4: Benzyl 1-ethyl-4-iodo-3-methyl-1H-pyrazol-5-carboxylate o Bro Se
[0537] [0537] A mixture of benzyl 1-ethyl-3-methyl-1H-pyrazol-S-carboxylate (31.6 g, 129 mmol), 1-iodopyrrolidine-2,5-dione (34.9 g, 155 mmol ) and DMF (400 mL) was stirred at 90 ° C for 2 days. After that, the mixture was allowed to cool to room temperature, dissolved in DCM and washed with a saturated aqueous sodium thiosulfate solution. The organic layer was dried over Na2SO. anhydrous, filtered, concentrated under reduced pressure and purified by column chromatography (petroleum ether / EtOAc = 10: 1) to obtain benzyl 1-ethyl-4-iodo-3-methyl-1H-pyrazol-5-carboxylate (42 , 6 g, 115 mmol, 89% yield). LCMS [M + HJ * =
[0538] [0538] A mixture of ethyl 3-methyl-1- (pent-4-in-1-yl) -1H-pyrazol-S-carboxylate (10.0 g, 45.4 mmol), 1-ethyl-4 benzyl-iodo-3-methyl-1H-pyrazol-S-carboxylate (16.8 g, 454 mmol), copper (l) iodide (0.864 g, 4.54 mmol), bis (triphenylphosphine) palladium ( II) (0.319 g, 0.454 mmol) and EtaN (200 mL) was stirred at 60 ° C overnight in a nitrogen gas atmosphere. After that, the mixture was dissolved in DCM and washed with water. The organic phase was dried over anhydrous Na2SO.s, filtered, concentrated under reduced pressure and purified by silica gel column chromatography (petroleum ether / EtOAc = 5: 1) to obtain 4- (5- (5- (ethoxycarbonyl) ) - benzyl 3-methyl-1H-pyrazol-1-yl) pent-1-in-1-i1) -1-ethyl-3-methyl-1 H-pyrazol-5-carboxylate (9.5 g, 20 , 5 mmol, 45.3% yield) as a yellow solid. LCMS [M + H] * = 463.
[0539] [0539] A mixture of 4- (5- (5- (ethoxycarbonyl) -3-methyl-1H-pyrazol-1-yl) pent-1-in-1-i1) -1-ethyl-3-methyl-1H benzyl-pyrazole-S-carboxylate (19.0 g, 41.10 mmol), 10% Pd / C (0.22 g, 2.05 mmol) and THF (500 mL) was stirred at room temperature in an atmosphere of hydrogen gas (4 atm) for 2 days. Then, the reaction mixture was filtered and concentrated under reduced pressure. The residue obtained was recrystallized from EtOAc / petroleum ether (1: 5, v / v) to obtain 4- (5- (5- (ethoxycarbonyl) -3-methyl-pyrazol-1-yl) pentyl) - 1-ethyl-3-methyl-pyrazol-5-carboxylic (10.5 g, 27.90 mmol, 67.9% yield). * H NMR (400 MHz, CDCl3) 5 ppm 6.63 (s, 1 H), 4.57-4.48 (m, 4 H), 4.38-4.32 (m, 2 H), 2.74-2.62 (m, 2 H), 2.32 (s, 3 H), 2.23 (s, 3 H), 1.91-1.86 (m, 2H), 1.59 -1.54 (m, 2 H), 1.45-1.37 (m, 8 H). LCMS [M + HJ] * = 377.
[0540] [0540] To a suspension of 4- (5- (5- (ethoxycarbonyl) -3-methyl-1H-pyrazol-1-iN) pentyl) -1-ethyl-3-methyl-1H-pyrazole-5-carboxylic acid (9.0 g, 23.9 mmol) in MeOH (120 mL) and water (120 mL) stirred at room temperature, a solution of aq. 2 M (60 mL, 119.5 mmol). The reaction mixture was stirred at room temperature for 30 min. Thereafter, the mixture was acidified to pH 4 with the addition of a 6 M HCI solution, whereby a solid precipitated from the reaction mixture. The solid was collected by filtration and dried under reduced pressure to obtain 4- (5- (5-carboxy-3-methyl-1H-pyrazol-1-yl) pentyl) - 1-ethyl-3-methyl-1H-pyrazole acid -5-carboxylic (6.5 g, 18.7 mmol, 78.1% yield) as a white solid. * H NMR (400 MHz, DMSO-ds) 5 ppm 6.57 (s, 1 H), 4.40-4.34 (m, 4
[0541] [0541] To a solution of 4-fluor-3-nitrobenzamide (10.0 g, 54.3 mmol) in DMF (60 mL), allylamine (36.6 mL, 489 mmol) was added dropwise at temperature room, and the mixture was stirred for 5 min. After that period, K2CO; 3 (15.01 g, 109 mmol) was added in one portion, and the mixture was stirred at room temperature for 30 min. Then, the DMF was removed in vacuo. The residue was suspended in 500 ml of water, and the resulting orange precipitate was obtained by filtration, washed with water and dried under vacuum.
[0542] [0542] The above precipitate was dissolved in ACOH (600 mL), and the flask was introduced into a 20 ° C water bath. Zinc (10.65 g, 163 mmol) was cautiously added in small portions. The reaction was monitored by LCMS and more zinc (about 3 eq.) Was added in small portions as needed until the reduction was complete. Upon completion of the reaction by LCMS, the solids were removed by filtration, and the filtrate was concentrated in vacuo. The evaporation residue was taken up in DCM (500 ml) and EtOH (150 ml) and washed with K2CO; 3 aq. 15% (100 mL). The organic layer was separated, dried over Na2SO4, filtered and concentrated in vacuo.
[0543] [0543] The above evaporation residue was dissolved in MeOH (200 mL), 5.0 M cyanogen bromide in CHs3CN (11.95 mL, 59.7 mmol) was added quickly in one portion, and the mixture was stirred at room temperature for 18 h. After this period, the reaction mixture was concentrated in vacuo, then dissolved again in MeOH (200 ml). A mixture of toluene (100 ml) and CH3CN (100 ml) was added, and the resulting mixture was concentrated to dryness at 40 ° C (0 to 1 mbar) and dried in vacuo for 16 h to obtain 1-allyl-2- amino-1H-benzo [d] imidazole-5-carboxamide, hydrobromide (11.3 g, 38.0 mmol, 70.0% yield) as a dark purple powder. * H NMR (400 MHz, DMSO-ds) 5 ppm 8.83 (s, 2 H), 8.07 (br. S., 1 H), 7.88 (d, J = 1.00 Hz, 1 H), 7.82 (dd, J = 8.41, 1.38 Hz, 1 H), 7.52 (d, J = 8.53 Hz, 1 H), 7.43 (br. S. , 1 H), 5.87 - 6.02 (m, 1 H), 5.25 (dd, J = 10.42, 0.88 Hz, 1 H), 5.17 (dd, J = 17, 32, 1.00 Hz, 1 H), 4.84 (d, J = 5.02 Hz, 2 H); LCMS [M + H] * = 216.9.
[0544] [0544] A sealed 5.0 mL Biotage tube was charged with 4- (5- (5-carboxy-3-methyl-1H-pyrazol-1-yl) pentyl) -1-ethyl-3-methyl-1H acid -pyrazole-S5-carboxylic (634 mg, 1.820 mmol), 1-allyl-2-amino-1H-benzo [d] imidazole-5-carboxamide, hydrobromide (1352 mg, 4.55 mmol), HATU (1730 mg, 4.55 mmol) and NMP (13 mL). After 1 minute of stirring at room temperature, DIPEA (3.17 mL, 18.20 mmol) was added, and the mixture was stirred at room temperature for 5 min, then heated in a microwave reactor at 140º C for 1 h. After that period, 5.0 ml of water were added, and the mixture was stirred at room temperature for 5 min. Then, it was poured into 250 mL of ice water and stirred vigorously for 1h. The resulting solid was removed by filtration, washed with water, dissolved from the filter using MeOH / DCM, concentrated in vacuo and subjected to silica gel chromatography (100 g SiO2 Biotageº Ultra SNAP column: 0% to 40% MeOH / EtOAc) to obtain 1-allyl-2- (1- (5- (5 - ((1-allyl-5-carbamoyl-1H-benzo [d] imidazo | -2-yl) carbamoyl) -1-ethyl -3-methyl-1H-pyrazol-4-yl) pentyl) -3-methyl-1H-pyrazol-5-carboxamido) -1H-benzo [d] imidazole | -5-carboxamide (840 mg, 1.125 mmol, 62% yield) as a pink solid. 1H NMR (400 MHz, DMSO-ds) 5 ppm 12.88 (s, 1 H), 12.81 (s, 1 H), 7.99 - 8.02 (m, 2 H), 7.97 (br. s., 2 H), 7.77 (ddd, J = 8.34, 3.66, 1.39 Hz, 2 H), 7.41 (dd, J = 16.93, 8.34 Hz, 2 H), 7.34 (br., 2 H), 6.65 (s, 1 H), 5.87 - 6.02 (m, 2 H), 4.99 - 5.22 (m, 4 H), 4.82 (dd, J = 11.62, 4.80 Hz, 4 H), 4.50 - 4.61 (m, 4 H), 2.73 (t, J = 7.45 Hz, 2 H), 2.15 (s, 3 H), 2.08 (s, 3 H), 1.71 - 1.85 (m, 2 H), 1.45 - 1.55 (m, 2 H), 1.27 - 1.34 (m, 5 H); LCMS [M + HJ * = 745.7.
[0545] [0545] Four sealed 20 ml Biotageº microwave tubes were loaded with a total of 1-allyl 2- (1- (5- (5 - ((1-allyl-5-carbamoyl-1H-benzo [d ] imidazol-2-yl) carbamoyl) -1-ethyl-3-methyl-1 H-pyrazol-4-yl) pentyl) -3-methyl-1 H-pyrazol-5-carboxamido) - 1H-benzo [d] imidazole-5-carboxamide (160 mg, 0.215 mmol), Hoveyda-Grubbs catalyst | (26.9 mg, 0.043 mmol) and freshly degassed 1,2-dichloroethane (DCE) (80 mL). The sealed tubes were heated in a microwave reactor for 4 h at 100º C. After the mixture cooled to room temperature, MeOH (1.0 mL) was added to each tube, and the resulting clear solution was stirred at room temperature for 5 min. A solution of potassium 2-isocianoacetate (15 mg in 1.5 mL of
[0546] [0546] A round bottom flask was loaded with 10% Pd / C (200 mg, 0.188 mmol) and purged with nitrogen. A solution of 8-ethyl-10,18-dimethyl-7,20-dioxo-6,7,8,11,12,13,14,15,20,21,28,31-dodecahydrobenzo [4,5] imidazo [1,2- albenzo [4,5] imidazo [2,1-pldipyrazolo [5,1-e: 4 ', 3 "- 1] 1 [1,3,6,15,17] pentaazacyclohenicosine-3,24 -dicarboxamide (100 mg, 0.140 mmol, 7: 1 mixture of trans: cis) in a mixture of MeOH (20.0 mL) and THF (20.0 mL) was added, the flask was purged with hydrogen, and the The reaction mixture was stirred in a hydrogen atmosphere (1 atm) for 23 h. After that, the flask was opened in air, shaken vigorously for 15 min and filtered, the Pd / C was washed with MeOH / THF, and the filtrate was concentrated in vacuo and subjected to silica gel chromatography (25 g SiO2 Biotageº Ultra SNAP column; 0% to 20% MeOH / DCM) to obtain 8-ethyl-10,18-dimethyl-7,20-dioxo- 6,7,8,11,12,13,14,15,20,21,28,29,30,31- tetradecahydrobenzo [4,5] imidazo [1,2-a] benzo [4,5] imidazo [ 2,1-p] dipyrazolo [5,1-e: 4 ', 3 "- 1] 1 [1,3,6,15,17] pentaazacyclohenicosin-3,24-dicarboxamide (56 mg, 0.078 mmol, 55, 8% yield) in the form of a pale pink solid. 1H NMR (400 MHz, DMSO-ds) 5 ppm 12.88 (br. S., 2 H), 8.02 (s, 4 H), 7.79 - 7.87 (m, 2 H), 7.67 (d, J = 8.34 Hz, 1 H), 7.63 (d, J = 8.34 Hz, 1 H), 7.37 (br. S., 2 H), 6.57 (s, 1 H), 4.74 (t, J = 6.57 Hz, 2 H), 4.48 (q, J = 6.99 Hz, 2 H), 4.19 - 4.31 (m , 4 H), 2.78 - 2.86 (m, 2H), 2.16 (s, 3 H), 2.08 (s, 3 H), 1.91 (br. S., 4 H) , 1.77 - 1.86 (m, 2 H), 1.44 - 1.54 (m, 2 H), 1.35 - 1.42 (m, 2 H), 1.29 (t, J = 7.07 Hz, 3 H); LCMS (m / z): 719.7 [M + HJ ”.
[0547] [0547] To a solution of 8-ethyl-10,18-dimethyl-7,20-dioxo- 6,7,8,11,12,13,14,15,20,21,28,29,30,31 -tetradecahidrobenzo [4,5] imidazo [1,2- albenzo [4,5] imidazo [2,1-p] dipirazolo [5,1-e: 4 ', 3 "- 1 [1,3,6,15 , 17] pentaazacyclohenicosin-3,24-dicarboxamide (85 mg, 0.118 mmol) in DMF (3 mL), methyl iodide (0.015 mL of methyl iodide, 0.236 mmol, 83 µl of a 180 stock solution was added uL of methyl iodide in 820 µl of DMF) The reaction was stirred at room temperature for 3 h The reaction was dry loaded on silica gel and purified by silica gel chromatography (ISCO-Rf, column 12 g, 0% to 30% MeOH / DCM gradient) to obtain a pale yellow solid The material was suspended in MeCN and concentrated to dryness under air flow over the weekend to obtain (5aE, 21E) - 8-ethyl-5,10,18,22-tetramethyl-7,20-dioxo- 5,7,8,11,12,13,14,15,20,22,28,29,30,31-tetradecahydrobenzo [ 4.5] imidazo [1,2-albenzo [4,5] imidazo [2,1-p] ldipyrazolo [5,1-e: 4 ', 3 "- 1 [1,3,6,15,17] pentaazacyclohenicosin-3,24-dic arboxamide (58 mg, 0.077 mmol, 65.0% yield) as a white solid. * H NMR (400 MHz, METANOL-da4) 5 ppm 8.08 (dd, J = 6.97, 1.39 Hz, 2 H), 7.87 - 7.99 (m, 2 H), 7 , 63 (d, J = 8.62 Hz, 1 H), 7.51 (d, J = 8.62 Hz, 1 H), 6.53 (s, 1 H), 4.63 (t, J = 6.97 Hz, 2 H), 4.52 (q, J = 7.18 Hz, 2 H), 4.20 - 4.32 (m, 4 H), 3.61 (s, 6 H) , 2.73 - 2.84 (m, 2 H), 2.26 (s, 3 H), 2.21 (s, 3 H), 1.87 (br., 6 H), 1, 53 - 1.63 (m, 2 H), 1.30 - 1.40 (m, 5 H). LCMS m / z = 747 [M + HJ *.
[0548] [0548] To a suspension of (E) -7- (3 - ((tert-butyldimethylsilyl) oxy) propoxy) -1- (4- (5-carbamoyl-2- (1-ethyl-3-methyl-1H- pyrazol-5-carboxamido) -1H-benzo [d] imidazol | -1-yl) but-2-en-1-11) -2- (1-ethyl-3-methyl-1H-pyrazol-5-carboxamido) -1H-benzo [d] imidazole-5-carboxamide (78 mg, 0.068 mmol) in DMF (3 mL), cesium carbonate (66.1 mg, 0.203 mmol) and 2.5 eq. methyl iodide (50 µl of a stock solution composed of 220 µL of methyl iodide in 780 µl of DMF). The reaction was stirred at room temperature for 4 h. A precipitate formed in the yellow reaction mixture. More methyl iodide (2.5 eq.) Was added, and the reaction immediately lost its yellow color. The reaction was stirred at room temperature over the weekend. More cesium carbonate (66 mg, 0.20 mmol) and methyl iodide solution (2.5 eq.) Were needed to drive the reaction to completion. Water was added, and the aqueous layer was extracted with DCM (3x), then with —15% EtOH / DCM (2x). The combined organic extracts were washed with brine, dried over sodium sulfate and concentrated to dryness. The resulting residue was dry loaded onto a 12 g silica gel column eluted with a 0% to 20% MeOH / DCM gradient to obtain (E) -7- (3 - ((tert-butyldimethylsilyl) oxide) propoxy) -1 - ((E) -4 - ((E) -5-carbamoyl-2 - (((1-ethyl-3-methyl-1 H-pyrazol-5-carbonyl) imino) -3-methyl-2 , 3-dihydro-1H-benzo [d] imidazo | -1-yl) but-2-en-1-i1) -2 - ((1-ethyl-3-methyl-1H-pyrazol-5-carbonyl) imino ) -3-methyl-2,3-dihydro-1H-benzo [d] imidazole | -5-carboxamide (20 mg, 0.022 mmol, 33.1% yield) as a white solid. LCMS m / z = 893 [M + HJ *.
[0549] [0549] To a solution of (E) -7- (3 - ((tert-butyldimethylsily) oxy) propoxy) -1 - ((E) -4- ((E) -5-carbamoyl-2 - ((1 -ethyl-3-methyl-1 H-pyrazol-5-carbonyl) imino) -3-methyl-2,3-dihydro-1H-benzo [d] imidazol-1-yl) but-2-en-1-i1 ) -2 - ((1-ethyl-3-methyl-1 H-pyrazol-S5-carbonyl) imino) -3-methyl-2,3-dihydro-1H-benzo [d] imidazole | -5-carboxamide (20 mg, 0.022 mmol) in 1,4-dioxane (0.5 mL), 4 M HCl in dioxane (0.011 mL, 0.045 mmol) was added.
[0550] [0550] To a suspension of (E) -7- (3 - ((tert-butyldimethylsilyl) oxy) propoxy) -1- (4- (5-carbamoyl-2- (1-ethyl-3-methyl-1H- pyrazol-5-carboxamido) -1H-benzo [d] imidazol | -1-yl) but-2-en-1-11) -2- (1-ethyl-3-methyl-1H-pyrazol-5-carboxamido) -1H-benzo [d] imidazole-5-carboxamide (50 mg, 0.058 mmol) in DMF (2 mL), cesium carbonate (75 mg, 0.231 mmol) and iodoethane (27.0 mg, 0.173 mmol) were added . After 3 h, more ethyl iodide (15 µl) was added, and the reaction was stirred for 15 min. The reaction was split between DCM and water. The aqueous layer was extracted with DCM / EtOH (3x). The combined organic layers were washed with brine, dried over sodium sulfate, loaded dry on silica gel and purified by silica gel chromatography (12 g column, gradient 0% to 20% MeOH / DCM) to obtain (E) -7- (3- ((tert-butyldimethylsilyl) oxy) propoxy) -1 - ((E) -4 - ((Z) -S-carbamoyl-3-ethyl-2 - ((1-ethyl- 3-methyl-1 H-pyrazol-5-carbonyl) imino) -2,3-dihydro-1H-benzo [d] imidazo | -1-yl) but-2-en-1-11) -3-ethyl- 2- ((1-ethyl-3-methyl-1H-pyrazol-S-carbonyl) imino) -2,3-dihydro-1H-benzo [d] imidazole-5-carboxamide (18 mg, 0.020 mmol, 33.8 % of yield). LCMS m / z = 921 [M + H] *.
[0551] [0551] To a solution of (E) -7- (3 - ((tert-butyldimethylsilyl) oxy) propoxy) -1 - ((E) -4- ((Z) -5-carbamoyl-3-ethyl-2 - (((1-ethyl-3-methyl-1 H-pyrazol-5-carbonyl) imino) -2,3-dihydro-1H-benzo [d] imidazol | -1-yl) but-2-en-1- i1) -3-ethyl-2 - (((1-ethyl-3-methyl-1 H-pyrazol-5-carbonyl) imino) -2,3-dihydro-1H-benzo [d] imidazole-5-carboxamide (17 mg, 0.018 mmol) in 1,4-dioxane (923 µL), HCl in dioxane (27.7 µl, 0.111 mmol) was added. After 1h at room temperature, the reaction was filtered, and the filter cake was washed with diethyl ether and dried in a vacuum oven at 55º C overnight to obtain (E) -1 - ((E) - 4 - ((Z) -5-carbamoyl-3-ethyl-2 - (((1-ethyl-3-methyl-1 H-pyrazol-S5-carbonyl) imino) -2,3-dihydro-1H-benzo [d ] imidazol | -1-yl) but-2-en-1-i1) -3-ethyl-2 - ((1-ethyl-3-methyl-1H-pyrazol-5-carbonyl) imino) -7- (3 -hydroxypropoxy) -2,3-dihydro-1H-benzo [d] imidazole-5-carboxamide, 2 hydrochloride (14 mg, 0.015 mmol, 81% yield) as a white solid. * H NMR (400 MHz, DMSO-ds) 5 ppm 8.03 - 8.14 (m, 3 H), 7.68 - 7.87 (m, 2H), 7.42 - 7.52 (m , 4 H), 6.38 (s, 2 H), 5.80 - 5.97 (m, 1 H), 5.41 - 5.68 (m, 1 H), 4.81 - 4.94 (m, 2 H), 4.67 - 4.78 (m, 2 H), 4.34 - 4.45 (m, 4 H), 4.01 - 4.22 (m, 7 H), 3 , 32 - 3.51 (m, 2 H), 2.12 (s, 3 H), 2.10 (s, 3 H), 1.68 - 1.76 (m, 2 H), 1.11 - 1.382 (m, 12H). LCMS m / z = 807 [M + H] *.
[0552] [0552] The compound prepared by the above process can exist in a tautomeric / isomeric form, for example, (E) -1 - ((E) -4 - ((E) -5-carbamoyl-3-ethyl-2- ( (1-ethyl-3-methyl-1H-pyrazol-5-carbonyl) imino) -2,3-dihydro-1H-benzo [d] imidazo | -1-yl) but-2- en-1-i1) - 3-ethyl-2 - ((1-ethyl-3-methyl-1 H-pyrazol-5-carbonyl) imino) -7- (3-hydroxypropoxy) -2,3-dihydro-1H-benzo [d] imidazole | -5-carboxamide, 2 hydrochloride o Is q WA nºs NA ' N
[0553] [0553] 2,2,3,3-tetrafluorbutane-1,4-diamine (1.25 g, 7.81 mmol) and potassium carbonate (3.24 g, 23.4 mmol) in DMF (50 mL ) at room temperature, 4-fluorine-3-nitrobenzamide (3.59 g, 19.5 mmol) was added over 5 min, and the reaction was stirred overnight. The mixture was quenched with water, and the resulting solid was collected by filtration and triturated with MeOH to obtain the title compound (600 mg, 1.23 mmol, 16% yield) as a yellow solid. LCMS [M + H] * = 489, Step 2: 4.4 '- ((2,2,3,3-tetrafluorbutane-1,4-diyl) bis (azanediyl)) bis (3-aminobenzamide) o e HN F F. F F
[0554] [0554] 4.4 '- ((2,2,3,3-tetrafluorbutane-1,4-diyl) bis (azanediyl)) bis (3-nitrobenzamide) (1.15 g, 2.36 mmol) was stirred ) and Pd on carbon (0.251 g, 2.36 mmol) in MeOH (100 mL) under H2 at 30 ° C overnight. The reaction was filtered and the filtrate concentrated to obtain the title compound (250 mg, 0.584 mmol, 25% yield). LCMS [M + H] * = 429.1 Step 3: 1,1- (2,2,3,3-tetrafluorbutane-1,4-diyl) bis (2-amino-1H-benzo [d] imidazole-5 -carboxamide) o N HNA O " N F F. F F
[0555] [0555] JA 4,4 '- ((2,2,3,3-tetrafluorbutane-1,4-diyl) bis (azanediyl)) bis (3-aminobenzamide) (20 mg, 0.047 mmol) in MeOH (1 mL ) and water (2 mL), cyanogen bromide (29.7 mg, 0.280 mmol) was added, and the reaction was stirred at 30 ° C overnight. The MeOH was removed in vacuo, and the resulting solid was collected by filtrate to obtain the title compound (15 mg, 0.031 mmol, 67% yield). LCMS [M + H] * = 479.0 Step 4: 1.1 '- (2,2,3,3-tetrafluorbutane-1,4-diyl) bis (2- (1-ethyl-3-methyl-1H -pyrazol- 5-carboxamido) -1 H-benzo [dlimidazo | -5-carboxamide) D) N
[0556] [0556] HATU (763 mg, 2.01 mmol) and 1-ethyl-3-methyl-1H-pyrazole-5-carboxylic acid (227 mg, 1, A7 Mmol) in DMF (20 mL) at room temperature , EDC (385 mg, 2.01 mmol), 1.1 '- (2,2,3,3-tetrafluorbutane-1,4-diyl) bis (2-amino-1H-benzo [d] imidazole- 5-carboxamide) (320 mg, 0.667 mmol) and DIEA (0.467 mL, 2.68 mmol) in one charge. The reaction was heated to 70 ° C for 12 h, concentrated and purified to produce the title compound (8 mg, 0.01 mmol, 2% yield). * H NMR (400 MHz, DMSO-ds) 5 ppm 13.05 (s, 2 H), 8.01 (d, J = 8.6 Hz, 4 H), 7.81 (d, J = 8 , 2 Hz, 2 H), 7.53 (d, J = 8.3 Hz, 2 H), 7.38 (s, 2H), 6.73 (s, 2H), 5.32 (t, J = 16.0 Hz, 4 H), 4.59 (dd, J = 14.0, 6.9 Hz, 4 H), 2.06 (s, 6 H), 1.33 (t, J = 7 , 1 Hz, 6 H); LCMS [M + H] * = 751.1 Step 5: (2E, 2'E) -1.1 '- (2,2,3,3-tetrafluorbutane-1,4-diyl) bis (2 - (( 1-ethyl-3-methyl-1H-pyrazol-5-carbonyl) imino) -3-methyl-2,3-dihydro-1 H-benzo [d] imidazole-5-carboxamide), trifluoroacetic acid salt o
[0557] [0557] To a 100 ml round bottom flask, 1,1- (2,2,3,3-tetrafluorbutane-1,4-diyl) bis (2- (1-ethyl-3-methyl-) were added 1 H-pyrazol-5-carboxamido) -1H-benzo [d] imidazole-5-carboxamide) (49 mg, 0.065 mmol) and DMF (0.653 ml). To this solution, cesium carbonate (63.8 mg, 0.196 mmol) was added, followed by methyl iodide (10.20 µL, 0.163 mmol). The mixture was stirred at room temperature. After 30 minutes, more methyl iodide (10 µL; 0.16 mmol) was added, and the mixture was stirred overnight (-14 hours) at room temperature. This clear crude mixture was injected directly into a preparative reverse phase and purified HPLC system (Dual Phase ISCO, gradient of 20% to 50% CH; CN / H2O, TFA modifier). The pure fractions were combined and concentrated to obtain (2E, 2'E) -1.1 '- (2,2,3,3-tetrafluorbutane-1,4-diyl) bis (2 - ((1-ethyl-3 -methyl-1H-pyrazol-5-carbonyl) imino) -3-methyl-2,3-dihydro-1H-benzo [d] imidazole-5-carboxamide), trifluoroacetic acid salt (3 mg, 3.19 umol, 4.89% yield) in the form of an off-white semi-solid. * H NMR (400 MHz, METANOL-d4) 5 ppm 1.34 (t, J = 7.10 Hz, 6 H) 2.25 (s, 6 H) 3.70 (s, 6 H) 4, 60 (q, J = 7.10 Hz, 4 H) 5.19 (t, J = 15.33 Hz, 4 H) 6.66 (s, 2 H) 7.60 (d, J = 8.36 Hz, 2 H) 7.96 (dd, J = 8.36, 1.52 Hz, 2 H) 8.11 (d, J = 1.27 Hz, 2 H). LCMS m / z = 779 [M + H] *. Example 7 1 - ((E) -4 - ((E) -5-carbamoyl-2 - (((1-ethyl-3-methyl-1H-pyrazol-5-carbonyl) imino) -7-methoxy-3-methyl -2,3-dihydro-1H-benzo [d] imidazo | -1-yl) but-2-en-1-11) -2- (1-ethyl-3-methyl-1H-pyrazol-5-carboxamidoan) -1H-benzo [d] imidazole-5-carboxamide, 2 trifluoroacetic acid salt o HoN Ná ox On À N y
[0558] [0558] 4-Fluorine-3-nitrobenzamide (86 mg, 0.467 mmol), (E) -1- ((E) -4-aminobut-2-en-1-i1) -2 - ((1 -ethyl-3-methyl-1H-pyrazol-5-carbonyl) imino) -7-methoxy-3-methyl-2,3-dihydro-1H-benzo [d] imidazo | -5-carboxamide, 3 Hydrochloride (name used in PU66420P: (Z) -1 - ((E) -4-aminobut-2-en-1-i1) -2 - ((1-ethyl-3-methyl-1H-pyrazol-S-carbonyl) imino) -7 -methoxy-3-methyl-2,3-dihydro-1H-benzo [d] imidazole-5-carboxamide, 3 hydrochloride (250 mg, 0.467 mmol) and DIPEA (0.245 mL, 1.402 mmol) in isopropanol (2 mL), which were then heated to 120º C in a sealed ampoule. After 18 h, the reaction was diluted with 25 ml of EtOAc and washed with 2 x 25 ml of water, 25 ml of saturated sodium bicarbonate solution and 25 ml of brine. The aqueous layers were extracted back with 25 ml of EtOAc, the organic layers were collected and concentrated in vacuo to obtain the solid crude product The crude product was dissolved in 6 ml of DMSO, filtered and purified by mass directed prep-HPLC The pure fractions were combined, The organic layers were removed in vacuo, and the compound was extracted from the aqueous solvent with 2 x 50 ml of DCM. The volatile substances were removed in vacuo to obtain the title compound as a yellow solid (102 mg, 0.173 mmol, 37% yield). LCMS m / z = 590 [M + H] I *.
