Phenyl-sulfamoylbenzoic acid derivatives as ERAP1 modulators

Abstract

The present invention relates to a compound represented by formula (I) 2 -; Z is a monocyclic or polycyclic cycloalkyl group or a monocyclic or polycyclic heterocycloalkyl group, each of which is selected from haloalkyl, alkyl, alkenyl, alkynyl and -(CR 16 R 17 ) m R 18 wherein m is 0 to 6; L is a direct bond or (CR 14 R 15 ) n group, n is 1 or 2; R 1 is H, CN, Cl or F or alkyl; R 2 is selected from COOH and a tetrazolyl group; R 3 is selected from H, halo, alkoxy, and alkyl; R 4 is selected from H and halo; R 5 is H, alkyl, haloalkyl, SO 2 - selected from alkyl, Cl, alkoxy, OH, CN, hydroxyalkyl, alkylthio, heteroaryl, cycloalkyl, heterocycloalkyl and haloalkoxy; R 6 is H;R 7 H, CN, haloalkyl, halo, SO 2 -Alkyl, SO 2 NR 12 R 13 , Heteroaryl, CONR 10 R 11 and alkyl, said heteroaryl group being optionally substituted with one or more substituents selected from alkyl, halo, alkoxy, CN, haloalkyl, and OH; R 9 is selected from H, alkyl and halo; R 10 , R 11 , R 12 and R 13 are each independently H or alkyl; R 14 and R 15 are each independently H, halo, or alkyl; R 16 and R 17are each independently H, halo, haloalkyl, or alkyl; 18 are independently selected from OH, CN, alkoxy and halo, or a pharma- ceutically acceptable salt or hydrate thereof. A further aspect of the invention relates to such compounds for use in the field of immuno-oncology and related applications. [Formula 1] JPEG2024530447000173.jpg4870

Description

[Technical field]

[0001] The present invention relates to a compound capable of modulating ERAP1. The compound has potential therapeutic applications in the treatment of various disorders, including proliferative, viral, immune and inflammatory disorders. [Background technology]

[0002] ERAP1 (Endoplasmic Reticulum Aminopeptidase 1; also called APPILS or ARTS1) is an aminopeptidase important for the generation of a proportion of antigens and neoantigens as part of the antigen presentation pathway. 1 The antigen presentation pathway begins with proteolysis into peptides by the proteasome. These peptides are delivered to the endoplasmic reticulum, where a proportion are processed by ERAP1 before binding to the Major Histocompatibility Complex Class I (MHC Class I). 1 The antigen bound to MHC class I is then transported to the cell surface and bound to CD8 + Neoantigens are presented to T cells and recognized as self or non-self. Neoantigens are antigens specific to cancer and can be recognized as foreign by the immune system leading to the destruction of cancer cells. Neoantigens arise as a direct result of somatic mutations in the DNA of cancer cells leading to the production of mutant proteins, or as an indirect consequence of somatic mutations on protein processing and expression. Those cancers with higher mutation rates, and correspondingly higher levels of neoantigens, have much higher response rates to checkpoint inhibitor immunotherapeutics anti-PD-1 (e.g. pembrolizumab, nivolumab), anti-PD-L1 (e.g. atezolizumab, avelumab, durvalumab) and anti-CTLA4 antibodies (e.g. ipilimumab, tremelimuab) compared to cancers with a lower number of neoantigens. 2,3 .

[0003] The role of ERAP1 in the antigen presentation pathway is to trim a certain percentage of peptides by its aminopeptidase activity to form antigens and neoantigens of optimal length for binding to MHC class I. ERAP1 also excessively trims some neoantigens, preventing their binding to MHC class I and presentation on the cell surface. 4 It has been shown that removal of ERAP1 activity alters the antigen and neoantigen repertoire, resulting in increased presentation of certain antigens / neoantigens and completely new antigens / neoantigens. 5 Furthermore, ERAP1 deletion suppressed CD8 + Inducing T cell-dependent tumor rejection 4 .

[0004] Therefore, modulators of ERAP1 activity may be useful in cancer treatment, either alone or in combination with current cancer immunotherapy agents, including checkpoint inhibitors, to change the antigens and neoantigens presented on the surface of cancer cells, making them more visible to the immune system and resulting in tumor attack and destruction.

[0005] Knockdown of ERAP1 has also been shown to reduce levels of regulatory T cells and enhance cancer cell killing by natural killer cells. 6,7 This suggests that modulators of ERAP1 activity may be effective cancer therapeutics by modulating cancer cell visibility and generating higher antitumorigenic immune responses. The role of ERAP1 in peptide processing in antigen presentation is also applicable to infectious viral diseases.

[0006] Maben et al (J. Med. Chem. 2020; 63, 103-121) disclose compounds that selectively inhibit ERAP1 relative to its paralogs ERAP2 and IRAP. WO 2020 / 104822, WO 2020 / 225569, WO 2021 / 094763 and WO 2022 / 064187 (Grey Wolf Therapeutics Limited) disclose a series of arylsulfonamide compounds that can modulate ERAP1. [Prior art documents] [Patent documents]

[0007] [Patent Document 1] International Publication No. 2020 / 104822 Brochure [Patent Document 2] International Publication No. 2020 / 225569 Brochure [Patent Document 3] International Publication No. 2021 / 094763 Brochure [Patent Document 4] International Publication No. 2022 / 064187 Brochure [Non-patent literature]

[0008] [Non-Patent Document 1] Maben et al (J. Med. Chem. 2020; 63, 103-121) Summary of the Invention [Problem to be solved by the invention]

