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    • 专利摘要:
    production process of cycloalkylcarboxamido-indole compounds. the present invention features processes for preparing compounds such as (r)-1-(2,2-difluorobenzo[d] [1,3]dioxol-5-yl)-n-(1-2(2,3-) dihydroxypropyl)-6-fluoro-2-(1-hydroxy-2-methylpropan-2-yl)-1h-indol-5-yl)cyclopropanecarboxamide (compound 1), useful for the treatment of cftr-mediated diseases such as fibrosis cystic.
    公开号:BR112012027056B1
    申请号:R112012027056-7
    申请日:2011-04-21
    公开日:2021-08-24
    发明作者:Cristian Harrison；Elaine Chungmin Lee；Peter Jamison Rose；Robert Michael Hughes；David Andrew Siesel；Daniel T Belmont；Young Chun Jung；Gerald J. Tanoury；Benjamin Joseph Littler
    申请人:Vertex Pharmaceuticals Incorporated；
    IPC主号:
    专利说明:

    CROSS REFERENCE TO RELATED ORDERS
    [0001] This application claims priority to US Provisional Patent Applications serial numbers 61/333,870, filed May 12, 2010; 61/327,095 filed April 22, 2010; 61/327,057, filed April 22, 2010; 61/329,493 filed April 29, 2010; 61/327,091, filed April 22, 2010; 61/329,510, filed April 29, 2010; 61/327,099, filed April 22, 2010; and 61/329,500, filed April 29, 2010, the contents of all applications being incorporated herein by reference. TECHNICAL FIELD OF THE INVENTION
    [0002] The present invention describes processes for preparing compounds useful for the treatment of diseases mediated by CFTR, such as cystic fibrosis. BACKGROUND OF THE INVENTION
    [0003] CFTR is a cAMP/ATP-mediated anion channel that is expressed in a variety of cell types, including secretory and absorption epithelial cells, where it regulates anion flux across the membrane, as well as the activity of other ion channels and proteins. In epithelial cells, the normal functioning of CFTR is essential for the maintenance of electrolyte transport throughout the body, including the respiratory and digestive tissue. CFTR is composed of about 1,480 amino acids that encode a protein made up of a tandem repeat of transmembrane domains, each containing six transmembrane helices and a nucleotide binding domain. The two transmembrane domains are linked by a large, polar regulatory (R)-domain with multiple phosphorylation sites that regulate channel activity and cell traffic.
    The gene encoding CFTR has been identified and sequenced (see Gregory, RJ et al., (1990) Nature 347:382-386; Rich, DP et al., (1990) Nature 347:358-362) (Riordan , JR et al., (1989) Science 245:1066-1073). A defect in this gene causes mutations in the CFTR, resulting in cystic fibrosis (“CF”), the most common fatal genetic disease in humans. Cystic fibrosis affects approximately one in every 2,500 children in the United States. Among the general population of the United States, up to 10 million people carry a single copy of the defective gene, with no apparent ill effects. In contrast, individuals with two copies of the associated CF gene suffer from the debilitating and fatal effects of CF, including chronic lung disease.
    [0005] In patients with cystic fibrosis, mutations in CFTR endogenously expressed in the respiratory epithelium lead to reduced apical anion secretion, causing an imbalance in the transport of ions and fluids. The resulting decrease in anion transport contributes to increased mucus accumulation in the lung and the associated microbial infections that ultimately cause death in CF patients. In addition to respiratory illnesses, patients with CF often suffer from gastrointestinal problems and pancreatic insufficiency which, if left untreated, result in death. Also, most men with cystic fibrosis are infertile and fertility is decreased in women with cystic fibrosis. In contrast to the severe effects of two copies of the CF-associated gene, individuals with a single copy of the CF-associated gene exhibited increased resistance to cholera and dehydration resulting from diarrhea, perhaps explaining the relatively high frequency of the CF gene in the population.
    CFTR gene sequence analysis of the CF chromosomes has revealed a variety of disease-causing mutations (Cutting, GR et al., (1990) Nature 346:366-369; Dean, M. et al., (1990) Cell 61:863:870; and Kerem, BS. et al., (1989) Science 245:1073-1080; Kerem, BS et al., (1990) Proc. Natl. Acad. Sci. USA 87:8447-8451 ). To date, more than 1,000 disease-causing mutations in the CF gene have been identified (http://www.genet.sickkids.on.ca/cftr/). The most prevalent mutation is a phenylalanine deletion at position 508 of the CFTR amino acid sequence, and is commonly referred to as ΔF508-CFTR. This mutation occurs in approximately 70% of cystic fibrosis cases and is associated with serious disease. Other mutations include R117H and G551D.
    [0007] The elimination of residue 508 in ΔF508-CFTR prevents the nascent protein from folding correctly. This results in the mutant protein's inability to leave the ER and travel to the plasma membrane. As a result, the number of channels present in the membrane is much smaller than that observed in cells expressing wild-type CFTR. In addition to impaired traffic, the mutation results in faulty opening of the channel. Together, the reduced number of channels in the membrane and the defective opening result in reduced transport of anions through epithelia, leading to defective transport of ions and fluid. (Quinton, P.M. (1990) FASEB J. 4:2709-2727). Studies have shown, however, that the reduced numbers of ΔF508-CFTR in the membrane are functional, albeit lower than wild-type CFTR. (Dalemans et al., (1991) Nature Lond. 354: 526-528; Denning et al., supra; Pasyk and Foskett (1995) J. Cell. Biochem. 270: 12347-50). In addition to ΔF508-CFTR, other disease-causing mutations in CFTR that result in defective trafficking, synthesis, and/or channel opening can be up-regulated or down-regulated to alter anion secretion and modify disease progression and/or severity.
    [0008] Although CFTR transports a variety of molecules in addition to anions, it is evident that this role (anion transport) represents an element in an important mechanism of transport of ions and water through the epithelium. The other elements include the epithelial Na+ channel, ENaC, Na+/2Cl-/K+ cotransporter, Na+-K+-ATPase pump, and the basolateral membrane K+ channels, which are responsible for chloride uptake in the cell.
    [0009] These elements work together to carry out directional transport across the epithelium by their selective expression and location within the cell. Chloride absorption is accomplished by the coordinated activity of ENaC and CFTR present in the apical membrane and the Na+-K+- ATPase pump and Cl- channels expressed on the basolateral surface of the cell. Secondary active transport of chloride from the luminal side leads to intracellular chloride accumulation, which can then passively leave the cell through the Cl- channels, resulting in vector transport. The arrangement of the Na+/2Cl-/K+ cotransporter, Na+-K+-ATPase pump, and the basolateral membrane K+ channels on the basolateral surface and CFTR on the luminal side coordinate chloride secretion via CFTR on the luminal side. Since water is likely never actively transported by itself, its flow through the epithelium depends on tiny transepithelial osmotic gradients generated by the bulk flow of sodium and chloride.
    [0010] As discussed above, it is believed that the deletion of residue 508 in ΔF508-CFTR prevents the nascent protein from folding correctly, resulting in the inability of this mutant protein to leave the ER and proceed to the plasma membrane. As a result, insufficient amounts of the mature protein are present in the plasma membrane and chloride transport in epithelial tissues is significantly reduced. In fact, this cellular phenomenon of defective processing of the endoplasmic reticulum (ER) transporters (ABC) by the ER machinery has been shown to be the fundamental basis, not only for CF disease, but also for a wide variety of other isolated and hereditary diseases. The two ways in which ER machinery can malfunction are either by loss of export coupling of ER proteins, which leads to degradation, or by accumulation in the ER of these defective/misfolded proteins [Aridor M, et al., Nature Med., 5(7) pp 745-751 (1999); Shastry, B.S., et al., Neurochem. International, 43, pp 1-7 (2003); Rutishauser, J., et al., Swiss Med Wkly, 132, pp 211-222 (2002); Morello, JP et al., TIPS, 21, pp. 466-469 (2000); Bross P., et al., Human Mut., 14, pp. 186-198 (1999)].
    [0011] (R)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(1-(2,3-dihydroxypropyl)-6-fluor-2-( 1-hydroxy-2-methylpropan-2-yl)-1H-indol-5-yl)cyclopropanecarboxamide is disclosed in Published US Patent Application US20090131492 (said publication being incorporated herein in its entirety) as a modulator of CFTR activity and thus useful in treating CFTR-mediated diseases such as cystic fibrosis. There remains, however, a need for economical processes for the preparation of the cycloalkylcarboxamido-indole compounds described herein. SUMMARY OF THE INVENTION
    [0012] As described herein, the present invention provides processes for preparing CFTR correctors useful in the treatment of CFTR-mediated diseases such as cystic fibrosis. Such compounds include (R)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(1-(2,3-dihydroxy propyl)-6-fluor-2- (1-hydroxy-2-methylpropan-2-yl)-1H-indol-5-yl)cyclopropanecarboxamide (hereinafter "Compound 1") which has the following structure:
    Compound 1
    Compound 1 and the pharmaceutically acceptable compositions thereof are useful for treating or alleviating the severity of CFTR-mediated diseases such as, for example, cystic fibrosis. Compound 1 can exist in a number of different solid forms, such as substantially crystalline forms or amorphous forms. DETAILED DESCRIPTION OF THE INVENTION Definitions
    [0014] As used in this document, the following definitions shall apply unless otherwise indicated.
    [0015] The term "CFTR" as used herein means cystic fibrosis transmembrane conductance regulator or a mutation thereof capable of regulatory activity, including, but not limited to, ΔF508 CFTR and G551D CFTR (see, for example, , http://www.genet.sickkids.on.ca/cftr/, for CFTR mutations).
    [0016] The term "modulation", as used herein, means increase or decrease, for example, of activity, by a measurable amount.
    [0017] The term "chemically stable", as used herein, means that the solid form of Compound 1 does not decompose into one or more different chemical compounds when subjected to specified conditions, for example, 40°C/75% of relative humidity, for a specified period of time, for example, 1 day, 2 days, 3 days, 1 week, 2 weeks, or more. In some embodiments, less than 25% of the solid form of Compound 1 decomposes, in some embodiments, less than about 20%, less than about 15%, less than about 10%, less than about 5%, less of about 3%, less than about 1%, less than about 0.5% of the Compound 1 form decomposes under the specified conditions. In some embodiments, no detectable amount of the solid form of Compound 1 decomposes.
    [0018] The term "physically stable", as used herein, means that the solid form of Compound 1 does not change into one or more physical forms other than Compound 1 (e.g., different solid forms, as measured by XRPD , DSC, etc.) when subjected to specific conditions, eg 40°C/75% relative humidity, for a specific period of time, eg 1 day, 2 days, 3 days, 1 week, 2 weeks or most. In some embodiments, less than 25% of the solid form of Compound 1 changes into one or more different physical forms when subjected to specified conditions. In some embodiments, less than about 20%, less than about 15%, less than about 10%, less than about 5%, less than about 3%, less than about 1%, less than about 0.5% of the solid form of Compound 1 changes into one or more physical forms other than Compound 1 when subjected to specified conditions. In some embodiments, no detectable amount of the solid form of Compound 1 changes into one or more solid forms physically different from Compound 1.
    [0019] As used herein, the terms "about" and "approximately", when used in connection with doses, amounts, or percentage by weight of ingredients of a composition or dosage form, mean a dose , amount or percentage by weight that is recognized by one skilled in the art to provide a pharmacological effect equivalent to that obtained from the specified dose, amount or percentage by weight. Specifically, the term "about" or "approximately" means an acceptable error for a specific value, as determined by one of skill in the art, which depends in part on how the value is measured or determined. In certain embodiments, the term "about" or "approximately" means within 1, 2, 3, or 4 standard deviations. In certain embodiments, the term "about" or "approximately" means within 30%, 25%, 20%, 15%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, 0.5%, 0.1%, or 0.05% of a given value or range.
    [0020] Unless otherwise indicated, structures depicted herein are also meant to include all isomeric forms (e.g., enantiomeric, diastereomeric, and geometric (or conformational)) of the structure; for example, the R and S configurations for each asymmetric center, (Z) and (E) double bond isomers, and (Z) and (E) conformational isomers. Therefore, single stereochemical isomers as well as enantiomeric, diastereomeric and geometric (or conformational) mixtures of the present compounds are within the scope of the invention. All tautomeric forms of Compound 1 are included herein. For example, Compound 1 may exist as tautomers, both of which are included herein:
    [0021] Furthermore, unless otherwise indicated, structures depicted herein are also meant to include compounds that differ only in the presence of one or more isotopically enriched atoms.
    For example, Compound 1, in which one or more hydrogen atoms are replaced with deuterium or tritium, or one or more carbon atoms are replaced by a carbon enriched with 13C or 14C are within the scope of the present invention. Such compounds are useful, for example, as analytical tools, probes in biological assays, or compounds with an improved therapeutic profile.
    [0022] The term "protecting group", abbreviated as P, as used herein refers to any chemical group introduced into a molecule by chemical modification of a functional group so as to obtain chemoselectivity in a subsequent chemical reaction. Non-limiting examples of alcohol protecting groups include acetyl (Ac), benzoyl (Bz), benzyl (Bn), β-methoxyethoxymethyl ether (MEM), dimethoxytrityl (DMT), methoxymethyl ether (MOM), methoxytrityl (MMT), ether p - methoxybenzyl (PMB), pivaloyl (PIV), tetrahydropyranyl (THP), trityl (Tr) and trimethylsilyl (TMS). In one embodiment, the protecting group is Bn, which has the structure -CH2C6H5.
    [0023] The abbreviation "DCM" stands for dichloromethane. The abbreviation “IPA” stands for isopropyl alcohol. The abbreviation "DMSO" stands for dimethylsulfoxide. The abbreviation “MTBE” stands for methyl t-butyl ether. The abbreviation "THF" stands for tetrahydrofuran. The abbreviation “TEA” stands for triethylamine. The abbreviation "dba" as in Pd(dba)2 means dibenzylideneacetone. The abbreviation "dppf" as in Pd(dppf)Cl2 means 1,1'-bis(diphenylphosphino)-ferrocene.
    em que, independentemente para cada ocorrência: o anel A é um anel cicloalquila, heterocicloalquila, arila ou heteroarila, o mesmo sendo fundido; R1 é independentemente selecionado de -RJ, -ORJ, -N(RJ)2, -NO2, halogênio, -CN, -haloalquila C1-4, -haloalcóxi C1-4, -C(O)N(RJ)2, -NRJC(O)RJ, -SORJ, -SO2RJ, -SO2N(RJ)2, -NRJSO2RJ, -CORJ, -CO2RJ, -NRJSO2N(RJ)2, -COCORJ; RJ é hidrogênio ou alifático C1-6; m é um número inteiro de 0 a 3 inclusive; e Hal é um haleto; com um composto de fórmula IB: em que RJ é hidrogênio ou alifático C1-6, para formar um composto de fórmula IC: em que, independentemente para cada ocorrência: o anel A é um anel cicloalquila, heterocicloalquila, arila ou heteroarila, o mesmo sendo fundido; R1 é independentemente selecionado de -RJ, -ORJ, -N(RJ)2, -NO2, halogênio, -CN, -haloalquila C1-4, -haloalcóxi C1-4, -C(O)N(RJ)2, -NRJC(O)RJ, -SORJ, -SO2RJ, -SO2N(RJ)2, -NRJSO2RJ, -CORJ, -CO2RJ, -NRJSO2N(RJ)2, -COCORJ; RJ é hidrogênio ou alifático C1-6; X é CN ou CO2R; R é alifático C1-6 ou arila; e m é um número inteiro de 0 a 3 inclusive; e b) remoção do grupo -CO2RJ do composto IC em um segundo solvente orgânico para formar um composto de fórmula I.[0024] In one aspect, the invention features a method for preparing a compound of formula I:
    where, independently for each occurrence: ring A is a cycloalkyl, heterocycloalkyl, aryl or heteroaryl ring, the same being fused; R1 is independently selected from -RJ, -ORJ, -N(RJ)2, -NO2, halogen, -CN, -C1-4 haloalkyl, -C14 haloalkoxy, -C(O)N(RJ)2, -NRJC( O)RJ, -SORJ, -SO2RJ, -SO2N(RJ)2, -NRJSO2RJ, -CORJ, -CO2RJ, -NRJSO2N(RJ)2, -COCORJ; Rj is hydrogen or C1-6 aliphatic; X is CN or CO2R; R is C1-6 aliphatic or aryl; em is an integer from 0 to 3 inclusive; comprising the steps of: reacting a compound of formula IA in a first organic solvent wherein, independently for each occurrence: ring A is a cycloalkyl, heterocycloalkyl, aryl or heteroaryl ring, the same being fused; R1 is independently selected from -RJ, -ORJ, -N(RJ)2, -NO2, halogen, -CN, -C1-4 haloalkyl, -C1-4 haloalkoxy, -C(O)N(RJ)2, - NRJC(O)RJ, -SORJ, -SO2RJ, -SO2N(RJ)2, -NRJSO2RJ, -CORJ, -CO2RJ, -NRJSO2N(RJ)2, -COCORJ; Rj is hydrogen or C1-6 aliphatic; m is an integer from 0 to 3 inclusive; and Hal is a halide; with a compound of formula IB: where RJ is hydrogen or C1-6 aliphatic, to form a compound of formula IC: wherein, independently for each occurrence: ring A is a cycloalkyl, heterocycloalkyl, aryl or heteroaryl ring, the same being fused; R1 is independently selected from -RJ, -ORJ, -N(RJ)2, -NO2, halogen, -CN, -C1-4 haloalkyl, -C1-4 haloalkoxy, -C(O)N(RJ)2, - NRJC(O)RJ, -SORJ, -SO2RJ, -SO2N(RJ)2, -NRJSO2RJ, -CORJ, -CO2RJ, -NRJSO2N(RJ)2, -COCORJ; Rj is hydrogen or C1-6 aliphatic; X is CN or CO2R; R is C1-6 aliphatic or aryl; em is an integer from 0 to 3 inclusive; and b) removing the -CO2 Rj group from compound IC in a second organic solvent to form a compound of formula I.
    [0025] In another embodiment, the invention describes the above method wherein ring A is heterocycloalkyl or fused heteroaryl. In another embodiment, ring A is selected from
    [0026] In another embodiment, ring A is
    [0027] In another embodiment, the invention describes the above method wherein X is CN. In another embodiment, X is CO2Et.
    [0028] In another embodiment, the invention describes the above method wherein m is 0.
    [0029] In another embodiment, the invention describes the above method wherein RJ is a C1-6 aliphatic. In another embodiment, RJ is -CH2CH3.
    [0030] In another embodiment, the invention describes the above method wherein Hal is Br.
    [0031] In another embodiment, the invention describes the above method wherein the first organic solvent is an aprotic solvent. In another embodiment, the first organic solvent is selected from 1,2-dimethoxyethane, dioxane, acetonitrile, toluene, benzene, xylenes, methyl t-butyl ether, methyl ethyl ketone, methyl isobutyl ketone, acetone, N,N-dimethylformamide, N ,N-dimethylacetamide, N-methyl pyrrolidinone, ethyl acetate, dichloromethane or -and dimethylsulfoxide. In another embodiment, the first organic solvent is selected from acetonitrile, toluene, benzene,—or and xylenes. In another embodiment, the first organic solvent is toluene.
    [0032] In another embodiment, the invention describes the above method in which step a) is performed in the presence of a transition metal catalyst. In another embodiment, step a) is carried out in the presence of a palladium catalyst. In another embodiment, step a) is carried out in the presence of a palladium catalyst selected from palladium(II) acetate, Pd(dppf)Cl2, Pd(dba)2, tetracis(triphenylphosphine)palladium(0) or and tris( dibenzylidene acetone)dipalladium(0). In another embodiment, step a) is performed in the presence of Pd(dba)2.