[0559] [0559] To a suspension of (E) -1 - ((E) -4 - ((4-carbamoyl-2-nitrophenyl) amino) but-2-en-1-i1) -2 - ((1-ethyl -3-methyl-1H-pyrazol-S-carbonyl) imino) -7-methoxy-3-methyl-2,3-dihydro-1H-benzo [d] imidazole | -5-carboxamide (105 mg, 0.178 mmol) in acetic acid (0.500 ml) and MeOH (0.5 ml), 1% by weight of Pt and 2% by weight of vanadium on activated carbon, 50% to 70% of wet powder (34.7 mg, 1.781 umol, Strem, 78-1536). The flask was evacuated and purged with nitrogen, which was repeated twice more. The flask was evacuated and discharged with a hydrogen balloon, and was shaken at room temperature in a hydrogen atmosphere. Because of the incomplete conversion after 5 h, the reaction mixture was filtered through a small plug of diatomaceous earth using MeOH. The reaction mixture was concentrated in vacuo and stored in a freezer. The crude product was redissolved in acetic acid (0.500 ml) and MeOH (0.5 ml), and 1% by weight of Pt and 2% by weight of vanadium V on activated carbon, 50% to 70% of powder were added moistened (34.7 mg, 1.781 umol). The flask was evacuated and purged with nitrogen, which was repeated twice more. The flask was evacuated and discharged with a hydrogen balloon, and was shaken at room temperature in a hydrogen atmosphere. After 2 h, the reaction mixture was filtered through a small plug of diatomaceous earth using MeOH, then concentrated in vacuo to obtain the title compound as a red oil (163 mg, 0.148 mmol, 82% yield) . LCMS m / z = 280 [M + 2H / 2] *.
[0560] [0560] A (E) -1 - ((E) -4 - ((2-amino-4-carbamoylphenyl) amino) but-2-en-1-i1) -2 - ((1- ethyl-3- methyl-1H-pyrazol-5-carbonyl) imino) -7-methoxy-3-methyl-2,3-dihydro-1H-benzo [d] imidazole-5-carboxamide (100 mg, 0.179 mmol) in DMF (1 mL ) at 0 ° C, 1-ethyl-3-methyl-1H-pyrazol-S-carbonyl isothiocyanate (0.491 ml, 0.197 mmol, 0.4 M in dioxane) was added and the mixture was stirred at 0 ° C for 1 H. After 1 h, EDC (51.4 mg, 0.268 mmol) and triethylamine (0.075 mL, 0.536 mmol) were added, and the reaction was stirred at 40 ° C for 3 h and overnight at room temperature. The reaction was diluted with 1.5 ml of DMSO, and the title compound was purified by preparative mass directed HPLC (basic modifier). The pure fractions were collected, and the organic layers were removed under vacuum. After that, the compound was extracted with 2 x 25 ml of DCM, and the organic layers were washed with 10 ml of brine. The volatile substances were removed in vacuo to obtain the title compound (- 80% purity by LCMS). The compound was diluted with 2.0 mL of DMSO and repurified by preparative mass-directed HPLC (TFA modifier). The pure fractions were collected, and the solvents were removed in vacuo to obtain the title compound as a yellow oil (15 mg, 0.016 mmol, 8.8% yield). 1H NMR (400 MHz, METANOL-da) 5 ppm 1.31 - 1.38 (m, 6 H), 2.24 - 2.26 (m, 6 H), 3.71 (s, 3 H) , 3.88 (s, 3 H), 4.50 (q, J = 7.10 Hz, 2 H), 4.60 (q, J = 7.10 Hz, 2 H), 4.88 (d , J = 5.83 Hz, 2 H), 5.11 (d, J = 5.07 Hz, 2 H), 5.78 (dt, J = 15.40, 5.73 Hz, 1 H), 5.95 - 6.03 (m, 1 H), 6.63 (s, 1 H), 6.65 (s, 1 H), 7.36 (d, J = 8.36 Hz, 1 H) , 7.51 (d, J = 1.27 Hz, 1 H), 7.74 (dd, J = 8.36, 1.52 Hz, 1 H), 7.79 (d, J = 1.01 Hz, 1 H), 8.00 (d, J = 1.52 Hz, 1 H). LCMS m / z = 721 [M + H] *.
[0561] [0561] 4-chloro-3-methoxy-5-nitrobenzamide (108 mg, 0.467 mmol), (E) -1 - ((E) -4-aminobut-2-en-1-yl) -2 - ((1-ethyl-3-methyl-1 H-pyrazol-5-carbonyl) imino) - 7-methoxy-3-methyl-2,3-dihydro-1H-benzo [d] imidazole-5-carboxamide, 3 Hydrochloride (250 mg, 0.467 mmol) and DIPEA (0.245 mL, 1.402 mmol) in isopropanol (2 mL), then heated to 120º C in a sealed ampoule. After 22 h, the reaction was diluted with 25 ml of EtOAc and washed with 2 x 25 ml of water, 25 ml of saturated sodium bicarbonate solution and 25 ml of brine. The aqueous layers were extracted with 25 ml of EtOAc. The organic layers were collected and concentrated in vacuo to obtain the crude product as an orange solid. The crude product was dissolved in 12 ml of DMSO, filtered and purified directly by mass-directed prep-HPLC (high pH modifier, multiple injections). The pure fractions were combined, the organic layers were removed in vacuo, and the title compound was extracted from the aqueous solvent with 2 x 50 ml DCM. The volatile substances were removed in vacuo to obtain the title compound as an orange solid (53 mg, 0.086 mmol, 18.3% yield). LCMS m / z = 620 [M + HJ *.
[0563] [0563] JA (E) 1 - ((E) -4 - ((2-amino-4-carbamoyl-6-methoxyphenyl) amino) but-2-en-1- i1) -2 - ((1-ethyl -3-methyl-1 H-pyrazol-5-carbonyl) imino) -7-methoxy-3-methyl-2,3-dihydro-1H-benzo [d] imidazole | -5-carboxamide (60 mg, 0.102 mmol) in DMF (1 ml) at 0 ° C, 1-ethyl-3-methyl-1H-pyrazol-S5-carbonyl isothiocyanate (0.280 ml, 0.112 mmol) was added as a 0.4 M solution in dioxane and the mixture was stirred at 0 ° C for 1 h. After 1 h, EDC (29.3 mg, 0.153 mmol) and triethylamine (0.043 mL, 0.305 mmol) were added, and the reaction was stirred at 40 ° C for 2 h, then at room temperature for 18 h. The reaction mixture was diluted with 1.5 ml of DMSO and purified on a mass-directed HPLC-prep (high pH modifier). A second prep-HPLC purification step was necessary (using a TFA modifier) to obtain the pure title compound as an off-white solid (5.0 mg,
[0564] [0564] 3- (3 - ((tert-butyldimethylsilyl) oxy) propoxy) -4-chloro-5-nitrobenzamide (182 mg, 0.467 mmol), (E) -1 - ((E) -4- aminobut-2-en-1-i1) -2 - ((1-ethyl-3-methyl-1H-pyrazol-5-carbonyl) imino) -7-methoxy-3-methyl-2,3-dihydro-1H- benzo [d] imidazole-5-carboxamide, 3 Hydrochloride (250 mg, 0.467 mmol) and DIPEA (0.245 mL, 1.402 mmol) in isopropanol (2 mL) and the mixture was heated to 120º C in a sealed ampoule After 22 h, the reaction was diluted with 25 ml of EtOAc and washed with 2 x 25 ml of water, 25 ml of saturated sodium bicarbonate solution and 25 ml of brine. The aqueous layers were back extracted with 25 ml of EtOAc. The organic layers were collected and concentrated in vacuo. The crude product was dissolved in 6 ml of DMSO, filtered and purified by mass-directed prep-HPLC (high pH modifier). The pure fractions were combined, the organic layers were removed in vacuo, and the compound was extracted from the aqueous solvent with 2 x 50 ml of DCM. Evaporation of the solvents produced the title compound as an orange solid (80 mg, 0.103 mmol, 22% yield). LCMS m / z = 778 [M + HF.
[0565] [0565] To a suspension of (E) -1 - ((E) -4 - ((2- (3 - ((tert-butyldimethylsilyl) oxy) propoxy) -4-carbamoyl-6-nitrophenyl) amino) but- 2-en-1-i1) -2 - ((1-ethyl-3-methyl-1H-pyrazol-S-carbonyl) imino) -7-methoxy-3-methyl-2,3-dihydro-1H-benzo [ d] imidazo | - B5-carboxamide - (name used in PU66420P: (Z) 1 - ((E) 4 - ((2- (3 - ((tert-
[0566] [0566] A (E) -1 - ((E) -4 - ((2-amino-6- (3 - ((tert-butyldimethylsilyl) oxy) propoxy) -4-carbamoylphenyl) amino) but-2-en -1-i1) -2 - ((1-ethyl-3-methyl-1 H-pyrazol-5-carbonyl) imino) -7-methoxy-3-methyl-2,3-dihydro-1H-benzo [d] imidazole-5-carboxamide (80 mg, 0.107 mmol) in DMF (1 mL) at 0 ° C, 1-ethyl-3-methyl-1H-pyrazol-5-carbonyl isothiocyanate (0.294 mL, 0.118 mmol, 0 , 4 M) in dioxane and the mixture was stirred at 0 ° C for 1 h. EDC (30.8 mg, 0.160 mmol) and triethylamine (0.045 mL, 0.321 mmol) were added, and the reaction was stirred at 40 ° C for 2 h and at room temperature for 18h. The reaction was diluted with 1.5 ml of DMSO and purified using mass-directed prep-HPLC (high pH modifier). The pure fractions were collected, and the organic layers were removed under vacuum.
[0568] [0568] In a 20 mL ampoule, (E) -1- (4- (5-carbamoyl-2- (1-ethyl-3-methyl-1H-pyrazol-5-carboxamido) -7- ( 3-morpholinopropoxy) -1H-benzo [d] imidazol | -1- yl) but-2-en-1-i1) -2- (1-ethyl-3-methyl-1 H-pyrazol-5-carboxamido) - 7-methoxy-1H-benzol [d] imidazole-5-carboxamide (200 mg, 0.235 mmol) and DMF (2.35 ml). To this solution, cesium carbonate (230 mg, 0.706 mmol) and methyl iodide (37 ul, 0.588 mmol) were added. The solution was stirred at room temperature for 15 min. DMF (2 ml) and water (2 ml) were added directly to the ampoule. This mixture was purified directly using mass-directed preparative HPLC (15% 55% MeCN / water gradient with NH.4OH as a modifier). The corresponding fractions were combined and concentrated. The concentrated mixture was further purified by preparative mass directed HPLC (5% to 35% MeCN / water gradient with TFA as a modifier). The corresponding fractions were combined and concentrated to obtain (E) -1 - ((E) -4 - ((E) -5-carbamoyl-2 - ((1-ethyl-3-methyl-1H-pyrazol-5-carbonyl) ) imino) -3-methyl-7- (3-morpholinopropoxy) -2,3-dihydro-1H-benzo [d] imidazol-1-yl) but-2-en-1-i1) -2 - ((1 -ethyl-3-methyl-1H-pyrazol-S-carbonyl) imino) -7-methoxy-3-methyl-2,3-dihydro-1H-benzo [d] imidazole-5-
[0569] [0569] In a 20 ml ampoule, (E) -1- (4- (5-carbamoyl-2- (1- ethyl-3-methyl-1H-pyrazol-5-carboxamido) -7- ( 3-morpholinopropoxy) -1H-benzo [d] imidazol | -1- yl) but-2-en-1-i1) -2- (1-ethyl-3-methyl-1 H-pyrazol-5-carboxamido) - 7-methoxy-1H-benzo [d] imidazole-5-carboxamide (200 mg, 0.235 mmol) and DMF (2.35 ml). To this solution, cesium carbonate (230 mg, 0.706 mmol) and methyl iodide (37 ul, 0.588 mmol) were added. The solution was stirred at room temperature for 15 min. DMF (2 ml) and water (2 ml) were added directly to the ampoule. This mixture was purified directly using mass-directed preparative HPLC (15% 55% MeCN / water gradient with NH.OH as a modifier). The corresponding fractions were combined and concentrated. The concentrated mixture was purified by preparative reverse phase HPLC (5% to 35% MeCN / water gradient with TFA as modifier) using an acid modifier. The corresponding fractions were combined and concentrated to obtain the title compound (6 mg, 4.81 umol, 2.04% yield) as a clear oil. * H NMR (400 MHz, DMSO-ds) δ ppm 8.08 (br. S., 2 H), 7.81 (s, 2H), 7.77 (s, 1 H), 7.53 ( br., 3 H), 7.39-7.40 (m, 3 H), 6.41 (s, 1 H), 6.40 (s, 1 H), 5.60-5.75 (m, 2 H), 4.74 - 4.97 (m, 4 H), 4.35-4.51 (m, 4 H), 4.02 (t, J = 5.32 Hz, 2 H ), 3.82-3.98 (m, 4 H), 3.67 (s, 3 H), 3.50-3.54 (m, 8 H), 3.08 (s, 3 H), 2.12 (s, 6 H), 1.95-2.05 (m., 2 H), 1.24-1.20 (m, 6 H). LCMS (m / z): 892.7 [M] * Example 12 (2E, 2'E) -1.1 '- (pentane-1,4-diyl) bis (2 - ((1-ethyl-3- methyl-1H-pyrazol-5-carbonyl) imino) -3-methyl-2,3-dihydro-1H-benzo [d] imidazole | -5-carboxamide) o fe) “N =
[0570] [0570] In a reaction flask, pentane-1,4-diamine, 2 hydrochloride (1 g, 5.71 mmol) and isopropanol (9.52 mL) were introduced. To this solution, 4-fluor-3-nitrobenzamide (1.052 9, 5.71 mmol) was added, followed by DIPEA (4.49 mL, 25.7 mmol). The flask was capped, and the reaction was heated to 105º C. After 4 hours,
[0571] [0571] To a 100 ml round-bottom flask, 4,4'- (pentane-1,4-diylbis (azanediyl)) bis (3-nitrobenzamide) (500 mg, 1.162 mmol) and MeOH (11 , 6 mL). To this solution, ammonium chloride (249 mg, 4.65 mmol) and 5.5 ml of a saturated aqueous ammonium chloride solution were added. To that solution, zinc (759 mg, 11.62 mmol) was added. The heterogeneous mixture was stirred at room temperature for 15 min. The mixture was filtered, and the collected solid was rinsed with MeOH (10 ml). To the combined filtrates, diatomaceous earth was added, and the crude product was purified by flash chromatography (dry loading technique, 12 g SiO2 cartridge, 2% to 40% MeOH / DCM as eluent containing NHOH as a modifier). The corresponding fractions were combined and concentrated. 4.4 '- (pentane-1,4-diylbis (azanediyl)) bis (3-aminobenzamide) (368 mg, 0.944 mmol, 81% yield) was obtained as a colorless oil. LCMS (m / z): 371.2 [M + HJ * Step 3: 1.1 '- (pentane-1,4-diyl) bis (2- (1-ethyl-3-methyl-1H-pyrazol-5 - carboxamido) -1H-benzo [d] imidazole-5-carboxamide)
[0572] [0572] To a 100 mL round-bottom flask, 4,4'- (pentane-1,4-diylbis (azanediyl)) bis (3-aminobenzamide) (368 mg, 0.993 mmol) and DMF (9 , 9 mL). This solution was cooled to 0 ° C. After 5 min of stirring at 0 ° C, 1-ethyl-3-methyl-1H-pyrazol-5-carbonyl isothiocyanate (3 ml of a -0.4 dioxane solution was added M, -1.2 mmol). After 15 min, more 1-ethyl-3-methyl-1H-pyrazole-S5-carbonyl isothiocyanate (1 ml of a 0.4 M dioxane solution, -0.4 mmol) was added. The reaction was allowed to stir for another 15 min at 0 ° C. After that, EDC (476 mg, 2.483 mmol) and triethylamine (0.692 mL, 4.97 mmol) were added. The reaction mixture was allowed to warm to room temperature and stir overnight (-14 h). The reaction mixture was poured into 4: 1 of water / saturated aqueous ammonium chloride (25 mL). The product was extracted with ethyl acetate (3 x 15 ml). The combined organic phase was washed with water (20 ml), brine (20 ml) and dried over magnesium sulfate. The crude product was concentrated and purified by flash chromatography (249 SiO2 cartridge, 2% to 40% MeOH / DCM as eluent containing NHXOH as a modifier). The corresponding fractions were combined and concentrated. 1.1 "- (pentane-1,4-diyl) bis (2- (1-ethyl-3-methyl-1H-pyrazol-5-carboxamido) -1H-benzo [d] imidazole-5-carboxamide was obtained ) (303 mg, 0.429 mmol, 43.1% yield) as a white powder. * H NMR (400 MHz, DMSO-ds) 5 ppm 12.88 (br. S, 1 H), 12, 80 (br. S, 1 H), 7.95 - 7.99 (m, 4 H), 7.70 - 7.73 (m, 2 H), 7.61 (d, J = 8.62 Hz , 1 H), 7.34 - 7.42 (m, 3 H), 6.61 (m, 2 H), 5.20 (br. S., 1 H), 4.53 - 4.60 ( m, 4 H), 4.32 (br. s,
[0573] [0573] In a 10 mL ampoule, 1,1 '- (pentane-1,4-diyl) bis (2- (1-ethyl-3-methyl-1 H-pyrazol-5-carboxamido) - 1H-benzo [d] imidazole | -5-carboxamide) - (50 mg, 0.072 mmol) and DMF (1.4 mL). To the heterogeneous solution, cesium carbonate (70.5 mg, 0.217 mmol) was added, followed by the addition of methyl iodide (0.011 mL, 0.180 mmol). The ampoule was capped, and the mixture was stirred overnight (-14 h) at room temperature. The mixture was diluted with DMSO (1 ml) and water (1 ml) to form a clear homogeneous solution. This solution was directly purified by preparative reverse phase HPLC (biphasic ISCO system, 5% to 35% MeCN / water gradient with 0.1% NHOH modifier). The corresponding fractions were combined and concentrated. The product was lyophilized with MEeCN and water (-30 ml). (2E, 2'E) -1,1 '- (pentane-1,4-diyl) bis (2 - ((1-ethyl-3-methyl-1H-pyrazol-5-carbonyl) imino) - 3-methyl-2,3-dihydro-1H-benzo [d] imidazole-5-carboxamide) (25 mg, 0.035 mmol, 48.1% yield) as a white fuzzy solid. * H NMR (400 MHz, METANOL-da) 5 ppm 7.87 (d, J = 2.28 Hz, 2 H), 7.82 (dd, J = 8.36, 1.52 Hz, 1 H ), 7.73 - 7.80 (m, 1 H), 7.54 (d, J = 8.36 Hz, 1 H), 7.41 (d, J = 8.62 Hz, 1 H), 6.63 (s, 2 H), 4.85 (m, 1 H), 4.63 (q, J = 7.18 Hz, 4 H), 4.25 - 4.41 (m, 1 H) , 4.06 - 4.20 (m, 1 H), 3.57 (s, 3 H), 3.55 (s, 3 H), 2.25 (s, 6 H), 2.23 (m ,
[0574] [0574] In a 24 ml ampoule, 4-methylpentane-1,4-diamine (0.49 g, 4.22 mmol) and isopropanol (14.0 ml) were introduced. To this solution, 4-fluorine-3-nitrobenzamide (1.63 g, 8.85 mmol) was added, followed by the addition of DIPEA (2.58 ml, 14.76 mmol). The ampoule was capped, and the heterogeneous solution was stirred overnight (- 14 h) at 105º C. A precipitate was removed by filtration and rinsed with isopropanol (2 x 5 mL). 4.4 '- ((4-methylpentane-1,4-diyl) bis (azanediyl)) bis (3-nitrobenzamide) was obtained (1.46 g, 3.02 mmol, 71.7% yield, 92 % purity) as an orange solid. LCMS (m / z): 445.3 [M + HJ *.
[0575] [0575] To a 100 mL round bottom flask, 4.4 '- (((4-methylpentane-1,4-diyl) bis (azanediyl)) bis (3-nitrobenzamide) (500 mg, 1.035 mmol ) and MeOH (15 mL). To this solution, ammonium chloride (1,107 mg, 20.70 mmol), 10 mL of a solution of saturated aqueous ammonium chloride and zinc (677 mg, 10.35 mmol) were added. The heterogeneous mixture was stirred at room temperature. After min, more zinc (350 mg, 5.35 mmol) and ammonium chloride (600 mg, 11.22 mmol) were added. After stirring for a total of 90 min at room temperature, the mixture was filtered. The remaining solid was rinsed with MeOH (20 ml). To the combined filtrate, diatomaceous earth was added, and the crude product was purified by silica gel chromatography (dry loading technique, 12 g SiO2z cartridge, 2% to 40% NH MeOH / DCM gradient. KOH as a modifier). The corresponding fractions were combined and concentrated. 4.4 '- ((4-methylpentane-1,4-diyl) bis (azanediyl)) bis (3-aminobenzamide) (247 mg, 0.610 mmol, 59.0% yield) was obtained as a film White. LCMS (m / z): 385.4 [M + HJ * Step 3: 1.1 '- (4-methylpentane-1,4-diyl) bis (2- (1-ethyl-3-methyl-1 H- pyrazole-5-carboxamido) -1H-benzo [d] imidazole-5-carboxamide) oo “No Hv
[0576] [0576] To a 100 mL round-bottom flask, 4.4 '- (((4-methylpentane-1,4-diyl) bis (azanediyl)) bis (3-aminobenzamide) (247 mg, 0.642 mmol) was added ) and DMF (6.42 ml). This solution was cooled to 0º C.
[0577] [0577] In a 10 ml ampoule, 1.1 '- (4-methylpentane-1,4-diyl) bis (2- (1-ethyl-3-methyl-1H-pyrazole-5-carboxamido) was introduced -1H-benzo [d] imidazole-5-carboxamide) (49 mg, 0.069 mmol) and DMF (0.693 mL). To this solution, cesium carbonate (67.8 mg, 0.208 mmol) was added, followed by the addition of methyl iodide (10.84 µL, 0.173 mmol). The ampoule was capped, and the mixture was stirred overnight (-14 h) at room temperature. The mixture was diluted with DMSO (1 ml) and water (1 ml) to form a clear homogeneous solution. This solution was injected directly and purified by preparative reverse phase HPLC (biphasic ISCO system, 5% to 35% MeCN / water gradient with 0.1% NH4OH modifier). The corresponding fractions were combined and concentrated. (2E, 2'E) -1.1 "- (4-methylpentane-1,4-diyl) bis (2 - ((1-ethyl-3-methyl-1H-pyrazol-5-carbonyl) imino was obtained ) -3-methyl-2,3-dihydro-1H-benzo [d] imidazole | -5-carboxamide) (15.8 mg, 0.022 mmol, 31.0% yield) as a clear oil. * H (400 MHz, METANOL-da) 5 ppm 7.64 - 7.85 (m, 5 H), 7.34 (d, J = 8.36 Hz, 1 H), 6.65 (s, 1 H), 6.57 (s, 1 H), 4.64 (m, 4 H), 4.20 (t, J = 5.96 Hz, 2 H), 3.54 (s, 3 H), 3.40 (s, 3 H), 2.24 - 2.31 (m, 5 H), 2.23 (s, 3 H), 1.82 - 1.95 (m, 8 H), 1, 41 (m, 6 H) LCMS (m / z): 735.4 [M + HJ ”.
