Modulators of ATP-binding cassette transporters

[0001] This patent application claims priority over the initial patent application in the United States. Am. No. 60 / 790,459 filed on April 7, 2006.

FIELD OF THE INVENTION [0002] The invention relates to transporter modulators having an ATP binding cassette ("ABC") or fragments thereof, including cystic fibrosis transmembrane conductivity regulator ("CFTR"), compositions and methods including these modulators. The invention also relates to the use of such modulators for the treatment of diseases mediated by the ABC transporter, which are selected from the treatment of male infertility and pancreatic failure. The invention also relates to a method for obtaining such modulators.

BACKGROUND OF THE INVENTION [0003] ABC transporters are a family of membrane transport proteins that regulate the transport of many different pharmacological agents, potentially toxic drugs and xenobiotics, and anions. ABC transporters are homologous membrane proteins that bind and use cellular adenosine triphosphate (ATP) for their activity.

Some of these transporters have been discovered as multi-drug resistance proteins (such as MDR1-P glycoprotein or multi-drug resistance protein, MRP1) that protect malignant tumor cells from chemotherapeutic agents. To date, 48 ABC transporters have been identified and grouped into 7 families based on sequence compatibility and function.

[0004] ABC transporters play a role regulating many important physiological functions in the body and provide protection against harmful compounds from the environment. For this reason, they present important potential targets for drugs in the treatment of diseases associated with damage in the transporter, prevention of drug transport outside the target cell and activities in other diseases in which modulation of ABC transporter activity may be beneficial.

[0005] The ABC family of transporters usually associated with the disease is the anAMP channel regulated by cAMP / ATP, CFTR. CFTR is expressed in a variety of cell types, including absorption and secretory epithelial cells, in which it regulates the flow of anions across the cell membrane as well as the activity of other ion channels and proteins. In epithelial cells, normal CFTR function is critical to maintaining electrolyte transport in the body, including the tissues of the respiratory tract and gastrointestinal tract. CFTR consists of about 1480 amino acid residues that form a protein consisting of a tandem repeat of transmembrane domains, each containing six transmembrane helices and a nucleotide binding domain. The two transmembrane domains are connected by a large, polar (R) regulatory domain - with many phosphorylation sites that regulate channel activity as well as cellular transport and protein segregation.

[0006] The gene encoding CFTR has been identified and sequenced (see Gregory RJ et al. (1990) Science 347: 382-386;

Rich, DP et al (1990) Science 347: 358-362), (Riordan, JR et al (1989) Science 245: 1066-1073). A defect in this gene causes mutations in CFTR, causing Cystic fibrosis (CF), the most common lethal genetic disease in humans. Cystic fibrosis affects approximately one in 2,500 newborns in the United States. In the general US population, up to 10 million people have one copy of the defective gene, with no visible disease symptoms. In contrast, people with two copies of the cystic fibrosis related gene suffer from the debilitating and fatal effects of cystic fibrosis, including chronic lung disease.

[0007] In patients with cystic fibrosis, mutations in CFTR endogenously expressed in the airway epithelium lead to a decrease in peak anion secretion resulting in imbalances in ion and fluid transport. The resulting reduction in anion transport contributes to an increase in mucus accumulation in the lungs and associated microbial infections, which ultimately causes the death of cystic fibrosis patients. In addition to respiratory diseases, CF patients usually suffer from gastrointestinal problems and pancreatic insufficiency that, if left untreated, cause the patient to die. In addition, most men with cystic fibrosis are infertile and fertility in women with cystic fibrosis is reduced. In contrast to severe symptoms in people with two copies of the CF-associated gene, people with one copy of the CF-associated gene show increased resistance to cholera and dehydration due to diarrhea, which perhaps explains the relatively high incidence of CF in the population.

[0008] Sequence analysis of the CFTR gene from CF chromosomes revealed a number 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,&gt; 1,000 mutations in the CF gene have been identified that cause disease (<a href="http://www.genet.sicckids.on.ca/cftr/">http://www.genet.sicckids.on.ca/cftr/</a>). The most common mutation is a phenylalanine deletion at position 508 of the amino acid sequence of the CFTR protein and is commonly referred to as ΔF508-CFTR. This mutation occurs in approximately 70% of cases of cystic fibrosis and is associated with severe disease.

[0009] Deletion of residue 508 in ΔF508-CFTR prevents proper folding of the forming protein. This leads to the inability of the mutated protein to leave the ER and move to the cell membrane. As a result, the number of channels found in the membrane is much smaller than that observed in cells expressing wild-type CFTR. In addition to weakened transport, this mutation leads to faulty channel gating. All together, a decrease in the number of channels in the membrane and faulty gating leads to a reduction in the transport of anions throughout the epithelium leading to incorrect transport of ions and fluids. (Quinton, PM (1990), FASEB J. 4: 2709-2727). Studies have shown, however, that the reduced number of ΔF508-CFTR in the membrane is functional, but to a lesser extent 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 transport, synthesis and / or channel gating could be strengthened or weakened to alter anion secretion and modify disease progression and / or severity.

[0010] Although CFTR transports a number of different molecules in addition to anions, it is obvious that its role (transport of anions) includes one important element in the mechanism of ion and water transport through the epithelium. Other elements include Na epithelial sodium channel⁺, ENaC channel, co-transporter Na⁺/ 2Cl^-/ K⁺, sodium potassium pump ATPase Na⁺K⁺- and K channels⁺ basolateral membranes, which are responsible for the uptake of chloride ion into the cell.

[0011] These elements interact with each other to achieve directional transport across the epithelium through the result of their selective expression and location in the cell. Absorption of chloride ion occurs through the coordinated activity of ENaC and CFTR present in the apical membrane and the sodium potassium pump ATPase Na⁺-K⁺and Cl channels^- expressed on the side-cell surface of the cell. Secondary active transport of chloride from the lumen side of the duct leads to the accumulation of intracellular chloride, which can then passively leave the cell through the Cl channels^-, which leads to vector transport. Co-transporter system Na⁺/ 2Cl^-/ K⁺, sodium potassium pump ATPase Na⁺-K⁺and K channels⁺ lateral basal membrane on the laterol basal surface and CFTR on the lumen side of the duct coordinates the secretion of chloride through CFTR on the lumen side. Due to the fact that, probably, water is never actively transported, its flow through the epithelium depends on small osmotic gradients generated by the mass flow of sodium and chloride ions.

[0012] In addition to cystic fibrosis, modulation of CFTR activity may be beneficial for other diseases that are not directly caused by mutations in CFTR, such as secretory diseases and other diseases associated with CFTR-mediated protein folding. These include, but are not limited to, chronic obstructive pulmonary disease (COPD), dry eye disease, and Sjogren's syndrome.

[0013] COPD is characterized by a limited airflow that is progressive and not fully reversible. The restriction of airflow is caused by excessive mucus secretion, emphysema and bronchiolitis. Mutant CFTR or wild-type CFTR activators provide treatment for mucus secretion and mucociliary clearance disorders that are common in COPD disease. In particular, by increasing the anion secretion by CFTR, fluid transport to the liquid surface in the airways can be facilitated to hydrate mucus and optimize fluid viscosity surrounding the cilia. This will lead to an increase in mucociliary clearance and reduce the symptoms associated with COPD. Dry eye syndrome is characterized by a decrease in tear production and abnormal lipid film, protein and mucin profiles. There are many causes of dry eye syndrome, some of which include age, Lasik vision correction surgery, arthritis, drugs, chemical / thermal burns, allergies and diseases such as cystic fibrosis and Sjogrens syndrome. By increasing the anion secretion by CFTR, fluid transport from the corneal endothelial cells and secretory glands surrounding the eye will increase, leading to increased corneal hydration. This would help alleviate the symptoms associated with dry eye disease. Sjogrens syndrome is an autoimmune disease in which the immune system attacks the glands that produce moisture in the body, including the glands of the eye, mouth, skin, respiratory tissue, liver, vagina and intestine. Symptoms include dry eye, mouth and vagina as well as lung disease. The disease is also associated with arthritis, systemic rheumatoid erythematosus, polymyositis / systemic inflammation and dermatomyositis.

lupus inflammation

Defective transport and segregation of proteins is thought to be the cause of the disease, whose treatment options are limited. Modulators of CFTR activity can lead to hydration of various organs affected by the disease and help to relieve associated symptoms.

[0014] As mentioned above, deletion of residue 508 in ΔF508-CFTR is believed to counteract the correct folding of the forming protein, rendering the mutated protein unable to leave the ER and enter the cell membrane. As a result, there is insufficient amounts of mature protein in the membrane and the transport of chloride ions in epithelial tissues is significantly reduced. In fact, it has been shown that this cellular mechanism of defective processing by ABC transporters by ER provides an essential basis not only for cystic fibrosis disease, but for a number of other separate and hereditary diseases. There are two mechanisms by which the ER system may malfunction, or as a result of loss of conjugation with ER protein export leading to degradation or by the accumulation of defective / incorrectly folded proteins in the ER [Aridor M, et al., Natur Med., 5 (7 ), pp. 745-751 (1999); Shastry, BS, 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)]. Diseases associated with the first type of ER abnormality are cystic fibrosis (due to poorly folded ΔF508-CFTR, as discussed above), hereditary emphysema (induced by antitrypsin a1; non Piz variants), hereditary hemochromatosis, clotting factor fibrinolysis deficiencies such as protein C deficiency, hereditary Type 1 angioedema, lipid disorders such as familial hypercholesterolemia, type 1 chylomicronemia, abetalipoproteinemia, lysosomal storage diseases, such as internal storage diseases / pseudo-Hurler, mucopolysaccharidosis (caused by lysosomal processing enzymes), Sandhof / Tay-Sachs disease (caused by β-hexosaminidase), Crigler-Najjar syndrome type II (caused by UDP-glucuronyl-sialotransferase), polyiendocrinopathy / hyperinsulinemia, diabetes mellitus (due to the insulin receptor), Laron type dwarfism (due to the growth hormone receptor), myeloperoxidase deficiency, primary hypoparathyroidism (associated with prepro hormone) parathyroid) melanoma (caused by tyrosinase). Diseases associated with the second type of ER malfunction are type 1 CDG glycanosis, hereditary emphysema (induced by αl antitrypsin (Variant PiZ), congenital hyperactivity, congenital bone fragility (caused by procollagen type I, II, IV), hereditary hypofibrinogenemia (caused by fibrinogen deficiency) , ACT deficiency (al anti-chemotrypsin), diabetes insipidus (Latin diabetes insipidus DI), pituitary DI (vasopressin / V2 receptor hormone), renal DI (aquaporin-induced)

II)

Charcot-Marie-Tooth disease (caused by peripheral myelin 22 protein), Pelizaeus-Merzbacher disease, neurodegenerative diseases such as Alzheimer's disease (caused by βΑΡΡ and presenilins), Parkinson's disease, amyotrophic lateral sclerosis, progressive supranuclear palsy, Pick's disease, various polyglutin neurological diseases such as Huntington's disease, cerebellum cerebellar ataxia type I, spinal muscular atrophy, atrophy of the dentate nucleus, red nucleus, knob and low-hypothalamic nucleus and myotonic dystrophy, such as spongiform encephalopathies, for example hereditary Creutzfeldt-Jakob disease (caused by a defect in prion protein processing), Fabry disease (caused by lysosomal α-galactosidase A) and Straussler-Scheinker syndrome (PR-induced) ).

[0015] In addition to increasing CFTR activity, reducing anion secretion by CFTR modulators may be beneficial in the treatment of secretory diarrhea in which epithelial water transport increases significantly as a result of activated substances secreting chloride transport secretion. The mechanism involves raising cAMP levels and stimulation

CFTR.

[0016] Although there are many causes of diarrhea, the main consequences of diseases with diarrhea resulting from excessive chlorine transport are common to all, and include dehydration, acidosis, growth disorders and death.

[0017] Acute and chronic diarrhea is a serious medical problem in many places around the world. Diarrhea is both an important factor in malnutrition and a major cause of death (5 million deaths / year) for children under five years of age.

[0018] Secretory diarrhea is also a dangerous disorder in patients with acquired immunodeficiency syndrome (AIDS) and chronic inflammatory bowel disease (IBD). Each year, 16 million people traveling to developing countries from industrialized countries experience diarrhea with varying degrees of diarrhea severity and cases depending on the country and destination.

[0019] Diarrhea in farm and domestic animals, such as cows, pigs and horses, sheep, goats, dogs and cats, also known as animal diarrhea is the main cause of death of these animals. Diarrhea can result from any major changes ranging from withdrawal from breast milk or physical activity, as well as occurring in response to a wide variety of bacterial or viral infections that generally occur during the first few hours of the animal's life.

[0020] The most common bacterium that causes diarrhea is the enterotoxinogenic E. coli strain with the ciliary antigen K99. The most common viral causes of diarrhea include rotavirus and coronavirus. Other infectious agents include, but are not limited to, Cryptosporidium, caudate (giardia lamblia), and salmonella.

[0021] Symptoms of rotavirus infection include excretion of watery feces, dehydration and weakness. Coronavirus causes more serious disease in newborn animals and a higher mortality rate than rotavirus infection. More often, however, a young animal can be infected with more than one virus or a combination of viral and bacterial microorganisms at one time. This significantly increases the severity of the disease.

[0022] Accordingly, there is a need for modulators of ABC transporter activity and compositions thereof that can be used to modulate ABC transporter activity in a cell membrane in mammals.

[0023] There is a need for methods for treating diseases mediated by the ABC transporter using such modulators of ABC transporter activity.

[0024] There is a need for methods to modulate the activity of an ABC transporter ex vivo in a cell membrane in mammals.

[0025] There is a need for modulators of CFTR activity that can be used to modulate CFTR activity in a cell membrane in mammals.

[0026] There is a need for methods of treating CFTR mediated diseases with such modulators of CFTR activity.

[0027] There is a need for methods to modulate ex vivo CFTR activity in a mammalian cell membrane.

SUMMARY OF THE INVENTION [0028] The invention relates to compounds of formula Ic for use in the treatment of male infertility or pancreatic insufficiency as defined in the appended claims. The invention also relates to a method for preparing compounds of formula Ic as defined in the appended claims. It has now been found that the compounds of the invention and their pharmaceutically acceptable compositions are useful as modulators of ABC transporter activity, in particular CTFR activity. These compounds have the general formula I:

<img file="PL2674428T3_D0001.tif" />

or a pharmaceutically acceptable salt thereof, in which R1, R2, ring A, ring B and n are as defined below. [0029] These compounds and their pharmaceutically acceptable compositions are useful for treating or reducing the severity of various diseases, disorders or disease states, including but not limited to cystic fibrosis, hereditary emphysema, hereditary hemochromatosis, coagulation deficiencies and fibrinolysis, such as deficiency protein C, hereditary angioedema type 1, deficiencies in the lipid processing system, such as hypercholesterolemia, chylomicronemia as type 1 familial, abetalipoproteinemia, lysosomal storage diseases, (inclusion disease mucopolysaccharidosis, such as intracellular mucolipidosis II) / Pseudo-Hurler,

Sandhof / Tay-Sachs, Crigler-Najjar type II syndrome, poliendocrinopathy / hyperinsulinemia, diabetes mellitus, Laron type dwarfism, myeloperoxidase deficiency, primary hypoparathyroidism, melanoma, type 1 glycanosis, hereditary emphysema, congenital hyperthyroidism , hereditary hypofibrinogenemia, ACT deficiency, diabetes insipidus (DI), central diabetes insipidus, diabetes insipidus, Charcot-Marie Thooth disease, Pelizaeus-Merzbacher disease, neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, progressive supranuclear palsy, Pick's disease, several polyglutamine neurological disorders such as Huntington's chorea, type I cerebellar ataxia, dermatocerebral atrophy, and nuclei atrophy , pale knob and low-hypothalamic nucleus and myotonic dystrophy, as well as spongiform encephalopathies, such as hereditary Creutzfeldt-Jakob disease, Fabry disease, Straussler-Scheinker syndrome, COPD, dry eye disease and Sjogren's disease.

Detailed description of the invention

I. DEFINITIONS [0030] The following definitions apply throughout the specification, unless otherwise indicated.

[0031] The term "ABC transporter" as used herein means an ABC transporter protein or fragment thereof comprising at least one binding domain, wherein the protein or fragment thereof occurs in vivo or in vitro. The term "binding domain" as used herein means a domain present in an ABC transporter that can bind to a modulator. See, e.g., Hwang, TC et al., J. Gen. Physiol. (1998) 111 (3), 477-90.

[0032] The term "CFTR" herein means membrane conductance regulator or mutation thereof capable of regulatory activity including, but not limited to, ΔF508 CFTR and

G551D CFTR (see, for example, http: // www. Gen. Sickkids. On. Ca / cftr /, for the CFTR mutation).

[0033] The term "modulating" as used herein means an increase or decrease in a measurable manner, for example, of activity. Compounds that modulate ABC transporter activity, e.g., CFTR protein activity, by increasing the activity of the ABC transporter, e.g., the CFTR anion channel, are called agonists. Compounds that modulate ABC transporter activity, such as CFTR protein activity, reducing the activity of ABC transporters, for example the CFTR anion channel, are called antagonists. The agonist interacts with an ABC transporter, such as the CFTR anion channel, to increase the receptor's ability to transmit an intracellular signal in response to endogenous ligand binding. The antagonist interacts with the ABC transporter, such as CFTR, and competes with endogenous ligand (s) or substrate (s) for binding sites (s) on the receptor, which leads to a decrease in the receptor's ability to transmit an intracellular signal in response to endogenous ligand binding.

[0034] The expression "for treating or reducing the severity of an ABC transporter mediated disease" refers to both the treatment of diseases that are directly caused by the activity of the ABC transporters and / or the activity of the CFTR anion channel, and the relief of symptoms of diseases not directly caused by the activity of the ABC transporters and / or CFTR anion channel activity. Examples of diseases that may be affected by ABC transporter activity and / or CFTR activity include, but are not limited to, cystic fibrosis, hereditary emphysema, hereditary hemochromatosis, coagulation deficiencies and fibrinolysis, such as protein C deficiency, hereditary type 1 angioedema. deficiencies in the lipid processing system, such as familial hypercholesterolemia, chylomicronemia type 1, abetalipoproteinemia, lysosomal storage diseases, such as mucolipidosis II / PseudoHurler, mucopolysaccharidosis, Sandhof / Tay-Sachs, Crigler-Najjar type II syndrome, poliendocrinopathy / hyperinsulinemia, diabetes mellitus, Laron-type dwarfism, myeloperoxidase deficiency, primary glomerulopathy, CD lung, congenital hyperthyroidism, congenital bone fragility, hereditary hypofibrinogenemia, ACT deficiency, diabetes insipidus (DI), central diabetes insipidus, diabetes insipidus, Charcot-Marie-Tooth disease, Pelizaeus Merzbacher disease, neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, progressive supranuclear palsy, Pick's disease, several polyglutamine neurological disorders such as Huntington's chorea, such as Huntington's disease type I, bulbous spinal muscular atrophy, atrophy of the dentate nucleus, red nucleus, knob and low-hypothalamic nucleus and myotonic dystrophy, as well as spongiform encephalopathies such as hereditary Creutzfeldt-Jakob disease, Fabry disease, Straussler-Scheinker syndrome, COPD, dry eye disease and Sjogren's disease.

[0035] For the purposes of the invention, chemical elements are identified according to the periodic table of elements CAS version, Handbok of Chemistry and Physics, 75thEd.

In addition, general principles of organic chemistry are described in "Organic Chemistry", Thomas Sorrell, University Science Boxing, Sausolito: 1999, and "March's Advanced Organic Chemistry", 5th Ed. , Ed .: Smith, MB and March, J., John Wiley &amp; Sons, New York: 2001, all of which is incorporated herein by reference.

[0036] As described herein, the compounds of the invention may be optionally substituted with one or more substituents, as generally shown above or in the examples, by the particular classes, subclasses and types of the invention.

[0037] The term "aliphatic", as used herein, includes the terms alkyl, alkenyl, alkynyl, any of which may be optionally substituted as defined below.

[0038] As used herein, an "alkyl" group refers to saturated aliphatic hydrocarbon groups containing 1-12 carbon atoms (for example, 1-8, 1-6 or 14). The alkyl group can be straight or branched. Examples of alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, n-heptyl or 2-ethylhexyl. The alkyl group may be substituted (i.e., optionally substituted) with one or more substituents, such as halogen, phosphorus, cycloaliphatic [e.g. cycloalkyl or cycloalkenyl], heterocycloaliphatic [e.g. heterocycloalkyl or heterocycloalkenyl], aryl, heteroaryl, alkoxy, aroyl, heteroaroyl, acyl [for example, (aliphatic) carbonyl, (cycloaliphatic) carbonyl or (heterocycloaliphatic) carbonyl], nitro, cyano, amido [for example alkyl] cycloalkyl) , arylcarbonylamino, aralkylcarbonylamino, (heterocycloalkyl) carbonylamino, (heterocycloalkylalkyl) carbonylamino, heteroarylcarbonylamino, heteroaralkylcarbonylaminoalkylaminocarbonyl, cycloalkylaminocarbonyl, heterocycloalkylaminocarbonyl, arylaminocarbonyl or heteroarylaminocarbonyl] amino [e.g. aliphaticamino, cycloaliphaticamino or heterocycloaliphaticamino] sulfonyl [for example, aliphatic-SO2-], sulfinyl, sulfanyl, sulfoxy, urea, thiourea, sulfamoyl, sulfamide, oxo, carboxyl, carbamoyl, oxycycloaliphatic, heteroaryloxyaryl , heteroarylalkoxy, alkoxycarbonyl, alkylcarbonyloxy or hydroxyl. Without limitation, some examples of substituted alkyls include carboxyalkyl (such as HOC-alkyl, alkoxycarbonylalkyl and cyanoalkyl, hydroxyalkyl, aralkyl, (alkoxyaryl) alkyl, (alkyl-SO2-amino) alkyl), alkylcarbonyloxyalkyl), alkoxyalkyl, acylalkyl, sulfonylamino) alkyl (such aminoalkyl, amidoalkyl, (cycloaliphatic) alkyl or haloalkyl.

[0039] As used herein, an "alkenyl" group means an aliphatic carbon group containing 28 carbon atoms (e.g., 2-12, 2-6 or 2-4) and at least one double bond. Like the alkyl group, the alkenyl group can be straight or branched. Examples of alkenyl groups include, but are not limited to allyl, isoprenyl, 2-butenyl and 2-hexenyl. The alkenyl group may be optionally substituted by one or more substituents, such as halogen, phospho, cycloaliphatic [e.g. cycloalkyl or cycloalkenyl], heterocycloaliphatic [e.g. heterocycloalkyl or heterocycloalkenyl], aryl, heteroaryl, alkoxy, aroyl, heteroaroyl, acyl [for example, (aliphatic) carbonyl, (cycloaliphatic) carbonyl or (heterocycloaliphatic) carbonyl], nitro, cyano, amido [for example alkyl] cycloalkyl) , arylcarbonylamino, aralkylcarbonylamino, (heterocycloalkyl) carbonylamino, (heterocycloalkylalkyl) carbonylamino, heteroarylcarbonylamino, heteroaralkylcarbonylaminoalkylaminocarbonyl, cycloalkylaminocarbonyl, heterocycloalkylaminocarbonyl, arylaminocarbonyl or heteroarylaminocarbonyl] amino [e.g. aliphaticamino, cycloaliphaticamino or heterocycloaliphaticamino] sulfonyl [for example, aliphatic-SO2-], sulfinyl, sulfanyl, sulfoxy, urea, thiourea, sulfamoyl, sulfamide, oxo, carboxy, carbamoyl, oxycycloaliphoxy, alkoxyhexyloxy, alkoxyloxy , heteroarylalkoxy, alkoxycarbonyl, alkylcarbonyloxy or hydroxyl. Without limitation, some examples of substituted alkenyls include cyanoalkenyl, alkoxyalkenyl, acylalkenyl, hydroxylalkenyl, arylalkenyl, (alkoxyaryl) alkenyl, (sulfonylamino) alkenyl (such as (alkyl-SO2-amino) alkenyl), aminoalkenyl, amidoalkenyl, (alkenyl or alkenyl) .

[0040] As used herein, an "alkynyl" group means an aliphatic carbon group containing 28 carbon atoms (e.g., 2-12, 2-6 or 2-4) and at least one triple bond. The alkynyl group can be straight or branched. Examples of alkynyl groups include, but are not limited to, propargyl and butynyl. The alkynyl group may be optionally substituted with one or more substituents, such as aroyl, heteroaroyl, alkoxy, cycloalkyloxy, heterocycloalkyloxy, aryloxy, heteroaryloxy, aralkyloxy, nitro, carboxy, cyano, halogen, hydroxyl, sulfo, mercapto, sulfanyl [e.g. aliphatic sulfanyl or cycloaliphatic sulfanyl], sulfinyl [e.g. aliphatic sulfinyl or cycloaliphatic sulfinyl] sulfonyl [for example, aliphatic-SO2-, aminoaliphatic-SO2-, or cycloaliphatic-SO2-], amido [for example, aminocarbonyl, alkylaminocarbonyl, alkylcarbonylamino, cycloalkylaminocarbonyl, heterocycloalkylaminocarbonyl, cycloalkylamino) aralkylcarbonylamino, (heterocycloalkyl) carbonylamino, (cycloalkylalkyl) carbonylamino, heteroaralkylcarbonylamino, heteroarylcarbonylamino or heteroarylaminocarbonyl], urea, thiourea, sulfamoyl, sulfamido, alkoxycarbonyl, alkylcarbonyloxy, cycloaliphatic, heterocycloaliphatic, aryl, heteroaryl, acyl [example (cycloaliphatic) carbonyl or (heterocycloaliphatic) amino aminoaliphatic], sulfoxy, oxo, carboxy, carbamoyl, (cycloaliphatic) oxy, (heterocycloaliphatic) oxy, or (heteroaryl) alkoxy.

[0041] As used herein, the term "amide" includes both "aminocarbonyl" and "carbonylamino". When used alone or in combination with another group, these terms mean an amide group such as -N (R^X) -C (O) -R^Y or -C (O) -N (R^X)₂, when they occur last, and -C (O) -N (R^X) - or -N (R^X) -C (O) - when they occur in the middle where R^X and R^Y are set out below. Examples of amide groups include an alkylamido (such as an alkylcarbonylamino or alkylaminocarbonyl), (heterocycloaliphatic) amide, (heteroaralkyl) amide, (heteroaryl) amide, (heterocycloalkyl) alkylamido, arylamido, aralkylamido, (cycloalkyl) alkylamido) alkylamido

[0042] As used herein, an "amino" group refers to an -NR moiety^XR^Yin which each of the R substituents^X and R^Y independently represents hydrogen, aliphatic, cycloaliphatic, (cycloaliphatic) aliphatic, aryl, araliphatic, heterocycloaliphatic, (heterocycloaliphatic) aliphatic, heteroaryl, carboxy, sulfanyl, sulfinyl, sulfonyl, (aliphatic) carbonyl, (cycloaliphatic) heterocycloaliphatic) aliphatic) carbonyl, arylcarbonyl, (araliphatic) carbonyl, (heterocycloaliphatic) carbonyl, ((heterocycloaliphatic) aliphatic) carbonyl, (heteroaryl) carbonyl or (heteroaraliphatic) carbonyl, each group being defined in the present description and is optionally substituted. Examples of amino groups include alkylamino, dialkylamino or arylamino. When the term "amino" does not mean an end group (e.g., alkylcarbonylamino), it is represented by -NR^X-. R^X has the same meaning as defined above.

[0043] As used herein, an "aryl" group used alone or as part of a larger moiety such as "aralkyl", "aralkoxy" or tricyclic tricyclic "aryloxyalkyl" rings refers to monocyclic (e.g., phenyl); bicyclic (e.g. indenyl, naphthalenyl, tetrahydronaphthyl, tetrahydroindenyl); and tricyclics (e.g. fluorenyl tetrahydrofluorenyl or tetrahydroantracenyl, anthracenyl) ring systems in which the monocyclic ring system is aromatic or at least one of the rings in the bicyclic ring system or is aromatic. Bicyclic groups include benzofused 2-3 membered carbocyclic. For example, a benzofused group includes phenyl fused with two or more C4-8 carbocyclic groups. Aryl is optionally substituted with one or more substituents, including aliphatic substituents [e.g. alkyl, cycloaliphatic;

heterocycloaliphatic;

aryl; heteroaryl; (Cycloaliphatic) oxy;

alkenyl or alkynyl];

(Cycloaliphatic) aliphatic; (Heterocycloaliphatic) aliphatic; alkoxy; (heterocycloaliphatic) oxy group; aryloxy; heteroaryloxy; (Araliphatic) oxy; (Heteroaraliphatic) oxy; aroyl;

heteroaroyl; amino; oxo (on a non-aromatic carbocyclic ring of a benzofused bicyclic or tricyclic aryl); nitro; carboxy; amide; acyl [e.g. (aliphatic) carbonyl group;

(Cycloaliphatic) carbonyl; ((Cycloaliphatic) aliphatic) carbonyl; (Araliphatic) carbonyl; (Heterocycloaliphatic) carbonyl;

aliphatic) carbonyl;

((heterocycloaliphatic) or (heteroaraliphatic) carbonyl]; sulfonyl [e.g., aliphatic-SO2 or -amino-SO2-]; sulfinyl [e.g., aliphatic-S (O) - or cycloaliphatic-S (O) -]; sulfanyl [e.g., aliphatic-S-]; cyano; halo; hydroxyl; mercaptan; sulfoxy; urea; thiourea; sulfamoyl; sulfamide; or carbamoyl. Alternatively, aryl may be unsubstituted.

[0044] Non-limiting examples of substituted aryls include haloaryl [for example, mono-, di- (such as p, m-dihaloaryl) and (trihalo) aryl]; (carboxy) aryl [example (alkoxycarbonyl) aryl, ((aralkyl) carbonyloxy) aryl, and (alkoxycarbonyl) aryl]; (amido) aryl [example (aminocarbonyl) aryl, (((alkylamino) alkyl) aminocarbonyl) aryl, (alkylcarbonyl) aminoaryl, (arylaminocarbonyl) aryl, and (((heteroaryl) amino) carbonyl) aryl]; aminoaryl [example ((alkylsulfonyl) amino) aryl or ((dialkyl) amino) alkyl]; (Cyanoalkyl) aryl; (Alkoxy) aryl; (sulfamoyl) aryl [example (aminosulfonyl) aryl]; (Alkylsulfonyl) aryl; (Cyano) aryl; (Hydroxyalkyl) aryl; ((Alkoxy) alkyl) aryl; (hydroxy) aryl, ((carboxy) alkyl) aryl; (((Dialkyl) amino) alkyl) aryl; (Nitroalkyl) aryl; (((Alkylsulfonyl) amino) alkyl) aryl; ((heterocycloaliphatic) carbonyl) aryl; ((Alkylsulfonyl) alkyl) aryl; (Cyanoalkyl) aryl; (Hydroxyalkyl) aryl; (Alkylcarbonyl) aryl; alkylaryl; (Trihaloalkyl) aryl; pamino-m-alkoxycarbonylaryl, p-amino-m-cyanoaryl; pfluorowco-m-aminoaryl; or (m- (heterocycloaliphatic) o- (alkyl)) aryl.

[0045] As used herein, the term "arylaliphatic" such as "aralkyl" means an aliphatic (e.g., C1-4alkyl) group which is substituted with an aryl group. "Aliphatic", "alkyl" and "aryl" are defined herein. An example of an araliphatic group, such as an aralkyl group, is benzyl. [0046] As used herein, an "aralkyl" group refers to an alkyl group (for example, a C1-4alkyl group) that is substituted with an aryl group. Both "alkyl" and "aryl" have been defined above.

An example of an aralkyl group is benzyl. Aralkyl is optionally substituted with one or more substituents, such as an aliphatic group [for example, alkyl, alkenyl or alkynyl, including carboxyalkyl, hydroxyalkyl or haloalkyl, such as trifluoromethyl], cycloaliphatic [e.g. cycloalkyl or cycloalkenyl], (cycloalkyl) alkyl, heterocycloalkyl, (heterocycloalkyl) alkyl, aryl, heteroaryl, alkoxy, cycloalkyloxy, heterocycloalkyloxy, aryloxy, heteroaryloxy, aralkyloxy, heteroaralkyloxy, aroyl, heteroaroyl, nitroxylcarboxyl, carboxyloxy [for example, aminocarbonyl, alkylcarbonylamino, cycloalkylcarbonylamino, (cycloalkylalkyl) carbonylamino, arylcarbonylamino, aralkylcarbonylamino, (heterocycloalkyl) carbonylamino, (heterocycloalkylalkyl) carbonylamino, heteroarylcarbonylamino or heteroaralkylcarbonylamino], cyano, halo, hydroxy, acyl, mercapto, alkylsulfanyl, sulfoxy, urea, thiourea, sulfamoyl, sulfamide, oxo group

[0047] As used herein, the term "bicyclic ring system" includes 8-12 membered structures (e.g., 9, 10 or 11) that form two rings, wherein the two rings have at least one common atom (e.g. 2 common atoms). Bicyclic ring systems include bicycloaliphatic (e.g., bicycloalkyl or bicycloalkenyl), bicycloheteroaliphatic, bicyclic aryls and bicyclic heteroaryls.

[0048] The term "carbocycle" and "cycloaliphatic" as used herein, includes a "cycloalkyl" group and a "cycloalkenyl" group, each of which may be optionally substituted as defined below.

[0049] As used herein, the term "cycloalkyl" means a saturated carbocyclic monolocyclic (fused or bridged) ring with 3-10 (e.g., 5-10) carbon atoms. Examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, adamantyl, norbornyl, cubyl, octahydro-indenyl, decahydro-naphthyl, bicyclo [3.2.1] octyl, bicyclo [2.2.2] octyl, bicyclo [3.3.1] nonyl, bicyclo [3.3.2] decyl, bicyclo [2.2.2] octyl, adamantyl, or ((aminocarbonyl) cycloalkyl) cycloalkyl.

[0050] A "cycloalkenyl" group, as used herein, means a non-aromatic carbocyclic ring with 3-10 (e.g. 4-8) carbon atoms with one or more double bonds. Examples of cycloalkenyl groups include cyclopentenyl, 1,4-cyclohexa-di-enyl, cycloheptenyl, hexahydro-octahydro-indenyl, naphthyl, cyclopentenyl, bicyclo [2.2.2] octenyl or bicyclo [3.3.1] nonenyl.

[0051] The cycloalkyl or cycloalkenyl group may be optionally substituted with one or more substituents, such as phosphorus, aliphatic groups [e.g.

cyclooctenyl, cyclohexenyl, alkyl, alkenyl or alkynyl], cycloaliphatic, (cycloaliphatic) aliphatic, heterocycloaliphatic, (heterocycloaliphatic) aliphatic, aryl, heteroaryl, alkoxy, (aliphatic group) oxy, araliphatic) oxy, nitroxy carboxyloxycarboxyloxy (heterocycloaryloxy, heteroaryloxy, ((heteroaraliphatic) oxy, aroyl, heteroaroyl, amino, amido [for example, (aliphatic) carbonylamino, (cycloaliphatic) carbonylamino, ((cycloaliphatic) aliphatic) carbonylamino, (aryl) carbonylamino, (araliphatic) carbonylamino, (heterocycloaliphatic) carbonylamino, ((heterocycloaliphatic) aliphatic) carbonylamino or (hetero) carbonylamino) HOC-, alkoxycarbonyl or acyl [for example, (cycloaliphatic) carbonyl, ((cycloaliphatic) aliphatic) carbonyl, (araliphatic) carbonyl, (heterocycloaliphatic) carbonyl, ((heterocycloaliphatic) aliphatic) carbonylyl or carbonyl) halo, hydroxy, mercapto, sulfonyl [for example, alkyl-SO2- and aryl-SO2-], sulfinyl [for example, alkylS (O) -], sulfanyl [for example, alkyl-S-], sulfoxy, urea, thiourea sulfamoyl sulfamide group, oxo or carbamoyl.

[0052] The term "heterocycle" or "heterocycloaliphatic" as used herein includes a heterocycloalkyl group and a heterocycloalkenyl group, each of which may be optionally substituted as defined below.

[0053] As used herein, a "heterocycloalkyl" group refers to a 3-10 membered mono- or bicyclic (condensed or bridged) (e.g., octahydropyridinyl, benzo [b] thiophenyl,

5- to 10-membered mono- or bicyclic), saturated ring structure in which one or more ring atoms is a heteroatom (for example N, O, S or a combination thereof). Examples of the heterocycloalkyl group include piperidyl, piperazl, tetrahydropyranyl, tetrahydrofuryl, 1,4-dioxolanyl, 1,4-dithanyl, 1,3-dioxolanyl, oxazolidyl, isoxazolidyl, morpholinyl, thiomorpholyl, octahydrobenzofuryl, octahydrochthylchloro, oxa-bicyclo [2.2.2] octyl, 1-azabicyclo [2.2.2] octyl, 3-aza-bicyclo [3.2.1] octyl and 2,6-dioxatricyclo [3.3.1.0^3,7] Nonyl. ^.A monocyclic heterocycloalkyl group may be fused to a phenyl moiety to form a structure, such as tetrahydroisoquinoline, that would be classified as heteroaryl.

[0054] A "heterocycloalkenyl" group, as used herein, refers to a mono- or bicyclic (e.g., 5 to 10-membered mono- or bicyclic) non-aromatic ring structure containing one or more double bonds, and in which one or more of the ring atoms is a heteroatom (e.g., N, O or S). Monocyclic and bicyclic heterocycloaliphatic groups are numbered according to standard chemical nomenclature.

[0055] Heterocycloalkyl or heterocycloalkenyl may be optionally substituted with one or more substituents, such as phosphorus, aliphatic groups [e.g. alkyl, alkenyl or alkynyl], (cycloaliphatic) aliphatic, (heterocycloaliphatic) aliphatic, cycloaliphatic, heterocycloaliphatic, aryl, heteroaryl, alkoxy, (cycloaliphatic) oxy, (heterocycloaliphatic) oxy, aryloxy, heteroaryloxy, oxyalato group (heteroaraliphatic) oxy, aroyl, heteroaroyl, amino, amide [for example, (aliphatic) carbonylamino, (cycloaliphatic) carbonylamino, ((cycloaliphatic) aliphatic) carbonylamino, (aryl) carbonylamino, (araliphatic) carbonylamino, (heterocycloaliphatic) carbonylamino, ((heterocycloaliphatic) aliphatic) carbonylamino, (heteroaryl) carbonylamino, HOC-, alkoxycarbonyl or alkylcarbonyloxy], acyl [for example, (cycloaliphatic) carbonyl, ((cycloaliphatic) aliphatic) carbonyl, (araliphatic) carbonyl, (heterocycloaliphatic) carbonyl ((heterocycloaliphatic) carbonyl) aliphatic ], nitro, cyano, halo, hydroxy, mercapto, sulfonyl [e.g., alkylsulfonyl or arylsulfonyl] sulfinyl [e.g. alkylsulfinyl] sulfanyl [e.g. alkylsulfanyl], sulfoxy, urea, thiourea, sulfamoyl, sulfamide, oxo or carbamoyl.

[0056] As used herein, a "heteroaryl" group, as used herein, means a monocyclic, bicyclic or tricyclic ring system containing 4 to 15 ring atoms in which one or more ring atoms is a heteroatom (e.g., N, O, S or combinations thereof) and wherein the monocyclic ring system is aromatic or at least one of the rings in the bicyclic or tricyclic ring system is aromatic. The heteroaryl group includes a benzofused ring system containing from 2 to 3 rings.

For example, a benzofused group includes a benzo fused group with one or two 4 to 8 membered moieties (e.g., indolizil, indolyl, isoindolyl, 3Hindolyl, indolinyl, benzo [b] furyl, benzo [b] thiophenyl, quinolinyl or isoquinolinyl). Some examples of heteroaryl groups include azetidinyl, pyridyl, 1H-indazolyl, furyl, pyrrolyl, thienyl, thiazolyl, oxazolyl, imidazolyl, tetrazolyl, benzofuryl, isoquinolinyl, benzothiazolyl, xanthene, thioxanthene, phenothiazine, dihydroindol] [b] furyl, benzo [b] thiophenyl, indazolyl, benzimidazolyl, benzothiazolyl, puryl, cynolyl, quinolyl, quinazolyl, cininyl, phthalazine, quinazolyl, quinoxalil, isoquinolyl, 4H-quinolizil, benzo-1,2,5 or thiadium 8-naphthyridyl.

[0057] Without limitation, monocyclic heteroaryl groups include furyl, thiophenyl, 2H-pyrrolyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, 1,3,4-thiadiazolyl, 2H-pyranyl, 4-H- pranyl, pyridyl, pyridazl, pyrimidyl, pyrazolyl, pyrazyl or 1,3,5-triazyl. Monocyclic heteroaryl groups are numbered according to standard chemical nomenclature.

[0058] Without limitation, bicyclic heteroaryl groups include indolizil, indolyl, isoindolyl, 3Hindolyl, indolinyl, benzo [b] furyl, benzo [b] thiophenyl, quinolinyl, isoquinolinyl, indolizinyl, isoindolyl, indolyl, benzo [b] furyl benzo [b] thiophenyl, indazolyl, benzimidazyl, benzothiazolyl, purinyl, 4H-quinolizil, quinolyl, isoquinolyl, cinolyl, phthalazine, quinazolyl, quinoxalil, 1,8-naphthyridyl or pteridyl. Bicyclic heteroaryl groups are numbered according to standard chemical nomenclature.

tricyclic acyl [e.g.

aliphacyclo groups [0059] Heteroaryl is optionally substituted with one or more substituents, such as aliphatic groups [e.g. alkyl, alkenyl or alkynyl]; cycloaliphatic groups; (Cycloaliphatic) aliphatic; heterocycloaliphatic; (Heterocycloaliphatic) aliphatic; aryl; heteroaryl; alkoxy; (Cycloaliphatic) oxy; (Heterocycloaliphatic) oxy; aryloxy; heteroaryloxy; (Araliphatic) oxy; (Heteroaraliphatic) oxy; aroyl; heteroaroyl; amino; oxo (on a non-aromatic carbocyclic or heterocyclic bicyclic or heteroaryl ring); carboxy; amide;

tycznokarbonylowa; (Cycloaliphatic) carbonyl; aliphatic) aliphatic) carbonyl; (Araliphatic) carbonyl; (Heterocycloaliphatic) carbonyl; ((heterocycloaliphatic) aliphatic) carbonyl; or (heteroaraliphatic) carbonyl]; -sulfonyl [e.g. aliphatic sulfonyl or aminosulfonyl group]; sulfinyl [e.g. aliphatic sulfinyl group]; sulfanyl aliphatic sulfanyl]; nitro; hydroxy; mercaptan; thiourea; sulfamoyl; sulfamide; or carbamoyl. Alternatively, heteroaryl may be unsubstituted.

[0060] Non-limiting examples of substituted heteroaryl groups include (halo) heteroaryl [for example, mono- and di- (halo) heteroaryl]; (carboxy) heteroaryl [example (alkoxycarbonyl) heteroaryl]; cyanoheteroaryl; aminoheteroaryl [example ((alkylsulfonyl) amino) heteroaryl and ((dialkyl) amino) heteroaryl]; (amido) heteroaryl [e.g. aminocarbonylheteroaryl, ((alkylcarbonyl) amino) heteroaryl, ((((alkyl) amino) alkyl) aminocarbonyl) heteroaryl, (((hetero [e.g. cyano group; Hello; sulfoxyl group; urea;

aryl) amino) carbonyl) heteroaryl, ((heterocycloaliphatic) carbonyl) heteroaryl, and ((alkylcarbonyl) amino) heteroaryl]; (Cyanoalkyl) heteroaryl; (Alkoxy) heteroaryl; (sulfamoyl) heteroaryl [example (aminosulfonyl) heteroaryl]; (sulfonyl) heteroaryl [example (alkylsulfonyl) heteroaryl]; (Hydroxyalkyl) heteroaryl; (Alkoxyalkyl) heteroaryl; (Hydroxy) heteroaryl; ((Carboxy) alkyl) heteroaryl; (((dialkyl) amino) alkyl] heteroaryl; (heterocycloaliphatic) heteroaryl; (Cycloaliphatic) heteroaryl; (Nitroalkyl) heteroaryl; (((Alkylsulfonyl) amino) alkyl) heteroaryl; ((Alkylsulfonyl) alkyl) heteroaryl; (Cyanoalkyl) heteroaryl; (acyl) heteroaryl [for example, (alkylcarbonyl) heteroaryl], (alkyl) heteroaryl; and (haloalkyl) heteroaryl [e.g. trihaloalkylheteroaryl].

[0061] A "heteroaraliphatic" group (such as a heteroaralkyl group), as used herein, means an aliphatic (e.g., C1-4alkyl) group which is substituted with a heteroaryl group. The "aliphatic", "alkyl" and "heteroaryl" groups have been defined above.

[0062] A "heteroaralkyl" group, as used herein, refers to an alkyl group (e.g., a C1-4alkyl group) that is substituted with a heteroaryl group. Both "alkyl" and "heteroaryl" have been defined above. Heteroarylalkyl is optionally substituted with one or more substituents, such as alkyl (including carboxyalkyl, hydroxyalkyl and haloalkyl, such as trifluoromethyl), alkenyl, alkynyl, cycloalkyl, (cycloalkyl) alkyl, heterocycloalkyl, (heterocycloalkyl) alkyl, aryl, heteroaryl, alkoxy , cycloalkyloxy, heterocycloalkyloxy, aryloxy, heteroaryloxy, aralkyloxy, heteroaralkyloxy, aroyl, heteroaroyl, nitro, carboxy, alkoxycarbonyl, alkylcarbonyloxy, aminocarbonyl, alkylcarbonylamino, arylcarbonylamino, cycloalkyl) carbonylamino, alkyl) carbonylamino, alkylcarbonylamino, cyclo (cycloalkylalkyl) carbonylamino, aralkylcarbonylamino, (hetero (heterocycloalkylheteroarylcarbonylamino, heteroaralkyloxyalkylcarbonylcarboxyloxy) , sulfamoyl, sulfamide, oxo or carbamoyl. [0063] As used herein, "cyclic moiety" and "cyclic group" refers to mono-, bi- and tri-cyclic ring systems including cycloaliphatic, heterocycloaliphatic, aryl or heteroaryl, each of which has been previously defined.

[0064] As used herein, the term "bridged bicyclic ring system" refers to a bicyclic heterocycloaliphatic ring system or bicyclic cycloaliphatic ring system in which the rings are bridged. Examples of bridged bicyclic ring systems include, but are not limited to, adamantanyl, norbornanyl, bicyclo [3.2.1] octyl, bicyclo [2.2.2] octyl, bicyclo [3.3.1] nonyl, bicyclo [3.2.3] nonyl, 2-oxabicyclo [2.2.2] octyl, 1-azabicyclo [2.2.2] octyl, 3-azabicyclo [3.2.1] octyl and 2,6-dioxa-tricyclo [3.3.1.0^3,7] Nonyl. The bridged bicyclic ring system may be optionally substituted with one or more substituents, such as alkyl (including carboxyalkyl, hydroxyalkyl and haloalkyl, such as trifluoromethyl), alkenyl, alkynyl, cycloalkyl, (cycloalkyl) alkyl, heterocycloalkyl, (heterocycloalkyl) alkyl, aryl , heteroaryl, alkoxy, cycloalkyloxy, heterocycloalkyloxy, aryloxy, heteroaryloxy, aralkyloxy, heteroaralkyloxy, aroyl, heteroaroyl, nitro, carboxy, alkoxycarbonyl, alkylcarbonyloxy, aminocarbonyl, alkylcarbonylamino, cycloalkylcarbonylamino, (cycloalkylalkyl) carbonylamino, arylcarbonylamino, aralkylcarbonylamino, (heterocycloalkyl) carbonylamino, (heterocycloalkylalkyl) carbonylamino, heteroarylcarbonylalkyl, hydrocarbylamino, heteroarylcarbonyl, hydrocarbylamino, thiourea, sulfamoyl, sulfamide, oxo or carbamoyl group.

[0065] As used herein, an "acyl" group means a formyl or R group^XC (O) - (such as alkyl-C (O) -, also referred to as "alkylcarbonyl") in which R^X and "alkyl" have the previously defined meanings. Acetyl and pivaloyl are examples of acyl groups.

[0066] As used herein, "aroyl" or "heteroaroil" refers to aryl-C (O) - or heteroaryl-C (O) -. Wherein the aryl and heteroaryl fragment of the aroyl and heteroaroyl groups is optionally substituted as defined above.

[0067] As used herein, an "alkoxy" group refers to an alkyl-O- group in which "alkyl"

has been previously defined.

[0068] As used herein, a "carbamoyl" group means a group with the structure -O-CO-NR^XR^Y or

NR^X-CO-OR^FROM, in which R^X and R^Y have been defined above and R^FROM may be an aliphatic group, aryl, araliphatic, heterocycloaliphatic, heteroaryl, or heteroaraliphatic group [0069] As used herein, a "carboxy" group refers to a -COH, -COR group^X, -OC (O) H, -OC (O) R^X when used as an end group^; or -OC (O) or -C (O) O- used as an internal group.

[0070] As used herein, a "haloaliphatic" group means an aliphatic group substituted with 1-3 halogen. For example, the term haloalkyl includes the group -CF3.

[0071] As used herein, the group "mercapto" means -SH.

[0072] As used herein, the group "sulfo" means -SO3H or -SO3R^Xwhen used as an end group or -S (O) 3- when used as an internal group.

[0073] As used herein, a "sulfamide" group refers to the structure -NR^XS (O) 2-NR^YR^FROM when used as an end group and -NR^X-S (O) 2-NR^Y- when used as an internal group in which R^X, R^Y, and R^FROMhave been defined above.

[0074] As used herein, a "sulfonamide" group refers to the structure, -S (O) 2-NR^XR^Y or -NR^XS (O) 2-R^FROM when used as an end group; or -S (O) 2NR^X- or -NR^X-S (O) 2- when used as an internal group in which R^X, R^Y, and R^FROM have the meanings given above.

[0075] As used herein, a "sulfanyl" group refers to the -SR group^X when used as an end group and to the group -S- when used as an internal group, with R^X has been defined above. Examples of sulfanyls include an aliphatic-S-, cycloaliphatic-S-, aryl-S- group or the like.

[0076] As used herein, a "sulfinyl" group is -S (O) R^X when used as an end group and -S (O) - when used as an internal group, with R^X has been defined above. Exemplary sulfinyl groups include aliphatic-S (O) -, aryl-S (O) -, (cycloaliphatic (aliphatic)) - S (O) -, cycloalkyl-S (O) -, heterocycloaliphatic-S (O) -, heteroaryl-S (O) - and the like.

[0077] As used herein, a "sulfonyl" group refers to the -S (O) 2-R group^X when used as an end group and -S (O) 2- when used as an internal group, with R^X has been defined above.

Exemplary sulfonyl groups include aliphatic-S (O) 2-, aryl-S (O) 2-, (cycloaliphatic (aliphatic)) - S (O) 2-, cycloaliphatic-S (O) 2-, heterocycloaliphatic-S ( O) 2-, heteroaryl-S (O) 2-, (cycloaliphatic (amido (aliphatic))) - S (O) 2- or similar.

[0078] As used herein, a "sulfoxyl" group refers to -O-SO-R^X or -SO-OR^X when used as an end group and -OS (O) - or -S (O) -O- when used as an internal group in which R^X defined above.

[0079] As used herein, the term "halo" or "halogen" refers to fluoro, chloro, bromo or iodo.

[0080] As used herein, an "alkoxycarbonyl" group which is encompassed by the term carboxy, used alone or in combination with another group, refers to groups such as alkyl-OC (O) -.

[0081] As used herein, the term "alkoxyalkyl" means an alkyl group, such as alkyl-Oalkyl-, in which alkyl has been defined above.

[0082] As used herein, the term "carbonyl" refers to -C (O) -.

<td> [0083]</td><td>As used herein</td><td>description,</td><td>term</td>

<td>"Oxo"</td><td>means = O.</td><td></td><td></td>

<td> [0084]</td><td>As used herein</td><td>description,</td><td>term</td>

<td>"phospho</td><td>"means phosphonates and phosphonates.</td><td colspan="2">Examples include</td>

phosphonates and phosphonates, -P (O) (R^P) 2, in which R^P is aliphatic, alkoxy, aryloxy, heteroaryloxy, (cycloaliphatic) oxy (heterocycloaliphatic) oxy aryl, heteroaryl, cycloaliphatic or amino.

[0085] As used herein, "aminoalkyl" refers to the structure (R^X) 2N-alkyl-.

[0086] As used herein, the term "cyanoalkyl" refers to the structure (NC) -alkyl-.

[0087] As used herein, "urea" refers to the structure -NR^X-CO-NR^YR^FROM and "thiourea" refers to the structure -NR^X-CS-NR^YR^FROM when used as end groups and -NR^X-CO-NR^Y- or -NR^X-CS-NR^Y- when used internally, in which R^X, R^Y, R^FROM have been defined above.

[0088] As used herein, a "guanidine" group refers to the structure -N = C (N (R^XR^Y)) N (R^XR^Y) or

NR^XC (= NR^X) NR^XR^Yin which R^X and R^Y have been defined above.

[0089] As used herein, the term "amidino" refers to the group -C (= NR^X) N (R^XR^Y) in which R^X and R^Y have been defined above.

[0090] Generally, the term "vicinal" refers to the position of substituents on a group containing two or more carbon atoms, the substituents being attached to adjacent carbon atoms.

[0091] Generally, "geminal" refers to the positioning of substituents in a group containing two or more carbon atoms, the substituents being attached to the same carbon atom.

[0092] The terms "final" and "inside" refer to the position of the group in the substituent. A group is an end group when the group is present at the end of the substituent and is not attached to the rest of the chemical structure. Carboxyalkyl, or R^XO (O) Calkyl is an example of a carboxy group used at the end of a part. A group is an internal group when it is present inside the chemical structure substituent. Alkylcarboxy (e.g., alkyl-C (O) O- or alkyl-OC (O) -) and alkylcarboxyalkyl (e.g., alkyl-C (O) O-aryl- or alkyl-O (CO-aryl)) are examples carboxyl groups used internally in the particle.

[0093] As used herein, an "aliphatic chain" means a branched or straight chain aliphatic group (for example, alkyl groups, alkenyl groups or alkynyl groups). The straight aliphatic chain has the structure - [CH2] v-, in which v is 1-12. Branched aliphatic chain means a straight aliphatic chain that is substituted by one or more aliphatic groups. The branched aliphatic chain has the structure - [CQQ] v-, wherein each Q group is independently a hydrogen atom or an aliphatic group; However, Q should be an aliphatic group in at least one case. The term aliphatic chain includes alkyl chains, alkenyl chains and alkynyl chains, wherein alkyl, alkenyl, and alkynyl are as defined above.

[0094] The phrase "optionally substituted" is used interchangeably with the phrase "substituted or unsubstituted". As described herein, the compounds of the invention may be optionally substituted with one or more substituents, as is generally illustrated above or in the examples by the particular classes, subclasses and types of the invention. As described herein, the variables R1, R2 and R3 and other variables contained in the formulas described herein include specific groups such as alkyl and aryl. Unless otherwise indicated, each of these specific groups included in the variables R1, R2 and R3, and other variables contained therein may be optionally substituted with one or more substituents described herein. Each substituent of a particular group is optionally further substituted with one to three halogen, cyano, oxo, alkoxy, hydroxy, amino, nitro, aryl, cycloaliphatic, heterocycloaliphatic, heteroaryl, haloalkyl and alkyl. For example, the alkyl group may be substituted by alkylsulfanyl and the alkylsulfanyl may be optionally substituted by one to three halogen atoms, a cyano group, an oxo group, alkoxy, hydroxy, an amino group, a nitro group, aryl, haloalkyl, and alkyl. As an additional example, the cycloalkyl part of the (cycloalkyl) carbonylamino group may be optionally substituted with one to three halogen atoms, a cyano group, an alkoxy group, a hydroxyl group, a nitro group, a haloalkyl group, and alkyl. When two alkoxy groups are attached to the same atom or adjacent atoms, the two alkoxy groups may form a ring together with the atom (s) to which they are attached.

[0095] Generally, the term "substituted", whether or not preceded by the term "optionally", means the replacement of hydrogen radicals in a given structure with the radical of a specific substituent. Specific substituents are described above in the definitions and below in the description of the compounds and examples thereof. Unless otherwise indicated, an optionally substituted group may have a substituent at each substitutable group position, and when more than one position in any given structure may be substituted with more than one substituent selected from a particular group, the substituent may be either the same or different in every position. A ring substituent, such as a heterocycloalkyl, may be attached to another ring, such as a cycloalkyl, to form a spiro-bicyclic ring system, for example, both rings have one common atom. One skilled in the art will recognize that the combinations of substituents envisioned by the present invention are those combinations that result in the formation of stable or chemically possible compounds.

[0096] The term "stable (stable) or chemically acceptable" as used herein refers to compounds that do not change significantly when subjected to conditions that allow their production, detection and favorable recovery, purification and use thereof one or more purposes of this compound disclosed here. In some embodiments, the stable compound or chemically feasible compound is such a compound that does not change significantly when stored at 40 ° C or below, in the absence of moisture or other chemically reactive conditions, for at least a week.

[0097] The term "effective amount" as used herein is defined as the amount required to determine the therapeutic effect in a treated patient and is usually determined based on the age, surface area, weight and condition of the patient. The relationship between dosing in animals and humans (calculated per milligram per square meter body surface area) is described by Freireich et al., Cancer Chemother. Rep. , 50: 219 (1966). Body surface area can be approximately determined by the patient's height and weight. See, for example, Scientific Tables, Geigy Pharmaceuticals, Ardsley, New York, 537 (1970). The term "patient" as used herein refers to a mammal, including a human.

[0098] Unless otherwise indicated, the structures depicted herein are also intended to include all isomeric forms of the structure (e.g., enantiomeric, diastereomeric and geometric (or conformational)); For example, R and S configurations for each asymmetric center, isomers of the (Z) and (E) double bond, and conformational (Z) and (E) isomers. Thus, individual stereochemical isomers as well as enantiomeric, diastereomeric and geometric (or conformational) mixtures of the present compounds are within the scope of the present invention. Unless otherwise stated, all tautomeric forms of the compounds of the invention are within the scope of the invention. In addition, unless stated otherwise, the structures depicted herein also include compounds that differ only in the presence of one or more isotopically enriched atoms. For example, compounds having the present structures, with the exception of the replacement of a hydrogen atom with deuterium or tritium, or the replacement of a carbon atom with an enriched¹³C- or ¹⁴C is within the scope of the present invention. Such compounds are useful, for example, as analytical tools or samples for biological analysis, or as therapeutic agents.

[0099] The compounds of the present invention are useful as modulators of ABC transporters and are useful in the treatment of diseases in which the ABC transporter is involved.

II. UNIONS

A. General compounds [0100] The invention relates to compounds of formula I, useful as modulators of ABC transporter activity:

<img file="PL2674428T3_D0002.tif" />

or a pharmaceutically acceptable salt thereof.

[0101] R1 is -Z^ANDR4, in which each Z^AND is independently a bond or an optionally substituted C1-6 straight or branched aliphatic chain in which up to two carbon units with^AND is optionally and independently replaced by -CO-, -CS-, CONR^AND-, -CONR^ANDNO^AND-, -CO2-, -OCO-, -NR^ANDCO2-,

O-, -NR^ANDCONR^AND-, -OCONR^AND-, -NR^ANDNO^AND-, -NR^ANDCO-, -S-, -SO-, -SO2-,

NR^AND-, -SO2NR^AND-, -NR^ANDSO2-, or -NR^AND2 NR^AND- Each R4 is independently R^AND, halo, -OH, -NH2, -NO2, -CN, or -OCF3.

Each R^AND independently represents a hydrogen atom, an optionally substituted aliphatic group, an optionally substituted cycloaliphatic group, an optionally substituted heterocycloaliphatic group, an optionally substituted aryl group, or an optionally substituted heteroaryl group.

[0102] R2 is -Z^BR5, in which each Z^B is independently a bond or an optionally substituted C1-6 straight or branched aliphatic chain, with up to two Z carbon units^B is optionally and independently replaced by -CO-, -CS-, -CONR^B-, -CONR^BNO^B-, CO2-, -OCO-, -NR^BCO2-,

-O-, -NR^BCONR^B-, -OCONR^B-, -NR^BNO^B-, NO^BCO- -S-, -SO-, SO2-,

NO^B-, -SO2NR^B-, -NR^BSO2- or -NR^B2 NR^B-. Each R5 is independently R^B, halogen, -OH, -NH2,

-NO2, -CN, -CF3, or -OCF3. Each R^B independently represents a hydrogen atom, an optionally substituted aliphatic group, an optionally substituted cycloaliphatic group, an optionally substituted heterocycloaliphatic group, an optionally substituted aryl group, or an optionally substituted heteroaryl group. Alternatively, any two adjacent R2 groups together with the atoms to which they are attached form a carbocycle or heterocycle.

[0103] Ring A is an optionally substituted 3-7 membered monocyclic ring containing 0-3 heteroatoms selected from N, O and S;

[0104] Ring B is a group of formula Ia:

<img file="PL2674428T3_D0003.tif" />

or a pharmaceutically acceptable salt thereof, wherein p is 0-3 and R3 and R'3 are each independently -Z^CR6, in which each Z^C independently represents a bond or an optionally substituted straight or branched C1-6 aliphatic chain, with up to two Z carbon units^C is optionally and independently replaced by -CO-, -CS-, CONR^C-, -CONR^CNO^C-, -CO2-,

-OCO-, -NR^CCO2-, -O-, -NR^CCONR^C-, -OCONR^C-, -NR^CNO^C-, -NR^CCO-, -S-, -SO-, -SO2-, -NR^C-, -SO2NR^C-, -NR^CSO2-, or -NR^C2 NR^C-. Each R6 is independently R^C, halogen, -OH, -NH2, NO2, -CN or -OCF3. Each R^C independently represents a hydrogen atom, an optionally substituted aliphatic group, an optionally substituted cycloaliphatic group, an optionally substituted heterocycloaliphatic group, an optionally substituted aryl group, or an optionally substituted heteroaryl group. Alternatively, any two adjacent R3 groups together with the atoms to which they are attached form an optionally substituted carbocyclic ring or an optionally substituted heterocyclic ring. In addition, group R^'3 and the adjacent R3 group together with the atoms to which they are attached form an optionally substituted heterocyclic ring.

[0105] n is 1-3, [0106] However, in several embodiments, if ring A is unsubstituted cyclopentyl, n is 1, R2 is 4-chloro and R1 is hydrogen, then ring B is not 2- (tert-butyl) indol-5-yl, or (2,6-dichlorophenyl (carbonyl)) -3-methyl-1H-indol-5-yl; and when ring A is unsubstituted cyclopentyl, n is 0 and a

<img file="PL2674428T3_D0004.tif" />

or

<img file="PL2674428T3_D0005.tif" />

B. Specific relationships

1. Group R₁ [0107] R1 is -Z^ANDR4, in which each Z^AND independently represents a bond or an optionally substituted branched or straight C1-6 aliphatic chain in which up to two Z carbon units^ANDis optionally and independently replaced by -CO-, -CS-, CONR^AND-, CONR^ANDNO^AND-, -CO2-, -OCO-, -NR^ANDCO2-, -O-, NR^ANDCONR^AND-, -OCONR^AND-, NO^ANDNO^AND-, -NR^ANDCO-, -S-, -SO-, -SO2-, -NR^AND-, -SO2NR^AND-, -NR^ANDSO2- or -NR^AND2 NR^AND-. Each R4 is independently R^AND, halogen, -OH, -NH2, -NO2, -CN or -OCF3. Each R^ANDis independently hydrogen, optionally substituted aliphatic, optionally substituted cycloaliphatic, optionally substituted heterocycloaliphatic, optionally substituted aryl or optionally substituted heteroaryl.

[0108] In several embodiments, R1 is -Z^ANDR4,

<td>wherein</td><td>each of^AND independently represents a bond or</td>

<td>possibly</td><td>substituted C1-6 branched or straight chain</td>

<td>aliphatic</td><td>and each R4 is hydrogen.</td>

[0109] In other embodiments, R1 is -Z^ANDR4 in which everyone

FROM^AND is a bond and each R4 is hydrogen.

2. Group R₂ [0110] Each R2 independently is a -Z group^BR5, in which each Z^B independently represents a bond or an optionally substituted branched or straight C1-6 aliphatic chain in which a maximum of two Z carbon units^B are optionally and independently replaced by -CO-, -CS-, -CONR^B-, CONR^BNO^B, -CO2-, -OCO-, NR^BCO2-, -O-, NR^BCONR^B-, -OCONR^B-, -NR^BNO^B-,

NR^BCO-, -S-, -SO-, SO2-, -NR^B-, -SO2NR^B-, -NR^BSO2- or

<td>NR^BSO₂NO^B-.</td><td>Each R5 is independently R^B, halogen,</td>

<td>-OH-, -NH2,</td><td>-NO2, -CN, -CF3, and -OCF3. Each R^B means</td>

<td>independently</td><td>a hydrogen atom, an optionally substituted group</td>

aliphatic, optionally substituted cycloaliphatic group,

<td>possibly</td><td>substituted heterocycloaliphatic group,</td>

<td>possibly</td><td>substituted aryl or optionally substituted</td>

<td>heteroaryl.</td><td>Alternatively, any two adjacent R2 groups</td>

together with the atoms to which they are attached, they form

<td>possibly</td><td>substituted carbocyclic or optionally</td>

<td>substituted</td><td>heterocyclic or optionally substituted</td>

<td>heteroaryl.</td><td></td>

halogen, cycloaliphatic, [0111] In several embodiments, R2 is an optionally substituted aliphatic group. For example, R2 is an optionally substituted branched or straight C1-6 aliphatic chain. In other embodiments, R2 is an optionally substituted C1-6 alkyl branched or straight chain, optionally substituted C2-6 alkenyl straight or branched chain, or optionally substituted branched or straight C2-6 alkynyl chain. In alternative embodiments, R2 is a branched or straight C1-6 aliphatic chain which is optionally substituted with 1-3 hydroxy, cyano, heterocycloaliphatic, aryl, heteroaryl groups, or combinations thereof. For example, R2 is a branched or straight C1-6 alkyl chain which is optionally substituted with 1-3 halogen atoms, hydroxy, cyano, cycloaliphatic, heterocycloaliphatic, aryl, heteroaryl groups, or combinations thereof. In yet other embodiments, R2 is methyl, ethyl, propyl, butyl, isopropyl or tert-butyl, each of which is optionally substituted with 1-3 halogen, hydroxy, cyano, aryl, heteroaryl, cycloaliphatic or heterocycloaliphatic groups. In yet other embodiments, R2 is methyl, ethyl, propyl, butyl, isopropyl or tert-butyl, each of which is unsubstituted.

[0112] In various other embodiments, R2 is an optionally substituted C1-5 alkoxy branched or straight chain. For example, R2 is C1-5 alkoxy which is optionally substituted with 1-3 hydroxy, aryl, heteroaryl, cycloaliphatic, heterocycloaliphatic or combinations thereof.

In other embodiments, R2 is methoxy, ethoxy, propoxy, butoxy or pentoxy, each of which is optionally substituted with 1-3 hydroxyl, aryl, heteroaryl, cycloaliphatic, heterocycloaliphatic, or combinations thereof.

[0113] In other embodiments, R2 is hydroxyl, halogen or cyano.

BB [0114] In several embodiments, R2 is -Z^BR5 and Z^B independently represents a bond or an optionally substituted branched or straight C1-4 aliphatic chain in which up to two units _B carbon Z^B is optionally and independently replaced by -C (O) -, -O-, -S-, -S (O) 2-, or a -NH- group, and R5 is R^B, halogen, -OH, -NH2, -NO2, -CN, -CF3 or -OCF3, and R^Bis hydrogen or aryl.

[0115] In several embodiments, two adjacent R2 groups form an optionally substituted carbocyclic ring or an optionally substituted heterocyclic ring. For example, two adjacent R2 groups form an optionally substituted carbocyclic ring or optionally substituted heterocyclic ring, each of which is fused to a phenyl group of formula I, wherein the carbocyclic ring or heterocyclic ring has the general formula Ib:

<img file="PL2674428T3_D0006.tif" />

a bond, -CR7R'7-, -C (O) -, -NR7-, or -O-; each R7 is independently -Z^DR8, in which each Z^D is independently a bond or an optionally substituted branched or straight C1-6 aliphatic chain in which up to two Z carbon units^D is optionally and independently replaced by -CO-, -CS-, CONR^D-, -CO2-, -OCO-, - NO^DCO2-, -O-, NR^DCONR^D-, -OCONR^D-, NO^DNO^D-, -NR^DCO-, -S-, -SO-, -SO2-, -NR^D-,

-SO 2 NR^D-, -NR^DSO2-, or -NR^D2 NR^D-. Each

R8 is independently R^D, halogen, -OH, -NH2, -NO2, -CN, -CF3 and -OCF3. Each R^D is independently hydrogen, optionally substituted cycloaliphatic, optionally substituted heterocycloaliphatic, optionally substituted aryl or optionally substituted heteroaryl. Each R'7 is independently hydrogen, optionally substituted C1-6 aliphatic, hydroxy, halogen, cyano, nitro, or combinations thereof. Alternatively, any two adjacent R7 groups together with the atoms to which they are attached form an optionally substituted 3-7 membered carbocyclic ring, such as an optionally substituted cyclobutyl ring, or any two groups of R7 and R'7 together with the atom or atoms to which they are attached. are attached to form an optionally substituted 3-7 membered carbocyclic ring or heterocarbocyclic ring.

[0117] In many other embodiments, two adjacent R2 groups form an optionally substituted carbocyclic ring. For example, two adjacent R2 groups form an optionally substituted 5-7 membered carbocyclic ring that is optionally substituted with 1-3 halogen, hydroxy, cyano, oxo, cyano, alkoxy, alkyl, or combinations thereof. In another embodiment, two adjacent R2 groups form a 5-6 membered carbocyclic ring, which is optionally substituted with 1-3 halogen, hydroxy, cyano, oxo, cyano, alkoxy, alkyl, or combinations thereof. In yet another embodiment, two adjacent R2 groups form an unsubstituted 5-7 membered carbocyclic ring.

[0114] In alternative examples, two adjacent R2 groups form an optionally substituted heterocyclic group. For example, two adjacent R2-optionally substituted 5-7 groups form a heterocyclic ring containing 1-3 heteroatoms independently selected from N, O and S. In several examples, two adjacent R2 groups form an optionally substituted 5-6 membered group heterocyclic ring having 1-2 oxygen atoms. In other embodiments, two adjacent R2 groups form an unsubstituted 5-7 membered heterocyclic ring containing 1-2 oxygen atoms. In other embodiments, two adjacent R2 groups form a ring selected from:

<img file="PL2674428T3_D0007.tif" />

<img file="PL2674428T3_D0008.tif" />

<img file="PL2674428T3_D0009.tif" />

[0119] In alternative examples, two adjacent R2 groups form an optionally substituted carbocyclic ring or optionally substituted heterocyclic ring, and the third R2 group is attached to any chemically feasible position on the phenyl group of formula I. For example, an optionally substituted carbocyclic ring or an optionally substituted heterocyclic ring, both of which are formed by two adjacent R2 groups; and a third group R2; and phenyl of formula I form a group having formula Ic:

<img file="PL2674428T3_D0010.tif" />

[0120] Z1, Z2, Z3, Z4, Z5 are defined above in formula Ib, and R2 is defined above in formula I.

[0121] In several embodiments, each R2 group is independently selected from the group consisting of hydrogen, halogen, OCH3, -OH, -CH2OH, -CH3, and -OCF3, and / or two adjacent groups

<img file="PL2674428T3_D0011.tif" />

<img file="PL2674428T3_D0012.tif" />

selected from the group consisting of hydrogen, halogen, methoxy, phenylmethoxy, hydroxy, hydroxymethyl, trifluoromethoxy and methyl.

