 heterocyclic compounds useful as dual atx / ca inhibitors
专利摘要:
the invention provides new compounds which are endowed with the general formula (i) in which r1 is selected from phenyl, pyridinyl or substituted thiophenyl, r2 is selected from amino sulfonylphenyl, aminosulfenylpyridinyl, substituted aminosulfonyl thiophenyl or substituted aminosulfonylthiazolyl, x is understood by nitrogen or carbon, y is comprised of a bonding group, z is comprised of a direct bond or a bonding group, m = 0.5, n = 0.5, with the proviso that m + n is comprised of 2-5, compositions that include the compounds and the use of the compounds in the treatment or prophylaxis of eye conditions. 公开号:BR112019019017A2 申请号:R112019019017 申请日:2018-03-13 公开日:2020-04-14 发明作者:Hunziker Daniel；Gomme Justin；Hert Jérôme；Rudolph Markus；Di Giorgio Patrick；Mattei Patrizio；Schmitz Petra 申请人:Hoffmann La Roche； IPC主号:
专利说明:
HETEROCYCLIC COMPOUNDS OF UTILITY AS DUAL ATX / CA INHIBITORS [001] This invention relates to organic compounds useful for therapy or prophylaxis in a mammal, and in particular to dual inhibitors of autotaxin (ATX) / carbonic anhydrase which are inhibitors of the production of lysophosphatidic acid (LPA) and thus modulators of levels of LPA and associated signaling, for the treatment or prophylaxis of inflammatory conditions, nervous system conditions, vascular and cardiovascular conditions, cancer, and eye conditions. [002] The present invention provides new compounds of formula (I) in which R 1 is selected from i) phenyl substituted by R 3 , R 4 and R 5 , ii) pyridinyl substituted by R 3 , R 4 and R 5 , and iii) thiophenyl substituted by R 3 , R 4 and R 5 ; X is selected from i) N, and ii) CH; Y is selected from i) -CH 2 -OC (O) -, ii) - (CH 2 ) q C (O) -, iii) - (CH = CH) r -C (O) -, and Petition 870190091123, of 9/13/2019, p. 8/164 2/132 iv) - (CH ^ CH) r -C (0) W is selected from i) - (CR 9 R 10 ) p -, ii) - (CR 9 R 10 ) p -C (0) -, iii) - (CR 9 R 10 ) p-0-, iv) - (CR 9 R 10 ) pS-, v) - (CR 9 R 10 ) pS (0) -, and (vi) - (CR 9 R 10 ) p -S (0) 2 -; R and selected from i) substituted phenyl, where the phenyl ring is replaced by R 6 , R 7 and R 8 , ii) pyridinyl substituted, in what O ring in pyridinyl is replaced by R 6 , R 7 and R 8 , iii) substituted thiophenyl, in what O ring in thiophenyl is replaced byiv) thiazolyl R 6 , R 7 and R 8 , and replaced, in what O ring in thiazolyl is replaced by R 6 , R 7 and R 8 ; R and selected from i) halo-Ci-6-alkoxy, ii) Cs-g-cycloalkyl, iii) C3-8 cycloalkyl-CI 6 -alkyl, iv) C 3-8 cycloalkyl-CI 6-alkoxy, v) C 3-8 cycloalkoxy, vi) C3-8-cycloalkoxy-CI 6 -alkyl, vii) tetrazolilmetil viii) triazolylmethyl ix) pyrazolylmethyl, x) C1-6-alkylthetrazolylmethyl, xi) C1-6-alkyltriazolylmethyl, xii) C1-6-alkylpyrazolylmethyl, Petition 870190091123, of 9/13/2019, p. 9/164 3/132 xiii) heterocycloalkyl-C1-6-alkoxy; R 4 is selected from i) halogen, il) hydroxy, iii) cyano, iv) C1-6-alkyl, v) CI - 6 alkoxy, vi) Ci-e-alkoxy-Ci-e-alkyl, vii) halo-Ci-6-alkoxy, vii) halo-Ci-6-alkyl, ix) hydroxy-Ci-6 alkyl, x) Cs-g-cycloalkyl, xi) Cs-g-cycloalkyl-C1-e-alkyl, xii) C3-8-cycloalkyl-C1-6-alkoxy, xiii) Cs-s-cycloalkoxy, xiv) Cs-s- cycloalkoxy-C1-e-alkyl, xv) C1-6-alkylcarbonylamino, xvi) Cs-s-cycloalkyl carbonylamino, R 5 is selected from i) H, ii) halogen, iii) hydroxy, iv) cyan, v) Ci-6-alkyl, vi) Ci-6-alkoxy, vii) Ci-6-alkoxy-CI 6 -alkyl, viii) halo-Ci-6-alkoxy, ix) halo-Ci-6-alkyl, x) hydroxy-C1-6-alkyl, xi) C3-8-cycloalkyl, Petition 870190091123, of 9/13/2019, p. 10/164 4/132 xii) C3- 8 -cycloalkyl-Ci- 6 -alkyl, xiii) C3- 8 -cycloalkyl-Ci- 6 -alkoxy, xiv) C 3 _ 8 -cycloalkoxy, xv) C3- 8 -cycloalkoxy-Ci- 6- alkyl, xvi) C1-6-alkylcarbonylamino, xvii) C3- 8 -cycloalkylcarbonylamino, R 6 is comprised of aminosulfonyl; R 7 and R 8 are independently selected from i) H, ii) halogen, iii) hydroxy, iv) cyan, v) Ci-6-alkyl, vi) Ci-6-alkoxy, vii) Ci-e-alkoxy-Ci-e-alkyl, viii) halo-Ci-6-alkoxy, ix) halo-Ci-6-alkyl, x) hydroxy-Ci-6-alkyl, xi) C 3 -C 8 -cicloalquila xii) C 3 -C 8 -cicloalquila-CI 6 -alkyl, xiii) C 3 -C 8 -cicloalquila CI-6 alkoxy, xii) 3- 8 -cicloalcoxi, and xv) C 3 -C 8 -cicloalcoxi-CI 6 -alkyl; R 9 and R 10 are selected independently from i) H, ii) C 1-6 alkyl, and iii) C 3-8 cycloalkyl; men are independently selected from Petition 870190091123, of 9/13/2019, p. 11/164 5/132 of zero, 1, 2, 3, 4 or 5, with the proviso that the sum of m and n be understood by 2 , 3, 4 or 5; p is selected The leave in zero, 1 or 2; q is selected The leave in zero or 2; r is selected The leave in zero and 1; or the pharmaceutically acceptable salts. [003] Autotaxin (ATX) is a secreted enzyme also called ectonucleotide pyrophosphatase / phosphodiesterase 2 or lysophospholipase D which is important for converting lysophosphatidyl choline (LPC) to the bioactive signaling molecule of lysophosphatidic acid (LPA). It has been demonstrated that plasma levels of LPA are perfectly related to ATX activity and for this reason ATX is believed to be an important source of extracellular LPA. Initial experiments with an ATX inhibitor prototype demonstrated that such a compound is capable of inhibiting the synthesis activity of LPA in mouse plasma. The work done in the 1970s and early 1980s demonstrated that LPA can elicit a wide range of cellular responses; including contraction of smooth muscle cells, platelet activation, cell proliferation, chemotaxis and others. LPA mediates its effects via signaling to several G protein-coupled receptors (GPCRs); the first limbs were originally called Edg receptors (endothelial cell differentiation gene) or ventricular zone 1 gene (vzg-1), but are now called LPA receptors. The prototypical group now consists of LPA1 / Edg-2 / VZG-1, LPA2 / Edg-4 and LPA3 / Edg-7. Recently, three additional LPA receptors have been described, LPA4 / p2y9 / GPR23, LPA5 / Petition 870190091123, of 9/13/2019, p. 12/164 6/132 GPR92 and LPA6 / p2Y5, which are more closely related to purinergic receptors selective for nucleotides than to prototypes of LPA receptors13. The ATX-LPA signaling axis is involved in a wide range of physiological and pathophysiological functions, including, for example, nervous system function, vascular development, cardiovascular physiology, reproduction, immune system function, chronic inflammation, metastasis and tumor progression. , organic fibrosis as well as obesity and / or other metabolic disorders, such as diabetes mellitus. For this reason, increased ATX activity and / or increased LPA levels, altered LPA receptor expression and altered responses to LPA may contribute to the onset, progression and / or outcome of several different pathophysiological conditions related to ATX / LPA axis. [004] Carbonic anhydrases (AC) are a family of zinc-dependent enzymes, which catalyze the balance between carbon dioxide and hydrogen and hydrogen and a proton. The CA reaction is involved in many physiological and physiological processes. The inhibition of carbonic anhydrase is useful for the treatment of eye conditions, reduced blood flow conditions, cancer, edema and inflammatory conditions, including bacterial infection. [005] Carbonic anhydrases (AC) are a family of zinc-dependent enzymes, which catalyze the balance between carbon dioxide and hydrogen and hydrogen and a proton. The CA reaction is involved in many physiological and pathological processes. Inhibition of Petition 870190091123, of 9/13/2019, p. 13/164 7/132 carbonic anhydrase is useful for the treatment of eye conditions, reduced blood flow conditions, cancer, edema and inflammatory conditions, including bacterial infections. [006] Double-acting ATX / CA inhibitors are expected to reduce intraocular pressure by facilitating two independent pathways, such as inhibiting the production of aqueous humor (HA) by inhibiting AC in the ciliary body and facilitating HA flow by inhibiting of ATX within the AH drainage system. Under conditions of vascular leakage in the eye, such as diabetic retinopathy, age-related macular disease or retinal vein occlusion, CA levels have been shown to increase in the eye and facilitate pH increase. This is expected to activate many hydrolytic enzymes that can contribute to the progression of the disease, including ATX, suggesting further inhibition of ATX, by shifting to the optimum pH. [007] and according to the invention, the compounds of formula (I) or their pharmaceutically acceptable salts and esters can be used for the treatment or prophylaxis of diseases, disorders or conditions that are associated with autotaxin activity and / or biological activity lysophosphatidic acid (LPA). [008] The compounds of formula (I) or their pharmaceutically acceptable salts and esters in the present case inhibit autotaxin activity and carbonic anhydrase activity, therefore, inhibit LPA production and modulate LPA levels and associated signaling. The dual ATX / CA-II inhibitors described in the present case Petition 870190091123, of 9/13/2019, p. 14/164 8/132 are useful as agents for the treatment or prevention of illnesses or conditions in which ATX activity and / or LPA signaling participate, are involved in the etiology or pathology of the illness, or are associated with at least one symptom of the illness . The ATX-LPA axis was found to be involved, for example, in angiogenesis, chronic inflammation, autoimmune diseases, fibrotic diseases, cancer and tumor metastasis and progression, eye conditions, metabolic conditions such as obesity and / or diabetes mellitus, conditions such such as cholestatic or other forms of chronic itching, as well as acute and chronic rejection of organ transplants. [009] The objects of the present invention are the compounds of formula (I) and their salts and esters mentioned above in the present case and their use as therapeutically active substances, a process for the manufacture of said compounds, intermediates, pharmaceutical compositions, medicaments containing said compounds, their pharmaceutically acceptable salts or esters, the use of said compounds, salts or esters for the treatment or prophylaxis of disorders or conditions that are associated with ATX activity and / or the biological activity of lysophosphatidic acid (LPA), with particularity in the treatment or prophylaxis of inflammatory conditions, nervous system conditions, respiratory system conditions, vascular and cardiovascular diseases, fibrotic diseases, cancer, eye conditions, metabolic, cholestatic conditions and other forms of chronic and acute itching and chronic transplant rejection d and organs, and the use of Petition 870190091123, of 9/13/2019, p. 15/164 9/132 said compounds, salts or esters for the production of drugs for the treatment or prophylaxis of inflammatory conditions, nervous system conditions, respiratory system conditions, vascular and cardiovascular conditions, fibrotic diseases, cancer, eye conditions, metabolic conditions, cholestatic and other forms of chronic itching and acute rejection of organ transplantation. More particularly, the compounds of formula (I) and their salts and esters mentioned above in this context and their use as therapeutically active substances, a process for the manufacture of said compounds, intermediates, pharmaceutical compositions, drugs containing said compounds, their pharmaceutically acceptable salts or esters, the use of said compounds, salts or esters for the treatment or prophylaxis of ocular conditions, more particularly with glaucoma. [0010] The term Ci-Ce-alkoxy means a group of the formula -OR ', where R' is comprised of a Ci-Ce-alkyl group. Examples of the C 1 -C-alkoxy group include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy and tert-butoxy. [0011] The term Ci-C6-alkoxy-CI 6 - alkyl means a Ci-Ce-alkyl group in which at least one of the hydrogen atoms of the Ci-Ce-alkyl group is substituted by a group -C EC- alkoxy. Particular examples are comprised of methoxymethyl, methoxyethyl, ethoxymethyl, ethoxyethyl, iso-propoxymethyl and iso-propoxyethyl. [0012] The term Ci-Ce-alkyl means a Petition 870190091123, of 9/13/2019, p. 16/164 10/132 monovalent linear or branched saturated hydrocarbon group, from 1 to 6 carbon atoms. Examples of Ci-Ce alkyls include methyl, ethyl, propyl, isopropyl, n-butyl, iso-butyl, sec-butyl, tert-butyl and pentyl. Alkyl groups in particular include methyl, isopropyl and tert-butyl. [0013] The term Ci-Ce-alkylcarbonyl means a group of the formula -C (O) -R ', where R' is comprised of a Ci-Ce-alkyl group. Examples of the C 1 -C-alkylcarbonyl group include groups where R 'is comprised of methoxy, ethoxy, n-propoxy, isopropoxy, nbutoxy, isobutoxy and tert-butoxy. [0014] The term Ci-Ce-alkylcarbonyl amino means an amino group in which the nitrogen atom is replaced by an H atom and a Ci-Cealkylcarbonyl group. A particular example is comprised of an amino group in which the nitrogen atom is replaced by H and tert-butylcarbonyl. [0015] The term Ci-Ce-alkylpyrazolyl means a pyrazolyl group in which one of the nitrogen atoms is replaced by a Ci-Ce-alkyl group. A particular example is comprised of a pyrazolyl group in which one of the nitrogen atoms is replaced with methyl. [0016] The term Ci-Ce-alkylpyrazolyl-Ci-Ce alkyl means a Ci-Ce-alkyl group in which one of the H atoms is replaced by a Ci-C 6 alkylpyrazolyl group. A particular example is comprised of a methyl group or an ethyl group in which one of the nitrogen atoms is replaced with methyl pyrazolyl. [0017] The term Ci-Ce-alkyliltetrazolyl means a tetrazolyl group in which one of the atoms Petition 870190091123, of 9/13/2019, p. 17/164 11/132 nitrogen is replaced by a Ci-Ce-alkyl group. A particular example is comprised of a tetrazolyl group in which one of the nitrogen atoms is replaced with methyl. [0018] The Ci-C term6-alkyltetrazolyl-C1-C6alkyl means a Ci-Ce-alkyl group in which one of the H atoms is replaced by a Ci-Ce group alkylthetrazolyl. A particular example is comprised of a methyl group or an ethyl group in which one of the hydrogen atoms is replaced with methyl tetrazolyl. [0019] The term Ci-Ce-alkyltriazolyl means a triazolyl group in which one of the nitrogen atoms is replaced by a Ci-Ce-alkyl group. A particular example is comprised of a triazolyl group in which one of the nitrogen atoms is replaced with methyl. [0020] The term Ci-Ce-alkyltriazolyl-Ci-Cealkyl means a Ci-Ce-alkyl group in which one of the H atoms is replaced by a Ci-Cealkyltriazolyl group. A particular example is comprised of a methyl group or an ethyl group in which one of the hydrogen atoms is replaced with methyltriazolyl. [0021] 0 term amino means a group - nh 2 . [0022] 0 term cyan means a group - C ^ N. [0023] 0 term C 3 -C 8 -cycloalkoxy ' '' means a group of the formula -O-R ', where R' is comprised of a Cs-Cg-cycloalkyl. A particular example is comprised of a group in which R 'is comprised of cyclopropyl. [0024] The term C3-C 8 -cycloalkoxy-C 1 -C 6 alkyl means a C 1 -C-alkyl group in which at least Petition 870190091123, of 9/13/2019, p. 18/164 12/132 one of the hydrogen atoms of the C 1 -C-alkyl group is replaced by a C 3 -C 8 -cycloalkoxy group. A particular example is comprised of a methyl group or an ethyl group in which the Cs-Cg-cycloalkoxy group is comprised of cyclopropoxy. [0025] The term Cs-Cg-cycloalkyl means a saturated, monovalent monocyclic or bicyclic hydrocarbon group of 3 to 8 ring carbon atoms. Bicyclic means a ring system that consists of two saturated carbocycles that have two carbon atoms in common. Examples for monocyclic cycloalkyl are comprised of cyclopropyl, cyclobutanil, cyclopentyl, cyclohexyl or heptyl cycle. Examples for bicyclic C3Cg-cycloalkyl are comprised of bicycles [2.2.1] heptanil or bicycles [2.2.2] octanyl. A particular C 8 _ 8 cycloalkyl group is comprised of cyclopropyl. [0026] The term Cs-Cg-cycloalkyl-Ci-Cealcoxy means a Ci-Ce-alkoxy group in which at least one of the hydrogen atoms in the Ci-Ce-alkoxy group is replaced by a Cs-Cg-cycloalkyl group. Particular examples are methoxy or ethoxy groups in which at least one of the hydrogen atoms is replaced by a cyclopropyl. [0027] The term C3-C8 -cicloalquila Ci-C6-alkyl means a Ci-Ce-alkyl group in which at least one of the hydrogen atoms of the Ci-Ce-alkyl group is substituted with a C3-C8 group -cycloalkyl. Particular examples are comprised of methyl or ethyl groups in which at least one of the hydrogen atoms is replaced by a cyclopropyl. Petition 870190091123, of 9/13/2019, p. 19/164 13/132 [0028] The term Cs-Cg-cycloalkyl carbonyl means a group of the formula -C (O) -R ', where R' is comprised of a Cs-Cg-cycloalkyl group. Examples of Cs-Cg-cycloalkyl carbonyl are comprised of groups in which R 'is comprised of cyclopropyl. [0029] The term Cs-Cg-cycloalkyl carbonylamino means an amino group in which the nitrogen atom is replaced by an H atom and a Cs-Cg-cycloalkyl carbonyl group. A particular example is comprised of an amino group in which the nitrogen atom is replaced by an H and a cyclopropyl. [0030] The term halo-Ci-Ce-alkoxy means a Ci-Ce-alkoxy group in which at least one of the hydrogen atoms of the Ci-Ce-alkoxy group has been replaced by itself or by different halogen atoms. Particular examples are comprised of difluoromethoxy, trifluoromethoxy, difluoroethoxy and trifluoroethoxy. An example of greater particularity is comprised of trifluoromethoxy. [0031] The terms halogen and halo are used interchangeably in the present case and mean fluorine, chlorine, bromine or iodine. Particular halogen is comprised of chlorine. [0032] The term halo-Ci-Ce-alkyl means a Ci-Ce-alkyl group in which at least one of the hydrogen atoms in the Ci-Ce-alkyl group has been replaced by itself or by different halogen atoms. Particular examples are comprised of difluoromethyl, trifluoromethyl, difluoroethyl and trifluoroethyl. An example of greater particularity is understood by trifluoromethyl. Petition 870190091123, of 9/13/2019, p. 20/164 14/132 [0033] The term heterocycloalkyl, alone or in combination, means a saturated or partially unsaturated, monovalent, mono- or bicyclic ring system of 4 to 9 ring atoms, comprising 1, 2, or 3 ring heteroatoms selected from N, O and S, the other ring atoms being comprised of carbon. Bicyclic means that it consists of two cycles that have two ring atoms in common, that is, the bridge that separates the two rings is comprised either by a single bond or a chain of one or two ring atoms. Examples for saturated monocyclic hetero cycloalkyl are comprised of 4,5-dihydro-oxazolyl, oxetanil, azetidinyl, pyrrolidinyl, 2-oxo-pyrrolidin-3-yl, tetrahydrofuranyl, tetrahydro-thienyl, pyrazolidinyl, imidazolidinyl, oxazolidinyl, isoxazolidinyl, thiazole , piperidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, piperazinyl, morpholinyl, or oxazepanil. Examples for saturated bicyclic heterocycloalkyl are comprised of 8- aza-bicycles [3.2.1] octyl, quinuclidinyl, 8-oxa-3-azabicycles [3.2.1] octyl, 9-aza-bicycles [3.3.1] nonyl, 3-oxa- 9- aza-biciclo [3.3.1] nonil, or 3-tia-9-aza-biciclo [3.3.1] nonil. Examples for partially unsaturated heterocycloalkyl are comprised of dihydrofuryl, imidazolinyl, dihydro-oxazolyl, tetrahydro-pyridinyl, or dihydropyranyl. A particular example is comprised of tetrahydropyranyl. [0034] The term heterocycloalkyl-Ci-Cealcoxy means a Ci-Ce-alkoxy group in which at least one of the hydrogen atoms in the alkoxy group is replaced by a hetero cycloalkyl group. Particular examples Petition 870190091123, of 9/13/2019, p. 21/164 15/132 are comprised of methoxy hydropyranyl tetra. [0035] The term hydroxy means an OH group. [0036] The term hydroxy-Ci-Ce-alkoxy means a Ci-Ce-alkoxy group in which one of the hydrogen atoms of the Ci-Ce-alkoxy is replaced by a hydroxy group. Particular examples hydroxyethoxy and hydroxypropoxy. [0037] The term means a Ci-Ce-alkyl hydrogen group of the Ci-Ce-hydroxy group. Particular examples hydroxymethyl and hydroxyethyl. are comprised of hydroxy -Ci-Ce - alkyl in which one of the atoms is replaced by a group are comprised of [0038] The term phenyl-Ci-Ce-alkyl means a Ci-Ce-alkyl group in which one of the atoms hydrogen of the Ci-Ce-alkyl group is replaced by a phenyl group. A particular example is comprised of phenyl methyl. [0039] The term pyrazolyl-Ci-Ce-alkyl means a Ci-Ce-alkyl group in which one of the H atoms is replaced by a pyrazolyl group. A particular example is comprised of a methyl group or an ethyl group in which one of the hydrogen atoms is replaced by pyrazolyl. [0040] The term tetrazolyl-Ci-Ce-alkyl means a Ci-Ce-alkyl group in which one of the H atoms is replaced by a tetrazolyl group. A particular example is comprised of a methyl group or an ethyl group in which one of the hydrogen atoms is replaced by tetrazolyl. [0041] The term triazolyl-Ci-Ce-alkyl means a Ci-Ce-alkyl group in which one of the atoms of H Petition 870190091123, of 9/13/2019, p. 22/164 16/132 is replaced by a triazolyl group. A particular example is comprised of a methyl group or an ethyl group in which one of the hydrogen atoms is replaced by triazolyl. [0042] The term pharmaceutically acceptable salts refers to those salts that retain the efficiency and biological properties of free bases or free acids, which are not biologically or otherwise undesirable. Salts are formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and the like, in particular hydrochloric acid, and organic acids such as acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methane sulfonic acid, ethane sulfonic acid, p-toluene sulfonic acid, salicylic acid, Nacetylcysteine and others similar . In addition, these salts can be prepared by adding an inorganic base or an organic base to the free acid. Salts derived from an inorganic base include, but are not limited to, the salts of sodium, potassium, lithium, ammonium, calcium, magnesium and the like. Salts derived from organic bases include, but are not limited to, the same primary, secondary, auxiliary amine salts, substituted by naturally occurring substituted amines, cyclic amines and basic ion exchange resins, such as isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, lysine, arginine, N-ethylpiperidine, piperidine, resin Petition 870190091123, of 9/13/2019, p. 23/164 17/132 polyimine and the like. The particular pharmaceutically acceptable salts of compounds of formula (I) are the hydrochloride salts, methane sulfonic acid salts and the citric acid salts. [0043] Pharmaceutically acceptable esters means that the compounds of the general formula (I) can be derived in functional groups to provide derivatives that are capable of conversion back to compounds of in vivo origin. Examples of such compounds include physiologically acceptable and metabolically labile ester derivatives, such as methoxymethyl esters, methyl thiomethyl esters and pivaloyloxymethyl esters. In addition, any physiologically acceptable equivalents of the compounds of the general formula (I), similar to the metabolically labile esters, which are capable of producing the parent compounds of the general formula (I) in vivo, are within the scope of the present invention. [0044] The term protecting group (PG) means a group that selectively blocks a reactive site in a multifunctional compound in such a way that a chemical reaction can be carried out selectively at another reactive site unprotected in the meaning conventionally associated with it in synthetic chemistry . Protection groups can be removed at the appropriate point. Exemplary protection groups are comprised of amino protection groups, carboxy protection groups or hydroxy protection groups. Particular protection groups are comprised of the tert-butoxycarbonyl (Boc), benzyloxycarbonyl (Cbz), fluorenyl methoxycarbonyl (Fmoc) and benzyl (Bn) groups. Other private protection groups are Petition 870190091123, of 9/13/2019, p. 24/164 18/132 comprised of the tert-butoxycarbonyl (Boc) and fluorenyl methoxycarbonyl (Fmoc) groups. A protection group with a greater partixularity is comprised of the tert-butoxycarbonyl (Boc) group. [0045] The abbreviation μΜ means microMolar and is equivalent to the symbol μΜ.