[0578] [0578] In a 10 ml ampoule, 1.1 '- (4-methylpentane-1,4-diyl) bis (2- (1-ethyl-3-methyl-1H-pyrazole-5-carboxamido) was added -1H-benzo [d] imidazole-5-carboxamide) (a synthetic intermediate of Example 13) (100 mg, 0.141 mmol) and DMF (1.415 ml). To this solution, cesium carbonate (138 mg, 0.424 mmol) was added, followed by the addition of methyl iodide (0.044 mL, 0.707 mmol). The ampoule was capped, and the mixture was stirred overnight (-14 h) at room temperature. This mixture was purified directly by preparative reverse phase HPLC (biphasic ISCO system, MeCN / water gradient with 0.1% NHOH modifier). The corresponding fractions were combined and concentrated. (E) -1- (5 - ((E) -5-carbamoyl-2 - (((1-ethyl-3-methyl-1H-pyrazol-5-carbonyl) imino) -3-methyl-2 was obtained, 3- dihydro-1H-benzo [d] imidazo | -1-yl) -2-methylpentan-2-i1) -2 - ((1-ethyl-3-methyl-1H-pyrazol-5-carbonyl) imino) - N, 3-dimethyl-2,3-dihydro-1H-benzo [d] imidazole | -5-carboxamide (7.1 mg, 0.0087 mmol, 6.16% yield) as a white film. * H NMR (400 MHz, METANOL-da) 5 ppm 7.56 - 7.85 (m, 5 H), 7.25 - 7.37 (m, 1 H), 6.66 (s, 1 H ), 6.58 (s, 1 H), 4.54 - 4.76 (m, 4 H), 4.20 (t, J = 5.96 Hz, 2 H), 3.55 (d, J = 5.58 Hz, 3 H), 3.40 (s, 3 H), 3.02 (s, 3 H), 2.26 (s, 3 H), 2.26 (m, 1 H), 2.23 (s, 3 H), 2.23 (m, 1 H), 1.87 (s, 6 H), 1.87 (m, 2 H), 1.42 (m, 6 H). LCMS (m / z): 749.4 [M + HJ ”.
[0579] [0579] In a 10 ml ampoule, 7- (3 - ((tert-butyldimethylsilyl) oxy) propoxy) -1- (5- (5-carbamoyl-2- (1-ethyl-3-methyl-) 1H-pyrazol-5-carboxamido) -1H-benzo [d] imidazol-1-yl) hexan-2-i1) -2- (1-ethyl-3-methyl-1H-pyrazol-5-carboxamido) -1H- benzo [d] imidazole-5-carboxamide (25 mg, 0.028 mmol, for example, intermediate 14B, second eluting diastereomer) and DMF (559 µL). To this heterogeneous solution, cesium carbonate (27.3 mg, 0.084 mmol) was added, followed by methyl iodide (4.37 µl, 0.070 mmol). The ampoule was capped, and the mixture was stirred overnight (-14 h) at room temperature. The mixture was diluted with DMSO (1 ml) and water (1 ml) to form a clear homogeneous solution. This solution was injected directly and purified by preparative reverse phase HPLC (biphasic ISCO system, 3% to 35% MeCN / water gradient with 0.1% NH4OH modifier). The corresponding fractions were combined and concentrated to obtain (E) -7- (3 - ((tert-butyldimethylsily) oxy) propoxy) -1 - (- 5 - ((E) -5-carbamoyl-2 - ((1- ethyl-3-methyl-1H-pyrazol-5-carbonyl) imino) -3-methyl-2,3-dihydro-1H-benzo [d] imidazol-1-yl) hexan-2-i1) -2 - (( 1-ethyl-3-methyl-1 H-pyrazol-5-carbonyl) imino) -3-methyl-2,3-dihydro-1H-benzo [d] imidazo | -5-carboxamide (18 mg, 0.019 mmol, 66 , 3% yield) as a white solid. LCMS: 923.4 [M + H] *, retention time 1.30 min (Acquity UPLC CSH C18 column, 1.7 µm, 50 mm x 2.1 mm; 3% to 95% gradient over 1.5 min, MeCN / 10 mM ammonium bicarbonate in water with pH adjusted to 10 with 25% ammonium hydroxide solution).
[0580] [0580] In a 20 ml ampoule, (E) -7- (3 - ((tert-butyldimethylsilyl)> oxy) propoxy) -1 - (- 5 - ((E) -5-carbamoyl-2) - (((1-ethyl-3-methyl-1H-pyrazol-5-carbonylN) imino) -3-methyl-2,3-dihydro-1H-benzo [d] imidazol-1-yl) hexan-2-i1) -2 - (((1-ethyl-3-methyl-1H-pyrazol-5-carbonyl) imino) -3-methyl-2,3-dihydro-1H-benzo [d] imidazole | -5-carboxamide (25 mg, 0.027 mmol) and MeOH (2 mL). To that solution, it was added
[0582] [0582] In a 20 ml ampoule, (E) -7- (3 - ((tert-butyldimethylsilyl) oxy) propoxy) -1 - (- 5 - ((E) -5-carbamoyl-2- ((1-ethyl-3-methyl-1H-pyrazol-5-carbonyl) imino) -3-methyl-2,3-dihydro-1H-benzo [d] imidazol | -1-yl) hexan-2-i1) -2 - ((1-ethyl-3-methyl-1H-pyrazol-5-carbonyl) imino) -3-methyl-2,3-dihydro-1H-benzo [d] imidazole | -5-
[0583] [0583] To a stirred suspension of 4-chloro-3-hydroxy-5-nitrobenzamide (30 g, 139 mmol) and potassium carbonate (57.4 g, 416 mmol) in DMF (200 mL) under nitrogen, was added at room temperature a solution of ((3-bromopropoxy) methyl) benzene (47.6 g, 208 mmol) dropwise over 1 minute. The reaction mixture was stirred at 80 ° C overnight. The reaction mixture was cooled to room temperature and quenched by the addition of 200 ml of water. The aqueous phase was then extracted with DCM (3 x 100 ml). The combined organic layer was washed with water (4 x 200 ml) and brine (200 ml), dried and concentrated in vacuo. The crude product was purified by chromatography on silica gel (100 g column, 1: 2 petroleum ether / EtOAc). The appropriate fractions were combined and concentrated to obtain 3- (3- (benzyloxy) propoxy) -4-chloro-5-nitrobenzamide (33 g, 90 mmol, 65.3% yield) as a yellow solid. LCMS (m / z): 365 [M + HJ ".
[0584] [0584] A suspension of 2,2,3,3-tetrafluorbutane-1,4-diamine (4 g, 24.98 mmol), 3- (3- (benzyloxy) propoxy) -4-chloro-5-nitrobenzamide ( 4.56 g, 12.49 mmol) and DIPEA (6 mL, 34.4 mmol) in isopropanol (18 mL) was stirred overnight in a sealed tube at 135º C. When cooled, the volatile substances were vacuum removed. The crude product was purified by chromatography on silica gel (20 g column, 60% to 100% EtOAc / petroleum ether gradient). The appropriate fractions were pooled and concentrated to obtain 4 - ((4-amino-2,2,3,3-tetrafluorbyl) amino) -3- (3- (benzyloxy) propoxy) -S-nitrobenzamide (3 g, 6, 14 mmol, 24.6% yield) as a reddish brown oil. LCMS (m / z): 489 [IM + HJ ”. Step 3: 3- (3- (benzyloxy) propoxy) d - ((4 - ((4-carbamoyl-2-nitrophenyl) amino) - 2,2,3,3-tetrafluorbyl) amino) -S-nitrobenzamide O.
[0585] [0585] A suspension of 4 - ((4-amino-2,2,3,3-tetrafluorbyl) amino) -3- (3- (benzyloxy) propoxy) -S-nitrobenzamide (3 g, 6.14 mmol) , 4-fluorine-3-nitrobenzamide (1.696 g, 9.21 mmol) and potassium carbonate (1.698 g, 12.28 mmol) in DMF (30 mL) was stirred under nitrogen at 60 ° C overnight. When cooled, water (50 ml) was added and the aqueous phase was extracted with EtOAc (2 x 100 ml). The combined organic layer was washed with water (3 x 200 ml) and brine (200 ml),
[0586] [0586] To a stirred suspension of 3- (3- (benzyloxy) propoxy) -4 - ((4 - ((4-carbamoyl-2-nitrophenyl) amino) -2,2,3,3-tetrafluorbutil) amino) -S-nitrobenzamide (1.9 g, 2.91 mmol) in acetic acid (20 mL) under nitrogen, solid zinc (1.904 g, 29.1 mmol) was added in one portion. The reaction mixture was stirred at 25 ° C for 2 h. Then, the reaction solution was filtered, and the filtrate was concentrated in vacuo to obtain 3-amino-4 - ((4 - (((2-amino-4-carbamoylphenyl) amino) -2,2,3,3- tetrafluorbyl) amino) -5- (3- (benzyloxy) propoxy) benzamide (1.5 g, 2.53 mmol, 87% yield) as a brown solid. LCMS (m / z): 593 [M + HJ *.
[0587] [0587] To a solution of 3-amino-4 - ((4 - ((2-amino-4-carbamoylphenyl) amino) - 2,2,3,3-tetrafluorbyl) amino) -5- (3- (benzyloxy ) propoxy) benzamide (2.1 g, 3.54 mmol) in MeOH (20 mL), cyanogen bromide (1.126 g, 10.63 mmol) was added. The reaction mixture was stirred at 25 ° C for 16 h. The mixture was diluted with diethyl ether (30 ml). The mixture was filtered, and the filter cake was washed with diethyl ether. The filtrate was concentrated under reduced pressure to obtain 2-amino-1- (4- (2-amino-5-carbamoyl-1H-benzo [d] imidazol-1-i1) -2,2,3,3-tetrafluorbyl) -7- (3- (benzyloxy) propoxy) -1H-benzo [d] imidazole-5-carboxamide (1.8 g, 2.381 mmol, 67.2% yield, -85% purity) as a solid Grey. The product was used directly without further purification. LCMS (m / z): 643 [M + HJ *.
[0588] [0588] To a solution of 1-ethyl-3-methyl-1H-pyrazol-5-carboxylic acid (0.864 g, 5.60 mmol), 2-amino-1- (4- (2-amino-5-carbamoyl) -1H-benzo [d] imidazole-1-11) -2,2,3,3-tetrafluorbyl) -7 - (3- (benzyloxy) propoxy) -1H-benzo [d] imidazole-5-carboxamide (1, 8.9, 2.80 mmol) and DIPEA (1.957 ml, 11.20 mmol) in DMF (20 ml), HATU (2.66 g, 7.00 mmol) was added. The reaction mixture was stirred at 60 ° C for 16 h. The mixture was poured into water. The precipitate was collected by filtration, washed with water, MeCN and diethyl ether and then vacuum dried to obtain 7- (3-
[0589] [0589] To a solution of 7- (3- (benzyloxy) propoxy) -1- (4- (5-carbamoyl-2- (1-ethyl-3-methyl-1H-pyrazol-5-carboxamido) -1H- benzo [d] imidazole | -1-i1) -2,2,3,3-tetrafluorbyl) -2- (1-ethyl-3-methyl-1H-pyrazol-5-carboxamido) -1H-benzo [d] imidazole -5-carboxamide (1.1 g, 1.2 mmol) in MeOH (30 ml) and NMP (10.0 ml), Pd on carbon (1.279 g) was added. The reaction was hydrogenated using the H-cube system (4 atm of hydrogen) at 60º C for 72 h. The mixture was diluted with DMF (20 ml). Then, the catalyst was removed by filtration, and the filtrate was concentrated under reduced pressure. The crude product was purified by preparative HPLC (Gemini-C18 column, 5 u silica, 21 x 150 mm, 10% to 60% MeCN / water gradient with 0.1% TFA modifier). The pure fractions were combined and evaporated to dryness to obtain 1- (4- (5- carbamoyl-2- (1-ethyl-3-methyl-1H-pyrazol-5-carboxamido) -1H-benzo [d] imidazole | - 1-yl) - 2,2,3,3-tetrafluorbyl) -2- (1-ethyl-3-methyl-1H-pyrazol-5-carboxamido) -7- (3-hydroxypropoxy) -1H-benzo [d] imidazole-5-carboxamide (75 mg, 0.086 mmol, 7.19% yield) as a pink solid. 1H NMR (400 MHz, DMSO) 5 13.06-
[0590] [0590] In an 8 ml ampoule, 1- (4- (5-carbamoyl-2- (1-ethyl-3-methyl-1H-pyrazol-5-carboxamido) -1H-benzo [d] imidazo | -1-i1) -2,2,3,3-tetrafluorbyl) -2- (1-ethyl-3-methyl-1H-pyrazol-5-carboxamido) -7- (3-hydroxypropoxy) -1H-benzo [ d] imidazo carboxamide (25 mg, 0.030 mmol), cesium carbonate (49.4 mg, 0.152 mmol) and DMF (1 mL). To this solution, methyl iodide (4.26 µL, 0.068 mmol) was added. The ampoule was capped, and the mixture was stirred at room temperature overnight (-14 hours). The sample was diluted with more DMF and purified directly by preparative mass-directed HPLC (XSELECT CSH C18 column, 5 µm packaging, 150x30 mm, 15% to 55% MeCN / water gradient with 0.1% TFA modifier) . The corresponding fractions were combined and concentrated in vacuo to obtain (E) -1- (4 - ((E) -5-carbamoyl-2 - ((1-ethyl-3-methyl-1H-pyrazol-5-carbonyl) imino ) -3-methyl-2,3-dihydro-1H-benzo [d] imidazo | -1-11) -2,2,3,3-tetrafluorbyl) -2 - ((1-ethyl-3-methyl-1 H-pyrazol-5-carbonyl) imino) -7- (3-hydroxypropoxy) -3-
[0591] [0591] To a solution of (E) -2- (4-amino-2,3-dimethylbut-2-en-1-yl) isoindoline-1,3-dione (5.7 g, 23.33 mmol) and 4-fluorine-3-nitrobenzamide (3.9 g, 21.18 mmol) in DMSO (65 ml), potassium carbonate (6.44 g, 46.6 mmol) was added. The reaction was stirred at room temperature for 3 h. The reaction mixture was poured into a flask containing 300 mL of rapidly stirring water. The mixture was stirred for 5 min and filtered, and the filtered solids were rinsed in sequence with water, diethyl ether (2x) and ethyl acetate (2x). The solid was collected, stirred in hexanes (30 mL), filtered and dried to obtain (E) —- 4 - ((4- (1,3-dioxoisoindolin-2-i1) -2,3-dimethylbut-2-en - 1-yl) amino) -3-nitrobenzamide (6.77 g, 16.6 mmol, 78% yield) as a bright yellow solid. LCMS (m / z): 409.2 [M + HI *.
[0592] [0592] To a suspension of (E) -4 - ((4- (1,3-dioxoisoindolin-2-yl) -2,3-dimethylbut- 2-en-1-yl)> amino) -3-nitrobenzamide (6.4 g, 15.67 mmol) in EtoH (100 mL), hydrazine monohydrate (0.84 mL, 17.2 mmol) was added. After 10 min, EtoOH (50 ml) was added to facilitate stirring. The reaction mixture was heated to 80º C for 20 h. The reaction was filtered while still warm, and the desired product was found in both the solids and the filtrate. The solids and the filtrate were combined, concentrated to dryness and used crude in the next reaction.
[0593] [0593] To a bright yellow suspension of (E) -4 - ((4-amino-2,3-dimethylbut-2-en-1-yl) amino) -3-nitrobenzamide (4.65 g 1053 mmol) and 4-chloro-3 - ((4-
[0594] [0594] To a suspension of (E) -4 - ((4 - ((4-carbamoyl-2-nitrophenyl) amino) -2,3-dimethylbut-2-en-1-yl) amino) -3- ( (4-methoxybenzyl) oxy) -S-nitrobenzamide (3.46 g, 5.98 mmol) in MeOH (25 mL) and acetic acid (20 mL), 1% Pt was added with V on activated carbon at 2 % (50% to 70% wet powder, 1.167 g, 0.060 mmol). The flask was shaken in a hydrogen atmosphere (hydrogen balloon) at room temperature for 6 h. MeOH (10 mL) was used to rinse the sides of the flask to remove solids from them, and stirring was continued for another 16 h. After removing the hydrogen, the reaction was filtered through diatomaceous earth, rinsed with MeOH and concentrated to obtain a thick orange oil. DCM (15 ml) was added and, with stirring, the resulting mixture was treated with saturated NaHCO3 solution (in 1 ml portions until the boiling stopped and the aqueous layer became basic). The liquid was decanted, and the remaining solid was partitioned between 3: 1 CHCIB: EtOH and brine. The organic layer was dried over sodium sulfate and concentrated to obtain a light brown foam. The foam was triturated with MeOH to obtain (E) -3-amino-4 - ((4 - (((2-amino-4-carbamoylphenyl) amino) -2,3-dimethylbut-2-en-1-yl) amino ) -5 - ((Amethoxybenzyl) oxy) benzamide (1.4 g, 2.70 mmol, 45.1% yield). LCMS (m / z): 519.4 [M + HJ *.
[0596] [0596] To a solution of (E) -1- (4- (5-carbamoyl-2- (1-ethyl-3-methyl-1H-pyrazol-5-carboxamido) -1H-benzo [d] imidazole | - 1-i1) -2,3-dimethylbut-2-en-1-i1) -2- (1-ethyl-3-methyl-1H-pyrazol-5-carboxamido) -7 - ((4-methoxybenzyl) oxy) -1H-benzo [d] imidazole | -5-carboxamide (1.30 g, 1.546 mmol) in DMF (12 mL), cesium carbonate (1.511 9,
[0597] [0597] To a suspension of (E) -1 - ((E) -4 - ((E) -S-carbamoyl-2 - ((1-ethyl-3-methyl-1H-pyrazol-5-carbonyl) imino ) -3-methyl-2,3-dihydro-1H-benzo [d] imidazole | -1-i1) -2,3-dimethylbut-2-en-1-i1) -2 - ((1-ethyl-3 -methyl-1 H-pyrazol-5-carbonyl) imino) -7 - ((4-
[0598] [0598] A (E) -2,3-dimethylbut-2-ene-1,4-diamine, 2 hydrochloride (4.4 g, 23.52 mmol) and ethanol (81 ml), a carbonate solution was added potassium (6.76 g, 48.9 mmol) in water (81 ml). Once all the solids had dissolved, 4-fluorine-3-nitrobenzamide (3.0 g, 16.29 mmol) was added in one portion to the purplish brown solution at room temperature. The reaction mixture was stirred at room temperature for 105 min, then heated to 50 ° C for 90 min and filtered. The filtrate was acidified with 6N HCI. The aqueous layer was washed with DCM (2x). The organic layers were extracted with water (1x). The combined aqueous layers were basified with 6 N NaOH and saturated sodium bicarbonate and extracted with a 3: 1 mixture of chloroform / ethanol (3x). The combined organic extracts were dried over sodium sulfate, filtered and concentrated to dryness to obtain (E) -4 - ((4-amino-2,3-dimethylbut-2-en-1-yl) amino) -3-nitrobenzamide (1.8 g, 5.80 mmol, 32.5% yield) as a brownish yellow residue. LCMS (m / z): 279.1 [M + HJ *. Step 2: (E) 3- (3 - ((tert-butyldimethylsili) oxy) propoxy) -4 - ((4 - ((4-carbamoyl-2-nitrophenyl) amino) -2,3-dimethylbut-2-en -1-yl) amino) -5-nitrobenzamide
[0599] [0599] To a suspension of (E) -4 - ((4-amino-2,3-dimethylbut-2-en-1-yl) amino) -3-crude nitrobenzamide (715 mg, 2.312 mmol) in 1- butanol (10.9 ml), DIE (1.14 ml, 6.56 mmol) was added. The mixture was stirred for 10 min, then 3- (3 - ((tert-butyldimethylsilyl) oxy) propoxy) -4-chloro-S-nitrobenzamide (850 mg, 2.186 mmol) was added. The reaction mixture was heated to 120 ° C overnight. The reaction was cooled to room temperature, and an orange solid precipitated. The mixture was filtered, and the filter cake was washed with ethyl acetate to obtain (E) -3- (3 - ((tert-butyldimethylsilyl) oxy) propoxy) -4 - ((4 - (((4-carbamoyl- 2-nitrophenyl) amino) -2,3-dimethylbut-2-en-1-yl) amino) -5-crude nitrobenzamide (786 mg, 1.022 mmol, 46.8% yield) as a bright orange solid, still containing residual n-BuOH, but which was used in the next step anyway. LCMS (m / z): 631.3 [M + HJ *.
[0600] [0600] To a mixture of (E) -3- (3 - ((tert-butyldimethylsilyl) oxy) propoxy) -4 - ((4 - ((4-carbamoyl-2-nitrophenyl) amino) -2,3- dimethylbut-2-en-1-yl) amino) -5-nitrobenzamide (1.82 g, 2.453 mmol) in methanol (53.3 ml), ammonium chloride (2.62 g, 49.1 mmol) was added ), followed by the addition of zinc (3.21 g, 49.1 mmol). The heterogeneous mixture was stirred at room temperature for 10 min. The reaction mixture was filtered, and the filter cake was washed with methanol. The filtrate was dry loaded on silica gel and purified by silica gel chromatography (80 g column, 0% to 20% methanol,
[0601] [0601] To a solution of (E) -3-amino-4 - ((4 - (((2-amino4-carbamoylphenyl)> amino) -2,3-dimethylbut-2-en-1-yl) amino) - 5- (3 - ((tert-butyldimethylsilyl) oxy) propoxy) benzamide (500 mg, 0.876 mmol) in DMF (8.8 ml) at 0 ° C, 1-ethyl- isothiocyanate is added dropwise and in portions 3-methyl-1H-pyrazol-5-carbonyl in dioxane (-0.4 M, 4.82 ml, 1.93 mmol). After 15 min, more isothiocyanate (-0.4 M, 400 µL) was added, and the reaction mixture was stirred for 10 min. The reaction was treated with EDC (420 mg, 2,190 mmol) and TEA (610 µl, 4,388 mmol) and stirred at room temperature over the weekend. The reaction mixture was poured into 4: 1 of water / saturated ammonium chloride (200 mL), and the resulting suspension was filtered. The filter cake was dried under nitrogen flow to obtain (E) -7- (3 - ((tert-butyldimethylsilyl) oxy) propoxy) -1- (4- (5-carbamoyl-2- (1-ethyl-3 -methyl-1H-pyrazol-5-carboxamido) -1H-benzo [d] imidazole | -1-i1) -2,3-dimethylbut-2-en-1-i1) -2- (1-ethyl-3- methyl-1H-pyrazol-5-carboxamido) -1H-benzo [d] imidazole-S5-carboxamide (614 mg, 0.687 mmol, 78% yield). 1H NMR (400 MHz, DMSO-ds) 5 ppm 12.92 (d, J = 11.66 Hz, 2 H), 7.99 - 8.08 (m, 2 H), 7.90 (br. s., 1 H), 7.70 (s, 1 H), 7.65 (d, J = 8.11 Hz, 1 H),
[0602] [0602] A mixture of (E) -7- (3 - ((tert-butyldimethylsilyl) oxy) propoxy) -1- (4- (5-carbamoyl-2- (1-ethyl-3-methyl-1H-pyrazole -5-carboxamido) -1H-benzo [d] imidazo | -1-11) -2,3- dimethylbut-2-en-1-i1) -2- (1-ethyl-3-methyl-1 H-pyrazole -5-carboxamido) -1H-benzo [d] imidazole-5-carboxamide (0.245 g, 0.274 mmol), cesium carbonate (0.268 g, 0.823 mmol) and methyl iodide (0.043 mL, 0.686 mmol) in DMF (2 mL) was stirred at room temperature for 18 h. The reaction mixture was partitioned between EtOAc (20 ml) and brine (20 ml). The aqueous layer was extracted with EtOAc (2x10 ml). The combined EtOAc layer was dried over magnesium sulfate, filtered and concentrated in vacuo. The crude product was purified by silica gel chromatography (40 g HP RediSepRf High Performance Gold silica column, 40% to 80% gradient (3: 1 ethanol / ethyl acetate / hexane with 2% NHXOH modifier) to obtain (E) -7- (3- ((tert-butyldimethylsilyl) oxy) propoxy) -1 - ((E) -4 - ((E) -5-carbamoyl-2 - ((1-ethyl-3- methyl-1H-pyrazol-5-carbonyl) imino) -3-methyl-2,3-dihydro-1H-benzo [d] imidazo | -1-11) -2,3-dimethylbut- 2-en-1-i1 ) -2 - ((1-ethyl-3-methyl-1 H-pyrazol-5-carbonyl) imino) -3-methyl-2,3-dihydro-1H-
[0603] [0603] To a mixture of (E) -7- (3 - ((tert-butyldimethylsilyl) oxy) propoxy) -1 - ((E) -4- ((E) -5-carbamoyl-2 - ((1 -ethyl-3-methyl-1 H-pyrazol-5-carbonyl) imino) -3-methyl-2,3-dihydro-1H-benzo [d] imidazo | -1-i1) -2,3-dimethylbut-2 -en-1-i1) -2 - ((1-ethyl-3-methyl-1H-pyrazol-5-carbonyl) imino) -3-methyl-2,3-dihydro-1H-benzo [d] imidazole-5 -carboxamide - (0.030 9, 0.033 mmol) in MeOH (0.5 mL), HCl in dioxane (4 M, 0.163 mL, 0.651 mmol) was added, stirred at room temperature for 16 h. The reaction mixture was concentrated in vacuo. The crude product was purified by chromatography on silica gel (RediSepRf High Performance Gold 40 g HP silica column, 40% to 90% gradient (3: 1 ethanol / ethyl acetate / hexane with 2% NHOH modifier) to obtain (E) -1 - ((E) -4 - ((E) -5-carbamoyl-2 - ((1-ethyl-3-methyl-1 H-pyrazol-5-carbonyl) imino) -3- methyl-2,3-dihydro-1H-benzo [d] imidazole | -1-i1) -2,3-dimethylbut-2-en-1-i) - 2 - ((1-ethyl-3-methyl-1H -pyrazol-5-carbonyl) imino) -7- (3-hydroxypropoxy) -3-methyl-2,3-dihydro-1H-benzo [d] imidazole-5-carboxamide (0.007 g, 7.72 umol, 23, 7% yield) 1H NMR (600 MHz, DMSO-ds) 5 8.12 (s, 2 H), 8.03 (br s, 1 H), 7.81 (d, J = 8.66 Hz, 1H), 7.78 (s, 1 H), 7.50 (s, 1 H), 7.47 (s, 1 H), 7.45 (br s, 1 H), 7.24 ( d, J = 8.85 Hz, 1 H), 6.68 (br s, 1 H), 6.45 (s, 1 H), 6.34 (s, 1 H), 5.06 (br s , 2 H), 4.85 (s, 2 H), 4.49-
[0604] [0604] Table 1 shows Examples 21 to 28, which can be prepared according to the methods given below: Scheme No. Name / Structure NMR of * H Example LCMS (m / z) [IM + HT "Example | Method 1 | (E) -1- (4- (5-carbamoyl-2 - ((1-ethyl-3- | 1H NMR (400 MHz, 21 methyl-1H-pyrazol-5-METHANOL-da) 5 ppm carbonyl ) imino) -3-methyl-2,3-1,37 (dt, J = 11.15, 7.10 dihydro-1H-benzo [d] imidazole-1-i1) - | Hz, 6 H) 2, 22 (s, 6 H) 2,2,3,3-tetrafluorbyl) -2- (1-ethyl-3- | 3.72 (s, 3 H) 4.54 - 4.72 methyl-1H-pyrazole- 5-carboxamido) - | (m, 4 H) 5.12 - 5.43 (m, 1H-benzo [d] imidazole-5- 4 H) 6.68 (s, 1 H) 6.74 carboxamide, salt of acid | (s, 1H) 7.54 (d, J = 8.87 trifluoroacetic Hz, 1 H) 7.62 (d, J = 8.11, Hz, 1 H) 7.88 (d, J = 8.36 PARIS Hz, 1 H) 7.97 (d, J = 8.62 SA Hz, 1 H) 8.03 (s, 1 H) A 8.12 (s, 1H)
[0607] [0607] To a light brown solution of (E) -3-amino-4 - ((4 - (((2-amino-6 - (((4-methoxybenzyl) oxy) phenyl) amino) -2,3-dimethylbut- 2-en-1-yl) amino) benzamide (1.93 g, 3.86 mmol) in DMF (20 mL) cooled in an ice / water bath, 1-ethyl-3-methyl-1H isothiocyanate was added -pyrazole-S-carbonyl (-1 M in dioxane, 7.71 mL, 7.71 mmol) quickly dropwise (over -1 minute). The reaction mixture was stirred for 25 minutes. EDC (1.848 g, 9.684 mmol) and TEA (2.69 mL, 19.28 mmol) were added, and the reaction mixture was warmed to room temperature and stirred for 18 h. The reaction mixture was poured into 1: 1 of saturated aqueous NHaCl solution: water (100 mL) with rapid stirring to obtain a fine precipitate. The precipitate was washed with water (2 x 15 ml), triturated twice with ethyl acetate (20 ml) and dried to obtain (E) -2- (1-ethyl-3-methyl-1H-pyrazol-5- carboxamido) -1- (4- (2- (1-ethyl-3-methyl-1H-pyrazol-5-carboxamido) -7 - ((4-methoxybenzyl) oxy) -1H-benzo [d] imidazo | -1 -i1) -2,3-dimethylbut-2-en-1-i1) -1H-benzo [d] imidazo | -5-carboxamide (2.32 9, 2.83 mmol, 73% yield) as a brown solid. LCMS (m / z): 798.4 [M + H]) *.
