ES2367844T3 - MODULATORS OF THE REGULATOR OF THE TRANSMEMBRANE CONDUCTANCE OF THE CHYSICAL FIBROSIS. - Google Patents

Abstract

A compound of formula I or formula II: that the two RXs are not simultaneously hydrogen; or the two RXs taken together form ring (a): X is CH2, CF2, CH2-CH2 or CF2-CF2; Ring A is a 3-7 membered monocyclic cycloalkyl ring; RAA and RBB, taken together with the nitrogen atom, form a pyrrolidinyl ring substituted with OR '; R 'is hydrogen or C1-C6 aliphatic, in which up to two carbon units of said aliphatic are optionally and independently replaced by -CO-, -CS-, -COCO-, -CONR-, -CONRNR-, -CO2- , -OCO-, -NRCO2-, -O-, -NRCONR-, -OCONR-, -NRNR, -NRNRCO-, -NRCO-, -S-, -SO, -SO2-, -NR-, -SO2NR- NRSO2- or -NRSO2NR-; R is hydrogen or C1-C6 aliphatic; Z is halo, CN, COOH, CF3 or difluoromethylenedioxy; and q is 0-3.

Description

Technical Field of the Invention

The present invention relates to modulators of the cystic fibrosis transmembrane conductance regulator ("CFTR"), compositions thereof and methods therewith. The present invention also relates to the use of said modulators to treat diseases mediated by the CFTR.

Background of the invention

ABC transporters are a family of membrane transport proteins that regulate the transport of a wide variety of pharmacological agents, potentially toxic and xenobiotic drugs, as well as anions. ABC transporters are homologous membrane proteins that bind to and use cellular adenosine triphosphate (ATP) for their specific activities. Some of these transporters were discovered as multi-drug resistance proteins (such as MDR1-P glycoprotein, or MRP1 drug multi-drug protein), which defend malignant cancer cells against chemotherapeutic agents. To date, 48 ABC transporters have been identified and grouped into 7 families based on their sequence and function identity.

ABC transporters regulate several important physiological roles within the body and provide a defense against harmful environmental compounds. Due to this, they represent potential pharmacological targets important for the treatment of diseases associated with defects in the transporter, the prevention of drug transport outside the target cell and the intervention in other diseases in which the modulation of the activity of ABC transporters can be beneficial

A member of the ABC transporter family commonly associated with disease is the anion channel mediated by cAMP / ATP, CFTR. CFTR is expressed in several cell types, including secretory and absorption epithelial cells, in which it regulates the flow of anions through the membrane, as well as the activity of other ionic channels and proteins. In epithelial cells, the normal functioning of the CFTR is critical for the maintenance of electrolyte transport throughout the body, including respiratory and digestive tissue. The CFTR is composed of approximately 1480 amino acids that encode a protein composed of a tandem repeat of transmembrane domains, each containing six transmembrane helices and a nucleotide binding domain. The two transmembrane domains are linked by a large polar (R) regulatory domain with multiple phosphorylation sites that regulates channel activity and cell transit.

The gene encoding the CFTR has been identified and sequenced (See Gregory, RJ et al. (1990) Nature 347: 382386; Rich, DP et al. (1990) Nature 347: 358-362), (Riordan, JR et al. . (1989) Science 245: 1066-1073). A defect in this gene causes mutations in the CFTR that result in cystic fibrosis, the most common fatal genetic disease in humans. Cystic fibrosis affects approximately one in 2,500 infants in the United States. Within the general population of the United States, up to 10 million people carry a single copy of the defective gene without obvious pathological effects. In contrast, individuals with two copies of the cystic fibrosis-associated gene suffer from the debilitating and fatal effects of cystic fibrosis, including chronic lung disease.

In patients with cystic fibrosis, mutations in the CFTR expressed endogenously in the respiratory epithelia lead to a reduced apical anion secretion that causes an imbalance in the transport of ions and fluid. The resulting decrease in anion transport contributes to an increased accumulation of mucus in the lung and accompanying microbial infections that ultimately cause death in patients with cystic fibrosis. In addition to respiratory disease, patients with cystic fibrosis usually suffer from gastrointestinal problems and pancreatic insufficiency that, if left untreated, results in death. In addition, most men with cystic fibrosis are infertile and fertility is decreased among women with cystic fibrosis. Unlike the severe effects of two copies of the cystic fibrosis-associated gene, individuals with a single copy of the cystic fibrosis-associated gene have an increased resistance to cholera and dehydration resulting from diarrhea - which perhaps explains the frequency relatively high of the cystic fibrosis gene within the population.

Sequence analysis of the cystic fibrosis chromosome CFTR gene has revealed several disease-causing mutations (Cutting, G. R. et al. (1990) Nature 346: 366-369; Dean, M. et al. (1990) Cell

61: 863: 870; and Kerem, B-S. et al. (1989) Science 245: 1073-1080; Kerem, B-S et al. (1990) Proc. Natl Acad. Sci. USA 87: 8447-8451). To date,> 1000 disease-causing mutations have been identified in the cystic fibrosis gene (http://www.genet.sickkids.on.ca/cftr/). The most prevalent mutation is a deletion of phenylalanine at position 508 of the amino acid sequence of CFTR, and is commonly referred to as ΔF508-CFTR. This mutation appears in approximately 70% of cases of cystic fibrosis and is associated with a serious disease.

The deletion of the 508 residue in the ΔF508-CFTR prevents the nascent protein from folding correctly. This results in the inability of the mutant protein to exit the endoplasmic reticulum ("RE"), and travel to the plasma membrane. As a result, the number of channels present in the membrane is considerably less than that observed in cells expressing wild-type CFTR. In addition to altered traffic, the mutation results in a defective opening and closing of channels. Together, the reduced number of channels in the membrane and the defective opening and closing lead to reduced anion transport through epithelia that leads to defective ion and fluid transport. (Quinton, P. M. (1990), FASEB J. 4: 2709-2727). However, studies have shown that reduced amounts of ΔF508-CFTR in the membrane are functional, although less than wild-type CFTR. (Dalemans et al. (1991), Nature Lond. 354: 526-528; Denning et al., Above; Pasyk and Foskett (1995), J. Cell. Biochem. 270: 12347-50). In addition to ΔF508-CFTR, other disease-causing mutations in the CFTR that result in transit, synthesis and / or opening and closing of defective channels could be regulated positively or negatively to alter anion secretion and modify disease progression and / or its severity.

Although the CFTR transports several molecules in addition to anions, it is clear that this role (the transport of anions) represents an element in an important mechanism of transport of ions and water through the epithelium. The other elements include the Na + epithelial channel, ENaC, the Na + / 2Cl - / K + cotransporter, the Na + -K + -ATPase pump and the K + channels of the basolateral membrane, which are responsible for the uptake of chloride in the cell.

These elements work together to achieve directional transport through the epithelium through its expression and selective location within the cell. Chloride absorption takes place through the coordinated activity of ENaC and CFTR present in the apical membrane and the Na + -K + -ATPase pump and Cl-channels expressed in the basolateral surface of the cell. The secondary active transport of chloride from the luminal side leads to the accumulation of intracellular chloride, which can then passively leave the cell through Cl - channels, resulting in a vector transport. The arrangement of the Na + / 2Cl - / K + cotransporter, the Na + K + -ATPase pump and the K + channels of the basolateral membrane on the basolateral surface and of the CFTR on the luminal side coordinate chloride secretion by means of CFTR on the side luminal Because water is probably never actively transported by itself, its flow through the epithelia depends on tiny transepithelial osmotic gradients generated by the massive flow of sodium and chloride.

In addition to cystic fibrosis, modulation of CFTR activity may be beneficial for other diseases not directly caused by mutations in the 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 Sjögren's syndrome.

COPD is characterized by a limitation of air flow that is progressive and not fully reversible. The limitation of air flow is due to hypersecretion of mucus, emphysema and bronchiolitis. Activators of wild-type or mutant CFTRs offer a potential treatment for mucus hypersecretion and altered mucociliary clearance that is common in COPD. Specifically, increasing anion secretion through CFTR can facilitate the transport of fluid to the liquid on the surface of the airways to hydrate the mucus and optimize the viscosity of the pericilliary fluid. This would lead to increased mucociliary clearance and a reduction in symptoms associated with COPD. Dry eye disease is characterized by a decrease in aqueous tear production and abnormal lipid, protein and mucin profiles in the tear film. There are many causes of dry eye, some of which include age, Lasik eye surgery, arthritis, medications, chemical / thermal burns, allergies and diseases, such as cystic fibrosis and Sjögren's syndrome. Increasing anion secretion through the CFTR would increase fluid transport from the corneal endothelial cells and secretory glands surrounding the eye to increase corneal hydration. This would help relieve the symptoms associated with dry eye disease. Sjögren's syndrome is an autoimmune disease in which the immune system attacks moisture-producing glands throughout the body, including the eye, mouth, skin, respiratory tissue, liver, vagina and intestines. Symptoms include dry eyes, mouth and vaginal, as well as lung disease. The disease is also associated with rheumatoid arthritis, systemic lupus, systemic sclerosis and polymyositis / dermatomyositis. It is believed that a defective protein transit causes the disease, for which treatment options are limited. Modulators of CFTR activity can hydrate the various organs affected by the disease and help elevate the associated symptoms.

As discussed above, it is believed that the deletion of the 508 moiety in the ΔF508-CFTR prevents the nascent protein from folding correctly, resulting in the inability of this mutant protein to exit the ER and travel to the plasma membrane. As a result, insufficient amounts of the mature protein are present in the plasma membrane and the transport of chloride within the epithelial tissues is significantly reduced. In fact, it has been shown that this cellular phenomenon of defective ER processing of ABC transporters by RE machinery is the underlying basis, not only for cystic fibrosis disease, but for a wide variety of other isolated and hereditary diseases . The two ways in which the machinery of the ER can malfunction are by loss of the coupling with the export of the ER of the proteins leading to their degradation, or by accumulation in the ER of these defective / wrongly folded proteins (Aridor M, et al., Nature Med., 5 (7), pp. 745-751 (1999); Shastry, BS, et al., Neurochem. International, 43, pp. 1-7 (2003); Rutishauser, J., et al., Swiss Med Wkly, 132, pp. 211-222 (2002); Morello, JP et al., TIPS, 21, pp.

466-469 (2000); Bross P., et al., Human Mut., 14, p. 186-198 (1999)). The diseases associated with the first type of ER malfunction are cystic fibrosis (due to erroneously folded ΔF508-CFTR, as discussed above), hereditary emphysema (due to AI antitrypsin; non-Piz variants), hereditary hemochromatosis, Coagulation-fibrinolysis deficiencies, such as protein C deficiency, hereditary Type 1 angioedema, deficiencies in lipid processing, such as familial hypercholesterolemia, Type 1 chylomicronemia, abetalipoproteinemia, lysosomal storage diseases, such as cell I / pseudo-Hurler disease, mucopolysaccharidosis (due to lysosomal processing enzymes), Sandhof / Tay-Sachs (due to β-hexosaminidase), Crigler-Najjar type II (due to UDP-glucuronyl-sialotransferase), polndocrinopathy / hyperinsulinemia, diabetes mellitus (due to insulin receptor), Laron dwarfism (due to growth hormone receptor), deficiency Myeloperoxidase, primary hypoparathyroidism (due to preproparathyroid hormone), melanoma (due to tyrosinase). The diseases associated with the last type of ER malfunction are type 1 CDG glycanosis, hereditary emphysema (due to α1 antitrypsin (PiZ variant), congenital hyperthyroidism, imperfect osteogenesis (due to Type I, II, IV procollagen) , hereditary hypofibrinogenemia (due to fibrinogen), ACT deficiency (due to α1-antichymotrypsin), diabetes insipidus (DI), neurofiseal DI (due to vasopressin / V2 receptor hormone), nephrogenic DI (due to aquaporin) II), Charcot-Marie Tooth syndrome (due to peripheral myelin protein 22), Perlizaeus-Merzbacher disease, neurodegenerative diseases such as Alzheimer's disease (due to βAPP and presenilins), Parkinson's disease , amyotrophic lateral sclerosis, progressive supranuclear paralysis, Pick's disease, various neurological disorders of polyglutamine such as Huntington, spinocere ataxia belar type I, spinal and bulbar muscular atrophy, palidoluisian dentatorubal atrophy and myotonic dystrophy, as well as spongiform encephalopathies, such as hereditary Creutzfeldt-Jakob disease (due to a defect in prion protein processing), Fabry disease (due to lysosomal α-galactosidase A), Straussler-Scheinker syndrome, chronic obstructive pulmonary disease (COPD), dry eye disease and Sjögren's syndrome.

In addition to the positive regulation of CFTR activity, the reduction of anion secretion by modulators of the CFTR can be beneficial for the treatment of secretory diarrhea, in which the transport of epithelial water is dramatically increased as a result of the transport of activated chloride. by secretagogues. The mechanism involves the elevation of the cAMP and the stimulation of the CFTR.

Although there are numerous causes of diarrhea, the main consequences of diarrheal diseases, which occur as a result of excessive chloride transport, are common to all and include dehydration, acidosis, altered growth and death.

Acute and chronic diarrhea represent a very important medical problem in many areas of the world. Diarrhea is both an important factor in malnutrition and the leading cause of death (5,000,000 deaths / year) in children under five years of age.

Secretory diarrhea is also a dangerous condition in patients with acquired immunodeficiency syndrome (AIDS) and chronic inflammatory bowel disease (IBD). Sixteen million travelers to developing countries from industrialized nations develop diarrhea each year, varying the severity and number of diarrhea cases depending on the country and the area of the trip.

Diarrhea in farm animals and pets such as cows, pigs and horses, sheep, goats, cats and dogs, also known as neonatal diarrhea, is a leading cause of death in these animals. Diarrhea can be the result of any major transition, such as weaning or physical movement, as well as in response to various bacterial and viral infections and usually occurs in the first few hours of the animal's life.

The most common diarrhea causing bacterium is enterotoxigenic E. coli (ETEC) that has the K99 pili antigen. Common viral causes of diarrhea include rotavirus and coronavirus. Other infectious agents include Cryptosporidium, Giardia lamblia and Salmonella, among others.

Symptoms of rotaviral infection include excretion of watery stool, dehydration and weakness. Coronaviruses cause a more serious disease in newborn animals and have a higher mortality rate than rotaviral infection. Often, however, a young animal can become infected with more than one virus.

or with a combination of viral and bacterial microorganisms at the same time. This greatly increases the severity of the disease.

Accordingly, there is a need for modulators of CFTR activity, and compositions thereof, that can be used to modulate the activity of CFTR in a mammalian cell membrane.

There is a need for CFTR-mediated disease treatment procedures using such modulators of CFTR activity.

There is a need for methods of modulating CFTR activity in an ex vivo cell membrane of a mammal. WO 2005/049018 A1 and WO 2005/075435 A1 describe thiazoles as modulators of ATP binding cassette transporters.

Summary of the invention

It has now been discovered that the compounds of the present invention, and a pharmaceutically acceptable composition, are useful as modulators of CFTR activity. This formula I or formula II:

image 1

5 or a pharmaceutically acceptable salt thereof, wherein Rx, ring A, RAA, RBB, Z and q are described below.

These pharmaceutically acceptable compounds and compositions are useful for treating or reducing the severity of various diseases, disorders or conditions, including, but not limited to, cystic fibrosis, hereditary emphysema, hereditary hemochromatosis, coagulation-fibrinolysis deficiencies, such as protein deficiency. C, 10 hereditary Type 1 angioedema, deficiencies in lipid processing, such as familial hypercholesterolemia, Type 1 chylomicronemia, abetalipoproteinemia, lysosomal storage diseases, such as I / pseudo-Hurler cell disease, mucopolysaccharidosis, Sandhof / Tay-Sachs, Crigler-Najjar type II, polndocrinopathy / hyperinsulinemia, diabetes mellitus, Laron dwarfism, myeloperoxidase deficiency, primary hypoparathyroidism, melanoma, CDG type 1 glucanosis, hereditary emphysema, congenital hyperthyroidism, 15 osteogenesis imperfect, hypophyrinogenic hypofreditary disease ACT, diabetes ins order (DI), neurophysal DI, nephrogenic DI, Charcot-Marie Tooth syndrome, Perlizaeus-Merzbacher disease, neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, progressive supranuclear paralysis, disease Pick, Huntington, spinocerebelar ataxia type I, spinal and bulbar muscular atrophy, palidoluisian dentatorubal atrophy and myotonic dystrophy, encephalopathies

20 spongiforms, such as hereditary Creutzfeldt-Jakob disease (due to a defect in prion protein processing), Fabry disease, Straussler-Scheinker disease, secretory diarrhea, polycystic kidney disease, chronic obstructive pulmonary disease ( COPD), dry eye disease or Sjögren's syndrome.

Detailed description of the invention

25 I. General Description of Compounds of the Invention:

The present invention provides compounds of formula I or formula II:

image 1

or a pharmaceutically acceptable salt thereof, in which:

each Rx is independently hydrogen, halo, CF3, C1-C4 alkyl or -O-C1-C4 alkyl; with the proviso that the two Rx are not simultaneously hydrogen; or the two RXs taken together form the ring (a):

image 1

X is CH2, CF2, CH2-CH2 or CF2-CF2; Ring A is a 3-7 membered monocyclic cycloalkyl ring; RAA and RBB, taken together with the nitrogen atom, form a pyrrolidinyl ring substituted with OR '; R 'is hydrogen or C1-C6 aliphatic, in which up to two carbon units of said aliphatic are optional and

independently replaced by -CO-, -CS-, -COCO-, -CONR-, -CONRNR-, -CO2-, -OCO-, -NRCO2-, -O, -NRCONR-, -OCONR-, -NRNR, - NRNRCO-, -NRCO-, -S-, -SO, -SO2-, -NR-, -SO2NR-NRSO2-or -NRSO2NR-; R is hydrogen or C1-C6 aliphatic; Z is halo, CN, COOH, CF3 or difluoromethylenedioxy; Y

q is 0-3.

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

The term "CFTR", as used herein, means the cystic fibrosis transmembrane conductance regulator, or a mutation thereof, capable of regulatory activity, including, but not limited to, ΔF508 CFTR and G551D CFTR ( see, for example, http: //www.genet.sickkids.on.ca/cftr/, for CFTR mutations).

The term "modular," as used herein, means increasing or decreasing by a measurable amount.

The term "correction", as used herein, means increasing the number of CFTRs in a cell membrane.

The term "enhancer", as used herein, means a compound that increases the opening and closing activity of the CFTR in a cell membrane.

The term "electron withdrawal substituent", as used herein, means an atom or a group that is electronegative with respect to hydrogen. See, for example, "Advanced Organic Chemistry: Reactions, Mechanisms, and Structure," Jerry March, 4th Ed., John Wiley & Sons (1992), for example, p. 14-16, 18-19, etc. Exemplary substituents of this type include halo, CN, COOH, CF3, etc.

For the purposes of the present invention, chemical elements are identified in accordance with the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 75th Ed. In addition, the general principles of organic chemistry are described in "Organic Chemistry ", Thomas Sorrell, University Science Books, Sausalito: 1999, and in" March's Advanced Organic Chemistry ", 5th Ed., Ed .: Smith, MB and March, J., John Wiley & Sons, New York: 2001, whose content Complete is hereby incorporated by reference.

Unless otherwise specified, the term "aliphatic" or "aliphatic group", by itself, as used herein, refers to a straight chain (ie unbranched) or branched hydrocarbon chain. , substituted or unsubstituted, that is completely saturated or that contains one or more units of unsaturation, or a monocyclic hydrocarbon or bicyclic hydrocarbon that is fully saturated or that contains one or more units of unsaturation, but is not aromatic (also referred to as the present document "carbocycle", "cycloaliphatic" or "cycloalkyl"), which has a single point of attachment with the rest of the molecule. Unless otherwise specified, aliphatic groups contain 1-20 aliphatic carbon atoms. In some embodiments, the aliphatic groups contain 1-10 aliphatic carbon atoms. In other embodiments, the aliphatic groups contain 1-8 aliphatic carbon atoms. In yet other embodiments, the aliphatic groups contain 1-6 aliphatic carbon atoms, and still in other embodiments the aliphatic groups contain 1-4 aliphatic carbon atoms. In some embodiments, "cycloaliphatic" (or "carbocycle" or "cycloalkyl") refers to a monocyclic C3-C8 hydrocarbon or bicyclic C8-C12 hydrocarbon that is fully saturated or that contains one or more unsaturation units, but which is not aromatic, which has a single point of attachment with the rest of the molecule in which any single ring of said bicyclic ring system has 3-7 members. Suitable aliphatic groups include, but are not limited to, linear or branched, substituted or unsubstituted alkyl, alkenyl and alkynyl groups, and hybrids thereof such as (cycloalkyl) alkyl, (cycloalkenyl) alkyl or (cycloalkyl) alkenyl.

The term "unsaturated", as used herein, means that a remainder has one or more units of unsaturation.

Unless it is specified stereochemically, the structures represented herein are also intended to include all isomeric (eg, enantiomeric, diastereomeric, and geometric (or conformational)) forms of the structure; for example, the R and S configurations for each asymmetric center, double bond isomers (Z) and (E) and conformational isomers (Z) and (E), including mixtures containing an excess of one enantiomer with respect to the other enantiomer or an excess of one diastereomer with respect to another. Unless otherwise specified, the individual stereochemical isomers as well as enantiomeric, diastereomeric and geometric (or conformational) mixtures of the compounds of the present invention are within the scope of the invention. Unless otherwise indicated, all tautomeric forms of the compounds of the invention are within the scope of the invention. In addition, unless otherwise indicated, the structures represented herein are also intended to include compounds that differ only in the presence of one or more atoms enriched with isotopes. For example, the compounds having the structures of the present invention except for the replacement of hydrogen by deuterium or tritium, or the replacement of a carbon with a 13C or 14C enriched carbon are within the scope of the present invention. Such compounds are useful, for example, as analytical tools or probes in biological assays.

In one embodiment, each RX is independently hydrogen, halo or CF3; with the proviso that the two RXs are not simultaneously hydrogen. In another embodiment, one RX is hydrogen and the other RX is halo or CF3. In another embodiment, the two RXs are halo.

In one embodiment, the two RX groups taken together form the ring (a).

In certain embodiments, X is CH2. In other embodiments, X is CF2. Or, X is CH2-CH2. In certain other embodiments, X is CF2-CF2;

In one embodiment, ring A is cyclopropyl, cyclopentyl, or cyclohexyl. In another embodiment, ring A is cyclopropyl

or cyclopentyl. In certain embodiments, ring A is cyclopropyl.

In one embodiment, R is hydrogen. Or, R is C1-C6 alkyl. Exemplary R includes methyl, ethyl or propyl.

In one embodiment, R 'is hydrogen. Or, R 'is C1-C6 alkyl. Exemplary R 'include methyl, ethyl, propyl or C (O) Me.

In one embodiment, RAA and RBB, taken together, form a pyrrolidinyl with an OH substituent.

In one embodiment, Z is selected from halo, CF3 or difluoromethylenedioxy.

In one embodiment, q is 0, O, q is 1-2. In certain embodiments, q is 1, O, q is 2.

In another embodiment, the compounds of formula I or formula II comprise one or more, and preferably all, of the following characteristics:

the two Rx are taken together to form the ring (a);

X is CH2;

ring A is cyclopropyl;

R 'is hydrogen;

q is 1 or 2; Y

Z is halo, CF3 or difluoromethylenedioxy.

In another embodiment, the compounds of formula I or formula II comprise one or more, and preferably all, the following characteristics:

the two Rx are taken together to form the ring (a);

X is CH2;

R is hydrogen;

ring A is cyclopropyl;

R 'is hydrogen;

q is 1 or 2; Y

Z is halo, CF3 or difluoromethylenedioxy.

In another embodiment, the compounds of formula I or formula II comprise one or more, and preferably all, the following characteristics:

the two Rx are taken together to form the ring (a);

X is CF2;

ring A is cyclopropyl;

R 'is hydrogen;

q is 1 or 2; Y

Z is halo, CF3 or difluoromethylenedioxy.

In another embodiment, the compounds of formula I or formula II comprise one or more, and preferably all, the following characteristics:

the two RXs are taken together to form the ring (a);

X is CF2;

R is hydrogen;

ring A is cyclopropyl;

R 'is hydrogen;

q is 1 or 2; Y

Z is halo, CF3 or difluoromethylenedioxy.

In an embodiment of compounds of formula I, RAA and RBB, taken together with the nitrogen atom, form the following ring (i):

image 1

In an embodiment of compounds of formula II, RAA and RBB, taken together with the nitrogen atom, form the following ring (ii):

image 1

In an embodiment of compounds of formula I, RAA and RBB, taken together with the nitrogen atom, form the following ring (iii):

image 1

In an embodiment of compounds of formula II, RAA and RBB, taken together with the nitrogen atom, form the following ring (iv):

image 1

In an alternative embodiment, the present invention provides intermediates having formula I 'or formula II':

image 1

in which:

RX, R, ring A, Z and q are as defined above; L is a linker selected from C (O), SO2; p is 0 or 1; Y CA is a suitable chiral auxiliary.

The term "chiral auxiliary," as used herein, refers to an asymmetric molecular molecule or fragment that is used to achieve the chemical resolution of a racemic or diastereomeric mixture. Such chiral auxiliaries may possess a chiral center such as methylbenzylamine or several chiral centers such as menthol. The purpose of a chiral auxiliary, once it has been formed in the starting material, is to allow the

5 simple separation of the resulting diastereomeric mixture. See, for example, J. Jacques et al., "Enantiomers, Racemates And Resolutions," pp. 251-369, John Wiley and Sons, New York (1981); E. L. Eliel and S. H. Wilen, "Stereochemistry of Organic Compounds," pp. 868-870, John Wiley and Sons (1994).

Suitable chiral auxiliaries useful in the present invention include those that are susceptible to binding with the above L-linker (ie, p is 1) or directly with the oxygen atom (i.e., p is 0). You can find each other

10 examples of such chiral auxiliaries, for example, in E. L. Eliel S. H. Wilen, ibid, pp. 337-340.

In one embodiment, CA, L, p and the oxygen atom attached to them, taken together, are (+) - 10-camphorsulfonate, ester (1S, 4R) - (-) - ω-canphanic, (1R, 2S, 5R ) - (-) - Mentholcarbonate, (1S, 2R, 5S) - (+) - Mentholcarbonate, (1R, 2R) -1-phenyl-2-cyclopropyl ester or (3R) -tetrahydrofuran-3-carbonate.

Exemplary compounds of the present invention are shown below in Table 1.

fifteen

Table 1

image 1

image 1

In one embodiment, the present invention provides a process for producing a compound of formula I or formula II:

image 1

comprising the step of reacting under a suitable first conditions a compound of formula R1 with a compound of formula I-A to produce said compound of formula I, or a compound of formula II-A to produce said compound of formula II:

image 1

10 in which:

each Rx is independently hydrogen, halo, CF3, C1-C4 alkyl or -O-C1-C4 alkyl; with the proviso that the two Rx are not simultaneously hydrogen; or the two Rx taken together form the ring (a):

image 1

X is CH2, CF2, CH2-CH2 or CF2-CF2; Ring A is a 3-7 membered monocyclic cycloalkyl ring; RAA and RBB, taken together with the nitrogen atom, form a pyrrolidinyl ring substituted with OR '; R 'is hydrogen or C1-C6 aliphatic, in which up to two carbon units of said aliphatic are optional and independently replaced by -CO-, -CS-, -COCO-, -CONR-, -CONRNR-, -CO2-, -OCO-, -NRCO2-, -O

5

10

fifteen

twenty

25

30

35

40

, -NRCONR-, -OCONR-, -NRNR, -NRNRCO-, -NRCO-, -S-, -SO, -SO2-, -NR-, -SO2NR-, NRSO2-or -NRSO2NR;

R is hydrogen or C1-C6 aliphatic;

Z is an electron extraction substituent; Y

q is 0-3; Y

LG1 is a suitable first outgoing group

As used herein, the term "first reaction conditions" refers to conditions suitable for effecting the reaction between the compound of formula IA and the compound of formula R-1 or between the compound of formula II-A and the compound of formula R-1. Such suitable conditions include, for example, a suitable first solvent, a suitable first temperature and a suitable reducing agent. One skilled in the art will know several of said suitable conditions that effect the reaction between the compound of formula IA and the compound of formula R-1 or between the compound of formula II-A and the compound of formula R-1.

In one embodiment, the first suitable solvent is a polar aprotic solvent, a polar protic solvent, an apolar solvent or a suitable combination thereof. Exemplary solvents useful as a suitable first solvent include methanol, ethanol, propanol, isopropanol, t-butanol, dichloromethane, dichloroethane, toluene, tetrahydrofuran, dioxane, diethyl ether, dimethyl ether, acetonitrile, dimethylformamide, DMAC or NMP.

In one embodiment, the first suitable temperature is a temperature that is sufficient to effect the reaction between the compound of formula I-A and the compound of formula R-1 in the first suitable solvent. In another embodiment, the first suitable temperature is a temperature that is sufficient to effect the reaction between the compound of formula II-A and the compound of formula R-1 in the first suitable solvent. The first exemplary suitable temperature includes between about 0 ° C and about 110 ° C. In one embodiment, the first suitable temperature is between about 0 ° C and about 25 ° C.

In one embodiment, the suitable reducing agent is a reducing agent that is capable of effecting the reaction between the compound of formula I-A and the compound of formula R-1. In another embodiment, the suitable reducing agent is a reducing agent that is capable of effecting the reaction between the compound of formula II-A and the compound of formula R-1. One skilled in the art will know suitable reducing agents for that reaction. Suitable agents for the present invention include a metallo-borohydride or a reagent that can undergo catalytic hydrogenation. Examples of such suitable reducing agents include sodium borohydride, sodium cyanoborohydride, lithium borohydride, sodium triacetoxyborohydride, calcium borohydride, hydrogen in the presence of a transition metal catalyst such as Pd / C.

In another embodiment, LG1 is a suitable first leaving group that can be displaced to produce the compound of formula I or the compound of formula II. See, "Advanced Organic Chemistry: Reactions, Mechanisms, and Structure," pp. 339-357, Jerry March, 4th Ed., John Wiley and Sons (1992).

The process according to claim 1, wherein LG1 is selected from alkyl sulfonate, arylsulfonate, halide, alkylcarboxylate.

In one embodiment, the compound of formula I-A is produced from formula I-B:

image 1

wherein [CA] is a suitable chiral auxiliary;

said method comprising the step of removing said chiral auxiliary under second conditions adequate. In an alternative embodiment, the compound of formula II-A is produced from formula II-B:

image 1

wherein [CA] is a suitable chiral auxiliary;

said method comprising the step of removing said chiral auxiliary under suitable second conditions.

A "suitable chiral auxiliary" above in a compound of formula II-B or formula I-B is a chiral auxiliary that can be linked to an amino group. An isomeric mixture of a compound containing said amino group with a chiral auxiliary attached thereto is easily separated into its individual isomers by suitable chiral separation means. See, for example, J. Jacques et al., "Enantiomers, Racemates And Resolutions," pp. 251-369, John Wiley and Sons, New York (1981); E. L. Eliel and S. H. Wilen, "Stereochemistry of Organic Compounds," pp. 868-870, John Wiley and

10 Sons (1994).

In one embodiment, said suitable chiral auxiliary is an alkylsulfoxyl group.

