JP2014517004A - Heterocyclic sulfonamide derivatives - Google Patents

Abstract

The present invention relates to compound (I) and pharmaceutically acceptable salts thereof. The compounds have been demonstrated as inhibitors of MEK and can therefore be useful in the treatment of hyperproliferative diseases such as cancer and inflammation.

Description

CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of priority from the patent application 1634 / DEL / 11, which was filed in India on 06 May 09, 2011. The entire disclosure of this application is incorporated herein by reference in its entirety for all purposes.

The present invention relates to heterocyclic sulfonamide compounds and pharmaceutical compositions thereof, and in particular to heterocyclic sulfonamide compounds that are specific inhibitors of MEK kinase activity. The invention also relates to the use of said compounds and compositions thereof in the management of hyperproliferative diseases such as cancer and inflammation.

BACKGROUND OF THE INVENTION Hyperproliferative diseases such as cancer and inflammation have received much attention from the scientific community, and there is a strong desire to find compounds that provide therapeutic utility for the treatment of hyperproliferative diseases. . In this regard, efforts have been made to identify and target specific mechanisms that play a role in proliferating the diseases.

  One interesting target is the overactivation of the mitogen-activated protein (MAP) kinase cascade, which is known to play an important role in cell proliferation and differentiation. This pathway can be activated when a growth factor binds to its receptor tyrosine kinase. This interaction promotes RAS association with RAF and triggers a phosphorylation cascade from MEK (MAP kinase) via ERK. Inhibition of this pathway is known to be beneficial in the treatment of hyperproliferative diseases. MEK is an attractive therapeutic target because the only known substrates for MEK phosphorylation are MAP kinases, ERK1 and ERK2. Constitutive activation of MEK / ERK has been seen in pancreatic, colon, lung, kidney and ovarian primary tumor samples.

  Phosphorylation of MEK appears to increase its affinity for ERK and its catalytic activity and affinity for ATP. The present invention describes compounds that inhibit MEK activity by modulating ATP binding, association of MEK and ERK by competitive and / or allosteric and / or non-competitive mechanisms.

Activation of MEK has been demonstrated in many disease models, and thus inhibition of MEK has been demonstrated in various diseases such as pain (e.g., Evidence of efficacy in pain models described in J. Neurosci . 22: 478, 2002). Acta Pharmacol Sin. 26: 789 2005; Expert Opin Ther Targets . 9: 699, 2005; and Mol. Pain . 2: 2, 2006): Stroke (eg, J. Pharmacol. Exp. Ther. 304 : 172, 2003, see Evidence of efficacy in stroke models significant neuroprotection against ischemic brain injury by inhibition of the MEK; and Brain Res. 996: 55, 2004); diabetes (e.g., Am. J. Physiol. Renal. 286, see F120 2004, Evidence in diabetic complications); inflammation (see, for example, Evidence of efficacy in inflammation models described in Biochem Biophy. Res. Com. 268: 647, 2000); And arthritis (e.g., Evidence of efficacy in experime described in J. Clin. Invest. 116: 163. 2006 ntal osteoarthritis and arthritis (see ntal osteoarthritis and arthritis) have been suggested to have potential therapeutic utility.

  Although inhibition of MEK has been shown to have potential therapeutic utility in several studies, there is still a need to find compounds with commercial utility.

を提供する。 SUMMARY OF THE INVENTION The present invention relates to a compound: (S) -N- (4,5-difluoro-6-((2-fluoro-4-iodophenyl) amino) benzofuran-7-yl) -1- (2,3 -Dihydroxypropyl) cyclopropane-1-sulfonamide and (R) -N- (4,5-difluoro-6-((2-fluoro-4-iodophenyl) amino) benzofuran-7-yl) -1- ( 2,3-dihydroxypropyl) cyclopropane-1-sulfonamide:

I will provide a.

  These compounds of the present invention exist as isomeric configurations with asymmetric centers. Both isomeric forms are considered to be within the scope of the present invention. Each compound can be prepared as a single isomer and / or separated into single isomers by techniques known to those skilled in the art. Therefore, the compounds of the present invention can be used in their single isomer or isomeric form. The pharmaceutically acceptable salt is also conceivable.

  In another aspect of the invention, there is provided a pharmaceutical composition comprising the above compound, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

Definitions Unless otherwise noted, the term “compound of the invention” refers to (S) —N- (4,5-difluoro-6-((2-fluoro-4-iodophenyl) amino) benzofuran-7-yl. ) -1- (2,3-dihydroxypropyl) cyclopropane-1-sulfonamide or (R) -N- (4,5-difluoro-6-((2-fluoro-4-iodophenyl) amino) benzofuran- 7-yl) -1- (2,3-dihydroxypropyl) cyclopropane-1-sulfonamide, and their salts, and all isotopically labeled compounds (including deuterium substitution) and intrinsic Inherently formed moieties (eg, polymorphs, solvates and / or hydrates).

DESCRIPTION OF THE PREFERRED EMBODIMENTS The invention is regulated by inhibition of the kinase activity of MEK, provides useful compounds and pharmaceutical compositions thereof in a disease, the treatment of symptoms and / or disorders (Treatment).

  The compounds of the present invention can be synthesized by synthetic routes including methods analogous to those well known in the chemical arts, particularly in light of the description contained herein. Starting materials are generally available from commercial sources such as Aldrich Chemicals (Milwaukee, Wis.) Or are readily prepared using methods well known to those skilled in the art (e.g., Louis F. Fieser and Mary Fieser , Reagents for Organic Synthesis, v. 1-19, Wiley, New York (1967-1999 ed.), Or Beilsteins Handbuch der organischen Chemie, 4, including the supplement, Aufl. Ed. Springer-Verlag, Berlin (Beilstein (Also available via an online database)).

  See the Examples section below for a detailed description of the individual reaction steps. One skilled in the art will appreciate that other synthetic routes can be used to synthesize the compounds of the invention. Although specific starting materials and reagents are described, one of ordinary skill in the art understands that other starting materials and reagents can be readily substituted to provide various derivatives and / or reaction conditions. Will.

  The compounds of the present invention can form salts with bases, particularly pharmaceutically acceptable bases such as those well known in the art; suitable such salts include metal salts, particularly alkali metals or alkaline earths. Metal salts such as sodium, potassium, magnesium or calcium salts, or salts with ammonia or pharmaceutically acceptable organic amines or heterocyclic bases such as ethanolamine, benzylamine or pyridine. These salts can be prepared by known salt forming procedures.

The present invention includes isotopically labeled or enriched compounds of the present invention. Representative examples of isotopes suitable for inclusion in the compounds of the present invention include hydrogen isotopes such as ² H and ³ H, carbon isotopes such as ¹¹ C, ¹³ C and ¹⁴ C, chlorine isotopes Isomers such as ³⁶ Cl, fluorine isotopes such as ¹⁸ F, iodine isotopes such as ¹²³ I and ¹²⁵ I, nitrogen isotopes such as ¹³ N and ¹⁵ N, oxygen isotopes such as ¹⁵ O, ¹⁷ O and ¹⁸ O, phosphorus isotopes such as ³² P, and sulfur isotopes such as ³⁵ S.

Substitution with heavier isotopes, e.g. deuterium, i.e. ² H, may give certain therapeutic benefits due to greater metabolic stability, e.g. increased in vivo half-life or reduced required dose And therefore may be preferred in some situations.

  Isotopically-labeled compounds of the present invention can be substituted for previously unlabeled reagents by conventional techniques known to those skilled in the art or by methods similar to those described in the appended examples and preparation sections. It can generally be prepared using an isotope-labeled reagent.

  The compounds of the present invention may exist in unsolvated as well as solvated forms with pharmaceutically acceptable solvents such as water, ethanol and the like, and the present invention includes both solvated and unsolvated forms. Intended. For the purposes of the present invention, solvates (including hydrates) are considered to be, for example, pharmaceutical compositions combining a compound of the present invention and an excipient, where The excipient is a solvent.

  The invention also relates to pharmaceutical compositions comprising a compound of the invention and a pharmaceutically acceptable excipient.

  Suitable excipients are generally corn starch, potato starch, tapioca starch, starch paste, pre-gelatinized starch, sugars, gelatin, natural gums, synthetic rubber (synthetic gums), sodium alginate, alginic acid, tragacanth, guar gum, cellulose, ethyl cellulose, cellulose acetate (cellulose acetate), carboxymethylcellulose calcium, sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, microcrystalline cellulose, aluminum silicate Magnesium, polyvinyl pyrrolidone, talc, calcium carbonate, powdered cellulose, dextranate, kaolin, mannitol, silicic acid, sorbitol, agar, sodium carbonate, Roscarmellose sodium, crospovidone, polacrilin potassium, sodium starch glycolate, clays, sodium stearate, calcium stearate, magnesium stearate, stearic acid, mineral oil, light oil, glycerin, sorbitol, mannitol, Polyethylene glycol, other glycols, sodium lauryl sulfate, hydrogenated vegetable oil, peanut oil, cottonseed oil, sunflower oil, sesame oil, olive oil, corn oil, soybean oil, zinc stearate, sodium oleate, ethyl oleate, Examples include ethyl laureate, silica, and combinations thereof.

  A typical formulation is prepared by mixing a compound of the present invention and a carrier, diluent or excipient. Suitable carriers, diluents and excipients are well known to those skilled in the art and include, for example, carbohydrates, waxes, water soluble and / or swellable polymers, hydrophilic or hydrophobic materials, gelatin, oils, solvents, water, etc. Material is included. The particular carrier, diluent or excipient used will depend upon the means and purpose for which the compound of the present invention is to be applied. Solvents are generally selected based on (GRAS) solvents that are recognized as safe by those skilled in the art when administered to mammals. In general, safe solvents are non-toxic aqueous solvents such as water and other non-toxic solvents that are soluble or miscible in water. Suitable aqueous solvents include water, ethanol, propylene glycol, polyethylene glycol (eg, PEG400, PEG300) and the like and mixtures thereof. The formulation may also include one or more buffers, stabilizers, surfactants, wetting agents, lubricants, emulsifiers, suspending agents, preservatives, antioxidants, opaquing agents, glidants, processing Auxiliaries, colorants, sweeteners, fragrances, flavorings and other, provide a beautiful appearance of a drug (ie, a compound of the present invention or a pharmaceutical composition thereof), or in the manufacture of a medicament (ie, a medicament) Auxiliary known additives may be included.

  The formulation can be prepared using conventional dissolution and mixing procedures. For example, a bulk drug substance (i.e., a compound of the invention or a stabilized form of the compound (e.g., a complex with a cyclodextrin derivative or other known complexing agent)) is suitable in the presence of one or more excipients. Dissolved in a suitable solvent. The compounds of the present invention are typically formulated into pharmaceutical dosage forms that provide an easily controllable dosage of the drug, giving the patient a beautiful and easily handleable product.

  Compositions are generally tablets, troches, medicinal candy, aqueous or oily suspensions, ointments, patches, gels, lotions, dentifrices, capsules, emulsions, creams, sprays, drops, dispersible powders or granules, hard Or formulated into various dosage forms selected from the group comprising emulsions, syrups and elixirs in soft gel capsules.

  The pharmaceutical composition (or formulation) for application may be packaged in various ways depending on the method used to administer the drug. In general, an article for distribution includes a container having a pharmaceutical formulation in an appropriate form attached thereto. Suitable containers are well known to those skilled in the art and include materials such as bottles (plastic and glass), sachets, ampoules, plastic bags, metal cylinders and the like. The container may also include an tamper-evident assembly to prevent inadvertent access to the contents of the package. In addition, the container has a label attached to its surface that describes the contents of the container. The sign may also include appropriate notices.

  The compounds of the present invention are useful as both prophylactic and therapeutic treatments for diseases or conditions associated with hyperactivity of MEK and for diseases or conditions modulated by the Raf / Ras / Mek pathway.

  Thus, as a further aspect, the present invention relates to a method of treating a disease or condition associated with hyperactivity of MEK, or a disease or condition modulated by the MEK cascade, comprising administration of a therapeutically effective amount of a compound of the present invention. .

  In a further aspect, the present invention relates to a method of treating a proliferative disease, such as cancer, comprising administration of an effective amount of a compound of the present invention.

