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    • 专利摘要:
    "QUINAZOLINE DERIVATIVES FOR TREATMENT OF VIRAL INFECTIONS AND OTHER DISEASES". The present invention relates to quinazoline derivatives, processes for their preparation, pharmaceutical compositions, and its use in therapy of disorders where modulation of Toll-like receptors is involved.
    公开号:BR112013029537B1
    申请号:R112013029537-6
    申请日:2012-05-18
    公开日:2020-06-30
    发明作者:David Mc Gowan；Pierre Jean-Marie Bernard Raboisson；Tim Hugo Maria Jonckers；Stefaan Julien Last；Werner Embrechts；Serge Maria Aloysius Pieters
    申请人:Janssen Sciences Ireland Uc；
    IPC主号:
    专利说明:

    [0001] [0001] The present invention relates to quinazoline derivatives, processes for their preparation, pharmaceutical compositions, and their use in therapy.
    [0002] [0002] The present invention relates to the use of quinazoline derivatives in the treatment of viral infections, immune or inflammatory disorders, where the modulation, or agonism, of Toll-like receptors (TLRs) is involved. Type Toll receptors are primary transmembrane proteins characterized by an extracellular domain rich in leucine and a cytoplasmic extension that contains a conserved region. The innate immune system is able to recognize molecular patterns associated with pathogens through these TLRs expressed on the cell surface of certain types of immune cells. The recognition of foreign pathogens activates the production of cytokines and the positive regulation of co-stimulating molecules in phagocytes. This leads to the modulation of the behavior of T cells.
    [0003] [0003] It has been estimated that most mammal species have between ten and fifteen types of Toll-like receptors. Thirteen TLRs (simply called TLR1 to TLR13) have been identified in humans and mice together, and equivalent forms of many of these have been found in other species of mammals. However, equivalents of certain TLRs found in humans are not present in all mammals. For example, a gene encoding a protein analogous to TLR10 in humans is present in mice, but appears to have been damaged at some point in the past by a retrovirus. On the other hand, mice express TLRs 11, 12, and 13, none of which are represented in humans. Other mammals can express TLRs that are not found in humans. Other non-mammalian species may have TLRs other than mammals, as demonstrated by TLR14, which is found in the puffer Takifugu. This can complicate the process of using experimental animals as models of human innate immunity.
    [0004] [0004] For detailed reviews of Toll-type receivers, see the following magazine articles. Hoffmann, JA, Nature, 426 , p33-38, 2003; Akira, S., Takeda, K., and Kaisho, T., Annual Rev. Immunology, 21 , p335-376, 2003; Ulevitch, RJ, Nature Reviews: Immunology, 4 , p512520, 2004.
    [0005] [0005] Compounds indicating activity at Toll Type receptors have previously been described such as purine derivatives in WO 2006 117670, adenine derivatives in WO 98/01448 and WO 99/28321, and pyrimidines in WO 2009/067081.
    [0006] [0006] However, there is a great need for new Toll-type receptor modulators having preferential selectivity, higher potency, higher metabolic stability, and an improved safety profile compared to prior art compounds.
    [0007] [0007] In the treatment of certain viral infections, they can be administered with regular injections of interferon (IFNa), as is the case with the hepatitis C virus (HCV), (Fried et. Al. Peginterferon-alfa plus ribavirin for chronic hepatitis C virus infection, N Engl J Med 2002; 347: 975-82). Orally available small molecule IFN inducers offer the potential advantages of reduced immunogenicity and convenience of administration. Thus, new IFN inducers are potentially new potentially effective classes of drugs for treating viral infections. For an example in the literature of a small molecule IFN inducer having an antiviral effect see De Clercq, E .; Descamps, J .; De Somer, P. Science 1978 , 200, 563-565.
    [0008] [0008] IFNα is also given in combination with other drugs in the treatment of certain types of cancer (see Eur. J. Cancer 46, 284957, and Cancer Res. 1992 , 52, 1056 for examples). TLR 7/8 agonists are also of interest as vaccine adjuvants due to their ability to induce a pronounced Th1 response.
    [0009] [0009] According to the present invention there is provided a compound of formula (I)
    [0010] [00010] In a first embodiment, the present invention provides the compounds of formula (I), in which R 1 is butyl, pentyl or 2-pentyl and in which R 2, R 3, R 4 and R 5 are as described above .
    [0011] [00011] In a further embodiment, the present invention relates to compounds of formula (I) in which R 1 is C 4-8 alkyl substituted with a hydroxyl and in which R 2, R 3, R 4 and R 5 are as specified above.
    [0012] [00012] Another modality relates to compounds of the formula (I) in which R 1 , when being C- 8 alkyl substituted by hydroxyl, is one of the following:
    [0013] [00013] In another embodiment, the present invention provides the compounds of formula (I), wherein R 5 is preferably hydrogen or fluorine and R 1, R 2, R 3 and R 4 are as described above.
    [0014] [00014] The compounds of the formula (I) and solvate, polymorph or a pharmaceutically acceptable salt thereof have activity as pharmacists, in particular as modulators of Toll-like Receptor activity (especially TLR7 and / or TLR8).
    [0015] [00015] Thus, in a further aspect, the present invention provides a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable solvate, polymorph or salt thereof together with one or more pharmaceutically acceptable excipients, diluents or carriers.
    [0016] [00016] Furthermore, a compound of formula (I) or a solvate, polymorph or pharmaceutically acceptable salt thereof according to the current invention, or a pharmaceutical composition comprising said compound of formula (I) or a solvate, polymorph or pharmaceutically acceptable salt thereof can be used as a medicine.
    [0017] [00017] Another aspect of the invention is that a compound of formula (I) or a solvate, polymorph or pharmaceutically acceptable salt thereof, or said pharmaceutical composition comprising said compound of formula (I) or a solvate, polymorph or pharmaceutically salt acceptable value can be used accordingly in the treatment of a disorder in which the modulation of TLR7 and / or TLR8 is involved.
    [0018] [00018] The term "alkyl" refers to a saturated straight chain or branched chain aliphatic hydrocarbon containing the specified number of carbon atoms.
    [0019] [00019] The term "halogen" refers to fluorine, chlorine, bromine or iodine.
    [0020] [00020] The term "alkenyl" refers to an alkyl as defined above consisting of at least two carbon atoms and at least one carbon-carbon double bond.
    [0021] [00021] The term "alkynyl" refers to an alkyl as defined above consisting of at least two carbon atoms and at least one carbon-carbon triple bond.
    [0022] [00022] The term "cycloalkyl" refers to a carbocyclic ring containing the specified number of carbon atoms.
    [0023] [00023] The term "alkoxy" refers to a unique alkyl group (carbon and hydrogen chain) bonded to oxygen, such as a methoxy group or ethoxy group.
    [0024] [00024] The term "aryl" means an aromatic ring structure optionally comprising one or two heteroatoms selected from N, O and S, in particular N and O. Said aromatic ring structure can have 5, 6 or 7 atoms in ring. In particular, said aromatic ring structure can have 5 or 6 ring atoms.
    [0025] [00025] The term "aryloxy" refers to an aromatic ring structure. Said aromatic group is singularly bound to oxygen, such as phenol.
    [0026] [00026] The term "heteroaryloxy" refers to an aromatic ring structure optionally comprising one or two heteroatoms selected from N, O and S. Said aromatic group, containing 5 to 7 atoms in the ring, one of which is uniquely linked to oxygen, such as hydroxypyridine.
    [0027] [00027] The term "bicyclic heterocycle" means an aromatic ring structure, as defined for the term "aryl" comprised of two fused aromatic rings. Each ring is optionally comprised of heteroatoms selected from N, O and S, in particular N and O.
    [0028] [00028] The term "arylalkyl" means an aromatic ring structure as defined as the term "aryl" optionally substituted by an alkyl group.
    [0029] [00029] The term "heteroarylalkyl" means an aromatic ring structure as defined for the term "heteroaryl" optionally substituted by an alkyl group.
    [0030] [00030] Heterocycle refers to molecules that are saturated or partially saturated and include ethyloxide, tetrahydrofuran, dioxane or other cyclic ethers. Nitrogen-containing heterocycles include, for example, azetidine, morpholine, piperidine, piperazine, pyrrolidine, and the like. Other heterocycles include, for example, thiomorpholine, dioxolinyl, and cyclic sulfones.