In another embodiment, said suitable second conditions comprise a suitable protic acid and a suitable second solvent.

In one embodiment, said second suitable solvent is selected from a polar aprotic solvent or a protic solvent.

Exemplary polar aprotic solvents include dioxane, tetrahydrofuran, diethyl ether, dichloromethane, etc. Exemplary protic solvents include methanol, ethanol, i-propanol, t-butanol, etc.

In one embodiment, said second suitable solvent is a polar aprotic solvent.

In another embodiment, said compound of formula I-B and the compound of formula II-B are produced by making

20, respectively, reacting a compound of formula I-C or of formula II-C with a compound of formula R-2 under suitable third conditions:

image 1

in which:

R is hydrogen or C1-C6 aliphatic; R1 is hydrogen or a suitable first protecting group; [CA] is a suitable chiral auxiliary; Y LG2 is a second suitable outgoing group.

In one embodiment, LG2 is selected from halide, OC (O) (C1-C6 alkyl), pentafluorophenoxy, C1-C6 alkoxy,

OCO2 (C1-C6 alkyl) or hydroxy. In one embodiment, R1 is hydrogen. In another embodiment, said suitable third conditions comprise a third coupling agent.

suitable and a suitable third solvent. In another embodiment, said suitable coupling agent is selected from DCC, DCI, HATU, TCPH or HBTU. In one embodiment, said third suitable solvent is selected from dichloromethane, dioxane, acetonitrile, DMF,

dichloroethane or tetrahydrofuran. In another embodiment, said compound of formula I-C or of formula II-C is produced from an isomeric mixture of a compound of formula R-3:

image 1

10

in which:

R, Z and q are as defined above; PG1 is a second suitable protecting group; Y [CA] is a suitable chiral auxiliary;

Said process comprising two stages, in which one of said two stages is to separate said isomeric mixture using suitable separation means, and the other of said two stages is the conversion of PG1 to R1 under suitable fourth conditions.

In one embodiment, said suitable separation means comprise suitable chromatographic means. Examples of such media include column chromatography or thin layer chromatography.

In another embodiment, said suitable separation means comprise suitable crystallization means.

In another embodiment, said fourth suitable conditions comprise a suitable deprotection reagent and a suitable fourth solvent. An exemplary suitable deprotection reagent is trifluoroacetic acid.

In one embodiment, said fourth suitable solvent is a polar aprotic solvent. Exemplary solvents include dichloromethane, tetrahydrofuran, dioxane, diethyl ether, etc.

In another embodiment, said compound of formula R-3 is produced from a compound of formula R-4 and a compound of formula R-5:

image 1

in which:

PG1 is a second suitable protecting group; M is a suitable metal cation; Y [CA] is a suitable chiral auxiliary;

said process comprising the steps of reacting said compound of formula R-4 with said compound of formula R-5 under suitable fifth conditions.

In one embodiment, said M is selected from Li +, Na + or Mg ++.

In another embodiment, said PG1 is selected from an alkylcarbamate, trifluoroacetyl, trialkylsilyl or pivaloyl. OR,

said PG1 is BOC or trimethylsilyl. In one embodiment, said fifth suitable conditions comprise a suitable fifth solvent and a fifth adequate temperature In one embodiment, said suitable temperature is about -78 ° C.

In another embodiment, said fifth suitable solvent is tetrahydrofuran. In an alternative embodiment, said compound of formula R-1 is:

Or, said compound of formula R-1 is:

image 1

In another embodiment, said compound of formula I or formula II is selected from Table 1.

4. General Synthetic Schemes

The compounds of the present invention can be prepared by methods known in the art. Exemplary synthetic routes for preparing the compounds of the present invention are illustrated below. Scheme I-A shown below illustrates a procedure for producing intermediate A:

image2

a) 50% NaOH, Y (CH2) nY, BTEAC (benzyl triethyl ammonium chloride); Y = suitable leaving group. Scheme I-B shown below illustrates a procedure for producing intermediate B.

image 1

a) Br2; b) thiourea, (Me) 2NCH (OMe) 2; c) HCl

Scheme I-C shown below illustrates a process for producing compounds of formula I or formula II:

image 1

a) SOCl2, DMF; b) 1,4-dioxane, Et3N; c) NaBH4, MeOH; d) i) CH3SO2Cl, DCM, Et3N; ii) RAARBBNH; e) chiral chromatography

Scheme I-D illustrates the synthesis of an exemplary compound of the present invention.

image 1

a) 50% aqueous NaOH, 1,2-chlorobromoethane, BTEAC

image 1

a) Br2; b) thiourea, (Me) 2NCH (OMe) 2; c) HCl

image3

image 1

a) SOCl2, DMF; b) 1,4-dioxane, Et3N; c) NaBH4, MeOH; d) i) CH3SO2Cl, DCM, Et3N; ii) (R) -pyrrolidinol; e) chiral chromatography

Scheme II-A shown below illustrates another exemplary process for preparing compounds of the present invention using a chiral auxiliary.

image 1

image 1

Scheme II-B shown below illustrates a process for preparing an exemplary compound of the present invention using a chiral auxiliary.

image 1

image 1

Scheme III shown below illustrates another process for preparing a compound of the present invention.

image 1

b) Ti (OPr) 4, dioxane; b) (Boc) 2O, Et3N, DMAP, THF; c) n-BuLi, -78 ° C, THF; d) 50% TFA, CH2Cl2.

image 1

a) SOCl2, DMF, 60 ° C; b) Et3N, CH2Cl2; c) HCl in dioxane, CH3OH; d) NaBH4 (LG = outgoing group).

image 1

a) SOCl2, DMF, 60 ° C; b) Et3N, CH2Cl2; c) HCl in dioxane, CH3OH; d) NaBH4 (LG = outgoing group).

5 Further illustrative examples for preparing compounds of the present invention are listed below.

5. Uses, formulation and administration

Pharmaceutically Acceptable Compositions

As discussed above, the present invention provides compounds that are useful as modulators of CFTR and, therefore, are useful in the treatment of diseases, disorders or conditions such as cystic fibrosis, hereditary emphysema, hereditary hemochromatosis, deficiencies of coagulation fibrinolysis, such as protein C deficiency, hereditary Type 1 angioedema, deficiencies in lipid processing, such as familial hypercholesterolemia, Type 1 chylomicronemia, abetalipoproteinemia, lysosomal storage diseases, such as cell I / pseudo-Hurler, mucopolysaccharidosis, Sandhof / Tay-Sachs, Crigler-Najjar type II, polyocrinopathy / hyperinsulinemia, diabetes 15 mellitus, Laron dwarfism, myeloperoxidase deficiency, primary hypoparathyroidism, melanoma, CDG type 1 glycanosis, hereditary emphysema, congenital hyperthyroidism, osteogenesis imperfecta, hered hypofibrinogenemia itaria, ACT deficiency, diabetes insipidus (DI), neurophysical DI, nephrogenic DI, Charcot-Marie Tooth syndrome,

Perlizaeus-Merzbacher disease, neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, progressive supranuclear paralysis, Pick's disease, various neurological disorders of polyglutamine such as Huntington, spinocerebelar ataxia type I, spinal and bulbar muscular atrophy, palidoluisian dentatorubal atrophy and myotonic dystrophy, as well as spongiform encephalopathies, such as hereditary Creutzfeldt-Jakob disease (due to a defect in prion protein processing), Fabry disease and Straussler-Scheinker syndrome.

Accordingly, in another aspect of the present invention pharmaceutically acceptable compositions are provided, in which these compositions comprise any of the compounds described herein and, optionally, comprise a pharmaceutically acceptable carrier, adjuvant or excipient. In certain embodiments, these compositions optionally further comprise one or more additional therapeutic agents.

It will also be appreciated that certain of the compounds of the present invention may exist in free form for treatment, or when appropriate, as a pharmaceutically acceptable derivative thereof. In accordance with the present invention, a pharmaceutically acceptable derivative includes, but is not limited to, salts, esters, salts of said esters, or any pharmaceutically acceptable adduct or derivative, which upon administration to a patient in need thereof is capable of providing, directly or indirectly, a compound as otherwise described herein, or a metabolite or remainder thereof.

As used herein, the term "pharmaceutically acceptable salt" refers to those salts that, within the scope of good medical judgment, are suitable for use in contact with the tissues of humans and lower animals without toxicity, irritation. , excessive allergic response and similar, and correspond to a reasonable benefit / risk ratio. A "pharmaceutically acceptable salt" means any non-toxic salt.

or salt of an ester of a compound of the present invention which, upon administration to a recipient, is capable of providing, directly or indirectly, a compound of the present invention or an inhibitory active metabolite or remainder thereof. As used herein, the term "inhibitory active metabolite or remainder thereof" means that a metabolite or remainder thereof is also an inhibitor of ATP binding cassette transporters.

Pharmaceutically acceptable salts are well known in the art. For example, S. M. Berge, et al. describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 1977, 66, 1-19, incorporated herein by reference. Pharmaceutically acceptable salts of the compounds of the present invention include those derived from suitable organic and inorganic acids and bases. Examples of pharmaceutically acceptable non-toxic acid addition salts are salts of an amino group formed with 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 salts of adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, canforate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecyl sulfate, ethanesulfonate, format, fumarate, glucoheponate phosphate sulfate, glucohephonate, glucoheponate, glucoheponate, glucoheponate, glucoheponate, glucohephosphate , heptanoate, hexanoate, iodhydrate, 2-hydroxyethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate 3-, persulfate, persulfate phenylpropionate, phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate and the like. Salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium and N + (C1-4 alkyl) 4 salts. The present invention also provides for the quaternization of any basic nitrogen-containing group of the compounds disclosed herein. Products soluble or dispersible in water or oil can be obtained by means of said quaternization. Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium and the like. Additional pharmaceutically acceptable salts include, where appropriate, non-toxic cations of ammonium, quaternary ammonium and amine formed using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, lower alkyl sulfonate and aryl sulphonate.

As described above, the pharmaceutically acceptable compositions of the present invention further comprise a pharmaceutically acceptable carrier, adjuvant or excipient which, as used herein, includes any and all solvents, diluents or other liquid carriers, adjuvants of dispersion or suspension, surfactants, isotonic agents, thickening or emulsifying agents, preservatives, solid binders, lubricants and the like, as appropriate for the particular dosage form desired. Remington's Pharmaceutical Sciences, Sixteenth Edition, E. W. Martin (Mack Publishing Co., Easton, Pa., 1980) discloses various vehicles used in the formulation of pharmaceutically acceptable compositions and known techniques for the preparation thereof. Except insofar as any conventional vehicle medium is incompatible with the compounds of the invention, such as by producing any undesirable biological effect or otherwise interacting in a harmful manner with any other component or components of the pharmaceutically acceptable composition, It is contemplated that its use is within the scope of the present invention. Some examples of materials that can serve as pharmaceutically acceptable carriers include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, whey proteins, such as human serum albumin, buffer 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, polyacrylate , 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; tragacanth powder; malt; jelly; talcum powder; excipients such as cocoa butter and suppository waxes; oils such as peanut oil, cottonseed oil; safflower oil; Sesame oil; olive oil; corn oil and soybean oil; glycols; such as propylene glycol or polyethylene glycol; esters such as ethyl oleate and ethyl laurate; agar; buffering agents such as magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogenic water; isotonic saline solution; Ringer's solution; ethyl alcohol and phosphate buffer solutions, as well as other compatible non-toxic lubricants such as sodium lauryl sulfate and magnesium stearate, as well as coloring agents, releasing agents, coating agents, sweetening, flavoring and perfuming agents, preservatives and antioxidants may also be present in the composition, according to the formulator's judgment.

Uses of pharmaceutically acceptable compounds and compositions

The compounds of the invention can be used in the manufacture of a medicament for treating a condition, disease or disorder in which CFTR is involved. In certain embodiments, a compound of formula (I) may be used in the manufacture of a medicament to treat a condition, disease or disorder in which a CFTR deficiency is involved.

In certain preferred embodiments, the compounds of the invention can be used in the manufacture of a medicament for treating cystic fibrosis, hereditary emphysema (due to AI antitrypsin; non-Piz variants), hereditary hemochromatosis, coagulation-fibrinolysis deficiencies, such as protein C deficiency, hereditary Type 1 angioedema, deficiencies in lipid processing, such as familial hypercholesterolemia, Type 1 chylomicronemia, abetalipoproteinemia, lysosomal storage diseases, such as cell I / pseudo-disease Hurler, mucopolysaccharidosis (due to lysosomal processing enzymes), Sandhof / Tay-Sachs (due to β-hexosaminidase), Crigler-Najjar type II (due to UDP-glucuronyl-sialotransferase), polndocrinopathy / hyperinsulinemia, diabetes mellitus (due to insulin receptor), Laron dwarfism (due to growth hormone receptor), myeloperoxidase deficiency, hypopa primary ratiroidismo (due to the preproparatiroidea hormone), melanoma (due to tyrosinase). The diseases associated with the last type of ER malfunction are type 1 CDG glycanosis, hereditary emphysema (due to α1 antitrypsin (PiZ variant), congenital hyperthyroidism, imperfect osteogenesis (due to Type I, II, IV procollagen) , hereditary hypofibrinogenemia (due to fibrinogen), ACT deficiency (due to α1-antichymotrypsin), diabetes insipidus (DI), neurofiseal DI (due to vasopressin / V2 receptor hormone), nephrogenic DI (due to aquaporin) II), Charcot-Marie Tooth syndrome (due to peripheral myelin protein 22), Perlizaeus-Merzbacher disease, neurodegenerative diseases such as Alzheimer's disease (due to βAPP and presenilins), Parkinson's disease , amyotrophic lateral sclerosis, progressive supranuclear paralysis, Pick's disease, various neurological disorders of polyglutamine such as Huntington, spinocere ataxia belar type I, spinal and bulbar muscular atrophy, palidoluisian dentatorubal atrophy and myotonic dystrophy, as well as spongiform encephalopathies, such as hereditary Creutzfeldt-Jakob disease (due to a defect in prion protein processing), Fabry disease (due to lysosomal α-galactosidase A), Straussler-Scheinker syndrome, chronic obstructive pulmonary disease (COPD), dry eye disease and Sjögren's syndrome, which comprises the step of administering to said mammal an effective amount of a composition comprising a compound of formula (I),

or a preferred embodiment thereof as set forth above.

According to an alternative preferred embodiment, a compound of formula (I), or a preferred embodiment thereof, as set forth above, can be used in the manufacture of a medicament for treating cystic fibrosis.

In accordance with the invention, an "effective amount" of the pharmaceutically acceptable compound or composition is that amount effective to treat or decrease the severity of one or more cystic fibrosis, hereditary emphysema (due to AI antitrypsin; non-Piz variants) , hereditary hemochromatosis, coagulation-fibrinolysis deficiencies, such as protein C deficiency, hereditary Type 1 angioedema, deficiencies in lipid processing, such as familial hypercholesterolemia, Type 1 chylomicronemia, abetalipoproteinemia, storage diseases lysosomal, such as cell I / pseudo-Hurler disease, mucopolysaccharidosis (due to lysosomal processing enzymes), Sandhof / Tay-Sachs (due to β-hexosaminidase), Crigler-Najjar type II (due to UDP-glucuronyl- sialic transferase), polyocrinopathy / hyperinsulinemia, diabetes mellitus (due to insulin receptor), Laron dwarfism (due to hormone receptor d growth), myeloperoxidase deficiency, primary hypoparathyroidism (due to preproparathyroid hormone), melanoma (due to tyrosinase). The diseases associated with the last type of ER malfunction are CDG type 1 glycanosis, hereditary emphysema (due to α1-antitrypsin (PiZ variant), congenital hyperthyroidism, imperfect osteogenesis (due to Type I, II procollagen, IV), hereditary hypofibrinogenemia (due to fibrinogen), ACT deficiency (due to α1-antichymotrypsin), diabetes insipidus (DI), neurofiseal DI (due to vasopressin hormone / V2 receptor), nephrogenic DI ( due to aquaporin II), Charcot-Marie Tooth syndrome (due to peripheral myelin protein 22), Perlizaeus-Merzbacher disease, neurodegenerative diseases such as Alzheimer's disease (due to βAPP and presenilins), Parkinson's disease, amyotrophic lateral sclerosis, progressive supranuclear palsy, Pick's disease, various neurological disorders of polyglutamine such as Huntington, spinoce ataxia Rebel type I, spinal and bulbar muscular atrophy, palidoluisian dentatorubal atrophy and myotonic dystrophy, as well as spongiform encephalopathies, such as hereditary Creutzfeldt-Jakob disease (due to a defect in prion protein processing), Fabry disease (due to lysosomal α-galactosidase A), Straussler-Scheinker syndrome, chronic obstructive pulmonary disease (COPD), dry eye disease and Sjögren's syndrome.

The compounds and compositions, according to the process of the present invention, can be administered using any amount and any route of administration effective to treat or decrease the severity of one or more cystic fibrosis, hereditary emphysema (due to AI antitrypsin). ; non-Piz variants), hereditary hemochromatosis, coagulation-fibrinolysis deficiencies, such as protein C deficiency, hereditary Type 1 angioedema, deficiencies in lipid processing, such as familial hypercholesterolemia, Type 1 chylomicronemia, Abetalipoproteinemia, lysosomal storage diseases, such as cell I / pseudo-Hurler disease, mucopolysaccharidosis (due to lysosomal processing enzymes), Sandhof / Tay-Sachs (due to β-hexosaminidase), Crigler-Najjar type II (due to UDP-glucuronyl-sialotransferase), polyocrinopathy / hyperinsulinemia, diabetes mellitus (due to insulin receptor), ena Laron's nism (due to growth hormone receptor), myeloperoxidase deficiency, primary hypoparathyroidism (due to preproparathyroid hormone), melanoma (due to tyrosinase). The diseases associated with the last type of ER malfunction are type 1 CDG glycanosis, hereditary emphysema (due to α1 antitrypsin (PiZ variant), congenital hyperthyroidism, imperfect osteogenesis (due to Type I, II, IV procollagen) , hereditary hypofibrinogenemia (due to fibrinogen), ACT deficiency (due to α1-antichymotrypsin), diabetes insipidus (DI), neurofiseal DI (due to vasopressin / V2 receptor hormone), nephrogenic DI (due to aquaporin) II), Charcot-Marie Tooth syndrome (due to peripheral myelin protein 22), Perlizaeus-Merzbacher disease, neurodegenerative diseases such as Alzheimer's disease (due to βAPP and presenilins), Parkinson's disease , amyotrophic lateral sclerosis, progressive supranuclear paralysis, Pick's disease, various neurological disorders of polyglutamine such as Huntington, spinocere ataxia belar type I, spinal and bulbar muscular atrophy, palidoluisian dentatorubal atrophy and myotonic dystrophy, as well as spongiform encephalopathies, such as hereditary Creutzfeldt-Jakob disease (due to a defect in prion protein processing), Fabry disease (due to lysosomal α-galactosidase A), Straussler-Scheinker syndrome, chronic obstructive pulmonary disease (COPD), dry eye disease and Sjögren's syndrome.

The exact amount required will vary from one subject to another, depending on the species, age and general condition of the subject, the severity of the infection, the particular agent, its mode of administration and the like. The compounds of the invention are preferably formulated in unit dosage form because of their ease of administration and uniformity of dosage. The term "unit dosage form", as used herein, refers to a physically separate unit of agent appropriate for the patient to be treated. However, it will be understood that the total daily use of the compounds and compositions of the present invention will be decided by the attending physician within the scope of good medical judgment. The specific effective dose level for any particular patient or organism will depend on several factors, including the disorder being treated and the severity of the disorder; the activity of the specific compound employed; the specific composition used; the age, body weight, general health, sex and diet of the patient; the time of administration, the route of administration and the rate of excretion of the specific compound employed; the duration of treatment; drugs used in combination or coinciding with the specific compound employed, and similar factors well known in the medical art. The term "patient", as used herein, means an animal, preferably a mammal, and more preferably a human being.

The pharmaceutically acceptable compositions of the present invention can be administered to humans and other animals orally, rectally, parenterally, intracisternally, intravaginally, intraperitoneally, topically (such as by powders, ointments or drops), buccally, as an oral or nasal spray, or similar, depending on the severity of the infection being treated. In certain embodiments, the compounds of the invention may be administered orally or parenterally at dosage levels of from about 0.01 mg / kg to about 50 mg / kg, and preferably from about 1 mg / kg to about 25 mg / kg of subject body weight per day, one

or more times a day, to obtain the desired therapeutic effect.

Liquid dosage forms for oral administration include, but are not limited to, pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs. In addition to the active compounds, liquid dosage forms may contain inert diluents commonly used in the art such as, for example, water or other solvents, solubilizing and emulsifying agents such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate , benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils (in particular, cottonseed oils, peanut, corn, germ, olive, castor and sesame), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and esters of sorbitan fatty acids, and mixtures thereof. Apart from inert diluents, oral compositions may also include adjuvants, such as wetting agents, emulsifying and suspending agents, sweetening, flavoring and perfuming agents.

Injectable preparations may be formulated, for example, sterile injectable aqueous or oleaginous suspensions, according to the known technique using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation may also be a sterile injectable solution, suspension or emulsion in a nontoxic parenterally acceptable diluent or solvent, for example, as a solution in 1,3-butanediol. Among the acceptable vehicles and solvents that may be employed are water, Ringer's solution, isotonic sodium chloride solution and U.S.P. In addition, sterile nonvolatile oils are conventionally employed as a solvent or suspending medium. For this purpose, any mild nonvolatile oil, including synthetic mono- or diglycerides, can be used. In addition, fatty acids such as oleic acid are used in the preparation of injectables.

Injectable formulations can be sterilized, for example, by filtration through a bacteria retention filter, or by incorporation of sterilizing agents in the form of sterile solid compositions that can be dissolved or dispersed in sterile water or other sterile injectable medium before use.

To prolong the effect of a compound of the present invention, it is often desirable to slow the absorption of the compound from subcutaneous or intramuscular injection. This can be achieved by using a liquid suspension of crystalline or amorphous material with poor water solubility. The absorption rate of the compound then depends on its dissolution rate, which, in turn, may depend on the crystal size and the crystalline form. Alternatively, delayed absorption of a compound form administered parenterally is achieved by dissolving or suspending the compound in an oily vehicle. Injectable forms of extended release are generated by forming microencapsulated matrices of the compound in biodegradable polymers such as polylactide-polyglycolide. Depending on the proportion of compound with respect to polymer and the nature of the particular polymer employed, the rate of release of the compound can be controlled. Examples of other biodegradable polymers include poly (orthoesters) and poly (anhydrides). Injectable formulations of prolonged release are also prepared by entrapment of the compound in liposomes or microemulsions that are compatible with body tissues.

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 vehicles such as cocoa butter, polyethylene glycol or a suppository wax, which are solid at room temperature but liquid at temperature. body and, therefore, fuse in the rectum or vaginal cavity and release the active compound.

Solid dosage forms for oral administration include capsules, tablets, pills, powders and granules. In said solid dosage forms the active compound is mixed with at least one pharmaceutically acceptable inert carrier or excipient, such as sodium citrate or dicalcium phosphate and / or) fillers or diluents such as starches, lactose, sucrose, glucose, mannitol and silicic acid , b) binders such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose and gum arabic, c) humectants such as glycerol, d) disintegrating agents such as agar-agar, calcium carbonate, potato or tapioca starch, acid alginic, 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 glyceryl monostearate, h ) absorbents such as kaolin and bentonite clay, and i) lubricants such as talc, calcium stearate, magnesium stearate, polye solid ileylene glycols, sodium lauryl sulfate and mixtures thereof. In the case of capsules, tablets and pills, the dosage form may also comprise buffering agents.

Solid compositions of a similar type can also be used as fillers in hard and soft filled gelatin capsules, using excipients such as lactose or milk sugars, as well as high molecular weight polyethylene glycols and the like. Solid dosage forms of tablets, dragees, capsules, pills and granules can be prepared with coatings and carcasses such as enteric coatings and other coatings well known in the art of pharmaceutical formulation. They may optionally contain opacifying agents, and they may also be of a composition that releases the active ingredient or principles only, or preferably, in a particular part 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 can also be employed as fillers in hard and soft filled gelatin capsules, using excipients such as lactose or milk sugars, as well as high molecular weight polyethylene glycols and the like.

The active compounds may also be in microencapsulated form with one or more excipients as indicated above. Solid dosage forms of tablets, dragees, capsules, pills and granules can be prepared with coatings and carcasses such as enteric coatings, release control coatings and other coatings well known in the art of pharmaceutical formulation. In said solid dosage forms the active compound may be mixed with at least one inert diluent such as sucrose, lactose or starch. Such dosage forms may also comprise, as is normal practice, additional substances other than inert diluents, for example, tablet manufacturing lubricants and other tablet manufacturing adjuvants such as magnesium stearate and microcrystalline cellulose. In the case of compressed capsules and pills, the dosage forms may also comprise buffering agents. They may optionally contain opacifying agents and may also be of a composition that releases the active ingredient or principles only, or preferably, in a particular part of the intestinal tract, optionally delayed. Examples of embedding compositions that can be used include polymeric substances and waxes.

Dosage forms for topical or transdermal administration of a compound of the present invention include ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalers or patches. The active component is mixed under sterile conditions with a pharmaceutically acceptable carrier and any necessary preservative or buffer that may be required. It is also contemplated that ophthalmic formulations, ear drops and eye drops are within the scope of the present invention. In addition, the present invention contemplates the use of transdermal patches, which have the added advantage of providing controlled administration of a compound to the body. Said dosage forms are prepared by dissolving or dispensing the compound in the appropriate medium. Absorption enhancers can also be used to increase the flow of the compound through the skin. The speed can be controlled by providing a speed control membrane or by dispersing the compound in a polymer matrix or gel.

As described in general above, the compounds of the invention are useful as CFTR modulators. Therefore, without wishing to be bound by any particular theory, the compounds and compositions are particularly useful for treating or decreasing the severity of a disease, condition or disorder in which a hyperactivity or inactivity of CFTR is implicated in the disease, condition or disorder. When a hyperactivity or inactivity of a CFTR is implicated in a particular disease, condition or disorder, the disease, condition or disorder may also be referred to as a "CFTR-mediated disease, condition or disorder." Therefore, in another aspect, the present invention provides a method for treating or decreasing the severity of a disease, condition or disorder in which a hyperactivity or inactivity of a CFTR is involved in the pathology.

The activity of a compound used in the present invention as a modulator of a CFTR can be tested in accordance with procedures generally described in the art and in the Examples herein.

It will also be appreciated that the pharmaceutically acceptable compounds and compositions of the present invention can be employed in combination therapies, that is, the pharmaceutically acceptable compounds and compositions can be administered at the same time as, before, or after, one or more therapeutic agents or different medical procedures The particular combination of therapies (therapeutic agents or procedures) to be used in a combination regimen will take into account the compatibility of the desired therapeutic agents and / or procedures and the desired therapeutic effect to be achieved. It will also be appreciated that the therapies employed can achieve a desired effect for the same disorder (for example, a compound of the invention can be administered at the same time as another agent used to treat the same disorder), or they can achieve different effects (for example, control of any adverse effects). As used herein, additional therapeutic agents that are normally administered to treat or prevent a particular disease or condition are known as "appropriate for the disease or condition being treated."

The amount of additional therapeutic agent present in the compositions of the present invention will not exceed the amount that would normally be administered in a composition comprising that therapeutic agent as the sole active agent. Preferably, the amount of additional therapeutic agent in the presently disclosed compositions will vary from about 50% to 100% of the amount normally present in a composition comprising that agent as the only therapeutically active agent.

The compounds of the present invention or pharmaceutically acceptable compositions thereof can also be incorporated into compositions for the coating of an implantable medical device, such as prostheses, artificial valves, vascular grafts, stents and catheters. Accordingly, the present invention, in another aspect, includes a composition for coating an implantable device comprising a compound of the present invention, as described generally above, and in classes and subclasses herein, and a suitable vehicle 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 generally above, and in classes and subclasses herein, and a vehicle suitable for coating said implantable device Suitable coatings and the general preparation of coated implantable devices are described in US Patents 6,099,562; 5,886,026; and 5,304,121. The coatings are normally biocompatible polymeric materials such as a hydrogel polymer, polymethyldisiloxane, polycaprolactone, polyethylene glycol, polylactic acid, ethylene vinyl acetate and mixtures thereof. The coatings may optionally be additionally coated by a suitable upper coating of fluorosilicone, polysaccharides, polyethylene glycol, phospholipids or combinations thereof to confer controlled release characteristics in the composition.

Another aspect of the invention relates to modulating the activity of CFTR in a biological sample (for example, in vitro), said method comprising contacting said biological sample with a compound of formula I

or a composition comprising said compound. The term "biological sample", as used herein, includes, without limitation, cell cultures or extracts thereof; biopsied material obtained from a mammal or extracts thereof; and blood, saliva, urine, feces, semen, tears and other body fluids or extracts thereof.

Modulation of CFTR activity in a biological sample is useful for several purposes that are known to one skilled in the art. Examples of such purposes include, but are not limited to, the study of CFTR in biological and pathological phenomena; and the comparative evaluation of new modulators of CFTR.

In yet another embodiment, a method of modulating the activity of an in vitro anion channel is provided, which comprises the step of contacting said channel with a compound of formula (I). In preferred embodiments, the anion channel is a chloride channel or a bicarbonate channel. In other preferred embodiments, the anion channel is a chloride channel.

According to an alternative embodiment, the present invention provides a method of increasing the number of functional CFTRs in a cell membrane, which comprises the step of contacting said cell with a compound of formula (I). The term "functional ABC transporter," as used herein, means a CFTR that is capable of a transport activity.

According to another preferred embodiment, the activity of the CFTR is measured by measuring the transmembrane voltage potential. The means for measuring the voltage potential across a membrane in the biological sample can employ any of the methods known in the art, such as an optical assay of the membrane potential or other electrophysiological procedures.

The membrane potential optical 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): 269-77), in combination with instrumentation to measure fluorescence changes such as the 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).

These voltage-sensitive assays are based on the change in fluorescence resonance energy transfer (FRET) between the voltage-sensitive dye in the DiSBAC2 membrane (3) and a fluorescent phospholipid, CC2-DMPE, which binds to the outer leaf of the plasma membrane and acts as a donor of FRET. Changes in membrane potential (Vm) cause the negatively charged DiSBAC2 (3) to be redistributed through the plasma membrane and that the amount of energy transfer of CC2-DMPE changes accordingly. Changes in fluorescence emission can be controlled using VIPR ™ II, which is a liquid manipulator and integrated fluorescent detector designed to perform cell-based scans on 96 or 384 well microtiter plates.

In another aspect, the present invention provides a kit for use in measuring the activity of a CFTR, or a fragment thereof, in an in vitro or in vivo biological sample, comprising (i) a composition comprising a compound of formula (I) or any of the above embodiments; and (ii) instructions for a) putting the composition in contact with the biological sample and b) measuring the activity of said CFTR or a fragment thereof. In one embodiment, the kit further comprises instructions for a) contacting an additional composition with the biological sample; b) measuring the activity of said CFTR, or a fragment thereof in the presence of said additional compound, and c) comparing the activity of the CFTR in the presence of the additional compound with the density of the CFTR in the presence of a composition of formula (I). In preferred embodiments, the kit is used to measure the density of CFTR.

