ES2719790T3 - N-Substituted-5 Phthalamic Acids Substituted as Sortilin Inhibitors - Google Patents

Abstract

A compound of the formula A ** Formula ** wherein R1 represents H or F, R2 represents halogen, C1-C6 alkyl, C2-C6 alkenyl or halogenated C1-C6 alkyl, R3 represents halogen, H, C1-C6 alkyl, or halogenated C1-C6 alkyl, L is a direct bond or represents CH2, R4 is selected from the group comprising ** Formula ** optionally substituted with C≡N, 1 or 2 C1-C3 alkyls, 1 or 2 halogenated alkyls, 1 or 2 C1-C3 or 1 or 2 halogen alkoxy, X represents C or N, where N is present in 1 or 2 positions and * indicates the point of attachment, and pharmaceutically acceptable salts thereof.

Description

DESCRIPTION

N-Substituted-5 Phthalamic Acids Substituted as Sortilin Inhibitors

Field of the Invention

The present invention relates to certain substituted N-substituted-5 phthalamic acids that are inhibitors of the sortilin receptor and, therefore, are useful in therapy and pharmaceutical compositions comprising said compounds.

Background of the invention

Sortilin (also called NTR-3 or GP95) is a type I membrane receptor that belongs to the family of the Vps10p domain (vacuolar protein selection protein 10) of selection receptors (Willnow et al, Nat Rev Neurosci, 12 : 899-909 (2008)) which also includes SorLA, SorCS1, SorCS2 and SorCS3. The Vps10p family shares the Vps10p extracellular domain of approximately 700 amino acids, originally identified as a selection receptor in Saccharomyces cerevisiae, which in the sortilina covers all the extracellular part that forms the so-called 10-sheet beta propellant, whose structure has been published ( Quistgaard et al, Nat Struct Mol Biol, 1: 96-8 (2009)). Sortilin is widely expressed in the central and peripheral nervous system in neurons, as well as in other tissues and cells including the liver, heart, testicles, uterus, kidney, skeletal muscle, T cells, B cells and NK cells (Petersen et al., J. Biol. Chem., 272: 3599-3605 (1997); Herman-Borgmeyer et al., Mol. Brain Res., 65: 216-219 (1999)). Herda et al, Immunity, 37 (5): 854-66 (2012)). Only a small fraction of the protein is expressed on the cell surface, while an estimated 90% is located intracellularly, although the distribution of the spellin may be regulated by ligand interactions. It has been shown that the average sortiline in the pro-apoptotic effects of pro-neurotrophins, including pro-NGF, proNT3 and pro-BDNF which, through binding to a P75-spellin complex, induces degeneration and cell death in cell and animal models of a series of neurodegenerative disorders (Nykjaer et al, Nature, 427 (6977): 843-8 (2004)). In addition, the average spellin in traffic and in the selection of neurotrophin receptors and is also a regulator of proBDNF secretion (Evans et al, J Biol Chem, 86 (34): 29556-67 (2011)). Therefore, sortiline is considered a key regulator of the balance between the generally opposite effects of mature neurotrophins and neurotrophin pro-forms. It has been suggested to take sortiline-P75-mediated apoptosis as a protective mechanism in neurodegenerative disorders based on studies in cellular and animal models related to acute and chronic neurodegenerative conditions. Specifically, it has been suggested that spellin has beneficial effects on pain since it has been found that knockout mice with sortiline are protected in a pain model from preserved nerve injury (Nykjaer et al, WO 2009/155932 A2).

In addition to pro-neurotrophins, several binding partners for the sortiline have been identified. Sortilin has been shown to be a neurotensin neuropeptide receptor (Mazella et al, J Biol Chem., 273 (41): 26273-6 (1998)), and more recently it also functions as a receptor for programnulin (PGRN ) (Hu et al, Neuron, 68 (4): 654-67, (2010), Carrasquillo et al., Am J Hum Genet, 87 (6): 890-7 (2010)). The neurotensin and programnulin binding sites have been characterized and have been shown to be located in the same amino acids (Hu et al, Neuron, 68 (4): 654-67, (2010), Quistgaard et al., Nat Struct Mol Biol, 1: 96-8 (2009), Zheng et al, PLoS One. 2011; 6 (6): e21023 (2011), while it has been suggested that the pro-neurotrophin binding site is located at one site separated from the neurotensin binding site (Serup Andersen et al., J Biol Chem. 285 (16): 12210-22 (2010)) although pro-neurotrophin binding is inhibited by neurotensin in functional tests. has demonstrated that the average sortilin in the clearance of the PGRN by the union followed by the cell uptake and distribution to the lysosomes.The PGRN has neurotrophic properties and has been linked to the frontotemporal lobular degeneration (FTLD), a neurodegenerative disorder characterized by inclusions positive for RNA binding protein RNA protein 43 DNA binding (TDP-43). In a subset of patients with FTLD, PGRN expression decreases due to mutations in the GRN gene. In knockout mice with sortiline, it has been reported that PGRN levels increased and it has been found that sortiline deficiency in PGRN / - mice increases PGRN to at least the level of WT (wild type). Therefore, it has been suggested to target spellin to relieve or normalize PGRN expression levels to stop or delay neurodegeneration in FTLD (Prudencio et al, Proc Natl Acad Sci USA. 109 (52): 21510-5 ( 2012)). A comprehensive genome screening associated with a SNP near the SORT1 gene locus with PGRN expression levels and also a study of altered expression and splicing after reducing TDP-43 in the mouse brain by means of Antisense oligonucleotides have identified sortiline as one of the different genes spliced alternately that suggests a role for sortilin in the pathology of ALS and TSDP-43 (Polymenidou et al, Nat Neurosci. 14 (4): 459-68 (2011) , Carrasquillo et al., Am J Hum Genet .; 87 (6): 890-7 (2010)).

In addition to the pathology of TDP-43, other functions have been attributed to the PGRN, including inflammation and tissue repair. It has been published that PGRN binds to TNF receptors (tumor necrosis factor) with high affinity (Tang et al, Science, 332 (6028): 478-84 (2011)), thereby modulating TNF binding -alpha and showing a pro-inflammatory effect in mouse models of rheumatoid arthritis. Therefore, it has been suggested that the selection of sortiline as a target exerts anti-inflammatory effects by inhibiting the clearance of PGRN (Nykjaer and Willnow, Trends Neurosci., 35 (4): 261-70 (2012))

Sortilin is expressed in immune cells and has been implicated in inflammatory disorders since it has been recently published that the loss of sortiline reduces the release of IFN-gamma from CTL and TH1 T cells and NK cells. It has been suggested that sortiline modulates adaptive and innate immune responses by regulating IFN-gamma secretion and that sortiline may be a target (Herda et al, Immunity, 37 (5): 854 66 (2012)) in inflammatory bowel disease and other inflammatory disorders dependent on IFN gamma. A number of other binding partners with the sortiline have been described. It was shown that the growth factor CNTF (ciliary neurotrophic factor) binds to the sortiline with high affinity and is purified by cell uptake (Larsen et al, Mol Cell Biol. (17): 4175-87 (2010)), so that the signaling is modulated by the sortiline through the GP103 / LIFRbeta receptor complex, presumably through a direct interaction with LIFRbeta. A similar effect was observed for the related cytokines CT-1, LIF, OSM and IL-6. Therefore, it has been suggested that sortilin facilitates LIFRbeta-dependent signaling such that modulation of sortilin may be beneficial in disorders in which CNTF and related cytokines are important. It has also been published that the sortilina mediates in the internalization of the opioid receptor kappa (Liu-Chen, 2012, poster, annual meeting of the Society for Neuroscience, 2012) and it has been published that a peptide, spadin, which is cleaved from the pro -sortiline, joins the potassium channels TREK-1 (Mazella et al, PLoS Biol. 8 (4): e1000355, (2010)).

In addition, sortilin is a major constituent of vesicles containing glucose transporters 4 (Morris et al., J Biol Chem. 273 (6): 3582-7 (1998)) and is believed to be involved as an adapter protein charged in the formation of intracellular vesicles sensitive to insulin of the trans-Golgi network (Bogan et al, Curr Opin Cell Biol. (4): 506-12 (2010)). Intracellularly, sortiline interacts with apolipoprotein B100 (apoB100, Kjolby et al, Cell Metab, 12 (3): 213-23 (2010)). Recently, it has been published that the sortiline-apoB100 interaction was stimulated by insulin (Chamberlain, Biochem Biophys Res Commun. S0006-291X (12) 02182-1 (2012) electronic publication before printing). Sortilin is also involved in the traffic of prosaposin, acid sphingomyelinase and cathepsin H and Da lysosomes. It has recently been published that sortilin binds to APOE (apolipoprotein E), an important risk factor in Alzheimer's disease, as well as to APP (soluble amyloid precursor protein) in primary hippocampal neurons (Carlo et al, J Neurosci, 33 (1): 358-70 (2013); Gustafsen et al, J Neurosci, 33 (1): 64-71 (2013)).

Genetic polymorphisms on chromosome 1p13 have linked Sort1 with low-density lipoprotein cholesterol (LDL) metabolism and with the risk of myocardial infarction or coronary artery disease in human patients (Linsel-Nitschke et al, Atherosclerosis, 208 (1) : 183-9 (2010), Musunuru et al, Nature, 466 (7307): 714-9 (2010)). In one study, the increase in spellin expression associated with the rs599839 polymorphism was found to be correlated with lower levels of LDL cholesterol in plasma and with the decreased risk of coronary artery disease (Linsel-Nitschke et al, Atherosclerosis. , 208 (1): 183-9 (2010)). However, other studies suggested that the absence of spellin produced a decrease in plasma cholesterol levels and a decrease in plaque formation in the aorta in mice deficient for the LDL receptor (Kjolby et al, Cell Metab, 12 (3): 213-23 (2010))). Therefore, the mechanism that links the sortilina with the metabolism of the LDL and the net effect of the alteration of the expression of the sortilina is still a subject of debate (Dubé et al, Bioessays., 33 (6): 430- 7 (2011), Strong et al, Curr Atheroscler Rep., 14 (3): 211-8 (2012)) although there is agreement that sortilin is associated with circulating cholesterol / LDL levels and that modulation of function of spellin may represent a strategy to reduce circulating LDL levels and relieve cardiovascular risk. WO 01/81345 describes phthalamic acid derivatives for use in the treatment of neurodegenerative diseases such as Alzheimer's dementia and Parkinson's disease.

Due to the studies that associate the function of the sortilina with the disease and the union of the sortilina with diverse proteins involved in pathologies in the central nervous system as well as in the peripheral one, the sortilina can represent an attractive therapeutic objective. However, although the binding site of the neurotensin and programnulin sortiline ligands has been identified, to date no specific small molecule modulator of the function of the sortilin has been described.

The present invention aims to provide compounds that are inhibitors of sortilin and, as such, useful in the treatment of diseases associated with sortilin.

Summary of the invention

The present inventors have surprisingly found certain compounds that are inhibitors of sortiline. Accordingly, in one embodiment, the invention provides compounds of the formula A, which follows

where

R1 represents H or F,

R2 represents halogen, C1-C6 alkyl, C2-C6 alkenyl or halogenated C1-C6 alkyl,

R3 represents halogen, H, C1-C6 alkyl, or halogenated C1-C6 alkyl,

L is a direct link or represents CH2,

R4 represents

* indicates the point of attachment.

optionally it is substituted with C ^and N, 1 or 2 C1-C3 alkyls, 1 or 2 halogenated alkyls, 1 or 2 C1-C3 alkoxy or 1 or 2 halogens, where X indicates C or N and N is present in 1 or 2 positions .

and pharmaceutically acceptable salts thereof.

In one embodiment, the invention provides a pharmaceutical composition comprising a compound of the above formula A and pharmaceutically acceptable salts thereof together with a pharmaceutically acceptable excipient.

In one embodiment, the invention provides compounds of the above formula A and their pharmaceutically acceptable salts for use in therapy.

In one embodiment, the invention provides compounds of the above formula A and their pharmaceutically acceptable salts for use in the treatment of a neurodegenerative disease, psychiatric disease, motor neuron disease, peripheral neuropathies, pain, neuroinflammation or atherosclerosis.

In one embodiment, the invention relates to the use of a compound of the above formula A and its pharmaceutically acceptable salts in the manufacture of a medicament for use in the treatment of a neurodegenerative disease, psychiatric disease, motor neuron disease, peripheral neuropathies. , pain, neuroinflammation or atherosclerosis.

In one embodiment, the invention relates to a compound for use in a method for the treatment of a neurodegenerative disease, psychiatric disease, motor neuron disease, peripheral neuropathies, pain, neuroinflammation or atherosclerosis, the method comprising administering a quantity Therapeutically effective of a compound of the above formula A and pharmaceutically acceptable salts thereof to a patient in need.

Brief description of the drawings

Figure 1 shows that the addition of neurotensin (NT) or the compound of Example 1 in the presence of PGRN blocks interaction with the sortiline, as seen in the figure by the increase in PGRN levels.

Figure 2 shows that the addition of neurotensin or the compound of Example 1 blocks the binding or endocytosis of PGRN to cells expressing sortilin.

Detailed description of the invention

In further embodiments, said R4 group of the above formula A may be selected from the group comprising

* indicates the point of attachment.

whose groups may be optionally substituted with C = N, 1 or 2 C1-C3 alkyls, 1 or 2 halogenated alkyls, 1 or 2 C1-C3 alkoxy 1 or 2 halogens, wherein X indicates C or N and N is present in 1 or 2 positions.

In yet another embodiment, the C1-C6 alkyl halogenated in R2 and R3 of the formula A can each be independently CF3. In another embodiment, R2 may be Cl, Br or Cf3 and R3 may be H or Cl.

In still other additional embodiments, the compound according to formula A above may have a group R4 selected from the group comprising

* indicates the junction point

whose groups may be optionally substituted with C = N, 1 or 2 C1-C3 alkyls, 1 or 2 halogenated alkyls, 1 or 2 C1-C3 alkoxy or 1 or 2 halogens.

