KR20110089170A - Modulators of atp-binding cassette transporters - Google Patents

Abstract

Compounds of the present invention and pharmaceutically acceptable compositions thereof are useful as modulators of ATP-binding cassette (“ABC”) transporters or fragments thereof comprising a cystic fibrosis transmembrane conductivity modulator (“CFTR”). The invention also relates to methods of treating ABC transporter mediated diseases using the compounds of the invention.

Description

Modulator of ATP-binding cassette transporter {MODULATORS OF ATP-BINDING CASSETTE TRANSPORTERS}

Cross Reference to Related Application

This application claims priority to US Application No. 61 / 112,152, filed November 6, 2008. The entire contents of US Application No. 61 / 112,152 are incorporated herein by reference.

Technical Field of the Invention

The present invention relates to regulators of ATP-binding cassette ("ABC") transporters or fragments thereof, such as Cystic Fibrosis Transmembrane Conductance Regulator ("CFTR"), compositions thereof and the use thereof. It is about a method. The present invention also relates to methods of treating ABC transporter mediated diseases using such modulators.

ABC transporters are a class of membrane transporter proteins that regulate the transport of a wide variety of pharmacological agents, potentially toxic drugs and bioforeigns, and also anions. ABC transporters are homologous membrane proteins that bind to and use adenosine triphosphate (ATP) in cells for specific activities. Some of these transporters have been found as multidrug resistant proteins (eg, MDR1-P glycoproteins or multidrug resistant proteins, MRP1) that defend malignant cancer cells against chemotherapeutic agents. To date, 48 ABC transporters have been identified and groups have been grouped into seven classes based on their sequence identity and function.

ABC transporters regulate various important physiological roles in the body and provide protection against harmful environmental compounds. As such, they are potentially important for intervention in other diseases where treatment of a disease associated with the defect of the transporter, prevention of drug transport outside the target cell, and modulation of ABC transporter activity may be beneficial. Represent the drug target.

One member of the ABC transporter class that is generally associated with disease is CFTR, a cAMP / ATP-mediated anion channel. CFTR is expressed in a variety of cell types, for example uptake and secretory epithelial cells, where it regulates the anion flow that occurs across the membrane and also the activity of other ion channels and proteins. In epithelial cells, normal functioning of CFTR is important for the maintenance of electrolyte transport throughout the body, including respiratory and digestive tissue. CFTR consists of approximately 1480 amino acids encoding a protein consisting of a transmembrane domain (containing six transmembrane helices each) and a parallel repeat of a nucleotide binding domain. The two transmembrane domains are linked by large polar regulatory (R) -domains with multiple phosphorylation sites that regulate channel activity and cellular trafficking.

Genes encoding CFTR have been identified and sequenced (Gregory, RJ et al. (1990) Nature 347: 382-386, Rich, DP et al. (1990) Nature 347: 358-362), [ Riordan, JR et al. (1989) Science 245: 1066-1073). Defects in this gene cause mutations in CFTR that lead to cystic fibrosis ("CF"), the most common fatal genetic disease in humans. In the United States, about 1 in 2,500 infants develop cystic fibrosis. Within the general US population, up to 10 million people have a single copy of a defective gene with no apparent pathological effects. In contrast, individuals with two copies of the CF related genes suffer from the debilitating and lethal effects of CF, including chronic lung disease.

In patients with cystic fibrosis, mutations in endogenously expressed CFTR in the respiratory epithelium result in a decrease in apical anion secretion resulting in imbalances in ion and fluid transport. The resulting decrease in anion transport contributes to the accumulation of mucus in the lungs and the subsequent enhancement of microbial infections, which ultimately results in death of CF patients. In addition to respiratory diseases, CF patients typically suffer from gastrointestinal problems and pancreatic insufficiency and, if not treated, die. In addition, the majority of men with cystic fibrosis are infertile, and women with cystic fibrosis have reduced fertility. In contrast to the severe effects of two copies of the CF related genes, individuals with a single copy of the CF related genes show increased resistance to dehydration due to cholera and diarrhea-presumably due to the relatively high frequency of CF genes in the population. It is considered high.

Sequence analysis of the CFTR gene of the CF chromosome revealed various disease-causing mutations (Cutting, GR et al. (1990) Nature 346: 366-369, Dean, M. et al. (1990) Cell 61: 863: 870 and Kerem, BS. Et al. (1989) Science 245: 1073-1080, Kerem, BS et al. (1990) Proc. Natl. Acad. Sci. USA 87: 8447-8451). To date, more than 1000 disease-causing mutations have been identified in the CF gene (http://www.genet.sickkids.on.ca/cftr/). The most common mutation is the deletion of phenylalanine at position 508 of the CFTR amino acid sequence, generally referred to as ΔF508-CFTR. This mutation occurs in approximately 70% of cystic fibrosis cases and is associated with severe disease.

Residue 508 deletion in ΔF508-CFTR prevents neonatal proteins from correctly folding. This prevents the mutant protein from exiting the ER and trafficking into the plasma membrane. As a result, the number of channels present in the membrane is much less than that observed in cells expressing wild type CFTR. In addition to trafficking damage, these mutations result in defective channel gating. Overall, membrane channel count and gating defects in the membrane reduce anion transport across the epithelium, resulting in defects in ion and fluid transport (Quinton, P. M. (1990), FASEB J. 4: 2709-2727). However, studies have shown that a reduced number of ΔF508-CFTR present in the membrane is functional, although less than that of 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 cause defects in trafficking, synthesis, and / or channel gating can be up or down regulated to alter anion secretion and modify disease progression and / or severity. .

While CFTR transports not only anions but also various molecules, it is clear that this role (anion transport) is an important component of the transport of ions and water across the epithelium. Other elements are the epithelial Na ⁺ channel, ENaC, Na ⁺ / 2Cl involved in the uptake of chloride into the cell ^- comprises / K ⁺ co-transporter, Na ⁺ -K ⁺ -ATPase pump and the basolateral membrane K ⁺ channels.

These elements work together to achieve directional transport that occurs across the epithelium through their selective expression and intracellular localization. Chloride uptake is caused by the coordinated activity of ENaC and CFTR present in the apical membrane and the Na ⁺ -K ⁺ -ATPase pump and Cl ^- channel expressed on the basal surface of the cell. Secondary active transport of chloride from the luminal side results in the accumulation of intracellular chloride, which can then passively leave the cell through the Cl ⁻ channel, resulting in directional transport. Basolateral surface of Na ⁺ / 2Cl of ^- / K ⁺ co-transporter, Na ⁺ -K ⁺ -ATPase pump and the basolateral membrane K ⁺ channels and the placement of the inner cavity side CFTR balances the secretion of chloride via CFTR on the lumen side . Since water is probably not active transport per se, its flow across the epithelium depends on a small epithelial osmotic gradient generated by the mass flow of sodium and chloride.

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

COPD is characterized by airflow blockage that is progressive and not completely reversible. Airflow blockage is due to mucus oversecretion, emphysema and bronchiolitis. Activators of mutant or wild type CFTR provide a potential treatment for mucosal hypersecretion and mucosal c clearance clearance common to COPD. In particular, the increase in anion secretion across the CFTR may facilitate fluid transport to the airway surface liquid to hydrate the mucus and to optimize the ciliary fluid viscosity. This enhances mucosal clearance and reduces symptoms associated with COPD. Dry eye disease is characterized by the aqueous production of tears and reduction of abnormal tear film lipids, proteins and mucin profiles. There are many causes of dry eye, some of which include aging, LASIK surgery, arthritis, medications, chemical / thermal burns, allergies, and diseases such as cystic fibrosis and Sjogren's syndrome. Increasing anion secretion through CFTR increases corneal hydration by enhancing fluid transport from corneal endothelial cells and peri-eye glands. This will help alleviate the symptoms associated with dry eye disease. Sjogren's syndrome is an autoimmune disease in which the immune system attacks the entire moist glands of the body, including the eyes, mouth, skin, respiratory tissue, liver, vagina and digestive tract. Symptoms of this include dryness of the eyes, mouth and vagina and also lung disease. The disease is also associated with rheumatoid arthritis, systemic lupus, systemic sclerosis and polymyositis / dermatitis. Defects in protein trafficking are believed to cause the disease, which limits the treatment options available. Modulators of CFTR activity can hydrate several organs attacked by the disease and help increase the associated symptoms.

As discussed above, deletion of residue 508 of ΔF508-CFTR is believed to prevent the neoplastic protein from correctly folding, preventing these mutant proteins from exiting the ER and trafficking into the plasma membrane. As a result, mature proteins are present in insufficient amounts in the plasma membrane and chloride transport in epithelial tissues is significantly reduced. In fact, these cellular phenomena, the ER processing deficiencies of ABC transporters by the ER machinery, have been found to be the fundamental basis of not only CF disease but a wide variety of other isolated and genetic diseases. Two ways in which the ER mechanism may not function properly are loss of coupling with the ER efflux of proteins that induce proteolysis or ER accumulation of these defects / misfolding proteins (Aridor M, et al., Nature 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), Cross P., et al., Human Mut. , 14, pp. 186-198 (1999)]. Diseases associated with the first class of ER dysfunction include cystic fibrosis (due to misfolded ΔF508-CFTR as discussed above), hereditary emphysema (due to a1-antitrypsin (non-Piz variant)), hereditary hemochromatosis , Coagulation-fibrinolysis deficiency, such as protein C deficiency, type 1 hereditary angioedema, lipid processing deficiency, such as familial hypercholesterolemia, type 1 stromal granulomatosis, mubetaziproteinemia, lysosomal accumulation disease such as I-cell disease / Pseudo-Hurler, mucopolysaccharide deposition (due to lysosomal processing enzymes), Sandhof / Tay-Sachs (due to β-hexosaminidase), Crigler-Nazar -Najjar) Type II (due to UDP-glucuronyl-sialic acid-transferase), polyendocrine disease / hyperinsulinemia, diabetes mellitus (due to insulin receptor), laron dwarfism (due to growth hormone receptor), mai Eloperoxida Deficiency, primary hypothyroidism (due to preproparathyroid hormone), melanoma (duty to tyrosinase). Diseases associated with the second class of ER dysfunction include glycanosis CDG type 1, hereditary emphysema (due to α1-antitrypsin (PiZ variant)), congenital hyperthyroidism, incomplete osteoplasia (type I) , II, IV due to procollagen), hereditary hypofibrinemia (due to fibrinogen), ACT deficiency (due to α1-antichymotrypsin), diabetes insipidus (DI), neurophysiological DI (due to vasopressin hormone / V2-receptor) , Identity DI (due to aquaporin II), Charcot-Marie Tooth syndrome (due to peripheral myelin protein 22), Perlizaeus-Merzbacher disease, neurodegenerative disease Such as Alzheimer's disease (due to βAPP and presenilin), Parkinson's disease, amyotrophic lateral sclerosis, progressive nuclear palsy, peak disease, various polyglutamine nervous system disorders such as Huntington, spinal cord cerebellar ataxia type I, spinal cord and soft muscle Atrophy, dentatorubal pallidoluysian and myotonic dystrophy, and also cavernous encephalopathy such as hereditary Creutzfeldt-Jakob disease (due to prion protein processing defects), Fabry disease (lysosomal α-) Due to galactosidase A) and Straussler-Scheinker syndrome (due to Prp processing defects).

In addition to upregulation of CFTR activity, the reduction of anion secretion by CFTR modulators may be beneficial for the treatment of secretory diarrhea in which epithelial water transport is greatly increased due to the activation of chloride transport by secretagogues. The mechanism involves an increase in cAMP and stimulation of CFTR.

Although there are numerous causes of diarrhea, the main consequences of diarrheal disease due to excessive chloride transport are common to all, and include dehydration, acidosis, growth disorders, and death.

Acute and chronic diarrhea are major medical problems in many parts of the world. Diarrhea is a significant cause of malnutrition and is the primary cause of death (5,000,000 deaths annually) in children under five years of age.

Secretory diarrhea is also dangerous in patients with acquired immunodeficiency syndrome (AIDS) and chronic inflammatory bowel disease (IBD). Diarrhea occurs annually in 16 million travelers from developed industrial countries to developing countries, and the severity and number of cases of diarrhea vary by country and region of travel.

Diarrhea in livestock and pets such as cattle, pigs and horses, sheep, goats, cats, and dogs (also known as Scouts) is the leading cause of death for these animals. Diarrhea may occur due to any major metastasis, such as wetting or physical movement, and may also occur in response to various bacterial or viral infections, and generally occurs within the first few hours of the animal's life.

The most common diarrhea-causing bacteria is enterotoxin producing E. An E. coli (enterotoxigenic E. coli, ETEC). Common viral causes of diarrhea include rotavirus and coronavirus. Other infectious agents, particularly Cryptosporidium (Cryptosporidium), giardia (Giardia lamblia) and Salmonella (including Salmonella).

Symptoms of rotavirus infection include drainage, dehydration and weakness of wet feces. Coronaviruses cause more serious disease than newborn animals and have a higher mortality rate than rotavirus infections. However, often young animals can be infected with more than one virus or combination of viral and bacterial microorganisms at one time. This greatly increases the severity of the disease.

Thus, there is a need for modulators of ABC transporter activity and compositions thereof that can be used to modulate the activity of ABC transporters in mammalian cell membranes.

There is a need for a method of treating ABC transporter mediated diseases using such modulators of ABC transporter activity.

There is a need for a method of modulating ABC transporter activity in mammalian ex vivo cell membranes.

There is a need for modulators of CFTR activity that can be used to modulate the activity of CFTR in mammalian cell membranes.

There is a need for a method of treating CFTR-mediated diseases using such modulators of CFTR activity.

There is a need for a method of modulating CFTR activity in mammalian ex vivo cell membranes.

Summary of the Invention

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 are compounds having the formula (I) or a pharmaceutically acceptable salt thereof:

<Formula I>

Wherein R ₁ , R ₂ , ring A, ring B and n are defined below.

It has now also been found that the compounds of the present invention and their pharmaceutically acceptable compositions are useful as modulators of ABC transporter activity. These compounds are compounds having the formula (II) or a pharmaceutically acceptable salt thereof:

<Formula II>

Wherein R, R ₁ , R ₂ , R ₃ , R ₄ and R ₅ are defined below.

The compounds and pharmaceutically acceptable compositions include cystic fibrosis, hereditary emphysema, hereditary hemochromatosis, coagulation-fibrinolytic deficiency, such as protein C deficiency, type 1 hereditary angioedema, lipid processing deficiency, such as familial hypercholesterolemia, type 1 cancer Particulates, mubetalipoproteinemia, lysosomal accumulating diseases such as I-cell disease / caustic-Huller, mucopolysaccharide deposition, Sandhof / Tey-Sachs, Krigler-Nazar type II, polyendocrine disease / hyperinsulinemia, diabetes mellitus , Laron dwarfism, myeloperoxidase deficiency, primary hypothyroidism, melanoma, glycanosis CDG type 1, hereditary emphysema, congenital hyperthyroidism, incomplete osteoplasia, hereditary hypofibrosis, ACT deficiency, diabetes insipidus, Neurophysiological, identity, Sharco-Marytooth syndrome, Felizius-Mertzvaer's disease, neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, Atrophic lateral sclerosis, progressive nuclear palsy, peak disease, various polyglutamine nervous system disorders such as Huntington, spinal cord cerebellar ataxia type I, spinal cord and softening muscular dystrophy, dentatorumal palidoliusian and myotonic dystrophy, and also cavernous encephalopathy, such as It is useful for treating or reducing the severity of various diseases, disorders or conditions, including but not limited to hereditary Creutzfeldt-Jakob disease, Fabry disease, Straussler-Schainker syndrome, COPD, dry eye disease, and Sjogren's disease.

Detailed description of the invention

I. Definition

As used herein, the following definitions shall apply unless otherwise indicated.

As used herein, the term “ABC-transporter” means an ABC-transporter protein or fragment thereof comprising at least one binding domain, wherein the protein or fragment thereof is present in vivo or in vitro. As used herein, the term "binding domain" refers to the domain of an ABC-transporter capable of binding to a modulator. See, eg, Hwang, T. C. et al., J. Gen. Physiol. (1998): 111 (3), 477-90.

As used herein, the term “CFTR” means a cystic fibrosis transmembrane conductivity modulator or a mutation thereof that may have modulator activity, such as, but not limited to, ΔF508 CFTR and G551D CFTR (CFTR mutations). For example, see http://www.genet.sickkids.on.ca/cftr/).

As used herein, the term “modulation” means, for example, increasing or decreasing activity by a measurable amount. Compounds that modulate ABC transporter activity, such as CFTR activity by increasing the activity of ABC transporters, such as CFTR anion channels, are called agonists. Compounds that modulate ABC transporter activity, such as CFTR activity by reducing the activity of ABC transporters, such as CFTR anion channels, are called antagonists. Agonists interact with ABC transporters such as CFTR anion channels to increase the ability of the receptor to introduce intracellular signals in response to endogenous ligand binding. Antagonists interact with ABC transporters, such as CFTR, and compete with endogenous ligand (s) or substrate (s) for binding site (s) on the receptor to introduce intracellular signals in response to receptors on endogenous ligand binding. Reduces ability

The phrase “treating or reducing the severity of ABC transporter mediated disease” is not directly caused by the treatment of diseases caused directly by ABC transporter and / or CFTR activity and by ABC transporter and / or CFTR anion channel activity. Refers to both improving the symptoms of the disease. Examples of diseases with symptoms that may be affected by ABC transporter and / or CFTR activity include cystic fibrosis, hereditary emphysema, hereditary hemochromatosis, coagulation-fibrinolytic deficiency such as protein C deficiency, type 1 hereditary angioedema, lipids Processing deficiencies such as familial hypercholesterolemia, type 1 stromal granemia, mubetalipoproteinemia, lysosomal accumulation diseases such as I-cell disease / caustic-huller, mucopolysaccharide deposition, sandhof / tei-sax, Krigler-Nazar Type II, polyendocrine disease / hyperinsulinemia, diabetes mellitus, laron dwarfism, myeloperoxidase deficiency, primary hypothyroidism, melanoma, glycanosis CDG type 1, hereditary emphysema, congenital hyperthyroidism, incomplete bone Dysplasia, hereditary hypofibrosis, ACT deficiency, diabetes insipidus (DI), neurophysiological DI, neoplastic DI, Sharco-Marytus syndrome, Felizius-Mertzvacher's disease, renal Degenerative diseases such as Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, progressive nuclear palsy, peak disease, various polyglutamine nervous system disorders such as Huntington, spinal cord cerebellar ataxia type I, spinal cord and softening muscular dystrophy, dentatoruba palidoluitian And myotonic dystrophy, and also cavernous encephalopathy such as hereditary Creutzfeldt-Jakob disease, Fabry's disease, Straussler-Schainker syndrome, COPD, dry eye disease, and Sjogren's disease.

For the purposes of the present invention, chemical elements are identified according to Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 75th Ed. In addition, the general principles of organic chemistry are described in "Organic Chemistry", Thomas Sorrell, University Science Books, Sausolito: 1999 and "March's Advanced Organic Chemistry", 5th Ed., Ed .: Smith, M.B. and March, J., John Wiley & Sons, New York: 2001, the entire contents of which are incorporated herein by reference.

As described herein, a compound of the present invention may be optionally substituted with one or more substituents, for example as generally exemplified above or as exemplified by the particular class, subclass and species of the present invention.

As used herein, the term "aliphatic" includes the terms alkyl, alkenyl, alkynyl, each of which is optionally substituted as described below.

As used herein, an "alkyl" group refers to a saturated aliphatic hydrocarbon group containing 1 to 12 (eg 1 to 8, 1 to 6 or 1 to 4) carbon atoms. do. Alkyl groups may be linear 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. Alkyl groups include one or more substituents, such as halo, phospho, cycloaliphatic [eg, cycloalkyl or cycloalkenyl], heterocycloaliphatic [eg, heterocycloalkyl or heterocycloalkenyl], aryl, heteroaryl , Alkoxy, aroyl, heteroaroyl, acyl [eg, (aliphatic) carbonyl, (cycloaliphatic) carbonyl or (heterocycloaliphatic) carbonyl], nitro, cyano, amido [eg, (Cycloalkylalkyl) carbonylamino, arylcarbonylamino, aralkylcarbonylamino, (heterocycloalkyl) carbonylamino, (heterocycloalkylalkyl) carbonylamino, heteroarylcarbonylamino, heteroaralkylcarbonyl Amino alkylaminocarbonyl, cycloalkylaminocarbonyl, heterocycloalkylaminocarbonyl, arylaminocarbonyl or heteroarylaminocarbonyl], amino [ex. For example, aliphatic amino, cycloaliphatic amino or heterocycloaliphatic amino], sulfonyl [eg, aliphatic-SO _2- ], sulfinyl, sulfanyl, sulfoxy, urea, thiourea, sulfamoyl, sulfamide, oxo , Carboxy, carbamoyl, cycloaliphaticoxy, heterocycloaliphaticoxy, aryloxy, heteroaryloxy, aralkyloxy, heteroarylalkoxy, alkoxycarbonyl, alkylcarbonyloxy or hydroxy (ie Optionally substituted). Some non-limiting examples of substituted alkyl include carboxyalkyl (eg, HOOC-alkyl, alkoxycarbonylalkyl and alkylcarbonyloxyalkyl), cyanoalkyl, hydroxyalkyl, alkoxyalkyl, acylalkyl, aralkyl , (Alkoxyaryl) alkyl, (sulfonylamino) alkyl (eg (alkyl-SO ₂ -amino) alkyl), aminoalkyl, amidoalkyl, (cycloaliphatic) alkyl or haloalkyl.

As used herein, an "alkenyl" group contains 2 to 8 (eg, 2 to 12, 2 to 6, or 2 to 4) carbon atoms and at least one double bond. It refers to the aliphatic carbon group containing. Like alkyl groups, alkenyl groups can be linear or branched. Examples of alkenyl groups include, but are not limited to, allyl, isoprenyl, 2-butenyl and 2-hexenyl. Alkenyl groups include one or more substituents, such as halo, phospho, cycloaliphatic [eg, cycloalkyl or cycloalkenyl], heterocycloaliphatic [eg, heterocycloalkyl or heterocycloalkenyl], aryl, hetero Aryl, alkoxy, aroyl, heteroaroyl, acyl [eg, (aliphatic) carbonyl, (cycloaliphatic) carbonyl or (heterocycloaliphatic) carbonyl], nitro, cyano, amido [eg , (Cycloalkylalkyl) carbonylamino, arylcarbonylamino, aralkylcarbonylamino, (heterocycloalkyl) carbonylamino, (heterocycloalkylalkyl) carbonylamino, heteroarylcarbonylamino, heteroaralkylcarbon Carbonylamino alkylaminocarbonyl, cycloalkylaminocarbonyl, heterocycloalkylaminocarbonyl, arylaminocarbonyl or heteroarylaminocarbonyl], amino [example For example, aliphatic amino, cycloaliphatic amino, heterocycloaliphaticamino or aliphaticsulfonylamino], sulfonyl [eg, alkyl-SO _2- , cycloaliphatic-SO ₂ -or aryl-SO _2- ], sulfinyl , Sulfanyl, sulfoxy, urea, thiourea, sulfamoyl, sulfamide, oxo, carboxy, carbamoyl, cycloaliphaticoxy, heterocycloaliphaticoxy, aryloxy, heteroaryloxy, aralkyloxy, heteroaralkoxy, Optionally substituted with alkoxycarbonyl, alkylcarbonyloxy or hydroxy. Some non-limiting examples of substituted alkenyl include cyanoalkenyl, alkoxyalkenyl, acylalkenyl, hydroxyalkenyl, aralkenyl, (alkoxyaryl) alkenyl, (sulfonylamino) alkenyl (eg (Alkyl-SO ₂ -amino) alkenyl), aminoalkenyl, amidoalkenyl, (cycloaliphatic) alkenyl or haloalkenyl.

As used herein, an "alkynyl" group contains from 2 to 8 (eg, 2 to 12, 2 to 6 or 2 to 4) carbon atoms and at least one triple bond. It refers to the aliphatic carbon group containing. Alkynyl groups can be linear or branched. Examples of alkynyl groups include, but are not limited to, propargyl and butynyl. Alkynyl groups include one or more substituents, such as aroyl, heteroaroyl, alkoxy, cycloalkyloxy, heterocycloalkyloxy, aryloxy, heteroaryloxy, aralkyloxy, nitro, carboxy, cyano, halo, hydroxy, Sulfo, mercapto, sulfanyl [eg, aliphaticsulfanyl or cycloaliphaticsulfanyl], sulfinyl [eg, aliphatic sulfinyl or cycloaliphaticsulfinyl], sulfonyl [eg, aliphatic-SO ₂ -, Aliphatic amino-SO ₂ -or cycloaliphatic-SO _2- ], amido [eg, aminocarbonyl, alkylaminocarbonyl, alkylcarbonylamino, cycloalkylaminocarbonyl, heterocycloalkylaminocarbonyl , Cycloalkylcarbonylamino, arylaminocarbonyl, arylcarbonylamino, aralkylcarbonylamino, (heterocycloalkyl) carbonylamino, (cycloalkylalkyl) carbonylamino, heteroaralkylcarbon Carbonylamino, heteroarylcarbonylamino or heteroarylaminocarbonyl], urea, thiourea, sulfamoyl, sulfamide, alkoxycarbonyl, alkylcarbonyloxy, cycloaliphatic, heterocycloaliphatic, aryl, heteroaryl, acyl [ For example, (cycloaliphatic) carbonyl or (heterocycloaliphatic) carbonyl], amino [eg, aliphaticamino], sulfoxy, oxo, carboxy, carbamoyl, (cycloaliphatic) oxy, (heterocyclo And optionally substituted with aliphatic) oxy or (heteroaryl) alkoxy.

As used herein, "amido" includes both "aminocarbonyl" and "carbonylamino". When these terms are used alone or in combination with another group, these are amido groups, such as -N (R ^X ) -C (O) -R ^Y or -C (O) -N (R ^X ) ₂ (terminal When used in and -C (O) -N (R ^X )-or -N (R ^X ) -C (O)-(if used internally), where R ^X and R ^Y are defined below ). Examples of amido groups include alkylamido (eg, alkylcarbonylamino or alkylaminocarbonyl), (heterocycloaliphatic) amido, (heteroaralkyl) amido, (heteroaryl) amido, (heterocyclo Alkyl) alkylamido, arylamido, aralkylamido, (cycloalkyl) alkylamido or cycloalkylamido.

As used herein, an “amino” group is —NR ^X R ^Y wherein each of R ^X and R ^Y is independently hydrogen, aliphatic, cycloaliphatic, (cycloaliphatic) aliphatic, aryl, araliphatic, heterocycloaliphatic, (Heterocycloaliphatic) aliphatic, heteroaryl, carboxy, sulfanyl, sulfinyl, sulfonyl, (aliphatic) carbonyl, (cycloaliphatic) carbonyl, ((cycloaliphatic) aliphatic) carbonyl, arylcarbonyl, (ar Aliphatic) carbonyl, (heterocycloaliphatic) carbonyl, ((heterocycloaliphatic) aliphatic) carbonyl, (heteroaryl) carbonyl or (heteroaraliphatic) carbonyl, each of which is defined herein and optionally substituted It is referred to. Examples of amino groups include alkylamino, dialkylamino or arylamino. If the term "amino" is not a terminal group (eg alkylcarbonylamino), it is represented by -NR ^X- . R ^X has the same meaning as defined above.

As used herein, an "aryl" group is used alone or as part of a larger moiety, such as in "aralkyl", "aralkoxy" or "aryloxyalkyl", and is monocyclic (eg, phenyl ), Bicyclic (eg, indenyl, naphthalenyl, tetrahydronaphthyl, tetrahydroindenyl) and tricyclic (eg, fluorenyl, tetrahydrofluorenyl or tetrahydroanthracenyl, anthra Cenyl) ring system, wherein the monocyclic ring system is aromatic or at least one ring of the bicyclic or tricyclic ring system is aromatic. Bicyclic and tricyclic groups include benzo-fused 2- to 3-membered carbocyclic rings. For example, a benzo-fused groups include two or more C ₄ carboxylic _-8-phenyl fused with carbocyclic moieties. Aryl is one or more substituents, for example aliphatic [eg, alkyl, alkenyl or alkynyl]; Cycloaliphatic; (Cycloaliphatic) aliphatic; Heterocycloaliphatic; (Heterocycloaliphatic) aliphatic; Aryl; Heteroaryl; Alkoxy; (Cycloaliphatic) oxy; (Heterocycloaliphatic) oxy; Aryloxy; Heteroaryloxy; (Araliphatic) oxy; (Heteroaraliphatic) oxy; Aroyl; Heteroaroyl; Amino; Oxo (in the non-aromatic carbocyclic ring of benzo-fused bicyclic or tricyclic aryl); Nitro; Carboxy; Amido; Acyl [eg, (aliphatic) carbonyl; (Cycloaliphatic) carbonyl; ((Cycloaliphatic) aliphatic) carbonyl; (Araliphatic) carbonyl; (Heterocycloaliphatic) carbonyl; ((Heterocycloaliphatic) aliphatic) carbonyl; Or (heteroaraliphatic) carbonyl]; Sulfonyl [eg, aliphatic-SO ₂ -or amino-SO _2- ]; Sulfinyl [eg, aliphatic-S (O)-or cycloaliphatic-S (O)-]; Sulfanyl [eg, aliphatic-S-]; Cyano; Halo; Hydroxy; Mercapto; Sulfoxy; Urea; Thiourea; Sulfamoyl; Sulfamide; Or optionally substituted with carbamoyl. Alternatively, aryl may be unsubstituted.

Non-limiting examples of substituted aryls include haloaryl [eg, monohaloaryl, dihaloaryl (eg, p, m-dihaloaryl) and (trihalo) aryl]; (Carboxy) aryl [eg, (alkoxycarbonyl) aryl, ((aralkyl) carbonyloxy) aryl and (alkoxycarbonyl) aryl); (Amido) aryl [eg, (aminocarbonyl) aryl, (((alkylamino) alkyl) aminocarbonyl) aryl, (alkylcarbonyl) aminoaryl, (arylaminocarbonyl) aryl and ((( Heteroaryl) amino) carbonyl) aryl]; Aminoaryl [eg, ((alkylsulfonyl) amino) aryl or ((dialkyl) amino) aryl]; (Cyanoalkyl) aryl; (Alkoxy) aryl; (Sulfamoyl) aryl [eg, (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; p-amino-m-alkoxycarbonylaryl; p-amino-m-cyanoaryl; p-halo-m-aminoaryl; Or (m- (heterocycloaliphatic) -o- (alkyl)) aryl.

As used herein, (e.g., C _{1 -4} alkyl group), "araliphatic", e.g., "aralkyl" group is an aliphatic group substituted with an aryl group refers to. "Alkali", "alkyl" and "aryl" are defined herein. An example of an araliphatic, such as aralkyl group is benzyl.

As used herein, "aralkyl" group (e.g., C _{1 -4} alkyl group), a substituted alkyl group with an aryl group refers to. "Alkyl" and "aryl" are both defined above. An example of an aralkyl group is benzyl. Aralkyl has one or more substituents such as aliphatic [eg, alkyl, alkenyl or alkynyl such as carboxyalkyl, hydroxyalkyl, or haloalkyl such as trifluoromethyl], cycloaliphatic [eg , Cycloalkyl or cycloalkenyl], (cycloalkyl) alkyl, heterocycloalkyl, (heterocycloalkyl) alkyl, aryl, heteroaryl, alkoxy, cycloalkyloxy, heterocycloalkyloxy, aryloxy, heteroaryloxy, ar Alkyloxy, heteroaralkyloxy, aroyl, heteroaroyl, nitro, carboxy, alkoxycarbonyl, alkylcarbonyloxy, amido [eg, 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 or carba Optionally substituted with moles.

As used herein, “bicyclic ring system” includes structures of 8 to 12 members (eg, 9, 10 or 11 members) that form two rings, wherein the two rings Shares at least one atom (eg, shares two atoms). Bicyclic ring systems include bicycloaliphatic (eg, bicycloalkyl or bicycloalkenyl), bicycloheteroaliphatic, bicyclic aryl and bicyclic heteroaryl.

As used herein, a "carbocycle" or "cycloaliphatic" group includes a "cycloalkyl" group and a "cycloalkenyl" group, each of which is optionally substituted as described below.

As used herein, a "cycloalkyl" group refers to a saturated carbocyclic monocyclic or bicyclic (fused or bridged) ring of 3 to 10 (eg 5 to 10) carbon atoms. Refer. Examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, adamantyl, norbornyl, kubil, 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.

As used herein, a "cycloalkenyl" group refers to a non-aromatic carbocyclic ring of 3 to 10 (eg, 4 to 8) carbon atoms with one or more double bonds. Examples of cycloalkenyl groups include cyclopentenyl, 1,4-cyclohexa-di-enyl, cycloheptenyl, cyclooctenyl, hexahydro-indenyl, octahydro-naphthyl, cyclohexenyl, cyclopentenyl, b Cyclo [2.2.2] octenyl or bicyclo [3.3.1] nonenyl.

A cycloalkyl or cycloalkenyl group is one or more substituents, such as phosphors, aliphatic [eg alkyl, alkenyl or alkynyl], cycloaliphatic, (cycloaliphatic) aliphatic, heterocycloaliphatic, (heterocycloaliphatic) aliphatic , Aryl, heteroaryl, alkoxy, (cycloaliphatic) oxy, (heterocycloaliphatic) oxy, aryloxy, heteroaryloxy, (araliphatic) oxy, (heteroaraliphatic) oxy, aroyl, heteroaroyl, amino, Amido [eg, (aliphatic) carbonylamino, (cycloaliphatic) carbonylamino, ((cycloaliphatic) aliphatic) carbonylamino, (aryl) carbonylamino, (araliphatic) carbonylamino, (hetero Cycloaliphatic) carbonylamino, ((heterocycloaliphatic) aliphatic) carbonylamino, (heteroaryl) carbonylamino or (heteroaraliphatic) carbonylamino], nitro, carboxy [eg, HOOC-, alkoxycarbonyl or alkylcarbonyloxy], acyl [e.g. (cycloaliphatic) carbonyl, ((cycloaliphatic) aliphatic) carbonyl, (araliphatic) carbonyl, (heterocycloaliphatic) carbonyl , ((Heterocycloaliphatic) aliphatic) carbonyl or (heteroaraliphatic) carbonyl], cyano, halo, hydroxy, mercapto, sulfonyl [e.g. alkyl-SO ₂ -and aryl-SO _2- ], Sulfinyl [eg alkyl-S (O)-], sulfanyl [eg alkyl-S-], sulfoxy, urea, thiourea, sulfamoyl, sulfamide, oxo or carbamoyl May be optionally substituted with.

As used herein, the term “heterocycle” or “heterocycloaliphatic” includes heterocycloalkyl groups and heterocycloalkenyl groups, each of which is optionally substituted as follows.

As used herein, a "heterocycloalkyl" group is a 3-10 membered monocyclic or bicyclic (fused or bridged) (eg, 5-10 membered monocyclic or bicyclic) group. Refers to a saturated ring structure, wherein at least one ring atom is a heteroatom (eg, N, O, S, or a combination thereof). Examples of heterocycloalkyl groups are piperidyl, piperazil, tetrahydropyranyl, tetrahydrofuryl, 1,4-dioxolanyl, 1,4-ditianyl, 1,3-dioxolanyl, oxazolidyl, isox Sazolidyl, morpholinyl, thiomorpholinyl, octahydrobenzofuryl, octahydrochromenyl, octahydrothiochromenyl, octahydroindolyl, octahydropyridinyl, decahydroquinolinyl, octahydrobenzo [b ] Thiopheneyl, 2-oxa-bicyclo [2.2.2] octyl, 1-aza-bicyclo [2.2.2] octyl, 3-aza-bicyclo [3.2.1] octyl and 2,6-dioxa -Tricyclo [3.3.1.0 ^3,7 ] nonyl. Monocyclic heterocycloalkyl groups can be fused with a phenyl moiety to form a structure classified as heteroaryl, such as tetrahydroisoquinoline.

As used herein, a "heterocycloalkenyl" group is a monocyclic or bicyclic (eg, 5-10 membered monocyclic or bicyclic) non-aromatic ring structure having one or more double bonds. Wherein at least one ring atom is a heteroatom (eg, N, O or S). Monocyclic and bicyclic heterocycloaliphatics are numbered according to standard chemical nomenclature.

Heterocycloalkyl or heterocycloalkenyl groups include one or more substituents, such as phosphors, aliphatic [eg, alkyl, alkenyl or alkynyl], cycloaliphatic, (cycloaliphatic) aliphatic, heterocycloaliphatic, (heterocycloaliphatic) ) Aliphatic, aryl, heteroaryl, alkoxy, (cycloaliphatic) oxy, (heterocycloaliphatic) oxy, aryloxy, heteroaryloxy, (araliphatic) oxy, (heteroaraliphatic) oxy, aroyl, heteroaroyl, Amino, amido [eg, (aliphatic) carbonylamino, (cycloaliphatic) carbonylamino, ((cycloaliphatic) aliphatic) carbonylamino, (aryl) carbonylamino, (araliphatic) carbonylamino, (Heterocycloaliphatic) carbonylamino, ((heterocycloaliphatic) aliphatic) carbonylamino, (heteroaryl) carbonylamino or (heteroaraliphatic) carbonylamino], nitro, carboxy [Eg HOOC-, alkoxycarbonyl or alkylcarbonyloxy], acyl [eg (cycloaliphatic) carbonyl, ((cycloaliphatic) aliphatic) carbonyl, (araliphatic) carbonyl, (hetero Cycloaliphatic) carbonyl, ((heterocycloaliphatic) aliphatic) carbonyl or (heteroaraliphatic) carbonyl], nitro, cyano, halo, hydroxy, mercapto, sulfonyl [e.g., alkylsulfonyl or Arylsulfonyl], sulfinyl [eg, alkylsulfinyl], sulfanyl [eg, alkylsulfanyl], sulfoxy, urea, thiourea, sulfamoyl, sulfamide, oxo or carbamoyl, optionally Can be substituted.

As used herein, a "heteroaryl" group refers to a monocyclic, bicyclic or tricyclic ring system having 4 to 15 ring atoms, wherein at least one ring atom is a heteroatom (eg, N, O, S, or a combination thereof) and the monocyclic ring system is aromatic or at least one ring of the bicyclic or tricyclic ring system is aromatic. Heteroaryl groups include benzo-fused ring systems having two or three rings. For example, benzo-fused groups include benzo fused with one or two 4- to 8-membered heterocycloaliphatic moieties (eg, indoli, indolyl, isoindoleyl, 3H-indolyl) , Indolinyl, benzo [b] furyl, benzo [b] thiophenyl, quinolinyl or isoquinolinyl). Some examples of heteroaryls are azetidinyl, pyridyl, 1H-indazolyl, furyl, pyrrolyl, thienyl, thiazolyl, oxazolyl, imidazolyl, tetrazolyl, benzofuryl, isoquinolinyl, benzthiazolyl , Xanthene, thioxanthene, phenothiazine, dihydroindole, benzo [1,3] dioxol, benzo [b] furyl, benzo [b] thiophenyl, indazolyl, benzimidazolyl, benzthiazolyl, Furyl, cinnoyl, quinolyl, quinazolyl, cinnoyl, phthalazyl, quinazolyl, quinoxalyl, isoquinolyl, 4H-quinolizyl, benzo-1,2,5-thiadiazolyl or 1,8- It is naphthyridil.

Non-limiting, monocyclic heteroaryl is furyl, thiophenyl, 2H-pyrrolyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, 1,3,4 -Thiadiazolyl, 2H-pyranyl, 4H-pyranyl, pyridyl, pyridazyl, pyrimidyl, pyrazolyl, pyrazyl or 1,3,5-triazyl. Monocyclic heteroaryls are numbered according to standard chemical nomenclature.

Non-limitingly, bicyclic heteroaryls include indolizil, indolyl, isoindoleyl, 3H-indolyl, indolinyl, benzo [b] furyl, benzo [b] thiophenyl, quinolinyl, isoquinolinyl, Indolinyl, isoindoleyl, indolyl, benzo [b] furyl, benzo [b] thiophenyl, indazolyl, benzimidazyl, benzthiazolyl, purinyl, 4H-quinolizyl, quinolyl, isoquinolyl , Cinnalol, phthalazyl, quinazolyl, quinoxalyl, 1,8-naphthyridyl or pteridyl. Bicyclic heteroaryls are numbered according to standard chemical nomenclature.

Heteroaryl may be selected from one or more substituents such as aliphatic [eg, alkyl, alkenyl or alkynyl]; Cycloaliphatic; (Cycloaliphatic) aliphatic; Heterocycloaliphatic; (Heterocycloaliphatic) aliphatic; Aryl; Heteroaryl; Alkoxy; (Cycloaliphatic) oxy; (Heterocycloaliphatic) oxy; Aryloxy; Heteroaryloxy; (Araliphatic) oxy; (Heteroaraliphatic) oxy; Aroyl; Heteroaroyl; Amino; Oxo (in the non-aromatic carbocyclic or heterocyclic ring of bicyclic or tricyclic heteroaryl); Carboxy; Amido; Acyl [eg, aliphatic carbonyl; (Cycloaliphatic) carbonyl; ((Cycloaliphatic) aliphatic) carbonyl; (Araliphatic) carbonyl; (Heterocycloaliphatic) carbonyl; ((Heterocycloaliphatic) aliphatic) carbonyl; Or (heteroaraliphatic) carbonyl]; Sulfonyl [eg, aliphaticsulfonyl or aminosulfonyl]; Sulfinyl [eg, aliphatic sulfinyl]; Sulfanyl [eg, aliphaticsulfanyl]; Nitro; Cyano; Halo; Hydroxy; Mercapto; Sulfoxy; Urea; Thiourea; Sulfamoyl; Sulfamide; Or optionally substituted with carbamoyl. Alternatively, heteroaryl may be unsubstituted.

Non-limiting examples of substituted heteroaryls include (halo) heteroaryl [eg, mono- (halo) heteroaryl and di- (halo) heteroaryl]; (Carboxy) heteroaryl [eg, (alkoxycarbonyl) heteroaryl]; Cyanoheteroaryl; Aminoheteroaryl [eg, ((alkylsulfonyl) amino) heteroaryl and ((dialkyl) amino) heteroaryl]; (Amido) heteroaryl [e.g., aminocarbonylheteroaryl, ((alkylcarbonyl) amino) heteroaryl, ((((alkyl) amino) alkyl) aminocarbonyl) heteroaryl, ((((heteroaryl ) Amino) carbonyl) heteroaryl, ((heterocycloaliphatic) carbonyl) heteroaryl and ((alkylcarbonyl) amino) heteroaryl]; (Cyanoalkyl) heteroaryl; (Alkoxy) heteroaryl; (Sulfamoyl) heteroaryl [eg, (aminosulfonyl) heteroaryl]; (Sulfonyl) heteroaryl [eg, (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 [e.g., (alkylcarbonyl) heteroaryl]; (alkyl) heteroaryl and (haloalkyl) heteroaryl [ For example, trihaloalkylheteroaryl].

As used herein, the term "heteroaryl araliphatic" (e.g., a heteroaralkyl group) refers to an aliphatic group (e.g., C _{1 -4} alkyl group) substituted with a heteroaryl group. "Alkali", "alkyl" and "heteroaryl" are defined above.

As used herein, (e.g., C _{1 -4} alkyl group) "heteroaralkyl" group is an alkyl group substituted with a heteroaryl group refers to. Both "alkyl" and "heteroaryl" are defined above. Heteroaralkyl has one or more substituents, such as alkyl (eg carboxyalkyl, hydroxyalkyl, and haloalkyl such as trifluoromethyl), alkenyl, alkynyl, cycloalkyl, (cycloalkyl) alkyl, hetero Cycloalkyl, (heterocycloalkyl) alkyl, aryl, heteroaryl, alkoxy, cycloalkyloxy, heterocycloalkyloxy, aryloxy, heteroaryloxy, aralkyloxy, heteroaralkyloxy, aroyl, heteroaroyl, nitro , Carboxy, alkoxycarbonyl, alkylcarbonyloxy, aminocarbonyl, alkylcarbonylamino, cycloalkylcarbonylamino, (cycloalkylalkyl) carbonylamino, arylcarbonylamino, aralkylcarbonylamino, (heterocyclo Alkyl) carbonylamino, (heterocycloalkylalkyl) carbonylamino, heteroarylcarbonylamino, heteroaralkylcarbonylamino, cyano, halo, hydroxide , Acyl, mercapto, alkyl sulfanyl, and is optionally substituted with sulfoxides, urea, thiourea, sulfamoyl, sulfanyl imide, oxo, or carbamoyl.

As used herein, "cyclic moieties" and "cyclic groups" refer to monocyclic, bicyclic and tricyclic ring systems such as cycloaliphatic, heterocycloaliphatic, aryl or heteroaryl (each of which is already Defined).

As used herein, “bridged bicyclic ring system” refers to a bicyclic heterocyclic aliphatic ring system or a bicyclic cycloaliphatic ring system bridged. Examples of bridged bicyclic ring systems include 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, including but not limited to. Bridged bicyclic ring systems include one or more substituents, such as alkyl (eg, 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, heteroaro 1, nitro, carboxy, alkoxycarbonyl, alkylcarbonyloxy, aminocarbonyl, alkylcarbonylamino, cycloalkylcarbonylamino, (cycloalkylalkyl) carbonylamino, arylcarbonylamino, aralkylcarbonylamino, (Heterocycloalkyl) carbonylamino, (heterocycloalkylalkyl) carbonylamino, heteroarylcarbonylamino, heteroaralkylcarbonylamino, cyano, halo , Hydroxy, it may be optionally substituted with acyl, mercapto, alkyl sulfanyl, sulfoxide, urea, thiourea, sulfamoyl, sulfanyl imide, oxo, or carbamoyl.

As used herein, an "acyl" group is a formyl group or R ^X -C (O)-(eg, alkyl-C (O)-(also referred to as "alkylcarbonyl")) (here , R ^X and "alkyl" have already been defined). Acetyl and pivaloyl are examples of acyl groups.

As used herein, "aroyl" or "heteroaroyl" refers to aryl-C (O)-or heteroaryl-C (O)-. The aryl and heteroaryl portions of aroyl or heteroaroyl are optionally substituted as previously defined.

As used herein, an "alkoxy" group refers to an alkyl-O- group, where "alkyl" has already been defined.

As used herein, a "carbamoyl" group is a structure -O-CO-NR ^X R ^Y or -NR ^X -CO-OR ^Z where R ^X and R ^Y are defined above and R ^Z is aliphatic , Aryl, araliphatic, heterocycloaliphatic, heteroaryl or heteroaraliphatic).

As used herein, a "carboxy" group is -COOH, -COOR ^X , -OC (O) H, -OC (O) R ^X (if used as terminal group) or -OC (O)-or -C ( O) O- (if used as internal group).

As used herein, "haloaliphatic" group refers to an aliphatic group substituted with 1 to 3 halogens. For example, the term haloalkyl includes a -CF ₃ group.

As used herein, a "mercapto" group refers to -SH.

As used herein, "sulfo" group refers to -SO ₃ H or -SO ₃ R ^X (if used at the end) or -S (O) _3- (if used internally).

As used herein, a "sulfamid" group has the structure -NR ^X -S (O) ₂ -NR ^Y R ^Z (if used at the end) and -NR ^X -S (O) ₂ -NR ^Y- (internal) As used herein, wherein R ^X , R ^Y and R ^Z are defined above.

As used herein, a "sulfonamide" group has the structure -S (O) ₂ -NR ^X R ^Y or -NR ^X -S (O) ₂ -R ^Z (if used at the end) or -S (O) ₂ -NR ^X -or -NR ^X -S (O) _2- (when used internally), wherein R ^X , R ^Y and R ^Z are defined above.

As used herein, “sulfanyl” groups refer to —SR ^X (when used at the end) and —S— (when used internally) where R ^X is defined above. Examples of sulfanyl include aliphatic-S-, cycloaliphatic-S-, aryl-S- and the like.

As used herein, "sulfinyl" groups are -S (O) -R ^X (when used at the end) and -S (O)-(when used internally), where R ^X is defined above Present). Exemplary sulfinyl groups are aliphatic-S (O)-, aryl-S (O)-, (cycloaliphatic (aliphatic))-S (O)-, cycloalkyl-S (O)-, heterocycloaliphatic-S ( O)-, heteroaryl-S (O)-, and the like.

As used herein, "sulfonyl" groups are -S (O) ₂ -R ^X (when used at the end) and -S (O) _2- (when used internally), where R ^X is Defined). Exemplary sulfonyl groups are aliphatic-S (O) _2- , aryl-S (O) _2- , (cycloaliphatic (aliphatic))-S (O) _2- , cycloaliphatic-S (O) _2- , heterocyclo Aliphatic-S (O) _2- , heteroaryl-S (O) _2- , (cycloaliphatic (amido (aliphatic)))-S (O) ₂ -and the like.

As used herein, "sulfoxy" groups are -O-SO-R ^X or -SO-OR ^X (if used at the end) and -OS (O)-or -S (O) -O- (internal) As used herein, wherein R ^X is defined above.

As used herein, "halogen" or "halo" group refers to fluorine, chlorine, bromine or iodine.

As used herein, "alkoxycarbonyl" is included in the term carboxy and used alone or in combination with another group to refer to a group such as alkyl-O-C (O)-.

As used herein, "alkoxyalkyl" refers to an alkyl group, such as alkyl-O-alkyl-, where alkyl is defined above.

As used herein, "carbonyl" refers to -C (O)-.

As used herein, “oxo” refers to ═O.

As used herein, the term “phospho” refers to phosphinates and phosphonates. Examples of phosphinates and phosphonates include -P (O) (R ^P ) ₂ , wherein R ^P is aliphatic, alkoxy, aryloxy, heteroaryloxy, (cycloaliphatic) oxy, (heterocycloaliphatic) oxy aryl , Heteroaryl, cycloaliphatic or amino).

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

As used herein, “cyanoalkyl” refers to the structure (NC) -alkyl-.

As used herein, a "urea" group refers to the structure -NR ^X -CO-NR ^Y R ^Z , a "thiourea" group refers to the structure -NR ^X -CS-NR ^Y R ^Z (when used at the end) and -NR ^X -CO-NR ^Y -or -NR ^X -CS-NR ^Y- (when used internally), wherein R ^X , R ^Y and R ^Z are defined above.

As used herein, a “guanidine” group has the structure —N═C (N (R ^X R ^Y )) N (R ^X R ^Y ) or —NR ^X —C (═NR ^X ) NR ^X R ^Y , wherein R ^X and R ^Y are defined above).

As used herein, the term “amidino” group refers to the structure —C═ (NR ^X ) N (R ^X R ^Y ), wherein R ^X and R ^Y are defined above.

In general, the term “vicinal” refers to the arrangement of substituents attached to adjacent carbon atoms in a group comprising two or more carbon atoms.

In general, the term “geminal” refers to the arrangement of substituents attached to the same carbon atom in a group comprising two or more carbon atoms.

The terms "terminally" and "inwardly" refer to the position of the corresponding group in the substituent. If a group is present at the end of a substituent and is not further bonded to the rest of the chemical structure, the group is terminal. Carboxyalkyl, ie R ^X O (O) C-alkyl, is an example where a carboxyl group is used at the end. If the group is in the middle of the substituent of the chemical structure the group is internal. Alkylcarboxy (eg alkyl-C (O) O- or alkyl-OC (O)-) and alkylcarboxyaryl (eg alkyl-C (O) O-aryl- or alkyl-O (CO) -Aryl-) is an example in which a carboxyl group is used therein.

As used herein, “aliphatic chain” refers to a branched or linear aliphatic group (eg, an alkyl group, alkenyl group or alkynyl group). The linear aliphatic chain has the structure-[CH ₂ ] _v- , where v is 1 to 12. Branched aliphatic chains are linear aliphatic chains substituted with one or more aliphatic groups. Branched aliphatic chains have the structure — [CQQ] _v −, wherein each Q is independently a hydrogen or aliphatic group, but Q is 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 defined above.

The phrase "optionally substituted" is used indistinguishably from the phrase "substituted or unsubstituted". As described herein, a compound of the present invention may be optionally substituted with one or more substituents, for example as generally exemplified above or as exemplified by the particular class, subclass and species of the present invention. As described herein, variable groups R ₁ , R ₂ and R ₃ , and other variable groups contained in the formulas described herein, include certain groups such as alkyl and aryl. Unless stated otherwise, each of the particular groups for the variable groups R ₁ , R ₂ and R ₃ and the other variable groups contained therein may be optionally substituted with one or more substituents described herein. Each substituent of a particular group is further optionally substituted with 1 to 3 halo, cyano, oxo, alkoxy, hydroxy, amino, nitro, aryl, cycloaliphatic, heterocycloaliphatic, heteroaryl, haloalkyl and alkyl. For example, an alkyl group may be substituted with alkylsulfanyl, wherein the alkylsulfanyl is optionally substituted with one to three halo, cyano, oxo, alkoxy, hydroxy, amino, nitro, aryl, haloalkyl and alkyl. Can be. As a further example, the cycloalkyl moiety of (cycloalkyl) carbonylamino may be optionally substituted with one to three halo, cyano, alkoxy, hydroxy, nitro, haloalkyl and alkyl. When two alkoxy groups are bonded to the same atom or to adjacent atoms, the two alkoxy groups may form a ring together with the atom (s) to which they are attached.

In general, the term "substituted" refers to the replacement of a hydrogen radical in a given structure with a radical of a specified substituent, whether or not preceded by the term "optionally". Specific substituents are described above in the definition section and below in the description of compounds and examples thereof. Unless otherwise indicated, optionally substituted groups may have a substituent at each substitutable position of that group, and in any given structure more than one position may be substituted with more than one substituent selected from the specified group May have the same or different substituents at all positions. Ring substituents, such as heterocycloalkyl, may be bonded to another ring, such as cycloalkyl, to form a spiro-bicyclic ring system, eg, both rings share one common atom. As will be appreciated by those skilled in the art, combinations of substituents contemplated in the present invention are those in which stable or chemically possible compounds are formed.

As used herein, the phrase “stable or chemically possible” is substantially used under conditions that allow the production, detection, and preferably recovery, purification, and use of one or more of the purposes disclosed herein. It refers to a compound that does not change to. In some embodiments, a stable compound or chemically possible compound is a compound that is substantially unchanged when maintained at a temperature of 40 ° C. or less for at least one week without moisture or other chemically reactive conditions.

As used herein, an "effective amount" is defined as the amount necessary to provide a therapeutic effect to a patient to be treated, and is typically determined based on the age, surface area, weight and condition of the patient. (Also in the body surface 1 m ² based on milligrams per) Correlation between dosages for animals and humans literature [Freireich et al., Cancer Chemother . Rep., 50: 219 (1966). Body surface area can be approximately determined from the height and weight of the patient. See, eg, Scientific Tables, Geigy Pharmaceuticals, Ardsley, New York, 537 (1970). As used herein, “patient” refers to a mammal, including humans.

Unless stated otherwise, the structures shown herein also include all isomeric (eg, enantiomers, diastereomers, and geometric (or conformational)) forms of the structure, eg, R for each asymmetric center and S configuration, (Z) and (E) double bond isomers, and (Z) and (E) form isomers. Accordingly, single stereochemical isomers and also enantiomeric, diastereomeric and geometric (or conformational) mixtures of the compounds of the invention are within the scope of the invention. Unless stated otherwise, all tautomeric forms of the compounds of the invention are included within the scope of the invention. Additionally, unless stated otherwise, the structures shown herein also include compounds that differ only in the presence of one or more isotope rich atoms. For example, compounds having the same structure as in the present invention are also included within the scope of the present invention except that hydrogen is replaced with deuterium or tritium, or carbon is replaced with ¹³ C- or ¹⁴ C-rich carbon. . Such compounds are useful, for example, as analytical tools or probes in biological assays or as therapeutic agents.

Compounds of the invention are useful modulators of ABC transporters and are useful for the treatment of ABC transporter mediated diseases.

II . compound

A. General Compound

The present invention relates to compounds of formula (I) or pharmaceutically acceptable salts thereof, useful as modulators of ABC transporter activity:

R ₁ is -Z ^A R _4, wherein each Z ^A is independently a bond or an optionally substituted branched or straight chain C _{1 -6} aliphatic chain wherein two carbon units of no more than the Z ^A is optionally and independently -CO-, -CS-, -CONR ^A- , -CONR ^A NR ^A- , -CO _2- , -OCO-, -NR ^A CO _2- , -O-, -NR ^A CONR ^A- , -OCONR ^A -, -NR ^A NR ^A- , -NR ^A CO-, -S-, -SO-, -SO _2- , -NR ^A- , -SO ₂ NR ^A- , -NR ^A SO ₂ -or -NR ^A Replaced by SO ₂ NR ^A −. Each R ₄ is independently R ^A , halo, —OH, —NH ₂ , —NO ₂ , —CN or —OCF ₃ . Each R ^A is independently hydrogen, optionally substituted aliphatic, optionally substituted cycloaliphatic, optionally substituted heterocycloaliphatic, optionally substituted aryl or optionally substituted heteroaryl.

R ₂ is -Z ^B R _5, wherein each of Z ^B are independently a bond or an optionally substituted branched or straight chain C _{1 -6} aliphatic chain wherein two carbon units of Z or fewer of ^B are optionally and independently -CO-, -CS-, -CONR ^B- , -CONR ^B NR ^B- , -CO _2- , -OCO-, -NR ^B CO _2- , -O-, -NR ^B CONR ^B- , -OCONR ^B -, -NR ^B NR ^B- , -NR ^B CO-, -S-, -SO-, -SO _2- , -NR ^B- , -SO ₂ NR ^B- , -NR ^B SO ₂ -or -NR ^B Replaced by SO ₂ NR ^B −. Each R ₅ is independently R ^B , halo, —OH, —NH ₂ , —NO ₂ , —CN, —CF ₃ or —OCF ₃ . Each R ^B is independently hydrogen, optionally substituted aliphatic, optionally substituted cycloaliphatic, optionally substituted heterocycloaliphatic, optionally substituted aryl or optionally substituted heteroaryl. Optionally, any two adjacent R ₂ groups together with the atoms to which they are attached form an optionally substituted carbocycle or an optionally substituted heterocycle.

Ring A is an optionally substituted 3-7 membered monocyclic ring having 0-3 heteroatoms selected from N, O and S.

Ring B is a group having the general formula (la) or a pharmaceutically acceptable salt thereof:

<Formula Ia>

Wherein, p is 0-3, and each R ₃ and R _'3 are independently -Z ^C R _6, wherein each Z ^C is independently a bond or an optionally substituted branched or straight chain C _{1 -6} aliphatic Chain and wherein up to _two carbon units of Z ^C are optionally and independently -CO-, -CS-, -CONR ^C- , -CONR ^C NR ^C- , -CO _2- , -OCO-, -NR ^C CO _2- , -O-, -NR ^C CONR ^C- , -OCONR ^C- , -NR ^C NR ^C- , -NR ^C CO-, -S-, -SO-, -SO _2- , -NR ^C- , Is replaced by -SO ₂ NR ^C- , -NR ^C SO ₂ -or -NR ^C SO ₂ NR ^C- . Each R ₆ is independently R ^C , halo, —OH, —NH ₂ , —NO ₂ , —CN or —OCF ₃ . Each R ^C is independently hydrogen, optionally substituted aliphatic, optionally substituted cycloaliphatic, optionally substituted heterocycloaliphatic, optionally substituted aryl or optionally substituted heteroaryl. Optionally, any two adjacent R ₃ groups together with the atoms to which they are attached form an optionally substituted carbocycle or an optionally substituted heterocycle. In addition, together with the atoms to which they are attached, the R ' ₃ and adjacent R ₃ groups form an optionally substituted heterocycle.

n is 1-3.

However, in some embodiments, when ring A is unsubstituted cyclopentyl, n is 1, R ₂ is 4-chloro and R ₁ is hydrogen, ring B is 2- (tert-butyl) indole-5 Not -yl or (2,6-dichlorophenyl (carbonyl))-3-methyl-1H-indol-5-yl; When ring A is unsubstituted cyclopentyl, n is 0 and R ₁ is hydrogen, ring B is

가 아니다.

Is not.

B. Specific Compounds

1.R ₁ group

R ₁ is -Z ^A R _4, wherein each Z ^A is independently a bond or an optionally substituted branched or straight chain C _{1 -6} aliphatic chain wherein two carbon units of no more than the Z ^A is optionally and independently -CO-, -CS-, -CONR ^A- , -CONR ^A NR ^A- , -CO _2- , -OCO-, -NR ^A CO _2- , -O-, -NR ^A CONR ^A- , -OCONR ^A -, -NR ^A NR ^A- , -NR ^A CO-, -S-, -SO-, -SO _2- , -NR ^A- , -SO ₂ NR ^A- , -NR ^A SO ₂ -or -NR ^A Replaced by SO ₂ NR ^A −. Each R ₄ is independently R ^A , halo, —OH, —NH ₂ , —NO ₂ , —CN or —OCF ₃ . Each R ^A is independently hydrogen, optionally substituted aliphatic, optionally substituted cycloaliphatic, optionally substituted heterocycloaliphatic, optionally substituted aryl or optionally substituted heteroaryl.