[0608] [0608] To a solution of (E) -2- (1-ethyl-3-methyl-1H-pyrazol-5-carboxamido) -1- (4- (2- (1-ethyl-3-methyl-1H- pyrazol-5-carboxamido) -7 - ((4-methoxybenzyl) oxy) -1H-benzol [d] imidazo | -1-i1) -2,3-dimethylbut-2-en-1-i1) -1H-benzo [d] imidazole | -5-carboxamide (1.09 g, 1.366 mmol) in DMF (15 mL), cesium carbonate (1.335 9, 4.10 mmol) and methyl iodide (0.214 mL, 3, 42 mmol). The reaction mixture was stirred at room temperature for 5 h. More methyl iodide (0.060 mL, 0.956 mmol) was added, and the mixture was stirred for an additional 18 h. More methyl iodide (0.060 mL, 0.956 mmol) and cesium carbonate (1.335 g, 4.10 mmol) were added and the mixture was heated at 50 ° C for 4 h. The mixture was diluted with water (30 ml), and a sticky solid precipitated. Vigorous stirring produced a filterable solid, which was subsequently collected in a filter and rinsed with water. Chromatography on silica gel (40 g silica, 10% to 90% gradient of [3: 1 EtOAc: EtoH] / heptane) produced (E) -2 - ((1-ethyl-3-methyl-1H- pyrazol-5-carbonyl) imino) -1- ((E) -4 - ((E) -2 - ((1-ethyl-3-methyl-1H-pyrazol-5-carbonyl) imino) -7 - (( 4-methoxybenzyl) oxy) -3-methyl-2,3-dihydro-1H-benzo [d] imidazo | -1-i1) -2,3-dimethylbut-2-en-1-i1) -3-methyl- 2,3-dihydro-1H-benzo [d] imidazole | -5-carboxamide (430 mg, 0.50 mmol, 37% yield) as a brown foam. 1H NMR (400 MHz, DMSO-ds) ppm 8.14 (s, 1 H), 8.01 (br. S., 1 H), 7.78 (dd, J = 8.4, 1.4 Hz, 1 H), 7.45 (br., 1 H), 7.25-7.32 (m, 1 H), 7.13-7.23 (m, 4 H), 7.08 (d, J = 8.0 Hz, 1 H), 6.71 (d, J = 8.5 Hz, 2 H), 6.43 (s, 1 H), 6.37 (s, 1 H) , 5.03 (s, 2 H), 4.97 (s, 2 H), 4.78 (s, 2 H), 4.45-4.53 (m, 4 H), 3.63 (s , 3 H), 3.60 (s, 3 H), 3.54 (s, 3 H), 2.10 (s, 3 H), 2.09 (s, 3 H), 1.56 (s , 3 H), 1.19-1.31 (m, 6 H), 1.48 (s, 3 H). LCMS (m / z): 826.5 [M + HJ *.
[0609] [0609] To a suspension of (E) -2 - ((1-ethyl-3-methyl-1H-pyrazol-5-carbonyl) imino) - 1 - ((E) -4 - ((E) -2- ((1-ethyl-3-methyl-1H-pyrazol-5-carbonyl) imino) -7-hydroxy-3-methyl-2,3-dihydro-1H-benzo [d] imidazo | -1-i1) -2 , 3-dimethylbut-2-en-1-i1) -3-methyl-2,3-dihydro-1H-benzo [d] imidazole-5-carboxamide (45 mg, 0.055 mmol) in DMF (1 mL), added (bromomethyl) benzene (7.26 µl, 0.061 mmol), followed by potassium carbonate (9.97 mg, 0.072 mmol). The reaction mixture was initially stirred at 50º C for 3 h and then at room temperature for 16 h. The mixture was diluted with water. The aqueous layer was extracted several times with 3: 1 CHClz: EtOH. The solvents were evaporated in vacuo, and the residue was purified by mass directed HPLC (XSELECT CSH C18 column, 5 µm packaging, 150x30 mm, 30% to 85% MeCN / water gradient with 0.1% TFA modifier ). A few drops of saturated sodium bicarbonate solution were added to each clean fraction. ACN was removed using nitrogen flow. The suspended solids were filtered, rinsed with water and dried to obtain (E) -1 - ((E) -4 - ((E) -7- (benzyloxy) -2 - ((1-ethyl-3-methyl-1H -pyrazol-S-carbonyl) imino) -3-methyl-2,3-dihydro-1H-benzo [d] imidazo | -1-i1) -2,3-dimethylbut-2-en-1-i1) -2 - (((1-ethyl-3-methyl-1 H-pyrazol-5-carbonyl) imino) -3-methyl-2,3-dihydro-1H-benzo [d] imidazole-5-carboxamide (30 mg, 0.037 mmol, 67%) as a white solid. * H NMR (400 MHz, DMSO-ds) 5 ppm 8.12 (s, 1 H), 8.01 (br. S., 1 H), 7.76 (dd, J = 8.4, 1 , 4 Hz, 1 H), 7.44 (br., 1 H), 7.12-7.32 (m, 8 H), 7.07 (d, J = 7.8
[0610] [0610] A (E) - (4-amino-2,3-dimethylbut-2-en-1-yl) tert-butyl carbamate (0.5 g, 2.33 mmol) in ethanol (11.67 mL ), 1-bromo-3-fluorine-2-nitrobenzene (0.529 g, 2.33 mmol) and DIEA (1.22 mL, 7.00 mmol) were added. The mixture was stirred at 80 ° C for 18 h. The mixture was partitioned between ethyl acetate (50 ml) and brine (20 ml). The aqueous layer was extracted with EtOAc (2 x 10 ml). The combined EtOAc layers were dried over magnesium sulfate, filtered and concentrated. The residue was purified by chromatography on silica gel (40 g silica, 10% to 20% ethyl acetate / hexane gradient) to obtain (E) - (4 - ((3-bromo-2-nitrophenyl) amino ) Tert-butyl carbamate -2,3-dimethylbut-2-en-1-yl (0.740 g, 1.78 mmol, 77% yield). LCMS (m / z): 414.1 [M + HJ *.
[0611] [0611] JA (E) - (4 - ((3-bromo-2-nitrophenyl) amino) -2,3-dimethylbut-2-en-1-yl) tert-butyl carbamate (0.44 g, 1 , 06 mmol) in methanol (5 mL), 4 M HCI in dioxane (1.06 mL, 4.25 mmol) was added. The mixture was stirred at room temperature for 3 h. More 4 M HCl in dioxane (1.0 mL, 4.0 mmol) was added and stirred for an additional 3 hours. The reaction mixture was concentrated in vacuo to remove HCl and solvents. To this residue, 4-fluoro-3-nitrobenzamide (0.214 g, 1.46 mmol), DIEA (0.927 mL, 5.31 mmol) and 1-butanol (15 mL) were added, and the mixture was stirred at 110 ° C for 16 h. The mixture was partitioned between ethyl acetate (50 ml) and brine (20 ml). The aqueous layer was extracted with EtOAc (2 x 10 ml). The combined EtOAc layers were dried over magnesium sulfate, filtered and concentrated. The concentration produced a precipitate, which was filtered and dried to obtain (E) 4 - ((4 - ((3-bromo-2-nitrophenyl) amino) -2,3-dimethylbut-2-en-1- i) jamino ) -3-nitrobenzamide (0.40 g, 0.836 mmol, 79% yield) as a solid. LCMS (m / z): 478.1 [M + HJ *. Step 3: (E) -3-amino-4 - ((4 - ((2-amino-3-bromophenyl) amino) -2,3-dimethylbut-2-en-1-i) amino) benzamide o. "ho 4 NH Br
[0612] [0612] JA (E) -4 - ((4 - (((3-bromo-2-nitrophenyl) amino) -2,3-dimethylbut-2-en-1-iN)> amino) -3-nitrobenzamide (0.050 g, 0.105 mmol) in methanol (1.6 mL),
[0615] [0615] To a suspension of (E) -1- (4-aminobut-2-en-1-i1) -2- (1-ethyl-3-methyl-1 H-pyrazol-5-carboxamido) -7- methoxy-1H-benzo [d] imidazole-5-carboxamide, 2 hydrochloride (10.4 g, 21, A7 mmol) in 1-butanol (150 mL) at room temperature, DIEA (7.50 mL, 42 , 9 mmol). The reaction mixture was then stirred at room temperature for 2 h. 3- (3 - ((tert-butyldimethylsilyl) oxy) propoxy) -4-chloro-5-nitrobenzamide (10.9 g, 28.0 mmol) and then sodium bicarbonate (5.41 9, 64.4 mmol). After that, the reaction mixture was stirred at 100 ° C for 4 days. The reaction mixture was cooled to room temperature and concentrated. The resulting orange sludge was suspended in acetonitrile and then filtered. The solid was washed with acetonitrile and water. After that, the solid was dried to obtain (E) -1- (4 - ((2- (3 - ((tert-butyldimethylsilyl) oxy) propoxy) -4-carbamoyl-6-nitrophenyl) amino) but-2- en-1-i1) -2- (1-ethyl-3-methyl-1H-pyrazol-5-carboxamido) -7-methoxy-1H-benzo [d] imidazole-5-carboxamide (10.94 g, 14, 32 mmol, 67% yield) as a reddish orange solid. * H NMR (400MHz, DMSO-ds) 5 ppm 13.27 - 12.18 (m, 1 H), 8.14 (d, J = 1.8 Hz, 1 H), 7.97 (br. s., 2 H), 7.78 - 7.62 (m, 2 H), 7.49 (d, J = 1.8 Hz, 1 H), 7.38 - 7.24 (m, 3 H ), 6.60 (s, 1 H), 5.92 - 5.63 (m, 2 H), 4.90 (d, J = 5.3 Hz, 2 H), 4.58 (q, J = 7.1 Hz, 2 H), 4.13 (t, J = 5.4 Hz, 2 H), 4.00 (t, J = 6.0 Hz, 2 H), 3.87 (s, 3 H), 3.64 (t, J = 6.1 Hz, 2 H), 2.16 (s, 3 H), 1.82 (quin, J = 6.0 Hz, 2 H), 1, 33 (t, J = 7.0 Hz, 3 H), 0.79 (s, 9 H), -0.05 (s, 6 H). LCMS (m / z): 764.7 [M + HJ *.
[0616] [0616] To a suspension of (E) -1- (4 - ((2- (3 - ((tert-butyldimethylsilyl) oxy) propoxy) - 4-carbamoyl-6-nitrophenyl) amino) but-2-en- 1-i1) -2- (1-ethyl-3-methyl-1 H-pyrazol-5-carboxamido) -7-methoxy-1H-benzo [d] imidazole-5-carboxamide (10.1 g, 13.22 mmol) in methanol (200 mL) being stirred at 60 ° C, a solution of sodium dithionite (25.0 g, 121 mmol) in water (200 mL) was added. After that, the reaction mixture was stirred at the same temperature for 1 h. After that, the reaction mixture was cooled to room temperature and quenched with 500 ml of water. The resulting mixture was filtered. The collected solid was washed with water (500 ml x 3) and then rinsed with diethyl ether (300 ml). After that, the solid was dried in the vacuum oven to obtain (E) -1- (4 - ((2-amino-6- (3 - ((tert-butyldimethylsilyl) oxy) propoxy) -4-carbamoylphenyl) amino) but-2-en-1-yl) -2- (1-ethyl-3-methyl-1 H-pyrazol-5-carboxamido) -7-methoxy-1H-benzo [d] imidazole | -5-carboxamide partially pure (7.36 g, - 10 mmol, 76% yield) as a light brown solid. The approximate purity of the title compound by LCMS was 63% (UV, m / z = 734.6 [M + H] *) along with 20% (UV, m / z = 620.5 [M + H] * ) of the by-product unprotected by silyl. The mixture was used in the next reaction without further purification.
[0617] [0617] JA a solution of (E) -1- (4 - ((2-amino-6- (3 - ((tert-butyldimethylsilyl) oxy) propoxy) -4-carbamoylphenyl) amino) but-2-en- 1-i1) -2- (1-ethyl-3-methyl-1H-pyrazol-5-carboxamido) -7-methoxy-1H-benzo [d] imidazole-5-carboxamide (7.36 g, 10.03 mmol , -76% purity) in DMF (60 mL) at room temperature, a 1 M solution of 1-ethyl-3-methyl-1H-pyrazole-S5 isothiocyanate was added dropwise through an addition funnel -carbonyl (15.1 mL, 15.10 mmol) in 1.4 dioxane. The reaction mixture was then stirred at room temperature for 1 h. To the reaction mixture, EDC (3.84 g, 20.06 mmol) and TEA (5.6 mL, 40.2 mmol) were then added at room temperature. The reaction mixture was stirred at room temperature for 48 h. The reaction mixture was diluted with EtOAc and washed with water. A solid was removed by filtration and identified as the alcohol derivative unprotected by silyl. The organic layer was then washed a second time. The combined aqueous layers were extracted back with EtOAc (1x). The combined organic matter was washed with brine, dried over magnesium sulfate and concentrated. The crude and solid product isolated earlier in the work-up was suspended in EtOH and filtered. The solid was washed with EtOH and then dried to obtain an off-white solid (6.0 g). A second crop of solid was also obtained (824 mg). The composition of the combined mixture (6.8249, -7.6 mmol, 76%) was characterized by LCMS and NMR as a mixture about 3: 1 of (E) - 7- (3 - ((tert-butyldimethylsilyl) ox ) propoxy) -1- (4- (5-carbamoyl-2- (1-ethyl-3-methyl-1H-pyrazol-5-
[0618] [0618] To a solution of (E) -7- (3 - ((tert-butyldimethylsily) oxy) propoxy) -1- (4- (5-carbamoyl-2- (1-ethyl-3-methyl-1H- pyrazol-5-carboxamido) -7-methoxy-1H-benzo [d] imidazol-1-yl) but-2-en-1-11) -2- (1-ethyl-3-methyl-1 H-pyrazole- 5-carboxamido) -1H-benzo [d] imidazo | -5-carboxamide (6.0 g, 6.70 mmol, as a 3: 1 mixture of silyl ether / alcohol) in THF (50 mL) at room temperature , 4 M HCl solution in dioxane (8.4 mL, 33.6 mmol) was added. The reaction mixture was then stirred at room temperature for 5 h. More HCI solution (4.2 ml, 16.80 mmol) was added and the reaction mixture was stirred overnight. More HCI solution (4.2 mL, 16.80 mmol) was added, and the reaction mixture was stirred for 24 h. More HCI solution (8.4 mL, 33.6 mmol) was added. The mixture was stirred at room temperature for 1 h and then at 40º C for 5 h. More HCI solution (8.4 mL, 33.6 mmol) was added, and the reaction mixture was stirred at 40 ° C over the weekend. The reaction mixture was cooled to room temperature, then filtered. The solid was washed with THF and dried to obtain (E) -1- (4- (5-carbamoyl-2- (1-ethyl-3-methyl-1H-pyrazol-5-carboxamido) -7- (3-hydroxypropoxy ) -1H-benzo [d] limidazol-1-yl) but-2-en-1-i1) -2- (1-ethyl-3-methyl-1 H-pyrazol-5-carboxamido) -7-methoxy- 1H-benzo [d] imidazole-5-carboxamide, 2 hydrochloride (5.6 g, 6.56 mmol, 98% yield) as a white solid * H NMR (400MHz, DMSO-ds) 5 ppm 7, 98 (br. S., 2 H), 7.65 (dd, J = 1.1, 3.6 Hz, 2 H), 7.33 (s, 4 H), 6.53 (d, J = 1.5 Hz, 2 H), 5.86 - 5.81 (m, 2 H), 4.93 (dd, J = 3.8, 6.8 Hz, 4 H), 4.57 - 4, 47 (m, 4 H), 4.07 (t, J = 6.4 Hz, 2H), 3.75 (s, 3 H), 3.49 - 3.42 (m, 2 H), 2, 11 (two s, 6 H), 1.80 - 1.64 (m, 2 H), 1.27 (two t, J = 7.2 Hz, 6 H). LCMS (m / z): 781.7 [M + HJ ".
[0619] [0619] To a suspension of (E) -1- (4- (5-carbamoyl-2- (1-ethyl-3-methyl-1H-pyrazol-5-carboxamido) -7- (3-hydroxypropoxy) -1H -benzo [d] imidazol | -1-yl) but-2-en-1-11) -2- (1-ethyl-3-methyl-1H-pyrazol-5-carboxamido) -7-methoxy-1H-benzo [d] imidazole | -5-carboxamide, 2 hydrochloride (5.45 g, 6.38 mmol) and cesium carbonate (10.40 g, 31.9 mmol) in DMF (35 mL) at 0 ° C using a water bath ice, methyl iodide (0.918 mL,
[0620] [0620] To a suspension of (E) -1 - ((E) -4 - ((E) -5-carbamoyl-2 - ((1-ethyl-3-methyl-1H-pyrazol-5-carbonyl) imino ) -7- (3-hydroxypropoxy) -3-methyl-2,3-dihydro-1H-benzo [d] imidazol-1-yl) but-2-en-1-i1) -2 - ((1-ethyl -3-methyl-1 H-pyrazol-S-carbonyl) imino) -7-methoxy-3-methyl-2,3-dihydro-1H-benzo [d] imidazole | -5-carboxamide (5.2 g, 6 , 43 mmol) in tert-butanol (52 mL) and water (13 mL), NMO (1.130 g, 9.64 mmol) was added. After stirring for 5 min at room temperature, 2.5% osmium tetroxide in tert-butanol (4.04 mL, 0.321 mmol) was added, and the mixture was stirred for 18 h. After concentration, the residue was suspended in water and filtered. The collected solid was rinsed with water and dried under vacuum to obtain (E) -1- (4 - ((E) -5-carbamoyl-2 - ((1-ethyl-3-methyl-1H-pyrazol-S5-carbonyl) ) imino) -7- (3-hydroxypropoxy) -3-methyl-2,3-dihydro-1H-benzol [d] imidazo | -1-i1) -2,3-dihydroxybutyl) -2 - ((1-ethyl -3-methyl-1H-pyrazol-5-carbonyl) imino) -7-methoxy-3-methyl-2,3-dihydro-1H-benzo [d] imidazole | -5-carboxamide (4.0 g, 73, 8% yield) as a mixture of stereoisomers. LCMS (-90% UV210-350 nm purity; m / z): 843.2 [M + HJ *.
[0621] [0621] For registration and screening, a 1,500 mg portion of crude product was separated into separate enantiomers by a two-step sequence of preparative HPLC purification. First purification step
[0622] [0622] The purpose of this step was to separate the desired racemic mixture of enantiomers from several smaller by-products that eluted close to the coeluting enantiomer pair. The following methods were employed: HPLC method HPLC method Preparative analytical HPLC method Analytical 1 Input: 1,500 mg of System: prep-HPLC System: HPLC Agilent crude product (Agilent 1100 1100 mixture of stereoisomers) Column: Chiralpak IC 5p Column: Phenomenex System: 4.6 x 150 mm system Luna C18 (2) 37, 4.6 x prep-HPCL Agilent 1200 | Solvents: 150 mm methanol Column: Chiralpak IC 5p | 100% Solvents: A = H2O (TFA x 250 mm Flow rate: 1.0 mL / 0.1% imine |); B = CH; CN (TFA Solvent: methanol a Detector: uv 254 nm at 0.1%) 100% Temperature: temperature | Gradient: Flow rate: 45 ambient Time (min); % B mL / min Injection: 5 ul O min; 20% B Detector: uv 254 nm Retention time: 7 min; 20% B Temperature: Racemic enantiomers: 20 min; 90% B at room temperature 4.9 min 21 min; 20% B Injection: 30 injections Flow rate: 1.0 mL / min 50 mg of crude product Detector: uv 254 nm in 4 mL of methanol Temperature: temperature Retention time: 7.1 min environment Injection: 5 ul Time retention time: 5.08 min desired product
[0623] [0623] Outcome: The purest fractions were combined and concentrated to a volume of 10 mL. The resulting precipitate was filtered and dried at 35 ° C to obtain a racemic mixture of enantiomers (600 mg, 0.71 mmol). A C18 HPLC method (Method 2) was also used to demonstrate the effectiveness of the purification (98.95% purity). LCMS (m / z): 843.3 [M + HJ] *. A similar treatment of fractions with slightly lower purity (i.e., frontal and final fractions) produced additional amounts of the racemic mixture of enantiomers (310 mg).
[0624] [0624] Second purification step: The purpose of this step was to separate and isolate each enantiomer. The following methods were employed: Preparative HPLC method Analytical HPLC method Input: 520 mg racemic mixture | System: Agilent 1100 prep-HPLC purified enantiomers Column: Chiralpak IC 5p 4.6 x 150 mm System: Agilent 1100 prep-HPLC Solvents: A = DCM; B = EtOH; 12% B, Column: Chiralpak IC 5py 30 x 250 mm | 88% A Solvents: A = DCM; B = EtOH; 12% | Flow rate: 1.0 mL / min B, 88% À Detector: uv 254 nm Flow rate: 45 mL / min Temperature: room temperature Detector: uv 254 nm Injection: 10 ul Temperature: room temperature Retention times: Injection : 10 injections of 52 mg (in 2 First eluting enantiomer: ml of EtOH and 3 ml of DCM) 4.6 min Retention times: Second eluting enantiomer: First eluting enantiomer: 5.9 min
[0625] [0625] Outcome: The pure fractions of each enantiomer were concentrated and dried under high vacuum at 40º C to obtain the following solids. The attribution of absolute stereochemistry was made possible by the subsequent resynthesis from chiral building blocks Example 32 (first isomer eluting): the Ea) HAN ”x IA N o S“. S so u O Ns Y
[0626] [0626] To a solution of tert-butyl (E) - (4-aminobut-2-en-1-yl) carbamate (2.2 g, 11.81 mmol) and DIEA (4.37 mL, 25, 00 mmol) in isopropanol (30 mL) at 25 ° C, 1-bromo-2-fluoro-3-nitrobenzene (2.5 g, 11.36 mmol) was added. After that, the reaction mixture was stirred at 25 ° C for 4 days. The reaction mixture was concentrated. The resulting material was divided between water and EtOAc. The aqueous layer was separated and extracted with EtOAc (1x). The combined organic layers were then washed with brine, dried with magnesium sulfate and concentrated to obtain (E) - (4 - ((2-bromo-6-nitrophenyl) amino) but-2-en-1-yl) carbamate tert-butyl (4.6 g, 12 mmol, 100% yield) as a yellow solid. The isolated material was used without further purification. LCMS (m / z): 332.0 ([M + H] J * - t-butyl). Step 2: (T) - (4 - ((2-amino-6-bromophenyl) amino) but-2-en-1-yl) tert-butyl carbamate NH Soo O — M € AEO
[0627] [0627] To a mixture of tert-butyl (E) - (4 - ((2-bromo-6-nitrophenyl) amino) but-2-en-1-yl) carbamate (4.4 g, 11.39 mmol) and ammonium chloride (6.09 g, 114 mmol) in methanol (50 mL), zinc (7.45 g, 114 mmol) was added. After that, the reaction mixture was stirred at room temperature for 30 min. The reaction mixture was filtered and concentrated. The isolated residue was divided between EtOAc and water. The aqueous layer was separated, and the organic layer was washed with water a second time. The combined aqueous layer was extracted with EtOAc (1x). The combined organic layer was then washed with brine, dried over magnesium sulfate, filtered and concentrated to obtain the crude title compound (4.0 g, -11.23 mmol) as a light brown oil. LCMS (77% UV210-350 nm purity; m / z): 356.1 [M + H] *. The product was used without further purification. Step 3: (E) - (4- (7-bromo-2- (1-ethyl-3-methyl-1H-pyrazol-5-carboxamido) -1H-benzo [d] imidazol | -1-yl) but- 2-en-1-yl) tert-butyl carbamate
[0628] [0628] To a solution of tert-butyl (E) - (4 - ((2-amino-6-bromophenyl) amino) but-2-en-1-yl) carbamate (4.0 g, 11.23 mmol) in DMF (40 mL) at room temperature, a solution of 1-ethyl-3-methyl-1H-pyrazol-5-carbonyl isothiocyanate (1 M in 1,4-dioxane, 12.4 mL, 12.40 mmol). After that, the reaction mixture was stirred for 45 min. To the reaction mixture, EDC (3.23 g, 16.84 mmol) and TEA (4.7 mL, 33.7 mmol) were then added at room temperature. After stirring for 2 h, the mixture was diluted with EtOAc and washed with water (2x). The combined aqueous layer was extracted back with EtOAc (1x). The combined organic layer was washed with brine, dried over magnesium sulfate, filtered and concentrated. The residue was purified by normal phase chromatography (ISCO CombiFlash, 120 gq Gold column, DCM / MeOH) to obtain the title compound (4.5 g, 8.70 mmol, 77% yield) as a solid whitish after solvent evaporation. LCMS (m / z): 517.2 [M + HJ *.