[0123] In some embodiments, two adjacent R2 groups, together with the atoms to which they are attached, form

<img file="PL2674428T3_D0013.tif" />

3. Ring A [0124] Ring A is optionally substituted with a 3-7 membered monocyclic ring containing 0-3 heteroatoms selected from N, O and S.

[0125] In several embodiments, ring A is optionally substituted with a 3-7 membered monocyclic cycloaliphatic group. For example, ring A is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl, each of which is optionally substituted with 1-3 halogen atoms, hydroxy groups, C1-5 aliphatic groups, or combinations thereof.

[0126] In other embodiments, ring A is optionally substituted with a 3-7 membered monocyclic heterocycloaliphatic group. For example, ring A is optionally substituted with a 3-7 membered monocyclic heterocycloaliphatic group having 1-2 heteroatoms independently selected from N, O and S. At other embodiments, ring A is tetrahydrofuran-yl, tetrahydro-2H-pyranyl, pyrrolidonyl or piperidinyl, each of which is optionally substituted.

[0127] In yet other embodiments, ring A is selected from

<img file="PL2674428T3_D0014.tif" />

[0128] Each R8 is independently -Z^ER9, in which each Z^Eindependently represents a bond or an optionally substituted branched or straight C 1-5 aliphatic chain in which a maximum of two carbon Z units^E are optionally and independently replaced by -CO-, -CS-, CONR^E-, CO2-, -OCO, -NR^ECO2-, -O-, NR^ECONR^E-, -OCONR^E-, -NR^ENO^E-, -NR^ECO-, -S-, -SO-, -SO2-, -NR^E-, -SO2NR^E-, -NR^ESO2-, or -NR^E2 NR^E-, each R9 is independently R^E, -OH, -NH2, -NO2, -CN, -CF3, oxo or -OCF3. Each R^E independently is hydrogen, optionally substituted cycloaliphatic, optionally substituted heterocycloaliphatic, optionally substituted aryl or optionally substituted heteroaryl.

[0129] q is 0-5.

[0130] In other embodiments, ring A is selected from one of:

<img file="PL2674428T3_D0015.tif" />

XC1

XC2

<img file="PL2674428T3_D0016.tif" />

XC3

XC4

XC5

XC6 .o.

XC4 [0131] In several embodiments, ring A is

4. Ring B [0132] Ring B is a group of formula Ia:

<img file="PL2674428T3_D0017.tif" />

or a pharmaceutically acceptable salt thereof, wherein p is 0-3.

[0133] R3 and R'3 are each independently -Z^CR6, in which each Z^C independently represents a bond or an optionally substituted branched or straight C1-6 aliphatic chain in which a maximum of two Z carbon units^C are optionally and independently replaced by -CO-, -CS-, -CONR^C-, -CONR^CNO^C-, -CO2-, -OCO-, -NR^CCO2-, -O-, -NR^CCONR^C-, -OCONR^C-, -NR^CNO^C-, NO^CCO-, -S-, -SO-, -SO2-, -NR^C-, -SO2NR^C-, -NR^CSO2- or NR^C2 NR^C-. Each R6 is independently R^C, halogen, -OH, -NH2, -NO2, -CN, or -OCF3. Each R^C is independently hydrogen, optionally substituted aliphatic, optionally substituted cycloaliphatic, optionally substituted heterocycloaliphatic, optionally substituted aryl or optionally substituted heteroaryl. Alternatively, any two adjacent R3 groups together with the atoms to which they are attached form an optionally substituted carbocyclic ring or an optionally substituted heterocyclic ring, or R'3 and adjacent R3, i.e. bonded to the 2-position of the indole of formula la, together with the atoms, to which they are attached form an optionally substituted heterocyclic group.

[0134] In several embodiments, ring B is

<img file="PL2674428T3_D0018.tif" />

[0135] wherein q is 0-3 and each R20 is -Z^GR21, where each Z^G independently represents a bond or an optionally substituted branched or straight C 1-5 aliphatic chain, _G in which a maximum of two coal units Z^G are optionally and independently replaced by -CO, -CS-, CONR^G-, CO2-, -OCO, NR^GCO2-, -O-, -OCONR^G-, NO^GNO^G-, -NR^GCO-, -S-, -SO-, -SO2-, -NR^G-, -SO2NR^G-, -NR^GSO2-, -NR^G2 NR^G-. Each R21 is independently R^G, halogen, -OH, -NH2, -NO2, -CN or -OCF3. Each R^G is independently hydrogen, optionally substituted aliphatic, optionally substituted cycloaliphatic, optionally substituted heterocycloaliphatic, optionally substituted aryl or optionally substituted heteroaryl.

[0136] For example, ring B is

<img file="PL2674428T3_D0019.tif" />

[0137] In several embodiments, R'3 is hydrogen and R3 is bonded to the 2, 3, 4, 5, 6 or 7 position in the indole of formula Ia. In other embodiments, R3 is bonded to the 2- or 3-position of the indole of formula Ia, and R3 is independently an optionally substituted aliphatic group. For example, R3 is an optionally substituted acyl group. In several cases, R3 is an optionally substituted (alkoxy) carbonyl group. In other cases, R3 is (methoxy) carbonyl, (ethoxy) carbonyl, (propoxy) carbonyl or (butoxy) carbonyl, each of which is optionally substituted with 1-3 halogen, hydroxy, or combinations thereof. In other cases, R3 is optionally a substituted (aliphatic) carbonyl group. For example, R3 is optionally a substituted (alkyl) carbonyl group which is optionally substituted with 1-3 halogen, hydroxy, or combinations thereof. In other embodiments, R3 is (methyl) carbonyl, (ethyl) carbonyl, (propyl) carbonyl or (butyl) carbonyl, each of which is optionally substituted with 1-3 halogen, hydroxy, or combinations thereof.

[0138] Substituted optionally carbonyl.

substituted in several embodiments, R3 is optionally a (cycloaliphatic) carbonyl group or a substituted (heterocycloaliphatic) group In several examples, R3 is optionally (C3-7cycloaliphatic) carbonyl group. For example, R3 is (cyclopropyl) carbonyl, (cyclobutyl) carbonyl, (cyclopentyl) carbonyl, (cyclohexyl) carbonyl or (cycloheptyl) carbonyl, each of which is optionally substituted with an aliphatic group, halogen, hydroxy, nitro, cyano, or their combinations. In various alternative examples, R3 is optionally a substituted (heterocycloaliphatic) carbonyl group. For example, R3 is an optionally substituted (heterocycloaliphatic) carbonyl group containing 1-3 heteroatoms independently selected from N, O and S. At other embodiments, R3 is optionally a substituted (heterocycloaliphatic) carbonyl group containing 1-3 heteroatoms independently selected from N and O. In yet other embodiments, R3 is optionally a substituted 4-7 membered monocyclic (heterocycloaliphatic) carbonyl group containing 1-3 heteroatoms independently selected from N and O. In an alternative embodiment, R3 is (piperidin-1-yl) carbonyl, (pyrrolidine -1-yl) carbonyl, or (morpholin-4-yl) carbonyl, (piperazin-1-yl) carbonyl, each of which is optionally substituted with 1-3 halogen, hydroxy, cyano, nitro, or aliphatic groups.

[0139] In yet other cases, R3 is an optionally substituted (aliphatic) amide group, such as (aliphatic (amino (carbonyl)), which is bonded to the 2- or 3- position of the indole ring of formula Ia. In certain embodiments, R3 an optionally substituted (alkyl (amino)) carbonyl group that is attached to the 2 or 3 position of the indole ring of formula Ia. In other embodiments, R3 is optionally a substituted straight or branched (aliphatic (amino)) carbonyl group that is bonded to the 2 or 3 position of the indole ring of formula Ia. In some examples, R3 is (N, N-dimethyl (amino)) carbonyl, (methyl (amino)) carbonyl, (ethyl (amino)) carbonyl, (propyl (amino)) carbonyl, (prop-2yl (amino)) carbonyl , (dimethyl (but-2-yl (amino))) carbonyl, (tert-butyl (amino)) carbonyl, (butyl (amino)) carbonyl, each of which is optionally substituted with 1-3 halogen, hydroxy, groups cycloaliphatic, heterocycloaliphatic, aryl, heteroaryl, or combinations thereof. [0140] In other embodiments, R3 is optionally a substituted (alkoxy) carbonyl group. For example, R3 is (methoxy) carbonyl, (ethoxy) carbonyl, (propoxy) carbonyl or (butoxy) carbonyl, each of which is optionally substituted with 1-3 halogen, hydroxy, or combinations thereof. In several cases, R3 is an optionally substituted straight or branched C1-6 aliphatic chain. For example, R3 is optionally substituted straight or branched C1-6alkyl. In other embodiments, R3 is independently optionally substituted methyl, ethyl, propyl, butyl, isopropyl, or tert-butyl, each of which is optionally substituted with 1-3 halogen, hydroxy, cyano, nitro, or combinations thereof, in other embodiments R3 is an optionally substituted C36cycloaliphatic chain. Exemplary embodiments include cyclopropyl, 1-methyl-cycloprop-1-yl, etc. In other embodiments, p is 2 and the two R3 substituents are attached to the indole of formula Ia at the 2,4- or 2,6- or 2,7- positions. Exemplary embodiments include: 6-F, 3- (optionally substituted C1-6 aliphatic or C3-6 cycloaliphatic); 7-F-2 - (- (optionally substituted C1-6 aliphatic or C3-6 cycloaliphatic)), 4F-2- (optionally substituted C1-6 aliphatic or C3-6 cycloaliphatic); 7-CN-2- (optionally substituted C1-6 aliphatic or C3-6 cycloaliphatic); 7-Me-2- (optionally substituted C1-6 aliphatic or C36cycloaliphatic) and 7-OMe-2- (optionally substituted C1-6 aliphatic or C3-6 cycloaliphatic).

[0141] In several embodiments, R3 is hydrogen. In several cases, R3 is an optionally substituted straight or branched C1-6 aliphatic group. In other embodiments, R 3 is an optionally substituted C 3-6 cycloaliphatic group. [0142] In several embodiments, R3 is selected from: -H, -CH3, -CH2OH, -CH2CH3, -CH2CH2OH, CH2CH2CH3, -NH2, halogen, -

<img file="PL2674428T3_D0020.tif" />

<img file="PL2674428T3_D0021.tif" />

<img file="PL2674428T3_D0022.tif" />

[0143] In another embodiment, two adjacent R3 groups form

<img file="PL2674428T3_D0023.tif" />

[0144] In several embodiments, R'3 is independently -Z^CR6, in which each Z^C independently represents a bond or an optionally substituted branched or straight C1-6 aliphatic chain in which a maximum of two Z carbon units^C are optionally and independently replaced by -CO-, -CS-, -CONR^C-, -CONR^CNO^C, -CO2-, -OCO-, -NR^CCO2-, -O-, -NR^CCONR^C-, -OCONR^C-, -NR^CNO^C-, NO^CCO-, -S-, -SO-, -SO2-, -NR^C-, -SO2NR^C-, -NR^CSO2- or NR^C2 NR^C-. Each R6 is independently R^C, halogen, -OH, -NH2, -NO2, -CN or -OCF3. Each R^C independently is hydrogen, optionally substituted aliphatic, optionally substituted cycloaliphatic, optionally substituted heterocycloaliphatic, or optionally substituted heteroaryl. In one embodiment, each R^C represents a hydrogen atom, a C 1-6 aliphatic or C 3-6 cycloaliphatic group in which one of the aliphatic or cycloaliphatic groups is optionally substituted with up to 4 -OH substituents. In another embodiment, R^C is hydrogen or C1-6alkyl optionally substituted with up to 4 -OH substituents.

[0145] For example, in many embodiments, R'3 is independently -Z^CR6, in which each Z^C independently represents a bond or an optionally substituted branched or straight C 1-6 aliphatic chain in which up to two carbon units with Z^C is optionally and independently replaced by the group -C (O) -, -C (O) NR^C-, -C (O) O-, -NR^CC (O) O-, -O-, -NR^C(O) 2- or NR^C-. Each R6 is independently R^C, -OH or -NH2. Each R^C independently is hydrogen, optionally substituted cycloaliphatic, optionally substituted heterocycloaliphatic, or optionally substituted heteroaryl. In one embodiment, each R^C represents a hydrogen atom, a C 1-6 aliphatic or C 3-6 cycloaliphatic group in which one of the aliphatic or cycloaliphatic groups is optionally substituted with up to 4 -OH substituents. In another embodiment, R^C is hydrogen or C1-6alkyl optionally substituted with up to 4 -OH substituents.

[0146] In other embodiments, R'3 is hydrogen or

<img file="PL2674428T3_D0024.tif" />

[0143] wherein R31 is H or a C1-2 aliphatic group which is optionally substituted with 1-3 halogen, -OH, or combinations thereof. R32 is -LR33 wherein L is a bond, -CH2-, -CH2O-, -CH2NHS (O) 2-, -CH2C (O) -, -CH2NHC (O) or -CH2NH-; and R33 represents a hydrogen atom or a C1-2 aliphatic, cycloaliphatic, heterocycloaliphatic, or heteroaryl group, each of which is optionally substituted with one -OH, -NH2 or -CN group. For example, in one embodiment, R31 is hydrogen and R32 is C1-2aliphatic optionally substituted with -OH, -NH2 or -CN.

[0148] In several embodiments, R'3 is independently selected from the following groups: -H, -CH3, -CH2CH3, -C (O) CH3,

CH2CH2OH, -C (O) OCH3,

<img file="PL2674428T3_D0025.tif" />

<img file="PL2674428T3_D0026.tif" />

5. term n [0149] n is 1-3.

[0150] In several embodiments, n is 1. In other embodiments, n is 2. In yet other embodiments, n is 3.

C. Exemplary Compounds of the Present Invention [0151] Exemplary compounds of the present invention include, but are not limited to, those illustrated in

Table 1 below.

<td> 1</td><td> 2</td><td> 3</td>

<td></td><td>"^ ^ Ο -Οελ-ΙO"</td><td>.XcH / °</td>

<td> ....... 4</td><td> 5</td><td> 6"...............</td>

<td>v °^ηΝί</td><td> % .</td><td>'fe ... Ά</td>

<td> 7</td><td> 8</td><td> 9</td>

<td></td><td>UC ^ O ^ -F</td><td>t&gt; s</td>

<td> 10</td><td> 11</td><td> 12</td>

<td>JtUO</td><td></td><td>&gt; J ° these ° £ XH-</td>

<td> 13</td><td> 14</td><td> --</td>

<td>V .ο; s' ο 'nh S</td><td>SIO / JJC &amp; O ·</td><td>F χχ ^ ι</td>

<td></td><td> 17</td><td>Τ8 ""</td>

<td>γ1</td><td>YY?</td><td>ΧΟΗ.9 \ -ο</td>

<td> 19</td><td> 20</td><td>........ ~ Ζϊ ...... ........</td>

<td>S</td><td>oO ^ jCdH^-</td><td>Ν. '' C γ</td>

<td> 22</td><td> 23</td><td> 24</td>

<td></td><td>Ύγ, γί</td><td></td>

<td> 25</td><td> 26</td><td> 27</td>

<td> \</td><td></td><td>γ. ν ° ο Ρ ΧΧ $ ^_ΚΧΧΗ ~</td>

<td> 28</td><td> 29</td><td> 30</td>

<td></td><td>° '- &lt;Χ ο rY "^N\ I οΛ1 &lt;Υν · ~ ΥΥΥι</td><td>χ ^ Υ) ο Υ</td>

<td> 31 ·</td><td> 32</td><td> 33</td>

<td>-about ^H3 ΧΧΥΑλΧΗ^-</td><td>And OQl</td><td>Λ-9 X ° cSa Η</td>

<td> 34</td><td> 35</td><td> 36</td>

<td>^ οΧ_Η-Ο&gt; _ ^ + ^^</td><td>V Η /^θτίΥ ίί ηΛ ι ίΛΧ ^ ΑΛΗ-</td><td>Ν._νΗ Ν⁷ ϊ Γ ΟΎ ίί ιΓΥΥ— ρ οΑΥΑ ^ ΛΥ / I</td>

<td> 37</td><td> 38</td><td> 39</td>

<td>ę?</td><td></td><td>,,,,, Λ</td>

<td> 40</td><td> 41</td><td> 42</td>

<td> ° 1</td><td></td><td>^Ηο , ϊ η, ΧχυΆ ,, FA ° F</td>

<td> 43</td><td> 44</td><td> 45</td>

<td>H . ABOUT_p X ... h_nXXH ~ ZyYso 07 ^ Ύ</td><td>H ABOUT / γγ in tJrA I JL JL JL JL-zi</td><td>0 ΧΧΧλ ^ λΧΗ^-</td>

<td> 46</td><td> 47</td><td> 48</td>

<td></td><td>Ά / Ύ = ι η ιΧτΧ</td><td>ΧΧχοΧΧχ Χ53Η^-</td>

<td> 39</td><td> 50 ~</td><td> -</td>

<td>Β &lt;Jt J Π AJLzi</td><td> £0^00^</td><td></td>

<td> 52</td><td> 53</td><td> 54</td>

<td></td><td>&lt;"° τΡί ° fPx^M) 1</td><td></td>

<td> 55</td><td> 56</td><td> 57</td>

<td>5 η_ν)03+ 0 7^</td><td>&lt;Χιϊ ΧΧ ^</td><td>F ο «-Χγ-Α 1 &lt;XXXΧΧΗ ~</td>

<td> ' 58</td><td> 59</td><td> 60</td>

<td>Η Ν-Ν Μ «· ^ .Ν ΧπΗΔΑ_Ο07 ^ Κ-Ο</td><td>\ Α ^ ΧΖΧ ^ Λ- | .</td><td>CCr ττχ&gt; 4 Ά</td>

<img file="PL2674428T3_D0027.tif" />

<img file="PL2674428T3_D0028.tif" />

<img file="PL2674428T3_D0029.tif" />

<td>-Ί57</td><td>S8</td><td> ' "§9</td>

<td>ΎΧΧΐΥΥ</td><td></td><td></td>

<td> 100</td><td> 101</td><td> 102</td>

<td>8 ο / Χι ° [ιτΎ I &lt;JL JL</td><td>Αχγ ^ Ν-θΑ - (-</td><td>^vabout s v ° jOA^-l^-</td>

<td> 103</td><td> 104</td><td> 105</td>

<td></td><td>α "_and33e._B-What +</td><td></td>

<td> 106</td><td> 107</td><td> 108</td>

<td>in / χΥ</td><td>θ3 and</td><td>H ABOUT α η "Χ0ί&gt; ΔΛο about hr °</td>

<td>- 109 OH</td><td> ' " 110</td><td>~ -O Ό</td><td>ΓΠ H about iftorA I JL Ate / r \ H</td>

<td> 112</td><td> 113</td><td colspan="2"> 114</td>

<td>JCO ~</td><td>at P ^ ^ ΟΧΡ ΧΧΉ^-</td><td>l xl</td><td>H O and &lt;^L»|-*^IN\ | JL AtetoT _ϊ H</td>

<td> 115</td><td> 116</td><td colspan="2"> 117</td>

<td>° pO ^ + ^ JCO</td><td>o-teto ° tete-N H</td><td>^fromT °)</td><td>t ° ito^ssr^Ms__L L JL Ato / r</td>

<td> 118</td><td> 119</td><td colspan="2"> 120</td>

<td>λ P H "Xtototo Ato% of</td><td>Φ / Λη</td><td colspan="2"></td>

<td>ABOUT ter °</td><td></td><td></td><td></td>

<td> -</td><td> 122</td><td> 123</td>

<td>/ ο</td><td>^ θτΧι u jTKz) I</td><td>^Ηο^CXXA χχ ^ I</td>

<td> 124</td><td> 125</td><td> 126</td>

<td>Η Χθ / Χ ΧΧ ^ ι</td><td></td><td>SC ^ CYH-gg</td>

<td> 127</td><td> 128</td><td> ' 129</td>

<td>οϊχ ^^ 'Οΰ ^ ^ -χ</td><td>θ jC ^ Cy¹</td><td>at γύ5 ί θ^οΛ^ δ</td>

<td> ‘ 130</td><td> 131</td><td> 132</td>

<td>Χ5 .ο5- £ ^ £ _ (</td><td>9 Ό^C'ó ^ xxS l</td><td></td>

<td>- Ϊ33 ~</td><td> 134</td><td>T3tT</td>

<td>cS^hOare jQA 1</td><td>icy. ^ ^ monovalent hydrocarbon jcó- · * '</td><td>JkjCCA</td>

<td> 136</td><td> 137</td><td> 138</td>

<td>at X</td><td>H</td><td>_n"R cqVtcc&gt;</td>

<td> 139</td><td> 140</td><td> 141</td>

<td>Y ^ Z¹AND about .</td><td> £0^.03-^</td><td>, ° v ^ ia AL</td>

<td> 142</td><td> 143</td><td> 144</td>

<td>ZaYYo ρΑ "° F</td><td>X Ν N. ΗΧΧ ^ νΧΧΗ^- .</td><td>YoXXY_andJ03 +</td>

<td>-Ϊ45--</td><td>Ϊ46 ————</td><td> 147</td>

<td></td><td>&lt;Χ ^_Β.αΥ</td><td></td>

<td> 148</td><td> 149</td><td> 150</td>

<td></td><td>Χϊ ΧΧμ £ ^&gt;</td><td>&lt;° τΎ ϊ jfP&gt; οΛΛ ^ ΑΛν</td>

<td> 151</td><td> 152</td><td> 153</td>

<td>ΠΗ</td><td>ζί βίο-ζ ^ ^</td><td>/ - &lt;? t. OXD&gt; r °</td>

<td> 154</td><td> 155</td><td> 156</td>

<td></td><td>y * o "ίΧ</td><td> "^Ο\ ___ H</td>

<td>Τ57</td><td>Ϊ58 "</td><td>-Ϊ53 κ ο</td>

<td>Η · η Κ. _η</td><td>ίΊ Λ -</td><td></td>

<td></td><td>^ || η u ί) j5) _ &lt;3</td><td> ^^ο3θ ^ Χ jO-j 'I 162</td>

<td> 160</td><td> 161</td><td>^Ηο</td>

<td></td><td>&lt;χ</td><td> , $</td>

<td>ΡΧ R ιΡ'ίΡι_I</td><td>V</td><td>η_νΧΧΜ ~</td>

<td>Μ1_νλ / Ρι</td><td>VT ° Η</td><td>Δτ- ^ Ο</td>

<td></td><td>^ΗΧΡ</td><td>0 7 ^ Ρτ ° F 1RR</td>

<td>163 "" ΧΧΗ-</td><td>164 . οοΧρ</td><td>Η ^ "τΡί ° ΡτΧI</td>

<td>ΖαΧ ^ ο</td><td></td><td>'^ ^ Ρϊ Ο</td>

<td>ιί]</td><td>η</td><td>ΥΥ</td>

<td>ο '^ Τ \ _ο</td><td>\ __ ο</td><td> " " 168</td>

<td>- 166 ρ £</td><td> 167</td><td>Η Ο</td>

<td>η_νχχΗ " Ζ-Υ ^ Ο</td><td>V " ^ θ-τί ^?, rPr \ I ρ^χοΛ ΛνΛΑ ^ ^ Ί</td><td>^&lt;θΧ5 ^ Χ J0 | X |</td>

<td>\ _ο</td><td></td><td></td>

<td> 169</td><td> 170</td><td> 171</td>

<td>HN γ</td><td></td><td>"^ Οΐ_Η-θά νο + ^ _</td>

<td> 172</td><td> 173</td><td>174 I</td>

<td>ΧΰΥ ΥΑο AND</td><td>ςΧΧβ XX? C in Ν</td><td>&lt;X ΥοΧ ^ μΧΧΗ^-</td>

<td> ”" 175</td><td> 176</td><td> 177</td>

<td>ΐ Η^&lt;οΧΧα jQcS I</td><td>Ϊ Η ΑΪΧ λ £ ΧΗ-</td><td>^ σΧΡο</td>

<td> ' 178</td><td> - 179</td><td> 180</td>

<td>ν ° "Η Υ ΝΧτχΧϊΉ-</td><td>$ »- μ^η^Ν λ r jOY AND</td><td>_ρ Ρ Η "ΧΧ) + ΔχΧ ^ οΎ \ _ο</td>

<img file="PL2674428T3_D0030.tif" />

<td> " 193</td><td> 194</td><td> 195</td>

<td>&lt;5 γ</td><td> 0^ ^Ηογ</td><td>&lt;°: 0 ° C 8. jq3 I °</td>

<td> 196</td><td> 197</td><td>^Jl ' 198</td>

<td>&lt;Jo /_sJok</td><td>. X</td><td>/ ° ΥΥ 9 ιΧτΆ I YJL JL Λ ΛΥ / ι</td>

<td> 199</td><td> 200</td><td> 201</td>

<td>^Ηο_Ρ S "ΧΰΥ ΔΑ_Ο\ _ο</td><td></td><td>"ν ^ οΧΧθ ΧΧν Η</td>

<td> 202</td><td> 203</td><td> 204</td>

<td></td><td>Q ρ Ο Y ^ y-Ή. AND ρΚαΧΛ ^ ΧλΉ^-</td><td>'χ ^ ϊ cŚl ·</td>

<img file="PL2674428T3_D0031.tif" />

<td> 217</td><td> 218</td><td>-5Τ0</td>

<td></td><td>_Λ.ο</td><td> 0=1=0 ^ΗΧ Η ζ ° τγ ^ ι a ΑτΆ 1 &lt;Η JL X JLJLyi</td>

<td> -550 "</td><td> 221</td><td> 222</td>

<td>ν ° JpJ I</td><td>Η ΗΝ</td><td>/ γγ a AA 1</td>

<td> 223</td><td> “ 224</td><td> ” 225</td>

<td>SO-G ^ JCO</td><td>coYoX Η</td><td> |</td>

<td> 226</td><td> 227</td><td> 228</td>

<td>Η ΧΧυ ι</td><td>F / Υή fl ΑτΑηυ</td><td>ζχ φο5 ~ ^ α</td>

<td> 229</td><td> 230</td><td> 231</td>

<td>γ ο » this &gt; CClXjO3 +</td><td>"UX ^" XXW&gt;</td><td>AND a. o texS |</td>

<td> 232</td><td> 233</td><td> 234</td>

<td>H</td><td>* :: Ο /_Β.0ΰ +</td><td></td>

<td> 235</td><td> 236</td><td> 237</td>

<td>FROM about^&lt;OX5 ^ l_{! j}Joo +</td><td>Ctotetotototo</td><td></td>

<td> 238</td><td> 239</td><td> 240</td>

<td>j0c $ 1</td><td>this" HM X ° F X5tentoXtot-</td><td></td>

<img file="PL2674428T3_D0032.tif" />

<td> -553</td><td>25ί</td><td> 255</td>

<td>_η Τ η^Η and</td><td>? η ΧΧΑΧΧΗ-</td><td></td>

<td> 256</td><td> 257</td><td> 258</td>

<td>ρΥΧΧλ Χ ^ ΰΗ^-</td><td>&lt;: Πο / "αΎ</td><td></td>

<td> 259</td><td> 260</td><td> 261</td>

<td>OO / "jCcY</td><td>° = ζ</td><td>ί¹'ΐί ηΧΧΗ^-ΖΧο 0 7 ^ \ _ο _</td>

<td> 262</td><td> 263</td><td>Τ53</td>

<td>/ - Ο Υ.^Μρα&gt;</td><td>χργ 1</td><td>η&gt; ΧίΎ \ -1 οΛΧ ° ΌΤνΥΓ π</td>

<td> -265</td><td> 266</td><td> -267———</td>

<td>Ρ</td><td>'O ° /_andxte</td><td>H^Hthese H / "- rtoto o linA l LA / 1 Ji AJtoi</td>

<td> ' 268</td><td> 269</td><td> 270</td>

<td>^ ^ ΧΡ ΧΧΗ "Χ &lt;;_:ν</td><td>this °</td><td>teijooto</td>

<td> 271</td><td> 272</td><td rowspan="2"></td>

<td>v ° HM these jQjX |</td><td>this jQU l</td>

<td> 273</td><td> -273</td><td> 275</td>

<td> £ '</td><td>° -Ν "V</td><td>ο</td>

<td>Ύ</td><td>^θϊ?: Θ ΗΝ</td><td>-? = Ο ΗΝ</td>

<td></td><td> *%</td><td>Η</td>

<td>ΚηΧΧΛ ΧΧΗ^-</td><td></td><td>toOU. Jouy</td>

<td> 276</td><td> 277</td><td> 278</td>

<td>Η Ο^Η°·^</td><td></td><td></td>

<td>γχσγ YL ^Ηγ</td><td></td><td>γχ / Υαχ Η</td>

<td> 279</td><td> 280</td><td> 281</td>

<td></td><td>Η Ο \</td><td></td>

<td> ;&gt;&lt;:0/_Β-0Υθ</td><td>Μ&gt;</td><td>s _Fχχχχ ΧΧυ-ρ</td>

<td> 282</td><td> 283</td><td> 284</td>

<td> \</td><td>COG °</td><td>% fu</td>

<td>0-2 ~? = Ο</td><td>r&gt;</td><td></td>

<td>^ lOtoCoH-</td><td>Η ^ CO ^ jCcH^-</td><td> ----</td>

<img file="PL2674428T3_D0033.tif" />

<img file="PL2674428T3_D0034.tif" />

[0152] Another aspect of the present invention provides a compound that is useful in modulating ABC transporter activity. The compound has the formula Ic:

<img file="PL2674428T3_D0035.tif" />

or a pharmaceutically acceptable salt thereof.

[0153] R1, R2 and ring A are as defined above for formula I, and ring B, R3 and p are as defined in formula Ia. In addition, when ring A is unsubstituted cyclopentyl, n is 1, R2 is 4-chloro, and R1 is hydrogen, then ring B is not 2- (tert-butyl) indol-5-yl or (2,6-dichlorophenyl (carbonyl) ) -3-methyl-1H-indol-5-yl; and when ring A is unsubstituted cyclopentyl, n is 0, and R1 is

<img file="PL2674428T3_D0036.tif" />

useful for modulating ABC transporter activity. Compound of formula Id:

<img file="PL2674428T3_D0037.tif" />

Ri, R₂ and ring A have the meanings given above for formula I, and ring B, R₃ and p are as defined in formula Ia.

[0156] However, when R₁ is H, n is 0, ring A is substituted with cyclopentyl, and ring B is indol5-yl substituted with 1-2 R groups₃, it's each R group₃ means independently -z^GR12, in which each Z^G independently represents a bond or unsubstituted branched or straight chain C1-6 aliphatic in which up to two carbon units of the group Z^G is optionally and independently replaced by -CS-, CONR^gNO^g-, -CO2-, -OCO-, -NR^gCO2-, -O-, -NR^gCONR^g-, -OCONR^g-,

-No^gNo.^g-, -s-, -so, so2-, -no^g-, -so2nr^g-, -no^gso2-, -no^g2 NR^c, each R12 is independently R^G, halogen, -OH, -NH2, -NO₂, -CN or -OCF₃and each of R^G is independently hydrogen, unsubstituted aliphatic, optionally substituted cycloaliphatic, optionally substituted heterocycloaliphatic, substituted aryl, or optionally substituted heteroaryl; or any two adjacent R groups₃ together with the atoms to which they are attached they form an optionally substituted heterocyclic group. In addition, when R₁ is H, n is 1, R₂is 4-chloro, ring A is substituted with cyclopentyl, and ring B is indol-5-yl substituted with 1-2 groups R3, then each R3 is independently a group Z^hR22, in which each Z^H independently represents a bond or unsubstituted branched or straight Cx-3 aliphatic chain in which up to two Z carbon units^H, is optionally and independently replaced by -CS-, -CONR^HNO^H' ^-CO2- -OCO-, -NR^hCO2-, -O-, -NR^hCONR^h-, -OCONR^h-, -NR^hNO^h-, -S-, -SO-, -SO2-, -NR^h-, -SO2NR^h-, -NR^hSO2-, or -NR^H2 NR^H-, each R22 is independently R^H, halogen, -OH, -NH2, -NO2, -CN or -OCF3, and each R^H is independently hydrogen, substituted C4-alkyl, optionally substituted C2-6 alkenyl, optionally substituted C2_-6 alkynyl, optionally substituted with C4_-alkenyl, optionally substituted with C4_-alkynyl, optionally substituted cycloaliphatic, optionally substituted heterocycloaliphatic, optionally substituted heteroaryl, unsubstituted phenyl, or monosubstituted phenyl or any two adjacent R3 groups together with the atoms to which they are attached form an optionally substituted heterocyclic group.

[0157] Another aspect of the present invention provides a compound that is useful in modulating ABC transporter activity. The compound has formula IIa:

<img file="PL2674428T3_D0038.tif" />

or a pharmaceutically acceptable salt thereof.

[0158] R1, R2 and ring A are as defined above in formula I; R3, R'3, and p are as defined above in formula Ia; and Z1, Z2, Z3, Z4, and Z5 are as defined above in formula Ib.

[0159] Another aspect of the present invention provides a compound that is useful in modulating ABC transporter activity. The compound has formula IIb:

<img file="PL2674428T3_D0039.tif" />

IIb or a pharmaceutically acceptable salt thereof.

[0160] R1, R2 and ring A are as defined above in formula I; R3, R'3, and p are as defined above in formula Ia; and Z1, Z2, Z3, Z4, and Z5 are as defined above in formula Ib.

[0161] Another aspect of the present invention provides a compound that is useful in modulating ABC transporter activity. The compound has formula IIb:

<img file="PL2674428T3_D0040.tif" />

or a pharmaceutically acceptable salt thereof.

[0162] R1, R2 and ring A are as defined above for formula I; and R3, R'3 and p are defined as in formula Ib.

[0163] Another aspect of the present invention provides a compound that is useful in modulating ABC transporter activity. The compound has formula IIc:

<img file="PL2674428T3_D0041.tif" />

[0164] R₁, R₂ and n are as defined above for formula I, and R₃, R '₃ and p are defined as in the formula

Ia.

[0165] Another aspect of the present invention provides a compound that is useful in modulating transporter activity

ABC. The compound has formula IId:

<img file="PL2674428T3_D0042.tif" />

or a pharmaceutically acceptable salt thereof.

[0166] Both groups of R₂, together with the atoms to which they are attached, form a group selected from:

<img file="PL2674428T3_D0043.tif" />

<a name="caption1"></a>U. and A.,

H oh

ΧΑ19

ΧΑ20

ΧΑ21 [0161] R '₃ is independently selected from the following groups: -H, -CH₃, -CH2CH3, -C (O) CH₃, CH2CH2OH, -C (O) OCH3,

<img file="PL2674428T3_D0044.tif" />

and each R₃ is independently selected from the group consisting of -H, -CH3, -CH2OH, -CH2CH3, CH2CH2OH, CH2CH2CH3, -NH2, halogen,

<img file="PL2674428T3_D0045.tif" />

<img file="PL2674428T3_D0046.tif" />

IV. GENERAL SYNTHESIS SCHEMES [0168] Compounds of formulas (I, Ic, Id, II, IIa, IIb, IIc and IId) can be easily synthesized by known methods from commercially available or known starting materials. Exemplary synthetic routes for the preparation of compounds of formulas (I, Ic, Id, II, IIa, IIb and IIc and IId) are shown below in Schemes 1-22.

[0169] The preparation of compounds of the invention is obtained by coupling the amine ring B to the carboxylic acid ring A, as shown in Scheme 1.

Diagram 1

<img file="PL2674428T3_D0047.tif" />

DCM / DMF.

[0170] According to scheme 1, acid 1a can be converted to the corresponding acid chloride using thionyl chloride 1b in the presence of a catalytic amount of dimethylformamide. Acid chloride reaction with an amine

<img file="PL2674428T3_D0048.tif" />

provides compounds of the invention 1. Alternatively, acid 1a can be directly coupled to an amine using known coupling reagents such as, for example, HATU in the presence of triethylamine.

[0171] The preparation of acids 1a can be carried out as shown in scheme 2.

Diagram 2

<img file="PL2674428T3_D0049.tif" />

a) NaOH, BTEAC; b) NaOH, Δ [0172] According to scheme 2, nitrile 2a reacts with the appropriate bromochloroalkane in the presence of sodium hydroxide and a phase transfer catalyst such as butyltriethylammonium chloride resulting in intermediate 2b. Hydrolysis of nitrile 2b leads to the formation of acid 1a. In some cases, isolation of intermediate 2b is not necessary.

[0173] Phenylacetonitrile 2a is commercially available or can be prepared as shown in scheme 3.

Diagram 3

<img file="PL2674428T3_D0050.tif" />

[0174] According to scheme 3, the reaction of aryl bromide 3a with carbon monoxide in the presence of methanol and tetrakis (triphenylphosphine) palladium (0) results in the formation of ester 3b. Reduction of 3b with lithium aluminum hydride results in the production of 3c alcohol, which is converted into a halide

3d using thionyl chloride. The reaction of compound 3d with sodium cyanide leads to the formation of nitrile 2a.

[0175] Other methods for producing nitrile 2a are outlined in Schemes 4 and 5 below.

Diagram 4

<img file="PL2674428T3_D0051.tif" />

a) TosMIC; b) NaBH₄, THF; c) SOC1₂; d) NaCN

Diagram 5

<img file="PL2674428T3_D0052.tif" />

[0176] Preparation

<img file="PL2674428T3_D0053.tif" />

individual elements are illustrated in the following diagrams. A number of processes have been reported for the preparation of compounds having a B ring in which the B ring is indole. For example, Angew. Chem. 2005, 44, 606; J. Am. Chem. Soc. 2005, 127, 5342); J. Comb. Chem. 2005 7, 130;

Tetrahedron 2006, 62, 3439; J. Chem. Soc. Perkin Trans. 1

2000, 1045.

[0177] One method for preparing rn- (b) is illustrated in Scheme 6.

Diagram 6

<img file="PL2674428T3_D0054.tif" />

[0178] According to scheme 6, nitroaniline 6a is converted to a hydrazine compound 6b with nitric acid in the presence of hydrogen chloride and tin chloride. Reaction 6b with an aldehyde or ketone CH₃C (O) R₃, provides the hydrazone compound 6c, which after treatment with phosphoric acid in toluene results in a mixture of 6d and 6e nitroindoles. Catalytic hydrogenation in the presence of palladium on carbon results in a mixture of 6f and 6g aminoindoles, which can be separated by known methods such as, for example, chromatography.

[0179] Another method is illustrated in Scheme 7.

Diagram 7

<img file="PL2674428T3_D0055.tif" />

7f 7g 7h

a) R_3aCOCl, Et₃N, CH₂C1₂; b) n-BuLi, THF; c) NaBH₄, AcOH; d) KNO₃, H₂SO₄; e) DDQ,

1,4-dioxane; f) NaNO₂, HCl, Sn.Cl₂.2H₂Oh₂ABOUT; g) MeCOR₃, EtOH; h) PPA; i) Pd / C, EtOH or H₂, Raney Ni, EtOH or MeOH

Diagram 8

<img file="PL2674428T3_D0056.tif" />

a) HNO₃, H₂SO₄; b) Me₂NCH ​​(OMe)₂, DMF; c) H.₂, Raney Ni, EtOH

100

<img file="PL2674428T3_D0057.tif" />

Diagram 10

<img file="PL2674428T3_D0058.tif" />

<img file="PL2674428T3_D0059.tif" />

101

Diagram 12

<img file="PL2674428T3_D0060.tif" />

a) R_3aCH₂COR_3b, AcOH, EtOH; b) H.₃AFTER₄, toluene; c) H._from, Pd / C, EtOH

Diagram 13

<img file="PL2674428T3_D0061.tif" />

a) NaBH₃CN; b) when PG = SO₂Ph: PhSO₂Cl, Et₃N, DMAP, CH₂C1₂; when PG = Ac: AcCl, NaHCO₃, CH₂C1₂; c) when R^v= RCO: (RCO) 2O, A1C13, CH2C12; when R^v= Br: Br2, AcOH; d) HBr or HCl; e) KNO₃, H₂SO₄; f) MnO₂, CH₂C1₂ or DDQ, 1,4-dioxane; g) H₂, Raney Ni, EtOH.

Diagram 14

<img file="PL2674428T3_D0062.tif" />

(^R3) p-1 (^R3) p-1

a) NaBH₃CN; b) RSO₂C1, DMAP, Et₃N, CH₂C1₂; c) R^DC (O) C1, A1C1₃, CH₂C1₂; d) NaBH₄,

THF; e) HBr; f) KNO₃, H₂SO₂; g) MnO₂; g) Raney Ni, H₂, EtOH

102

<img file="PL2674428T3_D0063.tif" />

Diagram 16

<img file="PL2674428T3_D0064.tif" />

Diagram 17

<img file="PL2674428T3_D0065.tif" />

a) Br₂, AcOH; b) RC (O) C1, Et₃N, CH₂C1₂; c) HCsCR_3a, Pd (PPh₃) ₂C1₂, Cul, Et₃N; d) TBAF, THF or tBuOK, DMF or Pd (PPh₃) ₂C1₂, Cul, DMF; e) H.₂, Pd / C, EtOH and SnCl₂, MeOH or HCO2NH4, Pd / C, EtOH

103

Diagram 18

<img file="PL2674428T3_D0066.tif" />

a) Br₂, AcOH, CHCl₃; b) R_3aC = CH, Cul, Et₃N, Pd (PPh₃) ₂C1₂; c) RCOC1, Et₃N, CH₂C1₂; d) TBAF, DMF; e) Raney Ni, H₂, MeOH; f) YEAR, DMF

<img file="PL2674428T3_D0067.tif" />

Diagram 20

<img file="PL2674428T3_D0068.tif" />

a) H₂NR₃; b) X = Br: Br₂, HOAc; X = I: NIS; c) HC = CR₃, Pd (PPh₃)₂cl₂, Cul, Et₃N; d) Cul, DMF or TBAF, THF; e) H.₂, Pd / C, EtOH or SnCl₂, MeOH or HCO₂NH4, Pd / C, EtOH

104

<img file="PL2674428T3_D0069.tif" />

Diagram 22

<img file="PL2674428T3_D0070.tif" />

a) R_3aCs = CH, Cul, TEA, Pd (PPh₃) ₂C1₂; b) TBAF, THF; c) Raney Ni, MeOH

<img file="PL2674428T3_D0071.tif" />

105

Diagram 24

<img file="PL2674428T3_D0072.tif" />

<img file="PL2674428T3_D0073.tif" />

Diagram 26

<img file="PL2674428T3_D0074.tif" />

a) LiOH; b) EDC, HOBt, Et₃N, HNRyRz; c) BH3-THF; d&gt; śiiRz-H, RC (O) C1 (Z = RC (O) -) i_ubRSO2CI (Z = RSO₂-) or RO (CO) C1 (Z = RO (CO) -) or (RO (CO))₂O (Z = Z = RO (CO) -), Et₃N, CH₂C1₂

106

Diagram 27

<img file="PL2674428T3_D0075.tif" />

Diagram 28

<img file="PL2674428T3_D0076.tif" />

Diagram 29

<img file="PL2674428T3_D0077.tif" />

Diagram 30

<img file="PL2674428T3_D0078.tif" />

NRyRz

a) NaOH or LiOH; b) ROH, HCl; c) NaBH₄or LiAlH₄or DIBAL-H, THF; d) HNRyRz, HATU, Et₃N, EtOH or DMF; e) LiAlH₄, THFiub BH₃ THF; f) H.₂ABOUT₂, H₂O (Ry = Rz = H); g) H₂, Pd / C

107

Diagram 31

<img file="PL2674428T3_D0079.tif" />

a) R_and-X, NaH; R_b-X, NaH; b) PC1₅, CH₂C1₂; c) NaOH; d) NaNH₂, DMSO; e) CH₂N₂; f) Pd (PPh₃) 4, Cul, Et₃N; g) RC (O) Cl,_Pir_Vd, CH₂C1₂; h) Pd (CH₃CN) ₂C1₂, CH₃CN; i) Raney Ni, H₂, MeOH

Diagram 32

<img file="PL2674428T3_D0080.tif" />

a) LiOH, THF / H2O; b) HNRyRz, HATU, TEA, DMF / CH₂C1₂

Diagram 33

<img file="PL2674428T3_D0081.tif" />

a) LiBH₄, THF / H₂Oiub L1AIH4, THF; b) R_and-Li, THF

108

Diagram 34

<img file="PL2674428T3_D0082.tif" />

Diagram 35

<img file="PL2674428T3_D0083.tif" />

Diagram 36

<img file="PL2674428T3_D0084.tif" />

a) NaH, DMF-THF; R₃-X (X = C1, Br, I, or OTs)

Diagram 37

<img file="PL2674428T3_D0085.tif" />

R₃

a) NBS; b) Ar-B (OR)₂, Pd-FibreCat 1007, K₂WHAT₃, EtOH

109

Diagram 38

<img file="PL2674428T3_D0086.tif" />

r₃

a) RSOiCl, NaH, THF-DMF; b) R₃-X (X = Br, I, or OTs), NaH, THF-DMF; c) ethylene oxide, InCl₃; d) POC1₃, DMF; e) H.₂N-OH, CH₂C1₂; ac₂ABOUT

Diagram 39

<img file="PL2674428T3_D0087.tif" />

110

Diagram 40

<img file="PL2674428T3_D0088.tif" />

a) TsCl, Et₃N, CH₂C1₂; b) NaCN, DMF; c) NaOH, MeOH; d) NaN₃, NH4Cl; e) NaN₃, DMF; f) Pd / C, H₂, MeOH (R = H); h) R^XC (O) C1 (Z = R^XC (O) -) and R^xSO2Cl (Z = R^XSO2-) or R^XO (CO) C1 (Z = R^XO (CO) -) or (R^xO (C0)) 2O (Z = R^XO (CO) -), Et3N, CH₂C1₂

Diagram 41

<img file="PL2674428T3_D0089.tif" />

nh₂ NHZ

a) C1CH₂CHO, NaHB (OAc)₃, CH₂C1₂; CDC1₃, lights, b) NaN₃, Nal, DMF; c) H.₂, Pd / C,

MeOH, AcOH; d) RC (O) C1 (Z = RC (O) -) and RSPO₂Cl (Z = RSO₂-) or RO (CO) C1 (Z = RO (CO) -) or (RO (CO)) ₂O (Z = RO (CO) -), Et₃N, CH₂C1₂ [0180] In the above schemes, the R radical used is a substituent, for example RW, as defined above. [0180] One skilled in the art will readily recognize that the appropriate synthetic routes for the various substituents of the present invention are such that the reaction conditions and steps used do not affect the intended substituents.

111

V. PREPARATIONS, ADMINISTRATION AND APPLICATIONS [0181] Accordingly, in another aspect of the invention, pharmaceutically acceptable compositions are provided, wherein these compositions comprise any of the compounds as described herein, and optionally contain a pharmaceutically acceptable carrier, adjuvant or vehicle. In some embodiments, these compositions optionally further comprise one or more additional therapeutic agents.

[0182] It will also be appreciated that certain compounds of the present invention may be used in the treatment in free form, or as appropriate, in the form of a pharmaceutically acceptable derivative or prodrug thereof. According to the invention, a pharmaceutically acceptable derivative or prodrug includes, but is not limited to, pharmaceutically acceptable salts, esters, salts of such esters or any other adduct or derivative which, when administered to a patient in need thereof, is capable of delivering, directly or indirectly unless otherwise indicated compound or metabolite or residue thereof.

[0183] As used herein, the term "pharmaceutically acceptable salt" refers to those salts that are, within reasonable medical judgment, suitable for use in contact with human tissues and lower animals without excessive toxicity, irritation, allergic reaction and similar, and are appropriate in the appropriate balance of benefits and risks. "Pharmaceutically acceptable salt" means any non-toxic salt or salt of an ester of a compound of this invention that, when administered to a patient, is capable of delivering, directly or indirectly, a compound

112 according to the present invention or an inhibitory active metabolite or a residue thereof.

[0184] Pharmaceutically acceptable salts are well known in the art. For example, S. M Berge, et al. Describes in detail pharmaceutically acceptable salts in J. Pharmaceutical Sciences, 1977, 66, 1-19, incorporated herein by reference. Pharmaceutically acceptable salts of the compounds of the invention include those that are derived from the appropriate inorganic or organic acids and bases.

Examples of pharmaceutically acceptable, non-toxic acid addition salts are salts of the amino group formed using inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid, or with organic acids such as acetic acid, oxalic acid, maleic acid , tartaric acid, citric acid, succinic acid or malonic acid, or using other methods used in the art, such as ion exchange. Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphors, camphorsulfonate, citrate, cyclopentanopropionate, digluconate, dodecyl sulfate, ethane sulfonate, formate, phosphonate, gluconate, gluconate, gluconate , hemisulfate, heptanoate, 2-hydroxyethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, pamoate, pectate, phosphate, picrate, oleate, oxalate, palmitate, persulfate, 3-phenylpropionate, pivalate, propionate, stearate,

113 succinate, sulfate, tartrate, thiocyanate, ptoluenesulfonate, undecanoate, valerate salts and the like. Salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium and N + (C14alkyl) 4 salts. The invention also provides for the quaternization of any nitrogen-containing groups of the basic compounds disclosed herein. Products soluble in water or in oil or for suspension can be obtained by such quaternization. Suitable alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium salts and the like. Further pharmaceutically acceptable salts include, if appropriate, non-toxic ammonium, quaternary ammonium and counterions, carboxylate, hydroxide, amine cations, formed from halides, sulfate, phosphate, nitrate, lower alkyl sulfonate and aryl sulfonate.

[0185] As described above, the pharmaceutically acceptable compositions of the invention further comprise a pharmaceutically acceptable carrier, adjuvant, or vehicle which, as used in the invention, includes any and all solvents, diluents or other liquid vehicles, dispersion or suspension aids, surface agents active, isotonic, thickening or emulsifying agents, preservatives, solid binders, glidants and the like, suitable for the particular dosage form required. Remington's Pharmaceutical Sciences XVI edition, EW Martin (Mack Publishing Co., Easton, Pa., 1980) discloses various carriers used to form pharmaceutically acceptable forms

114 compositions and known techniques for their preparation. Insofar as any conventional carrier is not incompatible with the compounds of the invention, as long as it does not cause undesirable biological effects or otherwise, it does not adversely interact with any other component (s) of the pharmaceutically acceptable composition, and its use is considered 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 serum albumin, buffering substances such as phosphates, glycine, sorbic acid , or potassium sorbate, mixtures of partial saturated glycerides of vegetable fatty acids, water, salts or electrolytes such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinylpyrrolidone, polyacrylates, waxes, polyethylene-polyoxypropylene block polymers, wool fat, sugars such as lactose, glucose and sucrose; starch 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; talc; an excipient 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; for example propylene glycol or polyethylene glycol; esters such as ethyl oleate and ethyl laurate; agar; buffering agents such as magnesium hydroxide and aluminum hydroxide; acid

115 alginic; pyrogen-free water; isotonic saline; Ringer's solution; ethyl alcohol and phosphate buffer solutions, as well as other non-toxic compatible lubricants such as sodium lauryl sulfate and magnesium stearate, as well as coloring agents, release agents, coating agents, sweeteners, flavors and flavors, preservatives and antioxidants may also be present in the composition, according to the decision of the person preparing the character.

[0186] Still another aspect, the invention provides a method of treating a condition, disease or disorder in which ABC transporter activity is involved. In some embodiments, the invention provides a method of treating a condition, disease or disorder associated with an ABC transporter deficiency, comprising administering a composition comprising a compound of formulas (I, Ic, Id, II, IIa, IIb, IIc and IId) to a patient, preferably a mammal who needs it.

[0187] In certain preferred embodiments, the invention provides a method of treating cystic fibrosis, hereditary emphysema, hereditary hemochromatosis, clotting factor-fibrinolysis deficiencies such as protein C deficiency, hereditary Type 1 angioedema, lipid processing disorders such as familial hypercholesterolemia, chylomicronemia 1, abetalipoproteinemia, lysosomal storage diseases, such as intracellular / pseudo-Hurler inclusion disease, mucopolysaccharidosis, Sandhof / Tay-Sachs disease, Crigler-Najjar type II syndrome, poliendocrinopathy / hyperinsulinemia, diabetes mellitus, Laron type dwarfism, myeloperoxidase deficiency, primary hypoparathyroidism, melanoma, glycanosis

116

Type I CDG, hereditary emphysema, congenital hyperactivity, congenital bone fragility, hereditary hypofibrinogenemia, ACT deficiency, and diabetes insipidus (Latin. diabetes insipidus DI), pituitary DI, renal DI, Charcot-MarieTooth disease, Pelizaeus-Merzbacher disease, neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, progressive supranuclear palsy, Pick's disease, various polyglutamine neurological disorders such as disease Huntington's, cerebellar ataxia type I, spinal muscular atrophy, atrophy of the dentate nucleus, red nucleus, pale knob and low-hypothalamic nucleus and myotonic dystrophy, such as spongiform encephalopathies, for example hereditary Creutzfeldt-Jakob disease, Fabry disease and Straussler's syndrome, COPD, dry eye disease, Sjogren's disease comprising the step of administering to the mammal an effective amount of a composition containing a compound of formulas (I , Ic, Id, II, IIa, IIb, IIc and IId), or a preferred embodiment thereof, as set out above.

[0188] According to another preferred embodiment, the invention provides a method of treating cystic fibrosis, comprising the step of administering to the mammal a composition, comprising the step of administering to said mammal an effective amount of a composition comprising a compound of the formulas (I, Ic Id, II, IIa, IIb, IIc and IId), or a preferred embodiment thereof as defined above. [0189] According to the invention, an "effective amount" of a compound or a pharmaceutically acceptable composition is an amount effective to treat or reduce the severity of the symptoms of one or more of the following: cystic fibrosis, hereditary emphysema, hereditary hemochromatosis, deficiency of factors

117 clotting-fibrinolysis, such as protein C deficiency, hereditary Type 1 angioedema, lipid disorder such as familial hypercholesterolemia, type 1 chylomicronemia, abetalipoproteinemia, lysosomal storage diseases, such as intracellular inclusion / pseudo-polysaccharis disease Tay-Sachs, Crigler-Najjar type II syndrome, poliendocrinopathy / hyperinsulinemia, diabetes mellitus, Laron's dwarfism, myeloperoxidase deficiency, primary hypoparathyroidism, melanoma, type I CDG glycanosis, hereditary emphysema, congenital hyperactivity, congenital bone fragility, hereditary hypofibrinogenemia, ACT deficiency, and diabetes insipidus (Latin. diabetes insipidus DI), pituitary DI, renal DI, Charcot-MarieTooth disease, Pelizaeus-Merzbacher disease, neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, progressive supranuclear palsy, Pick's disease, various polyglutamine neurological disorders such as disease Huntington's, cerebellar ataxia type I, spinal muscular atrophy, atrophy of the dentate nucleus, red nucleus, pale knob and low-hypothalamic nucleus and myotonic dystrophy, such as spongiform encephalopathies, for example hereditary Creutzfeldt-Jakob disease, Fabry disease and Straussler's syndrome, COPD, dry eye disease, Sjogren's disease. [0190] The compounds and compositions of the method of the present invention may be administered using any amount and any route of administration effective to treat or reduce the severity of one or more of cystic fibrosis, hereditary emphysema, hereditary hemochromatosis, deficiencies

118 clotting-fibrinolysis factors such as protein C deficiency, hereditary Type 1 angioedema, lipid disorder such as familial hypercholesterolemia, type 1 chylomicronemia, abetalipoproteinemia, lysosomal storage diseases, such as intracellular inclusion / pseudosclerotic disease / Tay-Sachs, type II Crigler-Najjar syndrome, poliendocrinopathy / hyperinsulinemia, diabetes, Laron's dwarfism, myeloperoxidase deficiency, primary hypoparathyroidism, melanoma, type I CDG glycanosis, hereditary emphysema, congenital hyperactivity, congenital bone fragility, hereditary hypofibrinogenemia, ACT deficiency, and diabetes insipidus (Latin. diabetes insipidus DI), pituitary DI, renal DI, Charcot-MarieTooth disease, Pelizaeus-Merzbacher disease, neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, progressive supranuclear palsy, Pick's disease, various polyglutamine neurological disorders such as disease Huntington's, cerebellar ataxia type I, spinal muscular atrophy, atrophy of the dentate nucleus, red nucleus, pale knob and low-hypothalamic nucleus and myotonic dystrophy, such as spongiform encephalopathies, for example hereditary Creutzfeldt-Jakob disease, Fabry disease and Straussler's syndrome, COPD, dry eye disease, Sjogren's disease. [0191] The exact amount required will vary from individual to individual, depending on the species, age and general condition of the individual, severity of infection symptoms, specific agent, method of administration and the like. The compounds of the invention are preferably formulated in unit dosage form

119 for ease of administration and uniformity of dosage. The expression "unit dosage form" as used herein refers to a physically separate unit of the appropriate agent for the patient undergoing treatment. It is understood, however, that the total daily dose of the compounds and compositions of the invention will be determined by the attending physician in the field of sound medical judgment. The specific effective dose level for any particular patient or organism will depend on a variety of factors including the disorder being treated and the severity of the disorder; activity of the specific compound employed; the specific composition used; the patient's age, weight, general health, sex and diet; the time of administration, route of administration, and rate of excretion of the particular compound used; duration of treatment; drugs used in combination or concurrently with the particular compound employed, and the like, factors well known in the medical arts. The term "patient" as used herein means an animal, preferably a mammal, and most preferably a human.

[0192] Pharmaceutically acceptable compositions of the present invention may be administered to humans and other living entities orally, intrathecally, parenterally, into the subarachnoid reservoir, vaginally, intraperitoneally, topically (as powders, ointments or drops), buccal or as a nasal or oral spray or similarly, depending on the severity of the infection being treated. In some embodiments, compounds of the invention may be administered orally or parenterally in doses of from about 0.01 mg / kg to about 50 mg / kg, and preferably from about 1 mg / kg to about 25

120 mg / kg patient weight per day, one or more times a day, to achieve the desired therapeutic effect. [0193] Liquid dosage forms for oral administration include, but are not limited to, pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs. In addition to the active compounds, liquid dosage forms may contain inert diluents commonly used in the art, such as, for example, water or other solvents, dissolving agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzoate benzyl, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils (in particular cottonseed, peanut, corn oil, germ, olive oil, castor oil and sesame oil), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid esters with sorbitan and mixtures thereof. In addition to inert diluents, the oral compositions may also contain adjuvants such as wetting, emulsifying and suspending agents, sweetening, flavoring and flavoring agents.

[0194] Injectable preparations, for example, aqueous or oily sterile injectable suspensions may be formulated according to the known art using suitable dispersing or wetting 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. Acceptable substrates and solvents that can be used include water, Ringer's solution, USP and isotonic sodium chloride solution.

121

In addition, sterile, fixed oils are typically used as a solvent or suspending medium. For this purpose, any neutral, fixed oil may be used, including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid find use in the preparation of injectables.

[0195] Injectable formulations may be sterilized, for example, by filtration through a bacterial-retaining 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 prior to use.

[0196] In order to prolong the effect of a compound of the present invention, it is often desirable to slow the absorption of the compound from subcutaneous or intramuscular injection. This can be achieved by the use of a liquid crystalline or amorphous suspension of substances with poor water solubility. The rate of absorption of a compound then depends on its dissolution rate, which in turn may depend on the crystal size and the crystal form. Optionally, delayed absorption of the parenterally administered compound form is carried out by dissolving or suspending the compound on an oily base. Injectable depot preparations are prepared by forming microencapsule matrices of the compound in biodegradable polymers such as polylactidpolyglycolide. Depending on the ratio of compound to polymer and the nature of the particular polymer used, the release rate of the compound can be controlled. Examples of other biodegradable polymers include poly (orthoesters) and poly (anhydrides).

122

Injectable depot formulations are also prepared by entrapping the compound in liposomes or microemulsions that are compatible with body tissues.

[0197] Compositions for rectal or vaginal administration are preferably suppositories that can be prepared by mixing the compounds of the invention with suitable non-irritating excipients or carriers such as cocoa butter, polyethylene glycol or suppository wax which are solid at room temperature but liquid at temperature bodies and thus melt in the rectum or vaginal cavity and release the active compound.

[0198] 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 diluents 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) disintegrants such as agar-agar, calcium carbonate, potato starch or tapioca starch, alginic acid, certain silicates and sodium carbonate, e) dissolution retarding agents such as paraffin, f) agents accelerating absorption 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)

123 lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof. In the case of capsules, tablets and pills, the dosage form may also comprise buffering agents.

[0199] Solid compositions of a similar type may also be employed as fillers in soft and hard gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polyethylene glycols and the like. Solid dosage forms in the form of tablets, dragees, capsules, pills and granules can be prepared with coatings and coatings, such as enteric coatings and other coatings well known in the art of pharmaceutical preparations. They may optionally contain opacifying agents and may also have such a composition that they release only the active ingredient (s), or selectively, in a certain part of the intestinal tract, optionally in a delayed manner. Examples of coating compositions that can be used include polymeric substances and waxes. Solid compositions of a similar type may also be employed as fillers in soft and hard gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polyethylene glycols and the like.

[0200] The active compounds may also be in microencapsulated form with one or more of the above-mentioned additives. Solid dosage forms in the form of tablets, dragees, capsules, pills and granules can be prepared coated and coated, such as enteric coatings, release controlling coatings and others.

124 coatings well known in the field of pharmaceutical preparations. 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 contain, in accordance with normal practice, additional substances other than inert diluents, for example tabletting lubricants and other tableting additives such as magnesium stearate and microcrystalline cellulose. In the case of capsules, tablets and pills, the dosage forms may also comprise buffering agents. They may optionally contain opacifying agents and may also have such a composition that they release only the active ingredient (s), or selectively, in a certain part of the intestinal tract, optionally in a delayed manner. Examples of coating compositions that can be used include polymeric substances and waxes.

[0201] Dosage forms for topical or transdermal administration of a compound of the invention include ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalants or patches. The active ingredient is mixed under sterile conditions with a pharmaceutically acceptable carrier and any needed preservatives or buffering agents, if required. Ophthalmic preparations, ear drops and eye drops are also contemplated to be within the scope of the present invention. In addition, the invention contemplates the use of transdermal patches that have the added advantage of providing controlled delivery of a compound to the body. Such dosage forms are prepared by dissolving or preparing the compound in a suitable carrier. The compounds

125 absorption enhancers can also be used to increase the passage of the compound through the skin. The rate can be controlled either by providing a rate controlling membrane or by dispersing the compound in a polymer matrix or gel.

[0202] As described generally above, the compounds of the invention are useful as modulators of ABC transporters. Thus, without wishing to be bound by any particular theory, the compounds and compositions are particularly useful for treating or reducing the severity of a disease, condition or disorder in which excessive activity or inactivity of ABC transporters affects the disease, condition or disorder. If the excessive activity or absence of an ABC transporter affects a particular disease, condition or disorder, the disease, condition or disorder may also be referred to as "disease, condition or disorder mediated by the ABC transporter". In another aspect, the invention provides a method of treating or reducing the severity of a disease, condition or disorder in which excessive activity or inactivity of the ABC transporter affects the disease state.

[0203] The activity of the compound used in the present invention as an ABC transporter modulator can be determined by methods generally described in the prior art and examples.

[0204] It will also be appreciated that the compounds and pharmaceutically acceptable compositions of the present invention may be used in combination therapies, that is, the compounds and pharmaceutically acceptable compositions may be administered simultaneously with, before or after the use of one or more other desired therapeutic agents or medical procedures. Special therapies should be included

126 combination (therapeutic agents or procedures) for use in a combination therapy regimen, compatibility of desired therapeutic agents and / or procedures, and desired therapeutic effect. It will also be understood that therapies may have the desired effect on the same disorder (e.g., a compound of the invention may be administered concurrently with another agent used to treat the same disorder) or may have other effects (e.g., affecting any side effects). As used herein, additional therapeutic agents that are normally administered to treat or prevent a particular disease or condition are known to be "appropriate for the disease or condition being treated".

[0205] The amount of additional therapeutic agent present in the compositions of the present invention will not be greater than the amount that would normally be administered in a composition containing that therapeutic agent as the only active ingredient. Preferably, the amount of additional therapeutic agent in the presently disclosed compositions will range from about 50% to 100% of the amount normally present in a composition containing that agent as the only therapeutically active agent.

[0206] The compounds of the present invention or pharmaceutically acceptable compositions thereof may also be incorporated into compositions for coating an implantable medical device, such as prostheses, artificial valves, vascular grafts, stents and catheters. Accordingly, the invention, in another aspect, comprises a composition for coating an implantable device, comprising a compound of the present invention as described generally above and in sections and items of the description, and a carrier suitable for

127 coating said implantable device. In yet another aspect, the invention includes an implantable device coated with a composition comprising a compound of the present invention as described generally above and in sections and subsections of the description, and a carrier suitable for coating said implantable device. Suitable coatings and a general method for making coated implantation devices are described in US Patent Nos. 6,099,562; 5,886,026; and 5,304,121. Coatings are typical biocompatible polymer materials, such as hydrogel polymer, polymethyldisiloxane, polycaprolactone, polyethylene glycol, polylactic acid, ethylene vinyl acetate and mixtures thereof. The shells can optionally be further coated with a suitable fluorosilicon topcoat, polysaccharides, polyethylene glycol, phospholipids or combinations thereof to provide a controlled release feature of the composition.

[0207] Another aspect of the disclosure relates to modulating ABC transporter activity in a biological sample or a patient (for example, in vitro or in vivo), which method comprises administering to a patient, or combining these biological samples with a compound of formula I or a composition including that compound . The term "biological sample", as used herein, includes, without limitation, cell cultures or their extracts; mammalian biopsy material or extracts thereof; and blood, saliva, urine, feces, semen, tears or other body fluids or extracts thereof.

[0208] Modulation of ABC transporter activity in a biological sample is useful for various known purposes

128 specialists in this field. Examples of such purposes include, but are not limited to, research on ABC transporters in biological and pathological phenomena; and comparative assessment of new ABC transporter modulators.

[0209] In yet another embodiment, a method is provided for modulating anion channel activity in vitro or in vivo, comprising the step of contacting said channel with a compound of formula (I, Ic, Id, II, IIa, IIb, IIc, and IId). In preferred embodiments, the channel is an anion chloride channel or a bicarbonate channel. In other preferred embodiments, the anion channel is a chloride channel.

[0210] According to another embodiment, the invention provides a method of increasing the number of functional ABC transporters in a cell membrane, including the step of contacting said cell with compounds of formulas (I, Ic, Id, II, IIa, IIb, Iic, and IId). The term "functional ABC transporter" as used herein means an ABC transporter that is capable of transporting activity. In preferred embodiments, the functional ABC transporter is CFTR.

[0211] According to another preferred embodiment, the ABC transporter activity is measured by measuring the transmembrane voltage potential. Means for measuring membrane voltage potential in a biological sample may use any of the methods known in the art, such as optical membrane potential determination or other electrophysiological methods. [0212] The optical potential measurement test uses voltage sensitive FRET sensors described by Gonzalez and Tsien (see Gonzalez, JE and RY Tsien (1995) "Voltage sensing

129 by fluorescence resonance energy transfer in single cells "Biophys J 69 (4): 1272-80 i Gonzalez, JE and RY Tsien (1997)" Improved indicators of cell membrane potential that use fluorescence resonance energy transfer "Chem Biol 4 (4): 269-77) in combination with instruments for measuring the change in fluorescence, such as voltage / Ion Probe Reader (VIPR) (see, Gonzalez, JE, K. Oades, et al. (1999) "Cell-based assays and instrumentation for screening ion-channel targets" Drug Discov Today 4 (9), 431-439).

[0213] These voltage-sensitive tests are based on a change in resonance fluorescence excitation energy transfer (FRET) between a water-soluble, voltage-sensitive DiSBAC dye₂(3) and the fluorescent phospholipid, CC2DMPE, which is associated with the outer membrane of the cell membrane and serves as a FRET donor. Changes in membrane potential (Vm) lead to negatively charged DiSBAC₂(S), which is distributed in the membrane and the amount of energy transferred from CC2-DMPE changes accordingly. Changes in fluorescence emissions can be monitored using VIPR ™ II, which is an integrated liquid dispenser and fluorescence detector designed to perform cellular assays in 96- or 384-well microplates.

[0214] In another aspect, the present invention provides a kit for use in measuring the activity of an ABC transporter or fragment thereof in an in vitro or in vivo biological sample, comprising (i) a composition comprising a compound of formula (I, Ic, Id, II, IIa, IIb, IIc, and IId) or any of the above; and (ii) instructions for a) combining the composition with the biological sample and b) measuring the activity of this ABC transporter or a fragment thereof. In one example,

130 the kit further includes instructions for a) contacting the additional composition with the biological sample; b) measuring the activity of the ABC transporter or a fragment thereof in the presence of said additional compound, and c) comparing the activity of the ABC transporter in the presence of an additional compound with an ABC transporter density in the presence of compositions of formula (I, Ic, Id, II, IIa, Iib , Iic, and IId). In preferred embodiments, the kit is used to measure the CFTR density. [0215] In order that the invention described herein may be fully understood, the following examples are given. It should be understood that these examples are illustrative only and should not be construed as limiting the invention in any way.

VI. MANUFACTURE AND EXAMPLES

General procedure I: Carboxylic acid forming elements

<img file="PL2674428T3_D0090.tif" />

[0217] Benzyltriethylammonium chloride (0.025 equivalent) and the corresponding dihalo compound (2.5 equivalents) were added to substituted phenylacetonitrile. The mixture was heated at 70 ° C and then 50% sodium hydroxide (10 equivalents) was slowly added to the mixture. The reaction mixture was stirred at 70 ° C for 12-24 hours to ensure complete formation of the cycloalkyl moiety and then heated at 130 ° C for 24-48 hours to ensure complete

131 conversion of nitrile to carboxylic acid. The dark brown / black reaction mixture was diluted with water and extracted with dichloromethane three times to remove by-products. The basic aqueous solution was acidified with concentrated hydrochloric acid to a pH less than one, and the precipitate that began to form at pH 4 was filtered off and washed twice with 1 M hydrochloric acid solution. The solid was dissolved in dichloromethane and extracted twice with 1 M hydrochloric acid solution and once with saturated aqueous sodium chloride solution. The organic solution was dried over sodium sulfate and evaporated to dryness to give the cycloalkylcarboxylic acid. Yields and purities were usually greater than 90%.

Example 1: Cyclopropane carboxylic acid

1-benzo [1,3] dioxol-5-yl [0211]

<img file="PL2674428T3_D0091.tif" />

[0219] A mixture of 2- (benzo [d] [1,3] dioxol-5-yl) acetonitrile (5.10 g 31.7 mmol), 1-bromo-2-chloroethane (9.00 mL, 109 mmol) and benzyltriethylammonium chloride (0.181 g, 0.795 mmol) was heated at 70 ° C, followed by the slow addition of a 50% (w / w) aqueous sodium hydroxide solution (26 ml) to the mixture. The reaction mixture was stirred at 70 ° C for 24 hours and then heated at 130 ° C for 48 hours. The dark brown reaction mixture was diluted with water (400 ml) and extracted once with the same volume of ethyl acetate and once with the same volume

132 dichloromethane. The basic aqueous solution was acidified with concentrated hydrochloric acid to a pH less than one, and the precipitate was filtered off and washed with 1 M hydrochloric acid. The solid was dissolved in dichloromethane (400 mL) and extracted twice with the same volumes of 1 M hydrochloric acid and once with saturated aqueous sodium chloride. The organic solution was dried over sodium sulfate and evaporated to dryness to give a white to slightly white solid (5.23 g, 80%), ESI-MS m / z calcd. 206.1, found 207.1 (M + 1) +.

