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    • 专利摘要:
    The present invention belongs to the field of EP1 receptor ligands. More specifically it refers to compounds of general formula (I) having great affinity and selectivity for the EP1 receptor. The invention also refers to the process for their preparation, to their use as medicament for the treatment and/or prophylaxis of diseases or disorders mediated by the EP1 receptor as well as to pharmaceutical compositions comprising them.
    公开号:AU2012307326A1
    申请号:U2012307326
    申请日:2012-09-14
    公开日:2014-03-27
    发明作者:Francesc Xavier CALDENTEY FRONTERA；Elena Carceller Gonzalez；Ramon Merce Vidal；Antonio David Rodriguez Garrido；Jordi SALAS SOLANA；Antoni Torrens Jover
    申请人:Laboratorios del Dr Esteve SA；
    IPC主号:C07D209-08
    专利说明:
    WO 2013/037960 PCT/EP2012/068101 1 EP1 RECEPTOR LIGANDS FIELD OF THE INVENTION The present invention belongs to the field of EP1 receptor ligands. More specifically 5 it refers to compounds of general formula (1) having great affinity and selectivity for the EP1 receptor. The invention also refers to the process for their preparation, to their use as medicament for the treatment and/or prophylaxis of diseases or disorders mediated by the EP1 receptor as well as to pharmaceutical compositions comprising them. 10 BACKGROUND OF THE INVENTION Prostanoids are a family of eicosanoids that comprise prostaglandins (PGs), prostacyclins (PGls), and thromboxanes (Txs). Their receptors belong to the G protein coupled receptor (GPCR) superfamily of receptors and may be grouped into 15 five classes, namely, prostaglandin D (DP), prostaglandin E (EP), prostaglandin F (FP), prostaglandin I (IP), and Thromboxane A (TP) based on their sensitivity to five naturally occurring prostanoids, PGD2, PGE2, PGF2[alpha], PGI2, and TxA2, respectively (Coleman, R. A., 2000). 20 Prostaglandins contribute to the sensitization of peripheral and central nociceptive neurons during peripheral inflammation (Dirig and Yaksh, 1999) and play an important role in the pathogenesis of neuropathic pain following nerve injury (Syriatowicz et al 1999; Kawahara et al, 2001; Samad et al, 2002; Ma and Eisenach,2003; Durrenberger et al., 2006). 25 Prostaglandin E2 (PGE2) is considered to be the dominant pro-nociceptive prostanoid. Guay and colleagues, analyzing the concentrations of different prostaglandins in the cerebrospinal fluid, found that PGE2 was the most prevalent prostanoid and exhibited the highest increase after peripheral carrageenan-induced 30 inflammation (Guay et al., 2004). PGE2 is generated in most cells in response to mechanical, thermal or chemical injury and inflammatory insult, resulting in sensitization or direct activation of nearby sensory nerve endings. Its production requires the activity of at least one of the two cyclooxygenase isoforms, COX-1 constitutively expressed or COX-2 which is inducible and particularly relevant for WO 2013/037960 PCT/EP2012/068101 2 inflammation-induced PGE2 formation. Therefore, non-selective inhibitors of COX-1 and COX-2, and selective COX-2 inhibitors provide good pain relief. However, the long-term use is associated with gastrointestinal or cardiovascular side effects, respectively. 5 Downstream components of the inflammatory cascade could be an alternative approach for the treatment of the PGE2 associated pain. PGE2 binds to four different G-protein coupled receptors named EP1, EP2, EP3 and EP4 (Narumiya et al., 1999). 10 Studies employing antagonists suggest that blocking EP1, EP2, EP3 or EP4 receptors may reduce certain types of pain (Oka et al. 1997; Omote et al., 2002; Lin et al, 2006) and agonists increase nociceptive responses (Minami et al., 1994). Among these PGE2 receptor subtypes, most of drug discovery studies have focused 15 on the EP1 receptors (Hall et al., 2007). EP1 receptor stimulation mediates increases in intracellular calcium ions, facilitating neurotransmitter release (Asb6th et al., 1996). EP1 receptor is preferentially expressed in primary sensory neurons, including their spinal cord terminals (Oidda 20 et al., 1995) although it is also distributed in other tissues (Breyer et al., 2000; Schl6tzer-Schrehardt et al., 2002). In the brain, marked differences in the level of EP1 expression among the cerebral regions were found. The strongest levels of EP1 mRNA were found in parietal cortex and cerebellum, followed in descending order by frontal cortex and striatum. The hypothalamus, hippocampus and brain 25 stem displayed a low-level EP1 mRNA signal (Candelario-Jalil et al., 2005). In the spinal cord, several studies have reported the effects of PGE2 on neuronal excitability or synaptic transmission (Baba et al., 2001) and pain transmission (Nakayama et al., 2004). Therefore, EP1 receptor antagonists, blocking the positive feedback cascade mediated by PGE 2 , may result in analgesic efficacy. In this 30 regard, using EP receptor deficient mice, a prominent contribution of EP1 receptors has been described (Minami et al., 2001). EP1 -/- knockout mice demonstrated a role of this receptor in mediating peripheral heat sensitization after subcutaneous PGE2 injection (Moriyama et al. 2005; Johansson et al. 2011), and EP1 receptor antagonism has been reported to reduce mechanical hyperalgesia in nerve injured WO 2013/037960 PCT/EP2012/068101 3 rats (Kawahara et al., 2001), in the carrageenan model (Nakayama et al. 2002), or in the incisional model of postoperative pain (Omote et al 2002). Moreover, EP1 antagonists demonstrated analgesic activity in a complete Freund's adjuvant model of knee joint arthritis (Giblin et al, 2007; Hall et al, 2009). It has also been reported 5 that the contribution of PGE2 in human visceral pain hypersensitivity is mediated through the EP1 receptor (Sarkar et al., 2003). In addition to being useful for modulating pain, EP1 antagonists may also be useful for the treatment or prevention of other EP1 receptor-mediated diseases such as 10 motility-related disorders including gastrointestinal disorders, urinary incontinence and other urinary tract diseases; dysmenorrhea; preterm labour; diabetic retinopathy; tumour angiogenesis; cancer; metastatic tumour growth; neurodegenerative diseases including senile dementia, Alzheimer's disease, Pick's disease, Huntington's chorea, Parkinson's disease, Creutzfeldt-Jakob disease, or 15 amyotrophic lateral sclerosis; neuroprotection/stroke; glaucoma; osteoporosis; bone fractures; Paget's disease; hyperthermia including different types of fever as rheumatic fever; symptoms associated with influenza or other viral infections; gastrointestinal disorders related with chemotherapy or irritable bowel syndrome; gastrointestinal bleeding; coagulation disorders including anaemia, 20 hypoprothrombinemia, haemophilia or other bleeding problems; kidney diseases including nephritis, particularly mesangial proliferative glomerulonephritis and nephritic syndrome; thrombosis and occlusive vascular diseases. In turn, EP1 receptor agonists also may have a number of utilities. These include, 25 but are not limited to treatment of influenza, bone fracture healing, bone disease, glaucoma, ocular hypertension, dysmenorrhoea, pre-term labour, immune disorders, osteoporosis, asthma, allergy, fertility, male sexual dysfunction, female sexual dysfunction, periodontal disease, gastric ulcer, and renal disease. EP receptor agonists may also be useful for expansion of hematopoietic stem cell populations. 30 Based on the above mentioned results coming from animal and human studies, EP1 receptor has been identified as a selective target for the development of new potential therapies for the treatment of those disorders where PGE2 action is involved. In view of the potential therapeutic applications of agonists and WO 2013/037960 PCT/EP2012/068101 4 antagonists of the EP1 receptor, a great effort is being directed to find selective ligands. Despite intense research efforts in this area, very few compounds with selective EP1 activity have been reported. 5 There is thus still a need to find compounds having pharmacological activity towards the EP1 receptor, being both effective and selective, and having good "druggability" properties, i.e. good pharmaceutical properties related to administration, distribution, metabolism and excretion. 10 The present invention hereby provide some novel compounds complying with the above mentioned properties. OBJECT OF THE INVENTION 15 The present invention discloses novel compounds with great affinity to EP1 receptors which might be used for the treatment of EP1-related disorders or diseases. Specifically, it is an object of the invention a compound of general formula 1:
    R
    9 .. R
    R
    9 'R9 B 20 wherein:
    W
    1 is phenyl or a 6-membered heteroaromatic ring containing 1 or 2 N atoms, wherein W 1 is substituted by one R 1 and optionally substituted by one or more R2;
    W
    2 is a 5- or 6-membered heterocyclic ring that contains 1 N atom and can 25 additionally contain 1 or 2 heteroatoms selected from the group consisting of N, 0, and S; wherein said ring is aromatic, partially unsaturated or saturated, and which is optionally substituted by one or more R3;
    R
    1 is -R 6
    -R
    7
    -
    WO 2013/037960 PCT/EP2012/068101 5 each R 2 is independently selected from the group consisting of H, halogen, C1-6 alkyl, C 1 6 -haloalkyl, -O-C 6 -alkyl, -O-C 6 -haloalkyl, hydroxyC, 1 6 -alkyl, CN, NR 14
    COR
    15 , -NR 14
    SO
    2
    R
    15 and -S0 2
    R
    15 ; each R 3 is independently selected from the group consisting of H, halogen, C 1
    -
    6 -alkyl 5 C 1 6 -haloalkyl, -O-C 6 -alkyl, -O-C 6 -haloalkyl, hydroxyC, 1 6 -alkyl, -C_ 4 -alkylene
    OR
    14 , -C2_ 4 -alkenylene-COOH, =0 and CN; each R 4 is independently selected from the group consisting of H and C 1
    -
    6 -alkyl, or both R 4 together with the C atom to which they are bonded form a C 3
    -
    6 cycloalkyl;
    R
    5 is selected from the group consisting of H, halogen, C 1 6 -haloalkyl, -O-C 6 -alkyl, 10 -O-C 6 -haloalkyl, -OH, C 1
    -
    6 -alkyl, C 3
    -
    6 cycloalkyl and -SO 2
    R
    15 ;
    R
    6 is selected from the group consisting of a direct bond, -C_ 4 -alkylene-, -O-C1_4 alkylene- and -C2_ 4 -alkenylene-;
    R
    7 is selected from the group consisting of -CO 2 H, -SO 3 H, 5-tetrazolyl, -OPOH 2 , PO 3
    H
    2 , -CONR 12
    R
    12
    -CONH-SO
    2
    R
    12 , -NR 14
    CONR
    14
    -SO
    2
    R
    15 and -SO 2
    -NHCOR
    15 , 15 Y is selected from the group consisting of -C2.
    4 -alkylene-, -O-C_ 4 -alkylene-, -C2_4 alkenylene- , -C_ 4 -alkylene-O-, -NR 13
    -C
    1
    _
    4 -alkylene- and -C_ 4 -alkylene-NR 13 -; B is selected from the group consisting of C 2
    -
    6 -alkyl, C2-6 alkenyl and Cy, any of them optionally substituted by one or more R 8 ; each R 8 is independently selected from the group consisting of halogen, C1-6 20 haloalkyl, -O-Cl- 6 -alkyl, -O-Cl- 6 -haloalkyl, Cl 1 6 -alkyl,-OH, -CN, -CH 2
    OR
    14 and CONR 12
    R
    12 ; each R 9 is independently selected from the group consisting of CR 1 and N; each R 10 is independently selected from the group consisting of H, halogen, C16 alkyl, C- 6 -haloalkyl, -0-C- 6 -alkyl, -0-C- 6 -haloalkyl and hydroxyC, 6 -alkyl; 25 R" is CR 5 or N, each R 12 is independently selected from the group consisting of H, C 1 6 -alkyl, C16 haloalkyl, -NR 14
    R
    14 and C 3 6 cycloalkyl; each R 13 is independently selected from the group consisting of H, C 1 6 -alkyl, C16 haloalkyl, and C 3 6 cycloalkyl; 30 each R 14 is independently selected from the group consisting of H and C 1 6 -alkyl; each R 15 is independently selected from the group consisting of C 16 -alkyl; Cy is a 3-6 membered monocyclic or 8-12 membered polycyclic ring which can be carbocyclic or heterocyclic containing 1 to 3 heteroatoms selected from N, 0 and S WO 2013/037960 PCT/EP2012/068101 6 and which can be aromatic, partially unsaturated or saturated and wherein one or more C or S atoms in Cy can be oxidized to form CO, SO or SO 2 ; with the proviso that when W1 and W2 is a benzimidazole, R6 and R7 are not at the same time respectively a -O-C 4 -alkylene- and a -CO 2 H or that R 7 is not -CONH 5 S0 2
    R
    12 ; and the salts, solvates and prodrugs thereof. It is also an object of the invention the process for the preparation of compounds of general formula (1). 10 In another aspect, the invention relates to a compound of general formula (1) for use as a medicament. Yet another object of the invention is a compound of general formula (1) for use in 15 the treatment and/or prophylaxis of diseases or disorders mediated by the EP1 receptor. This includes but is not limited to diseases such as inflammatory related pain including low back and neck pain, skeletal pain, post-partum pain, toothache, sprains and straits, myositis, neuralgia, synovitis, arthritis, including rheumatoid arthritis, degenerative joint diseases, gout and ankylosing spondylitis, bursitis, burns 20 including radiation and corrosive chemical injuries and sunburns; postoperative pain; neuropathic pain; visceral pain; tension headache; cluster headaches; migraine; motility-related disorders including gastrointestinal disorders, urinary incontinence and other urinary tract diseases; dysmenorrhea; preterm labour; diabetic retinopathy; tumour angiogenesis; cancer; metastatic tumour growth; 25 neurodegenerative diseases including senile dementia, Alzheimer's disease, Pick's disease, Huntington's chorea, Parkinson's disease, Creutzfeldt-Jakob disease, or amyotrophic lateral sclerosis; neuroprotection/stroke; glaucoma; osteoporosis; bone fractures; Paget's disease; hyperthermia including different types of fever as rheumatic fever; symptoms associated with influenza or other viral infections; 30 gastrointestinal disorders related with chemotherapy or irritable bowel syndrome; gastrointestinal bleeding; coagulation disorders including anaemia, hypoprothrombinemia, haemophilia or other bleeding problems; kidney diseases including nephritis, particularly mesangial proliferative glomerulonephritis and nephritic syndrome; thrombosis and occlusive vascular diseases.
    WO 2013/037960 PCT/EP2012/068101 7 It is another object of the invention a pharmaceutical composition comprising at least one compound of general formula (1) and at least one pharmaceutically acceptable carrier, additive, adjuvant or vehicle. 5 DETAILED DESCRIPTION OF THE INVENTION In a first aspect the invention relates to compounds of general formula (1):
    R
    9 .. R
    R
    9 'R9 B 10 wherein:
    W
    1 is phenyl or a 6-membered heteroaromatic ring containing 1 or 2 N atoms, wherein W 1 is substituted by one R 1 and optionally substituted by one or more R2;
    W
    2 is a 5- or 6-membered heterocyclic ring that contains 1 N atom and can additionally contain 1 or 2 heteroatoms selected from the group consisting of N, 0, 15 and S; wherein said ring is aromatic, partially unsaturated or saturated, and which is optionally substituted by one or more R3;
    R
    1 is -R 6
    -R
    7 ; each R 2 is independently selected from the group consisting of H, halogen, C1-6 alkyl, C 1 6 -haloalkyl, -O-C 6 -alkyl, -O-C 6 -haloalkyl, hydroxyC, 1 6 -alkyl, CN, 20 NR 14
    COR
    15 , -NR 14
    SO
    2
    R
    15 and -S0 2
    R
    15 ; each R 3 is independently selected from the group consisting of H, halogen, C 1
    -
    6 -alkyl
    C
    1 6 -haloalkyl, -O-C 6 -alkyl, -O-C 6 -haloalkyl, hydroxyC, 1 6 -alkyl,-C_ 4 -alkylene
    OR
    14 , -C2_ 4 -alkenylene-COOH, =0 and CN; each R 4 is independently selected from the group consisting of H and C 1
    -
    6 -alkyl, or 25 both R 4 together with the C atom to which they are bonded form a C 3
    -
    6 cycloalkyl;
    R
    5 is selected from the group consisting of H, halogen, C 1 6 -haloalkyl, -O-C 6 -alkyl,
    -O-C
    6 -haloalkyl, -OH, C 1
    -
    6 -alkyl, C 3
    -
    6 cycloalkyl and -SO 2
    R
    15 ;
    R
    6 is selected from the group consisting of a direct bond, -C_ 4 -alkylene-, -O-C_4 alkylene- and -C2.
    4 -alkenylene-; WO 2013/037960 PCT/EP2012/068101 8
    R
    7 is selected from the group consisting of -C0 2 H, -SO 3 H, 5-tetrazolyl, -OPO 3
    H
    2 , P0 3
    H
    2 , -CONR 12
    R
    12
    -CONH-SO
    2
    R
    12 , -NR 14
    CONR
    14
    -SO
    2
    R
    15 and -S0 2
    -NHCOR
    15 ; Y is selected from the group consisting of -C2_ 4 -alkylene-, -O-C_ 4 -alkylene-, -C2_4 alkenylene- , -C_ 4 -alkylene-O-, -NR 1 3
    -C_
    4 -alkylene- and -C_ 4 -alkylene-NR 1 3 -; 5 B is selected from the group consisting of C 2
    -
    6 -alkyl, C2-6 alkenyl and Cy, any of them optionally substituted by one or more R 8 ; each R 8 is independently selected from the group consisting of halogen, C1-6 haloalkyl, -O-C 6 -alkyl, -O-C 6 -haloalkyl, C 1 6 -alkyl,-OH, -CN, -CH 2 0R 14 and CONR 12
    R
    12 10 each R 9 is independently selected from the group consisting of CR 0 and N; each R 1 0 is independently selected from the group consisting of H, halogen, C1-6 alkyl, Cl 6 -haloalkyl, -O-Cl- 6 -alkyl, -O-Cl- 6 -haloalkyl and hydroxyC, 6 -alkyl; R" is CR 5 or N, each R 12 is independently selected from the group consisting of H, C 1
    -
    6 -alkyl C1-6 15 haloalkyl, -NR 14
    R
    14 and C 3
    -
    6 cycloalkyl; each R 13 is independently selected from the group consisting of H, C 1
    -
    6 -alkyl C1-6 haloalkyl, and C 3
    -
    6 cycloalkyl; each R 14 is independently selected from the group consisting of H and C 1
    -
    6 -alkyl; each R 15 is independently selected from the group consisting of C 1
    -
    6 -alkyl; 20 Cy is a 3-6 membered monocyclic or 8-12 membered polycyclic ring which can be carbocyclic or heterocyclic containing 1 to 3 heteroatoms selected from N, 0 and S and which can be aromatic, partially unsaturated or saturated and wherein one or more C or S atoms in Cy can be oxidized to form CO, SO or SO 2 ; with the proviso that when W1 and W2 is a benzimidazole, R6 and R7 are not at the 25 same time respectively a -O-Cl_ 4 -alkylene- and a -CO 2 H or that R 7 is not -CONH S0 2
    R
    12 ; and the salts, solvates and prodrugs thereof. Also included within the scope of the invention are the isomers, polymorphs, 30 isotopes, salts, solvates and prodrugs of the compounds of formula (1). Any reference to a compound of formula (1) throughout the present specification includes a reference to any isomer, polymorph, isotope, salt, solvate or prodrug of such compound of formula 1.
    WO 2013/037960 PCT/EP2012/068101 9 The compounds of formula I may exist in different physical forms, i.e. amorphous and crystalline forms. Moreover, the compounds of the invention may have the ability to crystallize in more than one form, a characteristic which is known as polymorphism. Polymorphs can be distinguished by various physical properties well 5 known in the art such as X-ray diffraction pattern, melting point or solubility. All physical forms of the compounds of formula I, including all polymorphic forms ("polymorphs") thereof, are included within the scope of the invention. Some of the compounds of the present invention may exist as several optical 10 isomers and/or several diastereoisomers. Diastereoisomers can be separated by conventional techniques such as chromatography or fractional crystallization. Optical isomers can be resolved by conventional techniques of optical resolution to give optically pure isomers. This resolution can be carried out on any chiral synthetic intermediate or on the products of formula 1. Optically pure isomers can also be 15 individually obtained using enantiospecific synthesis. The present invention covers all individual isomers as well as mixtures thereof (for example racemic mixtures or mixtures of diastereomers), whether obtained by synthesis or by physically mixing them. 20 In addition, any formula given herein is intended to represent unlabeled forms as well as isotopically labeled forms of the compounds. Isotopically labeled compounds have structures depicted by the formulas given herein except that one or more atoms are replaced by an atom having a selected atomic mass or mass number. Examples of isotopes that can be incorporated into compounds of the invention 25 include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, fluorine, chlorine, and iodine, such as 2 H, 3 H, C, 13c, 14c, 15 N, 180, 170 31 p, 32 p, 36S, 18 F , 3601, and 1251 respectively, Such isotopically labelled compounds are useful in metabolic studies (preferably with 14C), reaction kinetic studies (with, for example 2H or 3 H), detection or imaging techniques [such as positron emission tomography 30 (PET) or single- photon emission computed tomography (SPECT)] including drug or substrate tissue distribution assays, or in radioactive treatment of patients. In particular, an 18 F or 11C labeled compound may be particularly preferred for PET or SPECT studies. Further, substitution with heavier isotopes such as deuterium (i.e., 2 H) may afford certain therapeutic advantages resulting from greater metabolic WO 2013/037960 PCT/EP2012/068101 10 stability, for example increased in vivo half-life or reduced dosage requirements. In addition to the unlabeled form, all isotopically labeled forms of the compounds of formula I are included within the scope of the invention. 5 "Halogen" or "halo" as referred in the present invention represent fluorine, chlorine, bromine or iodine. The term "alkyl," alone or in combination, means an acyclic radical, linear or branched, preferably containing from 1 to about 6 carbon atoms. Examples of such radicals include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert 10 butyl, pentyl, iso-amyl, hexyl, heptyl, octyl, and the like. Where no specific substitution is specified, alkyl radicals may be optionally substituted with groups consisting of hydroxy, sulfhydryl, methoxy, ethoxy, amino, cyano, chloro, and fluoro. The carbon atom content of various hydrocarbon-containing moieties is indicated by suffix designating a lower and upper number of carbon atoms in the moiety. Thus, 15 for example, 'C -6-alkyl' refers to alkyl of 1 to 6 carbon atoms, inclusive. The term "alkenyl," alone or in combination, means an acyclic radical, linear or branched, preferably containing from 1 to about 6 carbon atoms and containing at least one double bond. Examples of such radicals include ethenyl, propenyl, isopropenyl, butenyl, isobutenyl, sec-butenyl tert-butenyl and the like. Where no 20 specific substitution is specified, alkenyl radicals may be optionally substituted with groups consisting of hydroxy, sulfhydryl, methoxy, ethoxy, amino, cyano, chloro, and fluoro. The carbon atom content of various hydrocarbon-containing moieties is indicated by suffix designating a lower and upper number of carbon atoms in the moiety. Thus, for example, 'C1-6-alkenyl' refers to alkenyl of 1 to 6 carbon atoms, 25 inclusive. An "alkylene" linking group preferably contains 1-4 carbon atoms and represents for example methylene, ethylene, propylene, butylene. The carbon atom content of various hydrocarbon-containing moieties is indicated by suffix designating a lower and upper number of carbon atoms in the moiety. Thus, for example, 'C1-4-alkylene' 30 refers to an alkylene of 1 to 4 carbon atoms, inclusive. An "alkenylene" linking group preferably contains 2 to 4 carbon atoms and represents for example ethenylene, 1,3-propenylene, 1,4-but-1-enylene, 1,4-but-2 ethylene. The carbon atom content of various hydrocarbon-containing moieties is indicated by suffix designating a lower and upper number of carbon atoms in the WO 2013/037960 PCT/EP2012/068101 11 moiety. Thus, for example, 'C2-4-alkenylene' refers to alkenylene of 2 to 4 carbon atoms, inclusive. "Cycloalkyl" is preferably a monocyclic cycloalkyl containing from three to six carbon atoms. Examples include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. The 5 carbon atom content of various hydrocarbon-containing moieties is indicated by suffix designating a lower and upper number of carbon atoms in the moiety. Thus, for example, 'C3-6-cycloalkyl' refers to cycloalkyl of 3 to 6 carbon atoms, inclusive. The term "carbocyclic", "carbocyclic ring" and "carbocyclyl" refer to a saturated, unsaturated or aromatic mono- or multi-ring cycloalkyl only formed from carbon 10 atoms. The terms "heterocycle", "heterocyclic ring" and "heterocyclyl" refer to a saturated, unsaturated or aromatic mono- or multi-ring cycloalkyl wherein one or more carbon atoms is replaced by N, S, or 0. The terms "heterocycle", "heterocyclic ring system," and "heterocyclyl" include fully saturated ring structures such as piperazinyl, 15 dioxanyl, tetrahydrofuranyl, oxiranyl, aziridinyl, morpholinyl, pyrrolidinyl, piperidinyl, thiazolidinyl, and others. The terms "heterocycle", "heterocyclic ring system," and "heterocyclyl" also include partially unsaturated ring structures such as dihydrofuranyl, dihydropyrrolyl, pyrazolinyl, imidazolinyl, pyrrolinyl, chromanyl, dihydrothienyl, and others. The term "heterocycle", "heterocyclic ring system," and 20 "heterocyclyl" also include aromatic structures such as pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, thienyl, furanyl, pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, and tetrazolyl, optionally substituted. The term "heteroaromatic ring" refers to an aromatic heterocyclic ring. Examples of 25 "heteroaromatic ring" include pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, thionyl, furanyl, pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, and tetrazolyl, optionally substituted. The term "ring" or "ring system" according to the present invention refers to ring systems comprising saturated, unsaturated or aromatic carbocyclic ring systems 30 which contain optionally at least one heteroatom as ring member and which are optionally at least mono-substituted. Said ring systems may be condensed to other carbocyclic ring systems. The term "monocyclic ring" refers to a ring system composed of a single ring. The term "polycyclic ring" refers to a ring system composed of at least two rings.
    WO 2013/037960 PCT/EP2012/068101 12 The term "salt" must be understood as any form of an active compound used in accordance with this invention in which the said compound is in ionic form or is charged and coupled to a counter-ion (a cation or anion) or is in solution. This definition also includes quaternary ammonium salts and complexes of the active 5 molecule with other molecules and ions, particularly complexes formed via ionic interactions.The definition particularly includes physiologically acceptable salts; this term must be understood as equivalent to "pharmaceutically acceptable salts". The term "pharmaceutically acceptable salts" in the context of this invention means any salt that is tolerated physiologically (normally meaning that it is not toxic, 10 particularly as a result of the counter-ion) when used in an appropriate manner for a treatment, particularly applied or used in humans and/or mammals. These pharmaceutically acceptable salts may be formed with cations or bases and, in the context of this invention, are understood to be salts formed by at least one compound used in accordance with the invention - normally an acid (deprotonated) 15 - such as an anion and at least one physiologically tolerated cation, preferably inorganic, particularly when used on humans and/or mammals. Salts with alkali and alkali earth metals are particularly preferred, as well as those formed with ammonium cations (NH 4 '). Preferred salts are those formed with (mono) or (di)sodium, (mono) or (di)potassium, magnesium or calcium.These physiologically 20 acceptable salts may also be formed with anions or acids and, in the context of this invention, are understood as being salts formed by at least one compound used in accordance with the invention - normally protonated, for example in nitrogen - such as a cation and at least one physiologically tolerated anion, particularly when used on humans and/or mammals.This definition specifically includes in the context of this 25 invention a salt formed by a physiologically tolerated acid, i.e. salts of a specific active compound with physiologically tolerated organic or inorganic acids particularly when used on humans and/or mammals. Examples of this type of salts are those formed with: hydrochloric acid, hydrobromic acid, sulphuric acid, methanesulfonic acid, formic acid, acetic acid, oxalic acid, succinic acid, malic acid, 30 tartaric acid, mandelic acid, fumaric acid, lactic acid or citric acid. The term "solvate" in accordance with this invention should be understood as meaning any form of the active compound in accordance with the invention in which said compound is bonded by a non-covalent bond to another molecule (normally a WO 2013/037960 PCT/EP2012/068101 13 polar solvent), especially including hydrates and alcoholates, for example methanolate. The term "prodrug" is used in its broadest sense and encompasses those 5 derivatives that are converted in vivo to the compounds of the invention. Examples of prodrugs include, but are not limited to, derivatives and metabolites of the compounds of formula (1) that include biohydrolyzable moieties such as biohydrolyzable amides, biohydrolyzable esters, biohydrolyzable carbamates, biohydrolyzable carbonates, biohydrolyzable ureides, and biohydrolyzable 10 phosphate analogues. Preferably, prodrugs of compounds with carboxyl functional groups are the lower alkyl esters of the carboxylic acid. The carboxylate esters are conveniently formed by esterifying any of the carboxylic acid moieties present on the molecule. Prodrugs can typically be prepared using well-known methods, such as those described by Burger "Medicinal Chemistry and Drug Discovery 6th ed. 15 (Donald J. Abraham ed., 2001 , Wiley) and "Design and Applications of Prodrugs" (H. Bundgaard ed., 1985, Harwood Academic Publishers). The terms "prevention", "preventing", "preventive" "prevent" and "prophylaxis" refer to the capacity of a therapeutic to avoid, minimize or difficult the onset or 20 development of a disease or condition before its onset. The terms "treating" or "treatment" is meant at least a suppression or an amelioration of the symptoms associated with the condition afflicting the subject, where suppression and amelioration are used in a broad sense to refer to at least a reduction in the magnitude of a parameter, e.g., symptom associated with the 25 condition being treated, such as pain. As such, the method of the present invention also includes situations where the condition is completely inhibited, terminated, such that the subject no longer experiences the condition. In a particular and preferred embodiment of the present invention each R 9 in the 30 general formula (1) is CR 1 and each R 1 is preferably H. In another preferred embodiment of the invention each R 4 is H.
    WO 2013/037960 PCT/EP2012/068101 14 In still another particular embodiment, Y preferably is -O-C_ 4 -alkylene- or -Cl_4 alkylene-O- and more preferably -0-CH 2 - or -CH 2 -0-. In a preferred embodiment, Y is -O-C_ 4 -alkylene-. In a more preferred embodiment, Y is -0
    CH
    2 -. 5 In another embodiment R" is CR 5 and R 5 is selected from the group consisting of H, halogen, C 1 6 -haloalkyl, -O-C 6 -alkyl, -O-C 6 -haloalkyl, -OH and C 1 6 -alkyl. In another preferred embodiment of the invention R 5 is selected from the group 10 consisting of H, halogen and -C 6 -haloalkyl. Another preferred embodiment is that in which B is Cy, this being preferably phenyl,
    C
    3
    -
    6 -cycloalkyl, C 2
    -
    6 -alkyl, C2-6 alkenyl or a 5-6 membered monocyclic heterocycle containing 1 or 2 N atom which can be aromatic, partially unsaturated or saturated, 15 any of them optionally substituted by one or more R . In another embodiment B is phenyl or cyclopropyl, any of them optionally substituted by one or more R 8 . 20 In another embodiment B is phenyl and C 2
    -
    6 -alkyl In a preferred embodiment B is preferably a phenyl optionally substituted by 1-5 R , more preferably by 1-4 R . In another embodiment B is: - (R') 0 -3 25 H In another embodiment B is R 8
    -(R
    8
    )
    0 -2 30 In another embodiment B is WO 2013/037960 PCT/EP2012/068101 15 R8 sH (R 8
    )
    0 _ R8 H In another embodiment R 8 is independently selected from the group consisting of halogen, C 1
    -
    6 -haloalkyl, -O-C 6 -alkyl, -O-C 6 -haloalkyl, C 1
    -
    6 -alkyl, and -OH. 5 In another embodiment R 8 is selected from the group consisting of halogen and -Cl_ 6 -haloalkyl. In a particular embodiment of the invention 10 represents R1 15 where E 1 , E 2 and E 3 are CR 2 ; or one of E 1 , E 2 or E 3 is N and the others are CR 2 ; or two of E 1 , E 2 or E are N and the other is CR 2 . In another embodiment E 1 , E 2 and E3 are CR 2 . 20 In another embodiment E' is N and E 2 and E 3 are CR 2 . In another embodiment E 2 is N and E' and E 3 are CR 2 . In another embodiment E 3 is N and El and E 2 are CR 2 . 25 In another embodiment El and E 3 are N and E 2 is CR 2
    .
    WO 2013/037960 PCT/EP2012/068101 16 In another particular embodiment of the invention represents 5 D N where G is selected from the group consisting of CR 3 , CR 3
    R
    3 , OCR 3
    R
    3 , OCR 3 ,
    CR
    3
    R
    3
    -CR
    3
    R
    3 and N; D is selected from the group consisting of CR 3 , CR 3
    R
    3 and N; 10 and -- - represents a single bond or a double bond. In another embodiment G is selected from the group consisting of CR 3 , CR 3
    R
    3 , 0, S and N. 15 In another embodiment G is selected from the group consisting of CR 3
    =CR
    3 ,
    CR
    3
    R
    3
    -CR
    3
    R
    3 , N-CR 3 , N-CR 3
    R
    3 , CR 3
    R
    3 -N, O-CR 3 , O-CR 3
    R
    3 , CR 3
    R
    3 -O, S-CR 3 ,
    S-CR
    3
    R
    3 and CR 3
    R
    3 -S. In another embodiment G is selected from the group consisting of CR 3 , CR 3
    R
    3 and 20 N. In another embodiment G is CR 3
    R
    3
    -CR
    3
    R
    3 . In another embodiment G is selected from the group consisting of CR 3 , CR 3 R, N, 25 CR 3
    =CR
    3 , CR 3
    R
    3
    -CR
    3
    R
    3 , N-CR 3 , N-CR 3
    R
    3 , CR 3
    R
    3 -N;. In another embodiment G is selected from the group consisting of CR 3 , CR 3
    R
    3 , N and CR 3
    R
    3
    -CR
    3
    R
    3 . 30 In another embodiment WO 2013/037960 PCT/EP2012/068101 17 represents D 5 G is selected from the group consisting of CR 3 , CR 3
    R
    3 and N; D is selected from the group consisting of CR', CR 3
    R
    3 and N; -- - represents a single bond or a double bond. In another embodiment 10 represents G N D G is selected from the group consisting of CR 3
    R
    3
    -CR
    3
    R
    3 ; 15 D is selected from the group consisting of CR , CR 3
    R
    3 and N; -- - represents a single bond or a double bond. In another embodiment D is selected from the group consisting of CR , CR 3
    R
    3 and 20 N. In another embodiment 25 WO 2013/037960 PCT/EP2012/068101 18 is selected from the group consisting of R1 R3 R1 R3 R3 R1 R3 R1 R3 R3RN R3 N R 3 IxN " R1 R3 R3 R3R1 NR1 NR1 R3 R R 3 3 ; N 3 (R2)-3 (R)o-3(R2o-2(R 2
    )-
    2 R R3 1 >-R R R~ Nik R 3 ;and R R 3 RN N N N N ( 2 )x Q (R2)03 1 R3 (R - 3 (R2 )-2 (2) 5 In a preferred embodiment of the invention is selected from the group consisting of WO 2013/037960 PCT/EP2012/068101 19
    R
    1 R 3 RR3 3 R R 3
    R
    1 R 3 R N NN I N R2 N R 2 N R 3 R2 N R 2 N N R2 R 2 -j R
    R
    1 R 3 R3 R 1 R R R 3 R R C N ~ N>.N 2R 3 R2 N 2N 2N R2 NRRR R2 R R 2 R jR 2
    R
    1
    R
    1
    R
    3
    R
    1 R3 R R R 3 R 3 R3 R2 0
    R
    3 R 2 R R R 2 R FR3 N N R N NR R 2 N N
    R
    3
    R
    2 R3NR N RRN R 3 RR 2~ R 32 R' R2 R R 3 R R 3 3 N ~ ~ ~ n R R3 R I R3I R NN3R 3 NIt N 3 2 N R RI R3 2 R R N R 2 3
    RR
    2 1 and RR N' N R 3 2N N3 NN N NR R NR o 2
    <
    WO 2013/037960 PCT/EP2012/068101 20 In another preferred embodiment 5 represents Ri R3
    R
    2 N In another preferred embodiment 10 represents
    R
    1
    R
    3
    R
    3
    R
    3 R 2 N R 3 15 In another embodiment R 6 is a direct bond. In another embodiment R 7 is selected from the group consisting of -C0 2 H, -SO 3 H and 5-tetrazolyl. 20 In another embodiment R7 is -C0 2 H. Another preferred embodiment of the invention is that in which R 6 is a direct bond and R 7 is -C0 2
    H.
    WO 2013/037960 PCT/EP2012/068101 21 In a particular embodiment R 2 is independently selected from the group consisting of H, halogen, C 1
    -
    6 -alkyl, C 1
    -
    6 -haloalkyl, -O-C 6 -alkyl, -O-C 6 -haloalkyl, hydroxyCj- 6 alkyl and CN. In another embodiment R 2 is independently selected from the group consisting of H 5 and halogen. In another embodiment R 3 is H. In another embodiment, each R 2 is independently selected from the group consisting of H and halogen and each R 3 is H. 10 Among all the compounds encompassed by the general formula (1) the following compounds are particularly preferred: - (E)-1 -(5-chloro-2-(4-chloro-2-fluorostyryl)benzyl)-1 H-indole-4-carboxylic acid, - 1-(2-(benzyloxy)-5-bromobenzyl)-1 H-indole-4-carboxylic acid, 15 - 1-(2-(benzyloxy)-5-(trifluoromethyl)benzyl)-1 H-indole-4-carboxylic acid, - 1-(5-bromo-2-((4-fluorobenzyl)oxy)benzyl)-1 H-indole-4-carboxylic acid, - 1-(5-chloro-2-((4-fluorobenzyl)oxy)benzyl)-1 H-indole-4-carboxylic acid, - 1-(2-((4-chloro-2-fluorobenzyl)oxy)-5-(trifluoromethyl)benzyl)-1 H-indole-4 carboxylic acid, 20 - 1-(5-chloro-2-(cyclopropylmethoxy)benzyl)-1 H-indole-4-carboxylic acid, - 1-(5-bromo-2-(cyclopropylmethoxy)benzyl)-1 H-indole-4-carboxylic acid, - 1-(5-bromo-2-((4-chloro-2-fluorobenzyl)oxy)benzyl)-1 H-indole-4-carboxylic acid, - 1-(4-chloro-2-isobutoxybenzyl)-1 H-indole-4-carboxylic acid, 25 - 1 -(5-chloro-2-((4-(trifluoromethyl)benzyl)oxy)benzyl)-1 H-indole-4-carboxylic acid, - 1-(5-chloro-2-((2-chloro-4-fluorobenzyl)oxy)benzyl)-1 H-indole-4-carboxylic acid, - 1-(5-chloro-2-((2,3,5,6-tetrafluorobenzyl)oxy)benzyl)-1 H-indole-4-carboxylic 30 acid, - 1-(2-((2,4-bis(trifluoromethyl)benzyl)oxy)-5-chlorobenzyl)-1 H-indole-4 carboxylic acid, - 1-(5-chloro-2-((2,4,5-trifluorobenzyl)oxy)benzyl)-1 H-indole-4-carboxylic acid, - 1-(5-fluoro-2-((2,4,5-trifluorobenzyl)oxy)benzyl)-1 H-indole-4-carboxylic acid, WO 2013/037960 PCT/EP2012/068101 22 - 1-(2-((3-bromo-4-fluorobenzyl)oxy)-5-chlorobenzyl)-1 H-indole-4-carboxylic acid, - 1-(5-fluoro-2-((4-fluoro-2-(trifluoromethyl)benzyl)oxy)benzyl)-1 H-indole-4 carboxylic acid, 5 - 1-(2-((2-chloro-4-fluorobenzyl)oxy)-5-fluorobenzyl)-1 H-indole-4-carboxylic acid, - 1-(5-fluoro-2-((4-fluoro-2-(trifluoromethyl)benzyl)oxy)benzyl)-1 H-indole-4 carboxylic acid, - 1-(5-chloro-2-((2,3,4-trifluorobenzyl)oxy)benzyl)-1 H-indole-4-carboxylic acid, 10 - 1-(5-bromo-2-((2,3,4-trifluorobenzyl)oxy)benzyl)-1 H-indole-4-carboxylic acid, - 1-(5-chloro-2-(1-(2,4-difluorophenyl)ethoxy)benzyl)-1 H-indole-4-carboxylic acid, - 1-(2-((3-bromo-4-fluorobenzyl)oxy)-5-fluorobenzyl)-1 H-indole-4-carboxylic acid, 15 - 1-(5-bromo-2-((3-bromo-4-fluorobenzyl)oxy)benzyl)-1 H-indole-4-carboxylic acid, - 1 -(5-bromo-2-((4-fluoro-2-(trifluoromethyl)benzyl)oxy)benzyl)-1 H-indole-4 carboxylic acid, - 1-(5-bromo-2-((2-chloro-4-fluorobenzyl)oxy)benzyl)-1 H-indole-4-carboxylic 20 acid, - 1-(3-bromo-2-((4-bromo-2-fluorobenzyl)oxy)-5-chlorobenzyl)-1 H-indole-4 carboxylic acid, - 1-(5-chloro-2-((2,5-difluorobenzyl)oxy)benzyl)-1 H-indole-4-carboxylic acid, - 1-(5-chloro-2-((2-chloro-5-fluorobenzyl)oxy)benzyl)-1 H-indole-4-carboxylic 25 acid, - 1-(5-chloro-2-((2-chloro-4,5-difluorobenzyl)oxy)benzyl)-1 H-indole-4 carboxylic acid, - 1-(2-((2,5-difluorobenzyl)oxy)-5-fluorobenzyl)-1 H-indole-4-carboxylic acid, - 1-(2-((2,6-difluorobenzyl)oxy)-5-fluorobenzyl)-1 H-indole-4-carboxylic acid, 30 - 1-(5-fluoro-2-((3,4,5-trifluorobenzyl)oxy)benzyl)-1 H-indole-4-carboxylic acid, - 1-(5-fluoro-2-((4-fluorobenzyl)oxy)benzyl)-1 H-indole-4-carboxylic acid, - 1-(2-((2-chloro-4,5-difluorobenzyl)oxy)-5-fluorobenzyl)-1 H-indole-4-carboxylic acid, WO 2013/037960 PCT/EP2012/068101 23 - 1-(2-((2,6-difluorobenzyl)oxy)-5-(trifluoromethyl)benzyl)-1 H-indole-4 carboxylic acid, - 1-(2-((2-chloro-5-fluorobenzyl)oxy)-5-fluorobenzyl)-1 H-indole-4-carboxylic acid, 5 - 1-(2-((2,5-difluorobenzyl)oxy)-5-(trifluoromethyl)benzyl)-1 H-indole-4 carboxylic acid, - 1-(3-bromo-5-chloro-2-((2,6-difluorobenzyl)oxy)benzyl)-1 H-indole-4 carboxylic acid, - 1-(5-chloro-2-((3,5-difluorobenzyl)oxy)benzyl)-1 H-indole-4-carboxylic acid, 10 - 1-(1 -(5-chloro-2-((4-chloro-2-fluorobenzyl)oxy)phenyl)ethyl)-1 H-indole-4 carboxylic acid, - 1-(5-chloro-2-((2,4-difluorobenzyl)oxy)benzyl)-1 H-indole-4-carboxylic acid, - 1-(2-(benzyloxy)-5-chlorobenzyl)-1 H-indole-4-carboxylic acid, - 1-(5-chloro-2-((2-fluorobenzyl)oxy)benzyl)-1 H-indole-4-carboxylic acid, 15 - 1-(2-((4-bromo-2-fluorobenzyl)oxy)-5-chlorobenzyl)-1 H-indole-4-carboxylic acid, - 1 -(5-chloro-2-((2-fluoro-4-(trifluoromethyl)benzyl)oxy)benzyl)-1 H-indole-4 carboxylic acid, - 1-(5-chloro-2-((4-chloro-2-fluorobenzyl)oxy)benzyl)-1 H-indole-4-carboxylic 20 acid, - 1-(2-((3-fluorobenzyl)oxy)-5-(trifluoromethyl)benzyl)-1 H-indole-4-carboxylic acid, - 1-(2-((4-bromo-2-fluorobenzyl)oxy)-5-(trifluoromethyl)benzyl)-1 H-indole-4 carboxylic acid, 25 - 1-(2-((2,4-difluorobenzyl)oxy)-5-(trifluoromethyl)benzyl)-1 H-indole-4 carboxylic acid, - 1-(2-((2-fluorobenzyl)oxy)-5-(trifluoromethyl)benzyl)-1 H-indole-4-carboxylic acid, - 1-(2-((2,4-difluorobenzyl)oxy)-5-fluorobenzyl)-1 H-indole-4-carboxylic acid, 30 - 1-(2-((2,4-difluorobenzyl)oxy)benzyl)-1 H-indole-4-carboxylic acid, - 1-(5-bromo-2-((4-bromo-2-fluorobenzyl)oxy)benzyl)-1 H-indole-4-carboxylic acid, - 1-(2-((4-bromo-2-fluorobenzyl)oxy)-5-fluorobenzyl)-1 H-indole-4-carboxylic acid, WO 2013/037960 PCT/EP2012/068101 24 - 1-(5-chloro-2-((4-chloro-2,6-difluorobenzyl)oxy)benzyl)-1 H-indole-4 carboxylic acid, - 1-(2-((4-bromo-2,6-difluorobenzyl)oxy)-5-chlorobenzyl)-1 H-indole-4 carboxylic acid, 5 - 1-(3,5-dichloro-2-((4-chloro-2-fluorobenzyl)oxy)benzyl)-1 H-indole-4 carboxylic acid, - 1-(5-bromo-2-((4-chloro-2,6-difluorobenzyl)oxy)benzyl)-1 H-indole-4 carboxylic acid, - 1-((3-((4-chloro-2-fluorobenzyl)oxy)pyridin-2-yl)methyl)-1 H-indole-4 10 carboxylic acid, - 3-(1-(5-chloro-2-((4-chloro-2-fluorobenzyl)oxy)benzyl)-1 H-indol-4 yl)propanoic acid, - 1-(5-chloro-2-(4-chloro-2-fluorophenethyl)benzyl)-1 H-indole-4-carboxylic acid, 15 - 1-(5-chloro-2-(cyclopropylmethoxy)benzyl)-1 H-indole-5-carboxylic acid, - 1-(5-fluoro-2-((2,4,5-trifluorobenzyl)oxy)benzyl)-1 H-indole-5-carboxylic acid, - 1-(2-((2-chloro-4-fluorobenzyl)oxy)-5-fluorobenzyl)-1 H-indole-5-carboxylic acid, - 1 -(5-chloro-2-((4-fluoro-2-(trifluoromethyl)benzyl)oxy)benzyl)-1 H-indole-5 20 carboxylic acid, - 1-(2-((3-bromo-4-fluorobenzyl)oxy)-5-fluorobenzyl)-1 H-indole-5-carboxylic acid, - 1 -(5-bromo-2-((4-fluoro-2-(trifluoromethyl)benzyl)oxy)benzyl)-1 H-indole-5 carboxylic acid, 25 - 1-(5-bromo-2-((2-chloro-4-fluorobenzyl)oxy)benzyl)-1 H-indole-5-carboxylic acid, - 1-(5-fluoro-2-((3,4,5-trifluorobenzyl)oxy)benzyl)-1 H-indole-5-carboxylic acid, - 1-(2-((2-chloro-4,5-difluorobenzyl)oxy)-5-fluorobenzyl)-1 H-indole-5-carboxylic acid, 30 - 1-(2-((2-chloro-5-fluorobenzyl)oxy)-5-fluorobenzyl)-1 H-indole-5-carboxylic acid, - 1-(5-bromo-2-((2,4-difluorobenzyl)oxy)benzyl)-1 H-indole-5-carboxylic acid, - 1-(2-((4-bromo-2-fluorobenzyl)oxy)-5-(trifluoromethyl)benzyl)-1 H-indole-5 carboxylic acid, WO 2013/037960 PCT/EP2012/068101 25 - 1-(5-chloro-2-((4-chloro-2-fluorobenzyl)oxy)benzyl)-1 H-indole-5-carboxylic acid, - 1-(5-chloro-2-((4-fluorobenzyl)oxy)benzyl)-1 H-indole-5-carboxylic acid, - 1-(5-chloro-2-((2,4-difluorobenzyl)oxy)benzyl)-1 H-indole-5-carboxylic acid, 5 - (E)-3-(1 -(2-(benzyloxy)-5-(trifluoromethyl)benzyl)-1 H-indol-4-yl)acrylic acid, - (E)-3-(1-(5-bromo-2-(cyclopropylmethoxy)benzyl)-1 H-indol-4-yl)acrylic acid, - (E)-3-(1-(5-chloro-2-(cyclopropylmethoxy)benzyl)-1 H-indol-4-yl)acrylic acid, - (E)-3-(1-(5-chloro-2-((2,4-difluorobenzyl)oxy)benzyl)-1 H-indol-4-yl)acrylic acid, 10 - (E)-3-(1-(5-chloro-2-((4-chloro-2-fluorobenzyl)oxy)benzyl)-1 H-indol-4 yl)acrylic acid, - 2-((1-(2-((4-chloro-2-fluorobenzyl)oxy)-5-(trifluoromethyl)benzyl)-1 H-indol-4 yl)oxy)acetic acid, - 2-((1-(5-chloro-2-(cyclopropylmethoxy)benzyl)-1 H-i ndol-4-yl)oxy)acetic acid, 15 - 2-((1-(5-chloro-2-(cyclopropylmethoxy)benzyl)-1 H-indol-4-yl)oxy)acetic acid, - 1-(2-(benzyloxy)-5-bromobenzyl)-1 H-indole-6-carboxylic acid, - 1-(5-chloro-2-((2,4-difluorobenzyl)oxy)benzyl)-1 H-indole-6-carboxylic acid, - 3-(1-(5-chloro-2-((4-chloro-2-fluorobenzyl)oxy)benzyl)-1 H-indol-4 yl)propanoic acid, 20 - 1-(5-chloro-2-((4-chloro-2-fluorobenzyl)oxy)benzyl)-1 H-pyrrolo[2,3-b]pyridine 4-carboxylic acid, - 1-(5-chloro-2-((2,4-difluorobenzyl)oxy)benzyl)-1 H-pyrrolo[2,3-b]pyridine-4 carboxylic acid, - 1-(5-chloro-2-((4-chloro-2-fluorobenzyl)oxy)benzyl)-1 H-benzo[d]imidazole-4 25 carboxylic acid, - 1-(5-chloro-2-((4-chloro-2-fluorobenzyl)oxy)benzyl)indoline-4-carboxylic acid, - 1-(5-chloro-2-((4-chloro-2-fluorobenzyl)oxy)benzyl)-1,2,3,4 tetrahydroquinoline-5-carboxylic acid, - 1-(5-chloro-2-((2,4-difluorobenzyl)oxy)benzyl)-1,2,3,4-tetrahydroquinoline-5 30 carboxylic acid, - 7-(5-chloro-2-((4-chloro-2-fluorobenzyl)oxy)benzyl)-7H-pyrrolo[2,3 d]pyrimidine-4-carboxylic acid, - 7-(5-chloro-2-((2,4-difluorobenzyl)oxy)benzyl)-7H-pyrrolo[2,3-d]pyrimidine-4 carboxylic acid, WO 2013/037960 PCT/EP2012/068101 26 - 1-(5-chloro-2-((2,4-difluorobenzyl)oxy)benzyl)-7-fluoro-1 H-indole-4-carboxylic acid, - 1-{2-[(2,4-difluorobenzyl)oxy]-5-methoxybenzyl}-1 H-indole-4-carboxylic acid, - 1-[5-chloro-2-(cyclohexylmethoxy)benzyl]-1 H-indole-4-carboxylic acid, 5 - 1-[5-chloro-2-(cyclopentylmethoxy)benzyl]-1 H-indole-4-carboxylic acid, - 1-(5-fluoro-2-propoxybenzyl)-1 H-indole-4-carboxylic acid, - 1-(5-chloro-2-(cyclopentyloxy)benzyl)-1 H-indole-4-carboxylic acid, - 1-(5-chloro-2-propoxybenzyl)-1 H-indole-4-carboxylic acid, - 1-(5-chloro-2-(2-(tetrahydro-2H-pyran-4-yl)ethoxy)benzyl)-1 H-indole-4 10 carboxylic acid, - 1-(5-fluoro-2-isobutoxybenzyl)-1 H-indole-4-carboxylic acid, - 1-(2-isobutoxybenzyl)-1 H-indole-4-carboxylic acid, - 1-[5-chloro-2-(2,2-difluoroethoxy)benzyl]-1 H-indole-4-carboxylic acid, - 1-[5-chloro-2-(2-fluoroethoxy)benzyl]-1 H-indole-4-carboxylic acid, 15 - 1-[5-chloro-2-(2,2,2-trifluoroethoxy)benzyl]-1 H-indole-4-carboxylic acid, - 1-[5-chloro-2-(neopentyloxy)benzyl]-1 H-indole-4-carboxylic acid, - 4-(5-chloro-2-cyclobutoxybenzyl)-3-oxo-3,4-dihydro-2H benzo[b][1,4]oxazine-8-carboxylic acid, - 4-(5-bromo-2-(4-chloro-2-fluorobenzyloxy)benzyl)-3-oxo-3,4-dihydro-2H 20 benzo[b][1,4]oxazine-8-carboxylic acid, - 4-(5-chloro-2-(2-fluoro-2-methylpropoxy)benzyl)-3,4-dihydro-2H benzo[b][1,4]oxazine-8-carboxylic acid - 4-(5-chloro-2-((4-chloro-2-fluorobenzyl)oxy)benzyl)-3,4-dihydro-2H benzo[b][1,4]oxazine-8-carboxylic acid, 25 - 4-(5-chloro-2-((2,4-difluorobenzyl)oxy)benzyl)-3,4-dihydro-2H benzo[b][1,4]oxazine-8-carboxylic acid, - 4-(2-((4-chloro-2-fluorobenzyl)oxy)benzyl)-3,4-dihydro-2H benzo[b][1,4]oxazine-8-carboxylic acid, - 4-(2-(benzyloxy)benzyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-8-carboxylic 30 acid, - 4-(2-((2-chloro-4-fluorobenzyl)oxy)-5-fluorobenzyl)-3,4-dihydro-2H benzo[b][1,4]oxazine-8-carboxylic acid, - 4-(2-((2,4-difluorobenzyl)oxy)benzyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-8 carboxylic acid, WO 2013/037960 PCT/EP2012/068101 27 - 1-(2-((2-chlorobenzyl)oxy)-5-fluorobenzyl)-1 H-indazole-4-carboxylic acid, - 1-(5-chloro-2-((4-chloro-2-fluorobenzyl)oxy)benzyl)-1 H-indazole-4-carboxylic acid, - 1-(5-chloro-2-(2-fluoro-2-methylpropoxy)benzyl)-1 H-indazole-4-carboxylic 5 acid, - 1-(5-chloro-2-((2-fluorobenzyl)oxy)benzyl)-1 H-indazole-4-carboxylic acid, - 1-(2-((2-chlorobenzyl)oxy)-5-methylbenzyl)-1 H-indazole-4-carboxylic acid, - 1-(5-fluoro-2-((2-fluorobenzyl)oxy)benzyl)-1 H-indazole-4-carboxylic acid, - 1-(2-((2-fluorobenzyl)oxy)-5-methylbenzyl)-1 H-indazole-4-carboxylic acid, 10 - 1-(5-chloro-2-((2-chlorobenzyl)oxy)benzyl)-1 H-indazole-4-carboxylic acid, - 1-(5-chloro-2-(3-fluoro-2-methylpropoxy)benzyl)-1 H-indazole-4-carboxylic acid, - 1-(5-chloro-2-propoxybenzyl)-1 H-indazole-4-carboxylic acid, - 1-(5-chloro-2-(cyclopentyloxy)benzyl)-1 H-indazole-4-carboxylic acid, 15 - 1-(5-fluoro-2-isobutoxybenzyl)-1 H-indazole-4-carboxylic acid, - 1-(5-fluoro-2-propoxybenzyl)-1 H-indazole-4-carboxylic acid, - 1-(5-bromo-2-(4-chloro-2-fluorobenzyloxy)benzyl)-1 H-indazole-4-carboxylic acid, - 1-(5-chloro-2-cyclobutoxybenzyl)-1 H-indazole-4-carboxylic acid, 20 - 1-(5-chloro-2-(neopentyloxy)benzyl)-1 H-indazole-4-carboxylic acid, - 1-(5-chloro-2-((4-chloro-2-fluorobenzyl)oxy)benzyl)-1 H-pyrrolo[3,2-c]pyridine 4-carboxylic acid, - 1-(2-((2,4-difluorobenzyl)oxy)benzyl)-7-fluoro-1 H-indole-4-carboxylic acid, - 1-(5-chloro-2-((4-chloro-2-fluorobenzyl)oxy)benzyl)-3-(hydroxymethyl)-1 H 25 indole-4-carboxylic acid, - 1-(5-chloro-2-((2,4-difluorobenzyl)oxy)benzyl)-3-(hydroxymethyl)-1 H-indole 4-carboxylic acid, - 1 -(2-((2,4-difluorobenzyl)oxy)benzyl)-3-(hydroxymethyl)-1 H-indole-4 carboxylic acid, 30 - 1 -(2-((4-chloro-2-fluorobenzyl)oxy)benzyl)-3-(hydroxymethyl)-1 H-indole-4 carboxylic acid, - 1 -(2-((2,4-difluorobenzyl)oxy)-5-fluorobenzyl)-3-(hydroxymethyl)-1 H-indole-4 carboxylic acid, WO 2013/037960 PCT/EP2012/068101 28 - 1-(2-((4-chloro-2-fluorobenzyl)oxy)-5-fluorobenzyl)-3-(hydroxymethyl)-1
    H
    indole-4-carboxylic acid, - 1 -(5-chloro-2-(2-fluoro-2-methylpropoxy)benzyl)-3-(hydroxymethyl)-1 H indole-4-carboxylic acid, 5 - 1 -(2-cyclobutoxy-5-fluorobenzyl)-3-(hydroxymethyl)- 1 H-indole-4-carboxylic acid, - 1 -(5-fluoro-2-((4-fluorobenzyl)oxy)benzyl)-3-(hydroxymethyl)-1 H-indole-4 carboxylic acid, - 1 -(5-chloro-2-((4-fluorobenzyl)oxy)benzyl)-3-(hydroxymethyl)-1 H-indole-4 10 carboxylic acid, - 1 -(5-chloro-2-(3-fluoro-2-methylpropoxy)benzyl)-3-(hydroxymethyl)-1 H indole-4-carboxylic acid, - 1-(5-chloro-2-((2,4-difluorobenzyl)oxy)benzyl)-3-(hydroxymethyl)-1 H pyrrolo[2,3-b]pyridine-4-carboxylic acid, 15 - 1-(5-chloro-2-((4-chloro-2-fluorobenzyl)oxy)benzyl)-3-(hydroxymethyl)-1 H pyrrolo[2,3-b]pyridine-4-carboxylic acid, - 1-(5-chloro-2-((4-chloro-2-fluorobenzyl)oxy)benzyl)-3-(2-hydroxyethyl)-1 H indole-4-carboxylic acid, - 1-(5-chloro-2-((2,4-difluorobenzyl)oxy)benzyl)-3-(2-hydroxyethyl)-1 H-indole 20 4-carboxylic acid, - 1-(5-fluoro-2-isobutoxybenzyl)-3-(2-hydroxyethyl)-1 H-indole-4-carboxylic acid, - 1-(5-chloro-2-isobutoxybenzyl)-3-(2-hydroxyethyl)-1 H-indole-4-carboxylic acid, 25 - 1-(5-chloro-2-(2-fluoro-2-methylpropoxy)benzyl)-3-(2-hydroxyethyl)-1 H indole-4-carboxylic acid, - 1-(2-((2,4-difluorobenzyl)oxy)-5-fluorobenzyl)-3-(2-hydroxyethyl)-1 H-indole-4 carboxylic acid, - 1-(5-chloro-2-(3-fluoro-2-methylpropoxy)benzyl)-3-(2-hydroxyethyl)-1 H 30 indole-4-carboxylic acid, - (E)-3-(2-carboxylatovinyl)-1 -(5-chloro-2-((4-chloro-2 fluorobenzyl)oxy)benzyl)-1 H-indole-4-carboxylic acid, - (E)-3-(2-carboxylatovinyl)-1 -(5-chloro-2-((2,4-difluorobenzyl)oxy)benzyl)-1
    H
    indole-4-carboxylic acid, WO 2013/037960 PCT/EP2012/068101 29 - 1-(5-chloro-2-((2,4-difluorobenzyl)oxy)benzyl)-1 H-pyrrolo[2,3-c]pyridine-4 carboxylic acid, - 1-(5-chloro-2-((4-chloro-2-fluorobenzyl)oxy)benzyl)-1 H-pyrrolo[2,3-c]pyridine 4-carboxylic acid, 5 - 1-(5-chloro-2-((2,4-difluorobenzyl)oxy)benzyl)indoline-4-carboxylic acid, - 1-(5-chloro-2-(2-fluoro-2-methylpropoxy)benzyl)indoline-4-carboxylic acid, - 1-(5-chloro-2-((4-chloro-2-fluorobenzyl)oxy)benzyl)indoline-4-carboxylic acid, - 1-(2-((2-chloro-4-fluorobenzyl)oxy)-5-fluorobenzyl)indoline-4-carboxylic acid, - 1-(5-chloro-2-isobutoxybenzyl)indoline-4-carboxylic acid, 10 - 1-(5-fluoro-2-isobutoxybenzyl)indoline-4-carboxylic acid, - 1-(5-chloro-2-cyclobutoxybenzyl)indoline-4-carboxylic acid, - 1-(2-((2,4-difluorobenzyl)oxy)benzyl)-1,2,3,4-tetrahydroquinoline-5-carboxylic acid, - 1-(5-chloro-2-((2,4-difluorobenzyl)oxy)benzyl)-1,2,3,4-tetrahydroquinoline-5 15 carboxylic acid, - 1-(5-chloro-2-(cyclobutylmethoxy)benzyl)-1,2,3,4-tetrahydroquinoline-5 carboxylic acid, - 1-(5-chloro-2-isobutoxybenzyl)-1,2,3,4-tetrahydroquinoline-5-carboxylic acid, - 1-[5-chloro-2-(1,2-dimethylpropoxy)benzyl]-1,2,3,4-tetrahydroquinoline-5 20 carboxylic acid, - 1-[5-chloro-2-(2-fluoro-2-methylpropoxy)benzyl]-1,2,3,4-tetrahydroquinoline 5-carboxylic acid, - 1-[5-chloro-2-(cyclobutyloxy)benzyl]-1,2,3,4-tetrahydroquinoline-5-carboxylic acid, 25 - 1-{5-chloro-2-[(2-methylprop-2-enyl)oxy]benzyl}-1,2,3,4-tetrahydroquinoline 5-carboxylic acid, - 1-[5-chloro-2-(3-fluoro-2-methylpropoxy)benzyl]-1,2,3,4-tetrahydroquinoline 5-carboxylic acid, - 1-[5-chloro-2-(2-fluoropropoxy)benzyl]-1,2,3,4-tetrahydroquinoline-5 30 carboxylic acid, - 1-(5-chloro-2-{[2-(fluoromethyl)prop-2-enyl]oxy}benzyl)-1,2,3,4 tetrahydroquinoline-5-carboxylic acid, - 1-(5-chloro-2-((4-chloro-2-fluorobenzyl)oxy)benzyl)-1,2,3,4 tetrahydroquinoline-5-sulfonic acid, WO 2013/037960 PCT/EP2012/068101 30 - 1 -(5-chloro-2-((2,4-difluorobenzyl)oxy)benzyl)-1,2,3,4-tetrahydroquinoline-5 sulfonic acid, - 1-(2-((4-chloro-2-fluorobenzyl)oxy)benzyl)-1,2,3,4-tetrahydroquinoline-5 sulfonic acid, 5 - N-((1 -(5-chloro-2-((2,4-difluorobenzyl)oxy)benzyl)-1,2,3,4-tetrahydroquinolin 5-yl)sulfonyl)acetamide, - N-((1 -(5-chloro-2-((4-chloro-2-fluorobenzyl)oxy)benzyl)-1,2,3,4 tetrahydroquinolin-5-yl)sulfonyl)acetamide, - 1-(5-chloro-2-((4-chloro-2-fluorobenzyl)oxy)benzyl)-3-(hydroxymethyl)-1 H 10 indazole-4-carboxylic acid, - 1 -(5-chloro-2-(2-fluoro-2-methylpropoxy)benzyl)-3-(hydroxymethyl)-1 H indazole-4-carboxylic acid, - 1-(5-chloro-2-(cyclopentyloxy)benzyl)-1,2,3,4-tetrahydroquinoline-5 carboxylic acid, 15 - 1-(5-chloro-2-(propooxy)benzyl)-1,2,3,4-tetrahydroquinoline-5-carboxylic acid, - 1-(2-(4-chloro-2-fluorobenzyloxy)-5-methylbenzyl)-1,2,3,4 tetrahydroquinoline-5-carboxylic acid, - 1-(5-chloro-2-(neopentyloxy)benzyl)-1,2,3,4-tetrahydroquinoline-5-carboxylic 20 acid, - 4-(2-(4-chloro-2-fluorobenzyloxy)-5-methylbenzyl)-3,4-dihydro-2H benzo[b][1,4]oxazine-8-carboxylic acid, - 4-(5-fluoro-2-isobutoxybenzyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-8 carboxylic acid, 25 - 4-(5-chloro-2-isobutoxybenzyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-8 carboxylic acid, - 4-(5-chloro-2-cyclobutoxybenzyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-8 carboxylic acid, - 4-(5-chloro-2-(cyclopropylmethoxy)benzyl)-3,4-dihydro-2H 30 benzo[b][1,4]oxazine-8-carboxylic acid, - 4-(5-chloro-2-(neopentyloxy)benzyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-8 carboxylic acid, - 1-(5-chloro-2-(3-methoxypropoxy)benzyl)indoline-4-carboxylic acid, - 1-(5-chloro-2-(2-methoxyethoxy)benzyl)indoline-4-carboxylic acid, WO 2013/037960 PCT/EP2012/068101 31 - 1-(5-chloro-2-(cyclopropylmethoxy)benzyl)indoline-4-carboxylic acid, - 1-(5-chloro-2-(neopentyloxy)benzyl)indoline-4-carboxylic acid, - 1-(5-chloro-2-((3-methyloxetan-3-yl)methoxy)benzyl)indoline-4-carboxylic acid, 5 - (S)-1-(5-chloro-2-(3-hydroxy-2-methylpropoxy)benzyl)indoline-4-carboxylic acid, - 1-(5-chloro-2-(4-chloro-2-fluorobenzyloxy)benzyl)-3-(methoxymethyl)-1 H indole-4-carboxylic acid, - 1-(5-chloro-2-(4-chloro-2-fluorobenzyloxy)benzyl)-2-oxoindoline-4-carboxylic 10 acid, - 1-(2-(4-chloro-2-fluorobenzyloxy)-5-cyclopropylbenzyl)-1 H-indazole-4 carboxylic acid, - 1-(5-chloro-2-(4-chloro-2-fluorobenzyloxy)benzyl)-3-(methoxymethyl)-1 H indole-4-carboxylic acid, 15 - 1-{5-chloro-2-[(4-chloro-2-ethylbenzyl)oxy]benzyl}-1 H-indole-4-carboxylic acid, - 1-{5-chloro-2-[(4-chloro-2-fluorobenzyl)oxy]benzyl}-1 H-pyrazolo[3,4 b]pyridine-4-carboxylic acid, - 1-[5-chloro-2-(2-fluoro-2-methylpropoxy)benzyl]-1 H-pyrazolo[3,4-b]pyridine 20 4-carboxylic acid, - 1-[5-chloro-2-(cyclobutyloxy)benzyl]-1 H-pyrazolo[3,4-b]pyridine-4-carboxylic acid, - 1-{5-chloro-2-[(4-chloro-2-fluorobenzyl)oxy]benzyl}-2-oxo-1,2,3,4 tetrahydroquinoline-5-carboxylic acid, 25 - 1-{5-chloro-2-[(4-chloro-2-fluorobenzyl)oxy]benzyl}-2,3-dihydro-1 H pyrrolo[2,3-b]pyridine-4-carboxylic acid, - 1-{5-chloro-2-[(2,4-difluorobenzyl)oxy]benzyl}-2,3-dihydro-1 H-pyrrolo[2,3 b]pyridine-4-carboxylic acid, - 1-{5-chloro-2-[(4-chlorobenzyl)oxy]benzyl}-2,3-dihydro-1 H-pyrrolo[2,3 30 b]pyridine-4-carboxylic acid, WO 2013/037960 PCT/EP2012/068101 32 - 1-{5-chloro-2-[(2-fluorobenzyl)oxy]benzyl}-2,3-dihydro-1 H-pyrrolo[2,3 b]pyridine-4-carboxylic acid, - 1-{5-chloro-2-[(4-fluorobenzyl)oxy]benzyl}-2,3-dihydro-1 H-pyrrolo[2,3 b]pyridine-4-carboxylic acid, 5 - 1-[5-chloro-2-(2-fluoro-2-methylpropoxy)benzyl]-2,3-dihydro-1 H-pyrrolo[2,3 b]pyridine-4-carboxylic acid, - 1-(5-chloro-2-isobutoxybenzyl)-2,3-dihydro-1 H-pyrrolo[2,3-b]pyridine-4 carboxylic acid, - 1-{5-chloro-2-[(4-chloro-2-fluorobenzyl)oxy]benzyl}-4-(1 H-tetrazol-5-yl)-2,3 10 dihydro-1 H-pyrrolo[2,3-b]pyridine, - 8-{5-chloro-2-[(2,4-difluorobenzyl)oxy]benzyl}-5,6,7,8-tetrahydro-1,8 naphthyridine-4-carboxylic acid, - 8-{5-chloro-2-[(4-chloro-2-fluorobenzyl)oxy]benzyl}-5,6,7,8-tetrahydro-1,8 naphthyridine-4-carboxylic acid, 15 - 1-{5-chloro-2-[(4-chloro-2-fluorobenzyl)oxy]benzyl}-1,2,3,4-tetrahydro-1,7 naphthyridine-5-carboxylic acid, - 1-{5-chloro-2-[(2,4-difluorobenzyl)oxy]benzyl}-1,2,3,4-tetrahydro-1,7 naphthyridine-5-carboxylic acid, - 1-{5-chloro-2-[(2,4-difluorobenzyl)oxy]benzyl}-1,2,3,4-tetrahydro-1,6 20 naphthyridine-5-carboxylic acid, - 1-{5-chloro-2-[(4-chloro-2-fluorobenzyl)oxy]benzyl}-1,2,3,4-tetrahydro-1,6 naphthyridine-5-carboxylic acid, - 1-{5-chloro-2-[(4-chloro-2-fluorobenzyl)oxy]benzyl}-1,2,3,4 tetrahydroquinoxaline-5-carboxylic acid, 25 - 1-{5-chloro-2-[2-(2,4-difluorophenyl)ethoxy]benzyl}-1 H-indole-4-carboxylic acid, - 1-{5-chloro-2-[(4-chloro-2-fluorobenzyl)oxy]benzyl}-N-(methylsulfonyl)-1 H indole-4-carboxamide, WO 2013/037960 PCT/EP2012/068101 33 - 1-{5-chloro-2-[(4-chloro-2-fluorobenzyl)oxy]benzyl}-N-(methylsulfonyl)-1 H indole-4-carboxamide, - 1-(5-chloro-2-isobutoxybenzyl)-N-(methylsulfonyl)-2,3-dihydro-1 H pyrrolo[2,3-b]pyridine-4-carboxamide, 5 - 1-{5-chloro-2-[(4-chloro-2-fluorobenzyl)oxy]benzyl}-N-(methylsulfonyl) 1,2,3,4-tetrahydroquinoline-5-carboxamide, - 1-{5-chloro-2-[(4-chloro-2-fluorobenzyl)oxy]benzyl}-N [(dimethylamino)sulfonyl]-1,2,3,4-tetrahydroquinoline-5-carboxamide, - 1-{5-chloro-2-[(4-chloro-2-fluorobenzyl)oxy]benzyl}-N 10 [(dimethylamino)sulfonyl]-1,2,3,4-tetrahydroquinoline-5-carboxamide, - N-({1 -(5-chloro-2-[(4-chloro-2-fluorobenzyl)oxy]benzyl})-1,2,3,4 tetrahydroquinolin-5-yl]amino}carbonyl) methanesulfonamide, - 1-{5-chloro-2-[(4-chloro-2-fluorobenzyl)oxy]benzyl}-N-(methylsulfonyl)-2,3 dihydro-1 H-pyrrolo[2,3-b]pyridine-4-carboxamide, 15 - 1-{5-chloro-2-[(2,4-difluorobenzyl)oxy]benzyl}-1,2,3,4-tetrahydro-1,7 naphthyridine-5-carboxylic acid, - 1-{2-[(4-chloro-2-fluorobenzyl)oxy]benzyl}-1,2,3,4-tetrahydro-1,7 naphthyridine-5-carboxylic acid, - 1-{2-[(2,4-difluorobenzyl)oxy]benzyl}-1,2,3,4-tetrahydro-1,7-naphthyridine-5 20 carboxylic acid, - 1-[5-chloro-2-(2-fluoro-2-methylpropoxy)benzyl]-1,2,3,4-tetrahydro-1,7 naphthyridine-5-carboxylic acid - 1-{2-[(2,4-difluorobenzyl)oxy]-5-fluorobenzyl}-1,2,3,4-tetrahydro-1,7 naphthyridine-5-carboxylic acid 25 - 1-(2-((2,4-difluorobenzyl)oxy)-5-methylbenzyl)-1,2,3,4-tetrahydro-1,7 naphthyridine-5-carboxylic acid - 1-{2-[(4-chloro-2-fluorobenzyl)oxy]-5-fluorobenzyl}-1,2,3,4-tetrahydro-1,7 naphthyridine-5-carboxylic acid - 1-{2-[(4-chloro-2-fluorobenzyl)oxy]-5-methylbenzyl}-1,2,3,4-tetrahydro-1,7 30 naphthyridine-5-carboxylic acid - 4-(2-cyclobutoxy-5-fluorobenzyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-8 carboxylic acid, - 1-{5-chloro-2-[(4-chloro-2-fluorobenzyl)oxy]benzyl}-2,3-dihydro-1 H pyrrolo[2,3-c]pyridine-4-carboxylic acid, WO 2013/037960 PCT/EP2012/068101 34 - 1-(5-chloro-2-cyclobutoxybenzyl)-2-oxoindoline-4-carboxylic acid - 1-(5-chloro-2-(2-fluoro-2-methylpropoxy)benzyl)-2-oxoindoline-4-carboxylic acid 5 and the salts, solvates and prodrugs thereof. In another embodiment, the sodium salt of the previous compounds is preferred. In another aspect the invention refers to a process for preparing the compounds of 10 the invention. The compounds of the invention may be made by a variety of methods, including standard chemistry. Any previously defined variable will continue to have the previously defined meaning unless otherwise indicated. Illustrative general synthetic 15 methods are set out below and then the preparation of specific compounds of the invention is described in more detail in the Experimental Section. For instance, a process for preparing compounds of general formula (1) comprises the reaction between a compound of general formula (II): 20 LG R4 ,R9-... R4
    R
    9 \ / y
    R
    9 -R9 B || wherein LG is a leaving group, preferably bromo, with a compound of general formula (Ill), or a protected form thereof where the R 7 group in W 1 is protected: 25 lil WO 2013/037960 PCT/EP2012/068101 35 followed if necessary by the removal of any protecting group that may be present. In general, a compound of formula Ill is preferably used in protected form, i.e. with the R 7 group in W1 protected with a suitable protecting group. If Ill is reacted with II 5 in protected form, a subsequent step to remove the protecting group on R7 will be required to yield a compound of formula I, which is performed under standard conditions well known in the art. When in a compound of formula Ill R7 is -C0 2 H, compound Ill is used in protected form as an ester, and therefore the acid must be deprotected after the reaction of II with Ill under standard conditions; a suitable set 10 of conditions comprises the treatment of the corresponding ester with NaOH (10%), in tetrahydrofuran or methanol at about 509C. A compound of formula I thus obtained can be converted into a salt using standard procedures. For example, when R in a compound of formula I is -C0 2 H, the 15 sodium salt can be obtained for example by treatment of the corresponding carboxylic acid with sodium tert-butoxide in methanol at room temperature. The process for the synthesis of compound of general formula I can be summarised as follows: 20 LG R4 R'R9 IR4 + Rlw2I R9 R4
    R
    9 9
    R
    R
    9 'R9 \ / y B R 9 'R9 B 11 Ill I In the above scheme W 1 , W 2 , R 4 , Y, B, R 9 and R" have the meaning previously defined and LG represents a leaving group. A leaving group is a group that in an heterolytic bond cleavage keeps the electron pair of the bond. Suitable leaving 25 groups are well known in the art and include Cl, Br, I and -O-SO 2
    R
    14 , wherein R 1 4 is F, C 1 4 -alkyl, C 1 4 -haloalkyl, or optionally substituted phenyl. The preferred leaving groups are: Cl, Br, I, tosylate, mesylate, triflate, nonaflate and fluorosulphonate. Preferably, compounds of formula (II) wherein LG is bromo are used.