In a specific embodiment, the compound according to formula A may be selected from the group comprising, N- (6-methyl-pyridin-2-yl) -5-trifluoromethylphthalamic acid

5-Bromo-N- (6-methyl-pyridin-2-yl) -phthalamic acid

5-methyl-N- (6-methyl-pyridin-2-yl) -phthalamic acid

5-Chloro-N- (6-methyl-pyridin-2-yl) -phthalamic acid

4,5-Dichloro-N- (6-methyl-pyridin-2-yl) -phthalamic acid

5-Bromo-N- (3-methyl-4,5,6,7-tetrahydro-benzo [b] thiophene-2-yl) -phthalamic acid

N- (5,6-dimethyl-pyridin-2-yl) -5-trifluoromethylphthalamic acid

N- (4-methyl-pyridin-2-yl) -5-trifluoromethylphthalamic acid

N- (2-methyl-pyridin-4-yl) -5-trifluoromethylphthalamic acid

4,5-Dichloro-N- (4-methyl-pyridin-2-yl) -phthalamic acid

4,5-Dichloro-N- (5,6-dimethyl-pyridin-2-yl) -phthalamic acid

4,5-Dichloro-N- (2-methyl-pyridin-4-yl) -phthalamic acid

4,5-Dichloro-N- (2-methyl-pyrimidin-4-yl) -phthalamic acid

5-Chloro-6-fluoro-N- (6-methyl-pyridin-2-yl) -phthalamic acid

4,5-dimethyl-N- (6-methyl-pyridin-2-yl) -phthalamic acid

2 - ((3-Chloro-5- (trifluoromethyl) pyridin-2-yl) carbamoyl) -5- (trifluoromethyl) benzoic acid

2 - ((4-methylpyrimidin-2-yl) carbamoyl) -5- (trifluoromethyl) benzoic acid

2 - ((5,6-Dimethylpyrazin-2-yl) carbamoyl) -5- (trifluoromethyl) benzoic acid

5-Bromo-N- (5-methyl-pyridin-2-yl) -phthalamic acid

5-Bromo-N- (5-chloro-pyridin-2-yl) -phthalamic acid

5-Bromo-N-pyridin-2-yl-phthalamic acid

5-Bromo-N- (6-chloro-pyridin-2-yl) -phthalamic acid

5-Bromo-N- (5,6-dimethyl-pyridin-2-yl) -phthalamic acid

5-Bromo-N- (4-methyl-pyridin-2-yl) -phthalamic acid

5-Bromo-N- (2-methyl-pyridin-4-yl) -phthalamic acid

5-Bromo-N-pyridin-3-yl) -phthalamic acid

5-Bromo-N- (3-methyl-pyridin-2-yl) -phthalamic acid

5-Bromo-N- (4-methyl-thiazol-2-yl) -phthalamic acid

5-Bromo-N-quinolin-2-yl-phthalamic acid

5-Bromo-N- (5,6-dichloro-pyridin-2-yl) -phthalamic acid

5-Bromo-N- (6-methyl-pyridin-3-yl) -phthalamic acid

5-Bromo-N- (6-methyl-pyridazin-3-yl) -phthalamic acid

5-Bromo-N- (4,6-dimethyl-pyridin-2-yl) -phthalamic acid

5-Bromo-N- (2-methyl-pyrimidin-4-yl) -phthalamic acid

5-Bromo-N- (6-methyl-pyrimidin-4-yl) -phthalamic acid

N- (2-methoxy-pyridin-4-yl) -5-trifluoromethylphthalamic acid

N- (6-methoxy-pyridin-2-yl) -5-trifluoromethylphthalamic acid

N-pyridin-2-ylmethyl-5-trifluoromethylphthalamic acid

N-pyridin-4-ylmethyl-5-trifluoromethylphthalamic acid

N-pyridin-3-ylmethyl-5-trifluoromethylphthalamic acid

N- (6-methyl-pyridin-2-yl) -5-propylphthalamic acid

N5-isopropenyl-N- (6-methyl-pyridin-2-yl) -phthalamic acid

N5-Isopropyl-N- (6-methyl-pyridin-2-yl) -phthalamic acid

2 - ((2-methylpyrimidin-4-yl) carbamoyl) -5- (trifluoromethyl) benzoic acid

2 - ((4,5-Dimethylpyrimidin-2-yl) carbamoyl) -5- (trifluoromethyl) benzoic acid

2 - ((5,6,7,8-tetrahydroquinolin-2-yl) carbamoyl) -5- (trifluoromethyl) benzoic acid

2 - ((6-methylpyridin-2-yl) carbamoyl) -4,5-bis (trifluoromethyl) benzoic acid

2 - ((5,6,7,8-tetrahydroquinolin-2-yl) carbamoyl) -4,5-bis (trifluoromethyl) benzoic acid

2 - ((5,6-Dimethylpyridin-2-yl) carbamoyl) -4,5-bis (trifluoromethyl) benzoic acid

2 - ((2-methylpyrimidin-4-yl) carbamoyl) -4,5-bis (trifluoromethyl) benzoic acid

2 - ((2,6-Dimethylpyridin-4-yl) carbamoyl) -5- (trifluoromethyl) benzoic acid

or a pharmaceutically acceptable salt thereof.

The compounds mentioned above may be in a composition as the only active ingredient or in combination with other active ingredients. Additionally, one or more pharmaceutically acceptable carriers or diluents may be in the composition.

In certain aspects, the invention also relates to prodrugs of the formula A, and therefore to the use of certain compounds as products in therapy, which are compounds of the formula C described below.

By "prodrug" is meant a medication that is initially administered to the body in an inactive or not fully active form, which becomes its active form through the normal metabolic processes of the body. In a further aspect, the invention relates to a prodrug according to formula C and the use of these compounds in therapy:

where

R9 represents C1-C6 alkyl

R10 represents halogen, C1-C6 alkyl, C2-C6 alkenyl or halogenated C1-C6 alkyl,

R11 represents halogen, H, C1-C6 alkyl or halogenated C1-C6 alkyl,

n is 0 or 1,

R12 represents

and its pharmaceutically acceptable salts.

In another embodiment, R9 represents Ci-C4 alkyl.

In another embodiment, the prodrugs according to formula C may have R10 representing CH3, CHCH2, Br, Cl, C = N or CF3 and R7 representing H, CF3 or Cl.

In a specific embodiment, the prodrug according to formula C can be selected from the group comprising 5-bromo-N- (5,6-dimethyl-pyridin-2-yl) -phthalamic acid ferc-butyl ester

N- (6-methyl-pyridin-2-yl) -5-trifluoromethyl-phthalamic acid ferc-butyl ester

5-Bromo-N- (6-methyl-pyridin-2-yl) -phthalamic acid ferc-butyl ester

5-Bromo-N- (5-methyl-pyridin-2-yl) -phthalamic acid ferc-butyl ester

5-Bromo-N- (2-methyl-pyridin-4-yl) -phthalamic acid ferc-butyl ester

5-Bromo-N-pyridin-3-yl-phthalamic acid ferc-butyl ester

5-Bromo-N- (3-methyl-pyridin-2-yl) -phthalamic acid ferc-butyl ester

5-Bromo-N- (4-methyl-thiazol-2-yl) -phthalamic acid ferc-butyl ester

5-Bromo-N-quinolin-2-yl-phthalamic acid ferc-butyl ester

5-Bromo-N- (5,6-dichloro-pyridin-2-yl) -phthalamic acid ferc-butyl ester

5-Bromo-N- (6-methyl-pyridin-3-yl) -phthalamic acid ferc-butyl ester

5-Bromo-N- (6-methyl-pyridazin-3-yl) -phthalamic acid ferc-butyl ester

5-Bromo-N- (4,6-dimethyl-pyridin-2-yl) -phthalamic acid ferc-butyl ester

5-Bromo-N- (2-methyl-pyrimidin-4-yl) -phthalamic acid ferc-butyl ester

5-Bromo-N- (6-methyl-pyrimidin-4-yl) -phthalamic acid ferc-butyl ester

N- (2-methoxy-pyridin-4-yl) -5-trifluoromethylphthalamic acid ferc-butyl ester

N- (6-methoxy-pyridin-2-yl) -5-trifluoromethyl-phthalamic acid ferc-butyl ester

N-pyridin-2-ylmethyl-5-trifluoromethyl-phthalamic acid ferc-butyl ester

N-pyridin-4-ylmethyl-5-trifluoromethyl-phthalamic acid ferc-butyl ester

N-pyridin-3-ylmethyl-5-trifluoromethylphthalamic acid ferc-butyl ester

Not applicable - not a prodrug

5-Isopropenyl-N- (6-methyl-pyridin-2-yl) -phthalamic acid ferc-butyl ester

N- (6-methyl-pyridin-2-yl) -5-propyl-phthalamic acid ferc-butyl ester

N- (2-methyl-pyrimidin-4-yl) -5-trifluoromethylphthalamic acid ferc-butyl ester

N- (4,5-dimethyl-pyrimidin-2-yl) -5-trifluoromethyl-phthalamic acid ferc-butyl ester

N- (5,6,7,8-tetrahydro-quinolin-2-yl) -5-trifluoromethylphthalamic acid ferc-butyl ester

5-Isopropyl-N- (6-methyl-pyridin-2-yl) -phthalamic acid ferc-butyl ester

N- (2,6-dimethyl-pyridin-4-yl) -5-trifluoromethyl-phthalamic acid ferc-butyl ester

4,5-Dichloro-N- (6-methyl-pyridin-2-yl) -phthalamic acid ferc-butyl ester

4,5-dichloro-N- (6-methyl-pyridin-2-yl) -phthalamic acid isopropyl ester

4,5-Dichloro-N- (6-methyl-pyridin-2-yl) -phthalamic acid methyl ester

4,5-dichloro-N- (2-methyl-pyrimidin-4-yl) -phthalamic acid isopropyl ester

4,5-Dichloro-N- (2-methyl-pyrimidin-4-yl) -phthalamic acid ethyl ester

N- (5,6-dimethyl-pyridin-2-yl) -4,5-bis-trifluoromethylphthalamic acid methyl ester

or a pharmaceutically acceptable salt thereof.

It is envisioned that the prodrugs of the formula C can be administered in pharmaceutical formulations together with one or more pharmaceutically acceptable carriers or diluents. The use of these prodrugs is intended for the same medical conditions as the compounds of the formula A.

The compounds of the present invention may have one or more asymmetric centers and it is intended that all optical isomers (i.e. enantiomers or diastereoisomers) such as separate, pure or partially purified optical isomers and any mixture thereof, including racemic mixtures thereof , that is, a mixture of stereoisomers, are included within the scope of the invention.

In this context, it is understood that when the shape of the diastereoisomers is specified, the compound is in enantiomeric excess, for example, essentially in pure form. Accordingly, one embodiment of the invention relates to a compound of the invention having an enantiomeric excess of at least 60%, at least 70%, at least 80%, at least 85%, at least 90%, at least 96 %, preferably at least 98%.

The racemic forms can be resolved in the optical antipodes by known methods, for example, by separating their diastereoisomeric salts with an optically active acid, and releasing the optically active amine compound by treatment with a base. Another method for solving racemates in optical antipodes is based on chromatography on an optically active matrix. The compounds of the present invention can also be resolved by the formation of diastereoisomeric derivatives. Additional methods for the resolution of optical isomers, known to those skilled in the art, can be used. Such methods include those set forth by J. Jaques, A. Collet and S. Wilen in "Enantiomers, Racemates, and Resolutions", John Wiley and Sons, New York (1981). Optically active compounds can also be prepared from optically active starting materials.

In addition, when a double bond or a fully or partially saturated ring system is present in the molecule, geometric isomers can be formed. It is intended that all geometric isomers such as separate, pure or partially purified geometric isomers or mixtures thereof be included within the scope of the invention. Similarly, molecules that have a restricted rotation bond can form geometric isomers. It is also intended that these be included within the scope of the present invention.

In addition, some of the compounds of the present invention may exist in different tautomeric forms and it is intended that all tautomeric forms that the compounds may form be included within the scope of the present invention.

In the present context, "pharmaceutically acceptable salts" include pharmaceutically acceptable acid addition salts, pharmaceutically acceptable metal salts, ammonium and alkylated ammonium salts. Acid addition salts include salts of inorganic acids as well as organic acids.

Examples of metal salts include lithium, sodium, potassium, magnesium salts and the like.

Examples of ammonium and alkylated ammonium salts include ammonium, methyl, dimethyl, trimethyl, ethyl, hydroxyethyl, diethyl, n-butyl, sec-butyl, ferc-butyl, tetramethylammonium and the like salts.

In the present context, "alkyl" and "alkenyl" means a saturated linear or branched hydrocarbon. The term "alkenyl" includes radicals that have at least one carbon-carbon double bond. In particular, C1-6 alkyl or C2-6 alkenyl are intended to indicate a hydrocarbon having 1, 2, 3, 4, 5 or 6 carbon atoms or 2, 3, 4, 5 or 6 carbon atoms, respectively, and equally , C1-3 alkyl or C2-3 alkenyl are intended to indicate a hydrocarbon having 1, 2 or 3 carbon atoms or 2 or 3 carbon atoms, respectively.

Typical alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl, isopentyl, hexyl and the like. The "alkyl" group may be substituted with one or more, such as 1, 2 or 3, halogens, thus constituting a halogenated alkyl such as fluoroethyl, trifluoromethyl or trifluoroethyl.

The term "alkoxy" as used herein refers to a group of the formula -O-alkyl, wherein alkyl is defined as above. In particular, it is intended that C1-C3 alkoxy indicates a hydrocarbon having 1, 2 or 3 carbon atoms. Examples of alkoxy groups include methoxy, ethoxy, n-propoxy and isopropoxy.

In the present context, "halogen" indicates the members of the main 7th group of the periodic table of the elements, such as fluoro, chloro, bromo and iodo.

By "heteroatom" is meant to mean sulfur, oxygen or nitrogen.

The term "aromatic" refers to a cyclic or polycyclic moiety that has an unsaturated conjugated electron system (4n 2) n (where n is a positive integer), sometimes referred to as a delocalized n electron system.

The term "heterocyclic," as used herein, alone or in combination, refers to saturated or unsaturated aromatic or non-aromatic rings containing 5 to 6 atoms in the ring, where 1 or 2 of the atoms in the ring They are heteroatoms.

The term "heteroaromatic" as used herein, alone or in combination, refers to an aromatic ring containing 5 to 6 ring atoms, where 1 or 2 of the atoms in the ring are heteroatoms.

The term "bicyclic heterocyclic ring" refers to 2 fused cyclic rings where each can be saturated or unsaturated to form a "bicyclic heterocyclic ring" of a total of 8-10 members. This bicyclic heterocyclic ring may have 1 or 2 heteroatoms in one or both rings. In one embodiment, the bicyclic ring constitutes a heteroaromatic ring fused with a saturated or unsaturated carbocyclic ring (i.e., a cyclic ring in which all ring members are carbon atoms) or a heterocyclic ring.

The terms "substituents" or "substitutes" as used herein, alone or in combination, refer to groups that can be used to replace hydrogen. The substituted molecule may be further substituted in some embodiments of the invention.

In the present context, the term "therapeutically effective amount" of a compound is intended to indicate an amount sufficient to cure, alleviate or partially stop the clinical manifestations of a given disease and its complications in a therapeutic intervention comprising the administration of said compound. An adequate amount to achieve this is defined as "therapeutically effective amount". The effective amounts for each purpose will depend on the severity of the disease or injury, as well as the weight and general condition of the subject. It can be understood that the determination of an appropriate dose can be achieved using routine experimentation, for example, by constructing a matrix of values and testing different points of the matrix, which is within the normal abilities of a trained physician.

In the present context, the term "treatment" and "treat" means the control and care of a patient in order to combat a disease. The term is intended to include the full spectrum of treatments for a given disease that the patient suffers, such as the administration of an active compound to relieve symptoms or complications, delay disease progression, relieve or alleviate symptoms and complications, and / or to cure or eliminate the disease. The patient to be treated is preferably a mammal, in particular a human being. In the present context, "disease" can be used as a synonym for disorder, condition, malfunction, dysfunction and the like.

As stated above, sortilin inhibitors can be used in the treatment of neurodegenerative disease, psychiatric disease, motor neuron disease, peripheral neuropathies, pain, neuroinflammation or atherosclerosis.

Therefore, the compounds described in formula A, the compounds of formula C as prodrugs or the composition comprising said compounds can be used in a method for the treatment selected from the group comprising Alzheimer's disease, Parkinson's disease, stroke, traumatic brain injury, retinal degeneration, light-induced photoreceptor degeneration, epilepsy, bipolar disorder, amyotrophic lateral sclerosis (ALS), frontotemporal lobular degeneration (FTLD), spinal muscular atrophy, peripheral neuropathy, diabetic neuropathy, acute pain and chronic, prevention and treatment of established pain, neuropathic pain, low back pain, postoperative pain, inflammatory pain, rheumatoid arthritis, Crohn's disease, ulcerative colitis, multiple sclerosis and atherosclerosis.