Retention time 2.37 minutes. ^XH NMR (400 MHz, DMSO-d₆) δ 1.0711.11 (m, 2H), 1.38-1.42 (m, 2H), 5.98 (s, 2H), 6.79 (m, 2H);

6.88 (m, 1H), 12.26 (s, 1H).

General procedure II: Carboxylic acid forming elements [0220]

<img file="PL2674428T3_D0092.tif" />

Hal = Cl, Br, I, all other variables are as defined herein [0221] Sodium hydroxide (50% aqueous solution, 7.4 equivalents) is slowly added to a mixture of the corresponding phenylacetonitrile, benzyltriethylammonium chloride (1.1 equivalents) and the corresponding dihalide compound (2.3 equivalents) at 70 ° C. The reaction mixture was stirred overnight at 70 ° C and the reaction mixture was diluted with water (30 ml) and extracted with ethyl acetate. The combined organic layers were dried over sodium sulfate and evaporated to dryness to afford crude cyclopropanecarbonitrile, which was used directly in the next step.

133 [0222] The crude cyclopropanecarbonitrile was heated to reflux in a 10% aqueous sodium hydroxide solution (7.4 equivalents) for 2.5 hours. The cooled reaction mixture was washed with ether (100 ml) and the aqueous phase was acidified to pH 2 using 2 M hydrochloric acid. The precipitate was filtered off to give the cyclopropane carboxylic acid as a white solid.

General procedure III: Carboxylic acid forming elements [0223]

<img file="PL2674428T3_D0093.tif" />

Example 2: 1- (2,2-difluoro-benzo [1,3] dioxol-5-yl) cyclopropanecarboxylic acid [0224]

134

<img file="PL2674428T3_D0094.tif" />

2,2-difluoro-benzo [1,3] dioxole-5-carboxylic acid methyl ester [0225] Solution of 5-bromo-2,2-difluoro-benzo [1,3] dioxole (11.8 g, 50.0 mmol) and tetrakis (triphenylphosphine) palladium (0) [Pd (PPh3)₄, 5.78 g, 5.00 mmol] in methanol (20 mL) containing acetonitrile (30 mL) and triethylamine (10 mL) was stirred in a carbon monoxide atmosphere (55 bar) at 75 ° C (oil bath temperature) for 15 hours. The cooled reaction mixture was filtered and the filtrate evaporated to dryness. The residue was purified by silica gel column chromatography to give crude 2,2-difluorobenzo [1,3] dioxole-5-carboxylic acid methyl ester (11.5 g), which was used directly in the next step.

<img file="PL2674428T3_D0095.tif" />

(2,2-difluoro-benzo [1,3] dioxol-5-yl) methanol [0226] Crude 2,2-difluorobenzo [1,3] dioxole-5-carboxylic acid methyl ester (11.5 g) dissolved in

135 mL of anhydrous tetrahydrofuran (THF) was slowly added to a suspension of lithium aluminum hydride (4.10 g, 106 mmol) in anhydrous THF (100 mL) at 0 ° C. The mixture was then warmed to room temperature. After stirring at room temperature for 1 hour, the reaction mixture was cooled to 0 ° C and water (4.1 g) was added, followed by sodium hydroxide (10% aqueous solution, 4.1 mL). The resulting suspension was filtered and washed with THF. The combined filtrate was evaporated to dryness and the residue was purified by silica gel column chromatography to obtain (2,2-difluoro-benzo [1,3] dioxol-5-yl) -methanol (7.2 g, 38 mmol, 76% after two stages) in the form of a colorless oil.

<img file="PL2674428T3_D0096.tif" />

5-chloromethyl-2,2-difluoro-benzo [1,3] dioxol [0227] Thionyl chloride (45 g, 38 mmol) was added slowly to the solution (2,2-difluoro-benzo [1,3] dioxol-5 -yl) -methanol (7.2 g, 38 mmol) in dichloromethane (200 mL) at 0 ° C. The resulting mixture was stirred overnight at room temperature and then evaporated to dryness. The residue was partitioned between an aqueous saturated sodium bicarbonate solution (100 ml) and dichloromethane (100 ml).

The separated aqueous layer was extracted with dichloromethane (150 mL) and the organic layer was dried over sodium sulfate, filtered and evaporated to dryness to give crude 5-chloromethyl-2,2-difluoro-benzo [1,3] dioxol (4.4 g ), which was used directly in the next step.

136

<img file="PL2674428T3_D0097.tif" />

(2,2-difluoro-benzo [1,3] dioxol-5-yl) -acetonitrile [0228] A mixture of crude 5-chloromethyl-2,2-difluorobenzo [1,3] dioxol (4.4 g) and sodium cyanide (1.36 g, 27.8 mmol) in dimethyl sulfoxide (50 mL) was stirred at room temperature overnight. The reaction mixture was poured into ice and extracted with ethyl acetate (300 mL). The organic layer was dried over sodium sulfate and evaporated to dryness to give the crude product (2,2-difluoro-benzo [1,3] dioxol-5-yl) acetonitrile (3.3 g), which was used directly in the next step.

<img file="PL2674428T3_D0098.tif" />

1- (2,2-difluoro-benzo [1,3] dioxol-5-yl) -cyclopropanecarbonitrile [0229] Sodium hydroxide (50% aqueous solution, 10 mL) was slowly added to the mixture of the crude product (2,2-difluorobenzo [ 1,3] dioxol-5-yl) -acetonitrile, benzyltriethylammonium chloride (3.00 g, 15.3 mmol) and 1-bromo-2-chloroethane (4.9 g, 38 mmol) at 70 ° C.

[0230] The reaction mixture was stirred overnight at 70 ° C, after which the reaction mixture was diluted with water (30 mL) and extracted with ethyl acetate. The combined organic layers were dried over sodium sulfate and evaporated to dryness to afford the crude product 1- (2,2-difluoro-benzo [1,3] dioxol-5-yl) -cyclopropanecarbonitrile, which was used directly in the next step.

<img file="PL2674428T3_D0099.tif" />

1- (2,2-difluoro-benzo [1,3] dioxol-5-yl) -cyclopropanecarboxylic acid 1- (2,2-difluoro-benzo [1,3] dioxol-5-yl) cyclopropanecarbonitrile ( crude from the last step) was heated to reflux in 10% aqueous sodium hydroxide solution (50 ml) for 2.5 hours. The cooled reaction mixture was washed with ether (100 ml) and the aqueous phase was acidified to pH 2 using 2 M hydrochloric acid. The precipitate was filtered off to give 1- (2,2-difluorobenzo [1,3] dioxol-5-yl) -cyclopropane-carboxylic acid as a white solid (0.15 g, 1.6% after four steps). ESI-MS m / z calculated 244.04, found 241.58 (M + 1) +;^XH NMR (CDCls) δ 7.14-7.04 (m, 2H), 6, 98-6, 96 (m, 1H), 1.74-1, 64 (m, 2H), 1.26-1 , 08 (m, 2H),

Example 3: 2- (2,2-dimethylbenzo [d] [1,3] dioxol-5-yl) acetonitrile [0225]

<img file="PL2674428T3_D0100.tif" />

138 (3,4-dihydroxy-phenyl) -acetonitrile [0226] To a solution of benzo [1,3] dioxol-5-yl-acetonitrile (0.50 g, 3.1 mmol) in CH₂cl₂ (15 ml) BBr was added dropwise₃ (0.78 g, 3.1 mmol) at -78 ° C under nitrogen. The mixture was slowly warmed to room temperature and stirred overnight. Then H was added₂O (10 mL) to complete the reaction and the CH layer separated₂cl₂. The aqueous phase was extracted with CH₂cl₂ (2 x 7 ml). The combined organic phases were washed with brine, dried over Na₂SO₄ and purified by silica gel column chromatography (petroleum ether / ethyl acetate 5: 1) to obtain (3,4-dihydroxy-phenyl) acetonitrile (0.25 g, 54%) as a white solid. ¹1 H NMR (DMSO-d₆, 400 MHz) δ 9.07 (s, 1H), 8.95 (s, 1H), 6, 68-6, 70 (m, 2H), 6.55 (dd, J =

8.0, 2.0 Hz, 1H), 3.32 (s, 2H).

<img file="PL2674428T3_D0101.tif" />

2- (2,2-dimethylbenzo [d] [1,3] dioxol-5-yl) acetonitrile [0234] To (3,4-dihydroxy-phenyl) -acetonitrile solution (0.20 g, 1.3 mmol) in toluene (4 mL), 2,2-dimethoxy-propane (0.28 g, 2.6 mmol) and TsOH (0.010 g 0.065 mmol) were added. The mixture was heated to reflux overnight. The reaction mixture was evaporated to remove the solvent and the residue was dissolved in ethyl acetate. The organic layer was washed with a NaHCO solution₃, H₂Oh, brine and dried over Na₂SO₄. The solvent was evaporated under reduced pressure to give a residue, which was purified by silica gel column chromatography (petroleum ether / ethyl acetate 10: 1) to obtain

139

2- (2,2-dimethylbenzo [d] [1,3] dioxol-5-yl) acetonitrile (40 mg, 20%). ¹H NMR (CDCl3, 400 MHz) δ 6.68-6.71 (m, 3H), 3.64 (s,

2H), 1.67 (s, 6H).

Example 4: 1- (3,4-dihydroxy-phenyl) -cyclopropanecarboxylic acid [0235]

<img file="PL2674428T3_D0102.tif" />

1- (3,4-bis-benzyloxy-phenyl) -cyclopropanecarbonitrile [0236] To the mixture (nC₄H₉)₄NBr (0.50 g, 1.5 mmol), toluene (7 mL) and (3,4-bis-benzyloxy-phenyl) -acetonitrile (14 g, 42 mmol) in NaOH (50 g) and H₂O (50 ml) BrCH was added₂CH₂Cl (30 g, 0.21 mol). The reaction mixture was stirred at 50 ° C for 5 h, then cooled to room temperature. Toluene (30 ml) was added and the organic layer was separated and washed with H₂O, brine, dried over anhydrous MgSO₄, and concentrated. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate 10: 1) to give 1- (3,4-bis-benzyloxy-phenyl) cyclopropanecarbonitrile (10 g, 66%),¹H NMR (DMSO 300 MHz) δ 7.46-7.30 (m, 10H), 7.03 (d, J = 8.4 Hz, 1H), 6.94 (d, J =

2.4 Hz, 1H), 6.89 (dd, J = 2.4, 8.4 Hz, 1H), 5.12 (d, J = 7.5

Hz, 4H), 1.66-1.62 (m, 2H), 1.42-1.37 (m, 2H).

<img file="PL2674428T3_D0103.tif" />

140

1- (3,4-dihydroxy-phenyl) -cyclopropanecarbonitrile [0237] To a solution of 1- (3,4-bis-benzyloxy-phenyl) cyclopropanecarbonitrile (10 g, 28 mmol) in MeOH (50 mL) was added Pd / C ( 0.5 g) under nitrogen. The mixture was stirred under a hydrogen atmosphere (1 atm) at room temperature for 4 hours. The catalyst was filtered off through a celite pad, and the filtrate was evaporated under reduced pressure to give 1- (3,4-dihydroxy-phenyl) -cyclopropanecarbonitrile (4.5 g, 92%).¹H NMR (DMSO 400 MHz) δ 9.06 (br s, 2H), 6.67-6.71 (m, 2H),

6.54 (dd, J = 2.4, 8.4 Hz, 1H), 1.60-1.57 (m, 2H), 1.30-1.27 (m, 2H).

<img file="PL2674428T3_D0104.tif" />

1- (3,4-dihydroxy-phenyl) -cyclopropanecarboxylic acid [0238] To a solution of NaOH (20 g, 0.50 mol) in H₂O (20 ml) 1- (3,4-dihydroxy-phenyl) -cyclopropanecarbonitrile (4.4 g, 25 mmol) was added. The mixture was heated to reflux for 3 hours and then cooled to room temperature. The mixture was neutralized with HCl (0.5 N) to pH = 3-4 and extracted with ethyl acetate (20 mL × 3). The combined organic layers were washed with water, brine, dried over anhydrous MgSO₄ and concentrated under reduced pressure to obtain 1- (3,4-dihydroxy-phenyl) cyclopropanecarboxylic acid (4.5 g crude product). From 900 mg of crude product, 500 mg of pure 1- (3,4-dihydroxy-phenyl) -cyclopropanecarboxylic acid was obtained using preparative HPLC.¹H NMR (DMSO, 300 MHz) δ 12.09 (br s, 1H),

141

8.75 (br s, 2H), 6, 50-6, 67 (m, 3H), 1.35-1.31 (m, 2H), 1,010.97 (m, 2H).

Example 5: 1- (2-Oxo-2,3-dihydrobenzo [d] oxazol-5-yl) cyclopropane carboxylic acid.

[0239]

<img file="PL2674428T3_D0105.tif" />

cyclopropane carboxylic ester [0240] For acid solution

1- (4-methoxy-phenyl) 1- (4-methoxy-phenyl) cyclopropanecarboxylic acid (50 g, 0.26 mol) in MeOH (500 ml) toluene-4-sulfonic acid monohydrate (2.5 g, 13 mmol) room temperature. The reaction mixture was heated at reflux for 20 hours. Then MeOH was removed by evaporation under reduced pressure and EtOAc (200 mL) was added. The organic layer was washed with saturated aqueous NaHCO₃ (100 ml) and brine, dried over anhydrous Na₂SO₄ and evaporated under reduced pressure to give 1- (4-methoxyphenyl) cyclopropanecarboxylic acid methyl ester (53 g, 99%

H NMR (CDCl3 400 MHz) 7.25-7.27 (m, 2H), 6.85 (d, J = 8.8 Hz, 2H),

142

3.80 (s, 3H), 3.62 (s, 3H), 1.58 (q, J = 3.6 Hz, 2H), 1.15 (q,

J = 3.6 Hz, 2H).

MeO.

/at.

HNO3 / Ac2O ^Meo\ Z \ / Yz^WELL2

OMe

OMe 1- (4-methoxy-3-nitro-phenyl) cyclopropanecarboxylic acid methyl ester To a solution of 1- (4-methoxyphenyl) cyclopropanecarboxylic acid methyl ester (30.0 g, 146 mmol)₂O (300 mL) HNO solution was added₃ (14.1 g, 146 mmol, 65%) in AcOH (75 mL) at 0 ° C. The reaction mixture was stirred at 0 ~ 5 ° C for 3 h then aqueous HCl (20%) was added dropwise at 0 ° C. The resulting mixture was extracted with EtOAc (200 mL × 3). The organic layer was washed with a saturated aqueous NaHCO solution₃and then brine, dried over anhydrous Na₂SO₄ and evaporated under reduced pressure to give 1- (4-methoxy-3-nitro-phenyl) -cyclopropanecarboxylic acid methyl ester (36.0 g, 98%), which is used directly in the next step. ¹1 H NMR (CDCl₃,

<td> 300</td><td>MHz) δ 7.84</td><td>(d, J</td><td>= 2.1 Hz, 1H),</td><td> 7,54</td><td>(dd, J =</td><td> 2,1, 8,7</td>

<td>Hz,</td><td>1H), 7.05 (</td><td>d, J =</td><td>8.7 Hz, 1H),</td><td> 3,97</td><td>(s, 3H),</td><td>3.65 (s,</td>

<td>3H);</td><td> 1,68-1,64 (</td><td>m, 2H),</td><td>1.22-1.18 (m,</td><td>2H).</td><td></td><td></td>

<img file="PL2674428T3_D0106.tif" />

cyclopropane carboxylic acid methyl ester

1- (4-hydroxy-3-nitro-phenyl) 143 [0242] To a solution of 1- (4-methoxy-3-nitro-phenyl) -cyclopropanecarboxylic acid methyl ester (10.0 g, 39.8 mmol) in CH₂cl₂ (100 ml) BBr added₃ (12.0 g, 47.8 mmol) at -70 ° C. The mixture was stirred at -70 ° C for 1 hour and then allowed to warm to 30 ° C and stirred at this temperature for 3 hours. Then water (50 mL) was added dropwise at -20 ° C and the resulting mixture was allowed to warm to room temperature, after which the mixture was extracted with EtOAc (200 mL x 3). The combined organic layers were dried over anhydrous Na₂SO₄ and evaporated under reduced pressure to give a crude product which was purified by silica gel column chromatography (petroleum ether / ethyl acetate 15: 1) to obtain 1- (4-hydroxy-3-nitrophenyl) -cyclopropanecarboxylic acid methyl ester (8.3 g, 78%). ¹1 H NMR (CDCl₃, 400 MHz) δ 10.5 (s, 1H), 8.05 (d, J = 2.4 Hz, 1H) 7.59 (dd, J = 2.0, 8.8 Hz, 1H), 7 , 11 (d, J = 8.4 Hz, 1H), 3.64 (s,

3H), 1.68-1.64 (m, 2H), 1.20-1.15 (m, 2H).

<img file="PL2674428T3_D0107.tif" />

1- (3-Amino-4-hydroxy-phenyl) cyclopropanecarboxylic acid methyl ester To a solution of 1- (4-hydroxy-3-nitrophenyl) cyclopropanecarboxylic acid methyl ester (8.3 g, 35 mmol) in MeOH (100 ml) Raney Nickel (0.8 g) was added under a nitrogen atmosphere. The mixture was stirred under a hydrogen atmosphere (1 atm) at 35 ° C for 8 hours. The catalyst was filtered off through a celite pad, and the filtrate was evaporated under reduced pressure

144 pressure to give the crude product which was purified by silica gel column chromatography (petroleum ether / ethyl acetate 1: 1) to obtain 1- (3-amino-4-hydroxy-phenyl) -cyclopropanecarboxylic acid methyl ester (5.3 g, 74%). these NMR (CDCl₃, 400 MHz) δ 6.77 (s, 1H), 6.64 (d, J = 2.0 Hz, 2H), 3.64 (s, 3H), 1.55-1.52 (m, 2H ), 1.15-1.12 (m,

2H).

<img file="PL2674428T3_D0108.tif" />

1- (2-Oxo-2,3-dihydro-benzoxazol-5-yl) -cyclopropanecarboxylic acid methyl ester To solution of 1- (3-amino-4-hydroxy-phenyl) -cyclopropanecarboxylic acid methyl ester (2.0 g, 9 , 6 mmol) in THF (40 ml) triphosgene (4.2 g, 14 mmol) was added at room temperature. The mixture was stirred for 20 minutes at this temperature, then water (20 ml) was added dropwise at 0 ° C. The resulting mixture was extracted with EtOAc (100 mL × 3). The combined organic layers were dried over anhydrous Na₂SO₄ and evaporated under reduced pressure to give 1- (2-oxo-2,3-dihydrobenzoxazol-5-yl) cyclopropanecarboxylic acid methyl ester (2.0 g, 91%) which is used directly in the next step. these NMR (CDCl₃, 300 MHz) δ 8.66 (s, 1H), 7.13-7.12 (m, 2H), 7.07 (s,

1H), 3.66 (s, 3H), 1.68-1.65 (m, 2H), 1.24-1.20 (m, 2H).

<img file="PL2674428T3_D0109.tif" />

145 1- (2-oxo-2,3-dihydrobenzo [d] oxazol-5-yl) cyclopropane carboxylic acid [0245] To a solution of 1- (2-oxo-2,3-dihydro-benzoxazol-5-yl) cyclopropanecarboxylic acid methyl ester ( 1.9 g, 8.1 mmol) in MeOH (20 ml) and water (2 ml) were added in portions of LiOH.H₂O (1.7 g, 41 mmol) at room temperature. The reaction mixture was stirred for 20 hours at 50 ° C. Then MeOH was removed by evaporation under reduced pressure, followed by the addition of water (100 mL) and EtOAc (50 mL). The aqueous layer was separated, acidified with HCl (3 mol / L) and extracted with EtOAc (100 mL × 3). The combined organic layers were dried over anhydrous Na₂SO₄ and evaporated under reduced pressure to give 1- (2-oxo-2,3-dihydrobenzo [d] oxazol-5-yl) cyclopropanecarboxylic acid (1.5 g,

<td> 84%). ¹H NMR (</td><td>DMSO</td><td> 400</td><td>MHz) δ</td><td> 12,32</td><td>(Brs,</td><td>1H)</td><td> , 11, , 11,</td><td> 59</td><td>(Brs,</td>

<td>1H), 7.16 (d,</td><td>J =</td><td> 8,4</td><td>Hz, 1H)</td><td> , 7,00</td><td>(D,</td><td>J =</td><td> 8,0</td><td>Hz,</td><td>1H),</td>

<td>1.44-1.41 (m,</td><td>2H);</td><td> 1,13</td><td> -1,10 (</td><td>m, 2H).</td><td>MS (</td><td>ESI)</td><td>m / e</td><td>(M</td><td>_{+ H}⁺⁾</td>

218,1.

Example 6: 1- (6-fluoro-benzo [1,3] dioxol-5-yl) cyclopropane carboxylic acid [0246]

<img file="PL2674428T3_D0110.tif" />

146

2-fluoro-4,5-dihydroxy-benzaldehyde [0247] To a mixed suspension of 2-fluoro-4,5-dimethoxybenzaldehyde (3.00 g, 16.3 mmol) in dichloromethane (100 mL) BBr was added dropwise₃ (12.2 mL, 130 mmol) at -78 ° C under a nitrogen atmosphere. After the addition was complete, the mixture was warmed to -30 ° C and stirred at this temperature for 5 hours. The reaction mixture was poured into ice water, and the precipitate was filtered off and washed with dichloromethane to give 2-fluoro-4,5-dihydroxy-benzaldehyde (8.0 g), which was used directly in the next step.

<img file="PL2674428T3_D0111.tif" />

[0248] 6-Fluoro-benzo [1,3] dioxole-5-carbaldehyde

To a mixed solution of 2-fluoro-4,5-dihydroxy-benzaldehyde (8.0 g) and BrClCH₂ (24.8 g, 190 mmol) in dry DMF (50 mL) was added in portions of Cs₂WHAT₃ (62.0 g, 190 mmol). The resulting mixture was stirred at 60 ° C overnight and then poured into water. The mixture was extracted with EtOAc (200 mL × 3). The combined organic layers were washed with brine (200 mL), dried over Na₂SO₄ and evaporated under reduced pressure to give a crude product which was purified by silica gel column chromatography (5-20% ethyl acetate / petroleum ether) to obtain 6-fluorobenzo [1,3] dioxole-5-carbaldehyde (700 mg, yield after two stages: 24%). ¹H-NMR (400 MHz, CDCl₃) δ 10.19 (s, 1H), 7.23 (d, J = 5.6, 1H), 6.63 (d, J = 9.6, 1H), 6.08 (s, 2H).

<img file="PL2674428T3_D0112.tif" />

147 (6-fluoro-benzo [1,3] dioxol-5-yl) methanol [0249] To a mixed solution of 6-fluoro-benzo [1,3] dioxole-5-carbaldehyde (7 mg, 4.2 mmol) in MeOH ( 50 ml) was added in portions of NaBH₄ (320 mg, 8.4 mmol) at 0 ° C.

The reaction mixture was stirred at this temperature for 30 minutes and then concentrated under reduced pressure to give a residue. The residue was dissolved in EtOAc and the organic layer was washed with water, dried over Na₂SO₄ and concentrated under reduced pressure to give (6-fluorobenzo [1,3] dioxol-5-yl) methanol (650 mg, 92%) which was used directly in the next step.

<img file="PL2674428T3_D0113.tif" />

5-chloromethyl-6-fluoro-benzo [1,3] dioxol [0250] (6-fluoro-benzo [1,3] dioxol-5-yl) -methanol (650 mg, 3.8 mmol) was added in portions to SOCl₂ (20 ml) at 0 ° C. The mixture was warmed to room temperature over 1 h and then heated to reflux for 1 hour. Excess SOCl₂ evaporated under reduced pressure to give a crude product which was basified with saturated NaHCO solution₃ to pH about 7. The aqueous phase was extracted with EtOAc (50 mL × 3). The combined organic layers were dried over Na₂SO₄ and evaporated under reduced pressure to give 5-chloromethyl-6-fluorobenzo [1,3] dioxol (640 mg, 90%) which was used directly in the next step.

<img file="PL2674428T3_D0114.tif" />

148 (6-fluoro-benzo [1,3] dioxol-5-yl) -acetonitrile [0251] A mixture of 5-chloromethyl-6-fluoro-benzo [1,3] dioxole (640 mg, 3.4 mmol) and NaCN ( 340 mg, 6.8 mmol) in DMSO (20 mL) was stirred at 30 ° C for 1 h, then poured into water. The mixture was extracted with EtOAc (50 mL × 3). The combined organic layers were washed with water (50 ml) and brine (50 ml), dried over Na₂SO₄ and evaporated under reduced pressure to give a crude product which was purified by silica gel column chromatography (5-10% ethyl acetate / petroleum ether) to obtain (6-fluoro-benzo [1,3] dioxol-5-yl) acetonitrile (530 mg, 70%). ¹H-NMR (300 MHz, CDCl₃) δ 6.82 (d, J = 4.8, 1H), 6.62 (d, J = 5.4, 1H), 5.99 (s, 2H), 3.65 (s, 2H).

<img file="PL2674428T3_D0115.tif" />

1- (6-fluoro-benzo [1,3] dioxol-5-yl) -cyclopropane-carbonitrile [0252] The flask was filled with water (10 mL), followed by rapid addition of NaOH (10 g) in three portions over 5 min. 0.25 mole). The reaction mixture was allowed to cool to room temperature. Then, toluene (6 ml) was added to the flask, tetrabutylammonium bromide (50 mg, 0.12 mmol), (6-fluoro-benzo [1,3] dioxol-5-yl) acetonitrile (600 mg, 3.4 mmol) was added and 1-bromo-2-chloroethane (1.7 g, 12 mmol). The mixture was stirred vigorously at 50 ° C overnight. The cooled flask was filled with additional toluene (20 mL). The organic layer was separated and washed with water (30 ml) and brine (30 ml). The organic layer was removed under reduced pressure to give a crude product that was purified

149 silica gel column chromatography (5-10% ethyl acetate / petroleum ether) to give 1- (6-fluorobenzo [1,3] dioxol-5-yl) -cyclopropanenitrile (400 mg, 60%). ¹1 H NMR (300 MHz, CDCl₃) δ 6.73 (d, J = 3.0 Hz, 1H), 6.61 (d, J = 9.3 Hz, 1H) 5.98 (s, 2H), 1.67-1, 62 ( m, 2H), 1.31-1.27 (m, 2H).

<img file="PL2674428T3_D0116.tif" />

1- (6-Fluoro-benzo [1,3] dioxol-5-yl) -cyclopropanecarboxylic acid A mixture of 1- (6-fluoro-benzo [1,3] dioxol-5-yl) -cyclopropanecarbonitrile (400 mg , 0.196 mmol) and 10% NaOH (10 mL) was stirred at 100 ° C overnight. After that, the reaction mixture was cooled, 5% HCl was added until pH &lt;5, followed by the addition of EtOAc (30 mL). The layers were separated and the combined organic layers were evaporated under reduced pressure to give 1- (6-fluoro-benzo [1,3] dioxol-5-yl) cyclopropanecarboxylic acid (330 mg, 76%). ¹H-NMR (400 MHz,

DMSO) δ 12.2 (s, 1H), 6, 87-6, 85 (m, 2H), 6.00 (s, 1H), 1.421,40 (m, 2H), 1.14-1.07 (m, 2H).

Example 7: 1- (benzofuran-5-yl) cyclopropane carboxylic acid [0254]

150

<img file="PL2674428T3_D0117.tif" />

1- [4- (2,2-diethoxy-ethoxy) phenyl] -cyclopropanecarboxylic acid [0255] To a mixed solution of 1- (4-hydroxy-phenyl) cyclopropanecarboxylic acid methyl ester (15.0 g, 84.3 mmol) in DMF ( 50 ml), sodium hydride (6.7 g, 170 mmol, 60% in mineral oil) was added at 0 ° C. After the evolution of hydrogen had ceased, 2-bromo-1,1-diethoxyethane (16.5 g, 84.3 mmol) was added dropwise to the reaction mixture. The reaction mixture was stirred at 160 ° C for 15 hours. The reaction mixture was poured onto ice (100 g) and extracted with CH₂cl₂. The combined organic phases were dried over Na₂SO₄. The solvent was evaporated under reduced pressure to give 1- [4- (2,2-diethoxy-ethoxy) -phenyl] -cyclopropanecarboxylic acid (10 g), which was used directly in the next step without further

<img file="PL2674428T3_D0118.tif" />

151 1-Benzofuran-5-yl-cyclopropane carboxylic acid [0256] To a suspension of 1- [4- (2,2-diethoxy-ethoxy) -phenyl] cyclopropanecarboxylic acid (20 g, ~ 65 mmol) in xylene (100 mL) was added in PPA room temperature (22.2 g, 64.9 mmol). The mixture was heated at reflux (140 ° C) for 1 hour, then cooled to room temperature and decanted from the PPA. The solvent was evaporated under reduced pressure to give a crude product which was purified by preparative HPLC to give 1- (benzofuran-5-yl) cyclopropanecarboxylic acid (1.5 g, 5%). these NMR (400 MHz, DMSO-d₆) δ 12.25 (br s, 1H), 7.95 (d, J = 2.8 Hz, 1H),

7.56 (d, J = 2.0 Hz, 1H), 7.47 (d, J = 11.6 Hz, 1H), 7.25 (dd, J = 2.4, 11.2 Hz, 1H ), 6.89 (d, J = 1.6 Hz, 1H), 1.471.44 (m, 2H), 1.17-1.14 (m, 2H).

Example 8 1- (2,3-dihydrobenzofuran-6-yl) cyclopropane carboxylic acid [0257]

<img file="PL2674428T3_D0119.tif" />

[0258] To a solution of 1- (benzofuran-6-yl) cyclopropanecarboxylic acid (370 mg, 1.8 mmol) in MeOH (50 mL), PtO was added at room temperature₂ (75 mg, 20%).

The reaction mixture was stirred under a hydrogen atmosphere (1 atm) at 20 ° C for 3 days. The reaction mixture was filtered and the solvent was evaporated under reduced pressure to give a crude product which was purified by preparative HPLC to give 1152 (2,3-dihydrobenzofuran-6-yl) cyclopropanecarboxylic acid (155 mg, 42%). Y NMR (300 MHz, MeOD) δ 7.13 (d, J = 7.5 Hz, 1H), 6.83 (d, J = 7.8 Hz, 1H), 6.74 (s, 1H), 4.55 (t, J = 8.7 Hz,

2H), 3.18 (t, J = 8.7 Hz, 2H), 1.56-1.53 ​​(m, 2H), 1.19-1.15 (m, 2H).

Example 9: 1- (3,3-dimethyl-2,3-dihydrobenzofuran-5-yl) cyclopropanecarboxylic acid.

[0259]

<img file="PL2674428T3_D0120.tif" />

1- (4-hydroxy-phenyl) 1- (4-methoxyphenyl) 10.0 g, 48.5 mmol) in cyclopropane carboxylic acid methyl ester [0260] To a solution of methyl cyclopropanecarboxylate dichloromethane (80 mL) was added EtSH (16 mL) in cooling conditions on an ice-water bath. The mixture was stirred at 0 ° C for 20 minutes and then AlCl was added slowly at 0 ° C₃ (19.5 g, 0.15 mmol). The mixture was stirred at 0 ° C for 30 minutes. The reaction mixture was poured into ice-water, the organic layer was separated, and the aqueous phase was extracted with dichloromethane (50 mL × 3). The combined organic layers were washed with H₂Oh, brine, dried over Na₂SO₄ and evaporated under reduced pressure,

153 to give 1- (4-hydroxyphenyl) cyclopropanecarboxylic acid methyl ester (8.9 g, 95%). ¹1 H NMR (400 MHz, CDCl₃) δ 7.20-7.17 (m, 2H), 6, 75-6, 72 (m, 2H), 5.56 (s, 1H),

3.63 (s, 3H), 1.60-1.57 (m, 2H), 1.17-1.15 (m, 2H).

<img file="PL2674428T3_D0121.tif" />

1- (4-hydroxy-3,5-diiodo-phenyl) cyclopropanecarboxylic acid methyl ester To a solution of 1- (4-hydroxyphenyl) cyclopropanecarboxylic acid methyl ester (8.9 g, 46 mmol) in CH₃NIS (15.6 g, 69 mmol) was added CN (80 mL). The reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate 10: 1) to obtain 1- (4-hydroxy-3,5-diiodo-phenyl) -cyclopropanecarboxylic acid methyl ester (3.5 g, 18%).¹1 H NMR (400 MHz, CDCl₃) δ 7.65 (s, 2H), 5.71 (s, 1H), 3.63 (s, 3H), 1.59-1.56 (m, 2H), 1.151.12 (m, 2H) .

<img file="PL2674428T3_D0122.tif" />

1- [3,5-Diiodo-4- (2-methyl-allyloxy) phenyl] -cyclopropanecarboxylic acid methyl ester [0262] Mixture of 1- (4-hydroxy-3,5-diodo-phenyl) -cyclopropanecarboxylic acid methyl ester (3, 2 g, 7.2 mmol),

154

3-chloro-2-methyl-propene (1.0 g, 11 mmol), K₂WHAT₃ (1.2 g, 8.6 mmol), NaI (0.1 g, 0.7 mmol) in acetone (20 mL) was stirred at 20 ° C overnight. The solid was filtered off and the filtrate was concentrated under reduced pressure to give 1- [3,5-diiodo-4- (2-methyl-allyloxy) -phenyl] cyclopropanecarboxylic acid methyl ester (3.5 g, 97%).^XH NMR (300 MHz, CDCl3) δ 7.75 (s, 2H), 5.26 (s, 1H), 5.06 (s, 1H), 4.38 (s,

2H), 3.65 (s, 3H) 1.98 (s, 3H), 1.62-1.58 (m, 2H), 1.18-1.15 (m, 2H).

<img file="PL2674428T3_D0123.tif" />

1- (3,3-Dimethyl-2,3-dihydro-benzofuran-5-yl) -cyclopropanecarboxylic acid methyl ester To a solution of 1- [3,5-Diodo-4- (2-methyl-allyloxy) -phenyl acid ] -cyclopropane carboxyl (3.5 g, 7.0 mmol) in toluene (15 mL) was added Bu₃SnH (2.4 g, 8.4 mmol) and AlBN (0.1 g, 0.7 mmol). The mixture was heated to reflux overnight. The reaction mixture was concentrated under reduced pressure and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate 20: 1) to give 1- (3,3-dimethyl-2,3-dihydrobenzofuran-5-yl) acid methyl ester -cyclopropane carboxylic acid (1.05 g, 62%).^X1 H NMR (400 MHz, CDCl₃) δ 7.10-7.07 (m, 2H), 6.71 (d, J = 8

Hz, 1H), 4.23 (s, 2H), 3.62 (s, 3H), 1.58-1.54 (m, 2H), 1.34 (s, 6H), 1.17- 1.12 (m, 2H).

155

<img file="PL2674428T3_D0124.tif" />

1- (3,3-Dimethyl-2,3-dihydrobenzofuran-5-yl) cyclopropane carboxylic acid [0264] To a solution of 1- (3,3-dimethyl-2,3-dihydro-benzofuran-5-yl) -cyclopropane-carboxylic acid methyl ester (1.0 g, 4.0 mmol) in MeOH (10 mL), LiOH (0.40 g 9.5 mmol) was added. The reaction mixture was stirred at 40 ° C overnight. HCl (10%) was added slowly to adjust the pH to 5. The resulting mixture was extracted with ethyl acetate (10 mL × 3). The extracts were washed with brine and dried over Na₂SO₄. The solvent was removed under reduced pressure and the crude product was purified by preparative HPLC to give 1- (3,3-dimethyl-2,3-dihydrobenzofuran-5-yl) cyclopropanecarboxylic acid (0.37 g, 41%).¹H NMR (400 MHz, CDCls) δ 7.11-7.07 (m, 2H), 6.71 (d, J = 8 Hz, 1H), 4.23 (s, 2H), 1.66-1 , 63 (m, 2H), 1.32 (s, 6H),

1.26-1.23 (m, 2H).

Example 10: 2- (7-methoxybenzo [d] [1,3] dioxol-5-yl) acetonitrile.

[0265]

<img file="PL2674428T3_D0125.tif" />

156

Methyl 3,4-dihydroxy-5-methoxybenzoate [0266] To a solution of 3,4,5-trihydroxybenzoic acid methyl ester (50 g, 0.27 mol) and Na₂B₄ABOUT₇ (50 g) in water (1000 ml) was added successively at room temperature Me₂SO₄ (120 ml) and aqueous NaOH (25%, 200 ml). The reaction mixture was stirred at room temperature for 6 hours then cooled to 0 ° C. The mixture was acidified to a pH of about 2 by the addition of concentrated H acid₂SO₄ and then filtered. The filtrate was extracted with EtOAc (500 mL × 3). The combined organic layers were dried over anhydrous Na₂SO₄ and evaporated under reduced pressure to give methyl 3,4-dihydroxy-5-methoxybenzoate (15.3 g 47%) which was used in the next step without further purification.

<img file="PL2674428T3_D0126.tif" />

Methyl 7-methoxybenzo [d] [1,3] dioxole-5-carboxylate [0267] To a solution of methyl 3,4-dihydroxy-5-methoxybenzoate (15.3 g, 0.07 mol) in acetone (500 ml), CH added₂BrCl (34.4 g, 0.270 mol) and K₂WHAT₃ (75.0 g, 0.540 mol) at 80 ° C. The resulting mixture was heated to reflux for 4 hours. The mixture was cooled to room temperature and solid K₂WHAT₃filtered. The filtrate was concentrated under reduced pressure and the residue was dissolved in EtOAc (100 mL). The organic layer was washed with water, dried over anhydrous Na₂SO₄ and evaporated under reduced pressure to give a crude product which was purified by gel column chromatography

157 silica (petroleum ether / ethyl acetate = 10: 1) to obtain methyl 7-methoxybenzo [d] [1,3] dioxole-5-carboxylate (12.6 g, 80%). ¹1 H NMR (400 MHz, CDCl₃) δ 7.32 (s, 1H),

7.21 (s, 1H) 6.05 (s, 2H), 3.93 (s, 3H), 3.88 (s, 3H).

<img file="PL2674428T3_D0127.tif" />

(7-methoxybenzo [d] [1,3] dioxol-5-yl) methanol [0268] To a solution of methyl 7-methoxybenzo [d] [1,3] dioxole-5-carboxylate (14 g, 0.040 mol) in THF (100 ml) was added in portions of LiAlH₄ (3.1 g, 0.080 mol) at room temperature. The mixture was stirred for 3 hours at room temperature. The reaction mixture was cooled to 0 ° C and water (3.1 g) and NaOH (10%, 3.1 ml) were added successively. The suspension was filtered and washed with THF. The combined filtrates were evaporated under reduced pressure to give (7-methoxybenzo [d] [1,3] dioxol-5-yl) methanol (7.2 g, 52%).¹1 H NMR (400 MHz, CDCl₃) δ 6.55 (s, 1H), 6.54 (s, 1H), 5.96 (s, 2H), 4.57 (s, 2H), 3.90 (s, 3H).

<img file="PL2674428T3_D0128.tif" />

6- (chloromethyl) -4-methoxybenzo [d] [1,3] dioxol [0269] For SOCl solution₂ (150 ml) (7-methoxybenzo [d] [1,3] dioxol-5-yl) methanol (9.0 g, 54 mmol) was added in portions at 0 ° C. The mixture was stirred for 0.5 hour.

Excess SOCl₂ evaporated under reduced pressure,

158 to give a crude product which was basified with saturated aqueous NaHCO solution₃ to a pH value of about 7. The aqueous phase was extracted with ethyl acetate (100 mL × 3). The combined organic layers were dried over anhydrous Na₂SO₄ and evaporated to give 6- (chloromethyl) -4-methoxybenzo [d] [1,3] dioxol (10 g 94%) which was used in the next step without further purification. ¹1 H NMR (400 MHz, CDCl₃) δ 6.58 (s, 1H), 6.57 (s, 1H), 5.98 (s, 2H), 4.51 (s, 2H), 3.90 (s, 3H).

<img file="PL2674428T3_D0129.tif" />

OMe EIGHT

2- (7-methoxybenzo [d] [1,3] dioxol-5-yl) acetonitrile [0270] To a solution of 6- (chloromethyl) -4-methoxybenzo [d] [1,3] dioxol (10 g, 40 mmol) in DMSO (100 mL) was added at room temperature NaCN (2.4 g, 50 mmol). The mixture was stirred for 3 hours and poured into water (500 ml). The aqueous layer was extracted with EtOAc (100 mL × 3). The combined organic layers were dried over anhydrous Na₂SO₄ and evaporated to give a crude product which was washed with ether to give

2- (7-methoxybenzo [d] [1,3] dioxol-5-yl) acetonitrile (4.6 g, 45%). ¹H NMR (400 MHz, CDCl3) δ 6.49 (s, 2H), 5.98 (s, 2H), 3.91 (s, 3H), 3.65 (s, 2H). ¹³C NMR (400 MHz, CDCl3) δ 148.9, 143.4, 134.6, 123.4, 117.3, 107.2, 101.8, 101.3, 56.3, 23.1.

Example 11: 2- (3- (benzyloxy) -4-methoxyphenyl) acetonitrile.

[0264]

<img file="PL2674428T3_D0130.tif" />

159 [0272] To a suspension of t-BuOK (20.2 g, 0.165 mol) in THF (250 ml) was added a solution of TosMIC (16.1 g, 82.6 mmol) in THF (100 ml) at -78 ° C. The mixture was stirred for 15 minutes, then a solution of 3-benzyloxy-4-methoxybenzaldehyde (10.0 g, 51.9 mmol) in THF (50 mL) was added dropwise and stirring was continued for 1.5 hours at -78 ° C. Methanol (50 mL) was added to the cooled reaction mixture. The mixture was heated to reflux for 30 minutes. The solvent was removed to give the crude product, which was dissolved in water (300 ml). The aqueous layer was extracted with EtOAc (100 mL × 3). The combined organic layers were dried and evaporated under reduced pressure to give a crude product which was purified by column chromatography (petroleum ether / ethyl acetate 10: 1) to give 2- (3- (benzyloxy) -4-methoxyphenyl) acetonitrile (5 , 0 g, 48%).²H NMR (300 MHz, CDCl3) δ 7.48-7.33 m, 3H), 5.17 (s, 2H), 3.90 (s, 3H), 3.66

Hz, CDCl3) δ 149.6, 148.6, 136.8, 128.8,

<td>(m, 5H</td><td> ), 6,89-6,86</td>

<td>(s, 2H)</td><td> . ¹³C NMR (75</td>

<td> 128,8,</td><td> 128,2, 127,</td>

<td> 112,2,</td><td> 71,2 , 56,2,</td>

Example 12: 2- (3- (benzyloxy) -4-chlorophenyl) acetonitrile.

[0273]

<img file="PL2674428T3_D0131.tif" />

160 (4-chloro-3-hydroxy-phenyl) acetonitrile [0274] BBr₃(17 g, 66 mmol) was slowly added to a solution of 2- (4-chloro-3-methoxyphenyl) acetonitrile (12 g, 66 mmol) in dichloromethane (120 mL) at -78 ° C under a nitrogen atmosphere. The temperature of the reaction mixture was slowly increased to room temperature. The reaction mixture was stirred overnight and then poured into a mixture of ice and water. The organic layer was separated and the aqueous layer was extracted with dichloromethane (40 mL × 3). The combined organic layers were washed with water, brine, dried over Na₂SO₄ and concentrated under reduced pressure to give (4-chloro-3-hydroxyphenyl) acetonitrile (9.3 g, 85%). these NMR (300 MHz, CDCl₃) δ 7.34 (d, J = 8.4 Hz, 1H), 7.02 (d, J = 2.1 Hz, 1H), 6.87 (dd,

J = 2.1, 8.4 Hz, 1H), 5.15 (brs, 1H), 3.72 (s, 2H).

<img file="PL2674428T3_D0132.tif" />

2- (3- (benzyloxy) -4-chlorophenyl) acetonitrile [0275] To a solution of (4-chloro-3-hydroxyphenyl) acetonitrile (6.2 g, 37 mmol) in CH₃CN (80 ml) was added K₂WHAT₃ (10 g, 74 mmol) and BnBr (7.6 g, 44 mmol). The reaction mixture was stirred at room temperature overnight. The solids were filtered off and the filtrate was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate 50: 1) to give 2- (3- (benzyloxy) -4-chlorophenyl) acetonitrile (5.6 g, 60%). these NMR (400 MHz, CDCl₃) δ 7.48-7.32 (m, 6H), 6.94

161 (d, J = 2 Hz, 2H), 6.86 (dd, J = 2.0, 8.4 Hz, 1H), 5.18 (s,

2H), 3.71 (s, 2H).

Example 13: 2- (3- (benzyloxy) -4-methoxyphenyl) acetonitrile.

[0276]

<img file="PL2674428T3_D0133.tif" />

resulting in methoxyphenyl) acetonitrile [0277] To a suspension of t-BuOK (20.2 g, 0.165 mol) in THF (250 ml) a solution of TosMIC (16.1 g, 82.6 mmol) in THF (100 ml) was added at a temperature of -78 ° C. The mixture was stirred for 15 minutes, 3-benzyloxy-4-methoxy-benzaldehyde (10.0 g, 51.9 mmol) in THF (50 mL) was added dropwise to the solution, and stirring was continued for 1.5 hours at -78 ° C. Methanol (50 mL) was added to the cooled reaction mixture. The mixture was heated to reflux for 30 minutes. The solvent from the reaction mixture was removed to give the crude product, which was dissolved in water (300 ml). The aqueous layer was extracted with EtOAc (100 mL × 3). The combined organic layers were dried and evaporated under reduced pressure to give a crude product which was purified by column chromatography (petroleum ether / ethyl acetate 10: 1) to give 2- (3- (benzyloxy) -4 (5.0 g, 48%) .¹H NMR (300 MHz,

CDCl₃) δ 7.48-7.33 (m, 5H), 6, 89-6, 86 (m, 3H), 5.17 (s, 2H), 3.90 (s, 3H), 3.66 (s, 2H). ¹³C NMR (75 MHz, CDCl₃) δ 149.6, 148.6, 136.8, 128.8, 128.8, 128.2, 127.5, 127.5, 122.1,

120,9, 118,2, 113,8, 112,2, 71,2, 56,2, 23,3.

162

Example 14: 2- (3-chloro-4-methoxyphenyl) acetonitrile.

[0278]

<img file="PL2674428T3_D0134.tif" />

[0279] To a suspension of t-BuOK (4.8 g, 40 mmol) in THF (30 mL) was added a solution of TosMIC (3.9 g, 20 mmol) in THF (10 mL) at -78 ° C. The mixture was stirred for 10 minutes, then a solution of 3-chloro-4-methoxy-benzaldehyde (1.7 g, 10 mmol) in THF (10 mL) was added dropwise and stirring was continued for 1.5 hours at -78 ° C. Methanol (10 mL) was added to the cooled reaction mixture. The mixture was heated to reflux for 30 minutes. The solvent from the reaction mixture was removed to give the crude product, which was dissolved in water (20 ml). The aqueous layer was extracted with EtOAc (20 mL × 3). The combined organic layers were dried and evaporated under reduced pressure to give a crude product which was purified by column chromatography (petroleum ether / ethyl acetate 10: 1) to give 2- (3-chloro-4-methoxyphenyl) acetonitrile (1.5 g 83%) .¹H NMR (400 MHz, CDCl3) δ 7.33 (d, J = 2.4 Hz, 1H), 7.20 (dd, J = 2.4, 8.4 Hz, 1H), 6.92 (d , J = 8.4 Hz, 1H), 3.91 (s, 3H), 3.68 (s, 2H). ¹³C NMR (100 MHz, CDCl3) δ 154.8, 129.8, 127.3, 123.0, 122.7; 117.60, 112.4, 56.2, 22.4.

Example 15: 2- (3-fluoro-4-methoxyphenyl) acetonitrile.

[0280]

163

<img file="PL2674428T3_D0135.tif" />

[0281] To a suspension of t-BuOK (25.3 g, 0.207 mol) in THF (150 ml) was added a solution of TosMIC (20.3 g, 0.104 mol) in THF (50 ml) at -78 ° C. The mixture was stirred for 15 minutes, then a solution of 3-fluoro-4-methoxy-benzaldehyde (8.00 g, 51.9 mmol) in THF (50 mL) was added dropwise and stirring was continued for 1.5 hours at -78 ° C. Methanol (50 mL) was added to the cooled reaction mixture. The mixture was heated to reflux for 30 minutes. The solvent from the reaction mixture was removed to give the crude product, which was dissolved in water (200 ml). The aqueous layer was extracted with EtOAc (100 mL × 3). The combined organic layers were dried and evaporated under reduced pressure to give a crude product which was purified by column chromatography (petroleum ether / ethyl acetate 10: 1) to give 2- (3-fluoro-4-methoxyphenyl) acetonitrile (5.0 g, 58% ).¹H NMR (400 MHz, CDCH) δ 7.02-7.05 (m, 2H), 6.94 (t, J = 8.4 Hz, 1H), 3.88 (s, 3H), 3.67 (s, 2H). ¹³C NMR (100

MHz, CDCl3) δ 152.3, 147.5, 123.7, 122.5, 117.7, 115.8,

113,8, 56,3, 22,6.

Example 16: 2- (4-chloro-3-methoxyphenyl) acetonitrile.

[0282]

<img file="PL2674428T3_D0136.tif" />

164 chloro-2-methoxy-4-methyl-benzene [0283] To a solution of 2-chloro-5-methyl-phenol (93 g, 0.65 mol) in CH₃CN (700 ml) was added CH₃I (110 g, 0.78 mol) and K₂WHAT₃ (180 g, 1.3 mole). The reaction mixture was stirred at 25 ° C overnight. The solid was filtered off and the filtrate evaporated under reduced pressure to give 1-chloro-2-methoxy-4-methyl-benzene (90 g, 89%).^X1 H NMR (300 MHz, CDCl₃) δ 7.22 (d, J = 7.8 Hz, 1H), 6, 74-6, 69 (m, 2H), 3.88 (s, 3H), 2.33 (s,

3H).

<img file="PL2674428T3_D0137.tif" />

4-bromomethyl-1-chloro-2-methoxy-benzene For solution of 1-chloro-2-methoxy-4-methyl-benzene (50 g,

0.32 mol) in CCl₄ (350 ml) NBS (57 g, 0.32 mol) and AlBn (10 g, 60 mmol) were added. The mixture was heated to reflux for 3 hours. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 20: 1) to obtain 4-bromomethyl-1-chloro-2-methoxy-benzene (69 g, 92%).^X1 H NMR (400 MHz, CDCl₃) δ 7.33-7.31 (m, 1H), 6.95-6.91 (m, 2H), 4.46 (s, 2H), 3.92 (s, 3H).

<img file="PL2674428T3_D0138.tif" />

165

2- (4-chloro-3-methoxyphenyl) acetonitrile [0285] To a solution of 4-bromomethyl-1-chloro-2-methoxy-benzene (68.5 g, 0.290 mol) in C₂H₅OH (90%, 500 ml) NaCN (28.5 g, 0.580 mol) was added. The reaction mixture was stirred at 60 ° C overnight. Ethanol was evaporated and the residue was dissolved in H₂O. The mixture was extracted with ethyl acetate (300 mL × 3). The combined organic layers were washed with brine, dried over Na₂SO₄ and purified by silica gel column chromatography (petroleum ether / ethyl acetate 30: 1) to give 2- (4-chloro-3-methoxyphenyl) acetonitrile (25 g, 48%). ¹H NMR (400 MHz, CDO3) δ 7.36 (d, J = 8 Hz, 1H), 6.886.84 (m, 2H), 3.92 (s, 3H), 3.74 (s, 2H). ¹³C NMR (100 MHz,

CDCl3) δ 155.4, 130.8, 129.7, 122.4, 120.7, 117.5, 111.5,

56,2, 23,5.

Example 17: 1- (3- (hydroxymethyl) -4-methoxyphenyl) cyclopropanecarboxylic acid.

<img file="PL2674428T3_D0139.tif" />

1- (4-methoxyphenyl) cyclopropanecarboxylic acid methyl ester [0287] To a solution of 1- (4-methoxyphenyl) cyclopropanecarboxylic acid (50 g, 0.26 mol) in MeOH (500 ml) toluene-4-sulfonic acid monohydrate was added (2.5 g, 13

166 mmol) at room temperature. The reaction mixture was heated at reflux for 20 hours. MeOH was removed by evaporation under reduced pressure and EtOAc (200 mL) was added. The organic layer was washed with a saturated aqueous NaHCO solution₃ (100 ml) and brine, dried over anhydrous Na₂SO₄ and evaporated under reduced pressure to give 1- (4-methoxyphenyl) cyclopropanecarboxylic acid methyl ester (53 g, 99%). ¹1 H NMR (CDCl₃, 400 MHz) 7.25-7.27 (m, 2H), 6.85 (d, J = 8.8 Hz, 2H),

3.80 (s, 3H), 3.62 (s, 3H), 1.58 (m, 2H), 1.15 (m, 2H).

<img file="PL2674428T3_D0140.tif" />

1- (3-Chloromethyl-4-methoxyphenyl) cyclopropanecarboxylic acid methyl ester To solution of 1- (4-methoxyphenyl) cyclopropanecarboxylic acid methyl ester (30.0 g, 146 mmol) and MOMCl (29.1 g, 364 mmol) ) in CS₂ (300 mL) TiCl was added₄ (8.30 g, 43.5 mmol) at 5 ° C. The reaction mixture was heated at 30 ° C for 1 day and poured into ice water. The mixture was extracted with CH₂cl₂ (150 ml x 3). The combined organic extracts were evaporated under reduced pressure to give 1- (3-chloromethyl-4-methoxyphenyl) cyclopropanecarboxylic acid methyl ester (38.0 g), which was used in the next step without further purification.

<img file="PL2674428T3_D0141.tif" />

167 1- (3-hydroxymethyl-4-methoxyphenyl) cyclopropanecarboxylic acid methyl ester [0289] To a suspension of 1- (3-chloromethyl4-methoxyphenyl) cyclopropanecarboxylic acid methyl ester (20 g) in water (350 mL) was added Bu₄NBr (4.0 g) and Na₂WHAT₃ (90 g, 0.85 mol) at room temperature. The reaction mixture was heated at 65 ° C overnight. The resulting solution was acidified with an aqueous HCl solution (2 mol / L) and extracted with EtOAc (200 mL × 3). The organic layer was washed with brine, dried over anhydrous Na₂SO₄ and evaporated under reduced pressure to give a crude product which was purified by column chromatography (petroleum ether / ethyl acetate 15: 1) to give 1- (3-hydroxy-4-methoxyphenyl) cyclopropanecarboxylic acid methyl ester (8.0 g, 39% ). ¹1 H NMR (CDCl₃, 400 MHz) δ 7.23-7.26 (m, 2H), 6.83 (d, J = 8.0 Hz, 1H) 4.67 (s, 2H), 3.86 (s, 3H) , 3.62 (s, 3H), 1.58 (q, J = 3.6 Hz,

2H), 1.14-1.17 (m, 2H).

<img file="PL2674428T3_D0142.tif" />

1- [3- (tert-butyl-dimethyl-silanyloxymethyl) -4-methoxy-phenyl] -cyclopropanecarboxylic acid methyl ester [0290] To a solution of 1- (3-hydroxy-4-methoxy-phenyl) -cyclopropanecarboxylic acid methyl ester (8.0) g, 34 mmol) in CH₂cl₂ (100 ml) imidazole (5.8 g, 85 mmol) and TBSCl (7.6 g, 51 mmol) were added at room temperature. The reaction mixture was stirred overnight at room temperature. The mixture was washed with brine, dried over anhydrous Na₂SO₄ and evaporated under reduced pressure to give a crude product which

168

<td>g.</td><td> 56%). ¹H</td>

<td>(Dd,</td><td>J = 2.0,</td>

<td>2H);</td><td>3.81 (s,</td>

<td> 1,18</td><td>(m, 2H),</td>

purified by column chromatography (petroleum ether / ethyl acetate 30: 1) to give 1- [3- (tert-butyl-dimethyl-silanyloxymethyl) -4-methoxyphenyl] cyclopropane carboxylic acid methyl ester (6.7 g, 56%

NMR (CDCl₃, 400 MHz) 7.44-7.45 (m, 1H), 7.19 (dd, J = 2.0,

8.4 Hz, 1H), 6.76 (d, J = 8.4 Hz, 1H), 4.75 (s, 2H), 3.81 (s,

3H), 3.62 (s, 3H), 1.57-1, 60 (m, 2H), 1.15-1.1

0.96 (s, 9H), 0.11 (s, 6H),

<img file="PL2674428T3_D0143.tif" />

1- (3-hydroxymethyl-4-methoxy-phenyl) -cyclopropanecarboxylic acid [0291] To a solution of 1- [3- (tert-butyldimethyl-silanyloxymethyl) -4-methoxyphenyl] cyclopropanecarboxylic acid methyl ester (6.2 g, 18 mmol) in MeOH (75 mL) a solution of LiOH was added. H₂O (1.5 g, 36 mmol) in water (10 ml) at 0 ° C. The reaction mixture was stirred overnight at 40 ° C. MeOH was removed by evaporation under reduced pressure. AcOH (1 mol / L, 40 mL) and EtOAc (200 mL) were added. The organic layer was separated, washed with brine, dried over anhydrous Na₂SO₄ and evaporated under reduced pressure to give 1- (3-hydroxymethyl-4-methoxyphenyl) cyclopropanecarboxylic acid (5.3 g).

Example 18: 2- (7-chlorobenzo [d] [1,3] dioxol-5-yl) acetonitrile.

[0292]

169

<img file="PL2674428T3_D0144.tif" />

3-chloro-4,5-dihydroxybenzaldehyde [0293] To a suspension of 3-chloro-4-hydroxy-5-methoxybenzaldehyde (10 g, 54 mmol) in dichloromethane (300 ml) BBr was added dropwise₃ at -40 ° C (26.7 g, 107 mmol) under a nitrogen atmosphere. After the addition was complete, the mixture was stirred at this temperature for 5 h and then poured into ice water. The precipitate was filtered off and washed with petroleum ether. The filtrate was evaporated under reduced pressure to give 3-chloro-4,5-dihydroxybenzaldehyde (9.8 g, 89%), which was used directly in the next step.

<img file="PL2674428T3_D0145.tif" />

7-chlorobenzo [d] [1,3] dioxole-5-carbaldehyde [0294] For a solution of 3-chloro-4,5-dihydroxybenzaldehyde (8.0 g, 46 mmol) and BrClCH₂ (23.9 g, 185 mmol) in dry DMF (100 mL) added Cs₂WHAT₃ (25 g, 190 mmol). The reaction mixture was stirred at 60 ° C overnight and then poured into water. The resulting mixture was extracted with EtOAc (50 mL × 3).

170

The combined extracts were washed with brine (100 mL), dried over Na₂SO₄ and concentrated under reduced pressure to give 7-chlorobenzo [d] [1,3] dioxole-5-carbaldehyde (6.0 g, 70%). ^X1 H NMR (400 MHz, CDCl₃) δ 9.74 (s, 1H), 7.42 (d, J = 0.4 Hz,

1H), 7.2 6 (d, J = 3.6 Hz, 1H), 6.15 (s, 2H).

<img file="PL2674428T3_D0146.tif" />

(7-chlorobenzo [d] [1,3] dioxol-5-yl) methanol [0295] To a solution of 7-chlorobenzo [d] [1,3] dioxole-5-carbaldehyde (6.0 g, 33 mmol) in THF ( 50 ml) was added in portions of NaBH₄ (2.5 g, 64 mmol) at 0 ° C. The reaction mixture was stirred at this temperature for 30 minutes and then poured into an aqueous NH solution₄Cl. The organic layer was separated and the aqueous phase was extracted with EtOAc (50 mL × 3). The combined extracts were dried over Na₂SO₄ and evaporated under reduced pressure to give (7-chlorobenzo [d] [1,3] dioxol-5-yl) methanol, which was used directly in the next step.

<img file="PL2674428T3_D0147.tif" />

4-chloro-6- (chloromethyl) benzo [d] [1,3] dioxol [0296] A mixture of (7-chlorobenzo [d] [1,3] dioxol-5-yl) methanol (5.5 g, 30 mmol) and SOCl₂ (5.0 mL), 67 mmol) in dichloromethane (20 mL) was stirred at room temperature for 1 h and then poured into ice water. The organic layer was separated and the aqueous phase was extracted

171 dichloromethane (50 ml x 3). The combined extracts were washed with water and aqueous NaHCO₃, dried over Na₂SO₄ and evaporated under reduced pressure to give 4-chloro6- ​​(chloromethyl) benzo [d] [1,3] dioxol, which was directly used in the next step.

<img file="PL2674428T3_D0148.tif" />

2- (7-chlorobenzo [d] [1,3] dioxol-5-yl) acetonitrile [0297] A mixture of 4-chloro-6- (chloromethyl) benzo [d] [1,3] dioxol (6.0 g, 29 mmol) and NaCN (1.6 g, 32 mmol) in DMSO (20 mL) was stirred at 40 ° C for 1 h and then poured into water. The mixture was extracted with EtOAc (30 mL × 3). The combined organic layers were washed with water and brine, dried over Na₂SO₄ and evaporated under reduced pressure to give 2- (7-chlorobenzo [d] [1,3] dioxol-5-yl) acetonitrile (3.4 g, 58%). ¹H NMR δ 6.81 (s, 1H), 6.71 (s, 1H), 6.07 (s, 2H), 3.64 (s, 2H). ¹³C-NMR δ 149, 2, 144.3,

124,4, 122,0, 117,4, 114,3, 107,0, 102,3, 23,1.

Example 19: 1- (benzo [d] oxazol-5-yl) cyclopropane carboxylic acid.

<img file="PL2674428T3_D0149.tif" />

172 1-Benzoxazol-5-yl-cyclopropanecarboxylic acid methyl ester [0299] To a solution of 1- (3-amino-4-hydroxyphenyl) cyclopropanecarboxylic acid methyl ester (3.00 g, 14.5 mmol) in DMF, trimethyl orthoformate (5.30 g, 14.5 mmol) and a catalytic amount of p-toluenesulfonic acid monohydrate (0.3 g) at room temperature. The mixture was stirred for 3 hours at room temperature. It was diluted with water and extracted with EtOAc (100 mL × 3). The combined organic layers were dried over anhydrous Na₂SO₄ and evaporated under reduced pressure to give 1-benzoxazol-5-yl-cyclopropanecarboxylic acid methyl ester (3.1 g), which was used directly for the next step. ¹1 H NMR (CDCl₃ 400 MHz) δ 8.09 (s, 1), 7.75 (d, J = 1.2 Hz, 1H), 7.53-7.51 (m, 1H),

7.42-7.40 (m, 1H), 3.66 (s, 3H), 1.69-1.67 (m, 2H), 1.27-1.24 (m, 2H).

<img file="PL2674428T3_D0150.tif" />

1- (benzo [d] oxazol-5-yl) cyclopropanecarboxylic acid [0300] To a solution of 1-benzoxazol-5-cyclopropanecarboxylic acid methyl ester (2.9 g) in EtSH (30 mL) was added in portions of AlCl₃ (5.3 g, 40 mmol) at 0 ° C.

The reaction mixture was stirred for 18 hours at room temperature. Water (20 ml) was added dropwise at 0 ° C. The mixture kept was extracted with EtOAc (100 mL × 3). The combined organic layers were dried over anhydrous Na₂SO₄ and evaporated under reduced pressure to give a crude product which was purified by column chromatography

173 on silica gel (petroleum ether / ethyl acetate 1: 2) to give 1- (benzo [d] oxazol-5-yl) cyclopropanecarboxylic acid (280 mg, 11% after two steps). ¹H NMR (DMSO, 400 MHz) δ 12.25 (broad s, 1H), 8.71 (s, 1H), 7.70-7.64 (m,

2H), 7.40 (dd, J = 1.6, 8.4 Hz, 1H), 1.49-1.46 (m, 2H), 1.211,18 (m, 2H). MS (ESI) m / e (M + H +) 204.4.^.

Example 20: 2- (7-fluorobenzo [d] [1,3] dioxol-5-yl) acetonitrile [0301]

<img file="PL2674428T3_D0151.tif" />

3-fluoro-4,5-dihydroxy-benzaldehyde [0302] To a suspension of 3-fluoro-4-hydroxy-5-methoxybenzaldehyde (1.35 g, 7.94 mmol) in dichloromethane (100 ml) BBr was added dropwise₃ (1.5 mL, 16 mmol) at -78 ° C under nitrogen. After the addition, the mixture was warmed to -30 ° C and stirred at this temperature for 5 hours. The reaction mixture was poured into ice water. The precipitate was filtered off and washed with dichloromethane to give 3-fluoro-4,5-dihydroxy-benzaldehyde (1.1 g, 89%), which was used directly in the next step.

174

<img file="PL2674428T3_D0152.tif" />

7-fluoro-benzo [1,3] dioxole-5-carbaldehyde [0303] To a solution of 3-fluoro-4,5-dihydroxy-benzaldehyde (1.5 g, 9.6 mmol) and BrClCH₂(4.9 g, 38.5 mmol) in dry DMF (50 mL) added Cs₂WHAT₃ (12.6 g, 39 mmol). The mixture was stirred at 60 ° C overnight and then poured into water. The resulting mixture was extracted with EtOAc (50 mL × 3). The combined organic layers were washed with brine (100 mL), dried over Na₂SO₄ and evaporated under reduced pressure to give a crude product which was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 10/1) to give 7-fluoro-benzo [1,3] dioxole-5-carbaldehyde (0.80 g, 49%). ¹1 H NMR (300 MHz, CDCl₃) δ 9.78 (d, J = 0.9 Hz, 1H), 7.26 (dd, J = 1.5, 9.3 Hz, 1H), 7.19 (d, J =

1.2 Hz, 1H), 6.16 (s, 2H).

<img file="PL2674428T3_D0153.tif" />

(7-fluoro-benzo [1,3] dioxol-5-yl) methanol [0304] To a solution of 7-fluoro-benzo [1,3] dioxole-5-carbaldehyde (0.80 g, 4.7 mmol) in MeOH (50 ml) was added in portions of NaBH₄(0.36 g, 9.4 mmol) at 0 ° C. The reaction mixture was stirred at this temperature for 30 minutes and then concentrated to dryness. The residue was dissolved in EtOAc. The EtOAc layer was washed with water, dried over Na₂SO₄ and concentrated to dryness,

175 to give (7-fluoro-benzo [1,3] dioxol-5-yl) methanol (0.80 g, 98%) which is used directly in the next step.

<img file="PL2674428T3_D0154.tif" />

6-chloromethyl-4-fluoro-benzo [1,3] dioxol. To SOCl₂ (20 ml) (7-fluorobenzo [1,3] dioxol-5-yl) methanol (0.80 g, 4.7 mmol) was added in portions at 0 ° C. The mixture was warmed to room temperature over 1 hour and then heated under reflux for 1 hour. Excess SOCl₂evaporated under reduced pressure to give a crude product which was basified with saturated aqueous solution

NaHCO₃ to pH about 7. The aqueous phase was extracted with EtOAc (50 mL × 3). The combined organic layers were dried over Na₂SO₄ and evaporated under reduced pressure to give 6-chloromethyl-4-fluoro-benzo [1,3] dioxol (0.80 g, 92%) which was used directly in the next step.

<img file="PL2674428T3_D0155.tif" />

2- (7-fluorobenzo [d] [1,3] dioxol-5-yl) acetonitrile [0306] A mixture of 6-chloromethyl-4-fluoro-benzo [1,3] dioxole (0.80 g, 4.3 mmol ) and NaCN (417 mg, 8.51 mmol) in DMSO (20 mL) was stirred at 30 ° C for 1 h and then poured into water. The mixture was extracted with EtOAc (50 mL × 3).

The combined organic layers were washed with water (50 ml) and brine

176 (50 ml), dried over Na₂SO₄ and evaporated under reduced pressure to give a crude product which was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 10/1) to give 2- (7fluorobenzo [d] [1,3] dioxol-5-yl) acetonitrile (530 mg, 70%). ¹1 H NMR (300 MHz, CDCl₃) δ 6, 68-6,64 (m, 2H), 6,05 (s, 2H),

3.65 (s, 2H). ¹³C-NMR δ 151, 1, 146.2, 134.1, 124.2, 117.5,

110,4, 104,8, 102,8, 23,3.

Example 21: 1- (1H-indol-5-yl) cyclopropane carboxylic acid

<img file="PL2674428T3_D0156.tif" />

<img file="PL2674428T3_D0157.tif" />

Methyl 1-phenylcyclopropanecarboxylate [0308] To a solution of 1-phenylcyclopropanecarboxylic acid (25 g, 0.15 mol) in CH₃OH (200 mL) was added TsOH (3 g, 0.1 mol) at room temperature. The mixture was refluxed overnight. The solvent was evaporated under reduced pressure to give a crude product which was dissolved in EtOAc. The EtOAc layer was washed with saturated aqueous NaHCO solution₃. The organic layer was dried over anhydrous

177

On₂SO₄ and evaporated under reduced pressure to give methyl 1-phenylcyclopropanecarboxylate (26 g, 96%) which was used directly in the next step. ¹H-NMR (400 MHz, CDCl₃) δ 7.37-7.26 (m, 5H), 3.63 (s, 3H), 1, 63-1, 60 (m, 2H), 1.221.19 (m, 2H).

<img file="PL2674428T3_D0158.tif" />

Methyl 1- (4-nitrophenyl) cyclopropanecarboxylate [0309] To a solution of 1-phenylcyclopropanecarboxylate (20.62 g, 0.14 mol) in H₂SO₄/ CH₂cl₂ (40 ml / 40 ml) was added in portions of KNO₃(12.8 g, 0.13 mol) at 0 ° C. The mixture was stirred for 0.5 hour at 0 ° C. Ice water was added and the mixture was extracted with EtOAc (100 mL × 3). The organic layers were dried over anhydrous Na₂SO₄ and evaporated to give methyl 1- (4-nitrophenyl) cyclopropanecarboxylate (21 g, 68%), which was used directly in the next step. ¹1 H NMR (300 MHz, CDCl₃) δ 8.18 (dd, J = 2.1, 6.9 Hz, 2H), 7.51 (dd, J = 2.1, 6.9 Hz, 2H), 3.64 (s, 3H) , 1.72-1, 69 (m, 2H),

1.25-122 (m, 2H).