  Examples of cancer include, but are not limited to: hemangiosarcoma, fibrosarcoma, rhabdomyosarcoma, liposarcoma, myxoma, rhabdomyosarcoma, fibroma, lipoma, teratoma; bronchogenic lung cancer , Squamous cell carcinoma, undifferentiated small cell carcinoma, undifferentiated large cell carcinoma, alveolar (bronchiole) cancer, bronchial adenoma, lymphoma, chondromatous hanlartoma, endothelial tumor, esophageal squamous cell carcinoma, leiomyosarcoma , Leiomyosarcoma, ductal adenocarcinoma, insulinoma, glucagon producing tumor, gastrin producing tumor, VIP producing tumor, gastric and small intestine carcinoid tumor, adenocarcinoma, Kaposi's sarcoma, leiomyoma, hemangioma, lipoma, neurofibroma, fibroma , Tubular adenoma, chorionic adenoma, hamartoma, Wilms tumor (nephroblastoma, leukemia, bladder and urethral squamous cell carcinoma, transitional cell carcinoma, adenocarcinoma, seminoma, teratomas, embryonal carcinoma, teratocareinoma, Choriocarcinoma, stromal cell carcinoma, line Adenoma, adenomatous tumor, hepatocellular carcinoma (hepatocellular carcinoma), cholangiocarcinoma, hepatoblastoma, hepatocellular adenoma, hemangiomas, osteogenic sarcoma (osteosarcoma), malignant fibrous histiocytoma Chondrosarcoma, Ewing sarcoma, malignant lymphoma (reticulosarcoma), multiple myeloma, malignant giant cell chordoma, osteochondroma (osteocartilaginous exostoses), benign chondroma, chondroblastoma, cartilage Myxofibromas, osteoid and giant cell tumors, osteomas, granulomas, xanthomas, osteoarthritis, meningiomas, meningiosarcoma, glioma, astrocytoma, medulloblastoma , Glioma, ependymoma, germinoma [pineomas], glioblastoma multiforme, oligodendroglioma, Schwannoma, retinoblastoma, congenital tumor, spinal neurofibroma, meninges Tumor, glioma, endometrial cancer, cervical cancer, pre-tumor cervical dysplasia, ovarian cancer, serous cystadenocarcinoma, mucinous cystadenocarcinoma, granulosa Membrane cell tumor, Sertoli Leydig cell tumor, Undifferentiated germ cell tumor, Malignant teratoma, Carcinoma in situ, Adenocarcinoma, Melanoma), Clear cell carcinoma, Gravesous sarcoma (fetal rhabdomyosarcoma), Fallopian tube Cancer, acute and chronic myelogenous leukemia, acute lymphoblastic leukemia, chronic lymphocytic leukemia, myeloproliferative disease, multiple myeloma, myelodysplastic syndrome, Hodgkin's disease, non-Hodgkin's lymphoma, malignant lymphoma, malignant melanoma, basal cell Cancer, mitochondria, dysplastic nevi, hemangioma, dermal fibroma, keloid, psoriasis, and neuroblastoma.

  The present invention includes non-small cell lung cancer, pancreatic cancer, bladder cancer, colon cancer, myeloid disorder, breast cancer, prostate cancer, thyroid cancer, melanoma, ovary, eye, liver, biliary system, and nervous system adenoma and Including treating a cancer selected from carcinoma and advanced solid tumors with KRAS, NRAS and BRAF mutations, such methods comprising administering to a subject in need of such treatment an effective amount of a compound of the invention. Including.

  The compounds of the present invention may also be useful in the treatment of other diseases or conditions associated with MEK hyperactivity. Thus, as a further aspect, the present invention relates to a method of treating a disorder selected from: xenotransplantation (cellos), skin, limb, organ or bone marrow transplantation rejection; osteoarthritis; rheumatoid arthritis; cyst Fibrosis; diabetic complications (including diabetic retinopathy and diabetic nephropathy); hepatomegaly; cardiac enlargement; stroke (eg, acute focal ischemic stroke and global cerebral ischemia); heart failure; septic Asthma; chronic obstructive pulmonary disease; Alzheimer's disease; and chronic or neuropathic pain.

  The term “chronic pain” for the purposes of the present invention includes, but is not limited to, idiopathic pain and pain associated with chronic alcoholism, vitamin deficiency, uremia, or hypothyroidism. Chronic pain is associated with a number of symptoms, including but not limited to inflammation and postoperative pain.

  As used herein, the term “neuropathic pain” is associated with a number of symptoms, including but not limited to inflammation, postoperative pain, phantom limb pain, burn pain. ), Gout, trigeminal neuralgia, acute herpes zoster and postherpetic pain, burning pain, diabetic neuropathy, plexus avulsion, neuroma, vasculitis, viral infection, extinction, tightening wound, tissue injury , Amputation of the lower limbs, and nerve damage between the peripheral and central nervous systems.

  The compounds of the present invention may also be useful as antiviral agents for treating viral infections, such as HIV, hepatitis (B) virus (HBV), human papillomavirus (HPV) , Cytomegalovirus (CMV), and Epstein-Barr virus (EBV).

  The compounds of the present invention may also be useful in the treatment of restenosis, psoriasis, allergic contact dermatitis, autoimmune diseases, atherosclerosis and inflammatory bowel diseases such as Crohn's disease and ulcerative colitis.

  The MEK inhibitor of the present invention is usefully used in combination with another pharmacologically active compound (further therapeutic agent) or two or more other pharmacologically active compounds, particularly in the treatment of cancer. be able to. For example, a compound of the invention as defined above may comprise one or more additional therapeutic agents selected from anticancer agents (or chemotherapeutic agents), pain medications, antiemetics, antidepressants or anti-inflammatory agents. They can be administered in combination, simultaneously, sequentially or separately. Chemotherapeutic agents include, for example, mitotic inhibitors such as taxanes, vinca alkaloids, paclitaxel, docetaxel, vincristine, vinblastine, vinorelbine or vinflunine, and other anticancer agents such as cisplatin, 5-fluorouracil or 5-fluoro- 2-4 (1 H, 3H) -pyrimidinedione (5FU), flutamide or gemcitabine.

  Such combinations can provide significant advantages in therapy, including synergistic activity.

  The compounds of the present invention can also be advantageously used in combination with other antiproliferative compounds. Such antiproliferative compounds include, but are not limited to, aromatase inhibitors; antiestrogens; topoisomerase I inhibitors; topoisomerase II inhibitors; microtubule active compounds; alkylating compounds; histone deacetylases Inhibitors, such as LBH589; Compounds that induce cell differentiation processes; Cyclooxygenase inhibitors; MMP inhibitors; mTOR inhibitors, such as RAD001; Anti-neoplastic antimetabolite; Platinum compounds; Protein or lipid kinase activity Compounds that target / reduce and anti-angiogenic compounds; compounds that target, reduce or inhibit the activity of protein or lipid phosphatases; gonadorelin agonists; antiandrogens; methionine aminopeptidase inhibitors; bisphosphonates Biological response modifiers; anti-proliferation Antibodies; heparanase inhibitors; Ras oncogenic isoform inhibitors; telomerase inhibitors; proteasome inhibitors; compounds used in the treatment of hematological malignancies; targeting, reducing Flt-3 activity, Or inhibiting compounds, such as PKC412; Hsp90 inhibitors, such as 17-AAG (17-allylamino-geldanamycin, NSC330507), 17-DMAG (17-dimethylaminoethylamino-17-demethoxy-geldanamycin, NSC707545 ), IPI-504, CNF1010, CNF2024, CNF1010 and AUY922 from Conforma Therapeutics; Temozolomide (TEMODAL); kinesin spindle protein inhibitors, for example, SB715992 or SB743921 from GlaxoSmithKline, or pentamine from CombinatoRx PI3K inhibitors such as BEZ235; RAF inhibitors such as RAF265 and LGX818; EDG binding agents, anti-leukemic compounds, Ribonucleotide reductase inhibitors, S- adenosylmethionine decarboxylase inhibitors, antiproliferative antibodies or other chemotherapeutic compounds. Additionally or alternatively, they can be combined with other tumor treatment approaches, such as surgery, ionizing radiation, photodynamic therapy, implants, such as those with corticosteroids, hormones, etc. Or they can be used as radiosensitizers. Also included are combinations with anti-inflammatory drugs in anti-inflammatory and / or anti-proliferative treatments. The combination may also be an antihistamine drug substance, a bronchodilatatory drug, an NSAID or chemokine receptor antagonist.

  The term “aromatase inhibitor”, as used herein, relates to compounds which inhibit estrogen production, ie, conversion of the substrates androstenedione and testosterone to estrone and estradiol, respectively. Such terms include, but are not limited to, steroids, in particular atamestan, exemestane and formestane, and especially non-steroids, in particular aminoglutethimide, roglethimide, pyridoglutethimide, trilostane, test lactone , Ketokonazole, borozole, fadrozole, anastrozole and letrozole. Exemestane can be administered, eg, in the form as it is marketed, eg under the trademark AROMASIN. Formestane can be administered, eg, in the form as it is marketed, eg under the trademark LENTARON. Fadrozole can be administered, eg, in the form as it is marketed, eg under the trademark AFEMA. Anastrozole can be administered, eg, in the form as it is marketed, eg under the trademark ARIMIDEX. Letrozole can be administered, eg, in the form as it is marketed, eg under the trademark FEMARA or FEMAR. Aminoglutethimide can be administered, eg, in the form as it is marketed, eg under the trademark ORIMETEN. A combination of the invention comprising a chemotherapeutic agent that is an aromatase inhibitor is particularly useful for the treatment of hormone receptor positive tumors, eg breast tumors.

  The term “anti-estrogenic agent” as used herein relates to a compound that antagonizes the effect of estrogen at the estrogen receptor level. Such terms include, but are not limited to tamoxifen, fulvestrant, raloxifene and raloxifene hydrochloride. Tamoxifen can be administered, eg, in the form as it is marketed, eg under the trademark NOLVADEX. Raloxifene hydrochloride can be administered, eg, in the form as it is marketed, eg under the trademark EVISTA. Fulvestrant can be formulated as disclosed in US 4,659,516, or it can be administered, eg, in the form in which it is marketed, eg under the trademark FASLODEX. A combination of the invention comprising a chemotherapeutic agent that is an anti-estrogen agent is particularly useful for the treatment of estrogen receptor positive tumors, eg, breast tumors.

  The term “antiandrogen” as used herein refers to any substance capable of inhibiting the biological effects of androgen, including but not limited to, for example, disclosed in US Pat. No. 4,636,505. Bicalutamide (CASODEX), which can be formulated as described, is included.

  The term “gonadorelin agonist” as used herein includes, but is not limited to, abarelix, goserelin and goserelin acetate. Goserelin is disclosed in US 4,100,274 and can be administered, eg, in the form in which it is marketed, eg under the trademark ZOLADEX. Abarelix can be formulated, for example, as disclosed in US 5,843,901.

  The term “topoisomerase I inhibitor” as used herein includes, but is not limited to, topotecan, gaimatecan, irinotecan, camptothecin and analogs thereof, 9-nitrocamptothecin and macromolecular camptothecin conjugate PNU-166148 ( Compound A1) in WO99 / 17804 is included. Irinotecan can be administered, eg, in the form as it is marketed, eg under the trademark CAMPTOSAR. Topotecan can be administered, eg, in the form as it is marketed, eg under the trademark HYCAMTIN.

  The term “topoisomerase II inhibitor” as used herein includes, but is not limited to, anthracyclines such as doxorubicin (including liposomal formulations such as CAELYX), daunorubicin, epirubicin, idarubicin and nemorubicin. ), Anthraquinones, mitoxantrone and rosoxantrone, and podophillotoxine, etoposide and teniposide. Etoposide can be administered, eg, in the form as it is marketed, eg under the trademark ETOPOPHOS. Teniposide can be administered, eg, in the form as it is marketed, eg under the trademark VM 26-BRISTOL. Doxorubicin can be administered, eg, in the form as it is marketed, eg under the trademark ADRIBLASTIN or ADRIAMYCIN. Epirubicin can be administered, eg, in the form as it is marketed, eg under the trademark FARMORUBICIN. Idarubicin can be administered, eg, in the form as it is marketed, eg under the trademark ZAVEDOS. Mitoxantrone can be administered, eg, in the form as it is marketed, eg under the trademark NOVANTRON.

  The term “microtubule active compound” relates to microtubule stabilization, microtubule destabilization compounds and microtublin polymerization inhibitors, including, but not limited to, taxanes such as paclitaxel and docetaxel, vinca alkaloids. Vinblastine, in particular vinblastine sulfate, vincristine, in particular vincristine sulfate, and vinorelbine, discodermolide, cochicine and epothilone and derivatives thereof, such as epothilone B or D or derivatives thereof. Paclitaxel can be administered, eg, in the form in which it is marketed, eg, TAXOL. Docetaxel can be administered, eg, in the form as it is marketed, eg under the trademark TAXOTERE. Vinblastine sulfate can be administered, eg, in the form as it is marketed, eg under the trademark VINBLASTIN R.P. Vincristine sulfate can be administered, eg, in the form as it is marketed, eg under the trademark FARMISTIN. Discodermride can be obtained, for example, as disclosed in US 5,010,099. Also included are epothilone derivatives, which are disclosed in WO 98/10121, US 6,194,181, WO 98/25929, WO 98/08849, WO 99/43653, WO 98/22461 and WO 00/31247. Particularly preferred is epothilone A and / or B.