    [0031] [00031] Heteroaryl groups are heterocyclic groups that are aromatic in nature. These are monocyclic, bicyclic or polycyclic containing one or more heteroatoms selected from N, O or S. Heteroaryl groups can be, for example, imidazolyl, isoxazolyl, furyl, oxazolyl, pyrrolyl, pyridonyl, pyridyl, pyridazinyl, pyrazinyl.
    [0032] [00032] Pharmaceutically acceptable salts of the compounds of formula (I) include their acid and basic addition salts. Suitable acid addition salts are formed from acids that form non-toxic salts. Suitable basic salts are formed from bases that form non-toxic salts.
    [0033] [00033] The compounds of the invention can also exist in unsolvated and solvated forms. The term "solvate" is used here to describe a molecular complex comprising the compound of the invention and one or more pharmaceutically acceptable solvent molecules, for example, ethanol.
    [0034] [00034] The term "polymorph" refers to the ability of the compound of the invention to exist in more than one crystalline form or structure.
    [0035] [00035] The compounds of the present invention can be administered as crystalline or amorphous products. They can be obtained, for example, as solid buffers, powders, or films by methods such as precipitation, crystallization, lyophilization, spray drying, or evaporative drying. They can be administered alone or in combination with one or more other compounds of the invention or in combination with one or more other drugs. Generally, they will be administered as a formulation in combination with one or more pharmaceutically acceptable excipients. The term "excipient" is used here to describe any ingredient other than the compound (s) of the invention. The choice of excipient depends largely on factors such as the particular mode of administration, the effect of the excipient on solubility and stability, and the nature of the dosage form.
    [0036] [00036] The compounds of the present invention or any subgroup thereof can be formulated in various dosage forms for administration purposes. As appropriate compositions, all compositions usually used for systemic drug administration can be cited. To prepare the pharmaceutical compositions of this invention, an effective amount of the particular compound, optionally in the form of an addition salt, as the active ingredient is combined in admixture with a pharmaceutically acceptable carrier, the carrier of which can take a wide variety of forms depending on the form desired preparation for administration. These pharmaceutical compositions are desirably in unit dosage form suitable, for example, for oral, rectal, or percutaneous administration. For example, in the preparation of compositions in oral dosage form, any of the usual pharmaceutical means can be employed such as, for example, water, glycols, oils, alcohols and the like in the case of liquid oral preparations such as suspensions, syrups, elixirs , emulsions, and solutions; or solid carriers such as starches, sugars, kaolin, thinners, lubricants, binders, disintegrating agents and the like in the case of powders, pills, capsules, and tablets. Due to their ease of administration, tablets and capsules represent the most advantageous oral unit dosage forms, in which case solid pharmaceutical carriers are obviously employed. Also included are preparations in solid form that can be converted, shortly before use, into liquid forms. In compositions suitable for percutaneous administration, the carrier optionally comprises a penetration enhancing agent and / or a suitable wetting agent, optionally combined with suitable additives of any nature in minimal proportions, the additives of which do not introduce a significant deleterious effect on the skin. Said additives can facilitate administration to the skin and / or can be useful for preparing the desired compositions. These compositions can be administered in various ways, for example, as a transdermal dressing, as an adhesive, as an ointment. The compounds of the invention can also be administered via inhalation or insufflation using methods and formulations employed in the art for administration in this way. Thus, in general, the compounds of the present invention can be administered to the lungs in the form of a solution, a suspension or a dry powder.
    [0037] [00037] It is especially advantageous to formulate the pharmaceutical compositions mentioned above in unit dosage form for ease of administration and uniformity of dosage. The unit dosage form as used herein refers to physically discrete units suitable as unitary dosages, each unit containing a predetermined amount of active ingredient calculated to produce the desired therapeutic effect in association with the required pharmaceutical carrier. Examples of such unit dosage forms are tablets (including grooved or coated tablets), capsules, pills, powder packages, wafers, suppositories, injectable solutions or suspensions, and the like, and their multiple secretions.
    [0038] [00038] Those skilled in the art in the treatment of infectious diseases will be able to determine the effective amount from the test results presented hereinafter. In general it is contemplated that an effective daily amount would be 0.01 mg / kg to 50 mg / kg of body weight, more preferably 0.1 mg / kg to 10 mg / kg of body weight. It may be appropriate to administer the required dose as two, three, four or more underdoses at appropriate intervals throughout the day. Said underdoses can be formulated as unit dosage forms, for example, containing 1 to 1000 mg, and in particular 5 to 200 mg of active ingredient per unit dosage form.
    [0039] [00039] The exact dosage and frequency of administration depend on the particular compound of formula (I) used, the particular condition being treated, the severity of the condition being treated, the age, weight and general physical condition of the particular patient as well as other medication that the individual may be taking, as is well known to those skilled in the art. Furthermore, it is evident that the effective amount can be reduced or increased depending on the response of the treated subject and / or depending on the physician's judgment in prescribing the compounds of the current invention. The ranges of effective amounts mentioned above are therefore guidelines only and are not intended to limit the scope or use of the invention to any extent. Preparation of compounds
    [0040] [00040] The compounds of formula (I) are prepared according to scheme 1. 2,4-dichloroquinazolines can be reacted in separate steps providing 2,4-diaminoquinazolines in acceptable yield. In the first step, 2,4-dichloroquinazoline is mixed or heated with an amine with or without a transition metal catalyst to provide 2-chloro-4-aminoquinazoline. After processing the crude 2-chloro-4-aminoquinazoline, the intermediate is heated in a pressure vessel with an ammonia origin (for example, ammonia in methanol) and optionally with CuO. Layout 1
    [0041] [00041] The compounds of formula (I) can also be prepared according to scheme 2. Substituted anthranilic esters ( IV ) were heated under acidic conditions in the presence of excess cyanamide, using an alcoholic solvent (for example, ethanol) or digests according to the method described in the literature (O'Hara et. al. JOC (1991) 56, p776). Subsequent amine substitution of 2-amino-4-hydroxyquinazolines ( V ) can take place via several different routes. In one example, intermediates V can be heated in the presence of phosphorus oxychloride (POCI3) with or without solvent. After removing the solvents, the amine can be added pure or in the presence of a polar solvent (for example acetonitrile) to provide VI at room temperature or by heating. A second approach is to react intermediates V with a coupling agent such as BOP or PyBOP in the presence of DBU and the amine. The reaction takes place in a polar solvent (for example, DMF). A third method is to protect the amine group 2 in intermediate V with an acyl group. Intermediate V is reacted with anhydride (e.g., acetic anhydride), typically at reflux for several hours. The solvents can be removed under reduced pressure and the crude can be subsequently reacted with POCI 3 as described above. The easy removal of the protecting acyl group is done by reaction in a basic solvent (for example, sodium methoxide in methanol). SCHEME 2
    [0042] [00042] To a mixture of 2,4-dichloro-6,7-dimethoxyquinazoline (500 mg, 1.9 mmol), diisopropylethylamine (0.73 mL, 4.2 mmol), and acetonitrile (0.1 mL ) a solution of n- butylamine (0.19 ml, 1.9 mmol) in acetonitrile (5 ml) was added dropwise while stirring. The mixture was stirred for one day at room temperature. Ethyl acetate was added, the organic layer was washed with saturated aqueous ammonium chloride. The organic layer was removed and dried over magnesium sulfate. The solids were removed by filtration to provide crude A , thus used in the next step. Preparation of compound 1
    [0043] [00043] Intermediate A (0.5 g, 1.7 mmol) was placed in a 20 mL pressure vessel with 7N ammonia in methanol (15 mL) and to this was added CuO (242 mg, 1.7 mmol) . The vessel was sealed and the mixture was heated to 130 ° C with stirring for 18 hours. The reaction was then allowed to cool to room temperature. The solids were removed by filtration and the solvents in the filtrate were removed under reduced pressure. The crude material was purified by reverse phase column chromatography (Vydac Denali C18 column 10 µm, 250 g, 5 cm). Mobile phase (0.25% NH 4 HCO 3 solution in water, CH 3 CN). Preparation of 9
    [0044] [00044] Step 1. In a 500 ml round-bottom flask equipped with a magnetic stir bar, methyl 2-amino-6-methoxybenzoate (25 g, 149.6 mmol), ethanol (200 mL), cyanamide were placed (9.43 g, 224 mmol), and concentrated HCI (6 mL). The mixture was allowed to stir at reflux for 6 hours. At hourly intervals, HCI (0.5 ml) was added. The reaction mixture was allowed to cool to room temperature and solid V-1 was isolated by filtration and washed with ethanol.