[0009] The present invention further aims to provide a compound that can modulate ERAP1. Such a compound has potential therapeutic applications in the treatment of various disorders, including proliferative disorders, immune disorders, and inflammatory disorders. [Means for solving the problem]

[0010] The first aspect of the present invention is a compound represented by formula (I) [ka] (In the formula, The XY group is -NHSO 2 - and; Z is a monocyclic or polycyclic cycloalkyl group or a monocyclic or polycyclic heterocycloalkyl group, each of which is selected from the group consisting of haloalkyl, alkyl, alkenyl, alkynyl and -(CR 16 R 17 ) m R 18 wherein m is 0 to 6; L is a direct bond or (CR 14 R 15 ) n group, n is 1 or 2; R 1 is selected from H, CN, Cl, F and alkyl; R 2 is selected from COOH and a tetrazolyl group; R 3 is selected from H, halo, alkoxy, and alkyl; R 4 is selected from H and halo; R 5 is H, alkyl, haloalkyl, SO 2 - selected from alkyl, Cl, alkoxy, OH, CN, hydroxyalkyl, alkylthio, heteroaryl, cycloalkyl, heterocycloalkyl and haloalkoxy; R 6 is H; R 7 H, CN, haloalkyl, halo, SO 2 -Alkyl, SO 2 NR 12 R 13 , Heteroaryl, CONR 10 R 11and alkyl, said heteroaryl group being optionally substituted with one or more substituents selected from alkyl, halo, alkoxy, CN, haloalkyl, and OH; R 8 is selected from H, alkyl, haloalkyl, and halo; R 9 is selected from H, alkyl and halo; R 10 , R 11 , R 12 and R 13 are each independently selected from H and alkyl; R 14 and R 15 are each independently selected from H, halo, and alkyl; R 16 and R 17 are each independently selected from H, halo, haloalkyl, and alkyl; Each R 18 are independently selected from OH, CN, alkoxy, and halo. or a pharma- ceutically acceptable salt or hydrate thereof.

[0011] The present invention also includes the enantiomers of the compounds of formula (I) and mixtures of enantiomers, including racemates.

[0012] Advantageously, the compounds claimed in the present application can modulate ERAP1, which makes the compounds therapeutically interesting in the treatment of various disorders, for example, in the fields of oncology and immuno-oncology. In particular, the compounds according to the present invention show excellent ability against ERAP1.

[0013] A second aspect of the present invention relates to a pharmaceutical composition comprising at least one compound as described above and a pharma- ceutically acceptable carrier, diluent or excipient.

[0014] A third aspect of the invention relates to a compound as described above for use in medicine.

[0015] A fourth aspect of the invention relates to a compound as described above for use in the treatment or prevention of a disorder selected from a proliferative disorder, an immune disorder, a viral disorder and an inflammatory disorder.

[0016] A fifth aspect of the invention relates to the use of a compound as described above in the preparation of a medicament for the treatment or prevention of a disorder selected from a proliferative disorder, an immune disorder, a viral disorder and an inflammatory disorder.

[0017] A sixth aspect of the present invention relates to the above-mentioned compound for use in preventing or treating a disorder caused by, related to, or accompanied by any abnormal ERAP1 activity.

[0018] A seventh aspect of the present invention relates to use of the above-mentioned compound in preparing a medicine for preventing or treating a disorder caused by, related to, or accompanied by abnormal ERAP1 activity.

[0019] An eighth aspect of the present invention relates to a method for treating a mammal having a disease condition that is alleviated by modulating ERAP1, the method comprising administering a therapeutically effective amount of the above-mentioned compound to the mammal.

[0020] A ninth aspect of the present invention relates to the above-mentioned compound for use in the treatment or prevention of a disease state that is alleviated by modulating ERAP1.

[0021] A tenth aspect of the present invention relates to use of the above-mentioned compound in preparing a medicament for treating or preventing a disease state that is alleviated by modulating ERAP1.

[0022] An eleventh aspect of the present invention relates to a method of treating or preventing a disorder selected from a proliferative disorder, an immune disorder, a viral disorder and an inflammatory disorder in a subject, the method comprising the step of administering to the subject a therapeutically effective amount of a compound as described above. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0023] The present invention relates to a bis-arylsulfonamide compound capable of modulating ERAP1.

[0024] "Alkyl" as used herein refers to a linear or branched alkyl radical, preferably C 1-20 Alkyl, more preferably C 1-12 Alkyl, even more preferably C 1-10 Alkyl or C 1-6 Alkyl is defined as, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, hexyl. Preferably, the alkyl group is 1-4 It is an alkyl group.

[0025] "Cycloalkyl" as used herein refers to a cyclic alkyl ring, preferably C 3-7 -cycloalkyl, more preferably C 3-6 -cycloalkyl. Preferred examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl, or fused bicyclic ring systems such as norbornane.

[0026] "Halogen" is defined herein as chloro, fluoro, bromo, or iodo.

[0027] "Haloalkyl" is defined herein as a straight or branched alkyl radical as defined above, substituted with one or more halogen atoms, which may be the same or different, such as fluorine, chlorine, bromine and iodine, e.g., methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, hexyl. Preferably, haloalkyl is a C 1-20 Haloalkyl, more preferably C 1-12 Haloalkyl, even more preferably C 1-10 Haloalkyl or C 1-6 Haloalkyl or C 1-3 A preferred example is CF 3 and CHF 2and CF 3 is particularly preferred.

[0028] "Alkoxy" is defined herein as an oxygen atom attached to an alkyl group as defined above, e.g., methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, tert-butoxy, pentoxy, and hexoxy. Preferably, alkoxy is C 1-20 Alkoxy, more preferably C 1-12 Alkoxy, even more preferably C 1-10 Alkoxy or C 1-6 Alkoxy or C 1-3 A particularly preferred example is methoxy (-OCH 3 ).