So that the invention described herein can be more fully understood, the following examples are set forth. It should be understood that these examples are for illustrative purposes only and should not be construed as limiting the present invention in any way.

Examples

Example 1:

(2) 1- (benzo [d] [1,3] dioxol-6-yl) -N- (5 - ((R) - (2-chlorophenyl) ((R) -3-hydroxypyrrolidine-1- hydrochloride il) methyl) thiazol-2il) cyclopropanecarboxamide and (1) 1- (benzo [d] [1,3] dioxol-6-yl) -N- (5 - ((S) - (2-chlorophenyl)) hydrochloride ( (R) -3hydroxypyrrolidin-1-yl) methyl) thiazol-2-yl) cyclopropanecarboxamide

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1-Benzo [1,3] dioxol-5-yl-cyclopropanecarboxylic acid

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A mixture of benzo [1,3] dioxol-5-carbonitrile (5.10 g 31.7 mmol), 1-bromo-2-chloro-ethane (9,000 ml 108.6 mmol) and

The benzyltriethylammonium chloride (BTEAC, 0.181 g 0.795 mmol) was heated to 70 ° C and then 50% aqueous sodium hydroxide (w / w) (26 ml) was added slowly. The reaction was stirred at 70 ° C for 24 hours and then heated to reflux (bath temperature 130 ° C) for 72 hours. The dark brown / black reaction mixture was diluted with water (400 ml) and extracted twice with equal volumes of ethyl acetate and dichloromethane. The basic aqueous solution was acidified with concentrated hydrochloric acid at a pH lower than one and the precipitate was filtered and

10 washed with 1 M hydrochloric acid. The solid material was dissolved in dichloromethane (400 ml) and extracted twice with equal volumes of 1 M hydrochloric acid and once with a saturated aqueous solution of sodium chloride. The organic solution was dried over sodium sulfate and evaporated to dryness, giving a white to slightly off-white solid (5.23 g, 25.4 mmol, 80.1%). ESI-MS m / z calc. 206.1, found 207.1 (M + 1) +. Retention time of 2.37 minutes. 1H NMR (400 MHz, DMSO-d6) δ 1.07-1.11 (m, 2H), 1.38-1.42 (m, 2H), 5.98 (s, 2H), 6.79

15 (m, 2H), 6.88 (m, 1H), 12.26 (s, 1H).

2-Bromo-1- (chloro-phenyl) -ethanone

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Bromine (3.8 ml, 65 mmol) was added dropwise to a solution of 1- (2-chloro-phenyl) -ethanone (10 g, 65 mmol) in acetic acid (75 ml) at 0 ° C. Then, the mixture was heated to room temperature and stirred overnight. The mixture was evaporated to dryness and used in the next step without further purification.

N '- [5- (2-Chloro-benzoyl) -thiazol-2-yl] -N, N-dimethylformamidine

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A mixture of thiourea (4.95 g, 65.0 mmol) and dimethoxymethyl dimethyl amine (23.2 g, 195 mmol) in methanol (80 ml) was heated at reflux for 30 minutes. After allowing the mixture to cool, triethylamine (19.8 g, 195) was added

25 mmol) and a solution of 2-bromo-1- (chloro-phenyl) -ethanone (crude from the last stage) in methanol (50 ml). The mixture was heated at reflux for 4 hours. The solvent was removed and the residue was used directly in the following procedure.

(2-Amino-thiazol-5-yl) - (2-chloro-phenyl) -methanone

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The crude N '- [5- (2-chloro-benzoyl) -thiazol-2-yl] -N, N-dimethylformamidine was dissolved in 10% HCl (150 ml) and heated at 70 ° C for 4 hours. The precipitate was filtered, washed with ether and then suspended in a 10% solution of sodium carbonate (250 ml). The suspension was stirred for 1 hour and the precipitate was filtered, washed with ether and air dried, giving (2-amino-thiazol-5-yl) - (2-chloro-phenyl) -methanone as a solid. brown (8.5 g, 36 mmol, 55% from 1- (2-chloro-phenyl) -ethanone). 1H NMR (400 MHz, DMSO-d6) δ 7.27 (s, 1H), 7.41-7.58 (m, 4H), 8.37 (s, 2H). ESI-MS m / z calc. 238.0, found; 239.3 (M + 1) +

1-Benzo [1,3] dioxol-5-yl-cyclopropanecarboxylic acid [5- (2-chloro-benzoyl) -thiazol-2-yl] -amide

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1-Benzo [1,3] dioxol-5-yl-cyclopropanecarboxylic acid (1.29 g, 6.28 mmol) was placed in an oven-dried flask in a nitrogen atmosphere. Thionyl chloride (3 ml) and N, N-dimethylformamide (0.3 ml) were added and the solution was allowed to stir for 2 hours. The excess thionyl chloride was removed in vacuo and the resulting solid was suspended in 30 ml of anhydrous 1,4-dioxane containing triethylamine (1.77 ml, 12.6 mmol). To this suspension was added slowly (2-amino-thiazol-5-yl) - (2-chlorophenyl) -methanone (1.50 g, 6.28 mmol) suspended in 10 ml of aqueous 1,4-dioxane. The resulting suspension was allowed to stir for 20 minutes. The mixture was filtered and then the filtrate was evaporated to dryness. The crude product was dissolved in 50 ml of dichloromethane and washed three times with 50 ml of 1 N HCl, saturated aqueous sodium bicarbonate and saturated aqueous sodium chloride. Then, the organic phase was dried over sodium sulfate and evaporated to dryness, yielding the product as a beige solid (1.51 g, 3.54 mmol, 56.4%). 1H NMR (400 MHz, DMSO-d6) δ 1.20-1.24 (m, 2H), 1.54-1.57 (m, 2H), 6.01 (s, 2H), 6.88 ( d, J = 1.3 Hz, 2H), 6.98 (s, 1H), 7.48-7.52 (m, 1H), 7.56-7.60 (m, 3H), 7.77 (s, 1H), 11.98 (s, 1H). ESI-MS m / z calc. 426.0, found; 427.3 (M + 1) +; Retention time 3.46 minutes.

1- (Benzo [d] (1,3] dioxol-6-yl) -N- (5 - ((2-chlorophenyl) (hydroxy) methyl) thiazol-2-yl) cyclopropanecarboxamide

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1-Benzo [1,3] dioxol-5-yl-cyclopropanecarboxylic acid [1.0 (2-chloro-benzoyl) -thiazol-2-yl] -amide (1.0 g, 2.3 mmol) was suspended in 150 ml of anhydrous methanol. Sodium borohydride (1.3 g, 35 mmol) was added slowly and the resulting pale yellow solution was allowed to stir for 1 hour at room temperature. The crude product was evaporated to dryness and then dissolved in a minimum amount of ethyl acetate. The organic extract was washed three times with an equal volume of 1 N hydrochloric acid, saturated aqueous sodium bicarbonate and saturated aqueous sodium chloride. Then, the organic phase was dried over sodium sulfate, filtered and evaporated to dryness, yielding the product as a beige solid (0.64 g, 1.5 mmol, 63%). 1H NMR (400 MHz, DMSO = d6) δ 1.10-1.14 (m, 2H), 1.41-1.45 (m, 2H), 6.00 (s, 2H), 6.14 ( s, 1H), 6.86 (d, J = 1.0 Hz, 2H), 6.95 (t, J = 1.0 Hz, 1H), 7.14 (d, J = 0.6 Hz, 1H) ,, 7.29-7.34 (m, 1H), 7.38-7.43 (m, 2H), 7.71 (d, J = 7.5 Hz, 1H), 10.93 ( s, 1H) IENEM m / z calc. 428.1, found; 429.5 (M + 1) + Retention time 3.17 minutes.

1- (Benzo [d] [1,3] dioxol-5-yl) -N- (5 - ((2-chlorophenyl) ((R) -3-hydroxypyrrolidin-1-yl) methyl) thiazol-2-yl) cyclopropanecarboxamide

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1-Benzo [1,3] dioxol-5-yl-cyclopropanecarboxylic acid [5 - [(2-chloro-phenyl) -hydroxymethyl] -thiazol-2-yl] -amide (0.500 g, 1.17 mmol) ) in 10 ml of anhydrous dichloromethane containing triethylamine (984 µl, 7.02 mmol). The mixture was cooled to 0 ° C and methanesulfonyl chloride (364 µl, 4.68 mmol) was added, followed immediately by (R) -pyrrolidin-35 ol (945 µl, 11.7 mmol) and the solution was allowed to stir for 10 minutes at room temperature. The crude product was washed three times with an equal volume of a saturated aqueous solution of sodium bicarbonate, followed by a saturated aqueous solution of sodium chloride. Then, the organic phase was dried over sodium sulfate and evaporated to dryness. The crude mixture was purified by column chromatography (20-90% ethyl acetate in hexanes on silica gel), yielding the product as a white solid (194.2 mg, 0.390 mol,

10 33.3%). 1H NMR (400 MHz, DMSO-d6) δ 1.09-1.15 (m, 2H), 1.41-1.44 (m, 2H), 1.54-1.63 (m, 1H), 1.93-2.77 (m, 5H), 4.20 (s, 1H), 4.72-4.77 (m, 1H), 4.96 (d, J = 7.0 Hz, 1H) , 6.00 (s, 2H), 6.85 (d, J = 0.9 Hz, 2H), 6.95 (s, 1H), 7.24-7.29 (m, 1H), 7, 37-7.43 (m, 3H), 7.76-7.80 (m, 1H), 11.03 (s, 1H). ESI-MS m / z calc. 497.1, found; 498.1 (M + 1) +; Retention time 2.36 minutes.

1- (benzo [d] [1,3] dioxol-5-yl) -N- (5 - ((2-chlorophenyl) ((R) -3-hydroxypyrrolidin-1-yl) methyl) thiazole-215 hydrochloride il) cyclopropanecarboxamide

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A solution of HCl in ether (0.1556 ml, 0.3112 mmol, 1 M) was added slowly to a stirred solution of 1 (benzo [d] [1,3] dioxol-5-yl) -N- (5 - ((2-Chlorophenyl) ((R) -3-hydroxypyrrolidin-1-yl) methyl) thiazol-2-yl) cyclopropanecarboxamide (0.1550 g, 0.3112 mmol) in 100 ml of anhydrous dichloromethane. The solution was evaporated to dryness, giving the

20 pure product (0.1654 g, 0.3095, 99.45%). ESI-MS m / z calc. 497.1, found; 498.1 (M + 1) +; Retention time 5.74 minutes.

(1) 1- (benzo [d] [1,3] dioxol-6-yl) -N- (5 - ((S) - (2-chlorophenyl) ((R) -3-hydroxypyrrolidine-1- hydrochloride il) methyl) thiazol-2il) cyclopropanecarboxamide and (2) 1- (benzo [d] [1,3] dioxol-6-yl) -N- (5 - ((R) - (2-chlorophenyl) ((R ) -3-hydroxypyrrolidin-1-yl) methyl) thiazol-2-yl) cyclopropanecarboxamide

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1- (Benzo [d] [1,3) dioxol-6-yl) -N- (5 - ((2-chlorophenyl) ((R) -3-hydroxypyrrolidin-1-yl) methyl) thiazole hydrochloride 2il) cyclopropanecarboxamide prepared above was separated using a Chiralpak AS-H 4.6 mm x 250 mm column from Chiral Technologies.

20-25 µl of a 2 mg / ml solution of 1- (benzo [d] [1,3] dioxol-6-yl) -N- hydrochloride (5 - ((2

Chlorophenyl) ((R) -3-hydroxypyrrolidin-1-yl) methyl) thiazol-2-yl) cyclopropanecarboxamide in methanol on the Chiralpak AS-H column and eluted with a 10% mixture of a 50/50 mixture ( v / v) ethanol and methanol in hexanes at 1.5 ml / min.

The first product to elute under these conditions had a retention time of 8.2 min (Chiralpak AS-H column).

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This product had a retention time of 14.5 min on a Chiralpak OJ-H 4.6 mm x 250 mm column (25% of a 50/50 (v / v) mixture of ethanol and methanol in hexanes at 1.0 ml / min)

The second product eluted at 9.6 min using a Chiralpak AS-H column. This second product had a retention time of 10.9 min on a Chiralpak OJ-H 4.6 mm x 250 mm column (25% of a 50/50 (v / v) mixture of ethanol and methanol in hexanes at 1, 0 ml / min).

Example 2

(1S, 2R, 5S) -2-Isopropyl-5-methylcyclohexylcarbonate of (R) -1 - ((2- (1- (benzo [d] [1,3] dioxol-6il) cyclopropanecarboxamido) thiazol-5-yl ) (2-chlorophenyl) methyl) pyrrolidin-3-yl

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1- (benzo [d] [1,3] dioxol-5-yl) -N- (5 - ((2-chlorophenyl) ((R) -3-hydroxypyrrolidin-1-yl) methyl) thiazol-2il was suspended ) cyclopropanecarboxamide (3.00 g, 6.02 mmol) in 200 ml of anhydrous dichloromethane containing N, N-dimethylpyridine-4-amine (2.20 g, 18.0 mmol). To the suspension was slowly added (1S, 2R, 5S) -2-isopropyl-5-methylcyclohexyl chloroformate (1.91 ml, 9.00 mmol) and the resulting mixture was heated under reflux for 16 hours. The resulting pale yellow solution was allowed to cool to room temperature, diluted with 20 ml of methanol and then evaporated to dryness. The crude reaction mixture was separated on 330 g of silica gel using a gradient of 0-5% methanol in dichloromethane, yielding the pure product as a pale yellow solid (2.0087 g, 2.9529 mmol, 49.1%). ESI-MS m / z calc. 679.3, found; 680.5 (M + 1) +; Retention time 3.88 minutes.

(1S, 2R, 5S) -2-Isopropyl-5-methylcyclohexylcarbonate of (R) -1 - ((S) - (2- (1- (benzo [d] [1,3] dioxol-6il) cyclopropanecarboxamido) thiazole -5-yl) (2-chlorophenyl) methyl) pyrrolidin-3-yl and (1S, 2R, 5S) -2-isopropyl-5-methylcyclohexylcarbonate of (R) -1 - ((R) - (2- (1- (benzo [d] [1,3] dioxol-6-yl) cyclopropanecarboxamido) thiazol-5yl) (2-chlorophenyl) methyl) pyrrolidin-3-yl

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(R) -1- (2- (1- (benzo [d] [1,3] dioxol-6-yl) cyclopropanecarboxamido) thiazole-5 (1S, 2R, 5S) -2-isopropyl -il) (2-chlorophenyl) methyl) pyrrolidin-3-yl prepared above using a Chiralpak AD 21 mm x 250 mm column from Chiral Technologies. 1 ml of a 30 mg / ml solution of the compound prepared above in isopropanol was injected into the Chiralpak AD column and eluted with a mixture of 7.5% isopropanol in heptane at 15 ml / min. The first product to elute, ((1S, 2R, 5S) -2-isopropyl-5-methylcyclohexyl) carbonate of ((R) -1 - ((S) - (2- (1- (benzo [d] [1,3]] dioxol-6-yl) cyclopropanecarboxamido) thiazol-5-yl) (2-chlorophenyl) methyl) pyrrolidin-3-yl, had a retention time of 14.4 min (Chiralpak AD column); 1H NMR (400 MHz, CD3OD) δ 0.79 (d, J = 7.0 Hz, 3H), 0.85-1.84 (m, 18H), 1.86-2.04 (m, 3H), 2.23-2.34 (m, 1H), 2.43-2.51 (m, 1H), 2.62-2.69 (m, 1H), 2.73-2.78 (m, 2H), 4.45-4 , 54 (m, 1H), 5.04-5.08 (m, 1H), 5.12 (s, 1H), 5.99 (s, 2H), 6.82 (d, J = 8.5 Hz, 1H), 6.93-6.97 (m, 2H), 7.25 (t, J = 6.8 Hz, 1H), 7.32 (s, 1H), 7.34-7.40 (m, 2H), 7.85 (dd, J = 8.1, 1.6 Hz, 1H) IEN-MS m / z calc 679.3, found; 680.5 (M + 1) +; Retention time 3.91 minutes.

The second product to elute, ((1S, 2R, 5S) -2-isopropyl-5-methylcyclohexyl) carbonate of ((R) -1 - ((R) - (2- (1 (benzo [d] [1,3) ] dioxol-6-yl) cyclopropanecarboxamido) thiazol-5-yl) (2-chlorophenyl) methyl) pyrrolidin-3-yl), had a retention time of 28.6 min (Chiralpak AD column). ESI-MS m / z calc. 679.3, found; 680.5 (M + 1) +; Retention time 3.86 minutes.

(1) 1- (benzo [d] [1,3] dioxol-6-yl) -N- (5 - ((S) - (2-chlorophenyl) ((R) -3-hydroxypyrrolidine-1- hydrochloride il) methyl) thiazol-2il) cyclopropanecarboxamide and (2) 1- (benzo [d] [1,3] dioxol-6-yl) -N- (5 - ((R) - (2-chlorophenyl)) hydrochloride ( (R) -3hydroxypyrrolidin-1-yl) methyl) thiazol-2-yl) cyclopropanecarboxamide

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The first product to elute from the previous step (1.20 g, 1.76 mmol) was stirred at room temperature for 4 days in 182 ml of methanol containing (0.9153 g, 16.31 mmol) of potassium hydroxide. Then, the solution was cooled to 0 ° C and 16.31 ml of 1 N HCl was slowly added to the reaction mixture. The resulting solution was evaporated to dryness and then partitioned between 100 ml of dichloromethane and 100 ml of an aqueous solution. saturated sodium bicarbonate. The phases were separated and the organic phase was washed twice with an equal volume of a saturated aqueous solution of sodium bicarbonate followed by three washes with a saturated aqueous solution of sodium chloride. Then, the organic phase was dried over anhydrous sodium sulfate, concentrated and purified on 120 g of silica gel using a gradient of 20-100% ethyl acetate in hexanes for 40 minutes, yielding pure product 1 as a a white solid (0.70 g, 1.4 mmol). This material was then dissolved in a minimum amount of dichloromethane and 1.4 ml of 1M HCl in ether was added to the solution. The solution was evaporated to dryness, yielding the HCl salt as a white solid (0.7818 g, 1.463 mmol, 83.1%). ESI-MS m / z calc. 497.1, found; 498.3 (M + 1) +; Retention time 2.36 minutes. Retention time of this product 14.5 min on a Chiralpak OJ-H 4.6 mm x 250 mm column (25% of a 50/50 (v / v) mixture of ethanol and methanol in hexanes at 1.0 ml / min) 1H NMR (400 MHz, DMSO-d6) δ (free base) 1.07-1.15 (m, 2H), 1.40-1.44 (m, 2H), 1.51-1.65 (m , 1H), 1.95-2.08 (m, 1H), 2.32-2.58 (m, 4H), 4.10-4.31 (m, 1H), 4.76 (d, J = 4.3 Hz, 1H), 4.95 (s, 1H), 6.00 (s, 2H), 6.85 (s, 2H), 6.95 (d, J = 0.9 Hz, 1H ), 7.26 (t, J = 7.6 Hz, 1H), 7.34-7.44 (m, 3H), 7.78 (d, J = 7.7 Hz, 1H), 11.02 (s, 1H)

The second product to elute from the previous step (0.1018 g, 0.1497 mmol) was stirred at room temperature for 3 days in 15 ml of methanol containing (9.5 mg, 0.17 mmol) of potassium hydroxide. An additional aliquot of potassium hydroxide (64.8 mg, 1.15 mmol) was added and the solution was allowed to stir for a further 3 days. Then, the solution was cooled to 0 ° C and 1,319 ml of 1N HCl was slowly added to the reaction mixture. The resulting solution was evaporated to dryness and then partitioned between 10 ml of dichloromethane and 10 ml of a saturated aqueous solution of sodium chloride. Then, the organic phase was dried over anhydrous sodium sulfate, concentrated and purified on 12 g of silica gel using a gradient of 20-100% ethyl acetate in hexanes for 40 minutes. Then, the column was washed with ethyl acetate containing 2.5% triethylamine. The pure fractions were combined and evaporated to dryness, yielding pure product 2 as a white solid (15.7 mg, 0.0315 mmol). This material was then dissolved in a minimum amount of dichloromethane and 0.0315 ml of 1 M HCl in ether was added to the solution. The solution was evaporated to dryness, yielding the HCl salt as a white solid (16.8 g, 0.0315 mmol, 21.0%). ESI-MS m / z calc. 497.1, found; 498.3 (M + 1) +; Retention time 2.42 minutes. Retention time 10.9 minutes on a Chiralpak OJ-H column 4.6 mm x 250 mm (25% of a 50/50 (v / v) mixture of ethanol and methanol in hexanes at 1.0 ml / min)

(R) -N- (2-Chlorobenzylidene) -1-dimethylethylsulfinamide

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To anhydrous dioxane (500 ml) was added 2-chlorobenzaldehyde (34.8 g, 247.5 mmol) and the solution was cooled to 0 ° C in an ice bath. To the aldehyde solution was added a solution of (R) -2-methylpropanesulfinamide (30.0 g, 247.5 mmol) in anhydrous dioxane (100 ml). Then, Ti (OPr) 4 (105.5 g, 371.3 mmol) was slowly added to the solution while stirring at 0 ° C. The reaction mixture was allowed to warm to 25 ° C, stirred at 25 ° C for 18 h, quenched with NaHCO3 and then filtered through a short bed of Celite using EtOAc. The organic phase was separated from the aqueous layer, dried over Na2SO4 and concentrated. The crude product was purified by column chromatography (0-25% EtOAc / Hexane) to provide (R) -N- (2-chlorobenzylidene) -1,1-dimethylethylsulfinamide as a yellow liquid (45, 1 g, 75%). 1H NMR (400 MHz, CDCl3) δ 9.05 (s, 1H), 8.06 (dd, J = 7.9, 1.1 Hz, 1H), 7.47-7.41 (m, 2H) , 7.37-7.33 (m, 1H), 1.28 (s, 9H). HPLC retention time 3.45 min, 10-99% CH3CN, embodiment 5 min; ESI-MS 244.3 m / z (MH +).

Tert-Butyl thiazol-2-ylcarbamate

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To a solution of 2-aminothiazole (20.0 g, 199.7 mmol) and (Boc) 2O (48.0 g, 219.7 mmol) in anhydrous THF (100 ml) DMAP (20 mg) was added and Et3N (36.0 ml, 260.0 mmol). The reaction mixture was stirred at 25 ° C for 18 h, diluted with CH2Cl2 and washed with 0.1 N HCl (x 1), brine (x 1) and H2O (x 1). The organic phase was separated from the aqueous phase, dried over Na2SO4 and concentrated. The crude product was purified by column chromatography (0-40% EtOAc / Hexane) to provide, providing tert-butyl thiazol-2-ylcarbamate as a white solid (20.7 g, 72%) . 1H NMR (400 MHz, CDCl3) δ 11.44 (s, 1H), 7.38 (d, J = 3.6 Hz, 1H), 6.89 (d, J = 3.6 Hz, 1H), 1.58 (s, 9H). HPLC retention time 2.61 min, 10-99% CH3CN, embodiment 5 min; ESI-MS 145.1 m / z (MH +).

(R) -N (1 - ((2-t-Butoxycarbonylamino) thiazol-5-yl) -1- (2-chlorophenyl) -methyl) -1,1-dimethylethylsulfinamide

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A solution of tert-butyl thiazol-2-ylcarbamate (15.0 g, 75.0 mmol) in anhydrous THF (175 ml) was stirred and cooled to -78 ° C. To this solution was added slowly n-BuLi (2.5 M in hexane: 60.0 ml, 150.0 mmol). After the addition of n-BuLi was finished, the mixture was allowed to warm to -40 ° C, kept at -40 ° C for 1 h and then cooled to -78 ° C. To the above solution was slowly added a solution of (R) -N- (2-chlorobenzylidene) -1,1-dimethylethylsulfinamide (10.0 g, 41.0 mmol) in anhydrous THF (175 ml) previously cooled to -78 ° C by cannulation The reaction was maintained at -78 ° C for 0.5 h, allowed to warm to room temperature and stirred at room temperature for 2 h. Then, the reaction was stopped with aqueous NH4Cl and the crude product was extracted with EtOAc (x 3). The combined organic phases were dried over Na2SO4 and concentrated. The crude product was purified by column chromatography (0-80% EtOAc / Hexane), providing, providing a diastereomeric mixture of (R) -N- (1 - ((2-t-butoxycarbonylamino) thiazol-5-yl ) -1- (2-chlorophenyl) -methyl) -1,1-dimethylethylsulfinamide as a yellow solid (15.1 g, 83%) that was used directly in the next step.

(R) -N- (S) -1- (2-Aminothiazol-5-yl) -1- (2-chlorophenyl) methyl) -1,1-dimethylethylsulfinamide and (R) -N- (R) -1- (2-Aminothiazol-5il) -1- (2-chlorophenyl) methyl) -1,1-dimethylethylsulfinamide

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To a solution of (R) -N- (1 - ((2-t-butoxycarbonylamino) thiazol-5-yl) -1- (2-chlorophenyl) -methyl) -1,1-dimethyl-ethylsulfinamide (7.0 g, 15.8 mmol) in CH2Cl2 (28 ml), trifluoroacetic acid (28 ml) was added. The reaction was stirred at room temperature for 3.5 h. Trifluoroacetic acid and CH2Cl2 were removed in vacuo. The crude product was dissolved again in CH2Cl2, washed with aqueous NaHCO3 (20 ml x 2) and water (20 ml x 1), dried over Na2SO4 and concentrated. The crude product was purified by column chromatography (0-5% EtOH / EtOAc), providing (R) -N- (S) -1 (2-aminothiazol-5-yl) -1- (2-chlorophenyl) methyl) -1,1-dimethylethylsulfinamide and (R) -N- (R) -1- (2-aminothiazol-5-yl) -1- (2-chlorophenyl) methyl) -1,1-dimethylethylsulfinamide.

(R) -N- (S) -1- (2-aminothiazol-5-yl) -1- (2-chlorophenyl) methyl) -1,1-dimethylethylsulfinamide: yellow solid, 4.3 g (79% ). 1H NMR (400 MHz, CDCl3) δ 7.53 (dd, J = 7.6, 1.8 Hz, 1H), 7.38 (dd, J = 7.7, 1.5 Hz, 1H), 7 , 32 (td, J = 7.5, 1.6 Hz, 1H), 7.27 (td, J = 7.5, 1.8 Hz, 1H), 6.84 (d, J = 0.7 Hz, 1H), 6.17 (s, 2H), 6.07 (d, J = 4.5 Hz, 1H), 4.17 (d, J = 4.6 Hz, 1H), 1.26 ( s, 9H). HPLC retention time 2.11 min, 10-99% CH3CN, embodiment 5 min; ESI-MS 344.0 m / z (MH +).

(R) N- (R) -1- (2-Aminothiazol-5-yl) -1- (2-chlorophenyl) methyl) -1,1-dimethylethylsulfinamide: yellow solid, 596 mg, (11%). HPLC retention time 2.35 min, 10-99% CH3CN, embodiment 5 min; ESI-MS 344.0 m / z (MH +).

(S) -N- (5 - ((R) -t-Butylsulfinylamino (2-chlorophenyl) methyl) thiazol-2-yl) -1- (benzo [d] [1,3] dioxol-5yl) cyclopropanecarboxamide

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To the 1- (benzo [d] [1,3] dioxol-5-yl) cyclopropanecarboxylic acid (2.16 g, 10.5 mmol) SOCl2 (2.3 mL, 31.5 mmol) was slowly added followed by DMF (3 drops). The reaction mixture was heated at 60 ° C for 0.5 h. The excess SOCl2 was removed in vacuo. Then, the acid chloride (10.5 mmol) was dissolved in anhydrous CH2Cl2 (16 ml) and slowly added to a cooled solution (temperature ~ 0 ° C) of (R) -N- (S) -1- (2 -aminothiazol-5-yl) -1- (2-chlorophenyl) methyl-1,1-dimethylethylsulfamide (3.6 g, 10.5 mmol) and Et3N (7.33 ml, 52.6 mmol) in anhydrous CH2Cl2 (16 ml ). The reaction mixture was stirred at 25 ° C for 18 h, diluted with CH2Cl2 and washed with 1N HCl (50 ml x 2), NaHCO3 (50 ml x 1) and brine (50 ml x 1). The organic phase was separated from the aqueous phase, dried over Na2SO4 and concentrated. The crude product was purified by column chromatography (0-80% EtOAc / Hexane) to provide (S) -N- (5 ((R) -t-butylsulfinylamino- (2-chlorophenyl) methyl) thiazol-2- il) -1- (benzo [d] [1,3] dioxol-5-yl) cyclopropanecarboxamide as a yellow solid (4.7 g, 84%). 1H NMR (400 MHz, CDCl3) δ 8.52 (s, 1H), 7.60 (dd, J = 7.7, 1.7 Hz, 1H), 7.35 (dd, J = 7.8, 1.4 Hz, 1H), 7.32 (dd, J = 7.5, 1.4 Hz, 1H), 7.29 (d, J = 0.7 Hz, 1H), 7.23 (dd, J = 7.6.1.7 Hz, 1H), 6.89 (dd, J = 7.9, 1.8 Hz, 1H), 6.86 (d, J = 1.6 Hz, 1H), 6.81 (d, J = 7.9 Hz ,,, 6.21 (d, J = 4.0 Hz, 1H), 6.01 (s, 2H), 3.93 (d, J = 4, 0 Hz ,, 1H), 1.75-1.66 (m, 2H), 1.27 (s, 9H), 1.22 (t, J = 3.3 Hz, 2H) HPLC retention time 3.52 min, CH3CN at 10-99%, embodiment 5 min; ESI-MS 532.0 m / z (MH +).

(S) -N- (5- (Amino (2-chlorophenyl) methyl) thiazol-2-yl) -1- (benzo [d] [1,3] dioxol-5-yl) cyclopropanecarboxamide

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To a solution of (S) -N- (5 - ((R) -t-butylsulfinylamino- (2-chlorophenyl) methyl) thiazol-2-yl) -1- (benzo [d] [1,3] dioxol- 5il) cyclopropanecarboxamide (11.25 g, 21.19 mmol) in MeOH (100 ml) 4M HCl in dioxane (32 ml, 128 mmol) was added. The reaction mixture was stirred at 25 ° C for 1.5 h and evaporated to dryness. The crude product was dissolved in CH2Cl2. The organic phase was washed with aqueous NaHCO3 (50 ml x 2) and brine (50 ml x 1), dried over Na2SO4 and concentrated. The crude product was purified by column chromatography (0-2.5% Et3N-EtOAc) to provide (S) -N- (5- (amino (2-chlorophenyl) methyl) thiazol-2-yl) -1 - (benzo [d] [1,3] dioxol-5-yl) cyclopropanecarboxamide (6.5 g, 72%,> 99% ee). 1H NMR (400 MHz, CDCl3) δ 8.51 (s, 1H), 7.60 (dd, J = 7.7, 1.7 Hz, 1H), 7.33 (dd, J = 7.9, 1.3 Hz, 1H), 7.29-7.25 (m, 1H), 7.20 (td, J = 7.6, 1.7 Hz, 1H), 7.16 (d, J = 1 , 0 Hz, 1H), 6.89 (td, J = 7.8, 1.7 Hz, 2H), 6.80 (d, J = 7.9 Hz, 1H), 6.01 (s, 2H ), 5.79 (s, 1H), 1.86 (sa, 2H), 1.72-1.69 (m, 2H), 1.22-1.19 (m, 2H). HPLC retention time 2.66 min, 10-99% CH3CN, embodiment 5 min; ESI-MS 428.1 m / z (MH +).