In one embodiment, the compound of the present invention is administered in an amount of about 0.001 mg / kg of body weight to about 100 mg / kg of body weight per day. In particular, daily doses may be in the range of 0.01 mg / kg of body weight to about 50 mg / kg of body weight per day. The exact doses will depend on the frequency and mode of administration, sex, age, weight and general condition of the subject to be treated, the nature and severity of the condition to be treated, any concomitant disease to be treated, the desired effect of the treatment and other factors known to those skilled in the art. A typical oral dose for adults will be in the range of 1-1000 mg / day of a compound of the present invention, such as 1-500 mg / day.

The compounds of the present invention can be administered alone as a pure compound or in combination with pharmaceutically acceptable carriers or excipients, in single or multiple doses. The pharmaceutical compositions according to the invention can be formulated with pharmaceutically acceptable carriers or diluents, as well as any other adjuvant and excipient known according to conventional techniques such as those described in Remington: The Science and Practice of Pharmacy, 21 Edition, PA, 2005. In the In this context, "excipient", "vehicle", "diluent", "adjuvant" and the like are used as synonyms and are intended to mean the same. Pharmaceutical compositions may be formulated specifically for administration by any suitable route, such as oral, rectal, nasal, pulmonary, topical (including buccal and sublingual), transdermal, intracisternal, intraperitoneal, vaginal and parenteral (including subcutaneous, intramuscular, intrathecal) , intravenous and intradermal). It will be appreciated that the preferred route will depend on the general condition and the age of the subject to be treated, the nature of the condition to be treated and the active ingredient chosen.

Pharmaceutical compositions for oral administration include solid pharmaceutical forms such as capsules, tablets, dragees, pills, lozenges, powders and granules. When appropriate, they can be prepared with coatings.

Liquid pharmaceutical forms for oral administration include solutions, emulsions, suspensions, syrups and elixirs.

Pharmaceutical compositions for parenteral administration include sterile injectable, aqueous and non-aqueous solutions, dispersions, suspensions or emulsions, as well as sterile powders to be reconstituted into sterile injectable solutions or dispersions before use.

Other suitable administration forms include suppositories, sprays, ointments, creams, gels, inhalants, dermal patches, implants, etc.

Conveniently, the compounds of the invention are administered in a unit dosage form containing said compounds in an amount of about 0.1 to 500 mg, such as 10 mg, 50 mg, 100 mg, 150 mg, 200 mg or 250 mg of a compound of the present invention.

For parenteral administration, solutions of the compound of the invention in sterile aqueous solution, aqueous propylene glycol, aqueous vitamin E or sesame or peanut oil can be employed. Such aqueous solutions should be buffered properly, if necessary, and the liquid diluent must first be converted to isotonic with sufficient saline or glucose. Aqueous solutions are particularly suitable for intravenous, intramuscular, subcutaneous and intraperitoneal administration. The sterile aqueous media employed are readily available by standard methods known to those skilled in the art.

Suitable pharmaceutical carriers include inert solid diluents or fillers, sterile aqueous solution and various organic solvents. Examples of solid vehicles are lactose, terra alba, sucrose, cyclodextrin, talc, gelatin, agar, pectin, gum arabic, magnesium stearate, stearic acid and cellulose ethers and lower alkyl. Examples of liquid vehicles are syrup, peanut oil, olive oil, phospholipids, fatty acids, fatty acid amines, polyoxyethylene and water. The pharmaceutical compositions formed by combining the compound of the invention and pharmaceutically acceptable carriers are then easily administered in a variety of pharmaceutical forms suitable for the described routes of administration.

Formulations of the present invention suitable for oral administration may be presented as discrete units, such as capsules or tablets, each of which contains a predetermined amount of the active ingredient, and which may include a suitable excipient. In addition, orally available formulations may be in the form of powder or granules, of a solution or suspension in an aqueous or non-aqueous liquid, or of a liquid emulsion of oil in water or water in oil.

If a solid carrier is used for oral administration, the preparation may be a tablet, for example, placed in a hard gelatin capsule in the form of powder or pellet or in the form of a lozenge or tablet. The amount of solid carrier may vary, but will generally be from about 25 mg to about 1 g.

If a liquid carrier is used, the preparation may be in the form of a syrup, emulsion, soft gelatin capsule or sterile injectable liquid, such as an aqueous or non-aqueous liquid suspension or solution.

The tablets may be prepared by mixing the active ingredient with ordinary adjuvants and / or diluents, followed by compression of the mixture in a conventional compressing machine. Examples of adjuvants or diluents comprise: corn starch, potato starch, talc, magnesium stearate, gelatin, lactose, gums and the like. Any other adjuvant or additive generally used for these purposes such as dyes, flavorings, preservatives, etc. can be used. provided they are compatible with the active ingredients.

The use of the terms "a", "one" and "one" and "the" and "the" and similar references in the context of the description of the invention should be construed to encompass both the singular and the plural, unless otherwise indicated herein or clearly contradicted by the context. For example, the phrase "the compound" should be understood to refer to several "compounds" of the invention or particular aspect described, unless otherwise indicated. The description herein of any aspect or aspects of the invention using terms such as "comprising", "having", "including" or "containing" with reference to an element or elements attempts to provide support for one aspect similar or aspect of the invention that "consists of", "consists essentially of", or "substantially comprises" that particular element or elements, unless otherwise indicated or clearly contradicted by the context (eg, a Composition described herein comprising a particular element should be understood to also describe a composition consisting of that element, unless otherwise stated or clearly contradicted by the context).

Experimental

Abbreviations and chemicals used

aq = aqueous. Brine = saturated aqueous sodium chloride solution (eg, Sigma-Aldrich S7653). CDCh = deuterated chloroform (e.g., Aldrich 225789). DCM = methylene chloride / dichloromethane (eg, Sigma-Aldrich 270997). DIPEA = di- / so-propyl ethyl amine (eg, Sigma-Aldrich 387649). DMF = dimethylformamide (eg, Sigma-Aldrich 227056). DMSO-d6 = deuterated dimethylsulfoxide (e.g., Aldrich 296147). Et3N = triethylamine (eg, Sigma-Aldrich T0886). Et2O = diethyl ether (eg Sigma-Aldrich 346136). EtOAc = ethyl acetate (e.g., Fluka 34972). EtOH = ethanol (e.g., Sigma-Aldrich 459844). h = hour or hours. HATU = O- (7-azabenzotriazol-1-yl) -N, N, N ', N'-tetramethyluronium hexafluorophosphate. Heptans (e.g., Sigma-Aldrich 730491). K3PO4 (e.g., Sigma -Aldrich P5629). LCMS = liquid chromatography / mass spectrometry. LiOH = lithium hydroxide (eg, Sigma-Aldrich 545856). MeOH = methanol (e.g., Sigma-Aldrich 34860). MgSO4 (e.g., Sigma-Aldrich M7506). Microwave = a microwave reactor initiator of Biotage. Min = minute or minutes. NaHCO3 (e.g., Sigma-Aldrich S6014). NaOt-Bu = sodium tert- butoxide (eg, Aldrich 359270). Na2SO4 = sodium sulfate (e.g., Sigma-Aldrich 238597). NMP = 1-methyl-2-pyrrolidinone (e.g., Sigma-Aldrich 443778). NMR = nuclear magnetic resonance. PDA = array of photodiodes. Pd (OAc) 2 = palladium (II) acetate (e.g., Aldrich 683124). Pd (PPh3) 2Cl2 = bis (triphenylphosphine) palladium (II) dichloride (eg, Aldrich 208671). Petroleum ether (e.g., Sigma-Aldrich 77379). POCl3 = phosphoryl chloride (e.g., Aldrich 262099). Preparative HPLC = high resolution preparative liquid chromatography. Pyridine (e.g., Sigma-Aldrich 270970). Rt = room temperature. Silica gel = particle size 100-200 meshes (75-150 pm). SFC = supercritical fluid chromatography. SOCl2 = thionyl chloride (eg, Sigma-Aldrich 320536). TFA = trifluoroacetic acid (eg, Sigma-Aldrich T6508). THF = tetrahydrofuran (eg, Sigma-Aldrich 401757). TLC = thin layer chromatography. Toluene (e.g., Sigma-Aldrich 244511). tR = retention time.

Name (s

Chemical names were obtained using the MDL ISIS / DRAW 2.5 software from the MDL information systems

The compounds of the general formula 1 can be prepared according to Scheme 1 where a corresponding phthalimide X intermediate is hydrolyzed with a base such as, for example, lithium hydroxide.

For illustrative purposes, groups A and B are used in the following schemes.

It will be appreciated that when the substituent A ^ B a mixture of two isomers 1 and 1a (scheme 1) can be obtained, these isomers can be separated to obtain the pure compounds by, for example, preparative HPLC. When B = H only isomer 1 is the object of this invention, and alternative isomer 1a can be discarded. When A = B, only a single compound will be obtained, that is 1 and 1a are identical. Individual isomers 1 and 1a can be unambiguously characterized by NMR techniques

Scheme 1

The phthalimide intermediates of the general formula X can be prepared in turn, by treating the corresponding phthalic anhydride W with the corresponding amino compound V in, for example, acetic acid at reflux (scheme 2).

Scheme 2

Alternatively, the compounds of the general formula 1 (and 1a) can also be prepared by direct reaction of an amino compound V and the corresponding phthalic anhydride W in, for example, acetone (scheme 3).

Scheme 3

Alternatively the compounds of the general formula 1 can be prepared according to the chemical reaction of scheme 4. The coupling of an amino compound V using, for example, a coupling agent such as HATU, with an intermediate of the general formula Z provides an intermediate And, from which the compound of the general formula 1 can be obtained by debutilation of the ester using, for example, TFA

Scheme 4

Type Z (and Za) intermediates can be prepared by alcoholysis of a corresponding phthalic anhydride W with, for example, alkoxide in water, and separation of the Z and Za isomers by supercritical fluid chromatography (SFC) (scheme 5) .

Scheme 5

Type Y intermediates can also be prepared by modification or functionalization of one of the substituents of another type Y intermediate, for example, a Y 'intermediate (scheme 6). For example, in an intermediate of type Y 'where substituent A' contains an alkene or alkyne, substituent A 'can be reduced, for example, with hydrogen and palladium on a carbon catalyst to an alternative substituent A (scheme 6 ) to obtain intermediate Y

Scheme 6

In addition, an intermediate of type Z can also be prepared by modification or functionalization of one of the substituents of another intermediate of type Z, for example, an intermediate of type Z '(scheme 7). For example, when the substituent A 'of an intermediate of type Z' is a bromine atom, the bromine can be converted into another substituent A (scheme 7) using, for example, a transition metal catalyzed coupling, to obtain a type Z intermediate.

Scheme 7

Additionally, the compounds of the general formula 1 can be prepared according to the chemical reaction of scheme 8. The coupling of an amino compound V using, for example, a coupling agent such as HATU, to a symmetrical intermediate (ie, A = B) of the general formula T can provide the compounds of the general formula 1 directly.

Scheme 8

Additionally, the compounds of the general formula 1 can be prepared according to the chemical reaction of scheme 9. The coupling of an amino compound V using, for example, trimethylaluminum, to a symmetrical intermediate (ie, A = B) of the general formula R provides an intermediate S. The compound of the general formula 1 can now be obtained by hydrolysis of the ester using, for example, lithium hydroxide.

Scheme 9

Examples

The invention will be illustrated by the following non-limiting examples.

Analytical methods

LC-MS

Method A:

LC-MS were performed in Waters Aquity UPLC-MS consisting of Waters Aquity, which includes the column manager, the binary solvent manager, the sample organizer, the PDA detector (operating at 254 nM), the ELS detector and SQ-MS equipped with an APPI source that works in positive ion mode.

LC conditions: The column was Acquity UPLC BEH C18 1.7 pm; 2.1 x 50 mm operating at 60 ° C with 1.2 mL / min of a binary gradient consisting of 0.1% formic acid water (A) and 0.1% acetonitrile water 0.1% formic acid.

Method B:

LC-MS were performed in Waters Aquity UPLC-MS consisting of Waters Aquity, which includes the column manager, the binary solvent manager, the sample organizer, the PDA detector (operating at 254 nM), the ELS detector and TQ-MS equipped with an APPI source that works in positive ion mode.

LC conditions: The column was Acquity UPLC BEH C18 1.7 pm; 2.1 x 50 mm operating at 55 ° C with 0.4 mL / min of a binary gradient consisting of 0.1% formic acid water (A) and 0.1% formic acid acetonitrile.

Method C:

LC-MS were performed in Waters Aquity UPLC-MS consisting of Waters Aquity, which includes the column manager, the binary solvent manager, the sample organizer, the PDA detector (operating at 254 nM), the ELS detector and TQ-MS equipped with an APPI source that works in positive ion mode.

LC conditions: The column was ZORBAX RX C18 1.8 p; 2.1 x 50 mm operating at 55 ° C with 0.4 mL / min of a binary gradient consisting of 0.01% formic acid water (A) and 0.01 (B) formic acid acetonitrile

Method D:

LC-MS were performed in Waters Aquity UPLC-MS consisting of Waters Aquity, which includes the column manager, the binary solvent manager, the sample organizer, the PDA detector (operating at 254 nM), the ELS detector and the TQ-MS equipped with an APPI source that works in positive ion mode.

LC conditions: The column was BEH C18 1,7p; 2.1 x 100 mm operating at 55 ° C with 0.4 mL / min of a binary gradient consisting of 0.1% formic acid water (A) and 0.1 (B) formic acid acetonitrile.

Retention times (tR) are expressed in minutes based on the UV trace at 254 nm.

CFS

The SFCs were performed on a Thar SFC-80 system consisting of a sample manager, an injector and a manifold, P-50 pumps for CO2 and co-solvent and a Gilson UV-Visible detector (model 151, operating at 235 nm). A Lux Cellulose-2 column (250x30 mm) was used together with 25% 0.5% DEA in ethanol as co solvent with a total flow of 80 g / min at 160 bar. Samples were loaded at 50 mg / injection.

Preparative HPLC

Method 1:

Preparative HPLCs were performed in a Gilson GX-281 purification system consisting of a sample manager, an injector and a manifold, binary solvent pumps (model 334) and a Gilson UV-Visible detector (model 155, which operates at 254 nm and 215 nm). A CHIRAlPAk IC 5 ^ column was used: 250x30 mm eluted with hexane / ethanol (70:30) with a flow rate of 25 mL / min.

Method 2:

Preparative HPLCs were performed in a Gilson GX-281 purification system consisting of a sample manager, an injector and a manifold, binary solvent pumps (model 334) and a Gilson UV-Visible detector (model 155, which operates at 254 nm and 215 nm). A CHIRAlPAk IC 5 ^ column: 250x30 mm was used which was eluted with 0.1% DEA in hexane / ethanol (90:10) with a flow rate of 25 mL / min.

NMR

The 1H NMR spectra were recorded at 400 MHz on Varian-VNMRS-400 or Varian MR-400 instruments or at 600 MHz on a Bruker Avance AV-NI-600 instrument. Chemical shift values are expressed in ppm values relative to tetramethylsilane, unless otherwise indicated. The following abbreviations or combinations thereof are used for the multiplicity of n MR signals: br = width, d = doublet, m = multiplet, q = quadruplet, quint = quintet, s = singlet and t = triplet.