    [0045] [00045] LC-MS m / z = 192 (M + H).
    [0046] [00046] 1 H NMR (400 MHz, DMSO-d 6 ) δ ppm 3.88 (s, 3 H), 6.96 (dd, J = 8.2, 3.1 Hz, 2 H), 7, 69 (t, J = 8.3 Hz, 1 H), 8.28 (br. S., 2 H), 12.67 (br. S., 1 H) Step 2.
    [0047] [00047] V-1 (250 mg, 1.24 mmol), anhydrous DMF (5 mL), DBU (0.6 g, 3.73 mmol), and BOP (659 mg, 1.49 mmol). To the mixture stirred at room temperature for 2 hours, n- butylamine (287 mg, 3.73 mmol) was added and the reaction was stirred at room temperature for 15 hours. The solvent was reduced in volume and the residue was purified by silica column chromatography using 10% methanol dichloromethane in dichloromethane gradient. The best fractions were grouped, and the solvents were removed under reduced pressure to provide 9 .
    [0048] [00048] The following intermediates were prepared according to the V-1 preparation method.
    [0049] [00049] LC-MS m / z = 240/242
    [0050] [00050] 1 H NMR (400 MHz, DMSO-d 6 ) δ ppm 3.09 - 3.55 (m, 2 H), 7.09 (br. S., 1 H), 7.26 (dd, J = 7.9, 1.3 Hz, 1 H), 7.37 - 7.48 (m, 2H)
    [0051] [00051] LC-MS m / z = 196 (M + H)
    [0052] [00052] 1 H NMR (400 MHz, DMSO-d 6 ) δ ppm 7.00 (br. S., 2 H) 7.13 (d, J = 7.78 Hz, 1 H) 7.18 (d , J = 8.28 Hz, 1 H) 7.50 (t, J = 8.03 Hz, 1 H), not observed phenotypic proton.
    [0053] [00053] LC-MS m / z = 176 (M + H)
    [0054] [00054] LC-MS m / z = 180 (M + H)
    [0055] [00055] 1 H NMR (400 MHz, DMSO-d 6 ) δ ppm 6.98 (dd, J = 11.0, 8.3 Hz, 1 H), 7.13 (d, J = 8.3 Hz , 1 H), 7.51 (br. S, 2 H), 7.64 (td, J = 8.3, 5.8 Hz, 1 H), 12.30 (br. S, 1 H)
    [0056] [00056] LC-MS m / z = 180 (M + H)
    [0057] [00057] LC-MS m / z = 239/241 (M + H)
    [0058] [00058] 1 H NMR (400 MHz, DMSO-d 6 ) δ ppm 7.32 (d, J = 8.8 Hz, 1 H), 7.49 (s, 2 H), 7.71 (br. s., 1 H), 7.81 (dd, J = 8.6, 2.4 Hz, 1 H), 8.00 (d, J = 2.4 Hz, 1 H)
    [0059] [00059] LC-MS m / z = 192 (M + H)
    [0060] [00060] LC-MS m / z = 176 (M + H)
    [0061] [00061] LC-MS m / z = 180 (M + H)
    [0062] [00062] 1 H NMR (400 MHz, DMSO-d 6 ) δ ppm 7.01 - 7.16 (m, 2 H), 7.56 (br. S., 2 H), 7.99 (t, J = 7.7 Hz, 1 H), 10.38 - 13.48 (m, 1 H)
    [0063] [00063] LC-MS m / z = 196 (M + H)
    [0064] [00064] 1 H NMR (400 MHz, DMSO-d 6 ) δ ppm 7.41 (dd, J = 8.5, 2.0 Hz, 1 H), 7.55 (d, J = 2.0 Hz , 1 H), 7.98 (d, J = 8.5 Hz, 1 H), 8.49 (br. S., 2 H), 10.79-13.69 (m, 1 H)
    [0065] [00065] LC-MS m / z = 176 (M + H)
    [0066] [00066] 1 H NMR (400 MHz, DMSO-d 6 ) δ ppm 2.43 (s, 3 H), 7.22 (d, J = 1.0 Hz, 1 H), 7.24 (s, 1 H), 7.89 (d, J = 8.0 Hz, 1 H), 8.29 (br. S., 2 H), 12.65 (br. S, 1 H)
    [0067] [00067] LC-MS m / z = 192 (M + H)
    [0068] [00068] LC-MS m / z = 220 (M + H)
    [0069] [00069] 1 H NMR (400 MHz, DMSO- d 6 ) δ ppm 3.87 - 3.95 (m, 3 H), 7.12 - 7.47 (m, 1 H), 7.83 (dd , J = 8.3, 1.4 Hz, 1 H), 7.99 (d, J = 1.3 Hz, 1 H), 8.07 - 8.13 (m, 1 H), 8.43 (br. s, 2 H)
    [0070] [00070] LC-MS m / z = 198 (M + H)
    [0071] [00071] LC-MS m / z = 298 (M + H)
    [0072] [00072] 1 H NMR (400 MHz, DMSO- d 6 ) δ ppm 3.85 (s, 3 H), 5.10 (s, 2 H), 6.17 (br. S., 2 H), 6.70 (s, 1 H), 7.30 - 7.36 (m, 2 H), 7.40 (t, J = 7.4 Hz, 2 H), 7.44 - 7.48 (m , 2 H), 10.82 (br. S., 1 H)
    [0073] [00073] LC-MS m / z = 180 (M + H)
    [0074] [00074] 1 H NMR (400 MHz, DMSO- d 6 ) δ ppm 6.51-6.67 (m, 2H), 7.00-7.08 (m, 1H), 7.42 (ddd, J = 11.2, 7.9 1.3Hz, 1H), 7.69 (dd, J = 7.9, 0.6Hz, 1H), 11.08 (br. S., 1H)
    [0075] [00075] LC-MS m / z = 196 (M + H)
    [0076] [00076] LC-MS m / z = 176 (M + H)
    [0077] [00077] 1 H NMR (400 MHz, DMSO- d 6 ) δ ppm 2.41 (s, 3 H), 7.15 (t, J = 7.5 Hz, 1 H), 7.43 (br. s., 2 H), 7.55 (d, J = 7.0 Hz, 1 H), 7.80 (d, J = 7.8 Hz, 1 H), 11.17-12.49 (m , 1H) Preparation of 10
    [0078] [00078] Step 1. Preparation of V-6. In a 50 mL flask equipped with a magnetic stir bar, V-3 (500 mg, 2.16 mmol), phenylboronic acid (342 mg, 2.8 mmol), potassium carbonate (1.19 g, 8 , 62 mmol), dioxane (5.5 mL), water (1.8 mL), and tetrakis (triphenylphosphine) palladium (249 mg, 0.215 mmol). Nitrogen gas was bubbled through the reaction mixture for 10 minutes. The flask was sealed and heated to 130 ° C. The reaction cooled to room temperature and the solvents were removed under reduced pressure. The crude was purified by reverse phase column chromatography (RP Vydac Denali C18 - 10 µm, 200 g, 5 cm. Mobile phase 0.25% NH 4 HCO 3 solution in water, CH 3 CN) to provide V-6 .