In many embodiments, R ₁ is -Z ^A R _4, wherein each Z ^A is independently a bond or an optionally substituted branched or straight chain C _{1 -6} aliphatic chain, and each R ₄ is hydrogen.

In other embodiments, R ₁ is —Z ^A R ₄ , wherein each Z ^A is a bond and each R ₄ is hydrogen.

2.R ₂ group

Each R ₂ is independently -Z ^B R _5, wherein each of Z ^B are independently a bond or an optionally branched or straight chain C _{1 -6} aliphatic chain substituted and wherein two carbon units of Z or fewer of ^B is Optionally and independently -CO-, -CS-, -CONR ^B- , -CONR ^B NR ^B- , -CO _2- , -OCO-, -NR ^B CO _2- , -O-, -NR ^B CONR ^B- , -OCONR ^B- , -NR ^B NR ^B- , -NR ^B CO-, -S-, -SO-, -SO _2- , -NR ^B- , -SO ₂ NR ^B- , -NR ^B SO _2- Or -NR ^B SO ₂ NR ^B- . Each R ₅ is independently R ^B , halo, —OH, —NH ₂ , —NO ₂ , —CN, —CF ₃ or —OCF ₃ . Each R ^B is independently hydrogen, optionally substituted aliphatic, optionally substituted cycloaliphatic, optionally substituted heterocycloaliphatic, optionally substituted aryl or optionally substituted heteroaryl. Optionally, any two adjacent R ₂ groups together with the atoms to which they are attached form an optionally substituted carbocycle or an optionally substituted heterocycle.

In some embodiments, R ₂ is optionally substituted aliphatic. For example, R ₂ is an optionally substituted branched or straight chain C _{1 -6} aliphatic chain. In another example, R ₂ is an optionally substituted branched or straight chain C _{1 -6} alkyl chain, optionally substituted branched or straight-chain C _{2 -6} alkenyl chain or optionally branched or straight chain C _{2 -6} substituted Alkynyl chains. In an alternative embodiment, R ₂ is one to three halo, hydroxy, cyano, cycloaliphatic, heterocyclo aliphatic, aryl, branched or straight chain, optionally substituted by heteroaryl or a combination thereof C _{1 -6} aliphatic chain . For example, R ₂ is one to three halo, hydroxy, cyano, a cycloaliphatic, heterocyclo aliphatic, aryl, heteroaryl or an optionally substituted branched or straight-chain minutes combination thereof C _{1 -6} alkyl. In yet other examples, R ₂ is methyl, ethyl, propyl, butyl, isopropyl or tert-butyl, each of 1-3 halo, hydroxy, cyano, aryl, heteroaryl, cycloaliphatic or heterocyclo Optionally substituted with aliphatic; In yet other examples, R ₂ is methyl, ethyl, propyl, butyl, isopropyl or tert-butyl, each of which is unsubstituted.

In various other embodiments, R ₂ is an optionally substituted branched or straight chain C _{1 -5} alkoxycarbonyl. For example, R ₂ is an optionally substituted C _{1 -5} alkoxycarbonyl with 1 to 3 hydroxy, aryl, heteroaryl, cycloaliphatic, heteroaryl, cycloaliphatic, or combinations thereof. In another example, R ₂ is methoxy, ethoxy, propoxy, butoxy or pentoxy, each of which is optionally substituted with 1-3 hydroxy, aryl, heteroaryl, cycloaliphatic, heterocycloaliphatic or combinations thereof do.

In other embodiments, R ₂ is hydroxy, halo or cyano.

In many embodiments, R ₂ is -Z ₅ and R ^B, Z ^B is independently a bond or an optionally substituted branched or straight chain C _{1 -4} aliphatic chain wherein two carbon units of Z or fewer of ^B are optionally and Independently is replaced by -C (O)-, -O-, -S-, -S (O) ₂ -or -NH-, R ₅ is R ^B , halo, -OH, -NH ₂ , -NO ₂ , -CN, -CF ₃ or -OCF ₃ , and R ^B is hydrogen or aryl.

In various embodiments, two adjacent R ₂ groups form an optionally substituted carbocycle or an optionally substituted heterocycle. For example, two adjacent R ₂ groups form an optionally substituted carbocycle or an optionally substituted heterocycle, one of which is fused to a phenyl of Formula I, wherein the carbocycle or heterocycle is represented by Formula Ib Has:

<Formula Ib>

.

.

Each Z ₁ , Z ₂ , Z ₃ , Z ₄ and Z ₅ is independently a bond, —CR ₇ R ′ _7- , —NR ₇ — or —O—; Each R ₇ is independently -Z ^D R _8, wherein each Z ^D are independently selected from optionally branched or straight chain C _{1 -6} aliphatic chain substituted and wherein no more than two carbon units of Z are optionally and ^D Independently -CO-, -CS-, -CONR ^D- , -CO _2- , -OCO-, -NR ^D CO _2- , -O-, -NR ^D CONR ^D- , -OCONR ^D- , -NR ^D NR ^D- , -NR ^D CO-, -S-, -SO-, -SO _2- , -NR ^D- , -SO ₂ NR ^D- , -NR ^D SO ₂ -or -NR ^D SO ₂ NR ^D- Is replaced by Each R ₈ is independently R ^D , halo, —OH, —NH ₂ , —NO ₂ , —CN, —CF ₃ or —OCF ₃ . 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 C _1-6 aliphatic, hydroxy, halo, cyano, nitro or combinations thereof. Optionally, any two adjacent R ₇ 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 R ₇ and R ' ₇ group together with the atom or atoms to which they are attached form an optionally substituted 3-7 membered carbocyclic ring or heterocarbocyclic ring.

In other instances, two adjacent R ₂ groups form an optionally substituted carbocycle. For example, two adjacent R ₂ groups form an optionally substituted 5-7 membered carbocycle optionally substituted with 1-3 halo, hydroxy, cyano, oxo, cyano, alkoxy, alkyl or combinations thereof do. In another example, two adjacent R ₂ groups form a 5-6 membered carbocycle optionally substituted with 1-3 halo, hydroxy, cyano, oxo, cyano, alkoxy, alkyl or combinations thereof. In yet another example, two adjacent R ₂ groups form an unsubstituted 5-7 membered carbocycle.

In an alternative example, two adjacent R ₂ groups form an optionally substituted heterocycle. For example, two adjacent R ₂ groups form an optionally substituted 5-7 membered heterocycle having 1-3 heteroatoms independently selected from N, O and S. In many instances, two adjacent R ₂ groups form an optionally substituted 5-6 membered heterocycle having 1-2 oxygen atoms. In another example, two adjacent R ₂ groups form an unsubstituted 5-7 membered heterocycle having 1-2 oxygen atoms. In other embodiments, two adjacent R ₂ groups form a heterocyclic ring selected from:

In an alternative example, two adjacent R ₂ groups form an optionally substituted carbocycle or optionally substituted heterocycle and a third R ₂ group is attached at any chemically possible position on the phenyl of Formula (I). For example, two adjacent R ₂ groups; Third R ₂ group; And optionally substituted carbocycle or optionally substituted heterocycle formed by phenyl of formula (I) forms a group having formula (Ic):

<Formula Ic>

.

.

Z ₁ , Z ₂ , Z ₃ , Z ₄ and Z ₅ are defined above in formula Ib and R ₂ is defined above in formula I.

In various embodiments, each R ₂ group is independently selected from hydrogen, halo, —OCH ₃ , —OH, —CH ₂ OH, —CH ₃ and —OCF ₃ and / or two adjacent R ₂ groups to which they are attached With atoms

을 형성한다.

To form.

In other embodiments, R ₂ is one or more selected from hydrogen, halo, methoxy, phenylmethoxy, hydroxy, hydroxymethyl, trifluoromethoxy and methyl.

를 형성한다.In some embodiments, two adjacent R ₂ groups are taken together with the atoms to which they are attached

To form.

3. Ring A

Ring A is an optionally substituted 3-7 membered monocyclic ring having 0-3 heteroatoms selected from N, O and S.

In various embodiments, Ring A is optionally substituted 3-7 membered monocyclic cycloaliphatic. For example, ring A is cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl or cycloheptyl, each of which is optionally substituted with one to three halo, hydroxy, C _{1 -5} aliphatic or a combination thereof.

In other embodiments, Ring A is optionally substituted 3-7 membered monocyclic heterocycloaliphatic. For example, ring A is an optionally substituted 3-7 membered monocyclic heterocycloaliphatic having 1-2 heteroatoms independently selected from N, O and S. In another example, Ring A is tetrahydrofuran-yl, tetrahydro-2H-pyran-yl, pyrrolidone-yl or piperidin-yl, each of which is optionally substituted.

In yet another example, Ring A is

로부터 선택된다.

Is selected from.

Each R ₈ is independently -Z ^E R _9, wherein each Z ^E is independently a bond or an optionally substituted branched or straight chain C _{1 -5} aliphatic chain wherein two carbon units of Z ^E is no more than the Optionally and independently -CO-, -CS-, -CONR ^E- , -CO _2- , -OCO-, -NR ^E CO _2- , -O-, -NR ^E CONR ^E- , -OCONR ^E -,- NR ^E NR ^E- , -NR ^E CO-, -S-, -SO-, -SO _2- , -NR ^E- , -SO ₂ NR ^E- , -NR ^E SO ₂ -or -NR ^E SO ₂ NR Substituted by ^E −, each R ₉ is independently R ^E , —OH, —NH ₂ , —NO ₂ , —CN, —CF ₃ , oxo or —OCF ₃ . Each R ^E is independently hydrogen, optionally substituted cycloaliphatic, optionally substituted heterocycloaliphatic, optionally substituted aryl or optionally substituted heteroaryl.

q is 0-5.

In other embodiments, Ring A is

로부터 선택된다.

Is selected from.

이다.In various embodiments, Ring A is

to be.

4. Ring B

Ring B is a group having the general formula (la) or a pharmaceutically acceptable salt thereof:

<Formula Ia>

Wherein p is 0-3.

Each of R ₃ and R _'3 are independently -Z ^C R _6, wherein each Z ^C is independently a bond or an optionally substituted branched or straight chain C _{1 -6} aliphatic chain wherein up to two of Z ^C The carbon units of are optionally and independently -CO-, -CS-, -CONR ^C- , -CONR ^C NR ^C- , -CO _2- , -OCO-, -NR ^C CO _2- , -O-, -NR ^C CONR ^C- , -OCONR ^C- , -NR ^C NR ^C- , -NR ^C CO-, -S-, -SO-, -SO _2- , -NR ^C- , -SO ₂ NR ^C- , -NR ^C SO ₂ -or -NR ^C SO ₂ NR ^C- . Each R ₆ is independently R ^C , halo, —OH, —NH ₂ , —NO ₂ , —CN or —OCF ₃ . 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 R ₃ groups form a carbocycle or heterocycle optionally substituted optionally substituted with atoms to which they are attached, or attached to the 2-position of the formula (Ia) indole, R _'3, and Adjacent R ₃ together with the atoms to which they are attached form an optionally substituted heterocycle.

In various embodiments, ring B is

이다.

to be.

Where q is 0 to 3 and each R ₂₀ is R ₂₁ ^G -Z, wherein Z each ^G is independently a bond or an optionally substituted branched or straight chain C _{1 -5} aliphatic chain wherein up to two of Z ^G The carbon units of are optionally and independently -CO-, -CS-, -CONR ^G- , -CO _2- , -OCO-, -NR ^G CO _2- , -O-, -OCONR ^G- , -NR ^G NR ^G- , -NR ^G CO-, -S-, -SO-, -SO _2- , -NR ^G- , -SO ₂ NR ^G- , -NR ^G SO ₂ -or -NR ^G SO ₂ NR ^G- Replaced by Each R ₂₁ is independently R ^G , halo, —OH, —NH ₂ , —NO ₂ , —CN or —OCF ₃ . Each R ^G is independently hydrogen, optionally substituted aliphatic, optionally substituted cycloaliphatic, optionally substituted heterocycloaliphatic, optionally substituted aryl or optionally substituted heteroaryl.

For example, ring B

이다.

to be.

In various embodiments, R ' ₃ is hydrogen and R ₃ is attached at the 2, 3, 4, 6 or 7 position of the indole of formula la. In other instances, R ₃ is attached at position 2 or 3 of the indole of Formula Ia and R ₃ is independently an optionally substituted aliphatic. For example, R ₃ is an optionally substituted acyl group. In many instances, R ₃ is optionally substituted (alkoxy) carbonyl. In another example, R ₃ is (methoxy) carbonyl, (ethoxy) carbonyl, (propoxy) carbonyl or (butoxy) carbonyl, each of 1-3 halo, hydroxy or combinations thereof Optionally substituted. In other instances, R ₃ is optionally substituted (aliphatic) carbonyl. For example, R ₃ is optionally substituted (alkyl) carbonyl, optionally substituted with 1-3 halo, hydroxy or combinations thereof. In another example, R ₃ is (methyl) carbonyl, (ethyl) carbonyl, (propyl) carbonyl or (butyl) carbonyl, each of which is optionally substituted with 1-3 halo, hydroxy or combinations thereof .

In various embodiments, R ₃ is optionally substituted (cycloaliphatic) carbonyl or optionally substituted (heterocycloaliphatic) carbonyl. In many instances, R ₃ is optionally substituted (C _3-7 cycloaliphatic) carbonyl. For example, R ₃ is (cyclopropyl) carbonyl, (cyclobutyl) carbonyl, (cyclopentyl) carbonyl, (cyclohexyl) carbonyl or (cycloheptyl) carbonyl, each of which is aliphatic, halo, Optionally substituted with hydroxy, nitro, cyano or combinations thereof. In some alternative examples, R ₃ is optionally substituted (heterocycloaliphatic) carbonyl. For example, R ₃ is optionally substituted (heterocycloaliphatic) carbonyl having 1-3 heteroatoms independently selected from N, O and S. In another example, R ₃ is optionally substituted (heterocycloaliphatic) carbonyl having 1-3 heteroatoms independently selected from N and O. In yet other examples, R ₃ is optionally substituted 4-7 membered monocyclic (heterocycloaliphatic) carbonyl having 1-3 heteroatoms independently selected from N and O. Optionally, R ₃ is (piperidin-1-yl) carbonyl, (pyrrolidin-1-yl) carbonyl or (morpholin-4-yl) carbonyl, (piperazin-1-yl) carbon Carbonyl, each of which is optionally substituted with 1-3 halo, hydroxy, cyano, nitro or aliphatic.

In yet other examples, R ₃ is optionally substituted (aliphatic) amido, such as (aliphatic (amino (carbonyl)), attached at the 2 or 3 position on the indole ring of Formula (Ia) In some embodiments, R ₃ is Optionally substituted (alkyl (amino)) carbonyl attached at position 2 or 3 on the indole ring of Formula Ia In another embodiment, R ₃ is optionally substituted attached at position 2 or 3 on the indole ring of Formula Ia Straight or branched (aliphatic (amino)) carbonyl In many instances, R ₃ is (N, N-dimethyl (amino)) carbonyl, (methyl (amino)) carbonyl, (ethyl (amino)) Carbonyl, (propyl (amino)) carbonyl, (prop-2-yl (amino)) carbonyl, (dimethyl (but-2-yl (amino))) carbonyl, (tert-butyl (amino)) Carbonyl, (butyl (amino)) carbonyl, each of 1-3 halo, hydroxy, cycloaliphatic, heterocycloaliphatic, aryl, he It is optionally substituted with Loa reel or a combination thereof.

In other embodiments, R ₃ is optionally substituted (alkoxy) carbonyl. For example, R ₃ is (methoxy) carbonyl, (ethoxy) carbonyl, (propoxy) carbonyl or (butoxy) carbonyl, each of 1-3 halo, hydroxy or combinations thereof Optionally substituted. In several examples, R ₃ is a straight or branched C _{1 -6} aliphatic group optionally substituted. For example, R ₃ is an optionally substituted straight or branched C _{1 -6} alkyl. In another example, R ₃ is independently optionally substituted methyl, ethyl, propyl, butyl, isopropyl or tert-butyl, each of which is optionally substituted with 1-3 halo, hydroxy, cyano, nitro or combinations thereof do. In another embodiment, R ₃ is optionally substituted C _{3 -6} cycloaliphatic. Exemplary embodiments include cyclopropyl, 1-methyl-cycloprop-1-yl, and the like. In another example, p is 2 and two R ₃ substituents are attached at the 2,4- or 2,6- or 2,7-position to the indole of formula (Ia). An exemplary embodiment is 6-F, 3- (optionally substituted C _{1 -6} aliphatic or cycloaliphatic C _{3 -6);} 7-F-2 - (- ( optionally substituted C _{1 -6} aliphatic or cycloaliphatic C _{3 -6)),} 4F-2- (optionally substituted C _{1 -6} aliphatic or cycloaliphatic C _{3 -6);} 7-CN-2- (optionally substituted C _1-6 aliphatic or cycloaliphatic C _{3 -6);} It includes a 7-Me-2- (optionally substituted C _{1 -6} aliphatic or cycloaliphatic C _{3 -6)} and 7-OMe-2- (optionally substituted C _{1 -6} aliphatic or cycloaliphatic C _{3 -6)} .

In various embodiments, R ₃ is hydrogen.

In various embodiments, R ₃ is

-H, -CH ₃ , -CH ₂ OH, -CH ₂ CH ₃ , -CH ₂ CH ₂ OH, -CH ₂ CH ₂ CH ₃ , -NH ₂ , halo, -OCH ₃ , -CN, -CF ₃ , -C (O) OCH ₂ CH ₃ , -S (O) ₂ CH ₃ , -CH ₂ NH ₂ , -C (O) NH ₂ ,

.

를 형성한다.In another embodiment, two adjacent R ₃ groups

To form.

In many embodiments, R _'3 are independently -Z ^C R _6, wherein each Z ^C is independently a bond or an optionally substituted branched or straight chain C _{1 -6} aliphatic chain wherein up to two of Z ^C The carbon units of are optionally and independently -CO-, -CS-, -CONR ^C- , -CONR ^C NR ^C- , -CO _2- , -OCO-, -NR ^C CO _2- , -O-, -NR ^C CONR ^C- , -OCONR ^C- , -NR ^C NR ^C- , NR ^C CO-, -S-, -SO-, -SO _2- , -NR ^C- , -SO ₂ NR ^C- , -NR ^C Is replaced by SO ₂ -or -NR ^C SO ₂ NR ^C- . Each R ₆ is independently R ^C , halo, —OH, —NH ₂ , —NO ₂ , —CN or —OCF ₃ . Each R ^C is independently hydrogen, optionally substituted aliphatic, optionally substituted cycloaliphatic, optionally substituted heterocycloaliphatic or optionally substituted heteroaryl. In one embodiment, each R ^C is hydrogen, C _{1 -6} aliphatic or cycloaliphatic C _{3 -6,} wherein one of the aliphatic or cycloaliphatic is optionally substituted with up to four -OH substituents. In another embodiment, R ^C is an optionally substituted C _{1 -6} alkyl substituted with -OH or less of hydrogen, or is 4.

For example, in many embodiments, R _'3 is independently -Z ^C R _6, wherein each Z ^C are independently a bond or an optionally substituted branched or straight chain C _{1 -6} aliphatic chain wherein Z ^C The up to two carbon units of may optionally and independently be -C (O)-, -C (O) NR ^C- , -C (O) O-, -NR ^C C (O) O-, -O-, Is replaced by -NR ^C S (O) ₂ -or -NR ^C- . Each R ₆ is independently R ^C , —OH or —NH ₂ . Each R ^C is independently hydrogen, optionally substituted cycloaliphatic, optionally substituted heterocycloaliphatic, or optionally substituted heteroaryl. In one embodiment, each R ^C is hydrogen, C _{1 -6} aliphatic or cycloaliphatic C _{3 -6,} wherein one of the aliphatic or cycloaliphatic is optionally substituted with up to four -OH substituents. In another embodiment, R ^C is an optionally substituted C _{1 -6} alkyl substituted with -OH or less of hydrogen, or is 4.

이고,In other embodiments, R ' ₃ is hydrogen or

ego,

Wherein R ₃₁ is H or one to three halo, -OH or by a combination thereof, optionally substituted aliphatic C _{1 -2.} R ₃₂ is -LR ₃₃ , where L is a bond, -CH _2- , -CH ₂ O-, -CH ₂ NHS (O) _2- , -CH ₂ C (O)-, -CH ₂ NHC (O) -Or -CH ₂ NH-; R ₃₃ is hydrogen, or C _{1 -2} aliphatic, a cycloaliphatic, heteroaryl, cycloaliphatic, or heteroaryl, each of which is optionally substituted with one of -OH, -NH ₂ or -CN. For example, in one embodiment, R ₃₁ is hydrogen and R ₃₂ is an optionally substituted aliphatic C _{1 -2} with -OH, -NH ₂ or -CN.

In various embodiments, R ' ₃ is

-H, -CH ₃ , -CH ₂ CH ₃ , -C (O) CH ₃ , -CH ₂ CH ₂ OH, -C (O) OCH ₃ ,

중 하나로부터 독립적으로 선택된다.

Independently from one of them.

In various embodiments, ring B is

로부터 선택된다.

Is selected from.

5. n terminology

n is 1-3.

In various embodiments n is 1. In other embodiments n is 2. In another embodiment n is 3.

In one aspect, the present invention relates to a compound of formula II or a pharmaceutically acceptable salt thereof useful as a modulator of ABC transporter activity:

<Formula II>

Wherein, in each case independently:

R is H, OH, or OCH _3, or two R's together form a -OCH ₂ O- or -OCF ₂ O-;

R ₁ is H or alkyl;

R ₂ is H or F;

R ₃ is H or CN;

R ₄ is H, —CH ₂ OCH ₂ CH (OH) CH ₂ OH, —CH ₂ CH ₂ N (CH ₃ ) ₃ or —CH ₂ CH ₂ OH;

R ₅ is H, OH, —CH ₂ OCH ₂ CH (OH) CH ₂ OH, —CH ₂ OH, or R ₄ and R ₅ together form a five membered ring.

In one embodiment, the present invention provides a compound of Formula II, except for the compounds set forth below:

.

.

In one embodiment of the compound, two R together form -OCF ₂ O-, R ₁ is H and R ₂ is F. In another embodiment, two R together form -OCF ₂ O-, R ₁ is H, R ₂ is F, and R ₃ is H. In another embodiment, two R together form -OCF ₂ O-, R ₁ is H, R ₂ is F, R ₃ is H, and R ₄ is H. In another embodiment, two R together form -OCF ₂ O-, R ₁ is H, R ₂ is F, R ₃ is H, and R ₄ is -CH ₂ CH ₂ N ⁺ (CH ₃ ) ₃ . In another embodiment, two R together form -OCF ₂ O-, R ₁ is H, R ₂ is F, R ₃ is H, and R ₄ is -CH ₂ OCH ₂ CH (OH) CH ₂ OH. In another embodiment, two R together form —OCF ₂ O—, R ₁ is H, R ₂ is F, R ₃ is H, and R ₄ and R ₅ together form a five membered ring do.

In one embodiment of the compound, two R together form -OCH ₂ O-, R ₁ is H and R ₂ is F. In another embodiment, two R together form -OCH ₂ O-, R ₁ is H, R ₂ is F, and R ₃ is H. In another embodiment, two R together form -OCH ₂ O-, R ₁ is H, R ₂ is F, R ₃ is H, and R ₄ is -CH ₂ OCH ₂ CH (OH) CH ₂ OH.

In one embodiment of the compound, R is OH, R ₁ is H, R ₂ is H, R ₃ is H, and R ₄ is —CH ₂ OCH ₂ CH (OH) CH ₂ OH.

In one embodiment of the compound, at least one R is OCH ₃ , at least two R ₁ is methyl, R ₂ is H, R ₃ is H, and R ₄ is H. In another embodiment, at least one R is OCH ₃ , at least two R ₁ is methyl, R ₂ is H, R ₃ is H, and R ₄ is —CH ₂ OCH ₂ CH (OH) CH ₂ OH.

In one embodiment of the compound, two R together form -CH ₂ CH ₂ CH _2- , R ₁ is H, R ₂ is H, R ₃ is H, and R ₄ is -CH ₂ OCH ₂ CH (OH) CH ₂ OH.

In one embodiment, the compound is represented by Formula IIa or a pharmaceutically acceptable salt thereof:

<Formula IIa>

Where

R ₄ is H, —CH ₂ OCH ₂ CH (OH) CH ₂ OH, —CH ₂ CH ₂ N ⁺ (CH ₃ ) ₃ or —CH ₂ CH ₂ OH;

R ₅ is H, OH, —CH ₂ OCH ₂ CH (OH) CH ₂ OH, —CH ₂ OH, or R ₄ and R ₅ together form a five membered ring.

In one embodiment of the compound, R ₄ is —CH ₂ OCH ₂ CH (OH) CH ₂ OH, —CH ₂ CH ₂ N ⁺ (CH ₃ ) ₃ or —CH ₂ CH ₂ OH. In another embodiment, R ₅ is OH, —CH ₂ OCH ₂ CH (OH) CH ₂ OH or —CH ₂ OH. In another embodiment, R ₄ is —CH ₂ OCH ₂ CH (OH) CH ₂ OH, —CH ₂ CH ₂ N ⁺ (CH ₃ ) ₃ or —CH ₂ CH ₂ OH; R ₅ is OH, —CH ₂ OCH ₂ CH (OH) CH ₂ OH or —CH ₂ OH.

C. Exemplary Compounds of the Invention

Exemplary compounds of the invention include, but are not limited to, those described in Table 1 below.

TABLE 1 Exemplary Compounds of the Invention

In another aspect, the invention relates to a pharmaceutical composition comprising (i) a compound of the invention and (ii) a pharmaceutically acceptable carrier. In another embodiment, the composition further comprises an additional agent selected from a mucolytic, bronchodilator, antibiotic, anti-infective, anti-inflammatory, CFTR corrector or nutrient. In another embodiment, the composition is a compound disclosed in U.S. Patent Application No. 11 / 165,818, published as U.S. Patent Application Publication No. 2006/0074075, filed Jun. 24, 2005, which is hereby incorporated by reference in its entirety. Further agents selected from. In another embodiment, the composition further comprises N- (5-hydroxy-2,4-ditert-butyl-phenyl) -4-oxo-1H-quinoline-3-carboxamide. These compositions are useful for the treatment of the following diseases including cystic fibrosis. These compositions are also useful in the kits described below.

In another aspect, the present invention relates to a method of increasing the number of functional ABC transporters in a membrane of a cell, comprising contacting the cell with a compound of Formula II:

<Formula II>

Wherein, in each case independently:

R is H, OH, or OCH _3, or two R together are -CH ₂ CH ₂ CH ₂ - to form a, -OCH ₂ O- or -OCF ₂ O-;

R ₁ is H or alkyl;

R ₂ is H or F;

R ₃ is H or CN;

R ₄ is H, —CH ₂ OCH ₂ CH (OH) CH ₂ OH, —CH ₂ CH ₂ N ⁺ (CH ₃ ) ₃ or —CH ₂ CH ₂ OH;

R ₅ is H, OH, —CH ₂ OCH ₂ CH (OH) CH ₂ OH, —CH ₂ OH, or R ₄ and R ₅ together form a five membered ring.

In one embodiment of the method, the ABC transporter is CFTR.

In one embodiment of the method, two R together form -OCF ₂ O-, R ₁ is H and R ₂ is F. In another embodiment, two R together form -OCF ₂ O-, R ₁ is H, R ₂ is F, and R ₃ is H. In another embodiment, two R together form -OCF ₂ O-, R ₁ is H, R ₂ is F, R ₃ is H, and R ₄ is H. In another embodiment, two R together form -OCF ₂ O-, R ₁ is H, R ₂ is F, R ₃ is H, and R ₄ is -CH ₂ CH ₂ N ⁺ (CH ₃ ) ₃ . In another embodiment, two R together form -OCF ₂ O-, R ₁ is H, R ₂ is F, R ₃ is H, and R ₄ is -CH ₂ OCH ₂ CH (OH) CH ₂ OH. In another embodiment, two R together form —OCF ₂ O—, R ₁ is H, R ₂ is F, R ₃ is H, and R ₄ and R ₅ together form a five membered ring do.

In one embodiment of the method, two R together form —OCH ₂ O—, R ₁ is H and R ₂ is F. In another embodiment, two R together form -OCH ₂ O-, R ₁ is H, R ₂ is F, and R ₃ is H. In another embodiment, two R together form -OCH ₂ O-, R ₁ is H, R ₂ is F, R ₃ is H, and R ₄ is -CH ₂ OCH ₂ CH (OH) CH ₂ OH.

In one embodiment of the method, R is OH, R ₁ is H, R ₂ is H, R ₃ is H, and R ₄ is -CH ₂ OCH ₂ CH (OH) CH ₂ OH.

In one embodiment of the method, at least one R is OCH ₃ , at least two R ₁ is methyl, R ₂ is H, R ₃ is H, and R ₄ is H. In another embodiment, at least one R is OCH ₃ , at least two R ₁ is methyl, R ₂ is H, R ₃ is H, and R ₄ is —CH ₂ OCH ₂ CH (OH) CH ₂ OH.

In one embodiment of the method, two R together form -CH ₂ CH ₂ CH _2- , R ₁ is H, R ₂ is H, R ₃ is H, and R ₄ is -CH ₂ OCH ₂ CH (OH) CH ₂ OH.

In one embodiment of the above process, the compound is represented by the formula (IIa) or a pharmaceutically acceptable salt thereof:

<Formula IIa>

Where:

R ₄ is H, —CH ₂ OCH ₂ CH (OH) CH ₂ OH, —CH ₂ CH ₂ N ⁺ (CH ₃ ) ₃ or —CH ₂ CH ₂ OH;

R ₅ is H, OH, —CH ₂ OCH ₂ CH (OH) CH ₂ OH, —CH ₂ OH, or R ₄ and R ₅ together form a five membered ring.

In one embodiment of the method, R ₄ is —CH ₂ OCH ₂ CH (OH) CH ₂ OH, —CH ₂ CH ₂ N ⁺ (CH ₃ ) ₃ or —CH ₂ CH ₂ OH. In another embodiment, R ₅ is OH, —CH ₂ OCH ₂ CH (OH) CH ₂ OH or —CH ₂ OH. In another embodiment, R ₄ is —CH ₂ OCH ₂ CH (OH) CH ₂ OH, —CH ₂ CH ₂ N ⁺ (CH ₃ ) ₃ or —CH ₂ CH ₂ OH; R ₅ is OH, —CH ₂ OCH ₂ CH (OH) CH ₂ OH or —CH ₂ OH.

In one embodiment of the method, the compound is selected from Table 1.

In another aspect, the invention relates to a method of treating a condition, disease or disorder in a patient comprising administering to a patient associated with ABC transporter activity a compound of formula II or a pharmaceutically acceptable salt thereof It is about:

<Formula II>

Wherein, in each case independently:

R is H, OH, or OCH _3, or two R together are -CH ₂ CH ₂ CH ₂ - to form a, -OCH ₂ O- or -OCF ₂ O-;

R ₁ is H or alkyl;

R ₂ is H or F;

R ₃ is H or CN;

R ₄ is H, —CH ₂ OCH ₂ CH (OH) CH ₂ OH, —CH ₂ CH ₂ N ⁺ (CH ₃ ) ₃ or —CH ₂ CH ₂ OH;

R ₅ is H, OH, —CH ₂ OCH ₂ CH (OH) CH ₂ OH, —CH ₂ OH, or R ₄ and R ₅ together form a five membered ring.

In one embodiment of the method, two R together form -OCF ₂ O-, R ₁ is H and R ₂ is F. In another embodiment, two R together form -OCF ₂ O-, R ₁ is H, R ₂ is F, and R ₃ is H. In another embodiment, two R together form -OCF ₂ O-, R ₁ is H, R ₂ is F, R ₃ is H, and R ₄ is H. In another embodiment, two R together form -OCF ₂ O-, R ₁ is H, R ₂ is F, R ₃ is H, and R ₄ is -CH ₂ CH ₂ N ⁺ (CH ₃ ) ₃ . In another embodiment, two R together form -OCF ₂ O-, R ₁ is H, R ₂ is F, R ₃ is H, and R ₄ is -CH ₂ OCH ₂ CH (OH) CH ₂ OH. In another embodiment, two R together form —OCF ₂ O—, R ₁ is H, R ₂ is F, R ₃ is H, and R ₄ and R ₅ together form a five membered ring do.

In one embodiment of the method, two R together form —OCH ₂ O—, R ₁ is H and R ₂ is F. In another embodiment, two R together form -OCH ₂ O-, R ₁ is H, R ₂ is F, and R ₃ is H. In another embodiment, two R together form -OCH ₂ O-, R ₁ is H, R ₂ is F, R ₃ is H, and R ₄ is -CH ₂ OCH ₂ CH (OH) CH ₂ OH.

In one embodiment of the method, R is OH, R ₁ is H, R ₂ is H, R ₃ is H, and R ₄ is -CH ₂ OCH ₂ CH (OH) CH ₂ OH.

In one embodiment of the method, at least one R is OCH ₃ , at least two R ₁ is methyl, R ₂ is H, R ₃ is H, and R ₄ is H. In another embodiment, at least one R is OCH ₃ , at least two R ₁ is methyl, R ₂ is H, R ₃ is H, and R ₄ is —CH ₂ OCH ₂ CH (OH) CH ₂ OH.

In one embodiment of the method, two R together form -CH ₂ CH ₂ CH _2- , R ₁ is H, R ₂ is H, R ₃ is H, and R ₄ is -CH ₂ OCH ₂ CH (OH) CH ₂ OH.

In one embodiment of the method, the compound is represented by the formula (IIa) or a pharmaceutically acceptable salt thereof:

<Formula IIa>

Where:

R ₄ is H, —CH ₂ OCH ₂ CH (OH) CH ₂ OH, —CH ₂ CH ₂ N ⁺ (CH ₃ ) ₃ or —CH ₂ CH ₂ OH;

R ₅ is H, OH, —CH ₂ OCH ₂ CH (OH) CH ₂ OH, —CH ₂ OH, or R ₄ and R ₅ together form a five membered ring.

In one embodiment of the method, R ₄ is —CH ₂ OCH ₂ CH (OH) CH ₂ OH, —CH ₂ CH ₂ N ⁺ (CH ₃ ) ₃ or —CH ₂ CH ₂ OH. In another embodiment, R ₅ is OH, —CH ₂ OCH ₂ CH (OH) CH ₂ OH or —CH ₂ OH. In another embodiment, R ₄ is —CH ₂ OCH ₂ CH (OH) CH ₂ OH, —CH ₂ CH ₂ N ⁺ (CH ₃ ) ₃ or —CH ₂ CH ₂ OH; R ₅ is OH, —CH ₂ OCH ₂ CH (OH) CH ₂ OH or —CH ₂ OH.

In one embodiment of the method, the compound is selected from Table 1.

In one embodiment of the method, the condition, disease or disorder is cystic fibrosis, hereditary emphysema, hereditary hemochromatosis, coagulation-fibrinolysis deficiency such as protein C deficiency, type 1 hereditary angioedema, lipid processing deficiency, such as familial hyperplasia Hypercholesterolemia, type 1 stromal granulomatosis, mubetalipoproteinemia, lysosomal accumulation diseases such as I-cell disease / caustic-hallower, mucopolysaccharide deposition, sandhof / Tey-sax, Krigler-Nazar type II, polyendocrine disease / Hyperinsulinemia, diabetes mellitus, laron dwarfism, myeloperoxidase deficiency, primary parathyroidism, melanoma, glycanosis CDG type 1, hereditary emphysema, congenital hyperthyroidism, incomplete osteoplasia, hereditary hypofibrosis , ACT deficiency, diabetes insipidus (di), neurophysiological di, identity DI, Sharco-Maritus syndrome, Felizius-Mertzvacher's disease, neurodegenerative diseases such as Tsheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, progressive nuclear palsy, peak disease, various polyglutamine nervous system disorders such as Huntington, spinal cord cerebellar ataxia type I, spinal cord and softening muscular dystrophy, dentatorbal palidoluitian and myotonic Dystrophy, and also cavernous encephalopathy such as hereditary Creutzfeldt-Jakob disease, Fabry disease, Straussler-Schainker syndrome, COPD, dry eye disease, and Sjogren's disease.

In another aspect, the invention provides a composition comprising (i) a first composition comprising a compound of formula II:

<Formula II>

(In the above formula, in each case independently:

R is H, OH, or OCH _3, or two R together are -CH ₂ CH ₂ CH ₂ - to form a, -OCH ₂ O- or -OCF ₂ O-;

R ₁ is H or alkyl;

R ₂ is H or F;

R ₃ is H or CN;

R ₄ is H, —CH ₂ OCH ₂ CH (OH) CH ₂ OH, —CH ₂ CH ₂ N ⁺ (CH ₃ ) ₃ or —CH ₂ CH ₂ OH,

R ₅ is H, OH, —CH ₂ OCH ₂ CH (OH) CH ₂ OH, —CH ₂ OH, or R ₄ and R ₅ together form a 5-membered ring)

And (ii) a) contacting said composition with a biological sample, and b) instructions for measuring activity of the ABC transporter or fragment thereof. ABC transporter or fragment thereof of the biological sample in vitro or in vivo. A kit for use in determining the activity of a.

In one embodiment, the kit comprises a) contacting a further composition with a biological sample, b) measuring the activity of the ABC transporter or fragment thereof in the presence of the additional compound, c) ABC in the presence of the additional compound Further included are instructions for comparing the activity of the transporter with the density of the ABC transporter in the presence of the first composition.

In one embodiment, the kit is used to measure the density of CFTR.

In one embodiment of this kit, two R's together form -OCF ₂ O-, R ₁ is H and R ₂ is F. In another embodiment, two R together form -OCF ₂ O-, R ₁ is H, R ₂ is F, and R ₃ is H. In another embodiment, two R together form -OCF ₂ O-, R ₁ is H, R ₂ is F, R ₃ is H, and R ₄ is H. In another embodiment, two R together form -OCF ₂ O-, R ₁ is H, R ₂ is F, R ₃ is H, and R ₄ is -CH ₂ CH ₂ N ⁺ (CH ₃ ) ₃ . In another embodiment, two R together form -OCF ₂ O-, R ₁ is H, R ₂ is F, R ₃ is H, and R ₄ is -CH ₂ OCH ₂ CH (OH) CH ₂ OH. In another embodiment, two R together form —OCF ₂ O—, R ₁ is H, R ₂ is F, R ₃ is H, and R ₄ and R ₅ together form a five membered ring do.

In one embodiment of this kit, two R's together form -OCH ₂ O-, R ₁ is H and R ₂ is F. In another embodiment, two R together form -OCH ₂ O-, R ₁ is H, R ₂ is F, and R ₃ is H. In another embodiment, two R together form -OCH ₂ O-, R ₁ is H, R ₂ is F, R ₃ is H, and R ₄ is -CH ₂ OCH ₂ CH (OH) CH ₂ OH. In another embodiment, R is OH, R ₁ is H, R ₂ is H, R ₃ is H, and R ₄ is —CH ₂ OCH ₂ CH (OH) CH ₂ OH. In another embodiment, at least one R is OCH ₃ , at least two R ₁ is methyl, R ₂ is H, R ₃ is H, and R ₄ is H. In another embodiment, at least one R is OCH ₃ , at least two R ₁ is methyl, R ₂ is H, R ₃ is H, and R ₄ is —CH ₂ OCH ₂ CH (OH) CH ₂ OH. In another embodiment, two R together form -CH ₂ CH ₂ CH _2- , R ₁ is H, R ₂ is H, R ₃ is H, and R ₄ is -CH ₂ OCH ₂ CH (OH) CH ₂ OH.

In one embodiment of this kit, the compound is represented by the formula (IIa) or a pharmaceutically acceptable salt thereof:

<Formula IIa>

Where:

R ₄ is H, —CH ₂ OCH ₂ CH (OH) CH ₂ OH, —CH ₂ CH ₂ N ⁺ (CH ₃ ) ₃ or —CH ₂ CH ₂ OH;

R ₅ is H, OH, —CH ₂ OCH ₂ CH (OH) CH ₂ OH, —CH ₂ OH, or R ₄ and R ₅ together form a five membered ring.

In one embodiment of this kit, R ₄ is —CH ₂ OCH ₂ CH (OH) CH ₂ OH, —CH ₂ CH ₂ N ⁺ (CH ₃ ) ₃ or —CH ₂ CH ₂ OH. In another embodiment, R ₅ is OH, —CH ₂ OCH ₂ CH (OH) CH ₂ OH or —CH ₂ OH. In another embodiment, R ₄ is —CH ₂ OCH ₂ CH (OH) CH ₂ OH, —CH ₂ CH ₂ N ⁺ (CH ₃ ) ₃ or —CH ₂ CH ₂ OH; R ₅ is OH, —CH ₂ OCH ₂ CH (OH) CH ₂ OH or —CH ₂ OH.

In one embodiment of this kit, the compound is selected from Table 1.

III. Sub-Compounds Of The Invention

Another aspect of the invention provides compounds useful for modulating ABC transporter activity. The compound is a compound having Formula Id or a pharmaceutically acceptable salt thereof:

<Formula Ic>

.

.

R ₁ , R ₂ and ring A are as defined above in formula (I) and rings B, R ₃ and p are defined in formula (Ia). In addition, when ring A is unsubstituted cyclopentyl, n is 1, R ₂ is 4-chloro and R ₁ is hydrogen, ring B is 2- (tert-butyl) indol-5-yl or (2 , 6-dichlorophenyl (carbonyl))-3-methyl-1H-indol-5-yl; When ring A is unsubstituted cyclopentyl, n is 0 and R ₁ is hydrogen, ring B is

가 아니다.

Is not.

Another aspect of the invention provides compounds useful for modulating ABC transporter activity. The compound is a compound having the formula Id or a pharmaceutically acceptable salt thereof:

<Formula Id>

.

.

R ₁ , R ₂ and ring A are as defined above in formula (I) and rings B, R ₃ and p are defined in formula (Ia).

However, when R ₁ is H, n is 0, Ring A is unsubstituted cyclopentyl and Ring B is indol-5-yl substituted with 1-2 R ₃ , each R ₃ is independently- Z is R ₁₂ ^G, where each ^G is a bond Z independently, or an unsubstituted branched or straight chain C _{1 -6} aliphatic chain ring, in which two carbon units of Z or fewer of ^G is optionally and independently CS-, -CONR ^G NR ^G- , -CO _2- , -OCO-, -NR ^G CO _2- , -O-, -NR ^G CONR ^G- , -OCONR ^G- , -NR ^G NR ^G -,- S-, -SO-, -SO _2- , -NR ^G- , -SO ₂ NR ^G- , -NR ^G SO ₂ -or -NR ^G SO ₂ NR ^C- , each R ₁₂ is independent And R ^G , halo, -OH, -NH ₂ , -NO ₂ , -CN or -OCF ₃ and each R ^G is independently hydrogen, unsubstituted aliphatic, optionally substituted cycloaliphatic, optionally substituted heterocycloaliphatic , Unsubstituted aryl or optionally substituted heteroaryl; Or any two adjacent R ₃ groups together with the atoms to which they are attached form an optionally substituted heterocycle. In addition, when R ₁ is H, n is 1, R ₂ is 4-chloro, Ring A is unsubstituted cyclopentyl and Ring B is indol-5-yl substituted with 1-2 R ₃ , each R ₃ is independently ^H R ₂₂ -Z, wherein each Z is ^H or a bond independently or unsubstituted branched or straight chain C _{1 -3} aliphatic chain wherein up to two of Z ^H The carbon unit is optionally and independently -CS-, -CONR ^H NR ^H , -CO _2- , -OCO-, -NR ^H CO _2- , -O-, -NR ^H CONR ^H- , -OCONR ^H -,- NR ^H NR ^H- , -S-, -SO-, -SO _2- , -NR ^H- , -SO ₂ NR ^H- , -NR ^H SO ₂ -or -NR ^H SO ₂ NR ^H- , Each R ₂₂ is independently R ^H , halo, —OH, —NH ₂ , —NO ₂ , —CN or —OCF ₃ , and each R ^H is independently hydrogen, substituted C ₄ alkyl, optionally substituted C _2-6 alkenyl, optionally substituted C _{2 -6-alkynyl,} an optionally substituted C ₄ alkenyl, optionally substituted C ₄ alkynyl, an optionally substituted cycloaliphatic, p. Optionally substituted heterocycloaliphatic, optionally substituted heteroaryl, unsubstituted phenyl or monosubstituted phenyl, or any two adjacent R ₃ groups together with the atoms to which they are attached form an optionally substituted heterocycle.

Another aspect of the invention provides compounds useful for modulating ABC transporter activity. The compound is a compound having Formula II: or a pharmaceutically acceptable salt thereof:

<Formula II>

.

.

R ₁ , R ₂ and ring A are as defined above in formula (I); R ₃ , R ' ₃ and p are as defined above in formula la; Z ₁ , Z ₂ , Z ₃ , Z ₄ and Z ₅ are defined above in Formula Ib.

Another aspect of the invention provides compounds useful for modulating ABC transporter activity. The compound is a compound having Formula IIa or a pharmaceutically acceptable salt thereof:

<Formula IIa>

.

.

R ₁ , R ₂ and ring A are as defined above in formula (I); R ₃ , R ' ₃ and p are as defined above in formula la; Z ₁ , Z ₂ , Z ₃ , Z ₄ and Z ₅ are defined above in Formula Ib.

Another aspect of the invention provides compounds useful for modulating ABC transporter activity. The compound is a compound having the formula (IIb) or a pharmaceutically acceptable salt thereof:

<Formula IIb>

.

.

R ₁ , R ₂ and ring A are as defined above in formula (I); R ₃ , R ' ₃ and p are as defined above in formula la; Z ₁ , Z ₂ , Z ₃ , Z ₄ and Z ₅ are defined above in Formula Ib.

Another aspect of the invention provides compounds useful for modulating ABC transporter activity. The compound is a compound having Formula IIc or a pharmaceutically acceptable salt thereof:

<Formula IIc>

.

.

R ₁ , R ₂ and n are as defined above in formula (I); R ₃ , R ′ ₃ and p are defined in formula Ia.

Another aspect of the invention provides compounds useful for modulating ABC transporter activity. The compound is a compound having the formula IId or a pharmaceutically acceptable salt thereof:

<Formula IId>

.

.

Both R ₂ groups together with the atoms to which they are attached

로부터 선택된 기를 형성한다.

To form a group selected from.

R ′ ₃ is —H, —CH ₃ , —CH ₂ CH ₃ , —C (O) CH ₃ , —CH ₂ CH ₂ OH, —C (O) OCH ₃ ,

중 하나로부터 독립적으로 선택되고; 각각의 R₃은 -H, -CH₃, -CH₂OH, -CH₂CH₃, -CH₂CH₂OH, -CH₂CH₂CH₃, -NH₂, 할로, -OCH₃, -CN, -CF₃, -C(O)OCH₂CH₃, -S(O)₂CH₃, -CH₂NH₂, -C(O)NH₂,

Independently selected from one of; Each R ₃ is -H, -CH ₃ , -CH ₂ OH, -CH ₂ CH ₃ , -CH ₂ CH ₂ OH, -CH ₂ CH ₂ CH ₃ , -NH ₂ , halo, -OCH ₃ , -CN , -CF ₃ , -C (O) OCH ₂ CH ₃ , -S (O) ₂ CH ₃ , -CH ₂ NH ₂ , -C (O) NH ₂ ,

로부터 독립적으로 선택된다.

Is independently selected from.

IV. General Synthetic Method

Compounds of formula (I, Ic, Id, II, IIa, IIb, IIc and IId) are commercially available by known methods or can be readily synthesized from known starting materials. Exemplary synthetic routes for producing compounds of formula (I, Ic, Id, II, IIa, IIb, IIc and IId) are provided below in Scheme 1-22.

The preparation of compounds of the present invention is accomplished by coupling ring B amines to ring A carboxylic acids, as illustrated in Scheme 1.

<Scheme 1>

, pyr.; c)

, HATU, TEA, DCM/DMF. a) SOCl ₂ , DMF (catalyst), DCM; b)

, pyr .; c)

, HATU, TEA, DCM / DMF.

과 산 클로라이드의 반응은 본 발명의 화합물 I을 제공한다. 선택적으로, 산 1a를, 공지된 커플링 시약, 예를 들어, HATU를 이용하여 트리에틸아민의 존재 하에 아민에 직접적으로 커플링시킬 수 있다. In connection with Scheme 1, acid 1a can be converted to the corresponding acid chloride 1b with thionyl chloride in the presence of a catalytic amount of dimethylformamide. Amine

The reaction of with acid chloride provides compound I of the present invention. Optionally, the acid 1a can be coupled directly to the amine in the presence of triethylamine using known coupling reagents such as HATU.

The preparation of acid 1a can be accomplished as described in Scheme 2.

<Scheme 2>

a) NaOH, BTEAC; b) NaOH, Δ

In connection with Scheme 2, nitrile 2a is reacted with a suitable bromochloroalkane in the presence of sodium hydroxide and a phase transfer catalyst such as butyltriethylammonium chloride to provide intermediate 2b. Hydrolysis of the nitrile of 2b gives the acid 1a. In some cases, isolation of intermediate 2b is unnecessary.

Phenylacetonitrile 2a is commercially available or can be prepared as illustrated in Scheme 3.

<Scheme 3>

a) Pd (PPh ₃ ) ₄ , CO, MeOH; b) LiAlH ₄ , THF; c) SOCl ₂ ; d) NaCN

In connection with Scheme 3, aryl bromide 3a is reacted with carbon monoxide in the presence of methanol and tetrakis (triphenylphosphine) palladium (0) to give ester 3b. 3b is reduced with lithium aluminum hydride to give alcohol 3c, which is converted to halide 3d with thionyl chloride. Sodium cyanide is reacted with 3d to give nitrile 2a.

Another method of preparing nitrile 2a is illustrated in Schemes 4 and 5 below.

<Scheme 4>

a) TosMIC; b) NaBH ₄ , THF; c) SOCl ₂ ; d) NaCN

Scheme 5

a) NBS, AIBN, CCl ₄ ; b) NaCN, EtOH

성분의 제조는 하기 반응식에 설명된다. 고리 B가 인돌인 고리 B 화합물을 제조하기 위한 수많은 방법이 보고되었다. 예를 들어, 문헌 [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] 참조.

The preparation of the components is illustrated in the following scheme. Numerous methods have been reported for preparing ring B compounds in which ring B is an indole. See, eg, 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.

를 제조하기 위한 방법 중 하나가 반응식 6에 설명된다.

One of the methods for preparing is described in Scheme 6.

<Scheme 6>

a) NaNO ₂ , HCl, SnCl ₂ ; b) NaOH, R ₃ CH ₂ C (O) R ₃ , EtOH; c) H ₃ PO ₄ , toluene; d) H ₂ , Pd-C, EtOH

In connection with Scheme 6, nitroaniline 6a is converted to hydrazine 6b with nitrous acid in the presence of HCl and tin chloride. 6b is reacted with aldehyde or ketone CH ₃ C (O) R ₃ to give hydrazone 6c, which is treated with phosphoric acid in toluene to give a mixture of nitro indole 6d and 6e. Catalytic hydrogenation in the presence of palladium on carbon provides a mixture of amino indole 6f and 6g, which can be separated using known methods such as, for example, chromatography.

An alternative method is illustrated in Scheme 7.

<Reaction Scheme 7>

a) R _3a COCl, Et ₃ N, CH ₂ Cl ₂ ; b) n-BuLi, THF; c) NaBH ₄ , AcOH; d) KNO ₃ , H ₂ SO ₄ ; e) DDQ, 1,4-dioxane; _{f) NaNO 2, HCl, SnCl} 2 .2H 2 O, H 2 O; g) MeCOR ₃ , EtOH; h) PPA; i) Pd / C, EtOH or H ₂ , Raney Ni, EtOH or MeOH

<Reaction Scheme 8>

a) HNO ₃ , H ₂ SO ₄ ; b) Me ₂ NCH (OMe) ₂ , DMF; c) H ₂ , Raney Ni, EtOH

<Reaction Scheme 9>

a) NBS, DMF; b) KNO ₃ , H ₂ SO ₄ ; c) HC≡C-TMS, Pd (PPh ₃ ) ₂ Cl ₂ , CuI, Et ₃ N, toluene, H ₂ O; d) CuI, DMF; e) H ₂ , Raney Ni, MeOH

<Reaction formula 10>

a) HNO ₃ , H ₂ SO ₄ ; b) SOCl ₂ ; EtOH; c) DMA, DMF; d) Raney Ni, H ₂ , MeOH

<Reaction Scheme 11>

a) DMA, DMF; b) Raney Ni, H ₂ , MeOH

<Reaction Scheme 12>

a) R _3a CH ₂ COR _3b , AcOH, EtOH; b) H ₃ PO ₄ , toluene; c) H ₂ , Pd / C, EtOH

Scheme 14

a) NaBH ₃ CN; b) when PG = SO ₂ Ph: PhSO ₂ Cl, Et ₃ N, DMAP, CH ₂ Cl ₂ ; When PG = Ac: AcCl, NaHCO ₃ , CH ₂ Cl ₂ ; c) when R ^V = RCO: (RCO) ₂ 0, AlCl ₃ , CH ₂ Cl ₂ ; When R ^V = Br: Br ₂ , AcOH; d) HBr or HCl; e) KNO ₃ , H ₂ SO ₄ ; f) MnO ₂ , CH ₂ Cl ₂ or DDQ, 1,4-dioxane; g) H ₂ , Raney Ni, EtOH.

Scheme 14

a) NaBH ₃ CN; b) RSO ₂ Cl, DMAP, Et ₃ N, CH ₂ Cl ₂ ; c) R ^D C (O) Cl, AlCl ₃ , CH ₂ Cl ₂ ; d) NaBH ₄ , THF; e) HBr; f) KNO ₃ , H ₂ SO ₂ ; g) MnO ₂ ; g) Raney Ni, H ₂ , EtOH

Scheme 15

a) R ₃ X (X = Br, I), zinc triflate, TBAI, DIEA, toluene; b) H ₂ , Raney Ni, EtOH or H ₂ , Pd / C, EtOH or SnCl ₂ H ₂ O, EtOH; c) ClSO ₂ NCO, DMF, CH ₃ CN

Scheme 16

a) for X = Cl, Br, I or OTs: R ′ ₃ X, K ₂ CO ₃ , DMF or CH ₃ CN; b) H ₂ , Pd / C, EtOH or SnCl ₂ H ₂ O, EtOH or SnCl ₂ H ₂ O, DIEA, EtOH.

Scheme 17

a) Br ₂ , AcOH; b) RC (O) Cl, Et ₃ N, CH ₂ Cl ₂ ; c) HC≡CR _3a , Pd (PPh ₃ ) ₂ Cl ₂ , CuI, Et ₃ N; d) TBAF, THF or tBuOK, DMF or Pd (PPh ₃ ) ₂ Cl ₂ , CuI, DMF; e) H ₂ , Pd / C, EtOH or SnCl ₂ , MeOH or HCO ₂ NH ₄ , Pd / C, EtOH

Scheme 18

a) Br ₂ , AcOH, CHCl ₃ ; b) R _3a C≡CH, CuI, Et ₃ N, Pd (PPh ₃ ) ₂ Cl ₂ ; c) RCOCl, Et ₃ N, CH ₂ Cl ₂ ; d) TBAF, DMF; e) Raney Ni, H ₂ , MeOH; f) ROK, DMF

Scheme 19

a) Br ₂ , AcOH; b) HC≡CR _3a , Pd (PPh ₃ ) ₂ Cl ₂ , CuI, Et ₃ N; c) Pd (PPh ₃ ) ₂ Cl ₂ , CuI, DMF; d) H ₂ , Pd / C, EtOH or SnCl ₂ , MeOH or HCO ₂ NH ₄ , Pd / C, EtOH

Scheme 20

a) H ₂ NR '₃; b) X = Br: Br ₂ , HOAc; X = I: NIS; c) HC≡CR ₃ , Pd (PPh ₃ ) ₂ Cl ₂ , CuI, Et ₃ N; d) CuI, DMF or TBAF, THF; e) H ₂ , Pd / C, EtOH or SnCl ₂ , MeOH or HCO ₂ NH ₄ , Pd / C, EtOH

Scheme 21

a) R ' ₃ NH ₂ , DMSO; b) Br ₂ , AcOH; c) TMS-C≡CH, CuI, TEA, Pd (PPh ₃ ) ₂ Cl ₂ ; d) CuI, DMSO; e) Raney Ni, H ₂ , MeOH

Scheme 22

a) R _3a C≡CH, CuI, TEA, Pd (PPh ₃ ) ₂ Cl ₂ ; b) TBAF, THF; c) Raney Ni, MeOH

Scheme 23

a) NaBH ₄ , NiCl ₂ , MeOH; b) RC (O) Cl; c) Pd (PPh ₃ ) Cl ₂ , HC≡CR ₃ , CuI, Et ₃ N; d) tBuOK, DMF; e) KNO ₃ , H ₂ SO ₄ ; f) NaBH ₄ , NiCl ₂ , MeOH

Scheme 24

a) SnCl ₂ , EtOH or Pd / C, HCO ₂ NH ₄ or H ₂ , Pd / C, EtOH or Raney Ni, H ₂ , EtOH

Scheme 25

a) PPh ₃ , HBr; b) Cl (O) CCH ₂ CO ₂ Et; c) tBuOK; d) (Boc) ₂ O, DMAP; e) KHMDS, RX; KHMDS, RX; f) TFA; g) NaNO ₃ , H ₂ SO ₄ ; h) LiAlH ₄ , THF; i) SnCl ₂ , EtOH

Scheme 26

a) LiOH; b) EDC, HOBt, Et ₃ N, HNRyRz; c) BH ₃ -THF; d) Rz = H, RC (O) Cl (Z = RC (O)-) or RSO ₂ Cl (Z = RSO _2- ) or RO (CO) Cl (Z = RO (CO)-) or (RO ( CO)) ₂ O (Z = Z = RO (CO)-), Et ₃ N, CH ₂ Cl ₂

Scheme 27

a) R ' ₃ -X (X = Br, I, or OTs), base (K ₂ CO ₃ or Cs ₂ CO ₃ ), DMF or CH ₃ CN; b) H ₂ , Pd / C, EtOH or Pd / C, HCO ₂ NH ₄

Scheme 28

a) R _3a X (X = Cl, Br, I), AlCl ₃ , CH ₂ Cl ₂ ; b) Raney Ni, H ₂ , MeOH

Scheme 29

a) HCl / MeOH; PtO ₂ , H ₂ ; b) (Boc) ₂ O, Et ₃ N, THF

Scheme 30

a) NaOH or LiOH; b) ROH, HCl; c) NaBH ₄ or LiAlH ₄ or DIBAL-H, THF; d) HNRyRz, HATU, Et ₃ N, EtOH or DMF; e) LiAlH ₄ , THF or BH ₃ .THF; f) H ₂ O ₂ , H ₂ O (Ry = Rz = H); g) H ₂ , Pd / C

Scheme 31

a) R _a -X, NaH; R _b -X, NaH; b) PCl ₅ , CH ₂ Cl ₂ ; c) NaOH; d) NaNH ₂ , DMSO; e) CH ₂ N ₂ ; f) Pd (PPh ₃ ) ₄ , CuI, Et ₃ N; g) RC (O) Cl, pyr, CH ₂ Cl ₂ ; h) Pd (CH ₃ CN) ₂ Cl ₂ , CH ₃ CN; i) Raney Ni, H ₂ , MeOH

Scheme 32

a) LiOH, THF / H ₂ O; b) HNRyRz, HATU, TEA, DMF / CH ₂ Cl ₂

Scheme 33

a) L _i BH ₄ , THF / H ₂ O or LiAlH ₄ , THF; b) R _a -L _i , THF

Scheme 34

a) NaNO ₂ , AcOH / H ₂ O; b) Zn, AcOH

Scheme 35

a) NaBH ₃ CN; b) R ' ₃ CHO, NaHB (OAc) ₃ , TFA, DCE; c) chloranyl or CDCl ₃ , light or DDQ

Scheme 36

a) NaH, DMF-THF; R ₃ -X (X = Cl, Br, I or OTs)

Scheme 37

a) NBS; b) Ar-B (OR) ₂ , Pd-FibreCat 1007, K ₂ CO ₃ , EtOH

Scheme 38

a) RSO ₂ Cl, NaH, THF-DMF; b) R ₃ -X (X = Br, I or OTs), NaH, THF-DMF; c) ethylene dioxide, InCl ₃ ; d) POCl ₃ , DMF; e) H ₂ N-OH, CH ₂ Cl ₂ ; Ac ₂ O

Scheme 39

a) NaH, THF-DMF; Epichlorohydrin; b) ROH; c) HNRyRz

Scheme 40

a) TsCl, Et ₃ N, CH ₂ Cl ₂ ; b) NaCN, DMF; c) NaOH, MeOH; d) NaN ₃ , NH ₄ Cl; e) NaN ₃ , DMF; f) Pd / C, H ₂ , MeOH (R = H); h) R ^x C (O) Cl (Z = R ^x C (O)-) or R ^x SO ₂ Cl (Z = R ^x SO _2- ) or R ^x O (CO) Cl (Z = R ^x O ( CO)-) or (R ^x O (CO)) ₂ O (Z = R ^x O (CO)-), Et ₃ N, CH ₂ Cl ₂

Scheme 41

a) ClCH ₂ CHO, NaHB (OAc) ₃ , CH ₂ Cl ₂ ; CDCl ₃ , light; b) NaN ₃ , NaI, DMF; c) H ₂ , Pd / C, MeOH, AcOH; d) RC (O) Cl (Z = RC (O)-) or RSO ₂ Cl (Z = RSO _2- ) or RO (CO) Cl (Z = RO (CO)-) or (RO (CO)) ₂ O (Z = RO (CO)-), Et ₃ N, CH ₂ Cl ₂ .