    WO 2013/037960 PCT/EP2012/068101 36 Compounds of formula (II) and (Ill) are suitably reacted together in the presence of a base in an inert organic solvent which includes, aromatic hydrocarbons such as toluene, o-, m-, p- xylene; halogenated hydrocarbons such as methylene chloride, 5 chloroform, and chlorobenzene; ethers such as diethylether, diisopropyl ether, tert butyl methyl ether, 5 dioxane, anisole, and tetrahydrofuran; nitriles such as acetonitrile and propionitrile; ketones such as acetone, methyl ethyl ketone, diethyl ketone and tert-butyl methyl ketone; alcohols such as methanol, ethanol, n propanol, n-butanol, tert-butanol and also DMF (N,N-dimethylformamide), DMSO 10 (N,N-dimethyl sulfoxide) and water. The preferred list of solvents includes DMSO, DMF, acetonitrile and THF. Mixtures of these solvents in varying ratios can also be used. Suitable bases are, generally, inorganic compounds such as alkali metal hydroxides and alkaline earth metal hydroxides, such as lithium hydroxide, sodium hydroxide, potassium hydroxide and calcium hydroxide; alkali metal oxides and 15 alkaline earth metal oxides, lithium oxide, sodium oxide, magnesium oxide and calcium oxide; alkali metal hydrides and alkaline earth metal hydrides such as lithium hydride, sodium hydride, potassium hydride and calcium hydride; alkali metal, amides and alkaline earth metal amides such as lithium amide, sodium amide, potassium amide and calcium amide; alkali metal carbonates and alkaline 20 earth metal carbonates such as lithium carbonate and calcium carbonate; and also alkali metal hydrogencarbonates and alkaline earth metal hydrogencarbonates such as sodium hydrogencarbonate; organometallic compounds, particularly alkali-metal alkyls such as methyl lithium, butyllithium, phenyl lithium; alkyl magnesium halides such as methyl magnesium chloride, and alkali metal alkoxides and alkaline earth 25 metal alkoxides such as sodium methoxide, sodium ethoxide, potassium ethoxide, potassium tertbutoxide and di-methoxymagnesium, further more organic bases e.g. triethylamine, triisopropylamine, N-methylpiperidine, pyridine. Sodium hydroxide, Sodium methoxide, Sodium ethoxide, potassium hydroxide, potassium carbonate and triethylamine are especially preferred. Suitably the reaction may be effected in 30 the presence of a phase transfer catalyst such as tetra-n-butylammonium hydrogensulphate and the like. The inert atmosphere may be maintained by using inert gases such as N 2 , Ar or He. Reaction times may vary from 1 to 24 hrs, preferably from 2 to 6 hours, whereafter, if desired, the resulting compound is transformed into a salt thereof.
    WO 2013/037960 PCT/EP2012/068101 37 The starting compounds of general formula (II) can be prepared in several ways. A general scheme of preparation of compound of formula (II) is represented below: 0 0 HO R4 R H 9 H Reduction 9 R4 + LG-C1- 4 Akyl-B R R / A 3 RR R9'R I \9 A 3 -C1.
    4 AIkyl-B R'R A 3 -C1.
    4 AIkyl-B H Via Va IVa COOMe COOMe HO R4 PBra R R9~.- [R 4 ]- R__ R4 R + '3R R C1.
    4 A IkY B / C1.4Al kyl R PBr 3 R LG R 9 3-B R C14Alkyl Br R4 Vib Vb IVb ,R 9
    R
    4 0 HO R94 Y CN H R-PRr R Reduction R4 PB R 1R R R R R9 C2-4Alkeyl, R R-C -Akl 4AIk Ri R B R R9 C24l y 9 R9 C 4AkyK Vic B [H21 VC IVc 9 N0 HO R PBr 3 CN R9 - H Reduction R R 1,RR 9- C2-4AIkenyI N, A ( t A R R/ C 2 -4AIkeny, B R 9 4A~eR9. 5 R 'RB R VdIVd IVd CN 5 9 / -A' (OEt) 2 In the above scheme: - LG represents a leaving group. A leaving group is a group that in an 10 heterolytic bond cleavage keeps the electron pair of the bond. Suitable leaving groups are well known in the art and include Cl, Br, I and -O-SO 2
    R
    1 6 , wherein R 16 is F, C 1
    -
    4 -alkyl, C 1
    -
    4 -haloalkyl, or optionally substituted phenyl. The preferred leaving groups are: Cl, Br, I, tosylate, mesylate, triflate, nonaflate and fluorosulphonate. - A 1 represents a C- 2 -alkylene group. 15 - A 2 represents -Cn-alkyl-CO-Cm-alkyl-B, wherein n and m independently have a value of 0 to 2 and wherein n+ms2.
    WO 2013/037960 PCT/EP2012/068101 38 - A 3 represents either an -0- or-NR 1 -. - all remaining substituents have the same meanings as previously defined in relation to a compound of formula (1). 5 Suitable reaction conditions for the preparation a compound of formula (II) include conventional methods for converting the hydroxyl group of the compounds of formula (IVa), (lVb), (IVc) and (lVd) to a leaving group, for example Br. When LG=bromo, the compound of formula (IV) may be reacted with phosporous tribromide in a solvent, e.g. dichloromethane, at reduced temperatures, e.g. less 10 than 00C. Such transformations are well known to those skilled in the art and are described in for example L. G. Wade, Jr., Organic Chemistry, 6th ed., p. 477, Pearson/Prentice Hall, Upper Saddle River, New Jersey, USA, 2005. Suitable reaction conditions for the preparation a compound of formula (IV) include 15 conventional methods for reducing the carbonyl group of the compounds of formula (V) to a hydroxyl group. The reduction step may be carried out using a reducing agent such as NaBH 4 , NaCNBH 3 , LiAIH 4 , LiBH 4 or Zn(BH4) 2 . For compounds of formula (Va), (Vc) and (Vd), preferably, the reduction step is carried out using NaBH4. Preferably, an excess of NaBH4 is used. Preferably, the reduction step is 20 carried out in an alcohol solvent. Typical alcohols are methanol, ethanol, isopropanol, and mixtures thereof. A preferred alcohol is methanol. For compounds of formula (Vb) preferably, the reduction step is carried out using LiAIH 4 . Preferably, an excess of LiAIH 4 is used. Preferably, the reduction step is carried out in an alkylether solvent. Typical alkylether solvents are tetrahydrofuran, diethyleter, 25 dioxane, diisopropylether, and mixtures thereof. A preferred alkylether is tetrahydrofuran. Such transformations are well known to those skilled in the art and are described in for example Banfi, L.; Narisano, E.; Riva, R.; Stiasni, N.; Hiersemann, M. "Sodium Borohydride" in Encyclopedia of Reagents for Organic Synthesis (Ed: L. Paquette) 2004, J. Wiley & Sons, New York.; and Seyden-Penne, 30 J. "Reductions by the Alumino- and Borohydrides in Organic Synthesis"; VCH Lavoisier: Paris, 1991. Suitable reaction conditions for the preparation a compound of formula (Va) and (Vb) include conventional methods for the alkylation of the compounds of formula WO 2013/037960 PCT/EP2012/068101 39 (Via) and (VIb) wherein A3 represents either an -0- or-NR 13 -. A suitable LG group is bromine or chloride. The alkylation reaction of the compounds of formula (VIa) and (VIb) may be carried out in an inert organic solvent such as tetrahydrofuran or dimethylformamide at ambient or elevated temperature, optionally in the presence of 5 a suitable base such as potassium or cesium carbonate or a strong base such as sodium t-butoxide or lithium bis(trimethylsilyl)amide (LiHMDS). Suitable reaction conditions for the preparation a compound of formula (Vc) and (Vd) include conventional methods for reducing the cyano group of the compounds 10 of formula (VIc) and (VId) to a hydroxyl group. The reduction step may be carried out using a reducing agent such as DIBA-H in an inert organic solvent such as hexane, heptane or cyclohexane, at ambient or low temperature, preferably from 09C to 59C. 15 Intermediates of formula (VI) wherein A 3 represents either an -0- or-NR 13 -, are commercially available, or may readily be prepared by methods known to those skilled in the art, for example from suitable commercially available starting materials. Compounds of formula (Ill) are either commercially available or can be obtained by 20 conventional methods. Particular embodiments of the preparation of compounds of general formula (II) and (Ill) are provided below in the experimental section under the heading "Intermediate compounds". 25 Certain substituents in any of the reaction intermediates described above and in the compounds of formula (1) may be converted to other substituents by conventional methods known to those skilled in the art. Examples of such transformations include the Wittig reaction of an aldehyde group to give an alkene group; hydrolysis of 30 esters, alkylation of hydroxy and amino groups; and formation of salts of carboxylic acids. Such transformations are well known to those skilled in the art and are described in for example, Richard Larock, Comprehensive Organic Transformations, 2nd edition, Wiley-VCH, ISBN 0-471-19031-4.
    WO 2013/037960 PCT/EP2012/068101 40 It will be appreciated that in any of the routes described above, the precise order of the synthetic steps by which the various groups and moieties are introduced into the molecule may be varied. It will be within the skill of the practitioner in the art to ensure that groups or moieties introduced at one stage of the process will not be 5 affected by subsequent transformations and reactions, and to select the order of synthetic steps accordingly. In some instances it may be appropriate to use protecting groups to prevent reactions between one or more groups or moieties. Such procedures are familiar to those skilled in the art (see, for example, "Protective groups in organic synthesis" by T.W. Greene and P.G.M. Wuts (John Wiley & sons 10 10 1999) or "Protecting Groups" by P.J. Kocienski (Georg Thieme Verlag 1994). An additional aspect of the invention relates to the therapeutic use of the compounds of general formula (1). As mentioned above, compounds of general formula (1) show a strong affinity to EP1 receptors. For this reason, they are suitable 15 for the treatment and/or the prophylaxis of disorders and diseases mediated by EP1 receptors. Compounds of the invention are particularly useful for modulating pain. The compounds of the present invention can treat or prevent the pain associated with 20 several pathological conditions comprising, among others, inflammatory related pain (Hall et al. 2007) including low back and neck pain, skeletal pain, post-partum pain, toothache, sprains and straits, myositis, neuralgia, synovitis, arthritis, including rheumatoid arthritis, degenerative joint diseases (osteoarthritis), gout and ankylosing spondylitis, bursitis, burns including radiation and corrosive chemical injuries and 25 sunburns; postoperative pain (Omote et al. 2001) including dental procedures; neuropathic pain (Kawahara et al. 2001); visceral pain (Sarkar et al. 2003); tension headache; cluster headaches; migraine and the like. Moreover, by inhibition of prostanoid-induced smooth muscle contraction by 30 antagonizing contractile prostanoids or mimicking relaxing prostanoids, EP1 modulators may be used in the treatment of motility -related disorders (with or without pain) such as as gastroinstestinal disorders (Sarkar et al. 2003; Mizuguchi et al 2010) and urinary incontinence and other urinary tract diseases (Teramura et al.
    WO 2013/037960 PCT/EP2012/068101 41 2000; Lee et al. 2007; Okada et al., 2010; Wilbraham et al 2010; Miki et al 2010), dysmenorrhea and preterm labour. The compounds of the invention can also be useful in prostaglandin-mediated 5 proliferation disorders such as in diabetic retinopathy and tumour angiogenesis, cancer (Watanabe et al. 1999; Niho et al. 2005), the inhibition of cellular neoplasic transformations and metastatic tumour growth. They can further be used in the treatment of neurodegenerative diseases (including 10 senile dementia, Alzheimer's disease, Pick's disease, Huntingdon's chorea, Parkinson's disease, Creutzfeldt-Jakob disease, or Amyotrophic Lateral Sclerosis) (Li et al. 2011), neuroprotection/stroke (Abe et al 2009), glaucoma (Woodward et al 1997), bone loss (osteoporosis) and the proportion of bone formation (treatment of fractures) (Zhang et al 2011; Lee et al. 2007) and other bone diseases such as 15 Paget's disease. As PGE2-induced hyperthermia in the rat is mediated predominantly through the EP1 receptor (H6nemann et al. 2001; Oka et al. 2003) different kinds of fever as rheumatic fever, symptoms associated with influenza or other viral infections as well 20 as common cold can be also target diseases for EP1 modulators. The compounds of the invention can also have a cytoprotective activity in patients under different gastrointestinal disorders as related with chemotherapy, or irritable bowel disease. Other diseases that can be treated or prevented with the compounds 25 of the invention include gastrointestinal bleeding, coagulation disorders including anaemia such as hypoprothrombinemia, haemophilia or other bleeding problems; kidney diseases (nephritis (Rahal et al. 2006), particularly mesangial proliferative glomerulonephritis and nephritic syndrome); thrombosis, and occlusive vascular diseases. 30 In this sense, compounds of formula (1) are suitable to treat or to prevent diseases or disorders comprising inflammatory related pain including low back and neck pain, skeletal pain, post-partum pain, toothache, sprains and straits, myositis, neuralgia, synovitis, arthritis, including rheumatoid arthritis, degenerative joint diseases (such WO 2013/037960 PCT/EP2012/068101 42 as osteoarthritis), gout and ankylosing spondylitis, bursitis, burns including radiation and corrosive chemical injuries and sunburns; postoperative pain; neuropathic pain; visceral pain; tension headache; cluster headaches; migraine; motility-related disorders including gastrointestinal disorders, urinary incontinence and other urinary 5 tract diseases; dysmenorrhea; preterm labour; diabetic retinopathy; tumour angiogenesis; cancer; metastatic tumour growth; neurodegenerative diseases including senile dementia, Alzheimer's disease, Pick's disease, Huntington's chorea, Parkinson's disease, Creutzfeldt-Jakob disease, or amyotrophic lateral sclerosis; neuroprotection/stroke; glaucoma; osteoporosis; bone fractures; Paget's disease; 10 hyperthermia including different types of fever as rheumatic fever; symptoms associated with influenza or other viral infections; common cold, gastrointestinal disorders related with chemotherapy or irritable bowel syndrome; gastrointestinal bleeding; coagulation disorders including anaemia, hypoprothrombinemia, haemophilia or other bleeding problems; kidney diseases including nephritis, 15 particularly mesangial proliferative glomerulonephritis and nephritic syndrome; thrombosis and occlusive vascular diseases. The invention thus relates to a compound of formula (1) for use in the treatment and/or prophylaxis of an EP1 -mediated disease or disorder. In one embodiment, the 20 EP1 -mediated disease or disorder is selected from the group consisting of pain, motility-related disorders, gastrointestinal disorders, urinary tract diseases, cancer, neurodegenerative diseases, stroke, glaucoma, bone diseases, fever, coagulation disorders and occlusive vascular diseases. In a preferred embodiment, the EP1 mediated disease or disorder is pain. In another embodiment, the EP1-mediated 25 disease or disorder is selected from the group consisting of inflammatory related pain including low back and neck pain, skeletal pain, post-partum pain, toothache, sprains and straits, myositis, neuralgia, synovitis, arthritis, including rheumatoid arthritis, degenerative joint diseases (such as osteoarthritis), gout and ankylosing spondylitis, bursitis, burns including radiation and corrosive chemical injuries and 30 sunburns; postoperative pain; neuropathic pain; visceral pain; tension headache; cluster headaches; migraine; motility-related disorders including gastrointestinal disorders, urinary incontinence and other urinary tract diseases; dysmenorrhea; preterm labour; diabetic retinopathy; tumour angiogenesis; cancer; metastatic tumour growth; neurodegenerative diseases including senile dementia, Alzheimer's WO 2013/037960 PCT/EP2012/068101 43 disease, Pick's disease, Huntington's chorea, Parkinson's disease, Creutzfeldt Jakob disease, or amyotrophic lateral sclerosis; neuroprotection/stroke; glaucoma; osteoporosis; bone fractures; Paget's disease; hyperthermia including different types of fever as rheumatic fever; symptoms associated with influenza or other viral 5 infections; common cold, gastrointestinal disorders related with chemotherapy or irritable bowel syndrome; gastrointestinal bleeding; coagulation disorders including anaemia, hypoprothrombinemia, haemophilia or other bleeding problems; kidney diseases including nephritis, particularly mesangial proliferative glomerulonephritis and nephritic syndrome; thrombosis and occlusive vascular diseases. In a 10 preferred embodiment, the EP1-mediated disease or disorder is pain comprising inflammatory related pain, including low back and neck pain, skeletal pain, post partum pain, toothache, sprains and straits, myositis, neuralgia, synovitis, arthritis, including rheumatoid arthritis, degenerative joint diseases (such as osteoarthritis), gout and ankylosing spondylitis, bursitis, burns including radiation and corrosive 15 chemical injuries and sunburns; postoperative pain; neuropathic pain; visceral pain; tension headache; cluster headaches; migraine. A related aspect refers to the use of at least one compound of general formula (1) for the manufacture of a medicament for the treatment and/or prophylaxis diseases or 20 disorders mediated by EP1 receptors or in which EP1 receptors are involved. In one embodiment, the EP1-mediated disease or disorder is selected from the group consisting of pain, motility-related disorders, gastrointestinal disorders, urinary tract diseases, cancer, neurodegenerative diseases, stroke, glaucoma, bone 25 diseases, fever, coagulation disorders and occlusive vascular diseases. In a preferred embodiment, the EP1-mediated disease or disorder is pain. In another embodiment, the EP1-mediated disease or disorder is selected from the group consisting of inflammatory related pain including low back and neck pain, skeletal pain, post-partum pain, toothache, sprains and straits, myositis, neuralgia, synovitis, 30 arthritis, including rheumatoid arthritis, degenerative joint diseases (such as osteoarthritis), gout and ankylosing spondylitis, bursitis, burns including radiation and corrosive chemical injuries and sunburns; postoperative pain; neuropathic pain; visceral pain; tension headache; cluster headaches; migraine; motility-related disorders including gastrointestinal disorders, urinary incontinence and other urinary WO 2013/037960 PCT/EP2012/068101 44 tract diseases; dysmenorrhea; preterm labour; diabetic retinopathy; tumour angiogenesis; cancer; metastatic tumour growth; neurodegenerative diseases including senile dementia, Alzheimer's disease, Pick's disease, Huntington's chorea, Parkinson's disease, Creutzfeldt-Jakob disease, or amyotrophic lateral sclerosis; 5 neuroprotection/stroke; glaucoma; osteoporosis; bone fractures; Paget's disease; hypertermia including different types of fever as rheumatic fever; symptoms associated with influenza or other viral infections; common cold, gastrointestinal disorders related with chemotherapy or irritable bowel syndrome; gastrointestinal bleeding; coagulation disorders including anaemia, hypoprothrombinemia, 10 haemophilia or other bleeding problems; kidney diseases including nephritis, particularly mesangial proliferative glomerulonephritis and nephritic syndrome; thrombosis and occlusive vascular diseases. In another embodiment, the EP1 mediated disease or disorder is selected from the group consisting of inflammatory related pain (including low back and neck pain, skeletal pain, post-partum pain, 15 toothache, sprains and straits, myositis, neuralgia, synovitis, arthritis, including rheumatoid arthritis, degenerative joint diseases (such as osteoarthritis), gout and ankylosing spondylitis, bursitis, burns including radiation and corrosive chemical injuries and sunburns); postoperative pain; neuropathic pain; visceral pain; tension headache; cluster headaches; and migraine. 20 An aspect of the invention related to the therapeutic use of the compounds of general formula (1) is a method of treatment and/or prophylaxis of disorders and diseases mediated by EP1 receptors which comprises administering to a patient in need thereof a therapeutically effective amount of at least one compound of general 25 formula (1). In one embodiment, the EP1-mediated disease or disorder is selected from the group consisting of pain, motility-related disorders, gastrointestinal disorders, urinary tract diseases, cancer, neurodegenerative diseases, stroke, glaucoma, bone diseases, fever, coagulation disorders and occlusive vascular diseases. In a preferred embodiment, the EP1 -mediated disease or disorder is pain. 30 In another embodiment, the EP1-mediated disease or disorder is selected from the group consisting of inflammatory related pain including low back and neck pain, skeletal pain, post-partum pain, toothache, sprains and straits, myositis, neuralgia, synovitis, arthritis, including rheumatoid arthritis, degenerative joint diseases (such as osteoarthritis), gout and ankylosing spondylitis, bursitis, burns including radiation WO 2013/037960 PCT/EP2012/068101 45 and corrosive chemical injuries and sunburns; postoperative pain; neuropathic pain; visceral pain; tension headache; cluster headaches; migraine; motility-related disorders including gastrointestinal disorders, urinary incontinence and other urinary tract diseases; dysmenorrhea; preterm labour; diabetic retinopathy; tumour 5 angiogenesis; cancer; metastatic tumour growth; neurodegenerative diseases including senile dementia, Alzheimer's disease, Pick's disease, Huntington's chorea, Parkinson's disease, Creutzfeldt-Jakob disease, or amyotrophic lateral sclerosis; neuroprotection/stroke; glaucoma; osteoporosis; bone fractures; Paget's disease; hyperthermia including different types of fever as rheumatic fever; symptoms 10 associated with influenza or other viral infections; common cold, gastrointestinal disorders related with chemotherapy or irritable bowel syndrome; gastrointestinal bleeding; coagulation disorders including anaemia, hypoprothrombinemia, haemophilia or other bleeding problems; kidney diseases including nephritis, particularly mesangial proliferative glomerulonephritis and nephritic syndrome; 15 thrombosis and occlusive vascular diseases. In another embodiment, the EP1 mediated disease or disorder is selected from the group consisting of inflammatory related pain (including low back and neck pain, skeletal pain, post-partum pain, toothache, sprains and straits, myositis, neuralgia, synovitis, arthritis, including rheumatoid arthritis, degenerative joint diseases (such as osteoarthritis), gout and 20 ankylosing spondylitis, bursitis, burns including radiation and corrosive chemical injuries and sunburns); postoperative pain; neuropathic pain; visceral pain; tension headache; cluster headaches; and migraine. The amount of active ingredient that must be administered to the patient depends on 25 the patient's weight, the type of application, the condition and severity of the disease. Normally, in human beings 1 to 1500 mg of the active compound is administered daily in one or several doses. A further aspect of the invention regards a pharmaceutical composition which 30 comprises a compound of general formula (1), and at least a pharmaceutically acceptable carrier, additive, adjuvant or vehicle. The auxiliary materials or additives can be selected among carriers, excipients, support materials, lubricants, fillers, solvents, diluents, colorants, flavour WO 2013/037960 PCT/EP2012/068101 46 conditioners such as sugars, antioxidants and/or agglutinants. In the case of suppositories, this may imply waxes or fatty acid esters or preservatives, emulsifiers and/or carriers for parenteral application. The selection of these auxiliary materials and/or additives and the amounts to be used will depend on the form of application 5 of the pharmaceutical composition. The pharmaceutical composition in accordance with the invention can be adapted to any form of administration, be it orally or parenterally, for example pulmonarily, nasally, rectally and/or intravenously. Therefore, the formulation in accordance with 10 the invention may be adapted for topical or systemic application, particularly for dermal, subcutaneous, intramuscular, intra-articular, intraperitoneal, pulmonary, buccal, sublingual, nasal, percutaneous, vaginal, oral or parenteral application. Suitable preparations for oral applications are tablets, pills, chewing gums, capsules, 15 granules, drops or syrups.Suitable preparations for parenteral applications are solutions, suspensions, reconstitutable dry preparations or sprays. The compounds of the invention as deposits in dissolved form or in patches, for percutaneous application. 20 Skin applications include ointments, gels, creams, lotions, suspensions or emulsions. The preferred form of rectal application is by means of suppositories. 25 In the following paragraphs, some specific examples of preparation of intermediate compounds (II) and (Ill) and compounds of formula (1) are provided, together with examples of the biological activity of the compounds of the invention. 30 EXPERIMENTAL SECTION The following abbreviations are used along the experimental section: ACN: Acetonitrile AcOH: Acetic acid WO 2013/037960 PCT/EP2012/068101 47 CDI: 1,1'-Carbonyldiimidazole DAST: Diethylaminosulfur trifluoride DBU: 1,8-Diazabicyclo[5.4.0]undec-7-ene DCM: Dichloromethane 5 DIBAL-H: Diisobutylaluminium hydride DIPEA: N,N-Diisopropylethylamine DMAP: 4-(Dimethylamino)pyridine DMF: Dimethylformamide DMSO: Dimethyl sulfoxide 10 DPPA: Diphenyl phosphoryl azide Dppf: 1,1'-Bis(diphenylphosphino)ferrocene EDCI.HCI: N-(3-Dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride EDTA: Ethylenediaminetetraacetic acid Et 2 0: Diethyl ether 15 EtAcO: Ethyl acetate EtOH: Ethanol Hex: hexane HMTA: Hexamethylenetetramine HPLC: High Performance Liquid Chromatography 20 LC-MS: Liquid chromatography-mass spectrometry LDA: Lithium diisopropylamide Mel: lodomethane MEM-CI: 2-Methoxyethoxymethyl chloride MeOH: Methanol 25 MES: 2-(N-Morpholino)ethanesulfonic acid Me-THF: 2-Methyltetrahydrofurane MsCI: Methanesulfonyl chloride NaAcO: Sodium acetate NaBH(OAc)3: Sodium triacetoxyborohydride 30 NaHMDS: Sodium hexamethyldisilazide NBS: N-bromosuccinimide n-BuLi: Butyllithium NMR: Nuclear magnetic resonance Pd/C: Palladium on carbon WO 2013/037960 PCT/EP2012/068101 48 Pd(OAc) 2 : Palladium(II) acetate P(OEt) 3 : Triethylphosphite Pd(PPh 3
    )
    4 : Tetrakis(triphenylphosphine)palladium PPTS: Pyridinium p-toluenesulfonate 5 p-TsCI: p-Toluenesulfonyl chloride p-TsOH: p-Toluenesulfonic acid Rf: Retention factor RT: Room temperature TBAF: Tetrabutylammonium fluoride 10 t-BuONa: Sodium tert-butoxide TEA: Triethylamine TFA: Trifluoroacetic acid THF: Tetrahydrofurane TLC: Thin layer cromatography 15 TMSN 3 : Trimethylsilyl azide tr: Retention time X-Phos: 2-Dicyclohexylphosphino-2',4',6'-triisopropylbipheny Intermediate compounds 20 Intermediate compound 1: Synthesis of 2-(bromomethyl)-4-chloro-1-((2,4 difluorobenzyl)oxy)benzene a) To a solution of 5-chloro-2-hydroxybenzaldehyde (2.04 g, 13 mmol) in DMF, potassium carbonate (2.64 g, 15.6 mmol) and 1-(bromomethyl)-2,4 25 difluorobenzene (2.83 g, 13.7 mmol) were added. The resulting yellow mixture was stirred at 40 9C overnight. Then, it was diluted with water and HCI 1 M was added until neutral pH was reached. The mixture was extracted with EtAcO (x3) and the combined organic phase 30 washed with brine and dried over MgSO 4 . b) The white solid obtained after removing the solvent (3.67 g, 100%) was suspended in 25 mL of absolute EtOH. The mixture was cooled at 0C and then 560 mg (14.7 mmol) of NaBH 4 were added. After 10 minutes the white suspension had 35 turned into a colourless solution and TLC showed no starting material left. It was WO 2013/037960 PCT/EP2012/068101 49 diluted with water and HCI 1 M was added until acid pH was reached. The mixture was extracted with EtAcO (x3) and the combined organic phase washed with brine and dried over MgSO 4 . Solvent was evaporated to yield 3.42g (12 mmol, 93%) of (5 chloro-2-((2,4-difluorobenzyl)oxy)phenyl)methanol. 5 c) To a solution of 3.42 g of (5-chloro-2-((2,4 difluorobenzyl)oxy)phenyl)methanol in 50 mL dry DCM under argon and at 09C PBr 3 (3.25 g, 12 mmol) was added dropwise. The solution was stirred at 0C for 90 minutes, then at room temperature overnight. A saturated solution of sodium 10 hydrogen carbonate was then added until neutral pH was reached. The mixture diluted with dichloromethane and water. The organic phase was separated, washed with water then dried over Na 2
    SO
    4 and evaporated to dryness. The crude was purified by column chromatography eluting with Hex/EtAcO 8:2. 2 (bromomethyl)-4-chloro-1 -((2,4-difluorobenzyl)oxy)benzene was obtained as a white 15 solid (3.67 g, 88%). 'H NMR (400 MHz CDCI 3 ) 6 7.59 (1H, m), 7.36 (1H, d), 7.26 (1H, dd,), 6.96 (1H, m), 6.89 (2H, m), 5.17 (2H, s), 4.53 (2H, s). 20 The following compounds were prepared using the same procedure as in intermediate compound 1: Intermediate compound Compound name Starting materials NMR 'H NMR (400 MHz,
    CDC
    3 ) 6 7.40 5-chloro-2- 7.31 (m, 2H), 7.30 2-(broomethyl- hydroxybenzaldeh - 7.23 (m, 1 H), 14a-chfluoro-1-( ) yde and 2- 7.13 - 6.97 (m, adfurbenzy ) (bromomethyl)-1,4- 2H), 6.88 (d, 1H), benzene difluorobenzene 5.20 (s, 2H), 4.54 (s, 2H).
    WO 2013/037960 PCT/EP2012/068101 50 Intermediate compound Compound name Starting materials NMR 5-chloro-2- "'H NMR (400 MHz, 2-(bromomethyl)- CDC1 3 ) 6 7.52 (dd, 4-chloro-1-((2- ydxandeh 1 H), 7.35 (d, 1 H), yde and 1 1b chloro-4,5- 7.29 - 7.23 (m, difluorobenzyl)oxy) (b ro - - 2H), 6.82 (d, 1 H), chloro-4,5 benzene 5.15 (s, 2H), 4.53 difluorobenzene (s, 2H). "H NMR (400 MHz, 5-chloro-2- CDC1 3 ) 6 7.43 2-(bromomethyl)- 7.36 (m, 1 H), 7.35 4-chloro-1-((2- ydxand (d, 1 H), 7.27 1c yde and 2 chloro-5- 7.21 (m, 1 H), 7.03 fluorobenzyl)oxy)b (broo -1- - 6.96 (m, 1 H), chloro-4 enzene fluorobenzene 6.83 (d, 1H), 5.19 (s, 2H), 4.55 (s, 2H). 'H NMR (400 MHz, 2-(bromomethyl)- 5-fluoro-2- ODd 3 ) 6 7.33 4-fluoro-1-((2,5- hydroxybenzaldeh (ddd, 1H), 7.11 1d 7.03 (mn, 2H), 7.02 difluorobenzyl)oxy) yde and 2 - 6.95 (mn, 2H), benzene (bromomethyl)-1,4 6.87 (dd, 1H), 5.17 difluorobenzene (s, 2H), 4.54 (s, 2H). "H NMR (400 MHz, 5-fluoro-2- CDC1 3 ) 6 7.42 l4-(rom-((2,6- hydroxybenzaldeh 7.31 (m, 1 H), 7.07 le 4fluoro-1-((2,) yde and 2- (dd, 1H), 7.01 difurbenzneo) (bromomethyl)-1,3- 6.95 (m, 4H), 5.18 benzene difluorobenzene (s, 2H), 4.56 (s, 2H).
    WO 2013/037960 PCT/EP2012/068101 51 Intermediate compound Compound name Starting materials NMR 'H NMR (400 MHz, 5-fluoro-2- CDC1 3 ) 6 7.45 (dd, 2-(b ro me-h((4- hydroxybenzaldeh 2H), 7.15 - 7.02 ffluoro-1 ((4 oyde and 1- (m, 3H), 6.96 (td, (bromomethyl)-4- 1 H), 6.84 (dd, 1 H), enzene fluorobenzene 5.08 (s, 2H), 4.53 (s, 2H). 5-fluoro-2- 'H NMR (400 MHz, 2-(bromomethyl)- hydroxybenzaldeh CDC1 3 ) 6 7.17 4-fluoro-1-((3,4,5- yde and 5- 7.06 (m, 3H), 6.97 trifluorobenzyl)oxy) (bromomethyl)- (td, 1 H), 6.79 (dd, benzene 1,2,3- 1 H), 5.05 (s, 2H), trifluorobenzene 4.53 (s, 2H). "H NMR (400 MHz, 5-fluoro-2- CDC1 3 ) 6 7.53 (dd, 2-(brome-h((2- hydroxybenzaldeh 1 H), 7.27 (dd, 2H), 1h 4-loro-1-(- yde and 1- 7.11 (dd, 1H), 7.02 chloro-4,5 (bromomethyl)-2- - 6.95 (m, 1 H), rbenzne ) chloro-4,5- 6.84 (dd, 1 H), 5.14 benzene difluorobenzene (s, 2H), 4.55 (s, 2H). "H NMR (400 MHz, ODCd 3 ) 6 7.63 2-(bromomethyl)- 2-hydroxy-5- 7.52 ( 7.39 4-trifluoromethyl-1 - (trifluoromethyl)be 7.3 (, H), ((2,6- nzaldehyde and 2 7.13 (d, 1H), 7.00 difluorobenzyl)oxy) (bromomethyl)-1,3 - 6.89 (mn, 2H), benzene difluorobenzene 5.25 (s, 2H), 4.47 (s, 2H).
    WO 2013/037960 PCT/EP2012/068101 52 Intermediate compound Compound name Starting materials NMR 'H NMR (400 MHz, 5-fluoro-2- CDC1 3 ) 6 7.41 (dd, 2-brome-h((2- hydroxybenzaldeh 1 H), 7.37 (dd, 1 H), 1j 4-loro--- yde and 2- 7.11 (dd, 1H), 7.04 chloro-5 (bromomethyl)-1- - 6.94 (m, 2H), chloro-4- 6.84 (dd, 1H), 5.19 enzene fluorobenzene (s, 2H), 4.57 (s, 2H). "H NMR (400 MHz, 2-(bromomethyl)- 2-hydroxy-5- CDC1 3 ) 6 7.61 (d, 1k 4-trifluoromethyl-1 - (trifluoromethyl)be 1 H), 7.56 (dd, 1 H), ((2,5- nzaldehyde and 2- 7.09 (d, 1 H), 6.76 difluorobenzyl)oxy) (bromomethyl)-1,4- - 6.71 (m, 2H), benzene difluorobenzene 5.18 (s, 2H), 4.59 (s, 2H). 3-bromo-5-chloro- "H NMR (400 MHz, 2-(bromomethyl)- 2- CDC1 3 ) 6 7.54 (d, 6-bromo-4-chloro- 1 H), 7.42 - 7.32 1((2,6 hydroxybenzaldeh (i,2)6.4 11 1-((2,6- yd n -(m, 2H), 6.94 yde and 2 difluorobenzyl)oxy) 7.00 (m, 2H), 5.22 (bromomethyl)-1 ,3 benzene difluorobenzene (s, 2H), 4.50 (s, 2H).
    WO 2013/037960 PCT/EP2012/068101 53 Intermediate compound Compound name Starting materials NMR 'H NMR (400 MHz, 5-chloro-2- CDC1 3 ) 6 7.35 (d, 2-(blroomethyl- hydroxybenzaldeh 1 H), 7.22 (dd, 1 H), 14-chdfluoro-((3,5yde and 1- 7.02 - 7.00 (m, 1obenzne (bromomethyl)-3,5- 2H), 6.82 - 6.74 benzene difluorobenzene (m, 2H), 5.12 (s, 2H), 4.53 (s, 2H). 'H NMR (400 MHz 5-chloro-2- CDC1 3 ) 6 7.56 (1 H, 1n4-(brome-h((4- hydroxybenzaldeh t), 7.36 (1 H, d), i-chloro-1- yde and 1- 7.26 (1H, dd), 7.22 chloro-2 (bromomethyl)-4- (1H, dd), 7.17 (1H, chloro-2- dd), 6.89 (1 H, d), enzene fluorobenzene 5.19 (2H, s), 4.53 (2H, s). 'H NMR (400 MHz 4-bromo-1- 4-bromo-2- CDC1 3 ) 6 7.41 (2H, (bromomethyl)-2- hydroxybenzaldeh n), 7.37 (1 H, t), ((3,5- yde and 1- 7.25 (1H, d), 7.14 dichlorobenzyl)oxy (bromomethyl)-3,5- (1 H, dd), 7.04 (1 H, )benzene dichlorobenzene d), 5.10 (2H, s), 4.55 (2H, s). 5-chloro-2- "'H NMR (400 MHz ODCd 3 ) 6 7.50-7.35 S1-(benzyloxy)-2- hydroxybenzaldeh (5H, i 7.23 7.H5 (bromomethyl)-4- yde and dd), 6.87 (1H, d), chlorobenzene (bromomethyl)ben 5.16 (H, 4.5 5.16 (2H, s), 4.55 zene (2H, s).
    WO 2013/037960 PCT/EP2012/068101 54 Intermediate compound Compound name Starting materials NMR 'H NMR (400 MHz 5-chloro-2- CDC1 3 ) 6 7.62 (1 H, 2-(bromomethyl)- t), 7.40-7.32 (2H, 4-chloro-1-((2- mydxandeh in), 7.28-7.19 (2H, fluorobenzyl)oxy)b e), 7.11 (1H, t), (bromomethyl)-2- 6.0(Hd,52 enzene 6.90 (1H, d), 5.23 fluorobenzene (2H, s), 4.55 (2H, s). 'H NMR (400 MHz 4-bromo-1-((2- 5-chloro-2- ODd 3 ) 67.49 (1H, t), 7.36 (1 H, dd), (bromomethyl)-4- hydroxybenzaldeh 7.3 (1H, dd), chlorophenoxy)met yde and 4-bromo (1H, dd), 7.25 (1H, hyl)-2- 1-(bromomethyl)- dd), .87 (1H, fluorobenzene 2-fluorobenzene 5.17 (2H, s), 4.52 (2H, s). 5-chloro-2- "'H NMR (400 MHz CDCds) 6 7.79 (1 H, 2-(bromomethyl)- hydroxybenzaldeh t), 7. (1 H, 4-chloro-1-((2- yde 1-7. ( H, d), fluoro-4- (bromomethyl)-2- ( H, d), 7.7 (trifluoromethyl)be fluoro-4 dd), 6.88 (iH, d), nzyl)oxy)benzene (trifluoromethyl)be 5.27 (H, 4.5 5.27 (2H, s), 4.54 nzene (2H, s). 'H NMR (400 MHz 2-(bromomethyl)- CDC 3 ) 6 7.64 2-hydroxy-5 1-((3- (trifluoro ethyl)be (1 H,d), 7.55 (1 H, fluorobenzyl)oxy)- nzaldehyde and 1 - dd), 7.40 (1 H, n), 4- 7.28-7.23 (2H, n), (trifluoromethyl)be (broom e 7.06 (1 H, td), 6.98 fluorobenzene nzene (1H, d), 5.23 (2H, s), 4.61 (2H, s).
    WO 2013/037960 PCT/EP2012/068101 55 Intermediate compound Compound name Starting materials NMR 'H NMR (400 MHz 2-hydroxy-5- CDC1 3 ) 6 7.63 (1 H, 4broo--((2- (trifluoromethyl)be d), 7.57 (1H, dd), 1v (roomethyl)4 nzaldehyde and 4- 7.50 (1 H, t), 7.37 (trifluoromethyl)p- bromo-1- (1H, dd), 7.33 (1H, enoxyzmehy- (bromomethyl)-2- dd), 7.02 (1 H, d), fluorobenzene fluorobenzene 5.24 (2H, s), 4.57 (2H, s). "H NMR (400 MHz 2-(bromomethyl)-'HNR(0Mz 1-(2 - 2-hydroxy-5- CDC1 3 ) 6 7.64-7.53 (trifluoromethyl)be (3H, in), 7.35 (1H, 1x 4- nzaldehyde and 1- q), 7.22 (1 H, t), (bromomethyl)-2- 7.12 (1H, t), 7.05 fluorobenzene (1 H, d), 5.31 (2H, nzene s), 4.60 (2H, s). 4-bromo-2- 5-bromo-2- 'H NMR (400 MHz CDCds) 6 7.60-7.53 (bromomethyl)-1- hydroxybenzaldeh (1, i 7.49 7.H3 ((2,4- yde and 1- d)),7.4 (1H, difluorobenzyl)oxy) (bromomethyl)-2,4- 6.4 (3H, in), benzene difluorobenzene 5.19 (2H, s), 4.51 (2H, s). 'H NMR (400 MHz 2- CDC1 3 ) 6 7.65-7.60 hydroxybenzaldeh (1H, in), 7.37 (1H, y (brooethyl)ph 2,4 yde and 1- dd), 7.31 (1H, td), nifluoxomeyl-,4 (bromomethyl)-2,4- 7.00-6.85 (4H, in), difluorobenzene difluorobenzene 5.20 (2H, s), 4.61 (2H, s).
    WO 2013/037960 PCT/EP2012/068101 56 Intermediate compound Compound name Starting materials NMR 4-bromo-1-((4- 5-bromo-2- "H NMR (400 MHz 1aa bromo-2- hydroxybenzaldeh CDC1 3 ) 6 7.50-7.30 (bromomethyl)phe yde and 4-bromo- (5H, in), 6.85 (1 H, noxy)methyl)-2- 1-(bromomethyl)- d), 5.17 (2H, s), fluorobenzene 2-fluorobenzene 4.52 (2H, s). 'H NMR (400 MHz 4-bromo-1-((2- 5-fluoro-2- ODd 3 ) 67.50 (1H, t), 7.36 (1 H, dd), (bromomethyl)-4- hydroxybenzaldeh 7.3 (H, dd), fluorophenoxy)met yde and 4-bromo (1H, dd), 7.01-6.97 hyl)-2- 1-(bromomethyl)- (1H, in), 6.88-6.H7 fluorobenzene 2-fluorobenzene dd), 5.16 (2H, s), 4.54 (2H, s). 5-chloro-2- "H NMR (400 MHz 2-((2 - hydroxybenzaldeh CDC1 3 ) 6 7.34 (1 H, 1(ac bromom y)-4- yde and 2- d), 7.27 (1 H, dd), hy-chloron 3met (bromomethyl)-5- 7.11-6.97 (3H, n), hyl)-5-chloro-1 ,3 difluorobenzene chloro-1,3- 5.16 (2H, s), 4.44 difluorobenzene (2H, s). 5-chloro-2- 'H NMR (400 MHz 5-bromo-2-((2- CDC 3 ) 6 7.32 (1 H, (bromomethyl)-4- ydxand d), 7.26 (1 H, dd), lad yde and 2 chlorophenoxy)met 7.21-7.15 (2H, in), hyl)-1,3- bromo - - 6.97 (1H, d), 5.13 bromo-1 ,3 difluorobenzene (2H, s), 4.44 (2H, s).
    WO 2013/037960 PCT/EP2012/068101 57 Intermediate compound Compound name Starting materials NMR 5-bromo-2- "'H NMR (400 MHz 2-((4-bromo-2- CDC1 3 ) 6 7.48 (1 H, (bromomethyl)phe ydxand d), 7.41 (1 H, dd), 1 ae yde and 2 noxy)methyl)-5- 7.21-7.15 (2H, in), (bromomethyl)-5- 69 1,d,51 chloro-1,3- 6.93 (1H, d), 5.15 chloro-1 ,3 difluorobenzene (2H, s), 4.43 (2H, s). 3,5-dichloro-2- 'H NMR (400 MHz 15-(bcoroometh- hydroxybenzaldeh CDC1 3 ) 6 7.58 (1H, 1af chloro-2- yde and 1- t), 7.39 (1H, d), chloro-2 (bromomethyl)-4- 7.33 (1 H, d), 7.23 chloro-2- (1H, dd), 7.17 (1H, enzene fluorobenzene dd), 5.18 (2H, s), 4.46 (2H, s). 3- "H NMR (400 MHz 2-(bromomethyl)- hydroxypicolinalde CDC1 3 ) 6 8.22 (1 H, 1ag 3-((4-chloro-2- hyde and 1- dd), 7.55 (1H, t), fluorobenzyl)oxy)p (bromomethyl)-4- 7.28-7.15 (4H, in), yridine chloro-2- 5.21 (2H, s), 4.68 fluorobenzene (2H, s). 5-fluoro-2- "TH NMR (400 MHz 2-(bromomethyl)-
    CDC
    3 ) 6 7.12 (1H, lah 1-((3,5- ydxand dd), 7.05-6.98 (3H, yde and 1 difluorobenzyl)oxy) m), 6.83-6.80 (2H, (bromomethyl)-3,5- i) .3(H ) -4-fluorobenzene m), 5.13 (2H, s), difluorobenzene 4.57 (2H, s).
    WO 2013/037960 PCT/EP2012/068101 58 Intermediate compound Compound name Starting materials NMR 'H NMR (400 5-bromo-2- MHz, CDC1 3 ) 6 1-(benzyloxy)-4- hydroxybenzaldeh 7.48 - 7.43 lai bromo-2- (3H, m), 7.43 yde and en (momethyl)ben 7.37 (2H, in), (bromomethyl)ben 73 2,i) zene 7.35 (2H, m), zene 5.14 (2H, s), 4.53 (2H, s). "H NMR (400 MHz, CDC1 3 ) 6 7.61 (1H, d), 2-hydroxy-5- 7.52 (1 H, dd), 1aj (b etzyloxy) (trifluoromethyl)be 7.49 - 7.47 (brioomnethyl)4 nzaldehyde and (2H, in), 7.43 (bromomethyl)ben 7.39 (2H, in), nzene zene 7.37-7.33 (1 H, in), 6.98 (1 H, d), 5.21 (2H, s), 4.59 (2H, s). "H NMR (400 MHz, CDC1 3 ) 6 4-bromo-2- 5-bromo-2- 7.50-7.40 (m, 3H), 7.50-7.40 (bromomethyl)-1- hydroxybenzaldeh 3H, dd), 7.36 lak (4- yde and 1 fluorobenzyloxy)be (bromomethyl)-4- (1H, dd), 7.14 - 7.04 (1 H, in), nzene fluorobenzene 6.78 (1H, d), 5.09 (2H, s), 4.50 (2H, s).
    WO 2013/037960 PCT/EP2012/068101 59 Intermediate compound Compound name Starting materials NMR 'H NMR (400 MHz, 5-chloro-2- CDC1 3 ) 6 7.44 (2H, 2-(bromomethyl)- dd), 7.33 (1H, d), 4-chloro-1-(4- ydxand 7.22 (1H, dd), 7.14 fluoobenylox~be yde and 1 lal fluorobenzyloxy)be - 7.01 (2H, m), nzene (broom e 6.83 (1 H, d), 5.09 fluorobenzene (2H, s), 4.51 (2H, s). "H NMR (400 MHz, 2-hydroxy-5 2-(bromomethyl)- (trifluoromethyl)be CDC 3 ) 6 7.62 (1 H, 1-(4-chloro-2- nzaldehyde and 1- d), 7.54 (1 H, t), lam fluorobenzyloxy)-4- 7.21 (1 H, dd), 7.16 (trifluoromethyl)be (bromo -- (1H, dd), 7.00 (1H, chloro-2 nzene fluorobenzene d), 5.24 (s, 2H), 4.56 (s, 2H). 5-chloro-2- 'H NMR (400 MHz, CDCds) 6 7.46 (2H, hydroxybenzaldeh CC3 .6(H 2-(bromomethyl)- ydxand dd), 7.32 (1 H, d), yde and 1 lan 4-chloro-1-((4- 7.22 (1H, dd), 7.14 (trifluoromethyl)be (bromo -2- - 7.01 (2H, m), fluoro-4 nzyl)oxy)benzene 6.83 (1H, d), 5.09 (trifluoromethyl)be (H ) .1(H (2H, s), 4.51 (2H, nzene
    S).
    WO 2013/037960 PCT/EP2012/068101 60 Intermediate compound Compound name Starting materials NMR 'H NMR (400 MHz, 4-bromo-2- 5-bromo-2- CDC1 3 ) 6 7.53 (1 H, hydroxybenzaldeh t), 7.47 (1 H, d), lp (br lomom l-- yde and 1- 7.38 (1H, dd), 7.19 lap (4-chylo-- (bromomethyl)-4- (1H, dd), 7.14 (1H, chloro-2- dd), 6.81 (1 H, d), nzene fluorobenzene 5.16 (s, 2H), 4.49 (2H, s). 'H NMR (400 MHz, CDC1 3 ) 6 7.31 (1 H, 5-chloro-2- d), 7.20 (1 H, dd), 14- lroomethyl- hydroxybenzaldeh 6.76 (1 H, d), 4.52 1aq 4-chloro-1 (cyclopropylmetho yde and (2H, s), 3.87 (2H, xy)benzene (bromomethyl)cycl d), 1.39 - 1.15 opropane (1 H, in), 0.75 0.53 (2H, in), 0.48 - 0.28 (2H, n). "H NMR (400 MHz, CDC1 3 ) 6 7.45 (1 H, 4-bromo-2- 5-bromo-2- d), 7.34 (1 H, dd), 1ar hydroxybenzaldeh 6.72 (1 H, d), 4.51 (bromometyl)-1-o yde and (2H, s), 3.87 (2H, (cycloproyeth (bromomethyl)cycl d), 1.35 - 1.25 xy)benzene opropane (1 H, in), 0.70 0.56 (2H, in), 0.45 - 0.32 (2H, in). 5-chloro-2- "H NMR (400 MHz, 3-((2 - hydroxybenzaldeh CDC1 3 ) 6 7.32 (1 H, (blromomtyl)-4- yde and 3- d), 7.19 (1H, dd), 1has loroheoxyme (bromomethyl)- 6.81 (1 H, d), 6.57 hyl)-1 ,2,4,5 tetrafluorobenzene 1,2,4,5- (1H, n), 5.16 (2H, tetrafluorobenzene s), 4.56 (2H, s).