    [0079] [00079] LC-MS m / z = 238 (M + H)
    [0080] [00080] Step 2. V-6 (148 mg, 0.624 mmol), anhydrous DMF (3.5 mL), DBU (0.373 mL, 2.5 mmol) were placed in a 50 mL flask equipped with a magnetic stir bar ), BOP (345 mg, 0.78 mmol), and then (S) -2-aminopentanol (322 mg, 3.12 mmol). The reaction mixture was allowed to stir for 3 days. The volatiles were removed under reduced pressure and the crude was partitioned between water and ethyl acetate. The organic layers were combined, dried (magnesium sulfate), the solids were removed by filtration, and the filtrate solvents were removed under reduced pressure. The crude was purified by reverse phase column chromatography (RP SunFire Prep C18 OBD-10 µm, 30 x 150 mm). Mobile phase (0.25% NH4HCO 3 solution in water, CH 3 CN) to provide 10 . Preparation of 11
    [0081] [00081] Step 1. V-1 (8.8 g, 46.03 mmol) in acetic anhydride (150 mL) was placed in a 1 L round-bottom flask equipped with a magnetic stir bar. The flask was equipped with a reflux condenser and the mixture was heated to reflux with stirring for 15 hours. The precipitate was isolated by filtration and washed with diisopropyl ether and then dried in vacuo to provide a white solid, V-9 .
    [0082] [00082] LC-MS m / z = 234 (M + H)
    [0083] [00083] Step 2. In a 250 ml round-bottom flask equipped with a magnetic stir bar, V-9 (4.5 g, 19.3 mmol) in acetonitrile (100 ml) was added. POCl 3 (5.56 ml, 59.8 mmol) was added dropwise over 30 minutes, followed by the addition of DIPEA (10.3 ml, 59.8 mmol). The reaction mixture became a brown solution and was stirred for 2 hours at room temperature. The reaction mixture was poured into 1M NaOH (100 ml) and extracted with ethyl acetate (2 x 100 ml). The combined organic layers were dried over MgS04, the solids filtered off and the filtrate was used as such in the next step.
    [0084] [00084] Step 3. The filtrate solution from step 2 in ethyl acetate was treated with DIPEA (9.2 ml, 53.6 mmol) and n- butylamine (3.5 ml, 35.8 mmol). The reaction mixture was stirred for 16 hours at room temperature. The solvent was removed under reduced pressure and the crude was reconstituted in dichloromethane and washed with water. The organic layer was dried (MgS04), the solids were removed by filtration and the solvents in the filtrate were evaporated until dry to obtain an orange solid, V-11 .
    [0085] [00085] LC-MS m / z = 289 (M + H)
    [0086] [00086] Step 4. V-11 (2.8 g, 9.71 mmol), pyridine hydrochloride (6.73 g, 58.26 mmol), and pyridine (50) were placed in a 30 mL pressure tube. ml) and the mixture was heated to 120 ° C for 16 hours. Pyridine was removed under reduced pressure. The crude was dissolved in a mixture of dichloromethane / methanol: 95/5 and washed with a solution of 1N HCI and water. The organic layer was dried (MgS04), the solids were removed by filtration and the solvents in the filtrate were removed under reduced pressure to provide V-11 .
    [0087] [00087] LC-MS m / z = 231 (M-H)
    [0088] [00088] 1 H NMR (400 MHz, d 6 ) δ ppm 0.92 (t, J = 7.37 Hz, 3 H) 1.33 - 1.43 (m, 2 H) 1.50 - 1, 59 (m, 2 H) 3.41 - 3.49 (m, 2 H) 5.79 - 5.88 (m, 1 H) 6.02 (d, J = 8.14 Hz, 1 H) 6 , 91 (br., 2 H) 6.99 - 7.04 (m, 1 H) 10.78 (br., 1 H) 13.35 (br., 1 H)
    [0089] [00089] Step 5. VI-1 (175 mg, 0.753 mmol), cesium carbonate (0.74 g, 2.26 mmol) and DMF (15 mL) were placed in a 100 mL vial. The mixture was stirred at room temperature for 30 minutes. 2-bromoethyl methyl ether (0.089 ml, 0.94 mmol) was added and the mixture was stirred for 16 hours at room temperature. The solvent was removed under reduced pressure and the crude residue was purified by HPLC (RP Vydac Denali C18 - 10 µm, 250 g, 5 cm. Mobile phase (0.25% NH 4 HCO 3 solution in water, methanol), the best fractions were collected and the solvents were removed under reduced pressure to provide 11 as a solid. Preparation of 12
    [0090] [00090] Step 1. V-2 was dissolved in DMF (15 mL) and purged with N 2 in an oil bath at 80 ° C for 10 minutes. Then, bis (triphenylphosphine) palladium (ll) dichloride (69 mg, 0.098 mmol), triphenylphosphine (57.6 mg, 0.22 mmol) and copper iodide (42.5 mg, 0.22 mmol) were added. After 5 minutes of purging with N2, diethylamine (3.15 ml, 30.31 mmol) was added followed by the addition of 2-pyridylethine (168 mg, 1.63 mmol). The vessel was closed and the reaction stirred at 80 ° C for 16 hours. The reaction mixture was poured into ice water and the precipitate was isolated by filtration, washed with water and dried under vacuum. The product was stirred in dichloromethane for 30 minutes. The precipitate was isolated by filtration, washed with dichloromethane and diisopropyl ether and dried under vacuum at 50 ° C to obtain V-12 .
    [0091] [00091] LC-MS m / z = 263 (MH)
    [0092] [00092] Step 2. To a solution of V-12 (300 mg, 1.15 mmol) in THF (50 mL) was placed 10% Pd / C (100 mg) under an N 2 atmosphere (g). The reaction mixture was stirred for 16 hours at room temperature and subsequently filtered with packaged decalite. The filtrate solvent was removed under reduced pressure to provide crude V-13 used as such in the next step.
    [0093] [00093] LC-MS m / z = 267 (MH)
    [0094] [00094] Step 3. Example 12 was prepared according to the method for preparing 9. Preparation of 14
    [0095] [00095] Step 1. Intermediates VI-2 and VI-3 were prepared according to the method for preparing VI-1. VI-3 was isolated after stirring with diisopropylether at room temperature.
    [0096] [00096] VI-2 : LC-MS m / z = 337 (M + H)
    [0097] [00097] VI-3 : LC-MS m / z = 379 (M + H)
    [0098] [00098] Step 2. Compound 14 was prepared according to the method for preparing intermediate V-12. Preparation of 15
    [0099] [00099] Step 1. In a 500 mL round-bottom flask equipped with a magnetic stir bar, 3-aminophthalic acid hydrochloride (25 g, 115 mmol), ethanol (250 mL), cyanamide (7.25 g , 172 mmol), and concentrated HCI (6 mL). The flask was equipped with a reflux condenser and the mixture was stirred at reflux for 6 hours. At hourly intervals, concentrated HCI (0.5 ml) was added via a glass pipette. The reaction was allowed to cool to room temperature, the solvents were removed under reduced pressure to provide a yellow oil. The crude was dried over silica gel and then partially purified by silica gel column chromatography using a dichloromethane to 10% methanol in dichloromethane gradient. The crude yellow solid V-14 was used as such in the next step.
    [0100] [000100] LC-MS m / z = 234 (M + H).