[0046] The abbreviationand is equivalent to the pL symbol.[0047] The abbreviationand is equivalent to the pg symbol.[0048] The compoundscontain several asymmetric centers pL stands for microliterpg means microgramof formula (I) can and can be present at optically pure enantiomers, mixtures of enantiomers such as, for example, racemates, optically pure diastereoisomers, mixtures of diastereoisomers, isomeric diastere racemates or mixtures of isomeric diastere racemates. [0049] According to the CahnIngold-Prelog Convention, the asymmetric carbon atom can be of the R or S configuration. [0050] Also an embodiment of the present invention is comprised of the compounds according to formula (I) as described above in the present case and their pharmaceutically acceptable salts or esters, in particular compounds according to formula (I) as described in the present case and their pharmaceutically acceptable salts, more particularly the compounds according to formula (I) as described in the present case. [0051] Another embodiment of this Petition 870190091123, of 9/13/2019, p. 25/164 The invention comprises the compounds according to formula (I) as described in the present case, in which R 1 is selected from i) phenyl substituted by R 3 , R 4 and R 5 , and ii) pyridinyl substituted by R 3 , R 4 and R 5 ; X is selected from iii) N, and iv) CH; Y is selected from v) -CH2-OC (0) -, and vi) - (CH 2 ) q C (0) W is selected from vii) - (CR 9 R 10 ) p -, viii) - (CR 9 R 10 ) pC (0) -, ix) - (CR 9 R 10 ) p-0-, x) - (CR 9 R 10 ) P -S-, xi) - (CR 9 R 10 ) pS (0) -, and xii) - (CR 9 R 10 ) p -S (0) 2 -; O R is selected from xiii) substituted phenyl, where the phenyl ring is replaced by R 6 , R 7 and R 8 , xiv) substituted pyridinyl, where the pyridinyl ring is replaced by R 6 , R 7 and R 8 , xv) substituted thiophenyl, in which the thiophenyl ring is replaced by R 6 , R 7 and R 8 , and xvi) substituted thiazolyl, in which the thiazolyl ring is replaced by R 6 , R 7 and R 8 ; O R is selected from xvii) halo-C1-6-alkoxy, Petition 870190091123, of 9/13/2019, p. 26/164 20/132 xviii) cyano, xix) C 3-8 cycloalkyl-CI 6-alkoxy, xx) C 3 -C 8 -cicloalcoxi xxi) -C 6 -alkyl tetrazolilmetil, and xxii) tetrahydro-yl-Ci-e alkoxy; R 4 is selected from xxiii) halogen, xxiv) cyano, xxv) halo-C1-6-alkoxy, xxvi) halo-C1-6-alkyl, xxvii) Cs-s-cycloalkyl, and xxviii) C1-6 carbonylamino alkyl; R 5 is comprised of Η; R 6 is comprised of amino sulfonyl; R 7 and R 8 are independently selected from xxix) H, and xxx) halogen; R 9 and R 10 are both comprised by H; m is selected from zero, 1 and 2 and is not selected from 1, 2 and 3, with the proviso that the sum of m and n is understood by 2, 3, 4 or 5; p is selected from zero, 1 and 2; q is selected from zero and 2; or the pharmaceutically acceptable salts. [0051] A particular embodiment of the present invention is comprised of the compounds according to formula (I) as described in the present case, where R 1 is selected from xxxi) phenyl substituted by R 3 , R 4 and R 5 , and Petition 870190091123, of 9/13/2019, p. 27/164 21/132 xxxii) pyridinyl substituted by R 3 , R 4 and R 5 . [0052] Another particular embodiment of the present invention is comprised of the compounds according to formula (I) as described in the present case, wherein R 1 is comprised of phenyl substituted by R 3 , R 4 and R 5 . [0053] A particular embodiment of the present invention is comprised of the compounds according to formula (I) as described in the present case, where Y is selected from xxxiii) -CH2-OC (O) -, and xxxiv) - (CH 2 ) q C (O) -. [0054] A particular embodiment of the present invention is comprised of the compounds according to formula (I) as described in the present case, where Y is comprised of - (CH 2 ) q C (O). [0055] A particular embodiment of the present invention is comprised of the compounds according to formula (I) as described in the present case, where W is selected from xxxv) - (CR 9 R 10 ) p- , xxxvi) - (CR 9 R 10 ) pS-, and xxxvii) - (CR 9 R 10 ) pS (O) 2 -. [0056] Another particular embodiment of the present invention is comprised of the compounds according to formula (I) as described in the present case, where R is selected from xxxviii) substituted phenyl, in which the ring phenyl is replaced by R 6 , R 7 and R 8 , and xxxix) substituted pyridinyl, where the ring of Petition 870190091123, of 9/13/2019, p. 28/164 22/132 pyridinyl is replaced by R 6 , R 7 and R 8 . [0057] A particular embodiment of the present invention is comprised of the compounds according to formula (I) as described in the present case, wherein R is selected from xl) halo-C1-6-alkoxy, xli) cyano, xlii) Cs-g-cycloalkyl-C1-e-alkoxy, xliii) Cs-g-cycloalkoxy, xliv) C1-6-alkylthetrazolyl methyl, and xlv) tetrahydropyranyl-C1-e-alkoxy. [0058] Another particular embodiment of the present invention is comprised of the compounds according to (I) as described in the present case, where R is selected from xlvi) C1-6-alkyl tetrazolylmethyl, and xliii ) hydropyranyl-C1-e-alkoxy tetra. [0059] A particular embodiment of the present invention is comprised of the compounds according to formula (I) as described in the present case, wherein R 4 is selected from xlviii) halogen, xlix) cyan, 1) halo-Ci-6-alkoxy, ii) halo-Ci-6-alkyl, lii) C 3 -C 8 -cicloalquila and LIII) Ci-6 alkyl-carbonylamino. [0060] A particular embodiment of the present invention is comprised of the compounds according to formula (I) as described in Petition 870190091123, of 9/13/2019, p. 29/164 23/132 present case, in which R 4 is selected from liv) halo-C 1 -6-alkyl, and iv) Cs-g-cycloalkyl. [0061] A particular embodiment of the present invention is comprised of the compounds according to formula (I) as described in the present case, where R 5 is comprised by H. [0062] A particular embodiment of the present invention is comprised of the compounds according to formula (I) as described in the present case, wherein R 7 and R 8 are independently selected from ivi) H, and ivii) halogen. [0063] A particular embodiment of the present invention is comprised of the compounds according to formula (I) as described in the present case, wherein R 7 is comprised of halogen. [0064] A particular embodiment of the present invention is comprised of the compounds according to formula (I) as described in the present case, where R 8 is selected from iviii) H, and lix) halogen. [0065] A more specific embodiment of the present invention is comprised of the compounds according to formula (I) as described in the present case, where R 9 and R 10 are both comprised by H. [0066] A particular embodiment of Petition 870190091123, of 9/13/2019, p. 30/164 The present invention is comprised of the compounds according to formula I (a) as described in the present case, where m is selected from zero, 1 and 2 and n is selected from 1, 2 and 3, with the proviso that the sum of men is comprised of 2, 3, 4 or 5. [0067] A particular embodiment according to the present invention is comprised of the compounds according to formula I (a) as described in the present case, where p is selected from zero and 1. [0068] A particular embodiment of the present invention is comprised of the compounds according to formula I (a) as described in the present case, where p is comprised by zero. [0069] A particular embodiment of the present invention is comprised of the compounds according to formula I (a) as described in the present case, where q is comprised of 2. [0070] A particular embodiment of the present invention is comprised of the compounds according to formula I (a) as described in the present case, wherein R 1 is selected from i) phenyl substituted by R 3 , R 4 and R 5 , and ii) pyridinyl substituted by R 3 , R 4 and R 5 ; X is selected from iii) N, and iv) CH; Y is selected from v) -CH 2 -OC (O) -, and Petition 870190091123, of 9/13/2019, p. 31/164 25/132 vi) - (CH 2 ) q C (Ο) W is selected from vii) - (CR 9 R 10 ) p -, viii) - (CR 9 R 10 ) pC (O) ix) - (CR 9 R 10 ) pO-, x) - (CR 9 R 10 ) P -S-, xi) - (CR 9 R 10 ) pS (O) and xii) - (CR 9 R 10 ) p -S (O) 2 -; O R is selected from xiii) substituted phenyl, where the phenyl ring is replaced by R 6 , R 7 and R 8 , xiv) substituted pyridinyl, where the pyridinyl ring is replaced by R 6 , R 7 and R 8 , xv) substituted thiophenyl, in which the thiophenyl ring is replaced by R 6 , R 7 and R 8 , and xvi) substituted thiazolyl, in which the thiazolyl ring is replaced by R 6 , R 7 and R 8 ; R is selected from xvii) halo-Ci-6-alkoxy, xviii) cyano, xix) C 3-8 cycloalkyl-CI 6-alkoxy, xx) g-Cs-cycloalkoxy, xxi) -C 6 -alkyl tetrazolylmethyl, and xxii) tetrahydropyranyl-C1-e-alkoxy; R 4 is selected from xxiii) halogen, xxiv) cyano, xxv) halo-C1-6-alkoxy, xxvi) halo-C1-6-alkyl, xxvii) Cs-s-cycloalkyl, and Petition 870190091123, of 9/13/2019, p. 32/164 26/132 xxviii) C1-6 - alkylcarbonamino; R 5 is comprised of Η; R 6 is comprised of amino sulfonyl; R 7 and R 8 are independently selected from xxix) H, and xxx) halogen; R 9 and R 10 are both comprised by H; m is selected from zero, 1 and 2 and n is selected from 1, 2 and 3, with the proviso that the sum of m and n is understood by 2, 3, 4 or 5; p is selected from zero, 1 and 2; q is selected from zero and 2; or the pharmaceutically acceptable salts. [0071] Particular examples of compounds of formula (I) as described in the present case are selected from - (((5-methyl -2H -tetrazol -2 -ii) methyl) -4 (trifluoromethyl) benzyl 4 - (2-fluoro -4-sulfamoyl phenyl) piperazine -1-carboxylate; [2-cyclopropyl -6 - (oxan -4-ylmethoxy) pyridin -4 -ii] methyl 4 - [(4-sulfamoyl phenyl) methyl] piperidine -1-carboxylate; [5-cyano -3 - (2,2-dimethyl propanoyl amino) pyridin -2 -ii] methyl 4 - [(4-sulfamoyl phenyl) methyl] piperidine -1-carboxylate; [5-chloro -3 - [(5-methyltetrazol -2 -ii) methyl] pyridin -2 -ii] methyl 4 - (2-fluoro -4-sulfamoyl phenyl) sulfonylpiperidine -1-carboxylate; [2 - [(5-methyltetrazol -2 -ii) methyl] -4 Petition 870190091123, of 9/13/2019, p. 33/164 27/132 (trifluoromethyl) phenyl] methyl 4 - (2-fluoro -4-sulfamoyl phenyl) sulfonylpiperidine -1-carboxylate; -fluoro -4 - [[4 - [3 - [2 - [(5-methyltetrazol -2-yl) methyl] -4 - (trifluoromethyl) phenyl] propanoyl] piperazin -1 -yl] methyl] benzene sulfonylamide; -fluoro -4 - [[4 - [3 - [2 - [(5-methylthetrazol -2-yl) methyl] -4 - (trifluoromethyl) phenyl] propanoyl] piperazin -1 -yl] methyl] benzene sulfonylamide; - [[4 - [2-cyclopropyl-6 - (oxan -4-ylmethoxy) pyridine -4-carbonyl] piperazin -1 -yl] methyl] -3 fluorobenzene sulfonylamide; -fluoro -4 - [4 - [3 - [2 - [(5-methyltetrazol -2 yl) methyl] -4 - (trifluoromethyl) phenyl] propanoyl] piperazine -1 -carbonyl] benzene sulfonylamide; -fluoro -4 - [4 - [3 - [2 - [(5-methyltetrazol -2 yl) methyl] -4 - (trifluoromethyl) phenyl] propanoyl] piperazine -1 -carbonyl] benzene sulfonylamide; 3,5 -difluoro -4 - [4 - [3 - [2 - [(5-methylthetrazol -2-yl) methyl] -4 - (trifluoromethyl) phenyl] propanoyl] piperazine -1-carbonyl] benzene sulfonylamide; -fluoro -4 - [4 - [3 - [2 - [(5-methyltetrazol -2 yl) methyl] -4 - (trifluoromethyl) phenyl] propanoyl] piperazine -1 -carbonyl] benzene sulfonylamide; - (4 - (3 - (2 - ((5-methyl -2H -tetrazol -2 -yl) methyl) -4 - (trifluoromethyl) phenyl) propanoyl) piperazine -1-carbonyl) benzene sulfonylamide; - [[1 - [2-cyclopropyl-6 - (oxan -4-ylmethoxy) pyridine -4-carbonyl] piperidin -4 -yl] methyl] -4 fluorobenzene sulfonylamide; -fluoro -4 - [1 - [3 - [2 - [(5 -methyltetrazole -2 Petition 870190091123, of 9/13/2019, p. 34/164 28/132 yl) methyl] -4 - (trifluoromethyl) phenyl] propanoyl] piperidin -4-yl] sulfanylbenzene sulfonylamide; -fluoro -4 - (4 - (3 - (2 - ((5-methyl -2H tetrazol -2-yl) methyl) -4 - (trifluoromethyl) phenyl) propanoyl) piperazin -1-yl) benzene sulfonylamide; - [[1 - [2-cyclopropyl-6 - (oxan -4-ylmethoxy) pyridine -4-carbonyl] piperidin -4 -yl] methyl] benzene sulfonylamide; - [[1 - [3 - [2 - [(5-methyltetrazol -2-yl) methyl] -4 - (trifluoromethyl) phenyl] propanoyl] piperidin -4 -yl] methyl] benzene sulfonylamide; - [[1 - [3 - [2 - [(5-methyltetrazol -2-yl) methyl] -4 - (trifluoromethyl) phenyl] propanoyl] pyrrolidin -2-yl] methoxy] benzene sulfonylamide; - [[1 - [3 - [2 - [(5-methyl-tetrazol-2-yl) methyl] -4 - (trifluoromethyl) phenyl] propanoyl] pyrrolidin -3-yl] methoxy] benzene sulfonylamide; - (1 - (3 - (2 - ((5-methyl -2H -tetrazol -2 -yl) methyl) -4 - (trifluoromethyl) phenyl) propanoyl) piperidin -4 -yl) benzene sulfonylamide; - (4 - (3 - (2 - ((5-methyl -2H -tetrazol -2 -yl) methyl) -4 - (trifluoromethyl) phenyl) propanoyl) piperazin -1 -yl) benzene sulfonylamide; -fluoro -3 - [[1 - [3 - [2 - [(5-methylthetrazol -2 -yl) methyl] -4 - (trifluoromethyl) phenyl] propanoyl] piperidin -4 -yl] methyl] benzene sulfonylamide; 2,3-difluoro -4 - [1 - [3 - [2 - [(5-methylthetrazol -2-yl) methyl] -4 - (trifluoromethyl) phenyl] propanoyl] piperidin -4 -yl] sulfanyl benzene sulfonylamide; 2,3 -difluoro -4 - [1 - [3 - [2 - [(5-methyltetrazole Petition 870190091123, of 9/13/2019, p. 35/164 29/132 -2 -11) methyl] -4 - (trifluoromethyl) phenyl] propanoyl] piperidin -4 —yl] sulfinyl benzene sulfonylamide; 2,3 -difluoro -4 - [1 - [3 - [2 - [(5-methylthetrazol -2 -yl) methyl] -4 - (trifluoromethyl) phenyl] propanoyl] piperidin -4 -yl] sulfonylbenzene sulfonylamide; 2,3 -difluoro -4 - [2 - [1 - [3 - [2 - [(5 methyltetrazol -2-yl) methyl] -4 - (trifluoromethyl) phenyl] propanoyl] piperidin -4 -yl] ethylsulfonyl] benzene sulfonylamide; - [1 - [3 - [2 - [(5-methylthetrazol -2-yl) methyl] -4 - (trifluoromethyl) phenyl] propanoyl] piperidin -4-yl] sulfanyl -1,3-thiazole -5-sulfonamide; - [1 - [3 - [2 - [(5-methylthetrazol -2-yl) methyl] -4 - (trifluoromethyl) phenyl] propanoyl] piperidin -4-yl] sulfonyl -1,3-thiazole -5-sulfonamide; - [2 - [1 - [3 - [2 - [(5-methyltetrazol -2-yl) methyl] -4 - (trifluoromethyl) phenyl] propanoyl] piperidin -4 -yl] ethylsulfinyl] -1,3-thiazole - 5 -sulfonamide; -fluoro -4 - [[1 - [3 - [2 - [(5-methylthetrazol -2 -yl) methyl] -4 - (trifluoromethyl) phenyl] propanoyl] piperidin -4 -yl] methylsulfanyl] benzene sulfonylamide; -fluoro -4 - [[1 - [3 - [2 - [(5-methylthetrazol -2 -yl) methyl] -4 - (trifluoromethyl) phenyl] propanoyl] piperidin -4 -yl] methylsulfinyl] benzene sulfonylamide; -fluoro -4 - [[1 - [3 - [2 - [(5-methylthetrazol -2 -yl) methyl] -4 - (trifluoromethyl) phenyl] propanoyl] piperidin -4 -yl] methylsulfonyl] benzene sulfonylamide; -fluoro -4 - [1 - [3 - [2 - [(5-methyltetrazol -2 yl) methyl] -4 - (trifluoromethyl) phenyl] propanoyl] azetidin -3 -yl] sulfanyl benzene sulfonylamide; Petition 870190091123, of 9/13/2019, p. 36/164 30/132 -fluoro -4 - [1 - [3 - [2 - [(5-methylthetrazol -2 11) methyl] -4 - (trifluoromethyl) phenyl] propanoyl] azetidin -3 -yl] sulfinyl benzene sulfonylamide; -fluoro -4 - [1 - [3 - [2 - [(5-methylthetrazol -2 yl) methyl] -4 - (trifluoromethyl) phenyl] propanoyl] azetidin -3 -yl] sulfonylbenzene sulfonylamide; -fluoro -4 - [1 - [3 - [2 - [(5-methyltetrazol -2 yl) methyl] -4 - (trifluoromethyl) phenyl] propanoyl] piperidin -4 -yl] sulfinyl benzene sulfonylamide; -fluoro -4 - [1 - [3 - [2 - [(5-methyltetrazol -2 yl) methyl] -4 - (trifluoromethyl) phenyl] propanoyl] piperidin -4 -yl] sulfonylbenzene sulfonylamide; -fluoro -4 - [2 - [1 - [3 - [2 - [(5-methyltetrazol -2-yl) methyl] -4 - (trifluoromethyl) phenyl] propanoyl] piperidin -4 -yl] ethylsulfanyl] benzene sulfonylamide; -fluoro -4 - [2 - [1 - [3 - [2 - [(5-methyltetrazol -2-yl) methyl] -4 - (trifluoromethyl) phenyl] propanoyl] piperidin -4 -yl] ethylsulfinyl] benzene sulfonylamide; -fluoro -4 - [2 - [1 - [3 - [2 - [(5-methyltetrazol -2-yl) methyl] -4 - (trifluoromethyl) phenyl] propanoyl] piperidin -4 -yl] ethylsulfonyl] benzene sulfonylamide; -fluoro -4 - [2 - [1 - [6 - (2,2,2-trifluoroethoxy) -5 - (trifluoromethyl) pyridine -3-carbonyl] piperidin -4 yl] ethylsulfonyl] benzene sulfonylamide; -fluoro -4 - [4 - [3 - [2 - [(5-methyltetrazol -2 yl) methyl] -4 - (trifluoromethyl) phenyl] propanoyl] piperazin -1 -yl] sulfonylbenzene sulfonylamide; - [[1 - [2-cyclopropyl-6 - (oxan -4-ylmethoxy) pyridine -4-carbonyl] piperidin -4 -yl] methylsulfanyl] -3-fluorobenzene sulfonylamide; Petition 870190091123, of 9/13/2019, p. 37/164 31/132 - [[1 - [2-cyclopropyl-6 - (oxan -4-ylmethoxy) pyridine -4-carbonyl] piperidin -4 -yl] methylsulfinyl] -3-fluorobenzene sulfonylamide; - [[1 - [2-cyclopropyl-6 - (oxan -4-ylmethoxy) pyridine -4-carbonyl] piperidin -4 -yl] methylsulfonyl] -3-fluorobenzene sulfonylamide; - [1 - (6-cyclobutyloxy -5-cyclopropylpyridine -3-carbonyl) piperidin -4 -yl] sulfonyl -3-fluorobenzene sulfonylamide; - [1 - [2-cyclopropyl-6 - (oxan -4-ylmethoxy) pyridine -4-carbonyl] azetidin-3 -yl] sulfanyl-3 fluorobenzene sulfonylamide; - [1 - [2-cyclopropyl -6 - (oxan -4-ylmethoxy) pyridine -4-carbonyl] azetidin -3 -yl] sulfinyl -3 fluorobenzene sulfonylamide; - [1 - [2-cyclopropyl-6 - (oxan -4-ylmethoxy) pyridine -4-carbonyl] azetidin-3 -yl] sulfonyl-3 fluorobenzene sulfonylamide; - [1 - [2-cyclopropyl -6 - (oxan -4-ylmethoxy) pyridine -4-carbonyl] piperidin -4 -yl] sulfonyl -2,3 difluorobenzene sulfonylamide; - [1 - [2-cyclopropyl-6 - (oxan -4-ylmethoxy) pyridine -4-carbonyl] piperidin -4 -yl] sulfonyl-3 fluorobenzene sulfonylamide; - [1 - [3 - [4-chloro -2 - [(5-methyltetrazol -2 yl) methyl] phenyl] propanoyl] piperidin -4 -yl] sulfonyl -3-fluorobenzene sulfonylamide; - [1 - [3 - [4-cyano -2 - [(5-methyltetrazol -2 yl) methyl] phenyl] propanoyl] piperidin -4 -yl] sulfonyl -3-fluorobenzene sulfonylamide; Petition 870190091123, of 9/13/2019, p. 38/164 32/132 - [2 - [1 - [2 -cyclopropyl -6 - (oxan -4 ylmethoxy) pyridine -4-carbonyl] piperidin -4 -yl] ethylsulfanyl] -3-fluorobenzene sulfonylamide; - [2 - [1 - [2 -cyclopropyl -6 - (oxan -4 ylmethoxy) pyridine -4-carbonyl] piperidin -4 -yl] ethylsulfinyl] -3-fluorobenzene sulfonylamide; - [2 - [1 - [2-cyclopropyl -6 - (oxan -4 ylmethoxy) pyridine -4-carbonyl] piperidin -4 -yl] ethylsulfonyl] -3-fluorobenzene sulfonylamide; - [2 - [1 - [5 -cyclopropyl -6 (cyclopropylmethoxy) pyridine -3-carbonyl] piperidin -4 yl] ethylsulfonyl] -3-fluorobenzene sulfonylamide; - [4 - [2-cyclopropyl -6 - (oxan -4-ylmethoxy) pyridine -4-carbonyl] piperazin -1 -yl] sulfonyl -3 fluorobenzene sulfonylamide; - [4 - [3 - [2 - [(5-methyltetrazol -2-yl) methyl] -4 - (trifluoromethyl) phenyl] propanoyl] piperazin -1 -yl] sulfonylbenzene sulfonylamide; - [1 - [3 - [2 - [(5-methylthetrazol -2-yl) methyl] -4 - (trifluoromethyl) phenyl] propanoyl] piperidin -4-yl] sulfanylthiophene -2-sulfonamide; - [2 - [1 - [3 - [2 - [(5-methyltetrazol -2-yl) methyl] -4 - (trifluoromethyl) phenyl] propanoyl] piperidin -4 -yl] ethylsulfonyl] thiophene -2-sulfonamide; -fluoro -6 - [1 - [3 - [2 - [(5-methylthetrazol -2 yl) methyl] -4 - (trifluoromethyl) phenyl] propanoyl] piperidin -4 -yl] sulfanylpyridine -3 -sulfonamide; - [1 - [2-cyclopropyl -6 - (oxan -4-ylmethoxy) pyridine -4-carbonyl] piperidin -4 -yl] sulfanyl -5 fluoropyridine -3-sulfonamide; Petition 870190091123, of 9/13/2019, p. 39/164 33/132 - [1 - [3 - [4 - (difluoromethoxy) -2 - [(5 methyltetrazol -2-yl) methyl] phenyl] propanoyl] piperidin -4-yl] sulfonyl -3-fluorobenzene sulfonylamide; - [2 - [1 - [3 - [4 - (difluoromethoxy) -2 - [(5 methyltetrazol -2-yl) methyl] phenyl] propanoyl] piperidin -4 -yl] ethylsulfinyl] -2,3-difluorobenzene sulfonylamide; 2,3 -difluoro -4 - [2 - [1 - [3 - [2 - [(5 - methyltetrazol -2-yl) methyl] -4 - (trifluoromethyl) phenyl] propanoyl] piperidin -4 -yl] ethylsulfinyl] benzene sulfonylamide; - [2 - [1 - [3 - [4 - (difluoromethoxy) -2 - [(5 methyltetrazol -2-yl) methyl] phenyl] propanoyl] piperidin -4 -yl] ethylsulfinyl] -1,3-thiazole -5 -sulfonamide; - [2 - [1 - [3 - [2 - [(5-methyltetrazol -2-yl) methyl] -4 - (trifluoromethyl) phenyl] propanoyl] piperidin -4 -yl] ethylsulfonyl] -1,3-thiazole - 5 -sulfonamide; (+) -3-fluoro -4 - [[1 - [3 - [2 - [(5 methyltetrazol -2-yl) methyl] -4 - (trifluoromethyl) phenyl] propanoyl] piperidin -4 -yl] sulfinyl] benzene sulfonylamide; (+) -4 - [[1 - [3 - [2 - [(5-methylthetrazol -2-yl) methyl] -4 - (trifluoromethyl) phenyl] propanoyl] pyrrolidin -2 -yl] methoxy] benzene sulfonylamide; (+) -4 - [[1 - [3 - [2 - [(5-methylthetrazol -2-yl) methyl] -4 - (trifluoromethyl) phenyl] propanoyl] pyrrolidin -3 -yl] methoxy] benzene sulfonylamide; (-) -3-fluoro -4 - [[1 - [3 - [2 - [(5 methyltetrazol -2-yl) methyl] -4 - (trifluoromethyl) phenyl] propanoyl] piperidin -4 -yl] sulfinyl] benzene sulfonylamide; Petition 870190091123, of 9/13/2019, p. 40/164 34/132 (-) -4 - [[1 - [3 - [2 - [(5-methyltetrazol -2-yl) methyl] -4 - (trifluoromethyl) phenyl] propanoyl] pyrrolidin -2 -yl] methoxy] benzene sulfonylamide; (-) -4 - [[1 - [3 - [2 - [(5-methyltetrazol -2-yl) methyl] -4 - (trifluoromethyl) phenyl] propanoyl] pyrrolidin -3 -yl] methoxy] benzene sulfonylamide; - (((4 - (3 - (2 - ((5-methyl -2H -tetrazol -2 -yl) methyl) -4 - (trifluoromethyl) phenyl) propanoyl) piperazin -1 -yl) methyl) benzene sulfonylamide; and their pharmaceutically acceptable salts. [0072] Other particular examples of compounds of formula (I) as described in the present case are selected from -fluoro -4 - [[4 - [3 - [2 - [(5-methylthetrazol -2-yl) methyl] -4 - (trifluoromethyl) phenyl] propanoyl] piperazin -1 -yl] methyl] benzene sulfonylamide; 2,3 -difluoro -4 - [1 - [3 - [2 - [(5-methylthetrazol -2 -yl) methyl] -4 - (trifluoromethyl) phenyl] propanoyl] piperidin -4 -yl] sulfonylbenzene sulfonylamide; -fluoro -4 - [1 - [3 - [2 - [(5-methyltetrazol -2 yl) methyl] -4 - (trifluoromethyl) phenyl] propanoyl] piperidin -4 -yl] sulfonylbenzene sulfonylamide; -fluoro -4 - [4 - [3 - [2 - [(5-methyltetrazol -2 yl) methyl] -4 - (trifluoromethyl) phenyl] propanoyl] piperazin -1 -yl] sulfonylbenzene sulfonylamide; - [1 - [2-cyclopropyl -6 - (oxan -4-ylmethoxy) pyridine -4-carbonyl] piperidin -4 -yl] sulfonyl -2,3 difluorobenzene sulfonylamide; - [1 - [2-cyclopropyl -6 - (oxan -4-ylmethoxy) pyridine -4-carbonyl] piperidin -4 -yl] sulfonyl -3 Petition 870190091123, of 9/13/2019, p. 41/164 35/132 fluorobenzene sulfonylamide; -fluoro -6 - [1 - [3 - [2 - [(5-methylthetrazol -2 yl) methyl] -4 - (trifluoromethyl) phenyl] propanoyl] piperidin -4 -yl] sulfanylpyridine -3 -sulfonamide; and their pharmaceutically acceptable salts. [0073] Processes for the manufacture of compounds of formula (I) as described in the present case are objects of the invention. [0074] The preparation of the compounds of formula (I) of the present invention can be carried out in sequential or convergent synthetic paths. Syntheses of the invention are illustrated in the general schemes set out below. The practices required to carry out the reactions and purifications of the resulting products are known to those skilled in the art. If a mixture of enantiomers or diastereoisomers is produced during a reaction, these enantiomers or diastereoisomers can be separated by methods described in this context or by the knowledge of the person skilled in the art, such as, for example, chromatography (chiral) or crystallization . The substituents and indices used in the following description of the processes have the meaning set out in the present case. [0075] The compounds of the general formula (I) can be synthesized from the amine precursor 1 and appropriate reagents, using methods widely known in the art. X, r2 HN X-W 1 Petition 870190091123, of 9/13/2019, p. 42/164 36/132 [0076] For example, amine 1 is reacted with a suitable carboxylic acid of formula R 1 -Y-OH (2) leading to a compound of formula (I), where Y is comprised of - (CH 2 ) q C (O) -, - (CH = CH) r -C (O) -, or - (CH ^ CH) r -C (O) -. The reaction is carried out in the presence of a coupling agent such as 1,1'-carbonyl diimidazole, N / N'-dicyclohexyl carbodiimide, 1- (3-dimethyl aminopropyl) -3-ethyl-carbodiimide hydrochloride, O-hexafluorophosphate - (benzotriazol-l-yl) -N, N, Ν ', Ν'-tetramethyl urone, O- (7-azabenzotriazol-l-yl) N, N, Ν', Ν'-tetramethyl uronium or bromotris-pyrrolidine-phosphonium hexafluoro phosphate, in aprotic solvents such as dichloromethane, tetrahydrofuran, N, N-dimethylformamide, Nmethyl pyrrolidinone and their mixtures under temperatures between -40 ° C and 80 ° C in the presence or absence of a base such as triethylamine, diisopropyl ethylamine, 4-methylmorpholine and / or 4- (dimethylamino) pyridine. [0077] Amine 1 can also be reacted with suitable acylating reagents such as acyl chloride of formula R 1 -Y-C1 (3) to lead to the compound of formula (I), where Y is comprised of ( CH 2 ) q C (O) -, - (CH = CH) r -C (O) -, or - (CH ^ CH) r -C (O) -. The reaction is carried out in a solvent such as dichloromethane, tetrahydrofuran or N, N-dimethylformamide, in the presence of a base such as triethylamine or 4-methylmorpholine, at temperatures between) ° C and 8) ° C. [0078] Alternatively, amine 1 is reacted with a suitable chloroformate ester of the formula R 1 -CH 2 -OC (O) -Cl (4), or with an imidazole1-carboxylate ester of the formula ( 5), which leads to a compound of Petition 870190091123, of 9/13/2019, p. 43/164 37/132 formula (I) where Y is comprised of -CH 2 -OC (O). O IX * v ^ = N [0079] The reaction is carried out in a suitable solvent such as dichloromethane, tetrahydrofuran, N, Ndimethylformamide, acetonitrile, acetone, water, or their mixtures, in the presence of a base, for example, triethylamine, diisopropyl ethylamine, pyridine, potassium hydrogencarbonate, potassium carbonate, at temperatures between 0 ° C and the boiling point of the solvent or mixture of solvents. [0080] Chloroformate esters 4 are commercially available or can be synthesized from the corresponding alcohol of formula R1-CH2-OH (6), by reaction with phosgene or a phosgene equivalent (eg diphosgene, triphosgene) , as described in the literature. [0081] Imidazole-1-carboxylate esters 5 are synthesizer from the corresponding alcohols of formula R 1 - CH 2 -OH (6), by reaction with 1,1'carbonyl diimidazole. The reaction is carried out at room temperature, in a solvent such as dichloromethane, tetrahydrofuran or acetonitrile. The esters of imidazole 1-carboxylate 5 are typically not isolated, but caused to react directly with amines 1 as previously described in the present case. [0082] The alcohols of the formula R 1 -CH 2 -OH (6), are found commercially available or can be produced using methods described in the present case Petition 870190091123, of 9/13/2019, p. 44/164 38/132 or known in the art. [0083] Carboxylic acids (2) and acyl halides (3) are found commercially available or can be prepared as described in the present case or in the literature. [0084] The amines of general formula 1 are synthesized from precursors 7 suitably protected 7. XR 2 PG-N ^ X-W 7 [0085] Suitable protecting groups (PG) are comprised of tert-butoxycarbonyl, benzyloxycarbonyl, or acetyl. Deprotection of intermediates 7 can be carried out using methods and reagents as are known in the art. [0086] For example, in the case where PG is comprised of benzyloxycarbonyl, deprotection can be carried out by hydrogenation under pressures between 1 bar and 100 bar, in the presence of a suitable catalyst such as palladium on activated charcoal, under temperatures between 20 ° C and 150 ° C in solvents such as methanol or ethanol. [0087] Alternatively, in the case where PG is comprised of tert-butoxycarbonyl, deprotection may be carried out in the presence of a suitable acid, for example, hydrochloric acid or trifluoroacetic acid in a solvent such as water, 2-propanol , dichloromethane, or 1,4dioxane at temperatures between 0 ° C and 30 ° C. Petition 870190091123, of 9/13/2019, p. 45/164 39/132 [0088] Alternatively, in the case where PG is comprised of acetyl, deprotection can be carried out in the presence of a suitable acid, for example, aqueous hydrochloric acid at temperatures between 0 ° C and 100 ° C. [0089] intermediates 7 where X is comprised of N, W is comprised of - (CR 9 R 1) ) p -C (O) - and p is comprised of zero can be represented by the general structure 7A. PG is comprised of a suitable protecting group, for example, tert-butoxycarbonyl, benzyloxycarbonyl, or acetyl, R, men are as defined above in this context. [0090] Amides 7A can be produced from amine precursors of general formula 8 by reaction with appropriate reagents, using methods known in the art. PG-N N H [0091] For example, the amine 8 ions is reacted with a suitable carboxylic ad of formula R -COOH (9), which leads to the compounds of formula 8A. The reaction is carried out in the presence of a coupling agent such as 1,1'-carbonyldiimidazole, N, N'-dicyclohexyl carbodiimide, 1- (3-dimethylaminopropyl) -3-ethyl-carbodiimide hydrochloride, O-hexafluoro-phosphate - (benzotriazol-l-yl) -N, N, Ν ', Ν' tetramethyl uronium, hexafluoro-phosphate O- (7-azabenzotriazol1-yl) -N, N, Ν ', Ν'-tetramethyl uronium or hexafluoro-phosphate in Petition 870190091123, of 9/13/2019, p. 46/164 40/132 bromo-tris-pyrrolidine-phosphonium, in aprotic solvents such as dichloromethane, tetrahydrofuran, N, Ndimethylformamide, N-methyl pyrrolidinone and their mixtures under temperatures between -40 ° C and 80 ° C in the presence or absence of base such as triethylamine, diisopropylethylamine, 4-methylmorpholine and / or 4 (dimethylamino) pyridine. [0092] Intermediates 7 where X is comprised of N, W is comprised of - (CR 9 R 1) ) p -S (O) 2 _ and p is comprised of zero can be represented by the general structure 7B. PG is comprised of a suitable protection group, for example, tert-butoxycarbonyl, benzyloxycarbonyl, or 2 acetyl, R, me n are such as previously defined in this context. PG — N NS = n 7B V δ [0093] Sulfonamides produced from precursors of 7B can beformula amine general 8 by reaction with appropriate reagents, using methods as are known in the art. For example, amine 8 is reacted with a suitable sulfonyl chloride of formula R -SO2 Cl (10), which leads to compounds of formula 7B. The reaction is carried out in a suitable solvent such as dichloromethane, tetrahydrofuran, N, N-dimethylformamide, acetonitrile, acetone, water, or mixtures thereof, in the presence of a base, for example, triethylamine, diisopropylethylamine, pyridine, hydrogen potassium carbonate , potassium carbonate, at temperatures between 0 ° C and the boiling point of Petition 870190091123, of 9/13/2019, p. 47/164 41/132 solvent or mixture of solvents. [0094] Amines 8, carboxylic acids 9, and sulfonyl chlorides 10 are found commercially available or can be synthesized as described in the present case or in the literature. [0095] Intermediates 7 where W is comprised of - (CR 9 R 1) ) p -can be represented by the general structure 7C. Intermediates 70 are found commercially available or can be produced as described in the present case or using methods as are known in the art. PG is comprised of a suitable protecting group, for example, tert-butoxycarbonyl, benzyloxycarbonyl, or acetyl, R 2 , R 9 , R 1 ', m, nep are as defined above in the present case. PG — N 7C o [0096] Intermediates 7C in which R is comprised of substituted phenyl can be represented by the general structure 7CA. PG is comprised of a suitable protecting group, for example, tert-butoxycarbonyl, benzyloxycarbonyl, or acetyl, R 2 , R 7 , R 8 , R 9 , R 1 ', m, nep are as previously defined in the present case. Petition 870190091123, of 9/13/2019, p. 48/164 42/132 [0097] Intermediates 7CA can be produced from compounds 11 using methods as are known in the art. [0098] For example, the chlorosulfonation of compound 11 leads to sulfonyl chloride 12. The reaction can be carried out with an appropriate reagent, for example, chlorosulfonic acid, without solvent or in a suitable solvent, for example, dichloromethane, under temperatures between 0 ° C and 100 ° C. [0099] In a second stage, the reaction of sulfonyl chloride 12 with ammonia leads to 7CA. This reaction can be carried out in a suitable solvent, for example, water, ethanol, tetrahydrofuran, or mixtures thereof, at temperatures between 0 ° C and 50 ° C. [00100] Compounds 11 are found commercially available or can be synthesized as described in the present case or exposed in the literature. [00101] Intermediates 7 where X is comprised of CH and W is comprised of - (CR 9 R 10 ) pS- or - (CR 9 R 10 ) pO- can be represented by the general structure 7D. V is comprised of oxygen or Petition 870190091123, of 9/13/2019, p. 49/164 43/132 sulfur, R 2 , R 9 , R 1 ', m, nep are as previously described in the present case, PG is comprised of a protecting group, for example, benzyloxy carbonyl, tert-butoxycarbonyl, or acetyl. R 9 7D [00102] The compounds of formula 7D can be synthesized from alcohol or thiol 13 using methods and reagents as are known in the art. [00103] For example, alcohol or thiol 13 is reacted with a suitable halide, R-Hal (14). Hal is comprised of F (preferred), Cl, Br, or I. The reaction can be carried out in the presence of a base, for example, sodium hydride, cesium carbonate, or potassium carbonate, in a suitable solvent, for example , tetrahydrofuran or N, Ndimethylacetamide, at temperatures between -78 ° and + 100 ° C. It may be necessary to protect the amino sulfonyl group in halide 14. A suitable sulfonamide protecting group is comprised of the sulfonyl formamidine group, which can be obtained by reacting the main sulfonamide with dimethyl acetal dimethylamide, as described in present case or as it is exposed in the literature. [00104] Alternatively, the compounds Petition 870190091123, of 9/13/2019, p. 50/164 44/132 of formula 7D can be synthesized from alcohol 13A and phenol R 2 -OH (15) or thiophenol R 2 -SH (16) using reagents and methods as are known in the art. R 9 --- O — H 13A [00105] This reaction can be carried out using a phosphine, for example, triphenyl phosphine, an azodicarboxylate, for example, diethyl azodicarboxylate or diisopropyl azodicarboxylate, in a solvent such as dichloromethane, toluene or tetrahydrofuran and under temperatures between 0 ° C and 40 ° C. It may be necessary to protect the amino sulfonyl group in phenol 15 or thiophenol 16. A suitable sulfonamide protecting group is comprised of the sulfonyl formamidine group, which can be obtained by reacting the primary sulfonamide with N, N-dimethylamide dimethyl acetal, as is described in the present case or in the literature. [00106] Alcohols and thiools 13 are found commercially available and can be produced as described in the present case or using methods as are known in the art. [00107] Intermediates 7D in which V is comprised of sulfur can be represented by means of the general structure 7DA. R 2 , R 9 , R 1 ', men are as described above, PG is comprised of a protecting group, for example, benzyloxycarbonyl, tert-butoxycarbonyl, or acetyl. Petition 870190091123, of 9/13/2019, p. 51/164 45/132 PG-N R 9 S — R 2 7DA R 1 ° - p [00108] Intermediates 7 where X is comprised of CH and W is comprised of - (0 R 9 R 1) ) p S (O) - can be represented by the general structure 7E. R 2 , R 9 , R 1 ', m, nep are as previously described in this context, PG is comprised of a protecting group, for example, benzyloxycarbonyl, tert-butoxycarbonyl, or acetyl. P 7E [00109] Sulfoxides 7E can be produced from sulfides 7DA using methods and reagents such as they are known in the art. For example, the reaction can be performed on presence of a reagent in peroxide, for example, peroxide hydrogen or acid 3- chloroperbenzoic, in a solvent, for example, dichloromethane, Acetic Acid or formic acid, under temperatures between 0 ° C and + 50 ° C.- [00110] Intermediaries 7 in that X is comprised of CH and W is comprised of - (CR 9 R 1) ) p S (O) 2 _ can be represented by the general structure 7F. R 2 , R 9 , R 1 ', m, nep are as previously described in the present case, PG is comprised of a protecting group, for example, benzyloxycarbonyl, tert-butoxycarbonyl, or acetyl. Petition 870190091123, of 9/13/2019, p. 52/164 46/132 PG — N R 9 R 10 - J p: S — R II 0, 2 7F [00111] Sulfones 7F can be produced from intermediate sulfides 7DA or sulfoxides 7D using a suitable peroxide reagent, for example, hydrogen peroxide or 3-chloroperbenzoic acid in a solvent, for example, dichloromethane, acetic acid or formic acid, at temperatures between 0 ° C and + 50 ° C. [00112] The compounds of formula (I) in which X is comprised of N, W is comprised of - (CR 9 R 1) ) pC (O) or - (CR 9 R 1) ) pS (O) 2 _ and is comprised of zero can be represented by the general structure 17. Z is comprised of C (O) or S (O) 21 R f R, m and m are as described above in the present case. XR 2 Y-N N-z '17 R * V [00113] The compounds of formula 17 in which Z is comprised of C (O) can be represented by the general structure 17A. R, R, men are as previously described in the present case. XR 2 Y-N N-Z 17A R X o [00114] Amides 17A can be produced from amine precursors of general formula 8 by reaction with appropriate reagents, using methods Petition 870190091123, of 9/13/2019, p. 53/164 47/132 as they are known in the art. [00115] For example, amine 18 is reacted with a suitable carboxylic acid of formula R -COOH (9), which leads to compounds of formula 17A. The reaction is carried out in the presence of a coupling agent such as 1,1'-carbonyl diimidazole, N, N'-dicyclohexyl carbodiimide, 1- (3-dimethyl aminopropyl) -3-ethylcarbodiimide hydrochloride, O- (hexafluorophosphate) benzotriazol-l-yl) N, N, Ν ', Ν'-tetramethyluronium, O- (7azabenzotriazol-l-yl) -Ν, Ν, Ν', Ν'-tetramethyluronium or bromo-tris-pyrrolidine hexafluorophosphate phosphonium, in aprotic solvents such as dichloromethane, tetrahydrofuran N, N-dimethylformamide, methyl pyrrolidinone and mixtures under temperatures between -40 ° C and 80 ° C in the presence or absence of a base, such as triethylamine, diisopropylethylamine, 4- methylmorpholine and / or 4- (dimethylamino) pyridine. [00116] The compounds of formula 17 wherein Z is comprised of S (O) 2 can be represented by the general structure 17B. R, R, men are as described above in the present case. 17B [00117] Sulphonamides 17B can be produced from amine precursors of general formula 18 by reaction with appropriate reagents, using methods as are known in the art. Petition 870190091123, of 9/13/2019, p. 54/164 48/132 For example, amine 18 is reacted with a suitable sulfonyl chloride of formula R -SO2 Cl (10), leading to compounds of formula 17B. The reaction is carried out in a suitable solvent such as dichloromethane, tetrahydrofuran, Ν, Ν-dimethyl formamide, acetonitrile, acetone, water, or mixtures thereof, in the presence of a base, for example, triethylamine, diisopropylethylamine, pyridine, hydrogen carbonate potassium, potassium carbonate, at temperatures between 0 ° C and the boiling point of the solvent or mixture of solvents. [00118] The compounds of formula (I) in which X is comprised of N, W is comprised of - (CR 9 R 1) ) p -, R 1 'is comprised of H and is comprised of 1 can be represented by of the general structure 17C. R, R, m and n are as previously described in the present case. [00119] The compounds of formula 17C can be produced from amine precursors 18 by reaction with appropriate reagents, using methods as are known in the art. [00120] For example, amine 18 is reacted with aldehyde or ketone, R -C (O) -R (21) in the presence of a suitable reducing agent, for example, sodium triacetoxy boron hydride, boron hydride sodium, or cyano boron sodium hydride. The reaction is carried out in a suitable solvent, for example, dichloromethane, 1,2-dichloroethane, acetic acid, methanol, or mixtures thereof, at temperatures between 0 ° C and the boiling point of Petition 870190091123, of 9/13/2019, p. 55/164 49/132 solvent. [00121] Alternatively, amine 18 is reacted with halide, R 2 -CH (R 9 ) -Hal (22) (Hal is comprised of Cl, Br, or I) in the presence of a suitable base, for example, potassium carbonate, cesium carbonate, or triethylamine. The reaction is carried out in a suitable solvent, for example, methanol, acetone, acetonitrile, or N, N, dimethylformamide, at a temperature between 0 ° C and the boiling point of the solvent. [00122] Aldehydes or ketones (21) and halides (22) are found commercially available or can be produced in the manner described in the present case or on literature.[00123] At formula amines 18 can be prepared from of precursors 19 properly protected. YN Z .Am'Μ — PG 19r 1 '> • 'n [00124] The protection groups (PG) suitable are understood by terc-butoxi carbonyl or benzyloxycarbonyl. Deprotection of intermediates 19 can be carried out using methods and reagents which are known in the art. [00125] For example, in the case where PG is comprised of benzyloxycarbonyl, deprotection can be carried out by hydrogenation under pressures between 1 bar and 100 bar, in the presence of a suitable catalyst such as activated carbon palladium, at temperatures between 20 ° C and 150 ° C in solvents such as methanol or ethanol. Petition 870190091123, of 9/13/2019, p. 56/164 50/132 [00126] Alternatively, in the case where PG is comprised of tert-butoxycarbonyl, deprotection can be carried out in the presence of a suitable substance, for example, hydrochloric acid or trifluoroacetic acid, in a solvent such as water, 2propanol, dichloromethane, or 1,4-dioxane at temperatures between 0 o and 30 ° C. [00127] The compounds of formula 19 can be synthesized from amine precursors 20 and appropriate reagents using methods as are known in the art. HN Z ll-PG 20 [00128] For example, amine 20 is reacted with a suitable carboxylic acid of formula R 1 -Y-OH (2) leading to a compound of formula (I), where Y is comprised of - (CH 2 ) q C (O) -, - (CH = CH) r -C (O) -, or (CH ^ CH) r -C (O). The reaction is carried out in the presence of a coupling agent, such as 1,1'-carbonyl diimidazole, N, N'-dicyclohexylcarbodiimide, 1- (3-dimethylaminopropyl) -3-ethyl-carbodiimide hydrochloride, 0-hexafluoro phosphate - ^ θηζο1Γί3ζο1-1-ί1) -Ν, Ν, Ν, Ν '- tetramethyl the ilurôni, hexafluoro phosphate O- (7-azabenzotriazole-l-yl) -N, N, Ν', Ν 'or tetramethyluronium hexafluoro bromo-trispirrolidino phosphonium phosphate, in aprotic solvents such as dichloromethane, tetrahydrofuran, N, N-dimethylformamide, Nmethylpyrrolidinone and their mixtures under temperatures between -40 ° C and 80 ° C in the presence or absence of a base such as triethylamine, diisopropyl ethylamine, 4methylmorpholine and / or 4- (dimethylamino) pyridine. Petition 870190091123, of 9/13/2019, p. 57/164 51/132 [00129] Amine 20 can also be reacted with suitable acetylating reagents such as acetyl chlorides of formula R 1 -Y-C1 (3) to lead to a compound of formula (I), where Y is comprised of (CH 2 ) q C (O) -, - (CH = CH) r -C (O) or - (CH ^ CH) r -C (O) -. The reaction is carried out in a solvent such as dichloromethane, tetrahydro-furan, or N, N-dimethylformamide, in the presence of a base such as triethylamine or 4-methylmorpholine, at temperatures between 0 ° C and 80 ° C. [00130] Alternatively, amine 20 is reacted with a suitable chloroformate ester of formula R 1 -CH2-OC (O) -Cl (4), or with an imidazole ester 1-carboxylate of formula ( 5), which leads to a compound of formula (I) in which Y is comprised of -CH2-OC (O) -. The reaction is carried out in a suitable solvent such as dichloromethane, tetrahydrofuran, N, N-dimethylformamide, acetonitrile, acetone, water, or mixtures thereof, in the presence of a base, for example, triethylamine, diisopropylethylamine, pyridine, potassium hydrogencarbonate, potassium carbonate, at temperatures between 0 ° C and the boiling point of the solvent or mixture of solvents. [00131] Amines 20 are found commercially available or can be prepared in the manner described in the present case or in the literature. [00132] Also one embodiment of the present invention is comprised of a process for preparing a compound of formula (I) as defined above, which comprises the reaction of a compound of formula (II) in Petition 870190091123, of 9/13/2019, p. 58/164 52/132 presence of a compound of formula (III); R 1 / Y G / (III) / HN X-W ----------- Υ-ΝΓ X-W XR (li) (I) where R, R, Y, W, X, men are as defined in the present case and if Y is comprised of - (CH 2 ) q C (0) - (CH = CH ) r -C (0) - or - (CH ^ CH) r -C (0) -, then G is comprised of halogen or hydroxy and if it is understood by -0C (0) -, then G is understood by chlorine. [00133] In particular, in the presence of a coupling agent such as 1,1'-carbonyl diimidazole, N, N'dicyclohexylcarbodiimide, 1- (3-dimethylaminopropyl) -3-ethyl-carbodiimide hydrochloride, 0-hexafluoro phosphate - (benzotriazol-l-yl) -N, N, N, N'-tetramethyluronium tetrafluoroborate, hexafluoro phosphate 0- (7-azabenzotriazole-l-yl) -N, N, Ν ', Ν' tetramethyluronium hexafluorophosphate or bromo phosphate -tris pyrrolidine phosphonium, with particular hexafluoro phosphate of 0- (7-azabenzotriazol-1-yl) -N, N, Ν ', Ν'-tetramethyluronium, in an aprotic solvent such as dichloromethane, tetrahydrofuran, N, N-dimethylformamide, Nmethylpyrrolidinone and mixtures thereof, with particularity N, N-dimethylformamide, in the presence or absence of a base such as triethylamine, diisopropylethylamine, 4methylmorpholine and / or 4- (dimethylamino) pyridine, particularly in the presence of 4-methyl morpholine and under a temperature between -78 ° C and reflux, with Petition 870190091123, of 9/13/2019, p. 59/164 53/132 between -10 ° C and room temperature. [00134] Also an object of the present invention is comprised by a compound according to formula (I) as described in the present case for use as a therapeutically active substance. [00135] Similarly, an objective of the present invention is comprised of a pharmaceutical composition comprising a compound according to formula (I) as described in the present case and a therapeutically inert carrier. [00136] A particular embodiment of the present invention is comprised of a compound according to formula (I) as described in the present case for the treatment or prophylaxis of ocular conditions, with particular glaucoma. [00137] The present invention also relates to the use of a compound according to formula (I) as described in the present case for the preparation of a medicament for the treatment or prophylaxis of ocular conditions, with particular glaucoma. [00138] Also an objective of the invention is understood by a method for the treatment or prophylaxis of ocular conditions, with particular glaucoma, which method comprises administering an effective amount of a compound according to formula (I) as it stands described in the present case. [00139] Inflammatory conditions include, but are not limited to, arthritis, osteoarthritis, multiple sclerosis, systemic lupus erythematosus, inflammatory bowel disease, disorder Petition 870190091123, of 9/13/2019, p. 60/164 54/132 of abnormal evacuation and the like, as well as inflammatory diseases of the respiratory tract, such as idiopathic pulmonary fibrosis (IPF), illness pulmonary chronic obstructive (COPD) or asthma bronchial chronic. [00140] Others conditions of system respiratory diseases include, but are not limited to, other diffuse parenchymal lung diseases of different etiologies, including drug-induced iatrogenic fibrosis, occupational and / or environmental fibrosis, systemic and vasculitis diseases, granulomatous diseases (sarcoidosis, hypersensitivity pneumonia), vascular collagen disease, alveolar proteinosis, Langerhans cell granulomatosis, lymphangioma leiomyomatosis, hereditary diseases (Hermansky-Pudlak syndrome, tuberous sclerosis, neurofibromatosis, metabolic storage disorders, familial interstitial lung disease), radiation-induced fibrosis, pulmonary fibrosis, fibrosis induced asbestos or syndrome of discomfort acute respiratory (SDRA).