Heterocyclic modulators of atp-binding cassette transporters

[0001] This application claims benefits under US 35 § 119 of US Provisional Application No. 60 / 734,506, filed November 8, 2005, US Provisional Application No. 60 / 754,086, filed December 27, 2005, and US Provisional Application No. 60 / 802,458, filed on May 22, 2006.

TECHNICAL BACKGROUND OF THE INVENTION [0002] The present invention relates to transporter modulators comprising an ATP binding cassette ("ABC") or fragments thereof, including cystic fibrosis diaphragmatic conductivity regulator ("CFTR"), its compositions and associated methods. The present invention also relates to such modulators for use in the treatment of diseases mediated by the ABC transporter.

BACKGROUND OF THE INVENTION [0003] ABC transporters are a family of transmembrane transmembrane proteins that regulate the transport of many different pharmacological agents, potentially toxic drugs and xenobiotics, and anions. ABC transporters are homogeneous membrane proteins that bind and use cellular adenosine triphosphate (ATP) for their specific activities. Some of these transporters have been discovered as multi-drug resistance proteins (e.g., MDR1-P glycoprotein or multi-drug resistance protein, MRP1), protecting malignant tumor cells from chemotherapeutic agents. So far, 48 ABC transporters have been identified and divided into 7 families based on the sequence and activities.

[0004] ABC transporters regulate a variety of important physiological processes in the body and provide defense against harmful compounds in the environment. Therefore, they are important potential targets for drugs in the treatment of diseases associated with transporter defects, prevention of drug transport outside the target cell, and intervention in other diseases where modulation of ABC transporter activity may be beneficial.

[0005] One member of the ABC transporter family often associated with disease is the anAMP channel mediated by cAMP / ATP, CFTR. CFTR is expressed in a wide variety of cell types, including absorbing and secreting epithelial cells, where it regulates the flow of anions across membranes and the activity of other ion channels and proteins. In epithelial cells, the proper functioning of CFTR plays a key role in maintaining electrolyte transport in the body, including respiratory and digestive tissue. CFTR consists of about 1480 amino acids that encode a protein consisting of tandem repeats of transmembrane domains, each containing six transmembrane helices and a nucleotide binding domain. The two transmembrane domains are joined by a large, polar regulatory (R) domain having multiple phosphorylation sites that regulates channel activity and its movement in the cell.

[0006] The gene encoding CFTR has been identified and sequenced (see Gregory, RJ et al. (1990) Nature 347: 382-386; Rich, DP et al. (1990) Nature 347: 358-362), (Riordan, JR et al. (1989) Science 245: 1066-1073). A defect in this gene causes mutations in CFTR leading to cystic fibrosis ("CF"), the most common fatal genetic disease in humans. About one in 2,500 babies in the United States has cystic fibrosis. In the general US population, up to 10 million people carry a single copy of a defective gene with no apparent adverse effects. In contrast, people who have two copies of the CF-related gene suffer from the debilitating and fatal effects of CF, including chronic lung disease.

[0007] In patients with cystic fibrosis, mutations in CFTR endogenously expressed in the respiratory epithelium lead to reduced peak anion secretion, resulting in imbalance in ion and fluid transport. As a result, anion transport is reduced, which contributes to increased mucus accumulation in the lung and associated microbial infections that ultimately lead to the death of CF patients. In addition to respiratory disease, CF patients typically suffer from gastrointestinal problems and pancreatic failure, which, if left untreated, are fatal. In addition, most men with cystic fibrosis are infertile and the fertility of women with cystic fibrosis is reduced. Unlike the severe consequences of the presence of two copies of the CF-related gene, individuals with a single copy of the CF-associated gene show increased resistance to cholera and dehydration due to diarrhea - which perhaps explains the relatively high frequency of CF incidence in the population.

[0008] CFTR gene sequence analysis from CF chromosomes revealed the presence of 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, over 1,000 mutations in the CF gene have been identified that cause disease (<a href="http://www.genet.sickkids.on.ca/cftr/">http://www.genet.sickkids.on.ca/cftr/</a>). The most common mutation is a phenylalanine deletion at position 508 of the CFTR amino acid sequence, often referred to as AF508-CFTR. This mutation occurs in about 70% of cases of cystic fibrosis and is associated with severe disease.

[0009] Deletion of residue 508 in Δ F508-CFTR prevents correct folding of the resulting protein. This makes the mutated protein unable to exit the endoplasmic reticulum and transport to the cell membrane. As a result, the number of channels found in the cell membrane is much smaller than that found in cells expressing wild-type CFTR. In addition to impaired cellular transport, the mutation leads to faulty channel gating. Together, the reduced number of channels in the membrane and defective gating lead to reduced transport of anions across the epithelium, leading to defective transport of ions and fluids. (Quinton, PM (1990), FASEB J. 4: 2709-2727). However, studies have shown that the reduced number of ΔF508-CFTR in the membrane retains its function, although it is reduced compared to 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 lead to defective intracellular transport, synthesis and / or gating of the channel can be regulated up or down, altering anion secretion and modifying disease progression and / or severity.

[0010] Although CFTR transports various molecules in addition to anions, this role (anion transport) is undoubtedly one of the elements of an important mechanism for transporting ions and water across the epithelium. Other elements are the epithelial Na + channel, ENaC, Na co-transporter⁺/ 2Cl'K⁺, Na + -K + -ATPase pump and basal-lateral K + channels, which are responsible for the uptake of chlorine into the cell.

[0011] These elements interact with each other in directional transport across the epithelium due to their selective expression and location within the cell. Chlorine absorption occurs through coordinated action of ENaC and CFTR occurring on the apical membrane and Na pump⁺-K⁺-ATPase and Cl-channels expressed on the side of the basilar cell. Secondary active chlorine transport from the luminal side leads to the accumulation of chloride inside the cell, and then the chloride can passively leave the cell through the Cl channels^-, which leads to vector transport. Arranging the transporter Na⁺/ 2Cl^-/ K⁺, Na pumps⁺-K⁺-ATPazy and K channels⁺ laterol basal membrane on the laterol basal surface, and CFTR on the luminal side coordinates chloride secretion by CFTR on the luminal side. Since water alone is probably never actively transported, its flow through the epithelium depends on the tiny transepithelial osmotic gradients produced by the flow of sodium and chloride. [0012] In addition to cystic fibrosis, modulation of CFTR activity may be beneficial in other diseases not directly caused by mutations in CFTR, such as secretory diseases and other CFTR-mediated protein folding diseases. These include, but are not limited to, chronic obstructive pulmonary disease (COPD), dry eye disease, and Sjogren's syndrome.

[0013] COPD is characterized by a restriction of airflow that is progressive and not fully reversible. The restriction of airflow is caused by excessive mucus secretion, emphysema and bronchiolitis. Mutant or wild type CFTR activators are potential treatments for mucus hypersecretion and impaired mucociliary clearance often associated with COPD. In particular, the increased anion secretion by CFTR can facilitate fluid transport to the airway surface fluid, hydrating mucus and optimizing the viscosity of periciliary fluid. This may lead to increased mucociliary clearance and reduction of COPD related symptoms. Dry eye disease is characterized by a decrease in the production of tear fluid and an abnormal profile of tear film lipids, proteins and mucin. There are many reasons for dry eye; some of them are: age, Lasik ophthalmic surgery, arthritis, medications, chemical / thermal burns, allergies and diseases such as cystic fibrosis and Sjogren's syndrome. Increased anion secretion by CFTR may increase fluid transport through the corneal epithelial cells and secretory glands surrounding the eye, with increased corneal hydration. This can help alleviate the symptoms of dry eye disease. Sjogren's syndrome is an autoimmune disease in which the immune system attacks the glands that produce fluids throughout the body, including the eye, mouth, skin, respiratory tissue, liver, vagina, and intestine. Symptoms include dry eyes, mouth and vagina, and lung disease. This disease is also associated with rheumatoid arthritis, systemic lupus erythematosus, systemic sclerosis and polymyositis / dermatomyositis. Defective intracellular protein transport is thought to cause this disease in which treatment options are limited. Modulators of CFTR activity can hydrate various affected organs and help relieve related symptoms.

[0014] As discussed above, deletion of residue 508 in Δ F508-CFTR is believed to prevent proper folding of the resulting protein, rendering it unable to exit the endoplasmic reticulum and transport to the cell membrane. As a result, there is insufficient mature protein in the cell membrane and chloride transport in epithelial tissue is significantly reduced. In fact, it has been shown that this cellular phenomenon of defective processing in the endoplasmic reticulum of ABC transporters by endoplasmic reticulum machinery underlies not only CF disease, but also a wide range of other isolated and congenital diseases. Two ways in which machinery may malfunction are loss of conjugation with export from endoplasmic protein proteins leading to their degradation or accumulation of these defective / poorly folded proteins [Aridor M, et al., Nature Med., 5 (7), p. 745-751 (1999); Shastry,

BS, et al., Neurochem. International, 43, pp. 1-7 (2003); Rutishauser, J., et al., Swiss Med Wkly, 132, pp. 211-222 (2002); Morello, JP et al., TIPS, 21, pp. 466-469 (2000); Bross P., et al., Human Mut., 14, pp. 186-198 (1999)]. Diseases associated with the first class of endoplasmic reticulum malfunction are: cystic fibrosis (caused by misfolding ΔF508-CFTR, as discussed above), congenital emphysema (caused by? 1-antitrypsin; PiZ variant), congenital hemochromatosis, clotting deficiencies - fibrinolysis, such as protein C deficiency, congenital angioedema type 1, lipid processing disorders, such as congenital hypercholesterolemia, chylomi4 type 1 chronism, abetalipoproteinemia, lysosomal storage diseases, such as intracellular disease pseudo Hurler, mucopolysaccharidosis (caused by lysosomal processing enzymes), Sandhof / Tay-Sachs syndrome (caused by β-hexosaminidase), Crigler-Najjar type II syndrome (caused by UDPglucuronyl-sialyl transferase), polyiendocrinopathy / hyperinsulinemia, diabetes mellitus (caused by insulin receptor), Laron's dwarfism (caused by growth hormone receptor), myeloperoxidase deficiency, primary hypoparathyroidism (caused by preproparathoma) ). Diseases associated with this second class of endoplasmic malfunction are: CDG type 1 glycanose, congenital emphysema (caused by a1-antitrypsin deficiency; PiZ variant), congenital hyperthyroidism, congenital bone fragility (caused by procollagen type I, II, IV), congenital hypofibrinogenemia (caused by fibrinogen), ACT deficiency (caused by a1-antichymotrypsin), diabetes insipidus (DI), neuropsulmonary DI (caused by vasopressin hormone) / V2 receptor), neurogenic DI (caused by aquaporin II), Charcot-Marie-Tooth syndrome (caused by peripheral myelin protein 22), Pelizaeus-Merzbacher disease, neurodegenerative diseases, such as Alzheimer's disease (caused by APP and presenilins), Parkinson's disease, amyotrophic lateral sclerosis, progressive supranuclear palsy, Pick's disease, various polyglutamine neurological disorders such as Huntington's disease, type I cerebral ataxia, bulbar spinal muscular atrophy, atrophy toothed nucleus, red nucleus, pale knob and low-hypothalamic nucleus and myotonic dystrophy, and spongiform encephalopathies, such as congenital Creutzfeldt-Jakob disease (caused by a defect in prion protein processing), Fabry disease (caused by lysosomal αgalactosidase A) and Straussler-Scheinker syndrome (caused by a defect in Prp processing). [0015] In addition to upregulation of CFTR activity, reduction of anion secretion by CFTR modulators may be beneficial in the treatment of secretory diarrhea in which epithelial water transport is dramatically increased as a result of transport of activated chloride by secretion stimulants. The mechanism involves an increase in cAMP concentration and stimulation of CFTR.

[0016] Although there are numerous causes of diarrhea, the main consequences of diarrheal diseases resulting from excessive chloride transport are common and include dehydration, acidosis, impaired growth and death.

[0017] Acute and chronic diarrhea are an important medical problem in many regions of the world. Diarrhea is both a significant factor in malnutrition and a leading cause of death (5,000,000 deaths per year) in children under five years of age.

[0018] Secretory diarrhea is also a serious condition in patients with acquired immune deficiency syndrome (AIDS) and chronic inflammatory bowel disease (IBD). Diarrhea occurs in 16 million people traveling to developing countries from industrialized countries, with the severity and number of diarrhea cases varying depending on the country and region of travel.

[0019] Diarrhea in farm animals and pets, such as cows, pigs and horses, sheep, goats, cats and dogs, called animal diarrhea, is an important cause of death in these animals. Diarrhea can be the result of any major change, such as weaning or physical transfer and response to various bacterial or viral infections, and generally occurs during the first few hours of the animal's life. [0020] The most common diarrhea-causing bacterium is E-coli enterotoxic (ETEC) having the K99 pilus antigen. Rotavirus and coronavirus are common viral causes of diarrhea. Other infectious agents include, but are not limited to, cryptosporidium, giardia lamblia and salmonella.

[0021] Symptoms of rotavirus infection include excretion of watery stools, dehydration and weakness. Coronavirus causes more severe disease in newborn animals and has a higher mortality rate than rotavirus infection. Often, however, a young animal may be simultaneously infected with more than one virus or a combination of virus and bacteria. This dramatically increases the severity of the disease.

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

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

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

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

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

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

SUMMARY OF THE INVENTION [0028] It has now been found that the compounds of this invention and their pharmaceutically acceptable compositions are useful as modulators of ABC transporter activity.

These compounds are within the scope of general formula I

<img file="PL1945632T3_D0001.tif" />

or a pharmaceutically acceptable salt thereof, wherein R₁, R₂, R₃, R '₃, R₄ and n are described herein.

Each R₁ is an optionally substituted C group_1-6 aliphatic, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted C_3-10 cycloaliphatic, optionally substituted 3 to 10-membered heterocycloaliphatic, carboxy, amide, amino, halogen, or hydroxyl, wherein at least one of R1 is an optionally substituted cycloaliphatic, optionally substituted heterocycloaliphatic, optionally substituted aryl, or an optionally substituted heteroaryl group attached at the 5- or 6-position to the pyridyl ring;

Each R2 is hydrogen, methyl, ethyl, propyl, butyl;

Each of R3 and R'3 together with the carbon atom to which they are attached forms an optionally substituted C group_3-7 cycloaliphatic or optionally substituted heterocycloaliphatic;

Each R4 is an optionally substituted aryl or an optionally substituted heteroaryl; and Each n is 1, 2, 3 or 4.

In another aspect, the present invention includes compounds of formula (I '):

or a pharmaceutically acceptable salt thereof,

<img file="PL1945632T3_D0002.tif" />

(D where:

one of G₁ and G₂ means N and the other of G₁ and G₂ is CH;

Each R₁ is an optionally substituted C group_1-6 aliphatic, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted 3 to 10 membered cycloaliphatic, optionally substituted 3 to 10 membered heterocycloaliphatic, carboxy, amide, amino, halogen, or hydroxyl, wherein at least one of R1 is an optionally substituted aryl or an optionally substituted heteroaryl group attached in the 5- or 6-position to the pyridazine ring or pyrazine ring;

Each R2 is hydrogen, methyl, ethyl, propyl, butyl;

Each of R₃ and R '₃ together with the carbon atom to which they are attached forms an optionally substituted C3-7 cycloaliphatic group or an optionally substituted heterocycloaliphatic group;

Each R4 is an optionally substituted aryl or an optionally substituted heteroaryl; and Each n is 1, 2, 3, or 4.

[0029] These compounds and pharmaceutically acceptable compositions are useful for treating or reducing the severity of various diseases, disorders or conditions, including but not limited to cystic fibrosis, congenital emphysema, congenital hemochromatosis, coagulation deficiencies - fibrinolysis, for example, protein C deficiency, congenital angioedema type 1, lipid processing disorders, e.g. family hypercholesterolemia, type 1 chylomicronemia, abetalipoproteinemia, lysosomal storage diseases, e.g. intracellular inclusion / pseudo-Hurler diseases, mucopolysaccharidoses, Sandhof / Tay-Sachs syndrome, Crigler-Najjar type II syndrome, poliendocrinopathy / hyperinsulinemia, diabetes mellitus, Laron's dwarfism, CDL deficiency, myeloperoxidase type 1, congenital emphysema, congenital hyperparathyroidism, congenital bone fragility, congenital hypofibrinogenemia, ACT deficiency, diabetes insipidus (DI), pituitary DI, renal DI, Charcot-Marie-Tooth syndrome, Pelizaeus-Merzbacher disease, neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, progressive supranuclear palsy, Pick's disease, various polyglutamine neurological disorders such as Huntington's disease, type I cerebral ataxia, cerebrospinal muscular atrophy, atrophy of the dentate nucleus, red nucleus, pale and low-hypothalamic nuclei and myotonic dystrophy and spongiform encephalopathies such as congenital Creutzfeldt-Jakob disease, Fabry disease and Gerstmann-Straussler-Scheinker syndrome, COPD, dry eye disease and Sjogren's disease.

WO 2005 075435 A1 relates to compounds of formula I as modulators of ABC transporters or fragments thereof. The core structure of Formula I as defined herein includes the phenyl ring B, monocyclic ring A and carboxy-amide group. This document also relates to methods of treating diseases mediated by the ABC transporter using compounds of formula I.

DETAILED DESCRIPTION OF THE INVENTION

DEFINITIONS [0030] As used herein, the following definitions apply, unless otherwise indicated.

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

[0032] The term "CFTR" as used herein means cystic fibrosis diaphragmatic conduction regulator or a mutation thereof capable of regulatory activity, including but not limited to AF508 CFTR and G551D CFTR (for CFTR mutations see, e.g. <a href="http://www.genet.sickkids.on.ca/cftr/">http://www.genet.sickkids.on.ca/cftr/</a>).

[0033] The term "modulation" as used herein means increasing or decreasing, e.g., activity, by a measurable amount. Compounds that modulate ABC transporter activity, e.g. CFTR activity, by increasing the activity of the ABC transporter, e.g. the CFTR anion channel, are called agonists. Compounds that modulate ABC transporter activity, e.g., CFTR activity, by reducing the activity of the ABC transporter, e.g., the CFTR anion channel, are called antagonists. The agonist interacts with the ABC transporter, for example the CFTR anion channel, increasing the ability of the receptor to carry an intracellular signal in response to endogenous ligand binding. The antagonist interacts with the ABC transporter, for example CFTR, and competes with endogenous (s) ligand (s) or substrate (s) for binding site (s) on the receptor, reducing the ability of the receptor to carry an intracellular signal in response to endogenous ligand binding.

[0034] The expression "treating or reducing the severity of the disease mediated by the ABC transporter" refers to both the treatment of diseases that are directly caused by the ABC transporter and / or CFTR activity and to alleviate the symptoms of diseases not directly caused by the ABC transporter and / or CFTR anion channel activity. Examples of diseases that may be affected by the ABC transporter and / or CFTR activity include, but are not limited to, cystic fibrosis, congenital emphysema, congenital hemochromatosis, coagulation defects - fibrinolysis, for example, protein C deficiency, type 1 congenital angioedema, processing disorders lipids, e.g. family hypercholesterolaemia, chylomicronemia type 1, abetalipoproteinemia, lysosomal storage diseases, for example, diseases of intracellular inclusions / pseudo Hurler, mucopolysaccharidosis, Sandhof / Tay-Sachs syndrome, Crigler-Najjar type II syndrome, myelopoliendocrinopathy / hyperinsulinemia, diabetes mellitus, Laron's dwarfism, myeloperoxidase deficiency, primary hypoparathyroidism, CD parathyroidism lungs, congenital hyperparathyroidism, congenital bone fragility, congenital hypofibrinogenemia, ACT deficiency, diabetes insipidus (DI), pituitary DI, renal DI, Charcot-Marie-Tooth syndrome, Pelizaeus-Merzbacher disease, neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, progressive supranuclear palsy, Pick's disease, various polyglutamine neurological disorders such as Huntington's disease, spinal ataxia type I, bulbous-muscular atrophy, atrophy of the dentate nucleus, red nucleus, pale knob and low hypothalamic nuclei and myotonic dystrophy, and spongiform encephalopathies such as congenital Creutzfeldt-Jakob disease, Fabry disease and Gerstmann-Straussler-Scheinker syndrome, COPD, dry eye disease and Sjogren's disease.

[0035] For the purposes of the present invention, chemical elements are identified according to the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 75th edition. In addition, the general principles of organic chemistry are described by Thomas Sorrell in "Organic Chemistry", University Science Books, Sausalito (1999), and by MB Smith and J. March in "March's Advanced Organic Chemistry", 5th edition, John Wiley &amp; Sons , New York (2001).

[0036] For the purposes of the present invention, chemical elements are identified according to the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 75th edition. In addition, the general principles of organic chemistry are described by Thomas Sorrell in "Organic Chemistry", University Science Books, Sausalito (1999), and by MB Smith and J. March in "March's Advanced Organic Chemistry", 5th edition, John Wiley &amp; Sons, New York (2001).

[0037] As used herein, "aliphatic" includes the terms alkyl, alkenyl, and alkynyl, each of which is optionally substituted, as explained below.

[0038] As used herein, an "alkyl" group means a saturated aliphatic hydrocarbon group having 1-8 (e.g., 1-6 or 1-4) carbon atoms. The alkyl group can be straight or branched. Examples of alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl; n-heptyl or 2-ethylhexyl. The alkyl group may be substituted (i.e., optionally substituted) with one or more substituents, such as halogen, cycloaliphatic [e.g. cycloalkyl or cycloalkenyl], heterocycloaliphatic [e.g. heterocycloalkyl or heterocycloalkenyl], aryl, heteroaryl, alkoxy, aroyl, heteroaroyl, acyl [e.g. (aliphatic) carbonyl, (cycloaliphatic) carbonyl or (heterocycloaliphatic) carbonyl], nitro, cyano, amide [e.g. (cycloalkylalkyl) carbonylamino, arylcarbonylamino, aralkylcarbonylamino, (heterocycloalkyl) carbonylamino, (heterocycloalkylalkyl) carbonylamino, heteroarylcarbonylamino, heteroaralkylcarbonylamino], amino group [e.g. aliphaticamino, cycloaliphaticamino or heterocycloaliphaticamino], sulfonyl [e.g. aliphatic sulfonyl group], sulfinyl, sulfanyl, sulfoxy, urea, thiourea, sulfamoyl, sulfamide, oxo, carboxy, carbamoyl, oxycycloaliphatic, oxyheterocycloaliphatic, aryloxy, heteroaryloxy, aralkyloxy, heteroarylcarboxyloxy, alkoxy. Without limitation, some examples of substituted alkyl include carboxyalkyl (such as HOOC-alkyl, alkoxycarbonylalkyl and alkylcarbonyloxyalkyl), cyanoalkyl, hydroxyalkyl, alkoxyalkyl, acylalkyl, hydroxyalkyl, aralkyl, (alkoxyaryl) alkyl, (sulfonylamino) alkyl (such as (sulfonylamino) alkyl ) alkyl), aminoalkyl, amidoalkyl, (cycloaliphatic) alkyl, cyanoalkyl or haloalkyl.

[0039] As used herein, an "alkenyl" group means an aliphatic carbon group containing 2-8 (e.g., 2-6 or 2-4) carbon atoms and at least one double bond. Like the alkyl group, the alkenyl group can be straight or branched. Examples of alkenyl groups include, but are not limited to, allyl, isoprenyl, 2-butenyl and 2-hexenyl. The alkenyl group may be optionally substituted with one or more substituents, such as halogen, cycloaliphatic, heterocycloaliphatic, aryl, heteroaryl, alkoxy, aroyl, heteroaroyl, acyl [e.g. (cycloaliphatic) carbonyl or hetero (cycloaliphatic) carbonyl], nitro, cyano, acyl [e.g. aliphatic carbonyl, cycloaliphatic carbonyl, arylcarbonyl, heterocycloaliphatic carbonyl or heteroarylcarbonyl], amide [e.g. group (cycloalkylalkyl) carbonylamino, arylcarbonylamino, aralkilokarbonyloaminowa, (heterocycloalkyl) carbonylamino, (heterocycloalkylalkyl) carbonylamino, heteroarylcarbonylamino, heteroaralkylcarbonylamino, alkylaminocarbonyl, cycloalkylaminocarbonyl, heterocykloalkiloaminokarbonyl, arylaminocarbonyl, or heteroarylaminocarbonyl), amino (eg. alifatycznoaminowa or alifatycznosulfonyloaminowa) sulfonyl [e. alkylsulfonyl, cycloaliphatic sulfonyl or arylsulfonyl], sulfinyl, sulfanyl, sulfoxy, urea, thiourea, sulfamoyl, sulfamide, oxo, carboxy, carbamoyl, oxy-cycloaliphatic, oxy-heterocycloaliphatic, aryloxy, alkoxyalkyloxy alkylcarbonyloxy or hydroxyl. [0040] As used herein, an "alkynyl" group means an aliphatic carbon group containing 2-8 (e.g. 2-6 or 2-4) carbon atoms and having at least one triple bond. The alkynyl group can be straight or branched. Examples of alkynyl groups include, but are not limited to, propargyl and butynyl. The alkynyl group may be optionally substituted with one or more substituents such as aroyl, heteroaroyl, alkoxy, cycloalkyloxy, heterocycloalkyloxy, aryloxy, heteroaryloxy, aralkyloxy, nitro, carboxy, cyano, halogen, hydroxyl, sulfone, mercapto, sulfanyl [ for example. aliphatic sulfanyl or cycloaliphatic sulfanyl group], sulfinyl [e.g. aliphatic sulfinyl or cycloaliphatic sulfinyl group], sulfonyl [e.g. aliphatic sulfonyl, aliphaticaminosulfonyl or cycloaliphatic sulfonyl group], amide group [e.g. aminocarbonyl, alkylaminocarbonyl, alkylcarbonylamino, cycloalkylaminocarbonyl, heterocykloalkiloaminokarbonyl group, cycloalkylcarbonylamino, arylaminocarbonyl, arylcarbonylamino, aralkilokarbonyloaminowa, (heterocycloalkyl) carbonylamino, (cycloalkylalkyl) carbonylamino, heteroaralkylcarbonylamino, heteroarylcarbonylamino or heteroarylaminocarbonyl], urea, thiourea, sulfamoyl, sulfamide, alkoxycarbonyl, alkylcarbonyloxy, cycloaliphatic, heterocycloaliphatic, aryl, heteroaryl, acyl [e.g. (cycloaliphatic) carbonyl or (heterocycloaliphatic) carbonyl], amino [e.g. aliphaticamino], sulfoxy, oxo, carboxy, carbamoyl, oxy (cycloaliphatic), oxy (heterocycloaliphatic) or (heteroaryl) alkoxy.

[0041] As used herein, an "amide" group includes both "aminocarbonyl" and "carbonylamino". The above terms, when used alone or in combination with another group, mean an amide group such as

-N (R^XR^Y) -C (O) - or -R^YC (O) -N (R^X) if they relate to the final group; and -C (O) -N (R^X) - or XXY

N (R) -C (O) - if they refer to an internal group, where R and R are as defined below. Examples of amide groups include alkylamido (such as alkylcarbonylamino or alkylcarbonylamino), (heterocycloaliphatic) amide, (heteroaralkyl) amide, (heteroaryl) amide, (heterocycloalkyl) alkylamide, arylamide, aralkylamide, (cycloalkyl) alkylalkyl) alkyl.

[0042] As used herein, an "amino" group refers to -NR^XR^Y,

XY where each of R and R is independently hydrogen, alkyl, cycloaliphatic, (cycloaliphatic) aliphatic, aryl, araliphatic, heterocycloaliphatic, (heterocycloaliphatic) aliphatic, heteroaryl, carboxyl, sulfanyl, sulfinyl, sulfonyl, (aliphatic), carbonyl (cycloaliphatic) carbonyl, ((cycloaliphatic) aliphatic) carbonyl, arylcarbonyl, (araliphatic) carbonyl, (heterocycloaliphatic) carbonyl, ((heterocycloaliphatic) aliphatic) carbonyl, (heteroaryl) carbonyl or (heteroaraliphatic) carbonyl group, each of which is defined herein and is optionally substituted. Examples of amino groups include alkylamino, dialkylamino or arylamino. In the event that the term "amino" does not mean an end group (e.g., an alkylcarbonylamino), it is represented

XX via -NR -. R has the same meaning as defined above.

[0043] As used herein, an "aryl" group used alone or as part of a larger moiety such as "aralkyl", "aralkoxy" or "aryloxyalkyl" means monocyclic (e.g., phenyl); bicyclic (e.g. indenyl, naphthalenyl, tetrahydronaphthyl, tetrahydroindenyl); and tricyclic (e.g. fluorenyl, tetrahydrofluorenyl or tetrahydroantracenyl, anthracenyl) ring system in which the monocyclic ring system is aromatic or at least one of the rings in the bicyclic or tricyclic ring system is aromatic. Bicyclic and tricyclic ring systems include benzofused 2- to 3-membered carbocyclic rings. For example, a benzofused group includes phenyl fused with two or more C moieties_4-8 carbocyclic. Aryl is optionally substituted with one or more substituents, such as an aliphatic group (e.g. alkyl, alkenyl or alkynyl); cycloaliphatic; (Cycloaliphatic) aliphatic; heterocycloaliphatic; (Heterocycloaliphatic) aliphatic; aryl; heteroaryl; alkoxy; oxy (cycloaliphatic) group; (heterocycloaliphatic) oxy; aryloxy; heteroaryloxy; oxy (araliphatic) group; (heteroaraliphatic) oxy; aroyl; heteroaroyl; amino group; oxo (on a non-aromatic carbocyclic ring of a benzofused bicyclic or tricyclic aryl); nitro group; carboxyl; amide group; acyl (e.g. aliphatic carbonyl; (cycloaliphatic) carbonyl; ((cycloaliphatic) aliphatic) carbonyl; (araliphatic) carbonyl; (heterocycloaliphatic) carbonyl; ((heterocycloaliphatic) aliphatic) carbonylcarbonyl; sulfonyl [e.g. aliphatic sulfonyl or aminosulfonyl group]; sulfinyl [e.g. aliphatic sulfinyl or cycloaliphatic sulfinyl group]; sulfanyl [e.g. aliphatic sulfanyl group]; cyano group; halogen; hydroxy; mercapto group; sulfoxy; urea; thiourea; sulfamoyl; sulfamide; or carbamoyl. Alternatively, aryl may be unsubstituted.

[0044] Non-limiting examples of substituted aryls include haloaryl [e.g. mono-, di- (such as p, m-dihaloaryl) or (trihalo) aryl]; (carboxy) aryl [e.g. (alkoxycarbonyl) aryl, ((aralkyl) carbonyloxy) aryl or (alkoxycarbonyl) aryl]; (amido) aryl [e.g. (aminocarbonyl) aryl, (((alkylamino) alkyl) aminocarbonyl) aryl, (alkylcarbonyl) aminoaryl, (arylaminocarbonyl) aryl and (((heteroaryl) amino) carbonyl) aryl]; aminoaryl [e.g. ((alkylsulfonyl) amino) aryl or ((dialkyl) amino) aryl); (Cyanoalkyl) aryl; (Alkoxy) aryl; (sulfamoyl) aryl [e.g. (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-malkoksykarbonyloaryl; p-amino-m-cyanoaryl; p-halo-m-aminoaryl; or (m- (heterocycloaliphatic) - (alkyl)) aryl.

[0045] As used herein, an "araliphatic" group such as "aralkyl" means an aliphatic group [e.g. group C_1-4 alkyl) which is substituted with an aryl group. "Aliphatic," "alkyl," and "aryl" are as defined herein. An example of an araliphatic group such as aralkyl is benzyl.

[0046] As used herein, an "aralkyl" group means an alkyl group (e.g., group C_1-4 alkyl) which is substituted with an aryl group. Both the terms "alkyl" and "aryl" have been defined above. An example of an aralkyl group is benzyl. Aralkyl is optionally substituted with one or more substituents, such as an aliphatic group [e.g. alkyl, alkenyl or alkynyl, including carboxyalkyl, hydroxyalkyl or haloalkyl, such as trifluoromethyl], cycloaliphatic [e.g. cycloalkyl or cycloalkenyl], (cycloalkyl) alkyl, heterocycloalkyl, (heterocycloalkyl) alkyl, aryl, heteroaryl, alkoxy, cycloalkyloxy, heterocycloalkyloxy, aryloxy, heteroaryloxy, aralkyloxy, heteroaralkyloxy, aroyl, heteroaroyl, nitroxycarbonyl, carboxyloxy, [e. aminocarbonyl, alkylcarbonylamino, cycloalkylcarbonylamino, (cycloalkylalkyl) carbonylamino, arylcarbonylamino, aralkylcarbonylamino, (heterocycloalkyl) carbonylamino, (heterocycloalkylalkyl) carbonylamino, heteroarylcarbonylamino, heteroaralkyloxy, haloalkyl, haloalkyl, haloalkyl, , thiourea, sulfamoyl, sulfamido, oxo or carbamoyl.

[0047] As used herein, a "bicyclic ring system" includes 8- to 12- (e.g., 9, 10 or 11) membered structures that form two rings, wherein the two rings have at least one common atom ( e.g. 2 common atoms). Bicyclic ring systems include bicycloaliphatic (e.g., bicycloalkyl or bicycloalkenyl), bicycloheteroaliphatic, bicyclic aryls and bicyclic heteroaryls. [0048] As used herein, a "cycloaliphatic" group includes a "cycloalkyl" group and a "cycloalkenyl" group, each of which may be optionally substituted, as explained below.

[0049] As used herein, a "cycloalkyl" group means a saturated carbocyclic mono- or bicyclic (fused or bridged) ring containing 3-10 (e.g., 5-10) carbon atoms. Examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, adamantyl, norbornyl, cubyl, octahydroindenyl, decahydronaphthyl, bicyclo [3.2.1] octyl, bicyclo [2.2.2] octyl, bicyclo [3.3.1] nonyl, [3.3.2.] Decyl, bicyclo [2.2.2] octyl, adamantyl, azacycloalkyl or ((aminocarbonyl) cycloalkyl) cycloalkyl. A "cycloalkenyl" group, as used herein, means a non-aromatic carbocyclic ring of 3-10 (e.g.

4-8) carbon atoms containing one or more double bonds. Examples of cycloalkenyl groups include cyclopentenyl, 1,4-cyclohexadienyl, cycloheptenyl, cyclooctenyl, hexahydroindenyl, octahydronaphthyl, cyclohexenyl, cyclopentenyl, bicyclo [2.2.2] octenyl or bicyclo [3.3.1] nonenyl. The cycloalkyl or cycloalkenyl group may be optionally substituted with one or more substituents, such as an aliphatic group [e.g. alkyl, alkenyl or alkynyl], cycloaliphatic, (cycloaliphatic) aliphatic, heterocycloaliphatic, (heterocycloaliphatic) aliphatic, aryl, heteroaryl, alkoxy, oxy (cycloaliphatic), oxy (heterocycloaliphatic), aryloxy, heteroaryloxy, oxooxy heteroaraliphatic), aroyl, heteroaroyl, amino, amide [e.g. (aliphatic) carbonylamino, (cycloaliphatic) carbonylamino, ((cycloaliphatic) aliphatic) carbonylamino, (aryl) carbonylamino, (araliphatic) carbonylamino, (heterocycloaliphatic) carbonylamino or (heterocycloaliphatic) alcarbonylamino) carbonylamino), nitro, carboxy (e.g. HOOC-, alkoxycarbonyl or alkylcarbonyloxy), acyl [(e.g. (cycloaliphatic) carbonyl, ((cycloaliphatic) aliphatic) carbonyl, (araliphatic) carbonyl, (heterocycloaliphatic) carbonyl, ((heterocycloaliphatic) aliphatic) carbonyl, or (heteroaraliphatic) mercyloxy, halogen atom, carbonyl group, [e. alkylsulfonyl and arylsulfonyl], sulfinyl [e.g. alkylsulfinyl], sulfanyl [e.g. alkylsulfanyl], sulfoxy, urea, thiourea, sulfamoyl, sulfamide, oxo or carbamoyl.

[0050] As used herein, a "cyclic moiety" includes a cycloaliphatic, heterocycloaliphatic, aryl or heteroaryl group, each of which has been previously defined.

[0051] As used herein, the term "heterocycloaliphatic" includes a heterocycloalkyl group and a heterocycloalkenyl group, each of which is optionally substituted as defined below.

[0052] As used herein, a "heterocycloalkyl" group means a 3-10 membered mono- or bicyclic (fused or bridged) (e.g., 5- to 10-membered mono- or bicyclic) saturated ring structure in which one or more atoms in the ring is a heteroatom (e.g., N, O, S, or a combination thereof). Examples of the heterocycloalkyl group include piperidyl, piperazl, tetrahydropyranyl, tetrahydrofuryl, 1,4-dioxolanyl, 1,4-dithanyl, 1,3-dioxolanyl, oxazolidyl, isoxazolidyl, morpholinyl, thiomorpholyl, octahydrobenzofuryl, octahydrohydropyrochthylhydroxylhydroxy , octahydrobenzo [b] thiophenyl, 2-oxa-bicyclo [2.2.2] octyl, 1-azabicyclo [2.2.2] octyl, 3-azabicyclo [3.2.1] octyl and 2,6-dioxatricyclo [3.3.1.0 '] nonyl. The monocyclic heterocycloalkyl group may be fused to a phenyl moiety such as a tetrahydroisoquinoline moiety. A "heterocycloalkenyl" group, as used herein, means a mono- or bicylic (e.g., 5- to 10-membered mono- or bicyclic) non-aromatic ring structure that has one or more double bonds, and in which one or more the number of atoms in the ring is a heteroatom (e.g. N, O or S). Monocyclic and bicycloheteroaliphatic groups are numbered according to standard chemical nomenclature.

[0053] The heterocycloalkyl or heterocycloalkenyl group may be optionally substituted with one or more substituents, such as an aliphatic group [e.g. alkyl, alkenyl or alkynyl], cycloaliphatic, (cycloaliphatic) aliphatic, heterocycloaliphatic, (heterocycloaliphatic) aliphatic, aryl, heteroaryl, alkoxy, oxy (cycloaliphatic) oxy (heterocycloaliphatic), aryloxy, heteroaryloxy (heteroaraliphatic), aroyl, heteroaroyl, amino, amide [e.g. (aliphatic) carbonylamino, (cycloaliphatic) carbonylamino, ((cycloaliphatic) aliphatic) carbonylamino, (aryl) carbonylamino, (araliphatic) carbonylamino, (heterocycloaliphatic) carbonylamino or (heterocycloaliphatic) alcarbonylamino) carbonylamino), nitro, carboxy (e.g. HOOC-, alkoxycarbonyl or alkylcarbonyloxy), acyl [(e.g. (cycloaliphatic) carbonyl, ((cycloaliphatic) aliphatic) carbonyl, (araliphatic) carbonyl, (heterocycloaliphatic) carbonyl, ((heterocycloaliphatic) aliphatic) carbonyl, or (heteroaraliphatic) carbonyl, nitro, carbonyl, halo, , sulfonyl [e.g. alkylsulfonyl or arylsulfonyl], sulfinyl [e.g. alkylsulfinyl], sulfanyl [e.g. alkylsulfanyl], sulfoxy, urea, thiourea, sulfamoyl, sulfamido, oxo or carbamoyl.

[0054] A "heteroaryl" group, as used herein, means a monocyclic, bicyclic or tricyclic ring system containing 4 to 15 atoms in a ring system in which one or more ring atoms (rings) is a heteroatom (e.g. N, O, S or combinations thereof), and wherein the monocyclic ring system is aromatic or at least one of the rings in bicyclic or tricyclic ring systems is aromatic. The heteroaryl group includes a benzofused ring system containing 2 to 3 rings. For example, a benzofused group includes a benzofused group with one or two 4 to 8 membered heterocycloaliphatic moieties (e.g. indolizyl, indolyl, isoindolyl, 3H-indolyl, indolinyl, benzo [b] furyl, benzo [b] thiophenyl, quinolinyl or isoquinolinyl). Some examples of a heteroaryl group are azetidinyl, pyridyl, 1H-indazolyl, furyl, pyrrolyl, thienyl, thiazolyl, oxazolyl, imidazolyl, tetrazolyl, benzofuryl, isoquinolinyl, benzothiazolyl, xanthene, thioxantol, dihydroindino] benzo [b] furyl, benzo [b] thiophenyl, indazolyl, benzimidazolyl, benzothiazolyl, puryl, cinnolyl, quinolyl, quinazolyl, cinnolyl, phthalazine, quinazolyl, quinoxalil, isoquinolyl, 4H-quinolizil, Benzo-1,2,5-thiadiazolyl or 1,8-naphthyridyl.

[0055] Without limitation, monocyclic heteroaryl groups include furyl, thiophenyl, 2H-pyrrolyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, 1,3,4-thiadiazolyl, 2H-pyranyl, 4-H -pyranyl, pyridyl, pyridazl, pyrimidyl, pyrazolyl, pyrazyl or 1,3,5-triazyl. Monocyclic heteroaryl groups are numbered according to standard chemical nomenclature [0056] Without limitation, bicyclic heteroaryl groups include indolizil, indolyl, isoindolyl, 3H-indolyl, indolinyl, benzo [b] furyl, benzo [b] thiophenyl, quinolinyl, quinolinyl , indolizil, isoindolyl, indolyl, benzo [b] furyl, benzo [b] thiophenyl, indazolyl, benzimidazyl, benzothiazolyl, purinyl, 4H-quinolizil, quinolyl, isoquinolyl, cinnolyl, phthalazil, quinazolyl, quinoxalil 1,8-naphthyridyl or pteridyl. Bicyclic heteroaryl groups are numbered according to standard chemical nomenclature.

[0057] Heteroaryl is optionally substituted with one or more substituents, such as an aliphatic group (e.g. alkyl, alkenyl or alkynyl); cycloaliphatic; (Cycloaliphatic) aliphatic; heterocycloaliphatic; (Heterocycloaliphatic) aliphatic; aryl; heteroaryl; alkoxy; oxy (cycloaliphatic) group; (heterocycloaliphatic) oxy; aryloxy; heteroaryloxy; oxy (araliphatic) group; (heteroaraliphatic) oxy; aroyl; heteroaroyl; amino group; oxo (on a non-aromatic carbocyclic or heterocyclic ring of a bicyclic or tricyclic heteroaryl group); carboxyl; amide group; acyl [e.g. aliphatic carbonyl group; (Cycloaliphatic) carbonyl; ((Cycloaliphatic) aliphatic) carbonyl; (Araliphatic) carbonyl; (Heterocycloaliphatic) carbonyl; ((Heterocycloaliphatic) aliphatic) carbonyl; or (heteroara13 lifetime) carbonyl]; sulfonyl [e.g. aliphatic sulfonyl or aminosulfonyl group]; sulfinyl [e.g. aliphatic sulfinyl group]; sulfanyl [e.g. aliphatic sulfanyl group]; nitro group; cyano group; halogen; hydroxy; mercapto group; sulfoxy; urea; thiourea moiety; sulfamoyl; sulfamide group; or carbamoyl. Alternatively, heteroaryl may be unsubstituted.

[0058] Non-limiting examples of substituted heteroaryl groups include (halo) heteroaryl [e.g. mono- and di- (halo) heteroaryl]; (carboxy) heteroaryl [e.g. (Alkoxycarbonyl) heteroaryl]; cyanoheteroaryl; aminoheteroaryl [e.g. ((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 [e.g. (Aminosulfonyl) heteroaryl]; (sulfonyl) heteroaryl [(e.g. (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 [e.g. trihaloalkylheteroaryl]. [0059] A "heteroaraliphatic" group (such as a heteroaralkyl group), as used herein, means an aliphatic group (e.g., a C1-4 alkyl group) that is substituted with a heteroaryl group. "Aliphatic", "alkyl" and "heteroaryl" have been defined above.

[0060] A "heteroaralkyl" group, as used herein, means an alkyl group (e.g., a C1-4 alkyl group) that is substituted with a heteroaryl group. Both "alkyl" and "heteroaryl" have been defined above. Heteroaralkyl is optionally substituted with one or more substituents, such as alkyl (including carboxyalkyl, hydroxyalkyl and haloalkyl, such as trifluoromethyl), alkenyl, alkynyl, cycloalkyl, (cycloalkyl) alkyl, heterocycloalkyl, (heterocycloalkyl) alkyl, aryl, heteroaryl, alkoxy , cycloalkyloxy, heterocycloalkyloxy, aryloxy, heteroaryloxy, aralkyloxy, heteroaralkyloxy, aroyl, heteroaroyl, nitro, carboxy, alkoxycarbonyl, alkylcarbonyloxy, aminocarbonyl, alkylcarbonylamino, cycloalkylcarbonylamino, (cycloalkylalkyl) carbonylamino, arylcarbonylamino, aralkylcarbonylamino, (heterocycloalkyl) carbonylamino, (heterocycloalkylalkyl) carbonylamino, heteroarylcarbonylamino, heteroaralkyloxyalkyloxyalkyloxyalkyloxy , sulfamoyl, sulfamido, oxo or carbamoyl.

[0061] As used herein, a "cyclic moiety" includes cycloalkyl, heterocycloalkyl, cycloalkenyl, heterocycloalkenyl, aryl or heteroaryl, each of which has been previously defined.

[0062] As used herein, an "acyl" group means a formyl or R group^X-C (O) - (such as alkyl-C (O) -, also referred to as "alkylcarbonyl"), wherein R and "alkyl" have been previously defined. Examples of acyl groups are acetyl and pivaloyl.

[0063] As used herein, "aroyl" or "heteroaroil" means an aryl-C (O) - or heteroaryl-C (O) - group. The aryl and heteroaryl portion of aroyl or heteroaroyl is optionally substituted as previously defined.

[0064] As used herein, an "alkoxy" group means an alkyl-O- group in which "alkyl" has been previously defined.

[0065] As used herein, a "carbamoyl" group means a group having the structure -O-CO-NR^XR or -NR^X-CO-OR in which R^X and R^Y have been defined above and R^FROM it may be an aliphatic group, aryl, araliphatic group, heterocycloaliphatic, heteroaryl or heteroaraliphatic group.

[0066] As used herein, a "carboxy" group is -COOH, -COOR^X, -OC (O) H, -OC (O) R^X when used as an end group or -OC (O) - or -C (O) O- when used as an internal group. [0067] As used herein, a "haloaliphatic" group means an aliphatic group substituted with 1, 2 or 3 halogen atoms. For example, the term haloalkyl includes the group -CF3.

[0068] As used herein, the group "mercapto" means -SH. [0069] As used herein, the group "sulfo" means -SO₃H or -SO3R^X when used as an end group or -S (O)₃- when used as an internal group.

[0070] As used herein, a "sulfamide" group means a group with the structure -NR -S (O)₂-NR R when used as the end group and

-NR^x-S (O)₂-NR^s- when used as an internal group, with R^X,

YZ

R and R have been defined above.

[0071] As used herein, a "sulfamoyl" group means

XYXZ group about construction -S (O)₂-NR R or -NR -S (O)₂-R when used as an end group; or -S (O)₂-NR^X- or -NR^X-S (O)₂- where it is used as

XYZ internal group, with R, R and R as defined above.

[0072] As used herein, a "sulfanyl" group is -SR^Xwhen used as an end group and -S- when used as an internal group, with R^X has been defined above. Examples of sulfanyl groups include alkylsulfanyl.

[0073] As used herein, a "sulfinyl" group means -S (O)_X

R when used as an end group and -S (O) - when used as an internal group, with R^X has been defined above.

[0074] As used herein, a "sulfonyl" group means _X

-S (O)₂-R when used as an end group and -S (O)₂- when used as an internal group, with R^X has been defined above.

[0075] As used herein, a "sulfoxy" group is -OSO-R^X or -SO-OR^Xwhen used as an end group and -OS (O) - or _X

-S (O) -O- when used as an internal group, with R as defined above.

[0076] As used herein, "halogen" or "halo" means fluoro, chloro, bromo or iodo.

[0077] As used herein, an "alkoxycarbonyl" group, which includes the term "carboxy", used alone or in combination with another group, means a group such as alkyl-OC (O) [0078] As used herein, a group "Alkoxyalkyl" means an alkyl group, such as alkyl-O-alkyl-, in which alkyl has been defined above.

[0079] As used herein, a "carbonyl" group means -C (O) -.

[0080] As used herein, an "oxo" group means = O.

[0081] As used herein, an "aminoalkyl" group means

XY group with (RR) N-alkyl- structure.

[0082] As used herein, a "cyanoalkyl" group means a (NC) -alkyl- group.

[0083] As used herein, a "urea" moiety means

XYZ group with the structure -NR -CO-NR R and the group "thiourea" means the group with the structure -NR^X-CS-NR^YR^FROM when used as an end grouping and

-NR^X-CO-NR^Y- or -NR^X-CS-NR^Y- when used as a grouping

XYZ internal, with R^X, R^Y and R^FROM have been defined above.

[0084] As used herein, a "guanidine" group means a group YXYXY with the structure -N = C (N (R^XR^Y)) N (R^XR^Y) in which R^X and R^Y have been defined above. [0085] As used herein, the term "amidine" means a group having the structure -C = (NR^X) N (R^XR^Y) in which R^X and R^Y have been defined above.

[0086] Generally, the term "adjacent" refers to the positioning of substituents in a group having two or more carbon atoms, the substituents being attached to adjacent carbon atoms.

[0087] Generally, the term "geminal" refers to the positioning of substituents in a group containing two or more carbon atoms, the substituents being attached to the same carbon atom.

[0088] The terms "final" and "internal" refer to the position of the group in the structure of the substituent. A group is an end group if it is at the end of a substituent not further linked to the rest of the chemical structure. Carboxyalkyl, i.e., R^XO (O) C-alkyl is an example of a carboxy group used as an end group. A group is an internal group if it is in the middle of a substituent up to the end of the substituent attached to the rest of the chemical structure. Alkyl carboxyl groups (e.g., alkyl-C (O) -O or alkyl-OC (O) -) and alkylcarboxaryl (e.g., alkyl-C (O) -O-aryl- or alkyl-OC (O) aryl-) are examples of groups carboxylic acid used as internal groups.

[0089] As used herein, an "amidine" group means a group

XXYXY with the structure -C = (NR) N (RR, where R and R have been defined above.

[0090] As used herein, a "cyclic" group includes mono-, bi- and tri-cyclic ring systems such as cycloaliphatic, heterocycloaliphatic, aryl or heteroaryl, each of which is defined above.

[0091] As used herein, a "bridged bicyclic ring system" means a bicyclic heterocycloaliphatic ring system or bicyclic cycloaliphatic ring system in which the rings are bridged. Examples of bridged bicyclic ring systems include, but are not limited to, adamantanyl, norbornanyl, bicyclo [3.2.1] octyl, bicyclo [2.2.2] octyl, bicyclo [3.3.1] nonyl, bicyclo [3.2.3] nonyl, 2-oxabicyclo [2.2.2] octyl, 1-azabicyclo [2.2.2] octyl,

3-azabicyclo [3.2.1] octyl and 2,6-dioxatricyclo [3.3.1.0^3,7] Nonyl. The bridged bicyclic ring system may be optionally substituted with one or more substituents, such as alkyl (including carboxyalkyl, hydroxyalkyl and haloalkyl, such as trifluoromethyl), alkenyl, alkynyl, cycloalkyl, (cycloalkyl) alkyl, heterocycloalkyl, (heterocycloalkyl) alkyl, aryl , heteroaryl, alkoxy, cycloalkyloxy, heterocycloalkyloxy, aryloxy, heteroaryloxy, aralkyloxy, heteroaralkyloxy, aroyl, heteroaroyl, nitro, carboxy, alkoxycarbonyl, alkylcarbonyloxy, aminocarbonyl, alkylcarbonylamino, cycloalkylcarbonylamino, (cycloalkylalkyl) carbonylamino, arylcarbonylamino, aralkylcarbonylamino, (heterocycloalkyl) carbonylamino, (heterocycloalkylalkyl) carbonylamino, heteroarylcarbonylalkyl, heteroalkylarboxylate, heteroarylcarbonylacrylate, heteroalkylarboxylate, , thiourea, sulfamoyl, sulfamide moiety, oxo or carbamoyl group.

[0092] As used herein, an "aliphatic chain" means a branched or straight chain aliphatic group (e.g., alkyl groups, alkenyl groups, or alkynyl groups). The straight aliphatic chain has the structure - [CH2] v-, where v is 16. A branched aliphatic chain is a straight aliphatic chain which is substituted by one or more aliphatic groups. The branched aliphatic chain has the structure - [CHQ] v- where Q is a hydrogen atom or an aliphatic group; however, at least in one case Q should be an aliphatic group. The term aliphatic chain includes alkyl chains, alkenyl chains and alkynyl chains, wherein alkyl, alkenyl and alkynyl are as defined above.