    WO 2013/037960 PCT/EP2012/068101 61 Intermediate compound Compound name Starting materials NMR 'H NMR (400 MHz, 5-chloro-2- CDC1 3 ) 6 8.06 (1 H, hydroxybenzaldeh d), 7.96 (1H, s), bistriloomeyl) yde and 1- 7.89 (1H, d), 7.37 1bat eoxy)-- (bromomethyl)-2,4- (1 H, d), 7.24 (1 H, (boromom e-4 bis(trifluoromethyl) dd), 6.78 (1 H, d), chlorobenzene benzene 5.39 (2H, s), 4.56 (2H, s).
    WO 2013/037960 PCT/EP2012/068101 62 Intermediate compound Compound name Starting materials NMR 'H NMR (400 MHz, 5-chloro-2- CDC1 3 ) 6 7.61 (1 H, 2-boromomethy- hydroxybenzaldeh dd), 7.35 (1 H, d), 4- chloro-1-- yde and 1- 7.24 (1H, dd), 7.18 1au chloro-4 (bromomethyl)-2- (1 H, dd), 7.05 (1 H, chloro-4- td), 6.84 (1 H, d), enzene fluorobenzene 5.18 (2H, s), 4.53 (2H, s). "H NMR (400 MHz, 4-bromo-2- 5-bromo-2- CDC1 3 ) 6 7.61 (1 H, hydroxybenzaldeh dd), 7.48 (1 H, d), 1 av ((b ehyl)o-- yde and 1- 7.38 (1H, dd), 7.18 lay ((2-chl~oro-4 (bromomethyl)-2- (1H, dd), 7.04 (1H, chloro-4- td), 6.80 (1 H, d), enzene fluorobenzene 5.18 (2H, s), 4.53 (2H, s). 5-chloro-2- 'H NMR (400 MHz, 1-((2- CDC1 3 ) 6 7.47 (bromomethyl)-4- ydxand 7.40 (1H, in), 7.19 yde and 1 1ax chlorophenoxy)met (1 H, dd), 7.02 hyl)-2,4,5- ( ,me5 - 6.94 (2H, in), 6.86 trifluorobenzene 2,4,5- (1H, dd), 5.12 (2H, trifluorobenzene s), 4.52 (2H, s). 'H NMR (400 MHz, 2-bromo-4-((2- 5-chloro-2- ODd 3 ) 6 7.67 (1 H, dd), 7.44 (1H, d), (bromomethyl)-4- hydroxybenzaldeh 7.3 7.2 (H, chlorophenoxy)met yde and 2-bromo lay mn), 7.15 (1H, t), hyl)-1- 4-(bromomethyl)- 6.76 (H, 5.0 fluorobenzene 1 -fluorobenzene (2H, s), 4.50 (2H, s).
    WO 2013/037960 PCT/EP2012/068101 63 Intermediate compound Compound name Starting materials NMR 'H NMR (400 MHz, 5-chloro-2- CDC1 3 ) 6 7.48 (1 H, hydroxybenzaldeh d), 7.39 (1H, dd), 1(bz crom nomhyl)- yde and 1- 7.35 - 7.27 (1 H, lhlorophenoxme (bromomethyl)- in), 7.02 (1H, tdd), hyifl)-2,3,- 2,3,4- 6.81 (1H, d), 5.16 trifluorobenzene trifluorobenzene (2H, s), 4.48 (2H, s). "H NMR (400 MHz, 5-fluoro-2- CDC1 3 ) 6 7.62 (1 H, 2-(bromomethyl)- hydroxybenzaldeh dd), 7.17 (1H, dd), 1ba 1-((2-chloro-4- yde and 1- 7.10 (1H, dd), 7.05 fluorobenzyl)oxy)- (bromomethyl)-2- (1 H, td), 7.01 4-fluorobenzene chloro-4- 6.94 (1 H, in), 6.86 fluorobenzene (1H, dd), 5.17 (2H, s), 4.55 (2H, s). 5-fluoro-2- "'H NMR (400 MHz, 1-((2- hCDC1 3 ) 6 7.51 (bromomethyl)-4- ydxand 7.40 (1H, n), 7.09 yde and 1 lbb fluorophenoxy)met (1 H, dd), 7.02 hyl)-2,4,5- ( ,me5 - 6.94 (2H, in), 6.86 2,4,5-(Hd)5.2(H trifluorobenzene (1H, dd), 5.12 (2H, trifluorobenzene s), 4.52 (2H, s). 5-fluoro-2- 'H NMR (400 MHz, 2-(bromomethyl)- hydroxybenzaldeh ODd 3 ) 6 7.85 (1 H, 4-fluoro-1 -((4- yde and 1- dd), 7.42 (1 H, dd), 7.31 (1 H, td), 7.10 1bc fluoro-2- (bromomethyl)-4- (1H, d), 7.0 (trifluoromethyl)be fluoro-2 6.93 (1 H, in), 6.81 nzyl)oxy)benzene (trifluoromethyl)be (1 H, d), .8 (1 H, dd), 5.28 (2H, nzene s), 4.55 (2H, s).
    WO 2013/037960 PCT/EP2012/068101 64 Intermediate compound Compound name Starting materials NMR 'H NMR (400 MHz, CDC1 3 ) 6 7.84 (1 H, 5-chloro-2- dd), 7.43 (dd, J= 2-(bromomethyl)- hydroxybenzaldeh 8.8, 2.7 Hz, 1 H), 7.35 (d, J= 2.6 Hz, 4-chloro-1-((4- yde and 1 1H), 7.30 (td, J= fluoro-2- (bromomethyl)-4- 83 . z ) 1 bd8.,27H ,1 ) (trifluoromethyl)be fluoro-2 7.23 (dd, J= 8.8, nzyl)oxy)benzene (trifluoromethyl)be 2.6 Hz, 1 H), 6.79 nzene (d, J= 8.8 Hz, 1H), 5.29 (s, 1 H), 4.54 (s, 1H). "H NMR (400 MHz, 5-bromo-2- CDC1 3 ) 6 7.48 (1 H, 1((4-rnomo-2-y e hydroxybenzaldeh d), 7.39 (1H, dd), (bromomethyl)phe yde and 1- 7.35 - 7.27 (1 H, 1be 2,3,4 - (bromomethyl)- in), 7.02 (1H, tdd), 2,3,4 trifluorobenzene 2,3,4- 6.81 (1H, d), 5.16 trifluorobenzene (2H, s), 4.48 (2H, s). "H NMR (400 MHz, CDC1 3 ) 6 7.69 (1 H, 2-bromo-4-((2- 5-fluoro-2- dd), 7.44 - 7.37 (1 H, in), 7.44 (bromomethyl)-4- hydroxybenzaldeh (1H, n), 7.15 1bf fluorophenoxy)met yde and 2-bromo (1H, t), 7.09 (1 H, hyl)-1- 4-(bromomethyl)- dd), 6.9 (1H, fluorobenzene 1 -fluorobenzene ddd), 6.82 (1H, dd), 5.06 (2H, s), 4.52 (2H, s).
    WO 2013/037960 PCT/EP2012/068101 65 Intermediate compound Compound name Starting materials NMR 'H NMR (400 MHz, 2-bromo-4-((4- 5-bromo-2- ODd 3 ) 6 7.69 (1 H, dd), 7.47 (1H, d), bromo-2- hydroxybenzaldeh 7.4 (17.8 (2H 1bg (bromomethyl)phe yde and 2-bromo noxy)methyl)-1- 4-(bromomethyl)- in), 7.15 (1H, t), 6.76 (1 H, d), 5.07 fluorobenzene 1 -fluorobenzene (2H, s), 4.50 (2H, s). 5-bromno-2- "H NMR (400 MHz, CDCds) 6 7.83 (1 H, 4-bromo-2- hydroxybenzaldeh d) 7. (1 H, (bromomethyl)-1- yde and 1 7.43 (1H, dd), 7.37 lbh ((4-fluoro-2- (bromomethyl)-4- (1H, dd), 7.3 (trifluoromethyl)be fluoro-2 td), 6.74 (1 H, d), nzyl)oxy)benzene (trifluoromethyl)be 5.28 (H, 4.5 5.28 (2H, s), 4.53 nzene (2H, s). 3-bromo-5-chloro- "H NMR (400 MHz, bromo-2-4 2- CDC1 3 ) 6 7.57 bromo-2 hydroxybenzaldeh 7.51 (2H, in), 7.37 ibi oroboenyl~)- yde and 4-bromo- (2H, dd), 7.31 (1H, 3-(blrooethl 1-(bromomethyl)- dd), 5.14 (2H, s), 5-chlorobenzene 2-fluorobenzene 4.46 (2H, s). "H-NMR (CDC1 3 , 250 MHz, 6): 7.57 2-(bromomethyl)- 2-hydroxy-5- (dd, J= 15.0, 8.4 1-[(2,4- methoxybenzaldeh Hz, 1H, ArH); 6.99 difluorobenzyl)oxy] yde 1- 6.78 (m, 5H, ArH); -4- (bromomethyl)-2,4- 5.12 (s, 2H, CH2); methoxybenzene difluorobenzene 4.55 (s, 2H, CH2); 3.77 (s, 3H, OCH3).
    WO 2013/037960 PCT/EP2012/068101 66 Intermediate compound Compound name Starting materials NMR 5-chloro-2 2-(bromomethyl)- hydroxybenzaldeh lbk 4-chloro-1 (cyclohexylmethox yde and (bromomethyl)cycl y)benzeneohxe ohexane 5-chloro-2 2-(bromomethyl)- hydroxybenzaldeh 4-chloro-1 1bl yde and * (cyclopentylmetho bomehlcl (bromomethyl)cycl xy)benzene opentane 'H NMR (300 MHz, CDC13) 6 : 7.09 5-fluoro-2- 6.89 (m, 2H, ArH); 2-(bromomethyl)- 6.83-6.75 (m, 1H, hydroxybenzaldehAr)4.1(,2; 1bm 4-fluoro-1-- ArH); 4.51 (s, 2H); yde and 1 propoxybenzene . 3.96 (t, J= 6.4 Hz, 2H); 1.97-1.74 (m, 2H); 1.08 (t, J= 7.41 Hz, 3H). "H NMR (300 MHz, CDC13) 6 : 7.31 7.16 (mn, 2H, ArH); 2-(bromomethyl)- 5-chloro-2 4-chloro-1- hydroxybenzaldeh 6.78 (d, J= 8.74 1 bn Hz, 1H, ArH); 4.85 (cyclopentyloxy)be yde and 1 4.77 (mn, 1H); 4.44 nzene iodocyclopentane (.772H); 1 H9- .76 (s, 2H); 1.98-1.76 (m, 6H); 1.71-1.56 (m, 2H).
    WO 2013/037960 PCT/EP2012/068101 67 Intermediate compound Compound name Starting materials NMR 'H NMR (300 MHz, CDC13) 6 : 7.35 7.17 (m, 2H, ArH); 5-chloro-2- 6.78 (d, J= 8.76 o- oroomethyl- hydroxybenzaldeh Hz, 1 H, ArH); 4.49 1bo 4-chloro-1 propoxybenzene yde and 1- (s, 2H); 3.97 (t, J= iodopropane 6.4 Hz, 2H); 1.98 1.74 (m, 2H); 1.08 (t, J= 7.44 Hz, 3H). 1 -(bromomethyl)- salicylaldehyde 1bp 2- and 1-iodo-2 isobutoxybenzene methylpropane 5-chloro-2 2-(bromomethyl)- hydroxybenzaldeh * lbq 4-chloro-1-(2,2- yde and 1,1 difluoroethoxy)ben difluoro-2 zene iodoethane 2- 5-chloro-2 (bromomethyl)-4- hydroxybenzaldeh 1br chloro-1 -(2- yde and 2 fluoroethoxy)benze fluoroethyl-4 ne methylbenzenesulf onate 2- 5-chloro-2 (bromomethyl)-4- hydroxybenzaldeh * lbs chloro-1-(2,2,2- yde and 1,1,1 trifluoroethoxy)ben trifluoro-2 zene iodoethane WO 2013/037960 PCT/EP2012/068101 68 Intermediate compound Compound name Starting materials NMR 2- 5-chloro-2 (bromomethyl)-4- hydroxybenzaldeh * 1bt chloro-1- yde and 1-iodo (neopentyloxy)ben 2,2 zene dimethylpropane 5-chloro-2 hydroxybenzaldeh yde and 2-fluoro-2 2- methylpropyl trifluoromethanesul (bromomethyl)-4- fonate (prepared * chloro-1-(2-fluoro- following the 1 bufolwn th 2 method described methylpropoxy)ben in: Limanto, J. eta zene J. Org. Chem. 2005, 70, 2372 2375) 5-fluoro-2 2 hydroxybenzaldeh (bromomethyl)-1- 1bv ((4-chloro-2 1 by((4-hlor-2-(bromomethyl)-4 fluorobenzyl)oxy) 4-f luorobenzene fluorobenzene 5-chloro-2 2 (bromomethyl)-4- hydroxybenzaldeh yeand ** 1bw chloro-1- yde cyclobutylmethyl 4 (cyclobutylmethoxy eylbens If )benzenemethylbenzenesulf )benzene onate Intermediate compouns used directly in the next step without further analysis.
    WO 2013/037960 PCT/EP2012/068101 69 **LC-MS (method 4): tR = 1.55 [M-H]-= 289 Intermediate compound 2: Synthesis of 2-(1-bromoethyl)-4-chloro-1-((4-chloro 2-fluorobenzyl)oxy)benzene 5 a) 1-(5-chloro-2-((4-chloro-2-fluorobenzyl)oxy)phenyl)ethanol To a solution of 5-chloro-2-((4-chloro-2-fluorobenzyl)oxy)benzaldehyde (200 mg, 0.67 mmol) in dry diethyl ether, a solution of methylmagnesium bromide 3 M in ether (0.45 mL, 1.34 mmol) was added at 0 9C under nitrogen atmosphere. Mixture was stirred and allowed to reach room temperature. After 3 h, TLC showed no starting 10 material left. It was treated with a saturated solution of ammonium chloride, diluted with water and extracted with diethyl ether (x3). The combined organic phases were washed with brine and dried over MgSO 4 . Solvent was removed under vacuum to yield the crude desired product in quantitative yield. 15 b) The title compound was obtained following the general procedure as described intermediate compound 1 (step c) using 1-(5-chloro-2-((4-chloro-2 fluorobenzyl)oxy)phenyl)ethanol as starting material. 'H NMR (400 MHz, CDC1 3 ) 6 7.52 (t, 1 H), 7.49 (d, 1 H), 7.24 - 7.17 (m, 2H), 20 7.15 (dd, 1 H), 6.85 (d, 1H), 5.59 (q, 1H), 5.20 - 5.09 (m, 2H), 2.00 (d, 3H). Intermediate compound 3: Synthesis of 2-(bromomethyl)-4-chloro-1-(1-(2,4 difluorophenyl)ethoxy)benzene The title compound was obtained following the general procedure described in 25 intermediate compound 1 (step a, b, c) using 5-chloro-2-hydroxybenzaldehyde and 1 -(1 -bromoethyl)-2,4-difluorobenzene as starting materials. 'H NMR (400 MHz, CDC1 3 ) 6 7.61 (1H, dd), 7.35 (1H, d), 7.24 (1H, dd), 7.18 (1H, dd), 7.05 (1H, td), 6.84 (1H, d), 5.15 (1H, m), 4.53 (2H, s), 1.72 (3H, d). 30 Intermediate compound 4: Synthesis of 4-bromo-1-((4-bromo-2 (bromomethyl)benzyl)oxy)-2-fluorobenzene a) To a solution of 2.80 g (13 mmol) of 5-bromo-2-methylbenzoic acid in 11 mL of MeOH, 2.5 mL of HCI 4.0 M (10 mmol) in dioxane were added.
    WO 2013/037960 PCT/EP2012/068101 70 The reaction was heated at 70 9C and stirred at that temperature overnight. Then, the mixture was concentrated, cooled to 0 9C and neutralized with saturated NaHCO 3 . The resulting mixture was extracted with DCM and evaporated to obtain methyl 5-bromo-2-methylbenzoate as yellow oil (2.8 g, 94%), which solidified into 5 needles. b) 2.8 g (12.2 mmol) of 5-bromo-2-methylbenzoate was dissolved in 19 mL of CC14 and then NBS (2.6 g, 14.7 mmol) and benzoyl peroxide (0.28 g, 0.9 mmol) were added. The resulting yellow mixture was heated to 80 9C and stirred at that 10 temperature overnight. The solid was removed by filtration and washed with DCM. The yellow filtrate was concentrated and purified by column chromatography over silica gel eluting with hex/EtAcO 95:5 then 9:1 to yield methyl 5-bromo-2-(bromomethyl)benzoate. 15 c) To a solution of 255 mg (0.7 mmol) of methyl 5-bromo-2 (bromomethyl)benzoate and 111 mg (0.6 mmol) of 4-bromo-2-fluorophenol in 2 mL of dry DMF, K 2
    CO
    3 (117 mg, 0.85 mmol) was added. Reaction was stirred at 50 9C overnight. Then, it was allowed to cool to room temperature. Water was added and a white 20 precipitated appeared. The mixture was extracted with EtAcO (x3), and the organic phases combined and washed with a 10% solution of NaCl in water. It was dried with anhydrous Na 2
    SO
    4 , filtered and the solvent evaporated. The compound was purified by column chromatography over silica gel eluting with cyclohexane/EtAcO 9:1. 25 Methyl 5-bromo-2-((4-bromo-2-fluorophenoxy)methyl)benzoate (290 mg, 98%) was obtained as a white solid. d) To a solution of 290 mg (0.7 mmol) of methyl 5-bromo-2-((4-bromo-2 fluorophenoxy)methyl)benzoate in 4 mL of dry THF cooled at 0C under argon, 0.8 30 mL of LiAIH 4 1 .OM in THF were added dropwise. After 5 minutes TLC showed that there was no starting material left. Wet EtAcO was used to quench the reaction. The resulting mixture was dried over anhydrous Na 2
    SO
    4 and then filtered through celite. After solvent evaporation (5-bromo-2-((4- WO 2013/037960 PCT/EP2012/068101 71 bromo-2-fluorophenoxy)methyl)phenyl)methanol (267 mg, 99%) was obtained as white needles. e) The title compound was obtained following the general procedure 5 described in intermediate compound 1 (step c) using 4-bromo-1-((4-bromo-2 (bromomethyl)benzyl)oxy)-2-fluorobenzene as starting material. 'H NMR (400 MHz CDCI 3 ) 6 7.57 (1H, d), 7.49 (1H, dd), 7.35-7.28 (2H, m), 7.23-7.20 (1 H, m), 6.95 (1 H, t), 5.21 (2H, s), 4.57 (2H, s). 10 Intermediate compound 5: Synthesis of 2-(Bromomethyl)-4-chloro-1-(4-chloro 2-fluorophenethyl)benzene a) 2-(Bromomethyl)-5-chlorobenzonitrile 5-chloro-2-methylbenzonitrile (2.5 g, 16.5 mmol) was dissolved in carbon 15 tetrachloride (40 mL), and N-bromosuccinimide (2.94 g, 16.5 mmol) was added, followed by benzoyl peroxide (0.107 g, 0.33 mmol). The mixture was refluxed for 4 h, and the white succinimide residue was filtered off. The solvent was evaporated under reduced pressure and the residue was chromatographed on silica gel eluting with Hexanes:EtAcO (1:0 to 9:1). One pure fraction was collected (2.05 g, 54 % 20 yield) as a white crystalline solid. 'H NMR (400 MHz, CDC1 3 ) 6 7.65 (1H, d), 7.57 (1H, dd), 7.50 (1H, d), 4.60 (2H, s). 25 b) Diethyl 4-chloro-2-cyanobenzylphosphonate A solution of 2-(bromomethyl)-5-chlorobenzonitrile (1.95 g, 8.46 mmol) and P(OEt) 3 (3.63 mL, 21.15 mmol) in toluene were heated to 140 9C for 4 hours. Excess of P(OEt) 3 was removed in vacuo, and the product was extracted with ethyl acetate. Combined organic extracts were dried over MgSO 4 . Column chromatography on 30 silica gel gave the desired product as a slightly yellow oil (2.1 g, 86% yield). 'H NMR (400 MHz, CDCI 3 ) 6 7.65 - 7.58 (1H, m), 7.51 (2H, m), 4.19 - 4.00 (4H, m), 3.37 (2H, d), 1.29 (6H, t).
    WO 2013/037960 PCT/EP2012/068101 72 c) (E)-5-Chloro-2-(4-chloro-2-fluorostyryl)benzonitrile To a solution of 4-chloro-2-fluorobenzaldehyde (1.43 g, 9.04 mmol) and diethyl 4 chloro-2-cyanobenzylphosphonate (2.6 g, 9.04 mmo) in THF (50 mL) was added potassium tertbutoxide (2.03 g, 18.1 mmol) at room temperature, the reaction was 5 stirred for 3 hours. The mixture was then poured into water and extracted with ethyl acetate. After removing the solvent under vacuum, the crude product was purified by crystallization with methanol (2.6 g, 9.04 mmol). 'H NMR (400 MHz, CDC1 3 ) 6 7.76 (1 H, d), 7.67 - 7.53 (3H, m), 7.39 (2H, dd), 10 7.22 - 7.11 (2H, m). d) 5-Chloro-2-(4-chloro-2-fluorophenethyl)benzonitrile (E)-5-Chloro-2-(4-chloro-2-fluorostyryl)benzonitrile was dissolved in THF and a catalytic amount of Pd/C was added. The reaction vessel was purged with H 2 and 15 kept under H 2 (1 atm) for 24 h at room temperature. The reaction mixture was filtered over Celite and concentrated to give the desired product as a white solid. 'H NMR (400 MHz, CDC1 3 ) 6 7.59 (1H, d), 7.45 (1H, dd), 7.15 (1H, d), 7.08 7.00 (3H, m), 3.13 - 3.01 (2H, m), 3.04 - 2.76 (2H, m). 20 e) 5-Chloro-2-(4-chloro-2-fluorophenethyl)benzaldehyde In a dry Schlenk flask 5-chloro-2-(4-chloro-2-fluorophenethyl)benzonitrile (410 mg, 1.39 mmol) was dissolved in 20 mL of dry diclhoromethane. The solution is cooled to 0 9C and 1.54 mL of DIBAL-H in hexane (c = 1 mol/I) was added dropwise via 25 srynge while the temperature is maintained below 5 9C. After 20 minutes the cooling bath is removed and the mixture is stirred at room temperature. When TLC indicates the absence of starting material, 10 mL of diluted hydrochloric acid were carefully added. The mixture is demulsified by addition of aq. sat. NaCl solution and the aqueous phase was extracted with dichloromethane. The combined organic phases 30 were dried with MgSO 4 , filtered and concentrated at rotavap. The crude product is purified by flash chromatography (SiO 2 , hexanes/Et 2 0, 9:1). The product was obtained as a white solid.
    WO 2013/037960 PCT/EP2012/068101 73 'H NMR (400 MHz, CDC1 3 ) 6 10.14 (1H, s), 7.79 (1H, d), 7.44 (1H, dd), 7.13 (1 H, d), 7.08 - 6.87 (3H, m), 3.26 (2H, t), 2.89 (2H, t). f) 2-(Bromomethyl)-4-chloro-1-(4-chloro-2-fluorophenethyl)benzene 5 The title compound was obtained following the general procedure described in intermediate compound 1 (steps b, c) using 5-chloro-2-(4-chloro-2 fluorophenethyl)benzaldehyde as starting material. 'H NMR (500 MHz, CDC1 3 ) 6 7.40 (1 H, d), 7.20 (1 H, dd), 7.11 - 6.99 (4H, m), 10 4.67 (2H, s), 2.99 - 2.75 (4H, m). Intermediate compound 6: Synthesis of (E)-2-(Bromomethyl)-4-chloro-1-(4 chloro-2-fluorostyryl)benzene a) (E)-5-Chloro-2-(4-chloro-2-fluorostyryl)benzaldehyde 15 In a dry Schlenk flask (E)-5-chloro-2-(4-chloro-2-fluorostyryl)benzonitrile (335 mg, 1.15 mmol) was dissolved in 20 mL of dry diclhoromethane. The solution is cooled to 0 9C and 1.34 mL of DIBAL-H in hexane (c = 1 mol/I) was added dropwise via syringe while the temperature is maintained below 5 9C. After 20 minutes the cooling bath is removed and the mixture is stirred at room temperature. When TLC indicates 20 the absence of starting material, 10 mL of diluted hydrochloric acid were carefully added. The mixture is demulsified by addition of aq. sat. NaCl solution and the aqueous phase was extracted with dichloromethane. The combined organic phases were dried with MgSO 4 , filtered and concentrated at rotavap. The product was obtained as a white solid and used in the next step without further purification. 25 b) (E)-2-(Bromomethyl)-4-chloro-1-(4-chloro-2-fluorostyryl)benzene The title compound was obtained following the general procedure described inintermediate compound 1 (steps b, c) using (E)-5-chloro-2-(4-chloro-2 fluorostyryl)benzaldehyde as starting material. 30 'H NMR (500 MHz, CDC1 3 ) 6 7.58 (1H, d), 7.52 (1H, t), 7.41 (2H, dd), 7.31 (1H, dd), 7.18 - 7.06 (3H, m), 4.81 (2H, s).
    WO 2013/037960 PCT/EP2012/068101 74 Intermediate compound 7: Synthesis of methyl 7-fluoro-1H-indole-4 carboxylate a) 2-(Bromomethyl)-4-chloro-1-(4-chloro-2-fluorophenethyl)benzene 5 At -40 *C, vinylmagnesium bromide (75 mmol) in tetrahydrofuran (75 mL) was added dropwise, in the course of 30 min, to a solution of 4-bromo-1-fluoro-2 nitrobenzene (5.5 g, 25 mmol) in tetrahydrofuran (100 mL). After 1 h at -40 *C, the mixture was poured into a saturated aqueous solution (50 mL) of ammonium chloride. The organic layer was evaporated. The crude was submitted to flash 10 chromatography through silica gel to obtain 1.2 g (22% yield) of 4-bromo-7-fluoro 1 H-indole. b) Methyl 7-fluoro-1 H-indole-4-carboxylate Under inert atmosphere (glove box), in a stainless steel high pressure reactor with a 15 capacity of 25 mL and equipped with a magnetic stirrer were placed 4-bromo-7 fluoro-1H-indole (150 mg, 0.7 mmol), tetrakis(triphenylphosphane)palladium(0) (162 mg, 0.14 mmol), dry methanol (3 mL) and triethylamine (196 iL, 1.4 mmol). The system was purged three times with CO and pressurized to 25 bar. The reactor was warmed to 100 9C and stirred at 600 rpm overnight. Then was cooled to RT and the 20 product was concentrated under reduced pressure. The crude was submitted to flash chromatography through silica gel to obtain 41 mg (30% yield) of the desired product. 'H NMR (400 MHz, CDC1 3 ) 6 8.60 (1 H, s NH), 7.89 (1 H, dd), 7.38 - 7.35 (1 H, 25 m), 7.21 (1 H, td), 6.94 (1 H, dd), 3.98 (3H, s). Intermediate compound 8: Synthesis of methyl 7H-pyrrolo[2,3-d]pyrimidine-4 carboxylate 30 a) 4-iodo-7H-pyrrolo[2,3-d]pyrimidine A mixture of 4-chloro-7H-pyrrolo[2,3-d]pyrimidine (336 mg, 2.15 mmol) and 3.5 mL of 57% hydriodic acid was stirred at room temperature for 16 hours. The solid was filtered off, suspended in 3 mL of water and brought to pH = 8 with aqueous ammonia solution. The suspension was cooled down to 0 9C and the solid was WO 2013/037960 PCT/EP2012/068101 75 filtered off, washed with cold water and dried to give the desired product (410 mg). The product contains about 10% of the starting material. b) Methyl 7H-pyrrolo[2,3-d]pyrimidine-4-carboxylate 5 Under inert atmosphere (glove box), in a stainless steel high pressure reactor with a capacity of 25 mL and equiped with a magnetic stirrer were placed 4-iodo-7H pyrrolo[2,3-d]pyrimidine (300 mg, 1.22 mmol), tetrakis(triphenylphosphane)palladium(0) (283 mg, 0.25 mmol), dry methanol (4 mL) and triehtylamine (342 iL, 2.5 mmol). The system was purged three times with CO 10 and pressurized to 5 bar. The reactor was warmed to 100 9C and stirred at 600 rpm overnight. Then was cooled to RT and the product was concentrated under reduced pressure. The crude was submitted to flash chromatography through silica gel to obtain 200 mg (92% yield) of the desired product. 'H NMR (500 MHz, CDC1 3 ) 6 10.27 (1H, s NH), 9.08 (1H, s), 7.58 (1H, dd), 15 7.16 (1H, d), 4.11 (3H, s). Intermediate compound 9: Synthesis of of 4-(2-(2-(bromomethy)-4 chlorophenoxy)ethyl)tetrahydro-2H-pyran 00 r Br CI 20 a) To a suspension of 180 mg (7.5 mmol) of NaH 60% in mineral oil in 5 mL of benzene under argon and cooled at 09C 1.5 mL (7.5 mmol) of triethyl phosphonoacetate was added dropwise (caution: gases evolve). The mixture was stirred at 09C for 20 min, then 250 mg (2.5 mmol) of dihydro-2H-pyran-4(3H)-one was added. Reaction was stirred at room temperature for 2 hours. Then it was 25 quenched with a saturated solution of NH 4 CI, extracted with EtAcO and the combined organic layers washed with water and brine and dried over MgSO 4 . The crude was purified by column chromatography over silica gel eluting with mixtures of hex/EtAcO 95:5 to 8:2. The desired compound ethyl 2-(dihydro-2H-pyran-4(3H) ylidene)acetate was quantitatively obtained. 30 WO 2013/037960 PCT/EP2012/068101 76 b) To a solution of 425 mg (2.5 mmol) of ethyl 2-(dihydro-2H-pyran-4(3H) ylidene)acetate in 15 mL of MeOH, 133 mg of Pd on carbon 10% was added. Hydrogen atmosphere was set (1 atm, with a balloon) and the reaction was stirred at room temperature overnight. It was filtered through a pad of celite washing with 5 abundant EtAcO. After removing the solvent the desired compound ethyl 2 (tetrahydro-2H-pyran-4-yl)acetate was obtained as a colorless oil (99%). c) To a solution of 425 mg (2.5 mmol) of ethyl 2-(tetrahydro-2H-pyran-4 yl)acetate in 10 mL of dry THF cooled at 09C under argon, a 2.71 mL of a solution 10 of LiAIH 4 1M in THF was added. Bubbling was observed. It was stirred at room temperature for 30 min. Then it was quenched with wet EtAcO, dried with MgSO 4 and filtered through celite, washing with abundant EtAcO. After removing the solvent the desired compound, 2-(tetrahydro-2H-pyran-4-yl)ethanol, was obtained (300 mg, 93%). 15 d) To a solution of 300 mg (2.2 mmol) of 2-(tetrahydro-2H-pyran-4-yl)ethano in 10 mL of DCM at 09C TEA (0.38 mL, 2.7 mmol) and methanesulfonyl chloride (0.19 mL, 2.5 mmol) were added. The mixture was allowed to warm to room temperature and stirred at this temperature overnight. The reaction was stirred with 20 saturated NaHCO 3 for 15 min and the aqueous phase was extracted with DCM (x3). The combined organic layers were dried over MgSO 4 , filtered and concentrated to quantitatively yield 2-(tetrahydro-2 H-pyran-4-yl)ethyl methanesulfonate as a colorless oil. 25 e) To a solution of 465 mg (2.2 mmol) of 2-(tetrahydro-2H-pyran-4-yl)ethy methanesulfonate in 11 mL of acetone LiBr (970 mg, 11.1 mmol) was added. The resulting mixture was stirred at 509C for 5 hours. Then, it was allowed to cool to room temperature and the solvent was evaporated. Water was added and the mixture was extracted with DCM (x3). The combined extracts were dried over 30 MgSO 4 , filtered and the solvent removed. The crude was purified by column chromatography over silica gel eluting with mixtures hexane/EtAcO. 4-(2 bromoethyl)tetrahydro-2H-pyran was obtained as a colorless oil (200 mg, 46%).
    WO 2013/037960 PCT/EP2012/068101 77 f) To a solution of 5-chloro-2-hydroxybenzaldehyde 162 mg (1.0 mmol) in DMF (2 mL), 172 mg of K 2
    CO
    3 (1.2 mmol) and 4-(2-bromoethyl)tetrahydro-2H-pyran (200 mg, 1.0 mmol) were added. Reaction was stirred at 4 09C overnight. Then, it was allowed to cool to room temperature. Water was added and a white precipitated 5 appeared. The mixture was extracted with EtAcO (x3), and the organic phases combined and washed with a 10% solution of NaCl in water. It was dried with anhydrous Na 2
    SO
    4 , filtered and the solvent evaporated to obtain 5-chloro-2-(2 (tetrahydro-2H-pyran-4-yl)ethoxy)benzaldehyde (220 mg, 80%). 10 g) To a suspension of 220 mg of 5-chloro-2-(2-(tetrahydro-2H-pyran-4 yl)ethoxy)benzaldehyde in 4 mL of absolute ethanol cooled at 0C NaBH 4 (37 mg, 1.0 mmol) was added. After 15 minutes TLC showed no starting material left. Reaction was quenched with HCI 1 M and extracted with EtAcO (x3), washed with water, dried over anhydrous MgSO 4 and filtered. (5-chloro-2-(2-(tetrahydro-2H 15 pyran-4-yl)ethoxy)phenyl)methanol was quantitatively obtained. h) To a solution of (5-chloro-2-(2-(tetrahydro-2H-pyran-4 yl)ethoxy)phenyl)methanol (222 mg, 0.82 mmol) in 4 mL of DCM, cooled at 0C under argon, PBr 3 (77 pL, 0.82 mmol) was slowly added. The reaction was stirred at 20 09C for 1 h, then at room temperature overnight. It was quenched with a saturated solution of NaHCO 3 , extracted with DCM and the combined organic extracts were washed with a saturated solution of NaCl, dried over anhydrous Na 2
    SO
    4 , filtered and the solvent evaporated. 4-(2-(2-(bromomethyl)-4-chlorophenoxy)ethyl)tetrahydro 2H-pyran was obtained as a white solid (200 mg, 73%). 25 'H NMR CDCI 3 (400 MHz) 7.32 (1H, d, J= 3.4 MHz), 7.23 (1H, dd, J= 11.7, 3.4 MHz), 6.79 (1H, d, J= 11. 7 MHz), 4.49 (2H, s), 4.08 (2H, t, J= 8.2 MHz), 3.98 (2H, dd, J= 14.6, 5.0 MHz), 3.43 (2H, td, J= 14.6, 2.5 MHz), 1.94- 1.31 (7H, m). The following compounds were prepared using the same procedure (steps f, g and 30 h) as in 4-(2-(2-(bromomethyl)-4-chlorophenoxy)ethyl)tetrahydro-2H-pyrane. Intermediate compound Compound name Starting materials
    NMR
    WO 2013/037960 PCT/EP2012/068101 78 Intermediate compound Compound name Starting materials NMR 'H NMR (300 MHz, CDC1 3 ) 6 7.68 5-chloro-2- 7.57 (m, 1 H), 7.45 2-broomethy- hydroxybenzaldeh - 7.38 (m, 1 H), 9chloro-1-((b yde and 1- 7.37 - 7.27 (m, (bromomethyl)-2- 3H), 7.23 (dd, 1 H), enzene chlorobenzene 6.85 (d, 1 H), 5.24 (s, 2H), 4.56 (s, 2H). 'H NMR (300 MHz, CDC1 3 ) 6 7.69 5-fluoro-2- 7.59 (m, 1 H), 7.41 1-(bm e- hydroxybenzaldeh (dd, 1 H), 7.34 9b 1-((2- yde and 1- 7.27 (m, 2H), 7.10 chflorobenze- (bromomethyl)-2- (dd, 1 H), 6.97 4-flIuorobenzene chlorobenzene (ddd, 1 H), 6.86 (dd, 1H), 5.22 (s, 2H), 4.58 (s, 2H). 'H NMR (300 MHz, CDC1 3 ) 6 7.67 5-fluoro-2- 7.51 (m, 1 H), 7.33 2-(brome-h((2- hydroxybenzaldeh (tdd, 1H), 7.19 (td, 9c fluoro-1 -((2-yde and 1- 1H), 7.14 - 7.03 (bromomethyl)-2- (m, 2H), 7.01 enzene fluorobenzene 6.85 (m, 2H), 5.20 (s, 2H), 4.54 (s, 2H).
    WO 2013/037960 PCT/EP2012/068101 79 Intermediate compound Compound name Starting materials NMR 'H NMR (300 MHz, CDC1 3 ) 6 7.71 7.62 (m, 1 H), 7.40 2-(bromomethyl)- 2-hydro y (dd, 1 H), 7.35 9d 1-((2- den d eh 7.21 (m, 2H), 7.17 chlorobenzyl)oxy)- (d, 1H), 7.11 - 7.01 4-methylbenzene (broom e (m, 1 H), 6.81 (d, chlorobenzene 1H), 5.23 (s, 2H), 4.62 (s, 2H), 2.28 (s, 3H). 'H NMR (300 MHz,
    CDC
    3 ) 6 7.62 (td, 2-(bromomethyl)- 2-hydroxy 1 H), 7.30 (ddd, 9e 1-((2- eh an d eh 1H), 7.23 - 7.03 fluorobenzyl)oxy)- (m, 4H), 6.85 (d, 4-methylbenzene (bro ethl)2 1 H), 5.20 (s, 2H), fluorobenzene 4.58 (s, 2H), 2.28 (s, 3H). 'H NMR (300 MHz, CDC1 3 ) 6 7.58 (t, 2- 1 H), 7.36 (dd, 1 H), 1 -((2- pehydroxybenzaldeh 7.33 - 7.25 (m, 9fbrommethyl)pe yde and 1- 1H), 7.21 - 7.12 9cmhyl)o-- (bromomethyl)-4- (m, 2H), 7.03 chloro-2 fluorobenzene chloro-2- 6.85 (m, 2H), 5.19 fluorobenzene (s, 2H), 4.60 (s, 2H).
    WO 2013/037960 PCT/EP2012/068101 80 Intermediate compound Compound name Starting materials NMR 'H NMR (300 MHz, 5-chloro-2- CDC1 3 ) 6 7.51 2-boromomethy- hydroxybenzaldeh 7.31 (m, 5H), 7.23 9g chloro-1-((4- yde and 1- (dd, 1H), 6.83 (d, (bromomethyl)-4- 1H), 5.12 (s, 2H), enzene chlorobenzene 4.53 (s, 2H). 'H NMR (300 MHz, CDC1 3 ) 6 7.06 (dd, 5-fluoro-2- 1 H), 6.95 (ddd, 2-( oroomethy- hydroxybenzaldeh 1 H), 6.77 (dd, 1 H), 4-flIuoro-1 9h yde and 1-bromo- 4.52 (s, 2H), 3.76 2-methylpropane (d, 2H), 2.14 (hept, 1 H), 1.08 (d, 6H). 'H NMR (300 MHz, CDC1 3 ) 6 7.06 (dd, 1H), 6.92 (ddd, 1H), 6.65 (dd, 1H), 2-(bromomethyl)- 5-fluoro-2- 4.65 (p, 1 H), 4.51 hydroxybenzaldeh (s, 2H), 2.52 fi 1cycobutox- yde and 2.35 (m, 2H), 2.30 fluorobenzene bromocyclobutane - 2.10 (m, 2H), 1.94 - 1.81 (m, 1 H), 1.76 - 1.61 (m, 1H).
    WO 2013/037960 PCT/EP2012/068101 81 Intermediate compound Compound name Starting materials NMR 'H NMR (300 MHz, CDC1 3 ) 6 7.30 (d, 1H), 7.18 (dd, 1H), 6.64 (d, 1 H), 4.67 2-(bromomethyl)- 5-chloro-2- (p, 1 H), 4.49 (s, 4-chloro-1- hydroxybenzaldeh 2H), 2.57 - 2.36 cyclobutoxybenzen yde and (m, 2H), 2.27 e bromocyclobutane 2.14 (m, 2H), 2.01 - 1.82 (m, 1H), 1.78 - 1.62 (m, 1 H). 5 Intermediate compound 10: Synthesis of sodium 1,2,3,4-tetrahydroquinoline 5-sulfonate a) Thionyl chloride (4.2 mL) was added dropwise over 30 min to water (25 mL), cooled to 0 9C, maintaning the temperature of the mixture 0-7 9C. The solution was allowed to warm to 18 9C over 17 h. CuCl (15 mg, 0.14 mmol) was added, and 10 the resulting yellow-green solution was cooled to -3 9C. b) Concentrated hydrochloric acid (14 mL) was cooled to 0 9C for the portionwise addition of quinolin-5-amine (2 g, 13.9 mmol). This was allowed to warm sligthly between additions. After complete addition and at -5 9C a solution of sodium 15 nitrite (1.053 g, 15.3 mmol) in water (4 mL) was added dropwise over 45 min, maintaining the temperature of the reaction mixture between -5 to 0 9C. c) The slurry from step b, was cooled to -5 9C and added dropwise to the solution obtained from step a over 30 min, maintaining the temperature of the 20 reaction mixture between -3 to 0 9C (the slurry from step b was maintained at -5 9C throughout the addition). When the addition was complete, the reaction mixture was WO 2013/037960 PCT/EP2012/068101 82 agitated at 0 9C for 90 min. The solid precipitated was filtered, washed with water and dried under vacuum at 40 9C to give quinoline-5-sulfonyl chloride (1.5 g, 48% yield) as a red-orange solid. 'H NMR (400 MHz, Chloroform-d) 6 9.18 (dt, J = 8.7, 0.8 Hz, 1H), 9.12 (dd, J 5 = 4.3, 1.6 Hz, 1 H), 8.57 (d, J = 8.5 Hz, 1 H), 8.45 (dd, J = 7.6, 1.2 Hz, 1 H), 7.89 (dd, J = 8.5, 7.6 Hz, 1 H), 7.75 (dd, J = 8.8, 4.3 Hz, 1 H). d) Quinoline-5-sulfonyl chloride (500 mg, 2.2 mmol) was suspended in 10 mL of dioxane at RT. Sodium hydroxide (88 mg, 2.2 mmol) in 5 mL of water was added 10 followed by the addition of 1 mg of DMAP. The progress of the reaction was followed by hplc-mass. After 3h at 60 9C the solvents were removed under vacuum. The solid obtained was washed with cold EtAcO. 'H NMR (400 MHz, DMSO-d6) o 9.18 (dd, J = 8.7, 1.7 Hz, 1H), 8.88 (dd, J = 4.1, 1.8 Hz, 1 H), 7.98 (2H), 7.68 (t, J = 7.8 Hz, 1 H), 7.54 (dd, J = 8.6, 4.1 Hz, 1 H). 15 e) 330 mg of quinoline-5-sulfonic acid (1.43 mmol) were suspended in MeOH (25 mL) and Pd/C 10% was added (200 mg). The mixture was hydrogenated (H2 balloon) at RT. The progress of the reaction was followed by hplc-mass. After 4 hours the suspension was passed through a plug of Celite. The filtrate was 20 evaporated and the product was obtained as colorless oil (330 mg, 98% yield). 'H NMR (500 MHz, Deuterium Oxide) 6 7.31 (dd, J = 7.8, 1.2 Hz, 1H), 7.14 (t, J = 7.9 Hz, 1H), 6.86 (dd, J = 8.1, 1.3 Hz, 1H), 3.26 - 3.20 (m, 2H), 3.10 (t, J = 6.5 Hz, 2H), 1.98 - 1.90 (m, 2H). 25 Intermediate compound 11: Synthesis of methyl 3-formyl-1H-indole-4 carboxylate To a stirred solution of 573 mg (3.27 mmol) of methyl 1 H-indole-4-carboxylate in 6 mL of anhydrous DMF under dry argon atmosphere, 0.9 mL (9.8 mmol) of 30 phosphorus chloride oxide was added at 0 9C and the resulting mixture was stirred at room temperature for 1h. Then, the reaction mixture was poured into cold saturated NaH 2
    CO
    3 aqueous solution and stirred for 30 min. The resultant mixture was extracted with EtAcO (x3). The combined organic layer was dried over anhydrous Na 2
    SO
    4 and filtered. Then, the filtrate was condensed under reduced WO 2013/037960 PCT/EP2012/068101 83 pressure and purified by silica gel flash column chromatography to provide methyl 3 formyl-1 H-indole-4-carboxylate as a white solid (400 mg, 60%). 'H NMR (300 MHz, Chloroform-d) 6 10.49 (s, 1H), 9.93 (br s, 1H, NH), 8.05 5 (d, J= 3.3 Hz, 1H), 7.83 (dd, J= 7.5, 1.0 Hz, 1H), 7.64 (dd, J= 8.2, 1.0 Hz, 1H), 7.31 (t, J= 7.9 Hz, 1 H), 4.00 (s, 3H). Intermediate compound 12: Synthesis of ethyl 3-formyl-1H-pyrrolo[2,3 b]pyridine-4-carboxylate 10 a) Under inert atmosphere (glove box), in a stainlees steel high pressure reactor with a capacity of 100 mL and equiped with a magnetic stirrer were placed 4 bromo-1H-pyrrolo[2,3-b]pyridine (1.03 g, 5.2 mmol), Bis(benzonitrile)palladium(II) chloride (21 mg, 0.05 mmol), dppf (87 mg, 0.16 mmol), degassed ethanol (45 mL) and triehtylamine (876 iL, 6.3 mmol). The system was purged three times with CO 15 and pressurized to 25 bar. The reactor was warmed to 130 9C and stirred at 600 rpm overnight. Then was cooled to RT and DCM was added. The organic phase was washed with water, dried with MgSO4 and concentrated under reduced pressure. The crude was submitted to flash chromatography through silica gel eluting with Cyclohexane:EtAcO (4:1 to 2:1) to obtain 700 mg (70% yield) of ethyl 20 1 H-pyrrolo[2,3-b]pyridine-4-carboxylate as a slightly yellow solid. 'H NMR (300 MHz, CDCl3) 6 8.59 (s, 1H), 7.90 (dd, J = 8.4, 4.8 Hz, 1H), 7.36 (t, J = 2.8 Hz, 1H), 7.22 (dd, J = 5.6, 3.3 Hz, 1H), 6.94 (dd, J = 10.4, 8.4 Hz, 1 H), 4.45 (q, J = 7.1 Hz, 2H), 1.46 (t, J = 7.1 Hz, 3H). 25 b) ethyl 1 H-pyrrolo[2,3-b]pyridine-4-carboxylate (387 mg, 2.0 mmol) was suspended in 4 mL of AcOH 33%. HMTA (428 mg, 3.1 mmol) was added in one portion and the suspension was refluxed overnight. After 16 hours the mixture was cooled to RT and water was added. The reaction was filtrated and washed with 30 water to give the desired product as a white solid. 'H NMR (300 MHz, DMSO-d6) 6 13.06 (br s, 1H, NH), 10.09 (s, 1H), 8.55 (s, 1 H), 8.47 (d, J = 4.8 Hz, 1 H), 7.48 (d, J = 4.9 Hz, 1 H), 4.40 (q, J = 7.1 Hz, 2H), 1.30 (t, J = 7.1 Hz, 3H).
    WO 2013/037960 PCT/EP2012/068101 84 Intermediate compound 13: Synthesis of methyl 3-formyl-1H-indazole-4 carboxylate Procedure according to WO 2011/140325 5 'H NMR (300 MHz) CDCI 3 10.81 (1H, s), 8.10 (1H, d, J= 8.4 MHz), 8.10 (1H, d, J= 7.2 MHz), 7.56 (1H, t, J = 7.8 MHz). Intermediate compound 14: Synthesis of N-((1,2,3,4-tetrahydroquinolin-5 yl)sulfonyl)acetamide 10 a) An aqueous solution of NH40H (45 mL of 30% w/v) was added to a cold (09C) solution of quinoline-5-sulfonyl chloride (1 g, 4.4 mmol) in dioxane (35 mL) and the reaction was allowed to proceed overnight at RT. Water was added and extracted twice with EtAcO and twice with DCM. The combined organic fractions were dried and the solvent was evaporated to afford quinoline-5-sulfonamide as a 15 slighly brown solid /750 mg, 82% yield) 'H NMR (400 MHz, Chloroform-d) 6 9.13 - 8.92 (m, 2H), 8.36 (d, J = 7.9 Hz, 2H), 7.80 (t, J = 7.9 Hz, 1 H), 7.61 (dd, J = 8.7, 4.1 Hz, 1 H), 4.95 (s, 2H). b) Acetic anhydride (1 mL, 10.1 mmol) and DMAP (123 mg, 1.01 mmol) were 20 added to a suspension of quinoline-5-sulfonamide (700 mg, 3.36 mmol) in pyridine 2 mL and the reaction was allowed to proceed at RT with stirring for 6 h. HPLC-mass spectra showed complete conversion. EtAcO (150 mL) was added and this solution was washed twice with NH4CI sat (50 mL) and H20 (2 x 50 mL). The organic fraction was dried (Mg2SO4) and the solvent was removed in vacuo to 25 afford N-(quinolin-5-ylsulfonyl)acetamide as a slightly yellow solid. (350 mg, 42% yield) 'H NMR (300 MHz, Chloroform-d) 6 9.12 - 8.96 (m, 2H), 8.53 (dd, J = 7.5, 1.3 Hz, 1 H), 8.43 (dt, J = 8.4, 1.1 Hz, 1 H), 7.86 (dd, J = 8.5, 7.5 Hz, 1 H), 7.61 (dd, J 30 = 8.8, 4.2 Hz, 1 H), 2.05 (s, 3H). c) 330 mg of N-(quinolin-5-ylsulfonyl)acetamide (1.32 mmol) were suspended in MeOH (25 mL) and Pd/C 10% was added (281 mg). The mixture was WO 2013/037960 PCT/EP2012/068101 85 hydrogenated (H2 balloon) at RT. The progress of the reaction was followed by hplc-mass. 3h-complete conversion. The suspension was passed through a plug of Celite, and the solvent removed using a rotatory evaporator. (330 mg, 98% yield) Slighlty brown 5 foam. 'H NMR (500 MHz, Chloroform-d) 6 7.39 (dd, J = 7.9, 1.1 Hz, 1H), 7.08 (t, J = 8.0 Hz, 1H), 6.69 (dd, J = 8.1, 1.2 Hz, 1H), 3.36 - 3.26 (m, 2H), 3.10 (t, J = 6.4 Hz, 2H), 2.11 (s, 3H), 2.01 - 1.92 (m, 2H). 10 Intermediate compound 15: Synthesis of (1H-indol-7-y)boronic acid KH (62 mg, 1.53 mmol) was suspended in anhydrous THF (0.4 ml) under an argon atmosphere at 0 0C in a flask protected from light. 7-Bromoindole (300 mg, 1.53 mmol) in anhydrous THF (2.6 ml) was added and the mixture stirred for 15 min. 15 After cooling to -78 0C a solution of tBuLi in pentane (3.1 mmol), previously cooled to -78 9C, was added dropwise. The mixture was brought to rt and stirred for 15 min and re-cooled to -78 9C. B(OMe) 3 (341 1tl, 1.53 mmol) was added and stirring was continued for a further 3h at rt. H 2 0 (5 ml) was added and the mixture was extracted with EtAcO (2x10 ml). The aqueous phase was acidified to pH 1 with 10% HCI and 20 was re-extracted with EtAcO (3x10 ml). The combined organic extracts were dried over anhydrous MgSO 4 and filtered. The solvents were evaporated leaving the crude indolylboronic acid as a pale brown oil. 'H NMR (400 MHz, Chloroform-d) 6 9.52 (s, 1H), 8.03 (dd, J = 7.1, 1.2 Hz, 1H), 7.98 - 7.92 (m, 1H), 7.43 (dd, J = 3.2, 2.2 Hz, 1H), 7.33 (dd, J = 7.8, 7.0 Hz, 25 1 H), 6.68 (dd, J = 3.3, 2.0 Hz, 1 H). Intermediate compound 16: Synthesis of methyl 3,4-dihydro-2H benzo[b][1,4]oxazine-8-carboxylate To a solution of methyl 2-hydroxy-3-nitrobenzoate (11.1 mmol, 2.18 g) in 30 EtAcO (55 mL), 10% Pd/C was added. It was stirred at room temperature under H 2 atmosphere (1 atm) until consumption of starting material (TLC). It was filtered through Celite washing with more EtAcO. The solvent was removed under vacuum and the brownish solid was used without further purification.
    WO 2013/037960 PCT/EP2012/068101 86 b) To a solution of methyl 3-amino-2-hydroxybenzoate (11 mmol, 1.84 g) in dry DMF (55 mL), were added oven-dried K 2
    CO
    3 (33 mmol, 4.56 g) and 1,2-dibromoethane (13.2 mmol, 1.14 mL). It was stirred at 1209C until consumption of starting material. Then, it was cooled, quenched with water and extracted with EtAcO (x3). The 5 organic phases were washed with brine (x2) and solvent was evaporated. The crude product was purified by column chromatography, eluting with cyclohexane/EtAcO 2:1, to yield methyl 3,4-dihydro-2H-benzo[b][1,4]oxazine-8-carboxylate as a brown oil (81 %). 10 'H NMR (400 MHz, CDC1 3 ) 6 7.15 (dd, 1H), 6.79 - 6.68 (m, 2H), 4.36 - 4.30 (m, 2H), 3.95 (s, 1 H), 3.88 (s, 3H), 3.47 - 3.40 (m, 3H). Intermediate compound 17: Synthesis of ethyl 8-isobutoxy-1,2,3,4 tetrahydroquinoline-5-carboxylate 15 a) To a solution of 5-bromohydroxyquinoline in DMF, K 2
    CO
    3 was added giving a bright yellow solution. 2-Methylbromopropane was added dropwise and the mixture was stirred at 809C until total consumption of the starting quinolone. Then it was cooled, quenched with water and extracted with EtAcO (x3); the organic phases were washed with brine (x2) and dried with MgSO 4 . Solvent was removed and the 20 crude product was purified by SiO 2 CombiFlash chromatography, eluting with a gradient of cyclohexane/EtAcO from 9:1 to 1:1. The pure product was obtained as a yellowish solid (60% yield). 'H NMR (400 MHz, Chloroform-d) 6 8.97 (dd, 1H), 8.48 (dd, 1H), 7.70 (d, 1 H), 7.52 (dd, 1 H), 6.93 (d, 1 H), 3.98 (d, 2H), 2.39 (hept, 1 H), 1.11 (d, 6H). 25 b) Under inert atm (glove box), in a stainless high pressure reactor equipped with a stir bar, were placed 5-bromo-8-isobutoxyquinoline, palladium catalyst, dppf, degassed TEA and degassed EtOH. The system was purged with CO (x3) and pressurized to 25 bar. The reactor was warmed to 1309C and stirred at 600 rpm 30 overnight. Then the system was cooled, depressurized and the mixture diluted with DCM. This organic phase was washed with water, dried with MgSC 4 and solvents were removed under vacuum. The crude product was purified by SiC 2 CombiFlash chromatography, eluting with a gradient of cyclohex/EtAcO from 9:1 to 1:1, yielding the pure product as a yellow oil (91%).