    [0033] In another embodiment, the invention describes the above method wherein step a) is carried out at about 50°C to 90°C. In another embodiment, step a) is carried out at about 60°C to 80°C. In another embodiment, step a) is carried out at about 70°C.
    [0034] In another embodiment, the invention describes the above method wherein the second organic solvent is an aprotic solvent. In another embodiment, the second organic solvent is selected from 1,2-dimethoxyethane, dioxane, acetonitrile, toluene, benzene, xylenes, methyl t-butyl ether, methyl ethyl ketone, methyl isobutyl ketone, acetone, N,N-dimethylformamide, N ,N-dimethylacetamide, N-methyl pyrrolidinone, ethyl acetate, dichloromethane or and dimethylsulfoxide. In another embodiment, the second organic solvent is dimethylsulfoxide.
    [0035] In another embodiment, the invention describes the above method where step b) is performed in the presence of an inorganic acid. In another embodiment, step b) is carried out in the presence of an inorganic acid selected from hydrochloric, sulfuric, nitric, phosphoric or boric acid. In another embodiment, step b) is carried out in the presence of hydrochloric acid.
    [0036] In another embodiment, the invention describes the above method where step b) is carried out at about 55°C to 95°C. In another embodiment, step b) is carried out at about 65°C to 85°C. In another embodiment, step b) is carried out at about 75°C.
    em que, independentemente para cada ocorrência: o anel A é um anel cicloalquila, heterocicloalquila, arila ou heteroarila, o mesmo sendo fundido; Hal é um haleto; R1 é independentemente selecionado de —RJ, -ORJ, -N(RJ)2, -NO2, halogênio, -CN, -haloalquila C1-4, -haloalcóxi C1-4, -C(O)N(RJ)2, -NRJC(O)RJ, -SORJ, -SO2RJ, -SO2N(RJ)2, -NRJSO2RJ, - CORJ, -CO2RJ, -NRJSO2N(RJ)2, -COCORJ; RJ é hidrogênio ou alifático C1-6; m é um número inteiro de 0 a 3 inclusive; e n é um número inteiro de 1 a 4 inclusive; compreendendo as etapas de reação de um composto de fórmula IIA em um primeiro solvente orgânico em que, independentemente para cada ocorrência: o anel A é um anel cicloalquila, heterocicloalquila, arila ou heteroarila, o mesmo sendo fundido; R1 é independentemente selecionado de -RJ, -ORJ, -N(RJ)2, -NO2, halogênio, -CN, -haloalquila C1-4, -haloalcóxi C1-4, -C(O)N(RJ)2, -NRJC(O)RJ, -SORJ, -SO2RJ, -SO2N(RJ)2, -NRJSO2RJ, - CORJ, -CO2RJ, -NRJSO2N(RJ)2, -COCORJ; RJ é hidrogênio ou alifático C1-6; m é um número inteiro de 0 a 3 inclusive; e Hal é um haleto; com um composto de fórmula IIB: em que X é CN ou CO2R; R é alifático C1-6 ou arila; e RJ é hidrogênio ou alifático C1-6, para formar um composto de fórmula IIC: em que, independentemente para cada ocorrência: o anel A é um anel cicloalquila, heterocicloalquila, arila ou heteroarila, o mesmo sendo fundido; R1 é independentemente selecionado de -RJ, -ORJ, -N(RJ)2, -NO2, halogênio, -CN, -haloalquila C1-4, -haloalcóxi C1-4, -C(O)N(RJ)2, -NRJC(O)RJ, -SORJ, -SO2RJ, -SO2N(RJ)2, -NRJSO2RJ, - CORJ, -CO2RJ, -NRJSO2N(RJ)2, -COCORJ; RJ é hidrogênio ou alifático C1-6; X é CN ou CO2R; R é alifático C1-6 ou arila; e m é um número inteiro de 0 a 3 inclusive; b) remoção do grupo -CO2RJ do composto IIC em um segundo solvente orgânico para formar um composto de fórmula I: em que, independentemente para cada ocorrência: o anel A é um anel cicloalquila, heterocicloalquila, arila ou heteroarila, o mesmo sendo fundido; R1 é independentemente selecionado de -RJ, -ORJ, -N(RJ)2, -NO2, halogênio, -CN, -haloalquila C1-4, -haloalcóxi C1-4, -C(O)N(RJ)2, -NRJC(O)RJ, -SORJ, -SO2RJ, -SO2N(RJ)2, -NRJSO2RJ, - CORJ, -CO2RJ, -NRJSO2N(RJ)2, -COCORJ; RJ é hidrogênio ou alifático C1-6; X é CN ou CO2R; R é alifático C1-6 ou arila; e m é um número inteiro de 0 a 3 inclusive; c) reação de um composto de fórmula I com um composto de fórmula IID na presença de uma base: em que, independentemente para cada ocorrência: Hal é um haleto; e q é um número inteiro de 0 a 3 inclusive; para produzir um composto de fórmula IIE: em que, independentemente para cada ocorrência: o anel A é um anel cicloalquila, heterocicloalquila, arila ou heteroarila, o mesmo sendo fundido; R1 é independentemente selecionado de -RJ, -ORJ, -N(RJ)2, -NO2, halogênio, -CN, -haloalquila C1-4, -haloalcóxi C1-4, -C(O)N(RJ)2, -NRJC(O)RJ, -SORJ, -SO2RJ, -SO2N(RJ)2, -NRJSO2RJ, - CORJ, -CO2RJ, -NRJSO2N(RJ)2, -COCORJ; RJ é hidrogênio ou alifático C1-6; m é um número inteiro de 0 a 3 inclusive; X é CN ou CO2R; R é alifático C1-6 ou arila; e n é um número inteiro de 1 a 4 inclusive; d) reação sequencial de um composto de fórmula IIE com uma base hidróxido e ácido para formar um composto de fórmula IIF: em que, independentemente para cada ocorrência: o anel A é um anel cicloalquila, heterocicloalquila, arila ou heteroarila, o mesmo sendo fundido; R1 é independentemente selecionado de -RJ, -ORJ, -N(RJ)2, -NO2, halogênio, -CN, -haloalquila C1-4, -haloalcóxi C1-4, -C(O)N(RJ)2, -NRJC(O)RJ, -SORJ, -SO2RJ, -SO2N(RJ)2, -NRJSO2RJ, - CORJ, -CO2RJ, -NRJSO2N(RJ)2, -COCORJ; RJ é hidrogênio ou alifático C1-6; m é um número inteiro de 0 a 3 inclusive; e n é um número inteiro de 1 a 4 inclusive; e e) reação de um composto de fórmula IIF com um agente de halogenação em um terceiro solvente orgânico para formar um composto de fórmula II.[0037] In another aspect, the invention describes a method for preparing a compound of formula II: wherein, independently for each occurrence: ring A is a cycloalkyl, heterocycloalkyl, aryl or heteroaryl ring, the same being fused; Hal is a halide; R1 is independently selected from -RJ, -ORJ, -N(RJ)2, -NO2, halogen, -CN, -C1-4 haloalkyl, -C1-4 haloalkoxy, -C(O)N(RJ)2, - NRJC(O)RJ, -SORJ, -SO2RJ, -SO2N(RJ)2, -NRJSO2RJ, -CORJ, -CO2RJ, -NRJSO2N(RJ)2, -COCORJ; Rj is hydrogen or C1-6 aliphatic; m is an integer from 0 to 3 inclusive; en is an integer from 1 to 4 inclusive; comprising the steps of reacting a compound of formula IIA in a first organic solvent wherein, independently for each occurrence: ring A is a cycloalkyl, heterocycloalkyl, aryl or heteroaryl ring, the same being fused; R1 is independently selected from -RJ, -ORJ, -N(RJ)2, -NO2, halogen, -CN, -C1-4 haloalkyl, -C1-4 haloalkoxy, -C(O)N(RJ)2, - NRJC(O)RJ, -SORJ, -SO2RJ, -SO2N(RJ)2, -NRJSO2RJ, -CORJ, -CO2RJ, -NRJSO2N(RJ)2, -COCORJ; Rj is hydrogen or C1-6 aliphatic; m is an integer from 0 to 3 inclusive; and Hal is a halide; with a compound of formula IIB: where X is CN or CO2R; R is C1-6 aliphatic or aryl; and Rj is hydrogen or C1-6 aliphatic, to form a compound of formula IIC: wherein, independently for each occurrence: ring A is a cycloalkyl, heterocycloalkyl, aryl or heteroaryl ring, the same being fused; R1 is independently selected from -RJ, -ORJ, -N(RJ)2, -NO2, halogen, -CN, -C1-4 haloalkyl, -C1-4 haloalkoxy, -C(O)N(RJ)2, - NRJC(O)RJ, -SORJ, -SO2RJ, -SO2N(RJ)2, -NRJSO2RJ, -CORJ, -CO2RJ, -NRJSO2N(RJ)2, -COCORJ; Rj is hydrogen or C1-6 aliphatic; X is CN or CO2R; R is C1-6 aliphatic or aryl; em is an integer from 0 to 3 inclusive; b) removal of the -CO2RJ group from compound IIC in a second organic solvent to form a compound of formula I: wherein, independently for each occurrence: ring A is a cycloalkyl, heterocycloalkyl, aryl or heteroaryl ring, the same being fused; R1 is independently selected from -RJ, -ORJ, -N(RJ)2, -NO2, halogen, -CN, -C1-4 haloalkyl, -C1-4 haloalkoxy, -C(O)N(RJ)2, - NRJC(O)RJ, -SORJ, -SO2RJ, -SO2N(RJ)2, -NRJSO2RJ, -CORJ, -CO2RJ, -NRJSO2N(RJ)2, -COCORJ; Rj is hydrogen or C1-6 aliphatic; X is CN or CO2R; R is C1-6 aliphatic or aryl; em is an integer from 0 to 3 inclusive; c) reacting a compound of formula I with a compound of formula IID in the presence of a base: where, independently for each occurrence: Hal is a halide; eq is an integer from 0 to 3 inclusive; to produce a compound of formula IIE: wherein, independently for each occurrence: ring A is a cycloalkyl, heterocycloalkyl, aryl or heteroaryl ring, the same being fused; R1 is independently selected from -RJ, -ORJ, -N(RJ)2, -NO2, halogen, -CN, -C1-4 haloalkyl, -C1-4 haloalkoxy, -C(O)N(RJ)2, - NRJC(O)RJ, -SORJ, -SO2RJ, -SO2N(RJ)2, -NRJSO2RJ, -CORJ, -CO2RJ, -NRJSO2N(RJ)2, -COCORJ; Rj is hydrogen or C1-6 aliphatic; m is an integer from 0 to 3 inclusive; X is CN or CO2R; R is C1-6 aliphatic or aryl; en is an integer from 1 to 4 inclusive; d) sequential reaction of a compound of formula IIE with a hydroxide base and acid to form a compound of formula IIF: wherein, independently for each occurrence: ring A is a cycloalkyl, heterocycloalkyl, aryl or heteroaryl ring, the same being fused; R1 is independently selected from -RJ, -ORJ, -N(RJ)2, -NO2, halogen, -CN, -C1-4 haloalkyl, -C1-4 haloalkoxy, -C(O)N(RJ)2, - NRJC(O)RJ, -SORJ, -SO2RJ, -SO2N(RJ)2, -NRJSO2RJ, -CORJ, -CO2RJ, -NRJSO2N(RJ)2, -COCORJ; Rj is hydrogen or C1-6 aliphatic; m is an integer from 0 to 3 inclusive; en is an integer from 1 to 4 inclusive; and e) reacting a compound of formula IIF with a halogenating agent in a third organic solvent to form a compound of formula II.
    [0038] In another embodiment, the invention describes the above method wherein in step a), the first organic solvent is an aprotic solvent. In another embodiment, the first organic solvent is selected from 1,2-dimethoxyethane, dioxane, acetonitrile, toluene, benzene, xylenes, methyl t-butyl ether, methyl ethyl ketone, methyl isobutyl ketone, acetone, N,N-dimethylformamide, N ,N-dimethylacetamide, N-methylpyrrolidinone, ethyl acetate, dichloromethane,—or and dimethylsulfoxide. In another embodiment, the first organic solvent is toluene.
    [0039] In another embodiment, the invention describes the above method wherein in step a), m is 0.
    [0040] In another embodiment, the invention describes the above method wherein in step a), Hal is Br.
    Em outra concretização, o anel A é[0041] In another embodiment, the invention describes theIn another embodiment, ring A is
    [0042] In another embodiment, the invention describes the above method in which in step a), X is CN. In another embodiment X is CO2Et.
    [0043] In another embodiment, the invention describes the above method in which in step a), RJ is Et.
    [0044] In another embodiment, the invention describes the above method wherein in formula IIC, ring A is
    [0045] In another embodiment, the invention describes the above method where in step b), the second solvent is an aprotic solvent. In another embodiment, the second solvent is selected from 1,2-dimethoxyethane, dioxane, acetonitrile, toluene, benzene, xylenes, methyl t-butyl ether, methyl ethyl ketone, methyl isobutyl ketone, acetone, N,N-dimethylformamide, N, N-dimethylacetamide, N-methyl pyrrolidinone, ethyl acetate, dichloromethane or and dimethylsulfoxide. In another embodiment, the second solvent is dimethylsulfoxide.
    0, e X é CN.[0046] In another embodiment, the invention describes the above method wherein in formula I, the ring 0, and X is CN.
    [0047] In another embodiment, the invention describes the above method wherein in step c), the base is an inorganic base. In another embodiment, the base is a hydroxide. In another embodiment, the base is NaOH.
    [0048] In another embodiment, the invention describes the above method wherein in formula IID, q is 1.
    [0049] In another embodiment, the invention describes the above method wherein in formula IID, one Hal is Cl and the other Hal is Br.
    [0050] In another embodiment, the invention describes the above method in which in step d), the base is NaOH. In another embodiment, in step d), the acid is HCl.
    [0051] In another embodiment, the invention describes the above method in which in step d), the reaction with a hydroxide base is carried out at about 60°C to 100°C. In another embodiment, the reaction with a hydroxide is carried out at about 70°C to 90°C. In another embodiment, the reaction with a hydroxide is carried out at about 80°C.
    método acima em que na fórmula IIE, o anel A é , m é 0, n é 1, e X é CN.[0052] In another embodiment, the invention describes the above method wherein in formula IIE, ring A is , m is 0, n is 1, and X is CN.
    [0053] In another embodiment, the invention describes the above method wherein in step e), the third organic solvent is an aprotic solvent. In another embodiment, in step e), the third organic solvent is selected from 1,2-dimethoxyethane, dioxane, acetonitrile, toluene, benzene, xylenes, methyl t-butyl ether, methyl ethyl ketone, methyl isobutyl ketone, acetone, N, N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidinone, ethyl acetate, dichloromethane, or and dimethylsulfoxide. In another embodiment, in step e), the third organic solvent is toluene.
    [0054] In another embodiment, the invention describes the above method wherein in step e), the halogenating agent is SOCl2.
    [0055] In another embodiment, the invention describes the above method in which step e) is carried out at around 40°C to 80°C. In another embodiment, step e) is carried out at around 50°C to 70°C. In another embodiment, step e) is carried out around 60°C.
    é 0, e n é 1.[0056] In another embodiment, the invention describes the above method wherein in formula IIF, ring A is is 0, and n is 1.
    0, n é 1, e Hal é Cl.[0057] In another embodiment, the invention describes the 0, n is 1, and Hal is Cl.
    em que, independentemente para cada ocorrência: R2 é -RJ, -ORJ, -N(RJ)2, -NO2, halogênio, -CN, -haloalquila C1-4, -haloalcóxi C1-4, -C(O)N(RJ)2, -NRJC(O)RJ, -SORJ, -SO2RJ, -SO2N(RJ)2, -NRJSO2RJ, -CORJ, -CO2RJ, -NRJSO2N(RJ)2, -COCORJ; RJ é hidrogênio ou alifático C1-6; R3 é alifático C1-6 opcionalmente substituído com OH, OP, -O-alifático C1—6, arila, heteroarila, -O-arila ou -O- heteroarila; P é um grupo de proteção; e o é um número inteiro de 0 a 3; compreendendo as etapas de: reação de um composto de fórmula IIIA: onde, independentemente para cada ocorrência: R2 é -RJ, -ORJ, -N(RJ)2, -NO2, halogênio, -CN, -haloalquila C1-4, -haloalcóxi C1-4, -C(O)N(RJ)2, -NRJC(O)RJ, -SORJ, -SO2RJ, -SO2N(RJ)2, -NRJSO2RJ, -CORJ, -CO2RJ, -NRJSO2N(RJ)2, -COCORJ; RJ é hidrogênio ou alifático C1-6; e o é um número inteiro de 0 a 3; com um reagente de halogenação em um primeiro solvente orgânico para formar um composto de fórmula IIIB: em que, independentemente para cada ocorrência: R2 é -RJ, -ORJ, -N(RJ)2, -NO2, halogênio, -CN, -haloalquila C1-4, -haloalcóxi C1-4, -C(O)N(RJ)2, -NRJC(O)RJ, -SORJ, -SO2RJ, -SO2N(RJ)2, -NRJSO2RJ, -CORJ, -CO2RJ, -NRJSO2N(RJ)2, -COCORJ; RJ é hidrogênio ou alifático C1-6; o é um número inteiro de 0 a 3; e Hal é um haleto; b) reação do composto de fórmula IIIB em um segundo solvente orgânico com um composto de fórmula IIIC: em que: P é um grupo de proteção; seguido por redução e tratamento com ácido para formar um composto de fórmula IIID: em que: R2 é -RJ, -ORJ, -N(RJ)2, -NO2, halogênio, -CN, -haloalquila C1-4, -haloalcóxi C1-4, -C(O)N(RJ)2, -NRJC(O)RJ, -SORJ, -SO2RJ, -SO2N(RJ)2, -NRJSO2RJ, -CORJ, -CO2RJ, -NRJSO2N(RJ)2, -COCORJ; RJ é hidrogênio ou alifático C1-6; o é um número inteiro de 0 a 3; Hal é um haleto; P é um grupo de proteção; e A Θ é um ânion; c) neutralização de um composto de fórmula IIID na presença de uma base para formar um composto de fórmula IIID- a: -haloalquila C1-4, -haloalcóxi C1-4, -C(O)N(RJ)2, -NRJC(O)RJ, -SORJ, -SO2RJ, -SO2N(RJ)2, -NRJSO2RJ, - CORJ, -CO2RJ, -NRJSO2N(RJ)2, -COCORJ; RJ é hidrogênio ou alifático C1-6; o é um número inteiro de 0 a 3; Hal é um haleto; e P é um grupo de proteção; d) reação de um composto de fórmula IIID-a em um terceiro solvente orgânico com um composto de fórmula IIIE: em que, independentemente para cada ocorrência: R3 é um alifático C1-6 opcionalmente substituído com OH, OP, -O-alifático C1—6, arila, heteroarila, -O-arila ou -O- heteroarila; na presença de um catalisador para formar um composto de fórmula III.[0058] In another aspect, the invention describes a method for preparing a compound of formula III: where, independently for each occurrence: R2 is -RJ, -ORJ, -N(RJ)2, -NO2, halogen, -CN, -C1-4 haloalkyl, -C1-4 haloalkoxy, -C(O)N( RJ)2, -NRJC(O)RJ, -SORJ, -SO2RJ, -SO2N(RJ)2, -NRJSO2RJ, -CORJ, -CO2RJ, -NRJSO2N(RJ)2, -COCORJ; Rj is hydrogen or C1-6 aliphatic; R3 is C1-6 aliphatic optionally substituted with OH, OP, -O-C1-6 aliphatic, aryl, heteroaryl, -O-aryl or -O-heteroaryl; P is a protecting group; and o is an integer from 0 to 3; comprising the steps of: reacting a compound of formula IIIA: where, independently for each occurrence: R2 is -RJ, -ORJ, -N(RJ)2, -NO2, halogen, -CN, -C1-4 haloalkyl, -C1-4 haloalkoxy, -C(O)N(RJ )2, -NRJC(O)RJ, -SORJ, -SO2RJ, -SO2N(RJ)2, -NRJSO2RJ, -CORJ, -CO2RJ, -NRJSO2N(RJ)2, -COCORJ; Rj is hydrogen or C1-6 aliphatic; and o is an integer from 0 to 3; with a halogenating reagent in a first organic solvent to form a compound of formula IIIB: where, independently for each occurrence: R2 is -RJ, -ORJ, -N(RJ)2, -NO2, halogen, -CN, -C1-4 haloalkyl, -C1-4 haloalkoxy, -C(O)N( RJ)2, -NRJC(O)RJ, -SORJ, -SO2RJ, -SO2N(RJ)2, -NRJSO2RJ, -CORJ, -CO2RJ, -NRJSO2N(RJ)2, -COCORJ; Rj is hydrogen or C1-6 aliphatic; o is an integer from 0 to 3; and Hal is a halide; b) reaction of the compound of formula IIIB in a second organic solvent with a compound of formula IIIC: where: P is a protecting group; followed by reduction and acid treatment to form a compound of formula IIID: where: R2 is -RJ, -ORJ, -N(RJ)2, -NO2, halogen, -CN, -C1-4 haloalkyl, -C1-4 haloalkoxy, -C(O)N(RJ)2, - NRJC(O)RJ, -SORJ, -SO2RJ, -SO2N(RJ)2, -NRJSO2RJ, -CORJ, -CO2RJ, -NRJSO2N(RJ)2, -COCORJ; Rj is hydrogen or C1-6 aliphatic; o is an integer from 0 to 3; Hal is a halide; P is a protecting group; and A Θ is an anion; c) neutralizing a compound of formula IIID in the presence of a base to form a compound of formula IIID-a: -C1-4 haloalkyl, -C1-4 haloalkoxy, -C(O)N(RJ)2, -NRJC(O)RJ, -SORJ, -SO2RJ, -SO2N(RJ)2, -NRJSO2RJ, -CORJ, - CO2RJ, -NRJSO2N(RJ)2, -COCORJ; Rj is hydrogen or C1-6 aliphatic; o is an integer from 0 to 3; Hal is a halide; and P is a protecting group; d) reaction of a compound of formula IIID-a in a third organic solvent with a compound of formula IIIE: wherein, independently for each occurrence: R3 is a C1-6 aliphatic optionally substituted with OH, OP, -O-C1-6 aliphatic, aryl, heteroaryl, -O-aryl or -O-heteroaryl; in the presence of a catalyst to form a compound of formula III.