[0029] As used herein, the term "alkenyl" refers to both straight and branched carbon chains having at least one carbon-carbon double bond. In some embodiments, an alkenyl group is 2 -C 12 In another embodiment, the alkenyl is C 2 -C 10 , C 2 -C 8 , C 2 -C 6 Or C 2 -C 4 In one embodiment of alkenyl, the number of double bonds is 1-3, and in another embodiment of alkenyl, the number of double bonds is 1. Other ranges of carbon-carbon double bonds and carbon numbers are also contemplated depending on the location of the alkenyl moiety on the molecule. 2 -C 10 An "alkenyl" group may contain two or more double bonds within the chain.

[0030] As used herein, the term "alkynyl" refers to both straight and branched carbon chains having at least one carbon-carbon triple bond. In some embodiments, an alkynyl group is 2 -C 12In another embodiment, the alkynyl group is C 2 -C 10 , C 2 -C 8 , C 2 -C 6 Or C 2 -C 4 In one embodiment of alkynyl, the number of triple bonds is 1 to 3, and in another embodiment of alkynyl, the number of triple bonds is 1. A particularly preferred alkynyl group is -C≡CH.

[0031] As used herein, the term "polycyclic group" means a group that contains two or more cyclic groups, which may be fused, unfused, bridged, or spirocyclic.

[0032] As used herein, the term "aryl" refers to an optionally benzo-fused C 6-12 It refers to an aromatic group, such as phenyl or naphthyl.

[0033] "Heteroaryl" as used herein refers to a monocyclic or bicyclic C ring containing one or more heteroatoms (which may be the same or different), such as oxygen, nitrogen or sulfur. 2-12Examples of suitable heteroaryl groups include thienyl, furanyl, pyrrolyl, pyridinyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiadiazolyl, and the like, and benzo derivatives thereof, such as benzofuranyl, benzothienyl, benzimidazolyl, indolyl, isoindolyl, indazolyl, and the like; or pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl, tetrazolyl, and the like, and benzo derivatives thereof, such as quinolinyl, isoquinolinyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, naphthyridinyl, and the like.Particularly preferred heteroaryl groups are 1H-imidazol-5-yl, 1H-imidazol-4-yl, 1H-imidazol-2-yl, 1H-pyrrol-1-yl, 1H-pyrrol-2-yl, 1H-pyrrol-3-yl, 1H-pyrrol-4-yl, 1H-pyrrol-5-yl, 1H-pyrazol-1-yl, 1H-pyrazol-5-yl, 1H-pyrazol-3-yl, 1H-pyrazol-4-yl, oxazol-2 ...2-yl, 1H-pyrrol-2-yl, 1H-pyrrol-2-yl, 1H-pyrrol-2-yl, 1H-pyrrol-2-yl, 1H-pyrrol-2-yl, 1H-pyrrol-2-yl, 1H-pyrrol-2-yl, 1H-pyrrol-2-yl, 1H-pyrrol-2-yl, 1H-pyrrol-2-yl, 1H-pyrrol-2-yl, 1H-pyrrol-2-yl, 1H-pyrrol-2-yl, 1H-pyrrol-2-yl, 1H-pyrrol-2-yl, 1H-pyrrol-2-yl, 1H-pyrrol-2-yl, 1H-pyr -yl, oxazol-4-yl, oxazol-5-yl, 1H-1,2,4-triazol-3-yl, 1H-1,2,4-triazol-5-yl, 1H-1,2,4-triazol-1-yl, 1H-1,2,3-triazol-4-yl, 1H-1,2,3-triazol-5-yl, 1H-1,2,3-triazol-1-yl, thiazol-5-yl, thiazol-4-yl, 1H-1,2,3,4-tetrazolium 4-yl, 2H-1,2,3,4-tetrazol-5-yl, oxazol-5-yl, oxazol-4-yl, oxazol-2-yl, isoxazol-3-yl, isoxazol-4-yl, isoxazol-5-yl, isothiazol-3-yl, isothiazol-4-yl, isothiazol-5-yl, pyrazidin-3-yl, pyrazidin-4-yl, pyrazinyl, 1,3,4-oxadiazole- Examples of oxadiazol-2-yl include 1,3,4-oxadiazol-5-yl, 1,2,5-oxadiazol-3-yl, 1,2,5-oxadiazol-4-yl, 1,2,3-oxadiazol-4-yl, 1,2,3-oxadiazol-5-yl, 1,2,4-oxadiazol-3-yl, 1,2,4-oxadiazol-5-yl, isoxazol-5-yl, isoxazol-4-yl and isoxazol-3-yl.

[0034] "Heterocycloalkyl" refers to a cyclic aliphatic group containing one or more heteroatoms selected from nitrogen, oxygen and sulfur, which may be interrupted by one or more -(CO)- groups in the ring and / or may contain one or more double bonds in the ring. Preferably, the heterocycloalkyl group is monocyclic or bicyclic. Preferably, the heterocycloalkyl group is C 3-7-heterocycloalkyl, more preferably C 3-6 -heterocycloalkyl. Alternatively, the heterocycloalkyl group is 4-7 -heterocycloalkyl, more preferably C 4-6 -heterocycloalkyl. Preferred heterocycloalkyl groups include, but are not limited to, piperazinyl, piperidinyl, morpholinyl, thiomorpholinyl, pyrrolidinyl, tetrahydrofuranyl, and tetrahydropyranyl.

[0035] When the compounds of the present invention contain one or more chiral centers, the present invention includes all enantiomers and diastereomers thereof, as well as mixtures thereof.