    WO 2013/037960 PCT/EP2012/068101 87 'H NMR (300 MHz, Chloroform-d) 6 9.46 (dd, 1H), 8.98 (dd, 1H), 8.31 (d, 1H), 7.53 (dd, 1H), 7.03 (d, 1H), 4.44 (q, 2H), 4.06 (d, 2H), 2.42 (hept, 1H), 1.45 (t, 4H), 1.12 (d, 6H). 5 c) To a solution of ethyl 8-isobutoxyquinoline-5-carboxylate in acetic acid, sodium cyanoborohydride was added carefully in three portions, over 15 minutes at room temperature. After 2 h, there was no starting material left (TLC). The mixture was diluted with water, basified with NaOH 2M, extracted with DCM (x5), washed with brine and dried over MgSO 4 . The crude product was purified by SiO 2 10 Combiflash chromatography, eluting with a gradient of cyclohex/EtAcO from 9:1 to 1:1. The pure product was obtained as colorless oil (60% yield). 'H NMR (300 MHz, Chloroform-d) 6 7.27 (d, 2H), 6.59 (d, 1H), 4.38 (s, 1H), 4.29 (q, 3H), 3.78 (d, 2H), 3.44 - 3.25 (m, 2H), 3.12 (t, 2H), 2.13 (hept, 1 H), 2.03 1.83 (m, 2H), 1.36 (t, 3H), 1.04 (d, 6H). 15 Intermediate compound 18: Synthesis of (E)-methyl 3-(3-ethoxy-3-oxoprop-1 en-1-yI)-1H-indole-4-carboxylate To a suspension of NaH 60% in mineral oil (118 mg, 3.0 mmol) in 5 mL of benzene under argon and cooled at 09C triethyl phosphonoacetate (0.6 mL, 3.0 mmol) was 20 added dropwise (caution: gases evolve). The mixture was stirred at 0C for 20 min, then dihydromethyl 3-formyl-1 H-indole-4-carboxylate (200 mg, 1.0 mmol) was added as a solution in 5 mL of benzene. Reaction was stirred at room temperature for 2 hours. Then it was quenched with a saturated solution of NH 4 CI, extracted with EtAcO and the combined organic layers washed with water and brine and dried over 25 MgSO 4 . The crude was purified by column chromatography over silica gel eluting with mixtures of cyclohexane/EtAcO. (E)-methyl 3-(3-ethoxy-3-oxoprop-1-en-1-yl) 1 H-indole-4-carboxylate was obtained (220 mg, 82%). 'H NMR CDCI 3 (300 MHz) 8.99 (1H, bs), 8.42 (1H, d, J= 15.8 MHz), 7.80 30 (1 H, d, J = 7.7 MHz), 7.68 (1 H, d, J = 2.7 MHz), 7.58 (1 H, d, J = 7.7 MHz), 7.27 (1 H, t, J= 7.7 MHz), 6.16 (1H, d, J= 15.8 MHz), 4.28 (2H, q, J= 7.1 MHz), 4.01 (3H, s), 1.35 (3H, t, J= 7.1 MHz). Intermediate compound 19: Synthesis of 2-(bromomethyl)-4-chloro-1-(3 35 fluoro-2-methylpropoxy)benzene WO 2013/037960 PCT/EP2012/068101 88 a) 3-hydroxy-2-methylpropyl 4-methylbenzenesulfonate p-TsCI (1.00 g, 5.25 mmol) was added to a solution of 2-methylpropane-1,3-diol (2.30 mL, 26.23 mmol) and TEA (1.50 mL, 10.50 mmol) in DCM (20 mL) and stirred at room temperature. After 4 h, the reaction mixture was diluted with DCM (40 mL) 5 and washed with water (30 mL). The organic layer was dried over anhydrous Na 2
    SO
    4 and filtered. After removal of the solvent, the residue was purified by column chromatography on silica gel (15--50% EtAcO/hexanes), affording 0.86 g of 3 hydroxy-2-methylpropyl 4-methylbenzenesulfonate [Rf= 0.40 (40% EtAcO/hexanes), colorless oil, 67% yield]. 10 LC-MS ESI+ m/z: 245 (M+1, 99%) (method 5). b) 5-chloro-2-(3-hydroxy-2-methylpropoxy)benzaldehyde Following the general procedure, the title compound was obtained in 46% yield (pale yellow oil) after stirring at 80 0C for 17 h, using 5-chloro-2-hydroxybenzaldehyde 15 (2.27 g, 14.48 mmol), K 2
    CO
    3 (2.00 g, 14.48 mmol) and 3-hydroxy-2-methylpropyl 4 methylbenzenesulfonate (2.95 g, 12.07 mmol) as starting materials. LC-MS ESI+ m/z: 229 (M+1, 92%) (method 5). c) 3-(4-chloro-2-formylphenoxy)-2-methylpropy trifluoromethanesulfonate 20 Tf 2 0 (1.67 mL, 6.12 mmol) was added dropwise to a solution of 5-chloro-2-(3 hydroxy-2-methylpropoxy)benzaldehyde (1.40 g, 6.12 mmol) and DIPEA (2.10 mL, 12.24 mmol) in DCM (20 mL) cooled at -78 0C. After 15 min, the reaction mixture was diluted with DCM (20 mL) and washed with water (20 mL). The organic layer was dried over anhydrous Na 2
    SO
    4 and filtered. After removal of the solvent, 2.90 g 25 of 3-(4-chloro-2-formylphenoxy)-2-methylpropy trifluoromethanesulfonate were obtained [Rf= 0.60 (40% EtAcO/hexanes), brown solid, 100% yield], that were used without further purification. d) 5-chloro-2-(3-fluoro-2-methylpropoxy)benzaldehyde 30 TBAF (9.18 mL of 1 M solution in THF, 9.18 mmol) was added dropwise to a solution of 3-(4-chloro-2-formylphenoxy)-2-methylpropyl trifluoromethanesulfonate (2.20 g, 6.12 mmol) in THF (20 mL) cooled at 0 0C, and the mixture was allowed to reach room temperature. After 2 h, the solvent was removed by rotatory evaporation and the resulting residue was dissolved in EtAcO (40 mL) and washed with water WO 2013/037960 PCT/EP2012/068101 89 (30 mL). The organic layer was dried over anhydrous Na 2
    SO
    4 and filtered. After removal of the solvent, the residue was purified by column chromatography on silica gel (5--15% EtAcO/hexanes), affording 0.63 g of 5-chloro-2-(3-fluoro-2 methylpropoxy)benzaldehyde [Rf= 0.70 (30% EtAcO/hexanes), pale yellow oil, 45% 5 yield]. LC: purity 93% (method 5). 'H-NMR (CDC1 3 , 250 MHz, 6): 10.42 (s, 1H, CHO); 7.77 (d, J= 2.9 Hz, 1H, ArH); 7.48 (dd, J= 9.0, 2.9 Hz, 1 H, ArH); 6.95 (d, J= 9.0 Hz, 1 H, ArH); 4.68-4.38 (m, 2H); 4.12-3.98 (m, 2H); 2.52-2.27 (m, 1H); 1.13 (dd, J= 6.8, 1.0 Hz, 3H). 10 e) [5-chloro-2-(3-fluoro-2-methylpropoxy)phenyl]methanol Following the general procedure described in intermediate compound 1, section b, the title compound was obtained in 73% yield (colorless oil), using 5-chloro-2-(3 fluoro-2-methylpropoxy)benzaldehyde (0.66 g, 2.86 mmol) and NaBH 4 (0.11 g, 2.86 15 mmol) as starting materials. LC: purity 96% (method 5). 'H-NMR (CDC1 3 , 250 MHz, 6): 7.30 (d, J= 2.8 Hz, 1H, ArH); 7.20 (dd, J= 8.6, 2.8 Hz, 1H, ArH); 6.79 (d, J= 8.6 Hz, 1H, ArH); 4.66 (s, 2H); 4.64-4.32 (m, 2H); 4.02 3.90 (m, 2H); 2.47-2.25 (m, 1H); 1.99 (br s, 1H, OH); 1.10 (d, J= 7.8 Hz, 3H). 20 f) 2-(bromomethyl)-4-chloro-1 -(3-fluoro-2-methylpropoxy)benzene Following the general procedure described in intermediate compound 1, section c, the title compound was obtained in 98% yield (pale yellow oil), using [5-chloro-2-(3 fluoro-2-methylpropoxy)phenyl]methanol (0.48 g, 2.04 mmol) and PBr 3 (0.19 mL, 25 2.04 mmol) as starting materials. Intermediate compound 20: Synthesis of 2-(bromomethy)-4-chloro-1-(2 fluoropropoxy)benzene a) 4-chloro-2-(1,3-dioxolan-2-yl)phenol 30 A solution of 5-chloro-2-hydroxybenzaldehyde (5.00 g, 31.93 mmol), ethylene glycol (5.40 mL, 95.79 mmol) and p-TsOH (0.30 g, 1.60 mmol) in toluene (50 mL) was refluxed connected to a Dean-Stark apparatus. After 32 h, the reaction was allowed to reach room temperature, diluted with EtAcO (40 mL) and washed with water (2 x 30 mL). The organic layer was dried over anhydrous Na 2
    SO
    4 and filtered. After WO 2013/037960 PCT/EP2012/068101 90 removal of the solvent, the residue was purified by column chromatography on silica gel (5D10% EtAcO/hexanes), affording 3.40 g of 4-chloro-2-(1,3-dioxolan-2 yl)phenol [Rf= 0.40 (20% EtAcO/hexanes), white solid, 53% yield]. "H-NMR (CDC1 3 , 250 MHz, 6): 7.72 (s, 1H, ArH); 7.25-7.17 (m, 2H, ArH+OH); 6.83 5 (d, J= 7.7 Hz, 1 H, ArH); 5.92 (s, 1 H); 4.18-4.04 (m, 4H). b) 1-[4-chloro-2-(1,3-dioxolan-2-yl)phenoxy]acetone A mixture of 1-chloroacetone (0.29 mL, 3.59 mmol), K 2
    CO
    3 (0.62 g, 4.49 mmol) and 4-chloro-2-(1,3-dioxolan-2-yl)phenol (0.60 g, 2.99 mmol) in DMF (15 mL) was stirred 10 at room temperature for 2 h. The reaction mixture was poured over EtAcO (80 mL) and washed with water (2 x 30 mL); the organic layer was dried over anhydrous Na 2
    SO
    4 and filtered. After removal of the solvent, the residue was purified by column chromatography on silica gel (40% EtAcO/hexanes), affording 0.69 g of 1-[4-chloro 2-(1,3-dioxolan-2-yl)phenoxy]acetone [Rf= 0.25 (30% EtAcO/hexanes), pale yellow 15 solid, 90% yield]. LC-MS ESI+ m/z: 257 (M+1, 98%) (method 5). "H-NMR (CDC1 3 , 250 MHz, 6): 7.54 (d, J= 2.7 Hz, 1H, ArH); 7.26 (dd, J= 8.9, 2.7 Hz, 1H, ArH); 6.67 (d, J= 8.9 Hz, 1H, ArH); 6.20 (s, 1H); 4.56 (s, 2H); 4.18-4.01 (m, 4H); 2.29 (s, 3H). 20 c) 1 -[4-chloro-2-(1,3-dioxolan-2-yl)phenoxy]propan-2-ol NaBH 4 (0.12 g, 3.20 mmol) was added in small portions to a solution of 1-[4-chloro 2-(1,3-dioxolan-2-yl)phenoxy]acetone (0.77 g, 2.99 mmol) in MeOH (15 mL) cooled at 0 0C, observing gas evolution. After 10 min, the solvent was removed by rotatory 25 evaporation and the resulting residue was dissolved in DCM (20 mL), acidified with HCI (aqueous solution 10%, 3 mL), and washed with water (20 mL). The organic layer was dried over anhydrous Na 2
    SO
    4 and filtered. After removal of the solvent, the residue was purified by column chromatography on silica gel (30D45% EtAcO/hexanes), affording 0.53 g of 1-[4-chloro-2-(1,3-dioxolan-2 30 yl)phenoxy]propan-2-ol [Rf= 0.33 (40% EtAcO/hexanes), colorless oil, 69% yield]. LC-MS ESI+ m/z: 259 (M+1, 93%) (method 5). d) 2-[5-chloro-2-(2-fluoropropoxy)phenyl]-1,3-dioxolane WO 2013/037960 PCT/EP2012/068101 91 DAST (0.50 g, 3.07 mmol) was added dropwise to a solution of 1-[4-chloro-2-(1,3 dioxolan-2-yl)phenoxy]propan-2-ol (0.53 g, 2.05 mmol) in DCM (15 mL) cooled at 0 0C, and the mixture was allowed to reach room temperature. After 1.5 h, the reaction mixture was diluted with DCM (15 mL) and washed with water (20 mL). The organic 5 layer was dried over anhydrous Na 2
    SO
    4 and filtered. After removal of the solvent, the residue was purified by column chromatography on silica gel (8->15% EtAcO/hexanes), affording 0.30 g of 2-[5-chloro-2-(2-fluoropropoxy)phenyl]-1,3 dioxolane [Rf= 0.50 (20% EtAcO/hexanes), pale yellow oil, 58% yield]. LC-MS ESI+ m/z: 261 (M+1, 97%) (method 5). 10 e) 5-chloro-2-(2-fluoropropoxy)benzaldehyde PPTS (48 mg, 0.19 mmol) was added to a suspensi6n of 2-[5-chloro-2-(2 fluoropropoxy)phenyl]-1,3-dioxolane (0.50 g, 1.92 mmol) in a mixture of water (1 mL) and acetone (5 mL), and the reaction was heated at reflux for 6 h. The reaction was 15 allowed to reach room temperature and the volatiles were removed by rotatory evaporation; the resulting residue was dissolved in EtAcO (30 mL) and washed with water (30 mL) and NaOH (10%, 10 mL). The organic layer was dried over anhydrous Na 2
    SO
    4 and filtered. After removal of the solvent, 0.42 g of 5-chloro-2-(2 fluoropropoxy)benzaldehyde were obtained [Rf= 0.50 (20% EtAcO/hexanes), pale 20 yellow oil, 100% yield, crude], that were used without further purification. "H-NMR (CDC1 3 , 250 MHz, 6): 10.45 (s, 1H, CHO); 7.80 (d, J= 2.7 Hz, 1H, ArH); 7.49 (dd, J= 9.1, 2.7 Hz, 1H, ArH); 6.93 (d, J= 9.1 Hz, 1H, ArH); 5.23-4.90 (m, 1H); 4.22-4.10 (m, 2H); 1.56-1.42 (m, 3H). f) [5-chloro-2-(2-fluoropropoxy)phenyl]methanol 25 Following the general procedure described in intermediate compound 1, section b, the title compound was obtained in 71% yield (colorless oil), using 5-chloro-2-(2 fluoropropoxy)benzaldehyde (0.60 g, 2.77 mmol) and NaBH 4 (0.10 g, 2.77 mmol) as starting materials. "H-NMR (CDC1 3 , 250 MHz, 6): 7.31 (d, J= 2.8 Hz, 1H, ArH); 7.21 (dd, J= 8.6, 30 2.8 Hz, 1H, ArH); 6.77 (d, J= 8.6 Hz, 1H, ArH); 5.18-4.86 (m, 1H); 4.68 (dd, J= 15.5, 13.5 Hz, 2H); 4.15-3.99 (m, 2H); 1.92 (br s, 1 H, OH); 1.46 (dd, J= 23.5, 6.5 Hz, 3H). g) 2-(bromomethyl)-4-chloro-1 -(2-fluoropropoxy)benzene WO 2013/037960 PCT/EP2012/068101 92 Following the general procedure described in intermediate compound 1, section c, the title compound was obtained in 91% yield (pale yellow oil), using [5-chloro-2-(2 fluoropropoxy)phenyl]methanol (0.46 g, 2.09 mmol) and PBr 3 (0.20 mL, 2.09 mmol) as starting materials. 5 Intermediate compound 21: Synthesis of 5-chloro-2-(1,2 dimethylpropoxy)benzaldehyde a)N-(tert-butyl)-N-{(1 E)-[5-chloro-2-(1,2-dimethylpropoxy)phenyl]methylene} amine 10 3-methylbutan-2-ol (0.41 mL, 3.84 mmol) was added to a suspension of NaH [0.15 g (60% oil dispersion) 3.84 mmol] in 1,4-dioxane (10 mL) and heated at 50 0C. After 30 min, a solution of N-(tert-butyl)-N-[(1 E)-(5-chloro-2-fluorophenyl)methylene]amine (0.41 g, 1.92 mmol) in 6 mL of 1,4-dioxane was transferred via canula and the resulting mixture was heated at 70 0C for 15 h. The volatiles were removed by 15 rotatory evaporation; the resulting residue was dissolved in EtAcO (40 mL) and washed with water (30 mL). The organic layer was dried over anhydrous Na 2
    SO
    4 and filtered. After removal of the solvent, 0.60 g of N-(tert-butyl)-N-{(1 E)-[5-chloro-2 (1,2-dimethylpropoxy)phenyl]methylene}amine were obtained [Rf= 0.60 (10% EtAcO/hexanes), pale yellow oil, 100% yield, crude], that were used without further 20 purification. N-(tert-butyl)-N-[(1 E)-(5-chloro-2-fluorophenyl)methylene]amine was prepared following the method described in: Larock, R. C. et al J. Org. Chem. 2001, 66, 8042 8051. 25 b) 5-chloro-2-(1,2-dimethylpropoxy)benzaldehyde The crude N-(tert-butyl)-N-{(1 E)-[5-chloro-2-(1,2 dimethylpropoxy)phenyl]methylene}amine, obtained in the previous step (1.92 mmol), was dissolved in a mixture of THF (6 mL), water (6 mL) and AcOH (1 mL) and stirred at room temperature. After 1 h, THF was removed by rotatory 30 evaporation and the resulting residue was diluted with EtAcO (30 mL) and washed with water (20 mL) and NaOH (aqueous solution 10%, 5 mL). The organic layer was dried over anhydrous Na 2
    SO
    4 and filtered. After removal of the solvent, 0.50 g of 5 chloro-2-(1,2-dimethylpropoxy)benzaldehyde were obtained [Rf= 0.60 (10% WO 2013/037960 PCT/EP2012/068101 93 EtAcO/hexanes), pale yellow oil, 100% yield, crude], that were used without further purification. "H-NMR (CDC1 3 , 250 MHz, 6): 10.44 (s, 1H, CHO); 7.77 (d, J= 2.8 Hz, 1H, ArH); 7.45 (dd, J= 9.0, 2.8 Hz, 1 H, ArH); 6.93 (d, J= 9.0 Hz, 1 H, ArH); 4.34-4.23 (m, 5 1H); 2.08-1.92 (m, 1H); 1.29 (d, J= 6.2 Hz, 3H); 1.02 (d, J= 6.9 Hz, 3H); 0.99 (d, J= 6.6 Hz, 3H). c) [5-chloro-2-(1,2-dimethylpropoxy)phenyl]methanol Following the general procedure described in intermediate compound 1, section b, 10 the title compound was obtained in 77% yield (colorless oil), using 5-chloro-2-(1,2 dimethylpropoxy)benzaldehyde (0.44 g, 1.92 mmol) and NaBH 4 (0.04 g, 0.96 mmol) as starting materials. LC: purity 99% (method 5). 'H-NMR (CDC1 3 , 250 MHz, 6): 7.27 (d, J= 2.7 Hz, 1H, ArH); 7.18 (dd, J= 8.8, 15 2.7 Hz, 1 H, ArH); 6.78 (d, J= 8.8 Hz, 1 H, ArH); 4.72-4.57 (m, 2H); 4.27-4.16 (m, 1 H); 2.30 (t, J= 6.5 Hz, 1H, OH); 2.03-1.88 (m, 1H); 1.24 (d, J= 6.0 Hz, 3H); 1.03-0.95 (m, 6H). d) 2-(bromomethyl)-4-chloro-1 -(1,2-dimethylpropoxy)benzene 20 Following the general procedure described in intermediate compound 1, section c, the title compound was obtained in 95% yield (colorless oil), using [5-chloro-2-(1,2 dimethylpropoxy)phenyl]methanol (0.33 g, 1.44 mmol) and PBr 3 (0.07 mL, 0.72 mmol) as starting materials. 25 Intermediate compound 22: Synthesis of 2-(bromomethyl)-4-chloro-1 (cyclobutyloxy)benzene a) N-(tert-butyl)-N-{(1 E)-[5-chloro-2-(cyclobutyloxy)phenyl]methylene}amine 30 Cyclobutanol (0.20 mL, 2.55 mmol) was added to a stirred suspension of NaH [0.10 g (60% oil dispersion), 2.55 mmol] in 1,4-dioxane (8 mL) observing abundant gas evolution while a viscous solution was formed. After 20 min, a solution of N-(tert butyl)-N-[(1 E)-(5-chloro-2-fluorophenyl)methylene]amine (0.42 g, 1.96 mmol) in 4 mL of 1,4-dioxane was transferred via canula and the resulting mixture was heated WO 2013/037960 PCT/EP2012/068101 94 at 70 0C. After 15 h, the volatiles were removed by rotatory evaporation, rendering a sticky yellow solid, N-(tert-butyl)-N-{(1 E)-[5-chloro-2 (cyclobutyloxy)phenyl]methylene}amine, that was used without further purification. 5 b) 5-chloro-2-(cyclobutyloxy)benzaldehyde The crude N-(tert-butyl)-N-{(1 E)-[5-chloro-2-(cyclobutyloxy)phenyl]methylene}amine obtained in the previous step (1.96 mmol) was dissolved in a mixture of THF (6 mL) and HCI (aqueous solution 10%, 5 mL) and stirred at room temperature. After 1 h, THF was removed by rotatory evaporation and the resulting residue was diluted with 10 EtAcO (30 mL) and washed with NaOH (aqueous solution 10%, 10 mL). The organic layer was dried over anhydrous Na 2
    SO
    4 and filtered. After removal of the solvent, the residue was purified by column chromatography on silica gel (5% EtAcO/hexanes), affording 0.16 g of 5-chloro-2-(cyclobutyloxy)benzaldehyde [Rf= 0.40 (10% EtAcO/hexanes), colorless oil, 39% yield (2 steps)]. 15 LC: purity 93% (method 5). "H-NMR (CDC1 3 , 250 MHz, 6): 10.42 (s, 1H, CHO); 7.77 (d, J= 2.8 Hz, 1H, ArH); 7.43 (dd, J= 8.7, 2.8 Hz, 1 H, ArH); 6.77 (d, J= 8.7 Hz, 1 H, ArH); 4.79-4.65 (m, 1H); 2.58-2.42 (m, 2H); 2.34-2.14 (m, 2H); 2.00-1.66 (m, 2H). 20 c) [5-chloro-2-(cyclobutyloxy)phenyl]methanol Following the general procedure described in intermediate compound 1, section b, the title compound was obtained in 92% yield (white solid), using 5-chloro-2 (cyclobutyloxy)benzaldehyde (0.26 g, 1.23 mmol) and NaBH 4 (0.05 g, 1.23 mmol) as starting materials. 25 LC: purity 86% (method 5). "H-NMR (CDC1 3 , 250 MHz, 6): 7.27 (d, J= 2.8 Hz, 1H, ArH); 7.16 (dd, J= 8.8, 2.8 Hz, 1H, ArH); 6.63 (d, J= 8.8 Hz, 1H, ArH); 4.77-4.57 (m, 3H); 2.54 -2.38 (m, 2H); 2.26-2.06 (m, 2H); 1.96-1.61 (m, 2H + OH). 30 d) 2-(bromomethyl)-4-chloro-1 -(cyclobutyloxy)benzene Following the general procedure described in intermediate compound 1, section c, the title compound was obtained in 90% yield (colorless oil), using [5-chloro-2- WO 2013/037960 PCT/EP2012/068101 95 (cyclobutyloxy)phenyl]methanol (0.47 g, 2.21 mmol) and PBr 3 (0.10 mL, 1.10 mmol) as starting materials. Intermediate compound 23: Synthesis of 2-(bromomethy)-4-choro-1-[(2 5 methylprop-2-enyl)oxy]benzene Following the general procedure described in intermediate compound 1, section a, the title compound was obtained in 81% yield (pale yellow oil) after stirring at room temperature for 1 h, using 5-chloro-2-hydroxybenzaldehyde (1.00 g, 6.38 mmol), NaH [0.28 g (60% oil dispersion), 7.03 mmol] and 3-bromo-2-methylprop-1-ene 10 (0.86 g, 6.38 mmol) as starting materials. LC-MS ESI+ m/z: 211 (M+1, 90%) (method 5). b) {5-chloro-2-[(2-methylprop-2-enyl)oxy]phenyl}methanol Following the general procedure described in intermediate compound 1, section b, 15 the title compound was obtained in 50% yield (yellow oil), using 5-chloro-2-[(2 methylprop-2-enyl)oxy]benzaldehyde (0.54 g, 2.56 mmol) and NaBH 4 (0.05 g, 1.28 mmol) as starting materials. LC-MS ESI- m/z: 181 (M-1, 99%) (method 5). 'H-NMR (CDC1 3 , 250 MHz, 6): 7.30 (d, J= 2.8 Hz, 1H, ArH); 7.19 (dd, J= 8.8, 2.8 Hz, 20 1H, ArH); 6.78 (d, J= 8.8 Hz, 1H, ArH); 5.12-4.99 (m, 2H); 4.69 (d, J= 6.3 Hz, 2H); 4.46 (s, 2H); 2.23 (t, J= 6.3 Hz, 1H, OH); 1.83 (s, 3H). c) 2-(bromomethyl)-4-chloro-1 -[(2-methylprop-2-enyl)oxy]benzene Following the general procedure described in intermediate compound 1, section c, 25 the title compound was obtained in 81% yield (pale yellow oil), using {5-chloro-2-[(2 methylprop-2-enyl)oxy]phenyl}methano (0.26 g, 1.23 mmol) and PBr 3 (0.12 mL, 1.23 mmol) as starting materials. Intermediate compound 24: Synthesis of 2-(bromomethy)-4-chloro-1-[2 30 (fluoromethyl)prop-2-enyl]oxyjbenzene a) 5-chloro-2-{[2-(chloromethyl)prop-2-enyl]oxy}benzaldehyde Following the general procedure described in intermediate compound 1, section a, the title compound was obtained in 24% yield (white solid) after stirring at room temperature for 20 h, using 5-chloro-2-hydroxybenzaldehyde (0.50 g, 3.19 mmol), WO 2013/037960 PCT/EP2012/068101 96
    K
    2
    CO
    3 (0.53 g, 3.83 mmol) and 3-chloro-2-(chloromethyl)prop-1-ene (0.44 mL, 3.83 mmol) as starting materials. It was purified by column chromatography on silica gel (1 0--30% EtAcO/hexanes), Rf= 0.40 (10% EtAcO/hexanes). LC: purity 99% (method 5). 5 "H-NMR (CDC1 3 , 250 MHz, 6): 10.44 (s, 1H, CHO); 7.79 (d, J= 2.7 Hz, 1H, ArH); 7.48 (dd, J= 8.8, 2.7 Hz, 1 H, ArH); 6.98 (d, J= 8.8 Hz, 1 H, ArH); 5.47-5.44 (m, 1 H); 5.42-5.38 (m, 1 H); 4.74 (br s, 2H); 4.20 (br s, 2H). b) 5-chloro-2-{[2-(iodomethyl)prop-2-enyl]oxy}benzaldehyde 10 A solution of Nal (0.14 g, 0.98 mmol) and 5-chloro-2-{[2-(chloromethyl)prop-2 enyl]oxy}benzaldehyde (0.16 g, 0.65 mmol) was stirred at room temperature for 14 h. The volatiles were removed by rotatory evaporation; the resulting residue was dissolved in EtAcO (25 mL) and washed with water (10 mL). The organic layer was dried over anhydrous Na 2
    SO
    4 and filtered. After removal of the solvent, 0.22 g of 5 15 chloro-2-{[2-(iodomethyl)prop-2-enyl]oxy}benzaldehyde were obtained [Rf= 0.40 (10% EtAcO/hexanes), pale yellow oil, 100% yield, crude], that were used without further purification. "H-NMR (CDC1 3 , 250 MHz, 6): 10.45 (s, 1H, CHO); 7.81 (d, J= 2.8 Hz, 1H, ArH); 7.50 (dd, J= 9.0, 2.8 Hz, 1 H, ArH); 7.00 (d, J= 9.0 Hz, 1 H, ArH); 5.56-5.53 (m, 20 1 H); 5.35-5.32 (m, 1 H); 4.81 (br s, 2H); 4.03 (br s, 2H). c) 5-chloro-2-{[2-(fluoromethyl)prop-2-enyl]oxy}benzaldehyde TBAF (1.82 mL of 1 M solution in THF, 1.82 mmol) was added dropwise to a solution of 5-chloro-2-{[2-(iodomethyl)prop-2-enyl]oxy}benzaldehyde (0.21 g, 0.62 25 mmol) in THF (4 mL) and the mixture was stirred at room temperature. After 1 h, the reaction was diluted with EtAcO (30 mL) and washed with brine (20 mL). The organic layer was dried over anhydrous Na 2
    SO
    4 and filtered. After removal of the solvent, the residue was purified by column chromatography on silica gel (8% EtAcO/hexanes), affording 0.03 g of 5-chloro-2-{[2-(fluoromethyl)prop-2 30 enyl]oxy}benzaldehyde [Rf= 0.50 (10% EtAcO/hexanes), colorless oil, 21% yield (2 steps)]. "H-NMR (CDC1 3 , 250 MHz, 6): 10.43 (s, 1H, CHO); 7.79 (d, J= 2.8 Hz, 1H, ArH); 7.48 (dd, J= 9.1, 2.8 Hz, 1 H, ArH); 6.96 (d, J= 9.1 Hz, 1 H, ArH); 5.46-5.42 (m, 2H); 4.99 (d, J= 57.3 Hz, 2H); 4.71 (br s, 2H).
    WO 2013/037960 PCT/EP2012/068101 97 d) (5-chloro-2-{[2-(fluoromethyl)prop-2-enyl]oxy}phenyl)methano Following the general procedure described in intermediate compound 1, section b, the title compound was obtained in 56% yield (colorless oil), using 5-chloro-2-{[2 5 (fluoromethyl)prop-2-enyl]oxy}benzaldehyde (0.36 g, 1.56 mmol) and NaBH 4 (0.03 g, 0.78 mmol) as starting materials. "H-NMR (CDC1 3 , 250 MHz, D): 7.32 (d, J= 2.8 Hz, 1 H, ArH); 7.20 (dd, J= 8.5, 2.8 Hz, 1H, ArH); 6.80 (d, J= 8.5 Hz, 1H, ArH); 5.42-5.38 (m, 2H); 4.97 (d, J= 46.8 Hz, 2H); 4.68 (s, 2H); 4.63 (s, 2H). 10 e) 2-(bromomethyl)-4-chloro-1 -{[2-(fluoromethyl)prop-2-enyl]oxy}benzene Following the general procedure described in intermediate compound 1, section c, the title compound was obtained in 83% yield (pale yellow oil), using (5-chloro-2-{[2 (fluoromethyl)prop-2-enyl]oxy}phenyl)methanol (0.20 g, 0.85 mmol) and PBr 3 (0.08 15 mL, 0.85 mmol) as starting materials. Intermediate compound 25: Synthesis of (3-methyloxetan-3-yl)methyl trifluoromethanesulfonate To a solution of (3-methyloxetan-3-yl)methanol (0.58 ml. 5.87 mmol) and TEA (1.63 20 ml, 11.75 mmol) in DCM (29 ml), trifluoromethanesulfonic anhydride (0.98 ml, 5.87 mmol) was added at 09C. The reaction mixture was stirred at 09C for 1 h and then at room temperature for 1h. It was cooled and saturated NaHCO 3 aqueous solution was added. The aqueous layer was extracted with EtAcO (x3). The combined organic layers were washed with brine dried (MgSO4) filtered and concentrated. 25 After removal of the solvent, 1.20 g of the desired compound was obtained (87% yield, crude), that were used without further purification. 'H NMR (300 MHz, DMSO-d6) 6 : 4.48-4.13 (m, 2H); 3.58-3.02 (m, 4H); 1.17 (s, 3H). 30 The following compound was prepared using the same procedure as in intermediate compound 25: WO 2013/037960 PCT/EP2012/068101 98 Intermediate compound Compound name Starting materials NMR 'H NMR (300 MHz, (3-ethyloxetan-3- DMSO-d6) 6 yl)methyl 4.44-4.25 (m, 2H); trifluoromethanesul (3-ethan-3 3.52-2.99 (m, 4H); 25a y~tao fonate 1.17 (t, J= 7.1 Hz, 3H); 0.98-0.71 (m, 2H). Intermediate compound 26: Synthesis of 3-{5-chloro-2-[(4-chloro-2 fluorobenzyl)oxy]benzyl}-1,2,3-oxathiazolidine 2,2-dioxide 5 a) 2-({5-chloro-2-[(4-chloro-2-fluorobenzyl)oxy]benzyl}amino)ethanol 2-aminoethanol (5.98 mL, 98.9 mmol) was added dropwise to a solution of 2 (bromomethyl)-4-chloro-1-[(4-chloro-2-fluorobenzyl)oxy]benzene (4.50 g, 12.4 mmol) in ACN (50 mL) cooled at 0 0C. The reaction was allowed to reach room 10 temperature, while a white precipitate appeared. After 15 h, the volatiles were removed by rotatory evaporation. The residue was dissolved in EtAcO (100 mL) and washed with brine (100 mL) and water (50 mL); the organic layer was dried over anhydrous Na 2
    SO
    4 and filtered. After removal of the solvent, 3.50 g of 2-({5-chloro 2-[(4-chloro-2-fluorobenzyl)oxy]benzyl}amino)ethano were obtained [Rf= 0.15 (5% 15 MeOH/DCM), white solid, 82% yield], that were used without further purification. LC-MS ESI+ m/z: 344 (M+1, 86%) (method 5). b) 3-{5-chloro-2-[(4-chloro-2-fluorobenzyl)oxy]benzyl}-1,2,3-oxathiazolidine 2 oxide 20 A solution of SOC1 2 (0.81 mL, 11.1 mmol) in 10 mL of DCM was added dropwise to a suspension of 2-({5-chloro-2-[(4-chloro-2-fluorobenzyl)oxy]benzyl}amino)ethano (3.48 g, 10.1 mmol) and imidazole (2.75 g, 40.4 mmol) in TEA (3.1 mL, 22.2 mmol) and DCM (100 mL) cooled at 0 0C. The suspension turned into a yellowish solution, and the reaction was allowed to reach room temperature. After 4 h, the mixture was 25 poured over DCM (60 mL) and washed with brine (2 x 40 mL); the organic layer was WO 2013/037960 PCT/EP2012/068101 99 dried over anhydrous Na 2
    SO
    4 and filtered. After removal of the solvent, 4.1 g of 3-{5 chloro-2-[(4-chloro-2-fluorobenzyl)oxy]benzyl}-1,2,3-oxathiazolidine 2-oxide were obtained [Rf= 0.40 (20% EtAcO/hexanes), yellow oil, quantitative yield], that were used without further purification. 5 c) 3-{5-chloro-2-[(4-chloro-2-fluorobenzyl)oxy]benzyl}-1,2,3-oxathiazolidine 2,2-dioxide To an ice-cold solution of crude 3-{5-chloro-2-[(4-chloro-2-fluorobenzyl)oxy]benzyl} 1,2,3-oxathiazolidine 2-oxide (10.1 mmol) in ACN (60 mL) was added RuC 3
    -H
    2 0 10 (52 mg, 0.10 mmol), followed by NalO 4 (3.24 g, 15.2 mmol), and then water (40 mL). The reaction was allowed to reach room temperature over 2 h and stirred for additional 5 h. The mixture was diluted with Et 2 0 (60 mL) and the organic phase was separated. The aqueous phase was extracted with Et 2 0 (2 x 40 mL). The combined organic phase was washed with NaHCO 3 (saturated aqueous solution, 2 15 x 40 mL), dried over anhydrous Na 2
    SO
    4 and filtered. After removal of the solvent, the residue was purified by column chromatography on silica gel (20D30% EtAcO/hexanes), affording 1.31 g of 3-{5-chloro-2-[(4-chloro-2 fluorobenzyl)oxy]benzyl}-1,2,3-oxathiazolidine 2,2-dioxide [Rf= 0.30 (20% EtAcO/hexanes), white solid, 32% yield (3 steps)]. 20 LC-MS ESI- m/z: 404 (M-1, 97%) (method 5). "H-NMR (CDC1 3 , 250 MHz, 6): 7.51-7.10 (m, 5H, ArH); 6.92 (d, J= 8.7 Hz, 1H, ArH); 5.10 (s, 2H); 4.56-4.48 (m, 2H); 4.26 (s, 2H); 3.52-3.43 (m, 2H). The following compounds were prepared using the same procedure as in 25 intermediate compound 26: Intermediate compound Compound name Starting materials
    NMR
    WO 2013/037960 PCT/EP2012/068101 100 Intermediate compound Compound name Starting materials NMR 3-{5-chloro-2 [(2,4- 2-(bromomethyl) difluorobenzyl)ox 4-chloro-1 -[(2,4 26a y]benzyl}-1,2,3- difluorobenzyl)ox oxathiazolidine y]benzene 2,2-dioxide 1 H-NMR (CDCl 3 , 250 MHz, 8): 7.40 7.32 (m, 5H, 3-{5-chloro-2-[(4- 2-(bromomethyl)- ArH); 7.25 (dd, chlorobenzyl)oxy] J= 8.6, 2.8 Hz, 4-ohlIoro-1 -[(4 26b benzyl}-1,2,3- 1 H, ArH); 6.86 (d, oxathiazolidine benzene J= 8.6 Hz, 1 H, benzene 2,2-dioxide ArH); 5.05 (s, 2H); 4.55-4.48 (m, 2H); 4.27 (s, 2H); 3.51-3.44 (m, 2H). 3-{5-chloro-2-[(2- 2-(broioiethyl) fluorobenzyl)oxy] 4-ohIoro-1 -[(2 26c benzyl}-1,2,3- ** oxathazoldine fluorobenzyl)oxy] oxathiazolidine benzene 2,2-dioxide WO 2013/037960 PCT/EP2012/068101 101 Intermediate compound Compound name Starting materials NMR 1 H-NMR (CDCl 3 , 250 MHz, 8): 7.43 3-{5-chloro-2-[(4- 7.02 (i, 6H, fluorobenzyl)oxy] 5-chloro-2-[(4- ArH); 6.88 (d, J= 9.0 Hz, 1H, ArH); 26d benzyl}-1,2,3- fluorobenzyl)oxy] 5.04 (s, 2H); oxathiazolidine benzaldehyde 4.55-4.47 (m, 2,2-dioxide 2H); 4.26 (s, 2H); 3.51-3.43 (m, 2H). 3-[5-chloro-2-(2 fluoro-2- 5-chloro-2-(2 26e methylpropoxy)ben fluoro-2 zyl]-1,2,3- methylpropoxy)ben oxathiazolidine zaldehyde 2,2-dioxide WO 2013/037960 PCT/EP2012/068101 102 Intermediate compound Compound name Starting materials NMR 'H-NMR (CDC1 3 , 250 MHz, 6): 7.33 (d, J= 2.5 Hz, 1H, ArH); 7.23 (dd, J= 8.8, 2.5 Hz, 1H, 3-(5-chloro-2- ArH); 6.80 (d, J= isobutoxybenzyl)- 2-(bromomethyl)- 8.8 Hz, 1H, ArH); 26f 1,2,3- 4-chloro-1- 4.57-4.49 (m, 2H); oxathiazolidine isobutoxybenzene 4.26 (s, 2H); 3.72 2,2-dioxide (d, J= 6.4 Hz, 2H); 3.54-3.46 (m, 2H); 2.19-2.02 (m, 1H); 1.03 (d, J= 6.8 Hz, 6H). * LC-MS ESI- m/z: 388 (M-1, 97%) (method 5). ** LC-MS ESI+ m/z: 372 (M+1, 97%) (method 5). *** LC-MS ESI+ m/z: 338 (M+1, 98%) (method 5). Intermediate compound 27: Synthesis of 1-{5-chloro-2-[(2,4 5 difluorobenzyl)oxy]phenyljmethanamine A suspension of 5-chloro-2-[(2,4-difluorobenzyl)oxy]benzaldehyde (3.20 g, 12.4 mmol), NH 2 OH-HCI (1.29 g, 18.6 mmol) and NaAcO (1.63 g, 19.8 mmol) in EtOH (25 mL) was heated at reflux for 30 min. The reaction was allowed to reach room temperature and EtOH was removed by rotatory evaporation. The resulting residue 10 was dissolved in DCM (60 mL) and washed with brine (2 x 50 mL); the organic layer was dried over anhydrous Na 2
    SO
    4 and filtered. After removal of the solvent, 3.60 g of 5-chloro-2-[(2,4-difluorobenzyl)oxy]benzaldehyde oxime were obtained. This solid was suspended in 25 mL of AcOH and Zn dust (3.24 g, 49.6 mmol) was added in small portions over 2 h. After 3 h, the reaction was filtered through a pad of celite, 15 washing with MeOH. The volatiles were removed by rotatory evaporation and the resulting residue was dissolved in DCM (100 mL) and washed with an aqueous WO 2013/037960 PCT/EP2012/068101 103 saturated solution of NaHCO 3 (50 mL); the organic layer was dried over anhydrous Na 2
    SO
    4 and filtered. After removal of the solvent, the residue was purified by column chromatography on silica gel (7% DCM/MeOH), affording 1.70 g of 1-{5-chloro-2 [(2,4-difluorobenzyl)oxy]phenyl}methanamine [Rf= 0.25 (10% DCM/MeOH), white 5 solid, 52% yield]. LC-MS ESI+ m/z: 284 (M+1, 97%) (method 5). "H-NMR (CDC1 3 , 250 MHz, 6): 7.49-7.38 (m, 1H, ArH); 7.24 (d, J= 2.7 Hz, 1H, ArH); 7.18 (dd, J= 8.8, 2.7 Hz, 1H, ArH); 6.96-6.81 (m , 3H, ArH); 5.08 (s, 2H); 3.80 (s, 2H); 1.61 (br s, 2H, NH 2 ). 10 The following compounds were prepared using the same procedure as in intermediate compound 27: Intermediate compound Compound name Starting materials NMR 'H-NMR (CDC1 3 , 250 MHz, 6): 7.45-7.36 (m, 1H, ArH); 7.25 (d, 1-{5-chloro-2-[(4- J= 2.7 Hz, 1H, chloro-2- chloro-2- ArH); 7.21-7.11 cchloro-2 fluorobenzyl)oxy]p (m, 3H, ArH); 6.84 henyl}methanamin enzldoyb (d, J= 8.7 Hz, 1 H, e ArH); 5.09 (s, 2H); 3.81 (s, 2H); 1.75 (br s, 2H, NH 2
    ).
    WO 2013/037960 PCT/EP2012/068101 104 Intermediate compound Compound name Starting materials NMR 'H-NMR (CDC1 3 , 250 MHz, 6): 7.50 (t, J= 8.1 Hz, 1H, ArH); 7.37 1-{2-[(4-chl~oro-2 2-[(4-chloro-2- 7.22 (m, 2H, ArH); 27b .enylm oxyap fluorobenzyl)oxy]b 7.17-7.04 (m, 2H, enzaldehyde ArH); 6.95-6.85 e (m, 2H, ArH); 5.17 (s, 2H); 4.16 (br s, 2H). "H-NMR (CDC1 3 , 250 MHz, 6): 7.52-7.41 (m, 2-[(2,4- 1H, ArH); 7.29 27c .enylm oxy] difluorobenzyl)oxy] 7.20 (m, 2H, ArH); benzaldehyde 7.00-6.81 (m, 4H, ne ArH); 5.11 (s, 2H); 3.84 (s, 2H). "H-NMR (CDC1 3 , 250 MHz, 6): 7.32 (d, J= 2.6 Hz, 1H, ArH); 7.23 1-[5-chloro-2-(2- 5-chloro-2-(2- (dd, J= 8.7, 2.6 Hz, 27d fluoro-2- fluoro-2- 1H, ArH); 6.79 (d, methylpropoxy)phe methylpropoxy)ben J= 8.7 Hz, 1 H, nyl]methanamine zaldehyde ArH); 3.99 (d, J= 18.4 Hz, 2H); 3.98 (s, 2H); 1.49 (d, J= 21.4 Hz, 6H).
    WO 2013/037960 PCT/EP2012/068101 105 Intermediate compound Compound name Starting materials NMR 'H-NMR (CDC1 3 , 250 MHz, 1-{2-[(2,4- 2-[(2,4- 6): 7.50-7.39 (i, difluorobenzyl)oxy] difluorobenzyl)oxy] 1H, ArH); 7.01 (dd, 27e -J= 8.8, 2.7 Hz, 1H, ArH); 6.96-6.81 fluorophenyllmeth fluorobenzaldehyd ArH); .07 anamne e(m, 4H, ArH); 5.07 anamine e (s, 2H); 3.82 (s, 2H). "H-NMR (CDC1 3 , 250 MHz, 1-{2-[(2,4- 2-[(2,4- 6): 7.52-7.40 (m, difluorobenzyl)oxy] difluorobenzyl)oxy] 1H, ArH); 7.11 27f -5- -5- 6.74 (m, 5H, ArH); methylphenyllmeth methylbenzaldehy 5.08 (s, 2H); 3.81 anamine de (s, 2H); 2.29 (s, 3H). H-NMR (CDC1 3 , 250 MHz, 6): 7.46-7.37 (m, 1-{2-[(4-chloro-2- 2-[(4-chloro-2- 1H, ArH); 7.20 fluorobenzyl)oxy]- fluorobenzyl)oxy]- 7.10 (m, 2H, ArH); 27g 5- 5- 7.05-6.99 (m, 1H, fluorophenyllmeth fluorobenzaldehyd ArH); 6.94-6.84 anamine e (m, 2H, ArH); 5.08 (s, 2H); 3.83 (s, 2H).
    WO 2013/037960 PCT/EP2012/068101 106 Intermediate compound Compound name Starting materials NMR 'H-NMR (DMSO-d6, 250 MHz, 6): 7.59 (t, J= 8.2 Hz, 1H, ArH); 7.50 (dd, J= 9.8, 1-{2-[(4-chloro-2- 2-[(4-chloro-2- 2.2 Hz, 1H, ArH); fluorobenzyl)oxy]- fluorobenzyl)oxy]- 7.33 (dd, J= 8.2, 27h 5- 5- 2.2 Hz, 1H, ArH); methylphenyllmeth methylbenzaldehy 7.14 (d, J= 1.6 Hz, anamine de 1H, ArH); 7.02 6.90 (m, 2H, ArH); 5.10 (s, 2H); 3.64 (s, 2H); 3.22 (br s, 2H); 2.22 (s, 3H). The following examples illustrate the scope of the invention. 5 Examples of compounds of general formula I The following HPLC methods for LC-MS spectra have been used: Method 1: X-Bridge C18, 2.5 pm 4.6 x 50 mm column; temperature: 35 9C; rate 1.5 mL/min; eluent: A = NH 4 HCO3 10 mM, B = ACN; gradient: 98% A 0.5 min, 98 to 5% A in 4 min, 5% A 2 min, 5 to 98% A 0.75 min, 98% A 1.75 min. 10 Method 2: SunFire C18 3.5 um, 2.1x100 mm column; temperature 3 59C; rate 0.3 mL/min; eluent: A: ACN:MeOH (1:1), B: Water, C: Ammonium acetate 20 mM pH 7; gradient 10:85:5 (A:B:C) 3 min to 95:5 (A: C ) in 17 min and 10 min 95:5 (A: C ). The sample is previously solved in methanol. 15 Method 3: XDB-C18 5 um, 4.6x150 mm column; temperature 2 59C; rate 1 mL/min; eluent: A: Water (0.05% TFA), B: AcN; gradient 5% B to 95:5 (A:B) in 7 min and 4 min 95:5 (A:B).
    WO 2013/037960 PCT/EP2012/068101 107 Method 4: Acquity UPLC @ BEH C18 1.7 pm, 2.1x5O mm column; temperature 4 09C; rate 0.5 mL/min; eluent: A = NH 4 HCO3 10 mM, B = ACN; gradient: 90% A 0.25 min, 90 to 10% A in 2.75 min, 10% A 0.75 min, 10 to 90% A 5 0.01 min, 90% A 1.24 min. Method 5: SunFire C18 5 um, 2.1 x50 mm, rate 0.3 mL/min; eluent A: AcCN:MeOH (1:1), B: Ammonium acetate 5 mM pH 7; gradient 10:90 (A:B) 2 min, 10:90 (A:B) to 95:5 (A:B) in 2 min, 95:5 (A:B) 5 min. The sample is previously solved in methanol. 10 Example 1: (E)-1-(5-chloro-2-(4-chloro-2-fluorostyryl)benzyl)-1H-indole-4 carboxylic acid 15 a) To a suspension of NaH 60% in mineral oil (17 mg, 0.42 mmol) in dry DMF (1 mL) at 0 9C was added a solution of methyl 1 H-indole-4-carboxylate (70 mg, 0.4 mmol) in DMF (1 mL) dropwise. After 30 min, a solution of (E)-2-(bromomethyl) 4-chloro-1-(4-chloro-2-fluorostyryl)benzene (173 mg, 0.48 mmol) in 1 mL of DMF was added dropwise. 20 When TLC analysis showed total conversion, crushed ice was added and the solution was extracted with EtAcO (x3). Combined organic extracts were washed with water, brine and dried over Na2SO4. Column chromatography on silica gel gave (E)-methyl 1-(4-chloro-2-(4-chloro-2-fluorostyryl)benzyl)-1 H-indole-4 carboxylate as a white solid (155 mg, 85% yield). 25 'H NMR (500 MHz, CDCl3) 6 7.95 (1H, dd), 7.57 (1H, d), 7.49 (1H, d), 7.31 (1H, dd), 7.26 (1H, d), 7.21 (1H, dd), 7.19 - 7.11 (3H, m), 7.09 (1H, dd), 7.06 - 6.97 (2H, m), 6.82 (1 H, d), 3.99 (3H, s). 30 b) In a sealed tube, were placed the compound obtained above (135 mg, 0.3 mmol), THF (4 mL) and a solution of LiOH (21 mg, 0.9 mmol) in 1 mL of water. The mixture was stirred at 80 9C until TLC showed no starting material left. Then, it was cooled to room temperature and acidified with HCI 1 M. The mixture was extracted with EtAcO (x3). The organic phases were washed with brine, dried over Na2SO4 WO 2013/037960 PCT/EP2012/068101 108 and filtered. The solvent was removed in vacuo, and the residue was chromatographed using dichloromethane:MeOH (9.5:0.5) as eluent to give 110 mg (84% yield) of the title compound (example 1) as a white solid. 5 'H NMR (400 MHz, DMSO) 6 7.87 - 7.71 (4H, m), 7.63 (1 H, d), 7.55 (1 H, d), 7.48 (1H, dd), 7.38 (1H, dd), 7.33 (1H, dd), 7.21 (2H, dd), 7.05 (1H, dd), 6.66 (1H, d), 5.75 (2H, s). LC-MS: tR = 9.59 [M+H]*= 472 (method 3). 10 The following compounds were prepared using the same methodology as in example 1 using methyl 1 H-indole-4-carboxylate and the compound || specified as starting materials. LC-MS Examp Compound Starting Metho tR m/Z le name compound 11 d (mi [M+ n) H]* 2 1-(2-(benzyloxy)-5- 1 -(benzyloxy)-4 bromobenzyl)-1 H- bromo-2- 1 3.32 436 indole-4-carboxylic acid (bromomethyl)benzene 3 1-(2-(benzyloxy)-5- 1 -(benzyloxy)-2 (trifluoromethyl)benzyl)- (bromomethyl)-4- 1 3.37 426 1 H-indole-4-carboxylic (trifluoromethyl)benzen acid e 4 1-(5-bromo-2-((4- 4-bromo-2 fluorobenzyl)oxy)benzyl) (bromomethyl)-1-(4- 1 3.34 454 -1 H-indole-4-carboxylic fluorobenzyloxy)benze acid ne WO 2013/037960 PCT/EP2012/068101 109 LC-MS Examp Compound Starting Metho tR m/z le name compound 11 d (mi [M+ n) H]* 5 1-(5-chloro-2-((4- 2-(bromomethyl)-4 fluorobenzyl)oxy)benzyl) chloro-1 -(4- 1 3.31 410 -1 H-indole-4-carboxylic fluorobenzyloxy)benze acid ne 6 1 -(2-((4-chloro-2- 2-(bromomethyl)-1 -(4 fluorobenzyl)oxy)-5- chloro-2 (trifluoromethyl)benzyl)- fluorobenzyloxy)-4- 1 3.58 478 1 H-indole-4-carboxylic (trifluoromethyl)benzen acid e 7 1-(5-chloro-2- 2-(bromomethyl)-4 (cyclopropylmethoxy)be chloro- 1 1 3.19 356 nzyl)-1 H-indole-4- (cyclopropylmethoxy)b carboxylic acid enzene 8 1 -(5-bromo-2- 4-bromo-2 (cyclopropylmethoxy)be (bromomethyl)- 1 1 3.22 400 nzyl)-1 H-indole-4- (cyclopropylmethoxy)b carboxylic acid enzene 9 1 -(5-bromo-2-((4-chloro- 4-bromo-2 2- (bromomethyl)-1 -(4 fluorobenzyl)oxy)benzyl) chloro-2- 1 3.53 488 -1 H-indole-4-carboxylic fluorobenzyloxy)benze acid ne 10 4-bromo-1 1 -(4-chloro-2 (bromomethyl)-2-((3,5 isobutoxybenzyl)-1 H- 1 3.43 358 dichlIorobenzyl)oxy)ben indole-4-carboxylic acid zene WO 2013/037960 PCT/EP2012/068101 110 LC-MS Examp Compound Starting Metho tR m/z le name compound 11 d (mi [M+ n) H]* 11 1-(5-chloro-2-((4- 2-(bromomethyl)-4 (trifluoromethyl)benzyl)o chloro-1-((4- 1 3.56 460 xy)benzyl)-1 H-indole-4- (trifluoromethyl)benzyl) carboxylic acid oxy)benzene 1-(5-chloro-2-((2-chloro- 2-(bromomethyl)-4 12 2(rmmty)4 4 fluorobenzyl)oxy)benzyl) chloro-1-((2-chloro-4- 1 3.53 444 -1 H-indole-4-carboxylic fluorobenzyl)oxy)benz ene acid 13 1-(5-chloro-2-((2,3,5,6- 3-((2-(bromomethyl)-4 tetrafluorobenzyl)oxy)be chlorophenoxy)methyl) 1 3.38 464 nzyl)-1 H-indole-4- -1,2,4,5 carboxylic acid tetrafluorobenzene 1-(2-((2,4- 1-((2,4 14 bis(trifluoromethyl)benzy bis(trifluoromethyl)ben I)oxy)-5-chlorobenzyl)- zyl)oxy)-2- 1 3.79 528 1 H-indole-4-carboxylic (bromomethyl)-4 acid chlorobenzene 15 1-(5-chloro-2-((2,4,5- 1-((2-(bromomethyl)-4 trifluorobenzyl)oxy)benz chlorophenoxy)methyl) 1 3.40 446 yl)-1 H-indole-4 -2,4,5-trifluorobenzene carboxylic acid 16 1-(5-fluoro-2-((2,4,5- 1-((2-(bromomethyl)-4 trifluorobenzyl)oxy)benz fluorophenoxy)methyl)- 1 3.29 430 yl)-1 H-indole-4 2,4,5-trifluorobenzene carboxylic acid WO 2013/037960 PCT/EP2012/068101 111 LC-MS Examp Compound Starting Metho tR m/z le name compound 11 d (mi [M+ n) H]* 17 1-(2-((3-bromo-4- 2-bromo-4-((2 fluorobenzyl)oxy)-5- (bromomethyl)-4- 1 3.50 488 chlorobenzyl)-1H-indole- chlorophenoxy)methyl) 4-carboxylic acid -1-fluorobenzene 1 -(5-fluoro-2-((4-fluoro- 2-(bromomethyl)-4 2 (trifluoromethyl)benzyl)o fluoro-1-((4-fluoro-2- 1 3.47 462 xy)benzyl)-1 H-indole-4- (trifluoromethyl)benzyl) carboxylic acid oxy)benzene 19 1-(2-((2-chloro-4- 2-(bromomethyl)-1-((2 fluorobenzyl)oxy)-5- chloro-4 1 3.41 428 fluorobenzyl)-1 H-indole- fluorobenzyl)oxy)-4 4-carboxylic acid fluorobenzene 1-(5-fluoro-2-((4-fluoro- 2-(bromomethyl)-4 20 2 chloro-1 -((4-fluoro-2 (trifluoromethyl)benzyl)o 1 3.56 462 xy)benzyl)-1 H-indole-4- (trifluoromethyl)benzyl) carboxylic acid oxy)benzene 21 1 -(5-chloro-2-((2,3,4- 1 -((2-(bromomethyl)-4 trifluorobenzyl)oxy)benz chlorophenoxy)methyl) 1 3.43 446 yl)- H-ndol-4- -2,3,4-trifluorobenzene carboxylic acid 22 1-(5-bromo-2-((2,3,4- 1-((4-bromo-2 trifluorobenzyl)oxy)benz (bromomethyl)phenoxy 1 3.45 490 yl)-l H-indole-4- )methyl)-2,3,4 carboxylic acid trifluorobenzene WO 2013/037960 PCT/EP2012/068101 112 LC-MS Examp Compound Starting Metho tR m/Z le name compound 11 d (mi [M+ n) H]* 23 1-(5-chloro-2-(1-(2,4- 2-(bromomethyl)-4 difluorophenyl)ethoxy)b chloro-1-(1-(2,4- 1 3.50 442 enzyl)-1 H-indole-4- difluorophenyl)ethoxy) carboxylic acid benzene 24 1-(2-((3-bromo-4- 2-bromo-4-((2 fluorobenzyl)oxy)-5- (bromomethyl)-4- 1 3.39 472 fluorobenzyl)-1 H-indole- fluorophenoxy)methyl) 4-carboxylic acid 1 -fluorobenzene 25 1 -(5-bromo-2-((3-bromo- 2-bromo-4-((4-bromo 4- 2 fluorobenzyl)oxy)benzyl) (bromomethyl)phenoxy 1 2.94 532 -1 H-indole-4-carboxylic )methyl)-1 acid fluorobenzene 1-(5-bromo-2-((4-fluoro- 4-bromo-2 26 2- (bromomethyl)-1-((4 (trifluoromethyl)benzyl)o fluoro-2- 1 3.03 522 xy)benzyl)-1 H-indole-4- (trifluoromethyl)benzyl) carboxylic acid oxy)benzene 27 1 -(5-bromo-2-((2-chloro- 4-bromo-2 4- (bromomethyl)-1 -((2 fluorobenzyl)oxy)benzyl) chloro-4- 1 2.96 488 -1 H-indole-4-carboxylic fluorobenzyl)oxy)benz acid ene 28 1-(3-bromo-2-((4-bromo- 1 -bromo-2-((4-bromo 2-fluorobenzyl)oxy)-5- 2-fluorobenzyl)oxy)-3- 1 3.20 566 chlorobenzyl)-1 H-indole- (bromomethyl)-5 4-carboxylic acid chlorobenzene WO 2013/037960 PCT/EP2012/068101 113 LC-MS Examp Compound Starting Metho tR m/z le name compound 11 d (mi [M+ n) H]* 29 1-(5-chloro-2-((2,5- 2-(bromomethyl)-4 difluorobenzyl)oxy)benz chloro-1-((2,5- 1 3.35 428 yl)-1 H-indole-4- difluorobenzyl)oxy)ben carboxylic acid zene 30 1-(5-chloro-2-((2-chloro- 2-(bromomethyl)-4 5 fluorobenzyl)oxy)benzyl) chloro-1-((2-chloro-5- 1 3.52 440 -1 H-indole-4-carboxylic fluorobenzyl)oxy)benz ene acid 1-(5-chloro-2-((2-chloro 31 2-(bromomethyl)-4 4,5 chloro-1 -((2-chloro-4,5 difluorobenzyl)oxy)benz difluorobenzyl)oxy)ben 1 3.64 462 yl)-1 H-indole-4 zene carboxylic acid 321 -(2-((2,5- 2-(bromomethyl)-4 difluorobenzyl)oxy)-5- fluoro-1-((2,5- 1 3.23 412 fluorobenzyl)-1 H-indole- difluorobenzyl)oxy)ben 4-carboxylic acid zene 33 1-(2-((2,6- 2-(bromomethyl)-4 difluorobenzyl)oxy)-5- fluoro-1 -((2,6- 1 3.21 412 fluorobenzyl)-1 H-indole- difluorobenzyl)oxy)ben 4-carboxylic acid zene 34 1-(5-fluoro-2-((3,4,5- 2-(bromomethyl)-4 trifluorobenzyl)oxy)benz fluoro-1-((3,4,5- 1 3.34 430 yl)-1 H-indole-4- trifluorobenzyl)oxy)ben carboxylic acid zene WO 2013/037960 PCT/EP2012/068101 114 LC-MS Examp Compound Starting Metho tR m/Z le name compound 11 d (mi [M+ n) H]* 35 1-(5-fluoro-2-((4- 2-(bromomethyl)-4 fluorobenzyl)oxy)benzyl) fluoro-1-((4- 1 3.21 394 -1 H-indole-4-carboxylic fluorobenzyl)oxy)benz acid ene 36 1-(2-((2-chloro-4,5- 2-(bromomethyl)-4 difluorobenzyl)oxy)-5- fluoro-1 -((2-chloro-4,5- 1 3.43 446 fluorobenzyl)-1 H-indole- difluorobenzyl)oxy)ben 4-carboxylic acid zene 1 -(2-((2,6 37 2-(bromnomnethyl) -4 difluorobenzyl)oxy)-5- 2-(bromethyl-4 (trifluoromethyl)benzyl)- tifluoromethyl-1-((2,6 1 3.40 462 1 H-indole-4-carboxylic zene acid 38 1 -(2-((2-chloro-5- 2-(bromomethyl)-4 fluorobenzyl)oxy)-5- fluoro-1 -((2-chloro-5- 1 3.39 428 fluorobenzyl)-1 H-indole- fluorobenzyl)oxy)benz 4-carboxylic acid ene 1 -(2-((2,5 39 2-(bromnomnethyl) -4 difluorobenzyl)oxy)-5- 2-(bromethyl-4 (trifluoromethyl)benzyl)- tifluoromethyl(2) 1 3.42 462 difluorobenzyl)oxy) 1 H-indole-4-carboxylic benzene acid 40 1 -(3-bromo-5-chloro-2- 2-(bromomethyl)-6 ((2,6- bromo-4-chloro-1 difluorobenzyl)oxy)benz ((2,6- 1 2.94 506 yl)-1 H-indole-4- difluorobenzyl)oxy)ben carboxylic acid zene WO 2013/037960 PCT/EP2012/068101 115 LC-MS Examp Compound Starting Metho tR m/z le name compound 11 d (mi [M+ n) H]* 41 1-(5-chloro-2-((3,5- 2-(bromomethyl)-4 difluorobenzyl)oxy)benz chloro-1-((3,5- 1 3.77 428 yl)-1 H-indole-4- difluorobenzyl)oxy)ben carboxylic acid zene 1-(1 -(5-chloro-2-((4- 2-(1 -bromoethyl)-4 422-1booty)4 chloro-2 fluorobenzyl)oxy)phenyl) chloro-1 -((4-chloro-2- 1 4.03 458 ethyl)-1 H-indole-4- fluorobenzyl)oxy)benz ene carboxylic acid 43 1-(5-chloro-2-((2,4- 2-(bromomethyl)-4 difluorobenzyl)oxy)benz chloro-1-((2,4 1 3.36 428 yl)-1 H-indole-4- difluorobenzyl)oxy)ben carboxylic acid zene 44 1-(2-(benzyloxy)-5- 1 -(benzyloxy)-2 chlorobenzyl)-1 H-indole- (bromomethyl)-4- 1 3.32 392 4-carboxylic acid chlorobenzene 45 1-(5-chloro-2-((2- 2-(bromomethyl)-4 fluorobenzyl)oxy)benzyl) chloro-1 -((2 1 3.35 410 -1 H-indole-4-carboxylic fluorobenzyl)oxy)benz acid ene 46 1-(2-((4-bromo-2- 4-bromo-1 -((2 fluorobenzyl)oxy)-5- (bromomethyl)-4- 1 3.58 488 chlorobenzyl)-1H-indole- chlorophenoxy)methyl) 4-carboxylic acid -2-fluorobenzene WO 2013/037960 PCT/EP2012/068101 116 LC-MS Examp Compound Starting Metho tR m/z le name compound 11 d (mi [M+ n) H]* 1-(5-chloro-2-((2-fluoro- 2-(bromomethyl)-4 4 chloro-1 -((2-fluoro-4- 1 36 7 (trifluoromethyl)benzyl)o 1 3.61 478 xy)benzyl)-1 H-indole-4- (trifluoromethyl)benzyl) carboxylic acid oxy)benzene 48 1-(5-chloro-2-((4-chloro- 2-(bromomethyl)-4 2 fluorobenzyl)oxy)benzyl) chloro-1-((4-chloro-2- 1 3.54 444 -1 H-indole-4-carboxylic fluorobenzyl)oxy)benz ene acid 49 2-(bromomethyl)-1 -((3 fluorobenzyl)oxy)-5- fluorobenzyl)oxy)-4 (trifluoromethyl)benzyl)- 1 3.41 444 1 H-indole-4-carboxylic e acid 1-(2-((4-bromo-2- 4-bromo-1 -((2 50 fluorobenzyl)oxy)-5- (bromomethyl)-4 (trifluoromethyl)benzyl)- (trifluoromethyl)phenox 1 3.64 522 1 H-indole-4-carboxylic y)methyl)-2 acid fluorobenzene 51 1-(2-((2,4- 4-bromo-1 -((2 difluorobenzyl)oxy)-5- (bromomethyl)-4 (trifluoromethyl)benzyl)- (trifluoromethyl)phenox 1 3.45 462 1 H-indole-4-carboxylic y)methyl)-2 acid fluorobenzene WO 2013/037960 PCT/EP2012/068101 117 LC-MS Examp Compound Starting Metho tR m/z le name compound 11 d (mi [M+ n) H]* 52 2-(bromomethyl)-1-((2 fluorobenzyl)oxy)-5- fluorobenzyl)oxy)-4 (trifluoromethyl)benzyl)- 1 3.41 444 1 H-indole-4-carboxylic e acid 53 1-(2-((2,4- 2-(bromomethyl)-1 difluorobenzyl)oxy)-5- ((2,4- 1 3.26 412 fluorobenzyl)-1 H-indole- difluorobenzyl)oxy)-4 4-carboxylic acid fluorobenzene 54 1-(2-((2,4- 1-((2 difluorobenzyl)oxy)benz (bromomethyl)phenoxy 1 3.26 394 yl)-l H-indole-4- )methyl)-2,4 carboxylic acid difluorobenzene 55 1 -(5-bromo-2-((4-bromo- 4-bromo-1 -((4-bromo 2- 2 fluorobenzyl)oxy)benzyl) (bromomethyl)phenoxy 1 3.01 532 -1 H-indole-4-carboxylic )methyl)-2 acid fluorobenzene 56 1 -(2-((4-bromo-2- 4-bromo-1 -((2 fluorobenzyl)oxy)-5- (bromomethyl)-4- 1 2.86 472 fluorobenzyl)-1 H-indole- fluorophenoxy)methyl) 4-carboxylic acid 2-fluorobenzene 57 1-(5-chloro-2-((4-chloro- 2-((2-(bromomethyl)-4 2,6 2,6- chlorophenoxy)methyl) difluorobenzyl)oxy)benz chloronyel 1 2.91 462 -5-chloro-1 ,3 yl)-l H-indole-4 difluorobenzene carboxylic acid WO 2013/037960 PCT/EP2012/068101 118 LC-MS Examp Compound Starting Metho tR m/z le name compound 11 d (mi [M+ n) H]* 58 1-(2-((4-bromo-2,6- 5-bromo-2-((2 difluorobenzyl)oxy)-5- (bromomethyl)-4- 1 2.98 506 chlorobenzyl)-1H-indole- chlorophenoxy)methyl) 4-carboxylic acid -1,3-difluorobenzene 1-(3,5-dichloro-2-((4- 1 -(bromomethyl)-3,5 chloro-2 dichloro-2-((4-chloro-2 fluorobenzyl)oxy)benzyl) 1 3.12 478 -1 H-indole-4-carboxylic fluorobenzyl)oxy)benz ene acid 1-(5-bromo-2-((4-chloro- 2-((4-bromo-2 60 2(4boo2 2,6 (bromomethyl)phenoxy difluorobenzyl)oxy)benz 1 2.98 506 yI)-lH-indle-4- )methyl)-5-chloro-1 ,3 yl)-1 H-indole-4- ilo bezn difluorobenzene carboxylic acid 61 1-((3-((4-chloro-2- 2-(bromomethyl)-3-((4 fluorobenzyl)oxy)pyridin- chloro-2 1 3.54 411 2-yl)methyl)-1 H-indole- fluorobenzyl)oxy)pyridi 4-carboxylic acid ne 3-(1-(5-chloro-2-((4- 2-(bromomethyl)-1 62 chloro-2 ((3,5 fluorobenzyl)oxy)benzyl) 1 3.67 472 difluorobenzyl)oxy)-4 -1 H-indol-4-yl)propanoic fluorobenzene fluorobenzene acid WO 2013/037960 PCT/EP2012/068101 119 LC-MS Examp Compound Starting Metho tR m/Z le name compound 11 d (mi [M+ n) H]* 1-(5-chloro-2-(4-chloro- 2-(bromomethyl)-4 63 2 fluorophenethyl)benzyl)- chloro-1-(4-chloro-2- 1 4.02 442 fluorophenethyl)benze 1 H-indole-4-carboxylic ne acid Examples 64 to 78: Using methyl 1H-indole-5-carboxylate as stating material 5 The next compounds were obtained using the same methodology as in example 1 but using methyl 1 H-indole-5-carboxylate as starting material of formula Ill and the compound II indicated. LC-MS Exampi Compound Starting tR m/Z e Metho name compound 11 d (min [M+H dY ) ]* 64 1-(5-chloro-2- 2-(bromomethyl)-4 (cyclopropylmethoxy)b chloro-1 1 3.18 356 enzyl)-1 H-indole-5- (cyclopropylmethoxy) carboxylic acid benzene 1 -((2-(bromomethyl) 65 1-(5-fluoro-2-((2,4,5 4 trifluorobenzyl)oxy)ben fluorophenoxy)methyl 1 3.28 430 zyl)-1 H-indole-5 carboxylic acid trifluorobenzene WO 2013/037960 PCT/EP2012/068101 120 LC-MS Exampi Compound Starting tR m/z e Metho name compound 11 d (min [M+H ) ]* 1-(2-((2-chloro-4- 2-(bromomethyl)-1 66 fluorobenzyl)oxy)-5- ((2-chloro-4 fluorobenzyl)-1 H- 1 3.40 428 fluorobenzyl)oxy)-4 indole-5-carboxylic fluorobenzene acid 67 1-(5-chloro-2-((4- 2-(bromomethyl)-4 fluoro-2 (trifluoromethyl)benzyl) chloro-1-((4-fluoro-2- 1 3.58 478 oxy)benzyl)-1 H-indole- (trifluoromethyl)benzy 5-carboxylic acid I)oxy)benzene 1-(2-((3-bromo-4- 2-bromo-4-((2 68 2boo4(2 fluorobenzyl)oxy)-5- (bromomethyl)-4 fluorobenzyl)-1 H- 1 2.93 472 fluorophenoxy)methyl indole-5-carboxylic )-1 -fluorobenzene acid 69 1 -(5-bromo-2-((4- 4-bromo-2 fluoro-2- (bromomethyl)-1 -((4 (trifluoromethyl)benzyl) fluoro-2- 1 3.02 522 oxy)benzyl)-1 H-indole- (trifluoromethyl)benzy 5-carboxylic acid I)oxy)benzene 70 1 -(5-bromo-2-((2- 4-bromo-2 chloro-4- (bromomethyl)-1 -((2 fluorobenzyl)oxy)benz chloro-4- 1 2.99 488 yl)-1 H-indole-5- fluorobenzyl)oxy)ben carboxylic acid zene WO 2013/037960 PCT/EP2012/068101 121 LC-MS Exampi Compound Starting tR m/z e Metho name compound 11 d (min [M+H dY ) ]* 71 1-(5-fluoro-2-((3,4,5- 2-(bromomethyl)-4 trifluorobenzyl)oxy)ben fluoro-1-((3,4,5- 1 3.33 430 zyl)-1 H-indole-5- trifluorobenzyl)oxy)be carboxylic acid nzene 72 1 -(2-((2-chloro-4,5- 2-(bromomethyl)-4 difluorobenzyl)oxy)-5- fluoro-1-((2-chloro fluorobenzyl)-1 H- 4,5- 1 3.43 446 indole-5-carboxylic difluorobenzyl)oxy)be acid nzene 73 1-(2-((2-chloro-5- 2-(bromomethyl)-4 fluorobenzyl)oxy)-5- fluoro-1 -((2-chloro-5 fluorobenzyl)-1 H- 1 2.80 428 indoe-5-arboylic fluorobenzyl)oxy)ben indole-5-carboxylic zene acid 4-bromo-2 74 1-(5-bromo-2-((2,4 difluorobenzyl)oxy)ben ( (2,4-meth.40-472 zyl-1H-ndle5-((2,4- 1 3.40 472 c bl i acidole- - difluorobenzyl)oxy)be carboxylic acid nzene 75 1 -(2-((4-bromo-2- 4-bromo-1-((2 fluorobenzyl)oxy)-5- (bromomethyl)-4 (trifluoromethyl)benzyl) (trifluoromethyl)phen 1 3.62 522 -1 H-indole-5- oxy)methyl)-2 carboxylic acid fluorobenzene WO 2013/037960 PCT/EP2012/068101 122 LC-MS Exampi Compound Starting tR m/z e Metho name compound 11 d (min [M+H ) ]* 76 1-(5-chloro-2-((4- 2-(bromomethyl)-4 chloro-2 fluorobenzyl)oxy)benz chloro-1-((4-chloro-2- 1 3.51 444 yI)-l H-indole-5- fluorobenzyl)oxy)ben zene carboxylic acid 77 1 -(5-chloro-2-((4- 2-(bromomethyl)-4 fluorobenzyl)oxy)benz chloro-1 -(4- 1 3.34 410 yl)-l H-indole-5- fluorobenzyloxy)benz carboxylic acid ene Sodium 1-(5-chloro-2- 4-chloro-2 78 ((2,4- (bromomethyl)-1 difluorobenzyl)oxy)ben ((2,4- 1 3.79 428 zyl)-1 H-indole-5- difluorobenzyl)oxy)be carboxylate nzene Examples 79 to 83: Using (E)-ethyl 3-(1H-indol-4-yl)acrylate as stating material The next compounds were obtained using the same methodology as in example 1 5 but using (E)-ethyl 3-(1 H-indol-4-yl)acrylate as starting material of formula Ill and the compound II indicated. LC-MS Exapl R m/Z Exampi Compound name Starting compound 11 Meth e od (mi [M+H n)
    ]
    WO 2013/037960 PCT/EP2012/068101 123 LC-MS Exapl R m/Z Exampi Compound name Starting compound 11 Meth e od (mi [M+H n) ] 79(E)-3-(1-(2 (benzyloxy)-5- 1 -(benzyloxy)-2 (trifluoromethyl)benzyl (bromomethyl)-4- 1 3.45 452 )-1 H-indol-4-yl)acrylic (trifluoromethyl)benzene acid 80 (E)-3-(1-(5-bromo-2- 4-bromo-2 (cyclopropylmethoxy)b (bromomethyl)-1 1 3.34 426 enzyl)-1 H-indol-4- (cyclopropylmethoxy)be yl)acrylic acid nzene 81 (E)-3-(1-(5-chloro-2- 2-(bromomethyl)-4 (cyclopropylmethoxy)b chloro-1 1 3.29 382 enzyl)-1 H-indol-4- (cyclopropylmethoxy)be yl)acrylic acid nzene 82 (E)-3-(1-(5-chloro-2- 2-(bromomethyl)-4 ((2,4- chloro-1-((2,4 difluorobenzyl)oxy)be difluorobenzyl)oxy)benz 1 3.43 454 nzyl)-1 H-indol-4 ene yl)acrylic acid 83 (E)-3-(1-(5-chloro-2- 2-(bromomethyl)-4 ((4-chloro-2- chloro-1-((4-chloro-2 fluorobenzyl)oxy)benz 1 3.56 470 yI)-lH-indl-4- fluorobenzyl)oxy)benze yl)-1 H-indol-4 ne yl)acrylic acid WO 2013/037960 PCT/EP2012/068101 124 Examples 84 to 86: Using 2-((1H-indol-4-y)oxy)acetate as stating material The next compounds were obtained using the same methodology as in example 1 but using methyl 2-((1 H-indol-4-yl)oxy)acetate as starting material of formula Ill and the compound II indicated. 5 LC-MS Exampi tR m/Z e Compound name Starting compound 11 Meth od (mi [M+H od n) ] 84 2-((1-(2-((4-chloro-2- 2-(bromomethyl)-1 -(4 fluorobenzyl)oxy)-5- chloro-2 (trifluoromethyl)benzyl 1 3.54 508 )-1 -indl-4-fluorobenzyloxy)-4 y ) acet-i c acid (trifluorom ethyl)benzene yl)oxy)acetic acid 85 2-((1-(5-chloro-2- 2-(bromomethyl)-4 (cyclopropylmethoxy)b chloro-1 1 3.22 386 enzyl)-1 H-indol-4- (cyclopropylmethoxy)be yl)oxy)acetic acid nzene 86 2-((1-(5-chloro-2- 4-bromo-2 (cyclopropylmethoxy)b (bromomethyl)-1-(4- 1 3.34 484 enzyl)-1 H-indol-4- fluorobenzyloxy)benzen yl)oxy)acetic acid e Example 87: Synthesis of 1-(2-(benzyloxy)-5-bromobenzyl)-1H-indole-6 10 carboxylic acid) The title compound (example 87) was obtained from using the same methodology as in example 1 but using methyl 1 H-indole-6-carboxylate and 1 -(benzyloxy)-4 bromo-2-(bromomethyl)benzene as starting materials. 15 LCMS: tR = 3.33, [M+H]* = 438 WO 2013/037960 PCT/EP2012/068101 125 The next compounds were obtained from using the same methodology and methyl 1 H-indole-6-carboxylate the compound || specified LC-MS Exampi tR m/Z e Compound name Starting compound 11 Metho d (min [M+H d ) ]* Sodium 1-(5-chloro-2- 4-chloro-2 88 ((2,4- (bromomethyl)-1-((2,4 difluorobenzyl)oxy)ben 1 3.80 428 zyl)1 H-ndol-6- difluorobenzyl)oxy)benz zyl)-1 H-indole-6 ene carboxylate 5 Example 89: Synthesis of 3-(1-(5-chloro-2-((4-chloro-2 fluorobenzyl)oxy)benzyl)-1H-indol-4-yl)propanoic acid The title compound (example 89) was obtained using the same methodology as in example 1 but using ethyl 3-(1 H-indol-4-yl)propanoate and 2-(bromomethyl)-4 10 chloro-1-((4-chloro-2-fluorobenzyl)oxy)benzene as starting materials. 'H NMR (400 MHz CDC1 3 ) 6 7.26-7.10 (7H, m), 6.97 (1H, dd), 6.90 (1H, d,), 6.84 (1H, d), 6.59 (1H, dd), 5.29 (2H, s), 5.12 (2H, s), 3.29 (2H, t), 2.85 (2H, t). 15 LC-MS: tR = 9.28, [M+H]*= 472 (method 3). Example 90: Synthesis of 1-(5-chloro-2-((4-chloro-2-fluorobenzyl)oxy)benzyl) 1H-pyrrolo[2,3-b]pyridine-4-carboxylic acid The title compound (example 90) was obtained using the same methodology as in 20 example 1 but using methyl 1 H-pyrrolo[2,3-b]pyridine-4-carboxylate and 2 (bromomethyl)-4-chloro-1 -((4-chloro-2-fluorobenzyl)oxy)benzene as starting materials.