Scheme 42

b) R _a -X, NaH; R _b -X, NaH; b) PCl ₅ , CH ₂ Cl ₂ ; c) NaOH; d) NaNH ₂ , DMSO; e) R-OH, DCC; f) Pd (PPh ₃ ) ₂ Cl ₂ , CuI, Et ₃ N; g) PdCl ₂ , CH ₃ CN

Scheme 43

n = 0 or 1

a) DIBAL-H; b) P-LG; P = protecting groups such as TBDMS and LG = leaving groups such as Cl; c) R ₄ -LG, bases such as Cs ₂ CO ₃ ; R ₄ = alkyl, LG = tosylate, Rc = H or R ₄ ; d) reducing conditions such as Pd / C, H ₂ or ammonium formate.

Scheme 43

R ₄ -LG, bases such as Cs ₂ CO ₃ ; R ₄ = alkyl and LG = tosylate; b) LiAlH ₄ ; c) reducing conditions such as Pd / C, H ₂ or ammonium formate.

In the above scheme, the radical R used therein is a substituent, for example RW as defined above. It will be readily apparent to those skilled in the art that synthetic routes suitable for the various substituents of the present invention will ensure that the reaction conditions and steps used do not alter the intended substituents.

V. Formulations, Administration and Uses

Thus, in another aspect of the invention, there is provided a pharmaceutically acceptable composition comprising any compound as described herein and optionally comprising a pharmaceutically acceptable carrier, adjuvant or vehicle. In certain embodiments, these compositions optionally further comprise one or more additional therapeutic agents.

It will also be appreciated that certain compounds of the invention may exist in free form for treatment, or as appropriate pharmaceutically acceptable derivatives or prodrugs thereof. According to the present invention, pharmaceutically acceptable derivatives or prodrugs are pharmaceutically acceptable salts, esters which can provide, directly or indirectly, a compound as described herein or a metabolite or residue thereof upon administration to a patient in need thereof. , Salts of such esters, or any other adducts or derivatives.

As used herein, the term “pharmaceutically acceptable salts” is a reasonable and reasonable benefit for use in contact with tissues of humans and lower animals without excessive toxicity, irritation, allergic reactions, etc., within the scope of discerning medical judgment. It refers to such salts with a / risk ratio. A "pharmaceutically acceptable salt" is a salt of any non-toxic salt or ester of a compound of the present invention that can directly or indirectly provide a compound of the present invention or an inhibitory active metabolite or residue thereof when administered to a recipient. Means.

Pharmaceutically acceptable salts are known in the art. For example, S. M. SM Berge et al., Incorporated herein by reference. Pharmaceutical Sciences, 1977, 66, 1-19, describes pharmaceutically acceptable salts in detail. Pharmaceutically acceptable salts of the compounds of this invention include those derived from suitable inorganic and organic acids and bases. Examples of pharmaceutically acceptable non-toxic acid addition salts are formed using inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid, or organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid. Or salts of amino groups formed using other methods used in the art, such as ion exchange. Other pharmaceutically acceptable salts are adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropio Nate, Digluconate, Dodecyl Sulfate, Ethanesulfonate, Formate, Fumarate, Glucoheptonate, Glycerophosphate, Gluconate, Hemisulphate, Heptanoate, Hexanoate, Hydroiodide, 2- Hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, maleate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate , Oxalate, palmitate, palmoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivale Agent, propionitrile include carbonate, stearate, succinate, sulfate, tartrate, such as thiocyanate, p- toluenesulfonate, undecanoate, valerate salts. Salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium and N ⁺ _- include (C _{1 4} alkyl) ₄ salts. The present invention also contemplates quaternization of any basic nitrogen-containing groups of the compounds disclosed herein. Products soluble or dispersible in water or oil can be obtained by such quaternization. Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium and the like. If appropriate, additional pharmaceutically acceptable salts are non-toxic ammonium, quaternary ammonium, and counterions such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, lower alkyl sulfonates and aryl sulfonates Amine cations formed using;

As described above, the pharmaceutically acceptable composition of the present invention further comprises a pharmaceutically acceptable carrier, adjuvant or vehicle, as used herein, any and all solvents, diluents as appropriate for the particular dosage form desired. Or other liquid vehicles, dispersion or suspension aids, surface active agents, isotonic agents, thickeners or emulsifiers, preservatives, solid binders, lubricants, and the like. Remington's Pharmaceutical Sciences, Sixteenth Edition, EW Martin (Mack Publishing Co., Easton, Pa., 1980) disclose various carriers used in the formulation of pharmaceutically acceptable compositions and known techniques for their preparation. . Any conventional carrier medium is incompatible with the compounds of the present invention, such as causing any undesirable biological effect or otherwise interacting in a detrimental manner with any other component (s) of the pharmaceutically acceptable composition. Except where not provided, their use is considered to be within the scope of the present invention. Some examples of materials that can act as pharmaceutically acceptable carriers are ion exchangers, alumina, aluminum stearate, lecithin, serum proteins such as human serum albumin, buffers such as phosphate, glycine, sorbic acid or potassium sorbate, saturated Partially glyceride mixtures 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, polyvinyl pyrrolidone, polyacrylates, waxes , Polyethylene-polyoxypropylene-block polymers, wool fats, sugars such as lactose, glucose and sucrose; Starches such as corn starch and potato starch; Cellulose and its derivatives such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; Powdered tragacanth; malt; gelatin; talc; Excipients such as cocoa butter and suppository waxes; Oils such as peanut oil, cottonseed oil; Safflower oil; Sesame oil; olive oil; Corn oil and soybean oil; Glycols such as propylene glycol or polyethylene glycol; Esters such as ethyl oleate and ethyl laurate; Agar; Buffers such as magnesium hydroxide and aluminum hydroxide; Alginic acid; Pyrogen-free water; Isotonic saline; Ringer's solution; Ethyl alcohol and phosphate buffer solutions, and also other non-toxic compatible lubricants such as sodium lauryl sulfate and magnesium stearate, but also at the discretion of the manufacturer, colorants, mold release agents, coating agents, sweeteners, Flavoring and fragrances, preservatives and antioxidants may also be present in the compositions.

In another aspect, the present invention provides a method of treating a condition, disease or disorder associated with ABC transporter activity. In certain embodiments, the invention provides a composition comprising a compound of Formula (I, Ic, Id, II, IIa, IIb, IIc, and IId) in the treatment of a condition, disease or disorder associated with a lack of ABC transporter activity. A method of treating a condition, disease or disorder associated with a lack of ABC transporter activity, comprising administering to a subject in need, preferably a mammal.

In certain preferred embodiments, the invention provides a method of administering to a mammal an effective amount of a composition comprising a compound of formula (I, Ic, Id, II, IIa, IIb, IIc and IId) or a preferred embodiment thereof as described above Cystic fibrosis, hereditary emphysema, hereditary hemochromatosis, coagulation-fibrinolytic deficiency, such as protein C deficiency, type 1 hereditary angioedema, lipid processing deficiency, such as familial hypercholesterolemia, type 1 atheremia Beta lipoproteinemia, lysosomal accumulating diseases such as I-cell disease / caustic-hallower, mucopolysaccharide deposition, sandhof / Tei-Sachs, Krigler-Nazar type II, polyendocrine disease / hyperinsulinemia, diabetes mellitus, laron dwarfism, Myeloperoxidase deficiency, primary hypothyroidism, melanoma, glycanosis CDG type 1, hereditary emphysema, congenital hyperthyroidism, incomplete osteoplasia, Malleable hypofibrosis, ACT deficiency, diabetes insipidus (DI), neurophysiological DI, neoplastic DI, Charco-Maritus syndrome, Felizius-Mertzvacher's disease, neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, Amyotrophic lateral sclerosis , Progressive nuclear palsy, peak disease, various polyglutamine nervous system disorders such as Huntington, spinal cord cerebellar ataxia type I, spinal cord and softening muscular atrophy, dentatorumal palidoliusian and myotonic dystrophy, and also cavernous encephalopathy such as hereditary Creutzfeldt Methods for treating Jacob disease (due to prion protein processing defects), Fabry disease, Straussler-Shainger disease, secretory diarrhea, polycystic kidney disease, chronic obstructive pulmonary disease (COPD), dry eye disease and Sjogren's syndrome.

According to an alternative preferred embodiment, the present invention provides to a mammal an effective amount of a composition comprising a compound of formula (I, Ic, Id, II, IIa, IIb, IIc and IId) or a preferred embodiment thereof as described above. Provided is a method of treating cystic fibrosis, comprising administering.

According to the invention, an “effective amount” of a compound or pharmaceutically acceptable composition is defined as cystic fibrosis, hereditary emphysema, hereditary hemochromatosis, coagulation-fibrinolytic deficiency, such as protein C deficiency, type 1 hereditary angioedema, lipid processing deficiency, such as family Sexual hypercholesterolemia, type 1 stromal granules, mubetalipoproteinemia, lysosomal accumulating diseases such as I-cell disease / caustic-huller, mucopolysaccharide deposition, sandhof / tei-sax, Krigler-Nazar type II, polyendocrine Disease / hyperinsulinemia, diabetes mellitus, laron dwarfism, myeloperoxidase deficiency, primary parathyroidism, melanoma, glycanosis CDG type 1, hereditary emphysema, congenital hyperthyroidism, incomplete osteoplasia, hereditary hypoplasia Fibrosis, ACT deficiency, diabetes insipidus (DI), neurophysiological DI, identity DI, Sharco-Marytooth syndrome, Felizius-Mertzvaer's disease, neurodegenerative disease, For example, Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, progressive nuclear palsy, peak disease, various polyglutamine nervous system disorders, such as Huntington, spinal cord cerebellar ataxia, spinal cord and softening muscular dystrophy, dentatoruba palidoluitian and myotonic Treatment of dystrophy, and also cavernous encephalopathy such as hereditary Creutzfeldt-Jakob disease, Fabry disease, Straussler-Schainker disease, secretory diarrhea, polycystic kidney disease, chronic obstructive pulmonary disease (COPD), dry eye disease and Sjogren's syndrome Or an amount effective to reduce its severity.

According to the methods of the invention, the compounds and compositions are cystic fibrosis, hereditary emphysema, hereditary hemochromatosis, coagulation-fibrinolytic deficiency, such as protein C deficiency, type 1 hereditary angioedema, lipid processing deficiency, such as familial hypercholesterolemia, type 1 Osteomyelemia, mutalipoproteinemia, lysosomal accumulation diseases such as I-cell disease / caustic-Huller, mucopolysaccharide deposition, Sandhof / Tey-Sachs, Krigler-Nazar type II, polyendocrine disease / hyperinsulinemia, Diabetes mellitus, laron dwarfism, myeloperoxidase deficiency, primary hypothyroidism, melanoma, glycanosis CDG type 1, hereditary emphysema, congenital hyperthyroidism, incomplete osteoplasia, hereditary hypofibrosis, ACT deficiency, Diabetes insipidus (DI), Neurophysiological DI, Identity DI, Sharco-Marytooth Syndrome, Felizius-Mertzvacher's Disease, Neurodegenerative diseases such as Alzheimer's disease, Par Kinson's disease, amyotrophic lateral sclerosis, progressive nuclear palsy, peak disease, various polyglutamine nervous system disorders such as Huntington, spinal cord cerebellar ataxia type I, spinal cord and softening muscular dystrophy, dentatorum palidoliusian and myotonic dystrophy, and also Treatment or severity of cavernous encephalopathy such as hereditary Creutzfeldt-Jakob disease, Fabry disease, Straussler-Shainger disease, secretory diarrhea, polycystic kidney disease, chronic obstructive pulmonary disease (COPD), dry eye disease and Sjogren's syndrome It may be administered using any amount and any route of administration effective to reduce the dose.

The exact amount required will vary from subject to subject, depending on the species, age and general condition of the subject, the severity of the infection, the particular agent, the mode of administration thereof, and the like. The compounds of the invention are preferably formulated in dosage unit form for ease of administration and uniformity of dosage. As used herein, the expression “dosage unit form” refers to an agent in physically discrete units suitable for the patient to be treated. However, it will be understood that the total daily usage of the compounds and compositions of the invention will be determined by the attending physician within the scope of the discerning medical judgment. Specific effective dose levels for any particular patient or organism include the disorder to be treated and the severity of the disorder; The activity of the specific compound employed; The specific composition employed; The age, body weight, general health, sex and diet of the patient; Time of administration, route of administration, and rate of excretion of the specific compound employed; Treatment period; It will depend on various factors, including drugs used in combination or coincidental with the specific compound employed, and similar factors known in the medical arts. As used herein, the term "patient" refers to an animal, preferably a mammal, most preferably a human.

Pharmaceutically acceptable compositions of the present invention may be administered orally, rectally, parenterally, grouse, intravaginally, intraperitoneally, topically (by powder, ointment or drops), buccal to humans and other animals depending on the severity of the infection being treated. Iii) orally (as an oral or nasal spray). In certain embodiments, a compound of the invention is orally or parenterally administered at least once a day at a dosage level of about 0.01 mg to about 50 mg, preferably about 1 mg to about 25 mg per kg body weight of the subject. Can be administered to achieve the desired therapeutic effect.

Liquid dosage forms for oral administration include, but are not limited to, pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs. Liquid dosage forms are inert diluents commonly used in the art in addition to the active compound, such as water or other solvents, solubilizing and emulsifying agents such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl Alcohols, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils (especially cottonseed oil, peanut oil, corn oil, embryo oil, olive oil, castor oil and sesame oil), glycerol, tetrahydrofur Fatty acid esters of furyl alcohol, polyethylene glycol, and sorbitan, and mixtures thereof. In addition to inert diluents, oral compositions may also contain auxiliaries such as wetting agents, emulsifying and suspending agents, sweetening agents, flavoring agents and fragrances.

Injectable preparations, for example, sterile injectable aqueous or oleaginous suspensions can be formulated as known in the art using suitable dispersing or wetting agents and suspending agents. Injectable sterile preparations may also be sterile injectable solutions, suspensions or emulsions in nontoxic parenterally acceptable diluents or solvents, such as, for example, solutions in 1,3-butanediol. Acceptable vehicles and solvents that can be used are in particular water, Ringer's solution, U.S.P. And isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose any bland fixed oil may be employed including synthetic monoglycerides or diglycerides. In addition, fatty acids such as oleic acid are used in the preparation of injectable preparations.

Injectable preparations can be sterilized, for example, by filtration through a bacteria-retaining filter or by incorporating the sterilizing agent in the form of a sterile solid composition that can be dissolved or dispersed in sterile water or other sterile injectable media prior to use.

In order to prolong the effects of the compounds of the invention, it is often desirable to slow the absorption of the injected compound subcutaneously or intramuscularly. This can be achieved using a liquid suspension of crystalline or amorphous material with poor water solubility. The rate of absorption of the compound then depends upon its rate of dissolution which, in turn, may depend upon crystal size and crystalline form. Alternatively, delay in absorption of the parenterally administered compound form is achieved by dissolving or suspending the compound in an oil vehicle. Injectable depot forms are made by forming microcapsule matrices of the compound in biodegradable polymers such as polylactide-polyglycolide. The rate of compound release can be controlled depending on the ratio of compound to polymer and the nature of the particular polymer employed. Examples of other biodegradable polymers include poly (orthoesters) and poly (anhydrides). Injectable depot preparations are also prepared by entrapping the compound in liposomes or microemulsions suitable for body tissue.

Compositions for rectal or vaginal administration are preferably suppositories which 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 waxes, which are solid at ambient temperature but body temperature Is a liquid that melts in the rectal or vaginal cavity to release the active compound.

Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In such solid dosage forms, the active compound is one or more inert pharmaceutically acceptable excipients or carriers such as sodium citrate or dicalcium phosphate and / or a) fillers or extenders such as starch, lactose, sucrose, glucose, mannitol and silicic acid b) binders such as carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidinone, sucrose and acacia, c) humectants such as glycerol, d) disintegrants such as agar-agar, calcium carbonate, potatoes or Tapioca starch, alginic acid, certain silicates and sodium carbonate, e) dissolution retardants such as paraffin, f) absorption accelerators, such as quaternary ammonium compounds, g) wetting agents, such as cetyl alcohol and glycerol monostearate, h) absorbents, Such as kaolin and bentonite clay, and i) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene articles Cole, sodium lauryl La are mixed and sulfate, and a mixture thereof. In the case of capsules, tablets and pills, the dosage form may also comprise buffering agents.

Solid compositions of a similar type can also be used as fillers in soft and hard-filled gelatin capsules using excipients such as lactose or lactose and also high molecular weight polyethylene glycols and the like. Solid dosage forms of tablets, sugars, capsules, pills, and granules can be prepared using coatings and shells well known in the pharmaceutical formulation art, such as enteric coatings and other coatings. These may optionally contain a bleaching agent and may also be a composition which releases only the active ingredient (s) or preferentially releases the active ingredient (s) in a particular delayed manner at certain sites of the intestine. Examples of embedding compositions that can be used include polymeric substances and waxes. In addition, solid compositions of a similar type can be used as fillers in soft and hard-filled gelatin capsules using excipients such as lactose or lactose, and also high molecular weight polyethylene glycols and the like.

The active compound may also be in microencapsulated form with one or more excipients as described above. Solid dosage forms of tablets, sugars, capsules, pills, and granules can be prepared using coatings and shells well known in the pharmaceutical formulation art, such as enteric coatings, release controlling coatings and other coatings. In such solid dosage forms, the active compound may be mixed with one or more inert diluents such as sucrose, lactose or starch. Such dosage forms may also include, in accordance with conventional practice, additional substances other than inert diluents, such as tableting lubricants and other tableting aids such as magnesium stearate and microcrystalline cellulose. In the case of capsules, tablets and pills, the dosage form may also comprise buffering agents. These may optionally contain a bleaching agent and may also be a composition which releases only the active ingredient (s) or preferentially releases the active ingredient (s) in a particular delayed manner at certain sites of the intestine. Examples of embedding compositions that can be used include polymeric substances and waxes.

Dosage forms for topical or transdermal administration of a compound of this 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, if desired, any necessary preservatives or buffers. Ophthalmic formulations, ear drops and eye drops are also contemplated as being within the scope of this invention. In addition, the present invention contemplates the use of transdermal patches that have the added advantage of providing controlled delivery of the compound to the body. Such dosage forms are made by dissolving or dispersing the compound in the proper medium. Absorption enhancers can also be used to increase the flux of the compound through the skin. The rate can be controlled by providing a rate-controlling membrane or by dispersing the compound in a polymer matrix or gel.

As generally described above, the compounds of the present invention are useful as modulators of ABC transporters. Thus, although not wishing to be bound by any particular theory, the compounds and compositions are particularly useful for treating or reducing the severity of diseases, conditions or disorders involving the overactivity or inactivity of ABC transporters. If the overactivity or inactivity of the ABC transporter is associated with a particular disease, condition or disorder, the disease, condition or disorder may also be referred to as "ABC transporter-mediated disease, condition or disorder". Accordingly, in another aspect, the present invention provides a method of treating or reducing the severity of a disease, condition or disorder in which the overactivity or inactivity of an ABC transporter is associated with a disease condition.

The activity of the compounds used as modulators of ABC transporters in the present invention can be assayed according to the methods generally described in the art and in the examples herein.

In addition, the compounds of the present invention and pharmaceutically acceptable compositions may be used in combination therapy, i.e., the compounds and pharmaceutically acceptable compositions may be used in combination with, before, or after, one or more other desired therapeutic or medical procedures. It will be appreciated that it may be administered. The particular combination of therapy (therapeutic agent or procedure) to be used in the combination therapy will take into account the compatibility of the desired therapeutic agent and / or procedure and the desired therapeutic effect to be achieved. In addition, the therapy used may achieve the desired effect on the same disorder (eg, a compound of the invention may be administered in combination with another agent used to treat the same disorder), or different effects ( For example, it will be appreciated that any side effect of control) may be achieved. As used herein, additional therapeutic agents that are typically administered to treat or prevent a particular disease or condition are known to be “suitable for the disease or condition to be treated”.

The amount of additional therapeutic agent present in the compositions of the present invention is no greater than the amount normally administered in a composition comprising said therapeutic agent as the only active agent. Preferably, the amount of additional therapeutic agent in the compositions disclosed herein will range from about 50% to 100% of the amount typically present in a composition comprising said agent as the only therapeutically active agent.

The compounds of the present invention or pharmaceutically acceptable compositions thereof may also be incorporated into compositions for coating implantable medical devices such as prostheses, prostheses, vascular grafts, stents and catheters. Accordingly, the present invention provides in another aspect a composition for coating an implantable device comprising a compound of the present invention as generally described above and belonging to the classes and subclasses herein and a carrier suitable for coating the implantable device. Include. In another aspect, the invention generally includes an implantable device coated with a composition comprising a compound of the invention as described above and belonging to the classes and subclasses herein and a carrier suitable for coating the implantable device. General preparations of suitable coatings and coated implantable devices are described in US Pat. Nos. 6,099,562, 5,886,026 and 5,304,121. Coating agents are typically biocompatible polymer materials such as hydrogel polymers, polymethyldisiloxane, polycaprolactone, polyethylene glycol, polylactic acid, ethylene vinyl acetate, and mixtures thereof. The coating may optionally be further coated with a suitable topcoat of fluorosilicone, polysaccharide, polyethylene glycol, phospholipids or combinations thereof to impart controlled release characteristics to the composition.

Another aspect of the invention relates to a method of modulating ABC transporter activity in a biological sample or patient (eg, in vitro or in vivo), which method comprises a compound of formula (I) or comprising said compound in a patient Administering the composition or contacting a biological sample with a compound of formula (I) or a composition comprising said compound. As used herein, the term “biological sample” refers to a cell culture or extract thereof; Biopsied material obtained from a mammal or extracts thereof; And blood, saliva, urine, feces, semen, tears or other body fluids, or extracts thereof.

Modulation of ABC transporter activity in biological samples is useful for a variety of purposes known to those skilled in the art. Examples of this purpose include, but are not limited to, the study of ABC transporters in biological and pathological phenomena and the comparative assessment of new modulators of ABC transporters.

In another embodiment, an in vitro or in vivo anion channel comprising contacting an anion channel in vitro or in vivo with a compound of formula (I, Ic, Id, II, IIa, IIb, IIc and IId). A method of adjusting activity is provided. In a preferred embodiment, the anionic channel is a chloride channel or a bicarbonate channel. In another preferred embodiment, said anionic channel is a chloride channel.

According to an alternative embodiment, the present invention comprises contacting a cell with a compound of formula (I, Ic, Id, II, IIa, IIb, IIc and IId), wherein the number of functional ABC transporters in the membrane of said cell It provides a way to increase. As used herein, the term "functional ABC transporter" means an ABC transporter that may have transport activity. In a preferred embodiment, said functional ABC transporter is CFTR.

According to another preferred embodiment, the activity of the ABC transporter is determined by measuring the transmembrane voltage potential. Means for measuring the voltage potential across the membrane in a biological sample can use any method known in the art, such as optical membrane potential assays or other electrophysiology methods.

Optical membrane potential assays are described by Gonzalez and Tsien as voltage-sensitive FRET sensors (Gonzalez, JE and RY Tsien (1995) "Voltage sensing by fluorescence resonance energy transfer in single cells" Biophys J 69 (4): 1272-80 and Gonzalez, JE and RY Tsien (1997) "Improved indicators of cell membrane potential that use fluorescence resonance energy transfer" Chem Biol 4 (4): 269-77). Instruments for measurement, such as Voltage / Ion Probe Reader (VIPR) (Gonzalez, JE, K. Oades, et al. (1999) "Cell-based assays and instrumentation for screening ion-channel targets" Drug Discov Today 4 (9): 431-439).

This voltage sensitive assay is characterized by the fluorescence resonance energy transfer (FRET) between the membrane-soluble voltage-sensitive dye DiSBAC ₂ (3) and the fluorescent phospholipid CC2-DMPE (attached to the outer membrane of the plasma membrane to act as a FRET donor). Based on change. The change in membrane potential (V _m ) causes the negatively charged DiSBAC ₂ (3) to be redistributed to the plasma membrane, thus changing the amount of energy transfer from CC2-DMPE. Changes in fluorescence emission can be monitored with VIPR ™ II, an integrated liquid handler and fluorescence detector designed to perform cell-based screening in 96-well or 384-well microtiter plates.

In another aspect, the invention provides a composition comprising (i) a compound comprising a compound of formula (I, Ic, Id, II, IIa, IIb, IIc and IId) or any of the above embodiments, and (ii) a) said composition Contacting a biological sample, and b) a kit used to determine the activity of the ABC transporter or fragment thereof in a biological sample in vitro or in vivo, including instructions for measuring the activity of said ABC transporter or fragment thereof. to provide. In one embodiment, the kit comprises a) contacting a further composition with a biological sample, b) measuring the activity of the ABC transporter or fragment thereof in the presence of the additional compound, c) ABC in the presence of the additional compound Further included are instructions for comparing the activity of the transporter with the density of the ABC transporter in the presence of a compound of formula (I, Ic, Id, II, IIa, IIb, IIc and IId). In a preferred embodiment, the kit is used to measure the density of CFTR.

The following examples are set forth in order to provide a more complete understanding of the invention described herein. It is to be understood that these examples are for illustrative purposes only and are not to be construed as limiting the invention in any way.

VI . Manufacturing example  And Example

General Procedure I: Carboxylic Acid Building Blocks

Benzyltriethylammonium chloride (0.025 equiv) and the appropriate dihalo compound (2.5 equiv) were added to the substituted phenyl acetonitrile. The mixture was heated at 70 ° C. and then 50% sodium hydroxide (10 equiv) was slowly added to the mixture. The reaction was stirred at 70 ° C. for 12-24 hours to ensure complete cycloalkyl moiety, then heated at 130 ° C. for 24-48 hours to ensure complete conversion from nitrile to carboxylic acid. The dark brown / black reaction mixture was diluted with water and extracted three times with dichloromethane to remove byproducts. The basic aqueous solution was acidified to less than pH 1 with concentrated hydrochloric acid, and the precipitate which started to form at pH 4 was filtered and washed twice with 1M hydrochloric acid. The solid material was dissolved in dichloromethane and extracted twice with 1M hydrochloric acid and once with a saturated aqueous solution of sodium chloride. The organic solution was dried over sodium sulphate and evaporated to dryness to afford cycloalkylcarboxylic acid. Yield and purity are typically greater than 90%.

Example 1: 1-benzo [1,3] dioxol-5-yl-cyclopropanecarboxylic acid

2- (benzo [d] [1,3] dioxol-5-yl) acetonitrile (5.10 g, 31.7 mmol), 1-bromo-2-chloro-ethane (9.00 mL, 109 mmol), and benzyltri A mixture of ethylammonium chloride (0.181 g, 0.795 mmol) was heated at 70 ° C., then 50% (wt./wt.) Aqueous sodium hydroxide (26 mL) was slowly added to the mixture. The reaction 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 equal volume of ethyl acetate and once with equal volume of dichloromethane. The basic aqueous solution was acidified to less than pH 1 with concentrated hydrochloric acid, the precipitate was filtered off and washed with 1M hydrochloric acid. The solid material was dissolved in dichloromethane (400 mL) and extracted twice with an equal volume of 1M hydrochloric acid and once with a saturated aqueous solution of sodium chloride. The organic solution was dried over sodium sulphate and evaporated to dryness to give a white to slightly off-white solid (5.23 g, 80%).

General Procedure II: Carboxylic Acid Building Blocks

Sodium hydroxide (50% aqueous solution, 7.4 equiv) was slowly added to a mixture of appropriate phenyl acetonitrile, benzyltriethylammonium chloride (1.1 equiv), and the appropriate dihalo compound (2.3 equiv) at 70 ° C. The mixture was stirred at 70 ° C. overnight, the reaction mixture was diluted with water (30 mL) and extracted with ethyl acetate. The combined organic layers were dried over sodium sulphate and evaporated to dryness to afford crude cyclopropanecarbonitrile which was used directly in the next step.

Crude cyclopropanecarbonitrile was refluxed in 10% aqueous sodium hydroxide (7.4 equiv) for 2.5 h. The cooled reaction mixture was washed with ether (100 mL) and the aqueous phase was acidified to pH 2 with 2M hydrochloric acid. The precipitated solid was filtered to give cyclopropanecarboxylic acid as a white solid.

General Procedure III: Carboxylic Acid Building Blocks

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

2,2-difluoro-benzo [1,3] dioxol-5-carboxylic acid methyl ester

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

(2,2-Difluoro-benzo [1,3] dioxol-5-yl) -methanol

Crude 2,2-difluoro-benzo [1,3] dioxol-5-carboxylic acid methyl ester (11.5 g) dissolved in 20 mL of anhydrous tetrahydrofuran (THF) was hydrogenated in anhydrous THF (100 mL) To a suspension of lithium aluminum (4.10 g, 106 mmol) was added slowly at 0 ° C. The mixture was then warmed to room temperature. After stirring for 1 hour at room temperature, the reaction mixture was cooled to 0 ° C. and treated with water (4.1 g) followed by sodium hydroxide (10% aqueous solution, 4.1 mL). The resulting slurry was filtered and washed with THF. The combined filtrates were evaporated to dryness and the residue was purified by silica gel column chromatography to give (2,2-difluoro-benzo [1,3] dioxol-5-yl) -methanol (7.2 g over two steps). , 38 mmol, 76%) was obtained as a colorless oil.

5-chloromethyl-2,2-difluoro-benzo [1,3] dioxol

Thionyl chloride (45 g, 38 mmol) was dissolved in (2,2-difluoro-benzo [1,3] dioxol-5-yl) -methanol (7.2 g, 38 mmol) in dichloromethane (200 mL). To the solution was added slowly at 0 ° C. The resulting mixture was stirred at rt overnight then evaporated to dryness. The residue was partitioned between saturated aqueous 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 afford crude 5-chloromethyl-2,2-difluoro-benzo [1,3] di. Oxole (4.4 g) was obtained, which was used directly for the next step.

(2,2-Difluoro-benzo [1,3] dioxol-5-yl) -acetonitrile

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

1- (2,2-Difluoro-benzo [1,3] dioxol-5-yl) -cyclopropanecarbonitrile

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

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

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 2.5 hours in 10% aqueous sodium hydroxide (50 mL). At reflux. The cooled reaction mixture was washed with ether (100 mL) and the aqueous phase was acidified to pH 2 with 2M hydrochloric acid. The precipitated solid was filtered to give 1- (2,2-difluoro-benzo [1,3] dioxol-5-yl) -cyclopropanecarboxylic acid as a white solid (0.15 g, 1.6% over four steps) Obtained as

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

(3,4-dihydroxy-phenyl) -acetonitrile

To a solution of benzo [1,3] dioxol-5-yl-acetonitrile (0.50 g, 3.1 mmol) in CH ₂ Cl ₂ (15 mL) BBr ₃ (0.78 g, 3.1 mmol) at −78 ° C. under N ₂ . Was added drop wise. The mixture was slowly warmed to rt and stirred overnight. H ₂ O (10 mL) was added to quench the reaction and the CH ₂ Cl ₂ layer was separated. The aqueous phase was extracted with CH ₂ Cl ₂ (2 × 7 mL). The combined organics are washed with brine, dried over Na ₂ SO ₄ and purified by column chromatography on silica gel (petroleum ether / ethyl acetate 5: 1) to give (3,4-dihydroxy-phenyl) -acetonitrile ( 0.25 g, 54%) was obtained as a white solid.

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

To a solution of (3,4-dihydroxy-phenyl) -acetonitrile (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) was added. The mixture was heated at 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 NaHCO ₃ solution, H ₂ O, brine and dried over Na ₂ SO ₄ . The solvent was evaporated under reduced pressure to give a residue, which was purified by column chromatography on silica gel (petroleum ether / ethyl acetate 10: 1) to give 2- (2,2-dimethylbenzo [d] [1,3] di. Oxol-5-yl) acetonitrile (40 mg, 20%) was obtained.

Example 4 1- (3,4-Dihydroxy-phenyl) -cyclopropanecarboxylic acid

1- (3,4-bis-benzyloxy-phenyl) -cyclopropanecarbonitrile

(NC ₄ H ₉ ) ₄ NBr (0.50 g, 1.5 mmol), toluene (7 mL) and (3,4-bis-benzyloxy-phenyl) -aceto in NaOH (50 g) and H ₂ O (50 mL) To a mixture of nitrile (14 g, 42 mmol) was added BrCH ₂ CH ₂ Cl (30 g, 0.21 mol). The reaction mixture was stirred at 50 ° C. for 5 hours and then cooled to room temperature. Toluene (30 mL) was added and the organic layer was separated, washed with H ₂ O, brine, dried over anhydrous MgSO ₄ and concentrated. The residue was purified by column on silica gel (petroleum ether / ethyl acetate 10: 1) to give 1- (3,4-bis-benzyloxy-phenyl) -cyclopropanecarbonitrile (10 g, 66%).

1- (3,4-dihydroxy-phenyl) -cyclopropanecarbonitrile

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 a nitrogen atmosphere. The mixture was stirred at rt under hydrogen atmosphere (1 atm) for 4 h. The catalyst was filtered through a pad of celite and the filtrate was evaporated in vacuo to afford 1- (3,4-dihydroxy-phenyl) -cyclopropanecarbonitrile (4.5 g, 92%).

1- (3,4-dihydroxy-phenyl) -cyclopropanecarboxylic acid

To a solution of NaOH (20 g, 0.50 mol) in H ₂ O (20 mL) was added 1- (3,4-dihydroxy-phenyl) -cyclopropanecarbonitrile (4.4 g, 25 mmol). The mixture was heated at reflux for 3 hours and then cooled to room temperature. The mixture was neutralized to pH 3-4 with HCl (0.5 N) and extracted with ethyl acetate (20 mL × 3). The combined organic layers were washed with water, brine, dried over anhydrous MgSO ₄ and concentrated in vacuo to afford 1- (3,4-dihydroxy-phenyl) -cyclopropanecarboxylic acid (4.5 g crude). . From 900 mg of crude, 500 mg pure 1- (3,4-dihydroxy-phenyl) -cyclopropanecarboxylic acid was obtained by preparative HPLC.

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

1- (4-methoxy-phenyl) -cyclopropanecarboxylic acid methyl ester

Toluene-4-sulfonic acid monohydrate (2.5 g, 13 mmol) was added to a solution of 1- (4-methoxy-phenyl) -cyclopropanecarboxylic acid (50 g, 0.26 mol) in MeOH (500 mL) at room temperature. It was. The reaction mixture was heated at reflux for 20 hours. MeOH was removed by evaporation in vacuo and EtOAc (200 mL) was added. The organic layer was washed with saturated aqueous NaHCO ₃ (100 mL), brine, dried over anhydrous Na ₂ SO ₄ , and evaporated in vacuo to 1- (4-methoxy-phenyl) -cyclopropanecarboxylic acid methyl ester (53 g, 99%) was obtained.

1- (4-methoxy-3-nitro-phenyl) -cyclopropanecarboxylic acid methyl ester

HNO ₃ in AcOH (75 mL) to a solution of 1- (4-methoxy-phenyl) -cyclopropanecarboxylic acid methyl ester (30.0 g, 146 mmol) in Ac ₂ O (300 mL) A solution of (14.1 g, 146 mmol, 65%) was added at 0 ° C. The reaction mixture was stirred at 0-5 ° C. for 3 hours, then aqueous HCl (20%) was added dropwise at 0 ° C. The resulting mixture was extracted with EtOAc (200 mL x 3). The organic layer was washed with saturated aqueous NaHCO ₃ followed by brine, dried over anhydrous Na ₂ SO ₄ and evaporated in vacuo to give 1- (4-methoxy-3-nitro-phenyl) -cyclopropanecarboxylic acid methyl ester ( 36.0 g, 98%) were obtained and used directly in the next step.

1- (4-hydroxy-3-nitro-phenyl) -cyclopropanecarboxylic acid methyl ester

BBr ₃ (12.0 g, 47.8 mmol) in a solution of 1- (4-methoxy-3-nitro-phenyl) -cyclopropane-carboxylic acid methyl ester (10.0 g, 39.8 mmol) in CH ₂ Cl ₂ (100 mL). ) Was added 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. Water (50 mL) was added dropwise at −20 ° C. and the resulting mixture was allowed to warm to rt before it was extracted with EtOAc (200 mL × 3). The combined organic layers were dried over anhydrous Na ₂ SO ₄ and evaporated in vacuo to afford the crude product, which was purified by column chromatography on silica gel (petroleum ether / ethyl acetate 15: 1) to give 1- (4-hydroxy 3-nitro-phenyl) -cyclopropanecarboxylic acid methyl ester (8.3 g, 78%) was obtained.

1- (3-Amino-4-hydroxy-phenyl) -cyclopropanecarboxylic acid methyl ester

To a solution of 1- (4-hydroxy-3-nitro-phenyl) -cyclopropanecarboxylic acid methyl ester (8.3 g, 35 mmol) in MeOH (100 mL) was added Raney Nickel (0.8 g) under a nitrogen atmosphere. . The mixture was stirred at 35 ° C. under hydrogen atmosphere (1 atm) for 8 hours. The catalyst was filtered through a pad of celite and the filtrate was evaporated in vacuo to afford the crude product, which was purified by column chromatography on silica gel (petroleum ether / ethyl acetate 1: 1) to give 1- (3-amino- 4-hydroxy-phenyl) -cyclopropanecarboxylic acid methyl ester (5.3 g, 74%) was obtained.

1- (2-Oxo-2,3-dihydro-benzooxazol-5-yl) -cyclopropanecarboxylic acid methyl ester

Triphosgene (4.2 g, 14 mmol) was added to a solution of 1- (3-amino-4-hydroxy-phenyl) -cyclopropanecarboxylic acid methyl ester (2.0 g, 9.6 mmol) in THF (40 mL) at room temperature. Added. The mixture was stirred at this temperature for 20 minutes and then water (20 mL) was added dropwise at 0 ° C. The resulting mixture was extracted with EtOAc (100 mL x 3). The combined organic layers were dried over anhydrous Na ₂ SO ₄ and evaporated in vacuo to give 1- (2-oxo-2,3-dihydro-benzooxazol-5-yl) -cyclopropanecarboxylic acid methyl ester (2.0 g , 91%), which was used directly in the next step.

1- (2-oxo-2,3-dihydrobenzo [d] oxazol-5-yl) cyclopropanecarboxylic acid

Of 1- (2-oxo-2,3-dihydro-benzooxazol-5-yl) -cyclopropanecarboxylic acid methyl ester (1.9 g, 8.1 mmol) in MeOH (20 mL) and water (2 mL) LiOH.H ₂ O (1.7 g, 41 mmol) was added portionwise to the solution at room temperature. The reaction mixture was stirred at 50 ° C. for 20 hours. MeOH was removed by evaporation in vacuo, then water (100 mL) and EtOAc (50 mL) were added. 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 Na ₂ SO ₄ and evaporated in vacuo to give 1- (2-oxo-2,3-dihydrobenzo [d] oxazol-5-yl) cyclopropanecarboxylic acid (1.5 g, 84%) was obtained.

Example 6: 1- (6-Fluoro-benzo [1,3] dioxol-5-yl) -cyclopropanecarboxylic acid

2-fluoro-4,5-dihydroxy-benzaldehyde

To a stirred suspension of 2-fluoro-4,5-dimethoxy-benzaldehyde (3.00 g, 16.3 mmol) in dichloromethane (100 mL) was added dropwise BBr ₃ (12.2 mL, 130 mmol) at −78 ° C. under a nitrogen atmosphere. It was. After addition, 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 precipitated solid was collected by filtration and washed with dichloromethane to give 2-fluoro-4,5-dihydroxy-benzaldehyde (8.0 g) which was used directly in the next step. It was.

2-fluoro-4,5-dihydroxy-benzaldehyde (8.0 g) and BrClCH _{2 in} 6-fluoro-benzo [1,3] dioxol-5-carbaldehyde anhydrous DMF (50 mL) To a stirred solution of (24.8 g, 190 mmol) was added Cs ₂ CO ₃ (62.0 g, 190 mmol) in portions. The resulting mixture was stirred at 60 ° C. overnight and then poured into water. The mixture was extracted with EtOAc (200 mL x 3). The combined organic layers were washed with brine (200 mL), dried over Na ₂ SO ₄ and evaporated in vacuo to afford the crude product, which was subjected to column chromatography on silica gel (5-20% ethyl acetate / petroleum ether). Purification gave 6-fluoro-benzo [1,3] dioxol-5-carbaldehyde (700 mg, two step yield: 24%).

(6-Fluoro-benzo [1,3] dioxol-5-yl) -methanol

To a stirred solution of 6-fluoro-benzo [1,3] dioxol-5-carbaldehyde (700 mg, 4.2 mmol) in MeOH (50 mL) was added NaBH ₄ (320 mg, 8.4 mmol) in small portions at 0 ° C. Added. The mixture was stirred at this temperature for 30 minutes and then concentrated in vacuo to afford a residue. The residue is dissolved in EtOAc, the organic layer is washed with water, dried over Na ₂ SO ₄ and concentrated in vacuo (6-fluoro-benzo [1,3] dioxol-5-yl) -methanol (650 mg, 92%) was obtained and used directly in the next step.

5-chloromethyl-6-fluoro-benzo [1,3] dioxol

(6-Fluoro-benzo [1,3] dioxol-5-yl) -methanol (650 mg, 3.8 mmol) was added portionwise to SOCl ₂ (20 mL) at 0 ° C. The mixture was warmed to room temperature for 1 hour and then heated to reflux for 1 hour. Excess SOCl ₂ was evaporated under reduced pressure to give the crude product, which was basified to pH ˜7 with saturated NaHCO ₃ solution. The aqueous phase was extracted with EtOAc (50 mL x 3). The combined organic layers were dried over Na ₂ SO ₄ and evaporated under reduced pressure to afford 5-chloromethyl-6-fluoro-benzo [1,3] dioxol (640 mg, 90%), which was directly added to the next step. Used.

(6-Fluoro-benzo [1,3] dioxol-5-yl) -acetonitrile

A mixture of 5-chloromethyl-6-fluoro-benzo [1,3] dioxol (640 mg, 3.4 mmol) and NaCN (340 mg, 6.8 mmol) in DMSO (20 mL) was stirred at 30 ° C. for 1 hour. Then poured into water. The mixture was extracted with EtOAc (50 mL x 3). The combined organic layers were washed with water (50 mL) and brine (50 mL), dried over Na ₂ SO ₄ and evaporated under reduced pressure to give the crude product, which was column chromatography on silica gel (5-10% ethyl Acetate / petroleum ether) to give (6-fluoro-benzo [1,3] dioxol-5-yl) -acetonitrile (530 mg, 70%).

1- (6-Fluoro-benzo [1,3] dioxol-5-yl) -cyclopropanecarbonitrile

Water (10 mL) was combined into the flask, followed by rapid addition of NaOH (10 g, 0.25 mol) in three portions over a 5 minute period. The mixture was allowed to cool to room temperature. Subsequently, to the flask, toluene (6 mL), tetrabutyl-ammonium bromide (50 mg, 0.12 mmol), (6-fluoro-benzo [1,3] dioxol-5-yl) -acetonitrile (600 mg , 3.4 mmol) and 1-bromo-2-chloroethane (1.7 g, 12 mmol) were combined. The mixture was stirred vigorously at 50 ° C. overnight. Additional toluene (20 mL) was combined in the cooled flask. The organic layer was separated and washed with water (30 mL) and brine (30 mL). The organic layer was removed in vacuo to afford the crude product, which was purified by column chromatography on silica gel (5-10% ethyl acetate / petroleum ether) to give 1- (6-fluoro-benzo [1,3] dioxol. -5-yl) -cyclopropanecarbonitrile (400 mg, 60%) was obtained.

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 the reaction cooled down, 5% HCl was added until pH <5, then EtOAc (30 mL) was added to the reaction mixture. The layers were separated and the combined organic layers were evaporated in vacuo to give 1- (6-fluoro-benzo [1,3] dioxol-5-yl) -cyclopropanecarboxylic acid (330 mg, 76%). .

Example 7: 1- (benzofuran-5-yl) cyclopropanecarboxylic acid

1- [4- (2,2-diethoxy-ethoxy) -phenyl] -cyclopropanecarboxylic acid

To a stirred solution of 1- (4-hydroxy-phenyl) -cyclopropanecarboxylic acid methyl ester (15.0 g, 84.3 mmol) in DMF (50 mL) was added sodium hydride (6.7 g, 170 mmol, 60% in mineral oil). Add at 0 ° C. After hydrogen evolution ceased, 2-bromo-1,1-diethoxy-ethane (16.5 g, 84.3 mmol) was added dropwise to the reaction mixture. The reaction was stirred at 160 ° C. for 15 hours. The reaction mixture was poured into ice (100 g) and extracted with CH ₂ Cl ₂ . The combined organics were dried over Na ₂ SO ₄ . The solvent was evaporated in vacuo to give 1- [4- (2,2-diethoxy-ethoxy) -phenyl] -cyclopropanecarboxylic acid (10 g) which was used directly in the next step without purification.

1-benzofuran-5-yl-cyclopropanecarboxylic acid

PPA (22.2 g, 64.9 mmol) in a suspension of 1- [4- (2,2-diethoxy-ethoxy) -phenyl] -cyclopropanecarboxylic acid (20 g, ˜65 mmol) in xylene (100 mL). ) Was added at room temperature. The mixture was heated under reflux (140 ° C.) for 1 hour, after which it was cooled to room temperature and decanted from PPA. The solvent was evaporated in vacuo to afford the crude product which was purified by preparative HPLC to give 1- (benzofuran-5-yl) cyclopropanecarboxylic acid (1.5 g, 5%).

Example 8: 1- (2,3-dihydrobenzofuran-6-yl) cyclopropanecarboxylic acid

To a solution of 1- (benzofuran-6-yl) cyclopropanecarboxylic acid (370 mg, 1.8 mmol) in MeOH (50 mL) was added PtO ₂ (75 mg, 20%) at room temperature. The reaction mixture was stirred at 20 ° C. under hydrogen atmosphere (1 atm) for 3 days. The reaction mixture was filtered and the solvent was evaporated in vacuo to afford the crude product which was purified by preparative HPLC to give 1- (2,3-dihydrobenzofuran-6-yl) cyclopropanecarboxylic acid (155 mg, 42%) was obtained.

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

1- (4-hydroxy-phenyl) -cyclopropanecarboxylic acid methyl ester

To a solution of methyl 1- (4-methoxyphenyl) cyclopropanecarboxylate (10.0 g, 48.5 mmol) in dichloromethane (80 mL) was added EtSH (16 mL) under an ice water bath. The mixture was stirred at 0 ° C. for 20 minutes, then AlCl ₃ (19.5 g, 0.15 mmol) was added slowly at 0 ° C. The mixture was stirred at 0 ° C. for 30 minutes. The reaction mixture is poured into ice water, the organic layer is separated and the aqueous phase is extracted with dichloromethane (50 mL x 3). The combined organic layers were washed with H ₂ O, brine, dried over Na ₂ SO ₄ and evaporated in vacuo to 1- (4-hydroxy-phenyl) -cyclopropanecarboxylic acid methyl ester (8.9 g, 95%) Obtained.

1- (4-hydroxy-3,5-diiodo-phenyl) -cyclopropanecarboxylic acid methyl ester

To a solution of 1- (4-hydroxy-phenyl) -cyclopropanecarboxylic acid methyl ester (8.9 g, 46 mmol) in CH ₃ CN (80 mL) was added NIS (15.6 g, 69 mmol). The mixture was stirred at rt for 1 h. The reaction mixture is concentrated, and the residue is purified by column chromatography on silica gel (petroleum ether / ethyl acetate 10: 1) to give 1- (4-hydroxy-3,5-diiodo-phenyl) -cyclopropanecar Acid methyl ester (3.5 g, 18%) was obtained.

1- [3,5-Diiodo-4- (2-methyl-allyloxy) -phenyl] -cyclopropanecarboxylic acid methyl ester

1- (4-hydroxy-3,5-diiodo-phenyl) -cyclopropanecarboxylic acid methyl ester (3.2 g, 7.2 mmol) in acetone (20 mL), 3-chloro-2-methyl-propene (1.0 g, 11 mmol), a mixture of K ₂ CO ₃ (1.2 g, 8.6 mmol), NaI (0.1 g, 0.7 mmol) was stirred at 20 ° C. overnight. The solid was filtered off and the filtrate was concentrated in vacuo to give 1- [3,5-diiodo-4- (2-methyl-allyloxy) -phenyl] -cyclopropane-carboxylic acid methyl ester (3.5 g, 97 %) Was obtained.

1- (3,3-dimethyl-2,3-dihydro-benzofuran-5-yl) -cyclopropanecarboxylic acid methyl ester

Bu in a solution of 1- [3,5-diiodo-4- (2-methyl-allyloxy) -phenyl] -cyclopropane-carboxylic acid methyl ester (3.5 g, 7.0 mmol) in toluene (15 mL) ₃ SnH (2.4 g, 8.4 mmol) and AIBN (0.1 g, 0.7 mmol) were added. The mixture was heated at reflux overnight. The reaction mixture was concentrated in vacuo and the residue was purified by column chromatography on silica gel (petroleum ether / ethyl acetate 20: 1) to give 1- (3,3-dimethyl-2,3-dihydro-benzofuran-5 -Yl) -cyclopropanecarboxylic acid methyl ester (1.05 g, 62%) was obtained.

1- (3,3-dimethyl-2,3-dihydrobenzofuran-5-yl) cyclopropanecarboxylic acid

LiOH (0.40) in a solution of 1- (3,3-dimethyl-2,3-dihydro-benzofuran-5-yl) -cyclopropanecarboxylic acid methyl ester (1.0 g, 4.0 mmol) in MeOH (10 mL) g, 9.5 mmol) was added. The mixture was stirred at 40 ° C. overnight. The pH was adjusted to 5 by the slow addition of HCl (10%). The resulting mixture was extracted with ethyl acetate (10 mL x 3). The extract was washed with brine and dried over Na ₂ S0 ₄ . The solvent was removed in vacuo 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%) Obtained.

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

3,4-dihydroxy-5-methoxybenzoate

To a solution of 3,4,5-trihydroxy-benzoic acid methyl ester (50 g, 0.27 mol) and Na ₂ B ₄ O ₇ (50 g) in water (1000 mL) Me ₂ SO ₄ (120 mL) and aqueous NaOH solution (25%, 200 mL) were added sequentially. The mixture was stirred at rt for 6 h before it was cooled to 0 ° C. The mixture was acidified to pH ˜2 by addition of concentrated H ₂ SO ₄ and filtered. The filtrate was extracted with EtOAc (500 mL x 3). The combined organic layers were dried over anhydrous Na ₂ SO ₄ and evaporated under reduced pressure to afford methyl 3,4-dihydroxy-5-methoxybenzoate (15.3 g 47%), which was used in the next step without further purification. It was.

Methyl 7-methoxybenzo [d] [1,3] dioxol-5-carboxylate

CH ₂ BrCl (34.4 g, 0.270 mol) and K ₂ CO _{3 in} a solution of methyl 3,4-dihydroxy-5-methoxybenzoate (15.3 g, 0.0780 mol) in acetone (500 mL) (75.0 g, 0.540 mol) was added at 80 ° C. The resulting mixture was heated at reflux for 4 h. The mixture was cooled to room temperature and the solid K ₂ CO ₃ was filtered off. 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 Na ₂ SO ₄ and evaporated under reduced pressure to afford the crude product, which was purified by column chromatography on silica gel (petroleum ether / ethyl acetate = 10: 1) to give methyl 7- Methoxybenzo [d] [1,3] dioxol-5-carboxylate (12.6 g, 80%) was obtained.

(7-methoxybenzo [d] [1,3] dioxol-5-yl) methanol

LiAlH ₄ (3.1 g, 0.080 mol) was added to a solution of methyl 7-methoxybenzo [d] [1,3] dioxol-5-carboxylate (14 g, 0.040 mol) in THF (100 mL) at room temperature. A little bit was added. The mixture was stirred at rt for 3 h. The reaction mixture was cooled to 0 ° C. and treated successively with water (3.1 g) and NaOH (10%, 3.1 mL). The slurry was filtered and washed with THF. The combined filtrates were evaporated under reduced pressure to give (7-methoxy-benzo [d] [1,3] dioxol-5-yl) methanol (7.2 g, 52%).

6- (chloromethyl) -4-methoxybenzo [d] [1,3] dioxol

To a solution of SOCl ₂ (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 h. Excess SOCl ₂ was evaporated under reduced pressure to give the crude product, which was basified to pH ˜7 with saturated aqueous NaHCO ₃ . The aqueous phase was extracted with EtOAc (100 mL x 3). The combined organic layers were dried over anhydrous Na ₂ SO ₄ and evaporated to give 6- (chloromethyl) -4-methoxybenzo [d] [1,3] dioxol (10 g 94%), which was followed by Used without further purification.

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

To a solution of 6- (chloromethyl) -4-methoxybenzo [d] [1,3] dioxol (10 g, 40 mmol) in DMSO (100 mL) was added NaCN (2.4 g, 50 mmol) at room temperature. It was. The mixture was stirred for 3 hours and poured into water (500 mL). The aqueous phase was extracted with EtOAc (100 mL x 3). The combined organic layers were dried over anhydrous Na ₂ SO ₄ and evaporated to afford the crude product which was washed with ether to give 2- (7-methoxybenzo [d] [1,3] dioxol-5-yl) aceto Nitrile (4.6 g, 45%) was obtained.

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

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, treated dropwise with a solution of 3-benzyloxy-4-methoxy-benzaldehyde (10.0 g, 51.9 mmol) in THF (50 mL), and then stirred at -78 ° C for 1.5 hours. It was. Methanol (50 mL) was added to the cooled reaction mixture. The mixture was heated at reflux for 30 minutes. Solvent was removed to give crude product, which was dissolved in water (300 mL). The aqueous phase was extracted with EtOAc (100 mL x 3). The combined organic layers were dried and evaporated under reduced pressure to afford the 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%) was obtained.

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

(4-Chloro-3-hydroxy-phenyl) acetonitrile

BBr ₃ (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 N _2. Added. The reaction temperature slowly increased to room temperature. The reaction mixture was stirred overnight and then poured into ice and water. The organic layer was separated and the aqueous layer was extracted with dichloromethane (40 mL x 3). The combined organic layers were washed with water, brine, dried over Na ₂ SO ₄ and concentrated in vacuo to afford (4-chloro-3-hydroxy-phenyl) -acetonitrile (9.3 g, 85%).

2- (3- (benzyloxy) -4-chlorophenyl) acetonitrile

To a solution of (4-chloro-3-hydroxy-phenyl) acetonitrile (6.2 g, 37 mmol) in CH ₃ CN (80 mL) K ₂ CO ₃ (10 g, 74 mmol) and BnBr (7.6 g, 44 mmol) was added. The mixture was stirred at rt overnight. The solid was filtered off and the filtrate was evaporated in vacuo. The residue was purified by column chromatography on silica gel (petroleum ether / ethyl acetate 50: 1) to give 2- (3- (benzyloxy) -4-chlorophenyl) -acetonitrile (5.6 g, 60%). .

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

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, treated dropwise with a solution of 3-benzyloxy-4-methoxy-benzaldehyde (10.0 g, 51.9 mmol) in THF (50 mL), and then stirred at -78 ° C for 1.5 hours. It was. Methanol (50 mL) was added to the cooled reaction mixture. The mixture was heated at reflux for 30 minutes. Removal of the solvent of the reaction mixture gave the crude product, which was dissolved in water (300 mL). The aqueous phase was extracted with EtOAc (100 mL x 3). The combined organic layers were dried and evaporated under reduced pressure to afford the 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%) was obtained.

Example 14 2- (3-Chloro-4-methoxyphenyl) acetonitrile.

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, treated dropwise with a solution of 3-chloro-4-methoxy-benzaldehyde (1.7 g, 10 mmol) in THF (10 mL) and then stirred at -78 ° C for 1.5 h. . Methanol (10 mL) was added to the cooled reaction mixture. The mixture was heated at reflux for 30 minutes. Removal of the solvent of the reaction mixture gave the crude product, which was dissolved in water (20 mL). The aqueous phase was extracted with EtOAc (20 mL x 3). The combined organic layers were dried and evaporated under reduced pressure to afford 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%) was obtained.

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

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, treated dropwise with a solution of 3-fluoro-4-methoxy-benzaldehyde (8.00 g, 51.9 mmol) in THF (50 mL), and then stirred at -78 ° C for 1.5 hours. It was. Methanol (50 mL) was added to the cooled reaction mixture. The mixture was heated at reflux for 30 minutes. Removal of the solvent of the reaction mixture gave the crude product, which was dissolved in water (200 mL). The aqueous phase was extracted with EtOAc (100 mL x 3). The combined organic layers were dried and evaporated under reduced pressure to give the 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%) was obtained.

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

Chloro-2-methoxy-4-methyl-benzene

To a solution of 2-chloro-5-methyl-phenol (93 g, 0.65 mol) in CH ₃ CN (700 mL) was charged CH ₃ I (110 g, 0.78 mol) and K ₂ CO ₃ (180 g, 1.3 mol). Added. The mixture was stirred at 25 ° C. overnight. The solid was filtered off and the filtrate was evaporated in vacuo to give 1-chloro-2-methoxy-4-methyl-benzene (90 g, 89%).

4-bromomethyl-1-chloro-2-methoxy-benzene

To a solution of 1-chloro-2-methoxy-4-methyl-benzene (50 g, 0.32 mol) in CCl ₄ (350 mL) add NBS (57 g, 0.32 mol) and AIBN (10 g, 60 mmol) It was. The mixture was heated at reflux for 3 hours. The solvent was evaporated in vacuo and the residue was purified by column chromatography on silica gel (petroleum ether / ethyl acetate = 20: 1) to give 4-bromomethyl-1-chloro-2-methoxy-benzene (69 g, 92%) was obtained.

2- (4-chloro-3-methoxyphenyl) acetonitrile

To a solution of 4-bromomethyl-1-chloro-2-methoxy-benzene (68.5 g, 0.290 mol) in C ₂ H ₅ OH (90%, 500 mL) was added NaCN (28.5 g, 0.580 mol). . The mixture was stirred at 60 ° C. overnight. Ethanol was evaporated and the residue was dissolved in H ₂ O. The mixture was extracted with ethyl acetate (300 mL x 3). The combined organic layers were washed with brine, dried over Na ₂ SO ₄ and purified by column chromatography on silica gel (petroleum ether / ethyl acetate 30: 1) to give 2- (4-chloro-3-methoxyphenyl) aceto. Nitrile (25 g, 48%) was obtained.

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

1- (4-methoxy-phenyl) -cyclopropanecarboxylic acid methyl ester

Toluene-4-sulfonic acid monohydrate (2.5 g, 13 mmol) was added to a solution of 1- (4-methoxy-phenyl) -cyclopropanecarboxylic acid (50 g, 0.26 mol) in MeOH (500 mL) at room temperature. It was. The reaction mixture was heated at reflux for 20 hours. MeOH was removed by evaporation in vacuo and EtOAc (200 mL) was added. The organic layer was washed with saturated aqueous NaHCO ₃ (100 mL), brine, dried over anhydrous Na ₂ SO ₄ , and evaporated in vacuo to 1- (4-methoxy-phenyl) -cyclopropanecarboxylic acid methyl ester (53 g, 99%) was obtained.