Intermediate

Intermediate X1

A solution of trifluoromethyl-phthalic anhydride (1.5 g, 6.9 mmol) and 2-amino-6-picoline (0.75 g, 6.9 mmol) in acetic acid (10 mL) was refluxed for 5 h ). After cooling to room temperature, the reaction content was poured onto ice water and stirred for 10 minutes, during which time a solid precipitated. This solid was collected by filtration and washed with diethyl ether (25 mL) to obtain intermediate X1 (1.0 g, 3.3 mmol, 48%) as an off-white solid.

1H NMR (DMSO-d6, 400 MHz) 5: 8.32-8.30 (2H, m), 8.20-8.18 (1H, d, J = 7.2 Hz), 7.96-7 , 92 (1H, t, J = 7.6 Hz), 7.42 7.41 (1H, d, J = 7.2 Hz). 7.37-7.35 (1H, d, J = 8.0 Hz), 2.52 (3H, s).

Intermediates X2 to X18 were prepared from the corresponding phthalic anhydrides in a manner analogous to intermediate X1.

Intermediate X14

Synthesized according to Scheme 10.

Smoking sulfuric acid (30%, 4 mL) was added to 3-doro-2-fluoro-6- (trifluoromethyl) benzoic acid (G1, 0.294 g, 1.21 mmol) and the resulting brown solution was heated to 150 ° C for 2 h. After cooling to 0 ° C, cold MeOH (5 mL) was added and the mixture was stirred at room temperature for 0.5 h. Purification by rapid column chromatography (gradient gradient 0-100% EtOAc in heptane for 20 minutes) gave an inseparable mixture, approximately 1: 1, of 1-methyl ester of 4-chloro-3-fluoro-phthalic acid and ester 1-Methyl 3-chloro-2-fluoro-phthalic acid (G2 G3, 0.210 g, 0.91 mmol, 75%).

1H NMR (mixture of isomers approximately 1: 1, CDCl3600 MHz) 5: 10.67 (2H, br s), 7.85-7.81 (1H, d, J = 7.8 Hz), 7.74- 7.71 (1 H, d, J = 8.6 Hz), 7.57-7.50 (2H, m), 3.96 (3 ^h , s), 3.91 (3H, s).

Phosphoryl chloride (0.060 mL, 0.64 mmol) was added to a solution of 1-methyl ester of 4-chloro-3-fluorophthalic acid (0.050 g, 0.21 mmol), 1-methyl ester of 3-chloro acid -2-fluoro-phthalic (0.050 g, 0.21 mmol) and 2-amino-6-methylpyridine (0.046 g, 0.43 mmol) in pyridine (4 mL) at 0 ° C. The reaction was allowed to warm to room temperature and stirred for 1 h. Methanol (2 mL) was added and the solvents removed in vacuo to give a crude orange product that was purified by flash column chromatography (solvent gradient 0-100% EtOAc in heptane for 16 minutes and then 5 minutes 100% EtOAc ). Intermediate X15 (0.0198 g, 0.068 mmol, 33%) was isolated as a white solid.

1H NMR (DMSO-d6, 600 MHz) 5: 7.81-7.78 (1H, dd, J = 7.6, 8.7 Hz), 7.72-7.70 (1H, dd, J = 1.1, 8.5 Hz), 7.56-7.54 (1H, d, J = 8.7 Hz), 7.45-7.41 (1H, dd, J = 7.1, 8, 4 Hz), 6.89-6.86 (1H, d, J = 7.6 Hz), 2.60 (3H, s).

Scheme 10

Intermediate X19

Synthesized according to scheme 11.

To a solution of dimethyl 4,5-diiodophthalate (H1.4.0 g, 8.96 mmol) in DMF (40.0 mL) was added CuI (5.1 g, 26.9 mmol) and FSO2CF2CO2Me (13 , 77 g, 71.74 mmol) and the mixture was stirred at 80 ° C for 18 h. The mixture was then diluted with ice-cold water and extracted with EtOAc (100 mL), dried over anhydrous Na2SO4 and concentrated under reduced pressure to obtain intermediate R2 (1.8 g, 61%) as a white solid.

1H NMR (DMSO-d6, 400 MH z) 5: 8.18 (2H, s), 3.95 (6H, s).

Trimethylaluminum solution (0.45 mL, 0.909 mmol, 2.0 M toluene) was added to a solution of intermediate R2 (150 mg, 0.45 mmol) and 6-methylpyridine-2-amine (53.9 mg, 0 , 49 mmol) in toluene (2.0 mL) and the reaction was stirred at 110 ° C for 3 h. The solution was then partitioned between EtOAc and water, the organic layer was separated and the solvents were removed under reduced pressure. By purification by column chromatography, intermediate X19 (100 mg, 59%) was obtained as a pale yellow solid.

1H NMR (DMSO-d6, 400 MHz) 5: 8.45 (2H, s), 7.84-7.80 (1H, t, J = 7.6 Hz), 7.31-7.29 (1H , d, J = 7.6 Hz), 7.23-7.21 (1H, d, J = 8.0 Hz), 2.64 (3H, s).

Scheme 11

Intermediate X20

Synthesized according to scheme 12.

LiOHH2O (50 mg, 1,212 mmol) was added to a solution of intermediate R2 (200 mg, 0.606 mmol) in THF / H2O (1: 1, 6.0 mL) and the reaction mixture was stirred at room temperature for 16 h . Then, ^t H ^f was removed under reduced pressure, the crude product was acidified with 1 N HCl and filtered and the resulting solid dried to obtain intermediate T1 (140 mg, 77%) as a white solid.

1H NMR (DMSO-d6, 400 MHz) 5: 13.50 (2H, br), 8.29 (2H, s).

HATU (283 mg, 0.746 mmol) and DIPEA (0.27 mL, 1.49 mmol) were added to a solution of intermediate T1 (150 mg, 0.496 mmol) and 5,6,7,8-tetrahydroquinolin-2-amine (73 mg, 0.496 mmol) in DCM (5.0 mL) at 0 ° C. The reaction mixture was then stirred at room temperature for 18 h before being quenched with water (50 mL), extracted with EtOAc (50 mL), dried over anhydrous Na2SO4 and concentrated under reduced pressure. The crude product was purified by column chromatography to obtain intermediate X20 (85 mg, 41%) as a pale yellow solid.1

1H NMR (DMSO-d6, 400 MHz) 5: 8.53 (2H, s), 7.74-7.72 (1H, d, J = 8.4Hz), 7.28-7.26 (1H, d, J = 8.0Hz), 2.84-2.83 (4H, m), 1.86-1.79 (4H, m).

Scheme 12

Intermediate Y21

DIPEA (0.257 g, 1.99 mmol) was added to a suspension of intermediate Z48 (0.20 g, 0.66 mmol), 5,6-dimethylpyridine-2-amine (0.097 g, 0.80 mmol) and HATU (0.38 g, 1.00 mmol) in DCM (15 mL) at 0 ° C. The reaction was allowed to warm to room temperature and stirred for 18 h before being quenched with water, extracted with DCM (2 x 40 mL), washed with brine and dried over anhydrous Na2SO4. The solvents were removed in vacuo and the crude product was purified by flash column chromatography (10% ethyl acetate in hexane) to obtain intermediate Y21 (0.091 g, 0.22 mmol, 34%) as a white solid.

1H NMR (DMSO-d6, 400 MHz) 5: 10.86 (1H, s), 7.95-7.93 (1H, d, J = 8.4 Hz), 7.89-7.88 (1H , d, J = 2.0 Hz), 7.81-7.79 (1H, dd, J = 8.4 Hz, 2.0 Hz), 7.56-7.54 (1H, d, J = 8.4 Hz), 7.47-7.45 (1H, d, J = 8.0 Hz), 2.35 (3H, s), 2.22 (3H, s), 1.36 (9H, s).

The following intermediates Y22-42, Y44-Y46 and Y48 were prepared in a manner analogous to intermediate Y21 from intermediates Z49-Z51.

Intermediate Y43

To a solution of intermediate Y41 (250 mg, 0.71 mmol) in EtOH (2.5 mL) was added 10% palladium on carbon (250 mg) at room temperature. The reaction mixture was allowed to stir for 8 hours at room temperature under H2 (balloon pressure). After completing the reaction (controlled by TLC), the reaction mixture was filtered through celite and the filtrate was concentrated under reduced pressure to obtain intermediate Y43 (100 mg, 0.28 mmol, 40%).

1H NMR (CDCls, 400 MHz) 5: 8.18-8.16 (1H, d, J = 7.6 Hz), 8.06 (1H, br s), 7.72-7.71 (1H, d, J = 1.6 Hz), 7.65-7.61 (1H, t, J = 8.0 Hz), 7.45-7.43 (1H, d, J = 7.6 Hz), 7.35-7.32 (1H, dd, J = 1.6, 8.0 Hz), 6.92-6.90 (1H, d, J = 7.6 Hz), 2.67-2.63 ( 2H, t, J = 7.6 Hz), 2.43 (3H, s), 1.72-1.64 (2H, m), 1.57 (9H, s), 0.96-0.93 (3H, t, J = 7.2 Hz).

The next intermediate, Y47, was prepared analogously to intermediate Y43.

Y47 Intermediate

Synthesized from intermediate Y42 in MeOH under an atmosphere of H2 at 414 kPa (60 psi).

LCMS Method D: tR = 3.47 min, m / z = 355.10 [M H] +

Intermediate Z48

DMAP (10.8 g, 88 mmol) was added to a solution of 4-bromophthalic anhydride (20 g, 88 mmol) and t-BuOH (8.4 mL, 88 mmol) in DCM (200 mL) at room temperature. After stirring for 2 h, the reaction mixture was diluted with DCM (200 mL) and washed with 2M HCl (150 mL x 2). The solvents were removed under reduced pressure to obtain a white solid containing intermediate Z48 and its isomer. This mixture was separated by SFC to obtain intermediate Z48 (3.0 g, 10 mmol, 12%) as a white solid.

1H NMR (CDCls, 400 MHz) 5: 7.76-7.74 (2H, m), 7.67-7.65 (1H, dd J = 1.6, 8.0 Hz), 1.57 ( 9H, s).

The following intermediate, Z49, was prepared analogously to intermediate Z48,

Intermediate Z49

Synthesized from 4-trifluoromethyl-phthalic anhydride.

1H NMR (DMSO-d6, 400 MHz) 5: 13.72 (1H, s), 8.01-7.98 (2H, m), 7.83-7.81 (1H, d, J = 8, 0 Hz), 1.52 (9H, s).

Intermediate Z50

To a solution of intermediate Z48 (500 mg, 1.7 mmol) in DMF (5 mL), DIPA (2 mL), Pd (PPh3) 2Cl2 (58 mg, 0.083 mmol) and Cul (31 mg, 0, were added 17 mmol) at room temperature. The reaction mixture was cooled to -78 ° C and purged with tip gas for 20 minutes before the reaction mixture was heated to 80 ° C and stirred for 16 h. At the end of the reaction (controlled by TLC), the reaction mixture was diluted with EtOAc (20 mL), washed with water (20 mL), dried (Na2SO4) and evaporated under reduced pressure. By purification by flash column chromatography (20% EtOAc in petroleum ether) intermediate Z50 (300 mg, 1.2 mmol, 68%) was obtained as a white solid.

1H NMR (DMSO-d6, 400 MHz) 5: 13.30 (1H, s), 7.64-7.55 (3H, m), 2.08 (3H, s), 1.51 (9H, s ).

Intermediate Z51

To a solution of intermediate Z48 (1.0 g, 3.3 mmol) and 2-isopropenyl-4,4,5,5-tetramethyl- [1,3,2] dioxaborolane (0.80 mL, 6.66 mmol ) in DMF / water (10.0 mL, 4: 1) Kip04 (1.55 mg, 7.32 mmol) and S-Phos (34 mg, 0.83 mmol) were added at room temperature and the reaction mixture purged with argon for 30 min. Pd (OAc) 2 (93 mg, 0.42 mmol) was added and the mixture was heated to 85 ° C and stirred for 22 h. After completion of the reaction (controlled by T LC), the mixture was cooled to room temperature, diluted with EtOAc (30 mL) and washed with water (20 mL). The organic layer was washed with brine solution (20 mL), dried over anhydrous Na2SO4 and the solvents evaporated under reduced pressure. By purification by flash column chromatography (50% EtOAc in petroleum ether) intermediate Z51 (700 mg, 2.7 mmol, 81%) was obtained as a white solid.

1H NMR (DMSO-d6, 400 MHz): 13.15 (1H, br s), 7.69-7.68 (2H, d, J = 0.8 Hz), 7.62 (1H, s), 5.56 (1H, s), 5.25 (1H, s), 2.13 (3H, s), 1.50 (9H, s).

LCMS Method C: tR = 3.34 min, m / z = 263.16 [M-H] +

Intermediate Z52

T-BuOH (0.160 g, 2.30 mmol) was added to a solution of 5,6-dichloroisobenzofuran-1,3-dione (0.500 g, 2.30 mmol) and DMAP (0.281 g, 2.304 mmol) in DCM ( 10 mL) at 0 ° C. The reaction mixture was stirred at room temperature for 12 h before concentration in vacuo to obtain intermediate Z52 (0.631 g, 94%). The raw product is used without further purification.

Intermediate Z53

A solution of 5,6-didoroisobenzofuran-1,3-dione (500 mg, 2.3 mmol) in 2-propanol (5 mL) was heated at reflux for 18 h. The reaction was concentrated in vacuo to give intermediate Z3 (500 mg, 79%) as a white solid.

1H NMR (DMSO, 400 MHz) 5: 13.73 (1H, s, br), 7.97 (1H, s), 7.92 (1H, s), 5.12 to 5.06 (1H, m ), 1.29 (6H, d, J = 4.0 Hz). Intermediate Z54

A solution of 5,6-dichloroisobenzofuran-1,3-dione (200 mg, 0.921 mmol) in MeOH (2 mL) was refluxed for 18 h. The reaction mixture was concentrated in vacuo to give intermediate Z54 (200 mg, 87%) as a white solid.

1H NMR (DMSO, 400 MHz) 5: 13.77 (1H, s, br), 8.00 (1H, s), 7.96 (1H, s), 3.81 (3H, s).

Intermediate Z55

A mixture of 5,6-dichloroisobenzofuran-1,3-dione (600 mg, 2.76 mmol) in EtOH (20.0 ml) was heated at 100 ° C for 16 h. After completion of the reaction (controlled by TLC), the reaction mixture was concentrated in vacuo to obtain intermediate Z55 (600 mg, 83%).

1H NMR (DMSO-d6, 400 MHz) 5: 13.73 (1H, br), 7.99 (1H, s), 7.94 (1H, s), 4.30-4.25 (2H, q , J = 7.0 Hz), 1.30-1.26 (3H, t, J = 7.2 Hz).

Intermediate S52

To a solution of intermediate R2 (100 mg, 0.303 mmol) and 5,6-dimethylpyridine-2-amine (43 mg, 0.333 mmol) in toluene (2.0 mL) was added trimethyl aluminum (2.0 M in toluene , 0.29 mL, 0.606 mmol) at 0 ° C. The reaction mixture was stirred at 100 ° C for 3 h. After completion of the reaction (controlled by TLC), the reaction mixture was quenched with water, extracted with EtOAc (50 ml), dried over anhydrous Na2SO4 and the solvent was evaporated under reduced pressure. The crude product was purified by column chromatography to obtain intermediate S52 (60 mg, 47%) as a pale yellow solid.1

1H NMR (DMSO-d6, 400 MHz) 5: 11.12 (1H, s), 8.35 (1H, s), 8.29 (1 H, s), 7.91-7.89 (1H, d, J = 8.0Hz), 7.59-7.57 (1H, d, J = 7.6Hz), 3.82 (3H, s), 2.38 (3H, s), 2.23 ( 3H, s).