Ranney Ni • "rb,

Methyl 1- (4-aminophenyl) cyclopropane carboxylate [0310] To a solution of methyl 1- (4-nitrophenyl) cyclopropane carboxylate (20 g, 0.09 mol) in MeOH (400 ml) was added Ni (2 g) under a nitrogen atmosphere. The mixture was stirred under an atmosphere of hydrogen (1

178 atm) at room temperature overnight. The catalyst was filtered off through a celite pad, and the filtrate was evaporated under reduced pressure to obtain a crude product which was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 10: 1) to obtain methyl 1- (4-aminophenyl) cyclopropanecarboxylate (11 , 38 g,

<td> 66%).</td><td>¹H</td><td>NMR</td><td>(300 MHz, CDCl₃)</td><td>δ 7.16 (</td><td>d, J = 8.1 Hz, 2H),</td>

<td> 6,86</td><td>(D,</td><td>J =</td><td>7.8 Hz, 2H), 4.31</td><td>(br, 2H)</td><td>, 3.61 (s, 3H), 1.55-</td>

<td> 1,50</td><td>(M,</td><td>2H);</td><td>1.30-1.12 (m, 2H)</td><td> .</td><td></td>

<img file="PL2674428T3_D0159.tif" />

Methyl 1- (4-amino-3-bromophenyl) cyclopropanecarboxylate [0311] To a solution of methyl 1- (4-aminophenyl) cyclopropanecarboxylate (10.38 g, 0.05 mol) in acetonitrile (200 ml) was added NBS (9.3 g, 0.05 mol) at room temperature. The mixture was stirred overnight. Water (200 ml) was added. The organic layer was separated and the aqueous phase was extracted with EtOAc (80 mL × 3). The organic layers were dried over anhydrous Na₂SO₄ and evaporated to give methyl 1- (4-amino-3-bromophenyl) cyclopropane carboxylate (10.6 g, 78%) which was used directly in the next

<td>stage. ¹H NMR (400</td><td>MHz, CDCl₃) δ</td><td> 7,38</td><td>(D,</td><td>J = 2.0</td><td>Hz,</td><td>1H),</td>

<td>7.08 (dd, J = 1.6,</td><td>8.4 Hz, 1H),</td><td> 6,70</td><td>(D,</td><td>J = 8.4</td><td>Hz,</td><td>1H),</td>

<td>3.62 (s, 3H), 1.56-</td><td>1. 54 (m, 2H),</td><td> 1,14-</td><td> 1,11</td><td>(m, 2H)</td><td> .</td><td></td>

<img file="PL2674428T3_D0160.tif" />

179

Methyl 1- (4-amino-3 - ((trimethylsilyl) ethynyl) phenyl) cyclopropane carboxylate [0312] To degassed solution of 1- (4 amino-3-bromo-phenyl) -cyclopropane-carboxylic acid methyl ester (8 g, 0.03 mol ) in Et₃N (100 mL) added ethynyl trimethyl silane (30 g, 0.3 mol), DMAP (5 mol%) and Pd (PPh₃)₂cl₂ (5 mol%) under a nitrogen atmosphere. The mixture was refluxed at 70 ° C overnight. The insoluble solid was filtered off and washed with EtOAc (100 mL × 3). The filtrate was evaporated under reduced pressure to give a residue, which was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 20: 1) to give 1- (4-amino-3 - ((trimethylsilyl) ethynyl) phenyl) -

<td>cyclopropanecarboxylate</td><td>methyl</td><td>(4.8 g,</td><td> 56%). ¹H</td><td>NMR</td><td> (300</td>

<td>MHz, CDCl3) δ7.27 (s, 1H)</td><td> , 7,10</td><td>(dd, J =</td><td> 2,1, 8,4</td><td>Hz,</td><td>1H),</td>

<td>6.64 (d, J = 8.4 Hz, 1H)</td><td> , 3,60</td><td>(s, 3H),</td><td> 1,55-1,51</td><td>(M,</td><td>2H);</td>

1.12-1.09 (m, 2H), 0.24 (s, 9H).

<img file="PL2674428T3_D0161.tif" />

Methyl 1- (1H-indol-5-yl) cyclopropanecarboxylate [0313] To degassed solution of methyl 1- (4 amino-3 - ((trimethylsilyl) ethynyl) phenyl) cyclopropanecarboxylate methyl ester (4.69 g, 0.02 mol) in DMF (20 ml) was added

CuI (1.5 g, 0.008 mol) under nitrogen at room temperature. The mixture was stirred for 3 hours at room temperature. The insoluble solid was filtered off, and washed with ethyl acetate (50 mL × 3). The filtrate was evaporated under

180 under reduced pressure to give a residue that was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 20: 1) to give ethyl 1- (1H-indol-5-yl) cyclopropanecarboxylate (2.2 g, 51%). ¹1 H NMR (400 MHz, CDCl₃) δ 7.61 (s, 1H), 7.33 (d, J = 8.4 Hz, 1H), 7.23-7.18 (m, 2H), 6.52-6.51 (m, 1H)

3.62 (s, 3H), 1.65-1, 62 (m, 2H), 1.29-1.23 (m, 2H).

<img file="PL2674428T3_D0162.tif" />

1- (1H-indol-5-yl) cyclopropanecarboxylic acid To a solution of methyl 1- (1H-indol-5-yl) cyclopropanecarboxylate (1.74 g, 8 mmol) in CH₃OH (50 mL) and water (20 mL) LiOH (1.7 g, 0.04 mol) was added. The mixture was heated at 45 ° C for 3 hours. Water was added and the mixture was acidified with concentrated HCl to pH ~ 3 and then extracted with EtOAc (20 mL × 3). The organic layers were dried over anhydrous Na₂SO₄

1- (1H-indol-5i was evaporated to give yl) cyclopropanecarboxylic acid (1.4 g, 87%). ¹1 H NMR.

MHz, DMSO-de) 7.43 (s, 1H), 7.30-7.26 (m, 2H), 7.04 (dd, J =

1.5, 8.4 Hz, 1H), 6.35 (s, 1H), 1.45-1.41 (m, 2H), 1.14-1.10 (m, 2H).

300

Example 22: 1- (4-Oxochroman-6-yl) cyclopropane carboxylic acid [0315]

181

<img file="PL2674428T3_D0163.tif" />

1- [4- (2-tert-butoxycarbonyl-ethoxy) phenyl] cyclopropanecarboxylic acid methyl ester [0316] To a solution of 1- (4-hydroxyphenyl) cyclopropanecarboxylic acid methyl ester (7.0 g, 3.6 mmol) in ester tert-butyl acrylic acid (50 mL) was added Na (42 mg, 1.8 mmol) at room temperature. The mixture was heated at 110 ° C for 1 hour. After cooling to room temperature, the resulting reaction mixture was stopped with water and extracted with EtOAc (100 mL × 3). The combined organic extracts were dried over anhydrous Na₂SO₄ and evaporated under reduced pressure to give a crude product which was purified by silica gel column chromatography (petroleum ether / ethyl acetate 20: 1) to give 1- [4- (2-tert-butoxycarbonyl-ethoxy) -phenyl] cyclopropane-carboxylic acid methyl ester (6.3 g, 54%) and unreacted starting material (3.0 g) ¹1 H NMR (300 MHz, CDCl₃) δ 7.24 (d, J = 8.7 Hz, 2H), 6.84 (d, J = 8.7 Hz, 2H), 4.20 (t, J = 6.6 Hz, 2H), 3.62 (s, 3H), 2.69 (t, J = 6.6 Hz, 2H), 1.59-1.56 (m, 2H), 1.47 (s, 9H), 1.171, 42 (m, 2H).

182

<img file="PL2674428T3_D0164.tif" />

1- [4- (2-carboxy-ethoxy) -phenyl] cyclopropanecarboxylic acid methyl ester solution [0317] Solution of 1- [4- (2-tert-butoxycarbonyl-ethoxy) phenyl] cyclopropanecarboxylic acid methyl ester (6.3 g, 20 mmol) in HCl (20%, 200 mL) was heated at 110 ° C for 1 hour. After cooling to room temperature, the resulting mixture was filtered. The solid was washed with water and dried under reduced pressure to give 1- [4- (2-carboxyethoxy) -phenyl] cyclopropanecarboxylic acid methyl ester (5.0 g, 96%). NMR (300 MHz, DMSO) δ 7.23 -7.19 (m, 2H), 6.85-6.81 (m, 2H),

4.13 (t, J = 6.0 Hz, 2H), 3.51 (s, 3H), 2.66 (t, J = 6.0 Hz,

2H), 1.43-1.39 (m, 2H), 1.14-1.10 (m, 2H).

<img file="PL2674428T3_D0165.tif" />

1- (4-Oxochroman-6-yl) cyclopropanecarboxylic acid [0318] To a solution of 1- [4- (2-carboxyethoxy) phenyl] cyclopropanecarboxylic acid methyl ester (5.0 g, 20 mmol) in CH₂cl₂ (50 ml) oxalyl chloride (4.8 g, 38 mmol) and two drops of DMF at 0 ° C were added. The reaction mixture was stirred at 0 ~ 5 ° C for 1 hour and then evaporated under reduced pressure. CH was added to the resulting mixture₂cl₂ (50 ml) at 0 ° C and stirring continued at 0-5 ° C for 1 hour. The reaction was slowly quenched with water and extracted with ethyl acetate (50 mL x

183

3). The combined organic extracts were dried over anhydrous Na₂SO₄ and evaporated under reduced pressure to give a crude product which was purified by silica gel column chromatography (petroleum ether / ethyl acetate 20: 1 - 2: 1) to obtain 1- (4-oxochroman-6-yl) cyclopropanecarboxylic acid (830 mg, 19 %) and methyl 1- (4-oxochroman-6-yl) cyclopropane carboxylate (1.8 g, 38%). 1- (4-Oxochroman-6-yl) cyclopropane carboxylic acid:¹H NMR (400 MHz, DMSO) δ 12.33 (br s, 1H), 7.62 (d, J = 2.0 Hz, 1H), 7.50 (dd, J = 2.4, 8.4 Hz, 1H), 6.95 (d, J = 8.4 Hz,

1H), 4.50 (t, J = 6.4 Hz, 2H), 2.75 (t, J = 6.4 Hz, 2H), 1.441.38 (m, 2H), 1.10-1, 07 (m, 2H). MS (ESI) m / z (M + H +) 231.4. Ethyl 1- (4-oxochroman-6-yl) cyclopropane carboxylate:¹1 H NMR

<td> (400</td><td>MHz,</td><td>CDCl3) δ</td><td> 7,83</td><td>(D,</td><td>J =</td><td> 2,4</td><td>Hz,</td><td>1H), 7.48 (dd, J =</td>

<td> 2,4,</td><td> 8,4</td><td>Hz, 1H),</td><td> 6,93 (</td><td>d</td><td>J =</td><td> 8,4</td><td>Hz,</td><td>1H), 4.55-4.52 (m,</td>

<td>2H);</td><td> 3,62</td><td>(s, 3H),</td><td> 2,80</td><td>(T,</td><td>J =</td><td> 6,4</td><td>Hz,</td><td>2H), 1.62-1.56 (m,</td>

<td>2H);</td><td> 1,18-</td><td>1.15 (m,</td><td>2H).</td><td></td><td></td><td></td><td></td><td></td>

Example 23: 1- (4-hydroxy-4-methoxychroman-6-yl) cyclopropane carboxylic acid [0319]

<img file="PL2674428T3_D0166.tif" />

1- (4-Hydroxy-4-methoxy-chroman-6-yl) cyclopropane carboxylic acid [0320] To a solution of ethyl 1- (4-oxochroman-6-yl) cyclopropane carboxylate (1.0 g, 4.1 mmol) in MeOH (20 mL) and water (20 ml) LiOH → H was added in portions₂O (0.70 g, mmol) at room temperature. Reaction mixture

184 stirred overnight at room temperature after which methanol was removed by evaporation under reduced pressure. Water and Et 2 O were added to the residue and the aqueous layer was separated, acidified with HCl and extracted with EtOAc (50 mL × 3). The combined organic extracts were dried over anhydrous Na2SO4 and evaporated under reduced pressure to give 1- (4-hydroxy-4-methoxychroman-6-yl) cyclopropanecarboxylic acid (480 mg, 44%).¹H NMR (400 MHz, CDCl) δ 12.16 (s, 1H), 7.73 (d, J = 2.0 Hz, 1H), 7.47 (dd, J = 2.0, 8.4 Hz , 1H), 6.93 (d, J =

8.8 Hz, 1H), 3.83-3.80 (m, 2H), 3.39 (s, 3H), 3.28-3.25 (m,

2H), 1.71-1.68 (m, 2H), 1.25-1.22 (m, 2H). MS (ESI) m / z (M + H +) 263.1.

Example 24: 1- (4-hydroxy-4-methoxychroman-6-yl) cyclopropane carboxylic acid

<img file="PL2674428T3_D0167.tif" />

1-Chroman-6-yl-cyclopropanecarboxylic acid methyl ester [0322] To trifluoracetic acid (20 ml) was added in portions NaBH4 (0.70 g, 130 mmol) at 0 ° C under nitrogen. After stirring for 5 minutes, 1- (4-oxo-chroman-6-yl) cyclopropanecarboxylic acid methyl ester (1.6 g, 6.5 mmol) was added at 15 ° C. The reaction mixture was stirred for 1 hour at room temperature,

185 then slowly stopped with water. The resulting mixture was extracted with EtOAc (50 mL × 3). The combined organic extracts were dried over anhydrous Na₂SO₄ and evaporated under reduced pressure to give 1-chroman-6-yl-cyclopropanecarboxylic acid methyl ester. (1.4 g, 92%), which was used directly in the next step.¹1 H NMR (300 MHz, CDCl₃) δ 7, 07-7, 00 (m, 2H), 6.73 (d, J = 8.4 Hz, 1H) 4.17 (t, J = 5.1 Hz, 2H), 3.62 ( s, 3H), 2.79-2.75 (m, 2H), 2.0051.96 (m, 2H), 1.57-1.54 (m, 2H), 1.16-1.13 (m, 2H).

MeOOC '

<img file="PL2674428T3_D0168.tif" />

<img file="PL2674428T3_D0169.tif" />

<img file="PL2674428T3_D0170.tif" />

1- (4-hydroxy-4-methoxy-chroman-6-yl) cyclopropanecarboxylic acid To a solution of 1-chroman-6-ylcyclopropanecarboxylic acid methyl ester (1.4 g, 60 mmol) in MeOH (20 mL) and water ( 20 ml) LiOH → H was added₂O (1.0 g, 240 mmol) in portions at room temperature. The reaction mixture was stirred overnight at room temperature after which the methanol was removed by evaporation under reduced pressure. Water and Et. Were added₂O and the aqueous layer was separated, acidified with HCl and extracted with EtOAc (50 mL × 3). The combined organic extracts were dried over anhydrous Na₂SO₄ and evaporated under reduced pressure to give 1- (4-hydroxy-4-methoxychroman-6- acid

<td>yl</td><td>) cyclopropane carboxyl (</td><td> 1,0</td><td>g.</td><td> 76%). ¹H</td><td>NMR (400 MHz,</td>

<td>DMS</td><td>O) δ 12.10 (br s, 1H), 6.95</td><td>(D,</td><td>J =</td><td>2.4 Hz</td><td>2H), 6.61-6.59</td>

<td>(M,</td><td>1H), 4.09-4.06 (m, 2H), 2,</td><td> 70-2</td><td> ,67</td><td>(m, 2H),</td><td>1.88-1.86 (m,</td>

<td>2H)</td><td>, 1.37-1.35 (m, 2H), 1.04-1</td><td> ,01</td><td>(M,</td><td>2H). MS</td><td>(ESI) m / z (M +</td>

<td>H⁺)</td><td> 217,4.</td><td></td><td></td><td></td><td></td>

186

Example 25: 1- (3-Methyl-benzo [d] isoxazol-5-yl) cyclopropanecarboxylic acid [0324]

<img file="PL2674428T3_D0171.tif" />

1- (3-Acetyl-4-hydroxy-phenyl) -cyclopropanecarboxylic acid methyl ester [0325] For mixed AlCl suspension₃ (58 g, 440 mmol) in CS₂(500 mL) acetyl chloride (7.4 g, 95 mmol) was added at room temperature. After stirring for 5 minutes, methyl 1- (4-methoxyphenyl) cyclopropane carboxylate (15 g, 73 mmol) was added. The reaction mixture was heated to reflux for 2 hours, after which ice water was carefully added to the mixture at room temperature. The resulting mixture was extracted with EtOAc (150 mL × 3). The combined organic extracts were dried over anhydrous Na₂SO₄ and evaporated under reduced pressure to give 1- (3-acetyl-4-hydroxyphenyl) cyclopropanecarboxylic acid methyl ester (15 g, 81%) which was used in ₁ next step without further purification. ¹H NMR (CDCl3,

187

<td> 400</td><td>MHz)</td><td>δ 12</td><td> ,28</td><td>(S,</td><td>1H)</td><td>, 7.67 (d, J = 2.0</td><td>Hz,</td><td>1H), 7.47</td><td>(dd</td>

<td>J =</td><td> 2,0,</td><td> 8,4</td><td>Hz,</td><td>1H),</td><td> 6,</td><td>94 (d, J = 8.4 Hz,</td><td>1H)</td><td>, 3.64 (s,</td><td>3H)</td>

<td> 2,64</td><td>(S,</td><td>3H);</td><td> 1,</td><td> 65-1,</td><td> 62</td><td>(m, 2H), 1.18-1.16</td><td>(M,</td><td>2H).</td><td></td>

<img file="PL2674428T3_D0172.tif" />

1- [4-hydroxy-3- (1-hydroxyimino-ethyl) phenyl] -cyclopropanecarboxylic acid methyl ester To a mixed solution of 1- (3-acetyl-4-hydroxy-phenyl) -cyclopropanecarboxylic acid methyl ester (14.6 g , 58.8 mmol) in EtOH (500 mL) hydroxylamine hydrochloride (9.00 g, 129 mmol) and sodium acetate (11.6 g, 141 mmol) were added at room temperature. The resulting mixture was heated to reflux overnight. After removing ethanol under reduced pressure, water (200 mL) and EtOAc (200 mL) were added. The organic layer was separated and the aqueous layer was extracted with EtOAc (100 mL × 3). The combined organic layers were dried over anhydrous Na₂SO₄ and evaporated under reduced pressure to give 1- [4-hydroxy-3- (1-hydroxyimino-ethyl) phenyl] cyclopropanecarboxylic acid methyl ester (14.5 g, 98%), which was used in the next step without further purification. ¹1 H NMR (CDCl₃, 400 MHz) δ 11.09 (s, 1H), 7.39 (d, J = 2.0 Hz,

1H), 7.23 (d, J = 2.0 Hz, 1H), 7.14 (s, 1H), 6.91 (d, J =

8.4 Hz, 1H), 3.63 (s, 3H), 2.36 (s, 3H), 1.62-1.59 (m, 2H),

1.18-1.15 (m, 2H).

188

<img file="PL2674428T3_D0173.tif" />

(E) -methyl 1- (3- (1- (acetoxyimino) ethyl) -4-hydroxy-phenyl) cyclopropanecarboxylate solution 1- [4-Hydroxy-3- (1-hydroxyimino-ethyl) phenyl] cyclopropanecarboxylic acid methyl ester (10.0 g, 40.1 mmol) in Ac₂O (250 ml) was heated at 45 ° C for 4 hours. ac₂O was removed by evaporation under reduced pressure, then water (100 mL) was added and EtOAc (100 mL) was added. The organic layer was separated and the aqueous layer was extracted with EtOAc (100 mL × 2

The combined organic layers were dried over anhydrous Na₂SO₄ and evaporated under reduced pressure to give (E) methyl 1- (3- (1- (acetoxyimino) ethyl) -4-hydroxyphenyl) cyclopropanecarboxylate (10.5 g, 99%) which was used in the next step without further purification.

<img file="PL2674428T3_D0174.tif" />

Methyl 1- (3-methylbenzo [d] isoxazol-5-yl) cyclopropane carboxylate. Solution of (E) methyl 1- (3- (1- (acetoxyimino) ethyl) -4-hydroxyphenyl) cyclopropane carboxylate (10.5) g, 39.6 mmol) and pyridine (31.3 g, 396 mmol) in DMF (150 ml) was heated at 125 ° C for 10 hours. The cooled reaction mixture was poured into water (250 mL) and extracted with EtOAc (100 mL x 3). The combined organic layers were dried over anhydrous Na₂SO₄ and evaporated under reduced pressure,

189 to obtain a crude product which was purified by column chromatography on silica gel (ethyl acetate 50: 1) to obtain methyl benzo [d] isoxazol-5-yl) cyclopropane carboxylate

<td> (7,5</td><td>g, 82%).</td><td>¹1 H NMR (CDCl 3</td>

<td>(Dd,</td><td>J = 1.5,</td><td>8.1 Hz, 1H),</td>

<td> 1,68</td><td>(m, 2H),</td><td>1.27-1.23 (m,</td>

<img file="PL2674428T3_D0175.tif" />

method (ether

1- (3-methyl, 7.48

1,711- (3-methyl-benzo [d] isoxazol-5-yl) cyclopropanecarboxylate [0329] To a solution of methyl 1- (3-methyl-benzo [d] isoxazol-5-yl) cyclopropanecarboxylate (1.5 g, 6.5 mmol ) in MeOH (20 ml) and water (2 ml) was added in portions of LiOH ^ H₂O (0.80 g, 19 mmol) at room temperature. The reaction mixture was stirred at room temperature overnight after which the methanol was removed by evaporation under reduced pressure. Water and Et. Were added₂O and the aqueous layer was separated, acidified with HCl and extracted with EtOAc (50 mL × 3). The combined organic extracts were dried over anhydrous Na₂SO₄ and evaporated under reduced pressure to give 1- (3-methyl-benzo [d] isoxazol-5-yl) cyclopropanecarboxylic acid (455 mg, 32%). these

<td>NMR</td><td colspan="2">(400 MHz, DMSO) δ 12.</td><td> 40</td><td colspan="2">(br s, 1H), 7.76 (s,</td><td>1H), 7. 60-</td>

<td> 7.</td><td>57 (m, 2H), 2.63</td><td>(S,</td><td>3H)</td><td> , 1,52-1,48</td><td>(m, 2H),</td><td> 1,23- 1,19</td>

<td>(M,</td><td>2H). MS (ESI) m / z</td><td>(M</td><td>+ H⁺</td><td> ) 218,1.</td><td></td><td></td>

cyclobutane] -5-yl) cyclopropane carboxyl

Example 26:

acid 1- (spiro [benzo [d] [1,3] dioxol-2,1'190 [0330]

<img file="PL2674428T3_D0176.tif" />

1- (3,4-dihydroxy-phenyl) cyclopropanecarboxylic acid methyl ester [0331] To a solution of 1- (3,4-dihydroxyphenyl) cyclopropanecarboxylic acid (4.5 g) in MeOH (30 ml), TsOH (0.25) was added g, 1.3 mmol). Stirring was continued at 50 ° C overnight, after which the mixture was cooled to room temperature. The mixture was concentrated under reduced pressure and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate 3: 1) to give 1- (3,4-dihydroxy-phenyl) -cyclopropanecarboxylic acid methyl ester (2.1 g). ¹H NMR (DMSO 300 MHz) δ

8.81 (brs, 2H), 6.66 (d, J = 2.1 Hz, 1H), 6.61 (d, J = 8.1

Hz, 1H), 6.53 (dd, J = 2.1, 8.1 Hz, 1H), 3.51 (s, 3H), 1.381.35 (m, 2H), 1.07-1.03 (m, 2H).

<img file="PL2674428T3_D0177.tif" />

Methyl 1- (spiro [benzo [d] [1,3] dioxol-2,1'-cyclobutane] -5-yl) cyclopropane carboxylate

191 [0332] To a solution of 1- (3,4-dihydroxyphenyl) cyclopropanecarboxylic acid methyl ester (1.0 g, 4.8 mmol) in toluene (30 mL), TsOH (0.10 g, 0.50 mmol) was added and cyclobutanone (0.70 g, 10 mmol). The reaction mixture was heated at reflux for 2 hours and then concentrated under reduced pressure. The residue was purified by silica gel chromatography (petroleum ether / ethyl acetate 15: 1) to obtain methyl 1- (spiro [benzo [d] [1,3] dioxole-2,1'-cyclobutane] -5-yl) cyclopropane carboxylate (0, 6 g, 50%). ¹1 H NMR (CDCl₃ 300 MHz) δ 6, 78-6, 65 (m, 3H), 3.62 (s, 3H), 2.64-2.58 (m, 4H), 1.89-1.78 (m, 2H), 1.56-1.54 (m, 2H), 1.53-1.12 (m,

2H).

<img file="PL2674428T3_D0178.tif" />

1- (spiro [benzo [d] [1,3] dioxol-2,1'-cyclobutane] -5-yl) cyclopropane carboxylic acid

To a mixture of methyl 1- (spiro [benzo [d] [1,3] dioxol-2,1'cyclobutane] -5-yl) cyclopropanecarboxylate (0.60 g, 2.3 mmol) in THF / H₂O (4: 1, 10 mL) LiOH (0.30 g, 6.9 mmol) was added. The reaction mixture was stirred at 60 ° C for 24 hours. HCl (0.5 N) was slowly added to the mixture at 0 ° C until pH 2-3 was reached. The mixture was extracted with EtOAc (10 mL × 3). The combined organic phases were washed with brine, dried over anhydrous MgSO₄ and washed with petroleum ether to give 1- (spiro [benzo [d] [1,3] dioxol-2,1'-cyclobutan] -5-yl) cyclopropanecarboxylic acid (330 mg, 59%). ¹1 H NMR (400 MHz, CDCl₃) δ 6, 78-6, 65 (m, 3H), 2.65192

2.58 (m, 4H), 1.86-1.78 (m, 2H), 1.63-1.60 (m, 2H), 1.261.19 (m, 2H).

Example 27: 2- (2,3-dihydrobenzo [b] [1,4] dioxin-6-yl) acetonitrile

<img file="PL2674428T3_D0179.tif" />

2,3-dihydro-benzo [1,4] dioxine-6-carboxylic acid ethyl ester [0334] For Cs suspension₂WHAT₃(270 g, 1.49 mol) in DMF (1000 ml) 3,4-dihydroxybenzoic acid ethyl ester (54.6 g, 0.3 mol) and 1,2-dibromoethane (54.3 g, 0.29) mol) at room temperature. The resulting mixture was stirred at 80 ° C overnight and then poured into ice water. The mixture was extracted with EtOAc (200 mL × 3). The combined organic layers were washed with water (200 mL x 3) and brine (100 mL), dried over Na₂SO₄ and concentrated to a dry residue. The residue was purified by column chromatography (petroleum ether / ethyl acetate 50: 1) on silica gel to give 2,3-dihydrobenzo [1,4] dioxine-6-carboxylic acid ethyl ester (18 g, 29%).¹1 H NMR (300

MHz, CDCl₃) δ 7.53 (dd, J = 1.8, 7.2 Hz, 2H), 6, 84-6, 87 (m,

1H), 4.22-4.34 (m, 6H), 1.35 (t, J = 7.2 Hz, 3H).

193

<img file="PL2674428T3_D0180.tif" />

(2,3-dihydro-benzo [1,4] dioxin-6-yl) methanol [0335] For LiAlH suspension₄ (2.8 g, 74 mmol) in THF (20 mL), a solution of 2,3-dihydrobenzo [1,4] dioxine-6-carboxylic acid ethyl ester (15 g, 72 mmol) in THF (10 mL) was added dropwise at a temperature of 0 C in nitrogen atmosphere. The reaction mixture was stirred at room temperature for 1 h and then the reaction was carefully quenched by adding water (2.8 mL) and NaOH (10%, 28 mL) with cooling. The precipitate was filtered off and the filtrate was evaporated to dryness to give (2,3-dihydrobenzo [1,4] dioxin-6-yl) methanol (10.6 g).^XH NMR (300 MHz,

DMSO- d₆) δ 6, 73-6, 78 (m, 3H), 5.02 (t, J = 5.7 Hz, 1H), 4.34 (d, J = 6.0 Hz, 2H), 4.17 -4.20 (m, 4H).

<img file="PL2674428T3_D0181.tif" />

6-chloromethyl-2,3-dihydrobenzo [1,4] dioxine. A mixture of (2,3-dihydro-benzo [1,4] dioxin-6-yl) methanol (10.6 g) in SOCl₂ (10 ml) was stirred at room temperature for 10 minutes and then poured into ice water. The organic layer was separated and the aqueous phase was extracted with dichloromethane (50 mL × 3). The combined organic layers were washed with NaHCO₃ (saturated solution), water and brine, dried over Na₂SO₄ and concentrated to dryness to give 6-chloromethyl-2,3-dihydro-benzo [1,4] dioxine (12 g, 88% after two steps), which was used directly in the next step.

194

<img file="PL2674428T3_D0182.tif" />

2- (2,3-dihydrobenzo [b] [1,4] dioxin-6-yl) acetonitrile [0331] A mixture of 6-chloromethyl-2,3-dihydrobenzo [1,4] dioxine (12.5 g, 67, 7 mmol) and NaCN (4.30 g, 87.8 mmol) in DMSO (50 mL) was stirred at room temperature for 1 hour. The mixture was poured into water (150 mL), followed by extraction with dichloromethane (50 mL × 4). The combined organic layers were washed with water (50 mL x 2) and brine (50 mL), dried over Na₂SO₄ and concentrated to dryness. The residue was purified by column chromatography (petroleum ether / ethyl acetate 50: 1) on silica gel to obtain

2- (2,3-dihydrobenzo [b] [1,4] dioxin-6-yl) acetonitrile as a yellow oil (10.2 g, 86%). ¹H-NMR (300 MHz, CDCl₃) δ 6, 78-6,86 (m, 3H), 4.25 (s, 4H), 3.63 (s, 2H).

[0338] The following Table 2 lists the carboxylic acid forming elements that were commercially available or made by one of the three methods described above: Table 2: Carboxylic acid forming elements

<td>Name</td><td>Structure</td>

<td>1-benzo [1,3] dioxol-5-cyclopropane-1-carboxylic acid</td><td></td>

<td>1- (2,2-difluorobenzo [1,3] dioxol5-yl) cyclopropane-1-carboxylic acid</td><td></td>

<td>1- (3,4-dihydroxyphenyl) acid cyclopropane-1-carboxylic acid</td><td>O-Ν'L,^pH&lt;K °^h</td>

<td>1- (3-methoxy-phenyl) cyclopropane-1-carboxylic acid</td><td>"HCF</td>

195

<td></td><td>HO x</td>

<td>1- (2-methoxy-phenyl) cyclopropane acid</td><td></td>

<td>1-carboxylic acid</td><td>CT⁰"</td>

<td>1- [4- (trifluoromethoxy) phenyl] acid</td><td>_c F AYo</td>

<td>cyclopropane-1-carboxylic acid</td><td>YpA-A HO</td>

<td>1- (2,2-dimethylbenzoic acid)</td><td>Fyg</td>

<td>[D] [1,3] dioxol-5-yl) cyklopropano-</td><td>ρύ cA ° h</td>

<td>carboxylic acid</td><td></td>

<td>tetrahydro-4- (4-methoxyphenyl) -2H- acid</td><td></td>

<td>pyran-4-carboxylic acid</td><td>cX_OH</td>

<td>1-phenylcyclopropane-1- acid</td><td></td>

<td>carboxylic acid</td><td>AND</td>

<td>1- (4-methoxyphenyl) cyclopropane-1- acid</td><td>iPtP^oh</td>

<td>carboxylic acid</td><td>ΧθΑΡ o</td>

<td>1- (4-chlorophenyl) cyclopropane-1- acid</td><td>jfvV^OH</td>

<td>carboxylic acid</td><td>ο, ΥΥ ó ΗΟ- ^ Χθ P *</td>

<td>1- (3-hydroxyphenyl) acid</td><td></td>

<td>cyclopropanecarboxylic</td><td>&lt;y</td>

<td>1-phenylcyclopentanecarboxylic acid</td><td>V</td>

<td>1- (2-oxo-2,3-dihydrobenzo [d] acid</td><td></td>

<td>oxazol-5-yl) cyclopropanecarboxylic acid</td><td></td>

<td>1- (benzofuran-5-yl) acid</td><td>hcp</td>

<td>cyclopropanecarboxylic</td><td></td>

<td>1- (4-methoxyphenyl) cyclohexane acid</td><td>XVP</td>

<td>carboxylic acid</td><td>HOH</td>

<td>1- (4-chlorophenyl) acid -</td><td>κχΡ</td>

<td>cyclohexanecarboxylic acid</td><td>Χ-ΟΗ</td>

<td>1- (2,3-dihydrobenzofuran-5-yl) acid</td><td>TH</td>

<td>cyclopropanecarboxylic</td><td></td>

196

<td>1- (3,3-dimethyl-2,3-dihydrobenzofuran-5-yl) cyclopropanecarboxylic acid</td><td>YY</td>

<td>1- (7-methoxybenzo [d] [1,3] dioxol5-yl) cyclopropane carboxylic acid</td><td></td>

<td>1- (3-hydroxy-4-methoxyphenyl) acid cyclopropanecarboxylic</td><td>&lt;Xz^OH /^0H&lt;rCr%</td>

<td>1- (4-chloro-3-hydroxyphenyl) acid cyclopropanecarboxylic</td><td>Ογ ° ΗΡ^ΗYd^cl</td>

<td>1- (3- (benzyloxy) -4-chlorophenyl acid) cyclopropanecarboxylic</td><td></td>

<td>1- (4-chlorophenyl) cyclopentanecarboxylic acid</td><td>^cYP θΌΗ</td>

<td>1- (3- (benzyloxy) -4-methoxyphenyl) cyclopropane carboxylic acid</td><td>1 YY OH</td>

<td>1- (3-chloro-4-methoxyphenyl) acid cyclopropanecarboxylic</td><td> 0:9'..-</td>

<td>1- (3-fluoro-4-methoxyphenyl) acid cyclopropanecarboxylic</td><td> °~^{/ H} /</td>

<td>1- (4-methoxy-3-methylphenyl) acid cyclopropanecarboxylic</td><td>YY</td>

<td>1- (4- (benzyloxy) -3-methoxyphenyl) cyclopropane carboxylic acid</td><td>-ącY⁰</td>

<td>1- (4-chloro-3-methoxyphenyl) acid cyclopropanecarboxylic</td><td>YY</td>

<td>1- (3-chloro-4-hydroxyphenyl) acid cyclopropanecarboxylic</td><td>YYY^0H</td>

<td>1- (3- (hydroxymethyl) -4 acid</td><td>ΥΓΗ</td>

197

<td>methoxyphenyl) cyclopropane carboxylic acid</td><td></td>

<td>1- (4-methoxyphenyl) acid</td><td></td>

<td>cyclopentanecarboxylic</td><td>O ^ OH</td>

<td>1-phenylcyclohexane carboxylic acid</td><td>op θ '' 'ΌΗ omm^OH P ~</td>

<td>1- (3,4-dimethoxyphenyl) acid</td><td></td>

<td>cyclopropanecarboxylic</td><td></td>

<td>acid 1- (7-chlorobenzo [d] [1,3] dioxol-5-</td><td>"Pp</td>

<td>yl) cyclopropanecarboxylic acid</td><td>cf</td>

<td>acid 1- (benzo [d] oxazol-5-</td><td>"PP</td>

<td>yl) cyclopropanecarboxylic acid</td><td></td>

<td>acid 1- (7-fluorobenzo [d] [1,3] dioxol-5-</td><td>"PP</td>

<td>yl) cyclopropanecarboxylic acid</td><td>F HCKp ° _ /</td>

<td>1- (3,4-difluorophenyl) acid</td><td></td>

<td>cyclopropanecarboxylic</td><td></td>

<td>1- (1H-indol-5-yl) acid</td><td>p-CA</td>

<td>cyclopropanecarboxylic</td><td></td>

<td>1- (1H-benzo [d] imidazol-5-yl) acid</td><td>^NH</td>

<td>cyclopropanecarboxylic</td><td></td>

<td>1- (2-methyl-1H-benzo [d] imidazol-5- acid</td><td>&lt;RCV^NH</td>

<td>yl) cyclopropanecarboxylic acid</td><td></td>

<td>1 - (- methyl-1H-benzo [d] imidazol-5- acid</td><td>PP</td>

<td>yl) cyclopropanecarboxylic acid</td><td></td>

<td>1- (3-methylbenzo [d] isoxazol-5- acid</td><td>HCPP</td>

<td>yl) cyclopropanecarboxylic acid</td><td>&lt;lK Z °</td>

<td>acid 1- (spiro [benzo [d] [1,3] dioxolo-</td><td>hckA / 0?</td>

<td>2,1 '-cyclobutane] -5-</td><td>&lt;HCR^about</td>

<td>yl) cyclopropanecarboxylic acid</td><td></td>

<td>acid 1- (1H-benzo [d] [1,2,3] triazol-5-</td><td>GGG</td>

<td>yl) cyclopropanecarboxylic acid</td><td></td>

198

<td>1- (1-methyl-1H-benzo [d] [1,2,3] triazol-5-yl) cyclopropane carboxylic acid</td><td>HO-_</td><td>KI</td><td>pi</td>

<td>1- (1,3-dihydroisobenzofuran-5- acid</td><td>HO</td><td>k</td><td>k</td>

<td>yl) cyclopropanecarboxylic acid</td><td></td><td></td><td></td>

<td>acid 1- (6-fluorobenzo [d] [1,3] dioxol-5-</td><td>HO</td><td>k</td><td>k</td>

<td>yl) cyclopropanecarboxylic acid</td><td></td><td>/ F</td><td></td>

<td>1- (2,3-dihydrobenzofuran-6- acid</td><td>HO</td><td>AND</td><td>k</td>

<td>yl) cyclopropanecarboxylic acid</td><td></td><td></td><td></td>

<td>1- (chroman-6-yl) cyclopropane acid</td><td>HO</td><td>k</td><td>k</td>

<td>carboxylic acid</td><td></td><td></td><td></td>

<td></td><td></td><td></td><td>OH</td>

<td>1- (4-hydroxy-4-methoxychroman-6- acid</td><td>HO.</td><td>JO</td><td></td>

<td>yl) cyclopropanecarboxylic acid</td><td></td><td>/ V</td><td>J *</td>

<td>acid 1- (4-oxochroman-6-</td><td>HO.</td><td>JO</td><td></td>

<td>yl) cyclopropanecarboxylic acid</td><td></td><td>/ V</td><td></td>

<td>1- (3,4-dichlorophenyl) acid -</td><td>HO</td><td>k</td><td>AND</td>

<td>cyclopropanecarboxylic</td><td></td><td></td><td></td>

<td>1- (2,3-dihydrobenzo [b] [1,4] dioxin-6-yl) cyclopropanecarboxylic acid</td><td>HO</td><td>C&gt; Γν</td><td>y ~^about?</td>

<td>acid 1- (benzofuran-6-</td><td>HO</td><td>ik</td><td>k</td>

<td>yl) cyclopropanecarboxylic acid</td><td></td><td></td><td></td>

[0339] Detailed procedures:

Synthesis of aminoindol forming elements Example 28: 3-methyl-1H-indole-6-amine

<img file="PL2674428T3_D0183.tif" />

199

<img file="PL2674428T3_D0184.tif" />

(3-nitro-phenyl) -hydrazine hydrochloride [0341] 3-nitro-phenylamine (27.6 g, 0.2 mol) was dissolved in a mixture of H₂O (40 ml) and 37% HCl (40 ml). A NaNO solution was added to the mixture at 0 ° C₂ (13.8 g, 0.2 mol) in H₂O (60 ml), and then a SnCl solution was added at this temperature₂. H₂O (135.5 g, 0.6 mol) in 37% HCl (100 ml). After stirring at 0 ° C for 0.5 h, insoluble material was separated by filtration and washed with water to give (3-nitrophenyl) hydrazine hydrochloride (27.6 g,

73%).

<img file="PL2674428T3_D0185.tif" />

N- (3-nitro-phenyl) -N'-propylidene-hydrazine [0342] Sodium hydroxide solution (10%, 15 mL) was slowly added to the stirred suspension of (3-nitrophenyl) hydrazine hydrochloride (1.89 g, 10 mmol) in ethanol (20 mL) until pH 6. Acetic acid (5 mL) was added to the mixture followed by propionic aldehyde (0.7 g, 12 mmol). After stirring for 3 h at room temperature, the mixture was poured into ice water and the resulting precipitate was filtered off, washed with water and air dried to obtain (E) -1- (3-nitrophenyl) -2-propylidene hydrazine, which was used directly in the next step.

<img file="PL2674428T3_D0186.tif" />

200

3-methyl-4-nitro-1H-indole and 3-methyl-6-nitro-1H-indole [0343] A mixture of (E) -1- (3-nitrophenyl) -2-propylidene hydrazine dissolved in 85% H₃AFTER₄ (20 ml) and toluene (20 ml) were heated at 90-100 ° C for 2 hours. After cooling, toluene was removed under reduced pressure. The resulting oil was basified to pH 8 with

10% NaOH. The aqueous layer was extracted with EtOAc (100 mL × 3).

The combined organic layers were dried, filtered and concentrated under reduced pressure to give a mixture of 3-methyl-4-nitro-1H-indole and 3-methyl-6-nitro-1H-indole [1.5 g in 86% after two steps from the hydrochloride (3- nitrophenyl) hydrazine] which was used in the next step without further purification.

<img file="PL2674428T3_D0187.tif" />

3-methyl-1H-indole-6-amine [0344] The crude mixture from the previous step (3 g, 17 mmol) and 10% Pd-C (0.5 g) in ethanol (30 mL) was stirred overnight under an atmosphere of H₂(1 atm) at room temperature. Pd-C was filtered off and the filtrate was concentrated under reduced pressure. The solid residue was purified by column chromatography to give 3-methyl-1H-indole-6-amine (0.6 g, 24%). NMR (CDCls) δ 7.59 (br s, 1H), 7.34 (d, J = 8.0 Hz, 1H), 6.77 (s,

1H), 6.64 (s, 1H), 6.57 (m, 1H), 3.57 (brs, 2H), 2.28 (s, 3H); MS (ESI) m / e (M + H +) 147.2.

Example 29: 3-tert-butyl-1H-indole-5-amine [0345]

201

<img file="PL2674428T3_D0188.tif" />

3-tert-butyl-5-nitro-1H-indole [0346] To a mixture of 5-nitro-1H-indole (6.0 g, 37 mmol) and AlCl₃ (24 g, 0.18 mol) in CH₂cl₂ (100 ml) 2-bromo-2-methyl-propane (8.1 g, 37 mmol) was added dropwise at 0 ° C. After stirring at 15 ° C overnight, the mixture was poured onto ice (100 mL). The precipitated salts were removed by filtration and the aqueous layer was extracted with CH₂cl₂ (30 ml x 3). The combined organic layers were washed with water, brine, dried over Na₂SO₄ and concentrated under reduced pressure to give a crude product which was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 20: 1) to give 3-tert-butyl-5-nitro-1H-indole (2.5 g,

31%). ¹1 H NMR (CDCl₃, 4 00 MHz) δ 8.49 (d, J = 1.6 Hz, 1H), 8.31 (brs, 1H), 8.05 (dd, J = 2.0, 8.8 Hz, 1H) , 7.33 (d, J = 8.8

Hz, 1H), 6.42 (d, J = 1.6 Hz, 1H), 1.42 (s, 9H).

<img file="PL2674428T3_D0189.tif" />

3-tert-butyl-1H-indole-5-amine To a solution of 3-tert-butyl-5-nitro-1H-indole (2.5 g, 12 mmol) in MeOH (30 mL) was added Nickel Raney ( 0.2 g) in a protective nitrogen atmosphere. The mixture was stirred under a hydrogen atmosphere (1 atm) at 15 ° C for 1 hour.

202

The catalyst was filtered off and the filtrate was concentrated to dryness under reduced pressure. The residue was purified by preparative HLPC to give 3-tert-butyl-1H-indole-5-amine (0.43 g, 19%).¹1 H NMR (CDCl₃, 400 MHz) δ 7.72 (br s, 1H),

7.11 (d, J = 8.4 Hz, 1H), 6.86 (d, J = 2.0 Hz, 1H), 6.59 (dd,

J = 2.0, 8.4 Hz, 1H), 6.09 (d, J = 1.6 Hz, 1H), 1.37 (s, 9

H); MS (ESI) m / e (M + H +) 189.1.

Example 30: 2-tert-butyl-6-fluoro-1H-indole-5-amine and 6tert-butoxy-2-tert-butyl-1H-indole-5-amine [0348]

<img file="PL2674428T3_D0190.tif" />

(6.5 g, 42.2 Br2 added dropwise)

2-bromo-5-fluoro-4-nitroaniline [0349] To a mixture of 3-fluoro-4-nitroaniline mmol) in AcOH (80 ml) and chloroform (25 ml) (2.15 ml, 42.2 mmol) 0 ° C.

the resulting mixture was stirred at room temperature for 2 h and then poured into ice water. The mixture was basified with aqueous NaOH (10%) to pH -8.0-9.0 using cooling and then extracted with EtOAc (50 mL x

3). The combined organic layers were washed with water (80 mL x 2) and

203 brine (100 ml), dried over Na₂SO₄ and concentrated under reduced pressure to give 2-bromo-5-fluoro-4-nitroaniline (9 g, 90%). ¹H-NMR (400 MHz, DMSO-d₆) δ 8.26 (d, J = 8.0 Hz, 1H), 7.07 (brs, 2H), 6.62 (d, J = 9.6 Hz, 1H).

<img file="PL2674428T3_D0191.tif" />

2- (3,3-dimethylbut-1-ynyl) -5-fluoro-4-nitroaniline [0350] A mixture of 2-bromo-5-fluoro-4-nitroaniline (9.0 g,

38.4 mmol), 3,3-dimethyl-but-1-yn (9.95 g, 121 mmol), Cul (0.5 g 2.6 mmol), Pd (PPh₃)₂cl₂ (3.4 g, 4.86 mmol) and Et₃N (14 mL, 6.9 mmol) in toluene (100 mL) and water (50 mL) were heated at 70 ° C for 4 hours. The aqueous layer was separated and the organic layer was washed with water (80 mL × 2) and brine (100 mL), dried over Na₂SO₄ and concentrated under reduced pressure to dryness. The residue was recrystallized from ether to give 2- (3,3-dimethylbut-1-ynyl) 5-fluoro-4-nitroaniline (4.2 g, 46%).¹H-NMR (400 MHz, DMSOdg) 5 7, 84 (d, J = 8.4 Hz, 1H), 6.84 (brs, 2H), 6.54 (d, J =

14.4 Hz, 1H), 1.29 (s, 9H).

<img file="PL2674428T3_D0192.tif" />

N- (2- (3,3-dimethylbut-1-ynyl) -5-fluoro-4-nitrophenyl) butyramide For solution of 2- (3,3-dimethylbut-1-ynyl) -5-fluoro-4-nitroaniline (4 , 2 g, 17.8 mmol) in dichloromethane (50 ml) and

204

et₃N (10.3 mL, 71.2 mmol) was added butyryl chloride (1.9 g, 17.8 mmol) at 0 ° C. The reaction mixture was stirred at room temperature for 1 h and then poured into water. The aqueous layer was separated and the organic layer was washed with water (50 ml × 2) and brine (100 ml), dried over Na₂SO₄ and concentrated under reduced pressure to dryness. The residue was washed with ether to give N- (2- (3,3-dimethylbut-1-ynyl) -5-fluoro-4-nitrophenyl) butyramide (3.5 g, 67%) which was used in the next step without further purification.

<img file="PL2674428T3_D0193.tif" />

2-tert-butyl-6-fluoro-5-nitro-1H-indole [0352] Solution of N- (2- (3,3-dimethylbut-1-ynyl) -5-fluoro-4-nitrophenyl) butyramide (3.0 g , 9.8 mmol) and TBAF (4.5 g, 17.2 mmol) in DMF (25 ml) was heated at 100 ° C overnight. The mixture was poured into water and then extracted with EtOAc (80 mL × 3). The combined extracts were washed with water (50 ml) and brine (50 ml), dried over Na₂SO₄ and concentrated under reduced pressure to dryness. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate 20: 1) to obtain a compound

2-tert-butyl-6-fluoro-5-nitro-1H-indole (1.5 g, 65%),¹H-NMR (400 MHz, CDCl₃) δ 8.30 (d, J = 7.2 Hz, 1H), 7.12 (d, J =

11.6 Hz, 1H), 6.3 5 (d, J = 1.2 Hz, 1H), 1.4 0 (s, 9H).

<img file="PL2674428T3_D0194.tif" />

205

2-tert-butyl-6-fluoro-1H-indole-5-amine [0353] A suspension of 2-tert-butyl-6-fluoro-5-nitro-1H-indole (1.5 g, 6.36 mmol) and Ni (0.5 g) in MeOH (20 ml) was stirred under H atmosphere₂ (1 atm) at room temperature for 3 hours. The catalyst was filtered off and the filtrate was concentrated under reduced pressure to dryness. The residue was recrystallized from ether to give 2-tert-butyl-6-fluoro-1H-indol-5-amine (520 mg, 38%).¹H-NMR (300 MHz, DMSO-d₆) δ

10.46 (brs, 1H), 6.90 (d, J = 8.7 Hz, 1H), 6.75 (d, J = 9.0

Hz, 1H), 5.86 (s, 1H), 4.37 (brs, 2H), 1.29 (s, 9H); MS (ESI) m / e 2 0 6, 6.

<img file="PL2674428T3_D0195.tif" />

6-tert-butoxy-2-tert-butyl-5-nitro-1H-indole [0354] Solution of N- (2- (3,3-dimethylbut-1-ynyl) -5-fluoro-4-nitrophenyl) butyramide (500 mg , 1.63 mmol) it-BuOK (0.37 g, 3.26 mmol) in DMF (10 mL) was heated at 70 ° C for 2 hours. The mixture was poured into water and then extracted with EtOAc (50 mL × 3). The combined extracts were washed with water (50 ml) and brine (50 ml), dried over Na₂SO₄ and concentrated under reduced pressure to give 6-tert-butoxy-2-tert-butyl-5-nitro-1H-indole (100 mg, 21%). ¹H-NMR (300 MHz,

DMSO-d₆) δ 11.35 (brs, 1H), 7.99 (s, 1H), 7.08 (s, 1H), 6.25 (s, 1H), 1.34 (s, 9H), 1.30 (s, 9H).

<img file="PL2674428T3_D0196.tif" />

206

6-tert-butoxy-2-tert-butyl-1H-indole-5-amine [0355] A suspension of 6-tert-butoxy-2-tert-butyl-5-nitro-1Hindole (100 mg, 0.36 mmol) and Raney nickel (0.5 g) in MeOH (15 ml) was stirred under H atmosphere₂ (1 atm) at room temperature for 2.5 hours. The catalyst was filtered off and the filtrate was concentrated under reduced pressure to dryness. The residue was recrystallized from ether to give 6-tert-butoxy-2-tert-

<td>butyl-1H-indole-5-amine</td><td> (30</td><td>mg</td><td> 32%)</td><td> . ¹H-NMR (300</td><td>MHz,</td>

<td>MeOD), 6.98 (s, 1H), 6.90</td><td>(S,</td><td>1H),</td><td> 5,94</td><td>(d, J = 0.6 Hz,</td><td>1H),</td>

<td>1.42 (s, 9H), 1.36 (s, 9H)</td><td>; MS</td><td>(ESI</td><td>) m / e</td><td> 205,0.</td><td></td>

Example 31: 1-tert-butyl-1H-indole-5-amine [0356]

<img file="PL2674428T3_D0197.tif" />

N-tert-butyl-4-nitroaniline [0357] A solution of 1-fluoro-4-nitrobenzene (1 g, 7.1 mmol) and tert-butylamine (1.5 g, 21 mmol) in DMSO (5 mL) was stirred in at 75 ° C overnight. The mixture was poured into water (10 mL) and extracted with ethyl acetate (7 mL x 3). The combined organic layers were washed with water, brine, dried over Na₂SO₄ and concentrated under reduced pressure to dryness. The residue was purified by column chromatography on

207 silica gel (petroleum ether / ethyl acetate 30: 1) to give N-tert-butyl-4-nitroaniline (1 g, 73%). ¹1 H NMR (CDCl₃, 400 MHz) δ 8.03-8.00 (m, 2H), 6.61-6.57 (m, 2H), 4.67 (brs, 1H), 1.42 (s, 9H).

<img file="PL2674428T3_D0198.tif" />

(2-bromo-4-nitro-phenyl) -tert-butyl-amine [0358] To a solution of N-tert-butyl-4-nitroaniline (1 g, 5.1 mmol) in AcOH (5 mL) was added Br₂ (0.86 g, 54 mmol) at 15 ° C. After the addition, the reaction mixture was stirred at 30 ° C for 30 minutes and then filtered. The filter cake was basified to pH 8-9 with an aqueous solution

NaHCO₃. The aqueous layer was extracted with EtOAc (10 mL × 3).

The combined organic layers were washed with water, brine, dried over Na₂SO₄ and concentrated under reduced pressure to give (2-bromo-4-nitro-phenyl) -tert-butylamine (0.6 g, 43%). ¹HNMR (CDCl₃, 400 MHz) δ 8.37 (dd, J = 2.4 Hz, 1H), 8.07 (dd, J = 2.4, 9.2 Hz, 1H), 6.86 (d, J = 9 , 2 Hz, 1H), 5.19 (brs, 1H),

1.48 (s, 9H).

<img file="PL2674428T3_D0199.tif" />

tert-butyl- (4-nitro-2-trimethylsilanylethynyl-phenyl) -amine [0359] To a solution of (2-bromo-4-nitro-phenyl) -tert-butyl-amine (0.6 g, 2.2 mmol) in Et₃N (10 mL) Pd (PPh₃)₂cl₂ (70 mg, 0.1 mmol), CuI (20.9 mg, 0.1 mmol) and ethynyl 20 trimethylsilane (0.32 g, 3.3 mmol) under a protective nitrogen atmosphere. The reaction mixture was heated at 70 ° C overnight. The solvent was removed under reduced pressure, and the residue was washed with ethyl acetate (10 mL × 3). The combined organic layers were washed with water, brine, dried over Na2SO4 and concentrated in vacuo to dryness. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate 20: 1) to give tert-butyl- (4-nitro-2-trimethylsilanylethynyl-phenyl) -amine (100 mg, 16%). ¹H-NMR (CDCl3, 400 MHz) δ 8.20 (d, J = 2.4 Hz, 1H), 8.04 (dd, J = 2.4, 9.2 Hz, 1H), 6.79 ( d, J = 9.6 Hz, 1H), 5.62 (brs, 1H),

1.41 (s, 9H), 0.28 (s, 9H).

<img file="PL2674428T3_D0200.tif" />

1-tex * t-butyl-5-nitro-1H-indole [0360] To a solution of tert-butyl- (4-nitro-2-trimethylsilanylethynyl-phenyl) -amine (10 mg, 0.035 mmol) in DMF (2 mL) was added CuI (13 mg, 0.07 mmol) under a protective nitrogen atmosphere. The reaction mixture was stirred at 100 ° C overnight. At this time, EtOAc (4 mL) was added to the mixture. The mixture was filtered and the filtrate was washed with water, brine, dried over Na2SO4 and concentrated under reduced pressure to give 1-tert-butyl-5-nitro-1H-indole (7 mg, 93%).¹H-NMR (CDCl₃, 300 MHz) δ 8.57 (d, J = 2.1 Hz, 1H),

8.06 (dd, J = 2.4, 9.3 Hz, 1H), 7.65 (d, J = 9.3 Hz, 1H)

209

7.43 (d, J = 3.3 Hz, 1H), 6.63 (d, J = 3.3 Hz, 1H), 1.76 (s,

9H).

<img file="PL2674428T3_D0201.tif" />

1-tert-butyl-1H-indole-5-amine [0361] To a solution of 1-tert-butyl-5-nitro-1H-indole (6.5 g, 0.030 mol) in MeOH (100 ml) Raney 'nickel was added a (0.65 g, 10%) in a protective nitrogen atmosphere. The mixture was stirred under an atmosphere of hydrogen (1 atm) at 30 ° C for 1 hour. The catalyst was filtered off and the filtrate was concentrated under reduced pressure to dryness. The residue was purified by silica gel column chromatography (PE / EtOAc 1: 2) to give 1-tert-butyl-1H-indole-5-amine (2.5 g, 45%). ¹H-NMR (CDCl₃, 400 MHz) δ 7.44 (d, J = 8.8 Hz,

1H), 7.19 (dd, J = 3.2 Hz, 1H), 6.96 (d, J = 2.0 Hz, 1H),

6.66 (d, J = 2.0, 8.8 Hz, 1H), 6.26 (d, J = 3.2 Hz, 1H), 1.67 (s, 9H). MS (ESI) m / e (M + H +) 189.2.

Example 32: 2-tert-butyl-1-methyl-1H-indole-5-amine

<img file="PL2674428T3_D0202.tif" />

210 (2-bromo-4-nitro-phenyl) -methyl-amine [0363] To a solution of methyl- (4-nitro-phenyl) -amine (15.2 g, 0.1 mol) in AcOH (150 ml) and CHCl3 (50 ml) Br2 (16.0 g, 0.1 mol) was added at 5 ° C. The mixture was stirred at 10 ° C for 1 hour, then basified with saturated aqueous NaHCO 3 solution. The resulting mixture was extracted with EtOAc (100 mL × 3) and the combined organic layers were dried over anhydrous Na 2 SO 4 and evaporated under reduced pressure to give (2-bromo-4-nitro-phenyl) -methyl-amine (23.0 g,

<td> 99%)</td><td>that was used</td><td>in</td><td>next</td><td>stage</td><td>without</td><td>further</td>

<td colspan="2">purification. ¹1 H NMR</td><td> (300</td><td>MHz, CDCl₃)</td><td>δ 8.37</td><td>(d, J</td><td>= 2.4 Hz,</td>

<td>1H),</td><td>8.13 (dd, J =</td><td> 2,4,</td><td>9.0 Hz, 1H)</td><td> , 6,58</td><td>(d, J</td><td>= 9.0 Hz</td>

<td>1H),</td><td>5.17 (brs, 1H),</td><td> 3,01</td><td>(d, J = 5.4</td><td>Hz, 3H)</td><td></td><td></td>

<img file="PL2674428T3_D0203.tif" />

[2- (3,3-Dimethyl-but-1-ynyl) -4-nitro-phenyl] -methyl-amine [0364] To the solution of (2-bromo-4-nitro-phenyl) -methyl-amine (22, 5 g, 97.4 mmol) in toluene (200 ml) and water (100 ml) were successively added Et3N (19.7 g, 195 mmol), Pd (PPh3) 2Cl2 (6.8 g, 9.7 mmol), CuI (0.7 g, 3.9 mmol) and 3,3-dimethyl-but-1-yn (16.0 g, 195 mmol) under a protective nitrogen atmosphere. The mixture was heated at 70 ° C for 3 hours and then cooled to room temperature. The resulting mixture was extracted with EtOAc (100 mL × 3). The combined organic extracts were dried over anhydrous Na2SO4 and evaporated under reduced pressure to give [2- (3,3-dimethyl-but-1-ynyl) -4-nitro-phenyl] -methyl-amine (20.1 g, 94%), which

211 used in the next step without further purification. ^X1 H NMR (400 MHz, CDCl₃) δ 8.15 (d, J = 2.4 Hz, 1H), 8.08 (dd, J =

2.8, 9.2 Hz, 1H), 6.50 (d, J = 9.2 Hz, 1H), 5.30 (brs, 1H),

3.00 (s, 3H), 1.35 (s, 9H).

<img file="PL2674428T3_D0204.tif" />

2-tert-butyl-1-methyl-5-nitro-1H-indole [0365] Solution of [2- (3,3-dimethyl-but-1-ynyl) -4-nitro-phenyl] methyl-amine (5, 0 g, 22.9 mmol) and TBAF (23.9 g, 91.6 mmol) in THF (50 ml), refluxed overnight. The solvent was removed by evaporation under reduced pressure, and the residue was dissolved in brine (100 mL) and ethyl acetate (100 mL). The organic phase was separated, dried over Na₂SO₄ and evaporated under reduced pressure to give 2-tert-butyl-1-methyl-5-nitro-1Hindole (5.0 g, 99%), which was used in the next step without further purification. ^X1 H NMR (CDCl₃, 400 MHz) δ 8.47 (d, J =

2.4 Hz, 1H), 8.07 (dd, J = 2.4, 9.2 Hz, 1H), 7.26-7.28 (m,

1H), 6.47 (s, 1H), 3.94 (s, 3H), 1.50 (s, 9H).

<img file="PL2674428T3_D0205.tif" />

2-tert-butyl-1-methyl-1H-indole-5-amine [0366] To a solution of 2-tert-butyl-1-methyl-5-nitro-1H-indole (3.00 g, 13.7 mmol) in MeOH (30 ml) Ni Raney (0.3 g) was added under a nitrogen atmosphere. The mixture was stirred under an atmosphere of hydrogen

212 (1 atm) at room temperature overnight. The mixture was filtered through a Celite pad and the filtrate was evaporated under reduced pressure. The crude residue was purified by silica gel column chromatography (PE / EtOAc 20: 1) to give 2-tert-butyl-1-methyl-1H-indol-5-amine (1.7 g, 66%).¹1 H NMR (300 MHz, CDCl₃) δ 7.09 (d, J = 8.4 Hz, 1H), 6.89-6.9 (m, 1H), 6.66 (dd, J = 2.4, 8.7

Hz, 1H), 6.14 (d, J = 0.6 Hz, 1H), 3.83 (s, 3H), 3.40 (brs,

2H), 1.45 (s, 9H); MS (ESI) m / e (M + H +) 203.1.

Example 33: 2-cyclopropyl-1H-indole-5-amine [0367]

<img file="PL2674428T3_D0206.tif" />

2-bromo-4-nitroaniline [0368] To a solution of 4-nitro-aniline (25 g, 0.18 mol) in HOAc (150 mL), liquid Br₂ (30 g, 0.19 mol) at room temperature. The reaction mixture was stirred for 2 hours. The solid was filtered off and poured into water (100 ml), which was basified with saturated aqueous NaHCO solution₃ to pH = 7 and extracted with EtOAc (300 mL × 3). The combined organic layers were dried over anhydrous Na₂SO₄ and evaporated under reduced pressure,

213 was used to give 2-bromo-4-nitroaniline (30 g, 80%) which directly in the next step.

<img file="PL2674428T3_D0207.tif" />

Pd (PPh₃) CI₂

2- (cyclopropylethynyl) -4-nitroaniline To an oxygen-depleted solution of 2-bromo-4-nitroaniline (2.17 g, 0.01 mmol) ethynyl-cyclopropane (1 g, 15 mmol) and Cu (10 mg, 0.05 mmol) in triethylamine (20 ml) Pd (PPh₃)₂cl₂ (210 mg, 0.3 mmol) under a nitrogen atmosphere. The mixture was heated at 70 ° C and stirred for 24 hours. The solid was filtered off and washed with ethyl acetate (50 mL × 3). The filtrate was evaporated under reduced pressure and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 10/1) to give 2- (cyclopropylethynyl) -4-nitroaniline (470 mg,

23%). ¹1 H NMR (300 MHz, CDCl₃) δ 8.14 (d, J = 2.7 Hz, 1H),

7.97 (dd, J = 2.7, 9.0 Hz, 1H), 6.63 (d, J = 9.0 Hz, 1H),

4.81 (brs, 2H), 1.55-1.46 (m, 1H), 0. 98-0, 90 (m, 2H), 0.890.84 (m, 2H).

<img file="PL2674428T3_D0208.tif" />

H

N- (2- (cyclopropylethynyl) phenyl) -4-nitrobutyramide [0370] To a solution of 2- (cyclopropylethynyl) -4-nitroaniline (3.2 g, 15.8 mmol) and pyridine (2.47 g, 31.7 mmol) in CH₂cl₂

214 (60 ml) butyryl chloride (2.54 g, 23.8 mmol) was added at 0 ° C. The mixture was warmed to room temperature and stirred for 3 hours. The resulting mixture was poured into ice water. The organic layer was separated. The aqueous phase was extracted with CH₂cl₂ (30 ml x 3). The combined organic layers were dried over anhydrous Na₂SO₄ and evaporated under reduced pressure to give a crude product which was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 10/1) to obtain N- (2- (cyclopropylethynyl) phenyl) -4-nitrobutyroamide (3.3 g, 76%). ¹1 H NMR (400 MHz, CDCl₃) δ 8.61 (d, J = 9.2 Hz, 1H), 8.22 (d, J = 2.8 Hz, 1H), 8.18 (brs, 1H), 8.13 (dd, J = 2.4, 92 Hz,

1H), 2.46 (t, J = 7.2 Hz, 2H), 1.83-1.76 (m, 2H), 1.59-1.53 ​​(m, 1H), 1.06 (t , J = 7.2 Hz, 3H), 1.03-1.01 (m, 2H), 0.910.87 (m, 2H).

<img file="PL2674428T3_D0209.tif" />

2-cyclopropyl-5-nitro-1H-indole [0371] A mixture of N- (2- (cyclopropylethynyl) phenyl) -4-nitrobutyroamide (3.3 g, 0.01 mol) and TBAF (9.5 g, 0.04 mol ) in THF (100 ml) was refluxed for 24 hours. The mixture was cooled to room temperature and poured into ice water. The mixture was extracted with CH₂cl₂(50 ml x 3). The combined organic layers were dried over anhydrous Na₂SO₄ and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 10/1) to obtain

215

2-cyclopropyl-5-nitro-1H-indole (1.3 g, 64%). ¹H-NMR (400

MHz, CDCl₃) δ 8.44 (d, J = 2.0 Hz, 1H), 8.40 (brs, 1H), 8.03 (dd, J = 2.0, 8.8 Hz, 1H), 7.30 (d, J = 8.8 Hz, 1H), 6.29 (d,

J = 0.8 Hz, 1H), 2.02-1.96 (m, 1H), 1.07-1.02 (m, 2H), 0.850.81 (m, 2H).

<img file="PL2674428T3_D0210.tif" />

2-cyclopropyl-1H-indole-5-amine To a solution of 2-cyclopropyl-5-nitro-1H-indole (1.3 g, 6.4 mmol) in MeOH (30 mL) was added Nickel Raney (0, 3 g) under a nitrogen atmosphere. The mixture was stirred under a hydrogen atmosphere (1 atm) at room temperature overnight. The catalyst was filtered off through a celite pad, and the filtrate was evaporated under reduced pressure to obtain a crude product which was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 5/1) to give 2-cyclopropyl-1H-indole-5-amine (510 mg, 56%). these NMR (400

<td>MHz,</td><td>CDCl.sub.3</td><td>) δ 6.89</td><td>(D,</td><td>J = 8.4</td><td>Hz, 1H), 6,</td><td> 50</td><td>(d, J = 1.6 Hz,</td>

<td>1H),</td><td> 6,33</td><td>(dd, J =</td><td> 2,0,</td><td>8.4 Hz</td><td>1H), 5.76</td><td>(S,</td><td>1H), 4.33 (brs,</td>

<td>2H);</td><td> 1,91-</td><td>1.87 (m,</td><td>1H),</td><td> 0,90-0,</td><td>85 (m, 2H),</td><td> 0,</td><td>70-0.66 (m, 2H);</td>

MS (ESI) m / e (M + H +) 173.2.

Example 34: 3-tert-butyl-1H-indole-5-amine [0373]

<img file="PL2674428T3_D0211.tif" />

216

<img file="PL2674428T3_D0212.tif" />

3-tert-butyl-5-nitro-1H-indole [0374] To a mixture of 5-nitro-1H-indole (6 g, 36.8 mmol) and

AlCl₃ (24 g, 0.18 mol) in CH₂cl₂ (100 ml) 2-bromo-2-methyl-propane (8.1 g, 36.8 mmol) was added dropwise at 0 ° C. After stirring at 15 ° C overnight, the reaction mixture was poured into ice (100 mL). The precipitated salts were removed by filtration and the aqueous layer was extracted with CH₂cl₂(30 ml x 3).

The combined organic layers were washed with water, brine, dried over Na₂SO₄ and concentrated under reduced pressure to give a crude product which was purified by silica gel column chromatography (petroleum ether / ethyl acetate 20: 1) to give 3-tert-butyl-5-nitro-1H-indou (2.5 g, 31 %). ¹1 H NMR (CDCl₃, 400 MHz) δ 8.49 (d, J = 1.6 Hz, 1H), 8.31 (brs, 1H), 8.05 (dd, J = 2.0, 8.8 Hz, 1H), 7.33 (d, J = 8.8 Hz,

1H), 6.42 (d, J = 1.6 Hz, 1H), 1.42 (s, 9H).

<img file="PL2674428T3_D0213.tif" />

3-tert-butyl-1H-indole-5-amine [0375] To a solution of 3-tert-butyl-5-nitro-1H-indole (2.5 g, 11.6 mmol) in MeOH (30 mL) was added Nickel Raney (0.2 g) in a protective nitrogen atmosphere. The mixture was stirred under a hydrogen atmosphere (1 atm) at 15 ° C for 1 hour. The catalyst was filtered off and the filtrate was concentrated under reduced pressure to dryness. The residue was purified by method

217 preparative HLPC to give 3-tert-butyl-1H-indole-5-amine

<td>(0.43 g,</td><td> 19%</td><td> ). ¹1 H NMR</td><td>(CDCl₃, 400 MHz)</td><td colspan="2">δ 7.72 (brs, 1H),</td><td> 7,11</td>

<td>(d, J =</td><td> 8,4</td><td>Hz, 1H), 6</td><td>, 86 (d, J = 2.0</td><td>Hz,</td><td>1H), 6.59 (dd,</td><td>J =</td>

<td> 2,0, 8,4</td><td>Hz,</td><td>1H), 6.09</td><td>(d, J = 1.6 Hz,</td><td>1H)</td><td>, 1.37 (s, 9H)</td><td>; MS</td>

(ESI) m / e (M + H⁺) 189,1.

Example 35: 2-phenyl-1H-indole-5-amine [0376]

<img file="PL2674428T3_D0214.tif" />

2-bromo-4-nitroaniline [0377] To a solution of 4-nitroaniline (50 g, 0.36 mol) in AcOH (500 mL) liquid Br₂ (60 g, 0.38 mol) at 5 ° C. The mixture was stirred for 30 minutes at this temperature. The insoluble solid was filtered off and transferred to EtOAc (200 mL). The mixture was basified with saturated aqueous NaHCO solution₃ to pH 7. The organic phase was separated. The aqueous layer was extracted with EtOAc (300 mL × 3). The combined organic layers were dried and evaporated under reduced pressure to give 2-bromo-4-nitroaniline (56 g, next step.

which was used directly in

72%)

218

<img file="PL2674428T3_D0215.tif" />

4-nitro-2- (phenylethynyl) aniline To an oxygen-depleted solution of 2-bromo-4-nitroaniline (2.17 g, 0.01 mmol) ethinyl benzene (1.53 g, 0.015 mol) and CuI ( 10 mg, 0.05 mmol) in triethylamine (20 ml) Pd (PPh₃)₂cl₂ (210 mg, 0.2 mmol) under a nitrogen atmosphere. The mixture was heated at 70 ° C and stirred for 24 hours. The solid was filtered off and washed with EtOAc (50 mL × 3). The filtrate was evaporated under reduced pressure and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 10/1) to obtain 4-nitro-2- (phenylethynyl) aniline (340 mg, 14%).¹1 H NMR (300 MHz, CDCl₃) δ 8.37-8.29 (m, 1H), 8.08-8.00 (m, 1H),

7.56-7.51 (m, 2H), 7.41-7.37 (m, 3H), 6.72 (m, 1H), 4.95 (brs, 2H).

<img file="PL2674428T3_D0216.tif" />

N- (2- (phenylethynyl) phenyl) -4-nitrobutyramide [0379] To a solution of 4-nitro-2- (phenylethynyl) aniline (17 g, 0.07 mmol) and pyridine (11.1 g, 0.14 mol ) in CH₂cl₂ (100 ml) butyryl chloride (11.5 g, 0.1 mol) was added dropwise at 0 ° C. The mixture was warmed to room temperature and stirred for 3 hours. The resulting mixture was poured into ice water. The organic layer was separated. The aqueous phase was extracted with CH₂cl₂ (30 ml x 3). The combined organic layers were dried over

219 anhydrous Na₂SO₄ and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 10/1) to obtain N- (2- (phenylethynyl) phenyl) -4-nitrobutyramide (12 g, 55%).¹1 H NMR (400 MHz, CDCl₃) δ 8.69 (d, J = 9.2 Hz, 1H),

8.39 (d, J = 2.8 Hz, 1H), 8.25-8.20 (m, 2H), 7.58-7.55 (m,

2H), 7.45 7.42 (m, 3H), 2.49 (t, J = 7.2 Hz, 2H), 1.85-1.79 (m, 2H), 1.06 (t, J = 7.2 Hz, 3H).