    [0059] In another embodiment, the invention describes the above method wherein in formula IIIA, o is 1. In another embodiment, o is 1 and R2 is F.
    [0060] In another embodiment, the invention describes the above method wherein in step a), the halogenating reagent is N-bromosuccinimide.
    [0061] In another embodiment, the invention describes the above method where in step a), the first organic solvent is an aprotic solvent. In another embodiment, the first organic solvent is selected from 1,2-dimethoxyethane, dioxane, acetonitrile, toluene, benzene, xylenes, methyl t-butyl ether, methyl ethyl ketone, methyl isobutyl ketone, acetone, N,N-dimethylformamide, N ,N-dimethylacetamide, N-methylpyrrolidinone, ethyl acetate, dichloromethane or -and dimethylsulfoxide. In another embodiment, the first organic solvent is ethyl acetate.
    [0062] In another embodiment, the invention describes the above method where step a) is carried out at about 2°C to 42°C. In another embodiment, step a) is carried out at about 12°C to 32°C. In another embodiment, step a) is carried out at about 22°C.
    [0063] In another embodiment, the invention describes the above method where in formula IIIB, o is 1, R2 is F, and Hal is Br.
    [0064] In another embodiment, the invention describes the above method where in formula IIIC, P is benzyl.
    [0065] In another embodiment, the invention describes the above method where in step b), the second organic solvent is an aprotic solvent. In another embodiment, in step b), the second organic solvent is selected from 1,2-dimethoxyethane, dioxane, acetonitrile, toluene, benzene, xylenes, methyl t-butyl ether, methyl ethyl ketone, methyl isobutyl ketone, acetone, N, N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidinone, ethyl acetate, dichloromethane or—and—dimethylsulfoxide. In another embodiment, in step b), the second organic solvent is toluene.
    [0066] In another embodiment, the invention describes the above method where in step b), the reaction with a compound of formula IIIC is carried out at around 60°C to 100°C. In another embodiment, in step b), the reaction with a compound of formula IIIC is carried out at around 70°C to 90°C. In another embodiment, in step b), the reaction with a compound of formula IIIC is carried out at around 80°C.
    [0067] In another embodiment, the invention describes the above method, where in step b), the reduction is carried out with hydrogen.
    [0068] In another embodiment, the invention describes the above method where in step b), the acid is p-toluenesulfonic acid.
    [0069] In another embodiment, the invention describes the above method where in formula IIID, o is 1, R2 is F, Hal is Br, A- is Tos- and P is benzyl.
    [0070] In another embodiment, the invention describes the above method where in formula IIIE, R3 is C(CH3)2CH2O(benzyl).
    [0071] In another embodiment, the invention describes the above method where in step c), the base is an inorganic base.
    [0072] In another embodiment, the invention describes the above method where in step c), the base is NaHCO3.
    [0073] In another embodiment, the invention describes the above method where in step d), the third organic solvent is an aprotic solvent. In another embodiment, in step d), the third organic solvent is selected from 1,2-dimethoxyethane, dioxane, acetonitrile, toluene, benzene, xylenes, methyl t-butyl ether, methyl ethyl ketone, methyl isobutyl ketone, acetone, N, N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidinone, ethyl acetate, dichloromethane or -e-dimethylsulfoxide. In another embodiment, in step d), the third organic solvent is acetonitrile.
    [0074] In another embodiment, the invention describes the above method where step d) is carried out at around 60°C to 100°C. In another embodiment, step d) is carried out at around 70°C to 90°C. In another embodiment, step d) is carried out around 80°C.
    [0075] In another embodiment, the invention describes the above method where in step d) the catalyst is a palladium catalyst. In another embodiment, in step d) the catalyst is selected from palladium(II) acetate, Pd(dppf)Cl2, Pd(dba)2, (MeCN)2PdCl2, tetracis(triphenylphosphine)palladium(0) or and tris(dibenzylideneacetone )dipalladium(0). In another embodiment, in step d) the catalyst is palladium(II) acetate.
    em que, independentemente para cada ocorrência: o anel A é um anel cicloalquila, heterocicloalquila, arila ou heteroarila, o mesmo sendo fundido; R1 e R2 são independentemente selecionados de -RJ, -ORJ, -N(RJ)2, -NO2, halogênio, -CN, -haloalquila C1-4, -haloalcóxi C1-4, -C(O)N(RJ)2, -NRJC(O)RJ, -SORJ, -SO2RJ, -SO2N(RJ)2, -NRJSO2RJ, -CORJ, -CO2RJ, -NRJSO2N(RJ)2, -COCORJ; RJ é hidrogênio ou alifático C1-6; R3 é um alifático C1-6 opcionalmente substituído com OH, OP, -O-alifático C1-6, arila, heteroarila, -O-arila ou -O- heteroarila; P é um grupo de proteção; m é um número inteiro de 0 a 3 inclusive; n é um número inteiro de 1 a 4 inclusive; e o é um número inteiro de 1 a 3 inclusive; compreendendo as etapas de: reação de um composto de fórmula IIIA: em que, independentemente para cada ocorrência: R2 é -RJ, -ORJ, -N(RJ)2, -NO2, halogênio, -CN, -haloalquila C1-4, -haloalcóxi C1-4, -C(O)N(RJ)2, -NRJC(O)RJ, -SORJ, -SO2RJ, -SO2N(RJ)2, -NRJSO2RJ, -CORJ, -CO2RJ, -NRJSO2N(RJ)2, -COCORJ; RJ é hidrogênio ou alifático C1-6; e o é um número inteiro de 0 a 3; com um reagente de halogenação em um primeiro solvente orgânico para formar um composto de fórmula IIIB em que, independentemente para cada ocorrência: R2 é -RJ, -ORJ, -N(RJ)2, -NO2, halogênio, -CN, -haloalquila C1-4, -haloalcóxi C1-4, -C(O)N(RJ)2, -NRJC(O)RJ, -SORJ, -SO2RJ, -SO2N(RJ)2, -NRJSO2RJ, -CORJ, -CO2RJ, -NRJSO2N(RJ)2, -COCORJ; RJ é hidrogênio ou alifático C1-6; o é um número inteiro de 0 a 3; e Hal é um haleto; b) reação do composto de fórmula IIIB em um segundo solvente orgânico com um composto de fórmula IIIC: me em que: P é um grupo de proteção; seguido por redução e tratamento com ácido para formar um composto de fórmula IIID: em que: R2 é -RJ, -ORJ, -N(RJ)2, -NO2, halogênio, -CN, -haloalquila C1-4, -haloalcóxi C1-4, -C(O)N(RJ)2, -NRJC(O)RJ, -SORJ, -SO2RJ, -SO2N(RJ)2, -NRJSO2RJ, -CORJ, -CO2RJ, -NRJSO2N(RJ)2, -COCORJ; RJ é hidrogênio ou alifático C1-6; o é um número inteiro de 0 a 3; Hal é um haleto; P é um grupo de proteção; e A Θ é um ânion; c) neutralização de um composto de fórmula IIID na presença de uma base para formar um composto de fórmula IIID- a: em que: R2 é -RJ, -ORJ, -N(RJ)2, -NO2, halogênio, -CN, -haloalquila C1-4, -haloalcóxi C1-4, -C(O)N(RJ)2, -NRJC(O)RJ, -SORJ, -SO2RJ, -SO2N(RJ)2, -NRJSO2RJ, -CORJ, -CO2RJ, -NRJSO2N(RJ)2, -COCORJ; RJ é hidrogênio ou alifático C1-6; o é um número inteiro de 0 a 3; Hal é um haleto; e P é um grupo de proteção; d) reação de um composto de fórmula IIID-a em um terceiro solvente orgânico com um composto de fórmula IIIE: em que, independentemente para cada ocorrência: R3 é um alifático C1-6 opcionalmente substituído com OH, OP, -O-alifático C1-6, arila, heteroarila, -O-arila ou -O- heteroarila; na presença de um catalisador para formar um composto de fórmula III: em que, independentemente para cada ocorrência: R2 é -RJ, -ORJ, -N(RJ)2, -NO2, halogênio, -CN, -haloalquila C1-4, -haloalcóxi C1-4, -C(O)N(RJ)2, -NRJC(O)RJ, -SORJ, -SO2RJ, -SO2N(RJ)2, -NRJSO2RJ, -CORJ, -CO2RJ, -NRJSO2N(RJ)2, -COCORJ; RJ é hidrogênio ou alifático C1-6; R3 é alifático C1-6 opcionalmente substituído com OH, OP, -O-alifático C1—6, arila, heteroarila, -O-arila ou -O- heteroarila; P é um grupo de proteção; e o é um número inteiro de 0 a 3; e) reação do composto de fórmula III em um quarto solvente orgânico com um composto de fórmula II: em que, independentemente para cada ocorrência: o anel A é um anel cicloalquila, heterocicloalquila, arila ou heteroarila, o mesmo sendo fundido; Hal é um haleto; R1 é independentemente selecionado de -RJ, -ORJ, -N(RJ)2, -NO2, halogênio, -CN, -haloalquila C1-4, -haloalcóxi C1-4, -C(O)N(RJ)2, -NRJC(O)RJ, -SORJ, -SO2RJ, -SO2N(RJ)2, -NRJSO2RJ, - CORJ, -CO2RJ, -NRJSO2N(RJ)2, -COCORJ; RJ é hidrogênio ou alifático C1-6; m é um número inteiro de 0 a 3 inclusive; e n é um número inteiro de 1 a 4 inclusive; para formar o composto de fórmula IV.[0076] In another aspect, the invention describes a method for preparing a compound of formula IV: wherein, independently for each occurrence: ring A is a cycloalkyl, heterocycloalkyl, aryl or heteroaryl ring, the same being fused; R1 and R2 are independently selected from -RJ, -ORJ, -N(RJ)2, -NO2, halogen, -CN, -C1-4 haloalkyl, -C1-4 haloalkoxy, -C(O)N(RJ)2 , -NRJC(O)RJ, -SORJ, -SO2RJ, -SO2N(RJ)2, -NRJSO2RJ, -CORJ, -CO2RJ, -NRJSO2N(RJ)2, -COCORJ; Rj is hydrogen or C1-6 aliphatic; R3 is a C1-6 aliphatic optionally substituted with OH, OP, -O-C1-6 aliphatic, aryl, heteroaryl, -O-aryl or -O-heteroaryl; P is a protecting group; m is an integer from 0 to 3 inclusive; n is an integer from 1 to 4 inclusive; and o is an integer from 1 to 3 inclusive; comprising the steps of: reacting a compound of formula IIIA: where, independently for each occurrence: R2 is -RJ, -ORJ, -N(RJ)2, -NO2, halogen, -CN, -C1-4 haloalkyl, -C1-4 haloalkoxy, -C(O)N( RJ)2, -NRJC(O)RJ, -SORJ, -SO2RJ, -SO2N(RJ)2, -NRJSO2RJ, -CORJ, -CO2RJ, -NRJSO2N(RJ)2, -COCORJ; Rj is hydrogen or C1-6 aliphatic; and o is an integer from 0 to 3; with a halogenating reagent in a first organic solvent to form a compound of formula IIIB where, independently for each occurrence: R2 is -RJ, -ORJ, -N(RJ)2, -NO2, halogen, -CN, -C1-4 haloalkyl, -C1-4 haloalkoxy, -C(O)N( RJ)2, -NRJC(O)RJ, -SORJ, -SO2RJ, -SO2N(RJ)2, -NRJSO2RJ, -CORJ, -CO2RJ, -NRJSO2N(RJ)2, -COCORJ; Rj is hydrogen or C1-6 aliphatic; o is an integer from 0 to 3; and Hal is a halide; b) reaction of the compound of formula IIIB in a second organic solvent with a compound of formula IIIC: me where: P is a protection group; followed by reduction and acid treatment to form a compound of formula IIID: where: R2 is -RJ, -ORJ, -N(RJ)2, -NO2, halogen, -CN, -C1-4 haloalkyl, -C1-4 haloalkoxy, -C(O)N(RJ)2, - NRJC(O)RJ, -SORJ, -SO2RJ, -SO2N(RJ)2, -NRJSO2RJ, -CORJ, -CO2RJ, -NRJSO2N(RJ)2, -COCORJ; Rj is hydrogen or C1-6 aliphatic; o is an integer from 0 to 3; Hal is a halide; P is a protecting group; and A Θ is an anion; c) neutralizing a compound of formula IIID in the presence of a base to form a compound of formula IIID-a: where: R2 is -RJ, -ORJ, -N(RJ)2, -NO2, halogen, -CN, -C1-4 haloalkyl, -C1-4 haloalkoxy, -C(O)N(RJ)2, - NRJC(O)RJ, -SORJ, -SO2RJ, -SO2N(RJ)2, -NRJSO2RJ, -CORJ, -CO2RJ, -NRJSO2N(RJ)2, -COCORJ; Rj is hydrogen or C1-6 aliphatic; o is an integer from 0 to 3; Hal is a halide; and P is a protecting group; d) reaction of a compound of formula IIID-a in a third organic solvent with a compound of formula IIIE: wherein, independently for each occurrence: R3 is a C1-6 aliphatic optionally substituted with OH, OP, -O-C1-6 aliphatic, aryl, heteroaryl, -O-aryl or -O-heteroaryl; in the presence of a catalyst to form a compound of formula III: where, independently for each occurrence: R2 is -RJ, -ORJ, -N(RJ)2, -NO2, halogen, -CN, -C1-4 haloalkyl, -C1-4 haloalkoxy, -C(O)N( RJ)2, -NRJC(O)RJ, -SORJ, -SO2RJ, -SO2N(RJ)2, -NRJSO2RJ, -CORJ, -CO2RJ, -NRJSO2N(RJ)2, -COCORJ; Rj is hydrogen or C1-6 aliphatic; R3 is C1-6 aliphatic optionally substituted with OH, OP, -O-C1-6 aliphatic, aryl, heteroaryl, -O-aryl or -O-heteroaryl; P is a protecting group; and o is an integer from 0 to 3; e) reaction of the compound of formula III in a fourth organic solvent with a compound of formula II: wherein, independently for each occurrence: ring A is a cycloalkyl, heterocycloalkyl, aryl or heteroaryl ring, the same being fused; Hal is a halide; R1 is independently selected from -RJ, -ORJ, -N(RJ)2, -NO2, halogen, -CN, -C1-4 haloalkyl, -C1-4 haloalkoxy, -C(O)N(RJ)2, - NRJC(O)RJ, -SORJ, -SO2RJ, -SO2N(RJ)2, -NRJSO2RJ, -CORJ, -CO2RJ, -NRJSO2N(RJ)2, -COCORJ; Rj is hydrogen or C1-6 aliphatic; m is an integer from 0 to 3 inclusive; en is an integer from 1 to 4 inclusive; to form the compound of formula IV.
    . Em outra concretização, na fórmula IV, o anel A é .[0077] In another embodiment, the invention describes the above method wherein in formula IV, ring A is selected from . In another embodiment, in formula IV, ring A is .
    [0078] In another embodiment, the invention describes the above method wherein in formula IV, m is 0. In another embodiment, in formula IV, n is 1. In another embodiment, in formula IV, o is 1 and R2 is F .
    [0079] In another embodiment, the invention describes the above method where in formula IV, P is benzyl.
    é OP . Em outra concretização, na fórmula IV, R3 é [0080] In another embodiment, the invention describes the above method where in formula IV, R3 is a C4 aliphatic optionally substituted with OP. In another embodiment, in formula IV, R3 is OP. In another embodiment, in formula IV, R3 is
    m é 0, n é 1, o é 1 e R2 é F, P é benzila, e R3 é Em outra concretização, a invenção descreve o[0081] In another embodiment, the invention describes the above method where in formula IV, ring A is m is 0, n is 1, o is 1 and R2 is F, P is benzyl, and R3 is In another embodiment, the invention describes the
    [0082] In another embodiment, the invention describes the above method where in step a), the halogenating reagent is N-bromosuccinimide.
    [0083] In another embodiment, the invention describes the above method where in step a) the first organic solvent is an aprotic solvent. In another embodiment, in step a), the first organic solvent is selected from 1,2-dimethoxyethane, dioxane, acetonitrile, toluene, benzene, xylenes, methyl t-butyl ether, methyl ethyl ketone, methyl isobutyl ketone, acetone, N, N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidinone, ethyl acetate, dichloromethane, or and dimethylsulfoxide. In another embodiment, in step a) the first organic solvent is ethyl acetate.