[00141 ] At conditions of nervous system include, being not if is limited to them, pain neuropathic, schizophrenia, neuroinflammation (for example, astrogliosis), peripheral and / or autonomic (diabetic) and similar neuropathies. [00142] Vascular conditions include, but are not limited to, atherosclerosis, thrombotic vascular disease, as well as thrombotic micro angiopathies, proliferating arteriopathy (such as cells Petition 870190091123, of 9/13/2019, p. 61/164 55/132 swollen myointimals surrounded by mucinous extracellular matrix and nodular thickening), atherosclerosis, decreased vascular compliance (such as stiffness, reduced ventricular compliance and reduced vascular compliance), endothelial dysfunction and the like. [00143] Cardiovascular conditions include, but are not limited to, acute coronary syndrome, coronary heart disease, myocardial infarction, arterial and pulmonary hypertension, cardiac arrhythmia such as atrial fibrillation, stroke and other vascular damage. [00144] Fibrotic diseases include, but are not limited to, myocardial and vascular fibrosis, pulmonary fibrosis, skin fibrosis, scleroderma and encapsulation peritonitis. [00145] Cancer and cancer metastasis include, among others, breast cancer, ovarian cancer, lung cancer, prostate cancer, mesothelioma, glioma, gastrointestinal cancer and their progression and metastatic aggressiveness. [00146] Eye conditions include, but are not limited to, proliferating and non-proliferating (diabetic) retinopathy, age-related dry and wet macular degeneration (AMD), macular edema, central arterial / venous occlusion, traumatic injury , glaucoma and the like. In particular, the eye condition is understood by glaucoma. [00147] Metabolic conditions include, but are not limited to, obesity and diabetes. Petition 870190091123, of 9/13/2019, p. 62/164 [00148] Also an embodiment of the present invention is comprised of the compounds of formula (I) as described in the present case, when manufactured according to any of the described processes. Assay Procedures PRODUCTION OF HUMAN ATX OF FULL LENGTH, WITH AND WITHOUT ITS TAG [00149] Autotaxin cloning (ATX -ENPP2): The cDNA was prepared from total RNA from commercial human hematopoietic cells and used as a template in PCR with overlap to generate a full-length ORE of human ENPP2 with or without a 3'-6xHis tag. These complete inserts were cloned into the vector pcDNA3.1V5-HÍS TOPO (Invitrogen). The DNA sequences of several individual clones were verified. The DNA of a correct full size clone was used to transfect Hek293 cells for verification of protein expression. The sequence of the encoded ENPP2 conforms to the Swisschiv Q13822 entry, with or without the additional 6xHis C-terminal tag. [00150] ATX fermentation: The recombinant protein was produced by transient large-scale transfection in 2 tank bioreactors under agitation controlled by L (Sartorius). During cell growth and transfection, temperature, agitator speed, pH and dissolved oxygen concentration were maintained under 37 ° C, 120 rpm, 7.1 and 30% DO, respectively. Freestyle 293-F cells (Invitrogen) were grown in suspension in Freestyle 293 medium (Invitrogen) Petition 870190091123, of 9/13/2019, p. 63/164 57/132 and transected under about 1-1.5 x 1) E6 cells / mL with the aforementioned plasma DNA using X-tremeGENE Ro1539 (commercial product, Roche Diagnostics) as a complexing agent. The cells were fed with a concentrated nutrient solution (J Immunol Methods 194 (1996), 19, 1-199 (page 193)) and induced by sodium butyrate (2 mM) 72 h after transfection and harvested 96 hours after transfection. Expression was analyzed using Western Blot, enzymatic assay and / or IMAC analytical chromatography. After cooling the cell suspension to 4 ° C in a pass-through heat exchanger, cell separation and sterile filtration of the supernatant was performed by filtration through Zeta Plus 6) M) 2 E16 (Cuno) and Sartopore 2 filtration units XLG (Sartorius). 0 supernatant was stored under the temperature of 4 ° C before gives purification.[00151] Purification of ATX: 2 0 liters in culture supernatant were conditioned for ultrafiltration by adding / by Brij 35 for an final concentration of 0.02% and by adjusting of pH for 7.0 using 1 M HCl. So, the supernatant was first micro filtrate through a 0.2 pm Ultran-Pilot Open Channel PES filter (Whatman) and afterwards concentrated to 1 liter through an Ultran-Pilot Screen Channel PES filter with 30 kDa MWCO (Whatman). Before IMAC chromatography, N1SO4 was added to a final concentration of 1 mM. The clarified supernatant was then applied to a HisTrap column (GE Healthcare) previously equilibrated in 50 mM Na2HPO4 pH 7.0, 0.5 M NaCl, 10% glycerol 0.3% CHAPS, 0.02% NaN 3 . The column was Petition 870190091123, of 9/13/2019, p. 64/164 58/132 washed in stages with the same buffer that contained 20 mM, 40 mM and 50 mM imidazole, respectively. The protein was subsequently eluted using a linear gradient to 0.5 M imidazole in a 15 volume column. Fractions containing ATX were pooled and concentrated using an Amicon cell equipped with a 30 kDa PES filter membrane. The protein was further purified by size exclusion chromatography in preparation class Superdex S-200 (XK 26/100 (GE Healthcare) in 20 mM BICINE, pH 8.5, 0.15 M NaCl, 10% glycerol , 0.3% CHAPS, 0.02% NaNs. The final protein yield after purification was 5-10 mg ATX per liter of culture supernatant. The protein was stored at -80 ° C. HUMAN ATX ENZYME INHIBITION TEST [00152] ATX inhibition was measured using a fluorescence extinction assay using a specifically labeled substrate analog (substrate MR121). To obtain this MR121 substrate, there were 6-aminohexanoic protected by BOO and TBS (R) -3 - ({2- [3- (2- {2 [2- (2-amino-ethoxy) -ethoxy] -ethoxy] -ethoxy) -propionylamino The] -ethoxy] -hydroxy-phosphoryloxy) -2-hydroxy-propyl ester (Ferguson et al., Org Lett 2006, 8 (10), 2023) was marked with fluorophore MR121 (CAS 1853) 8- 24-1, 1- (3carboxypropyl) -11-ethyl-1, 2,3,4,8,9, 1), 11-octahydrodipyride [3,2-b: 2 ', 3'-i] phenoxazin -13-i) on the free amine on the ethanolamine side and, after deprotection, subsequently with tryptophan on the amino hexanoic acid side. [00153] The working solutions of the test were performed as follows: Petition 870190091123, of 9/13/2019, p. 65/164 59/132 Assay buffer (50 mM Tris-HCl, 140 mM NaCl, 5 mM KCl, 1 mM CaCl 2 , 1 mM MgCl 2 , 0.01% Triton-X-100, pH 8.0; ATX solution: ATX stock solution (labeled human His) (1.08 mg / mL in 20 mM bicine, pH 8.5, 0.15 M NaCl, 10% glycerol, 0.3% CHAPS, 0.02 % NaN 3 ), diluted to 1.4 - 2.5x final concentration in the assay buffer; MR121 substrate solution: MR121 substrate stock solution (800 μΜ MR121 substrate in DMSO), diluted to final concentration 2 - 5x in assay buffer. [00154] Test compounds (10 mM in DMSO, 8 µl) were obtained in 384-well sample plates (Corning Gostar # 3655) and diluted with 8 µl of DMSO. Serial dilutions in rows were performed by transferring 8 pL of cpd solution to the next row to row O. Compound and control solutions were mixed five times and 2 pL were transferred to 384-well plates (Corning Gostar # 3702). Then, 15 µl of the 41.7 nM ATX solution (final concentration 30 nM) was added, mixed five times and then incubated for 15 minutes at 30 ° C. 10 pL of the MR121 substrate solution (final concentration 1 μΜ) was added, mixed 30 times and then incubated for 15 minutes at 30 ° C. Fluorescence was then measured every 2 minutes for 1 hour (Perkin Elmer plate: multimode vision reader); light intensity: 2.5%; exp. time: 1.4 s, Filter: Fluo_63) / 69) nm) and IC5) were calculated from these readings. Inhibition test of human carbonic anhydrase II [00155] Inhibition of carbonic anhydrase II Petition 870190091123, of 9/13/2019, p. 66/164 Human 60/132 (hCA-II) was measured using an absorbance method using 4-nitrophenyl acetate (4-NPA) as a substrate. 4-NPA can be catalyzed by active hCA II by means of a zinc hydroxide mechanism. The nitrophenolate in the products can be ionized to generate a bright yellow anion with high absorbance under 348 at 400 nm, as described in the literature (Armstrong et al., J. Biol. Chem. 1966, 241, 5137-5149). OD340 nm was chosen to detect the conversion of the substrate hCA II. [00156] Test work solutions were prepared as follows: Test solution: 50 mM MOPS, 33 mM Na2 SO2 1 mM EDTA, 0.5 mg / mL BSA, pH 7.5; Enzyme solution: hCA-II stock solution (human, full length) tion (1.0 mg / mL in 20 mM HEPES, 50 mM NaCl, pH 7.4), diluted to 2133x final concentration in assay buffer; 4-NPA substrate solution: 4-NPA substrate stock solution (250 mM in DMSO, stored under -20 ° C), diluted to 50x final concentration in deionized water. [00157] Test compounds (10 mM stock in DMSO, 100 pL) were obtained in 96-well sample plates (Corning Gostar # 3655) and diluted to 0.5 mM. Serial column dilutions were performed by transferring 20 pL of compound solutions to the next column, from column 3 to 22. After that, 1.2 pL were transferred to 384-well assay plates (Corning Gostar # 3701). Then, 30 pL of the 16 nM hCA II solution (8 nM final concentration) was added, mixed five times. 30 pL of 4-NPA substrate solution was added Petition 870190091123, of 9/13/2019, p. 67/164 61/132 (final concentration of 2.5 mM), mixed five times. The absorbance under 340 nm was then immediately measured as time zero. The test plates were incubated at room temperature for 1 hour and then measured as time 1 hour (Perkin Elmer Envision 2103; Filter: Photometric 340; Luminous intensity 60%; Number of flashes: 100. IC50 values θ values K ± values were calculated from these readings. Petition 870190091123, of 9/13/2019, p. 68/164 62/132 Ex ATX IC50 (μΜ) CA-11IC50 (μΜ) 1, 00 0.023 0.0096 1.01 0.018 0.2925 1.02 0.312 0.072 1.03 0.0731, 04 0082.00 008 0.0344 2.01 002 0.0013 2.02 007 0.0155 3.00 002 0.0211 3.00 009 0.0094 4.00 001 0.0176 4, 01 002 0.0342 4, 02 0.013 0.0343 5.00 0.014 1.0986 5, 01 004 0.0207 5, 02 005 0.0271 5, 03 001 0.1089 5, 04 005 0.0133 5, 05 0.0675, 06 0.0275, 07 0.024 0.1334 5, 08 0.014 0.1118 5, 09 009 0.0685 6.00 001 0.0067 6, 01 004 0.0063 6, 02 005 0.0018 Petition 870190091123, of 9/13/2019, p. 69/164 63/132 Ex ATX IC50 (μΜ) CA-11IC50 (μΜ) 6, 03 001 007 6, 04 005 0.0113 6.05 006 0.01 6, 06 004 0.014 6, 07 003 0.0131 6, 08 0.01 0.07 6, 09 0.012 0.0172 6, 10 002 0.0095 6, 11 0.01 0.0062 6, 12 008 0.0013 6, 13 001 0.0175 6, 14 005 0.0008 6, 15 0.013 0.0079 6.16 004 0.0123 6, 17 002 0.0071 6, 18 001 0.0129 6, 19 002 0.0178 6.20 0.019 0.0206 6.21 0.068 0.015 6, 22 0.011 0.0072 6, 23 004 0.0029 6, 24 009 0.0089 6.25 0.01 0.0062 6.26 008 0.0124 6, 27 001 0.0092 6.28 004 0.0102 6.29 009 0.0084 Petition 870190091123, of 9/13/2019, p. 70/164 64/132 Ex ATX IC50 (μΜ) CA-IIIC50 (μΜ) 6.30 0.015 0.0024 6, 31 0.01 0.0178 6, 32 003 0.0041 6, 33 003 0.02 6, 34 0.012 0.0079 6, 35 0.014 0.0198 6.36 0.062 0.0606 6, 37 006 0.0163 6, 38 001 0.0073 6, 39 001 008 6.40 007 009 6.41 001 0.0025 6, 42 0036, 43 0066, 44 0076.45 001 0.0051 7.00 0037, 01 0.072 0.0207 7, 02 0.024 0.1174 8.00 0058, 01 0.01 0.2339 8, 02 006 0.1463 9.00 0.027 [00158] The compounds of formula (I) and their pharmaceutically acceptable salts or esters as described in the present case have IC 50 values located Petition 870190091123, of 9/13/2019, p. 71/164 65/132 between 0, 00001 μΜ and 1000 μΜ, the particular compounds have IC50 values between 0.0005 μΜ and 500 μΜ, other particular compounds have IC50 values between 0.0005 μΜ and 50 μΜ, more particular compounds have IC 50 values between 0.0005 μΜ and 5 μΜ. These results were obtained using the enzyme assay described above in this context. [00159] The compounds of formula (I) and their pharmaceutically acceptable salts can be used as medicaments (for example, in the form of pharmaceutical preparations). Pharmaceutical preparations can be administered internally, such as orally (for example, in the form of tablets, coated tablets, pills, hard and soft gelatin capsules, solutions, emulsions or suspensions), nasally (for example, in the form of sprays nasal), rectally (for example, in the form of suppositories) or topically ocular (for example, in the form of solutions, ointments, gels or water-soluble polymeric inserts). However, administration can also be carried out parenterally, such as intramuscularly, intravenously or intraocularly (for example, in the form of sterile injection solutions). [00160] The compounds of formula (I) and their pharmaceutically acceptable salts can be processed with pharmaceutically inert, inorganic or organic adjuvants for the production of tablets, coated tablets, pills, hard gelatin capsules, injectable solutions or topical formulations of Lactose , corn starch or its derivatives, talc, stearic acid or its Petition 870190091123, of 9/13/2019, p. 72/164 66/132 salts and the like, can be used, for example, as adjuvants for tablets, capsules and hard gelatin tablets. [00161] Adjuvants suitable for hard gelatin capsules are, for example, vegetable oils, waxes, fats, semi-solid substances and liquid polyols, and the like. [00162] Adjuvants suitable for the production of solutions and syrups are comprised, for example, of water, polyols, sucrose, inverted sugar, glucose, and the like. [00163] Adjuvants suitable for injection solutions are comprised, for example, of water, alcohols, polyols, glycerol, vegetable oils, and the like. [00164] Adjuvants suitable for suppositories are comprised, for example, of natural or hardened oils, waxes, fats, semi-solid or liquid polyols, and the like. [00165] Adjuvants suitable for topical ocular formulations are comprised, for example, of cyclodextrins, mannitol or many other carriers and excipients as are known in the art. [00166] In addition, pharmaceutical preparations may contain preservatives, solubilizers, substances that increase viscosity, stabilizers, wetting agents, emulsifiers, sweeteners, dyes, flavorings, salts to vary the osmotic pressure, buffers, masking agents or antioxidants. They may also contain other therapeutically valuable substances. Petition 870190091123, of 9/13/2019, p. 73/164 67/132 [00167] The dosage can vary over wide limits and will, of course, be adjusted according to the individual requirements in each particular case. In general, in the case of oral administration, a dosage of about 0.1 mg to 20 mg per kg of body weight, preferably about 0.5 mg to 4 mg per kg of body weight (for example , about 300 mg per person), preferably divided into 1-3 individual doses, which may consist of, for example, the same amounts, if appropriate. In the case of topical administration, the formulation may contain 0.001% to 15%, by weight, of medication and the necessary dose, which may be between 0.1 and 25 mg, may be administered in a single dose per day or per week, or in multiple doses (2 to 4) per day, or in multiple doses per week. However, it will be clear that the upper or lower limit indicated in this document can be exceeded when indicated. [00168] The invention is hereinafter illustrated by means of Examples, which do not have any limiting character. [00169] In the event that the preparation examples are obtained in the form of a mixture of enantiomers, the pure enantiomers may be obtained by means of methods described in the present case or by methods known to those skilled in the art, such as, for example, example, chiral chromatography or crystallization. Examples [00170] All examples and intermediates were prepared under a nitrogen atmosphere if not otherwise specified. Petition 870190091123, of 9/13/2019, p. 74/164 68/132 [00171] Abbreviations: aq. = aqueous; CAS-RN = Chemical Abstracts Servicer registration number; HPLC = high performance liquid chromatography; MS = mass spectrum; PS-BEMP = polystyrene bond 2-tert-butylimino-2-diethylamino-1,3-dimethylperhydro-1,2,2-diazaphosphorin; salt. = saturated. Example 1 [2 - [(5-Methyltetrazol -2-yl) methyl] -4 (trifluoromethyl) phenyl] methyl 4 - (2-fluoro -4-sulfamoyl phenyl) piperazine -1-carboxylate [00172] To a solution of [2 - [(5-methyl-tetrazol-2-yl) methyl] -4 - (trifluoromethyl) phenyl] methanol (intermediate 1; 30 mg, 110 pmol) in acetonitrile (2 ml) was added 1 , 1'-carbonyldiimidazole (17.9 mg, 110 pmol) at room temperature. The reaction mixture was heated to 50 ° C and stirred for 2 h, then a suspension of 3-fluoro -4-piperazin -1-ylbenzene sulfonylamide (CAS -RN 847971 -84 0; 28.6 mg, 110 pmol ) and triethylamine (55.8 mg, 551 pmol) in acetonitrile (2 ml) was added and the reaction mixture was heated to reflux. After 15 h the reaction mixture was partitioned between saturated aqueous ammonium chloride solution and ethyl acetate. The organic layer was washed with saline, dried over magnesium sulfate, filtered and Petition 870190091123, of 9/13/2019, p. 75/164 69/132 evaporated. Chromatography (silica gel, gradient dichloromethane to dichloromethane / methanol / 25% aqueous ammonium solution 90: 10: 0.25) produced the title compound (15 mg, 24%). White solid, MS: 558.1 (M + H) + . [00173] The following examples were prepared according to example 1, replacing 3-fluoro-4 piperazin-1-ylbenzene sulfonylamide with the appropriate amine or carbamate and [2 - [(5-methyltetrazole -2 -11) methyl] -4 - (trifluoromethyl) phenyl] methanol by the appropriate alcohol. In cases where the tert-butylcarbamate derivative of the amines are used as starting materials (examples 1.03 and 1.04), the carbamates were first deprotected with trifluoroacetic acid in analogy to example 6. Ex. Systematic name Amine or carbamate / alcohol MS, m / e 1.01 [2 -cyclopropyl -6 - (oxan -4-ylmethoxy) pyridin -4 11] methyl 4 - [(4 sulfamoyl phenyl) methyl] piperidine -1-carboxylate 9 cr ÃÀ. ° JJ L1. X o 'NH; 4 - Hydrochloride(piperidin -4ilmethyl) benzenesulfonylamide (CAS RN 333986 -77 -9) /[2 -cyclopropyl -6 (oxan -4ylmethoxy) pyridin -4 11] methanol(intermediate 6) 544.4 (M + H) + Petition 870190091123, of 9/13/2019, p. 76/164 70/132 Ex. Systematic name Amine or carbamate / alcohol MS, m / e 1.02 [5-cyano -3 - (2,2 dimethyl propanoyl amino) pyridin -2 -ii] methyl 4 - [(4-sulfamoyl phenyl) methyl] piperidine - 1-carboxylate rdi 1 laugh L. ° Y λ '^ ΝΗ HN ^ OO ° 4 - Hydrochloride(piperidin -4ilmethyl) benzene sulfonylamide (CAS RN 333986 -77 -9) /(N - [5-cyano -2 (hydroxymethyl) pyridin -3 -ii] -2,22dimethylpropanamide (intermediate 12) 512.4(M-H) ~ 1.03 [5-chloro -3 - [(5 methyltetrazol -2 yl) methyl] pyridin -2 yl] methyl 4 - (2-fluoro -4-sulfamoyl phenyl) sulfonylpiperidine -1 carboxylate Cl O Γ 'r- ° / = ° Na * ΜΗ ^ nh O —f O 0 F tert-butyl-4 - (2 fluoro -4-sulfamoyl phenyl) sulfonylpiperidine -1carboxylate(intermediate 11) /[5-chloro -3 - [(5 methyltetrazol -2 -ii) methyl] pyridin -2 ii] methanol2 (intermediate 14) 588.2 (M + H) + Petition 870190091123, of 9/13/2019, p. 77/164 71/132 Ex. Name systematic Amine or carbamate alcohol / MS, m / e 1.04 [2 - [(5-methyltetrazol -2 -11) methyl] -4 (trifluoromethyl) phenyl] methyl 4 - (2-fluoro -4 sulfamoyl phenyl) sulfonylpiperidine - 1-carboxylate -N ° <.