[0036] By way of example, the point of attachment to the Z group (shown for purposes of illustration as a simple 5-membered monocycloalkyl group, but equally applicable to Z groups in general) may be in one of the following configurations: [ka]

[0037] The present invention encompasses compounds of any of the above configurations, as well as mixtures thereof, including racemic mixtures.Those skilled in the art will appreciate that the absolute stereochemistry (R- and S-) at the chiral centers marked * depends on the nature of the Z group and the nature and position of any substituents on the Z group.

[0038] In one preferred embodiment, the compound is in the form of a mixture of R- and S-enantiomers. In one preferred embodiment, the mixture is a racemic mixture, i.e. a 50:50 mixture of R- and S-enantiomers of the compound.

[0039] The enantiomerically pure R- and S-forms can be prepared from the racemic mixture by standard methods known to those skilled in the art, such as chemical transformation with an optically active acid or column chromatography using a substantially optically active (or "chiral") stationary phase or reverse phase column chromatography to separate the enantiomers. The racemic mixture can also be used to prepare enantiomerically enriched mixtures of the S- and R-forms. Mixtures enriched in the R- or S-enantiomer can also be obtained from appropriate enantiomerically enriched precursors.

[0040] In one preferred embodiment of the invention, the compound is in the form of a mixture comprising enantiomers in a weight:weight ratio of at least about 2:1 or more, preferably at least about 5:1 or more, and most preferably at least about 10:1 or more, in favor of the enantiomer (eutomer) that exhibits greater in vitro and / or in vivo activity.

[0041] In one embodiment, the compound is in the form of a mixture comprising the S-enantiomer and the R-enantiomer in a weight:weight ratio of R-enantiomer to S-enantiomer greater than 1.05:1, more preferably greater than 2:1, even more preferably greater than 5:1, and even more preferably greater than 10:1.

[0042] In one embodiment, the compound is in the form of a mixture comprising the S- and R-enantiomers, substantially enriched in the R-enantiomer.

[0043] In one embodiment, the compound is in the form of a mixture comprising S-enantiomers and R-enantiomers in a weight:weight ratio of S-enantiomer to R-enantiomer greater than 1.05:1, more preferably greater than 2:1, even more preferably greater than 5:1, and even more preferably greater than 10:1.

[0044] In one embodiment, the compound is in the form of a mixture comprising the S- and R-enantiomers, substantially enriched in the S-enantiomer.

[0045] Compounds of formula (I) One aspect of the present invention is a compound represented by formula (I) [ka] (In the formula, The XY group is -NHSO 2 -OR-SO 2 NH-; Z is a monocyclic or polycyclic cycloalkyl group or a monocyclic or polycyclic heterocycloalkyl group, each of which is selected from the group consisting of haloalkyl, alkyl, alkenyl, alkynyl and -(CR 16 R 17 ) m R 18 wherein m is 0 to 6; L is a direct bond or (CR 14 R 15 ) n group, n is 1 or 2; R 1 is selected from H, CN, Cl, F and alkyl; R 2 is selected from COOH and a tetrazolyl group; R 3 is selected from H, halo, alkoxy, and alkyl; R 4 is selected from H and halo; R 5 is H, alkyl, haloalkyl, SO 2 - selected from alkyl, Cl, alkoxy, OH, CN, hydroxyalkyl, alkylthio, heteroaryl, cycloalkyl, heterocycloalkyl and haloalkoxy; R 6 is H; R 7 H, CN, haloalkyl, halo, SO 2 -Alkyl, SO2 NR 12 R 13 , Heteroaryl, CONR 10 R 11 and alkyl, said heteroaryl group being optionally substituted with one or more substituents selected from alkyl, halo, alkoxy, CN, haloalkyl, and OH; R 8 is selected from H, alkyl, haloalkyl, and halo; R 9 is selected from H, alkyl and halo; R 10 , R 11 , R 12 and R 13 are each independently selected from H and alkyl; R 14 and R 15 are each independently selected from H, halo, and alkyl; R 16 and R 17 are each independently selected from H, halo, haloalkyl, and alkyl; Each R 18 are independently selected from OH, CN, alkoxy, and halo. and pharma- ceutically acceptable salts and hydrates thereof.

[0046] In one preferred embodiment, XY is -NHSO 2 -, i.e., the compound has the formula [ka] It is a compound of the formula:

[0047] In a preferred embodiment, L is a direct bond.

[0048] In another preferred embodiment, L is (CR 14 R 15 ) n and n is 1 or 2. More preferably, n is 1.

[0049] In one preferred embodiment, R 14 and R 15 are each independently selected from H, Cl and Me. More preferably, R 14 and R 15 are both H.

[0050] In another preferred embodiment, L is (CH 2 ) n and n is 1 or 2. More preferably, n is 1.

[0051] In one highly preferred embodiment, L is CH 2 or CH(Me), even more preferably CH 2 It is.

[0052] In the following embodiments, when Z is a heterocycloalkyl group, the heterocycloalkyl group contains one or more heteroatoms selected from O, S and N, more preferably one or more heteroatoms selected from O and N. Even more preferably, the heterocycloalkyl group contains one or more O atoms. Even more preferably, the heterocycloalkyl group contains one O atom.