<img file="PL2674428T3_D0217.tif" />

5-nitro-2-phenyl-1H-indole [0380] A mixture of N- (2- (phenylethynyl) phenyl) -4-nitrobutyramide (5.0 g, 0.020 mol) and TBAF (12.7 g, 0.050 mol) in THF (30 ml) was heated to reflux for 24 h. The mixture was cooled to room temperature and poured into ice water. The mixture was extracted with CH₂cl₂ (50 ml x 3). The combined organic layers were dried over anhydrous Na₂SO₄ and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 10/1) to obtain 5-nitro-2-phenyl-1H-indole (3.3 g, 69%).¹H

NMR (400 MHz, CDCl₃) δ 8.67 (s, 1H), 8.06 (dd, J = 2.0, 8.8

Hz, 1H), 7.75 (d, J = 7.6 Hz, 2H), 7.54 (d, J = 8.8 Hz, 1H),

7.45 (t, J = 7.6 Hz, 2H), 7.36 (t, J = 7.6 Hz, 1H), 6.95 (s,

1H).

<img file="PL2674428T3_D0218.tif" />

220

2-phenyl-1H-indole-5-amine [0374] To a solution of 5-nitro-2-phenyl-1H-indole (2.83 g, 0.01 mol) in MeOH (30 ml) was added Ni Raney ( 510 mg) under a nitrogen atmosphere. The mixture was stirred under a hydrogen atmosphere (1 atm) at room temperature overnight. The catalyst was filtered off through a celite pad, and the filtrate was evaporated under reduced pressure to obtain a crude product which was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 5/1) to give 2-phenyl-1H-indole-5-

<td>amines</td><td>ę (1.6 g</td><td> , 77%). ¹1 H NMR</td><td> (400</td><td>MHz, CDCl3)</td><td>δ</td><td> 7,7</td><td>6 (d,</td><td>J =</td>

<td> 7,6</td><td>Hz, 2H),</td><td>7.39 (t, J = 7,</td><td>6 Hz</td><td>, 2H), 7.24</td><td>(t</td><td>J</td><td> = 7,6</td><td>Hz,</td>

<td>1H),</td><td>7.07 (d,</td><td>J = 8.4 Hz, 1H</td><td> ) , 6,</td><td>64 (d, J = 1</td><td> ,6</td><td>Hz,</td><td>1H),</td><td> 6,60</td>

<td>(D,</td><td>J = 1.2</td><td>Hz, 1H), 6.48</td><td>(Dd,</td><td>J = 2.0, 8,</td><td> 4</td><td>Hz,</td><td>1H),</td><td> 4,48</td>

(brs, 2H); MS (ESI) m / e (M + H +) 209.0.

Example 36: 2-tert-butyl-4-fluoro-1H-indole-5-amine

<img file="PL2674428T3_D0219.tif" />

2-bromo-3-fluoroaniline [0383] To a solution of 2-bromo-1-fluoro-3-nitrobenzene (1.0 g, 5.0 mmol) in CH₃OH (50 mL) was added NiCl₂ (2.2 g 10 mmol) and NaBH₄ (0.50 g 14 mmol) at 0 ° C. After the addition was complete, the mixture was stirred for 5 minutes. Water added (20

221 ml) and the mixture was extracted with EtOAc (20 ml × 3). The organic layers were dried over anhydrous Na₂SO₄ and evaporated under reduced pressure to give 2-bromo-3-fluoroaniline (600 mg, 70%). ¹1 H NMR (400 MHz, CDCl₃) δ 7, 07-7,02 (m, 1H),

6, 55-6, 49 (m, 1H), 4.22 (br s, 2H).

<img file="PL2674428T3_D0220.tif" />

N- (2-bromo-3-fluoro-phenyl) -butyramide [0384] To a solution of 2-bromo-3-fluoroaniline (2.0 g, 11 mmol) in CH₂cl₂ (50 ml) butyryl chloride (1.3 g, 13 mmol) and pyridine (1.7 g, 21 mmol) were added dropwise at 0 ° C. The reaction mixture was stirred at room temperature for 24 hours. Water (20 ml) was added and the mixture was extracted with CH₂cl₂ (50 ml x

3). The organic layers were dried over anhydrous Na₂SO₄ and evaporated under reduced pressure to give N- (2-bromo-3-fluorophenyl) butyramide (2.0 g, 73%) which was used directly in the next step.

<img file="PL2674428T3_D0221.tif" />

N- (2- (3,3-dimethylbut-1-ynyl) -3-fluorophenyl) butyramide [0385] To a solution of N- (2-bromo-3-fluorophenyl) butyramide (2.0 g, 7.0 mmol) in Et₃N (100 ml) was added successively at room temperature under nitrogen atmosphere 4,4-dimethylpent-2-yn (6.0 g, 60 mmol), CuI (70 mg, 3.8 mmol) and Pd (PPh₃)₂cl₂ (500 mg).

The mixture was heated at 80 ° C overnight. The cooled

222 the mixture was filtered and the filtrate extracted with EtOAc (40 mL × 3). The organic layers were washed with sat. NaCl, dried over anhydrous Na₂SO₄ and evaporated under reduced pressure. The crude compound was purified by silica gel column chromatography (10% EtOAc in petroleum ether) to give N- (2- (3,3-dimethylbut-1-ynyl) -3-fluorophenyl) butyramide (1.1 g, 55 %).¹H NMR (400

MHz, CDCl₃) δ 8.20 (d, J = 7.6, 1H), 7.95 (s, 1H), 7.21 (m,

1H), 6.77 (t, J = 7.6 Hz, 1H), 2.39 (t, J = 7.6 Hz, 2H), 1.821,75 (m, 2H), 1.40 (s, 9H), 1.12 (t, J = 7.2 Hz, 3H).

<img file="PL2674428T3_D0222.tif" />

2-tert-butyl-4-fluoro-1H-indole [0386] To a solution of N- (2- (3,3-dimethylbut-1-ynyl) -3-fluoro-phenyl) -butyramide (6.0 g, 20 mmol) in DMF ( 100 ml) t-BuOK (5.0 g, 50 mmol) was added at room temperature. The mixture was heated at 90 ° C overnight, poured into water and extracted with EtOAc (100 mL × 3). The organic layers were washed with sat. NaCl and water, dried over anhydrous Na₂SO₄ and evaporated under reduced pressure to give 2-tert-butyl-4-fluoro-1H-indole (5.8 g, 97%). ¹HNMR (400 MHz, CDCl₃) δ 8.17 (br s, 1H), 7.11 (d, J = 7.2 Hz,

1H), 7.05-6.99 (m, 1H), 6.76-6.71 (m, 1H), 6.34 (m, 1H), 1.41 (s, 9H).

<img file="PL2674428T3_D0223.tif" />

223

2-tert-butyl-4-fluoro-5-nitro-1H-indole [0387] To a solution of 2-tert-butyl-4-fluoro-1H-indole (2.5 g, 10 mmol) in H₂SO₄ (30 ml) KNO was added₃ (1.3 g, 10 mmol) at 0 ° C. The mixture was stirred for 0.5 hour at -10 ° C. The mixture was poured into water and extracted with ethyl acetate (100 mL × 3). The organic layers were washed with sat. NaCl and water, dried over anhydrous Na₂SO₄ and evaporated under reduced pressure. The crude compound was purified by silica gel column chromatography (10% EtOAc in petroleum ether) to give 2-tert-butyl-4-fluoro-5-nitro-1H-indole (900 mg, 73%).¹1 H NMR (400 MHz, CDCl₃) δ 8.50 (br s, 1H), 7.86 (dd, J = 7.6, 8.8 Hz, 1H), 7.13 (d, J = 8.8

Hz, 1H), 6.52 (dd, J = 0.4, 2.0 Hz, 1H), 1.40 (s, 9H).

<img file="PL2674428T3_D0224.tif" />

2-tert-butyl-4-fluoro-1H-indole-5-amine [0388] To a solution of 2-tert-butyl-4-fluoro-5-nitro-1H-indole (2.1 g, 9.0 mmol) in methanol (50 ml) NiCl was added₂ (4.2 g, 18 mmol) and NaBH₄ (1.0 g, 27 mmol) at 0 ° C. After the addition was complete, the mixture was stirred for 5 minutes. Water (20 mL) was added and the mixture was extracted with EtOAc (30 mL x

3). The organic layers were washed with sat. NaCl and water, dried over anhydrous Na₂SO₄, evaporated under reduced pressure to give 2-tert-butyl-4-fluoro-1H-indole-5-amine (900 mg,

50%). 1 H-NMR (300 MHz, CDCl₃) δ 7.80 (brs, 1H), 6.91 (d, J =

8.4 Hz, 1H), 6.64 (dd, J = 0.9, 2.4 Hz, 1H), 6.23 (s, 1H),

1.38 (s, 9H).

224

Example 37: 2,3,4,9-tetrahydro-1H-carbazole-6-amine [0389]

<img file="PL2674428T3_D0225.tif" />

2,3,4,9-tetrahydro-1H-carbazole-6-amine [0390] 6-Nitro-2,3,4,9-tetrahydro-1H-carbazole (0.100 g, 0.462 mmol) was placed in a scintillation vial for 40 ml containing a magnetic stir bar and dissolved in 2 ml ethanol. Tin (II) chloride dihydrate (1.04 g, 4.62 mmol) was added to the reaction mixture, and the resulting suspension was heated at 70 ° C for 16 hours. The crude reaction mixture was diluted with 15 mL saturated aqueous sodium bicarbonate solution and extracted three times with an equivalent volume of ethyl acetate. The ethyl acetate extracts were combined, dried over sodium sulfate and evaporated to dryness to give 2,3,4,9-tetrahydro-1H-carbazole-6amine (82 mg, 95%) which was used without further purification.

Example 38:

2-tert-butyl-7-fluoro-1H-indole-5-amine [0391]

<img file="PL2674428T3_D0226.tif" />

225

2-bromo-6-fluoro-4-nitro-phenylamine [0392] To a solution of 2-fluoro-4-nitro-phenylamine (12 g, 77 mmol) in AcOH (50 mL) was added Br₂ (3.9 mL, 77 mmol) at 0 ° C. The mixture was stirred at 20 ° C for 3 hours. The reaction mixture was basified with saturated aqueous NaHCO solution₃ and extracted with EtOAc (100 mL × 3). The combined organic layers were dried over anhydrous Na₂SO₄ and evaporated under reduced pressure to give 2-bromo-6-fluoro-4-nitro-phenylamine (18 g, 97%). ¹H-NMR (400

MHz, CDCl₃) δ 8.22 (m, 1H), 7.90 (dd, J = 2.4, 10.8 Hz, 1H),

4.88 (brs, 2H).

<img file="PL2674428T3_D0227.tif" />

2- (3,3-dimethyl-but-1-ynyl) -6-fluoro-4-nitro-phenylamine [0393] To a solution of 2-bromo-6-fluoro-4-nitro-phenylamine (11 g, 47 mmol) in dry Et₃N (100 mL) was added Cul (445 mg, 5 mol%), Pd (PPh₃)₂cl₂ (550 mg, 5 mol%) and 3,3-dimethyl-but-1-yn (9.6 g, 120 mmol) under a protective nitrogen atmosphere. The reaction mixture was stirred at 80 ° C for 10 hours. The reaction mixture was filtered, poured into ice (100 g) and extracted with EtOAc (50 mL × 3). The combined organic extracts were dried over anhydrous Na₂SO₄ and evaporated under reduced pressure to give a crude product which was purified by silica gel column chromatography (petroleum ether / ethyl acetate 50: 1) to give 2- (3,3-dimethyl-but-1-ynyl) -6-fluoro-4- nitro-phenylamine (4.0 g, 36%). these NMR (400 MHz, CDCl₃) δ 8.02 (d, J = 1.2 Hz, 1H),

226

7.84 (dd, J = 2.4, 10,

Hz, 1H), 4.85 (brs,

2H), 1.36 s, 9

H).

<img file="PL2674428T3_D0228.tif" />

N- [2- (3,3-dimethyl-but-1-ynyl) -6-fluoro-4-nitrophenyl] butyramide [0394] To solution 2- (3,3-dimethyl-but-1-ynyl) -6 -fluoro-4-nitro-phenylamine (4.0 g, 17 mmol) and pyridine (2.7 g, 34 mmol) in anhydrous CH₂cl₂ (30 ml) butyryl chloride (1.8 g, 17 mmol) was added dropwise at 0 ° C. After stirring for 5 hours at 0 ° C, the reaction mixture was poured onto ice (50 g) and extracted with CH₂cl₂ (30 ml x 3). The combined organic extracts were dried over anhydrous Na₂SO₄ and evaporated under reduced pressure to give N- [2- (3,3-dimethyl-but-1-ynyl) -6-fluoro-4-nitro-phenyl] -butyramide (3.2 g, 62%), which was used in the next stage without further purification. ¹H

<td>NMR</td><td> (300</td><td>MHz,</td><td>DMSO) δ</td><td> 8,10</td><td>(Dd,</td><td>J = 1.5,</td><td> 2,7</td><td>Hz,</td><td>1H), 7.95</td>

<td>(Dd,</td><td>J =</td><td> 2,4;</td><td>9.6 Hz</td><td>1H),</td><td> 7,22</td><td>(brs, 1H)</td><td> , 2</td><td> ,45 (</td><td>t, J = 7.5</td>

<td>Hz,</td><td>2H);</td><td> 1,82</td><td>(m, 2H)</td><td> , 1,36</td><td>(S,</td><td>9H), 1,</td><td> 06 (</td><td>t, J</td><td>= 7.5 Hz</td>

3H).

<img file="PL2674428T3_D0229.tif" />

2-tert-butyl-7-fluoro-5-nitro-1H-indole [0395] To solution of N- [2- (3,3-dimethyl-but-1-ynyl) -6-fluoro-4-nitro-phenyl] - butyramide (3.2 g, 10 mmol) in DMF (20 mL) was added t-BuOK (2.3 g, 21 mmol) at room temperature.

227

The mixture was heated at 120 ° C for 2 hours and then cooled to room temperature. To the mixture

<td>reaction</td><td>added</td><td>water</td><td> (50</td><td>ml)</td><td>and the resulting mixture</td>

<td>extracted</td><td>CH2Cl2</td><td> (30</td><td>ml</td><td>x</td><td>3). Combined extracts</td>

<td colspan="2">organic dried</td><td>above</td><td colspan="2">anhydrous</td><td>Na2SO4 and evaporated under</td>

<td>reduced</td><td colspan="2">pressure,</td><td colspan="2">to give the</td><td>2-tert-butyl-7-fluoro-5-</td>

nitro-1H-indole (2.0 g, 81%) which was used in the next step without further purification. ^X1 H NMR (300 MHz, CDCl₃) δ 9.95 (brs, 1H), 8.30 (d, J = 2.1 Hz, 1H), 7.74 (dd, J = 1.8, 11.1

Hz, 1H) 6.43 (dd, J = 2.4, 3.3 Hz, 1H), 1.43 (s, 9H).

<img file="PL2674428T3_D0230.tif" />

2-tert-butyl-7-fluoro-1H-indole-5-amine [0396] To a solution of 2-tert-butyl-7-fluoro-5-nitro-1H-indole (2.0 g, 8.5 mmol) in MeOH (20 ml) Ni (0.3 g) was added under a nitrogen atmosphere. The reaction mixture was stirred under a hydrogen atmosphere (1 atm) at room temperature overnight. The catalyst was filtered off through a celite pad, and the filtrate was evaporated under reduced pressure. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate 100: 1) to obtain

2-tert-butyl-7-fluoro-1H-indole-5-amine (550 mg, 24%). ^X1 H NMR (300 MHz, CDCl₃) δ 7.87 (brs, 1H), 6.64 (d, J = 1.5 Hz,

1H), 6.37 (dd, J = 1.8, 12.3 Hz, 1H), 6.11 (dd, J = 2.4, 3.6

Hz, 1H), 1.39 (s, 9H). MS (ESI) m / z (M + H +) 207.

Example 39: 5-amino-2-tert-butyl-1H-indole-7-carbonitrile, [0397]

228

<img file="PL2674428T3_D0231.tif" />

2-amino-3- (3,3-dimethylbut-1-ynyl) -5-nitrobenzonitrile [0398] To a stirred solution of 2-amino-3-bromo-5-nitrobenzonitrile (2.4 g, 10 mmol) in dry Et₃N (60 ml) was added CuI (380 mg, 5 mol%) and Pd (PPh₃)₂cl₂ (470 mg, 5 mol%) at room temperature. To the mixture, 3,3-dimethyl-but-1-yn (2.1 g, 25 mmol) was added dropwise at room temperature. The reaction mixture was stirred at 80 ° C for 10 hours. The reaction mixture was filtered and the filtrate poured into ice (60 g) and extracted with ethyl acetate. The phases were separated and the organic phase was dried over Na₂SO₄. The solvent was removed under reduced pressure to give a crude product which was purified by column chromatography (2-10% EtOAc in petroleum ether) to give 2-amino-3- (3,3-dimethylbut-1-ynyl) -5-nitrobenzonitrile (1, 7 g, 71%).¹1 H NMR (300 MHz, CDCl₃) δ

8.28 (d, J = 2.7 Hz, 1H), 8.27 (d, J = 2.7 Hz, 1H), 5.56 (br s, 2H), 1.37 (s, 9H ).

<img file="PL2674428T3_D0232.tif" />

2-ter^,t-butyl-5-nitro-1H-indole-7-carbonitrile [0399] To a solution of 2-amino-3- (3,3-dimethylbut-1-ynyl) -5-nitrobenzonitrile (1.7 g, 7.0 mmol) in THF (35 ml) was added

229

TBAF (9.5 g, 28 mmol) at room temperature. The mixture was heated to reflux overnight. The reaction mixture was cooled and then THF removed under reduced pressure. Water (50ml) was added to the residue and the mixture was extracted with ethyl acetate. The organics were dried over Na₂SO₄ and the solvent was evaporated under reduced pressure to obtain 0.87 g of a crude 2-tert-butyl-5-nitro-1H-indole-7-carbonitrile crude product which was used directly in the next step without purification.

<img file="PL2674428T3_D0233.tif" />

5-amino-2-tert-butyl-1H-indole-7-carbonitrile [0400] To a solution of the crude product 2-tert-butyl-5-nitro-1H-indole-7-carbonitrile (0.87 g, 3.6 mmol) in MeOH (10 mL) was added NiCl₂.6H₂O (1.8 g, 7.2 mmol) at -5 ° C. The reaction mixture was stirred for 30 minutes, and then NaBH was added to the reaction mixture₄ (0.48 g, 14.32 mmol) at 0 ° C. After 5 minutes, the reaction mixture was stopped with water, filtered and extracted with EtOAc. The combined organic layers were dried over Na₂SO₄ and concentrated under reduced pressure to give a crude product which was purified by column chromatography (5-20% EtOAc in petroleum ether) to obtain 5-amino-2-tert-butyl-1-indole-7-carbonitrile (470 mg, 32% after two stages). ¹1 H NMR (400 MHz, CDCl₃) δ 8.25 (s, 1H), 7.06 (d, J = 2.4 Hz, 1H),

6.84 (d, J = 2.4 Hz, 1H), 6.14 (d, J = 2.4 Hz, 1H), 3.57 (br s, 2H), 1.38 (s, 9 H ). MS (ESI) m / z: 214 (M + H +).

230

Example 40: Methyl 5-amino-2-tert-butyl-1H-indole-7-carboxylate [0401]

<img file="PL2674428T3_D0234.tif" />

2-tert-butyl-5-nitro-1H-indole-7-carboxylic acid [0402] 2-tert-butyl-5-nitro-1H-indole-7-carbonitrile (4.6 g, mmol) was added to the KOH solution in ethanol (10%, 100 ml) and the mixture was refluxed overnight. The solution was evaporated to remove alcohol, a small amount of water was added, and then the mixture was acidified with dilute hydrochloric acid. After standing in the fridge, an orange-yellow precipitate formed which was purified by silica gel chromatography (15% EtOAc in petroleum ether) to give 2-tert-butyl-5-nitro-1H-indole-7-carboxylic acid (4 , 0 g, 77%). ¹1 H NMR (CDCl₃,

300 MHz) δ 10.79 (brs, 1H), 8.66 (s, 1H), 8.45 (s, 1H), 6.57 (s, 1H), 1.39 (s, 9H).

<img file="PL2674428T3_D0235.tif" />

Methyl 2-tert-butyl-5-nitro-1H-indole-7-carboxylate

231 [0403] SOCl₂ (3.6 g, 30 moles) was added dropwise to a solution of 2-tert-butyl-5-nitro-1H-indole-7-carboxylic acid (4.0 g, 15 moles) and methanol (30 mL) at 0 ° C. The reaction mixture was stirred at 80 ° C for 12 hours. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (5% EtOAc in petroleum ether) to obtain methyl 2-tert-butyl-5-nitro-1H-indole-7-carboxylate (2.95 g, 70%).^X1 H NMR (CDCl₃, 300 MHz) δ 9.99 (brs, 1H), 8.70 (d, J = 2.1 Hz, 1H), 8.65 (d, J = 2.1

Hz, 1H), 6.50 (d, J = 2.4 Hz, 1H), 4.04 (s, 3H), 1.44 (s,

9H).

<img file="PL2674428T3_D0236.tif" />

Methyl 5-amino-2-tert-butyl-1H-indole-7-carboxylate [0404] Methyl 2-tert-butyl-5-nitro-1H-indole-7-carboxylate solution (2.0 g, 7.2 mmol ) and Raney nickel (200 mg) in CH₃OH (50 mL) was stirred for 5 hours at room temperature under a hydrogen atmosphere. The catalyst was filtered off through a celite pad, and the filtrate was evaporated under reduced pressure to give methyl 5-amino-2-tert-butyl-1H-indole-7-carboxylate (1.2 g, 68%).¹H-NMR (CDCl₃, 400 MHz) ó 9.34 (brs,

1H), 7.24 (d, J = 1.6 Hz, 1H), 7.10 (s, 1H), 6.12 (d, J = 1.6

Hz, 1H), 3.88 (s, 3H), 1.45 (s, 9H).

Example 41: (5-amino-2-tert-butyl-1H-indol-7-yl) methanol [0405]

<img file="PL2674428T3_D0237.tif" />

232

<img file="PL2674428T3_D0238.tif" />

(2-tert-butyl-5-nitro-1H-indol-7-yl) methanol [0406] To a solution of methyl 2-tert-butyl-5-nitro-1H-indole-7-carboxylate (6.15 g, 22.3 mmol) and dichloromethane (30 mL) added DIBAL-H (1.0 M, 20 mL, 20 mmol) at 78 ° C. The reaction mixture was stirred for 1 hour, then water (10 mL) was added slowly. The resulting mixture was extracted with EtOAc (120 mL × 3). The combined organic extracts were dried over anhydrous Na₂SO₄ and evaporated under reduced pressure to give (2-tert-butyl-5-nitro-1H-indol-7-yl) methanol (4.0 g, 73%), which is used directly in the next step.

<img file="PL2674428T3_D0239.tif" />

(5-amino-2-tert-butyl-1H-indol-7-yl) methanol [0407] A mixture of (2-tert-butyl-5-nitro-1H-indol-7-yl) methanol (4.0 g, 16 mmol ) and Raney nickel (400 mg) in CH₃OH (100 mL) was stirred for 5 hours at room temperature under H atmosphere₂. The catalyst was filtered off through a celite pad, and the filtrate was evaporated under reduced pressure to obtain (5-amino-2-tert-butyl-1H-indol-7-yl) methanol (3.4 g, 80%).¹1 H NMR (CDCl₃, 400 MHz) δ 8.53 (br s, 1H), 6.80 (d, J = 2.0 Hz, 1H), 6.38 (d, J = 1.6 Hz, 1H),

4.89 (s, 2H), 1.37 (s, 9H).

Example 42: 2- (1-methylcyclopropyl) -1H-indole-5-amine [0408]

233

<img file="PL2674428T3_D0240.tif" />

Trimethyl- (1-methyl-cyclopropylethynyl)-silane [0409] To a solution of cyclopropylethynyl-trimethylsilane (3.0 g, 22 mmol) in ether (20 mL) n-BuLi (8.6 mL, 21.7 mol) was added dropwise. , 2.5 M solution in hexane) at 0 ° C. The reaction mixture was stirred at ambient temperature for 24 h after which dimethyl sulfate (6.85 g, 54.3 mmol) was added dropwise at -10 ° C. The resulting solution was stirred at 10 ° C and then at 20 ° C for 30 minutes at each temperature. The reaction was quenched by the addition of a mixture of saturated NH solution₄Cl and 25% aqueous ammonia (1: 3, 100 ml). The mixture was then stirred at room temperature for 1 hour. The aqueous phase was extracted with diethyl ether (3 x 50 mL) and the combined organic layers were washed successively with 5% aqueous hydrochloric acid (100 mL), 5% aqueous NaHCO₃ (100 ml) and water (100 ml). The organics were dried over anhydrous NaSO₄ and concentrated at atmospheric pressure. Fractional distillation under reduced pressure gave trimethyl (1-methyl-cyclopropylethynyl) silane (1.7 g, 52%) as

234 colorless liquid. ¹H-NMR (400 MHz, CDCl₃) δ 1.25 (s, 3H),

0, 92-0, 86 (m, 2H), 0.58-0.56 (m, 2H), 0.15 (s, 9H).

<img file="PL2674428T3_D0241.tif" />

1-Ethynyl-1-methyl-cyclopropane [0410] To a solution of trimethyl- (1-methyl-cyclopropylethynyl) silane (20 g, 0.13 mol) in THF (250 ml) was added TBAF (69 g, 0.26 mol) . The reaction mixture was stirred overnight at 20 ° C. The mixture was poured into water and the organic layer was separated. The aqueous layer was extracted with THF (50 mL). The combined organic layers were dried over anhydrous Na₂SO₄ and distilled at atmospheric pressure to obtain 1-ethynyl-1-methyl-cyclopropane (7.0 g, 1/2 THF contained, 34%). ¹1 H NMR (400 MHz, CDCl₃) δ 1.82 (s,

1H), 1.26 (s, 3H), 0, 90-0, 88 (m, 2H), 0.57-0.55 (m, 2H).

<img file="PL2674428T3_D0242.tif" />

2-bromo-4-nitroaniline [0411] To a solution of 4-nitro-phenylamine (50 g, 0.36 mol) in

AcOH (500 ml) was added Br₂ (60 g, 0.38 mol) at 5 ° C. The mixture was stirred for 30 minutes at this temperature. The insoluble solid was filtered off and basified with saturated aqueous NaHCO solution₃ to pH 7. The aqueous phase was extracted with EtOAc (300 mL × 3). The combined organic layers were dried and evaporated under reduced pressure to give a 2-bromo-4-nitroaniline compound (56 g, 72%) which was used directly in the next step.

235

<img file="PL2674428T3_D0243.tif" />

2 - ((1-methylcyclopropyl) ethinyl) -4-nitroaniline To oxygen-free solution of 2-bromo-4-nitroaniline (430 mg, 2.0 mmol) and 1-ethynyl-1-methyl-cyclopropane (630 mg , 8.0 mmol) in triethylamine (20 mL) added Cul (76 mg, 0.40 mmol) and Pd (PPh₃)₂cl₂ (140 mg, 0.20 mmol) under a nitrogen atmosphere. The mixture was heated at 70 ° C and stirred for 24 h. The solid was filtered off and washed with EtOAc (50 mL × 3). The filtrate was evaporated under reduced pressure and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 10/1) to obtain 2 - ((1-methylcyclopropyl) ethynyl) -4-nitroaniline

<td> (340</td><td>mg, 79%</td><td> ). ¹H</td><td>NMR (</td><td> 300</td><td>MHz, CDCl₃) δ 8.15-8.14 (m,</td><td>1H),</td>

<td> 7,98</td><td>-7.95 (m,</td><td>1H),</td><td> 6,63</td><td>(D,</td><td>J = 6.9 Hz, 1H), 4.80 (brs,</td><td>2H);</td>

<td> 1,38</td><td>(s, 3H),</td><td> 1,04-</td><td> 1,01</td><td>(M,</td><td>2H), 0.76-0.73 (m, 2H).</td><td></td>

<img file="PL2674428T3_D0244.tif" />

N- [2- (1-methyl-cyclopropylethynyl) -4-nitro-phenyl] -butyramide [0413] To a solution of 2 - ((1-methylcyclopropyl) ethinyl) -4-nitroaniline (220 mg, 1.0 mmol) and pyridine (160 mg, 2.0 mole) in CH₂cl₂ (20 ml) butyryl chloride (140 mg, 1.3 mmol) was added at 0 ° C. The mixture was warmed to room temperature and stirred for 3 hours. The mixture was poured into ice cold

236 water. The organic layer was separated and the aqueous phase was extracted with CH₂cl₂ (30 ml x 3). The combined organic layers were dried over anhydrous Na₂SO₄ and evaporated under reduced pressure to give N- [2- (1-methyl-cyclopropyl-ethynyl) -4-nitro-phenyl] -butyramide (230 mg, 82%), which is used directly in the next step.

<img file="PL2674428T3_D0245.tif" />

2- (1-methylcyclopropyl) -5-nitro-1H-indole [0414] A mixture of N- [2- (1-methyl-cyclopropylethynyl) -4-nitrophenyl] -butyramide (1.3 g, 4.6 mmol) and TBAF (2.4 g, 9.2 mmol) in THF (20 mL) was heated to reflux for 24 hours. The mixture was cooled to room temperature and poured into ice water. The mixture was extracted with CH₂cl₂(30 ml x 3). The combined organic layers were dried over anhydrous Na₂SO₄ and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 10/1) to give 2- (1-methylcyclopropyl) -5-nitro-1Hindole (0.70 g, 71%).¹H-NMR (400 MHz, CDCl₃) δ 8.56 (brs,

1H), 8.44 (d, J = 2.0 Hz, 1H), 8.01 (dd, J = 2.4, 8.8 Hz,

1H), 7.30 (d, J = 8.8 Hz, 1H), 6.34 (d, J = 1.6 Hz, 1H), 1.52 (s, 3H), 1.03-0, 97 (m, 2H), 0. 89-0.83 (m, 2H).

<img file="PL2674428T3_D0246.tif" />

237 evaporated purified

2- (1-methyl-cyclopropyl) -1H-indol-5-ylamine [0415] To a solution of 2- (1-methylcyclopropyl) -5-nitro-1H-indole (0.70 g, 3.2 mmol) in EtOH (20 ml), Raney nickel (100 mg) was added under a nitrogen atmosphere. The mixture was stirred under a hydrogen atmosphere (1 atm) at room temperature overnight.

The catalyst was filtered off through a celite pad and the filtrate under reduced pressure, residue by silica gel column chromatography (petroleum ether / ethyl acetate = 5/1) to give 2- (1-methylcyclopropyl) -1H-indol-5-ylamine (170 mg, 28%). ¹H

NMR (400 MHz, CDCla) δ 7.65 (brs, 1H), 7.08 (d, J = 8.4 Hz,

1H), 6.82 (s, 1H), 6.57 (d, J = 8.4 Hz, 1H), 6.14 (s, 1H),

3.45 (brs, 2H), 1.47 (s, 3H), 0.82-0.78 (m, 2H), 0.68-0.63 (m, 2H).

Example 43: Methyl 2- (5-amino-1H-indol-2-yl) -2-methylpropanoate [0409]

<img file="PL2674428T3_D0247.tif" />

<img file="PL2674428T3_D0248.tif" />

238

<img file="PL2674428T3_D0249.tif" />

Methyl 2,2-dimethyl-3-oxobutanoate [0417] To a suspension of NaH (42 g, 1.1 mole, 60%) in THF (400 mL), a solution of methyl 3-oxobutanoate (116 g, 1.00 mol) in THF (100 ml) at 0 ° C. The mixture was stirred for 0.5 hour at this temperature then MeI (146 g, 1.1 mol) was added dropwise at 0 ° C. The resulting mixture was warmed to room temperature and stirred for 1 hour. NaH (42 g, 1.05 mol, 60%) was added portionwise at 0 ° C and the resulting reaction mixture was still stirred for 0.5 hour at this temperature. MeI (146 g, 1.05 mol) was added dropwise at 0 ° C. The reaction mixture was warmed to room temperature and stirred overnight. The mixture was poured into ice water, the organic layer was separated. The aqueous layer was extracted with EtOAc (500 mL × 3). The combined organic layers were dried and evaporated under reduced pressure to give methyl 2,2-dimethyl-3-oxobutanoate (85 g), which was used directly in the next step.

<img file="PL2674428T3_D0250.tif" />

Methyl 3-chloro-2,2-dimethylbut-3-enoate [0418] For PCl suspension₅ (270 g, 1.3 mol) in CH₂cl₂ (1000 ml) methyl 2,2-dimethyl-3-oxobutanoate (85 g) was added dropwise at 0 ° C, followed by about 30 drops of anhydrous

DMF. The mixture was heated to reflux overnight. The reaction mixture was cooled

239 to room temperature and slowly poured into ice water. The organic layer was separated and the aqueous phase was extracted with CH₂cl₂ (500 ml x 3). The combined organic layers were washed with saturated aqueous NaHCO solution₃ and dried over anhydrous Na₂SO₄. The solvent was evaporated and the residue was distilled under reduced pressure to give methyl 3-chloro2,2-dimethylbut-3-enoate (37 g, 23%).¹H NMR (400 MHz, CDCl3) δ 5.33 (s, 1H), 3.73 (s, 3H), 1.44 (s, 6H).

<img file="PL2674428T3_D0251.tif" />

3-chloro-2,2-dimethylbut-3-enoic acid [0419] A mixture of methyl 3-chloro-2,2-dimethylbut-3-enoate (33 g, 0.2 mol) and NaOH (9.6 g, 0 , 24 mol) in water (200 ml) was heated to reflux for 5 h. The mixture was cooled to ambient temperature and extracted with ether. The organic layer was discarded. The aqueous layer was acidified with a cold 20% hydrochloric acid solution and extracted with ether (200 mL × 3). The combined organic layers were dried and evaporated under reduced pressure to give 3-chloro-2,2-dimethyl-but-3-enoic acid (21 g, 70%), which was used directly in the next step. ¹H-NMR (400 MHz, CDCl₃) δ 7.90 (brs, 1H), 5.37 (dd, J = 2.4, 6.8 Hz,

2H), 1.47 (s, 6H).

<img file="PL2674428T3_D0252.tif" />

240 2,2-dimethyl-but-3-ynoic acid [0420] Liquid NH₃ condensed in a 250 ml 3-necked round-bottomed flask at -78 ° C. Na (3.98 g, 0.173 mol) was added to the flask in portions. The reaction mixture was stirred for 2 hours at -78 ° C, then anhydrous DMSO (20 mL) was added dropwise at -78 ° C. The reaction mixture was stirred at room temperature until NH evolution ceased completely₃. Then, a solution of 3-chloro-2,2-dimethyl-but-3-enoic acid (6.5 g, 43 mmol) in DMSO (10 mL) was added dropwise at -40 ° C. The reaction mixture was warmed and stirred at 50 ° C for 5 hours, followed by stirring at room temperature overnight. The cloudy olive-green solution was poured into a cold 20% HCl solution, followed by extraction three times with ether. The ether extracts were dried over anhydrous Na₂SO₄ and concentrated to give crude 2,2-dimethyl-but-3-ynoic acid (2 g), which was used directly in the next step. ¹H-NMR (400 MHz, CDCl₃) δ 2.30 (s, 1H), 1.52 (s, 6H).

<img file="PL2674428T3_D0253.tif" />

Methyl 2,2-dimethylbut-3-ynoate [0421] To a solution of diazomethane (~ 10g) in ether (400 mL), 2,2-dimethyl-but-3-ynoic acid (10.5 g, 93.7 mmol) was added dropwise. at 0 ° C. The mixture was warmed to room temperature and stirred overnight. The mixture was distilled at atmospheric pressure to give crude

2,2-dimethylbut-3-citrate (14 g), which was used directly in

241 next stage. ¹H-NMR (400 MHz, CDCl3) δ 3.76 (s, 3H),

2.28 (s, 1H), 1.50 (s, 6H).

<img file="PL2674428T3_D0254.tif" />

4- (2-amino-5-nitrophenyl) -2,2-dimethylbut-3-ynoate To an oxygen-free solution of the 2-bromo-4-nitroaniline compound (9.43 g, 43.7 mmol), 2.2- methyl dimethylbut-3-ynoate (5.00 g, 39.7 mmol), CuI (754 mg, 3.97 mmol) and triethylamine (8.03 g, 79.4 mmol) in toluene / H2O (100/30 mL ) Pd (PPh3) 4 (6.17 g, 3.97 mmol) was added under a nitrogen atmosphere. The mixture was heated at 70 ° C and stirred for 24 h. After cooling, the solid was filtered off and washed with EtOAc (50 mL × 3). The organic layer was separated and the aqueous phase was washed with EtOAc (50 mL × 3). The combined organic layers were dried and evaporated under reduced pressure to give a residue, which was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 10/1) to give 4- (2-amino-5-nitrophenyl) -2,2-dimethylbut-3 methyl methylate (900 mg, 9%).¹H

<td>NMR (400</td><td>MHz,</td><td>CDCl3)</td><td>δ 8.17</td><td>(d, J = 2.8</td><td>Hz,</td><td>1H), 8.01 (</td><td>dd, J.</td>

<td> = 2,8, 9,</td><td>2 Hz</td><td>1H),</td><td>6.65 (d,</td><td>J = 9.2 Hz,</td><td>1H)</td><td>, 5.10 (brs,</td><td>2H);</td>

<td>3.80 (s,</td><td>3H);</td><td> 1,60 (</td><td>s, 6H).</td><td></td><td></td><td></td><td></td>

<img file="PL2674428T3_D0255.tif" />

242

Methyl 4- (2-butyroamido-5-nitrophenyl) -2,2-dimethylbut-3-citrate [0423] To a solution of methyl 4- (2-amino-5-nitrophenyl) -2,2-dimethylbut3-cyanate (260 mg , 1.0 mmol) and pyridine (160 mg, 2.0 moles) in CH2Cl2 (20 mL), butryl chloride (140 mg, 1.3 mmol) was added at 0 ° C. The reaction mixture was warmed to room temperature and stirred for 3 hours, after which the mixture was poured into ice water. The organic layer was separated and the aqueous phase was extracted with CH 2 Cl 2 (30 mL × 3).

The combined organic layers were dried over anhydrous Na2SO4 and evaporated under reduced pressure to give methyl 4- (2-butyramido-5-nitrophenyl) -2,2-dimethylbut-3-ynoate (150 mg, 45%) which was used directly in the next step. ¹1 H NMR (400 MHz, CDCl₃) δ 8.79 (brs, 1H), 8.71 (d, J = 9.2 Hz, 1H), 8.24 (d, J = 2.8 Hz, 1H), 8.17 (dd, J = 2.8,

9.2 Hz, 1H), 3.82 (s, 3H), 2.55 (t, J = 7.2 Hz, 2H), 1.85-1.75 (m, 2H), 1.63 ( s, 6H), 1.06 (t, J = 6.8 Hz, 3H).

<img file="PL2674428T3_D0256.tif" />

Methyl 2-methyl-2- (5-nitro-1H-indol-2-yl) propanoate To an oxygen-free solution of methyl 4- (2-butyroamido-5-nitrophenyl) -2,2-dimethylbut-3-cyanate (1 , 8 g, 5.4 mmol) in acetonitrile (30 ml) Pd (CH3CN) 2Cl2 (0.42 g, 1.6 = mmol) was added under a nitrogen atmosphere. The mixture was heated to reflux for 24 hours. After cooling the mixture to room temperature, the solid was filtered off and washed with EtOAc (50 mL × 3).

243

The filtrate was evaporated under reduced pressure to give a residue, which was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 30/1) to obtain methyl 2-methyl-2- (5-nitro-1H-indol-2-yl) propanoate (320 mg, 23%). ¹1 H NMR (400 MHz, CDCl₃) δ 9.05 (brs, 1H), 8.52 (d, J = 2.0 Hz, 1H), 8.09 (dd, J = 2.0,

8.8 Hz, 1H), 7.37 (d, J = 8.8 Hz, 1H), 6.54 (d, J = 1.6 Hz,

1H), 3.78 (d, J = 9.6 Hz, 3H), 1.70 (s, 6H).

<img file="PL2674428T3_D0257.tif" />

Methyl 2- (5-amino-1H-indol-2-yl) -2-methylpropanoate [0425] Suspension of ethyl 2-methyl-2- (5-nitro-1H-indol-2-yl) propanoate (60 mg, 0 , 23 mmol) and Raney nickel (10 mg) in MeOH (5 ml) were hydrogenated under hydrogen pressure (1 atm) at room temperature overnight. The catalyst was filtered off through a celite pad, and the filtrate was evaporated under reduced pressure to give a residue, which was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 5/1) to obtain 2- (5-amino-1H-indol-2-

<td>yl)</td><td>-2-methylpropanoate</td><td>methyl</td><td>(20 mg, 38%).</td><td>¹1 H NMR</td><td>(400 MHz,</td>

<td>CDCl</td><td colspan="2">3) δ 8.37 (br s, 1H), 7.13</td><td>(d, J = 8.4</td><td>Hz, 1H)</td><td>, 6.87 (d,</td>

<td>J =</td><td>2.0 Hz, 1H), 6.63</td><td>(dd, J =</td><td>2.0, 8.4 Hz,</td><td>1H), 6,</td><td>20 (d, J =</td>

<td> 1,2</td><td>Hz, 1H), 3.72 (d,</td><td>J = 7.6</td><td>Hz, 3H), 3.43</td><td>(br s,</td><td>1H), 1.65</td>

<td>(S,</td><td>6H); MS (ESI) m / e</td><td>(M + H⁺)</td><td> 233,2.</td><td></td><td></td>

Example 44: 2-isopropyl-1H-indole-5-amine [0426]

244

<img file="PL2674428T3_D0258.tif" />

2-Isopropyl-5-nitro-1H-indole [0427] A mixture of 4- (2-butyramido-5-nitrophenyl) -2,2-dimethylbut-3-citrate (0.50 g, 1.5 mmol) and TBAF (790 mg , 3.0 mmol) in DMF (20 ml) was heated at 70 ° C for 24 hours. The reaction mixture was cooled to room temperature and poured into ice water. The mixture was extracted with ether (30 mL × 3). The combined organic layers were dried over anhydrous Na₂SO₄ and evaporated under reduced pressure to give a residue, which was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 20/1) to give 2-isopropyl-5-nitro-1H-indole (100 mg, 33%). ¹1 H NMR (400 MHz, CDCl₃) δ 8.68 (s, 1H), 8.25 (br s, 1H), 8.21 (dd, J = 2.4, 10.0 Hz, 1H),

7.32 (d, J = 8.8 Hz, 1H), 6.41 (s, 1H), 3.07-3.14 (m, 1H),

1.39 (d, J = 6.8 Hz, 6H).

<img file="PL2674428T3_D0259.tif" />

2-Isopropyl-1H-indole-5-amine [0428] A suspension of 2-isopropyl-5-nitro-1H-indole (100 mg, 0.49 mmol) and Raney Nickel (10 mg) in MeOH (10 mL) hydrogenated under hydrogen atmosphere (1 atm) at room temperature overnight.

245

The catalyst was filtered off through a celite pad, and the filtrate was evaporated under reduced pressure to give a residue that was purified by column method (petroleum ether / ethyl acetate

<td>= 5/1) to produce</td><td>2-isopropyl-1H-indole-5-amine</td><td> (35</td><td>mg</td>

<td> 41%). ¹H NMR (400 MHz,</td><td>CDCl3) δ 7.69 (br s, 1H), 7.10</td><td>(D,</td><td>J =</td>

<td>8.4 Hz, 1H), 6.86 (d,</td><td>J = 2.4 Hz, 1H), 6.58 (dd, J =</td><td> 2,4,</td><td> 8,8</td>

<td>Hz, 1H), 6.07 (t, J =</td><td>1.2 Hz, 1H), 3.55 (br s, 2H), 3</td><td> ,06-</td><td> 2,99</td>

<td>(m, 1H), 1.33 (d, J</td><td>= 7.2 Hz, 6H); MS (ESI) m / e</td><td>(M +</td><td>H⁺)</td>

175,4.

Example 45: 1- (benzo [d] (1,3] dioxol-5-yl) -N- (2- (1-hydroxy2-methylpropan-2-yl) -1H-indol-5-yl) cyclopropanecarboskyamide [0429 ]

<img file="PL2674428T3_D0260.tif" />

triphenyl (2-aminobenzyl) phosphonium bromide [0430] 2-aminobenzyl alcohol (60.0 g, 0.487 mol) was dissolved in acetonitrile (2.5 L) and brought to reflux. Triphenylphosphine hydrobromide (167 g, 0.487 mol) was added and the mixture was heated to reflux for 3 hours. The reaction mixture was concentrated to about 500 mL and left at temperature

246 room for 1 hour. The precipitate was filtered off and washed with cold acetonitrile followed by hexane. The solid was dried overnight at 40 ° C under reduced pressure to give triphenyl (2-aminobenzyl) phosphonium bromide (193 g, 88%).

<img file="PL2674428T3_D0261.tif" />

triphenyl ((ethyl (2-carbamoyl) acetate) -2-benzyl) phosphonium bromide [0431] To a suspension of triphenyl- (2-aminobenzyl) phosphonium bromide (190 g, 0.43 mol) in anhydrous dichloromethane (1 L) was added chloride ethyl malonyl (55 ml, 0.43 mol). The reaction mixture was stirred for 3 hours at room temperature. The mixture was evaporated to dryness then ethanol (400 ml) was added. The mixture was heated to reflux until a clear solution was obtained. The solution was left at room temperature for 3 hours. The precipitate was filtered off, washed with cold ethanol followed by hexane and dried. A second crop was obtained from the mother liquor in the same manner. To remove residual ethanol, both crops were combined, warming dissolved in methylene chloride (about 700 mL) and evaporated. The solid was dried overnight under triphenyl ((ethyl (2-carbamoyl) acetate) -2-benzyl) phosphonium, (139 g, 58%).

temperature receiving

50 ° C under reduced bromide

247

<img file="PL2674428T3_D0262.tif" />

2- (1H-indol-2-yl) acetic acid ethyl ester [0432] Triphenyl bromide ((ethyl (2-carbamoyl) acetate) -2-benzyl) phosphonium (32.2 g, 57.3 mmol) was added to anhydrous toluene ( 150 ml) and the mixture was heated to reflux. A fresh solution of potassium tert-butoxide (7.08 g, 63.1 mmol) was added in portions over 15 minutes. Boiling continued for another 30 minutes. The mixture was filtered hot through a celite pad and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (0-30% ethyl acetate in hexane over 45 minutes) to give 2- (1H-indol-2-yl) acetic acid ethyl ester (9.12 g, 78%).

<img file="PL2674428T3_D0263.tif" />

Tert-butyl 2 - ((ethoxycarbonyl) methyl) -1H-indole-1-carboxylate To a solution of ethyl 2- (1H-indol-2-yl) acetate (14.7 g, 72.2 mmol) in dichloromethane (150 ml) 4-dimethylaminopyridine (8.83 g, 72.2 mmol) and di-t-butyl carbonate (23.7 g, 108 mmol) were added in portions. After stirring for 2 hours at room temperature, the mixture was diluted with dichloromethane, washed with water, dried over magnesium sulfate and purified by silica gel chromatography (0 to 20% EtOAc in hexane) to give 2248 ((ethoxycarbonyl) methyl) -1H-indole- Tert-butyl 1-carboxylate (20.0 g, 91%).

<img file="PL2674428T3_D0264.tif" />

Tert-butyl 2- (2- (ethoxycarbonyl) propan-2-yl) -1H-indole-1-carboxylate tert-butyl 2 - ((ethoxycarbonyl) methyl) -1H-indole-1-carboxylate (16, 7 g, 54.9 mmol) was added to anhydrous THF (100 mL) and cooled to -78 ° C. A 0.5M solution of potassium hexamethyldisilazate (165 mL, 82 mmol) was added slowly so that the internal temperature remained below -60 ° C. Stirring was continued for 30 minutes at -78 ° C. Methyl iodide (5.64 mL, 91 mmol) was added to this mixture. The mixture was stirred for 30 minutes at room temperature and then cooled to -78 ° C. A 0.5M solution of potassium hexamethyldisilazate (210 mL, 104 mmol) was slowly added and the mixture was stirred for another 30 minutes at -78 ° C. More methyl iodide (8.6 mL, 137 mmol) was added and the mixture was stirred for 1.5 hours at room temperature. The reaction was quenched by the addition of saturated aqueous ammonium chloride solution and partitioned between water and dichloromethane. The aqueous phase was extracted with dichloromethane and the combined organic phases were dried over magnesium sulfate and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (0 to 20% ethyl acetate in hexane) to give tert-butyl 2- (2- (ethoxycarbonyl) propan-2-yl) -1H-indole-1-carboxylate (17.1 g, 94 %).

249

<img file="PL2674428T3_D0265.tif" />

Ethyl 2- (1H-indol-2-yl) -2-methylpropanoate [0435] 2- (2- (ethoxycarbonyl) propan-2-yl) -1H-tert-butyl indole-1-carboxylate (22.9 g, 69, 1 mmol) was dissolved in dichloromethane (200 mL) before TFA (70 mL) was added. The reaction mixture was stirred for 5 hours at room temperature. The mixture was evaporated to dryness, dissolved in dichloromethane and washed with saturated sodium bicarbonate solution, water and brine. The product was purified by silica gel column chromatography (0-20% EtOAc in hexane) to give ethyl 2- (1H-indol-2-yl) -2-methylpropanoate (12.5 g, 78%).

<img file="PL2674428T3_D0266.tif" />

Ethyl 2-methyl-2- (5-nitro-1H-indol-2-yl) propanoate [0236] Ethyl 2- (1H-indol-2-yl) -2-methylpropanoate (1.0 g, 4.3 mmol ) was dissolved in concentrated sulfuric acid (6 ml) and cooled to -10 ° C (salt / ice mixture). A solution of sodium nitrate (370 mg, 4.33 mmol) in concentrated sulfuric acid (3 mL) was added dropwise over 30 minutes. Stirring was continued for another 30 minutes at -10 ° C. The mixture was poured into ice and the product was extracted with dichloromethane. The combined organic phases were washed with a small amount of saturated aqueous sodium bicarbonate. The product was purified by silica gel column chromatography (5-30%

250

EtOAc in hexane) to give ethyl 2-methyl-2- (5-nitro-1H-indol-2-yl) propanoate (0.68 g, 57%).

<img file="PL2674428T3_D0267.tif" />

2-methyl-2- (5-nitro-1H-indol-2-yl) propan-1-ol [0437] To a cooled LiAlH solution₄ (1.0 M in THF, 1.1 mL, 1.1 mmol) in THF (5 mL) at 0 ° C a solution of 2-methyl-2- (5-nitro-1H-indol-2-yl) was added dropwise. ethyl propanoate (0.20 g, 0.72 mmol) in THF (3.4 mL). After the addition, the mixture was allowed to warm to room temperature and stirred for 3 hours. The mixture was cooled to 0 ° C before water (2 mL) was slowly added followed by careful addition of 15% NaOH (2 mL) and water (4 mL). The reaction mixture was stirred at room temperature for 0.5 h, filtered through a short pad of celite using ethyl acetate. The organic layer was separated from the aqueous layer, dried over Na₂SO₄, filtered and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / hexane = 1/1) to give 2-methyl-2- (5-nitro-1H-indol-2-yl) propan-1-ol (0.098 g, 58% ).

<img file="PL2674428T3_D0268.tif" />

2- (5-amino-1H-indol-2-yl) -2-methylpropan-1-ol [0438] To a solution of 2-methyl-2- (5-nitro-1H-indol-2-yl) propan-1-ol (0.094 g, 0.40 mmol) in ethanol (4 mL) dihydrate was added

251 tin chloride (0.451 g 2.0 ramols). The mixture was heated in a microwave at 120 ° C for 1 hour. The mixture was diluted with ethyl acetate and water and then quenched with saturated aqueous NaHCO3 solution. The reaction mixture was filtered through a Celite pad using ethyl acetate. The organic layer was separated from the aqueous layer, dried over Na2SO4, filtered and evaporated under reduced pressure to give 2- (5-amino-1H-indol-2-yl) -2-methylpropan-1-ol (0.080 g, 98%).

2- (pyridin-2-yl) -1H-indol-5-amine

Example 46 [0439]

<img file="PL2674428T3_D0269.tif" />

4-nitro-2- (pyridin-2-ylethynyl) aniline [0440] To a solution of 2-iodo-4-nitroaniline (3.0 g, 11 mmol) in DMF (60 mL) and Et3N (60 mL) was added 2- ethinylpyridine (3.0 g, 45 mmol), Pd (PPh3) 2Cl2 (600 mg) and CuI (200 mg) under a nitrogen atmosphere. The reaction mixture was stirred at 60 ° C for 12 hours. The mixture was diluted with water and extracted with dichloromethane (3 x 100 mL). Combined organic layers

252 washed with brine, dried over anhydrous Na₂SO₄ and concentrated under reduced pressure. The residue was purified by silica gel chromatography (5-10% ethyl acetate / petroleum ether) to obtain 4-nitro-2- (pyridin-2-ylethynyl) aniline

<td>(1.5 g, 60%).</td><td>¹H-NMR (300 MHz</td><td colspan="2">, DMSO</td><td>CDCl3)</td><td> § 8,60</td><td>(S,</td><td>1H),</td>

<td>8.13 (d, J =</td><td>2.1 Hz, 1H), 7,</td><td> 98</td><td>(D,</td><td>J = 1,</td><td> 8, 6,9</td><td>Hz,</td><td>1H),</td>

<td>7.87-7.80 (m,</td><td>2H), 7.42-7.39</td><td>(M,</td><td>1H)</td><td> , 7,05</td><td>(Brs,</td><td>2H);</td><td> 6,80</td>

(d, J = 6.9 Hz, 1H).

<img file="PL2674428T3_D0270.tif" />

5-nitro-2- (pyridin-2-yl) -1H-indole [0441] To a solution of 4-nitro-2- (pyridin-2-ylethynyl) aniline (1.5 g, 6.3 mmol) in DMF ( 50 ml) t-BuOK (1.5 g, 13 mmol) was added. The reaction mixture was stirred at 90 ° C for 2 hours. The mixture was diluted with water and extracted with dichloromethane (3 x 50 mL). The combined organic layers were washed with brine, dried over anhydrous Na₂SO₄ and concentrated under reduced pressure. The residue was purified by silica gel chromatography (5-10% ethyl acetate / petroleum ether) to obtain 5-nitro-2- (pyridin-2-yl) -1H-indole (1.0 g, 67% yield).¹H-NMR (300 MHz, d-DMSO) δ 12.40 (s, 1H), 8.66 (d, J = 2.1 Hz, 1H), 8.58 (d, J = 1.8 Hz, 1H), 8.07-7.91 (m, 3H), 7.59 (d, J = 6.6 Hz, 1H), 7.42-7.37 (m, 2H).

<img file="PL2674428T3_D0271.tif" />

2- (pyridin-2-yl) -1H-indol-5-amine

253 [0442] To a solution of 5-nitro-2- (pyridin-2-yl) -1H-indole (700 mg, 2.9 mmol) in EtOH (20 mL) was added SnCl₂(2.6 g, 12 mmol). The mixture was heated to reflux for 10 hours. Water was added and the mixture was extracted with EtOAc (50 mL × 3). The combined organic layers were washed with brine, dried over anhydrous Na₂SO₄ and concentrated under reduced pressure. The residue was purified by silica gel chromatography (5-10% ethyl acetate / petroleum ether) to obtain 2- (pyridin-2-yl) -1H-indol-5-amine (120 mg, 20%).¹1 H NMR (400 MHz, CDCl₃) δ 9.33 (brs, 1H), 8.55 (dd, J = 1.2, 3.6 Hz, 1H), 7.76-7.67 (m, 2H),

7.23 (d, J = 6.4 Hz, 1H), 7.16-7.12 (m, 1H), 6.94 (d, J = 2.0

Hz, 1H), 6.84 (d, J = 2.4 Hz, IH), 6.71-6.69 (dd, J = 2.0,

8.4 Hz, 1H).

Example 47: 2- (pyridin-2-yl) -1H-indole-5-amine [0443]

<img file="PL2674428T3_D0272.tif" />

<img file="PL2674428T3_D0273.tif" />

[2- (tert-butyl-dimethyl-silanyloxy) ethyl] - (2-iodo-4-nitrophenyl) -amine [0444] To a solution of 2-iodo-4-nitroaniline (2.0 g, 7.6 mmol) and

- (tert-butyldimethylsilyloxy) -acetaldehyde (3.5 g,

254

75% purity, 15 mmol) in methanol (30 mL) was added TFA (1.5 mL) at 0 ° C. The reaction mixture was stirred at this temperature for 30 minutes before being added in portions of NaCNBH₃(900 mg, 15 mmol). The reaction mixture was stirred for 2 h and then stopped with water. The resulting mixture was extracted with EtOAc (30 mL × 3), the combined organic extracts dried over anhydrous Na₂SO₄ and evaporated under reduced pressure and the residue was purified by silica gel chromatography (5% ethyl acetate / petroleum ether) to obtain [2- (tert-butyl-dimethyl-silanyloxy) ethyl] - (2-iodo-4-nitrophenyl) amine (800 mg, 25%). ¹1 H NMR (300

<td>MHz, CDCl3)</td><td>δ 8.57</td><td>(d, J</td><td> = 2,</td><td>7 Hz, 1H), 8.12 (</td><td>dd,</td><td>J = 2.4,</td>

<td>9.0 Hz, 1H)</td><td> , 6,49</td><td>(d, J =</td><td> 9,3</td><td>Hz, 1H), 5.46 (br</td><td>s</td><td>1H), 3.89</td>

<td>(t, J = 5.4</td><td>Hz, 2H)</td><td> , 3,35</td><td>(Q, J</td><td>= 5.4 Hz, 2H), 0,</td><td> 93</td><td>(s, 9H),</td>

0.10 (s, 6H).

<img file="PL2674428T3_D0274.tif" />

5- {2- [2- (tert-butyl-dimethylsilanyloxy) ethylamino] -5-nitro-phenyl} -3,3-dimethyl-pent-4-acid acid ethyl ester [0445] To solution [2- (tert-butyl- dimethylsilanyloxy) ethyl] - (2-iodo-4-nitro-phenyl) -amine (800 mg, 1.9 mmol) in Et₃N (20 ml) was added sequentially Pd (PPh₃)₂cl₂ (300 mg, 0.040 mmol), CuI (76 mg, 0.040 mmol) and 3,3-dimethyl-but-1yn (880 mg, 5.7 mmol) under a protective nitrogen atmosphere. The reaction mixture was heated at 80 ° C for 6 hours and allowed to cool to temperature

255 room temperature. The resulting mixture was extracted with EtOAc (30 mL × 3). The combined organic extracts were dried over anhydrous Na₂SO₄ and evaporated under reduced pressure to give 5- {2- [2-ftert-butyl-dimethylsilanyloxy) ethylamino] -5-nitro-phenyl} -3,3-dimethyl-pent-4-acidic acid ethyl ester (700 mg, 82%), which was used in the next step without further purification. ¹1 H NMR (400 MHz, CDCl₃) δ 8.09 (s, 1H), 8.00 (d, J = 9.2 Hz, 1H), 6.54 (d, J = 9.2 Hz, 1H), 6.45 (brs, 1H ), 4.17-4.10 (m, 4H), 3.82 (t, J = 5.6 Hz, 2H), 3.43 (q, J = 5.6 Hz, 2H), 2, 49 (s, 2H), 1.38 (s, 6H), 1.28 (t, J =

7.2 Hz, 3H), 0.84 (s, 9H), 0.00 (s, 6H).

<img file="PL2674428T3_D0275.tif" />

3- [1- (2-hydroxy-ethyl) -5-nitro-1H-indol-2-yl] -3-methyl-butyric acid ethyl ester [0446] Solution of 5- {2- [2- (tert- butyl dimethyl silanyloxy) ethylamino] -5-nitrophenyl} -3,3-dimethylpent-4-yno (600 mg, 1.34 mmol) and PdCl₂ (650 mg) in CH₃CN (30 mL) was refluxed overnight. The resulting mixture was extracted with EtOAc (30 mL × 3). The combined organic extracts were dried over anhydrous Na₂SO₄ and evaporated under reduced pressure. The residue was dissolved in THF (20 mL) and TBAF (780 mg, 3.0 mmol) was added. The reaction mixture was stirred at room temperature for 1 hour, the solvent was removed under reduced pressure, and the residue was purified by chromatography

256 on silica gel (10% ethyl acetate / petroleum ether) to give 3- [1- (2-hydroxyethyl) -5-nitro-1H-indol-2-yl] -3-methyl-butyric acid ethyl ester ( 270 mg

<td> 60%)</td><td>_. 1_H</td><td>NMR</td><td>(300 MHz,</td><td>CDCl3) δ 8.45 (d,</td><td>J = 2.1</td><td>Hz, 1H),</td>

<td> 8,05</td><td>(Dd,</td><td>J =</td><td> 2,1, 9,0</td><td>Hz, 1H), 6.36 (d,</td><td>J = 9.0</td><td>Hz, 1H),</td>

<td> 6,48</td><td>(S,</td><td>1H),</td><td>4.46 (t,</td><td>J = 6.6 Hz, 2H), 4,</td><td> 00-3,91</td><td>(m, 4H),</td>

<td> 2,76</td><td>(S,</td><td>2H);</td><td>1.61 (s,</td><td>6H), 0.99 (t, J =</td><td>7.2 Hz</td><td>1H), 0.85</td>

<td>(S,</td><td>9H)</td><td> 0,03</td><td>(s, 6H).</td><td></td><td></td><td></td>

ABOUT

<img file="PL2674428T3_D0276.tif" />

3- [1- (2-hydroxy-ethyl) -5-nitro-1H-indol-2-yl] -3-methylbutan-1-ol [0447] For solution of 3- [1- (2-hydroxyethyl ethyl acid) ) -5-nitro-1H-indol-2-yl] -3-methylbutyric acid (700 mg,

2.1 mmol) in THF (25 ml) DIBAL-H (1.0 M, 4.2 ml, 4.2 mmol) was added at -78 ° C. The reaction mixture was stirred at room temperature for 1 hour. Water (2 mL) was added and the resulting mixture was extracted with EtOAc (15 mL × 3). The combined organic layers were dried over anhydrous Na2SO4 and evaporated under reduced pressure. The residue was purified by silica gel chromatography (15% ethyl acetate / petroleum ether) to obtain 3- [1- (2-hydroxy-ethyl) -5-nitro-1H-indol-2-yl] -3-methyl-butane -1-ol

<td> (300</td><td>mg, 49%)</td><td>_. 1_H</td><td>NMR</td><td> (300</td><td>MHz, d-</td><td>DMSO)</td><td>δ</td><td> 8,</td><td> 42</td><td>(D,</td><td>J =</td><td> 1,5</td>

<td>Hz,</td><td>1H), 7.95</td><td>(Dd,</td><td>J =</td><td> 1,2,</td><td>8.7 Hz</td><td>1H),</td><td> 6,</td><td> 36</td><td>(D,</td><td>J =</td><td> 9,3</td><td>Hz,</td>

<td>1H),</td><td>6.50 (s,</td><td>1H),</td><td> 5,25</td><td>(br</td><td>s, 1H),</td><td> 4,46</td><td> -4,</td><td> 42</td><td>(M,</td><td>4H</td><td> ), 3,</td><td> 69-</td>

3.66 (m, 2H), 3.24-3.21 (m, 2H), 1.42 (s, 6H).

257

<img file="PL2674428T3_D0277.tif" />

3- (5-amino-1- (2-hydroxy-ethyl) -1H-indol-2-yl] -3-methyl-butan-1-ol [0448] For solution of 3- [1- (2-hydroxy-ethyl) -5-nitro-1H-indol2-yl] -3-methyl-butan-1-ol (300 mg, 1.03 mmol) and Raney nickel (200 mg) in CH₃OH (30 mL) was stirred for 5 hours at room temperature under a hydrogen atmosphere. The catalyst was filtered off through a celite pad, and the filtrate was evaporated under reduced pressure to give a residue, which was purified by preparative TLC to give 3- (5-amino-1- (2-hydroxy-ethyl) -1H-indol-2-yl] -3-methyl -butan-1-ol (70

<td>mg</td><td> 26%).</td><td>¹1 H NMR (300 MHz, CDCl₃)</td><td>δ 7.07</td><td>(d, J =</td><td> 8,7</td><td>Hz, 1H),</td>

<td> 6,83</td><td>(D,</td><td>J = 2.1 Hz, 1H), 6.62</td><td>(dd, J</td><td> = 2,1,</td><td> 8,4</td><td>Hz, 1H),</td>

<td> 6,15</td><td>(S,</td><td>1H), 4.47 (t, J = 5.4 Hz,</td><td>2H);</td><td>4.07 (vol</td><td>, J =</td><td>5.4 Hz</td>

<td>2H);</td><td> 3,68</td><td>(t, J = 5.7 Hz, 2H),</td><td> 2,16 (</td><td>t, J =</td><td> 5,7</td><td>Hz, 2H),</td>

<td> 4,00</td><td> -3,91</td><td>(m, 4H), 2.76 (s, 2H) 1,</td><td> ,61 1 (</td><td>s, 6H),</td><td> 1,42</td><td>(s, 6H).</td>

Example 48: tert-butyl 2- (5-amino-1H-indol-2-yl) piperidine-1-carboxylate

<img file="PL2674428T3_D0278.tif" />

258

2- (piperidin-2-yl) -1H-indole-5-amine [0450] 5-Nitro-2- (pyridin-2-yl) -1H-indole (1.0 g, 4.2 mmol) was added to HCl / methanol solution (2 M, 50 ml). The reaction mixture was stirred at room temperature for 1 hour and the solvent was evaporated under reduced pressure. A solution of PtO2 (200 mg) in MeOH (50 mL) was added to the residue, and the reaction mixture was stirred under a hydrogen atmosphere (1 atm) at room temperature for 2 hours. The catalyst was filtered off through a celite pad, and the solvent was evaporated under reduced pressure to give 2- (piperidin-2-yl) -1H-indol-5-amine (1.0 g), which was used directly in the next step.

<img file="PL2674428T3_D0279.tif" />

Tert-butyl 2- (5-amino-1H-indol-2-yl) piperidine-1-carboxylate [0451] To a solution of 2- (piperidin-2-yl) -1H-indole-5-amine (1.0 g) in Et3N (25 mL) and THF (25 mL) were added Boc2O (640 mg, 2.9 mmol). The reaction mixture was stirred at room temperature overnight. The mixture was diluted with water and extracted with dichloromethane (3 x 25 mL). The combined organic layers were washed with brine, dried over anhydrous Na2SO4 and concentrated under reduced pressure. The residue was purified by silica gel chromatography (5-10% ethyl acetate / petroleum ether) followed by preparative HPLC to give tert-butyl 2- (5-amino-1H-indol-2-yl) piperidine-1-carboxylate ( 15 mg, 1% after 2 stages). ¹H NMR (400 MHz, CDCl3)

259 δ 8.82 (s, 1H), 7.58 (s, 1H), 7.22 (d, J = 8.8 Hz, 1H), 7.02 (d, J = 1.6, 8.0 Hz, 1H), 6.42 (s, 1H), 6.25 (s, 1H), 3.913,88 (m, 1H), 3.12-3.10 (m, 1H), 2.81-2 , 76 (m, 1H), 2.06-1.97 (m, 4H), 1.70-1.58 (m, 2H), 1.53 (s, 9H).

Example 49: 6-amino-1H-indole-2-carbonitrile

<img file="PL2674428T3_D0280.tif" />

<img file="PL2674428T3_D0281.tif" />

(3-nitrophenyl) hydrazine hydrochloride [0453] 3-nitroaniline (28 g, 0.20 mol) was dissolved in a mixture of H₂O (40 ml) and 37% HCl (40 ml). NaNO was added to the mixture at 0 ° C₂ (14 g, 0.20 mol) in H₂O (60 ml) followed by addition of a SnCl solution₂.H₂O (140 g, 0.60 mol) in 37% HCl (100 ml). After stirring at 0 ° C for 0.5 hours, insoluble material was separated, filtered off and washed with water to give (3-nitrophenyl) hydrazine hydrochloride (28 g, 73%).

<img file="PL2674428T3_D0282.tif" />

260

(E) -ethyl 2- (2- (3-nitrophenyl) hydrazone) propionate [0454] (3-nitrophenyl) hydrazine hydrochloride (30 g, 0.16 mol) 2-oxo-propanoic acid ethyl ester (22 g, 0.19 mol) was dissolved in ethanol (300 ml). The reaction mixture was stirred at room temperature for 4 hours, after which the solvent was evaporated under reduced pressure to obtain (E) ethyl 2- (2- (3-nitrophenyl) hydrazone) propionate, which was used directly in the next step.

<img file="PL2674428T3_D0283.tif" />

Ethyl 4-nitro-1H-indole-2-carboxylate and ethyl 6-nitro-1H-indole-2-carboxylate [0455] (E) -ethyl 2- (2- (3-nitrophenyl) hydrazone) propionate was dissolved in toluene (300 ml ) and PPA (30 g) was added.

The mixture was heated to reflux overnight and then cooled to room temperature. The solvent was decanted and evaporated to give a crude mixture which was used in the next step without further purification (15 g, 40%).

<img file="PL2674428T3_D0284.tif" />

4-nitro-1H-indole-2-carboxylic acid and 6-nitro-1H-indole-2-carboxylic acid [0456] A mixture of ethyl 6-nitro-1H-indole-2-carboxylate (0.5

g) and 10% NaOH (20 ml) was heated to reflux overnight and then cooled to

261 room temperature. The mixture was extracted with ether and the aqueous phase was acidified with HCl to pH 1 ~ 2. The insoluble solid was isolated by filtration to give a crude mixture which was used in the next step without purification (0.3 g, 68%).

<img file="PL2674428T3_D0285.tif" />

4-nitro-1H-indole-2-carboxamide and 6-nitro-1H-indole-2-carboxamide A mixture of 6-nitro-1H-indole-2-carboxylic acid (12 g, 58 mmol) and SOCl₂ (50 mL, 64 mmol) in benzene (150 mL) was heated to reflux for 2 hours. Benzene and excess SOCl₂ removed under reduced pressure. The residue was dissolved in anhydrous CH₂cl₂ (250 ml) and NH was added dropwise₃.H₂O (22 g, 0.32 mol) at 0 ° C. The reaction mixture was stirred at room temperature for 1 hour. The insoluble solid was filtered off to give a crude mixture (9.0 g, 68%), which was used directly in the next step.

<img file="PL2674428T3_D0286.tif" />

4-nitro-1H-indole-2-carbonitrile and 6-nitro-1H-indole-2-carbonitrile [0458] 6-Nitro-1H-indole-2-carboxamide (5.0 g, 24 mmol) was dissolved in CH₂cl₂ (200 ml). It was added dropwise to the Et₃N (24 g, 0.24 mol) and (CF₃WHAT)₂O (51 g, 0.24 mole), in

262 room temperature. The mixture was further stirred for 1 h and then poured into water (100 mL). The organic layer was separated and the aqueous layer was extracted with EtOAc (100 mL × 3). The combined organic layers were dried over Na₂SO₄, filtered and concentrated under reduced pressure to give a crude product which was purified by silica gel column chromatography to give an impure sample of 4-nitro-1H-indole-2-carbonitrile (2.5 g, 55%).

<img file="PL2674428T3_D0287.tif" />

6-amino-1H-indole-2-carbonitrile, A mixture of 6-nitro-1H-indole-2-carbonitrile (2.5 g, 13 mmol) and Raney nickel (500 mg) in EtOH (50 mL) ) was stirred at room temperature under H atmosphere₂ (1 atm) within 1 hour. Raney nickel was filtered off and the filtrate was evaporated under reduced pressure to give a residue, which was purified by silica gel column chromatography to obtain 6-amino-1H-indole-2-carbonitrile (1.0 g, 49%).^X1 H NMR (DMSO-d₆) δ 12.75 (br s, 1H), 7.82 (d, J = 8 Hz, 1H), 7.57 (s, 1H), 7.42 (s, 1H), 7.15 (d, J = 8 Hz, 1H); MS (ESI) m / e (M + H +) 158.2.