1- (Benzo [d] [1,3] dioxol-5-yl) -N- (5 - ((S) - (2-chlorophenyl) ((R) -3-dimethyl-t-butylsilylhydroxypyrrolidin-1-yl ) methyl) thiazol-2il) cyclopropanecarboxamide

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To a solution of (S) -N- (5- (amino (2-chlorophenyl) methyl) thiazol-2-yl) -1- (benzo [d] [1,3] dioxol-5-yl) cyclopropanecarboxamide (214 mg, 0.5 mmol) in MeOH (2.5 ml) was added (R) -4-chloro-3-dimethyl-t-butylhydroxybutanol (142 mg, 0.6 mmol). The reaction mixture was stirred at 25 ° C for 5 min before NaBH4 (28 mg, 0.75 mmol) was added. Stirring was continued at 25 ° C for 1 h. The reaction was diluted with H2O and extracted with EtOAc. The combined organic phases were washed with brine and dried over MgSO4. After solvent removal, the residue was purified by column chromatography (10-20% EtOAc -Hexan), giving 1- (benzo [d] [1,3] dioxol-5-yl) -N (5- ((S) - (2-Chlorophenyl) ((R) -3-dimethyl-1-butylsilylhydroxypyrrolidin-1-yl) methyl) thiazol-2-yl) cyclopropanecarboxamide (162 mg, 53%). 1H NMR (400 MHz, CDCl3) δ 8.45 (s, 1H), 7.81 (dd, J = 8.1, 1.6 Hz, 1H), 7.28 (s, 1H), 7.25 -7.22 (m, 2H), 7.137.09 (m, 1H), 6.85 (td, J = 7.7, 1.7 Hz, 2H), 6.77 (d, J = 7.9 Hz, 1H), 5.98 (s, 2H), 5.05 (s, 1H), 4.3 6-4.31 (m, 1H), 2.81 (dd, J = 9.8, 6 , 2 Hz, 1H), 2.57-2.46 (m, 2H), 2.37 (dd, J = 9.8, 4.5 Hz, 1H), 2.08-1.99 (m, 1H), 1: 73-1.62 (m, 3H),

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1.17 (t, J = 3.9 Hz, 2H), 0.85 (s, 9H), -0.01 (d, J = 6.9 Hz, 6H). HPLC retention time 3.51 min, 1099% CH3CN, embodiment 5 min; ESI-MS 612.41 m / z (MH +).

1- (Benzo [d] [1,3] dioxol-5-yl) -N- (5 - ((S) - (2-chlorophenyl) ((R) -hydroxypyrrolidin-1-yl) methyl) thiazol-2il ) cyclopropanecarboxamide (1)

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A mixture of 1- (benzo [d] [1,3] dioxol-5-yl) -N- (5 - ((S) - (2-chlorophenyl) ((R) -3-dimethyl-t-butylsilylhydroxypyrrolidine- 1il) methyl) thiazol-2-yl) cyclopropanecarboxamide (61 mg, 0.1 mmol) and TBAF (in 1M THF, 0.6 ml, 0.6 mmol) was stirred at 25 ° C for 3 h. The reaction was diluted with H2O and extracted with EtOAc. The combined organic phases were washed with brine and dried over MgSO4. After solvent removal, the residue was purified by column chromatography (10-20% EtOAc -Hexan), giving 1- (benzo [d] [1,3] dioxol-5-yl) -N- (5 - ((S) - (2-Chlorophenyl) ((R) hydroxypyrrolidin-1-yl) methyl) thiazol-2-yl) cyclopropanecarboxamide (1) (30 mg, 62%,> 99% ee). 1H NMR (400 MHz, DMSO-d6) δ 11.00 (s, 1H), 7.79 (dd, J = 7.8, 1.5 Hz, 1H), 7.43-7.37 (m, 3H), 7.26 (td, J = 7.6, 1.4 Hz, 1H), 6.95 (s, 1H), 6.86 (d, J = 0.7 Hz, 2H), 6, 00 (s, 2H), 4.96 (s, 1H), 4.76 (d, J = 4.4 Hz, 1H), 4.20 (ddd, J = 6.6, 3.4 Hz, 1H ), 2,562.45 (m, 2H), 2.43-2.36 (m, 2H), 2.06-1.97 (m, 1H), 1.62-1.54 (m, 1H), 1.43 (c, J = 3.7 Hz, 2H), 1.14-1.09 (m, 2H). HPLC retention time 2.85 min, 10-99% CH3CN, embodiment 5 min; ESI-MS 498.0 m / z (MH +).

(R) -N- (5 - ((R) -t-Butylsulfinylamino (2-chlorophenyl) methyl) thiazol-2-yl) -1- (benzo [d] [1,3] dioxol-5yl) cyclopropanecarboxamide

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(R) -N- (5 - ((R) -t-Butylsulfinylamino (2-chlorophenyl) methyl) thiazol-2-yl) -1- (benzo [d] [1,3] dioxol-5yl) cyclopropanecarboxamide was prepared from (R) -N- (R) -1- (2-aminothiazol-5-yl) -1- (2-chlorophenyl) methyl) -1,1-dimethylethylsulfinamide and 1- (benzo [d] [ 1,3] dioxol-5-yl) cyclopropanecarboxylic using the same protocol as for (S) -N- (5 - ((R) -t

1 HOUR

butylsulfinylamino (2-chlorophenyl) methyl) thiazol-2-yl) -1- (benzo [d] [1,3] dioxol-5-yl) cyclopropanecarboxamide. NMR (400 MHz, CDCl3) δ 8.55 (s, 1H), 7.62 (dd, J = 7.7, 1.7 Hz, 1H), 7.37 (d, J = 0.7 Hz, 1H), 7.34 (dd, J = 7.8, 1.4 Hz, 1H), 7.31-7.20 (m, 2H), 6.87 (td, J = 8.4, 1, 7 Hz, 2H), 6.81 (d, J = 7.9 Hz, 1H), 6.30 (d, J = 2.8 Hz, 1H) ,, 6.01 (s, 2H), 3, 74 (d, J = 2.8 Hz, 1H), 1.71-1.68 (m, 2H), 1.24 (s, 9H), 0.88 (t, J = 6.9 Hz, 2H ). HPLC retention time 3.59 min, CH3CN 10-99%, embodiment 5 min; ESI-MS 532.1 m / z (MH +).

(R) -N- (5- (Amino (2-chlorophenyl) methyl) thiazol-2-yl) -1- (benzo [d] [1,3] dioxol-5-yl) cyclopropanecarboxamide

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(R) -N- (5- (amino (2-chlorophenyl) methyl) thiazol-2-yl) -1- (benzo [d] [1,3] dioxol-5-yl) cyclopropanecarboxamide was prepared from ( R) -N- (5 - ((R) -t-Butylsulfinylamino (2-chlorophenyl) methyl) thiazol-2-yl) -1- (benzo [d] [1,3] dioxol-5-yl) cyclopropanecarboxamide using the same protocol described for (S) -N- (5- (amino (2-chlorophenyl) methyl) thiazol-2-yl) -1- (benzo [d] [1,3] dioxol-5yl) cyclopropanecarboxamide. 1H NMR (400 MHz, CDCl3) δ 8.47 (s, 1H), 7.60 (dd, J = 7.7, 1.7 Hz, 1H), 7.33 (dd, J = 7.9, 1.3 Hz, 1H), 7.27 (td, J = 7.4, 1.5 Hz, 1H), 7.20 (td, J = 7.6, 1.8 Hz, 1H), 7, 16 (d, J = 1.0 Hz, 1H), 6.89 (td, J = 8.2, 1.7 Hz, 2H), 6.81 (d, J = 7.9 Hz, 1H), 6.01 (s, 2H), 5.79 (s, 1H), 1.89 (s, 2H), 1.72-1.70 (m, 2H), 1.22-1.19 (m, 2H). HPLC retention time 2.52 min, 10-99% CH3CN, embodiment 5 min; ESI-MS 428.2 m / z (MH +).

1- (Benzo [d] [1,3] dioxol-5-yl) -N = (5 - ((R) - (2-chlorophenyl) ((R) -3-dimethyl-t-butylsilylhydroxypyrrolidin-1-yl ) methyl) thiazol-2il) cyclopropanecarboxamide

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1- (benzo [d] [1,3] dioxol-5-yl) -N- (5 - ((R) - (2-chlorophenyl) ((R) -3-dimethyl-1-butylsilylhydroxypyrrolidin-1) was prepared -yl) methyl) thiazol2-yl) cyclopropanecarboxamide from (R) -N- (5- (amino (2-chlorophenyl) methyl) thiazol-2-yl) -1- (benzo [d] [1,3] dioxol-5il) cyclopropanecarboxamide using the same protocol as for 1- (benzo [d] [1,3] dioxol-5-yl) -N- (5 - ((S) - (25 chlorophenyl) ((R) -3 -dimethyl-1-butylsilylhydroxypyrrolidin-1-yl) methyl) thiazol-2-yl) cyclopropanecarboxamide. 1H NMR (400 MHz, CDCl3) δ 8.45 (s, 1H), 7.79 (dd, J = 8.1, 1.5 Hz, 1H), 7.28-7.23 (m, 3H) , 7.14-7.10 (m, 1H), 6.85 (td, J = 8.1, 1.7 Hz, 2H), 6.78 (d, J = 7.9 Hz, 1H), 5.99 (s, 2H), 5.08 (s, 1H), 4.3 6-4.31 (m, 1H), 2.94 (dd, J = 9.9, 6.3 Hz, 1H ), 2.65 (td, J = 8.4, 3.9 Hz, 1H), 2.56 (c, J = 8.3 Hz, 1H), 2.16 (dd, J = 9.9, 4.6 Hz, 1H), 2.06-1.97 (m, 1H), 1.73-1.62 (m, 3H), 1,201.15 (m, 2H), 0.84 (s, 9H ), -0.01 (d, J = 7.9 Hz, 6H). HPLC retention time 3.51 min, 10-99% CH3CN,

10 embodiment 5 min; ESI-MS 612.41 m / z (MH +).

1- (Benzo [d] [1,3] dioxol-5-yl) N (5 - ((R) - (2-chlorophenyl) ((R) -hydroxypyrrolidin-1-yl) methyl) thiazol-2

il) cyclopropanecarboxamide (2)

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1- (benzo [d] [1,3] dioxol-5-yl) -N- (5 - ((R) - (2-chlorophenyl) ((R) -hydroxypyrrolidin-1-yl) methyl) thiazole was prepared -2

15-yl) cyclopropanecarboxamide of 1- (benzo [d] [1,3] dioxol-5-yl) -N- (5 - ((R) - (2-chlorophenyl) ((R) -3-dimethyl-t-butyl hydroxypyrrolidine 1-yl) methyl) thiazol-2-yl) cyclopropanecarboxamide using the same protocol described for 1 (benzo [d] [1,3] dioxol-5-yl) -N- (5 - ((S) - (2- chlorophenyl) ((R) -hydroxypyrrolidin-1-yl) methyl) thiazol-2-yl) cyclopropanecarboxamide. 1H NMR (400 MHz, DMSO-d6) δ 11.01 (s, 1H), 7.79 (dd, J = 7.8, 1.6 Hz, 1H), 7.45-7.39 (m, 3H), 7.30-7.26 (m, 1H), 6.97 (s, 1H), 6.87 (d, J = 0.9 Hz, 2H), 6.02 (s, 2H), 4.99 (s, 1H), 4.73 (d, J = 4.3 Hz, 1H), 4.24-4.18 (m, 1H), 2.72 (dd,

20 J = 9.9, 6.1 Hz, 1H), 2.62 (c, J = 7.8 Hz, 1H), 2.37-2.32 (m, 1H), 2.22 (dd, J = 9.9, 3.2 Hz, 1H), 2.04-1.96 (m, 1H), 1.64-1.57 (m, 1H), 1.44 (c, J = 3, 8 Hz, 2H), 1.13 (t, J = 3.8 Hz, 2H). HPLC retention time 2.56 min, 10-99% CH3CN, embodiment 5 min; ESI-MS 498.3 m / z (MH +).

The procedures described below in Scheme A, Scheme B and Scheme C were used to prepare representative compounds of the present invention as indicated below.

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a) Ti (OPr) 4, dioxane or THF; b) (Boc) 2O, Et3N, DMAP, THF; c) n-BuLi, -78 ° C, THF; d) 50% TFA, CH2Cl2.

Scheme B:

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a) SOCl2, DMF, 60 ° C; b) Et3N, CH2Cl2; c) HCl in dioxane, CH3OH; d) NaBH4 (LG = outgoing group).

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a) SOCl2, DMF, 60 ° C; b) Et3N, CH2Cl2; c) HCl in dioxane, CH3OH; d) NaBH4 (LG = outgoing group).

1- (benzo [d] [1,3] dioxol-5-yl) cyclopropanecarboxylic acid

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5 A mixture of 2- (benzo [d] [1,3] dioxol-5-yl) acetonitrile (5.10 g, 31.7 mmol), 1-bromo-2-chloroethane (9,000 ml 108.6 mmol) and benzyltriethylammonium chloride (BTEAC, 0.181 g, 0.795 mmol) was heated to 70 ° C and then 50% aqueous sodium hydroxide (w / w) (26 ml) was added slowly. The reaction was stirred at 70 ° C for 88 hours and then heated to reflux (bath temperature 130 ° C) for 24 hours. The dark brown / black reaction mixture was diluted with water (400 ml) and extracted twice with equal volumes of ethyl acetate and

10 dichloromethane. The basic aqueous solution was acidified with concentrated hydrochloric acid at a pH lower than one and the precipitate was filtered and washed with 1 M hydrochloric acid. The solid material was dissolved in dichloromethane (400 ml) and washed twice with equal volumes of 1M hydrochloric acid and once with brine. The organic solution was dried over sodium sulfate and evaporated to dryness, giving a white to slightly off-white solid (5.23 g, 80.1%). 1H NMR (400 MHz, DMSO-d6) δ 1.07-1.11 (m, 2H), 1.38-1.42 (m, 2H), 5.98 (s, 2H), 6.79 ( m, 2H),

15.88 (m, 1 H), 12.26 (s, 1 H); HPLC retention time 2.37 min, 10-99% CH3CN, embodiment 5 min; ESI-MS 206.1 m / z (MH +).

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Methyl 2,2-Difluorobenzo [d] [1,3] dioxol-5-carboxylate

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A solution of 5-bromo-2,2-difluorobenzo [d] [1,3] dioxol (11.8 g, 50.0 mmol) and tetrakis (triphenylphosphine) palladium (0) [5.78 g, 5.00 mmol] in methanol (20 ml) containing acetonitrile (30 ml) and triethylamine (10 ml) was stirred under an atmosphere of carbon monoxide (379.21 kPa (55 psi)) at 75 ° C (oil bath temperature) for 15 h. The cooled reaction mixture was filtered and the filtrate was evaporated to dryness. The residue was purified by column chromatography on silica gel, giving methyl 2,2-difluorobenzo [d] [1,3] dioxol-5-carboxylate (11.5 g), which was used directly in the next step.

(2,2-Difluorobenzo [d] [1,3] dioxol-5-yl) methanol

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Procedure A: Methyl 2,2-difluorobenzo [d] [1,3] dioxol-5-carboxylate from the previous step (11.5 g) dissolved in anhydrous tetrahydrofuran (20 ml) was slowly added to a suspension of hydride of lithium and aluminum (4.10 g, 106 mmol) in anhydrous THF (100 ml) at 0 ° C. Then, the mixture was heated to room temperature and stirred for 1

h. The reaction mixture was cooled to 0 ° C and treated with water (4.1 g), followed by sodium hydroxide (10% aqueous solution, 4.1 ml). The resulting suspension was filtered and washed with THF. The combined filtrate was evaporated to dryness and the residue was purified by column chromatography on silica gel, giving (2,2-difluorobenzo [d] [1,3] dioxol-5yl) methanol as a colorless oil (7, 2 g, 76% in two stages).

Procedure B: To a solution of 2,2-difluorobenzo [d] [1,3] dioxol-5-carbaldehyde (125 g, 0.67 mol) in anhydrous THF (400 ml) was added NaBH4 portions (28 g , 0.74 mol) at 0 ° C. The mixture was stirred for 1 h at 0 ° C and then poured into 500 ml of water. The mixture was extracted with ethyl acetate (200 ml x 3). The organic phase was dried over Na2SO4 and concentrated in vacuo, giving (2,2-difluorobenzo [d] [1,3] dioxol-5-yl) methanol as a colorless oil (120 g, 95%).

5- (Chloromethyl) -2,2-difluorobenzo [d] [1,3] dioxol

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A solution of (2,2-difluorobenzo [d] [1,3] dioxol-5-yl) methanol (120 g, 0.64 mol) in pure thionyl chloride (500 ml) was stirred for 2 h at 25 ° C. The excess thionyl chloride was removed by vacuum distillation. The residue was partitioned between saturated NaHCO3 (400 ml) and dichloromethane (200 ml). The separated aqueous phase was extracted with dichloromethane (300 ml x 3). The combined organic phases were dried, filtered and concentrated in vacuo to give 5- (chloromethyl) -2,2difluorobenzo [d] [1,3] dioxol (117.6 g, 89%), which was used directly in the next stage

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

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A mixture of 5- (chloromethyl) -2,2-difluorobenzo [d] [1,3] dioxol (117.6 g, crude from the last stage) and NaCN (84 g, 1.7 mmol) in DMSO ( 800 ml) was stirred for 2 h at 25 ° C. The reaction mixture was poured on ice and extracted with EtOAc (500 ml x 3). The combined organic phases were dried with anhydrous Na2SO4 and concentrated in vacuo to give the crude product that was purified by column chromatography (EP / EtOAc 10: 1), giving 2- (2,2-difluorobenzo [d] [1,3 ] dioxol-5-yl) acetonitrile (77.8 g, 66%). 1 H NMR (300 MHz, CDCl 3) δ 7.06-7.07 (m, 3 H), 3.75 (s, 2 H).

1- (2,2-Difluorobenzo [d] [1,3] dioxol-5-yl) cyclopropanecarboxylic acid

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1- (2,2-Difluorobenzo [d] [1,3] dioxol-5-yl) cyclopropanecarboxylic acid was prepared by the procedure used for 1- (benzo [d] [1,3] dioxol-5-yl) cyclopropanecarboxylic acid, starting with 2- (2,2-difluorobenzo [d] [1,3] dioxol-5yl) acetonitrile. Yield (86%) of a white solid. 1H NMR (400 MHz, CDCl3) δ 7.14-7.04 (m, 2 H), 6.98-6.96 (m, 1 H), 1.74-1.64 (m, 2 H) , 1.26-1.08 (m, 2 H); ESI-MS m / z calc. 242.04, found 241.58 (M-1).

Tert-Butyl thiazol-2-ylcarbamate

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To a solution of aminothiazole (20.0 g, 199.7 mmol) and (Boc) 2O (48.0 g, 219.7 mmol) in anhydrous THF (100 ml) DMAP (20 mg) and Et3N ( 36.0 ml, 260.0 mmol). The reaction mixture was stirred at room temperature.

10 for 18 h, diluted with DCM and washed with 0.1 N HCl, H2O and brine. The organic phase was separated from the aqueous phase, dried over Na2SO4 and concentrated. The crude product was purified by column chromatography (0-40% EtOAc / Hexane) to provide tert-butyl thiazol-2-ylcarbamate as a white solid (20.7 g, 72%). 1H NMR (400 MHz, CDCl3) δ 11.44 (s, 1H), 7.38 (d, J = 3.6 Hz, 1H), 6.89 (d, J = 3.6 Hz, 1H), 1.58 (s, 9H); ret time HPLC 2.61 min, CH3CN 10-99%, embodiment 5 min; ESI-MS 145.1 m / z (MH +).

Tert-Butyl 4-Methylthiazol-2-ylcarbamate

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To a solution of 4-methylthiazol-2-amine (25 g, 219 mmol) and (Boc) 2O (53 g, 241 mmol) in anhydrous THF (110 ml) DMAP (250 mg) and Et3N (39, 6 ml, 285 mmol). The reaction mixture was stirred at room temperature for 18 h. Then, the reaction was heated at reflux for 5 h, until no more starting material 20 was detected by LC-MS. The reaction was cooled to room temperature and filtered to remove the precipitate. The filtrate was concentrated, then dissolved in CH2Cl2 and washed with 0.1 N aqueous HCl, H2O and brine. The organic phase was dried over MgSO4 and concentrated. The residue was suspended in hexane and then filtered, obtaining tert-butyl 4-methylthiazol-2-carbamate as a cream-colored solid (30.9 g, 66%). 1H NMR (400 MHz, DMSO-d6) δ 11.30 (s, 1H), 6.68 (d, J = 1.0 Hz, 1H), 2.20 (d, J = 0.9 Hz, 3H ), 1.47 (s, 9H); ret time HPLC 2.68 min,

10-99% CH3CN, embodiment 5 min; ESI-MS 215.3 m / z (MH +).

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(R) -Dimethyl-2-hydroxysuccinate

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To a solution of (R) -2-hydroxysuccinic acid (134 g, 1 mol) in CH3OH (500 ml) was added toluene-4sulfonic acid (9.5 g, 0.05 mol). The mixture was heated at reflux overnight. The methanol was evaporated and then water (250 ml) was added to the residue. The mixture was basified with a sat. NaHCO3 at pH 7-8 and extracted with ethyl acetate. The combined organic phases were washed with brine, dried over anhydrous Na2SO4 and concentrated under reduced pressure, giving (R) -dimethyl 2-hydroxysuccinate (140 g, 86%). 1H NMR (300 MHz, CDCl3) δ 4.46 (dd, J = 6 Hz, 4.8 Hz, 1 H), 3.74 (s, 3 H), 3.64 (s, 3 H), 3 , 42 (s, 1 H), 2.69-2.85 (m, 2 H).

(R) -methyl 3,4-dihydroxybutanoate

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To a solution of (R) -dimethyl 2-hydroxysuccinate (140 g, 0.86 mol) in THF (1400 ml) was added dropwise Me2S · BH3 (86 ml, 10 M) at 20 ° C for 30 min . The mixture was stirred at 20 ° C for 30 min. NaBH4 (1.63 g, 42.9 mmol) was added at 10 ° C and stirred at 10 ° C for 30 min. The mixture was heated to room temperature and stirred for 1 h. CH3OH (200 ml) was slowly added to the mixture with cooling in an ice-water bath. The resulting mixture was evaporated, giving (R) -methyl 3,4-dihydroxybutanoate (130 g, crude).

(R) -methyl 4-Chloro-3-hydroxybutanoate

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To a solution of (R) -methyl 3,4-dihydroxybutanoate (125.1 g, 0.93 mol) in CH2Cl2 (1.8 L) was added PPh3 (244.5 g, 0.93 mol) and NCS (124.2 g, 0.93 mol) was slowly added with cooling with ice-cold water. The mixture was stirred at 5 ° C for 20 min and then stirred for 18 h at room temperature. After evaporating the solvent, the residue was purified by column chromatography (PE / EA 20: 1-5: 1, gradient), giving (R) -methyl 4-chloro-3-hydroxybutanoate (33 g, 26% in 3 steps ). 1 H NMR (300 MHz, CDCl 3) δ 4.18-4.25 (m, 1 H), 3.68 (s, 3 H), 3.55-3.60 (m, 2 H), 3.32 -3.33 (d, J = 4.2 Hz, 1 H), 2.52-2.68 (m, 2 H).

(R) -methyl tert-Butyldimethylsilyloxy) -4-chlorobutanoate

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A solution of (R) -methyl 4-chloro-3-hydroxybutanoate (15 g, 98.7 mmol) in CH2Cl2 (240 ml) was stirred overnight with tert-butyl-chloro-dimethyl-silane (17.82 g, 118.2 mmol), imidazole (33.6 g, 493.5 mmol) and a catalytic amount of DMAP (0.6 g, 4.92 mmol) at room temperature under an atmosphere of N2. The reaction mixture was poured into water (150 ml) and acidified to pH 6-7 by the dropwise addition of cold aqueous HCl (0.5 M). The aqueous phase was extracted with CH2Cl2 (3 x 60 ml). The combined organic phases were washed with a sat. Na2CO3 and brine, dried over anhydrous Na2SO4 and concentrated to give (R) -methyl 3- (tert-butyldimethylsilyloxy) -4-chlorobutanoate (30 g, crude).

(R) -3- (tert-Butyldimethylsilyloxy) -4-chlorobutanal

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To a solution of 3- (tert-butyldimethylsilyloxy) -4-chlorobutanoate of (R) -methyl (27.9 g, 104.7 mmol) in CH2Cl2 was added dropwise DIBAL-H (120 ml, 1 M in toluene, 120 mmol) at -78 ° C under an atmosphere of N2. The mixture was stirred at -78 ° C for 4 h. To the reaction mixture was added CH3OH (80 ml) slowly at -78 ° C. Then, the temperature was gradually increased to room temperature. The mixture was filtered and the cake was washed with CH2Cl2. The combined filtrates were concentrated under reduced pressure and purified by column chromatography (PE), giving (R) -3- (tert-butyldimethylsilyloxy) -4-chlorobutanal (13 g, 60% in 2 steps). 1H NMR (300 MHz, CDCl3) δ 9.80 (t, J = 1.6 Hz, 1 H), 4.35-4.42 (m, 1 H), 3.53 (dd, J = 11, 1 Hz, 4.8 Hz, 1 H), 3.46 (dd, J = 12 Hz, 6.3 Hz, 1 H), 2,632.82 (m, 2 H), 0.87 (s, 9 H ), 0.12 (s, 3 H), 0.08 (s, 3 H).

(S) -3- (tert-Butyldimethylsilyloxy) -4-chlorobutanal

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(S) -3- (tert-Butyldimethylsilyloxy) -4-chlorobutanal was prepared by the same route as (R) -3- (tert-butyldimethylsilyloxy) 4-chlorobutanal starting from (S) -2-hydroxysuccinic acid. 1H NMR (400 MHz, CDCl3) δ 9.72 (dd, J = 1.6, 2.2 Hz, 1H), 4.33 -4.28 (m, 1H), 3.46 (dd, J = 4.7, 11.1 Hz, 1H), 3.39 (dd, J = 6.4, 11.1 Hz, 1H), 2.68 (dd, J = 1.5, 4.7 Hz, 1H ), 2.62 (dd, J = 2.3, 6.8 Hz, 1H), 0.79 (s, 9H), 0.04 (s, 3H), 0.01 (s, 3H).

(R) -N- (2-Chlorobenzylidene) -2-methylpropane-2-sulfinamide

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To stirred anhydrous dioxane (500 ml) was added 2-chlorobenzaldehyde (34.8 g, 247.5 mmol) and the solution was cooled to 0 ° C in an ice bath. To the aldehyde solution was added a solution of (R) -2-methylpropanesulfinamide (30.0 g, 247.5 mmol) in anhydrous dioxane (100 ml). Then, Ti (OPr) 4 (105.5 g, 371.3 mmol) was slowly added to the solution while stirring at 0 ° C. The reaction mixture was allowed to warm to room temperature, stirred for 15-18 h, then quenched with a saturated aqueous NaHCO3 solution and filtered through a short bed of Celite using EtOAc. The organic phase was separated from the aqueous phase, dried over Na2SO4 and concentrated. The crude product was purified by column chromatography (0-25% EtOAc / Hexane) to provide (R) -N- (2-chlorobenzylidene) -2-methylpropane-2-sulfinamide as a yellow liquid (45, 1 g, 75%). 1H NMR (400 MHz, CDCl3) δ 9.05 (s, 1H), 8.06 (dd, J = 7.9, 1.1 Hz, 1H), 7.47-7.41 (m, 2H) , 7.37-7.33 (m, 1H), 1.28 (s, 9H); weather

20 ret. HPLC 3.45 min, 10-99% CH3CN, embodiment 5 min; ESI-MS 244.3 m / z (MH +).

(R) -N- (3,4-Dichlorobenzylidene) -2-methylpropane-2-sulfinamide

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(R) -N- (3,4-Dichlorobenzylidene) -2-methylpropane-2-sulfinamide was prepared by the procedure used for (R) -N- (2-chlorobenzylidene) -2-methylpropane-2-sulfinamide, starting from 3, 4-dichlorobenzaldehyde and (R) -2

25 methylpropanesulfinamide. Yield (93%) of a yellow oil that crystallized after a rest period. 1H NMR (400 MHz, CDCl3) δ 8.51 (s, 1H), 7.96 (d, J = 1.9 Hz, 1H), 7.66 (dd, J = 1.9, 8.3 Hz , 1H), 7.57 (d, J = 8.3 Hz, 1H), 1.27 (s, 9H); ret time HPLC 3.72 min, CH3CN 10-99%, embodiment 5 min; ESI-MS 278.1 m / z (MH +).

(R) -N- (2-Chloro-4-fluorobenzylidene) -2-methylpropane-2-sulfinamide

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(R) -N- (2-Chloro-4-fluorobenzylidene) -2-methylpropane-2-sulfinamide was prepared by the procedure used for (R) -N (2-chlorobenzylidene) -2-methylpropane-2-sulfinamide, starting of 2-chloro-4-fluorobenzaldehyde and (R) -2-methylpropanesulfinamide. Yield (74%) of a colorless solid. 1H NMR (400 MHz, CDCl3) δ 9.00 (s, 1H), 8.11 (dd, J = 8.8, 6.2 Hz, 1H), 7.23 (dd, J = 8.4, 2.5 Hz, 1H), 7.13-7.08 (m, 1H), 1.29 (s, 9H); ret time HPLC 3.46 min, CH3CN 10-99%, embodiment 5 min; ESI-MS 262.1 m / z (MH +).

(S) -N- (2-Chloro-4-fluorobenzylidene) -2-methylpropane-2-sulfinamide

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(S) -N- (2-Chloro-4-fluorobenzylidene) -2-methylpropane-2-sulfinamide was prepared by the procedure used for (R) -N

10 (2-Chlorobenzylidene) -2-methylpropane-2-sulfinamide, starting from 2-chloro-4-fluorobenzaldehyde and (S) -2-methylpropanesulfinamide. Yield (78%) of a colorless solid. 1H NMR (400 MHz, CDCl3) δ 9.00 (s, 1H), 8.11 (dd, J = 6.2, 8.8 Hz, 1H), 7.23 (dd, J = 2.5, 8.4 Hz, 1H), 7.13-7.08 (m, 1H), 1.29 (s, 9H); ret time HPLC 3.49 min, CH3CN 10-99%, embodiment 5 min; ESI-MS 262.1 m / z (MH +).