    [0101] [000101] Step 2. In a 100 mL round-bottom flask equipped with a magnetic stir bar, V-14 (1.7 g, 7.29 mmol), anhydrous DMF (25 mL), DBU (3, 3 g, 21.87 mmol), and PyBOP (4.55 g, 8.75 mmol). The reaction mixture was stirred for 1 hour at room temperature. Then n- butylamine (2.1 g, 29.2 mmol) was added and the mixture was stirred for 15 hours at room temperature. The solvent was removed under reduced pressure and the crude was filtered through silica gel using 20% methanol in dichloromethane. The filtrate solvents were removed under reduced pressure and the crude oil ( 15.4 g) was purified by reverse phase column chromatography (RP Vydac Denali C18 - 10 µm, 200 g, 5 cm). Mobile phase (0.25% NH 4 HCO 3 solution in water, CH 3 CN). Preparation of 16
    [0102] [000102] To a suspension of 10% Pd / C in methanol (25 ml) under an N 2 atmosphere, compound 14 (111 mg, 0.39 mmol) was added. The nitrogen atmosphere was removed and replaced with hydrogen gas. The mixture was stirred at room temperature until 2 equivalents of hydrogen gas were consumed. The reaction mixture was filtered through packaged decalite. The filtrate solvent was removed under reduced pressure. The crude product was purified by silica gel column chromatography using a dichloromethane to 10% methanol in a dichloromethane gradient to provide 16 . Preparation of 18
    [0103] [000103] 17 (625 mg, 2.28 mmol) was dissolved in anhydrous THF (10 ml). LAH (1M in THF, 3.42 ml, 3.42 mmol) was added dropwise and the reaction mixture was stirred for 3 hours at room temperature. LC-MS showed complete conversion to the desired product. The reaction mixture was cooled with saturated aqueous NH4 Cl, the solids were removed by filtration and the filtrate solvents were removed under reduced pressure. The residue was purified using an HPLC preparation giving the product as a white solid. Preparation of 19
    [0104] [000104] A mixture of VI-2 (500 mg, 1.48 mmol), tetrakis (triphenylphosphine) palladium (86 mg, 0.074 mmol), and zinc cyanide (106 mg, 0.89 mmol) in DMF (5 mL ) in a 10 mL tube was placed under microwave irradiation at 160 ° C for 10 minutes. The mixture was cooled to room temperature and concentrated in vacuo. The residue was divided between water and dichloromethane. The organic layer was separated, dried (MgSO 4 ), the solvents were removed by filtration and the solvents in the filtrate were concentrated in vacuo. The product was triturated in CH 3 CN, the solid was isolated by filtration. Deprotection of acyl was provided after treatment with sodium methoxide in methanol at 60 ° C for one hour. The mixture was cooled and the product precipitated. White solid 19 was isolated by filtration and dried under vacuum. Preparation of 20
    [0105] [000105] In a 50 mL flask equipped with a magnetic stir bar and sprinkled with nitrogen gas, VI-3 (300 mg, 0.79 mmol), the boronic ester (198 mg, 0.95 mmol), was placed, water (3 mL, degassed) and DME (6 mL, degassed), sodium bicarbonate (199 mg, 2.37 mmol) and PdCl 2 (PPh 3 ) 2 (55 mg, 0.079 mmol) was added and the mixture was heated up to 90 ° C for 1 hour. The mixture was cooled and ethyl acetate was added. The organic layer was separated, dried (MgSO 4 ), the solids were removed by filtration and the solvents in the filtrate were removed in vacuo. The residue was purified by silica gel column chromatography using a gradient from dichloromethane to 10% methanol in dichloromethane (containing ammonia). The product fractions were collected and concentrated in vacuo. Deprotection of acyl was provided after treatment with sodium methoxide in methanol at 60 ° C for one hour. The solvents were removed under reduced pressure and the residue was partitioned between water and dichloromethane. The organic layer was separated, dried (MgS04), the solvents were removed by filtration and the solvents in the filtrate were removed in vacuo. The product was crystallized from CH 3 CN, isolated by filtration and dried in vacuo to obtain a white solid, 20 µm . Preparation of 21
    [0106] [000106] In a first flask equipped with a magnetic stir bar and a screw cap septum, a solution of Pd2 (dba) 3 (6 mg, 0.007 mmol) and 2-di-tert-butylphosphino-3,4, 5,6-tetramethyl - 2 ', 4', 6'-tri-isopropyl - I-1,1'-biphenyl (6 mg, 0.013 mmol) in toluene (0.5 mL) was subjected to discharge gas and N 2 then stirred at 120 ° C for 3 minutes. A second flask equipped with a magnetic stir bar and a screw cap septum, was loaded with 2-methylimidazole (104 mg, 1.26 mmol) and K 3 PO 4 (224 mg, 1.05 mmol), then VI -3 (200 mg, 0.53 mmol) and also subject to discharge with N 2 (g). The pre-mixed catalyst solution followed by anhydrous toluene (0.5 ml) and t- butanol (1.0 ml) were added via syringe to the second flask (total 2 ml of toluene: t -BuOH solution 1: 1). The reaction was heated to 120 ° C for 12 hours. The mixture was cooled and sodium methoxide (30% in methanol) was added. The mixture was heated to 60 ° C for 1 hour. The mixture was cooled to room temperature and concentrated in vacuo. The residue was divided between water and dichloromethane. The organic layer was separated, dried (MgS04), the solids were removed by filtration and the solvents of the filtrate were concentrated in vacuo. The crude was purified by Prep HPLC (RP SunFire Prep C18 OBD-10 µm, 30 x 150 mm). Mobile phase (0.25% NH 4 HCO 3 solution in water, CH 3 CN). The product fractions were collected and concentrated in vacuo, providing a compound 21 . Preparation of 22
    [0107] [000107] A mixture of VI-2 (500 mg, 1.48 mmol), tributyl (1-ethoxyvinyl) thine (0.626 mL, 1.85 mmol), PdCl 2 (PPh 3 ) 2 (220 mg, 0.31 mmol) in DMF (10 mL) was heated to 80 ° C for 16 hours. The reaction mixture was cooled and HCI (1N, 2 ml) was added. The mixture was stirred at room temperature for 2 hours, then it was poured into saturated aqueous NaHCO 3 (100 ml) and the precipitate was isolated by filtration, reconstituted in dichloromethane, dried (MgSO 4 ), the solids were removed by filtration and the solvents filtrate were concentrated in vacuo. The product was purified by silica gel column chromatography using a gradient of dichloromethane to 5% methanol in dichloromethane, the product fractions were collected and concentrated in vacuo. The product was triturated in DIPE, filtered and dried in vacuo to become a pale yellow solid.
    [0108] [000108] To the mixture, methanol (6 ml) and sodium methoxide (0.716 ml) were added and it was stirred at 60 ° C for 1 hour. The mixture was cooled and concentrated in vacuo. The residue was divided between water and dichloromethane. The organic layer was separated, dried (MgSO 4 ), the solids were removed by filtration and the filtrate solvents were concentrated in vacuo. The product was triturated in DIPE, isolated by filtration and dried under vacuum to become a yellow solid 22 . Preparation of 23
    [0109] [000109] 22 (59 mg, 0.23 mmol) was suspended in methanol (2 ml) and sodium borohydride (9 mg, 0.23 mmol) was added. The mixture was stirred under N 2 (g) at room temperature for two hours. The mixture was diluted with dichloromethane (5 ml), then aqueous saturated NH 4 CI (0.5 ml) was added followed by the addition of NaHCO 3 . The organic layer was dried (MgSO 4 ), the solids were removed by filtration and the solvents in the filtrate were concentrated in vacuo. The product was triturated in DIPE, isolated by filtration and dried in vacuo to become a pale yellow solid 23 . Preparation of 24
    [0110] [000110] Step 1. A 75 mL stainless steel autoclave was charged under a nitrogen atmosphere with VI-2 (626 mg, 1.87 mmol), Pd (OAc) 2 (8 mg, 0.037 mmol), 1.3 bis (diphenylphosphino) propane (31 mg, 0.074 mmol), potassium acetate (364 mg, 3.71 mmol), THF (20 mL), and methanol (20 mL). The autoclave was closed and pressurized to 3 Mpa (30 bar) CO (g). The reaction mixture was stirred for 16 hours at 120 ° C. The reaction mixture was allowed to cool to room temperature and was then concentrated in vacuo. The residue was dissolved in water and extracted with dichloromethane. The organic layer was dried (MgSO 4 ), the solids were removed by filtration and the solvent of the filtrate was concentrated in vacuo. The product was purified through a silica column using dichloromethane to 5% methanol in a dichloromethane gradient. The product fractions were collected and concentrated in vacuo to obtain an off-white solid VI-4 .
    [0111] [000111] Step 2. To a solution of VI-4 (190 mg, 0.69 mmol) in anhydrous THF (20 mL) was added LAH (1M in THF, 1.04 mL, 1.04 mmol) at -75 ° C under a nitrogen atmosphere. The reaction was stirred for two hours while slowly heating to 0 ° C. Then the mixture was cooled in an ice and ethanol bath and carefully cooled with the addition of 15 ml of ethyl acetate followed by Na 2 SO 4 10H 2 O (2 g). The mixture was stirred for one hour and then dried over MgS04, the solids were removed by filtration and the filtrate solvent was removed under reduced pressure. The residue was purified by the HPLC preparation (RP Vydac Denali C18 - 10 µm, 200 g, 5 cm). Mobile phase (0.25% NH 4 HCO 3 solution in water, CH 3 CN), followed by SFC purification.