Prodrugs

It will be appreciated that an intermediate of type X can function as a prodrug of a compound of the formula [A], since after administration, an intermediate of type X can be converted in vivo to give a compound of the formula A, in fact in a process analogous to the synthesis of compounds of the formula A and type 1 according to scheme 1. It will be appreciated that when the substituent A # B a mixture of two isomers 1 and 1a can be obtained. When B = H, only isomer 1 is the object of this invention, and alternative isomer 1a is not. When A = B, only a single compound will be obtained.

For example, intermediate X1 can give example 1 and the corresponding regioisomer that is not an object of this invention, in a relationship that can be determined by the exact conditions of conversion in vivo. Symmetrically substituted intermediates X10,11,12,13,15, 19 and 20 could give the examples of single product 10,11,12,13,15,47 and 48 respectively.

Similarly, simple esters of molecules of the formula A could act as prodrugs from which a compound of the formula A is released in vivo . Such esters may include, but are not limited to intermediates of type Y and S .

Examples

Example 1: N- (6-methyl-pyridin-2-yl) -5-trifluoromethyl-phthalamic acid

Lithium hydroxide monohydrate (0.27 g, 6.5 mmol) was added to a suspension of intermediate X1 (1.0 g, 3.3 mmol) in THF / H2O (1: 1, 10 ml) and the mixture was stirred Mix for 1 hour at room temperature. The reaction was then acidified with a saturated solution of citric acid, and the resulting precipitate was filtered and washed with diethyl ether (20 ml). The solid was dried under vacuum to obtain a mixture of product isomers as a white solid. By separating the isomers by preparative HPLC (method 1) the title compound (0.075 g, 0.23 mmol, 7%) was obtained as a white solid.

1H NMR (DMSO-d6, 400 MHz) 5: 13.51 (1H, s), 10.96 (1H, s), 8.12 (1H, s), 8.01-7.98 (2H, m ), 7.75-7.69 (2H, m), 7.02-7.00 (1H, d, J = 7.6 Hz), 2.40 (3H, s).

LCMS Method A: tR = 0.46 min, m / z = 325.1 [M + H] +

In a manner analogous to the preparation of Intermediates Example 1, Examples 2-18, 47 and 48 were prepared from intermediates X2-20.

Example 2: 5-Bromo-N- (6-methyl-pyridin-2-yl) -phthalamic acid

From intermediate X2

Synthesized using sodium hydroxide in ethanol / water (2: 1)

1H NMR (DMSO-d6, 400 MHz) 5: 10.80 (1H, br s), 7.95-7.94 (2H, m), 7.83-7.80 (1H, dd, J = 8 , 4, 2.0 Hz), 7.72-7.68 (1H, t, J = 7.8 Hz), 7.48-7.46 (1H, d, J = 8.0 Hz), 7 , 00-6.98 (1H, d, J = 7.2 Hz), 2.39 (3H, s).

LCMS Method A: tR = 0.41 min, m / z = 335.0 [M + H] +

Example 3: 5-methyl-N- (6-methyl-pyridin-2-yl) -phthalamic acid

From intermediate X3

Synthesized using sodium hydroxide in MeOH / water (2: 1)

1H NMR (DMSO-d6, 400 MHz) 5: 12.87 (1H, br s), 10.70 (1H, s), 7.97-7.95 (1H, d, J = 8.4 Hz) , 7.70-7.66 (1H, t, J = 7.8 Hz), 7.63 (1H, s), 7.40 (2H, s), 6.98-6.97 (1H, d , J = 7.2 Hz), 2.39 (6H, s).

LCMS Method A: tR = 0.36 min, m / z = 271.2 [M + H] +

Example 4: 5-Chloro-N- (6-methyl-pyridin-2-yl) -phthalamic acid

From intermediate X4

Synthesized using sodium hydroxide in MeOH / water (2: 1)

1H NMR (DMSO-d6, 400 MHz) 5: 13.32 (1H, br s), 10.89 (1H, s), 7.97-7.95 (1H, d, J = 7.2 Hz) , 7.82-7.81 (1H, d, J = 2.0 Hz) 7.72-7.67 (2H, m), 7.55-7.53 (1H, d, J = 8.4 Hz), 7.00-6.98 (1H, d, J = 7.6 Hz), 2.40 (3H, s).

LCMS Method A: tR = 0.39 min, m / z = 291.1 [M + H] +

Example 5: 4,5-Dichloro-N- (6-methyl-pyridin-2-yl) -phthalamic acid

From intermediate X5

Synthesized using lithium hydroxide monohydrate in THF / water (1: 1)

1H NMR (DMSO-d6, 400 MHz) 5: 13.48 (1H, s), 10.97 (1H, s), 8.00 (1H, s), 7.97-7.95 (1H, d , J = 8.0 Hz), 7.85 (1H, s), 7.72-7.68 (1H, t, J = 8.0 Hz), 7.01-6.99 (1H, d, J = 7.6 Hz), 2.40 (3H, s).

LCMS Method A: tR = 0.51 min, m / z = 325.0 [M H] +

Example 6: 5-Bromo-N- (3-methyl-4,5,6,7-tetrahydro-benzo [b] thiophene-2-yl) -phthalamic acid

From intermediate X6

Synthesized using lithium hydroxide monohydrate in THF / water (1: 1)

1H NMR (DMSO-d6, 400 MHz) 5: 13.55 (1H, br s), 12.19 (1H, br s), 8.06-8.04 (1H, d, J = 2.1 Hz ), 7.91-7.88 (1H, dd, J = 8.2, 2.1 Hz), 7.51-7.49 (1H, d, J = 8.2 Hz), 2.65- 2.61 (2H, m), 2.53-2.49 (2H, m), 1.80-1.74 (4H, m).

LCMS Method B: tR = 1.71 min, m / z = 403.3 [M-H] +

Example 7: N- (5,6-dimethyl-pyridin-2-yl) -5-trifluoromethyl-phthalamic acid

From intermediate X7

Synthesized using lithium hydroxide monohydrate in THF / water (1: 1)

1H NMR (DMSO-d6, 400 MHz) 5: 13.48 (1H, br s), 10.87 (1H, s), 8.10 (1H, s), 8.00-7.98 (1H, d, J = 7.6 Hz), 7.91 7.89 (1H, d, J = 8.4 Hz), 7.74-7.72 (1H, d, J = 7.6 Hz), 7 , 56-7.54 (1H, d, J = 8.4 Hz), 2.35 (3H, s), 2.22 (3H, s).

LCMS Method A: tR = 0.46 min, m / z = 339.1 [M H] +

Example 8: N- (4-methyl-pyridin-2-yl) -5-trifluoromethyl-phthalamic acid

From intermediate X8

Synthesized using lithium hydroxide monohydrate in THF / water (1: 1)

1H NMR (DMSO-d6, 400 MHz) 5: 13.53 (1H, br s), 10.94 (1H, s), 8.19-8.17 (1H, d, J = 4.8 Hz) , 8.13 (1H, s), 8.03 8.01 (2H, m), 7.76-7.74 (1H, d, J = 7.6 Hz), 7.00-6.98 ( 1H, d, J = 4.8 Hz), 2.35 (3H, s).

LCMS Method A: tR = 0.42 min, m / z = 325.1 [M H] +

Example 9: N- (2-methyl-pyridin-4-yl) -5-trifluoromethyl-phthalamic acid

From intermediate X9

Synthesized using lithium hydroxide monohydrate in THF / water (1: 1)

1H NMR (DMSO-d6, 400 MHz) 5: 13.80 (1H, br, s), 10.89 (1H, s), 8.34-8.33 (1H, d, J = 6.0 Hz ), 8.17 (1H, s), 8.08 8.06 (1H, d, J = 8.0 Hz), 7.83-7.81 (1H, d, J = 8.0 Hz), 7.54 (1H, s), 7.42-7.41 (1H, d, J = 4.4 Hz), 2.44 (3H, s). LCMS Method A: tR = 0.40 min, m / z = 325.1 [M H] +

Example 10: 4,5-Dichloro-N- (4-methyl-pyridin-2-yl) -phthalamic acid

From intermediate X10

Synthesized using lithium hydroxide monohydrate in THF / water (1: 1)

1H NMR (DMSO-d6, 400 MHz) 5: 13.50 (1H, s), 10.93 (1H, s), 8.19-8.17 (1H, d, J = 4.8 Hz), 8.02 (2H, s), 7.86 (1H, s), 6.99-6.98 (1H, d, J = 4.8 Hz), 2.40 (3H, s).

LCMS Method A: tR = 0.46 min, m / z = 325.0 [M H] +

Example 11: 4,5-Dichloro-N- (5,6-dimethyl-pyridin-2-yl) -phthalamic acid

From intermediate X11

Synthesized using lithium hydroxide monohydrate in THF / water (1: 1)

1H NMR (DMSO-d6, 400 MHz) 5: 13.46 (1H, br s), 10.84 (1H, s), 7.99 (1H, s), 7.89-7.87 (1H, d, J = 8.4 Hz), 7.83 (1H, s), 7.55-7.53 (1H, d, J = 8.4 Hz), 2.35 (3H, s), 2, 22 (3H, s).

LCMS Method A: tR = 0.50 min, m / z = 339.1 [M + H] +

Example 12: 4,5-Dichloro-N- (2-methyl-pyridin-4-yl) -phthalamic acid

From intermediate X12

Synthesized using lithium hydroxide monohydrate in THF / H2O (1: 1)

1H NMR (DMSO-d6, 400 MHz) 5: 13.66 (1H, br s), 10.96 (1H, s), 8.34-8.33 (1H, d, J = 6.0 Hz) , 8.06 (1H, s), 7.95 (1H, s), 7.52 (1H, s), 7.41-7.40 (1H, d, J = 4.4 Hz), 2, 49 (3H, s).

LCMS Method A: tR = 0.45 min, m / z = 325.0 [M + H] +

Example 13: 4,5-Dichloro-N- (2-methyl-pyrimidin-4-yl) -phthalamic acid

From intermediate X13

Synthesized using lithium hydroxide monohydrate in THF / water (1: 1)

1H NMR (DMSO-d6, 400 MHz) 5: 13.61 (1H, s), 11.38 (1H, s), 8.61-8.59 (1H, d, J = 5.6 Hz), 8.04 (1H, s), 7.95-7.93 (1H, d, J = 5.2 Hz), 7.91 (1H, s), 2.51 (3H, s).

LCMS Method A: tR = 0.46 min, m / z = 326.0 [M + H] +

Example 14: 5-doro-6-fluoro-N- (6-methyl-pyridin-2-yl) -phthalamic acid

From intermediate X14

Synthesized using lithium hydroxide monohydrate in THF / water (1: 1)

1H NMR (DMSO-d6, 600 MHz): 11.11 (1H, s), 7.92-7.89 (1H, d, J = 8.6 Hz), 7.82-7.78 (1H, t, J = 7.5 Hz), 7.74-7.70 (1H, t, J = 7.5 Hz), 7.63-7.59 (1H, d, J = 9.7 Hz), 7.06-7.03 (1H, d, J = 7.5 Hz), 2.43 (3H, s).

LCMS Method A: tR = 0.37 min, m / z = 309.1 [M + H] +

Example 15: 4,5-Dimethyl-N- (6-methyl-pyridin-2-yl) -phthalamic acid

From intermediate X15

Synthesized using lithium hydroxide monohydrate in THF / water (1: 1)

1H NMR (DMSO-d6, 600 MHz) 5: 12.77 (1H, br s), 10.67 (1H, s), 8.00-7.95 (1H, br d, J = 7.0 Hz ), 7.71-7.67 (1H, t, J = 7.0 Hz), 7.62 (1H, s), 7.28 (1H, s), 6.99-6.96 (1H, d, J = 7.0 Hz), 2.40 (3H, s), 2.29 (6H, s).

LCMS Method A: tR = 0.41 min, m / z = 285.2 [M + H] +

Example 16: 2 - ((3-Chloro-5- (trifluoromethyl) pyridin-2-yl) carbamoyl) -5- (trifluoromethyl) benzoic acid

From intermediate X16

Synthesized using lithium hydroxide monohydrate in THF / H2O (1: 1)

1H NMR (DMSO-d6, 400 MHz) 5: 13.65 (1H, s), 11.20 (1H, s), 8.79 (1H, s), 8.55-8.54 (1H, d , J = 1.6 Hz), 8.14 (1H, s), 8.07-8.05 (1H, dd, J = 8.0, 1.2 Hz), 7.81-7.79 ( 1H, d, J = 8.0 Hz).

LCMS Method A: tR = 0.69 min, m / z = 413.0 [M + H] +

Example 17: 2 - ((4-methylpyrimidin-2-yl) carbamoyl) -5- (trifluoromethyl) benzoic acid

From intermediate X17

Synthesized using lithium hydroxide monohydrate in THF / H2O (1: 1)

1H NMR (DMSO-d6, 400 MHz) 5: 13.51 (1H, br s), 11.10 (1H, s), 8.39-8.38 (1H, d, J = 3.2 Hz) , 8.13 (1H, s) 7.99-7.97 (1H, d, J = 8.0 Hz), 7.64-7.62 (1H, d, J = 8.0 Hz), 7 , 00-6.99 (1H, d, J = 4.4 Hz), 2.22 (3H, s)

LCMS Method A: tR = 0.48 min, m / z = 326.1 [M + H] +

Example 18: 2 - ((5,6-Dimethylpyrazin-2-yl) carbamoyl) -5- (trifluoromethyl) benzoic acid

From intermediate X18

Synthesized using lithium hydroxide monohydrate in THF / H2O (1: 1)

1H NMR (DMSO-d6, 400 MHz) 5: 13.58 (1H, br s), 11.17 (1H, s), 9.09 (1H, s), 8.13 (1H, s), 8 , 04-8.02 (1H, d, J = 8.0 Hz), 7.79-7.77 (1H, d, J = 8.0 Hz), 2.46 (3H, s), 2, 43 (3H, s).

LCMS Method A: tR = 0.54 min, m / z = 340.1 [M + H] +

Example 19: 5-Bromo-N- (5-methyl-pyridin-2-yl) -phthalamic acid

A solution of 5-bromo-isobenzofuran-1,3-dione (1.0 g, 4.42 mmol) and 2-amino-5-picoline (0.41 g, 4.42 mmol) in acetone (140 ml) it was heated at reflux for 2 h. After cooling to room temperature, the solvents were removed under reduced pressure and the resulting isomer mixture was separated by preparative HPLC (method 2) to obtain the title compound (0.060 g, 0.18 mmol, 4%) as a solid White.

1H NMR (DMSO-d6, 400 MHz) 5: 13.33 (1H, br s), 10.85 (1H, s), 8.15 (1H, br, s), 8.06-8.04 ( 1H, d, J = 8.0 Hz), 7.96 7.95 (1H, d, J = 1.6 Hz), 7.83-7.81 (1H, dd, J = 2.0, 8 , 0 Hz) 7.65-7.63 (1H, d, J = 6.0 Hz), 7.49-7.47 (1H, d, J = 8.4), 2.26 (3H, s ).