  The term “alkylated compound” as used herein includes, but is not limited to, cyclophosphamide, ifosfamide, melphalan or nitrosourea (BCNU or Gliadel). Cyclophosphamide can be administered, eg, in the form as it is marketed, eg under the trademark CYCLOSTIN. Ifosfamide can be administered, eg, in the form as it is marketed, eg under the trademark HOLOXAN.

  The term “histone deacetylase inhibitor” or “HDAC inhibitor” relates to compounds which inhibit histone deacetylase and have antiproliferative activity. This includes compounds such as sodium butyrate, LDH589 disclosed in WO 02/22577, in particular N-hydroxy-3- [4-[[(2-hydroxyethyl) [2- (1H-indole-3- Yl) ethyl] -amino] methyl] phenyl] -2E-2-propenamide, N-hydroxy-3- [4-[[[2- (2-methyl-1H-indol-3-yl) -ethyl]- Amino] methyl] phenyl] -2E-2-propenamide and their pharmaceutically acceptable salts, particularly lactate. It more particularly includes suberoylanilide hydroxamic acid (SAHA), MS275, FK228 (formerly FR901228), trichostatin A and compounds disclosed in US 6,552,065, in particular N-hydroxy-3- [4- [[[2- (2-Methyl-1H-indol-3-yl) -ethyl] -amino] -methyl] phenyl] -2E-2-propenamide, or a pharmaceutically acceptable salt thereof.

  The term “anti-neoplastic antimetabolite” includes, but is not limited to, 5-fluorouracil or 5-FU, capecitabine, gemcitabine, DNA demethylated compounds such as 5-azacytidine and decitabine, methotrexate and edatrexate, And folate antagonists such as pemetrexed. Capecitabine can be administered, eg, in the form as it is marketed, eg under the trademark XELODA. Gemcitabine can be administered, eg, in the form as it is marketed, eg under the trademark GEMZAR.

  The term “platin compound” as used herein includes, but is not limited to, carboplatin, cis-platin, cisplatinum and oxaliplatin. Carboplatin can be administered, eg, in the form as it is marketed, eg under the trademark CARBOPLAT. Oxaliplatin can be administered, eg, in the form as it is marketed, eg under the trademark ELOXATIN.

  The term “a compound that targets / reduces protein or lipid kinase activity” or “protein or lipid phosphatase activity” or “further anti-angiogenic compound” as used herein includes, but is not limited to, a protein Tyrosine kinases and / or serine and / or threonine kinase inhibitors or lipid kinase inhibitors, for example, include:

  a) a compound that targets, decreases or inhibits the activity of platelet derived growth factor receptor (PDGFR), eg a compound which targets, decreases or inhibits the activity of PDGFR, in particular PDGF receptor Compounds that inhibit the body, such as N-phenyl-2-pyrimidin-amine derivatives, such as imatinib, SU101, SU6668 and GFB-111;

  b) a compound that targets, decreases or inhibits the activity of fibroblast growth factor receptor (FGFR);

  c) a compound that targets, decreases or inhibits the activity of insulin-like growth factor receptor I (IGF-IR), eg, a compound which targets, decreases or inhibits the activity of IGF-IR In particular, compounds that inhibit the kinase activity of the IGF-I receptor, such as compounds disclosed in WO 02/092599, or antibodies that target the extracellular domain of the IGF-I receptor or growth factors thereof;

  d) a compound that targets, decreases or inhibits the activity of the Trk receptor tyrosine kinase family, or an ephrin B4 inhibitor;

  e) a compound that targets, decreases or inhibits the activity of the Axl receptor tyrosine kinase family;

  f) a compound that targets, decreases or inhibits the activity of a Ret receptor tyrosine kinase;

  g) Compounds that target, decrease or inhibit the activity of Kit / SCFR receptor tyrosine kinases, ie C-kit receptor tyrosine kinases (part of the PDGFR family), for example c-Kit receptor type Compounds that target, decrease or inhibit the activity of the tyrosine kinase family, in particular compounds which inhibit the c-Kit receptor, e.g. imatinib;

  h) Compounds that target, decrease or inhibit the activity of c-Abl family members, their gene fusion products (e.g. BCR-Abl kinase) and mutants, e.g. c-AbI family members and Compounds that target, decrease or inhibit the activity of their gene fusion products, such as N-phenyl-2-pyrimidin-amine derivatives such as imatinib or nilotinib (AMN107); PD180970; AG957; NSC 680410; PD173955 from ParkeDavis; or dasatinib (BMS-354825);

  i) Raf family members of protein kinase C (PKC) and serine / threonine kinases, MEK, SRC, JAK, FAK, PDK1, PKB / Akt members, and Ras / MAPK family members, and / or cyclin-dependent kinase families Compounds that target, reduce or inhibit the activity of members of (CDK), and in particular staurosporine derivatives disclosed in US 5,093,330, for example midstaurine; For example, UCN-01, Safingal, BAY 43-9006, Bryostatin 1, Perifosine; Ilmofosine; RO 318220 and RO 320432; GO 6976; Isis 3521; LY333531 / LY379196; Isochinoline compounds, such as WO Compounds disclosed in 00/09495; FTI; BEZ235 (P13K inhibitor) or AT7519 (CDK inhibitor);

  j) a compound that targets, decreases or inhibits the activity of a protein tyrosine kinase inhibitor, eg, a compound that targets, decreases or inhibits the activity of a protein tyrosine kinase inhibitor, such as mesylate Imatinib (GLEEVEC) or tyrophostin. Tyrophostin is preferably a low molecular weight (mw <1500) compound, or a pharmaceutically acceptable salt thereof, in particular a benzylidene malonitrile class or S-arylbenzenemalonirile or bisubstrate quinoline. A compound selected from the class of compounds, more specifically, tyrophostin A23 / RG-50810; AG 99; tyrophostin AG 213; tyrophostin AG 1748; tyrophostin AG 490; tyrophostin B44; tyrophostin B44 (+) enantiomer; tyrophostin Any compound selected from the group consisting of AG 555; AG 494; Tyrophostin AG 556, AG957 and adaphostin (4-{[(2,5-dihydroxyphenyl) methyl] amino} -benzoic acid adamantyl ester; NSC 680410, adaphostin) Is;

  k) compounds that target, reduce or inhibit the activity of the epidermal growth factor family of receptor tyrosine kinases (EGFR, ErbB2, ErbB3, ErbB4 as homo- or heterodimers) and their mutants; For example, compounds that target, reduce or inhibit the activity of the epidermal growth factor receptor family are the following: in particular, the EGF receptor tyrosine kinase family, such as the EGF receptor, ErbB2, ErbB3 and ErbB4 Compounds, proteins or antibodies that inhibit members or bind to EGF or EGF related ligands, and in particular compounds, proteins or monoclonal antibodies disclosed in WO 97/02266, in particular generally and specifically, for example Example (ex.) 39 compounds or EP 0 564 409, WO 99/03854, EP 0520722, EP 0 566 226, EP 0 787 722, EP 0 837 063, US 5, 747,498, WO 98/10767, WO 97/30034, WO 97/49688, WO 97/38983, compounds, proteins or monoclonal antibodies, and in particular compounds, proteins disclosed in WO 96/30347 Or a monoclonal antibody (e.g., compound known as CP 358774), a compound, protein or monoclonal antibody (e.g., compound ZD 1839) disclosed in WO 96/33980 and a compound, protein or disclosed in WO 95/03283 Monoclonal antibodies (e.g., compound ZM105180); e.g., trastuzumab (Herceptin), cetuximab (Arbitux), Iressa, Tarceva, OSI-774, CI-1033, EKB-569, GW-2016, E1.1, E2.4, E2 7H-pyrrolo- [2,3-d] pyrimidine derivatives disclosed in .5, E6.2, E6.4, E2.11, E6.3 or E7.6.3, and WO 03/013541; and

  l) A compound that targets, decreases or inhibits the activity of c-Met receptor, eg a compound which targets, decreases or inhibits the activity of c-Met, in particular c-Met receptor Compounds that inhibit the body's kinase activity, or antibodies that target the extracellular domain of c-Met or bind to HGF.

  Additional anti-angiogenic compounds include compounds that have another mechanism for their activity, such as compounds not associated with protein or lipid kinase inhibition, such as thalidomide (THALOMID) and TNP-470.

  A compound that targets, decreases or inhibits the activity of a protein or lipid phosphatase is, for example, an inhibitor of phosphatase 1, phosphatase 2A, or CDC25, such as okadaic acid or a derivative thereof.

  The compound that induces the cell differentiation process is, for example, retinoic acid, or tocopherol or tocotrienol.

  The term cyclooxygenase inhibitor as used herein includes, but is not limited to, for example, Cox-2 inhibitors, 5-alkyl substituted 2-arylaminophenylacetic acids and derivatives such as celecoxib (CELEBREX), rofecoxib (VIOXX), etoroxixib, valdecoxib or 5-alkyl-2-arylaminophenylacetic acid, such as 5-methyl-2- (2′-chloro-6′-fluoroanilino) phenylacetic acid, lumiracoxib.

  The term `` bisphosphonate '' as used herein includes, but is not limited to etridonic acid, clodronic acid, tiludronic acid, pamidronic acid, alendronic acid, ibandronic acid, risedronic acid and zoledronic acid. It is. “Etridonic acid” can be administered, eg, in the form as it is marketed, eg under the trademark DIDRONEL. “Clodronic acid” can be administered, eg, in the form as it is marketed, eg under the trademark BONEFOS. “Tiludronic acid” can be administered, eg, in the form as it is marketed, eg under the trademark SKELID. “Pamidronic acid” can be administered, eg, in the form as it is marketed, eg under the trademark AREDIA. “Alendronic acid” can be administered, eg, in the form as it is marketed, eg under the trademark FOSAMAX. “Ibandronic acid” can be administered, eg, in the form as it is marketed, eg under the trademark BONDRANAT. “Risedronic acid” can be administered, eg, in the form as it is marketed, eg under the trademark ACTONEL. “Zoledronic acid” can be administered, eg, in the form as it is marketed, eg under the trademark ZOMETA.

  The term “mTOR inhibitor” relates to compounds that inhibit the mammalian target of rapamycin (mTOR) and have antiproliferative activity, such as sirolimus (Rapamune), everolimus (Cartican O), CCI-779 and ABT578.

  The term “heparanase inhibitor”, as used herein, relates to a compound which targets, decreases or inhibits heparin sulfate degradation. Such terms include, but are not limited to PI-88.

  The term “biological response modifier” as used herein refers to lymphokines or interferons, such as interferons.

  The term `` oncogenic isoform, e.g., an inhibitor of H-Ras, K-Ras, or N-Ras '' as used herein, refers to a reduction that targets Ras oncogenic activity. A compound that causes or inhibits, for example, a “farnesyltransferase inhibitor”, for example L-744832, DK8G557 or R115777 (Zarnestra).

  The term “telomerase inhibitor” as used herein refers to a compound that targets, decreases or inhibits the activity of telomerase. A compound that targets, decreases or inhibits the activity of telomerase is in particular a compound which inhibits the telomerase receptor, for example telomestatin.

  The term “methionine aminopeptidase inhibitor”, as used herein, refers to a compound that targets, decreases or inhibits the activity of methionine aminopeptidase. A compound that targets, decreases or inhibits the activity of methionine aminopeptidase is, for example, bengamide or a derivative thereof.

  The term “proteasome inhibitor” as used herein refers to a compound that targets, decreases or inhibits the activity of the proteasome. Compounds that target, decrease or inhibit the activity of the proteasome include, for example, Bortezomid (Velcade) and MLN 341.

  The term "matrix metalloproteinase inhibitor" or ("MMP" inhibitor) as used herein includes, but is not limited to, collagen peptidomimetic and non-peptidomimetic inhibitors Tetracycline derivatives, such as the hydroxamate peptidomimetic inhibitor batimastat and its orally bioavailable analogs, marimastat (BB-2516), purinomastert (AG3340), metastat (metastat ) (NSC 683551), BMS-279251, BAY 12-9566, TAA211, MMI270B or AAJ996.