[0053] In one preferred embodiment, Z is a monocyclic cycloalkyl group or a monocyclic heterocycloalkyl group, each of which may be substituted. Preferably, Z is a 3-, 4-, 5-, 6- or 7-membered monocyclic cycloalkyl group or a monocyclic heterocycloalkyl group, each of which may be substituted. More preferably, Z is a 4-, 5- or 6-membered monocyclic cycloalkyl group or a monocyclic heterocycloalkyl group, even more preferably a 4- or 5-membered monocyclic cycloalkyl group or a monocyclic heterocycloalkyl group, each of which may be substituted. More preferably, Z is a monocyclic cycloalkyl or a monocyclic heterocycloalkyl group selected from cyclobutyl, cyclopentyl, cyclohexyl, oxetanyl, tetrahydro-2H-pyranyl, azetidinyl and tetrahydrofuranyl. Even more preferably, Z is a monocyclic cycloalkyl or a monocyclic heterocycloalkyl group selected from cyclobutyl, cyclopentyl, oxetanyl, azetidinyl and tetrahydrofuranyl.

[0054] In one preferred embodiment, Z is a 4-membered monocyclic cycloalkyl or a 4-membered monocyclic heterocycloalkyl group, each of which may be optionally substituted. In one preferred embodiment, Z is an optionally substituted 4-membered monocyclic cycloalkyl group. In one preferred embodiment, Z is a cyclobutyl group optionally substituted with one or more substituents selected from CN, halo, alkyl, haloalkyl, OH, and alkoxy. More preferably, Z is selected from CN, F, Me, OH, OMe, and CF 3 In one highly preferred embodiment, Z is an unsubstituted cyclobutyl group.

[0055] In one preferred embodiment, Z is an optionally substituted 4-membered monocyclic heterocycloalkyl group. In one preferred embodiment, Z is an oxetanyl or azetidinyl group, each of which is optionally substituted with one or more substituents selected from alkyl and halo. More preferably, Z is an oxetanyl or azetidinyl group, each of which is optionally substituted with one or more substituents selected from Me and F.

[0056] In one preferred embodiment, Z is a 5-membered monocyclic cycloalkyl or a 5-membered monocyclic heterocycloalkyl group, each of which is optionally substituted.

[0057] In one preferred embodiment, Z is an optionally substituted 5-membered monocyclic cycloalkyl group. In one preferred embodiment, Z is a cyclopentyl group optionally substituted with one or more substituents selected from CN, alkynyl, halo, alkyl, OH, and alkoxy. More preferably, Z is a cyclopentyl group optionally substituted with one or more substituents selected from CN, F, -C≡CH, Me, OH, and OMe.

[0058] In one preferred embodiment, Z is an optionally substituted 5-membered monocyclic heterocycloalkyl group.

[0059] In one preferred embodiment, Z is an optionally substituted polycyclic cycloalkyl group or an optionally substituted polycyclic heterocycloalkyl group, which polycyclic group is fused, unfused, bridged or spirocyclized.

[0060] In one preferred embodiment, Z is an optionally substituted spirocyclic group. As used herein, a spirocyclic group refers to a polycyclic group in which two rings are linked through a common atom. A spirocyclic group may be fully carbocyclic (all carbon) or heterocyclic (having one or more non-carbon atoms). Preferably, each ring is independently a 3-, 4-, 5-, 6-, or 7-membered ring and may contain one or more heteroatoms selected from O, N, and S. More preferably, each ring is independently a 3-, 4-, 5-, or 6-membered ring and may contain one or more heteroatoms selected from O and N. Even more preferably, each ring is independently a 3-, 4-, or 5-membered ring and may contain one or more heteroatoms selected from O and N.

[0061] In a preferred embodiment, Z is an optionally substituted bicyclic spirocyclic group, such as an optionally substituted carbocyclic bicyclic spirocyclic group or an optionally substituted heterocyclic bicyclic spirocyclic group. More preferably, the bicyclic spirocyclic group is selected from the following: spiro[3,3]heptane, spiro[2,4]heptane, spiro[2,3]hexane, 1-oxaspiro[2,3]hexane, 4-oxaspiro[2,3]hexane, 2-oxaspiro[3,3]heptane, 1-oxaspiro[3,3]heptane, 4-oxaspiro[2,4]heptane, 5-oxaspiro[2,4]heptane and 1-oxaspiro[2,4]heptane. Even more preferably, the bicyclic spirocyclic group is selected from spiro[3,3]heptane, spiro[2,4]heptane, spiro[2,3]hexane and 2-oxaspiro[3,3]heptane.

[0062] In another preferred embodiment, Z is a polycyclic group that is a fused cycloalkyl or fused heterocycloalkyl group, each of which may be substituted. As used herein, a fused cycloalkyl or fused heterocycloalkyl group refers to a polycyclic group in which two or more rings are connected by two adjacent atoms. Preferably, each ring is independently a 3-, 4-, 5-, 6-, or 7-membered ring that may contain one or more heteroatoms selected from O, N, and S. More preferably, each ring is independently a 3-, 4-, or 5-membered ring that may contain one or more heteroatoms selected from O and N.

[0063] In another preferred embodiment, Z is a polycyclic group that is a non-fused polycyclic cycloalkyl or a non-fused polycyclic heterocycloalkyl group, each of which may be optionally substituted. As used herein, a non-fused cycloalkyl or a non-fused heterocycloalkyl group refers to a polycyclic group in which two or more rings are linked by direct bonds. Preferably, each ring is a 3-, 4-, 5-, 6-, or 7-membered ring that may independently contain one or more heteroatoms selected from O, N, and S. More preferably, each ring is a 3-, 4-, or 5-membered ring that may independently contain one or more heteroatoms selected from O and N. Preferably, for this embodiment, Z is a non-fused bicyclic cycloalkyl or a non-fused bicyclic heterocycloalkyl group, or a non-fused cycloalkyl-heterocycloalkyl group, each of which may be optionally substituted. In one particularly preferred embodiment, Z is selected from cyclopropyl-cyclobutyl, cyclopentyl-cyclobutyl, cyclopentyl-cyclopropyl, cyclobutyl-cyclobutyl, cyclopropyl-cyclopropyl, and cyclopentyl-cyclopentyl. More preferably, Z is 2-cyclopropyl-cyclobutyl or 3-cyclopropyl-cyclobutyl, even more preferably 2-cyclopropyl-cyclobutyl.