    [0084] In another embodiment, the invention describes the above method where step a) is carried out at around 2°C to 42°C. In another embodiment step a) is carried out at around 12°C to 32°C. In another embodiment step a) is carried out around 22°C.
    [0085] In another embodiment, the invention describes the above method where in formula IIIB, o is 1, R2 is F, and Hal is Br.
    [0086] In another embodiment, the invention describes the above method where in formula IIIC, P is benzyl.
    [0087] In another embodiment, the invention describes the above method where in step b), the second organic solvent is an aprotic solvent. In another embodiment, in step b), the second organic solvent is selected from 1,2-dimethoxyethane, dioxane, acetonitrile, toluene, benzene, xylenes, methyl t-butyl ether, methyl ethyl ketone, methyl isobutyl ketone, acetone, N, N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidinone, ethyl acetate, dichloromethane, or and dimethylsulfoxide. In another embodiment, in step b), the second organic solvent is toluene.
    [0088] In another embodiment, the invention describes the above method where in step b) the reaction with a compound of formula IIIC is carried out at around 60°C to 100°C. In another embodiment, in step b) the reaction with a compound of formula IIIC is carried out at around 70°C to 90°C. In another embodiment, in step b) the reaction with a compound of formula IIIC is carried out at around 80°C.
    [0089] In another embodiment, the invention describes the above method where in step b) the reduction is carried out with hydrogen.
    [0090] In another embodiment, the invention describes the above method where in step b) the acid is p-toluenesulfonic acid.
    [0091] In another embodiment, the invention describes the above method where in formula IIID, o is 1, R2 is F, Hal is Br, A- is Tos-, and P is benzyl.
    [0092] In another embodiment, the invention describes the above method where in formula IIIE, R3 is C(CH3)2CH2O(benzyl).
    [0093] In another embodiment, the invention describes the above method where in step c) the base is an inorganic base.
    [0094] In another embodiment, the invention describes the above method where in step c) the base is NaHCO3.
    [0095] In another embodiment, the invention describes the above method where in step d) the third organic solvent is an aprotic solvent. In another embodiment, in step d) the third organic solvent is selected from 1,2-dimethoxyethane, dioxane, acetonitrile, toluene, benzene, xylenes, methyl t-butyl ether, methyl ethyl ketone, methyl isobutyl ketone, acetone, N,N -dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidinone, ethyl acetate, dichloromethane, or and dimethylsulfoxide. In another embodiment, in step d), the third organic solvent is acetonitrile.
    [0096] In another embodiment, the invention describes the above method where step d) is carried out at around 60°C to 100°C. In another embodiment step d) is carried out at around 70°C to 90°C. In another embodiment step d) is carried out around 80°C.
    [0097] In another embodiment, the invention describes the above method where in step d) the catalyst is a palladium catalyst. In another embodiment, in step d) the catalyst is selected from palladium(II) acetate, Pd(dppf)Cl2, Pd(dba)2, tetracis(triphenylphosphine)palladium(0) or and tris(dibenzylideneacetone)dipalladium(0) . In another embodiment, in step d) the catalyst is palladium(II) acetate.
    m é 0, n é 1, e Hal é Cl.[0098] In another embodiment, the invention describes, . method above where in step e), ring A is , m is 0, n is 1, and Hal is Cl.
    [0099] In another embodiment, the invention describes the above method where in step e), the fourth organic solvent is an aprotic solvent. In another embodiment, in step e), the fourth organic solvent is selected from 1,2-dimethoxyethane, dioxane, acetonitrile, toluene, benzene, xylenes, methyl t-butyl ether, methyl ethyl ketone, methyl isobutyl ketone, acetone, N, N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidinone, ethyl acetate, dichloromethane or -e-dimethylsulfoxide. In another embodiment, in step e), the fourth organic solvent is dichloromethane.
    [0100] In another embodiment, the invention describes the above method where step e) is carried out at around -20°C to 20°C. In another embodiment, step e) is carried out at around -10°C to 10°C. In another embodiment, step e) is carried out around 0°C.
    [0101] In another embodiment, the invention describes the above method where in step e) the compound of formula II is prepared in situ by halogenation of the acid precursor and reaction with the compound of formula III without isolation.
    [0102] In another embodiment, the invention describes the above method further comprising removing two protecting groups from the compound of formula IV to form a compound of formula IVA:
    [0103] In another embodiment, the protecting groups are removed by hydrogenation.
    compreendendo as etapas de: reação do composto 2: com um reagente de brominação para formar o composto 3: b) reação do composto 3 com o composto 4: seguido por redução e tratamento com ácido p - toluenosulfônico para formar o composto 5: seguido por neutralização do composto 5 com uma base para fornecer o composto 5a: c) reação do composto 5a com o composto 6: na presença de um catalisador para formar o composto 7: d) reação do composto 7 com o composto 8: para formar o composto 9: e) remoção de dois grupos de proteção Bn para formar o composto 1.[0104] In another aspect, the invention describes a method for preparing Compound 1: comprising the steps of: reaction of compound 2: with a bromination reagent to form compound 3: b) reaction of compound 3 with compound 4: followed by reduction and treatment with p - toluenesulfonic acid to form compound 5: followed by neutralizing compound 5 with a base to provide compound 5a: c) reaction of compound 5a with compound 6: in the presence of a catalyst to form compound 7: d) reaction of compound 7 with compound 8: to form compound 9: e) removal of two Bn protecting groups to form compound 1.
    [0105] In another embodiment, the invention describes the above method where in step a) the brominating agent is N-bromosuccinimide.
    [0106] In another embodiment, the invention describes the above method where in step b), the reduction is carried out with hydrogen.
    [0107] In another embodiment, the invention describes the above method where in step b), the base is an inorganic base.
    [0108] In another embodiment, the invention describes the above method where in step b), the base is NaHCO3.
    [0109] In another embodiment, the invention describes the above method where in step c), the catalyst is a palladium catalyst. In another embodiment, in step c), the catalyst is selected from palladium(II) acetate, Pd(dppf)Cl2, Pd(dba)2, tetracis(triphenylphosphine)palladium(0) or and tris(dibenzylideneacetone)dipalladium(0) ). In another embodiment, in step c), the catalyst is palladium(II) acetate.
    [0110] In another embodiment, the invention describes the above method where in step d), compound 8 is obtained in situ by halogenation of the acid precursor without isolation.
    [0111] In another embodiment, the invention describes the above method where in step e), the protecting groups Bn are removed by hydrogenation.
    em que: o anel A é um anel cicloalquila, heterocicloalquila, arila ou heteroarila, o mesmo sendo fundido; R1 é independentemente selecionado de -RJ, -ORJ, -N(RJ)2, -NO2, halogênio, -CN, -haloalquila C1-4, -haloalcóxi C1-4, -C(O)N(RJ)2, -NRJC(O)RJ, -SORJ, -SO2RJ, -SO2N(RJ)2, -NRJSO2RJ, - CORJ, -CO2RJ, -NRJSO2N(RJ)2, -COCORJ; RJ é hidrogênio ou alifático C1-6; X é CN ou CO2R; R é alifático C1-6 ou arila; e m é um número inteiro de 0 a 3 inclusive.[0112] In another aspect, the invention describes a compound of formula 23: wherein: ring A is a cycloalkyl, heterocycloalkyl, aryl or heteroaryl ring, the same being fused; R1 is independently selected from -RJ, -ORJ, -N(RJ)2, -NO2, halogen, -CN, -C1-4 haloalkyl, -C1-4 haloalkoxy, -C(O)N(RJ)2, - NRJC(O)RJ, -SORJ, -SO2RJ, -SO2N(RJ)2, -NRJSO2RJ, -CORJ, -CO2RJ, -NRJSO2N(RJ)2, -COCORJ; Rj is hydrogen or C1-6 aliphatic; X is CN or CO2R; R is C1-6 aliphatic or aryl; em is an integer from 0 to 3 inclusive.
    Em outra concretização, o anel A é [0113] In another embodiment, the invention describes a compound of formula 23 and the present definitions, wherein ring A is heterocycloalkyl or fused heteroaryl. In another embodiment, ring A is selected fromIn another embodiment, ring A is
    [0114] In another embodiment, the invention describes a compound of formula 23 and the present definitions, where X is CN. In another embodiment X is CO2Et.
    [0115] In another embodiment, the invention describes a compound of formula 23 and the present definitions, where m is 0.
    [0116] In another embodiment, the invention describes a compound of formula 23 and the present definitions, where RJ is C1-6 aliphatic. In another embodiment, RJ is -CH2CH3.
    composto[0117] In another aspect, the invention describes the compound
    composto[0118] In another aspect, the invention describes the compound Methods for Preparation of Compounds of Formulas I, II, III and IV
    a = catalisador Pd(0); b = ácido; c = base; d = base hidróxido; e = ácido; f = agente de halogenação; em que o anel A, R1, m, X, RJ, Hal, q, e n são como definidos acima.[0119] Compounds of formulas I, II, III, and IV can be prepared by the methods of Schemes 1-3. Scheme 1. Compounds of formula I and II. a = Pd(0) catalyst; b = acid; c = base; d = hydroxide base; e = acid; f = halogenating agent; wherein ring A, R1, m, X, RJ, Hal, q, n are as defined above.
    [0120] In Scheme 1, the aryl halide IA reacts with the ester IB in the presence of a transition metal catalyst, in a suitable solvent (eg, toluene) to produce the ester IC. In esters IB and IC, X can be either CN or CO2R. Treatment of IC with an acid in a suitable solvent (eg, dimethylsulfoxide (DMSO)) produces I. Reaction of I with the dihalide IID in the presence of base gives the cycloalkylidene IIE. Hydrolyzing the remaining cyanide or ester group, depending on the identity of X, provides the carboxylic acid IIF, which is halogenated to provide the acid halide II.
    [0121] In one embodiment, AI is commercially available. In one embodiment, ring A is a 5-membered dioxy ring. In one embodiment, Hal in IA is Br. In one embodiment, the reaction of IA and IIB is carried out in toluene, in the presence of a Pd(0) catalyst, e.g., Pd(dba)2. In a further embodiment, the reaction takes place in the presence of an alkyl phosphine, eg t-Bu3P and phosphate salt, eg Na3PO4. In another embodiment, the reaction of IA and IIB takes place at about 70°C. In another embodiment, RJ is Et.
    [0122] In one embodiment, the deesterification of IC in I is performed with an inorganic acid. In a further embodiment, the inorganic acid is HCl. Conversion is carried out in an appropriate aprotic solvent (eg DMSO) at about 75°C.
    [0123] In one embodiment, I reacts with NaOH and an alkyl dihalide to yield the cycloalkylidene in a suitable solvent (eg, MTBE). The process is adaptable to various spirocyclic rings by choosing the appropriate alkyl dihalide. For example, a spirocyclic butane ring can be produced by reacting I with, for example, 1-bromo-3-chloropropane. A mixed bromine and chlorine dihalide has been found to work best on an economic scale, as the thermodynamics of the reaction are believed to be more favorable.
    [0124] In one embodiment, IIE is hydrolyzed to the carboxylic acid IIF, in the presence of water and a base (eg NaOH) in a suitable solvent (eg ethanol). Subsequent treatment with an acid, such as HCl, yields IIF. In another embodiment, IIF is obtained by recrystallization from toluene.
    [0125] In one embodiment, the halogenating agent that converts IIF to II is thionyl chloride. In another embodiment, thionyl chloride is added to IIF in toluene at about 60°C. In one embodiment, this step directly precedes the coupling between II and amine III (see below) and is carried out in the same reaction vessel.
    a = agente de halogenação, b = catalisador Zn (II), c = H2, Pt; d = ácido; e = base; f = catalisador de Pd(II); em que R2, o, Hal, Aθ, e P são definidos como acima.[0126] There are several non-limiting advantages to forming II according to Scheme 1 and the embodiments described above and elsewhere in the application. These advantages are even more apparent when producing II on an economic scale and include the following. The overall reaction requires only 5 steps, which is less than what was previously reported (ie from an aryl carboxylic acid, which is reduced to methyl alcohol, which is converted to a methyl chloride, which reacts with NaCN). This synthetic route introduces the CN or ester group (ie X) without a separate chlorination reaction. Using ethanol as a co-solvent in the hydrolysis of IIE to IIF results in a homogeneous reaction mixture making sampling and monitoring the reaction easier. Recrystallization of IIF from toluene eliminates the need for formation of a dicyclohexylamine (DCA) salt, as previously reported. Scheme 2. Compounds of formula III. a = halogenating agent, b = Zn(II) catalyst, c = H2, Pt; d = acid; e = base; f = Pd(II) catalyst; where R2, o, Hal, A', and P are defined as above.
    [0127] In one embodiment, in IIIA, R2 is F and is meta to the amino group. In another embodiment, IIIA is brominated with N-bromosuccinimide in a suitable solvent (eg, ethyl acetate) at about 22°C.
    [0128] In another embodiment, IIIB reacts with the epoxide IIIC effecting a ring opening reaction with the amine group of IIIB to form IIID. In one embodiment, the protecting group, P, in IIIC is benzyl (Bn). In another embodiment, the IIIC epoxide is chiral. In one embodiment, IIIC is (R)IIIC. In another embodiment, IIIC is (S)IIIC. In one embodiment, the ring opening reaction is carried out in a suitable solvent (eg, toluene) at about 80°C. In another embodiment, the ring opening reaction is carried out in the presence of a Zn(II) catalyst (for example, Zn(ClO4)2). In another embodiment, converting IIIB to IIID comprises ring opening reaction with the epoxide IIIC, followed by hydrogenation and then treatment with an acid to form IIID. In another embodiment, the hydrogenation is carried out with H2/Pt(S)/C. In a further embodiment, the acid is toluene sulfonic acid, such that Aθ is a tosylate anion.
    [0129] In another embodiment, the IIIE alkyne is coupled with IIID-a in a suitable solvent (eg, acetonitrile) at about 80°C. In another embodiment, the coupling reaction is carried out in the presence of a Pd(II) catalyst, such as Pd(OAc)2. The initial reaction does not result in ring closure, only the replacement of the halide in IIID. Ring closure is accomplished by reaction with another Pd(II) catalyst, such as (MeCN)2PdCl2 in a suitable solvent (eg, acetonitrile). In one embodiment, ring closure is performed at about 80°C. In one embodiment, R3 in alkyne IIIE is -C(CH3)2CH2OBn. In one embodiment, the product of the coupling reaction is not isolated, but taken up in acetonitrile and put to react with (MeCN)2PdCl2.
    a=agentedehalogenação, b=solventeaprótico; em que o anel A, R1, m, n, hal, R2, o, P, e R3 são como definidos acima.[0130] There are several non-limiting advantages to forming compound III, in accordance with Scheme 2 and the embodiments described above and elsewhere in the application. These advantages are even more apparent when producing III on an economic scale and include the following. The total number of steps has been reduced compared to what was previously released to just 3 steps. Other advantages include the elimination of chromatography and protecting group by-products. Scheme 3. Compounds of Formula IV. a=halogenation agent, b=aprotic solvent; wherein ring A, R1, m, n, hal, R2, o, P, and R3 are as defined above.
    [0131] An acid-base reaction between II and III in a suitable solvent (eg, dichloromethane (DCM)) produces the protected analogue of Compound 1. In one embodiment, the acid halide II is prepared from IIF, as depicted in Scheme 1, in the same reaction vessel and is not isolated. In another embodiment, the acid-base reaction is carried out in the presence of a base such as triethylamine (TEA). In one embodiment, the amount of TEA is 2 equivalents with respect to II. In one embodiment, after a reaction time of about 4 hours at about 0°C and warming to room temperature overnight, water is added to the mixture and stirred for a further 30 minutes. The organic phase is separated and IV is isolated by distilling off the reaction solvent. In one embodiment, IV is collected by silica block filtration.
    em que o anel A, R1, m, n, R2, o, R3 e P são como definidos acima.[0132] In another embodiment, compounds of formula IV can be deprotected to form compounds of formula IVa according to Scheme 4. Scheme 4. Deprotection of Compounds of Formula IV. wherein ring A, R1, m, n, R2, o, R3 and P are as defined above.
    [0133] In one embodiment, the pressurization of hydrogen is 3 Bar (300,000 Pa). In another embodiment, the hydrogenation agitation speed is increased to 800 rpm. In another embodiment, after decreasing rapid hydrogen absorption, the hydrogenation vessel is heated to about 50°C for 2 days. In another embodiment, after the 2 days, more catalyst is added and hydrogenation continues for another 4 days. In another embodiment, IV is dissolved in a suitable solvent (eg, THF).
    [0134] In another embodiment, Compound 1 can be prepared by coupling the 7-8 portion of the acid halide with the 7-8 portion of the amine to form compound 9, followed by deprotection, according to Scheme 5. 5: Preparation of Compound 1
    [0135] Wherein Compound 78 is prepared according to Scheme 6. Scheme 6.
    [0136] Wherein Compound 8 is prepared according to Scheme 7. Scheme 7. Uses, Formulation and Administration Pharmaceutically acceptable compositions
    [0137] In another aspect of the present invention, pharmaceutically acceptable compositions are provided, wherein these compositions comprise Compound 1 Form A or Compound 1 amorphous as described herein and optionally comprise a pharmaceutically acceptable carrier, adjuvant or vehicle . In certain embodiments, these compositions optionally further comprise one or more additional therapeutic agents.
    [0138] As described above, the pharmaceutically acceptable compositions of the present invention further comprise a pharmaceutically acceptable carrier, adjuvant or vehicle which, as used herein, includes any and all solvents, diluents, or other liquid vehicle, dispersion adjuvants or suspending agents, surface active agents, isotonic agents, thickeners or emulsifiers, preservatives, solid binders, lubricants and the like, as appropriate for the particular dosage form desired. Remington's Pharmaceutical Sciences, Sixteenth Edition, E.W. Martin (Mack Publishing Co., Easton, Pa., 1980) discloses various carriers used in formulating pharmaceutically acceptable compositions and known techniques for preparing the same. Except to the extent that any conventional carrier medium is incompatible with the compounds of the present invention, such as by producing any undesirable biological effect or otherwise by adversely interacting with any other component(s) of the composition pharmaceutically acceptable, its use is contemplated to be within the scope of the present invention. Some examples of materials that can serve as pharmaceutically acceptable carriers include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins such as human plasma albumin, buffer substances such as phosphates, glycine, sorbic acid, or potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, silica colloidal, magnesium trisilicate, polyvinylpyrrolidone, polyacrylates, waxes, polyethylene-polyoxypropylene block polymers, lanolin, sugars such as lactose, glucose and sucrose; starches such as corn starch and potato starch; cellulose and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; powdered tragacanth; malt; gelatin; baby powder; excipients such as cocoa butter and suppository waxes; oils such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; glycols such as propylene glycol or polyethylene glycol; esters such as ethyl oleate and ethyl laurate; agar; buffering agents such as magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen-free water; isotonic saline; Ringer's solution; ethyl alcohol and phosphate buffer solutions, as well as other compatible non-toxic lubricants such as sodium lauryl sulfate and magnesium stearate, as well as coloring agents, release agents, coating agents, sweeteners, flavors and perfumes, preservatives and antioxidants can also be present in the composition, according to the judgment of the formulator. Uses of Pharmaceutically Acceptable Compounds and Compositions
    [0139] In yet another aspect, the present invention provides a method of treating a condition, disease or disorder implicated by CFTR. In certain embodiments, the present invention provides a method of treating a condition, disease or disorder implicated by a deficiency of CFTR activity, the method comprising administering a composition comprising a Compound 1 described herein to a subject, preferably a mammal in need of it.