  The term “compounds used in the treatment of hematological malignancies” as used herein includes, but is not limited to, FMS-like tyrosine kinase inhibitors such as FMS-like tyrosine kinase receptors (Flt-3R Compounds that target, decrease or inhibit the activity of interferon, 1-bD-arabinofuranosylcytosine (ara-c) and bisulfan; and ALK inhibitors such as anaplastic lymphoma kinase Compounds that target, reduce or inhibit is included.

  Compounds that target, reduce or inhibit the activity of the FMS-like tyrosine kinase receptor (Flt-3R) are in particular compounds, proteins or antibodies that inhibit members of the Flt-3R receptor kinase family, such as PKC412, TKI258, midstaurine, staurosporine derivatives, SU11248 and MLN518.

  The term “HSP90 inhibitor”, as used herein, includes, but is not limited to, a compound that targets, decreases or inhibits the endogenous ATPase activity of HSP90; a ubiquitin proteosome pathway. Through which the HSP90 client protein is degraded, targeted, reduced or inhibited. Compounds that target, reduce or inhibit the endogenous ATPase activity of HSP90 are in particular compounds, proteins or antibodies that inhibit the ATPase activity of HSP90, such as 17-allylamino, 17-demethoxygeldanamycin ( 17AAG), geldanamycin derivatives; other geldanamycin-related compounds, and radicicol.

  The term "antiproliferative antibody" as used herein includes, but is not limited to, trastuzumab (Herceptin), trastuzumab-DM1, erbitux, bevacizumab (Avastin), rituximab (Rituxan), PRO64553 (anti-CD40 ) And 2C4 antibodies. By antibody is meant eg intact monoclonal antibodies, polyclonal antibodies, multi-selective antibodies formed from at least two intact antibodies, and antibody fragments so long as they exhibit the desired biological activity.

  For the treatment of acute myeloid leukemia (AML), the compounds of formula (I) can be used in combination with standard leukemia treatments, in particular in combination with the treatments used for the treatment of AML. In particular, the compounds of formula (I) are for example farnesyltransferase inhibitors and / or other drugs useful for the treatment of AML, such as daunorubicin, adriamycin, Ara-C, VP-16, teniposide, mitoxantrone Can be administered in combination with idarubicin, Carboplatinum and PKC412.

  The term “anti-leukemic compound” includes, for example, Ara-C, a pyrimidine analog that is a 2-alpha-hydroxyribose (arabinoside) derivative of deoxycytidine. Also included are purine analogs of hypoxanthine, 6-mercaptopurine (6-MP) and fludarabine phosphate.

  Somatostatin receptor antagonists, as used herein, refer to compounds that target, treat, or inhibit somatostatin receptors, such as octreotide and SOM230 (pasireotide).

  Tumor cell damage (damaging) approaches refer to approaches such as ionizing radiation. Above and hereinafter, the term “ionizing radiation” means ionizing radiation that occurs as either electromagnetic waves (eg, X-rays and gamma rays) or particles (eg, alpha and beta particles). Ionizing radiation is provided in, but not limited to, radiation therapy and is known in the art. See Hellman, Principles of Radiation Therapy, Cancer, in Principles and Practice of Oncology, Devita et al., Eds., 4th Edition, Vol. 1, pp. 248-275 (1993).

  The term “EDG binding agent” as used herein refers to a class of immunosuppressive agents that modulate lymphocyte recirculation, eg, FTY720.

  The term “ribonucleotide reductase inhibitor” refers to pyrimidine or purine nucleoside analogs such as, but not limited to, fludarabine and / or cytosine arabinoside (ara-C), 6-thioguanine, 5-fluorouracil, cladribine 6-mercaptopurine (especially in combination with ara-C for ALL) and / or pentostatin. Ribonucleotide reductase inhibitors are in particular hydroxyurea or 2-hydroxy-1H-isoindole-1,3-dione derivatives, such as Nandy et al., Acta Oncologica, Vol. 33, No. 8, pp. 953. -961 (1994), PL-1, PL-2, PL-3, PL-4, PL-5, PL-6, PL-7 or PL-8.

  The term “S-adenosylmethionine decarboxylase inhibitor” as used herein includes, but is not limited to, the compounds disclosed in US 5,461,076.

  In particular, compounds disclosed in WO 98/35958, proteins or monoclonal antibodies of VEGF, such as 1- (4-chloroanilino) -4- (4-pyridylmethyl) phthalazine or pharmaceutically acceptable salts thereof, such as Succinate or those disclosed in WO 00/09495, WO 00/27820, WO 00/59509, WO 98/11223, WO 00/27819 and EP 0 769 947; Prewett et al, Cancer Res, Vol. 59, pp. 5209-5218 (1999); Yuan et al., Proc Natl Acad Sci USA, Vol. 93, pp. 14765-14770 (1996); Zhu et al., Cancer Res, Vol. 58, pp. 3209 -3214 (1998); and Mordenti et al., Toxicol Pathol, Vol. 27, No. 1, pp. 14-21 (1999); disclosed in WO 00/37502 and WO 94/10202 Angiostatin described in O'Reilly et al., Cell, Vol. 79, pp. 315-328 (1994); O'Reilly et al., Cell, Vol. 88, pp. 277- 285 (1997) endostatin; anthranilic acid Amide; ZD4190; ZD6474; SU5416; SU6668; bevacizumab; or anti-VEGF or anti-VEGF receptor antibodies, such as rhuMAb and RHUFab, VEGF aptamers, such as Macugon; FLT-4 inhibitors, FLT-3 Also included are inhibitors, VEGFR-2 IgG1 antibodies, Angiozyme (RPI 4610) and bevacizumab (Avastin).

  Photodynamic therapy, as used herein, refers to a therapy that uses a specific chemical known as a photosensitizing compound to treat or prevent cancer. Examples of photodynamic treatment include treatment with compounds such as bisdyne and porfimer sodium.

  Angiogenesis-inhibiting steroids, as used herein, are compounds that prevent or inhibit angiogenesis, such as annecortab, triamcinolone, hydrocortisone, 11-epihydrocotisol, cortexolone, 17-hydroxyprogesterone, cortis It refers to costerone, desoxycorticosterone, testosterone, estrone and dexamethasone.

  Implants containing corticosteroids refer to compounds such as fluocinolone and dexamethasone, for example.

  “Other chemotherapeutic compounds” include, but are not limited to, plant alkaloids, hormone compounds and antagonists; biological response modifiers, preferably lymphokines or interferons; antisense oligonucleotides or oligonucleotide derivatives; shRNA or siRNA; or Included are miscellaneous compounds or compounds with other or unknown mechanisms of action.

  The structure of the active compound identified by code number, generic name or trade name must be obtained from the current edition or database of the standard abstract “The Merck Index”, eg Patents International (eg IMS World Publications) Can do.

  Any citation of a reference made in this disclosure should not be construed as an admission that such reference is prior art which may negatively affect the patentability of the present invention.

  The compounds of the present invention may also be administered simultaneously, separately or sequentially in combination with one or more other suitable active agents selected from the following classes of agents: anti-IL-1 agents such as : Anakinra; anti-cytokine and anti-cytokine receptor agents such as anti-IL-6 R Ab, anti-IL-15 Ab, anti-IL-17 Ab, anti-IL-12 Ab; B-cell and T-cell modulators, For example, anti-CD20 Ab; CTL4-Ig, disease-modulating anti-rheumatic drugs (DMARD), such as methotrexate, leflunamide, sulfasalazine; gold salts, penicillamine, hydroxychloroquine and chloroquine, azathioprine, glucocorticoids and non- Steroidal anti-inflammatory drugs (NSAIDs), such as cyclooxygenase inhibitors, selective COX-2 inhibitors, agents that modulate immune cell migration, such as chemokine receptor antagonists, adhesion molecules Modulator, for example, inhibitors of LFA-1, VLA-4.

  The pharmaceutical composition or combination of the present invention comprises about 1-1000 mg of active ingredient, or about 1-500 mg or about 1-250 mg or about 1-150 mg or about 0.5-100 for a subject of about 50-70 kg. mg, or about 1-50 mg of active ingredient in unit dosage. In general, a suitable daily dosage for oral administration is from about 0.1 to about 10 mg / kg. However, one of ordinary skill in the art will know the therapeutically effective dosage of a compound, pharmaceutical composition, or combination thereof is the species, weight, age and individual condition of the subject, the disorder or disease to be treated or its severity You will understand that it depends on. A physician, clinician, or veterinarian with ordinary abilities can easily determine the effective amount of each active ingredient needed to prevent, treat, or inhibit the progression of a disorder or disease can do.

The above dosage properties can be advantageously demonstrated in in vitro and in vivo studies using mammals such as mice, rats, dogs, monkeys or isolated organs, tissues and preparations thereof. The compounds according to the invention are applied in vitro in the form of solutions, for example in aqueous solution and in vivo enterally, parenterally, advantageously intravenously, for example as a suspension or in aqueous solution. be able to. In vitro dosages can range between about 10 ⁻³ molar and 10 ⁻⁹ molar. The therapeutically effective amount in vivo can vary depending on the route of administration and can be about 0.1-500 mg / kg, or about 1-100 mg / kg.

  In general, a therapeutically effective amount of a compound of the invention is administered to a patient in need of treatment. The term “therapeutically effective amount” of a compound of the invention is intended to induce a biological or medical response in a subject, such as a decrease or inhibition of enzyme or protein activity, or to ameliorate, ameliorate a symptom, Refers to the amount of a compound of the invention that will slow or slow the progression of the disease or prevent the disease.

  In yet another aspect, a method of treating cancer in a subject is provided, such method comprising administering an effective amount of a compound of the invention to a mammal in need of such treatment.

  As used herein, the term “subject” refers to an animal. Typically the animal is a mammal. A subject also refers to, for example, primates (eg, humans, males or females), cows, sheep, goats, horses, dogs, cats, rabbits, rats, mice, fish, birds, and the like. In certain embodiments, the subject is a primate. Preferably, the subject is a human.

  As used herein, the term “inhibit”, “inhibition” or “inhibiting” refers to the reduction or suppression of a given symptom, symptom, or disorder or disease, or the basis of a biological activity or process. Refers to a significant decrease in line activity.

  As used herein, the terms “treat”, “treat” or “treatment” of a disease or disorder refer to (i) ameliorating the disease or disorder (ie, progression of the disease or at least one thereof) (Ii) alleviate or ameliorate at least one physical parameter, including one that is not identifiable by the patient; or ( iii) To prevent or delay the onset or progression or progression of a disease or disorder. In general, the terms “treating” or “treatment” refer to the management and care of a patient for the purpose of combating a disease, condition, or disorder, and to prevent the onset of symptoms or complications. Administration of a compound of the invention to alleviate or eliminate a disease, condition or disorder.

  As used herein, a subject “needs” such treatment if such subject would benefit from treatment, biologically, medically or in quality of life.

  Another aspect of the present invention is to provide a compound of the present invention and at least one other therapeutic agent (or as a combined preparation for simultaneous, separate or sequential use in therapy to enhance apoptosis. Pharmaceutical product).

  In the combination therapy of the invention, the compound of the invention and the other therapeutic agent can be manufactured and / or formulated by the same or different manufacturers. In addition, the compounds of the invention and other therapeutic agents (or pharmaceutical agents) are: (i) prior to release of the combination product to the physician (e.g., in the case of a kit comprising the compounds of the invention and other therapeutic agents); (ii) immediately prior to administration by the physician himself (or under the supervision of the physician); (iii) combination therapy in the patient himself, for example during successive administrations of the compounds of the invention and other therapeutic agents. Can be taken together.

  Accordingly, the present invention provides the use of a compound of the present invention for treating a disease or condition by inhibiting the MAP kinase pathway, wherein the medicament is prepared for administration with other therapeutic agents It is what is done. The invention also provides the use of other therapeutic agents, wherein the medicament is to be administered as a combination of a compound of the invention and the other therapeutic agent.

  Embodiments of the invention are illustrated by the following examples. However, other modifications of the embodiments of the present invention will be known to those skilled in the art or will be apparent in light of the present disclosure, so that the embodiments of the present invention are limited to the specific details of these examples. It should be understood that it is not.

Methods for Making the Compounds of the Invention The invention also includes methods for the preparation of the compounds of the invention. In the reactions described, it may be necessary to protect the reactive functionality if desired in the final product to avoid its undesirable involvement in the reaction. Conventional protecting groups can be used in accordance with standard practice, see, for example, TW Greene and PGM Wuts in “Protective Groups in Organic Chemistry”, John Wiley and Sons, 1991.