LCMS Method A: tR = 0.40 min, m / z = 335.0 [M + H] +

The following examples, 20-22, were prepared in a manner analogous to example 19, starting from 5-bromoisobenzofuran-1,3-dione.

Example 20: 5-Bromo-N- (5-chloro-pyridin-2-yl) -phthalamic acid

Synthesized using 2-amino-5-chloropyridine

1H NMR (DMSO-d6, 400 MHz) 5: 13.40 (1H, brs), 11.19 (1H, br s), 8.39-8.38 (1H, d, J = 2.4 Hz) , 8.20-8.18 (1H, d, J = 8.4 Hz), 7.98-7.93 (2H, m), 7.85-7.83 (1H, d, J = 8, 0 Hz), 7.52-7.50 (1H, d, J = 8.4 Hz).

LCMS Method A: tR = 0.59 min, m / z = 354.9 [M + H] +

Example 21: 5-Bromo-N-pyridin-2-yl-phthalamic acid

Synthesized using 2-amino-pyridine

1H NMR (DMSO-d6, 400 MHz) 5: 13.36 (1H, br s), 10.92 (1H, s), 8.33-8.32 (1H, d, J = 3.6 Hz) , 8.16-8.14 (1H, d, J = 8.0 Hz), 7.98-7.97 (1H, d, J = 2.0 Hz), 7.85-7.80 (2H , m), 7.50-7.48 (1H, d, J = 8.0 Hz), 7.15-7.12 (1H, dd, J = 4.8, 6.4 Hz). LCMS Method A: tR = 0.38 min, m / z = 321.0 [M H] +

Example 22: 5-Bromo-N- (6-chloro-pyridin-2-yl) -phthalamic acid

Synthesized using 2-amino-6-chloropyridine.

1H NMR (DMSO-d6, 400 MHz) 5: 13.41 (1H, br s), 11.25 (1H, s), 8.15-8.13 (1H, d, J = 7.6 Hz) , 7.98-7.98 (1H, d, J = 1.6 Hz), 7.91-7.79 (2H, m), 7.51-7.49 (1H, d, J = 8, 0 Hz), 7.25-7.23 (1H, d, J = 7.6 Hz).

LCMS Method A: tR = 0.60 min, m / z = 354.9 [M H] +

Example 23: 5-Bromo-N- (5,6-dimethyl-pyridin-2-yl) -phthalamic acid

A solution of intermediate Y21 (0.090 g, 0.22 mmol) in TFA / DCM (1: 1, 2 mL) was stirred at room temperature for 4 h. After completing the reaction (controlled by TLC), the reaction mixture was concentrated in vacuo to obtain a solid that was washed with diethyl ether (6 x 9 mL) to give the title compound (0.045 g, 0.13 mmol, 59%) as a white solid.1

1H NMR (DMSO-d6, 400 MHz) 5: 13.29 (1H, br s), 10.75 (1H, s), 7.95-7.94 (1H, d, J = 2.0 Hz) , 7.89-7.87 (1H, d, J = 8.4 H z), 7.82-7.79 (1H, dd, J = 8.0, 1.6 Hz), 7.54- 7.52 (1H, d, J = 8.0 Hz), 7.47-7.45 (1H, d, J = 8.4 Hz), 2.35 (3H, s), 2.21 (3H , s).

LCMS Method A: tR = 0.41 min, m / z = 348.9 [M H] +

The following examples 1,2, 24-46 and 51 were prepared analogously to example 23 from the appropriate intermediates Y22-48,

Example 1: N- (6-methyl-pyridin-2-yl) -5-trifluoromethyl-phthalamic acid

From intermediate Y22

1H NMR (DMSO-d6, 400 MHz) 5: 13.51 (1H, s), 10.96 (1H, s), 8.12 (1H, s), 8.01-7.98 (2H, m ), 7.75-7.69 (2H, m), 7.02-7.00 (1H, d, J = 7.6 Hz), 2.40 (3H, s).

LCMS Method A: tR = 0.46 min, m / z = 325.1 [M H] +

Example 2: 5-Bromo-N- (6-methyl-pyridin-2-yl) -phthalamic acid

From intermediate Y23

1H NMR (DMSO-d6, 400 MHz) 5: 13.31 (1H, br s), 10.86 (1H, s), 7.95 (2H, m), 7.82-7.70 (2H, m), 7.48-7.46 (1H, d, J = 8.0 Hz), 7.00-6.98 (1H, d, J = 6.8 Hz), 2.39 (3H, s ).

LCMS Method A: tR = 0.41 min, m / z = 335.0 [M H] +

Example 24: 5-Bromo-N- (4-methyl-pyridin-2-yl) -phthalamic acid

From intermediate Y24

1H NMR (DMSO-d6, 400 MHz) 5: 13.34 (1H, br s), 10.84 (1H, s), 8.18 -8.17 (1H, d, J = 4.8 Hz) , 8.01 (1H, s), 7.97 7.96 (1H, d, J = 2.0 Hz), 7.84-7.82 (1H, dd, J = 2.0, 8.4Hz ) 7.48-7.46 (1H, d, J = 8.4 Hz), 6.98-6.97 (1H, d, J = 4.8), 2.34 (3H, s).

LCMS Method A: tR = 0.37 min, m / z = 335.0 [M H] +

Example 25: 5-Bromo-N- (2-methyl-pyridin-4-yl) -phthalamic acid

From intermediate Y251

1H NMR (DMSO-d6, 400 MHz) 5: 14.20 (1H, brs), 11.33 (1H, s), 8.52-8.50 (1H, d, J = 6.4 Hz), 8.07-8.07 (1H, d, J = 1.6 Hz), 7.96-7.94 (1H, dd, J = 1.6, 8.0 Hz), 7.83 (1H, s), 7.72-7.70 (1H, d, J = 8.4 Hz), 7.60-7.57 (1H, d, J = 8.0 Hz), 2.58 (3H, s ).

LCMS Method A: tR = 0.36 min, m / z = 335.0 [M + H] +

Example 26: 5-Bromo-N-pyridin-3-yl) -phthalamic acid

From intermediate Y26

1H NMR (DMSO-d6, 400 MHz) 5: 13.47 (1H, br s), 10.60 (1H, s), 8.81-8.80 (1H, d, J = 2.4 Hz) , 8.31-8.30 (1H, dd, J = 4.8, 1.2 Hz), 8.11-8.09 (1H, d, J = 8.8 Hz), 8.02-8.01 (1H, d, J = 2.0 Hz), 7.91-7.88 (1H, dd, J = 8.0, 2.0 Hz), 7.57 7.55 (1H, d, J = 8.0 Hz), 7.41-7.38 (1H, dd, J = 8.4, 4.8 Hz).

LCMS Method A: tR = 0.33 min, m / z = 321.0 [M + H] +

Example 27: 5-Bromo-N- (3-methyl-pyridin-2-yl) -phthalamic acid

From intermediate Y27

1H NMR (DMSO, 400 MHz) 5: 10.63 (1H, br s), 8.28 (1H, s), 7.96-7.95 (1H, d, J = 1.6 Hz), 7 , 88-7.86 (1H, dd, J = 1.6, 8.0 Hz), 7.79-7.77 (1H, d, J = 6.8 Hz), 7.57-7.55 (1H, d, J = 8.4 Hz), 7.29-7.26 (1H, t, J = 5.2 Hz), 2.30 (3H, s).

LCMS Method A: tR = 0.36 min, m / z = 335.0 [M + H] +

Example 28: 5-Bromo-N- (4-methyl-thiazol-2-yl) -phthalamic acid

From intermediate Y28

1H NMR (DMSO-d6, 400 MHz) 5: 13.43 (1H, br s), 12.66 (1H, s), 7.99-7.98 (1H, d, J = 2.0 Hz) , 7.87-7.84 (1H, dd, J = 8.0, 2.0 Hz), 7.56-7.54 (1H, d, J = 8.4 Hz), 6.81-6 , 81 (1H, d, J = 0.8 Hz), 2.27 (3H, s).

LCMS Method A: tR = 0.52 min, m / z = 341.0 [M + H] +

Example 29: 5-Bromo-N-quinolin-2-yl-phthalamic acid

From intermediate Y291

1H NMR (DMSO-d6, 400 MHz) 5: 13.40 (1H, brs), 11.27 (1H, s), 8.39 (2H, m), 7.99-7.92 (2H, m ), 7.87-7.84 (1H, dd, J = 2.0, 8.4 Hz), 7.80-7.50 (4H, m).

LCMS Method A: tR = 0.51 min, m / z = 370.9 [M + H] +

Example 30: 5-Bromo-N- (5,6-dichloro-pyridin-2-yl) -phthalamic acid

From intermediate Y30

1H NMR (DMSO-d6, 400 MHz) 5: 13.40 (1H, br s), 11.6 (1H, s), 8.17-8.12 (2H, m), 7.98-7, 97 (1H, d, J = 2.0 Hz), 7.85-7.83 (1H, dd, J = 1.6, 8.0 Hz), 7.53-7.50 (1H, d, J = 8.4 Hz).

LCMS Method A: tR = 0.68 min, m / z = 388.8 [M + H] +

Example 31: 5-Bromo-N- (6-methyl-pyridin-3-yl) -phthalamic acid

From intermediate Y31

1H NMR (DMSO-d6, 400 MHz) 5: 10.49 (1H, s), 8.67-8.66 (1H, d, J = 2.4 Hz), 8.00-7.95 (2H , m), 7.89-7.87 (1H, dd, J = 2.0, 8.0 Hz) 7.55-7.53 (1H, d, J = 8.0 Hz), 7.24 -7.22 (1H, d, J = 8.4 Hz), 2.49 (3H, s).

LCMS Method A: tR = 0.34 min, m / z = 335.0 M + H] +

Example 32: 5-Bromo-N- (6-methyl-pyridazin-3-yl) -phthalamic acid

From intermediate Y32

1H NMR (DMSO-d6, 400 MHz) 5: 13.42 (1H, br s), 11.45 (1H, s), 8.27-8.25 (1H, d, J = 9.2 Hz) , 8.00-7.99 (1H, d, J = 2.0 Hz), 7.87-7.85 (1H, dd, J = 8.0, 2.0 Hz), 7.61-7 , 59 (1H, d, J = 8.8 Hz), 7.54-7.52 (1H, d, J = 8.4 Hz), 2.49 (3H, s). LCMS Method A: tR = 0.39 min, m / z = 336.0 [M + H] +

Example 33: 5-Bromo-N- (4,6-dimethyl-pyridin-2-yl) -phthalamic acid

From intermediate Y33

1H NMR (DMSO-d6, 400 MHz) 5: 13.29 (1H, br, s), 10.79 (1H, s), 7.94 (1H, s), 7.82-7.80 (2H , d, J = 8.4 Hz), 7.46 7.44 (1H, d, J = 7.6 Hz), 6.84 (1H, s), 2.34 (3H, s), 2, 29 (3H, s)

LCMS Method A: tR = 0.40 min, m / z = 348.9 [M + H] +

Example 34: 5-Bromo-N- (2-methyl-pyrimidin-4-yl) -phthalamic acid

From l in te rm ed io Y 34

1H NMR (DMSO-d6, 400 MHz) 5: 13.40 (1H, br s), 11.41 (1H, s), 8.59-8.58 (1H, d, J = 5.6 Hz) , 7.98-7.94 (2H, m), 7.85-7.83 (1H, dd, J = 1.6, 8.0 Hz), 7.51-7.49 (1H, d, J = 8.0 Hz), 2.51 (3H, s).

LCMS Method A: tR = 0.38 min, m / z = 336.0 [M + H] +

Example 35: 5-Bromo-N- (6-methyl-pyrimidin-4-yl) -phthalamic acid

From intermediate Y35

1H NMR (DMSO-d6, 400 MHz) 5: 13.46 (1H, s), 11.28 (1H, s), 8.74 (1H, s), 8.04 (1H, s), 8, 00 (1H, s), 7.87-8.85 (1H, d, J = 7.6 Hz), 7.51-7.49 (1H, d, J = 8.0 Hz), 2.46 (3H, s).

LCMS Method A: tR = 0.41 min, m / z = 336.0 [M H] +

Example 36: N- (2-Methoxy-pyridin-4-yl) -5-trifluoromethyl-phthalamic acid

From intermediate Y36

1H NMR (DMSO-d6, 400 MHz) 5: 13.69 (1H, br s), 10.78 (1H, s), 8.18 (1H, s), 8.09-8.05 (2H, t, J = 7.2 Hz), 7.82-7.80 (1H, d, J = 8.0 Hz), 7.17 (1H, s), 7.15-7.14 (1H, d , J = 5.6 Hz), 3.83 (3H, s).

LCMS Method A: tR = 0.45 min, m / z = 341.1 [M H] +

Example 37: N- (6-methoxy-pyridin-2-yl) -5-trifluoromethylphthalamic acid

From intermediate Y37

1H NMR (DMSO-d6, 400 MHz) 5: 13.55 (1H, br s), 10.84 (1H, s), 8.14 (1H, s), 8.01-8.03 (1H, d, J = 8.0 Hz), 7.76 7.72 (3H, m), 6.56-6.55 (1H, d, J = 6.8Hz), 3.81 (3H, s).

LCMS Method A: tR = 0.62 min, m / z = 341.1 [M H] +

Example 38: N-pyridin-2-ylmethyl-5-trifluoromethylphthalamic acid

From l in te rm ed io Y 38

1H NMR (DMSO-d6, 400 MHz) 5: 13.55 (1H, br s), 9.11-9.08 (1H, t, J = 6.0 Hz), 8.51-8.50 ( 1H, d, J = 4.0 Hz), 8.07 (1H, s), 8.02-8.00 (1H, d, J = 8.0 Hz), 7.79-7.73 (2H , m), 7.53-7.51 (1H, d, J = 7.6 Hz), 7.29-7.26 (1H, q, J = 4.0 Hz), 4.54-4, 53 (2H, d, J = 6.4 Hz).

LCMS Method A: tR = 0.35 min m / z = 325.1 [M H] +

Example 39: N-pyridin-4-ylmethyl-5-trifluoromethylphthalamic acid

From intermediate Y39

1H NMR (DMSO-d6, 400 MHz) 5: 13.62 (1H, s), 9.10-9.07 (1H, t, J = 6.0 Hz), 8.52-8.51 (2H , d, J = 5.6 Hz), 8.08 (1H, s), 8.02-8.00 (1H, d, J = 8.0 Hz), 7.74-7.72 (1H, d, J = 8.0 Hz), 7.43-7.41 (2H, d, J = 5.6 Hz), 4.49-4.47 (2H, d, J = 6.0 Hz). LCMS Method 450: tR = 0.34 min, m / z = 325.1 [M H] +

Example 40: N-pyridin-3-ylmethyl-5-trifluoromethylphthalamic acid

From intermediate Y40

1H NMR (DMSO-d6, 400 MHz) 5: 9.12-9.10 (1H, t, J = 5.8 Hz), 8.72 (1H, s), 8.64-8.62 (1H , d, J = 4.4 Hz), 8.14-8.12 (1H, d, J = 8.0 Hz), 8.08 (1H, s), 8.02-8.00 (1H, d, J = 7.6 Hz), 7.73-7.71 (1H, d, J = 8.0 Hz), 7.67-7.63 (1H, q, J = 4.4 Hz), 4.56-4.54 (2H, d, J = 6.0 Hz).