[0093] The term "optionally substituted" is used interchangeably with the term "substituted or unsubstituted". As described herein, the compounds of the invention may be optionally substituted with one or more substituents, such as those described generally above, or as illustrated in the examples by the particular classes, subclasses, and types of the invention. As shown herein, the variables R₁, R₂, R₃ and R₄ and other variables present in Formula I include specific groups such as alkyl and aryl. Unless otherwise indicated, each of the specific groups included in the variables R1, R2, R3 and R4, and other variables that are described herein, may be optionally substituted with one or more substituents described herein. Each substituent of a particular group is additionally optionally substituted with one to three halogen atoms, cyano groups, oxoalkoxy, hydroxyls, amino groups, nitro groups, aryls, haloalkyls and alkyls. For example, the alkyl group may be substituted with alkylsulfanyl, and the alkylsulfanyl may be optionally substituted with one to three halogen atoms, cyano groups, oxoalkoxy, hydroxyls, amino groups, nitro groups, aryls, haloalkyls and alkyls. As an additional example, the cycloalkyl part of the (cycloalkyl) carbonylamino group may be optionally substituted with one to three halogen atoms, cyano groups, alkoxy, hydroxyls, nitro groups, haloalkyls and alkyls. If two alkoxy groups are attached to the same atom or adjacent atoms, the two alkoxy groups may form a ring together with the atom (s) to which they are attached. [0094] In general, the term "substituted", whether or not preceded by the term "optionally", means the replacement of hydrogen radicals in the given structure with the radicals of a particular substituent. Specific substituents are described above in the definitions and below in the description of the compounds and examples thereof. Unless otherwise indicated, an optionally substituted group may have a substituent at each substitutable position in the group, and if more than one position in any given structure may be substituted with more than one substituent selected from a particular group, the substituent may be either the same or different in every position. A ring substituent, such as a heterocycloalkyl, may be attached to another ring, such as a cycloalkyl, to form a spirobicyclic ring system, e.g., both rings have one common atom. Combinations of substituents envisioned by the present invention are those combinations that result in the formation of stable or chemically possible compounds.

[0095] The term "to", as used herein, means zero or any integer that is equal to or less than the number following it. For example, "to 3" means any number among 0, 1, 2 and 3.

[0096] The term "stable or chemically possible," as used herein, means compounds that do not change significantly when subjected to conditions that allow their production, detection and preferably their recovery, purification and application to one or more purposes disclosed in this description. In some embodiments, the stable compound or chemically possible compound is one that does not change significantly when stored at 40 ° C or lower, without access of moisture or other chemically reactive conditions, for at least a week.

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

[0098] Unless otherwise stated, structures described herein are believed to include all isomeric (e.g., enantiomeric, diastereomeric and geometric (or conformational) forms of the structure; for example, R and S configurations for each asymmetric center, (Z) and (E) double bond isomers, and (Z) and (E) conformational isomers. Thus, individual stereochemical isomers as well as enantiomeric, diastereomeric and geometric (or conformational) mixtures of the present compounds are within the scope of the invention. Unless otherwise stated, all tautomeric forms of the compounds of the invention are within the scope of the invention. In addition, unless stated otherwise, it is believed that the structures described herein also include compounds that differ only in the presence of one or more isotopically enriched atoms. For example, compounds having the structures of the invention with the exception that the hydrogen atom has been replaced with a deuterium or tritium atom or the carbon atom has been replaced with an enriched carbon atom¹³C- or ¹⁴C - are within the scope of the present invention. Such compounds are useful, for example, as analytical tools or samples in biological analyzes.

COMPOUNDS [0099] The compounds of the present invention are useful as modulators of ABC transporters and are useful in the treatment of diseases mediated by ABC transport.

Special characters

A. Substituent Rj_ [0100] Each R1 is independently an optionally substituted C group_1-6 aliphatic, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted C3-10 membered cycloaliphatic, optionally substituted 3 to 10 membered heterocycloaliphatic, carboxy [e.g. hydroxycarbonyl or alkoxycarbonyl], an amide group [e.g. aminocarbonyl], amino, halogen or hydroxyl.

[0101] In some embodiments, one R₁ is an optionally substituted C group_1-6aliphatic. In particular examples, one R1 is an optionally substituted C1-6 alkyl group, an optionally substituted C2-6 alkenyl group, or an optionally substituted C2-6 alkynyl group. In particular examples, one R1 is C1-6 alkyl, C2-6 alkenyl or C2-6 alkynyl.

[0102] In individual embodiments, one R₁ is aryl or heteroaryl containing 1 or 3 substituents. In particular examples, one R1 is monocyclic aryl or heteroaryl. In particular embodiments, R1 is aryl or heteroaryl having 1, 2 or 3 substituents. In particular examples, R1 is monocyclic aryl or heteroaryl.

[0103] In particular embodiments, at least one R₁ is an optionally substituted aryl or an optionally substituted heteroaryl group and R1 is bonded to the core structure at the 6 position of the pyridine ring.

[0104] In particular embodiments, at least one R₁ is an optionally substituted aryl or an optionally substituted heteroaryl group, and R1 is bonded to the core structure at the 5-position of the pyridine ring.

[0105] In individual embodiments, one R₁ is phenyl containing up to 3 substituents. In particular embodiments, R1 is phenyl having up to 3 substituents.

[0106] In individual embodiments, one R₁ is a heteroaryl ring containing up to 3 substituents. In some embodiments, one R₁ is a monocyclic heteroaryl ring containing up to 3 substituents. In other embodiments, one R1 is a bicyclic heteroaryl ring having up to 3 substituents. In particular embodiments, R1 is a heteroaryl ring containing up to 3 substituents. In some embodiments, R1 is a monocyclic heteroaryl ring containing up to 3 substituents. In other embodiments, R1 is a bicyclic heteroaryl ring containing substituents.

[0107] In individual embodiments, one R₁ is carboxy [e.g. hydroxycarbonyl or alkoxycarbonyl]. Optionally, one R1 is an amide group [e.g. aminocarbonyl]. Optionally, one R1 is amino. Optionally, it is halogen. Optionally, it represents a cyano group. Optionally, hydroxyl.

[0108] In some embodiments, R₁ is hydrogen, methyl, ethyl, i-propyl, t-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, allyl, F, Cl, methoxy, ethoxy i-propoxy, t-butoxy, CF3, OCF3, CN, hydroxyl or a group amino. In particular examples, R1 is hydrogen, methyl, methoxy, F, CF3 or OCF3. In particular examples, R1 may be hydrogen. Optionally, R1 may be methyl. Optionally, R1 may be CF3. Optionally, R1 may be methoxy.

[0109] In particular embodiments, R₁ is substituted with no more than three substituents selected from halogen, oxo or optionally substituted aliphatic, cycloaliphatic, heterocycloaliphatic, amino [e.g. (aliphatic) amino], amide [e.g. aminocarbonyl, ((aliphatic) amino) carbonyl and ((aliphatic) 2amino) carbonyl], carboxyl [e.g. alkoxycarbonyl and hydroxycarbonyl], sulfamoyl [e.g. aminosulfonyl, ((aliphatic) 2amino) sulfonyl, ((cycloaliphatic) aliphatic) aminosulfonyl and ((cycloaliphatic) amino) sulfonyl], cyano, alkoxy, aryl, heteroaryl [e.g. monocyclic heteroaryl and bicycloheteroaryl], sulfonyl [e.g. aliphatic sulfonyl or (heterocycloaliphatic) sulfonyl], sulfinyl [e.g. aliphatic sulfinyl], aroyl, heteroaroyl or heterocycloaliphatic carbonyl group.

[0110] In particular embodiments, R₁ is substituted with halogen. Examples of substituents for R1 include F, Cl and Br. In particular examples, R1 is substituted by F.

[0111] In particular embodiments, R₁ is substituted with an optionally substituted aliphatic group. Examples of substituents for R1 include an optionally substituted alkoxyaliphatic, heterocycloaliphatic, aminoalkyl, hydroxyalkyl, (heterocycloalkyl) aliphatic, alkylsulfonylaliphatic, alkylsulfonylaminoaliphatic, alkylcarbonylaminoaliphatic, alkylaminoaliphatic or alkylcarbonylaliphatic group.

[0112] In individual embodiments, R₁ is substituted with an optionally substituted amino. Examples of substituents for R1 include an aliphatic carbonylamino, aliphaticamino, arylamino or aliphatic sulfonylamino group.

[0113] In particular embodiments, R1 is substituted with sulfonyl. Examples of the substituents for R1 include heterocycloaliphatic sulfonyl, aliphatic sulfonyl, aliphaticaminosulfonyl, aminosulfonyl, aliphaticcarbonylaminosulfonyl, alkoxyalkylheterocycloalkylsulfonyl, alkylcycloalkylsulfonylalkyl, alkylheterylcycloalkylsulfonyl),

[0114] In particular embodiments, R₁ is substituted with carboxy. Examples of substituents for R1 include alkoxycarbonyl and hydroxycarbonyl.

[0115] In particular embodiments of R₁ is substituted with an amide group. Examples of substituents for R1 include alkylaminocarbonyl, aminocarbonyl, ((aliphatic) 2amino) carbonyl and [((aliphatic) aminoaliphatic) amino] carbonyl.

[0116] In particular embodiments, R₁ is substituted with carbonyl. Examples of substituents for R1 include arylcarbonyl, cycloaliphatic carbonyl, heterocycloaliphatic carbonyl and heteroarylcarbonyl.

[0117] In some embodiments, R₁ is hydrogen. In some embodiments, R₁means -Z^ANDR5, where each Z^AND is independently a bond or an optionally substituted, branched or straight C1-6 aliphatic chain in which up to two carbon units of the Z chain^AND is optionally and independently replaced by -CO-, -CS-, -CONR^AND-, -CONR^ANDNO^AND-, -CO2- -OCO-, -NR^ANDCO2-, -O-, -NR^ANDCONR^AND-, -OCONR^AND-,

-NR^ANDNO^AND-, -NR^ANDCO-, -S-, -SO-, -SO2-, -NR^AND-, -SO2NR^AND-, -NR^ANDSO2- or -NR^AND2 NR^AND-.

Each R5 is independently R^AND, halogen, -OH, -NH2, -NO2, -CN, -CF3 or -OCF3. Each RA is independently a C1-8 aliphatic, cycloaliphatic, heterocycloaliphatic, aryl or heteroaryl group, each of which is optionally substituted with 1, 2 or 3 R substituents^D. Each R^D means -Z^DR9, where each Z^D is independently a bond or an optionally substituted, branched or straight C1-6 aliphatic chain in which up to two carbon units of the Z chain^D is optionally and independently replaced by -CO-, -CS-, -CONR^E-, -CONR^ENO^E-, -CO2-, -OCO-, -NR^ECO2-, -O-, NR^ECONR^E-, -OCONR^E-, -NR^ENO^E-, -NR^ECO-, -S-, -SO-, -SO2-, -NR^E-, -SO2NR^E-, -NR^ESO2- or -NR^e2 NR^e-. Each R9 is independently R^E, halogen, -OH, -NH2, -NO2, -CN, -CF3 or -OCF3. Each R^E is independently hydrogen, optionally substituted C_1-8 aliphatic, optionally substituted cycloaliphatic, optionally substituted heterocycloaliphatic, optionally substituted aryl or optionally substituted heteroaryl.

[0118] In some embodiments, each R^D means independently -Z^DR⁹; where each Z^Dmay independently be a bond or an optionally substituted, branched or straight C1-6 aliphatic chain in which up to two carbon units of the Z chain^D is optionally and independently replaced by -O-, -NHC (O) -, -C (O) NR^E-, -SO2-, -NHSO₂-, -NHC (O) -, -NR^ESO2-, -SO2NH-, -SO2NR^E-, -NH- or -C (O) O-. In some embodiments, one carbon unit of the Z chain^D is replaced by -O-. Alternatively, by -NHC (O) -. Optionally, via -C (O) NR^E-. Alternatively, via -SO2-. Optionally, via -NHSO2-. Alternatively, by -NHC (O) -. Alternatively, via -SO-. Alternatively, by -NR^eSO 2. Alternatively, via -SO₂NH-. Alternatively, via -SO₂NO^E-. Alternatively, by -NH-. Optionally, by -C (O) O-.

[0119] In some embodiments, R₉ is hydrogen. In some embodiments, R₉is independently an optionally substituted aliphatic group. In some embodiments, R9 is an optionally substituted cycloaliphatic group. Optionally, it is an optionally substituted heterocycloaliphatic group. Optionally, it represents an optionally substituted aryl group. Optionally, it is an optionally substituted heteroaryl group. Optionally, H or halogen.

[0120] In some embodiments, one R₁ is aryl or heteroaryl, each optionally substituted with 1, 2 or 3 R substituents^D, with R^D has the meaning as defined above.

[0121] In individual embodiments, one R₁ is carboxy [e.g. hydroxycarbonyl or alkoxycarbonyl]. Optionally, one R1 is an amide group [e.g. aminocarbonyl]. Optionally, one R1 is amino. Optionally, it is halogen. [0122] In some embodiments, one R₁which is attached at the 5- or 6- position of the pyridyl ring is aryl or heteroaryl, each optionally substituted with 1, 2 or 3 substituents R^D, with R^D has the meaning as defined above. In some embodiments, this one R₁ attached in the 5- or 6- position of the pyridyl ring is phenyl optionally substituted with 1, 2 or 3 R substituents^D, with R^D has the meaning as defined above. In some embodiments, the one R1 attached at the 5- or 6- position of the pyridyl ring is heteroaryl optionally substituted with 1, 2 or 3 R substituents^D. In particular embodiments, the one R1 attached at the 5- or 6-position of the pyridyl ring is a 5 or 6 membered heteroaryl group containing 1, 2 or 3 heteroatoms independently selected from the group consisting of oxygen, nitrogen and sulfur. In other embodiments, the 5 or 6 membered heteroaryl group is substituted with 1 R^D [0123] In some embodiments, one R₁ attached in the 5- or 6- position of the pyridyl ring is phenyl substituted with 1 R^D. In some embodiments, one R1 attached at the 5- or 6- position of the pyridyl ring is a 2 R substituted phenyl^D. In some embodiments, one R₁ attached in the 5- or 6- position of the pyridyl ring is a 3 R substituted phenyl^D.

[0124] In particular embodiments, R₁ means:

<img file="PL1945632T3_D0003.tif" />

where

IN₁ means -C (O) -, -SO₂- or -CH₂-;

D is H, hydroxy or an optionally substituted group selected from an aliphatic, cycloaliphatic, alkoxy and amino group; and RD has the meaning as defined above.

[0125] In individual embodiments, W₁ means -C (O) -. Alternatively, in₁ means -SO₂-. Alternatively, in₁ means -CH₂-.

[0126] In particular embodiments, D is OH. Optionally, D is an optionally substituted C group_1-6 aliphatic or optionally substituted C group₃-C₈ cycloaliphatic. Optionally, D is optionally substituted alkoxy. Optionally, D is an optionally substituted amino.

[0127] In individual examples, D is

<img file="PL1945632T3_D0004.tif" />

wherein each A and B is independently H, an optionally substituted C group_1-6 aliphatic, optionally substituted C group₃-C₈ cycloaliphatic or

A and B, taken together, form an optionally substituted 3-7 membered heterocycloaliphatic ring.

[0128] In particular embodiments, A is H and B is an optionally substituted C group_1-6 aliphatic. In particular embodiments, B is substituted with 1, 2 or 3 substituents. Optionally, both A and B are H. Exemplary substituents include oxo, alkyl, hydroxy, hydroxyalkyl, alkoxy, alkoxyalkyl, dialkylamino or an optionally substituted group selected from cycloaliphatic, heterocycloaliphatic, aryl and heteroaryl.

[0129] In individual embodiments, A is H and B is an optionally substituted C group_1-6 aliphatic. Optionally, both A and B are H. Exemplary substituents include oxo, alkyl, hydroxy, hydroxyalkyl, alkoxy, alkoxyalkyl and an optionally substituted heterocycloaliphatic.

[0130] In individual embodiments, B is C_1-6 alkyl, optionally substituted with oxo, alkyl, hydroxy, hydroxyalkyl, alkoxy, alkoxyalkyl or an optionally substituted group selected from cycloaliphatic, heterocycloaliphatic, aryl and heteroaryl. In individual embodiments, B is substituted with an oxo group, C_1-6alkyl, hydroxyl, hydroxy (C_1-6) alkyl, (C_1-6alkoxy, (C_1-6) Alkoxy (C_1-6) alkyl, a C group_3-8 cycloaliphatic, 3-8 membered heterocycloaliphatic, phenyl or 5-10 membered heteroaryl groups. In one example, B is C 1-6 alkyl substituted with optionally substituted phenyl.

[0131] In individual embodiments, A and B, taken together, form an optionally substituted 3-7 membered heterocycloaliphatic ring. In particular examples, this heterocycloaliphatic ring is optionally substituted with 1, 2 or 3 substituents. Such exemplary rings include optionally substituted pyrrolidinyl, piperidinyl, morpholinyl and piperazinyl. Exemplary substituents for such rings include halogen, oxo, alkyl, hydroxy, hydroxyalkyl, alkoxy, alkoxyalkyl, acyl (e.g., alkylcarbonyl), amino, amide and carboxy. In some embodiments, this substituent is halogen, oxo, alkyl, hydroxy, hydroxyalkyl, alkoxy, alkoxyalkyl, amino, amide and carboxy.

[0132] In particular embodiments, R^D represents a hydrogen atom, a halogen atom or an optionally substituted group selected from an aliphatic, cycloaliphatic, amino, hydroxy, alkoxy, carboxyl, amide, carbonyl, cyano, aryl or heteroaryl group. In individual examples, R^D is hydrogen, halogen, optionally substituted C1-6 aliphatic or optionally substituted alkoxy. In individual examples, R^D is hydrogen, F, Cl, optionally substituted C1-6 alkyl or optionally substituted -O (C1-6 alkyl). Examples of substituents for R^D include hydrogen, F, Cl, methyl, ethyl, i-propyl, / -butyl, -OMe, -OEt i-propoxy, t-butoxy, CF3 or -OCF3. In some examples, R^Dis hydrogen, F, methyl, methoxy, CF3 or -OCF₃. R^D may be hydrogen. R^d may be F. R^D may be methyl. R^D can be methoxy.

[0133] In particular embodiments, R₁ means:

<img file="PL1945632T3_D0005.tif" />

where:

IN₁ means -C (O) -, -SO₂- or -CH₂-;

each of A and B is independently H, an optionally substituted C group_1-6 aliphatic, optionally substituted C 3 -C 8 cycloaliphatic; or

A and B, taken together, form an optionally substituted 3-7 membered heterocycloaliphatic ring.

[0134] In some embodiments, one R₁which is attached at the 5- or 6- position of the pyridyl ring is a cycloaliphatic or heterocycloaliphatic group, each optionally substituted with 1, 2 or 3 R substituents^D; with R^D means -Z^DR9; in which each Z^D is independently a bond or an optionally substituted, branched or straight C1-6 aliphatic chain in which up to two carbon units of the Z chain^D is optionally and independently replaced by -CO-, -CS-, -CONR^E-, -CONR^ENO^E-,

-CO2-, -OCO-, -NR^ECO2-, -O

-NR^ECONR^E-OCONR^E-,

-NR^ENO^E-NR^ECO-S-SO-, -SO2-, RN^e-, -SO2NR^e-, -NR^eSO2- or -NR^E2 NR^E-; each R9 is independently R^E, halogen, -OH, -NH2, -NO2, -CN, -CF3 or -OCF3; and each R^E is independently hydrogen, optionally substituted C_1-8 aliphatic, optionally substituted cycloaliphatic, optionally substituted heterocycloaliphatic, optionally substituted aryl or optionally substituted heteroaryl.

[0135] In individual examples, one R₁which is attached at the 5- or 6- position of the pyridyl ring is an optionally substituted C3-C8 cycloaliphatic.

[0136] In some embodiments, one R₁which is attached at the 5- or 6- position of the pyridyl ring is an optionally substituted C3-C8 cycloalkyl group or an optionally substituted C3-C8 cycloalkenyl group.

[0137] In individual embodiments, one R₁which is attached at the 5- or 6- position of the pyridyl ring is C3-C8 cycloalkyl or C3-C8 cycloalkenyl. Examples of cycloalkyl and cycloalkenyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclopentenyl, cyclohexenyl and cycloheptenyl.

<img file="PL1945632T3_D0006.tif" />

<img file="PL1945632T3_D0007.tif" />

<img file="PL1945632T3_D0008.tif" />

<img file="PL1945632T3_D0009.tif" />

<img file="PL1945632T3_D0010.tif" />

<img file="PL1945632T3_D0011.tif" />

<img file="PL1945632T3_D0012.tif" />

<img file="PL1945632T3_D0013.tif" />

[0139] In particular examples, R₁ means one selected from:

<img file="PL1945632T3_D0014.tif" />

<img file="PL1945632T3_D0015.tif" />

<img file="PL1945632T3_D0016.tif" />

<img file="PL1945632T3_D0017.tif" />

<img file="PL1945632T3_D0018.tif" />

B. Substituent R₂ [0140] Each R₂ may be hydrogen.

[0141] .R₂ may be methyl, ethyl, propyl or butyl.

[0142] In particular embodiments, R2 is hydrogen.

C. Substituents R3 and R'3 [0143] Each R₃ and R '₃ together with the carbon atom to which they are attached they form a group

C_3-7 cycloaliphatic or heterocycloaliphatic, each of which is optionally substituted with 1, 2 or 3 substituents.

[0144] In particular embodiments, R3 and R'3 together with the carbon atom to which they are attached form a C3-7 cycloaliphatic or C3-7 heterocycloaliphatic group, each of which is optionally substituted with 1, 2 or 3 -Z substituents^BR7, where each Z^B is independently a bond or an optionally substituted, branched or straight C1-4 aliphatic chain in which up to two carbon units of the Z chain^B is optionally and independently replaced by -CO-, -CS-, -CONRB-, -CONR^BNO^B-, -CO2-, -OCO-, -NR^bWHAT₂-, -O-, -NR^bCONR^b-, -OCONR^b-, -NR^BNO^B-, NRBCO-, -S-, -SO-, -SO2-, -NR^B-,

-SO₂NO^b-, -NR^bSO2- or -NR^b2 NR^b-; each R7 is independently R^B, halogen, -OH, -NH2, -NO₂ -CN, -CF₃ or -OCF₃; and each R^B is independently hydrogen, optionally substituted C1-8 aliphatic, optionally substituted cycloaliphatic, optionally substituted heterocycloaliphatic, optionally substituted aryl or optionally substituted heteroaryl.

[0145] In particular embodiments, R₃ and R '₃ together with the carbon atom to which they are attached, they form a 3, 4, 5 or 6 membered cycloaliphatic group which is optionally substituted with 1, 2 or 3 substituents. In particular examples, R3, R'3 and the carbon atom to which they are attached form an optionally substituted cyclopropyl group. In particular alternative examples, R3, R'3 and the carbon atom to which they are attached form an optionally substituted cyclobutyl group. In particular other examples, R3, R'3 and the carbon atom to which they are attached form an optionally substituted cyclopentyl group. In other examples, R3, R'3 and the carbon atom to which they are attached form an optionally substituted cyclohexyl group. In other examples, R3 and R'3 together with the carbon atom to which they are attached form unsubstituted cyclopropyl.

[0146] In particular embodiments, R₃ and R '₃ together with the carbon atom to which they are attached, they form a 5, 6 or 7 membered optionally substituted heterocycloaliphatic group. In other examples, R3, R'3 and the carbon atom to which they are attached form an optionally substituted tetrahydropyranyl group.

[0147] In some embodiments, R₃ and R '₃ together with the carbon atom to which they are attached they form an unsubstituted C 3-7 cycloaliphatic or unsubstituted heterocycloaliphatic group. In particular examples, R3 and R'3 together with the carbon atom to which they are attached form unsubstituted cyclopropyl, unsubstituted cyclopentyl or unsubstituted cyclohexyl.

D. Substituent R4 [0148] Each R₄ is independently an optionally substituted aryl or an optionally substituted heteroaryl.

[0149] In particular embodiments, R₄ is aryl having 6 to 10 members (e.g., 7 to 10 members) optionally substituted with 1, 2 or 3 substituents. Examples of substituents for R4 include optionally substituted benzene, naphthalene or indene. Optionally, examples of R4 substituents may be optionally substituted phenyl, optionally substituted naphthyl or optionally substituted indenyl.

[0150] In individual embodiments, R₄ is an optionally substituted heteroaryl group. Examples of substituents for R4 include monocyclic and bicyclic heteroaryl, such as a benzofused ring system in which the phenyl is fused to one or two 4-8 membered heterocycloaliphatic groups.

[0151] In some embodiments, R₄ is aryl or heteroaryl, each optionally substituted with 1, 2 or 3 -Z substituents^CR8. In some embodiments, R4 is aryl optionally substituted with 1, 2 or 3 -Z R8 substituents. In some embodiments, R4 is phenyl optionally substituted with 1, 2 or 3 -Z substituents^CR8. Optionally, R4 is cc heteroaryl optionally substituted with 1, 2 or 3 -Z R8 substituents. Each Z is independently a bond or an optionally substituted, branched or straight C1-6 aliphatic chain in which up to two carbon units of the Z chain^c is optionally and independently replaced by -CO-, -CS-, -CONRC-, -CONRCNRC-, -CO2-, -OCO-,

-NRCCO2-, -O-, -NRCCONRC-, -OCONRC-, -NR^CNO^C-, -NRCCO-, -S-, -SO-, -SO2-, NR^C-, -SO2NR^C-, -NR^cSO2- or -NR^C2 NR^C-. Each R8 is independently R^C, halogen, -OH, -NH2, -NO2, -CN, -CF3 or -OCF3. Each R^C is independently hydrogen, optionally substituted C1-8 aliphatic, optionally substituted cycloaliphatic, optionally substituted heterocycloaliphatic, optionally substituted aryl, or optionally substituted heteroaryl.

_C [0152] In some embodiments, two -ZR moieties₈, taken together with the carbon atoms to which they are attached, form a 4-8 membered, saturated, partially saturated or aromatic ring containing up to 3 ring atoms independently selected from the group consisting of O, NH, NR and S; wherein R is as defined herein.

[0153] In individual embodiments, R₄ means one selected from

<td>&lt;xx</td><td>XXX</td><td>° χχ</td><td>οΌα AND</td>

<td>eX</td><td>f₃What ^ \</td><td>· χχ</td><td>^{/ Ο}Τ1</td>

<td>α</td><td>XX</td><td>XX.</td><td>ęOyl</td>

<td>° XXX</td><td>cxx</td><td>. σχ.</td><td>eo *</td>

<td>ίχχ F</td><td>XXX</td><td></td><td>^ζ° Α ΟΗ</td>

<td></td><td>χχχ</td><td>χχχ</td><td></td>

<td></td><td>. ΧΧΧ</td><td>χχχ</td><td>&lt;Α</td>

<td>θ'ΎΠί</td><td> ,</td><td>and</td><td>Cl ^ η Ο</td>

E. Exemplary Families of Compounds [0154] In particular embodiments, R1 is an optionally substituted cyclic group that is attached to the core structure at the 5 or 6 position of the pyridine ring.

[0155] In individual examples, R₁ is an optionally substituted aryl which is attached at the 5-position of the pyridine ring. In other examples,

R1 is an optionally substituted aryl group that is attached at the 6-position of the pyridine ring.

[0156] In other examples, R₁ is an optionally substituted heteroaryl group that is attached at the 5-position of the pyridine ring. In yet other examples, R 1 is an optionally substituted heteroaryl group that is attached at the 6-position of the pyridine ring.

[0157] In other embodiments, R₁ is an optionally substituted cycloaliphatic group or an optionally substituted heterocycloaliphatic group that is attached at the 5 or 6 position of the pyridine ring.

[0158] Accordingly, another aspect of the present invention provides compounds of formula (II):

<img file="PL1945632T3_D0019.tif" />

or a pharmaceutically acceptable salt thereof, wherein R₁, R₂, R₃, R '₃ and R₄ is defined in formula I.

[0159] In some embodiments, each R 1 is aryl or heteroaryl optionally substituted with 1, 2 or 3 R substituents^D, with R^D means -Z^DR9, where each Z^Dis independently a bond or an optionally substituted, branched or straight C1-6 aliphatic chain in which up to two carbon units of the Z chain^D is optionally and independently replaced by -CO-, -CS-, -CONR^E-, -CONR^ENO^E-, -WHAT₂-, -OCO-NR^ENO^E-, -NR^ECO-NR^ECONR^E-, -OCONR^E-NR^e-CO2-, -OS-, -SO-, -SO2-,

-NR^E-, -SO2NR^e-, -NR^eSO2- or -NR^E2 NR^E-; each R9 is independently R^E, halogen, -OH, -NH2, -NO2, -CN, -CF3 or -OCF3; each R^E is independently hydrogen, optionally substituted C_1-8 aliphatic, optionally substituted cycloaliphatic, optionally substituted heterocycloaliphatic, optionally substituted aryl or optionally substituted heteroaryl.

[0160] In some embodiments, each R₁ is a cycloaliphatic or heterocycloaliphatic group optionally substituted with 1, 2 or 3 R substituents^D; with R^D has the meaning as defined above.

[0161] Another aspect of the present invention provides compounds of formula (III):

<img file="PL1945632T3_D0020.tif" />

or a pharmaceutically acceptable salt thereof, wherein R₁, R₂, R₃, R '₃ and R₄ is defined in formula I.

[0162] In some embodiments, each R₁ is aryl or heteroaryl optionally substituted with 1, 2 or 3 R substituents^D, with R^D means -Z^DR9, where each Z^Dis independently a bond or an optionally substituted, branched or straight C1-6 aliphatic chain in which up to two carbon units of the Z chain^D is optionally and independently replaced by -CO-, -CS-, -CONR^E-, -CONR^ENO^E-, -CO2-, -OCO-, -NR^ECO2-, -O-, -NR^ECONR^E-, -OCONR^E-, -NR^ENO^E-, -NR^ECO-, -S-, -SO-, -SO2-, -NR^E-, -SO2NR^E-, -NR^ESO2- or -NR^E2 NR^E-; each R9 is independently R^E, halogen, -OH, -NH2, -NO2, -CN, -CF3 or -OCF3; each R^E is independently hydrogen, optionally substituted C_1-8 aliphatic, optionally substituted cycloaliphatic, optionally substituted heterocycloaliphatic, optionally substituted aryl or optionally substituted heteroaryl.

[0163] In some embodiments, each R 1 is a cycloaliphatic or heterocycloaliphatic group optionally substituted with 1, 2 or 3 R substituents^D; with R^D has the meaning as defined above.

[0164] In another aspect, the present invention includes compounds of formula (IV):

<img file="PL1945632T3_D0021.tif" />

r^d (IV) or a pharmaceutically acceptable salt thereof, wherein R₂, R₃, R '₃ and R4 is defined in formula I. [0165] R^D means -Z^DR₉; where each Z^D is independently a bond or an optionally substituted, branched or straight C1-6 aliphatic chain in which up to two carbon units of the Z chain^D is optionally and independently replaced by -CO-, -CS-, -CONR^E-, -CONR^ENO^E-, -CO2-, -OCO-, -NR^ECO2-, -O-, -NR^ECONR^E-, -OCONR^E-, -NR^eNO^e-, -NOCO-, -S-, -SO-, -SO2-, -NR^e-, -SO2NR^e-, -NR^eSO2- or -NR^E2 NR^E-. [0166] R9 is independently R^E, halogen, -OH, -NH2, -NO2, -CN, -CF3 or -OCF3.

[0167] Each R^E is independently hydrogen, optionally substituted C_1-8aliphatic, optionally substituted cycloaliphatic, optionally substituted heterocycloaliphatic, optionally substituted aryl or optionally substituted heteroaryl.

[0168] In individual embodiments, Z^D is independently a bond or is an optionally substituted, branched or straight C1-6 aliphatic chain in which one carbon unit of the Z chain^D is optionally replaced by -SO2-, -CONR^E-, -NR^e-SO2- or -SO₂NO^e-. For example, Z^D is an optionally substituted, branched or straight C 1-6 aliphatic chain in which one carbon unit of the Z chain^Dis optionally replaced by -SO2-. In other examples, R₉ is an optionally substituted heteroaryl or an optionally substituted heterocycloaliphatic. In additional examples, R9 is an optionally substituted heterocycloaliphatic group having 1-2 nitrogen atoms and R₉ is attached directly to -SO₂through the ring nitrogen atom.

[0169] In another aspect, the present invention includes compounds of formula VA or formula VB:

<img file="PL1945632T3_D0022.tif" />

or a pharmaceutically acceptable salt thereof, where:

T is an optionally substituted C chain_1-2 aliphatic, in which each of the chain carbon units is optionally and independently replaced by -CO-, -CS-, -COCO-, -SO2-, -B (OH) - or -B (O (C1-6 alkyl)) - ;

Each of R₁'and R₁"Is independently a bond or an optionally substituted C group_1-6 aliphatic, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted 3 to 10 membered cycloaliphatic, optionally substituted 3 to 10 membered heterocycloaliphatic, carboxy, amide, amino, halogen or hydroxy;

RD¹ is attached to a 3 "or 4" carbon atom;

each R^D1 and RD² means -ZDR₉wherein each ZD is independently a bond or an optionally substituted, branched or straight C chain_1-6 aliphatic, in which up to two carbon units of the ZD chain are optionally and independently replaced by -CO-, -CS-, -CONR^e-, -CONR^eNO^e-, -CO2-, -OCO-, -NR^eCO2-, -O-, -NR^eCONR^e-, -OCONR^e-, -NR^eNO^e-, -NR^eCO-, -S-, -SO-, -SO2-, -NR^e-, -SO2NR^e-, -NR^eSO2- or -NR^e2 NR^e-;

R9 is independently R^E, halogen, -OH, -NH2, -NO2, -CN, -CF3 or -OCF3; or R^D1 and R^D2, taken together with the atoms to which they are attached, form a 3-8 membered, saturated, partially unsaturated or aromatic ring containing up to 3 ring members independently selected from the group consisting of O, NH, NR^E and S; and each R^E is independently hydrogen, optionally substituted C_1-8 aliphatic, optionally substituted cycloaliphatic, optionally substituted heterocycloaliphatic, optionally substituted aryl or optionally substituted heteroaryl.

[0170] In some embodiments, T is optionally substituted -CH2-. In some other embodiments, T is optionally substituted with -CH2CH2-.

[0171] In some embodiments, T is optionally substituted with -Z^ER10, where each Z^E is independently a bond or an optionally substituted, branched or straight C1-6 aliphatic chain in which up to two carbon units of the Z chain^E is optionally and independently replaced by -CO-, -CS-, -CONR^F-, -CONR^FNO^F-, -CO2-, -OCO-, -NR^FCO2-, -O-, -NR^FCONR^F-, -OCONR^F-, -NR^FNO^F-, -NR^FCO-, -S-, -SO-, -SO2-, -NR^f-, -SO2NR^f-, -NR^fSO2- or -NR^F2 NR^F-; R10 is independently R^F, halogen, -OH, -NH2, -NO2, -CN, -CF3 or -OCF3; each R^F is independently hydrogen, optionally substituted C_1-8 aliphatic, optionally substituted cycloaliphatic, optionally substituted heterocycloaliphatic, optionally substituted aryl or optionally substituted heteroaryl. In one example, Z^E means -O-.

[0172] In some embodiments, R₁₀ may be an optionally substituted C group_1-6alkyl, optionally substituted C2-6 alkenyl, optionally substituted C_3-7 cycloaliphatic or optionally substituted C group_6-10 aryl. In one embodiment, R10 is methyl, ethyl, i-propyl or t-butyl.

[0173] In some embodiments, up to two carbon units of the T chain are optionally replaced by -CO-, -CS-, -B (OH) - or -B (O (C_1-6 alkyl) -.

[0174] In some embodiments, T is selected from the group consisting of -CH₂-, -CH₂CH₂-, -CF2-, -C (CH₃)₂-, -WHAT)-,

<img file="PL1945632T3_D0023.tif" />

-C (phenyl) 2-, -B (OH) - and -CH (OEt) -. In some embodiments, T is -CH2-, -CF2-, -C (CH₃)₂-,

<img file="PL1945632T3_D0024.tif" />

or -C (phenyl) 2-. In other embodiments, T is -CH2H2-, -C (O) -, -B (OH) - and -CH (OEt) -. In particular embodiments, T is -CH₂-, -CF₂-, -C (CH₃)₂-, or

<img file="PL1945632T3_D0025.tif" />

<img file="PL1945632T3_D0026.tif" />

More preferably, T is -CH₂-, -CF₂- or -C (CH₃)₂-. In particular embodiments, T is -CH₂-. Optionally, T is -CF₂-. Optionally, T is -C (CH₃)₂-. Optionally, T is -CH2CH2.

[0175] In some embodiments, each of R₁'and R₁"Means a hydrogen atom. In some embodiments, each of R₁'and R₁"Means independently -Z^ANDR5, where each Z^AND is independently a bond or an optionally substituted, branched or straight C1-6 aliphatic chain in which up to two carbon units of the Z chain^AND is optionally and independently replaced by -CO-, -CS-, -CONR^AND-, -CONR^ANDNO^AND-, -CO2-, -OCO-, -NR^ANDCO2-,

-O-, -NR^ANDCONR^AND-, -OCONR^AND-, -NR^ANDNO^AND-, -NR^ANDCO-, -S-, -SO-, -SO2-, -NR^AND-, -SO2NR^and-, -NR^andSO2- or -NR^and2 NR^and-. Each R5 is independently R^AND, halogen, -OH, -NH2, -NO2, -CN, -CF3 or -OCF3. Each R^AND is independently an optionally substituted group selected from the group C_1-8 aliphatic, cycloaliphatic, heterocycloaliphatic, aryl and heteroaryl.

[0176] In some embodiments, R₁'is selected from the group consisting of H, group C_1-6 aliphatic, halogen, CF₃, CHF₂, group -O (C_1-6 aliphatic), C3-C5 cycloalkyl or C4C6 heterocycloalkyl containing one oxygen atom. In some embodiments, R₁'is selected from the group consisting of H, methyl, ethyl, i-propyl, Z-butyl, F, Cl, CF₃, CHF₂, -OCH₃, -OCH₂CH₃, -O- (Z-propyl) or -O- (Z-butyl). More preferably, R₁'means H. Optionally, R₁'means methyl. Alternatively, ethyl. Alternatively, CF3.

[0177] In some embodiments, R₁"Is selected from the group consisting of H, group C_1-6 aliphatic, halogen, CF₃, CHF₂ and the group -O (C_1-6 aliphatic). In some embodiments, R₁"Is selected from the group consisting of H, methyl, ethyl, i-propyl, Z-butyl, F, Cl, CF₃, CHF₂, -OCH₃, -OCH₂CH₃, -O- (Z-propyl) or -O- (Z-butyl). More preferably, R₁"Means H. Optionally, R₁"Means methyl. Alternatively, ethyl. Alternatively, CF₃.

[0178] In some embodiments, R^D1 is attached to the 3 "or 4" carbon atom and is -Z^DR9, where each Z^D is independently a bond or an optionally substituted, branched or straight C chain_1-6 aliphatic, in which up to two carbon units of the Z chain^D is optionally and independently replaced by -CO-, -CS-, -CONR^E-, -CONR^ENO^E-, -CO2-, -OCO-, -NR^ECO-, -O-, -NR^ECONR^E-, -OCONR^E-,

-NR^ENO^E-NR^ECO-NR^eSO2- or -NR^e2 NR^eS-, -SO-, -SO2-, -NR^E-, -SO2NR^EIn still some other forms, Z^D is independently a bond or an optionally substituted, branched or straight C1-6 aliphatic chain in which one carbon unit of the Z chain^D is optionally replaced by -CO-, -SO-, -SO2-, -COO-, -OCO-, -CONR^E-, -NR^ECO-, NR^ECO2-, -O-, -NR^ESO2- or -SO2NR^E-. In some embodiments, one carbon unit of the Z chain^D is optionally replaced by -CO-. Alternatively, via -SO-. Alternatively, via -SO2-. Alternatively, via -COO-. Alternatively, via -OCO-. Alternatively, via -CONR^E-. Alternatively, by -NR^EWHAT-. Alternatively, by -NR^ECO2-. Alternatively, by -O-. Alternatively, by -NR^ESO 2. Alternatively, via -SO₂NO^e-.

[0179] In particular embodiments, R₉ is hydrogen, halogen, -OH, -NH2, -CN, -CF3, -OCF3 or an optionally substituted group selected from the group consisting of C_1-6 aliphatic, C._3-8 cycloaliphatic, 3-8 membered heterocycloaliphatic, group C_6-10 aryl and 5-10 membered heteroaryl group. In particular examples, R9 is hydrogen, F, Cl, -OH, -CN, -CF3 or -OCF3. In some embodiments, R⁹means group C_1-6 aliphatic, C._3-8 cycloaliphatic, 3-8 membered heterocycloaliphatic, group C_6-10 aryl and 5-10 membered heteroaryl, each of which is optionally substituted with 1 or 2 substituents independently selected from the group consisting of R^E, oxo group, halogen, -OH, -NR^ER^E, -OR^E, -COOR^E and -CONR^ER^E. In particular examples, R9 is optionally substituted with 1 or 2 substituents independently selected from the group consisting of oxo, F, Cl, methyl, ethyl, i-propyl, Z-butyl,

-CH2OH, -CH2CH2OH, -C (O) OH, -C (O) NH2, -CH2O (C1-6 alkyl), -CHiCHiO ^ alkyl) and -C (O) (C1-6 alkyl).

[0180] In one embodiment, R9 is hydrogen. In some embodiments, R9 is selected from the group consisting of straight or branched C_1-6 alkyl or straight or branched chain C_2-6 alkenyl; wherein said alkyl or alkenyl is optionally substituted with 1 or 2 substituents independently selected from the group consisting of R^E, oxo group, halogen, -OH, -NR^ER^E, -OR^E, -COOR^E and -CONR^ER^E.

[0181] In other embodiments, R₉ means group C_3-8 cycloaliphatic optionally substituted with 1 or 2 substituents independently selected from the group consisting of R^E, oxo group, halogen, -OH, -NR^ER^E, -OR^E, -COOR^E and -CONR^ER^E. Examples of cycloaliphatic groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl.

[0182] In yet other embodiments, R₉ is a 3-8 membered heterocyclic group containing 1 or 2 heteroatoms independently selected from the group consisting of O, NH, NR^E and S; wherein the heterocyclic group is optionally substituted with 1 or 2 substituents independently selected from the group consisting of R^E, oxo group, halogen, -OH, -NR^eR^e, -OR^e, -COOR^e and -CONR^eR^e. Examples of the 3-8 membered heterocyclic group include, but are not limited to

<img file="PL1945632T3_D0027.tif" />

and

<img file="PL1945632T3_D0028.tif" />

[0183] In yet other certain embodiments, R₉ is an optionally substituted 5-8 membered heteroaryl group containing one or two ring atoms independently selected from the group consisting of O, S and NR^E. Examples of 5-8 membered heteroaryl include, but are not limited to

<img file="PL1945632T3_D0029.tif" />

[0184] In some embodiments, R^D1 and R^D2, taken together with the carbon atoms to which they are attached, form an optionally substituted 4-8 membered saturated, partially unsaturated or aromatic ring containing 0-2 ring atoms independently selected from the group consisting of O, NH, NR^E and S. Examples of substituents for R^D1 and R^D2, taken together with phenyl containing 3 "and 4" carbon atoms, include, but are not limited to

<img file="PL1945632T3_D0030.tif" />

<img file="PL1945632T3_D0031.tif" />

and

<img file="PL1945632T3_D0032.tif" />

[0185] In some embodiments, R^D2 is selected from the group consisting of H, R^E, halogen, -OH, - (CIMAIRR ', - (CH2) r-OR^E, -SO2-R^E, -NR^E-SO2-R^E, -SO2NR^ER^E, -C (O) R^E,

-C (O) OR^e, -OC (O) OR^e, -NR^eC (O) OR^e and -C (O) NR^eR^e; wherein r is 0, 1 or 2. W

D2 in other embodiments, R is selected from the group consisting of H, group C_1-6 aliphatic, halogen, -CN, -NH₂, the -NH group (C_1-6 aliphatic), -N (C_1-6 aliphatic)₂, -CH₂-N (C_1-6 aliphatic) ^ -CH₂-NH (C_1-6 aliphatic), -CH₂NH₂, -OH, -O (C_1-6 aliphatic), -CH₂OH, -CH₂-O (C_1-6 aliphatic), -SO₂(C_1-6 aliphatic), -N (C_1-6 aliphatic) SO₂(C_1-6 aliphatic), -NH-SO₂(C_1-6 aliphatic), -SO₂NH₂, -SO₂NH (C_1-6 aliphatic), -SO₂N (C_1-6 aliphatic) ^ -C (O) (C._1-6 aliphatic), -C (O) O (C_1-6 aliphatic), -C (O) OH, -OC (O) o (c_1-6 aliphatic), -NhC (O) (C._1-6 aliphatic), -NHC (O) O (C_1-6 aliphatic), -N (C_1-6 aliphatic) C (O) O (C_1-6 aliphatic), -C (O) NH₂ and -C (O) N (C_1-6 aliphatic)₂. In individual examples, R^D2 is selected from the group consisting of H, group C_1-6 aliphatic, halogen, -CN, -NH₂, -CH₂NH₂, -OH, group -O (C_1-6 aliphatic), -CH₂OH, group -SO₂(C_1-6aliphatic), -NH-SO₂(C_1-6 aliphatic), -C (O) O (C_1-6 aliphatic), -C (O) OH, a group

-NHC (O) (C_1-6 aliphatic), -C (O) NH₂, -C (O) NH (C_1-6 aliphatic) and -C (O) N (C_1-6 aliD2 fatal) 2. For example, R^D2 is selected from the group consisting of H, methyl, ethyl, n-propyl, ipropyl, t-butyl, F, Cl, CN, -NH2, -CH2NH2, -OH, -OCH3, -O-ethyl, -O- (i- propyl), -O- (npropyl), - CH2OH, -SO2CH3 -NH-SO2CH3, -C (O) OCH3, -C (O) OCH2CH3, -C (O) OH, -NHC (O) CH3, -C (O) NH2 and -C (O) N (CH3) 2. In one form, R^D2 is hydrogen. In another embodiment, R^D2 is methyl. Alternatively, R^D2 means ethyl. Alternatively, R^D2is F. Optionally, R^D2 is Cl, Optionally, -OCH3.

[0186] In one embodiment, the present invention provides compounds of formula VI-Ai or

<img file="PL1945632T3_D0033.tif" />

[0187] In one embodiment, T is -CH₂-, -CF₂- or -C (CH₃)₂-.

[0188] In one embodiment, R₁'is selected from the group consisting of H, group C_1-6 aliphatic, halogen, CF₃, CHF₂, group -O (C_1-6 aliphatic), C3-C5 cycloalkyl or C4-C6 heterocycloalkyl containing an oxygen atom. Exemplary forms include H, methyl, ethyl, i-propyl, Z-butyl, F, Cl, CF₃, CHF₂, -OCH₃, -OCH₂CH₃, -O- (z-propyl), -O- (Z-butyl), cyclopropyl or oxetanyl. More preferably, R₁'means H. Optionally, R₁'means methyl. Alternatively, ethyl. Alternatively, CF3. Optionally, oxetanyl.

[0189] In one embodiment, R^D1 means Z^DR9, where Z^D is selected from CONH, NHCO, SO2NH, SO2N (C1-6 alkyl), NHSO2, CH2NHSO2, CH2N (CH3) SO2, CH2NHCO, COO, SO2 or CO. In one form, R^D1 means Z^DR₉, where with^D is selected from CONH, SO2NH SO2N (C1-6 alkyl), CH2NHSO2, CH2N (CH3) SO2, CH2NHCO, COO, SO2 or CO.

[0190] In one embodiment, Z^D is COO and R9 is H. In one embodiment, Z^D means COO and R₉ is an optionally substituted straight or branched chain C group_1-6 aliphatic. In one form, Z^D means COO and R₉ is an optionally substituted straight or branched chain C group_1-6 alkyl group. In one form,

FROM^D is COO and R9 is C1-6 alkyl. In one form, Z^D is COO and R9 is methyl.

[0191] In one embodiment, Z^D is CONH and R9 is H. In one embodiment, Z^Dis CONH and R9 is an optionally substituted straight or branched chain C1-6 aliphatic group. In one form, Z^D is CONH and R9 is straight or branched C1-6 alkyl. In one form, Z^D is CONH and R9 is methyl. In one form, Z^D is CONH and R9 is optionally substituted straight or branched chain C1-6 alkyl. In one form, Z^D is CONH and R9 is 2- (dimethylamino) ethyl.

[0192] In some embodiments, Z^D is CH2NHCO and R9 is an optionally substituted straight or branched chain C1-6 aliphatic group or an optionally substituted alkoxy group. In some forms, Z^D is CH2NHCO and R9 is a straight or branched C1-6 alkyl group optionally substituted by halogen, oxo, hydroxyl or an optionally substituted group selected from an aliphatic, cyclic, aryl, heteroaryl, alkoxy, amino, carboxy or carbonyl group. In one form, Z^D is CH2NHCO and R9 is methyl. In one form, Z^D is CH2NHCO and R9 is CF3. In one form, Z^D is CH2NHCO and R9 is t-butoxy.

[0193] In one embodiment, Z^D is SO2NH and R9 is H. In some embodiments, Z^D is SO2NH and R₉ is an optionally substituted straight or branched chain C group_1-6 aliphatic. In some forms, Z^D is SO2NH and R9 is a straight or branched C1-6 alkyl group optionally substituted by halogen, oxo, hydroxyl or an optionally substituted group selected from a C1-6 aliphatic group, a 3-8 membered cyclic group, C6-10 aryl, 5- 8 membered heteroaryl, alkoxy, amino, amide, carboxy or carbonyl. In one form, Z^D is SO2NH and R₉ is methyl. In one form, Z^D is SO2NH and R9 is ethyl. In one form, Z^D is SO2NH and R₉ means i-propyl. In one form, Z^D is SO2NH and R9 is t-butyl. In one form, Z^D is SO2NH and R₉ is 3,3-dimethylbutyl. In one form, Z^D is SO2NH and R9 is CH2CH2OH. In one form, Z^D is SO2NH and R₉ is CH (CH₃) CH 2 OH. In one form, Z^D is SO2NH and R9 is CH2CH (CH3) OH. In one form, Z^D is SO2NH and R₉ is CH (CH₂OH)₂. In one form, Z^D is SO2NH and R9 is CH2CH (OH) CH2OH. In one form, Z^D is SO2NH and R₉ means CH₂CH (OH) CH₂CH₃. In one form, Z^D is SO2NH and R9 is C (CH3) 2CH2OH. In one form, Z^D is SO2NH and R₉ is CH (CH2CH3) CH2OH. In one form, Z^D is SO2NH and R9 is CH2CH2OCH2CH2OH. In one form, Z^D is SO2NH and R9 is C (CH3) (CH2OH) 2. In one form, Z^D is SO2NH and R9 is CH2CH (OH) CH2C (O) OH. In one form, Z^D is SO2NH and R9 is CH2CH2N (CH3) 2. In one form, Z^D is SO2NH and R9 is CH2CH2NHC (O) CH3. In one form, Z^D is SO2NH and R9 is CH (CH (CH3) 2) CH2OH. In one form, Z^D is SO2NH and R9 is CH (CH2CH2CH3) CH2OH. In one form, Z^D is SO2NH and R₉ means 1-tetrahydrofurylmethyl. In one form, Z^D is SO2NH and R9 is furylmethyl. In one form, Z^D is SO2NH and R9 is (5-methylfuryl) methyl. In one form, Z^D is SO2NH and R9 is 2-pyrrolidinylethyl. In one form, Z^D is SO2NH and R9 is 2- (1-methylpyrrolidinyl) ethyl. In one form, Z^D is SO2NH and R9 is 2- (4-morpholinyl) ethyl. In one form, Z^D is SO2NH and R9 is 3- (4-morpholinyl) propyl. In one form, Z^D is SO2NH and R9 is C (CH2CH₃) (CH₂OH)₂. In one form, Z^D is SO2NH and R9 is 2- (1 Himidazol-4-yl) ethyl. In one form, Z^D is SO2NH and R₉ is 3- (1H-imidazol-1-yl) propyl. In one form, Z^D is SO2NH and R9 is 2- (2-pyridinyl) ethyl. [0194] In some embodiments, Z^D is SO2NH and R₉ is an optionally substituted C group_1-6 cycloaliphatic. In individual examples, ZD is SO₂NH and R₉ is an optionally substituted C group_1-6 cycloalkyl. In individual examples, ZD is SO₂NH and R₉ means C_1-6 cycloalkyl. In one embodiment, ZD is SO₂NH and R₉ means cyclobutyl. In one embodiment, ZD is SO₂NH and R₉ means cyclopentyl. In one form, Z^D is SO2NH and R9 is cyclohexyl.