[0629] [0629] To a solution of (E) - (4- (7-bromo-2- (1-ethyl-3-methyl-1H-pyrazol-5-carboxamido) -1H-benzo [d] imidazol-1-yl ) tert-butyl carbamate (1.1 g, 2.126 mmol) in methanol (10 mL) at room temperature, but-2-en-1-yl), HCI (4 M in dioxane, 5.00 mL, 20 mmol). The reaction mixture was then stirred at room temperature overnight. The reaction mixture was concentrated in vacuo and suspended in diethyl ether. The resulting solid was filtered, washed with diethyl ether and then dried to obtain (E) -N- (1- (4-aminobut-2-en-1-yl) -7-bromo-1H-benzol [d ] imidazo | -2-i1) -1-ethyl-3-methyl-1 H-pyrazol-5-carboxamide, Hydrochloride (1.06 9) as a white solid. The isolated material was used without further purification. LCMS (m / z): 417.1 [M + HJ *.
[0630] [0630] Step 5: (E) -N- (7-bromo-1- (4 - (((4-carbamoyl-2-nitrophenyl) amino) but-2- en-1-yl) -1H-benzo [d ] imidazo | -2-i1) -1-ethyl-3-methyl-1H-pyrazol-5-carboxamide
[0631] [0631] To a suspension of (E) -N- (1- (4-aminobut-2-en-1-i1) -7-bromo-1H-benzo [d] imidazo | -2-i1) -1- ethyl-3-methyl-1H-pyrazol-5-carboxamide, hydrochloride (0.965 9, 2.126 mmol) and 4-fluor-3-nitrobenzamide (0.431 g, 2.339 mmol) in isopropanol (10 mL) at room temperature, was added DIEA (0.780 mL, 4.46 mmol). The reaction mixture was stirred at 70 ° C overnight. After that, the reaction mixture was cooled to room temperature, and the solids were collected on a filter. The solid was washed with isopropanol and dried to obtain (E) -N- (7-bromo-1- (4 - ((4-carbamoyl-2-nitrophenyl) amino) but-2-en-1-i1) -1H -benzo [d] imidazo | -2-i1) -1-ethyl-3-methyl-1H-pyrazol-5-carboxamide (1.2 g, 2.06 mmol, 97% yield) as a yellow solid . The isolated material was used without further purification. LCMS (m / z): 581.1 [IM + HJ *.
[0632] [0632] To a solution of (E) -N- (7-bromo-1- (4 - ((4-carbamoyl-2-nitrophenyl) amino) but-2-en-1-yl) -1 H-benzo [d] imidazo | -2-yl) -1-ethyl-3-methyl-1H-pyrazol-5-carboxamide (1.2 g, 2.064 mmol) and ammonium chloride (1.1 g, 20.56 mmol) in methanol (15 ml), zinc (1.3 g, 19.88 mmol) was added. The reaction mixture was then stirred at room temperature for 8 h. Another 10 eq. of ammonium chloride (1.1 g, 20.56 mmol) and zinc (1.3 g, 19.88 mmol), and the mixture was stirred at room temperature overnight. As the reduction remained incomplete, acetic acid (1.5 mL) was added and the mixture was then stirred at room temperature for 30 min.
[0633] [0633] The reaction mixture was filtered, and the filtrate was concentrated. The isolated material was divided between EtOAc and water. The solid that emerged was collected in a filter, washed with EtOAc and water. The filtrate was then inserted into a separating funnel. The aqueous layer was extracted with EtOAc (1x). The combined organic layers were then washed with brine, dried (MgSO4) and concentrated. The residue and solids isolated above were dissolved in MeOH and evaporated on diatomaceous earth. Chromatography on silica gel (dry loaded, 409 column, 0% to 10% MeOH / DCM gradient) produced an off-white solid (911 mg, —- 1.6 mmol) as a - (E) -N- (1- (4 - ((2-amino-4-carbamoylphenyl) amino) but-2-en-1-yl) -7-bromo-1H-benzo [d] imidazo 3: 1 -2-i1) -1-ethyl-3-methyl-1H-pyrazol-5-carboxamide (LCMS (m / z): 551.2 [M + H] *) and the de-foamed product. The isolated material was used directly in the next reaction.
[0634] [0634] To a solution of (E) -N- (1- (4 - ((2-amino-4-carbamoylphenyl) amino) but-2- en-1-i1) -7-bromo-1H-benzo [ d] imidazole | -2-i1) -1-ethyl-3-methyl-1 H-pyrazol-5-carboxamide (911 mg, -1.6 mmol, containing —25% deficient in bromine atom) in DMF ( 10 ml) at room temperature, a 1 M solution of 1-ethyl-3-methyl-1H-pyrazol-5-carbonyl isothiocyanate (1.82 ml, 1.82 mmol) in 1.4 dioxane was added. The reaction mixture was then stirred at room temperature for 1.5 h. After that, EDC (633 mg, 3.80 mmol) and TEA (0.921 mL, 6.61 mmol) were added at room temperature. After stirring it overnight at room temperature, the reaction mixture was diluted with EtOAc and water. The suspended solids were filtered and washed with EtOAc, water, EtOAc and then diethyl ether. Drying the off-white solid produced an 85:15 mixture of (E) -1- (4- (7-bromo-2- (1-ethyl-3-methyl-1 H-pyrazol-5-carboxamido) -1H- benzo [d] imidazo | -1-yl) but-2-en- 1-i1) -2- (1-ethyl-3-methyl-1 H-pyrazol-5-carboxamido) -1H-benzo [d] imidazole -5-carboxamide
[0636] [0636] To a suspension of imino (E) -1 - ((E) -4 - ((E) -7-bromo-2 - ((1-ethyl-3-methyl-1H-pyrazol-5-carbonyl)) ) -3-methyl-2,3-dihydro-1H-benzo [d] imidazol-1-yl) but-2-en-1-i1) -2- ((1-ethyl-3-methyl-1H-pyrazole -5-carbonyl) imino) -3-methyl-2,3-dihydro-1H-benzo [d] imidazole-B5-carboxamide (54 mg, 0.073 mmol) in tert-butanol (0.8 mL) and water (0 , 2 mL), NMO (26 mg, 0.22 mmol) was added. After stirring for 5 min at room temperature, 2.5% osmium tetroxide in tert-butanol (0.183 ml, 0.015 mmol) was added, and stirring was continued for 2 h at room temperature. The reaction mixture was filtered, and the filtrate was purified directly by reverse phase HPLC (30 mm x 50 mm Gemini C18, ACN / water gradient with 0.1% ammonium hydroxide modifier). (E) -1- (4 - ((E) -7-bromo-2 - (((1-ethyl-3-methyl-1H-pyrazol-5-carbonyl) imino) -3-methyl-2 was obtained, 3-dihydro-1H-benzo [d] imidazo | -1-i1) -2,3-dihydroxybutyl) -2 - ((1-ethyl-3-methyl-1H-pyrazol-5-carbonyl) imino) -3- methyl-2,3-dihydro-1H-benzo [d] imidazo | 37-carboxamide (37 mg, 0.48 mmol, 65% yield) as a white solid. 1H NMR (400MHz, DMSO-ds) 5 pom 8.09 - 8.00 (m, 2 H), 7.85 (dd, J = 1.5, 8.4 Hz, 1H), 7.61 - 7.56 (m, 2 H), 7.48 - 7.39 (m, 2 H), 7.23 (t, J = 8.0 Hz, 1 H), 6.47 (d, J = 7 ,1
[0637] [0637] To the mixture of 4-fluorine-3-nitrobenzamide (0.985 g, 5.35 mmol) in 1-butanol (10 mL), (2S, 3S) -2,3-dimethoxybutane-1,4- diamine (0.46 g, 2.61 mmol) and DIEA (1.82 mL, 10.4 mmol). The mixture was stirred at 110 ° C for 2 h. When cooled to room temperature, the solids were collected in a filter, washed with a mixture of diethyl ether and 2-propanol (1: 1) and dried to obtain 4.4'- (((28.3S) -2.3 -dimethoxybutane-1,4-diyl) bis (azanediyl)) bis (3-nitrobenzamide) (0.63 9, 1.25 mmol, 48% yield) as an orange solid. * H NMR (400 MHz, DMSO-ds) 5 ppm 1.13 (t, J = 7.0 Hz, 6 H), 3.45 - 3.74 (m, 8 H), 3.79 - 3 , 89 (m, 2
[0638] [0638] To a 100 ml round bottom flask, 4.4 "(((28.3S) -2,3-dimethoxybutane-1,4-diyl) bis (azanediyl)) bis (3-nitrobenzamide) was added ) (0.63 9, 1.25 mmol) and methanol (20 mL). To this mixture, 10 mL of saturated aqueous ammonium chloride solution were added. To this mixture, zinc (0.812 9, 12 , 5 mmol), and the heterogeneous mixture was stirred at room temperature for 15 min. The mixture was passed through a filter and rinsed using MeOH, then concentrated. Silica gel chromatography (24 g column, 6 % to 20% MeOH / DCM with 1% ammonium hydroxide as a modifier) produced 4.4 '- (((28.3S) -2.3-dimethoxybutane-1,4-diyl) bis (azanediyl)) bis (3-aminobenzamide) (0.446 g, 1.00 mmol, 80% yield) as a light yellow solid. LCMS (m / z): 445.4 [M + HJ *. Step 3: 1.1 '- (((28,38) -2,3-dimethoxybutane-1,4-diyl) bis (2- (1-ethyl-3-methyl-1H-pyrazol-5-carboxamido) -1H-benzo [d] imidazole -5-carboxamide)
[0639] [0639] The 4,4 '- (((28,3S) -2,3-dimethoxybutane-1,4-diyl) bis (azanediyl)) bis (3-aminobenzamide) solution (0.446 g, 1.00 mmol ) in DMF (20 ml), 1-ethyl-3-methyl-1H-pyrazol-S-carbonyl isothiocyanate (-04 M in dioxane, 5.02 ml, 2.00 mmol) was added. The mixture was stirred for 15 minutes. EDC (0.481 g, 2.51 mmol) and TEA (0.699 mL, 5.02 mmol) were added, and the reaction mixture was stirred at room temperature for 18 h. The mixture was poured into 3: 1 of water: saturated aqueous ammonium chloride solution (100 mL). Fine solids formed immediately, and stirring was continued for another 10 min. The resulting solids were filtered, washed with water and dried to obtain 1,1 '- ((28,3S) -2,3-dimethoxybutane-1,4-diyl) bis (2- (1-ethyl-3-methyl- 1 H-pyrazol-5-carboxamido) -1H-benzo [d] imidazole-5-carboxamide) (0.539 mg, 0.701 mmol, 70% yield) as a white solid. LCMS (m / z): 767.5 [M + HJ *.
[0640] [0640] To a mixture of 1,1 '- ((28,3S) -2,3-dimethoxybutane-1,4-diyl) bis (2- (1-ethyl-3-methyl-1H-pyrazol-5- carboxamido) -1H-benzo [d] Jimidazole | -5-carboxamide) (0.09 g, 0.117 mmol) in DMF (5 mL), cesium carbonate (0.103 g, 0.317 mmol) and methyl iodide ( 0.018 mL, 0.282 mmol). The reaction mixture was stirred at room temperature for 18 h. More cesium carbonate (0.019 g, 0.059 mmol) and methyl iodide (0.015 ml, 0.235 mmol) were added. The mixture was stirred for 1ha50º C. The reaction was diluted with water and extracted with EtOAc (3 x 50 mL). The organic phase was washed with brine (10 ml), dried over magnesium sulfate and concentrated. Mass-directed HPLC (XSelect CSH Prep C18, 5 µm, gradient from 15% to 55% ACN / water with 0.1% TFA as a modifier) was used to purify the product. The fractions were combined and the ACN was removed. The aqueous phase was basified with saturated ammonium bicarbonate solution. The resulting solids were filtered and dried in a freeze dryer to obtain (2E, 2'E) -1.1 '- ((28.3S) -2.3-dimethoxybutane-1,4-diyl) bis (2- ((1-ethyl-3-methyl-1H-pyrazol-5-carbonyl) imino) -3-methyl-2,3-dihydro-1H-benzo [d] imidazole | -5-carboxamide) (13 mg, 0.016 mmol , 14% yield) as a white solid. * H NMR (400 MHz, DMSO-ds) 5 ppm 8.01 - 8.15 (m, 4 H) 7.80 - 7.93 (m, 2 H) 7.61 (d, J = 8, 36 Hz, 2 H) 7.46 (br., 2 H) 6.51 (s, 2 H) 4.46 - 4.62 (m, 6 H) 4.38 (dd, J = 14, 45, 8.87 Hz, 2 H) 3.78 - 3.93 (m, 2 H) 3.60 (s, 6 H) 3.25 - 3.33 (m, 2 H) 3.02 (dd , J = 9.38, 7.10 Hz, 2 H) 2.12 (s, 6 H) 1.31 (t, J = 7.10 Hz, 6 H) 0.59 (t, J = 6, 97 Hz, 6 H). LCMS (m / z): 795.3 [IM + HJ ”. Example 36 (E) -1 - ((((4R, 5R) -5 - (((E) -5-carbamoyl-2 - ((1-ethyl-3-methyl-1H-pyrazol-5-carbonyl) imino) -3-methyl-2,3-dihydro-1H-benzo [d] imidazol | -1-yl)] methyl) -2,2-dimethyl-1,3-dioxolan-4-yl)] methyl) -2- ((1-ethyl-3-methyl-1H-pyrazol-S5-carbonyl) imino) -7- (3-hydroxypropoxy) - 3-methyl-2,3-dihydro-1 H-benzoldlimidazor-S-carboxamide N SE X O
[0642] [0642] To a solution of 4 - (((((4R, 5R) -5- (aminomethyl) -2,2-dimethyl-1,3-dioxolan-4-yl)] Mmethyl) amino) -3- (3 - (benzyloxy) propoxy) -S-nitrobenzamide (1.4 g, 2.87 mmol) and 4-fluor-3-nitrobenzamide (0.580 g, 3.15 mmol) in DMSO (15 mL), K2CO3 ( 0.792 g, 5.73 mmol). The reaction mixture was stirred at 25 ° C for 16h. The mixture was poured into water (100 ml). The precipitate was collected by filtration,
[0643] [0643] To a solution of 3- (3- (benzyloxy) propoxy) 4 - (((((4R, 5R) -5 - (((4-carbamoyl-2-nitrophenyl) amino) methyl) -2,2- dimethyl-1,3-dioxolan-4-yl)] methyl) amino) -5-nitrobenzamide (1.35 g, 2.068 mmol) in acetic acid (20 mL), zinc (1.352 g, 20.68 mmol) was added ). The reaction mixture was stirred at 25 ° C for 3 h. The mixture was diluted with DCM (50 ml) and filtered. The filtrate was concentrated under reduced pressure to obtain 3-amino-4 - (((((4R, 5R) -5 - ((((2-amino-4-carbamoylphenyl) amino) Mmethyl) -2,2-dimethyl-1, Crude 3-dioxolan-4-yl) methyl) amino) -5- (3- (benzyloxy) propoxy) benzamide (1.3 g, 1.755 mmol, 85% yield) as a gray solid. LCMS (m / z): 593 [M + HJ *. Step 4: 2-amino-1 - ((((4R, 5R) -5 - ((2-amino-5-carbamoyl-1H-benzo [d] imidazo | - 1-yl) Mmethyl) -2,2-dimethyl -1,3-dioxolan-4-yl)] methyl) -7- (3- (benzyloxy) propoxy) -1H-benzo [d] imidazole-5-carboxamide
[0644] [0644] To a solution of 3-amino-4 - (((((4R, 5R) -5 - ((((2-amino-4-carbamoylphenyl) amino) methyl) -2,2-dimethyl-1,3- dioxolan-4-yl) methyl) amino) -5- (3- (benzyloxy) propoxy) benzamide (1.35 g, 2.278 mmol) in methanol (20 mL), cyanogen bromide (0.724 g, 6, 83 mmol). The reaction mixture was stirred at 25 ° C for 16 h. The mixture was diluted with diethyl ether (80 ml). The mixture was filtered and washed with diethyl ether. The filtrate was concentrated under reduced pressure to obtain 2-amino-1 - ((((4R, 5R) -5 - ((2-amino-5-carbamoyl-1H-benzo [d] imidazo | -1-yl) meti | ) -2,2-dimethyl-1,3-dioxolan-4-yl)] methyl) -7- (3- (benzyloxy) propoxy) -1H-benzo [d] imidazole | -5-carboxamide (800 mg, 1 , 12 mmol, 49.2% yield) as a gray solid. LCMS (m / z): 643 [M + H] J *.
[0645] [0645] To a mixture of 1-ethyl-3-methyl-1H-pyrazole-S-carboxylic acid (336 mg, 2.178 mmol), 2-amino-1 - ((((4R, 5R) -5 - ((2 -amino-5-carbamoyl-1H-benzo [d] imidazo | -1- yl) methyl) -2,2-dimethyl-1,3-dioxolan-4-yl) methyl) -7- (3- (benzyloxy) propoxy) -1H-benzol [d] imidazole | -5-carboxamide (700 mg, 1.089 mmol) and DIPEA (0.951 mL, 5.45 mmol) in DMF (10 mL), HATU (1035 mg, 2, 72 mmol). The reaction mixture was stirred at 60 ° C for 16 h. The mixture was poured into water. The precipitate was collected by filtration, washed with water and diethyl ether and then vacuum dried to obtain 7- (3- (benzyloxy) propoxy) -1 - ((((4R, 5R) -5 - ((5- carbamoyl-2- (1-ethyl-3-methyl-1H-pyrazol-5-carboxamido) -1H-benzo [d] imidazol | -1-yl) methyl) -2,2-dimethyl-1,3-dioxolan- 4-yl)] methyl) -2- (1-ethyl-3-methyl-1 H-pyrazol-5-carboxamido) -1H-benzo [d] imidazo | - Bb-carboxamide (800 mg, 0.743 mmol, 68, 2% yield) as a brown solid. LCMS (-85% UV purity, m / z): 915 [M + HJ *.
[0646] [0646] To a solution of 7- (3- (benzyloxy) propoxy) -1 - ((((4R, 5R) -5 - ((5-carbamoyl- 2- (1-ethyl-3-methyl-1H-pyrazole -5-carboxamido) -1H-benzo [d] imidazol | -1-yl)] methyl) -2,2-dimethyl-1,3-dioxolan-4-yl) methyl) -2- (1-ethyl-3 -methyl-1 H-pyrazol-5-carboxamido) -1H-benzo [d] imidazole-5-carboxamide (650 mg, 0.710 mmol) in methanol (20 mL), Pd-C (756 mg, 7, 10 mmol). The reaction was hydrogenated using the H-cube (4 atm) at 60º C for 72 h. The mixture was diluted with DMF (20 ml). The mixture was filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was purified by preparative HPLC (Gemini-C18 column, 5 py silica, 21 x 150 mm; 30% to 40% ACN / water gradient with 0.1% TFA modifier) to obtain 1 - (( (4R, 5R) -5 - ((5-carbamoyl-2- (1-ethyl-3-methyl-1H-pyrazol-5-carboxamido) -1H-benzo [d] imidazol | -1-yl) methyl) - 2,2-dimethyl-1,3-dioxolan-4-yl) methyl) -2- (1-ethyl-3-methyl-1H-pyrazol-5-carboxamido) -7- (3-hydroxypropoxy) -1H-benzo [d] limidazole carboxamide (30 mg, 0.035 mmol, 4.9% yield) as an off-white solid. * H NMR (400 MHz, MeOH-d4) 5 7.58 (s, 1 H), 7.48 (d, J = 8.4 Hz, 1H), 7.33 (s, 1 H), 7 , 17 (d, J = 8.4 Hz, 1 H), 6.89 (s, 1 H), 6.58 (s, 2 H), 5.11 - 4.99 (m, 1 H), 4.93 (s, 1 H), 4.61 (dad, J = 26.0, 13.2, 6.9 Hz, 5 H), 4.46 - 4.36 (m, 1 H), 4 , 31 (dd, J = 13.4, 3.2 Hz, 1 H), 4.19 (dd, J = 14.0, 3.4 Hz, 1 H), 4.03 (dd, J = 15 , 1, 6.4 Hz, 1 H), 3.88 (dd, J = 14.9, 6.4 Hz, 1 H), 3.83 - 3.72 (m, 1 H), 2.23 (s, 3 H), 2.18 (s, 3 H), 2.05 (dd, J = 11.5, 5.9 Hz, 2 H), 1.64 (d, J = 10.3 Hz , 6 H), 1.50 - 1.28 (m, 6 H). LCMS (m / z): 825 [M + HJ ”.
[0647] [0647] To a mixture cooled in an ice bath of 1 - (((4R, 5R) -5 - ((5-carbamoyl-2- (1-ethyl-3-methyl-1H-pyrazol-5-carboxamido) - 1H-benzo [d] imidazo | -1-yl)] methyl) - 2,2-dimethyl-1,3-dioxolan-4-yl) methyl) -2- (1-ethyl-3-methyl-1H-pyrazole -S5-carboxamido) -7- (3-hydroxypropoxy) -1H-benzo [d] imidazole-S5-carboxamide (21 mg, 0.025 mmol) and cesium carbonate (24.88 mg, 0.076 mmol) in DMF (0, 5 ml), methyl iodide (4 µl, 0.064 mmol) was added. The ice bath was removed, and the mixture was stirred at room temperature for 16 h. After filtration, the filtrate was purified directly by mass-directed preparative HPLC (XSELECT CSH C18 column, 5 µm packaging, 150x30 mm, 30% to 85% MeCN / 10 mM ammonium bicarbonate gradient with pH adjusted to 10 with ammonia). Concentration of the pure fractions produced the title compound (12 mg, 0.014 mmol, 55% yield). * H NMR (400 MHz, DMSO-ds) 5 ppm 1.28 - 1.35 (m, 12 H) 1.89 - 1.94 (m, 2 H) 2.08 (s, 3 H) 2 , 13 (s, 3 H) 3.28 (s, 3 H) 3.30 (s, 3 H) 3.53 - 3.57 (m, 2 H) 4.01 - 4.07 (m, 1 H) 4.11 - 4.16 (m, 1 H) 4.27 - 4.31 (m, 2 H) 4.37 (dd, J = 12.67, 4.31 Hz, 1 H) 4, 49 - 4.56 (m, 6 H) 4.60 - 4.66 (m, 2 H) 6.59 (d, J = 7.10 Hz, 2 H) 7.27 (s, 1 H) 7 , 42 - 7.50 (m, 4 H) 7.72 (dd, J = 8.49, 1.39 Hz, 1 H) 7.79 (s, 1 H) 8.05 (d, J = 16 , 48 Hz, 2 H). LCMS (m / z): 853.4 [M + HJ *. Example 37 (E) -1- (4 - ((E) -5-carbamoyl-2 - (((1-ethyl-3-methyl-1H-pyrazol-5-carbonyl) imino) -3-methyl-2,3 -dihydro-1H-benzo [d] imidazo | -1-yl) -2,2,3,3-tetrafluorbyl) -2 - ((1-ethyl-3-methyl-1H-pyrazol-5-carbonyl) imino) -7-isopropyl-3-methyl-2,3-dihydro-1H-benzo [d] imidazole-5-carboxamide 8 1 A
[0648] [0648] To a solution of 3-bromo-4-fluorine-S-nitrobenzamide (1.4 g, 5.32 mmol) and 2,2,3,3-tetrafluorbutane-1,4-diamine, 2 hydrochloride (1 , 3 g, 5.58 mmol) in ethanol (30 mL) at room temperature, DIEA (3.53 mL, 20.23 mmol) was added. The reaction mixture was then heated to 70 ° C and stirred for 4 h. The reaction mixture was cooled to room temperature and then concentrated. The resulting material was divided between water and EtOAc. The aqueous layer was separated and extracted with EtOAc (1x). The combined organic layers were then washed with brine, dried with magnesium sulfate and concentrated to obtain 4 - ((4-amino-2,2,3,3-tetrafluorbyl) amino) -3-bromo-S5-nitrobenzamide (2, 15 g, 5.3 mmol, 100% yield) as a yellow solid. The solid was used without further purification. LCMS (m / z): 403.0 [M + HJ *.
[0649] [0649] To a suspension of 4-fluor-3-nitrobenzamide (1.5 g, 8.15 mmol) and 4- ((4-amino-2,2,3,3-tetrafluorbyl) amino) -3-bromine -S5-nitrobenzamide (2.15 g, 5.3 mmol) in ethanol (25 mL) at room temperature, DIEA (2.8 mL, 16.03 mmol) was added. The reaction mixture was then heated to 80 ° C and stirred for 48 h. After that, the reaction mixture was cooled to room temperature and filtered. The solid was washed with EtOH and then dried to obtain 3-bromo-4 - ((4 - ((4-carbamoyl-2-nitrophenyl) amino) -2,2,3,3-tetrafluorbutil) amino) - 5-nitrobenzamide (2.6 g, 4.58 mmol, 86% yield) as a yellow solid. LCMS (m / z): 567.0 [M + HJ *.