    [0140] A "CFTR-mediated disease" as used herein is a disease selected from cystic fibrosis, asthma, smoke-induced COPD, chronic bronchitis, rhinosinusitis, constipation, pancreatitis, pancreatic insufficiency, male infertility caused by congenital bilateral absence of the vas deferens (CBAVD), mild pulmonary disease, idiopathic pancreatitis, allergic bronchopulmonary aspergillosis (ABPA), liver disease, hereditary emphysema, hereditary hemochromatosis, coagulation-fibrinolysis deficiencies such as protein C deficiency, hereditary angioedema type 1 , lipid processing deficiencies such as familial hypercholesterolemia, Type 1 chylomicronemia, abetalipoproteinemia, lysosomal storage disorders such as cell I/pseudo-Hurler disease, mucopolysaccharidoses, Sandhoff/Tay-Sachs, Crigler-Najjar syndrome type II, polyendocrinopathy /hyperinsulemia, Diabetes mellitus, Laron's dwarfism, myeloperoxidase deficiency, hi primary poparathyroidism, melanoma, type 1 CDG glycanosis, congenital hyperthyroidism, osteogenesis imperfecta, hereditary hypofibrinogenemia, ACT deficiency, Diabetes insipidus (DI), neurohypophyseal DI, neurogenic nephrogenic DI, Charcot-Marie Tooth syndrome, Perlizaeus-Merzbacher disease, neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, progressive supranuclear plasia, Pick's disease, various polyglutamine neurological disorders such as Huntington, type I spinocerebuelar ataxia, bulbar and spinal muscular atrophy, dentatorubro-palidolusian and myotonic dystrophy, as well as spongiform encephalopathies such as hereditary Creutzfeldt-Jakob disease (due to prion protein processing defect), Fabry disease, Straussler-Scheinker syndrome, COPD, dry eye disease, or Sjogren's disease, osteoporosis, osteopenia, bone healing and bone growth (including bone repair, to regenerate bone action, reduced bone resorption and increased bone deposition), Gorham's syndrome, chloride channelopathies such as congenital myotonia (Thomson and Becker forms), type III Bartter syndrome, Dent's disease, hypereplexia, epilepsy, disease of lysosomal storage, Angelman syndrome, and primary ciliary dyskinesia (PCD), a term for inherited disorders of cilia structure and/or function, including PCD with situs inversus (also known as Kartagener syndrome), PCD without situs inversus, and aplasia ciliary In another embodiment, the CFTR-mediated disease is cystic fibrosis, emphysema, COPD or osteoporosis. In another embodiment, the CFTR-mediated disease is cystic fibrosis.
    [0141] In certain embodiments, the present invention provides a method of treating a CFTR-mediated disease in a human, comprising the step of administering to said human an effective amount of a composition comprising Compound 1 described herein.
    [0142] According to the invention, an "effective amount" of Compound 1 Form A or amorphous Compound 1 or a pharmaceutically acceptable composition thereof is the amount effective to treat or lessen the severity of any of the aforementioned diseases.
    [0143] Compound 1 or a pharmaceutically acceptable composition thereof may be administered using any amount and any route of administration effective for treating or lessening the severity of one or more of the aforementioned diseases.
    [0144] In certain embodiments, Compound 1 described herein or a pharmaceutically acceptable composition thereof is useful for treating or lessening the severity of cystic fibrosis in patients who exhibit residual CFTR activity in the apical membrane of the respiratory and non-respiratory epithelium. The presence of residual CFTR activity on the epithelial surface can be readily detected using methods known in the art, for example, standard electrophysiological, biochemical or histochemical techniques. Such methods identify CFTR activity using in vivo or ex vivo electrophysiological techniques, measurement of Cl- concentration in sweat or saliva, or ex vivo biochemical or histochemical techniques to monitor cell surface density. Using such methods, residual CFTR activity can be readily detected in patients heterozygous or homozygous for a variety of different mutations, including patients homozygous or heterozygous for the most common mutation, ΔF508.
    [0145] In one embodiment, Compound 1 described herein or a pharmaceutically acceptable composition thereof is useful for treating or lessening the severity of cystic fibrosis in patients within certain genotypes that exhibit residual CFTR activity, e.g. class III (poor regulation or opening), class IV mutations (altered conductance), or class V mutations (reduced synthesis) (Lee R. Choo-Kang, Pamela L., Zeitlin, Type I, II, III, IV, and V cystic fibrosis Tansmembrane Conductance Regulator Defects and Opportunities of Therapy; Current Opinion in Pulmonary Medicine 6:521-529, 2000). Genotypes from other patients who exhibit residual CFTR activity include patients homozygous for one of these classes or heterozygous for any other class of mutations, including class I mutations, class II mutations, or a mutation that has no classification.
    [0146] In one embodiment, Compound 1 as described herein, or a pharmaceutically acceptable composition thereof, is useful for treating or lessening the severity of cystic fibrosis in patients within certain clinical phenotypes, e.g., clinical phenotype moderate to mild which typically correlates with the amount of residual CFTR activity in the apical membrane of the epithelium. Such phenotypes include patients exhibiting pancreatic insufficiency or patients diagnosed with idiopathic pancreatitis and congenital bilateral absence of the vas deferens or mild pulmonary disease.
    [0147] The exact amount required will vary from individual to individual depending on the species, age and general condition of the individual, the severity of the infection, the particular agent, its mode of administration and the like. The compounds of the present invention are preferably formulated in dosage unit form for ease of administration and uniformity of dosage. The term "unit dosage form" as used herein refers to a physically separate unit of the agent appropriate for the patient to be treated. It should be understood, however, that the total daily usage of the compounds and compositions of the present invention will be decided by the attending physician within the scope of good medical judgment. The specific level of effective dose for any particular patient or organism will depend on a variety of factors, including the disorder being treated and the severity of the illness, the activity of the specific compound employed, the specific composition used, age, body weight, health general, sex and diet of the patient, the time of administration, route of administration and excretion rate of the specific compound employed; duration of treatment; drugs used in combination or coincidental with the specific compound employed and similar factors well known in the medical art. The term "patient" or "individual" as used herein means an animal, preferably a mammal, and more preferably a human being.
    [0148] The pharmaceutically acceptable compositions of the present invention can be administered to humans and other animals orally, rectally, parenterally, intracisternally, intravaginally, intraperitoneally, topically (as powders, ointments or drops), buccally, as an oral spray or nasal, or the like, depending on the severity of the infection being treated. In certain embodiments, the compounds of the present invention can be administered orally or parenterally at dosage levels of from about 0.01 mg/kg to about 50 mg/kg and preferably from about 1 mg/kg to about 25 mg /kg of subject's body weight per day, one or more times a day, to obtain the desired therapeutic effect.
    In certain embodiments, the dosage amount of Compound 1 in unit dosage form is from 100 mg to 1000 mg. In another embodiment, the dosage amount of Compound 1 is 200 mg to 900 mg. In another embodiment, the dosage amount of Compound 1 is from 300 mg to 800 mg. In another embodiment, the dosage amount of Compound 1 is 400 mg to 700 mg. In another embodiment, the dosage amount of Compound 1 is 500 mg to 600 mg.
    [0150] Injectable preparations, eg aqueous or oleaginous sterile injectable suspensions may be formulated according to the known art using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation may also be a sterile injectable solution, suspension or emulsion in a non-toxic parenterally acceptable diluent or solvent, for example, as a solution in 1,3-butanediol. Among the acceptable vehicles and solvents that may be employed are water, Ringer's solution, and USP and isotonic sodium chloride solution. Furthermore, sterile fixed oils are conventionally employed as a solvent or suspending medium. For this purpose any bland fixed oil can be used, including synthetic mono- or diglycerides. Also, fatty acids such as oleic acid are used in the preparation of injectables.
    [0151] Injectable formulations can be sterilized, for example, by filtration through a bacterial retention filter, or by incorporating sterilizing agents in the form of sterile solid compositions that can be dissolved or dispersed in sterile water or other sterile injectable medium before of use.
    Compositions for rectal or vaginal administration are preferably suppositories which can be prepared by mixing the compounds of this invention with suitable non-irritating excipients or vehicles, such as cocoa butter, polyethylene glycol or a suppository wax, which are solid at room temperature, however liquids at body temperature and therefore melt in the rectum or vaginal cavity and release the active compound.
    [0153] Solid dosage forms for oral administration include capsules, tablets, pills, powders and granules. In such solid dosage forms, the active compound is mixed with at least one inert, pharmaceutically acceptable excipient or carrier such as sodium citrate or dicalcium phosphate and/or a) fillers or extenders such as starches, lactose, sucrose, glucose , mannitol, and silicic acid, b) binders such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose and acacia, c) humectants such as glycerol, d) disintegrating agents such as agar-agar, carbonate calcium, tapioca or potato starch, alginic acid, certain silicates and sodium carbonate, e) solution retarding agents, such as paraffin, f) absorption accelerators, such as quaternary ammonium compounds, g) wetting agents, such as , for example, cetyl alcohol and glycerol monostearate, h) absorbents such as kaolin and bentonite clay, and i) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, lauryl sulfa sodium and mixtures thereof. In the case of capsules, tablets and pills, the dosage form can also comprise buffering agents.
    [0154] Solid compositions of a similar type can also be employed as fillers in soft and hard gelatine capsules using excipients such as lactose or milk sugar as well as high molecular weight polyethylene glycols and the like. Solid dosage forms of tablets, pills, capsules, pills, and granules can be prepared with coatings and shells, such as enteric coatings and other coatings well known in the pharmaceutical formulating art. They may optionally contain opacifying agents and may also be of a composition that they release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner. Examples of embedding compositions which can be used include polymeric substances and waxes. Solid compositions of a similar type can also be employed as fillers in soft and hard gelatine capsules using excipients such as lactose or milk sugar as well as high molecular weight polyethylene glycols and the like.
    [0155] The active compounds can also be in microencapsulated form with one or more excipients, as noted above. Solid dosage forms of tablets, pills, capsules, pills and granules can be prepared with coatings and shells, such as enteric coatings, controlled release coatings and other coatings well known in the pharmaceutical formulation art. In such solid dosage forms, the active compound can be mixed with at least one inert diluent such as sucrose, lactose or starch. Such dosage forms may also comprise, as is normal practice, additional substances in addition to inert diluents, for example, compression lubricants and other compression aids, such as magnesium stearate and microcrystalline cellulose. In the case of capsules, tablets and pills, the dosage forms can also comprise buffering agents. They may optionally contain opacifying agents and may also be of a composition that they release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner. Examples of embedding compositions which can be used include polymeric substances and waxes.
    [0156] It will also be appreciated that Compound 1 described herein or a pharmaceutically acceptable composition thereof may be used in combination therapies, i.e. Compound 1 may be administered concurrently with, prior to, or subsequent to one or more other desired therapeutic or medical procedures. The particular combination of therapies (therapeutics or procedures) to be employed in a combined regimen will take into account the compatibility of the desired therapies and/or procedures and the desired therapeutic effect to be achieved. It will also be appreciated that the therapies used may achieve a desired effect for the same disorder (eg, a compound of the invention may be administered concurrently with another agent used to treat the same disorder), or may achieve different effects (eg, control of any adverse effects). As used herein, additional therapeutic agents that are normally administered to treat or prevent a particular disease or condition are known as "appropriate for the disease or condition being treated".
    [0157] In one embodiment, the additional therapeutic agent is selected from a mucolytic agent, bronchodilator, an antibiotic, an anti-infective agent, an anti-inflammatory agent, a CFTR modulator that is not a compound of the present invention,—or and a nutritional agent.
    [0158] In one embodiment, the additional therapeutic agent is an antibiotic. Exemplary antibiotics useful herein include tobramycin, including tobramycin inhaled powder (TIP), azithromycin, aztreonam, including the aerosol form of aztreonam, amikacin, including liposomal formulations thereof, ciprofloxacin, including formulations thereof suitable for administration by inhalation, levoflaxacin, including aerosol formulations thereof, and combinations of two antibiotics, eg fosfomycin and tobramycin.
    [0159] In another embodiment, the additional agent is a mucolytic. Exemplary mucolytics useful herein include Pulmozyme®.
    [0160] In another embodiment, the additional agent is a bronchodilator. Exemplary bronchodilators include albuterol, metaprotenerol sulfate, pirbuterol acetate, salmeterol, or tetrabulin sulfate.
    [0161] In another embodiment, the additional agent is effective in restoring fluid from the surface of the lung airways. Such agents improve the movement of salt in and out of cells, allowing mucus in the lung's airways to be more hydrated and therefore more easily cleared. Examples of such agents include hypertonic saline, tetrasodium denufosol ([[(3S,5R)-5-(4-amino-2-oxo pyrimidin-1-yl)-3-hydroxyoxolan-2-yl]methoxy-hydroxy phosphoryl][ [[(2R,3S,4R,5R)-5-(2,4-dioxopyrimidin-1-yl)-3,4-dihydroxyoxolan-2-yl]methoxyhydroxyphosphoryl]oxyhydroxyphosphoryl]hydrogenphosphate), or bronchitol (inhaled formulation of mannitol).
    [0162] In another embodiment, the additional agent is an anti-inflammatory agent, that is, an agent that can reduce inflammation in the lungs. Examples of such agents useful herein include ibuprofen, docosahexanoic acid (DHA), sildenafil, inhaled glutathione, pioglitazone, hydroxychloroquine or simvastatin.
    [0163] In another embodiment, the additional agent is a CFTR modulator other than Compound 1, that is, an agent that has the effect of modulating CFTR activity. Examples of such agents include ataluren ("PTC124®"; 3-[5-(2-fluorophenyl)-1,2,4-oxadiazol-3-yl]benzoic acid), sinapultide, lancovutide, depelestat (an inhibitor of elastase of recombinant human neutrophil), cobiprostone (7-{(2R,4aR,5R,7aR)-2-[(3S)-1,1-difluoro-3-methylpentyl]-2-hydroxy-6-oxooctahydrocyclopenta[b]pyran acid -5-yl}heptanoic) and N-(5-hydroxy-2,4-ditert-butyl-phenyl)-4-oxo-1H-quinoline-3-carboxamide.
    [0164] In another embodiment, the additional agent is a nutritional agent. Examples of nutritional agents include pancrelipase (pancreatic enzyme replacement), including Pancrease®, Pancreacarb®, Ultrase®, or Creon®, Liprotomase® (formerly Trizytek®), Aquadeks®, or glutathione inhalation. In one embodiment, the additional nutritional agent is pancrelipase.
    [0165] In another embodiment, the additional agent is a compound selected from gentamicin, curcumin, cyclophosphamide, 4-phenylbutyrate, miglustat, felodipine, nimodipine, Filoxin B, genistein, apigenin, cAMP/cGMP modulators such as rolipram, sildenafil, milrinone, tadalafil, amrinone, isoproterenol, albuterol and almeterol, deoxyspergualin, HSP 90 inhibitors, HSP 70 inhibitors, proteosome inhibitors such as epoxomicin, lactacystin, etc.
    [0166] In another embodiment, the additional agent is a compound disclosed in WO 2004028480, WO 2004110352, WO 2005094374, WO 2005120497, or WO 2006101740.
    [0167] In another embodiment, the additional agent is a benzo[c]quinolizinium derivative that exhibits CFTR modulating activity or a benzopyran derivative that exhibits CFTR modulating activity.
    [0168] In another embodiment, the additional agent is a compound disclosed in US 7,202,262, US 6,992,096, US20060148864, US20060148863, US20060035943, US20050164973, WO2006110483, WO2006044456, WO2006044682, WO2006044505, WO2006044503, WO2006044502, or WO20041502.
    [0169] In another embodiment, the additional agent is a compound disclosed in WO2004080972, WO2004111014, WO2005035514, WO2005049018, WO2006099256, WO2006127588, or WO2007044560.
    [0170] These combinations are useful for treating the diseases described herein, including cystic fibrosis. These combinations are also useful in the kits described in this document.
    [0171] The amount of additional therapeutic agent present in the compositions of this invention will be no more than an amount that would normally be administered in a composition comprising this therapeutic agent as the only active agent. Preferably, the amount of additional therapeutic agent in the compositions disclosed herein will range from about 50% to 100% of the amount normally present in a composition comprising that agent as the only therapeutically active agent.
    [0172] In order that the invention described in this document may be more fully understood, the following examples are presented. It is to be understood that these examples are for illustrative purposes only and are not to be considered as limiting the invention in any way. EXAMPLES Methods and Materials
    [0173] Vitride® (bis(2-methoxyethoxy)aluminum hydride (or NaAlH2(OCH2CH2OCH3)2], 65% by weight solution in toluene) was purchased from Aldrich Chemicals. 3-Fluoro-4-nitroaniline was purchased from Capot Chemicals. 5-Bromo-2,2-difluoro-1,3-benzodioxol was purchased from Alfa Aesar. 2,2-Difluoro-1,3-benzodioxol-5-carboxylic acid was purchased from Saltigo (an affiliate of Lanxess Corporation).