Example 50: 6-amino-1H-indole-3-carbonitrile, [0460]

<img file="PL2674428T3_D0288.tif" />

263

<img file="PL2674428T3_D0289.tif" />

6-nitro-1H-indole-3-carbonitrile [0461] To a solution of 6-nitroindole (4.9 g 30 mmol) in DMF (24 ml) and CH₃CN (240 mL) solution of ClSO was added dropwise₂NCO (5.0 mL) in CH₃CN (39 ml) at 0 ° C. After the addition, the reaction mixture was allowed to warm to room temperature and stirred for 2 hours. Then, the mixture was poured into ice water and made basic with saturated NaHCO solution₃ to pH 7 ~ 8. The mixture was extracted with ethyl acetate. The organic phases were washed with brine, dried over Na₂SO₄ and concentrated to give 6-nitro-1H-indole-3-carbonitrile (4.6 g,

82%).

<img file="PL2674428T3_D0290.tif" />

6-amino-1H-indole-3-carbonitrile [0461] A suspension of 6-nitro-1H-indole-3-carbonitrile (4.6 g, 25 mmol) and 10% Pd-C (0.46 g) in EtOH ( 50 ml) was stirred under H atmosphere₂ (1 atm) at room temperature during the night. After filtration, the filtrate was concentrated and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 3/1) to obtain 6-amino-1H-indole-3-carbonitrile (1.0 g, 98%) as a pink solid .¹1 H NMR (DMSO-d₆) δ 11.51 (s, 1H), 7.84 (d, J = 2.4 Hz, 1H), 7.22 (d, J = 8.4 Hz, 1H), 6.62 (s, 1H ), 6.56 (d, J = 8.4 Hz,

1H), 5.0 (s, 2H); MS (ESI) m / e (M + H +) 157.1.

264

Example 51: 2-tert-butyl-1H-indole-6-amine

<img file="PL2674428T3_D0291.tif" />

No-tolylpivalamide [0464] To a solution of o-tolylamine (21 g, 0.20 mol) and Et₃N (22 g, 0.22 mol) in CH₂cl₂ 2,2-dimethyl propionyl chloride (25 g, 0.21 mol) was added at 10 ° C. After the addition, the reaction mixture was stirred overnight at room temperature. The mixture was washed with aqueous HCl (5%, 80 mL), saturated aqueous NaHCO₃ and brine. The organic layer was dried over Na₂SO₄ and concentrated under reduced pressure to give N-otolylpivalamide (35 g, 91%). ¹1 H NMR (300 MHz, CDCl₃) δ 7.88 (d, J = 7.2 Hz, 1H), 7.15-7.25 (m, 2H), 7.05 (t, J = 7.2 Hz,

1H), 2.26 (s, 3H), 1.34 (s, 9H).

<img file="PL2674428T3_D0292.tif" />

2-tert-butyl-1H-indole [0465] To a solution of No-tolylpivalamide (30.0 g, 159 mmol) in dry THF (100 mL) n-BuLi (2.5 M in hexane, 190 mL) was added dropwise at a temperature of 15 ° C. After the addition, the reaction mixture was stirred overnight at 15 ° C. The mixture was cooled in an ice-water bath and treated with a saturated NH solution₄Cl. The organic layer was separated and the aqueous layer

265 extracted with ethyl acetate. The combined organic layers were dried over anhydrous Na₂SO₄, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give 2-tert-butyl-1H-indole (24 g, 88%). these NMR (300 MHz, CDCl₃) δ 7.99 (br. s, 1H), 7.54 (d, J = 7.2 Hz, 1H), 7.05 (d, J = 7.8

Hz, 1H), 7.06 -7.13 (m, 2H), 6.26 (s, 1H), 1.39 (s, 9H).

<img file="PL2674428T3_D0293.tif" />

2-tert-butylindoline [0466] To a solution of 2-tert-butyl-2H-indole (10 g, 48 mmol) in AcOH (40 mL) was added NaBH₄ at 10 ° C. The mixture was stirred for 20 minutes at 10 ° C, then H was added dropwise₂During ice cooling. The mixture was extracted with ethyl acetate. The combined organic layers were dried over anhydrous Na₂SO₄, filtered and concentrated under reduced pressure to give 2-tert-butylindoline (9.8 g), which was used directly in the next step.

<img file="PL2674428T3_D0294.tif" />

2-tert-butyl-6-nitroindoline and 2-tert-butyl-5-nitro-1Hindole [0467] To a solution of 2-tert-butylindoline (9.7 g) in H₂SO₄ (98%, ml) KNO was slowly added₃ (5.6 g, 56 mmol) at temperature

0 ° C. After the addition, the reaction mixture was stirred at room temperature for 1 hour. The mixture was carefully poured into

266 crushed ice, basified Na₂WHAT₃ to pH 8 and extracted with ethyl acetate. The combined extracts were washed with brine, dried over anhydrous Na₂SO₄ and concentrated under reduced pressure. The residue was purified by column chromatography to give 2-tert-butyl-6-nitroindoline (4.0 g, 31% after two steps).¹1 H NMR (300 MHz, CDCl₃) δ 7.52 (dd, J = 1.8, 8.1 Hz, 1H), 7.30 (s, 1H), 7.08 (d, J = 7.8 Hz, 1H), 3.76 (t, J = 9.6 Hz, 1H), 2.98 - 3, 07 (m,

1H), 2.82 - 2.91 (m, 1H), 0.91 (s, 9H).

<img file="PL2674428T3_D0295.tif" />

2-tert-butyl-6-nitro-1H-indole [0468] To a solution of 2-tert-butyl-6-nitroindoline (2.0 g, 9.1 mmol) was added DDQ (6.9 g, 30 mmol) in 1,4-dioxane (20 ml) at room temperature. The mixture was heated at reflux for 2.5 hours, then filtered and concentrated under reduced pressure. The residue was purified by column chromatography to give 2-tert-butyl-6-nitro-1H-indole (1.6 g, 80%).¹H

NMR (300 MHz, CDCl₃) δ 8.30 (br. s, 1H), 8.29 (s, 1H), 8.00 (dd, J = 2.1, 8.7 Hz, 1H), 7.53 (d, J = 9.3 Hz, 1H), 6.38 (s,

1H), 1.43 (s, 9H).

<img file="PL2674428T3_D0296.tif" />

2-tert-butyl-1H-indole-6-amine

267 [0469] To a solution of 2-tert-butyl-6-nitro-1H-indole (1.3 g, 6.0 mmol) in MeOH (10 mL) was added Raney Nickel (0.2 g). The mixture was hydrogenated under 1 atmosphere of hydrogen at room temperature for 3 hours. The reaction mixture was filtered and the filtrate concentrated. The residue was washed with petroleum ether to give 2-tert-butyl-1H-indole-6-amine (1.0 g,

<td> 89%)</td><td> . ¹H-NMR</td><td> (300</td><td>MHz, DMSO-d6)?</td><td>δ</td><td> 10,19 (</td><td>s, 1H)</td><td>6.99 (d, J =</td>

<td> 8,1</td><td>Hz, 1H),</td><td> 6,46</td><td>(s, 1H), 6,</td><td> 25</td><td>(dd, J</td><td> = 1,8,</td><td>8.1 Hz, 1H),</td>

<td> 5,79</td><td>( d, J =</td><td> 1,8</td><td>Hz, 1H), 4,</td><td> 52</td><td>(s, 2H)</td><td> , 1,24</td><td>(s, 9H); MS</td>

<td>(ESI</td><td>) m / e (M</td><td>+ H⁺)</td><td> 189,1.</td><td></td><td></td><td></td><td></td>

Example 52: 3-tert-butyl-1H-indole-6-amine [0470]

<img file="PL2674428T3_D0297.tif" />

3-tert-butyl-6-nitro-1H-indole [0471] To a mixture of 6-nitroindole (1.0 g, 6.2 mmol), zinc trifluoromethanesulfonate (2.1 g, 5.7 mmol) and TBAI (1 , 7 g, 5.2 mmol) in anhydrous toluene (11 mL) was added DIEA (1.5 g, 11 mmol) at room temperature under nitrogen. The reaction mixture was stirred for 10 minutes at 120 ° C, followed by the addition of t-butyl bromide (0.71 g, 5.2 mmol). The resulting mixture was stirred for 45 minutes at 120 ° C. The solid was filtered off and the filtrate concentrated to dryness. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate =

268 : 1) to obtain 3-tert-butyl-6-nitro-1H-indole (0.25 g,

19%) as a yellow solid. ¹H-NMR (CDCl₃) δ

8.32 (d, J = 2.1 Hz, 1H), 8.00 (dd, J = 2.1, 14.4 Hz, 1H),

7.85 (d, J = 8.7 Hz, 1H), 7.25 (s, 1H), 1.46 (s, 9H).

<img file="PL2674428T3_D0298.tif" />

3-tert-butyl-1H-indole-6-amine [0472] A suspension of 3-tert-butyl-6-nitro-1H-indole (3.0 g, 14 mmol) and Raney nickel (0.5 g) was hydrogenated with H₂ (1 atm) at room temperature for 3 hours. The catalyst was filtered off and the filtrate concentrated to dryness. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 4: 1) to obtain 3-tert-butyl-1H-indol-6-amine (2.0 g, 77%) as a gray solid.¹H-NMR (CDCl3) δ 7.58 (m, 2H), 6.73 (d, J = 1.2 Hz,

1H), 6.66 (s, 1H), 6.57 (dd, J = 0.8, 8.6 Hz, 1H), 3.60 (br,

2H), 1.42 (s, 9H).

Example 53: 5- (trifluoromethyl) -1H-indole-6-amine [0473]

<img file="PL2674428T3_D0299.tif" />

269

1-methyl-2,4-dinitro-5- (trifluoromethyl) benzene [0474] To the HNO mixture₃ (98%, 30 ml) and H₂SO₄ (98%, 30 ml) 1-methyl-3-trifluoromethyl-benzene (10 g, 63 mmol) was added dropwise at 0 ° C. After the addition was complete, the mixture was stirred at room temperature for 30 minutes and then poured into ice water. The precipitate was filtered off and washed with water to give 1-methyl-2,4-dinitro-5-trifluoromethyl-benzene (2.0 g, 13%).

<img file="PL2674428T3_D0300.tif" />

<img file="PL2674428T3_D0301.tif" />

(E) -2- (2,4-dinitro-5- (trifluoromethyl) phenyl) -N, N-dimethylethyleneamine [0475] A mixture of 1-methyl-2,4-dinitro-5-trifluoromethylbenzene (2.0 g, 8.0 mmol) and DMA (1.0 g, 8.2 mmol) in DMF (20 mL) were stirred at 100 ° C for 30 minutes. The mixture was poured into ice water and stirred for 1 hour. The precipitate was filtered off and washed with water to give (E) -2- (2,4-dinitro-5- (trifluoromethyl) phenyl) -N, N-dimethylethenoamine (2.1 g, 86%).

<img file="PL2674428T3_D0302.tif" />

5- (trifluoromethyl) -1H-indole-6-amine [0476] Suspension (E) -2- (2,4-dinitro-5- (trifluoromethyl) phenyl) -N, N-dimethylethenoamine (2.1 g, 6, 9 mmol) and Raney Nickel (1 g) in ethanol (80 ml) was stirred under a hydrogen atmosphere (1 atm) at room temperature for 5

270 hours. The catalyst was filtered off and the filtrate concentrated to dryness. The residue was purified by silica gel column chromatography to obtain 5-

<td>(Trifluoromethyl) -1 H-indole-6-amine</td><td> 200</td><td>mg</td><td> 14%)</td><td>_. 1_H</td><td>NMR</td>

<td>(DMSO-d₆) δ 10.79 (br s, 1H), 7.55</td><td>(S,</td><td>1H),</td><td> 7,12</td><td>(S,</td><td>1H),</td>

<td>6.78 (s, 1H), 6.27 (s, 1H), 4.92 (s,</td><td>2H)</td><td>; MS</td><td>(ESI)</td><td>m / e</td><td>(M +</td>

H +): 200.8.

Example 54: 5-ethyl-1H-indole-6-amine [0477]

<img file="PL2674428T3_D0303.tif" />

[0478] To a mixture of DMAP (1.5 g), benzenesulfonyl chloride (24.0 g, 136 mmol) and indoline (14.7 g, 124 mmol) in CH₂cl₂(200 ml) Et.₃N (19.0 g, 186 mmol) at 0 ° C. The reaction mixture was stirred at room temperature overnight. The organic layer was washed with water (2x), dried over Na₂SO₄ and concentrated to dryness under reduced pressure to give 1- (phenylsulfonyl) indoline (30.9 g, 96%).

271

<img file="PL2674428T3_D0304.tif" />

1- (1- (phenylsulfonyl) indolin-5-yl) ethanone [0479] Acetic anhydride (54 ml) was added to a suspension of AlCl3 (144 g, 1.08 mol) in CH2Cl2 (1070 mL). The mixture was stirred for 15 minutes and then a solution of 1- (phenylsulfonyl) indoline (46.9 g, 0.180 mol) in CH 2 Cl 2 (1070 ml) was added dropwise. The reaction mixture was stirred for 5 hours and quenched by the slow addition of crushed ice. The organic layer was separated and the aqueous layer was extracted with CH2Cl2. The combined organic phases were washed with saturated aqueous NaHCO3 solution and brine, dried over Na2SO4 and concentrated under reduced pressure to obtain 1- (1- (phenylsulfonyl) indolin-5-yl) ethanone (42.6 g).

<img file="PL2674428T3_D0305.tif" />

5-ethyl-1- (phenylsulfonyl) indoline [0480] To TFA (1600 ml) at 0 ° C, sodium borohydride (64.0 g, 1.69 mol) was added over 1 hour. To this mixture, a solution of 1- (1- (phenylsulfonyl) indolin-5-yl) ethanone (40.0 g, 0.133 mol) in TFA (700 mL) was added dropwise over 1 hour. The mixture was then stirred overnight at 25 ° C. After dilution with H2O (1600 mL), the mixture

272 basified by the addition of sodium hydroxide pellets at 0 ° C. The organic layer was separated and the aqueous layer was extracted with CH₂Cl 2. The combined organic layers were washed with brine, dried over Na₂SO₄ and concentrated under reduced pressure. The residue was purified on a silica gel column to give 5-ethyl-1- (phenylsulfonyl) indoline (16.2 g, 47% after two steps).

<img file="PL2674428T3_D0306.tif" />

5-ethylindoline [0481] A mixture of 5-ethyl-1- (phenylsulfonyl) indoline (15 g, 0.050 mol) in HBr (48%, 162 ml) was heated at reflux for 6 hours. The mixture was basified with saturated NaOH to pH = 9, followed by extraction with ethyl acetate. The organic layer was washed with brine, dried over Na₂SO₄ and concentrated under reduced pressure. The residue was purified on a silica gel column to give 5-ethylindoline (2.5 g, 32%).

<img file="PL2674428T3_D0307.tif" />

5-ethyl-6-nitroindoline [0482] To a solution of 5-ethylindoline (2.5 g, 17 mmol) in H₂SO₄ (98%, 20 ml) KNO was slowly added₃ (1.7 g, 17 mmol) at 0 ° C. The mixture was stirred at 0-10 ° C for 10 minutes. The mixture was carefully poured into ice,

273 basified with sodium hydroxide solution to pH 9 and extracted with ethyl acetate. The combined extracts were washed with brine, dried over Na₂SO₄ and concentrated to dryness. The residue was purified on a silica gel column to give

5-ethyl-6-nitroindoline (1.9 g, 58%).

<img file="PL2674428T3_D0308.tif" />

5-ethyl-6-nitro-1H-indole [0483] To a solution of 5-ethyl-6-nitroindoline (1.9 g, 9.9 mmol) in CH₂cl₂ (30 ml) MnO was added₂ (4.0 g, 46 mmol). The mixture was stirred at ambient temperature for 8 hours. The precipitate was filtered off and the filtrate was concentrated to dryness to give 5-ethyl-6-nitro-1H-indole (1.9 g).

<img file="PL2674428T3_D0309.tif" />

5-ethyl-1H-indole-6-amine [0484] A suspension of 5-ethyl-6-nitro-1H-indole (1.9 g, 10 mmol) and Raney nickel (1 g) was hydrogenated under H₂ (1 atm) at room temperature for 2 hours. The catalyst was filtered off and the filtrate concentrated to dryness. The residue was purified on a silica gel column to give 5-ethyl-1H-indol-6-amine (760 mg, 48% after two steps).^X1 H NMR (CDCl₃) δ 7.90 (br s, 1H), 7.41 (s, 1H), 7.00 (s, 1H), 6.78 (s, 2H), 6.39 (s, 1H), 3, 39 (br s, 2H), 2.63 (q, J = 7.2 Hz, 2H), 1.29 (t, J = 6.9 Hz, 3H); MS (ESI) m / e (M + H +) 161.1.

274

Example 55: ethyl 6-amino-1H-indole-4-carboxylate [0485]

<img file="PL2674428T3_D0310.tif" />

2-methyl-3,5-dinitrobenzoic acid [0486] To the HNO mixture₃ (95%, 80 ml) and H₂SO₄ (98%, 80 ml) 2-methylbenzoic acid (50 g, 0.37 mol) was slowly added at 0 ° C. After the addition, the reaction mixture was stirred at a temperature below 30 ° C for 1.5 hours. The mixture was then poured into ice water and stirred for 15 minutes. The precipitate was filtered off and washed with water to give 2-methyl-3,5-dinitrobenzoic acid (70 g, 84%).

<img file="PL2674428T3_D0311.tif" />

Ethyl 2-methyl-3,5-dinitrobenzoate [0487] A mixture of 2-methyl-3,5-dinitrobenzoic acid (50 g, 0.22 mol) in SOCl₂ (80 ml) was refluxed for 4 h and then concentrated to dryness. The residue was dissolved in CH₂cl₂ (50 mL), to which EtOH (80 mL) was added, and the reaction mixture was stirred at room temperature

275 for 1 hour. The mixture was poured into ice water and extracted with EtOAc (3 x 100 mL). The combined extracts were washed with saturated Na₂WHAT₃ (80 ml), water (2 x 100 ml) and brine (100 ml), dried over Na₂SO₄ and concentrated to dryness to give ethyl 2-methyl-3,5-dinitrobenzoate (50 g, 88%).

<img file="PL2674428T3_D0312.tif" />

(E) -ethyl 2- (2- (dimethylamino) vinyl) -3,5-dinitrobenzoate [0488] A mixture of ethyl 2-methyl-3,5-dinitrobenzoate (35 g, 0.14 mol) and DMA (32 g, 0.27 mol) in DMF (200 ml) was heated at 100 ° C for 5 hours. The mixture was poured into ice water and the precipitate was filtered off and washed with water to give (E) -ethyl 2- (2- (dimethylamino) vinyl) -3,5-dinitrobenzoate (11 g, 48%)

<img file="PL2674428T3_D0313.tif" />

Ethyl 6-amino-1H-indole-4-carboxylate [0489] A mixture of (E) -ethyl 2- (2- (dimethylamino) vinyl) -3,5-dinitrobenzoate (11 g, 0.037 mol) and SnCl₂ (83 g, 0.37 mol) in ethanol was heated to reflux for 4 hours. The mixture was concentrated to dryness and the residue was poured into water and basified with saturated aqueous Na solution₂WHAT₃ to pH 8. The precipitate was filtered off and the filtrate was extracted with ethyl acetate (3 x 100 mL). Connected

276 the extracts were washed with water (2 x 100 ml) and brine (150 ml), dried over Na₂SO₄ and concentrated to dryness. The residue was purified by silica gel column chromatography to give ethyl 6-amino-1H-indole-4-carboxylate (3.0 g, 40%).¹H-NMR (DMSO-d₆) δ 10.76 (br s, 1H), 7.11-7.14 (m, 2H), 6.81-6.82 (m, 1H), 6, 67-6, 68 (m, 1H) , 4.94 (br s,

2H), 4.32-4, 25 (q, J = 7.2 Hz, 2H), 1.35-1.31 (t, J = 7.2, 3H); MS (ESI) m / e (M + H +) 205.0.

Example 56: 5-fluoro-1H-indole-6-amine [0490]

<img file="PL2674428T3_D0314.tif" />

1-fluoro-5-methyl-2,4-dinitrobenzene [0491] For mixed HNO solution₃ (60 ml) and H₂SO₄ (80 mL) under ice-cooling, 1-fluoro-3-methylbenzene (28 g, 25 mmol) was added dropwise at such a rate that the temperature did not rise above 35 ° C. The mixture was stirred for 30 minutes at room temperature and then poured into ice water (500 ml). The resulting precipitate (a mixture of 1-fluoro-5-methyl-2,4-dinitrobenzene and 1-fluoro-3-methyl-2,4-dinitrobenzene, 32 g, in a ratio of about 7: 3) was filtered off and purified by crystallization from 50 ml of isopropyl ether to give pure 1-fluoro-5-methyl-2,4-dinitro-benzene as a white solid (18 g, 36%).

277

<img file="PL2674428T3_D0315.tif" />

(E) -2- (5-fluoro-2,4-dinitrophenyl) -W, N-dimethylethyleneamine. A mixture of 1-fluoro-5-methyl-2,4-dinitro-benzene (10 g, 50 mmol), DMA (12 g, 100 mmol) and DMF (50 mL) were heated at 100 ° C for 4 hours. The solution was then cooled and poured into water. The red precipitate formed, washed with water and dried to give (E) -2- (5-fluoro-2,4-dinitrophenyl) -N, N-dimethylethenoamine (8.0 g, 63%).

<img file="PL2674428T3_D0316.tif" />

5-fluoro-1H-indole-6-amine [0493] A suspension of (E) -2- (5-fluoro-2,4-dinitrophenyl) -N, N-dimethylethyleneamine (8.0 g, 31 mmol) and Raney Nickel (8 g) in ethanol (80 mL) was stirred under a hydrogen atmosphere (40 psi) at room temperature for 1 hour. After filtration, the filtrate was concentrated and the residue was purified by column chromatography (petroleum ether / ethyl acetate = 5/1) to give 5-fluoro-1H-indole-6-amine (1.0 g, 16%) as a brown solid.¹1 H NMR (DMSO-d₆) δ 10.56 (br s, 1H), 7.07 (d, J = 12 Hz, 1H), 7.02 (m, 1H), 6.71 (d, J = 8 Hz, 1H), 6 , 17 (s, 1H), 3.91 (br s, 2H); MS (ESI) m / e (M + H +)

150,1.

278

Example 57: 5-chloro-1H-indole-6-amine [0494]

<img file="PL2674428T3_D0317.tif" />

1-chloro-5-methyl-2,4-dinitrobenzene [0495] For a mixed HNO solution₃ (55 ml) and H₂SO₄ (79 ml) 1-chloro-3-methylbenzene (25.3 g, 200 mmol) was added dropwise under ice-cooling, the addition was carried out at such a rate that the temperature did not rise above 35 ° C. The mixture was stirred for 30 minutes at ambient temperature and then poured into ice water (500 ml). The resulting precipitate was filtered off and purified by crystallization to obtain 1-chloro-5-methyl-2,4-dinitrobenzene (26 g, 60%).

<img file="PL2674428T3_D0318.tif" />

And no₂ (E) -2- (5-chloro-2,4-dinitrophenyl) -N, N-dimethylethyleneamine [0496] A mixture of 1-chloro-5-methyl-2,4-dinitro-benzene (11.6 g, 50, 0 mmol), DMA (11.9 g, 100 mmol) in DMF (50 mL) was heated at 100 ° C for 4 hours. The solution was then cooled and poured into water. The precipitated red precipitate was filtered off, washed with water and dried to give (E) -2- (5279 chloro-2,4-dinitrophenyl) -N, N-dimethylethenoamine (9.84 g,

72%).

<img file="PL2674428T3_D0319.tif" />

5-chloro-1H-indole-6-amine [0497] A suspension of (E) -2- (5-chloro-2,4-dinitrophenyl) -N, N-dimethylethyleneamine (9.8 g, 36 mmol) and Raney nickel (9 , 8 g) in

EtOH (140 mL) was stirred under a hydrogen atmosphere (1 atm) at room temperature for 4 hours. After filtration, the filtrate was concentrated and the residue purified by column chromatography (petroleum ether / ethyl acetate = 10: 1) to obtain 5-chloro-1H-indole-6-amine (0.97 g, 16%) as a gray powder. these NMR (CDCl₃) δ 7.85 (br s, 1H), 7.52 (s,

1H), 7.03 (s, 1H), 6.79 (s, 1H), 6.34 (s, 1H), 3.91 (br s,

1H); MS (ESI) m / e (M + H +) 166.0.

Example 58: ethyl 6-amino-1H-indole-7-carboxylate [0498]

<img file="PL2674428T3_D0320.tif" />

3-methyl-2,6-dinitrobenzoic acid [0499] To the HNO mixture₃ (95%, 80 ml) and H₂SO₄ (98%, 80 ml) 3-methylbenzoic acid (50 g, 0.37 mol) was slowly added at 0 ° C. After the addition, the reaction mixture was stirred

280 at a temperature below 30 ° C for 1.5 hours. The mixture was then poured into ice water and stirred for 15 minutes. The precipitate was filtered off and washed with water to obtain a mixture of 3-methyl-2,6-dinitro-benzoic acid and 5-methyl-2,4-dinitrobenzoic acid (70 g, 84%). To a solution of the mixture (70 g, 0.31 mol) in EtOH (150 ml) was added SOCl dropwise₂(54 g, 0.45 mol). The mixture was heated at reflux for 2 hours and then concentrated to dryness under reduced pressure. The residue was partitioned between EtOAc (100 mL) and aqueous Na₂WHAT₃ (10%, 120 ml). The organic layer was washed with brine (50 ml), dried over Na₂SO₄ and concentrated to dryness to give ethyl 5-methyl-2,4-dinitrobenzoate (20 g) which was set aside.

The aqueous layer was acidified with HCl to pH ~ 2-3, and the precipitate was filtered off, washed with water and air dried to give 3-methyl-2,6-dinitrobenzoic acid (39 g, 47%).

<img file="PL2674428T3_D0321.tif" />

Ethyl 3-methyl-2,6-dinitrobenzoate [0500] A mixture of 3-methyl-2,6-dinitrobenzoic acid (39 g, 0.15 mol) and SOCl₂ (80 ml) was heated to reflux for 4 hours. Excess SOCl₂evaporated under reduced pressure, and the residue was added dropwise to a solution of ethanol (100 ml) and Et₃N (50 ml). The mixture was stirred at 20 ° C for 1 hour and then concentrated to dryness. The residue was dissolved in EtOAc (100 mL), washed with Na₂WHAT₃ (10%, 40 ml x 2), water (50 ml x 2) and

281 brine (50 ml), dried over Na₂SO₄ and concentrated to give ethyl 3-methyl-2,6-dinitrobenzoate (20 g, 53%).

<img file="PL2674428T3_D0322.tif" />

(E) -ethyl 3- (2- (dimethylamino) vinyl) -2,6-dinitrobenzoate [0501] A mixture of 3-methyl-2,6-dinitrobenzoic acid ethyl ester (35 g, 0.14 mol) and DMA (32 g, 0.27 mol) in DMF (200 ml) was heated at 100 ° C for 5 hours. The mixture was poured into ice water. The precipitate was filtered off and washed with water to obtain (E) ethyl 3- (2- (dimethylamino) vinyl) -2,6-dinitrobenzoate (25 g, 58%).

<img file="PL2674428T3_D0323.tif" />

Ethyl 6-amino-1H-indole-7-carboxylate [0502] A mixture of (E) -ethyl 3- (2- (dimethylamino) vinyl) -2,6-dinitrobenzoate (30 g, 0.097 mol) and Raney Nickel (10 g ) in ethanol (1000 ml) was hydrogenated at room temperature under 50 psi for 2 hours. The catalyst was filtered off and the filtrate concentrated to dryness. The residue was purified by silica gel column chromatography to give 6-amino-1H-indole-7-carboxylic acid ethyl ester as an off-white solid (3.2 g, 16%).¹1 H NMR (DMSO-d₆) δ 10.38 (s, 1H), 7.42 (d, J = 8.7 Hz, 1H), 6.98 (t, J = 3.0 Hz, 1H), 6.65 (s, 2H ), 6.48 (d,

282

J = 8.7 Hz, 1H), 6, 27-6, 26 (m, 1H), 4.38 (q, J = 7.2 Hz, 2H),

1.35 (t, J = 7.2 Hz, 3H).

Example 59: ethyl 6-amino-1H-indole-5-carboxylate [0503]

<img file="PL2674428T3_D0324.tif" />

(E) -ethyl 5- (2- (dimethylamino) vinyl) -2,4-dinitrobenzoate [0504] A mixture of ethyl 5-methyl-2,4-dinitrobenzoate (39 g, 0.15 mol) and DMA (32 g, 0.27 mol) in DMF (200 ml) was heated at 100 ° C for 5 hours. The mixture was poured into ice water and the precipitate was filtered off and washed with water to give (E) -ethyl 5- (2- (dimethylamino) vinyl) -2,4-dinitrobenzoate (15 g, 28%).

<img file="PL2674428T3_D0325.tif" />

Ethyl 6-amino-1H-indole-5-carboxylate [0505] A mixture of (E) -ethyl 5- (2- (dimethylamino) vinyl) -2,4-dinitrobenzoate (15 g, 0.050 mol) and Raney nickel (5 g) in ethanol (500 ml) was hydrogenated at room temperature under 50 psi hydrogen for 2 hours. The catalyst was filtered off and the filtrate concentrated to dryness. The residue was purified by silica gel column chromatography to give ethyl 6-amino-1H-indole-5-carboxylate (3.0 g, 30%).^X1 H NMR (DMSO-d₆) δ 10.68 (s, 1H), 7.99 (s, 1H),

283

7.01-7.06 (m, 1H), 6.62 (s, 1H), 6, 27-6, 28 (m, 1H), 6.16 (s,

2H), 4.22 (q, J = 7.2 Hz, 2H), 1.32-1.27 (t, J = 7.2 Hz, 3H).

Example 60: 5-tert-butyl-1H-indole-6-amine [0506]

<img file="PL2674428T3_D0326.tif" />

Diethyl 2-tert-butyl-4-methylphenyl phosphate [0507] To a suspension of NaH (60% in mineral oil, 8.4 g, 0.21 mol) in THF (200 mL), a solution of 2-tert-butyl-4-methylphenol ( 33 g, 0.20 mol) in THF (100 ml) at 0 ° C. The mixture was stirred at 0 ° C for 15 minutes and then phosphochloric acid diethyl ester (37 g, 0.21 mol) was added dropwise at 0 ° C. After the addition, the reaction mixture was stirred at room temperature for 30 minutes. The reaction was quenched by the addition of saturated NH₄Cl (300 mL) and then extracted with Et₂O (350 ml x 2). The combined organic layers were washed with brine, dried over anhydrous Na₂SO₄ and then evaporated under reduced pressure to give diethyl 2-tert-butyl-4-methylphenyl phosphate (contaminated with mineral oil) as a colorless oil (60 g, ~ 100%), which was used directly in the next step.

284

<img file="PL2674428T3_D0327.tif" />

1-tert-butyl-3-methylbenzene [0508] For NH₃ (liquid, 1000 ml) a solution of diethyl 2-tert-butyl4-methylphenyl phosphate (60 g, crude product from previous step, 0.2 mol) in Et was added in Et₂O (anhydrous, 500 ml) at - 78 ° C, under nitrogen. Lithium metal was added to the solution in small pieces until the blue color remained. The reaction mixture was stirred at 78 ° C for 15 min and then stopped with saturated NH₄Cl, until the mixture has become colorless. Liquid NH₃evaporated and the residue dissolved in water. The mixture was extracted with Et₂O (400 ml x 2). The combined organic phases were dried over Na₂SO₄ and evaporated to give 1-tert-butyl-3-methylbenzene (contaminated with mineral oil) as a colorless oil (27 g, 91%), which was used directly for the next step.

<img file="PL2674428T3_D0328.tif" />

1-tert-butyl-5-methyl-2,4-dinitrobenzene and 1-tert-butyl-3-methyl-2,4-dinitro-benzene.

[0509] For HNO₃ (95%, 14 ml) H was added₂SO₄ (98%, 20 ml) at 0 ° C, followed by the dropwise addition of 1-tert-butyl-3-methylbenzene (7.4 g, ~ 50 mmol, crude from the previous step), the temperature being kept below 30 ° C. The reaction mixture was stirred at room temperature for 30 minutes,

285 poured onto crashed ice (100 g) and extracted with EtOAc (50 mL × 3). The combined organic layers were washed with water and brine, and then evaporated to give a brown oil, which was purified by column chromatography to give a mixture of 1-tert-butyl-5-methyl-2,4-dinitrobenzene and 1-tert-butyl-3-methyl-2, 4-dinitrobenzene (2: 1 NMR analysis) as a yellow oil (9.0 g, 61%).

<img file="PL2674428T3_D0329.tif" />

(E) -2- (5-tert-butyl-2,4-dinitrophenyl) -N, N-dimethylethyleneamine [0510] A mixture of 1-tert-butyl-5-methyl-2,4-dinitrobenzene and 1-tert-butyl-3 -methyl-2,4-dinitrobenzene (9.0 g, 38 mmol, 2: 1 NMR analysis) and DMA (5.4 g, 4.5 mmol) in DMF (50 mL) was refluxed for 2 hours, after which was cooled to room temperature. The reaction mixture was poured into ice water and extracted with EtOAc (50 mL × 3). The combined organic layers were washed with water and brine, and then evaporated to give a brown oil which was purified on a column to give (E) -2- (5-tert-butyl-2,4-

<img file="PL2674428T3_D0330.tif" />

5-tert-butyl-1H-indole-6-amine [0511] Solution (E) -2- (5-tert-butyl-2,4-dinitrophenyl) -N, N-dimethylethenoamine (5.3 g, 18 mmol) and tin chloride dihydrate

286 (II) (37 g, 0.18 mol) in ethanol (200 ml) was refluxed overnight. The mixture was cooled to room temperature and the solvent removed under reduced pressure. The residual suspension was diluted with water (500 mL) and basified with 10% aqueous Na₂WHAT₃ to pH 8. The resulting suspension was extracted with ethyl acetate (3 x 100 mL). The ethyl acetate extract was washed with water and brine, dried over Na₂SO₄ and concentrated. The remaining solid was washed with CH₂cl₂ to give a yellow powder, which was purified by column chromatography to give 5-tert-butyl-1H-indol-6-amine (0.40 g, 12%). ¹H NMR (DMSO d₆) δ 10.34 (br s, 1H), 7.23 (s, 1H), 6.92 (s, 1H), 6.65 (s, 1H), 6.14 (s, 1H), 4, 43 (br s, 2H), 2.48 (s, 9H); MS (ESI) m / e (M + H +) 189.1.

General Procedure IV: Synthesis of acylaminoindoles [0512]

<img file="PL2674428T3_D0331.tif" />

[0513] One equivalent of the corresponding carboxylic acid and one equivalent of the corresponding amine were dissolved in N, N-dimethylformamide (DMF) containing triethylamine (3 equivalents). O- (7-azabenzotriazol-1-yl) -N, N, N ', N'-tetramethyluronium hexafluorophosphate (HATU) was added and the solution was stirred. The crude product was purified by reverse phase preparative liquid chromatography to give pure product.

287

Example 61:

N- (2-tert-butyl-1H-indol-5-yl) -1- (4-methoxyphenyl) cyclopropanecarboxamide [0514]

<img file="PL2674428T3_D0332.tif" />

[0515] 2-tert-butyl-1H-indole-5-amine (19 mg, 0.10 mmol) and 1- (4-methoxyphenyl) cyclopropanecarboxylic acid (19 mg, 0.10 mmol) were dissolved in N, N- dimethylformamide (1.00 ml) containing triethylamine (28 pL, 0.20 mmol). O- (7-azabenzotriazol-1-yl) Ν, Ν, Ν ', Ν'-tetramethyluronium hexafluorophosphate (42 mg, 0.11 mmol) was added to the mixture, and the resulting solution was stirred for 3 hours. The crude reaction mixture was filtered and purified by reverse phase HPLC. ESI-MS m / z calcd 362.2, found 363.3 (M + 1) +; Retention time 3.48 minutes.

General procedure V: Synthesis of [0516] acylaminoindoles

<img file="PL2674428T3_D0333.tif" />

<img file="PL2674428T3_D0334.tif" />

[0517] One equivalent of the corresponding carboxylic acid is placed in an oven-dried flask under a nitrogen atmosphere. A minimum amount (3 equivalents) of thionyl chloride and a catalytic amount of N, N-dimethylformamide were added and the solution was stirred for 20 minutes at 60 ° C. Excess thionyl chloride was removed under reduced pressure, and the obtained solid was suspended in a minimum amount of anhydrous pyridine.

288

This solution was slowly added with stirring to the solution one equivalent of the appropriate amine dissolved in the minimum amount of anhydrous pyridine. The resulting mixture was stirred for 15 hours at 110 ° C. The mixture was evaporated to dryness, suspended in methylene chloride, followed by extraction three times with 1 N HCl. The organic layer was dried over sodium sulfate, evaporated to dryness and then purified by column chromatography.

Example 62: ethyl 5- (1- (benzo [d] [1,3] dioxol-5-yl) cyclopropanecarboxamido) -1H-indole-2-carboxylate (Compound 28) [0518]

<img file="PL2674428T3_D0335.tif" />

[0519] 1-Benzo [1,3] dioxol-5-yl-cyclopropanecarboxylic acid (2.07 g, 10.0 mmol) was dissolved in thionyl chloride (2.2 mL) under a nitrogen atmosphere. N, N-dimethylformamide (0.3 mL) was added and the solution was stirred for 30 minutes. Excess thionyl chloride was removed under reduced pressure, and the obtained solid was dissolved in anhydrous dichloromethane (15 mL) containing triethylamine (2.8 mL, 20.0 mmol). Ethyl 5-amino-1H-indole-2-carboxylate (2.04 g, 10.0 mmol) in 15 mL anhydrous dichloromethane was slowly added to the reaction mixture. The resulting solution was allowed to stir for 1 hour. The reaction mixture was diluted with 50 ml of dichloromethane and washed three times with 50 ml of 1 N HCl,

289 saturated aqueous sodium bicarbonate solution and saturated aqueous sodium chloride solution. The organic layer was dried over sodium sulfate and evaporated to dryness to give ethyl 5- (1- (benzo [d] [1,3] dioxol-5-yl) cyclopropanecarboxamido) -1H-indole-2-carboxylate as a substance solid gray (3.44 g, 88%). ESI-MS m / z calculated 392.4; found 393.1 (M + 1) + Retention time 3.17

<td>min. ¹H</td><td>NMR</td><td>(4 00 MHz, DMSO-de) δ</td><td>11.80 (s,</td><td>1H),</td><td> 8,64</td><td>(S,</td><td>1H),</td>

<td colspan="2">7.83 (m, 1H</td><td>), 7.33-7.26 (m, 2H),</td><td>7.07 (m,</td><td>1H),</td><td> 7,02</td><td>(M,</td><td>1H),</td>

<td> 6,96-6,</td><td> 89 (</td><td>m, 2H), 6.02 (s, 2H)</td><td> , 4,33 (</td><td>q, J =</td><td> 7,1</td><td>Hz,</td><td>2H);</td>

<td> 1,42-1,</td><td> 39 (</td><td>m, 2H), 1.33 (t, J =</td><td>7.1 Hz</td><td>3H);</td><td> 1,06-</td><td> 1,03</td><td>(M,</td>

2H).

Example 63: 1- (benzo [d] [1,3] dioxol-5-yl) N- (2-tert-butyl1H-indol-5-yl) -cyclopropanecarboxamide [0520]

<img file="PL2674428T3_D0336.tif" />

[0521] 1-Benzo [1,3] dioxol-5-ylcyclopropanecarboxylic acid (1.09 g, 5.30 mmol) was dissolved in 2 mL of thionyl chloride under nitrogen. A catalytic amount (0.3 mL) of N, N-dimethylformamide (DMF) was added and the reaction mixture was stirred for 30 minutes. The excess thionyl chloride was evaporated and the residue obtained was dissolved in 15 ml of dichloromethane. This solution was added slowly to a solution of 2-tert-butyl-1H-indole-5-amine (1.0 g, 5.3 mmol) in 10 mL of dichloromethane containing triethylamine (1.69 mL, 12.1 mmol). The resulting solution was stirred for 10 minutes.

290

The solvent was evaporated to dryness and the crude reaction mixture was purified by silica gel column chromatography using a 5-50% gradient of ethyl acetate in hexanes. The pure fractions were combined and evaporated to dryness to afford a pale pink powder (1.24 g 62%). ESI-MS m / z calculated 376.18, found 377.3 (M + 1) +. Retention time 3.47 minutes.^XH NMR (400 MHz, DMSO) δ 10.77 (s, 1H), 8.39 (s, 1H), 7.56 (d, J = 1.4 Hz, 1H), 7.15 (d, J = 8.6 Hz

1H), 7.05-6, 87 (m, 4H), 6.03 (s, 3H), 1.44-1.37 (m, 2H), 1.33 (s, 9H), 1.05 -1.00 (m, 2H).

Example 64: 1- (benzo [d] [1,3] dioxol-5-yl) -W- (1-methyl-2- (1-methylcyclopropyl) -1H-indol-5-yl) -cyclopropanecarboxamide [0522]

<img file="PL2674428T3_D0337.tif" />

[0523] 1-Methyl-2- (1-methylcyclopropyl) -1H-indole-5-amine (20.0 mg, 0.100 mmol) and 1- (benzo [d] [1,3] dioxol-5-yl) cyclopropanecarboxylic acid (20.6 mg, 0.100 mmol) was dissolved in a solution of N, N-dimethylformamide (1 mL) containing triethylamine (42.1 µL, 0.300 mmol) and a magnetic stirrer. O- (7-azabenzotriazol-1-yl) -N, N, N ', N'-tetramethyluronium hexafluorophosphate (42 mg, 0.11 mmol) was added to the mixture, and the resulting solution was stirred for 6 hours at 80 ° C. The crude product was purified by preparative HPLC using a gradient of 0-99% acetonitrile in water containing 0.05% trifluoracetic acid to give ESI-MS m / z calc. 388.2, found 389.2 (M + 1) +. Retention time 3.05 minutes.

291

Example 65: 1- (benzo [d] [1,3] dioxol-5-yl) - W- (1,1-dimethyl2,3-dihydro-1H-pyrrolo [1,2-a] indol-7-yl) cyclopropanecarboxamide

<img file="PL2674428T3_D0338.tif" />

Amine (40.0 mg, 0.200 mmol) and 1- (benzo [d] [1,3] dioxol5-yl) cyclopropanecarboxylic acid (41.2 mg, 0.200 mmol) were dissolved in N, N-dimethylformamide (1 mL) containing triethylamine (84.2 μ !, 0.600 mmol) and magnetic stir bar. O- (7-azabenzotriazol-1-yl) -N, N, N ', N' -tetramethyluronium hexafluorophosphate (84 mg, 0.22 mmol) was added to the mixture, and the resulting solution was stirred for 5 minutes at room temperature. The crude product was purified by preparative HPLC gradient acetonitrile containing water

0,05%

0-99% trifluoracetic acid to give ESI-MS m / z calcd. 388.2, 389.2 found (M + 1) +. Retention time 2.02 minutes.¹1 H NMR

<td> (400</td><td>MHz,</td><td>DMSO-d6)?</td><td>δ 8.41 (s,</td><td>1H), 7.59 (d, J =</td><td>1.8 Hz</td><td>1H),</td>

<td> 7,15</td><td>(D,</td><td>J = 8.6</td><td>Hz, 1H), 7,</td><td>06-7.02 (m, 2H),</td><td> 6,96-6,90</td><td>(M,</td>

<td>2H);</td><td> 6,03</td><td>(s, 2H),</td><td>5.98 (d, J</td><td>= 0.7 Hz, 1H), 4,</td><td>06 (t, J =</td><td> 6,8</td>

<td>Hz,</td><td>2H);</td><td>2.35 (t,</td><td>J = 6.8 Hz</td><td>, 2H), 1.42-1.38</td><td>(m, 2H),</td><td> 1,34</td>

<td>(S,</td><td>6H),</td><td> 1,05-1,01</td><td>(m, 2H).</td><td></td><td></td><td></td>

Example 66: methyl 5- (1- (benzo [d] [1,3] dioxol-5-yl) cyclopropane carboxamido) -2-ter-butyl-1H-indole-7-carboxylate

292 [0526]

<img file="PL2674428T3_D0339.tif" />

[0527] 1- (Benzo [d] [1,3] dioxol-5-yl) cyclopropanecarbonyl chloride (45 mg, 0.20 mmol) and methyl 5-amino-2-tert-butyl-1H-indole-7-carboxylate ( 49.3 mg, 0.200 mmol) was dissolved in a solution of N, N-dimethylformamide (2 mL) containing a magnetic stirrer and triethylamine (0.084 mL, 0.60 mmol). The resulting solution was stirred for 10 minutes at room temperature. The crude product was purified by preparative HPLC using a 0-99% gradient of acetonitrile in water containing 0.05% trifluoracetic acid to give 5- (1- (benzo [d] [1,3] dioxol-5-yl) cyclopropanecarboxamido) 2 methyl tert-butyl-1H-indole-7-carboxylate. ESI-MS m / z calculated 434.2, found 435.5. (M + 1) +. Retention time 2.12 minutes.

Example 67: 1- (benzo [d] [1,3] dioxol-5-yl) -N- (2- (1-hydroxy2-methylpropan-2-yl) -1H-indol-5-yl) cyclopropanecarboxamide [0528 ]

<img file="PL2674428T3_D0340.tif" />

[0529]

To the solution

1- (benzo [d] [1,3] dioxol-50,075 g, 0.36 mmol) in yl) cyclopropanecarboxylic acetonitrile (1.5 mL) added HBTU (0.138 g, 0.36 mmol) and Et₃N (152 mL, 1.09 mmol) at room temperature.

The reaction mixture was stirred at room temperature for minutes, then 2- (5-amino-1H-indol-2-yl) -2293 methylpropan-1-ol (0.074 g, 0.36 mmol) in acetonitrile (1.94 mL) was added. ). After the addition, the reaction mixture was stirred at room temperature for 3 hours. The solvent was evaporated under reduced pressure, and the residue was dissolved in dichloromethane. The organic layer was washed with 1 N HCl (3 x 1 mL) and saturated aqueous NaHCO₃ (1 x 3 ml). The organic layer was dried over Na₂SO₄, filtered and evaporated under reduced pressure. The crude material was purified by silica gel column chromatography (ethyl acetate / hexane = 1/1) to obtain 1- (benzo [d] [1,3] dioxol-5-yl) -N- (2- (1-hydroxy-2 -methylpropan-2-yl) -1H-indol-5-yl) cyclopropanecarboxamide (0.11 g, 75%).¹H NMR (400 MHz,

<td>DMSO-d6) δ</td><td> 10</td><td> ,64</td><td>(s, 1H), 8.3 (s,</td><td colspan="2">1H), 7.55</td><td>(s, 1H),</td><td> 7,</td><td> 15</td><td>(D,</td>

<td>J = 8.6 Hz</td><td>^,</td><td>1H),</td><td>7, 04-6, 90 (m,</td><td>4H),</td><td> 6,06</td><td>(s, 1H),</td><td> 6,</td><td> 03</td><td>(S,</td>

<td>2H), 4.79</td><td>(t</td><td>, J</td><td>= 2.7 Hz, 1H),</td><td> 3,46</td><td>(D,</td><td>J = 0.0</td><td>h</td><td>^,</td><td>2H);</td>

<td> 1,41-1,39 (</td><td>m</td><td>2H)</td><td>, 1.26 (s, 6H),</td><td colspan="2"> 1,05-1,02</td><td>(m, 2H).</td><td></td><td></td><td></td>

Example 67: 1- (benzo [d] [1,3] dioxol-5-yl) -N- (2,3,4,9-tetrahydro-1H-carbazol-6-yl) cyclopropanecarboxamide

<img file="PL2674428T3_D0341.tif" />

2,3,4,9-tetrahydro-1H-carbazole-6-amine (81.8 mg,

0.439 mmol) and 1- (benzo [d] [1,3] dioxol-5-yl) cyclopropanecarboxylic acid (90.4 mg, 0.439 mmol) were dissolved in acetonitrile (3 mL) containing diisopropylethylamine (0.230 mL, 1.32 mmol) and magnetic stirrer. O- (7-azabenzotriazol-1-yl) -N, N, N ', N'-tetramethyluronium hexafluorophosphate (183 mg,

294

0.482 mmol) and the resulting solution was stirred for 16 hours at 70 ° C. The solvent was evaporated and the crude product was purified on 40 g silica gel using a 5-50% gradient of ethyl acetate in hexanes to afford 1- (benzo [d] [1,3] dioxol-5-yl) -N ( 2,3,4,9-tetrahydro-1H-carbazol-6-yl) cyclopropanecarboxamide in the form of a beige powder (0.115 g, 70%). ESI-MS m / z calculated 374.2, found 375.3 (M + 1) +. Retention time: 3.43 min.¹H NMR (400 MHz, DMSO-d₆) δ 10.52 (s, 1H), 8.39 (s, 1H), 7.46 (d, J = 1.8 Hz, 1H), 7.106.89 (m, 5H), 6.03 (s , 2H), 2, 68-2, 65 (m, 2H), 2.56-2.54 (m,

2H), 1.82-1.77 (m, 4H), 1.41-1.34 (m, 2H), 1.04-0.97 (m, 2H).

Example 69: tert-butyl 4- (5- (1- (benzo [d] [1,3] dioxol-5-yl) cyclopropanecarboxamido) -1H-indol-2-yl) piperidine-1-carboxylate

<img file="PL2674428T3_D0342.tif" />

[0533] 1- (Benzo [d] [1,3] dioxol-5-yl) cyclopropanecarbonyl chloride (43 mg, 0.19 mmol) and 4- (5-amino-1H-indol-2-yl) piperidine-1- tert-butyl carboxylate (60 mg, 0.19 mmol) was dissolved in a solution of dichloromethane (1 mL) containing a magnetic stir bar and triethylamine (0.056 mL, 0.40 mmol). The resulting solution was stirred for two days at room temperature. The crude product was then evaporated to dryness, dissolved in a minimal amount of N, N-dimethylformamide and then purified by

295 preparative HPLC using a gradient of 0-99% acetonitrile in water containing 0.05% trifluoracetic acid to obtain

- tert-butyl (5- (benzo [d] [1,3] dioxol-5-yl) cyclopropanecarboxamido) -1H-indol-2-yl) piperidine-1-carboxylate. ESI-MS m / z calculated 503.2, found 504.5. (M + 1) +. Retention time 1.99 minutes.

Example 70: ethyl 2- (5- (1- (benzo [d] [1,3] dioxol-5-yl) cyclopropanecarboxamido) -1H-indol-2-yl) propanoate [0534]

<img file="PL2674428T3_D0343.tif" />

butyl [0535] tert-butyl 2- (2-ethoxy-2-oxoethyl) -1H-indole-1-carboxylate (3.0 g, 9.9 mmol) was added to anhydrous THF (29 mL) and cooled to -78 ° C . A 0.5 M solution of potassium hexamethyldisilazate (20 mL, 9.9 mmol) was then added so that the internal temperature remained below -60 ° C. Stirring was continued for 1 hour at -78 ° C. Methyl iodide (727 μL, 11.7 mmol) was added to the mixture. The mixture was stirred for 30 minutes at room temperature. The mixture was stopped with a saturated aqueous solution of ammonium chloride and partitioned between water and dichloromethane. The aqueous phase was extracted with dichloromethane and the combined organic phases

296 dried over Na₂SO₄ and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / hexane = 1/9) to obtain tert-butyl 2- (1-ethoxy-1-oxopropan-2-yl) -1H-indole-1-carboxylate (2.8 g, 88 %).

<img file="PL2674428T3_D0344.tif" />

Ethyl 2- (1H-indol-2-yl) propanoate [0536] Tert-Butyl 2- (1-ethoxy-1-oxopropan-2-yl) -1H-indole-1-carboxylate (2.77 g, 8.74 mmol ) was dissolved in dichloromethane (25 mL) before TFA (9.8 mL) was added. The mixture was stirred for 1.5 hours at room temperature. The mixture was evaporated to dryness, dissolved in dichloromethane and washed with saturated aqueous sodium bicarbonate solution, water and brine. The product was purified by silica gel column chromatography (0-20% EtOAc in hexane) to give ethyl 2- (1H-indol-2-yl) propanoate (0.92 g, 50%).

NaNO_and

WHAT₂Et concentrated H2SO4

N CO₂Et H

Ethyl 2- (5-nitro-1H-indol-2-yl) propanoate [0237] Ethyl 2- (1H-indol-2-yl) propanoate (0.91 g, 4.2 mmol) was dissolved in concentrated sulfuric acid ( 3.9 ml) and cooled to -10 ° C (salt / ice mixture). A solution of sodium nitrate (0.36 g, 4.2 mmol) in concentrated sulfuric acid (7.8 ml) was added dropwise over 35 minutes. Mixing continued for

297 another 30 minutes at -10 ° C. The mixture was poured into ice and the product was extracted with ethyl acetate. The combined organic phases were washed with a small amount of saturated aqueous sodium bicarbonate. The product was purified by silica gel column chromatography (5-30% EtOAc in hexane) to give ethyl 2- (5-nitro-1H-indol-2-yl) propanoate (0.34 g, 31%).

<img file="PL2674428T3_D0345.tif" />

Ethyl 2- (5-amino-1H-indol-2-yl) propanoate [0538] To a solution of ethyl 2- (5-nitro-1H-indol-2-yl) propanoate (0.10 g, 0.38 mmol) in ethanol (4 mL) tin chloride dihydrate (0.431 g, 1.91 mmol) was added. The mixture was heated in a microwave reactor at 120 ° C for 1 hour. The mixture was diluted with ethyl acetate then water and saturated aqueous NaHCO solution₃. The reaction mixture was filtered through a pad of Celite using ethyl acetate. The organic layer was separated from the aqueous layer. The organic layer was dried over Na₂SO₄, filtered and evaporated under reduced pressure to give methyl 2- (5-amino-1H-indol-2-yl) propanoate (0.088 g, 99%).

<img file="PL2674428T3_D0346.tif" />

Ethyl 2- (5- (1- (benzo [d] [1,3] dioxol-5-yl) cyclopropanecarboxamido) -1H-indol-2-yl) propanoate [0539] For 1- (benzo [d] [1] acid solution , 3] dioxol-5-yl) cyclopropane carboxylic acid (0.079 g, 0.384 mmol) in

298 acetonitrile (1.5 mL) was added at room temperature HBTU (0.146 g, 0.384 mmol) and Et₃N (160 mL, 1.15 mmol).

The mixture was stirred at room temperature for 10 minutes before a solution of ethyl 2- (5-amino-1H-indol-2-yl) propanoate (0.089 g, 0.384 mmol) in acetonitrile (2.16 mL) was added. After the addition, the reaction mixture was stirred at room temperature for 2 hours. The solvent was evaporated under reduced pressure, and the residue was dissolved in dichloromethane. The organic layer was washed with 1 N HCl (3 x 1 mL) followed by a saturated aqueous NaHCO solution₃ (1 x 3 ml). The organic layer was dried over Na₂SO₄, filtered and evaporated under reduced pressure. The crude material was purified by silica gel column chromatography (ethyl acetate / hexane = 1/1) to give 2- (5- (1 (benzo [d] [1,3] dioxol-5-yl) cyclopropanecarboxamido) -1Hindol-2 -yl) ethyl propanoate (0.081 g, 50%).^X1 H NMR (400 MHz, CDCl₃) δ 8.51 (s, 1H), 7.67 (s, 1H), 7.23-7.19 (m, 2H), 7.04-

<td> 7,01</td><td>(M,</td><td>3H), 6.89</td><td>(D,</td><td>J = 0.0 Hz, 1H),</td><td>6.28 (s,</td><td>1H), 6.06</td>

<td>(S,</td><td>2H);</td><td> 4,25-4,17</td><td>(M,</td><td>2H), 3.91 (q, J</td><td>= 7.2 Hz</td><td>1H), 1.72-</td>

<td> 1,70</td><td>(M,</td><td>2H), 1.61</td><td>(S,</td><td>2H), 1.29 (t, J</td><td>= 7.1 Hz,</td><td>4H), 1.13-</td>

<td> 1,11</td><td>(M,</td><td>2H).</td><td></td><td></td><td></td><td></td>

Example 71: tert-butyl 2- (5- (1- (benzo [d] [1,3] dioxol-5-yl) cyclopropanecarboxamido) -1H-indol-2-yl) -2-methylpropylcarbamate [0540]

299

<img file="PL2674428T3_D0347.tif" />

<img file="PL2674428T3_D0348.tif" />

<img file="PL2674428T3_D0349.tif" />

"Ν

Η

<img file="PL2674428T3_D0350.tif" />

2-methyl-2- (5-nitro-1H-indol-2-yl) propanoic acid [0541] 2-methyl-2- (5-nitro-1H-indol-2-yl) ethyl propanoate (4.60 g , 16.7 mmol) was dissolved in a THF / water mixture (2: 1, 30 ml). LiOH'H was added₂O (1.40 g, 33.3 mmol) and the reaction mixture was stirred at 50 ° C for 3 hours. The mixture was acidified by the careful addition of 3N HCl. The product was extracted with ethyl acetate and the combined organic phases were washed with brine, dried over magnesium sulfate to give 2-methyl-2- (5-nitro-1H-indol-2-yl) propanoic acid (4.15 g,

99%)

<img file="PL2674428T3_D0351.tif" />

2-methyl-2- (5-nitro-1H-indol-2-yl) propanamide 2-methyl-2- (5-nitro-1H-indol-2-yl) propanoic acid (4.12 g, 16.6 mmol) was dissolved in acetonitrile (80 mL).

EDC (3.80 g, 0.020 mmol), HOBt (2.70 g, 0.020 mmol) were added

et₃N (6.9 mL, 0.050 mmol) and ammonium chloride (1.34 g, 0.025 mmol) and the mixture was stirred overnight at room temperature. Water was added and the mixture was extracted with acetate

300 acetate. The combined organic phases were washed with brine, dried over magnesium sulfate and dried to give 2-methyl-2- (5-nitro-1H-indol-2-yl) propanamide (4.3 g, 99%).

<img file="PL2674428T3_D0352.tif" />

2-methyl-2- (5-nitro-1H-indol-2-yl) propan-1-amine [0543] 2-methyl-2- (5-nitro-1H-indol-2-yl) propanamide (200 mg , 0.81 mmol) was suspended in THF (5 mL) and cooled to 0 ° C. The borane-THF complex solution (1.0 M, 2.4 mL, 2.4 mmol) was added slowly and the mixture was stirred overnight at room temperature. The mixture was cooled to 0 ° C and carefully acidified with 3N HCl. THF was evaporated, water was added and the mixture was washed with ethyl acetate. The aqueous layer was basified with 50% NaOH solution and the mixture was extracted with ethyl acetate. The combined organic layers were dried over magnesium sulfate, filtered and evaporated to give 2-methyl-2- (5-nitro-1H-indol-2-yl) propan-1-amine (82 mg, 43%).

°^2NTX&gt; -X ^B0C2°

YY NH₂ NEt₃, THF YYm NHBoc

Tert-butyl 2-methyl-2- (5-nitro-1H-indol-2-yl) propylcarbamate [0544] 2-methyl-2- (5-nitro-1H-indol-2-yl) propan-1-amine ( 137 mg, 0.587 mmol) was dissolved in THF (5 mL) and cooled to 0 ° C. Added Et₃N (82 pL, 0.59 mmol) and di-tert-butyl dicarbonate (129 mg, 0.587 mmol) and the reaction mixture was stirred at room temperature overnight. Water was added and the mixture was extracted with ethyl acetate. The residue was purified by method

301 silica gel chromatography (10-40% ethyl acetate in hexane) to give tert-butyl 2-methyl-2- (5-nitro-1H-indol-2-yl) propylcarbamate (131 mg, 67%).

<img file="PL2674428T3_D0353.tif" />

Tert-butyl 2- (5-amino-1H-indol-2-yl) -2-methylpropylcarbamate [0545] To a solution of tert-butyl 2-methyl-2- (5-nitro-1H-indol-2-yl) propylcarbamate (80 mg, 0.24 mmol) in THF (9 mL) and water (2 mL) was added ammonium formate (60 mg, 0.96 mmol) followed by 10% Pd / C (50 mg). The reaction mixture was stirred at room temperature for 45 minutes. Pd / C was filtered off and the organic solvent was evaporated. The remaining aqueous phase was extracted with dichloromethane. The combined organic phases were dried over magnesium sulfate and evaporated to give tert-butyl 2- (5-amino-1H-indol-2-yl) -2-methylpropylcarbamate (58 mg, 80%).

<img file="PL2674428T3_D0354.tif" />

Tert-butyl 2- (5- (1- (benzo [d] [1,3] dioxol-5-yl) cyclopropanecarboxamido) -1H-indol-2-yl) -2-methylcarbamate [0546] 2 - (5-amino-1H- tert-butyl indol-2-yl) -2-methylpropylcarbamate (58 mg, 0.19 mmol), 1- (benzo [d] [1,3] dioxol6-yl) cyclopropanecarboxylic acid (47 mg, 0.23 mmol) , EDC (45 mg, 0.23 mmol), HOBt (31 mg, 0.23 mmol) and Et₃N (80 pL, 0.57

302 mmol) was dissolved in DMF (4 mL) and stirred overnight at room temperature. The mixture was diluted with water and extracted with ethyl acetate. The combined organic phases were dried over magnesium sulfate and evaporated to dryness. The residue was purified by silica gel chromatography (10-30% ethyl acetate in hexane) to give 2- (5- (1- (benzo [d] [1,3] dioxol-5-yl) cyclopropanecarboxamido) 1-indol-2-yl Tert-butyl -2-methylpropylcarbamate (88

<td>mg</td><td> 94%).</td><td>¹H NMR (400 MHz,</td><td>CDCl.sub.3</td>

<td> = 1,</td><td>5 Hz</td><td>1H), 7.18-7.16 (m,</td><td>, 2H)</td>

<td>J =</td><td>7.8 Hz</td><td>, 1H), 6.19 (d, J</td><td> = 1,</td>

<td>(M,</td><td>1H), 3</td><td>, 33 (d, J = 6.2 Hz</td><td>, 2H)</td>

<td>2H);</td><td> 1,36</td><td>(s, 9H), 1.35 (s,</td><td>6H)</td>

<td>2H).</td><td></td><td></td><td></td>

δ 8.32 (s, 1H), 7.62 (d, J 7.02-6.94 (m, 3H), 6.85 (d, Hz, 1H), 6.02 (s, 2H); 4.54 1.68 (dd, J = 3.7, 6.8 Hz, 1.09 (dd, J = 3.7, 6.8 Hz,

Example 72: (R) -N- (2-tert-butyl-1- (2,3-dihydroxypropyl) 1H-indol-5-yl) -1- (2,2-difluorobenzo [d] [1,3] dioxol-5-yl) cyclopropanecarboxamide

<img file="PL2674428T3_D0355.tif" />

303 (R) -2-tert-butyl-1 - ((2,2-dimethyl-1,3-dioxolan-4-yl) methyl) -5-nitro-1H-indole [0548] To a mixed solution of 4-methylbenzenesulfonate ( S) - (2,2-dimethyl-1,3-dioxolan-4-yl) methyl (1.58 g, 5.50 mmol) in anhydrous DMF (10 mL) under 2-tert-butyl-5- nitro-1H-indole (1.00 g, 4.58 mmol) followed by Cs2CO3 (2.99 g, 9.16 mol). The mixture was stirred and heated at 80 ° C under a nitrogen atmosphere. After 20 hours, 50% conversion was observed by LCMS. The reaction mixture was again treated with Cs2CO3 (2.99 g, 9.16 mol) and (S) - (2,2-dimethyl-1,3-dioxolan-4-yl) methyl 4-methylbenzenesulfonate (1.58 g, 5.50 mmol) and heated at 80 ° C for 24 hours. The reaction mixture was cooled to room temperature. The solids were filtered off and washed with ethyl acetate and hexane (1: 1). The layers were separated and the organic layer was washed with water (2 x 10 mL) and brine (2 x 10 mL). The organic layer was dried over Na2SO4, filtered and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane / hexane = 1.5 / 1) to obtain (R) -2-tert-butyl-1 - ((2,2-dimethyl-1,3-dioxolan4-yl) methyl) -5-nitro-1H-indole (1.0 g, 66%).¹H NMR (400 MHz, CDCl3) δ 8.48 (d, J = 2.2 Hz, 1H), 8.08 (dd, J = 2.2, 9.1 Hz,

1H), 7.49 (d, J = 9.1 Hz, 1H), 6.00 (s, 1H), 4.52-4.45 (m,

3H), 4.12 (dd, J = 6.0, 8.6 Hz, 1H), 3.78 (dd, J = 6.0, 8.6

Hz, 1H), 1.53 (s, 3H), 1.51 (s, 9H), 1.33 (s, 3H).

<img file="PL2674428T3_D0356.tif" />

304 (R) -2-tert-butyl-1 - ((2,2-dimethyl-1,3-dioxolan-yl) methyl 1H-indole-5-amine [0549] For a mixed solution of (R) -2-tert- butyl-1 - ((2,2-dimethyl-1,3-dioxolan-4-yl) methyl) -5-nitro-1H-indole (1.0 g, 3.0 mmol) in ethanol (20 ml) and water ( 5 ml), ammonium formate (0.76 g, 12 mmol) was added and then 10% palladium on carbon (0.4 g) was slowly added. The reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was filtered through a pad of celite and rinsed ethyl acetate. The filtrate was evaporated under reduced pressure and the crude product was dissolved in ethyl acetate. The organic layer was washed with water (2 x 5 mL) and brine (2 x 5 mL). The organic layer was dried over Na2SO4, filtered and evaporated under reduced pressure to give (R) -2-tert-butyl-1 ((2,2-dimethyl-1,3-dioxolan-4-yl) methyl-1H-indole- 5-amine

<td>(0.89 g,</td><td> 98%).</td><td>¹H NMR (400 MHz,</td><td>CDCl3) δ 7.04 (</td><td>d, J = 4</td><td>Hz,</td>

<td>1H), 6.70</td><td>(D,</td><td>J = 2.2 Hz, 1H), 6,</td><td>48 (dd, J = 2.2,</td><td>8.6 Hz</td><td>1H),</td>

<td>6.05 (s,</td><td>1H,),</td><td>4.38-4.1 (m, 2H),</td><td>4.21 (dd, J =</td><td> 7,5, 16,5</td><td>Hz,</td>

<td>1H), 3.87</td><td>(Dd,</td><td>J = 6.0, 8.6 Hz,</td><td>1H), 3.66 (dd,</td><td>J = 6.0,</td><td> 8,6</td>

<td>Hz, 1H),</td><td> 3,33</td><td>(br s, 2H), 1.40</td><td>(s, 3H), 1.34</td><td>(s, 9H),</td><td> 1,25</td>

(s, 3H).

<img file="PL2674428T3_D0357.tif" />

305

N - ((R) -2-tert-butyl-1 - ((2,2-dimethyl-1,3-dioxolan-4-yl) methyl) -1H-indol-5-yl) -1- (2,2difluorobenzo [ d] [1,3] dioxol-5-yl) cyclopropanecarboxamide [0550] To 1- (benzo [d] [1,3] dioxol-5-yl) cyclopropanecarboxylic acid (0.73 g, 3.0 mmol), chloride was added thionyl (660 µL, 9.0 mmol) and DMF (20 µL) at room temperature. The mixture was stirred for 30 minutes, after which excess thionyl chloride was evaporated under reduced pressure. To the resulting acid chloride, dichloromethane (6.0 mL) was added, Et₃N (2.1 mL, 15 mmol). To the cold acid chloride solution was added a solution of (R) -2-tert-butyl-1 - ((2,2-dimethyl-1,3-dioxolan-4-yl) methyl-1H-indole-5-amine (3.0 mmol) in dichloromethane (3.0 mL) After the addition, the reaction mixture was stirred at room temperature for 45 minutes The reaction mixture was filtered and the filtrate was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / hexane = 3/7) to give N - ((R) -2-tert-butyl-1 - ((2,2-dimethyl-1,3-dioxolan-4-yl) methyl) -1Hindol-5-yl) -1- (2,2-difluorobenzo [d] [1,3] dioxol-5-yl) cyclopropanecarboxamide (1.33 g, 84%). ¹1 H NMR (400 MHz, CDCl₃) δ 7.48 (d, J = 2 Hz, 1H,), 7.31 (dd, J = 2.8 Hz, 1H),

7.27 (dd, J = 2.8 Hz, 1H), 7.23 (d, J = 8 Hz, 1H), 7.14 (d, J = 8 Hz, 1H), 7.02 (dd, J = 2.8 Hz, 1H), 6.92 (br s, 1H),

6.22 (s, 1H), 4.38-4.05 (m, 3H), 3.91 (dd, J = 5.8 Hz, 1H),

3.75 (dd, J = 5, 8 Hz, 1H), 2.33 (q, J = 8 Hz, 2H), 1.42 (s,

3H), 1.37 (s, 9H), 1.22 (s, 3H), 1.10 (q, J = 8 Hz, 2H).

306

<img file="PL2674428T3_D0358.tif" />

N- ((R) -2-ter ^ t-butyl-1- ((2,3-dihydroxypropyl) -1H-indol-5-yl) -1- (2,2-difluorobenzo [d] [1,3] dioxol-5-yl) cyclopropanecarboxamide To a mixed solution of N - ((R) -2-tert-butyl-1 - ((2,2-dimethyl-1,3-dioxolan-4-yl) methyl) -1H-indol-5 -yl) -1- (2,2-difluorobenzo [d] [1,3] dioxol-5-yl) cyclopropanecarboxamide (1.28 g, 2.43 mmol) in methanol (34 mL) and water (3.7 mL) para-toluenesulfonic acid hydrate (1.87 g, 9.83 mmol) was added. The reaction mixture was stirred and heated at 80 ° C for 25 minutes. The solvent was evaporated under reduced pressure. The crude product was dissolved in ethyl acetate. The organic layer was washed with saturated aqueous NaHCO3 (2 x 10 mL) and brine (2 x 10 mL). The organic layer was dried over Na2SO4, filtered and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / hexane 13/7) to give N - ((R) -2-tert-butyl-1 - ((2,3-dihydroxypropyl) -1H-indol-5-yl) - 1- (2,2-difluorobenzo [d] [1,3] dioxol-5-yl) cyclopropanecarboxamide (0.96 g, 81%). ²1 H NMR (400 MHz, CDCl₃) δ 7.50 (d, J = 2 Hz, 1H), 7.31 (dd, J = 2.8 Hz, 1H), 7.27 (dd, J = 2.8 Hz, 1H), 7.23 (d, J = 8

Hz, 1H), 7.14 (d, J = 8 Hz, 1H), 7.02 (br s, 1H,), 6.96 (dd,

J = 2.8 Hz, 1H), 6.23 (s, 1H), 4.35 (dd, J = 8, 15 Hz, 1H),

4.26 (dd, J = 4, 15 Hz, 1H,), 4.02-3.95 (m, 1H), 3.60 (dd, J = 4, 11Hz, 1H), 3.50 (dd , J = 5, 11 Hz, 1H), 1.75 (q, J = 8

Hz, 3H), 1.43 (s, 9H), 1.14 (q, J = 8 Hz, 3H).