ζ Νί n x z N rV o _ FN Ο I JJ 0 F Τ ΪΓ 1 T o F 0 (tert-butyl-4 - ((2 fluoro -4-sulfamoyl phenyl) sulfonyl) -piperidine -1carboxylate / 2 - (((5-methyl -2H -tetrazol -2 -11) methyl) -4(trifluoromethyl)2 phenyl) methanol(intermediate 1) 619.3(M-H) ~ Example 2 -Fluoro -4 - [[4 - [3 - [2 - [(5 -methyltetrazol -2 -yl) methyl] -4 - (trifluoromethyl) phenyl] propanoyl] piperazin —1 -11] methyl] benzene sulfonylamide 001 / 4j To a solution of tert-butyl 4 - (3 fluoro -4-sulfamoyl benzoyl) piperazine -1-carboxylate (CAS -RN 1395398 -34 -1; 150 mg, 3 8'7 pmol) in tetrahydrofuran (3 mL) complex was added Petition 870190091123, of 9/13/2019, p. 78/164 72/132 tetrahydrofuran borane (1 M in tetrahydrofuran; 1.16 mb, 1.16 mm.ol) at room temperature, then after 14 h the reaction mixture was heated to 60 ° C for 4 h, So 2 M aqueous solution < le hydrochloric acid (2 mL) and beyond dl S SO hydrochloric acid ( 25% in water; 1.0 m L, 8.2 mm 1.) were add c. 1 o n o o s g o z a. The drop. The foJ mixture su.omeLio.a a agitation under 60 ° C during and 45 min., then the mixture was evapor ada directly b high vacuum and the residue was combined with N, N-dimethylformamide (3 mL) and N meillmorpholine (392 mg, 3.87 mmol), 3 - [2 - [(5 methyltetrazol -2 -11) methyl] -4 - (trifluoromethyl) phenyl] propanol (CAS -RN 1646783 -83 -6; 122 mg, 387 pmol) and 0 - (7 -azabenzotriazole -1 -11) af, Ν, Ν ', N' -tetramethyluronium (147 mg, 38 ' 7 pmol), then after 48 h at room temperature the reaction mixture was partitioned between saturated aqueous ammonium chloride solution and ethyl acetate. The organic layer was washed with saline, dried over magnesium sulfate, filtered and evaporated. Chromatography (silica gel, using flash chromatography on silica, elution with a dichloromethane gradient to dichloromethane / methanol / 25% aqueous ammonia solution, 90:10: 0.25)Colorless gum, produced the title compound (87 mg, 40%). MS: 5'70.3 (M + H) + . [00175] The examples set out below were prepared from according to example 2, replacing the tert-butyl-4 - (3-fluoro -4-sulfamoyl benzoyl) piperazine 1-carboxylate by the appropriate carbamate and 3 - [2 - [(5 methyltetrazol -2 -11) methyl] -4 - (trifluoromethyl) phenyl] propanoic acid appropriate carboxylic acid. Petition 870190091123, of 9/13/2019, p. 79/164 73/132 Ex. Systematic Name Carbamate / Carboxylic acid MS, m / e 2.01 3 -fluoro -4 - [[4 - [3 - [2- [(5-methyltetrazole -2il) methyl] -4(trifluoromethyl) phenyl] -propanoyl] piperazin -1 yl] methyl] benzene sulfonylamideF f X> = N-N/ __ / __ / '0fr— N N — fO f tert-butyl 4 - (2fluoro -4sulfamoyl benzoyl) piperazine -1carboxylate (intermediate 5) /3 - [2 - [(5 methyltetrazol -2 yl) methyl] -4 acid(trifluoromethyl) phenyl] propanoic(CAS -RN 1646783 -83 -6) 570.4 (M + H) + 2.02 4 - [[4 - [2-cyclopropyl -6 - (oxan -4 ylmethoxy) pyridine -4 carbonyl] piperazin -1 yl] methyl] -3 fluorobenzene sulfonylamide y — WO x , NH 2 P- 7 > NK f = ~ n / / n-j7 O —f tert-butyl-4 - (2 fluoro -4sulfamoyl benzoyl) piperazine -1carboxylate (intermediate 5) /2 -cyclopropyl acid -6 - (oxan -4ylmethoxy) pyridine -4-carboxylic (CAS -RN 181) 776 -23 -8) 533.3 (M + H) + Example 3 Petition 870190091123, of 9/13/2019, p. 80/164 74/132 -Fluoro -4 - [4 - [3 - [2 - [(5-methyltetrazol -2 yl) methyl] -4 - (trifluoromethyl) phenyl] propanoyl] piperazine —1 -carbonyl] benzene sulfonylamide [00176] The title compound was obtained as a by-product in the preparation of example 2 (48 mg, 21%). White solid, MS: 584.3 (M + H Example 4 3,5 -Difluoro -4 - [4 - [3 - [2 - [(5-methyltetrazole -2 -11) methyl] -4 - (trifluoromethyl) phenyl] propanoyl] piperazine -1-carbonyl] benzene sulfonylamide [00177 j To a solution of 3 - [2 - [(5 methyltetrazol -2 -11) methyl] -4 - (trifluoromethyl) phenyl] -1-piperazin -1 -ilpropan -1 -one (intermediate 2; 40 mg, 100 umol) in N, N-dimethylformamide (3 mL) was added N -methylmorpholine (40.6 mg, 402 pmol), 2,6-difluoro -4-sulfamoylbenzoic acid (intermediate 3; 26.2 mg, 110 pmol) and 0- (7 -azabenzotriazole -1 -11) hexafluoro phosphate Petition 870190091123, of 9/13/2019, p. 81/164 75/132 Ν, Ν, Ν ', Ν' -tetramethyluronium (42 mg, 11) pmol), then after 18 h at room temperature a. The reaction mixture was divided between saturated aqueous ammonium chloride solution and ethyl acetate. The organic layer was washed with saline, dried over magnesium sulfate, filtered and evaporated. Chromatography (silica gel, gradient from dichloromethane to dichloromethane / methanol / 25% aqueous ammonia solution, 90: 10: 0.25) gave the title compound (51 mg, 84%). White solid, MS: 602.3 (M + H) + . [00178] The examples set out below were prepared according to example 4, by substituting 2,6-difluoro -4-sulfamoyl benzoic acid (intermediate 3) with the appropriate carboxylic acid. Ex. Systematic name carboxylic acid MS, m / e 4.01 3-fluoro -4 - [4 - [3 - [2 - [(5-methyltetrazol -2 yl) methyl] -4 (trifluoromethyl) phenyl] propanoyl] piperazine -1 -carbonyl] benzene sulfonylamide F p L x ii cn ' 2 OR 1 > o ΜΪ ^ 0 0 '-' 0 2-Fluoro -4 sulfamoyl benzoic acid (CAS -RN 714968 -420) 584.3 (M + H) + Petition 870190091123, of 9/13/2019, p. 82/164 76/132 Example 5 - [[1 - [2 -Cyclopropyl -6 - (oxan -4-ylmethoxy) pyridine -4-carbonyl] piperidin -4 -11] methyl] -4 fluorobenzene sulfonylamide [00179] To a solution of 4-fluoro-3 - (piperidin -4-ylmethyl) benzene sulfonylamide hydrochloride (intermediate 7; 5'1.6 mg, 159 | .im.oi; in N, N dimethylformamide (3 mL) N -metiimorpholin (72.9 mg, 721 μπιοί), 2-cyclopropyl -6 - {oxan -4 ylmethoxy) pyridine -4-carboxylic acid (CAS -RN 181 · 776 -23 -8; 4) mg, 144 | imoi ; and O - hexafluoro phosphate (7 Petition 870190091123, of 9/13/2019, p. 83/164 77/132 azabenzotriazole -1 -11) -Ν, Ν, Ν ', N' -tetramethyluronium (60.3 mg, 159 umol), then after 18 h at room temperature the reaction mixture was partitioned between saturated aqueous solution ammonium chloride and ethyl acetate. The organic layer was washed with saline, dried over magnesium sulfate, filtered and evaporated. Chromatography (silica gel, gradient from dichloromethane to dichloromethane / methanol / 25% aqueous ammonia solution, 90: 10: 0.25) gave the title compound (75 mg, 98%). White solid, MS: 532.3 (M + H) + . [00180] The examples set out below were prepared according to example 5 by replacing 4-fluoro-3 - (piperidin -4-ylmethyl) benzene sulfonylamide hydrochloride with the appropriate amine and 2-cyclopropyl acid -6 - ( oxan-4-ylmethoxy) pyridine-4 carboxylic acid with the appropriate carboxylic acid. Ex. Systematic name Amine / acidcarboxylic MS, m / e Petition 870190091123, of 9/13/2019, p. 84/164 78/132 5.01 3-fluoro -4 - [1 - [3 - [2 [(5-methyltetrazole -2 11) met11] -4 (trifluoromethyl) phenyl] propanoyl] piperidin -4 yl] sulfanyl benzene sulfonylamide 5 / nAn nh 2 2 = / N - N > 0 V / F-Ζλ yj N) —SO ' 3-fluoro-hydrochloride -4piperidin -4 ylsulfanyl benzene sulfonylamide (intermediate 8) / 3 - [2 - [(5-methyltetrazol -2-yl) methyl] -4 (trifluoromethyl) phenyl] propanoic (CAS -RN 1646783 83 -6) 587.3 (M + H) + 5.02 3-fluoro -4 - [4 - [3 - [2 [(5-methyltetrazol -2-yl) methyl] -4 (trifluoromethyl) phenyl] - propanoyl] piperazin -1 yl] benzene sulfonylamide V F N ^ N F Cr 7 f __ __ O Ά-8-ΝΗ 2 o O 3-fluoro -4 piperazin -1 ylbenzene sulfonylamide (CAS -RN 847971 -84 -)) / 3 - [2 [(5-methyltetrazol -2 -yl) methyl] -4 (trifluoromethyl) phenyl] - propanoic acid (CAS - RN 1646783 83 -6) 556.2 (M + H) + Petition 870190091123, of 9/13/2019, p. 85/164 79/132 5.03 4 - [[1 - [2 -cyclopropyl -6 - (oxan -4-ylmethoxy)pyridine -4-carbonyl] piperidin -4 -11] methyl] benzene sulfonylamide/ - °S- 'O.í x ° 4 (Piperidin -4-ylmethyl) benzene sulfonylamide hydrochloride (CAS -RN 333986 -77 -9) / acid 2cyclopropyl -6 (oxan -4ylmethoxy) pyridine -4-carboxylic(CAS -RN 181) 77 6 -23 -8) 514.4 (M + H) + 5.04 4 - [[1 - [3 - [2 - [(5 - methyltetrazol -2 -ii) methyl] -4 (trifluoromethyl) phenyl] propanoyl] piperidin -4 yl] methyl] benzene sulfonylamide 3/1 «o x - NH 'U = _ y N ' N 7o y- n 2— 'o' 4 (piperidin -4 ylmethyl) benzene sulfonylamide hydrochloride (CAS -RN 333986 -77 -9) / 3 - [2 - [(5-methyltetrazol -2 -11) methyl] -4 (trifluoromethyl) phenyl] - propanoic acid ( CAS -RN 1646783 83 -6) 551.3 (M + H) + Petition 870190091123, of 9/13/2019, p. 86/164 80/132 5.05 4 - [[1 - [3 - [2 - [(5 - methyltetrazol -2 ii) methyl] -4 (trifluoromethyl) phenyl] propanoyl] pyrrolidin -2 ii] methoxy] benzene sulfonylamide «A z NH 2 z A * N —No 4 (pyrrolidin -2 ylmethoxy) benzene sulfonylamide hydrochloride (CAS -RN 18) 3591 -) 6 -1) / acid 3 - [2 - [(5 methyltetrazole -2 ii) methyl] -4(trifluoromethyl) fe nil] - propanoic(CAS -RN 1646783 83 -6) 553.2 (M + H) + 5.06 4 - [[1 - [3 - [2 - [(5 - methyltetrazole -2 ii) methyl] -4 (trifluoromethyl) phenyl] propanoyl] pyrrolidin -3 ii] methoxy] benzene sulfonylamide O yN | AZ vQ fV ju ° ' N 2 y. F n ^ n F 1 4 (pyrrolidin-3-ylmethoxy) benzene sulfonylamide (CAS -RN 18) 359) -92 2) / 3 - [2 [(5-methyltetrazol -2 -ii) methyl] -4 (trifluoromethyl) phenyl] - propanoic acid (CAS -RN 1646783 83 -6) 553.2 (M + H) + Petition 870190091123, of 9/13/2019, p. 87/164 81/132 5.07 4 - [1 - [3 - [2 - [(5 - methyltetrazol -2 yl) methyl] -4 (trifluoromethyl) phenyl] propanoyl] -piperidin -4 yl] benzene sulfonylamide F f LV F n ^ n N N - <j—. o A— N S-NH, <S _f ^ Tg 4 -piperidin -4 ylbenzene sulfonylamide (CAS -RN 119737 -31 -4) / 3 - [2 - [(5-methylthetrazol -2 -yl) methyl] -4 (trifluoromethyl) phenyl] - propanoic acid (CAS -RN 1646783 83 -6) 537.2 (M + H) + 5.)8 4 - [4 - [3 - [2 - [(5 - methyltetrazol -2 yl) methyl] -4 (trifluoromethyl) phenyl] - propanoyl] piperazin -1 yl] benzene sulfonylamide N ^ J) 1 F 2 = _ / ' n ' O f == 11 —NN — 4 ff — n - o V — o 4 -piperazin -1 ylbenzene sulfonylamide (CAS -RN 17) 856 -87 8) / 3 - [2 [(5-methylthetrazol -2-yl) methyl] -4 (trifluoromethyl) phenyl] - propanoic acid (CAS -RN 1646783 83 -6) 538.2 (M + H) + Petition 870190091123, of 9/13/2019, p. 88/164 82/132 5.09 4 -fluoro -3 - [[1 - [3 - [2 - [(5-methyltetrazol -2 yl), methyl] -4 (trifluoromethyl), phenyl] propanoyl], piperidin -4 yl], methyl], benzene sulfonylamide 4 - 569.3 fluoro -3 - (M + H) + (piperidin -4 ylmethyl) hydrochloride, benzene sulfonylamide (intermediate 7) / 3 - [2 - [(5-methylthetrazol -2-yl) methyl] - 4 (trifluoromethyl) fe nil] - propanoic (CAS -RN 1646783 83 -6) Example 6 2,3 -Difluoro -4 - [1 - [3 - [2 - [(5-methyltetrazole -2 -yl) methyl] -4 - (trifluoromethyl) phenyl] propanoyl] piperidin -4 -yl] sulfanyl benzene sulfonylamide [00181] To a solution of tert-butyl 4 - (2,3 difluoro -4-sulfamoyl phenyl) sulfanylpiperidine -1 carboxylate (intermediate 9.2; 31 mg, 6) gmol) in dichloromethane (3 ml) was added trifluoroacetic acid (137 mg, 1.2 mmol) at room temperature. A. The reaction mixture was stirred at 40 ° C for 8) min., Petition 870190091123, of 9/13/2019, p. 89/164 83/132 then the mixture was evaporated directly and the residue was taken up in N, N-dimethylformamide (3 mh) and N methylmorpholine (61.9 mg, 600 pmol)> acid 3 - [2 - [(5 methyltetrazole -2 - il) methyl] -4 - (trifluoromethyl) phenyl] propanio (CAS -RN 1646783 -83 -6; 20.7 mg, 65.9 pmol) and O hexafluoro-phosphate - (7 -azabenzotriazole -1 -yl) Ν, Ν , Ν ', Ν' -tetramethyluronium (25.3 mg, 65.9 pmol) were added. After 18 h at room temperature, the reaction mixture was partitioned between saturated aqueous ammonium chloride solution and ethyl acetate. The organic layer was washed with saline, dried over magnesium sulfate, filtered and evaporated. Chromatography (silica gel, using flash chromatography on silica, eluting with a gradient of dichloromethane to dichloromethane / methanol / 25% aqueous ammonia solution 90:10: 0.25) produced the title compound (27 mg, 74% ). White solid, MS: 605.2 (M + H) + . [00182] The following examples were prepared according to example 6, substituting the tert-butyl 4 - (2,3-difluoro -4-sulfamoyl phenyl) sulfanylpiperidine -1-carboxylate (intermediate 9.20 by means of the appropriate carbamate and acid 3 - [2 - [(5 methyltetrazol -2-yl) methyl] -4 “(trifluoromethyl) phenyl] propanoic (CAS -RN 1646783 -83 -6) by means of the appropriate carboxylic acid. Ex. Systematic name Carbamate / carboxylic acid MS, m / e Petition 870190091123, of 9/13/2019, p. 90/164 84/132 6.01 2,3 -difluoro -4 - [1 - [3 - [2 - [(5 -methyltetrazol -2 -11) methyl] -4 (trifluoromethyl) phenyl] propanoyl] -piperidin -4 -yl] sulfinyl benzene sulfonylamide FF V n ^ n mh > = NN F f-H '° Z- s <ο X — fo tert-butyl-4 - (2,3 difluoro -4sulfamoyl phenyl) sulfinylpiperidine -1carboxylate (intermediate 1).2) / acid 3 - [2 [((5-methyltetrazole 2 -11) methyl] -4(trifluoromethyl) phenyl] - propanoic(CAS -RN 1646783 -83 -6) 621.2 (M + H) + 6.02 2,3 -difluoro -4 - [1 - [3 - [2 - [(5-methyl-tetrazol -2 -11) methyl] -4 (trifluoromethyl) phenyl] propanoyl] piperidin -4 -yl] sulfonylbenzene sulfonylamide F p LV F n ^ n f V / FF X__ ___ o X— / o / X 11 fíA 11 Y — N _ s — ff S-NH 2 • Γ / II / li * O '-' OO tert-butyl-4 - (2,3 difluoro -4sulfamoyl phenyl)sulfonyl-piperidine -1-carboxylate(intermediate 15) / acid 3 - [2 - [(5 methyltetrazole -2 11) methyl] -4(trifluoromethyl) phenyl] - propanoic(CAS -RN 1646783 -83 -6) 637.2 (M + H) + Petition 870190091123, of 9/13/2019, p. 91/164 85/132 6.03 2,3 -difluoro -4 - [2 - [1 - [3 - [2 - [(5 methyltetrazol -2 yl) methyl] -4 (trifluoromethyl) phenyl] propanoyl] -piperidin -4 -yl] ethylsulfonyl] benzene sulfonylamide V F ιΛν) = N N '--- K / --- k FF —N . O - (O / 11 // Vi 11 O> —f S— < Z S-NH, II / II z oo tert-butyl-4 - [2 (2,3-difluoro -4 sulfamoyl phenyl)sulfonylethyl] piperidine -1carboxylate(intermediate 15.3) / acid 2cyclopropyl -6(oxan -4ylmethoxy) pyridine-4-carboxylic (CAS RN 181) 776-23-8) 665, 2 (M + H) + 6.04 2 - [1 - [3 - [2 - [(5 - methyltetrazol -2-yl) methyl] -4 (trifluoromethyl) phenyl] propanoyl] -piperidin -4 -yl] sulfanyl -1,3 thiazole -5 sulfonamide F p LV N / 1 ) 1 fA o ^> r NH2 v_V n yr ° NS O ' tert-butyl-4 - [(5 sulfamoyl -1,3thiazole -2il) sulfanyl] piperidine -1carboxylate (intermediate 9.5) / acid 3 - [2 - [(5 methyltetrazol -2 yl) methyl] -4(trifluoromethyl) pheni1] propanoic (CAS RN 1646783 -83 -6) 576, 1 (M + H) + Petition 870190091123, of 9/13/2019, p. 92/164 86/132 6.05 2 - [1 - [3 - [2 - [(5 - methyltetrazole -2 11) methyl] -4 (trifluoromethyl) phenyl] propanoyl] piperidin -4-yl] sulfonyl -1,3 thiazole -5 sulfonamide F p L F F θ4Α, o'nh 2 tert-butyl-4 - [(5 sulfamoyl -1,3thiazole -211) sulfonyl] piperidine -1carboxylate (intermediate 15.2) / acid 3 - [2 - [(5 methyltetrazol -2 yl) methyl] -4(trifluoromethyl) phenyl] propanoic(CAS -RN 1646783 -83 -6) 608, 1 (M + H) + 6.06 2 - [2 - [1 - [3 - [2 - [(5 methyltetrazol -2-yl) methyl] -4 (trifluoromethyl) phenyl] propanoyl] -piperidin -4 -yl] ethylsulfinyl] -1,3 thiazole -5 sulfonamide F v FF n ' N O 2 tert-butyl-4 - [2[(5 -sulfamoyl -1.3-thiazole -211) sulfinyl] ethyl]piperidine -1carboxylate(intermediate 1).5) / acid 2cyclopropyl -6(oxan -4ilmethoxy) pyridine -4-carboxylic (CASRN 181) 776-23-8) 620.2 (M + H) + Petition 870190091123, of 9/13/2019, p. 93/164 87/132 6.07 3 - [2 - [(5 methyltetrazole -2 11) methyl] -4 (trifluoromethyl) phenyl] propanoic acid (CAS -RN 1646783 -83 6) N ^ N fV n U ' F y_ o —v / —v S— çV-S-NH 2 O '—f 6.08 3-fluoro -4 - [[1 - [3 [2 - [(5-methyltetrazol 2 -ii) methyl] -4 (trifluoromethyl) phenyl] propanoyl] -piperidin -4 -ii] methylsulfinyl] - benzene sulfonylamide F p L γΛ X tt F ) = N N Vf Ο V o -s_ZA_g_NH 2 ^ -N) —f O O '-' tert-butyl-4 - [(2 fluoro -4-sulfamoyl phenyl) sulfanylmethyl] -piperidine -1carboxylate (intermediate 9) /3 - [2 - [(5 methyltetrazole -2 11) methyl] -4 acid(trifluoromethyl) phenyl] propanoic(CAS -RN 1646783 -83 -6) 601.3 (M + H) + tert-butyl-4 - [(2 fluoro -4-sulfamoyl phenyl) sulfinylmethyl] piperidine -1carboxylate (intermediate 1).1) / acid 3 - [2 [(5-methylthetrazol 2 -11) methyl] -4(trifluoromethyl) phenyl] propanoic(CAS -RN 1646783 -83 -6) 617.3 (M + H) + Petition 870190091123, of 9/13/2019, p. 94/164 88/132 6.09 3-fluoro -4 - [[1 - [3 [2 - [(5-methyltetrazol 2 -11) methyl] -4 (trifluoromethyl) phenyl] propanoyl] -piperidin -4 -11] methylsulfonyl] - benzene sulfonylamide F v A F -OW 0 ο X — f tert-butyl-4 - [(2 fluoro -4-sulfamoyl phenyl) sulfonylmethyl] -piperidine -1carboxylate (intermediate 11.1) / acid 2cyclopropyl -6(oxan -4ylmethoxy) pyridine-4-carboxylic acid (CAS RN 181) 776-23-8) 633, (M + H) + 6.10 3-fluoro -4 - [1 - [3 - [2 - [(5-methyltetrazole -2 11) methyl] -4 (trifluoromethyl) phenyl] propanoyl] -azetidin -3 11] sulfanyl benzene sulfonylamide O y — N Z —S F PN Ν · ^ Ν NH 2 terc-buti! 3 - (2fluoro -4 -sulfamoyl phenyl)sulfanilazetidine -1-carboxylate(intermediate 9.3)/ acid 3 - [2 - [(5 -methyltetrazole -211) methyl] -4(trifluoromethyl) pheni1] propanoic (CAS -RN 1646783 -83 -6) 559, 2 (M + H) + Petition 870190091123, of 9/13/2019, p. 95/164 89/132 6.11 3-fluoro -4 - [1 - [3 - [2 - [(5-methylthetrazol -2 11) methyl] -4 (trifluoromethyl) phenyl] propanoyl] -azetidin -3 11] sulfinyl benzene sulfonylamide fC F ^ o F < O ° ^ h 2 F 1 tert-butyl3 - (2 fluoro -4-sulfamoyl phenyl) sulfinylazetidine -1-carboxylate (intermediate 1).3) / acid 3 - [2 [((5-methyl-tetrazole 2 -11) methyl] -4(trifluoromethyl) pheni 1] propanoic (CAS RN 1646783 -83 -6) 573.2(M-H) ~ 6.12 3-fluoro -4 - [1 - [3 - [2 - [(5-methylthetrazol -2 11) methyl] -4 (trifluoromethyl) phenyl] propanoyl] -azetidin -3 11] sulfonylbenzene sulfonylamide OO 0 h N 0 ^ - O-ír NH * / - 'O) -' ° Txp _N F 1 tert-butyl3 - (2 fluoro -4-sulfamoyl phenyl) sulfonylazetidine -1-carboxylate (intermediate 15.1) / acid 2cyclopropyl -6(oxan -4ylmethoxy) pyridine-4-carboxylic acid (CAS RN 181) 776-23-8) 589, 2(M-H) ~ Petition 870190091123, of 9/13/2019, p. 96/164 90/132 6.13 3-fluoro -4 - [1 - [3 - [2 - [(5-methyltetrazol -2 yl) methyl] -4 (trifluoromethyl) phenyl] propanoyl] -piperidin -4 -yl] sulfinyl benzene sulfonylamide FFX M / N MU fA 'o x / nh 2> = NN * S X / / __ / O F - / = O' —f O tert-butyl-4 - (2 fluoro -4-sulfamoyl phenyl) sulfinylpiperidine -1-carboxylate (intermediate 10)/ 3 - [2 - [(5 methyltetrazol -2 yl) methyl] -4 acid(trifluoromethyl) phenyl] propanoic(CAS -RN 1646783 -83 -6) 603.2 (M + H) + 6.14 3-fluoro -4 - [1 - [3 - [2 - [(5-methyltetrazol -2 yl) methyl] -4 (trifluoromethyl) phenyl] propanoyl] -piperidin -4 yl] sulfonylbenzene sulfonylamide F f L f 5 = tf -. .___ o _ o i 11 11 λ — N) - S — V S-NH, '> / II / II 2 O' —fo O tert-butyl-4 - (2 fluoro -4-sulfamoyl phenyl) sulfonylpiperidine -1-carboxylate (intermediate 11) / acid 3 - [2 - [(5 methyltetrazole -2 11) methyl] -4(trifluoromethyl) pheni 1] propanoic (CAS RN 1646783 -83 -6) 619, 2 (M + H) + Petition 870190091123, of 9/13/2019, p. 97/164 91/132 6.15 3-fluoro -4 - [2 - [1 - [3 - [2 - [(5-methyltetrazol -2 -11) methyl] -4 (trifluoromethyl) phenyl] propanoyl] -piperidin -4 -11] ethylsulfanyl] benzene sulfonylamide -N II N xz N F N F ύγο-γ ... tert-butyl-4 - [2 - (2-fluoro -4sulfamoyl phenyl)sulfanylethyl] piperidine -1carboxylate(intermediate 9.4)/ acid 2cyclopropyl -6(oxan -4ylmethoxy) pyridine-4-carboxylic (CAS RN 181) 776-23-8) 613.3(M-H) ~ 6.16 3-fluoro -4 - [2 - [1 - [3 - [2 - [(5-methylthetrazol -2 -11) methyl] -4 (trifluoromethyl) phenyl] propanoyl] -piperidin -4 -11] ethylsulfinyl] benzene sulfonylamide -N N í χΝ c FN OF S o ' NH 2 tert-butyl-4 - [2 - (2-fluoro -4sulfamoyl phenyl) sulfinylethyl] piperidine -1carboxylate (intermediate 1).4) / 3 - [2 [((5-methyltetrazole 2 -11) methyl] -4 acid(trifluoromethyl) phenyl] propanoic(CAS -RN 1646783 -83 -6) 631.3 (M + H) + Petition 870190091123, of 9/13/2019, p. 98/164 92/132 6.1 3 -fluoro -4 - [2 - [1 - [3 tert-butyl-4 - [2 - (2 647.2 7 - [2 - [(5-methyltetrazol -2-yl) methyl] -4 (trifluoromethyl) phenyl] propanoyl] -piperidin -4 -yl] ethylsulfonyl] benzene sulfonylamide F / n- ^ n F / = N N w -7 '___X 7 --- x F 0 — NY— θ í oo ^ = 7 o -fluoro -4sulfamoyl phenyl)sulfonylethyl] piperidine -1carboxylate (intermediate 16) / acid 3 - [2 - [(5 methyltetrazol -2 yl) methyl] -4(trifluoromethyl) phenyl] propanoic(CAS -RN 1646783 -83 -6) (M + H) + 6.1 3-fluoro -4 - [2 - [1 - [6 tert-butyl-4 - [2 - (2 622.1 8 - (2,2,2-trifluoroethoxy) -5 - (trifluoromethyl) pyridine -3 -carbonyl] piperidin -4 —yl] ethylsulfonyl] benzene sulfonylamide w „ _M _ O _ O ztf ii n ii O '- - 7 1— S— ('VS-NH, II / II 2 o ^ = 7 o -fluoro -4sulfamoyl phenyl) sulfonylethyl] piperidine -1carboxylate (intermediate 16) / acid 6 - (2,2,2trifluoroethoxy) -5 (trifluoromethyl) pyridine -3-carboxylic acid (CAS -RN 15885) 7 32 -7) (M + H) + Petition 870190091123, of 9/13/2019, p. 99/164 93/132 6.19 3-fluoro -4 - [4 - [3 - [2 - [(5-methyltetrazol -2 yl) methyl] -4 (trifluoromethyl) phenyl] propanoyl] -piperazin -1 -yl] s ulfonylbenzene sulfonylamide FFX c'A ·· FN ' N --- V> --- <° <O ''11 / ¾ 11 Λ — N NS — V V- S-NH, •'! / II / II í O '-' o ^ = 7 o tert-butyl-4 - (2 fluoro -4-sulfamoyl phenyl)sulfonylpiperazine1-carboxylate(intermediate 4.1)/ 3 - [2 - [(5 methyltetrazol -2 yl) methyl] -4 acid(trifluoromethyl) phenyl] propanoic(CAS -RN 1646783 -83-6) 618.4(M-H) ~ 6.20 4 - [[1 - [2 -cyclopropyl -6 - (oxan -4-ylmethoxy) pyridine -4-carbonyl] piperidin -4 -yl] methylsulfanyl] -3 fluorobenzene sulfonylamide y— O o— /. , N "/ F 'y. i — s-nh 2 - / = z θ O '-' tert-butyl-4 - [(2 fluoro -4-sulfamoyl phenyl)sulfanylmethyl] -piperidine -1carboxylate (intermediate 9) /acid 2cyclopropyl -6(oxan -4ylmethoxy) pyridine-4-carboxylic (CAS RN 181) 776-23-8) 564.3 (M + H) + Petition 870190091123, of 9/13/2019, p. 100/164 94/132 6.21 4 - [[1 - [2 -cyclopropyl -6 - (oxan -4-ylmethoxy) pyridine -4-carbonyl] piperidin -4 -ii] methylsulfinyl] -3 fluorobenzene sulfonylamide / - ° o — f | S - (/ oko s — s-nh 2 Ο '—f tert-butyl-4 - [(2 fluoro -4-sulfamoyl phenyl) sulfinylmethyl] -piperidine -1carboxylate (intermediate 1).1) / acid 2cyclopropyl -6(oxan -4ylmethoxy) pyridine-4-carboxylic acid (CAS RN 181) 776-23-8) 580.3 (M + H) + 6.22 4 - [[1 - [2 -cyclopropyl -6 - (oxan -4-ylmethoxy) pyridine -4-carbonyl] piperidin -4 -ii] methylsulfonyl] -3 fluorobenzene sulfonylamide o F .. S- NH 2 1 1 ° J 1 0 0 tert-butyl-4 - [(2 fluoro -4-sulfamoyl phenyl) sulfonylmethyl] -piperidine -1carboxylate (intermediate 11.1) / acid 2cyclopropyl -6(oxan -4ylmethoxy) pyridine-4-carboxylic acid (CAS RN 181) 776-23-8) 596.3 (M + H) + Petition 870190091123, of 9/13/2019, p. 101/164 95/132 6.23 4 - [1 - (6-cyclobutyloxy -5-cyclopropylpyridine -3-carbonyl) piperidin -4 -11] sulfonyl -3 fluorobenzene sulfonylamide O _ ο o 11 β 11 N) —S — f V- S-NH 2 ff / II / ii * O> - 'O ^ = 7 O tert-butyl-4 - (2 fluoro -4-sulfamoyl phenyl)sulfoniipiperIdine1-carboxylate(intermediate 11) / acid 6cyclobutyloxy -5cyclopropylpyridine -3-carboxylic(intermediate 17) 536, 0(M-H) ~ 6.24 4 - [1 - [2-cyclopropyl - 6 - (oxan -4 ylmethoxy) pyridine -4 carbonyl] azetidin -3 - 11] sulfanyl -3 fluorobenzene sulfonylamide A ° ° X f Xa ' n ! already terc-butyl3 - (2fluoro -4 -sulfamoyl phenyl)sulfanylazetidine -1-carboxylate(intermediate 9.3)/ acid 2cyclopropyl -6(oxan -4ilmethoxy) pyridine -4-carboxylic (CASRN 181) 776-23-8 520.5(M-H) ~ Petition 870190091123, of 9/13/2019, p. 102/164 96/132 6.25 4 - [1 - [2-cyclopropyl 6 - (oxan -4-ylmethoxy) pyridine -4-carbonyl] azetidin -3 -ii] sulfinyl -3 fluorobenzene sulfonylamide Λ Γ— ° JFV NH 2 ° N x ° II 0 tert-butyl3 - (2 fluoro -4-sulfamoyl phenyl)sulfinylazetidine -1-carboxylate(intermediate 1).3) / acid 2cyclopropyl -6(oxan-4-ylmethoxy)pyridine -4carboxylic (CAS -RN 181) 776 -23 -8) 536, 2(M-H) ~ 6.26 4 - [1 - [2 -cyclopropyl - 6 - (oxan -4 ylmethoxy) pyridine -4 carbonyl] azetidin -3 - 11] sulfonyl -3 fluorobenzene sulfonylamide / - OO— 'AF = / o o Vn Y s— f x > —s-nh 2 ooo tert-butyl3 - (2 fluoro -4-sulfamoyl phenyl) sulfonylazetidine -1-carboxylate (intermediate 15.1) / acid 2cyclopropyl -6(oxan -4ylmethoxy) pyridine-4-carboxylic acid (CAS RN 181) 776-23-8) 553.3(M-H) ~ Petition 870190091123, of 9/13/2019, p. 103/164 97/132 6.27 4 - [1 - [2-cyclopropyl 6 - (oxan -4-ylmethoxy) pyridine -4-carbonyl] piperidin -4 -yl] sulfonyl -2,3 difluorobenzene sulfonylamide y — O o— / NZ |> -VΛ FF = z ____ O _ (o 'X 11 11 λ — N) - S— (f S — NH 2 Jf / II / II * O' —f 0 X = / 0 tert-butyl-4 - (2,3 difluoro -4sulfamoyl phenyl)sulfonylpiperidine1-carboxylate(intermediate 15) / 2-cyclopropyl acid -6 - (oxan -4ylmethoxy) pyridine-4-carboxylic acid (CAS RN 181) 776-23-8) 600.2 (M + H) + 6.28 4 - [1 - [2-cyclopropyl 6 - (oxan -4-ylmethoxy) pyridine -4-carbonyl] piperidin -4 -yl] sulfonyl -3 fluorobenzene sulfonylamide / - o O — f> - // Λ F λ-Ν ) - S — V y — S — NH 2 Λ / __ / 11 O '—fo' - 'O tert-butyl-4 - (2 fluoro -4-sulfamoyl phenyl)sulfonylpiperidine 1-carboxylate(intermediate 11) / 2-cyclopropyl acid -6 - (oxan -4ylmethoxy) pyridine 4-carboxylic (CAS -RN 181) 776 -23 -8) 582.2 (M + H) + Petition 870190091123, of 9/13/2019, p. 104/164 98/132 6.29 4 - [1 - [3 - [4-chloro -2 - [(5-methyltetrazol -2 yl) methyl] phenyl] propanoyl] -piperidin -4 -11] sulfonyl -3 fluorobenzene sulfonylamide Cl V = NN Cf F h - H í V $ - NH 2 o '-' oo tert-butyl-4 - (2 fluoro -4-sulfamoyl phenyl)sulfonylpiperidine1-carboxylate (intermediate 11) / acid 3 - [4-chlorine -2 - [(5 methyltetrazol -2 yl) methyl] phenyl] propanoic(intermediate 13.1) 585.2 (M + H) + 6.30 4 - [1 - [3 - [4-cyano -2 - [(5-methyltetrazol -2 yl) methyl] phenyl] propanoyl] piperidine n -4 -yl] sulfonyl -3 fluorobenzene sulfonylamide NX XO Cc Y — N Ys— u s-nh 2 V / li __ / II * O '-' O '-' O tert-butyl-4 - (2 fluoro -4-sulfamoyl phenyl)sulfonylpiperidine1-carboxylate (intermediate 11) / acid 3 - [4-cyano -2 - [(5 methyltetrazol -2 yl) methyl] phenyl] propanoic(intermediate 13) 576, (M + H) + Petition 870190091123, of 9/13/2019, p. 105/164 99/132 6.31 4 - [2 - [1 - [2cyclopropyl -6 - (oxan -4-ylmethoxy) pyridine -4 carbonyl] piperidin -4 11] ethylsulfanyl] -3fluorobenzene sulfonylamide9 Λ ° χ .. tert-butyl-4 - [2 - (2-fluoro -4sulfamoyl phenyl) sulfanylethyl] piperidine -1carboxylate(intermediate 9.4) / acid 2cyclopropyl -6(oxan-4-ylmethoxy)pyridine -4carboxylic (CAS -RN 181) 776 -23 -8) 576, 4(M-H) ~ 6.32 4 - [2 - [1 - [2 cyclopropyl -6 - (oxan -4-ylmethoxy) pyridine -4 carbonyl] piperidin -4 11] ethylsulfinyl] -3 fluorobenzene sulfonylamide 9 cr o ° O ' NH 2 tert-butyl-4 - [2 - (2-fluoro -4sulfamoyl phenyl)sulfinylethyl] piperidine -1carboxylate (intermediate 1).4) / acid 2cyclopropyl -6(oxan-4-ylmethoxy)pyridine -4carboxylic (CAS -RN 181) 776 -23 -8) 594.2 (M + H) + Petition 870190091123, of 9/13/2019, p. 106/164 100/132 6.33 4 - [2 - [1 - [2 cyclopropyl -6 - (oxan -4-ylmethoxy) pyridine -4 carbonyl] piperidin -4 yl] ethylsulfonyl] -3 fluorobenzene sulfonylamide y— OO— '[> / H = / J --ç FN . O . O // ' / II / 1 O. II O>-' S— ('V- S-NH, II / II' O ^ = 7 O tert-butyl-4 - [2 - (2-fluoro -4sulfamoylphenyl) sulfonylethyl] piperidine -1carboxylate (intermediate 16) / 2-cyclopropyl acid -6 - (oxan -4ylmethoxy) pyridine-4-carboxylic (CAS RN 181) 776-23-8) 610.3 (M + H) + 6.34 4 - [2 - [1 - [5 - cyclopropyl-6- (cyclopropylmethoxy) pyridine -3-carbonyl] -piperidin - 4-yl] ethylsulphonyl] -3 - fluorobenzene sulfonylamide 0% / 9 ra 'yN) - <q vo' / 11 fí II O '-' s — S — nh 2 II ___ / II 2 Ο λ 'O tert-butyl-4 - [2 - (2-fluoro -4sulfamoylphenyl) sulfonylethyl] -piperidine -1carboxylate (intermediate 16) /5-cyclopropyl-6 acid (cyclopropylmethoxy)pyridine -3carboxylic (CAS -RN 1427) 64 -97 -8) 566.2 (M + H) + Petition 870190091123, of 9/13/2019, p. 107/164 101/132 6.3 4 - [4 - [2 -cyclopropyl - tert-butyl-4 - (2 583.3 5 6 - (oxan -4 ylmethoxy) pyridine -4 carbonyl] piperazin -1 - 11] sulfonyl -3 fluorobenzene sulfonylamide y — O o — f rs __ (/ F _ / __ o _ o> -N NS-Ç Vs -NH 2 fluoro -4-sulfamoyl phenyl) sulfonylpipera zine -1-carboxylate (intermediate 4.1) / acid 2cyclopropyl -6(oxan -4ylmethoxy) pyridine-4-carboxylic (CAS RN 181) 776-23-8) (M + H) + 6.3 4 - [4 - [3 - [2 - [(5 - tert-butyl-4 - (4 602.3 6 methyltetrazole -2 11) methyl] -4 (trifluoromethyl) phenyl] - propanoyl] piperazin -1 -11] sulfonylbenzene sulfonylamide F p L) = N N O '-' o '-' o sulfamoyl phenyl)sulfonylpiperazine 1-carboxylate(intermediate 4) /3 - [2 - [(5 methyltetrazole -2 11) methyl] -4 acid(trifluoromethyl) pheni 1] propanoic (CAS RN 1646783 -83 -6) (M + H) + Petition 870190091123, of 9/13/2019, p. 108/164 102/132 6.37 5 - [1 - [3 - [2 - [(5 - methyltetrazol -2 yl) methyl] -4 (trifluoromethyl) phenyl] propanoyl] -piperidin -4 -11] suitanylthiophene -2 sulfonamide F p 1 V N I 1 ) 1 F 5 = ; U O -7 Z ^ rV NH2 N) —s O ' 6.38 5 - [2 - [1 - [3 - [2 - [(5 methyltetrazol -2 yl) methyl] -4 (trifluoromethyl) phenyl] - propanoyl] piperidin -4 -11] ethylsulfonyl] thiophene -2 sulfonamide -H _ - o F n 'n' n F 7 1 s 0 o tert-butyl-4 - [(5 sulfamoyl -1,3thiazole -2 -11)sulfanyl] piperidine -1-carboxylate(intermediate 9.5) / 3 - [2 - [(5 methyltetrazol -2 yl) methyl] -4 (trifluoromethyl) phenyl] propanoic acid(CAS -RN 1646783 -83 -6) 575, 1 (M + H) + tert-butyl-4 - [2 - (5-sulfamoylthiofen -2-yl) sulfonylethyl]piperidine -1carboxylate (intermediate 15.4) / acid 3 - [2 - [(5 methyltetrazol -2 yl) methyl] -4 (trifluoromethyl) pheni 1] propanoic (CAS RN 1646783 -83 -6) 635, 2 (M + H) + Petition 870190091123, of 9/13/2019, p. 109/164 103/132 6.39 5-fluoro -6 - [1 - [3 - [2 - [(5-methylthetrazol -2 11) methyl] -4 (trifluoromethyl) phenyl] propanoyl] -piperidin -4 -ii] sulfanylpyridine -3 sulfonamide FFNSN Kl M / __ / __ / * '- / - xy ~ N. > —So —f tert-butyl-4 - (3fluoro -5sulfamoylpyridin -2-ii)sulfanylpiperidine1-carboxylate(intermediate 9.1)/ acid 3 - [2 - [(5 methyltetrazole -211) methyl] -4(trifluoromethyl) phenyl] propanoic(CAS -RN 1646783 -83 -6) 588.2 (M + H) + 6.40 6 - [1 - [2-cyclopropyl - 6 - (oxan -4-ylmethoxy) pyridine -4-carbonyl] piperidin -4 -ii] sulfanyl -5 fluoropyridine -3 sulfonamide y— ° Οχ N H 2 O— <* Sx x = ç / —X / - N NS O ' tert-butyl-4 - (3 fluoro -5sulfamoylpyridin -2-ii) sulfanylpiperidine1-carboxylate(intermediate 9.1) / acid 2cyclopropyl -6(oxan-4-ylmethoxy)pyridine -4carboxylic (CAS -RN 181) 776 -23 -8) 551.2 (M + H) + Petition 870190091123, of 9/13/2019, p. 110/164 104/132 6.41 4 - [1 - [3 - [4(difluoromethoxy) -2 - [(5-methyltetrazole -2 -11)methyl] phenyl] propanoyl] piperidin -4 -11]sulfonyl -3fluorobenzene sulfonylamideV h .yy-tΌΟγΟ * 'o tert-butyl-4 - (2 fluoro -4-sulfamoyl phenyl)sulfonylpiperidine1-carboxylate(intermediate 11) / acid 3 - [4(difluoromethoxy) -2 - [(5-methyltetrazole -2 -11) methyl]phenyl] propanoic(intermediate 13.2) 617.2 (M + H) + 6.42 4 - [2 - [1 - [3 - [4 -(difluoromethoxy) -2 - [(5-methyltetrazole -2il) methyl] phenyl]propanoyl] piperidin -4 -11] ethylsulfinyl] -2.3-difluorobenzene sulfonylamideVi V O F tert-butyl-4 - [2 (2,3-difluoro -4 sulfamoyl phenyl)sulfinylethyl] piperidine -1carboxylate (intermediate 1).6) / acid 3 - [4 (difluoromethoxy) -2- [(5-methyltetrazole -2 -11) methyl]phenyl] propanoic(intermediate 13.2) 647.3 (M + H) + Petition 870190091123, of 9/13/2019, p. 111/164 105/132 6.43 2,3 -difluoro -4 - [2 - [1 - [3 - [2 - [(5methyl-tetrazol-2-yl) methyl] -4(trifluoromethyl) phenyl] propanoyl] -piperidin -4 -yl] ethylsulfinyl]benzene sulfonylamidey * N N F N OF tert-butyl-4 - [2 (2,3-difluoro -4 sulfamoyl phenyl)sulfinylethyl] piperidine -1carboxylate (intermediate 1).6) / 3 - [2 [(5-methyltetrazole 2 -11) methyl] -4 (trifluoromethyl) pheni 1] propanoic acid (CAS RN 1646783 -83 -6) 649.3 (M + H) + 6.44 2 - [2 - [1 - [3 - [4 - (difluoromethoxy) -2 - [(5-methyltetrazol -2 yl) methyl] phenyl] - propanoyl] piperidin -4 11] ethylsulfinyl] -1,3 thiazole -5 sulfonamide -nu FF N. NTY V o O'v nh 2 tert-butyl-4 - [2 [(5 -sulfamoyl -1,3-thiazole -2il) sulfinyl] ethyl]piperidine -1carboxylate(intermediate 1).5) / 3 - [4 (difluoromethoxy) -2 - [(5-methyltetrazol -2-yl) methyl] phenyl] propanoic acid(intermediate 13.2) 618.2 (M + H) + Petition 870190091123, of 9/13/2019, p. 112/164 106/132 6.4 2 - [2 - [1 - [3 - [2 - [(5 5 methyltetrazol -2 yl) methyl] -4 (trifluoromethyl) phenyl] propanoyl] piperidin -4 -yl] ethylsulfonyl] -1,3 -thiazole-5 sulfonamide tert-butyl-4 - [2 [(5-sulfamoyl -1,3-thiazol -2-yl) sulfonyl] ethyl] piperidine -1 carboxylate (intermediate 11.2) / acid 3 - [2 - [(5 methyltetrazol -2 yl ) methyl] -4 (trifluoromethyl) pheni 1] propanoic (CAS RN 1646783 -83 -6) Example 7 and 8 -Fluoro -4 - [1 - [3 - [2 - [(5-methyltetrazol -2 yl) methyl] -4 - (trifluoromethyl) phenyl] propanoyl] piperidin -4 -yl] sulfinyl benzene sulfonylamide enantiomer 1 and enantiomer 2 [ 00183] 3-Fluoro -4 - [1 - [3 - [2 [(5-methyltetrazol -2-yl) methyl] -4 - (trifluoromethyl) phenyl] propanoyl] piperidin -4 -yl] sulfinyl benzene sulfonylamide racemic (example 6.13; 40 mg, 66.4 pmol) by means of preparation HPLC using a Reprosil Chiral -NR column as the stationary phase and heptane / ethanol 3: 2 as the mobile phase. This produced the fastest (+) -enantiomer 1 elution (example 7; 17 mg, 43%; white gum, MS: 601.3 (MH) ~) and the slowest (-) enantiomer 2 (example 8 ; 14 mg, 35%; white solid, MS: 6) 1.4 (MH). Petition 870190091123, of 9/13/2019, p. 113/164 107/132 [00184] The following examples were produced in analogy to examples 7 and 8 by means of separation by Chiral HPLC of its racemates. Ex. Starting material(racemic) Sign ofoptical rotation Stationary phase; eluent MS, m / e 7.01 4 - [[1 - [3 - [2 - [(5 methyltetrazol -2-yl) methyl] -4(trifluoromethyl) -phenyl] propanoyl] pyrrolidin 2 -yl] methoxy] benzenesulfonylamide (example5.) 5) (+)(enantiomerelutionfaster) ReprosilChiral -NR;heptane /ethanol 3: 2 553.3 (M + H) + 8.01 (-)(enantiomerelutionslower) 553.3 (M + H) + 7.02 4 - [[1 - [3 - [2 - [(5 methyltetrazole -2il) methyl] -4(trifluoromethyl) -phenyl] propanoyl] pyrrolidin -3-yl] methoxy] benzene sulfonylamide (example5, 06) (+) ReprosilChiral -NR;heptane /ethanol 3: 2 553.3 (M + H) + 8. ) 2 (-) 553.4 (M + H) + Example 9 - [[4 - [3 - [2 - [(5 -Methyltetrazol -2-yl) methyl] -4 - (trifluoromethyl) phenyl] propanoyl] piperazin -1 -yl] methyl] benzene sulfonylamide Petition 870190091123, of 9/13/2019, p. 114/164 108/132 [00185] To a solution of 3 - [2 - [(5 methyltetrazol -2 -11) methyl] -4 - (trifluoromethyl) phenyl] -1-piperazin -1 -ilpropan -1 -one (intermediate 2; 4) mg , 105 pmol) in dichloromephane (2 ml) 4 formiibenzene sulfonylamide (CAS -RN 3240-35 -5; 23.2 mg, 126 pmol), sodium triacetoxy boron hydride (28.8 mg, 136 pmol) and acid were added acetic (12.6 mg, 2) 9 pmol) at room temperature. The mixture was subjected to stirring at room temperature for 16 h and then at 50 ° C for 24 h, then the reaction mixture was partitioned between saturated aqueous sodium hydrogencarbonate solution and ethyl acetate. The organic layer was washed with saline, dried over magnesium sulfate, filtered and evaporated. Chromatography (silica gel, using flash chromatography on silica, eluting with a gradient of dichloromethane to dichloromethane / methanol / 25% aqueous ammonia solution 90: 10: 0.25) yielded the title compound (6 mg, 10%). White solid, MS: 552.2 (M + H) + . Intermediaries Intermediate 1 [2 - [(5 -Methyltetrazol -2 -yl) methyl] -4 (trifluoromethyl) phenyl] methanol Step 1: Ethyl 2 ~ [(5-methyltetrazol -2-yl) methyl] -4 - (trifluoromethyl) benzoate Petition 870190091123, of 9/13/2019, p. 115/164 109/132 [00186] To a solution of 2 - [[2-bromo -5 (trifluoromethyl) phenyl] methyl] -5 -methyltetrazole (CAS -RN 1646389 -14 -1; 2) 9 mg, 651 pmol) in ethanol (3 mL) 1.1-bis (diphenylphosphino) dichloropalladium (II) ferrocene (CAS -RN 95464 -05 -4; 21.3 mg, 26 pmol), triethylamine (98.8 mg, 976 pmol) were added and placed in a carbon monoxide atmosphere. The reaction mixture was stirred for 18 h under an atmosphere of carbon monoxide (70 bar) under 110 ° C. The reaction mixture was filtered and evaporated directly. Chromatography (silica gel, using flash chromatography on silica, eluting with a gradient of pure heptane to heptane: ethyl acetate = 2: 1) produced the title compound (186 mg, 91%), Colorless oil, MS: 315 , 1 (M + H) + . Step 2: [2 - [(5 -Methyltetrazol -2-yl) methyl] -4 - (trifluoromethyl) phenyl] methanol [00187] To a light yellow color solution of ethyl 2 - [(5-methyltetrazole -2-yl ) methyl] -4 (trifluoromethyl) benzoate (182 mg, 579 pmol) in tetrahydrofuran (5 ml) a solution of calcium chloride (129 mg, 1.16 mmol) in ethanol (5 ml) was added. Boron sodium hydride (CAS -RN 1694) -66-2; 65.7 mg, 1.74 mmol) was added in 3 parts over a period of 30 min. to provide a white suspension. After 3 h at room temperature the reaction mixture was partitioned between saturated aqueous ammonium chloride solution and ethyl acetate. The organic layer was washed with saline, dried over magnesium sulfate, filtered and evaporated to produce the title compound with 96% purity (NMR) (164 mg, quant.). Color oil Petition 870190091123, of 9/13/2019, p. 116/164 110/132 light yellow, MS: 273.1 (M + H) + . Intermediate 2 - [2 - [(5 -Methyltetrazol -2 -yl) methyl] -4 (trifluoromethyl) phenyl] -1 -piperazin -1 -ilpropan -1 -one Step 1: tert-butyl-4 - [3 - [2 - [(5-methyltetrazol -2-yl) methyl] -4 - (trifluoromethyl) phenyl] propanoyl] piperazine -1-carboxylate [00188] To a colorless solution of 3 - [2 - [(5-methyltetrazole -2-yl acid ) methyl] -4 - (trifluoromethyl) phenyl] propanoic (101 mg, 309 pmol), 4-methylmorpholine (156 mg, 1.54 mmol) tert-butylpiperazine -1-carboxylate (57.5 mg, 309 pmol) in N, N -dimethylformamide (3 mL) was added hexafluoro phosphate O - (7 -azabenzotriazole -1 -yl) -Ν, Ν, Ν ', N' -tetramethyluronium (117 mg, 309 pmol) at room temperature, then after 18 The reaction mixture was divided between saturated aqueous ammonium chloride solution and ethyl acetate. The organic layer was washed with saline, dried over magnesium sulfate, filtered and evaporated. Chromatography (silica gel, using flash chromatography on silica, eluting with a gradient of dichloromethane to dichloromethane / methanol / 25% aqueous ammonia solution 90: 10: 0.25) produced the title compound (149 mg, quant .). Colorless oil, MS: 483.2 (M + H) + . Step 2: 3 - [2 - [(5 -Methyltetrazol -2-yl) methyl] -4 - (trifluoromethyl) phenyl] -1-piperazin -1 -ilpropan -1 one [00189] To a solution of tert-butyl- 4 - [3 - [2 [(5-methylthetrazol -2-yl) methyl] -4 - (trifluoromethyl) phenyl] propanoyl] piperazine -1-carboxylate (140 mg, 290 Petition 870190091123, of 9/13/2019, p. 117/164 111/132 pmol) in dichloromethane (3 ml) trifluoroacetic acid (496 mg, 4.35 mmol) was added. The reaction mixture was stirred at room temperature for 18 h. The mixture was evaporated directly and the residue was partitioned between 2 M aqueous sodium hydroxide solution and dichloromethane. The aqueous phase was washed twice more with dichloromethane, then the organic phase was dried over magnesium sulfate, filtered and evaporated to provide the title compound (90 mg, 81%). White solid, MS: 383.2 (M + H) + . Intermediate 3 2,6-Difluoro -4-sulfamoylbenzoic acid [00190] To a suspension subjected to agitation of 3,5-difluoro -4-methyl-benzene sulfonylamide (CAS -RN 1239964 -24-9; 500 mg, 2.41 mmol) in water (25 mL) under reflux was added by potassium permanganate parts (1.72 g , 10.9 mmol) for 1 h, then the suspension was filtered and washed with water. The mother liquor was extracted twice with ethyl acetate to separate impurities. The aqueous layer was acidified to pH 1 with conc. Hydrochloric acid HCl and extracted 3 times with ethyl acetate. The combined organic layers were dried over magnesium sulfate and evaporated to dryness to provide the title compound (356 mg, 62%). Light yellow solid, MS: 235.9 (M-H) ~. Intermediate 4 tert-butyl 4 - (4-sulfamoyl phenyl) sulfonylpiperazine -1-carboxylate [00191] To a yellow colored solution of tertbutylpiperazine -1-carboxylate (CAS -RN 57260 -71 -6; 50 Petition 870190091123, of 9/13/2019, p. 118/164 112/132 mg, 263 pmol) in pyridine (208 mg, 2.63 mmol) and tetrahydrofuran (1 ml) a solution of 4-sulfamoyl benzene sulfonyl chloride (CAS -RN 46249 -41 -6; 80.7 mg, 316 pmol) in tetrahydrofuran (1 ml) at room temperature. The reaction mixture was stirred at room temperature for 18 h and became a white suspension, then it was partitioned between saturated aqueous ammonium chloride solution and ethyl acetate. The organic layer was washed with saline, dried over magnesium sulfate, filtered and evaporated. Chromatography (silica gel, gradient dichloromethane to dichloromethane / methanol / 25% aqueous ammonia solution 90: 10: 0.25) gave the title compound (64 mg, 60%). White solid, MS: 4) 4.3 (ΜΗ) A Intermediate 4.1 tert-butyl-4 - (2-fluoro -4-sulfamoyl phenyl) sulfonylpiperazine -1-carboxylate [00192] The title compound was produced in analogy to intermediate 4, replacing 4-sulfamoyl benzene sulfonyl chloride with 2-fluoro -4 sulfamoyl benzene sulfonyl chloride (CAS -RN 52295 -72 -4). White solid, MS: 422.3 (M-H) ~. Intermediate 5 tert-butyl-4 - (2-fluoro -4-sulfamoyl benzoyl) piperazine -1-carboxylate [00193] To a colorless solution of 2 fluoro -4-sulfamoyl benzoic acid (CAS -RN 714968 -42 -0; 69, 4 mg, 301 pmol) in N, N -dimethylformamide (3 ml) 4-methylmorpholine (111 mg, 1.09 mmol), tertetition 870190091123, of 9/13/2019, p. 119/164 113/132 butylpiperazine -1-carboxylate (CAS -RN 5726) -71 -6; 52 mg, 274 pmol) and 0 - (7 azabenzotriazole -1-yl) -Ν, Ν, Ν ', N' -tetramethyluronium (114 mg, 301 pmol) hexafluoro-phosphate at room temperature, then after 18 ha The reaction mixture was divided between saturated aqueous ammonium chloride solution and ethyl acetate. The organic layer was washed with saline, dried over magnesium sulfate, filtered and evaporated. Chromatography (silica gel, using flash chromatography on silica, eluting with a gradient of dichloromethane to dichloromethane / methanol / 25% aqueous ammonia solution 90: 10: 0.25) produced the title compound (1) 7 mg, quant). White foam, MS: 38 6, 3 (MH) A Intermediate 6 [2-Cyclopropyl -6 - (oxan -4-ylmethoxy) pyridin 4-yl] methanol [00194] To a solution of 2-cyclopropyl acid 6 - (oxan-4-ylmethoxy) pyridine-4-carboxylic acid (CAS -RN 1810776 -23 -8; 300 mg, 1.08 mmol) in tetrahydrofuran (5 mL) was added slowly to a solution of borane tetrahydrofuran complex (CAS -RN 14044 -65-6; 1M in tetrahydrofuran; 2.7 mL, 2.7 mmol) at room temperature. The reaction mixture was stirred at room temperature for 18 h. More borane tetrahydrofuran complex solution (1.62 ml, 1.62 mmol) was added and stirring was continued for 6 h. The reaction was carefully treated with 3 ml of methanol, left to stir for 10 min. at room temperature and was then completely evaporated. The residue was divided between ethyl acetate and 1M aqueous solution of Petition 870190091123, of 9/13/2019, p. 120/164 114/132 sodium hydroxide. The organic layer was washed with saline, dried over magnesium sulfate, filtered and evaporated to produce the title compound (239 mg, 84%). Colorless oil, MS: 264.3 (M + H) + . Intermediate 7 4-Fluoro-3 - (piperidin -4 ylmethyl) benzene sulfonylamide hydrochloride Step 1: 1 - [4 - [(2-Fluorophenyl) methyl] -1 piperidyl] ethanone [00195] 4 - [(2 fluorophenyl) methyl] piperidine hydrochloride (CAS -RN 193357 -26 -5; 350 mg, 1.48 mmol) with dichloromethane (5 mL) and N methylmorpholine (149 mg, 162 μΐ, 1.48 mmol) was added, then acetic anhydride (317 mg, 3.1 mmol) was added dropwise under 0 ° C with stirring , and the mixture was subjected to stirring at room temperature for 1 h. The mixture was concentrated directly in vacuo. The residue was partitioned between ethyl acetate and saturated aqueous sodium bicarbonate solution. The organic layer was washed with saline, dried over magnesium sulfate, filtered and evaporated to provide the title compound with a purity of approximately 90% (NMR) (388 mg, quant.) Light yellow oil, MS: 236.2 (M + H) + . Step 2: 3 - [(1-Acetyl -4-piperidyl) methyl] -4-fluoro-benzene sulfonylamide [00196] A solution of 1 - [4 - [(2 fluorophenyl) methyl] -1-piperidyl] ethanone (384 mg, 1.47 mmol) in dichloromethane (5 mL) was added dropwise to hydrochloric acid (856 mg, 7.34 mmol) under 0 ° C with stirring, then stirred under 0 ° C for 30 Petition 870190091123, of 9/13/2019, p. 121/164 115/132 min. and at room temperature for 2 h. The reaction mixture was evaporated directly under high vacuum. The residue was combined with tetrahydrofuran (5 ml) and cooled to 0 ° C, then 25% aqueous ammonia solution (3 ml) was added dropwise. The reaction mixture was stirred at 0 ° C for 30 min. and then at room temperature for 18 h, then evaporated directly to remove the tetrahydrofuran. The aqueous residue was divided between ethyl acetate and 1 Μ hydrochloric acid aqueous solution. The organic layer was washed with saline, dried over magnesium sulfate, filtered and evaporated. Chromatography (silica gel, heptane gradient: ethyl acetate = 4: 1 to 9: 1 then pure ethyl acetate and finally pure ethyl acetate to pure methanol) produced the title compound (353 mg, 76%). White foam, MS: 315.2 (M + H) + . Step 3: 4-Fluoro-3 - (piperidin 4-ylmethyl) benzene sulfonylamide [00197] 3 - [(1-Acetyl -4 piperidyl) methyl] -4-fluoro-benzene sulfonylamide (345 mg, 1 , 1 mmol) with aqueous hydrochloric acid (25% in water; 4.8 g, 32.9 mmol) and was stirred under reflux for 6 h. The reaction mixture was evaporated directly and dried under high vacuum to provide the title compound with a purity of approximately 95% (NMR) (305 mg, 86%). White foam, MS: 273.2 (M + H) + . Intermediate 8 3-Fluoro-4-piperidin-4-ylsulfanyl benzene sulfonylamide hydrochloride Petition 870190091123, of 9/13/2019, p. 122/164 116/132 Step 1: Ν '- (4-Bromo-3-fluoro-phenyl) sulfonyl -N, N -dimethyl-formamidine [00198] A solution of 1,1-dimethoxy -N, N dimethylmethanamine (CAS -RN 4637 - 24 -5; 170 mg, 1.38 mmol) in acetonitrile (1 mL) was added dropwise at room temperature to a stirring solution of 4 bromo -3-fluorobenzene sulfonylamide (CAS -RN 263349 -73 1; 302 mg, 1.15 mmol) in acetonitrile (3 mL). After 1 h the mixture was evaporated directly under high vacuum to provide the title compound (369 mg, quant.). White solid, MS: 309.0 (M + H) + . Step 2: 3-Fluoro-4-piperidin-4-sulfanyl benzene sulfonylamide hydrochloride [00199] A solution of tert-butyl-4-sulfanylpiperidine -1-carboxylate (CAS -RN 134464 -79 -2; 244 mg, 1.1 mmol) in N, N-dimethylformamide (2 mL) was added dropwise to a stirring mixture of sodium hydride (50% oil dispersion; 52.9 mg, 1.1 mmol) and N, N-dimethylformamide (2 mL). After 30 min. at room temperature the evolution of gas was complete and another solution of Ν '- (4-bromo -3-fluoro-phenyl) sulfonyl -N, N dimethylformamide (351 mg, 1.1 mmol) in N, N dimethylformamide (2 ml) was added dropwise. The reaction mixture was stirred at 60 ° C for 3 h and then evaporated directly to remove the N, N dimethylformamide. The residue was combined with methanol (4 ml) and 2.5 M aqueous sodium hydroxide solution (4.4 ml, 11 mmol) and then subjected to stirring under 100 ° C for 1 h. The mixture was evaporated directly again to remove methanol, then