LCMS Method A: tR = 0.34 m in, m / z = 325.1 [M H] +

Example 41: N- (6-methyl-pyridin-2-yl) -5-propylphthalamic acid

From intermediate Y431

1H NMR (DMSO-d6, 400 MHz) 5: 12.88 (1H, br s), 10.70 (1H, s), 7.97-7.95 (1H, d, J = 8.0 Hz) , 7.70-7.66 (1H, t, J = 7.8 Hz), 7.63 (1H, s), 7.42 (2H, s), 6.98-6.97 (1H, d , J = 7.6 Hz), 2.66-2.62 (2H, t, J = 7.8 Hz), 2.39 (3H, s), 1.66-1.57 (2H, m) , 0.92-0.89 (3H, t, J = 7.2 Hz).

LCMS Method A: tR = 0.48 min, m / z = 299.1 [M H] +

Example 42: N 5-Isopropenyl-N- (6-methyl-pyridin-2-yl) -phthalamic acid

From l in te rm ed io Y 42

1H NMR (DMSO-d6, 400 MHz) 5: 10.81 (1H, s), 7.96-7.95 (1H, m), 7.90 (1H, s), 7.74-7.69 (2H, m), 7.51-7.49 (1H, d, J = 8 Hz), 7.01-6.99 (1H, d, J = 6.8 Hz), 5.55 (1H, s), 5.23 (1H, s), 2.40 (3H, s), 2.15 (3H, s).

LCMS Method A: tR = 0.45 min, m / z = 297.2 [M + H] +

Example 43: N 5-Isopropyl-N- (6-methyl-pyridin-2-yl) -phthalamic acid

From intermediate Y47

1H NMR (DMSO-d6, 400 MHz) 5: 12.90 (1H, br s), 10.70 (1H, s), 7.96-7.94 (1H, d, J = 8.0 Hz) , 7.70-7.66 (2H, t, J = 7.8 Hz), 7.49-7.43 (2H, m), 6.98-6.96 (1h, d, J = 7, 6 Hz), 3.17-2.96 (1H, m), 2.39 (3H, s), 1.24 (6H, d, J = 8.8 Hz). LCMS Method A: tR = 0.47 min, m / z = 299.2 [M + H] +

Example 44: 2 - ((2-Methylpyrimidin-4-yl) carbamoyl) -5- (trifluoromethyl) benzoic acid

From intermediate Y44

1H NMR (DMSO-d6, 400 MHz) 5: 11.52 (1H, s), 8.65-8.63 (1H, d, J = 5.6 Hz), 8.15 (1H, s), 8.06-8.04 (1H, d, J = 8.0 Hz), 8.01-8.00 (1H, d, J = 5.2 Hz), 7.79-7.77 (1H, d, J = 7.6 Hz), 2.53 (3H, s).

LCMS Method A: tR = 0.43 min, m / z = 326.1 [M + H] +

Example 45: 2 - ((4,5-Dimethylpyrimidin-2-yl) carbamoyl) -5- (trifluoromethyl) benzoic acid

From intermediate Y45

1H NMR (DMSO-d6, 400 MHz) 5: 13.44 (1H, br s), 10.97 (1H, s), 8.21 (1H, s), 8.12 (1H, s), 7 , 97-7.96 (1H, d, J = 7.2 Hz), 7.62-7.60 (1H, d, J = 8.0 Hz), 2.17 (3H, br s), 2 , 10 (3H, s).

LCMS Method A: tR = 0.51 min, m / z = 340.1 [M + H] +

Example 46: 2 - ((5,6,7,8-tetrahydroquinolin-2-yl) carbamoyl) -5- (trifluoromethyl) benzoic acid

From intermediate Y46

1H NMR (DMSO-d6, 400 MHz) 5: 13.49-13.46 (1H, d, J = 10 Hz), 10.92 (1H, s), 8.10 (1H, s), 8, 00-7.98 (1H, d, J = 7.6 Hz), 7.92-7.90 (1H, d, J = 7.6 Hz), 7.74-7.72 (1H, d, J = 7.6 Hz), 7.50-7.48 (1H, d, J = 8.0 Hz), 2.72-2.60 (4H, m), 1.81-1.73 (4H , m).

LCMS Method A: tR = 0.51 min, m / z = 365.1 [M + H] +

Example 47: 2 - ((6-methylpyridin-2-yl) carbamoyl) -4,5-bis (trifluoromethyl) benzoic acid

From intermediate X19

Synthesized using lithium hydroxide monohydrate in THF / H2O (1: 1)

1H NMR (DMSO-d6, 400 MHz) 5: 14.0 (1H, s, br), 11.29 (1H, s), 8.33 (1H, s), 8.23 (1H, s), 7.98 (1H, s) 7.75-7.71 (1H, t, J = 8.0 Hz), 7.039-7.021 (1H, d, J = 7.2 Hz), 2.41 (3H, s).

LCMS Method A: tR = 0.61 min, m / z = 392.9 [M + H] +

Example 48: 2 - ((5,6,7,8-tetrahydroquinolin-2-yl) carbamoyl) -4,5-bis (trifluoromethyl) benzoic acid

From intermediate X20

Synthesized using lithium hydroxide monohydrate in THF / H2O (1: 1)

1H NMR (DMSO-d6, 400 MHz) 5: 13.90 (1H, br), 11.05 (1H, s), 8.33 (1H, s), 8.20 (1H, s), 7, 92-7.90 (1H, d, J = 8.4Hz), 7.52-7.50 (1H, d, J = 8.0Hz), 2.72-2.71 (4H, m), 1.76 -1.74 (4H, m).

LCMS Method A: tR = 0.66 min, m / z = 433.1 [M + H] +

Example 49: 2 - ((5,6-Dimethylpyridin-2-yl) carbamoyl) -4,5-bis (trifluoromethyl) benzoic acid

From intermediate S52

LiOH.H2O (12 mg, 0.285 mmol) was added to a solution of intermediate S52 (60 mg, 0.142 mmol) in THF / H2O (1: 1) (3.0 ml) and the reaction mixture was stirred at room temperature for 1 h. Then, t Hf was removed in vacuo and the crude material was acidified with 1 N HCl. The resulting solid was filtered, washed with pentane and dried under reduced pressure to obtain the title compound (45 mg, 78%). as a white solid.1

1H NMR (DMSO-d6, 400 MHz) 5: 11.41 (1H, s), 8.30 (1H, s), 8.23 (1H, s), 7.92-7.90 (1H, d , J = 7.2Hz), 7.57-7.55 (1H, d, J = 8.4Hz), 2.36 (3H, s), 2.22 (3H, s).

LCMS Method A: tR = 0.61 min, m / z = 407.0 [M + H] +

Example 50: 2 - ((2-Methylpyrimidin-4-yl) carbamoyl) -4,5-bis (trifluoromethyl) benzoic acid

From intermediate T1

To a solution of intermediate T1 (100 mg, 0.331 mmol) and 2-methylpyrimidin-4-amine (36 mg, 0.331 mmol) in DCM (3.0 mL) were added HATU (188 mg, 0.496 mmol) and DIP ^e A (0.18 mL, 0.993 mmol) at 0 ° C. The reaction mixture was stirred at room temperature for 18 h. After completion of the reaction (controlled by TLC), the reaction mixture was diluted with water (50 ml), extracted with EtOAc (50 ml) and dried over anhydrous Na2SO4. The crude product was purified by column chromatography to obtain the title compound (100 mg, 77%) as a white solid.

1H NMR (DMSO-d6, 400 MHz) 5: 14.07 (1H, br), 11.61 (1H, s), 8.63-8.62 (1H, d, J = 6.0Hz), 8 , 36 (1H, s), 8.30 (1H, s), 7.95 (1H, s), 2.49 (3H, s).

LCMS Method A: tR = 0.55 min, m / z = 393.9 [M H] +

Example 51: 2 - ((2,6-Dimethylpyridin-4-yl) carbamoyl) -5- (trifluoromethyl) benzoic acid

From intermediate Y48

1H NMR (DMSO-d6, 400 MHz) 5: 14.0 (1H, br), 11.56 (1H, s), 8.23 (1H, s), 8.16-8.14 (1H, d , J = 8.0 Hz), 7.87-7.85 (1H, d, J = 8.0 Hz), 7.73 (2H, s), 2.61 (6H, s).

LCMS Method A: tR = 0.42 min, m / z = 339.0 [M H] +

Expression and purification of proteins.

The extracellular domain of human sortilin (78-755) that includes the propeptide (34-77) of Q99425 and a 6xHis label in C-terminal was expressed in HEK 293 cells using the episomal expression vector pCEP-PU. The expressed extracellular domain of sortiline was purified from culture medium on a Ni2 + NTA-agarose (Qiagen) column according to the manufacturer's instructions.

Human programnulin (P28799; 18-593) was expressed in HEK 293F cells using the pcDNA 3.1 (-) expression vector. Purification from the culture medium was carried out by capture on capto-Q (GE-healthcare). Fractions eluting from the column were precipitated with 2M ammonium sulfate and centrifuged. The precipitate was dissolved in PBS and separated on an S200 size exclusion column. Programnulin fractions were identified by SDS-PAGE and grouped accordingly.

The pro part of the human beta nerve growth factor (P01138; 19-121) was expressed as a C-terminal fusion to GST using the pGEX expression plasmid in E. coli BL21 cells . Induction was started by adding 1 mM IPTG and continued for 4 hours. Cells were collected by centrifugation and lysed using the "block destroyer protein" kit from Novagen. The clean lysate was purified using the GSTtrap columns (GE healthcare) according to the manufacturer's instructions.

The mouse his-sortilina was purchased from R&D Systems.

Affinity test for hSortiline

The affinity of the compound was determined by measuring the displacement of the 3H-neurotensin binding to the hSortiline using a SPA-based assay format.

The sortiline assay was carried out in a total volume of 40 µl in 50 mM HEPES assay buffer pH 7.4 containing 100 mM NaCl, 2.0 mM CaCh, 0.1% BSA and Tween-20 at 0.1% Variable concentrations of compounds were pre-incubated for 30 minutes at room temperature with 150 nM 6his-sortiline. 5 nM [3H] -neurotensin was added as radioligand and nonspecific binding was defined as binding in the presence of 20 µM neurotensin. Ni chelate image beads (Perkin Elmer) were added and the plate was slowly stirred in the dark for 60 minutes. The image beads were allowed to have a minimum standby time of 6 hours before the plate was read on a ViewLux with an exposure time of 360 seconds. The dose-response evaluation of the compounds was carried out with 10 concentrations of drugs (covering 3 tens). IC50 values were calculated by non-linear regression using the sigmoid concentration-response (variable slope) using Xlfit 4 (IDBS, United Kingdom). The results were given as Ki (nM) values derived from computer-adjusted IC50 values converted to Ki values using the Cheng-Prusoff equation (Ki = IC50 / (1+ (L / Kd))). The Kd for neurotensin (NTS) was determined at 100 nM

* Inhibition at 50 pM

Affinity test for mSortiline

The affinity of the compound was determined by measuring the displacement of the 3H-neurotensin binding to mSortiline using a SPA-based assay format.

The sortiline assay was carried out in a total volume of 40 pl in 50 mM HEPES assay buffer pH 7.4 containing 100 mM NaCl, 2.0 mM CaCh, 0.1% BSA and 0 Tween-20 ,one %. Variable concentrations of compounds were pre-incubated for 30 minutes at room temperature with 6his-Sortiline 150 nM. Was added [3H] 5 nM neurotensin as radioligand and nonspecific binding was defined as binding in the presence of 20 | jM neurotensin. Ni chelate image beads (Perkin Elmer) were added and the plate was slowly stirred in the dark for 60 minutes. The image beads were allowed to have a minimum standby time of 6 hours before the plate was read on a ViewLux with an exposure time of 36o seconds. The dose-response evaluation of the compounds was carried out with 10 concentrations of drugs (covering 3 tens). The IC50 values were calculated by non-linear regression using the sigmoid concentration-response (variable slope) using Xlfit 4 (iDBS, United Kingdom). The results were given as Ki (nM) values derived from computer-adjusted IC50 values converted to Ki values using the Cheng-Prusoff equation (Ki = IC50 / (1+ (L / Kd))). The Kd for neurotensin was determined at 100 nM

Inhibition of the ProNGF Pro part to hSortiline

The inhibition of proNGF to sortiline was determined by measuring the binding of the proNGF pro part to sortiline using time-resolved homogeneous fluorescence technology. The proNGF pro part was merged with the GST brand and the sortiline was marked with His. A GST antibody with Europium labeling and a His antibody with XL665 label was used to detect the binding of pro-GST to his-sortiline. The signal is generated once the proteins interact with each other to bring the labeled antibodies closer together.

The pro-sortiline assay was carried out in a total volume of 20 jl in 50 mM HEPES assay buffer pH 7.4 containing 100 mM NaCl, 22.0 mM CaCl, 0.1% BSA and Tween-20 at 0.1% Variable concentrations of compounds were incubated for 15 minutes at room temperature with 50 nM 6his-sortiline and 6 nM pro-GST. Anti-GST-Eu 4 nM and anti-His-XL66525 nM were added together with KF (final concentration 200 mM) and after 150 minutes incubation at room temperature in the dark, fluorescence was measured with an excitation of 320 nm and dual emission of 665 and 615 nm in an envision reader (Perkin Elmer). The signal was expressed in terms of HTRF ratio (fluorescence intensity at 665 nm / fluorescence intensity at 615 nm x 10,000). Inhibition of the binding of proGST to sortiline was expressed as a percentage inhibition of the control response to 20 µM neurotensin (100% inhibition) in relation to a baseline buffer control (0% inhibition). IC50 values were calculated by nonlinear regression using the sigmoid concentration-response (variable slope) using Xlfit 4 (I ^d B ^s , United Kingdom).

Inhibition of hProgranulin to hSortiline

The inhibition of the programnulin to the sortilina was determined measuring the union of the programnulin of proNGF to hissortilina using homogeneous fluorescence technology resolved in time. A europium-labeled programnulin antibody and an XL665-labeled His antibody was used to detect the binding of programnulin to his-sortiline. The signal is generated once the proteins interact with each other to bring the labeled antibodies closer together.

The programnulin-sortiline test was performed in a total volume of 20 μl in a 50 mM phosphate buffer, pH 7.0 containing 0.1% BSA. Variable concentrations of compounds were incubated for 15 min at room temperature with 50 nM 6his-sortiline and 4 nM programnulin. 0.7 nM anti-progranulin-Eu and anti-His-XL6657 nM were added together with KF (200 mM final concentration) and after 120 minutes of incubation at room temperature in the dark, the plate was kept at 4 ° C for the night and the next day, fluorescence was measured with an excitation of 320 nm and dual emission of 665 and 615 nm in the envision reader (Perkin Elmer). The signal was expressed in terms of HTRF ratio (fluorescence intensity at 665 nm / fluorescence intensity at 615 nm x 10,000). Inhibition of the binding of programnulin to sortiline was expressed as a percentage of inhibition of the control response to 20 μM neurotensin (100% inhibition) in relation to a baseline buffer control (0% inhibition). IC50 values were calculated by non-linear regression using the sigmoid concentration-response (variable slope) using Xlfit 4 (IDBS, United Kingdom).

Endocytosis assay of endogenous PGRN

Stable cell lines expressing human sortilin (S-18) were generated by transfecting HEK293 cells with a human sortilin expression vector, followed by a few rounds of passes with the appropriate selection agent.