    WO 2013/037960 PCT/EP2012/068101 126 'H NMR (400 MHz, DMSO) o 8.35 (1 H, d), 7.64 (1 H, d), 7.60 (1 H, d), 7.56 (2H, t), 7.49 (1 H, dd), 7.32 (2H, ddd), 7.21 (1 H, d), 6.91 (1 H, d), 6.82 (1 H, d), 5.49 (2H, s), 5.20 (2H, s). LC-MS: tR = 9.9 [M+H]*= 445 (method 3) 5 The next compounds were obtained using the same methodology and 1 H pyrrolo[2,3-b]pyridine-4-carboxylic acid as staring material of formula Ill and the compound || specified LC-MS Exampi tR m/Z e Compound name Starting compound 11 Metho d (min [M+H d ) 1 Sodium 1-(5-chloro-2 91 ((2,4- 4-chloro-2 difluorobenzyl)oxy)ben (bromomethyl)-1-((2,4- 1 3.55 429 zyl)-1 H-pyrrolo[2,3- difluorobenzyl)oxy)benz b]pyridine-4- ene carboxylate 10 Example 92: Synthesis of 1-(5-chloro-2-((4-chloro-2-fluorobenzyl)oxy)benzyl) 1H-benzo[d]imidazole-4-carboxylic acid 15 To a suspension of NaH 60% (13 mg, 0.31 mmol) in dry DMF (4 mL) at 0 9C was added dropwise a solution of 1H-benzo[d]imidazole-4-carboxylic acid (50 mg, 0.3 mmol) in DMF (1 mL). After 30 min a solution of 2-(bromomethyl)-4-chloro-1-((4 chloro-2-fluorobenzyl)oxy)benzene (103 mg, 0.28 mmol) in 1 mL of DMF was added dropwise and the mixture kept at RT for 16 h. After evaporation of the solvent the 20 residue was chromatographed on silica gel eluting with DCM:MeOH (9.5:0.5 to 9:1) to gave the title compound (example 92)as a white solid (96 mg, 72% yield).
    WO 2013/037960 PCT/EP2012/068101 127 'H NMR (400 MHz, DMSO) o 8.29 (1H, d), 7.99 (1H, d), 7.82 (1H, dd), 7.54 (1H, t), 7.48 (1H, d), 7.40 (2H, ddd), 7.31 (1H, t), 7.24 (1H, d), 7.19 (1H, dd), 5.44 (2H, s), 5.22 (2H, s). LC-MS: tR = 7.27; [M+H]*= 445 (method 3) 5 Example 93: Synthesis of 1-(5-chloro-2-((4-chloro-2 fluorobenzyl)oxy)benzyl)indoline-4-carboxylic acid a) To a suspension of K2CO 3 (43 mg, 0.31 mmol) and methyl indoline-4 carboxylate (53 mg, 0.3 mmol) in dry DMF (1 mL) at 0 9C was added dropwise a 10 solution of 2-(bromomethyl)-4-chloro-1 -((4-chloro-2-fluorobenzyl)oxy)benzene (114 mg, 0.31 mmol) in DMF (1mL). The reaction was stirred at RT overnight (TLC analysis showed complete conversion) and then the solution was poured onto crushed ice and extracted with EtAcO (x3). Combined organic extracts were washed with water, brine and dried over Na2SO4. Column chromatography on silica gel 15 eluting with DCM gave methyl 1-(5-chloro-2-((4-chloro-2 fluorobenzyl)oxy)benzyl)indoline-4-carboxylate as a white solid (111 mg, 81% yield). 'H NMR (400 MHz, CDCI 3 ) 6 7.36 (1 H, dd), 7.30 (1 H, d), 7.29 - 7.26 (2H, m), 7.21 (1H, dd), 7.14 - 7.09 (1H, m), 6.49 (1H, d), 5.09 (2H, s), 4.26 (2H, s), 3.88 (3H, 20 s), 3.49 - 3.42 (2H, m), 3.41 - 3.34 (2H, m). b) In a sealed tube were placed methyl 1-(5-chloro-2-((4-chloro-2 fluorobenzyl)oxy)benzyl)indoline-4-carboxylate (85 mg, 0.19 mmol), EtOH (1.5 mL), THF (0.5 mL) and a solution of LiOH (13 mg, 0.55 mmol) in 0.23 mL of water. The 25 mixture was stirred at 75 9C overnight. Then the mixture was cooled to RT and acidified with HCI 1M to pH-2-3. The reaction mixture was extracted with EtAcO (x3). The organic phases were washed with brine dried over Na2SO4 and filtered. The solvent was removed in vacuo and the crude was chromatographed on silica gel eluting with DCM:MeOH (98:2) to give 75 mg (91% yield) of the title compound 30 (example 93) as a slightly yellow solid. 'H NMR (500 MHz, DMSO) 6 7.60 (1 H, t), 7.50 (1 H, dd), 7.36 - 7.28 (3H, m), 7.21 (1H, d), 7.10 (1H, d), 7.00 (1H, t), 6.56 (1H, d), 5.20 (2H, s), 4.25 (2H, s), 3.36 (2H, t), 3.22 (2H, t).
    WO 2013/037960 PCT/EP2012/068101 128 LC-MS: tR = 2.98 min, [M+H]*= 446, (Method 1). Example 94: Synthesis of 1-(5-chloro-2-((4-chloro-2-fluorobenzyl)oxy)benzyl) 1,2,3,4-tetrahydroquinoline-5-carboxylic acid 5 The title compound (example 94) was obtained following the general procedure described in example 1 using methyl 1,2,3,4-tetrahydroquinoline-5-carboxylate and 2-(bromomethyl)-4-chloro-1 -((4-chloro-2-fluorobenzyl)oxy)benzene as starting materials. 10 'H NMR (400 MHz, DMSO) 6 7.63 (1H, t), 7.51 (1H, dd), 7.34 (1H, dd), 7.30 (1 H, dd), 7.22 (1 H, d), 6.98 (1 H, d), 6.95 - 6.84 (2H, m), 6.39 - 6.28 (1 H, m), 5.23 (2H, s), 4.40 (2H, s), 3.39 - 3.32 (2H, m), 2.97 (2H, t), 1.93 - 1.84 (2H, m). LC-MS: tR = 9.61, [M+H]*= 460 (method 3). 15 The next compounds were obtained using the same methodology and methyl 1,2,3,4-tetrahydroquinoline-5-carboxylate as starting material of formula (Ill) and the compound || specified LC-MS Exampi tR m/Z e Compound name Starting compound 11 Metho d (min [M+H d ) ]* 1-(5-chloro-2-((2,4- 2-(bromomethyl)-4 95 difluorobenzyl)oxy)ben chloro-1-((2,4 zyl)-1,2,3,4- 1 3.82 444 tetrahydroquinoline-5 ene carboxylic acid 20 Example 96: Synthesis of Sodium 1-(5-chloro-2-((4-chloro-2 fluorobenzyl)oxy)benzyl)-1H-indole-4-carboxylate a) Methyl 1-(5-chloro-2-((4-chloro-2-fluorobenzyl)oxy)benzyl)-1H-indole-4 carboxylate was obtained following the general method described in example 1, using methyl 1H-indole-4-carboxylate and 2-(bromomethyl)-4-chloro-1-((4-chloro-2 25 fluorobenzyl)oxy)benzene as starting materials.
    WO 2013/037960 PCT/EP2012/068101 129 b) To a solution of compound obtained above (640 mg, 1.40 mmol) in EtOH, a solution of NaOH 2M (1.75 mL, 3.5 mmol) was added at room temperature. The mixture was stirred at 80 9C until TLC showed there was not starting material left. It 5 was cooled and EtOH was removed in vacuo. The residue was dissolved in EtAcO, washed with water (x3) and brine, and dried with MgSO 4 . The crude product was purified by SiC 2 column chromatography, eluting with a gradient of hexane/EtAcO. Title compound (example 96) was obtained as a white solid (540 mg, 83% yield). 10 'H NMR (400 MHz, DMSO) 6 7.72 (1H, dd), 7.61 (1H, d), 7.58 - 7.50 (3H, m), 7.34 - 7.30 (2H, m), 7.20 (1H, d), 7.13 (1H, t), 6.98 (1H, d), 6.86 (1H, d), 5.39 (2H, s), 5.21 (2H, s). LC-MS: tR = 3.73; [M+H]*= 444 (method 1). 15 Example 97: Synthesis of Sodium 1-(5-chloro-2-((2,4 difluorobenzyl)oxy)benzyl)-1H-indole-4-carboxylate The title compound (example 97) was obtained using the same methodology as in Example 96 but using 1-(5-chloro-2-((2,4-difluorobenzyl)oxy)benzyl)-1H-indole-4 20 carboxylic acid as starting material. 'H NMR (400 MHz DMF-d 7 ) o 8.05 (1H, d), 7.92-7.86 (2H, m), 7.79 (1H, d), 7.54-7.30 (6H, m), 7.13 (1H, d,), 5.70 (2H, s), 5.46 (2H, s) 25 LC-MS: tR = 3.95, [M+H]*= 428 (method 1). Examples 98 to 99: Using 2-methyl-7H-pyrrolo[2,3-d]pyrimidine-4-carboxylate as starting material The next compounds were obtained using the same methodology as in Example 96 30 but using 2-methyl-7H-pyrrolo[2,3-d]pyrimidine-4-carboxylate as starting material of formula Ill and the compound II indicated. Exampi Compound name Starting compound 11 LC-MS WO 2013/037960 PCT/EP2012/068101 130 e Metho tR m/Z d (min [M+H ) ]* sodium 7-(5-chloro-2 98 ((4-chloro-2- 2-(bromomethyl)-4 fluorobenzyl)oxy)benzy chloro-1-((4-chloro-2- 1 3.56 446 I)-7H-pyrrolo[2,3- fluorobenzyl)oxy)benze d]pyrimidine-4- ne carboxylate sodium 7-(5-chloro-2 99 ((2,4- 2-(bromomethyl)-4 difluorobenzyl)oxy)ben chloro-1-((2,4- 1 3.47 430 zyl)-7H-pyrrolo[2,3- difluorobenzyl)oxy)benz d]pyrimidine-4- ene carboxylate Example 100: Synthesis of sodium 1-(5-chloro-2-((2,4 difluorobenzyl)oxy)benzyl)-7-fluoro-1H-indole-4-carboxylate The title compound (example 100) was obtained using the same methodology as in 5 Example 96 but using methyl 7-fluoro-1 H-indole-4-carboxylate and 2-(bromomethyl) 4-chloro-1-((2,4-difluorobenzyl)oxy)benzene as starting materials. 'H NMR (500 MHz, DMSO) 6 7.71 (1 H, dd), 7.60 - 7.54 (1 H, m), 7.53 (1 H, d), 10 7.37 - 7.28 (2H, m), 7.23 (1H, d), 7.11 (1H, td), 7.06 (1H, t), 6.94 (1H, dd), 6.54 (1H, d), 5.51 (2H, s), 5.19 (2H, s). LC-MS: tR = 3.85; [M+H]*= 444 (Method 1) 15 Example 101: Synthesis of sodium 1-{2-[(2,4-difluorobenzyl)oxy]-5 methoxybenzyl}-1H-indole-4-carboxylate t-BuONa (32 mg, 0.33 mmol) was added to a suspension of 1-{2-[(2,4 difluorobenzyl)oxy]-5-methoxybenzyl}-1H-indole-4-carboxylic acid (140 mg, 0.33 WO 2013/037960 PCT/EP2012/068101 131 mmol) in MeOH (10 mL) and stirred at room temperature. After 2 h, the solvent was removed out of the clear solution, rendering a white solid that was triturated with Et 2 0 (10 mL) and vacuum dried, affording 130 mg of sodium 1-{2-[(2,4 difluorobenzyl)oxy]-5-methoxybenzyl}-1 H-indole-4-carboxylate (87% yield) (example 5 101). LC-MS ESI- m/z: 422 [M-Na]-, tR = 18.14 (Method 2) "H-NMR (DMSO-d 6 , 250 MHz, 6): 7.67-7.52 (m, 2H, ArH); 7.40-7.07 (m, 6H, ArH); 6.94 (dd, J= 8.0, 7.4 Hz, 1H, ArH); 6.79 (dd, J= 8.6, 3.2 Hz, 1H, ArH); 6.29 (d, 10 J= 2.8 Hz, 1H, ArH); 5.27 (s, 2H, CH2); 5.14 (s, 2H, CH2); 3.56 (s, 3H, OCH3). Example 102: Synthesis of sodium 1-[5-chloro-2-(cyclohexylmethoxy)benzyl] 1H-indole-4-carboxylate The title compound (example 102) was obtained using the same methodology as in 15 Example 101 but methyl 1H-indole-4-carboxylate and 2-(bromomethyl)-4-chloro-1 (cyclohexylmethoxy)benzene as starting materials. LC-MS ESI- m/z: 396 [M-Na]-, tR = 21.18 (Method 2) "H-NMR (DMSO-d 6 , 250 MHz, 6): 7.57 (dd, J= 7.4, 1.0 Hz, 1H, ArH); 7.36 20 7.18 (m, 4H, ArH); 7.07-6.98 (m, 2H, ArH); 6.64 (d, J= 2.7 Hz, 1H, ArH); 5.33 (s, 2H, CH2); 3.85 (d, J= 5.5 Hz, 2H, CH2); 1.91-1.60 (m, 6H); 1.38-1.00 (m, 5H). Example 103: Synthesis of sodium 1-[5-chloro-2-(cyclopentylmethoxy)benzyl] 1H-indole-4-carboxylate 25 The title compound (example 103) was obtained using the same methodology as in Example 15 but methyl 1H-indole-4-carboxylate and 2-(bromomethyl)-4-chloro-1 (cyclopentylmethoxy)benzene as starting materials. LC-MS ESI- m/z: 382 [M-Na]-, tR = 20.40 (Method 2) 30 "H-NMR (DMSO-d 6 , 250 MHz, 6): 7.57 (d, J= 7.0 Hz, 1H, ArH); 7.39-7.17 (m, 4H, ArH); 7.10-6.90 (m, 2H, ArH); 6.67 (br s, 1H, ArH); 5.32 (s, 2H, CH2); 3.93 (d, J= 6.2 Hz, 2H, CH2); 2.47-2.30 (m, 1 H); 1.93-1.11 (m, 8H).
    WO 2013/037960 PCT/EP2012/068101 132 Examples 104 to 113: Using methyl 1H-indole-4-carboxylate as starting material The next compounds were obtained using the same methodology as in Example 96 but using methyl 1 H-indole-4-carboxylate as starting material of formula Ill and the 5 compound II indicated. LC-MS Example Starting compound tR m/z Compound name Metho II (mi [M+H n) ] Sodium 1-(5-fluoro- 2-(bromomethyl)-4 2-propoxybenzyl)- fluoro-1
    -
    4 1.78 328 1 H-indole-4 104 carboxylate propoxybenzene Sodium 1-(5- 2-(bromomethyl)-4 chloro-2 chloro-1 105 (cyclopentyloxy)ben 4 2.00 370 zyl)1 H-ndol-4- (cyclopentyloxy)ben zyl)-1 H-indole-4 zene carboxylate Sodium 1-(5-chloro- 2-(bromomethyl)-4 2-propoxybenzyl) 106 chloro-1- 4 1.84 344 1 H-indole-4 carboxylate propoxybenzene Sodium 1-(5-chloro 2-(2-(tetrahydro- (bromomethyl)-4 107 2H-pyran-4- chlorophenoxy)ethyl 1 3.44 414 yl)ethoxy)benzyl)- )tetrahydro-2H 1 H-indole-4 carboxylate pyran WO 2013/037960 PCT/EP2012/068101 133 Sodium 1 -(5-fl 2-(bromomethyl)-4 2-isobutoxybenzyl) 108 fluoro-1- 1 3.57 340 1 H-indole-4 carboxylate isobutoxybenzene 1-(bromomethyl)-2 isobutoxybenzene Sodium 1-(2 isobutoxybenzyl)- 18.6 109 2 324 1 H-indole-4- 5 carboxylate Sodium 1-[5-chloro- 2-(bromomethyl)-4 2-(2,2- chloro-1-(2,2- 10.1 110 difluoroethoxy)benz 2 366 yI-lH-ndle4- difluoroethoxy)benz 1 yl]-1 H-indole-4 ene carboxylate Sodium 1-[5-chloro- 2-(bromomethyl)-4 2-(2- chloro-1 -(2- 15.7 111 fluoroethoxy)benzyl fluoroethoxy)benzen 2 2 348 ]-1 H-indole-4 e carboxylate Sodium 1-[5-chloro- 2-(bromomethyl)-4 2-(2,2,2- chloro-1-(2,2,2- 16.0 112 trifluoroethoxy)benz 2 384 yI-lH-ndle4- trifluoroethoxy)benz 7 yl]-1 H-indole-4 ene carboxylate WO 2013/037960 PCT/EP2012/068101 134 Sodium 1-[5-chloro- 2-(bromomethyl)-4 2 chloro-1- 20.0 113 (neopentyloxy)benz 2 372 yl-lH-ndle4- (neopentyloxy)benz 0 yl]-1 H-indole-4 ene carboxylate m/z [M-H] instead of m/z [M+H]* 5 Examples 114 to 115: Using methyl 3-oxo-3,4-dihydro-2H benzo[b][1,4]oxazine-8-carboxylate as starting material The next compounds were obtained using the same methodology as in Example 96 but using methyl 3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-8-carboxylate as starting material of formula Ill and the compound II indicated. LC-MS Example Starting compound tR m/z Compound name Metho II (mi [M+H n) ] Sodium 4-(5-chloro 2 cyclobutoxybenzyl)- 2-(bromomethyl)-4 114 3-oxo-3,4-dihydro- chloro-1- 4 1.67 388 2H- cyclobutoxybenzene benzo[b][1,4]oxazin e-8-carboxylate Sodium 4-(5 bromo-2-(4-chloro- 4-bromo-2 2 fluorobenzyloxy)be (bromomethyl)-1 -(4 115 chloro-2- 4 1.88 520 nzyl)-3-oxo-3,4- fluorobenzyloxy)ben dihydro-2H zene benzo[b][1,4]oxazin e-8-carboxylate WO 2013/037960 PCT/EP2012/068101 135 Examples 116 to 122: Using methyl 3,4-dihydro-2H-benzo[b][1,4]oxazine-8 5 carboxylate as starting material The following compounds were prepared using the same methodology as in example 96 using methyl 3,4-dihydro-2H-benzo[b][1,4]oxazine-8-carboxylate and the compound || specified as starting materials. 10 LC-MS Example Starting compound tR m/z Compound name Metho II (mi [M+H n) ] Sodium 4-(5-chloro 2-(2-fluoro-2- 2-(bromomethyl)-4 116 methylpropoxy)ben chloro-1-(2-fluoro-2- 1.72 394 zyl)-3,4-dihydro-2H- methylpropoxy)benz benzo[b][1,4]oxazin ene e-8-carboxylate Sodium 4-(5-chloro 2-((4-chloro-2- 2-(bromomethyl)-4 fluorobenzyl)oxy)be chloro-1 -((4-chloro 117 nzyl)-3,4-dihydro- 2- 1 3.71 462 2H benzo[b][1,4]oxazin fluorobenzyl)oxy)be nzene e-8-carboxylate WO 2013/037960 PCT/EP2012/068101 136 Sodium 4-(5-chloro 2-((2,4- 2-(bromomethyl)-4 difluorobenzyl)oxy) chloro-1 -((2,4 118 benzyl)-3,4- 1 3.60 446 di hd ro2 H- difluorobenzyl)oxy)b dihydro-2H enzene benzo[b][1,4]oxazin e-8-carboxylate Sodium 4-(2-((4 chloro-2 fluorobenzyl)oxy)be nzyl)-3,4-dihydro- (bromomethyl)phen 119 oxy)methyl)-4- 1 3.64 428 chloro-2 benzo[b][1,4]oxazin fluorobenzene e-8-carboxylate Sodium 4-(2 (benzyloxy)benzyl)- 1 -(benzyloxy)-2 120 3,4-dihydro-2H- (bromomethyl)benz 1 3.39 376 benzo[b][1,4]oxazin ene e-8-carboxylate Sodium 4-(2-((2 chloro-4 fluorobenzyl)oxy)-5- 2-(bromomethyl)-1 121 fluorobenzyl)-3,4- ((2-chloro-4- 1 3.57 445 dihydro-2H- fluorobenzyl)oxy)-4 benzo[b][1,4]oxazin fluorobenzene e-8-carboxylate WO 2013/037960 PCT/EP2012/068101 137 Sodium 4-(2-((2,4 difluorobenzyl)oxy) 2-(bromomethyl)-1 122 benzyl)-3,4- ((2,4- 1 3.48 412 dihydro-2H- difluorobenzyl)oxy)b benzo[b][1,4]oxazin enzene e-8-carboxylate Example 123: Synthesis of sodium 1-(2-((2-chlorobenzyl)oxy)-5-fluorobenzyl) 1H-indazole-4-carboxylate 5 a) To a suspension of NaH 60% (30 mg, 0.75 mmol) in dry DMF (1 mL) at 0 9C was added dropwise a solution of methyl 1 H-indazole-4-carboxylate (120 mg, 0.68 mmol) in DMF (2 mL). After 10 min a solution of 2-(bromomethyl)-1-((2 chlorobenzyl)oxy)-4-fluorobenzene (236 mg, 0.72 mmol) in 1.5 mL of DMF was 10 added dropwise. After 16 h at 0 9C water was added and extracted with EtAcO (x3). Combined organic extracts were washed with water, brine and dried over Na2SO4. The crude was purified by column chromatography using a combiflash system with a RediSep Rf Gold Normal Phase column and using cyclohexane/EtAcO as solvent. Methyl 1-(2-((2-chlorobenzyl)oxy)-5-fluorobenzyl)-1 H-indazole-4-carboxylate 15 compound as a slightly brown solid (144 mg, 50% yield). 'H NMR (400 MHz, CDC1 3 ) 6 8.84 (s, 1H), 8.56 (s, 1H), 7.37 (d, J = 3.1 Hz, 1H), 7.28 (dd, J = 8.8, 2.6 Hz, 1H), 7.18 - 7.07 (m, 3H), 6.99 (d, J = 2.6 Hz, 1H), 6.92 (d, J = 8.8 Hz, 1 H), 6.70 (dd, J = 3.1, 0.8 Hz, 1 H), 5.37 (s, 2H), 5.05 (s, 2H). 20 b) To a suspension of methyl 1-(2-((2-chlorobenzyl)oxy)-5-fluorobenzyl)-1 H indazole-4-carboxylate (120 mg, 0.28 mmol) in EtOH (3 mL), and THF (0.3 mL) a solution of NaOH (34 mg, 0.85 mmol) in H 2 0 (0.3 mL) was added at room temperature. The mixture was stirred at 80 9C overnight. It was cooled and water 25 was added. The aqueous layer was extracted with EtAcO (x3). The combined organic layers were washed with brine dried (MgSO4) filtered and concentrated. LC-MS: tR = 3.44; [M+H]*= 411 (Method 1) WO 2013/037960 PCT/EP2012/068101 138 'H NMR (300 MHz, Methanol-d4) 6 8.59 (s, 1H), 7.72 (d, J = 7.1 Hz, 1H), 7.55 - 7.39 (m, 3H), 7.41 - 7.22 (m, 3H), 7.02 (dtd, J = 17.1, 8.9, 3.9 Hz, 2H), 6.57 (dd, J = 8.9, 3.0 Hz, 1 H), 5.65 (s, 2H), 5.22 (s, 2H). 5 Examples 124 to 138: Using methyl 1H-indazole-4-carboxylate as starting material The next compounds were obtained using the same methodology as in Example 123 but using the compound II indicated. 10 LC-MS Example Starting compound tR m/Z Compound name Metho II (mi [M+H n) ] Sodium 1-(5-chloro- 2-(bromomethyl)-4 2-((4-chloro-2- chloro-1 -((4-chloro 124 fluorobenzyl)oxy)be 2- 1 3.65 445 nzyl)-1 H-indazole- fluorobenzyl)oxy)be 4-carboxylate nzene Sodium 1-(5-chloro- 2-(bromomethyl)-4 2-(2-fluoro-2- chloro-1-(2-fluoro-2 125 methylpropoxy)ben 1 3.21 377 zyl- 1H-ndaole4-methylpropoxy)benz zyl)-1 H-indazole-4 ene carboxylate Sodium 1-(5-chloro 2-((2- 2-(bromomethyl)-4 126 fluorobenzyl)oxy)be chloro-1-((2 1 3.43 411 nzyl)-1 H-indazole- fluorobenzyl)oxy)be 4-carboxylate nzene WO 2013/037960 PCT/EP2012/068101 139 Sodium 1-(2-((2 chlorobenzyl)oxy)- ( 2 ((2 127 5-methylbenzyl)- 1 3.56 407 1 H-idazoe-4- chlorobenzyl)oxy)-4 1 H-indazole-4 carboxylate methylbenzene Sodium 1-(5-fluoro 2-((2- 2-(bromomethyl)-4 128 fluorobenzyl)oxy)be fluoro-1-((2- 1 3.33 395 nzyl)-1 H-indazole- fluorobenzyl)oxy)be 4-carboxylate nzene Sodium 1 -(2-((2- 2-(bromomethyl)-1 fluorobenzyl)oxy)-5- ((2 129 methylbenzyl)-1H- 1 3.43 391 indazle-4- fluorobenzyl)oxy)-4 indazole-4 carboxylate methylbenzene Sodium 1-(5-chloro- 2-(bromomethyl)-4 chloro-1-((2 130 chlorobenzyl)oxy)b 1 3.54 427 enzy)-1H-idazle-chlorobenzyl)oxy)be enzyl)-1 H-indazole nzene 4-carboxylate Sodium 1-(5-chloro- 2-(bromomethyl)-4 2-(3-fluoro-2- chloro-1-(3-fluoro-2 131 methylpropoxy)ben 1 3.30 377 zyl- 1H-ndaole4-methylpropoxy)benz zyl)-1 H-indazole-4 ene carboxylate Sodium 1-(5-chloro 2-propoxybenzyl)- f 2-(bromomethyl)-4 132 1H-indazole-4- chloro-1- 4 1.70 345 carboxylate propoxybenzene WO 2013/037960 PCT/EP2012/068101 140 Sodium 1-(5 chloro-2 (cyclopentyloxy) (bromomethyl)-37 133 4-chloro-1- 4 benzyl)-1 H- 1.79 1 (cyclopentyloxy) i ndazole-4 benzene carboxylate Sodium 1 -(5-fl 2-(bromomethyl)-4 2-isobutoxybenzyl) 134 fluoro-1- 4 1.74 343 1 H-indazole-4 carboxylate isobutoxybenzene Sodium 1 -(5-fl 2-(bromomethyl)-4 2-propoxybenzyl) 135 fluoro-1- 4 1.60 329 1 H-indazole-4 carboxylate propoxybenzene Sodium 1-(5- 4-bromo-2 bromo-2-(4-chloro- (bromomethyl)-1 -(4 2 136 chloro-2- 4 1.95 491 fluorobenzyloxy)be fluorobenzyloxy)ben nzyl)-1 H-indazole zene 4-carboxylate Sodium 1-(5-chloro 2- 2-(bromomethyl)-4 137 cyclobutoxybenzyl)- chloro-1- 4 1.76 357 1 H-indazole-4- cyclobutoxybenzene carboxylate Sodium 1-(5-chloro- 2-(bromomethyl)-4 2 chloro-1 138 (neopentyloxy)benz 4 1.94 373 yI)l Hindzol-4- (neopentyloxy)benz yl)-1 H-indazole-4 ene carboxylate WO 2013/037960 PCT/EP2012/068101 141 Example 139: Using methyl 1H-pyrrolo[3,2-c]pyridine-4-carboxylate as starting material 5 The next compound was obtained using the same methodology as in Example 123 but using methyl 1 H-pyrrolo[3,2-c]pyridine-4-carboxylate as starting material and the compound II indicated. LC-MS Example Starting compound tR m/z Compound name Metho II (mi [M+H n) ] Sodium 1-(5-chloro 2-((4-chloro-2- 2-(bromomethyl)-4 fluorobenzyl)oxy)be chloro-1-(4-chloro-2 139 nzyl)-1H- fluorobenzyloxy)ben 1 3.65 445 pyrrolo[3,2 zene c]pyridine-4 carboxylate 10 Example 140: Using ethyl 7-fluoro-1H-indole-4-carboxylate as starting material The next compound was obtained using the same methodology as in Example 123 but using ethyl 7-fluoro-1H-indole-4-carboxylate as starting material and the compound II indicated. 15 LC-MS EapeStarting tR m/Z Example Compound name Meth compound II (mi [M od n) H] WO 2013/037960 PCT/EP2012/068101 142 Sodium 1-(2-((2,4 difluorobenzyl)oxy)b (bromomethyl)ph 140 enzyl)-7-fluoro-1H- enoxy)methyl)- 1 3.65 410 2,4 indole-4-carboxylate duo z difluorobenzene Example 141. Synthesis of sodium 1-(5-chloro-2-((4-chloro-2 fluorobenzyl)oxy)benzyl)-3-(hydroxymethyl)- 1H-indole-4-carboxylate 5 a) To a suspension of 41.3 mg (1.0 mmol) of NaH 60% in mineral oil in 3mL of DMF under argon and cooled at 09C 200 mg (0.98 mmol) of methyl 3-formyl-1 H indole-4-carboxylate was added as a solution in 3mL of DMF. The resulting solution was stirred at 09C for 15 minutes. Then, a solution of 2-(bromomethyl)-4-chloro-1 ((4-chloro-2-fluorobenzyl)oxy)benzene in 4 mL of DMF was added dropwise. 10 Reaction was stirred at 09C for 1.5 h. It was quenched with water, extracted with EtAcO and the combined organic extracts were washed with brine, dried over anhydrous Na 2 SO4, filtered and the solvent evaporated. The crude was purified by column chromatography over silica gel, eluting with mixtures cyclohexane/EtAcO. Methyl 1-(5-chloro-2-((4-chloro-2-fluorobenzyl)oxy)benzyl)-3-formyl-1 H-indole-4 15 carboxylate (450 mg, 94%) was obtained as a white solid. b) To a suspension of corresponding aldehyde (195 mg) in ethanol (0.2 M), NaBH 4 was added (1.2 eq, 21 mg) at 09C. Mixture was stirred for 5 minutes and then 1 mL of THF was added to get complete solution. After 30 minutes, TLC 20 showed there was not starting material left. It was quenched with water and extracted with EtOAc (x3). The organic phases were washed with brine and dried over MgSO 4 . The crude white solid was used without further purification in the follow step reaction. 'H NMR (300 MHz, CDC13) 6 7.83 (d, 1H), 7.45 (d, 1H), 7.32 - 7.06 (m, 6H), 25 6.96 - 6.79 (m, 2H), 5.25 (s, 2H), 5.08 (s, 2H), 4.77 (s, 2H), 4.00 (s, 3H).
    WO 2013/037960 PCT/EP2012/068101 143 c) To a suspension of 440 mg (0.9 mmol) of methyl 1-(5-chloro-2-((4-chloro 2-fluorobenzyl)oxy)benzyl)-3-(hydroxymethyl)-1H-indole-4-carboxylate in 18 mL of absolute ethanol, 1.12 mL of an aqueous solution of NaOH 2M was added. The resulting mixture was stirred at 809C for 1h. Then water was added and it was 5 extracted with EtAcO. After evaporating the solvent sodium 1-(5-chloro-2-((4-chloro 2-fluorobenzyl)oxy)benzyl)-3-(hydroxymethyl)-1H-indole-4-carboxylate was obtained (385 mg, 86%). LC-MS: tR = 3.71; [M-H]= 472 (Method 1) 10 Examples 142 to 151: Using methyl 3-formyl-1H-indole-4-carboxylate as starting material The next compounds were obtained using the same methodology as in example 141 using methyl 3-formyl-1H-indole-4-carboxylate as starting material and the 15 compound II indicated. Example Compound name Starting LC-MS compound 11 Method tR m/z (min [M-H] ) Sodium 1-(5- 2-(bromomethyl)- 1 3.57 456 chloro-2-((2,4- 4-chloro-1-((2,4 142 difluorobenzyl)oxy) difluorobenzyl)ox benzyl)-3- y)benzene (hydroxymethyl) 1 H-indole-4 carboxylate Sodium 1-(2-((2,4- 2-(bromomethyl)- 1 3.20 422 difluorobenzyl)oxy) 1-((2,4 143 benzyl)-3- difluorobenzyl)ox (hydroxymethyl)- y)benzene 1 H-indole-4 carboxylate WO 2013/037960 PCT/EP2012/068101 144 Sodium 1-(2-((4- 1-((2- 1 3.53 438 chloro-2- (bromomethyl)ph 144 fluorobenzyl)oxy)b enoxy)methyl)-4 enzyl)-3- chloro-2 (hydroxymethyl)- fluorobenzene 1 H-indole-4 carboxylate Sodium 1-(2-((2,4- 2-(bromomethyl)- 1 3.21 440 difluorobenzyl)oxy) 1-((2,4 145 -5-fluorobenzyl)-3- difluorobenzyl)ox (hydroxymethyl)- y)-4 1 H-indole-4- fluorobenzene carboxylate Sodium 1-(2-((4- 2-(bromomethyl)- 1 3.53 456 chloro-2- 1-((4-chloro-2 fluorobenzyl)oxy)- fluorobenzyl)oxy) 146 5-fluorobenzyl)-3- 4-fluorobenzene (hydroxymethyl) 1 H-indole-4 carboxylate Sodium 1-(5- 2-(bromomethyl)- 1 3.25 404 chloro-2-(2-fluoro- 4-chloro-1-(2 2- fluoro-2 147 methylpropoxy)ben methylpropoxy)be zyl)-3- nzene (hydroxymethyl) 1 H-indole-4 carboxylate Sodium 1-(2- 2-(bromomethyl)- 1 3.30 368 cyclobutoxy-5- 4-fluoro-1 148 fluorobenzyl)-3- cyclobutoxybenze WO 2013/037960 PCT/EP2012/068101 145 (hydroxymethyl)- ne 1 H-indole-4 carboxylate Sodium 1-(5-fluoro- 2-(bromomethyl)- 1 3.40 422 2-((4- 4-fluoro-1 -((4 149 fluorobenzyl)oxy)b fluorobenzyl)oxy) enzyl)-3- benzene (hydroxymethyl) 1 H-indole-4 carboxylate Sodium 1-(5- 2-(bromomethyl)- 1 3.50 438 chloro-2-((4- 4-chloro-1-((4 fluorobenzyl)oxy)b fluorobenzyl)oxy) 150 enzyl)-3- benzene (hydroxymethyl) 1 H-indole-4 carboxylate Sodium 1-(5-chloro-2- 2-(bromomethyl)- 1 3.36 404 151 (3-fluoro-2- 4-chloro-1-(3 methylpropoxy)benzyl)- fluoro-2 3-(hydroxymethyl)-1 H indole-4-carboxylate methylpropoxy)be nzene Examples 152 to 153: Using methyl 3-formyl-1H-pyrrolo[2,3-b]pyridine-4 carboxylate as starting material 5 The next compounds were obtained using the same methodology as in example 141 but using methyl 3-formyl-1H-pyrrolo[2,3-b]pyridine-4-carboxylate as starting material and the compound II indicated. Example Compound name Starting compound LC-MS WO 2013/037960 PCT/EP2012/068101 146 Metho tR m/Z d (mi [M+H n) ] Sodium 1-(5-chloro 2-((2,4 difluorobenzyl)oxy) 2-(bromomethyl)-4 benzyl)-3- chloro-1 -((2,4 152 (hydroxymethyl)- difluorobenzyl)oxy)b 1 3.45 459 1 H-pyrrolo[2,3 enzene b]pyridine-4 carboxylate Sodium 1-(5-chloro 2-((4-chloro-2- 2-(bromomethyl)-4 fluorobenzyl)oxy)be chloro-1 -((4-chloro nzyl)-3 153 2- 1 3.57 475 (hydroxymethyl) 1 d H-ro l[ethyl)- fluorobenzyl)oxy)be 1 H-pyrrolo[2,3 nzene b]pyridine-4 carboxylate Example 154: Synthesis of sodium 1-(5-chloro-2-((4-chloro-2 5 fluorobenzyl)oxy)benzyl)-3-(2-hydroxyethyl)- 1H-indole-4-carboxylate a) To a suspension of 310 mg (0.9 mmol) of (methoxymethyl)triphenylphosphonium chloride in 2mL of toluene under argon at 09C NaHMDS 0.6M in toluene (1.2 mL, 0.72 mmol) was added via syringe. After stirring at 09C for 20 min methyl 1-(5-chloro-2-((4-chloro-2-fluorobenzyl)oxy)benzyl) 10 3-formyl-1 H-indole-4-carboxylate was added as a solution in 5mL of toluene and 3.5 mL of DCM. The resulting mixture was stirred at room temperature for 2 hours. Then it was allowed to warm to room temperature and quenched with a saturated solution of NH 4 CI. It was extracted with EtAcO and the combined organic layers WO 2013/037960 PCT/EP2012/068101 147 were washed with water and brine, dried over MgSO 4 and evaporated. The crude was purified by column chromatography eluting with mixtures cyclohexane/EtAcO. Methyl 1-(5-chloro-2-((4-chloro-2-fluorobenzyl)oxy)benzyl)-3-(2-methoxyvinyl)-1 H indole-4-carboxylate was obtained as a yellow oil (230 mg, 99%). 5 b) To a solution of methyl 1-(5-chloro-2-((4-chloro-2 fluorobenzyl)oxy)benzyl)-3-(2-methoxyvinyl)-1H-indole-4-carboxylate (230 mg, 0.45 mmol) in 9 mL of acetone HCI 1M ((2.1 mL, 2.1 mmol) was added. The resulting mixture was stirred at 509C for 1 hour. Then, water was added and it was extracted 10 with EtAcO (x3). The combined organic layers were washed with water and brine, dried over MgSO 4 . Methyl 1-(5-chloro-2-((4-chloro-2-fluorobenzyl)oxy)benzyl)-3-(2 oxoethyl)-1 H-indole-4-carboxylate was obtained (190 mg, 85%). c) To a solution of methyl 1-(5-chloro-2-((4-chloro-2 15 fluorobenzyl)oxy)benzyl)-3-(2-oxoethyl)-1H-indole-4-carboxylate (190 mg, 0.38 mmol) in 7.5 mL of THF, NaBH4 (17 mg, 0.46 mmol) was added. Reaction was stirred at room temperature for 1 h. Water was added, and the mixture was extracted with EtAcO, dried over MgSO 4 . 1-(5-chloro-2-((4-chloro-2-fluorobenzyl)oxy)benzyl) 3,4-dihydrooxepino[5,4,3-cd]indol-6(1 H)-one was obtained (120 mg, 65%). 20 d) To a suspension of 70 mg (0.15 mmol) of 1-(5-chloro-2-((4-chloro-2 fluorobenzyl)oxy)benzyl)-3,4-dihydrooxepino[5,4,3-cd]indol-6(1H)-one in 3 mL of absolute ethanol 0.18 mL of an aqueous solution of NaOH 2M was added. The resulting mixture was stirred at 809C for 1h. Then water was added and it was 25 extracted with EtAcO, dried over MgSO 4 . Sodium 1-(5-chloro-2-((4-chloro-2 fluorobenzyl)oxy)benzyl)-3-(2-hydroxyethyl)-1H-indole-4-carboxylate was obtained as a yellow solid (63 mg, 83%). tR = 3.61 min; m/x (M+H)* 488 30 Examples 155 to 160: Using methyl 3-formyl-1H-indole-4-carboxylate as starting material The next compounds were obtained using the same methodology as in example 141 step a using methyl 3-formyl-1H-indole-4-carboxylate as starting material and the WO 2013/037960 PCT/EP2012/068101 148 compound II indicated in the table below, followed by the use of the same methodology as in example 154. LC-MS Example Starting compound tR m/z Compound name Metho II (mi [M+H n) ] Sodium 1 (5-chloro-2 ((2,4 difluorobenz methyl 1-(5-chloro yl)oxy)benz 2-(2,4 155 yl)-3-(2- difluorobenzyloxy)b 1 3.51 472 hydroxyethy enzyl)-3-formyl-1 H 1)-1 H-indole- indole-4-carboxylate 4 carboxylate Sodium 1-(5-fluoro 2-isobutoxybenzyl)- methyl 1-(5-fluoro-2 156 3-(2-hydroxyethyl)- isobutoxybenzyl)-3- 1 3.38 386 1 H-indole-4- formyl-1 H-indole-4 carboxylate carboxylate Sodium 1-(5 chloro-2 methyl 1-(5-chloro isobutoxybenzyl)-3-2-sbtyeny) 157 (2-hydroxyethyl)- 1 3.48 402 1 H-indole-4- 3-formyl-1 H-indole carboxylate 4-carboxylate WO 2013/037960 PCT/EP2012/068101 149 Sodium 1-(5-chloro 2-(2-fluoro-2- methyl 1-(5-chloro methylpropoxy)ben 2(2fluoro2 158 zyl)-3-(2 158 h yl)- H- methylpropoxy)benz 1 3.09 420 hydroxyethyl)-1 H- l3-om -1H indole-4-yl)-3-formyl-1
    H
    indole-4 carboxylate indole-4-carboxylate Sodium 1-(2-((2,4 difluorobenzyl)oxy)- methyl 1-(2-(2,4 5-fluorobenzyl)-3- difluorobenzyloxy) 159 (2-hydroxyethyl)- 5-fluorobenzyl)-3- 1 3.40 456 1 H-indole-4- formyl-1 H-indole-4 carboxylate carboxylate Sodium 1-(5-chloro 2-(3-fluoro-2- methyl 1-(5-chloro methylpropoxy)ben 2-(3-fluoro-2 160 zyl)-3-(2- methylpropoxy)benz 1 hydroxyethyl)-1 H- yl)-3-formyl-1 H indole-4- indole-4-carboxylate carboxylate Example 161: Synthesis of sodium (E)-3-(2-carboxylatovinyl)-1-(5-chloro-2-((4 chloro-2-fluorobenzyl)oxy)benzyl)-1H-indole-4-carboxylate 5 a) To a suspension of NaH 60% in mineral oil (19 mg, 0.46 mmol) in 2 mL of DMF under argon and cooled at 09C (E)-methyl 3-(3-ethoxy-3-oxoprop-1-en-1-yl) 1H-indole-4-carboxylate (120 mg, 0.44 mmol) was added as a solution in 2 mL of DMF. The resulting solution was stirred at 09C for 15 minutes. Then, a solution of 2 (bromomethyl)-4-chloro-1-((4-chloro-2-fluorobenzyl)oxy)benzene (176 mg, 0.48 10 mmol) in 2mL of DMF was added dropwise. Reaction was stirred at 0C for 3h. Reaction was quenched with water, extracted with EtAcO and the combined organic WO 2013/037960 PCT/EP2012/068101 150 extracts were washed with brine, dried over anhydrous Na 2
    SO
    4 , filtered and the solvent evaporated. The crude was purified by column chromatography over silica gel, eluting with mixtures cyclohexane/EtAcO to yield (E)-methyl 1-(5-chloro-2-((4 chloro-2-fluorobenzyl)oxy)benzyl)-3-(3-ethoxy-3-oxoprop-1-en-1-yl)-1H-indole-4 5 carboxylate (230 mg, 94%). b) To a suspension of (E)-methyl 1-(5-chloro-2-((4-chloro-2 fluorobenzyl)oxy)benzyl)-3-(3-ethoxy-3-oxoprop-1-en-1-yl)-1H-indole-4-carboxylate (150 mg, 0.27 mmol) in 4 mL of absolute EtOH, 0.28 mL (0.56 mmol) of an aqueous 10 solution of NaOH 2M was added. The mixture was heated at 809C overnight. It was allowed to cool to room temperature. A white solid appeared. It was filtterd and washed with cold water. The title compound was obtained (143 mg, 93%). LC-MS: tR = 3.28; [M+H]*= 514 (Method 1) 15 Example 162: Using (E)-methyl 3-(3-ethoxy-3-oxoprop-1-en-1-yI)-1H-indole-4 carboxylate as starting material. The next compound was obtained using the same methodology as in Example 161 with (E)-methyl 3-(3-ethoxy-3-oxoprop-1 -en-1 -yl)-1 H-indole-4-carboxylate but using 20 the compound II indicated. LC-MS Example Starting compound tR m/z Compound name Metho II (mi [M+H n) ] Sodium (E)-3-(2 carboxylatovinyl)-1 - 2-(bromomethyl)-4 162 (5-chloro-2-((2,4- chloro-1-((2,4- 1 3.16 498 difluorobenzyl)oxy) difluorobenzyl)oxy)b benzyl)-1 H-indole- enzene 4-carboxylate WO 2013/037960 PCT/EP2012/068101 151 Example 163: Synthesis of sodium 1-(5-chloro-2-((2,4 difluorobenzyl)oxy)benzyl)-1H-pyrrolo[2,3-c]pyridine-4-carboxylate a) To a suspension of NaH 60% (19 mg, 0.47 mmol) in dry DMF (1 mL) at 0 9C was added dropwise a solution of 1 H-pyrrolo[2,3-c]pyridine-4-carbonitrile (67 5 mg, 0.45 mmol) in DMF (1 mL). After 10 min a solution of 2-(bromomethyl)-4 chloro-1-((2,4-difluorobenzyl)oxy)benzene (162 mg, 0.47 mmol) in 1 mL of DMF was added dropwise. After 16 h at 0 9C water was added and extracted with EtAcO (x3). Combined organic extracts were washed with water, brine and dried over Na2SO4. Column chromatography on silica gel eluting with DCM:MeOH (95:5) gave the 10 desired compound as a slightly brown solid (159 mg, 87% yield). 'H NMR (400 MHz, CDCl3) 6 8.83 (s, 1H), 8.55 (s, 1H), 7.37 (d, J = 3.1 Hz, 1H), 7.29 (dd, J = 8.8, 2.6 Hz, 1H), 7.22 - 7.14 (m, 1H), 6.99 (d, J = 2.6 Hz, 1H), 6.94 (d, J = 8.8 Hz, 1H), 6.90 - 6.82 (m, 2H), 6.70 (dd, J = 3.1, 0.8 Hz, 1H), 5.37 (s, 15 2H), 5.04 (s, 2H). b) To a suspension of 1-(5-chloro-2-((2,4-difluorobenzyl)oxy)benzyl)-1 H pyrrolo[2,3-c]pyridine-4-carbonitrile (148 mg, 0.36 mmol) in EtOH (3 mL), a solution of NaOH (144 mg, 3.61 mmol) in H20 (0.75 mL) was added at room temperature. 20 The mixture was stirred at 90 9C overnight. It was cooled and the mixture was acidified with HCI 1 M. Water and EtAcO were added and the aqueous phase was extracted with EtAcO (x3). The combined organic phases were washed with brine and dried with Na2SO4. The crude product was purified by SiC 2 column cromatography, eluting with a gradient of DCM:MeOH (9.5-0.5 to 9-1). Title 25 compound was obtained as a white powder (90 mg, 58% yield). 'H NMR (300 MHz, DMSO) 6 8.95 (s, 1H), 8.68 (s, 1H), 7.67 (d, J = 3.0 Hz, 1H), 7.55 (dd, J = 15.3, 8.5 Hz, 1H), 7.37 (dd, J = 8.8, 2.6 Hz, 1H), 7.34 - 7.25 (m, 1H), 7.22 (d, J = 8.9 Hz, 1H), 7.14 (d, J = 2.6 Hz, 1H), 7.09 (td, J = 8.5, 1.8 Hz, 1H), 30 6.90 (d, J = 2.8 Hz, 1H), 5.49 (s, 2H), 5.17 (s, 2H). c) t-BuONa (19 mg, 0.2 mmol) was added to a suspension of 1-(5-chloro-2 ((2,4-difluorobenzyl)oxy)benzyl)-1 H-pyrrolo[2,3-c]pyridine-4-carboxylic acid (87 mg, 0.2 mmol) in MeOH (5 mL) and stirred at room temperature. After 2 h, the solvent WO 2013/037960 PCT/EP2012/068101 152 was removed out of the clear solution, rendering a slightly yellow solid that was triturated with Et 2 0 and vacuum dried, affording 81.5 mg of sodium 1-(5-chloro-2 ((2,4-difluorobenzyl)oxy)benzyl)-1H-pyrrolo[2,3-c]pyridine-4-carboxylate (89% yield). 5 1H NMR (400 MHz, DMSO) 6 8.64 (s, 1H), 8.55 (s, 1H), 7.59 (dd, J = 15.3, 8.6 Hz, 1H), 7.45 (d, J = 3.0 Hz, 1H), 7.38 - 7.28 (m, 2H), 7.22 (d, J = 8.8 Hz, 1H), 7.16 - 7.05 (m, 2H), 6.91 (d, J = 2.6 Hz, 1 H), 5.42 (s, 2H), 5.21 (s, 2H). LC-MS: tR = 3.37 [M+H]*= 429 (method 1). 10 Example 164: Using 1H-pyrrolo[2,3-c]pyridine-4-carbonitrile as starting material. The next compound was obtained using the same methodology as in Example 163, but starting with 1 H-pyrrolo[2,3-c]pyridine-4-carbonitrile and the compound II 15 indicated. LC-MS Example Starting tR m/Z Compound name Meth compound II (mi [M+ od n) H]* Sodium 1-(5-chloro- 2-(bromomethyl) 2-((4-chloro-2- 4-chloro-1-((4 fluorobenzyl)oxy)be 164 chloro-2- 1 3.45 445 nzyl)-1 H-pyrrolo[2,3- fluorobenzyl)oxy) c]pyridine-4 benzene carboxylate Example 165: synthesis of sodium 1-(5-chloro-2-((2,4 20 difluorobenzyl)oxy)benzyl)indoline-4-carboxylate a) To a suspension of K2CO3 (176 mg, 1.27 mmol) and methyl indoline-4 carboxylate (215 mg, 1.21 mmol) in dry DMF (3 mL) at 0 9C was added 2 (bromomethyl)-4-chloro-1-((2,4-difluorobenzyl)oxy)benzene (443 mg, 1.27 mmol) in DMF (3 mL). The reaction was stirred at RT overnight and then the solution was WO 2013/037960 PCT/EP2012/068101 153 poured onto crushed ice and extracted with EtAcO (x2). Combined organic extracts were washed with water, brine and dried over Na2SO4. Column chromatography on silica gel eluting with hexane:EtAcO gave the desired compound as a white solid.(430 mg, 80% yield). 5 'H NMR (400 MHz, Chloroform-d) 6 7.39 (td, J = 8.6, 6.3 Hz, 1 H), 7.28 (dd, J = 15.4, 1.8 Hz, 1 H), 7.21 (dd, J = 8.6, 2.7 Hz, 1 H), 7.04 (t, J = 7.8 Hz, 1 H), 6.90 (d, J = 8.7 Hz, 1 H), 6.89 - 6.79 (m, 2H), 6.49 (dd, J = 7.8, 1.0 Hz, 1 H), 5.08 (s, 2H), 4.25 (s, 2H), 3.88 (s, 3H), 3.50 - 3.41 (m, 2H), 3.41 - 3.32 (m, 2H). 10 b) To a solution of methyl 1-(5-chloro-2-((2,4 difluorobenzyl)oxy)benzyl)indoline-4-carboxylate (400 mg, 0.9 mmol) in EtOH (8 mL), a solution of NaOH (108 mg, 2.7 mmol) in H20 (2 mL) was added at room temperature. The mixture was stirred at 80 9C overnight. It was cooled and water 15 was added. The aqueous layer was extracted with EtAcO (x3). The combined organic layers were washed with brine dried (Na2SO4) filtered and concentrated. (380 mg, 93% yield). LC-MS: tR = 3.79 [M+H]*= 430 (method 1). 20 'H NMR (400 MHz, DMSO) 6 7.63 (dd, J = 15.3, 8.6 Hz, 1H), 7.35 - 7.27 (m, 3H), 7.20 (d, J = 8.6 Hz, 1H), 7.10 (td, J = 8.5, 1.7 Hz, 1H), 7.04 (dd, J = 7.7, 0.9 Hz, 1H), 6.81 (t, J = 7.7 Hz, 1H), 6.27 (d, J = 7.0 Hz, 1H), 5.17 (s, 2H), 4.15 (s, 2H), 3.24 - 3.17 (m, 4H). 25 Examples 166 to 171: Using methyl indoline-4-carboxylate as starting material The next compounds were obtained using the same methodology as in example 165 but using the compound II indicated. LC-MS EapeStarting t R m/Z Example Compound name Meth I compound II (mi [M+H od __ __ __ __ _ __ __ __ __ __ __ __ _ __ __ __ __ __ _ __ _j n) ] WO 2013/037960 PCT/EP2012/068101 154 2-(bromomethyl)-4 Sodium 1-(5-chloro-2- chloro-1 -2-fl (2-flu ro-2-chloro-1-(2-fluoro (2-flIuoro-2 166 2- 1 3.45 378 methylpropoxy)benzyl)in methylpropoxy)ben doline-4-carboxylate zene 2-(bromomethyl)-4 So 1(-chloro-2- chloro-1 -((4-chloro ((4-chloro-2 167 2- 1 3.92 446 fluorobenzyl)oxy)benzyl) fluorobenzyl)oxy)b indoline-4-carboxylate enzene Sodium 1-(2-((2-chloro- 2-(bromomethyl)-1 4-fluorobenzyl)oxy)-5- ((2-chloro-4- 1 3.72 430 168 fluorobenzyl)indoline-4- fluorobenzyl)oxy) carboxylate 4-fluorobenzene Sodium 1-(5-chloro-2- 2-(bromomethyl)-4 isobutoxybenzyl)indoline 169 chloro-1 - 1 3.70 360 -4-carboxylate isobutoxybenzene Sodium 1-(5-fluoro-2- 2-(bromomethyl)-4 isobutoxybenzyl)indoline 170 fluoro-1 - 1 3.56 344 -4-carboxylate isobutoxybenzene Sodium 1-(5-chloro-2- 2-(bromomethyl)-4 cyclobutoxybenzyl)indoli chloro-1 171 1 3.64 358 ne-4-carboxylate cyclobutoxybenzen e WO 2013/037960 PCT/EP2012/068101 155 Examples 172 to 182: Using methyl 1,2,3,4-tetrahydroquinoline-5-carboxylate as starting material The next compounds were obtained using the same methodology as in Example 165 but using methyl 1,2,3,4-tetrahydroquinoline-5-carboxylate as starting material 5 and the compound II indicated. In the preparation of compounds 175 to 182 1 equivalent of KI was added to the reaction mixture in step a) LC-MS EapeStarting tR m/Z Example Compound name Metho compound II (mi [M+H d n) ] Sodium 1-(2-((2,4 difluorobenzyl)oxy)benzy 1 -((2 172 1)-1,2,3,4- omomethyl)phen 1 3.62 410 oxy)methyl)-2,4 tetrahydroquinoline-5- difluorobenzene carboxylate Sodium 1-(5-chloro-2 ((2,4- 2-(bromomethyl)-4 173 difluorobenzyl)oxy)benzy chloro-1 -((2,4- 1 3.73 444 1)-1,2,3,4- difluorobenzyl)oxy)b tetrahydroquinoline-5- enzene carboxylate Sodium 1-(5-chloro-2 174 (cyclobutylmethoxy)benz 2-(bro -4 yl)-1,2,3,4- 4 2.10 386 (cyclobutylmethoxy) tetrahydroquinoline-5- benzene carboxylate WO 2013/037960 PCT/EP2012/068101 156 Sodium 1-(5-chloro-2 isobutoxybenzyl)- 2-(bromomethyl)-4- 19.0 175 1,2,3,4- chloro-1- 2 374 tetrahydroquinoline-5- isobutoxybenzene carboxylate Sodium 1-[5-chloro-2 (1,2- 2-(bromomethyl)-4 dimethylpropoxy)benzyl] chloro-1-(1,2- 19.5 176 -1,2,3,4- dimethylpropoxy)be 2 tetrahydroquinoline-5- nzene carboxylate Sodium 1-[5-chloro-2-(2 fluoro-2- 2-(bromomethyl)-4 methylpropoxy)benzyl]- chloro-1-(2-fluoro-2- 17.0 177 1,2,3,4- hlr--2fuo2- 2 392 ' ' methylpropoxy)ben 9 tetrahydroquinoline-5- zene carboxylate Sodium 1-[5-chloro-2 (cyclobutyloxy)benzyl]- 2-(bromomethyl)-4 chloro-1- 18.3 178 1,2,3,4- 2 372 tetrahydroquinoline-5- (cyclobutyloxy)benz 6 carboxylate ene Sodium 1-{5-chloro-2 [(2-methylprop-2- 2-(bromomethyl)-4 179 enyl)oxy]benzyl}-1,2,3,4- chloro-1-[(2 2 18.0 372 tetrahydroquinoline-5- methylprop-2- 2 carboxylate enyl)oxy]benzene WO 2013/037960 PCT/EP2012/068101 157 Sodium 1-[5-chloro-2-(3 fluoro-2- 2-(bromomethyl)-4 methylpropoxy)benzyl]- chloro-1-(3-fluoro-2- 2 17.4 392 180 1,2,3,4- methylpropoxy)ben 6 tetrahydroquinoline-5- zene carboxylate Sodium 1-[5-chloro-2-(2 fluoropropoxy)benzyl]- 2-(bromomethyl)-4 1, 4 chloro-1-(2- 16.2 181 1,2,3,4- 2 378 tetrahydroquinoline-5- fluoropropoxy)benz 5 carboxylate ene Sodium 1-(5-chloro-2 {[2-(fluoromethyl)prop-2- 2-(bromomethyl)-4 182 enyl]oxy}benzyl)-1,2,3,4- chloro-1-{[2 2 17.0 390 tetrahydroquinoline-5- (fluoromethyl)prop- 2 carboxylate 2-enyl]oxy}benzene Example 183: Synthesis of sodium 1-(5-chloro-2-((4-chloro-2 fluorobenzyl)oxy)benzyl)-1,2,3,4-tetrahydroquinoline-5-sulfonate 5 To a suspension of K2C3 (176 mg, 1.28 mmol) and sodium 1,2,3,4 tetrahydroquinoline-5-sulfonate (100 mg, 0.43 mmol) in dry DMF (4 mL) at RT was added 2-(bromomethyl)-4-chloro-1-((4-chloro-2-fluorobenzyl)oxy)benzene (186 mg, 0.51 mmol). The reaction was stirred at RT overnight. Water was added and the 10 solution extracted with EtAcO (x3). Combined organic extracts were concentrated. Column chromatography on C18 column eluting with AcN:Water (2% of AcN to 95% in 10 min) gave the desired compound as a sligthly brown solid. LC-MS: tR = 3.95 [M+H]*= 496 (method 1). 15 WO 2013/037960 PCT/EP2012/068101 158 'H NMR (400 MHz, Methanol-d4) 6 7.53 (t, J = 8.2 Hz, 1H), 7.30 - 7.17 (m, 4H), 7.08 (d, J = 8.7 Hz, 1 H), 7.04 (d, J = 2.5 Hz, 1 H), 6.88 (t, J = 8.0 Hz, 1 H), 6.36 (dd, J = 8.4, 1.1 Hz, 1H), 5.19 (s, 2H), 4.43 (s, 2H), 3.38 (t, 2H), 3.31 (t, 2H), 2.01 (q, J = 8.7, 5.9 Hz, 2H). 5 Examples 184 to 185: Using sodium 1,2,3,4-tetrahydroquinoline-5-sulfonate as starting material The next compounds were obtained using the same methodology as in Example 10 183 but using the compound II indicated. LC-MS Example Starting tR m/Z Compound name Meth compound II (mi [M+H od n) ] Sodium 1-(5-chloro 2-((2,4- 2-(bromomethyl)-4 184 difluorobenzyl)oxy)be chloro-1-((2,4- 1 3.81 480 nzyl)-1,2,3,4- difluorobenzyl)oxy) tetrahydroquinoline- benzene 5-sulfonate Sodium 1-(2-((4 chloro-2 fluorobenzyl)oxy)ben (bromomethyl)phen 185 oxy)methyl)- 4- 1 3.85 462 zyl)-1 ,2,3,4-choo2 chloro-2 tetrahydroquinoline- fluorobenzene 5-sulfonate Examples 186 to 187: Using N-((1,2,3,4-tetrahydroquinolin-5 15 yl)sulfonyl)acetamide as starting material The next compounds were obtained using the same methodology as in the Example 183 but using N-((1,2,3,4-tetrahydroquinolin-5-yl)sulfonyl)acetamide and the compound II indicated as starting materials.