    [0112] [000112] (Chiralpak Diacel AD 30 x 250 mm). Mobile phase (CO 2 , methanol with 0.2% isopropylamine), the desired fractions were collected and the solvents were removed under reduced pressure to provide 24 . Preparation of 25
    [0113] [000113] Step 1. V-14 was reacted with trimethylacetylene according to the method for preparing compound 14, to provide V-15 .
    [0114] [000114] LC-MS m / z = 258 (M + H)
    [0115] [000115] Step 2. VI-5 was prepared according to the method to prepare 9. Deprotection of the TMS group was carried out in a mixture of NaHC03, water and methanol.
    [0116] [000116] LC-MS m / z = 357 (M + H)
    [0117] [000117] Step 3. Hydrogenation was carried out according to the method to prepare 16. Preparation of 26
    [0118] [000118] Step 1. 2-bromo-4-isopropylaniline palladium catalyzed carbonylation was carried out according to the procedure to prepare VI-4 except that the reaction was carried out at 110 ° C to provide 2-amino acid -5-isopropylbenzoic.
    [0119] [000119] LC-MS m / z = 180 (M + H)
    [0120] [000120] Step 2. V- 16 was prepared according to the method for preparing V-1.
    [0121] [000121] LC-MS m / z = 204 (M + H)
    [0122] [000122] Step 3. Example 26 was prepared according to the method to prepare 15. Preparation of 27
    [0123] [000123] Step 1. Cyanamide was dissolved in ether and the mixture was stirred under nitrogen gas. HCI (2M in ether) was added dropwise to the reaction mixture at room temperature and stirring continued for two hours at room temperature. The precipitate A-2 was isolated by filtration and dried in vacuo at 50 ° C.
    [0124] [000124] Step 2. SO 2 (CH 3 ) 2 (20.4 g, 217 mmol) was heated until melted. A-2 (3.3 g, 29 mmol) was added and the resulting mixture was stirred and heated to 120 ° C until it dissolved completely. Methyl 5- (2-chloro-4-trifluoromethylphenoxy) anthranylate (5 g, 14.5 mmol) was added in one part to the reaction mixture. Stirring was continued for 30 minutes. The reaction mixture was treated with water (10 ml) and stirred for 10 minutes. The precipitate V-17 , a white solid, was isolated by filtration and dried in a vacuum oven.
    [0125] [000125] LC-MS m / z = 356 (M + H)
    [0126] [000126] Step 3. Compound 27 was formed according to the method to prepare 15. Preparation of 28
    [0127] [000127] Step 1. A-3 (101 g, 0.44 mol) was dissolved in sulfuric acid (850 ml). This solution was cooled to 0 ° C. HNO 3 (18.3 ml, 0.44 mol) in sulfuric acid (200 ml) was added dropwise over 2 hours. The reaction mixture was stirred for 45 minutes at - 10 ° C, then poured into ice water (6 L). The solvents were decanted and the residue was dissolved in dichloromethane (1.5 L). The aqueous layer was extracted with dichloromethane (1 L). The combined organic layers were dried (MgSO 4 ), the solids were removed by filtration and the solvent was removed under reduced pressure to provide A-4 , and the by-product isomer A-5 , separated by silica gel column chromatography using a heptane for ethyl acetate gradient.
    [0128] [000128] Step 2. Into a 500 mL flask equipped with a magnetic stir bar and sprinkled with nitrogen gas, methanol (100 mL, containing 2% thiophene), 5% Pt / C (2 g, 0.513 mmol) then placed under a hydrogen atmosphere. The reaction mixture was stirred for 16 hours at room temperature. The catalyst was removed by filtration and the filtrate volatiles were removed under reduced pressure. The residue was purified on silica using a dichloromethane to dichloromethane: methanol 9: 1 gradient providing a yellow oil, IV-2 .
    [0129] [000129] LC-MS m / z = 244 (M + H)
    [0130] [000130] Step 3. Intermediate V-18 was prepared according to the method for preparing V-17.
    [0131] [000131] LC-MS m / z = 254 (M + H)
    [0132] [000132] Step 4. The procedure for preparing compound 9 was applied to the synthesis of 28 of V-18. Preparation of compound 29
    [0133] [000133] Step 1. Example 29 was provided after catalytic hydrogenation of 27, according to the method described in the preparation of 25. Preparation of 90
    [0134] [000134] Step 1. 17 (12.515 g, 45.62 mmol) was dissolved in THF (100 ml). LiOH (3.83 g, 91.2 mmol) dissolved in water (20 ml) was added, followed by methanol (50 ml). The reaction mixture was stirred overnight at room temperature. The volatiles were removed under reduced pressure, the solid was washed with water and ground with DIPE to provide VI-6 as an off-white solid.
    [0135] [000135] 1 H NMR (400 MHz, DMSO- d 6 ) δ ppm 0.95 (t, J = 7.4 Hz, 3 H), 1.40 (dq, J = 14.9, 7.3 Hz , 2 H), 1.68 (quin, J = 7.3 Hz, 2 H), 3.54 - 3.65 (m, 2 H), 7.89 - 8.05 (m, 2 H), 8.14 - 8.31 (m, 2 H), 9.11 (br. S, 1 H), 11.10 (br. S., 1 H), 16.37 (br. S., 1 H)
    [0136] [000136] Step 2. VI-6 (200 mg, 0.768 mmol), DMF (10 mL), triethylamine (0.641 mL, 4.61 mmol), 3-aminopyridine (181 mg, 1 , 92 mmol) and diethyl cyanophosphonate (0.233 mL, 1.54 mmol). The reaction was allowed to stir for 2 hours at room temperature. The solvent was removed under reduced pressure and the crude was purified by reverse phase column chromatography (Sunfire Prep C18, OBD 10 δ m, 30 x 150 mm. Mobile phase (0.25% NH 4 HCO 3 solution in water, methanol ) to provide 90 . Synthetic scheme for the preparation of AA-9
    [0137] [000137] To a solution of valeraldehyde (43 g, 500 mmol) in THF (1 L) was added AA-2 (200 g, 532 mmol) and the reaction mixture was stirred for 16 hours at room temperature. The solvents were evaporated and the residue was diluted with petroleum ether and filtered. The filtrate solvents were removed under reduced pressure and the residue was purified by chromatography on silica using a gradient of petroleum ether to 3% ethyl acetate in petroleum ether to give AA-3 (90 g) as a colorless oil.
    [0138] [000138] 1 H NMR (400 MHz, CDCl 3 ): δ ppm 6.81-6.77 (m, 1H), 5,685.64 (td, J = 1.2 Hz, 15.6 Hz, 1H), 2 , 11-2.09 (m, 2H), 1.406 (s, 9H), 1.38-1.26 (m, 4H), 0.85-0.81 (t, J = 7.2Hz, 3H) . Synthesis of compound AA-5
    [0139] [000139] n-Butyl lithium (290 mL, 725 mmol, 1.5 eq.) Was added to a stirred solution of AA-4 (165 g, 781 mmol) in THF (800 mL) at -78 ° C. The reaction mixture was stirred for 30 minutes and then AA-3 (90 g, 488.4 mmol) in THF (400 ml) was added and the reaction was stirred for 2 hours at -78 ° C. The mixture was quenched with NH 4 Cl aq solution. sat. and heated to room temperature. The product was partitioned between ethyl acetate and water. The organic phase was washed with brine, dried and evaporated. The residue was purified by column chromatography eluting with 5% ethyl acetate in petroleum ether to give a colorless oil, AA-5 (132 g).