[0195] In some embodiments, ZD is SO₂N (C_1-6 alkyl) and R₉ is an optionally substituted straight or branched chain C group_1-6 an aliphatic or optionally substituted cycloaliphatic group. In some embodiments, ZD is SO₂N (C_1-6 alkyl) and R₉ is an optionally substituted straight or branched chain C group_1-6aliphatic. In some embodiments, ZD is SO₂N (C_1-6 alkyl) and R₉ is an optionally substituted, straight or branched C group_1-6 alkyl or an optionally substituted straight or branched chain C group_1-6 alkenyl. In one form, Z^D is SO2N (CH3) and R9 is methyl. In one form, Z^D is SO2N (CH3) and R9 is n-propyl. In one embodiment, ZD is SO2N (CH3) and R9 is n-butyl. In one form, Z^D is SO2N (CH3) and R9 is cyclohexyl. In one form, Z^D is SO2N (CH3) and R9 is allyl. In one form, Z^D is SO2N (CH₃) and R₉ means CH₂CH₂OH. In one embodiment, ZD is SO₂N (CH₃) and R9 is CH2CH (OH) CH2OH. In one form, Z^D is SO2N (CH2CH2CH3) and R9 is cyclopropylmethyl.

[0196] In one embodiment, ZD is CH₂NHSO₂and R₉ is methyl. In one embodiment, ZD is CH₂N (CH₃) SO₂and R₉ is methyl.

[0197] In some embodiments, ZD is SO₂and R₉ is an optionally substituted straight or branched chain C group_1-6 an aliphatic or optionally substituted 38 membered heterocyclic group having 1, 2 or 3 ring members selected from the group consisting of nitrogen, oxygen, sulfur, SO or SO₂. In some embodiments, ZD is SO₂and R₉ is a straight or branched chain C group_1-6 an alkyl or 38 membered heterocycloaliphatic group, each of which is optionally substituted with 1, 2 or 3 substituents from oxo, halogen, hydroxyl or optionally substituted group selected from group C_1-6 aliphatic, carbonyl, amine and carboxylic acid. In one embodiment, ZD is SO₂and R₉ is methyl. In some

<img file="PL1945632T3_D0034.tif" />

<img file="PL1945632T3_D0035.tif" />

<img file="PL1945632T3_D0036.tif" />

D2 [0198] In some embodiments, R is H, hydroxy, halogen, C_1-6 alkyl, C._1-6 alkoxy, C._3-6 cycloalkyl or NH₂. In individual examples, R^D2 is H, halogen, C_1-4 alkyl or C._1-4 alkoxy. Examples of substituents for R^D2 include H, F, Cl, methyl, ethyl and methoxy.

[0199] In some embodiments, the present invention provides compounds of formula (I'-A) or formula (I'-B):

<img file="PL1945632T3_D0037.tif" />

(Γ-Α) (Γ-Β) or a pharmaceutically acceptable salt thereof, where R₁, R₂, R₃, R '₃, R₄ in are defined above.

[0200] In some embodiments, R₁ is an optionally substituted aryl. In particular examples, R1 is phenyl optionally substituted with 1, 2 or 3 halogen, OH, -O (C_1-6 aliphatic), amino, group C_1-6 aliphatic, C._1-7 cycloaliphatic, 3-8 membered heterocycloaliphatic, group C_6-10 aryl or 5-8 membered heteroaryl group. In some embodiments, R1 is phenyl optionally substituted with alkoxy, halogen or amino. In one embodiment, R 1 is phenyl. In one embodiment, R 1 is Cl, methoxy, ethoxy or dimethylamino substituted phenyl.

[0201] In some embodiments, R2 is hydrogen. In some embodiments, R2 is an optionally substituted C group_1-6 aliphatic.

[0202] In some embodiments, R3, R'3 and the carbon atom to which they are attached form an optionally substituted C3-8 cycloaliphatic or optionally substituted group

3-8 membered heterocycloaliphatic. In some embodiments, R₃, R '₃ and the carbon atom to which they are attached form an optionally substituted C 3-8 cycloalkyl group. In one example, R3, R'3 and the carbon atom to which they are attached is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl, each of which is optionally substituted. In one example, R3, R'3 and the carbon atom to which they are attached is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl. In particular examples, R3, R'3 and the carbon atom to which they are attached is cyclopropyl.

[0203] In some embodiments, R₄ is an optionally substituted aryl or an optionally substituted heteroaryl group. In some embodiments, R4 is optionally substituted phenyl. In particular embodiments, R4 is phenyl condensed with a 3, 4, 5 or 6 membered heterocyclic group having 1, 2 or 3 ring members selected from oxygen, sulfur and nitrogen. In individual forms, R₄ means

<img file="PL1945632T3_D0038.tif" />

where T is as defined above. In individual examples, T is

-CH2-.

[0204] Alternative forms of R₁, R₂, R₃, R '₃, R4 and n in formula (I'-A) or formula (I'-B) have the meanings as defined for formula (I), formula (I ') and their forms.

[0205] Exemplary compounds of the present invention include, but are not limited to, those illustrated in Table 1 below.

Examples of compounds of the present invention

<img file="PL1945632T3_D0039.tif" />

<td> 13</td><td colspan="4"> 14</td><td colspan="3"> 15</td>

<td>H V7</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td>

<td rowspan="2">emoO</td><td></td><td></td><td></td><td></td><td>«\ Y</td><td></td><td></td>

<td></td><td></td><td></td><td></td><td>FYR</td><td>ΥΠτ</td><td>Λ</td>

<td></td><td>Ύ ^ ί</td><td>H</td><td></td><td></td><td> \/^{N 0}</td><td>M-</td><td>V</td>

<td></td><td>U AL fi Tr 3l</td><td>^ .N</td><td></td><td>^ .O u \</td><td>ΊΓ</td><td></td><td></td>

<td>o = s = o 1</td><td>¹</td><td>ABOUT</td><td></td><td> 1 '</td><td>JTJ</td><td></td><td></td>

<td>0 AND</td><td></td><td></td><td></td><td></td><td>° H</td><td></td><td></td>

<td> 16</td><td colspan="4"> 17</td><td colspan="3"> 18</td>

<td>^Η V</td><td colspan="2">S \ f</td><td> 7</td><td></td><td>Η V7</td><td></td><td></td>

<td rowspan="2">CisW</td><td colspan="2"></td><td></td><td rowspan="2"> 0</td><td></td><td>ΥΊτ</td><td>-ABOUT \</td>

<td></td><td>about</td><td></td><td>θ</td><td></td><td>/ -about</td>

<td>Αχ</td><td>(Tl</td><td></td><td></td><td></td><td></td><td></td><td></td>

<td></td><td>oA&gt;</td><td></td><td></td><td></td><td>As J *</td><td></td><td></td>

<td>° H</td><td> &gt;</td><td></td><td></td><td></td><td>-r</td><td></td><td></td>

<td>1s</td><td colspan="4"> 20</td><td colspan="3"> 21</td>

<td></td><td></td><td></td><td></td><td></td><td>η V</td><td></td><td></td>

<td></td><td></td><td></td><td></td><td></td><td>ΓτΆ</td><td></td><td> -°\</td>

<td>fi uT Π ru \</td><td></td><td>HV , N ^ 3</td><td></td><td rowspan="2">jQ</td><td></td><td>V ·</td><td> »&lt;?</td>

<td>Oh kjhęf</td><td></td><td>about</td><td></td><td></td><td></td><td></td>

<td> ’</td><td></td><td></td><td></td><td></td><td>c&gt;</td><td></td><td></td>

<td> 22</td><td colspan="4"> 23</td><td colspan="3"> -:-25-</td>

<td>HV</td><td>H</td><td>V</td><td></td><td></td><td></td><td></td><td></td>

<td rowspan="2">Of5W</td><td>fV^N'</td><td>If "</td><td></td><td rowspan="2"> :&gt;</td><td></td><td></td><td></td>

<td>[li</td><td></td><td>LJ</td><td>H</td><td></td><td></td>

<td></td><td></td><td></td><td></td><td></td><td>ru ^</td><td>No ^</td><td>^ ιΓ&gt;</td>

<td></td><td>Γι]</td><td></td><td></td><td></td><td>O ^ ZXZ%.^N&lt;u η</td><td>OU</td><td>Ko</td>

<td></td><td></td><td></td><td></td><td></td><td>OAA</td><td></td><td></td>

<td>&lt;J-j&gt; u Λ</td><td>o = s = o 1</td><td></td><td></td><td></td><td></td><td></td><td></td>

<td colspan="3"> 25</td><td colspan="3"> 26</td><td> 27</td>

<td></td><td></td><td></td><td>H</td><td></td><td></td><td></td>

<td>ό V</td><td></td><td></td><td></td><td></td><td></td><td rowspan="2">γΜολ</td>

<td>ιΤνΊΤ</td><td>α</td><td>r&gt;</td><td></td><td> 0</td><td>ID A / &lt;O</td>

<td>^θ</td><td></td><td>ao</td><td>JL</td><td></td><td></td><td>D «o</td>

<td>ίΐυ</td><td></td><td></td><td>h_nJM</td><td></td><td></td><td>(ίι</td>

<td></td><td></td><td></td><td>about II -wII about</td><td></td><td></td><td>οΎή</td>

<td colspan="3"> 28</td><td colspan="3"> 29</td><td> 30</td>

<td></td><td></td><td></td><td></td><td></td><td></td><td>ii V7</td>

<td>Η \ /</td><td>r</td><td></td><td></td><td></td><td></td><td rowspan="2">ara?</td>

<td>ιΓυΥ</td><td></td><td></td><td></td><td>Η '</td><td></td>

<td> 0</td><td>Until</td><td>ao</td><td>ίί ^ Ύ</td><td></td><td rowspan="2">KJD</td><td></td>

<td>AND</td><td></td><td></td><td>^ ιτν</td><td>about</td><td>Lji</td>

<td>IIi</td><td></td><td></td><td>V</td><td></td><td></td><td rowspan="2">0 = ^ 0 = JM</td>

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

<td>ο 1</td><td></td><td></td><td>° H</td><td></td><td></td><td>fi ° H</td>

<td colspan="3"> 31</td><td colspan="3"> 32</td><td> 33</td>

<td>η Υ7</td><td></td><td></td><td></td><td></td><td></td><td></td>

<td>f V **^NY ^</td><td></td><td></td><td></td><td></td><td></td><td>Η Γ7</td>

<td>il II *%from-^N °</td><td></td><td>ABOUT</td><td>Δ N</td><td>H</td><td></td><td rowspan="2">Γ π π pY rfM * "° W</td>

<td>T</td><td></td><td></td><td>Υγγ</td><td></td><td rowspan="2"></td>

<td>IIi</td><td></td><td></td><td></td><td>about</td><td></td>

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

<td colspan="3"> 34</td><td colspan="3"> 35</td><td> 36</td>

<td>»V</td><td></td><td></td><td>H</td><td>V</td><td></td><td></td>

<td>ΓΜίΛ</td><td>about</td><td>Λ "ABOUT</td><td>Efi</td><td></td><td>oo</td><td></td>

<td>| Ax</td><td></td><td></td><td>fi</td><td></td><td></td><td>IL · »oa ^ Aa</td>

<td></td><td></td><td></td><td>M</td><td></td><td></td><td rowspan="2">zV a N 1⁰</td>

<td>, O-S-O / " about^x</td><td></td><td></td><td colspan="2">a = | = o H O ° "</td><td></td>

<td>H</td><td></td><td></td><td></td><td></td><td></td><td></td>

<td colspan="4"> 37</td><td colspan="4"> 38</td><td colspan="2"> 39</td>

<td></td><td></td><td></td><td></td><td></td><td>H</td><td>V7</td><td></td><td></td><td></td>

<td></td><td></td><td></td><td></td><td>r &lt;x</td><td>M</td><td></td><td rowspan="2">in</td><td></td><td></td>

<td></td><td></td><td></td><td>H</td><td colspan="2">RZN</td><td></td><td></td><td></td>

<td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td rowspan="2">H \ 7 / Λμ, Γ o τΓΚ &lt;?</td>

<td>ii θΎ-</td><td>ABOUT</td><td>rr II H</td><td>UCO</td><td>r ' L</td><td>j</td><td></td><td></td><td>oy¹' α</td>

<td></td><td></td><td></td><td></td><td>h_mJ</td><td></td><td></td><td></td><td></td><td></td>

<td></td><td></td><td></td><td></td><td>; A °</td><td></td><td></td><td></td><td></td><td></td>

<td></td><td></td><td></td><td></td><td>^r F</td><td></td><td></td><td></td><td></td><td></td>

<td colspan="4"> 40</td><td colspan="4"> 41</td><td colspan="2"> 42</td>

<td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td>H</td><td></td>

<td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td>/ Ά</td><td>ays</td>

<td></td><td>in</td><td rowspan="2"></td><td></td><td>l</td><td></td><td></td><td></td><td></td><td></td>

<td rowspan="2">lT ER</td><td></td><td>vu</td><td>HE vS u ζΥχ</td><td>H</td><td>H , N.</td><td>YY O</td><td rowspan="2">T</td><td></td>

<td></td><td></td><td></td><td></td><td>about</td><td> 1 0</td><td></td><td></td>

<td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td> 0·"% 1</td><td></td>

<td colspan="4"> 43</td><td colspan="4"> 44</td><td colspan="2"> 45</td>

<td></td><td>H</td><td>V7</td><td></td><td></td><td>H</td><td>V</td><td></td><td></td><td></td>

<td></td><td> *1</td><td>Λ</td><td>in\</td><td></td><td> %</td><td>AND</td><td></td><td></td><td>Β V</td>

<td></td><td></td><td></td><td></td><td>(And 2</td><td></td><td> )</td><td>γί-Ο</td><td>ffi</td><td rowspan="2"> ;.</td>

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

<td>ril</td><td></td><td></td><td></td><td>ΓΪ1</td><td></td><td></td><td></td><td></td><td></td>

<td>ψ)</td><td></td><td></td><td></td><td>V</td><td></td><td></td><td></td><td>o (Tl</td><td></td>

<td>H_NJ AND</td><td></td><td></td><td></td><td>f</td><td></td><td></td><td></td><td>Λ,</td><td></td>

<td colspan="4"> 46</td><td colspan="4"> 47</td><td colspan="2"> 48</td>

<td></td><td></td><td></td><td></td><td></td><td>H</td><td></td><td></td><td></td><td></td>

<td rowspan="2">Π</td><td>_f3</td><td></td><td>Vy ° \</td><td></td><td>AND</td><td>and</td><td>rx °&gt;</td><td></td><td rowspan="3">&lt;55 ^ 1 O YA-O</td>

<td></td><td>II</td><td>TT?</td><td></td><td colspan="2">ABOUT</td><td></td><td></td>

<td></td><td></td><td>about</td><td>k ^ Ao</td><td></td><td></td><td></td><td></td><td></td>

<td></td><td></td><td></td><td></td><td>iS</td><td></td><td></td><td></td><td colspan="2"></td>

<td>xj</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td>

<td>F</td><td></td><td></td><td></td><td>HI</td><td></td><td></td><td></td><td></td><td></td>

<td></td><td></td><td></td><td></td><td>N</td><td></td><td></td><td></td><td></td><td></td>

<td colspan="3"> 49</td><td colspan="5"> 50</td><td colspan="3"> 51</td>

<td></td><td>H \ 7</td><td></td><td></td><td></td><td>Η V</td><td></td><td></td><td></td><td></td><td></td>

<td></td><td>NMX and Ύ Yii¹&lt;Y ° kJ '</td><td>about ^ 0</td><td></td><td>YY &lt;5 ° C</td><td>about</td><td></td><td>yo &gt; *-about</td><td>«ΥΪ ΙγΆ</td><td>ri</td><td>r °&gt;</td>

<td>o. o. o</td><td> •</td><td></td><td>&lt;QT</td><td></td><td></td><td></td><td></td><td>¹ Y&gt; °</td><td>Y</td><td>ao</td>

<td colspan="3"> 52</td><td colspan="5"> 53</td><td colspan="3"> 54</td>

<td></td><td></td><td></td><td> &gt;</td><td></td><td></td><td></td><td></td><td>at V7</td><td></td><td></td>

<td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td>Y&gt;</td><td rowspan="3"> 3</td>

<td></td><td>H V7</td><td></td><td></td><td></td><td>Η \</td><td></td><td></td><td>ίι I «1</td><td>T</td>

<td></td><td>ji X</td><td>n</td><td></td><td></td><td> 3&lt; &gt;</td><td></td><td>n</td><td rowspan="2">IL ^ and o.</td><td></td>

<td>and</td><td>Y Tr)</td><td rowspan="2">"&gt; "ABOUT</td><td></td><td></td><td></td><td>* γγ</td><td rowspan="2">&gt; ao</td><td></td><td></td>

<td>AA</td><td>3 »o kY</td><td>yr</td><td colspan="2">V °</td><td></td><td>u ° "</td><td></td><td></td>

<td></td><td></td><td></td><td>kA</td><td rowspan="2">CI</td><td></td><td></td><td></td><td></td><td></td><td></td>

<td></td><td></td><td></td><td></td><td></td><td></td><td></td><td>OAY 1</td><td></td><td></td>

<td colspan="3"> 55</td><td colspan="5"> 56</td><td colspan="3"> 57</td>

<td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td> 8</td><td></td><td></td>

<td></td><td>H V7 [^ T SA</td><td>Γ&gt;</td><td>pL</td><td>γ</td><td>Η X, -N</td><td>ri</td><td>r °&gt;</td><td>yAⁿ °</td><td>* c</td><td>r&gt;</td>

<td></td><td></td><td>aq</td><td></td><td></td><td> 0</td><td></td><td>ao</td><td></td><td></td><td></td>

<td colspan="3"> 58 ^Ί</td><td colspan="5"> 59</td><td colspan="3"> 60</td>

<td></td><td>h W</td><td></td><td></td><td>H</td><td> \~7</td><td></td><td></td><td></td><td></td><td></td>

<td>Q</td><td>y L sy</td><td> 3</td><td colspan="2"></td><td></td><td>about</td><td> :&gt;</td><td>pA *</td><td></td><td rowspan="2"> 0</td>

<td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td>A 0</td><td>yx</td>

<td>Π</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td>Ύ</td><td></td><td></td>

<td></td><td></td><td></td><td>^ Fr.</td><td> )</td><td></td><td></td><td></td><td>JLjL</td><td></td><td></td>

<td>Y</td><td></td><td></td><td>h._nAND ñ</td><td> 0</td><td></td><td></td><td></td><td></td><td></td><td></td>

<td colspan="4"> 61</td><td colspan="4"> 62</td><td colspan="4"> 63</td>

<td></td><td>1 Η V</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td>

<td></td><td>_ΖΗ V</td><td>'ύ⁵^</td><td>^ ~ Ο_χ</td><td></td><td></td><td></td><td></td><td>Η</td><td>V</td><td></td><td></td>

<td>ΙΑίΝ</td><td>Ο</td><td></td><td>L /</td><td> ,</td><td rowspan="2">Η V u η</td><td></td><td></td><td>FLF '</td><td>Λ</td><td>rt</td><td> ’°&gt;</td>

<td></td><td></td><td></td><td></td><td></td><td>V?</td><td rowspan="2"> 0</td><td></td><td>about</td><td>ΛΑ</td><td>"ABOUT</td>

<td>'ri)</td><td></td><td></td><td></td><td></td><td>Μ Ο</td><td>Ι &lt;5&gt;</td><td>AND</td><td></td><td></td><td></td>

<td>Ο</td><td></td><td></td><td></td><td> ,_CAA</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td>

<td></td><td></td><td></td><td></td><td>Ν⁵·</td><td></td><td></td><td></td><td>ιΓ&gt;</td><td></td><td></td><td></td>

<td colspan="4"> 64</td><td colspan="4"> 65</td><td colspan="4"> 66</td>

<td></td><td>η Υ7</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td>

<td></td><td>^ΝΑ &lt;</td><td></td><td rowspan="2"> :&gt;</td><td></td><td></td><td></td><td></td><td> 0</td><td>V</td><td></td><td></td>

<td rowspan="2">&gt; Α: Ν</td><td rowspan="2"></td><td rowspan="2">AA</td><td rowspan="2"></td><td rowspan="2">Η V</td><td rowspan="2"></td><td rowspan="2"></td><td rowspan="2">ΓΤ ''</td><td rowspan="2">Λ</td><td rowspan="2">ΓΎ</td><td rowspan="2"> '°&gt;</td>

<td></td>

<td>φ</td><td></td><td></td><td></td><td>' ^ ΛΐΐΎ</td><td>, Μ Ο</td><td> ^0</td><td>_ο Γ&gt;</td><td>Α ^^Ν</td><td>about</td><td>AA</td><td>-about</td>

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

<td>o = s = o</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td>

<td>Α</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td>AA</td><td></td><td></td><td></td>

<td>AND</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td>cl</td><td></td><td></td><td></td>

<td colspan="4"> 67</td><td colspan="4"> . 68</td><td colspan="4"> 69</td>

<td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td>H</td><td>V7</td><td></td><td></td>

<td></td><td>$ Α</td><td></td><td>η</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td>Λ</td>

<td></td><td>&gt; τ</td><td></td><td>ΓΤ^- \</td><td></td><td></td><td></td><td></td><td>And 0</td><td>Π</td><td>T Γ</td><td> &gt;</td>

<td>IL ^ m</td><td></td><td></td><td>L-o^?</td><td>ίίΑ Μ</td><td>Η V7</td><td></td><td></td><td></td><td>about</td><td>AA</td><td>"Ό</td>

<td></td><td></td><td></td><td></td><td>IN\</td><td></td><td></td><td rowspan="2">Λ "Ο</td><td>χ</td><td></td><td></td><td></td>

<td>Α</td><td></td><td></td><td></td><td>F</td><td>ο</td><td>Μ</td><td>Γ⁵!)</td><td></td><td></td><td></td>

<td>ΑΑ</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td>ΛΑ Oh</td><td></td><td></td><td></td>

<td>CI</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td>\-about</td><td></td><td></td><td></td>

<td colspan="4"> 70</td><td colspan="4"> 71</td><td colspan="4"> . 72</td>

<td></td><td>^Η \</td><td> ~7</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td>

<td></td><td>/ 'Ν</td><td></td><td rowspan="2">κ:&gt;</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td>

<td>Χχ,</td><td>Ν Ο</td><td>Α</td><td></td><td>Η V /</td><td></td><td></td><td>_n-*</td><td></td><td></td><td></td>

<td>Γ</td><td></td><td></td><td></td><td>Γ ιΓ</td><td>,, Ν, ύζ Ο</td><td>ίθ</td><td>^ 0 Q</td><td>'° A and I</td><td>H V</td><td></td><td>_about ιΓ&gt;</td>

<td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td>1 L,</td><td></td><td>at Λ</td><td>&gt; about</td>

<td>r, Λ ° α</td><td>Ο</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td>

<img file="PL1945632T3_D0040.tif" />

<td> 85</td><td> 86</td><td> 87</td>

<td>Φ »Jao nu '</td><td>r τ fl | Γ 5 '• Ο' ^ + ^ Ο 1</td><td>MrYm Ο- °</td>

<td> 88</td><td> 89</td><td> 90</td>

<td>oYrn \_about ,</td><td>iV / what</td><td>ov ^ Cc&gt; o = s = o about</td>

<td> 91</td><td> 92</td><td> 93</td>

<td>Γ^?^^Ν'^1ί^^ϊίΧίΓ^ο) c . III IN</td><td>about MY</td><td>aV00</td>

<td> 94</td><td> 95</td><td> 96</td>

<td>o ^ oo Jir</td><td>ΜΥοο h "JM Λ_ο</td><td>"ΓΜ o W 1</td>

<td colspan="3"> 97</td><td colspan="3"> 98</td><td colspan="4"> 99</td>

<td>Η</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td>

<td>ρΛ</td><td>Λ</td><td>Γτ °&gt;</td><td>β-γγ</td><td>γ</td><td rowspan="2"> 0</td><td></td><td>Η V ~ -^at 2 iT Ti</td><td></td><td rowspan="2">-ABOUT D '"•ABOUT</td>

<td></td><td></td><td>ΥΥο</td><td></td><td>at</td><td></td><td> &lt;5^^{n 0}</td><td>AT</td>

<td>X .0</td><td></td><td></td><td>IYJ</td><td></td><td></td><td rowspan="2">θζ</td><td></td><td></td><td></td>

<td colspan="2">η "Ύ</td><td></td><td>AND</td><td></td><td></td><td></td><td></td><td></td>

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

<td></td><td></td><td></td><td>Η</td><td></td><td></td><td></td><td></td><td></td><td></td>

<td colspan="3"> 100</td><td colspan="3">1O1</td><td colspan="4"> 102</td>

<td></td><td></td><td></td><td>Η V7</td><td></td><td></td><td></td><td>h V7</td><td></td><td></td>

<td>Η Or</td><td>d</td><td>Oc °&gt; 5l ^&gt; ^ O *</td><td>Υ55 &gt;&gt;^Η\ Υ&gt; ΙΜ θ</td><td>about</td><td>&gt; "-ABOUT</td><td>Q</td><td>about</td><td>about</td><td></td>

<td>J</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td>

<td></td><td></td><td></td><td>Yjj</td><td></td><td></td><td>Π</td><td></td><td></td><td></td>

<td>AND</td><td></td><td></td><td>&gt; Αθ</td><td></td><td></td><td></td><td></td><td></td><td></td>

<td></td><td></td><td></td><td>AND</td><td></td><td></td><td>h._n&gt;</td><td></td><td></td><td></td>

<td></td><td></td><td></td><td></td><td></td><td></td><td>H</td><td></td><td></td><td></td>

<td colspan="3"> 103</td><td colspan="3">--Τ04</td><td colspan="4">Ϊ05--</td>

<td>Η</td><td>V7</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td>

<td>Q "</td><td></td><td>ο $</td><td></td><td></td><td></td><td></td><td>H JJ. .</td><td></td><td>about</td>

<td>Γ</td><td></td><td></td><td>Η X</td><td></td><td></td><td></td><td>if Ύπ</td><td>Χγν</td><td rowspan="2">Q</td>

<td>(ΙΊ</td><td></td><td></td><td>γϊγ V</td><td>M</td><td rowspan="2">q</td><td></td><td>YJ θ</td><td></td>

<td></td><td></td><td></td><td>&gt; &lt;s ^ W ο</td><td>M</td><td>ER</td><td></td><td></td><td></td>

<td> 0=5=0</td><td></td><td></td><td>And ιΤ</td><td></td><td></td><td></td><td></td><td></td><td></td>

<td> ?</td><td></td><td></td><td>ΥΑ</td><td></td><td></td><td>° γ^ΜΗ</td><td></td><td></td><td></td>

<td>Ό</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td>

<td colspan="3"> 106</td><td colspan="3"> 107</td><td colspan="4"> 108</td>

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

<td>ίίΥ</td><td>Η X</td><td></td><td>ΡτΆ</td><td>AND</td><td>AND</td><td>rime</td><td rowspan="2">Η XMN and ii T.</td><td></td><td></td>

<td>&lt;o &lt;JJ ΧΧί</td><td>gl., Ο</td><td rowspan="2">Υο</td><td>Ly, Η</td><td>V</td><td>V</td><td>V-</td><td></td><td>Γ&gt;</td>

<td>r</td><td></td><td>about</td><td></td><td></td><td>H</td><td></td><td></td><td>&gt; ~ O</td>

<td colspan="3"> 109</td><td colspan="5">110 I</td><td colspan="4"> 111</td>

<td>H V7</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td>

<td>, Υ'Α</td><td rowspan="2"> 33</td><td></td><td></td><td></td><td></td><td></td><td></td><td>Η</td><td>V</td><td></td><td></td>

<td>ΐ! χΝ 0</td><td></td><td></td><td></td><td></td><td></td><td></td><td>X¹</td><td>. 3C</td><td></td><td>ο</td>

<td></td><td></td><td></td><td></td><td></td><td>Η V</td><td></td><td></td><td></td><td></td><td></td><td></td>

<td>JL</td><td></td><td></td><td></td><td></td><td>, ίθ</td><td rowspan="2"></td><td>ο</td><td>¹</td><td>II</td><td></td><td> &gt;</td>

<td>ί it</td><td></td><td></td><td></td><td></td><td></td><td rowspan="2">ο + ~ Ο</td><td></td><td> 0</td><td>ΑΑ-</td><td>"Ο</td>

<td>τ</td><td></td><td></td><td>JY</td><td>k -</td><td> 0</td><td></td><td></td><td></td><td></td><td></td>

<td>o = s = o ύ</td><td></td><td></td><td colspan="2">AAci</td><td></td><td></td><td></td><td></td><td>IN</td><td></td><td></td>

<td>Q</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td>Μ</td><td></td><td></td><td></td>

<td>Η °</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td>

<td colspan="3"> 112</td><td colspan="5">'ΐϊ3——</td><td colspan="4"> 114</td>

<td></td><td></td><td></td><td></td><td></td><td></td><td></td><td>Η</td><td></td><td></td><td></td><td></td>

<td></td><td></td><td></td><td></td><td></td><td></td><td></td><td>, Ν</td><td></td><td></td><td></td><td></td>

<td>β V</td><td>Γ</td><td></td><td></td><td></td><td></td><td>UL</td><td></td><td></td><td></td><td></td><td></td>

<td>Err</td><td>Ό</td><td>Λ Ό</td><td></td><td> %</td><td>yt ζ-^ΝΗ</td><td></td><td></td><td></td><td>Η $ 11 .. ΪΓ [Γ Μ 0</td><td></td><td>_ο Γ&gt; "ό</td>

<td>ΪΎ ° Ί</td><td></td><td></td><td></td><td></td><td> 7</td><td></td><td></td><td>mk</td><td></td><td></td><td></td>

<td></td><td></td><td></td><td></td><td>ί</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td>

<td></td><td></td><td></td><td>V?</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td>

<td colspan="3"> • 115</td><td colspan="5"> 116</td><td colspan="4"> 117</td>

<td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td>^Η \7</td><td></td><td></td>

<td>Η Υ7</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td>ιΓΥ</td><td>"ΊΤ</td><td>Άτ</td><td rowspan="2"> :&gt;</td>

<td></td><td>Άγ</td><td></td><td></td><td></td><td>Η \</td><td></td><td></td><td></td><td></td><td>kA</td>

<td>Η Π ο</td><td>CJ</td><td>^ -Ο</td><td></td><td></td><td>AJ ..</td><td></td><td>Τ ° 5</td><td></td><td></td><td></td><td></td>

<td>AND</td><td></td><td></td><td></td><td></td><td>JJ 0</td><td></td><td>Ó.</td><td>Ο</td><td></td><td></td><td></td>

<td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td> 0=5=0</td><td></td><td></td><td></td>

<td> .</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td>ν »</td><td></td><td></td><td></td>

<td colspan="3"> 118</td><td colspan="5"> 119</td><td colspan="4"> 120</td>

<td>^Η V</td><td> 7</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td>

<td>Γ + ν</td><td>Ϋϊ</td><td rowspan="2"> :&gt;</td><td></td><td>V</td><td>ν</td><td></td><td></td><td></td><td></td><td></td><td></td>

<td>ks ^ n ο</td><td>AT^L</td><td></td><td></td><td></td><td></td><td>° r \</td><td></td><td></td><td></td><td></td>

<td>(Γί</td><td></td><td></td><td colspan="2"></td><td></td><td>AT</td><td>L_about&gt;</td><td>^χΟΆ</td><td>Η</td><td></td><td></td>

<td></td><td></td><td></td><td></td><td rowspan="2">Η ΰ</td><td></td><td></td><td></td><td>Α.Α</td><td>J &lt;Ji.</td><td></td><td> . 0</td>

<td>LJ</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td> ¥</td><td></td><td> » &gt;</td>

<td> 0=5=0</td><td></td><td></td><td>Α</td><td></td><td>Η</td><td></td><td></td><td></td><td>(Τ '</td><td>Ο</td><td>Αο^?</td>

<td></td><td></td><td></td><td> you</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td>

<td colspan="4"> 121</td><td> 122</td><td colspan="5"> 123</td>

<td>Η</td><td>V7</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td>

<td>LFV '</td><td>Y "</td><td>rir</td><td>Λ</td><td></td><td></td><td></td><td></td><td></td><td></td>

<td>Ca</td><td></td><td></td><td></td><td> (fA H \ ”7</td><td>IIi</td><td></td><td>H r</td><td></td><td></td>

<td></td><td></td><td></td><td></td><td rowspan="2">GO άΆΑ? Χ-ο Tu r &amp; '</td><td>CA</td><td></td><td>AND¹ AND</td><td>YY</td><td>Γ \</td>

<td>about</td><td></td><td></td><td></td><td>Y</td><td>k ^</td><td>yo</td><td>AT</td><td> /</td>

<td> 0</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td>

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

<td colspan="4"> 124</td><td> 125</td><td colspan="5"> 126</td>

<td></td><td></td><td></td><td></td><td>/ AJiyO. Χμ about TjLy '</td><td></td><td></td><td></td><td></td><td></td>

<td>and</td><td>H</td><td></td><td></td><td>T</td><td>fi</td><td></td><td>at V</td><td></td><td></td>

<td>r-, AAZ¹</td><td></td><td></td><td>Q</td><td>iii</td><td>A A%</td><td> .11.</td><td>N&gt;</td><td rowspan="2">si</td><td>_ABOUT</td>

<td>α</td><td></td><td>γ</td><td rowspan="2">r&gt; • *&gt; - about</td><td></td><td></td><td></td><td></td><td rowspan="2">c&gt; </td>

<td>these</td><td>I) Fr.</td><td>and.</td><td></td><td></td><td></td><td>JJ</td><td>UJ</td>

<td></td><td></td><td></td><td></td><td>o = s = o</td><td></td><td></td><td></td><td></td><td></td>

<td></td><td></td><td></td><td></td><td>NH</td><td></td><td></td><td></td><td></td><td></td>

<td></td><td></td><td></td><td></td><td>CT ° '</td><td></td><td></td><td></td><td></td><td></td>

<td colspan="4"> --</td><td> 128</td><td colspan="5"> 129</td>

<td>H</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td>

<td>EF</td><td>AND</td><td>ABOUT</td><td> :&gt;</td><td>jf^fiT^NY ^ firs &lt;AU about YAo</td><td>cl and</td><td>N ΊΥ</td><td>Η V αΆ</td><td>YY</td><td rowspan="2">c °&gt;</td>

<td>l</td><td></td><td></td><td></td><td></td><td></td><td></td><td>Γ o</td><td>AT</td>

<td></td><td></td><td></td><td></td><td>about</td><td></td><td></td><td></td><td></td><td></td>

<td>TSA</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td>

<td>F</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td>

<td colspan="4"> 130</td><td> 131</td><td colspan="5"> 132</td>

<td></td><td></td><td></td><td></td><td>H V7</td><td></td><td></td><td>a \ 7</td><td></td><td></td>

<td>'OY</td><td>H Η Y</td><td></td><td>Y °&gt;</td><td>EFA »</td><td></td><td>ay n</td><td>g</td><td>Ό</td><td>about</td>

<td></td><td>, M 0</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td>

<td>l</td><td></td><td></td><td></td><td>and'</td><td>jj (Y</td><td>Ύ, Ά</td><td></td><td></td><td></td>

<td></td><td></td><td></td><td></td><td> '</td><td>AND</td><td></td><td></td><td></td><td></td>

<td colspan="3"> 133</td><td colspan="4"> 134</td><td colspan="2"> ——₁₃5——-</td>

<td>Η Γ7⁰</td><td>about</td><td>.0 -o&gt;</td><td>H</td><td>AND</td><td>Π</td><td>AND</td><td>Η - ^ Ν</td><td>No. ιΓ "&gt;</td>

<td>T</td><td></td><td></td><td></td><td> 0</td><td>Y&gt;</td><td>~~ Ό</td><td>Α »</td><td>° ΑΧ⁷</td>

<td></td><td></td><td></td><td>T</td><td></td><td></td><td></td><td>τ</td><td></td>

<td></td><td></td><td></td><td>iii</td><td></td><td></td><td></td><td>1 Α I</td><td>• S.</td>

<td> 0=5=0</td><td></td><td></td><td>YA</td><td></td><td></td><td></td><td>HA</td><td></td>

<td>CY</td><td></td><td></td><td>οΎ) H</td><td></td><td></td><td></td><td>ΥΥ</td><td></td>

<td colspan="3"> 136</td><td colspan="4"> 137</td><td colspan="2"> 138</td>

<td></td><td></td><td></td><td>H</td><td></td><td></td><td></td><td></td><td>ιΥτΎ</td>

<td>ιΤΥ'Ά</td><td></td><td></td><td>iTV "·</td><td>ίΛ</td><td>rar</td><td>Λ</td><td></td><td>ΥΥΥ</td>

<td></td><td>YJ</td><td>ABOUT</td><td></td><td></td><td></td><td>-ABOUT</td><td></td><td>Α</td>

<td> [</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td>muj</td>

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

<td>r fig</td><td></td><td></td><td>[Yjj</td><td></td><td></td><td></td><td></td><td>^Ο· · Ί5Ζ^ΝΗ</td>

<td>Uh</td><td></td><td></td><td rowspan="3">^hm^x^ o AND</td><td></td><td></td><td></td><td>γ</td><td>γν</td>

<td>* and</td><td></td><td></td><td></td><td></td><td></td><td></td><td>JI</td>

<td>Yk_about</td><td></td><td></td><td></td><td> •</td><td></td><td>θ 7 \ -ο</td><td></td>

<td colspan="3"> 139</td><td colspan="4"> 140</td><td colspan="2"> 141</td>

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

<td>&gt; AX</td><td></td><td></td><td>H JM</td><td></td><td>YYr</td><td></td><td>Α</td><td>AC</td>

<td rowspan="2">ζϊΆ</td><td>fi</td><td>r °&gt;</td><td>ΧίΝ</td><td>about</td><td>AT</td><td>&gt; ^ -ο</td><td>ace</td><td></td>

<td>AND</td><td>^ o⁷</td><td>Y</td><td></td><td></td><td></td><td></td><td></td>

<td>AND</td><td></td><td></td><td></td><td></td><td></td><td></td><td> 0:5=0</td><td></td>

<td>about</td><td></td><td></td><td>ljJ</td><td></td><td></td><td></td><td>ό</td><td></td>

<td></td><td></td><td></td><td></td><td></td><td></td><td></td><td> &lt;/</td><td></td>

<td></td><td></td><td></td><td></td><td></td><td></td><td></td><td>Η</td><td></td>

<td colspan="3"> 142</td><td colspan="4"> 143</td><td colspan="2"> . 144</td>

<td>HS &lt;-VV</td><td></td><td rowspan="2">jf&gt; Άθ</td><td></td><td></td><td></td><td></td><td></td><td>Η Τ7</td>

<td>AV °</td><td></td><td>OLH</td><td>H \ J</td><td></td><td>ο</td><td>ίΥι</td><td>Yi ° ΥΎ&gt;</td>

<td>WO</td><td></td><td></td><td>Tf and</td><td></td><td></td><td>ΪΓ&gt;</td><td></td><td></td>

<td>AND</td><td></td><td></td><td></td><td>ABOUT</td><td>Y *</td><td>^ΑΟ</td><td> 0</td><td></td>

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

<td colspan="4"> 145</td><td colspan="5"> 146</td><td colspan="3"> 147</td>

<td></td><td></td><td></td><td></td><td></td><td></td><td>H V7</td><td></td><td></td><td>H</td><td></td><td></td>

<td>JL</td><td>H \ JJ '</td><td></td><td>about</td><td colspan="2">YY Axⁿ</td><td>about</td><td>ABOUT</td><td>-0 &gt; "ABOUT</td><td>and Y '</td><td> 0</td><td>0C&gt;</td>

<td>If '*</td><td></td><td></td><td rowspan="2">ABOUT Ύ</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td>

<td rowspan="2"></td><td>J 0</td><td>N.</td><td>(f</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td>

<td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td>AA</td><td></td><td></td>

<td>cl</td><td></td><td></td><td></td><td>Q-</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td>

<td colspan="4"> 148</td><td colspan="5"> 149</td><td colspan="3"> 150</td>

<td>H</td><td> \7</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td>

<td>Irv "-</td><td>ΠΙ</td><td>and·</td><td rowspan="2">Λ "ABOUT</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td>

<td>AA</td><td>about</td><td>AA</td><td></td><td></td><td>uu</td><td></td><td>_about</td><td></td><td>H \ J &lt;,</td><td></td>

<td></td><td></td><td></td><td></td><td></td><td>at</td><td></td><td></td><td>U \</td><td></td><td>u! |</td><td rowspan="2">yp</td>

<td>fil</td><td></td><td></td><td></td><td></td><td>(AND</td><td> °</td><td></td><td></td><td>&lt;γΥ</td><td>WELL</td>

<td>AA</td><td></td><td></td><td></td><td>H ° γΆ</td><td>IJ</td><td></td><td></td><td></td><td>A&gt;</td><td></td><td></td>

<td> 1</td><td></td><td></td><td></td><td>ABOUT</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td>

<td>o = s = o</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td>

<td>Α »</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td>

<td colspan="4"> 151</td><td colspan="5"> 152</td><td colspan="3"> 153</td>

<td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td>H</td><td></td>

<td></td><td></td><td></td><td></td><td></td><td></td><td>Η V</td><td></td><td></td><td></td><td></td><td>Xw O</td>

<td>AND</td><td>H</td><td></td><td></td><td></td><td colspan="2">rr Ak&gt; rf Ίτ</td><td></td><td rowspan="2">_-ABOUT r&gt; '"ABOUT</td><td></td><td>ΪΓ H.</td><td>rt&gt;</td>

<td>ρΑ ^ Αλ</td><td>fl 1 n</td><td></td><td rowspan="2">X °&gt;</td><td>r ^ V</td><td colspan="2"> °</td><td>AT</td><td>nc *</td><td>&gt; o</td><td>xx * o</td>

<td>F Az</td><td>&gt; o</td><td></td><td>Caj</td><td></td><td></td><td></td><td></td><td>AND</td><td></td><td></td>

<td colspan="4"> 154</td><td colspan="5"> 155</td><td colspan="3">--- ϊ3§</td>

<td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td>Η V</td><td></td>

<td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td rowspan="2">ιΑτ</td><td></td><td></td>

<td></td><td>^H</td><td> 7</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td rowspan="2">IN</td>

<td></td><td>Y</td><td></td><td rowspan="2"> 0</td><td></td><td></td><td></td><td></td><td></td><td>LJL</td><td>g</td>

<td>AA</td><td></td><td>Αχ</td><td>Ca</td><td>at</td><td> 8 5</td><td> 7</td><td></td><td>AND</td><td></td><td></td>

<td></td><td></td><td></td><td></td><td></td><td>r '</td><td>rV</td><td>ΥΊ</td><td rowspan="2"> 0</td><td>V</td><td></td><td></td>

<td>pish</td><td></td><td></td><td></td><td></td><td></td><td>11 sts</td><td></td><td></td><td></td><td></td>

<td>° &lt;γΑΑ</td><td></td><td></td><td></td><td></td><td>tl *</td><td></td><td></td><td></td><td colspan="2">O = S = tf&gt; 1</td><td></td>

<td>° H</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td>

<img file="PL1945632T3_D0041.tif" />

<td> 164</td><td> '" 165</td><td> 166</td>

<td>zyO «Α&gt; τ at</td><td>α ίΓ · χ / - / · ° Μ &lt;&gt; ' ο /</td><td>jj ο ίίΎ ΥγΤΓ Λ oMkJ ° kAo | · ⁰</td>

<td> 167</td><td> 168</td><td> 169</td>

<td>° ΜΜ</td><td>0 = 5 0 Λ » Η °</td><td>A "rS</td>

<td> 170</td><td> 171</td><td> 172</td>

<td>Μ Αν η</td><td>.Cu jh</td><td>α "ί%:&gt; o = s = o &gt; H ° Υ</td>

<td> 173</td><td> 174</td><td> 175</td>

<td>'ώ V</td><td>^ ΜΜν ο kjM ο = | = ο χ-^Μχ</td><td>o = s = o ά-</td>

<td colspan="4"> 176</td><td> 177</td><td colspan="2"> 178</td>

<td> «7-</td><td>c</td><td>r:&gt;</td><td></td><td>about</td><td colspan="2">G / tU</td>

<td>0 = 5 = 0 ι</td><td></td><td></td><td></td><td>⁰ "ΧΜ-Α / Αχο f i.e. sCkj ^ f</td><td colspan="2">o = s = o AND</td>

<td>x&gt; H</td><td></td><td></td><td></td><td></td><td>AND</td><td></td>

<td colspan="4"> 179</td><td> 180</td><td colspan="2"> 181</td>

<td>1 N.</td><td></td><td></td><td></td><td>Λ \ '</td><td></td><td></td>

<td></td><td></td><td>ΥΎ</td><td> ,0 &gt;</td><td>ace</td><td>ER</td><td></td>

<td>0 hrs χ ,, Α H o</td><td>VJ</td><td></td><td>•about</td><td>about so a = Ό</td><td>^hmJ θΎ) +</td><td></td>

<td colspan="4"> 182</td><td> 183</td><td colspan="2">Ϊ84</td>

<td>em</td><td>c</td><td>K&gt;</td><td></td><td>^ N^HO = S; O</td><td>ar Ά^μ</td><td> 5¾}</td>

<td> □</td><td></td><td></td><td></td><td> ^_nh</td><td>V</td><td></td>

<td>a = | = oo m-</td><td></td><td></td><td></td><td> $&gt;</td><td>χ "^Ηο'η ' H</td><td></td>

<td colspan="4"> 185</td><td> 186</td><td colspan="2"> 187</td>

<td>H X Jk Jk Ep^!at</td><td></td><td>G</td><td>.about &gt; •about</td><td>T Ύ ^^ν'^ ΤΑγ^ο'&gt; &lt;yA ° Ao</td><td>jj φ AND</td><td>lh V7 NPV °&gt;</td>

<td> 188</td><td> 189</td><td> "790</td>

<td></td><td>and J &lt;AX / vO H 9 ΙΓΎ ΥΤΪ&gt; at °</td><td>_about aj αχ? "I</td>

<td> 191</td><td> 192</td><td> 193</td>

<td></td><td>• O = SxO fi] $&gt; ° s</td><td>^H/ vyU θ UU</td>

<td> 194</td><td> 195</td><td> 196</td>

<td>UV 5XiC?</td><td>1 "\ ζΆΧ&gt; ί · ^ Ο n 9 ii Ύ ^^ ΤιΤ V about kO-C)</td><td>ζίκΑυ ^ θ ^ ΑΧ &lt;? about</td>

<td> 197</td><td> 198</td><td> 199</td>

<td>ψΥοο 9 o = s = o^HABOUT^x^ R '^MFL(y H</td><td>U * C ¥ » ^ N ^ O AND</td><td>Gp * loo o = s = o "Vⁿh fi H</td>

<td> 200</td><td colspan="2"> 201</td><td> 202</td>

<td> "^ABOUTAND?</td><td></td><td></td><td>Άί?</td>

<td>O = C = O</td><td></td><td>fil</td><td>A: S: O</td>

<td>about</td><td> »«'</td><td>JL ·^N ΓΪ Ś 0</td><td>T</td>

<td>ΓΪ u</td><td></td><td>_about UAX ^ about</td><td>AND</td>

<td>AND</td><td>oO AND</td><td> •</td><td>• y about \</td>

<td> 203</td><td colspan="2"> 204</td><td> 205</td>

<td></td><td>ΓΥ</td><td>οΛ%&gt;</td><td>oYoo</td>

<td>o = s = o</td><td></td><td></td><td>LsJI</td>

<td>/ T</td><td>'(Yo AND</td><td></td><td>O = S = O Ηο - '^ Ρ'η</td>

<td>20o</td><td colspan="2"> 207</td><td> 208</td>

<td></td><td></td><td rowspan="2">JUŚU oUjtj</td><td>aVoo</td>

<td>juto</td><td></td><td> 9</td>

<td>C (A&gt;</td><td>N o</td><td></td><td>o = s = o</td>

<td></td><td></td><td></td><td>σ "^Η</td>

<td> 209</td><td colspan="2"> 210</td><td> 211</td>

<td>'s</td><td></td><td>«\ 7 yV'l Y. o jCT) about LsjCj</td><td>N, O</td>

<td>T</td><td>°, -SR</td><td></td><td>ABOUT-/¹' ABOUT</td>

<td> |</td><td>"Y</td><td></td><td>Yo 6</td>

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

<td> 212</td><td>Z13</td><td> 214</td>

<td>EW » o = s = o Λ Η</td><td>γσ "Χ:&gt;</td><td>05: 0 Λ Mf / l oM. Ά</td>

<td> 215</td><td> 216</td><td> 217</td>

<td>^ Κίο '</td><td>° ΥΛ-c?</td><td>ΜΑγ N, N *^L ° kAo</td>

<td> 218</td><td> 219</td><td> 220</td>

<td>'•% Wo "</td><td>KX?</td><td>OsSsO an Karfi 6_?</td>

<td> 221</td><td> 77?</td><td> 223</td>

<td>05: 0 about An kAtfi ο Δ ^ &lt;k</td><td>^ θρό ^ Λχ&gt;</td><td>with - K ^cl_ Γη o &lt;? "Γ s AaJA Α-ΎΆ η AA^Η ο II</td>

<td> 224</td><td> 225</td><td> 226</td>

<td>/in</td><td>E / yfOO</td><td>"ABOUT</td>

<td> 227</td><td> 228</td><td> 229</td>

<td>AJ «Oc? ° H</td><td>05: 0 T AND IIj-M_fromabout</td><td>(p ¥ π YY \ o cl</td>

<td> 230'</td><td> 231</td><td> 232</td>

<td>° kX &lt;?</td><td>WAY, ° Άο ° H</td><td>0 ^ 0 ox</td>

<td> 233</td><td> 234</td><td> 235</td>

<td>and "/ a o = s = o^Η°"^0</td><td>CfToO about a &amp; o 0 /</td><td>&gt; About ¥ ca</td>

<td> 236</td><td colspan="3"> 237</td><td colspan="3"> 238</td>

<td>Ά</td><td></td><td></td><td></td><td></td><td></td><td></td>

<td>OZS O</td><td></td><td></td><td></td><td></td><td>H V7</td><td></td>

<td>AND</td><td>cl Keel</td><td>about lAl</td><td></td><td></td><td>Ά</td><td rowspan="2"> 03</td>

<td></td><td>KJL</td><td>11 Β -l</td><td></td><td></td><td>about</td>

<td>ir?</td><td></td><td>Λ ^Mxi</td><td rowspan="2">xy</td><td>paradise</td><td></td><td></td>

<td>kAijH</td><td></td><td></td><td></td><td></td><td></td>

<td>° so</td><td></td><td></td><td></td><td>^hmX&gt;</td><td></td><td></td>

<td></td><td></td><td></td><td></td><td>H</td><td></td><td></td>

<td>V</td><td></td><td></td><td></td><td></td><td></td><td></td>

<td>cl</td><td></td><td></td><td></td><td></td><td></td><td></td>

<td> 239</td><td colspan="3"> 240</td><td colspan="3"> 241</td>

<td></td><td></td><td>"N"</td><td></td><td>H</td><td>V7</td><td></td>

<td></td><td></td><td>A: Ś O</td><td></td><td></td><td>V</td><td></td>

<td></td><td></td><td> 1</td><td></td><td>Tγ T</td><td></td><td rowspan="3">x&gt;</td>

<td></td><td></td><td>ίιΜ</td><td></td><td>IT</td><td> 1 1</td>

<td></td><td></td><td>LJ ·</td><td></td><td colspan="2">ABOUT</td>

<td>M rr °^N</td><td></td><td>AND*</td><td></td><td></td><td></td><td></td>

<td rowspan="2">σ °.</td><td></td><td></td><td></td><td>Q</td><td></td><td></td>

<td></td><td></td><td></td><td>, T</td><td></td><td></td>

<td></td><td></td><td>ril</td><td></td><td>o = s = o</td><td></td><td></td>

<td></td><td></td><td>kJ cl</td><td></td><td>AND</td><td></td><td></td>

<td> 242</td><td colspan="3"> 243</td><td colspan="3"> 144</td>

<td>"% P</td><td></td><td></td><td></td><td>&lt;= Y "</td><td>JL</td><td></td>

<td>Ś O = O</td><td></td><td></td><td></td><td>hi</td><td>tr</td><td>V&gt;</td>

<td></td><td></td><td>1 hy</td><td></td><td>are</td><td>° Y</td><td>ao</td>

<td>about</td><td></td><td>ay and! Λ &amp; o</td><td>XX&gt;</td><td>X</td><td></td><td></td>