  The individual enantiomers of the invention can be obtained from racemic chiral separations or can be synthesized individually from optically pure reagents using Reaction Scheme I:

Reaction scheme I:

  The compound of formula 4a is obtained by combining a compound of formula 2 and a compound of formula 3a with a suitable amine (eg, triethylamine, N, N-diisopropylethylamine, triisopropylamine, etc.), a suitable catalyst (eg, N, N— Dimethylpyridin-4-amine and the like) and a suitable solvent (for example, DCM, 1,2-dichloromethane, toluene, tetrahydrofuranyl and the like). The reaction proceeds at a temperature of about 25 ° C. and can take about 12 hours to complete.

  Compounds of formula 5a can be prepared from compounds of formula 4a in the presence of a suitable base such as potassium trimethylsilanoate. The reaction proceeds at a temperature of about 25 ° C. and can take about 12 hours to complete.

  S-enantiomers are derived from compounds of formula 5a from suitable Lewis acids (eg trichlorborane, boron trifluoride, boron tribromide etc.) and suitable solvents (eg dichloromethane, 1,2-dichloromethane etc. ) In the presence of The reaction proceeds at a temperature of about 25 ° C. and can take up to about 1 hour to complete.

  The compound of formula 4b is obtained by combining a compound of formula 2 and a compound of formula 3b with a suitable amine (eg, triethylamine, N, N-diisopropylethylamine, triisopropylamine, etc.), a suitable catalyst (eg, N, N— Dimethylpyridin-4-amine and the like) and a suitable solvent (for example, DCM, 1,2-dichloromethane, toluene, tetrahydrofuran and the like). The reaction proceeds at a temperature of about 25 ° C. and can take about 12 hours to complete.

  Compounds of formula 5b can be prepared from compounds of formula 4b in the presence of a suitable base such as potassium trimethylsilanoate. The reaction proceeds at a temperature of about 25 ° C. and can take about 12 hours to complete.

  The R-enantiomer is obtained from the compound of formula 5b in the presence of a suitable Lewis acid (eg trichloroborane, boron trifluoride, boron tribromide etc.) and a suitable solvent (eg dichloromethane, 1,2-dichloromethane etc.) Can be prepared below. The reaction proceeds at a temperature of about 25 ° C. and can take up to about 1 hour to complete.

Examples The following abbreviations used herein below have corresponding meanings: TEA (triethylamine); EA (ethyl acetate); MCC (microcrystalline cellulose; DMAP (4-dimethylaminopyridine); DCM (dichloromethane); THF (tetrahydrofuran); DMF (dimethylformamide); LHMDS (lithium bis (trimethylsilyl) amide); CDI (1,1-carbonyldiimidazole); PTSA (p-toluenesulfonic acid); RT (room temperature) TLC (thin layer chromatography); NMR (nuclear magnetic resonance); LC-MS (liquid chromatography mass spectrometry); and HPLC (high pressure liquid chromatography or high performance liquid chromatography).

Preparation of key intermediates
Preparation of (2,3,5-trifluoro-N- (2-fluoro-4-iodophenyl) -6-nitroaniline

1.0M LHMDS (153 mL, 153 mmol) in hexane was added to a solution of 2-fluoro-4-iodoaniline (30.0 g, 128 mmol) in dry THF (600 mL) at −78 ° C. for 30 min. The resulting mixture was stirred at −78 ° C. for an additional 30 minutes. After this time 2,3,4,6-tetrafluoronitrobenzene (25 g, 128 mmol) in dry THF (150 mL) was added and stirring was continued for an additional hour at 20-40 ° C. The reaction was monitored by TLC (10% ethyl acetate in hexane). The reaction mixture was quenched with 2N HCl (100 mL), concentrated, and the concentrate was partitioned between water (500 mL) and ethyl acetate (300 mL). The aqueous layer was washed with ethyl acetate (2 × 200 mL). The combined organic phases were washed with water, brine solution, dried over anhydrous Na ₂ SO ₄ and concentrated to give 38 g of crude product. Purification by column chromatography on silica gel (0-5% ethyl acetate in hexane) gave 31 g of product (58.8% yield). LCMS: 95.5%, m / z = 410.9 (M-1).

For large scale synthesis, 1,2,3,5-tetrafluoro-4-nitrobenzene was precooled with a solution of HNO ₃ (990 g) in H ₂ SO ₄ (973 mL) and it was Prepared by adding a cold solution of 1,2,3,5-tetrafluorobenzene (973.1 g) in ₂ SO ₄ (2920 mL) at a temperature between 0 ° C. and 10 ° C. over 1.5 hours. After the addition, the yellow solution was stirred at a temperature between 0 ° C. and 10 ° C. for 1 hour until analysis showed that the reaction was complete. Water (9730 g) was added in portions to the yellow solution at a temperature below 25 ° C., then the aqueous layer was extracted by the addition of DCM (9730 mL). The DCM layer was then washed twice with water (10 L). DCM was then concentrated to give a yellow oil. The oil was distilled under pressure (2.5 mbar) from 70 ° C. to −75 ° C., resulting in a yellow oil product (98% purity; 72.4% yield).

LiHMDS (1732 mL) was added to a solution of aniline in 2.5 L of THF at −72 ° C. to −65 ° C. over 30 minutes. The resulting suspension was stirred at -70 ° C. for 30 minutes. A solution of nitrobenzene in 300 mL of THF was then added dropwise to the above suspension at −75 ° C. to −70 ° C. over 1 hour and stirred at this temperature for an additional 15 minutes. An additional 100 mL of LiHMDS was added at -70 ° C and stirred at this temperature for 15 minutes. HPLC analysis revealed 23.4% aniline, 6.6% nitrobenzene and 68.3% product. The solution was concentrated at 35 ° C. The resulting oil was then dissolved in 3 L DCM and then 2.5 L water was added at a temperature below 30 ° C. HCl (500 mL) was added (exothermic) and the solution was stirred for 15 minutes before separation. 2.5 L water and 500 mL HCl were added to the DCM layer and the wash was repeated 3 times. The DCM layer was concentrated to dryness and the batches were added together to give about 1.4 kg of crude product. The solid was added to 20 L of hot heptane solution (72 ° C.) and stirred for 1 hour. 200 g of activated carbon was added with stirring for 20 minutes. The suspension was hot filtered with MCC (2 kg) and rinsed with 5 L of hot heptane (75 ° C.). The combined solution was then concentrated to 15 L and kept overnight. The suspension was filtered to give 777 g of an orange solid with 99% purity. The mother liquor was concentrated to about 5 L, stirred at room temperature and filtered to give an additional 120 g of orange solid. The overall yield was 46.8%. ¹ H NMR (DMSO-d _6, 400 MHz): δ 8.80 (s, 1H), 7.60-7.67 (m, 2H), 7.41 (d, 1H), 6.86 (t, 1H).

Preparation of 3- (2,2-diethoxyethoxy) -5,6-difluoro-N- (2-fluoro-4-iodophenyl) -2-nitroaniline

2,2-diethoxy-ethanol (0.209 g, 1.2135 mmol) was added to a cooled suspension of NaH (0.034 g, 1.456 mmol) in THF (5 mL) at 0 ° C. and the resulting mixture was added for 30 min. Stir at RT. (2-Fluoro-4-iodophenyl)-(2,3,5-trifluoro-6-nitro-phenyl) -amine (0.5 g, 1.2135 mmol) in THF (10 mL) was slowly added to the reaction mass at 0 ° C. And stirring was continued for an additional 15 minutes. The reaction mass was stirred overnight at room temperature. The reaction was monitored by TLC (20% ethyl acetate in hexane). The reaction mass was concentrated under reduced pressure and the concentrate was extracted with ethyl acetate. The organic layer was washed with water and brine solution, dried over sodium sulfate and concentrated under reduced pressure to give the crude compound. Purification by column chromatography on silica gel (15% ethyl acetate in hexane) gave 0.3 g of product (47% yield). Two by-products are isolated in this reaction. ¹ H NMR (CDCl _3, 300 MHz): δ 7.42 (d, 1H), 7.35 (d, 1H), 6.90 (bs, 1H), 6.58-6.68 (m, 2H), 4.58 (t, 1H), 4.15 (d, 2H), 3.51-3.80 (m, 4H), 1.22 (t, 6H).

For large-scale synthesis, 2,2-diethoxyethanol was added dropwise to a suspension of 60% sodium hydride in 5 L of THF at 1-2 ° C over 30 minutes, then 1.5 ° C at 0-5 ° C. Stir for hours. A solution of 750 g 2,3,5-trifluoro-N- (2-fluoro-4-iodophenyl) -6-nitroaniline in 2.25 L THF is then added dropwise to the above suspension at 0-5 ° C. did. After the addition, the purple solution was stirred at room temperature for 2 days and 17 hours. HPLC analysis showed 4.1% of the remaining 2,3,5-trifluoro-N- (2-fluoro-4-iodophenyl) -6-nitroaniline. 150 mL of water was added very slowly (gas evolution) to the pre-cooled solution at 10 ° C. The solution was then concentrated to dryness. The resulting oil was then suspended in 5 L heptane and pure 3- (2,2-diethoxyethoxy) -5,6-difluoro-N- (2-fluoro-4-iodophenyl)- It was seeded with 2-nitroaniline crystals and stirred for 30 minutes. After stirring for 1 hour, the precipitate was filtered and dried to give 520 g (54.3%) of product in 96.4% purity. In addition, the product was available in the mother liquor. ¹ H NMR (CDCl _3, 400 MHz): δ 7.42 (dd, 1H), 7.34 (d, 1H), 6.87 (bs, 1H), 6.56-6.67 (m, 2H), 4.79 (t, 1H), 4.06 (d, 2H), 3.74-3.82 (m, 2H), 3.59-3.66 (m, 2H); 1.24 (t, 6H).

(4,5-Difluoro-7-nitro-benzofuran-6-yl)-(2-fluoro-4-iodophenyl) -amine:

[3- (2,2-diethoxy-ethoxy) -5,6-difluoro-2-nitro-phenyl]-(2-fluoro-4-iodophenyl) -amine (1 g, 1.9011 mmol) in glacial acetic acid (10 mL) And concentrated under reduced pressure. The resulting residue was dissolved in dry DCM (10 mL) and cooled to 0 ° C. This was followed by the addition of BF ₃ .etherate (2.04 g, 14.476 mmol). The reaction was stirred for 12-16 hours at 20-40 ° C. The reaction was monitored by TLC (10% ethyl acetate in hexane). The reaction was quenched with 2N NaOH solution (15 mL), extracted with ethyl acetate (3 × 30 mL), the combined organic extracts were dried over sodium sulfate and concentrated under reduced pressure to give the crude compound. Purification by column chromatography on silica gel (5% ethyl acetate in hexane) gave 0.260 g of product (31% yield). ¹ H NMR (CDCl _3, 300 MHz): δ 8.95 (bs, 1H), 7.77 (d, 1H), 7.38-7.50 (1dd, 1d, 2H), 6.99 (d, 1H), 6.70-6.82 (m, 1H).

For scale-up, 3- (2,2-diethoxyethoxy) -5,6-difluoro-N- (2-fluoro-4-iodophenyl) -2-nitroaniline (75 g) in 300 mL DCM Was quickly added to a solution of BF ₃ .ET ₂ O in 100 mL DCM at 28-32 ° C. with stirring for an additional 15 minutes. After about 2 hours, the analysis showed complete conversion. Prior to separation, the solution was then quenched to pH 10 with 1N NaOH (drip) at temperatures below 30 ° C. The DCM was then washed twice with water to a pH of about 7 and concentrated to dryness. 210 mL of MBTE was then added. The suspension was stirred for 30 minutes, filtered and dried to give 43 g of an orange solid. ¹ H NMR (CDCl _3, 400 MHz): δ 8.80 (bs, 1H), 7.75 (d, 1H), 7.48 (dd, 1H), 7.41 (d; 1H); 6.97 (d, 1H), 6.75-6.80 (m, 1H).

4,5-Difluoro-N6- (2-fluoro-4-iodophenyl) -benzofuran-6,7-diamine:

Concentrated HCl (1 mL) was added to (4,5-difluoro-7-nitro-benzofuran-6-yl)-(2-fluoro-4-iodophenyl) -amine (0.260 g, 0.599 mmol) in THF (5 mL). To the solution was added at 0 ° C. This was followed by the addition of zinc dust (0.179 g, 5.99 mmol) at 0 ° C. The reaction was stirred for 1 hour at 20-40 ° C. The reaction was monitored by TLC (20% ethyl acetate in hexane). The reaction was concentrated under reduced pressure and the concentrate was extracted with ethyl acetate (50 mL). The organic layer was washed with water, brine solution, dried over sodium sulfate and concentrated under reduced pressure to give 0.240 g of crude compound that was used in the next step without further purification. ¹ H NMR (CDCl _3, 300 MHz): δ 7.53 (d, 1H), 7.49 (dd, 1H), 7.20 (d, 1H), 6.00 (d, 1H), 6.20 (t, 1H), 5.42 (bs , 1H), 4.10 (bs, 2H).