(R) -N- (4-Chloro-2-fluorobenzylidene) -2-methylpropane-2-sulfinamide

(R) -N- (4-Chloro-2-fluorobenzylidene) -2-methylpropane-2-sulfinamide was prepared by the procedure used for (R) -N (2-chlorobenzylidene) -2-methylpropane-2-sulfinamide, starting from 4-chloro-2-fluorobenzaldehyde and (R) -2-methylpropanesulfinamide. Yield (65%) of a colorless solid. 1H NMR (400 MHz, CDCl3) δ 8.84 (s, 1H), 7.97 7.93 (m, 1H), 7.28-7.19 (m, 2H), 1.27 (s, 9H ); ret time HPLC 3.53 min, CH3CN 10-99%, embodiment 5 min; ESI-MS 262.0 m / z (MH +).

20 (5) - ((2-Chloro-4-fluorophenyl) (1,1-dimethylethylsulfinamide) methyl) thiazol-2-ylcarbamate of (R) -terc-butyl

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A solution of tert-butyl thiazol-2-ylcarbamate (2.0 g, 10.0 mmol) in anhydrous THF (25 ml) was stirred and cooled to 78 ° C. To this solution was added slowly n-BuLi (2.5 M in hexane: 8.0 ml, 20.0 mmol). After the addition of n-BuLi was completed, the mixture was maintained at -78 ° C for 1 h. To the above solution was slowly added a solution of (R, E) -N- (2-chloro-4-fluorobenzylidene) -2-methylpropane-2-sulfinamide (1.4 g, 5.4 mmol) in 5 THF anhydrous (25 ml) previously cooled to -78 ° C by cannulation. The reaction was maintained at -78 ° C for 0.5 h, allowed to warm to room temperature, quenched with an aqueous NH4Cl solution and extracted with EtOAc (x 3). The combined organic phases were dried over MgSO4 and concentrated. The crude product was purified by column chromatography (0-80% EtOAc / Hexane) to provide a diastereomeric mixture of 5 ((2-chloro-4-fluorophenyl) (1,1-dimethylethylsulfinamide) methyl) thiazole-2- (R) -terc-butyl ilcarbamate in the form of a solid of

10 yellow color (2.1 g, 84%) that was used without further purification.

(S) -terc-butyl 5 - ((2-Chloro-4-fluorophenyl) (1,1-dimethylethylsulfinamide) methyl) thiazol-2-ylcarbamate

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(S) -terc-butyl 5 - ((2-chloro-4-fluorophenyl) (1,1-dimethylethylsulfinamide) methyl) thiazol-2-ylcarbamate was prepared by the procedure used for 5 - ((2-chloro-4 -fluorophenyl) (1,1-dimethylethylsulfinamide) methyl) thiazol-2-ylcarbamate of (R) -terc

15 butyl, starting from tert-butyl thiazol-2-ylcarbamate and (S) -N- (2-chloro-4-fluorobenzylidene) -2-methylpropane-2-sulfinamide. The crude product was purified by column chromatography to provide a diastereomeric mixture of 5- ((2-chloro-4-fluorophenyl) (1,1-dimethylethylsulfinamide) methyl) thiazol-2-ylcarbamate of (S) -terc-butyl in the form of an orange-yellow solid (95%) that was used without further purification.

(R) -terc-Butyl 5 - ((4-Chloro-2-fluorophenyl) (1,1-dimethylethylsulfinamide) methyl) thiazol-2-ylcarbamate

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5 - ((4-Chloro-2-fluorophenyl) (1,1-dimethylethylsulfinamide) methyl) thiazol-2-ylcarbamate of (R) -terc-butyl was prepared by the procedure used for 5 - ((2-chloro-4 -fluorophenyl) (1,1-dimethylethylsulfinamide) methyl) thiazol-2-ylcarbamate of (R) -butylbutyl, starting from thiazol-2-ylcarbamate of tert-butyl and (R) -N- (4-chloro-2-fluorobenzylidene ) -2-methylpropane-2sulfinamide. The crude product was purified by column chromatography, providing a mixture.

5 - ((4-Chloro-2-fluorophenyl) (1,1-dimethylethylsulfinamide) methyl) thiazol-2-ylcarbamate (78) dimethyl ether (78%) which was used without further purification.

(R) -terc-butyl 5 ((3,4-dichlorophenyl) (1,1-dimethylethylsulfinamide) methyl) thiazol-2-ylcarbamate

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(R) -terc-Butyl 5 - ((3,4-dichlorophenyl) (1,1-dimethylethylsulfinamide) methyl) thiazol-2-ylcarbamate was prepared by

procedure used for (R) -tercbutyl 5 - ((2-chloro-4-fluorophenyl) (1,1-dimethylethylsulfinamide) methyl) thiazol-2-ylcarbamate, starting from tert-butyl thiazol-2-ylcarbamate and (R ) -N- (3,4-dichlorobenzylidene) -2-methylpropane-2-sulfinamide. The crude product was purified by column chromatography (excess tert-butyl thiazol-2-ylcarbamate is eluted in 70% EtOAc / hexane, the desired product is followed in 0-15% MeOH / EtOAc), providing a diastereomeric mixture of 5 - ((3,4-dichlorophenyl) (1,1-dimethylethylsulfinamide) methyl) thiazol-2-ylcarbamate of (R) -terc-butyl as a yellow solid (92%) which is used without further purification.

(R) -terc-Butyl 5 - ((2-Chlorophenyl) (1,1-dimethylethylsulfinamide) methyl) -4-methylthiazol-2-ylcarbamate

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(R) -terc-Butyl 5 - ((2-chlorophenyl) (1,1-dimethylethylsulfinamide) methyl) -4-methylthiazol-2-ylcarbamate was prepared by

10 procedure used for (R) -tercbutyl 5 - ((2-chloro-4-fluorophenyl) (1,1-dimethylethylsulfinamide) methyl) thiazol-2-ylcarbamate starting from tert-butyl 4-methylthiazol-2-ylcarbamate and (R) -N- (2-Chlorobenzylidene) -2-methylpropane-2sulfinamide. The crude product was absorbed on silica gel and purified by column chromatography (20-80% EtOAc / hexanes) to provide a diastereomeric mixture of 5 - ((2-chlorophenyl) (1,1-dimethylethylsulfinamide) methyl) -4 (R) -terc-butyl methylthiazol-2-ylcarbamate in the form of a cream-colored solid (90%)

15 which was used without further purification.

(R) -N - ((S) - (2-Aminothiazol-5-yl) (2-chloro-4-fluorophenyl) methyl) -2-methylpropane-2-sulfinamide

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To a solution of 5 ((2-chloro-4-fluorophenyl) (1,1-dimethylethylsulfinamide) methyl) thiazol-2-ylcarbamate of (R) -terc-butyl (1,6

g, 3.5 mmol) in CH2Cl2 (6 ml) TFA (6 ml) was added. The reaction was stirred at room temperature for 2 h. The TFA and CH2Cl2 were removed in vacuo. The crude product was dissolved again in CH2Cl2, washed with a solution.

NaHCO3 aqueous, dried over MgSO4 and concentrated. The crude product was recrystallized from EtOAc,

providing (R) -N - ((S) - (2-aminothiazol-5-yl) (2-chloro-4-fluorophenyl) methyl) -2-methylpropane-2-sulfinamide as

a colorless solid (672 mg, 53%). 1H NMR (400 MHz, CDCl3) δ 7.56 (dd, J = 8.7, 5.9 Hz, 1H), 7.16 (dd, J = 8.4, 2.6

Hz, 1H), 7.06 (td, J = 8.2, 2.6 Hz, 1H), 6.89 (d, J = 0.8 Hz, 1H), 6.07 (d, J = 4 , 6 Hz, 1H), 5.22 (d, J = 2.9 Hz, 2H), 4.06 25 (d, J = 4.6 Hz, 1H), 1.28 (s, 9H); ret time HPLC 2.28 min, 10-99% CH3CN, embodiment 5 min; IEN-EM

362.3 m / z (MH +).

(S) -N - ((R) - (2-Aminothiazol-5-yl) (2-chloro-4-fluorophenyl) methyl) -2-methylpropane-2-sulfinamide

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(S) -N - ((R) - (2-aminothiazol-5-yl) (2-chloro-4-fluorophenyl) methyl) -2-methylpropane-2-sulfinamide was prepared by the procedure used for (R) -N - ((S) - (2-aminothiazol-5-yl) (2-chloro-4-fluorophenyl) methyl) -2-methylpropane-2-sulfinamide,

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starting from (S) -terc-butyl 5 - ((4-chloro-2-fluorophenyl) (1,1-dimethylethylsulfinamide) methyl) thiazol-2-ylcarbamate. The crude product was purified by column chromatography (0-5% EtOH / EtOAc) to provide the desired product (38%). 1H NMR (400 MHz, CDCl3) δ 9.14 (sa, 2H), 7.54 (dd, J = 5.7, 8.7 Hz, 1H), 7.21 (dd, J = 2.6, 8.1 Hz, 1H), 7.13-7.08 (m, 1H), 6.73 (d, J = 0.6 Hz, 1H), 6.00 (d, J = 5.6 Hz, 1H), 4.67 (d, J = 5.7 Hz, 1H), 1.26 (s, 9H); ret time HPLC 2.23 min, CH3CN 10-99%, embodiment 5 min; ESI-MS 362.3 m / z (MH +).

(R) -N - ((S) - (2-Aminothiazol-5-yl) (4-chloro-2-fluorophenyl) methyl) -2-methylpropane-2-sulfinamide

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(R) -N - ((S) - (2-aminothiazol-5-yl) (4-chloro-2-fluorophenyl) methyl) -2-methylpropane-2-sulfinamide was prepared by the procedure used for (R) - N - ((S) - (2-aminothiazol-5-yl) (2-chloro-4-fluorophenyl) methyl) -2-methylpropane-2-sulfinamide, starting from 5 - ((4-chloro-2-fluorophenyl) (R) -terc-Butyl (1,1-dimethylethylsulfinamide) methyl) thiazol-2-ylcarbamate. The crude product was purified by column chromatography (0-5% EtOH / EtOAc) to provide an orange solid (87%). 1H NMR (400 MHz, CDCl3) δ 8.62 (sa, 2H), 7.36 (t, J = 8.1 Hz, 1H), 7.21 (dd, J = 1.7, 8.3 Hz , 1H), 7.16 (dd, J = 1.9, 10.1 Hz, 1H), 6.74 (s, 1H), 5.81 (d, J = 5.9 Hz, 1H), 4 , 18 (d, J = 5.9 Hz, 1H), 1.25 (s, 9H); ret time HPLC 2.29 min, 10-99% CH3CN, embodiment 5 min; ESI-MS 362.3 m / z (MH +).

1- (Benzo [d] [1,3] dioxol-5-yl) -N- (5 - ((S) - (2-chloro-4-fluorophenyl) ((R) -1,1-dimethylethylsulfinamide) methyl ) thiazol-2il) cyclopropanecarboxamide

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To a solution of 1- (benzo [d] [1,3] dioxol-5-yl) cyclopropanecarboxylic acid (618 mg, 3.0 mmol) in anhydrous CH2Cl2 (6 mL) was added slowly (COCl) 2 (0 , 3 ml, 3.4 mmol) at -10 ° C followed by DMF (3 drops). The reaction mixture was stirred at -10 ° C for 0.5 h. The excess (COCl) 2 was removed in vacuo. Then, the acid chloride (10.5 mmol) was dissolved in anhydrous CH2Cl2 (3 ml) and slowly added to a solution of (R) -N - ((S) - (2-aminothiazol-5-yl) ( 2-Chloro-4fluorophenyl) methyl) -2-methylpropane-2-sulfinamide (648 mg, 1.8 mmol) and Et3N (1.8 mL, 6 mmol) in anhydrous CH2Cl2 (3 mL). The reaction mixture was stirred at room temperature for 1 h, diluted with CH2Cl2 and washed with 1N HCl, NaHCO3 and brine. The organic phase was separated from the aqueous phase, dried over MgSO4 and concentrated. The crude product was purified by column chromatography (40-60% EtOAc / Hexane) to provide 1 (benzo [d] [1,3] dioxol-5-yl) -N- (5 - ((S) - (2-Chloro-4-fluorophenyl) ((R) -1,1-dimethylethylsulfinamide) methyl) thiazol-2-yl) cyclopropanecarboxamide as a colorless solid (680 mg, 69%). 1H NMR (400 MHz, CDCl3) δ 8.60 (s, 1H), 7.60 (dd, J = 8.7, 5.9 Hz, 1H), 7.28 (d, J = 2.0 Hz , 1H), 7.13 (dd, J = 8.3; 2.6 Hz, 1H), 7.05 (td, J = 8.2, 2.6 Hz, 1H), 6.90 (td, J = 8.3, 1.7 Hz, 2H), 6.83 (d, J = 7.9 Hz, 1H), 6.18 (d, J = 4.3 Hz, 1H), 6.04 ( s, 2H), 3.90 (d, J = 4.3 Hz, 1H), 1.73 (td, J = 5.4, 2.0 Hz, 2H), 1.28 (t, J = 7 , 1 Hz, 2H), 1.29 (s, 9H). ret time HPLC 3.65 min, CH3CN 10-99%, embodiment 5 min; ESI-MS 550.5 m / z (MH +).

N- (5 - ((S) - (2-Chloro-4-fluorophenyl) ((R) -1,1-dimethylethylsulfinamide) methyl) thiazol-2-yl) -1- (2,2difluorobenzo [d] [1 , 3] dioxol-5-yl) cyclopropanecarboxamide

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N- (5 - ((S) - (2-Chloro-4-fluorophenyl) ((R) -1,1-dimethylethylsulfinamide) methyl) thiazol-2-yl) -1- (2,2-difluorobenzo [d] [1,3] dioxo1-5-yl) cyclopropanecarboxamide by the procedure used for 1- (benzo [d] [1,3] dioxol-5il) -N- (5 - ((S) - (2-chloro-4 -fluorophenyl) ((R) -1,1-dimethylethylsulfinamide) methyl) thiazol-2-yl) cyclopropanecarboxamide, starting

5 1- (2,2-Difluorobenzo [d] [1,3] dioxol-5-yl) cyclopropanecarboxylic acid and (R) -N - ((S) - (2-aminothiazol-5-yl) (2- chloro-4fluorophenyl) methyl) -2-methylpropane-2-sulfinamide. Yield (77%). 1H NMR (400 MHz, CDCl3) δ 8.63 (s, 1H), 7.59 (dd, J = 8.7, 5.9 Hz, 1H), 7.28 (s, 1H), 7.21 -7.11 (m, 4H), 7.06 (td, J = 8.2, 2.5 Hz, 1H), 6.18 (d, J = 4.2 Hz, 1H), 3.92 ( d, J = 4.3 Hz, 1H), 1.82-1.79 (m, 2H), 1.32-1.25 (m, 11H); ret time HPLC 3.90 min, CH3CN 10-99%, embodiment 5 min; ESI-MS 586.3 m / z (MH +).

10 1- (Benzo [d] [1,3] dioxol-5-yl) -N- (5 - ((R) - (2-chloro-4-fluorophenyl) ((S) -1,1-dimethylethylsulfinamide) methyl) thiazol-2il) cyclopropanecarboxamide

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1- (benzo [d] [1,3] dioxol-5-yl) -N- (5 - ((R) - (2-chloro-4-fluorophenyl) ((S) -1,1-dimethylethylsulfmamide was prepared ) methyl) thiazol-2il) cyclopropanecarboxamide by the procedure used for 1- (benzo [d] [1,3] dioxol-5-yl) -N- (5 - ((S) - (2-chloro-415 fluorophenyl) ((R) -1,1-dimethylethylsulfinamide) methyl) thiazol-2-yl) cyclopropanecarboxamide, starting from 1 (benzo [d] [1,3] dioxol-5-yl) cyclopropanecarboxylic acid and (S) -N- ( (R) - (2-Aminothiazol-5-yl) (2-chloro-4-fluorophenyl) methyl) -2-methylpropane-2-sulfinamide. Yield (50%). 1H NMR (400 MHz, DMSO-d6) δ 11.10 (s, 1H), 7.78 (dd, J = 6.3, 8.8 Hz, 1H), 7.45 (dd, J = 2, 6, 8.8 Hz, 1H), 7.35 (td, J = 8.6, 2.7 Hz, 1H), 7.03 (s, 1H), 6.95 (s, 1H), 6, 86 (s, 2H), 6.45 (d, J = 6.7 Hz, 1H), 6.00 (s, 2H), 5.95 (d, J = 6.5 Hz, 1H), 1, 46 -1.43 (m, 2H), 1.25 -1.24 (m, 2H), 1.14 (s, 9H);

20 ret time HPLC 3.65 min, CH3CN 10-99%, embodiment 5 min; ESI-MS 550.5 m / z (MH +).

N- (5 - ((R) - (2-Chloro-4-fluorophenyl) ((S) -1,1-dimethylethylsulfinamide) methyl) thiazol-2-yl) -1- (2,2difluorobenzo [d] [1 , 3] dioxol-5-yl) cyclopropanecarboxamide

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N- (5 - ((R) - (2-Chloro-4-fluorophenyl) ((S) -1,1-dimethylethylsulfmamido) methyl) thiazol-2-yl) -1- (2,2) was prepared

Difluorobenzo [d] [1,3] dioxol-5-yl) cyclopropanecarboxamide by the procedure used for 1- (benzo [d] [1,3] dioxol-5-yl) N- (5 - ((S) - (2-Chloro-4-fluorophenyl) ((R) -1,1-dimethylethylsulfinamide) methyl) thiazol-2-yl) cyclopropanecarboxamide, starting from 1- (2,2-difluorobenzo [d] [1,3] dioxol acid -5-yl) cyclopropanecarboxylic and (S) -N - ((R) - (2-aminothiazol-5-yl) (2-chloro-4-fluorophenyl) methyl) -2-methylpropane-2-sulfinamide. Yield (50%). 1H NMR (400 MHz, DMSO-d6) δ 11.38 (s, 1H), 7.78 (dd, J = 6.2, 8.8 Hz, 1H), 7.47-7.44 (m, 2H), 7.37-7.32 (m, 2H), 7.21 (dd, J = 1.6, 8.3 Hz, 1H), 7.04 (s, 1H), 6.45 (d , J = 6.6 Hz, 1H), 5.95 (d, J = 6.5 Hz, 1H), 1.54 -1.50 (m, 2H), 1.22 -1.21 (m, 2H), 1.14 (s, 9H); ret time HPLC 3.90 min, CH3CN 10-99%, embodiment 5 min; ESI-MS 586.3 m / z (MH +).

1- (Benzo [d] [1,3] dioxol-5-yl) -N- (5 - ((S) - (4-chloro-2-fluorophenyl) ((R) -1,1-dimethylethylsulfinamide) methyl ) thiazol-2il) cyclopropanecarboxamide

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1- (benzo [d] [1,3] dioxol-5-yl) -N- (5 - ((S) - (4-chloro-2-fluorophenyl) ((R) -1,1-dimethylethylsulfmamide was prepared ) methyl) thiazol-2il) cyclopropanecarboxamide by the procedure used for 1- (benzo [d] [1,3] dioxol-5-yl) -N- (5 - ((S) - (2-chloro-4fluorophenyl) ( (R) -1,1-dimethylethylsulfinamide) methyl) thiazol-2-yl) cyclopropanecarboxamide, starting from acid 1

10 (benzo [d] [1,3] dioxol-5-yl) cyclopropanecarboxylic acid and (R) -N - ((S) - (2-aminothiazol-5-yl) (4-chloro-2-fluorophenyl) methyl) -2-methylpropane-2-sulfinamide. Yield (64%). 1H NMR (400 MHz, CDCl3) δ 8.56 (s, 1H), 7.43 (t, J = 8.1 Hz, 1H), 7.18 (s, 1H), 7.16 (dd, J = 1.5, 8.3 Hz, 1H), 7.08 (dd, J = 2.0, 10.0 Hz, 1H), 6.89 (td, J = 8.0, 1.7 Hz, 2H), 6.81 (d, J = 7.9 Hz, 1H), 6.01 -5.99 (m, 3H), 3.90 (d, J = 5.0 Hz, 1H), 1, 73 -1.70 (m, 2H), 1.28 -1.23 (m, 11H); ret time HPLC 3.69 min, CH3CN 10-99%, embodiment 5 min; ESI-MS 550.5 m / z (MH +).

15 N- (5 - ((S) - (4-Chloro-2-fluorophenyl) ((R) -1,1-dimethylethylsulfinamide) methyl) thiazol-2-yl) -1- (2,2-difluorobenzo [d] [ 1,3] dioxol-5-yl) cyclopropanecarboxamide

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N- (5 - ((S) - (4-Chloro-2-fluorophenyl) ((R) -1,1-dimethylethylsulfinamide) methyl) thiazol-2-yl) -1- (2,2) was prepared

difluorobenzo [d] [1,3] dioxol-5-yl) cyclopropanecarboxamide by the procedure used for 1- (benzo [d] [1,3] dioxol-5-yl) 20 N- (5 - ((S) - (2-Chloro-4-fluorophenyl) ((R) -1,1-dimethylethylsulfinamide) methyl) thiazol-2-yl) cyclopropanecarboxamide, starting from

1- (2,2-Difluorobenzo [d] [1,3] dioxol-5-yl) cyclopropanecarboxylic acid and (R) -N - ((S) - (2-aminothiazol-5-yl) (4-chloro- 2

fluorophenyl) methyl) -2-methylpropane-2-sulfinamide. Yield (53%). 1H NMR (400 MHz, DMSO-d6) δ 11.37 (s, 1H),

7.66 (t, J = 8.3 Hz, 1H), 7.45-7.42 (m, 2H), 7.38 (dd, J = 2.0, 8.4 Hz, 1H), 7 , 34 (d, J = 8.3 Hz, 1H), 7.21 (dd, J = 1.5,

8.3 Hz, 1H), 7.11 (s, 1H), 6.33 (d, J = 6.7 Hz, 1H), 5.89 (d, J = 6.5 Hz, 1H), 1 , 55 -1.52 (m, 2H), 1.24 -1.22 (m, 2H), 25 1.13 (d, J = 9.5 Hz, 9H); ret time HPLC 3.93 min, CH3CN 10-99%, embodiment 5 min; IEN-EM 586.5 m / z

(MH +).

(S) -N- (5- (Amino (2-chloro-4-fluorophenyl) methyl) thiazol-2-yl) -1- (benzo [d] [1,3] dioxol-5-yl) cyclopropanecarboxamide

image 1

To a solution of 1- (benzo [d] [1,3] dioxol-5-yl) -N- (5 - ((S) - (2-chloro-4-fluorophenyl) ((R) -1,1 -dimethyl ethyl sulfma5

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mido) methyl) thiazol-2-yl) cyclopropanecarboxamide (659 mg, 1.2 mmol) in MeOH (5 mL) 4M HCl in dioxane (1.8 mL, 7.2 mmol) was added. The reaction mixture was stirred at room temperature for 1.5 h and evaporated to dryness. The crude product was dissolved in CH2Cl2. The organic phase was washed with an aqueous solution of NaHCO3 (50 ml x 2) and brine (50 ml x 1), dried over MgSO4 and concentrated to provide (S) -N- (5- (Amino (2-chlorine -4fluorophenyl) methyl) thiazol-2-yl) -1- (benzo [d] [1,3] dioxol-5-yl) cyclopropanecarboxamide as a colorless solid that was used without further purification. 1H NMR (400 MHz, CDCl3) δ 8.48 (sa, 1H), 7.63 (dd, J = 6.1, 8.7 Hz, 1H), 7.18 (s, 1H), 7.08 (dd, J = 2.6, 8.4 Hz, 1H), 6.99 (td, J = 8.3, 2.6 Hz, 1H), 6.91 -6.86 (m, 2H), 6.81 (d, J = 7.9 Hz, 1H), 6.01 (s, 2H), 5.78 (s, 1H), 3.80 (s, 2H), 1.74 -1.67 (m, 2H), 1.30-1.22 (m, 2H); ret time HPLC 2.67 min, CH3CN 10-99%, embodiment 5 min; ESI-MS 446.3 m / z (MH +).

(S) -N- (5- (Amino (2-chloro-4-fluorophenyl) methyl) thiazol-2-yl) -1- (2,2-difluorobenzo [d] [1,3] dioxol-5yl) cyclopropanecarboxamide

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(S) -N- (5- (amino (2-chloro-4-fluorophenyl) methyl) thiazol-2-yl) -1- (2,2-difluorobenzo [d] [1,3] dioxol-5il was prepared ) cyclopropanecarboxamide by the procedure used for (S) -N- (5- (amino (2-chloro-4-fluorophenyl) methyl) thiazol-2-yl) -1 (benzo [d] [1,3] dioxol-5 -yl) cyclopropanecarboxamide, starting from N- (5 - ((S) - (2-chloro-4-fluorophenyl) ((R) -1,1-dimethylethylsulfinamide) methyl) thiazol-2-yl) -1- (2,2 -difluorobenzo [d] [1,3] dioxo1-5-yl) cyclopropanecarboxamide. The crude product was used without further purification. 1H NMR (400 MHz, CDCl3) δ 8.35 (s, 1H), 7.65 (dd, J = 6.1, 8.7 Hz, 1H), 7.22-7.17 (m, 3H) , 7.12 -7.10 (m, 2H), 7.02 (td, J = 8.3, 2.6 Hz, 1H), 5.80 (s, 1H), 3.83 (s, 2H ), 1.83 -1.77 (m, 2H), 1.28 -1.25 (m, 2H); ret time HPLC 2.87 min, 10-99% CH3CN, embodiment 5 min; ESI-MS 482.3 m / z (MH +).

(R) -N- (5- (Amino (2-chloro-4-fluorophenyl) methyl) thiazol-2-yl) -1- (benzo [d] [1,3] dioxol-5-yl) cyclopropanecarboxamide

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(R) -N- (5- (Amino (2-chloro-4-fluorophenyl) methyl) thiazol-2-yl) -1- (benzo [d] [1,3] dioxol-5-yl) cyclopropanecarboxamide was prepared by the procedure used for (S) -N- (5- (amino (2-chloro-4-fluorophenyl) methyl) thiazol-2-yl) -1- (benzo [d] [1,3] dioxol-5il) cyclopropanecarboxamide, starting from 1- (benzo [d] [1,3] dioxol-5-yl) -N- (5 - ((R) - (2-chloro-4-fluorophenyl) ((S) -1,1-dimethylethylsulfinamide ) methyl) thiazol-2-yl) cyclopropanecarboxamide. The crude product was purified by column chromatography (0-2.5% Et3N / EtOAc) to provide a pale yellow solid (77%). 1H NMR (400 MHz, DMSO-d6) δ 10.80 (sa, 1H), 7.80 (dd, J = 6.4, 8.8 Hz, 1H), 7.38 (dd, J = 2, 6.8.8 Hz, 1H), 7.27 (td, J = 8.5, 2.7 Hz, 1H), 7.07 (d, J = 0.9 Hz, 1H), 6.95 ( s, 1H), 6.86 (d, J = 0.9 Hz, 2H), 6.00 (s, 2H), 5.53 (s, 1H), 1.44 -1.41 (m, 2H ), 1.13-1.10 (m, 2H); ret time HPLC 2.67 min, CH3CN 10-99%, embodiment 5 min; ESI-MS 446.3 m / z (MH +).

(R) -N- (5- (Amino (2-chloro-4-fluorophenyl) methyl) thiazol-2-yl) -1- (2,2-difluorobenzo [d] [1,3] dioxol-5yl) cyclopropanecarboxamide

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(R) -N- (5- (amino (2-chloro-4-fluorophenyl) methyl) thiazol-2-yl) -1- (2,2-difluorobenzo [d] [1,3] dioxol-5il was prepared ) cyclopropanecarboxamide by the procedure used for (R) -N- (5- (amino (2-chloro-4-fluorophenyl) methyl) thiazol-2-yl) -1 (benzo [d] [1,3] dioxol-5 -yl) cyclopropanecarboxamide, starting from N- (5 - ((R) - (2-chloro-4-fluorophenyl) ((S) -1,1-dimethylethylsulfmamide) methyl) thiazol-2-yl) -1- (2,2 -difluorobenzo [d] [1,3] dioxol-5-yl) cyclopropanecarboxamide (79%). 1H NMR (400 MHz, DMSO-d6) δ 7.80 (dd, J = 6.4, 8.8 Hz, 1H), 7.43 (d, J = 1.7 Hz, 1H), 7.3 (dd, J = 2.6, 8.8 Hz, 1H), 7.34 (d, J = 8.3 Hz, 1H), 7.27 (td, J = 8.5, 2.6 Hz, 1H), 7.20 (dd, J = 1.8, 8.3 Hz, 1H), 7.07 (d, J = 0.9 Hz, 1H), 5.53 (s, 1H), 1, 52 -1.49 (m, 2H), 1.21 -1.19 (m, 2H); ret time HPLC 2.91 min, 10-99% CH3CN, embodiment 5 min; IENEM 482 m / z (MH +).

(S) -N- (5- (Amino (4-chloro-2-fluorophenyl) methyl) thiazol-2-yl) -1- (benzo [d] [1,3] dioxol-5-yl) cyclopropanecarboxamide

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(S) -N- (5- (amino (4-chloro-2-fluorophenyl) methyl) thiazol-2-yl) -1- (benzo [d] [1,3] dioxol-5-yl) cyclopropanecarboxamide was prepared by the procedure used for (R) -N- (5- (amino (2-chloro-4-fluorophenyl) methyl) thiazol-2-yl) -1- (benzo [d] [1,3] dioxol-5il) cyclopropanecarboxamide, starting from 1- (benzo [d] [1,3] dioxol-5-yl) -N- (5 - ((S) - (4-chloro-2-fluorophenyl) ((R) -1,1-dimethylethylsulfinamide ) methyl) thiazol-2-yl) cyclopropanecarboxamide (79%). 1H NMR (400 MHz, CDCl3) δ 8.48 (s, 1H),

15 7.47 (t, J = 8.2 Hz, 1H), 7.14 -7.12 (m, 2H), 7.05 (dd, J = 2.0, 10.1 Hz, 1H), 6.91 -6.87 (m, 2H), 6.81 (d, J = 7.9 Hz, 1H), 6.01 (s, 2H), 5.61 (s, 1H), 1.86 (s, 2H), 1.71 (dd, J = 3.6, 6.7 Hz, 2H), 1.22-1.19 (m, 2H); ret time HPLC 2.71 min, 10-99% CH3CN, embodiment 5 min; ESI-MS 446.3 m / z (MH +).

(S) -N- (5- (Amino (4-chloro-2-fluorophenyl) methyl) thiazol-2-yl) -1- (2,2-difluorobenzo [d] [1,3] dioxol-5yl) cyclopropanecarboxamide

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(S) -N- (5- (amino (4-chloro-2-fluorophenyl) methyl) thiazol-2-yl) -1- (2,2-difluorobenzo [d] [1,3] dioxol-5il was prepared ) cyclopropanecarboxamide by the procedure used for (R) -N- (5- (amino (2-chloro-4-fluorophenyl) methyl) thiazol-2-yl) -1 (benzo [d] [1,3] dioxol-5 -yl) cyclopropanecarboxamide, starting from N- (5 - ((S) - (4-chloro-2-fluorophenyl) ((R) -1,1-dimethylethylsulfinamide) methyl) thiazol-2-yl) -1- (2,2 -difluorobenzo [d] [1,3] dioxol-5-yl) cyclopropanecarboxamide (88%). NMR

25 1H (400 MHz, DMSO-d6) δ 11.20 (sa, 1H), 7.66 (t, J = 8.3 Hz, 1H), 7.43 (d, J = 1.7 Hz, 1H ), 7.39-7.30 (m, 3H), 7.20 (dd, J = 1.7, 8.3 Hz, 1H), 7.09 (s, 1H), 5.45 (s, 1H), 1.52-1.49 (m, 2H), 1.22-1.20 (m, 2H); ret time HPLC 2.94 min, 10-99% CH3CN, embodiment 5 min; ESI-MS 482.3 m / z (MH +).