<td>AND</td><td>ΥΎ</td><td></td><td>YY-O</td><td>YJ</td><td></td><td></td>

<td></td><td>YA</td><td></td><td></td><td> 0=1=0</td><td></td><td></td>

<td></td><td></td><td> 1</td><td></td><td>AND</td><td></td><td></td>

<td> 245</td><td colspan="3"> 246</td><td colspan="3"> 247</td>

<td>with a = S = o</td><td></td><td></td><td></td><td></td><td></td><td></td>

<td>Ifs</td><td></td><td></td><td></td><td></td><td></td><td></td>

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

<td>CK</td><td>ARE about</td><td>.yA</td><td>about" 5 &lt;0</td><td>8 Oi J rii</td><td>ΊΓ ABOUT</td><td>Il&gt; Yo</td>

<td>° 5p</td><td></td><td></td><td>cr</td><td>¹ kj *</td><td></td><td></td>

<td>V</td><td></td><td></td><td></td><td></td><td></td><td></td>

<td>about</td><td></td><td></td><td></td><td></td><td></td><td></td>

<td> \</td><td></td><td></td><td></td><td></td><td></td><td></td>

<td> 248</td><td> 249</td><td> 250</td>

<td>. 1 ABOUT ^H - XXV about⁵'</td><td>οΆχΐ o = s = o 0</td><td>«ΜΙΑ Υ" ο</td>

<td> 251</td><td> 252</td><td> 253</td>

<td>^Η&lt;? γγΑ ^ ° AA &lt;?</td><td>^ θΑΖ ° Ca &lt;?</td><td>^andam^aboutSXA '^t2Y '⁵&lt;J °</td>

<td> 254</td><td> 255</td><td> 256</td>

<td>_about AaJ flw V *</td><td>YrW ° '_ANDabout_g»iV</td><td>ί ° AjΑϊΧ</td>

<td> 257</td><td> 258</td><td> 259</td>

<td>jjyA¹ ° aa &lt;?</td><td>(JOYctt^HijAo</td><td>Υ OzŚzO Γΐ IN 0- ^ 0 ct</td>

<td colspan="3"> 260</td><td> 261</td><td> 262</td>

<td></td><td>Η V</td><td></td><td></td><td>-rf &lt; O = C = O \ / J</td>

<td></td><td>, fl · «J &lt;Ύ Ίτ</td><td rowspan="2">Ux.C XjP</td><td></td><td></td>

<td>rar</td><td>about</td><td>KJT</td><td>AND UAJ »</td>

<td>AND</td><td></td><td></td><td>O = S: O AND (4</td><td>οΚΔ</td>

<td></td><td>° H</td><td></td><td>s</td><td>Φ</td>

<td></td><td></td><td></td><td>AND</td><td>«X</td>

<td colspan="3"> 263</td><td> 264</td><td> 265</td>

<td>AND r</td><td colspan="2">ϊΥοο ti</td><td>ZS / A about UAo '</td><td>.ΑΧΑ θΑο ^</td>

<td></td><td></td><td></td><td></td><td>h^mh</td>

<td>H</td><td></td><td></td><td></td><td></td>

<td colspan="3"> 266</td><td> ----------267..........</td><td> 268</td>

<td></td><td>Η V Jk 3</td><td>Ux? S-O</td><td>EAU</td><td>ΑΑυ</td>

<td>OT</td><td>T) Ί π k ^ jN O</td><td>aO</td><td>about</td><td>φ</td>

<td>from °</td><td></td><td></td><td>o = s = o AND HWA \ = N</td><td>0 = 4 = 0 Α "^ΗΗ</td>

<td colspan="3"> 269</td><td> 270</td><td> 271</td>

<td></td><td>1 Η V</td><td></td><td>ΑΑοφ</td><td rowspan="2">AT^H° = S = O</td>

<td></td><td rowspan="2">AU I^{11 0}</td><td rowspan="2">As ^ -O uX&gt;</td><td>AND</td>

<td>CT</td><td>T</td><td rowspan="2">0ύ0</td>

<td></td><td></td><td></td><td>oso</td>

<td></td><td></td><td></td><td>Ό</td><td></td>

<img file="PL1945632T3_D0042.tif" />

<td> . 284</td><td> 285</td><td> 286</td>

<td>O - Ś O Γ! Υ CI.</td><td>$ oVSo Q = SxO ^ »H M AT</td><td>fW about</td>

<td> 287</td><td> 288</td><td> 289</td>

<td>σΥσ&gt; &gt;</td><td>_about ΥϊΌ_ο' ΊΓ'ο</td><td></td>

<td> 290</td><td> 291 '</td><td> 292</td>

<td>s0t_about&gt;</td><td>= H</td><td>EF / what τ θΧ 1</td>

<td> 293</td><td> 294</td><td> 295</td>

<td></td><td>° H</td><td>AĆfVo3 »ιΑο H</td>

<td> 296</td><td> 297</td><td> 298</td>

<td></td><td>Λν "νΑ&gt; · ° , ΥΧΥΑ Α-ΥΥ¹ · Ο</td><td> ?</td>

<td> 299</td><td> 300 ·</td><td> 301</td>

<td>AAγο ° AA?</td><td>ΥγΧ ⁰ ΧΑ</td><td>ΧΑ ο γΛΑ Η °</td>

<td> 302</td><td> 303</td><td> 304</td>

<td>θίθ AND Μγ ο · ΑΛ ά ° ',</td><td>ίΑΜωο</td><td>0 ^ * $ 0 V o = s = o ο A H^L,H</td>

<td> 305</td><td> 306</td><td> 307</td>

<td>ο ^ ζΧο&gt;</td><td>οΑο 0 = 5 = 0 C? "</td><td>Ο? Υθ3 0 = 5 = 0 &gt;_H&lt;H * O n ^H° H</td>

<td colspan="4"> ' 308 ...... ^—</td><td colspan="2"> 309</td><td> 310</td>

<td></td><td>IH \</td><td></td><td></td><td></td><td>H V7</td><td></td>

<td></td><td>A AL z * ν / Π</td><td>'and</td><td>^ .0 T \</td><td></td><td></td><td>ηγ π | T \</td>

<td>II IOR '</td><td>WITH JN ⁰</td><td>AND-</td><td>*-about</td><td> 1</td><td>AJ 0 uA</td><td rowspan="2">H fjj '*⁵” °</td>

<td>OJ</td><td></td><td></td><td></td><td>/ 'YU</td><td></td>

<td></td><td></td><td></td><td></td><td>about</td><td></td><td> 0</td>

<td colspan="4"> 311</td><td colspan="2"> - </td><td> ' 313</td>

<td></td><td>Η γ7</td><td></td><td></td><td></td><td>H V7</td><td></td>

<td></td><td></td><td></td><td rowspan="2"> :&gt;</td><td>IDT</td><td rowspan="2">^ • JOszO ϊΧο</td><td></td>

<td>Μ</td><td></td><td>V</td><td>1L5M</td><td>1H V7</td>

<td>Al</td><td></td><td></td><td></td><td>ry</td><td> -</td><td>ίΑΑγΑν ° χ</td>

<td>'V.</td><td></td><td></td><td></td><td>V</td><td></td><td>° Mo</td>

<td> 0=^=0</td><td></td><td></td><td></td><td>o = s = o and</td><td></td><td>AA</td>

<td>σ ''</td><td></td><td></td><td></td><td>fi</td><td></td><td></td>

<td colspan="4"> 314</td><td colspan="2">-5TS-</td><td> 316</td>

<td></td><td>η vi N \</td><td></td><td>n</td><td></td><td></td><td>rfAx&gt;</td>

<td colspan="2">PY π °</td><td>AND</td><td>about * ^ O</td><td>H</td><td>H V7 aN 0 Υ π rh 5</td><td>AND</td>

<td></td><td></td><td></td><td></td><td>IDL</td><td>AND ⁰ *and-._about&gt;</td><td></td>

<td rowspan="2"> »_fao AND</td><td></td><td></td><td></td><td>I</td><td></td><td>o = s = o</td>

<td></td><td></td><td></td><td></td><td></td><td>AND</td>

<td></td><td></td><td></td><td></td><td></td><td></td><td>H ° O "H</td>

<td colspan="4"> 317</td><td colspan="2"> 318</td><td> 319</td>

<td></td><td></td><td></td><td></td><td></td><td> . .</td><td>^ t | Z</td>

<td></td><td></td><td>AND</td><td></td><td></td><td></td><td>O? O</td>

<td></td><td>^ Ν 'Ό'</td><td>AA</td><td></td><td></td><td></td><td></td>

<td>«Ν</td><td>AA^;about</td><td></td><td></td><td colspan="2"></td><td>oh Λ Use</td>

<td>ril</td><td></td><td></td><td></td><td> 0 0</td><td></td><td>Az * 5q</td>

<td></td><td></td><td></td><td></td><td></td><td></td><td> 0</td>

<td>α</td><td></td><td></td><td></td><td></td><td></td><td>V^F F</td>

<td> -3^-</td><td>33ΐ</td><td> -322-</td>

<td>οΛ-'ΛΧ ' Njl ^ O</td><td>γ * ΑΑγ \ HO</td><td>A JL 5L a juto</td>

<td> 323</td><td> 324</td><td> 325</td>

<td></td><td>? D #UQ hMA</td><td>^ VSo3 o = s = o AND</td>

<td> 326</td><td> 327</td><td> 328</td>

<td>ο</td><td>JOiRu ?</td><td>\ Y ^ * o3</td>

<td> 329</td><td> 330</td><td> 331</td>

<td>^ ΟίΥτχ</td><td>ęJAo3 0 = ^ 0 = / H AND</td><td>wx'Yk:&gt;</td>

<td> 535———</td><td> -333-</td><td> -333-</td>

<td>with a = S = o AND Ν . cr</td><td>and</td><td>gp 5ζϊ₀&gt;</td>

<td> 335</td><td> 336</td><td> 337</td>

<td>ΟΓϊΧΟ 0 = 1 = 0 yr</td><td>o = s = o er H</td><td></td>

<td> 338</td><td> 339</td><td> 340</td>

<td>Ep%&gt; o = s = o \ A * h</td><td> 0=5=0 /'</td><td>** Wireless? O = C = O CL</td>

<td> 341</td><td> 342</td><td> 343</td>

<td>A °</td><td>oAcj o = s = o 2 A °</td><td>_OjoX »s W Ύ.</td>

<td>~ HERE</td><td> -335-</td><td>-35δ-</td>

<td>Y / w o = s = o / ' η ^ΗΗ °</td><td>A / AAX_H ο Λ</td><td>ΧΧ</td>

<td> 347</td><td> 348</td><td> . 349</td>

<td>0 = 8 = 0. χ^ΝΗ h_mJ Λο</td><td>a0O. η "η</td><td>^Hk^from - IfA ΠΑ</td>

<td> 350</td><td> 351</td><td> 352</td>

<td>Υω h_nJ Η</td><td>_ΎΎ ΙΎΤ&gt; / Υ \ Χ Ο ΧΧ-Ο</td><td>Υχρ</td>

<td> 353</td><td> 354</td><td> 355</td>

<td></td><td>UAOA ^ o ^ x ^ JAs5^N ° Αχ "· Ο</td><td>Λ ο '-Τν ^' ηΤ ^ νθ'ί 'ΥΛ " ^{0 IN}</td>

<td> -353-</td><td> -357-^:</td><td>-35S-</td>

<td>o = s = o hⁿh</td><td>_about^ Y ^ NOR₀&gt;</td><td>λ sm °] k_Hoh yor »^J'TIV^J'^oJG^N°</td>

<td> 359</td><td> 360</td><td> 361</td>

<td>AAW AJ ΚΧ? A (r about</td><td>about o = s = o AND</td><td>Car</td>

<td> 362</td><td> 363</td><td> 364</td>

<td></td><td>"Ν» OiŚsO AND YA_nh οΑδ C R ° '</td><td>ęfAoo o = s = oo fi Η H</td>

<td> 365</td><td> 366</td><td> 367</td>

<td>yyA »^Hon_ABOUTH</td><td>ςΛ * ζ &amp; O - O = S about . sr r¹</td><td>cr H</td>

<td> -355-</td><td> 355</td><td colspan="2"> -375-</td>

<td>H V7</td><td>• 'NH</td><td></td><td></td>

<td>Υ 3C ο</td><td>0x5 0</td><td></td><td></td>

<td>Χί Γφ</td><td rowspan="2">Φ Αν</td><td></td><td rowspan="2">poVw</td>

<td></td><td>Αΐ</td>

<td></td><td>ΙΧ_ΝΗ</td><td>YJ</td><td></td>

<td>Α</td><td></td><td>cr</td><td></td>

<td>^χνΑ 1</td><td>ό.</td><td>Η</td><td></td>

<td> 371</td><td> 372</td><td colspan="2"> 373</td>

<td></td><td> “°·4? 0:5:0</td><td></td><td></td>

<td>[LJ</td><td>Α</td><td></td><td>Ο</td>

<td></td><td>kA ^ n</td><td></td><td>o = s = o</td>

<td>^HljlA&gt;</td><td></td><td>HQX</td><td>ψ »Η</td>

<td></td><td>ό</td><td></td><td></td>

<td> 374 .</td><td> 375</td><td></td><td></td>

<td>yUXy</td><td>ΑΆυ</td><td></td><td></td>

<td>^ τχΧοΝ Ο ΥΪο&gt;</td><td>οΧΧΧ ° 0Ś&gt;</td><td></td><td></td>

<td>»Ί] 'Ό.</td><td>A / X ο</td><td></td><td></td>

<img file="PL1945632T3_D0043.tif" />

<td colspan="6"> 389</td><td colspan="4"> 390</td><td colspan="3"> 391</td>

<td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td>^Η V7</td><td></td>

<td>Η 0,</td><td>ρ</td><td></td><td></td><td></td><td></td><td>^νΌ</td><td></td><td></td><td></td><td>^FJCF</td><td>Ύ</td><td>XX</td>

<td>κ * '</td><td>Γ Λ</td><td>HL af</td><td>Η V Ν \ 0</td><td>Ό</td><td>C⁰Xf &lt;_ο^F</td><td>H ° JU Ο</td><td>ν XJ ί</td><td>Fr..</td><td>ν-0 _FΪΥ</td><td>ΥI ό</td><td></td><td></td>

<td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td>&gt; .- b *</td><td></td><td></td>

<td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td>θΎ Η</td><td></td><td></td>

<td colspan="6"> 392</td><td colspan="4"> 393</td><td colspan="3"> 394</td>

<td>Ο</td><td></td><td></td><td></td><td></td><td></td><td>S ο</td><td></td><td></td><td></td><td>Αο</td><td></td><td></td>

<td>η₀Α</td><td>ιίΑ</td><td></td><td>Η</td><td></td><td></td><td>Α</td><td></td><td></td><td></td><td></td><td></td><td></td>

<td></td><td>L4</td><td>.44 &gt; ο Α-</td><td>Μ &gt; Ο</td><td></td><td>uu 0 0 Μ</td><td>UL τ</td><td>η ν; , IŁ JŁ V ^ • χν νΑ θ</td><td>Ό</td><td>AO F</td><td>Sool</td><td>"N ϋ J4 X θ</td><td>Γ-ΑΎ-θ F</td>

<td colspan="6"> 395</td><td colspan="4"></td><td colspan="3"> 397</td>

<td></td><td></td><td>Η</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td>

<td colspan="2">rir</td><td></td><td></td><td>ir</td><td>-Ο \</td><td></td><td></td><td></td><td></td><td>Η</td><td></td><td></td>

<td colspan="2">'Ι</td><td colspan="2"> 0</td><td></td><td>/ Ό</td><td></td><td></td><td></td><td></td><td> 0.0</td><td></td><td></td>

<td>ί</td><td>and</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td>UA</td><td>Η \ 7 Ν ΥΥ Η Π τ</td><td></td>

<td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td>sq.</td><td colspan="2"></td>

<td colspan="6"> 398</td><td colspan="4"> 399</td><td colspan="3"> 400</td>

<td>Η Ο</td><td> #·°</td><td></td><td></td><td></td><td></td><td>BEHIND FXL</td><td>Η V7 υΑ η π_ΖΜ 0</td><td>Ο</td><td>"V &lt;0^KF</td><td>υζΧ</td><td>Yc</td><td>XX</td>

<td>Κ</td><td></td><td rowspan="2">Ν^χ Υγ</td><td>Η V</td><td></td><td></td><td>^F V [</td><td></td><td></td><td></td><td>Fi</td><td></td><td></td>

<td>FA</td><td>at</td><td>_ζν 1</td><td></td><td rowspan="2">_0 F IX</td><td>r *</td><td>Τ</td><td></td><td></td><td>F 1 ιΑί</td><td></td><td></td>

<td></td><td>II</td><td></td><td>Ο</td><td>Α</td><td>"• οΧ</td><td></td><td></td><td></td><td>° UAC</td><td>'F</td><td></td>

<td></td><td></td><td></td><td></td><td></td><td></td><td>&lt;Α</td><td>"Ο Η</td><td></td><td></td><td>Η °</td><td></td><td></td>

<td>4σ^!ι</td><td> 402</td><td> 403</td>

<td>oh ΧυΜύυ kA 0 YAc&gt; ^F</td><td>HV ΥΛγΝ ^ ζΝΑΑ ^ .0 F JU ΚΜ</td><td>8 ο ΑΆΆνν ΥΑ ο ΥΑο^Λρ</td>

<td> 404</td><td> 405 ,</td><td> 406</td>

<td>^Η&lt;ΑΑ u Γ7 ιζΤ δζΑ_οΑ</td><td>Π ° ΑΧ Η τν ΑΨΆγΥ AA ° YAo f</td><td>νΧΧοΑ^F jó οΑο Η ..</td>

<td> 407</td><td> 408</td><td> 409</td>

<td>0 Αγ-ΜΆιτν YJI 0 YAc&gt; F</td><td>«Ί ΐ</td><td>/But V ° ο * ΝΛ Λ Ρ ΟΓ ° Ύ *</td>

<td> 410</td><td> 411</td><td> 412</td>

<td>οΥα&gt; η ·^νη</td><td>EO Η °</td><td>X γ&gt; ο ΥΑ &lt;?</td>

<td> 413</td><td> 414</td><td> 416</td>

<td>_n fi</td><td>F ' «" Χυγ-ΧγΟ F O in ° V-_ABOUTY</td><td>O ^ O H</td>

<td> 416</td><td> 417</td><td> 418</td>

<td></td><td>H Oh, oh</td><td>Οφ '</td>

<td> 419</td><td> 420</td><td> 421</td>

<td>oh</td><td>gVY&gt;</td><td>h x-7 ΑΛμ »Η 5ζ ^ _. Ο _F</td>

<td> 422</td><td colspan="2" rowspan="2"></td>

<td>ABOUT Au ΚΪΑ</td>

SYNTHESIS SCHEME [0206] The compounds of the invention can be prepared by known methods or as illustrated in the examples. In the case where R₁ is aryl or heteroaryl, compounds of the invention can be prepared as illustrated in Scheme I.

Diagram I

<img file="PL1945632T3_D0044.tif" />

AND

a) 50% NaOH, XR₃-R '₃-Y, BTEAC; X, Y = leaving group; b) SOCl₂, DMF; c) pyridine; d) R1-B (ORJ, Pd (dppf) Cl2, K2CO3, DMF, H2O

Diagram II

<img file="PL1945632T3_D0045.tif" />

a) Pd (PPh3) 4, CO, MeOH; b) LiAlHą, THF; c) SOCh; d) NaCN; e) NBS or NCS, AIBN, 5 CX₄(X = Br or Cl)

Diagram III

<img file="PL1945632T3_D0046.tif" />

a) pyridine, DCM; b) R_rB (OR) 2, Pd (dppf) Cl2, K2CO3, DMF, H2O Scheme IV

<img file="PL1945632T3_D0047.tif" />

R₂HN ^ N wedding

<img file="PL1945632T3_D0048.tif" />

AND

a) pyridine, DCM; b) Ri-B (OR) 2, Pd (dppf) Cl2, K2CO3, DMF, H2O [0207] Referring to Scheme I, a nitrile of formula and is alkylated (step a) using a dihaloaliphatic compound in the presence of a base such as, for example, 50% sodium hydroxide and, optionally, an interfacial transfer reagent, such as, for example, benzyltriethylammonium chloride (BTEAC), to give the corresponding alkylated nitrile (not shown), from which hydrolysis gives acid ii. Compounds of formula II are converted to acid chloride iii using a suitable reagent such as, for example, thionyl chloride / DMF. Reaction of acid chloride iii with aminopyridine, where X is a halogen atom, of formula iv (step c) gives an amide of formula v. As a result of the reaction of the amide vz with an optionally substituted boronic acid derivative (step d) in the presence of a catalyst such as, for example, palladium acetate or dichloro [1,1-bis (diphenylphosphino) ferrocene] palladium (II) (Pd (dppf) Cl₂), compounds of the invention are obtained, wherein R₁ is aryl, heteroaryl or cycloalkenyl. Boronic acid derivatives vi are commercially available or can be prepared by known methods such as the reaction of aryl bromide with a diborane ester in the presence of a coupling reagent such as, for example, palladium acetate as described in the examples.

[0208] In another case, where one R₁ is aryl and the other R is₁ is an aliphatic, alkoxy, cycloaliphatic or heterocycloaliphatic group, the compounds of the invention may be prepared as described in steps a, b and c of Scheme I using a suitably substituted aminopyridine such as

<img file="PL1945632T3_D0049.tif" />

where X is halogen and Q is Ci_-6 aliphatic, aryl, heteroaryl or 3 to 10 membered cycloaliphatic or heterocycloaliphatic as a replacement for the aminopyridine of formula iv.

PREPARATIONS, ADMINISTRATION AND APPLICATION

Pharmaceutically Acceptable Compositions [0209] Accordingly, in a further aspect of the present invention, pharmaceutically acceptable compositions are provided, said compositions comprising any of the compounds described herein and optionally comprising a pharmaceutically acceptable carrier, adjuvant or vehicle. In some embodiments, these compositions optionally further comprise one or more additional therapeutic agents. [0210] It will further be appreciated that some of the compounds of the present invention may exist, for treatment purposes, in free form or, where appropriate, as a pharmaceutically acceptable derivative or prodrug thereof. In accordance with the present invention, a pharmaceutically acceptable derivative or prodrug includes, but is not limited to, pharmaceutically acceptable salts, esters, salts of such esters, or any other adduct or derivative that, when administered to a patient in need thereof, is capable of delivering the compound directly or indirectly as described herein, or a metabolite or residue thereof.

[0211] As used herein, the term "pharmaceutically acceptable salt" refers to those salts that, based on competent medical judgment, are suitable for use in contact with human and lower animal tissues without undue toxic effects, irritation, and allergic reaction. similar, with a reasonable benefit-risk balance. "Pharmaceutically acceptable salt" means any non-toxic salt or ester salt of a compound of the present invention that, when administered to a recipient, is capable of delivering, directly or indirectly, a compound of the present invention or its inhibitory active metabolite or residue.

[0212] Pharmaceutically acceptable salts are well known in the art. For example, S.

M. Berge et al., Describe in detail the pharmaceutically acceptable salts in J. Pharmaceutical Sciences, 1977, 66, 1-19, which publication is incorporated herein by reference. Pharmaceutically acceptable salts of the compounds of the present invention include those derived from appropriate inorganic and organic acids and bases. Examples of pharmaceutically acceptable, non-toxic acid addition salts are salts of the amino group prepared using inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid or with organic acids such as acetic acid, oxalic acid, maleic acid , tartaric acid, citric acid, succinic acid or malonic acid, or using other methods used in the art, such as ion exchange. Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspargate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphors, camphorsulfonate, citrate, cyclopentanopropionate, digluconate, dodecyl sulfate, ethane sulfonate, gluconate, gluconate, phosphonate heptanoate, hexanoate, hydroiodide, 2-hydroxyethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalene sulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, pheocyanate the like. Salts derived from appropriate bases include alkali metal salts, alkaline earth metal salts, ammonium salts and N salts⁺(C1-4 alkyl) 4. The present invention also provides for the quaternization of any groups containing basic nitrogen atoms of the compounds disclosed herein. As a result of quaternization, products soluble or dispersible in water or oils can be obtained. Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium salts and the like. In addition, pharmaceutically acceptable salts contain, if appropriate, non-toxic ammonium, quaternary ammonium and amine cations formed using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, lower alkyl sulfonate and aryl sulfonate.

[0213] As described above, the pharmaceutically acceptable compositions of the present invention further include a pharmaceutically acceptable carrier, excipient or excipient, which, as described, includes any or all solvents, diluents or other liquid excipients, dispersing or suspending agents. , surfactants, isotonic agents, thickeners or emulsifiers, preservatives, solid binders, lubricants and the like, suitable for the particular dosage form desired. Remington: The Science and Practice of Pharmacy, 21st Edition, 2005, ed. DB Troy, Lippincott Williams &amp; Wilkins, Philadelphia, and Encyclopedia of Pharmaceutical Technology, ed. J. Swarbrick and JC Boylan, 1988-1999, Marcel Dekker, New York, which publication is incorporated herein by reference, discloses the various carriers used to formulate pharmaceutically acceptable compositions and known techniques for their preparation. Unless any conventional carrier is incompatible with the compounds of the invention, i.e. it does not cause undesirable biological effects or otherwise does not adversely affect any other compound or compounds of the pharmaceutically acceptable composition, its use is considered to be within the scope of this invention. . Some examples of materials that can serve as pharmaceutically acceptable carriers include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins such as human serum albumin, buffering substances such as phosphates, glycine, sorbic acid or potassium sorbate, mixtures of partial glycerides of saturated vegetable fatty acids, water, salts or electrolytes such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinylpyrrolidone, polyacrylates, waxes, polyethylene-polyoxypropylene block polymers, wool fat, sugars such as lactose, glucose and sucrose; 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; buffering agents such as magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen-free water; isotonic saline; Ringer's solution; ethyl alcohol and phosphate buffer solutions, and other non-toxic, compatible lubricants such as sodium lauryl sulfate and magnesium stearate, as well as coloring agents, release agents, coating agents, sweeteners, flavors and flavors, may be present in the composition. preservatives and antioxidants may also be present in the composition, according to the formulation's assessment

Use of Compounds and Pharmaceutically Acceptable Compositions [0214] According to yet another aspect, the present invention provides a compound of formulas (I, II, III, IV, VA, VB, I ', I'-A, and I'-B) for use in treating a condition, disease or disorder resulting from ABC transporter activity. In some embodiments, the present invention provides a method of treating a condition, disease or disorder resulting from an deficiency of the ABC transporter activity.

[0215] In certain preferred embodiments, the present invention provides a compound of formulas (I, II, III, IV, VA, VB, I ', I'-A, and I'-B) for use in the treatment of cystic fibrosis, congenital emphysema, congenital hemochromatosis, clotting deficiencies - fibrinolysis, e.g. protein C deficiency, congenital angioedema type 1, lipid processing disorders, e.g. family hypercholesterolemia, type 1 chylomicronemia, abetalipoproteinemia, lysosomal storage diseases, for example, diseases of intracellular inclusions / pseudo-Hurler, mucopolysaccharidoses, Sandhof / Tay-Sachs syndrome, Crigler-Najjar type II syndrome, poliendocrinopathy / hyperinsulinemia, diabetes mellitus, Laron dwarfism, myeloperoxidase deficiency, primary hypoparathyroidism, CD emphysema, congenital hyperparathyroidism, congenital bone fragility, congenital hypofibrinogenemia, ACT deficiency, diabetes insipidus (DI), pituitary DI, renal DI, Charcot-Marie syndrome, Pelizaeus-Merzbacher disease, neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, progressive supranuclear palsy, Pick's disease, various polyglutamine neurological disorders such as Huntington's disease, spinal cord ataxia , cerebrospinal muscular atrophy, atrophy of the dentate nucleus, red nucleus, pale knobs and low-hypothalamic nuclei and myotonic dystrophy, and spongiform encephalopathies such as congenital Creutzfeldt-Jakob disease (caused by a defect in prion protein processing), Fabry disease and Gerstmann-Straussler-Scheinker syndrome, secretory diarrhea, polycystic kidney disease lung disease (COPD), dry eye disease and Sjogren's syndrome.

[0216] According to an alternative preferred embodiment, the present invention provides a compound of formulas (I, II, III, IV, VA, VB, I ', I'-A, and I'-B) for use in the treatment of cystic fibrosis comprising the step administering to the mammal an effective amount of the composition.

[0217] According to the invention, an "effective amount" of a compound or a pharmaceutically acceptable composition means that amount which is effective to treat or reduce the severity of one or more of cystic fibrosis, congenital emphysema, congenital hemochromatosis, coagulation deficiencies - fibrinolysis, for example, protein deficiency C, congenital angioedema type 1, lipid processing disorders, e.g. family hypercholesterolemia, type 1 chylomicronemia, abetalipoproteinamii, lysosomal storage diseases, e.g. intracellular inclusion / pseudo-Hurler disease, mucopolysaccharidoses, Sandhof / Tay-Sachs syndrome, Crigler-Najjar type II syndrome, poliendocrinopathy / hyperinsulinemia, diabetes mellitus, hypoparathyroidism, type 1 CDG glycanosis, congenital emphysema, congenital hyperparathyroidism, congenital bone fragility, congenital hypofibrinogenemia, ACT deficiency, diabetes insipidus (DI), pituitary DI, renal DI, Charcot-Marie-Tooth syndrome, Pelizacus-Merzbacher disease, neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, progressive supranuclear palsy, Pick disease , various polyglutamine neurological disorders, such as Huntington's disease, type I cerebellar ataxia, cerebrospinal muscular atrophy, atrophy of the dentate nucleus, red nucleus, pale knob and low-hypothalamic nuclei and myotonic dystrophy, and spongiform encephalopathies such as congenital Creutzfeldt Jakob disease (caused by a defect in prion protein processing), Fabry disease and Gerstmann-Straussler-Scheinker syndrome, secretory diarrhea, polycystic kidney disease, chronic COP ), dry eye disease and Sjogren's syndrome.

[0218] The compounds and compositions according to the method of the present invention can be administered using any amount and any route of administration effective to treat or reduce the severity of one or more of cystic fibrosis, congenital emphysema, congenital hemochromatosis, coagulation deficiencies - fibrinolysis, on example of protein C deficiency, congenital angioedema type 1, lipid processing disorders, e.g. family hypercholesterolemia, type 1 chylomicronemia, abetalipoproteinemia, lysosomal storage diseases, for example, intracellular inclusion / pseudo-Hurler disease, mucopolysaccharidoses, Sandhoff-Tay-Sachs syndrome, Crigler-Najjar type II syndrome, poliendocrynopathy, primary hyperglycaemia, hypoglycaemia parathyroid glands, melanoma, type 1 CDG glycanosis, congenital emphysema, congenital hyperparathyroidism, congenital bone fragility, congenital hypofibrinogenemia, ACT deficiency, diabetes insipidus (DI), pituitary DI, renal DI, Charcot-Marie syndrome, Pelizacus-Merzbacher disease, neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, progressive supranuclear palsy Pick, various polyglutamine neurological disorders, such as Huntington's disease, cerebellar cerebral ataxia type I, cerebrospinal muscular atrophy, atrophy of the nucleus, red nucleus, pale knob and low hypothalamic nucleus and myotonic dystrophy and spongiform encephalopathies, such as congenital Creutzfeldt-Jakob disease (caused by a defect in prion protein processing), Fabry disease and Gerstmann-Straussler-Scheinker syndrome, secretory diarrhea, chronic obstructive pulmonary disease (COPD), dry eye disease and Sjogren's syndrome.

[0219] The specific amount will vary from individual to individual and will depend on the species, age and general condition of the individual, the severity of the infection, the particular agent, the method of its administration and the like. The compounds of the invention are preferably formulated in unit dosage form to facilitate administration and uniformity of dosage. The term "unit dosage form" as used herein refers to a physically discrete unit of agent suitable for the patient undergoing treatment. However, it will be understood that the total daily dose of the compounds and compositions of the present invention will depend on the decision of the treating physician regarding competent medical judgment. The specific effective dose level for any particular patient or organism will depend on a variety of factors including the disorder being treated and the severity of the disorder, the activity of the particular compound employed; the specific composition used; the age, body weight, general health, sex and diet of the patient; the time of administration, route of administration and rate of excretion of the particular compound employed, the duration of treatment; drugs used in combination or accidentally with the specific compound employed, and compatibility factors well known in medical technology. The term "patient" as used herein means a living being, preferably a mammal, and most preferably a human.

[0220] The pharmaceutically acceptable compositions of the present invention may be administered to humans and other living entities orally, rectally, parenterally, into the subarachnoid space, vaginal, intraperitoneal, topical (as powders, ointments or drops), buccal or as oral or nasal sprays and the like depending on the severity of the infection being treated. In some embodiments, the compounds of the invention may be administered orally or parenterally in doses of about 0.01 mg / kg to about 50 mg / kg, and preferably from about 1 mg / kg to about 25 mg / kg, patient's weight per day, one or more times a day to achieve the desired therapeutic effect.

[0221] Liquid dosage forms for oral administration include, but are not limited to, pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs. In addition to the active compounds, liquid dosage forms may contain inert commonly used diluents, such as, for example, water or other solvents, solubilizers and emulsifiers, such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate , propylene glycol, 1,3-butylene glycol, dimethylformamide, oils (especially cottonseed, peanut, corn oil, germ oil, olive oil, castor oil and sesame oil), glycerin, tetrahydrofurfuryl alcohol, polyethylene glycols and sorbitan fatty acid esters, and mixtures thereof. In addition to inert diluents, the oral compositions may also contain adjuvants such as wetting agents, emulsifiers and suspending agents, sweeteners, flavors and flavors.

[0222] Injectable preparations, for example, sterile, injectable, aqueous or oily suspensions may be formulated according to the known technique using suitable dispersing or wetting agents or suspending agents. Sterile injectable preparations may also be sterile injectable solutions, suspensions or emulsions in a non-toxic parenterally-acceptable diluent or solvent, for example, a solution in 1,3-butanediol. Acceptable excipients and solvents that may be used include water, USP Ringer's solution, and isotonic sodium chloride. In addition, sterile, non-volatile vegetable oils have traditionally been used as a solvent or suspension medium. For this purpose any non-irritating, non-volatile vegetable oil may be used, including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid are used in the preparation of injectables.

[0223] Injectable preparations can be sterilized, for example, by filtration through a bacterial-retaining filter or by the inclusion of sterilizing agents in the form of sterile solid compositions which can be dissolved or dispersed in sterile water or other sterile delivery medium just before use. for injection.

[0224] In order to prolong the effect of a compound of the present invention, it is often desirable to slow the absorption of the compound after subcutaneous or intramuscular injection. This can be achieved by using a liquid suspension of crystalline or amorphous material with poor water solubility. The rate of absorption of the compound will then depend on its dissolution rate, which in turn may depend on the size of the crystals or the crystal form. Alternatively, parenteral administration delayed absorption is achieved by dissolving or suspending the compound in an oily vehicle. Injectable depot forms are made by forming microencapsule matrices of the compound in biodegradable polymers such as polylactide-polyglycolide. Depending on the ratio of compound to polymer and the nature of the particular polymer used, the release rate of the compound can be controlled. Examples of other biodegradable polymers include poly (orthoesters) and poly (anhydrides). Injectable depot preparations are also prepared by "entrapping" the compound in liposomes or microemulsions that are compatible with body tissues.

[0225] Compositions for rectal or vaginal administration are preferably suppositories that can be prepared by mixing the compounds of the present invention with suitable non-irritating excipients or carriers, such as cocoa butter, polyethylene glycol or suppository wax, which are solid at room temperature but liquid at body temperature and thus melt in the rectum or vagina and release the active compound.

[0226] Solid dosage forms for oral administration include capsules, tablets, pills, powders and granules. In such solid dosage forms, the active compound is mixed with at least one inert, pharmaceutically acceptable excipient or carrier such as sodium citrate or dicalcium phosphate and / or (a) fillers or fillers such as starches, lactose, sucrose, glucose, mannitol and silicic acid, (b) binders such as, for example, carboxymethyl cellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose and acacia, (c) humectants such as glycerin, (d) disintegrants such as agar, calcium carbonate, potato starch or tapioca starch, alginic acid, certain silicates and sodium carbonate, (e) solution retarding agents, such as paraffin, (f) absorption accelerators, such as quaternary ammonium compounds, (g) wetting agents, such as, for example, cetyl alcohol and glycerol monostearate, (h) absorbents, such as kaolin and bentonite clay, and (i) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate and mixtures thereof. In the case of capsules, tablets and pills, the dosage form may also comprise buffering agents.

[0227] Solid compositions of a similar type may also be employed as fillers in soft and hard gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polyethylene glycols and the like. Solid dosage forms in the form of tablets, dragees, capsules, pills and granules can be prepared with coatings and coatings, such as enteric coatings and other coatings well known in the pharmaceutical formulation art. They may optionally contain opacifying agents and may also be formulated to release active ingredient (s) only or, preferably, in a certain portion of the intestinal tract, optionally, in a delayed manner. Examples of embedding compositions that can be used include polymeric substances and waxes. Solid compositions of a similar type may also be employed as fillers in soft and hard gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polyethylene glycols and the like.

[0228] The active compounds may also be in micro-encapsulated form with one or more of the above-mentioned excipients. Solid dosage forms in the form of tablets, dragees, capsules, pills and granules can be prepared with coatings and coatings such as enteric coatings, release control coatings and other coatings well known in the pharmaceutical formulation art. In such dosage forms, the active ingredient can be mixed with at least one inert diluent, such as sucrose, lactose or starch. Such dosage forms may also, in accordance with common practice, additional substances other than inert diluents, for example tabletting glidants and other tableting additives such as magnesium stearate and microcrystalline cellulose. In the case of capsules, tablets and pills, the dosage forms may also comprise buffering agents. They may optionally contain opacifying agents and may also be formulated to release active ingredient (s) only or, preferably, in a certain portion of the intestinal tract, optionally, in a delayed manner. Examples of usable embedding compositions include polymeric substances and waxes.

[0229] Dosage forms for topical or transdermal administration of a compound of the invention include ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalants or patches. The active ingredient is mixed under sterile conditions with a pharmaceutically acceptable carrier and any needed preservatives or buffering agents, if required. Ophthalmic preparations, ear drops and eye drops are also considered within the scope of the invention. In addition, the present invention contemplates the use of transdermal patches, which has the additional advantage of providing controlled administration of a compound of the invention to the body. Such dosage forms are prepared by dissolving or placing the compound in the appropriate medium. Absorption enhancers can be used to increase the flow of the compound through the skin. The rate can be controlled either by introducing a rate controlling membrane or by dispersing the compound in a polymer matrix or gel.

[0230] As described above, the compounds of the invention are useful as modulators of ABC transporters. Thus, without intending to be bound by any theory, these compounds and compositions are particularly useful for treating or reducing the severity of a disease, condition or disorder, where the hyperactivity or inactivity of ABC transporters is involved in that disease, condition or disorder. When the hyperactivity or inactivity of the ABC transporter is involved in a particular disease, condition or disorder, that disease, condition or disorder may also be referred to as "disease, condition or disorder mediated by the ABC transporter." Accordingly, in another aspect, the present invention provides a method of treating or reducing the severity of a disease, condition and disorder wherein an overactive or inactive ABC transporter is involved in that disease state.

[0231] The performance of the compound used in the present invention as an ABC transporter modulator can be evaluated in accordance with methods generally described in the art and in the examples provided herein.

[0232] It will be appreciated that the compounds of the invention and the pharmaceutically acceptable compositions of the invention may be used in combination therapies, ie, the compounds and pharmaceutically acceptable compositions may be administered simultaneously with, before or after the use of one or more desired drugs or medical procedures. When choosing a specific combination of therapies (drugs or procedures) for use in combination therapy mode, consideration should be given to the compatibility of desired drugs and / or procedures and the desired therapeutic effect to be achieved. It should also be noted that the therapies used may have an effect on the disorder itself (for example, a compound of the invention may be administered concurrently with another agent used to treat the same disorder) or may produce other effects (e.g., control any effects side effects). Additional therapeutic agents used herein that are normally administered to treat or prevent a particular disease or condition occur under the name "appropriate for the disease or condition being treated."

[0233] The amount of additional therapeutic agent present in the compositions of the present invention will not be greater than the amount that would normally be administered in a composition containing that therapeutic agent as the only active agent. Preferably, the amount of additional therapeutic agent in the presently disclosed compositions will range from about 50% to 100% of the amount normally present in a composition containing that agent as the only therapeutically active agent.

[0234] The compounds of the present invention or pharmaceutically acceptable compositions thereof can also be incorporated into compositions for coating implantable medical devices such as prostheses, artificial valves, vascular implants, stents and catheters. Accordingly, the present invention, in another aspect, comprises a composition for coating an implantable device, comprising a compound of the present invention as described generally above and in points and subsections of the description, and a carrier suitable for coating said implantable device. In yet another aspect, the present invention includes an implantable device coated with a composition comprising a compound of the present invention as described above generally, and in points and subsections of the description, and a carrier suitable for coating said implantable device. Suitable coatings and general method of making coated implantable devices are described in US Patent Nos. 6099562, 5886026 and 5304121. Coatings are typically biocompatible polymeric materials such as hydrogel polymer, polymethyldisiloxane, polycaprolactone, polyethylene glycol, polylactic acid, ethylene / vinyl acetate and mixtures thereof. Optionally, the coatings may be further coated with appropriate fluorosilicone topcoats, polysaccharides, polyethylene glycol, phospholipids or combinations thereof to provide controlled release characteristics in the composition.

[0235] Another aspect of this invention relates to modulation of ABC transporter activity in a biological sample or in a patient (e.g., in vitro or in vivo), this method comprising administering to the patient or contacting said biological sample with a compound of formula I or a composition containing that compound . The term "biological sample" as used herein includes, without limitation, cell cultures or their extracts; biopsy materials obtained from a mammal or their extracts and blood, saliva, urine, feces, semen, tears or other body fluids or their extracts.

[0236] Modulation of ABC transporter activity in a biological sample is useful for a variety of purposes that are known to the person skilled in the art. Examples of such purposes include, but are not limited to, the study of ABC transporters in biological and pathological phenomena, and a comparative assessment of new ABC transporter modulators.

[0237] In yet another embodiment, a method is provided for modulating anion channel activity in vitro or in vivo, comprising the step of contacting said channel with a compound of formula (I, II, III, IV, VA, VB, I ', I'-A and I'-B). In preferred embodiments, the anion channel is a chloride channel or bicarbonate channel. In other preferred embodiments, the anion channel is a chloride channel.

[0238] According to an alternative embodiment, the present invention provides a method of increasing the number of functional ABC transporters in a cell membrane, comprising the step of contacting that cell with a compound of formula (I, II, III, IV, VA, VB, I ', I'-A and I'-B). The term "functional ABC transporter" as used herein means an ABC transporter that is capable of transporting activity. In preferred embodiments, the functional ABC transporter is CFTR.

[0239] According to another preferred embodiment, the ABC transporter activity is measured by measuring the transmembrane potential voltage. Methods for measuring transmembrane potential voltage in a biological sample may include any known method in the art, for example, optical membrane potential test or other electrophysiological methods.

[0240] The optical membrane potential test uses voltage sensitive FRET sensors described by Gonzalez and Tsien (See, Gonzalez, JE and RY Tsien (1995) "Voltage sensing by fluorescence resonance energy transfer in single cells" Biophys J 69 (4) : 1272-80 and Gonzalez, JE and RY Tsien (1997) "Improved indicators of cell membrane potential that use fluorescence resonance energy transfer" Chem Biol 4 (4): 26977) in combination with devices for measuring fluorescence changes, such as Voltage / Ion Probe Reader (VIPR) (See, Gonzalez, JE, K. Oades, et al. (1999) "Cell-based assays and instrumentation for screening ion-channel targets" Drug Discov Today 4 (9): 431-439).

[0241] These voltage sensitive tests are based on a change in resonance fluorescence excitation energy transfer (FRET) between a membrane soluble, voltage sensitive dye, DiSBAC₂(3) and the fluorescent phospholipid, CC2DMPE, which is attached to the outer layer of the plasma membrane and acts as a FRET donor. Changes in membrane potential (V_m) cause the redistribution of negatively charged DiSBAC2 (3) in the plasma membrane and the amount of energy transferred from CC2-DMPE changes accordingly. Changes in fluorescence emissions can be monitored using the VIPR II, which is an integrated liquid dispenser and fluorescence detector designed to perform cell-based screening in 96- or 384-well microtiter plates.

[0242] In another aspect, the present invention provides a kit for use in measuring the activity of an ABC transporter or fragment thereof in an in vitro or in vivo biological sample, comprising (i) a composition comprising a compound of formula (I, II, III, IV, VA, VB, I ', I'-A and I'-B) or any of the above forms, and (ii) instructions for a) contacting the composition with the biological sample and b) measuring the activity of this ABC transporter or fragment thereof. In one embodiment, the kit further includes instructions for a) contacting the additional composition with the biological sample; b) measuring the activity of this ABC transporter or a fragment thereof in the presence of this additional compound, and c) comparing the activity of the ABC transporter in the presence of an additional compound with the density of the ABC transporter in the presence of a compound of formula (I, II, III, IV, VA, VB, I ', I'-A and I'-B). In preferred embodiments, the kit is used to measure the density of the ABC transporter.

REGULATIONS AND EXAMPLES

General Procedure I: Carboxylic acid building block [0243]

<img file="PL1945632T3_D0050.tif" />

[0244] Benzyltriethylammonium chloride (0.025 equivalent) and the corresponding dihalide compound (2.5 equivalents) were added to the substituted phenylacetonitrile. The mixture was heated at 70 ° C and then 50% sodium hydroxide (10 equivalents) was slowly added to the mixture. The reaction mixture was stirred at 70 ° C for 12-24 hours to ensure complete formation of the cycloalkyl moiety and then heated at 130 ° C for 24-48 hours to ensure complete conversion of the nitrile to carboxylic acid. The dark brown / black reaction mixture was diluted with water and extracted with ethyl acetate followed by dichloromethane each three times to remove by-products. The basic aqueous solution was acidified using concentrated hydrochloric acid to a pH of less than one and the precipitate that began to form at pH 4 was filtered off and washed twice with 1 M hydrochloric acid. The solid was dissolved in dichloromethane and extracted twice with 1 M hydrochloric acid and once with saturated aqueous sodium chloride. The organic solution was dried over sodium sulfate and evaporated to dryness to give the cycloalkylcarboxylic acid.

A. 1-Benzo [1,31-dioxol-5-ylcyclopropanecarboxylic acid] [0245]

<img file="PL1945632T3_D0051.tif" />

[0246] A mixture of benzo [1,31-dioxol-5-acetonitrile (5.10 g, 31.7 mmol), 1-bromo-2-chloroethane (9.00 mL, 109 mmol) and benzyltriethylammonium chloride (0.181 g, 0.795 mmol) was heated at 70 ° C, and then a 50% (w / w) aqueous sodium hydroxide solution (26 ml) was slowly added to the mixture. The reaction mixture was stirred at 70 ° C for 18 hours and then heated at 130 ° C for 24 hours. The dark brown reaction mixture was diluted with water (400 mL) and extracted once with an equal volume of ethyl acetate and once with an equal volume of dichloromethane. The basic aqueous solution was acidified with concentrated hydrochloric acid to a pH less than one and the precipitate was filtered off and washed with 1 M hydrochloric acid. The solid was dissolved in dichloromethane (400 mL) and extracted twice with equal volumes of 1 M hydrochloric acid and once with saturated aqueous sodium chloride. The organic solution was dried over sodium sulfate and evaporated to dryness to give a white to slightly off-white solid (5.23 g, 80%) ESI-MS mlz calculated 206.1, found 207.1 (M + 1) +. Retention time 2.37 minutes.¹H NMR (400 MHz, DMSO - &lt;&gt; δ 1.07-1.11 (m, 2H), 1.38-1.42 (m, 2H), 5.98 (s, 2H), 6.79 ( m, 2H), 6.88 (m, 1H), 12.26 (s, 1H).

General Procedure II: Carboxylic acid building block [0247]

<img file="PL1945632T3_D0052.tif" />

Hal = Cl, Br, I, all other variables are as defined in the text [0248] Sodium hydroxide (50% aqueous solution, 7.4 equivalents) was slowly added to a mixture of the appropriate phenylacetonitrile, benzyltriethylammonium chloride (1.1 equivalent) and the corresponding compound dihalide (2.3 equivalents) at 70 ° C. The mixture was stirred overnight at 70 ° C, after which the reaction mixture was diluted with water (30 mL) and extracted with ethyl acetate. The combined organic layers were dried over sodium sulfate and evaporated to dryness to afford crude cyclopropanecarbonitrile, which was used directly in the next step.

[0249] The crude cyclopropanecarbonitrile was heated to reflux in a 10% aqueous sodium hydroxide solution (7.4 equivalents) for

2.5 hours. The cooled reaction mixture was washed with ether (100 ml) and the aqueous phase was acidified to pH 2 with 2 M hydrochloric acid. The precipitate was filtered off to give cyclopropanecarboxylic acid as a white solid.

General Procedure III: Carboxylic acid building block [0250]

<img file="PL1945632T3_D0053.tif" />

B. 1- (2,2-difluorobenzo [1,31-dioxol-5-yl) cyclopropanecarboxylic acid

<img file="PL1945632T3_D0054.tif" />

[0252] Step a: 2,2-difluorobenzo [1,31-dioxol-5-carboxylic acid methyl ester solution of 5-bromo-2,2-difluorobenzo [1,31-dioxol (11.8 g, 50.0 mmol) and tetraxis (triphenylphosphine) palladium (0) [Pd (PPh₃)₄, 5.78 g, 5.00 mmol] in methanol (20 mL) containing acetonitrile (30 mL) and triethylamine (10 mL) was stirred under carbon monoxide (55 PSI) at 75 ° C (oil bath temperature) for 15 hours . The cooled reaction mixture was filtered and the filtrate evaporated to dryness. The residue was purified by silica gel column chromatography to give crude 2,2-difluorobenzo [1,31-dioxole-5-carboxylic acid methyl ester (11.5 g), which was used directly in the next step.

Step b: (2,2-Difluorobenzo [1,31-dioxol-5-yl) methanol [0253] Crude 2,2-difluorobenzo [1,31-dioxol-5-carboxylic acid methyl ester (11.5 g) dissolved in anhydrous 20 ml tetrahydrofuran (THF) was slowly added to a suspension of lithium aluminum hydride (4.10 g, 106 mmol) in anhydrous THF (100 mL) at 0 ° C. The mixture was then warmed to room temperature. The reaction mixture was stirred at room temperature for 1 hour before being cooled to 0 ° C and treated with water (4.1 g) followed by sodium hydroxide (10% aqueous solution, 4.1 ml). The resulting suspension was filtered and washed with THF. The combined filtrate was evaporated to dryness and the residue was purified by silica gel column chromatography to give (2,2-difluorobenzo [1,31-dioxol-5-yl) methanol (7.2 g, 38 mmol, 76% for two steps ) in the form of a colorless oil.

Step c: 5-Chloromethyl-2,2-difluorobenzo [1,31-dioxol [0254] Thionyl chloride (45 g, 38 mmol) was slowly added to a solution of (2,2-difluorobenzo [1,31-dioxol-5-yl) methanol (7 , 2 g, 38 mmol) in dichloromethane (200 ml) at 0 ° C. The resulting mixture was stirred overnight at room temperature and then evaporated to dryness. The residue was partitioned between an aqueous solution of saturated sodium bicarbonate (100 mL) and dichloromethane (100 mL). The separated aqueous layer was extracted with dichloromethane (150 mL) and the organic layer was dried over sodium sulfate, filtered and evaporated to dryness to give crude 5-chloromethyl-2,2-difluorobenzo [1.31-dioxol (4.4 g) which was used directly in the next stage.

Step d: (2,2-Difluorobenzo [1,31-dioxol-5-yl) acetonitrile [0255] A mixture of crude 5-chloromethyl-2,2-difluorobenzo [1,3] dioxol (4.4 g) and sodium cyanide (1 , 36 g, 27.8 mmol) in dimethyl sulfoxide (50 mL) was stirred at room temperature overnight. The reaction mixture was poured into ice and extracted with ethyl acetate (300 mL). The organic layer was dried over sodium sulfate and evaporated to dryness to afford crude (2,2-difluorobenzo [1,3] dioxol-5-yl) acetonitrile (3.3 g), which was used directly in the next step.