[0650] [0650] To a 40 ml scintillation ampoule containing 3-bromo-4 - ((4 - ((4-carbamoyl-2-nitrophenyl) amino) -2,2,3,3-tetrafluorbutil) amino) -S- nitrobenzamide (300 mg, 0.529 mmol), trifluorine (prop-1-en-2-yl) -1,4-borane, potassium salt (196 mg, 1,322 mmol) and K3PO. (393 mg, 1.851 mmol) in DMF (2.5 mL) and water (0.25 mL) at room temperature, PdCla (dppf) -CH2CI adduct (44 mg, 0.054 mmol) was added. The reaction vessel was then evacuated and refilled with nitrogen. After that, the reaction mixture was heated to 80 ° C and stirred overnight. When cooled to room temperature, the mixture was diluted with EtOAc and water. The biphasic mixture was filtered through a layer of diatomaceous earth. After that, the aqueous layer was separated, and the organic layer was washed with water (2 more times). The combined aqueous layers were then extracted back with EtOAc (1x). The combined organic matter was washed with saturated brine, dried over magnesium sulfate and concentrated. The residue was purified by normal phase silica gel chromatography (0% to 20% MeOH / DCM gradient) to produce 4 - ((4 - ((4-carbamoyl-2-nitrophenyl) amino) - 2.2 , 3,3-tetrafluorbyl) amino) -3-nitro-5- (prop-1-en-2-yl) benzamide (111 mg, 0.211 mmol, 40% yield) as an orange solid. The solid was used without further purification. LCMS (m / z): 529.2 [M + H] J *. Step 4: 3-amino-4 - ((4 - ((2-amino-4-carbamoylphenyl) amino) -2,2,3,3-tetrafluorbyl) amino) -5-isopropylbenzamide o No e and NH LO . À FAN Fr O
[0652] [0652] To a solution of 3-amino-4 - ((4 - (((2-amino-4-carbamoylphenyl) amino) - 2,2,3,3-tetrafluorbyl) amino) -5-isopropylbenzamide (72 mg, -— 40% purity) in DMF (1.5 mL) at room temperature, a solution of 1-ethyl-3-methyl-1H-pyrazol-S-carbonyl isothiocyanate (1 M in 1,4- dioxane, 0.306 ml, 0.306 mmol). The reaction mixture was then stirred at room temperature for 1 h. To the mixture, EDC (110 mg, 0.574 mmol) and TEA (0.160 mL, 1.148 mmol) were then added at room temperature. After stirring it overnight, the mixture was filtered, and the filtrate was purified directly by mass directed reverse phase HPLC (XSELECT CSH C18 column, 5 µm packaging, 150x30 mm, 30% to 85% gradient of MeCN / water with 0.1% TFA modifier) to obtain 1- (4- (5- carbamoyl-2- (1-ethyl-3-methyl-1H-pyrazol-5-carboxamido) -1H-benzo [d] imidazole | -1-i1) - 2,2,3,3-tetrafluorbyl) -2- (1-ethyl-3-methyl-1H-pyrazol-5-carboxamido) -7-isopropyl-1H-benzol [ d] imidazole-5-carboxamide (31 mg, 0.039 mmol, 26% yield). LCMS (m / z): 793.4 [M + HJ *.
[0653] [0653] JA a mixture of 1- (4- (5-carbamoyl-2- (1-ethyl-3-methyl-1H-pyrazol-5-carboxamido) -1H-benzo [d] imidazole | -1-i1) -2,2,3,3-tetrafluorbyl) -2- (1-ethyl-3-methyl-1H-pyrazol-5-carboxamido) -7-isopropyl-1H-benzo [d] imidazole-5-carboxamide - (22 mg, 0.028 mmol) and cesium carbonate (46 mg, 0.141 mmol) in DMF (1 mL) at room temperature, iodomethane (5 µl, 0.080 mmol) was added. After that, the reaction mixture was stirred for 5 h. The mixture was filtered, and the filtrate was purified directly by mass directed reverse phase HPLC (XSELECT CSH C18 column, 5 µm packaging, 150x30 mm, 15% to 55% MeCN / water gradient with 0.075 NHs.OH %, 10 mM ammonium bicarbonate, pH 10) to obtain (E) -1- (4 - ((E) -5-carbamoyl-2 - ((1-ethyl-3-methyl-1H-pyrazole-5- carbonyl) imino) -3-methyl-2,3-dihydro-1H-benzo [d] imidazo | -1-i1) -2,2,3,3-tetrafluorbyl) -2 - ((1-ethyl-3- methyl-1H-
[0654] [0654] To a suspension of 4-chloro-3 - ((4-methoxybenzyl) oxy) -5-nitrobenzamide (1.2 g, 3.56 mmol) and 2,2,3,3-tetrafluorbutane-1,4 -diamine, 2 Hydrochloride (19, 4.29 mmol) in 1-butanol (40 mL) at room temperature, sodium bicarbonate (1.078 g, 12.83 mmol) was added. After that, the reaction mixture was heated to 120º
[0655] [0655] To a suspension of 1-fluor-2-nitrobenzene (0.16 ml, 1.52 mmol) and 1-fluor-2-nitrobenzene (0.16 ml, 1.52 mmol) in 1-butanol (4 ml) at room temperature, sodium bicarbonate (191 mg, 2.27 mmol) was added. After that, the reaction mixture was heated to 80º C and stirred for 12 days. The mixture was cooled to room temperature and quenched with water. The aqueous layer was extracted with EtOAc (3x). The combined organic layers were washed with brine, dried and concentrated. The residue was suspended in DCM. After that, the solids were filtered, washed with DCM and dried to obtain 3 - ((4-methoxybenzyl) Oxy) -S-nitro-4- ((2,2,3,3-tetrafluoro-4 - ((2- nitrophenyl) amino) butyl) amino) benzamide (330 mg, 0.569 mmol, 75% yield) as an orange solid. LCMS (m / z): 582.2 [M + HJ.
[0656] [0656] To a solution of 3 - ((4-methoxybenzyl) oxy) -S-nitro-4 - ((2,2,3,3-tetrafluoro-4 - ((2-nitrophenyl) amino) butyl) amino) benzamide (328 mg, 0.564 mmol) and ammonium chloride (302 mg, 5.684 mmol) in methanol (5 mL) at room temperature, zinc (369 mg, 5.64 mmol) was added. After that, the reaction mixture was stirred at room temperature overnight. The mixture was filtered through diatomaceous earth, concentrated and partitioned between water and EtOAc. The aqueous layer was separated and extracted with EtOAc (1x). After that, the combined organic layer was washed with brine, dried over magnesium sulfate and concentrated. The residue was suspended in DCM. The solids were filtered, washed with DCM and dried to obtain the impure title compound (70 mg, -24% yield). The filtrate was concentrated, and the residue was purified by preparative mass-directed HPLC (XSELECT CSH C18 column, 5 µm packaging, 150x30 mm, 15% to 55% MeCN / water gradient with 0.075% NH4O0H, 10 mM of ammonium bicarbonate, pH 10) to produce 3-amino-4 - ((4 - ((2-aminophenyl) amino) -2,2,3,3-tetrafluorbyl) amino) -5 - ((4-methoxybenzyl) oxy ) pure benzamide (92 mg, 0.18 mmol, 31% yield) as a light brown solid. LCMS (m / z): 522.3 [M + H] J *.
[0658] [0658] To a mixture of 2- (1-ethyl-3-methyl-1H-pyrazol-5-carboxamido) -1- (4- (2- (1-ethyl-3-methyl-1H-pyrazol-5- carboxamido) -1H-benzo [d] imidazole | -1-i1) -2,2,3,3- tetrafluorbyl) -7 - ((4-methoxybenzyl) oxy) -1H-benzo [d] imidazole-5-carboxamide (65 mg, 0.077 mmol) and cesium carbonate (125 mg, 0.885 mmol) in DMF (1 mL) at room temperature, iodomethane (0.012 mL, 0.19 mmol) was added. After that, the reaction mixture was stirred overnight. The reaction mixture was filtered, and the filtrate was purified directly by mass directed reverse phase HPLC (XSELECT CSH C18 column, 5 µm pack, 150x30 mm, 50% to 99% MeCN / water gradient with 0.075 NHaOH %, MM ammonium bicarbonate, pH 10) to produce (E) -2 - ((1-ethyl-3-methyl-1 H-pyrazol-5-carbonyl) imino) -1- (4- ((E) -2 - (((1-ethyl-3-methyl-1 H-pyrazol-5-carbonyl) imino) -3-methyl-2,3-dihydro-1H-benzo [d] imidazo | -1-i1) -2 , 2,3,3-tetrafluorbyl) -7 - ((4-methoxybenzyl) oxy) -3-methyl-2,3-dihydro-1H-benzo [d] imidazole-5-carboxamide (33 mg, 0.088 mmol, 49 % yield) as an off-white solid. * H NMR (400 MHz, DMSO-ds) δ ppm 8.10 (s, 1 H), 7.78 (d, J = 1.0 Hz, 1 H), 7.68 - 7.65 (m , 1 H), 7.61 (dd, J = 1.9.7.0 Hz, 1 H), 7.52 (s, 1 H), 7.48 - 7.33 (m, 5 H), 6.77 (d, J = 8.6 Hz, 2 H), 6.49 (d, J = 0.8 Hz, 2 H), 5.25 - 5.09 (m, 4 H), 4, 72 (t, J = 16.6 Hz, 2 H), 4.49 (q, J = 7.0 Hz, 4 H), 3.58 (s, 6 H), 3.49 (s, 3 H ), 2.12 (s, 3 H), 2.11 (s, 3 H), 1.23 (t, J = 7.1 Hz, 3 H), 1.24 (t, J = 7.1 Hz, 3 H). LCMS (m / z): 872.4 [M + HJ ”.
[0659] [0659] To a solution of (E) -1 - ((E) -4 - ((E) -S-carbamoyl-2 - ((1-ethyl-3-methyl-1H-pyrazol-5-carbonyl) imino ) -3-methyl-2,3-dihydro-1H-benzo [d] imidazo | -1-i1) -2,3-dimethylbut- 2-en-1-i1) -2 - ((1-ethyl-3 -methyl-1 H-pyrazol-5-carbonyl) imino) -7-hydroxy-3-methyl-2,3-dihydro-1H-benzo [d] imidazole-5-carboxamide (49 mg, 0.063 mmol) in DMF ( 1 mL), 3- (bromomethyl) tetrahydrofuran (20.95 mg, 0.127 mmol) was added, followed by potassium carbonate (11.40 mg, 0.083 mmol). The reaction mixture was stirred at 90 ° C for 24 h. The mixture was purified directly by preparative HPLC (Phenomenex Eclipse column, 5 µm packaging, 50x30 mm, 25% to 55% MeCN / water gradient with 0.1% TFA modifier). The corresponding fractions were combined and concentrated in vacuo. The residue was partitioned between EtOAc and an aqueous sodium bicarbonate solution. The organic layer was separated, dried over sodium sulfate and evaporated in vacuo to obtain (E) -1 - ((E) -4 - ((E) -5-carbamoyl-2 - ((1-ethyl-3-methyl -1H-pyrazol-S-carbonyl) imino) -3-methyl-2,3-dihydro-1H-benzo [d] imidazol | -1-yl) - 2,3-dimethylbut-2-en-1-i1) -2 - (((1-ethyl-3-methyl-1 H-pyrazol-5-carbonyl) | mino) -3-methyl-7- ((tetrahydrofuran-3-yl) methoxy) -2,3-dihydro-1H -benzo [d] imidazole-5-carboxamide - (22.5 mg, 0.027 mmol, 42.6% yield) as a white solid. * H NMR (400 MHz, DMSO-ds) 5 ppm 8.11 - 8.15 (m, 1 H), 8.05 - 8.11 (m, 1 H), 7.99 - 8.05 ( m, 1H), 7.79 (s, 2H), 7.50 (br. s, 3 H), 7.18 - 7.28 (m, 1 H), 6.46 (s, 1 H) , 6.37 (s, 1H),
[0660] [0660] To a solution of (E) -2 - ((1-ethyl-3-methyl-1H-pyrazol-5-carbonyl) imino) -1- ((E) -4 - ((E) -2- ((1-ethyl-3-methyl-1H-pyrazol-5-carbonyl) imino) -7 - ((4-methoxybenzyl) oxy) -3-methyl-2,3-dihydro-1H-benzo [d] imidazo | -1-i1) -2,3-dimethylbut-2-en-1-i1) -3-methyl-2,3-dihydro-1H-benzo [d] imidazole-5-carboxamide (400 mg, 0.484 mmol) in DCM (8 ml), a solution of HCI (4 M in dioxane, 0.726 ml, 2.91 mmol) was added dropwise. Most of the DCM was removed under vacuum. 1,4-dioxane (8 ml) and more HCI solution (4 M in dioxane, 0.726 ml, 2.91 mmol) were added. The container was sonicated and shaken vigorously for 2.5 h (gum still present and reaction incomplete). The mixture was concentrated again in vacuo and resuspended in THF (6 ml) and water (1 ml). More HCI solution (4 M in dioxane, 0.726 mL, 2.91 mmol) was added, and the mixture was stirred for 3 h. The reaction mixture was concentrated and dissolved in 20% methanol / DCM (6 ml). To this homogeneous solution, HCI solution (4 M in dioxane, 0.726 mL, 2.91 mmol) was added, and the mixture was stirred for 30 min.
[0661] [0661] To the mixture of 4-chloro-3 - ((4-methoxybenzyl) oxy) -S-nitrobenzamide (1.55 9, 4.60 mmol) in 1-butanol (15 mL), (28, 3S) -2,3-dimethoxybutane-1,4-diamine (1.01 g, 5.75 mmol) and DIEA (2.41 mL, 13.8 mmol). The mixture was stirred at 120 ° C for 2 h. After that, 4-fluoro-3-nitrobenzamide (0.848 g, 4.60 mmol) was added. The mixture was stirred at 120 ° C for 18 h. The mixture was cooled and filtered to remove suspended solids. After removing the solvents, chromatography on silica gel (40 g of silica, gradient of 5% to 20% MeOH / DCM) produced 4- (((28.3S) -4 - ((4-carbamoyl-2 -nitrophenyl) amino) -2,3-dimethoxybutyl) amino) -3 - ((4-methoxybenzyl) oxy) -5-nitrobenzamide (0.86 g, -25% yield, contaminated by
[0662] [0662] The collected precipitate produced 4.4 '- (((28.3S) -2,3-dimethoxybutane-1,4-diyl) bis (azanediyl)) bis (3 - (((4-methoxybenzyl) Oxy) - S-nitrobenzamide) (423 mg, 0.545 mmol, 12% yield, LCMS (m / z): 777.5 [M + H] *), which can be used to prepare other examples. | O, if AA,
[0663] [0663] To a 100 mL round-bottom flask, 4 - (((28.3S) - 4 - (((4-carbamoyl-2-nitrophenyl) amino) -2,3-dimethoxybutyl) amino) - 3 - ((4-methoxybenzyl) oxy) -5-nitrobenzamide (0.86 g, 1.342 mmol) and methanol (20 mL). To this mixture, 10 ml of saturated aqueous ammonium chloride solution were added. To this mixture, zinc (0.878 g, 13.42 mmol) was added, and the heterogeneous mixture was stirred at room temperature for 15 min. The mixture was filtered, and the filter cake was rinsed with MeOH. The filtrate was concentrated.
[0664] [0664] The crude product was purified by silica gel chromatography (24 grams of silica, gradient from 6% to 20% MeOH / DCM with 1% NHOH modifier) to obtain 3-amino-4 - (((28 , 38S) -4 - ((2-amino-4-carbamoylphenyl) amino) -2,3-
[0665] [0665] solution of 3-amino-4 - ((((2S8,3S) -4 - (((2-amino-4-carbamoylphenyl) amino) -2,3-dimethoxybutyl) amino) -5 - ((4-methoxybenzyl ) oxy) benzamide (0.127 g, 0.219 mmol) in DMF (6 ml), 1-ethyl-3-methyl-1H-pyrazol-S-carbonyl isothiocyanate (-0.4 in dioxane, 1.094 ml, 0.437 mmol). The mixture was stirred for 15 minutes. EDC (0.105 g, 0.547 mmol) and TEA (0.152 mL, 1.094 mmol) were added, and the reaction was stirred at 50 ° C for 18 h. The reaction mixture was poured into 3: 1 of water: saturated aqueous ammonium chloride solution (20 mL). The resulting solid was filtered, washed with water and dried to obtain 1 - ((2S, 3S) -4- (5-carbamoyl-2- (1-ethyl-3-methyl-1H-pyrazol-5-carboxamido) -1H -benzo [d] imidazo | -1-i1) -2,3-dimethoxybutyl) -2- (1-ethyl-3-methyl-1 H-pyrazol-5-carboxamido) -7 - ((4-methoxybenzyl) oxide ) -1H-benzo [d] imidazole-5-carboxamide (0.142 g, 0.157 mmol, 72% yield) as a solid. LCMS (m / z): 903.3 [M + HJ *.
[0666] [0666] To a solution of 1 - ((28.3S) -4- (5-carbamoyl-2- (1-ethyl-3-methyl-1H-pyrazol-5-carboxamido) -1H-benzo [d] imidazo | -1-i1) -2,3-dimethoxybutyl) -2- (1-ethyl-3-methyl-1H-pyrazol-5-carboxamido) -7 - ((4-methoxybenzyl) oxy) -1H-benzo [d ] imidazo carboxamide (0.112 g, 0.124 mmol) in DMF (5 mL), cesium carbonate (0.121 g, 0.372 mmol) and methyl iodide (0.031 mL, 0.496 mmol) were added. The reaction mixture was stirred at room temperature for 18 h. The reaction mixture was diluted with water and extracted with EtOAc (3 x 50 ml). The organic phase was washed with brine (10 ml), dried over magnesium sulfate, filtered and concentrated. The crude product was purified using mass directed reverse phase HPLC (XSELECT CSH C18 column, 5 µm packaging, 150x30 mm, 15% to 55% MeCN / water gradient with 0.075% NH4O0H, 10 mM ammonium bicarbonate , pH 10). The pure fractions were combined and concentrated to obtain (E) -1 - ((2S, 3S) -4 - ((E) -5-carbamoyl-2 - ((1-ethyl-3-methyl-1H-pyrazole-S5 -carbonyl) imino) -3-methyl-2,3-dihydro-1H-benzol [d] imidazo | -1-i1) -2,3-dimethoxybutyl) -2 - ((1-ethyl-3-methyl-1H -pyrazol-5-carbonyl) imino) -7 - ((4-methoxybenzyl) oxy) -3-methyl-2,3-dihydro-1H-benzo [d] imidazole-5-carboxamide (34 mg, 0.36 mmol , 29% yield) as a white solid. 1H NMR (400 MHz, DMSO-ds) 5 ppm 8.00 - 8.25 (m, 3 H) 7.86 (dd, J = 8.49, 1.39 Hz, 1 H) 7.77 ( d, J = 1.01 Hz, 1 H) 7.62 (s, 1 H) 7.36 - 7.53 (m, 5 H) 6.75 (d, J = 8.62
[0667] [0667] Table 2 shows Examples 43 to 92, which can be prepared according to the methods given below: NMR of * H Scheme No. Name / Structure LCMS (m / z) [M + H] * Example NMR of * H (400 MHz, METANOL-da) 5 ppm (2E, 2'E) -1,1 '- ((E) -2,3-dimethylbut- 8.13 (d, J = 1.27 Hz, 2 2-ene-1,4-diyl) bis (2 - ((1-ethyl-3-H) 7.86 (dd, J = 8.36, methyl-1H-pyrazol-5- 1.52 Hz, 2 H) 7.36 (d, carbonyl) imino) -3-methyl-2,3- J = 8.62 Hz, 2 H) 6.59 dihydro-1H-benzo [d] imidazole | -5- (s , 2 H) 4.97 (s, 4 H) Example carboxamide) (Method 1 o CG 4.62 (q, J = 7.10 Hz, 4 42 IA x NH: A Ne H) 3.71 (s , 6 H) 2.23 Ro (s, 6 H) 1.73 (s, 6 H) 1 1.39 (t, J = 7.10 Hz, 6
[0668] [0668] To a light yellow suspension of (E) -4 - ((4-amino-2,3-dimethylbut-2-en-1-yl) amino) -3-nitrobenzamide, Hydrochloride (1.05 g, 3.34 mmol) and 1-bromo-2-fluorine-3-nitrobenzene (0.734 g, 3.34 mmol) in 1-butanol (25 mL), DIEA (1.75 mL, 10.01 mmol) was added . The reaction was stirred at 80º C for 5 h and then stirred at room temperature for 16 h. The solids were filtered and rinsed with butanol (20 ml) and water (3 x 20 ml). The solids were dried to obtain the title compound (1.16 g, 2.40 mmol, 72% yield) as an orange solid. * H NMR (DMSO-ds, 400 MHz) 5 8.66 (d, J = 2.0 Hz, 1 H), 8.3-8.4 (m, 1 H), 7.99 (br s , 1 H), 7.9-8.0 (m, 1 H), 7.87 (dd, J = 1.5, 7.8 Hz, 1 H), 7.81 (dd, J = 1, 5, 8.3 Hz, 1 H), 7.31 (br s, 1 H), 6.8-6.9 (m, 1 H), 6.77 (d, J = 9.0 Hz, 1 H), 6.06 (t, J = 6.0 Hz, 1 H), 3.98 (br d, J = 5.8 Hz, 2 H), 3.85 (d, J = 6.0 Hz , 2 H), 1.64 (s, 3 H), 1.59 (d, J = 1.3 Hz, 3 H). LCMS (m / z): 478.2 [M + HJ *. Step 2: (E) —4-amino-3 - ((4 - ((2-amino-6-bromophenyl) amino) -2,3-dimethylbut-2-en-1-yl) amino) benzamide NH, the N
[0669] [0669] To a mixture of (E) 3 - ((4 - ((2-bromo-6-nitrophenyl) amino) -2,3-dimethylbut-2-en-1-yl) amino) -4-nitrobenzamide ( 1.06 g, 2.216 mmol) and ammonium chloride (1.778 g, 33.2 mmol) in MeOH (50 mL) cooled in an ice / water bath, zinc (1.449 g, 22.16 mmol) was added, and the reaction mixture was stirred at room temperature for 40 min. The mixture was filtered through diatomaceous earth and rinsed with methanol. The filtrate was concentrated and purified by silica gel chromatography (249 silica column; 10% to 60% gradient of [31 EA: EtoH] / heptane, plus 1% NH.OH solution, 12 min; 60% [3: 1 EA: EtOH] / heptane, 5 min). The purest fractions were combined and concentrated. The mixed fractions were concentrated and repurified (12 g silica column; 10% to 55% gradient of [3: 1 EA: EtoH] / heptane, without NHOH modifier, 10 min .; 55% of [3: 1 EA: EtOH] / heptane, 5 min). The fractions were combined and dried to obtain the title compound (571 mg, 1.09 umol, 49.3% yield) as a brown foam. LCMS (m / z): 418.3 [M + H] J *, -80% purity by UV210-350 nm).
[0670] [0670] To a light brown solution of (E) 4-amino-3 - ((4 - ((2-amino-6-bromophenyl) amino) -2,3-dimethylbut-2-en-1-yl) amino ) benzamide (570 mg, 1.090 mmol) in DMF (10 mL) cooled in an ice / water bath, 1-ethyl-3-methyl-1H-pyrazol-5-carbonyl isothiocyanate (-1 M in dioxane) , 2.18 mL, 2.18 mmol) dropwise rapidly. After stirring for 15 min, EDC (522 mg, 2.73 mmol) and TEA (0.760 mL, 545 mmol) were added, and the reaction mixture was warmed to room temperature and stirred for 16 h. To the stirred reaction mixture, a 5: 1 solution of water: saturated aqueous NHaCI solution (120 mL) was quickly added. The resulting suspension was stirred rapidly for 15 min. The solids were filtered and rinsed with water (3 x 20 ml). The solids were stirred in diethyl ether (15 mL) for 30 min and then filtered and rinsed with diethyl ether. After drying, the title compound (772 mg, 0.94 mmol, 86% yield) was obtained as a light yellow solid. * H NMR (DMSO-ds) 5: 13.02 (br. S, 1 H), 12.90 (s, 1 H), 8.02 (s, 1 H), 7.94 (br. s., 1 H), 7.71 (d, J = 8.4 Hz, 1 H), 7.61 (d, J = 7.9 Hz, 1 H), 7.44 (d, J = 7 , 9 Hz, 1 H), 7.35 (br. S., 1 H), 7.26 (d, J = 8.4 Hz, 1H), 7.19 (t, J = 8.0 Hz, 1 H), 6.64 (s, 1 H), 6.52 (s, 1 H), 5.26 (br., 2 H), 5.00 (br., 2 H), 4.53-4.63 (m, 4 H), 2.12 (s, 3 H), 2.10 (s, 3 H), 1.69 (br., 3 H), 1.63 (br. s., 3 H), 1.35 (t, J = 7.1 Hz, 3 H), 1.32 (t, J = 7.1 Hz, 3 H). LCMS (m / z): 740.2 / 742.4 [M + HJ ", —- 90% purity by UV210-350 nm).
[0671] [0671] To a solution of (E) -1- (4- (7-bromo-2- (1-ethyl-3-methyl-1H-pyrazol-5-carboxamido) -1H-benzo [d] imidazole | - 1-i1) -2,3-dimethylbut-2-en-1-i1) -2- (1-ethyl-3-methyl-1H-pyrazol-5-carboxamido) -1H-benzo [d] imidazole-5- carboxamide (760 mg, 0.923 mmol) in DMF (15 mL), potassium carbonate (319 mg, 2.309 mmol) and methyl iodide (0.13 mL, 2.12 mmol) were added. The reaction mixture was stirred at room temperature for 3 h. The reaction mixture was diluted with water (30 ml), and lumpy solids formed. After that, the mixture was divided between DOM and water. Then, the organic phase was washed with brine and concentrated. To purification by chromatography on silica gel (24 g silica column; 10% to 60% gradient of [3: 1 EA: EtOH] / heptane, plus 1% NHOH, 15 min; 60% of [3 : 1 EA: EtoH] / heptane, plus 1% NHOH, 10 min) produced the title compound (386 mg, 0.477 mmol, 51.7% yield) as a light orange foam after solvent evaporation . * H NMR (DMSO-ds) 5: 8.08-8.12 (m, 1 H), 8.01 (br. S., 1 H), 7.80 (dd, J = 8.4, 1.4 Hz, 1 H), 7.62-7.67 (m, 1 H), 7.49-7.53 (m, 1 H), 7.43 (br. S., 1 H), 7.25-7.34 (m, 2 H), 6.49 (s, 1 H), 6.44 (s, 1 H), 5.16 (s, 2 H), 4.89 (s, 2 H), 4.47-4.57 (m, 4 H), 3.59 (s, 3 H), 3.56 (s, 3 H), 2.13 (s, 3 H), 2, 12 (s, 3 H), 1.59 (s, 3 H), 1.50 (s, 3 H), 1.24-1.33 (m, 6 H). LCMS (m / z): 768.5 / 770.5 [M + HJ *.