1- (3-Chloromethyl-4-methoxy-phenyl) -cyclopropanecarboxylic acid methyl ester

TiCl ₄ (8.30 g, in a solution of 1- (4-methoxy-phenyl) -cyclopropanecarboxylic acid methyl ester (30.0 g, 146 mmol) and MOMCl (29.1 g, 364 mmol) in CS ₂ (300 mL) 43.5 mmol) was added at 5 ° C. The reaction mixture was heated at 30 ° C. for 1 day and poured into ice water. The mixture was extracted with CH ₂ Cl ₂ (150 mL × 3). The combined organic extracts were evaporated in vacuo to afford 1- (3-chloromethyl-4-methoxy-phenyl) -cyclopropanecarboxylic acid methyl ester (38.0 g), which was used in the next step without further purification.

1- (3-hydroxymethyl-4-methoxy-phenyl) -cyclopropanecarboxylic acid methyl ester

To a suspension of 1- (3-chloromethyl-4-methoxy-phenyl) -cyclopropanecarboxylic acid methyl ester (20 g) in water (350 mL) Bu ₄ NBr (4.0 g) and Na ₂ CO ₃ ( 90 g, 0.85 mol) was added at room temperature. The reaction mixture was heated at 65 ° C. overnight. The resulting solution was acidified with aqueous HCl (2 mol / L) and extracted with EtOAc (200 mL × 3). The organic layer was washed with brine, dried over anhydrous Na ₂ SO ₄ and evaporated in vacuo to afford the crude product, which was purified by column (petroleum ether / ethyl acetate 15: 1) to give 1- (3-hydroxymethyl 4-Methoxy-phenyl) -cyclopropanecarboxylic acid methyl ester (8.0 g, 39%) was obtained.

1- [3- (tert-butyl-dimethyl-silanyloxymethyl) -4-methoxy-phenyl] cyclopropane carboxylic acid methyl ester

Imidazole (5.8 g, 85 in a solution of 1- (3-hydroxymethyl-4-methoxy-phenyl) -cyclopropanecarboxylic acid methyl ester (8.0 g, 34 mmol) in CH ₂ Cl ₂ (100 mL) mmol) and TBSCl (7.6 g, 51 mmol) were added at room temperature. The mixture was stirred at rt overnight. The mixture was washed with brine, dried over anhydrous Na ₂ SO ₄ and evaporated in vacuo to afford the crude product, which was purified by column (petroleum ether / ethyl acetate 30: 1) to give 1- [3- (tert-butyl -Dimethyl-silanyloxymethyl) -4-methoxy-phenyl] -cyclopropanecarboxylic acid methyl ester (6.7 g, 56%) was obtained.

1- (3-hydroxymethyl-4-methoxy-phenyl) -cyclopropanecarboxylic acid

Water in a solution of 1- [3- (tert-butyl-dimethyl-silanyloxymethyl) -4-methoxy-phenyl] -cyclopropane carboxylic acid methyl ester (6.2 g, 18 mmol) in MeOH (75 mL). A solution of LiOH.H ₂ O (1.5 g, 36 mmol) in (10 mL) was added at 0 ° C. The reaction mixture was stirred at 40 ° C. overnight. MeOH was removed by evaporation in vacuo. AcOH (1 mol / L, 40 mL) and EtOAc (200 mL) were added. The organic layer was separated, washed with brine, dried over anhydrous Na ₂ SO ₄ and evaporated in vacuo to 1- (3-hydroxymethyl-4-methoxy-phenyl) -cyclopropanecarboxylic acid (5.3 g) Obtained.

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

3-chloro-4,5-dihydroxybenzaldehyde

To a suspension of 3-chloro-4-hydroxy-5-methoxy-benzaldehyde (10 g, 54 mmol) in dichloromethane (300 mL) was charged BBr ₃ (26.7 g, 107 mmol) at −40 ° C. under N ₂ . Added dropwise. After addition, the mixture was stirred at this temperature for 5 hours and then poured into ice water. The precipitated solid was filtered off and washed with petroleum ether. The filtrate was evaporated under reduced pressure to afford 3-chloro-4,5-dihydroxybenzaldehyde (9.8 g, 89%), which was used directly in the next step.

7-chlorobenzo [d] [1,3] dioxol-5-carbaldehyde

Cs ₂ CO ₃ (25 g, 190 mmol) in a solution of 3-chloro-4,5-dihydroxybenzaldehyde (8.0 g, 46 mmol) and BrClCH ₂ (23.9 g, 185 mmol) in anhydrous DMF (100 mL). Was added. The mixture was stirred at 60 ° C. overnight and then poured into water. The resulting mixture was extracted with EtOAc (50 mL x 3). The combined extracts were washed with brine (100 mL), dried over Na ₂ SO ₄ , and concentrated under reduced pressure to give 7-chlorobenzo [d] [1,3] dioxol-5-carbaldehyde (6.0 g, 70% ) Was obtained.

(7-chlorobenzo [d] [1,3] dioxol-5-yl) methanol

To a solution of 7-chlorobenzo [d] [1,3] dioxol-5-carbaldehyde (6.0 g, 33 mmol) in THF (50 mL) was added NaBH ₄ (2.5 g, 64 mmol)) at 0 ° C. A little bit was added. The mixture was stirred at this temperature for 30 minutes and then poured into aqueous NH ₄ Cl solution. The organic layer was separated and the aqueous phase extracted with EtOAc (50 mL x 3). The combined extracts were dried over Na ₂ SO ₄ and evaporated under reduced pressure to give (7-chlorobenzo [d] [1,3] dioxol-5-yl) methanol, which was used directly in the next step.

4-chloro-6- (chloromethyl) benzo [d] [1,3] dioxol

A mixture of (7-chlorobenzo [d] [1,3] -dioxol-5-yl) methanol (5.5 g, 30 mmol) and SOCl ₂ (5.0 mL, 67 mmol) in dichloromethane (20 mL) was cooled to room temperature. After stirring for 1 h, it was poured into ice water. The organic layer was separated and the aqueous phase extracted with dichloromethane (50 mL x 3). Combine the extracts with water and aqueous NaHCO ₃ Washed with solution, dried over Na ₂ SO ₄ and evaporated under reduced pressure to afford 4-chloro-6- (chloromethyl) benzo [d] [1,3] dioxol, which was used directly in the next step.

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

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 added at 40 ° C. Stir for hours and then pour into water. The mixture was extracted with EtOAc (30 mL x 3). The combined organic layers were washed with water and brine, dried over Na ₂ SO ₄ and evaporated under reduced pressure to give 2- (7-chlorobenzo [d] [1,3] dioxol-5-yl) acetonitrile (3.4 g , 58%) was obtained.

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

1-benzooxazol-5-yl-cyclopropanecarboxylic acid methyl ester

Trimethyl orthoformate (5.30 g, 14.5 mmol) and a catalytic amount of p-toluenesulfonic acid in a solution of 1- (3-amino-4-hydroxyphenyl) cyclopropanecarboxylic acid methyl ester (3.00 g, 14.5 mmol) in DMF Monohydrate (0.3 g) was added at room temperature. The mixture was stirred at rt for 3 h. The mixture was diluted with water and extracted with EtOAc (100 mL x 3). The combined organic layers were dried over anhydrous Na ₂ SO ₄ and evaporated in vacuo to afford 1-benzooxazol-5-yl-cyclopropanecarboxylic acid methyl ester (3.1 g) which was used directly in the next step.

1- (benzo [d] oxazol-5-yl) cyclopropanecarboxylic acid

To a solution of 1-benzooxazol-5-yl-cyclopropanecarboxylic acid methyl ester (2.9 g) in EtSH (30 mL) was added AlCl ₃ (5.3 g, 40 mmol) in portions at 0 ° C. The reaction mixture was stirred at rt for 18 h. Water (20 mL) was added dropwise at 0 ° C. The resulting mixture was extracted with EtOAc (100 mL x 3). The combined organic layers were dried over anhydrous Na ₂ SO ₄ and evaporated in vacuo to afford the crude product, which was purified by column chromatography on silica gel (petroleum ether / ethyl acetate 1: 2) to give 1- (benzo [d] Oxazol-5-yl) cyclopropanecarboxylic acid (280 mg, 11% over two steps) was obtained.

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

3-fluoro-4,5-dihydroxy-benzaldehyde

To a suspension of 3-fluoro-4-hydroxy-5-methoxy-benzaldehyde (1.35 g, 7.94 mmol) in dichloromethane (100 mL) BBr ₃ (1.5 mL, 16 mmol) at −78 ° C. under N ₂ . Was added dropwise. After 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 precipitated solid was collected by filtration and washed with dichloromethane to give 3-fluoro-4,5-dihydroxy-benzaldehyde (1.1 g, 89%), which was used directly in the next step.

7-fluoro-benzo [1,3] dioxol-5-carbaldehyde

3-fluoro-4,5-dihydroxy-benzaldehyde (1.5 g, 9.6 mmol) and BrClCH _{2 in} anhydrous DMF (50 mL) To a solution of (4.9 g, 38.5 mmol) was added Cs ₂ CO ₃ (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 x 3). The combined organic layers were washed with brine (100 mL), dried over Na ₂ S0 ₄ and evaporated under reduced pressure to afford the crude product, which was subjected to column chromatography on silica gel (petroleum ether / ethyl acetate = 10/1). Purification gave 7-fluoro-benzo [1,3] dioxol-5-carbaldehyde (0.80 g, 49%).

(7-Fluoro-benzo [1,3] dioxol-5-yl) -methanol

To a solution of 7-fluoro-benzo [1,3] dioxol-5-carbaldehyde (0.80 g, 4.7 mmol) in MeOH (50 mL) was added NaBH ₄ (0.36 g, 9.4 mmol) in portions at 0 ° C. It was. The 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 Na ₂ SO ₄ and concentrated to dryness (7-fluoro-benzo [1,3] dioxol-5-yl) -methanol (0.80 g, 98%), It was used directly in the next step.

6-chloromethyl-4-fluoro-benzo [1,3] dioxol

To SOCl ₂ (20 mL) (7-fluoro-benzo [1,3] dioxol-5-yl) -methanol (0.80 g, 4.7 mmol) was added in portions at 0 ° C. The mixture was warmed to rt over 1 h and then heated to reflux for 1 h. Excess SOCl ₂ was evaporated under reduced pressure to give the crude product, which was basified to pH ˜7 with saturated aqueous NaHCO ₃ . The aqueous phase was extracted with EtOAc (50 mL x 3). The combined organic layers were dried over Na ₂ SO ₄ and evaporated under reduced pressure to give 6-chloromethyl-4-fluoro-benzo [1,3] dioxol (0.80 g, 92%), which was directly added to the next step. Used.

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

A mixture of 6-chloromethyl-4-fluoro-benzo [1,3] dioxol (0.80 g, 4.3 mmol) and NaCN (417 mg, 8.51 mmol) in DMSO (20 mL) was stirred at 30 ° C. for 1 hour. Then poured into water. The mixture was extracted with EtOAc (50 mL x 3). The combined organic layers were washed with water (50 mL) and brine (50 mL), dried over Na ₂ SO ₄ and evaporated under reduced pressure to give the crude product, which was column chromatography on silica gel (petroleum ether / ethyl acetate = 10/1) to give 2- (7-fluorobenzo [d] [1,3] dioxol-5-yl) acetonitrile (530 mg, 70%).

Example 21 1- (1H-indol-5-yl) cyclopropanecarboxylic acid

Methyl 1-phenylcyclopropanecarboxylate

To a solution of 1-phenylcyclopropanecarboxylic acid (25 g, 0.15 mol) in CH ₃ OH (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 afford the crude product, which was dissolved in EtOAc. EtOAc layer was washed with aq. Sat. NaHCO ₃ . The organic layer was dried over anhydrous Na ₂ SO ₄ and evaporated under reduced pressure to afford methyl 1-phenylcyclopropanecarboxylate (26 g, 96%) which was used directly in the next step.

Methyl 1- (4-nitrophenyl) cyclopropanecarboxylate

KNO _{3 in} a solution of 1-phenylcyclopropanecarboxylate (20.62 g, 0.14 mol) in H ₂ SO ₄ / CH ₂ Cl ₂ (40 mL / 40 mL). (12.8 g, 0.13 mol) was added in portions at 0 ° C. The mixture was stirred at 0 ° C for 0.5 h. Ice water was added and the mixture was extracted with EtOAc (100 mL x 3). The organic layer was dried over anhydrous Na ₂ SO ₄ and evaporated to afford methyl 1- (4-nitrophenyl) cyclopropanecarboxylate (21 g, 68%), which was used directly in the next step.

Methyl 1- (4-aminophenyl) cyclopropanecarboxylate

To a solution of methyl 1- (4-nitrophenyl) cyclopropanecarboxylate (20 g, 0.09 mol) in MeOH (400 mL) was added Ni (2 g) under a nitrogen atmosphere. The mixture was stirred at rt under hydrogen atmosphere (1 atm) overnight. The catalyst was filtered through a pad of celite and the filtrate was evaporated in vacuo to afford the crude product, which was purified by chromatography on chromatography silica gel (petroleum ether / ethyl acetate = 10: 1) to give methyl 1- (4 -Aminophenyl) cyclopropanecarboxylate (11.38 g, 66%) was obtained.

Methyl 1- (4-amino-3-bromophenyl) cyclopropanecarboxylate

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 extracted with EtOAc (80 mL x 3). The organic layer was dried over anhydrous Na ₂ SO ₄ and evaporated to afford methyl 1- (4-amino-3-bromophenyl) cyclopropanecarboxylate (10.6 g, 78%), which was used directly in the next step It was.

Methyl 1- (4-amino-3-((trimethylsilyl) ethynyl) phenyl) cyclopropane carboxylate

To a degassed solution of methyl 1- (4-amino-3-bromophenyl) cyclopropane carboxylate (8 g, 0.03 mol) in Et ₃ N (100 mL) ethynyl-trimethyl-silane (N ₂₎ under N ₂ g, 0.3 mol), DMAP (5% mol) and Pd (PPh ₃ ) ₂ Cl ₂ (5% mol) was added. The mixture was refluxed at 70 ° C. overnight. 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 column on chromatography silica gel (petroleum ether / ethyl acetate = 20: 1) to methyl 1- (4-amino-3-((trimethylsilyl)). Tinyl) phenyl) cyclopropanecarboxylate (4.8 g, 56%) was obtained.

Methyl 1- (1H-indol-5-yl) cyclopropanecarboxylate

In a degassed solution of methyl 1- (4-amino-3-((trimethylsilyl) ethynyl) phenyl) cyclopropanecarboxylate (4.69 g, 0.02 mol) in DMF (20 mL) at room temperature under N ₂ in CuI ( 1.5 g, 0.008 mol) was added. The mixture was stirred at rt for 3 h. Insoluble solid was filtered off and washed with EtOAc (50 mL × 3). The filtrate was evaporated under reduced pressure to give a residue, which was purified by column on chromatography silica gel (petroleum ether / ethyl acetate = 20: 1) to methyl 1- (1H-indol-5-yl) cyclopropanecarboxyl Yield (2.2 g, 51%) was obtained.

1- (1H-indol-5-yl) cyclopropanecarboxylic acid

LiOH (1.7 g, 0.04 mol) in a solution of methyl 1- (1H-indol-5-yl) cyclopropanecarboxylate (1.74 g, 8 mmol) in CH ₃ OH (50 mL) and water (20 mL) Was added. The mixture was heated at 45 ° C. for 3 hours. Water was added and the mixture was acidified to pH ˜3 with concentrated HCl and then extracted with EtOAc (20 mL × 3). The organic layer was dried over anhydrous Na ₂ SO ₄ and evaporated to afford 1- (1H-indol-5-yl) cyclopropanecarboxylic acid (1.4 g, 87%).

Example 22 1- (4-oxochroman-6-yl) cyclopropanecarboxylic acid

1- [4- (2-tert-butoxycarbonyl-ethoxy) -phenyl] -cyclopropanecarboxylic acid methyl ester

To a solution of 1- (4-hydroxy-phenyl) -cyclopropanecarboxylic acid methyl ester (7.0 g, 3.6 mmol) in acrylic acid tert-butyl ester (50 mL) was added Na (42 mg, 1.8 mmol) at room temperature. It was. The mixture was heated at 110 ° C. for 1 hour. After cooling to rt, the resulting mixture was quenched with water and extracted with EtOAc (100 mL × 3). The combined organic extracts were dried over anhydrous Na ₂ SO ₄ and evaporated in vacuo to afford the crude product, which was purified by column chromatography on silica gel (petroleum ether / ethyl acetate 20: 1) to give 1- [4- (2 -tert-butoxycarbonyl-ethoxy) -phenyl] -cyclopropanecarboxylic acid methyl ester (6.3 g, 54%) and unreacted starting material (3.0 g) were obtained.

1- [4- (2-carboxy-ethoxy) -phenyl] -cyclopropanecarboxylic acid methyl ester

A solution of 1- [4- (2-tert-butoxycarbonyl-ethoxy) -phenyl] -cyclopropanecarboxylic acid methyl ester (6.3 g, 20 mmol) in HCl (20%, 200 mL) was charged at 110 ° C. Heated at 1 h. After cooling to room temperature, the resulting mixture was filtered. The solid was washed with water and dried under vacuum to afford 1- [4- (2-carboxy-ethoxy) -phenyl] -cyclopropanecarboxylic acid methyl ester (5.0 g, 96%).

1- (4-oxochroman-6-yl) cyclopropanecarboxylic acid

Oxalyl chloride (4.8 g, in a solution of 1- [4- (2-carboxy-ethoxy) -phenyl] -cyclopropanecarboxylic acid methyl ester (5.0 g, 20 mmol) in CH ₂ Cl ₂ (50 mL) 38 mmol) and two drops of DMF at 0 ° C. The mixture was stirred at 0-5 ° C. for 1 h and then evaporated in vacuo. To the resulting mixture was added CH ₂ Cl ₂ (50 mL) at 0 ° C. and stirring was continued at 0-5 ° C. for 1 hour. The reaction was quenched slowly with water and extracted with EtOAc (50 mL x 3). The combined organic extracts were dried over anhydrous Na ₂ SO ₄ and evaporated in vacuo to afford the crude product, which was purified by column chromatography on silica gel (petroleum ether / ethyl acetate 20: 1-2: 1) to give 1- ( 4-oxochroman-6-yl) cyclopropanecarboxylic acid (830 mg, 19%) and methyl 1- (4-oxochroman-6-yl) cyclopropanecarboxylate (1.8 g, 38%) Obtained. 1- (4-oxochroman-6-yl) cyclopropane-carboxylic acid:

 1- (4-oxochroman-6-yl) cyclopropane-carboxylate:

Example 23 1- (4-hydroxy-4-methoxychroman-6-yl) cyclopropanecarboxylic acid

1- (4-hydroxy-4-methoxychroman-6-yl) cyclopropanecarboxylic acid

To a solution of methyl 1- (4-oxochromen-6-yl) cyclopropanecarboxylate (1.0 g, 4.1 mmol) in MeOH (20 mL) and water (20 mL), LiOH.H ₂ O (0.70 g, 16 mmol) was added in portions at room temperature. After the mixture was stirred at rt overnight, MeOH was removed by evaporation in vacuo. Water and Et ₂ O were added to the residue, the aqueous layer was separated, acidified with HCl and extracted with EtOAc (50 mL × 3). The combined organic extracts were dried over anhydrous Na ₂ SO ₄ and evaporated in vacuo to afford 1- (4-hydroxy-4-methoxychroman-6-yl) cyclopropanecarboxylic acid (480 mg, 44%). It was.

Example 24 1- (4-hydroxy-4-methoxychroman-6-yl) cyclopropanecarboxylic acid

1-Chroman-6-yl-cyclopropanecarboxylic acid methyl ester

N ₂ in trifluoroacetic acid (20 mL) NaBH ₄ (0.70 g, 130 mmol) was added portionwise at 0 ° C. under atmosphere. After stirring for 5 minutes, a solution of 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 at rt for 1 h and then quenched slowly with water. The resulting mixture was extracted with EtOAc (50 mL x 3). The combined organic extracts were dried over anhydrous Na ₂ SO ₄ and evaporated in vacuo to afford 1-chroman-6-yl-cyclopropanecarboxylic acid methyl ester (1.4 g, 92%), which was used directly in the next step. It was.

1- (4-hydroxy-4-methoxychroman-6-yl) cyclopropanecarboxylic acid

LiOH.H ₂ O (1.0 g, 240 mmol) in a solution of 1-chroman-6-yl-cyclopropanecarboxylic acid methyl ester (1.4 g, 60 mmol) in MeOH (20 mL) and water (20 mL). Was added little by little at room temperature. After the mixture was stirred at rt overnight, MeOH was removed by evaporation in vacuo. Water and Et ₂ O were added, the aqueous layer was separated, acidified with HCl and extracted with EtOAc (50 mL × 3). The combined organic extracts were dried over anhydrous Na ₂ SO ₄ and evaporated in vacuo to afford 1- (4-hydroxy-4-methoxychroman-6-yl) cyclopropanecarboxylic acid (1.0 g, 76%). It was.

Example 25 1- (3-Methylbenzo [d] isoxazol-5-yl) cyclopropanecarboxylic acid

1- (3-acetyl-4-hydroxy-phenyl) -cyclopropanecarboxylic acid methyl ester

To a stirred suspension of AlCl ₃ (58 g, 440 mmol) in CS ₂ (500 mL) was added acetyl chloride (7.4 g, 95 mmol) at room temperature. After stirring for 5 minutes, methyl 1- (4-methoxyphenyl) cyclopropanecarboxylate (15 g, 73 mmol) is added. After the reaction mixture was heated at reflux for 2 hours, ice water was carefully added to the mixture at room temperature. The resulting mixture was extracted with EtOAc (150 mL x 3). The combined organic extracts were dried over anhydrous Na ₂ SO ₄ and evaporated under reduced pressure to give 1- (3-acetyl-4-hydroxy-phenyl) -cyclopropanecarboxylic acid methyl ester (15 g, 81%), This was used in the next step without further purification.

1- [4-hydroxy-3- (1-hydroxyimino-ethyl) -phenyl] -cyclopropanecarboxylic acid methyl ester

To a stirred 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 at reflux overnight. After EtOH was removed in vacuo, water (200 mL) and EtOAc (200 mL) were added. The organic layer was separated and the aqueous layer extracted with EtOAc (100 mL x 3). The combined organic layers were dried over anhydrous Na ₂ SO ₄ and evaporated in vacuo to 1- [4-hydroxy-3- (1-hydroxyimino-ethyl) -phenyl] -cyclopropanecarboxylic acid methyl ester (14.5 g , 98%) was obtained, and used in the next step without further purification.

(E) -methyl 1- (3- (1- (acetoxyimino) ethyl) -4-hydroxyphenyl) cyclopropane carboxylate

A solution of 1- [4-hydroxy-3- (1-hydroxyimino-ethyl) -phenyl] -cyclopropanecarboxylic acid methyl ester (10.0 g, 40.1 mmol) in Ac ₂ O (250 mL) was heated to 45 ° C. Heated at 4 h. Ac ₂ O was removed by evaporation in vacuo, then water (100 mL) and EtOAc (100 mL) were added. The organic layer was separated and the aqueous layer was extracted with EtOAc (100 mL x 2). The combined organic layers were dried over anhydrous Na ₂ SO ₄ and evaporated in vacuo to (E) -methyl 1- (3- (1- (acetoxyimino) ethyl) -4-hydroxyphenyl) cyclopropanecarboxylate ( 10.5 g, 99%) were obtained, and used in the next step without further purification.

Methyl 1- (3-methylbenzo [d] isoxazol-5-yl) cyclopropanecarboxylate

(E) -methyl 1- (3- (1- (acetoxyimino) ethyl) -4-hydroxyphenyl) cyclopropane carboxylate (10.5 g, 39.6 mmol) and pyridine (31.3 g) in DMF (150 mL) , 396 mmol) 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 Na ₂ SO ₄ and evaporated in vacuo to afford the crude product, which was purified by column chromatography on silica gel (petroleum ether / ethyl acetate 50: 1) to give methyl 1- (3-methyl Benzo [d] isoxazol-5-yl) cyclopropanecarboxylate (7.5 g, 82%) was obtained.

1- (3-methylbenzo [d] isoxazol-5-yl) cyclopropanecarboxylic acid

LiOH.H ₂ O in a solution of methyl 1- (3-methylbenzo [d] isoxazol-5-yl) cyclopropanecarboxylate (1.5 g, 6.5 mmol) in MeOH (20 mL) and water (2 mL). (0.80 g, 19 mmol) was added portionwise at room temperature. The reaction mixture was stirred at rt overnight, then MeOH was removed by evaporation in vacuo. Water and Et ₂ O were added, the aqueous layer was separated, acidified with HCl and extracted with EtOAc (50 mL × 3). The combined organic extracts were dried over anhydrous Na ₂ SO ₄ and evaporated in vacuo to give 1- (3-methylbenzo [d] isoxazol-5-yl) cyclopropanecarboxylic acid (455 mg, 32%).

Example 26 1- (spiro [benzo [d] [1,3] dioxol-2,1'-cyclobutan] -5-yl) cyclopropane carboxylic acid

1- (3,4-dihydroxy-phenyl) -cyclopropanecarboxylic acid methyl ester

To a solution of 1- (3,4-dihydroxyphenyl) cyclopropanecarboxylic acid (4.5 g) in MeOH (30 mL) was added TsOH (0.25 g, 1.3 mmol). After stirring was continued at 50 ° C. overnight, the mixture was cooled to room temperature. The mixture was concentrated in vacuo and the residue was purified by column chromatography on silica gel (petroleum ether / ethyl acetate 3: 1) to give 1- (3,4-dihydroxy-phenyl) -cyclopropanecarboxylic acid methyl ester (2.1 g) was obtained.

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

To a solution of 1- (3,4-dihydroxy-phenyl) -cyclopropanecarboxylic acid methyl ester (1.0 g, 4.8 mmol) in toluene (30 mL) TsOH (0.10 g, 0.50 mmol) and cyclobutanone ( 0.70 g, 10 mmol) was added. The reaction mixture was heated at reflux for 2 h and then concentrated in vacuo. The residue was purified by chromatography on silica gel (petroleum ether / ethyl acetate 15: 1) to give methyl 1- (spiro [benzo [d] [1,3] dioxol-2,1'-cyclobutane] -5- 1) cyclopropanecarboxylate (0.6 g, 50%) was obtained.

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

Methyl 1- (spiro [benzo [d] [1,3] dioxol-2,1'-cyclobutan] -5-yl) cyclopropanecarboxylate in THF / H ₂ O (4: 1, 10 mL) To a mixture of (0.60 g, 2.3 mmol) was added LiOH (0.30 g, 6.9 mmol). The mixture was stirred at 60 ° C for 24 h. HCl (0.5 N) was slowly added to the mixture at 0 ° C. until the pH was 2-3. The mixture was extracted with EtOAc (10 mL x 3). The combined organic phases were washed with brine, dried over anhydrous MgSO ₄ and washed with petroleum ether to give 1- (spiro [benzo [d] [1,3] -dioxol-2,1'-cyclobutane] -5- I) cyclopropane carboxylic acid (330 mg, 59%) was obtained.

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

2,3-dihydro-benzo [1,4] dioxine-6-carboxylic acid ethyl ester

To a suspension of Cs ₂ CO ₃ (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) was added 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 x 3). The combined organic layers were washed with water (200 mL × 3) and brine (100 mL), dried over Na ₂ SO ₄ and concentrated to dryness. The residue was purified by column (petroleum ether / ethyl acetate 50: 1) on silica gel to give 2,3-dihydro-benzo [1,4] dioxin-6-carboxylic acid ethyl ester (18 g, 29%) Obtained.

(2,3-Dihydro-benzo [1,4] dioxin-6-yl) -methanol

To a suspension of LiAlH ₄ (2.8 g, 74 mmol) in THF (20 mL) at ₂ ° C. in THF (10 mL) at 0 ° C. under N ₂ at 2 ° C. A solution of acid ethyl ester (15 g, 72 mmol) was added dropwise. The mixture was stirred at rt for 1 h and then quenched by careful addition of water (2.8 mL) and NaOH (10%, 28 mL) while cooling. The precipitated solid was filtered off and the filtrate was evaporated to dryness to give (2,3-dihydro-benzo [1,4] dioxin-6-yl) -methanol (10.6 g).

6-chloromethyl-2,3-dihydro-benzo [1,4] dioxine

A mixture of (2,3-dihydro-benzo [1,4] dioxin-6-yl) methanol (10.6 g) in SOCl ₂ (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 extracted with dichloromethane (50 mL x 3). The combined organic layers were washed with NaHCO ₃ (saturated solution), water and brine, dried over Na ₂ SO ₄ and concentrated to dryness to give 6-chloromethyl-2,3-dihydro-benzo [1,4] dioxine ( 12 g, 88%) were obtained over two steps, which were used directly in the next step.

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

A mixture of 6-chloromethyl-2,3-dihydro-benzo [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. Stirred. The mixture was poured into water (150 mL) and then extracted with dichloromethane (50 mL x 4). The combined organic layers were washed with water (50 mL × 2) and brine (50 mL), dried over Na ₂ SO ₄ and concentrated to dryness. The residue was purified by column (petroleum ether / ethyl acetate 50: 1) on silica gel to give 2- (2,3-dihydrobenzo [b] [1,4] dioxin-6-yl) acetonitrile as a yellow oil. Obtained as (10.2 g, 86%).

Table 2 below contains a list of carboxylic acid building blocks available commercially or made by one of the three methods above.

TABLE 2

Specific Procedure: Synthesis of Aminoindole Building Blocks

Example 28: 3-methyl-1H-indol-6-amine

(3-nitro-phenyl) -hydrazine hydrochloride salt

3-nitro-phenylamine (27.6 g, 0.2 mol) was dissolved in a mixture of H ₂ O (40 mL) and 37% HCl (40 mL). A solution of NaNO ₂ (13.8 g, 0.2 mol) in H ₂ O (60 mL) was added to the mixture at 0 ° C., followed by SnCl ₂ .H ₂ O (135.5 g, 0.6 mol) in 37% HCl (100 mL). Solution was added at that temperature. After stirring for 0.5 h at 0 ° C., the insoluble material was isolated by filtration and washed with water to give (3-nitrophenyl) hydrazine hydrochloride (27.6 g, 73%).

N- (3-nitro-phenyl) -N'-propylidene-hydrazine

Sodium hydroxide solution (10%, 15 mL) was added slowly to a stirred suspension of (3-nitrophenyl) hydrazine hydrochloride (1.89 g, 10 mmol) in ethanol (20 mL) until the pH reached 6. Acetic acid (5 mL) was added to the mixture, followed by propionaldehyde (0.7 g, 12 mmol). After stirring at room temperature for 3 hours, the mixture is poured into ice water and the resulting precipitate is isolated by filtration, washed with water and dried in air to give (E) -1- (3-nitrophenyl) -2-propylidene Hydrazine was obtained and used directly in the next step.

3-methyl-4-nitro-1H-indole 3 and 3-methyl-6-nitro-1H-indole

A mixture of (E) -1- (3-nitrophenyl) -2-propylidenehydrazine dissolved in 85% H ₃ PO ₄ (20 mL) and toluene (20 mL) was 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 x 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 [total 1.5 g, 86%, (3- Two steps from nitrophenyl) hydrazine hydrochloride] were used in the next step without further purification.

3-methyl-1H-indol-6-amine

The crude mixture (3 g, 17 mmol) and 10% Pd-C (0.5 g) from ethanol (30 mL) were stirred overnight at room temperature under H ₂ (1 atm). Pd-C was filtered off and the filtrate was concentrated under reduced pressure. The solid residue was purified by column to give 3-methyl-1H-indol-6-amine (0.6 g, 24%).

Example 29: 3-tert-butyl-1H-indol-5-amine

3-tert-butyl-5-nitro-1H-indole

Of from _{0 ℃ CH 2 Cl 2 (100} mL) 5- nitro -1H- indole (6.0 g, 37 mmol) and AlCl ₃ mixture of 2-bromo-2-methyl-a (24 g, 0.18 mol) - propane ( 8.1 g, 37 mmol) was added dropwise. 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 CH ₂ Cl ₂ (30 mL × 3). The combined organic layers were washed with water, brine, dried over Na ₂ SO ₄ and concentrated in vacuo to afford the crude product, which was purified by column chromatography on silica gel (petroleum ether / ethyl acetate = 20: 1). 3-tert-butyl-5-nitro-1H-indole (2.5 g, 31%) was obtained.

3-tert-butyl-1H-indol-5-amine

To a solution of 3-tert-butyl-5-nitro-1H-indole (2.5 g, 12 mmol) in MeOH (30 mL) was added Raney nickel (0.2 g) under N ₂ protection. The mixture was stirred at 15 ° C. under hydrogen atmosphere (1 atm) for 1 hour. The catalyst was filtered off and the filtrate was concentrated to dryness in vacuo. The residue was purified by preparative HLPC to give 3-tert-butyl-1H-indol-5-amine (0.43 g, 19%).

Example 30 2-tert-Butyl-6-fluoro-1H-indol-5-amine and 6-tert-butoxy-2-tert-butyl-1H-indol-5-amine

2-bromo-5-fluoro-4-nitroaniline

Br ₂ (2.15 mL, 42.2 mmol) was added dropwise at 0 ° C. to a mixture of 3-fluoro-4-nitroaniline (6.5 g, 42.2 mmol) in AcOH (80 mL) and chloroform (25 mL). After addition, the resulting mixture was stirred at room temperature for 2 hours and then poured into ice water. The mixture was basified to pH ~ 8.0-9.0 with aqueous NaOH (10%) under cooling and then extracted with EtOAc (50 mL x 3). The combined organic layers were washed with water (80 mL × 2) and brine (100 mL), dried over Na ₂ SO ₄ and concentrated under reduced pressure to give 2-bromo-5-fluoro-4-nitroaniline (9 g , 90%) was obtained.

2- (3,3-dimethylbut-1-ynyl) -5-fluoro-4-nitroaniline

2-bromo-5-fluoro-4-nitroaniline (9.0 g, 38.4 mmol), 3,3-dimethyl-but-1-yne (9.95 g, 121 in toluene (100 mL) and water (50 mL) mmol), CuI (0.5 g 2.6 mmol), Pd (PPh ₃ ) ₂ Cl ₂ (3.4 g, 4.86 mmol) and Et ₃ N (14 mL, 6.9 mmol) were heated at 70 ° C. for 4 h. The aqueous layer was separated and the organic layer was washed with water (80 mL × 2) and brine (100 mL), dried over Na ₂ SO ₄ and concentrated to dryness under reduced pressure. The residue was recrystallized from ether to give 2- (3,3-dimethylbut-1-ynyl) -5-fluoro-4-nitroaniline (4.2 g, 46%).

N- (2- (3,3-dimethylbut-1-ynyl) -5-fluoro-4-nitrophenyl) butyramide

Of 2- (3,3-dimethylbut-1-ynyl) -5-fluoro-4-nitroaniline (4.2 g, 17.8 mmol) in dichloromethane (50 mL) and Et ₃ N (10.3 mL, 71.2 mmol) To the solution was added butyryl chloride (1.9 g, 17.8 mmol) at 0 ° C. The mixture was stirred at rt for 1 h and then poured into water. The aqueous phase was separated and the organic layer was washed with water (50 mL x 2) and brine (100 mL), dried over Na ₂ S0 ₄ and concentrated to dryness under reduced pressure. The residue was washed with ether to give N- (2- (3,3-dimethylbut-1-ynyl) -5-fluoro-4-nitrophenyl) butyramide (3.5 g, 67%) The next step was used without further purification.

2-tert-butyl-6-fluoro-5-nitro-1H-indole

N- (2- (3,3-dimethylbut-1-ynyl) -5-fluoro-4-nitrophenyl) butyramide (3.0 g, 9.8 mmol) and TBAF (4.5 g, in DMF (25 mL) 17.2 mmol) was heated at 100 ° C. overnight. The mixture was poured into water and then extracted with EtOAc (80 mL x 3). The combined extracts were washed with water (50 mL) and brine (50 mL), dried over Na ₂ SO ₄ and concentrated to dryness under reduced pressure. The residue was purified by column chromatography on silica gel (petroleum ether / ethyl acetate 20: 1) to give compound 2-tert-butyl-6-fluoro-5-nitro-1H-indole (1.5 g, 65%). It was.

2-tert-butyl-6-fluoro-1H-indol-5-amine

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 heated at room temperature in H ₂ atmosphere (1 atm). Under stirring for 3 hours. The catalyst was filtered off and the filtrate was concentrated to dryness under reduced pressure. The residue was recrystallized from ether to give 2-tert-butyl-6-fluoro-1H-indol-5-amine (520 mg, 38%).

6-tert-butoxy-2-tert-butyl-5-nitro-1H-indole

N- (2- (3,3-dimethylbut-1-ynyl) -5-fluoro-4-nitrophenyl) butyramide (500 mg, 1.63 mmol) and t-BuOK (0.37) in DMF (10 mL) g, 3.26 mmol) was heated at 70 ° C. for 2 hours. The mixture was poured into water and extracted with EtOAc (50 mL x 3). The combined extracts were washed with water (50 mL) and brine (50 mL), dried over Na ₂ SO ₄ , concentrated under reduced pressure to give 6-tert-butoxy-2-tert-butyl-5-nitro-1H-indole (100 mg, 21%) was obtained.

6-tert-butoxy-2-tert-butyl-1H-indol-5-amine

Suspension of 6-tert-butoxy-2-tert-butyl-5-nitro-1H-indole (100 mg, 0.36 mmol) and Raney Ni (0.5 g) in MeOH (15 mL) was heated at room temperature in H ₂ atmosphere ( 1 atm) for 2.5 hours. The catalyst was filtered off and the filtrate was concentrated to dryness under reduced pressure. The residue was recrystallized with ether to give 6-tert-butoxy-2-tert-butyl-1H-indol-5-amine (30 mg, 32%).

Example 31 1-tert-butyl-1H-indol-5-amine

N-tert-butyl-4-nitroaniline

A solution of 1-fluoro-4-nitro-benzene (1 g, 7.1 mmol) and tert-butylamine (1.5 g, 21 mmol) in DMSO (5 mL) was stirred at 75 ° C. overnight. The mixture was poured into water (10 mL) and extracted with EtOAc (7 mL x 3). The combined organic layers were washed with water, brine, dried over Na ₂ SO ₄ and concentrated to dryness in vacuo. The residue was purified by column chromatography on silica gel (petroleum ether / ethyl acetate 30: 1) to give N-tert-butyl-4-nitroaniline (1 g, 73%).

(2-Bromo-4-nitro-phenyl) -tert-butyl-amine

Br ₂ (0.86 g, 54 mmol) was added dropwise at 15 ° C. to a solution of N-tert-butyl-4-nitroaniline (1 g, 5.1 mmol) in AcOH (5 mL). After addition, the mixture was stirred at 30 ° C. for 30 minutes and then filtered. The filter cake was basified to pH 8-9 with aqueous NaHCO ₃ . The aqueous layer was extracted with EtOAc (10 mL x 3). The combined organic layers were washed with water, brine, dried over Na ₂ SO ₄ and concentrated in vacuo to afford (2-bromo-4-nitro-phenyl) -tert-butyl-amine (0.6 g, 43%). It was.

tert-butyl- (4-nitro-2-trimethylsilanylethynyl-phenyl) -amine

Pd (PPh ₃ ) ₂ Cl ₂ (70) under N ₂ protection in a solution of (2-bromo-4-nitro-phenyl) -tert-butyl-amine (0.6 g, 2.2 mmol) in Et ₃ N (10 mL). mg, 0.1 mmol), CuI (20.9 mg, 0.1 mmol) and ethynyl-trimethyl-silane (0.32 g, 3.3 mmol) were added sequentially. The reaction mixture was heated at 70 ° C. overnight. The solvent was removed in vacuo and the residue was washed with EtOAc (10 mL × 3). The combined organic layers were washed with water, brine, dried over Na ₂ SO ₄ and concentrated to dryness in vacuo. The residue was purified by column chromatography on silica gel (petroleum ether / ethyl acetate 20: 1) to give tert-butyl- (4-nitro-2-trimethylsilanylethynyl-phenyl) -amine (100 mg, 16%) Obtained.

1-tert-butyl-5-nitro-1H-indole

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 N ₂ protection. Added. The reaction mixture was stirred at 100 ° C. overnight. At this time, EtOAc (4 mL) was added to the mixture. The mixture was filtered, the filtrate was washed with water, brine, dried over Na ₂ SO ₄ and concentrated in vacuo to give 1-tert-butyl-5-nitro-1H-indole (7 mg, 93%). .

1-tert-butyl-1H-indol-5-amine

To a solution of 1-tert-butyl-5-nitro-1H-indole (6.5 g, 0.030 mol) in MeOH (100 mL) was added Raney nickel (0.65 g, 10%) under N ₂ protection. The mixture was stirred at 30 ° C. under hydrogen atmosphere (1 atm) for 1 hour. The catalyst was filtered off and the filtrate was concentrated to dryness in vacuo. The residue was purified by column chromatography on silica gel (PE / EtOAc 1: 2) to give 1-tert-butyl-1H-indol-5-amine (2.5 g, 45%).

Example 32 2-tert-butyl-1-methyl-1H-indol-5-amine

(2-Bromo-4-nitro-phenyl) -methyl-amine

Br ₂ (16.0 g, 0.1 mol) was added dropwise at 5 ° C. to a solution of methyl- (4-nitro-phenyl) -amine (15.2 g, 0.1 mol) in AcOH (150 mL) and CHCl ₃ (50 mL). The mixture was stirred at 10 ° C. for 1 h and then basified with saturated aqueous NaHCO ₃ . The resulting mixture is extracted with EtOAc (100 mL × 3) and the combined organics are dried over anhydrous Na ₂ SO ₄ and evaporated in vacuo to (2-bromo-4-nitro-phenyl) -methyl-amine (2- Bromo-4-nitro-phenyl) -methyl-amine (23.0 g, 99%) was obtained, which was used in the next step without further purification.

[2- (3,3-Dimethyl-but-1-ynyl) -4-nitro-phenyl] -methyl-amine

Et ₃ N (19.7 g, 195) under N ₂ protection in a solution of (2-bromo-4-nitro-phenyl) -methyl-amine (22.5 g, 97.4 mmol) in toluene (200 mL) and water (100 mL) mmol), Pd (PPh ₃ ) ₂ Cl ₂ (6.8 g, 9.7 mmol), CuI (0.7 g, 3.9 mmol) and 3,3-dimethyl-but-1-yne (16.0 g, 195 mmol) were added sequentially It was. 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 x 3). The combined organic extracts were dried over anhydrous Na ₂ SO ₄ and evaporated in vacuo to [2- (3,3-dimethyl-but-1-ynyl) -4-nitro-phenyl] -methyl-amine (20.1 g, 94% ) Was obtained and used in the next step without further purification.

2-tert-butyl-1-methyl-5-nitro-1H-indole

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) The solution was heated at reflux overnight. The solvent was removed by evaporation in vacuo and the residue was dissolved in brine (100 mL) and EtOAc (100 mL). The organic phase was separated, dried over Na ₂ SO ₄ and evaporated in vacuo to afford 2-tert-butyl-1-methyl-5-nitro-1H-indole (5.0 g, 99%), which was obtained in the next step. Used without further purification.

2-tert-butyl-1-methyl-1H-indol-5-amine

To a solution of 2-tert-butyl-1-methyl-5-nitro-1H-indole (3.00 g, 13.7 mmol) in MeOH (30 mL) was added Raney Ni (0.3 g) under a nitrogen atmosphere. The mixture was stirred at rt under hydrogen atmosphere (1 atm) overnight. The mixture was filtered through a pad of celite and the filtrate was evaporated in vacuo. The crude residue was purified by column chromatography on silica gel (P.E / EtOAc 20: 1) to give 2-tert-butyl-1-methyl-1H-indol-5-amine (1.7 g, 66%).

Example 33: 2-cyclopropyl-1H-indol-5-amine

2-bromo-4-nitroaniline

To a solution of 4-nitro-aniline (25 g, 0.18 mol) in HOAc (150 mL) was added dropwise liquid Br ₂ (30 g, 0.19 mol) at room temperature. The mixture was stirred for 2 hours. The solid was collected by filtration and poured into water (100 mL), which was basified with saturated aqueous NaHCO ₃ to pH 7 and extracted with EtOAc (300 mL × 3). The combined organic layers were dried over anhydrous Na ₂ SO ₄ and evaporated under reduced pressure to afford 2-bromo-4-nitroaniline (30 g, 80%), which was used directly in the next step.

2- (cyclopropylethynyl) -4-nitroaniline

Deoxygenated 2-bromo-4-nitroaniline (2.17 g, 0.01 mmol), ethynyl-cyclopropane (1 g, 15 mmol) and CuI (10 mg, 0.05 mmol) in triethylamine (20 mL) To the solution was added Pd (PPh ₃ ) ₂ Cl ₂ (210 mg, 0.3 mmol) under N ₂ . The mixture was heated at 70 ° C. overnight and stirred for 24 h. The solid was filtered off and washed with EtOAc (50 mL x 3). The filtrate was evaporated under reduced pressure and the residue was purified by column chromatography on silica gel (petroleum ether / ethyl acetate = 10/1) to give 2- (cyclopropylethynyl) -4-nitroaniline (470 mg, 23% ) Was obtained.

N- (2- (cyclopropylethynyl) phenyl) -4-nitrobutyramide

Butyryl chloride (2.54 g, 23.8 mmol) in a solution of 2- (cyclopropylethynyl) -4-nitroaniline (3.2 g, 15.8 mmol) and pyridine (2.47 g, 31.7 mmol) in CH ₂ Cl ₂ (60 mL). ) Was added at 0 ° C. The mixture was warmed to rt and stirred for 3 h. The resulting mixture was poured into ice water. The organic layer was separated. The aqueous phase was extracted with CH ₂ Cl ₂ (30 ml L × 3). The combined organic layers were dried over anhydrous Na ₂ S0 ₄ and evaporated under reduced pressure to afford the crude product, which was purified by column chromatography on silica gel (petroleum ether / ethyl acetate = 10/1) to give N- (2- ( Cyclopropylethynyl) phenyl) -4-nitrobutyramide (3.3 g, 76%) was obtained.

2-cyclopropyl-5-nitro-1H-indole

A mixture of N- (2- (cyclopropylethynyl) phenyl) -4-nitrobutyramide (3.3 g, 0.01 mol) and TBAF (9.5 g, 0.04 mol) in THF (100 mL) was refluxed for 24 hours. Heated. The mixture was cooled to room temperature and poured into ice water. The mixture was extracted with CH ₂ Cl ₂ (50 mL × 3). The combined organic layers were dried over anhydrous Na ₂ SO ₄ and evaporated under reduced pressure. The residue was purified by column chromatography on silica gel (petroleum ether / ethyl acetate = 10/1) to afford 2-cyclopropyl-5-nitro-1H-indole (1.3 g, 64%).

2-cyclopropyl-1H-indol-5-amine

To a solution of 2-cyclopropyl-5-nitro-1H-indole (1.3 g, 6.4 mmol) in MeOH (30 mL) was added Raney nickel (0.3 g) under a nitrogen atmosphere. The mixture was stirred at rt under hydrogen atmosphere (1 atm) overnight. The catalyst was filtered through a pad of celite and the filtrate was evaporated in vacuo to afford the crude product, which was purified by column chromatography on silica gel (petroleum ether / ethyl acetate = 5/1) to 2-cyclopropyl-1H. -Indol-5-amine (510 mg, 56%) was obtained.

Example 34 3-tert-butyl-1H-indol-5-amine

3-tert-butyl-5-nitro-1H-indole

₂ -bromo-2-methyl-propane (8.1 g, in a mixture of 5-nitro-1H-indole (6 g, 36.8 mmol) and AlCl ₃ (24 g, 0.18 mol) in CH ₂ Cl ₂ (100 mL) 36.8 mmol) was added dropwise at 0 ° C. After stirring at 15 ° C. overnight, the reaction mixture was poured onto ice (100 mL). The precipitated salts were removed by filtration and the aqueous layer was extracted with CH ₂ Cl ₂ (30 mL × 3). The combined organic layers were washed with water, brine, dried over Na ₂ SO ₄ and concentrated in vacuo to afford the crude product, which was purified by column chromatography on silica gel (petroleum ether / ethyl acetate 20: 1) to give 3 -tert-butyl-5-nitro-1H-indole (2.5 g, 31%) was obtained.

3-tert-butyl-1H-indol-5-amine

To a solution of 3-tert-butyl-5-nitro-1H-indole (2.5 g, 11.6 mmol) in MeOH (30 mL) was added Raney nickel (0.2 g) under N ₂ protection. The mixture was stirred at 15 ° C. under hydrogen atmosphere (1 atm) for 1 hour. The catalyst was filtered off and the filtrate was concentrated to dryness in vacuo. The residue was purified by preparative HLPC to give 3-tert-butyl-1H-indol-5-amine (0.43 g, 19%).

Example 35 2-phenyl-1H-indol-5-amine

2-bromo-4-nitroaniline

To a solution of 4-nitroaniline (50 g, 0.36 mol) in AcOH (500 mL) was added dropwise liquid Br ₂ (60 g, 0.38 mol) at 5 ° C. The mixture was stirred at that temperature for 30 minutes. Insoluble solid was collected by filtration and poured into EtOAc (200 mL). The mixture was basified to pH 7 with saturated aqueous NaHCO ₃ . The organic layer was separated. The aqueous phase was extracted with EtOAc (300 mL x 3). The combined organic layers were dried and evaporated under reduced pressure to afford 2-bromo-4-nitroaniline (56 g, 72%), which was used directly in the next step.

4-nitro-2- (phenylethynyl) aniline

Deoxygenated solution of 2-bromo-4-nitroaniline (2.17 g, 0.01 mmol), ethynyl-benzene (1.53 g, 0.015 mol) and CuI (10 mg, 0.05 mmol) in triethylamine (20 mL) To Pd (PPh ₃ ) ₂ Cl ₂ (210 mg, 0.2 mmol) was added under N ₂ . The mixture was heated at 70 ° C. overnight and stirred for 24 h. The solid was filtered off and washed with EtOAc (50 mL x 3). The filtrate was evaporated under reduced pressure and the residue was purified by column chromatography on silica gel (petroleum ether / ethyl acetate = 10/1) to give 4-nitro-2- (phenylethynyl) aniline (340 mg, 14%) Obtained.

N- (2- (phenylethynyl) phenyl) -4-nitrobutyramide

Butyryl chloride (11.5 g, 0.1 mol) in a solution of 4-nitro-2- (phenylethynyl) aniline (17 g, 0.07 mmol) and pyridine (11.1 g, 0.14 mol) in CH ₂ Cl ₂ (100 mL) Was added at 0 ° C. The mixture was warmed to rt and stirred for 3 h. The resulting mixture was poured into ice water. The organic layer was separated. The aqueous phase was extracted with CH ₂ Cl ₂ (30 ml L × 3). The combined organic layers were dried over anhydrous Na ₂ SO ₄ and evaporated under reduced pressure. The residue was purified by column chromatography on silica gel (petroleum ether / ethyl acetate = 10/1) to give N- (2- (phenylethynyl) phenyl) -4-nitrobutyramide (12 g, 55%). Obtained.

5-nitro-2-phenyl-1H-indole

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 hours It was. The mixture was cooled to room temperature and poured into ice water. The mixture was extracted with CH ₂ Cl ₂ (50 mL × 3). The combined organic layers were dried over anhydrous Na ₂ SO ₄ and evaporated under reduced pressure. The residue was purified by column chromatography on silica gel (petroleum ether / ethyl acetate = 10/1) to give 5-nitro-2-phenyl-1H-indole (3.3 g, 69%).

2-phenyl-1H-indol-5-amine

To a solution of 5-nitro-2-phenyl-1H-indole (2.83 g, 0.01 mol) in MeOH (30 mL) was added Raney Ni (510 mg) under a nitrogen atmosphere. The mixture was stirred at rt under hydrogen atmosphere (1 atm) overnight. The catalyst was filtered through a pad of celite and the filtrate was evaporated in vacuo to afford the crude product, which was purified by column chromatography on silica gel (petroleum ether / ethyl acetate = 5/1) to give 2-phenyl-1H-. Indole-5-amine (1.6 g, 77%) was obtained.

Example 36 2-tert-butyl-4-fluoro-1H-indol-5-amine

2-bromo-3-fluoroaniline

CH ₃ OH To a solution of 2-bromo-1-fluoro-3-nitrobenzene (1.0 g, 5.0 mmol) in (50 mL) was added NiCl ₂ (2.2 g 10 mmol) and NaBH ₄ (0.50 g 14 mmol) at 0 ° C. Added. After addition, the mixture was stirred for 5 minutes. Water (20 mL) was added and the mixture was extracted with EtOAc (20 mL x 3). The organic layer was dried over anhydrous Na ₂ SO ₄ and evaporated in vacuo to give 2-bromo-3-fluoroaniline (600 mg, 70%).

N- (2-bromo-3-fluorophenyl) butyramide

To a solution of 2-bromo-3-fluoroaniline (2.0 g, 11 mmol) in CH ₂ Cl ₂ (50 mL) added butyryl chloride (1.3 g, 13 mmol) and pyridine (1.7 g, 21 mmol) to 0 It was added at ℃. The mixture was stirred at rt for 24 h. Water (20 mL) was added and the mixture was extracted with CH ₂ Cl ₂ (50 mL × 3). The organic layer was dried over anhydrous Na ₂ S0 ₄ and evaporated in vacuo to afford N- (2-bromo-3-fluorophenyl) butyramide (2.0 g, 73%) which was used directly in the next step. It was.

N- (2- (3,3-dimethylbut-1-ynyl) -3-fluorophenyl) butyramide

Et ₃ N To a solution of N- (2-bromo-3-fluorophenyl) butyramide (2.0 g, 7.0 mmol) in (100 mL) was 4,4-dimethylpent-2-yne at room temperature under N ₂ . (6.0 g, 60 mmol), CuI (70 mg, 3.8 mmol), and Pd (PPh ₃ ) ₂ Cl ₂ (500 mg) were added sequentially. The mixture was heated at 80 ° C overnight. The cooled mixture was filtered and the filtrate was extracted with EtOAc (40 mL x 3). The organic layer was washed with saturated NaCl, dried over anhydrous Na ₂ SO ₄ , and evaporated in vacuo. The crude compound was purified by column chromatography on silica gel (10% EtOAc in petroleum ether) to give N- (2- (3,3-dimethylbut-1-ynyl) -3-fluorophenyl) butyramide (1.1 g , 55%) was obtained.

2-tert-butyl-4-fluoro-1H-indole

T-BuOK in a solution of N- (2- (3,3-dimethylbut-1-ynyl) -3-fluorophenyl) butyramide (6.0 g, 20 mmol) in DMF (100 mL) (5.0 g, 50 mmol) was added at room temperature. The mixture was heated at 90 ° C. overnight, then it was poured into water and extracted with EtOAc (100 mL × 3). The organic layer was washed with saturated NaCl and water, dried over anhydrous Na ₂ SO ₄ and evaporated in vacuo to give 2-tert-butyl-4-fluoro-1H-indole (5.8 g, 97%).

2-tert-butyl-4-fluoro-5-nitro-1H-indole

KNO ₃ (1.3 g, 10 mmol) was added at 0 ° C. to a solution of 2-tert-butyl-4-fluoro-1H-indole (2.5 g, 10 mmol) in H ₂ SO ₄ (30 mL). The mixture was stirred at -10 ° C for 0.5 h. The mixture was poured into water and extracted with EtOAc (100 mL x 3). The organic layer was washed with saturated NaCl and water, dried over anhydrous Na ₂ SO ₄ and evaporated in vacuo. The crude compound was purified by column chromatography on silica gel (10% EtOAc in petroleum ether) to give 2-tert-butyl-4-fluoro-5-nitro-1H-indole (900 mg, 73%).

2-tert-butyl-4-fluoro-1H-indol-5-amine

NiCl ₂ (4.2 g, 18 mmol) and NaBH ₄ (1.0 g, in a solution of 2-tert-butyl-4-fluoro-5-nitro-1H-indole (2.1 g, 9.0 mmol) in methanol (50 mL) 27 mmol) was added at 0 ° C. After addition, 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 layer was washed with saturated NaCl and water, dried over anhydrous Na ₂ SO ₄ and evaporated in vacuo to give 2-tert-butyl-4-fluoro-1H-indol-5-amine (900 mg, 50%). It was.

Example 37 2,3,4,9-tetrahydro-1H-carbazole-6-amine

2,3,4,9-tetrahydro-1H-carbazole-6-amine

6-Nitro-2,3,4,9-tetrahydro-1H-carbazole (0.100 g, 0.462 mmol) was dissolved in a 40 mL scintillation vial containing 2 mL of ethanol with a stirring magnetic rod. 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 h. The crude reaction mixture was then diluted with saturated aqueous solution of 15 mL sodium bicarbonate and extracted three times with equal volume of ethyl acetate. The ethyl acetate extracts were combined, dried over sodium sulfate and evaporated to dryness to afford 2,3,4,9-tetrahydro-1H-carbazole-6-amine (82 mg, 95%), which was used without further purification. It was.

Example 38 2-tert-butyl-7-fluoro-1H-indol-5-amine

2-bromo-6-fluoro-4-nitro-phenylamine

Br ₂ (3.9 mL, 77 mmol) was added dropwise at 0 ° C. to a solution of 2-fluoro-4-nitro-phenylamine (12 g, 77 mmol) in AcOH (50 mL). The mixture was stirred at 20 ° C. for 3 hours. The reaction mixture was basified with saturated aqueous NaHCO ₃ and extracted with EtOAc (100 mL × 3). The combined organics were dried over anhydrous Na ₂ SO ₄ and evaporated in vacuo to afford 2-bromo-6-fluoro-4-nitro-phenylamine (18 g, 97%).

2- (3,3-dimethyl-but-1-ynyl) -6-fluoro-4-nitro-phenylamine

CuI (445 mg, 5% mol), Pd under N ₂ protection in a solution of 2-bromo-6-fluoro-4-nitro-phenylamine (11 g, 47 mmol) in anhydrous Et ₃ N (100 mL) (PPh ₃ ) ₂ Cl ₂ (550 mg, 5% mol) and 3,3-dimethyl-but-1-yne (9.6 g, 120 mmol) were added. The mixture was stirred at 80 ° C for 10 h. The reaction mixture was filtered, poured into ice (100 g) and extracted with EtOAc (50 mL x 3). The combined organic extracts were dried over anhydrous Na ₂ SO ₄ and evaporated in vacuo to afford the crude product, which was purified by column chromatography on silica gel (petroleum ether / ethyl acetate 50: 1) to give 2- (3,3- Dimethyl-but-1-ynyl) -6-fluoro-4-nitro-phenylamine (4.0 g, 36%) was obtained.

N- [2- (3,3-dimethyl-but-1-ynyl) -6-fluoro-4-nitro-phenyl] -butyrylamide

2- (3,3-dimethyl-but-1-ynyl) -6-fluoro-4-nitro-phenylamine (4.0 g, 17 mmol) and pyridine (2.7 g, in anhydrous CH ₂ Cl ₂ (30 mL) 34 mmol) was added dropwise butyryl chloride (1.8 g, 17 mmol) at 0 ° C. After stirring at 0 ° C. for 5 h, the reaction mixture was poured onto ice (50 g) and extracted with CH ₂ Cl ₂ (30 mL × 3). The combined organic extracts were dried over anhydrous Na ₂ SO ₄ and evaporated in vacuo to N- [2- (3,3-dimethyl-but-1-ynyl) -6-fluoro-4-nitro-phenyl] -butyr Amide (3.2 g, 62%) was obtained, which was used in the next step without further purification.

2-tert-butyl-7-fluoro-5-nitro-1H-indole

To a 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) t-BuOK (2.3 g, 21 mmol) was added at room temperature. The mixture was heated at 120 ° C. for 2 g and then cooled to room temperature. Water (50 mL) was added to the reaction mixture and the resulting mixture was extracted with CH ₂ Cl ₂ (30 mL × 3). The combined organic extracts were dried over anhydrous Na ₂ SO ₄ and evaporated in vacuo to afford 2-tert-butyl-7-fluoro-5-nitro-1H-indole (2.0 g, 81%), which was taken to the next step. Used without further purification.

2-tert-butyl-7-fluoro-1H-indol-5-amine

To a solution of 2-tert-butyl-7-fluoro-5-nitro-1H-indole (2.0 g, 8.5 mmol) in MeOH (20 mL) was added Ni (0.3 g) under a nitrogen atmosphere. The reaction mixture was stirred at rt under hydrogen atmosphere (1 atm) overnight. The catalyst was filtered through a pad of celite and the filtrate was evaporated in vacuo. The crude product was purified by column chromatography on silica gel (petroleum ether / ethyl acetate 100: 1) to give 2-tert-butyl-7-fluoro-1H-indol-5-amine (550 mg, 24%). .