1- (Benzo [d] [1,3] dioxol-5-yl) -N- (5 - ((S) - ((R) -3- (tert-butyldimethylsilyloxy) pyrrolidin-1-yl) (2- chloro-4fluorophenyl) methyl) thiazol-2-yl) cyclopropanecarboxamide

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To a solution of (S) -N- (5- (amino (2-chloro-4-fluorophenyl) methyl) thiazol-2-yl) -1- (benzo [d] [1,3] dioxol-5yl) cyclopropanecarboxamide (1.2 mmol) in MeOH (10 ml) was added (R) -3- (tert-butyldimethylsilyloxy) -4-chlorobutanal (341 mg, 1.4 mmol). The reaction mixture was stirred at room temperature for 5 min. Then, NaBH4 (68 mg, 1.8 mmol) was added and stirring was continued at room temperature for 1 h. The reaction was diluted with H2O and extracted with EtOAc. The combined organic phases were washed with brine and dried over MgSO4. After solvent removal, the residue was purified by column chromatography (10-20% EtOAc / Hexane), yielding 1- (Benzo [d] [1,3] dioxol-5-yl) -N- (5 - ((S) - ((R) -3- (tert-Butyldimethylsilyloxy) pyrrolidin-1-yl) (2-chloro-4-fluorophenyl) methyl) thiazol-2-yl) cyclopropanecarboxamide (446 mg, 59% in two stages) . 1H NMR (400 MHz, CDCl3) δ 8.45 (s, 1H), 7.79 (dd, J = 8.6, 6.3 Hz, 1H), 7.25 (d, J = 6.4 Hz , 1H), 7.01-6.94 (m, 2H), 6.85 (td, J = 8.3, 1.7 Hz, 2H), 6.78 (d, J = 7.9 Hz, 1H), 5.99 (s, 2H), 4.99 (s, 1H), 4.35-4.30 (m, 1H), 2.77 (dd, J = 9.9, 6.2 Hz , 1H), 2.51-2.48 (m, 2H), 2.36 (dd, J = 9.9, 4.3 Hz, 1H), 2.06-2.01 (m, 1H), 1.71-1.65 (m, 3H), 1.18 (t, J = 3.0 Hz, 2H), 0.85 (s, 9H), -0.01 (d, J = 7.3 Hz, 6H); ret time HPLC 3.59 min, CH3CN 10-99%, embodiment 5 min; ESI-MS 630.6 m / z (MH +).

N- (5 - ((S) - ((R) -3- (tert-Butyldimethylsilyloxy) pyrrolidin-1-yl) (2-chloro-4-fluorophenyl) methyl) thiazol-2-yl) -1- (2 , 2difluorobenzo [d] [1,3] dioxol-5-yl) cyclopropanecarboxamide

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N- (5 - ((S) - ((R) -3- (tert-Butyldimethylsilyloxy) pyrrolidin-1-yl) (2-chloro-4-fluorophenyl) methyl) thiazol-2-yl) -1- (2,2difluorobenzo [d] [1,3] dioxol-5-yl) cyclopropanecarboxamide by the procedure used for 1- (benzo [d] [1,3] dioxol-5-yl) N- (5 - ((S ) - ((R) -3- (tert-Butyldimethylsilyloxy) pyrrolidin-1-yl) (2-chloro-4-fluorophenyl) methyl) thiazol-2-yl) cyclopropanecarboxamide, starting from (S) -N- (5- (amino (2-chloro-4-fluorophenyl) methyl) thiazol-2-yl) -1- (2,2-difluorobenzo [d] [1,3] dioxol-5yl) cyclopropanecarboxamide and (R) -3- (tert -butyldimethylsilyloxy) -4-chlorobutanal (56% in two stages). 1H NMR (400 MHz, CDCl3) δ 8.31 (s, 1H), 7.79 (dd, J = 8.6, 6.3 Hz, 1H), 7.25 (d, J = 7.9 Hz , 1H), 7.13 (td, J = 8.4, 1.6 Hz, 2H), 7.06 (d, J = 8.1 Hz, 1H), 7.01-6.95 (m, 2H), 4.99 (s, 1H), 4.35-4.30 (m, 1H), 2.76 (dd, J = 9.8, 6.2 Hz, 1H), 2.50 (t , J = 6.9 Hz, 2H), 2.37 (dd, J = 10.0, 4.2 Hz, 1H), 2.08 -1.98 (m, 1H), 1.79-1, 64 (m, 3H), 1.24 -1.19 (m, 2H), 0.85 (s, 9H), -0.01 (d, J = 7.4 Hz, 6H); ret time HPLC 3.80 min, CH3CN 10-99%, embodiment 5 min; ESI-MS 666.4 m / z (MH +).

1- (Benzo [d] [1,3] dioxol-5-yl) -N- (5 - ((R) - ((R) -3- (tert-butyldimethylsilyloxy) pyrrolidin-1-yl) (2- chloro-4-fluorophenyl) methyl) thiazol-2il) cyclopropanecarboxamide

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1- (benzo [d] [1,3] dioxol-5-yl) -N- (5 - ((R) - ((R) -3- (tert-butyldimethylsilyloxy) pyrrolidin-1-yl) ( 2-Chloro-4fluorophenyl) methyl) thiazol-2-yl) cyclopropanecarboxamide by the procedure used for 1- (benzo [d] [1,3] dioxol-5-yl) -N- (5 ((S) - (( R) -3- (tert-Butyldimethylsilyloxy) pyrrolidin-1-yl) (2-chloro-4-fluorophenyl) methyl) thiazol-2-yl) cyclopropanecarboxamide, starting from (R) -N- (5- (amino (2 -chloro-4-fluorophenyl) methyl) thiazol-2-yl) -1- (benzo [d] [1,3] dioxol-5yl) cyclopropanecarboxamide and (R) -3- (tert-butyldimethylsilyloxy) -4-chlorobutanal ( 99%) 1H NMR (400 MHz, DM-SO-d6) δ 11.01 (s, 1H), 7.77 (dd, J = 6.4, 8.8 Hz, 1H), 7.38-7.36 ( m, 2H), 7.29 (td, J = 8.5, 2.7 Hz, 1H), 6.94 (s, 1H), 6.85 (m, 2H), 5.99 (s, 2H ), 4.99 (s, 1H), 4.38 -4.34 (m, 1H), 2.83 (dd, J = 6.2, 9.9 Hz, 1H), 2.58 -2, 54 (m, 1H), 2.46 -2.42 (m, 1H), 2.14 (dd, J = 3.7, 9.9 Hz, 1H), 2.05 -1.99 (m, 1H), 1.68-1.57 (m, 1H), 1.43-1.40 (m, 2H), 1.12-1.10 (m, 2H), 0.82 (s, 9H) , -0.00 (s, 3H), -0.02 (s, 3H); ret time HPLC 3.60 min, CH3CN 10-99%, embodiment 5 min; ESI-MS 630.5 m / z (MH +).

N- (5 - ((R) - ((R) -3- (tert-butyldimethylsilyloxy) pyrrolidin-1-yl) (2-chloro-4-fluorophenyl) methyl) thiazol-2-yl) -1- (2 , 2difluorobenzo [d] [1,3] dioxol-5-yl) cyclopropanecarboxamide

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N- (5 - ((R) - ((R) -3- (tert-butyldimethylsilyloxy) pyrrolidin-1-yl) (2-chloro-4-fluorophenyl) methyl) thiazol-2-yl) -1- (2.2

5 difluorobenzo [d] [1,3] dioxol-5-yl) cyclopropanecarboxamide by the procedure used for 1- (benzo [d] [1,3] dioxol-5-yl) N- (5 - ((S) - ((R) -3- (tert-Butyldimethylsilyloxy) pyrrolidin-1-yl) (2-chloro-4-fluorophenyl) methyl) thiazol-2-yl) cyclopropanecarboxamide, starting from (R) -N- (5- (amino (2-Chloro-4-fluorophenyl) methyl) thiazol-2-yl) -1- (2,2-difluorobenzo [d] [1,3] dioxol-5yl) cyclopropanecarboxamide and (R) -3- (tert-butyldimethylsilyloxy ) -4-chlorobutanal (92%). 1H NMR (400 MHz, DMSO-d6) δ 11.32 (s, 1H), 7.77 (dd, J = 6.4, 8.8 Hz, 1H), 7.43 (d, J = 1, 4 Hz, 1H), 7.39-7.30 (m, 4H), 7.20 (dd, J = 1.5, 8.3 Hz,

10 1H), 4.99 (s, 1H), 4.40 -4.35 (m, 1H), 2.83 (dd, J = 6.1, 9.9 Hz, 1H), 2.60 - 2.52 (m, 1H), 2.46 -2.41 (m, 1H), 2.15 (dd, J = 3.7, 9.9 Hz, 1H), 2.07 -1.99 ( m, 1H), 1.63 -1.57 (m, 1H), 1.51-1.48 (m, 2H), 1.25 -1.24 (m, 2H), 0.83 (s, 9H), 0.01 (s, 3H), -0.02 (s, 3H); ret time HPLC 3.79 min, CH3CN 10-99%, embodiment 5 min; ESI-MS 666.3 m / z (MH +).

1- (Benzo [d] [1,3] dioxol-5-yl) -N- (5 - ((S) - ((R) -3- (tert-butyldimethylsilyloxy) pyrrolidin-1-yl) (4- chloro-215 fluorophenyl) methyl) thiazol-2-yl) cyclopropanecarboxamide

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1- (benzo [d] [1,3] dioxol-5-yl) -N- (5 - ((S) - ((R) -3- (tert-butyldimethylsilyloxy) pyrrolidin-1-yl) ( 4-Chloro-2fluorophenyl) methyl) thiazol-2-yl) cyclopropanecarboxamide by the procedure used for 1- (benzo [d] [1,3] dioxol-5-yl) -N- (5 ((S) - (( R) -3- (tert-Butyldimethylsilyloxy) pyrrolidin-1-yl) (2-chloro-4-fluorophenyl) methyl) thiazol-2-yl) cyclopropanecarboxamide,

20 starting from (S) -N- (5- (amino (4-chloro-2-fluorophenyl) methyl) thiazol-2-yl) -1- (benzo [d] [1,3] dioxol-5yl) cyclopropanecarboxamide and (R) -3- (tert-Butyldimethylsilyloxy) -4-chlorobutanal (89%). 1H NMR (400 MHz, CDCl3) δ 8.48 (s, 1H), 7.64 (t, J = 8.1 Hz, 1H), 7.22 (s, 1H), 7.11 (dd, J = 1.9, 8.4 Hz, 1H), 6.99 (dd, J = 2.0.9.9 Hz, 1H), 6.90 -6.85 (m, 2H), 6.80 ( d, J = 7.9 Hz, 1H), 6.00 (s, 2H), 4.91 (s, 1H), 4.35 -4.33 (m, 1H), 2.83 (dd, J = 6.2, 9.8 Hz, 1H), 2.55 2.50 (m, 2H), 2.35 (dd, J = 4.4, 9.8 Hz, 1H), 2.07 -2 , 02 (m, 1H), 1.93 -1.91 (m, 1H), 1.73 -1.70 (m, 2H), 1.22 -1.20

25 (m, 2H), 0.86 (s, 9H), 0.01 (s, 3H), 0.00 (s, 3H); ret time HPLC 3.59 min, CH3CN 10-99%, embodiment 5 min; ESI-MS 630.5 m / z (MH +).

N- (5 - ((S) - ((R) -3- (tert-Butyldimethylsilyloxy) pyrrolidin-1-yl) (4-chloro-2-fluorophenyl) methyl) thiazol-2-yl) -1- (2 , 2difluorobenzo [d] [1,3] dioxol-5-yl) cyclopropanecarboxamide

image 1

N- (5 - ((S) - ((R) -3- (tert-Butyldimethylsilyloxy) pyrrolidin-1-yl) (4-chloro-2-fluorophenyl) methyl) thiazol-2-yl) -1- (2,2difluorobenzo [d] [1,3] dioxol-5-yl) cyclopropanecarboxamide by the procedure used for 1- (benzo [d] [1,3] dioxol-5-yl) N- (5 - ((S ) - ((R) -3- (tert-Butyldimethylsilyloxy) pyrrolidin-1-yl) (2-chloro-4-fluorophenyl) methyl) thiazol-2-yl) cyclopropanecarboxamide,

5 starting from (S) -N- (5- (amino (4-chloro-2-fluorophenyl) methyl) thiazol-2-yl) -1- (2,2-difluorobenzo [d] [1,3] dioxol- 5il) cyclopropanecarboxamide and (R) -3- (tert-butyldimethylsilyloxy) -4-chlorobutanal (90%). 1H NMR (400 MHz, DMSO-d6) δ 11.33 (s, 1H), 7.63 (t, J = 8.2 Hz, 1H), 7.43-7.32 (m, 5H), 7 , 20 (dd, J = 1.5, 8.3 Hz, 1H), 4.93 (s, 1H), 4.39 -4.34 (m, 1H), 2.69 (dd, J = 6 , 1, 9.8 Hz, 1H), 2.49 -2.45 (m, 2H), 2.34 (dd, J = 3.9, 9.9 Hz, 1H), 2.10 -1, 99 (m, 1H), 1.62 -1.55 (m, 1H), 1.52 -1.49 (m, 2H), 1.24 -1.19 (m, 2H), 0.83 ( s, 9H), 0.01 (s, 3H), -0.01 (s, 3H); ret time HPLC

10 3.79 min, CH3CN 10-99%, embodiment 5 min; ESI-MS 666.3 m / z (MH +).

1- (Benzo [d] [1,3] dioxol-5-yl) -N- (5 - ((S) - (2-chloro-4-fluorophenyl) ((R) -3-hydroxypyrrolidin-1-yl ) methyl) thiazol-2

il) cyclopropanecarboxamide

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A mixture of 1- (benzo [d] [1,3] dioxol-5-yl) -N- (5 - ((S) - ((R) -3- (tert-butyldimethylsilyloxy) pyrrolidin-1-yl) (2-Chloro-4

15 fluorophenyl) methyl) thiazol-2-yl) cyclopropanecarboxamide (365 mg, 0.58 mmol) and TBAF (1 M in THF, 2.3 ml, 2.3 mmol) was stirred at room temperature overnight. The reaction was diluted with H2O and extracted with EtOAc. The combined organic phases were washed with brine and dried over MgSO4. After removal of the solvent, the residue was purified by column chromatography (20-50% EtOAc / Hexane) to provide 1 (Benzo [d] [1,3] dioxol-5-yl) -N- (5- ((S) - (2-Chloro-4-fluorophenyl) ((R) -3-hydroxypyrrolidin-1-yl) methyl) thiazol-2

20 il) cyclopropanecarboxamide (183 mg, 61%,> 99% ed). 1H NMR (400 MHz, DMSO-d6) δ 8.41 (s, 1H), 7.72 (t, J = 7.1 Hz, 1H), 7.20 (d, J = 8.3 Hz, 2H ), 6.95 (t, J = 7.2 Hz, 2H), 6.80 (td, J = 8.5, 1.6 Hz, 2H), 6.73 (d, J = 7.9 Hz , 1H), 5.94 (s, 2H), 4.95 (s, 1H), 4.25 (s, 1H), 2.75 (s, 1H), 2.58-2.56 (m, 1H), 2.42 (s, 1H), 2.28-2.27 (m, 1H), 2.12-2.11 (m, 1H), 1.71-1.61 (m, 3H) , 1.19-1.10 (m, 2H); ret time HPLC 2.68 min, CH3CN 10-99%, embodiment 5 min; ESI-MS 516.2 m / z (MH +).

25 N- (5 - ((S) - (2-Chloro-4-fluorophenyl) ((R) -3-hydroxypyrrolidin-1-yl) methyl) thiazol-2-yl) -1- (2,2-difluorobenzo [d] [1,3] dioxol5-yl) cyclopropanecarboxamide

image 1

N- (5 - ((S) - (2-chloro-4-fluorophenyl) ((R) -3-hydroxypyrrolidin-1-yl) methyl) thiazol-2-yl) -1- (2,2-difluorobenzo [ d] [1,3] dioxol-5-yl) cyclopropanecarboxamide by the procedure used for 1- (benzo [d] [1,3] dioxol-5-yl) N- (5 - ((S) - (2- chloro-4-fluorophenyl) ((R) -3-hydroxypyrrolidin-1-yl) methyl) thiazol-2-yl) cyclopropanecarboxamide, starting from N

5 (5 - ((S) - ((R) -3- (tert-Butyldimethylsilyloxy) pyrrolidin-1-yl) (2-chloro-4-fluorophenyl) methyl) thiazol-2-yl) -1- (2, 2difluorobenzo [d] [1,3] dioxol-5-yl) cyclopropanecarboxamide (77%). 1H NMR (400 MHz, DMSO-d6) δ 8.36 (s, 1H), 7.80 (t, J = 7.2 Hz, 1H), 7.30 (d, J = 10.6 Hz, 1H ), 7.17 (td, J = 8.5, 1.7 Hz, 2H), 7.11-7.01 (m, 4H), 5.05 (s, 1H), 4.35-4, 33 (m, 1H), 2.84-2.83 (m, 1H), 2.67-2.64 (m, 1H), 2.50 (dd, J = 10.0, 4.9 Hz, 1H), 2.38-2.34 (m, 1H), 2.20 (dd, J = 12.9, 5.8 Hz, 1H), 1.87-1.76 (m, 3H), 1 , 30-1.23 (m, 2H); ret time HPLC 2.91 min, 10-99% CH3CN, embodiment

10 5 min; ESI-MS 552.4 m / z (MH +).

1- (Benzo [d] [1,3] dioxol-5-yl) -N- (5 - ((R) - (2-chloro-4-fluorophenyl) ((R) -3-hydroxypyrrolidin-1-yl ) methyl) thiazol-2

il) cyclopropanecarboxamide

image 1

1- (benzo [d] [1,3] dioxol-5-yl) -N- (5 - ((R) - (2-chloro-4-fluorophenyl) ((R) -3-hydroxypyrrolidin-1 was prepared -il) methyl) thiazol-2

15-yl) cyclopropanecarboxamide by the procedure used for 1- (benzo [d] [1,3] dioxol-5-yl) -N- (5 - ((S) - (2-chloro-4-fluorophenyl) ((R) - 3-hydroxypyrrolidin-1-yl) methyl) thiazol-2-yl) cyclopropanecarboxamide, starting from 1- (benzo [d] [1,3] dioxol-5il) -N- (5 - ((R) - ((R ) -3- (tert-Butyldimethylsilyloxy) pyrrolidin-1-yl) (2-chloro-4-fluorophenyl) methyl) thiazol-2-yl) cyclopropanecarboxamide (61%,> 99% ed). 1H NMR (400 MHz, DMSO-d6) δ 11.01 (s, 1H), 7.80 (dd, J = 6.4, 8.8 Hz, 1H), 7.39-7.36 (m, 2H), 7.30 (td, J = 8.5, 2.6 Hz, 1H), 6.95 (s, 1H), 6.85 (s, 2H), 6.00 (s, 2H), 4.94 (s, 1H), 4.72 (d, J = 4.3 Hz, 1H), 4.19

20 4.18 (m, 1H), 2.70 -2.66 (m, 1H), 2.60 -2.56 (m, 1H), 2.34 -2.30 (m, 1H), 2 , 20 (dd, J = 3.1, 9.9 Hz, 1H), 2.00 -1.95 (m, 1H), 1.60 -1.57 (m, 1H), 1.44 -1 , 41 (m, 2H), 1.14-1.08 (m, 2H); ret time HPLC 2.72 min, 1099% CH3CN, embodiment 5 min; ESI-MS 516.3 m / z (MH +).

N- (5 - ((R) - (2-Chloro-4-fluorophenyl) ((R) -3-hydroxypyrrolidin-1-yl) methyl) thiazol-2-yl) -1- (2,2-difluorobenzo [ d] [1,3] dioxol5-yl) cyclopropanecarboxamide

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N- (5 - ((R) - (2-Chloro-4-fluorophenyl) ((R) -3-hydroxypyrrolidin-1-yl) methyl) thiazol-2-yl) -1- (2,2-difluorobenzo [ d] [1,3] dioxol-5-yl) cyclopropanecarboxamide by the procedure used for 1- (benzo [d] [1,3] dioxol-5-yl) N- (5 - ((S) - (2- chloro-4-fluorophenyl) ((R) -3-hydroxypyrrolidin-1-yl) methyl) thiazol-2-yl) cyclopropanecarboxamide, starting from N (5 - ((R) - ((R) -3- (tert) butyldimethylsilyloxy) pyrrolidin-1-yl) (2-chloro-4-fluorophenyl) methyl) thiazol-2-yl) -1- (2,2difluorobenzo [d] [1,3] dioxol-5-yl) cyclopropanecarboxamide (73% ,> 99% of ed). 1H NMR (400 MHz, DMSO-d6) δ 11.32 (s, 1H), 7.80 (dd, J = 6.4, 8.8 Hz, 1H), 7.43 (d, J = 1, 4 Hz, 1H), 7.39-7.28 (m, 4H), 7.20 (dd, J = 1.6, 8.3 Hz, 1H), 4.94 (s, 1H), 4, 72 (d, J = 4.3 Hz, 1H), 4.20 -4.19 (m, 1H), 2.71 -2.67 (m, 1H), 2.63 -2.57 (m, 1H), 2.34 -2.29 (m, 1H), 2.20 (dd, J = 3.2, 9.8 Hz, 1H), 2.02 -1.93 (m, 1H), 1 , 62 -1.54 (m, 1H), 1.54 -1.48 (m, 2H), 1.23 -1.17 (m, 2H); ret time HPLC 2.94 min, 10-99% CH3CN, embodiment 5 min; ESI-MS 552.5 m / z (MH +).

1- (Benzo [d] [1,3] dioxol-5-yl) -N- (5 - ((S) - (4-chloro-2-fluorophenyl) ((R) -3-hydroxypyrrolidin-1-yl ) methyl) thiazol-2il) cyclopropanecarboxamide

image 1

1- (benzo [d] [1,3] dioxol-5-yl) -N- (5 - ((S) - (4-chloro-2-fluorophenyl) ((R) -3-hydroxypyrrolidin-1 was prepared -yl) methyl) thiazol-2il) cyclopropanecarboxamide by the procedure used for 1- (benzo [d] [1,3] dioxol-5-yl) -N- (5 - ((S) - (2-chloro-4-fluorophenyl) ) ((R) -3-hydroxypyrrolidin-1-yl) methyl) thiazol-2-yl) cyclopropanecarboxamide, starting from 1- (benzo [d] [1,3] dioxol-5il) -N- (5 - (( S) - ((R) -3- (tert-Butyldimethylsilyloxy) pyrrolidin-1-yl) (4-chloro-2-fluorophenyl) methyl) thiazol-2-yl) cyclopropanecarboxamide (37%,> 99% ed). 1H NMR (400 MHz, CDCl3) δ 8.48 (s, 1H), 7.62 (t, J = 8.1 Hz, 1H), 7.22 (s, 1H), 7.13 (dd, J = 1.9, 8.4 Hz, 1H), 7.01 (dd, J = 2.1, 9.9 Hz, 1H), 6.90 -6.85 (m, 2H), 6.81 ( d, J = 7.9 Hz, 1H), 6.01 (s, 2H), 4.92 (s, 1H), 4.34 -4.28 (m, 1H), 2.86-2.80 (m, 1H), 2.63 (d, J = 10.1 Hz, 1H), 2.50-2.46 (m, 1H), 2.34-2.23 (m, 1H), 2, 21 2.12 (m, 1H), 1.80-1.70 (m, 4H), 1.24-1.18 (m, 2H); ret time HPLC 2.77 min, CH3CN 10-99%, embodiment 5 min; ESI-MS 516.3 m / z (MH +).

N- (5 - ((S) - (4-chloro-2-fluorophenyl) ((R) -3-hydroxypyrrolidin-1-yl) methyl) thiazol-2-yl) -1- (2,2-difluorobenzo [ d] [1,3] dioxol-5il) cyclopropanecarboxamide

image 1

N- (5 - ((S) - (4-chloro-2-fluorophenyl) ((R) -3-hydroxypyrrolidin-1-yl) methyl) thiazol-2-yl) -1- (2,2-difluorobenzo [ d] [1,3] dioxol-5-yl) cyclopropanecarboxamide by the procedure used for 1- (benzo [d] [1,3] dioxol-5-yl) N- (5 - ((S) - (2- chloro-4-fluorophenyl) ((R) -3-hydroxypyrrolidin-1-yl) methyl) thiazol-2-yl) cyclopropanecarboxamide, starting from N (5 - ((S) - ((R) -3- (tert) butyldimethylsilyloxy) pyrrolidin-1-yl) (4-chloro-2-fluorophenyl) methyl) thiazol-2-yl) -1- (2,2difluorobenzo [d] [1,3] dioxol-5-yl) cyclopropanecarboxamide (78% ,> 99% of ed). 1H NMR (400 MHz, DMSO-d6) δ 11.32 (s, 1H), 7.66 (t, J = 8.1 Hz, 1H), 7.43 (d, J = 1.5 Hz, 1H ), 7.39 -7.33 (m, 4H), 7.20 (dd, J = 1.6, 8.3 Hz, 1H), 4.88 (s, 1H), 4.75 (d, J = 4.4 Hz, 1H), 4.21 -4.16 (m, 1H), 2.57 (dd, J = 6.1, 9.8 Hz, 1H), 2.51 -2.44 (m, 1H), 2.41 2.33 (m, 2H), 2.04 -1.95 (m, 1H), 1.60 -1.45 (m, 3H), 1.24 -1, 15 (m, 2H); ret time HPLC 2.97 min, 10-99% CH3CN, embodiment 5 min; ESI-MS 552.5 m / z (MH +).

(R) -N - ((R) - (2-Amino-4-methylthiazol-5-yl) (2-chlorophenyl) methyl) -2-methylpropane-2-sulfinamide and (R) -N - ((S) - (2-Amino-4methylthiazol-5-yl) (2-chlorophenyl) methyl) -2-methylpropane-2-sulfinamide

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To a solution of S ((2-chlorophenyl) (1,1-dimethylethylsulfinamide) methyl) -4-methylthiazol-2-ylcarbamate of (R) -terc-butyl (19.0 g, 41.6 mmol) in CH2Cl2 (83 ml) TFA (83 ml) was added. The reaction was stirred at room temperature for 1 h. The reaction was concentrated and then partitioned between CH2Cl2 and a saturated aqueous solution of NaHCO3. The aqueous phase was basified to pH> 12 by the addition of a 1 N solution of NaOH and extracted with CH2Cl2. The combined organic phases were dried over MgSO4 and concentrated. The crude product was absorbed on silica gel and purified by column chromatography (70 -100% EtOAc / hexanes. The EtOAc contained 2% NH4OH and stirred to maintain the mixture), providing (R) -N- ((R) - (2-amino-4-methylthiazol-5-yl) (2-chlorophenyl) methyl) -2-methylpropane-2-sulfinamide and (R) -N - ((S) - (2-amino-4- methylthiazol-5-yl) (2-chlorophenyl) methyl) -2-methylpropane-2-sulfinamide and a mixture of the two diastereomers (7.1 g, 47%). First eluted product (Isomer A) (white solid, 3.0 g, 20%,> 99% ed); 1H NMR (400 MHz, CDCl3) δ 7.60 (dd, J = 1.6, 7.7 Hz, 1H), 7.38-7.22 (m, 3H), 6.15 (d, J = 2.5 Hz, 1H), 4.94 (s, 2H), 3.87 (d, J = 2.3 Hz, 1H), 2.34 (s, 3H), 1.27 (s, 9H) ; ret time HPLC 3.08 min, CH3CN 10-99%, embodiment 15 min; ESI-MS 358.3 m / z (MH +). Second eluted product (Isomer B) (yellow waxy solid, 5.0 g, 33%. 98% ed); 1H NMR (400 MHz, CDCl3) δ 7.64 (dd, J = 7.7, 1.7 Hz, 1H), 7.36 (dd, J = 7.8, 1.4 Hz, 1H), 7 , 32-7.21 (m, 2H), 6.19 (d, J = 1.8 Hz, 1H), 4.86 (s, 2H), 3.65 (d, J = 1.2 Hz, 1H), 2.33 (s, 3H), 1.26 (s, 9H); ret time HPLC 3.77 min, CH3CN 10-99%, embodiment 15 min; ESI-MS 358.3 m / z (MH +).

(R) -N - ((R) - (2-aminothiazol-5-yl) (3,4-dichlorophenyl) methyl) -2-methylpropane-2-sulfinamide and (R) -N - ((S) - ( 2-aminothiazol5-yl) (3,4-dichlorophenyl) methyl) -2-methylpropane-2-sulfinamide

image 1

(R) -N- (S) -1- (2-aminothiazol-5-yl) -1- (3,4-dichlorophenyl) methyl) -1,1-dimethylethylsulfinamide and (R) -N- (R ) -1- (2 aminothiazol-5-il) -1- (3,4-dichlorophenyl) methyl) -1,1-dimethylethylsulfinamide by the procedure described for (R) -N - ((R) - (2 amino-4- methylthiazol-5-yl) (2-chlorophenyl) methyl) -2-methylpropane-2-sulfinamide and (R) -N - ((S) - (2-amino-4-methylthiazol-5-yl) (2-chlorophenyl) methyl ) -2-methylpropane-2-sulfinamide starting from 5 - ((3,4-dichlorophenyl) (1,1-dimethylethylsulfinamido) methyl) thiazol2-ylcarbamate of (R) -terc-butyl. The crude product was purified by column chromatography (5% EtOH / EtOAc elutes Isomer A, 20% EtOH / EtOAc elutes Isomer B). Isomer A (yellow solid, 5.67 g, 35%,> 99% ed); 1H NMR (400 MHz, CDCl3) δ 7.49 (d, J = 2.1 Hz, 1H), 7.44 (d, J = 8.3 Hz, 1H), 7.25 (dd, J = 2 , 2, 8.5 Hz, 1H), 6.95 (s, 1H), 5.63 (d, J = 3.5 Hz, 1H), 5.03 (s, 2H), 3.84 (d , J = 3.5 Hz, 1H), 1.26 (s, 9H); ret time HPLC 2.37 min, 10-99% CH3CN, embodiment 5 min; ESI-MS 378.0 m / z (MH +). Isomer B (yellow solid, 3.64 g, 23%, 96% ed); 1H NMR (400 MHz, CDCl3) δ 7.50 (d, J = 2.1 Hz, 1H), 7.44 (d, J = 8.3 Hz, 1H), 7.25 (dd, J = 2 , 1, 8.5 Hz, 1H), 6.88 (d, J = 0.5 Hz, 1H), 5.65 (d, J = 2.5 Hz, 1H), 5.02 (s, 2H ), 3.88 (d, J = 2.3 Hz, 1H), 1.26 (s, 9H); ret time HPLC 2.50 min, CH3CN 10-99%, embodiment 5 min; ESI-MS 378.2 m / z (MH +).