    [0140] [000140] 1 H NMR (400 MHz, CDCI 3 ): δ ppm 7.36-7.16 (m, 10H), 3.75-3.70 (m, 2H), 3.43-3.39 ( d, J = 15.2Hz, 1H), 3.33-3.15 (m, 1H), 1.86-1.80 (m, 2H), 1.47-1.37 (m, 2H), 1.32 (s, 9H), 1.26-1.17 (m, 7H), 0.83-0.79 (t, J = 7.2 Hz, 3H). Synthesis of AA-6
    [0141] [000141] AA-5 (130 g, 328 mmol) was dissolved in THF (1.5 L) and LAH (20 g, 526 mmol) was added at 0 ° C in small portions. The resulting mixture was stirred at the same temperature for 2 hours and then allowed to warm to room temperature. The mixture was inhibited with aq. sat. The product was partitioned between ethyl acetate and water. The organic phase was washed with brine, dried and evaporated. The combined organic layers were dried over sodium sulfate, the solids were filtered off and concentrated to give crude AA-6 (100 g), which was used in the next step without further purification.
    [0142] [000142] H NMR (400 MHz, CDCl 3 ): δ ppm 7.33-7.14 (m, 10H), 3.91-3.86 (m, 1H), 3.80-3.77 (d , J = 13.6Hz, 1H), 3.63-3.60 (d, J = 13.6Hz, 1H), 3.43-3.42 (m, 1 H), 3.15-3.10 (m, 1H), 2.70-2.63 (m, 2H), 1.65-1.28 (m, 10H), 0.89-0.81 (m, 3H). Synthesis of AA-9
    [0143] [000143] A solution of AA-6 (38 g, 116.75 mmol) and 10% Pd / C in methanol (200 mL ) was hydrogenated under 44.74 KPa (50 PSI) of hydrogen at 50 ° C for 24 hours. The reaction mixture was filtered and the solvent was evaporated to give the crude product AA-7 (17 g).
    [0144] [000144] The crude product was dissolved in dichloromethane (200 ml), triethylamine (26.17 g, 259.1 mmol) and di- tert-butyl dicarbonate (84.7 g, 194.4 mmol) was added at 0 ° Ç. The resulting mixture was stirred for 16 hours. The mixture was partitioned between dichloromethane and water. The organic phase was washed with brine, dried and evaporated. The residue was purified by chromatography on silica gel eluting with 20% ethyl acetate in petroleum ether to give AA-8 (13 g) as a colorless oil.
    [0145] [000145] 1 H NMR (400 MHz, CDCl 3 ): δ ppm 4.08-4.03 (br, 1H), 3.68 (m, 1H), 3.58-3.55 (m, 2H) , 3.20-2.90 (br, 1H), 1.80-1.73 (m, 1H), 1.42-1.17 (m, 15 H), 0.85-0.82 (t , J = 6.8 Hz, 3H).
    [0146] [000146] AA-8 (42 g, 0.182 mol) was dissolved in dioxane (200 ml) and dioxane / HCI (4M, 200 ml) was added at 0 ° C. The resulting mixture was stirred at room temperature for 2 h. The solvent was evaporated to give the crude product. A dichloromethane / petroleum ether mixture (50 ml, 1: 1, v / v) was added to the crude product, and the supernatant was decanted. This procedure was repeated twice to obtain an oil, AA-9 (26.6 g).
    [0147] [000147] 1 H NMR (400 MHz, DMSO- d 6 ): δ ppm 8.04 (s, 3H), 3.603.49 (m, 2H), 3.16-3.15 (m, 1H), 1 , 71-1.67 (m, 2H), 1.60-1.55 (m, 2H), 1.33-1.26 (m, 4H), 0.90-0.87 (t, J = 6.8 Hz, 3H). Preparation of AA-10
    [0148] [000148] AA-10 was prepared according to the preparation of 9-AA using butyraldehyde instead of valeraldehyde.
    [0149] [000149] 1 H NMR (400 MHz, DMSO- d 6 ): δ ppm 8.07 (s, 3H), 4.85 (la, 1H), 3.57-3.45 (m, 2H), 3 , 14-3.12 (m, 1H), 1.70-1.64 (m, 2H), 1.56-1.49 (m, 2H), 1.38-1.30 (m, 2H) , 0.90-0.80 (t, J = 6.8 Hz, 3H). Table 1. Compounds of formula (I)
    [0150] [000150] Analytical Methods.
    [0151] [000151] All compounds were characterized by LC-MS. The following LC-MS methods were used:
    [0152] [000152] Method A. Reverse phase UPLC (Ultra Performance Liquid Chromatography) was carried out on a C18 column of ethyl siloxane / bridged silica (BEH) (1.7 µm, 2.1 x 50 mm; Waters Acquity) at a flow rate of 0.8 ml / min. Two mobile phases (10 mM ammonium acetate in H 2 O / acetonitrile 95/5; mobile phase B: acetonitrile) were used to operate a gradient condition from A to 95% and B to 5% to A to 5% and 95% B in 1.3 minutes and maintained for 0.7 minutes. An injection volume of 0.75 µL was used. The cone voltage was 30 V for positive ionization mode and 30 V for negative ionization mode.
    [0153] [000153] Method B. Reverse phase HPLC was carried out on a C18 Xterra MS column (3.5 pm, 4.6 x 100 mm) at a flow rate of 1.6 ml / min. Three mobile phases (mobile phase A: 95 mM 25% ammonium acetate + 5% acetonitrile; mobile phase B: acetonitrile; mobile phase C: methanol) were employed to operate a gradient condition from A to 100% to B 50% and 50% C in 6.5 minutes, 100% B in 0.5 minutes, 100% B for 1 minute and rebalanced with 100% A for 1.5 minutes. An injection volume of 10 µL was used.
    [0154] [000154] Method C. Reverse phase UPLC (Ultra Performance Liquid Chromatography) was carried out on a C18 column of ethyl siloxane / bridged silica (BEH) (1.7 pm, 2.1 x 50 mm; Waters Acquity) at a flow rate of 0.8 ml / min. Two mobile phases (mobile phase A: 10 mM ammonium acetate in H 2 O / acetonitrile 95/5; mobile phase B: acetonitrile) were used to operate a gradient condition from A to 95% and B to 5% to A at 5% and B at 95% in 1.3 minutes and maintained for 0.2 minutes. An injection volume of 0.5 µL was used. Biological activity of compounds of formula (I) Description of Biological Assays Evaluation of TLR7 and TLR8 activity
    [0155] [000155] The ability of the compounds to activate human TLR7 and / or TLR8 was evaluated in a cell reporter assay using HEK293 cells transiently transfected with a TLR7 or TLR8 expression vector and NFh B-luc reporter construct. In one instance, the TLR expression construct expresses the respective wild-type sequence or a mutant sequence comprising a deletion in the second leucine-rich repeat of the TLR. Such mutant TRL proteins have previously been shown to be more susceptible to agonist activation (US 7498409).
    [0156] [000156] Soon, HEK293 cells were cultured in culture medium (DMEM supplemented with 10% SFB and 2 mM Glutamine). For the transfection of cells in 10 cm dishes, the cells were separated with Trypsin-EDTA, transfected with a mixture of plasmid CMV-TLR7 or TLR8 (750 ng), plasmid NFh B-luc (375 ng) and a transfection reagent and incubated for 24 hours at 37 ° C in a humidified atmosphere of 5% CO 2 . The transfected cells were then separated with Trypsin-EDTA, washed in PBS and resuspended in medium to a density of 1.67 x 10 5 cells / ml. Thirty microliters of cells were then dispensed into each well in 384-well plates, where 10 µL of the compound in 4% DMSO was already present. After 6 hours of incubation at 37 ° C, 5% CO 2 , luciferase activity was determined by adding 15 µl of Steady Lite Plus substrate (Perkin Elmer) to each well and reading on a ViewLux ultraHTS microplate imager (Perkin Elmer). Dose response curves were generated from quadruplicate measurements. The values of the lowest effective concentrations (LEC), defined as the concentration that induces an effect at least twice above the standard deviation of the assay, were determined for each compound.