[0064] In one preferred embodiment, Z is a fused cycloalkyl or fused heterocycloalkyl group selected from bicyclo[3.1.0]hexane, bicyclo[4.2.0]octane, decahydronaphthalene, bicyclo[4.1.0]heptane, bicyclo[3.2.0]heptane, octahydropentalene, octahydro-1H-indene, and (1s,2s,3s,4s,6s,7s)-cubane, each of which is optionally substituted.

[0065] In another preferred embodiment, Z is a polycyclic group that is a bridged cycloalkyl or bridged heterocycloalkyl group, each of which may be substituted. As used herein, a bridged cycloalkyl or bridged heterocycloalkyl group refers to a polycyclic group in which two (or more) rings are connected by two non-adjacent atoms. Preferably, each ring is independently a 3-, 4-, 5-, 6-, or 7-membered ring that may contain one or more heteroatoms selected from O, N, and S. More preferably, each ring is independently a 4-, 5-, or 6-membered ring that may contain one or more heteroatoms selected from O and N.

[0066] In one preferred embodiment, Z is a bridged cycloalkyl or bridged heterocycloalkyl group selected from bicyclo[1.1.1]pentane, bicyclo[2.1.1]hexane, 2-oxabicyclo[2.1.1]hexane, 5-oxabicyclo[2.1.1]hexane, bicyclo[2.2.1]heptane, bicyclo[3.2.1]octane, bicyclo[2.2.2]octane, 2-oxabicyclo[2.2.2]octane, 7-oxabicyclo[2.2.1]heptane and 2-oxabicyclo[2.2.1]heptane, each of which may be substituted. More preferably, Z is a bridged cycloalkyl group selected from bicyclo[1.1.1]pentane and 2-oxabicyclo[2.1.1]hexane, each of which may be substituted.

[0067] In one preferred embodiment, Z is a bicyclic cycloalkyl or a bicyclic heterocycloalkyl group, each of which is fused, bridged or spirocyclized, each of which is optionally substituted.

[0068] Throughout this disclosure, Z groups include halogen, haloalkyl, alkyl, alkenyl, alkynyl, and -(CR 16 R 17 ) m R 18 and m is 0 to 6. Preferably, m is 0, 1, 2 or 3, more preferably 0 or 1, and even more preferably 0.

[0069] In one preferred embodiment, R 16 and R 17 are independently H, Cl, F, and C. 1 -C 4 -Alkyl and C 1 -C 1 -haloalkyl. More preferably, R 16 and R 17 are each independently H, Cl, F, or CF 3 and Me. Even more preferably, R 16 and R 17 are both H.

[0070] In one preferred embodiment, the Z group is a halogen, C 1-4 -Haloalkyl, C 1-4 -Alkyl, C 1-4 -Alkenyl, C 1-4 -Alkynyl and -(CR 16 R 17 ) m R 18 and m is 0, 1, 2 or 3. More preferably, m is 0.

[0071] In one preferred embodiment, R 18 is selected from OH, CN, OMe, Cl, Br and F.

[0072] In one preferred embodiment, the Z group is Me, CF 3 , OH, CN, F, OMe, -C≡CH, -CH 2 -C≡CH and -CH 2 CN.

[0073] In one preferred embodiment, Z is [ka] and each Q is independently selected from alkyl, alkoxy, haloalkyl, alkynyl, halo, OH, and CN. More preferably, each Q is independently selected from Me, OMe, CF 3 , F, OH, C≡CH and CN.

[0074] In one preferred embodiment, Z is [ka] and each Q is independently selected from alkyl, alkoxy, haloalkyl, alkynyl, halo, OH, and CN. More preferably, each Q is independently selected from Me, OMe, CF 3 , F, OH, C≡CH and CN.

[0075] In one preferred embodiment, LZ is [ka] is selected from.

[0076] In one preferred embodiment, Z is [ka] JPEG2024530447000010.jpg 186116 JPEG2024530447000011.jpg 177136 JPEG2024530447000012.jpg 196153 JPEG2024530447000013.jpg 170126 JPEG2024530447000014.jpg 187133 JPEG2024530447000015.jpg 92129 are selected.

[0077] Preferably, for the above embodiments, L is a direct bond. In one preferred embodiment, L is a direct bond and Z is a group selected from Z1 to Z-72 above.

[0078] In another preferred embodiment, L is (CR 14 R 15 ) n The LZ is [ka] Selected from JPEG2024530447000017.jpg65132.

[0079] In one highly preferred embodiment, Z is [ka] is selected from.

[0080] In one preferred embodiment, R 1 is selected from H, CN, F and alkyl.

[0081] In one preferred embodiment, R 1 is selected from H, CN and alkyl.

[0082] In one preferred embodiment, R 1 is H.

[0083] In one preferred embodiment, R2 is COOH.

[0084] In one particularly preferred embodiment, X is NH and Y is SO 2 In another preferred embodiment, X is SO 2 and Y is NH. Preferably, X is NH and Y is SO 2 It is.

[0085] In one preferred embodiment, R 3 is selected from H, Cl, F, OMe and Me. More preferably, R 3 is selected from H and F. Even more preferably, R 3 is H.

[0086] In one preferred embodiment, R 4 is selected from H, Cl and F. More preferably, R 4 is selected from H and F.