    [0174] In any part of the present application where a name of a compound may not correctly describe the structure of the compound, the structure supersedes the name and will govern. Synthesis of Compound 1 Acid Fraction Synthesis of (2,2-difluoro-1,3-benzodioxol-5-yl)-1-ethyl acetate-acetonitrile
    [0175] A reactor was purged with nitrogen and charged with 900 mL of toluene. The solvent was degassed with a nitrogen sparge for not less than 16 hours. To the reactor was then charged Na3PO4 (155.7g, 949.5mmol), followed by bis(dibenzylideneacetone)palladium(0) (7.28g, 12.66mmol). A 10% w/w solution of t-butylphosphine in hexanes (51.23 g, 25.32 mmol) was charged for 10 min. at 23°C from a nitrogen purged addition funnel. The mixture was allowed to stir for 50 minutes, at which time 5-bromo-2,2-difluoro-1,3-benzodioxol (75 g, 316.5 mmol) was added over 1 minute. After stirring for an additional 50 minutes, the mixture was charged with ethyl cyanoacetate (71.6 g, 633.0 mmol) for 5 min followed by water (4.5 mL) in one portion. The mixture was heated at 70°C for 40 minutes and analyzed by HPLC every 1 to 2 hours for percentage conversion of reagent to product. After complete conversion was observed (typically 100% conversion after 5 to 8 hours), the mixture was cooled to 20-25°C and filtered through a pad of celite. The celite pad was rinsed with toluene (2 X 450 mL) and the combined organics were concentrated to 300 mL under vacuum at 60-65°C. The concentrate was charged with 225 mL of DMSO and concentrated under vacuum at 70-80°C until active solvent distillation ceased. The solution was cooled to 20-25°C and diluted to 900 mL with DMSO in preparation for Step 2. 1H NMR (500 MHz, CDCl3) δ 7.16 — 7.10 (m, 2H), 7.03 ( d, J = 8.2 Hz, 1H), 4.63 (s, 1H), 4.19 (m, 2H), 1.23 (t, J = 7.1 Hz, 3H). Synthesis of (2,2-difluoro-1,3-benzodioxol-5-yl)-acetonitrile
    [0176] The DMSO solution of (2,2-difluoro-1,3-benzodioxol-5-yl)-1-ethylacetate-acetonitrile from the above step was charged with 3N HCl (617.3 mL, 1.85 mol) for 20 min while maintaining an internal temperature < 40°C. The mixture was then heated at 75°C for 1 hour and analyzed by HPLC every 1 to 2 hours for percent conversion. When >99% conversion was observed (typically after 5 to 6 hours), the reaction was cooled to 20-25°C and extracted with MTBE (2 X 525 mL), with sufficient time to allow complete phase separation during the extractions. The combined organic extracts were washed with 5% NaCl (2 X 375 mL). The solution was then transferred to appropriate equipment for vacuum distillation at 1.5-2.5 Torr (199.9333.3 Pa), which was equipped with a cooled receiving flask. The solution was concentrated under vacuum at <60°C to remove solvents. (2,2-Difluoro-1,3-benzodioxol-5-yl)-acetonitrile was then distilled from the resulting oil at 125-130°C (oven temperature) and 1.5-2.0 Torr (199, 9-266.6 Pa). (2,2-Difluoro-1,3-benzodioxol-5-yl)-acetonitrile was isolated as a clear oil in 66% yield from 5-bromo-2,2-difluoro-1,3-benzodioxol (2 steps) and with an HPLC purity of 91.5% ASC (corresponds to the 95% w/w assay). 1H NMR (500 MHz, DMSO) δ 7.44 (br s, 1H), 7.43 (d, J = 8.4 Hz, 1H), 7.22 (dd, J = 8.2, 1.8 Hz, 1H), 4.07 (s, 2H). Synthesis of (2,2-difluoro-1,3-benzodioxol-5-yl)-cyclopropanecarbonitrile
    [0177] A 50% w/w NaOH stock solution was degassed via nitrogen injection for not less than 16 hours. An appropriate amount of MTBE was similarly degassed for several hours. To a nitrogen purged reactor was charged degassed MTBE (143 mL) followed by (2,2-difluoro-1,3-benzodioxol-5-yl)-acetonitrile (40.95 g, 207.7 mmol) and tetrabutylammonium bromide (2.25 g, 10.38 mmol). The volume of the mixture was observed and the mixture was degassed via nitrogen injection for 30 min. Sufficiently degassed MTBE is loaded to bring the mixture to its original volume prior to degassing. To the stirred mixture at 23.0°C was charged 50% w/w degassed NaOH (143 mL) over 10 minutes, followed by 1-bromo-2-chloroethane (44.7 g, 311.6 mmol) for 30 minutes. The reaction was analyzed by HPLC at 1 hour intervals for percentage conversion. Before sampling, stirring was stopped and the phases were allowed to separate. The upper organic phase was sampled for analysis. When percentage conversion >99% was observed (typically after 2.5-3 hours), the reaction mixture was cooled to 10°C and charged with water (461 mL) at such a rate as to maintain a temperature < 25 °C. The temperature was adjusted to 20 - 25°C and the phases were separated. Note: Sufficient time must be allowed for complete phase separation. The aqueous phase was extracted with MTBE (123 ml) and the combined organic phase was washed with 1N HCl (163 ml) and 5% NaCl (163 ml). A solution of (2,2-difluoro-1,3-benzodioxol-5-yl)-cyclopropanecarbonitrile in MTBE was concentrated to 164 ml under vacuum at 40-50°C. The solution was charged with ethanol (256 ml) and again concentrated to 164 ml under vacuum at 50-60°C. Ethanol (256 ml) was charged and the mixture was concentrated to 164 ml under vacuum at 50-60°C. The resulting mixture was cooled to 20 - 25°C and diluted with ethanol to 266 mL in preparation for the next step. 1H NMR (500 MHz, DMSO) δ 7.43 (d, J = 8.4 Hz, 1H), 7.40 (d, J = 1.9 Hz, 1H), 7.30 (dd, J = 8 .4, 1.9 Hz, 1H), 1.75 (m, 2H), 1.53 (m, 2H). Synthesis of 1-(2,2-difluoro-1,3-benzodioxol-5-yl)-cyclopropanecarboxylic acid
    [0178] The solution of (2,2-difluoro-1,3-benzodioxol-5-yl)-cyclopropanecarbonitrile in ethanol from the previous step was charged with 6N NaOH (277 mL) over 20 minutes and heated to an internal temperature 77-78°C over 45 minutes. Reaction progress was monitored by HPLC after 16 hours. Note: The consumption of both (2,2-difluoro-1,3-benzodioxol-5-yl)-cyclopropanecarbonitrile and the primary amide resulting from partial hydrolysis of (2,2-difluoro-1,3-benzodioxol-5-yl) )cyclopropanecarbonitrile were monitored. When percentage conversion >99% was observed (typically 100% conversion after 16 hours), the reaction mixture was cooled to 25°C and charged with ethanol (41 mL) and DCM (164 mL). The solution was cooled to 10°C and charged with 6N HCl (290 mL) at such a rate as to maintain a temperature below 25°C. After heating to 20-25°C, the phases were separated. The lower organic phase was collected and the upper aqueous phase was back extracted with DCM (164 ml). Note: the aqueous phase was somewhat cloudy, before and after extraction, due to the high concentration of inorganic salts. The organics were combined and concentrated in vacuo to 164 ml. Toluene (328 ml) was charged and the mixture was condensed to 164 ml at 70 - 75°C. The mixture was cooled to 45°C, charged with MTBE (364 ml) and stirred at 60°C for 20 minutes. The solution was cooled to 25°C and improved filtered to remove residual inorganic salts. MTBE (123 mL) was used to rinse the reactor and solids were collected. The combined organics were transferred to a clean reactor in preparation for the next step. Isolation of 1-(2,2-difluoro-1,3-benzodioxol-5-yl)-cyclopropanecarboxylic acid
    I. Vitríde (2 equiv) PhCHj (10 vol) 2. NaOHaq 10%(p/p) (4 equiv) X 11 F 86-92% rendimento[0179] The 1-(2,2-difluoro-1,3-benzodioxol-5-yl)-cyclopropanecarboxylic acid solution from the previous step is concentrated under vacuum to 164 ml, charged with toluene (328 ml) and concentrated to 164 ml at 70-75°C. The mixture was then heated to 100-105°C to provide a homogeneous solution. After stirring at this temperature for 30 minutes, the solution was cooled to 5°C over 2 hours and held at 5°C for 3 hours. The mixture was then filtered and the reactor and the collected solid washed with cold 1:1 toluene/n-heptane (2 X 123 mL). The material was dried under vacuum at 55°C for 17 hours to furnish 1-(2,2-difluoro-1,3-benzodioxol-5-yl)-cyclopropanecarboxylic acid as an off-white crystalline solid. 1-(2,2-Difluoro-1,3-benzodioxol-5-yl)-cyclopropanecarboxylic acid was isolated in 79% yield from (2,2-difluoro-1,3-benzodioxol-5-yl) -acetonitrile (3 steps including isolation) and with an HPLC purity of 99.0% ASC. ESI-MS m/z calc. 242.04, found 241.58 (M+1)+; 1H NMR (500 MHz, DMSO) δ 12.40 (s, 1H), 7.40 (d, J = 1.6 Hz, 1H), 7.30 (d, J = 8.3 Hz, 1H), 7.17 (dd, J = 8.3, 1.7 Hz, 1H), 1.46 (m, 2H), 1.17 (m, 2H). Alternative Acid Moiety Synthesis Synthesis of (2,2-difluoro-1,3-benzodioxol-5-yl)-methanol I. Vitride (2 equiv) PhCHj (10 vol) 2. NaOHaq 10%(w/w) (4 equiv) X 11 F 86-92% yield
    [0180] Commercially available 2,2-difluoro-1,3-benzodioxol-5-carboxylic acid (1.0 eq.) was slurried in toluene (10 vol). Vitride® (2 eq) is added via addition funnel at a rate so as to maintain the temperature at 15-25°C. At the end of the addition, the temperature is increased to 40°C for 2 hours (h), then aq. 10% (w/w) (4.0 eq) is added carefully through the addition funnel, keeping the temperature at 4050°C. After stirring for an additional 30 minutes, the layers are allowed to separate at 40°C. The organic phase is cooled to 20°C, then washed with water (2 x 1.5 vol), dried (Na2SO4), filtered and concentrated to give (2.2-difluoro-1,3-benzodioxol-5-yl )-crude methanol, which is used directly in the next step. Synthesis of 5-chloromethyl-2,2-difluoro-1,3-benzodioxol
    [0181] (2,2-Difluoro-1,3-benzodioxol-5-yl)-methanol (1.0 eq.) was dissolved in MTBE (5 vol). A catalytic amount of (DMAP) (1 mol%) was added and SOCl2 (1.2 eq.) was added via addition funnel. SOCl2 was added at a rate so as to maintain the temperature in the reactor at 15-25°C. The temperature was increased to 30°C for 1 hour, then cooled to 20°C, then water (4 vol) was added via addition funnel, keeping the temperature below 30°C. After stirring for an additional 30 minutes, the layers were allowed to separate. The organic layer was shaken and NaOH aq. 10% (w/v) (4.4 vol) was added. After stirring for 15 to 20 minutes, the layers were allowed to separate. The organic phase was then dried (Na2SO4), filtered and concentrated to provide crude 5-chloromethyl-2,2-difluoro-1,3-benzodioxol, which was used directly in the next step. Synthesis of (2,2-difluoro-1,3-benzodioxol-5-yl)-acetonitrile 1. NaCN (1.4 equiv) DMSO (3 vol) 3040°C 95-100% yield
    [0182] A solution of 5-chloromethyl-2,2-difluoro-1,3-benzodioxol (1 eq) in DMSO (1.25 vol) is added to a suspension of NaCN (1.4 eq) in DMSO (3 vol), keeping the temperature between 30-40°C. The mixture is stirred for 1 hour and then water (6 vol) is added, followed by MTBE (4 vol). After stirring for 30 minutes, the layers are separated. The aqueous layer is extracted with MTBE (1.8 vol). The combined organic layers are washed with water (1.8 vol), dried (Na2SO4), filtered and concentrated to give crude (2,2-difluoro-1,3-benzodioxol-5-yl)-acetonitrile (95%), which is employed directly in the next step.
    [0183] The remaining steps are the same as described above for the synthesis of the acid fraction. Amine Fraction Synthesis of 2-Bromo-5-fluoro-4-nitroaniline
    [0184] A vial was charged with 3-fluoro-4-nitroaniline (1.0 equiv), followed by ethyl acetate (10 vol) and shaken to dissolve all solids. N-Bromosuccinimide (1.0 equiv) was added portionwise so as to maintain the internal temperature of 22°C. At the end of the reaction, the reaction mixture was concentrated under vacuum on a rotaevaporator. The residue was suspended in distilled water (5 vol) to dissolve and remove the succinimide. (Succinimide can also be removed through a dewatering procedure). The water was decanted and the solid was suspended in 2-propanol (5 vol) overnight. The resulting suspension was filtered and the wet cake was washed with 2-propanol, dried in a vacuum oven at 50°C overnight with N2 drainage until constant weight. A dark yellowish solid was isolated (50% yield, 97.5% ASC). Other impurities were a bromine regioisomer (1.4% ASC) and a di-bromine adduct (1.1% ASC). 1H NMR (500 MHz, DMSO) δ 8.19 (1H, d, J = 8.1 Hz), 7.06 (br.s, 2H), 6.64 (d, 1H, J = 14.3 Hz). Synthesis of the p -toluenesulfonic acid salt of (R)-1-((4-amino-2-bromo-5-fluorophenyl)amino)-3-(benzyloxy)-propan-2-ol
    [0185] A vial carefully dried under N2 was charged with the following: activated powders of 4A molecular sieves (50% by weight based on 2-bromo-5-fluor-4-nitroaniline), 2-bromo-5-fluor- 4-nitroaniline (1.0 equiv.), zinc perchlorate dihydrate (20% mol) and toluene (8 vol.). The mixture was stirred at room temperature for 30 minutes NMT. Finally, (R)-benzyl glycidyl ether (2.0 equiv.) in toluene (2 vol.) was added in a constant stream. The reaction was heated to 80°C (internal temperature) and stirred for about 7 hours or until 2-bromo-5-fluoro-4-nitroaniline was <5% ASC.
    [0186] The reaction was cooled to room temperature and Celite (50% by weight) was added, followed by ethyl acetate (10 vol). The resulting mixture was filtered to remove Celite and sieves, and washed with ethyl acetate (2 vol). The filtrate was washed with ammonium chloride solution (4 vol., 20% w/v). The organic layer was washed with sodium bicarbonate solution (4 x 2.5% w/v). The organic layer was concentrated under vacuum on a rotaevaporator. The resulting suspension was dissolved in isopropyl acetate (10 vol.), and this solution was transferred to a Buchi hydrogenator.
    [0187] The hydrogenator was charged with Pt(S)/C 5% by weight (1.5 mol%) and the mixture was stirred under N2 at 30°C (internal temperature). The reaction was purged with N2, followed by hydrogen. The hydrogenator pressure was adjusted to 1 Bar (100000 Pa) of hydrogen and the mixture was stirred rapidly (> 1200 rpm). At the end of the reaction, the catalyst was filtered through a pad of Celite and washed with dichloromethane (10 vol). The filtrate was concentrated in vacuo. Any remaining isopropyl acetate was chased away with dichloromethane (2 vol.) and concentrated on a rotary evaporator to dryness.
    [0188] The resulting residue was dissolved in dichloromethane (10 vol.). p-Toluenesulfonic acid monohydrate (1.2 equiv.) was added and stirred overnight. The product was filtered and washed with dichloromethane (2 vol.) and suction dried. The wet cake was transferred to drying trays and into a vacuum oven and dried at 45°C with N2 purge until constant weight was obtained. (R)-1-((4-amino-2-bromo-5-fluorophenyl)amino)-3-(benzyloxy)-propan-2-ol p-toluenesulfonic acid salt was isolated as an off-white solid.
    [0189] Chiral purity was determined to be >97% ee. Synthesis of (3-chloro-3-methylbut-1-ynyl)trimethylsilane
    [0190] Propargyl alcohol (1.0 equiv.) was charged into a container. Aqueous hydrochloric acid (37%, 3.75 vol.) was added and stirring started. During dissolution of the solid alcohol, a modest endotherm (5-6°C) is observed. The resulting mixture was stirred overnight (16 hours), slowly turning dark red. A 30 L jacketed container is charged with water (5 vol.), which is then cooled to 10°C. The reaction mixture is transferred slowly into water by vacuum, keeping the internal temperature of the mixture below 25°C. Hexanes (3 vol.) are added and the resulting mixture is stirred for half an hour. The phases were settled and the aqueous phase (pH < 1) was drained and discarded. The organic phase was concentrated in vacuo using a rotaevaporator, providing the product as a red oil. Synthesis of (4-(Benzyloxy)-3,3-dimethylbut-1-ynyl) Trimethylsilane
    [0191] All equivalent and volume descriptors in this part are based on a 250 g reaction. Magnesium shavings (69.5 g, 2.86 mol, 2.0 equiv.) were charged to a 3 L reactor with 4 necks and stirred with a magnetic stirrer under nitrogen for half an hour. The reactor was immersed in an ice-water bath. A solution of propargyl chloride (250 g, 1.43 mol, 1.0 equiv.) in THF (1.8 L, 7.2 vol.) was added slowly to the reactor, with stirring, until an initial exotherm ( ~10°C) was observed. Grignard reagent formation was confirmed by IPC using1H-NMR spectroscopy. Once the exothermic reaction subsided, the remainder of the solution was added slowly, keeping the batch temperature at < 15°C. The addition required ~3 and a half hours. The resulting dark green mixture was poured into a 2 L bottle with a stopper.
    [0192] All equivalent and volume descriptors in this part are based on a 500g reaction. A 22 L reactor was charged with a solution of benzyl chloromethyl ether (95%, 375 g, 2.31 mol, 0.8 equiv.) in THF (1.5 L, 3 vol). The reactor was cooled in an ice-water bath. Two batches of Grignard reagent prepared as described above were combined and then added slowly to a solution of benzyl chloromethyl ether via an addition funnel, keeping the batch temperature below 25°C. The addition required 1.5 hours. The reaction mixture was stirred overnight (16 hours).
    [0193] All equivalent and volume descriptors in this part are based on a 1 kg reaction. A 15% ammonium chloride solution was prepared in a 30 liter jacketed reactor (1.5 kg in 8.5 kg of water, 10 vol.). The solution was cooled to 5°C. Two Grignard reaction mixtures prepared as described above were combined and then transferred to the ammonium chloride solution through a communication vessel. An exotherm was observed at this saturation, which was carried out at a rate such as to maintain the internal temperature below 25°C. Once the transfer was complete, the temperature of the coating pan was adjusted to 25°C. Hexane (8 L, 8 volumes) was added and the mixture was stirred for half an hour. After settling the phases, the aqueous phase (pH 9) was drained and discarded. The remaining organic phase was washed with water (2 L, 2 vol). The organic phase was concentrated in vacuo using a 22 L rotaevaporator, providing the crude product as an orange oil. Method B
    [0194] Magnesium shavings (106 g, 4.35 mol, 1.0 eq.) were added to a 22 L reactor and then suspended in THF (760 ml, 1 vol). The container was cooled in an ice-water bath such that the batch temperature reached 2°C. A solution of propargyl chloride (760 g, 4.35 mol, 1.0 equiv.) in THF (4.5 L, 6 vol.) was added slowly to the reactor. After 100 mL had been added, the addition was stopped and the mixture stirred until an exotherm of 13°C was observed, indicating the start of the Grignard reagent. Once the exotherm subsided, an additional 500 mL of propargyl chloride solution was added slowly, keeping the batch temperature below 20°C. Grignard reagent formation was confirmed by IPC using1H-NMR spectroscopy. The remainder of the propargyl chloride solution was added slowly, keeping the batch temperature below 20°C. The addition required ~ an hour and a half. The resulting dark green solution was stirred for half an hour. Grignard reagent formation was confirmed by IPC using1H-NMR spectroscopy. Pure benzyl chloromethyl ether was charged to the reactor addition funnel and then added dropwise to the reactor, keeping the batch temperature below 25°C. The addition was done in 1 hour. The reaction mixture was stirred overnight. Aqueous elaboration and concentration was carried out using the same procedure and relative amounts of materials as in Method A to provide the product as an orange oil. Synthesis of 4-Benzyloxy-3,3-dimethylbut-1-yne
    [0195] A 30 L jacketed reactor was charged with methanol (6 vol.) which was then cooled to 5°C. Potassium hydroxide (85%, 1.3 equiv.) was added to the reactor. An exotherm of 15-20°C was observed as the potassium hydroxide dissolved. The jacket temperature was set to 25°C. A solution of 4-benzyloxy-3,3-dimethyl-1-trimethylsilylbut-1-yne (1.0 equiv.) in methanol (2 vol.) was added and the resulting mixture was stirred until completion of the reaction, as was monitored by HPLC. Typical reaction time at 25°C is 3 to 4 hours. The reaction mixture is diluted with water (8 vol.) and then stirred for half an hour. Hexane (6 vol.) was added and the resulting mixture was stirred for half an hour. The phases were allowed to settle and then the aqueous phase (pH 1011) was drained and discarded. The organic phase was washed with a solution of KOH (85%, 0.4 equiv.) in water (8vol), followed by water (8vol). The organic phase was then concentrated down using a rotaevaporator to obtain the title material as a yellow-orange oil. The typical purity of this material is in the 80% range with an essentially single primary impurity present. 1H NMR (400 MHz, C6D6) δ 7.28 (d, 2H, J = 7.4 Hz), 7.18 (t, 2H, J = 7.2 Hz), 7.10 (d, 1H, J = 7.2 Hz), 4.35 (s, 2H), 3.24 (s, 2H), 1.91 (s, 1H), 1.25 (s, 6H). Synthesis of N-benzylglycolate-5-amino-2-(2-benzyloxy-1,1-dimethylethyl)-6-fluorindole Method A Synthesis of (R )-1-((4-amino-2-(4-(benzyloxy) )-3,3-dimethylbut-1-yn-1-yl)-5-fluorophenyl)amino)-3-(benzyloxy) propan-2-ol
    [0196] The p-toluenesulfonic acid salt of (R)-1-((4-amino-2-bromo-5-fluorophenyl)amino)-3-(benzyloxy)propan-2-ol in free base was obtained by stirring the solid in dichloromethane (5 vol) and saturated NaHCO3 solution (5 vol) until a clear organic layer was obtained. The resulting layers were separated and the organic layer was washed with saturated NaHCO3 solution (5 vol.), followed by brine and concentrated in vacuo to obtain (R)-1-((4-amino-2-bromo-5-fluorophenyl) )amino)-3-(benzyloxy)propan-2-ol in free base as an oil.