[0672] [0672] To a suspension of (E) -1- (4- (5-carbamoyl-2- (1-ethyl-3-methyl-1H-pyrazol-B5-carboxamido) -7- (3-morpholinopropoxy) -1H -benzo [d] imidazol | -1-yl) but-2-en-1-i1) -2- (1-ethyl-3-methyl-1H-pyrazol-5-carboxamido) -7-methoxy-1H-benzo [d] imidazole-5-carboxamide (125 mg, 0.147 mmol, can be prepared as described in the International PCT Application Example WO 2017175147) and potassium carbonate (44.7 mg, 0.324 mmol) in DMF (1, 4 ml), a solution of methyl iodide (0.019 ml, 0.31 mmol) in DMF (0.4 ml) was added. The mixture was stirred at room temperature for 18 h and then diluted with water. The mixture was extracted with dichloromethane (3x). The combined organic layer was washed with water, dried over magnesium sulfate, filtered and concentrated. The residue was purified by preparative mass-directed reverse phase HPLC (XSELECT CSH C18 column, 5 µm packaging, 150x30 mm, 15% to 55% ACN / water gradient with 0.1% TFA modifier). The fractions containing the desired product were passed through a basic PL-HCO3 MP SPE cartridge. The eluate was concentrated to obtain (E) -1 - ((E) -4 - ((E) -5-carbamoyl-2 - (((1-ethyl-3-methyl-1H-pyrazol-5-carbonyl) imino) -3-methyl-7- (3-morpholinopropoxy) -2,3-dihydro-1H-benzo [d] imidazo | -1-yl) but-2-en-1-i1) -2 - ((1-ethyl -3-methyl-1H-pyrazol-5-carbonyl) imino) -7-methoxy-3-methyl-2,3-dihydro-1H-benzo [d] imidazo | -5-carboxamide (45 mg, 0.051 mmol, 34 , 8% yield). * H NMR (DMSO-ds) 7 ppm 8.04 (br. S., 2H), 7.71-7.75 (m, 2H), 7.38-7.48 (m, 4H), 6 , 40 (s, 1H), 6.35 (s, 1H), 5.66-5.80 (m, 2H), 4.79-4.89 (m, 4H), 4.38-4.49 (m, 4H), 4.02 (br. t., J = 6.3 Hz, 2H),
[0673] [0673] To a mixture of imino (E) -1 - ((E) -4 - ((E) -S-carbamoyl-2 - ((1-ethyl-3-methyl-1H-pyrazol-S5-carbonyl)) ) -3-methyl-7- (3-morpholinopropoxy) -2,3-dihydro-1H-benzol [d] imidazol-1-yl) but-2-en-1-i1) -2 - ((1-ethyl -3-methyl-1 H-pyrazol-S-carbonyl) imino) -7-methoxy-3-methyl-2,3-dihydro-1H-benzo [d] imidazole-5-carboxamide (26 mg, 0.030 mmol) and NMO (5.20 mg, 0.044 mmol) in tert-butanol (1.2 mL) and water (0.3 mL), 2.5% osmium tetroxide in tert-butanol (0.019 mL, 1, 5 umol). The mixture was stirred at room temperature for 64 h and then filtered. The filtrate was purified directly by mass-directed preparative HPLC (XSELECT CSH C18 column, 5 µm packaging, 150x30 mm, 15-55% ACN / water gradient with 0.1% TFA modifier). Fractions containing the title compound were passed through a PL-HCO3 MP SPE cartridge. The eluate was concentrated to obtain (E) - 1- (4 - ((E) -5-carbamoyl-2 - ((1-ethyl-3-methyl-1H-pyrazol-5-carbonyl) imino) -3-methyl -7- (3-morpholinopropoxy) -2,3-dihydro-1H-benzo [d] imidazo | -1-i1) -2,3-dihydroxybutyl) -2 - ((1-ethyl-3-methyl-1H- pyrazol-5-carbonyl) imino) -7-methoxy-3-methyl-2,3-dihydro-1H-benzo [d] imidazole-5-carboxamide (11 mg, 0.012 mmol, 40.7% yield). * H NMR (400 MHz, DMSO-ds) 5 ppm 1.24 - 1.29 (m, 6 H) 1.81 - 1.86 (m, 2 H) 2.09 - 2.12 (m, 6 H) 2.27
[0674] [0674] A mixture of (E) -1 - ((E) 4 - ((E) -S-carbamoyl-2 - ((1-ethyl-3-methyl-1H-pyrazol-5-carbonyl) imino) - 3-methyl-2,3-dihydro-1H-benzo [d] imidazo | -1-i1) -2,3-dimethylbut- 2-en-1-i1) -2 - ((1-ethyl-3-methyl -1 H-pyrazol-5-carbonyl) imino) -7-hydroxy-3-methyl-2,3-dihydro-1H-benzo [d] imidazole-5-carboxamide (384 mg, 0.513 mmol), (3-bromopropyl ) tert-butyl carbamate (733 mg, 3.08 mmol) and K2CO; 3 (425 mg, 3.08 mmol) in DMF (10 mL) was heated to 90º C for nine days. LCMS analysis indicated partial conversion to the O-alkylated intermediate, increasing with time until reaching about 50% conversion in 9 days. The reaction mixture was filtered and concentrated. The residue was purified by preparative mass-directed HPLC (XSELECT CSH C18 column, 5 µm packaging, 150x30 mm, 15-55% ACN / water gradient with 0.1% TFA modifier) to obtain 100 mg of a residue brown after solvent evaporation. The residue was a mixture of the intermediate N-Boc and the title compound (removal of the Boc group occurred during evaporation of the solvent). The residue was dissolved in methanol (1 ml) and 1,4-dioxane (2 ml) and sonicated in a brown solution, then HCI (4 M in dioxane, 1.282 ml, 5.13 mmol) was added. The mixture was sonicated again, and the mixture was stirred at room temperature for 3 h. The reaction mixture was concentrated, dissolved in DMSO and then purified by preparative mass-directed HPLC (XSELECT CSH C18 column, 5 µm packaging, 150x30 mm, 15-55% ACN / water gradient with formic acid modifier 0.1%) to obtain (E) -7- (3-aminopropoxy) -1 - ((E) -4 - ((E) -5-carbamoyl-2 - ((1-ethyl-3-methyl- 1H-pyrazol-5-carbonyl) imino) -3-methyl-2,3-dihydro-1H-benzo [d] imidazo | -1-i1) -2,3-dimethylbut-2-en-1-yl) - 2 - ((1-ethyl-3-methyl-1H-pyrazol-5-carbonyl) imino) -3-methyl-2,3-dihydro-1H-benzo [d] imidazole-5-carboxamide, formic acid salt ( 8.0 mg, 9.4 umol, 1.8% yield) as a white solid. * H NMR (400 MHz, DMSO-ds) 5 ppm 8.36 (s, 1 H), 8.12 (s, 2 H), 8.05 (br. S, 1 H), 7.76 -7.84 (m, 2 H), 7.53 (s, 1 H), 7.47 (s, 1 H), 7.44 (s, 1 H), 7.25 (d, J = 8 , 5 Hz, 1 H), 6.47 (s, 1 H), 6.32 (s, 1 H), 5.06 (s, 2 H), 4.85 (s, 2 H), 4, 41-4.57 (m, 4 H), 4.22 (t, J = 6.4 Hz, 2 H), 3.59 (s, 3 H), 3.56 (s, 3 H), 2 , 77 (t, J = 6.9 Hz, 2 H), 2.12 (s, 3 H), 2.06 (s, 3 H), 1.84 (quin, J = 6.5 Hz, 2 H), 1.63 (s, 3 H), 1.49 (s, 3 H), 1.29 (t J = 7.1 Hz, 3 H), 1.24 (t, J = 7.1 Hz, 3 H). LCMS (m / z): 806.3 [M + HJ *.
[0675] [0675] Table 3 shows Examples 93 to 109, which can be prepared according to the methods given below: EE and E Scheme Name / Structure Example LCMS (m / z) [M + H] * (E) - 2 - ((1-ethyl-3-methyl-1H-pyrazol-5- | * H NMR (DMSO-ds) 5 Example | Method 1 | carbonyl) imino) -1 - ((E) -4 - (( E) -2- ppm 9.67 (br. S., 1 H), 93 1-ethyl-3-methyl-1 H-pyrazol-5- 8.07 (br. S., 1 H), 7, 83 carbonyl) imino) -3-methyl-2,3- (s, 1 H), 7.62 (d, J = 8.0 dihydro-1H-benzo [d] imidazole-1-i1) - | Hz, 1 H), 7.51 (s, 2H), 2,3-dimethylbut-2-en-1-i) -3-methyl- / 7.34 (ddd, J = 8.1, 6.2 , 7- (3-morpholinopropoxy) -2,3- 2,3 Hz, 1 H), 7,17-7,24 dihydro-1Hbenzo [d] imidazole-5- (m, 2 H), 647 (s, 1 H), carboxamide, 6.31 (s, 1H) acid salt, 5.07 (s, 2 trifluoroacetic H), 4.84 (s, 2 H), 4.44-AH 4.56 (m, 4 H), 4.19 (t, NJ = 6.0 Hz, 2 H), 3.93 (br.
[0676] [0676] A 1- (4- (5-carbamoyl-2- (1-ethyl-3-methyl-1H-pyrazol-5-carboxamido) -1H-benzo [d] imidazo | -1 bis trifluoroacetic acid salt -yl) butyl) -2- (1-ethyl-3-methyl-1H-pyrazole-
[0677] [0677] Acid - 1- (4- (5-Carbamoyl-2- (1-ethyl-3-methyl-1H-pyrazol-5-carboxamido) - 1H-benzo [d] imidazol-1-yl) butyl) - 2- (1-ethyl-3-methyl-1 H-pyrazol-5-carboxamido) -1H-benzo [d] imidazole-5-carboxylic (10 mg, 0.015 mmol) was dissolved (with sonication) in DMSO (300 uL ) at 37º C. To this mixture, a solution of (9H-fluoren-9-yl)] methyl (2-aminoethyl) carbamate hydrochloride (6.9 mg, 0.022 mmol) and HATU (7.6 mg, 0.020 mmol) in DMSO (100 µL), followed by DIEA (10 µL, 0.057 mmol). After stirring overnight, the reaction was diluted with DMF (600 µl), 4-methylpiperidine (400 µl) was added, and the reaction was stirred at RT for 1 hour. The mixture was concentrated, and the resulting residue was diluted with 1: 1 DMSO: MeOH (<1 mL) and purified by reverse phase chromatography (preparative column Jupiter C18, 10 mL / min), eluting with 30% to 100% (9: 1 ACN: water) in water (0.1% TFA additive) to obtain the title compound (8.45 mg, 10.1 umol, 69% yield). LCMS: Rt = 0.62 min, [M + H] * = 722.4 Step 2: 3 ', 6'-diamino-5 - ((2- (1- (4- (5-carbamoyl-2- (1-ethyl-3-methyl-1H-pyrazol-5-carboxamido) -1H-benzo [d] imidazol-1-yl) butyl) -2- (1-ethyl-3-methyl-1H-pyrazol-5- carboxamido) -1H-benzo [d] imidazole-5-carboxamido) ethyl) carbamoyl) -3-0x0-3H- spiro [isobenzofuran-1,9'-xanthene] -4 ', 5'-disulfonic o OB ss
[0678] [0678] Trifluoroacetic acid salt of N- (2-aminoethyl) -1- (4- (5-carbamoyl-2- (1-ethyl-3-methyl-1H-pyrazol-5-carboxamido) -1H-benzo [ d] imidazol-1-yl) butyl) -2- (1-ethyl-3-methyl-1H-pyrazol-5-carboxamido) -1H-benzo [d] imidazole-5-carboxamide (8.45mg, 10.1 umol) was dissolved in DMF (200 µl) and added to solid (5.6-) Alexa Fluor 488-ONSu (5.00 mg, 7.92 µmol). The commercial reagent Alexa Fluor 488-ONSu was a mixture of positional isomers 5 and 6. o + 5-isomer * ”o o 1 HN <>) A) os,% no o À Cd%. Ss NH —6 isomer in To
[0679] [0679] When the solution was made, DIPEA (2 µl, 0.01 mmol) was added, and the mixture was stirred (by vortexing) overnight in the absence of light. LCMS revealed peak product formation eluting earlier and later with the expected molecular weight ([M + H] 1238.6). The reaction was concentrated, and the residue was dissolved in 1: 1 DMSO: MeOH (<1 mL) and purified by reverse phase chromatography (preparative column Jupiter C18, 10 mL / min), eluting with 15-100% ( 9: 1 ACN: water) in water (0.1% TFA additive). The positional isomer eluting earlier was obtained in high purity. In contrast, the isomer fractions eluting later also contained unreacted starting material. Those fractions containing the isomer eluting later impure were pooled and concentrated. This residue was dissolved in 1: 1 DMSO: MeOH (<1 mL) and purified by reverse phase chromatography (Waters SymmetryPrep preparative column, 10 mL / min), eluting with 15-100% (9: 1 ACN: water) in water (0.1% TFA additive) to obtain the title compound (isomer eluting later, 1.94 mg, 1.49 umol, 19% yield). LCMS: Rt = 0.69 min, [M + H] * = 1238.6. Note that the putative structure of the title compound (5-isomer) is not based on rigorous structural determination, but instead is based on earlier observations that positional isomer 5 is typically the isomer eluting later by reverse phase HPLC methods.
[0680] [0680] As mentioned above, the compounds of the present invention are modulators of STING and useful in the treatment of STING-mediated diseases. The biological activities of the compounds of the present invention can be determined using any suitable assay to determine the activity of a compound as a modulator of the STING, as well as tissue and in vivo models.
[0681] [0681] The plC5so value for each compound was obtained by at least one experiment or by the average of multiple experiments. It is understood that the data described in this document may have reasonable variations depending on the specific conditions and procedures used by the professional conducting the experiments.
[0682] [0682] A radioligand binding assay was developed to measure the interactions between compounds of Formula (1) and the carbon-terminal domain (CTD) of STING by competition with 3H-cCGAMP (guanine monophosphate (2 ', 5') -cyclic (3 ', 5') adenine labeled with tritium). See also Li et al. (Nature Chemical Biology, 10, 1043-1048, (2014)). A protein encoding the human STING sequence spanning residues 149 to 379 (Gene ID 340061) was expressed in bacteria with a Carbo-terminal Flagº peptide fused to AviTag "Y for biotinylation and a hexahystine tag for purification of affinity The purified STING-Flag-AviTag-6Xhis protein was biotinylated to completion using the BirA enzyme (Beckett D. et al., Protein Science, 1999, 8: 921-929). The relative potency of the Formula (1) compounds was determined by competition in equilibrium binding reactions containing 50 nM biotinylated STING, 50 nM 3H-cCGAMP and 1.25 mg / mL scintillation proximity test beads coated with streptavidin (Perkin Elmer) in buffered saline buffer with phosphate containing 0.02% (w / v) of Pluronic F127 and 0.02% (w / v) of bovine serum albumin in 384 white Greiner wells (tt catalog 784075) pre-stamped with 100 to 250 nL of compound in pure DMSO. The binding reactions were incubated in for 60 minutes. Luminescence was measured (ViewLux '") and crude counts were expressed as% inhibition using the formula pel - (=)' or, where U is the unknown value, C1 is the average response of complete inhibition by 10 µM of CGAMP , and C2 is the mean of the maximum response. The curve adjustment was performed using Y = A + [E equation 1 +), where A is the minimum response, B is the maximum response, C is logio * XC50, D is the slope factor, ex is log of the concentration of the compound
[0683] [0683] Using the SPA assay described above, the compounds of Examples 1 to 5e7a9, 11a14,16e19 were tested and exhibited plCs5o values in the range of 7 beyond the upper assay limit of 7.4.
[0684] [0684] The binding power of molecules with the C-terminal Domain (CTD) of human STING was determined using a competition binding assay. In this assay, the recombinant protein STING (149-379) with a biotinylated C-terminal Avi-tag was employed. When connected to STING, an Alexa488-labeled orthostatic site probe (see pages 347 to 350 about FRET assay ligand synthesis) accepts 490 nm emission from Tb-Streptavidin-Avi-STING and an increase in fluorescence is measured at 520 nm. The molecules that compete for the probe binding site will result in a low 520 nm signal. The assay was performed on 384 black Greiner well plates (Catalog tt 784076) with 100 nL of compounds in pure DMSO. A 500 pM STING solution, 500 pM Streptavidin-Lumi4-Tb and 100 nM Alexa488 probe in phosphate buffered saline containing 0.02% (w / v) Pluronic F127 and 0.02% (w / v ) of bovine serum albumin was added to the plate using a Combi liquid handler (ThermoFisher). The plates were centrifuged for 1 min at 500 rpm, incubated for min at room temperature, and thereafter the fluorescent emission at 520 nm, followed by laser excitation at 337 nm in an Envision plate reader (Perkin-Elmer), was measured. The plC5o values were determined using the standard four-parameter curve fit in ABASE XE described above.
[0685] [0685] Using the FRET assay described above, Examples 1 to 42, 44 to 89 and 91 to 108 were tested and exhibited plCs5o values in the range of 5.0 beyond the upper limit of the assay at 9.9.
[0686] [0686] For example, the PLT of the FRET assay for the following examples was: as as s8 to as ss Functional Cellular Assays
[0687] [0687] The function of the compounds of Formula (|) can be determined in cell assays that detect specific STING activation and / or inhibition of IFNB protein secretion. (1) Functional Test | (PBMC antagonist assay): Inhibition of STING by compounds of Formula (1) can be determined by measuring the loss of B interferons secreted by peripheral blood mononuclear cells (PBMCs) stimulated with a STING agonist (Example 167 described in the publication PCT No. WO 2017175147) at a concentration of EC80 or 77 nM Bacmam virus,
[0688] [0688] Using the Functional Assay | (PBMC antagonist assay) described above, Examples 1 to 4, 12, 13, 18 to 20, 23 to 25, 27, 29 to 34, 36, 38, 40, 41, 45, 47, 48 were tested , 50, 53, 54, 56 to 60, 63, 65 to 67, 69 to 72, 74.76 to 89, 91 and 93 to 105. Examples 2, 3, 13, 18-20, 23 to 25, 27 , 29-34, 38, 40, 41, 45, 47, 48, 50, 53, 54, 56 to 60, 63, 65 to 67, 69 to 72, 74, 76 to 89, 91 and 93 to 105 exhibited values plCs5o in the range of 4.3 beyond the upper limit of the assay at 8.1.
[0689] [0689] For example, the plCso of the assay with PBMC antagonists for the following examples was: Example No. PBMCs (plC50 NM
[0690] [0690] Using Functional Il Assay (assay with PBMC agonists) described above, Examples 1 to 4, 12, 13, 18 to 20, 23 to 25, 27, 29 to 34, 36, 38, 40 were tested , 41, 45, 47, 48, 50, 53, 54, 56 to 60, 63, 65 to 67, 69 to 72, 74, 76 to 89, 91, 93 and 94 to 105. Examples 1 to 4, 12 , 13, 81 and 88 exhibited pEC50 values in the range of 4.3 to 7.3. All other compounds tested exhibited a pEC50 less than 4.3.
[0691] [0691] Using the functional assay Ill (HEK WT agonist assay) described above, Examples 1 to 9, 11 to 22, 24 to 28, 35, 36, 39, 45 to 52 and 72 to 74 were tested. Examples 1 to 9 are 11 to 16, 24, 26 to 28, 35, 39, 48, 49 and 73 exhibited pECs5o values in the range of 5.1 beyond the upper limit of the assay at 8.1. Maximum responses ranged from 5% to 139% of control wells.
[0692] [0692] Inhibition of STING by compounds of Formula | was determined by measuring the loss of B interferons secreted by human PBMCs or immortalized THP-1 cells stimulated with a baculovirus-containing dsDNA (Bacmam virus). THP-1 cells arranged in 96-well round-bottom plates at a density of 1 x 10 th cells / well in a medium (RPMI-1640 with 1.5 g / L NaHCO ;, 4.5 g / L glucose, 10 mM Hepes and 1 mM NaPyruvate, 10% FBS, 1% PSF, 50 UM B-MeOH) were incubated with varying concentrations of STING antagonists for 60 minutes, followed by the addition of Bacmam virus (final MOI of 40 pfu / cell). The level of IFNB protein secreted in the growth medium was measured after 6 to 20 hours of incubation at 37º C using an IFNB electrochemiluminescence kit (Meso Scale Diagnostics) following the manufacturer's instructions. IFNEB levels (pg / ml) were converted to the percentage of inhibition compared to controls without treatment with the compound (control 1) or infection with the Bacmam virus (Control 2) and adjusted using a minimum four square fit model sigmoidal parameters to define the potency of the compound given by plC50. 100 x (1- (Sample well- (Control 2)) / (Control 1- Control 2).
[0693] [0693] Using the functional assay IV (assay with THP-1 antagonists) described above, Examples 1, 3 to 5, 7-9, 12 to 14, 16 to 20,22, 24 to 26, were tested,
[0694] [0694] For example, the plCso of the assay with THP-1 antagonists for the following examples was: Pa No. of Example THP-1 (plC50 1st bone o oa o as a s6 | a | s6 | e

权利要求:
Claims (26)
[1]