    WO 2013/037960 PCT/EP2012/068101 159 LC-MS Example Starting tR m/Z Compound name Meth compound II (mi [M+H od n) ] N-((1-(5-chloro-2 ((2,4- 2-(bromomethyl)-4 186 difluorobenzyl)oxy)be chloro-1-((2,4- 1 3.76 521 nzyl)-1,2,3,4- difluorobenzyl)oxy) tetrahydroquinolin-5- benzene yl)sulfonyl)acetamide N-((1 -(5-chloro-2-((4 chloro-2- 2-(bromomethyl)-4 fluorobenzyl)oxy)ben chloro-1 -((4-chloro 187 zyl)-1,2,3,4- 2- 1 3.92 537 tetrahydroquinolin-5- fluorobenzyl)oxy)be yl)sulfonyl)acetamide nzene Example 188: synthesis of sodium 1-(5-chloro-2-((4-chloro-2 5 fluorobenzyl)oxy)benzyl)-3-(hydroxymethyl)- 1H-indazole-4-carboxylate a) To a solution of methyl 3-formyl-1H-indazole-4-carboxylate (76 mg, 0.4 mmol) in 4.5 mL of DMF at 09C NaH 60% in mineral oil (16 mg, 0.4 mmol) and 2 (bromomethyl)-4-chloro-1 -((4-chloro-2-fluorobenzyl)oxy)benzene (135 mg, 0.4 mmol) were added. Reaction was stirred at room temperature for 30 min. Then, 10 water was added. The resulting mixture was extracted with EtAcO (x3) and the combined organic layers were washed with a saturated solution of NH 4 CI and brine and dried over MgSO 4 . After evaporating the solvent the crude was purified by column chromatography over silica gel eluting with mixtures cyclohexane/EtAcO 9:1 to 6:4. Methyl 1-(5-chloro-2-((4-chloro-2-fluorobenzyl)oxy)benzyl)-3-formyl-1 H 15 indazole-4-carboxylate was obtained (76 mg, 42%).
    WO 2013/037960 PCT/EP2012/068101 160 b) To a solution of methyl 1-(5-chloro-2-((4-chloro-2 fluorobenzyl)oxy)benzyl)-3-formyl-1 H-indazole-4-carboxylate (76 mg, 0.2 mmol) in 3 mL of THF cooled at 09C NaBH4 (12 mg, 0.3 mmol) was added. After 1 h water was added and the resulting mixture was extracted with EtAcO. The combined organic 5 phases were washed with brine, dried over MgSO 4 . After evaporating the solvent methyl 1 -(5-chloro-2-((4-chloro-2-fluorobenzyl)oxy)benzyl)-3-(hydroxymethyl)-1 H indazole-4-carboxylate was added (60 mg, 79%). c) To a solution of methyl 1-(5-chloro-2-((4-chloro-2 10 fluorobenzyl)oxy)benzyl)-3-(hydroxymethyl)-1H-indazole-4-carboxylate (60 mg, 0.1 mmol) in absolute EtOH (2.5 mL) an aqueous solution of NaOH 2M was added (0.15 mL, 0.3 mmol). The mixture was stirred at 809C for 1h, then, it was allowed to cool to room temperature. Water was added and the resultin mixture was extracted with EtAcO and the organic layers washed with water and dried over MgSO 4 . After 15 removing the solvent sodium 1-(5-chloro-2-((4-chloro-2-fluorobenzyl)oxy)benzyl)-3 (hydroxymethyl)-1H-indazole-4-carboxylate was obtained (42 mg, 69%). tR = 3.60 min, m/z (M+H)* = 475. Example 189: Synthesis of Sodium 1-(5-chloro-2-(2-fluoro-2 20 methylpropoxy)benzyl)-3-(hydroxymethyl)-1H-indazole-4-carboxylate This compound was synthesized using the same methodology as compound 188 using 2-(bromomethyl)-4-chloro-1-(2-fluoro-(2-methylpropyl)oxy)benzene. tR = 3.23 min, m/z (M+H)* = 407. 25 Example 190: Synthesis of sodium 1-(5-chloro-2-(propoxy)benzyl)-1,2,3,4 tetrahydroquinoline-5-carboxylate a) To a suspension of methyl 1,2,3,4-tetrahydroquinoline-5-carboxylate hydrochloride (172 mg, 0.75 mmol) in dry THF (5 mL), was added dropwise a solution of 5-chloro-2-propoxybenzaldehyde (150 mg, 0.75 mmol) in THF (3 mL) and 30 AcOH (2 drops). The reaction mixture was stirred at room temperature overnight. At 09C, NaBH(AcO) 3 was added portion wise and the reaction mixture was stirred at room temperature overnight. The solvent was evaporated to dryness, the residue was diluted with H 2 0 and extracted with EtAcO thrice. The combined organic phases were dried over anhydrous Na 2
    SO
    4 , filtered and concentrated. The crude WO 2013/037960 PCT/EP2012/068101 161 residue was chromatographed on a silica gel flash system (Biotage SP1) using hexanes/EtAcO mixtures of increasing polarity as eluent to afford 94 mg of the desired product (33.3.% yield). LC-MS (method 4): tR = 3.43 min; m/z = 374 (MH+). 5 b) Following a similar procedure to that described in example 123 (section b), but using the compound obtained in previous section as starting material, the desired compound was obtained. LC-MS (method 4): tR = 1.89 [M+H]*= 360 (Method 4) 10 'H NMR (300 MHz, DMSO-d6) 6 7.32-7.25 (m, 1H, ArH); 7.11-6.98 (m, 2H, ArH); 6.75 (t, J= 7.7 Hz, 1H, ArH); 6.54 (d, J= 6.5 Hz, 1H, ArH); 6.07 (d, J= 7.3 Hz, 1H, ArH); 4.39 (s, 2H); 4.05 (t, J= 6.4 Hz, 2H); 3.42-3.29 (m, 2H); 2.95 (t, J= 6.2 Hz, 2H); 1.97-1.87 (m, 2H); 1.86-1.75 (m, 2H); 1.07 (t, J= 7.3, 3H). 15 Examples 191 to 193: Using methyl 1,2,3,4-tetrahydroquinoline-5-carboxylate hydrochloride as starting material The next compounds were obtained using the same methodology as in Example 190 but using the corresponding aldehyde specified as starting materials. LC-MS Example tR m/Z Compound name Starting aldehyde Metho d (mi [M+H n) ] Sodium 1-(5-chloro 2 5-chloro-2 191 (cyclopentyloxy)ben (cyclopentyloxy)ben 4 2.03 385 zyl)-1,2,3,4 tetrahydroquinoline 5-carboxylate WO 2013/037960 PCT/EP2012/068101 162 Sodium 1-(2-(4 chloro-2 fluorobenzyloxy)-5- 2-(4-chloro-2 192 methylbenzyl)- fluorobenzyloxy)-5- 2.14 440 methylbenzaldehyd 1,2,3,4 e tetrahydroquinoline 5-carboxylate Sodium 1-(5-chloro 2 5-chloro-2 193 (neopentyloxy)benz (neopentyloxy)benz 4 2.13 388 yl)-1,2,3,4 tetrahydroquinoline 5-carboxylate Examples 194 to 199: Using methyl 3,4-dihydro-2H-benzo[b][1,4]oxazine-8 carboxylate as starting material 5 The following compounds were prepared using the same methodology as in Example 190 using methyl 3,4-dihydro-2H-benzo[b][1,4]oxazine-8-carboxylate and the corresponding aldehyde specified as starting materials. LC-MS Example tR m/Z Compound name Starting aldehyde Metho d (mi [M+H n) ] Sodium 4-(2-(4 chloro-2 fluorobenzyloxy)-5- 2-(4-chloro-2 methylbenzyl)-3,4- fluorobenzyloxy)-5- 4 2.03 442 methylbenzaldehyd di hyd ro-2H e benzo[b][1,4]oxazin e-8-carboxylate WO 2013/037960 PCT/EP2012/068101 163 Sodium 4-(5-fluoro 2-isobutoxybenzyl)- 5-fluoro-2 195 3,4-dihydro-2H- isobutoxybenzaldeh 4 1.79 360 benzo[b][1,4]oxazin yde e-8-carboxylate Sodium 4-(5-chloro 2-isobutoxybenzyl)- 5-chloro-2 196 3,4-dihydro-2H- isobutoxybenzaldeh 4 1.86 376 benzo[b][1,4]oxazin yde e-8-carboxylate Sodium 4-(5-chloro 2 5-chloro-2 197 cyclobutoxybenzyl) 197 3,4-dihy H- cyclobutoxybenzald 4 1.83 374 3,4-dihydro-2H- hd benzo[b][1,4]oxazin e-8-carboxylate Sodium 4-(5-chloro 2 (cyclopropylmethox 5-chloro-2 198 y)benzyl)-3,4- (cyclopropylmethoxy 4 1.79 374 dihydro-2H- )benzaldehyde benzo[b][1,4]oxazin e-8-carboxylate Sodium 4-(5-chloro 2 5-chloro-2 199 (neopentyloxy)benz (neopentyloxy)benz 4 2.01 390 yl)-3,4-dihydro-2H benzo[b][1,4]oxazin e-8-carboxylate WO 2013/037960 PCT/EP2012/068101 164 Example 200: Synthesis of sodium 1-(5-chloro-2-(3 methoxypropoxy)benzyl)i ndol i ne-4-carboxylate a) Following a similar procedure to that described in example 190 (step a), but starting from methyl indoline-4-carboxylate instead of methyl 1,2,3,4 5 tetrahydroquinoline-5-carboxylate hydrochloride and 5-chloro-2 hydroxybenzaldehyde instead of 5-chloro-2-propoxybenzaldehyde, methyl 1-(5 chloro-2-hydroxybenzyl)-1 H-indole-4-carboxylate was obtained (83 % yield) LC-MS (method 4): tR = 2.58 min; m/z = 318 (MH+). 10 b) To a solution of the compound obtained in the previous section (250 mg, 0.78 mmol) in DMF (10 mL), potassium carbonate (217 mg, 1.57 mmol) and 1 bromo-3-methoxypropane (181 mg, 1.18 mmol) were added. The reaction mixture was stirred at 60 9C overnight. The reaction mixture was diluted by adding EtAcO and saturated NH 4 CI aqueous solution (15 mL) and extracted with EtAcO (3x15 mL). 15 The combined organic phases were dried over anhydrous Na 2
    SO
    4 , filtered and concentrated. The crude residue was chromatographed on a silica gel flash system (Biotage SP1) using hexanes/EtAcO mixtures of increasing polarity as eluent, to afford the desired product in quantitative yield. LC-MS (method 4): tR = 3.09 [M+H]*= 390 20 c) Following a similar procedure to that described in example 123 (section b), but using the compound obtained in previous section as starting material, the desired compound was obtained LC-MS (method 4): tR = 1.72 [M+H]*= 376 25 'H NMR (300 MHz, DMSO-d6) 6 7.31-7.23 (m, 2H, ArH); 7.1-6.99 (m, 2H, ArH); 6.87 (t, J= 7.68 Hz, 1H, ArH); 6.36 (d, J= 7.5 Hz, 1H, ArH); 4.17 (s, 2H); 4.05 (t, J= 6.15 Hz, 2H); 3.47 (t, J= 6.2 Hz, 2H); 3.4-3.31 (m, 2H); 3.26-3.22 (m, 2H); 3.21 (s, 3H); 2.01-1.88 (m, 2H). 30 Examples 201 to 206: Using methyl indoline-4-carboxylate as starting material The next compounds were obtained using the same methodology as in example 200, but using in each case the corresponding starting materials: WO 2013/037960 PCT/EP2012/068101 165 LC-MS Example Starting material tR m/z Compound name Metho (step b) d (mi [M+H n) ] Sodium 1-(5-chloro 2-(2- 1-bromo-2 201 methoxyethoxy)ben 4 1.59 362 zyl)indoline-4 carboxylate Sodium 1-(5-chloro 3. 2- 1. (bromom 4. 202 (cyclopropylmethox ethyl)cyclopropa 2. 5 9 y)benzyl)indoline-4- ne 8 1 carboxylate Sodium 1-(5-chloro 2 1 -iodo-2,2 203 (neopentyloxy)benz 4 2.19 374 yl)indoline-4- dimethyipropane carboxylate Sodium 1-(5-chloro 2-((3-methyloxetan- (3-methyloxetan-3 204 3- yl)methyl 4 1.68 388 yl)methoxy)benzyl)i trifluoromethanesulf ndoline-4- onate carboxylate Sodium 1-(5-chloro- (3-ethyloxetan-3 2-((3-ethyloxetan-3- yI)methyl 205 yl)methoxy)benzyl)i trifluoromethanesulf 4 1.80 402 ndoline-4 onate carboxylate WO 2013/037960 PCT/EP2012/068101 166 Sodium (S)-1-(5 chloro-2-(3 206 hydroxy-2- (S)-3-bromo-2- 4 1.61 376 methylpropoxy)ben methylpropan-1-ol zyl)indoline-4 carboxylate Example 207: Sodium 1-(5-chloro-2-(4-chloro-2-fluorobenzyloxy)benzyl)-3 (methoxymethyl)-1H-indole-4-carboxylate 5 a) To a suspension of 1-(5-chloro-2-((4-chloro-2-fluorobenzyl)oxy)benzyl)-3 (hydroxymethyl)-1H-indole-4-carboxylic acid, obtained as in example 141 but extracting with EOAc at pH=2, (855 mg, 1.8 mmol) in THF (10 mL) at 09C, NaH 55% (236 mg, 5.41 mmol) and Mel (0.45 mL, 7.21 mmol) were added. The resulting mixture was stirred at room temperature overnight and concentrated to dryness. It 10 was cooled to 09C, 2M aqueous HCI solution was added up to pH = 2 and it was extracted 3 times with DCM. The combined organic phases were dried over Na 2
    SO
    4 and concentrated to dryness. The crude residue was washed successively with EtAcO and DCM 236 mg (25.8 % yield) of the desired compound were obtained. LC-MS (method 4): tR = 2.05 [M+H]-= 486 15 b) Following a similar procedure to that described in example 123 (section b), but using the compound obtained in previous section as starting material, the desired compound was obtained (quantitative yield). LC-MS (method 4): tR = 2.05 [M+H]-= 486 20 'H NMR (300 MHz, DMSO-d6) 6 7.72-7.55 (m, 2H, ArH); 7.47-7.11 (m, 6H, ArH); 7.04-6.89 (m, 1H, ArH); 6.85-6.74 (m, 1H, ArH); 5.4-5.22 (m, 4H); 4.88-4.78 (m, 2H); 3.31 (s, 3H). Example 208: Synthesis of sodium 1-(5-chloro-2-(4-chloro-2 25 fluorobenzyloxy)benzyl)-2-oxoindoline-4-carboxylate a) To a suspension of methyl 1-(5-chloro-2-(4-chloro-2 fluorobenzyloxy)benzyl)-1 H-indole-4-carboxylate, obtained in example 48 section a, (785 mg, 1.7 mmol) in DCM (15 mL), N-chlorosuccinimide (240 mg, 1.79 mmol) was WO 2013/037960 PCT/EP2012/068101 167 added. The resulting mixture was stirred at room temperature for 2h, then concentrated to dryness. The resulting foamy residue was dissolved in acetic acid (7 mL) and the reaction mixture was heated at 70 9C. 85 % H 3
    PO
    4 (197 mg, 1.71 mmol) was added and the reaction mixture was refluxed for 1 h. The reaction mixture 5 was cooled to room temperature, poured into ice water, basified to pH=1 1 with Na 2 CO3 and extracted with EtAcO (x3). The combined organic phases were dried over Na 2
    SO
    4 and concentrated to dryness. The crude residue was chromatographed on a silica gel flash system (Biotage SP1) using hexanes/EtAcO mixtures of increasing polarity as eluent. An abundant white solid appeared during the fraction 10 collection that it was filtered and washed with and diethyl ether to afford 230 mg (28.31% yield) of the desired compound. LC-MS (method 4): tR = 2.99 [M+H]*= 474 b) Following a similar procedure to that described in example 123 (section 15 b), but using the compound obtained in previous section as starting material, the desired compound was obtained (93 % yield). LC-MS (method 4): tR = 1.94 [M+H]*= 460 'H NMR (300 MHz, DMSO-d6) 6 7.77-7.49 (m, 3H, ArH); 7.46-7.25 (m, 3H, ArH); 7.16-7.01 (m, 2H, ArH); 6.64 (d, J= 7.6 Hz, 1H, ArH); 5.31 (s, 2H); 4.84 (s, 20 2H); 3.89 (s, 2H). Example 209: Synthesis of sodium 1-(2-(4-chloro-2-fluorobenzyloxy)-5 cyclopropylbenzyl)-1H-indazole-4-carboxylate 25 a) To a suspension of methyl 1-(5-bromo-2-(4-chloro-2 fluorobenzyloxy)benzyl)-1 H-indazole-4-carboxylate, obtained in example 136, section a, (197 mg, 0.39 mmol) in THF (15 mL), K 3
    PO
    4 (166 mg, 0.78 mmol), X Phos (37 mg, 0.078 mmol), Pd(AcO) 2 (8.8 mg, 0.04 mmol) and cyclopropylboronic acid (40 mg, 0.47 mmol) were added. The reaction mixture was refluxed overnight. 30 The crude reaction was filtered through a plug of Celite*, and evaporated to dryness. The crude product was diluted with saturated NaCl aqueous solution (10 mL) and extracted with EtAcO (3x15 mL). The combined organic phases were dried over anhydrous Na 2
    SO
    4 , filtered and concentrated. The crude residue was cromatographed on a silica gel flash system (SP1 Biotage) using EtAcO/hexanes WO 2013/037960 PCT/EP2012/068101 168 mixtures of increasing polarity as eluent to afford 70 mg (38.5 % yield) of the desired compound. LC-MS (method 4): tR = 3.24 [M+H]*= 465 b) Following a similar procedure to that described in example 123 (section 5 b), but using the compound obtained in previous section as starting material, the desired compound was obtained (8.65 % yield). LC-MS (method 4): tR = 2.02 [M+H]-= 449 'H NMR (300 MHz, DMSO-d6) 6 7.73 (d, J= 7 Hz, 1H, ArH); 7.49 (d, J= 8.5 Hz, 1 H, ArH); 7.22-6.99 (m, 3H, ArH); 6.94-6.8 (m, 3H, ArH); 6.7-6.65 (m, 1 H, ArH); 10 5.48 (s, 2H); 4.94 (s, 2H); 1.52 (m, 1H); 1.34-1.06 (m, 4H). Example 210: Synthesis of sodium (S)-1 -(5-chloro-2-(3-hydroxy-2 methyl propoxy)benzyl)i ndoli ne-4-carboxylate 15 a) To a suspension of (S)-methyl 1-(5-chloro-2-(3-hydroxy-2 methylpropoxy)benzyl)indoline-4-carboxylate, obtained as in example 206 (360 mg, 0.9 mmol) in THF (15 mL) at 09C, NaH 55% (55 mg, 1.38 mmol) and Mel (0.07 mL, 1.1 mmol) were added. The resulting mixture was stirred at room temperature overnight and concentrated to dryness. It was cooled to 09C, 2M aqueous HCI 20 solution was added up to pH = 2 and it was extracted 3 times with EtAcO. The combined organic phases were dried over MgSO 4 and concentrated to dryness. The residue was purified by reverse phase chromatography 24 mg (7 % yield) of of 1-(5 chloro-2-(4-chloro-2-fluorobenzyloxy)benzyl)-3-(methoxymethyl)-1 H-indole-4 carboxylic acid was obtained. 25 LC-MS (method 4): tR = 1.89 [M+H]*= 390 b) Following a similar procedure to that described in example 123 (section b), but using the compound obtained in previous section as starting material, the desired compound was obtained (97 % Yield). 30 LC-MS (method 4): tR = 1.89 [M+H]-= 390 'H NMR (300 MHz, DMSO-d6) 6 7.3-7.22 (m, 2H, ArH); 7.1-6.98 (m, 2H, ArH); 6.87 (t, J= 7.65 Hz, 1 H, ArH); 6.36 (d, J= 7.5 Hz, 1 H, ArH); 3.98-3.84 (m, 2H); 3.47-3.24 (m, 6H); 3.21 (s, 3H); 2.24-1.99 (m, 1H); 0.99 (d, J= 6.9 Hz, 3H).
    WO 2013/037960 PCT/EP2012/068101 169 Example 211. Synthesis of sodium 1-{5-chloro-2-[(4-chloro-2 ethylbenzyl)oxy]benzyl}-1H-indole-4-carboxylate a) A mixture of methyl 1-(5-chloro-2-hydroxybenzyl)-1 H-indole-4-carboxylate (0.20 g, 0.63 mmol), K 2
    CO
    3 (0.13 g, 0.95 mmol) and 1-(bromomethyl)-4-chloro-2 5 ethylbenzene (0.18 g, 0.76 mmol) in DMF (8 mL) was stirred at room temperature for 17 h. The reaction mixture was poured over EtAcO (40 mL) and washed with water (2 x 20 mL); the organic layer was dried over anhydrous Na 2
    SO
    4 and filtered. After removal of the solvent, the residue was purified by column chromatography on silica gel (10% EtAcO/hexanes), affording 0.20 g of methyl 1-{5-chloro-2-[(4-chloro 10 2-ethylbenzyl)oxy]benzyl}-1 H-indole-4-carboxylate [Rf= 0.50 (20% EtAcO/hexanes), white solid, 68% yield]. 'H-NMR (CDC1 3 , 250 MHz, 6): 7.89 (d, J= 6.6 Hz, 1H, ArH); 7.40 (d, J= 8.3 Hz, 1H, ArH); 7.28-7.09 (m, 7H, ArH); 6.89 (d, J= 8.8 Hz, 1H, ArH); 6.74 (d, J= 2.4 Hz, 1H, ArH); 5.28 (s, 2H); 5.02 (s, 2H); 3.99 (s, 3H); 2.63 (q, J= 7.5 Hz, 2H); 1.22 (t, 15 J= 7.5 Hz, 3H). b) NaOH (aqueous solution 10%, 0.3 mL) was added to a solution of methyl 1-{5-chloro-2-[(4-chloro-2-ethylbenzyl)oxy]benzyl}-1H-indole-4-carboxylate (0.19 g, 0.41 mmol) in EtOH (10 mL) and heated at 80 0C for 2 h. After removal of the 20 volatiles by rotatory evaporation, the resulting residue was dissolved in DCM (20 mL), acidified with HCI (aqueous solution 10%, 5 mL), and washed with water (20 mL). The organic layer was dried over anhydrous Na 2
    SO
    4 and filtered. After removal of the solvent, the residue was purified by column chromatography on silica gel (5D75% EtAcO/hexanes), affording 0.12 g of 1-{5-chloro-2-[(4-chloro-2 25 ethylbenzyl)oxy]benzyl}-1 H-indole-4-carboxylic acid, white solid, 65% yield. LC-MS ESI+ m/z: 454 (M+1, 93%) (Method 5). c) t-BuONa (25 mg, 0.26 mmol) was added to a suspension of 1-{5-chloro-2 [(4-chloro-2-ethylbenzyl)oxy]benzyl}-1 H-indole-4-carboxylic acid (117 mg, 0.26 30 mmol) in MeOH (8 mL) and stirred at room temperature. After 1.5 h, the solvent was removed out of the clear solution, rendering a pale yellow solid that was triturated with Et 2 0 (2 x 5 mL) and vacuum dried, affording 90 mg of sodium 1-{5-chloro-2-[(4 chloro-2-ethylbenzyl)oxy]benzyl}-1 H-indole-4-carboxylate, white solid, 74% yield. LC-MS ESI+ m/z: 454 (M+2-Na, 92%) (Method 2).
    WO 2013/037960 PCT/EP2012/068101 170 "H-NMR (DMSO-d 6 , 250 MHz, 6): 7.56-7.46 (m, 2H, ArH); 7.39-7.15 (m, 7H, ArH); 6.94 (t, J= 7.7 Hz, 1H, ArH); 6.61 (br s, 1H, ArH); 5.32 (s, 2H); 5.20 (s, 2H); 2.72 (q, J= 7.3 Hz, 2H); 1.20 (t, J= 7.3 Hz, 3H). 5 Example 212: Synthesis of sodium 1-{5-chloro-2-[(4-chloro-2 fluorobenzyl)oxy]benzyl}-1 H-pyrazolo[3,4-b]pyridine-4-carboxylat a) Hydrazine monohydrate (0.78 mL, 15.94 mmol) was added dropwise to a suspensi6n of 2-fluoro-4-iodonicotinaldehyde (2.00 g, 7.97 mmol) in 2-propanol (20 10 mL) and heated at 60 0C. After 2 h, the solvent was removed by rotatory evaporation and the residue dissolved in EtAcO (40 mL) and washed with water (30 mL). The organic layer was dried over anhydrous Na 2
    SO
    4 and filtered. After removal of the solvent, the residue was purified by column chromatography on silica gel (10w40% EtAcO/hexanes), affording 1.62 g of 4-iodo-1H-pyrazolo[3,4-b]pyridine, 15 [Rf= 0.30 (20% EtAcO/hexanes), white solid, 82% yield]. LC-MS ESI+ m/z: 246 (M+1, 99%) (Method 5). "H-NMR (CDC1 3 , 250 MHz, 6): 12.45 (br s, 1H); 8.23 (d, J= 5.0 Hz, 1H, ArH); 7.98 (s, 1 H, ArH); 7.61 (d, J= 5.0 Hz, 1 H, ArH). 20 b) Following the general procedure described in example 1, section a, 1-{5 chloro-2-[(4-chloro-2-fluorobenzyl)oxy]benzyl}-4-iodo-1 H-pyrazolo[3,4-b]pyridine was obtained in 31% yield (white solid) after 3 h, using 4-iodo-1H-pyrazolo[3,4 b]pyridine (0.17 g, 0.69 mmol), NaH (33 mg, 0.82 mmol) and 2-(bromomethyl)-4 chloro-1-[(4-chloro-2-fluorobenzyl)oxy]benzene (0.30 g, 0.83 mmol) as starting 25 materials. LC-MS ESI+ m/z: 528 (M+1, 87%) (Method 5). "H-NMR (CDC1 3 , 250 MHz, 6): 8.05 (d, J= 4.6 Hz, 1H, ArH); 7.90 (s, 1H, ArH); 7.53 (d, J= 4.6 Hz, 1H, ArH); 7.36-7.05 (m, 4H, ArH); 6.94 (d, J= 2.4 Hz, 1H, ArH); 6.86 (d, J= 8.6 Hz, 1 H, ArH); 5.69 (s, 2H); 5.04 (s, 2H). 30 c) A suspension of 1-{5-chloro-2-[(4-chloro-2-fluorobenzyl)oxy]benzyl}-4 iodo-1H-pyrazolo[3,4-b]pyridine (0.30 g, 0.56 mmol), dppf (31 mg, 0.06 mmol) and TEA (0.16 mL, 1.13 mmol) in EtOH (8 mL) was thoroughly purged with argon; Pd(AcO) 2 (13 mg, 0.06 mmol) was added and the mixture was purged again with WO 2013/037960 PCT/EP2012/068101 171 carbon monoxide. The reaction was heated at reflux under carbon monoxide pressure (balloon) for 3 h. After removal of the solvent, the residue was purified by column chromatography on silica gel (5--10% EtAcO/hexanes), affording 105 mg of ethyl 1-{5-chloro-2-[(4-chloro-2-fluorobenzyl)oxy]benzyl}-1 H-pyrazolo[3,4-b]pyridine 5 4-carboxylate [Rf= 0.60 (20% EtAcO/hexanes), white solid, 40% yield]. LC-MS ESI+ m/z: 474 (M+1, 73%) (Method 5). d) Following the general procedure described in example 211, section b, 1 {5-chloro-2-[(4-chloro-2-fluorobenzyl)oxy]benzyl}-1 H-pyrazolo[3,4-b]pyridine-4 10 carboxylic acid was obtained in 58% yield (pale pink solid), using ethyl 1-{5-chloro-2 [(4-chloro-2-fluorobenzyl)oxy]benzyl}-1H-pyrazolo[3,4-b]pyridine-4-carboxylate (0.17 g, 0.37 mmol) as starting material. LC-MS ESI+ m/z: 446 (M+1, 96%) (Method 5). 15 e) Following the general procedure described in example 211, section c, sodium 1-{5-chloro-2-[(4-chloro-2-fluorobenzyl)oxy]benzyl}-1 H-pyrazolo[3,4 b]pyridine-4-carboxylate was obtained in 95% yield (pale brown solid), using 1-{5 chloro-2-[(4-chloro-2-fluorobenzyl)oxy]benzyl}-1 H-pyrazolo[3,4-b]pyridine-4 carboxylic acid (96 mg, 0.22 mmol) as starting material. 20 LC-MS ESI+ m/z: 446 (M+2-Na, 98%) (Method 2). 'H-NMR (CD 3 OD, 250 MHz, 6): 8.50 (s, 1H, ArH); 8.45 (d, J= 5.0 Hz, 1H, ArH); 7.58 (d, J= 5.0 Hz, 1H, ArH); 7.37-7.11 (m, 4H, ArH); 7.05 (d, J= 8.8 Hz, 1H, ArH); 6.87 (d, J= 2.6 Hz, 1 H, ArH); 5.70 (s, 2H); 5.07 (s, 2H). 25 Examples 213 to 214: Using 4-iodo-1H-pyrazolo[3,4-b]pyridine as starting material The next compound was obtained using the same methodology as in Example 212 but using the compound II indicated. 30 LC-MS Example Starting tR m/Z Compound name Meth compound II (mi [M+ od n) H]* WO 2013/037960 PCT/EP2012/068101 172 Sodium 1-[5-chloro 2-(2-fluoro-2- 2-(bromomethyl) methylpropoxy)benz 4-chloro-1-(2- 14.4 213 yl]-1 H-pyrazolo[3,4- fluoro-2- 2 378 b]pyridine-4- methylpropoxy)be 3 carboxylic acid nzene Sodium 1-[5-chloro 2- 2-(bromomethyl) (cyclobutyloxy)benz 4-chloro-1- 15.0 214 yl]-1 H-pyrazolo[3,4- (cyclobutyloxy)be 2 9 358 b]pyridine-4- nzene carboxylate Example 215: Synthesis of Sodium 1-{5-chloro-2-[(4-chloro-2 fluorobenzyl)oxy]benzyl}-2-oxo-1,2,3,4-tetrahydroquinoline-5-carboxylate 5 a) Following the general procedure described in example 212, section c, ethyl 2-oxo-1,2,3,4-tetrahydroquinoline-5-carboxylate was obtained in 61% yield (pale orange solid) after 4 h, using 2-oxo-1,2,3,4-tetrahydroquinolin-5-y trifluoromethanesulfonate (66 mg, 0.22 mmol) as starting material. The latter was obtained from the known 5-hydroxy-3,4-dihydroquinolin-2(1H)-one under standard 10 conditions. 'H-NMR (CDC1 3 , 250 MHz, 6): 8.36 (br s, 1H, NH); 7.59 (d, J= 7.7 Hz, 1H, ArH); 7.23 (t, J= 7.8 Hz, 1H, ArH); 6.93 (d, J= 7.8 Hz, 1H, ArH); 4.36 (q, J= 7.1 Hz, 2H); 3.43-3.35 (m, 2H); 2.65-2.56 (m, 2H); 1.40 (t, J= 7.1 Hz, 3H). 15 b) Following the general procedure described in example 1, section a, ethyl 1-{5-chloro-2-[(4-chloro-2-fluorobenzyl)oxy]benzyl}-2-oxo-1,2,3,4 tetrahydroquinoline-5-carboxylate was obtained forming part of an uncharacterized mixture, using ethyl 2-oxo-1,2,3,4-tetrahydroquinoline-5-carboxylate (0.17 g, 0.54 WO 2013/037960 PCT/EP2012/068101 173 mmol), NaH (37 mg, 0.93 mmol) and 2-(bromomethyl)-4-chloro-1-[(4-chloro-2 fluorobenzyl)oxy]benzene (0.34 g, 1.01 mmol) as starting materials. c) Following the general procedure described in example 211, section b,1 -{5 5 chloro-2-[(4-chloro-2-fluorobenzyl)oxy]benzyl}-2-oxo-1,2,3,4-tetrahydroquinoline-5 carboxylic acid was obtained in 26% yield (white solid), using the mixture obtained in the previous step as starting material. LC-MS ESI+ m/z: 474 (M+1, 98%) (Method 5). 10 d) Following the general procedure described in example 211, section c, sodium 1-{5-chloro-2-[(4-chloro-2-fluorobenzyl)oxy]benzyl}-2-oxo-1,2,3,4 tetrahydroquinoline-5-carboxylate was obtained in 85% yield (white solid), using 1 {5-chloro-2-[(4-chloro-2-fluorobenzyl)oxy]benzyl}-2-oxo-1,2,3,4-tetrahydroquinoline 5-carboxylic acid (62 mg, 0.13 mmol) as starting material. 15 LC-MS ESI+ m/z: 474 (M+2-Na, 98%) (Method 2). 'H-NMR (CD 3 OD, 250 MHz, 6): 7.58 (t, J= 8.5 Hz, 1H, ArH); 7.33-7.02 (m, 6H, ArH); 6.88 (d, J= 2.5 Hz, 1H, ArH); 6.73 (d, J= 8.0 Hz, 1H, ArH); 5.22 (s, 2H); 5.12 (s, 2H); 3.22-3.10 (m, 2H); 2.75-2.65 (m, 2H). 20 Example 216: Synthesis of sodium 1-{5-chloro-2-[(4-chloro-2 fluorobenzyl)oxy]benzyl}-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-4-carboxylate a) Freshly prepared LDA (1.44 mmol) was added to a solution of 2-fluoro-3 iodopyridine (0.32 g, 1.44 mmol) in THF (12 mL) cooled at -78 0C. After 1.5 h, a 25 solution of 3-{5-chloro-2-[(4-chloro-2-fluorobenzyl)oxy]benzyl}-1,2,3-oxathiazolidine 2,2-dioxide (0.70 g, 1.72 mmol) in 8 mL of THF was transferred via canula to the anion solution, allowing to reach room temperature (overnight). TLC showed an intense polar spot corresponding to the sulfamic acid intermediate. The solvent was evaporated and the resulting residue was dissolved in 1,4-dioxane (6 mL) and 30 treated with 1.0 mL of HCI (4 M in 1,4-dioxane), stirring at room temperature. After 16 h, the reaction was cooled to 0 0C and slowly basified with NaOH (aqueous solution 10%, 5 mL). The mixture was poured over EtAcO (40 mL) and washed with brine (2 x 20 mL); the organic layer was dried over anhydrous Na 2
    SO
    4 and filtered. After removal of the solvent, the residue was purified by column chromatography on WO 2013/037960 PCT/EP2012/068101 174 silica gel (10D30% EtAcO/hexanes), affording 0.51 g of N-{5-chloro-2-[(4-chloro-2 fluorobenzyl)oxy]benzyl}-N-[2-(2-fluoro-4-iodopyridin-3-yl)ethyl]amine [Rf= 0.70 (10% MeOH/DCM), colorless oil, 64% yield]. LC-MS ESI+ m/z: 549 (M+1, 90%) (Method 5). 5 'H-NMR (CDC1 3 , 250 MHz, 6): 7.68 (d, J= 5.1 Hz, 1H, ArH); 7.58 (d, J= 5.1 Hz, 1H, ArH); 7.43-7.11 (m, 5H, ArH); 6.83 (d, J= 8.8 Hz, 1H, ArH); 5.07 (s, 2H); 3.82 (s, 2H); 3.01-2.74 (m, 4H). b) A mixture of N-{5-chloro-2-[(4-chloro-2-fluorobenzyl)oxy]benzyl}-N-[2-(2 10 fluoro-4-iodopyridin-3-yl)ethyl]amine (0.51 g, 0.92 mmol) and K 2
    CO
    3 (0.15 g, 1.10 mmol) in DMF (10 mL) was heated at 100 0C for 4 h. The reaction was allowed to reach room temperature, poured over EtAcO (40 mL) and washed with water (2 x 20 mL); the organic layer was dried over anhydrous Na 2
    SO
    4 and filtered. After removal of the solvent, the residue was purified by column chromatography on silica gel 15 (10w20% EtAcO/hexanes), affording 0.34 g of 1-{5-chloro-2-[(4-chloro-2 fluorobenzyl)oxy]benzyl}-4-iodo-2,3-dihydro-1 H-pyrrolo[2,3-b]pyridine [Rf= 0.65 (20% EtAcO/hexanes), white solid, 69% yield]. LC-MS ESI+ m/z: 529 (M+1, 99%) (Method 5). 'H-NMR (CDC1 3 , 250 MHz, 6): 7.47-7.37 (m, 2H, ArH); 7.28-7.07 (m, 4H, ArH); 6.86 20 (d, J= 8.5 Hz, 1 H, ArH); 6.76 (d, J= 5.4 Hz, 1 H, ArH); 5.05 (s, 2H); 4.55 (s, 2H); 3.46 (t, J= 8.4 Hz, 2H); 2.91 (t, J= 8.4 Hz, 2H). c) Following the general procedure described in example 212, section c, ethyl 1-{5-chloro-2-[(4-chloro-2-fluorobenzyl)oxy]benzyl}-2,3-dihydro-1H-pyrrolo[2,3 b]pyridine-4-carboxylate was obtained in 71% yield (pale yellow solid) after 7 h, 25 using 1-{5-chloro-2-[(4-chloro-2-fluorobenzyl)oxy]benzyl}-4-iodo-2,3-dihydro-1 H pyrrolo[2,3-b]pyridine (0.33 g, 0.61 mmol) as starting material. LC-MS ESI+ m/z: 475 (M+1, 97%) (Method 5). 'H-NMR (CDC1 3 , 250 MHz, 6): 7.90 (d, J= 5.8 Hz, 1H, ArH); 7.41 (t, J= 8.7 Hz, 1H, ArH); 7.27-7.07 (m, 4H, ArH); 6.92-6.84 (m, 2H, ArH); 5.06 (s, 2H); 4.63 (s, 30 2H); 4.35 (q, J= 7.2 Hz, 2H); 3.55-3.28 (m, 4H); 1.39 (t, J= 7.2 Hz, 3H). d) Following the general procedure described in example 211, section b, 1 {5-chloro-2-[(4-chloro-2-fluorobenzyl)oxy]benzyl}-2,3-dihydro-1 H-pyrrolo[2,3 b]pyridine-4-carboxylic acid was obtained in 96% yield (white solid), using ethyl 1-{5- WO 2013/037960 PCT/EP2012/068101 175 chloro-2-[(4-chloro-2-fluorobenzyl)oxy]benzyl}-2,3-dihydro-1 H-pyrrolo[2,3-b]pyridine 4-carboxylate (0.20 g, 0.42 mmol) as starting material. LC-MS ESI- m/z: 445 (M-1, 92%) (Method 5). 5 e) Following the general procedure described in example 211, section c, sodium 1-{5-chloro-2-[(4-chloro-2-fluorobenzyl)oxy]benzyl}-2,3-dihydro-1 H pyrrolo[2,3-b]pyridine-4-carboxylate was obtained in 90% yield (white solid), using 1 {5-chloro-2-[(4-chloro-2-fluorobenzyl)oxy]benzyl}-2,3-dihydro-1 H-pyrrolo[2,3 b]pyridine-4-carboxylic acid (0.18 g, 0.40 mmol) as starting material. 10 LC-MS ESI+ m/z: 447 (M+2-Na, 97%) (Method 2). "H-NMR (CD 3 OD, 250 MHz, 6): 7.64 (d, J= 6.1 Hz, 1H, ArH); 7.49 (t, J= 8.0 Hz, 1H, ArH); 7.28-7.03 (m, 5H, ArH); 6.79 (d, J= 5.4 Hz, 1H, ArH); 5.14 (s, 2H); 4.55 (s, 2H); 3.48-3.21 (m, 4H). 15 Examples 217 to 222: Using different starting materials The next compound was obtained using the same methodology as in Example 216 but using the corresponding starting material as indicated. LC-MS Example tR m/Z Compound name Starting material Meth od (mi [M+ n) H]* Sodium 1-{5-chloro 2-[(2,4- 3-{5-chloro-2 difluorobenzyl)oxy]b [(2,4 enzyl}-2,3-dihydro- difluorobenzyl)ox 16.5 1 H-pyrrolo[2,3- y]benzyl}-1,2,3- 9 b]pyridine-4- oxathiazolidine carboxylate 2,2-dioxide WO 2013/037960 PCT/EP2012/068101 176 Sodium 1-{5-chloro 2-[(4- 3-{5-chloro-2-[(4 chlorobenzyl)oxy]be chlorobenzyl)oxy] 17.3 218 nzyl}-2,3-dihydro- benzyl}-1,2,3- 2 1 429 1 H-pyrrolo[2,3- oxathiazolidine b]pyridine-4- 2,2-dioxide carboxylate Sodium 1-{5-chloro 2-[(2- 3-{5-chloro-2-[(2 fluorobenzyl)oxy]be fluorobenzyl)oxy] 16.6 219 nzyl}-2,3-dihydro- benzyl}-1,2,3- 2 1 413 1 H-pyrrolo[2,3- oxathiazolidine 1 b]pyridine-4- 2,2-dioxide carboxylate Sodium 1-{5-chloro 2-[(4- 3-{5-chloro-2-[(4 fluorobenzyl)oxy]be fluorobenzyl)oxy] 220 nzyl}-2,3-dihydro- benzyl}-1,2,3- 2 1 413 1 H-pyrrolo[2,3- oxathiazolidine b]pyridine-4- 2,2-dioxide carboxylate Sodium 1-[5-chloro 2-(2-fluoro-2- 3-[5-chloro-2-(2 methylpropoxy)benz fluoro-2 221 yl]-2,3-dihydro-1 H- methylpropoxy)be 2 14.8 379 pyrrolo[2,3- nzyl]-1,2,3- 1 b]pyridine-4- oxathiazolidine carboxylate 2,2-dioxide WO 2013/037960 PCT/EP2012/068101 177 Sodium 1-(5-chloro 2-isobutoxybenzyl)- 3-(5-chloro-2 2,3-dihydro-1 H- isobutoxybenzyl)- 16.4 222 pyrrolo[2,3- 1,2,3- 2 7 361 b]pyridine-4- oxathiazolidine carboxylate 2,2-dioxide Example 223: Synthesis of 1-{5-chloro-2-[(4-chloro-2-fluorobenzyl)oxy]benzyl} 4-(1H-tetrazol-5-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine sodium salt 5 a) A solution of 1-{5-chloro-2-[(4-chloro-2-fluorobenzyl)oxy]benzyl}-4-iodo 2,3-dihydro-1 H-pyrrolo[2,3-b]pyridine (0.14 g, 0.26 mmol) and Zn(CN) 2 (37 mg, 0.31 mmol) in DMF (4 mL) was thoroughly purged with argon; Pd(PPh 3
    )
    4 (6 mg, 0.01 mmol) was added and the mixture was purged again and heated at 90 0C. After 16 h, the reaction was allowed to reach room temperature, poured over EtAcO (20 mL) 10 and washed with water (2 x 10 mL); the organic layer was dried over anhydrous Na 2
    SO
    4 and filtered. After removal of the solvent, the residue was purified by column chromatography on silica gel (10--15% EtAcO/hexanes), affording 0.10 g 1-{5 chloro-2-[(4-chloro-2-fluorobenzyl)oxy]benzyl}-2,3-dihydro-1 H-pyrrolo[2,3-b]pyridine 4-carbonitrile [Rf= 0.35 (20% EtAcO/hexanes), pale yellow solid, 90% yield]. 15 LC-MS ESI+ m/z: 428 (M+1, 99%) (Method 5). b) TMSN 3 (91 1L, 0.69 mmol) was added to a suspension of 1-{5-chloro-2 [(4-chloro-2-fluorobenzyl)oxy]benzyl}-2,3-dihydro-1 H-pyrrolo[2,3-b]pyridine-4 carbonitrile (100 mg, 0.23 mmol) and Bu 2 SnO (17 mg, 0.07 mmol) in toluene and 20 heated at 120 0C in a sealed tube. An abundant white solid appeared during the reaction. After 22 h, the reaction was allowed to reach room temperature, and toluene was removed by rotatory evaporation; the solid residue was dissolved in Me-THF (30 mL) and washed with water (10 mL) and HCI (aqueous solution 10%, 5 mL). The organic layer was dried over anhydrous Na 2
    SO
    4 and filtered. After removal 25 of the solvent, the residue was purified by column chromatography on silica gel (3 -10% MeOH/DCM), affording 40 mg of 1-{5-chloro-2-[(4-chloro-2- WO 2013/037960 PCT/EP2012/068101 178 fluorobenzyl)oxy]benzyl}-4-(1 H-tetrazol-5-yl)-2,3-dihydro-1 H-pyrrolo[2,3-b]pyridine [Rf= 0.25 (10% MeOH/DCM), pale yellow solid, 37% yield]. LC-MS ESI+ m/z: 471 (M+1, 83%) (Method 5). 5 c) Following the general procedure described in example 211, section c, 1 {5-chloro-2-[(4-chloro-2-fluorobenzyl)oxy]benzyl}-4-(1 H-tetrazol-5-yl)-2,3-dihydro 1 H-pyrrolo[2,3-b]pyridine sodium salt was obtained in 71% yield (pale yellow solid), using 1-{5-chloro-2-[(4-chloro-2-fluorobenzyl)oxy]benzyl}-4-(1 H-tetrazol-5-yl)-2,3 dihydro-1 H-pyrrolo[2,3-b]pyridine (40 mg, 0.085 mmol) as starting material. 10 LC-MS ESI+ m/z: 471 (M+2-Na, 98%) (Method 2). "H-NMR (DMSO-d6, 250 MHz, 6): (diluted) 7.78-7.45 (m, 3H, ArH); 7.38-7.07 (m, 5H, ArH); 5.20 (s, 2H); 4.49 (s, 2H). The signals of CH2 are under the peak of water. 15 Example 224: Synthesis of sodium 8-{5-chloro-2-[(2,4 difluorobenzyl)oxy]benzyl}-5,6,7,8-tetrahydro-1,8-naphthyridine-4-carboxylate a) Freshly prepared LDA (8.97 mmol) was added to a solution of 2-fluoro-3 iodopyridine (2.00 g, 8.97 mmol) in THF (15 mL) cooled at -78 0C. After 1 h, 1 20 chloro-3-iodopropane (0.96 mL, 8.97 mmol) was added to the anion solution, allowing to reach room temperature (overnight). The reaction volume was reduced to ca. 10 mL and the mixture was poured over EtAcO (60 mL) and washed with water (2 x 20 mL); the organic layer was dried over anhydrous Na 2
    SO
    4 and filtered. After removal of the solvent, the residue was purified by column chromatography on 25 silica gel (2->4% EtAcO/hexanes), affording 1.88 g of 3-(3-chloropropyl)-2-fluoro-4 iodopyridine [Rf= 0.70 (5% EtAcO/hexanes), colorless oil, 70% yield]. LC-MS ESI+ m/z: 300 (M+1, 98%) (Method 5). 'H-NMR (CDC1 3 , 250 MHz, 6): 7.70 (d, J= 5.2 Hz, 1H, ArH); 7.61 (d, J= 5.2 Hz, 1H, ArH); 3.62 (t, J= 6.5 Hz, 2H); 2.99-2.90 (m, 2H); 2.10-1.97 (m, 2H). 30 b) A mixture of 3-(3-chloropropyl)-2-fluoro-4-iodopyridine (0.23 g, 0.77 mmol), 1-{5-chloro-2-[(2,4-difluorobenzyl)oxy]phenyl}methanamine (0.26 g, 0.92 mmol), KI (0.15 g, 0.92 mmol) and K 2
    CO
    3 (0.22 g, 1.62 mmol) in DMF (10 mL) was heated at 80 0C for 24 h. The reaction was allowed to reach room temperature, WO 2013/037960 PCT/EP2012/068101 179 poured over EtAcO (40 mL) and washed with water (2 x 10 mL); the organic layer was dried over anhydrous Na 2
    SO
    4 and filtered. After removal of the solvent, the residue was purified by column chromatography on silica gel (5--10% EtAcO/hexanes), affording 0.29 g of 1-{5-chloro-2-[(2,4-difluorobenzyl)oxy]benzyl}-5 5 iodo-1,2,3,4-tetrahydro-1,8-naphthyridine [Rf= 0.65 (20% EtAcO/hexanes), white solid, 71% yield]. LC-MS ESI+ m/z: 527 (M+1, 92%) (Method 5). "H-NMR (CDC1 3 , 250 MHz, 6): 7.50-7.37 (m, 2H, ArH); 7.16 (dd, J= 8.5, 2.6 Hz, 1H, ArH); 7.11 (d, J= 2.6 Hz, 1H, ArH); 6.97-6.79 (m, 4H, ArH); 5.05 (s, 2H); 10 4.84 (s, 2H); 3.36-3.27 (m, 2H); 2.81-2.73 (m, 2H); 2.00-1.88 (m, 2H). c) Following the general procedure described in example 212, section c, ethyl 8-{5-chloro-2-[(2,4-difluorobenzyl)oxy]benzyl}-5,6,7,8-tetrahydro-1,8 naphthyridine-4-carboxylate was obtained in 74% yield (pale yellow solid) after 6 h, 15 using 1-{5-chloro-2-[(2,4-difluorobenzyl)oxy]benzyl}-5-iodo-1,2,3,4-tetrahydro-1,8 naphthyridine (0.28 g, 0.53 mmol) as starting material. LC-MS ESI+ m/z: 473 (M+1, 83%) (Method 5). 'H-NMR (CDC1 3 , 250 MHz, 6): 7.96 (d, J= 5.2 Hz, 1H, ArH); 7.49-7.38 (m, 1H, ArH); 7.16 (dd, J= 8.6, 2.6 Hz, 1H, ArH); 7.09 (d, J= 2.6 Hz, 1H, ArH); 6.93-6.77 20 (m, 4H, ArH); 5.06 (s, 2H); 4.87 (s, 2H); 4.35 (q, J= 7.2 Hz, 2H); 3.39-3.31 (m, 2H); 3.09-3.01 (m, 2H); 1.99-1.87 (m, 2H); 1.39 (t, J= 7.2 Hz, 3H). d) Following the general procedure described in example 211, section b, 8 {5-chloro-2-[(2,4-difluorobenzyl)oxy]benzyl}-5,6,7,8-tetrahydro-1,8-naphthyridine-4 25 carboxylic acid was obtained in 60% yield (white solid), using ethyl 8-{5-chloro-2 [(2,4-difluorobenzyl)oxy]benzyl}-5,6,7,8-tetrahydro- 1 ,8-naphthyridine-4-carboxylate (0.15 g, 0.32 mmol) as starting material. LC-MS ESI+ m/z: 445 (M+1, 91%) (Method 5). 30 e) Following the general procedure described in example 211, section c, Sodium 8-{5-chloro-2-[(2,4-difluorobenzyl)oxy]benzyl}-5,6,7,8-tetrahydro-1,8 naphthyridine-4-carboxylate was obtained in 79% yield (white solid), using 8-{5 chloro-2-[(2,4-difluorobenzyl)oxy]benzyl}-5,6,7,8-tetrahydro-1,8-naphthyridine-4 carboxylic acid (85 mg, 0.19 mmol) as starting material.
    WO 2013/037960 PCT/EP2012/068101 180 LC-MS ESI+ m/z: 445 (M+2-Na, 98%) (Method 2). "H-NMR (CD 3 OD, 250 MHz, 6): 7.70 (d, J= 5.6 Hz, 1H, ArH); 7.64-7.53 (m, 1H, ArH); 7.20 (dd, J= 8.6, 2.7 Hz, 1H, ArH); 7.10-6.95 (m, 4H, ArH); 6.52 (d, J= 5.6 Hz, 1H, ArH); 5.15 (s, 2H); 4.75 (s, 2H); 3.41-3.34 (m, 2H); 2.95-2.87 (m, 2H); 2.01 5 1.88 (m, 2H). Examples 225: Using a different starting material The next compound was obtained using the same methodology as in Example 224 but using the corresponding starting material as indicated. 10 LC-MS Example tR m/Z Compound name Starting material Meth od (mi [M+ n) H]* Sodium 8-{5-chloro 2-[(4-chloro-2- 1-{5-chloro-2-[(4 fluorobenzyl)oxy]be chloro-2 18.0 225 nzyl}-5,6,7,8- fluorobenzyl)oxy] 2 3 461 tetrahydro-1,8- phenyllmethana naphthyridine-4- mine carboxylate Example 226: Sodium 1-{5-chloro-2-[(4-chloro-2-fluorobenzyl)oxy]benzyl} 1,2,3,4-tetrahydro-1,7-naphthyridine-5-carboxylate 15 a) Freshly prepared LDA (20.46 mmol) was added to a solution of 3-bromo 5-fluoropyridine (3.00 g, 17.05 mmol) in THF (20 mL) cooled at -78 0C. After 40 min, a solution of 1-chloro-3-iodopropane (6.98 g, 34.09 mmol) in THF (10 mL) was transferred via canula was added to the anion solution, allowing to reach room temperature. After 1 h, the volatiles were removed by rotatory evaporation and the 20 residue was dissolved in EtAcO (60 mL) and washed with water (2 x 30 mL); the organic layer was dried over anhydrous Na 2
    SO
    4 and filtered. After removal of the solvent, the residue was purified by column chromatography on silica gel (2D4% WO 2013/037960 PCT/EP2012/068101 181 EtAcO/hexanes), affording 3.07 g of 3-bromo-4-(3-chloropropyl)-5-fluoropyridine [Rf= 0.60 (20% EtAcO/hexanes), colorless oil, 71% yield]. LC-MS ESI+ m/z: 300 (M+1, 98%) (Method 5). 'H-NMR (CDC1 3 , 250 MHz, 6): 8.50 (s, 1H, ArH); 8.33 (s, 1H, ArH); 3.59 (t, J= 5 6.7 Hz, 2H); 3.05-2.92 (m, 2H); 2.16-1.98 (m, 2H). b) A mixture of 3-bromo-4-(3-chloropropyl)-5-fluoropyridine (0.60 g, 2.38 mmol), 1-{5-chloro-2-[(4-chloro-2-fluorobenzyl)oxy]phenyl}methanamine (0.93 g, 3.09 mmol), KI (0.39 g, 2.38 mmol) and K 2
    CO
    3 (0.82 g, 5.94 mmol) in DMF (10 mL) 10 was heated at 150 0C for 5 h. The reaction was allowed to reach room temperature, poured over EtAcO (60 mL) and washed with brine (2 x 25 mL); the organic layer was dried over anhydrous Na 2
    SO
    4 and filtered. After removal of the solvent, the residue was purified by column chromatography on silica gel (12% EtAcO/hexanes), affording 0.68 g of 5-bromo-1-{5-chloro-2-[(4-chloro-2-fluorobenzyl)oxy]benzyl} 15 1,2,3,4-tetrahydro-1,7-naphthyridine [Rf= 0.35 (20% EtAcO/hexanes), white solid, 58% yield]. LC-MS ESI+ m/z: 496 (M+1, 98%) (Method 5). 'H-NMR (CDC1 3 , 250 MHz, 6): 7.96 (s, 1H, ArH); 7.60 (s, 1H, ArH); 7.38 (t, J= 8.2 Hz, 1H, ArH); 7.23-7.10 (m, 3H, ArH); 7.05 (d, J= 2.4 Hz, 1H, ArH); 6.89 (d, J= 20 8.5 Hz, 1H, ArH); 5.10 (s, 2H); 4.46 (s, 2H); 3.40-3.33 (m, 2H); 2.86-2.79 (m, 2H); 2.09-1.98 (m, 2H). c) A suspension of 5-bromo-1-{5-chloro-2-[(4-chloro-2 fluorobenzyl)oxy]benzyl}-1,2,3,4-tetrahydro-1,7-naphthyridine (0.50 g, 1.01 mmol), 25 dppf (28 mg, 0.05 mmol) and TEA (0.42 mL, 3.03 mmol) in EtOH (60 mL) was thoroughly purged with argon; Pd(AcO) 2 (11 mg, 0.05 mmol) was added and the mixture was purged again with carbon monoxide. The mixture was placed in a stainless steel pressure reactor and heated at 130 0C under carbon monoxide pressure (30 bar) for 16 h. The reaction was allowed to reach room temperature and 30 carbon monoxide was released. After removal of the solvent, the residue was purified by column chromatography on silica gel (20D25% EtAcO/hexanes), affording 0.42 g of ethyl 1-{5-chloro-2-[(4-chloro-2-fluorobenzyl)oxy]benzyl}-1,2,3,4 tetrahydro-1,7-naphthyridine-5-carboxylate [Rf= 0.50 (40% EtAcO/hexanes), pale yellow solid, 85% yield].