[0087] In one preferred embodiment, R 5 is alkyl, haloalkyl, SO 2 -alkyl, Cl, alkoxy, OH, CN, hydroxyalkyl, alkylthio, heteroaryl, cycloalkyl, heterocycloalkyl, and haloalkoxy.

[0088] In one preferred embodiment, R 5 is selected from alkyl, alkoxy and cycloalkyl. More preferably, R 5 is cycloalkyl, more preferably cyclopropyl, cyclobutyl or cyclopentyl.

[0089] In one particularly preferred embodiment, R 5 is selected from OMe, OEt, Me, Et and cyclopropyl.

[0090] In another preferred embodiment, R 5 H, Me, CF 3, CHF 2 , S.O. 2 -Me, Cl, MeO, OH, CH 2 More preferably, R is selected from the group consisting of OH, SMe, cyclopropyl, triazolyl, oxetanyl and CN. 5 H, CN, Me, SO 2 -Me, CF 3 and CHF 2 , C.H. 2 OH, SMe, cyclopropyl, 3,4-triazol-1-yl and oxetan-3-yl. More preferably, R 5 H, CN, Me, SO 2 -Me, CF 3 and CHF 2 is selected from.

[0091] In another preferred embodiment, R 5 is selected from OMe, Me, Et, Pr and Cl, more preferably OMe or Et.

[0092] In one particularly preferred embodiment, R 5 is selected from OMe, Et and cyclopropyl.

[0093] In one particularly preferred embodiment, R 5 is cyclopropyl.

[0094] In another preferred embodiment, R 5 is OMe.

[0095] In another preferred embodiment, R 5 is Et.

[0096] In one preferred embodiment, R 7 is H, CN, haloalkyl, Cl, F, SO 2 -Alkyl, CONR 10 R 11 , S.O. 2 NR 16 R 17, heteroaryl and alkyl, said heteroaryl group being optionally substituted with one or more substituents selected from alkyl, halo, alkoxy, CN, haloalkyl and OH.

[0097] In one preferred embodiment, R 7 is H, CN, haloalkyl, Cl, F, SO 2 -Alkyl, CONR 10 R 11 , S.O. 2 NR 12 R 13 , heteroaryl and alkyl, said heteroaryl group being optionally substituted with one or more substituents selected from alkyl, halo, alkoxy, CN, haloalkyl and OH.

[0098] In one preferred embodiment, R 7 is a heteroaryl group optionally substituted with one or more substituents selected from alkyl, halo, alkoxy, CN, haloalkyl, and OH.

[0099] In one preferred embodiment, R 7 is a heteroaryl group selected from pyridinyl, thienyl, imidazolyl, pyrimidinyl, pyrazolyl, pyrazinyl, pyrazidinyl, thiazolyl, isothiazolyl, triazinyl, pyrrolyl, furanyl, oxazolyl, isoxazolyl, oxadiazolyl, tetrazolyl, and triazolyl, each of which is optionally substituted with one or more substituents selected from alkyl, halo, alkoxy, CN, haloalkyl, and OH.

[0100] In one preferred embodiment, R 7is a heteroaryl group selected from imidazolyl, pyrazolyl, pyrazinyl, pyrazidinyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, tetrazolyl, and triazolyl, each of which is optionally substituted with one or more substituents selected from alkyl, halo, alkoxy, CN, haloalkyl, and OH.

[0101] In one preferred embodiment, R 7are 1H-imidazol-5-yl, 1H-imidazol-4-yl, 1H-imidazol-2-yl, 1H-pyrrol-1-yl, 1H-pyrrol-2-yl, 1H-pyrrol-3-yl, 1H-pyrrol-4-yl, 1H-pyrrol-5-yl, 1H-pyrazol-1-yl, 1H-pyrazol-5-yl, 1H-pyrazol-3-yl, 1H-pyrazol-4-yl, oxazol-2-yl, oxazol-4-yl, oxazol-5-yl, 1H-1,2 ,4-triazol-3-yl, 1H-1,2,4-triazol-5-yl, 1H-1,2,4-triazol-1-yl, 1H-1,2,3-triazol-4-yl, 1H-1,2,3-triazol-5-yl, 1H-1,2,3-triazol-1-yl, thiazol-5-yl, thiazol-4-yl, 1H-1,2,3,4-tetrazol-4-yl, 2H-1,2,3,4-tetrazol-5-yl, tetrazol-1-yl, oxazol-5-yl oxazol-4-yl, oxazol-2-yl, isoxazol-3-yl, isoxazol-4-yl, isoxazol-5-yl, isothiazol-3-yl, isothiazol-4-yl, isothiazol-5-yl, pyrazidin-3-yl, pyrazidin-4-yl, pyrazinyl, 1,3,4-oxadiazol-2-yl, 1,3,4-oxadiazol-5-yl, 1,2,5-oxadiazol-3-yl, 1,2,5-oxadiazol- and heteroaryl groups selected from 1,2,3-oxadiazol-4-yl, 1,2,3-oxadiazol-5-yl, 1,2,4-oxadiazol-3-yl, 1,2,4-oxadiazol-5-yl, isoxazol-5-yl, isoxazol-4-yl and isoxazol-3-yl, each of which is optionally substituted by one or more substituents selected from alkyl, halo, CN, alkoxy, haloalkyl and OH.