Step e: 1- (2,2-Difluorobenzo [1,3] dioxol-5-yl) cyclopropanecarbonitrile [0256] Sodium hydroxide (50% aqueous solution, 10 mL) was slowly added to the crude mixture (2,2-difluorobenzo [1 , 3] dioxol-5-yl) acetonitrile, benzyltriethylammonium chloride (3.00 g, 15.3 mmol) and 1-bromo-2-chloroethane (4.9 g, 38 mmol) at 70 ° C. The mixture was stirred overnight at 70 ° C, after which the reaction mixture was diluted with water (30 mL) and extracted with ethyl acetate. The combined organic layers were dried over sodium sulfate and evaporated to dryness to afford crude 1- (2,2-difluorobenzo [1,3] dioxol-5-yl) cyclopropanecarbonitrile, which was used directly in the next step.

Step f: 1- (2,2-difluorobenzo [1,3] dioxol-5-yl) cyclopropanecarboxylic acid 1- (2,2-Difluorobenzo [1,3] dioxol-5-yl) cyclopropanecarbonitrile (crude from previous stage) was heated to reflux in a 10% aqueous sodium hydroxide solution (50 ml) for 2.5 hours. The cooled reaction mixture was washed with ether (100 ml) and the aqueous phase was acidified to pH 2 with 2 M hydrochloric acid. The precipitate was filtered off to give 1- (2,2-difluorobenzo [1,3] dioxol-5-yl) cyclopropanecarboxylic acid as a white solid (0.15 g, 1.6% for four steps). ESI-MS m / z calcd 242.2, found 243.3 (M + 1) +;¹1 H NMR (CDCl₃) δ 7.14-7.04 (m, 2H), 6.98-6.96 (m, 1H), 1.74-1.64 (m, 2H), 1.26-1.08 (m , 2H).

C. 2- (4-Chloro-3-methoxyphenyl) acetonitrile [0258]

<img file="PL1945632T3_D0055.tif" />

Step a: 1-Chloro-2-methoxy-4-methylbenzene [0259] To a solution of 2-chloro-5-methylphenol (93 g, 0.65 mol) in CH3CN (700 ml) was added CH₃I (111 g, 0.78 mol) and K₂WHAT₃ (180 g, 1.3 mole). The mixture was stirred at 25 ° C overnight. The solid was filtered off and the filtrate evaporated in vacuo to give 1-chloro-2-methoxy-4-methylbenzene (90 g, 89%).¹H NMR (300 MHz, CDCl₃) δ 7.22 (d, J = 7.8 Hz, 1H), 6.74-6.69 (m, 2H), 3.88 (s, 3H), 2.33 (s, 3 H).

Step b: 4-Bromomethyl-1-chloro-2-methoxybenzene [0260] To a solution of 1-chloro-2-methoxy-4-methylbenzene (50 g, 0.32 mol) in CCl4 (350 ml) was added NBS (57, 2 g, 0.32 mole) and AIBN (10 g, 60 mmol). The mixture was heated to reflux for 3 hours. The solvent was evaporated in vacuo and the residue was purified by silica gel column chromatography (petroleum ether / EtOAc = 20: 1) to give 4-bromomethyl-1-chloro-2-methoxybenzene (69 g, 92%). ¹1 H NMR (400 MHz, CDCl₃) δ 7.3337.31 (m, 1H), 6.95-6.91 (m, 2H), 4.46 (s, 2H), 3.92 (s, 3H).

Step c: 2- (4-Chloro-3-methoxyphenyl) acetonitrile [0261] To a solution of 4-bromomethyl-1-chloro-2-methoxybenzene (68.5 g, 0.29 mol) in C₂H₅OH (90%, 500 ml) NaCN (28.5 g, 0.58 mol) was added. The mixture was stirred at 60 ° C overnight. Ethanol was evaporated and the residue was dissolved in H2O. The mixture was extracted with ethyl acetate (300 mL χ 3). The combined organic layers were washed with brine, dried over Na₂SO₄ and purified by silica gel column chromatography (petroleum ether / EtOAc 30: 1) to give 2- (4-chloro-3-methoxyphenyl) acetonitrile (25 g, 48%). ¹1 H NMR (400 MHz, CDCl₃) δ 7.36 (d, J = 8 Hz, 1

H), 6.88-6.84 (m, 2H), 3.92 (s, 3H), 3.74 (s, 2H). ¹³C NMR (100 MHz, CDCl 3) δ 155.4, 130.8, 129.7, 122.4, 120.7, 117.5, 111.5, 56.2, 23.5.

D. (4-Chloro-3-hydroxyphenyl) acetonitrile [0262]

<img file="PL1945632T3_D0056.tif" />

[0263] BBr₃ (16.6 g, 66 mmol) was slowly added to a solution of 2- (4-chloro-3-methoxyphenyl) acetonitrile (12 g, 66 mmol) in DCM (120 mL) at -78 ° C under N₂. The temperature of the reaction mixture was slowly raised to room temperature. The reaction mixture was stirred overnight and then poured into ice-water. The organic layer was separated and the aqueous layer was extracted with DCM (40 mL × 3). The combined organic layers were washed with water, brine, dried over Na2SO4 and concentrated in vacuo to give (4-chloro-3-hydroxyphenyl) acetonitrile (9.3 g, 85%).¹H NMR (300 MHz, CDCl3) δ 7.34 (d, J = 8.4 Hz, 1H), 7.02 (d, J = 2.1 Hz, 1H), 6.87 (dd, J = 2.1, 8.4 Hz, 1H), 5.15 (brs, 1H), 3.72 (s, 2H).

E. 1- (3- (hydroxymethyl) -4-methoxyphenyl) cyclopropane carboxylic acid [0264]

<img file="PL1945632T3_D0057.tif" />

[0265] Step a: 1- (4-Methoxyphenyl) cyclopropanecarboxylic acid methyl ester To a solution of 1- (4-methoxyphenyl) cyclopropanecarboxylic acid (50.0 g, 0.26 mol) in MeOH (500 ml), toluene monohydrate was added 4-sulfone (2.5 g, 13 mmol) at room temperature. The reaction mixture was heated to 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 NaHCO3 (100 mL) and brine, dried over anhydrous Na2SO4 and evaporated in vacuo to give 1- (4-methoxyphenyl) cyclopropanecarboxylic acid methyl ester (53.5 g, 99%). ¹1 H NMR (CDCl₃, 400 MHz) δ 7.25-7.27 (m, 2 H), 6.85 (d, J = 8.8 Hz, 2 H), 3.80 (s, 3 H), 3.62 ( s, 3H), 1.58 (m, 2H), 1.15 (m, 2H).

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

Step c: 1- (3-Hydroxymethyl-4-methoxyphenyl) cyclopropanecarboxylic acid methyl ester [0267] To a suspension of crude 1- (3-chloromethyl-4-methoxyphenyl) cyclopropanecarboxylic acid methyl ester (20.0 g) in water (350 ml) was added Bu4NBr (4.0 g) and Na2CO3 (90.0 g, 0.85 mol) 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 water, dried over anhydrous Na₂SO₄ and evaporated in vacuo to give a crude product which was purified using a column (petroleum ether / EtOAc 15: 1) to give 1- (3-hydroxymethyl-4-methoxyphenyl) cyclopropanecarboxylic acid methyl ester (8, 0 g, 39%). ¹1 H NMR (CDCl₃, 400 MHz) δ 7.23-7.26 (m, 2H), 6.83 (d, J = 8.0 Hz, 1H), 4.67 (s, 2H), 3.86 ( s, 3H), 3.62 (s, 3H), 1.58 (q, J = 3.6 Hz, 2H), 1.14-1.17 (m, 2H).

Step d: 1- [3- (tert-butyldimethylsilanyloxymethyl) -4-methoxyphenyl] cyclopropanecarboxylic acid methyl ester To solution of 1- (3-hydroxymethyl-4-methoxyphenyl) cyclopropanecarboxylic acid methyl ester (8.0 g, 34 mmol) in CH₂cl₂ (100 ml) imidazole (5.8 g, 85 mmol) and TBSCl (7.6 g, 51 mmol) were added at room temperature. The mixture was stirred overnight at room temperature. The mixture was washed with brine, dried over anhydrous Na₂SO₄ and evaporated in vacuo to give the crude product which was purified using a column (petroleum ether / EtOAc 30: 1) to give 1- [3- (tert-butyldimethylsilanyloxymethyl) -4-methoxyphenyl] cyclopropanecarboxylic acid methyl ester (6.7 g, 56%). ¹1 H NMR (CDCl₃, 400 MHz) δ 7.4447.45 (m, 1H), 7.19 (dd, J = 2.0, 8.4 Hz, 1H), 6.76 (d, J = 8.4 Hz, 1 h), 4.75 (s, 2H), 3.81 (s, 3H), 3.62 (s, 3H), 1.57-1.60 (m, 2H), 1.15 -1.18 (m, 2H), 0.96 (s, 9h), 0.11 (s, 6H). Step e: 1- (3-Hydroxymethyl-4-methoxyphenyl) cyclopropanecarboxylic acid [0269] To a solution of 1- [3- (tert-butyldimethylsilanyloxymethyl) -4-methoxyphenyl] cyclopropanecarboxylic acid methyl ester (6.2 g, 18 mmol) in MeOH (75 ml) LiOH.H solution was added₂O (1.50 g, 35.7 mmol) in water (10 mL) at 0 ° C. The reaction mixture was stirred overnight at 40 ° C. 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 Na2SO4 and evaporated in vacuo to give 1- (3-hydroxymethyl-4-methoxyphenyl) cyclopropanecarboxylic acid (5.3 g).

F. 2- (3-Fluoro-4-methoxyphenyl) acetonitrile [0270]

<img file="PL1945632T3_D0058.tif" />

[0271] 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, a solution of 3-fluoro-4-methoxybenzaldehyde (8.00 g, 51.9 mmol) in THF (50 mL) was added dropwise and stirring was continued for 1.5 hours at -78 ° C. Methanol (50 mL) was added to the cooled reaction mixture. The mixture was heated to reflux for 30 minutes. The solvent of the reaction mixture was removed to give a crude product which was dissolved in water (200 ml). The aqueous phase was extracted with EtOAc (100 mL χ 3). The combined organic layers were dried and evaporated under reduced pressure to give a crude product which was purified by column chromatography (petroleum ether / EtOAc 10: 1) to give 2- (3-fluoro-4-methoxyphenyl) acetonitrile (5.0 g , 58%).¹H NMR (400 MHz, CDCl3) δ 7.02-7.05 (m, 2H), 6.94 (t, J = 8.4 Hz, 1H), 3.88 (s, 3H), 3.67 (s, 2H). ¹³C NMR (100 MHz, CDCb) δ 152.3, 147.5, 123.7, 122.5, 117.7, 115.8, 113.8, 56.3, 22.6.

G. 2- (3-Chloro-4-methoxyphenyl) acetonitrile [0272]

<img file="PL1945632T3_D0059.tif" />

[0273] 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, a solution of 3-chloro-4-methoxybenzaldehyde (1.65 g, 10 mmol) in THF (10 ml) added dropwise and stirring continued for 1.5 hours at -78 ° C. Methanol (10 mL) was added to the cooled reaction mixture. The mixture was heated to reflux for 30 minutes. The solvent of the reaction mixture was removed to give the crude product, which was dissolved in water (20 ml). The aqueous phase was extracted with EtOAc (20 mL × 3). The combined organic layers were dried and evaporated under reduced pressure to give a crude product which was purified by column chromatography (petroleum ether / EtOAc 10: 1) to give 2- (3-chloro-4-methoxyphenyl) acetonitrile (1.5 g , 83%).¹H NMR (400 MHz, CDCl3) δ 7.33 (d, J = 2.4 Hz, 1H), 7.20 (dd, J = 2.4, 8.4 Hz, 1H), 6.92 (d, J = 8.4 Hz, 1H), 3.91 (s, 3H), 3.68 (s, 2H). ¹³C NMR (100 MHz, CDCl3) δ 154.8, 129.8, 127.3, 123.0, 122.7, 117.60, 112.4, 56.2, 22.4.

H. 1- (3,3-Dimethyl-1-2,3-dihydrobenzofuran-5-yl) cyclopropanecarboxylic acid [0274]

<img file="PL1945632T3_D0060.tif" />

Step a: 1- (4-Hydroxyphenyl) cyclopropane carboxylic acid methyl ester To a solution of methyl 1- (4-methoxyphenyl) cyclopropane carboxylate (10.0 g, 48.5 mmol) in DCM (80 mL) was added EtSH (16 mL) ) in an ice-water bath. The mixture was stirred at 0 ° C for 20 min before AlCl 3 (19.5 g, 0.15 mmol) was slowly added at 0 ° C. The mixture was stirred at 0 ° C for 30 min. The reaction mixture was poured into ice-water, the organic layer was separated and the aqueous phase was extracted with DCM (50 mL × 3). The combined organic layers were washed with H₂Oh, brine, dried over Na₂SO₄ and evaporated in vacuo to give 1- (4-hydroxyphenyl) cyclopropanecarboxylic acid methyl ester (8.9 g, 95%). ¹1 H NMR (400 MHz, CDCl₃) δ 7.20-7.17 (m, 2H), 6.75-6.72 (m, 2H), 5.56 (s, 1H), 3.63 (s, 3H), 1.60-1.57 (m, 2H), 1.17-1.15 (m, 2H).

Step b: 1- (4-Hydroxy-3,5-diiodophenyl) cyclopropanecarboxylic acid methyl ester To a solution of 1- (4-hydroxyphenyl) cyclopropanecarboxylic acid methyl ester (8.9 g, 46 mmol) in CH₃NIS (15.6 g, 69 mmol) was added CN (80 mL). The mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated and the residue was purified by silica gel column chromatography (petroleum ether / EtOAc 10: 1) to give 1- (4-hydroxy-3,5-diiodophenyl) cyclopropanecarboxylic acid methyl ester (3.5 g, 18%) .¹H NMR (400 MHz, CDCl3) δ 7.65 (s, 2H), 5.71 (s, 1H), 3.63 (s, 3H), 1.59-1.56 (m, 2 H), 1.15-1.12 (m, 2H).

Step c: 1- [3,5-Diiodo-4- (2-methylallyloxy) phenyl] cyclopropanecarboxylic acid methyl ester Mixture of 1- (4-hydroxy-3,5-diodophenyl) cyclopropanecarboxylic acid methyl ester (3.2 g, 7.2 mmol), 3-chloro-2-methylpropene (1.0 g, 11 mmol), K2CO3 (1.2 g, 8.6 mmol), NaI (0.1 g, 0.7 mmol) in acetone (20 mL) was stirred at 20 ° C overnight. The solid was filtered off and the filtrate was concentrated in vacuo to give 1- [3,5-diiodo-4- (2-methylallyloxy) phenyl] cyclopropanecarboxylic acid methyl ester (3.5 g, 97%). ¹H NMR (300 MHz, CDCk) δ 7.75 (s, 2H), 5.26 (s, 1H), 5.06 (s, 1H), 4.38 (s, 2H), 3 , 65 (s, 3H), 1.98 (s, 3H), 1.62-1.58 (m, 2h), 1.18-1.15 (m, 2H).

Step d: 1- (3,3-Dimethyl-2,3-dihydrobenzofuran-5-yl) cyclopropanecarboxylic acid methyl ester [0278] To a solution of 1- [3,5-Diodo-4- (2-methylallyloxy) acid ) phenyl-cyclopropanecarboxylic acid (3.5 g, 7.0 mmol) in toluene (1.5 ml) added Bu₃SnH (2.4 g, 8.4 mmol) and AIBN (0.1 g, 0.7 mmol). The mixture was heated to reflux overnight. The reaction mixture was concentrated in vacuo and the residue was purified by silica gel column chromatography (petroleum ether / EtOAc 20: 1) to give 1- (3,3-dimethyl-2,3-dihydrobenzofuran-5-yl) acid methyl ester cyclopropanecarboxylic (1.05 g, 62%).¹H NMR (400 MHz, CDCk) δ 7.10-7.07 (m, 2 h), 6.71 (d, J = 8 Hz, 1H), 4.23 (s, 2H), 3, 62 (s, 3H), 1.58-1.54 (m, 2H), 1.34 (s, 6H), 1.17-1.12 (m, 2H).

Step e: 1- (3,3-Dimethyl-2,3-dihydrobenzofuran-5-yl) cyclopropane carboxylic acid [0279] To a solution of 1- (3,3-dimethyl-2,3-dihydrobenzofuran-5-yl) cyclopropanecarboxylic acid methyl ester (1 g, 4 mmol) in MeOH (10 mL) LiOH (0.40 g,

9.5 mmol). The mixture was stirred at 40 ° C overnight. HCl (10%) was slowly added to adjust the pH of the mixture to pH 5. The resulting mixture was extracted with ethyl acetate (10 mL χ 3). The extracts were washed with brine and dried over Na₂SO₄. 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%).¹1 H NMR (400 MHz, CDCl₃) δ 7.11-7.07 (m, 2H), 6.71 (d, J = 8 Hz, 1H), 4.23 (s, 2H), 1.66-1.63 (m , 2H), 1.32 (s, 6H), 1.26-1.23 (m, 2H).

1. 2- (7-Methoxybenzo [d1 [1.31 dioxol-5-yl) acetonitrile [0280]

<img file="PL1945632T3_D0061.tif" />

Step a: 3,4-Dihydroxy-5-methoxybenzoate [0281] To a solution of 3,4,5-trihydroxybenzoic acid methyl ester (50 g, 0.27 mol) and Na₂B₄ABOUT₇ (50 g) in water (1000 ml) Me. Was successively added₂SO₄ (120 ml) and aqueous NaOH (25%, 200 ml) at room temperature. The mixture was stirred at room temperature for 6 h before it was cooled to 0 ° C. The mixture was acidified to pH ~ 2 by the addition of concentrated H₂SO₄and then filtered. The filtrate was extracted with EtOAc (500 mL χ 3). The combined organic layers were dried over anhydrous Na₂SO₄ and evaporated under reduced pressure to give methyl 3,4-dihydroxy-5-methoxybenzoate (15.3 g 47%), which was used without further purification in the next step.

Step b: Methyl 7-Methoxybenzo [d1 [1,31-dioxol-5-carboxylate] [0282] To a solution of methyl 3,4-dihydroxy-5-methoxybenzoate (15.3 g, 0.078 mol) in acetone (500 ml) was added CH₂BrCl (34.4 g, 0.27 mol) and K₂WHAT₃ (75 g, 0.54 mol) at 80 ° C. The resulting mixture was heated at reflux for 4 h. The mixture was cooled to room temperature and solid K2CO3 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 Na₂SO₄ and evaporated under reduced pressure to give a crude product which was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 10: 1) to obtain methyl 7-methoxybenzo [d1 [d1 [1,31-dioxole-5-carboxylate] 12.6 g, 80%). ¹H NMR (400 MHz, CDCk) δ 7.32 (s, 1H), 7.21 (s, 1H), 6.05 (s, 2H), 3.93 (s, 3H), 3 , 88 (s, 3H).

Step c: (7-Methoxybenzo [d1 [1,31-dioxol-5-yl) methanol. To a solution of methyl 7-methoxybenzo [d1 [1,31-dioxol-5-carboxylate (13.9 g, 0.040 mol) in THF ( 100 ml) LiAlH was added in portions₄ (3.1 g, 0.080 mol) at room temperature. The mixture was stirred for 3 h at room temperature. The reaction mixture was cooled to 0 ° C and successively treated with water (3.1 g) and NaOH (10%, 3.1 ml). The suspension was filtered and washed with THF. The combined filtrates were evaporated under reduced pressure to give (7-methoxybenzo [d1 [1,31-dioxol-5-yl) methanol (7.2 g, 52%).¹1 H NMR (400 MHz, CDCl₃) δ 6.55 (s, 1H), 6.54 (s, 1H), 5.96 (s, 2H), 4.57 (s, 2H), 3.90 (s, 3H).

Step d: 6- (Chloromethyl) -4-methoxybenzo [d1 [1,31-dioxol [0284] To SOCl solution₂ (150 ml) (7-methoxybenzo [d1 [1,31-dioxol-5-yl) methanol (9.0 g, 54 mmol) was added portionwise at 0 ° C. The mixture was stirred for 0.5 h. Excess SOCl₂evaporated under reduced pressure to give a crude product which was basified with saturated aqueous NaHCO₃ to pH ~ 7. The aqueous phase was extracted with EtOAc (100 mL χ 3). The combined organic layers were dried over anhydrous Na₂SO₄ and evaporated to give 6- (chloromethyl) -4-methoxybenzo [d1 [1,31-dioxol (10.2 g 94%), which was used without further purification in the next step. ¹1 H NMR (400 MHz, CDCl₃) δ 6.58 (s, 1H), 6.57 (s, 1H), 5.98 (s, 2H), 4.51 (s, 2H), 3.90 (s, 3H) ).

Step e: 2- (7-Methoxybenzo [d1 [1,31-dioxol-5-yl) acetonitrile [0285] To a solution of 6- (chloromethyl) -4-methoxybenzo [d1 [1,31-dioxol (10.2 g, 40 mmol) in DMSO (100 mL) NaCN (2.43 g, 50 mmol) was added at room temperature. The mixture was stirred for 3 h and poured into water (500 ml). The aqueous phase was extracted with EtOAc (100 mL χ 3). The combined organic layers were dried over anhydrous Na₂SO₄ and evaporated to give a crude product which was washed with ether to give 2- (7-methoxybenzo [d1 [1,31-dioxol-5-yl) acetonitrile (4.6 g, 45%). ¹H NMR (400 MHz, CDCl3) δ 6.49 (s, 2H), 5.98 (s, 2H), 3.91 (s, 3H), 3.65 (s, 2H). ¹³C NMR (400 MHz, CDCl3) δ 148.9, 143.4, 134.6, 123.4, 117.3, 107.2, 101.8, 101.3, 56.3, 23.1.

J. 1- (Benzofuran-5-yl) cyclopropane carboxylic acid [0286]

<img file="PL1945632T3_D0062.tif" />

Step a: 1- [4- (2,2-diethoxyethoxy) phenyl1-cyclopropanecarboxylic acid [0287] To a solution of 1- (4-hydroxyphenyl) cyclopropanecarboxylic acid methyl ester (15.0 g, 84.3 mmol) in DMF (50 mL) while stirring, sodium hydride (6.7 g, 170 mmol, 60% in mineral oil) was added at 0 ° C. After the evolution of hydrogen ceased, 2-bromo-1,1-diethoxyethane (16.5 g, 84.3 mmol) was added dropwise to the reaction mixture. The reaction mixture was stirred at 160 ° C for 15 hours. The reaction mixture was poured into ice (100 g) and extracted with CH₂cl₂. The combined organics were dried over Na₂SO₄. The solvent was evaporated in vacuo to give crude 1- [4- (2,2-diethoxyethoxy) phenyl 1-cyclopropanecarboxylic acid (10 g) which was used directly in the next step without purification.

Step b: 1-Benzofuran-5-ylcyclopropanecarboxylic acid To a suspension of crude 1- [4- (2,2-diethoxyethoxy) phenyl1-cyclopropanecarboxylic acid (20 g, ~ 65 mmol) in xylene (100 ml) was added PPA (22, 2 g, 64.9 mmol) at room temperature. The mixture was heated to reflux (140 ° C) for 1 hour, then cooled to room temperature and decanted from PPA. The solvent was evaporated in vacuo to give a crude product which was purified by preparative HPLC to give 1- (benzofuran-5-yl) cyclopropanecarboxylic acid (1.5 g, 5%). ¹H NMR (400 MHz, DMSO-J5) δ 12.25 (br s, 1H), 7.95 (d, J = 2.8 Hz, 1H), 7.56 (d, J = 2.0 Hz, 1H), 7.47 (d, J = 11.6 Hz, 1H), 7.25 (dd, J = 2.4, 11.2 Hz, 1H), 6.89 (d, J = 1.6 Hz, 1H), 1.47-1.44 (m, 2H), 1.17-1.14 (m, 2H).

K. 1- (2,3-dihydrobenzofuran-5-yl) cyclopropanecarboxylic acid [0289]

<img file="PL1945632T3_D0063.tif" />

[0290] To a solution of 1- (benzofuran-5-yl) cyclopropanecarboxylic acid (700 mg, 3.47 mmol) in MeOH (10 mL) was added PtO₂ (140 mg, 20%) at room temperature. The reaction mixture was hydrogenated with hydrogenation (1 atm) at 10 ° C for 3 days with stirring. The reaction mixture was filtered. The solvent was evaporated in vacuo to give a crude product which was purified by preparative HPLC to give 1- (2,3-dihydrobenzofuran-5-yl) cyclopropanecarboxylic acid (330 mg, 47%).¹H NMR (400 MHz, CDCh) δ 7.20 (s, 1H), 7.10 (d, J =

10.8 Hz, 1H), 6.73 (d, J = 1.2 Hz, 1H), 4.57 (t, J = 11.6 Hz, 2H), 3.20 (t, J = 11.6 Hz, 2H), 1.67-1.63 (m, 2H), 1.25-1.21 (m, 2H).

L. 2- (2,2-Dimethylbenzo [d] [1,3] dioxol-5-yl) acetonitrile [0291]

<img file="PL1945632T3_D0064.tif" />

Step a: (3,4-Dihydroxyphenyl) acetonitrile [0292] To a solution of benzo [1,3] dioxol-5-ylacetonitrile (0.50 g, 3.1 mmol) in CH₂cl₂(15 ml) BBr3 (0.78 g, 3.1 mmol) was added dropwise at -78 ° C under N2. The mixture was slowly warmed to room temperature and stirred overnight. To quench the reaction, H2O (10 mL) was added and the CH2Cl2 layer was separated. The aqueous phase was extracted with CH2Cl2 (2 χ 7 mL). The combined organics were washed with brine, dried over Na₂SO₄ and purified by silica gel column chromatography (petroleum ether / EtOAc 5: 1) to afford (3,4-dihydroxyphenyl) acetonitrile (0.25 g, 54%) as a white solid. ¹H NMR (DMSO- &lt;A, 400 MHz) δ 9.07 (s, 1H),

8.95 (s, 1H), 6.68-6.70 (m, 2H), 6.55 (dd, J = 8.0, 2.0 Hz, 1H), 3.32 (s , 2H).

Step b: 2- (2,2-Dimethylbenzo [d] [1,3] dioxol-5-yl) acetonitrile [0293] To a solution of (3,4-dihydroxyphenyl) acetonitrile (0.2 g, 1.3 mmol) in toluene (4 mL), 2,2-dimethoxypropane (0.28 g, 2.6 mmol) and TsOH (0.010 g, 0.065 mmol) were added. The mixture was heated to reflux overnight. The reaction mixture was evaporated to remove the solvent and the residue was dissolved in ethyl acetate. The organic layer was washed with NaHCO3 solution, H2O, brine and dried over Na2SO4. The solvent was evaporated under reduced pressure to give a residue, which was purified by silica gel column chromatography (petroleum ether / EtOAc 10: 1) to give 2- (2,2-dimethylbenzo [d] [1,3] dioxol-5-yl ) acetonitrile (40 mg, 20%).¹1 H NMR (CDCl₃, 400 MHz) δ 6.68-6.71 (m, 3 h), 3.64 (s, 2 H), 1.67 (s, 6 H).

M. 2- (3- (Benzyloxy) -4-chlorophenyl) acetonitrile [0294]

100

<img file="PL1945632T3_D0065.tif" />

Step a: (4-Chloro-3-hydroxyphenyl) acetonitrile [0295] BBr₃ (16.6 g, 66 mmol) was slowly added to a solution of 2- (4-chloro-3-methoxyphenyl) acetonitrile (12 g, 66 mmol) in DCM (120 mL) at -78 ° C under N₂. The temperature of the reaction mixture was slowly raised to room temperature. The reaction mixture was stirred overnight, then poured into ice and water. The organic layer was separated and the aqueous layer was extracted with DCM (40 mL × 3). The combined organic layers were washed with water, brine, dried over Na₂SO₄ and concentrated in vacuo to give (4-chloro-3-hydroxyphenyl) acetonitrile (9.3 g, 85%). ¹H NMR (300 MHz, CDCl3) δ 7.34 (d, J = 8.4 Hz, 1H), 7.02 (d, J = 2.1 Hz, 1H), 6.87 (dd, J = 2.1, 8.4 Hz, 1H), 5.15 (brs, 1H), 3.72 (s, 2H).

Step b: 2- (3- (Benzyloxy) -4-chlorophenyl) acetonitrile [0296] To a solution of (4-chloro-3-hydroxyphenyl) acetonitrile (6.2 g, 37 mmol) in CH₃CN (80 mL) was added K2CO3 (10.2 g, 74 mmol) and BnBr (7.6 g, 44 mmol). The mixture was stirred at room temperature overnight. The solids were filtered off and the filtrate was evaporated in vacuo. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate 50: 1) to give 2- (3- (benzyloxy) -4-chlorophenyl) acetonitrile (5.6 g, 60%).¹H NMR (400 MHz, CDCl3) δ 7.4877,32 (m, 6H), 6.94 (d, J = 2 Hz, 2 H), 6.86 (dd, J = 2.0, 8.4 Hz , 1H), 5.18 (s, 2H), 3.71 (s, 2H).

N. 2- (Quinoxalin-6-yl) acetonitrile [0297]

<img file="PL1945632T3_D0066.tif" />

Step a: 6-Methylquinoxaline [0298] To a solution of 4-methylbenzene-1,2-diamine (50.0 g, 0.41 mol) in isopropanol (300 ml) was added a solution of glyoxal (40% in water, 65.3 g , 0.45 mol) at room temperature. The reaction mixture was heated at 80 ° C for 2 hours and evaporated in vacuo to give 6-methylquinoxaline (55 g, 93%), which was used directly in the next step.¹H NMR (300 MHz, CDCl₃) δ 8.77 (dd, J = 1.5, 7.2 Hz, 2H), 7.99 (d, J = 8.7 Hz, 1H), 7.87 (s, 1H), 7.60 (dd, J = 1.5, 8.4 Hz, 1H), 2.59 (s, 3H). Step b: 6-Bromomethylquinoxaline [0299] To a solution of 6-methylquinoxaline (10.0 g, 69.4 mmol) in CCl4 (80 ml) was added NBS (13.5 g, 76.3 mmol) and benzoyl peroxide (BP, 1.7 g, 6.9 mmol) at room temperature. The mixture was heated to reflux for 2 hours. After cooling, the mixture was evaporated in vacuo to give a yellow solid which was extracted with petroleum ether (50 mL × 5). The extracts were concentrated in vacuo. The organics were combined and concentrated to give crude 6-bromomethylquinoxaline (12.0 g), which was used directly in the next step.¹H NMR (300 MHz, CDCl₃) δ 8.85-8.87 (m, 2H), 8.10-8.13 (m, 2H), 7.82 (dd, J = 2.1, 8.7 Hz, 1H) , 4.70 (s, 2H).

Step c: 2- (Quinoxalin-6-yl) acetonitrile [0300] To a solution of crude 6-bromomethylquinoxaline (36.0 g) in 95% ethanol (200 mL) was added NaCN (30.9 g, 0.63 mol) in room temperature. The mixture was heated

101 at 50 ° C for 3 hours and then concentrated in vacuo. Water (100 ml) and ethyl acetate (100 ml) were added. The organic layer was separated and the aqueous layer was extracted with ethyl acetate. The combined organics were washed with brine, dried over Na2SO4 and concentrated in vacuo. The residue was purified using a silica gel column (petroleum ether / EtOAc 10: 1) to give 2- (quinoxalin-6-yl) acetonitrile (7.9 g, 23% for two steps).^JH NMR (300 MHz, CDCl₃) δ 8.88-8.90 (m, 2H), 8.12-8.18 (m, 2H), 7.74 (dd, J = 2.1, 8.7 Hz, 1H) , 4.02 (s, 2H). MS (ESI) m / z (m + H) + 170.0.

O. 2- (Chinolin-6-yl) acetonitrile [0301]

<img file="PL1945632T3_D0067.tif" />

Step a: 6-Bromomethylquinoline [0302] To a solution of 6-methylquinoline (2.15 g, 15.0 mmol) in CCl4 (30 mL) was added NBS (2.92 g, 16.5 mmol) and benzoyl peroxide (BP, 0.36 g, 1.5 mmol) at room temperature. The mixture was heated to reflux for 2 hours. After cooling, the mixture was evaporated in vacuo to give a yellow solid, which was extracted with petroleum ether (30 ml χ 5). The extracts were concentrated in vacuo to give crude 6-bromomethylquinoline (1.8 g), which was used directly in the next step.

Step b: 2- (Quinolin-6-yl) acetonitrile [0303] To a solution of crude 6-bromomethylquinoline (1.8 g) in 95% ethanol (30 mL) was added NaCN (2.0 g, 40.8 mmol) in room temperature. The mixture was heated at 50 ° C for 3 hours and then concentrated in vacuo. Water (50 ml) and ethyl acetate (50 ml) were added. The organic layer was separated and the aqueous layer was extracted with ethyl acetate. The combined organics were washed with brine, dried over Na2SO4 and concentrated in vacuo. The combined crude product was purified using a column (petroleum ether / EtOAc 5: 1) to give 2- (quinolin-6-yl) acetonitrile (0.25 g, 8% for two steps). 1 H NMR (300 MHz, CDCl₃) δ 8.95 (dd, J = 1.5, 4.2 Hz, 1H), 8.128.19 (m, 2H), 7.85 (s, 1H), 7.62 (dd, J = 2.1, 8.7 Hz, 1H), 7.46 (q, J = 4.2 Hz, 1H), 3.96 (s, 2H). MS (ESI) m / e (M + H) + 169.0.

P. 2- (2,3-Dihydrobenzo [b] [1,4] dioxin-6-yl) acetonitrile [0304]

<img file="PL1945632T3_D0068.tif" />

Step a: 2,3-dihydrobenzo [1,4] dioxine-6-carboxylic acid ethyl ester [0305] To a suspension of Cs2CO3 (270 g, 1.49 mol) in DMF (1000 ml), 3,4- acid ethyl ester dihydroxybenzoate (54.6 g, 0.3 mole) and 1,2-dibromoethane (54.3 g, 0.29 mole) 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 χ 3). The combined organic layers were washed with water (200 ml χ 3) and brine (100 ml), dried over Na₂SO₄ and concentrated to dryness. The residue was purified using a silica gel column (petroleum ether / ethyl acetate 50: 1) to give 2,3-dihydrobenzo [1,4] dioxine-6-carboxylic acid ethyl ester (18 g, 29%). 1 H NMR (300 MHz, CDCl₃) δ 7.53 (dd, J = 1.8, 7.2 Hz, 2H), 6.84-6.87 (m, 1H), 4.22-4.34 (m, 6H) , 1.35 (t, J = 7.2 Hz, 3H).

102

Step b: (2,3-Dihydrobenzo [1,4] dioxin-6-yl) methanol [0306] To a suspension of LAH (2.8 g, 74 mmol) in THF (20 mL), a solution of 2.3 acid ethyl ester was added dropwise. dihydrobenzo [1,4] dioxine-6-carboxyl (15 g, 72 mmol) in THF (10 mL) at 0 ° C under N₂. The mixture was stirred at room temperature for 1 h, then water (2.8 mL) and NaOH (10%, 28 mL) were carefully added while cooling. The precipitate was filtered off and the filtrate was evaporated to dryness to afford (2,3-dihydrobenzo [1,4] dioxin-6-yl) methanol (10.6 g).^JH NMR (300 MHz, DMSO-de) δ 6.73-6.78 (m, 3H), 5.02 (t, J = 5.7 Hz, 1H), 4.34 (d, J = 6.0 Hz, 2H), 4.174.20 (m, 4H).

Step c: 6-Chloromethyl-2,3-dihydrobenzo [1,4] dioxine [0307] A mixture of (2,3-dihydrobenzo [1,4] dioxin-6-yl) methanol (10.6 g) in SOCl₂ (10 ml) was stirred at room temperature for 10 min and then poured into ice-water. The organic layer was separated and the aqueous phase extracted with dichloromethane (50 mL χ 3). The combined organic layers were washed with NaHCO3 (saturated solution), water and brine, dried over Na2SO4 and concentrated to dryness to give 6-chloromethyl2,3-dihydrobenzo [1,4] dioxine (12 g, 88% for two steps), which was used directly in the next stage.

Step d: 2- (2,3-Dihydrobenzo [b] [1,4] dioxin-6-yl) acetonitrile [0308] A mixture of 6-chloromethyl-2,3-dihydrobenzo [1,4] dioxine (12.5 g , 67.7 mmol) and NaCN (4.30 g, 87.8 mmol) in DMSO (50 mL) was stirred at RT for 1 h. The mixture was poured into water (150 mL), followed by extraction with dichloromethane (50 mL χ 4 ). The combined organic layers were washed with water (50 ml χ 2) and brine (50 ml), dried over Na₂SO₄ and concentrated to dryness. The residue was purified using a silica gel column (petroleum ether / ethyl acetate 50: 1) to give 2- (2,3-dihydrobenzo [b] [1,4] dioxin-6-yl) acetonitrile as a yellow oil (10 , 2 g, 86%).^JHNMR (300 MHz, CDCl₃) δ 6.78-6.86 (m, 3H), 4.25 (s, 4H), 3.63 (s, 2H).

Q. 2- (2,2,4,4-Tetrafluoro-4H-benzo [d] [1,3] dioxin-6-yl) acetonitrile [0309]

<img file="PL1945632T3_D0069.tif" />

Step a: 2,2,4,4-tetrafluoro-4H-benzo [1,3] dioxin-6-carboxylic acid methyl ester [0310] Suspension of 6-bromo-2,2,4,4-tetrafluoro-4H-benzo [1,3] dioxins (4.75 g, 16.6 mmol) and Pd (PPh3) 4 (950 mg, 8.23 ​​mmol) in MeOH (20 ml), MeCN (30 ml) and Et3N (10 ml) stirred under carbon monoxide (55 psi) atmosphere at 75 ° C (oil bath temperature) overnight. The cooled reaction mixture was filtered and the filtrate was concentrated. The residue was purified using a silica gel column (petroleum ether) to give 2,2,4,4-tetrafluoro-4H-benzo [1,3] dioxine-6-carboxylic acid methyl ester (3.75 g, 85%) . ^J1 H NMR (CDCl₃, 300 MHz) δ 8.34 (s, 1H), 8.26 (dd, J = 2.1, 8.7 Hz, 1H), 7.22 (d, J = 8.7 Hz, 1 H), 3.96 (s, 3H).

Step b: (2,2,4,4-Tetrafluoro-4H-benzo [1,3] dioxin-6-yl) methanol [0311] To a suspension of LAH (2.14 g, 56.4 mmol) in anhydrous THF ( 200 ml), a solution of 2,2,4,4-tetrafluoro-4H-benzo [1,3] dioxine-6-carboxylic acid methyl ester (7.50 g, 28.2 mmol) in anhydrous THF (50 ml) at 0 ° was added dropwise. C. The reaction mixture was stirred at 0 ° C for 1 h before it was treated with water (2.14 g) and 10%

NaOH (2.14 mL). The suspension was filtered and washed with THF. The combined filtrates were evaporated to dryness to afford crude (2,2,4,4-tetrafluoro-4Hbenzo [1,3] dioxin-6-yl) methanol (6.5 g), which was used directly in the next step.¹1 H NMR (CDCl₃, 300 MHz) δ 7.64 (s, 1H), 7.57-7.60 (m, 1H), 7.58 (d, J = 8.7 Hz,

H), 4.75 (s, 2H).

Step c: 6-Chloromethyl-2,2,4,4-tetrafluoro-4H-benzo [1,3] dioxine [0312] A mixture of (2,2,4,4-tetrafluoro-4H-benzo [1,3] dioxin -6-yl) methanol (6.5 g) in thionyl chloride (75 mL) was heated to reflux overnight. The resulting mixture was concentrated in vacuo. The residue was basified with saturated aqueous NaHCO3 solution. The aqueous layer was extracted with dichloromethane (50 mL χ 3). The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure to give 6-chloromethyl-2,2,4,4-tetrafluoro-4H-benzo [1,3] dioxine (6.2 g), which was used directly in the next stage. ¹1 H NMR (CDCl₃, 300 MHz) δ 7.65 (s, 1H), 7.61 (dd, J = 2.1, 8.7 Hz, 1H), 7.15 (d, J = 8.4 Hz, 1 H), 4.60 (s, 2H).

Step d: (2,2,4,4-Tetrafluoro-4H-benzo [1,3] dioxin-6-yl) acetonitrile [0313] A mixture of 6-chloromethyl-2,2,4,4-tetrafluoro-4H-benzo [1,3] dioxins (6.2 g) and NaCN (2.07 g, 42.3 mmol) in DMSO (50 mL) were stirred at room temperature for

h. The reaction mixture was poured into ice and extracted with EtOAc (50 mL χ 3). The combined organic layers were dried over anhydrous Na2SO4 and evaporated to give the crude product which was purified using a silica gel column (petroleum ether / EtOAc 10: 1) to give (2,2-difluorobenzo [1,3] dioxol-5-yl ) acetonitrile (4.5 g, 68% for 3 steps).¹1 H NMR (CDCl₃, 300 MHz) δ 7.57-7.60 (m, 2H), 7.20 (d, J = 8.7 Hz, 1H), 3.82 (s, 2H).

R. 2- (4H-Benzo [d] [1,3] dioxin-7-yl) acetonitrile [0314]

<img file="PL1945632T3_D0070.tif" />

<img file="PL1945632T3_D0071.tif" />

Step a: (3-Hydroxyphenyl) acetonitrile [0315] To a solution of (3-methoxyphenyl) acetonitrile (150 g, 1.03 mol) in CH₂cl₂ (1000 ml) BBr was added dropwise₃ (774 g, 3.09 mol) at -70 ° C. The mixture was stirred and slowly warmed to room temperature. Water (300 ml) was added at 0 ° C. The resulting mixture was extracted with CH₂cl₂. The combined organic layers were dried over anhydrous Na₂SO₄, filtered and evaporated in vacuo. The crude residue was purified using a column (petroleum ether / EtOAc 10: 1) to give (3-hydroxyphenyl) acetonitrile (75.0 g, 55%).¹1 H NMR (CDCl₃, 300 MHz) δ 7.18-7.24 (m, 1H), 6.79-6.84 (m, 3H), 3.69 (s, 2H).

Step b: 2- (4H-Benzo [d] [1,3] dioxin-7-yl) acetonitrile [0316] To a solution of (3-hydroxyphenyl) acetonitrile (75.0 g, 0.56 mol) in toluene (750 ml) paraformaldehyde (84.0 g, 2.80 mol) and toluene-4-sulfonic acid monohydrate (10.7 g, 56.0 mmol) were added at room temperature. The reaction mixture was heated at reflux for 40 minutes. Toluene was removed by evaporation. Water (150 ml) and ethyl acetate (150 ml) were added. The organic layer was separated and the aqueous layer was extracted with ethyl acetate. The combined organics were washed with brine, dried over anhydrous Na2SO4 and evaporated in vacuo. The residue was separated by preparative HPLC to give 2- (4H-benzo [d] [1,3] dioxin-7-yl) acetonitrile (4.7 g, 5%).¹H NMR (300 MHz, CDCl₃) δ 6.85-6.98 (m, 3H), 5.25 (d, J = 3.0 Hz, 2H), 4.89 (s, 2H), 3.69 (s, 2 H).

S. 2- (4H-Benzo [d] [1,3] dioxin-6-yl) acetonitrile [0317]

104

<img file="PL1945632T3_D0072.tif" />

[0318] To a solution of (4-hydroxyphenyl) acetonitrile (17.3 g, 0.13 mol) in toluene (350 mL) was added paraformaldehyde (39.0 g, 0.43 mmol) and toluene-4-sulfonic acid monohydrate (2, 5 g, 13 mmol) at room temperature. The reaction mixture was heated at reflux for 1 hour. Toluene was removed by evaporation. Water (150 ml) and ethyl acetate (150 ml) were added. The organic layer was separated and the aqueous layer was extracted with ethyl acetate. The combined organics were washed with brine, dried over Na₂SO₄ and evaporated in vacuo. The residue was separated by preparative HPLC to give 2- (4Hbenzo [d1 [1,31-dioxo-6-yl) acetonitrile (7.35 g, 32%).¹1 H NMR (400 MHz, CDCl₃) δ 7.0710 7.11 (m, 1H), 6.95-6.95 (m, 1H), 6.88 (d, J = 11.6 Hz, 1H), 5.24 ( s, 2H), 4.89 (s, 2H),

3.67 (s, 2H).

T. 2- (3- (Benzyloxy) -4-methoxyphenyl) acetonitrile [0319]

<img file="PL1945632T3_D0073.tif" />

[0320] To a suspension of t-BuOK (20.15 g, 0.165 mol) in THF (250 ml) was added a solution of To15 sMIC (16.1 g, 82.6 mmol) in THF (100 ml) at -78 ° C. The mixture was stirred for 15 minutes, a solution of 3-benzyloxy-4-methoxybenzaldehyde (10.0 g, 51.9 mmol) in THF (50 mL) was added dropwise and stirring was continued for 1.5 hours at -78 ° C. Methanol (50 mL) was added to the cooled reaction mixture. The mixture was heated to reflux for 30 minutes. The solvent of the reaction mixture was removed to give the crude product, which was dissolved in water (300 ml). The aqueous phase was extracted with EtOAc (100 mL χ 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 / EtOAc 10: 1) to give 2- (3- (benzyloxy) -4-methoxyphenyl) acetonitrile (5, 0 g, 48%).

¹H NMR (300 MHz, CDCC) δ 7.48-7.33 (m, 5H), 6.89-6.86 (m, 3H), 5.17 (s, 2H), 3.90 (s, 3H), 3.66 (s, 2H). ¹³C NMR (75 MHz, CDCC) δ 149.6, 148.6, 136.8, 128.8, 128.8,

128,2, 127,5, 127,5, 122,1, 120,9, 118,2, 113,8, 112,2, 71,2, 56,2, 23,3.

[0321] The following Table 2 lists the commercially available or prepared by one of the methods described above carboxylic acid building blocks:

Table 2: Carboxylic acid building blocks

<td>Relationship</td><td>Name</td>

<td>A-1</td><td>1-Benzo [1,31-dioxol-5-ylcyclopropane-1-carboxylic acid</td>

<td>A-2</td><td>1- (2,2-difluorobenzo [1,31-dioxol-5-yl) cyclopropane-1-carboxylic acid</td>

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

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

<td>A-5</td><td>1- (2-methoxyphenyl) cyclopropane-1-carboxylic acid</td>

<td>A-6</td><td>1- [4- (Trifluoromethoxy) phenyl 1-cyclopropane-1-carboxylic acid</td>

<td>A-8</td><td>Tetrahydro-4- (4-methoxyphenyl) -2H-pyran-4-carboxylic acid</td>

<td>A-9</td><td>1-phenylcyclopropane-1-carboxylic acid</td>

<td>A-10</td><td>1- (4-methoxyphenyl) cyclopropane-1-carboxylic acid</td>

105

<td>Relationship</td><td>Name</td>

<td>A-11</td><td>1- (4-chlorophenyl) cyclopropane-1-carboxylic acid</td>

<td>A-13</td><td>1-phenylcyclopentanecarboxylic acid</td>

<td>A-14</td><td>1-phenylcyclohexane carboxylic acid</td>

<td>A-15</td><td>1- methoxyphenyl cyclopentanecarboxylic acid</td>

<td>A-16</td><td>1- (4-methoxyphenyl) cyclohexanecarboxylic acid</td>

<td>A-17</td><td>1- (4-chlorophenyl) cyclohexanecarboxylic acid</td>

<td>A-18</td><td>1- (2,3-dihydrobenzo [b] [1,4] dioxyl-yl-cyclopropanecarboxylic acid</td>

<td>A-19</td><td>1- (4H-benzo [d] [1,3] dioxin-7-yl) cyclopropanecarboxylic acid</td>

<td>A-20</td><td>1- (2,2,4,4-tetrafluoro-4H-benzo [d] [1,3] dioxin-6-yl) cyclopropanecarboxylic acid</td>

<td>A-21</td><td>1- (4H-benzo [d] [1,3] dioxin-6-yl) cyclopropanecarboxylic acid</td>

<td>A-22</td><td>1- (Quinoxalin-6-yl) cyclopropane carboxylic acid</td>

<td>A-23</td><td>1- (quinolin-6-yl) cyclopropane carboxylic acid</td>

<td>A-24</td><td>1- chlorophenyl cyclopentanecarboxylic acid</td>

<td>A-25</td><td>1- (Benzofuran-5-yl) cyclopropane carboxylic acid</td>

<td>A-26</td><td>1- (4-Chloro-3-methoxyphenyl) cyclopropane carboxylic acid</td>

<td>A-27</td><td>1- (3- (Hydroxymethyl ^ -methoxyphenyl) cyclopropanecarboxylic acid</td>

<td>A-28</td><td>1- (2,3-dihydrobenzofuran-5-yl) cyclopropanecarboxylic acid</td>

<td>A-29</td><td>1- (3-Fluoro-4-methoxyphenyl) cyclopropane carboxylic acid</td>

<td>A-30</td><td>1- (3-Chloro-4-methoxyphenyl) cyclopropane carboxylic acid</td>

<td>A-31</td><td>1- (3-hydroxy-4-methoxyphenyl) cyclopropane carboxylic acid</td>

<td>A-32</td><td>1- (4-hydroxy-3-methoxyphenyl) cyclopropane carboxylic acid</td>

<td>A-33</td><td>1- (2,2-dimethylbenzo [d] [1,3] dioxol-5-yl) cyclopropanecarboxylic acid</td>

<td>A-34</td><td>1- (3,3-dimethyl-2,3-dihydrobenzofuran-5-yl) cyclopropanecarboxylic acid</td>

<td>A-35</td><td>1- (7-methoxybenzo [d] [1,3] dioxol-5-yl) cyclopropanecarboxylic acid</td>

<td>A-36</td><td>1- (4-Chloro-3-hydroxyphenyl) cyclopropane carboxylic acid</td>

<td>A-37</td><td>1- (4-methoxy-3-methylphenyl) cyclopropane carboxylic acid</td>

<td>A-38</td><td>1- (3- (benzyloxy) -4-chlorophenyl) cyclopropanecarboxylic acid</td>

<td>A-45</td><td>1- (4-methoxy-3- (methoxymethyl) phenyl) cyclopropanecarboxylic acid</td>

U. 6-Chloro-5-methylpyridin-2-amine [0322]

<img file="PL1945632T3_D0074.tif" />

106

Step a: 2,2-Dimethyl-A- (5-methylpyridin-2-yl) propionamide [0323] To a solution of 5-methylpyridin-2-amine (200 g, 1.85 mol) in anhydrous CH₂Cl2 (1000 ml) solution Et. dropwise with stirring₃N (513 ml, 3.70 mol) and 2,2-dimethylpropionyl chloride (274 ml, 2.22 mol) at 0 ° C under N₂. The ice bath was removed and stirring was continued at room temperature for 2 hours. The reaction mixture was poured into ice (2000 g). The organic layer was separated and the remaining aqueous layer was extracted with CH₂cl₂ (3X). The combined organics were dried over Na₂SO₄ and evaporated to give 2,2-dimethyl-Y- (5-methylpyridin-2-yl) propionamide (350 g), which was used without further purification in the next step. ¹1 H NMR (400 MHz, CDCl₃) δ 8.12 (d, J = 8.4 Hz, 1H), 8.06 (d, J = 1.2 Hz, 1H), 7.96 (s, 1H), 7.49 ( dd, J = 1.6, 8.4 Hz, 1H), 2.27 (s, 1H), 1.30 (s, 9H).

Step b: 2,2-Dimethyl-A- (5-methyl-1-oxypyridin-2-yl) propionamide [0324] To a solution of 2,2-dimethyl-Y- (5-methylpyridin-2-yl) propionamide (100 g, 0.52 mol) in AcOH (500 ml) 30% H was added dropwise with stirring₂ABOUT₂ (80 ml, 2.6 mol) at room temperature. The mixture was stirred at 80 ° C for 12 hours. The reaction mixture was evaporated in vacuo to give 2,2-dimethyl-A- (5-methyl-1-oxypyridin-2-yl) propionamide (80 g, 85% purity).¹1 H NMR (400 MHz, CDCl₃) δ 10.26 (br s, 1H), 8.33 (d, J = 8.4 Hz, 1H), 8.12 (s, 1H), 7.17 (dd, J = 0, 8.8.8 Hz, 1H), 2.28 (s, 1H), 1.34 (s, 9H).