Example 39: 5-amino-2-tert-butyl-1H-indole-7-carbonitrile

2-amino-3- (3,3-dimethylbut-1-ynyl) -5-nitrobenzonitrile

To a stirred solution of 2-amino-3-bromo-5-nitrobenzonitrile (2.4 g, 10 mmol) in anhydrous Et ₃ N (60 mL) CuI (380 mg, 5% mol) and Pd (PPh ₃ ) ₂ Cl ₂ (470 mg, 5% mol) was added at room temperature. 3,3-dimethyl-but-1-yne (2.1 g, 25 mmol) was added dropwise to the mixture at room temperature. The reaction mixture was stirred at 80 ° C for 10 h. The reaction mixture was filtered, the filtrate was poured into ice (60 g) and extracted with ethyl acetate. The phases were separated and the organic phase was dried over Na ₂ SO ₄ . The solvent was removed in vacuo to afford the 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%) was obtained.

2-tert-butyl-5-nitro-1H-indole-7-carbonitrile

To a solution of 2-amino-3- (3,3-dimethylbut-1-ynyl) -5-nitrobenzonitrile (1.7 g, 7.0 mmol) in THF (35 mL) add TBAF (9.5 g, 28 mmol) to room temperature. Was added. The mixture was heated at reflux overnight. The reaction mixture was cooled down and THF was removed under reduced pressure. Water (50 ml) was added to the residue and the mixture was extracted with EtOAc. The organics were dried over Na ₂ SO ₄ and the solvent was evaporated in vacuo to yield 0.87 g of crude product 2-tert-butyl-5-nitro-1H-indole-7-carbonitrile which was used directly in the next step without purification. It was.

5-amino-2-tert-butyl-1H-indole-7-carbonitrile

To a solution of crude product 2-tert-butyl-5-nitro-1H-indole-7-carbonitrile (0.87 g, 3.6 mmol) in MeOH (10 mL) was added NiCl ₂ .6H ₂ O (1.8 g, 7.2 mmol). Add at -5 ° C. The reaction mixture was stirred for 30 minutes, then NaBH ₄ (0.48 g, 14.32 mmol) was added to the reaction mixture at 0 ° C. After 5 minutes, the reaction mixture was quenched with water, filtered and extracted with EtOAc. The combined organic layers were dried over Na ₂ SO ₄ and concentrated in vacuo to afford the crude product, which was purified by column chromatography (5-20% EtOAc in petroleum ether) to 5-amino-2-tert-butyl-1H. -Indole-7-carbonitrile (470 mg, 32% over two steps) was obtained.

Example 40 Methyl 5-amino-2-tert-butyl-1H-indole-7-carboxylate

2-tert-butyl-5-nitro-1H-indole-7-carboxylic acid

2-tert-butyl-5-nitro-1H-indole-7-carbonitrile (4.6 g, 19 mmol) was added to a solution of KOH in EtOH (10%, 100 mL) and the mixture was heated at reflux overnight. The solution was evaporated to remove the alcohol, a small amount of water was added and the mixture was acidified with dilute hydrochloric acid. After standing in the refrigerator, an orange-yellow solid precipitated out, which was purified by chromatography on silica gel (15% EtOAc in petroleum ether) to 2-tert-butyl-5-nitro-1H-indole-7-carboxyl. Acid (4.0 g, 77%) was obtained.

Methyl 2-tert-butyl-5-nitro-1H-indole-7-carboxylate

SOCl ₂ (3.6 g, 30 mol) was added dropwise at 0 ° C. to a solution of 2-tert-butyl-5-nitro-1H-indole-7-carboxylic acid (4.0 g, 15 mol) in methanol (30 mL). The mixture was stirred at 80 ° C for 12 h. The solvent was evaporated in vacuo and the residue was purified by column chromatography on silica gel (5% EtOAc in petroleum ether) to give methyl 2-tert-butyl-5-nitro-1H-indole-7-carboxylate (2.95 g , 70%) was obtained.

Methyl 5-amino-2-tert-butyl-1H-indole-7-carboxylate

A solution of 2-tert-butyl-5-nitro-1H-indole-7-carboxylate (2.0 g, 7.2 mmol) and Raney nickel (200 mg) in CH ₃ OH (50 mL) was added at room temperature under H ₂ atmosphere. Stir for 5 hours. The catalyst was filtered through a pad of celite and the filtrate was evaporated in vacuo to afford methyl 5-amino-2-tert-butyl-1H-indole-7-carboxylate (1.2 g, 68%).

Example 41: (5-amino-2-tert-butyl-1H-indol-7-yl) methanol

(2-tert-butyl-5-nitro-1H-indol-7-yl) methanol

To a solution of methyl 2-tert-butyl-5-nitro-1H-indole-7-carboxylate (6.15 g, 22.3 mmol) and dichloromethane (30 ml) add DIBAL-H (1.0 M, 20 mL, 20 mmol). Add at 78 ° C. The mixture was stirred for 1 h, then water (10 mL) was added slowly. The resulting mixture was extracted with EtOAc (120 mL x 3). The combined organic extracts were dried over anhydrous Na ₂ SO ₄ and evaporated in vacuo to give (2-tert-butyl-5-nitro-1H-indol-7-yl) methanol (4.0 g, 73%), which was followed by It was used directly in the step.

(5-Amino-2-tert-butyl-1 H-indol-7-yl) methanol

A mixture of (2-tert-butyl-5-nitro-1H-indol-7-yl) methanol (4.0 g, 16 mmol) and Raney nickel (400 mg) in CH ₃ OH (100 mL) at room temperature under H ₂ Stir for 5 g. The catalyst was filtered through a pad of celite and the filtrate was evaporated in vacuo to give (5-amino-2-tert-butyl-1H-indol-7-yl) methanol (3.4 g, 80%).

Example 42: 2- (1-methylcyclopropyl) -1H-indol-5-amine

Trimethyl- (1-methyl-cyclopropylethynyl) -silane

To a solution of cyclopropylethynyl-trimethyl-silane (3.0 g, 22 mmol) in ether (20 mL) was added dropwise n-BuLi (8.6 mL, 21.7 mol, 2.5 M solution in hexane) at 0 ° C. The reaction mixture was stirred at ambient temperature for 24 hours, then dimethyl sulfate (6.85 g, 54.3 mmol) was added dropwise at -10 ° C. The resulting solution was stirred at 10 ° C. for 30 minutes and then at 20 ° C. for 30 minutes. The reaction was quenched by addition of a mixture of saturated aqueous NH ₄ Cl and 25% aqueous ammonia (1: 3, 100 mL). The mixture was then stirred at ambient temperature for 1 hour. The aqueous phase is extracted with diethyl ether (3 x 50 mL) and the combined organic layers are washed successively with 5% aqueous hydrochloric acid (100 mL), 5% aqueous NaHCO ₃ solution (100 mL), and water (100 mL). It was. The organics were dried over anhydrous NaSO ₄ and concentrated at ambient pressure. After fractional distillation under reduced pressure, trimethyl- (1-methyl-cyclopropylethynyl) -silane (1.7 g, 52%) was obtained as a colorless liquid.

1-ethynyl-1-methyl-cyclopropane

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 mixture was stirred at 20 ° C. overnight. The mixture was poured into water and the organic layer was separated. The aqueous phase was extracted with THF (50 mL). The combined organic layers were dried over anhydrous Na ₂ SO ₄ and distilled under atmospheric pressure to give 1-ethynyl-1-methyl-cyclopropane (7.0 g, containing 1/2 THF, 34%).

2-bromo-4-nitroaniline

Br ₂ (60 g, 0.38 mol) was added dropwise at 5 ° C. to a solution of 4-nitro-phenylamine (50 g, 0.36 mol) in AcOH (500 mL). The mixture was stirred at that temperature for 30 minutes. Insoluble solids were collected by filtration and basified to pH 7 with saturated aqueous NaHCO ₃ . The aqueous phase was extracted with EtOAc (300 mL x 3). The combined organic layers were dried and evaporated under reduced pressure to afford compound 2-bromo-4-nitroaniline (56 g, 72%), which was used directly in the next step.

2-((1-methylcyclopropyl) ethynyl) -4-nitroaniline

N in deoxygenated 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) Under ₂ CuI (76 mg, 0.40 mmol) and Pd (PPh ₃ ) ₂ Cl ₂ (140 mg, 0.20 mmol) were added. The mixture was heated at 70 ° C. overnight and stirred for 24 h. The solid was filtered off and washed with EtOAc (50 mL x 3). The filtrate was evaporated under reduced pressure and the residue was purified by column chromatography on silica gel (petroleum ether / ethyl acetate = 10/1) to give 2-((1-methylcyclopropyl) ethynyl) -4-nitroaniline ( 340 mg, 79%) was obtained.

N- [2- (1-Methyl-cyclopropylethynyl) -4-nitro-phenyl] -butyrylamide

Butyryl chloride in a solution of 2-((1-methylcyclopropyl) ethynyl) -4-nitroaniline (220 mg, 1.0 mmol) and pyridine (160 mg, 2.0 mol) in CH ₂ Cl ₂ (20 mL) ( 140 mg, 1.3 mmol) was added at 0 ° C. The mixture was warmed to rt and stirred for 3 h. The mixture was poured into ice water. The organic layer was separated and the aqueous phase extracted with CH ₂ Cl ₂ (30 mL × 3). The combined organic layers were dried over anhydrous Na ₂ SO ₄ and evaporated under reduced pressure to give N- [2- (1-methyl-cyclopropyl-ethynyl) -4-nitro-phenyl] -butyrylamide (230 mg, 82% ) Was obtained and used directly in the next step.

2- (1-methylcyclopropyl) -5-nitro-1H-indole

A mixture of N- [2- (1-methyl-cyclopropylethynyl) -4-nitro-phenyl] -butyramide (1.3 g, 4.6 mmol) and TBAF (2.4 g, 9.2 mmol) in THF (20 mL) Heated at reflux for 24 h. The mixture was cooled to room temperature and poured into ice water. The mixture was extracted with CH ₂ Cl ₂ (30 mL × 3). The combined organic layers were dried over anhydrous Na ₂ SO ₄ and evaporated under reduced pressure. The residue was purified by column chromatography on silica gel (petroleum ether / ethyl acetate = 10/1) to give 2- (1-methylcyclopropyl) -5-nitro-1H-indole (0.70 g, 71%). .

2- (1-Methyl-cyclopropyl) -1 H-indol-5-ylamine

To a solution of 2- (1-methylcyclopropyl) -5-nitro-1H-indole (0.70 g, 3.2 mmol) in EtOH (20 mL) was added Raney nickel (100 mg) under a nitrogen atmosphere. The mixture was stirred at rt under hydrogen atmosphere (1 atm) overnight. The catalyst was filtered through a pad of celite and the filtrate was evaporated in vacuo. The residue was purified by column chromatography on silica gel (petroleum ether / ethyl acetate = 5/1) to give 2- (1-methyl-cyclopropyl) -1H-indol-5-ylamine (170 mg, 28%). Obtained.

Example 43 Methyl 2- (5-amino-1 H-indol-2-yl) -2-methylpropanoate

Methyl 2,2-dimethyl-3-oxobutanoate

To a suspension of NaH (42 g, 1.1 mol, 60%) in THF (400 mL) was added dropwise a solution of methyl 3-oxobutanoate (116 g, 1.00 mol) in THF (100 mL) at 0 ° C. The mixture was stirred at that temperature for 0.5 h and then MeI (146 g, 1.1 mol) was added dropwise at 0 ° C. The resulting mixture was warmed to rt and stirred for 1 h. NaH (42 g, 1.05 mol, 60%) was added in portions at 0 ° C. and the resulting mixture was subsequently stirred at this temperature for 0.5 h. MeI (146 g, 1.05 mol) was added dropwise at 0 ° C. The reaction mixture was allowed to warm up to room temperature and stirred overnight. The mixture was poured into ice water and the organic layer was separated. The aqueous phase was extracted with EtOAc (500 mL x 3). The combined organic layers were dried and evaporated under reduced pressure to afford methyl 2,2-dimethyl-3-oxobutanoate (85 g), which was used directly in the next step.

Methyl 3-chloro-2,2-dimethylbut-3-enoate

To a suspension of PCl ₅ (270 g, 1.3 mol) in CH ₂ Cl ₂ (1000 mL) was added dropwise methyl 2,2-dimethyl-3-oxobutanoate (85 g) at 0 ° C., followed by approximately 30 drops. Anhydrous DMF was added. The mixture was heated at reflux overnight. The reaction mixture was cooled to ambient temperature and poured slowly into ice water. The organic layer was separated and the aqueous phase extracted with CH ₂ Cl ₂ (500 mL × 3). The combined organic layers were washed with saturated aqueous NaHCO ₃ and dried over anhydrous Na ₂ SO ₄ . The solvent was evaporated and the residue was distilled off under reduced pressure to afford methyl 3-chloro-2,2-dimethylbut-3-enoate (37 g, 23%).

3-Chloro-2,2-dimethylbut-3-enoic acid

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 at reflux for 5 hours. The mixture was cooled to ambient temperature and extracted with ether. The organic layer was discarded. The aqueous layer was acidified with cold 20% HCl solution and extracted with ether (200 mL × 3). The combined organic layers were dried and evaporated under reduced pressure to afford 3-chloro-2,2-dimethyl-but-3-enoic acid (21 g, 70%), which was used directly in the next step.

2,2-dimethyl-but-3-phosphate

Liquid NH ₃ was condensed at −78 ° C. in a three neck, 250 mL round bottom flask. Na (3.98 g, 0.173 mol) was added in portions to the flask. The mixture was stirred at -78 ° C for 2 h, then anhydrous DMSO (20 mL) was added dropwise at -78 ° C. The mixture was stirred at room temperature until no NH ₃ was generated. 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 mixture was warmed and stirred at 50 ° C. for 5 hours and then at room temperature overnight. The cloudy, olive green solution was poured into cold 20% HCl solution and then extracted three times with ether. The ether extract was dried over anhydrous Na ₂ SO ₄ and concentrated to give crude 2,2-dimethyl-but-3-phosphate (2 g), which was used directly in the next step.

Methyl 2,2-dimethylbut-3-inoate

To a solution of diazomethane (˜10 g) in ether (400 mL) 2,2-dimethyl-but-3-phosphate (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 under atmospheric pressure to give crude methyl 2,2-dimethylbut-3-inoate (14 g), which was used directly in the next step.

Methyl 4- (2-amino-5-nitrophenyl) -2,2-dimethylbut-3-inoate

Compound 2-bromo-4-nitroaniline (9.43 g, 43.7 mmol), methyl 2,2-dimethylbut-3-inoate (5.00 g, 39.7 mmol) in toluene / H ₂ O (100/30 mL), To deoxygenated solution of CuI (754 mg, 3.97 mmol) and triethylamine (8.03 g, 79.4 mmol) was added Pd (PPh ₃ ) ₄ (6.17 g, 3.97 mmol) under N ₂ . The mixture was heated at 70 ° C. overnight and stirred for 24 h. After cooling, the solid was filtered off and washed with EtOAc (50 mL x 3). The organic layer was separated and the aqueous phase washed with EtOAc (50 mL x 3). The combined organic layers were dried and evaporated under reduced pressure to afford a residue, which was purified by column chromatography on silica gel (petroleum ether / ethyl acetate = 10/1) to give methyl 4- (2-amino-5-nitrophenyl ) -2,2-dimethylbut-3-inoate (900 mg, 9%) was obtained.

Methyl 4- (2-butyramido-5-nitrophenyl) -2,2-dimethylbut-3-inoate

Methyl 4- (2-amino-5-nitrophenyl) -2,2-dimethylbut-3-inoate (260 mg, 1.0 mmol) and pyridine (160 mg, 2.0 mol) in CH ₂ Cl ₂ (20 mL) To a solution of butyryl chloride (140 mg, 1.3 mmol) was added at 0 ° C. The reaction mixture was allowed to warm to room temperature and stirred for 3 hours before the mixture was poured into ice water. The organic layer was separated and the aqueous phase extracted with CH ₂ Cl ₂ (30 mL × 3). The combined organic layers were dried over anhydrous Na ₂ SO ₄ and evaporated under reduced pressure to afford methyl 4- (2-butyramido-5-nitrophenyl) -2,2-dimethylbut-3-inoate (150 mg, 45 %) Was obtained and used directly in the next step.

Methyl 2-methyl-2- (5-nitro-1H-indol-2-yl) propanoate

N ₂ to deoxygenated solution of methyl 4- (2-butyramido-5-nitrophenyl) -2,2-dimethylbut-3-inoate (1.8 g, 5.4 mmol) in acetonitrile (30 mL) Pd (CH ₃ CN) ₂ Cl ₂ (0.42 g, 1.6 = mmol) was added. The mixture was heated at reflux for 24 h. After the mixture was cooled to ambient temperature, the solid was filtered off and washed with EtOAc (50 mL x 3). The filtrate was evaporated under reduced pressure to give a residue, which was purified by column chromatography on silica gel (petroleum ether / ethyl acetate = 30/1) to give methyl 2-methyl-2- (5-nitro-1H-indole- 2-yl) propanoate (320 mg, 23%) was obtained.

Methyl 2- (5-amino-1 H-indol-2-yl) -2-methylpropanoate

Suspension of methyl 2-methyl-2- (5-nitro-1H-indol-2-yl) propanoate (60 mg, 0.23 mmol) and Raney nickel (10 mg) in MeOH (5 mL) was diluted with hydrogen (1 atm) overnight at room temperature. The catalyst was filtered through a pad of celite and the filtrate was evaporated in vacuo to give a residue, which was purified by column chromatography on silica gel (petroleum ether / ethyl acetate = 5/1) to give methyl 2- (5- Amino-1H-indol-2-yl) -2-methylpropanoate (20 mg, 38%) was obtained.

Example 44: 2-isopropyl-1H-indol-5-amine

2-isopropyl-5-nitro-1H-indole

Methyl 4- (2-butyramido-5-nitrophenyl) -2,2-dimethylbut-3-inoate (0.50 g, 1.5 mmol) and TBAF (790 mg, 3.0 mmol) in DMF (20 mL) The mixture of was heated at 70 ° C. for 24 h. The reaction mixture was cooled to room temperature and poured into ice water. The mixture was extracted with ether (30 mL x 3). The combined organic layers were dried over anhydrous Na ₂ S0 ₄ and evaporated under reduced pressure to give a residue, which was purified by column chromatography on silica gel (petroleum ether / ethyl acetate = 20/1) to 2-isopropyl-5 Nitro-1H-indole (100 mg, 33%) was obtained.

2-isopropyl-1H-indol-5-amine

Suspension of 2-isopropyl-5-nitro-1H-indole (100 mg, 0.49 mmol) and Raney nickel (10 mg) in MeOH (10 mL) was hydrogenated overnight at room temperature under hydrogen (1 atm). The catalyst was filtered through a pad of celite and the filtrate was evaporated in vacuo to give a residue, which was purified by column (petroleum ether / ethyl acetate = 5/1) to give 2-isopropyl-1H-indole-5- Amine (35 mg, 41%) was obtained.

Example 45: 1- (benzo [d] [1,3] dioxol-5-yl) -N- (2- (1-hydroxy-2-methylpropan-2-yl) -1H-indole-5 -Yl) cyclopropanecarboxamide

Triphenyl (2-aminobenzyl) phosphonium bromide

2-aminobenzyl alcohol (60.0 g, 0.487 mol) was dissolved in acetonitrile (2.5 L) and refluxed. Triphenylphosphine hydrobromide (167 g, 0.487 mol) was added and the mixture was heated at reflux for 3 hours. The reaction mixture was concentrated to approximately 500 mL and left at room temperature for 1 hour. The precipitate was filtered off and washed with cold acetonitrile followed by hexane. The solid was dried at 40 ° C. under vacuum overnight to give triphenyl (2-aminobenzyl) phosphonium bromide (193 g, 88%).

Triphenyl ((ethyl (2-carbamoyl) acetate) -2-benzyl) phosphonium bromide

To a suspension of triphenyl (2-aminobenzyl) phosphonium bromide (190 g, 0.43 mol) in anhydrous dichloromethane (1 L) was added ethyl malonyl chloride (55 ml, 0.43 mol). The reaction was stirred at rt for 3 h. After the mixture was evaporated to dryness, ethanol (400 mL) was added. The mixture was heated under reflux until a clear solution was obtained. The solution was allowed to stand for 3 hours at room temperature. The precipitate was filtered off, washed with cold ethanol followed by hexanes and dried. A second crop was obtained from the mother liquor in the same manner. To remove residual ethanol, both harvests were combined, dissolved in dichloromethane (approximately 700 mL) under heating and evaporated. The solid was dried under vacuum at 50 ° C. overnight to give triphenyl ((ethyl (2-carbamoyl) acetate) -2-benzyl) -phosphonium bromide (139 g, 58%).

Ethyl 2- (1H-indol-2-yl) acetate

Triphenyl ((ethyl (2-carbamoyl) acetate) -2-benzyl) phosphonium bromide (32.2 g, 57.3 mmol) was added to anhydrous toluene (150 mL) and the mixture was heated to reflux. Fresh potassium tert-butoxide (7.08 g, 63.1 mmol) was added in portions over 15 minutes. Reflux was continued for another 30 minutes. The mixture was filtered hot through a plug of celite and evaporated under reduced pressure. The residue was purified by column chromatography on silica gel (0-30% ethyl acetate in hexanes over 45 minutes) to give ethyl 2- (1H-indol-2-yl) acetate (9.12 g, 78%).

tert-butyl 2-((ethoxycarbonyl) methyl) -1H-indole-1-carboxylate

4-dimethylaminopyridine (8.83 g, 72.2 mmol) and di-tert-butyl carbo in a solution of ethyl 2- (1H-indol-2-yl) acetate (14.7 g, 72.2 mmol) in dichloromethane (150 mL) Nate (23.7 g, 108 mmol) was added portionwise. After stirring at room temperature for 2 hours, the mixture is diluted with dichloromethane, washed with water, dried over magnesium sulfate and purified by silica gel chromatography (0-20% EtOAc in hexane) to tert-butyl 2-(( Ethoxycarbonyl) methyl) -1H-indole-1-carboxylate (20.0 g, 91%) was obtained.

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. 0.5M solution of potassium hexamethyldisilazane (165 mL, 82 mmol) was added slowly to maintain the internal temperature below -60 ° C. Stirring was continued at −78 ° C. for 30 minutes. To this mixture, methyl iodide (5.64 mL, 91 mmol) was added. The mixture was stirred at rt for 30 min and then cooled to -78 ° C. 0.5M solution of potassium hexamethyldisilazane (210 mL, 104 mmol) was added slowly and the mixture was stirred at -78 ° C for another 30 minutes. Additional amount of methyl iodide (8.6 mL, 137 mmol) was added and the mixture was stirred at rt for 1.5 h. The reaction was quenched with saturated aqueous ammonium chloride and partitioned between water and dichloromethane. The aqueous phase was extracted with dichloromethane and the combined organic phases were dried over magnesium sulphate and evaporated under reduced pressure. The residue was purified by column chromatography on silica gel (0-20% ethyl acetate in hexane) to give tert-butyl 2- (2- (ethoxycarbonyl) propan-2-yl) -1H-indole-1-car Cylates (17.1 g, 94%) were obtained.

Ethyl 2- (1H-indol-2-yl) -2-methylpropanoate

tert-butyl 2- (2- (ethoxycarbonyl) propan-2-yl) -1H-indole-1-carboxylate (22.9 g, 69.1 mmol) was dissolved in dichloromethane (200 mL) and then TFA (70 mL) was added. The mixture was stirred at rt for 5 h. The mixture was evaporated to dryness, taken up in dichloromethane and washed with saturated sodium bicarbonate solution, water, and brine. The product was purified by column chromatography on silica gel (0-20% EtOAc in hexanes) to give ethyl 2- (1H-indol-2-yl) -2-methylpropanoate (12.5 g, 78%).

Ethyl 2-methyl-2- (5-nitro-1H-indol-2-yl) propanoate

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 on ice and the product extracted with dichloromethane. The combined organic phases were washed with a small amount of saturated aqueous sodium bicarbonate. The product was purified by column chromatography on silica gel (5-30% EtOAc in hexane) to ethyl 2-methyl-2- (5-nitro-1H-indol-2-yl) propanoate (0.68 g, 57%) Obtained.

2-methyl-2- (5-nitro-1H-indol-2-yl) propan-1-ol

To a cooled solution of LiAlH ₄ (1.0 M in THF, 1.1 mL, 1.1 mmol) in THF (5 mL) at 0 ° C., ethyl 2-methyl-2- (5-nitro-1H-indole- in THF (3.4 mL) A solution of 2-yl) propanoate (0.20 g, 0.72 mmol) was added dropwise. After addition, the mixture was allowed to warm to room temperature and stirred for 3 hours. After the mixture was cooled to 0 ° C., water (2 mL) was added slowly followed by 15% NaOH (2 mL) and water (4 mL) carefully. The mixture was stirred at rt for 0.5 h and filtered through a short plug of celite using ethyl acetate. The organic layer was separated from the aqueous layer, dried over Na ₂ SO ₄ , filtered and evaporated under reduced pressure. The residue was purified by column chromatography on silica gel (ethyl acetate / hexane = 1/1) to give 2-methyl-2- (5-nitro-1H-indol-2-yl) propan-1-ol (0.098 g, 58%) was obtained.

2- (5-amino-1H-indol-2-yl) -2-methylpropan-1-ol

Tin chloride dihydrate (0.451 g, 2.0 mmol) in 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) ) Was added. The mixture was heated in microwave at 120 ° C. for 1 hour. The mixture was diluted with ethyl acetate and water and then quenched with saturated aqueous NaHCO ₃ . The reaction mixture was filtered through a plug of celite using ethyl acetate. The organic layer was separated from the aqueous layer, dried over Na ₂ SO ₄ , filtered and evaporated under reduced pressure to afford 2- (5-amino-1 H-indol-2-yl) -2-methylpropan-1-ol (0.080 g, 98%) was obtained.

Example 46: 2- (pyridin-2-yl) -1H-indol-5-amine

4-nitro-2- (pyridin-2-ylethynyl) aniline

DMF (60mL) and Et ₃ N (60 mL) of 2-iodo-4-nitroaniline pyridine (3.0 g, 45 mmol) 2-ethynyl under N ₂ to a solution of (3.0 g, 11 mmol), Pd ( PPh ₃ ) ₂ Cl ₂ (600 mg) and CuI (200 mg) were added. The reaction mixture was stirred at 60 ° C. for 12 h. The mixture was diluted with water and extracted with dichloromethane (3 x 100 mL). The combined organic layers were washed with brine, dried over anhydrous Na ₂ SO ₄ , and concentrated in vacuo. The residue was purified by chromatography on silica gel (5-10% ethyl acetate / petroleum ether) to give 4-nitro-2- (pyridin-2-ylethynyl) aniline (1.5 g, 60%).

5-nitro-2- (pyridin-2-yl) -1H-indole

To a solution of 4-nitro-2- (pyridin-2-ylethynyl) aniline (1.5 g, 6.3 mmol) in DMF (50 mL) was added t-BuOK (1.5 g, 13 mmol). 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 Na ₂ SO ₄ , and concentrated in vacuo. The residue was purified by chromatography on silica gel (5-10% ethyl acetate / petroleum ether) to give 5-nitro-2- (pyridin-2-yl) -1H-indole (1.0 g, 67% yield). .

2- (pyridin-2-yl) -1H-indol-5-amine

To a solution of 5-nitro-2- (pyridin-2-yl) -1H-indole (700 mg, 2.9 mmol) in EtOH (20 mL) was added SnCl ₂ (2.6 g, 12 mmol). The mixture was heated at reflux for 10 h. Water was added and the mixture was extracted with EtOAc (50 mL x 3). The combined organic layers were washed with brine, dried over anhydrous Na ₂ SO ₄ , and concentrated in vacuo. The residue was purified by chromatography on silica gel (5-10% ethyl acetate / petroleum ether) to give 2- (pyridin-2-yl) -1H-indol-5-amine (120 mg, 20%).

Example 47 2- (pyridin-2-yl) -1H-indol-5-amine

[2- (tert-Butyl-dimethyl-silanyloxy) -ethyl]-(2-iodo-4-nitro-phenyl) -amine

To a solution of 2-iodo-4-nitroaniline (2.0 g, 7.6 mmol) and 2- (tert-butyldimethylsilyloxy) -acetaldehyde (3.5 g, 75% purity, 15 mmol) in methanol (30 mL) TFA (1.5 mL) was added at 0 ° C. The reaction mixture was stirred at this temperature for 30 minutes and then NaCNBH ₃ (900 mg, 15 mmol) was added in portions. The mixture was stirred for 2 hours and then quenched with water. The resulting mixture is extracted with EtOAc (30 mL × 3), the combined organic extracts are dried over anhydrous Na ₂ SO ₄ , evaporated in vacuo and the residue is chromatographed on silica gel (5% ethyl acetate / petroleum). Purification gave [2- (tert-butyl-dimethyl-silanyloxy) -ethyl]-(2-iodo-4-nitro-phenyl) -amine (800 mg, 25%).

5- {2- [2- (tert-Butyl-dimethyl-silanyloxy) -ethylamino] -5-nitro-phenyl} -3,3-dimethyl-pent-4-phosphate ethyl ester

To a solution of [2- (tert-butyl-dimethyl-silanyloxy) -ethyl]-(2-iodo-4-nitro-phenyl) -amine (800 mg, 1.9 mmol) in Et ₃ N (20 mL). Pd (PPh ₃ ) ₂ Cl ₂ (300 mg, 0.040 mmol), CuI (76 mg, 0.040 mmol) and 3,3-dimethyl-but-1-yne (880 mg, 5.7 mmol) under N ₂ protection in succession Added. The reaction mixture was heated at 80 ° C. for 6 hours and allowed to cool to room temperature. The resulting mixture was extracted with EtOAc (30 mL x 3). The combined organic extracts were dried over anhydrous Na ₂ SO ₄ and evaporated in vacuo to afford 5- {2- [2- (tert-butyl-dimethyl-silanyloxy) -ethylamino] -5-nitro-phenyl} -3, 3-Dimethyl-pent-4- phosphate ethyl ester (700 mg, 82%) was obtained, which was used in the next step without further purification.

3- [1- (2-hydroxy-ethyl) -5-nitro-1H-indol-2-yl] -3-methyl-butyric acid ethyl ester

5- {2- [2- (tert-Butyl-dimethyl-silanyloxy) -ethylamino] -5-nitro-phenyl} -3,3-dimethyl-pent-4-phosphate in CH ₃ CN (30 mL) A solution of ethyl ester (600 mg, 1.34 mmol) and PdCl ₂ (650 mg) was heated at reflux overnight. The resulting mixture was extracted with EtOAc (30 mL x 3). The combined organic extracts were dried over anhydrous Na ₂ SO ₄ and evaporated in vacuo. The residue was dissolved in THF (20 mL) and TBAF (780 mg, 3.0 mmol) was added. The mixture is stirred at rt for 1 h, the solvent is removed in vacuo and the residue is purified by chromatography on silica gel (10% ethyl acetate / petroleum) to give 3- [1- (2-hydroxy-ethyl)- 5-nitro-1H-indol-2-yl] -3-methyl-butyric acid ethyl ester (270 mg, 60%) was obtained.

3- [1- (2-hydroxy-ethyl) -5-nitro-1H-indol-2-yl] -3-methyl-butan-1-ol

To a solution of 3- [1- (2-hydroxy-ethyl) -5-nitro-1H-indol-2-yl] -3-methyl-butyric acid ethyl ester (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 mixture was stirred at rt for 1 h. Water (2 mL) was added and the resulting mixture was extracted with EtOAc (15 mL x 3). The combined organic layers were dried over anhydrous Na ₂ SO ₄ and evaporated in vacuo. The residue was purified by chromatography on silica gel (15% ethyl acetate / petroleum) to give 3- [1- (2-hydroxy-ethyl) -5-nitro-1H-indol-2-yl] -3-methyl- Butan-1-ol (300 mg, 49%) was obtained.

3- [5-Amino-1- (2-hydroxy-ethyl) -1 H-indol-2-yl] -3-methyl-butan-1-ol

3- [1- (2-hydroxy-ethyl) -5-nitro-1H-indol-2-yl] -3-methyl-butan-1-ol (300 mg, 1.03 mmol in CH ₃ OH (30 mL)) ) And Raney nickel (200 mg,) were stirred for 5 hours at room temperature under H ₂ atmosphere. The catalyst was filtered through a pad of celite and the filtrate was evaporated in vacuo 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 mg, 26%) was obtained.

Example 48 tert-butyl 2- (5-amino-1 H-indol-2-yl) piperidine-1-carboxylate

2- (piperidin-2-yl) -1H-indol-5-amine

5-nitro-2- (pyridin-2-yl) -1H-indole (1.0 g, 4.2 mmol) was added to HCl / MeOH (2 M, 50 mL). The reaction mixture was stirred at rt for 1 h and the solvent was evaporated in vacuo. PtO ₂ (200 mg) was added to a solution of the residue in MeOH (50 mL) and the reaction mixture was stirred at room temperature under hydrogen atmosphere (1 atm) for 2 hours. The catalyst was filtered through a pad of celite and the solvent was evaporated in vacuo to afford 2- (piperidin-2-yl) -1H-indol-5-amine (1.0 g), which was used directly in the next step. .

tert-butyl 2- (5-amino-1H-indol-2-yl) piperidine-1-carboxylate

To a solution of 2- (piperidin-2-yl) -1H-indol-5-amine (1.0 g) in Et ₃ N (25 mL) and THF (25 mL) add Boc ₂ O (640 mg, 2.9 mmol). Added. The reaction mixture was stirred at rt 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 Na ₂ SO ₄ , and concentrated in vacuo. The residue was purified by chromatography on silica gel (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% over 2 steps) was obtained.

Example 49 6-amino-1H-indole-2-carbonitrile

(3-nitrophenyl) hydrazine hydrochloride

3-nitroaniline (28 g, 0.20 mol) was dissolved in a mixture of H ₂ O (40 mL) and 37% HCl (40 mL). A solution of NaNO ₂ (14 g, 0.20 mol) in H ₂ O (60 mL) was added to the mixture at 0 ° C., followed by SnCl ₂ .H ₂ O (140 g, 0.60 mol) in 37% HCl (100 mL). Solution was added. After stirring for 0.5 h at 0 ° C., the insoluble material was isolated by filtration and washed with water to give (3-nitrophenyl) hydrazine hydrochloride (28 g, 73%).

(E) -ethyl 2- (2- (3-nitrophenyl) hydrazono) propanoate

(3-nitrophenyl) hydrazine hydrochloride (30 g, 0.16 mol) and 2-oxo-propionic acid ethyl ester (22 g, 0.19 mol) were dissolved in ethanol (300 mL). After the mixture was stirred at rt for 4 h, the solvent was evaporated under reduced pressure to give (E) -ethyl 2- (2- (3-nitrophenyl) hydrazono) propanoate, which was used directly in the next step. .

Ethyl 4-nitro-1H-indole-2-carboxylate and ethyl 6-nitro-1H-indole-2-carboxylate

(E) -ethyl 2- (2- (3-nitrophenyl) hydrazono) propanoate dissolved in toluene (300 mL) and PPA (30 g) was added. The mixture was heated at reflux overnight and then cooled to room temperature. The solvent was poured off and evaporated to give a crude mixture which was used without purification in the next step (15 g, 40%).

4-nitro-1H-indole-2-carboxylic acid and 6-nitro-1H-indole-2-carboxylic acid

A mixture of ethyl 6-nitro-1H-indole-2-carboxylate (0.5 g) and 10% NaOH (20 mL) was heated at reflux overnight and then cooled to room temperature. The mixture was extracted with ether and the aqueous phase was acidified to pH 1-2 with HCl. The insoluble solid was isolated by filtration to give the crude mixture, which was used without purification in the next step (0.3 g, 68%).

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 SOCl ₂ (50 mL, 64 mmol) in benzene (150 mL) was heated at reflux for 2 hours. Benzene and excess SOCl ₂ were removed under reduced pressure. The residue was dissolved in anhydrous CH ₂ Cl ₂ (250 mL) and NH ₃ .H ₂ O (22 g, 0.32 mol) was added dropwise at 0 ° C. The mixture was stirred at rt for 1 h. The insoluble solid was isolated by filtration to give a crude mixture (9.0 g, 68%) which was used directly in the next step.

4-nitro-1H-indole-2-carbonitrile and 6-nitro-1H-indole-2-carbonitrile

6-nitro-1H-indole-2-carboxamide (5.0 g, 24 mmol) was dissolved in CH ₂ Cl ₂ (200 mL). Et ₃ N (24 g, 0.24 mol) and (CF ₃ CO) ₂ O (51 g, 0.24 mol) were added dropwise to the mixture at room temperature. The mixture was continued to stir for 1 hour and then poured into water (100 mL). The organic layer was separated and the aqueous layer extracted with EtOAc (100 mL x 3). The combined organic layers were dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to afford the crude product, which was purified by column chromatography on silica gel to give an impure sample of 4-nitro-1H-indole-2-carbonitrile. (2.5 g, 55%) was obtained.

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 ₂ (1 atm) for 1 hour. Raney nickel was removed by filtration and the filtrate was evaporated under reduced pressure to give a residue, which was purified by column chromatography on silica gel to give 6-amino-1H-indole-2-carbonitrile (1.0 g, 49% ) Was obtained.

Example 50 6-amino-1H-indole-3-carbonitrile

6-nitro-1H-indole-3-carbonitrile

To a solution of 6-nitroindole (4.9 g 30 mmol) in DMF (24 mL) and CH ₃ CN (240 mL) was added dropwise a solution of ClSO ₂ NCO (5.0 mL) in CH ₃ CN (39 mL) at 0 ° C. . After addition, the reaction was allowed to warm to room temperature and stirred for 2 hours. The mixture was then poured into ice water and basified to pH 7-8 with saturated NaHCO ₃ solution. The mixture was extracted with ethyl acetate. The organics were washed with brine, dried over Na ₂ SO ₄ and concentrated to give 6-nitro-1H-indole-3-carbonitrile (4.6 g, 82%).

6-amino-1H-indole-3-carbonitrile

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 added to H ₂ at room temperature. Stir overnight at (1 atm). After filtration, the filtrate was concentrated and the residue was purified by column chromatography on silica gel (petroleum ether / ethyl acetate = 3/1) to give 6-amino-1H-indole-3-carbonitrile (1.0 g, 98 %) Was obtained as a pink solid.

Example 51: 2-tert-butyl-1H-indol-6-amine

N-o-tolylpivalamide

To a solution of o-tolylamine (21 g, 0.20 mol) and Et ₃ N (22 g, 0.22 mol) in CH ₂ Cl ₂ , 2,2-dimethyl-propionyl chloride (25 g, 0.21 mol) was added at 10 ° C. Added. After addition, the mixture was stirred at rt overnight. The mixture was washed with aqueous HCl (5%, 80 mL), saturated aqueous NaHCO ₃ and brine. The organic layer was dried over Na ₂ SO ₄ and concentrated in vacuo to give No-tolylpivalamide (35 g, 91%).

2-tert-butyl-1H-indole

To a solution of No-tolylpivalamide (30.0 g, 159 mmol) in anhydrous THF (100 mL) was added dropwise n-BuLi (2.5 M in hexane, 190 mL) at 15 ° C. After addition, the mixture was stirred at 15 ° C. overnight. The mixture was cooled in an ice water bath and treated with saturated NH ₄ Cl. The organic layer was separated and the aqueous layer was extracted with ethyl acetate. The combined organic layers were dried over anhydrous Na ₂ SO ₄ , filtered and concentrated in vacuo. The residue was purified by column chromatography on silica gel to give 2-tert-butyl-1H-indole (24 g, 88%).

2-tert-butylindoline

To a solution of 2-tert-butyl-1H-indole (10 g, 48 mmol) in AcOH (40 mL) was added NaBH ₄ at 10 ° C. The mixture was stirred at 10 ° C. for 20 minutes and then treated dropwise with H ₂ O while cooling with ice. The mixture was extracted with ethyl acetate. The combined organic layers were dried over anhydrous Na ₂ SO ₄ , filtered and concentrated in vacuo to give 2-tert-butylindolin (9.8 g), which was used directly in the next step.

2-tert-butyl-6-nitroindolin and 2-tert-butyl-5-nitro-1H-indole

To a solution of 2-tert-butylindolin (9.7 g) in H ₂ SO ₄ (98%, 80 mL) was added slowly KNO ₃ (5.6 g, 56 mmol) at 0 ° C. After addition, the reaction mixture was stirred at rt for 1 h. The mixture was carefully poured onto crushed ice, basified to pH 8 with Na ₂ CO ₃ and extracted with ethyl acetate. The combined extracts were washed with brine, dried over anhydrous Na ₂ S0 ₄ and concentrated in vacuo. The residue was purified by column chromatography to give 2-tert-butyl-6-nitroindolin (4.0 g, 31% over two steps).

2-tert-butyl-6-nitro-1H-indole

To a solution of 2-tert-butyl-6-nitroindolin (2.0 g, 9.1 mmol) in 1,4-dioxane (20 mL) was added DDQ (6.9 g, 30 mmol) at room temperature. The mixture was heated at reflux for 2.5 h, then filtered and concentrated in vacuo. The residue was purified by column chromatography to give 2-tert-butyl-6-nitro-1H-indole (1.6 g, 80%).

2-tert-butyl-1H-indol-6-amine

Raney nickel (0.2 g) was added to a solution of 2-tert-butyl-6-nitro-1H-indole (1.3 g, 6.0 mmol) in MeOH (10 mL). The mixture was hydrogenated at room temperature under 1 atm of hydrogen for 3 hours. The reaction mixture was filtered and the filtrate was concentrated. The residue was washed with petroleum ether to give 2-tert-butyl-1H-indol-6-amine (1.0 g, 89%).

Example 52: 3-tert-butyl-1H-indol-6-amine

3-tert-butyl-6-nitro-1H-indole

DIEA (1.5 g) at room temperature under nitrogen to a mixture of 6-nitroindole (1.0 g, 6.2 mmol), zinc triflate (2.1 g, 5.7 mmol), and TBAI (1.7 g, 5.2 mmol) in anhydrous toluene (11 mL). , 11 mmol) was added. The reaction mixture was stirred at 120 ° C. for 10 minutes, then t-butyl bromide (0.71 g, 5.2 mmol) was added. The resulting mixture was stirred at 120 ° C. for 45 minutes. The solid was filtered off and the filtrate was concentrated to dryness. The residue was purified by column chromatography on silica gel (petroleum ether / ethyl acetate = 20: 1) to give 3-tert-butyl-6-nitro-1H-indole (0.25 g, 19%) as a yellow solid.

3-tert-butyl-1H-indol-6-amine

Suspension of 3-tert-butyl-6-nitro-1H-indole (3.0 g, 14 mmol) and Raney nickel (0.5 g) was hydrogenated at room temperature under H ₂ (1 atm) for 3 hours. The catalyst was filtered off and the filtrate was concentrated to dryness. The residue was purified by column on silica gel (petroleum ether / ethyl acetate = 4: 1) to give 3-tert-butyl-1H-indol-6-amine (2.0 g, 77%) as a gray solid.

Example 53: 5- (trifluoromethyl) -1H-indol-6-amine

1-methyl-2,4-dinitro-5- (trifluoromethyl) benzene

HNO ₃ To a mixture of (98%, 30 mL) and H ₂ SO ₄ (98%, 30 mL) was added dropwise 1-methyl-3-trifluoromethyl-benzene (10 g, 63 mmol) at 0 ° C. After addition, the mixture was stirred for 30 minutes at room temperature 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%).

(E) -2- (2,4-dinitro-5- (trifluoromethyl) phenyl) -N, N-dimethylethenamine

A mixture of 1-methyl-2,4-dinitro-5-trifluoromethyl-benzene (2.0 g, 8.0 mmol) and DMA (1.0 g, 8.2 mmol) in DMF (20 mL) was stirred at 100 ° C. for 30 minutes. Stirred. 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-dimethylethenamine (2.1 g, 86%) It was.

5- (trifluoromethyl) -1H-indol-6-amine

(E) -2- (2,4-dinitro-5- (trifluoromethyl) phenyl) -N, N-dimethylethenamine (2.1 g, 6.9 mmol) and Raney nickel (in ethanol (80 mL) 1 g) suspension was stirred at room temperature under H ₂ (1 atm) for 5 hours. The catalyst was filtered off and the filtrate was concentrated to dryness. The residue was purified by column on silica gel to give 5- (trifluoromethyl) -1H-indol-6-amine (200 mg, 14%).

Example 54: 5-Ethyl-1H-indol-6-amine

1- (phenylsulfonyl) indolin

To a mixture of DMAP (1.5 g), benzenesulfonyl chloride (24.0 g, 136 mmol) and indolin (14.7 g, 124 mmol) in CH ₂ Cl ₂ (200 mL) was charged Et ₃ N (19.0 g, 186 mmol). Dropwise at 0 ° C. The mixture was stirred at rt overnight. The organic layer was washed with water (2 ×), dried over Na ₂ SO ₄ and concentrated to dryness under reduced pressure to give 1- (phenylsulfonyl) indolin (30.9 g, 96%).

1- (1- (phenylsulfonyl) indoline-5-yl) ethanone

To a suspension of AlCl ₃ (144 g, 1.08 mol) in CH ₂ Cl ₂ (1070 mL) was added acetic anhydride (54 mL). After the mixture was stirred for 15 minutes, a solution of 1- (phenylsulfonyl) indolin (46.9 g, 0.180 mol) in CH ₂ Cl ₂ (1070 mL) was added dropwise. The 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 CH ₂ Cl ₂ . The combined organics are washed with saturated aqueous NaHCO ₃ and brine, dried over Na ₂ SO ₄ and concentrated in vacuo to give 1- (1- (phenylsulfonyl) indolin-5-yl) ethanone (42.6 g). It was.

5-ethyl-1- (phenylsulfonyl) indolin

Sodium borohydride (64.0 g, 1.69 mol) was added to TFA (1600 mL) at 0 ° C. over 1 hour. To this mixture was added dropwise a solution of 1- (1- (phenylsulfonyl) indolin-5-yl) ethanone (40.0 g, 0.133 mol) in TFA (700 mL) over 1 hour. The mixture was then stirred at 25 ° C. overnight. After dilution with H ₂ O (1600 mL), the mixture was basified by addition of sodium hydroxide pellets at 0 ° C. The organic layer was separated and the aqueous layer was extracted with CH ₂ Cl ₂ . The combined organic layers were washed with brine, dried over Na ₂ S0 ₄ and concentrated under reduced pressure. The residue was purified by silica column to give 5-ethyl-1- (phenylsulfonyl) indolin (16.2 g, 47% over two steps).

5-ethylindolin

A mixture of 5-ethyl-1- (phenylsulfonyl) indolin (15 g, 0.050 mol) in HBr (48%, 162 mL) was heated under reflux for 6 hours. The mixture was basified to pH 9 with saturated NaOH and then extracted with ethyl acetate. The organic layer was washed with brine, dried over Na ₂ S0 ₄ and concentrated under reduced pressure. The residue was purified by silica column to give 5-ethylindoline (2.5 g, 32%).

5-ethyl-6-nitroindolin

To a solution of 5-ethylindolin (2.5 g, 17 mmol) in H ₂ S0 ₄ (98%, 20 mL) was slowly added KNO ₃ (1.7 g, 17 mmol) at 0 ° C. The mixture was stirred at 0-10 ° C. for 10 minutes. The mixture was then carefully poured onto ice, basified to pH 9 with NaOH solution and extracted with ethyl acetate. The combined extracts were washed with brine, dried over Na ₂ SO ₄ and concentrated to dryness. The residue was purified by silica column to give 5-ethyl-6-nitroindolin (1.9 g, 58%).

5-ethyl-6-nitro-1H-indole

To a solution of 5-ethyl-6-nitroindolin (1.9 g, 9.9 mmol) in CH ₂ Cl ₂ (30 mL) was added MnO ₂ (4.0 g, 46 mmol). The mixture was stirred at ambient temperature for 8 hours. The solid was filtered off and the filtrate was concentrated to dryness to afford 5-ethyl-6-nitro-1H-indole (1.9 g).

5-ethyl-1H-indol-6-amine

Suspension of 5-ethyl-6-nitro-1H-indole (1.9 g, 10 mmol) and Raney nickel (1 g) was hydrogenated at room temperature under H ₂ (1 atm) for 2 hours. The catalyst was filtered off and the filtrate was concentrated to dryness. The residue was purified by silica gel column to give 5-ethyl-1H-indol-6-amine (760 mg, 48% over two steps).

Example 55 Ethyl 6-amino-1 H-indole-4-carboxylate

2-Methyl-3,5-dinitrobenzoic acid

HNO ₃ (95%, 80 mL) and H ₂ SO ₄ To the mixture of (98%, 80 mL) was slowly added 2-methylbenzoic acid (50 g, 0.37 mol) at 0 ° C. After addition, the reaction mixture was stirred at less than 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 afford 2-methyl-3,5-dinitrobenzoic acid (70 g, 84%).

Ethyl 2-methyl-3,5-dinitrobenzoate

SOCl ₂ A mixture of 2-methyl-3,5-dinitrobenzoic acid (50 g, 0.22 mol) in (80 mL) was heated at reflux for 4 h and then concentrated to dryness. The residue was dissolved in CH ₂ Cl ₂ (50 mL), to which EtOH (80 mL) was added and the mixture was stirred at rt for 1 h. The mixture was poured into ice water and extracted with EtOAc (3 x 100 mL). The combined extracts are washed with saturated Na ₂ CO ₃ (80 mL), water (2 × 100 mL) and brine (100 mL), dried over Na ₂ SO ₄ , concentrated to dryness and ethyl 2-methyl-3,5- Dinitrobenzoate (50 g, 88%) was obtained.

(E) -ethyl 2- (2- (dimethylamino) vinyl) -3,5-dinitrobenzoate

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 is poured into ice water and the precipitated solid is filtered and washed with water to give (E) -ethyl 2- (2- (dimethylamino) vinyl) -3,5-dinitrobenzoate (11 g, 48%). It was.

Ethyl 6-amino-1H-indole-4-carboxylate

A mixture of (E) -ethyl 2- (2- (dimethylamino) vinyl) -3,5-dinitrobenzoate (11 g, 0.037 mol) and SnCl ₂ (83 g, 0.37 mol) in ethanol was refluxed to 4 Heated for hours. The mixture was concentrated to dryness and the residue was poured into water and basified to pH 8 with saturated aqueous Na ₂ CO ₃ . The precipitated solid was filtered off and the filtrate was extracted with ethyl acetate (3 x 100 mL). The combined extracts were washed with water (2 × 100 mL) and brine (150 mL), dried over Na ₂ SO ₄ and concentrated to dryness. The residue was purified by column on silica gel to give ethyl 6-amino-1H-indole-4-carboxylate (3.0 g, 40%).

Example 56: 5-Fluoro-1H-indol-6-amine

1-fluoro-5-methyl-2,4-dinitrobenzene

HNO ₃ (60 mL) and H ₂ SO ₄ (80 mL) were added dropwise 1-fluoro-3-methylbenzene (28 g, 25 mmol) at a rate not exceeding 35 ° C. under ice-cooling. . The mixture was allowed to stir at room temperature for 30 minutes 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, about 7: 3 ratio) was taken Collected by filtration and purified by recrystallization from 50 mL isopropyl ether to give pure 1-fluoro-5-methyl-2,4-dinitro-benzene as a white solid (18 g, 36%). .

(E) -2- (5-fluoro-2,4-dinitrophenyl) -N, N-dimethylethenamine

A mixture of 1-fluoro-5-methyl-2,4-dinitro-benzene (10 g, 50 mmol), DMA (12 g, 100 mmol) and DMF (50 mL) was heated at 100 ° C. for 4 hours. . The solution was cooled down and poured into water. The precipitated red solid was collected, washed with water and dried to (E) -2- (5-fluoro-2,4-dinitrophenyl) -N, N-dimethylethenamine (8.0 g, 63%) Obtained.

5-fluoro-1H-indol-6-amine

Of (E) -2- (5-fluoro-2,4-dinitrophenyl) -N, N-dimethylethenamine (8.0 g, 31 mmol) and Raney nickel (8 g) in EtOH (80 mL) Suspension at room temperature with H ₂ (40 psi) was stirred 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-indol-6-amine (1.0 g, 16%). Obtained as a brown solid.

Example 57 5-chloro-1H-indol-6-amine

1-chloro-5-methyl-2,4-dinitrobenzene

HNO ₃ (55 mL) and H ₂ SO ₄ (79 mL) were added dropwise with 1-chloro-3-methylbenzene (25.3 g, 200 mmol) at a rate such that the temperature did not exceed 35 ° C. under ice-cooling. The mixture was allowed to stir at ambient temperature for 30 minutes and then poured into ice water (500 mL). The resulting precipitate was collected by filtration and purified by recrystallization to give 1-chloro-5-methyl-2,4-dinitrobenzene (26 g, 60%).

(E) -2- (5-chloro-2,4-dinitrophenyl) -N, N-dimethylethenamine

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 cooled down and poured into water. The precipitated red solid was collected by filtration, washed with water and dried to give (E) -2- (5-chloro-2,4-dinitrophenyl) -N, N-dimethylethenamine (9.84 g, 72 %) Was obtained.

5-chloro-1H-indol-6-amine

Suspension of (E) -2- (5-chloro-2,4-dinitrophenyl) -N, N-dimethylethenamine (9.8 g, 36 mmol) and Raney nickel (9.8 g) in EtOH (140 mL) Water was stirred at rt under H ₂ (1 atm) for 4 h. After filtration, the filtrate was concentrated and the residue was purified by column chromatograph (petroleum ether / ethyl acetate = 10: 1) to give 5-chloro-1H-indol-6-amine (0.97 g, 16%) as gray Obtained as a powder.

Example 58: ethyl 6-amino-1H-indole-7-carboxylate

3-Methyl-2,6-dinitrobenzoic acid

HNO ₃ (95%, 80 mL) and H ₂ SO ₄ To the mixture of (98%, 80 mL) was added slowly 3-methylbenzoic acid (50 g, 0.37 mol) at 0 ° C. After addition, the mixture was stirred at less than 30 ° C. for 1.5 hours. The mixture was then poured into ice water and stirred for 15 minutes. The precipitate solid was filtered and washed with water to give a mixture of 3-methyl-2,6-dinitro-benzoic acid and 5-methyl-2,4-dinitrobenzoic acid (70 g, 84%). To a solution of this mixture (70 g, 0.31 mol) in EtOH (150 mL) was added dropwise SOCl ₂ (54 g, 0.45 mol). The mixture was heated at reflux for 2 h and then concentrated to dryness under reduced pressure. The residue was partitioned between EtOAc (100 mL) and aqueous Na ₂ CO ₃ (10%, 120 mL). The organic layer was washed with brine (50 mL), dried over Na ₂ SO ₄ and concentrated to dryness to afford ethyl 5-methyl-2,4-dinitrobenzoate (20 g), which was collected. The aqueous layer was acidified to pH 2-3 with HCl and the solid precipitated was filtered, washed with water and dried in air to afford 3-methyl-2,6-dinitrobenzoic acid (39 g, 47%). .

Ethyl 3-methyl-2,6-dinitrobenzoate

3-Methyl-2,6-dinitrobenzoic acid (39 g, 0.15 mol) and SOCl ₂ (80 mL) was heated at reflux for 4 h. Excess SOCl ₂ was evaporated under reduced pressure and the residue was added dropwise to a solution of EtOH (100 mL) and Et ₃ N (50 mL). The mixture was stirred at 20 ° C. for 1 hour and then concentrated to dryness. The residue is dissolved in EtOAc (100 mL), washed with Na ₂ CO ₃ (10%, 40 mL × 2), water (50 mL × 2) and brine (50 mL), dried over Na ₂ SO ₄ and , Concentrated to give ethyl 3-methyl-2,6-dinitrobenzoate (20 g, 53%).

(E) -ethyl 3- (2- (dimethylamino) vinyl) -2,6-dinitrobenzoate

A mixture of ethyl 3-methyl-2,6-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. The precipitated solid was filtered and washed with water to give (E) -ethyl 3- (2- (dimethylamino) vinyl) -2,6-dinitrobenzoate (25 g, 58%).

Ethyl 6-amino-1H-indole-7-carboxylate

A mixture of (E) -ethyl 3- (2- (dimethylamino) vinyl) -2,6-dinitrobenzoate (30 g, 0.097 mol) and Raney nickel (10 g) in EtOH (1000 mL) at room temperature Hydrogenated at 50 psi for 2 hours. The catalyst was filtered off and the filtrate was concentrated to dryness. The residue was purified by column on silica gel to give ethyl 6-amino-1H-indole-7-carboxylate as off-white solid (3.2 g, 16%).

Example 59 ethyl 6-amino-1H-indole-5-carboxylate

(E) -ethyl 5- (2- (dimethylamino) vinyl) -2,4-dinitrobenzoate

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 is poured into ice water and the solid precipitated is filtered and washed with water to give (E) -ethyl 5- (2- (dimethylamino) vinyl) -2,4-dinitrobenzoate (15 g, 28%). It was.

Ethyl 6-amino-1H-indole-5-carboxylate

A mixture of (E) -ethyl 5- (2- (dimethylamino) vinyl) -2,4-dinitrobenzoate (15 g, 0.050 mol) and Raney nickel (5 g) in EtOH (500 mL) at room temperature Hydrogenated under 50 psi of hydrogen for 2 hours. The catalyst was filtered off and the filtrate was concentrated to dryness. The residue was purified by column on silica gel to give ethyl 6-amino-1H-indole-5-carboxylate (3.0 g, 30%).

Example 60 5-tert-butyl-1H-indol-6-amine

2-tert-butyl-4-methylphenyl diethyl phosphate

To a suspension of NaH (60% in mineral oil, 8.4 g, 0.21 mol) in THF (200 mL) was added a solution of 2-tert-butyl-4-methylphenol (33 g, 0.20 mol) in THF (100 mL). It was added dropwise at ℃. The mixture was stirred at 0 ° C. for 15 minutes, then chlorophosphate diethyl ester (37 g, 0.21 mol) was added dropwise at 0 ° C. After addition, the mixture was stirred at ambient temperature for 30 minutes. The reaction was quenched with saturated NH ₄ Cl (300 mL) and then extracted with Et ₂ O (350 mL × 2). The combined organic layers were washed with brine, dried over anhydrous Na ₂ SO _{4 and} then evaporated in vacuo to afford 2-tert-butyl-4-methylphenyl diethyl phosphate (contaminated with mineral oil) as a colorless oil (60 g, ˜100). %), Which was used directly in the next step.

1-tert-butyl-3-methylbenzene

Solution of 2-tert-butyl-4-methylphenyl diethyl phosphate in NH ₃ (liquid, 1000 mL) at -78 ° C. under N ₂ atmosphere (60 g, crude from last step, Et ₂ O (anhydrous, 500 mL) ) About 0.2 mol)). Lithium metal was added to the solution in small pieces until blue persisted. The reaction mixture was stirred at −78 ° C. for 15 minutes and then quenched with saturated NH ₄ Cl until the mixture turned colorless. Liquid NH ₃ was evaporated and the residue dissolved in water. The mixture was extracted with Et ₂ O (400 mL × 2). The combined organics were dried over Na ₂ SO ₄ and evaporated to give 1-tert-butyl-3-methylbenzene (contaminated with mineral oil) as a colorless oil (27 g, 91%), which was used directly in the next step. .

1-tert-butyl-5-methyl-2,4-dinitrobenzene and 1-tert-butyl-3-methyl-2,4-dinitro-benzene

To HNO ₃ (95%, 14 mL) was added H ₂ SO ₄ (98%, 20 mL) at 0 ° C., followed by 1-tert-butyl-3-methylbenzene (7.4 g, ˜50 mmol, final Crude material from the step) was added dropwise while maintaining the temperature below 30 ° C. The mixture was stirred at ambient temperature for 30 minutes, poured into crushed ice (100 g) and extracted with EtOAc (50 mL x 3). The combined organic layers were washed with water and brine and then evaporated to afford a brown oil which was purified by column chromatography to give 1-tert-butyl-5-methyl-2,4-dinitrobenzene and 1-tert-butyl A mixture of -3-methyl-2,4-dinitrobenzene (2: 1, by NMR) was obtained as a yellow oil (9.0 g, 61%).

(E) -2- (5-tert-butyl-2,4-dinitrophenyl) -N, N-dimethylethenamine

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 ) And DMA (5.4 g, 45 mmol) in DMF (50 mL) were heated at reflux for 2 hours and then cooled to room temperature. The reaction mixture was poured into water-ice and extracted with EtOAc (50 mL x 3). The combined organic layers were washed with water and brine and then evaporated to afford a brown oil, which was purified by column to give (E) -2- (5-tert-butyl-2,4-dinitrophenyl) -N, N -Dimethylethen-amine (5.0 g, 68%) was obtained.