1- (Benzo [d] [1,3] dioxol-5-yl) -N- (5 - ((R) - (2-chlorophenyl) ((R) -1,1-dimethylethylsulfinamide) methyl) -4- methylthiazol-2il) cyclopropanecarboxamide and 1- (Benzo [d] [1,3] dioxol-5-yl) -N- (5 - ((S) - (2-chlorophenyl) ((R) -1,1-dimethylethylsulfinamide) methyl ) -4-methylthiazol-2-yl) cyclopropanecarboxamide

image5

To 1- (benzo [d] [1,3] dioxol-5-yl) cyclopropanecarboxylic acid (864 mg, 4.2 mmol) SOCl2 (916 µl, 12.6 mmol) was added slowly followed by DMF (3 drops ). The reaction mixture was heated at 60 ° C for 0.5 h. Excess of 5

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SOCl2 was removed in vacuo. Then, the acid chloride was dissolved in anhydrous CH2Cl2 (6 ml) and slowly added to a solution of (R) -N - ((2-amino-4-methylthiazol-5-yl) (2-chlorophenyl) methyl) -2-methylpropane-2-sulfinamide (Isomer A) (1.35 g, 3.8 mmol) and Et3N (2.92 ml, 21.0 mmol) in anhydrous CH2Cl2 (18 ml). The reaction mixture was stirred at room temperature for 18 h, diluted with CH2Cl2 and washed with a 1 N solution of HCl, a saturated aqueous solution of NaHCO3 and brine. The organic phase was dried over MgSO4 and concentrated to provide 1 (benzo [d] [1,3] dioxol-5-yl) -N- (5 - ((2-chlorophenyl) ((R) -1,1- dimethylethylsulfinamide) methyl) -4-methylthiazol-2il) cyclopropanecarboxamide (Isomer A) in the form of an orange solid (1.54 g, 75%) that was used without further purification. ret time HPLC 3.59 min, CH3CN 10-99%, embodiment 5 min; ESI-MS 546.5 m / z (MH +).

1- (benzo [d] [1,3] dioxol-5-yl) -N- (5 - ((2-chlorophenyl) ((R) -1,1-dimethylethylsulfinamide) methyl) -4-methylthiazole- 2il) cyclopropanecarboxamide (Isomer B) by the procedure used for Isomer A starting from 1 (benzo [d] [1,3] dioxol-5-yl) cyclopropanecarboxylic acid and (R) -N - ((2-amino-4- methylthiazol-5-yl) (2-chlorophenyl) methyl) -2-methylpropane-2-sulfinamide (Isomer B). The crude product was absorbed on silica gel and purified by column chromatography (25-60% EtOAc / hexanes), yielding the product as a light orange solid (62%). 1H NMR (400 MHz, CDCl3) δ 8.48 (s, 1H), 7.70 (dd, J = 7.8, 1.6 Hz, 1H), 7.34-7.20 (m, 3H) , 6.88-6.79 (m, 3H), 6.26 (d, J = 1.9 Hz, 1H), 6.01 (s, 2H), 3.55 (d, J = 1.7 Hz, 1H), 2.40 (s, 3H), 1.68 (m, 2H), 1,281.18 (m, 11H); ret time HPLC 3.69 min, CH3CN 10-99%, embodiment 5 min; ESI-MS 546.5 m / z (MH +).

N- (5 - ((R) - (2-Chlorophenyl) ((R) -1,1-dimethylethylsulfinamide) methyl) -4-methylthiazol-2-yl) -1- (2,2difluorobenzo [d] [1, 3] dioxol-5-yl) cyclopropanecarboxamide and N- (5 - ((S) - (2-Chlorophenyl) ((R) -1,1-dimethylethylsulfinamide) methyl) -4-methylthiazol-2-yl) -1- (2 , 2-difluorobenzo [d] [1,3] dioxol-5il) cyclopropanecarboxamide

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N- (5 - ((2-chlorophenyl) ((R) -1,1-dimethylethylsulfinamide) methyl) -4-methylthiazol-2-yl) -1- (2,2difluorobenzo [d] [1,3] dioxol-5-yl) cyclopropanecarboxamide (Isomer A) by the procedure used for 1 (benzo [d] [1,3] dioxol-5-yl) -N- (5 - ((2-chlorophenyl) ((R) - 1,1-dimethylethylsulfinamide) methyl) -4-methylthiazol-2il) cyclopropanecarboxamide (Isomer A) starting from 1- (2,2-difluorobenzo [d] [1,3] dioxol-5yl) cyclopropanecarboxylic acid and (R) -N - ((2-Amino-4-methylthiazol-5-yl) (2-chlorophenyl) methyl) -2-methylpropane-2-sulfinamide (Isomer A). The crude product was absorbed on silica gel and purified by column chromatography (25-100% EtOAc / hexanes), yielding an orange solid (55%). 1H NMR (400 MHz, CDCl3) δ 8.36 (s, 1H), 7.67 (dd, J = 7.7, 1.6 Hz, 1H), 7.35-7.21 (m, 3H) , 7.17-7.07 (m, 3H), 6.21 (d, J = 2.5 Hz, 1H), 3.80 (d, J = 2.4 Hz, 1H), 2.41 ( s, 3H), 1.80-1.70 (m, 2H), 1.26-1.18 (m, 11H); ret time HPLC 3.81 min, CH3CN 10-99%, embodiment 5 min; ESI-MS 582.3 m / z (MH +).

N- (5 - ((2-chlorophenyl) ((R) -1,1-dimethylethylsulfinamide) methyl) -4-methylthiazol-2-yl) -1- (2,2difluorobenzo [d] [1,3] dioxol-5-yl) cyclopropanecarboxamide (Isomer B) by the procedure used for 1 (benzo [d] [1,3] dioxol-5-yl) -N- (5 - ((2-chlorophenyl) ((R) - 1,1-dimethylethylsulfinamide) methyl) -4-methylthiazol-2il) cyclopropanecarboxamide (Isomer A) starting from 1- (2,2-difluorobenzo [d] [1,3] dioxol-5yl) cyclopropanecarboxylic acid and (R) -N - ((2-Amino-4-methylthiazol-5-yl) (2-chlorophenyl) methyl) -2-methylpropane-2-sulfinamide (Isomer B). The crude product was absorbed on silica gel and purified by column chromatography (30-80% EtOAc / hexanes), yielding an orange solid (37%) 1H NMR (400 MHz, CDCl3) δ 8.33 (s, 1H), 7.70 (dd, J = 7.8, 1.7 Hz, 1H), 7.35-7.20 (m, 3H), 7.16-7.07 (m, 3H ), 6.26 (d, J = 2.0 Hz, 1H), 3.55 (d, J = 1.8 Hz, 1H), 2.39 (s, 3H), 1.79-1.71 (m, 2H), 1.28-1.21 (m, 11H); ret time HPLC 3.98 min, CH3CN 10-99%, embodiment 5 min; ESI-MS 582.3 m / z (MH +).

1- (Benzo [d] [1,3] dioxol-5-yl) -N- (5 - ((R) - (3,4-dichlorophenyl) ((R) -1,1-dimethylethylsulfinamide) methyl) thiazole -2il) cyclopropanecarboxamide and 1- (Benzo [d] [1,3] dioxol-5-yl) -N- (5 - ((S) - (3,4-dichlorophenyl) ((R) -1,1-dimethylethylsulfinamide) methyl) thiazol-2-yl) cyclopropanecarboxamide

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1- (Benzol [d] [1,3] dioxol-5-yl) -N- (5 - ((3,4-dichlorophenyl) ((R) -1,1-dimethylethylsulfinamide) methyl) thiazol-2il was prepared ) cyclopropanecarboxamide (Isomer A) by the procedure used for 1- (benzo [d] [1,3] dioxol-5-yl) -N- (5 - ((2-chlorophenyl) ((R) -1,1-dimethylethylsulfinamide) methyl) -4-methylthiazol-2-yl) cyclopropanecarboxamide (Isomer A) starting from 1- (benzo [d] [1,3] dioxol-5-yl) cyclopropanecarboxylic acid, (COCl) 2 and (R) -N- ((2-Aminothiazol-5-yl) (3,4-dichlorophenyl) methyl) 2-methylpropane-2-sulfinamide (Isomer A). The crude product was purified by column chromatography (60-80% EtOAc / Hexane) to provide a yellow solid (2.70 g, 72%). 1H NMR (400 MHz, CDCl3) δ 8.57 (s, 1H), 7.49 (d, J = 2.1 Hz, 1H), 7.43 (d, J = 8.3 Hz, 1H), 7.28 -7.26 (m, 2H), 6.90 (dd, J = 1.8, 7.9 Hz, 1H), 6.87 (d, J = 1.6 Hz, 1H), 6 , 82 (d, J = 7.9 Hz, 1H), 6.02 (s, 2H), 5.74 (d, J = 3.1 Hz, 1H), 3.73 (d, J = 3, 2 Hz, 1H), 1.73-1.71 (m, 2H), 1.28 -1.21 (m, 11H); ret time HPLC 3.80 min, CH3CN 10-99%, embodiment 5 min; ESI-MS 566.2 m / z (MH +).

1- (benzo [d] [1,3] dioxol-5-yl) -N- (5 - ((3,4-dichlorophenyl) ((R) -1,1-dimethylethylsulfinamide) methyl) thiazol-2il was prepared ) cyclopropanecarboxamide (Isomer B) by the procedure used for 1- (benzo [d] [1,3] dioxol-5-yl) -N- (5 - ((2-chlorophenyl) ((R) -1,1-dimethylethylsulfinamide) methyl) -4-methylthiazol-2-yl) cyclopropanecarboxamide (Isomer A) starting from 1- (benzo [d] [1,3] dioxol-5-yl) cyclopropanecarboxylic acid, (COCl) 2 and (R) -N- ((2-Aminothiazol-5-yl) (3,4-dichlorophenyl) methyl) 2-methylpropane-2-sulfinamide (Isomer B). The crude product was purified by column chromatography (60-100% EtOAc / Hexane) to provide a yellow solid (2.65 g, 71%). 1H NMR (400 MHz, CDCl3) δ 8.59 (s, 1H), 7.52 (d, J = 2.1 Hz, 1H), 7.42 (d, J = 8.3 Hz, 1H), 7.29 -7.26 (m, 2H), 6.90 -6.86 (m, 2H), 6.81 (d, J = 7.9 Hz, 1H), 6.02 (dd, J = 1.4, 1.9 Hz, 2H), 5.77 (d, J = 1.8 Hz, 1H), 3.72 (d, J = 1.9 Hz, 1H), 1.72 (dd, J = 3.2, 6.7 Hz, 2H), 1.28 -1.22 (m, 11H); ret time HPLC 3.91 min, CH3CN 10-99%, embodiment 5 min; ESI-MS 566.4 m / z (MH +).

(R) -N- (5- (Amino (2-chlorophenyl) methyl) -4-methylthiazol-2-yl) -1- (benzo [d] [1,3] dioxol-5-yl) cyclopropanecarboxamide and (S ) -N- (5- (Amino (2-chlorophenyl) methyl) -4-methylthiazol-2-yl) -1- (benzo [d] [1,3] dioxol-5-yl) cyclopropanecarboxamide

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To a solution of 1- (benzo [d] [1,3] dioxol-5-yl) -N- (5 - ((2-chlorophenyl) ((R) -1,1-dimethylethylsulfinamide) methyl) -4- methylthiazol-2-yl) cyclopropanecarboxamide (Isomer A) (1.47 g, 2.69 mmol) in MeOH (13 ml) 4M HCl in dioxane (4 ml, 16 mmol) was added. The reaction mixture was stirred at room temperature for 3 h and then concentrated. The crude product was dissolved in CH2Cl2 and washed with a saturated aqueous solution of NaHCO3 (x2) and brine, then dried over MgSO4 and concentrated. The crude product was absorbed on silica gel and purified by column chromatography (70-100% EtOAc / hexanes) to provide N- (5- (amino (2-chlorophenyl) methyl) -4methylthiazol-2-yl) -1- (benzo [d] [1,3] dioxol-5-yl) cyclopropanecarboxamide (Isomer A), in the form of an orange solid (540 mg, 45%). 1H NMR (400 MHz, DMSO-d6) δ 7.80 (d, J = 7.9 Hz, 1H), 7.40-7.36 (m, 2H), 7.27 (m, 1H), 6 , 94 (s, 1H), 6.85 (m, 2H), 6.00 (s, 2H), 5.56 (s, 1H), 2.19 (s, 3H), 1.40 (m, 2H), 1.10 (m, 2H); ret time HPLC 2.65 min, CH3CN 10-99%, embodiment 5 min; ESI-MS 442.5 m / z (MH +).

N- (5- (amino (2-chlorophenyl) methyl) -4-methylthiazol-2-yl) -1- (benzo [d] [1,3] dioxol-5-yl) cyclopropanecarboxamide (Isomer B) was prepared by the procedure used for Isomer A starting from 1- (benzo [d] [1,3] dioxol-5-yl) -N- (5 - ((2-chlorophenyl) ((R) -1,1-dimethylethylsulfinamide) methyl) - 4-methylthiazol-2-yl) cyclopropanecarboxamide (Isomer B) (90%). 1H NMR (400 MHz, DMSO-d6) δ 7.80 (d, J = 7.8 Hz, 1H), 7.40-7.36 (m, 2H), 7.27 (m, 1H), 6 , 94 (s, 1H), 6.85 (m, 2H), 6.00 (s, 2H), 5.56 (s, 1H), 2.19 (s, 3H), 1.40 (m, 2H), 1.10 (m, 2H); ret time HPLC 2.69 min, 10-99% CH3CN, embodiment 5 min; ESI-MS 442.3 m / z (MH +).

(R) -N- (5- (Amino (2-chlorophenyl) methyl) -4-methylthiazol-2-yl) -1- (2,2-difluorobenzo [d] [1,3] dioxol-5yl) cyclopropanecarboxamide and (S) -N- (5- (Amino (2-chlorophenyl) methyl) -4-methylthiazol-2-yl) -1- (2,2difluorobenzo [d] [1,3] dioxol-5-yl) cyclopropanecarboxamide

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N- (5- (amino (2-chlorophenyl) methyl) -4-methylthiazol-2-yl) -1- (2,2-difluorobenzo [d] [1,3] dioxol-5yl) cyclopropanecarboxamide (Isomer A was prepared ) by the procedure used for N- (5- (amino (2-chlorophenyl) methyl) -4-methylthiazol2-yl) -1- (benzo [d] [1,3] dioxol-5-yl) cyclopropanecarboxamide (Isomer A ) starting from N- (5 - ((2-chlorophenyl) ((R) -1,1-dimethylethylsulfinamide) methyl) -4-methylthiazol-2-yl) -1- (2,2-difluorobenzo [d] [1,3 ] dioxol-5-yl) cyclopropanecarboxamide (Isomer A) (83%). 1H NMR (400 MHz, DMSO-d6) δ 7.81 (m, 1H), 7.41-7.32 (m, 4H), 7.27 (m, 1H), 7.18 (dd, J = 1.7, 8.3 Hz, 1H), 5.57 (s, 1H), 2.20 (s, 3H), 1.48 (m, 2H), 1.17 (m, 2H); ret time HPLC 2.84 min, 10-99% CH3CN, embodiment 5 min; ESI-MS 478.1 m / z (MH +).

N- (5- (amino (2-chlorophenyl) methyl) -4-methylthiazol-2-yl) -1- (2,2-difluorobenzo [d] [1,3] dioxol-5yl) cyclopropanecarboxamide (Isomer B was prepared ) by the procedure used for N- (5- (amino (2-chlorophenyl) methyl) -4-methylthiazol2-yl) -1- (benzo [d] [1,3] dioxol-5-yl) cyclopropanecarboxamide (Isomer A ) starting from N- (5 - ((2-chlorophenyl) ((R) -1,1-dimethylethylsulfinamide) methyl) -4-methylthiazol-2-yl) -1- (2,2-difluorobenzo [d] [1,3 ] dioxol-5-yl) cyclopropanecarboxamide (Isomer B) (65%). 1H NMR (400 MHz, DMSO-d6) δ 7.81 (m, 1H), 7.41-7.32 (m, 4H), 7.28 (m, 1H), 7.18 (dd, J = 1.7, 8.3 Hz, 1H), 5.56 (s, 1H), 2.19 (s, 3H), 1.48 (m, 2H), 1.18 (m, 2H); ret time HPLC 2.84 min, 10-99% CH3CN, embodiment 5 min; ESI-MS 478.1 m / z (MH +).

(R) -N- (5- (Amino (3,4-dichlorophenyl) methyl) thiazol-2-yl) -1- (benzo [d] [1,3] dioxol-5-yl) cyclopropanecarboxamide and (S) -N (5- (Amino (3,4-dichlorophenyl) methyl) thiazol-2-yl) -1- (benzo [d] [1,3] dioxol-5-yl) cyclopropanecarboxamide

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N- (5- (amino (3,4-dichlorophenyl) methyl) thiazol-2-yl) -1- (benzo [d] [1,3] dioxol-5-yl) cyclopropanecarboxamide (Isomer A) was prepared by the procedure used for N- (5- (amino (2-chlorophenyl) methyl) -4-methylthiazol-2-yl) -1- (benzo [d] [1,3] dioxol5-yl) cyclopropanecarboxamide (Isomer A) starting from 1- (benzo [d] [1,3] dioxol-5-yl) -N- (5 - ((3,4-dichlorophenyl) ((R) -1,1-dimethylethylsulfinamide) methyl) thiazol-2-yl) cyclopropanecarboxamide (Isomer A). The crude product was purified by column chromatography (0-20% MeOH / DCM) (98%). 1H NMR (400 MHz, DMSO-d6) δ 10.8 (sa, 1H), 7.70 (d, J = 2.0 Hz, 1H), 7.58 (d, J = 8.3 Hz, 1H ), 7.40 (dd, J = 2.0, 8.4 Hz, 1H), 7.16 (d, J = 0.8 Hz, 1H), 6.96 (s, 1H), 6.86 (d, J = 0.9 Hz, 2H), 6.01 (s, 2H), 5.29 (s, 1H), 1.44 -1.42 (m, 2H), 1.13 -1, 10 (m, 2H); ret time HPLC 2.81 min, CH3CN 10-99%, embodiment 5 min; ESI-MS 462.3 m / z (MH +).

N- (5- (amino (3,4-dichlorophenyl) methyl) thiazol-2-yl) -1- (benzo [d] [1,3] dioxol-5-yl) cyclopropanecarboxamide (Isomer B) was prepared by the procedure used for (Isomer A) starting from 1- (benzo [d] [1,3] dioxol-5-yl) -N- (5 - ((3,4

1 HOUR

dichlorophenyl) ((R) -1,1-dimethylethylsulfinamide) methyl) thiazol-2-yl) cyclopropanecarboxamide (Isomer B) (quant.). NMR (400 MHz, DMSO-d6) δ 10.8 (sa, 1H), 7.70 (d, J = 2.0 Hz, 1H), 7.58 (d, J = 8.3 Hz, 1H) , 7.40 (dd, J = 2.0, 8.4 Hz, 1H), 7.16 (d, J = 0.7 Hz, 1H), 6.96 (s, 1H), 6.86 ( d, J = 0.9 Hz, 2H), 6.01 (s, 2H), 5.29 (s, 1H), 1.44 -1.42 (m, 2H), 1.13 -1.10 (m, 2H); ret time HPLC 2.81 min, CH3CN 10-99%, embodiment 5 min; ESI-MS 462.1 m / z (MH +).

1- (Benzo [d] [1,3] dioxol-5-yi) -N- (5 - ((R) - ((S) -3- (tert-butyldimethylsilyloxy) pyrrolidin-1-yl) (2- chlorophenyl) methyl) -4methylthiazol-2-yl) cyclopropanecarboxamide and 1- (Benzo [d] [1,3] dioxol-5-yl) -N- (5 - ((S) - ((S) -3- ( tert-butyldimethylsilyloxy) pyrrolidin-1-yl) (2-chlorophenyl) methyl) -4-methylthiazol-2-yl) cyclopropanecarboxamide

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To a solution of N- (5- (amino (2-chlorophenyl) methyl) -4-methylthiazol-2-yl) -1- (benzo [d] [1,3] dioxol-5yl) cyclopropanecarboxamide (Isomer A) ( 450 mg, 1.02 mmol) in MeOH (5 ml) was added (S) -3- (tert-butyldimethylsilyloxy) -4-chlorobutanal (289 mg, 1.22 mmol). The reaction mixture was stirred at room temperature for 20 min before NaBH4 (58 mg, 1.53 mmol) was added. Stirring was continued at room temperature for 3 h. After about 1 h, some precipitate / gum began to form in the reaction solution, so MeOH (5 ml) and CH2Cl2 (2 ml) were added to keep everything in solution. The reaction was diluted with H2O and extracted with EtOAc. The combined organic phases were washed with brine, dried over MgSO4 and concentrated. The residue was absorbed on silica gel and purified by column chromatography (0-25% EtOAc / hexanes) to provide 1- (benzo [d] [1,3] dioxol-5-yl) -N- (5 - (((S) -3- (tert-butyldimethylsilyloxy) pyrrolidin-1-yl) (2-chlorophenyl) methyl) -4-methylthiazol-2-yl) cyclopropanecarboxamide (Isomer A) in the form of a pale yellow solid (470 mg, 74%). 1H NMR (400 MHz, CDCl3) δ 8.40 (s, 1H), 7.83 (dd, J = 8.1, 1.6 Hz, 1H), 7.28-7.25 (m, 2H) , 7.13 (m, 1H), 6.88-6.83 (m, 2H), 6.79 (d, J = 7.9 Hz, 1H), 6.00 (s, 2H), 5, 08 (s, 1H), 4.33 (m, 1H), 2.94 (dd, J = 9.9, 6.3 Hz, 1H), 2.67 (td, J = 8.3, 3, 4 Hz, 1H), 2.53 (c, J = 8.4 Hz, 1H), 2.37 (s, 3H), 2.17 (dd, J = 9.9, 4.7 Hz, 1H) , 2.00 (m, 1H), 1.74-1.61 (m, 3H), 1.17 (m, 2H), 0.86 (m, 9H), 0.01 (s, 3H), -0.01 (s, 3 H); ret time HPLC 3.45 min, 10-99% CH3CN, embodiment 5 min; ESI-MS 626.5 m / z (MH +).

1- (benzo [d] [1,3] dioxol-5-yl) -N- (5 - (((S) -3- (tert-butyldimethylsilyloxy) pyrrolidin-1-yl) (2-chlorophenyl) was prepared methyl) -4-methylthiazol-2-yl) cyclopropanecarboxamide (Isomer B) by the procedure used for (Isomer A) starting from N- (5 (amino (2-chlorophenyl) methyl) -4-methylthiazol-2-yl) -1- (benzo [d] [1,3] dioxol-5-yl) cyclopropanecarboxamide (Isomer B) and (S) -3 (tert-butyldimethylsilyloxy) -4-chlorobutanal (81%). 1H NMR (400 MHz, CDCl3) δ 8.41 (s, 1H), 7.86 (dd, J = 7.2, 0.7 Hz, 1H), 7.27-7.24 (m, 2H) , 7.12 (m, 1H), 6.88-6.84 (m, 2H), 6.79 (d, J = 7.9 Hz, 1H), 6.00 (s, 2H), 5, 05 (s, 1H), 4.34 (m, 1H), 2.84 (dd, J = 9.7, 6.3 Hz, 1H), 2.56-2.46 (m, 2H), 2 , 37-2.32 (m, 4H), 2.03 (m, 1H), 1.74-1.62 (m, 3H), 1.18 (m, 2H), 0.86 (m, 9H ), 0.02 (s, 3H), 0.00 (s, 3H); ret time HPLC 3.54 min, CH3CN 10-99%, embodiment 5 min; ESI-MS 626.3 m / z (MH +).

N- (5 - ((R) - ((S) -3- (tert-Butyldimethylsilyloxy) pyrrolidin-1-yl) (2-chlorophenyl) methyl) -4-methylthiazol-2-yl) -1- (2, 2difluorobenzo [d] [1,3] dioxol-5-yl) cyclopropanecarboxamide and N- (5 - ((S) - ((S) -3- (tert-Butyldimethylsilyloxy) pyrrolidin-1-yl) (2-chlorophenyl) methyl) -4-methylthiazol-2-yl) -1- (2,2-difluorobenzo [d] [1,3] dioxol-5-yl) cyclopropanecarboxamide

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N- (5 - (((S) -3- (tert-Butyldimethylsilyloxy) pyrrolidin-1-yl) (2-chlorophenyl) methyl) -4-methylthiazol-2-yl) -1- (2,2- difluorobenzo [d] [1,3] dioxol-5-yl) cyclopropanecarboxamide (Isomer A) by the procedure used for 1 (benzo [d] [1,3] dioxol-5-yl) -N- (5 - (( (S) -3- (tert-Butyldimethylsilyloxy) pyrrolidin-1-yl) (2-chlorophenyl) methyl) -4-methylthiazol-2-yl) cyclopropanecarboxamide (Isomer A) starting from N- (5- (amino (2-chlorophenyl) methyl) -4-methylthiazol-2-yl) -1- (2,2difluorbenzo [d] [1,3] dioxol-5-yl) cyclopropanecarboxamide (Isomer A) and (S) -3- (tert-butyldimethylsilyloxy) - 4-chlorobutanal (73%). 1H NMR (400 MHz, CDCl3) δ 8.25 (s, 1H), 7.83 (dd, J = 8.1, 1.6 Hz, 1H), 7.28-7.25 (m, 2H) , 7.16-7.11 (m, 3H), 7.06 (d, J = 8.1 Hz, 1H), 5, 08 (s, 1H), 4.3 (m, 1H), 2, 94 (dd, J = 9.9, 6.2 Hz, 1H), 2.66 (td, J = 8.3, 3.7 Hz, 1H), 2.54 (c, J = 8.3 Hz , 1H), 2.36 (s, 3H), 2.18 (dd, J = 9.9, 4.7 Hz, 1H), 2.02 (m, 1H), 1.75 (m, 2H) , 1.65 (m, 1H), 1.20 (m, 2H), 0.86 (m, 9H), 0.01 (s, 3H), -0.01 (s, 3H); ret time HPLC 3.69 min, CH3CN 10-99%, embodiment 5 min; ESI-MS 662.1 m / z (MH +).

N- (5 - (((S) -3- (tert-Butyldimethylsilyloxy) pyrrolidin-1-yl) (2-chlorophenyl) methyl) -4-methylthiazol-2-yl) -1- (2,2- difluorobenzo [d] [1,3] dioxol-5-yl) cyclopropanecarboxamide (Isomer B) by the procedure used for 1 (benzo [d] [1,3] dioxol-5-yl) -N- (5 - (( (S) -3- (tert-Butyldimethylsilyloxy) pyrrolidin-1-yl) (2-chlorophenyl) methyl) -4-methylthiazol-2-yl) cyclopropanecarboxamide (Isomer A) starting from N- (5- (amino (2-chlorophenyl) methyl) -4-methylthiazol-2-yl) -1- (2,2difluorbenzo [d] [1,3] dioxol-5-yl) cyclopropanecarboxamide (Isomer B) and (S) -3- (tert-butyldimethylsilyloxy) - 4-chlorobutanal (93%). 1H NMR (400 MHz, CDCl3) δ 8.26 (s, 1H), 7.85 (dd, J = 8.1, 1.7 Hz, 1H), 7.28-7.24 (m, 2H) , 7.16-7.10 (m, 3H), 7.07 (d, J = 8.2 Hz, 1H), 5.05 (s, 1H), 4.34 (m, 1H), 2, 83 (dd, J = 9.7, 6.3 Hz, 1H), 2.55-2.47 (m, 2H), 2.36-2.33 (m, 4H), 2.04 (m, 1H), 1.79-1.63 (m, 3H), 1.21 (m, 2H), 0.86 (m, 9H), 0.02 (s, 3H), 0.00 (s, 3H ); ret time HPLC 3.73 min, CH3CN 10-99%, embodiment 5 min; ESI-MS 662.1 m / z (MH).

1- (Benzo [d] [1,3] dioxol-5-yl) -N- (5 - ((R) - ((R) -3- (tert-butyldimethylsilyloxy) pyrrolidin-1-yl) (3, 4-dichlorophenyl) methyl) thiazol2-yl) cyclopropanecarboxamide and 1- (Benzo [d] [1,3] dioxol-5-yl) -N- (5 - ((S) - ((R) -3- (tert) -butyldimethylsilyloxy) pyrrolidin-1-yl) (3,4-dichlorophenyl) methyl) thiazol-2-yl) cyclopropanecarboxamide

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1- (benzo [d] [1,3] dioxol-5-yl) -N- (5 - (((R) -3- (tert-butyldimethylsilyloxy) pyrrolidin-1-yl) (3,4- dichlorophenyl) methyl) thiazol-2il) cyclopropanecarboxamide (Isomer A) by the procedure used for 1- (benzo [d] [1,3] dioxol-5-yl) -N- (5 - (((S) -3 ( tert-butyldimethylsilyloxy) pyrrolidin-1-yl) (2-chlorophenyl) methyl) -4-methylthiazol-2-yl) cyclopropanecarboxamide (Isomer A) starting from N- (5- (amino (3,4-dichlorophenyl) methyl) thiazole -2-yl) -1- (benzo [d] [1,3] dioxol-5-yl) cyclopropanecarboxamide (Isomer A) and (R) -3- (tert-butyldimethylsilyloxy) -4-chlorobutanal (85%). 1H NMR (400 MHz, CDCl3) δ8.47 (s, 1H), 7.51 (d, J = 2.0 Hz, 1H), 7.35 (d, J = 8.3 Hz, 1H), 7 , 30 (dd, J = 2.0, 8.3 Hz, 1H), 7.19 (s, 1H), 6.90 -6.85 (m, 2H), 6.80 (d, J = 7 , 9 Hz, 1H), 6.01 (s, 2H), 4.47 (s, 1H), 4.34 (m, 1H), 2.84 (dd, J = 6.2, 9.8 Hz , 1H), 2.55 -2.44 (m, 2H), 2.31 (dd, J = 4.4.9.9 Hz, 1H), 2.17 (s, 1H), 1.73 - 1.64 (m, 3H), 1.26-1.19 (m, 2H), 0.91 (s, 3H), 0.86 (s, 6H), 0.02 (s, 6H); ret time HPLC 3.66 min, CH3CN 10-99%, embodiment 5 min; ESI-MS 646.5 m / z (MH +).