It was found that HEK293 cells and S-18 cells secrete PGRN continuously in the medium without any stimulation. Programnulin binds to spellin and undergoes endocytosis (Hu et al. 2010). The blockade of the interaction of sortilina and progranulina produces an accumulation of PGRN in the middle. Compounds that do not block the interaction of spellin and programnulin have no effect on the levels of PGRN in the medium.

On day 1, S-18 cells are seeded in a 96-well plate. After 24 hours, the medium is completely replaced or with medium or with one of the test compounds. All compounds were tested at 10 µM unless otherwise specified. The medium is collected on day 3 and analyzed using ELISA for PGRN (R&D). Cell viability is evaluated by Cell TiterGlo (Pro Mega) to evaluate the cytotoxic effect of the compounds.

Different compounds were added to the S-18 cells to evaluate the effect on the programnulin. Neurotensin is a natural ligand for the sortilina and blocks the union of the sortilina to the programnulina what produces an accumulation of programnulina in the means. The addition of neurotensin or Example 1 to S-18 cells shows an increase in PGRn in the cell culture medium by 85-100% compared to control wells.

On the other hand, the encoded neurotensin (LIYPRNEYELRKP) or Standard 1 does not bind to spellin and the levels of PGRN in the medium are similar to those in untreated wells.

In a similar but slightly different experimental model, the PGRN is allowed to accumulate for 24 hours, so that the compounds can compete with the PGRN to bind to the spellin. On day 2, the compounds are added to the cells and incubated for an additional 24 hours, when the medium is collected and the PGRN levels are analyzed using the ELISA kit.

Neurotensin and Example 1, compete with PGRN in the medium, increase PGRN levels in the cell culture medium. The coded neurotensin and Standard 1 had no effect on PGRN endocytosis as shown in Figure 1.

Programming test by Cellomics

In this assay, transfected HEK 293 cells (with control or sortilin expression plasmids) or stable HEK293 cells expressing human sortilin (S-18) were used. The cells are trypsinized and placed in 96-well plates. In the case of transiently transfected cells, they were placed 24 hours after transfection in 96-well plates. The next day, the medium was completely changed and the test compounds were added to the cells for 30 min followed by PGRN for 60 min. At the end of the study (after 1.5 hours), the cells were fixed and stained to determine the sortiline and the programnulin. All stained plates were analyzed by Cellomics Array Scan (Thermo Fischer) and the average staining intensity for the PGRN and the sortiline per cell in each well was calculated.

The progranulin used in this assay was collected from the medium after transient transfection of programnulin expression plasmids into HEK 293 cells. PGRN levels were measured using the ELISA kit for PGRN (R&D).

The addition of PGRN to the wells easily underwent endocytosis and led to an increase in the fluorescent signal in the wells transfected with sortilin. The addition of neurotensin, or the compound of Example 1, prevents the binding of sortiline to programnulin (Figure 2). Therefore, the PGRN did not undergo endocytosis and the fluorescence intensity of the PGRN was similar to the control levels.

The coded neurotensin did not bind to spellin and was used as a negative control. In wells treated with neurotensin encoded or with Standard 1, the PGRN bound to the spellin and underwent endocytosis and the fluorescence intensity increased significantly as seen in wells treated only with PGRN.

The encoded neurotensin has the sequence of: LIYPRNEYELRKP

Claims (16)

1. A compound of the formula A

R1 represents H or F, R2 represents halogen, Ci-C6 alkyl, C2-C6 alkenyl or halogenated Ci-C6 alkyl, R3 represents halogen, H, Ci-C6 alkyl, or halogenated Ci-C6 alkyl, L is a direct link or represents CH2, R4 is selected from the group comprising

optionally substituted with C = N, 1 or 2 C1-C3 alkyls, 1 or 2 halogenated alkyls, 1 or 2 C1-C3 alkoxy or 1 or 2 halogens, X represents C or N, where N is present in 1 or 2 positions and * indicates the point of attachment, and pharmaceutically acceptable salts thereof. 2. The compound according to claim 1, wherein the halogenated alkyl is CF3. 3. The compound according to claim 1, wherein R2 is Cl, Br or CF3 and R3 is H or Cl. 4. The compound according to claim 1, wherein R4 is selected from the group comprising

optionally substituted with C = N, 1 or 2 Ci-C3 alkyls, 1 or 2 halogenated alkyls, 1 or 2 Ci-C3 alkoxy or 1 or 2 halogens, where * indicates the point of attachment. 5. The compound according to claim 1, said compound being selected from the group comprising N- (6-methyl-pyridin-2-yl) -5-trifluoromethylphthalamic acid 5-Bromo-N- (6-methyl-pyridin-2-yl) -phthalamic acid 5-methyl-N- (6-methyl-pyridin-2-yl) -phthalamic acid 5-Chloro-N- (6-methyl-pyridin-2-yl) -phthalamic acid 4,5-Dichloro-N- (6-methyl-pyridin-2-yl) -phthalamic acid N- (5,6-dimethyl-pyridin-2-yl) -5-trifluoromethylphthalamic acid N- (4-methyl-pyridin-2-yl) -5-trifluoromethylphthalamic acid N- (2-methyl-pyridin-4-yl) -5-trifluoromethylphthalamic acid 4,5-Dichloro-N- (4-methyl-pyridin-2-yl) -phthalamic acid 4,5-Dichloro-N- (5,6-dimethyl-pyridin-2-yl) -phthalamic acid 4,5-Dichloro-N- (2-methyl-pyridin-4-yl) -phthalamic acid 4,5-Dichloro-N- (2-methyl-pyrimidin-4-yl) -phthalamic acid 5-doro-6-fluoro-N- (6-methyl-pyridin-2-yl) -phthalamic acid 4,5-dimethyl-N- (6-methyl-pyridin-2-yl) -phthalamic acid 2- ((3-Chloro-5- (trifluoromethyl) pyridin-2-yl) carbamoyl) -5- (trifluoromethyl) benzoic acid 2- ((4-methylpyrimidin-2-yl) carbamoyl) -5- (trifluoromethyl) benzoic 2 - ((5,6-Dimethylpyrazin-2-yl) carbamoyl) -5- (trifluoromethyl) benzoic acid 5-Bromo-N- (5-methyl-pyridin-2-yl) -phthalamic acid 5-Bromo-N- (5-chloro-pyridin-2-yl) -phthalamic acid 5-Bromo-N-pyridin-2-yl-phthalamic acid 5-Bromo-N- (6-chloro-pyridin-2-yl) -phthalamic acid 5-Bromo-N- (5,6-dimethyl-pyridin-2-yl) -phthalamic acid 5-Bromo-N- (4-methyl-pyridin-2-yl) -phthalamic acid 5-Bromo-N- (2-methyl-pyridin-4-yl) -phthalamic acid 5-Bromo-N-pyridin-3-yl) -phthalamic acid 5-Bromo-N- (3-methyl-pyridin-2-yl) -phthalamic acid 5-Bromo-N-quinolin-2-yl-phthalamic acid 5-Bromo-N- (5,6-dichloro-pyridin-2-yl) -phthalamic acid 5-Bromo-N- (6-methyl-pyridin-3-yl) -phthalamic acid 5-Bromo-N- (6-methyl-pyridazin-3-yl) -phthalamic acid 5-Bromo-N- (4,6-dimethyl-pyridin-2-yl) -phthalamic acid 5-Bromo-N- (2-methyl-pyrimidin-4-yl) -phthalamic acid 5-Bromo-N- (6-methyl-pyrimidin-4-yl) -phthalamic acid N- (2-methoxy-pyridin-4-yl) -5-trifluoromethylphthalamic acid N- (6-methoxy-pyridin-2-yl) -5-trifluoromethylphthalamic acid N-pyridin-2-ylmethyl-5-trifluoromethylphthalamic acid N-pyridin-4-ylmethyl-5-trifluoromethylphthalamic acid N-pyridin-3-ylmethyl-5-trifluoromethylphthalamic acid N- (6-methyl-pyridin-2-yl) -5-propylphthalamic acid N 5-isopropenyl-N- (6-methyl-pyridin-2-yl) -phthalamic acid N 5-Isopropyl-N- (6-methyl-pyridin-2-yl) -phthalamic acid 2 - ((2-methylpyrimidin-4-yl) carbamoyl) -5- (trifluoromethyl) benzoic acid 2 - ((4,5-dimethylpyrimidin-2-yl) carbamoyl) -5- (trifluoromethyl) benzoic acid 2 - ((5,6,7,8-tetrahydroquinolin-2-yl) carbamoyl) -5- (trifluoromethyl ) benzoic acid 2 - ((6-methylpyridin-2-yl) carbamoyl) -4,5-bis (trifluoromethyl) benzoic acid 2 - ((5,6,7,8-tetrahydroquinolin-2-yl) carbamoyl) -4 , 5-bis (trifluoromethyl) benzoic acid 2 - ((5,6-dimethylpyridin-2-yl) carbamoyl) -4,5-bis (trifluoromethyl) benzoic acid 2 - ((2-methylpyrimidin-4-yl) carbamoyl) -4,5-bis (trifluoromethyl) benzoic acid 2 - ((2,6-dimethylpyridin-4-yl) carbamoyl) -5- (trifluoromethyl) benzoic acid or one of its pharmaceutically acceptable salts. 6. A pharmaceutical composition comprising a compound according to any one of the preceding claims, and one or more pharmaceutically acceptable excipients or diluents. 7. A compound or a pharmaceutical composition according to any one of the preceding claims, for use in therapy. 8. A compound or pharmaceutical composition according to any one of the preceding claims, for use in a method for the treatment of a neurodegenerative disease, psychiatric disease, motor neuron disease, peripheral neuropathies, pain, neuroinflammation or atherosclerosis. 9. A compound or pharmaceutical composition for use according to claim 8, in a method for the treatment of Alzheimer's disease, Parkinson's disease, stroke, traumatic brain injury, retinal degeneration, light-induced photoreceptor degeneration , epilepsy, bipolar disorder, amyotrophic lateral sclerosis, frontotemporal lobular degeneration, spinal muscular atrophy, peripheral neuropathy, diabetic neuropathy, acute and chronic pain, prevention and treatment of established pain, neuropathic pain, lumbar pain, postoperative pain, inflammatory pain, rheumatoid arthritis , Crohn's disease, ulcerative colitis, atherosclerosis and multiple sclerosis. 10. A prodrug of the compound of claim 1 according to formula C

R9 represents Ci-C6 alkyl R10 represents halogen, C1-C6 alkyl, C2-C6 alkenyl or halogenated C1-C6 alkyl, R11 represents halogen, H, C1-C6 alkyl or halogenated C1-C6 alkyl, n is 0 or 1, R12 is selected from the group comprising

and its pharmaceutically acceptable salts. 11. The prodrug according to claim 10, wherein R10 represents CH3, CHCH2, Br, Cl, C = N or CF3 and R7 represents H, CF3 or Cl. 12. The prodrug according to claim 10, said prodrug being selected from the group comprising 5-bromo-N- (5,6-dimethyl-pyridin-2-yl) -phthalamic acid ferc-butyl ester N- (6-methyl-pyridin-2-yl) -5-trifluoromethyl-phthalamic acid ferc-butyl ester 5-Bromo-N- (6-methyl-pyridin-2-yl) -phthalamic acid ferc-butyl ester 5-Bromo-N- (5-methyl-pyridin-2-yl) -phthalamic acid ferc-butyl ester 5-Bromo-N- (2-methyl-pyridin-4-yl) -phthalamic acid ferc-butyl ester 5-Bromo-N-pyridin-3-yl-phthalamic acid ferc-butyl ester 5-Bromo-N- (3-methyl-pyridin-2-yl) -phthalamic acid ferc-butyl ester 5-Bromo-N-quinolin-2-yl-phthalamic acid ferc-butyl ester 5-Bromo-N- (5,6-dichloro-pyridin-2-yl) -phthalamic acid ferc-butyl ester 5-Bromo-N- (6-methyl-pyridin-3-yl) -phthalamic acid ferc-butyl ester 5-Bromo-N- (6-methyl-pyridazin-3-yl) -phthalamic acid ferc-butyl ester 5-Bromo-N- (4,6-dimethyl-pyridin-2-yl) -phthalamic acid ferc-butyl ester 5-Bromo-N- (2-methyl-pyrimidin-4-yl) -phthalamic acid ferc-butyl ester 5-Bromo-N- (6-methyl-pyrimidin-4-yl) -phthalamic acid ferc-butyl ester N- (2-methoxy-pyridin-4-yl) -5-trifluoromethylphthalamic acid ferc-butyl ester N- (6-methoxy-pyridin-2-yl) -5-trifluoromethyl-phthalamic acid ferc-butyl ester N-pyridin-2-ylmethyl-5-trifluoromethyl-phthalamic acid ferc-butyl ester N-pyridin-4-ylmethyl-5-trifluoromethyl-phthalamic acid ferc-butyl ester N-pyridin-3-ylmethyl-5-trifluoromethylphthalamic acid ferc-butyl ester 5-Isopropenyl-N- (6-methyl-pyridin-2-yl) -phthalamic acid ferc-butyl ester N- (6-methyl-pyridin-2-yl) -5-propyl-phthalamic acid ferc-butyl ester N- (2-methyl-pyrimidin-4-yl) -5-trifluoromethylphthalamic acid ferc-butyl ester N- (4,5-dimethyl-pyrimidin-2-yl) -5-trifluoromethyl-phthalamic acid ferc-butyl ester N- (5,6,7,8-tetrahydro-quinolin-2-yl) -5-trifluoromethylphthalamic acid ferc-butyl ester 5-Isopropyl-N- (6-methyl-pyridin-2-yl) -phthalamic acid ferc-butyl ester N- (2,6-dimethyl-pyridin-4-yl) -5-trifluoromethyl-phthalamic acid ferc-butyl ester 4,5-didoro-N- (6-methyl-pyridin-2-yl) -phthalamic acid ferc-butyl ester 4,5-dichloro-N- (6-methyl-pyridin-2-yl) -phthalamic acid isopropyl ester 4,5-Dichloro-N- (6-methyl-pyridin-2-yl) -phthalamic acid methyl ester 4,5-dichloro-N- (2-methyl-pyrimidin-4-yl) -phthalamic acid isopropyl ester 4,5-Dichloro-N- (2-methyl-pyrimidin-4-yl) -phthalamic acid ethyl ester N- (5,6-dimethyl-pyridin-2-yl) -4,5-bis-trifluoromethylphthalamic acid methyl ester or a pharmaceutically acceptable salt thereof. 13. A pharmaceutical composition comprising a prodrug according to claim 10 and one or more pharmaceutically acceptable carriers or diluents. 14. A prodrug according to claim 10 or a pharmaceutical composition according to claim 13, for use in therapy. 15. A prodrug according to claim 10 or a pharmaceutical composition according to claim 13, for use in a method for the treatment of a neurodegenerative disease, psychiatric disease, motor neuron disease, peripheral neuropathies, pain, neuroinflammation or atherosclerosis. 16. A prodrug or a pharmaceutical composition according to claim 15, for use in a method for the treatment of Alzheimer's disease, Parkinson's disease, stroke, traumatic brain injury, retinal degeneration, light-induced photoreceptor degeneration, epilepsy, bipolar disorder, amyotrophic lateral sclerosis, frontotemporal lobular degeneration, spinal muscular atrophy, peripheral neuropathy, diabetic neuropathy, acute and chronic pain, prevention and treatment of established pain, neuropathic pain, low back pain, postoperative pain, inflammatory pain, rheumatoid arthritis, Crohn's disease, ulcerative colitis, atherosclerosis and multiple sclerosis.