(4,5-difluoro-7-nitro-benzofuran-6-yl)-(2-fluoro-4-iodophenyl) -amine (165 g) in 2.5 L THF and 2.5 L water for scale-up synthesis ) And NH ₄ Cl solution was cooled from 0 ° C. to 5 ° C. Zinc dust was added (in portions) at temperatures below 25 ° C (exothermic during the first half of the addition) over 30 minutes. As a result of the addition of zinc dust, the color changed from yellow to dark purple and pale yellow. Complete conversion was achieved by addition of NH ₄ Cl (50 g) and zinc (60 g), followed by vigorous stirring for 20 minutes and a further 1.5 hours. The purity was 89.5%. The suspension was filtered and rinsed with 1 L water and 1.5 L THF. The combined solution was concentrated to remove THF (87.7% purity). 3 L of EA was added with stirring for 30 minutes. The layers were separated; the EA layer was washed twice with 2 L of water and then dried over MgSO ₄ . The EA was filtered and concentrated to dryness. The crude was used in the next step without further purification. ¹ H NMR (CDCl _3, 400 MHz): δ 8.06 (d, 1H), 7.46 (dd, 1H), 7.40 (bs, 1H), 7.19 (d, 1H), 7.07 (d, 1H), 6.11 (t ; 1H); 5.33 (bs, 1H).

4,5-Difluoro-3- (2-fluoro-4-iodophenyl) -1H-benzofuro [6,7-d] imidazol-2 (3H) -one:

Of CDI (0.144 g, 0.891 mmol) in 4,5-difluoro-N6- (2-fluoro-4-iodophenyl) -benzofuran-6,7-diamine (0.240 g, 0.5940 mmol) in dry DCM (5 mL). Added to the solution. The reaction mass was stirred for 12-16 hours at 20-40 ° C. The reaction was monitored by TLC (30% ethyl acetate in hexane). The reaction mass was concentrated under reduced pressure and the concentrate was extracted with ethyl acetate. The organic layer was washed with water and brine solution, dried over sodium sulfate and concentrated under reduced pressure to give the crude compound. Purification by column chromatography on silica gel (30% ethyl acetate in hexane) gave 0.180 g of product (70% yield). ¹ H NMR (DMSO-d _6, 300 MHz): δ 12.15 (bs, 1H), 8.12 (d, 1H), 7.95 (dd, 1H), 7.79 (d, 1H), 7.50 (t, 1H), 7.21 (d, 1H).

For scale-up synthesis, CDI (92.4 g, 570 mmol) was added to 4,5-difluoro-N6- (2-fluoro-4-iodophenyl) -benzofuran-6,7-diamine (153.6 g in 1500 mL DCM). , 380.1 mmol) at 0 ° C. The solution was then warmed to room temperature and stirred for approximately 48 hours. Analysis showed that 0.3% of the remaining 4,5-difluoro-N6- (2-fluoro-4-iodophenyl) -benzofuran-6,7-diamine was 86.1% pure. The solution was filtered to give a crude gray solid in 96.4% purity. The crude was dissolved in 1.5 L THF and then water (1.5 L) was added. The suspension was then concentrated to 1.7 L and filtered to give 87 g of product in 98.0% purity (53.2% yield). ¹ H NMR (DMSO-d _6, 400 MHz): δ 12.29 (bs, 1H), 8.09 (d, 1H), 7.94 (dd, 1H), 7.76 (d, 1H), 7.47 (t, 1H), 7.19 (d, 1H).

(I-34a) 1- (1-allylcyclopropylsulfonyl) -4,5-difluoro-3- (2-fluoro-4-iodophenyl) -1H-benzofuro [6,7-d] imidazol-2 (3H) -one:

(I-34a)

TEA (0.2611 g, 2.581 mmol) was added to 4,5-difluoro-3- (2-fluoro-4-iodophenyl) -1H-benzofuro [6,7-d] imidazole-2 (in dry DCM (20 mL)). To a solution of 3H) -one (0.37 g, 0.8604 mmol) was added at 0 ° C. This was followed by the addition of 1-allyl-cyclopropanesulfonyl chloride (0.229 g, 1.89 mmol) and a catalytic amount of DMAP (10 mg). The reaction mass was stirred for 12 hours at 20-40 ° C. The reaction was monitored by TLC (20% ethyl acetate in hexane). The reaction mass was diluted with DCM (50 mL) and partitioned between water and DCM. The organic layer was washed with water and an aqueous salt solution, and concentrated under reduced pressure to obtain a crude product. Purification by column chromatography on silica gel (20% ethyl acetate in hexane) gave 0.228 g of product (46% yield). ¹ H NMR (CDCl _3, 300 MHz): δ 7.71 (dd, 3H), 7.30 (t, 1H), 7.00 (s, 1H), 5.56-5.57 (m, 1H), 4.90 (t, 2H), 2.70 -2.80 (q, 2H), 1.90-2.05 (m, 2H), 1.10-1.19 (m, 2H). LCMS: 98.85%, m / z = 574.4 (M + 1). HPLC: 97.1%.

1-allyl-N- (4,5-difluoro-6- (2-fluoro-4-iodophenylamino) benzofuran-7-yl) cyclopropane-1-sulfonamide:

Potassium trimethyl silanolate (0.105 g, 0.82 mmol) in 1- (1-allylcyclopropylsulfonyl) -4,5-difluoro-3- (2-fluoro-4-iodo) in THF (5 mL) Phenyl) -1H-benzofuro [6,7-d] imidazol-2 (3H) -one (0.230 g, 0.4108 mmol) was added at 0 ° C. The reaction mass was stirred for 4 hours at 20-40 ° C. The reaction was monitored by TLC (10% ethyl acetate in hexane). The reaction mass was concentrated under reduced pressure and the concentrate was extracted with ethyl acetate. The organic layer was washed with water and brine solution, dried over sodium sulfate, and concentrated under reduced pressure to give the crude compound. Purification by column chromatography on silica gel (10% ethyl acetate in hexane) gave 0.177 g of product (78% yield). ¹ H NMR (CDCl _3, 300 MHz): δ 7.54 (d, 1H), 7.40 (dd, 1H), 7.25 (s, 1H), 7.05 (bs, 1H), 6.99 (d, 1H), 6.32-6.39 (m, 1H), 6.22 (s, 1H), 5.65-5.75 (m, 1H), 5.19 (s, 1H), 5.10 (d, 1H), 2.88 (d, 2H), 1.15 (t, 2H), 0.75 (t, 2H). LCMS: 96.32%, m / z = 548.8 (M + 1). HPLC: 97.19%.

Isopropyl cyclopropane sulfonate (sulfonate)

IPA (11 L) was added to pyridine (1850 g; 1890 mL) with stirring at 20 ° C. for 1 hour. The solution was cooled from −10 ° C. to 2 ° C., and cyclopropane sulfonic chloride (1100 g) was added dropwise and then stirred at this temperature for 70 hours. NMR analysis showed that 85% sulfonic chloride was consumed in the reaction. The reaction was cooled to 0 ° C. and NaOH (312 g) in water (600 mL) was added dropwise. The resulting product was concentrated to dryness at 45 ° C. and diluted with EtOAc (2750 mL), MTBE (1375 mL). The solution was stirred for 10 minutes and filtered. Heptane (1375 mL) was added, filtered and the filtrate was concentrated to dryness to give 1080 g of product as a red liquid (84% yield). ¹ H NMR (CDCl _3, 400 MHz): δ 4.86 (m, 1H), 2.83 (m, 1H), 1.33 (d, 6H), 0.98-1.10 (m, 4H).

(S) -2-((Benzyloxy) methyl) oxirane

A slurry of NaH (267 g) and NaI (26.5 g) in DMF (3000 mL) was cooled from −15 ° C. to −10 ° C. with an ice-brine mixture. A solution of glycidol (480 g) in DMF (1000 mL) was added with stirring for 10 minutes. BnCl (745.5 g) in DMF (800 mL) was added (slightly exothermic) and the reaction was allowed to warm to room temperature and then stirred for approximately 16 hours. The solution was stirred for an additional period until HPLC analysis showed that less than 1% BnCl remained. The reaction was cooled to −5 ° C. and water (4 L) was added. MBTE (5L) was added with stirring for 30 minutes. The organic and aqueous layers were separated and the aqueous layer was extracted using two additions of MBTE (5 L; 3.5 L). The combined organic layers were washed with brine (1.8 L (x2)) and dried over Na ₂ SO ₄ for 1 hour. The organic layer was concentrated to dryness and distilled under reduced pressure (5 mm Hg, 85 ° C.) to give the product as a yellow liquid (760 g). ¹ H NMR (CDCl _3, 400 MHz): δ 7.27-7.37 (m, 5H), 4.51 (s, 2H), 3.74 (dd, 1H), 3.29 (dd, 1H), 3.14 (m, 1H), 2.72 (dd, 1H), 2.55 (dd, 1H).

(R) -Isopropyl 1- (3- (benzyloxy) -2-hydroxypropyl) cyclopropane-1-sulfonic acid ester (sulfonate)

Cool a solution of (S) -2-((benzyloxy) methyl) oxirane (507 g), HMPA (450 mL) and THF (4 L) in a dry ice-acetone bath from -70 ° C to -60 ° C did. n-BuLi (1500 mL; 2.4 M) was added dropwise over 75 minutes. THF (450 g; 500 mL) was added to the reaction mixture, the temperature was gradually raised to −20 ° C., and the mixture was stirred for approximately 16 hours until HPLC analysis indicated that the reaction was complete. The reaction mixture was cooled to −30 ° C. and water (300 mL) and concentrated aqueous HCl (300 mL) were added. The solution was concentrated to dryness. Water (2 L) was added and the product was extracted twice with EtOAc (2.5 L (x2)). The combined organic layers were washed with water (2.5 L), brine (2 L), dried over Na ₂ SO ₄ (500 g) and filtered. The filtrate was concentrated and dried (at 45 ° C.) to give the crude product as a red liquid (712 g; 75% yield).

(R) -Isopropyl 1- (2,3-bis (benzyloxy) propyl) cyclopropane-1-sulfonate

Under a nitrogen atmosphere, NAH (91.5 g) in DMF (2 L) and (R) -isopropyl 1- (3- (benzyloxy) -2-hydroxypropyl) cyclopropane-1-in DMF (1 L) Sulfonate (715 g) was mixed at a temperature of -5 ° C to 5 ° C for 140 minutes. After an additional 5 minutes of stirring, NaI (5.1 g) was added. After the slow addition of BnCl (289.5 g) in DMF (300 mL), the reaction mixture was slowly warmed to room temperature and stirred for approximately 16 hours until HPLC analysis indicated that the reaction was complete. The reaction mixture was cooled to −5 ° C. and water (4 L) was added, followed by MTBE (2 L (x2)) with stirring for 20 minutes. The organic layer was separated, washed with water (2 L (x2)), brine (2 L), dried over Na ₂ SO ₄ and concentrated to give 830 g of product.

(R) -1- (2,3-Bis (benzyloxy) propyl) cyclopropane-1-sulfonic acid

(R) -Isopropyl 1- (2,3-bis (benzyloxy) propyl) cyclopropane-1-sulfonate (460 g) and KSCN in THF (2.2 L) and water (2.2 L) A mixture of (170 g) at 25 ° C. was refluxed at 90 ° C. for approximately 24 hours until HPLC analysis indicated that the reaction was complete. The reaction mixture was concentrated to about 2 L at 40 ° C. and extracted with MTBE (1.5 L (x3)). The organic layer was discarded and the aqueous layer was neutralized with KOH (30 g) in water (100 mL) to pH 14 and cooled to -5 ° C. The mixture was neutralized with concentrated HCl (205 mL) until the pH was 2 to 3, and extracted with ETOAc (2 L (x2)). The combined organic layers were dried over Na ₂ SO ₄ for approximately 16 hours, filtered and concentrated to dryness to give the product as a deep red oil (265 g).