5-tert-butyl-1H-indol-6-amine

(E) -2- (5-tert-butyl-2,4-dinitrophenyl) -N, N-dimethylethen-amine (5.3 g, 18 mmol) and tin (II) chloride in ethanol (200 mL) A solution of dihydrate (37 g, 0.18 mol) was heated at reflux overnight. The mixture was cooled to rt and the solvent was removed in vacuo. The residual slurry was diluted with water (500 mL) and basified to pH 8 with 10% aqueous Na ₂ CO ₃ . The resulting suspension was extracted with ethyl acetate (3 × 100 mL). The ethyl acetate extracts were washed with water and brine, dried over Na ₂ SO ₄ and concentrated. The residual solid was washed with CH ₂ Cl ₂ to give a yellow powder, which was purified by column chromatography to give 5-tert-butyl-1H-indol-6-amine (0.40 g, 12%).

General Procedure IV: Synthesis of Acylaminoindole

One equivalent of carboxylic acid and one equivalent of 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 allowed to stir. The crude product was purified by reverse phase preparative liquid chromatography to give pure product.

Example 61 N- (2-tert-butyl-1H-indol-5-yl) -1- (4-methoxyphenyl) -cyclopropanecarboxamide

2-tert-butyl-1H-indol-5-amine (19 mg, 0.10 mmol) and 1- (4-methoxyphenyl) -cyclopropanecarboxylic acid (19 mg, 0.10 mmol) were triethylamine (28 μL , 0.20 mmol) in N, N-dimethylformamide (1.00 mL). 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 It was allowed to stir for 3 hours. The crude reaction mixture was filtered and purified by reverse phase HPLC.

General Procedure V: Synthesis of Acylaminoindole

One equivalent of the appropriate carboxylic acid was placed in an oven-drying flask under nitrogen. A minimum amount (3 equivalents) of thionyl chloride and a catalytic amount of N, N-dimethylformamide were added and the solution was allowed to stir at 60 ° C. for 20 minutes. Excess thionyl chloride was removed under vacuum and the resulting solid was suspended in a minimum amount of anhydrous pyridine. This solution was slowly added to a stirred solution of 1 equivalent of a suitable amine dissolved in a minimum amount of anhydrous pyridine. The resulting mixture was allowed to stir at 110 ° C. for 15 hours. The mixture was evaporated to dryness, suspended in dichloromethane and extracted three times with 1N HCl. The organic layer was then dried over sodium sulphate, 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).

1-Benzo [1,3] dioxol-5-yl-cyclopropanecarboxylic acid (2.07 g, 10.0 mmol) was dissolved in thionyl chloride (2.2 mL) under N ₂ . N, N-dimethylformamide (0.3 mL) was added and the solution was allowed to stir for 30 minutes. Excess thionyl chloride was removed under vacuum and the resulting 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 of anhydrous dichloromethane was slowly added to the reaction. The resulting solution was allowed to stir for 1 hour. The reaction mixture was diluted to 50 mL with dichloromethane and washed three times with 1N HCl, saturated aqueous sodium bicarbonate, 50 mL and saturated aqueous sodium chloride. The organic layer was dried over sodium sulphate and evaporated to dryness to ethyl 5- (1- (benzo [d] [1,3] dioxol-5-yl) cyclopropanecarboxamido) -1H-indole-2-carboxyl The rate was obtained as a gray solid (3.44 g, 88%).

Example 63 1- (benzo [d] [1,3] dioxol-5-yl) -N- (2-tert-butyl-1H-indol-5-yl) cyclopropanecarboxamide

1-Benzo [1,3] dioxol-5-yl-cyclopropanecarboxylic acid (1.09 g, 5.30 mmol) was dissolved in 2 mL 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. Excess thionyl chloride was evaporated and the resulting residue was dissolved in 15 mL of dichloromethane. This solution was slowly added to a solution of 2-tert-butyl-1H-indol-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 allowed to stir for 10 minutes. The solvent was evaporated to dryness and the crude reaction mixture was purified by silica gel column chromatography using a gradient of 5-50% ethyl acetate in hexanes. Pure fractions were combined and evaporated to dryness to give a pale pink powder (1.24 g 62%).

Example 64 1- (benzo [d] [1,3] dioxol-5-yl) -N- (1-methyl-2- (1-methylcyclopropyl) -1H-indol-5-yl) cyclo Propanecarboxamide

1-methyl-2- (1-methylcyclopropyl) -1H-indol-5-amine (20.0 mg, 0.100 mmol) and 1- (benzo [d] [1,3] dioxol-5-yl) cyclopropane Carboxylic acid (20.6 mg, 0.100 mmol) was dissolved in N, N-dimethylformamide (1 mL) containing a magnetic rod for stirring and containing triethylamine (42.1 μL, 0.300 mmol). 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 It was allowed to stir at 80 ° C. for 6 hours. The crude product is then purified by preparative HPLC using a gradient of 0-99% acetonitrile in water containing 0.05% trifluoroacetic acid to give 1- (benzo [d] [1,3] dioxol-5- Il) -N- (1-methyl-2- (1-methylcyclopropyl) -1H-indol-5-yl) cyclopropanecarboxamide was obtained.

Example 65 1- (benzo [d] [1,3] dioxol-5-yl) -N- (1,1-dimethyl-2,3-dihydro-1H-pyrrolo [1,2-a ] Indol-7-yl) cyclopropanecarboxamide

1,1-dimethyl-2,3-dihydro-1H-pyrrolo [1,2-a] indol-7-amine (40.0 mg, 0.200 mmol) and 1- (benzo [d] [1,3] di Oxol-5-yl) cyclopropanecarboxylic acid (41.2 mg, 0.200 mmol) is a N, N-dimethylformamide (1 mL) containing a magnetic rod for stirring and containing triethylamine (84.2 μL, 0.600 mmol). In water. 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 It was allowed to stir at room temperature for 5 minutes. The crude product is then purified by preparative HPLC using a gradient of 0-99% acetonitrile in water containing 0.05% trifluoroacetic acid to give 1- (benzo [d] [1,3] dioxol-5- Il) -N- (1,1-dimethyl-2,3-dihydro-1H-pyrrolo [1,2-a] -indol-7-yl) cyclopropanecarboxamide was obtained.

Example 66 Methyl 5- (1- (benzo [d] [1,3] dioxol-5-yl) cyclopropanecarboxamido) -2-tert-butyl-1H-indole-7-carboxylate

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-car Voxylate (49.3 mg, 0.200 mmol) was dissolved in N, N-dimethylformamide (2 mL) containing a stirring magnetic rod and containing triethylamine (0.084 mL, 0.60 mmol). The resulting solution was allowed to stir at room temperature for 10 minutes. The crude product is then purified by preparative HPLC using a gradient of 0-99% acetonitrile in water containing 0.05% trifluoroacetic acid to give methyl 5- (1- (benzo [d] [1,3] di Oxol-5-yl) cyclopropanecarbox-amido) -2-tert-butyl-1H-indole-7-carboxylate was obtained.

Example 67 1- (benzo [d] [1,3] dioxol-5-yl) -N- (2- (1-hydroxy-2-methylpropan-2-yl) -1H-indole-5 -Yl) cyclopropanecarboxamide

HBTU (0.138 g, 0.36 mmol) in a solution of 1- (benzo [d] [1,3] dioxol-5-yl) cyclopropanecarboxylic acid (0.075 g, 0.36 mmol) in acetonitrile (1.5 mL) and Et ₃ N (152 μL, 1.09 mmol) was added at room temperature. The mixture was stirred at rt for 10 min, then 2- (5-amino-1 H-indol-2-yl) -2-methylpropan-1-ol (0.074 g, 0.36 mmol) in acetonitrile (1.94 mL) The solution was added. After addition, the reaction mixture was stirred at rt for 3 h. The solvent was evaporated under reduced pressure and the residue was dissolved in dichloromethane. The organic layer was washed with 1N HCl (1 x 3 mL) and saturated aqueous NaHCO ₃ Washed with (1 x 3 mL). The organic layer was dried over Na ₂ S0 ₄ , filtered and evaporated under reduced pressure. The crude material was purified by column chromatography on silica gel (ethyl acetate / hexane = 1/1) to give 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%) was obtained.

Example 67 1- (benzo [d] [1,3] dioxol-5-yl) -N- (2,3,4,9-tetrahydro-1H-carbazol-6-yl) cyclopropane Carboxamide

2,3,4,9-tetrahydro-1H-carbazole-6-amine (81.8 mg, 0.439 mmol) and 1- (benzo [d] [1,3] dioxol-5-yl) cyclopropanecar Acid (90.4 mg, 0.439 mmol) was dissolved in acetonitrile (3 mL) containing a magnetic bar for stirring and containing diisopropylethylamine (0.230 mL, 1.32 mmol). O- (7-azabenzotriazol-1-yl) -N, N, N ', N'-tetramethyluronium hexafluorophosphate (183 mg, 0.482 mmol) was added to the mixture and the resulting solution was It was allowed to stir at 70 ° C. for 16 hours. The solvent was evaporated and the crude product was then purified by 40 g of silica gel using a gradient of 5-50% ethyl acetate in hexanes and after drying 1- (benzo [d] [1,3] dioxol-5-yl ) -N- (2,3,4,9-tetrahydro-1H-carbazol-6-yl) cyclopropanecarboxamide was obtained as a beige powder (0.115 g, 70%).

Example 69 tert-butyl 4- (5- (1- (benzo [d] [1,3] dioxol-5-yl) cyclopropanecarbox-amido) -1H-indol-2-yl) pi Ferridine-1-carboxylate

1- (benzo [d] [1,3] dioxol-5-yl) cyclopropanecarbonyl chloride (43 mg, 0.19 mmol) and tert-butyl 4- (5-amino-1H-indol-2-yl) Piperidine-1-carboxylate (60 mg, 0.19 mmol) was dissolved in dichloromethane (1 mL) containing a magnetic rod for stirring and containing triethylamine (0.056 mL, 0.40 mmol). The resulting solution was allowed to stir at room temperature for 2 days. The crude product is then evaporated to dryness, dissolved in a minimum amount of N, N-dimethylformamide, and then purified by preparative HPLC using a gradient of 0-99% acetonitrile in water containing 0.05% trifluoroacetic acid. Tert-butyl 4- (5- (1- (benzo [d] [1,3] dioxol-5-yl) cyclopropanecarboxamido) -1H-indol-2-yl) piperidine-1 -Carboxylate was obtained.

Example 70: ethyl 2- (5- (1- (benzo [d] [1,3] dioxol-5-yl) cyclopropanecarboxamido) -1H-indol-2-yl) propanoate

tert-butyl 2- (1-ethoxy-1-oxopropan-2-yl) -1H-indole-1-carboxylate

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. . 0.5M solution of potassium hexamethyldisilazane (20 mL, 9.9 mmol) was added slowly to maintain the internal temperature below -60 ° C. Stirring was continued at -78 ° C for 1 hour. Methyl iodide (727 μL, 11.7 mmol) was added to the mixture. The mixture was stirred at rt for 30 min. The mixture was quenched with saturated aqueous ammonium chloride and partitioned between water and dichloromethane. The aqueous phase was extracted with dichloromethane and the combined organic phases were dried over Na ₂ SO ₄ and evaporated under reduced pressure. The residue was purified by column chromatography on silica gel (ethylacetate / hexane = 1/9) to tert-butyl 2- (1-ethoxy-1-oxopropan-2-yl) -1H-indole-1-car Cylates (2.8 g, 88%) were obtained.

Ethyl 2- (1H-indol-2-yl) propanoate

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) and then TFA (9.8 mL) was added. The mixture was stirred at rt for 1.5 h. The mixture was evaporated to dryness, taken up in dichloromethane and washed with saturated aqueous sodium bicarbonate, water, and brine. The product was purified by column chromatography on silica gel (0-20% EtOAc in hexanes) to give ethyl 2- (1H-indol-2-yl) propanoate (0.92 g, 50%).

Ethyl 2- (5-nitro-1H-indol-2-yl) propanoate

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. Stirring was continued for another 30 minutes at -10 ° C. The mixture was poured on ice and the product extracted with ethyl acetate. The combined organic phases were washed with a small amount of saturated aqueous sodium bicarbonate. The product was purified by column chromatography on silica gel (5-30% EtOAc in hexane) to give ethyl 2- (5-nitro-1H-indol-2-yl) propanoate (0.34 g, 31%).

Ethyl 2- (5-amino-1 H-indol-2-yl) propanoate

To a solution of ethyl 2- (5-nitro-1H-indol-2-yl) propanoate (0.10 g, 0.38 mmol) in ethanol (4 mL) was added tin chloride dihydrate (0.431 g, 1.91 mmol). The mixture was heated in microwave at 120 ° C. for 1 hour. The mixture was diluted with ethyl acetate and then water and saturated aqueous NaHCO ₃ were added. The reaction mixture was filtered through a plug of celite using ethyl acetate. The organic layer was separated from the aqueous layer. The organic layer was dried over Na ₂ SO ₄ , filtered and evaporated under reduced pressure to give ethyl 2- (5-amino-1H-indol-2-yl) propanoate (0.088 g, 99%).

Ethyl 2- (5- (1- (benzo [d] [1,3] dioxol-5-yl) cyclopropanecarboxamido) -1H-indol-2-yl) propanoate

HBTU (0.146 g, 0.384 mmol) in a solution of 1- (benzo [d] [1,3] dioxol-5-yl) cyclopropanecarboxylic acid (0.079 g, 0.384 mmol) in acetonitrile (1.5 mL) and Et ₃ N (160 μL, 1.15 mmol) was added at room temperature. The mixture was allowed to stir at room temperature for 10 minutes and then a solution of ethyl 2- (5-amino-1 H-indol-2-yl) propanoate (0.089 g, 0.384 mmol) in acetonitrile (2.16 mL) was added. . After addition, the reaction mixture was stirred at rt for 2 h. The solvent was evaporated under reduced pressure and the residue was dissolved in dichloromethane. The organic layer was washed with 1N HCl (1 × 3 mL) followed by saturated aqueous NaHCO _3. Washed with (1 x 3 mL). The organic layer was dried over Na ₂ S0 ₄ , filtered and evaporated under reduced pressure. The crude material was purified by column chromatography on silica gel (ethyl acetate / hexane = 1/1) to give ethyl 2- (5- (1- (benzo [d] [1,3] dioxol-5-yl) cyclopropane Carboxamido) -1H-indol-2-yl) propanoate (0.081 g, 50%) was obtained.

Example 71 tert-butyl 2- (5- (1- (benzo [d] [1,3] dioxol-5-yl) cyclopropanecarbox-amido) -1H-indol-2-yl)- 2-methylpropylcarbamate

2-Methyl-2- (5-nitro-1H-indol-2-yl) propanoic acid

Ethyl 2-methyl-2- (5-nitro-1H-indol-2-yl) propanoate (4.60 g, 16.7 mmol) was dissolved in THF / water (2: 1, 30 mL). LiOH.H ₂ O (1.40 g, 33.3 mmol) was added and the mixture was stirred at 50 ° C. for 3 hours. The mixture was acidified by careful addition of 3N HCl. The product was extracted with ethyl acetate and the combined organic phases were washed with brine and dried over magnesium sulfate to give 2-methyl-2- (5-nitro-1H-indol-2-yl) propanoic acid (4.15 g, 99%) Obtained.

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), Et ₃ N (6.9 mL, 0.050 mmol) and ammonium chloride (1.34 g, 0.025 mmol) were added and the mixture was stirred at rt overnight. Water was added and the mixture was extracted with ethyl 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%).

2-methyl-2- (5-nitro-1H-indol-2-yl) propan-1-amine

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. Borane-THF complex solution (1.0 M, 2.4 mL, 2.4 mmol) was added slowly and the mixture was allowed to stir 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 alkaline with 50% NaOH and the mixture was extracted with ethyl acetate. The combined organic layers were dried over magnesium sulfate, filtered and evaporated to afford 2-methyl-2- (5-nitro-1H-indol-2-yl) propan-1-amine (82 mg, 43%).

tert-butyl 2-methyl-2- (5-nitro-1H-indol-2-yl) propylcarbamate

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. Et ₃ N (82 μL, 0.59 mmol) and di-tert-butyl dicarbonate (129 mg, 0.587 mmol) were added and the mixture was stirred at rt overnight. Water was added and the mixture was extracted with ethyl acetate. The residue was purified by silica gel chromatography (10-40% ethyl acetate in hexanes) to give tert-butyl 2-methyl-2- (5-nitro-1H-indol-2-yl) propylcarbamate (131 mg, 67%) was obtained.

tert-butyl 2- (5-amino-1 H-indol-2-yl) -2-methylpropylcarbamate

Ammonium fort in 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) Mate (60 mg, 0.96 mmol) was added followed by 10% Pd / C (50 mg). The mixture was stirred at rt for 45 min. Pd / C was filtered off and the organic solvent was removed by evaporation. The remaining aqueous phase was extracted with dichloromethane. The combined organic phases were dried over magnesium sulphate and evaporated to afford tert-butyl 2- (5-amino-1 H-indol-2-yl) -2-methylpropylcarbamate (58 mg, 80%).

tert-butyl 2- (5- (1- (benzo [d] [1,3] dioxol-5-yl) cyclopropanecarboxamido) -1H-indol-2-yl) -2-methylpropylcart Barmate

tert-butyl 2- (5-amino-1 H-indol-2-yl) -2-methylpropylcarbamate (58 mg, 0.19 mmol), 1- (benzo [d] [1,3] dioxol-6 -Yl) cyclopropanecarboxylic acid (47 mg, 0.23 mmol), EDC (45 mg, 0.23 mmol), HOBt (31 mg, 0.23 mmol) and Et ₃ N (80 μL, 0.57 mmol) in DMF (4 mL) Dissolved in 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 sulphate and evaporated to dryness. The residue was purified by silica gel chromatography (10-30% ethyl acetate in hexane) to give tert-butyl 2- (5- (1- (benzo [d] [1,3] dioxol-5-yl) cyclopropane Carboxamido) -1H-indol-2-yl) -2-methylpropyl-carbamate (88 mg, 94%) was obtained.

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

(R) -2-tert-butyl-1-((2,2-dimethyl-1,3-dioxolan-4-yl) methyl) -5-nitro-1H-indole

To a stirred solution of (S)-(2,2-dimethyl-1,3-dioxolan-4-yl) methyl 4-methylbenzenesulfonate (1.58 g, 5.50 mmol) in anhydrous DMF (10 mL) under nitrogen gas. 2-tert-butyl-5-nitro-1H-indole (1.00 g, 4.58 mmol) was added followed by Cs ₂ CO ₃ (2.99 g, 9.16 mol). The mixture was stirred and heated at 80 ° C. under nitrogen gas. After 20 hours, the conversion was observed by LCMS to be 50%. The reaction mixture was prepared with Cs ₂ CO ₃ (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 h. The reaction mixture was cooled to room temperature. The solid was 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 Na ₂ S0 ₄ , filtered and evaporated under reduced pressure. The residue was purified by column chromatography on silica gel (dichloromethane / hexane = 1.5 / 1) to give (R) -2-tert-butyl-1-((2,2-dimethyl-1,3-dioxolane-4 -Yl) methyl) -5-nitro-1H-indole (1.0 g, 66%) was obtained.

(R) -2-tert-butyl-1-((2,2-dimethyl-1,3-dioxolan-4-yl) methyl-1H-indol-5-amine

(R) -2-tert-butyl-1-((2,2-dimethyl-1,3-dioxolan-4-yl) methyl) -5-nitro- in ethanol (20 mL) and water (5 mL) To a stirred solution of 1H-indole (1.0 g, 3.0 mmol) was added ammonium formate (0.76 g, 12 mmol), followed by the slow dropwise addition of 10% palladium on carbon (0.4 g). The mixture was stirred at rt for 1 h. The reaction mixture was filtered through a plug of celite and rinsed with 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 Na ₂ SO ₄ , filtered and evaporated under reduced pressure to give (R) -2-tert-butyl-1-((2,2-dimethyl-1,3-dioxolan-4-yl) methyl -1H-indol-5-amine (0.89 g, 98%) was obtained.

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- (benzo [d] [1,3] dioxol-5-yl) cyclopropanecarboxylic acid (0.73 g, 3.0 mmol) was dissolved in thionyl chloride (660 μL, 9.0 mmol) and DMF (20 μL) at room temperature. Was added. After the mixture was stirred for 30 minutes, the excess thionyl chloride was evaporated under reduced pressure. To the resulting acid chloride, dichloromethane (6.0 mL) and Et ₃ N (2.1 mL, 15 mmol) were added. (R) -2-tert-butyl-1-((2,2-dimethyl-1,3-dioxolan-4-yl) methyl-1H-indol-5-amine (3.0 mmol) in dichloromethane (3.0 mL) The reaction mixture was stirred for 45 minutes at room temperature The reaction mixture was filtered and the filtrate was evaporated under reduced pressure The residue was column chromatographed on silica gel Purification with (ethyl acetate / hexane = 3/7) 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 (1.33 g, 84%) was obtained. .

N-((R) -2-tert-butyl-1-((2,3-dihydroxypropyl) -1H-indol-5-yl) -1- (2,2-difluorobenzo- [d ] [1,3] dioxol-5-yl) cyclopropanecarboxamide

N- (2-tert-butyl-1-((2,2-dimethyl-1,3-dioxolan-4-yl) methyl) -1H-indole-5 in methanol (34 mL) and water (3.7 mL) Para-toluenesulfonic acid in a stirred solution of -yl) -1- (2,2-difluorobenzo [d] [1,3] dioxol-5-yl) cyclopropanecarboxamide (1.28 g, 2.43 mmol) -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 NaHCO ₃ (2 × 10 mL) and brine (2 × 10 mL). The organic layer was dried over Na ₂ S0 ₄ , filtered and evaporated under reduced pressure. The residue was purified by column chromatography on silica gel (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%) was obtained.

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

3- (2-tert-butyl-5- (1- (2,2-difluorobenzo [d] [1,3] dioxol-5-yl) cyclopropanecarbox-amido) -1H-indole -1-yl) -2-oxopropanoic acid

N- (2-tert-butyl-1- (2,3-dihydroxypropyl) -1H-indol-5-yl) -1- (2,2-difluorobenzo [d in DMSO (1 mL) To the solution of [1,3] dioxol-5-yl) cyclopropane-carboxamide (97 mg, 0.20 mmol) was added des-martin periodinan (130 mg, 0.30 mmol). The mixture was stirred at rt for 3 h. The solid was filtered off and washed with EtOAc. 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 MgSO ₄ . After removal of the solvent, the residue was purified by preparative TLC to give 3- (2-tert-butyl-5- (1- (2,2-difluorobenzo [d] [1,3] dioxol-5- I) cyclopropanecarboxamido) -1H-indol-1-yl) -2-oxopropanoic acid was obtained, which was used without further purification.

3- (2-tert-butyl-5- (1- (2,2-difluorobenzo [d] [1,3] dioxol-5-yl) cyclopropanecarbox-amido) -1H-indole -1-yl) -2-hydroxypropanoic acid

3- (2-tert-butyl-5- (1- (2,2-difluorobenzo [d] [1,3] dioxol-5-yl) cyclopropanecarboxamido in MeOH (1 mL) NaBH _{4 in} a solution of) -1H-indol-1-yl) -2-oxopropanoic acid (50 mg, 0.10 mmol) (19 mg, 0.50 mmol) was added at 0 ° C. The mixture was stirred at rt for 15 min. 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 MgSO ₄ . After removal of the solvent, the residue is taken up 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) -1H-indol-1-yl) -2-hydroxypropanoic acid was obtained.

Example 74: (R) -N- (2-tert-butyl-1- (2,3-dihydroxypropyl) -1H-indol-5-yl) -1- (2,2-diduteriumbenzo [ d] [1,3] dioxol-5-yl) cyclopropanecarboxamide

Methyl 1- (3,4-dihydroxyphenyl) cyclopropanecarboxylate

To a solution of 1- (3,4-dihydroxyphenyl) cyclopropanecarboxylic acid (190 mg, 1.0 mmol) in MeOH (3 mL) was added 4-methylbenzenesulfonic acid (19 mg, 0.10 mmol). The mixture was heated at 80 ° C overnight. The reaction mixture was concentrated in vacuo and partitioned between EtOAc and water. The aqueous layer was extracted twice with EtOAc and the combined organic layers were washed with saturated NaHCO ₃ and brine and dried over MgSO ₄ . After removal of the solvent, the residue was dried under vacuum to afford methyl 1- (3,4-dihydroxyphenyl) cyclopropanecarboxylate (190 mg, 91%), which was used without further purification.

Methyl 1- (2,2-dideuteriumbenzo [d] [1,3] dioxol-5-yl) cyclopropanecarboxylate

Cs ₂ CO ₃ in a solution of methyl 1- (3,4-dihydroxyphenyl) cyclopropanecarboxylate (21 mg, 0.10 mmol) and CD ₂ Br ₂ (35 mg, 0.20 mmol) in DMF (0.5 mL). (19 mg, 0.10 mmol) was added. 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 1N NaOH and brine and then dried over MgSO ₄ . After removal of the solvent, the residue was dried in vacuo to afford methyl 1- (2,2-didutheliumbenzo [d] [1,3] dioxol-5-yl) cyclopropanecarboxylate (22 mg). This was used without further purification.

1- (2,2-dideuteriumbenzo [d] [1,3] dioxol-5-yl) cyclopropanecarboxylic acid

NaOH (1N) in a solution of methyl 1- (2,2-dideuteriumbenzo [d] [1,3] dioxol-5-yl) cyclopropanecarboxylate (22 mg, 0.10 mmol) in THF (0.5 mL) , 0.25 mL, 0.25 mmol) was added. The mixture was heated at 80 ° C. for 2 hours. The reaction mixture was partitioned between EtOAc and 1N NaOH. The aqueous layer was extracted twice with EtOAc, neutralized with 1N HCl and extracted twice with EtOAc. The combined organic layers were washed with brine and dried over MgSO ₄ . After removal of the solvent, the residue was dried under vacuum to afford 1- (2,2-didutheliumbenzo [d] [1,3] dioxol-5-yl) cyclopropanecarboxylic acid (21 mg), It was used without further purification.

(R) -N- (2-tert-butyl-1-((2,2-dimethyl-1,3-dioxolan-4-yl) methyl) -1H-indol-5-yl) -1- (2 , 2-dideuteriumbenzo [d] [1,3] dioxol-5-yl) cyclopropanecarboxamide

1- (2,2-Duditheliumbenzo [d] [1,3] dioxol-5-yl) cyclopropanecarboxylic acid (21 mg, 0.10 mmol) in DMF (1 mL), (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 To the solution of) 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 and then dried over MgSO ₄ . After removing 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) -Dioxolan-4-yl) methyl) -1H-indol-5-yl) -1- (2,2-dideuteriumbenzo [d] [1,3] dioxol-5-yl) cyclopropanecarboxamide (24 mg, 49% from methyl 1- (3,4-dihydroxyphenyl) cyclopropanecarboxylate) was obtained.

(R) -N- (2-tert-butyl-1- (2,3-dihydroxypropyl) -1H-indol-5-yl) -1- (2,2-dideuterium-benzo [d] [ 1,3] dioxol-5-yl) cyclopropanecarboxamide

(R) -N- (2-tert-butyl-1-((2,2-dimethyl-1,3-dioxolan-4-yl) methyl) -1H in methanol (0.5 mL) and water (0.05 mL) -Indol-5-yl) -1- (2,2-dideuterium-benzo [d] [1,3] dioxol-5-yl) cyclopropanecarboxamide (24 mg, 0.050 mmol) in 4 Methylbenzenesulfonic acid (2.0 mg, 0.010 mmol) was added. 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 ₃ and brine and then dried over MgSO ₄ . After removal of the solvent, the residue was purified by preparative HPLC to give (R) -N- (2-tert-butyl-1-((2,2-dimethyl-1,3-dioxolan-4-yl) methyl) -1H-indol-5-yl) -1- (2,2-dideuteriumbenzo [d] [1,3] dioxol-5-yl) cyclopropanecarboxamide (12 mg, 52%) was obtained. .

Single-deuterated analogs for this compound can be synthesized by replacing reagent CD ₂ BR ₂ with CHDBR ₂ and following the procedure described in Example 74. In addition, mono-deuterated analogs of other compounds of the invention can be synthesized by replacing reagent CD ₂ BR ₂ with CHDBR ₂ and following the steps described herein.

Example 75: 4- (5- (1- (benzo [d] [1,3] dioxol-5-yl) cyclopropanecarboxamido) -1H-indol-2-yl) -4-methylphene Carbonic acid

1- (benzo [d] [1,3] dioxol-5-yl) -N- (2- (4-cyano-2-methylbutan-2-yl) -1H-indol-5-yl) cyclo Propanecarboxamide

Dissolve thionyl chloride (72 μL, 0.99 mmol) and DMF (20 μL) in 1- (benzo [d] [1,3] dioxol-5-yl) cyclopropanecarboxylic acid (0.068 g, 0.33 mmol). Was added. After the mixture was stirred for 30 minutes, the excess thionyl chloride was evaporated under reduced pressure. To the resulting acid chloride, dichloromethane (0.5 mL) and Et ₃ N (230 μL, 1.7 mmol) were added. A solution of 4- (5-amino-1 H-indol-2-yl) -4-methylpentanenitrile (0.33 mmol) in dichloromethane (0.5 mL) was added to the acid chloride solution and the mixture was stirred at room temperature for 1.5 hours. It was. The resulting mixture was diluted with dichloromethane and washed with 1N HCl (2 × 2 mL), saturated aqueous NaHCO ₃ (2 × 2 mL) and brine (2 × 2 mL). The organic layer was dried over anhydrous Na ₂ SO ₄ and evaporated under reduced pressure to yield 1- (benzo [d] [1,3] dioxol-5-yl) -N- (2- (4-cyano-2-methyl Butan-2-yl) -1H-indol-5-yl) cyclopropanecarboxamide was obtained.

4- (5- (1- (benzo [d] [1,3] dioxol-5-yl) cyclopropanecarboxamido) -1H-indol-2-yl) -4-methylpentanoic acid

1- (benzo [d] [1,3] dioxol-5-yl) -N- (2- (4-cyano-2-methylbutan-2-yl) in 50% EtOH / water (2 mL) A mixture of -1H-indol-5-yl) cyclopropanecarboxamide (0.060 g, 0.15 mmol) and KOH (0.081 g, 1.5 mmol) was heated with microwave 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 reverse phase preparative HPLC to afford 4- (5- (1- (benzo [d] [1,3] dioxol-5-yl) cyclopropanecar Voxamido) -1H-indol-2-yl) -4-methylpentanoic acid was obtained.

Example 76: 1- (benzo [d] [1,3] dioxol-5-yl) -N- (2- (1-hydroxypropan-2-yl) -1H-indol-5-yl) cyclo Propanecarboxamide

2- (5-nitro-1H-indol-2-yl) propan-1-ol

To a cooled solution of LiAlH ₄ (1.0 M in THF, 1.2 mL, 1.2 mmol) in THF (5.3 mL) at 0 ° C. ethyl 2- (5-nitro-1H-indol-2-yl) in THF (3.66 mL) A solution of propanoate (0.20 g, 0.76 mmol) was added dropwise. After 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 added slowly, followed by careful addition of 15% NaOH (2 mL) and water (4 mL). The mixture was stirred at rt for 0.5 h and then filtered through a short plug of celite using ethyl acetate. The organic layer was separated from the aqueous layer, dried over Na ₂ SO ₄ , filtered and evaporated under reduced pressure. The residue was purified by column chromatography on silica gel (ethyl acetate / hexane = 1/1) to give 2- (5-nitro-1H-indol-2-yl) propan-1-ol (0.14 g, 81%). Obtained.

2- (5-amino-1H-indol-2-yl) propan-1-ol

To a solution of 2- (5-nitro-1H-indol-2-yl) propan-1-ol (0.13 g, 0.60 mmol) in ethanol (5 mL) was added tin chloride dihydrate (0.67 g, 3.0 mmol). . The mixture was heated in microwave at 120 ° C. for 1 hour. The mixture was diluted with ethyl acetate and then water and saturated aqueous NaHCO ₃ were added. The reaction mixture was filtered through a plug of celite using ethyl acetate. The organic layer was separated from the aqueous layer, dried over Na ₂ SO ₄ , filtered and evaporated under reduced pressure to afford 2- (5-amino-1 H-indol-2-yl) propan-1-ol (0.093 g, 82% ) Was obtained.

1- (benzo [d] [1,3] dioxol-5-yl) -N- (2- (1-hydroxypropan-2-yl) -1H-indol-5-yl) cyclopropanecarboxamide

HBTU (0.185 g, 0.49 mmol) in a solution of 1- (benzo [d] [1,3] dioxol-5-yl) cyclopropanecarboxylic acid (0.10 g, 0.49 mmol) in acetonitrile (2.0 mL) and Et ₃ N (205 μL, 1.47 mmol) was added at room temperature. The mixture was allowed to stir at room temperature for 10 minutes, after which a slurry of 2- (5-amino-1H-indol-2-yl) propan-1-ol (0.093 g, 0.49 mmol) in acetonitrile (2.7 mL) was added. It was. After addition, the reaction mixture was stirred at rt for 5.5 h. The solvent was evaporated under reduced pressure and the residue was dissolved in dichloromethane. The organic layer was washed with 1N HCl (1 x 3 mL) and saturated aqueous NaHCO ₃ Washed with (1 x 3 mL). The organic layer was dried over Na ₂ S0 ₄ , filtered and evaporated under reduced pressure. The crude material was purified by column chromatography on silica gel (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%) was obtained.

Example 77 1- (benzo [d] [1,3] dioxol-5-yl) -N- (2-tert-butyl-1H-indol-5-yl) -N-methylcyclopropanecarboxamide

1- (benzo [d] [1,3] dioxol-5-yl) -N- (2-tert-butyl-1H-indol-5-yl) -N-methylcyclopropanecarboxamide

2-tert-butyl-N-methyl-1H-indol-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) was dissolved in N, N-dimethylformamide (1 mL) containing a stirring magnetic rod and containing triethylamine (42.1 μL, 0.300 mmol). 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 It was allowed to stir at 80 ° C. for 16 hours. The crude product is then purified by preparative HPLC using a gradient of 0-99% acetonitrile in water containing 0.05% trifluoroacetic acid to give 1- (benzo [d] [1,3] dioxol-5- Il) -N- (2-tert-butyl-1H-indol-5-yl) -N-methylcyclopropanecarboxamide was obtained.

Example 78: N- (2-tert-butyl-1-methyl-1H-indol-5-yl) -1- (benzo [d] [1,3] dioxol-6-yl) -N-methylcyclo Propanecarboxamide

Sodium hydride (0.028 g, 0.70 mmol, 60% by weight dispersion in oil) was mixed with N- (2-tert- in a mixture of 4.5 mL of anhydrous tetrahydrofuran (THF) and 0.5 mL of anhydrous N, N-dimethylformamide (DMF). To a stirred solution of butyl-1H-indol-5-yl) -1- (benzo [d] [1,3] dioxol-6-yl) cyclopropanecarboxamide (0.250 g, 0.664 mmol) was added slowly. The resulting suspension was allowed to stir 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 consume all the starting materials, which were monitored by LC / MS. The crude reaction product was evaporated to dryness, redissolved in minimal amount of DMF and purified by preparative LC / MS chromatography to give pure product (0.0343 g, 13%).

Example 79 1- (benzo [d] [1,3] dioxol-5-yl) -N- (2- (hydroxymethyl) -1H-indol-5-yl) cyclopropanecarboxamide

Ethyl 5- (1- (benzo [d] [1,3] dioxol-5-yl) cyclopropanecarboxamido) -1H-indole-2-carboxylate (1.18 g, 3.0 mmol) was diluted with THF ( 10 mL) and water (0.1 mL) to a solution of LiBH ₄ (132 mg, 6.0 mmol). The mixture was allowed to stir at 25 ° C. for 16 h and then quenched with water (10 mL) and acidified slowly by addition of 1N HCl. The mixture was extracted three times with 50-mL portions of ethyl acetate. The organic extract was dried over Na ₂ SO ₄ and evaporated to 1- (benzo [d] [1,3] dioxol-5-yl) -N- (2- (hydroxymethyl) -1H-indole-5- I) cyclopropanecarboxamide (770 mg, 73%) was obtained. Small amounts were further purified by reverse phase HPLC.

Example 80: 5- (1- (benzo [d] [1,3] dioxol-5-yl) cyclopropanecarboxamido) -N-tert-butyl-1H-indole-2-carboxamide

5- (1- (benzo [d] [1,3] dioxol-5-yl) cyclopropanecarboxamido) -1H-indole-2-carboxylic acid

Ethyl 5- (1- (benzo [d] [1,3] dioxol-5-yl) cyclopropanecarboxamido) -1H-indole-2-carboxylate (392 mg, 1.0 mmol) and LiOH ( 126 mg, 3 mmol) was dissolved in H ₂ O (5 mL) and 1,4-dioxane (3 mL). The mixture was heated in an oil bath at 100 ° C. for 24 hours and then it was cooled to room temperature. The mixture was acidified with 1N HCl and extracted three times with 20 mL portions of dichloromethane. The organic extract was dried over Na ₂ SO ₄ and evaporated to 5- (1- (benzo [d] [1,3] -dioxol-5-yl) cyclopropanecarboxamido) -1H-indole-2- Carboxylic acid (302 mg, 83%) was obtained. Small amounts were further purified by reverse phase HPLC.

5- (1- (benzo [d] [1,3] dioxol-5-yl) cyclopropanecarboxamido) -N-tert-butyl-1H-indole-2-carboxamide

5- (1- (benzo [d] [1,3] dioxol-5-yl) cyclopropane-carboxamido) -1H-indole-2-carboxylic acid (36 mg, 0.10 mmol) and 2- Methylpropan-2-amine (8.8 mg, 0.12 mmol) was dissolved in N, N-dimethylformamide (1.0 mL) containing triethylamine (28 μL, 0.20 mmol). O- (7-azabenzotriazol-1-yl) -N, N, N ', N'-tetramethyluronium hexafluorophosphate (46 mg, 0.12 mmol) was added to the mixture and the resulting solution was It was allowed to stir for 3 hours. The mixture was 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 was obtained.

Example 81 N- (3-amino-2-tert-butyl-1H-indol-5-yl) -1- (benzo [d] [1,3] dioxol-5-yl) cyclopropanecarboxamide

Of 1- (benzo [d] [1,3] dioxol-5-yl) -N- (2-tert-butyl-1H-indol-5-yl) cyclopropane carboxamide (50 mg, 0.13 mmol) The solution was dissolved in AcOH (2 mL) and warmed to 45 ° C. To the mixture was added a solution of NaNO ₂ (9 mg) in H ₂ O (0.03 mL). The mixture was allowed to stir at 45 ° C. for 30 minutes, then the precipitate was collected and washed with Et ₂ O. This material was used in the next step without further purification. Crude, 1- (benzo [d] [1,3] dioxol-5-yl) -N- (2-tert-butyl-3-nitroso-1H-indol-5-yl) cyclopropanecarboxamide To this was added AcOH (2 mL) and Zn dust (5 mg). The mixture was allowed to stir at ambient temperature for 1 hour. EtOAc and H ₂ O were added to the mixture. The layers were separated and the organic layer was washed with saturated aqueous NaHCO ₃ , dried over MgSO ₄ and concentrated in vacuo. The residue was taken up in DMF (1 mL) and purified using preparative HPLC.

Example 82: 1- (benzo [d] [1,3] dioxol-5-yl) -N- (2-tert-butyl-3- (methylsulfonyl) -1H-indol-5-yl) cyclo Propanecarboxamide

1- (benzo [d] [1,3] dioxol-5-yl) -N- (2-tert-butyl-3- (methylsulfonyl) -1H-indol-5-yl) cyclopropanecarboxamide

1- (benzo [d] [1,3] dioxol-5-yl) -N- (2-tert-butyl-1H-indol-5-yl) in anhydrous DMF-THF (3.3 mL, 1: 9) To a solution of cyclopropanecarboxamide (120 mg, 0.31 mmol) was added NaH (60% in mineral oil, 49 mg, 1.2 mmol) at room temperature. After 30 minutes under N ₂ , 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 at −15 ° C. for 30 minutes and then at room temperature for 6 hours. Water (0.5 mL) is added at 0 ° C., the solvent is removed, the residue is 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 was obtained.

Example 83 1- (benzo [d] [1,3] dioxol-5-yl) -N- (3-phenyl-1H-indol-5-yl) cyclopropane carboxamide

1- (benzo [d] [1,3] dioxol-5-yl) -N- (3-bromo-1H-indol-5-yl) cyclopropanecarboxamide

Freshly crystallized N-bromosuccinimide (0.278 g, 1.56 mmol) was added 1- (benzo [d] [1,3] dioxol-5-yl)-in N, N-dimethylformamide (2 mL). To a solution of N- (1H-indol-5-yl) cyclopropanecarboxamide (0.500 g, 1.56 mmol) was added in portions over 2 minutes. The reaction mixture was protected from light and rod stirred for 5 minutes. The resulting green solution was poured into 40 mL of water. The gray precipitate formed was filtered off and washed with water to give 1- (benzo [d] [1,3] dioxol-5-yl) -N- (3-bromo-1H-indol-5-yl) cyclopropanecarbox Amide (0.564 g, 91%) was obtained.

1- (benzo [d] [1,3] dioxol-5-yl) -N- (3-phenyl-1H-indol-5-yl) cyclopropanecarboxamide

Phenyl boronic acid (24.6 mg, 0.204 mmol) in 1- (benzo [d] [1,3]-in ethanol (1 mL) containing fibrecat 1001 (6 mg) and 1M aqueous potassium carbonate (0.260 mL). To a solution of dioxol-5-yl) -N- (3-bromo-1H-indol-5-yl) cyclopropanecarboxamide (39.9 mg, 0.100 mmol). The reaction mixture was then heated at 130 ° C. for 20 minutes in a microwave reactor. The crude product is then purified by preparative HPLC using a gradient of 0-99% acetonitrile in water containing 0.05% trifluoroacetic acid to give 1- (benzo [d] [1,3] dioxol-5- Il) -N- (3-phenyl-1H-indol-5-yl) cyclopropane carboxamide was obtained.

Example 84 1- (benzo [d] [1,3] dioxol-5-yl) -N- (2-tert-butyl-3-cyano-1H-indol-5-yl) cyclopropanecarbox amides

1- (benzo [d] [1,3] dioxol-5-yl) -N- (2-tert-butyl-3-formyl-1H-indol-5-yl) cyclopropane-carboxamide

POCl ₃ (12 g, 80 mmol) was added dropwise to DMF (40 mL) maintained at −20 ° C. After the addition was complete, 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 warmed to 25 ° C. After stirring for 30 minutes, the reaction mixture is poured onto ice and stirred for 2 hours. The mixture was then heated at 100 ° C. for 30 minutes. The mixture was cooled down and the solid precipitate collected and washed with water. The solid was then dissolved in 200 mL dichloromethane and washed with 200 mL saturated aqueous NaHCO ₃ . The organics were dried over Na ₂ SO ₄ and evaporated to 1- (benzo [d] [1,3] dioxol-5-yl) -N- (2-tert-butyl-3-formyl-1H-indole- 5-yl) cyclopropane-carboxamide (2.0 g, 61%) was obtained.

(Z) -1- (Benzo [d] [1,3] dioxol-5-yl) -N- (2-tert-butyl-3-((hydroxyimino) methyl) -1H-indole-5- (1) cyclopropanecarboxamide

1- (benzo [d] [1,3] dioxol-5-yl) -N- (2-tert-butyl-3-formyl-1H-indol-5-yl) cyclo in dichloromethane (5 mL) To a solution of propanecarboxamide (100 mg, 0.25 mmol) was added hydroxylamine hydrochloride (21 mg, 0.30 mmol). After stirring for 48 hours, 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- Il) -N- (2-tert-butyl-3-((hydroxyimino) methyl) -1H-indol-5-yl) cyclopropanecarboxamide (81 mg, 77%) was obtained.

1- (benzo [d] [1,3] dioxol-5-yl) -N- (2-tert-butyl-3-cyano-1H-indol-5-yl) cyclopropane-carboxamide

(Z) -1- (Benzo [d] [1,3] dioxol-5-yl) -N- (2-tert-butyl-3-((hydroxyimino) -methyl) -1H-indole-5 -Yl) cyclopropanecarboxamide (39 mg, 0.090 mmol) was dissolved in acetic anhydride (1 mL) and heated at reflux for 3 hours. The mixture was cooled in an ice bath, the precipitate was collected and washed with water. The solid was further 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 was obtained.

Example 85: 1- (benzo [d] [1,3] dioxol-5-yl) -N- (2-tert-butyl-3-methyl-1H-indol-5-yl) cyclopropanecarboxamide

1- (benzo [d] [1,3] dioxol-5-yl) -N- (2-tert-butyl-1H-indol-5-yl) cyclo in N, N-dimethylformamide (1 mL) A solution of propanecarboxamide (75 mg, 0.20 mmol) and iodomethane (125 μL, 2.0 mmol) was heated in a sealed tube at 120 ° C. for 24 hours. The reaction was filtered and purified by reverse phase HPLC.

Example 86 1- (benzo [d] [1,3] dioxol-5-yl) -N- (2-tert-butyl-3- (2-hydroxyethyl) -1H-indol-5-yl Cyclopropanecarboxamide

Approximately 100 μL of ethylene dioxide was condensed at −78 ° C. in the reaction tube. 1- (benzo [d] [1,3] dioxol-5-yl) -N- (2-tert-butyl-1H-indol-5-yl) cyclopropanecarboxamide in dichloromethane (2 mL) 200 mg, 0.50 mmol) and indium trichloride (20 mg, 0.10 mmol) were added and the reaction mixture was irradiated with microwave at 100 ° C. for 20 minutes. The volatiles were removed and the residue was purified by column chromatography (0-100% ethyl acetate / hexanes) 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%) was obtained.

Example 87 2- (5- (1- (benzo [d] [1,3] dioxol-5-yl) cyclopropanecarboxamido) -1H-indol-2-yl) acetic acid

Ethyl 2- (5- (1- (benzo [d] [1,3] dioxol-5-yl) cyclopropanecarboxamido) -1H-indol-2-yl) acetate in THF (0.3 mL) ( To a solution of 0.010 g, 0.025 mmol) LiOH.H ₂ O (0.002 g, 0.05 mmol) was added and water (0.15 mL) was added. The mixture was stirred at rt for 2 h. Dichloromethane (3 mL) was added to the reaction mixture and the organic layer was washed with 1N HCl (2 × 1.5 mL) and water (2 × 1.5 mL). The organic layer was dried over Na ₂ S0 ₄ and filtered. The filtrate was evaporated under reduced pressure to afford 2- (5- (1- (benzo [d] [1,3] dioxol-5-yl) cyclopropanecarboxamido) -1H-indol-2-yl) -acetic acid Obtained.

Example 88 5- (1- (benzo [d] [1,3] dioxol-5-yl) cyclopropanecarboxamido) -2-tert-butyl-1H-indole-7-carboxylic acid

Methyl 5- (1- (benzo [d] [1,3] dioxol-5-yl) cyclopropanecarboxamido) -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 bar for stirring and containing 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 equal volume of dichloromethane. The dichloromethane extracts were combined, dried over sodium sulfate, filtered and evaporated to dryness. The residue was dissolved in a minimum amount of N, N-dimethylformamide and then purified by preparative HPLC using a gradient of 0-99% acetonitrile in water containing 0.05% trifluoroacetic acid to give 5- (1- (Benzo [d] [1,3] dioxol-5-yl) cyclopropanecarboxamido) -2-tert-butyl-1H-indole-7-carboxylic acid was obtained.

Example 89: 1- (benzo [d] [1,3] dioxol-5-yl) -N- (2-tert-butyl-1- (1,3-dihydroxypropan-2-yl)- 1H-indol-5-yl) cyclopropanecarboxamide

1- (benzo [d] [1,3] dioxol-5-yl) -N- (2-tert-butyl-1- (1,3-dihydroxypropan-2-yl) indoline-5- (1) cyclopropanecarboxamide

1- (benzo [d] [1,3] dioxol-5-yl) -N- (2-tert-butylindolin-5-yl) cyclopropanecarboxamide (50 mg, 0.13 mmol) was converted to dichloroethane. (0.20 mL) and 2,2-dimethyl-1,3-dioxan-5-one (0.20 mL). Trifluoroacetic acid (0.039 mL) was added and the resulting solution was allowed to stir for 20 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% trifluoroacetic acid.

1- (benzo [d] [1,3] dioxol-5-yl) -N- (2-tert-butyl-1- (1,3-dihydroxypropan-2-yl) -1H-indole- 5-yl) cyclopropanecarboxamide

1- (benzo [d] [1,3] dioxol-5-yl) -N- (2-tert-butyl-1- (1,3-dihydroxypropan-2-yl) indoline-5- I) cyclopropanecarboxamide (40.3 mg, 0.0711 mmol as trifluoroacetic acid salt) was dissolved in toluene (1 mL). To the resulting solution was added 2,3,5,6-tetrachlorocyclohexa-2,5-diene-1,4-dione (35 mg, 0.14 mmol). The resulting suspension was heated at 100 ° C. for 10 minutes in an oil bath. The crude product is 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% trifluoroacetic acid. 1- (benzo [d] [1,3] dioxol-5-yl) -N- (2-tert-butyl-1- (1,3-dihydroxypropan-2-yl) -1H-indole- 5-yl) cyclopropanecarboxamide was obtained.

Example 90 N- (7- (aminomethyl) -2-tert-butyl-1H-indol-5-yl) -1- (benzo [d] [1,3] -dioxol-5-yl) cyclo Propanecarboxamide

N- (7- (aminomethyl) -2-tert-butyl-1H-indol-5-yl) -1- (benzo [d] [1,3] dioxol-5-yl) cyclopropanecarboxamide

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 recycled for 8 hours at 100 ° C. under 100 bar of hydrogen through a continuous flow hydrogenation reactor containing 10% palladium on carbon. The crude product is then evaporated to dryness and purified by 12 g of 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-indol-5-yl) -1- (benzo [d] [1,3] -dioxol-5-yl) -cyclopropanecarboxamide (121 mg, 32%) was obtained.

Example 91 5- (1- (benzo [d] [1,3] dioxol-5-yl) cyclopropanecarboxamido) -2-tert-butyl-1H-indole-7-carboxamide

5- (1- (benzo [d] [1,3] dioxol-5-yl) cyclopropanecarboxamido) -2-tert-butyl-1H-indole-7-carboxamide

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 at rt for 72 h. Hydrogen peroxide was then quenched 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% trifluoroacetic acid to give 5- ( 1- (benzo [d] [1,3] dioxol-5-yl) cyclopropane-carboxamido) -2-tert-butyl-1H-indole-7-carboxamide was obtained.

Example 92: 1- (benzo [d] [1,3] dioxol-5-yl) -N- (2-tert-butyl-7- (methylsulfonamido-methyl) -1H-indole-5- (1) cyclopropanecarboxamide

1- (benzo [d] [1,3] dioxol-5-yl) -N- (2-tert-butyl-7- (methylsulfonamidomethyl) -1H-indol-5-yl) cyclopropanecar Voxamide

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 a stirring magnetic rod and containing triethylamine (20.6 μL, 0.147 mmol). Methanesulfonyl chloride (4.2 μL, 0.054 mmol) was then added to the reaction mixture. The reaction mixture was allowed to stir at room temperature for 12 hours. The crude product was purified by preparative HPLC using a gradient of 0-99% acetonitrile in water containing 0.05% trifluoroacetic acid to give 1- (benzo [d] [1,3] dioxol-5-yl) -N- (2-tert-butyl-7- (methylsulfonamidomethyl) -1H-indol-5-yl) cyclopropanecarboxamide was obtained.

Example 93: N- (7- (acetamidomethyl) -2-tert-butyl-1H-indol-5-yl) -1- (benzo [d] [1,3] -dioxol-5-yl Cyclopropanecarboxamide

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 a stirring magnetic rod and containing triethylamine (20.6 μL, 0.147 mmol). Acetyl chloride (4.2 μL, 0.054 mmol) was then added to the reaction mixture. The reaction mixture was allowed to stir at room temperature for 16 hours. The crude product was purified by preparative HPLC using a gradient of 0-99% acetonitrile in water containing 0.05% trifluoroacetic acid to give N- (7- (acetamidomethyl) -2-tert-butyl-1H -Indol-5-yl) -1- (benzo [d] [1,3] dioxol-5-yl) cyclopropanecarboxamide was obtained.

Example 94 N- (1-acetyl-2-tert-butyl-1H-indol-5-yl) -1- (benzo [d] [1,3] dioxol-5-yl) -cyclopropanecarbox amides

1- (benzo [d] [1,3] dioxol-5-yl) -N- (2-tert-butyl-1H-indol-5-yl) in anhydrous DMF-THF (3.3 mL, 1: 9) To a solution of cyclopropanecarboxamide (120 mg, 0.31 mmol) was added NaH (60% in mineral oil, 49 mg, 1.2 mmol) at room temperature. After 30 minutes under N ₂ , 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 at −15 ° C. for 30 minutes and then at room temperature for 6 hours. Water (0.5 mL) was added at 0 ° C., the solvent was removed, the residue diluted with MeOH, filtered and purified by preparative HPLC to give N- (1-acetyl-2-tert-butyl-1H-indole -5-yl) -1- (benzo [d] [1,3] dioxol-5-yl) cyclo-propanecarboxamide was obtained.

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

N- (1- (2-aminoethyl) -2-tert-butyl-6-fluoro-1H-indol-5-yl) -1- (2,2-difluorobenzo- [d] [1, 3] dioxol-5-yl) cyclopropanecarboxamide

Tert-butyl 2- (2-tert-butyl-5- (1- (2,2-difluorobenzo [d] [1,3] dioxol-5-yl) in CH ₂ Cl ₂ (8 mL)) To a solution of cyclopropanecarboxamido) -6-fluoro-1H-indol-1-yl) ethylcarbamate (620 mg, 1.08 mmol) was added TFA (2 mL). The reaction was stirred at rt for 1.5 h and then neutralized with solid NaHCO ₃ . The solution was partitioned between H ₂ O and CH ₂ Cl ₂ . The organic layer was dried over MgSO ₄ , filtered and concentrated to give the product as a cream solid (365 mg, 71%).

N- (1- (2-acetamidoethyl) -2-tert-butyl-6-fluoro-1H-indol-5-yl) -1- (2,2-difluorobenzo [d] [1 , 3] dioxol-5-yl) cyclopropanecarboxamide

N- (1- (2-aminoethyl) -2-tert-butyl-6-fluoro-1H-indol-5-yl) -1- (2,2-difluorobenzo [1] in DMF (1 mL) d] acetyl chloride (7.1 μL, 0.10 mmol) in a solution of [1,3] dioxol-5-yl) cyclopropane-carboxamide (47 mg, 0.10 mmol) and Et ₃ N (28 μL, 0.20 mmol) Was added. The mixture was stirred at rt for 1 h, then filtered and purified by reverse phase HPLC (10-99% CH ₃ CN / H ₂ O) to give N- (1- (2-acetamidoethyl) -2-tert- Butyl-6-fluoro-1H-indol-5-yl) -1- (2,2-difluorobenzo [d] [1,3] dioxol-5-yl) cyclopropanecarboxamide was obtained. .

Example 96: 1- (benzo [d] [1,3] dioxol-5-yl) -N- (2-tert-butyl-1- (2-hydroxy-3-methoxy-propyl) -1H -Indol-5-yl) cyclopropenecarboxamide

1-benzo [d] [1,3] dioxol-5-yl) -N- (2-tert-butyl-1H-indol-5-yl) cyclopropanecarboxamide (320 mg, 0.84 mmol) was anhydrous. It was dissolved under N ₂ in a mixture consisting of DMF (0.5 mL) and anhydrous THF (5 mL). NaH (60% in mineral oil, 120 mg, 3.0 mmol) was added at room temperature. After stirring for 30 minutes, the reaction mixture was cooled to −15 ° C. and then a solution of epichlorohydrin (79 μL, 1.0 mmol) in anhydrous DMF (1 mL) was added dropwise. The reaction mixture was stirred at −15 ° C. for 15 minutes and then at room temperature for 8 hours. MeOH (1 mL) was added and the mixture was heated in a microwave oven at 105 ° C. for 10 minutes. 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) -1H-indol-5-yl) cyclopropanecarboxamide was obtained.

Example 97: 1- (benzo [d] [1,3] dioxol-5-yl) -N- (2-tert-butyl-1- (2-hydroxy-3- (methyl-amino) propyl) -1H-indol-5-yl) cyclopropanecarboxamide

1- (benzo [d] [1,3] dioxol-5-yl) -N- (2-tert-butyl-1H-indol-5-yl) cyclopropanecarboxamide (320 mg, 0.84 mmol) It was dissolved under N ₂ in a mixture consisting of anhydrous DMF (0.5 mL) and anhydrous THF (5 mL). NaH (60% in mineral oil, 120 mg, 3.0 mmol) was added at room temperature. After stirring for 30 minutes, the reaction mixture was cooled to −15 ° C. and then a solution of epichlorohydrin (79 μL, 1.0 mmol) in anhydrous DMF (1 mL) was added dropwise. The reaction mixture was stirred at −15 ° C. for 15 minutes and then at room temperature for 8 hours. MeNH ₂ (2.0 M in MeOH, 1.0 mL) was added and the mixture was heated in a microwave oven at 105 ° C. for 10 minutes. 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 was obtained.

Example 98: (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

(R) -3- (2-tert-butyl-5- (1- (2,2-difluorobenzo [d] [1,3] dioxol-5-yl) cyclopropanecarbox-amido) -1H-indol-1-yl) -2-hydroxypropyl-4-methylbenzenesulfonate

(R) -N- (2-tert-butyl-1- (2,3-dihydroxypropyl) -1H-indol-5-yl) -1- (2,2-di in dichloromethane (20 mL) In a stirred solution of fluoro-benzo [d] [1,3] dioxol-5-yl) cyclopropanecarboxamide (3.0 g, 6.1 mmol) triethylamine (2 mL) and para-toluenesulfonylchloride ( 1.3 g, 7.0 mmol) was added. After 18 hours, the reaction mixture was partitioned between 10 mL of water and 10 mL of ethyl acetate. The organic layer was dried over magnesium sulphate, filtered and evaporated. The residue was purified using column chromatography on silica gel (0-60% ethyl acetate / hexanes) to give (R) -3- (2-tert-butyl-5- (1- (2,2-difluoro) Benzo [d] [1,3] -dioxol-5-yl) cyclopropanecarboxamido) -1H-indol-1-yl) -2-hydroxypropyl-4-methyl-benzenesulfonate (3.21 g , 86%) was obtained.

(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

(R) -3- (2-tert-butyl-5- (1- (2,2-difluorobenzo [d] [1,3] dioxol-5-yl) cyclopropane in DMF (6 mL) To a stirred solution of carboxamido) -1H-indol-1-yl) -2-hydroxypropyl-4-methylbenzenesulfonate (3.2 g, 5.0 mmol) was added sodium azide (2.0 g, 30 mmol). It was. The reaction 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 using column chromatography (0-85% ethyl acetate / hexanes) to give (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 (2.48 g) was obtained.

(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

(R) -N- (1- (3-azido-2-hydroxypropyl) -2-tert-butyl-1H-indol-5-yl) -1- (2,2- in MeOH (25 mL) 5% Pd / C (2.4 g) under a balloon filled with hydrogen gas in a stirred solution of difluorobenzo [d] [1,3] dioxol-5-yl) cyclopropanecarboxamide (2.4 g, 4.0 mmol) Was added. After 18 hours, the reaction mixture was filtered through celite and rinsed with 300 mL ethyl acetate. The organic layer was washed with 1N HCl and evaporated to (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) cyclopropane-carboxamide (1.37 g) was obtained.

Example 99 (S) -methyl 3- (2-tert-butyl-5- (1- (2,2-difluorobenzo [d] [1,3] dioxol-5-yl) cyclopropanecar Voxamido) -1H-indol-1-yl) -2-hydroxypropylcarbamate

(R) -N- (1- (3-amino-2-hydroxypropyl) -2-tert-butyl-1H-indol-5-yl) -1- (2,2-di in methanol (1 mL) Triethylamine and methylchloroformyl chloride (0.020 mL, 0.25 mmol) in a stirred solution of fluorobenzo [d] [1,3] dioxol-5-yl) cyclopropanecarboxamide (0.10 g, 0.20 mmol) 2 drops were added. After 30 minutes, the reaction mixture was filtered and purified using reverse phase HPLC to give (S) -methyl 3- (2-tert-butyl-5- (1- (2,2-difluorobenzo [d] [1] , 3] dioxol-5-yl) cyclo-propanecarboxamido) -1H-indol-1-yl) -2-hydroxypropylcarbamate. The residence time at 3 min run was 1.40 min.