1- (benzo [d] [1,3] dioxol-5-yl) -N- (5 - (((R) -3- (tert-butyldimethylsilyloxy) pyrrolidin-1-yl) (3,4- dichlorophenyl) methyl) thiazol-2il) cyclopropanecarboxamide (Isomer B) by the procedure used for 1- (benzo [d] [1,3] dioxol-5-yl) -N- (5 - ((((S) -3) tert-butyldimethylsilyloxy) pyrrolidin-1-yl) (2-chlorophenyl) methyl) -4-methylthiazol-2-yl) cyclopropane-carboxamide (Isomer A) starting from N- (5- (amino (3,4-dichlorophenyl) methyl ) thiazol-2-yl) -1- (benzo [d] [1,3] dioxol-5-yl) cyclopropanecarboxamide (Isomer B) and (R) -3- (tert-butyldimethylsilyloxy) -4-chlorobutanal (70% ). 1H NMR (400 MHz, CDCl3) δ 8.47 (s, 1H), 7.50 (d, J = 2.0 Hz, 1H), 7.36 (d, J = 8.3 Hz, 1H), 7.29 (dd, J = 2.0, 8.3 Hz, 1H), 7.19 (s, 1H), 6.90 -6.85 (m, 2H), 6.80 (d, J = 7.9 Hz, 1H), 6.01 (s, 2H), 4.51 (s, 1H), 4.34 (m, J = 3.4, 9.4 Hz, 1H), 2.88 ( dd, J = 6.2, 10.0 Hz, 1H), 2.67 2.62 (m, 1H), 2.53 (dd, J = 8.2, 16.7 Hz, 1H), 2, 17 (dd, J = 4.4, 10.0 Hz, 1H), 2.07 -1.78 (m, 1H), 1.75 -1.63 (m, 3H), 1.22 1.18 (m, 2H), 0.86 (d, J = 2.5 Hz, 9H), 0.01 (m, 6H); ret time HPLC 3.67 min, CH3CN 10-99%, embodiment 5 min; ESI-MS 646.4 m / z (MH +).

1- (Benzo [d] [1,3] dioxol-5-yl) -N- (5 - ((R) - (2-chlorophenyl) ((S) -3-hydroxypyrrolidin-l-yl) methyl) - 4-methylthiazol-2il) cyclopropanecarboxamide and 1- (Benzo [d] [1,3] dioxol-5-yl) -N- (5 - ((S) - (2-chlorophenyl) ((S) -3-hydroxypyrrolidine -1il) methyl) 4-methylthiazol-2-yl) cyclopropanecarboxamide

image 1

A mixture of 1- (benzo [d] [1,3] dioxol-5-yl) -N- (S - (((S) -3- (tert-butyldimethylsilyloxy) pyrrolidin-1-yl) (2-chlorophenyl ) methyl) -4-methylthiazol-2-yl) cyclopropanecarboxamide (Isomer A) (400 mg, 0.64 mmol) and TBAF (1 M in THF, 3.84 ml, 3.84 mmol) was stirred at room temperature for 5 h . The reaction was partitioned between H2O and EtOAc. The combined organic phases were washed with brine, dried over MgSO4 and concentrated. The residue was absorbed on silica gel and purified by column chromatography (25-75% EtOAc / hexanes) to provide 1 (benzo [d] [1,3] dioxol-5-yl) -N- (5- ((2-Chlorophenyl) ((S) -3-hydroxypyrrolidin-1-yl) methyl) -4-methylthiazol-2-yl) cyclopropanecarboxamide (Isomer A) in the form of a pale yellow solid (245 mg, 75%,> 99% of ed). 1H NMR (400 MHz, CDCl3) δ 8.41 (s, 1H), 7.85 (dd, J = 8.1, 1.7 Hz, 1H), 7.29-7.26 (m, 2H) , 7.14 (m, 1H), 6.88-6.84 (m, 2H), 6.79 (d, J = 7.9 Hz, 1H), 6.00 (s, 2H), 5, 07 (s, 1H), 4.30 (m, 1H), 2.79 (td, J = 8.6, 5.8 Hz, 1H), 2.63-2.56 (m, 2H), 2 , 36 (s, 3H), 2.29 (td, J = 9.0, 5.9 Hz, 1H), 2.15 (m, 1H), 1.85 (d, J = 7.9 Hz, 1H), 1.78-1.65 (m, 3H), 1.18 (m, 2H); ret time HPLC 2.70 min, CH3CN 10-99%, embodiment 5 min; ESI-MS 512.5 m / z (MH +).

1- (benzo [d] [1,3] dioxol-5-yl) -N- (5 - ((2-chlorophenyl) ((S) -3-hydroxypyrrolidin-1-yl) methyl) -4- methylthiazol-2il) cyclopropanecarboxamide (Isomer B) by the procedure used for (Isomer A) starting from 1 (benzo [d] [1,3] dioxol-5-yl) -N- (5 - (((S) -3 - (tert-Butyldimethylsilyloxy) pyrrolidin-1-yl) (2-chlorophenyl) methyl) -4-methylthiazol-2-yl) cyclopropanecarboxamide (Isomer B) (50%,> 99% ed). 1H NMR (400 MHz, CDCl3) δ 8.44 (s, 1H), 7.84 (dd, J = 7.8, 1.5 Hz, 1H), 7.29-7.25 (m, 2H) , 7.14 (td, J = 7.6, 1.7 Hz, 1H), 6.88-6.84 (m, 2H), 6.79 (d, J = 7.9 Hz, 1H), 6.00 (s, 2H), 5.07 (s, 1H), 4.29 (m, 1H), 2.83 (td, J = 8.6, 5.0 Hz, 1H), 2.61 (d, J = 10.1 Hz, 1H), 2.49 (m, 1H), 2.36-2.29 (m, 4H), 2.17 (m, 1H), 1.89 (d, J = 7.9 Hz, 1H), 1.76-1.66 (m, 3H), 1.19 (m, 2H); ret time HPLC 2.71 min, 10-99% CH3CN, embodiment 5 min; ESI-MS 512.5 m / z (MH +).

5

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twenty

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30

35

40

N- (5 - ((R) - (2-Chlorophenyl) ((S) -3-hydroxypyrrolidin-1-yl) methyl) -4-methylthiazol-2-yl) -1- (2,2-difluorobenzo [d ] [1,3] dioxol-5il) cyclopropanecarboxamide and N- (5 - ((S) - (2-Chlorophenyl) ((S) -3-hydroxypyrrolidin-1-yl) methyl) -4-methylthiazol-2-yl ) -1- (2,2-difluorobenzo [d] [1,3] dioxol-5-yl) cyclopropanecarboxamide

image 1

N- (5 - ((2-chlorophenyl) ((S) -3-hydroxypyrrolidin-1-yl) methyl) -4-methylthiazol-2-yl) -1- (2,2-difluorobenzo [d] [ 1,3] dioxol-5il) cyclopropanecarboxamide (Isomer A) by the procedure used for 1- (benzo [d] [1,3] dioxol-5-yl) -N- (5 - ((2-chlorophenyl) ((S) -3-hydroxypyrrolidin-1-yl) methyl) -4-methylthiazol-2-yl) cyclopropanecarboxamide (Isomer A) starting from N- (5 (((S) -3- (tert-Butyldimethylsilyloxy) pyrrolidin-1-yl) (2-Chlorophenyl) methyl) -4-methylthiazol-2-yl) -1- (2,2-difluorobenzo [d] [1,3] dioxol-5yl) cyclopropanecarboxamide (Isomer A) (72%). 1H NMR (400 MHz, CDCl3) δ 8.28 (s, 1H), 7.84 (dd, J = 8.1, 1.7 Hz, 1H), 7.30-7.26 (m, 2H) , 7.17-7.12 (m, 3H), 7.07 (d, J = 8.2 Hz, 1H); 5.07 (s, 1H), 4.30 (m, 1H), 2.79 (td, J = 8.6, 5.7 Hz, 1H), 2.62-2.55 (m, 2H) , 2.35 (s, 3H), 2.28 (td, J = 9.0, 5.9 Hz, 1H), 2.15 (m, 1H), 1.86 (d, J = 7.9 Hz, 1H), 1,801.71 (m, 3H), 1.21 (m, 2H); ret time HPLC 2.91 min, 10-99% CH3CN, embodiment 5 min; ESI-MS 548.3 m / z (MH +).

N- (5 - ((2-chlorophenyl) ((S) -3-hydroxypyrrolidin-1-yl) methyl) -4-methylthiazol-2-yl) -1- (2,2-difluorobenzo [d] [ 1,3] dioxol-5il) cyclopropanecarboxamide (Isomer B) by the procedure used for 1- (benzo [d] [1,3] dioxol-S-yl) -N- (5 - ((2-chlorophenyl) ((S) -3-hydroxypyrrolidin-1-yl) methyl) -4-methylthiazol-2-yl) cyclopropanecarboxamide (Isomer A) starting from N- (5 (((S) -3- (tert-Butyldimethylsilyloxy) pyrrolidin-1-yl) (2-Chlorophenyl) methyl) -4-methylthiazol-2-yl) -1- (2,2-difluorobenzo [d] [1,3] dioxol-5yl) cyclopropanecarboxamide (Isomer B) (85%). 1H NMR (400 MHz, CDCl3) δ 8.28 (s, 1H), 7.82 (dd, J = 7.7, 1.5 Hz, 1H), 7.30-7.25 (m, 2H) , 7.14 (m, 3H), 7.07 (d, J = 8.2 Hz, 1H), 5.07 (s, 1H), 4.29 (m, 1H), 2.83 (td, J = 8.7, 5.1 Hz, 1H), 2.61 (d, J = 10.0 Hz, 1H), 2.50 (dd, J = 10.1, 5.1 Hz, 1H), 2.36-2.29 (m, 4H), 2.17 (m, 1H), 1.88 (d, J = 7.8 Hz, 1H), 1.82-1.70 (m, 3H) , 1.22 (m, 2H); ret time HPLC 2.94 min, 10-99% CH3CN, embodiment 5 min; IENEM 548.3 m / z (MH +).

1- (Benzo [d] [1,3] dioxol-5-yl) -N- (5 - ((R) - (3,4-dichlorophenyl) ((R) -3-hydroxypyrrolidin-1-yl) methyl ) thiazol-2il) cyclopropanecarboxamide and 1- (Benzol [d] [1,3] dioxol-5-yl-N- (5 - ((S) - (3,4-dichlorophenyl) ((R) -3-hydroxypyrrolidin -1il) methyl) thiazol-2-yl) cyclopropanecarboxamide

image 1

1- (benzo [d] [1,3] dioxol-5-yl) -N- (5 - ((3,4-dichlorophenyl) ((R) -3-hydroxypyrrolidin-1-yl) methyl) thiazole was prepared -2il) cyclopropanecarboxamide (Isomer A) by the procedure used for 1- (benzo [d] [1,3] dioxol-5-yl) -N- (5 - ((2-chlorophenyl) ((S) -3-hydroxypropyl solidin- 1-yl) methyl) -4-methylthiazol-2-yl) cyclopropanecarboxamide (Isomer A) starting from 1 (benzo [d] [1,3] dioxol-5-yl) -N- (5 - (((R) -3- (tert-Butyldimethylsilyloxy) pyrrolidin-1-yl) (3,4-dichlorophenyl) methyl) thiazol-2-yl) cyclopropanecarboxamide (Isomer A) The crude product was purified by column chromatography (6090% EtOAc / Hexane) (74%, 98% ed). 1H NMR (400 MHz, CDCl3) δ 8.49 (s, 1H), 7.50 (d, J = 2.0 Hz, 1H), 7.37 (d, J = 8.3 Hz, 1H), 7.31 (dd, J = 2.0, 8.3 Hz, 1H), 7.20 (s, 1H), 6.90 -6.86 (m, 2H), 6.81 (d, J = 7.9 Hz, 1H), 6.01 (s, 2H), 4.48 (s, 1H), 4.32 (m, 1H), 2.82-2.76 (m, 1H), 2, 59 -2.57 (m, 1H), 2.51 (c, J = 5.1 Hz, 1H), 2.33 (td, J = 8.9, 6.1 Hz, 1H), 2.16 (dd, J = 5.3, 12.5 Hz, 1H), 1.81 -1.69 (m, 4H), 1.22 (dd, J = 5.0, 7.6 Hz, 2H); ret time HPLC 2.81 min, CH3CN 10-99%, embodiment 5 min; ESI-MS 532.2 m / z (MH +).

1- (benzo [d] [1,3] dioxol-5-yl) -N- (5 - ((3,4-dichlorophenyl) ((R) -3-hydroxypyrrolidin-1-yl) methyl) thiazole was prepared -2il) cyclopropanecarboxamide (Isomer B) by the procedure used for (Isomer A) starting from 1 (benzo [d] [1,3] dioxol-5-yl) -N- (5 - (((R) -3- (tert-Butyldimethylsilyloxy) pyrrolidin-1-yl) (3,4-dichlorophenyl) methyl) thiazol-2-yl) cyclopropanecarboxamide (Isomer B) (78%, 95% ed). 1H NMR (400 MHz, CDCl3) δ 8.49 (s, 1H), 7.52 (d, J = 2.0 Hz, 1H), 7.37 (d, J = 8.3 Hz, 1H), 7.30 (dd, J = 2.0, 8.3 Hz, 1H), 7.20 (s, 1H), 6.90 -6.86 (m, 2H), 6.81 (d, J = 7.9 Hz, 1H), 6.01 (s, 2H), 4.48 (s, 1H), 4.34 -4.32 (m, 1H), 2.76 (td, J = 8.5 , 6.0 Hz, 1H), 2.57 (m, 2H), 2.29 (m, 1H), 2.15 (c, J = 7.2 Hz, 1H), 1.81 -1.68 (m, 4H), 1.25-1.20 (m, 2H); ret time HPLC 2.80 min, CH3CN 10-99%, embodiment 5 min; ESI-MS 532.2 m / z (MH +).

Tests to detect and measure the correction properties of ΔF508-CFTR of compounds

I) optical membrane potential Procedures for assaying AF508 modulating properties of compounds-CFTR

The membrane potential optical 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): 269-77), in combination with instrumentation to measure fluorescence changes such as the 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).

These voltage-sensitive assays are based on the change in fluorescence resonance energy transfer (FRET) between the voltage-sensitive dye in the DiSBAC2 membrane (3) and a fluorescent phospholipid, CC2-DMPE, which binds to the outer leaf of the plasma membrane and acts as a donor of FRET. Changes in membrane potential (Vm) cause the negatively charged DiSBAC2 (3) to be redistributed through the plasma membrane and that the amount of energy transfer of CC2-DMPE changes accordingly. Changes in fluorescence emission were controlled using VIPR ™ II, which is a liquid manipulator and integrated fluorescent detector designed to perform cell-based scans on 96 or 384 well microtiter plates.

Cell culture

NIH3T3 mouse fibroblasts stably expressing AF508-of CFTR for optical measurements of membrane potential are used. The cells are maintained at 37 ° C in 5% CO2 and a humidity of 90% in Dulbecco's modified Eagle medium supplemented with 2 mM glutamine, 10% fetal bovine serum, 1 X AANE, β-ME, pen / strep 1 X and 25 mM HEPES in 175 cm2 culture flasks. For all optical assays, the cells were seeded at 30,000 / well in 384 well matrigel coated plates, and cultured for 2 h at 37 ° C before culturing at 27 ° C for 24 h for the enhancer assay. For correction assays, cells are cultured at 27 ° C or 37 ° C with and without compounds for 16-24 hours.

B) Electrophysiological tests to test the modulation properties of ΔF508-CFTR of compounds

1. Ussing camera test

Ussing chamber experiments were performed on polarized epithelial cells expressing ΔF508-CFTR to further characterize the ΔF508-CFTR modulators identified in the optical assays. FRΔF508-CFTR epithelial cells cultured in Costar Snapwell cell culture separators were mounted in a Ussing chamber (Physiologic Instruments, Inc., San Diego, CA), and the monolayers were continuously short-circuited using a voltage clamp system (Department of Bioengineering, University of Iowa, IA, and Physiologic Instruments, Inc., San Diego, CA). Transepithelial resistance was measured by applying a pulse of 2 mV. Under these conditions, the FRT epithelia showed resistance of 4 KΩ / cm2 or more. The solutions were kept at 27 ° C and with air bubble application. The electrode compensation potential and fluid resistance were corrected using a cellless separator. Under these conditions, the current reflects the flow of Cl-through AF508-CFTR of expressed in the apical membrane. The ISC was acquired digitally using an MP100A-CE interface and AcqKnowledge software (v3.2.6; BIOPAC Systems, Santa Barbara, CA).

Identification of correction compounds

The typical protocol used a concentration gradient of Cl - from basolateral to apical membrane. To establish this gradient, normal Ringer was used in the basolateral membrane, while the apical NaCl was replaced by equimolar sodium gluconate (adjusted to pH 7.4 with NaOH) to give a large gradient of Cl-concentration through the epithelium. All experiments were performed with intact monolayers. To fully activate the ΔF508-CFTR, forskolin (10 µM) and the PDE inhibitor, IBMX (100 µM) were applied, followed by the addition of the CFTR enhancer, genistein (50 µM).

As observed 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 the correction compounds, the cells were incubated with 10 µM of the test compound for 24 hours at 37 ° C and subsequently washed 3X before registration. The cAMP and genistein-mediated ISC in cells treated with compound was normalized with respect to the 27 ° C and 37 ° C controls and expressed as a percentage activity. Preincubation of the cells with the correction compound significantly increased the cAMP and genistein-mediated ISC compared to the 37 ° C controls.

To determine the activity of the correction compounds to increase the density of functional ΔF508-CFTR in the plasma membrane, the present inventors used the perforated zone recording techniques described above to measure the current density after a 24 h treatment with Correction compounds To fully activate AF508-CFTR the was added forskolin and genistein 10 uM at 5 uM 20 cells. Under the recording conditions of the present inventors, the current density after a 24 h incubation at 27 ° C was higher than that observed after a 24 h incubation at 37 ° C. These results are consistent with the known effects of low temperature incubation on the density of the plasma membrane ΔF508CFTR. To determine the effects of the correction compounds on the CFTR current density, the cells were incubated with 10 µM of the test compound for 24 hours at 37 ° C and the

The current density was compared with the controls of 27 ° C and 37 ° C (% activity). Prior to registration, the cells were washed 3X with extracellular recording medium to remove any remaining test compound. Preincubation with 10 uM of compounds correction significantly increased the cAMP-dependent current compared to genistein and controls 37 ° C.

Table 3 illustrates the EC50 and the relative efficacy of exemplary embodiments of the present invention. In Table 3, 15 the following meanings apply:

EC50: "+++" means <2 uM; "++" means between 2 uM and 20 µM; "+" means between 25 uM and 60 uM.

% Efficiency: "+" means <25%; "++" means between 25% and 100%; "+++" means> 100%.

Table 3

Comp. No.

EC 50 % Efficiency

one

+++ +++

2

++ +++

3

+++ +++

4

+++ +++

5

+++ +++

6

+++ +++

7

+++ +++

8

+++ +++

9

+++ +++

10

+++ +++

eleven

+++ +++

12

+++ ++

13

+++ +++

20 As illustrated in Table 3 above, the compounds of the present invention exhibit unexpectedly better correction activity as measured by the above tests.

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Claims (61)

1. A compound of formula I or formula II: that the two RXs are not simultaneously hydrogen; or the two RXs taken together form the ring (a): image 1 X is CH2, CF2, CH2-CH2 or CF2-CF2; Ring A is a 3-7 membered monocyclic cycloalkyl ring; AA and R BB, taken together with the nitrogen atom, form a pyrrolidinyl ring substituted with OR '; R 'is hydrogen or C1-C6 aliphatic, wherein up to two carbon units of said aliphatic are optionally and independently replaced by -CO-, -CS-, -COCO-, -CONR-, -CONRNR-, -CO2-, -OCO-, -NRCO2-, -O, -NRCONR-, -OCONR-, -NRNR, - NRNRCO-, -NRCO-, -S-, -SO, -SO2-, -NR-, -SO2NR-NRSO2-or -NRSO2NR-; R is hydrogen or C1-C6 aliphatic; Z is halo, CN, COOH, CF3 or difluoromethylenedioxy; Y q is 0-3.

2.

The compound according to claim 1, wherein two RX taken together form ring (a) and X is CH2.

3.

The compound according to claim 1, wherein two RX taken together form ring (a) and X is CF2.

Four.

The compound according to claim 1, wherein one Rx is hydrogen and the other RX is halo, CF3, C1-C4 alkyl or -O-C1-C4 alkyl.

5.

The compound according to claim 1, wherein one RX is hydrogen and the other RX is 4-methoxy.

6.

The compound according to any one of claims 1-5, wherein ring A is cyclopropyl, cyclopentyl or cyclohexyl.

7.

The compound according to claim 6, wherein ring A is cyclopropyl or cyclopentyl.

8.

The compound according to claim 6, wherein the ring A is cyclopropyl.

9.

The compound according to any one of claims 1-8, wherein R 'is hydrogen.

10.

The compound according to any one of claims 1-8, wherein R 'is C1-6 alkyl.

eleven.

The compound according to any one of claims 1-10, wherein RAA and RBB, taken together, form a pyrrolidinyl with an OH substituent.

12.

The compound according to any one of claims 1-11, wherein Z is selected from halo, CF3 or difluoromethylenedioxy.

13.

The compound according to any one of claims 1-12, wherein q is 0.

14.

The compound according to any one of claims 1-12, wherein q is 1.

fifteen.

The compound according to any one of claims 1-14, wherein R is hydrogen.

16.

The compound according to any one of claims 1-12 or 14, wherein compounds of formula

67 image2 I or of formula II comprise one or more, and preferably all of the following characteristics: two RXs taken together form the ring (a); X is CH2; ring A is cyclopropyl; R is hydrogen; q is 1; Y Z is halo, CF3 or difluoromethylenedioxy.

17.

The compound according to any one of claims 1-16, wherein RAA and RBB in formula I, taken together with the nitrogen atom, form the following ring (i):

18.

The compound according to any one of claims 1-16, wherein RAA and RBB in formula I, taken together with the nitrogen atom, form the following ring (ii):

19.

A compound selected from

twenty.

A pharmaceutical composition comprising:

(i)

a compound according to any one of claims 1-19; Y

(ii)

a pharmaceutically acceptable vehicle.

image 1 image 1 image 1 image 1 The composition of claim 20, optionally further comprising an additional agent selected from a mucolytic agent, a bronchodilator, an antibiotic, an anti-infective agent, an anti-inflammatory agent, a CFTR enhancer or a CFTR corrector other than a compound of the present invention, or a nutritional agent. 22. A method of increasing the number of functional CFTRs in a cell membrane in vitro, which 10 comprises the step of contacting said cell with a compound according to any one of claims 1-19. 23. A kit for use in the measurement of CFTR activity or a fragment thereof in a biological sample in vitro or in vivo, comprising: (i) a first composition comprising a compound according to any one of claims 1-19; Y (ii) instructions for: a) contacting the composition with the biological sample; b) measure the activity of said CFTR or a fragment thereof. 24. The kit according to claim 23, further comprising instructions for a) contacting an additional composition with the biological sample; b) measuring the activity of said CFTR or a fragment thereof in the presence of said additional compound, and c) compare the activity of the CFTR in the presence of the additional compound with the density of the CFTR in presence of said first composition. 25. The kit according to claim 24, wherein the kit is used to measure the density of CFTR. 5 10 fifteen

26.

The use of a compound according to any one of claims 1-19 in the manufacture of a medicament for treating a condition, disease or disorder in a patient in which the CFTR is involved.

27.

The use according to claim 26, wherein said condition, disease or disorder is selected from cystic fibrosis, hereditary emphysema, hereditary hemochromatosis, coagulation-fibrinolysis deficiencies, such as protein C deficiency, hereditary Type 1 angioedema , lipid processing deficiencies, such as familial hypercholesterolemia, Type 1 chylomicronemia, abetalipoproteinemia, lysosomal storage diseases, such as cell I / pseudo-Hurler disease, mucopolysaccharidosis, Sandhof / Tay-Sachs, Crigler-Najjar type II, polyocrinopathy / hyperinsulinemia, diabetes mellitus, Laron dwarfism, myeloperoxidase deficiency, primary hypoparathyroidism, melanoma, CDG type 1 glucanosis, hereditary emphysema, congenital hyperthyroidism, osteogenesis imperfecta, hereditary hypofibrinogenemia, DI deficiency (DI), diabetes insipidus (DI), diabetes insipidus neurophysal, nephrogenic DI, Charcot-Marie Tooth syndrome, nurse dad of Perlizaeus-Merzbacher, neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, progressive supranuclear paralysis, Pick's disease, Huntington, spinocerebelar ataxia type I, spinal and bulbar muscular atrophy, atrophy Palidoluisian dentatorubrub and myotonic dystrophy, spongiform encephalopathies, such as hereditary Creutzfeldt-Jakob disease (due to a defect in prion protein processing), Fabry disease, Straussler-Scheinker disease, secretory diarrhea, polycystic kidney disease , chronic obstructive pulmonary disease (COPD), dry eye disease or Sjögren's syndrome.

28.

A compound having the formula I 'or the formula II':

image3 in which: RX, ring A, Z and q are as defined in claim 1; L is a linker selected from C (O) or SO2; p is 0 or 1; CA is a suitable chiral auxiliary.

29.

The compound according to claim 28, wherein CA, L, p and the oxygen atom attached to them, taken together, are (+) - 10-camphorsulfonate, ester (1S, 4R) - (-) - ω- canphanic, (1R, 2S, 5R) - (-) - menthol carbonate, (1S, 2R, 5S) - (+) - mentholcarbonate, (1R, 2R) -1-phenyl-2-cyclopropyl ester or (3R) -tetrahydrofuran- 3-carbonate

30

A process for producing a compound of formula I or formula II:

image4 comprising the step of reacting under a suitable first conditions a compound of formula R1 with a compound of formula I-A to produce said compound of formula I, or a compound of formula II-A to produce said compound of formula II: image 1 5 10 fifteen twenty 25 30 in which: each RX is independently hydrogen, halo, CF3, C1-C4 alkyl or -O-C1-C4 alkyl; with the proviso that the two RXs are not simultaneously hydrogen; or the two RXs taken together form the ring (a): image 1 X is CH2, CF2, CH2-CH2 or CF2-CF2; Ring A is a 3-7 membered monocyclic cycloalkyl ring; AA and R BB, taken together with the nitrogen atom, form a pyrrolidinyl ring substituted with OR '; R 'is hydrogen or C1-C6 aliphatic, wherein up to two carbon units of said aliphatic are optionally and independently replaced by -CO-, -CS-, -COCO-, -CONR-, -CONRNR-, -CO2-, -OCO-, -NRCO2-, -O, -NRCONR-, -OCONR-, -NRNR, - NRNRCO-, -NRCO-, -S-, -SO, -SO2-, -NR-, -SO2NR-NRSO2-or -NRSO2NR-; R is hydrogen or C1-C6 aliphatic; Z is an electron extraction substituent; Y q is 0-3; Y LG1 is a suitable first outgoing group.

31.

The process according to claim 30, wherein LG1 is selected from sulfonate alkyl, aryl sulfonate, halide, alkylcarboxylate.

32

The process according to claim 30, wherein said first suitable conditions comprise a suitable first solvent, a suitable first temperature and a suitable reducing agent.

33.

The process according to claim 32, wherein said first suitable solvent is a polar or apolar, protic or aprotic solvent.

3. 4.

The process according to claim 33, wherein said solvent is selected from methanol, ethanol, propanol, isopropanol, tert-butanol, dichloromethane, dichloroethane, toluene, tetrahydrofuran, dioxane, diethyl ether, dimethyl ether, acetonitrile, DMF, DMAC or NMP.

35

The process according to claim 32, wherein said first suitable temperature is between about 0 ° C and about 110 ° C.

36.

The process according to claim 32, wherein said suitable reducing agent is a metalloborohydride or an agent that can undergo catalytic hydrogenation.

37.

The process according to claim 36, wherein said suitable reducing agent is selected from sodium borohydride, sodium cyanoborohydride, lithium borohydride, sodium triacetoxyborohydride, calcium borohydride, hydrogen in the presence of a transition metal catalyst.

38.

The process according to claim 30, wherein said compound of formula I-A and formula II-A is produced from formula I-B or formula II-B, respectively:

image 1 in which [CA] is a suitable chiral auxiliary; said method comprising the step of removing said chiral auxiliary under second conditions adequate. The method according to claim 38, wherein said suitable chiral auxiliary is an alkylsulfoxyl group. 40. The method according to claim 38, wherein said second suitable conditions comprise a suitable protic acid and a suitable second solvent. 41. The method according to claim 40, wherein said second suitable solvent is selected from a polar aprotic solvent or a protic solvent.

42

The process according to claim 41, wherein said second suitable solvent is a polar aprotic solvent.

43

The process according to claim 42, wherein said polar aprotic solvent is selected from dioxane, tetrahydrofuran, diethyl ether or dichloromethane.

The method according to claim 38, wherein said compound of formula IB and formula II-B is produced by reacting, respectively, a compound of formula IC or of formula II-C with a compound of formula R -2 under appropriate third conditions: image 1 20 in which: R1 is hydrogen or a suitable first protecting group; [CA] is a suitable chiral auxiliary; Y LG2 is a second suitable outgoing group. 45. The process according to claim 44, wherein LG2 is selected from halide, OC (O) alkyl, pentafluorophenoxy, alkoxy, OCO2alkyl or hydroxy.

46.

The process according to claim 44, wherein R1 is hydrogen.

47

The process according to claim 44, wherein said suitable third conditions comprise a suitable third coupling agent and a suitable third solvent.

48.

The method according to claim 47, wherein said suitable coupling agent is selected from triethylamine, pyridine, DIEA, lutidine, HATU, TCPH or HBTU.

49.

The process according to claim 47, wherein said third suitable solvent is selected from dichloromethane, dioxane, DMF, dichloroethane or tetrahydrofuran.

fifty.

The process according to claim 44, wherein said compound of formula I-C or of formula II-C is produced from an isomeric mixture of a compound of formula R-3:

image 1 in which: PG1 is a second suitable protecting group; and 10 [CA] is a suitable chiral auxiliary; said process comprising two stages, in which one of said two stages is to separate said isomeric mixture using suitable separation means, and the other of said two stages is the conversion of PG1 to R1 under suitable fourth conditions. 51. The method according to claim 50, wherein said suitable separation means comprise suitable chromatographic means.

52

The method according to claim 51, wherein said suitable chromatographic means are selected from column chromatography or thin layer chromatography.

53.

The method according to claim 50, wherein said suitable separation means comprise crystallization processes.

The method according to claim 50, wherein said fourth suitable conditions comprise a suitable deprotection reagent and a suitable fourth solvent. 55. The method according to claim 54, wherein said suitable deprotection reagent is trifluoroacetic acid. 56. The method according to claim 54, wherein said fourth suitable solvent is an apolar aprotic solvent.

57.

The process according to claim 56, wherein said polar aprotic solvent is dichloromethane.

58.

The process according to claim 50, wherein said compound of formula R-3 is produced from a compound of formula R-4 and a compound of formula R-5:

image 1 30 in which: PG1 is a second suitable protecting group; M is a suitable metal cation; Y [CA] is a suitable chiral auxiliary; said process comprising the steps of reacting said compound of formula R-4 with said compound of formula R-5 under suitable fifth conditions.

59.

The method according to claim 58, wherein said M is selected from Li +, Na + or Mg ++.

60

The process according to claim 58, wherein PG1 is selected from an alkylcarbamate, trifluoroacetyl, trialkylsilyl or pivaloyl.

61.

The process according to claim 60, wherein said PG1 is BOC or trimethylsilyl.

The method according to claim 58, wherein said fifth suitable conditions comprise a suitable fifth solvent and a suitable fifth temperature. 63. The method according to claim 62, wherein said suitable temperature is approximately -78 ° C. 64. The method according to claim 62, wherein said fifth suitable solvent is tetrahydrofuran.

65

The process according to claim 30, wherein said compound of formula R-1 is

66.

The process according to claim 30, wherein said compound of formula I or formula II is selected from