Step c: Y- (6-Chloro-5-methylpyridin-2-yl) -2,2-dimethylpropionamide [0325] To solution of 2,2-dimethyl-Y- (5-methyl-1-oxypyridin-2-yl) propionamide (10 g, 48 mmol) in anhydrous CH2Cl2 (50 mL) with stirring, Et3N (60 mL, 240 mmol) was added at room temperature. After stirring for 30 min, POCl3 (20 mL) was added dropwise to the reaction mixture. The reaction mixture was stirred at 50 ° C for 15 hours. The reaction mixture was poured into ice (200 g). The organic layer was separated and the remaining aqueous layer was extracted with CH2Cl2 (3x). The combined organics were dried over Na2SO4. The solvent was evaporated in vacuo to give a crude product which was purified by chromatography (petroleum ether / EtOAc 100: 1) to give A- (6-chloro-5-methylpyridin-2-yl) -2,2-dimethylpropionamide (0 , 5 g, 5%).¹1 H NMR (400 MHz, CDCl₃) δ 8.09 (d, J = 8.0 Hz, 1H), 7.94 (br s, 1H), 7.55 (d, J =

8.4 Hz, 1H), 2.33 (s, 1H), 1.30 (s, 9H).

Step d: 6-Chloro-5-methylpyridin-2-ylamine [0326] To A- (6-chloro-5-methylpyridin-2-yl) -2,2-dimethylpropionamide (4.00 g, 17.7 mmol) 6 N HCl (20 mL) was added at room temperature. The mixture was stirred at 80 ° C for 12 hours. The reaction mixture was basified by the dropwise addition of saturated NaHCO₃ to pH 8-9, and then the mixture was extracted with CH₂cl₂ (3X). The organic phases were dried over Na₂SO₄ and evaporated in vacuo to give 6-chloro-5-methylpyridin-2-ylamine (900 mg, 36%). ¹1 H NMR (400 MHz, CDCl₃) δ 7.28 (d, J = 8.0 Hz, 1H), 6.35 (d, J = 8.0 Hz, 1H), 4.39 (br s, 2H), 2.22 (s, 3H). MS (ESI) m / z: 143 (M + H +).

V. 6-Chloro-5- (trifluoromethyl) pyridin-2-amine [0327]

<img file="PL1945632T3_D0075.tif" />

[0328] 2,6-Dichloro-3- (trifluoromethyl) pyridine (5.00 g, 23.2 mmol) and 28% aqueous ammonia (150 mL) were placed in a 250 mL autoclave. The mixture was heated at 93 ° C for 21h. The reaction mixture was cooled to rt and extracted with EtOAc (100 mL × 3). The combined organic extracts were dried over anhydrous Na₂SO₄ and evaporated in vacuo to give a crude product which was purified by method

107 silica gel column chromatography (2-20% EtOAc in petroleum ether as eluant) to give 6-chloro-5- (trifluoromethyl) pyridin-2-amine (2.1 g, 46% yield). ¹H NMR (400 MHz, DMSO-A) δ 7.69 (d, J = 8.4 Hz, 1H), 7.13 (br s, 2H), 6.43 (d, J = 8.4 Hz, 1H). MS (ESI) m / z (M + H) + 197.2

General Procedure IV: Coupling reactions [0329]

<img file="PL1945632T3_D0076.tif" />

Hal = Cl, Br, I, all other variables. Ring A is the ring formed by R₃ and R '₃. X = C or N [0330] One equivalent of the corresponding carboxylic acid was placed in an oven-dried flask under a nitrogen atmosphere. Thionyl chloride (3 equivalents) and a catalytic amount of Α, Α-dimethylformamide were added and the solution was allowed to stir at 60 ° C for 30 minutes. Excess thionyl chloride was removed in vacuo and the resulting solid suspended in a minimum amount of anhydrous pyridine. This solution was slowly added with stirring to the solution of one equivalent of the corresponding aminoheterocyclic compound dissolved in the minimum amount of anhydrous pyridine. The resulting mixture was allowed to stir for 15 hours at 110 ° C. The mixture was evaporated to dryness, suspended in dichloromethane and then extracted three times with 1 N NaOH. The organic layer was then dried over sodium sulfate, evaporated to dryness and then purified by column chromatography.

W. 1- (Benzo [d] [1,3] dioxol-5-yl) -A- (5-bromopyridin-2-yl) cyclopropanecarboxamide and BJJ [0331]

<img file="PL1945632T3_D0077.tif" />

[0332] 1-Benzo [1,3] dioxol-5-ylcyclopropanecarboxylic acid (2.38 g, 11.5 mmol) was placed in an oven-dried flask under a nitrogen atmosphere. Thionyl chloride (2.5 mL) and A, A-dimethylformamide (0.3 mL) were added and the solution was allowed to stir for 30 minutes at 60 ° C. Excess thionyl chloride was removed in vacuo and the resulting solid suspended in 7 mL anhydrous pyridine. The solution was then slowly added to a solution of 5-bromopyridin-2-ylamine (2.00 g, 11.6 mmol) suspended in 10 mL of anhydrous pyridine. The resulting mixture was allowed to stir for 15 hours at 110 ° C. The mixture was then evaporated to dryness, suspended in 100 ml of dichloromethane and washed three times with 25 ml portions of 1 N NaOH. The organic layer was dried over sodium sulfate, evaporated to near dryness and then purified by column chromatography on silica gel using dichloromethane as the eluent to give pure product (3.46 g, 83%) ESI-MS m / z calculated 361 , 2, found 362.1 (M + 1) +; Retention time 3.40 minutes.¹H NMR (400 MHz, DMSO-A) δ 1.06-1.21 (m, 2H), 1.44-1.51 (m, 2H), 6.07 (s, 2H), 6.93- 7.02 (m, 2H), 7.10 (d, J = 1.6 Hz, 1H), 8.02 (d, J = 1.6 Hz, 2H), 8.34 (s, 1H), 8.45 (s, 1H).

1- (Benzo [^] [1,3] dioxol-6-yl) -A- (6-bromopyridin-2-yl) cyclopropanecarboxamide (B2) [0333]

108

<img file="PL1945632T3_D0078.tif" />

[0334] (1-Benzo [1,3] dioxol-5-ylcyclopropanecarboxylic acid (1.2 g, 5.8 mmol) was placed in an oven-dried flask under a nitrogen atmosphere. Thionyl chloride (2.5 mL) and A were added , A-dimethylformamide (0.3 mL) and the solution were allowed to stir at 60 ° C for 30 minutes The excess thionyl chloride was removed in vacuo and the resulting solid suspended in 5 mL of anhydrous pyridine. This solution was slowly added to a solution of 6-bromopyridin-2-amine (1.0 g, 5.8 mmol) suspended in 10 mL of anhydrous pyridine. The resulting mixture was allowed to stir for 15 hours at 110 ° C. The mixture was then evaporated to dryness, suspended in 50 ml of dichloromethane and washed with three 20 ml portions of 1 N NaOH. The organic layer was dried over sodium sulfate, evaporated to near dryness, and then purified by column chromatography on silica gel using dichloromethane containing 2.5% triethylamine as eluent to give pure product. ESI-MS m / z calculated 361.2, found 362.1 (M + 1) +; Retention time 3.43 minutes.¹H NMR (400 MHz, DMSO-J &lt;j) δ 1.10-1.17 (m, 2H),

1.42-1.55 (m, 2H), 6.06 (s, 2H), 6.92-7.02 (m, 2H), 7.09 (d, J = 1.6 Hz, 1H) , 7.33 (d, J =

7.6 Hz, 1H), 7.73 (t, J = 8.0 Hz, 1H), 8.04 (d, J = 8.2 Hz, 1H), 8.78 (s, 1H).

[0335] The compounds in Table 3 below were prepared in a manner analogous to that described above:

Table 3: Exemplary compounds synthesized according to the provisions of W and X.

<td>Relationship</td><td>Name</td><td>Retention time (min)</td><td>(M + 1) +</td><td>¹H NMR (400 MHz, DMSO-d6)</td>

<td>B-3</td><td>1- (Benzo [d] [1,3] dioxol-5-yl) -A (5-bromo-6-methylpyridin-2-yl) cyclopropanecarboxamide</td><td> 3,58</td><td> 375,3</td><td>¹H NMR (400 MHz, DMSO-Y) δ 8.39 (s, 1H), 7.95 (d, J = 8.7 Hz, 1H), 7.83 (d, J = 8.8 Hz, 1H ), 7.10 (d, J = 1.6 Hz, 1H), 7.01 6.94 (m, 2H), 6.06 (s, 2H), 2.41 (s, 3H), 1, 48 - 1.46 (m, 2H), 1.14 1.10 (m, 2H)</td>

<td>B-4</td><td>1- (Benzo [d] [1,3] dioxol-5-yl) -A (6-chloro-5-methylpyridin-2-yl) cyclopropanecarboxamide</td><td> 2,90</td><td> 331,0</td><td>¹H NMR (400 MHz, DMSO-Y) δ 8.64 (s, 1H), 7.94-7.91 (m, 1H), 7.79-7.77 (m, 1h), 7.09 ( m, 1H), 7.00-6.88 (m, 2H), 6.06 (s, 2H), 2.25 (s, 3H), 1.47-1.44 (m, 2H), 1 , 13-1.10 (m, 2H)</td>

109

<td>Relationship</td><td>Name</td><td>Retention time (min)</td><td>(M + 1) +</td><td>¹H NMR (400 MHz, DMSO-d6)</td>

<td>B-5</td><td>1- (Benzo [d] [1,3] dioxol-5-yl) -Y (5-bromo-4-methylpyridin-2-yl) cyclopropanecarboxamide</td><td> 3,85</td><td> 375,1</td><td>¹H NMR (400 MHz, DY1SO-Y) δ 8.36 (s, 1H), 8.30 (s, 1H), 8.05 (s, 1H), 7.09 (d, J = 1.6 Hz , 1H), 7.01 -6.95 (m, 2H), 6.07 (s, 2H), 2.35 (s, 3H), 1.49 - 1.45 (m, 2H), 1, 16 - 1.13 (m, 2H)</td>

<td>B-6</td><td>1- (Benzo [d] [1,3] dioxol-5-yl) -Y (5-bromo-3,4-dimethylpyridin-2-yl) cyclopropanecarboxamide</td><td> 3,25</td><td> 389,3</td><td>¹H NMR (400 MHz, DY1SO-Y) δ 8.82 (s, 1H), 8.35 (s, 1H), 7.01 (m, 1H), 6.96-6.89 (m, 2H) , 6.02 (s, 2H), 2.35 (s, 3H), 2.05 (s, 3H), 1.401.38 (m, 2H), 1.08-1.05 (m, 2H)</td>

<td>B-7</td><td>1- (Benzo [d] [1,3] dioxol-5-yl) -Y (5-bromo-3-methylpyridin-2-yl) cyclopropanecarboxamide</td><td> 2,91</td><td> 375,1</td><td></td>

<td>B-8</td><td>1- (Benzo [d] [1,3] dioxol-5-yl) -Y (6-chloropyridazin-3-yl) cyclopropanecarboxamide</td><td> 2,88</td><td> 318,3</td><td>¹H NMR (400 MHz, DY1SO-Y) δ 1.15-1.19 (m, 2H), 1.48-1.52 (m, 2H), 6.05 (s, 2H), 6.93- 7.01 (m, 2H), 7.09 (d, J = 1.7 Hz, 1H), 7.88 (d, J = 9.4 Hz, 1H), 8.31 (d, J = 9 , 4 Hz, 1H), 9.46 (s, 1H)</td>

<td>B-9</td><td>1- (Benzo [d] [1,3] dioxol-5-yl) -Y (5-bromopyrazin-2-yl) cyclopropanecarboxamide</td><td> 3,20</td><td> 318,3</td><td>¹H NMR (400 MHz, DY1SO-Y) δ 1.13-1.18 (m, 2H), 1.47-1.51 (m, 2H), 6.04 (s, 2H), 6.90- 6.99 (m, 2H), 7.06 (d, J = 1.6 Hz, 1H),, 8.47 (s, 1H), 9.21 (s, 1H), 9.45 (s, 1H)</td>

110

<td>Relationship</td><td>Name</td><td>Retention time (min)</td><td>(M + 1) +</td><td>¹H NMR (400 MHz, DMSO-d6)</td>

<td>B-10</td><td>1- (Benzo [d1 [1,31-dioxol-5-yl) -N (6-chloropyrazin-2-yl) cyclopropanecarboxamide</td><td> 3,45</td><td> 362,1</td><td>¹1 H NMR (400 MHz, DMSO-3₆) δ 1.12-1.23 (m, 2H), 1.41-1.58 (m, 2H), 6.04 (s, 2H), 6.90-7.00 (m, 2H), 7.07 (d, J = 1.6 Hz, 1H), 8.55 (s, 1H), 8.99-9.21 (m, 2H)</td>

<td>B-11</td><td>N- (6-bromopyridin-2-yl) -1- (2,2-difluorobenzo [d1 [1,31-dioxol-5-yl) cyclopropanecarboxamide</td><td> 2,12</td><td> 397,3</td><td>¹1 H NMR (400 MHz, DMSO-3₆) δ 9.46 (s, 1H), 8.01-7.99 (m, 1H), 7.75-7.71 (m, 1h), 7.54 (m, 1H), 7.41- 7.39 (m, 1H), 7.36-7.30 (m, 2h), 1.52-1.49 (m, 2h), 1.20-1.17 (m, 2H)</td>

<td>B-12</td><td>N- (6-chloro-5-methylpyridin-2-yl) -1- (2,2-difluorobenzo [d1 [1,31-dioxol-5-yl) cyclopropanecarboxamide</td><td> 2,18</td><td> 367,1</td><td>¹1 H NMR (400 MHz, DMSO-3₆) δ 9.30 (s, 1H), 7.89-7.87 (m, 1H), 7.78-7.76 (m, 1h), 7.53 (m, 1H), 7.41- 7.39 (m, 1H), 7.33-7.30 (m, 1h), 2.26 (s, 3H), 1.511,49 (m, 2H), 1.18-1.16 (m, 2H)</td>

<td>B-13</td><td>N- (6-chloro-5- (trifluoromethyl) pyridin-2-yl) -1- (2,2-difluorobenzo [d1 [1,31-dioxol-5-yl) cyclopropanecarboxamide</td><td> 1,98</td><td> 421,1</td><td>¹1 H NMR (400 MHz, DMSO-3₆) δ 10.09 (s, 1H), 8.29 (m, 1H), 8.16 (m, 1H), 7.53 (m, 1H), 7.41-7.38 (m, 1h) , 7.34-7.29 (m, 1H), 1.56-1.53 ​​(m, 2H), 1.24-1.22 (m, 2H)</td>

General Procedure V: Compounds of Formula I [0336]

111

<img file="PL1945632T3_D0079.tif" />

Hal = Cl, Br, I. Ring A is the ring formed by R₃ and R '₃.

[0337] The appropriate aryl halide (1 equivalent) was dissolved in 1 mL of N, N-dimethylformamide (DMF) in a reaction tube. The appropriate boronic acid (1.3 equivalents), 0.1 ml aqueous 2 M potassium carbonate solution (2 equivalents) and a catalytic amount of Pd (dppf) Cl2 (0.09 equivalents) were added and the reaction mixture was heated at 80 ° C for three hours or at 150 ° C for 5 min in a microwave oven. The resulting material was cooled to room temperature, filtered and purified by reverse phase preparative liquid chromatography.

Y. [1 - Benzo [1,3] dioxol-5-ylcyclopropanecarboxylic acid [5- (2,4-Dimethoxyphenyl) pyridin-2-yl] amide [0338]

<img file="PL1945632T3_D0080.tif" />

1-benzo [1,3] dioxol-5-ylcyclopropanecarboxylic acid (5-bromopyridin-2-yl) amide (36.1 mg, 0.10 mmol) was dissolved in 1 mL of N, N-dimethylformamide in a reaction tube . 2,4-Dimethoxybenzeneboronic acid (24 mg, 0.13 mmol), 0.1 mL of 2 M aqueous potassium carbonate solution and a catalytic amount of Pd (dppf) Cl2 (6.6 mg, 0.0090 mmol) were added and the reaction mixture was heated at 80 ° C for three hours. The resulting material was cooled to room temperature, filtered and purified by reverse phase preparative liquid chromatography to give the pure product as the trifluoroacetic acid salt. ESI-MS m / z calculated

418.2, found 419.0 (M + 1) +. Retention time 3.18 minutes. 1 H NMR (400 MHz, CD₃CN) δ 1.25-1.29 (m, 2H), 1.63-1.67 (m, 2H), 3.83 (s, 3H), 3.86 (s, 3H), 6.04 (s, 2H), 6.64-6.68 (m, 2H), 6.92 (d, J = 8.4 Hz, 1H), 7.03-7.06 (m, 2H), 7, 30 (d, J = 8.3 Hz, 1H), 7.96 (d, J =

8.9 Hz, 1H), 8.14 (dd, J = 8.9, 2.3 Hz, 1H), 8.38 (d, J = 2.2 Hz, 1H), 8.65 (s, 1H).

Z. [6- (4-Dimethylaminophenyl) pyridin-2-yl] amide 1-benzo [1,3] dioxol-5-ylcyclopropanecarboxylic acid [0340]

<img file="PL1945632T3_D0081.tif" />

1-benzo [1,3] dioxol-5-ylcyclopropanecarboxylic acid (6-bromopyridin-2-yl) amide (36 mg, 0.10 mmol) was dissolved in 1 mL of N, N-dimethylformamide in a reaction tube. 4- (dimethylamino) phenylboronic acid (21 mg, 0.13 mmol), 0.1 ml 2 M aqueous potassium carbonate solution and (Pd (dppf) Cl2 (6.6 mg, 0.0090 mmol) were added and the reaction mixture was heated at 80 ° C for three hours. The resulting material was cooled to room temperature, filtered and purified by reverse phase preparative liquid chromatography to give the pure product as the trifluoroacetic acid salt. ESI-MS m / z calculated 401.2, found 402.5 (M + 1) +. Retention time 2.96 minutes.^JH NMR (400 MHz, CD₃CN) δ 1.23-1.27 (m, 2H), 1.62-1.66 (m, 2H), 3.04 (s, 6H), 6.06 (s, 2H), 6.88 -6.90 (m, 2H), 6.936,96 (m, 1H), 7.05-7.07 (m, 2H), 7.53-7.56 (m, 1H), 7.77-7 , 81 (m, 3H), 7.84-7.89 (m, 1H),

8.34 (s, 1H).

112 [0342] The following schemes were used to prepare additional commercially unavailable boronic esters:

AA. 1-Methyl-4- [4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenyl] sulfonylpiperazine [0343]

<img file="PL1945632T3_D0082.tif" />

Step a: 1- (4-Bromophenylsulfonyl) -4-methylpiperazine [0344] Into a vial (40 ml) containing 5 ml saturated aqueous sodium bicarbonate solution, dichloromethane (5 ml) and 1-methylpiperazine (100 mg, 1.00 mmol ) a solution of 4-bromobenzene-1-sulfonyl chloride (256 mg, 1.00 mmol) in 1 mL of dichloromethane was slowly added. The reaction mixture was stirred at room temperature overnight. The phases were separated and the organic layer was dried over magnesium sulfate. Evaporation of the solvent under reduced pressure gave the desired product which was used without further purification in the next step. ESI-MS m / z calcd 318.0, found 318.9 (M + 1) +. Retention time 1.30 minutes.¹H NMR (300 MHz, CDCl₃) δ 7.65 (d, J = 8.7 Hz, 2H), 7.58 (d, J = 8.7 Hz, 2H), 3.03 (t, J = 4.2 Hz, 4H), 2.48 (t, J = 4.2 Hz,

4H), 2.26 (s, 3H).

Step b: 1-Methyl-4- [4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenyl] sulfonylpiperazine [0345] 50 ml A round bottom flask was charged with 1- (4 bromophenylsulfonyl) -4-methylpipe 20 times (110 mg, 0.350 mmol), bis (pinaconate) diboron (93 mg, 0.37 mmol), palladium acetate (6 mg, 0.02 mmol) and potassium acetate (103 mg, 1.05 mmol) in N, N-dimethylformamide (6 mL). The mixture was degassed by gently bubbling argon bubbles through the solution for 30 minutes at room temperature. The mixture was then heated at 80 ° C under argon until the reaction was complete (4 hours). Desired product, 1-methyl-4- [4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenyl] sulfonylpiperazine and bi-aryl product, 4- (4-methylpiperazine -1-ylsulfonyl) phenylphenylsulfonyl-4-methylpiperazine was obtained in a 1: 2 ratio, as shown by LC / MS analysis. The mixture was used without further purification.

BB. 4,4,5,5-Tetramethyl-2- (4- (2- (methylsulfonyl) ethyl) phenyl) -1,3,2-dioxaborolane [0346]

Br Br Br

<img file="PL1945632T3_D0083.tif" />

Step a: 4-Bromophenethyl-4-methylbenzenesulfonate [0347] In a 50 ml round bottom flask, p-bromophenethyl alcohol (1.0 g,

113

4.9 mmol), followed by the addition of pyridine (15 mL). To this clear solution, p-toluenesulfonyl chloride (TsCl) (1.4 g, 7.5 mmol) was added as a solid under an argon atmosphere. Argon was bubbled through the reaction mixture and stirred at room temperature for 18 hours. The crude mixture was treated with 1 N HCl (20 mL) and extracted with ethyl acetate (5 x 25 mL). The organic fractions were dried over Na2SO4, filtered and concentrated to give 4-bromophenethyl-4-methylbenzenesulfonate (0.60 g, 35%) as a yellowish liquid. ¹H-NMR (Acetone- ^, 300 MHz) δ 7.64 (d, J = 8.4 Hz, 2H), 7.40-7.37 (d, J = 8.7 Hz, 4H), 7, 09 (d, J = 8.5 Hz, 2H), 4.25 (t, J = 6.9 Hz, 2H), 2.92 (t, J = 6.3 Hz, 2H), 2.45 ( s, 3H).

Step b: (4-Bromophenethyl) (methyl) sulfane [0348] 4-bromophenethyl 4-methylbenzenesulfonate (0.354 g, 0.996 mmol) and CH are placed in a 20 mL round bottom flask.₃SNa (0.10 g, 1.5 mmol), followed by the addition of THF (1.5 mL) and A-methyl-2-pyrrolidinone (1.0 mL). The mixture was stirred at room temperature for 48 hours and then treated with saturated aqueous sodium bicarbonate (10 mL). The mixture was extracted with ethyl acetate (4 x 10 mL), dried over Na₂SO₄, filtered and concentrated to give (4-bromophenethyl) (methyl) sulfane (0.30 g crude) as a yellowish oil. ¹H-NMR (CDCl3, 300 MHz) δ 7.40 (d, J = 8.4 Hz, 2H), 7.06 (d, J = 8.4 Hz, 2H), 2.89-2.81 ( m, 2H), 2.74-2.69 (m, 2H), 2.10 (s, 3H).

Step c: 1-Bromo-4- (2-methylsulfonyl) ethylbenzene [0349] In a 20 ml round bottom flask was placed (4-bromophenethyl) - (methyl) sulfane (0.311g, 1.34 mmol) and Oxone (3.1 g , 0.020 mol), followed by the addition of a 1: 1 acetone / water mixture (10 ml). The mixture was vigorously stirred at room temperature for 20 hours and then concentrated. The aqueous mixture was extracted with ethyl acetate (3 x 15 mL) and dichloromethane (3 x 10 mL). The organic fractions were combined, dried with Na2SO4, filtered and concentrated to give a white semi-solid. Purification of the crude substance by flash chromatography gave 1-bromo-4- (2-methylsulfonyl) ethylbenzene (0.283 g, 80%).¹H-NMR (DMSO- ^ g, 300 MHz) δ 7.49 (d, J = 8.4 Hz, 2H), 7.25 (d, J = 8.7 Hz, 2H), 3.43 (m , 2H), 2.99 (m, 2H), 2.97 (s, 3H).

Step d: 4,4,5,5-Tetramethyl-2- (4- (2- (methylsulfonyl) ethyl) phenyl) -1,3,2-dioxaborolane [0350] 4,4,5,5-Tetramethyl-2 - (4- (2- (methylsulfonyl) ethyl) phenyl) -1,3,2-dioxaborolate was prepared in the same manner as described above for 1-methyl-4- [4- (4,4,5,5-tetramethyl-1 , 3,2-dioxaborolan-2-yl) phenylsulfonylpiperazine, Recipe AA.

CC. Tert-butyl methyl (4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) benzyl) carbamate [0351]

<img file="PL1945632T3_D0084.tif" />

Step a: tert-butyl 4-bromobenzylcarbamate [0352] Commercially available ^ -bromobenzylamine hydrochloride (1 g, 4 mmol) was treated with 10% aqueous NaOH (5 mL). To the clear solution, (Boc) 2O (1.1 g, 4.9 mmol) dissolved in dioxane (10 mL) was added. The mixture was vigorously stirred at room temperature for 18 hours. The resulting residue was concentrated, suspended in water (20 mL), extracted with ethyl acetate (4 x 20 mL), dried over Na₂SO₄, filtered and concentrated to give tert-butyl 4-bromobenzylcarbamate (1.23 g, 96%) as a white solid. ¹H NMR (300 MHz, DMSO-Jd) δ 7.48 (d, J = 8.4 Hz, 2H), 7.40 (t, J = 6 Hz, 1H), 7.17 (d, J = 8 , 4 Hz,

2H), 4.07 (d, J = 6.3 Hz, 2H), 1.38 (s, 9H).

Step b: tert-butyl 4-bromobenzyl (methyl) carbamate [0353] In a 60-mL vial, tert-butyl 4-bromobenzylcarbamate (1.25 g, 4.37 mmol) was dissolved in DMF (12 mL). Ag. Was added to this solution₂O (4.0 g, 17 mmol), followed by the addition of CH3I (0.68 mL, 11 mmol). The mixture was stirred at 50 ° C for 18 hours. The reaction mixture was filtered through a pad of celite and the celite was washed with methanol (2 x 20 mL) and dichloromethane (2 x 20 mL). The filtrate was concentrated to remove most of the DMF. The residue was treated with water (50 ml) and a white emulsion formed. The mixture was extracted with ethyl acetate (4 x 25 mL), dried over Na2SO4, and the solvent was evaporated to give tert-butyl 4-bromobenzyl (methyl) carbamate (1.3 g, 98%) as a yellow oil. ¹H NMR (300 MHz, DMSO-d6) δ 7.53 (d, J = 8.1 Hz,

2H), 7.15 (d, J = 8.4 Hz, 2H), 4.32 (s, 2H), 2.74 (s, 3H), 1.38 (s, 9H).

Step c: tertbutyl 4- (4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl) benzylmethylcarbamate [0354] The coupling reaction was carried out in the same manner as described above for 120 methyl-4- [ 4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenyl] sulfonylpiperazine, Preparation AA. After the coupling reaction, the Boc protecting group was removed by treating the reaction mixture with 0.5 mL of 1 N HCl in diethyl ether for 18 hours, then purified by HPLC.

[0355] The compounds of the additional examples described herein were prepared by following the above procedure without significant change using the arylboronic acids shown in Table 4.

Table 4: Additional exemplary compounds of formula I.

<td>Relationship No.</td><td>Amine</td><td>Boronic acid</td>

<td> 1</td><td>B-2</td><td>[2- (Dimethylaminomethyl) phenyl] boronic acid</td>

<td> 2</td><td>B-2</td><td>[4- (1-piperidyl) phenyl] boronic acid</td>

<td> 3</td><td>B-2</td><td>(3,4-dichlorophenyl) boronic acid</td>

<td> 4</td><td>B-2</td><td>(4-Morpholinosulfonylphenyl) boronic acid</td>

<td> 5</td><td>B-2</td><td>(3-Chloro-4-methoxyphenyl) boronic acid</td>

<td> 6</td><td>B-2</td><td>(6-methoxy-3-pyridyl) boronic acid</td>

<td> 7</td><td>B-2</td><td>(4-Dimethylaminophenyl) boronic acid</td>

<td> 8</td><td>B-2</td><td>(4-Morpholinophenyl) boronic acid</td>

<td> 9</td><td>B-2</td><td>[4- (acetylaminomethyl) phenyl] boronic acid</td>

<td> 10</td><td>B-2</td><td>(2-hydroxyphenyl) boronic acid</td>

<td> 11</td><td>B-1</td><td>2-dihydroxyboranylbenzoic acid</td>

<td> 12</td><td>B-1</td><td>(6-methoxy-3-pyridyl) boronic acid</td>

<td> 14</td><td>B-2</td><td>(2,4-Dimethylphenyl) boronic acid</td>

<td> 15</td><td>B-2</td><td>[3- (hydroxymethyl) phenyl] boronic acid</td>

<td> 16</td><td>B-2</td><td>3-dihydroxyboranyl benzoic acid</td>

<td> 17</td><td>B-2</td><td>(3-Ethoxyphenyl) boronic acid</td>

<td> 18</td><td>B-2</td><td>(3,4-Dimethylphenyl) boronic acid</td>

115

<td>Relationship No.</td><td>Amine</td><td>Boronic acid</td>

<td> 19</td><td>B-1</td><td>[4- (hydroxymethyl) phenyl] boronic acid</td>

<td> 20</td><td>B-1</td><td>3-Pyridylboronic acid</td>

<td> 21</td><td>B-2</td><td>(4-ethylphenyl) boronic acid</td>

<td> 23</td><td>B-2</td><td>4,4,5,5-tetramethyl-2- (4- (2- (methylsulfonyl) ethyl) phenyl) -1,3,2dioksaborolan</td>

<td> 24</td><td>B-1</td><td>Benzo [1,3] dioxol-5-ylboronic acid</td>

<td> 25</td><td>B-2</td><td>(3-chlorophenyl) boronic acid</td>

<td> 26</td><td>B-2</td><td>(3-Ethylsulfonylaminophenyl) bonic acid</td>

<td> 27</td><td>B-2</td><td>(3,5-di chlorophenyl) bonic acid</td>

<td> 28</td><td>B-2</td><td>(3-methoxyphenyl) boronic acid</td>

<td> 29</td><td>B-1</td><td>(3-hydroxyphenyl) boronic acid</td>

<td> 31</td><td>B-2</td><td>Phenylboronic acid</td>

<td> 32</td><td>B-2</td><td>(2,5-difluorophenyl) boronic acid</td>

<td> 33</td><td>B-8</td><td>Phenylboronic acid</td>

<td> 36</td><td>B-2</td><td>(2-Methylsulfonylaminophenyl) boronic acid</td>

<td> 37</td><td>B-1</td><td>1H-indol-5-ylboronic acid</td>

<td> 38</td><td>B-2</td><td>2,2,2-trifluoro-N- (4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) benzyl) acetates d</td>

<td> 39</td><td>B-2</td><td>(2-chlorophenyl) boronic acid</td>

<td> 40</td><td>B-1</td><td>M-Tolylboronic acid</td>

<td> 41</td><td>B-2</td><td>(2,4-dimethoxypyrimidin-5-yl) boronic acid</td>

<td> 42</td><td>B-2</td><td>(4-m ethoxycarbone onenyl) bonic acid</td>

<td> 43</td><td>B-2</td><td>Tert-butyl 4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) benzylmethylcarbamate ^(and)</td>

<td> 44</td><td>B-2</td><td>(4-Ethoxyphenyl) boronic acid</td>

<td> 45</td><td>B-2</td><td>(3-Methylsulfonylphenyl) boronic acid</td>

<td> 46</td><td>B-2</td><td>(4-Fluoro-3-ethyl ethyl phenyl) bonic acid</td>

<td> 47</td><td>B-2</td><td>(4-Cyanophenyl) boronic acid</td>

<td> 48</td><td>B-1</td><td>(2,5-Dimethoxyphenyl) boronic acid</td>

<td> 49</td><td>B-1</td><td>(4-Methylsulfonylphenyl) boronic acid</td>

<td> 50</td><td>B-1</td><td>Cyclopent-1-enylboronic acid</td>

<td> 51</td><td>B-2</td><td>O-tolylboronic acid</td>

<td> 52</td><td>B-1</td><td>(2,6-Dimethylphenyl) boronic acid</td>

<td> 53</td><td>B-8</td><td>2-chlorophenylboronic acid</td>

<td> 54</td><td>B-2</td><td>(2,5-Dimethoxyphenyl) boronic acid</td>

<td> 55</td><td>B-2</td><td>(2-fluoro-3-methoxyphenyl) boronic acid</td>

<td> 56</td><td>B-2</td><td>(2-methoxyphenyl) boronic acid</td>

<td> 57</td><td>B-9</td><td>Phenylboronic acid</td>

116

<td>Relationship No.</td><td>Amine</td><td>Boronic acid</td>

<td> 58</td><td>B-2</td><td>(4-Isopropoxyphenyl) boronic acid</td>

<td> 59</td><td>B-2</td><td>(4-carbamoylphenyl) boronic acid</td>

<td> 60</td><td>B-2</td><td>(3,5-Dimethylphenyl) boronic acid</td>

<td> 61</td><td>B-2</td><td>(4-Isobutylphenyl) boronic acid</td>

<td> 62</td><td>B-1</td><td>(4-Cyanophenyl) boronic acid</td>

<td> 63</td><td>B-10</td><td>Phenylboronic acid</td>

<td> 64</td><td>B-2</td><td>N-ethyl-4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) benzenesulfonamide</td>

<td> 65</td><td>B-1</td><td>2,3-dihydrob enzofuran-5-oboronic acid</td>

<td> 66</td><td>B-2</td><td>(4-chlorophenyl) boronic acid</td>

<td> 67</td><td>B-2</td><td>(4-chloro-3-ethyl ethyl phenyl) bonic acid</td>

<td> 68</td><td>B-2</td><td>(2-Fluorophenyl) boronic acid</td>

<td> 69</td><td>B-2</td><td>Benzo [1,3] dioxol-5-ylboronic acid</td>

<td> 70</td><td>B-2</td><td>(4-Morpholinocarbonylphenyl) boronic acid</td>

<td> 71</td><td>B-1</td><td>Cyclohex-1-enylboronic acid</td>

<td> 72</td><td>B-2</td><td>(3,4,5-trimethoxyphenyl) boronic acid</td>

<td> 73</td><td>B-2</td><td>[4- (Dimethylaminomethyl) phenyl] boronic acid</td>

<td> 74</td><td>B-2</td><td>M-Tolylboronic acid</td>

<td> 77</td><td>B-2</td><td>(3-Cyanophenyl) boronic acid</td>

<td> 78</td><td>B-2</td><td>[3- (tert-butoxycarbonylaminomethyl) phenyl] boronic acid^(and)</td>

<td> 79</td><td>B-2</td><td>(4-Methylsulfonylphenyl) boronic acid</td>

<td> 80</td><td>B-1</td><td>P-Tolylboronic acid</td>

<td> 81</td><td>B-2</td><td>(2,4-dimethoxyphenyl) boronic acid</td>

<td> 82</td><td>B-2</td><td>(2-m ethoxycarbone onenyl) bonic acid</td>

<td> 83</td><td>B-2</td><td>(2,4-difluorophenyl) boronic acid</td>

<td> 84</td><td>B-2</td><td>(4-Isopropylphenyl) boronic acid</td>

<td> 85</td><td>B-2</td><td>[4- (2-Dimethylaminoethylcarbamoyl) phenyl] boronic acid</td>

<td> 86</td><td>B-1</td><td>(2,4-dimethoxyphenyl) boronic acid</td>

<td> 87</td><td>B-1</td><td>Benzofuran-2-ylboronic acid</td>

<td> 88</td><td>B-2</td><td>2,3-dihydrob enzofuran-5-oboronic acid</td>

<td> 89</td><td>B-2</td><td>(3-Fluoro-4-m ethoxyphenyl) bonic acid</td>

<td> 91</td><td>B-1</td><td>(3-Cyanophenyl) boronic acid</td>

<td> 92</td><td>B-1</td><td>(4-Dimethylaminophenyl) boronic acid</td>

<td> 93</td><td>B-2</td><td>(2,6-dimethoxyphenyl) boronic acid</td>

<td> 94</td><td>B-2</td><td>(2-m ethoxy-5-methyl ophenyl) bonic acid</td>

<td> 95</td><td>B-2</td><td>(3-Acetylaminophenyl) boronic acid</td>

<td> 96</td><td>B-1</td><td>(2,4-dimethoxypyrimidin-5-yl) boronic acid</td>

117

<td>Relationship No.</td><td>Amine</td><td>Boronic acid</td>

<td> 97</td><td>B-2</td><td>(5-Fluoro-2-m ethoxyphenyl) bonic acid</td>

<td> 98</td><td>B-1</td><td>[3- (hydroxymethyl) phenyl] boronic acid</td>

<td> 99</td><td>B-1</td><td>(2-methoxyphenyl) boronic acid</td>

<td> 100</td><td>B-2</td><td>(2,4,6-trimethylphenyl) boronic acid</td>

<td> 101</td><td>B-2</td><td>[4- (Dimethylcarbamoyl) phenyl] boronic acid</td>

<td> 102</td><td>B-2</td><td>[4 - ((er) -butoxycarbonylaminomethyl) phenyl] boronic acid^(and)</td>

<td> 104</td><td>B-1</td><td>(2-chlorophenyl) boronic acid</td>

<td> 105</td><td>B-1</td><td>(3-Acetylaminophenyl) boronic acid</td>

<td> 106</td><td>B-2</td><td>(2-ethoxyphenyl) boronic acid</td>

<td> 107</td><td>B-2</td><td>3-furylboronic acid</td>

<td> 108</td><td>B-2</td><td>[2- (hydroxymethyl) phenyl] boronic acid</td>

<td> 110</td><td>B-9</td><td>2-chlorophenylboronic acid</td>

<td> 111</td><td>B-2</td><td>(2-fluoro-6-methoxyphenyl) boronic acid</td>

<td> 112</td><td>B-2</td><td>(2-ethoxy-5-methylphenyl) boronic acid</td>

<td> 113</td><td>B-2</td><td>1H-indol-5-ylboronic acid</td>

<td> 114</td><td>B-1</td><td>(3-chloro-4-five-royl) acid</td>

<td> 115</td><td>B-2</td><td>Cyclohex-1-enylboronic acid</td>

<td> 116</td><td>B-1</td><td>O-tolylboronic acid</td>

<td> 119</td><td>B-2</td><td>(2-Aminophenyl) boronic acid</td>

<td> 120</td><td>B-2</td><td>(4-methoxy-3,5-dimethylphenyl) boronic acid</td>

<td> 121</td><td>B-2</td><td>(4-methoxyphenyl) boronic acid</td>

<td> 122</td><td>B-2</td><td>(2-propoxyphenyl) boronic acid</td>

<td> 123</td><td>B-2</td><td>(2-Isopropoxyphenyl) boronic acid</td>

<td> 124</td><td>B-2</td><td>(2,3-di chlorophenyl) bonic acid</td>

<td> 126</td><td>B-2</td><td>(2,3-Dimethylphenyl) boronic acid</td>

<td> 127</td><td>B-2</td><td>(4-Fluorophenyl) boronic acid</td>

<td> 128</td><td>B-1</td><td>(3-methoxyphenyl) boronic acid</td>

<td> 129</td><td>B-2</td><td>(4-chloro-2-ethyl ethyl phenyl) bonic acid</td>

<td> 130</td><td>B-1</td><td>(2,6-dimethoxyphenyl) boronic acid</td>

<td> 131</td><td>B-2</td><td>(5-Isopropyl-2-methoxyphenyl) boronic acid</td>

<td> 132</td><td>B-2</td><td>(3-Isopropoxyphenyl) boronic acid</td>

<td> 134</td><td>B-2</td><td>4-dihydroxyboranylbenzoic acid</td>

<td> 135</td><td>B-2</td><td>(4-Dimethylamino-2-methoxyphenyl) boronic acid</td>

<td> 136</td><td>B-2</td><td>(4-Methylsulfinylphenyl) bonic acid</td>

<td> 137</td><td>B-2</td><td>[4- (Methylcarbamoyl) phenyl] boronic acid</td>

<td> 138</td><td>B-1</td><td>8-quinolylboronic acid</td>

<td> 139</td><td>B-2</td><td>Cyclopent-1-enylboronic acid</td>

118

<td>Relationship No.</td><td>Amine</td><td>Boronic acid</td>

<td> 140</td><td>B-2</td><td>P-Tolylboronic acid</td>

<td> 142</td><td>B-8</td><td>2-methoxyphenylboronic acid</td>

<td> 143</td><td>B-2</td><td>(2,5-Dimethylphenyl) boronic acid</td>

<td> 144</td><td>B-1</td><td>(3,4-Dimethoxyphenyl) boronic acid</td>

<td> 145</td><td>B-1</td><td>(3-chlorophenyl) boronic acid</td>

<td> 146</td><td>B-2</td><td>[4- (morpholinomethyl) phenyl] boronic acid</td>

<td> 147</td><td>B-10</td><td>4- (dimethylamino) phenylboronic acid</td>

<td> 148</td><td>B-2</td><td>[4- (Methylsulfamoyl) phenyl] boronic acid</td>

<td> 149</td><td>B-1</td><td>4-dihydroxyboranylbenzoic acid</td>

<td> 150</td><td>B-1</td><td>Phenylboronic acid</td>

<td> 151</td><td>B-2</td><td>(2,3-difluorophenyl) boronic acid</td>

<td> 152</td><td>B-1</td><td>(4-chlorophenyl) boronic acid</td>

<td> 153</td><td>B-9</td><td>2-methoxyphenylboronic acid</td>

<td> 154</td><td>B-2</td><td>3-dihydroxyboranyl benzoic acid</td>

<td> 155</td><td>B-10</td><td>2-methoxyphenylboronic acid</td>

<td> 157</td><td>B-2</td><td>(3-chloro-4-fluorophenyl) boronic acid</td>

<td> 158</td><td>B-2</td><td>(2,3-dimethoxyphenyl) boronic acid</td>

<td> 159</td><td>B-2</td><td>[4- (tert-butoxycarbonylaminomethyl) phenyl] boronic acid</td>

<td> 160</td><td>B-2</td><td>(4-Sulfamoylphenyl) boronic acid</td>

<td> 161</td><td>B-2</td><td>(3,4-Dimethoxyphenyl) boronic acid</td>

<td> 162</td><td>B-2</td><td>[4- (methylsulfonylaminomethyl) phenyl] boronic acid</td>

<td> 166</td><td>B-1</td><td>4- (Y, Y-dimethylsulfamoyl) phenylboronic acid</td>

<td> 167</td><td>B-6</td><td>2-Isopropylphenylboronic acid</td>

<td> 171</td><td>B-6</td><td>4- (methylcarbamoyl) phenylboronic acid</td>

<td> 173</td><td>B-2</td><td>3-Fluoro-phenylboronic acid</td>

<td> 174</td><td>B-6</td><td>3- (Y, Y-dimethylsulfamoyl) phenylboronic acid</td>

<td> 179</td><td>B-6</td><td>4- (Y-methylsulfamoyl) phenylboronic acid</td>

<td> 181</td><td>B-1</td><td>3 - ((ZerZ-butoxycarbonylamino) methyl) phenylboronic acid</td>

<td> 185</td><td>B-3</td><td>3-methoxyphenylboronic acid</td>

<td> 186</td><td>B-6</td><td>2-chlorophenylboronic acid</td>

<td> 187</td><td>B-7</td><td>3- (Dimethylcarbamoyl) phenylboronic acid</td>

<td> 188</td><td>B-6</td><td>3 - (hydroxymethyl) phenylboronic acid</td>

<td> 189</td><td>B-1</td><td>3- (Y, Y-dimethylsulfamoyl) phenylboronic acid</td>

<td> 190</td><td>B-1</td><td>4-sulfamoylphenylboronic acid</td>

<td> 191</td><td>B-1</td><td>2-Isopropylphenylboronic acid</td>

<td> 193</td><td>B-5</td><td>3-sulfamoylphenylboronic acid</td>

<td> 194</td><td>B-3</td><td>4-Isopropylphenylboronic acid</td>

119

<td>Relationship No.</td><td>Amine</td><td>Boronic acid</td>

<td> 195</td><td>B-3</td><td>3- (N, N-Dimethylsulfamoyl) phenylboronic acid</td>

<td> 196</td><td>B-7</td><td>4- (methylcarbamoyl) phenylboronic acid</td>

<td> 198</td><td>B-3</td><td>3- (Dimethylcarbamoyl) phenylboronic acid</td>

<td> 204</td><td>B-5</td><td>3- (Dimethylcarbamoyl) phenylboronic acid</td>

<td> 206</td><td>B-3</td><td>4-chlorophenylboronic acid</td>

<td> 207</td><td>b-1</td><td>4- (N-methylsulfamoyl) phenylboronic acid</td>

<td> 209</td><td>b-1</td><td>3- (m-ethylcarbamoyl) phenylboronic acid</td>

<td> 210</td><td>B-3</td><td>4-sulfamoylphenylboronic acid</td>

<td> 213</td><td>B-5</td><td>3-Isopropylphenylboronic acid</td>

<td> 215</td><td>B-7</td><td>4-methoxyphenylboronic acid</td>

<td> 216</td><td>B-6</td><td>3-chlorophenylboronic acid</td>

<td> 217</td><td>B-7</td><td>M-Tolylboronic acid</td>

<td> 219</td><td>B-5</td><td>4- (hydroxymethyl) phenylboronic acid</td>

<td> 222</td><td>B-6</td><td>M-Tolylboronic acid</td>

<td> 224</td><td>B-5</td><td>2-chlorophenylboronic acid</td>

<td> 225</td><td>b-1</td><td>3-Isopropylphenylboronic acid</td>

<td> 227</td><td>B-6</td><td>4- (hydroxymethyl) phenylboronic acid</td>

<td> 229</td><td>B-7</td><td>3-chlorophenylboronic acid</td>

<td> 230</td><td>B-6</td><td>O-tolylboronic acid</td>

<td> 231</td><td>b-1</td><td>2- (Hydroxymethyl) phenylboronic acid</td>

<td> 235</td><td>B-3</td><td>3-Isopropylphenylboronic acid</td>

<td> 238</td><td>B-5</td><td>3-carbamoylphenylboronic acid</td>

<td> 241</td><td>B-2</td><td>4- (N, N-Dimethylsulfamoyl) phenylboronic acid</td>

<td> 243</td><td>B-7</td><td>2-methoxyphenylboronic acid</td>

<td> 247</td><td>B-6</td><td>3- (Dimethylcarbamoyl) phenylboronic acid</td>

<td> 251</td><td>B-3</td><td>3-sulfamoylphenylboronic acid</td>

<td> 252</td><td>b-1</td><td>4-methoxyphenylboronic acid</td>

<td> 254</td><td>B-3</td><td>4- (N-methylsulfamoyl) phenylboronic acid</td>

<td> 255</td><td>b-1</td><td>4 - ((/ ert-butoxycarbonylamino) methyl) phenylboronic acid</td>

<td> 257</td><td>B-5</td><td>4-chlorophenylboronic acid</td>

<td> 258</td><td>B-3</td><td>3- (m-ethylcarbamoyl) phenylboronic acid</td>

<td> 260</td><td>B-3</td><td>2- (Hydroxymethyl) phenylboronic acid</td>

<td> 263</td><td>B-4</td><td>4- (hydroxymethyl) phenylboronic acid</td>

<td> 264</td><td>B-7</td><td>4-chlorophenylboronic acid</td>

<td> 265</td><td>B-6</td><td>4-carbamoylphenylboronic acid</td>

<td> 266</td><td>B-5</td><td>3-methoxyphenylboronic acid</td>

<td> 269</td><td>B-7</td><td>Phenylboronic acid</td>

120

<td>Relationship No.</td><td>Amine</td><td>Boronic acid</td>

<td> 272</td><td>B-3</td><td>4-methoxyphenylboronic acid</td>

<td> 274</td><td>B-6</td><td>2- (Hydroxymethyl) phenylboronic acid</td>

<td> 277</td><td>B-3</td><td>4- (hydroxymethyl) phenylboronic acid</td>

<td> 278</td><td>B-3</td><td>3- (methylcarbamoyl) phenylboronic acid</td>

<td> 280</td><td>B-3</td><td>4- (A, A-Dimethylsulfamoyl) phenylboronic acid</td>

<td> 283</td><td>B-3</td><td>4-carbamoylphenylboronic acid</td>

<td> 286</td><td>B-1</td><td>4- (methylcarbamoyl) phenylboronic acid</td>

<td> 287</td><td>B-2</td><td>4- (trifluoromethoxy) phenylboronic acid</td>

<td> 288</td><td>B-5</td><td>4- (A-Methylsulfamoyl) phenylboronic acid</td>

<td> 289</td><td>B-3</td><td>Phenylboronic acid</td>

<td> 290</td><td>B-6</td><td>4-Isopropylphenylboronic acid</td>

<td> 291</td><td>B-3</td><td>3- (hydroxymethyl) phenylboronic acid</td>

<td> 293</td><td>B-6</td><td>3-methoxyphenylboronic acid</td>

<td> 294</td><td>B-7</td><td>2- (hydroxymethyl) phenylboronic acid</td>

<td> 295</td><td>B-3</td><td>3-carbamoylphenylboronic acid</td>

<td> 296</td><td>B-5</td><td>M-Tolylboronic acid</td>

<td> 297</td><td>B-1</td><td>4- (dimethylcarbamoyl) phenylboronic acid</td>

<td> 298</td><td>B-3</td><td>2-methoxyphenylboronic acid</td>

<td> 299</td><td>B-7</td><td>P-Tolylboronic acid</td>

<td> 300</td><td>B-3</td><td>O-tolylboronic acid</td>

<td> 301</td><td>B-5</td><td>2- (hydroxymethyl) phenylboronic acid</td>

<td> 303</td><td>B-6</td><td>2-methoxyphenylboronic acid</td>

<td> 305</td><td>B-6</td><td>3-Isopropylphenylboronic acid</td>

<td> 308</td><td>B-7</td><td>4-Isopropylphenylboronic acid</td>

<td> 309</td><td>B-3</td><td>4- (dimethylcarbamoyl) phenylboronic acid</td>

<td> 310</td><td>B-5</td><td>4- (methylcarbamoyl) phenylboronic acid</td>

<td> 313</td><td>B-7</td><td>O-tolylboronic acid</td>

<td> 314</td><td>B-7</td><td>3- (methylcarbamoyl) phenylboronic acid</td>

<td> 315</td><td>B-3</td><td>P-Tolylboronic acid</td>

<td> 320</td><td>B-1</td><td>3- (Dimethylcarbamoyl) phenylboronic acid</td>

<td> 321</td><td>B-5</td><td>4-sulfamoylphenylboronic acid</td>

<td> 322</td><td>B-6</td><td>Phenylboronic acid</td>

<td> 323</td><td>B-5</td><td>O-tolylboronic acid</td>

<td> 324</td><td>B-3</td><td>4 - ((tert-butoxycarbonylamino) methyl) phenylboronic acid^(and)</td>

<td> 326</td><td>B-5</td><td>4- (dimethylcarbamoyl) phenylboronic acid</td>

<td> 327</td><td>B-5</td><td>2-methoxyphenylboronic acid</td>

<td> 328</td><td>B-1</td><td>4-Isopropylphenylboronic acid</td>

121

<td>Relationship No.</td><td>Amine</td><td>Boronic acid</td>

<td> 329</td><td>B-5</td><td>2-Isopropylphenylboronic acid</td>

<td> 331</td><td>B-3</td><td>M-Tolylboronic acid</td>

<td> 333</td><td>B-6</td><td>4-methoxyphenylboronic acid</td>

<td> 334</td><td>B-5</td><td>4-methoxyphenylboronic acid</td>

<td> 337</td><td>B-6</td><td>P-Tolylboronic acid</td>

<td> 343</td><td>B-5</td><td>4- (Y, Y-dimethylsulfamoyl) phenylboronic acid</td>

<td> 346</td><td>B-3</td><td>2-Isopropylphenylboronic acid</td>

<td> 348</td><td>B-6</td><td>4 - ((tert-butoxycarbonylamino) methyl) phenylboronic acid^(and)</td>

<td> 349</td><td>B-1</td><td>3-sulfamoylphenylboronic acid</td>

<td> 350</td><td>B-3</td><td>3 - ((tert-butoxycarbonylamino) methyl) phenylboronic acid^(and)</td>

<td> 351</td><td>B-5</td><td>Phenylboronic acid</td>

<td> 352</td><td>B-7</td><td>2-Isopropylphenylboronic acid</td>

<td> 353</td><td>B-6</td><td>4-chlorophenylboronic acid</td>

<td> 354</td><td>B-7</td><td>2-chlorophenylboronic acid</td>

<td> 355</td><td>B-5</td><td>3- (Y, Y-dimethylsulfamoyl) phenylboronic acid</td>

<td> 356</td><td>B-7</td><td>3-sulfamoylphenylboronic acid</td>

<td> 357</td><td>B-7</td><td>4- (A-Methylsulfamoyl) phenylboronic acid</td>

<td> 359</td><td>B-1</td><td>4-carbamoylphenylboronic acid</td>

<td> 361</td><td>B-3</td><td>3-chlorophenylboronic acid</td>

<td> 365</td><td>B-1</td><td>3-carbamoylphenylboronic acid</td>

<td> 367</td><td>B-7</td><td>3- (hydroxymethyl) phenylboronic acid</td>

<td> 368</td><td>B-4</td><td>4- (dimethylcarbamoyl) phenylboronic acid</td>

<td> 370</td><td>B-5</td><td>3- (hydroxymethyl) phenylboronic acid</td>

<td> 371</td><td>B-5</td><td>3- (methylcarbamoyl) phenylboronic acid</td>

<td> 374</td><td>B-6</td><td>4-sulfamoylphenylboronic acid</td>

<td> 375</td><td>B-5</td><td>4-carbamoylphenylboronic acid</td>

<td> 389</td><td>B-12</td><td>2-Methyl-3- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) benzoic acid</td>

<td> 390</td><td>B-11</td><td>3-methoxy-5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) benzoic acid</td>

<td> 391</td><td>B-13</td><td>4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) benzoic acid</td>

<td> 392</td><td>B-11</td><td>3-Methyl-4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) benzoic acid</td>

<td> 393</td><td>B-12</td><td>2-chloro-5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) benzoic acid</td>

<td> 394</td><td>B-12</td><td>3-methoxy-5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) benzoic acid</td>

<td> 395</td><td>B-2</td><td>4-cyclohexylphenylboronic acid</td>

122

<td>Relationship No.</td><td>Amine</td><td>Boronic acid</td>

<td> 397</td><td>B-11</td><td>3- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) benzoic acid</td>

<td> 398</td><td>B-12</td><td>3-fluoro-5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) benzoic acid</td>

<td> 399</td><td>B-13</td><td>2-methoxy-4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) benzoic acid</td>

<td> 400</td><td>B-13</td><td>3-fluoro-5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) benzoic acid</td>

<td> 401</td><td>B-11</td><td>2-Methyl-3- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) benzoic acid</td>

<td> 402</td><td>B-12</td><td>2-methoxy-4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) benzoic acid</td>

<td> 403</td><td>B-11</td><td>2-fluoro-5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) benzoic acid</td>

<td> 404</td><td>B-11</td><td>2-methoxy-4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) benzoic acid</td>

<td> 405</td><td>B-12</td><td>2-fluoro-4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) benzoic acid</td>

<td> 406</td><td>B-13</td><td>2-fluoro-4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) benzoic acid</td>

<td> 407</td><td>B-11</td><td>4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) benzoic acid</td>

<td> 408</td><td>B-13</td><td>2-fluoro-5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) benzoic acid</td>

<td> 410</td><td>B-2</td><td>4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) aniline</td>

<td> 411</td><td>B-13</td><td>3- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) benzoic acid</td>

<td> 412</td><td>B-2</td><td>2-methoxypyridin-3-ylboronic acid</td>

<td> 414</td><td>B-11</td><td>3-fluoro-5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) benzoic acid</td>

<td> 415</td><td>B-13</td><td>3-Methyl-4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) benzoic acid</td>

<td> 417</td><td>B-12</td><td>2-fluoro-5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) benzoic acid</td>

<td> 418</td><td>B-4</td><td>3- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) benzoic acid</td>

<td> 419</td><td>B-11</td><td>2-chloro-5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) benzoic acid</td>

<td> 420</td><td>B-2</td><td>4- (hydroxymethyl oboronic ophthalmic acid)</td>

<td> 421</td><td>B-11</td><td>2-fluoro-4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) benzoic acid</td>

<td> 422</td><td>B-12</td><td>3-Methyl-4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- acid</td>

123

<td>Relationship No.</td><td>Amine</td><td>Boronic acid</td>

<td></td><td></td><td>yl) benzoic acid</td>

<td colspan="3">(a) After the coupling reaction, the Boc protecting group was removed by treating the crude reaction mixture with 0.5 mL of 1 N HCl in diethyl ether for 18 hours, then purified by HPLC.</td>

[0356] Further exemplary compounds of the invention can be prepared by modifying intermediates as shown above.