    [0197] Palladium acetate (0.01 eq.), dppb (0.015 eq.), CuI (0.015 eq.) and potassium carbonate (3 eq.) are suspended in acetonitrile (1.2 vol). After stirring for 15 minutes, a solution of 4-benzyloxy-3,3-dimethylbut-1-yne (1.1 eq.) in acetonitrile (0.2 vol.) was added. The mixture is sparged with nitrogen gas for 1 hour and then a solution of (R)-1-((4-amino-2-bromo-5-fluoro-phenyl)amino)-3-(benzyloxy)- propan-2-ol in free base (1 eq.) in acetonitrile (4.1 vol.) was added. The mixture is sparged with nitrogen gas for one hour and then heated to 80°C. Reaction progress is monitored by HPLC and the reaction is generally complete within 3-5 hours. The mixture is cooled to room temperature and then filtered through Celite. The cake is washed with acetonitrile (4 vol). The combined filtrates are azeotroped to dryness and then the mixture is filtered to the next reactor. The acetonitrile solution of (R)-1-((4-amino-2-(4-(benzyloxy)-3,3-dimethylbut-1-yn-1-yl)-5-fluorophenyl)amino)-3- (benzyloxy)-propan-2-ol thus obtained is used directly in the following procedure (cyclization), without further manipulation. Synthesis of N-benzylglycolate-5-amino-2-(2-benzyloxy-1,1-dimethylethyl)-6-fluorindole
    MeCN, 80 °C ' 3. Filtração em silica gel[0198] Bis-acetonitriledichloropalladium (0.1 eq.) and Cul (0.1 eq.) are loaded into the reactor and then suspended in a solution of (R)-1-((4-amino-2- (4-(Benzyloxy)-3,3-dimethylbut-1-yn-1-yl)-5-fluorophenyl)amino)-3-(benzyloxy)-propan-2-ol obtained above (1 eq.) in acetonitrile ( total of 9.5 vol). The mixture is sparged with nitrogen gas for 1 hour and then heated to 80°C. Reaction progress is monitored by HPLC and the reaction is usually complete within 1-3 hours. The mixture is filtered through Celite and the cake is washed with acetonitrile. A solvent switch to ethyl acetate (7.5 vol.) is performed. The ethyl acetate solution is washed with an aqueous solution of NH3-NH4Cl (2 x 2.5 vol.), followed by 10% saline (2.5 vol.). The ethyl acetate solution is then stirred with silica gel (1.8 eq. by weight) and Si-TMT (0.1 eq. by weight) for 6 hours. After filtration, the resulting solution is concentrated downwards. The residual oil is dissolved in DCM/heptane (4 vol.) and then purified by column chromatography. The oil thus obtained is then crystallized from 25% EtOAc/heptane (4 vol). (R)-1-(5-amino-2-(1-(benzyloxy)-2-methylpropan-2-yl)-6-fluor-1H-indol-1-yl)-3-(benzyloxy)propan-2 Crystalline -ol is typically obtained in 27-38% yield. 1H NMR (400 MHz, DMSO) δ 7.38-7.34 (m, 4H), 7.32-7.23 (m, 6H), 7.21 (d, 1H, J=12, 8 Hz), 6.77 (d, 1H, J = 9.0 Hz), 6.06 (s, 1H), 5.13 (d, 1H, J = 4.9 Hz), 4.54 ( s, 2H), 4.46 (br.s, 2H), 4.45 (s, 2H), 4.33 (d, 1H, J = 12.4Hz), 4.09-4.04 (m, 2H), 3.63 (d, 1H, J = 9.2 Hz), 3.56 (d, 1H, J = 9.2 Hz), 3.49 (dd, 1H, J = 9 .8.8, 4.4 Hz), 3.43 (dd, 1H, J = 9.8, 5.7 Hz), 1.40 (s, 6H). Synthesis of N-benzylglycolate-5-amino-2-(2-benzyloxy-1,1-dimethylethyl)-6-fluorindole Method B MeCN, 80 °C ' 3. Silica gel filtration
    [0199] Palladium acetate (33 g, 0.04 eq.), dppb (94 g, 0.06 eq.), and potassium carbonate (1.5 kg, 3.0 eq.) are charged into a reactor . The 4-ammonium-2-bromo-5-fluoraniline benzylglycolate free base oil (1.5 kg, 1.0 eq.) was dissolved in acetonitrile (8.2 L, 4.1 vol.) and then added to the oil. reactor. The mixture was purged with nitrogen gas for not less than 1 hour. A solution of 4-benzyloxy-3,3-dimethylbut-1-yne (70%, 1.1 kg, 1.05 eq.) in acetonitrile was added to the mixture, which was then purged with nitrogen gas for not less than 1 hour. The mixture was heated to 80°C and then stirred overnight. IPC by HPLC is performed and the reaction is determined to be complete after 16 hours. The mixture was cooled to room temperature and then filtered through a pad of Celite (228 g). The reactor and Celite block were washed with acetonitrile (2 x 2 L, 2 vol). The combined phases are concentrated on a 22 L rotaevaporator until 8 L of solvent is collected, leaving the crude product in 7 L (3.5 vol.) of acetonitrile.
    [0200] Bis-acetonitrile dichloro palladium (144 g, 0.15 eq.) was charged to the reactor. The crude solution was transferred back into the reactor and the rotoevaporation bulb was washed with acetonitrile (4 L, 2 vol). The combined solutions were sparged with nitrogen gas for not less than 1 hour. The reaction mixture was heated to 80°C for not less than 16 hours. HPLC process control shows complete consumption of starting material. The reaction mixture was filtered through Celite (300 g). The reactor and filter cake were washed with acetonitrile (3 L, 1.5 vol). The combined filtrates were concentrated to an oil by rotary evaporation. The oil was dissolved in ethyl acetate (8.8 L, 4.4 vol). The solution was washed with 20% ammonium chloride (5 L, 2.5 vol.), followed by 5% saline (5 L, 2.5 vol.). Silica gel (3.5 kg, 1.8 eq. by weight) of silica gel was added to the organic phase, which was stirred overnight. Deloxan THP II metal scavenger (358 g) and heptane (17.6 L) were added and the resulting mixture was stirred for not less than 3 h. The mixture was filtered through a fritted glass funnel. The filter cake was washed with 30% ethyl acetate in heptane (25 L). The combined filtrates were concentrated under reduced pressure to provide N-benzylglycolate-5-amino-2-(2-benzyloxy-1-1-dimethylethyl)-6-fluorindole as a brown colored paste (1.4 kg). Synthesis of Compound 1 Synthesis of Benzyl Protected Compound 1
    [0201] 1-(2,2-Difluoro-1,3-benzodioxol-5-yl)-cyclopropanecarboxylic acid (1.3 equiv.) was suspended in toluene (2.5 vol., based on acid 1 -(2,2-difluoro-1,3-benzodioxol-5-yl)-cyclopropanecarboxylic). Thionyl chloride (SOCl 2 , 1.7 equiv.) was added via addition funnel and the mixture was heated to 60°C. The resulting mixture was stirred for 2 hours. Toluene and excess SOC12 were removed by distillation using rotaevaporator. Additional toluene (2.5 vol., based on 1-(2,2-difluoro-1,3-benzodioxol-5-yl)-cyclopropane carboxylic acid) was added and the mixture distilled to one volume of toluene. A solution of (R)-1-(5-amino-2-(1-(benzyloxy)-2-methylpropan-2-yl)-6-fluoro-1H-indol-1-yl)-3-(benzyloxy) propan-2-ol (1 eq.) and triethylamine (3 eq.) in DCM (4 vol.) is cooled to 0°C. A solution of acid chloride in toluene (1 vol.) is added, keeping the batch temperature below 10°C. Reaction progress is monitored by HPLC and the reaction is usually complete within minutes. After warming to 25°C, the reaction mixture is washed with 5% NaHCO3 (3.5 vol.), 1 M NaOH (3.5 vol.) and 1 M HCl (5 vol.). A solvent exchange to methanol (2 vol.) is carried out and the resulting solution of (R)-N-(1-(3-benzyloxy-2-hydroxypropyl)-2-(1-(benzyloxy)-2-methylpropan -2-yl)-6-fluoro-1H-indol-5-yl)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamide in methanol is used without further manipulation in the next step (hydrogenolysis). Synthesis of Compound 1
    [0202] 5% Palladium on carbon (~ 50% wet, 0.01 eq.) is charged to a suitable hydrogenation vessel. The solution of (R)-N-(1-(3-(benzyloxy)-2-hydroxypropyl)-2-(1-(benzyloxy)-2-methylpropan-2-yl)-6-fluor-1H-indole- 5-yl)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropane carboxamide in methanol (2 vol.) obtained above is added carefully, followed by a solution of 3M HCl in methanol. The container is purged with nitrogen gas and then with hydrogen gas. The mixture is stirred vigorously until the reaction is complete, as determined by HPLC analysis. Typical reaction time is 3 to 5 hours. The reaction mixture is filtered through Celite and the cake is washed with methanol (2 vol.). A solvent exchange to isopropanol (3 vol.) is performed. Crude Compound 1 is crystallized from 75% IPA-heptane (4 vol., ie, 1 vol. heptane added to 3 vol. IPA) and the resulting crystals are matured in 50% IPA-heptane (i.e. , 2 vol. of heptane added to the mixture). Typical yields of compound 4 from the two-step acylation/hydrogenolysis procedure range from 68% to 84%. Compound 14 can be recrystallized from IPA-heptane following the same procedure described above.
    [0203] Compound 1 can also be prepared by one of several synthetic routes described in published US patent application US20090131492, incorporated herein by reference.
    ENSAIOS Ensaios para Detecção e Medição das Propriedades de Correção de ΔF508-CFTR dos Compostos Métodos óticos de potencial de membrana para análise das propriedades de modulação de ΔF508-CFTR dos compostos[0204] Table 10 below cites the analytical data for Compound 1. Table 10. ASSAYS Assays for Detecting and Measuring the ΔF508-CFTR Correction Properties of Compounds Optical membrane potential methods for analyzing the ΔF508-CFTR modulating properties of compounds
    [0205] The optical membrane potential assay used voltage sensitive FRET sensors described by Gonzalez and Tsien (see Gonzalez, JE and RY Tsien (1995) "Voltage sensing by fluorescence resonance energy transfer in single cells" Biophys J 69(4) : 1272-80, and Gonzalez, JE and RY Tsien (1997) “Improved indicators of cell membrane potential that use fluorescence resonance energy transfer” Chem Biol 4(4): 269-77 along with instruments to measure changes in fluorescence, such as the Voltage/Ion Probe Reader (VIPR) (see Gonzalez, JE, K. Oades, et al. (1999) “Cell-based assays and instrumentation for ion-channel screening targets” Drug Discov Today 4(9): 431439 ).
    [0206] These voltage-sensitive assays are based on the change in fluorescence resonant energy transfer (FRET) between the membrane-soluble, voltage-sensitive dye DiSBAC2(3) and a fluorescent phospholipid, CC2-DMPE, which is attached to the outer side of the plasma membrane and acts as a FRET donor. Changes in membrane potential (Vm) cause negatively charged DiSBAC2(3) to be redistributed across the plasma membrane and the amount of energy transfer from CC2-DMPE to change accordingly. Changes in fluorescence emission were monitored using VIPRTM II, which is a liquid manipulator and fluorescent detector designed to conduct cell-based scans in either 96- or 384-well microtiter plates. 1. Identification of Correction Compounds
    [0207] To identify small molecules that correct the traffic defect associated with ΔF508-CFTR, a single addition HTS assay format was developed. Cells were incubated in serum-free medium for 16 hours at 37°C in the presence or absence (negative control) of the test compound. As a positive control, cells placed in 384-well plates were incubated for 16 hours at 27°C for “correct temperature” of ΔF508-CFTR. Cells were subsequently rinsed 3 times with Krebs Ringers solution and loaded with the voltage sensitive dyes. To activate ΔF508-CFTR, 10 μM forskolin and the CFTR enhancer, genistein (20 μM), were added along with Cl- free medium to each well. Addition of Cl- free medium promoted Cl- efflux in response to ΔF508-CFTR activation and the resulting membrane depolarization was optically monitored using FRET-based voltage sensor dyes. 2. Identification of Enhancer Compounds
    [0208] To identify ΔF508-CFTR enhancers, a double addition HTS assay format was developed. During the first addition, a Cl- free medium with or without test compound was added to each well. After 22 seconds, a second addition of Cl- free medium containing 2 - 10 µM forskolin was performed to activate ΔF508-CFTR. The extracellular concentration of Cl- after both additions was 28 mM, which promoted Cl- efflux in response to activation of ΔF508-CFTR and the resulting membrane depolarization was optically monitored using the FRET-based voltage sensor dyes. 3. Solutions
    [0209] Bath solution #1: (in mM) NaCl 160, KCl 4.5, CaCl 2 2, MgCl 2 1, HEPES 10, pH 7.4 with NaOH.
    [0210] Chloride Free Bath Solution: Chloride salts in Bath Solution #1 are replaced with gluconate salts.
    [0211] CC2-DMPE: Prepared as a 10 mM stock solution in DMSO and stored at -20°C.
    [0212] DiSBAC2(3): Prepared as a 10 mM stock solution in DMSO and stored at -20°C. 4. Cell Culture
    [0213] NIH3T3 mouse fibroblasts stably expressing ΔF508-CFTR are employed for optical measurements of membrane potential. Cells are maintained at 37°C in 5% CO2 and 90% humidity in Dulbecco's modified Eagle's medium supplemented with 2 mM glutamine, 10% fetal bovine serum, 1 X NEAA, β-ME, 1 X pen/ strep and 25 mM HEPES in 175 cm2 culture flasks. For all optical assays, cells were seeded at 30,000/well in 384-well matrigel-coated plates and cultured for 2 hours at 37°C before growing at 27°C for 24 hours for the enhancer assay. For correction assays, cells were cultured at 27°C or 37°C with and without compounds for 16 - 24 hours. Electrophysiological Assays for Analysis of ΔF508-CFTR Modulation Properties of Compounds 1. Ussing Chamber Test
    [0214] Experiments employing Ussing chamber were performed on polarized epithelial cells expressing ΔF508-CFTR to further characterize the ΔF508-CFTR modulators identified in optical assays. FRTΔF508-CFTR epithelial cells grown on the Costar Snapwell cell culture inserts were mounted in a Ussing chamber (Physiologic Instruments, Inc., San Diego, CA) and the monolayers were continuously short circuited employing a “voltage latch” system ( Department of Bioengineering, University of Iowa, IA, and Physiologic Instruments, Inc., San Diego, CA). Transepithelial resistance was measured by applying a 2 mV pulse. Under these conditions, FRT epithelia demonstrated resistances of 4 KQ/cm2 or more. Solutions were kept at 27°C and bubbled with air. The electrode fit potential and fluid resistance were corrected employing a cell-free insert. Under these conditions, the current reflects the Cl- flux through ΔF508-CFTR expressed in the apical membrane. The ISC was acquired digitally employing an MP100A-CE interface and the AcqKnowledge program (v3,2,6; BIOPAC Systems, Santa Barbara, CA). 2. Identification of Correction Compounds
    [0215] The typical protocol employed a Cl- concentration gradient from the basolateral to the apical membrane. In order to adjust this gradient, normal ringer was employed on the basolateral membrane, considering that apical NaCl was replaced by equimolar sodium gluconate (titrated to pH 7.4 with NaOH) to provide a large Cl- concentration gradient across the epithelium. All experiments were performed with intact monolayers. In order to fully activate ΔF508-CFTR, forskolin (10 µM) and the PDE inhibitor IBMX (100 µM) were applied, followed by addition of the CFTR enhancer, genistein (50 µM).
    [0216] As seen in other cell types, low temperature incubation of FRT cells expressing ΔF508-CFTR stably increases the functional density of CFTR in the plasma membrane. To determine the activity of the correction compounds, cells were incubated with 10 µM of the test compound for 24 hours at 37°C and were subsequently washed 3x prior to recording. cAMP- and genistein-mediated SSI in compound-treated cells was normalized to 27°C and 37°C controls and expressed as percent activity. Preincubation of cells with the correction compound significantly increased cAMP and genistein-mediated ISC compared to controls at 37°C. 3. Identification of Enhancer Compounds
    [0217] The typical protocol used a Cl- concentration gradient from the basolateral to the apical membrane. To adjust this gradient, normal ringer was employed on the basolateral membrane and permeabilized with nystatin (360 μg/ml), considering that apical NaCl was replaced by equimolar sodium gluconate (titrated to pH 7.4 with NaOH) in order to provide a large concentration gradient of Cl- across the epithelium. All experiments were performed 30 minutes after permeabilization with nystatin. Forskolin (10 µM) and all test compounds were added to both sides of the cell culture inserts. The efficacy of putative ΔF508-CFTR enhancers was compared to the known enhancer, genistein. 4. Solutions
    [0218] Basolateral solution (in mM): NaCl (135), CaCl2 (1.2), MgCl2 (1.2), K2HPO4 (2.4), KHPO4 (0.6), N-2-hydroxyethylpiperazine-acid N'-2-ethanesulfonic acid (HEPES) (10) and dextrose (10). The solution was titrated to pH 7.4 with NaOH.