307

Example 73: 3- (2-tert-butyl-5- (1- (2,2-difluorobenzo [d] [1,3] dioxol-5-yl) cyclopropanecarboxamido) -1H-indol-1-yl) -2-hydroxypropanoic acid

<img file="PL2674428T3_D0359.tif" />

3- (2-tert-butyl-5- (1- (2,2-difluorobenzo [d] [1,3] dioxol-5-yl) cyclopropanecarboxamido) -1H-indol-1-yl) -2oxopropanoic acid [0553 ] To a solution of N- (2-tert-butyl-1 - ((2,3-dihydroxypropyl) -1H-indol-5-yl) -1- (2,2-difluorobenzo [d] [1,3] dioxol-5- cyclo-propanecarboxamide (97 mg, 0.20 mmol) in DMSO (1 mL) Dess-Martin periodinane reagent (130 mg, 0.30 mmol) was added The reaction mixture was stirred at room temperature for 3 hours. The solid was filtered off and washed with acetate acetate. The filtrate was partitioned between EtOAc and water. The aqueous layer was extracted twice with EtOAc and the combined organic layers were washed with brine and dried over magnesium sulfate. After removing

308 solvent, the residue was purified by preparative TLC to give 3- (2-tert-butyl-5- (1- (2,2-difluorobenzo [d] [1,3] dioxol-5-yl) cyclopropanecarboxamido) -1H-indol-1- acid il) -2-oxypropane, which was used without further purification.

MeOH, temp, peaceful

NaBH &lt;

3- (2-tert-butyl-5- (1- (2,2-difluorobenzo [d] [1,3] dioxol5-yl) cyclopropanecarboxamido) -1H-indol-1-yl) -2-hydroxypropanoic acid [0554] To solution of 3- (2-tert-butyl-5- (1- (2,2-difluorobenzo [d] [1,3] dioxol-5-yl) cyclopropanecarboxamido) -1H-indol-1-yl) -2-oxo-propanoic acid (50 mg, 0.10 mmol) in MeOH (1 mL) was added NaBH4 (19 mg, 0.50 mmol) at 0 ° C. The reaction mixture was stirred at room temperature for 15 minutes. The resulting mixture was partitioned between EtOAc and water. The aqueous layer was extracted twice with EtOAc and the combined organic layers were washed with brine and dried over anhydrous magnesium sulfate. After removal of the solvent, the residue was dissolved in DMSO and purified by preparative LC / MS to give 3- (2-tert-butyl-5- (1- (2,2-difluorobenzo [d] [1,3] dioxol-5-yl) cyclopropanecarboxamido] acid ) -1H-indol-1-yl) -2hydroksypropanowy.¹H NMR (400 MHz, CDClg) δ 7.36 (s), 7.277.23 (m, 2H), 7.15-7.11 (m, 2H), 6.94 (d, J = 8.5 Hz , 1H),

309

6.23 (s, 1H), 4.71 (s, 3H), 4.59 (q, J = 10.3Hz, 1H), 4.404.33 (m, 2H), 1.70 (d, J = 1.9 Hz, 2H), 1.15 (q, J = 4.0 Hz,

2H). ¹³C NMR (400 MHz, CDCl3) δ 173.6, 173.1, 150.7, 144.1,

143.6, 136,2, 135,4, 134,3, 131,7, 129,2, 129,0, 127,6,

126.7, 116,6, 114,2, 112,4, 110,4, 110,1, 99,7, 70,3, 48,5,

32.6, 30.9, 30.7, 16.8. MS (ESI) m / e (M + H +) 501.2.

Example 74: (K) -N- (2-tert-butyl-1- (2,3-dihydroxypropyl) 1H-indol-5-yl) -1- (2,2-dideuterobenzo [d] [1,3] dioxol-5-yl) cyclopropanecarboxamide [0555]

<img file="PL2674428T3_D0360.tif" />

Methyl 1- (3,4-dihydroxyphenyl) cyclopropane carboxylate [0556] To a solution of 1- (3,4-dihydroxyphenyl) cyclopropane carboxylic acid (190 mg, 1.0 mmol) in MeOH (3 ml), 4-methylbenzenesulfonic acid (19 mg, 0.10 mmol). The mixture was heated at 80 ° C overnight. The reaction mixture was concentrated under reduced pressure

310 pressure and partitioned between EtOAc and water. The aqueous layer was extracted twice with EtOAc and the combined organic layers were washed with saturated NaHCO solution₃ and brine, dried over MgSO₄. After removal of the solvent, the residue was dried under reduced pressure to give methyl 1- (3,4-dihydroxyphenyl) cyclopropanecarboxylate (190 mg, 91%), which was used without further purification.¹H NMR (400 MHz, DMSO-d₆) δ 6.76-6.71 (m, 2H), 6.66 (d, J = 7.9 Hz, 1H), 3.56 (s, 3H), 1.50 (q, J = 3, 6 Hz, 2H), 1.08 (q, J = 3.6 Hz, 2H).

<img file="PL2674428T3_D0361.tif" />

Methyl 1- (2,2-dideuterobenzo [d] [1,3] dioxol-5-yl) cyclopropanecarboxylate [0557] To a solution of methyl 1- (3,4-dihydroxyphenyl) cyclopropanecarboxylate (21 mg, 0.10 mmol) and CD₂br₂(35 mg, 0.20 mmol) in DMF (0.5 mL) was added with Cs₂WHAT₃ (19 mg, 0.10 mmol). The mixture was heated at 120 ° C for 30 minutes. The reaction mixture was partitioned between EtOAc and water. The aqueous layer was extracted twice with EtOAc and the combined organic layers were washed with 1 N NaOH and brine, then dried over magnesium sulfate. After removal of the solvent, the residue was dried under reduced pressure to obtain methyl methyl 1- (2,2-dideouterobenzo [d] [1,3] dioxol-5-yl) cyclopropanecarboxylate (22 mg), which was used without further purification. ¹1 H NMR (400 MHz, CDCl₃) δ 6.76-6.71 (m, 2H), 6.66 (d, J = 7.9 Hz,

1H), 3.56 (s, 3H), 1.50 (q, J = 3.6 Hz, 2H), 1.08 (q, J = 3.6

Hz, 2H).

311

<img file="PL2674428T3_D0362.tif" />

1- (2,2-dideuterobenzo [d] [1,3] dioxol-5-yl) cyclopropanecarboxylic acid [0558] To a solution of 1- (2,2-dideuterobenzo [d] [1,3] dioxol-5-yl) cyclopropanecarboxylate methyl (22 mg, 0.10 mmol) in THF (0.5 mL) added NaOH (1N, 0.25 mL, 0.25 mmol). The mixture was heated at 80 ° C for 2 hours. The reaction mixture was partitioned between ethyl acetate and 1N NaOH. The aqueous layer was extracted twice with ethyl acetate, neutralized with 1N HCl and extracted with ethyl acetate twice. The combined organic layers were washed with brine and dried over magnesium sulfate. After removal of the solvent, the residue was dried under reduced pressure to give 1- (2,2-dideuterobenzo [d] [1,3] dioxol-5-yl) cyclopropanecarboxylic acid (21 mg) which was used without further purification.

<img file="PL2674428T3_D0363.tif" />

(R) -N- (2-tert-butyl-1 - ((2,2-dimethyl-1,3-dioxolan-4-yl) methyl) -1H-indol-5-yl) -1- (2,2dideuterobenzo [ d] [1,3] dioxol-5-yl) cyclopropanecarboxamide [0559] To a solution of 1- (2,2-dideouterobenzo [d] [1,3] dioxol-5312-yl) cyclopropanecarboxylic acid (21 mg, 0.10 mmol), (R) -2-tert-butyl-1 - ((2,2-dimethyl-1,3-dioxolan-4-yl) methyl) -1H-indol-5-amine (30 mg, 0.10 mmol), HATU (42 mg , 0.11 mol) in DMF (1 ml), triethylamine (0.030 ml, 0.22 mmol) was added. The mixture was heated at room temperature for 5 minutes. The reaction mixture was partitioned between EtOAc and water. The aqueous layer was extracted twice with EtOAc and the combined organic layers were washed with 1N NaOH, 1N HCl and brine, then dried over magnesium sulfate. After removal of the solvent, the residue was purified by column chromatography (20-40% ethyl acetate / hexane) to give (R) -N- (2-tert-butyl-1 - ((2,2-dimethyl-1,3-dioxolane-4- yl) methyl) -1H-indol-5-yl) -1- (2,2-dideouterobenzo [d] [1,3] dioxol-5-yl) cyclopropanecarboxamide (24 mg, 49% from 1- (3,4-dihydroxyphenyl) ) methyl cyclopropanecarboxylate). MS (ESI) m / e (M + H +) 493.5.

<img file="PL2674428T3_D0364.tif" />

(R) -N- (2-tert-butyl-1- (2,3-dihydroxypropyl) -1H-indol-5-yl) -1- (2,2-dideutero-benzo [d] [1,3] dioxol- 5yl) cyclopropanecarboxamide [0560] To solution (R) -N- (2-tert-butyl-1 - ((2,2-dimethyl-1,3-dioxolan-4-yl) methyl) -1H-indol-5-yl) -1- (2,2-dideouterobenzo [d] [1,3] dioxol-5-yl) cyclopropanecarboxamide (24 mg, 0.050 mmol) in methanol (0.5 mL) and water (0.05 mL) added 4-methylbenzenesulfonic acid (2.0 mg, 0.010 mmol).

313

The mixture was heated at 80 ° C for 30 minutes. The reaction mixture was partitioned between EtOAc and water. The aqueous layer was extracted twice with EtOAc and the combined organic layers were washed with saturated NaHCO solution₃ and brine, then dried over magnesium sulfate. After removal of the solvent, the residue was purified by preparative HPLC to afford (12 mg, 52%).¹1 H NMR (400 MHz, CDCl₃) δ 7.44 (d, J = 2.0 Hz, 1H), 7.14 (dd, J = 22.8, 14.0 Hz, 2H), 6, 95-6, 89 (m, 2H) , 6.78 (d, J = 7.8

Hz, 1H), 6.14 (s, 1H), 4.28 (dd, J = 15.1, 8.3Hz, 1H), 4.19 (dd, J = 15.1, 4.5 Hz, 1H), 4.05 (q, J = 7.1 Hz, 1H), 3.55 (dd, J = 11.3, 4.0 Hz, 1H), 3.45 (dd, J = 11.3, 5.4 Hz, 1H),

1.60 (q, J = 3.5 Hz, 2H), 1.35 (s, 9H), 1.02 (q, J = 3.5 Hz, 2H). ¹³C NMR (400 MHz, CDCl₃) δ 171.4, 149, 3, 147, 1, 146, 5,

134,8, 132,3, 129,2, 126,5, 123,6 , 114,3, 111,4, 110,4,

109, 0, 107, 8, 98.5, 70.4, 63, 1, 46, 6, 31, 6, 30, 0, 29, 8, 15, 3. MS (ESI) m / e (M + H +) 453.5.

[0561] It should further be noted that the mono-deuterated analogue of this compound can be synthesized by substitution with the CHDBR reagent₂ instead of the CD reagent₂BR₂ and by following the procedures described in Example 74. In addition, deuterated analogs of these compounds as described herein, for example of formula I, can be prepared using known synthetic methods such as the methods described herein. Deuterated analogs include both di- and mono-deuterated analogs of the compounds of the present invention. Di- and mono-deuterated analogues of the compounds show measurable activity when tested using the tests described below.

314

Example 75: 4- (5- (1- (benzo [d] [1,3] dioxol-5-yl) cyclopropanecarboxamido) -1H-indol-2-yl) -4-methylpentanoic acid [0562]

<img file="PL2674428T3_D0365.tif" />

1- (benzo [d] [1,3] dioxol-5-yl) -N- (2- (4-cyano-2-methylbutan-2-yl) -1H-indol-5-yl) cyclopropanecarboxamide [0563] To acid 1- (benzo [d] [1,3] dioxol-5-yl) cyclopropanecarboxylic acid (0.068 g, 0.33 mmol) thionyl chloride (72 µL, 0.99 mmol) and DMF (20 µL) were added at room temperature. The mixture was stirred for 30 minutes, after which excess thionyl chloride was evaporated under reduced pressure. Dichloromethane (0.5 mL) was added to the obtained acid chloride, and Et₃N (230 pl, 1.7 mmol). To a solution of the acid chloride was added a solution of 4- (5-amino-1Hindol-2-yl) -4-methylpentanenitrile (0.33 mmol) in dichloromethane (0.5 mL) and stirred at room temperature for 1.5 hours. The resulting mixture was diluted with dichloromethane, washed with 1 N HCl (2 x 2 mL), saturated aqueous NaHCO solution₃(2 x 2 ml) and brine (2 x 2 ml). The organic layer was dried over anhydrous Na₂SO₄ and

315 evaporated under reduced pressure to give 1- (benzo [d] [1,3] dioxol-5-yl) -N- (2- (4-cyano-2-methylbutan-2-yl) 1H-indol-5-yl ) cyclopropanecarboxamide.

<img file="PL2674428T3_D0366.tif" />

4- (5- (1- (benzo [d] [1,3] dioxol-5-yl) cyclopropanecarboxamido) -1H-indol-2-yl) -4-methylpentanoic acid [0564] A mixture of 1- (benzo [d ] [1,3] dioxol-5-yl) -N- (2- (4-cyano-2-methylbutan-2-yl) -1H-indol-5-yl) cyclopropanecarboxamide (0.060 g, 0.15 mmol) and KOH (0.081 g, 1.5 mmol) in 50% ethanol / water (2 ml), heated in a microwave reactor at 100 ° C for 1 hour. The solvent was evaporated under reduced pressure. The crude product was dissolved in DMSO (1 mL), filtered and purified by preparative reverse phase HPLC to give 4- (5- (1- (benzo [d] [1,3] dioxol-5-yl) cyclopropanecarboxamido) -1H- acid indol-2-yl) -4metylopentanowy. ¹H NMR (400 MHz, DMSO-d₆) δ 11.98 (s, 1H), 10.79 (s, 1H), 8.44 (s, 1H), 7.56 (s, 1H), 7.15 (d, J = 8.6

Hz, 1H), 7.03-6, 90 (m, 4H), 6.05 (s, 1H), 6.02 (s, 2H), 1.971.87 (m, 4H), 1.41-1 , 38 (m, 2H), 1.30 (s, 6H), 1.04-1.02 (m,

2H).

Example 76: 1- (benzo [d] [1,3] dioxol-5-yl) -N- (2- (1-hydroxypropan-2-yl) -1H-indol-5-yl) cyclopropanecarboxamide [0565]

316

<img file="PL2674428T3_D0367.tif" />

2- (5-nitro-1H-indol-2-yl) propan-1-ol [0566] To a cooled LiAlH solution₄ (1.0 M in THF, 1.2 mL, 1.2 mmol) in THF (5.3 mL) at 0 ° C, a solution of 2- (5-nitro-1H-indol-2- acid ethyl ester) was added propane (0.20 g, 0.76 mmol) in THF (3.66 mL). After the addition, the mixture was allowed to warm to room temperature and stirred at room temperature for 3 hours. The mixture was cooled to 0 ° C. Water (2 ml) was slowly added followed by careful addition of 15% NaOH (2 ml) and water (4 ml). The reaction mixture was stirred at room temperature for 0.5 hours and then filtered through a short pad of celite using ethyl acetate. The organic layer was separated from the aqueous layer, dried over Na₂SO₄, filtered and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / hexane = 1/1) to give 2- (5-nitro-1H-indol-2-yl) propan-1-ol (0.14 g, 81%).

<img file="PL2674428T3_D0368.tif" />

317

2- (5-Amino-1H-indol-2-yl) propan-1-ol [0567] For a solution of 2- (5-nitro-1H-indol-2-yl) propan-1-ol (0.13 g , 0.60 mmol) in ethanol (5 mL) tin chloride dihydrate (0.67 g, 3.0 mmol) was added. The mixture was heated in a microwave reactor at 120 ° C for 1 hour. The mixture was diluted with ethyl acetate, then water and saturated aqueous NaHCO solution were added₃. The reaction mixture was filtered through a Celite pad using ethyl acetate. The organic layer was separated from the aqueous layer, dried over Na₂SO₄, filtered and evaporated under reduced pressure to give 2- (5 amino-1H-indol-2-yl) propan-1-ol (0.093 g, 82%).

<img file="PL2674428T3_D0369.tif" />

1- (benzo [d] [1,3] dioxol-5-yl) -N-2- (1-hydroxypropan-2-yl) 1H-indol-5-yl) cyclopropanecarboxamide [0568] For acid solution 1- (benzo [d] [1,3] dioxol-5-yl) cyclopropanecarboxylic acid (0.10 g, 0.49 mmol) in acetonitrile (2.0 mL), HBTU (0.185 g, 0.49 mmol) and Et were added₃N (205 pl, 1.47 mmol) at room temperature. The mixture was stirred at room temperature for 10 minutes after which a suspension of 2- (5-amino-1H-indol-2-yl) propan-1ol (0.093 g, 0.49 mmol) in acetonitrile (2.7 mL) was added. After the addition, the reaction mixture was stirred at room temperature for 5.5 hours. The solvent was evaporated under reduced pressure, and the residue was dissolved in dichloromethane. The organic layer was washed with 1 N HCl (3 x 1 mL) and saturated aqueous NaHCO₃ (1 x 3 ml). The organic layer was dried over Na₂SO₄, filtered and evaporated under

318 reduced pressure. The crude material was purified by silica gel column chromatography (ethyl acetate / hexane = 13/7) to give 1- (benzo [d] [1,3] dioxol-5-yl) -N- (2- (1-hydroxypropan-2 -yl) -1H-indol-5-yl) cyclopropanecarboxamide (0.095 g, 51%). these NMR (400 MHz, DMSO-d6) δ 10.74 (s, 1H), 8.38 (s, 1H), 7.55 (s, 1H), 7.14 (d, J = 8.6 Hz , 1H), 7.02-6, 90 (m, 4H), 6.06 (s, 1H), 6.02 (s, 2H), 4.76 (t, J = 5.3 Hz, 1H) , 3, 68-3, 63 (m, 1H), 3.503,44 (m, 1H), 2.99-2.90 (m, 1H), 1.41-1.38 (m, 2H), 1 , 26 (d,

J = 7.0 Hz, 3H), 1.05-1.02 (m, 2H).

Example 77: 1- (benzo [d] [1,3] dioxol-5-yl) -N- (2-tert-butyl1H-indol-5-yl) -N-methylcyclopropanecarboxamide [0569]

<img file="PL2674428T3_D0370.tif" />

1- (benzo [d] [1,3] dioxol-5-yl) -N- (2-tert-butyl-1H-indol-5-yl) -N-methylcyclopropanecarboxamide [0570] 2-tert-butyl-N-methyl -1H-indole-5-amine (20.2 mg,

0.100 mmol) and 1- (benzo [d] [1,3] dioxol-5-yl) cyclopropanecarboxylic acid (20.6 mg, 0.100 mmol) were dissolved in N, N-dimethylformamide (1 mL) containing triethylamine (42.1 µL, 0.300 mmol) and magnetic stirrer. O- (7-azabenzotriazol-1-yl) -N, N, N ', N'-tetramethyluronium hexafluorophosphate (42 mg, 0.11 mmol) was added to the mixture, and the resulting solution was stirred for 16 hours at&gt; 0 ° C. The crude product was purified by method

HPLC using a 0-99% gradient in water containing preparative acetonitrile water temperature

0.05% acid

319 trifluoracetic acid to give 1- (benzo [d] [1,3] dioxol-5-yl) -N- (2-tert-butyl-1H-indol-5-yl) -N-methylcyclopropanecarboxamide. ESI-MS mi / z calculated 390.2, found 397.3 (M + 1) +. Retention time 3.41 minutes.

Example 78: N- (2-tert-butyl-1-methyl-1H-indol-5-yl) -1 (benzo [d] [1,3] dioxol-6-yl) -N-methylcyclopropanecarboxamide [0571]

<img file="PL2674428T3_D0371.tif" />

[0572] Sodium hydride (0.028 g, 0.70 mmol, 60% by weight dispersion in oil) was slowly added to a stirred solution of N- (2-tert-butyl-1H-indol-5-yl) -1- (benzo [d] [ 1,3] dioxol-6-yl) cyclopropanecarboxamide (0.250 g, 0.664 mmol) in a mixture of 4.5 mL anhydrous tetrahydrofuran (THF) and 0.5 mL anhydrous N, N-dimethylformamide (DMF). The resulting suspension was stirred for 2 minutes and then iodomethane (0.062 mL, 1.0 mmol) was added to the reaction mixture. Two additional aliquots of sodium hydride and iodomethane were required to react all the starting material, which was monitored by LC / MS. The crude reaction product was evaporated to dryness, redissolved in a minimal amount of DMF and purified by preparative LC / MS to give pure product (0.0343 g, 13%), ESI-MS m / z calc. 404.2, found 405.3 (M + 1) +. Retention time 3.65 minutes.

320

Example 79: 1- (benzo [d] [1,3] dioxol-5-yl) -N- (2- (hydroxymethyl) -1H-indol-5-yl) cyclopropanecarboxamide [0573]

<img file="PL2674428T3_D0372.tif" />

[0574] Ethyl 5- (1- (benzo [d] [1,3] dioxol-5-yl) cyclopropanecarboxamido) -1H-indole-2-carboxylate (1.18 g, 3.0 mmol) was added to the LiBH solution₄ (132 mg, 6.0 mmol) in THF (10 mL) and water (0.1 mL). The mixture was allowed to stir for 16 hours at 25 ° C, then the reaction was stopped with water (10 ml) and slowly acidified by the addition of 1 N HCl. The mixture was extracted with three 50 mL portions of ethyl acetate. The organic extracts were dried over Na₂SO₄ and evaporated to give 1- (benzo [d] [1,3] dioxol-5-yl) -N- (2- (hydroxymethyl) -1H-indol-5-yl) cyclopropanecarboxamide (770 mg, 73%) . A small amount was further purified by reverse phase HPLC. ESI-MS m / z calculated 350.4, found 351.3 (M + 1) +; retention time 2.59 minutes.

Example 80: 5- (1- (benzo [d] [1,3] dioxol-5-yl) cyclopropane carboxamido) -N-tert-butyl-1H-indole-2-carboxamide [0575]

<img file="PL2674428T3_D0373.tif" />

321 5- (1- (benzo [d] [1,3] dioxol-5-yl) cyclopropanecarboxamido) -1H-indole-2-carboxylic acid [0576] 5- (1- (benzo [d] [1,3] dioxol- Ethyl 5-cyclopropanecarboxamido) -1H-indole-2-carboxylate (392 mg, 1.0 mmol) and LiOH (126 mg, 3 mmol) were dissolved in

H₂O (5 ml) and 1,4-dioxane (3 ml). The mixture was heated in an oil bath at 100 ° C for 24 hours and then cooled to room temperature. The mixture was acidified with 1N HCl solution and extracted with three 20 ml portions of dichloromethane. The organic extracts were dried over Na₂SO₄and evaporated to give 5- (1- (benzo [d] [1,3] dioxol-5-yl) cyclopropanecarboxamido) -1H-indole-2-carboxylic acid (302 mg acid, 83%). A small amount was further purified by reverse phase HPLC. ESIMS mi / z calculated 364.1, found 365.1 (M + 1) +; retention time 2.70 minutes.

<img file="PL2674428T3_D0374.tif" />

5- (1- (benzo [d] [1,3] dioxol-5-yl) cyclopropanecarboxamido) N-tert-butyl-1H-indole-2-carboxamide [0577] 5- (1- (benzo [d] acid [1,3] dioxol-5-yl) cyclopropanecarboxamido) -1H-indole-2-carboxylic acid (36 mg, 0.10 mmol) and 2-methylpropane-2-amine (8.8 mg, 0.12 mmol) were dissolved in N, N-dimethylformamide (1.0 mL) containing triethylamine (28 pL, 0.20 mmol). O- (7-azabenzotriazol-1-yl) Ν, Ν, Ν ', Ν'-tetramethyluronium hexafluorophosphate (46 mg, 0.12 mmol) was added to the mixture, and the resulting solution was stirred for 3 hours. Then the mixture

322 filtered and purified by reverse phase HPLC to give 5- (1- (benzo [d] [1,3] dioxol-5-yl) cyclopropanecarboxamido) -N-tert-butyl-1H-indole-2-carboxamide. ESI-MS m / z calculated 419.2, found 420.3 (M + 1) +; retention time 3.12 minutes.

Example 81: N- (3-amino-2-tert-butyl-1H-indol-5-yl) -1 (benzo [d] [1,3] dioxol-5-yl) cyclopropanecarboxamide

<img file="PL2674428T3_D0375.tif" />

[0579] A solution of 1- (benzo [d] [1,3] dioxol-5-yl) -N- (2-tert-butyl-1H-indol-5-yl) cyclopropanecarboxamide (50 mg, 0.13 mmol) was dissolved in AcOH (2 mL) and heated to 45 ° C. A solution of NaNO2 (9 mg) in H2O (0.03 mL) was added to the mixture.

The mixture was stirred for 30 minutes at 45 ° C, then the precipitate was filtered off and washed with Et2O. This material was used in the next step without further purification. To the crude material, 1- (benzo [d] [1,3] dioxol-5-yl) -N- (2-tert-butyl-3-nitroso-1H-indol-5-yl) cyclopropanecarboxamide was added AcOH (2 mL) and Zn dust (5 mg). The mixture was stirred for 1 hour at room temperature. EtOAc and H2O were added to the mixture. The layers were separated and the organic layer was washed with a saturated aqueous NaHCO3 solution, dried over magnesium sulfate and concentrated under reduced pressure.

The residue was dissolved in DMF (1 mL) and purified by preparative HPLC. LCMS: m / z 392.3; retention time 2.18 min.

323

Example 82: 1- (benzo [d] [1,3] dioxol-5-yl) -N- (2-tert-butyl3- (methylsulfonyl) -1H-indol-5-yl) cyclopropanecarboxamide

<img file="PL2674428T3_D0376.tif" />

1- (benzo [d] [1,3] dioxol-5-yl) -N- (2-tert-butyl-3- (methylsulfonyl) -1H-indol-5-yl) cyclopropanecarboxamide [0581] For solution 1- ( benzo [d] [1,3] dioxol-5-yl) -N- (2-tert-butyl-1H-indol-5-yl) cyclopropanecarboxamide (120 mg, 0.31 mmol) in anhydrous DMF-THF (3.3 ml, 1: 9) NaH (60% in mineral oil, 49 mg, 1.2 mmol) was added at room temperature. After 30 min under nitrogen, the suspension was cooled to -15 ° C and a solution of methanesulfonyl chloride (1.1 eq) in DMF (0.5 mL) was added dropwise. The reaction mixture was stirred for 30 minutes at -15 ° C and then for 6 hours at room temperature. At 0 ° C water (0.5 ml) was added, the solvent removed and the residue diluted with MeOH, filtered and purified by preparative HPLC to give 1- (benzo [d] [1,3] dioxol-5-yl) -N- (2 tert-butyl-3- (methylsulfonyl) -1H-indol-5-yl) cyclopropanecarboxamide

NMR (400 MHz, DMSO) δ 11.6 (s, 1H), 8.7 (s, 1H), 7.94 (d, J =

1.7 Hz, 1H), 7.38 (d, J = 8.7 Hz, 1H), 7.33 (dd, J1 = 1.9

Hz, J2 = 8.7 Hz, 1H), 7.03 (d, J = 1.7 Hz, 1H), 6.95 (dd, J1 =

1.7 Hz, J2 = 8.0 Hz, 1H), 6.90 (d, J = 8.0 Hz, 1H), 6.02 (s,

2H), 3.07 (s, 3H), 1.56-1.40 (m, 9H), 1.41 (dd, J1 = 4.0 Hz,

J2 = 6.7 Hz, 2H), 1.03 (dd, J1 = 4.0 Hz, J2 = 6.7 Hz, 2H). MS (ESI) m / e (M + H +) 455.5.

324

Example 83: 1- (benzo [d] [1,3] dioxol-5-yl) -N- (3-phenyl-1Hindol-5-yl) cyclopropane carboxamide [0582]

<img file="PL2674428T3_D0377.tif" />

1- (benzo [d] [1,3] dioxol-5-yl) -N- (3-bromo-1H-indol-5-yl) cyclopropanecarboxamide [0583] Freshly recrystallized N-bromosuccinimide (0.278 g, 1.56 mmol) added in portions to a solution of 1 (benzo [d] [1,3] dioxol-5-yl) -N- (1H-indol-5-yl) cyclopropanecarboxamide (0.500 g, 1.56 mmol) in N, N-dimethylformamide (2 mL) in within 2 minutes. The mixture was protected from light and stirred for 5 minutes. The resulting green solution was poured into 40 ml of water. The gray precipitate was filtered off and washed with water to give 1- (benzo [d] [1,3] dioxol-5-yl) -N- (3-bromo-1H-indol-5-yl) cyclopropanecarboxamide (0.564 g, 91% ). ESI-MS m / z calculated 398.0, found 399.3 (M + 1) +. Retention time 3.38 minutes.¹H NMR (400 MHz, DMSO-d₆) 11.37 (s, 1H), 8.71 (s, 1H), 7.67 (d, J = 1.8 Hz, 1H), 7.50 (d, J = 2.6 Hz, 1H) , 7.29 (d, J = 8.8 Hz, 1H), 7.22 (dd, J = 2.0, 8.8 Hz, 1H), 7.02 (d,

J = 1.6 Hz, 1H), 6.96-6.88 (m, 2H), 6.03 (s, 2H), 1.43-1.40 (m, 2H), 1.09-1 , 04 (m, 2H).

<img file="PL2674428T3_D0378.tif" />

325

1- (benzo [d] [1,3] dioxol-5-yl) -N- (3-phenyl-1H-indol-5-yl) cyclopropanecarboxamide [0584] Phenylboronic acid (24.6 mg, 0.204 mmol) was added to the solution 1- (benzo [d] [1,3] dioxol-5-yl) -N- (3-bromo-1H-indol5-yl) cyclopropanecarboxamide (39.9 mg, 0.100 mmol) in ethanol (1 mL) containing FibreCAT 1001 (6 mg) and 1 M aqueous potassium carbonate solution (0.260 ml). The reaction mixture was then heated at 130 ° C in a microwave reactor for 20 minutes. The crude product was purified by preparative HPLC acetonitrile in trifluoracetic water to give il) -N- (3-phenyl-1H-indol-5ESI-MS m / z calc. 396.2,

<td>retention</td><td> 3,52</td><td>₁minutes. ¹H</td><td>NMR</td>

<td>= 1.9 Hz,</td><td>1H)</td><td>, 8.66 (s,</td><td>1H),</td>

<td>7.61 (m,</td><td>3H);</td><td> 7,46-7,40</td><td>(M,</td>

<td> 7,25-7,17</td><td>(M,</td><td>2H), 7.03</td><td>(D,</td>

<td>2H), 6.02</td><td>(S,</td><td>2H), 1.43-</td><td> 1,39</td>

using a 0-99% gradient containing 0.05% acid by 1- (benzo [d] [1,3] dioxol-5-yl) cyclopropane carboxamide. found 397.3 (M + 1) +. Time (400 MHz, DMSO-ak) δ 11.27 (d, J

8.08 (d, J = 1.6 Hz, 1H), 7.652H), 7.31 (d, J = 8.7 Hz, 1H),

J = 1.6 Hz, 1H), 6.98-6.87 (m, (m, 2H), 1.06-1.02 (m, 2H).

Example 84: 1- (benzo [d] [1,3] dioxol-5-yl) -N- (2-tert-butyl-3-cyano-1H-indol-5-yl) cyclopropanecarboxamide

<img file="PL2674428T3_D0379.tif" />

326

1- (benzo [d] [1,3] dioxol-5-yl) -N- (2-tert-butyl-3-formyl-1H-indol-5-yl) cyclopropane carboxamide [0586] POCl₃ (12 g, 80 mmol) was added dropwise to DMF (40 mL), the temperature was kept at -20 ° C. After the addition, the reaction mixture was allowed to warm to 0 ° C and stirred for 1 hour. 1 (benzo [d] [1,3] dioxol-5-yl) -N- (2-tert-butyl-1H-indol-5-yl) cyclopropanecarboxamide (3.0 g, 8.0 mmol) was added and the mixture was heated to 25 ° C. After stirring for 30 minutes, the reaction mixture was poured into ice and stirred for 2 hours. The mixture was then heated at 100 ° C for 30 minutes. The mixture was cooled and the precipitate was filtered off and washed with water. The solid was then dissolved in 200 mL of dichloromethane, and washed with 200 mL of saturated aqueous NaHCO solution₃. The organics were dried over Na₂SO₄ and evaporated to give 1- (benzo [d] [1,3] dioxol-5-yl) -N- (2-tert-butyl-3-methyl-1H-indol-5-yl) cyclopropane carboxamide (2 , 0 g, 61%). ESI-MS m / z calculated 404.5, found 405.5 (M + 1) +;

retention time 3.30 minutes. these NMR (400 MHz, DMSO-d₆) δ 11.48

<td>(s, 1H),</td><td> 10,</td><td>39 (s, 1H),</td><td> 8,72</td><td>(s, 1H), 8.21</td><td>(S,</td><td>1H), 7.35</td><td> -7,31</td>

<td>(m, 2H),</td><td> 7,</td><td>04-7,03 (m,</td><td>1H),</td><td>6, 97-6, 90 (m,</td><td>2H)</td><td>, 6.03 (s,</td><td>2H);</td>

<td>1.53 (s,</td><td>9H)</td><td> , 1,42-1,39</td><td>(M,</td><td>2H), 1.05-1.03</td><td>(m</td><td>, 2H).</td><td></td>

<img file="PL2674428T3_D0380.tif" />

((hydroxyimino) methyl) -1H-indol-5-yl) cyclopropanecarboxamide [0587] To a solution of 1- (benzo [d] [1,3] dioxol-5-yl) -N- (2-tert-butyl-3-formyl-1H indol-5-yl) cyclopropanecarboxamide

327 (100 mg, 0.25 mmol) in dichloromethane (5 mL) hydroxylamine hydrochloride (21 mg, 0.30 mmol) was added. After stirring for 48 h, the mixture was evaporated to dryness and purified by column chromatography (0-100% ethyl acetate / hexane) to give (Z) -1- (benzo [d] [1,3] dioxol-5-yl) N- (2-tert-butyl-3 - ((hydroxyimino) methyl) -1H-indol-5-yl) cyclopropanecarboxamide (81 mg, 77%). ESI-MS m / z calculated 419.5, found 420.5 (M + 1) +; retention time 3.42 minutes.^XH NMR (400 MHz, DMSO-d6) δ 10.86 (s, 0.5H), 10.55 (s, 0.5H), 8, 56-8.50 (m, 2H), 8.02 ( m, 1H), 7.24 -7.22 (m, 1H), 7.12-7.10 (m, 1H), 7.03 (m, 1H),

6, 96-6, 90 (m, 2H), 6.03 (s, 2H), 1.43 (s, 9H), 1.40-1.38 (m,

2H), 1.04-1.01 (m, 2H).

<img file="PL2674428T3_D0381.tif" />

1- (benzo [d] [1,3] dioxol-5-yl) -N- (2-tert-butyl-3-cyano-1Hindol-5-yl) cyclopropane carboxamide [0588] (Z) -1- (benzo [d] [1,3] dioxol-5-yl) -N- (2-tert-butyl-3 ((hydroxyimino) methyl) -1H-indol-5-yl) cyclopropanecarboxamide (39 mg, 0.090 mmol) was dissolved in acetic anhydride (1 mL) and heated to reflux for 3 hours. The mixture was cooled in an ice bath and the precipitate was filtered off and washed with water. The solid was dried under high vacuum to afford 1- (benzo [d] [1,3] dioxol-5-yl) -N- (2-tert-butyl-3-cyano-1H-indol-5-yl) cyclopropanecarboxamide. ESI-MS m / z calculated 401.5, found 402.5 (M + 1) +; retention time 3.70 minutes.^X1 H NMR

328

<td> (400</td><td>MHz, DMSO-d6)</td><td>δ 11.72 (s, 1H), 8.79</td><td>(s, 1H),</td><td> 7,79</td><td>(s</td>

<td>1H),</td><td>7.32 (m, 2H),</td><td>7.03-7,02 (m, 1H),</td><td> 6,95-6,89</td><td>(M,</td><td>2H)</td>

<td> 6,03</td><td>(s, 2H), 1.47</td><td>(s, 9H), 1.43-1.41 (m,</td><td>2H), 1.06</td><td> -1,04</td><td>(m</td>

<td>2H).</td><td></td><td></td><td></td><td></td><td></td>

Example 85: 1- (benzo [d] [1,3] dioxol-5-yl) -N- (2-tert-butyl3-methyl-1H-indol-5-yl) cyclopropanecarboxamide

<img file="PL2674428T3_D0382.tif" />

[0590] A solution of 1- (benzo [d] [1,3] dioxol-5-yl) -N- (2-tert-butyl-1H-indol-5-yl) cyclopropanecarboxamide (75 mg, 0.20 mmol) and iodomethane (125 µL, 2.0 mmol) in N, N-dimethylformamide (1 mL) was heated at 120 ° C in a sealed tube for 24 hours. The reaction mixture was filtered and purified by reverse phase HPLC. ESI-MS m / z calculated 390.5, found 397.3 (M + 1) +; retention time 2.04 minutes.¹H NMR (400 MHz, DMSOd6) δ 10.30 (s, 1H), 8.39 (s, 1H), 7.51 (m, 1H), 7.13-7.11 (m, 1H), 7 , 03-6, 90 (m, 4H), 6.03 (s, 2H), 2.25 (s, 3H), 1,

40-1.38 (m, 11H), 1.03-1.01 (m, 2H).

Example 86: 1- (benzo [d] [1,3] dioxol-5-yl) -N- (2-tert-butyl3- (2-hydroxyethyl) -1H-indol-5-yl) cyclopropane carboxamide [0591]

<img file="PL2674428T3_D0383.tif" />

OH

329 [0592] About 100 µL of ethylene dioxide was condensed in the reaction tube at -78 ° C. A solution of 1 (benzo [d] [1,3] dioxol-5-yl) -N- (2-tert-butyl-1H-indol-5-yl) cyclopropanecarboxamide (200 mg, 0.50 mmol) and indium trichloride (20) was added. mg, 0.10 mmol) in dichloromethane (2 mL) and the reaction mixture was irradiated in a microwave reactor for 20 minutes at 100 ° C. Volatiles were removed and the residue was purified by column chromatography (0-100% ethyl acetate / hexane) to give 1- (benzo [d] [1,3] dioxol-5-yl) -N- (2-tert-butyl- 3- (2-hydroxyethyl) -1H-indol-5-yl) cyclopropanecarboxamide (5 mg, 3%). ESI-MS m / z calculated 420.5, 421.3 found (M + 1) +; retention time 1.67 minutes.¹H NMR (400 MHz, CD₃CN) δ 8.78 (s,

1H), 7.40 (m, 1H), 7.33 (s, 1H), 7.08 (m, 1H), 6, 95-6, 87 (m,

3H), 6.79 (m, 1H), 5.91 (s, 2H), 3.51 (dd, J = 5.9, 7.8 Hz,

2H), 2.92-2.88 (m, 2H), 2.64 (t, J = 5.8 Hz, 1H), 1.50 (m,

2H), 1.41 (s, 9H), 1.06 (m, 2H).

Example 87: 2- (5- (1- (benzo [d] [1,3] dioxol-5-yl) cyclopropanecarboxamido) -1H-indol-2-yl) acetic acid [0593]

<img file="PL2674428T3_D0384.tif" />

[0594] To a solution of ethyl 2- (5- (1- (benzo [d] [1,3] dioxol-5-yl) cyclopropanecarboxamido) -1H-indol-2-yl) acetate (0.010 g, 0.025 mmol) in THF ( 0.3 ml) LiOH H was added₂O (0.002 g, 0.05 mmol) and water (0.15 ml) added. The reaction mixture was stirred at room temperature for 2 hours. Dichloromethane (3 mL) and layer were added to the reaction mixture

330 the organic was washed with 1 N HCl (2 x 1.5 mL) and water (2 x 1.5 mL).

The organic layer was dried over Na₂SO₄ and filtered.

The filtrate was evaporated under reduced pressure to give 2- (5- (1- (benzo [d] [1,3] dioxol-5-yl) cyclopropanecarboxamido) -1H-indol-2-yl) acetic acid. ¹H NMR (400 MHz, DMSO-d6) δ 12.53 (s, 1H), 10.90 (s, 1H), 8.42 (s,

1H), 7.57 (s, 1H), 7.17 (d, J = 8.6 Hz, 1H), 7.05-6, 90 (m,

4H), 6.17 (s, 1H), 6.02 (s, 2H), 3.69 (s, 2H), 1.41-1.39 (m,

2H), 1.04-1.02 (m, 2H).

Example 88: 5- (1- (benzo [d] [1,3] dioxol-5-yl) cyclopropane carboxamido) -2-tert-butyl-1H-indole-7-carboxylic acid [0595]

<img file="PL2674428T3_D0385.tif" />

Methyl 5- (1- (benzo [d] [1,3] dioxol-5-yl) cyclopropane carboxamido) -2-tert-butyl-1H-indole-7-carboxylate (30 mg, 0.069 mmol) was dissolved in a mixture of 1,4-dioxane (1.5 ml) and water (2 ml) containing a magnetic stir bar and lithium hydroxide (30 mg, 0.71 mmol). The resulting solution was stirred at 70 ° C for 45 minutes. The crude product was then acidified with 2.6 M hydrochloric acid and extracted three times with an equivalent volume of dichloromethane. The dichloromethane extracts were combined, dried over sodium sulfate, filtered and evaporated to dryness. The residue was dissolved in a minimal amount of N, N-dimethylformamide and then purified by preparative HPLC using a gradient of 099% acetonitrile in water containing 0.05% acid

331 trifluoracetic acid to give 5- (1 (benzo [d] [1,3] dioxol-5-yl) cyclopropanecarboxamido) -2-tert-butyl-1H-indole-7-carboxylic acid. ESI-MS m / z calculated

434.2, found 435.5. Retention time 1.85 minutes.¹H NMR (400 MHz, DMSO-d6) δ 13.05 (s, 1H), 9.96 (d, J = 1.6 Hz, 1H), 7.89 (d, J = 1.9 Hz, 1H ), 7.74 (d, J = 2.0 Hz, 1H), 7.02 (d,

J = 1.6 Hz, 1H), 6. 96-6. 88 (m, 2H), 6.22 (d, J = 2.3 Hz,

1H), 6.02 (s, 2H), 1.43-1.40 (m, 2H), 1.37 (s, 9H), 1.06-1.02 (m, 2H).

Example 89: 1- (benzo [d] [1,3] dioxol-5-yl) -N- (2-tert-butyl1- (1,3-dihydroxypropan-2-yl) -1ff-indol-5-yl) cyclopropanecarboxamide [0597]

<img file="PL2674428T3_D0386.tif" />

1- (benzo [d] [1,3] dioxol-5-yl) -N- (2-tert-butyl-1- (1,3-dihydroxypropan-2-yl) indolin-5-yl) cyclopropanecarboxamide [0598] 1 - (benzo [d] [1,3] dioxol-5-yl) -N- (2-tert-butylindolin-5-yl) cyclopropanecarboxamide (50 mg, 0.13 mmol) was dissolved in dichloroethane (0.20 mL) and 2 , 2-dimethyl-1,3-dioxan-5-one (0.20 ml). Trifluoracetic acid (0.039 ml) was added and the resulting solution was stirred for

332 minutes. Sodium triacetoxyborohydride (55 mg, 0.26 mmol) was added and the reaction mixture was stirred for 30 minutes. The crude reaction mixture was then evaporated to dryness, dissolved in N, N-dimethylformamide and purified by preparative HPLC using a gradient of 0-99% acetonitrile in water containing 0.05% trifluoracetic acid.

<img file="PL2674428T3_D0387.tif" />

1- (benzo [d] [1,3] dioxol-5-yl) -N- (2-tert-butyl-1- (1,3-dihydroxypropan-2-yl) -1H-indol-5-yl) cyclopropanecarboxamide [0599] 1- (benzo [d] [1,3] dioxol-5-yl) -N- (2-tert-butyl-1- (1,3-dihydroxypropan-2-yl) indolin-5-yl) cyclopropanecarboxamide (40.3 mg , 0.0711 mmol as the trifluoracetic acid salt) was dissolved in toluene (1 mL). 2,3,5,6-tetrachlorocyclohexa2,5-diene-1,4-dione (35 mg, 0.14 mmol) was added to the resulting solution. The resulting suspension was heated at 100 ° C in an oil bath for 10 minutes. The crude product was then evaporated to dryness, dissolved in 1 ml of N, N-dimethylformamide and purified by preparative HPLC using a gradient of 0-99% acetonitrile in water containing 0.05% trifluoracetic acid to give 1- (benzo [d] [1 , 1,3] dioxol-5-yl) -N- (2-tert-butyl-1- (1,3-dihydroxypropan-2-yl) -1H-indol-5-yl) cyclopropanecarboxamide ESI-MS mi / z calc.

450.2, found 451.5 (M + 1) +. Retention time 1.59 minutes.

333

Example 90: N- (7- (aminomethyl) -2-tert-butyl-1ff-indol-5-yl) -1- (benzo [d] [1,3] dioxol-5-yl) cyclopropanecarboxamide [0600]

<img file="PL2674428T3_D0388.tif" />

N- (7- (aminomethyl) -2-tert-butyl-1H-indol-5-yl) -1 (benzo [d] [1,3] dioxol-5-yl) cyclopropanecarboxamide [0601] 1- (benzo [ d] [1,3] dioxol-5-yl) -N- (2-tert-butyl-7-cyano-1H-indol-5-yl) cyclopropanecarboxamide (375 mg, 0.934 mmol) was dissolved in 35 mL of ethyl acetate. The solution was passed through a continuous stream from a hydrogenation reactor containing 10% palladium on carbon at 100 ° C and 100 bar hydrogen for 8 hours. The crude product was evaporated to dryness and the residue was purified on 12 g silica gel using a gradient of 0-100% ethyl acetate (containing 0.5% triethylamine) in hexanes to give N- (7- (aminomethyl) -2-tert-butyl-1H-indole -5-yl) -1 (benzo [d] [1,3] dioxol-5-yl) cyclopropanecarboxamide (121 mg, 32%). ESI-MS m / z calculated 405.2, found 406.5 (M + 1) +. Retention time 1.48 minutes.

Example 91: 5- (1- (benzo [d] [1,3] dioxol-5-yl) cyclopropane carboxamido) -2-tert-butyl-1H-indole-7-carboxamide

<img file="PL2674428T3_D0389.tif" />

334

5- (1- (benzo [d] [1,3] dioxol-5-yl) cyclopropanecarboxamido) 2-tert-butyl-1H-indole-7-carboxamide [0603] 1- (benzo [d] [1,3 ] dioxol-5-yl) -N- (2-tert-butyl-7-cyano-1H-indol-5-yl) cyclopropanecarboxamide (45 mg, 0.11 mmol) was suspended in a mixture of methanol (1.8 mL), 30% aqueous hydrogen peroxide (0.14 mL, 4.4 mmol) and 10% aqueous sodium hydroxide (0.150 mL). The resulting suspension was stirred for 72 hours at room temperature. The action of hydrogen peroxide was discontinued with sodium sulfite. The reaction mixture was diluted with 0.5 mL of N, N-dimethylformamide, filtered and purified by preparative HPLC using a gradient of 0-99% acetonitrile in water containing 0.05% trifluoracetic acid to give 5- (1- (benzo [d] [ 1,3] dioxol-5-yl) cyclopropane-carboxamido) -2-tert-butyl-1 H-indole-7-carboxamide. ESI-MS m / z calculated 419.2, found 420.3 (M + 1) +. Retention time 1.74 minutes.

Example 92: 1- (benzo [d] [1,3] dioxol-5-yl) -N- (2-tert-butyl7- (methylsulfonamide-methyl) -1H-indol-5-yl) cyclopropane carboxamide [0604]

<img file="PL2674428T3_D0390.tif" />

1- (benzo [d] [1,3] dioxol-5-yl) -N- (2-tert-butyl-7 (methylsulfonamidomethyl) -1H-indol-5-yl) cyclopropanecarboxamide

335 [0605] N- (7- (aminomethyl) -2-tert-butyl-1H-indol-5-yl) -1 (benzo [d] [1,3] dioxol-5-yl) cyclopropanecarboxamide (20 mg, 0.049 mmol) was dissolved in DMF (0.5 mL) containing triethylamine (20.6 µL, 0.147 mmol) and a magnetic stirrer. Methanesulfonyl chloride (4.2 mL, 0.054 mmol) was added to the reaction mixture. The reaction mixture was allowed to stir for 12 h at room temperature. The crude product was purified by preparative HPLC using a 0-99% gradient of acetonitrile in water containing 0.05% trifluoracetic acid to give 1- (benzo [d] [1,3] dioxol-5-yl) -N- (2-tert -butyl-7- (methylsulfonamidomethyl) -1H-indol-5-yl) cyclopropanecarboxamide ESI-MS m / z calcd. 483.2, found 484.3 (M + 1) +. Retention time 1.84 minutes.

Example 93: N- (7- (acetamidomethyl) -2-tert-butyl-1H-indol-5-yl) -1- (benzo [d] [1,3] dioxol-5-yl) cyclopropanecarboxamide

<img file="PL2674428T3_D0391.tif" />

[0607] N- (7- (aminomethyl) -2-tert-butyl-1H-indol-5-yl) -1 (benzo [d] [1,3] dioxol-5-yl) cyclopropanecarboxamide (20 mg, 0.049 mmol) was dissolved in DMF (0.5 mL) containing triethylamine (20.6 µL, 0.147 mmol) and a magnetic stirrer. Acetyl chloride (4.2 µL, 0.054 mmol) was added to the reaction mixture. The reaction mixture was allowed to stir for 16 h at room temperature. The crude product was purified by preparative HPLC using a gradient of 099% acetonitrile in water containing 0.05% acid

336 trifluoracetic acid to give N- (7- (acetamidomethyl) -2-tert-butyl-1H-indol-5-yl) -1- (benzo [d] [1,3] dioxol-5-yl) cyclopropanecarboxamide ESI-MS m / z calcd. 447.2, found 448.3 (M + 1) +. Retention time 1.76 minutes.

Example 94: N- (1-acetyl-2-tert-butyl-1H-indol-5-yl) -1 (benzo [d] [1,3] dioxol-5-yl) cyclopropanecarboxamide

<img file="PL2674428T3_D0392.tif" />

To a solution of 1- (benzo [d] [1,3] dioxol-5-yl) -N- (2-tertbutyl-1H-indol-5-yl) cyclopropanecarboxamide (120 mg, 0.31 mmol) in anhydrous DMF-THF (3.3 mL, 1: 9) was added NaH (60% in mineral oil, 49 mg, 1.2 mmol) at room temperature.

After 30 minutes under nitrogen, the suspension was cooled to -15 ° C and a solution of acetyl chloride (1.1 eq) in DMF (0.5 mL) was added dropwise. The reaction mixture was stirred for 30 minutes at 15 ° C and then for 6 hours at room temperature. At 0 ° C water (0.5 mL) was added, the solvent removed and the residue diluted with MeOH, filtered and purified by preparative HPLC to give N- (1-acetyl-2-tert-butyl-1H-indol-5-yl) ) 1 (benzo [d] [1,3] dioxol-5-yl) cyclo-propanecarboxamide. ¹1 H NMR

<td>(400 MHz, DMSO) δ 8.9 (s, 1H), 7.74</td><td>(d, J = 2.1 Hz,</td><td>1H),</td><td> 7,54</td>

<td>(d, J = 9.0 Hz, 1H), 7.28 (dd, J1 =</td><td>2.1 Hz, J2 = 9.0</td><td>Hz,</td><td>1H),</td>

<td>7.01 (d, J = 1.5 Hz, 1H), 6.93 (dd,</td><td>J1 = 1.7 Hz, J2</td><td> = 8,</td><td>0 Hz</td>

<td>1H), 6.89 (d, J = 8.0 Hz, 1H), 6.54</td><td>(bs, 1H), 6.02</td><td>(S,</td><td>2H);</td>

<td>2.80 (s, 3H), 1.42-1.40 (m, 11H), 1,</td><td>06-1.05 (m, 2H).</td><td>MS</td><td>(ESI)</td>

<td>m / e (M + H +) 419.3.</td><td></td><td></td><td></td>

337

Example 95: N- (1- (2-acetamidoethyl) -2-tert-butyl-6-fluoro-1H-indol-5-yl) -1- (2,2-difluorobenzo [d] [1,3] dioxol-5-yl ) cyclopropanecarboxamide

<img file="PL2674428T3_D0393.tif" />

N- (1- (2-aminoethyl) -2-tert-butyl-6-fluoro-1H-indol-5-yl) -1- (2,2-difluorobenzo- [d] [1,3] dioxol-5-yl) cyclopropanecarboxamide [0611] For a solution of 2- (2-tert-butyl-5- (1- (2,2-difluorobenzo [d] [1,3] dioxol-5-yl) cyclopropanecarboxamido) -6-fluoro-1H-indol-1-yl) ethylcarbamate tert-butyl (620 mg, 1.08 mmol) in CH₂cl₂ (8 ml) TFA (2 ml) was added. The reaction mixture was stirred at room temperature for 1.5 h and then neutralized with solid NaHCO₃. The solution was partitioned between layer H₂Oh and CH₂cl₂. The organic layer was dried over

MgSO₄, filtered and concentrated to give the product in ₁ cream solid form (365 mg, 71%). ¹H NMR (400 MHz, DMSO-G6) δ 8.38 (s, 1H), 7.87 (br s, 3H, NH3 +), 7.52 (s,

1H), 7.45-7.38 (m, 3H), 7.32 (dd, J

8.3, 1.5 Hz, 1H), 6.21

338

<td>(s, 1H), 4.46</td><td>(m, 2H), 3.02</td><td>(m, 2H),</td><td>1.46 (m,</td><td>2H), 1.41 (p</td>

<td>9H), 1.14 (m,</td><td>2H). HPLC time</td><td>retention</td><td>1.66 min,</td><td>10-99% CH3CN</td>

<td>analysis time 3</td><td colspan="2">min; ESI-MS 474.4 m / z</td><td>(M + H⁺).</td><td></td>

<img file="PL2674428T3_D0394.tif" />

N- (1- (2-acetamidoethyl) -2-tert-butyl-6-fluoro-1H-indol-5-yl) -1- (2,2-difluorobenzo [d] [1,3] dioxol-5-yl) cyclopropanecarboxamide [ 0612] To the solution N- (1- (2-aminoethyl) -2-tert-butyl-6-fluoro-1H-indol-5-yl) -1- (2,2-difluorobenzo- [d] [1,3] dioxol5 -yl) cyclopropanecarboxamide (47 mg, 0.10 mmol) and Et3N (28 pL, 0.20 mmol) in DMF (1 mL) added acetyl chloride (7.1 µL, 0.10 mmol). The reaction mixture was stirred at room temperature for 1 h before it was filtered and purified by reverse phase HPLC (10 - 99% CH3CN / H2O) to give N- (1- (2-acetamidoethyl) -2-tert-butyl-6 -fluoro-1Hindol-5-yl) -1- (2,2-difluorobenzo [d] [1,3] dioxol-5-yl) cyclopropanecarboxamide NMR (400 MHz, DMSO-d6). δ 8.35

<td>(S,</td><td>1H),</td><td> 8,15</td><td>(T,</td><td>J = 5.9 Hz, 1H),</td><td> 7,53</td><td>(s, 1H), 7.43-7.31</td>

<td>(M,</td><td>4H),</td><td> 6,17</td><td>(S,</td><td>1H), 4.22 (m, 2H)</td><td> ; 3,30</td><td>(m, 2H), 1.85 (s,</td>

<td>3H);</td><td> 1,47</td><td>(M,</td><td>2H)</td><td>, 1.41 (s, 9H),</td><td> 1,13 (</td><td>m, 2H). HPLC time</td>

retention 2.06 min, 10-99% CH3CN, 3 min analysis time; ESI-MS 516.4 m / z (M + H +).

Example 96: 1- (benzo [d] [1,3] dioxol-5-yl) -N- (2-tert-butyl1- (2-hydroxy-3-methoxy-propyl) -1H-indol-5-yl) cyclopropanecarboxamide

339 [0613]

<img file="PL2674428T3_D0395.tif" />

[0614] 1- (Benzo [d] [1,3] dioxol-5-yl) -N- (2-tert-butyl-1H-indol-5-yl) cyclopropanecarboxamide (320 mg, 0.84 mmol) was dissolved in the mixture consisting of anhydrous DMF (0.5 ml) and anhydrous THF (5 ml) under a nitrogen atmosphere. NaH (60% in mineral oil, 120 mg, 3.0 mmol) was added at room temperature. After 30 minutes of stirring, the reaction mixture was cooled to -15 ° C, after which a solution of epichlorohydrin (79 µL, 1.0 mmol) in anhydrous DMF (1 mL) was added dropwise. The reaction mixture was stirred for 15 minutes at -15 ° C, then for 8 hours at room temperature. MeOH (1 ml) was added and the reaction mixture was heated for 10 minutes at 105 ° C in a microwave. The mixture was cooled, filtered and purified by preparative HPLC to give 1- (benzo [d] [1,3] dioxol-5-yl) -N- (2-tert-butyl-1- (2-hydroxy-3-methoxy-propyl) -1Hindol-5-yl) cyclopropanecarboxamide NMR (400 MHz, DMSO-d6) δ

<td> 8,44</td><td>(S,</td><td>1H),</td><td> 7,59</td><td>(d, J = 1.9</td><td>Hz, 1H), 7.31 (d, J</td><td> = 8,9</td><td>Hz,</td>

<td>1H),</td><td> 7,03</td><td>(Dd,</td><td>J =</td><td>8.7, 1.9 Hz</td><td>, 2H), 6.95 (dd, J =</td><td> 8,0,</td><td> 1,7</td>

<td>Hz,</td><td>1H),</td><td> 6,90</td><td>(D,</td><td>J = 8.0 Hz,</td><td>1H), 6.16 (s, 1H),</td><td> 6,03</td><td>(S,</td>

<td>2H);</td><td> 4,33</td><td>(Dd,</td><td>J =</td><td>15.0, 4.0 Hz</td><td>, 1H), 4.19 (dd, J =</td><td> 15,0,</td><td> 8,1</td>

<td>Hz,</td><td>1H),</td><td> 4,02</td><td>(Ddd,</td><td>J = 8.7, 4,</td><td>8 Hz, 1H), 3.41-3.32</td><td>(M,</td><td>2H);</td>

<td> 3,30</td><td>(S,</td><td>3H);</td><td> 1,41</td><td colspan="2">(s, 9H), 1.41-1.38 (m, 2H), 1.03</td><td>(Dd,</td><td>J =</td>

6.7, 4.0 Hz, 2H). MS (ESI) m / e (M + H +) 465.0.

340

Example 97: 1- (benzo [d] [1,3] dioxol-5-yl) -N- (2-tert-butyl1- (2-hydroxy-3- (methylamino) propyl) -1H-indol- 5yl) cyclopropanecarboxamide [0615]

<img file="PL2674428T3_D0396.tif" />

[0616] 1- (benzo [d] [1,3] dioxol-5-yl) -N- (2-tert-butyl-1H-indol-5-yl) cyclopropanecarboxamide (320 mg, 0.84 mmol) was dissolved in the mixture consisting of anhydrous DMF (0.5 ml) and anhydrous THF (5 ml) under a nitrogen atmosphere. NaH (60% in mineral oil, 120 mg, 3.0 mmol) was added at room temperature. After 30 minutes of stirring, the reaction mixture was cooled to -15 ° C, after which a solution of epichlorohydrin (79 µL, 1.0 mmol) in anhydrous DMF (1 mL) was added dropwise. The reaction mixture was stirred for 15 minutes at 15 ° C, then for 8 h at room temperature. MeNH2 (2.0 M in MeOH, 1.0 mL) was added and the reaction mixture was heated for 10 minutes at 105 ° C in a microwave. The mixture was cooled, filtered and purified by preparative HPLC to give 1- (benzo [d] [1,3] dioxol-5-yl) -N- (2-tert-butyl-1- (2-hydroxy-3- (methylamino) ) propyl) 1H-indol-5-yl) cyclopropanecarboxamide NMR (400 MHz, DMSO-

<td>d6)</td><td>δ 8,</td><td>50 (s, 1H), 7</td><td> ,60-7,59</td><td>(M,</td><td>1H),</td><td> 7,35 (</td><td>dd, J.</td><td> = 14,3</td>

<td> 8,9</td><td>Hz,</td><td>1H), 7.10 (d,</td><td>J = 8.8</td><td>Hz,</td><td>1H)</td><td>, 1H),</td><td> 6,94 (</td><td>dd, J.</td>

<td> 8,0,</td><td> 1,6</td><td>Hz, 1H), 6.91</td><td>(d, J =</td><td> 7,9</td><td>Hz,</td><td>1H), 6,</td><td>20 (d,</td><td>J = 2,</td>

<td>Hz,</td><td>1H),</td><td>6.03 (s, 2H);</td><td>2.82 (d,</td><td>J =</td><td> 4,7</td><td>Hz, 1H)</td><td> , 2,72</td><td>(d, J</td>

4.7 Hz, 1H), 2.55 (dd, J

5.2, 5.2 Hz, 1H), 2.50 (s, 3H)

341

1.43 (s, 9H), 1.39 (dd, J = 6.4, 3.7 Hz, 2H), 1.04 (dd, J = 6.5, 3.9 Hz, 2H). MS (ESI) m / e (M + H +) 464.0.

Example 98: (S) -N- (1- (3-amino-2-hydroxypropyl) -2-tert-butyl-1H-indol-5-yl) -1- (2,2-difluorobenzo [d] [1,3 ] dioxol-5-yl) cyclopropanecarboxamide [0617]

<img file="PL2674428T3_D0397.tif" />

(R) -3- (2-tert-butyl-5- (1- (2,2-difluorobenzo [d] [1,3] dioxol-5-yl) cyclopropanecarboxamido) -1H-indol-1-yl) -2-hydroxypropyl 4-methylbenzenesulfonate [0618] For a mixed solution of (R) -N- (2-tert-butyl-1- (2,3-dihydroxypropyl) -1H-indol-5-yl) -1- (2,2-difluorobenzo [d] [1, 3] dioxol-5-yl) cyclopropanecarboxamide (3.0 g, 6.1 mmol) in dichloromethane (20 mL) added triethylamine (2 mL) and p-toluenesulfonyl chloride (1.3 g, 7.0 mmol). After 18 hours, the reaction mixture was partitioned between a layer of 10 mL water and 10 mL ethyl acetate. The organic layer was dried over magnesium sulfate, filtered and evaporated. The residue was purified by gel column chromatography

342 silica (0-60% ethyl acetate / hexane) to give (R) -3- (2-tert-butyl-5- (1- (2,2-difluorobenzo [d] [1,3] dioxol-5-yl) cyclopropanecarboxamido) 4-methylbenzenesulfonate) -1H-indol-1-yl) -2-hydroxypropyl (3.21 g, 86%). LC / MS (M + 1) = 641.2.¹1 H NMR

<td> (400</td><td>MHz,</td><td>CDCl.sub.3</td><td>) δ</td><td> 7,77</td><td>(d, 2H, J =</td><td>16 Hz)</td><td>, 7.55 (d,</td><td>1H, J = 2</td>

<td>Hz),</td><td> 7,35</td><td>(D,</td><td>2H,</td><td>J =</td><td>16 Hz), 7,</td><td>31 (m,</td><td>3H), 6.96</td><td>(s, 1H),</td>

<td> 6,94</td><td>(Dd,</td><td>1H, J</td><td> = 2</td><td> , 8</td><td>Hz), 6.22 (</td><td>s, 1H),</td><td>4.33 (m,</td><td>1H), 4.31</td>

<td>(Dd,</td><td>1H, J</td><td> = 6,</td><td> 15</td><td>Hz),</td><td>4.28 (dd,</td><td>1H, J =</td><td>11.15 Hz),</td><td>4.18 (m,</td>

<td>1H),</td><td> 3,40</td><td>(Dd,</td><td>1H,</td><td>J =</td><td>3, 6 Hz),</td><td colspan="2">3.36 (dd, 1H, J =</td><td>3.6 Hz),</td>

<td> 2,46</td><td>(S,</td><td>3H);</td><td> 2,40</td><td>(br</td><td>s, 1H), 1</td><td>, 74 (m,</td><td>2H), 1.40</td><td>(s, 9H),</td>

<td> 1,11</td><td colspan="2">(m, 2H).</td><td></td><td></td><td></td><td></td><td></td><td></td>

<img file="PL2674428T3_D0398.tif" />

(R) -N- (1- (3-azido-2-hydroxypropyl) -2-tert-butyl-1H-indol-5-yl) -1- (2,2-difluorobenzo [d] [1,3] dioxol- 5-yl) cyclopropanecarboxamide [0619] For a mixed solution of (R) 3- (2-tert-butyl-5- (1- (2,2-difluorobenzo [d] [1,3] dioxol-5-yl) cyclopropanecarboxamido) 4-methylbenzenesulfonate 1H-indol-yl) -2-hydroxypropyl (3.2 g, 5.0 mmol) in DMF (6 mL) was added sodium azide (2.0 g, 30 mmol). The reaction mixture was heated at 80 ° C for 2 hours. The mixture was partitioned between 20 mL ethyl acetate and 20 mL water. The layers were separated and the organic layer was evaporated. The residue was purified by column chromatography (0-85% ethyl acetate / hexane) to give (R) -N- (1- (3-azido-2-receiving)

343 hydroxypropyl) -2-tert-butyl-1H-indol-5-yl) -1- (2,2difluorobenzo [d] [1,3] dioxol-5-yl) cyclopropanecarboxamide

<td> (2,4</td><td>8 g)</td><td>^.</td><td>LC</td><td>/ MS (M + 1) = 512.5. ¹H</td><td>NMR</td><td>(400 MHz,</td><td>CDCl3) δ</td>

<td> 7,55</td><td>(D,</td><td colspan="2">1H,</td><td>J = 2 Hz), 7.31 (m, 3H),</td><td> 6,96</td><td>(s, 1H),</td><td>6.94 (dd,</td>

<td>1H,</td><td>J =</td><td> 2,</td><td> 8</td><td>Hz), 6.22 (s, 1H), 4.33</td><td>(M,</td><td>1H), 4.31</td><td>(dd, 1H, J</td>

<td> = 6,</td><td> 15</td><td>h</td><td> ),</td><td>4.28 (dd, 1H, J = 11, 15</td><td>Hz),</td><td>4.18 (m,</td><td>1H), 3.40</td>

<td>(Dd,</td><td>1H,</td><td>J</td><td> =</td><td>3, 6 Hz), 3.36 (dd, 1H, J</td><td> = 3,</td><td>6 Hz), 2,</td><td>40 (br s,</td>

<td>1H),</td><td> 1,7</td><td> 4</td><td>(m</td><td colspan="2">, 2H), 1.40 (s, 9H), 1.11 (m,</td><td>2H).</td><td></td>

<img file="PL2674428T3_D0399.tif" />

(S) -N- (1- (3-amino-2-hydroxypropyl) -2-tert-butyl-1H-indol-5-yl) -1- (2,2-difluoro-benzo [d] [1,3] dioxol-5-yl) cyclopropanecarboxamide [0620] To a mixed solution of (R) -N- (1- (3-azido-2-hydroxypropyl) -2-tert-butyl-1H-indol-5-yl) -1- (2,2-difluorobenzo [ d] [1,3] dioxol-5-yl) cyclopropanecarboxamide (2.4 g, 4.0 mmol) in MeOH (25 mL) was added 5% Pd / C (2.4 g) under a balloon filled with hydrogen gas. After 18 hours, the reaction mixture was filtered through celite and washed with 300 ml ethyl acetate. The organic layer was washed with 1 N HCl and evaporated to give (5) -N- (1- (3-amino-2-hydroxypropyl) 2-tert-butyl-1H-indol-5-yl) -1- (2,2- difluorobenzo [d] [1,3] dioxol-5-yl) cyclopropanecarboxamide (1.37 g).

MS (M + 1) = 486.5.

344

Example 99: 1,3- (2-tert-butyl-5- (1- (2,2-difluorobenzo [d] [1,3] dioxol-5-yl) cyclopropanecarboxamido) -1H-indol-1-yl) -2-hydroxypropylcarbamate (S ) -methyl

<img file="PL2674428T3_D0400.tif" />

[0622] For a mixed solution of (R) -N- (1- (3-amino-2-hydroxypropyl) -2-tert-butyl-1H-indol-5-yl) -1- (2,2-difluorobenzo [d] [1, 3] dioxol-5-yl) cyclopropanecarboxamide (0.10 g, 0.20 mmol) in methanol (1 mL) was added 2 drops of triethylamine and methyl chloroformform chloride (0.020 mL, 0.25 mmol). After 30 minutes, the reaction mixture was filtered and purified by reverse phase HPLC to provide 1,3- (2-tert-butyl-5- (1- (2,2-difluorobenzo [d] [1,3] dioxol-5-yl)) (cyclopropanecarboxamido) -1H-indol-1-yl) -2-hydroxypropylcarbamate (S) -methyl. The retention time over a three-minute analysis period is 1.40 min. LC / MS (M + 1) = 544.3.¹1 H NMR (400 MHz, CDCl₃) δ 7.52 (d, 1H, J = 2 Hz), 7.30 (dd, 1H, J = 2.8 Hz), 7.28 (m, 1H), 7.22 (d, 1H, J = 8 Hz),

7.14 (d, 1H, J = 8 Hz), 7.04 (br s, 1H), 6.97 (dd, 1H, J = 2.8

Hz), 6.24 (s, 1H), 5.19 (1H, br s), 4.31 (dd, 1H, J = 6.15

Hz), 4.28 (dd, 1H, J = 11.15 Hz), 4.18 (m, 1H), 3.70 (s, 3H),

3.40 (dd, 1H, J = 3.6 Hz), 3.36 (dd, 1H, J = 3, 6 Hz), 3.26 (m, 1H), 1.74 (m, 2H), 1.40 (s, 9H), 1.11 (m, 2H).

Example 100: 4- (5- (1- (benzo [d] [1,3] dioxol-5-yl) cyclopropanecarboxamido) -2-tert-butyl-1H-indol-1-yl) butanoic acid

345 [0623] ο

<img file="PL2674428T3_D0401.tif" />

1- (benzo [d] [1,3] dioxol-5-yl) -N- (2-tert-butylindolin-5-yl) cyclopropanecarboxamide [0624] For acid solution 1- (benzo [d] [1,3] dioxol -5-yl) -N- (2-tert-butyl-1H-indol-5-yl) cyclopropanecarboxamide (851 mg, 2.26 mmol) in acetic acid (60 ml) added NaBH₃CN (309 mg, 4.91 mmol) at 0 ° C. The reaction mixture was stirred for 5 minutes at room temperature after which no starting material was detected by LCMS. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (5-40% ethyl acetate / hexane) to obtain 1- (benzo [d] [1,3] dioxol-5-yl) -N- (2- tert-butylindolin-5-yl) cyclopropanecarboxamide (760 mg, 89%).

ABOUT

<img file="PL2674428T3_D0402.tif" />

OH 4- (5- (1- (benzo [d] [1,3] dioxol-5-yl) cyclopropanecarboxamido) -2-tert-butylindolin-1-yl) butanoic acid

346 [0625] To a solution of 1- (benzo [d] [1,3] dioxol-5-yl) -N- (2-tert-butylindolin-5-yl) cyclopropanecarboxamide (350 mg, 0.93 mmol, 1 equivalent) in anhydrous methanol (6.5 mL) and AcOH (65 µL) were added 4-oxobutanoic acid (15% in water, 710 mg, 1.0 mmol) at room temperature. After 20 minutes of mixing NaBH₃CN was added in one portion (130 mg, 2.0 mmol) and the reaction mixture was stirred for another 4 hours at room temperature. The reaction mixture was stopped by the addition of AcOH (0.5 mL) at 0 ° C and the solvent removed under reduced pressure. The residue was purified by silica gel column chromatography (5-75% ethyl acetate / hexane) to obtain 4-acid (5- (1- (benzo [d] [1,3] dioxol-5-yl) cyclopropanecarboxamido) -2-tert- butylindolin-1-yl) butane (130 mg,

30%).