Derivatization of a compound after coupling:

DD. 1- (Benzo [d] [1,3] dioxol-5-yl) -N- (6- (4- (2-methylpyrrolidin-1-ylsulfonyl) phenyl) pyridin-2-yl) cyclopropane carboxamide [0357]

<img file="PL1945632T3_D0085.tif" />

Step a: 4- (4,4'-dimethoxybenzhydryl) thiophenylboronic acid [0358] 4,4'-Dimethoxybenzhydrol (2.7 g, 11 mmol) and 4-mercaptophenyl boronic acid (1.54 g, 10 mmol) are dissolved in ml AcOH and heated at 60 ° C for 1h. The solvent was evaporated and the residue was dried under high vacuum. This substance was used without further purification.

Step b: 6- (4- (Bis (4-methoxyphenyl) methylthio) phenyl) pyridin-2-amine 4- (4,4'-dimethoxybenzhydryl) thiophenylboronic acid (10 mmol) and 2-amino-615 bromo pyridine (1.73 g, 10 mmol) was dissolved in MeCN (40 mL) and then added

Pd (PPh₃)₄ (~ 50 mg) and an aqueous solution of K₂WHAT₃ (1M, 22 ml). The reaction mixture was heated in portions in a microwave oven (160 ° C, 400 s). These products were partitioned between ethyl acetate and water. The organic layer was washed with water, brine and dried over MgSO4.

124

Evaporation of volatiles gave an oil that was used without purification in the next step. ESI-MS m / z calculated 428.0, found 429.1 (M + 1).

Step c: 1- (Benzo [d1 [1,31-dioxol-5-yl) -N- (6- (4- (bis (4-methoxyphenyl) methylthio) phenyl) pyridin-2-yl) opropanocarb with oxy d [ 0360] 6 - [(4,4'-Dimethoxybenzhydryl) -4-thiophenyl-pyridin-2-ylamine (~ 10 mmol) and 1-benzo [1,31-dioxol-5-yl-cyclopropanecarboxylic acid (2.28 g, 11 mmol) were dissolved in chloroform (25 mL) followed by TCPH (4.1 g, 12 mmol) and DIEA (5 mL, 30 mmol). The reaction mixture was heated at 65 ° C for 48 h after which the volatiles were removed under reduced pressure. The residue was transferred to a separatory funnel and partitioned between water (200 ml) and ethyl acetate (150 ml). The organic layer was washed with 5% NaHCO₃ (2 x 150 ml), water (1 x 150 ml), brine (1 x 150 ml) and dried over MgSO₄. Evaporation of the solvent gave crude 1- (benzo [d1 [1,31-dioxol-5-yl) -N- (6- (4- (bis (4-methoxyphenyl) methylthio) phenyl) pyridin-2-yl) cyclopropanecarboxamide as pale oil. ESI-MS m / z calculated 616.0, found 617.0 (M + 1) (HPLC purity ~ 85%, UV 254 nm).

Step d: 4- (6- (1- (benzo [d1 [1,31-dioxol-5-yl) cyclopropanecarboxamido) pyridin-2-yl) benzenesulfonic acid [0361] 1- (Benzo [d1 [1,31-dioxol-5-yl) -N- (6- (4- (bis (4-methoxyphenyl) methylthio) phenyl) pyridin-2-yl) cyclopropanecarboxamide (~ 8.5 mmol) was dissolved in AcOH (75 mL) followed by 30% H₂ABOUT₂ (10 ml). After 2 h, hydrogen peroxide (10 ml) was added. The reaction mixture was stirred at 35-45 ° C overnight (~ 90% conversion, HPLC). The volume of the reaction mixture was reduced to one-third by evaporation (bath temperature below 40 ° C). The reaction mixture was placed directly on a preparative RP HPLC column (C-18) and purified. Fractions containing 4- (6- (1- (benzo [d1- [1,31-dioxol5-yl) cyclopropanecarboxamido) pyridin-2-yl) benzenesulfonic acid were collected and evaporated (1.9 g, 43%, calculated as acid 4 -merkaptofenyloboronowy). ESI-MS m / z calculated 438.0, found 438.9 (M + 1).

Step e: 4- (6- (1- (benzo [d1 [1,31-dioxol-5-yl) cyclopropanecarboxamido) pyridin-2-yl) benzene-1-sulfonyl chloride [0362] 4- (6- (1- (benzo [d1 [1,31-dioxol-5-yl) cyclopropanecarboxamido) pyridin-2-yl) benzenesulfonic acid (1.9 g, 4.3 mmol) was dissolved in POCl₃ (30 ml) followed by SOCl₂ (3 ml) and DMF (100 g). The reaction mixture was heated at 70-80 ° C for 15 min. The volatiles were evaporated and then evaporated again with chloroformemtoluene. The residual brown oil was diluted with chloroform (22 mL) and immediately used for sulfonylation. ESI-MS m / z calculated 456.0, found 457.1 (M + 1). Step f: 1- (Benzo [d1 [1,31-dioxol-5-yl) -N- (6- (4- (2-methylpyrrolidin-1-ylsulfonyl) phenyl) pyridin-2-yl) opropanocarb with oxy d [ 0363] 4- (6- (1- (benzo [d1 [1,31-dioxol-5-yl) cyclopropanecarboxamido) pyridin-2-yl) benzene-1-sulfonyl chloride (~ 35 gmol, 400 g solution in chloroform) was treated with 2- methylpyrrolidine and then DIEA (100 g) was added. The reaction mixture was kept at room temperature for 1h, concentrated and then diluted with DMSO (400g). The resulting solution was purified by HPLC. Fractions containing the desired substance were combined and concentrated in a vacuum centrifuge at 40 ° C to give the trifluoroacetate salt of the desired substance (ESI-MS m / z calculated 505.0, found

505.9 (M + 1), retention time 4.06 min). ¹H NMR (250 MHz, DMSO-ffc) δ 1.15 (m, 2H), δ

1.22 (d, 3H, J = 6.3 Hz), δ 1.41-1 , 47 (m, 2H), δ 1.51 (m, 2H), δ 1.52-1.59 (m , 2H), δ 3.12 (m, 1h), δ 3.33 (m, 1h), δ 3.64 (m, 1H), δ 6.07 (s, 2H), δ 6.96-7 , 06 (m, 2H), δ 7.13 (d, 1H, J = 1.3 Hz), δ 7.78 (d, 1H, J = 8.2 Hz), δ 7.88 (d, 2H , J = 8.5 Hz), δ 7.94 (t, 1H, J = 8.2 Hz), δ 8.08 (d, 1H, J = 8.2 Hz), δ 8.16 (d, 2H, J = 8.5 Hz), δ 8.53 (s, 1h).

[0364] The compounds in the following table were synthesized as described above using commercially available amines. Additional exemplary compounds of the invention were prepared according to the above procedure without significant change using the amines shown in Table 5.

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Table 5: Additional exemplary compounds of formula I.

<td>Relationship No.</td><td>Amine</td>

<td> 13</td><td>1-methylpiperazine</td>

<td> 22</td><td>2,6-dimethylmorpholine</td>

<td> 30</td><td>piperidin-3-ylmethanol</td>

<td> 34</td><td>2- (methylamino) ethanol</td>

<td> 35</td><td>(R) -pyrrolidin-2-ylmethanol</td>

<td> 75</td><td>2- (pyrrolidin-1-yl) ethanamine</td>

<td> 76</td><td>pyrrolidine</td>

<td> 90</td><td>piperidine</td>

<td> 103</td><td>(Tetrahydrofuran-2-yl) methanamine</td>

<td> 109</td><td>piperidin-4-ol</td>

<td> 117</td><td>2-methylpropane-2-amine</td>

<td> 118</td><td>op entanoamine cycle</td>

<td> 125</td><td>(S) -2- (methoxymethyl) pyrrolidine</td>

<td> 133</td><td>(R) -2- (methoxymethyl) pyrrolidine</td>

<td> 141</td><td>piperidin-4-ylmethanol</td>

<td> 156</td><td>N-metylopropanoamina</td>

<td> 163</td><td>pyrrolidin-3-ol</td>

<td> 168</td><td>2- (2-aminoethoxy) ethanol</td>

<td> 172</td><td>2-morfolinoetanoamina</td>

<td> 175</td><td>furan-2-ylmethanamine</td>

<td> 176</td><td>piperidin-3-ol</td>

<td> 178</td><td>2- (1-methylpyrrolidin-2-yl) ethanamine</td>

<td> 180</td><td>3-methylpiperidine</td>

<td> 182</td><td>(S) -pyrrolidine-2-carboxamide</td>

<td> 184</td><td>(R) -1-amino-propan-2-ol</td>

<td> 197</td><td>2-aminopropane-1,3-diol</td>

<td> 199</td><td>2-amino-2-etylopropano-1,3-diol</td>

<td> 203</td><td>N^andN^and N-dimethylethane-1,2-diamine</td>

<td> 205</td><td>(R) -2-Amino-3-methylbutan-1-ol</td>

<td> 208</td><td>cvclohexanamine</td>

<td> 212</td><td>piperazin-2-one</td>

<td> 232</td><td>2-aminoethanol</td>

<td> 233</td><td>piperidin-2-ylmethanol</td>

<td> 234</td><td>2- (piperazin-1-yl) ethanol</td>

<td> 244</td><td>N- (cyclopropylmethyl) propane-1-amine</td>

<td> 249</td><td>3-morpholinopropane-1-amine</td>

126

<td>Relationship No.</td><td>Amine</td>

<td> 261</td><td>1- (piperazin-1-yl) ethanone</td>

<td> 267</td><td>2- (1H-imidazol-4-yl) ethanamine</td>

<td> 268</td><td>(R) -2-amino-propan-1-ol</td>

<td> 270</td><td>2-methylpiperidine</td>

<td> 273</td><td>2- (pyridin-2-yl) ethanamine</td>

<td> 275</td><td>3,3-difluoropyrrolidine</td>

<td> 276</td><td>2-amino-2-methylpropan-1-ol</td>

<td> 285</td><td>3- (1H-imidazol-1-yl) propane-1 -amine</td>

<td> 304</td><td>piperidine-3-carboxamide</td>

<td> 306</td><td>Cyklobutanoamina</td>

<td> 307</td><td>(S) -3-aminopropane-1,2-diol</td>

<td> 311</td><td>A-methylcyclohexanamine</td>

<td> 312</td><td>A-methylprop-2-ene-1-amine</td>

<td> 316</td><td>2-amino-2-methylpropane-1,3-diol</td>

<td> 325</td><td>(5-methyl-furan-2-yl) methanamine</td>

<td> 330</td><td>3,3-dimethylbut-1-amine</td>

<td> 332</td><td>2-methylpyrrolidine</td>

<td> 335</td><td>2,5-Dimethylpyrrolidine</td>

<td> 336</td><td>(R) -2-aminobutan-1-ol</td>

<td> 338</td><td>propane-2-amine</td>

<td> 339</td><td>A-methylbutane-1 -amine</td>

<td> 342</td><td>4-amino-3-hydroxybutanoic acid</td>

<td> 344</td><td>3- (methylamino) propane-1,2-diol</td>

<td> 347</td><td>A- (2-aminoethyl) acetamide</td>

<td> 360</td><td>1-aminobutane-2-ol</td>

<td> 364</td><td>(S) -pyrrolidine-2-carboxylic acid</td>

<td> 366</td><td>1- (2-methoxyethyl) piperazine</td>

<td> 373</td><td>(R) -2-aminopentan-1-ol</td>

EE. 1-Benzo [1,3] dioxol-5-yl-A- [6- [4 - [(methylmethylsulfonylamino) methyl] phenyl] -2-pyridyl] cyclopropane-1-carboxamide (Compound No. 292) [0365]

<img file="PL1945632T3_D0086.tif" />

[0366] To the starting amine (brown semi-solid, 0.100 g, ~ 0.2 mmol, obtained by treatment of the appropriate t-butyloxycarbonyl derivative with 1 N

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HCl in ether) added dichloroethane (DCE) (1.5 mL) followed by pyridine (0.063 mL, 0.78 mmol) and methanesulfonyl chloride (0.03 mL, 0.4 mmol). The mixture was stirred at 65 ° C for 3 hours. After this time, LC / MS analysis showed ~ 50% conversion to the desired product. An additional two equivalents of pyridine and 1.5 equivalents of methanesulfonyl chloride were added and the reaction mixture was stirred for 2 hours.

The residue was concentrated and purified by HPLC to give 1-benzo [1,3] dioxol-5-yl-N- [6- [4 - [(methylmethylsulfonylamino) methyl] phenyl] -2-pyridyl] cyclopropane-1-carboxamide (0.020 g , 21% yield) as a white solid. ESI-MS m / z calculated 479.2, found 480.1 (M + 1) +.

FF. (R) -1- (3-hydroxy-4-methoxyphenyl) -N- (6- (4- (2- (hydroxymethyl) pyrrolidine-1-sulfonyl) phenyl) pyridin-2-yl) cyclopropanecarboxamide

<img file="PL1945632T3_D0087.tif" />

(R) -1- (3- (Benzyloxy) -4-methoxyphenyl) -N- (6- (4- (2- (hydroxymethyl) pyrrolidin-1-ylsulfonyl) phenyl) pyridin-2-yl) cyclopropanecarboxamide ( 28 mg, 0.046 mmol) was dissolved in ethanol (3 mL). Palladium on charcoal (10%, 20 mg) was added and the reaction mixture was stirred overnight under 1 atm hydrogen pressure. The catalyst was filtered off and the product isolated by silica gel chromatography (5080% EtOAc in hexane) to give (R) -1- (3-hydroxy-4-methoxyphenyl) -N- (6- (4- (2- (hydroxymethyl)) pyrrolidin-1-ylsulfonyl) phenyl) pyridin-220-yl) cyclopropanecarboxamide (8 mg, 34%). ESI-MS m / z calculated 523.4, found 524.3 (M + 1) +. Retention time 3.17 minutes.

2-Amino-5-phenylpyridine (CAS [33421-40-8]) is C-1.

GG. (R) - (1- (4- (6-aminopyridin-2-yl) phenylsulfonyl) pyrrolidin-2-yl) methanol hydrochloride (C-2) [0369]

<img file="PL1945632T3_D0088.tif" />

Step a: (R) - (1- (4-Bromophenylsulfonyl) pyrrolidin-2-yl) methanol [0370] To a mixture of sat. aq. NaHCO₃ (44 g, 0.53 mol), CH₂cl₂ (400 ml) and pyrrolidin-2128 ylmethanol (53 g, 0.53 mol) a solution of 4-bromobenzenesulfonyl chloride (127 g, 0.50 mol) in CH was added₂cl₂ (100 ml). The reaction mixture was stirred at 20 ° C overnight. The organic phase was separated and dried over Na₂SO₄. Evaporation of the solvent under reduced pressure gave (R) - (1- (4-bromophenylsulfonyl) pyrrolidin-2-yl) methanol (145 g, crude) which was used without further purification in the next step.¹H NMR (CDCl3, 300 MHz) δ 7.66-7.73 (m, 4H), 3.59-3.71 (m, 3H), 3.43-3.51 (m, 1H) , 3.18-3.26 (m, 1H), 1.680-1.88 (m, 3H), 1.45-1.53 ​​(m, 1H).

Step b: (R) -1- (4-Bromobenzenesulfonyl) -2- (tert-butyldimethylsilanyloxymethyl) -pyrrolidine [0371] To a solution of [1- (4-bromobenzenesulfonyl) pyrrolidin-2-yl] methanol (50.0 g, 0.16 mol) and 1H-imidazole (21.3 g, 0.31 mol) in CH₂cl₂ (500 ml) tert-butylchlorodimethylsilane (35.5 g, 0.24 mol) was added portionwise. After the addition was complete, the mixture was stirred for 1 hour at room temperature. The reaction mixture was quenched with water (200 mL) and the separated aqueous layer was extracted with CH 2 Cl 2 (100 mL χ 3). The combined organic layers were washed with brine, dried over Na2SO4 and evaporated in vacuo to give 1- (4-bromo-benzenesulfonyl) -2- (tert-butyldimethylsilanyloxymethyl) pyrrolidine (68.0 g, 99%).¹H NMR (300 MHz, CDCl3) δ 7.63-7.71 (m, 4H), 3.77-3.81 (m, 1H), 3.51-3.63 (m, 2H) , 3.37-3.43 (m, 1H), 3.02-3.07 (m, 1H), 1.77-1.91 (m, 2H), 1.49-1.57 (m, 2H), 0.87 (s, 9H), 0.06 (d, J = 1.8 Hz, 6H).

Step c: (R) -4- (2 - ((tert-butyldimethylsilyloxy) methyl) pyrrolidin-1-ylsulfonyl) phenylboronic acid [0372] To a solution of 1- (4-bromobenzenesulfonyl) -2- (tert-butyldimethylsilanyloxymethyl) pyrrolidine ( 12.9 g, 29.7 mmol) and B (OiPr) 3 (8.4 g, 45 mmol) in anhydrous THF (100 mL) was added dropwise "-BuLi (2.5 M in hexane, 29.7 mL) in -70 ° C. After the addition was complete, the mixture was slowly warmed to -10 ° C and treated with HCl (1 M, 50 mL). The organic layer was separated and the aqueous layer was extracted with ethyl acetate. The combined organic layers were dried over Na₂SO₄ and evaporated in vacuo. The organics were combined to give crude (R) -4- (2 - ((tert-butyldimethylsilyloxy) methyl) pyrrolidin-1-ylsulfonyl) phenylboronic acid (15.0 g), which was used directly in the next step.

Step d: (6- {4- [2- (tert-butyldimethylsilanyloxymethyl) -pyrrolidine-1-sulfonyl] phenyl} pyridin-2-yl) -carbamic acid tert-butyl ester [0373] For tert- ester solution (6-bromopyridin-2-yl) carbamic acid (24.6 g, 90.0 mmol) in DMF (250 mL) added (R) -4- (2 - ((tert-butyldimethylsilyloxy) methyl) pyrrolidinic acid 1-ylsulfonyl) phenylboronic (45.0 g), Pd (PPh₃)₄ (10.4 g, 9.0 mmol), potassium carbonate (18.6 g, 135 mol) and water (200 ml). The resulting mixture was degassed by gently bubbling arum bubbles through the solution for 5 minutes at 20 ° C. The reaction mixture was then heated at 80 ° C overnight. DMF was removed in vacuo. EtOAc (300 mL) was added to the residue. The mixture was filtered through a pad of silica gel which was washed with EtOAc (50 mL × 3). The combined organic extracts were evaporated in vacuo. The crude residue was purified using a column (petroleum ether / EtOAc 20: 1) to give (6- {4- [2- (tert-butyldimethylsilanyloxymethyl) pyrrolidine-1-sulfonyl] phenyl} pyridin-2-yl) carbamic acid tert-butyl ester. (22.2 g, 45% for 2 stages). ¹H NMR (300 MHz, CDCl₃) δ 8.09 (d, J = 8.4 Hz, 2H), 7.88-7.96 (m, 3H), 8.09 (t, J = 7.8 Hz, 1H), 7.43-7.46 (m, 1H), 7.38 (s, 1H), 3.83-3.88 (m, 1H), 3.64-3.67 (m, 1H) ), 3.53-3.59 (m, 1H), 3.41-3.47 (m, 1H), 3.083.16 (m, 1H), 1.82-1.91 (m, 2H), 1.67-1.69 (m, 1H), 1.53-1.56 (m, 10H), 0.89 (s, 9H), 0.08 (d, J = 2.4 Hz, 6H).

Step e: {6- [4- (2-hydroxymethylpyrrolidine-1-sulfonyl) phenyl] pyridin-2-ylcarbamic acid tert-butyl ester [0374] Solution of crude acid tert-butyl ester (6- {4- [2- ( tert-butyldimethylsilanyloxymethyl) pyrrolidine-1-sulfonyl] phenyl} pyridin-2-yl) carbamate (22.2 g,

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40.5 mmol) and TBAF (21.2 g, 81.0 mmol) in DCM (300 mL) was stirred at room temperature overnight. The mixture was washed with brine (100 mL x 3), dried over Na₂SO₄ and evaporated in vacuo to give {6- [4- (2-hydroxymethylpyrrolidine-1-sulfonyl) phenyl] pyridin-2-yl} carbamic acid tert-butyl ester (15.0 g, 86%), which was used directly in next stage.

Step f: (R) - (1- (4- (6-aminopyridin-2-yl) phenylsulfonyl) pyrrolidin-2-yl) methanol hydrochloride (C-2) [0375] {6- [4- (2-hydroxymethylpyrrolidine-1-sulfonyl) phenyl] pyridin-2-yl} carbamate (15.0 g, 34.6 mmol) in HCl / MeOH (50 mL, 2 M) was heated to reflux for 2 h. After cooling to room temperature, the reaction mixture was evaporated in vacuo and washed with EtOAc to give (R) - (1- (4- (6-aminopyridin-2-yl) phenylsulfonyl) pyrrolidin-2-yl) methanol (C-2 hydrochloride; 11.0 g, 86%). ¹H NMR (300 MHz, DMSO-de) δ 8.18 (d, J = 8.7 Hz, 2 h), 7.93-7.99 (m, 3 H), 7.31 (d, J = 7.2 Hz, 1H), 7.03 (d, J = 8.7 Hz, 1H), 3.53-3.57 (m, 2H), 3.29-35 (m, 2H ), 3.05-3.13 (m, 1H), 1.77-1.78 (m, 2H), 1.40-1.45 (m, 2H). MS (ESI) m / z (M + H) + 334.2.

HH. N- (4- (6-Aminopyridin-2-yl) benzyl) methanesulfonamide (C-3) [0376]

<img file="PL1945632T3_D0089.tif" />

Step a: [6- (4-Cyanophenyl) pyridin-2-yl] carbamic acid tert-butyl ester [0377] A mixture of 4-cyanobenzeneboronic acid (7.35 g, 50 mmol), tert-butyl ester (6-bromopyridin-2 -yl) carbamic (13.8 g, 50 mmol), Pd (Ph3P) 4 (5.8 g, 0.15 mmol) and K₂WHAT₃ (10.4 g, 75 mmol) in DMF / H₂O (1: 1, 250 mL) was stirred under argon at 80 ° C overnight. DMF was evaporated under reduced pressure and the residue was dissolved in EtOAc (200 mL). The mixture was washed with water and brine, dried over Na2SO4 and concentrated to dryness. The residue was purified using silica gel column / EtOAc 50: 1 to give [6- (4-cyanophenyl) pyridin-2-yl] carbamic acid tert-butyl ester (7.0 g, 60% ).¹H NMR (300 MHz, CDCh) δ 8.02-8.07 (m, 2H), 7.95 (d, J = 8.4 Hz, 1H), 7.71-7.79 (m, 3H), 7.37-7.44 (m, 2H), 1.53 (s, 9H).

Step b: [6- (4-aminomethylphenyl) pyridin-2-yl] carbamic acid tert-butyl ester [0378] Suspension of [6- (4-cyanophenyl) pyridin-2-yl] carbamic acid tert-butyl ester (7.0 g , 24 mmol), Ni Raney (1.0 g) in EtOH (500 ml) and NH₃.H₂O (10 ml) was hydrogenated under H atmosphere₂ (50 psi) at 50 ° C for 6 h. The catalyst was filtered off and the filtrate concentrated to dryness to afford [6- (4-aminomethylphenyl) pyridin-2-yl] carbamic acid tert-butyl ester, which was used directly in next stage. ¹H NMR (300 MHz, CDCl₃) δ 7.83-7.92 (m, 3H), 7.70 (t, J = 7.8 Hz, 1H), 7.33-7.40 (m, 4H), 3.92 ( brs, 2H), 1.53 (s, 9H).

Step c: {6- [4- (methanesulfonylaminomethyl) phenyl] pyridin-2-yl} carbamic acid ZerZ-butyl ester [0379] To a solution of [6- (4-aminomethylphenyl) pyridin-2130-yl] carbamic acid tert-butyl ester (5 , 7 g 19 mmol) and Et₃N (2.88 g, 29 mmol) in dichloromethane (50 mL) was added MsCl (2.7 g, 19 mmol) dropwise at 0 ° C. The reaction mixture was stirred at this temperature for 30 min, then washed with water and brine, dried over Na2SO4 and concentrated to dryness. The residue was recrystallized from DCM / petroleum ether (1: 3) to give {6- [4- (methanesulfonylaminomethyl) phenyl] pyridin-2-yl} carbamic acid tert-butyl ester (4.0 g, 44% for two stages).¹H NMR (300 MHz, CDCl3) δ 7.90-7.97 (m, 3H), 7.75 (t, J = 8.4, 8.4 Hz, 1H), 7.54-7, 59 (m, 1H), 7,387.44 (m, 3H), 4.73 (br, 1H), 4.37 (d, J = 6.0 Hz, 2H), 2.90 (s , 3H), 1.54 (s, 9H).

Step d: N- (4- (6-Aminopyridin-2-yl) benzyl) methanesulfonamide (C-3) [0380] Mixture of {6- [4- (methanesulfonylaminomethyl) phenyl] pyridin-2-yl acid tert-butyl ester carbamic acid (11 g, 29 mmol) in HCl / MeOH (4M, 300 mL) was stirred at room temperature overnight. The mixture was concentrated to dryness. The residue was filtered off and washed with ether to give A- (4- (6-aminopyridin-2-yl) benzyl) methanesulfonamide (C-3) (7.6 g, 80%)¹H NMR (300 MHz, DMSO-d₆) δ 14.05 (br s, 1H), 8.24 (br s, 2H), 7.91-7.98 (m, 3H), 7.70 (t, J = 6.0 Hz , 1H), 7.53 (d, J = 8.1 Hz, 2H), 7.22 (d, J = 6.9 Hz, 1H), 6.96 (d, J = 9 Hz, 1H), 4.23 (d, J = 5.7 Hz, 2H), 2.89 (s, 3H). MS (ESI) m / z (m + H) +: 278.0,

II. 4- (6-aminopyridin-2-yl) -A-methylbenzenesulfonamide hydrochloride (C-4) [0381]

<img file="PL1945632T3_D0090.tif" />

Step a: 4-Bromo-A-methylbenzenesulfonamide [0382] To a mixture of saturated aqueous NaHCO3 (42 g, 0.5 mol), CH2Cl2 (400 ml) and methylamine (51.7 g, 0.5 mol, 30% in methanol) a solution of 4-bromobenzenesulfonyl chloride (127 g, 0.5 mol) in CH 2 Cl 2 (100 ml) was added. The reaction mixture was stirred at 20 ° C overnight. The organic phase was separated and dried over Na2SO4. Evaporation of the solvent under reduced pressure gave 4-bromo-Amethylbenzenesulfonamide (121 g, crude) which was used without further purification in the next step. ¹1 H NMR (CDCl₃, 300 MHz) δ 7.64-7.74 (m, 4H), 4.62-4.78 (m, 1H), 2.65 (d, J = 5.4 Hz, 3H).

Step b: 4- (A-Methylsulfamoyl) phenylboronic acid [0383] To a solution of 4-bromo-A-methylbenzenesulfonamide (24.9 g, 0.1 mol) and B (O^andPr) 3 (28.2 g, 0.15 mol) in THF (200 ml) n-BuLi (100 ml, 0.25 mol) was added at -70 ° C. The mixture was slowly warmed to 0 ° C, then a 10% HCl solution was added until pH 3 ~ 4. The resulting mixture was extracted with EtOAc. The organic layer was dried over Na2SO4 and evaporated under reduced pressure to give 4- (Amethylsulfamoyl) phenylboronic acid (22.5 g, 96%), which was used without further purification in the next step.¹H NMR (DMSO-J₆, 300 MHz) δ 8.29 (s, 2 H), 7.92 (d, J = 8.1 Hz, 2 H), 7.69 (d, J = 8.4 Hz, 2 H), 2 , 36 (d, J = 5.1 Hz, 3H).

Step c: tert-butyl 6- (4- (A-methylsulfamoyl) phenyl) pyridin-2-ylcarbamate [0384] To a solution of 4- (A-methylsulfamoyl) phenylboronic acid (17.2 g, 0.08 mol) and ester (6-bromopyridin-2-yl) carbamic acid tert-butyl (21.9 g, 0.08 mol) in DMF (125 ml) and H2O (125 ml) Pd (PPh3) 4 (9.2 g, 0.008 mol) and K2CO3 (16.6 g,

131

0.12 mole). The resulting mixture was degassed by gently bubbling argon bubbles through the solution for 5 minutes at 20 ° C. The reaction mixture was then heated at 80 ° C for 16 h. The mixture was evaporated under reduced pressure, then poured into H 2 O and extracted with EtOAc. The organic phase was dried over Na2SO4 and evaporated under reduced pressure to give tert-butyl 6- (4- (N-methylsulfamoyl) phenyl) pyridin-2-ylcarbamate (21 g, 58%), which was used without further purification in the next step.

Step d: 4- (6-aminopyridin-2-yl) -N-methylbenzenesulfonamide hydrochloride To a solution of tert-butyl 6- (4- (N-methylsulfamoyl) phenyl) pyridin-2-ylcarbamate (8.5 g, 23 , 4 mmol) in MeOH (10 mL) HCl / MeOH (2M, 50 mL) was added at room temperature. The suspension was stirred at room temperature overnight. The solid product was collected by filtration, washed with MeOH and dried to give 4- (6-aminopyridin-2-yl) -N-methylbenzenesulfonamide hydrochloride (5.0 g, 71%).¹H NMR (300 Hz, DMSO-O) δ 8.12 (d, J = 8.4 Hz, 2H), 7.91-7.96 (m, 3H), 7.58-7.66 ( m, 1

H), 7.31-7.53 (m, 1H), 7.27 (d, J = 6.6, 1H), 6.97 (d, J = 9.0, 1H), 2 , 43 (d, J = 4.8 Hz, 3

h). MS (ESI) m / z (M + H) + 264.0.

[0386] The compounds of the following table were synthesized as described above using commercially available or previously described carboxylic acids and amines.

Table 6: Additional exemplary compounds of formula I.

<td>Relationship No.</td><td>Carboxylic acid</td><td>Amine</td>

<td> 164</td><td>A-9</td><td>C-1</td>

<td> 165</td><td>A-3</td><td>C-2</td>

<td> 169</td><td>A-17</td><td>C-3</td>

<td> 170</td><td>A-3</td><td>C-4</td>

<td> 177</td><td>A-2</td><td>C-3</td>

<td> 183</td><td>A-13</td><td>C-4</td>

<td> 192</td><td>A-8</td><td>C-2</td>

<td> 200</td><td>A-14</td><td>C-2</td>

<td> 201</td><td>A-4</td><td>C-3</td>

<td> 202</td><td>A-15</td><td>C-2</td>

<td> 211</td><td>A-15</td><td>C-3</td>

<td> 214</td><td>A-6</td><td>C-2</td>

<td> 218</td><td>A-2</td><td>C-4</td>

<td> 220</td><td>A-4</td><td>C-2</td>

<td> 221</td><td>A-10</td><td>C-2</td>

<td> 223</td><td>A-17</td><td>C-4</td>

<td> 226</td><td>A-20</td><td>C-2</td>

<td> 228</td><td>A-10</td><td>C-3</td>

<td> 236</td><td>A-24</td><td>C-2</td>

<td> 237</td><td>A-11</td><td>C-3</td>

<td> 239</td><td>A-23</td><td>C-2</td>

<td> 240</td><td>A-11</td><td>C-4</td>

<td> 242</td><td>A-13</td><td>C-2</td>

132

<td>Relationship No.</td><td>Carboxylic acid</td><td>Amine</td>

<td> 245</td><td>A-15</td><td>C-4</td>

<td> 246</td><td>A-8</td><td>C-3</td>

<td> 248</td><td>A-13</td><td>C-3</td>

<td> 250</td><td>A-16</td><td>C-4</td>

<td> 253</td><td>A-22</td><td>C-2</td>

<td> 256</td><td>A-2</td><td>C-2</td>

<td> 259</td><td>A-24</td><td>C-4</td>

<td> 262</td><td>A-10</td><td>C-4</td>

<td> 271</td><td>A-14</td><td>C-4</td>

<td> 279</td><td>A-19</td><td>C-2</td>

<td> 281</td><td>A-16</td><td>C-2</td>

<td> 282</td><td>A-8</td><td>C-4</td>

<td> 284</td><td>A-17</td><td>C-2</td>

<td> 302</td><td>A-5</td><td>C-2</td>

<td> 317</td><td>A-10</td><td>C-1</td>

<td> 318</td><td>A-21</td><td>C-2</td>

<td> 319</td><td>A-6</td><td>C-4</td>

<td> 340</td><td>A-11</td><td>C-2</td>

<td> 341</td><td>A-5</td><td>C-3</td>

<td> 345</td><td>A-9</td><td>C-3</td>

<td> 358</td><td>A-18</td><td>C-2</td>

<td> 362</td><td>A-16</td><td>C-3</td>

<td> 363</td><td>A-5</td><td>C-4</td>

<td> 369</td><td>A-9</td><td>C-4</td>

<td> 372</td><td>A-9</td><td>C-2</td>

<td> 376</td><td>A-35</td><td>C-2</td>

<td> 377</td><td>A-32</td><td>C-2</td>

<td> 378</td><td>A-27</td><td>C-2</td>

<td> 379</td><td>A-36</td><td>C-2</td>

<td> 380</td><td>A-34</td><td>C-2</td>

<td> 381</td><td>A-29</td><td>C-2</td>

<td> 382</td><td>A-28</td><td>C-2</td>

<td> 383</td><td>A-25</td><td>C-2</td>

<td> 384</td><td>A-30</td><td>C-2</td>

<td> 385</td><td>A-33</td><td>C-2</td>

<td> 386</td><td>A-31</td><td>C-2</td>

<td> 387</td><td>A-37</td><td>C-2</td>

133

<td>Relationship No.</td><td>Carboxylic acid</td><td>Amine</td>

<td> 388</td><td>A-26</td><td>C-2</td>

<td> 409</td><td>A-38</td><td>C-2</td>

<td> 413</td><td>A-45</td><td>C-2</td>

[0387] Physical data for the compounds of the invention from the examples are given in Table 7. [0388] Additional exemplary compounds 164-388, which are shown in Table 1, can also be prepared using the appropriate starting materials and methods exemplified for the previously described compounds.

<td colspan="4">Table 7: Physical data of exemplary compounds.</td>

<td>No. Relationship</td><td>LCMS [M + H] +</td><td>LCMS RT</td><td>NMR</td>

<td> 1</td><td> 416,3</td><td> 2,39</td><td></td>

<td> 2</td><td> 442,5</td><td> 2,7</td><td></td>

<td> 3</td><td> 427,1</td><td> 4,1</td><td></td>

<td> 4</td><td> 508,3</td><td> 3,43</td><td></td>

<td> 5</td><td> 423,3</td><td> 3,72</td><td></td>

<td> 6</td><td> 390,1</td><td> 3,57</td><td></td>

<td> 7</td><td> 402,5</td><td> 2,96</td><td>1 H NMR (400 MHz, CD₃CN) δ 1.21-1.29 (m, 2H), 1.621,68 (m, 2H), 3.05 (s, 6H), 6.06 (s, 2H), 6.86-6.97 (m, 3H), 7.04-7.08 (m, 2H), 7.53-7.55 (m, 1H), 7.76-7.82 (m, 3H), 7.86 (t , J = 8.0 Hz, 1H), 8.34 (br s, 1H)</td>

<td> 8</td><td> 444,5</td><td> 3,09</td><td></td>

<td> 9</td><td> 430,5</td><td> 2,84</td><td></td>

<td> 10</td><td> 375,3</td><td> 3,39</td><td></td>

<td> 11</td><td> 403,5</td><td> 2,83</td><td></td>

<td> 12</td><td> 390</td><td> 3,14</td><td></td>

<td> 14</td><td> 520,2</td><td> 1,38</td><td></td>

<td> 15</td><td> 387,3</td><td> 3,71</td><td></td>

<td> 16</td><td> 389,3</td><td> 2,9</td><td></td>

<td> 17</td><td> 403,5</td><td> 3,33</td><td></td>

<td> 18</td><td> 403,5</td><td> 3,75</td><td></td>

<td> 19</td><td> 387,1</td><td> 3,76</td><td></td>

<td> 20</td><td> 389</td><td> 2,79</td><td>1 H NMR (400 MHz, CD₃CN / DMSO- ^₆) δ 1.15-1.23 (m, 2H), 1.56-1.61 (m, 2H), 4.60 (s, 2H), 6.05 (s, 2H), 6.94 ( d J = 8.3 Hz, 1H), 7.05-7.09 (m, 2H), 7.44 (d, J = 8.2 Hz, 2H), 7.57-7.62 (m, 2H), 7.92 (s, 1H), 8.00 (dd, J = 2.5, 8.6 Hz, 1H), 8.17 (d , J = 8.6 Hz, 1H), 8.48 (d, J = 1.8 Hz, 1H)</td>

<td> 21</td><td> 360</td><td> 2,18</td><td></td>

<td> 22</td><td> 387,3</td><td> 3,77</td><td></td>

<td> 23</td><td> 535,2</td><td> 2,81</td><td></td>

134

<td>No. Relationship</td><td>LCMS [M + H1 +</td><td>LCMS rt</td><td>nmr</td>

<td> 24</td><td> 464,1</td><td> 2,35</td><td>1H-NMR (DMSO- ^ 6, 300 MHz) δ 8.40 (s, 1H), 7.96 (d, J = 8.4 Hz, 1H), 7.86 (m, 2H), 7.82 (m, 1H), 7.62 (d, J = 7.8 Hz, 1H), 7.36 (d, J = 7.8 Hz, 1H), 7.11 (d, J = 2.1 Hz, 1H), 7.00 (m, 2H), 6.05 ( s, 2H), 3.42 (m, 2H, covered by water), 3.03 (m, J = 5.4 Hz, 2H), 2.98 (t, 1H), 1.49 (m, 2H) . 1.14 (m, 2H).</td>

<td> 25</td><td> 403</td><td> 3,29</td><td>1 H NMR (400 MHz, CD₃CN / DYISCM,) δ 1.14-1.17 (m, 2H), 1.52-1.55 (m, 2H), 6.01 (s, 2H), 6.03 (s, 2H), 6,896,96 (m, 2H), 7.01-7.12 (m, 3H), 7.15 (d, J = 1.8 Hz, 1H), 7.93 (dd, J = 8.7, 2.5 Hz, 1H), 8.05-8.11 (m, 2H), 8.339.41 (m, 1H)</td>

<td> 26</td><td> 393</td><td> 3,88</td><td></td>

<td> 27</td><td> 452,1</td><td> 3,11</td><td></td>

<td> 28</td><td> 427,1</td><td> 4,19</td><td></td>

<td> 29</td><td> 388,9</td><td> 3,58</td><td></td>

<td> 30</td><td> 375,3</td><td> 2,95</td><td></td>

<td> 31</td><td> 535,2</td><td> 2,42</td><td></td>

<td> 32</td><td> 359,1</td><td> 3,48</td><td></td>

<td> 33</td><td> 394,9</td><td> 3,77</td><td></td>

<td> 34</td><td> 360,3</td><td> 2,96</td><td></td>

<td> 35</td><td> 495,1</td><td> 2,24</td><td>1 H-NMR (300 MHz, CDCl₃) δ 8.22 (d, J = 8.7 Hz, 1H), 7.98 (m, 3H), 7.80 (m, 3H), 7.45 (d, J = 7.5 Hz, 1H ), 6.99 (dd, J = 8.1, 1.8 Hz, 2H), 6.95 (d, J = 1.5 Hz, 1H), 6.86 (d, J = 8.1 Hz, 1H), 6.02 (s, 2H), 3.77 (t, J = 5.1 Hz, 2H), 3.17 (m, J = 5.1 Hz, 2H) , 2.85 (s, 3H), 1.70 (q, J = 3.6 Hz, 2H), 1.19 (q, J = 3.6 Hz, 2H).</td>

<td> 36</td><td> 521,2</td><td> 2,36</td><td>1H-NMR (300 MHz, DMSO-d6) δ 8.51 (s, 1H), 8.15 (d, J = 9.0 Hz, 2H), 8.06 (d, J = 8.4 Hz, 1H), 7.92 (t, J = 7.8 Hz, 1h), 7.88 (d, J = 8.1Hz, 2H), 7.76 (d, J = 7.5 Hz, 1h), 7.11 (d, J = 1.2 Hz, 1H), 7.03 (dd, J = 7.8, 1.8 Hz, 1H), 6.97 (d, J = 7.8 Hz, 1H), 6.06 (s, 2H), 3.55 (m, 2H, covered by water), 3.15 (m, 2H), 3.07 (m, 1H), 1 , 77 (m, 2H), 1.50 (dd, J = 7.2, 4.5 Hz, 2H), 1.43 (m, 2H), 1.15 (dd, J = 6.9, 3.9 Hz, 2H).</td>

<td> 37</td><td> 452,3</td><td> 3,38</td><td></td>

<td> 38</td><td> 398</td><td> 3,02</td><td></td>

<td> 39</td><td> 483,1</td><td> 2,58</td><td>1 H-NMR (DMSO-d6, 300 MHz) δ 10.01 (t, J = 6.0 Hz, 1H), 8.39 (s, 1H), 7.97 (d, J = 7.8 Hz, 1H), 7.89 (d, J = 8.4 Hz, 1H), 7.83 (d, J = 7.8 Hz, 1H), 7.62 (d, J = 6.9 Hz, 1H), 7.33 (d, J = 8.4 Hz, 2H), 7.11 (d, J = 2.1 Hz, 1H), 7.03 (d, J = 1.5 Hz, 1H), 6.99 (dd, 7.8 Hz, 2H), 6.05 (s, 2h), 4.41 (d, J = 6 Hz, 2H), 1.48 (m, 2H), 1.14 (m, 2h).</td>

<td> 40</td><td> 393,1</td><td> 3,89</td><td></td>

135

<td>No. Relationship</td><td>LCMS [M + H] +</td><td>LCMS RT</td><td>NMR</td>

<td> 41</td><td> 373,1</td><td> 3,57</td><td></td>

<td> 42</td><td> 421,1</td><td> 3,33</td><td></td>

<td> 43</td><td> 417,3</td><td> 3,62</td><td></td>

<td> 44</td><td> 401,2</td><td> 1,26</td><td></td>

<td> 45</td><td> 403,5</td><td> 3,25</td><td></td>

<td> 46</td><td> 437,3</td><td> 3,19</td><td></td>

<td> 47</td><td> 391,1</td><td> 3,82</td><td></td>

<td> 48</td><td> 384,3</td><td> 3,74</td><td></td>

<td> 49</td><td> 419,3</td><td> 3,27</td><td></td>

<td> 50</td><td> 437</td><td> 3,02</td><td></td>

<td> 51</td><td> 349</td><td> 3,33</td><td></td>

<td> 52</td><td> 373,1</td><td> 3,58</td><td>1H NMR (400 MHz, CD3CN) δ 1.17-1.20 (m, 2H), 1.581.61 (m, 2H), 2.24 (s, 3H), 6.01 (s, 2H), 6 , 90 (d, J = 8.4 Hz, 1H), 7.04-7.06 (m, 2H), 7.16 (dd, J = 7.5, 0.8 Hz, 1H), 7.23-7.33 (m, 4H) , 7.79-7.89 (m, 2H), 8.10 (dd, J = 8.3, 0.8 Hz, 1H)</td>

<td> 53</td><td> 387</td><td> 3,62</td><td></td>

<td> 54</td><td> 394,1</td><td> 3,06</td><td></td>

<td> 55</td><td> 419,3</td><td> 2,92</td><td></td>

<td> 56</td><td> 407,5</td><td> 3,55</td><td></td>

<td> 57</td><td> 388,9</td><td> 2,91</td><td></td>

<td> 58</td><td> 360,2</td><td> 3,74</td><td></td>

<td> 59</td><td> 417,3</td><td> 3,64</td><td></td>

<td> 60</td><td> 402,5</td><td> 3,07</td><td></td>

<td> 61</td><td> 387,1</td><td> 3,84</td><td></td>

<td> 62</td><td> 415,3</td><td> 4,1</td><td></td>

<td> 63</td><td> 384</td><td> 3,35</td><td></td>

<td> 64</td><td> 360,3</td><td> 3,58</td><td></td>

<td> 65</td><td> 465,1</td><td> 2,47</td><td>1H-NMR (300 MHz, CDCla) δ 8.19 (d, J = 8.1 Hz, 1H), 7.97 (d, J = 8.4 Hz, 2H), 7.92 (s, 1H) , 7.89 (d, J = 8.4 Hz, 2H), 7.76 (t, J = 7.5 Hz, 1H), 7.44 (d, J = 7.5 Hz, 1H), 6 , 99 (m, 1H), 6.95 (br s, 1H), 6.86 (d, J = 8.1 Hz, 1H), 6.02 (s, 2H), 4.37 (t, J = 5.7 Hz, 1H), 3.02 (m, 2H), 1.70 (q, J = 3.9 Hz, 2H), 1.17 (q, J = 3.6 Hz, 2H), 1.11 (t, J = 7.2 Hz, 3H).</td>

<td> 66</td><td> 401</td><td> 3,24</td><td></td>

<td> 67</td><td> 393</td><td> 3,88</td><td></td>

<td> 68</td><td> 407,5</td><td> 4,04</td><td></td>

<td> 69</td><td> 377,1</td><td> 3,26</td><td></td>

<td> 70</td><td> 403,5</td><td> 3,69</td><td></td>

136

<td>No. Relationship</td><td>LCMS [M + H] +</td><td>LCMS RT</td><td>NMR</td>

<td> 71</td><td> 472,3</td><td> 3,02</td><td></td>

<td> 72</td><td> 363</td><td> 3,38</td><td></td>

<td> 73</td><td> 449,3</td><td> 3,4</td><td></td>

<td> 74</td><td> 416,3</td><td> 2,43</td><td></td>

<td> 75</td><td> 373,1</td><td> 3,69</td><td></td>

<td> 76</td><td> 534,2</td><td> 1,36</td><td></td>

<td> 77</td><td> 491,2</td><td> 2,7</td><td></td>

<td> 78</td><td> 384,3</td><td> 3,72</td><td></td>

<td> 79</td><td> 388,3</td><td> 2,32</td><td></td>

<td> 80</td><td> 437,3</td><td> 3,42</td><td></td>

<td> 81</td><td> 373</td><td> 3,51</td><td>1 H NMR (400 MHz, CD₃CN / DY1SO-U) δ 1.07-1.27 (m, 2H), 1.50-1.67 (m, 2H), 2.36 (s, 3H), 6.10 (s, 2H) , 6.92 (d, J = 7.9 Hz, 1H), 7.01-7.09 (m, 2H), 7.28 (d, J = 7.9 Hz, 2H), 7.50 (d, J = 8.2 Hz, 2H), 7.93-8.00 (m, 2H), 8.15 (d, J = 9.3 Hz, 1H), 8, 44 (d, J = 2.5 Hz, 1H)</td>

<td> 82</td><td> 419</td><td> 2,71</td><td>1H NMR (400 MHz, CD3CN) δ 1.29-1.32 (m, 2H), 1.681.71 (m, 2H), 3.90 (s, 3H), 3.99 (s, 3H), 6 , 04 (s, 2H), 6.706.72 (m, 2H), 6.93 (d, J = 8.4 Hz, 1H), 7.03-7.05 (m, 2H), 7.59 ( d, J = 8.2 Hz, 1H), 7.73 (t, J = 7.6 Hz, 2H), 8.01 (t, J = 8.1 Hz, 1H), 8.72 (br s , 1H)</td>

<td> 83</td><td> 417,3</td><td> 3,41</td><td></td>

<td> 84</td><td> 394,9</td><td> 3,74</td><td></td>

<td> 85</td><td> 401,3</td><td> 3,97</td><td></td>

<td> 86</td><td> 473,5</td><td> 2,69</td><td></td>

<td> 87</td><td> 419,1</td><td> 3,18</td><td>1H NMR (400 MHz, CD3CN) δ 1.25-1.31 (m, 2H), 1.621,69 (m, 2H), 3.84 (s, 3H), 3.86 (s, 3H), 6 , 04 (s, 2H), 6.662.70 (m, 2H), 6.92 (d, J = 8.4 Hz, 1H), 7.00-7.08 (m, 2H), 7.30 ( d, J = 8.3 Hz, 1H), 7.96 (d, J = 8.9 Hz, 1H), 8.14 (dd, J = 8.9, 2.3 Hz, 1H), 8.38 (d, J = 2.2 Hz, 1H), 8.65 (br s, 1H)</td>