(R) -1- (2,3-Bis (benzyloxy) propyl) cyclopropane-1-sulfonyl chloride

Reaction of a mixture of (R) -1- (2,3-bis (benzyloxy) propyl) cyclopropane-1-sulfonic acid (630 g) and DMF (30 mL) in SOCl ₂ (1.5 L) by HPLC analysis Reflux for 2 hours until indicated to be complete. The reaction mixture was concentrated to dryness and the residue was purified by silica gel chromatography using the following eluent: heptane for 5 minutes and then IPAC: heptane = 1:30; heptane 1:10 so that the product was red oil (298.5 g; 52% yield; 95% purity). ¹ H NMR (CDCl _3, 400 MHz): δ 7.34 (m, 10H), 4.68 (d, 1H), 4.56 (bs, 1H), 4.53 (d, 1H), 4.16 (m, 1H), 3.54-3.62 (m, 2H), 2.63 (dd, 1H), 2.01 (q, 1H), 1.52-1.81 (m, 3H), 1.16 (m, 1H), 2.22 (bs, 1H), 1.75 (t, 2H), 1.38-1.40 (m, 2H).

Example 1
1- (2,3-Dihydroxy-propyl) -cyclopropanesulfonic acid [4,5-difluoro-6- (2-fluoro-4-iodophenylamino) -benzofuran-7-yl] amide:

N-methylmorpholine oxide (0.035 g, 0.3041 mmol) was added to 1-allyl-cyclopropanesulfonic acid [4,5-difluoro-6- (2-fluoro-4-iodophenylamino) in THF (5 mL). ) -Benzofuran-7-yl] -amide (0.167 g, 0.3041 mmol) was added. Then osmium tetroxide (0.0077 g, 0.03041 mmol) in water (1 mL) was added. The reaction mass was stirred for 16 hours at 30-40 ° C. The reaction was monitored by TLC (10% methanol in chloroform). The reaction mass was partitioned between ethyl acetate (50 mL) and water. The organic layer was washed with water (3 × 50 mL), brine solution and concentrated under reduced pressure to give the crude product. Purification by column chromatography on silica gel (5% methanol in chloroform) gave 0.090 g of product (50% yield). ¹ H NMR (CDCl _3, 300 MHz): δ 7.69 (d, 2H), 7.40 (dd, 1H), 7.25 (s, 1H), 6.99 (d, 1H), 6.98 (bs, 1H), 6.38-6.40 (m, 1H), 4.25 (bs, 1H), 3.62 (dd, 2H), 3.32 (d, 1H), 2.55 (q, 1H), 2.22 (bs, 1H), 1.75 (t, 2H), 1.38- 1.40 (m, 2H). LCMS: 99.49%, m / z = 582.9 (M + 1). HPLC: 95.29%.

  For the preparation of enantiomers, 1- (2,3-dihydroxy-propyl) -cyclopropanesulfonic acid [4,5-difluoro-6- (2-fluoro-4-iodophenylamino) -benzofuran-7-yl] The synthesis of the amide (Example 1) was scaled as follows: N-methylmorpholine oxide (0.32 g, 2.7272 mmol) was added to 1-allyl-cyclopropanesulfonic acid [4] in THF (50 mL). , 5-Difluoro-6- (2-fluoro-4-iodophenylamino) benzofuran-7-yl] amide (1.5 g, 2.7272 mmol) was added. Then osmium tetroxide (0.695 g, 0.2737 mmol) in water (5 mL) was added. The reaction mass was stirred overnight at room temperature. The reaction was monitored by TLC (10% methanol in chloroform). The reaction mass was partitioned between ethyl acetate (100 mL) and water (50 mL). The organic layer was washed with water (3 × 75 mL), brine solution and concentrated under reduced pressure to give the crude product. Purification by column chromatography on silica gel (5% methanol in chloroform) gave 0.9 g (56%, HPLC purity, 85%) of the racemic mixture, which was further purified by preparative HPLC to give pure racemic Compound 0.7g (HPLC purity> 98%) was obtained.

Individual enantiomers were obtained by chiral column chromatography. 0.420 g of racemic 1- (2,3-dihydroxy-propyl) -cyclopropanesulfonic acid [4,5-difluoro-6- (2-fluoro-4-iodophenylamino) -benzofuran-7-yl] amide ® AD-H ^™ / 02 applied to a semi prep column at 25 ° C. The mobile phase consisted of 80% hexane / 10% IPA / 10% MeOH with a flow rate of 1 mL / min. The diluent was IPA. The first eluting enantiomer, Example 1B, has a retention time of 10.971 min (0.185 g, 44%) and the second eluting enantiomer, Example 1A, has a retention time of 14.961 min (0.175 g, 41%). %)Met.

Alternatively, racemic 1- (2,3-dihydroxy-propyl) -cyclopropanesulfonic acid [4,5-difluoro-6- (2-fluoro-4-iodophenylamino) -benzofuran-7-yl] amide can be converted to Chiralpak ( Registered AD-H ^™ / 03 applied to a semi prep column at 25 ° C. The mobile phase consisted of 80% hexane / 20% IPA and had a flow rate of 1 mL / min. The diluent was ethanol. The first eluting enantiomer, Example 1A, has a retention time of 10.465 minutes (49%), and the second eluting enantiomer, Example 1B, has a retention time of 13.535 minutes (46%). It was.

  The enantiomers were further purified by preparative HPLC to give Examples 1A and 1B with HPLC purity> 99%.

  The synthesis description below describes how (R) -N- (4,5-difluoro-6-((2-fluoro-4-iodophenyl) amino) benzofuran-7-yl) -1- (2 , 3-dihydroxypropyl) cyclopropane-1-sulfonamide is shown:

(R) -N- (4,5-Difluoro-6-((2-fluoro-4-iodophenyl) amino) benzofuran-7-yl) -1- (2,3-dihydroxypropyl) cyclopropane-1- Sulfonamide

For large scale synthesis, 4,5-difluoro-3- (2-fluoro-4-iodophenyl) -1H-benzofuro [6,7-d] imidazole-2 (3H) in DCM (75 mL) -One (7 g; 16.275 mmol), (R) -1- (2,3-bis (benzyloxy) propyl) -cyclopropane-1-sulfonyl chloride (9.641 g), TEA (4.94 g) and a catalytic amount of A suspension of DMAP (0.596 g) was stirred at room temperature for approximately 24 to 96 hours until HPLC analysis indicated that the reaction was complete. The solution was then added to 1N HCl (60 mL), stirred for 15 minutes and then separated. The DCM layer was dried over MgSO ₄ and concentrated to dryness. The resulting sulfur monoxide (R) -1- (1- (2,3-bis (benzyloxy) propyl) cyclopropoxy) -4,5-difluoro-3- (2 -Fluoro-4-iodophenyl) -1H-benzofuro [6,7-d] imidazol-2 (3H) -one compound (1: 1) was used in the following step without further purification.

  Potassium trimethyl silanolate (165.5g, 1.29mol) was added to (R) -1- (1- (2,3-bis (benzyloxy) propyl) with sulfur monoxide in THF (2.5L). ) Cyclopropoxy) -4,5-difluoro-3- (2-fluoro-4-iodophenyl) -1H-benzofuro [6,7-d] imidazol-2 (3H) -one compound (1: 1) (251.2 g, 318.5 mmol) was added at 0 ° C. The solution was allowed to warm to room temperature and stirred for 1-2 hours until HPLC analysis indicated that the reaction was complete. Water (1.5 L) was added to the solution and the separated THF layer was concentrated to dryness. MTBE (2 L) was added to dissolve the oil, then washed with 2N aqueous NaOH solution (1 L) and then with water (1.5 L). Activated carbon (50 g) was added to the MTBE solution for decolorization purposes, and after decolorization, the solution was concentrated to ˜400 mL. Heptane (1.2 L) is added and the suspension is purified with pure (R) -1- (2,3-bis (benzyloxy) propyl) -N- (4,5-difluoro-6-((2-fluoro Seeded with -4-iodophenyl) amino) benzofuran-7-yl) cyclopropane-1-sulfonamide crystals. The suspension was stirred at room temperature overnight, filtered and the white solid dried to give 165 g of product in 96% purity (68% overall yield).

(R) -1- (2,3-bis (benzyloxy) propyl) -N- (4,5-difluoro-6-((2-fluoro-4-iodophenyl) amino) in DCM (700 mL) To a solution of benzofuran-7-yl) cyclopropane-1-sulfonamide (140 g, 183.6 mmol) was added a 1M BCl ₃ solution in DCM (1.8 L, 1.84 mol) at −65 to −70 ° C. The mixture was stirred at -65 to -70 ° C for 30 minutes until HPLC analysis indicated that the reaction was complete. The cold solution was added to 1N HCl solution (1.8 L) at a temperature below 15 ° C., stirred for 15 minutes and separated. The DCM layer was washed with water (2L) and brine (1.5L). The DCM layer was concentrated to ~ 250 mL and filtered to give a white solid. The solid was dissolved in isobutyl acetate (240 mL) and heptane (500 mL) was added. The suspension was stirred overnight, filtered and dried, and 70 g of (R) -N- (4,5-difluoro-6-((2-fluoro-4-iodophenyl) amino) benzofuran-7-yl ) -1- (2,3-dihydroxypropyl) cyclopropane-1-sulfonamide was obtained in 98.4% purity (65.5% yield, ee> 99%).

  Comparing the retention times under the same HPLC conditions (80% hexane / 10% IPA / 10% MeOH), the retention time of the individually synthesized R-enantiomer is 10.43 minutes, corresponding to the position of Example 1B.

Pharmacological data
Inhibition of the compounds of the present invention can be demonstrated using any of the following test procedures:

  The BRAF-MEK-ERK cascade assay is used to evaluate the effect of these compounds as inhibitors of the MAP kinase pathway. Enzymatic cascade assays from Upstate, recombinant human activated BRAF (V599E) kinase (Cat. No. 14-557), human full length MEK1 kinase (Cat. No. 14-706) and human full length active MAP Kinase 2 / ERK2 (Cat. 14-536) Set using enzymes. TR-FRET (Time-Resolved Fluorescence Resonance Energy Transfer) detection technique is used for reading. Assay buffer solution is 50 mM Tris pH 7.5, 10 mM MgCl2, 1 mM DTT, 0.01% Tween 20, 0.1 nM activated BRAF, 2 nM inactive MEK1, 10 nM inactive ERK2, 100 μM ATP and 500 nM long chain Biotin-peptide substrate (LCB-FFKNIVTPRTPPP) is contained in a 384 well format. The kinase reaction was stopped after 90 min with 10 mM EDTA and the Lance detection mix (2 nM Eu-labeled phospho-serine / threonine antibody (Cat. # AD0176-Perkin Elmer), 20 nM SA-APC (Cat. # CR130-100) -Perkin Elmer) The TR-FRET signal (excitation at 340 nm, emission at 615 nm and 665 nm) is read on a Victor3 V fluorometer with a delay time of 50 μs. The final concentration of DMSO is 2.5% during the assay Compound is screened by preincubation with enzyme in the presence of test compound for 45 min at 10 μM concentration .

Each individual IC ₅₀ was generated by GraphPad Prism software Version 4 (San Diego, California, USA) using a non-linear regression curve fit for a sigmoidal dose response (variable slope) Determine using a 10-point dose-response curve.

  In this cascade assay, the IC50s of Examples 1, 1A and 1B were 2.1 ± 0.58 nM, 2 ± 0.25 nM and 1.6 ± 0.1 nM (mean ± SEM, n = 3), respectively.

  An in vitro MAP kinase assay is set up with activated MAP kinase 2 / ERK2 (Catalog No. 14-550) obtained from Upstate. TR-FRET detection technology is used for reading.

Assay buffer solution, 50 mM Tris pH 7.5,10 mM MgCl 2, 1 mM DTT, 0.01% Tween 20,1 nM activated ERK2,100 μM ATP and 500 nM long chain biotin - peptide substrate (LCB- FFKNIVTPRTPPP), Contained in 384 well format. The kinase reaction was stopped after 90 min with 10 mM EDTA, and the Lance detection mix (2 nM Eu-labeled phospho-serine / threonine antibody (catalog number AD0176-Perkin Elmer), 20 nM SA-APC (catalog number CR130-100- The TR-FRET signal (excitation at 340 nm, emission at 615 nm and 665 nm) is read on a Victor3 V fluorometer with a delay time of 50 μs. Calculate using the ratio to the 615 nm reading.The final concentration of DMSO is 2.5% during the assay.Compounds are screened by preincubation with the enzyme for 45 minutes in the presence of the test compound at a concentration of 10 μM.