Example 100: 4- (5- (1- (benzo [d] [1,3] dioxol-5-yl) cyclopropanecarboxamido) -2-tert-butyl-1H-indol-1-yl Butanoic acid

1- (benzo [d] [1,3] dioxol-5-yl) -N- (2-tert-butylindolin-5-yl) cyclopropanecarboxamide

1- (benzo [d] [1,3] dioxol-5-yl) -N- (2-tert-butyl-1H-indol-5-yl) cyclo-propanecarboxamide in acetic acid (60 mL) ( To a solution of 851 mg, 2.26 mmol), NaBH ₃ CN (309 mg, 4.91 mmol) was added at 0 ° C. The reaction mixture was stirred at room temperature for 5 minutes after which no starting material was detected in LCMS. The solvent was evaporated under reduced pressure and the residue was purified by column chromatography on silica gel (5-40% ethyl acetate / hexane) to give 1- (benzo [d] [1,3] dioxol-5-yl) -N -(2-tert-butylindolin-5-yl) cyclopropanecarboxamide (760 mg, 89%) was obtained.

4- (5- (1- (benzo [d] [1,3] dioxol-5-yl) cyclopropanecarboxamido) -2-tert-butylindolin-1-yl) butanoic acid

1- (benzo [d] [1,3] dioxol-5-yl) -N- (2-tert-butylindolin-5-yl) cyclopropane in anhydrous methanol (6.5 mL) and AcOH (65 μL) To a solution of carboxamide (350 mg, 0.93 mmol, 1 equiv) was added 4-oxobutanoic acid (15% in water, 710 mg, 1.0 mmol) at room temperature. After stirring for 20 minutes, NaBH ₃ CN (130 mg, 2.0 mmol) was added in one portion and the reaction mixture was stirred at room temperature for another 4 hours. The reaction mixture was quenched by addition of AcOH (0.5 mL) at 0 ° C. and solvent was removed under reduced pressure. The residue was purified by column chromatography on silica gel (5-75% ethyl acetate / hexane) to give 4- (5- (1- (benzo [d] [1,3] dioxol-5-yl) cyclopropanecar Voxamido) -2-tert-butylindolin-1-yl) butanoic acid (130 mg, 30%) was obtained.

4- (5- (1- (benzo [d] [1,3] dioxol-5-yl) cyclopropanecarboxamido) -2-tert-butyl-1H-indol-1-yl) butanoic acid

4- (5- (1- (benzo [d] [1,3] dioxol-5-yl) cyclopropanecarboxamido) -2-tert-butylindolin-1-yl) butanoic acid (130 mg , 0.28 mmol) was dissolved in a mixture of acetonitrile-H ₂ O-TFA. The solvent was removed under reduced pressure and the resulting residue was dissolved in CDCl ₃ . After brief exposure (5-10 minutes) to sunlight, the solution turned purple. The mixture was stirred at room temperature with open to atmosphere until complete disappearance of the starting material (8 h). The solvent was removed under reduced pressure and the residue was purified by reverse phase HPLC to afford 4- (5- (1- (benzo [d] [1,3] dioxol-5-yl) cyclopropanecarboxamido) -2- tert-butyl-1H-indol-1-yl) butanoic acid was obtained.

Example 101: 1- (benzo [d] [1,3] dioxol-5-yl) -N- (2-tert-butyl-1- (4- (2-hydroxyethyl-amino) -4- Oxobutyl) -1H-indol-5-yl) cyclopropanecarboxamide

4- (5- (1- (benzo [d] [1,3] dioxol-5-yl) cyclopropanecarboxamido) -2-tert-butyl-1H-indole- in anhydrous DMF (0.25 mL) To a solution of 1-yl) butanoic acid (10 mg) was added successively Et ₃ N (9.5 mL, 0.069 mmol) and HBTU (8.2 mg, 0.022 mmol). After stirring at 60 ° C. for 10 minutes, ethanolamine (1.3 μL, 0.022 mmol) was added and the mixture was stirred at 60 ° C. for another 4 hours. 1- (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.

Example 102: 1- (benzo [d] [1,3] dioxol-5-yl) -N- (2-tert-butyl-1- (2- (dimethylamino) -2-oxoethyl) -1H -Indol-5-yl) cyclopropanecarboxamide

1- (benzo [d] [1,3] dioxol-5-yl) -N- (2-tert-butylindolin-5-yl) cyclopropane in anhydrous DMF (0.11 mL) and THF (1 mL) To a solution of carboxamide (62 mg, 0.16 mmol) was added NaH (60% in mineral oil, 21 mg, 0.51 mmol) at room temperature under N ₂ . After stirring for 30 minutes, the reaction mixture is cooled to 0 ° C. and 2-chloro-N, N-dimethylacetamide (11 mL, 0.14 mmol,) is added. The reaction mixture was stirred at 0 ° C. for 5 minutes and then at room temperature for 10 hours. The mixture was purified by preparative HPLC and the resulting solid was dissolved in DMF (0.6 mL) in the presence of Pd-C (10 mg). The mixture was stirred overnight at room temperature with open air. The reaction mixture was filtered and purified by preparative HPLC to give 1- (benzo [d] [1,3] dioxol-5-yl) -N- (2-tert-butyl-1- (2- (dimethylamino) 2-oxoethyl) -1H-indol-5-yl) cyclopropanecarboxamide was obtained.

Example 103: 3- (2-tert-butyl-5- (1- (2,2-difluorobenzo [d] [1,3] dioxol-5-yl) cyclo-propanecarboxamido) -1H-indol-1-yl) propanoic acid

N- (2-tert-butyl-1- (2-chloroethyl) indolin-5-yl) -1- (2,2-difluorobenzo [d] [1,3] dioxol-5-yl Cyclopropanecarboxamide

N- (2-tert-butyl-1- (2-cyanoethyl) indolin-5-yl) -1- (2,2-difluorobenzo [d] [1 in anhydrous dichloromethane (1 mL) To a solution of, 3] dioxol-5-yl) cyclopropanecarboxamide (71 mg, 0.17 mmol) was added chloroacetaldehyde (53 μL, 0.41 mmol) at room temperature under N ₂ . After stirring for 20 minutes, NaBH (OAc) ₃ (90 mg, 0.42 mmol) was added in two portions. The reaction mixture was stirred at rt overnight. The product was purified by column chromatography on silica gel (2-15% ethyl acetate / hexane) to give N- (2-tert-butyl-1- (2-chloroethyl) indolin-5-yl) -1- (2 , 2-difluorobenzo [d] [1,3] dioxol-5-yl) cyclopropanecarboxamide (51 mg, 63%) was obtained.

N- (2-tert-butyl-1- (2-cyanoethyl) indolin-5-yl) -1- (2,2-difluorobenzo [d] [1,3] dioxol-5- (1) cyclopropanecarboxamide

N- (2-tert-butyl-1- (2-chloroethyl) indolin-5-yl) -1- (2,2-difluorobenzo [d in EtOH (0.6 mL) and water (0.3 mL) ] [1,3] dioxol-5-yl) cyclopropanecarboxamide (51 mg), NaCN (16 mg, 0.32 mmol) and KI (catalyst amount) were combined and heated in microwave at 110 ° C. for 30 minutes. . The solvent was removed under reduced pressure, and the residue was purified by column chromatography on silica gel (2-15% ethyl acetate / hexane) 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%) was obtained.

3- (2-tert-butyl-5- (1- (2,2-difluorobenzo [d] [1,3] dioxol-5-yl) cyclo-propanecarbox-amido) -1H- Indol-1-yl) propanoic acid

N- (2-tert-butyl-1- (2-cyanoethyl) indolin-5-yl) -1- (2,2-difluorobenzo [d] [1,3] dioxol-5- I) cyclopropane-carboxamide (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. Solvent was removed and the residue was purified by preparative HPLC. The residue was dissolved in CDCl ₃ (1 mL) and then briefly exposed to sunlight. The purple solution formed was stirred (1 h) until complete disappearance of the starting material. 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) cyclo-propanecarboxamido) -1H-indol-1-yl) propanoic acid was obtained.

Example 104: 1- (benzo [d] [1,3] dioxol-5-yl) -N- (2-tert-butyl-6-fluoro-1- (2-hydroxy-ethyl) -1H -Indol-5-yl) cyclopropenecarboxamide

1- (benzo [d] [1,3] dioxol-5-yl) -N- (2-tert-butyl-6-fluoroindolin-5 in anhydrous MeOH (5.7 mL) containing 1% acetic acid To a solution of -yl) cyclopropanecarboxamide (340 mg, 0.86 mmol) was added 40% (0.60 mL, 5.2 mmol) of glyoxal in water at room temperature under N ₂ . After stirring for 20 minutes, NaBH ₃ CN (120 mg, 1.9 mmol) was added in one portion and the reaction mixture was stirred at rt overnight. The solvent was removed under reduced pressure and the resulting residue was purified by column chromatography on silica gel (10-40% ethyl acetate / hexanes) to give a pale yellow oil, which was 50 / containing 0.05% TFA and CDCl ₃ . Treated with 50 CH ₃ CN-H ₂ O. The solvent was removed under reduced pressure and the residue was purified by column chromatography on silica gel (20-35% ethyl acetate / hexanes) to give 1- (benzo [d] [1,3] dioxol-5-yl) -N -(2-tert-butyl-6-fluoro-1- (2-hydroxyethyl) -1H-indol-5-yl) cyclopropanecarboxamide was obtained.

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.

3- (benzyloxy) propanal

To a suspension of PCC (606 mg, 2.82 mmol) in anhydrous dichloromethane (8 mL) at room temperature under N ₂ was added a solution of 3-benzyloxy-1-propanol (310 mg, 1.88 mmol) in anhydrous dichloromethane. The reaction mixture was stirred at rt overnight, filtered through celite and concentrated. The residue was purified by column chromatography on silica gel (1-10% ethyl acetate / hexanes) to give 3- (benzyloxy) propanal (243 mg, 79%).

1- (benzo [d] [1,3] dioxol-5-yl) -N- (2-tert-butyl-6-fluoro-1- (3-hydroxypropyl) -1H-indole-5- (1) cyclopropanecarboxamide

1- (benzo [d] [1,3] dioxol-5-yl) -N- (2-tert-butyl-6-fluoroindoline-5-yl) cyclopropane in anhydrous dichloromethane (3.4 mL) To a solution of carboxamide (160 mg, 0.50 mmol) was added 3- (benzyloxy) propanal (160 mg, 0.98 mmol) at room temperature. After stirring for 10 minutes, NaBH (OAc) ₃ (140 mg, 0.65 mmol) was added in one portion and the reaction mixture was stirred at rt for 4 h. The solvent was removed under reduced pressure and the residue was taken up in a mixture of 50/50 CH ₃ CN-H ₂ O containing 0.05% TFA. The mixture was concentrated to dryness and the residue was dissolved in CDCl ₃ (5 mL) and briefly exposed to sunlight. The purple solution was stirred with open to air for 2 hours at room temperature. The solvent was removed under reduced pressure and the residue was treated with Pd-C (10 mg) in MeOH (2 mL) for 2 h under 1 atm H ₂ . The catalyst was filtered through celite and the solvent was removed under reduced pressure. The residue was purified by preparative TLC 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, 1- (benzo [d] [1,3] dioxol-5-yl) -N- (2 8%) was obtained from -tert-butyl-6-fluoroindolin-5-yl) cyclopropane-carboxamide.

Example 106 N- (1- (2-acetamidoethyl) -2-tert-butyl-1H-indol-5-yl) -1- (benzo [d] [1,3] -dioxol-5 -Yl) cyclopropanecarboxamide

N- (1- (2-azidoethyl) -2-tert-butyl-1H-indol-5-yl) -1- (benzo [d] [1,3] dioxol-5-yl) -cyclopropane Carboxamide

1- (benzo [d] [1,3] dioxol-5-yl) -N- (2-tert-butylindolin-5-yl) cyclopropane-carboxamide in anhydrous dichloromethane (1.2 mL) To a solution of 73 mg, 0.19 mmol) chloroacetaldehyde (60 μL, 0.24 mmol) was added at room temperature. After stirring for 10 minutes, NaBH (OAc) ₃ (52 mg, 0.24 mmol) was added in one portion and the reaction mixture was stirred at room temperature for another 30 minutes. The solvent was removed under reduced pressure and the residue was purified by preparative HPLC to give indolin which was dissolved in CDCl ₃ and oxidized to the corresponding indole. The resulting indole was treated with NaN ₃ (58 mg, 0.89 mmol) and NaI (catalyst amount) 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] di Oxol-5-yl) cyclopropanecarboxamide (15 mg, 1- (benzo [d] [1,3] dioxol-5-yl) -N- (2-tert-butylindolin-5-yl) 18%) was obtained from cyclopropane-carboxamide.

N- (1- (2-acetamidoethyl) -2-tert-butyl-1H-indol-5-yl) -1- (benzo [d] [1,3] -dioxol-5-yl) cyclo Propanecarboxamide

N- (1- (2-azidoethyl) -2-tert-butyl-1H-indol-5-yl)-in MeOH-AcOH (0.2 mL, 99: 1) in the presence of Pd-C (2 mg)- A solution of 1- (benzo [d] [1,3] dioxol-5-yl) cyclopropanecarboxamide (13 mg, 0.029 mmol) was stirred at room temperature under 1 atm of H ₂ for 2 hours, and celite Filter through and concentrate under reduced pressure. The crude product was treated with AcCl (0.05 mL) and Et ₃ N (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-1H-indol-5-yl) -1- (benzo [d] [1,3]- Dioxol-5-yl) cyclopropanecarboxamide was obtained.

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

3- (2-tert-butyl-5- (1- (2,2-difluorobenzo [d] [1,3] dioxol-5-yl) cyclopropanecarbox-amido) -1H-indole -1-yl) -2-hydroxypropyl-4-methylbenzenesulfonate

N- (2-tert-butyl-1- (2,3-dihydroxypropyl) -1H-indole- in anhydrous dichloromethane (1.4 mL) in the presence of Et ₃ N (56 μL, 0.40 mmol) at 0 ° C. TsCl (71) in a solution of 5-yl) -1- (2,2-difluorobenzo [d] [1,3] -dioxol-5-yl) cyclopropanecarboxamide (172 mg, 0.35 mmol) mg, 0.37 mmol) was added. The reaction mixture was stirred at rt for 2 h, then cooled to 0 ° C. and another amount of TsCl (71 mg, 0.37 mmol) was added. After stirring for 1 hour at room temperature, the mixture was purified by column chromatography on silica gel (10-30% ethyl acetate / hexane) to give 3- (2-tert-butyl-5- (1- (2,2-di). Fluorobenzo [d] [1,3] dioxol-5-yl) cyclopropanecarboxamido) -1H-indol-1-yl) -2-hydroxypropyl-4-methylbenzene-sulfonate (146 mg, 64%).

N- (2-tert-butyl-1- (3-cyano-2-hydroxypropyl) -1H-indol-5-yl) -1- (2,2-difluorobenzo [d] [1, 3] dioxol-5-yl) cyclopropanecarboxamide

N- (2-tert-butyl-1- (3-cyano-2-hydroxypropyl) -1H-indol-5-yl) -1- (2,2-difluorobenzo [d] [1, 3] dioxol-5-yl) -cyclopropanecarboxamide (145 mg, 0.226 mmol) was treated with powdered NaCN (34 mg, 0.69 mmol) in anhydrous DMF (1.5 mL) for 2 hours at 85 ° C. After the reaction mixture was cooled to room temperature, it was diluted with dichloromethane (10 mL) and aqueous saturated NaHCO ₃ (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 column chromatography on silica gel (25-55% ethyl acetate / hexanes) to give N- (2-tert-butyl-1- (3-cyano-2-hydroxypropyl) -1H-indole- 5-yl) -1- (2,2-difluorobenzo [d] [1,3] dioxol-5-yl) cyclopropanecarboxamide (89 mg, 79%) was obtained.

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

N- (2-tert-butyl-1- (3-cyano-2-hydroxypropyl) -1H-indol-5-yl) -1- (2,2-difluoro in anhydrous DMF (1.2 mL) NH ₄ Cl (35 mg, 0.65 mmol) and NaN ₃ (43 mg, 0.65 mmol) in a solution of benzo [d] [1,3] dioxol-5-yl) cyclopropanecarboxamide (27 mg, 0.054 mmol) ) Was added continuously at room temperature. The reaction mixture was stirred in microwave at 110 ° C. for 4 hours, at which time 50% of the starting material was converted to the desired product. The reaction mixture was purified by preparative HPLC to give 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 was obtained.

Example 109 4- (2-tert-butyl-5- (1- (2,2-difluorobenzo [d] [1,3] dioxol-5-yl) cyclo-propanecarboxamido) -1H-indol-1-yl) -3-hydroxybutanoic acid

N- (2-tert-butyl-1- (3-cyano-2-hydroxypropyl) -1H-indol-5-yl) -1- (2 in methanol (0.8 mL) and 4M NaOH (0.8 mL) A solution of, 2-difluorobenzo [d] [1,3] dioxol-5-yl) cyclopropanecarboxamide (14 mg, 0.028 mmol) was stirred at 60 ° C. for 4 hours. The reaction mixture was neutralized with 4M HCl and concentrated. The residue was purified by preparative HPLC to give 4- (2-tert-butyl-5- (1- (2,2-difluorobenzo [d] [1,3] dioxol-5-yl) cyclopropanecar Voxamido) -1H-indol-1-yl) -3-hydroxybutanoic acid was obtained.

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

1- (benzo [d] [1,3] dioxol-5-yl) -N- (2-tert-butyl-1- (2-cyanoethyl) indolin-5-yl) -cyclopropanecarbox amides

1- (benzo [d] [1,3] dioxol-5-yl) -N- (2-tert-butyl-1- (2-chloroethyl) indole in ethanol (0.8 mL) and water (0.4 mL) To a solution of lin-5-yl) cyclopropanecarboxamide (66 mg, 0.15 mmol) was added NaCN (22 mg, 0.45 mmol) and KI (catalyst amount) at room temperature. The reaction mixture was stirred in microwave at 110 ° C. for 30 minutes and then purified by column chromatography on silica gel (5-15% ethyl acetate / hexane) to give 1- (benzo [d] [1,3] dioxol- 5-yl) -N- (2-tert-butyl-1- (2-cyano-ethyl) indoline-5-yl) cyclopropanecarboxamide (50 mg, 77%) was obtained.

N- (1- (2- (2H-tetrazol-5-yl) ethyl) -2-tert-butyl-1H-indol-5-yl) -1- (benzo [d] [1,3] dioxol -5-yl) cyclopropanecarboxamide

1- (benzo [d] [1,3] dioxol-5-yl) -N- (2-tert-butyl-1- (2-cyano-ethyl) indoline-5 in anhydrous DMF (2.6 mL) To a solution of -yl) cyclopropanecarboxamide (50 mg, 0.12 mmol) was added NH ₄ Cl (230 mg, 4.3 mmol) and NaN ₃ (280 mg, 4.3 mmol). The reaction mixture was stirred for 30 min at 110 ° C. in microwave, filtered and purified by preparative HPLC. The solid residue was dissolved in CDCl ₃ (3 mL) and briefly exposed to sunlight (2-4 minutes), which started to change color (purple). After stirring for 2 hours at room temperature with open air, 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-indol-5-yl) -1- (benzo [d] [1,3] dioxol-5-yl) cyclopropanecarboxamide was obtained.

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

1- (benzo [d] [1,3] dioxol-5-yl) -N- (2-tert-butyl-6-fluoroindolin-5 in anhydrous dichloromethane (2.3 mL) at room temperature under N ₂ To a solution of -yl) cyclopropane-carboxamide (150 mg, 0.38 mmol) was added tetrahydropyran-3-carbaldehyde (54 mg, 0.47 mmol). After stirring for 20 minutes, NaBH (OAc) ₃ (110 mg, 0.51 mmol) was added in one portion at room temperature. The reaction mixture was stirred at rt for 6 h and then purified by column chromatography on silica gel (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) indolin-5-yl) cyclopropanecarboxamide (95 mg, 50% ) Was obtained. CDCl ₃ was added to indoline and the solution was allowed to stir overnight at ambient 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 was obtained.

Example 112 1- (benzo [d] [1,3] dioxol-5-yl) -N- (2- (2-hydroxypropan-2-yl) -1H-indol-5-yl) cyclo Propanecarboxamide

Methyl 5- (1- (benzo [d] [1,3] dioxol-5-yl) cyclopropane-carboxamido) -1H-indole-2-carboxylate (100 mg, 0.255 mmol) was anhydrous. It was dissolved in tetrahydrofuran (2 mL) under argon atmosphere. After the solution was cooled to 0 ° C. in an ice water bath, methyllithium (0.85 mL, 1.6 M in diethyl ether) was added by syringe. The mixture was allowed to warm to room temperature. The crude product was then partitioned between saturated aqueous solution of sodium chloride (5 mL) and dichloromethane (5 mL). The organic layers were combined, dried over sodium sulfate, filtered, evaporated to dryness and purified by 12 g of silica gel using a gradient of 20-80% ethyl acetate in hexanes to give 1- (benzo [d] [1,3] di. Oxol-5-yl) -N- (2- (2-hydroxypropan-2-yl) -1H-indol-5-yl) cyclopropanecarboxamide (35 mg, 36%) was obtained as a white solid. .

Example 113: N- (2- (1-amino-2-methylpropan-2-yl) -1H-indol-5-yl) -1- (benzo [d] [1,3] -dioxol-5 -Yl) cyclopropanecarboxamide

Trifluoroacetic acid (0.75 mL) was added to tert-butyl 2- (5- (1- (benzo [d] [1,3] dioxol-5-yl) cyclopropanecarboxamido in dichloromethane (3 mL). To a solution of) -1H-indol-2-yl) -2-methylpropylcarbamate (77 mg, 0.16 mmol) and the mixture was stirred at rt for 1.5 h. The mixture was evaporated, dissolved in dichloromethane, washed with 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) cyclopropanecarboxamide (53 mg, 86%) was obtained.

Example 114: 1- (benzo [d] [1,3] dioxol-5-yl) -N- (2- (1- (dimethylamino) -2-methyl-propan-2-yl) -1H- Indol-5-yl) cyclopropanecarboxamide

N- (2- (1-amino-2-methylpropan-2-yl) -1H-indol-5-yl) -1- (benzo [d] [1,3] dioxol- in DMF (1 mL) To a solution of 5-yl) cyclopropanecarboxamide (20 mg, 0.051 mmol) was added potassium carbonate (35 mg, 0.26 mmol) and iodomethane (7.0 μL, 0.11 mmol). The mixture was stirred for 2 hours. Water was added and the mixture was extracted with dichloromethane. The combined organic phases were dried over magnesium sulphate, evaporated, co-evaporated with toluene (3 ×) and purified by silica gel chromatography (0-30% EtOAc in hexane) to 1- (benzo [d] [1,3] Dioxol-5-yl) -N- (2- (1- (dimethylamino) -2-methylpropan-2-yl) -1H-indol-5-yl) cyclopropanecarboxamide (7 mg, 33% ) Was obtained.

Example 115: N- (2- (1-acetamido-2-methylpropan-2-yl) -1H-indol-5-yl) -1- (benzo [d] [1,3] -dioxol -5-yl) cyclopropanecarboxamide

N- (2- (1-amino-2-methylpropan-2-yl) -1H-indol-5-yl) -1- (benzo [d] [1,3] dioxol in dichloromethane (1 mL) To a solution of -5-yl) cyclopropanecarboxamide (21 mg, 0.054 mmol) was added pyridine (14 μL, 0.16 mmol) followed by acetic anhydride (6.0 μL, 0.059 mmol). The mixture was stirred for 2 hours. Water was added, the mixture was extracted with dichloromethane, evaporated, co-evaporated with toluene (3 ×) and purified by 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%) was obtained.

Example 116 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

1- (benzo [d] [1,3] dioxol-5-yl) -N- (2- (4-cyano-2-methylbutan-2-yl) -1H-indol-5-yl) cyclo Propanecarboxamide (83 mg, 0.20 mmol) is an N, N-dimethylformamide containing a magnetic rod for stirring and containing ammonium chloride (128 mg, 2.41 mmol), sodium azide (156 mg, 2.40 mmol) ( 1 mL). The reaction mixture was heated at 110 ° C. for 40 minutes in a microwave reactor. The crude product was filtered off and then purified by preparative HPLC using a gradient of 0-99% acetonitrile in water containing 0.05% trifluoroacetic 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 was obtained. .

Example 117 1- (benzo [d] [1,3] dioxol-5-yl) -N- (2- (piperidin-2-yl) -1H-indol-5-yl) cyclopropanecar Voxamide

tert-butyl 2- (5- (1- (benzo [d] [1,3] dioxol-5-yl) cyclo-propanecarboxamido) -1H-indol-2-yl) piperidine-1 -Carboxylate (55 mg, 0.11 mmol) was dissolved in dichloromethane (2.5 mL) containing trifluoroacetic acid (1 mL). The reaction mixture was stirred at rt for 6 h. The crude product was purified by preparative HPLC using a gradient of 0-99% acetonitrile in water containing 0.05% trifluoroacetic acid to give 1- (benzo [d] [1,3] dioxol-5-yl) -N- (2- (piperidin-2-yl) -1H-indol-5-yl) cyclopropanecarboxamide was obtained.

Example 118 5-tert-butyl-1H-indol-6-ylamine

2-bromo-4-tert-butyl-phenylamine

To a solution of 4-tert-butyl-phenylamine (447 g, 3.00 mol) in DMF (500 mL) was added dropwise NBS (531 g, 3.00 mol) in DMF (500 mL) at room temperature. After completion, the reaction mixture was diluted with water and extracted with EtOAc. The organic layer was washed with water, brine, dried over Na ₂ S0 ₄ and concentrated. The crude product was used directly in the next step without further purification.

2-bromo-4-tert-butyl-5-nitro-phenylamine

2-bromo-4-tert-butyl-phenylamine (160 g, 0.71 mol) was added dropwise to H ₂ SO ₄ (410 mL) at room temperature to give a clear solution. This clear solution was then cooled to -5 to -10 ° C. A solution of KNO ₃ (83 g, 0.82 mol) in H ₂ SO ₄ (410 mL) was added dropwise while maintaining the temperature between -5 and -10 ° C. After completion, the reaction mixture was poured into ice / water and extracted with EtOAc. The combined organic layers were washed with 5% Na ₂ CO ₃ and brine, dried over Na ₂ SO ₄ 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%).

4-tert-butyl-5-nitro-2-trimethylsilanylethynyl-phenylamine

To a mixture of 2-bromo-4-tert-butyl-5-nitro-phenylamine (27.3 g, 100 mmol) in toluene (200 mL) and water (100 mL), Et ₃ N (27.9 mL, 200 mmol), Pd (PPh ₃ ) ₂ Cl ₂ (2.11 g, 3.00 mmol), CuI (950 mg, 0.500 mmol) and trimethylsilyl acetylene (21.2 mL, 150 mmol) were added. The reaction mixture was heated at 70 ° C. for 2.5 hours in a closed pressure flask, cooled to room temperature and filtered through a short plug of celite. The filter cake was washed with EtOAc. The combined filtrates were washed with 5% NH ₄ OH solution and water, dried over Na ₂ SO ₄ 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% Obtained).

5-tert-butyl-6-nitro-1H-indole

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. overnight in a closed pressure flask, cooled to room temperature and filtered through a short plug of celite. The filter cake was washed with EtOAc. The combined filtrates were washed with water, dried over Na ₂ SO ₄ and concentrated. The crude product was purified by column chromatography (10-20% ethyl acetate / hexanes) to give 5-tert-butyl-6-nitro-1H-indole as a yellow solid (13 g, 69%).

5-tert-butyl-1H-indol-6-ylamine

Raney nickel (3 g) was added to 5-tert-butyl-6-nitro-1H-indole (15 g, 67 mmol) in methanol (100 mL). The mixture was stirred at 30 ° C. under hydrogen (1 atm) for 3 hours. The catalyst was filtered off. The filtrate was dried over Na ₂ S0 ₄ 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%).

1- (2,3-dihydro-1H-inden-5-yl) cyclopropanecarboxylic acid

a) Ac ₂ O, AlCl ₃ , CH ₂ Cl ₂ ; b) NaClO; c) LiAlH ₄ , THF, -78 ° C; d) SOCl ₂ , CHCl ₃ ; e) NaCN, DMSO; f) BrCH ₂ CH ₂ Cl, NaOH, Bu ₄ NBr, toluene; g) NaOH

Step a: 1- (2,3-dihydro-1H-inden-6-yl) ethanone

A mixture of 2,3-dihydro-1H-indene (100.0 g, 0.85 mol) and acetic anhydride (104.2 g, 1.35 mol) was added to AlCl ₃ in CH ₂ Cl ₂ (1000 ml). (272.0 g, 2.04 mol) was added dropwise at 0 ° C. over a period of 3 hours. The reaction mixture was stirred at room temperature under nitrogen atmosphere for 15 hours. The reaction mixture was then poured into ice water (500 mL) and extracted with ethyl acetate (500 mL x 3). The combined organic layers were washed with brine (500 mL), dried over Na ₂ S0 ₄ and evaporated in vacuo. The residue was purified by column chromatography (petroleum ether: ethyl acetate = 20: 1) to give the product (120.0 g, 88%).

Step b: 2,3-dihydro-1H-indene-5-carboxylic acid

1- (2,3-dihydro-1H-inden-6-yl) ethanone (120.0 g, 0.75 mol) was added to a stirred aqueous sodium hypochlorite solution (2230 ml, 1.80 mmol, 6%) at 55 ° C, The mixture was stirred at 55 ° C. for 2 hours. After cooling to room temperature, saturated NaHCO ₃ solution was added until the solution became clear. The resulting precipitate was filtered, washed several times with water and dried to give the desired product (120.0 g, 99%).

Step c: (2,3-dihydro-1H-inden-5-yl) methanol

To a stirred solution of LAH (72.8 g, 1.92 mol) in THF (2.5 L) at 0 ° C. was slowly added 2,3-dihydro-1H-indene-5-carboxylic acid (100.0 g, 0.62 mol). The reaction mixture was stirred at 0 ° C for 1 h. The reaction was then quenched with H ₂ O (72 ml) and NaOH (68 ml, 20%). The mixture is filtered, the organic layer is dried over Na ₂ SO ₄ , evaporated in vacuo and the residue is purified by column chromatography (petroleum ether: ethyl acetate = 10: 1) to give the desired product (82.0 g, 90%). Obtained.

Step d: 5- (chloromethyl) -2,3-dihydro-1H-indene

Thionyl chloride (120 ml, 1.65 mol) is added dropwise at 0 ° C. to a rapidly stirred mixture of (2,3-dihydro-1H-inden-5-yl) methanol (81.4 g, 0.55 mol) in chloroform (500 ml). It was. After the addition was complete, the resulting mixture was allowed to warm to room temperature and stirring continued for an additional 12 hours. Chloroform was evaporated under reduced pressure to give a residue, which was purified by column chromatography (petroleum ether: ethyl acetate = 15: 1) to give 5- (chloromethyl) -2,3-dihydro-1H-indene (90.5 g , 99%) was obtained.

Step e: 2- (2,3-dihydro-1H-inden-5-yl) acetonitrile

To a stirred solution of 5- (chloromethyl) -2,3-dihydro-1H-indene (90.0 g, 0.54 mol) in DMSO (500 ml) was added sodium cyanide (54.0 g, 1.08 mol) in portions at 0 ° C. . The reaction mixture was then stirred at rt for 3 h. The reaction was quenched with water (1000 ml) and extracted with ethyl acetate (3 × 250 mL). The combined organic layers are washed with brine, dried over Na ₂ SO ₄ and evaporated in vacuo to give 2- (2,3-dihydro-1H-inden-5-yl) acetonitrile (82.2 g, 97%). It was used in the next step without further purification.

Step f: 1- (2,3-dihydro-1H-inden-6-yl) cyclopropanecarbonitrile

To a stirred solution of 2- (2,3-dihydro-1H-inden-5-yl) acetonitrile (50.0 g, 0.32 mol) in toluene (150 mL) sodium hydroxide (300 mL, 50 percent W / W in water) ), 1-bromo-2-chloroethane (92.6 ml, 1.12 mol) and (n-Bu) ₄ NBr (5 g, 15.51 mmol) were added. The mixture was heated at 60 ° C. overnight. After cooling to rt, the reaction mixture was diluted with water (400 mL) and extracted with EtOAc (3 × 200 mL). The combined organic extracts were washed with brine, dried over Na ₂ S0 ₄ , filtered, concentrated in vacuo and purified by column chromatography (petroleum ether: ethyl acetate = 10: 1) to give 1- (2,3-di Hydro-1H-inden-6-yl) cyclopropanecarbonitrile (9.3 g, 16%) was obtained.

Step g: 1- (2,3-dihydro-1H-inden-6-yl) cyclopropanecarboxylic acid

A solution of 150 mL of sodium hydroxide in stirred 1- (2,3-dihydro-1H-inden-6-yl) cyclopropanecarbonitrile (9.3 g, 50.8 mmol) in methanol (40 mL) (25% NaOH w in water) / w) was added. The mixture was heated at 100 ° C. for 8 hours. After cooling to rt, the reaction mixture was poured into ice water (0 ° C.), the pH was adjusted to pH = 4 with hydrogen chloride (1 N) and the mixture was extracted with dichloromethane (3 × 100 mL). The combined organic layers were dried over Na ₂ SO ₄ and evaporated in vacuo. The residue was purified by column chromatography (petroleum ether: ethyl acetate = 5: 1) to give 1- (2,3-dihydro-1H-inden-6-yl) cyclopropanecarboxylic acid (4.8 g, 47%) Obtained.

5-amino-2-tert-butyl-1H-indole-4-carbonitrile

a) KCN, DMSO; b) Pd / C, EtOAc

Step a: 2-tert-butyl-5-nitro-1H-indole-4-carbonitrile

To a solution of 2-tert-butyl-4-fluoro-5-nitro-1H-indole (4.0 g, 17 mmol) in DMSO (30 mL) was added KCN (3.4 g, 51 mmol). The mixture was stirred at 70 ° C. for 3 h, poured into water (80 mL) and extracted with ethyl acetate (50 mL × 3). The combined organic layers were washed with brine, dried over anhydrous Na ₂ SO ₄ , and concentrated in vacuo. The residue was purified by column chromatography on silica gel (7% EtOAc in petroleum ether) to give 2-tert-butyl-5-nitro-1H-indole-4-carbonitrile (2.2 g, 53%).

Step b: 5-Amino-2-tert-butyl-1 H-indole-4-carbonitrile

To a solution of 2-tert-butyl-5-nitro-1H-indole-4-carbonitrile (550 mg, 2.3 mmol) in EtOAc (10 mL) was added Raney Ni (0.1 g) under a nitrogen atmosphere. The mixture was stirred at rt under hydrogen atmosphere (1 atm) for 1 h. The catalyst was filtered through celite and the filtrate was evaporated in vacuo to afford 5-amino-2-tert-butyl-1H-indole-4-carbonitrile (250 mg, 51%).

N- (2-tert-butyl-4-cyano-1H-indol-5-yl) -1- (2,2-difluorobenzo [d] [1,3] dioxol-5-yl) cyclo Propanecarboxamide

Step a: N- (2-tert-butyl-4-cyano-1H-indol-5-yl) -1- (2,2-difluorobenzo [d] [1,3] dioxol-5- (1) cyclopropanecarboxamide

1- (2,2-difluorobenzo [d] [1,3] dioxol-5-yl) cyclopropanecarbonyl chloride (26 mg, 0.1 mmol) was added 5-amino-2 in DMF (1 mL). to a solution of -tert-butyl-1H-indole-4-carbonitrile (21 mg, 0.1 mmol) and triethylamine (41.7 μL, 0.3 mmol). The reaction was stirred at rt overnight, then filtered and purified by reverse phase HPLC to give the product, N- (2-tert-butyl-4-cyano-1H-indol-5-yl) -1- (2,2-di Fluorobenzo [d] [1,3] dioxol-5-yl) cyclopropanecarboxamide was obtained.

N- (2-tert-butyl-4-cyano-1- (2-hydroxyethyl) -1H-indol-5-yl) -1- (2,2-difluorobenzo [d] [1, 3] dioxol-5-yl) cyclopropanecarboxamide

Step a: 2-tert-butyl-1- (2-hydroxyethyl) -5-nitro-1H-indole-4-carbonitrile

2-tert-butyl-5-nitro-1H-indole-4-carbonitrile (200 mg, 0.82 mmol), 2-iodoethanol (77 μL, 0.98 mmol), cesium carbonate (534 mg, 1.64 mmol) and DMF (1.3 mL) was heated to 90 ° C. overnight. Then an additional amount of 2-iodoethanol (77 μL, 0.98 mmol) was added and the reaction stirred at 90 ° C. for 3 days. The reaction mixture was partitioned between ethyl acetate and water. The aqueous layer was washed with ethyl acetate, then the combined ethyl acetate layers were washed with water (x3) and brine, dried over MgSO ₄ and concentrated. The residue was purified by column chromatography (50-100% CH ₂ Cl ₂ -hexane) to afford the product as a yellow solid (180 mg, ˜25% purity (NMR), product co-eluate with indole starting material). It was.

Step b: 5-Amino-2-tert-butyl-1- (2-hydroxyethyl) -1 H-indole-4-carbonitrile

Pd- in a solution of 2-tert-butyl-1- (2-hydroxyethyl) -5-nitro-1H-indole-4-carbonitrile (180 mg, 0.63 mmol) in ethanol (6 mL) under N ₂ atmosphere. C (5% wt, 18 mg) was added. The reaction was flushed with N ₂ (g) followed by H ₂ (g) and stirred for 1.5 h at room temperature under H ₂ (atm). The reaction was filtered through celite and concentrated to give the product (150 mg, 93%).

Step c: N- (2-tert-butyl-4-cyano-1- (2-hydroxyethyl) -1H-indol-5-yl) -1- (2,2-difluorobenzo [d] [1,3] dioxol-5-yl) cyclopropanecarboxamide

1- (2,2-difluorobenzo [d] [1,3] dioxol-5-yl) cyclopropanecarbonyl chloride (196 mg, 0.75 mmol) was substituted with 5-amino- in dichloromethane (2 mL). To a solution of 2-tert-butyl-1- (2-hydroxyethyl) -1H-indole-4-carbonitrile (150 mg, 0.58 mmol) and triethylamine (242 μL, 1.74 mmol) was added. The reaction was stirred at rt overnight. The reaction mixture was diluted with dichloromethane and extracted with 1N HCl solution (x2), saturated NaHCO ₃ solution (x2), brine, dried over MgSO ₄ , filtered and concentrated. The residue was dissolved in DMSO and purified by reverse phase HPLC to give the product, N- (2-tert-butyl-4-cyano-1- (2-hydroxyethyl) -1H-indol-5-yl) -1- (2,2-Difluorobenzo [d] [1,3] dioxol-5-yl) cyclopropanecarboxamide was obtained.

2- (2-tert-butyl-5- (1- (2,2-difluorobenzo [d] [1,3] dioxol-5-yl) cyclopropanecarboxamido) -6-fluoro -1H-indol-1-yl) -N, N, N-trimethylethanealuminum chloride

Step a: tert-Butyl 2- (2-tert-butyl-5- (1- (2,2-difluorobenzo [d] [1,3] dioxol-5-yl) cyclopropanecarboxamido ) -6-fluoro-1H-indol-1-yl) ethylcarbamate

To 1- (2,2-difluorobenzo [d] [1,3] dioxol-5-yl) cyclopropanecarboxylic acid (90.14 mg, 0.3722 mmol) in thionyl chloride (81.28 μL, 1.117 mmol) N, N-dimethyl formamide (8.204 μL, 0.1064 mmol) was added. The reaction mixture was stirred for 30 minutes at room temperature, then excess thionyl chloride and N, N-dimethyl formamide were removed in vacuo to afford acid chloride. The acid chloride is then dissolved in dichloromethane (1.5 mL) and tert-butyl 2- (5-amino-2-tert-butyl-6-fluoro-1H-indol-1-yl in dichloromethane (1.5 mL). ) Was added slowly to a solution of ethylcarbamate (156.1 mg, 0.4467 mmol) and triethylamine (155.6 μL, 1.117 mmol). The resulting reaction mixture was stirred at rt for 21 h. The reaction mixture was diluted with dichloromethane (5 mL) and washed with 1N aqueous HCl (5 mL) and saturated aqueous NaHCO ₃ solution (5 mL). The organic layer was dried over Na ₂ S0 ₄ , filtered and evaporated under reduced pressure. The crude product was purified by column chromatography on silica gel (0-30% ethyl acetate in hexane) to give tert-butyl 2- (2-tert-butyl-5- (1- (2,2-difluorobenzo [d] ] [1,3] dioxol-5-yl) cyclopropanecarboxamido) -6-fluoro-1H-indol-1-yl) ethylcarbamate as white solid (140 mg, 66%) It was.

Step b: N- (1- (2-aminoethyl) -2-tert-butyl-6-fluoro-1H-indol-5-yl) -1- (2,2-difluorobenzo [d] [ 1,3] dioxol-5-yl) cyclopropanecarboxamide

Tert-butyl 2- (2-tert-butyl-5- (1- (2,2-difluorobenzo [d] [1,3] dioxol-5-yl) cyclopropane in dichloromethane (1.8 mL) To a solution of carboxamido) -6-fluoro-1H-indol-1-yl) ethylcarbamate (137.5 mg, 0.24 mmol) is added trifluoroacetic acid (444 μL, 5.8 mmol) and the mixture is Stir at room temperature for 1 hour. The reaction was diluted with dichloromethane and washed with saturated aqueous NaHCO ₃ solution (3 mL) and brine (3 mL). The organic layer was dried over Na ₂ S0 ₄ , filtered and evaporated under reduced pressure. The crude product was purified by column chromatography on silica gel (0-10% methanol in dichloromethane) to give N- (1- (2-aminoethyl) -2-tert-butyl-6-fluoro-1H-indole-5 -Yl) -1- (2,2-difluorobenzo [d] [1,3] dioxol-5-yl) cyclopropanecarboxamide was obtained as a white solid (93.7 mg, 82%).

Step c: 2- (2-tert-butyl-5- (1- (2,2-difluorobenzo [d] [1,3] dioxol-5-yl) cyclopropanecarboxamido) -6 -Fluoro-1H-indol-1-yl) -N, N, N-trimethylethanealuminum chloride

N- (1- (2-aminoethyl) -2-tert-butyl-6-fluoro-1H-indol-5-yl) -1- (2,2 in N, N-dimethyl formamide (1 mL) To a clear solution of -difluorobenzo [d] [1,3] dioxol-5-yl) cyclopropanecarboxamide (50 mg, 0.1056 mmol), methyl iodide (336.8 mg, 147.7 μL, 2.37 mmol ) And triethylamine (106.9 mg, 147.2 μL, 1.05 mmol) and the mixture was heated at 80 ° C. for 2 hours. The crude product was purified by reverse phase preparative HPLC. 22 mg of this product were dissolved in 1.25 M HCl (112 μL, 0.14 mmol) in methanol and heated at 60 ° C. for 1 hour. The reaction was cooled to room temperature. The product was first dried and then dissolved in dichloromethane and dried again. This procedure was repeated four times to give 2- (2-tert-butyl-5- (1- (2,2-difluorobenzo [d] [1,3] dioxol-5-yl) cyclopropanecarboxamidine Fig. 6) -Fluoro-1H-indol-1-yl) -N, N, N-trimethylethanealuminum chloride was obtained.

2- (4- (Tert-butyldimethylsilyloxy) -2-methylbutan-2-yl) -6-fluoro-5-nitro-1H-indole

Step a: 3-fluoro-4-nitroaniline

A mixture of N- (3-fluoro-4-nitro-phenyl) -2, 2-dimethyl-propionamide (87.0 g, 0.36 mol) in CH ₂ Cl ₂ (400 mL) and 6N hydrochloric acid (800 mL) was refluxed. Under heating for 2 hours. The reaction mixture was cooled to room temperature. The reaction mixture was diluted with 1000 mL of ethyl acetate and potassium carbonate (500.0 g) was added portionwise. The aqueous solution was separated and the organic layer was washed with brine and dried over anhydrous Na ₂ SO ₄ . The solvent was removed by evaporation under reduced pressure; The residue was purified by column chromatography on silica gel (petroleum ether / ethyl acetate 30: 1) to give 3-fluoro-4-nitroaniline (56.0 g, 99%).

Step b: 2-bromo-5-fluoro-4-nitroaniline

Bromine (17.7 mL, 0.36 mol) was added dropwise over 1 hour to a solution of 3-fluoro-4-nitroaniline (56 g, 0.36 mol) in acetic acid (500 mL). The reaction mixture was stirred at 0-5 ° C. for 1 hour in an ice bath. The reaction mixture was basified with saturated Na ₂ CO ₃ and extracted with ethyl acetate (200 mL × 3). The combined organic layers were washed with brine, dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a residue, which was purified by column chromatography on silica gel (petroleum ether / ethyl acetate 10: 1). To give 2-bromo-5-fluoro-4-nitroaniline (45.6 g, 84%) as a yellow solid.

Step c: ethyl 5- (2-amino-4-fluoro-5-nitrophenyl) -3,3-dimethylpent-4-inoate

Of 2-bromo-5-fluoro-4-nitroaniline (45.7 g, 0.19 mol) and ethyl 3,3-dimethylpent-4-inoate (88.3 g, 0.57 mol) in Et ₃ N (700 mL) To the solution was added Pd (PPh ₃ ) ₂ Cl ₂ (13.8 g, 0.02 mol) and CuI (3.6 g, 0.02 mol) under N ₂ . The reaction mixture was stirred at 70 ° C. for 8 hours. The reaction mixture was diluted with 500 mL of ethyl acetate and 1500 mL of water. The organic layer was separated, the aqueous phase extracted with ethyl acetate (500 mL × 3), the combined organic layers washed with brine, dried over anhydrous Na ₂ SO ₄ , filtered, evaporated under reduced pressure, and the residue was silica gel Purified by column chromatography on petroleum ether / ethyl acetate 10: 1) to ethyl-5- (2-amino-4-fluoro-5-nitrophenyl) -3,3-dimethylpent-4-inoate (34.5 g, 57%) was obtained.

Step d: Ethyl 3- (6-fluoro-5-nitro-1H-indol-2-yl) -3-methylbutanoate

Ethyl 5- (2-amino-4-fluoro-5-nitrophenyl) -3,3-dimethylpent-4-inoate (34.5 g, 0.11 mol) and PdCl _{2 in} CH ₃ CN (350 mL) (10.4 g, 58.6 nmol) was heated to reflux for 1.5 h. The reaction mixture was cooled to room temperature. Ethyl acetate (300 mL) was added and the precipitate was filtered off and washed with methanol. The filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography on silica gel (petroleum ether / ethyl acetate 40: 1) to give ethyl 3- (6-fluoro-5-nitro-1H-indol-2-yl. ) -3-methylbutanoate (34.0 g, 98%) was obtained as a deep yellow solid.

Step e: 3- (6-Fluoro-5-nitro-1H-indol-2-yl) -3-methylbutan-1-ol

DIBAL- in a solution of ethyl 3- (6-fluoro-5-nitro-1H-indol-2-yl) -3-methylbutanoate (34 g, 0.11 mol) in anhydrous CH ₂ Cl ₂ (400 mL). H (283.4 mL, 0.27 mol) was added dropwise at -78 ° C over 2 hours. The reaction mixture was stirred at −78 ° C. for 10 hours and then quenched by addition of water (200 mL). The precipitate was filtered off and washed with methanol. The filtrate was extracted with CH ₂ Cl ₂ (200 mL × 3) and the combined organic layers were washed with brine, dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (petroleum ether / ethyl acetate 50: 1) to give 3- (6-fluoro-5-nitro-1H-indol-2-yl) -3-methylbutan-1- Obtained (6.6 g, 22%).

Step f: 2- (4- (tert-Butyldimethylsilyloxy) -2-methylbutan-2-yl) -6-fluoro-5-nitro-1H-indole

CH ₂ Cl ₂ TBSCl (3.7 g, 25) in a solution of 3- (6-fluoro-5-nitro-1H-indol-2-yl) -3-methylbutan-1-ol (6.6 g, 25 mmol) in (80 mL) nmol) and imidazole (4.2 g, 62 nmol) were added at 0 ° C. The reaction mixture was stirred at rt for 12 h. The precipitate was filtered off and washed with methanol. The filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (petroleum ether / ethyl acetate 10: 1) to afford the desired product as a brown solid (5.0 g, 53%).

Benzyl 2,2-dimethylbut-3-inoate

Step a: Methyl 2,2-dimethyl-3-oxobutanoate

To a suspension of NaH (28.5 g, 0.718 mol, 60%) in THF (270 mL) was added dropwise a solution of 3-oxo-butyric acid methyl ester (78.6 g, 0.677 mol) in THF (70 mL) at 0 ° C. The mixture was stirred at 0 ° C for 0.5 h. MeI (99.0 g, 0.698 mol) was added dropwise at 0 ° C. The resulting mixture was warmed to rt and stirred for 1 h. NaH (28.5 g, 0.718 mol, 60%) was added in portions at 0 ° C. and the resulting mixture was subsequently stirred at 0 ° C. for 0.5 h. MeI (99.0 g, 0.698 mol) was then added dropwise at 0 ° C. The reaction mixture was allowed to warm up to room temperature and stirred overnight. The mixture was poured into ice water. The organic layer was separated. The aqueous phase was extracted with EtOAc (300 mL x 3). The combined organic layers were dried and evaporated under reduced pressure to afford methyl 2,2-dimethyl-3-oxobutanoate (52 g, 53%), which was used directly in the next step.

Step b: Methyl 3-chloro-2,2-dimethylbut-3-enoate

To a suspension of PCl ₅ (161 g, 0.772 mol) in dichloromethane (600 mL) was added methyl 2,2-dimethyl-3-oxobutanoate (52 g, 0.361 mol, crude from the last step) at 0 ° C. After dropwise addition, approximately 20 drops of anhydrous DMF were added. The mixture was heated at reflux overnight. After cooling, the reaction mixture was poured slowly into ice water. The organic layer was separated and the aqueous phase extracted with dichloromethane (300 mL x 3). The combined organic layers were washed with saturated aqueous NaHCO ₃ solution and dried over anhydrous Na ₂ SO ₄ . Evaporation of the solvent gave the product, methyl 3-chloro-2,2-dimethylbut-3-enoate, which was used without further purification (47 g, 82%).

Step c: 3-chloro-2,2-dimethylbut-3-enoic acid

A mixture of methyl 3-chloro-2,2-dimethylbut-3-enoate (42.0 g, 0.26 mol) and NaOH (12.4 g, 0.31 mol) in water (300 mL) was heated at reflux overnight. After cooling, the reaction mixture was extracted with ether. The organic layer contained 20 g (48% recovery) of methyl 3-chloro-2,2-dimethylbut-3-enoate. The aqueous layer was acidified with cold 20% HCl solution and extracted with ether (250 mL × 3). The combined organic layers were dried and evaporated under reduced pressure to afford 3-chloro-2,2-dimethylbut-3-enoic acid (17 g, 44%), which was used directly in the next step.

Step d: 2,2-dimethylbut-3-phosphate

To a three necked flask (500 mL) was added NaNH ₂ (17.8 g, 0.458 mmol, pellet) and DMSO (50 mL). The mixture was stirred at room temperature until no NH ₃ (g) was generated. A solution of 3-chloro-2,2-dimethylbut-3-enoic acid (17.0 g, 114 mmol) in DMSO (50 mL) was added dropwise at 0 ° C. The mixture was warmed and stirred at 50 ° C. for 5 hours and then at room temperature overnight. The mixture was poured into cold 20% HCl solution and then extracted three times with ether. The ether extract was dried over anhydrous Na ₂ S0 ₄ and concentrated to give a 6: 1 ratio of starting material and alkyne product. The residue was redried using ether and Na ₂ SO ₄ and placed back under the reaction conditions. The reaction mixture was worked up in the same manner to give 2,2-dimethylbut-3-phosphate (12.0 g, 94%).

Benzyl 2,2-dimethylbut-3-inoate

To a stirred solution of 2,2-dimethylbut-3-phosphate (87.7 g, 0.782 mmol) and benzyl alcohol (114.6 g, 0.938 mol) in dichloromethane (800 mL) add DCC (193.5 g, 0.938 mmol) at -20 ° C. Was added. The reaction mixture was stirred at rt overnight, then the solvent was evaporated in vacuo. The residue was purified by chromatography on silica gel (2% ethyl acetate in petroleum ether as eluent) to afford benzyl 2,2-dimethylbut-3-inoate (100 g, 59% yield).

2- (1- (Tert-butyldimethylsilyloxy) -2-methylpropan-2-yl) -6-fluoro-5-nitro-1H-indole

Step a: Benzyl 4- (2-amino-4-fluoro-5-nitrophenyl) -2,2-dimethylbut-3-inoate

To a solution of 2-bromo-5-fluoro-4-nitroaniline (23.0 g, 0.1 mol) in Et ₃ N (250 mL) benzoic acid 2,2-dimethylbut-3-phosphate anhydride (59.0 g, 0.29 mol ), CuI (1.85 g) and Pd (PPh ₃ ) ₂ Cl ₂ (2.3 g) were added at room temperature. The mixture was stirred at 80 ° C overnight. After cooling to rt, the reaction was quenched with water and the aqueous layer was extracted with ethyl acetate (100 mL x 3). The combined organic layers were dried over anhydrous Na ₂ SO ₄ and the solvent was evaporated in vacuo. The residue was purified by chromatography on silica gel (10% ethyl acetate in petroleum ether) to benzyl 4- (2-amino-4-fluoro-5-nitrophenyl) -2,2-dimethylbut-3-inoate (20.0 g, 56%) was obtained.

Step b: Benzyl 2- (6-fluoro-5-nitro-1H-indol-2-yl) -2-methylpropanoate

PdCl ₂ (20.0 g, 56 mmol) in a solution of benzyl 4- (2-amino-4-fluoro-5-nitrophenyl) -2,2-dimethylbut-3-inoate in acetonitrile (100 mL) 5.0 g, 28 mmol) was added at room temperature. The mixture was stirred at 80 ° C overnight. The mixture is filtered, the solvent is evaporated in vacuo and the residue is purified by chromatography on silica gel (10% EtOAc in petroleum ether) to benzyl 2- (6-fluoro-5-nitro-1H-indole-2- Il) -2-methylpropanoate (18.0 g, 90%) was obtained.

Step c: 2- (6-Fluoro-5-nitro-1H-indol-2-yl) -2-methylpropan-1-ol

CH ₂ Cl ₂ DIBAL-H (12 mL) in a solution of benzyl 2- (6-fluoro-5-nitro-1H-indol-2-yl) -2-methylpropanoate (18.0 g, 0.05 mol) in (100 mL) Was added at -78 ° C. The mixture was stirred at that temperature for 1 hour and warmed to room temperature. The reaction was quenched with water and the aqueous layer was extracted with EtOAc (100 mL x 3). The combined organic layers were dried over anhydrous Na ₂ SO ₄ and the solvent was evaporated in vacuo. The residue was purified by chromatography on silica gel (10% EtOAc in petroleum ether) to give 2- (6-fluoro-5-nitro-1H-indol-2-yl) -2-methylpropan-1-ol (10.0 g, 77%).

Step d: 2- (1- (tert-Butyldimethylsilyloxy) -2-methylpropan-2-yl) -6-fluoro-5-nitro-1H-indole

To a stirred solution of 2- (6-fluoro-5-nitro-1H-indol-2-yl) -2-methylpropan-1-ol (10.0g) in CH ₂ Cl ₂ TBSCl (8.9 g), imidazole (8.1 g, 0.12 mol) was added at room temperature. The mixture was stirred overnight. The solvent was evaporated in vacuo and the residue was purified by chromatography on silica gel (10% EtOAc in petroleum ether) to give 2- (1- (tert-butyldimethylsilyloxy) -2-methylpropan-2-yl)- 6-Fluoro-5-nitro-1H-indole (5.3 g, 38%) was obtained.

6-fluoro-1,1-dimethyl-7-nitro-2,3-dihydro-1H-pyrrolo [1,2-a] indole, (R) -3- (1-((2,2- Dimethyl-1,3-dioxolan-4-yl) methyl) -6-fluoro-5-nitro-1H-indol-2-yl) -3-methylbutan-1-ol, 2- (4-(( (R) -2,2-dimethyl-1,3-dioxolan-4-yl) methoxy) -2-methylbutan-2-yl) -1-(((R) -2,2-dimethyl-1 , 3-dioxolan-4-yl) methyl) -6-fluoro-5-nitro-1H-indole, 3- (6-fluoro-5-nitro-1H-indol-2-yl) -3-methyl Butan-1-ol and (R) -2- (4-((2,2-dimethyl-1,3-dioxolan-4-yl) methoxy) -2-methylbutan-2-yl) -6- Fluoro-5-nitro-1H-indole

Step a: 6-Fluoro-1,1-dimethyl-7-nitro-2,3-dihydro-1H-pyrrolo [1,2-a] indole, (R) -3- (1-((2 , 2-dimethyl-1,3-dioxolan-4-yl) methyl) -6-fluoro-5-nitro-1H-indol-2-yl) -3-methylbutan-1-ol, 2- (4 -(((R) -2,2-dimethyl-1,3-dioxolan-4-yl) methoxy) -2-methylbutan-2-yl) -1-(((R) -2,2- Dimethyl-1,3-dioxolan-4-yl) methyl) -6-fluoro-5-nitro-1H-indole, 3- (6-fluoro-5-nitro-1H-indol-2-yl)- 3-methylbutan-1-ol and (R) -2- (4-((2,2-dimethyl-1,3-dioxolan-4-yl) methoxy) -2-methylbutan-2-yl) -6-fluoro-5-nitro-lH-indole

2- (4- (tert-butyldimethylsilyloxy) -2-methylbutan-2-yl) -6-fluoro-5-nitro-1H-indole (1.9 g, 5.0 mmol) in DMF (10 mL) and Cs ₂ CO ₃ (4.88 g, 15.0 mmol) in a solution of (S)-(2,2-dimethyl-1,3-dioxolan-4-yl) methyl 4-methylbenzenesulfonate (2.86 g, 10.0 mmol) Was added. The mixture was heated at 90 ° C. for 24 h. The reaction was partitioned between ethyl acetate and water. The aqueous layer was extracted with ethyl acetate and the combined organic layers were washed with brine and dried over MgSO ₄ . After removal of the solvent, the residue was purified by column chromatography (10-50% ethyl acetate-hexanes) to 6-fluoro-1,1-dimethyl-7-nitro-2,3-dihydro-1H-pyrrolo [1,2-a] indole (600 mg, 48%) was obtained.

;

;

2- (4-(((R) -2,2-dimethyl-1,3-dioxolan-4-yl) methoxy) -2-methylbutan-2-yl) -1-(((R)- 2,2-dimethyl-1,3-dioxolan-4-yl) methyl) -6-fluoro-5-nitro-1H-indole (270 mg, (R) -2- (4-((2,2,2) Dimethyl-1,3-dioxolan-4-yl) methoxy) -2-methylbutan-2-yl) -6-fluoro-5-nitro-1H-indole).

;

;

(R) -3- (1-((2,2-dimethyl-1,3-dioxolan-4-yl) methyl) -6-fluoro-5-nitro-1H-indol-2-yl) -3 -Methylbutan-1-ol (1.0 g, containing some 3- (6-fluoro-5-nitro-1H-indol-2-yl) -3-methylbutan-1-ol).

(R) -2- (1-((2,2-dimethyl-1,3-dioxolan-4-yl) methyl) -6-fluoro-5-nitro-1H-indol-2-yl) -2 -Methylpropan-1-ol and 3- (6-fluoro-5-nitro-1H-indol-2-yl) -3-methylbutan-1-ol

(R) -2- (1-((2,2-dimethyl-1,3-dioxolan-4-yl) methyl) -6-fluoro-5-nitro-1H-indol-2-yl) -2 A mixture containing -methylpropan-1-ol and 3- (6-fluoro-5-nitro-1H-indol-2-yl) -3-methylbutan-1-ol was prepared according to the procedure indicated above in 2- ( Obtained starting from 1- (tert-butyldimethylsilyloxy) -2-methylpropan-2-yl) -6-fluoro-5-nitro-1H-indole. (R) -2- (1-((2,2-dimethyl-1,3-dioxolan-4-yl) methyl) -6-fluoro-5-nitro-1H-indol-2-yl) -2 Methylpropan-1-ol,

;

;

3- (6-fluoro-5-nitro-1H-indol-2-yl) -3-methylbutan-1-ol,

1- (2,2-difluorobenzo [d] [1,3] dioxol-5-yl) -N- (6-fluoro-1,1-dimethyl-2,3-dihydro-1H- Pyrrolo [1,2-a] indol-7-yl) cyclopropanecarboxamide

Step a: 6-fluoro-1,1-dimethyl-2,3-dihydro-1H-pyrrolo [1,2-a] indol-7-amine

To a solution of 6-fluoro-1,1-dimethyl-7-nitro-2,3-dihydro-1H-pyrrolo [1,2-a] indole (600 mg, 2.4 mmol) in ethanol (15 mL) Ammonium formate (600 mg, 9.5 mmol) and Pd / C (10%, 129 mg, 0.12 mmol) were added. The mixture was refluxed for 10 minutes. The Pd catalyst was removed by filtration through celite and washed with ethanol. The filtrate was concentrated and purified by column chromatography (20-40% ethyl acetate-hexane) to give 6-fluoro-1,1-dimethyl-2,3-dihydro-1H-pyrrolo [1,2-a ] Indole-7-amine (260 mg, 49%) was obtained.