<img file="PL2674428T3_D0403.tif" />

4- (5- (1- (benzo [d] [1,3] dioxol-5-yl) cyclopropanecarboxamido) -2-tert-butyl-1H-indol-1-yl) butanoic acid 4- (6) 5- (1- (benzo [d] [1,3] dioxol-5-yl) cyclopropanecarboxamido) -2-tert-butylindolin-1-yl) butane (130 mg, 0.28 mmol) was dissolved in acetonitrile-H₂O-TFA. The solvent was removed under reduced pressure and the obtained residue was dissolved in CDCl₃. After brief exposure to daylight (5-10 minutes), the solution turned purple. The reaction mixture was stirred with access

347 air at room temperature until complete disappearance of the starting material (8 hours). The solvent was removed under reduced pressure and the residue was purified by reverse phase HPLC to give 4- (5- (1 (benzo [d] [1,3] dioxol-5-yl) cyclopropanecarboxamido) -2-tert-butyl-1H-indol acid -1-yl) butanoic acid.¹H NMR (400 MHz, CDClp)

<td>δ 7,</td><td>52 (d,</td><td>J =</td><td colspan="2">1.9 Hz, 1H),</td><td> 7,18</td><td>(D,</td><td>J = 2</td><td>, 1Hz,</td><td>1H), 7.16 (</td><td>s</td>

<td>1H),</td><td> 7,03</td><td>(Dd,</td><td>J =</td><td> 9,4, 1,9</td><td>Hz,</td><td>1H),</td><td> 7,00</td><td> -6,98</td><td>(m, 2H), 6,</td><td> 85</td>

<td>(D,</td><td>J = 7,</td><td colspan="2">9 Hz, 1H</td><td> ), 6,16</td><td>(S,</td><td>1H),</td><td> 6,02</td><td>(S,</td><td>2H), 4.29-4,</td><td> 24</td>

<td>(M,</td><td>2H), 2</td><td> ,48</td><td>(Dd,</td><td>J = 6.9,</td><td> 6,9</td><td>Hz,</td><td>2H);</td><td> 2,12</td><td>-2.04 (m, 2H</td><td> ),</td>

<td> 1,69</td><td>(Dd,</td><td>J =</td><td> 6,8,</td><td>3.7 Hz</td><td>2H);</td><td> 1,43</td><td>(S,</td><td>9H)</td><td>1.09 (dd, J</td><td> =</td>

6.8, 3.7 Hz, 2H). MS (ESI) m / e (M + H +) 463.0.

Example 101: 1- (benzo [d] [1,3] dioxol-5-yl) -N- (2-tert-butyl-1- (4- (2-hydroxyethyl-amino) -4-oxobutyl) -1H-indole -5yl) cyclopropanecarboxamide [0627]

<img file="PL2674428T3_D0404.tif" />

[0628] For a solution of 4- (5- (1- (benzo [d] [1,3] dioxol-5-yl) cyclopropanecarboxamido) -2-tert-butyl-1H-indol-1-yl) butanoic acid (10 mg) in anhydrous DMF (0.25 mL) was added successively to Et3N (9.5 mL, 0.069 mmol) and HBTU (8.2 mg, 0.022 mmol). After stirring for 10 minutes at 60 ° C, ethanolamine (1.3 µL, 0.022 mmol) was added and the mixture was stirred for another 4 hours at 60 ° C. 1348 (benzo [d] [1,3] dioxol-5-yl) -N- (2-tert-butyl-1- (4- (2-hydroxyethyl-amino) -4-oxobutyl) -1H-indol-5-yl) cyclopropanecarboxamide (5.8 mg, 64%) was obtained after purification by preparative HPLC. MS (ESI) m / e (M + H +) 506.0.

Example 102: 1- (benzo [d] [1,3] dioxol-5-yl) -N- (2-tert-butyl-1- (2- (dimethylamino) -2-oxoethyl) -1H-indol-5-yl) cyclopropanecarboxamide

<img file="PL2674428T3_D0405.tif" />

[0630] To a solution of 1- (benzo [d] [1,3] dioxol-5-yl) -N- (2-tert-butylindolin-5-yl) cyclopropanecarboxamide (62 mg, 0.16 mmol) in anhydrous DMF (0 , 11 ml) and THF (1 ml) were added at room temperature under nitrogen NaH (60% in mineral oil, 21 mg, 0.51 mmol). After 30 minutes of stirring, the reaction mixture was cooled to 0 ° C and 2-chloro-N, N-dimethylacetamide (11 mL, 0.14 mmol) was added. The reaction mixture was stirred for 5 minutes at 0 ° C and then for 10 hours at room temperature. The mixture was purified by preparative HPLC and the resulting solid dissolved in DMF (0.6 mL) in the presence of Pd-C (10 mg). The reaction mixture was stirred in air overnight at room temperature. The reaction mixture was filtered and purified by preparative HPLC to ensure preparation

349

1- (benzo [d] [1,3] dioxol-5-yl) -N- (2-tert-butyl-1- (2- (dimethylamino) -2-oxoethyl) -1H-indol-5-yl) cyclopropanecarboxamide MS ( ESI) m / e (M + H +) 462.0.

Example 103: 3- (2-tert-butyl-5- (1- (2,2-difluorobenzo [d] [1,3] dioxol-5-yl) cyclopropanecarboxamido) -1H-indol-1-yl) propanoic acid [0631 ]

<img file="PL2674428T3_D0406.tif" />

α

N- (2-tert-butyl-1- (2-chloroethyl) indolin-5-yl) -1- (2,2-difluorobenzo [d] [1,3] dioxol-5-yl) cyclopropanecarboxamide [0632] For solution N - (2-tert-butyl-1- (2-cyanoethyl) indolin-5-yl) -1- (2,2-difluorobenzo [d] [1,3] dioxol-5-yl) cyclopropanecarboxamide (71 mg, 0.17 mmol ) in anhydrous dichloromethane (1 mL) was added chloroacetaldehyde (53 µL, 0.41 mmol) at room temperature under a nitrogen atmosphere. After 20 minutes of mixing, NaBH (OAc) was added in two portions.₃ (90 mg, 0.42 mmol). The reaction mixture was stirred overnight at room temperature. The product was purified by silica gel column chromatography (2-15% ethyl acetate / hexanes) to give N- (2-tert-butyl-1- (2350 chloroethyl) indolin-5-yl) -1- (2,2-difluorobenzo [d ] [1,3] dioxol-5-yl) cyclopropanecarboxamide (51 mg, 63%).

<img file="PL2674428T3_D0407.tif" />

N- (2-tert-butyl-1- (2-cyanoethyl) indolin-5-yl) -1- (2,2-difluorobenzo [d] [1,3] dioxol-5-yl) cyclopropanecarboxamide [0633] N- ( 2-tert-butyl-1- (2-chloroethyl) indolin-5-yl) -1 (2,2-difluorobenzo [d] [1,3] dioxol-5-yl) cyclopropanecarboxamide (51 mg), NaCN (16 mg, 0.32 mmol) and KI (cat) in EtOH (0.6 mL) and water (0.3 mL) were combined and heated at 110 ° C for 30 min in a microwave. The solvent was removed under reduced pressure, and the residue was purified by silica gel column chromatography (2-15% ethyl acetate / hexanes) to give N (2-tert-butyl-1- (2-cyanoethyl) indolin-5-yl) -1- (2,2-difluorobenzo [d] [1,3] dioxol-5-yl) cyclopropanecarboxamide (24 mg, 48%).

<img file="PL2674428T3_D0408.tif" />

3- (2-tert-butyl-5- (1- (2,2-difluorobenzo [d] [1,3] dioxol5-yl) cyclopropanecarboxamide) -1H-indol-1-yl) propanoic acid

351 [0634] N- (2-tert-butyl-1- (2-cyanoethyl) indolin-5-yl) -1 (2,2-difluorobenzo [d] [1,3] dioxol-5-yl) cyclopropanecarboxamide (24 mg, 0.050 mmol) was dissolved in 50% aqueous KOH (0.5 mL) and 1,4-dioxane (1 mL). The mixture was heated at 125 ° C for 2 hours. The solvent was removed and the residue was purified by preparative HPLC. The residue was dissolved in CDCl3 (1 mL) and then exposed to brief light. The purple solution thus formed was stirred until the disappearance of the starting material (1 hour). The solvent was removed under reduced pressure and the residue was purified by preparative HPLC to give 3- (2-tert-butyl-5- (1- (2,2-difluorobenzo [d] [1,3] dioxol-5-yl) cyclopropanecarboxamide) acid. ) -1H-indol-1-yl) propanoic acid. MS (ESI) m / e (M + H +) 485.0.

Example 104: 1- (benzo [d] [1,3] dioxol-5-yl) -N- (2-tert-butyl-6-fluoro-1- (2-hydroxy-ethyl) -1H-indol-5-yl) cyclopropanecarboxamide [0635]

<img file="PL2674428T3_D0409.tif" />

[0636] To a solution of 1- (benzo [d] [1,3] dioxol-5-yl) -N- (2-tert-butyl-6-fluoroindolin-5-yl) cyclopropanecarboxamide (340 mg, 0.86 mmol) in Anhydrous MeOH (5.7 mL) containing 1% acetic acid was added 40% glyoxal in water (0.60 mL, 5.2 mmol) at room temperature under a nitrogen atmosphere. After 20

352 minutes of mixing, NaBH was added in one portion₃CN (120 mg, 1.9 mmol) and the reaction mixture was stirred overnight at room temperature. The solvent was removed under reduced pressure and the obtained residue was purified by silica gel column chromatography (1040% ethyl acetate / hexane) to provide a light yellow oil which was treated with a 50/50 CH solution₃CN-H₂About 0.05% TFA and CDCl₃. The solvent was removed under reduced pressure, and the residue was purified by silica gel column chromatography (20-35% ethyl acetate / hexane) to obtain 1- (benzo [d] [1,3] dioxol-5-yl) -N- (2- tert-butyl-6-fluoro-1- (2-hydroxyethyl) -1H-indol-5-yl) cyclopropanecarboxamide NMR

<td>(400 MHz,</td><td>CDCl3) δ 8.02 (d, J = 7.7 Hz, 1H),</td><td> 7,30</td><td>(D,</td><td>J =</td>

<td colspan="2">2.1 Hz, 1H), 6.93 (dd, J = 1.6, 7.9 Hz, 1H), 6.90</td><td>(d</td><td>, J</td><td> = 1,6</td>

<td>Hz, 1H),</td><td>6.90 (d, J = 1.6 Hz, 1H), 6.78 (d, J =</td><td> 7,9</td><td>Hz,</td><td>1H),</td>

<td>6.08 (s,</td><td>1H), 5.92 (s, 2H), 4.21 (dd, J = 6.9,</td><td> 6,9</td><td>Hz,</td><td>2H);</td>

<td>3.68 (m,</td><td>2H), 2.28 (s, 1H), 1.60 (dd, J = 3.7,</td><td> 6,7</td><td>Hz,</td><td>2H);</td>

<td> 1,35-1,32</td><td>(m, 9H), 1.04 (dd, J = 3.7, 6.8 Hz,</td><td>2H).</td><td>MS</td><td>(ESI)</td>

m / e (M + H⁺) 439,0.

Example 105: 1- (benzo [d] [1,3] dioxol-5-yl) -N- (2-tert-butyl-6-fluoro-1- (3-hydroxy-propyl) -1H-indol-5-yl) cyclopropanecarboxamide

<img file="PL2674428T3_D0410.tif" />

353

3- (benzyloxy) propanal [0638] To a suspension of PCC (606 mg, 2.82 mmol) in anhydrous dichloromethane (8 mL) at room temperature under N2, a solution of 3-benzyloxy-1-propanol (310 mg, 1 , 88 mmol) in anhydrous dichloromethane. The reaction mixture was stirred overnight at room temperature, filtered through Celite and concentrated. The residue was purified by silica gel column chromatography (1-10% ethyl acetate / hexane) to obtain 3- (benzyloxy) propanal (243 mg,

<img file="PL2674428T3_D0411.tif" />

1- (benzo [d] [1,3] dioxol-5-yl) -N- (2-tert-butyl-6-fluoro-1- (3-hydroxypropyl) -1H-indol-5-yl) cyclopropane carboxamide [0639 ] To a solution of 1- (benzo [d] [1,3] dioxol-5-yl) -N- (2-tert-butyl-6-fluoroindolin-5-yl) cyclopropanecarboxamide (160 mg, 0.50 mmol) in anhydrous dichloromethane (3.4 mL) 3- (benzyloxy) propanal (160 mg, 0.98 mmol) was added at room temperature. After 10 minutes of stirring, NaBH (OAc) 3 (140 mg, 0.65 mmol) was added in one portion and the reaction mixture was stirred for 4 hours at room temperature.

The solvent was removed under reduced pressure, the residue was taken up in a 50/50 CH3CN-H2O mixture containing 0.05% TFA. The mixture was concentrated to dryness and the residue was dissolved in CDCl3 (5 mL) and briefly exposed to light. The purple solution was stirred at

354 air access at room temperature for 2 hours. The solvent was removed under reduced pressure and the residue was treated with Pd-C (10 mg) in MeOH (2 mL) at 1 atm H₂ for 2 hours The catalyst was filtered off through celite and the solvent removed under reduced pressure. The residue was purified by preparative TLC using 30% ethyl acetate / hexanes to give 1- (benzo [d] [1,3] dioxol-5-yl) N- (2-tert-butyl-6-fluoro-1- (3-hydroxypropyl ) -1H-indol-5-yl) cyclopropanecarboxamide (18 mg, 8% from 1 (benzo [d] [1,3] dioxol-5-yl) -N- (2-tert-butyl-6-fluoroindolin-5-yl) cyclopropane) carboxamide).^XH NMR (400

<td>MHz,</td><td>CDCl</td><td>3) δ 8.11</td><td>(D,</td><td>J = 7</td><td>, 8 Hz, 1H)</td><td> , 7,31 (</td><td>d, J.</td><td> = 2,</td><td>2 Hz,</td>

<td>1H),</td><td> 6,94</td><td>(dd, J</td><td> = 7,</td><td> 9, 1,7</td><td>Hz, 1H),</td><td>6.91 (d</td><td>, J =</td><td> 1,6</td><td>Hz,</td>

<td>1H),</td><td> 6,85</td><td>(d, J =</td><td> 11,</td><td>7 Hz</td><td>1H), 6.79</td><td>(d, J =</td><td> 7,9</td><td>Hz,</td><td>1H),</td>

<td> 6,10</td><td>(S,</td><td>1H), 5.94</td><td>(S,</td><td>2H);</td><td> 4,25-4,21 1</td><td>m, 2H),</td><td> 3,70</td><td>(Dd,</td><td>J =</td>

<td> 5,7,</td><td> 5,7</td><td>Hz, 2H),</td><td> 1,93</td><td> -1,86</td><td>(m, 2H), 1</td><td>, 61 (dd,</td><td>J =</td><td> 6,8,</td><td> 3,7</td>

<td>Hz,</td><td>2H);</td><td>1.35 (s,</td><td>9H)</td><td> , 1,04</td><td>(dd, J =</td><td> 6,8, 3,</td><td>7 Hz</td><td>2H)</td><td>. MS</td>

<td>(ESI</td><td>) m / e</td><td>(M + H⁺)</td><td> 453,</td><td> 0.</td><td></td><td></td><td></td><td></td><td></td>

Example 106: N- (1- (2-acetamidoethyl) -2-tert-butyl-1H-indol-5-yl) -1- (benzo [d] [1,3] dioxol-5-yl) cyclopropanecarboxamide [0640]

<img file="PL2674428T3_D0412.tif" />

355

<img file="PL2674428T3_D0413.tif" />

N- (1- (2-azidoethyl) -2-tert-butyl-1H-indol-5-yl) -1 (benzo [d] [1,3] dioxol-5-yl) cyclopropanecarboxamide [0641] To solution 1 - (benzo [d] [1,3] dioxol-5-yl) -N- (2-tert-butylindolin-5-yl) cyclopropane carboxamide (73 mg, 0.19 mmol) in anhydrous dichloromethane (1.2 mL) chloroacetaldehyde (60 µL, 0.24 mmol) was added at room temperature. After 10 minutes of stirring, NaBH (OAc) 3 (52 mg, 0.24 mmol) was added in one portion and the reaction mixture was stirred for another 30 minutes at room temperature. The solvent was removed under reduced pressure and the residue was purified by preparative HPLC to give indoline, which oxidized to the corresponding indole after reconstitution in CDCl3. The resulting indole was treated with NaN3 (58 mg, 0.89 mmol) and NaI (cat) in anhydrous DMF (0.8 mL) for 2 hours at 85 ° C. The reaction mixture was purified by preparative HPLC to give N- (1- (2-azidoethyl) -2-tert-butyl-1H-indol-5-yl) -1 (benzo [d] [1,3] dioxol-5-yl) cyclopropanecarboxamide (15 mg, 18% from 1- (benzo [d] [1,3] dioxol-5-yl) -N- (2-tert-butylindolin-5-yl) cyclopropane carboxamide).

<img file="PL2674428T3_D0414.tif" />

356

N- (1- (2-acetamidoethyl) -2-tert-butyl-1H-indol-5-yl) -1 (benzo [d] [1,3] dioxol-5-yl) cyclopropane carboxamide [0642] Solution N - (1- (2-azidoethyl) -2-tert-butyl-1H-indol-5-yl) -1- (benzo [d] [1,3] dioxol-5-yl) cyclopropanecarboxamide (13 mg, 0.029 mmol) in MeOH-AcOH (0.2 ml, 99: 1), in the presence of Pd-C (2 mg) was stirred at room temperature under 1 atm of H₂ for 2 hours, filtered through Celite and concentrated under reduced pressure. The crude product was treated with AcCl (0.05 mL) and Et₃N (0.05 mL) in anhydrous THF (0.2 mL) at 0 ° C for 30 minutes, followed by 1 hour at room temperature. The mixture was purified by preparative HPLC to give N- (1- (2-acetamidoethyl) -2-tert-butyl-1Hindol-5-yl) -1- (benzo [d] [1,3] dioxol-5-yl) cyclopropanecarboxamide MS (ESI) m / e (M + H +) 462.0.

Example 107: N- (2-tert-butyl-1- (3-cyano-2-hydroxypropyl) -1H-indol-5-yl) -1- (2,2-difluorobenzo [d] [1,3] dioxol-5-yl ) cyclopropanecarboxamide [0643]

<img file="PL2674428T3_D0415.tif" />

357

3- (2-tert-butyl-5- (1- (2,2-difluorobenzo [d] [1,3] dioxol-5-yl) cyclopropanecarboxamido) -1H-indol-1-yl) -2-hydroxypropyl 4-methyl-benzenesulfonate [0644 ] To a solution of N- (2-tert-butyl-1- (2,3-dihydroxypropyl) -1H-indol-5-yl) -1- (2,2-difluorobenzo [d] [1,3] dioxol-5-yl) cyclopropanecarboxamide (172 mg, 0.35 mmol) in anhydrous dichloromethane (1.4 mL) at 0 ° C, TsCl (71 mg, 0.37 mmol) was added in the presence of Et 3 N (56 pL, 0.40 mmol). The reaction mixture was stirred for 2 hours at room temperature, then cooled to 0 ° C and another portion of TsCl (71 mg, 0.37 mmol) was added. After 1 h stirring at room temperature, the mixture was purified by silica gel column chromatography (10-30% ethyl acetate / hexanes) to give 3- (2-tert-butyl-5- (1- (2,2- difluorobenzo [d] [1,3] dioxol-5-yl) cyclopropanecarboxamido) -1H-indol-1-yl) -2-hydroxypropyl (146 mg, 64%).

<img file="PL2674428T3_D0416.tif" />

N- (2-tert-butyl-1- (3-cyano-2-hydroxypropyl) -1H-indol-5-yl) -1- (2,2-difluorobenzo [d] [1,3] dioxol-5-yl) cyclopropanecarboxamide [ 0645] N- (2-tert-butyl-1- (3-cyano-2-hydroxypropyl) -1H-indol-5-yl) -1- (2,2-difluorobenzo [d] [1,3] dioxol-5- il) 358 cyclopropanecarboxamide (145 mg, 0.226 mmol) was treated with powdered NaCN (34 mg, 0.69 mmol) in anhydrous DMF (1.5 mL) at 85 ° C for 2 hours. The reaction mixture was cooled to room temperature and then diluted with dichloromethane (10 mL) and aqueous saturated NaHCO solution₃(10 ml). The organic phase was separated and the aqueous phase extracted with dichloromethane (2 x 10 mL). The organic phases were combined, washed with brine, dried over sodium sulfate, filtered and then concentrated. The residue was purified by silica gel column chromatography (25-55% ethyl acetate / hexanes) to give N- (2-tert-butyl-1- (3-cyano-2-hydroxypropyl) -1H-indol-5-yl) -1- ( 2,2-difluorobenzo [d] [1,3] dioxol-5-yl) cyclopropanecarboxamide (89 mg, 79%).¹1 H NMR (400 MHz, CDCl₃) δ 7.43 (d, J = 1.9 Hz,

1H), 7.20-7.16 (m, 2H), 7.08 (d, J = 8.8 Hz, 1H), 7.04 (d, J

<td>= 8.2 Hz, 1H), 6.94 (s,</td><td>1H),</td><td>6.88 (dd,</td><td>J = 8.7, 2.0</td><td>Hz,</td><td>1H),</td>

<td>6.16 (s, 1H), 4.32-4.19</td><td>(M,</td><td>3H) 2.83</td><td>(s, 1H), 2.40</td><td>(Dd,</td><td>J =</td>

<td>5.2, 5.2 Hz, 2H), 1.62</td><td>(Dd,</td><td>J = 6.6,</td><td>3.6 Hz, 2H),</td><td> 1,35</td><td>(S,</td>

<td>9H), 1.04 (dd, J = 6.9</td><td> , 3,</td><td>9 Hz, 2H).</td><td>MS (ESI) m / e</td><td>(M +</td><td>H⁺)</td>

496,0.

Example 108: N- (2-tert-butyl-1- (2-hydroxy-3- (2H-tetrazol-5-yl) propyl) -1H-indol-5-yl) -1- (2,2-difluorobenzo [d] [ 1,3] dioxol-5-yl) cyclopropanecarboxamide

<img file="PL2674428T3_D0417.tif" />

359 [0647] For a solution of N- (2-tert-butyl-1- (3-cyano-2-hydroxypropyl) -1H-indol-5-yl) -1- (2,2-difluorobenzo [d] [1,3] dioxol-5 -yl) -cyclopropanecarboxamide (27 mg, 0.054 mmol) in anhydrous DMF (1.2 mL) was added successively with NH4Cl (35 mg, 0.65 mmol) and NaN3 (43 mg, 0.65 mmol) at room temperature. The reaction mixture was stirred for 4 hours at 110 ° C in a microwave during which 50% of the starting material was converted to the desired product. The reaction mixture was purified by preparative HPLC to yield N- (2-tert-butyl-1- (2-hydroxy-3- (2H-tetrazol-5-yl) propyl) -1H-indol5-yl) -1- (2.2 -difluorobenzo [d] [1,3] dioxol-5-yl) cyclopropanecarboxamide MS (ESI) m / e (M + H +) 539.0.

Example 109: 4- (2-tert-butyl-5- (1- (2,2-difluorobenzo [d] [1,3] dioxol-5-yl) cyclopropanecarboxamido) -1H-indol-1-yl) -3- acid hydroxybutane [0648]

<img file="PL2674428T3_D0418.tif" />

[0649] N- (2-tert-butyl-1- (3-cyano-2-hydroxypropyl) -1H-indol-5-yl) -1- (2,2-difluorobenzo [d] [1,3] dioxol-5- yl) -cyclopropanecarboxamide (14 mg, 0.028 mmol) in methanol (0.8 mL) and 4 M NaOH (0.8 mL) was stirred at 60 ° C for 4 hours. The reaction mixture was neutralized with 4 M HCl and concentrated. The residue was purified by preparative HPLC to give 4360 (2-tert-butyl-5- (1- (2,2-difluorobenzo [d] [1,3] dioxol-5-yl) cyclopropanecarboxamido) -1H-indol-1- acid yl) -3hydroksybutanowy. MS (ESI) m / e (M + H +) 515.0.

Example 110: N- (1- (2- (2H-tetrazol-5-yl) ethyl) -2-tert-butyl-1H-indol-5-yl) -1- (benzo [d] [1,3] dioxol- 5-yl) cyclopropanecarboxamide

<img file="PL2674428T3_D0419.tif" />

1- (benzo [d] [1,3] dioxol-5-yl) -N- (2-tert-butyl-1- (2-cyanoethyl) indolin-5-yl) cyclopropanecarboxamide [0651] For solution 1- (benzo [ d] [1,3] dioxol-5-yl) -N- (2-tert-butyl-1- (2-chloroethyl) indolin-5-yl) cyclopropanecarboxamide (66 mg 0.15 mmol) in ethanol (0.8 mL) and water (0.4 mL) was added at room temperature NaCN (22 mg, 0.45 mmol) and KI (cat). The reaction mixture was stirred for 30 minutes at 110 ° C in a microwave reactor, then purified by silica gel column chromatography (5-15% ethyl acetate / hexanes) to obtain 1- (benzo [d] [1,3] dioxol] 5-yl) -N- (2-tert-butyl- 1- (2-cyano-ethyl) indolin-5-yl) cyclopropanecarboxamide (50 mg, 77%).

361

<img file="PL2674428T3_D0420.tif" />

N- (1- (2- (2H-tetrazol-5-yl) ethyl) -2-tert-butyl-1H-indol-5-yl) -1- (benzo [d] [1,3] dioxol-5-yl ) cyclopropanecarboxamide [0652] To a solution of 1- (benzo [d] [1,3] dioxol-5-yl) -N- (2-tert-butyl-1- (2-cyano-ethyl) indolin-5-yl) cyclopropanecarboxamide (50 mg , 0.12 mmol) in anhydrous DMF (2.6 mL), NH4Cl (230 mg, 4.3 mmol) and NaN3 (28.0 mg, 4.3 mmol) were added. The reaction mixture was stirred for 30 minutes at 110 ° C in a microwave reactor, filtered, and purified by preparative HPLC. The solid residue was dissolved in CDCl3 (3 mL) and briefly (2 to 4 min) exposed to light which initiated a color change (purple). After stirring for 2 hours under air, at room temperature, the solvent was removed and the residue was purified by preparative HPLC to give N- (1- (2- (2H-tetrazol-5-yl) ethyl) -2-tert-butyl 1H-indole -5-yl) -1- (benzo [d] [1,3] dioxol-5-yl) cyclopropanecarboxamide MS (ESI) m / e (M + H +) 473.0.

Example 111: 1- (benzo [d] [1,3] dioxol-5-yl) -N- (2-tert-butyl-6-fluoro-1 - ((tetrahydro-2H-pyran-3-yl) methyl) - 1H-indol-5-yl) cyclopropanecarboxamide

<img file="PL2674428T3_D0421.tif" />

362 [0654] To a solution of 1- (benzo [d] [1,3] dioxol-5-yl) -N- (2-tert-butyl-6-fluoroindolin-5-yl) cyclopropane carboxamide (150 mg, 0.38 mmol ) in anhydrous dichloromethane (2.3 mL) at room temperature under nitrogen, tetrahydropyran-3-carbaldehyde (54 mg, 0.47 mmol) was added. After 20 minutes of stirring, NaBH (OAc) was added in one portion at room temperature₃ (110 mg, 0.51 mmol). The reaction mixture was stirred for 6 hours at room temperature, then purified by silica gel column chromatography (5-20% ethyl acetate / hexanes) to give 1- (benzo [d] [1,3] dioxol-5-yl) -N- (2-tert-butyl-6-fluoro-1- ((tetrahydro-2H-pyran-3-yl) methyl) -1H-indol-5-yl) cyclopropanecarboxamide (95 mg, 50%). Then CDCl was added to indoline₃ and the solution was stirred overnight at room temperature. The solution was concentrated to give 1- (benzo [d] [1,3] dioxol-5-yl) -N- (2-tert-butyl-6-fluoro-1 ((tetrahydro-2H-pyran-3-yl) methyl) -1H-indol-5-yl) cyclopropanecarboxamide MS (ESI) m / e (M + H +) 493.0.

Example 112: 1- (benzo [d] [1,3] dioxol-5-yl) -N- (2- (2-hydroxypropan-2-yl) -1H-indol-5-yl) cyclopropane carboxamide [0656]

<img file="PL2674428T3_D0422.tif" />

Methyl 5- (1- (benzo [d] [1,3] dioxol-5-yl) cyclopropanecarboxamido) -N-indole-2-carboxylate (100 mg, 0.255 mmol) was dissolved in anhydrous tetrahydrofuran (2 mL ) in an argon atmosphere. The solution was cooled to 0 ° C in an ice-water bath and then methyllithium (0.85 mL, 1.6 M in diethyl ether) was added via syringe. The mixture was allowed to warm to room temperature. The crude product was partitioned between saturated aqueous sodium chloride (5 mL) and dichloromethane (5 mL). The organic layers were combined, dried over sodium sulfate, filtered, evaporated to dryness and purified on 12 g silica gel using a 20-80% ethyl acetate in hexanes gradient to afford 1- (benzo [d] [1,3] dioxol -5-yl) -N- (2- (2-hydroxypropan-2-yl) -1H-indol-5-yl) cyclopropanecarboxamide (35 mg, 36%) as a white solid. ESI-MS m / z calculated 378.2, found 379.1 (M + 1) +. Retention time 2.18 minutes.¹H NMR (400 MHz, DMSO-d₆) δ 10.78 (s, 1H), 8.39 (s, 1H), 7.57 (d, J = 1.7 Hz, 1H), 7.17 (d, J = 8.6 Hz, 1H )

7.03-6, 90 (m, 4H), 6.12 (d, J = 1.5 Hz, 1H), 6.03 (s, 2H),

5.18 (s, 1H), 1.50 (s, 6H), 1.41-1.38 (m, 2H), 1.05-0, 97 (m,

2H).

Example 113: N- (2- (1-amino-2-methylpropan-2-yl) -1H-indol-5-yl) -1- (benzo [d] [1,3] dioxol-5-yl) cyclopropanecarboxamide [ 0657]

<img file="PL2674428T3_D0423.tif" />

[0658] Trifluoracetic acid (0.75 mL) was added to a solution of 2- (5 (1- (benzo [d] [1,3] dioxol-5-yl) cyclopropane carboxamido) 1H-indol-2-yl) Tert-butyl -2-methylcarbamate (77 mg, 0.16 mmol) in dichloromethane (3 mL) and the mixture was stirred at room temperature for 1.5 hours. The mixture was evaporated, dissolved in dichloromethane, washed

364 saturated sodium bicarbonate solution, dried over magnesium sulfate and evaporated to dryness to give N- (2- (1 amino-2-methylpropan-2-yl) -1H-indol-5-yl) -1- (benzo [d] [1, 3] dioxol-5-yl) cyclopropane carboxamide (53 mg, 86%

1 H NMR

<td> (400</td><td>MHz, CDCl3) δ</td><td>9.58 (s, 1H)</td><td> , 7,60</td><td>(d, J</td><td> = 1,6</td><td>Hz,</td><td>1H),</td>

<td> 7,18</td><td>- 7.15 (m, 2H)</td><td> , 7,02-6, 94 (</td><td>m, 3H)</td><td> , 6,85 (</td><td>d, J.</td><td> = 7,8</td><td>Hz,</td>

<td>1H),</td><td>6.14 (d, J =</td><td>1.2 Hz, 1H),</td><td> 6,02 (</td><td>s, 2H),</td><td> 2,84</td><td>(S,</td><td>2H);</td>

<td> 1,68</td><td>(dd, J = 3.6,</td><td>6.7 Hz, 2H),</td><td> 1,32</td><td>(s, 6H),</td><td> 1,08</td><td>(Dd,</td><td>J =</td>

<td> 3,7,</td><td>6.8 Hz, 2H).</td><td></td><td></td><td></td><td></td><td></td><td></td>

Example 114: 1- (benzo [d] [1,3] dioxol-5-yl) -N- (2- (1 (dimethylamino) -2-methyl-propan-2-yl) -1H-indol-5-yl) cyclopropanecarboxamide [0659]

<img file="PL2674428T3_D0424.tif" />

[0660] For a solution of N- (2- (1-amino-2-methylpropan-2-yl) -1Hindol-5-yl) -1- (benzo [d] [1,3] dioxol-5-yl) cyclopropanecarboxamide (20 mg, 0.051 mmol) in DMF (1 mL) potassium carbonate (35 mg, 0.26 mmol) and iodomethane (7.0 µL, 0.11 mmol) were added. The reaction mixture was stirred for 2 hours. Water was added and the mixture was extracted with dichloromethane. The combined organic phases were dried over magnesium sulfate and evaporated, co-evaporated with toluene (3x) and purified by silica gel chromatography (0-30% EtOAc in hexane) to afford 1 (benzo [d] [1,3] dioxol-5 -yl) -N- (2- (1- (dimethylamino) -2-methylpropan-2-yl) -1H-indol-5-yl) cyclopropane carboxamide (7 mg, 33%). ¹1 H NMR (400 MHz, CDCl₃) δ 9.74 (s, 1H), 7.58 (d,

365

<td>J = 1.9</td><td>Hz,</td><td>1H), 7.20</td><td>(D,</td><td>J = 8,</td><td>6 Hz, 1H), 7.15 (s, 1H)</td>

<td> 7,01-6,95</td><td>(M,</td><td>3H), 6.85</td><td>(D,</td><td>J = 7.9</td><td>Hz, 1H), 6.10 (d, J = 0,</td>

<td>Hz, 1H),</td><td> 6,02</td><td>(s, 2H),</td><td> 2,43</td><td>(s, 2H)</td><td>, 2.24 (s, 6H), 1.68 (dd</td>

<td>J = 3.7,</td><td> 6,7</td><td>Hz, 2H),</td><td> 1,33</td><td>(s, 6H</td><td>, 1.08 (dd, J = 3.7, 6,</td>

Hz, 2H).

Example 115: N- (2- (1-acetamido-2-methylpropan-2-yl) -1Hindol-5-yl) -1- (benzo [d] [1,3] dioxol-5-yl) cyclopropanecarboxamide

<img file="PL2674428T3_D0425.tif" />

evaporated, then and purified by method [0662] To a solution of N- (2- (1-amino-2-methylpropan-2-yl) -1Hindol-5-yl) -1- (benzo [d] [1,3] dioxol -5yl) cyclopropanecarboxamide (21 mg, 0.054 mmol) in dichloromethane (1 mL) was added pyridine (14 µL, 0.16 mmol) followed by acetic anhydride (6.0 µL, 0.059 mmol). The reaction mixture was stirred for 2 hours. Water was added, the mixture was extracted with dichloromethane and co-evaporated with toluene (3x silica gel chromatography (60-100% ethyl acetate in hexane) to give N- (2- (1-acetamido-2-methylpropan-2-yl) 1H-indol- 5-yl) -1- (benzo [d] [1,3] dioxol-5-yl) cyclopropanecarboxamide (17 mg, 73%). ¹H NMR (400 MHz,

DMSO) δ 10.79 (s, 1H), 8.39 (s, 1H), 7.66 (t, J = 6.2 Hz,

1H), 7.56 (d, J = 1.7 Hz, 1H), 7.18-7.14 (m, 1H), 7.02-6.89 (m, 4H), 6.08 (d , J = 1.5 Hz, 1H), 6.03 (s, 2H), 3.31 (d, J =

6.2 Hz, 2H), 1.80 (s, 3H), 1.41-1.38 (m, 2H), 1.26 (s, 6H),

1.04-1.01 (m, 2H).

366

Example 116: 1- (benzo [d] [1,3] dioxol-5-yl) -N- (2- (2-methyl4- (1H-tetrazol-5-yl) butan-2-yl) -1H- indol-5-yl) cyclopropanecarboxamide

<img file="PL2674428T3_D0426.tif" />

[0664] 1- (benzo [d] [1,3] dioxol-5-yl) -N- (2- (4-cyano-2-methylbutan-2-yl) -1H-indol-5-yl) cyclopropanecarboxamide (83 mg, 0.20 mmol) was dissolved in N, N-dimethylformamide (1 mL) containing ammonium chloride (128 mg, 2.41 mmol), sodium azide (156 mg, 2.40 mmol) and a magnetic stirrer. The reaction mixture was heated at 110 ° C for 40 minutes in a microwave reactor. The crude product was filtered and then purified by preparative HPLC using a gradient of 0-99% acetonitrile in water containing 0.05% trifluoracetic acid to give 1- (benzo [d] [1,3] dioxol-5-yl) -N- ( 2- (2-methyl-4- (1H-tetrazol-5-yl) butan-2-yl) -1H-indol-5-yl) cyclopropanecarboxamide ESI-MS m / z calcd. 458.2, found 459.2 (M + 1) +. Retention time 1.53 minutes.¹H NMR (400 MHz, CD₃CN), 9.23 (s, 1H), 7.51-7.48 (m, 2H),

7.19 (d, J = 8.6 Hz, 1H), 7.06-7.03 (m, 2H), 6, 95-6, 89 (m,

2H), 6.17 (dd, J = 0.7, 2.2 Hz, 1H), 6.02 (s, 2H), 2.61-2.57 (m, 2H), 2.07-2 , 03 (m, 2H), 1.55-1.51 (m, 2H), 1.39 (s, 6H),

1.12-1.09 (m, 2H).

Example 117: 1- (benzo [d] [1,3] dioxol-5-yl) -N- (2- (piperidin-2-yl) -1H-indol-5-yl) cyclopropanecarboxamide

367

<img file="PL2674428T3_D0427.tif" />

[0666] Tert-butyl 2- (5- (1- (benzo [d] [1,3] dioxol-5-yl) cyclopropanecarboxamido) -1H-indol-2-yl) piperidine-1-carboxylate (55 mg, 0.11 mmol) was dissolved in dichloromethane (2.5 mL) containing trifluoracetic acid (1 mL). The reaction mixture was stirred for 6 hours at room temperature. The crude product was purified by preparative HPLC using a 0-99% gradient of acetonitrile in water containing 0.05% trifluoracetic acid to give 1- (benzo [d] [1,3] dioxol-5-yl) -N- (2- (-piperidin-2-yl) -1H-indol-5-yl) cyclopropanecarboxamide. ESI-MS m / z calculated 403.2, 404.4 found (M + 1) +. Retention time 0.95 minutes.

Example 118: 5-tert-butyl-1H-indol-6-ylamine [0667]

<img file="PL2674428T3_D0428.tif" />

2-bromo-4-tert-butyl-phenylamine [0668] To a solution of 4-tert-butyl-phenylamine (447 g, 3.00 mol) in DMF (500 ml) was added NBS (531 g, 3.00 mol) in dropwise DMF (500 ml) at room temperature. After the addition,

368 the reaction mixture was diluted with water and extracted with EtOAc. The organic layer was washed with water, brine, dried over Na₂SO₄ and concentrated. The crude product was used directly in the next step without further purification.

<img file="PL2674428T3_D0429.tif" />

2-bromo-4-tert-butyl-5-nitro-phenylamine [0669] 2-Bromo-4-tert-butyl-phenylamine (160 g, 0.71 mol) was added dropwise to H₂SO₄ (410 ml) at room temperature to give a clear solution. The clear solution was cooled to -5 to -10 ° C. KNO solution was added dropwise to the above₃(83 g, 0.82 mol) in H₂SO₄ (410 ml) maintaining the temperature between -5 to -10 ° C. After completion of the dropwise addition, the reaction mixture was poured into ice / water and extracted with EtOAc. The combined organic layers were washed with 5% Na₂WHAT₃ and brine, dried over Na₂SO₄ and concentrated. The residue was purified by column chromatography (ethyl acetate / petroleum ether 1:10) to give 2-bromo-4-tert-butyl-5-nitro-phenylamine as a yellow solid (150 g, 78%).

<img file="PL2674428T3_D0430.tif" />

4-tert-butyl-5-nitro-2-trimethylsilanylethynyl-phenylamine [0670] To a mixture of 2-bromo-4-tert-butyl-5-nitrophenylamine (27.3 g, 100 mmol) in toluene (200 mL) and water (100 ml), Et. Was added₃N (27.9 mL, 200 mmol), Pd (PPh₃)₂cl₂ (2.11 g, 3.00 mmol), CuI (950 mg, 0.500 mmol) and acetylene

369 trimethylsilyl (21.2 mL, 150 mmol) under a nitrogen atmosphere. The reaction mixture was heated at 70 ° C in a sealed pressure flask for 2.5 hours, cooled to room temperature and filtered through a short pad of celite. The filter cake was washed with ethyl acetate. The combined filtrates were washed with a 5% NH solution₄OH and water, dried over Na₂SO₄ and concentrated. The crude product was purified by column chromatography (0 -10% ethyl acetate / petroleum ether) to give 4-tert-butyl-5-nitro-2-trimethylsilanylethynyl-phenylamine as a brown viscous liquid (25 g, 81%).

<img file="PL2674428T3_D0431.tif" />

5-tert-butyl-6-nitro-1H-indole [0671] To a solution of 4-tert-butyl-5-nitro-2-trimethylsilanylethynyl-phenylamine (25 g, 86 mmol) in DMF (100 mL) was added CuI (8.2 g, 43 mmol) under a nitrogen atmosphere.

The mixture was heated at 135 ° C in a sealed pressure flask overnight, cooled to room temperature and filtered through a short pad of celite. The filter cake was washed with ethyl acetate. The combined filtrates were washed with water, dried over Na₂SO₄ and concentrated. The crude product was purified by column chromatography (10-20% aetate acetate / hexane) to give 5-tert-butyl-6-nitro-1H-indole as a yellow solid (13 g, 69%).

370

<img file="PL2674428T3_D0432.tif" />

Η₂, Raney Ni

<img file="PL2674428T3_D0433.tif" />

H₂N

N

H

5-tert-butyl-1H-indol-6-ylamine [0672] To 5-tert-butyl-6-nitro-1H-indole (15 g, 67 mmol) was added Raney Nickel (3 g) in methanol (100 mL) . The mixture was stirred under a hydrogen atmosphere (1 atm) at 30 ° C for 3 hours. The catalyst was filtered off. The filtrate was dried over Na₂SO₄ and concentrated. The crude dark brown viscous oil was purified by column chromatography (10-20% ethyl acetate / petroleum ether) to give 5-tert-butyl-1H-indol-6-ylamine as a gray solid (11 g, 87%).^XH NMR (300 MHz, DMSO-d6) δ 10.3 (br s, 1H), 7.2 (s, 1H), 6.9 (m, 1H), 6.6 (s,

1H), 6.1 (m, 1H), 4.4 (br s, 2H), 1.3 (s, 9H).

[0673] A skilled chemist may use examples and schemes as well as known synthetic methods to prepare compounds of the present invention, including the compounds listed in Table 3 below.

Table 3. Physical data of examples of compounds

371

<td>Compound Well.</td><td>LC / MS M + 1</td><td>LC / RT min</td><td>NMR</td>

<td> 1</td><td> 373.3</td><td> 2.49</td><td></td>

<td> 2</td><td> 469.4</td><td> 3.99</td><td></td>

<td> 3</td><td> 381.3</td><td> 3.69</td><td></td>

<td> 4</td><td> 448.3</td><td> 1.75</td><td></td>

<td> 5</td><td> 389.3</td><td> 3.3</td><td></td>

<td> 6</td><td> 463</td><td> 1.87</td><td></td>

<td> 7</td><td> 363.3</td><td> 3.7</td><td></td>

<td> 8</td><td> 405.5</td><td> 3.87</td><td></td>

<td> 9</td><td> 487.3</td><td> 2.12</td><td>H NMR (400 MHz, DMSOd6) 8.65 (s, 1H), 7.55 (d, J = 1.7 Hz, 1H), 7.49 (d, J = 1.4 Hz, 1H), 7.38 (d, J = 8.3 Ηζ, ΙΗ), 7.307.25 (m, 2H), 7.08 (dd, J = 8.8, 1.9 Hz, 1H), 6.11 (s, 1H), 4.31 (t, J = 7.4 Hz, 2H), 3.64 (1, J = 7.3 Hz, 2H), 3.20 (t, J = 7.6 Hz, 2H), 1.92 (t, J = 7.6 Hz, 2H), 1.45 (m, 2H), 1.39 (s, 6H), 1.10 (m, 2H)</td>

<td> 10</td><td> 388</td><td> 3.34</td><td></td>

<td> 11</td><td> 452.3</td><td> 2.51</td><td></td>

<td> 12</td><td> 527</td><td> 2.36</td><td></td>

<td> 13</td><td> 498</td><td> 1.85</td><td></td>

<td> 14</td><td> 404.5</td><td> 1.18</td><td></td>

<td> 15</td><td> 369.2</td><td> 3.81</td><td></td>

<td> 16</td><td> 419.2</td><td> 2.24</td><td></td>

<td>Compound Well.</td><td>LC / MS M + 1</td><td>LC / RT min</td><td>NMR</td>

<td> 17</td><td> 389.2</td><td> 2.02</td><td>H NMR (400 MHz, DMSO) 8.41 (s, 1H), 7.59 (d, J = 1.8 Hz, 1H), 7.15 (d, J = 8.6 Hz, 1H), 7.06 - 7.02 (m, 2H), 6.96 6.90 (m, 2H), 6.03 (s, 2H), 5.98 (d, J = 0.7 Hz, 1H), 4.06 (t, J = 6.8Hz, 2H), 2.35 (t, J = 6.8 Hz, 2H), 1.42-1.38 (m, 2H), 1.34 (s, 6H), 1.05-1.01 (m, 2H)</td>

<td>1S</td><td> 395.3</td><td> 3.6</td><td>H NMR (400 MHz, DMSO) 10.91 (s, 1H), 7.99 (s, 1H), 7.67 (d, J = 7.7 Hz, 1H), 7.086.92 (m, 4H), 6.09 - 6.03 (m, 3H), 1.47 - 1.42 (m, 2H), 1.31 (d, J = 7.3 Hz, 9H), 1.09-1.05 (m, 2H)</td>

<td> 19</td><td> 457.2</td><td> 1.97</td><td>H NMR (400 MHz, CD3CN) 7.50 (d, J = 1.9 Hz, 1H), 7.41 (d, J = 1.6 Hz, 2H), 7.36 (dd, J = 1.7, 8.3 Hz, IH), 7.29 - 7.24 (m, 2H), 7.02 (dd, J = 2.1, 8.8 Hz, 1H), 6.24 (s, 1H), 4.40 (t, J = 7.1 Hz, 2H), 3.80 (t, J = 7.1 Hz, 2H), 1.591.55 (m, 2H), 1.50 (s, 9H), 1.15-1.12 (m, 2H)</td>

<td> 20</td><td> 375.5</td><td> 3.71</td><td></td>

<td> 21</td><td> 496</td><td> 206</td><td></td>

<td> 22</td><td> 421.14</td><td> 1.53</td><td></td>

372

<td>Compound Well.</td><td>LC / MS M + 1</td><td>LC / RT min</td><td>NMR</td>

<td> 23</td><td> 363.3</td><td> 3.62</td><td></td>

<td> 24</td><td> 378.5</td><td> 2.66</td><td></td>

<td> 25</td><td> 417.5</td><td> 3.53</td><td></td>

<td> 26</td><td> 454.3</td><td> 3.18</td><td></td>

<td> 27</td><td> 596.2</td><td> 2.58</td><td></td>

<td> 28</td><td> 379.3</td><td> 2.92</td><td></td>

<td> 29</td><td> 481</td><td> 1.69</td><td></td>

<td> 30</td><td> 504.2</td><td> 1.95</td><td></td>

<td> 31</td><td> 517</td><td> 1.92</td><td></td>

<td> 32</td><td> 403.5</td><td> 3.5</td><td>H NMR (400 MHz, DMSO) 10.76 (s, 1H), 8.72 (s, 1H), 7.79 (d, J = 2.3 Hz, 1H), 7.62 (dd, J = 2.4, 8.6 Hz, 1H), 7.55 (d, J = 1.5 Hz, 1H), 7.14 (d, J = 8.6 Hz, 1H), 7.05 - 7.01 (m, 2H), 6.03 (d, J = 1.6 Hz, 1H), 4.54 (t, J = 6.4 Hz, 2H), 2.79 (t, J = 6.4 Hz, 2H), 1.44 (m, 2H), 1.32 (s, 9H), 1.03 (m, 2H)</td>

<td> 33</td><td> 321.3</td><td> 2.98</td><td></td>

<td> 34</td><td> 450.2</td><td> 2.02</td><td></td>

<td> 35</td><td> 395.1</td><td> 3.59</td><td></td>

<td> 36</td><td> 509</td><td> 2.01</td><td></td>

<td> 37</td><td> 447.2</td><td> 2.02</td><td></td>

<td> 38</td><td> 379.1</td><td> 2.16</td><td>H NMR (400 MHz, DMSO) 10.78 (s, 1H), 8.39 (s, 1H), 7.57 (d, J = 1.7 Hz, 1H), 7.17 (d, J = 8.6 Hz, 1H), 7.03 - 6.90 (m, 4H), 6.12 (d, J = 1.5 Hz, 1H), 6.03 (s, 2H), 5.18 (s, 1H), 1.50 (s, 6H), 1.41 - 1.38 (m, 2H), 1.050.97 (m, 2H)</td>

<td> 39</td><td> 373.3</td><td> 3.74</td><td></td>

<td> 40</td><td> 372.8</td><td> 3.8</td><td></td>

<td>Compound Well.</td><td>LC / MS M + 1</td><td>LC / RT min</td><td>NMR</td>

<td>41 J</td><td> 397.3</td><td> 3.41</td><td>H NMR (400 MHz, DMSO) 11.44 (s, 1H), 8.52 (s, 1H), 7.85 (d, J == 1.2 Hz, 2H), 7.71 (d, J = 1.7 Hz, 1H), 7.47-7.43 (m, 2H), 7.32 7.26 (m, 2H), 7.12 (dd, J = 2.0, 8.7 Hz, 1H), 7.04 (d, J = 1.6 Hz, 1H), 6.97 - 6.90 (m, 2H), 6.84 (d, J = 1.3 Hz, 1H), 6.03 (s, 2H), 1.43 - 1.40 (m, 2H), 1.07-1.03 (m, 2H)</td>

<td> 42</td><td> 505.3</td><td> 2.23</td><td>H NMR (400 MHz, DMSOd6) 8.33 (s, 1H), 7.52 (s, 1H), 7.42-7.39 (m, 2H), 7.337.25 (m, 2H), 6.14 (s, 1H), 4.99 (s, 1H), 4.31-4.27 (m, 3H), 3.64 (t, J = 7.0 Hz, 2H), 3.20 (t, J = 7.6 Hz, 2H), 1.91 (t, J = 7.6Hz, 2H), 1.46 (m, 2H), 1.39 (s, 6H), 1.13 (m, 2H)</td>

<td> 43</td><td> 505.4</td><td> 1.97</td><td></td>

<td> 44</td><td> 407.7</td><td> 1.76</td><td>H NMR (400 MHz, DMSO) 10.31 (s, 1H), 8.34 (s, 1H), 7.53 (d, J = 1.8 Hz, 1H), 7.03 (d, J = 1.6 Hz, 1H), 6.97 - 6.90 (m, 3H), 6.05 6.03 (m, 3H), 4.72 (s, 2H), 1.40-1.38 (m, 2H), 1.34 (s, 9H), 1.041.00 (m, 2H)</td>

<td> 45</td><td> 497.2</td><td> 2.26</td><td></td>

<td> 46</td><td> 391.3</td><td colspan="2">3.41 S.</td>

373

<td>Compound Well.</td><td>LC / MS M + 1</td><td>LC / RT min</td><td>NMR</td>

<td> 47</td><td> 377.5</td><td> 3.48</td><td></td>

<td> 48</td><td> 427.5</td><td> 4.09</td><td></td>

<td> 49</td><td> 402.2</td><td> 3.06</td><td></td>

<td> 50</td><td> 421.1</td><td> 1.81</td><td></td>

<td> 51</td><td> 407.5</td><td> 3.34</td><td></td>

<td> 52</td><td> 464.3</td><td> 2.87</td><td></td>

<td> 53</td><td> 405.3</td><td> 3.65</td><td></td>

<td> 54</td><td> 375</td><td> 1.84</td><td></td>

<td> 55</td><td> 505.4</td><td> 1.96</td><td></td>

<td> 56</td><td> 335.3</td><td> 3.18</td><td></td>

<td> 57</td><td> 445.2</td><td> 3.27</td><td></td>

<td> 58</td><td> 491</td><td> 1.88</td><td></td>

<td> 59</td><td> 478</td><td> 1.98</td><td></td>

<td> 60</td><td> 413.3</td><td> 3.95</td><td></td>

<td> 61</td><td> 402.5</td><td> 3.71</td><td></td>

<td> 62</td><td> 393.3</td><td> 1.98</td><td></td>

<td> 63</td><td> 407.2</td><td> 2.91</td><td></td>

<td> 64</td><td> 505.4</td><td> 1.98</td><td></td>

<td> 65</td><td> 377.5</td><td> 3.53</td><td></td>

<td> 66</td><td> 417.5</td><td> 4.06</td><td></td>

<td> 67</td><td> 333.3</td><td> 3.53</td><td></td>

<td> 68</td><td> 397.3</td><td> 3.86</td><td></td>

<td> 69</td><td> 506</td><td> 1.67</td><td></td>

<td> 70</td><td> 501</td><td> 2.1</td><td></td>

<td> 71</td><td> 335.3</td><td> 3.22</td><td></td>

<td> 72</td><td> 487</td><td> 1.93</td><td></td>

<td> 73</td><td> 417.5</td><td> 3.88</td><td></td>

<td> 74</td><td> 395</td><td> 1.95</td><td></td>

<td> 75</td><td> 548</td><td> 1.64</td><td></td>

<td> 76</td><td> 418.3</td><td> 2.9</td><td></td>

<td> 77</td><td> 377.3</td><td> 3.87</td><td></td>

<td> 78</td><td> 363.3</td><td> 3.48</td><td></td>

<td> 79</td><td> 476</td><td> 1.8</td><td></td>

<td> 80</td><td> 447.3</td><td> 2.18</td><td></td>

<td> 81</td><td> 492.4</td><td> 2</td><td></td>

<td> 82</td><td> 564.3</td><td> 1.35</td><td></td>

<td> 83</td><td> 467.3</td><td> 1.72</td><td></td>

<td> 84</td><td> 445.2</td><td> 3.08</td><td></td>

<td> 85</td><td> 389.5</td><td> 3.86</td><td></td>

<td> 86</td><td> 374.3</td><td> 3.11</td><td></td>

<td> 87</td><td> 435</td><td> 3.87</td><td></td>

<td> 88</td><td> 465</td><td> 1.89</td><td></td>

<td> 89</td><td> 411.3</td><td> 3.89</td><td></td>

<td> 90</td><td> 449.3</td><td> 3.92</td><td></td>

<td> 91</td><td> 393.3</td><td> 3.12</td><td></td>

<td> 92</td><td> ' 469.6</td><td> 1.75</td><td></td>

<td> 93</td><td> 476.5</td><td> 2.88</td><td></td>

<td> 94</td><td> 377.5</td><td> 3.41</td><td></td>

<td>Compound Well.</td><td>LC / MS M + 1</td><td>LC / RT min</td><td>NMR</td>

<td> 95</td><td> 375.3</td><td> 3.43</td><td>H NMR (400 MHz, DMSO) 10.52 (s, 1H), 8.39 (s, 1H), 7.46 (d, J = 1.8 Hz, 1H), 7.10 6.89 (m, 5H), 6.03 (s, 2H), 2.68 - 2.65 (m, 2H), 2.56 - 2.54 (m, 2H), 1.82 1.77 (m, 4H), 1.41 - 1.34 (m, 2H), 1.04 - 0.97 (m, 2H)</td>

<td> 96</td><td> 346.1</td><td> 3.1</td><td></td>

<td> 97</td><td> 367.3</td><td> 3.72</td><td></td>

<td> 98</td><td> 440.3</td><td> 3.26</td><td></td>

<td> 99</td><td> 393.1</td><td> 3.18</td><td>H NMR (400 MHz, DMSOd6) 11.80 (s, 1H), 8.64 (s, 1H), 7.83 (m, 1H), 7.33-7.26 (m, 2H), 7.07 (m, 1H), 7.02 (m, 1H), 6.966.89 (m, 2H), 6.02 (s, 2H), 4.33 (q, J = 7.1 Hz, 2H), 1.421.39 (m, 2H), 1.33 (t, J = 7.1 Hz, 3H), 1.061.03 (m, 2H)</td>

<td> 100</td><td> 421.3</td><td> 1.85</td><td>H NMR (400 MHz, DMSO) 13.05 (s, 1H), 9.96 (d, J-1.6 Hz, 1H), 7.89 (d, J = 1.9 Hz, 1H), 7.74 (d, J = 2.0 Hz, 1H), 7.02 (d, J - 1.6 Hz, 1H), 6.966.88 (m, 2H), 6.22 (d, J = 2.3 Hz, 1H), 6.02 (s, 2H), 1.43 1.40 (m, 2H), 1.37 (s, 9H), 1.06-1.02 (m, 2H)</td>

<td> 101</td><td> 387.5</td><td> 2.51</td><td></td>

<td> 102</td><td> 479</td><td> 3.95</td><td></td>

<td> 103</td><td> 420.3</td><td> 3.12</td><td></td>

<td> 104</td><td> 469.5</td><td> 3.97</td><td></td>

<td> 105</td><td> 391.3</td><td> 2.04</td><td></td>

374

<td>Compound Well.</td><td>LC / MS M + L</td><td>LC / RT min</td><td>NMR</td>

<td> 106</td><td> 375.2</td><td> 2.82</td><td></td>

<td> 107</td><td> 349.3</td><td> 3.33</td><td></td>

<td> 108</td><td> 503.3</td><td> 1.88</td><td></td>

<td> 109</td><td> 451.5</td><td> 1.59</td><td></td>

<td> 110</td><td> 361.5</td><td> 3.7</td><td></td>

<td> 111</td><td> 391.3</td><td> 3.65</td><td></td>

<td> 112</td><td> 335.3</td><td> 3.03</td><td></td>

<td> 113</td><td> 496.5</td><td> 1.68</td><td></td>

<td> 114</td><td> 381.5</td><td> 3.72</td><td></td>

<td> 115</td><td> 390.3</td><td> 3.22</td><td></td>

<td> 116</td><td> 397.3</td><td> 3.52</td><td>H NMR (400 MHz, DMSOd6) 11.27 (d, J = 1.9 Hz, 1H), 8.66 (s, 1H), 8.08 (d, J = 1.6 Hz, 1H), 7.657.61 (m, 3H), 7.46-7.40 (m, 2H), 7.31 (d, J = 8.7 Hz, 1H), 7.25-7.17 (m, 2H), 7.03 (d, J = 1.6 Hz, 1H), 6.98-6.87 (m, 2H), 6.02 (s, 2H), 1.43-1.39 (m, 2H), 1.061.02 (m, 2H)</td>

<td> 117</td><td> 377.5</td><td> 3.77</td><td></td>

<td> 118</td><td> 515.3</td><td> 2.3</td><td></td>

<td> 119</td><td> 381.3</td><td> 3.8</td><td></td>

<td> 120</td><td> 464.2</td><td> 2.1</td><td></td>

<td> 121</td><td> 465</td><td> 1.74</td><td></td>

<td> 122</td><td> 395.2</td><td> 3.74</td><td></td>

<td> 123</td><td> 383.3</td><td> 3.52</td><td></td>

<td> 124</td><td> 388.5</td><td> 3.56</td><td></td>

<td> 125</td><td> 411.3</td><td> 3.85</td><td></td>

<td> 126</td><td> 459.2</td><td> 1.53</td><td>H NMR (400 MHz, CD3CN) 9.23 (s, 1H), 7.51-7.48 (m, 2H), 7.19 (d, J = 8.6 Hz, 1H), 7.06 - 7.03 (m, 2H), 6.95 - 6.89 (m , 2H), 6.17 (dd, J = 0.7,2.2 Hz, 1H), 6.02 (s, 2H), 2.61 2.57 (m, 2H), 2.07 - 2.03 (m, 2H), 1.55-1.51 (m, 2H) , 1.39 (s, 6H), 1.121.09 (m, 2H)</td>

<td> 127</td><td> 408.5</td><td> 2.48</td><td></td>

<td>Compound Well.</td><td>LCZMS M + L</td><td>LC / RT min</td><td>NMR</td>

<td> 128</td><td> 393</td><td> 3.26</td><td></td>

<td> 129</td><td> 420.2</td><td> 2.16</td><td></td>

<td> 130</td><td> 406.3</td><td> 2.88</td><td></td>

<td> 131</td><td> 473.3</td><td> 4.22</td><td></td>

<td> 132</td><td> 417.3</td><td> 3.8</td><td></td>

<td> 133</td><td> 465</td><td> 1.74</td><td></td>

<td> 134</td><td> 464.3</td><td> 2.91</td><td></td>

<td> 135</td><td> 347.3</td><td> 3.42</td><td></td>

<td> 136</td><td> 511</td><td> 2.35</td><td></td>

<td> 137</td><td> 455.5</td><td> 3.29</td><td></td>

<td> 138</td><td> 393.3</td><td> 3.54</td><td></td>

<td> 139</td><td> 335.1</td><td> 3.08</td><td></td>

<td> 140</td><td> 434.5</td><td> 2,74</td><td></td>

<td> 141</td><td> 381.3</td><td> 2.91</td><td></td>

<td> 142</td><td> 431.5</td><td> 3.97</td><td></td>

<td> 143</td><td> 539</td><td> 1.89</td><td></td>

<td> 144</td><td> 515</td><td> 1.89</td><td></td>

<td> 145</td><td> 407.5</td><td> 3.6</td><td></td>

<td> 146</td><td> 379.5</td><td> 1.51</td><td></td>

<td> 147</td><td> 409.3</td><td> 4</td><td></td>

<td> 148</td><td> 392.2</td><td> 1.22</td><td></td>

<td> 149</td><td> 375.3</td><td> 3.37</td><td></td>

<td> 150</td><td> 377.3</td><td> 3.61</td><td></td>

<td> 151</td><td> 377.22</td><td> 3.96</td><td></td>

<td> 152</td><td> 504.5</td><td> 1.99</td><td></td>

<td> 153</td><td> 393.1</td><td> 3.47</td><td></td>

<td> 154</td><td> 363.3</td><td> 3.52</td><td></td>

<td> 155</td><td> 321.3</td><td> 3.13</td><td></td>

<td> 156</td><td> 407.5</td><td> 3.2</td><td></td>

<td> 157</td><td> 406.3</td><td> 1.43</td><td></td>

<td> 158</td><td> 379.3</td><td> 1.89</td><td></td>

<td> 159</td><td> 451</td><td> 3.34</td><td></td>

<td> 160</td><td> 375.3</td><td> 3.82</td><td></td>

<td> 161</td><td> 355.1</td><td> 3.32</td><td></td>

<td> 162</td><td> 475</td><td> 2.06</td><td></td>

<td> 163</td><td> 437.2</td><td> 2.35</td><td></td>

<td> 164</td><td> 379.2</td><td> 2.76</td><td></td>

<td> 165</td><td> 462</td><td> 3.44</td><td></td>

<td> 166</td><td> 465.2</td><td> 2.15</td><td></td>

<td> 167</td><td> 455.2</td><td> 2.45</td><td></td>

<td> 168</td><td> 451</td><td> 1.65</td><td></td>

<td> 169</td><td> 528</td><td> 1.71</td><td></td>

<td> 170</td><td> 374.3</td><td> 3.4</td><td></td>

<td> 171</td><td> 449.5</td><td> 1.95</td><td></td>

<td> 172</td><td> 381.3</td><td> 3.8</td><td></td>

<td> 173</td><td> 346.3</td><td> 2.93</td><td></td>

<td> 174</td><td> 483.1</td><td> 2.25</td><td></td>

<td> 175</td><td> 411.2</td><td> 3.85</td><td></td>

<td> 176</td><td> 431.5</td><td> 4.02</td><td></td>

<td> 177</td><td> 485.5</td><td> 4.02</td><td></td>

<td> 178</td><td> 528.5</td><td> 1.18</td><td></td>

<td> 179</td><td> 473</td><td> 1.79</td><td></td>

<td> 180</td><td> 479</td><td> 2.15</td><td></td>

<td> 181</td><td> 387.5</td><td> 2.56</td><td></td>

<td> 182</td><td> 365.3</td><td> 3.13</td><td></td>

<td> 183</td><td> 493</td><td> 2.3</td><td></td>

375

<td>Compound% Well.</td><td>LC / MS M + 1</td><td>LC / RT min</td><td>NMR</td>

<td> 184</td><td> 461.3</td><td> 2.4</td><td>H NMR (400 MHz, DMSOd6) 10.89 (s, 1H), 8.29 (s, 1H), 7.52 (s, 1H), 7.42-7.37 (m, 2H), 7.32 (dd, J = 8.3,1.4 Hz, 1H), 7.01 (d, J = 10.9 Hz, 1H), 6.05 (d, J = 1.7 Hz, 1H), 4.29 (t, J = 5.0 Hz, 1H), 3.23 (m, 2H), 1.81 (t, J = 7.7 Hz, 2H), 1.46 (m, 2H), 1.29 (s, 6H), 1.13 (m, 2H)</td>

<td> 185</td><td> 377.5</td><td> 3.63</td><td></td>

<td> 186</td><td> 464</td><td> 1.46</td><td></td>

<td> 187</td><td> 339.1</td><td> 3.2</td><td></td>

<td> 188</td><td> 435.5</td><td> 1.64</td><td></td>

<td> 189</td><td> 392.3</td><td> 2.18</td><td></td>

<td> 190</td><td> 435.5</td><td> 3.67</td><td>H NMR (400 MHz, DMSO) 11.83 (s, 1H), 10.76 (s, 1H), 8.53 (s, 1H), 7.93 (d, J = 1.8 Hz, 1H), 7.60 (dd, J = 2.3, 8.5 Hz, 1H), 7.53 (d, J = 1.4 Hz, 1H), 7.14 (d, J = 8.6 Hz, 1H), 7.02 - 6.97 (m, 2H), 6.02 (d, J = 1.5 Hz, 1H), 3.71 (t, J = 6.2 Hz, 2H), 3.37 (t, J = 6.2 Hz, 2H), 3.25 (s, 3H), 1.44 (m, 2Ή), 1.32 (s, 9H), 1.08 (m, 2H)</td>

<td> 191</td><td> 421.3</td><td> 3.32</td><td></td>

<td> 192</td><td> 404.4</td><td> 0.95</td><td></td>

<td> 193</td><td> 451</td><td> 1.71</td><td></td>

<td> 194</td><td> 465</td><td> 1.69</td><td></td>

<td> 195</td><td> 434.2</td><td> 2.29</td><td></td>

<td> 196</td><td> 363.3</td><td> 3.4</td><td></td>

<td> 197</td><td> 501</td><td> 1.91</td><td></td>

<td> 198</td><td> 411.2</td><td> 3.14</td><td></td>

<td> 199</td><td> 439</td><td> 1.89</td><td> . _</td>

<td> 200</td><td> 434.4</td><td> 1.53.</td><td></td>

<td>Compound 1 Well.</td><td>LC / MS M + 1</td><td>ΙΛ. / Κ1 min</td><td>lNŁVXt &lt;</td>

<td> 201</td><td> 462</td><td> 3.22</td><td></td>

<td> 202</td><td> 351.3</td><td> 2.59</td><td></td>

<td> 203</td><td> 495.2</td><td> 2.71</td><td></td>

<td> 204</td><td> 435</td><td> 3.94</td><td></td>

<td> 205</td><td> 397.3</td><td> 3.69</td><td></td>

<td> 206</td><td> 493</td><td> 2.26</td><td></td>

<td> 207</td><td> 487</td><td> 1.87</td><td></td>

<td> 208</td><td> 391.3</td><td> 2.94</td><td></td>

<td> 209</td><td> 397.2</td><td> 3.3</td><td></td>

<td> 210</td><td> 487.2</td><td> 1.85</td><td>H NMR (400 MHz, CD3CN) 7.50 (d, J = 2.0 Hz, 1H), 7.41 (d, J = 1.6 Hz, 2H), 7.37-7.32 (m, 2H), 7.25 (d, J = 8.3 Hz, 1H), 6.98 (dd, J = 2.1.8.8 Hz, 1H), 6.27 (d, J = 0.6 Hz, 1H), 4.40 - 4.28 (m, 2H), 4.12-4.06 (m, 1H), 3.59 3.51 (m, 2H), 1.59- 1.50 (m, 2H), 1.47 (s, 9H), 1.15-1.12 (m, 2H)</td>

<td> 211</td><td> 381.3</td><td> 3.69</td><td></td>

<td> 212</td><td> 461</td><td> 2.04</td><td></td>

<td> 213</td><td> 469</td><td> 1.72</td><td></td>

<td> 214</td><td> 363.3</td><td> 3.48</td><td></td>

<td> 215</td><td> 432.3</td><td> 3.07</td><td></td>

<td> 216</td><td> 403.5</td><td> 3.94</td><td></td>

<td> 217</td><td> 420.4</td><td> 1.27</td><td></td>

<td> 218</td><td> 475</td><td> 2.2</td><td></td>

<td> 219</td><td> 484.3</td><td> 1.84</td><td></td>

<td> 220</td><td> 419.3</td><td> 3.87</td><td></td>

<td> 221</td><td> 486.3</td><td> 0.91</td><td></td>

<td> 222</td><td> 391.3</td><td> 3.01</td><td></td>

<td> 223</td><td> 398.3</td><td> 1.3</td><td></td>

<td> 224</td><td> 349.2</td><td> 2.54</td><td></td>

<td> 225</td><td> 375.5</td><td> 3.74</td><td></td>

<td> 226</td><td> 377.5</td><td> 3.47</td><td>H NMR (400 MHz, DMSOd6) 10.76 (s, 1H), 8.39 (s, 1H), 7.55 (s, 1H), 7.15-7.13 (m, 1H), 7.036.89 (tn, 4H), 6.03 (m, 3H), 1.41-1.38 (m, 2H), 1.32 (s, 9H), 1.04-1.01 (m, 2H)</td>

376

<td>Compound Well.</td><td>LC / MS M + 1</td><td>LC / RT min</td><td>NMR</td>

<td> 227</td><td> 393.3</td><td> 2.03</td><td></td>

<td> 228</td><td> 398.3</td><td> 1.24</td><td></td>

<td> 229</td><td> 487.2</td><td> 1.78</td><td></td>

<td> 230</td><td> 361.1</td><td> 3.47</td><td></td>

<td> 231</td><td> 435.5</td><td> 2.12</td><td></td>

<td> 232</td><td> 321.3</td><td> 2.91</td><td></td>

<td> 233</td><td> 413.3</td><td> 3.77</td><td></td>

<td> 234</td><td> 393.3</td><td> 1.58</td><td></td>

<td> 235</td><td> 465</td><td> 1.92</td><td></td>

<td> 236</td><td> 361.3</td><td> 3.18</td><td></td>

<td> 237</td><td> 421</td><td> 1.8</td><td></td>

<td> 238</td><td> 405.5</td><td> 3.79</td><td></td>

<td> 239</td><td> 544.3</td><td> 1.4</td><td></td>

<td> 240</td><td> 405.3</td><td> 3.9</td><td></td>