    WO 2013/037960 PCT/EP2012/068101 182 LC-MS ESI+ m/z: 489 (M+1, 98%) (Method 5). 'H-NMR (CDC1 3 , 250 MHz, 6): 8.32 (s, 1H, ArH); 7.78 (s, 1H, ArH); 7.43-7.35 (m, 1H, ArH); 7.22-7.11 (m, 3H, ArH); 7.04 (d, J= 2.5 Hz, 1H, ArH); 6.89 (d, J= 8.7 Hz, 1H, ArH); 5.11 (s, 2H); 4.49 (s, 2H); 4.36 (q, J= 7.1 Hz, 2H); 3.42-3.36 (m, 2H); 5 3.18-3.10 (m, 2H); 2.07-1.96 (m, 2H); 1.39 (t, J= 7.1 Hz, 3H). d) Following the general procedure described in example 211, section b, 1 {5-chloro-2-[(4-chloro-2-fluorobenzyl)oxy]benzyl}-1,2,3,4-tetrahydro-1,7 naphthyridine-5-carboxylic acid was obtained in 91% yield (pale yellow solid), using 10 ethyl 1-{5-chloro-2-[(4-chloro-2-fluorobenzyl)oxy]benzyl}-1,2,3,4-tetrahydro-1,7 naphthyridine-5-carboxylate (0.40 g, 0.82 mmol) as starting material. LC-MS ESI+ m/z: 461 (M+1, 99%) (Method 5). e) Following the general procedure described in example 211, section c, 15 sodium 1-{5-chloro-2-[(4-chloro-2-fluorobenzyl)oxy]benzyl}-1,2,3,4-tetrahydro-1,7 naphthyridine-5-carboxylate was obtained in 99% yield (white solid), using 1-{5 chloro-2-[(4-chloro-2-fluorobenzyl)oxy]benzyl}-1,2,3,4-tetrahydro-1,7-naphthyridine 5-carboxylic acid (0.33 g, 0.72 mmol) as starting material. LC-MS ESI+ m/z: 461 (M+2-Na, 99%) (Method 2). 20 'H-NMR (CD 3 OD, 250 MHz, 6): 7.81 (s, 1H, ArH); 7.55 (t, J= 7.5 Hz, 1H, ArH); 7.44 (s, 1H, ArH); 7.31-7.20 (m, 3H, ArH); 7.10 (d, J= 8.6 Hz, 1H, ArH); 7.04 (d, J= 2.8 Hz, 1H, ArH); 5.20 (s, 2H); 4.49 (s, 2H); 3.46-3.39 (m, 2H); 3.03-2.95 (m, 2H); 2.07-1.94 (m, 2H). 25 Examples 227: Using 1-{5-chloro-2-[(2,4-difluorobenzyl)oxy]phenyl} methanamine material The next compound was obtained using the same methodology as in Example 226 but using the corresponding starting material as indicated. LC-MS Example tR m/Z Compound name Starting material Meth od (mi [M+ n) H]* WO 2013/037960 PCT/EP2012/068101 183 Sodium 1-{5-chloro 2-[(2,4- 1-{5-chloro-2 difluorobenzyl)oxy]b [(2,4 16.9 227 enzyl}-1,2,3,4- difluorobenzyl)ox 2 1 445 tetrahydro-1,7- y]phenyl}methan naphthyridine-5- amine carboxylate Example 228: 1-{5-chloro-2-[(2,4-difluorobenzyl)oxy]benzyl}-1,2,3,4-tetrahydro 1,6-naphthyridine-5-carboxylic acid 5 a) n-BuLi [0.93 mL (1.6 M in hexanes), 1.50 mmol] was added dropwise to a solution of 4-chloro-N,N-diisopropylpyridine-2-carboxamide (0.30 g, 1.25 mmol) in THF (6 mL) cooled at -78 0C. After 1.5 h, 1-chloro-3-iodopropane (0.33 mL, 1.75 mmol) was added to the anion solution, allowing to reach room temperature. After 30 min, the volatiles were removed by rotatory evaporation and the residue was 10 dissolved in EtAcO (40 mL) and washed with brine (2 x 15 mL); the organic layer was dried over anhydrous Na 2
    SO
    4 and filtered. After removal of the solvent, the residue was purified by column chromatography on silica gel (25% EtAcO/hexanes), affording 0.31 g of 4-chloro-3-(3-chloropropyl)-N,N-diisopropylpyridine-2 carboxamide [Rf= 0.65 (50% EtAcO/hexanes), colorless oil, 77% yield]. 15 LC-MS ESI+ m/z: 317 (M+1, 93%) (Method 5). 'H-NMR (CDC1 3 , 250 MHz, 6): 8.32 (d, J= 5.4 Hz, 1H, ArH); 7.28 (d, J= 5.4 Hz, 1H, ArH); 3.68-3.42 (m, 4H); 3.33 (t, J= 6.4 Hz, 2H); 2.29-2.12 (m, 2H); 1.58 (d, J= 6.5 Hz, 6H); 1.16 (d, J= 6.5 Hz, 6H). 20 b) A mixture of 4-chloro-3-(3-chloropropyl)-N,N-diisopropylpyridine-2 carboxamide (0.70 g, 2.21 mmol), 1-{5-chloro-2-[(2,4 difluorobenzyl)oxy]phenyl}methanamine (0.75 g, 2.65 mmol), KI (0.44 g, 2.65 mmol) and K 2
    CO
    3 (0.61 g, 4.41 mmol) in DMF (15 mL) was heated at 100 0C for 15 h. The reaction was allowed to reach room temperature, poured over EtAcO (100 mL) and 25 washed with water (2 x 60 mL); the organic layer was dried over anhydrous Na 2
    SO
    4 and filtered. After removal of the solvent, the residue was purified by column chromatography on silica gel (20D70% EtAcO/hexanes), affording 0.82 g of 1-{5- WO 2013/037960 PCT/EP2012/068101 184 chloro-2-[(2,4-difluorobenzyl)oxy]benzyl}-N,N-diisopropyl-1,2,3,4-tetrahydro-1 ,6 naphthyridine-5-carboxamide [Rf= 0.50 (70% EtAcO/hexanes), pale yellow solid, 70% yield]. LC-MS ESI+ m/z: 528 (M+1, 95%) (Method 5). 5 'H-NMR (CDC1 3 , 250 MHz, 6): 7.92 (d, J= 5.7 Hz, 1H, ArH); 7.48-7.36 (m, 1H, ArH); 7.22 (dd, J= 8.6, 2.6 Hz, 1H, ArH); 7.00 (d, J= 2.6 Hz, 1H, ArH); 6.97-6.81 (m, 3H, ArH); 6.15 (d, J= 5.7 Hz, 1H, ArH); 5.09 (s, 2H); 4.43 (s, 2H); 3.73-3.44 (m, 2H); 3.42-3.34 (m, 2H); 2.75 (br s, 2H); 2.05-1.94 (m, 2H); 1.58 (d, J= 6.8 Hz, 6H); 1.16 (d, J= 6.8 Hz, 6H). 10 c) A solution of DIBAL-H [1.52 mL (1.5 M in toluene), 2.29 mmol] was added dropwise to a solution of 1-{5-chloro-2-[(2,4-difluorobenzyl)oxy]benzyl}-N,N diisopropyl-1,2,3,4-tetrahydro-1,6-naphthyridine-5-carboxamide (0.81 g, 1.52 mmol) in THF (15 mL) cooled at -78 0C. After 1 h, the reaction mixture was warmed to 15 room temperature, and, after 5 h, quenched by dropwise addition of HCI (aqueous solution 10%, 2 mL). The volatiles were removed by rotatory evaporation and the residue was dissolved in EtAcO (50 mL) and washed with water (2 x 25 mL); the organic layer was dried over anhydrous Na 2
    SO
    4 and filtered. After removal of the solvent, the residue was purified by column chromatography on silica gel (5% 20 MeOH/DCM), affording 0.17 g of 1-{5-chloro-2-[(2,4-difluorobenzyl)oxy]benzyl} 1,2,3,4-tetrahydro-1,6-naphthyridine-5-carbaldehyde [Rf= 0.50 (10% MeOH/DCM), pale yellow oil, 25% yield]. LC-MS ESI+ m/z: 429 (M+1, 78%) (Method 5). 25 d) H 2 0 2 (aqueous solution 30%, 0.07 mL, 0.77 mmol) was added dropwise to a solution of 1-{5-chloro-2-[(2,4-difluorobenzyl)oxy]benzyl}-1,2,3,4-tetrahydro-1,6 naphthyridine-5-carbaldehyde (0.17 g, 0.38 mmol) in formic acid (5 mL) and stirred at room temperature for 22 h. Another 0.07 mL of H 2 0 2 were added and stirring was continued for additional 20 h. The reaction mixture was diluted with DCM (30 mL) 30 and washed with water (2 x 10 mL); the organic layer was dried over anhydrous Na 2
    SO
    4 and filtered. After removal of the solvent, the residue was purified by column chromatography on silica gel (4D15% MeOH/DCM), affording 0.08 g of 1-{5-chloro 2-[(2,4-difluorobenzyl)oxy]benzyl}-1,2,3,4-tetrahydro-1,6-naphthyridine-5-carboxylic acid, orange solid, 48% yield.
    WO 2013/037960 PCT/EP2012/068101 185 LC-MS ESI+ m/z: 445 (M+1, 99%) (Method 2). 'H-NMR (CD 3 OD, 250 MHz, 6): 7.59 (d, J= 6.5 Hz, 1H, ArH); 7.54-7.42 (m, 1H, ArH); 7.36 (dd, J= 8.6, 2.0 Hz, 1H, ArH); 7.22-7.15 (m, 2H, ArH); 7.05-6.92 (m, 2H, ArH); 6.72 (d, J= 6.5 Hz, 1 H, ArH); 5.11 (s, 2H); 4.68 (s, 2H); 3.48-3.40 (m, 2H); 5 3.22-3.12 (m, 2H); 1.98-1.85 (m, 2H). Examples 229: Using 4-chloro-3-(3-chloropropyl)-N,N-diisopropylpyridine-2 carboxamide and 1-{5-chloro-2-[(4-chloro-2-fluorobenzyl)oxy]phenyl} methanamine as starting materials 10 LC-MS Example tR m/Z Compound name Starting material Meth od (mi [M+ n) H]* Sodium 1-{5-chloro 2-[(4-chloro-2 fluorobenzyl)oxy]be 1-{5-chloro-2-[(4 nzyl}-1,2,3,4- chloro-2- 19.0 229 tetrahydro-1,6- fluorobenzyl)oxy] 2 1 461 naphthyridine-5- phenyllmethana carboxylate mine Example 230: Synthesis of sodium 1-{5-chloro-2-[(4-chloro-2 fI uorobenzyl)oxy] benzyl}-1,2,3,4-tetrahydroqui noxal i ne-5-carboxylate 15 a) A solution of 2-aminoethanol (0.70 mL, 11.50 mmol) and methyl 2-chloro 3-nitrobenzoate (0.62 g, 2.88 mmol) in DMF (7 mL) was heated at 70 0C for 30 min. The reaction was allowed to reach room temperature, poured over EtAcO (40 mL) and washed with water (2 x 30 mL) and brine (20 mL); the organic layer was dried over anhydrous Na 2
    SO
    4 and filtered. After removal of the solvent, 0.68 g of methyl 20 2-[(2-hydroxyethyl)amino]-3-nitrobenzoate were obtained [Rf= 0.30 (30% WO 2013/037960 PCT/EP2012/068101 186 EtAcO/hexanes), yellow-orange solid, 99% yield], that were used without further purification. LC-MS ESI+ m/z: 241 (M+1, 85%) (Method 5). NOTE: Prolonged reaction times lead to intramolecular cyclization. 5 b) A mixture of 0.25 g of Pd (5%, charcoal) and methyl 2-[(2 hydroxyethyl)amino]-3-nitrobenzoate (0.56 g, 2.33 mmol) in THF (12 mL) was stirred under hydrogen atmosphere (balloon) at room temperature. After 14 h, the reaction was filtered through a pad of celite and the solvent was removed by rotatory 10 evaporation. The residue was purified by column chromatography on silica gel (70% EtAcO/hexanes), affording 0.36 g of methyl 3-amino-2-[(2 hydroxyethyl)amino]benzoate [Rf= 0.15 (50% EtAcO/hexanes), colorless oil, 80% yield, 2 steps]. LC-MS ESI+ m/z: 211 (M+1, 99%) (Method 5). 15 c) MsCl (0.64 mL, 0.83 mmol) was added dropwise to a solution of methyl 3 amino-2-[(2-hydroxyethyl)amino]benzoate (0.18 g, 0.83 mmol) and TEA (0.35 mL, 2.50 mmol) in THF (10 mL) cooled at 0 0C, while a white suspension appeared. After 5 min, TLC showed complete conversion of the starting material; the reaction was 20 warmed to room temperature and stirred for additional 6 h. The volatiles were removed by rotatory evaporation and the residue was dissolved in EtAcO (20 mL) and washed with water (2 x 10 mL); the organic layer was dried over anhydrous Na 2
    SO
    4 and filtered. After removal of the solvent, the residue was purified by column chromatography on silica gel (30% EtAcO/hexanes), affording 99 mg of methyl 25 1,2,3,4-tetrahydroqu inoxaline-5-carboxylate [Rf= 0.45 (40% EtAcO/hexanes), yellow oil, 62% yield]. LC-MS ESI+ m/z: 193 (M+1, 99%) (Method 5). "H-NMR (CDC1 3 , 250 MHz, 6): 7.55 (br s, 1H, NH); 7.30 (d, J= 8.0 Hz, 1H, ArH); 6.58 (d, J= 7.4 Hz, 1H, ArH); 6.46-6.38 (m, 1H, ArH); 3.83 (s, 3H); 3.59-3.50 30 (m, 2H); 3.40-3.33 (m, 2H). d) Following the general procedure described in example 165, methyl 1-{5 chloro-2-[(4-chloro-2-fluorobenzyl)oxy]benzyl}-1,2,3,4-tetrahydroquinoxaline-5 carboxylate was obtained in 55% yield (yellow foam) after 3 h, using methyl 1,2,3,4- WO 2013/037960 PCT/EP2012/068101 187 tetrahydroquinoxaline-5-carboxylate (95 mg, 0.49 mmol), K 2
    CO
    3 (89 mg, 0.64 mmol), KI (82 mg, 0.49 mmol) and 2-(bromomethyl)-4-chloro-1-[(4-chloro-2 fluorobenzyl)oxy]benzene (234 mg, 0.64 mmol) as starting materials. LC-MS ESI+ m/z: 475 (M+1, 97%) (Method 5). 5 'H-NMR (CDC1 3 , 250 MHz, 6): 7.46-7.11 (m, 6H, ArH); 6.89 (d, J= 8.8 Hz, 1H, ArH); 6.45-6.36 (m, 2H, ArH); 5.10 (s, 2H); 4.40 (s, 2H); 3.84 (s, 3H); 3.63-3.56 (m, 2H); 3.45-3.38 (m, 2H). e) Following the general procedure described in example 211, section b, 1 10 {5-chloro-2-[(4-chloro-2-fluorobenzyl)oxy]benzyl}-1,2,3,4-tetrahydroquinoxaline-5 carboxylic acid was obtained in 68% yield (yellow solid), using methyl 1-{5-chloro-2 [(4-chloro-2-fluorobenzyl)oxy]benzyl}-1,2,3,4-tetrahydroquinoxaline-5-carboxylate (0.32 g, 0.67 mmol) as starting material. LC-MS ESI+ m/z: 461 (M+1, 96%) (Method 5). 15 f) Following the general procedure described in example 211, section c, sodium 1-{5-chloro-2-[(4-chloro-2-fluorobenzyl)oxy]benzyl}-1,2,3,4 tetrahydroquinoxaline-5-carboxylate was obtained in 99% yield (pale yellow solid), using 1-{5-chloro-2-[(4-chloro-2-fluorobenzyl)oxy]benzyl}-1,2,3,4 20 tetrahydroquinoxaline-5-carboxylic acid (53 mg, 0.11 mmol) as starting material. LC-MS ESI+ m/z: 461 (M+2-Na, 96%) (Method 2). 'H-NMR (CD 3 OD, 250 MHz, 6): 7.53 (t, J= 3.3 Hz, 1H, ArH); 7.30-7.13 (m, 5H, ArH); 7.06 (d, J= 3.3 Hz, 1 H, ArH); 6.36 (t, J= 7.8 Hz, 1 H, ArH); 6.26 (d, J= 7.8 Hz, 1H, ArH); 5.17 (s, 2H); 4.36 (s, 2H); 3.51-3.33 (m, 4H). 25 Example 231: Synthesis of sodium 1-{5-chloro-2-[2-(2,4 difluorophenyl)ethoxy]benzyl}-1H-indole-4-carboxylate a) A mixture of 5-chloro-2-hydroxybenzaldehyde (3.0 g, 19.2 mmol), K 2
    CO
    3 (3.4 g, 24.9 mmol) and MEM-CI (2.4 mL, 21.1 mmol) in DMF (20 mL) was stirred at 30 room temperature for 18 h. The reaction mixture was poured over EtAcO (100 mL) and washed with water (50 mL) and NaOH(aqueous solution 10%, 3 x 5 mL); the organic layer was dried over anhydrous Na 2
    SO
    4 and filtered. After removal of the solvent, 3.8 g of 5-chloro-2-[(2-methoxyethoxy)methoxy]benzaldehyde were WO 2013/037960 PCT/EP2012/068101 188 obtained [Rf= 0.20 (20% EtAcO/hexanes), pale yellow oil, 81% yield], that were used without further purification. b) NaBH 4 (0.59 g, 15.5 mmol) was added in small portions to a solution of 5 5 chloro-2-[(2-methoxyethoxy)methoxy]benzaldehyde (3.80 g, 15.5 mmol) in MeOH (25 mL) cooled at 0 0C, observing abundant gas evolution. After 20 min, the solvent was removed by rotatory evaporation and the resulting residue was dissolved in Et 2 0 (50 mL) and washed with water (50 mL). The organic layer was dried over anhydrous Na 2
    SO
    4 and filtered. After removal of the solvent, the residue was 10 purified by column chromatography on silica gel (30% EtAcO/hexanes), affording 3.15 g of {5-chloro-2-[(2-methoxyethoxy)methoxy]phenyl}methano [Rf= 0.33 (10% EtAcO/hexanes), colorless oil, 82% yield]. "H-NMR (CDC1 3 , 250 MHz, 6): 7.32 (d, J= 2.6 Hz, 1H, ArH); 7.20 (dd, J= 8.8, 2.6 Hz, 1 H, ArH); 7.06 (d, J= 8.8 Hz, 1 H, ArH); 5.30 (s, 2H); 4.65 (d, J= 6.0 Hz, 2H); 15 3.84-3.79 (m, 2H); 3.57-3.51 (m, 2H); 3.35 (s, 3H); 2.38 (t, J= 6.0, 1 H, OH). c) MsCl (1.00 mL, 12.89 mmol) was added dropwise to a solution of {5 chloro-2-[(2-methoxyethoxy)methoxy]phenyl}methano (2.65 g, 10.74 mmol) and TEA (2.98 mL, 21.48 mmol) in DCM, cooled at 0 0C, and the mixture was allowed to 20 reach room temperature. After 20 h, the reaction mixture was diluted with DCM (25 mL) and washed with HCI (aqueous solution 5%, 30 mL). The organic layer was dried over anhydrous Na 2
    SO
    4 and filtered. After removal of the solvent, 1.73 g of 4 chloro-2-(chloromethyl)-1 -[(2-methoxyethoxy)methoxy]benzene were obtained [Rf= 0.65 (40% EtAcO/hexanes), colorless oil, 50% yield], that were used without further 25 purification. d) NaH [0.21 g (60% in mineral oil), 5.23 mmol] was added to a solution of methyl 1 H-indole-4-carboxylate (0.76 g, 4.36 mmol) in DMF (10 mL) cooled at 0 C, leading to the formation of a yellow mixture. After 30 min, a solution of 4-chloro-2 30 (chloromethyl)-1-[(2-methoxyethoxy)methoxy]benzene (5 mL of DMF) was added, and the mixture was stirred for additional 2 h. The reaction was poured into EtAcO (50 mL) and washed with water (2 x 30 mL); the organic layer was dried over anhydrous Na 2
    SO
    4 and filtered. After removal of the solvent, the residue was dissolved in 25 mL of MeOH, H 2
    SO
    4 (0.23 mL, 4.36 mmol) was added and the WO 2013/037960 PCT/EP2012/068101 189 reaction was heated at reflux for 2 h; it was allowed to reach room temperature and MeOH was eliminated in the rotatory evaporator. The residue was dissolved in DCM (100 mL) and washed with water (50 mL). The organic layer was dried over anhydrous Na 2
    SO
    4 and filtered. After removal of the solvent, the residue was 5 purified by column chromatography on silica gel (30% EtAcO/hexanes), affording 1.22 g of methyl 1-(5-chloro-2-hydroxybenzyl)-1H-indole-4-carboxylate [Rf= 0.50 (40% EtAcO/hexanes), white solid, 88% yield]. LC-MS ESI+ m/z: 316 (M+1, 99%) (Method 5). "H-NMR (CDC1 3 , 250 MHz, 6): 7.94-7.89 (m, 1H, ArH); 7.58-7.53 (m, 1H, 10 ArH); 7.32 (d, J= 8.1 Hz, 1H, ArH); 7.24-7.17 (m, 2H, ArH); 7.10 (dd, J= 8.6, 2.5 Hz, 1H, ArH); 6.76 (d, J= 2.8 Hz, 1H, ArH); 6.72 (d, J= 8.6 Hz, 1H, ArH); 5.33 (s, 2H); 3.99 (s, 3H). e) A mixture of methyl 1-(5-chloro-2-hydroxybenzyl)-1 H-indole-4-carboxylate 15 (0.19 g, 0.59 mmol), K 2
    CO
    3 (0.12 g, 0.88 mmol) and 2-(2,4-difluorophenyl)ethyl 4 methylbenzenesulfonate (0.24 g, 0.77 mmol) in DMF (10 mL) was stirred at 60 IC for 16 h. The reaction mixture was allowed to reach room temperature and poured over EtAcO (40 mL) and washed with water (2 x 20 mL); the organic layer was dried over anhydrous Na 2
    SO
    4 and filtered. After removal of the solvent, the residue was 20 purified by column chromatography on silica gel (10% EtAcO/hexanes), affording 0.25 g of methyl 1-{5-chloro-2-[2-(2,4-difluorophenyl)ethoxy]benzyl}-1 H-indole-4 carboxylate [Rf= 0.60 (20% EtAcO/hexanes), yellow oil, 92% yield]. "H-NMR (CDC1 3 , 250 MHz, 6): 7.91 (dd, J= 7.7, 1.1 Hz, 1H, ArH); 7.41 (d, J= 8.0 Hz, 1H, ArH); 7.24-7.13 (m, 5H, ArH); 6.85-6.75 (m, 3H, ArH); 6.64 (d, J= 2.7 25 Hz, 1H, ArH); 5.23 (s, 2H); 4.19 (t, J= 6.7 Hz, 2H); 4.00 (s, 3H); 3.10 (t, J= 6.7 Hz, 2H). f) Following the general procedure described in example 211, section b, 1-{5 chloro-2-[2-(2,4-difluorophenyl)ethoxy]benzyl}-1 H-indole-4-carboxylic acid was 30 obtained in 62% yield (white solid), using methyl 1-{5-chloro-2-[2-(2,4 difluorophenyl)ethoxy]benzyl}-1H-indole-4-carboxylate (0.25 g, 0.54 mmol) as starting material. LC-MS ESI+ m/z: 442 (M+1, 95%) (Method 5).
    WO 2013/037960 PCT/EP2012/068101 190 g) Following the general procedure described in example 211, section c, sodium 1-{5-chloro-2-[2-(2,4-difluorophenyl)ethoxy]benzyl}-1 H-indole-4-carboxylate was obtained in 91% yield (white solid), using 1-{5-chloro-2-[2-(2,4 5 difluorophenyl)ethoxy]benzyl}-1H-indole-4-carboxylic acid (0.15 g, 0.33 mmol) as starting material. LC-MS ESI+ m/z: 442 (M+2-Na, 95%) (Method 2). "H-NMR (DMSO-d 6 , 250 MHz, 6): 7.61-7.46 (m, 2H, ArH); 7.32-6.91 (m, 8H, ArH); 6.59 (br s, 1H, ArH); 5.20 (s, 2H); 4.28 (t, J= 7.2 Hz, 2H); 3.14 (t, J= 7.2 Hz, 10 2H). Example 232: Synthesis of 1-{5-chloro-2-[(4-chloro-2-fluorobenzyl)oxy]benzyl} N-(methylsulfonyl)-1H-indole-4-carboxamide A mixture of EDCI (100 mg, 0.52 mmol), methanesulfonamide (49 mg, 0.52 mmol), 15 DMAP (5 mg, 0.04 mmol) and 1-{5-chloro-2-[(4-chloro-2-fluorobenzyl)oxy]benzyl} 1H-indole-4-carboxylic acid (0.19 g, 0.43 mmol) in DCM (6 mL) was stirred at room temperature for 18 h. The reaction mixture was diluted with DCM (20 mL) and washed with water (20 mL) and brine (10 mL); the organic layer was dried over anhydrous Na 2
    SO
    4 and filtered. After removal of the solvent, the residue was 20 purified by column chromatography on silica gel (5% MeOH/DCM), affording 1-{5 chloro-2-[(4-chloro-2-fluorobenzyl)oxy]benzyl}-N-(methylsulfonyl)-1 H-indole-4 carboxamide as a pale yellow solid. This solid was triturated with Et 2 0 (2 x 5 mL) and vacuum dried, rendering a white solid in 58% yield. LC-MS ESI+ m/z: 521 (M+1, 99%) (Method 2). 25 'H-NMR (CD 3 OD, 250 MHz, 6): 7.60-7.53 (m, 2H, ArH); 7.40-6.99 (m, 8H, ArH); 6.82 (d, J= 2.0 Hz, 1 H, ArH); 5.40 (s, 2H); 5.15 (s, 2H); 3.40 (s, 3H). Example 233: Synthesis of 1-{5-chloro-2-[(4-chloro-2-fluorobenzyl)oxy]benzyl} N-(methylsulfonyl)-1H-indole-4-carboxamide sodium salt 30 Following the general procedure described in example 211, section c, 1-{5-chloro-2 [(4-chloro-2-fluorobenzyl)oxy]benzyl}-N-(methylsulfonyl)-1 H-indole-4-carboxamide sodium salt was obtained in 93% yield (white solid), using 1-{5-chloro-2-[(4-chloro-2 fluorobenzyl)oxy]benzyl}-N-(methylsulfonyl)-1H-indole-4-carboxamide (53 mg, 0.10 mmol) as starting material.
    WO 2013/037960 PCT/EP2012/068101 191 LC-MS ESI+ m/z: 521 (M+2-Na, 98%) (Method 2). "H-NMR (CD 3 OD, 250 MHz, 6): 7.72 (d, J= 8.3 Hz, 1H, ArH); 7.43-7.03 (m, 9H, ArH); 6.69 (d, J= 2.0 Hz, 1H, ArH); 5.36 (s, 2H); 5.17 (s, 2H); 3.15 (s, 3H). 5 Example 234: Synthesis of 1-(5-chloro-2-isobutoxybenzyl)-N-(methylsulfonyl) 2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-4-carboxamide sodium salt a) A mixture of EDCI (180 mg, 0.94 mmol), methanesulfonamide (89 mg, 0.94 mmol), DMAP (8 mg, 0.07 mmol) and 1-(5-chloro-2-isobutoxybenzyl)-2,3 dihydro-1H-pyrrolo[2,3-b]pyridine-4-carboxylic acid (242 mg, 0.67 mmol) in DCM (10 10 mL) was stirred at room temperature for 21 h. The reaction mixture was diluted with DCM (20 mL) and washed with water (20 mL) and brine (15 mL); the organic layer was dried over anhydrous Na 2
    SO
    4 and filtered. After removal of the solvent, the residue was purified by column chromatography on silica gel (1115% MeOH/DCM), affording 115 mg of 1-(5-chloro-2-isobutoxybenzyl)-N-(methylsulfonyl)-2,3-dihydro 15 1H-pyrrolo[2,3-b]pyridine-4-carboxamide [Rf= 0.50 (10% MeOH/DCM), pale yellow solid, 39% yield]. LC-MS ESI+ m/z: 438 (M+1, 97%) (Method 5). b) Following the general procedure described in example 211, section c, 20 sodium 1-(5-chloro-2-isobutoxybenzyl)-N-(methylsulfonyl)-2,3-dihydro-1 H pyrrolo[2,3-b]pyridine-4-carboxamide was obtained in 98% yield (pale yellow solid), using 1-(5-chloro-2-isobutoxybenzyl)-N-(methylsulfonyl)-2,3-dihydro-1 H-pyrrolo[2,3 b]pyridine-4-carboxamide (115 mg, 0.26 mmol) as starting material. LC-MS ESI+ m/z: 438 (M+2-Na, 99%) (Method 2). 25 'H-NMR (DMSO-d6, 250 MHz, 6): 7.71 (d, J= 5.2 Hz, 1H, ArH); 7.25 (dd, J= 8.7, 2.5 Hz, 1H, ArH); 7.18 (d, J= 2.5 Hz, 1H, ArH); 7.00 (d, J= 8.7 Hz, 1H, ArH); 6.85 (d, J= 5.2 Hz, 1H, ArH); 4.47 (s, 2H); 3.77 (d, J= 6.3 Hz, 2H); 3.46-3.18 (m, 4H); 2.81 (s, 3H); 2.10-1.93 (m, 1H); 0.98 (d, J= 6.6 Hz, 6H). 30 Example 235: Synthesis of 1-{5-chloro-2-[(4-chloro-2-fluorobenzyl)oxy]benzyl} N-(methylsulfonyl)-1,2,3,4-tetrahydroquinoline-5-carboxamide sodium salt a) A mixture of CDI (99 mg, 0.61 mmol) and 1-{5-chloro-2-[(4-chloro-2 fluorobenzyl)oxy]benzyl}-1,2,3,4-tetrahydroquinoline-5-carboxylic acid (0.20 g, 0.43 WO 2013/037960 PCT/EP2012/068101 192 mmol) in DCM (10 mL) was stirred at 0 0C. After 1 h, DBU (0.09 mL, 0.61 mmol) and methanesulfonamide (59 mg, 0.61 mmol) were added, and the reaction was allowed to reach room temperature. After 16 h, more DBU (0.09 mL, 0.61 mmol) and methanesulfonamide (59 mg, 0.61 mmol) were added, and the mixture was heated 5 at 35 0C for 4 h. The reaction mixture was diluted with DCM (20 mL) and washed with water (20 mL) and HCI (aqueous solution 10%, 10 mL); the organic layer was dried over anhydrous Na 2
    SO
    4 and filtered. After removal of the solvent, the residue was purified by column chromatography on silica gel (1113% MeOH/DCM), affording 0.19 g 1-{5-chloro-2-[(4-chloro-2-fluorobenzyl)oxy]benzyl}-N-(methylsulfonyl) 10 1,2,3,4-tetrahydroquinoline-5-carboxamide [Rf= 0.45 (5% MeOH/DCM), white solid, 81% yield]. LC-MS ESI+ m/z: 537 (M+1, 95%) (Method 5). "H-NMR (CDC1 3 , 250 MHz, 6): 7.47-6.86 (m, 7H, ArH); 6.70 (d, J= 7.2 Hz, 1 H, ArH); 6.44 (d, J= 8.0 Hz, 1 H, ArH); 5.11 (s, 2H); 4.44 (s, 2H); 3.54-3.34 (m, 5H); 15 3.07-2.95 (m, 2H); 2.12-1.96 (m, 2H). b) Following the general procedure described in example 211, section c, 1 {5-chloro-2-[(4-chloro-2-fluorobenzyl)oxy]benzyl}-N-(methylsulfonyl)-1,2,3,4 tetrahydroquinoline-5-carboxamide sodium salt was obtained in 99% yield (white 20 solid), using 1-{5-chloro-2-[(4-chloro-2-fluorobenzyl)oxy]benzyl}-N-(methylsulfonyl) 1,2,3,4-tetrahydroquinoline-5-carboxamide (0.14 g, 0.25 mmol) as starting material. LC-MS ESI+ m/z: 536 (M+1 -Na, 96%) (Method 2). 'H-NMR (CD 3 OD, 250 MHz, 6): 7.55 (t, J= 8.5 Hz, 1H, ArH); 7.31-6.99 (m, 5H, ArH); 6.84 (t, J= 8.0 Hz, 1 H, ArH); 6.65 (dd, J= 7.5, 1.2 Hz, 1 H, ArH); 6.21 (d, J= 25 7.5 Hz, 1H, ArH); 5.19 (s, 2H); 4.41 (s, 2H); 3.41-3.33 (m, 2H); 3.09 (s, 3H); 3.01 2.91 (m, 2H); 2.05-1.93 (m, 2H). Example 236: Synthesis of 1-{5-chloro-2-[(4-chloro-2-fluorobenzyl)oxy]benzyl} 30 N-[(dimethylamino)sulfonyl]-1,2,3,4-tetrahydroquinoline-5-carboxamide A mixture of CDI (0.12 g, 0.76 mmol) and 1-{5-chloro-2-[(4-chloro-2 fluorobenzyl)oxy]benzyl}-1,2,3,4-tetrahydroquinoline-5-carboxylic acid (0.25 g, 0.54 mmol) in DCM (15 mL) was stirred at 0 0C. After 1 h, the solvent was removed and the residue was dissolved in 1,4-dioxane (15 mL); DBU (0.12 mL, 0.76 mmol) and WO 2013/037960 PCT/EP2012/068101 193 N,N-dimethylsulfamide (94 mg, 0.76 mmol) were added and the reaction was heated at 100 0C for 7 h and 80 0C overnight. The reaction mixture was allowed to reach room temperature and the volatiles were removed by rotatory evaporation. The residue was dissolved in EtAcO (30 mL) and washed with water (30 mL) and HCI 5 (aqueous solution 10%, 10 mL); the organic layer was dried over anhydrous Na 2
    SO
    4 and filtered. After removal of the solvent, the residue was purified by column chromatography on silica gel (10D20% EtAcO/hexanes), affording 0.15 g 1-{5 chloro-2-[(4-chloro-2-fluorobenzyl)oxy]benzyl}-N-[(dimethylamino)sulfonyl]-1,2,3,4 tetrahydroquinoline-5-carboxamide [Rf= 0.40 (40% EtAcO/hexanes), white solid, 10 50% yield]. LC-MS ESI+ m/z: 566 (M+1, 99%) (Method 2). 'H-NMR (DMSO-d6, 250 MHz, 6): 11.69 (s, 1H); 7.69-7.49 (m, 2H, ArH); 7.39-7.19 (m, 3H, ArH); 6.99-6.88 (m, 2H, ArH); 6.58 (d, J= 7.3 Hz, 1H, ArH); 6.30 (d, J= 8.4 Hz, 1H, ArH); 5.23 (s, 2H); 4.40 (s, 2H); 2.88 (s, 6H); 2.83-2.73 (m, 2H); 15 1.99-1.85 (m, 2H). One of the CH2 is under the peak of water. Example 237: Synthesis of 1-{5-chloro-2-[(4-chloro-2-fluorobenzyl)oxy]benzyl} N-[(dimethylamino)sulfonyl]-1,2,3,4-tetrahydroquinoline-5-carboxamide sodium salt 20 Following the general procedure described in example 211, section c, the title compound was obtained in 87% yield (white solid), using 1-{5-chloro-2-[(4-chloro-2 fluorobenzyl)oxy]benzyl}-N-[(dimethylamino)sulfonyl]-1,2,3,4-tetrahydroquinoline-5 carboxamide (95 mg, 0.17 mmol) as starting material. LC-MS ESI+ m/z: 566 (M+2-Na, 99%) (Method 2). 25 'H-NMR (CD 3 OD, 250 MHz, 6): 7.56 (t, J= 8.4 Hz, 1H, ArH); 7.33-7.00 (m, 5H, ArH); 6.84 (t, J= 7.8 Hz, 1 H, ArH); 6.66 (d, J= 7.6 Hz, 1 H, ArH); 6.20 (d, J= 8.0 Hz, 1H, ArH); 5.19 (s, 2H); 4.42 (s, 2H); 3.42-3.34 (m, 2H); 3.04-2.95 (m, 2H); 2.83 (s, 6H); 2.06-1.93 (m, 2H). 30 Example 238: Synthesis of N-({1-(5-chloro-2-[(4-chloro-2 fluorobenzyl)oxy]benzyl})- 1,2,3,4-tetrahydroquinolin-5-yl]aminojcarbonyl) methanesulfonamide sodium salt a) DPPA (0.06 mL, 0.28 mmol) was added to a suspension of 1-{5-chloro-2 [(4-chloro-2-fluorobenzyl)oxy]benzyl}-1,2,3,4-tetrahydroquinoline-5-carboxylic acid WO 2013/037960 PCT/EP2012/068101 194 (105 mg, 0.23 mmol), methanesulfonamide (22 mg, 0.23 mmol) and DIPEA (0.08 mL, 0.46 mmol) in toluene (8 mL) and heated at 85 0C. After 19 h, the reaction mixture was allowed to reach room temperature and the volatiles were removed by rotatory evaporation. The residue was dissolved in EtAcO (25 mL) and washed with 5 water (2 x 15 mL); the organic layer was dried over anhydrous Na 2
    SO
    4 and filtered. After removal of the solvent, the residue was purified by column chromatography on silica gel (5% MeOH/DCM), affording 52 mg of N-({1-(5-chloro-2-[(4-chloro-2 fluorobenzyl)oxy]benzyl})-1,2,3,4-tetrahydroquinolin-5 yl]amino}carbonyl)methanesulfonamide [Rf= 0.60 (10% MeOH/DCM), yellow solid, 10 41% yield]. LC-MS ESI+ m/z: 552 (M+1, 77%) (Method 5). b) Following the general procedure described in example 211, section c, N ({1 -(5-chloro-2-[(4-chloro-2-fluorobenzyl)oxy]benzyl})-1,2,3,4-tetrahydroquinolin-5 15 yl]amino}carbonyl)methanesulfonamide sodium salt was obtained in 65% yield (pale yellow solid), using N-({1-(5-chloro-2-[(4-chloro-2-fluorobenzyl)oxy]benzyl})-1,2,3,4 tetrahydroquinolin-5-yl]amino}carbonyl)methanesulfonamide (61 mg, 0.11 mmol) as starting material. LC-MS ESI+ m/z: 552 (M+2-Na, 95%) (Method 2). 20 'H-NMR (DMSO-d6, 250 MHz, 6): 7.69-6.94 (m, 7H, ArH); 6.68 (t, J= 7.8 Hz, 1H, ArH); 5.82 (d, J= 8.2 Hz, 1H, ArH); 5.22 (s, 2H); 4.33 (s, 2H); 3.33-3.18 (m, 2H); 2.73 (s, 3H); 1.97-1.79 (m, 2H). One of the CH2 is under the peak of water. Example 239: Synthesis of 1-{5-chloro-2-[(4-chloro-2-fluorobenzyl)oxy]benzyl} 25 N-(methylsulfonyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-4-carboxamide sodium salt a) A mixture of EDCI (111 mg, 0.58 mmol), methanesulfonamide (55 mg, 0.58 mmol), DMAP (5 mg, 0.04 mmol) and 1-{5-chloro-2-[(4-chloro-2 fluorobenzyl)oxy]benzyl}-2,3-dihydro-1 H-pyrrolo[2,3-b]pyridine-4-carboxylic acid 30 (185 mg, 0.41 mmol) in DCM (8 mL) was stirred at room temperature for 17 h. The reaction mixture was diluted with DCM (20 mL) and washed with water (10 mL) and HCI (aqueous solution 10%, 2 mL); the organic layer was dried over anhydrous Na 2
    SO
    4 and filtered. After removal of the solvent, the residue was purified by column chromatography on silica gel (0--5% MeOH/DCM), affording 83 mg of 1-{5-chloro-2- WO 2013/037960 PCT/EP2012/068101 195 [(4-chloro-2-fluorobenzyl)oxy]benzyl}-N-(methylsulfonyl)-2,3-dihydro-1 H-pyrrolo[2,3 b]pyridine-4-carboxamide [Rf= 0.60 (10% MeOH/DCM), pale yellow solid, 39% yield]. LC-MS ESI+ m/z: 524 (M+1, 99%) (Method 5). 5 b) Following the general procedure described in example 211, section c, sodium 1-{5-chloro-2-[(4-chloro-2-fluorobenzyl)oxy]benzyl}-N-(methylsulfonyl)-2,3 dihydro-1H-pyrrolo[2,3-b]pyridine-4-carboxamide was obtained in 91% yield (pale yellow solid), using 1-{5-chloro-2-[(4-chloro-2-fluorobenzyl)oxy]benzyl}-N 10 (methylsulfonyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-4-carboxamide (78 mg, 0.15 mmol) as starting material. LC-MS ESI- m/z: 522 (M-Na, 99%) (Method 2). "H-NMR (DMSO-d6, 250 MHz, 6): 7.73-7.60 (m, 2H, ArH); 7.50 (dd, J= 10.0, 2.5 Hz, 1H, ArH); 7.35-7.27 (m, 2H, ArH); 7.22 (d, J= 2.5 Hz, 1H, ArH); 7.17 (d, J= 15 8.8 Hz, 1H, ArH); 6.85 (d, J= 5.7 Hz, 1H, ArH); 5.19 (s, 2H); 4.46 (s, 2H); 3.41-3.17 (m, 4H); 2.81 (s, 3H). Examples 240 to 246: Using different starting materials 20 The next compound were obtained using the same methodology as in Example 224 but using the corresponding starting material as indicated. LC-MS Example tR m/Z Compound name Starting material Meth od (mi [M+ n) H]* Sodium 1-{2-[(4 chloro-2 1 -{2-[(4-chloro-2 fluorobenzyl)oxy]be 11-(-hoo2 fluroenyl~xybe fluorobenzyl)oxy] 17.0 240 nzyl}-1,2,3,4- 2 427 tetrahydro-1,7- phenyllmethana 9 mine naphthyridine-5 carboxylate WO 2013/037960 PCT/EP2012/068101 196 Sodium 1-{2-[(2,4 difluorobenzyl)oxy]b 1-{2-[(2,4 241 enzyl}-1,2,3,4- difluorobenzyl)ox 2 16.1 411 tetrahydro-1,7- y]phenyl}methan 4 naphthyridine-5- amine carboxylate Sodium 1-[5-chloro 2-(2-fluoro-2- 1-[5-chloro-2-(2 methylpropoxy)benz fluoro-2 15.1 242 yl]-1,2,3,4- methylpropoxy)ph 2 8 393 tetrahydro-1,7- enyl]methanamin naphthyridine-5- e carboxylate Sodium 1-{2 [(2,4- 1-{2-[(2,4 difluorobenzyl)oxy]- difluorobenzyl)ox 5-fluorobenzyl}- 16.0 243 y]-5- 2 429 1,2,3,4-tetrahydro- 6 fluorophenylimet 1,7-naphthyridine-5- hanamine carboxylate Sodium 1-(2 ((2,4- 1-{2-[(2,4 difluorobenzyl)oxy)- difluorobenzyl)ox 244 5-methylbenzyl)- y]-5- 2 16.8425 1,2,3,4-tetrahydro- 6 methylphenylimet 1,7-naphthyridine-5- hanamine carboxylate WO 2013/037960 PCT/EP2012/068101 197 Sodium 1-{2-[(4 chloro-2- 1-{2-[(4-chloro-2 fluorobenzyl)oxy]-5- fluorobenzyl)oxy] 17.2 245 fluorobenzyl}- 5- 2 445 2 1,2,3,4-tetrahydro- fluorophenyllmet 1,7-naphthyridine-5- hanamine carboxylate Sodium 1-{2-[(4 chloro-2- 1-{2-[(4-chloro-2 fluorobenzyl)oxy]-5- fluorobenzyl)oxy]- 17.7 246 methylbenzyl}- 5- 2 441 8 1,2,3,4-tetrahydro- methylphenyllmet 1,7-naphthyridine-5- hanamine carboxylate Example 247. Synthesis of sodium 4-(2-cyclobutoxy-5-fluorobenzyl)-3,4 di hydro-2 H-benzo[b] [1,4]oxazi ne-8-carboxylate 5 a) Following a similar procedure to that described in example 190 (step a), but starting from methyl 3,4-dihydro-2H-benzo[b][ 1,4]oxazine-8-carboxylate instead of methyl 1,2,3,4-tetrahydroqu inoline-5-carboxylate hydrochloride and 5-fluoro-2 hydroxybenzaldehyde instead of 5-chloro-2-propoxybenzaldehyde, the desired compound was obtained (31 % yield) 10 LC-MS (method 4): tR = 2.05 min; m/z = 318 (MH+). b) To a solution of the compound obtained in the previous section (250 mg, 0.78 mmol) in DMF (10 mL), potassium carbonate (217 mg, 1.57 mmol) and bromocyclobutane (160 mg, 1.18 mmol) were added. The reaction mixture was 15 stirred at 60 9C overnight. The reaction mixture was diluted by adding EtAcO and saturated NH 4 CI aqueous solution (15 mL) and extracted with EtAcO (3x15 mL). The combined organic phases were dried over anhydrous Na 2
    SO
    4 , filtered and concentrated. The crude residue was chromatographed on a silica gel flash system WO 2013/037960 PCT/EP2012/068101 198 (Biotage SP1) using hexanes/EtAcO mixtures of increasing polarity as eluent, to afford the desired product (96 % yield). LC-MS (method 4): tR = 2.9 [M+H]*= 372 5 c) Following a similar procedure to that described in example 123 (section b), but using the compound obtained in previous section as starting material, the desired compound was obtained (79 % yield). LC-MS (method 4): tR = 1.72 [M+H]*= 358 'H NMR (300 MHz, DMSO-d6) 6 : 7.08-6.78 (m, 3H, ArH); 6.6-6.41 (m, 2H, 10 ArH); 6.32-6.22 (m, 1H, ArH); 4.87-4.6 (m, 1H); 4.34 (s, 2H); 4.24-4.04 (m, 2H); 3.57-3.22 (m, 2H); 2.51-2.33 (m, 2H); 2.21-1.96 (m, 2H); 1.91-1.51 (m, 2H). Example 248. Synthesis of Sodium 1-{5-chloro-2-[(4-chloro-2 fluorobenzyl)oxy]benzyl}-2,3-dihydro-1H-pyrrolo[2,3-c]pyridine-4-carboxylate 15 a) Freshly prepared LDA (0.90 mmol) was added to a solution of 3-bromo-5 fluoropyridine (0.15 g, 0.82 mmol) in THF (10 mL) cooled at -78 0C. After 30 min, a solution of 3-{5-chloro-2-[(4-chloro-2-fluorobenzyl)oxy]benzyl}-1,2,3-oxathiazolidine 2,2-dioxide (0.37 g, 0.90 mmol) in 3 mL of THF was transferred via canula to the anion solution. After 20 min, TLC showed an intense polar spot corresponding to the 20 sulfamic acid intermediate. The solvent was evaporated and the resulting residue was dissolved in 1,4-dioxane (10 mL) and treated with 0.40 mL of HCI (4 M in 1,4 dioxane), stirring at room temperature. After 17 h, the reaction was cooled to 0 0C and slowly basified with NaOH (aqueous solution 10%, 4 mL). The mixture was poured over EtAcO (40 mL) and washed with water (30 mL); the organic layer was 25 dried over anhydrous Na 2
    SO
    4 and filtered. After removal of the solvent, the residue was purified by column chromatography on silica gel (201Wand filtered. After removal of the solveN-[2-(3-bromo-5-fluoropyridin-4-yl)ethyl]-N-{5-chloro-2-[(4-chloro-2 fluorobenzyl)oxy]benzyl}amine [Rf= 0.70 (5% MeOH/DCM), pale yellow oil, 74% yield]. 30 LC-MS ESI+ m/z: 503 (M+1, 93%) (Method 5). 'H-NMR (CDC1 3 , 250 MHz, 6): 8.48 (s, 1H, ArH); 8.31 (s, 1H, ArH); 7.42-7.33 (m, 1H, ArH); 7.25-7.10 (m, 4H, ArH); 6.84 (d, J= 8.5 Hz, 1H, ArH); 5.06 (s, 2H); 3.81 (s, 2H); 3.03-2.93 (m, 2H); 2.86-2.78 (m, 2H).
    WO 2013/037960 PCT/EP2012/068101 199 b) A mixture of N-[2-(3-bromo-5-fluoropyridin-4-yl)ethyl]-N-{5-chloro-2-[(4 chloro-2-fluorobenzyl)oxy]benzyl}amine (0.30 g, 0.60 mmol) and K 2
    CO
    3 (0.10 g, 0.72 mmol) in DMF (10 mL) was heated at 120 0C for 12 h and 140 0C for 2 h. The reaction was allowed to reach room temperature, poured over EtAcO (60 mL) and 5 washed with water (60 mL); the organic layer was dried over anhydrous Na 2
    SO
    4 and filtered. After removal of the solvent, the residue was purified by column chromatography on silica gel (5wand filtered. After removal of0.18 g of 4-bromo-1 {5-chloro-2-[(4-chloro-2-fluorobenzyl)oxy]benzyl}-2,3-dihydro-1 H-pyrrolo[2,3 c]pyridine [Rf= 0.75 (40% EtAcO/hexanes), white solid, 65% yield]. 10 LC-MS ESI+ m/z: 483 (M+1, 97%) (Method 5). 'H-NMR (CDC1 3 , 250 MHz, 6): 7.96 (s, 1H, ArH); 7.60 (s, 1H, ArH); 7.37-7.08 (m, 5H, ArH); 6.89 (d, J= 8.5 Hz, 1H, ArH); 5.08 (s, 2H); 4.27 (s, 2H); 3.52-3.42 (m, 2H); 3.06-2.98 (m, 2H). 15 c) A suspension of 4-bromo-1-{5-chloro-2-[(4-chloro-2 fluorobenzyl)oxy]benzyl}-2,3-dihydro-1H-pyrrolo[2,3-c]pyridine (0.18 g, 0.37 mmol), dppf (11 mg, 0.02 mmol) and TEA (0.15 mL, 1.11 mmol) in EtOH (60 mL) was thoroughly purged with argon; Pd(AcO) 2 (4 mg, 0.02 mmol) was added and the mixture was purged again with carbon monoxide. The mixture was placed in a 20 stainless steel pressure reactor and heated at 120 0C under carbon monoxide pressure (30 bar) for 16 h. The reaction was allowed to reach room temperature and carbon monoxide was released. After removal of the solvent, the residue was purified by column chromatography on silica gel (15D25% EtAcO/hexanes), affording 0.15 g of ethyl 1-{5-chloro-2-[(4-chloro-2-fluorobenzyl)oxy]benzyl}-2,3 25 dihydro-1H-pyrrolo[2,3-c]pyridine-4-carboxylate [Rf= 0.50 (40% EtAcO/hexanes), pale yellow solid, 84% yield]. LC-MS ESI+ m/z: 475 (M+1, 99%) (Method 5). 'H-NMR (CDC1 3 , 250 MHz, 6): 8.49 (s, 1H, ArH); 7.79 (s, 1H, ArH); 7.37-7.08 (m, 5H, ArH); 6.89 (d, J= 8.4 Hz, 1H, ArH); 5.09 (s, 2H); 4.37 (q, J= 7.2 Hz, 2H); 30 4.31 (s, 2H); 3.50-3.37 (m, 4H); 1.40 (t, J= 7.2 Hz, 3H). d) Following the general procedure described in example 211, section b, 1 {5-chloro-2-[(4-chloro-2-fluorobenzyl)oxy]benzyl}-2,3-dihydro-1 H-pyrrolo[2,3 c]pyridine-4-carboxylic acid was obtained in 88% yield (pale yellow solid), using WO 2013/037960 PCT/EP2012/068101 200 ethyl 1-{5-chloro-2-[(4-chloro-2-fluorobenzyl)oxy]benzyl}-2,3-dihydro-1H-pyrrolo[2,3 c]pyridine-4-carboxylate (0.14 g, 0.29 mmol) as starting material. LC-MS ESI+ m/z: 448 (M+1, 99%) (Method 5). 5 e) Following the general procedure described in example 211, section c, sodium 1-{5-chloro-2-[(4-chloro-2-fluorobenzyl)oxy]benzyl}-2,3-dihydro-1 H pyrrolo[2,3-c]pyridine-4-carboxylate was obtained in 80% yield (white solid), using 1 {5-chloro-2-[(4-chloro-2-fluorobenzyl)oxy]benzyl}-2,3-dihydro-1 H-pyrrolo[2,3 c]pyridine-4-carboxylic acid (0.11 g, 0.25 mmol) as starting material. 10 LC-MS ESI+ m/z: 447 (M+1 -Na, 99%) (Method 2). "H-NMR (CD 3 OD, 250 MHz, 6 ): 8.22 (s, 1H, ArH); 7.55 (s, 1H, ArH); 7.50 7.07 (m, 6H, ArH); 5.14 (s, 2H); 4.32 (s, 2H); 3.49-3.28 (m, 4H). 15 Examples 249 to 250: Using a different starting material The next compounds were obtained using the same methodology as in Example 208 but using the corresponding starting material as indicated. LC-MS Example tR m/Z Compound name Starting material Meth od (mi [M+ n) H]* Sodium 1-(5-chloro- methyl 1-(5 2- chloro-2 249 cyclobutoxybenzyl)- cyclobutoxybenzy 4 1.69 371 2-oxoindoline-4- 1)-1 H-indole-4 carboxylate carboxylate WO 2013/037960 PCT/EP2012/068101 201 methyl 1-(5 Sodium 1-(5-chloro- chloro-2-(2 2-(2-fluoro-2- fluoro-2 250 methylpropoxy)benz methylpropoxy)be 4 1.61 391 yl)-2-oxoindoline-4- nzyl)-1 H-indole-4 carboxylate carboxylate Examples of biological activity 5 In the following examples the biological activity of compounds of formula (1) towards EP1 receptors is shown. Test 1: Human EP1 receptor radioligand binding assay To investigate binding properties of EP1 receptor ligands to human EP1 receptor, transfected HEK-293 cell membranes and [3H]-PGE2 (Perkin Elmer) were used. In 10 96-well plates the assay was carried out with a total reaction volume of 250 pl, containing 25 pl of membrane suspension (30 pg protein/well), 25 pl of [3H]-PGE2 (10 nM) in either absence or presence of 25 pl of either buffer or PGE2 (10 pM) for total and non-specific binding, respectively. Binding buffer contained 10 mM MES, 1 mM MgCl2 and 1 mM EDTA at pH 6.0. Plates were incubated at 25 0C for 60 15 minutes. After the incubation period, 200 pl of incubate were transferred to MultiScreen HTS, FB plates (Millipore), filtered and plates were washed 6 times with ice-cold 10 mM MES, 1 mM MgCl2 and 1 mM EDTA at pH 6.0. Filters were dried and counted in a MicroBeta scintillation counter (Perkin-Elmer) using EcoScint liquid scintillation cocktail. 20 Percentage inhibition was calculated relating compounds activity to the 0% inhibition of the wells incubated with 10 nM [3H]-PGE2 alone (total binding) and 100% inhibition of the wells incubated with 10 nM [3H]-PGE2 plus 10 pM PGE2 (non specific binding).
    WO 2013/037960 PCT/EP2012/068101 202 Test 2: Measurement of IP1 responses by Homogeneous Time Resolved Fluorescence IP1 measurements on HEK-293 cells that stably expressed human EP1 receptors 5 were performed by using a system based on Homogeneous Time Resolved Fluorescense (HTRF) (Gabriel et al., 2003). This technology allows the direct measurement of IP1 in living cells. The principle of this assay is based on competition between IP1 produced by cells and IP1-d2 conjugate for the binding with monoclonal anti-IP1-cryptate conjugate. The HTRF IP1 kit from CisBio was 10 used according to the manufacturer's directions. The experimental procedure was performed as stated below. Suspended cells (30,000 cells per well) were added to 96-well culture plates in 40 pl of stimulation buffer (supplied by the kit). Compounds were then added in 20 pl of 15 stimulation buffer and incubated at 3 7 9C for 15 minutes followed by 10 pl of PGE2 to a final concentration of 30 nM. After 90 minutes at 3 7 9C, the reaction was stopped lysing the cells with a mixture of 15 pl of cryptate and 15 pl of IP1-d2 prepared in the lysis buffer supplied by the manufacturer. Plates were incubated for an additional hour at room temperature and read at 665 nm/620 nm using an UltraEvolution Plate 20 reader (Tecan). Antagonist percentage inhibition was calculated relating compounds activity to the 0% inhibition of the wells incubated with 10 nM PGE2 alone and 100% inhibition of the wells incubated with 10 nM PGE2 plus 1 pM of the reference antagonist. 25 Test 3: Measurement of IP1 responses by Homogeneous Time Resolved Fluorescence IP1 measurements on HEK-293 cells that stably expressed human EP1 receptors were performed by using a system based on Homogeneous Time Resolved 30 Fluorescense (HTRF) (Gabriel et al., 2003). This technology allows the direct measurement of IP1 in living cells. The principle of this assay is based on competition between IP1 produced by cells and IP1-d2 conjugate for the binding with monoclonal anti-IP1-cryptate conjugate. The HTRF IP1 kit from CisBio was WO 2013/037960 PCT/EP2012/068101 203 used according to the manufacturer's directions. The experimental procedure was performed as stated below. 40,000 cells per well were added to 96-well culture plates in 40 pl of Optimem and 5 incubated o/n at 3 7 9C. Optimem was replaced by 40 pl of stimulation buffer (supplied by the kit) and compounds were then added in 20 pl of stimulation buffer and incubated at 3 7 9C for 15 minutes followed by 10 pl of PGE2 to a final concentration of 10 nM. After 90 minutes at 3 7 9C, the reaction was stopped lysing the cells with a mixture of 15 pl of cryptate and 15 pl of IP1-d2 prepared in the lysis 10 buffer supplied by the manufacturer. Plates were incubated for an additional hour at room temperature and read at 665 nm/620 nm using an UltraEvolution Plate reader (Tecan). Antagonist percentage inhibition was calculated relating compounds activity to the 15 0% inhibition of the wells incubated with 10 nM PGE2 alone and 100% inhibition of the wells incubated with 10 nM PGE2 plus 10 pM of the reference antagonist. The results obtained in the biological assays disclosed in tests 1, 2 and 3 with 20 representative compounds of formula (1) are shown in the Table below. Example n 2 Results of Test 1* Results of Test 2** Results of Test 3** 2 $ 3 $ 4 $ 5 $ 6 $ 7 $ 8 $ 9 $ 10 $$ 11 # $ 12 # $ 13 ## $ WO 2013/037960 PCT/EP2012/068101 204 14 # $ 15 # 16 # 17 ## $ 18 $ 19 ## $ 20 $ 21 ## $ 22 ## 23 $ 24 ## $ 25 ## $ 26 # 27 # 28 $$ 29 # $ 30 ## 31 ## 32 ## 33 ## $ 34 ## $ 35 $ 36 $$ 37 $ 38 $ 39 $ 40 $$ 41 $ 42 $ 43 $ 44 # 45 # $ 46
    $
    WO 2013/037960 PCT/EP2012/068101 205 47 # $ 48 # $ 49 ## $ 50 # 51 ## $ 52 $ 53 $ 54 ## $ 55 # $ 56 # 57 # 58 $ 59 $$ 60 $ 61 $$ 62 $ 63 $ 64 $ 65 $ 66 $ 67 $$ 68 ## $ 69 ## $ 70 $ 71 $$ 72 $ 73 $$ 74 $$ 75 ## $ 76 $$ 78 $ 79 $ 80
    $
    WO 2013/037960 PCT/EP2012/068101 206 81 $ 82 $ 83 $ 84 $ 85 $ 86 $$ 87 $ 89 $$ 90 $ 91 # 92 $$ 93 $ 94 $ 95 $ 96 97 98 # 99 # $ 100 $ 101 ## 104 ## 105 # 106 ## 108 ## 111 ## 112 # 115 # $ 117 # $ 119 # $ 121 # $ 122 # $ 124 # $ 125 #
    $
    WO 2013/037960 PCT/EP2012/068101 207 133 # 135 ## 136 # $ 137 # $ 138 # $ 140 ## 141 # $ 142 # $ 144 # $ 145 # $ 146 # $ 147 # $ 148 # $ 149 # $ 151 # $ 152 # $ 153 # $ 157 # $ 158 # 159 # 166 # $ 169 # $ 170 # $ 171 # $ 175 # $ 176 ## 177 # $ 178 # $ 182 # $ 188 # $ 194 # $ 195 # $ 196 #
    $
    WO 2013/037960 PCT/EP2012/068101 208 197 # $ 201 ## 203 ## 207 # $ 208 # $ 212 # $ 213 # 214 ## 216 # $ 217 # $ 220 # $ 221 # $ 226 # $ 227 # $ 234 # $ 237 # $$ 240 # $ 242 # $ 243 # $ 248 # $ "* Binding assay (Test 1) at 10 pM # %inh > 75, ## 45 <%inh < 75; ** Functional assay (Test 2 and 3) at 10 pM $ %inh > 75 $$ 45 <%inh < 75. 5 WO 2013/037960 PCT/EP2012/068101 209 References Abe T, Kunz A, Shimamura M, Zhou P, Anrather J, ladecola C. (2009) The neuroprotective effect of prostaglandin E2 EP1 receptor inhibition has a wide 5 therapeutic window, is sustained in time and is not sexually dimorphic. J Cereb Blood Flow Metab. 29(1):66-72. Asb6th G, Phaneuf S, Europe-Finner GN, T6th M, Bernal AL. (1996) Prostaglandin E2 activates phospholipase C and elevates intracellular calcium in 10 cultured myometrial cells: involvement of EP1 and EP3 receptor subtypes. Endocrinology. 137(6):2572-9. Baba H, Kohno T, Moore KA, Woolf CJ. (2001) Direct activation of rat spinal dorsal horn neurons by prostaglandin E2 The Journal of Neuroscience, 21(5):1750 15 1756. Banfi, L.; Narisano, E.; Riva, R.; Stiasni, N.; Hiersemann, M. "Sodium Borohydride" in Encyclopedia of Reagents for Organic Synthesis (Ed: L. Paquette) 2004. 20 Breyer MD, Breyer RM. (2000) Prostaglandin receptors: their role in regulating renal function. Curr Opin Nephrol Hypertens. 2000 Jan;9(1):23-9. Candelario-Jalil E, Slawik H, Ridelis I, Waschbisch A, Akundi RS, Holl M, 25 Fiebich BL. (2005) Regional distribution of the prostaglandin E2 receptor EP1 in the rat brain: accumulation in Purkinje cells of the cerebellum. J Mol Neurosci. 27(3):303-10. Coleman, R. A., Prostanoid Receptors. IUPHAR compendium of receptor 30 characterization and classification, 2 nd edition, 338-353, 2000. Dirig DM, Yaksh TL. (1999) In vitro prostanoid release from spinal cord following peripheral inflammation: effects of substance P, NMDA and capsaicin. Br J Pharmacol. 126(6):1333-40.