an acid solution was added Petition 870190091123, of 9/13/2019, p. 123/164 117/132 hydrochloric (5 M in isopropanol; 4.4 mL, 22 mmol) and was stirred at 50 ° C for 1.5 h. The white suspension was filtered, and the mother liquor was evaporated to provide the title compound as a mixture of approximately 1: 1 (bromide isomer) with a purity of 80% (440 mg, 49%). Off-white foam, MS: 291.1 (M + H) + . Intermediate 9 tert-butyl-4 - [(2-fluoro -4-sulfamoyl phenyl) sulfanylmethyl] piperidine -1-carboxylate Step 1: Ν '- (3,4-Difluorophenyl) sulfonyl -N, N dimethyl-formamidine [00200] The title compound was produced in analogy to intermediate 8, step 1 from 3,4 difluorobenzene sulfonylamide (CAS - RN 1) 8966 -71 -8) and 1,1-dimethoxy -N, N -dimethylmethanamine (CAS -RN 4637-245). White solid, MS: 249.1.0 (M + H) + . Step 2: tert-butyl-4 - [(2-fluoro -4-sulfamoyl phenyl) sulfanylmethyl] piperidine -1-carboxylate [00201] Ν '- (3,4-difluorophenyl) sulfonyl -N, N-dimethyl -formamidine (315 mg, 1.27 mmol) to a stirred mixture of a mixture of sodium hydride (50% oil dispersion; 60.9 mg, 1.27 mmol) and N, N dimethylformamide (2 mL) under room temperature. For 5 min., Then tert-butyl-4 - (sulfanylmethyl) piperidine -1-carboxylate (CAS -RN 581) 60 -27-7; 281 mg, 1.27 mmol) was added. It was possible to observe a strong gas evolution and exothermic reaction. The reaction mixture was stirred at room temperature for 1 h and then evaporated directly to remove N, N Petition 870190091123, of 9/13/2019, p. 124/164 118/132 dimethylformamide. The residue was combined with methanol (4 ml) and 2.5 M aqueous sodium hydroxide solution (5.08 ml, 12.7 mmol) and the white suspension was stirred at room temperature for 3 h. The mixture was partitioned between ice and 1M aqueous hydrochloric acid solution and ethyl acetate. The organic layer was washed with saline, dried over magnesium sulfate, filtered and evaporated. Chromatography of the residue (silica gel, gradient dichloromethane to dichloromethane / methanol / 25% aqueous ammonia solution, 90: 10: 0.25) produced the title compound with a purity of approximately 95% (NMR) (463 mg, 89 %). Colorless gum, MS: 389, 3 (MH) L [00202] The intermediates shown below were prepared according to intermediate 9, substituting tert-butyl-4 - (sulfanylmethyl) piperidine -1-carboxylate (CAS -RN 581060 -27 -7) by the appropriate 3,4-difluorobenzene sulfonylamide thiol (CAS -RN 108966 71 -8) by the appropriate sulfonamide. At the . Systematic name Thiol / Sulfonamide MS, m / e 9.1 terc - butyl 4 - (3fluoro -5sulfamoylpyridin -2 -yl)sulfanylpiperidine -1 carboxylate terc - butyl 4 sulfanylpiperidine -1 carboxylate (CAS -RN134464 -79 -2) / 6 -chlorine -5-fluoropyridine -3 -sulfonamide (CAS -RN 1803571 -8) -3) 390.2(M-H) ~ Petition 870190091123, of 9/13/2019, p. 125/164 119/132 At the . Systematic name Thiol / Sulfonamide MS, m / e 9.2 terc - butyl 4 - (2,3 -difluoro-4-sulfamoyl phenyl)sulfanylpiperidine -1 carboxylate terc - butyl 4 sulfanylpiperidine -1 carboxylate (CAS -RN134464 -79 -2) / 2,3,4 trifluorobenzene sulfonylamide (CAS -RN 518070 -13 -8) 407.2(M-H) ~ 9.3 tert - butyl 3 - (2 fluoro -4-sulfamoyl phenyl) sulfanylazetidine—1 -carboxylate terc - butyl 3 sulfanylazetidine -1 carboxylate (CAS -RN941585 -25 -7) / 3,4 difluorobenzene sulfonylamide (CAS -RN 1) 8966 -71 -8) 361.2(M-H) ~ 9.4 tert - butyl 4 - [2 - (2 fluoro -4-sulfamoyl phenyl) sulfanylethyl] piperidine -1carboxylate terc - butyl 4 - (2sulfanylethyl) piperidine —1-carboxylate (CAS -RN 1420841 -79 -7) / 3,4 difluorobenzene sulfonylamide (CAS -RN 108966 -71 -8) 417.3(M-H) ~ 9.5 tert - butyl 4 - [(5 sulfamoyl -1,3-thiazole 2 -11) sulfanyl]piperidine -1carboxylate terc - butyl 4 sulfanylpiperidine -1 carboxylate (CAS -RN134464 -79 -2) / 2 -chlorine -1,3-thiazole -5 sulfonamide (CAS -RN848362 -)) -5) 378.2(M-H) ~ Petition 870190091123, of 9/13/2019, p. 126/164 120/132 At the . Systematic name Thiol / Sulfonamide MS, m / e 9.6 tert - butyl 4 - [2 - (2,3-difluoro -4-sulfamoyl phenyl) sulfanylethyl]piperidine -1carboxylate terc - butyl 4 - (2sulfanylethyl) piperidine —1-carboxylate (CAS -RN 1420841 -79 -7) / 2,3,4 -trifluorobenzene sulfonylamide (CAS -RN 518070 -13 -8) 435, 2(M-H) ~ 9.7 tert - butyl 4 - [2 - [(5 -sulfamoyl -1,3-thiazole -2 -11) sulfanyl] ethyl] piperidine -1carboxylate terc - butyl 4 - (2sulfanylethyl) piperidine —1-carboxylate (CAS -RN 1420841 -79 -7) / 2 -chlorine -1,3-thiazole -5 sulfonamide (CAS -RN848362 -00 -5) 406, 2(M-H) ~ 9.8 tert - butyl 4 - [2 - (5 sulfamoylthio-2-11) sulfanylethyl] piperidine —1-carboxylate terc - butyl 4 - (2sulfanylethyl) piperidine —1-carboxylate (CAS -RN 1420841 -79 -7) / 5 -bromothiophene -2sulfonamide (CAS -RN53595 -65 -6) 405, 3(M-H) ~ 9.9 terc - butyl 4 - (2fluoro -4 -sulfamoyl phenyl)sulfanylpiperidine -1 carboxylate terc - butyl 4 sulfanylpiperidine -1 carboxylate (CAS -RN134464 -79 -2) / 3,4 difluorobenzene sulfonylamide (CAS -RN 108966 -71 -8) 389, 3(M-H) ~ Petition 870190091123, of 9/13/2019, p. 127/164 121/132 At the . Systematic name Thiol / Sulfonamide MS, m / e 9.1 tert - butyl 4 - (2 - ((5-sulfamoylthiazole -2 -ii) thio) ethyl) piperidine -1-carboxylate terc - butyl 4 - (2sulfanylethyl) piperidine —1-carboxylate (CAS -RN 1420841 -79 -7) / 2 -chlorine -1,3-thiazole -5 sulfonamide (CAS -RN848362 -00 -5) 406, 2(M-H) ~ Intermediate 10 tert - butyl 4 - (2-fluoro -4-sulfamoyl phenyl) sulfinylpiperidine -1-carboxylate [00203] To a solution of tert - butyl 4- (2fluoro -4-sulfamoyl phenyl) sulfanylpiperidine -1 carboxylate (intermediate 9.9; 459 mg, 1.12 mmol) in glacial acetic acid (2 mL) was added hydrogen peroxide (35% in water; 369 mg, 3.8 mmol). The resulting solution was subjected to stirring at room temperature for 4 h. and then divided between ice and ethyl acetate. The organic layer was washed with water and saline, dried over magnesium sulfate, filtered and evaporated under high vacuum to provide the title compound (428 mg, 94%). White foam, MS: 405, 3 (MH) L [00204] The following intermediates were prepared according to intermediate 10, replacing tert - butyl 4 - (2-fluoro -4-sulfamoyl phenyl) sulfanylpiperidine -1 -carboxylate (intermediate 9.9) by the appropriate thioether. Petition 870190091123, of 9/13/2019, p. 128/164 122/132 At the . Systematic name Tioether MS, m / e 10.1 tert - butyl 4 - [(2 fluoro -4-sulfamoyl phenyl) sulfinylmethyl]piperidine -1carboxylate tert - butyl 4 - [(2 fluoro -4-sulfamoyl phenyl) sulfanylmethyl]piperidine -1carboxylate (intermediate 9) 419, 3(M-H) ~ 10.2 terc - butyl 4 - (2,3 -difluoro-4-sulfamoyl phenyl)sulfinylpiperidine -1 carboxylate terc - butyl 4 - (2,3 -difluoro-4-sulfamoyl phenyl)sulfanylpiperidine -1 carboxylate(intermediate 9.2) 423.2(M-H) ~ 10.3 tert - butyl 3 - (2 fluoro -4-sulfamoyl phenyl) sulfinylazetidine—1 -carboxylate tert - butyl 3 - (2 fluoro -4-sulfamoyl phenyl) sulfanylazetidine —1-carboxylate(intermediate 9.3) 377.3(M-H) ~ 10.4 tert - butyl 4 - [2 - (2 fluoro -4-sulfamoyl phenyl) sulfinylethyl]piperidine -1carboxylate tert - butyl 4 - [2 - (2 fluoro -4-sulfamoyl phenyl) sulfanylethyl]piperidine -1carboxylate (intermediate 9.4) 433.3(M-H) ~ Petition 870190091123, of 9/13/2019, p. 129/164 123/132 At the . Systematic name Tioether MS, m / e 10.5 tert - butyl 4 - [2 - [(5 -sulfamoyl -1,3-thiazol -2 -yl) sulfinyl] ethyl] piperidine -1carboxylate tert - butyl 4 - [2 - [(5 -sulfamoyl -1,3-thiazol -2 -yl) sulfanyl] ethyl] piperidine -1carboxylate (intermediate 9.7) 422.2(M-H) ~ 10.6 tert - butyl 4 - [2 - (2,3-difluoro -4-sulfamoyl phenyl) sulfinylethyl]piperidine -1carboxylate tert - butyl 4 - [2 - (2,3-difluoro -4-sulfamoyl phenyl) sulfanylethyl]piperidine -1carboxylate (intermediate 9.6) 451.2(M-H) ~ 10.7 tert - butyl 4 - (2 - ((5 -sulfamoyliazol-2-yl) sulfinyl) ethyl)piperidine -1carboxylate tert - butyl 4 - (2 - ((5-sulfamoyl--2-yl) thio) ethyl) piperidine -1-carboxylate 422.2(M-H) ~ Intermediate 11 tert - butyl 4 - (2-fluoro -4-sulfamoyl phenyl) sulfonylpiperidine -1-carboxylate [00205] To a colorless solution of tert - butyl 4 - (2-fluoro -4-sulfamoyl phenyl) sulfinylpiperidine -1 carboxylate ( intermediate 10; 374 mg, 920 pmol) in dichloromethane (4 ml) 3-chlorobenzene carboperoxoic acid (CAS -RN 937 -14 -4; 318 mg, 1.84 mmol) was added at room temperature. The reaction mixture was stirred at room temperature for 18 h and then Petition 870190091123, of 9/13/2019, p. 130/164 124/132 divided between ice and 1 M aqueous sodium carbonate solution and ethyl acetate. The organic layer was washed with saline, dried over magnesium sulfate, filtered and evaporated to provide the title compound with a purity of approximately 90% (NMR). [00206] This material was precipitated from 2 ml of dichloromethane (286 mg, 74%). Color solid white, MS: 421.3 (M-H). [00207] The intermediates exposed below were produced according to broker 11, replacing the terc - butyl 4 - (2-fluoro -4-sulfamoyl phenyl) sulfinylpiperidine -1-carboxylate with the appropriate sulfoxide. At the. Systematic name Sulfoxide MS, m / e 11.1 tert - butyl 4 - [(2 fluoro -4-sulfamoyl phenyl) -sulfonylmethyl] piperidine -1carboxylate tert - butyl 4 - [(2 fluoro -4 -sulfamoyl phenyl) -sulfinylmethyl] piperidine -1carboxylate (intermediate 10.1) 435, 3(M-H) ~ 11.2 tert - butyl 4 - [2 - [(5 -sulfamoyl -1,3-thiazol -2 -yl) sulfonyl] ethyl] piperidine -1carboxylate tert - butyl 4 - (2 - ((5-sulfamoylthiazol -2-yl) sulfinyl) ethyl)piperidine -1carboxylate (intermediate 10.7) 438.2(M-H) ~ Intermediate 12 Petition 870190091123, of 9/13/2019, p. 131/164 125/132 N - [5 -Cyan -2 - (hydroxymethyl) pyridin -3 -11] - 2,2-dimethyl propanamide Step 1: Methyl 5-bromo -3 - (2,2-dimethyl propanoyl amino) pyridine -2-carboxylate [00208] To a light yellow color suspension of methyl 3-amino -5-bromopyridine -2-carboxylate (CAS - RN 1072448 -08 -8; 900 mg, 3.7 mmol) in pyridine (15 mL) 2,2-dimethylpropanoyl chloride (CAS -RN 3282 30 -2; 546 mg, 4.44 mmol) was added. The color was changed to light red. More 2,2-dimethylpropanoyl chloride (1.092 g, 8.88 mmol) was added and the reaction was stirred at room temperature for 18 h, then divided between ice and 1 M aqueous hydrochloric acid and ethyl acetate . The organic layer was washed with saline, dried over magnesium sulfate, filtered and evaporated. Chromatography (silica gel, dichloromethane / heptane gradient 1: 1 to dichloromethane) gave the title compound (385 mg, 99%). White solid, MS: 317.0 (M + H) + . Step 2: Methyl 5-cyano -3 - (2,2-dimethyl propanoyl amino) pyridine -2-carboxylate [00209] To a microwave flask containing a solution of methyl 5-bromine -3 - (2,2-dimethyl amino propanoyl) pyridine -2-carboxylate (1.13 g, 3.59 mmol) in N, N-dimethylformamide (14.9 mL) and water (119 μΐ) Tris (dibenzylidene acetone) dipaladium (CAS -RN 51364) was added -51 3; 32.8 mg, 35.9 pmol), 1.1'-bis (diphenyl phosphine) ferrocene (CAS -RN 12150 -46 -8; 59.6 mg, 108 pmol), zinc cyanide (CAS -RN 557 -21 -1; 232 mg, 1.97 mmol), zinc (CAS -RN 744) -66 -6; 9.38 mg, 143 pmol) and acetate Petition 870190091123, of 9/13/2019, p. 132/164 126/132 zinc (CAS -RN 557 -34 -6; 26.3 mg, 143 pmol). The flask was capped and heated in the microwave under 140 ° C for 30 min. The reaction mixture was filtered and the mother liquor was evaporated. The residue was diluted with 50% aqueous sodium hydrogencarbonate solution and extracted with ethyl acetate. The organic layer was washed with water and saline, dried over magnesium sulfate, filtered and evaporated. Chromatography (silica gel, 50: 1 dichloromethane to dichloromethane / methanol gradient) gave the title compound (468 mg, 50%). Yellow solid, MS: 262.2 (M + H) + . Step 3: N - [5 -Cyan -2 - (hydroxymethyl) pyridin -3 -yl] -2,2-dimethyl propanamide [00210] To a solution, light yellow color of methyl 5-cyano -3 - (2, 2-dimethyl propanoyl amino) pyridine -2-carboxylate (453 mg, 1.73 mmol) in tetrahydrofuran (5 mL) and ethanol (5 mL) was added sodium boron hydride (262 mg, 6.94 mmol) in 3 parts for a period of 30 min. The reaction mixture was divided between saturated aqueous ammonium chloride solution and ethyl acetate. The organic layer was washed with saline, dried over magnesium sulfate, filtered and evaporated. Chromatography (silica gel, gradient dichloromethane to dichloromethane / methanol / 25% aqueous ammonia solution, 90: 10: 0.25) gave the title compound (378 mg, 94%). Light yellow viscous oil, MS: 234.2 (M + H) + . Intermediate 13 3 - [4 -Cyan -2 - [(5 -methyltetrazol -2 yl) methyl] phenyl] propanoic acid Step 1: Ethyl (E) -3 - [4-cyan -2 ~ [(5 Petition 870190091123, of 9/13/2019, p. 133/164 127/132 methyltetrazol -2 -yl) methyl] phenyl] prop -2 -enoate [00211] To a colorless solution of 4-bromo -3 [(5-methylthetrazol -2 -yl) methyl] benzonitrile (CAS -RN 1646784 - 84 -0; 450 mg, 1.62 mmol) in N, N -dimethylformamide (6 mL) was added ethyl acrylate (194 mg, 1.94 mmol), triethylamine (491 mg, 4.85 mmol), palladium acetate (II) (7.27 mg, 32.4 pmol) and tri-O-tolylphosphine (39.4 mg, 129 pmol). The reaction was aerated with argon and subjected to stirring at 120 ° C for 18 h, then divided between saturated aqueous ammonium chloride solution and dichloromethane. The organic layer was washed with saline, dried over magnesium sulfate, filtered and evaporated. Chromatography (silica gel, gradient dichloromethane to dichloromethane / methanol / 25% aqueous ammonia solution, 90: 10: 0.25) produced the title compound (431 mg, 9)%). Light brown solid. MS: 296, 2 (M + H) + . Step 2: Ethyl 3 - [4-cyano -2 - [(5-methyltetrazol -2-yl) methyl] phenyl] propanoate [00212] To a light brown color suspension of ethyl (E) -3 - [4-cyano -2 - [(5-methylthetrazol -2-yl) methyl] phenyl] prop -2 -enoate (431 mg, 1.45 mmol) in methanol (6 mL) palladium (CAS -RN 7440 -05 -3; 89.4 mg, 84) pmol) and a hydrogen atmosphere. After 17 h at room temperature the reaction was aerated with argon, filtered over a diatomaceous filter and rinsed with methanol. The mother liquor was completely evaporated to provide the crude title product (286 mg, 66%). Gray viscous oil, MS: 300.2 (M + H) + . Step 3: Acid 3 - [4 -Cyan -2 ~ [(5 Petition 870190091123, of 9/13/2019, p. 134/164 128/132 methyltetrazol -2 -11) methyl] phenyl] propanoic [00213] To a colorless solution of ethyl 3 - [4 - cyano -2 - [(5-methyltetrazol -2-yl) methyl] phenyl] propanoate (79, 1 mg, 264 pmol) in tetrahydrofuran (1 ml) and ethanol (0.5 ml) a 1 M aqueous solution of lithium hydroxide monohydrate (CAS -RN 1310 -66 -3; 793 μΐ, 793 pmol) was added . The reaction was subjected to stirring at room temperature for 4 h, then poured over ice and acidified with 2 M aqueous hydrochloric acid solution to pH 1. The aqueous phase was extracted with ethyl acetate, then the organic phase was washed with solution saline, dried over magnesium sulfate, filtered and evaporated to yield the title compound (66 mg, 92%). White solid. MS: 270.3 (M-H) ~. [00214] The intermediates set out below were prepared according to intermediate 13, substituting the appropriate starting material for 4-bromo -3 - [(5-methyltetrazol -2 -yl) methyl] benzonitrile. At the . Systematic name Starting material MS, m / e 13.1 Acid 3 - [4-chloro -2 [(5-methylthetrazol -2 yl) methyl] phenyl]propanoic 2 - [(2 -bromo -5chlorophenyl) methyl] -5 methyltetrazole (CAS -RN 1646389 -12 -9) 279, 2(M-H) ~ 13.2 Acid 3 - [4(difluoromethoxy) -2 - [(5-methyltetrazole -2 -yl)methyl] phenyl] propanoic 2 - [[2 -bromo -5(difluoromethoxy) phenyl] methyl] -5 -methyltetrazole(CAS -RN 1646786 -22 -2) 313, 1 (M + H) + Intermediate 14 Petition 870190091123, of 9/13/2019, p. 135/164 129/132 [5-Chloro -3 - [(5-methylthetrazol -2-yl) methyl] pyridin -2 -yl] methanol Step 1: Methyl 5-chloro -3 - [(5-methyltetrazol -2-yl) methyl] pyridine -2-carboxylate [00215] Methyl 3 - (bromomethyl) -5 chloropyridine -2-carboxylate (CAS -RN) was dissolved 1260667 -62 -6; 500 mg, 1.51 mmol) in acetone (10 mL) and potassium carbonate (209 mg, 1.51 mmol) and 5-methyl -2H -tetrazole (CAS -RN 4076 -36 -2 130 mg, 1.51 mmol) were added at room temperature. The resulting suspension was subjected to stirring for 2 h under reflux (60 ° C) and then partitioned between ice-water and ethyl acetate. The organic layer was washed with saline, dried over magnesium sulfate, filtered and evaporated. Chromatography (silica gel, gradient pure heptane to heptane: ethyl acetate = 2: 1) produced the title compound (185 mg, 46%). White solid, MS: 268.1 (M + H) +. Step 2: [5-Chloro -3 - [(5-methyltetrazol -2-yl) methyl] pyridin -2-yl] methanol [00216] The title compound was produced in analogy to intermediate 1, step 2 by replacing the ethyl 2 - [(5-methyltetrazol -2-yl) methyl] -4 - (trifluoromethyl) benzoate by methyl 5-chloro -3 - [((5-methyltetrazol -2-yl) methyl] pyridine -2-carboxylate. Semi-solid and white, MS: 240.1 (M + H) + . Intermediate 15 tert - butyl 4 - (2,3-difluoro -4-sulfamoyl phenyl) sulfonylpiperidine -1-carboxylate [00217] To a solution of tert - butyl 4 - (2,3 difluoro -4-sulfamoyl phenyl) sulfanylpiperidine -1 Petition 870190091123, of 9/13/2019, p. 136/164 130/132 carboxylate (intermediate 9.2; 94 mg, 23) pmol) in glacial acetic acid (3 mL) was added hydrogen peroxide (35% in water; 76 mg, 782 pmol). The resulting solution was subjected to stirring at room temperature for 96 h and then it was partitioned between ice and ethyl acetate. The organic layer was washed with water and saline, dried over magnesium sulfate, filtered and evaporated. Chromatography (silica gel, gradient from pure heptane to heptane: ethyl acetate = 1: 2) yielded the title compound (94 mg, 74%). White solid, MS: 439.2 (M-H) ~. [00218] The intermediates shown below were prepared according to intermediate 15, replacing tert - butyl 4 - (2,3-difluoro -4 sulfamoyl phenyl) sulfanylpiperidine -1-carboxylate (intermediate 9.2) with the appropriate thioether. No. Systematic name Tioether MS, m / e 15.1 terc - butyl 3 - (2-fluoro -4-sulfamoyl phenyl)sulfonylazetidine -1carboxylate terc - butyl 3 - (2-fluoro -4-sulfamoyl phenyl)sulfanilazetidine -1carboxylate (intermediate9.3) 393.3(M-H) ~ 15.2 terc - butyl 4 - [(5sulfamoyl -1,3-thiazol -2 yl) sulfonyl] piperidine -1 carboxylate terc - butyl 4 - [(5sulfamoyl -1,3-thiazol -2 yl) sulfanyl] piperidine -1 carboxylate (intermediate9.5) 410.1 (M-H) ~ 15.3 tert - butyl 4 - [2 - (2,3 difluoro -4-sulfamoyl phenyl) sulfonylethyl] piperidine -1 carboxylate tert - butyl 4 - [2 - (2,3 difluoro -4-sulfamoyl phenyl) sulfanylethyl] piperidine —1-carboxylate (intermediate 9.6) 467.2(M-H) ~ Petition 870190091123, of 9/13/2019, p. 137/164 131/132 No. Systematic name Tioether MS, m / e 15.4 terc - butyl 4 - [2 - (5sulfamoiltiofen -2 -yl)sulfonylethyl] piperidine -1 carboxylate terc - butyl 4 - [2 - (5sulfamoiltiofen -2 —il)sulfanylethyl] piperidine -1 carboxylate (intermediate9.8) 437.1(M-H) ~ Intermediate 16 tert-butyl-4 - [2 - (2-fluoro -4-sulfamoyl phenyl) sulfonylethyl] piperidine -1-carboxylate [00219] The title compound was produced in analogy to intermediate 15, replacing tert-butyl4 - (2,3-difluoro -4-sulfamoyl phenyl) sulfanyl piperidine 1-carboxylate (intermediate 9.2) by tert-butyl-4 - [2 - (2-fluoro -4-sulfamoyl phenyl) sulfinylethyl] piperidine -1 carboxylate (intermediate 10.4). White solid, MS: 449, 3 (M-H) h Intermediate 17 6-cyclobutyloxy-5-cyclopropylpyridine-3-carboxylic acid [00220] To a colorless solution of 5-bromo6-cyclobutyloxy pyridine-3-carboxylic acid (CAS-RN 1364678-465; 1 g, 3.68 mmol) in toluene (25 mL ) and water (2.8 mL) were added cesium carbonate (3.59 g, 11.0 mmol), palladium (II) acetate (16.5 mg, 73.5 pmol), potassium cyclopropyl trifluoroborate (CAS-RN 1065010 - 87-8; 598 mg, 4.) 4 mmol) and butyldi-1-adamantyl phosphine (CAS-RN 32192171-5; 79.1 mg, 221 pmol). The reaction mixture was degassed and aerated with argon three times and then stirred under 120 ° C for 16 h. The mixture was divided between ice and 1 M aqueous hydroxide solution Petition 870190091123, of 9/13/2019, p. 138/164 132/132 sodium and dichloromethane. The organic layer was washed with saline, dried over magnesium sulfate, filtered and evaporated. Recrystallization from ethyl acetate gave the title compound (610 mg, 71%). Off-white solid, 234.4 (M + H) + . Example A [00221] A compound of formula (I) can be used in a manner known per se as ingredient active for the production ofcomposition:Active ingredientMicro-crystalline celluloseMaize starchBaby powderHydroxypropyl methylcelluloseExample B tablets as followsPer pill200 mg155 mg2 5 mg2 5 mg20 mg42 5 mg [00222] A compound of formula (I ) Can be used in a manner known per se as an active ingredient for the production of capsules of the following composition: Per capsule Active ingredient 100, 0 mg Corn starch 20, 0 mg Lactose 95, 0 mg Baby powder 4.5 mg Magnesium stearate 0.5 mg 220.0 mg
权利要求:
Claims (34) [1] 1. Compounds of formula (I) / 1 / R Y-N X-W R 1 / Yf K (I) where R 1 is selected from 1) phenyl substituted by R 3 , R 4 and R 5 , ii) pyridinyl substituted by R 3 , R 4 and R 5 , and iii) thiophenyl substituted by R 3 , R 4 and R 5 ; X is selected from I) N, and II) CH; Y is selected from D -ch 2 -oc (O) 11) - (CH 2 ) q C (O) ill) - (CH = CH) r -C (O) and iv) - (CH ^ CH) r -C (O) W is selected from I) - (CR 9 R 10 ) p -, II) - (CR 9 R 10 ) p -C (O) ill) - (CR 9 R 10 ) P -O-, iv) - (CR 9 R 10 ) P -S-, v) - (CR 9 R 10 ) p -S (O) and vi) - (CR 9 R 10 ) p -S (O) 2 -; R and selected from 1) substituted phenyl, where the phenyl ring is replaced by R 6 , R 7 and R 8 , ii) substituted pyridinyl, where the pyridinyl ring is Petition 870190091123, of 9/13/2019, p. 140/164 [2] 2/20 replaced by R 6 , R 7 and R 8 , iii) substituted thiophenyl, where the thiophenyl ring is replaced by R 6 , R 7 and R 8 , and iv) substituted thiazolyl, where the thiazolyl ring is replaced by R 6 , R 7 and R 8 ; O R and selected from i) halo-C1-6-alkoxy, ii) Cs-g-cycloalkyl, iii) Cs-g-cycloalkyl-C1-e-alkyl, iv) C3-8-cycloalkyl-C1-alkoxy, v) Cs-s-cycloalkoxy, vi) Cs-s-cycloalkoxy-C1-e-alkyl, vii) tetrazolylmethyl, viii) triazolylmethyl, ix) pyrazolylmethyl, x) C1-6-alkylthetrazolylmethyl, xi) C1-6-alkyltriazolylmethyl, xii) C1-6-alkylpyrazolylmethyl, xiii) heterocycloalkyl-C1-6 alkoxy; R 4 is selected from i) halogen, ii) hydroxy, iii) cyano, iv) C1-6-alkyl, v) Ci-6-alkoxy, vi) Ci-6-alkoxy-CI 6 -alkyl, vii) halo-Ci-6-alkoxy, vii) halo-Ci-6-alkyl, ix) hydroxy-Ci-6 alkyl, x) C3-8-cycloalkyl, Petition 870190091123, of 9/13/2019, p. 141/164 [3] 3/20 xi) C3-C 8 -cicloalquila _ 6 alkyl, xii) C 3 -C 8 -alkyl -cicloalquila _ 6 alkoxy, xii) C 3 _ 8 -cicloalcoxi xiv) Cl - C3-8 -cicloalcoxi _ 6 alkyl, xv) C _ 6 alkylcarbonylamino, xvi) C 3 -C 8 -cicloalquila carbonylamino, R 5 is selected from i) H, ii) halogen, iii) hydroxy, iv) cyan, v) C 6 _ alkyl, vi) C 6 _ alkoxy, vii) C 6 _ alkoxy-6 _ alkyl, viii) halo-Ci-6 _ alkoxy, ix) halo-Ci-6 _ alkyl, x) hydroxy-C _ 6 alkyl, xi) C 3 -C 8 -cicloalquila xii) C 3 -C 8 -alkyl -cicloalquila _ 6 alkyl, xiii) C 3 -C 8 -alkyl -cicloalquila _ 6 alkoxy, xii) C 3 _ 8 -cycloalkoxy, xv) C3- 8 -cycloalkoxy-Ci- 6 _ alkyl, xvi) C1-6 _ alkylcarbonylamino, xvii) C3- 8 -cycloalkyl carbonylamino, R 6 is comprised of aminosulfonyl; R 7 and R 8 are independently selected from i) H, ii) halogen, iii) hydroxy, iv) cyan, Petition 870190091123, of 9/13/2019, p. 142/164 [4] 4/20 v) Ci-6-alkyl, vi) Ci-6-alkoxy, vii) Ci-6-alkoxy-CI 6 -alkyl, viii) halo-Ci-6-alkoxy, ix) halo-Ci-6-alkyl, x) hydroxy-C1-6-alkyl, xi) Cs-g-cycloalkyl, xii) Cs-g-cycloalkyl-C1-e-alkyl, xiii) C3-8-cycloalkyl-C1-6-alkoxy, xiv) Cs- s-cycloalkoxy, and xv) Cs-s-cycloalkoxy-C1-e-alkyl; R 9 and R 10 are selected independently from i) H, ii) C1-6 alkyl, and iii) Cs-s-cycloalkyl; men are selected independently from zero, 1, 2, 3, 4 or 5, with the proviso that the sum of m and n is understood by 2.3.4 or 5; p is selected a leave in zero, 1 or q is selected a leave in zero or 2; r is selected leave in zero and 1; or the pharmaceutically acceptable salts. A compound according to claim 1, wherein R 1 is selected from 1) phenyl substituted by R 3 , R 4 and R 5 , and ii) pyridinyl substituted by R 3 , R 4 and R 5 ; X is selected from i) N, and ii) CH; Y is selected from Petition 870190091123, of 9/13/2019, p. 143/164 [5] 5/20 i) -CH2-OC (Ο) -, and ii) - (CH 2 ) q C (Ο) -; W is selected from 1) - (CR 9 R 1) ) p-, ID-iCR ^ 1 ') PC (0) -, iii) - (CR 9 R 1) ) pO-, iv) - (CR 9 R 1) ) pS-, v) - (CR 9 R 1) ) P -S (0) -, and vi) - (0 R 9 R 1! ) P -S (O) 2 -; R and selected from 1) substituted phenyl, in which the phenyl ring is substituted by R 6 , R 7 and R 8 , ii) pyridinylsubstituted replaced, where the ring with R 6 , R 7 and R 8 , in pyridinyl is iii) thiophenylsubstituted replaced, where the ring with R 6 , R 7 and R 8 , and in thiophenyl is iv) substituted thiazolyl substituted, wherein the ring is R 6 , R 7 and R 8 ; in tiazolil is R and selected from 1) halo-Ci-6-alkoxy, ii) cyano, iii) C3-8 cycloalkyl-CI 6-alkoxy, iv) Cs-g-cycloalkoxy, v) C1-6-alkyl tetrazolylmethyl, and vi) tetrahydropyranyl-C1-8-alkoxy; R 4 is selected from 1) halogen, ii) cyano, iii) halo-C1-6-alkoxy, iv) halo-C1-6-alkyl, Petition 870190091123, of 9/13/2019, p. 144/164 [6] 6/20 v) C 3 - 8 -cycloalkyl, and vi) C1-6-alkyl carbonylamino; R 5 is comprised of Η; R 6 is comprised of aminosulfonyl; R 7 and R 8 are independently selected from i) H, and ii) halogen; R 9 and R 1 'are both comprised by H; m is selected from zero, 1 and 2 and n is selected from 1, 2 and 3, with the proviso that the sum of m and n is understood by 2, 3, 4 or 5; p is selected from zero, 1 and 2; q is selected from zero and 2; or the pharmaceutically acceptable salts. A compound according to claim 1 or 2, wherein R 1 is selected from i) phenyl substituted by R 3 , R 4 and R 5 , and ii) pyridinyl substituted by R 3 , R 4 and R 5 . A compound according to claim 1 or 2, wherein R 1 is comprised of phenyl substituted by R 3 , R 4 and R 5 . A compound according to claim 1 or 2, wherein Y is selected from i) -CH 2 -OC (0) -, and ii) - (CH 2 ) q C (0) -. A compound according to claim 1 or 2, wherein Y is comprised of - (CH 2 ) q C (O). [7] 7. A compound according to claim 1 or 2, wherein W is selected from i) (- (CR 9 R 4) ) p -, ii) - (CR 9 R 4) ) P -S-, and Petition 870190091123, of 9/13/2019, p. 145/164 7/20 iii) - (CR 9 R 1) ) p -S (O) 2 -. [8] A compound according to claim 1 or 2, wherein R is selected from i) substituted phenyl, in which the phenyl ring is replaced by R 6 , R 7 and R 8 , and ii) substituted pyridinyl, where the pyridinyl ring is replaced by R 6 , R 7 and R 8 . [9] A compound according to claim 1 or 2, wherein R is selected from i) halo-C1-6-alkoxy, ii) cyano, iii) Cs-g-cycloalkyl-C1-e-alkoxy, iv) Cs-s-cycloalkoxy, v) C1-6-alkylthetrazolylmethyl, and vi) tetrahydropyranyl-C1-e-alkoxy; [10] 10. A compound according to claim 1 or 2, wherein R is selected from i) C1-6-alkyl tetrazolylmethyl, and ii) tetrahydropyranyl-C1-8-alkoxy. [11] A compound according to claim 1 or 2, wherein R 4 is selected from i) halogen, ii) cyano, iii) halo-C1-6-alkoxy, iv) halo-C1-6-alkyl, v) C3-8-cycloalkyl, and vi) C1-6-alkyl carbonylamino; [12] 12. A compound according to claim 1 or 2, wherein R 4 is selected from i) halo-C1-6-alkyl, and Petition 870190091123, of 9/13/2019, p. 146/164 Ii) Cs-g-cycloalkyl. [13] A compound according to claim 12, wherein R 5 is comprised of Η. [14] A compound according to claim 1 2, where R 7 and R 8 are independently selected from i) H, and ii) halogen. [15] A compound according to claim 1 2, where R 7 is comprised of halogen. [16] 16. A compound according to claim 1 2, where R 8 is selected from i) H, and ii) halogen. [17] 17. A compound according to claim 1 2, where R 9 and R 1 'are both comprised by H. [18] 18. A compound according to claim 1 2, where m is selected from zero, 1 and 2 and n is selected from 1, 2 and 3, with the proviso that the sum of m and n is understood by 2, 3, 4 or 5. [19] 19. A compound according to claim 1 2, where men are both comprised of 2. [20] 20. A compound according to claim 1 2, where p is selected from zero and 1. [21] 21. A compound according to claim 1 2, where p is comprised of zero. [22] 22. A compound according to claim 1 2, where q is comprised of 2. [23] A compound according to claim 1 or 2 that either or or or or or or or or or or Petition 870190091123, of 9/13/2019, p. 147/164 9/20 R 1 is selected from i) phenyl substituted by R 3 , R 4 and R 5 , and ii) pyridinyl substituted by R 3 , R 4 and R 5 ; X is selected from i) N, and ii) CH; Y is selected from i) -CH2-OC (O) and ii) - (CH 2 ) q C (O) W is selected from D-ÍCR ^ 1 ') p -, iD-ÍCR ^ 1 ') p -C (O) -, iii) - (CR 9 R 4) ) pO-, iv) - (CR 9 R 4) ) P - S-, v) - (CR 9 R 4) ) pS (O) and vi) - (CR 9 R 4) ) pS (O) 2 -; R and selected from i) substituted phenyl, in which the phenyl ring is replaced by R 6 , R 7 and R 8 , ii) substituted pyridinyl, where the pyridinyl ring is replaced by R 6 , R 7 and R 8 , ii) substituted thiophenyl, where the thiophenyl ring is replaced by R 6 , R 7 and R 8 , and iv) substituted thiazolyl, wherein the thiazolyl ring is replaced by R 6 , R 7 and R 8 ; O R and selected from i) halo-Ci-6-alkoxy, ii) cyano, iii) C3-8 cycloalkyl-CI 6-alkoxy, iv) Cs-g-cycloalkoxy, Petition 870190091123, of 9/13/2019, p. 148/164 10/20 v) C1-6-alkyl tetrazolylmethyl, and vi) tetrahydropyranyl-C1-8-alkoxy; R 4 is selected from i) halogen, ii) cyano, iii) halo-C1-6-alkoxy, iv) halo-C1-6-alkyl, v) Cs-g-cycloalkyl, and vi) C1-6-alkyl carbonylamino; R 5 is comprised of Η; R 6 is comprised of aminosulfonyl; R 7 and R 8 are independently selected from i) H, and ii) halogen; R 9 and R 1 'are both comprised by H; m is selected from zero, 1 and 2 and n is selected from 1, 2 and 3, with the proviso that the sum of m and n is understood by 2, 3, 4 or 5; p is selected from zero, 1 and 2; q is selected from zero and 2; or the pharmaceutically acceptable salts. [24] 24. A compound according to any one of claims 1 to 20, selected from 2 - ((5-methyl -2H -tetrazol -2 -yl) methyl) -4 - (trifluoromethyl) benzyl 4 - (2-fluoro -4-sulfamoyl phenyl) piperazine -1-carboxylate; [2-cyclopropyl -6 - (oxan -4-ylmethoxy) pyridin 4 -yl] methyl 4 - [(4-sulfamoyl phenyl) methyl] piperidine -1-carboxylate; [5-cyano -3 - (2,2-dimethyl propanoyl amino) Petition 870190091123, of 9/13/2019, p. 149/164 11/20 pyridin -2 -11] methyl 4 - [(4-sulfamoyl phenyl) methyl piperidine -1-carboxylate; [5 -chloro -3 - [(5 -methyltetrazole -2 -11) methyl pyridin -2 -11] methyl 4 - (2-fluoro -4-sulfamoyl phenyl sulfonylpiperidine -1-carboxylate; [2 - [(5-methyltetrazol -2 -11) methyl] -4 (trifluoromethyl) phenyl] methyl 4 - (2-fluoro -4-sulfamoyl phenyl) sulfonylpiperidine -1-carboxylate; 2-fluoro -4 - [[4 - [3 - [2 - [(5-methyltetrazol -2-yl) methyl] -4 - (trifluoromethyl) phenyl] propanoyl] piperazin -1 -yl] methyl] benzene sulfonylamide; 3-fluoro -4 - [[4 - [3 - [2 - [(5-methyltetrazol -2-yl) methyl] -4 - (trifluoromethyl) phenyl] propanoyl] piperazin -1 -yl] methyl] benzene sulfonylamide; 4 - [[4 - [2-cyclopropyl-6 - (oxan -4-ylmethoxy) pyridine -4-carbonyl] piperazin -1 -11] methyl] -3 fluorobenzene sulfonylamide; 3-fluoro -4 - [4 - [3 - [2 - [(5-methyltetrazol -2 yl) methyl] -4 - (trifluoromethyl) phenyl] propanoyl] piperazine -1-carbonyl] benzene sulfonylamide; 2-fluoro -4 - [4 - [3 - [2 - [(5-methyltetrazol -2 yl) methyl] -4 - (trifluoromethyl) phenyl] propanoyl] piperazine -1-carbonyl] benzene sulfonylamide; 3,5 -difluoro -4 - [4 - [3 - [2 - [(5-methylthetrazol -2 -11) methyl] -4 - (trifluoromethyl) phenyl] propanoyl] piperazine -1 -carbonyl] benzene sulfonylamide; 3-fluoro -4 - [4 - [3 - [2 - [(5-methylthetrazol -2 yl) methyl] -4 - (trifluoromethyl) phenyl] propanoyl] piperazine -1 -carbonyl] benzene sulfonylamide; 4 - (4 - (3 - (2 - ((5-methyl -2H -tetrazole -2 -11) Petition 870190091123, of 9/13/2019, p. 150/164 12/20 methyl) -4 - (trifluoromethyl) phenyl) propanoyl) piperazine -1-carbonyl) benzene sulfonylamide; 3 - [[1 - [2-cyclopropyl-6 - (oxan -4-ylmethoxy) pyridine -4-carbonyl] piperidin -4 -yl] methyl] -4 fluorobenzene sulfonylamide; 3-fluoro -4 - [1 - [3 - [2 - [(5-methyltetrazol -2 yl) methyl] -4 - (trifluoromethyl) phenyl] propanoyl] piperidin -4 -yl] sulfanyl benzene sulfonylamide; 3-fluoro -4 - (4 - (3 - (2 - ((5-methyl -2H tetrazol -2-yl) methyl) -4 - (trifluoromethyl) phenyl) propanoyl) piperazin -1-yl) benzene sulfonylamide; 4 - [[1 - [2-cyclopropyl-6 - (oxan -4-ylmethoxy) pyridine -4-carbonyl] piperidin -4 -yl] methyl] benzene sulfonylamide; 4 - [[1 - [3 - [2 - [(5-methyltetrazol -2-yl) methyl] -4 - (trifluoromethyl) phenyl] propanoyl] piperidin -4 -yl] methyl] benzene sulfonylamide; 4 - [[1 - [3 - [2 - [(5-methyltetrazol -2-yl) methyl] -4 - (trifluoromethyl) phenyl] propanoyl] pyrrolidin -2 -yl] methoxy] benzene sulfonylamide; 4 - [[1 - [3 - [2 - [(5-methyl-tetrazol-2-yl) methyl] -4 - (trifluoromethyl) phenyl] propanoyl] pyrrolidin-3-yl] methoxy] benzene sulfonylamide; 4 - (1 - (3 - (2 - ((5-methyl -2H -tetrazol -2 -yl) methyl) -4 - (trifluoromethyl) phenyl) propanoyl) piperidin -4 -yl) benzene sulfonylamide; 4 - (4 - (3 - (2 - ((5-methyl -2H -tetrazol -2 -yl) methyl) -4 - (trifluoromethyl) phenyl) propanoyl) piperazin -1 -yl) benzene sulfonylamide; 4-fluoro -3 - [[1 - [3 - [2 - [(5-methyltetrazole -2 Petition 870190091123, of 9/13/2019, p. 151/164 13/20 -11) methyl] -4 - (trifluoromethyl) phenyl] propanoyl] piperidin -4 -yl] methyl] benzene sulfonylamide; 2,3-difluoro -4 - [1 - [3 - [2 - [(5-methylthetrazol -2-yl) methyl] -4 - (trifluoromethyl) phenyl] propanoyl] piperidin -4 -yl] sulfanyl benzene sulfonylamide; 2,3-difluoro -4 - [1 - [3 - [2 - [(5-methylthetrazol -2-yl) methyl] -4 - (trifluoromethyl) phenyl] propanoyl] piperidin -4 -yl] sulfinyl benzene sulfonylamide; 2,3 -difluoro -4 - [1 - [3 - [2 - [(5-methylthetrazol -2 -yl) methyl] -4 - (trifluoromethyl) phenyl] propanoyl] piperidin -4 -yl] sulfonylbenzene sulfonylamide; 2,3 -difluoro -4 - [2 - [1 - [3 - [2 - [(5 methyltetrazol -2-yl) methyl] -4 - (trifluoromethyl) phenyl] propanoyl] piperidin -4 -yl] ethylsulfonyl] benzene sulfonylamide; 2 - [1 - [3 - [2 - [(5-methyltetrazol -2-yl) methyl] -4 - (trifluoromethyl) phenyl] propanoyl] piperidin -4 -yl] sulfanyl -1,3-thiazole -5 -sulfonamide ; 2 - [1 - [3 - [2 - [(5-methyltetrazol -2-yl) methyl] -4 - (trifluoromethyl) phenyl] propanoyl] piperidin -4 -yl] sulfonyl -1,3-thiazole -5 -sulfonamide ; 2 - [2 - [1 - [3 - [2 - [(5-methyltetrazol -2-yl) methyl] -4 - (trifluoromethyl) phenyl] propanoyl] piperidin -4 -yl] ethylsulfinyl] -1,3-thiazole -5 -sulfonamide; 3-fluoro -4 - [[1 - [3 - [2 - [(5-methylthetrazol -2-yl) methyl] -4 - (trifluoromethyl) phenyl] propanoyl] piperidin -4 -yl] methylsulfanyl] benzene sulfonylamide; 3-fluoro -4 - [[1 - [3 - [2 - [(5-methylthetrazol -2-yl) methyl] -4 - (trifluoromethyl) phenyl] propanoyl] piperidin -4 -yl] methylsulfinyl] benzene sulfonylamide; Petition 870190091123, of 9/13/2019, p. 152/164 14/20 3-fluoro -4 - [[1 - [3 - [2 - [(5-methylthetrazol -2-yl) methyl] -4 - (trifluoromethyl) phenyl] propanoyl] piperidin -4 -yl] methylsulfonyl] benzene sulfonylamide; 3-fluoro -4 - [1 - [3 - [2 - [(5-methyltetrazol -2 yl) methyl] -4 - (trifluoromethyl) phenyl] propanoyl] azetidin -3 -yl] sulfanyl benzene sulfonylamide; 3-fluoro -4 - [1 - [3 - [2 - [(5-methylthetrazol -2 yl) methyl] -4 - (trifluoromethyl) phenyl] propanoyl] azetidin -3 -yl] sulfinyl benzene sulfonylamide; 3-fluoro -4 - [1 - [3 - [2 - [(5-methyltetrazol -2 yl) methyl] -4 - (trifluoromethyl) phenyl] propanoyl] azetidin -3 -yl] sulfonylbenzene sulfonylamide; 3-fluoro -4 - [1 - [3 - [2 - [(5-methyltetrazol -2 yl) methyl] -4 - (trifluoromethyl) phenyl] propanoyl] piperidin -4 -yl] sulfinyl benzene sulfonylamide; 3-fluoro -4 - [1 - [3 - [2 - [(5-methyltetrazol -2 yl) methyl] -4 - (trifluoromethyl) phenyl] propanoyl] piperidin -4 -yl] sulfonylbenzene sulfonylamide; 3-fluoro -4 - [2 - [1 - [3 - [2 - [(5-methyltetrazol -2-yl) methyl] -4 - (trifluoromethyl) phenyl] propanoyl] piperidin -4 -yl] ethylsulfanyl] benzene sulfonylamide ; 3-fluoro -4 - [2 - [1 - [3 - [2 - [(5-methyltetrazol -2-yl) methyl] -4 - (trifluoromethyl) phenyl] propanoyl] piperidin -4 -yl] ethylsulfinyl] benzene sulfonylamide ; 3-fluoro -4 - [2 - [1 - [3 - [2 - [(5-methyltetrazol -2-yl) methyl] -4 - (trifluoromethyl) phenyl] propanoyl] piperidin -4 -yl] ethylsulfonyl] benzene sulfonylamide ; 3-fluoro -4 - [2 - [1 - [6 - (2,2,2-trifluoroethoxy) -5 - (trifluoromethyl) pyridine -3-carbonyl] piperidin -4 yl] ethylsulfonyl] benzene sulfonylamide; Petition 870190091123, of 9/13/2019, p. 153/164 15/20 3-fluoro -4 - [4 - [3 - [2 - [(5-methyltetrazol -2 yl) methyl] -4 - (trifluoromethyl) phenyl] propanoyl] piperazin -1 -yl] sulfonylbenzene sulfonylamide; 4 - [[1 - [2-cyclopropyl-6 - (oxan -4-ylmethoxy) pyridine -4-carbonyl] piperidin -4 -yl] methylsulfanyl] -3-fluorobenzene sulfonylamide; 4 - [[1 - [2-cyclopropyl-6 - (oxan -4-ylmethoxy) pyridine -4-carbonyl] piperidin -4 -yl] methylsulfinyl] -3-fluorobenzene sulfonylamide; 4 - [[1 - [2-cyclopropyl-6 - (oxan -4-ylmethoxy) pyridine -4-carbonyl] piperidin -4 -yl] methylsulfonyl] -3-fluorobenzene sulfonylamide; 4 - [1 - (6-cyclobutyloxy -5-cyclopropylpyridine -3-carbonyl) piperidin -4-yl] sulfonyl -3-fluorobenzene sulfonylamide; 4 - [1 - [2-cyclopropyl-6 - (oxan -4-ylmethoxy) pyridine -4-carbonyl] azetidin-3 -yl] sulfanyl-3 fluorobenzene sulfonylamide; 4 - [1 - [2-cyclopropyl-6 - (oxan -4-ylmethoxy) pyridine -4-carbonyl] azetidin-3 -yl] sulfinyl-3 fluorobenzene sulfonylamide; 4 - [1 - [2-cyclopropyl -6 - (oxan -4-ylmethoxy) pyridine -4-carbonyl] azetidin -3 -yl] sulfonyl -3 fluorobenzene sulfonylamide; 4 - [1 - [2-cyclopropyl-6 - (oxan -4-ylmethoxy) pyridine -4-carbonyl] piperidin -4 -yl] sulfonyl -2,3 difluorobenzene sulfonylamide; 4 - [1 - [2-cyclopropyl -6 - (oxan -4-ylmethoxy) pyridine -4-carbonyl] piperidin -4 -yl] sulfonyl -3 fluorobenzene sulfonylamide; Petition 870190091123, of 9/13/2019, p. 154/164 16/20 4 - [1 - [3 - [4-chloro -2 - [(5-methyltetrazol -2 11) methyl] phenyl] propanoyl] piperidin -4 -11] sulfonyl -3-fluorobenzene sulfonylamide; 4 - [1 - [3 - [4-cyano -2 - [(5-methyltetrazol -2 11) methyl] phenyl] propanoyl] piperidin -4 -11] sulfonyl -3-fluorobenzene sulfonylamide; 4 - [2 - [1 - [2-cyclopropyl -6 - (oxan -4 ylmethoxy) pyridine -4-carbonyl] piperidin -4 — yl] ethylsulfanyl] -3-fluorobenzene sulfonylamide; 4 - [2 - [1 - [2 -cyclopropyl -6 - (oxan -4 ylmethoxy) pyridine -4-carbonyl] piperidin -4 — yl] ethylsulfinyl] -3-fluorobenzene sulfonylamide; 4 - [2 - [1 - [2 -cyclopropyl -6 - (oxan -4 ylmethoxy) pyridine -4-carbonyl] piperidin -4 — yl] ethylsulfonyl] -3-fluorobenzene sulfonylamide; 4 - [2 - [1 - [5 -cyclopropyl -6 (cyclopropylmethoxy) pyridine -3-carbonyl] piperidin -4 11] ethylsulfonyl] -3-fluorobenzene sulfonylamide; 4 - [4 - [2-cyclopropyl-6 - (oxan -4-ylmethoxy) pyridine -4-carbonyl] piperazin -1 -11] sulfonyl-3 fluorobenzene sulfonylamide; 4 - [4 - [3 - [2 - [(5-methyltetrazol -2 -11) methyl] -4 - (trifluoromethyl) phenyl] propanoyl] piperazin -1 -11] sulfonylbenzene sulfonylamide; 5 - [1 - [3 - [2 - [(5-methyltetrazole -2 -11) methyl] -4 - (trifluoromethyl) phenyl] propanoyl] piperidin -4 -11] sulfanylthiophene -2-sulfonamide; 5 - [2 - [1 - [3 - [2 - [(5-methyltetrazol -2 -11) methyl] -4 - (trifluoromethyl) phenyl] propanoyl] piperidin -4 -11] ethylsulfonyl] thiophene -2-sulfonamide; Petition 870190091123, of 9/13/2019, p. 155/164 17/20 5-fluoro -6 - [1 - [3 - [2 - [(5-methylthetrazol -2 yl) methyl] -4 - (trifluoromethyl) phenyl] propanoyl] piperidin -4 -yl] sulfanylpyridine -3 -sulfonamide; 6 - [1 - [2-cyclopropyl -6 - (oxan -4-ylmethoxy) pyridine -4-carbonyl] piperidin -4 -yl] sulfanyl -5 fluoropyridine -3-sulfonamide; 4 - [1 - [3 - [4 - (difluoromethoxy) -2 - [(5 methyltetrazole -2 -il) methyl] phenyl] propanoyl] piperidin -4 -il] sulfonyl -3 -fluorobenzene sulfonylamide; 4 - [2 - [1 - [3 - [4 - (difluoromethoxy ) -2 - [(5 - methyltetrazole -2 -il) methyl] phenyl] propanoyl] piperidin -4 -yl] ethylsulfinyl] -2,3-difluorobenzene sulfonylamide; 2,3 -difluoro -4 - [2 - [1 - [3 - [2 - [(5 - methyltetrazol -2-yl) methyl] -4 - (trifluoromethyl) phenyl] propanoyl] piperidin -4 -yl] ethylsulfinyl] benzene sulfonylamide; 2 - [2 - [1 - [3 - [4 - (difluoromethoxy) -2 - [(5 methyltetrazol -2-yl) methyl] phenyl] propanoyl] piperidin -4 -yl] ethylsulfinyl] -1,3-thiazole - 5 -sulfonamide; 2 - [2 - [1 - [3 - [2 - [(5-methyltetrazol -2-yl) methyl] -4 - (trifluoromethyl) phenyl] propanoyl] piperidin -4 -yl] ethylsulfonyl] -1,3-thiazole -5 -sulfonamide; (+) -3-fluoro -4 - [[1 - [3 - [2 - [(5 methyltetrazol -2-yl) methyl] -4 - (trifluoromethyl) phenyl] propanoyl] piperidin -4 -yl] sulfinyl] benzene sulfonylamide; (+) -4 - [[1 - [3 - [2 - [(5-methylthetrazol -2-yl) methyl] -4 - (trifluoromethyl) phenyl] propanoyl] pyrrolidin -2 -yl] methoxy] benzene sulfonylamide; (+) -4 - [[1 - [3 - [2 - [(5-methylthetrazol -2-yl) Petition 870190091123, of 9/13/2019, p. 156/164 18/20 methyl] -4 - (trifluoromethyl) phenyl] propanoyl] pyrrolidin -3-yl] methoxy] benzene sulfonylamide; (-) -3-fluoro -4 - [[1 - [3 - [2 - [(5 methyltetrazol -2-yl) methyl] -4 - (trifluoromethyl) phenyl] propanoyl] piperidin -4 -yl] sulfinyl] benzene sulfonylamide; (-) -4 - [[1 - [3 - [2 - [(5-methyltetrazol -2-yl) methyl] -4 - (trifluoromethyl) phenyl] propanoyl] pyrrolidin -2 -yl] methoxy] benzene sulfonylamide; (-) -4 - [[1 - [3 - [2 - [(5-methylthetrazol -2-yl) methyl] -4 - (trifluoromethyl) phenyl] propanoyl] pyrrolidin -3 -yl] methoxy] benzene sulfonylamide; 4 - ((4 - (3 - (2 - ((5-methyl -2H -tetrazol -2 -yl) methyl) -4 - (trifluoromethyl) phenyl) propanoyl) piperazin -1 -yl) methyl) benzene sulfonylamide; and their pharmaceutically acceptable salts. [25] 25. A compound according to any one of claims 1 to 21, selected from 3-fluoro -4 - [[4 - [3 - [2 - [(5-methyltetrazol -2-yl) methyl] -4 - (trifluoromethyl) phenyl] propanoyl] piperazin -1 -yl] methyl] benzene sulfonylamide; 2,3 -difluoro -4 - [1 - [3 - [2 - [(5-methylthetrazol -2 -yl) methyl] -4 - (trifluoromethyl) phenyl] propanoyl] piperidin -4 -yl] sulfonylbenzene sulfonylamide; 3-fluoro -4 - [1 - [3 - [2 - [(5-methyltetrazol -2 yl) methyl] -4 - (trifluoromethyl) phenyl] propanoyl] piperidin -4 -yl] sulfonylbenzene sulfonylamide; 3-fluoro -4 - [4 - [3 - [2 - [(5-methyltetrazol -2 yl) methyl] -4 - (trifluoromethyl) phenyl] propanoyl] piperazin -1 -yl] sulfonylbenzene sulfonylamide; Petition 870190091123, of 9/13/2019, p. 157/164 19/20 4 - [1 - [2-cyclopropyl-6 - (oxan -4-ylmethoxy) pyridine -4-carbonyl] piperidin -4 -11] sulfonyl -2,3 difluorobenzene sulfonylamide; 4 - [1 - [2-cyclopropyl-6 - (oxan -4-ylmethoxy) pyridine -4-carbonyl] piperidin -4 -11] sulfonyl-3 fluorobenzene sulfonylamide; 5-fluoro -6 - [1 - [3 - [2 - [(5-methylthetrazol -2 11) methyl] -4 - (trifluoromethyl) phenyl] propanoyl] piperidin -4 -11] sulfanylpyridine -3 -sulfonamide; and their pharmaceutically acceptable salts. [26] 26. Process for preparing a compound according to any one of claims 1 to 22, which comprises reacting a compound of formula (II) in the presence of a compound of formula (III); [27] 27. A compound according to any one of claims 1 to 22, for use in the form of a therapeutically active substance. [28] 28. Pharmaceutical composition comprising a Petition 870190091123, of 9/13/2019, p. 158/164 A compound according to any one of claims 1 to 22 and a therapeutically inert carrier. [29] 29. Use of a compound according to any one of claims 1 to 22, for the treatment or prophylaxis of eye conditions. [30] A compound according to any one of claims 1 to 22, for the treatment or prophylaxis of eye conditions. [31] 31. Use of a compound according to any one of claims 1 to 22, for the preparation of a medicament for the treatment or prophylaxis of eye conditions. [32] 32. Method for the treatment or prophylaxis of ocular conditions, which method comprises administering an effective amount of a compound according to any one of claims 1 to 22. [33] A compound according to any one of claims 1 to 22, when manufactured according to the process of claim 26. [34] 34. The invention as described in the present case.
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同族专利:
公开号 | 公开日 PE20191757A1|2019-12-12| CR20190423A|2019-11-01| AU2018233079A1|2019-08-29| EP3596059A1|2020-01-22| JP2020514355A|2020-05-21| CL2019002609A1|2020-02-14| WO2018167001A1|2018-09-20| SG11201908560SA|2019-10-30| CO2019009373A2|2019-09-09| US20200002297A1|2020-01-02| TW201838982A|2018-11-01| CA3053329A1|2018-09-20| RU2019132254A|2021-04-16| IL269188D0|2019-11-28| AU2018233079B9|2021-07-22| RU2019132254A3|2021-06-04| IL269188A|2021-12-01| CN110392679A|2019-10-29| AR111279A1|2019-06-26| US11059794B2|2021-07-13| MX2019010772A|2019-12-16| AU2018233079B2|2021-06-24| KR20190129924A|2019-11-20| PH12019502118A1|2020-07-06| MA49879A|2020-06-24|
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法律状态:
2021-07-20| B07D| Technical examination (opinion) related to article 229 of industrial property law [chapter 7.4 patent gazette]|Free format text: DE ACORDO COM O ARTIGO 229-C DA LEI N? 10196/2001, QUE MODIFICOU A LEI N? 9279/96, A CONCESS?O DA PATENTE EST? CONDICIONADA ? ANU?NCIA PR?VIA DA ANVISA. CONSIDERANDO A APROVA??O DOS TERMOS DO PARECER N? 337/PGF/EA/2010, BEM COMO A PORTARIA INTERMINISTERIAL N? 1065 DE 24/05/2012, ENCAMINHA-SE O PRESENTE PEDIDO PARA AS PROVID?NCIAS CAB?VEIS. | 2021-08-24| B07E| Notification of approval relating to section 229 industrial property law [chapter 7.5 patent gazette]| 2021-10-19| B350| Update of information on the portal [chapter 15.35 patent gazette]|
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申请号 | 申请日 | 专利标题 EP17161249|2017-03-16| PCT/EP2018/056140|WO2018167001A1|2017-03-16|2018-03-13|Heterocyclic compounds useful as dual atx/ca inhibitors| 相关专利
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