<td> 88</td><td> 399</td><td> 3,83</td><td></td>

<td> 89</td><td> 401,3</td><td> 3,62</td><td></td>

<td> 90</td><td> 407,3</td><td> 3,59</td><td></td>

<td> 91</td><td> 505,2</td><td> 2,88</td><td></td>

<td> 92</td><td> 384</td><td> 3,36</td><td>1H NMR (400 MHz, CD3CN) δ 1.27-1.30 (m, 2H), 1.651.67 (m, 2H), 6.05 (s, 2H), 6.93 (d, J = 8, 4 Hz, 1H), 7,047.09 (m, 2H), 7.67 (t, J = 7.7 Hz, 1H), 7.79-7.81 (m, 1H), 7.91-7, 94 (m, 1H), 8.02-8.08 (m, 2H), 8.23 ​​(dd, J = 8.9, 2.5 Hz, 1H), 8.50 (d, J = 1.9 Hz, 1H), 8.58 (br s, 1H)</td>

<td> 93</td><td> 402</td><td> 2,73</td><td>1H NMR (400 MHz, CD3CN) δ 1.16-1.24 (m, 2H), 1.571.62 (m, 2H), 6.05 (s, 2H), 6.95 (d, J = 7, 6 Hz, 1H), 7.05</td>

137

<td>No. Relationship</td><td>LCMS [M + H] +</td><td>LCMS RT</td><td>NMR</td>

<td></td><td></td><td></td><td>7.09 (m, 2H), 7.71-7.75 (m, 2H), 7.95 (br s, 1H), 8.04-8.10 (m, 3H), 8.22 (d , J = 8.7 Hz, 1H), 8.54 (d, J = 2.5 Hz, 1H)</td>

<td> 94</td><td> 419,3</td><td> 2,8</td><td></td>

<td> 95</td><td> 403,3</td><td> 2,98</td><td></td>

<td> 97</td><td> 416,5</td><td> 3,22</td><td></td>

<td> 98</td><td> 421</td><td> 3</td><td></td>

<td> 99</td><td> 407,1</td><td> 3,32</td><td></td>

<td> 100</td><td> 389</td><td> 2,83</td><td>1H NMR (400 MHz, CD3CN) δ 1.21-1.26 (m, 2H), 1.601.65 (m, 2H), 4.65 (s, 2H), 6.03 (s, 2H), 6 , 89-6.94 (m, 1H), 7.02-7.08 (m, 2H), 7.36-7.62 (m, 3H), 8.12 (s, 2H), 8.36 (br s, 1H), 8.45-8.47 (m, 1H)</td>

<td> 101</td><td> 388,9</td><td> 3,27</td><td>1H NMR (400 MHz, CD3CN) δ 1.22-1.24 (m, 2H), 1.611,63 (m, 2H), 3.82 (s, 3H), 6.04 (s, 2H), 6 , 92 (d, J = 8.4 Hz, 1H), 7.04-7.12 (m, 4H), 7.34 (dd, J = 7.6, 1.7 Hz, 1H), 7.38-7.43 (m, 1H) , 8.03 (dd, J = 8.7, 2.3 Hz, 1H), 8.10 (dd, J = 8.7, 0.7 Hz, 1H), 8.27 (br s, 1H), 8.37-8.39 (m, 1H)</td>

<td> 102</td><td> 401,3</td><td> 3,77</td><td></td>

<td> 103</td><td> 430,5</td><td> 3,04</td><td></td>

<td> 104</td><td> 388,3</td><td> 2,32</td><td></td>

<td> 105</td><td> 521,2</td><td> 2,46</td><td></td>

<td> 106</td><td> 393</td><td> 3,63</td><td></td>

<td> 107</td><td> 416</td><td> 2,84</td><td>1 H NMR (400 MHz, CD₃CN / DY1SO-U) δ 1.13-1.22 (m, 2H), 1.53-1.64 (m, 2H), 2.07 (s, 3H), 6.08 (s, 2H) , 6.906.95 (m, 1H), 7.01-7.09 (m, 2H), 7.28 (d, J = 8.8 Hz, 1H), 7.37 (t, J = 7.9 Hz, 1H), 7.61 (d, J = 8.8 Hz, 1H), 7.84 (d, J = 1.6 Hz, 1H), 7.95 (dd, J = 2.5, 8 , 7 Hz, 1H), 8.03 (br s, 1H), 8.16 (d, J = 8.7 Hz, 1H), 8.42 (d, J = 2.4 Hz, 1H), 9.64 (s, 1H)</td>

<td> 108</td><td> 403,3</td><td> 3,07</td><td></td>

<td> 109</td><td> 349,1</td><td> 3,29</td><td></td>

<td> 110</td><td> 389,2</td><td> 3,15</td><td></td>

<td> 111</td><td> 521,2</td><td> 2,27</td><td></td>

<td> 112</td><td> 394</td><td> 3,82</td><td></td>

<td> 113</td><td> 407,5</td><td> 3,3</td><td></td>

<td> 114</td><td> 417,1</td><td> 3,17</td><td></td>

<td> 115</td><td> 398,1</td><td> 3,22</td><td></td>

<td> 116</td><td> 394</td><td> 3,1</td><td>1 H NMR (400 MHz, CD₃CN) δ 1.18-1.26 (m, 2H), 1.591.64 (m, 2H), 6.05 (s, 2H), 6.95 (d, J = 8.4 Hz, 1H), 7.067.17 (m, 2H), 7.40 (d, J = 4.9 Hz, 1H), 7.92-7.96 (m, 2H), 8.26 (d, J = 9.3 Hz , 1H), 8.36 (d, J = 1.7 Hz, 1H), 8.56 (d, J = 5.0 Hz, 1H), 8.70 (s, 1H)</td>

138

<td>No. Relationship</td><td>LCMS [M + H] +</td><td>LCMS RT</td><td>NMR</td>

<td> 117</td><td> 363,3</td><td> 3,48</td><td></td>

<td> 118</td><td> 374,3</td><td> 3,54</td><td></td>

<td> 119</td><td> 494,3</td><td> 3,59</td><td></td>

<td> 120</td><td> 505,2</td><td> 2,9</td><td></td>

<td> 121</td><td> 374,3</td><td> 2,55</td><td></td>

<td> 122</td><td> 417,3</td><td> 3,63</td><td></td>

<td> 123</td><td> 389,3</td><td> 3,47</td><td></td>

<td> 124</td><td> 417,1</td><td> 3,29</td><td></td>

<td> 125</td><td> 417,3</td><td> 3,08</td><td></td>

<td> 126</td><td> 427,3</td><td> 3,89</td><td></td>

<td> 127</td><td> 535,2</td><td> 2,76</td><td></td>

<td> 128</td><td> 386,9</td><td> 3,67</td><td></td>

<td> 129</td><td> 377,1</td><td> 3,67</td><td></td>

<td> 130</td><td> 389,1</td><td> 3,4</td><td>1H NMR (400 MHz, CD3CN) δ 1.22-1.24 (m, 2H), 1.611,63 (m, 2H), 3.86 (s, 3H), 6.05 (s, 2H), 6 , 93 (d, J = 8.4 Hz, 1H), 6.97-7.00 (m, 1H), 7.05-7.08 (m, 2H), 7.16-7.21 (m, 2H), 7.41 (t, J = 8.0 Hz, 1H), 8.07-8.17 (m, 3H), 8.448.48 (m, 1H)</td>

<td> 131</td><td> 407,3</td><td> 3,49</td><td></td>

<td> 132</td><td> 419</td><td> 3,09</td><td>1H NMR (400 MHz, CD3CN) δ 1.17-1.25 (m, 2H), 1.571.64 (m, 2H), 3.72 (s, 6H), 6.04 (s, 2H), 6 , 74 (d, J = 8.4 Hz, 2H), 6.93 (d, J = 8.4 Hz, 1H), 7.05-7.08 (m, 2H), 7.35 (t, J = 8.4 Hz, 1H), 7.75 (d, J = 10.5 Hz, 1H), 8.07-8.14 (m, 3H)</td>

<td> 133</td><td> 431,3</td><td> 3,27</td><td></td>

<td> 135</td><td> 417,3</td><td> 3,81</td><td></td>

<td> 136</td><td> 535,2</td><td> 2,75</td><td></td>

<td> 137</td><td> 403,5</td><td> 3,35</td><td></td>

<td> 138</td><td> 432,5</td><td> 2,76</td><td>H NMR (400 MHz, CD3CN) δ 1.30-1.35 (m, 2H), 1.691,74 (m, 2H), 3.09 (s, 6H), 4.05 (s, 3H), 6 , 04 (s, 2H), 6.38 (d, J = 2.4 Hz, 1H), 6.50 (dd, J = 9.0, 2.4 Hz, 1H), 6.93 (d, J = 8.4 Hz, 1H), 7.03-7.06 (m, 2H), 7.31 (d, J = 7.7 Hz, 1H), 7.71 (d, J = 8.8 Hz, 2H), 7.97 (t, J = 8.3 Hz, 1H)</td>

<td> 139</td><td> 421,1</td><td> 2,71</td><td></td>

<td> 140</td><td> 416,5</td><td> 2,92</td><td></td>

<td> 141</td><td> 410</td><td> 2,83</td><td>1H NMR (400 MHz, CD3CN) δ 1.28-1.37 (m, 2H), 1.661.73 (m, 2H), 6.05 (s, 2H), 6.91-6.97 (m, 1H), 7.05-7.09 (m, 2H), 7.69-7.74 (m, 1H), 7.82 (t, J = 7.7 Hz, 1H), 7.93 (d , J = 7.2 Hz, 1H), 8.04 (d, J = 8.8 Hz, 1H), 8.15 (d, J = 8.2 Hz, 1H), 8.37 (d, J = 8.8 Hz, 1H), 8.58-8.65 (m, 2H), 8.82 (br s, 1H), 8.94 (d, J = 6.2 Hz, 1H)</td>

139

<td>No. Relationship</td><td>LCMS [M + H1 +</td><td>LCMS RT</td><td>NMR</td>

<td> 142</td><td> 349,3</td><td> 3,33</td><td></td>

<td> 143</td><td> 373,1</td><td> 3,68</td><td></td>

<td> 144</td><td> 535,2</td><td> 2,33</td><td></td>

<td> 145</td><td> 390,3</td><td> 3,4</td><td></td>

<td> 146</td><td> 386,9</td><td> 3,72</td><td></td>

<td> 147</td><td> 419,1</td><td> 3,13</td><td>1H NMR (400 MHz, CD3CN) δ 1.23-1.26 (m, 2H), 1.621,64 (m, 2H), 3.86 (s, 3H), 3.89 (s, 3H), 6 , 04 (s, 2H), 6.93 (d, J = 8.4 Hz, 1H), 7.03-7.07 (m, 3H), 7.17-7.19 (m, 2H), 8.06-8.15 (m, 2H), 8.38 (br s, 1H), 8.45-8.46 (m, 1H)</td>

<td> 148</td><td> 393,1</td><td> 3,72</td><td>1H NMR (400 MHz, CD3CN) δ 1.20-1.27 (m, 2H), 1.581.67 (m, 2H), 6.05 (s, 2H), 6.94 (d, J = 8, 4 Hz, 1H), 7.055.09 (m, 2H), 7.41-7.50 (m, 2H), 7.55-7.59 (m, 1H), 7.666.79 (m, 1H), 8.07 (d, J = 11.2 Hz, 1H), 8.11 (br s, 1H), 8.16 (d, J = 8.8 Hz, 1H), 8.48 (d, J = 1.9 Hz, 1H)</td>

<td> 149</td><td> 458,5</td><td> 2,42</td><td></td>

<td> 150</td><td> 403,5</td><td> 3,04</td><td></td>

<td> 151</td><td> 452,3</td><td> 3,44</td><td>H NMR (400 MHz, MeOD) δ 1.30-1.36 (m, 2H), 1.711,77 (m, 2H), 2.58 (s, 3H), 6.04 (s, 2H), 6 , 93 (dd, J = 0.8, 7.5 Hz, 1H), 7.04-7.08 (m, 2H), 7.86 (dd, J = 0.8, 7.7 Hz, 1H ), 8.00-8.02 (m, 2H), 8.08-8.12 (m, 3H), 8.19-8.23 (m, 1H)</td>

<td> 152</td><td> 403</td><td> 2,97</td><td></td>

<td> 153</td><td> 359,1</td><td> 3,36</td><td>1 H NMR (400 MHz, CD₃CN) δ 1.24-1.26 (m, 2H), 1.621,65 (m, 2H), 6.05 (s, 2H), 6.93 (d, J = 8.4 Hz, 1H), 7.057.08 (m, 2H), 7.42-7.46 (m, 1H), 7.49-7.53 (m, 2H), 7.663.76 (m, 2H), 8.10-8, 16 (m, 2h), 8.33 (br s, 1H), 8.48-8.48 (m, 1H)</td>

<td> 154</td><td> 395,1</td><td> 3,34</td><td></td>

<td> 155</td><td> 393</td><td> 3,7</td><td></td>

<td> 156</td><td> 390,2</td><td> 3,7</td><td></td>

<td> 157</td><td> 403,5</td><td> 3,33</td><td></td>

<td> 158</td><td> 390,2</td><td> 3,58</td><td></td>

<td> 159</td><td> 493,2</td><td> 2,85</td><td></td>

<td> 160</td><td> 411,3</td><td> 3,94</td><td></td>

<td> 161</td><td> 419,1</td><td> 3,2</td><td></td>

<td> 162</td><td> 488,1</td><td> 3,62</td><td></td>

<td> 163</td><td> 438,1</td><td> 3</td><td></td>

<td> 164</td><td> 314,1</td><td> 3,38</td><td></td>

<td> 165</td><td> 538,5</td><td> 3,28</td><td></td>

<td> 166</td><td> 466,1</td><td> 2,9</td><td></td>

140

<td>No. Relationship</td><td>LCMS [M + H] +</td><td>LCMS RT</td><td>NMR</td>

<td> 167</td><td> 429,3</td><td> 2,95</td><td></td>

<td> 168</td><td> 526,3</td><td> 3,189189</td><td></td>

<td> 169</td><td> 498,3</td><td> 3,7</td><td></td>

<td> 170</td><td> 468,3</td><td> 3,27</td><td></td>

<td> 171</td><td> 444,5</td><td> 2,24</td><td></td>

<td> 172</td><td> 551,1</td><td> 2,849824</td><td></td>

<td> 173</td><td> 377</td><td> 3,7</td><td></td>

<td> 174</td><td> 493,9</td><td> 2,69</td><td></td>

<td> 175</td><td> 517,9</td><td> 3,423179</td><td></td>

<td> 176</td><td> 522,3</td><td> 3,49262</td><td></td>

<td> 177</td><td> 502,1</td><td> 3,43</td><td></td>

<td> 178</td><td> 549,1</td><td> 2,906129</td><td></td>

<td> 179</td><td> 480,1</td><td> 2,51</td><td></td>

<td> 180</td><td> 520,3</td><td> 4,295395</td><td></td>

<td> 181</td><td> 488,2</td><td> 3,07</td><td></td>

<td> 182</td><td> 535,1</td><td> 3,267469</td><td></td>

<td> 183</td><td> 436,3</td><td> 3,62</td><td></td>

<td> 184</td><td> 496,3</td><td> 3,265482</td><td></td>

<td> 185</td><td> 403,5</td><td> 2,88</td><td></td>

<td> 186</td><td> 420,9</td><td> 2,86</td><td></td>

<td> 187</td><td> 444,3</td><td> 2,39</td><td></td>

<td> 188</td><td> 417,3</td><td> 2,24</td><td></td>

<td> 189</td><td> 466,1</td><td> 2,88</td><td></td>

<td> 190</td><td> 438,1</td><td> 2,39</td><td></td>

<td> 191</td><td> 401,1</td><td> 3,44</td><td></td>

<td> 192</td><td> 552,3</td><td> 3,18</td><td></td>

<td> 193</td><td> 452,3</td><td> 2,55</td><td></td>

<td> 194</td><td> 415</td><td> 4</td><td></td>

<td> 195</td><td> 479,1</td><td> 1,08</td><td></td>

<td> 196</td><td> 430,5</td><td> 2,34</td><td></td>

<td> 197</td><td> 512,3</td><td> 2,961206</td><td></td>

<td> 198</td><td> 444,5</td><td> 2,75</td><td>H NMR (400 MHz, DMSO-A) δ 1.11-1.19 (m, 2H), 1.461.52 (m, 2H), 2.31 (s, 3H), 2.94 (s, 3H) , 2.99 (s, 3H), 6.08 (s, 2H), 6.97-7.05 (m, 2H), 7.13 (d, J = 1.6 Hz, 1H), 7, 35 (t, J = 1.5 Hz, 1H), 7.41 (t, J = 7.8 Hz, 2H), 7.51 (t, J = 7.6 Hz, 1H), 7.68 ( d, J = 8.4 Hz, 1H), 7.97 (d, J = 8.4 Hz, 1H), 8.34 (s, 1H)</td>

<td> 199</td><td> 540,3</td><td> 3,18</td><td></td>

141

<td>No. Relationship</td><td>LCMS [M + H] +</td><td>LCMS RT</td><td>NMR</td>

<td> 200</td><td> 520,3</td><td> 3,79</td><td></td>

<td> 201</td><td> 452,3</td><td> 3,22</td><td></td>

<td> 202</td><td> 536,5</td><td> 3,63</td><td></td>

<td> 203</td><td> 509,1</td><td> 2,82</td><td></td>

<td> 204</td><td> 444,5</td><td> 2,5</td><td></td>

<td> 205</td><td> 524,3</td><td> 3,48</td><td></td>

<td> 206</td><td> 407,5</td><td> 3,6</td><td></td>

<td> 207</td><td> 452,1</td><td> 2,62</td><td></td>

<td> 208</td><td> 520,3</td><td> 4,06</td><td></td>

<td> 209</td><td> 416,1</td><td> 2,3</td><td></td>

<td> 210</td><td> 452,3</td><td> 2,8</td><td>H NMR (400 MHz, DMSO-Y) δ 1.11-1.19 (m, 2H), 1.471.52 (m, 2H), 2.31 (s, 6.08 (s, 2H), 6, 96-7.07 (m, 2H), 7.13 (d, J = 1.6 Hz, 1H), 7.43 (s, 1H), 7.57 (d, J = 8.1 Hz, 2H ), 7.69 (d, J = 8.5 Hz, 2H), 7.89 (d, J = 8.2 Hz, 2H), 7.99 (d, J = 8.4 Hz, 1H), 8.38 (s, 1H)</td>

<td> 211</td><td> 480,3</td><td> 3,33</td><td></td>

<td> 212</td><td> 521,1</td><td> 3,23</td><td></td>

<td> 213</td><td> 415,3</td><td> 3,4</td><td></td>

<td> 214</td><td> 562,3</td><td> 3,71</td><td></td>

<td> 215</td><td> 403,3</td><td> 2,67</td><td></td>

<td> 216</td><td> 421,1</td><td> 2,91</td><td></td>

<td> 217</td><td> 387,1</td><td> 2,89</td><td></td>

<td> 218</td><td> 488,3</td><td> 3,73</td><td></td>

<td> 219</td><td> 403,7</td><td> 2,43</td><td></td>

<td> 220</td><td> 508,5</td><td> 3,46</td><td></td>

<td> 221</td><td> 508,3</td><td> 3,46</td><td></td>

<td> 222</td><td> 401,1</td><td> 2,76</td><td></td>

<td> 223</td><td> 484,5</td><td> 3,95</td><td></td>

<td> 224</td><td> 407,5</td><td> 3,23</td><td></td>

<td> 225</td><td> 401,2</td><td> 3,49</td><td></td>

<td> 226</td><td> 608,3</td><td> 3,58</td><td></td>

<td> 227</td><td> 417,1</td><td> 2,24</td><td></td>

<td> 228</td><td> 452,3</td><td> 3,21</td><td></td>

<td> 229</td><td> 407,1</td><td> 3,08</td><td></td>

<td> 230</td><td> 401,3</td><td> 2,68</td><td></td>

<td> 231</td><td> 389,1</td><td> 2,36</td><td></td>

<td> 232</td><td> 481,9</td><td> 3,155919</td><td></td>

142

<td>No. Relationship</td><td>LCMS [M + H1 +</td><td>LCMS rt</td><td>nmr</td>

<td> 233</td><td> 535,9</td><td> 3,58</td><td></td>

<td> 234</td><td> 551,1</td><td> 2,90</td><td></td>

<td> 235</td><td> 415,3</td><td> 3,71</td><td>H NMR (400 MHz, DMSO-ύ.) Δ 1.12-1.17 (m, 2H), 1.23 (d, J = 6.9 Hz, 6H), 1.47-1.51 (m , 2H), 2.30 (s, 3H), 2.92 (septet, J = 6.9 Hz, 1H), 6.08 (s, 2H), 6.97-7.05 (m, 2H) , 7.12-7.17 (m, 2H), 7.20-7.22 (m, 1H), 7.24-7.26 (m, 1H), 7.36 (t, J = 7, 6 Hz, 1H), 7.65 (d, J = 8.4 Hz, 1H), 7.95 (d, J = 8.4 Hz, 1H), 8.32 (s, 1H)</td>

<td> 236</td><td> 540,3</td><td> 3,85</td><td></td>

<td> 237</td><td> 456,5</td><td> 3,35</td><td></td>

<td> 238</td><td> 416,5</td><td> 2,35</td><td></td>

<td> 239</td><td> 529,3</td><td> 2,29</td><td></td>

<td> 240</td><td> 442,3</td><td> 3,57</td><td></td>

<td> 241</td><td> 466,3</td><td> 3,5</td><td></td>

<td> 242</td><td> 506,3</td><td> 3,67</td><td></td>

<td> 243</td><td> 403,3</td><td> 2,69</td><td></td>

<td> 244</td><td> 534,3</td><td> 3,93</td><td></td>

<td> 245</td><td> 466,3</td><td> 3,6</td><td></td>

<td> 246</td><td> 496,3</td><td> 2,9</td><td></td>

<td> 247</td><td> 458,5</td><td> 2,3</td><td></td>

<td> 248</td><td> 450,3</td><td> 3,01</td><td></td>

<td> 249</td><td> 565,2</td><td> 2,89</td><td></td>

<td> 250</td><td> 480,5</td><td> 3,74</td><td></td>

<td> 251</td><td> 452,1</td><td> 1,07</td><td></td>

<td> 252</td><td> 389,1</td><td> 2,82</td><td></td>

<td> 253</td><td> 530,3</td><td> 2,8</td><td></td>

<td> 254</td><td> 466,1</td><td> 1,06</td><td></td>

<td> 255</td><td> 488,2</td><td> 3,05</td><td></td>

<td> 256</td><td> 558,3</td><td> 3,46</td><td></td>

<td> 257</td><td> 407,5</td><td> 3,27</td><td></td>

<td> 258</td><td> 430,5</td><td> 2,66</td><td>H NMR (400 MHz, DMSO-ύ.) Δ 1.12-1.18 (m, 2H), 1.471.54 (m, 2H), 2.30 (s, 3H), 2.79 (d, J = 4.5 Hz, 3H), 6.08 (s, 2H), 6.96-7.07 (m, 2H), 7.13 (d, J = 1.6 Hz, 1H), 7.448.57 (m, 2H), 7.70 (d, J = 8.4 Hz, 1H), 7.78 (d, J = 1.5 Hz, 1H), 7.84 (dt, J = 7.3, 1.7 Hz, 1H), 7.98 (d, J = 8.4 Hz, 1H), 8.36 (s, 1H), 8.50-8.51 (m, 1H)</td>

<td> 259</td><td> 470,3</td><td> 3,82</td><td></td>

<td> 260</td><td> 403,1</td><td> 2,27</td><td></td>

<td> 261</td><td> 549,1</td><td> 3,39</td><td></td>

143

<td>No. Relationship</td><td>LCMS [M + H] +</td><td>LCMS RT</td><td>NMR</td>

<td> 262</td><td> 438,1</td><td> 3,43</td><td></td>

<td> 263</td><td> 403,3</td><td> 2,8</td><td></td>

<td> 264</td><td> 407,1</td><td> 3,04</td><td></td>

<td> 265</td><td> 430,5</td><td> 2,18</td><td></td>

<td> 266</td><td> 403,3</td><td> 2,96</td><td></td>

<td> 267</td><td> 531,9</td><td> 2,81</td><td></td>

<td> 268</td><td> 496,3</td><td> 3,24</td><td></td>

<td> 269</td><td> 373,5</td><td> 2,76</td><td></td>

<td> 270</td><td> 520,3</td><td> 4,21</td><td></td>

<td> 271</td><td> 450,3</td><td> 3,77</td><td></td>

<td> 272</td><td> 403,2</td><td> 1,09</td><td></td>

<td> 273</td><td> 543,1</td><td> 2,89</td><td></td>

<td> 274</td><td> 417,3</td><td> 2,26</td><td></td>

<td> 275</td><td> 527,9</td><td> 3,91</td><td></td>

<td> 276</td><td> 510,3</td><td> 3,37</td><td></td>

<td> 277</td><td> 403,1</td><td> 2,2</td><td></td>

<td> 278</td><td> 430,5</td><td> 2,68</td><td>H NMR (400 MHz, DMSO-A) δ 1.12-1.19 (m, 2H), 1.471.51 (m, 2H), 2.31 (s, 3H), 2.80 (d, J = 4.5 Hz, 3H), 6.08 (s, 2H), 6.97-7.05 (m, 2H), 7.13 (d, J = 1.6 Hz, 1H), 7.45 ( d, J = 8.4 Hz, 2H), 7.68 (d, J = 8.4 Hz, 1H), 7.90 (d, J = 8.5 Hz, 2H), 7.97 (d, J = 8.3 Hz, 1H), 8.35 (s, 1H), 8.50 (q, J = 4.5 Hz, 1H)</td>

<td> 279</td><td> 536,5</td><td> 3,19</td><td></td>

<td> 280</td><td> 480,3</td><td> 3,25</td><td></td>

<td> 281</td><td> 550,5</td><td> 3,78</td><td></td>

<td> 282</td><td> 482,5</td><td> 3,15</td><td></td>

<td> 283</td><td> 416,3</td><td> 2,58</td><td></td>

<td> 284</td><td> 554,3</td><td> 3,99</td><td></td>

<td> 285</td><td> 546,3</td><td> 2,87</td><td></td>

<td> 286</td><td> 416,1</td><td> 2,29</td><td></td>

<td> 287</td><td> 443</td><td> 4,02</td><td></td>

<td> 288</td><td> 466,3</td><td> 2,76</td><td></td>

<td> 289</td><td> 373,1</td><td> 2,84</td><td></td>

<td> 290</td><td> 429,3</td><td> 3</td><td></td>

<td> 291</td><td> 403,1</td><td> 2,24</td><td></td>

<td> 292</td><td> 479,2</td><td> 2,49</td><td></td>

<td> 293</td><td> 417,3</td><td> 2,65</td><td></td>

<td> 294</td><td> 403,5</td><td> 2,39</td><td></td>

144

<td>No. Relationship</td><td>LCMS [M + H1 +</td><td>LCMS RT</td><td>NMR</td>

<td> 295</td><td> 416,3</td><td> 2,61</td><td>H NMR (400 MHz, DMSO-A) δ 1.14-1.18 (m, 2H), 1.461.54 (m, 2H), 2.31 (s, 3H), 6.08 (s, 2H) , 6.97-7.05 (m, 2H), 7.13 (d, J = 1.6 Hz, 1H), 7.44 (s, 1H), 7.49-7.56 (m, 2H ), 7.72 (d, J = 8.4 Hz, 1h), 7.83-7.85 (m, 1H), 7.87-7.91 (m, 1H), 7.99 (d, J = 8.4 Hz, 1H), 8.05 (s, 1H), 8.39 (s, 1H)</td>

<td> 296</td><td> 387,1</td><td> 3,09</td><td></td>

<td> 297</td><td> 430,2</td><td> 2,38</td><td></td>

<td> 298</td><td> 403,2</td><td> 2,72</td><td></td>

<td> 299</td><td> 387,3</td><td> 2,86</td><td></td>

<td> 300</td><td> 387,3</td><td> 3,03</td><td></td>

<td> 301</td><td> 403,5</td><td> 2,44</td><td></td>

<td> 302</td><td> 508,3</td><td> 3,45</td><td></td>

<td> 303</td><td> 417,3</td><td> 2,58</td><td></td>

<td> 304</td><td> 549,1</td><td> 3,35</td><td></td>

<td> 305</td><td> 429,5</td><td> 3,01</td><td></td>

<td> 306</td><td> 492,3</td><td> 3,81</td><td></td>

<td> 307</td><td> 512,3</td><td> 2,97</td><td></td>

<td> 308</td><td> 415,3</td><td> 2,85</td><td></td>

<td> 309</td><td> 444,5</td><td> 2,75</td><td></td>

<td> 310</td><td> 430,5</td><td> 2,41</td><td></td>

<td> 311</td><td> 534,3</td><td> 3,92</td><td></td>

<td> 312</td><td> 492,3</td><td> 3,99</td><td></td>

<td> 313</td><td> 387,3</td><td> 2,84</td><td></td>

<td> 314</td><td> 430,5</td><td> 2,37</td><td></td>

<td> 315</td><td> 387</td><td> 1,12</td><td></td>

<td> 316</td><td> 526,3</td><td> 3,08</td><td></td>

<td> 317</td><td> 344,2</td><td> 3,35</td><td></td>

<td> 318</td><td> 536,5</td><td> 3,17</td><td></td>

<td> 319</td><td> 492,3</td><td> 3,69</td><td></td>

<td> 320</td><td> 430,2</td><td> 2,38</td><td></td>

<td> 321</td><td> 452,3</td><td> 2,55</td><td></td>

<td> 322</td><td> 387,1</td><td> 2,6</td><td></td>

<td> 323</td><td> 387,1</td><td> 3,01</td><td></td>

<td> 324</td><td> 402,5</td><td> 2,14</td><td></td>

<td> 325</td><td> 531,9</td><td> 3,83</td><td></td>

<td> 326</td><td> 444,5</td><td> 2,5</td><td></td>

<td> 327</td><td> 403,3</td><td> 2,83</td><td></td>

145

<td>No. Relationship</td><td>LCMS [M + H] +</td><td>LCMS RT</td><td>NMR</td>

<td> 328</td><td> 401,1</td><td> 3,48</td><td></td>

<td> 329</td><td> 415,3</td><td> 3,36</td><td></td>

<td> 330</td><td> 522,3</td><td> 4,14</td><td></td>

<td> 331</td><td> 387,1</td><td> 3,01</td><td></td>

<td> 332</td><td> 505,9</td><td> 4,06</td><td></td>

<td> 333</td><td> 417,1</td><td> 2,58</td><td></td>

<td> 334</td><td> 403,5</td><td> 2,92</td><td></td>

<td> 335</td><td> 520,3</td><td> 4,22</td><td></td>

<td> 336</td><td> 510,3</td><td> 3,36</td><td></td>

<td> 337</td><td> 401,1</td><td> 2,73</td><td></td>

<td> 338</td><td> 479,9</td><td> 3,44</td><td></td>

<td> 339</td><td> 508,3</td><td> 3,83</td><td></td>

<td> 340</td><td> 512,5</td><td> 3,6</td><td></td>

<td> 341</td><td> 452,3</td><td> 3,15</td><td></td>

<td> 342</td><td> 540,3</td><td> 3,07</td><td></td>

<td> 343</td><td> 480,3</td><td> 3</td><td></td>

<td> 344</td><td> 526,3</td><td> 3,15</td><td></td>

<td> 345</td><td> 422,1</td><td> 3,21</td><td></td>

<td> 346</td><td> 415</td><td> 4,05</td><td></td>

<td> 347</td><td> 523,1</td><td> 3,10</td><td></td>

<td> 348</td><td> 416,3</td><td> 1,87</td><td></td>

<td> 349</td><td> 438,1</td><td> 2,4</td><td></td>

<td> 350</td><td> 402,5</td><td> 2,18</td><td></td>

<td> 351</td><td> 373,1</td><td> 3,08</td><td></td>

<td> 352</td><td> 415,7</td><td> 3,13</td><td></td>

<td> 353</td><td> 420,9</td><td> 2,9</td><td></td>

<td> 354</td><td> 407,3</td><td> 3,03</td><td></td>

<td> 355</td><td> 480,3</td><td> 2,96</td><td></td>

<td> 356</td><td> 452,3</td><td> 2,47</td><td></td>

<td> 357</td><td> 466,3</td><td> 2,63</td><td></td>

<td> 358</td><td> 536,5</td><td> 3,26</td><td></td>

<td> 359</td><td> 402,1</td><td> 2,2</td><td></td>

<td> 360</td><td> 510,3</td><td> 3,42</td><td></td>

<td> 361</td><td> 407</td><td> 3,11</td><td></td>

<td> 362</td><td> 494,5</td><td> 3,45</td><td></td>

<td> 363</td><td> 438,1</td><td> 3,42</td><td></td>

146

<td>No. Relationship</td><td>LCMS [M + H] +</td><td>LCMS RT</td><td>NMR</td>

<td> 364</td><td> 535,9</td><td> 3,44</td><td></td>

<td> 365</td><td> 402,1</td><td> 2,21</td><td></td>

<td> 366</td><td> 565,2</td><td> 3,01</td><td></td>

<td> 367</td><td> 403,5</td><td> 2,36</td><td></td>

<td> 368</td><td> 444,5</td><td> 2,97</td><td></td>

<td> 369</td><td> 408,5</td><td> 3,43</td><td></td>

<td> 370</td><td> 403,3</td><td> 2,45</td><td></td>

<td> 371</td><td> 430,5</td><td> 2,43</td><td></td>

<td> 372</td><td> 478,3</td><td> 3,47</td><td></td>

<td> 373</td><td> 524,3</td><td> 3,50</td><td></td>

<td> 374</td><td> 466,3</td><td> 2,35</td><td></td>

<td> 375</td><td> 416,5</td><td> 2,36</td><td></td>

<td> 376</td><td> 552,3</td><td> 3,42</td><td></td>

<td> 377</td><td> 524,5</td><td> 3,17</td><td></td>

<td> 378</td><td> 538,5</td><td> 3,07</td><td></td>

<td> 379</td><td> 528,3</td><td> 3,33</td><td></td>

<td> 380</td><td> 548,3</td><td> 3,75</td><td></td>

<td> 381</td><td> 526,3</td><td> 3,46</td><td></td>

<td> 382</td><td> 520,5</td><td> 3,48</td><td></td>

<td> 383</td><td> 518,1</td><td> 3,55</td><td></td>

<td> 384</td><td> 542,3</td><td> 3,59</td><td></td>

<td> 385</td><td> 550,5</td><td> 3,69</td><td></td>

<td> 386</td><td> 524,3</td><td> 3,15</td><td></td>

<td> 387</td><td> 522,5</td><td> 3,78</td><td></td>

<td> 388</td><td> 542,2</td><td> 3,6</td><td></td>

<td> 389</td><td> 467,3</td><td> 1,93</td><td></td>

<td> 390</td><td> 469,3</td><td> 1,99</td><td></td>

<td> 391</td><td> 507,5</td><td> 2,12</td><td></td>

<td> 392</td><td> 453,5</td><td> 1,99</td><td></td>

<td> 393</td><td> 487,3</td><td> 2,03</td><td></td>

<td> 394</td><td> 483,5</td><td> 1,92</td><td></td>

<td> 395</td><td> 441,3</td><td> 4,33</td><td></td>

<td> 397</td><td> 439,5</td><td> 1,94</td><td></td>

<td> 398</td><td> 471,3</td><td> 2</td><td></td>

<td> 399</td><td> 537,5</td><td> 2,1</td><td></td>

<td> 400</td><td> 525,3</td><td> 2,19</td><td></td>

147

<td>No. Relationship</td><td>LCMS [M + H] +</td><td>LCMS RT</td><td>NMR</td>

<td> 401</td><td> 453,5</td><td> 1,96</td><td></td>

<td> 402</td><td> 483,3</td><td> 1,87</td><td></td>

<td> 403</td><td> 457,5</td><td> 1,99</td><td></td>

<td> 404</td><td> 469,5</td><td> 1,95</td><td></td>

<td> 405</td><td> 471,3</td><td> 1,98</td><td></td>

<td> 406</td><td> 525,3</td><td> 2,15</td><td></td>

<td> 407</td><td> 439,4</td><td> 1,97</td><td></td>

<td> 408</td><td> 525,1</td><td> 2,14</td><td></td>

<td> 409</td><td> 618,7</td><td> 3,99</td><td></td>

<td> 410</td><td> 374,5</td><td> 2,46</td><td></td>

<td> 411</td><td> 507,5</td><td> 2,14</td><td></td>

<td> 412</td><td> 390,1</td><td> 3,09</td><td></td>

<td> 413</td><td> 552,3</td><td> 4,04</td><td></td>

<td> 414</td><td> 457,5</td><td> 2,06</td><td></td>

<td> 415</td><td> 521,5</td><td> 2,14</td><td></td>

<td> 416</td><td> 319</td><td> 3,32</td><td></td>

<td> 417</td><td> 471,3</td><td> 1,96</td><td></td>

<td> 418</td><td> 417,3</td><td> 1,75</td><td></td>

<td> 419</td><td> 473,3</td><td> 2,04</td><td></td>

<td> 420</td><td> 389,3</td><td> 2,94</td><td></td>

<td> 421</td><td> 457,5</td><td> 1,99</td><td></td>

<td> 422</td><td> 467,3</td><td> 1,96</td><td></td>

TESTS

Tests for the detection and measurement of the properties of correction compounds AF508-CFTR

JJ. Optical methods for testing membrane potential testing modulation properties

AF508-CFTR by compounds [0389] Voltage sensitive FRET sensors described by Gonzalez and Tsien (See, Gonzalez, JE and RY Tsien (1995) "Voltage sensing by fluorescence resonance energy transfer in single cells" Biophys are used in the optical membrane potential test. 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): 26977) in combination with devices for measuring fluorescence changes, such as Voltage / Ion Probe Reader (VIPR) (See, Gonzalez, JE, K. Oades, et al. (1999) "Cell-based assays and instrumentation for screening ion-channel targets" Drug Discov Today 4 (9): 431-439).

[0390] These voltage sensitive tests are based on a change in resonance fluorescence excitation energy transfer (FRET) between a membrane soluble, voltage sensitive dye, DiSBAC2 (3), and a fluorescent phospholipid, CC2DMPE, which is attached to the outer layer of the membrane plasma and acts as a FRET donor. Changes in membrane potential (Vm) cause redistribution of negatively charged DiSBAC2 (3) in the plasma membrane and the amount of energy changes accordingly

148 transferred from CC2-DMPE. Changes in fluorescence emissions were monitored using

TM of the VIPR II, which is an integrated liquid dispenser and fluorescence detector designed to conduct cell-based screening in 96- or 384-well microtiter plates.

1. Identification of corrective compounds [0391] To identify small molecules that correct the cell transport defect associated with AF508-CFTR, a single addition HTS assay format was developed. Cells were incubated in serum free medium for 16 hours at 37 ° C in the presence or absence (negative control) of the test compound. As a positive control, cells plated on 384-well plates were incubated for 16 hours at 27 ° C to achieve "temperature correction" AF508-CFTR. The cells were then washed three times with Krebs Ringer's solution and loaded with voltage sensitive dyes. To activate AF508-CFTR, 10 pM forskolin and CFTR enhancer, genistein (20 pM) were added to each well, together with Cl-free medium.. Addition of a medium containing no Cl^- conducive to the outflow of Cl^- in response to activation of AF508-CFTR and the obtained membrane depolarization was monitored optically using FRET-based voltage sensitive dyes.

2. Identification of enhancers [0392] To identify AF508-CFTR enhancers, a double addition HTS test format was developed. During the first addition, media containing no Cl was added to each well^- with or without test compounds. After 22 seconds, a second addition of Cl-free substrate was performed^-, containing 2 - 10 pM forskolin for activation of AF508-CFTR. Extracellular concentration of Cl^- after both additions it was 28 mM, which promoted the outflow of Cl^- and responses to AF508-CFTR activation and the obtained membrane depolarization were monitored optically using FRET-based voltage sensitive dyes.

.Roztwory

Washing solution No. 1: (in mM) NaCl 160, KCl 4.5, CaCl₂ 2, MgCl₂ 1, HEPES 10, pH

7.4 with NaOH.

Chloride-free washing solution: Chloride salts in washing solution No. replaced with gluconate salts

CC2-DMPE: Prepared as a 10 mM stock solution in DMSO and stored at -20 ° C.

DiSBAC₂(3): Prepared as a 10 mM stock solution in DMSO and stored at -20 ° C.

4. Cell culture [0393] For optical measurements of membrane potential, NIH3T3 mouse fibroblasts stably expressing AF508-CFTR are used. Cells are maintained at 37 ° C in 5% CO₂and 90% moisture in Dulbecco's modified Eagle medium supplemented with mM glutamine, 10% fetal bovine serum, 1 X NEAA, β-ME, 1 X pen / strep and ₂ mM HEPES in 175 cm culture bottles. For all optical tests, cells were plated at ~ 30,000 / well in 384 matrigel-coated plates and grown for 2 hours at 37 ° C before culturing at 27 ° C for 24 hours for the boost test. For the corrected tests, cells were cultured at 27 ° C or 37 ° C with or without compounds for 16-24 hours.

Electrophysiological tests to study the properties of AF508-CFTR modulation by compounds

1. Ussing chamber test [0394] Ussing chamber experiments were performed on polarized respiratory epithelial cells expressing AF508-CFTR to further characterize the AF508-CFTR modulators identified in optical tests. FRT epithelial cells—⁵⁰⁸'^{C tr} grown on Costar Snapwell cell culture inserts were embedded in a Ussing chamber (Physiologic Instruments, Inc., San Diego, CA) and single

149 cell layers were still contained using a potential stabilization system (Voltageclamp System, Department of Bioengineering, University of Iowa, IA, and, Physiologic Instruments, Inc., San Diego, CA). Transepithelial resistance was measured using a 2 mV pulse. Under these conditions, FRT epithelium showed resistance of 4 KQ / cm² or more. The solutions were kept at 27 ° C and aerated with air bubbles. The electrode's self potential and fluid resistance were corrected using a cell free insert. Under these conditions, the current reflects the flow of Cl 'through Δ F508-CFTR expressed in the apical membrane. AND_SC digitally recorded using the MP100A-CE interface and AcqKnowledge software (v3.2.6; BIOPAC Systems, Santa Barbara, CA).

2. Identification of corrective compounds [0395] A typical protocol used a Cl 'concentration gradient from the laterolabial to the apical membrane. To establish this gradient, normal Ringer's fluid was used on the laterolateral membrane, while on the apical membrane NaCl was replaced with an equimolar solution of sodium gluconate (adjusted to pH 7.4 with NaOH) to produce a large Cl 'concentration gradient across the epithelium. All experiments were performed on whole single layers of cells. To achieve full activation of ΔF508-CFTR, forskolin (10 μΜ) and PDE inhibitor, IBMX (100 μΜ) were added, followed by the addition of CFTR enhancer, genistein (50 μΜ).

[0396] As found in other cell types, incubation at low temperatures of FRT cells stably expressing ΔF508-CFTR increases the functional density of CFTR in the plasma membrane. To determine the activity of corrective compounds, cells were incubated with 10 μΜ of test compound for 24 hours at 37 ° C and then washed three times prior to registration. ISCs in cells treated with compound mediated by cAMP and genistein were normalized to controls 27 ° C and 37 ° C and expressed as percentage activity. Pre-incubation of the cells with the correcting compound significantly increased cAMP and genistein-mediated ISC compared to 37 ° C controls.

3. Identification of enhancer compounds [0397] A typical protocol used a Cl 'concentration gradient from the sidebasic to the apical membrane. To establish this gradient, normal Ringer's fluid was used on the laterolateral membrane and permeabilized with nystatin (360 μg / ml), while on the top NaCl membrane was replaced with an equimolar sodium gluconate solution (adjusted to pH 7.4 to NaOH) to produce a high concentration gradient Cl 'through the epithelium. All experiments were performed 30 minutes after nystatin permeabilization. Forskolin (10 μΜ) and all test compounds were added on both sides of the cell culture inserts. The performance of putative ΔF508CFTR enhancers was compared with the known enhancer genistein.

4. Solutions [0398]

Side-basal solution (in mM):

NaCl (135), CaCl₂ (1,2), MgCl₂ (1,2), K₂HPO4 (2.4), KHPO4 (0.6), N-2-hydroxyethylpiperazine-N'-2-ethanesulfonic acid (HEPES) (10) and dextrose (10). The solution was titrated with NaOH to pH 7.4.

Peak solution (in mM):

Same as side-basal solution, with NaCl replaced by Na (135) gluconate.

5. Cell culture [0399] Rat epithelial cells (FRT) expressing ΔF508-CFTR (FRT ^) were used for experiments in the Ussing chamber of the putative modulators identified in our optical tests.⁵⁰⁸'^CFTR). Cells were grown on Costar Snapwell cell culture inserts and grown for five days at 37 ° C and 5% CO₂ in

150 Hama F-12 bed modified by Coon, supplemented with 5% fetal bovine serum, 100 U / ml penicillin and 100 pg / ml streptomycin. Prior to use, to characterize the enhancer activity of the compounds, the cells were incubated at 27 ° C for 16 - 48 hours to correct for AF508-CFTR. To determine the activity of corrective compounds, the cells were incubated at 27 ° C or 37 ° C, with or without compounds for 24 hours.

6. Whole cell registrations [0400] Macroscopic current AF508-CFTR (Ia_F508) in NIH3T3 cells stably expressing AF508-CFTR, after temperature correction and test compound, were monitored using the perforated patch technique, whole cell registration. In short, Ia registrations_F508 voltage clamp technique was performed at room temperature using an amplifier for the method of stabilizing the Axopatch 200B membrane section (Axon Instruments Inc., Foster City, CA). All recordings were made at a sampling frequency of 10 kHz and a low pass filter at 1 kHz. The pipettes filled with the intracellular solution had a resistance of 5-6 MQ. Under these recording conditions, the reversal potential for Cl 'was calculated (E_C1) at room temperature was -28 mV. All registrations had seal resistance&gt; 20 GQ and series resistance &lt;15 MQ. Pulse generation, acquisition and data analysis were performed using a PC equipped with a Digidata 1320 A / D interface together with Clampex 8 (Axon Instruments Inc.). The washing solution contained &lt;250 [mu] l saline and was continuously passed at a rate of 2 ml / min using a gravity perfusion system.

7. Identification of corrective compound [0401] To determine the activity of corrective compounds to increase the density of functional AF508-CFTR in the plasma membrane, we used the recording techniques described above using a perforated patch to measure the current density after 24 hours of treatment with corrective compounds . To achieve full activation of AF508-CFTR, 10 pM forskolin and 20 pM genistein were added to the cells. In our recording conditions, the current density after 24-hour incubation at 27 ° C was higher than that found after 24-hour incubation at 37 ° C. These results are consistent with the known effect of low temperature incubation on the density of AF508-CFTR in the plasma membrane. To determine the effect of corrective compounds on CFTR current density, cells were incubated with 10 pM of test compound for 24 hours at 37 ° C and the current density was compared with the 27 ° C and 37 ° C controls (% activity). Before recording, the cells were washed three times with extracellular recording medium to remove remaining test compound. Pre-incubation with 10 pM correcting compounds significantly increased cAMP and genistein-dependent current compared to 37 ° C controls.

8. Identification of enhancers [0402] Ability of AF508-CFTR enhancers to increase the AF508-CFTR Cl- macroscopic current (Ia_F508) in NIH3T3 cells stably expressing AF508-CFTR were also examined using the perforated patch technique. Enhancers identified in optical tests induced a dose dependent increase in Ia_F508 with similar strength and performance observed in optical tests. In all cells tested, the reversal potential before and during use of the enhancer was about -30 mV, which is calculated ECl (28 mV).

9. Solutions [0403]

Intracellular solution (in mM):

Aspartate Cs (90), CsCl (50), MgCl₂ (1), HEPES (10) and 240 pg / ml amphoteric-B (pH adjusted to 7.35 using CsOH).

151

Extracellular solution (in mM):

N-methyl-D-glucamine (NMDG) -Cl (150), MgCl₂ (2), CaCl₂ (2), HEPES (10) (pH adjusted to 7.35 using HCl).

10. Cell culture [0404] NIH3T3 mouse fibroblasts stably expressing AP508-CFTR are used for whole cell registration. Cells are maintained at 37 ° C in 5% CO₂ and humidity of 90% in Eagle's Dulbecco's modified medium supplemented with 2 mM glutamine, 10% fetal bovine serum, 1 X NEAA, β-ME, 1 X pen / strep and 25 mM HEPES in 175 cm²breeding bottles. For whole-cell recording, 2,500-5,000 cells were plated onto poly-L-lysine-coated coverslips and cultured for 24-48 hours at 27 ° C before use to test for enhancer activity; and incubated with or without a correction compound at 37 ° C to measure the activity of the correction compounds.

11. Single Channel Registrations [0405] AF508-CFTR temperature corrected single channel activities of NIH3T3 stably expressed cells and enhancer activity were observed using recordings of cut and inverted sections of membrane. Briefly, voltage clamp recording of single channel activity was performed at room temperature using an amplifier for the Axopatch 200B membrane section stabilization method (Axon Instruments Inc.). All recordings were made with a sampling frequency of 10 kHz and a low-pass filter at 400 kHz. Pipette stabilization technique pipettes were manufactured from Corning Kovar Sealing No. 7052 (World Precision Instruments, Inc., Sarasota, FL) and filled with extracellular solution had a resistance of 5 - 8 MQ. After excision, AF508-CFTR was activated by the addition of 1 mM Mg-ATP and 75 nM cAMP-dependent protein kinase catalytic subunit (PKA; Promega Corp. Madison, WI). After stabilizing the channel activity, the membrane patch was perfused using a gravitational microperfusion system. The inflow was placed close to the scrap of membrane, so that complete solution exchange took place within 1-2 seconds. To maintain AF508-CFTR activity during rapid perfusion, a non-specific phosphatase inhibitor F was added to the wash solution.^- (10 mM NaF). Under these recording conditions, the channel activity remained constant throughout the entire recording period from the membrane patch (up to 60 minutes). Currents caused by the flow of positive charges from the intra-extracellular solution (anions flowing in the opposite direction) are shown as positive currents. Pipette potential (V_p) was maintained at 80 mV.

[0406] Channel activity was analyzed for membrane fragments containing &lt;2 active channels. The maximum number of simultaneous openings determined the number of active channels during the experiment. To determine the amplitude of the single channel intensity, the data recorded from 120 seconds of AF508-CFTR activity was filtered off-line at 100 Hz, and then used to construct amplitude histograms with all points that were matched with multigaussian functions using Bio-Patch Analysis software (Bio Logic Comp. France). Total microscopic current and opening probability (P_about) was determined from 120 seconds of channel activity. P_aboutdetermined using the Bio-Patch software or the relationship Po = I / i (N), where I = average current, i = current amplitude for a single channel, and N = number of active channels in a patch of membrane.

12. Solutions [0407]

Extracellular solution (in mM):

NMDG (150), aspartic acid (150), CaCl₂ (5), MgCl₂ (2) and HEPES (10) (pH adjusted to 7.35 using Tris base).

Intracellular solution (in mM):

152

NMDG-Cl (150), MgCl₂ (2), EGTA (5), TES (10) and Tris base (14) (pH adjusted to 7.35 with HCl).

13. Cell culture [0408] NIH3T3 mouse fibroblasts stably expressing AP508-CFTR are used for recording by membrane section stabilization using dissected membranes. Cells are maintained at 37 ° C in 5% CO₂ and humidity of 90% in Eagle's Dulbecco's modified medium supplemented with 2 mM glutamine, 10% fetal bovine serum, 1 X NEAA, β-ME, 1 X pen / strep and 25 mM HEPES in 175 cm² breeding bottles. For single-channel recording, 2500-5000 cells were plated on poly-L-lysine-coated coverslips and cultured for 24-48 h at 27 ° C before use.

[0409] Exemplary compounds of Table 1 have activity in the range of about 100 to 20 µM, measured using the tests described above. The exemplary compounds of Table 1 were found to be sufficiently effective as measured using the assays described above. OTHER EMBODIMENTS [0410] It is understood that while the invention is presented in connection with its detailed description, the above description is intended to illustrate, not to limit the scope of the invention, which is defined by the scope of the appended claims.