    WO 2013/037960 PCT/EP2012/068101 210 Durrenberger PF, Facer P, Casula MA, Yiangou Y, Gray RA, Chessell IP, Day NC, Collins SD, Bingham S, Wilson AW, Elliot D, Birch R, Anand P. (2006) Prostanoid receptor EP1 and Cox-2 in injured human nerves and a rat model of 5 nerve injury: a time-course study. BMC Neurol. 4;6:1. Gabriel D, Vernier M, Pfeifer MJ, Dasen B, Tenaillon L, Bouhelal R. (2003) High throughput screening technologies for direct cyclic AMP measurement. Assay Drug Dev. Technol. 1: 291-303. 10 Giblin GM, Bit RA, Brown SH, Chaignot HM, Chowdhury A, Chessell IP, Clayton NM, Coleman T, Hall A, Hammond B, Hurst DN, Michel AD, Naylor A, Novelli R, Scoccitti T, Spalding D, Tang SP, Wilson AW, Wilson R. (2007) The discovery of 6-[2-(5-chloro-2-{[(2,4-difluorophenyl)methyl]oxy}phenyl)-1-cyclopenten 15 1-yl]-2-pyridinecarboxylic acid, GW848687X, a potent and selective prostaglandin EP1 receptor antagonist for the treatment of inflammatory pain. Bioorg Med Chem Lett. 17(2):385-9. T.W. Greene and P.G.M. Wuts "Protective groups in organic synthesis" 20 (John Wiley & sons 10 1999) Guay J., Bateman, K., Gordon R., Mancini J., Riendeau D. (2004) Carrageenan-induced paw edema in rat elicits a predominant prostaglandin E2 (PGE2) response in the central nervous system associated with the induction of 25 microsomal PGE2 synthase-1 J. Biol Chem 2004. 279, 24866-24872. Hall, A., Billinton A., Giblin G.M. (2007) EP1 antagonists for the treatment of inflammatory pain. Curr Opin. Drug Discov. Devel. 10 (2007) 597-612. 30 Hall A, Brown SH, Budd C, Clayton NM, Giblin GM, Goldsmith P, Hayhow TG, Hurst DN, Naylor A, Anthony Rawlings D, Scoccitti T, Wilson AW, Winchester WJ. (2009) Discovery of GSK345931A: An EP(1) receptor antagonist with efficacy in preclinical models of inflammatory pain. Bioorg Med Chem Lett. 19(2):497-501.
    WO 2013/037960 PCT/EP2012/068101 211 H6nemann CW, Heyse TJ, M6|lhoff T, Hahnenkamp K, Berning S, Hinder F, Linck B, Schmitz W, van Aken H. (2001) The inhibitory effect of bupivacaine on prostaglandin E(2) (EP(1)) receptor functioning: mechanism of action. Anesth Analg. 93(3):628-634. 5 J. Wiley & Sons, New York.; and Seyden-Penne, J. "Reductions by the Alumino- and Borohydrides in Organic Synthesis"; VCH-Lavoisier: Paris, 1991 Johansson T, Narumiya S, Zeilhofer HU. (2011) Contribution of peripheral 10 versus central EP1 prostaglandin receptors to inflammatory pain. Neurosci Lett. 495(2):98-101. Kawahara H, Sakamoto A, Takeda S, Onodera H, Imaki J, Ogawa R. (2001) A prostaglandin E2 receptor subtype EP1 receptor antagonist (ONO-8711) reduces 15 hyperalgesia, allodynia, and c-fos gene expression in rats with chronic nerve constriction. Anesth Analg. 93(4):1012-7. P.J. Kocienski "Protecting Groups" (Georg Thieme Verlag 1994) 20 Richard Larock, Comprehensive Organic Transformations, 2nd edition, Wiley-VCH, ISBN 0-471-19031-4. Lee T, Hedlund P, Newgreen D, Andersson KE. (2007) Urodynamic effects of a novel EP(1) receptor antagonist in normal rats and rats with bladder outlet 25 obstruction. J Urol. 177(4):1562-1567. Lee C.M, Genetos DC, You Z, Yellowley CE. (2007b) Hypoxia regulates PGE(2) release and EP1 receptor expression in osteoblastic cells. J Cell Physiol. 212(1):182-188 30 Li X, Cudaback E, Keene CD, Breyer RM, Montine TJ. (2011) Suppressed microglial E prostanoid receptor 1 signaling selectively reduces tumor necrosis factor alpha and interleukin 6 secretion from toll-like receptor 3 activation. Glia. 59(4):569-576 WO 2013/037960 PCT/EP2012/068101 212 Lin CR, Amaya F, Barrett L, Wang H, Takada J, Samad TA, Woolf CJ (2006) Prostaglandin E2 receptor EP4 contributes to inflammatory pain hypersensitivity. J Pharmacol Exp Ther. 319(3):1096-103. 5 Ma W, Eisenach JC. (2003) Four PGE2 EP receptors are up-regulated in injured nerve following partial sciatic nerve ligation. Exp Neurol. 183(2):581-92. Miki, T.; Matsunami, M.; Okada, H.; Matsuya, H.; Kawabata, A (2010) ONO 10 8130, an EP1 antagonist, strongly attenuates cystitis-related bladder pain caused by cyclophosphamide in mice. J Pharmacol Sci 112(Suppl. 1): Abst P1J-1-2 Minami T, Uda R., Horiguchi S., Ito S. Hyodo M., Hayaishi 0. (1994) Allodynia evoked by intrathecal administration fo prostaglandin E2 to conscious 15 mice. Pain, 1994, 57: 217-223. Minami T, Nakano H, Kobayashi T, Sugimoto Y, Ushikubi F, Ichikawa A, Narumiya S, Ito S. (2001) Characterization of EP receptor subtypes responsible for prostaglandin E2-induced pain responses by use of EP1 and EP3 receptor knockout 20 mice. Br J Pharmacol. 133(3):438-44. Mizuguchi S, Ohno T, Hattori Y, Ae T, Minamino T, Satoh T, Arai K, Saeki T, Hayashi I, Sugimoto Y, Narumiya S, Saigenji K, Majima M. (2010) Roles of prostaglandin E2-EP1 receptor signaling in regulation of gastric motor activity and 25 emptying. Am J Physiol Gastrointest Liver Physiol. 299(5):G1078-1086 Moriyama T, Higashi T, Togashi K, lida T, Segi E, Sugimoto Y, Tominaga T, Narumiya S, Tominaga M. (2005) Sensitization of TRPV1 by EP1 and IP reveals peripheral nociceptive mechanism of prostaglandins. Mol Pain. 1: 3. 30 Nakayama Y, Omote K, Namiki A. (2002) Role of prostaglandin receptor EP1 in the spinal dorsal horn in carrageenan-induced inflammatory pain. Anesthesiology. 97(5):1254-62.
    WO 2013/037960 PCT/EP2012/068101 213 Nakayama Y, Omote K, Kawamata T, Namiki A. (2004) Role of prostaglandin receptor subtype EP1 in prostaglandin E2-induced nociceptive transmission in the rat spinal dorsal horn. Brain Res. 1010(1-2):62-8. 5 Narumiya S., Sugimoto Y., Ushikubi F. (1999) Protanoid receptors: structures, properties, and functions. Physiol Rev. 79 (1999) 1193-1226. Niho N, Mutoh M, Kitamura T, Takahashi M, Sato H, Yamamoto H, Maruyama T, Ohuchida S, Sugimura T, Wakabayashi K. (2005) Suppression of 10 azoxymethane-induced colon cancer development in rats by a prostaglandin E receptor EP 1-selective antagonist. Cancer Sci. 96(5):260-264. Oidda H., Namba T., Sugimoto Y., Ushikubi F., Ohishi H., Ichikawa A. et al (1995) In situ hybridization studies of prostacyclin receptor mRNA expression in 15 various mouse organs. Br J Pharmacol 1995, 116, 2828-2837. Oka T, Oka K, Saper CB. (2003) Contrasting effects of E type prostaglandin (EP) receptor agonists on core body temperature in rats. Brain Res. 968(2):256-262. 20 Oka T, Hosoi M, Oka K, Hori T. (1997) Biphasic alteration in the trigeminal nociceptive neuronal responses after intracerebroventricular injection of prostaglandin E2 in rats. Brain Res. 749(2):354-7. Erratum in: Brain Res 757(2):299. Okada, H., Konemura, T., Maruyama, T (2010) ONO-8539, a novel ep1 25 receptor antagonist, suppresses bladder hyperactivity via excessive production of prostaglandin e2 (pge2) induced by intravesical instillation of atp in urodynamic evaluation of cynomolgus monkeys. Eur Urol Suppl 9(2):72 30 Omote K, Yamamoto H, Kawamata T, Nakayama Y, Namiki A. (2002) The effects of intrathecal administration of an antagonist for prostaglandin E receptor subtype EP(1) on mechanical and thermal hyperalgesia in a rat model of postoperative pain. Anesth Analg. 95(6):1708-12.
    WO 2013/037960 PCT/EP2012/068101 214 Omote K, Kawamata T, Nakayama Y, Kawamata M, Hazama K, Namiki A. (2001) The effects of peripheral administration of a novel selective antagonist for prostaglandin E receptor subtype EP(1), ONO-871 1, in a rat model of postoperative pain. Anesth Analg.92(1):233-238. 5 Rahal S, McVeigh LI, Zhang Y, Guan Y, Breyer MD, Kennedy CR. (2006) Increased severity of renal impairment in nephritic mice lacking the EP1 receptor. Can J Physiol Pharmacol. 84(8-9):877-885. 10 Sarkar S, Hobson AR, Hughes A, Growcott J, Woolf CJ, Thompson DG, Aziz Q. (2003) The prostaglandin E2 receptor-1 (EP-1) mediates acid-induced visceral pain hypersensitivity in humans. Gastroenterology. 124(1):18-25. 15 Samad TA, Sapirstein A, Woolf CJ. (2002) Prostanoids and pain: unraveling mechanisms and revealing therapeutic targets. Trends Mol Med. 2002 Aug;8(8):390-6. Schl6tzer-Schrehardt U, Zenkel M, NOsing R.M. (2002) Expression and 20 Localization of FP and EP Prostanoid. Invest. Ophthalmol. Vis. Sci. 43(5) 1475 1487. Syriatowicz JP, Hu D, Walker JS, Tracey DJ. (1999) Hyperalgesia due to nerve injury: role of prostaglandins. Neuroscience. 94(2):587-94. 25 Teramura, T.; Kawatani, M.; Maruyama, T. (2000) Prostaglandin El facilitate primary afferent activity from the urinary bladder in the rat using selective EP1 receptor antagonist (ONO-871 1). BJU Int 86(Suppl. 3): Abst P6.3.19 30 L. G. Wade, Jr., Organic Chemistry, 6th ed., p. 477, Pearson/Prentice Hall, Upper Saddle River, New Jersey, USA, 2005. Watanabe K, Kawamori T, Nakatsugi S, Ohta T, Ohuchida S, Yamamoto H, Maruyama T, Kondo K, Ushikubi F, Narumiya S, Sugimura T, Wakabayashi K.
    WO 2013/037960 PCT/EP2012/068101 215 (1999) Role of the prostaglandin E receptor subtype EP1 in colon carcinogenesis. Cancer Res. 59(20):5093-5096. Wilbraham D., Masuda T.,Deacon S.,Kuwayama T., Vincent S. (2010) 5 Safety, tolerability and pharmacokinetic of multiple ascending doses of the ep-1 receptor antagonist ono-8539, a potential new and novel therapy to overactive bladder in healthy young and elderly subjects Eur Urol Suppl 9(2):250. Woodward DF, Regan JW, Lake S, Ocklind A. (1997) The molecular biology 10 and ocular distribution of prostanoid receptors. Surv Ophthalmol. 41 Suppl 2:S15 21. Zhang M, Ho HC, Sheu TJ, Breyer MD, Flick LM, Jonason JH, Awad HA, Schwarz EM, O'Keefe RJ.J (2011) EP1(-/-) mice have enhanced osteoblast 15 differentiation and accelerated fracture repair. Bone Miner Res. 26(4):792-802.
    权利要求:
    Claims (19)
    [1] 1. A compound of general formula 1: R 9 .. R R 9 'R9 B 5 wherein: W 1 is phenyl or a 6-membered heteroaromatic ring containing 1 or 2 N atoms, wherein W 1 is substituted by one R 1 and optionally substituted by one or more R2; W 2 is a 5- or 6-membered heterocyclic ring that contains 1 N atom and can additionally contain 1 or 2 heteroatoms selected from the group consisting of N, 0, 10 and S; wherein said ring is aromatic, partially unsaturated or saturated, and which is optionally substituted by one or more R3; R 1 is -R 6 -R 7 ; each R 2 is independently selected from the group consisting of H, halogen, C1-6 alkyl, C 1 6 -haloalkyl, -O-C 6 -alkyl, -O-C 6 -haloalkyl, hydroxyC, 1 6 -alkyl, CN, 15 NR 14 COR 15 , -NR 14 SO 2 R 15 and -S0 2 R 15 ; each R 3 is independently selected from the group consisting of H, halogen, C 1 - 6 -alkyl C 1 6 -haloalkyl, -O-C 6 -alkyl, -O-C 6 -haloalkyl, hydroxyC, 1 6 -alkyl, -C_ 4 -alkylene OR 14 , -C2_ 4 -alkenylene-COOH, =0 and CN; each R 4 is independently selected from the group consisting of H and C 1 6 -alkyl, or 20 both R 4 together with the C atom to which they are bonded form a C 3 - 6 cycloalkyl; R 5 is selected from the group consisting of H, halogen, C 1 6 -haloalkyl, -O-C 6 -alkyl, -O-C 6 -haloalkyl, -OH, C 1 6 -alkyl, C 3 - 6 cycloalkyl and -SO 2 R 15 ; R 6 is selected from the group consisting of a direct bond, -C_ 4 -alkylene-, -O-C_4 alkylene- and -C2_ 4 -alkenylene-; 25 R 7 is selected from the group consisting of -CO 2 H, -SO 3 H, 5-tetrazolyl, -OPOH 2 , PO 3 H 2 , -CONR 12 R 12 , -CONH-SO 2 R 12 , -NR 14 CONR 14 -SO 2 R 15 and -SO 2 -NHCOR 15 Y is selected from the group consisting of -C2. 4 -alkylene-, -O-C_ 4 -alkylene-, -C2_4 alkenylene- , -C_ 4 -alkylene-O-, -NR 13 -C 1 _ 4 -alkylene- and -C_ 4 -alkylene-NR 13 -; B is selected from the group consisting of C 2 - 6 -alkyl, C2-6 alkenyl and Cy, any of them 30 optionally substituted by one or more R 8 ; WO 2013/037960 PCT/EP2012/068101 217 each R 8 is independently selected from the group consisting of halogen, C-6 haloalkyl, -0-C 6 -alkyl, -0-C 6 -haloalkyl, C 1 6 -alkyl,-OH, -CN, -CH 2 0R 14 and CONR 12 R 12 ; each R 9 is independently selected from the group consisting of CR 1 and N; 5 each R 1 0 is independently selected from the group consisting of H, halogen, C-6 alkyl, C- 6 -haloalkyl, -0-C- 6 -alkyl, -0-C- 6 -haloalkyl and hydroxyC 6 -alkyl; R" is CR 5 or N, each R 12 is independently selected from the group consisting of H, C 16 -alkyl, C-6 haloalkyl,-NR 14 R 14 and C 3 6 cycloalkyl; 10 each R 13 is independently selected from the group consisting of H, C 16 -alkyl, C-6 haloalkyl, and C 3 6 cycloalkyl; each R 14 is independently selected from the group consisting of H and C 1 6 -alkyl; each R 15 is independently selected from the group consisting of C 16 -alkyl; Cy is a 3-6 membered monocyclic or 8-12 membered polycyclic ring which can be 15 carbocyclic or heterocyclic containing 1 to 3 heteroatoms selected from N, 0 and S and which can be aromatic, partially unsaturated or saturated and wherein one or more C or S atoms in Cy can be oxidized to form CO, SO or SO 2 ; with the proviso that when W1 and W2 is a benzimidazole, R6 and R7 are not at the same time respectively a -O-C_ 4 -alkylene- and a -C0 2 H or that R 7 is not -CONH 20 S0 2 R 12 ; and the salts, solvates and prodrugs thereof.
    [2] 2. The compound according to claim 1 wherein each R 9 is CR 1 and each R 1 is H. 25
    [3] 3. The compound according to any of the preceding claims wherein each R 4 is H.
    [4] 4. The compound according to any of the preceding claims wherein Y is -O-CH 2 or -CH 2 -0-, preferably -O-CH 2 - . 30
    [5] 5. The compound according to any of the preceding claims where R" is CR 5 and R 5 is selected from the group consisting of H, halogen and -C 6 -haloalkyl.
    [6] 6. The compound according to any of the preceding claims wherein B is phenyl, C3_ 6 -CyCloalkyl, C2- 6 -alkyl, 02-6 alkenyl or is a 5-6 membered monocyclic heterocycle WO 2013/037960 PCT/EP2012/068101 218 containing 1 or 2 N atom which can be aromatic, partially unsaturated or saturated, any of them optionally substituted by one or more R 8 .
    [7] 7. The compound according to any of the preceding claims wherein B is phenyl 5 optionally substituted by 1 to 5 R 8 .
    [8] 8. The compound according to any of claims 1 to 7 wherein R1 1 1 2 E N represents 10 where E 1 , E 2 and E 3 are CR 2 ; or one of E 1 , E 2 or E 3 is N and the others are CR 2 ; or two of E 1 , E 2 or E are N and the other is CR 2 .
    [9] 9. The compound according to any of claims 1 to 7 wherein QW2 D N represents 15 where G is selected from the group consisting of CR 3 , CR 3 R 3 , OCR 3 R 3 ; OCR 3 ;CR 3 R 3 -CR 3 R 3 and N; D is selected from the group consisting of CR , CR 3 R 3 and N; -- - represents a single bond or a double bond. 20
    [10] 10. The compound according to any of claims 1 to 7 wherein is selected from the group consisting of WO 2013/037960 PCT/EP2012/068101 219 R R 3 RR3 3 R2R ; R 1 R ; R N NN IN R2 R2 R 2 N R 2 N N R2 R 2 R2 R 1 R3R3 R 1 R 1 R 1 R 3 R RN2 N 2R 3 R2 N 2N 2N R2 NRRR R 2 R2 R 2R 2 R 1 R 1 R 3 R 1 R3 R3R 1 R 3 R 3 R3 S2 0 R 3 R 2 R R2 R FR3 N N R N NR R 2 N N R 1 R3R3 R 1 RNR R N R3 R2R3R 3 R 2 N' R 3 3 1 R R 3 N 1 R 3 2 N' 3 N 2R 2 s"" RRN R I 1and R 3 N N R 3 N-. N R 2 AR 2
    [11] 11. The compound according to claim 10 wherein b' represents R R1R R3 R R 1 R 3 R2 R 1 R 3 R 3 R3 R R 1 R 3 R2 R 1 R 3 R 3 R33 1 R 3 I R 3 R 3 INR 2 IN IN I 3 2~I N- N R 3 R 2 N N 3 R N' or N N R 5 1
    [12] 12. The compound according to any of the preceding claims wherein R 6 is a direct bond and R' iS-C0 2 H. WO 2013/037960 PCT/EP2012/068101 220
    [13] 13. The compound according to any of the preceding claims wherein each R 2 is independently selected from the group consisting of H and halogen and each R 3 is H. 5
    [14] 14. A compound according to claim 1 selected from: - (E)-1 -(5-chloro-2-(4-chloro-2-fluorostyryl)benzyl)-1 H-indole-4-carboxylic acid, - 1-(2-(benzyloxy)-5-bromobenzyl)-1 H-indole-4-carboxylic acid, - 1-(2-(benzyloxy)-5-(trifluoromethyl)benzyl)-1 H-indole-4-carboxylic acid, - 1-(5-bromo-2-((4-fluorobenzyl)oxy)benzyl)-1 H-indole-4-carboxylic acid, 10 - 1-(5-chloro-2-((4-fluorobenzyl)oxy)benzyl)-1 H-indole-4-carboxylic acid, - 1-(2-((4-chloro-2-fluorobenzyl)oxy)-5-(trifluoromethyl)benzyl)-1 H-indole-4 carboxylic acid, - 1-(5-chloro-2-(cyclopropylmethoxy)benzyl)-1 H-indole-4-carboxylic acid, - 1-(5-bromo-2-(cyclopropylmethoxy)benzyl)-1 H-indole-4-carboxylic acid, 15 - 1-(5-bromo-2-((4-chloro-2-fluorobenzyl)oxy)benzyl)-1 H-indole-4-carboxylic acid, - 1-(4-chloro-2-isobutoxybenzyl)-1 H-indole-4-carboxylic acid, - 1 -(5-chloro-2-((4-(trifluoromethyl)benzyl)oxy)benzyl)-1 H-indole-4-carboxylic acid, 20 - 1-(5-chloro-2-((2-chloro-4-fluorobenzyl)oxy)benzyl)-1 H-indole-4-carboxylic acid, - 1-(5-chloro-2-((2,3,5,6-tetrafluorobenzyl)oxy)benzyl)-1 H-indole-4-carboxylic acid, - 1-(2-((2,4-bis(trifluoromethyl)benzyl)oxy)-5-chlorobenzyl)-1 H-indole-4 25 carboxylic acid, - 1-(5-chloro-2-((2,4,5-trifluorobenzyl)oxy)benzyl)-1 H-indole-4-carboxylic acid, - 1-(5-fluoro-2-((2,4,5-trifluorobenzyl)oxy)benzyl)-1 H-indole-4-carboxylic acid, - 1-(2-((3-bromo-4-fluorobenzyl)oxy)-5-chlorobenzyl)-1 H-indole-4-carboxylic acid, 30 - 1-(5-fluoro-2-((4-fluoro-2-(trifluoromethyl)benzyl)oxy)benzyl)-1 H-indole-4 carboxylic acid, - 1-(2-((2-chloro-4-fluorobenzyl)oxy)-5-fluorobenzyl)-1 H-indole-4-carboxylic acid, - 1-(5-fluoro-2-((4-fluoro-2-(trifluoromethyl)benzyl)oxy)benzyl)-1 H-indole-4 35 carboxylic acid, WO 2013/037960 PCT/EP2012/068101 221 - 1-(5-chloro-2-((2,3,4-trifluorobenzyl)oxy)benzyl)-1 H-indole-4-carboxylic acid, - 1-(5-bromo-2-((2,3,4-trifluorobenzyl)oxy)benzyl)-1 H-indole-4-carboxylic acid, - 1-(5-chloro-2-(1-(2,4-difluorophenyl)ethoxy)benzyl)-1 H-indole-4-carboxylic acid, 5 - 1-(2-((3-bromo-4-fluorobenzyl)oxy)-5-fluorobenzyl)-1 H-indole-4-carboxylic acid, - 1-(5-bromo-2-((3-bromo-4-fluorobenzyl)oxy)benzyl)-1 H-indole-4-carboxylic acid, - 1 -(5-bromo-2-((4-fluoro-2-(trifluoromethyl)benzyl)oxy)benzyl)-1 H-indole-4 10 carboxylic acid, - 1-(5-bromo-2-((2-chloro-4-fluorobenzyl)oxy)benzyl)-1 H-indole-4-carboxylic acid, - 1-(3-bromo-2-((4-bromo-2-fluorobenzyl)oxy)-5-chlorobenzyl)-1 H-indole-4 carboxylic acid, 15 - 1-(5-chloro-2-((2,5-difluorobenzyl)oxy)benzyl)-1 H-indole-4-carboxylic acid, - 1-(5-chloro-2-((2-chloro-5-fluorobenzyl)oxy)benzyl)-1 H-indole-4-carboxylic acid, - 1-(5-chloro-2-((2-chloro-4,5-difluorobenzyl)oxy)benzyl)-1 H-indole-4 carboxylic acid, 20 - 1-(2-((2,5-difluorobenzyl)oxy)-5-fluorobenzyl)-1 H-indole-4-carboxylic acid, - 1-(2-((2,6-difluorobenzyl)oxy)-5-fluorobenzyl)-1 H-indole-4-carboxylic acid, - 1-(5-fluoro-2-((3,4,5-trifluorobenzyl)oxy)benzyl)-1 H-indole-4-carboxylic acid, - 1-(5-fluoro-2-((4-fluorobenzyl)oxy)benzyl)-1 H-indole-4-carboxylic acid, - 1-(2-((2-chloro-4,5-difluorobenzyl)oxy)-5-fluorobenzyl)-1 H-indole-4-carboxylic 25 acid, - 1-(2-((2,6-difluorobenzyl)oxy)-5-(trifluoromethyl)benzyl)-1 H-indole-4 carboxylic acid, - 1-(2-((2-chloro-5-fluorobenzyl)oxy)-5-fluorobenzyl)-1 H-indole-4-carboxylic acid, 30 - 1-(2-((2,5-difluorobenzyl)oxy)-5-(trifluoromethyl)benzyl)-1 H-indole-4 carboxylic acid, - 1-(3-bromo-5-chloro-2-((2,6-difluorobenzyl)oxy)benzyl)-1 H-indole-4 carboxylic acid, - 1-(5-chloro-2-((3,5-difluorobenzyl)oxy)benzyl)-1 H-indole-4-carboxylic acid, WO 2013/037960 PCT/EP2012/068101 222 - 1-(1 -(5-chloro-2-((4-chloro-2-fluorobenzyl)oxy)phenyl)ethyl)-1 H-indole-4 carboxylic acid, - 1-(5-chloro-2-((2,4-difluorobenzyl)oxy)benzyl)-1 H-indole-4-carboxylic acid, - 1-(2-(benzyloxy)-5-chlorobenzyl)-1 H-indole-4-carboxylic acid, 5 - 1-(5-chloro-2-((2-fluorobenzyl)oxy)benzyl)-1 H-indole-4-carboxylic acid, - 1-(2-((4-bromo-2-fluorobenzyl)oxy)-5-chlorobenzyl)-1 H-indole-4-carboxylic acid, - 1 -(5-chloro-2-((2-fluoro-4-(trifluoromethyl)benzyl)oxy)benzyl)-1 H-indole-4 carboxylic acid, 10 - 1-(5-chloro-2-((4-chloro-2-fluorobenzyl)oxy)benzyl)-1 H-indole-4-carboxylic acid, - 1-(2-((3-fluorobenzyl)oxy)-5-(trifluoromethyl)benzyl)-1 H-indole-4-carboxylic acid, - 1-(2-((4-bromo-2-fluorobenzyl)oxy)-5-(trifluoromethyl)benzyl)-1 H-indole-4 15 carboxylic acid, - 1-(2-((2,4-difluorobenzyl)oxy)-5-(trifluoromethyl)benzyl)-1 H-indole-4 carboxylic acid, - 1-(2-((2-fluorobenzyl)oxy)-5-(trifluoromethyl)benzyl)-1 H-indole-4-carboxylic acid, 20 - 1-(2-((2,4-difluorobenzyl)oxy)-5-fluorobenzyl)-1 H-indole-4-carboxylic acid, - 1-(2-((2,4-difluorobenzyl)oxy)benzyl)-1 H-indole-4-carboxylic acid, - 1-(5-bromo-2-((4-bromo-2-fluorobenzyl)oxy)benzyl)-1 H-indole-4-carboxylic acid, - 1-(2-((4-bromo-2-fluorobenzyl)oxy)-5-fluorobenzyl)-1 H-indole-4-carboxylic 25 acid, - 1-(5-chloro-2-((4-chloro-2,6-difluorobenzyl)oxy)benzyl)-1 H-indole-4 carboxylic acid, - 1-(2-((4-bromo-2,6-difluorobenzyl)oxy)-5-chlorobenzyl)-1 H-indole-4 carboxylic acid, 30 - 1-(3,5-dichloro-2-((4-chloro-2-fluorobenzyl)oxy)benzyl)-1 H-indole-4 carboxylic acid, - 1-(5-bromo-2-((4-chloro-2,6-difluorobenzyl)oxy)benzyl)-1 H-indole-4 carboxylic acid, WO 2013/037960 PCT/EP2012/068101 223 - 1-((3-((4-chloro-2-fluorobenzyl)oxy)pyridin-2-yl)methyl)-1 H-indole-4 carboxylic acid, - 3-(1-(5-chloro-2-((4-chloro-2-fluorobenzyl)oxy)benzyl)-1 H-indol-4 yl)propanoic acid, 5 - 1-(5-chloro-2-(4-chloro-2-fluorophenethyl)benzyl)-1 H-indole-4-carboxylic acid, - 1-(5-chloro-2-(cyclopropylmethoxy)benzyl)-1 H-indole-5-carboxylic acid, - 1-(5-fluoro-2-((2,4,5-trifluorobenzyl)oxy)benzyl)-1 H-indole-5-carboxylic acid, - 1-(2-((2-chloro-4-fluorobenzyl)oxy)-5-fluorobenzyl)-1 H-indole-5-carboxylic 10 acid, - 1 -(5-chloro-2-((4-fluoro-2-(trifluoromethyl)benzyl)oxy)benzyl)-1 H-indole-5 carboxylic acid, - 1-(2-((3-bromo-4-fluorobenzyl)oxy)-5-fluorobenzyl)-1 H-indole-5-carboxylic acid, 15 - 1 -(5-bromo-2-((4-fluoro-2-(trifluoromethyl)benzyl)oxy)benzyl)-1 H-indole-5 carboxylic acid, - 1-(5-bromo-2-((2-chloro-4-fluorobenzyl)oxy)benzyl)-1 H-indole-5-carboxylic acid, - 1-(5-fluoro-2-((3,4,5-trifluorobenzyl)oxy)benzyl)-1 H-indole-5-carboxylic acid, 20 - 1-(2-((2-chloro-4,5-difluorobenzyl)oxy)-5-fluorobenzyl)-1 H-indole-5-carboxylic acid, - 1-(2-((2-chloro-5-fluorobenzyl)oxy)-5-fluorobenzyl)-1 H-indole-5-carboxylic acid, - 1-(5-bromo-2-((2,4-difluorobenzyl)oxy)benzyl)-1 H-indole-5-carboxylic acid, 25 - 1-(2-((4-bromo-2-fluorobenzyl)oxy)-5-(trifluoromethyl)benzyl)-1 H-indole-5 carboxylic acid, - 1-(5-chloro-2-((4-chloro-2-fluorobenzyl)oxy)benzyl)-1 H-indole-5-carboxylic acid, - 1-(5-chloro-2-((4-fluorobenzyl)oxy)benzyl)-1 H-indole-5-carboxylic acid, 30 - 1-(5-chloro-2-((2,4-difluorobenzyl)oxy)benzyl)-1 H-indole-5-carboxylic acid, - (E)-3-(1 -(2-(benzyloxy)-5-(trifluoromethyl)benzyl)-1 H-indol-4-yl)acrylic acid, - (E)-3-(1-(5-bromo-2-(cyclopropylmethoxy)benzyl)-1 H-indol-4-yl)acrylic acid, - (E)-3-(1-(5-chloro-2-(cyclopropylmethoxy)benzyl)-1 H-indol-4-yl)acrylic acid, WO 2013/037960 PCT/EP2012/068101 224 - (E)-3-(1-(5-chloro-2-((2,4-difluorobenzyl)oxy)benzyl)-1 H-indol-4-yl)acrylic acid, - (E)-3-(1-(5-chloro-2-((4-chloro-2-fluorobenzyl)oxy)benzyl)-1 H-indol-4 yl)acrylic acid, 5 - 2-((1-(2-((4-chloro-2-fluorobenzyl)oxy)-5-(trifluoromethyl)benzyl)-1 H-indol-4 yl)oxy)acetic acid, - 2-((1-(5-chloro-2-(cyclopropylmethoxy)benzyl)-1 H-i ndol-4-yl)oxy)acetic acid, - 2-((1-(5-chloro-2-(cyclopropylmethoxy)benzyl)-1 H-indol-4-yl)oxy)acetic acid, - 1-(2-(benzyloxy)-5-bromobenzyl)-1 H-indole-6-carboxylic acid, 10 - 1-(5-chloro-2-((2,4-difluorobenzyl)oxy)benzyl)-1 H-indole-6-carboxylic acid, - 3-(1-(5-chloro-2-((4-chloro-2-fluorobenzyl)oxy)benzyl)-1 H-indol-4 yl)propanoic acid, - 1-(5-chloro-2-((4-chloro-2-fluorobenzyl)oxy)benzyl)-1 H-pyrrolo[2,3-b]pyridine 4-carboxylic acid, 15 - 1-(5-chloro-2-((2,4-difluorobenzyl)oxy)benzyl)-1 H-pyrrolo[2,3-b]pyridine-4 carboxylic acid, - 1-(5-chloro-2-((4-chloro-2-fluorobenzyl)oxy)benzyl)-1 H-benzo[d]imidazole-4 carboxylic acid, - 1-(5-chloro-2-((4-chloro-2-fluorobenzyl)oxy)benzyl)indoline-4-carboxylic acid, 20 - 1-(5-chloro-2-((4-chloro-2-fluorobenzyl)oxy)benzyl)-1,2,3,4 tetrahydroquinoline-5-carboxylic acid, - 1-(5-chloro-2-((2,4-difluorobenzyl)oxy)benzyl)-1,2,3,4-tetrahydroquinoline-5 carboxylic acid, - 7-(5-chloro-2-((4-chloro-2-fluorobenzyl)oxy)benzyl)-7H-pyrrolo[2,3 25 d]pyrimidine-4-carboxylic acid, - 7-(5-chloro-2-((2,4-difluorobenzyl)oxy)benzyl)-7H-pyrrolo[2,3-d]pyrimidine-4 carboxylic acid, - 1-(5-chloro-2-((2,4-difluorobenzyl)oxy)benzyl)-7-fluoro-1 H-indole-4-carboxylic acid, 30 - 1-{2-[(2,4-difluorobenzyl)oxy]-5-methoxybenzyl}-1 H-indole-4-carboxylic acid, - 1-[5-chloro-2-(cyclohexylmethoxy)benzyl]-1 H-indole-4-carboxylic acid, - 1-[5-chloro-2-(cyclopentylmethoxy)benzyl]-1 H-indole-4-carboxylic acid, - 1-(5-fluoro-2-propoxybenzyl)-1 H-indole-4-carboxylic acid, - 1-(5-chloro-2-(cyclopentyloxy)benzyl)-1 H-indole-4-carboxylic acid, WO 2013/037960 PCT/EP2012/068101 225 - 1-(5-chloro-2-propoxybenzyl)-1 H-indole-4-carboxylic acid, - 1-(5-chloro-2-(2-(tetrahydro-2H-pyran-4-yl)ethoxy)benzyl)-1 H-indole-4 carboxylic acid, - 1-(5-fluoro-2-isobutoxybenzyl)-1 H-indole-4-carboxylic acid, 5 - 1-(2-isobutoxybenzyl)-1 H-indole-4-carboxylic acid, - 1-[5-chloro-2-(2,2-difluoroethoxy)benzyl]-1 H-indole-4-carboxylic acid, - 1-[5-chloro-2-(2-fluoroethoxy)benzyl]-1 H-indole-4-carboxylic acid, - 1-[5-chloro-2-(2,2,2-trifluoroethoxy)benzyl]-1 H-indole-4-carboxylic acid, - 1-[5-chloro-2-(neopentyloxy)benzyl]-1 H-indole-4-carboxylic acid, 10 - 4-(5-chloro-2-cyclobutoxybenzyl)-3-oxo-3,4-dihydro-2H benzo[b][1,4]oxazine-8-carboxylic acid, - 4-(5-bromo-2-(4-chloro-2-fluorobenzyloxy)benzyl)-3-oxo-3,4-dihydro-2H benzo[b][1,4]oxazine-8-carboxylic acid, - 4-(5-chloro-2-(2-fluoro-2-methylpropoxy)benzyl)-3,4-dihydro-2H 15 benzo[b][1,4]oxazine-8-carboxylic acid - 4-(5-chloro-2-((4-chloro-2-fluorobenzyl)oxy)benzyl)-3,4-dihydro-2H benzo[b][1,4]oxazine-8-carboxylic acid, - 4-(5-chloro-2-((2,4-difluorobenzyl)oxy)benzyl)-3,4-dihydro-2H benzo[b][1,4]oxazine-8-carboxylic acid, 20 - 4-(2-((4-chloro-2-fluorobenzyl)oxy)benzyl)-3,4-dihydro-2H benzo[b][1,4]oxazine-8-carboxylic acid, - 4-(2-(benzyloxy)benzyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-8-carboxylic acid, - 4-(2-((2-chloro-4-fluorobenzyl)oxy)-5-fluorobenzyl)-3,4-dihydro-2H 25 benzo[b][1,4]oxazine-8-carboxylic acid, - 4-(2-((2,4-difluorobenzyl)oxy)benzyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-8 carboxylic acid, - 1-(2-((2-chlorobenzyl)oxy)-5-fluorobenzyl)-1 H-indazole-4-carboxylic acid, - 1-(5-chloro-2-((4-chloro-2-fluorobenzyl)oxy)benzyl)-1 H-indazole-4-carboxylic 30 acid, - 1-(5-chloro-2-(2-fluoro-2-methylpropoxy)benzyl)-1 H-indazole-4-carboxylic acid, - 1-(5-chloro-2-((2-fluorobenzyl)oxy)benzyl)-1 H-indazole-4-carboxylic acid, - 1-(2-((2-chlorobenzyl)oxy)-5-methylbenzyl)-1 H-indazole-4-carboxylic acid, WO 2013/037960 PCT/EP2012/068101 226 - 1-(5-fluoro-2-((2-fluorobenzyl)oxy)benzyl)-1 H-indazole-4-carboxylic acid, - 1-(2-((2-fluorobenzyl)oxy)-5-methylbenzyl)-1 H-indazole-4-carboxylic acid, - 1-(5-chloro-2-((2-chlorobenzyl)oxy)benzyl)-1 H-indazole-4-carboxylic acid, - 1-(5-chloro-2-(3-fluoro-2-methylpropoxy)benzyl)-1 H-indazole-4-carboxylic 5 acid, - 1-(5-chloro-2-propoxybenzyl)-1 H-indazole-4-carboxylic acid, - 1-(5-chloro-2-(cyclopentyloxy)benzyl)-1 H-indazole-4-carboxylic acid, - 1-(5-fluoro-2-isobutoxybenzyl)-1 H-indazole-4-carboxylic acid, - 1-(5-fluoro-2-propoxybenzyl)-1 H-indazole-4-carboxylic acid, 10 - 1-(5-bromo-2-(4-chloro-2-fluorobenzyloxy)benzyl)-1 H-indazole-4-carboxylic acid, - 1-(5-chloro-2-cyclobutoxybenzyl)-1 H-indazole-4-carboxylic acid, - 1-(5-chloro-2-(neopentyloxy)benzyl)-1 H-indazole-4-carboxylic acid, - 1-(5-chloro-2-((4-chloro-2-fluorobenzyl)oxy)benzyl)-1 H-pyrrolo[3,2-c]pyridine 15 4-carboxylic acid, - 1-(2-((2,4-difluorobenzyl)oxy)benzyl)-7-fluoro-1 H-indole-4-carboxylic acid, - 1-(5-chloro-2-((4-chloro-2-fluorobenzyl)oxy)benzyl)-3-(hydroxymethyl)-1 H indole-4-carboxylic acid, - 1-(5-chloro-2-((2,4-difluorobenzyl)oxy)benzyl)-3-(hydroxymethyl)-1 H-indole 20 4-carboxylic acid, - 1 -(2-((2,4-difluorobenzyl)oxy)benzyl)-3-(hydroxymethyl)-1 H-indole-4 carboxylic acid, - 1 -(2-((4-chloro-2-fluorobenzyl)oxy)benzyl)-3-(hydroxymethyl)-1 H-indole-4 carboxylic acid, 25 - 1 -(2-((2,4-difluorobenzyl)oxy)-5-fluorobenzyl)-3-(hydroxymethyl)-1 H-indole-4 carboxylic acid, - 1-(2-((4-chloro-2-fluorobenzyl)oxy)-5-fluorobenzyl)-3-(hydroxymethyl)-1 H indole-4-carboxylic acid, - 1 -(5-chloro-2-(2-fluoro-2-methylpropoxy)benzyl)-3-(hydroxymethyl)-1 H 30 indole-4-carboxylic acid, - 1 -(2-cyclobutoxy-5-fluorobenzyl)-3-(hydroxymethyl)- 1 H-indole-4-carboxylic acid, - 1 -(5-fluoro-2-((4-fluorobenzyl)oxy)benzyl)-3-(hydroxymethyl)-1 H-indole-4 carboxylic acid, WO 2013/037960 PCT/EP2012/068101 227 - 1 -(5-chloro-2-((4-fluorobenzyl)oxy)benzyl)-3-(hydroxymethyl)-1 H-indole-4 carboxylic acid, - 1 -(5-chloro-2-(3-fluoro-2-methylpropoxy)benzyl)-3-(hydroxymethyl)-1 H indole-4-carboxylic acid, 5 - 1-(5-chloro-2-((2,4-difluorobenzyl)oxy)benzyl)-3-(hydroxymethyl)-1 H pyrrolo[2,3-b]pyridine-4-carboxylic acid, - 1-(5-chloro-2-((4-chloro-2-fluorobenzyl)oxy)benzyl)-3-(hydroxymethyl)-1 H pyrrolo[2,3-b]pyridine-4-carboxylic acid, - 1-(5-chloro-2-((4-chloro-2-fluorobenzyl)oxy)benzyl)-3-(2-hydroxyethyl)-1 H 10 indole-4-carboxylic acid, - 1-(5-chloro-2-((2,4-difluorobenzyl)oxy)benzyl)-3-(2-hydroxyethyl)-1 H-indole 4-carboxylic acid, - 1-(5-fluoro-2-isobutoxybenzyl)-3-(2-hydroxyethyl)-1 H-indole-4-carboxylic acid, 15 - 1-(5-chloro-2-isobutoxybenzyl)-3-(2-hydroxyethyl)-1 H-indole-4-carboxylic acid, - 1-(5-chloro-2-(2-fluoro-2-methylpropoxy)benzyl)-3-(2-hydroxyethyl)-1 H indole-4-carboxylic acid, - 1-(2-((2,4-difluorobenzyl)oxy)-5-fluorobenzyl)-3-(2-hydroxyethyl)-1 H-indole-4 20 carboxylic acid, - 1-(5-chloro-2-(3-fluoro-2-methylpropoxy)benzyl)-3-(2-hydroxyethyl)-1 H indole-4-carboxylic acid, - (E)-3-(2-carboxylatovinyl)-1 -(5-chloro-2-((4-chloro-2 fluorobenzyl)oxy)benzyl)-1 H-indole-4-carboxylic acid, 25 - (E)-3-(2-carboxylatovinyl)-1 -(5-chloro-2-((2,4-difluorobenzyl)oxy)benzyl)-1 H indole-4-carboxylic acid, - 1-(5-chloro-2-((2,4-difluorobenzyl)oxy)benzyl)-1 H-pyrrolo[2,3-c]pyridine-4 carboxylic acid, - 1-(5-chloro-2-((4-chloro-2-fluorobenzyl)oxy)benzyl)-1 H-pyrrolo[2,3-c]pyridine 30 4-carboxylic acid, - 1-(5-chloro-2-((2,4-difluorobenzyl)oxy)benzyl)indoline-4-carboxylic acid, - 1-(5-chloro-2-(2-fluoro-2-methylpropoxy)benzyl)indoline-4-carboxylic acid, - 1-(5-chloro-2-((4-chloro-2-fluorobenzyl)oxy)benzyl)indoline-4-carboxylic acid, - 1-(2-((2-chloro-4-fluorobenzyl)oxy)-5-fluorobenzyl)indoline-4-carboxylic acid, WO 2013/037960 PCT/EP2012/068101 228 - 1-(5-chloro-2-isobutoxybenzyl)indoline-4-carboxylic acid, - 1-(5-fluoro-2-isobutoxybenzyl)indoline-4-carboxylic acid, - 1-(5-chloro-2-cyclobutoxybenzyl)indoline-4-carboxylic acid, - 1-(2-((2,4-difluorobenzyl)oxy)benzyl)-1,2,3,4-tetrahydroquinoline-5-carboxylic 5 acid, - 1-(5-chloro-2-((2,4-difluorobenzyl)oxy)benzyl)-1,2,3,4-tetrahydroquinoline-5 carboxylic acid, - 1-(5-chloro-2-(cyclobutylmethoxy)benzyl)-1,2,3,4-tetrahydroquinoline-5 carboxylic acid, 10 - 1-(5-chloro-2-isobutoxybenzyl)-1,2,3,4-tetrahydroquinoline-5-carboxylic acid, - 1-[5-chloro-2-(1,2-dimethylpropoxy)benzyl]-1,2,3,4-tetrahydroquinoline-5 carboxylic acid, - 1-[5-chloro-2-(2-fluoro-2-methylpropoxy)benzyl]-1,2,3,4-tetrahydroquinoline 5-carboxylic acid, 15 - 1-[5-chloro-2-(cyclobutyloxy)benzyl]-1,2,3,4-tetrahydroquinoline-5-carboxylic acid, - 1-{5-chloro-2-[(2-methylprop-2-enyl)oxy]benzyl}-1,2,3,4-tetrahydroquinoline 5-carboxylic acid, - 1-[5-chloro-2-(3-fluoro-2-methylpropoxy)benzyl]-1,2,3,4-tetrahydroquinoline 20 5-carboxylic acid, - 1-[5-chloro-2-(2-fluoropropoxy)benzyl]-1,2,3,4-tetrahydroquinoline-5 carboxylic acid, - 1-(5-chloro-2-{[2-(fluoromethyl)prop-2-enyl]oxy}benzyl)-1,2,3,4 tetrahydroquinoline-5-carboxylic acid, 25 - 1-(5-chloro-2-((4-chloro-2-fluorobenzyl)oxy)benzyl)-1,2,3,4 tetrahydroquinoline-5-sulfonic acid, - 1-(5-chloro-2-((2,4-difluorobenzyl)oxy)benzyl)-1,2,3,4-tetrahydroquinoline-5 sulfonic acid, - 1-(2-((4-chloro-2-fluorobenzyl)oxy)benzyl)-1,2,3,4-tetrahydroquinoline-5 30 sulfonic acid, - N-((1 -(5-chloro-2-((2,4-difluorobenzyl)oxy)benzyl)-1,2,3,4-tetrahydroquinolin 5-yl)sulfonyl)acetamide, - N-((1 -(5-chloro-2-((4-chloro-2-fluorobenzyl)oxy)benzyl)-1,2,3,4 tetrahydroquinolin-5-yl)sulfonyl)acetamide, WO 2013/037960 PCT/EP2012/068101 229 - 1-(5-chloro-2-((4-chloro-2-fluorobenzyl)oxy)benzyl)-3-(hydroxymethyl)-1 H indazole-4-carboxylic acid, - 1 -(5-chloro-2-(2-fluoro-2-methylpropoxy)benzyl)-3-(hydroxymethyl)-1 H indazole-4-carboxylic acid, 5 - 1-(5-chloro-2-(cyclopentyloxy)benzyl)-1,2,3,4-tetrahydroquinoline-5 carboxylic acid, - 1-(5-chloro-2-(propooxy)benzyl)-1,2,3,4-tetrahydroquinoline-5-carboxylic acid, - 1-(2-(4-chloro-2-fluorobenzyloxy)-5-methylbenzyl)-1,2,3,4 10 tetrahydroquinoline-5-carboxylic acid, - 1-(5-chloro-2-(neopentyloxy)benzyl)-1,2,3,4-tetrahydroquinoline-5-carboxylic acid, - 4-(2-(4-chloro-2-fluorobenzyloxy)-5-methylbenzyl)-3,4-dihydro-2H benzo[b][1,4]oxazine-8-carboxylic acid, 15 - 4-(5-fluoro-2-isobutoxybenzyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-8 carboxylic acid, - 4-(5-chloro-2-isobutoxybenzyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-8 carboxylic acid, - 4-(5-chloro-2-cyclobutoxybenzyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-8 20 carboxylic acid, - 4-(5-chloro-2-(cyclopropylmethoxy)benzyl)-3,4-dihydro-2H benzo[b][1,4]oxazine-8-carboxylic acid, - 4-(5-chloro-2-(neopentyloxy)benzyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-8 carboxylic acid, 25 - 1-(5-chloro-2-(3-methoxypropoxy)benzyl)indoline-4-carboxylic acid, - 1-(5-chloro-2-(2-methoxyethoxy)benzyl)indoline-4-carboxylic acid, - 1-(5-chloro-2-(cyclopropylmethoxy)benzyl)indoline-4-carboxylic acid, - 1-(5-chloro-2-(neopentyloxy)benzyl)indoline-4-carboxylic acid, - 1-(5-chloro-2-((3-methyloxetan-3-yl)methoxy)benzyl)indoline-4-carboxylic 30 acid, - (S)-1-(5-chloro-2-(3-hydroxy-2-methylpropoxy)benzyl)indoline-4-carboxylic acid, - 1-(5-chloro-2-(4-chloro-2-fluorobenzyloxy)benzyl)-3-(methoxymethyl)-1 H indole-4-carboxylic acid, WO 2013/037960 PCT/EP2012/068101 230 - 1 -(5-ch loro-2-(4-ch loro-2-fluorobenzyloxy)benzyl)-2-oxoindoline-4-carboxylic acid, - 1-(2-(4-chloro-2-fluorobenzyloxy)-5-cyclopropylbenzyl)-1 H-indazole-4 carboxylic acid, 5 - 1-(5-chloro-2-(4-chloro-2-fluorobenzyloxy)benzyl)-3-(methoxymethyl)-1 H indole-4-carboxylic acid, - 1-{5-chloro-2-[(4-chloro-2-ethylbenzyl)oxy]benzyl}-1 H-indole-4-carboxylic acid, - 1-{5-chloro-2-[(4-chloro-2-fluorobenzyl)oxy]benzyl}-1 H-pyrazolo[3,4 10 b]pyridine-4-carboxylic acid, - 1-[5-chloro-2-(2-fluoro-2-methylpropoxy)benzyl]-1 H-pyrazolo[3,4-b]pyridine 4-carboxylic acid, - 1-[5-chloro-2-(cyclobutyloxy)benzyl]-1 H-pyrazolo[3,4-b]pyridine-4-carboxylic acid, 15 - 1-{5-chloro-2-[(4-chloro-2-fluorobenzyl)oxy]benzyl}-2-oxo-1,2,3,4 tetrahydroquinoline-5-carboxylic acid, - 1-{5-chloro-2-[(4-chloro-2-fluorobenzyl)oxy]benzyl}-2,3-dihydro-1 H pyrrolo[2,3-b]pyridine-4-carboxylic acid, - 1-{5-chloro-2-[(2,4-difluorobenzyl)oxy]benzyl}-2,3-dihydro-1 H-pyrrolo[2,3 20 b]pyridine-4-carboxylic acid, - 1-{5-chloro-2-[(4-chlorobenzyl)oxy]benzyl}-2,3-dihydro-1 H-pyrrolo[2,3 b]pyridine-4-carboxylic acid, - 1-{5-chloro-2-[(2-fluorobenzyl)oxy]benzyl}-2,3-dihydro-1 H-pyrrolo[2,3 b]pyridine-4-carboxylic acid, 25 - 1-{5-chloro-2-[(4-fluorobenzyl)oxy]benzyl}-2,3-dihydro-1 H-pyrrolo[2,3 b]pyridine-4-carboxylic acid, - 1-[5-chloro-2-(2-fluoro-2-methylpropoxy)benzyl]-2,3-dihydro-1 H-pyrrolo[2,3 b]pyridine-4-carboxylic acid, - 1-(5-chloro-2-isobutoxybenzyl)-2,3-dihydro-1 H-pyrrolo[2,3-b]pyridine-4 30 carboxylic acid, WO 2013/037960 PCT/EP2012/068101 231 - 1-{5-chloro-2-[(4-chloro-2-fluorobenzyl)oxy]benzyl}-4-(1 H-tetrazol-5-yl)-2,3 dihydro-1 H-pyrrolo[2,3-b]pyridine, - 8-{5-chloro-2-[(2,4-difluorobenzyl)oxy]benzyl}-5,6,7,8-tetrahydro-1,8 naphthyridine-4-carboxylic acid, 5 - 8-{5-chloro-2-[(4-chloro-2-fluorobenzyl)oxy]benzyl}-5,6,7,8-tetrahydro-1,8 naphthyridine-4-carboxylic acid, - 1-{5-chloro-2-[(4-chloro-2-fluorobenzyl)oxy]benzyl}-1,2,3,4-tetrahydro-1,7 naphthyridine-5-carboxylic acid, - 1-{5-chloro-2-[(2,4-difluorobenzyl)oxy]benzyl}-1,2,3,4-tetrahydro-1,7 10 naphthyridine-5-carboxylic acid, - 1-{5-chloro-2-[(2,4-difluorobenzyl)oxy]benzyl}-1,2,3,4-tetrahydro-1,6 naphthyridine-5-carboxylic acid, - 1-{5-chloro-2-[(4-chloro-2-fluorobenzyl)oxy]benzyl}-1,2,3,4-tetrahydro-1,6 naphthyridine-5-carboxylic acid, 15 - 1-{5-chloro-2-[(4-chloro-2-fluorobenzyl)oxy]benzyl}-1,2,3,4 tetrahydroquinoxaline-5-carboxylic acid, - 1-{5-chloro-2-[2-(2,4-difluorophenyl)ethoxy]benzyl}-1 H-indole-4-carboxylic acid, - 1-{5-chloro-2-[(4-chloro-2-fluorobenzyl)oxy]benzyl}-N-(methylsulfonyl)-1 H 20 indole-4-carboxamide, - 1-{5-chloro-2-[(4-chloro-2-fluorobenzyl)oxy]benzyl}-N-(methylsulfonyl)-1 H indole-4-carboxamide, - 1-(5-chloro-2-isobutoxybenzyl)-N-(methylsulfonyl)-2,3-dihydro-1 H pyrrolo[2,3-b]pyridine-4-carboxamide, 25 - 1-{5-chloro-2-[(4-chloro-2-fluorobenzyl)oxy]benzyl}-N-(methylsulfonyl) 1,2,3,4-tetrahydroquinoline-5-carboxamide, - 1-{5-chloro-2-[(4-chloro-2-fluorobenzyl)oxy]benzyl}-N [(dimethylamino)sulfonyl]-1,2,3,4-tetrahydroquinoline-5-carboxamide, WO 2013/037960 PCT/EP2012/068101 232 - 1 -{5-chloro-2-[(4-chloro-2-fluorobenzyl)oxy]benzyl}-N [(dimethylamino)sulfonyl]-1,2,3,4-tetrahydroquinoline-5-carboxamide, - N-({1 -(5-chloro-2-[(4-chloro-2-fluorobenzyl)oxy]benzyl})-1,2,3,4 tetrahydroquinolin-5-yl]amino}carbonyl) methanesulfonamide, 5 - 1-{5-chloro-2-[(4-chloro-2-fluorobenzyl)oxy]benzyl}-N-(methylsulfonyl)-2,3 dihydro-1 H-pyrrolo[2,3-b]pyridine-4-carboxamide, - 1-{5-chloro-2-[(2,4-difluorobenzyl)oxy]benzyl}-1,2,3,4-tetrahydro-1,7 naphthyridine-5-carboxylic acid, - 1-{2-[(4-chloro-2-fluorobenzyl)oxy]benzyl}-1,2,3,4-tetrahydro-1,7 10 naphthyridine-5-carboxylic acid, - 1-{2-[(2,4-difluorobenzyl)oxy]benzyl}-1,2,3,4-tetrahydro-1,7-naphthyridine-5 carboxylic acid, - 1-[5-chloro-2-(2-fluoro-2-methylpropoxy)benzyl]-1,2,3,4-tetrahydro-1,7 naphthyridine-5-carboxylic acid 15 - 1-{2-[(2,4-difluorobenzyl)oxy]-5-fluorobenzyl}-1,2,3,4-tetrahydro-1,7 naphthyridine-5-carboxylic acid - 1-(2-((2,4-difluorobenzyl)oxy)-5-methylbenzyl)-1,2,3,4-tetrahydro-1,7 naphthyridine-5-carboxylic acid - 1-{2-[(4-chloro-2-fluorobenzyl)oxy]-5-fluorobenzyl}-1,2,3,4-tetrahydro-1,7 20 naphthyridine-5-carboxylic acid - 1-{2-[(4-chloro-2-fluorobenzyl)oxy]-5-methylbenzyl}-1,2,3,4-tetrahydro-1,7 naphthyridine-5-carboxylic acid - 4-(2-cyclobutoxy-5-fluorobenzyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-8 carboxylic acid, 25 - 1-{5-chloro-2-[(4-chloro-2-fluorobenzyl)oxy]benzyl}-2,3-dihydro-1 H pyrrolo[2,3-c]pyridine-4-carboxylic acid, - 1-(5-chloro-2-cyclobutoxybenzyl)-2-oxoindoline-4-carboxylic acid - 1-(5-chloro-2-(2-fluoro-2-methylpropoxy)benzyl)-2-oxoindoline-4-carboxylic acid 30 and the salts, solvates and prodrugs thereof.
    [15] 15. A compound according to any of the claims 1 to 14 for use as a medicament. WO 2013/037960 PCT/EP2012/068101 233
    [16] 16. A compound according to any of claims 1 to 14 for use in the treatment and/or prophylaxis of diseases or disorders mediated by the EP1 receptor.
    [17] 17. A compound according to claim 16 where the disease or disorders comprises 5 inflammatory related pain including low back and neck pain, skeletal pain, post partum pain, toothache, sprains and straits, myositis, neuralgia, synovitis, arthritis, including rheumatoid arthritis, degenerative joint diseases, gout and ankylosing spondylitis, bursitis, burns including radiation and corrosive chemical injuries and sunburns; postoperative pain; neuropathic pain; visceral pain; tension headache; 10 cluster headaches; migraine; motility-related disorders including gastrointestinal disorders, urinary incontinence and other urinary tract diseases; dysmenorrhea; preterm labour; diabetic retinopathy; tumour angiogenesis; cancer; metastatic tumour growth; neurodegenerative diseases including senile dementia, Alzheimer's disease, Pick's disease, Huntington's chorea, Parkinson's disease, Creutzfeldt 15 Jakob disease, or amyotrophic lateral sclerosis; neuroprotection/stroke; glaucoma; osteoporosis; bone fractures; Paget's disease; hyperthermia including different types of fever as rheumatic fever; symptoms associated with influenza or other viral infections; gastrointestinal disorders related with chemotherapy or irritable bowel syndrome; gastrointestinal bleeding; coagulation disorders including anaemia, 20 hypoprothrombinemia, haemophilia or other bleeding problems; kidney diseases including nephritis, particularly mesangial proliferative glomerulonephritis and nephritic syndrome; thrombosis and occlusive vascular diseases.
    [18] 18. A compound according to claim 16 where the disease or disorders comprises 25 pain, inflammatory related pain including low back and neck pain, skeletal pain, post-partum pain, toothache, sprains and straits, myositis, neuralgia, synovitis, arthritis, including rheumatoid arthritis, degenerative joint diseases, gout and ankylosing spondylitis, bursitis, burns including radiation and corrosive chemical injuries and sunburns; postoperative pain; neuropathic pain; visceral pain; tension 30 headache; cluster headaches; migraine.
    [19] 19. Pharmaceutical composition comprising at least one compound according to any of claims 1-14 and at least one pharmaceutically acceptable carrier, additive, adjuvant or vehicle.
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    同族专利:
    公开号 | 公开日
    MX346143B|2017-03-09|
    TN2014000112A1|2015-07-01|
    HK1201269A1|2015-08-28|
    EP2766344A1|2014-08-20|
    BR112014006305A2|2017-04-11|
    ES2629481T3|2017-08-10|
    CO6970588A2|2014-06-13|
    US9518015B2|2016-12-13|
    AR092288A1|2015-04-15|
    JP6041880B2|2016-12-14|
    US20140323475A1|2014-10-30|
    CN104220422B|2017-11-07|
    MA35444B1|2014-09-01|
    EP2570125A1|2013-03-20|
    WO2013037960A1|2013-03-21|
    CN104220422A|2014-12-17|
    MX2014003169A|2014-04-25|
    IN2014MN00697A|2015-07-03|
    EP2766344B1|2017-05-03|
    IL231518D0|2014-04-30|
    JP2014530184A|2014-11-17|
    CA2848786A1|2013-03-21|
    SG11201400680RA|2014-06-27|
    KR20140061475A|2014-05-21|
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    法律状态:
    2016-02-18| MK1| Application lapsed section 142(2)(a) - no request for examination in relevant period|
    优先权:
    申请号 | 申请日 | 专利标题
    EP11382296A|EP2570125A1|2011-09-16|2011-09-16|Ep1 receptor ligands|
    EP11382296.9||2011-09-16||
    PCT/EP2012/068101|WO2013037960A1|2011-09-16|2012-09-14|Ep1 receptor ligands|
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