Step b: 1- (2,2-Difluorobenzo [d] [1,3] dioxol-5-yl) -N- (6-fluoro-1,1-dimethyl-2,3-dihydro -1H-pyrrolo [1,2-a] indol-7-yl) cyclopropanecarboxamide

1- (2,2-difluorobenzo [d] [1,3] dioxol-5-yl) cyclopropanecarboxylic acid (346 mg, 1.4 mmol) in 6 mL of DMF (5 mL), 6-fluoro- Triethyl in a mixture of 1,1-dimethyl-2,3-dihydro-1H-pyrrolo [1,2-a] indol-7-amine (260 mg, 1.2 mmol) and HATU (543 mg, 1.4 mmol) Amine (0.40 mL, 2.9 mmol) was added. The reaction was stirred at rt overnight and then partitioned between ethyl acetate and water. The aqueous layer was extracted with ethyl acetate and the combined organic layers were washed with brine and dried over MgSO ₄ . After removal of the solvent, the residue was purified by column chromatography (10-20% ethyl acetate-hexanes) to give 1- (2,2-difluorobenzo [d] [1,3] dioxol-5-yl) -N- (6-fluoro-1,1-dimethyl-2,3-dihydro-1H-pyrrolo [1,2-a] indol-7-yl) cyclopropanecarboxamide (342 mg, 65% ) Was obtained.

(R) -1- (2,2-difluorobenzo [d] [1,3] dioxol-5-yl) -N- (1- (2,3-dihydroxypropyl) -6-fluoro Rho-2- (4-hydroxy-2-methylbutan-2-yl) -1H-indol-5-yl) cyclopropanecarboxamide

Step a: (R) -3- (5-amino-1-((2,2-dimethyl-1,3-dioxolan-4-yl) methyl) -6-fluoro-1H-indol-2-yl ) -3-methylbutan-1-ol

(R)-containing some 3- (6-fluoro-5-nitro-1H-indol-2-yl) -3-methylbutan-1-ol (500 mg, 1.3 mmol) in ethanol (10 mL) 3- (1-((2,2-dimethyl-1,3-dioxolan-4-yl) methyl) -6-fluoro-5-nitro-1H-indol-2-yl) -3-methylbutane- To a solution of 1-ol ammonium formate (500 mg, 7.9 mmol) and Pd / C (10%, 139 mg, 0.13 mmol) were added. The mixture was refluxed for 5 minutes. The Pd catalyst was removed by filtration through celite and washed with ethanol. The filtrate was evaporated to dryness and purified by column chromatography (30-50% ethyl acetate-hexane) to give (R) -3- (5-amino-1-((2,2-dimethyl-1,3-dioxolane). -4-yl) methyl) -6-fluoro-1H-indol-2-yl) -3-methylbutan-1-ol (220 mg, 48%, 3- (5-amino-6-fluoro-1H) -Indol-2-yl) -3-methylbutan-1-ol).

Step b: (R) -1- (2,2-Difluorobenzo [d] [1,3] dioxol-5-yl) -N- (1-((2,2-dimethyl-1,3 -Dioxolan-4-yl) methyl) -6-fluoro-2- (4-hydroxy-2-methylbutan-2-yl) -1H-indol-5-yl) cyclopropanecarboxamide

1- (2,2-difluorobenzo [d] [1,3] dioxol-5-yl) cyclopropanecarboxylic acid (183 mg, 0.75 mmol) in DMF (3.0 mL), some 3- (5 (R) -3- (5-amino-1-(() containing -amino-6-fluoro-1H-indol-2-yl) -3-methylbutan-1-ol (220 mg, 0.63 mmol) 2,2-dimethyl-1,3-dioxolan-4-yl) methyl) -6-fluoro-1H-indol-2-yl) -3-methylbutan-1-ol and HATU (287 mg, 0.75 mmol To the mixture of was added triethylamine (0.21 mL, 1.5 mmol). The reaction was stirred at rt overnight and then partitioned between ethyl acetate and water. The aqueous layer was extracted with ethyl acetate and the combined organic layers were washed with brine and dried over MgSO ₄ . After removal of the solvent, the residue was purified by column chromatography (20-40% ethyl acetate-hexane) to give (R) -1- (2,2-difluorobenzo [d] [1,3] dioxol- 5-yl) -N- (1-((2,2-dimethyl-1,3-dioxolan-4-yl) methyl) -6-fluoro-2- (4-hydroxy-2-methylbutane- 2-yl) -1H-indol-5-yl) cyclopropanecarboxamide (315 mg, 87%, 1- (2,2-difluorobenzo [d] [1,3] dioxol-5-yl ) -N- (6-fluoro-2- (4-hydroxy-2-methylbutan-2-yl) -1H-indol-5-yl) cyclopropanecarboxamide) was obtained.

Step c: (R) -1- (2,2-Difluorobenzo [d] [1,3] dioxol-5-yl) -N- (1- (2,3-dihydroxypropyl)- 6-fluoro-2- (4-hydroxy-2-methylbutan-2-yl) -1H-indol-5-yl) cyclopropanecarboxamide

Some 1- (2,2-difluorobenzo [d] [1,3] dioxol-5-yl) -N- (6-fluoro-2- in methanol (3 mL) and water (0.3 mL) (R) -1- (2,2-) containing (4-hydroxy-2-methylbutan-2-yl) -1H-indol-5-yl) cyclopropanecarboxamide (315 mg, 0.55 mmol) Difluorobenzo [d] [1,3] dioxol-5-yl) -N- (1-((2,2-dimethyl-1,3-dioxolan-4-yl) methyl) -6-fluoro P-TsOH.H ₂ O (21 mg, 0.11 mmol) in a solution of rho-2- (4-hydroxy-2-methylbutan-2-yl) -1H-indol-5-yl) cyclopropanecarboxamide Was added. The mixture was heated at 80 ° C. for 30 minutes. The reaction was partitioned between ethyl acetate and water and the aqueous layer was extracted twice with ethyl acetate. Saturated combined organic layer. Washed with NaHCO ₃ solution and brine and dried over MgSO ₄ . After removing the solvent, the residue was purified by column chromatography (20-80% ethyl acetate-hexane) to give (R) -1- (2,2-difluorobenzo [d] [1,3] dioxol- 5-yl) -N- (1- (2,3-dihydroxypropyl) -6-fluoro-2- (4-hydroxy-2-methylbutan-2-yl) -1H-indole-5- 1) cyclopropanecarboxamide (92 mg, 31%) was obtained.

1- (2,2-difluorobenzo [d] [1,3] dioxol-5-yl) -N- (2- (4-((S) -2,3-dihydroxypropoxy) -2-methylbutan-2-yl) -1-((R) -2,3-dihydroxypropyl) -6-fluoro-1H-indol-5-yl) cyclopropanecarboxamide and (S) -1- (2,2-difluorobenzo [d] [1,3] dioxol-5-yl) -N- (2- (4- (2,3-dihydroxypropoxy) -2- Methylbutan-2-yl) -6-fluoro-1H-indol-5-yl) cyclopropanecarboxamide

1- (2,2-difluorobenzo [d] [1,3] dioxol-5-yl) -N- (2- (4-((S) -2,3-dihydroxypropoxy) -2-methylbutan-2-yl) -1-((R) -2,3-dihydroxypropyl) -6-fluoro-1H-indol-5-yl) cyclopropanecarboxamide and (S) -1- (2,2-difluorobenzo [d] [1,3] dioxol-5-yl) -N- (2- (4- (2,3-dihydroxypropoxy) -2- Methylbutan-2-yl) -6-fluoro-1H-indol-5-yl) cyclopropanecarboxamide

1- (2,2-difluorobenzo [d] [1,3] dioxol-5-yl) -N- (2- (4-((S) -2,3-dihydroxypropoxy) -2-methylbutan-2-yl) -1-((R) -2,3-dihydroxypropyl) -6-fluoro-1H-indol-5-yl) cyclopropanecarboxamide and (S) -1- (2,2-difluorobenzo [d] [1,3] dioxol-5-yl) -N- (2- (4- (2,3-dihydroxypropoxy) -2- Methylbutan-2-yl) -6-fluoro-1H-indol-5-yl) cyclopropanecarboxamide was prepared in accordance with a scheme similar to that shown above, in part (R) -2- (4-((2,2- Dimethyl-1,3-dioxolan-4-yl) methoxy) -2-methylbutan-2-yl) -6-fluoro-5-nitro-1H-indole containing 2- (4-((( R) -2,2-dimethyl-1,3-dioxolan-4-yl) methoxy) -2-methylbutan-2-yl) -1-(((R) -2,2-dimethyl-1, Prepared from 3-dioxolan-4-yl) methyl) -6-fluoro-5-nitro-1H-indole. 1- (2,2-difluorobenzo [d] [1,3] dioxol-5-yl) -N- (2- (4-((S) -2,3-dihydroxypropoxy) -2-methylbutan-2-yl) -1-((R) -2,3-dihydroxypropyl) -6-fluoro-1H-indol-5-yl) cyclopropanecarboxamide,

;

;

(S) -1- (2,2-difluorobenzo [d] [1,3] dioxol-5-yl) -N- (2- (4- (2,3-dihydroxypropoxy) -2-methylbutan-2-yl) -6-fluoro-1H-indol-5-yl) cyclopropanecarboxamide,

1- (2,2-difluorobenzo [d] [1,3] dioxol-5-yl) -N- (6-fluoro-2- (1-hydroxy-2-methylpropane-2- Yl) -1H-indol-5-yl) cyclopropanecarboxamide

1- (2,2-difluorobenzo [d] [1,3] dioxol-5-yl) -N- (6-fluoro-2- (1-hydroxy-2-methylpropane-2- Yl) -1H-indol-5-yl) cyclopropanecarboxamide

1- (2,2-difluorobenzo [d] [1,3] dioxol-5-yl) -N- (6-fluoro-2- (1-hydroxy-2-methylpropane-2- (R) -2- (1-((2,2-dimethyl-1,3-dioxolan-4-yl) according to the reaction scheme shown above for 1) -1H-indol-5-yl) cyclopropanecarboxamide Methyl) -6-fluoro-5-nitro-1H-indol-2-yl) -2-methylpropan-1-ol and 3- (6-fluoro-5-nitro-1H-indol-2-yl) Prepared from a mixture containing 3-methylbutan-1-ol.

(R) -1- (2,2-difluorobenzo [d] [1,3] dioxol-5-yl) -N- (1- (2,3-dihydroxypropyl) -6-fluoro Rho-2- (1-hydroxy-2-methylpropan-2-yl) -1H-indol-5-yl) cyclopropanecarboxamide

Step a: (R) -Benzyl 2- (1-((2,2-dimethyl-1,3-dioxolan-4-yl) methyl) -6-fluoro-5-nitro-1H-indole-2- Yl) -2-methylpropanoate and ((S) -2,2-dimethyl-1,3-dioxolan-4-yl) methyl 2- (1-(((R) -2,2-dimethyl- 1,3-dioxolan-4-yl) methyl) -6-fluoro-5-nitro-1H-indol-2-yl) -2-methylpropanoate

Cesium carbonate (8.23 g, 25.3 mmol) was added to benzyl 2- (6-fluoro-5-nitro-1H-indol-2-yl) -2-methylpropanoate (3.0 g, 8.4 mmol) in DMF (17 mL). ) And (S)-(2,2-dimethyl-1,3-dioxolan-4-yl) methyl 4-methylbenzenesulfonate (7.23 g, 25.3 mmol). The reaction was stirred at 80 ° C. for 46 hours under a nitrogen atmosphere. The mixture was then partitioned between ethyl acetate and water. The aqueous layer was extracted with ethyl acetate. The combined ethyl acetate layers were washed with brine, dried over MgSO ₄ , filtered and concentrated. The crude product, viscous brown oil, containing both of the products indicated above was used directly in the next step without further purification. (R) -benzyl 2- (1-((2,2-dimethyl-1,3-dioxolan-4-yl) methyl) -6-fluoro-5-nitro-1H-indol-2-yl)- 2-methylpropanoate,

((S) -2,2-dimethyl-1,3-dioxolan-4-yl) methyl 2- (1-(((R) -2,2-dimethyl-1,3-dioxolan-4-yl ) Methyl) -6-fluoro-5-nitro-1H-indol-2-yl) -2-methylpropanoate,

Step b: (R) -2- (1-((2,2-dimethyl-1,3-dioxolan-4-yl) methyl) -6-fluoro-5-nitro-1H-indol-2-yl ) -2-methylpropan-1-ol

The crude reaction mixture obtained in step (a) was dissolved in THF (42 mL) and cooled in an ice water bath. LiAlH ₄ (16.8 mL of 1M solution, 16.8 mmol) was added dropwise. After the addition was complete, the reaction was stirred for an additional 5 minutes. The reaction was quenched by addition of water (1 mL), 15% NaOH solution (1 mL) followed by water (3 mL). The mixture was filtered through celite and the solids were washed with THF and ethyl acetate. The filtrate was concentrated and purified by column chromatography (30-60% ethyl acetate-hexane) to give the product as a brown oil (2.68 g, 87% over 2 steps).

Step c: (R) -2- (5-amino-1-((2,2-dimethyl-1,3-dioxolan-4-yl) methyl) -6-fluoro-1H-indol-2-yl ) -2-methylpropan-1-ol

(R) -2- (1-((2,2-dimethyl-1,3-dioxolan-4-yl) methyl) -6-fluoro-5-nitro-1H-indol-2-yl) -2 -Methylpropan-1-ol (2.5 g, 6.82 mmol) was dissolved in ethanol (70 mL) and the reaction was flushed with N ₂ . Then Pd-C (250 mg, 5% wt) was added. The reaction was flushed again with nitrogen and then stirred under H ₂ (atm). After 2.5 hours, only partial conversion to the product was observed by LCMS. The reaction was filtered through celite and concentrated. The residue was put back under the above conditions. After 2 hours, LCMS showed complete conversion to the product. The reaction mixture was filtered through celite. The filtrate was concentrated to give the product as a black solid (1.82 g, 79%).

Step d: (R) -1- (2,2-Difluorobenzo [d] [1,3] dioxol-5-yl) -N- (1-((2,2-dimethyl-1,3 -Dioxolan-4-yl) methyl) -6-fluoro-2- (1-hydroxy-2-methylpropan-2-yl) -1H-indol-5-yl) cyclopropanecarboxamide

DMF (3 drops) was added 1- (2,2-difluorobenzo [d] [1,3] dioxol-5-yl) cyclopropanecarboxylic acid (1.87 g, 7.7 mmol) and thionyl chloride (1.30 mL, 17.9 mmol) was added to the stirred mixture. After 1 hour, a clear solution was formed. The solution was concentrated in vacuo, then toluene (3 mL) was added and the mixture was concentrated again. The toluene step was repeated once more and the residue was placed under high vacuum for 10 minutes. The acid chloride is then dissolved in dichloromethane (10 mL) and (R) -2- (5-amino-1-((2,2-dimethyl-1,3-dioxolane-) in dichloromethane (45 mL). 4-yl) methyl) -6-fluoro-1H-indol-2-yl) -2-methylpropan-1-ol (1.8 g, 5.4 mmol) and triethylamine (2.24 mL, 16.1 mmol) Added. The reaction was stirred at rt for 1 h. The reaction was washed with 1N HCl solution, saturated NaHCO ₃ solution and brine, dried over MgSO ₄ and concentrated to give the product as a black effervescent solid (3 g, 100%).

Step e: (R) -1- (2,2-Difluorobenzo [d] [1,3] dioxol-5-yl) -N- (1- (2,3-dihydroxypropyl)- 6-fluoro-2- (1-hydroxy-2-methylpropan-2-yl) -1H-indol-5-yl) cyclopropanecarboxamide

(R) -1- (2,2-difluorobenzo [d] [1,3] dioxol-5-yl) -N- (1-((2,2-dimethyl-1,3-dioxolane -4-yl) methyl) -6-fluoro-2- (1-hydroxy-2-methylpropan-2-yl) -1H-indol-5-yl) cyclopropanecarboxamide (3.0 g, 5.4 mmol ) Was dissolved in methanol (52 mL). Water (5.2 mL) was added followed by p-TsOH.H ₂ O (204 mg, 1.1 mmol). The reaction was heated at 80 ° C. for 45 minutes. The solution was concentrated and then partitioned between ethyl acetate and saturated NaHCO ₃ solution. The ethyl acetate layer was dried over MgSO ₄ and concentrated. The residue was purified by column chromatography (50-100% ethyl acetate-hexanes) to give the product as a creamy effervescent solid. (1.3 g, 47%, ee> 98% (SFC)).

(S) -1- (2,2-difluorobenzo [d] [1,3] dioxol-5-yl) -N- (1- (2,3-dihydroxypropyl) -6-fluoro Rho-2- (1-hydroxy-2-methylpropan-2-yl) -1H-indol-5-yl) cyclopropanecarboxamide

Step a: (S) -benzyl 2- (1-((2,2-dimethyl-1,3-dioxolan-4-yl) methyl) -6-fluoro-5-nitro-1H-indole-2- Yl) -2-methylpropanoate and ((R) -2,2-dimethyl-1,3-dioxolan-4-yl) methyl 2- (1-(((S) -2,2-dimethyl- 1,3-dioxolan-4-yl) methyl) -6-fluoro-5-nitro-1H-indol-2-yl) -2-methylpropanoate

Cesium carbonate (2.74 g, 8.4 mmol) was added to benzyl 2- (6-fluoro-5-nitro-1H-indol-2-yl) -2-methylpropanoate (1.0 g, 2.8 mmol) in DMF (5.6 mL). ) And (S)-(2,2-dimethyl-1,3-dioxolan-4-yl) methyl 4-methylbenzenesulfonate (3.21 g, 11.2 mmol). The reaction was stirred at 80 ° C. for 64 h under a nitrogen atmosphere. The mixture was then partitioned between ethyl acetate and water. The aqueous layer was extracted with ethyl acetate. The combined ethyl acetate layers were washed with brine, dried over MgSO ₄ , filtered and concentrated. The crude product, viscous brown oil, containing both of the products indicated above was used directly in the next step without further purification. (S) -benzyl 2- (1-((2,2-dimethyl-1,3-dioxolan-4-yl) methyl) -6-fluoro-5-nitro-1H-indol-2-yl)- 2-methylpropanoate,

((R) -2,2-dimethyl-1,3-dioxolan-4-yl) methyl 2- (1-(((S) -2,2-dimethyl-1,3-dioxolan-4-yl ) Methyl) -6-fluoro-5-nitro-1H-indol-2-yl) -2-methylpropanoate,

Step b: (S) -2- (1-((2,2-dimethyl-1,3-dioxolan-4-yl) methyl) -6-fluoro-5-nitro-1H-indol-2-yl ) -2-methylpropan-1-ol

Mixture of crude reaction mixture of (S) -benzyl 2- (1-((2,2-dimethyl-1,3-dioxolan-4-yl) methyl) -6-fluoro-5-nitro-1H-indole -2-yl) -2-methylpropanoate and ((R) -2,2-dimethyl-1,3-dioxolan-4-yl) methyl 2- (1-(((S) -2,2 -Dimethyl-1,3-dioxolan-4-yl) methyl) -6-fluoro-5-nitro-1H-indol-2-yl) -2-methylpropanoate was dissolved in THF (15 mL) and Cooled in an ice-water bath. LiAlH ₄ (2.8 mL of 1M solution, 2.8 mmol) was added dropwise. After the addition was complete, the reaction was stirred for 5 minutes. The reaction was quenched by addition of water (0.5 mL), 15% NaOH solution (0.5 mL) followed by water (1.5 mL). The mixture was filtered through celite and the solids were washed with THF and ethyl acetate. The filtrate was concentrated and purified by column chromatography (30-60% ethyl acetate-hexane) to give the product as brown oil (505 mg, 49% over 2 steps).

Step c: (S) -2- (5-amino-1-((2,2-dimethyl-1,3-dioxolan-4-yl) methyl) -6-fluoro-1H-indol-2-yl ) -2-methylpropan-1-ol

(S) -2- (1-((2,2-dimethyl-1,3-dioxolan-4-yl) methyl) -6-fluoro-5-nitro-1H-indol-2-yl) -2 Methylpropan-1-ol (500 mg, 1.4 mmol) was dissolved in ethanol (15 mL) and the reaction was flushed with N ₂ . Then Pd-C (50 mg, 5% wt) was added. The reaction was flushed again with nitrogen and then stirred under H ₂ (atm). After 1 hour, only partial conversion to the product was observed by LCMS. The reaction was filtered through celite and concentrated. The residue was put back under the above conditions. After 1 hour, LCMS showed complete conversion to the product. The reaction mixture was filtered through celite. The filtrate was concentrated to give the product as a black solid (420 mg, 91%).

Step d: (S) -1- (2,2-Difluorobenzo [d] [1,3] dioxol-5-yl) -N- (1-((2,2-dimethyl-1,3 -Dioxolan-4-yl) methyl) -6-fluoro-2- (1-hydroxy-2-methylpropan-2-yl) -1H-indol-5-yl) cyclopropanecarboxamide

DMF (3 drops) was diluted with 1- (2,2-difluorobenzo [d] [1,3] dioxol-5-yl) cyclopropanecarboxylic acid (187 mg, 0.8 mmol) and thionyl chloride (0.13 mL, 1.8 mmol) was added to the stirred mixture. After 30 minutes, a clear solution formed. A small amount was mixed with piperidine to test if acid chloride was formed. The solution was concentrated by rotary evaporator, then toluene (1 mL) was added and the mixture was concentrated again. The toluene step was repeated once more and the residue was placed under high vacuum for 10 minutes. The acid chloride is then dissolved in dichloromethane (2 mL) and (S) -2- (5-amino-1-((2,2-dimethyl-1,3-dioxolane-) in dichloromethane (4 mL). 4-yl) methyl) -6-fluoro-1H-indol-2-yl) -2-methylpropan-1-ol (200 mg, 0.6 mmol) and triethylamine (0.25 mL, 1.8 mmol) Added. The reaction was stirred at rt for 45 min. The reaction was washed with 1N HCl solution, saturated NaHCO ₃ solution and brine, dried over MgSO ₄ and concentrated to give the product as a black effervescent solid (320 mg, 96%).

Step e: (S) -1- (2,2-Difluorobenzo [d] [1,3] dioxol-5-yl) -N- (1- (2,3-dihydroxypropyl)- 6-fluoro-2- (1-hydroxy-2-methylpropan-2-yl) -1H-indol-5-yl) cyclopropanecarboxamide

(S) -1- (2,2-difluorobenzo [d] [1,3] dioxol-5-yl) -N- (1-((2,2-dimethyl-1,3-dioxolane -4-yl) methyl) -6-fluoro-2- (1-hydroxy-2-methylpropan-2-yl) -1H-indol-5-yl) cyclopropanecarboxamide (290 g, 0.5 mmol ) Was dissolved in methanol (5 mL). Water (0.5 mL) was added followed by p-TsOH.H ₂ O (20 mg, 0.1 mmol). The reaction was heated at 80 ° C. for 45 minutes. The solution was then partitioned between ethyl acetate and saturated NaHCO ₃ solution. The ethyl acetate layer was dried over MgSO ₄ and concentrated. The residue was purified by column chromatography (50-100% ethyl acetate-hexanes) to give the product as a creamy effervescent solid. (146 mg, 54%, ee> 97% (SFC)).

(R) -1- (benzo [d] [1,3] dioxol-5-yl) -N- (2-tert-butyl-1- (2,3-dihydroxypropyl) -6-fluoro -1H-indol-5-yl) cyclopropanecarboxamide

(R) -1- (benzo [d] [1,3] dioxol-5-yl) -N- (2-tert-butyl-1- (2,3-dihydroxypropyl) -6-fluoro -1H-indol-5-yl) cyclopropanecarboxamide was subjected to 1- (benzo [d] [1,3] dioxol-5-yl) cyclopropanecarboxylic acid and using an experimental procedure similar to Example 72. Prepared from 2-tert-butyl-6-fluoro-5-nitro-1H-indole.

(S) -1- (benzo [d] [1,3] dioxol-5-yl) -N- (2-tert-butyl-1- (2,3-dihydroxypropyl) -6-fluoro -1H-indol-5-yl) cyclopropanecarboxamide

(S) -1- (benzo [d] [1,3] dioxol-5-yl) -N- (2-tert-butyl-1- (2,3-dihydroxypropyl) -6-fluoro -1H-indol-5-yl) cyclopropanecarboxamide was subjected to 1- (benzo [d] [1,3] dioxol-5-yl) cyclopropanecarboxylic acid and using an experimental procedure similar to Example 72. Prepared from 2-tert-butyl-6-fluoro-5-nitro-1H-indole.

(R) -N- (2-tert-butyl-1- (2,3-dihydroxypropyl) -1H-indol-5-yl) -1- (3,4-dihydroxyphenyl) cyclopropanecar Voxamide

(R) -N- (2-tert-butyl-1- (2,3-dihydroxypropyl) -1H-indol-5-yl) -1- (3,4-dihydroxyphenyl) cyclopropanecar Voxamide was prepared from 1- (3,4-dihydroxyphenyl) cyclopropanecarboxylic acid and 2-tert-butyl-5-nitro-1H-indole using an experimental procedure similar to Example 72.

(R) -N- (2-tert-butyl-1- (2,3-dihydroxypropyl) -1H-indol-5-yl) -1- (2,3-dihydro-1H-indene-5 -Yl) cyclopropanecarboxamide

(R) -N- (2-tert-butyl-1- (2,3-dihydroxypropyl) -1H-indol-5-yl) -1- (2,3-dihydro-1H-indene-5 -Yl) cyclopropanecarboxamide was subjected to 1- (2,3-dihydro-1H-inden-5-yl) cyclopropanecarboxylic acid and 2-tert-butyl-5 using an experimental procedure similar to Example 72. Prepared from -nitro-1H-indole.

Those skilled in the chemical art can use the examples and schemes in combination with known synthetic methods to synthesize compounds of the present invention comprising the compounds of Table 3 below.

[Table 3]

Assays to Detect and Measure ΔF508-CFTR Correction Properties of Compounds

Membrane Potential Optical Method to Assay ΔF508-CFTR Modulating Properties of Compounds

This assay uses a fluorescent voltage sensing dye to increase functional ΔF508-CFTR in NIH 3T3 cells via a fluorescence plate reader (eg, FLIPR III, Molecular Devices, Inc.). The change in membrane potential is measured as a reading for. The driving force for the reaction is the generation of a chloride ion gradient that occurs with channel activation by a single liquid addition step after the compound has been pretreated with the cell and then loaded with a voltage sensitive dye.

Identification of calibration compounds

A single-added HTS assay format was developed to identify small molecules that correct for trafficking defects related to ΔF508-CFTR. Assay plates containing cells were incubated for about 2-4 hours in a tissue culture incubator at 37 ° C., 5% CO ₂ , 90% humidity. Subsequently, after the cells were attached to the bottom of the assay plate, the cells were prepared for exposing the compound.

The cells were incubated with or without test compounds (negative control) in a tissue culture incubator at 37 ° C., 5% CO ₂ , 90% humidity in serum free medium for 16-24 hours. The cells were then rinsed three times with Krebs Ringer's solution and loaded with voltage sensitive redistribution dye. To activate ΔF508-CFTR, 10 μM forskolin and CFTR enhancer, Genistein (20 μM), were added to each well with Cl ⁻ -free medium. The addition of Cl ⁻ -free media promoted Cl ⁻ efflux in response to ΔF508-CFTR activation, and the membrane depolarization resulting from this was optically monitored using a voltage sensitive dye.

Identification of Enhancer Compounds

To identify enhancers of ΔF508-CFTR, a dual-added HTS assay format was developed. This HTS assay uses a fluorescence voltage sensing dye to measure the change in membrane potential as a measure of the gating (conductivity) increase in ΔF508 CFTR in temperature-corrected ΔF508 CFTR NIH 3T3 cells via FLIPR III. The driving force for the reaction is the Cl ⁻ ion gradient that occurs with channel activation by using forskolin as a single liquid addition step after the cells have been pretreated with the reinforcing compound (or DMSO vehicle control) and then the redistribution dye is loaded ( Fluorescent plate readers such as FLIPR III).

solution:

Bath solution # 1: (mM) NaCl 160, KCl 4.5, CaCl ₂ 2, MgCl ₂ 1, HEPES 10, pH 7.4 (using NaOH).

Chloride-Free Crude Solution: Replace the chloride salt in Crude Solution # 1 with the Gluconate salt.

Cell culture

NIH3T3 mouse fibroblasts stably expressing ΔF508-CFTR were used for optical measurement of membrane potential. The cells were treated with 2 mM glutamine, 10% fetal bovine serum, 1 × NEAA, β-ME, 1 × penicillin / streptomycin (pen / strep) in 175 cm 2 culture flasks at 37 ° C. with 5% CO ₂ and 90% humidity and It was maintained in Dulbecco's modified Eagle's medium supplemented with 25 mM HEPES. In all optical assays, cells were inoculated at about 20,000 / well in 384 well Matrigel-coated plates and incubated at 37 ° C. for 2 hours, followed by 24 hours at 27 ° C. for the enhancer assay. For calibration assays cells were incubated at 27 ° C. or 37 ° C. for 16-24 hours with and without compound.

Electrophysiological Assays to Assay ΔF508-CFTR Modulating Properties of Compounds

1.Ussing chamber assay

The Ussing chamber experiment was performed on polarized airway epithelial cells expressing ΔF508-CFTR to further characterize the ΔF508-CFTR modulators identified in the optical assay. Non-CF and CF airway epithelium is isolated from bronchial tissue and cultured as previously described ([Galietta, LJV, Lantero, S., Gazzolo, A., Sacco, O., Romano, L., Rossi, GA, & Zegarra-Moran, O. (1998) In Vitro Cell. Dev. Biol. 34, 478-481], plated onto a Costar ^® Snapwell ™ filter precoated with NIH3T3-conditioned medium. . After 4 days the apical medium was removed and the cells were used after growing for> 14 days at the air liquid interface. This produced a monolayer of fully differentiated columnar cells with cilia that were characteristic of airway epithelium. Non-CF HBE was isolated from non-smokers without any known lung disease. CF-HBE was isolated from patients homozygous for ΔF508-CFTR.

HBEs grown from Costa ^® Snapwell ™ cell culture inserts are mounted in a Eusing chamber (Physiologic Instruments, Inc., San Diego, CA, USA), for epithelial resistance and basal to apical The short-circuit current (I _SC ) in the presence of Cl ⁻ gradient was measured using a voltage-clamp system (Department of Bioengineering, University of Iowa, Iowa, USA). Briefly, HBE was irradiated at 37 ° C under voltage-clamp recording conditions (V _hold = 0 mV). The basal solution contained 145 NaCl, 0.83 K ₂ HPO ₄ , 3.3 KH ₂ PO ₄ , 1.2 MgCl ₂ , 1.2 CaCl ₂ , 10 glucose and 10 HEPES (adjust the pH to 7.35 using NaOH) (mM) The apical solution contained 145 Nagluconate, 1.2 MgCl ₂ , 1.2 CaCl ₂ , 10 glucose and 10 HEPES (adjust the pH to 7.35 with NaOH) (mM).

Identification of calibration compounds

A typical protocol used a membrane Cl ⁻ concentration gradient from basal to apical. To set up this gradient, a conventional Ringer was used for the basal membrane and the top NaCl was replaced with equimolar sodium gluconate (titrated to pH 7.4 using NaOH) to produce a high Cl ⁻ concentration gradient across the epithelium. It was. All experiments were performed with intact tomography. To fully activate ΔF508-CFTR, forskolin (10 μM), PDE inhibitor, IBMX (100 μM) and CFTR enhancer, Genistein (50 μM), were added to the apical side.

As observed in other cell types, cold incubation of FRT cells and human bronchial epithelial cells (isolated from diseased CF patients expressing ΔF508-CFTR) (CF-HBE) increases the functional density of CFTR in the plasma membrane. To determine the activity of the calibration compounds, cells were incubated with the test compounds at 37 ° C. for 24 to 48 hours and then washed and recorded three times. CAMP- and genistein-mediated I _SCs in cells treated with compounds were normalized to a 37 ° C. control and expressed as percentage activity relative to CFTR activity of wt-HBE. The pre-incubation of the cells with the calibration compound significantly increased cAMP- and genistein-mediated I _SC compared to the 37 ° C. control.

Identification of Enhancer Compounds

A typical protocol used a membrane Cl ⁻ concentration gradient from basal to apical. To set up this gradient, a conventional Ringer was used for the basal membrane and the top NaCl was replaced with equimolar sodium gluconate (titrated to pH 7.4 using NaOH) to produce a high Cl ⁻ concentration gradient across the epithelium. It was. Forskolin (10 μΜ) and all test compounds were added to the apical side of the cell culture insert. The efficacy of the putative ΔF508-CFTR enhancer was compared with the efficacy of known enhancer, Genistein.

2. Patch-clamp recording

Total Cl ⁻ currents in ΔF508-NIH3T3 cells were monitored using a perforated-patch recording device as described previously (Rae, J., Cooper, K., Gates, P., Watsky, M. ( 1991) J. Neurosci. Methods 37, 15-26]. Voltage-clamp recording was performed at 22 ° C. using an Axopatch 200B patch-clamp amplifier (Axon Instruments Inc., Foster City, CA, USA). Pipette solutions were prepared using 150 N-methyl-D-glucamine (NMDG) -Cl, 2 MgCl ₂ , 2 CaCl ₂ , 10 EGTA, 10 HEPES and 240 μg / mL amphotericin-B (HCl to pH 7.35). Adjusted) (mM). Extracellular medium contained 150 NMDG-Cl, 2 MgCl ₂ , 2 CaCl ₂ , 10 HEPES (adjust the pH to 7.35 with HCl) (mM). Pulse generation, data acquisition and analysis were performed with a PC equipped with Digidata 1320 A / D interface and Clampex 8 (Axon Instruments Inc.). To activate ΔF508-CFTR, 10 μM forskolin and 20 μM Genistein were added to the bath and the current-voltage relationship was monitored every 30 seconds.

Identification of calibration compounds

In order to determine the activity of the calibration compound to increase the density of functional ΔF508-CFTR in the plasma membrane, we measured the current density after 24 hours treatment of the calibration compound using the puncture-patch-recording technique described above. To fully activate ΔF508-CFTR, 10 μM Forskolin and 20 μM Genistein were added to the cells. Under our recording conditions, the current density after 24 hours incubation at 27 ° C. was higher than that observed after 24 hours incubation at 37 ° C. This result is consistent with the known effect of low temperature incubation on the ΔF508-CFTR density in plasma membranes. To determine the effect of the calibration compound on CFTR current density, the cells were incubated with 10 μM of test compound at 37 ° C. for 24 hours and the current density was compared with the 27 ° C. and 37 ° C. controls (% activity) ). Cells were washed three times with extracellular recording medium before recording to remove any residual test compound. Pre-incubation with 10 μM of calibration compound significantly increased cAMP- and genistein-dependent currents compared to 37 ° C. controls.

Identification of Enhancer Compounds

The ability of the ΔF508-CFTR enhancer to increase macroscopic ΔF508-CFTR Cl ⁻ current (I _ΔF508 ) in NIH3T3 cells stably expressing ΔF508-CFTR was also investigated using a puncture-patch-recording technique. _Enhancers identified in the optical assay _resulted in a dose-dependent increase in I _ΔF508 with potency and efficacy similar to that observed in the optical assay. In all the cells investigated, the inversion potential before and during the application of the adjuvant was about -30 mV, corresponding to the calculated E _Cl (-28 mV).

Cell culture

NIH3T3 mouse fibroblasts stably expressing ΔF508-CFTR were used for intact cell recording. The cells were supplemented with 2 mM glutamine, 10% fetal bovine serum, 1 × NEAA, β-ME, 1 × penicillin / streptomycin and 25 mM HEPES in 175 cm 2 culture flasks at 37 ° C. with 5% CO ₂ and 90% humidity. In Dulbecco's modified Eagle's medium. For intact cell recording, 2,500 to 5,000 cells were inoculated in poly-L-lysine-coated glass coverslips and incubated at 27 ° C. for 24 to 48 hours before use to test the activity of the enhancer, and calibration The activity of the corrective agent was measured by incubation at 37 ° C. with or without compound.

3. Single channel recording

Gating activity of wt-CFTR and temperature-corrected ΔF508-CFTR expressed in NIH3T3 cells was observed with an excised inner-outer membrane patch record as described previously using an Axpatch 200B patch-clamp amplifier (Axon Instruments Inc.). (Dalemans, W., Barbry, P., Champigny, G., Jallat, S., Dott, K., Dreyer, D., Crystal, RG, Pavirani, A., Lecocq, JP., Lazdunski, M (1991) Nature 354, 526-528). The pipette contained 150 NMDG, 150 aspartic acid, 5 CaCl ₂ , 2 MgCl ₂ and 10 HEPES (adjust the pH to 7.35 using Tris base) (mM). The bath contained 150 NMDG-Cl, 2 MgCl ₂ , 5 EGTA, 10 TES and 14 Tris base (adjust the pH to 7.35 using HCl) (mM). After ablation, both wt- and ΔF508-CFTR were added with 1 mM Mg-ATP, 75 nM cAMP-dependent protein kinase (PKA; Promega Corp., Madison, Wisconsin) catalytic subunit, and 10 mM NaF Activated to inhibit protein phosphatase, which inhibited current reduction. Pipette potential was maintained at 80 mV. Channel activity was analyzed from membrane patches containing ≦ 2 active channels. The maximum number open simultaneously determined the number of active channels during the experiment. In order to determine the single channel current magnitude, the data recorded from 120 seconds of ΔF508-CFTR activity was filtered “off-line” at 100 Hz and then used to produce the Bio-Patch analysis software ( All spot size histograms fitted with the multigaussian function of Bio-Logic Comp., France) were constructed. The total micro current and open probability (P _o ) were determined from 120 seconds of channel activity. P _o is determined using the bio-patch software, or determined from the relationship P _o = I / i (N), where I = average current, i = single channel current magnitude, N = number of active channels in the patch. It was.

Cell culture

NIH3T3 mouse fibroblasts stably expressing ΔF508-CFTR were used for excised-membrane patch-clamp recordings. The cells were supplemented with 2 mM glutamine, 10% fetal bovine serum, 1 × NEAA, β-ME, 1 × penicillin / streptomycin and 25 mM HEPES in 175 cm 2 culture flasks at 37 ° C. with 5% CO ₂ and 90% humidity. In Dulbecco's modified Eagle's medium. For single channel recording, 2,500 to 5,000 cells were used after inoculation into poly-L-lysine-coated glass coverslips and incubated at 27 ° C. for 24 to 48 hours.

The compounds in Table 1 were found to exhibit calibration activity as measured by the assay described above.

Compounds of the present invention are useful as modulators of ATP binding cassette transporters. Using the procedure described above, the activity of the compounds of the present invention, ie EC50, was determined to be about 3.8 nM to about 13.5 μM. In addition, using the methods described above, the efficacy of the compounds of the present invention was determined to be about 35% to about 110%.

In Table 4, the following meanings apply:

EC50: “+++” means <2 μM, “++” means 2 μM to 5 μM and “+” means 5 μM to 25 μM.

% Efficacy: "+" means <25%, "++" means 25% to 100%, and "+++" means> 100%.

[Table 4]

Other embodiments

While the invention has been described in detail with the description, it is to be understood that the foregoing description is intended to be illustrative, and not to limit the scope of the invention, which is defined by the appended claims. Other aspects, advantages and modifications fall within the scope of the following claims.

Claims (82)

A compound of formula II: or a pharmaceutically acceptable salt thereof:
<Formula II>

Wherein, in each case independently:
R is H, OH, or OCH _3, or two R together are -CH ₂ CH ₂ CH ₂ - to form a, -OCH ₂ O- or -OCF ₂ O-;
R ₁ is H or up to 2 C ₁ -C ₆ alkyl;
R ₂ is H or F;
R ₃ is H or CN;
R ₄ is H, —CH ₂ CH (OH) CH ₂ OH, —CH ₂ CH ₂ N ⁺ (CH ₃ ) ₃ or —CH ₂ CH ₂ OH;
R ₅ is H, OH, —CH ₂ OCH ₂ CH (OH) CH ₂ OH, —CH ₂ OH, or R ₄ and R ₅ together form a fused pyrrolidine ring. The compound of claim 1, wherein two R's together form —OCF ₂ O—, wherein R ₁ is H and R ₂ is F. 7. The compound of claim 1, wherein two R's together form —OCF ₂ O—, wherein R ₁ is H, R ₂ is F, and R ₃ is H. 6. The compound of claim 1, wherein two R's together form —OCF ₂ O—, wherein R ₁ is H, R ₂ is F, R ₃ is H, and R ₄ is H. ₆ . The compound of claim 1, wherein two R together form —OCF ₂ O—, R ₁ is H, R ₂ is F, R ₃ is H, and R ₄ is —CH ₂ CH ₂ N ⁺ (CH ₃ ) ₃ phosphorus compound. 2. The compound of claim 1, wherein two R together form —OCF ₂ O—, R ₁ is H, R ₂ is F, R ₃ is H, and R ₄ is —CH ₂ CH (OH) CH ₂ OH is a compound. 2. The compound of claim 1, wherein two R together form —OCF ₂ O—, R ₁ is H, R ₂ is F, R ₃ is H, and R ₄ is (R) —CH ₂ CH (OH ) CH ₂ OH. The compound of claim 1, wherein two R together form —OCF ₂ O—, R ₁ is H, R ₂ is F, R ₃ is H, and R ₄ is (S) —CH ₂ CH (OH ) CH ₂ OH. The pyrrolidine of claim 1, wherein two R together form —OCF ₂ O—, R ₁ is H, R ₂ is F, R ₃ is H, and R ₄ and R ₅ are fused together To form a ring. The compound of claim 1, wherein two R's together form —OCH ₂ O—, wherein R ₁ is H and R ₂ is F. 7. The compound of claim 1, wherein two R's together form —OCH ₂ O—, wherein R ₁ is H, R ₂ is F, and R ₃ is H. 6. The compound of claim 1, wherein two R together form —OCH ₂ O—, R ₁ is H, R ₂ is F, R ₃ is H, and R ₄ is —CH ₂ CH (OH) CH ₂ OH is a compound. 2. The compound of claim 1, wherein two R together form —OCH ₂ O—, R ₁ is H, R ₂ is F, R ₃ is H, and R ₄ is (R) —CH ₂ CH (OH ) CH ₂ OH. The compound of claim 1, wherein two R together form —OCH ₂ O—, R ₁ is H, R ₂ is F, R ₃ is H, and R ₄ is (S) —CH ₂ CH (OH ) CH ₂ OH. A compound according to claim 1 or a pharmaceutically acceptable salt thereof:
<Formula IIa>

Where:
R ₄ is H, —CH ₂ CH (OH) CH ₂ OH, —CH ₂ CH ₂ N ⁺ (CH ₃ ) ₃ or —CH ₂ CH ₂ OH;
R ₅ is H, OH, —CH ₂ OCH ₂ CH (OH) CH ₂ OH, —CH ₂ OH, or R ₄ and R ₅ together form a fused pyrrolidine ring. The compound of claim 15, wherein R ₄ is (R) —CH ₂ CH (OH) CH ₂ OH, (S) —CH ₂ CH (OH) CH ₂ OH, —CH ₂ CH ₂ N ⁺ (CH ₃ ) ₃ or -CH ₂ CH ₂ OH. The compound of claim 15, wherein R ₅ is OH, —CH ₂ OCH ₂ CH (OH) CH ₂ OH, or —CH ₂ OH. The compound of claim 15, wherein R ₄ is (R) —CH ₂ CH (OH) CH ₂ OH, (S) —CH ₂ CH (OH) CH ₂ OH, —CH ₂ CH ₂ N ⁺ (CH ₃ ) ₃ or -CH ₂ CH ₂ OH; R ₅ is OH, —CH ₂ OCH ₂ CH (OH) CH ₂ OH or —CH ₂ OH. Compound selected from Table 1. (i) the compound according to claim 1, and
(ii) pharmaceutically acceptable carriers
Pharmaceutical composition comprising a. The composition of claim 20 further comprising an additional agent selected from a mucolytic, bronchodilator, antibiotic, anti-infective, anti-inflammatory, CFTR corrector, CFTR enhancer or nutrient. A method of increasing the number of functional ABC transporters in a membrane of a cell, comprising contacting the cell with a compound of formula II:
<Formula II>

Wherein, in each case independently:
R is H, OH, or OCH _3, or two R together are -CH ₂ CH ₂ CH ₂ - to form a, -OCH ₂ O- or -OCF ₂ O-;
R ₁ is H or up to 2 C ₁ -C ₆ alkyl;
R ₂ is H or F;
R ₃ is H or CN;
R ₄ is H, —CH ₂ CH (OH) CH ₂ OH, —CH ₂ CH ₂ N ⁺ (CH ₃ ) ₃ or —CH ₂ CH ₂ OH;
R ₅ is H, OH, —CH ₂ OCH ₂ CH (OH) CH ₂ OH, —CH ₂ OH, or R ₄ and R ₅ together form a fused pyrrolidine ring. The method of claim 22, wherein the ABC transporter is CFTR. The method of claim 22, wherein two R's together form —OCF ₂ O—, wherein R ₁ is H and R ₂ is F. ₂₃ . The method of claim 22, wherein two R's together form —OCF ₂ O—, R ₁ is H, R ₂ is F, and R ₃ is H. The method of claim 22, wherein two R's together form —OCF ₂ O—, wherein R ₁ is H, R ₂ is F, R ₃ is H, and R ₄ is H. The compound of claim 22, wherein two R together form —OCF ₂ O—, R ₁ is H, R ₂ is F, R ₃ is H, and R ₄ is —CH ₂ CH ₂ N ⁺ (CH ₃ ) ₃ way. The compound of claim 22, wherein two R together form —OCF ₂ O—, R ₁ is H, R ₂ is F, R ₃ is H, and R ₄ is —CH ₂ CH (OH) CH ₂ Method that is OH. The compound of claim 22, wherein two R together form —OCF ₂ O—, R ₁ is H, R ₂ is F, R ₃ is H, and R ₄ is (R) —CH ₂ CH (OH ) CH ₂ OH. The compound of claim 22, wherein two R together form —OCF ₂ O—, R ₁ is H, R ₂ is F, R ₃ is H, and R ₄ is (S) —CH ₂ CH (OH ) CH ₂ OH. The pyrrolidine of claim 22, wherein two R together form -OCF ₂ O-, R ₁ is H, R ₂ is F, R ₃ is H, and R ₄ and R ₅ are fused together To form a ring. The method of claim 22, wherein two R together form —OCH ₂ O—, wherein R ₁ is H and R ₂ is F. ₂₃ . The method of claim 22, wherein two R together form —OCH ₂ O—, wherein R ₁ is H, R ₂ is F, and R ₃ is H. The compound of claim 22, wherein two R together form —OCH ₂ O—, R ₁ is H, R ₂ is F, R ₃ is H, and R ₄ is —CH ₂ CH (OH) CH ₂ Method that is OH. The compound of claim 22, wherein two R together form —OCH ₂ O—, R ₁ is H, R ₂ is F, R ₃ is H, and R ₄ is (R) —CH ₂ CH (OH ) CH ₂ OH. The compound of claim 22, wherein two R together form —OCH ₂ O—, R ₁ is H, R ₂ is F, R ₃ is H, and R ₄ is (S) —CH ₂ CH (OH ) CH ₂ OH manner. The method of claim 22, wherein the compound is represented by Formula IIa or a pharmaceutically acceptable salt thereof:
<Formula IIa>

Where:
R ₄ is H, —CH ₂ CH (OH) CH ₂ OH, —CH ₂ CH ₂ N ⁺ (CH ₃ ) ₃ or —CH ₂ CH ₂ OH;
R ₅ is H, OH, —CH ₂ OCH ₂ CH (OH) CH ₂ OH, —CH ₂ OH, or R ₄ and R ₅ together form a fused pyrrolidine ring. 38. The compound of claim 37, wherein R ₄ is (R) -CH ₂ CH (OH) CH ₂ OH, (S) -CH ₂ CH (OH) CH ₂ OH, -CH ₂ CH ₂ N ⁺ (CH ₃ ) ₃ or -CH ₂ CH ₂ OH. The method of claim 37, wherein R ₅ is OH, —CH ₂ OCH ₂ CH (OH) CH ₂ OH, or —CH ₂ OH. 38. The compound of claim 37, wherein R ₄ is (R) -CH ₂ CH (OH) CH ₂ OH, (S) -CH ₂ CH (OH) CH ₂ OH, -CH ₂ CH ₂ N ⁺ (CH ₃ ) ₃ or -CH ₂ CH ₂ OH; R ₅ is OH, —CH ₂ OCH ₂ CH (OH) CH ₂ OH or —CH ₂ OH. The method of claim 22, wherein the compound is selected from Table 1. A method of treating a condition, disease, or disorder associated with ABC transporter activity in a patient comprising administering to a patient involved in ABC transporter activity, a compound of Formula II or a pharmaceutically acceptable salt thereof :
<Formula II>

Wherein, in each case independently:
R is H, OH, or OCH _3, or two R together are -CH ₂ CH ₂ CH ₂ - to form a, -OCH ₂ O- or -OCF ₂ O-;
R ₁ is H or up to 2 C ₁ -C ₆ alkyl;
R ₂ is H or F;
R ₃ is H or CN;
R ₄ is H, —CH ₂ CH (OH) CH ₂ OH, —CH ₂ CH ₂ N ⁺ (CH ₃ ) ₃ or —CH ₂ CH ₂ OH;
R ₅ is H, OH, —CH ₂ OCH ₂ CH (OH) CH ₂ OH, —CH ₂ OH, or R ₄ and R ₅ together form a fused pyrrolidine ring. The method of claim 42, wherein two R together form —OCF ₂ O—, wherein R ₁ is H and R ₂ is F. 43. The method of claim 42, wherein two R's together form —OCF ₂ O—, wherein R ₁ is H, R ₂ is F, and R ₃ is H. 43. The method of claim 42, wherein two R's together form —OCF ₂ O—, wherein R ₁ is H, R ₂ is F, R ₃ is H, and R ₄ is H. 43. The compound of claim 42, wherein two R together form —OCF ₂ O—, R ₁ is H, R ₂ is F, R ₃ is H, and R ₄ is —CH ₂ CH ₂ N ⁺ (CH ₃ ) ₃ way. The compound of claim 42, wherein two R together form —OCF ₂ O—, R ₁ is H, R ₂ is F, R ₃ is H, and R ₄ is —CH ₂ CH (OH) CH ₂ Method that is OH. The compound of claim 42, wherein two R together form —OCF ₂ O—, R ₁ is H, R ₂ is F, R ₃ is H, and R ₄ is (R) —CH ₂ CH (OH ) CH ₂ OH. The compound of claim 42, wherein two R together form —OCF ₂ O—, R ₁ is H, R ₂ is F, R ₃ is H, and R ₄ is (S) —CH ₂ CH (OH ) CH ₂ OH. The pyrrolidine of claim 42, wherein two R together form -OCF ₂ O-, R ₁ is H, R ₂ is F, R ₃ is H, and R ₄ and R ₅ are fused together To form a ring. The method of claim 42, wherein two R together form —OCH ₂ O—, wherein R ₁ is H and R ₂ is F. 43. The method of claim 42, wherein two R together form —OCH ₂ O—, R ₁ is H, R ₂ is F, and R ₃ is H. 43. The compound of claim 42, wherein two R together form —OCH ₂ O—, R ₁ is H, R ₂ is F, R ₃ is H, and R ₄ is —CH ₂ CH (OH) CH ₂ Method that is OH. The compound of claim 42, wherein two R together form —OCH ₂ O—, R ₁ is H, R ₂ is F, R ₃ is H, and R ₄ is (R) —CH ₂ CH (OH). ) CH ₂ OH. The compound of claim 42, wherein two R together form —OCH ₂ O—, R ₁ is H, R ₂ is F, R ₃ is H, and R ₄ is (S) —CH ₂ CH (OH ) CH ₂ OH. The method of claim 42, wherein the compound is represented by formula IIa or a pharmaceutically acceptable salt thereof:
<Formula IIa>

Where:
R ₄ is H, —CH ₂ CH (OH) CH ₂ OH, —CH ₂ CH ₂ N ⁺ (CH ₃ ) ₃ or —CH ₂ CH ₂ OH;
R ₅ is H, OH, —CH ₂ OCH ₂ CH (OH) CH ₂ OH, —CH ₂ OH, or R ₄ and R ₅ together form a fused pyrrolidine ring. The compound of claim 56, wherein R ₄ is (R) —CH ₂ CH (OH) CH ₂ OH, (S) —CH ₂ CH (OH) CH ₂ OH, —CH ₂ CH ₂ N ⁺ (CH ₃ ) ₃ or -CH ₂ CH ₂ OH. The method of claim 56, wherein R ₅ is OH, —CH ₂ OCH ₂ CH (OH) CH ₂ OH, or —CH ₂ OH. The compound of claim 56, wherein R ₄ is (R) —CH ₂ CH (OH) CH ₂ OH, (S) —CH ₂ CH (OH) CH ₂ OH, —CH ₂ CH ₂ N ⁺ (CH ₃ ) ₃ or -CH ₂ CH ₂ OH; R ₅ is OH, —CH ₂ OCH ₂ CH (OH) CH ₂ OH or —CH ₂ OH. The method of claim 42, wherein the compound is selected from Table 1. 43. The method of claim 42, wherein the condition, disease or disorder is cystic fibrosis, hereditary emphysema, hereditary hemochromatosis, coagulofibrolysis deficiency, such as protein C deficiency, type 1 hereditary angioedema, lipid processing deficiency, such as familial hypercholesterolemia, Type 1 cancer granules, mubetalipoproteinemia, lysosomal accumulation diseases such as I-cell disease / pseudo-Hurler, mucopolysaccharide deposition, Sandhof / Tay-Sachs, Krigler Crigler-Najjar type II, polyendocrine disease / hyperinsulinemia, diabetes mellitus, laron dwarfism, myeloperoxidase deficiency, primary hypothyroidism, melanoma, glycanosis CDG type 1, Hereditary emphysema, congenital hyperthyroidism, incomplete osteoplasia, hereditary hypofibrosis, ACT deficiency, diabetes insipidus (di), neurophysiological di, identity DI, Charcot-Marie Tooth syndrome, Pell Perlizaeus-Merzbacher disease, neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, progressive nuclear palsy, peak disease, various polyglutamine nervous system disorders such as Huntington, spinal cerebellar ataxia types I, spinal cord and softening muscular dystrophy, dentatorubal pallidoluysian and myotonic dystrophy, and also cavernous encephalopathy, such as hereditary Creutzfeldt-Jakob disease, Fabry disease, Straussler-Shainger (Straussler-Scheinker) syndrome, COPD, dry eye disease and Sjogren's disease. (i) a first composition comprising a compound of formula II, and
(ii) a) contacting said composition with a biological sample,
b) for measuring the activity of ABC transporters or fragments thereof
guidebook
Kits used to determine the activity of ABC transporters or fragments thereof in biological samples in vitro or in vivo, comprising:
<Formula II>

Wherein, in each case independently:
R is H, OH, or OCH _3, or two R together are -CH ₂ CH ₂ CH ₂ - to form a, -OCH ₂ O- or -OCF ₂ O-;
R ₁ is H or up to 2 C ₁ -C ₆ alkyl;
R ₂ is H or F;
R ₃ is H or CN;
R ₄ is H, —CH ₂ CH (OH) CH ₂ OH, —CH ₂ CH ₂ N ⁺ (CH ₃ ) ₃ or —CH ₂ CH ₂ OH;
R ₅ is H, OH, —CH ₂ OCH ₂ CH (OH) CH ₂ OH, —CH ₂ OH, or R ₄ and R ₅ together form a fused pyrrolidine ring. 63. The method of claim 62,
a) contacting the additional composition with a biological sample,
b) the activity of said ABC transporter or fragment thereof is measured in the presence of said further compound,
c) for comparing the activity of the ABC transporter in the presence of a further compound with the density of the ABC transporter in the presence of the first composition
Kits including additional instructions. 63. The kit of claim 62, wherein the kit is used to measure the density of CFTR. 63. The kit of claim 62, wherein two R's together form -OCF ₂ O-, wherein R ₁ is H and R ₂ is F. 63. The kit of claim 62, wherein two R's together form -OCF ₂ O-, R ₁ is H, R ₂ is F, and R ₃ is H. 63. The kit of claim 62, wherein two R's together form -OCF ₂ O-, R ₁ is H, R ₂ is F, R ₃ is H, and R ₄ is H. 63. The compound of claim 62, wherein two R's together form -OCF ₂ O-, R ₁ is H, R ₂ is F, R ₃ is H, and R ₄ is -CH ₂ CH ₂ N ⁺ (CH ₃ ) ₃ person kit. 63. The compound of claim 62, wherein two R's together form -OCF ₂ O-, R ₁ is H, R ₂ is F, R ₃ is H, and R ₄ is -CH ₂ CH (OH) CH ₂ Kit that is OH. 63. The compound of claim 62, wherein two R's together form -OCF ₂ O-, R ₁ is H, R ₂ is F, R ₃ is H, and R ₄ is (R) -CH ₂ CH (OH). ) Kit that is CH ₂ OH. 63. The compound of claim 62, wherein two R's together form -OCF ₂ O-, R ₁ is H, R ₂ is F, R ₃ is H, and R ₄ is (S) -CH ₂ CH (OH). ) Kit that is CH ₂ OH. 63. The pyrrolidin of claim 62, wherein two R's together form -OCF ₂ O-, R ₁ is H, R ₂ is F, R ₃ is H, and R ₄ and R ₅ are fused together A kit that forms a ring. 63. The kit of claim 62, wherein two R's together form -OCH ₂ 0-, wherein R ₁ is H and R ₂ is F. 63. The kit of claim 62, wherein two R's together form -OCH ₂ 0-, R ₁ is H, R ₂ is F, and R ₃ is H. 63. The compound of claim 62, wherein two R s together form -OCH ₂ O-, R ₁ is H, R ₂ is F, R ₃ is H, and R ₄ is -CH ₂ CH (OH) CH ₂ Kit that is OH. 63. The compound of claim 62, wherein two R's together form —OCH ₂ O—, R ₁ is H, R ₂ is F, R ₃ is H, and R ₄ is (R) —CH ₂ CH (OH). ) Kit that is CH ₂ OH. 63. The compound of claim 62, wherein two R's together form -OCH ₂ O-, R ₁ is H, R ₂ is F, R ₃ is H, and R ₄ is (S) -CH ₂ CH (OH). ) Kit that is CH ₂ OH. 63. The kit of claim 62, wherein the compound is represented by Formula IIa or a pharmaceutically acceptable salt thereof:
<Formula IIa>

Where:
R ₄ is H, —CH ₂ CH (OH) CH ₂ OH, —CH ₂ CH ₂ N ⁺ (CH ₃ ) ₃ or —CH ₂ CH ₂ OH;
R ₅ is H, OH, —CH ₂ OCH ₂ CH (OH) CH ₂ OH, —CH ₂ OH, or R ₄ and R ₅ together form a fused pyrrolidine ring. 79. The compound of claim 78, wherein R ₄ is (R) -CH ₂ CH (OH) CH ₂ OH, (S) -CH ₂ CH (OH) CH ₂ OH, -CH ₂ CH ₂ N ⁺ (CH ₃ ) ₃ or A kit that is —CH ₂ CH ₂ OH. The kit of claim 78 wherein R ₅ is OH, —CH ₂ OCH ₂ CH (OH) CH ₂ OH, or —CH ₂ OH. 79. The compound of claim 78, wherein R ₄ is (R) -CH ₂ CH (OH) CH ₂ OH, (S) -CH ₂ CH (OH) CH ₂ OH, -CH ₂ CH ₂ N ⁺ (CH ₃ ) ₃ or -CH ₂ CH ₂ OH; R ₅ is OH, —CH ₂ OCH ₂ CH (OH) CH ₂ OH or —CH ₂ OH. 63. The kit of claim 62, wherein the compound is selected from Table 1.