    [0157] [000157] The toxicity of the compounds was determined in parallel using a series of similar dilutions of compound with 30 µL per well of cells transfected only with the construct CMV-TLR7 (1.67 x 10 5 cells / mL), in 384 plates wells. Cell viability was measured after 6 hours of incubation at 37 ° C, 5% CO 2 , by adding 15 µL of ATP lite (Perkin Elmer) per well and reading in a ViewLux ultraHTS microplate imager (Perkin Elmer). The data were recorded as CC 50 . Suppression of HCV replicon replication
    [0158] [000158] Activation of human TLR7 results in the robust production of interferon by plasmacytoid dendritic cells present in human blood. The potential of the compounds to induce interferon was evaluated by looking at the antiviral activity of the HCV replicon system after incubation with conditioned media from peripheral blood mononuclear cells (PBMC). The HCV replicon assay is based on a bicistronic expression construct, as described by Lohmann et al. (Science (1999) 285: 110-113; Journal of Virology (2003) 77: 3007-15 3019) with modifications described by Krieger et al. (Journal of Virology (2001) 75: 4614-4624). The assay used the stably transfected Huh-7 luc / neo cell line harboring an RNA encoding a bicistronic expression construct comprising the HC3 type 1b wild-type NS3-NS5B regions translated from an Internal Ribosomal Entry Site (IRES) of the virus encephalomyocarditis (EMCV), preceded by a reporter gene (firefly luciferase) and a selectable marker gene (neoR, neomycin phosphotransferase). The construct is flanked by 5 'and 3' NTRs (untranslated regions) of HCV type 1b. The continued culture of replicon cells in the presence of G418 (neoR) is dependent on HCV RNA replication. Stably transfected replicon cells that replicate HCV RNA autonomously and to high levels, encoding luciferase, among others, were used to obtain the profile of conditioned cell culture media.
    [0159] [000159] PBMCs were soon prepared from buffy coat layers from at least two donors using a standard Ficoll centrifugation protocol. Isolated PBMCs were resuspended in RPMI medium supplemented with 10% human AB serum and 2 x 10 5 cells / well were dispensed in 384-well plates containing the compounds (total volume 70 µL). After overnight incubation, 10 µL of the supernatant was transferred to 384-well plates containing 2.2 x 10 3 replicon cells / well in 30 µL (plated the previous day). After 24 hours of incubation, replication was measured by assessing luciferase activity using Steady Lite Plus substrate at 40 µL / well (Perkin Elmer) and measured with ViewLux ultraHTS microplate imager (Perkin Elmer). The inhibitory activity of each compound in Huh7-luc / neo cells was recorded as EC 50 values, defined as the concentration of compound applied to PBMCs resulting in a 50% reduction in luciferase activity which in turn indicates the degree of replicon RNA replication in transferring a defined amount of PBMC culture medium. Recombinant interferon a-2a (Roferon-A) was used as a standard control compound.
    [0160] [000160] Biological activity of the compounds of formula (I). All compounds showed CC50 of> 24h M in the HEK 293 TOX assay described above. Activation of ISRE promoters
    [0161] [000161] The potential of the compounds to induce IFN-I was also assessed by measuring the activation of interferon-stimulated response elements (ISRE) by conditioned means from PBMC. The GAAACTGAAACT sequence ISRE element is highly sensitive to the transcription factor STAT1-STAT2-IRF9, activation after binding IFN-I to its IFNAR receptor (Clontech, PT3372-5W). Clontech's pISRE-Luc plasmid (ref. 631913) contains 5 copies of that ISRE element, followed by the firefly luciferase ORF. A HEK293 cell line stably transfected with pISRE-Luc (HEK-ISREIuc) was established to obtain the profile of the conditioned media of PBMC cells.
    [0162] [000162] PBMCs were soon prepared from buffy coat layers from at least two donors using a standard Ficoll centrifugation protocol. Isolated PBMCs were resuspended in RPMI medium supplemented with 10% human AB serum and 2 x 10 5 cells / well were dispensed in 384-well plates containing the compounds (total volume 70 µL). After overnight incubation, 10 µL of the supernatant was transferred to 384-well plates containing 5 x 10 3 HEK-ISREIuc cells / well in 30 µL (plated the previous day). After 24 hours of incubation, the activation of the ISRE elements was measured by assessing luciferase activity using Steady Lite Plus substrate at 40 pL / well (Perkin Elmer) and measured with ViewLux ultraHTS microplate imager (Perkin Elmer). The stimulating activity of each compound in HEK-ISREIuc cells was recorded as an LEC value, defined as the concentration of compound applied to PBMC resulting in a luciferase activity at least twice above the standard deviation of the assay. The LEC in turn indicates the degree of activation of ISRE in the transfer of a defined amount of PBMC culture medium. Recombinant interferon a-2a (Roferon-A) was used as a standard control compound.
    [0163] [000163] For a given compound, the LEC values obtained from this assay were in the same range as the EC50 values obtained from the "suppression of the HCV replication assay". Thus, it is possible to compare the potential of the compounds to induce IFN-I by PBMC measured by any of the 2 assays.

    * Test performed in 48 hours











    权利要求:
    Claims (7)
    [0001]
    Compound, characterized by the fact that it presents the formula (I):
    [0002]
    Compound of formula (I) according to claim 1, characterized by the fact that R 1 is one of the following:
    [0003]
    Compound of formula (I) according to claim 1 or 2, characterized in that R 5 is preferably hydrogen or fluorine.
    [0004]
    Compound of formula (I) according to any one of claims 1 to 3, characterized by the fact that it is selected from the group consisting of:
    [0005]
    Compound of formula (I) according to any one of claims 1 to 4, characterized in that the compound has the following structure:
    [0006]
    Pharmaceutical composition, characterized in that it comprises a compound of formula (I) or a pharmaceutically acceptable salt, solvate or polymorph thereof, as defined in any one of claims 1 to 5, together with one or more pharmaceutically excipients, diluents or carriers acceptable.
    [0007]
    Use of a compound of formula (I) or a pharmaceutically acceptable salt, solvate or polymorph thereof, as defined in any one of claims 1 to 5, characterized in that it is for the preparation of a pharmaceutical composition in the treatment of a disorder in which it is modulation of TLR7 and / or TLR8 is involved.
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    AU2012258220B2|2017-01-19|
    DK2709989T3|2018-04-09|
    AU2012258220A1|2013-10-31|
    CN103748081A|2014-04-23|
    EP2709989A1|2014-03-26|
    JP6050329B2|2016-12-21|
    IL228906D0|2013-12-31|
    KR20190124337A|2019-11-04|
    HUE036220T2|2018-06-28|
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    ZA201308746B|2016-01-27|
    EP2709989B1|2017-12-20|
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    PT2709989T|2018-03-27|
    PL2709989T3|2018-06-29|
    SI2709989T1|2018-04-30|
    MY166557A|2018-07-16|
    EP2709989B8|2018-04-18|
    NO2709989T3|2018-05-19|
    EA201391719A1|2014-03-31|
    CL2013003313A1|2014-07-04|
    ES2663601T3|2018-04-16|
    CA2835229A1|2012-11-22|
    US20140073642A1|2014-03-13|
    EA028254B1|2017-10-31|
    CA2835229C|2020-05-05|
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    法律状态:
    2017-07-04| B25A| Requested transfer of rights approved|Owner name: JANSSEN SCIENCES IRELAND UC (IE) |
    2018-01-23| B07D| Technical examination (opinion) related to article 229 of industrial property law|
    2018-04-03| B06F| Objections, documents and/or translations needed after an examination request according art. 34 industrial property law|
    2019-07-02| B07E| Notice of approval relating to section 229 industrial property law|Free format text: NOTIFICACAO DE ANUENCIA RELACIONADA COM O ART 229 DA LPI |
    2019-09-10| B06U| Preliminary requirement: requests with searches performed by other patent offices: suspension of the patent application procedure|
    2019-12-31| B06A| Notification to applicant to reply to the report for non-patentability or inadequacy of the application according art. 36 industrial patent law|
    2020-04-28| B09A| Decision: intention to grant|
    2020-06-30| B16A| Patent or certificate of addition of invention granted|Free format text: PRAZO DE VALIDADE: 20 (VINTE) ANOS CONTADOS A PARTIR DE 18/05/2012, OBSERVADAS AS CONDICOES LEGAIS. |
    优先权:
    申请号 | 申请日 | 专利标题
    EP11166538|2011-05-18|
    EP11166538.6|2011-05-18|
    PCT/EP2012/059234|WO2012156498A1|2011-05-18|2012-05-18|Quinazoline derivatives for the treatment of viral infections and further diseases|
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