    [0219] Apical solution (in mM): The same as the basolateral solution with NaCl substituted with Na-Gluconate (135). 5. Cell Culture
    [0220] Fisher rat epithelial cells (FRT) expressing ΔF508-CFTR (FRTΔF508-CFTR) were employed for Ussing camera experiments for the putative ΔF508-CFTR modulators identified from our optical assays. Cells were grown on Costar Snapwell cell culture inserts and grown for five days at 37°C and 5% CO2 in Coon's modified Ham's F-12 medium supplemented with 5% fetal calf serum, penicillin 100 U/ ml and 100 µg/ml streptomycin. Before use to characterize the potentiating activity of the compounds, cells were incubated at 27°C for 16-48 hours to correct ΔF508-CFTR. To determine the activity of the correction compounds, cells were incubated at 27°C or 37°C with and without compounds for 24 hours. 6. Whole Cell Records
    [0221] The macroscopic current of ΔF508-CFTR (IΔF508) in NIH3T3 cells corrected by test compound and temperature stably expressing ΔF508-CFTR was monitored using the whole cell record with perforated stretch. Briefly, IΔF508 “voltage latch” recordings were performed at room temperature using an Axopatch 200B patch-clamp amplifier (Axon Instruments Inc., Foster City, CA). All recordings were acquired at a sampling frequency of 10 kHz and low-pass filtered at 1 kHz. The pipettes had a resistance of 5 to 6 MQ when filled with the intracellular solution. Under these recording conditions, the calculated reverse potential for Cl- (ECl) at room temperature was -28 mV. All registers had a seal resistance > 20 GQ and a series resistance < 15 MQ. Pulse generation, data acquisition and analysis were performed using a PC equipped with a Digidata 1320 A/D interface in conjunction with Clampex 8 (Axon Instruments Inc.). The bath contained < 250 µl of saline and was continuously perfused at a rate of 2 ml/min using a gravity-actuated perfusion system. 7. Identification of Correction Compounds
    [0222] To determine the activity of the correction compounds in order to increase the density of functional ΔF508-CFTR in the plasma membrane, we employed the perforated stretch recording techniques described above to measure the current density after 24-hour treatment with the correction compounds. To fully activate ΔF508-CFTR, 10 µM forskolin and 20 µM genistein were added to the cells. According to our recording conditions, the current density after incubation for 24 hours at 27°C was greater than that observed after 24 hours of incubation at 37°C. These results are consistent with the known effects of low temperature incubation on the density of ΔF508-CFTR in the plasma membrane. To determine the effects of correction compounds on CFTR current density, cells were incubated with 10 µM of test compound for 24 hours at 37°C and current density was compared to the 27°C and 37° controls. C (% activity). Prior to recording, cells were washed three times with extracellular recording medium to remove any remaining test compound. Preincubation with 10 μM of the correction compounds significantly increased the cAMP- and genistein-dependent current compared to controls at 37°C. 8. Identification of Enhancer Compounds
    [0223] The ability of ΔF508-CFTR enhancers to increase the macroscopic Cl- current in ΔF508-CFTR (IΔF508) in NIH3T3 cells stably expressing ΔF508-CFTR was also investigated using perforated stretch recording techniques. Enhancers identified in optical assays elicited a dose-dependent increase in IΔF508 with similar potency and efficacy seen in optical assays. In all cells examined, the reverse potential before and during the application of the enhancer was around -30 mV, which is the calculated ECl (-28 mV). 9. Solutions
    [0224] Intracellular solution (in mM): Cs-aspartate (90), CsCl (50), MgCl2 (1), HEPES (10) and 240 μg/ml amphotericin-B (pH adjusted to 7.35 with CsOH) .
    [0225] Extracellular solution (in mM): N-methyl-D-glucamine (NMDG)-Cl (150), MgCl2 (2), CaCl2 (2), HEPES (10) (pH adjusted to 7.35 with HCl) . 10. Cell culture
    [0226] NIH3T3 mouse fibroblasts stably expressing ΔF508-CFTR are employed for whole cell recordings. Cells are maintained at 37°C in 5% CO2 and 90% humidity in Dulbecco's modified Eagle's medium supplemented with 2 mM glutamine, 10% fetal bovine serum, 1 X NEAA, β-ME, 1 X pen/ strep and 25 mM HEPES in 175 cm2 culture flasks. For whole cell recordings, 2,500 - 5,000 cells were seeded onto poly-L-lysine-coated glass slides and cultured for 24-48 hours at 27°C prior to use to test enhancer activity; and incubated with or without correction compound at 37°C to measure the activity of the correctors. 11. Single Channel Records
    [0227] The single channel activities of temperature-corrected ΔF508-CFTR stably expressed in NIH3T3 cells and the activities of the enhancer compounds were observed employing the cut membrane passage from the inside out. In summary, single-channel activity “voltage latch” recordings were performed at room temperature with an Axopatch 200B patch-clamp amplifier (Axon Instruments Inc.). All recordings were acquired at a sampling frequency of 10 kHz and low pass filtered at 400 Hz. Pass pipettes were manufactured with Corning Kovar Sealing #7052 glass (World Precision Instruments, Inc., Sarasota, FL) and had a 5-8 MQ resistance when filled with extracellular solution. ΔF508-CFTR was activated after excision by addition of 1 mM Mg-ATP and 75 nM cAMP-dependent protein kinase, catalytic subunit (PKA; Promega Corp. Madison, WI). After stabilization of the channel activity, the passage was perfused using a gravity-driven microperfusion system. The inflow was placed adjacent to the passage, resulting in a complete change of solution within 1-2 seconds. In order to maintain ΔF508-CFTR activity during rapid perfusion, non-specific phosphatase inhibitor F- (10 mM NaF) was added to the bath solution. Under these logging conditions, channel activity remained constant throughout the entire duration of the pass logging (up to 60 minutes). Currents produced by positive charge movement from intra to extracellular solutions (anions moving in the opposite direction) are shown as positive currents. The pipette potential (Vp) was kept at 80 mV.
    [0228] Channel activity was analyzed from membrane passages containing < 2 active channels. The maximum number of simultaneous opens determined the number of active channels during the course of an experiment. To determine the single-channel current amplitude, the 120-second recorded data of ΔF08-CFTR activity was filtered “off-line” at 100 Hz and then used to construct the amplitude histograms of all points that were fitted with functions multigaussians, using the Bio-Patch Analysis program (Bio-Logic Comp. France). The total microscopic current and open probability (Po) were determined from 120 seconds of channel activity. Po was determined using the Bio-Patch program or from the ratio Po = I/i(N), where I = average current, i = single channel current amplitude and N = number of active channels in passage. 12. Solutions
    [0229] Extracellular solution (in mM): NMDG (150), aspartic acid (150), CaCl2 (5), MgCl2 (2) and HEPES (10) (pH adjusted to 7.35 with Tris base).
    [0230] Intracellular solution (in mM): NMDG-Cl (150), MgCl2 (2), EGTA (5), TES (10) and Tris base (14) (pH adjusted to 7.35 with HCl). 13. Cell Culture
    [0231] NIH3T3 mouse fibroblasts stably expressing ΔF508-CFTR are employed for patch clamp recordings of cut membrane. Cells are maintained at 37°C in 5% CO2 and 90% humidity in Dulbecco's modified Eagle's medium supplemented with 2 mM glutamine, 10% fetal bovine serum, 1 X NEAA, β-ME, 1 X pen/ strep and 25 mM HEPES in 175 cm2 culture flasks. For single-channel recordings, 2,500 - 5,000 cells were seeded onto poly-L-lysine-coated glass slides and cultured for 24-48 hours at 27°C prior to use.
    [0232] Using the procedures described above, the activity, ie EC50s, of Compound 1 was measured and is shown in Table 11. Table 11.
    权利要求:
    Claims (10)
    [0001]
    em que, independentemente para cada ocorrência: R2 é -RJ, -ORJ, -N(RJ)2, -NO2, halogênio, -CN ou C1-4- haloalquila; RJ é hidrogênio ou C1-6 alifático; R3 é C1-6 alifático opcionalmente substituído com OH, OP, -O-C1-6 alifático, arila, heteroarila, -O-arila ou -O- heteroarila; P é um grupo de proteção; e o é um número inteiro de 0 a 3; com a condição de que o composto de fórmula III não é caracterizado pelo fato de compreender as etapas de: a) reagir um composto de fórmula IIIA: em que, independentemente para cada ocorrência: R2 é -RJ, -ORJ, -N(RJ)2, -NO2, halogênio, -CN, C1-4- haloalquila, C1-4-haloalcóxi, -C(O)N(RJ)2, -NRJC(O)RJ, -SORJ, -SO2RJ, -SO2N(RJ)2, -NRJSO2RJ, -CORJ, -CO2RJ, -NRJSO2N(RJ)2, -COCORJ; RJ é hidrogênio ou C1-6 alifático; e o é um número inteiro de 0 a 3; com um reagente de halogenação em um primeiro solvente orgânico para formar um composto de fórmula IIIB: IIIB em que, independentemente para cada ocorrência: R2 é -RJ, -ORJ, -N(RJ)2, -NO2, halogênio, -CN, C1-4- haloalquila, C1-4-haloalcóxi, -C(O)N(RJ)2, -NRJC(O)RJ, -SORJ, -SO2RJ, -SO2N(RJ)2, -NRJSO2RJ, -CORJ, -CO2RJ, -NRJSO2N(RJ)2, -COCORJ; RJ é hidrogênio ou C1-6 alifático; o é um número inteiro de 0 a 3; e Hal é um haleto; b) reagir o composto de fórmula IIIB em um segundo solvente orgânico com um composto de fórmula IIIC: IIIC em que: P é um grupo de proteção; seguido por redução e tratamento com ácido para formar um composto de fórmula IIID: IIID em que: R2 é -RJ, -ORJ, -N(RJ)2, -NO2, halogênio, -CN, C1-4- haloalquila, C1-4-haloalcóxi, -C(O)N(RJ)2, -NRJC(O)RJ, -SORJ, -SO2RJ, -SO2N(RJ)2, -NRJSO2RJ, -CORJ, -CO2RJ, -NRJSO2N(RJ)2, -COCORJ; RJ é hidrogênio ou C1-6 alifático; o é um número inteiro de 0 a 3; Hal é um haleto; P é um grupo de proteção; e Θ A é um ânion; c) neutralizar um composto de fórmula IIID na presença de uma base para formar um composto de fórmula IIID-a: IIID-a em que: R2 é -RJ, -ORJ, -N(RJ)2, -NO2, halogênio, -CN, C1-4- haloalquila, C1-4-haloalcóxi, -C(O)N(RJ)2, -NRJC(O)RJ, -SORJ, -SO2RJ, -SO2N(RJ)2, -NRJSO2RJ, -CORJ, -CO2RJ, -NRJSO2N(RJ)2, -COCORJ; RJ é hidrogênio ou C1-6 alifático; o é um número inteiro de 0 a 3; Hal é um haleto; e P é um grupo de proteção; d) reagir um composto de fórmula IIID-a em um terceiro solvente orgânico com um composto de fórmula IIIE: IIIE em que, independentemente para cada ocorrência: R3 é um C1-6 alifático opcionalmente substituído com OH, OP, -O- C1-6 alifático, arila, heteroarila, -O-arila ou -O-heteroarila; na presença de um catalisador para formar um composto de fórmula III; em que a etapa a) ocorre a cerca de 2°C a 42°C, o primeiro solvente orgânico é um solvente aprótico que é acetato de etila e o reagente de halogenação é N- bromosuccinimida; e em que a etapa d) é realizada entre cerca de 60°C e 100°C, o terceiro solvente orgânico é um solvente aprótico que é acetonitrila e o catalisador é um catalisador de paládio, que é selecionado dentre acetato de paládio (II), Pd(dppf)Cl2, Pd(dba)2, tetrakis(trifenilfosfino)paládio(0), (MeCN)2PdCl2 e tris(dibenzilidenoacetona)dipaládio(0).1. Process for preparing a compound of formula III: wherein, independently for each occurrence: R2 is -RJ, -ORJ, -N(RJ)2, -NO2, halogen, -CN or C1-4-haloalkyl; Rj is hydrogen or C1-6 aliphatic; R3 is C1-6 aliphatic optionally substituted with OH, OP, -O-C1-6 aliphatic, aryl, heteroaryl, -O-aryl or -O-heteroaryl; P is a protecting group; and o is an integer from 0 to 3; with the proviso that the compound of formula III is not characterized by the fact that it comprises the steps of: a) reacting a compound of formula IIIA: where, independently for each occurrence: R2 is -RJ, -ORJ, -N(RJ)2, -NO2, halogen, -CN, C1-4-haloalkyl, C1-4-haloalkoxy, -C(O)N( RJ)2, -NRJC(O)RJ, -SORJ, -SO2RJ, -SO2N(RJ)2, -NRJSO2RJ, -CORJ, -CO2RJ, -NRJSO2N(RJ)2, -COCORJ; Rj is hydrogen or C1-6 aliphatic; and o is an integer from 0 to 3; with a halogenating reagent in a first organic solvent to form a compound of formula IIIB: IIIB where, independently for each occurrence: R2 is -RJ, -ORJ, -N(RJ)2, -NO2, halogen, -CN, C1-4-haloalkyl, C1-4-haloalkoxy, -C(O)N (RJ)2, -NRJC(O)RJ, -SORJ, -SO2RJ, -SO2N(RJ)2, -NRJSO2RJ, -CORJ, -CO2RJ, -NRJSO2N(RJ)2, -COCORJ; Rj is hydrogen or C1-6 aliphatic; o is an integer from 0 to 3; and Hal is a halide; b) reacting the compound of formula IIIB in a second organic solvent with a compound of formula IIIC: IIIC where: P is a protecting group; followed by reduction and acid treatment to form a compound of formula IIID: IIID where: R2 is -RJ, -ORJ, -N(RJ)2, -NO2, halogen, -CN, C1-4-haloalkyl, C1-4-haloalkoxy, -C(O)N(RJ)2, -NRJC(O)RJ, -SORJ, -SO2RJ, -SO2N(RJ)2, -NRJSO2RJ, -CORJ, -CO2RJ, -NRJSO2N(RJ)2, -COCORJ; Rj is hydrogen or C1-6 aliphatic; o is an integer from 0 to 3; Hal is a halide; P is a protecting group; and Θ A is an anion; c) neutralizing a compound of formula IIID in the presence of a base to form a compound of formula IIID-a: IIID-a where: R2 is -RJ, -ORJ, -N(RJ)2, -NO2, halogen, -CN, C1-4-haloalkyl, C1-4-haloalkoxy, -C(O)N(RJ) 2, -NRJC(O)RJ, -SORJ, -SO2RJ, -SO2N(RJ)2, -NRJSO2RJ, -CORJ, -CO2RJ, -NRJSO2N(RJ)2, -COCORJ; Rj is hydrogen or C1-6 aliphatic; o is an integer from 0 to 3; Hal is a halide; and P is a protecting group; d) reacting a compound of formula IIID-a in a third organic solvent with a compound of formula IIIE: IIIE wherein, independently for each occurrence: R3 is a C1-6 aliphatic optionally substituted with OH, OP, -O-C1-6 aliphatic, aryl, heteroaryl, -O-aryl or -O-heteroaryl; in the presence of a catalyst to form a compound of formula III; wherein step a) takes place at about 2°C to 42°C, the first organic solvent is an aprotic solvent which is ethyl acetate and the halogenating reagent is N-bromosuccinimide; and wherein step d) is carried out between about 60°C and 100°C, the third organic solvent is an aprotic solvent which is acetonitrile and the catalyst is a palladium catalyst, which is selected from palladium(II) acetate , Pd(dppf)Cl2, Pd(dba)2, tetrakis(triphenylphosphine)palladium(0), (MeCN)2PdCl2 and tris(dibenzylideneacetone)dipalladium(0).
    [0002]
    2. Process according to claim 1, characterized in that: in formula IIIA, o is 1 and R2 is F; in formula IIIB, o is 1, R2 is F, and Hal is Br; in formula IIIC, P is benzyl; in formula IIID, o is 1, R2 is F, Hal is Br, A is Tos-, and P is benzyl; in formula IIID-a, o is 1, R2 is F, Hal is Br and P is benzyl; and in formula IIIE, R3 is C(CH3)2CH2O(benzyl).
    [0003]
    3. Process according to any one of claims 1 to 2, characterized in that in step b), the second organic solvent is an aprotic solvent which is toluene, the reaction with a compound of formula IIIC is carried out between about 60°C and 100°C, the reduction is carried out with hydrogen and the acid is p-toluenesulfonic acid.
    [0004]
    4. Process according to any one of claims 1 to 3, characterized in that in step c) the base is an inorganic base.
    [0005]
    5. Process according to any one of claims 1 to 4, characterized in that in step d), the catalyst is palladium (II) acetate.
    [0006]
    III ou um sal do mesmo; em que em que, independentemente para cada ocorrência: R2 é -RJ, -ORJ, -N(RJ)2, -NO2, halogênio, -CN ou C1-4- haloalquila; RJ é hidrogênio ou C1-6 alifático; R3 é C1-6 alifático opcionalmente substituído com OH, OP, -O-C1-6 alifático, arila, heteroarila, -O-arila ou -O- heteroarila; P é um grupo de proteção; e o é um número inteiro de 0 a 3; com a condição de que o composto de fórmula III não é ou um sal do mesmo.6. Compound characterized by the fact that the compound has formula III III or a salt thereof; wherein wherein, independently for each occurrence: R2 is -RJ, -ORJ, -N(RJ)2, -NO2, halogen, -CN or C1-4-haloalkyl; Rj is hydrogen or C1-6 aliphatic; R3 is C1-6 aliphatic optionally substituted with OH, OP, -O-C1-6 aliphatic, aryl, heteroaryl, -O-aryl or -O-heteroaryl; P is a protecting group; and o is an integer from 0 to 3; with the proviso that the compound of formula III is not or a salt of it.
    [0007]
    7. A compound or a salt thereof, according to claim 6, characterized in that o is 1 and R2 is F.
    [0008]
    8. A compound or a salt thereof, according to claim 6 or 7, characterized in that R3 is C(CH3)2CH2O(benzyl).
    [0009]
    9. A compound or a salt thereof, according to any one of claims 6 to 8, characterized in that P is acetyl, benzoyl, benzyl, methoxyethoxymethyl, dimethoxytrityl, methoxymethyl, methoxytrityl, p-methoxybenzyl, pivaloyl, tetrahydropyranyl, trityl or trimethylsilyl.
    [0010]
    10. A compound or a salt thereof, according to any one of claims 6 to 9, characterized in that P is benzyl.
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    法律状态:
    2017-08-15| B15I| Others concerning applications: loss of priority|
    2017-10-10| B12F| Other appeals [chapter 12.6 patent gazette]|
    2019-02-12| B06T| Formal requirements before examination [chapter 6.20 patent gazette]|
    2019-05-21| B07D| Technical examination (opinion) related to article 229 of industrial property law [chapter 7.4 patent gazette]|Free format text: DE ACORDO COM O ARTIGO 229-C DA LEI NO 10196/2001, QUE MODIFICOU A LEI NO 9279/96, A CONCESSAO DA PATENTE ESTA CONDICIONADA A ANUENCIA PREVIA DA ANVISA. CONSIDERANDO A APROVACAO DOS TERMOS DO PARECER NO 337/PGF/EA/2010, BEM COMO A PORTARIA INTERMINISTERIAL NO 1065 DE 24/05/2012, ENCAMINHA-SE O PRESENTE PEDIDO PARA AS PROVIDENCIAS CABIVEIS. |
    2019-12-17| B07E| Notification of approval relating to section 229 industrial property law [chapter 7.5 patent gazette]|
    2021-03-16| B06A| Patent application procedure suspended [chapter 6.1 patent gazette]|
    2021-07-13| B09A| Decision: intention to grant [chapter 9.1 patent gazette]|
    2021-08-24| B16A| Patent or certificate of addition of invention granted [chapter 16.1 patent gazette]|Free format text: PRAZO DE VALIDADE: 20 (VINTE) ANOS CONTADOS A PARTIR DE 21/04/2011, OBSERVADAS AS CONDICOES LEGAIS. PATENTE CONCEDIDA CONFORME ADI 5.529/DF, QUE DETERMINA A ALTERACAO DO PRAZO DE CONCESSAO. |
    2021-08-31| B21F| Lapse acc. art. 78, item iv - on non-payment of the annual fees in time|Free format text: PAGAR RESTAURACAO. |
    2021-09-08| B16C| Correction of notification of the grant [chapter 16.3 patent gazette]|Free format text: REF. RPI 2642 DE 24/08/2021 QUANTO AO INVENTOR. |
    2021-09-28| B21H| Decision of lapse of a patent or of a certificate of addition of invention cancelled [chapter 21.8 patent gazette]|Free format text: ANULADA A PUBLICACAO CODIGO 21.6 NA RPI NO 2643 DE 31/08/2021 POR TER SIDO INDEVIDA. |
    优先权:
    申请号 | 申请日 | 专利标题
    US32709910P| true| 2010-04-22|2010-04-22|
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    PCT/US2011/033396|WO2011133751A2|2010-04-22|2011-04-21|Process of producing cycloalkylcarboxamido-indole compounds|
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