1. Composed according to Formula (!): D RX | We N R | RE =) N—. OO-; e É É NAN Re de RE Do Ad D. j RE - = - N No.
IS ly XY & RO RO Re (1) FEATURED by the fact that: gébdoul; reedoul; seboul; where q + r + s = 10 or 2; when q is O, each of Rº 'and RM is independently H, halogen, hydroxy, - -OP (O) (OH), - -OP (O) (RR!) and —-N (RNR), -COXR , -N (RJCOR ', -N (R9) SO2 (C1-alkyl) -N (RºN (R), - -N (R9) CO (C1-alkyl)) -N (RºP) (R'), - ( optionally substituted C 1 -C 6 alkyl) (optionally substituted C 1 -C 6 alkyl) amino-substituted (C 1 -C 6 alkyl) amino-substituted (C 1 -C 6 alkyl) (C 1 -C alkyl) where (C 1 -C 6 alkyl) is said optionally substituted (C 1 -C 6 alkyl), optionally substituted (C 1 -C 6 alkyl) -oxy, optionally substituted (C 1 -C: alkyl) + optionally substituted (C 1 -C) alkyl (C: -C 1) alkyl - optionally - optionally substituted substituted with 1 to 4 substituents, each independently selected from a hydroxy group, -OP (O) (OH) 2, -OP (O (RIR!) 2, Ci-Ca-, -N (RNR '), -COXR ), -CON (R (R '), optionally substituted phenyl,
optionally substituted 5 to 6 membered heterocycloalkyl and optionally substituted 5 to 6 membered heteroalkyl, wherein said phenyl, 5 to 6 membered heterocycloalkyl or optionally substituted 5 to 6 membered heteroaryl is optionally substituted with 1 to 4 substituents, each independently selected from Ci-Ca alkyl, halogen, hydroxy, -OP (O) (OH) 2, -O- P (OXRIR!) 2, amino, (C1-Cs alkyl) amino-, (C1-C6 alkyl) (C1-alkyl) ) amino-, - (C1-Cs alkyl) -NH2a, - halo (C1-Cs alkyl), - hydroxy- (C1-Ca alkyl) -, - - (C1-Ca alkyl) -O- P (O) (OH) 2, - (C1-Ca alkyl) -OP (O) (RIR "') 2, halo (C1-Ca alkoxy) -, C-Ca- alkoxy, hydroxy- (Ca-Ca alkoxy) -, (C2-Ca alkoxy) -OP (O) (OH) z, - (C2-alkoxy) -OP (O) (RIR!) 2, -C1-Ca- (alkoxy-C1-Ca) and C1-Ca- (alkoxy-C-alkoxy) -;
when r is O, each of Rº and RP is independently H, optionally substituted C1-Cs alkyl, —halo (C: alkyl + + - Cs), optionally substituted C2-Cs alkenyl, optionally substituted C2-Cs alkynyl, optionally substituted C3-Ce cycloalkyl, optionally substituted 4- to 6-membered heterocycloalkyl, phenyl optionally substituted, optionally substituted 5 to 6 membered heteroaryl, or optionally substituted 9 to 10 membered heteroaryl,
wherein said optionally substituted C: -Cs alkyl, optionally substituted C2-Cs alkenyl, optionally substituted C2-Cs alkynyl, optionally substituted C3-Cs cycloalkyl, optionally substituted 4- to 6-membered heterocycloalkyl, optionally substituted phenyl, 5- to 6-membered heteroaryl optionally optionally substituted 9 to 10 membered heteroarlia is optionally substituted with 1 to 4 substituents, each independently selected from halogen, nitro, -Rº, -OH, -OP (O) (OH)>, -OP (O) (RR! ) 2, -ORº, -NH2, -NRºRº, -NRºR $, -OCORº, -CO2H, -CO2Rº, -SORº, -SO2Rº, -CONH2, -CONRºRº, -SO2NH2, -SO2NRºRi, -OCONRºR, NRºCORº, -NRISORº, -NRÍCO2Rº, and -NRÍSO2Rº;
when s is O, Rº is H, halogen or C1-Ca alkyl, and Rº is optionally substituted C1-C4-alkyl, wherein said optionally substituted C1-C4-alkyl group is optionally substituted with a substituent selected from -ORº, -NRºR $ º, -CO2Rº, -CONRºRº, -SO2NRºRº and -OCONRºR $;
when q is 1, each of Rº 'and R * º is independently -CH2-, -NRº- or -O-, and A, together with Rº * and RM, forms a linking group, where A is -halo (C1-C12 alkyl) -, optionally substituted -C1-C12- alkyl, optionally substituted -C2-C12- alkenyl, optionally substituted -C2-C12- alkynyl, -C1-Ce- O -C1-Ce- alkyl- optionally substituted, -C1-Ce- alkyl- NRº-C1-Ce- optionally substituted, -C1-Ce- (cycloalkylC3-Cs) -C1-Ce- alkyl optionally substituted, -C1-Cs-phenyl-C1-Ce- optionally substituted, -C1-Ce- (heterocycloalkyl of 4 optionally substituted -C1-Cs-alkyl- or C-alkyl + -Cs- (5- to 6-membered heteroaryl) -C optionally substituted -Ce-,
wherein said alkyl group of said optionally substituted -C1-C12- alkyl, optionally substituted -C2-C12- alkenyl, optionally substituted -C2-C12- alkynyl, optionally substituted C1-C6-O-Ci-alkylCe- alkyl optionally substituted C1-Ce-NRº-C1-Ce6- alkyl, -C1-Ce- (C3-Cs cycloalkyl) -C1-Cs-alkyl optionally substituted, -C1-Cs-phenyl-C1-Cs-alkyl-optionally substituted, -C1-Cs- alkyl (4- to 6-membered heterocycloalkyl) -C1-Cs-optionally substituted or -C1 -C-alkyl- (5- to 6-membered heteroaryl) -C1-optionally substituted -Cs- is optionally substituted with 1 to 4 substituents independently selected from halogen, halo (C1-Ca alkyl), -OH, -OP (O) (OH) 2, -OP (O) (RIR ") 2, -ORº, -NHa, -NRºR $, -OCORº, -CO2H, -CO2Rº, -SORº, -SO2Rº, -CONH2, -CONRºRº, -SO2NHº, -SO2NRºRº, -OCONH> 2, -OCONRºR $ º, -NRICORº, -NRISORº, -NRCO2Rº and -NRISO2Rº, and the cycloalkyl group, from 4 to 6 5- or 6-membered heteroaryl of said -C1-alkyl + -Cse- (C3-Cs-cycloalkyl) - optionally substituted C1-Ce- alkyl, -C1-Ce-phenyl-C1-Ce- optionally substituted, -Cs- (heterocycloalkyl) (heterocycloalkyl) 4 to 6 members) - optionally substituted C 1 -Cs alkyl or -C 6 alkyl- (5 to 6 members heteroaryl) -C 1 optionally substituted alkyl is optionally substituted with 1 to 4 substituents, each independently selected from halogen, hydroxy, -OP (O) (OH) ,, -OP (O) (RIR!) 2, amino, (C1-Ca alkyl) amino-, (C1-Ca alkyl) (C1-Ca alkyl) amino-, C1-Ca alkyl, halo (C 1 -C alkyl), halo (C 1 -C alkoxy) -, C 1 -C alkoxy, hydroxy- (C 1 -C alkoxy) -, - (C 1 -C alkoxy) -OP (O) (OH) 2, - (C 1 -C alkoxy) ) -O- P (OX (RIR! ") 2 and C1-Ca alkoxy (C1-Ca alkoxy) -;
when r is 1, each of R8º and RE is independently -CRºRi-, and B, together with R8º and R8 , forms a bonding group, where B is a bond or B is -halo (C1-C10-alkyl) -, optionally substituted -C1-C10- -alkylenyl -C10- optionally substituted, -C2-C10 -alkynyl optionally substituted, -C1-Ce- O-alkylC1-Cs- optionally substituted, -C1-Ce-NRº -C1-Ce- optionally substituted, optionally substituted -C3-Cs cycloalkyl, optionally phenyl substituted, optionally substituted 4- to 6-membered heterocycloalkyl, optionally substituted 5- to 6-membered heteroaryl, -C1-C1-alkyl (C3-Cs cycloalkyl) -C1-C4-alkyl - optionally - substituted, - -C1-Ca-phenyl-C1-alkyl C4- optionally substituted, optionally substituted -C1-Ca- alkyl (4- to 6-membered heterocycloalkyl) -C1-C4-alkyl- or optionally substituted -C1-Ca- (5-6 membered heteroaryl) -C1-C4- alkyl
wherein the alkyl group of said optionally substituted -C1-C10- alkyl, -C2-C10- alkenyl - optionally - substituted, - optionally substituted -C2-Ci10- alkynyl, -C1-Ces-O-C1-C6- alkyl optionally substituted, - optionally substituted C1-Ce-NRº-C1-Ce- alkyl, -C1-Ca-alkyl-
(optionally substituted - C1-C4a- cycloalkyl) -C4-alkyl, - optionally substituted -C1-Ca-phenyl-C1-C4-alkyl, -C1-Ca- (4- to 6-membered heterocycloalkyl) -C1-C4- optionally substituted or -C1-Ca- alkyl (5- to 6-membered heteroaryl-C1-C4-alkyl) - optionally substituted is optionally substituted with 1 to 4 substituents, each selected from -C1-Ca-alkyl, halogen, halo (C1-Ca-alkyl), -OH , -OP (O) (OH) a, -OP (OKRIR!) A, -ORº, -NH2, -NRºRº, -OCORº, -CO2H, -CO2Rº, -SORº, -SO2Rº%, -CONH2z, -CONRºRº, -SO2NH>, -SO2NRºR%, -OCONH2, -OCONRºRº, -NRºCORº, -NRÍ $ SORº, -NRºCOXRº and -NRºSO> 2Rº, and the cycloalkyl group of C3-Cse, phenyl, heterocycloalkyl of 4 to 6 members or heteroar 6 members of said optionally substituted C3-C6 cycloalkyl, optionally substituted phenyl, optionally substituted 4- to 6-membered heterocycloalkyl, optionally substituted 5- to 6-membered heteroaryl, -C1-alkyl-Ca- (C3-Cse-cycloalkyl) -C4-alkyl-opium optionally substituted, optionally substituted -C1-Ca- phenyl-C1-C4-alkyl, -C1-C4-alkyl- (4- to 6-membered heterocycloalkyl) -C1-C4- optionally substituted -C1-Ca- (5- to 6-membered heteroaryl ) -C1-C4- optionally substituted alkyl is optionally substituted with 1 to 4 substituents, each independently selected from halogen, hydroxy, -OP (O) (OH) 2, -OP (O) (RIR! ') 2, amino, (C1-Ca alkyl) amino-, (C1-Ca alkyl) (C1-Ca alkyl) amino-, C1-Ca alkyl, halo (C 1 -C 4 alkyl), halo (C 1 -C alkoxy) -, C 1-Ca- alkoxy, (hydroxy- Ca) -, - (alkoxyCa-Ca) OP (O) (OH) 2, - (alkoxyCa-Ca) -O- P (OXRIR ") 2 and alkoxyC1-Ca- (alkoxyC1-Ca) -;
when s is 1, each of Rº and Rº is independently -CH2-, and C, together with Rº * and Rº , forms a linking group, where C is -halo (C1-C12alkyl) -, -C1-C12-alkyl - optionally - substituted, - -alkenylC2- C12- - optionally substituted, optionally substituted -C2-C12- alkynyl, optionally substituted -C1-Ce-alkylO-C1-Ce-, optionally substituted -C1alkyl-Ce-NRº -C1-Ce6- alkyl,
optionally substituted C1-Ce- (C3-Cs cycloalkyl) -C6-alkyl, optionally substituted -C1-Cse-phenyl-C1-Cs- alkyl, optionally substituted -C1-Cs- (4- to 6-membered heterocycloalkyl) -C1-Cs-optionally substituted or optionally substituted -C1-Ce- (5- to 6-membered heteroaryl) -C1-Cs- alkyl,
wherein the alkyl group of said optionally substituted -C1-C12- alkyl, - -C2-C12- alkenyl - optionally - substituted, - optionally substituted -C2-C12- alkynyl, -C1-Ce-O-C1-Cs- alkyl optionally substituted, - optionally substituted C1-Ce-NRº-C1-Ce- alkyl, -C1-Ce- (C3-cycloalkyl) -C1-alkyl + -Cs- - optionally - substituted, - -C1-Ce-phenyl-C1-Ces-optionally substituted, -alkylC-alkyl : -Ce- (4- to 6-membered heterocycloalkyl) -C1-Ce- optionally substituted or -C1-Ce- alkyl (5-6 membered heteroaryl) -C1-optionally substituted -Cs- is optionally substituted with 1 or 2 substituents, each independently selected from halogen, halo (C1-Ca alkyl), -OH, -OP (O) (OH) 2, -OP (O) (RIR!) 2nd, -ORº, -NH>, -NRºRº, -OCORº , -CO2H, -CO2Rº, -SORº, -SO2Rº, -CONH2, -CONRºRº, -SO2NH>, -SO2NRºRº, -OCONH2, -OCONRºRº, -NRICORº, -NRI $ SORº, -NRÍCORº and -NRÍRORO -Cs, phenyl, heterocycloalkyl from 4 to 6 members or from 5 to 6 members heteroaryl of said -Cse- (C3-Cs-cycloalkyl) -C1-Ce- alkyl optionally substituted, -C1-Ce-phenyl-C1-Ce- alkyl optionally substituted, -C-alkyl: -Ce- (4- to 6-membered heterocycloalkyl) - optionally substituted C1-Cs-alkyl or -C 6 -alkyl (5- to 6-membered heteroaryl) -C1-Cs-optionally substituted-alkyl is optionally substituted with 1 to 4 substituents, each selected independently from halogen, hydroxy, -OP (O) (OH) 2, -OP (O) (RIR!) 2, amino, (C1-Ca alkyl) amino-, (C1-Ca alkyl) (C1-Ca alkyl) amino-, C 1 -C alkyl, halo (C 1 -C alkyl), halo (C 1 -C alkoxy) -,
alkoxyC1-Ca-, hydroxy- (alkoxyCa-Ca) -, - (alkoxyCa-Ca) -OP (O) (OH) 2, - (alkoxyCa-Ca) -O- P (OXRIR! ") 2 and alkoxyCi-Ca - (C1-Ca alkoxy) -;
each of Rº and Rº is independently -CON (Rº) (R '), or one of Rê and Rº is -CON (Rº) (R') and the other of Rº and Rº is H, COOH or -CO2 (Rº );
each of Rº and R $ is independently selected from H, halogen, halo (C1-C6 alkyl), halo (C1-Cs alkoxy) -, hydroxy, -OP (O) (OH) 2, -OP (O) (RIR! ) 2, -NH>, “NRºRº, -NRºR9, -CORº, -CO2Rº, -N (RI) COR" º, -N (RI) SO2Rº, -N (R9) SOz (C1-C2 alkyl) - N (RP (RI), -N (R9) CO (C1-C6 alkyl) -N (R ") (R), optionally substituted (C1-C6 alkyl), optionally substituted (C1-C6 alkyl) 9oxy-, (C + -Cs alkyl) amino- optionally substituted and (optionally substituted C1-Ce) (C1-alkyl) amino-optionally,
wherein the optionally substituted (C1-Cs) alkyl (C1-Cs) is optionally substituted (C1-C6 alkyl) oxy- optionally substituted, (optionally substituted C + -Cs alkyl) and (alkyl C + -Ce) (alkylC + -Ca) amino- optionally - substituted - is optionally substituted with 1 to 4 substituents, each independently selected from a group -OH, -OP (O) (OH) 2, -OP (OX) (RIR! ") 2, -ORº, -NH > 2, -NRºRº, -NRºR $, -CO2H, -CO2RºY, -OCORº, -CO2H, -CO2Rº, -SORº, -SO2Rº, -CONH2, -CONRºRi, -SO2NH2, -SOaNRºRi, -OCONRº, NRºCORº, -NRISORº, - -NRÍCO2Rº, —-NRÍSO2Rº, optionally substituted phenyl, optionally substituted 5- to 6-membered heterocycloalkyl and optionally substituted 5 to 6-membered heteroaryl, in which the referred phenyl, 5 to 6-membered heterocycloalkyl or 5-to-heteroaryl optionally substituted 6-membered optionally substituted with 1 to 4 substituents, each independently selected from halogen, hydroxy, -OP (O) (OH) 2, -OP (O) (R'R ") 2, amino, (alkyl C1-Ca)> amino-, (C1-Ca alkyl) (C1-Ca alkyl) amino-, C1-Ca alkyl, halo (C1-Ca alkyl), hydroxy- (C1-Ca alkyl) -, - - (C1-Ca alkyl) -OP (O) (OH) 2, - - (C1-Ca alkyl) -OP (O) (RIR!) 2, halo (C1-Ca alkoxy) -, C1-Ca- alkoxy, hydroxy- (Ca-Ca alkoxy) -, - ( alkoxyCa-Ca) -OP (O) (OH) 2,
(C4-alkoxy) -O-P (O) (RIR!) 2, C1-Ca- (C1-alkoxy) -, -CORI, -CON (RINR ') and -CO2R *;
R * * Is optionally substituted C1-Ca alkyl, wherein said optionally substituted C1-Ca alkyl is optionally substituted with a substituent selected from -ORº, -NRºRº, -CO2Rº, -CONRºR $, -SO2NRºRº and -OCONRºR $ º;
R'º is H, halogen or C1-Ca alkyl;
each of R ** and R'7 is independently H, cyclopropyl or C1-Ca alkyl;
Rº is H, -Rº, -CORº, -CO2H, -CO2Rº, -SORº, -SO2Rº, -CONH2, -CONRºRº, -SO2NH> 2 or -SO2NRºR $ º;
each Rº is independently C-alkyl: -Ca, —halo (C1-C4 alkyl), - (C1-Ca alkyl) -OH, “(C1-Ca alkyl) -OP (O) (OH)>, - (C1-Ca alkyl) -OP (O) (RIR! ') 2, - (C1-Ca alkyl) -O- (C1-Ca alkyl), “(C1-Ca alkyl) -N (RºN (R), - (C1-Ca alkyl) -O- CO ( C1-C4alkyl) or - (C1-Ca4alkyl) -CO-O- (C1-Ca4alkyl);
each R ° is independently C: alkyl: -Ca, —halo (C1-alkyl), (C1-alkyl) -OH, (C1-alkyl) -OP (O) (OH) ,, (C1-alkyl) -OP (O) (RIR!) 2, - (C1-Ca4 alkyl) -O- (C1-C4 alkyl), - (C1-Ca alkyl) -N (Rº) (R), - (C1-Ca4 alkyl) -O- CO (C1-C4 alkyl) ), - (C1-Ca alkyl) -CO-O- (C1-C4 alkyl), optionally substituted C3-Ces cycloalkyl, optionally substituted phenyl, optionally substituted 4 to 6 heterocycloalkyl, optionally substituted 5 to 6 membered heteroaryl, 9 to 9 heteroaryl 10-membered optionally substituted, -C1-Ca- cycloalkylC3-Csyl - optionally - substituted, —-C1-alkyl-Ca-phenyl optionally substituted, -C6-alkyl + -Ca-heterocycloalkyl, 4- to 6-membered optionally, optionally substituted 6-membered or optionally substituted 9 to 10-membered C1-Ca-heteroaryl,
wherein the C3-Cs cycloalkyl group, phenyl, 4 to 6 membered heterocycloalkyl, 5 to 6 membered heteroaryl or 9 to 10 membered heteroaryl optionally - substituted from said substituted C3-Cs cycloalkylyl, optionally substituted phenyl, 4 to 6 membered heterocycloalkyl optionally substituted, optionally substituted 5 to 6 membered heteroaryl, optionally substituted 9 to 10 membered heteroaryl, -Ca-cycloalkylC3a-Cs optionally - substituted, -C1alkyl-Ca-phenyl - optionally - substituted, -C1alkyl-Ca- optionally substituted 4- to 6-membered heterocycloalkyl, optionally substituted 5- to 6-membered C1-alkyl-Ca-heteroaryl or optionally substituted 9 to 10-membered C1-alkyl-Ca-heteroaryl is optionally substituted with 1 to 4 substituents, each independently selected from among halogen, hydroxy, -OP (O) (OH) a, -OP (O) RIR!) a, amino, - (C 1 -C alkyl) NHs, (C 1 -C alkyl)> amino-, (C 1 -C alkyl) (C 1 alkyl) -Ca) amino-, -C1-Caalkyl, halo (C1-C4 alkyl), halo (C1-Ca alkoxy) -, C1-Ca- alkoxy, hydroxy- (C2-Ca alkoxy) -, - (C2-C4 alkoxy) -OP (O) (OH) z, - (C2-C4 alkoxy) ) -OP (O) (RIR! ") 2, C1-Ca- (C1-alkoxy) -, -COR, -CON (Rº) (R ') and -CO2Rº;
each R $ is independently H or C1-Ca alkyl;
each Rº is independently H, C1-Caalkyl, -CO (C1-Ca4alkyl), -OCO (C1-C4alkyl), -CO2 (C1-Ca4alkyl), - (C1-Ca4alkyl) NH> 2, - (C1-alkyl) C1-1 alkoxy, -CO- (optionally substituted 5-6 membered heterocycloalkyl), -CO (optionally substituted 5-6 membered heterocycloalkyl), -CO (optionally substituted 5-6 membered heteroarla) or -CO (C1-Ca alkyl) - (optionally substituted 5-6 membered heteroaryl),
wherein the optionally substituted 5- to 6-membered heterocycloalkyl or optionally substituted 5- to 6-membered heteroaryl is optionally substituted with 1 to 4 substituents, each independently selected from halogen, hydroxy, -OP (O) (OH) :, -OP (O) (RIR!) 2, amino, (C1-Ca alkyl) amino-, (C1-Ca alkyl) (C1-alkyl) amino-, C1-Ca alkyl, halo (C1-Ca alkyl), halo (C-alkoxy) - , C1-Ca- alkoxy, hydroxy- (alkoxy-Ca-Ca) -, - (alkoxyCa-Ca) OP (O) (OH) 2, - (alkoxyCa-Ca) -O- P (OXRIR!) 2, C1-alkoxy- (C1-C4 alkoxy) -, -COR, -CON (RI) (R ') and -CO2R $;
each R 'is independently H or C 1 -C 10 alkyl; each of Rº and R 'is independently H or C1-Caalkyl, or Rº and Rº, together with the atom or atoms through which they bond, form a 5-6 membered ring; and each occurrence of R 'and R! is independently (C 1 -C 6 alkyl) oxy-; at least one of R * or RY is independently C1-C4 alkyl and the other is H, or both R * and RY are independently C1-Ca alkyl; or a tautomer thereof; or a salt of it.
[2]
2. Compound or a tautomer or salt thereof, according to claim 1, CHARACTERIZED by the fact that, when s is O, each of Rºº and RºPéH.
[3]
3. Compound or a tautomer or salt thereof, according to claim 1 or 2, CHARACTERIZED by the fact that each of Rº and Rº is H.
[4]
4. A compound or a tautomer or salt thereof, according to any one of claims 1 to 3, CHARACTERIZED by the fact that R'º is H.
[5]
5. A compound or a tautomer or salt thereof, according to any one of claims 1 to 4, CHARACTERIZED by the fact that each of R * º, R'º and R'7 is independently C1-C3 alkyl.
[6]
6. A compound or a tautomer or salt thereof, according to any one of claims 1 to 5, CHARACTERIZED by the fact that each of R * and R) is independently methyl or ethyl.
[7]
7. A compound or a tautomer or salt thereof, according to any one of claims 1 to 6, CHARACTERIZED by the fact that RX and RY are both methyl.
[8]
8. A compound or a tautomer or salt thereof, according to any one of claims 1 to 7, CHARACTERIZED by the fact that each of R * and R / is methyl and the other is H.
[9]
Compound or a tautomer or salt thereof, according to claim 1, CHARACTERIZED for having the structure of Formula | -2: R "
SS Rº N
Ç RA
B / LD "Oo nN ne (12) where R'4, R'15, Rº And R7 are independently C1-C3alkyl; Rºº and R * º are independently H, hydroxy, COOH or (C1-Ce) -oxy optionally substituted, in which the optionally substituted (C + -Ce) 9oxy alkyl is optionally substituted with 1 to 4 substituents, each independently selected from the group consisting of hydroxy, -CO2 (R '), -N (Rº) ( R5), optionally substituted phenyl and optionally substituted 5- to 6-membered heterocycloalkyl, wherein said optionally substituted 5- to 6-membered phenyl or heterocycloalkyl is optionally substituted with 1 to 4 substituents, each independently selected from the group consisting of (C1 alkyl) -Ca) oxi- and C1-Ca alkyl; each of Rº and Rº is independently -CO-N (Rº) (R),
each of R $, Rº and R 'is independently H or C1-C3 alkyl; B is -C1 -Ca-substituted or -C2 -Ca-substituted alkenyl, wherein the alkyl group of said substituted -C1-C4- alkyl, or -C2-C4- substituted alkenyl, is substituted with 1 to 4 substituents, each independently selected among the group composed of halogen, hydroxy, (C1-Ca alkyl) Oxy- and C14 alkyl, at least one of R * or RY is independently C1-C4 alkyl and the other is H, or both R * and RY are independently C1-Ca alkyl; or a tautomer thereof, or a salt thereof.
[10]
10. Compound or a tautomer or salt thereof, according to claim 1 or 9, CHARACTERIZED by the fact that R '* and Rº are ethyl, and R '* and Ri are methyl.
[11]
11. A compound or a tautomer or salt thereof, according to claim 1 or 9, CHARACTERIZED by the fact that each of Rº and Rº is independently optionally substituted (C1-C4 alkyl) oxy (C1 alkyl) -Ca) Optionally substituted oxide is optionally substituted with 1 to 2 hydroxy substituents.
[12]
12. Compound or a tautomer or salt thereof, according to claim 1 or 9, CHARACTERIZED by the fact that Rº and Rº are -CO-NH>.
[13]
A compound or a tautomer or salt thereof, according to claim 1 or 9, CHARACTERIZED by the fact that B is -CH2-CH2- substituted with 1 to 2 hydroxy substituents.
[14]
14. Compound or a tautomer or salt thereof, according to claim 1 or 9, CHARACTERIZED by the fact that: R14, R'5, Rº and R7 are independently methyl or ethyl;
one of Rº and Rº is He the other of Rº! and R * is optionally substituted (C1-Ca) alkyl, where optionally substituted (C + -Ca) alkyl is optionally substituted with 1 to 2 hydroxy substituents; Rô and Rº are both -CO-NH> z; and B is -CH2-CH> 2- substituted or -CH = CH- substituted, where -CH2-CH> 2- substituted or -CH = CH- substituted is substituted with 1 to 4 substituents, each independently selected from among the group consisting of hydroxy and C 1-2 alkyl; and at least one of R * or RY is independently C1-C4 alkyl and the other is H, or both R * and RY are independently C1-Ca alkyl.
[15]
15. A compound or a tautomer or salt thereof, according to claim 1 or 9, characterized in that it is (E) -1 - ((2R, 3R) -4 - ((E) -5-carbamoyl 2- ( (1-ethyl-3-methyl-1 H-pyrazol-5-carbonyl) imino) -7- (3-hydroxypropoxy) -3-methyl-2,3-dihydro-1H-benzo [d] imidazo | -1- i1) -2,3-dihydroxybutyl) -2 - ((1-ethyl-3-methyl-1H-pyrazol-5-carbonyl) imino) -7-methoxy-3-methyl-2,3-dihydro-1H-benzo [d] imidazole-5-carboxamide with the structure:
Í DR BY os N o o x q. Ss HO N Or BO o 6 o
[16]
16. A compound or a tautomer or salt thereof, according to claim 1 or 9, CHARACTERIZED to be (E) -1 - ((28.3S) -4 - ((E) -5-carbamoyl-2- ( (1-ethyl-3-methyl-1 H-pyrazol-S-carbonyl) imino) -7- (3-hydroxypropoxy) -3-methyl-2,3-dihydro-
1H-benzo [d] imidazol-1-i1) -2,3-dihydroxybutyl) -2 - ((1-ethyl-3-methyl-1H-pyrazol-5-carbonyl) imino) -7-methoxy-3-methyl -2,3-dihydro-1H-benzo [d] imidazole-5-carboxamide with the structure: il DR Os “oo Ss no” N Í
OH BA o / 6th
[17]
17. A compound or a tautomer or salt thereof, according to any one of claims 1 to 16, CHARACTERIZED by the fact that the salt is a pharmaceutically acceptable salt of said compound.
[18]
Pharmaceutical composition CHARACTERIZED by comprising the compound or a pharmaceutically acceptable salt or tautomer thereof, according to claim 17, and at least one pharmaceutically acceptable excipient.
[19]
19. A compound or a pharmaceutically acceptable tautomer or salt thereof, according to claim 17, CHARACTERIZED for use in a therapy.
[20]
20. A compound or a pharmaceutically acceptable salt or tautomer thereof, according to claim 17, CHARACTERIZED for being used in the treatment of a disease or disorder mediated by STING.
[21]
21. Use of the compound or a tautomer or pharmaceutically acceptable salt thereof, according to claim 17, CHARACTERIZED because it occurs in the manufacture of a medicine for the treatment of a disease or disorder mediated by STING.
[22]
22. Method for treating a disease or disorder mediated by the STING CHARACTERIZED by comprising administering a therapeutically effective amount of the compound or a pharmaceutically acceptable salt or salt thereof, according to claim 17, to a human being in need thereof.
[23]
23. Compound, use or method, according to any of claims 20 to 22, CHARACTERIZED by the fact that the disease or disorder is selected from the group consisting of systemic lupus erythematosus (SLE), cutaneous lupus, lupus nephritis, psoriasis , diabetes mellitus, including insulin dependent diabetes mellitus (IDDM), dermatomyositis, systemic sclerosis (scleroderma), and Sjógren's syndrome (SS), rheumatoid arthritis, psoriasis arthritis, vasculitis beginning in childhood associated with STING (SAVI), Aicardi Goutiêres (AGS), lupus pernio and mixed connective tissue disease.
[24]
24. A compound, use or method, according to any one of claims 20 to 22, CHARACTERIZED by the fact that the disease or disorder is chronic lung disease, pulmonary fibrosis or asthma.
[25]
25. A compound, use or method, according to any one of claims 20 to 22, CHARACTERIZED by the fact that the disease or disorder is selected from Alzheimer's disease, amyotrophic lateral sclerosis (ALS) and Frontotemporal Lobar Degeneration (FTD), multiple sclerosis, Parkinson's disease and Huntington's disease.
[26]
26. A compound, use or method, according to any one of claims 20 to 22, CHARACTERIZED by the fact that the disease or disorder is myocardial infarction, heart failure, congenital heart disease, coronary artery disease, hypertension, cardiomyopathy.

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JP2020536103A|2020-12-10|

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WO2019069270A1|2019-04-11|

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EP3692034A1|2020-08-12|

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US20200291001A1|2020-09-17|

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法律状态:
2021-11-23| B350| Update of information on the portal [chapter 15.35 patent gazette]|

优先权:

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申请号 | 申请日 | 专利标题

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US201762568420P| true| 2017-10-05|2017-10-05|

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US62/568,420|2017-10-05|

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