  Radioactive filter binding assay standard using recombinant human activated BRAF (V599E) kinase (Cat # 14-557) and kinase dead MEK1 (K97R) (Cat # 14-737) from Upstate To do. Incorporation of 32P into MEK1 (K97R) by BRAF (V599E), 50 mM Tris pH 7.5, 10 mM MgCl2, 1 mM DTT, 100 mM sucrose, 100 μM sodium orthovanadate, 5 μM ATP and 2 μCi [γ 32P ] Measure with ATP and 500 mg MEK1 kinase dead substrate in final assay buffer conditions. The enzymatic reaction is stopped after 120 minutes with 8N HCl (hydrochloric acid) and 1 mM ATP. The solution is spotted on P81 filter paper and washed 4 times with 0.75% orthophosphoric acid and finally with acetone. Read the dried P81 filter paper with a Micro-beta Trilux scintillation counter. The final concentration of DMSO is 1% during the assay. Compounds are screened by preincubation with the enzyme for 45 minutes in the presence of the test compound at a concentration of 10 μM.

  These above assays are completely described by Han, Shulin, et. Al., Bioorganic & Medicinal Chemistry Letters (2005) 15, 5467-5473, and Yeh, et. Al., Clin Cancer Res (2007) 13 (5), 1576-1583.

  The cell viability assay on A375 cells is set up in 96-well plate format using XTT. XTT is a yellow tetrazolium salt that is cleaved by mitochondria of metabolically active cells to become an orange formazan dye. This procedure allows for rapid determination in the microtiter plate, and results are reproducible and accurate.

  A375 cells are cultured in DMEM medium containing 10% FBS and 1 mM sodium pyruvate. Cells are trypsinized and seeded at 1000 cells / well. After the cells are allowed to adhere overnight, compounds are added to the wells at the following final concentrations: 10, 3, 1, 0.3, 0.1, 0.03, 0.01, 0.001, and 0.0001 μM. The assay is set up in triplicate for each concentration. Maintain DMSO concentration at 0.5% / well. Three days after compound addition, an XTT assay is performed. The wells are washed once with PBS. Add 100 μL of DMEM medium without phenol red or FBS to each well. Prepare a working solution of XTT containing 1 mg / ml XTT per 5 ml and 100 μL PMS (stock concentration 0.383 mg / ml). Add 50 μL of XTT working solution to each well. The absorbance of the plate is read using a Spectramax 190 (Molecular Devices) at 465 nm. Absorbance from wells containing only media and XTT, but no cells, is considered blank and subtracted from readings from all wells.

  Cell viability assays are further described in Scudiero, et. Al., Cancer Research (1988) 48, 4827-4833; Weislow, et. Al., J. Natl. Cancer Institute, (1989) 81, 577-586; and Roehm, et. al., J. Immunol. Methods [1991] 142: 257-265.

Percentage survival is calculated assuming that the blank subtracted value from wells treated with DMSO alone is 100% survival. GI ₅₀ values are calculated using Graphpad Prism using a non-linear regression curve fit for a sigmoidal dose response (variable slope). The compounds of the invention were evaluated in this cell viability assay. The GI ₅₀ of Example 1A was 13.4 nM, the GI ₅₀ of Example 1B was 29.6 nM, while the GI ₅₀ of Example 1 was 17.6 nM.

A375 P-Erk (Intracellular Western):
Human melanoma A375 cells were seeded in 100 μl growth media in Costar 96 well black clear bottom plates at 50,000 cells / well and placed at 37 ° C./5% CO ₂ overnight. Test compounds were diluted in DMSO and a concentration curve was generated. 5 mM stock was used for the highest concentration at 500 times; a final concentration of 10 μM and a 3-fold dilution up to 0.0001 μM. 1 μl of diluted compound was added to 500 μl cell culture medium and mixed well. The medium was removed from the cells and medium containing 200 μl of compound was added. Cells were treated with compounds for 3 hours at 37 ° C., 5% CO ₂ .

Following compound incubation, cells were washed once with PBS (Mg ⁺⁺ , Ca ⁺⁺ ) and fixed with 4% paraformaldehyde / PBS for 1 hour at room temperature. After fixation, the cells were washed 3 times with PBS / 0.1% TritonX-100 (PBST) and then blocked with 5% skim milk / PBST for 1-2 hours. 50 μL of primary antibody (rabbit-anti-phospho-ERK1 / 2) per well was added at 1: 500 in 5% skim milk / PBST and incubated overnight at 4 ° C. Wash cells 4 times with 100 μl DELFIA wash buffer, add 50 μL per well of secondary antibody (DELFIA-EU-N1-labeled anti-rabbit antibody) at 1: 3000 in DELFIA assay buffer for 2 hours Incubated in the dark (coated) at room temperature. Cells were washed 4 times with 100 μl DELFIA wash buffer. 50 μL of Wallac-DELFIA enhancement solution was added per well. The plate was shaken for 20 minutes at room temperature and then read on a Perkin Elmer Victor3v reader in a europium setting (615/340 nm emission / excitation).

EC ₅₀ values were calculated using a DMSO diluent value of 0% inhibition and the highest tested reference inhibitor count as 100% inhibition. All concentrations with DMSO were done in triplicate. The EC ₅₀ of Example 1A was 6.4 nM, compared to Example 1B of 15.6 nM and Example 1 of 12.2 nM.

For pharmacokinetic pharmacokinetic studies in athymic nude rats , the following parameters were calculated by non-compartmental regression analysis using Winnonlin 5.0 software (Pharsight, Mountain View, CA, USA): Plasma half-life (t _{1 / 2term} ); plasma clearance (CL); plasma maximum concentration (Cmax); plasma-concentration-time-area under the curve (AUC); and percent oral bioavailability (F%).

  The pharmacokinetic parameters in rats for some of the compounds of the invention are shown in the following table:

  Examples 1A and 1B show improved PK-parameters compared to Example 1 (one-way analysis of variance).

A375 B-RafV600E human melanoma model in rats-PK-PD experiment:
A375 cells were thawed using a 37 ° C water bath. Cells were transferred to tubes containing 10 ml of warm DMEM medium. The tube was centrifuged for 5 minutes at 1200 rpm and the supernatant was discarded. The cell pellet was resuspended and transferred to a 75 cm ² tissue culture flask containing 15 ml of medium and cultured at 37 ° C. in a 5% CO ₂ incubator.

On the day of cell implantation, cells were harvested (approximately 85% confluent) and resuspended in cold medium containing 4 mg / mL Matrigel. This cell suspension was injected subcutaneously into preirradiated (500 rads) athymic nude rats. Twenty million cells (injection volume, 200 μL) were injected subcutaneously into the right flank of rats 24 hours after irradiation. Tumor-bearing rats were randomized when the tumor volume reached approximately 500 mm ³ after about 15 to 20 days. Three rats were used for each time point.

  Rats were treated orally with a single dose of 10, 30 and 60 mg / kg oral (p.o.) of Example 1A and Example 1B of 30 mg / kg. Plasma and tumor samples were collected at 4, 12, 24 and 36 hours after administration. The mRNA expression levels of two direct target genes (DUSP6 and SPRY4) and indirect target (BMF) of the MEK substrate P-Erk can be measured. Treatment with MEK inhibitors has been shown to regulate these genes in a dose-dependent manner in tumor cell lines cultured in vitro and in vivo. Tumor samples were ground, extracted and studied for expression of the transcription factor DUSP6 using real-time quantitative PCR.

  Surprisingly, by two-way analysis of variance, Example-1A compared to Example-1B for a decrease in the level of DUSP-6 at 12 and 24 hours (p = 0.003 and p = 0.006, respectively). It was shown to be significantly more effective.

Claims (16)

  (S) -N- (4,5-Difluoro-6-((2-fluoro-4-iodophenyl) amino) benzofuran-7-yl) -1- (2,3-dihydroxypropyl) cyclopropane-1- A compound which is a sulfonamide or a pharmaceutically acceptable salt thereof.   (R) -N- (4,5-Difluoro-6-((2-fluoro-4-iodophenyl) amino) benzofuran-7-yl) -1- (2,3-dihydroxypropyl) cyclopropane-1- A compound which is a sulfonamide; or a pharmaceutically acceptable salt thereof. Less than:

A compound that is Less than:

A compound that is   A pharmaceutical composition comprising a compound of any of claims 1, 2, 3 or 4 in admixture with at least one pharmaceutically acceptable excipient.   Excipients are corn starch, potato starch, tapioca starch, starch paste, pregelatinized starch, sugar, gelatin, natural gum, synthetic gum, sodium alginate, alginic acid, tragacanth, guar gum, cellulose, ethylcellulose, cellulose acetate, carboxymethylcellulose calcium, Sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, crystalline cellulose, magnesium silicate, polyvinyl pyrrolidone, talc, calcium carbonate, powdered cellulose, dextranate, kaolin, mannitol, silicic acid, sorbitol, agar, sodium carbonate, croscarme Loin sodium, crospovidone, polacrilin potassium, starch glycolate, B) Sodium stearate, calcium stearate, magnesium stearate, stearic acid, mineral oil, light oil, glycerin, sorbitol, mannitol, polyethylene glycol, other glycols, sodium lauryl sulfate, hydrogenated vegetable oil, peanut oil, cottonseed oil, sunflower oil, 6. The pharmaceutical composition of claim 5, selected from the group consisting of sesame oil, olive oil, corn oil, soybean oil, zinc stearate, sodium oleate, ethyl oleate, ethyl laurate, silica, and combinations thereof.   6. The pharmaceutical composition of claim 5, further comprising an additional therapeutic agent.   8. The pharmaceutical composition of claim 7, wherein the additional therapeutic agent is selected from anti-cancer compounds, analgesics, antiemetics, antidepressants, and anti-inflammatory agents.   A method of treating cancer mediated by MEK, wherein a subject in need of such treatment is treated with an effective amount of a compound of any of claims 1, 2, 3 or 4 or any of claims 5-8. Administering a pharmaceutical composition.   Non-small cell lung cancer, pancreatic cancer, bladder cancer, colon cancer, bone marrow disease, breast cancer, prostate cancer, thyroid cancer, melanoma, ovary, eye, liver, biliary system, and nervous system adenoma and carcinoma and KRAS, NRAS And the method of claim 9 selected from the group consisting of advanced solid tumors with and BRAF mutations.   12. The method of claim 10, further comprising administering an additional therapeutic agent to the subject.   12. The method of claim 11, wherein the additional therapeutic agent comprises an anticancer agent, analgesic, antiemetic, antidepressant or anti-inflammatory agent.   13. The method of claim 12, wherein the additional therapeutic agent is a MEK inhibitor or an inhibitor of RAF, mTOR, HSP90, AKT, PI3K, CDK9, PAK, protein kinase C, MAP kinase, MAPK kinase, or ERK.   14. The method of claim 13, wherein the MEK inhibitor is selected from: AS703026; MSC1936369B; GSK1120212; AZD6244; PD-0325901; ARRY-438162; RDEA119; GDC0941; GDC0973; TAK-733; RO5126766;   15. The method of claim 14, wherein an additional therapeutic agent is administered to the subject concurrently with the compound.   (R) -N- (4,5-difluoro-6-((2-fluoro-4-iodophenyl) amino) benzofuran-7-yl) -1- (2,3-dihydroxypropyl) by the following steps Method for producing cyclopropane-1-sulfonamide: (i) 4,5-difluoro-3- (2-fluoro-4-iodophenyl) -1H-benzofuro [6,7-d] imidazole-2 (3H)- The presence of a base selected from triethylamine, N, N-diisopropylethylamine and triisopropylamine with (R) -1- (2,3-bis (benzyloxy) propyl) cyclopropane-1-sulfonyl chloride (R) -1- (1- (2,3-bis (benzyloxy) propyl) cyclopropoxy) -4,5-difluoro-3- (2-fluoro-4 with sulfur monoxide -Iodophenyl) -1H-benzofuro [6,7-d] imidazol-2 (3H) -one compound (1: 1) forming step; (ii) (R) -1- (1- (2,3 -Bis (benzyloxy) propyl) Chloropropoxy) -4,5-difluoro-3- (2-fluoro-4-iodophenyl) -1H-benzofuro [6,7-d] imidazol-2 (3H) -one in the presence of potassium trimethylsilanoate (R) -7-((1- (2,3-bis (benzyloxy) propyl) cyclopropoxy) amino) -4,5-difluoro-N- (2-fluoro) with sulfur monoxide -4-iodophenyl) benzofuran-6-amine compound (1: 1); and (iii) (R) -7-((1- (2,3-bis (benzyl) with sulfur monoxide Oxy) propyl) cyclopropoxy) amino) -4,5-difluoro-N- (2-fluoro-4-iodophenyl) benzofuran-6-amine compound (1: 1) is added to trichloroborane, boron trifluoride and Reaction in the presence of a suitable catalyst selected from boron bromide yields (R) -N- (4,5-difluoro-6-((2-fluoro-4-iodophenyl) amino) benzofuran-7- Il) -1- (2,3 Forming dihydroxypropyl) cyclopropane-1-sulfonamide.