[0102] In one highly preferred embodiment, R 7is a heteroaryl group selected from 1H-pyrazol-5-yl, 1H-pyrazol-3-yl, 1H-pyrazol-4-yl, oxazol-2-yl, 1H-1,2,3-triazol-4-yl, 1H-1,2,3-triazol-5-yl, thiazol-5-yl, 1H-1,2,3,4-tetrazol-4-yl, 2H-1,2,3,4-tetrazol-5-yl, tetrazol-1-yl, isoxazol-4-yl, isoxazol-5-yl, isothiazol-5-yl, pyrazidin-3-yl, pyrazidin-4-yl, pyrazinyl and 1,3,4-oxadiazol-2-yl, each of which may be substituted by one or more substituents selected from Me, F, Cl, CN and MeO.

[0103] In one highly preferred embodiment, R 7 is a heteroaryl group selected from 1H-1,2,3,4-tetrazol-4-yl, tetrazol-1-yl and 2H-1,2,3,4-tetrazol-5-yl, each of which may be substituted with one or more substituents selected from Me, F, Cl, CN and MeO.

[0104] In one preferred embodiment, R 7 is H, CN, haloalkyl, Cl, F, SO 2 -Alkyl, CONR 10 R 11 , heteroaryl and alkyl, where the heteroaryl group is selected from pyrazol-3-yl, pyrazol-4-yl, pyrazol-5-yl, isothiazol-3-yl, isothiazol-4-yl, isothiazol-5-yl, 1,2,4-triazol-5-yl, tetrazol-1-yl, tetrazol-5-yl, isoxazol-3-yl, isoxazol-4-yl and isoxazol-5-yl, each of which is optionally substituted with one or more substituents selected from alkyl, halo, alkoxy, CN, haloalkyl and OH.

[0105] In one preferred embodiment, R 7CN, haloalkyl, SO 2 -Alkyl, SO 2 NR 16 R 17 ,CONR 10 R 11 and tetrazolyl.

[0106] In one preferred embodiment, R 7 CN, haloalkyl, SO 2 -Alkyl, SO 2 NR 12 R 13 ,CONR 10 R 11 and tetrazolyl.

[0107] In one preferred embodiment, R 7 CF 3 , C.N., C.O.N. 2 , 1H-1,2,3,4-tetrazol-1-yl, SO 2 NH 2 and S.O. 2 Me is selected.

[0108] In one preferred embodiment, R 7 H, CN, CF 3 , CHF 2 , Cl, F, SO 2 -Me, CONH 2 , S.O. 2 NH 2 , heteroaryl and Me. More preferably, R 7 H, CN, Me, SO 2 -Me, CONH 2 , S.O. 2 NH 2 , Tetrazolyl, CF 3 and CHF 2 is selected from.

[0109] In another preferred embodiment, R 7 CN, haloalkyl, SO 2 -Alkyl, SO 2 NH 2 ,CONR10 R 11 and tetrazolyl. More preferably for this embodiment, R 7 CF 3 , CN, SO 2 NH 2 , 1H-1,2,3,4-tetrazol-1-yl, CONH 2 and S.O. 2 From Me, more preferably CF 3 , CN, 1H-1,2,3,4-tetrazol-1-yl and SO 2 Me is selected.

[0110] In one preferred embodiment, R7 is haloalkyl or heteroaryl, more preferably tetrazolyl, isothiazolyl, or isoxazolyl, each of which is optionally substituted.

[0111] In one preferred embodiment, R 7 is selected from tetrazol-1-yl, isothiazol-5-yl, and isoxazol-4-yl, each of which is optionally substituted with one or more substituents selected from alkyl, halo, alkoxy, CN, haloalkyl, and OH.

[0112] In one preferred embodiment, R 7 CN, CF 3 , tetrazol-1-yl, isothiazol-5-yl and 5-methyl-isoxazol-4-yl.

[0113] In another preferred embodiment, R 7 is haloalkyl, more preferably CF 3 It is.

[0114] In one particularly preferred embodiment, R 7 is CN.

[0115] In another preferred embodiment, R 7 SO 2 -alkyl, more preferably SO 2It's me.

[0116] In another preferred embodiment, R 7 SO 2 NR 16 R 17 , more preferably SO 2 NH 2 It is.

[0117] In another preferred embodiment, R 7 SO 2 NR 12 R 13 , more preferably SO 2 NH 2 It is.

[0118] In one preferred embodiment, R 8 is selected from H, alkyl, haloalkyl, and Cl.

[0119] In another preferred embodiment, R 8 is selected from H, alkyl and halo.

[0120] In one preferred embodiment, R 8 is selected from H, Cl, F and Me. More preferably, R 8 is selected from H, Cl and F.

[0121] In another preferred embodiment, R 8 is selected from alkyl and halo. More preferably, R 8 is selected from Me, Cl and F.

[0122] In one preferred embodiment, R 8 is H or haloalkyl, more preferably H or CF 3 , and even more preferably H.

[0123] In one particularly preferred embodiment, R 8 is Cl.

[0124] In one preferred embodiment, R 9 is selected from H, F, Cl and Me, more preferably from H and F. Even more preferably, R 9 is H.

[0125] In one preferred embodiment, R 1 , R 3 , R 4 , R 6 , R 8 and R 9 are all H.

[0126] In one preferred embodiment, R 10 and R 11 are each independently H or Me. More preferably, R 10 and R 11 are both H.

[0127] In one preferred embodiment, R 12 and R 13 are each independently H or Me. More preferably, R 12 and R 13 are both H.

[0128] In one particularly preferred embodiment, XY is NH-SO 2 and; R 1 is H; R 2 is COOH; R 3 is H or F; R 4 is H or F; R 5 is selected from OMe, OEt, Me, Et and cyclopropyl, more preferably selected from OMe, cyclopropyl and Et; R 6 is H; R 7 is selected from CN, tetrazol-1-yl, isothiazol-5-yl and 5-methyl-isoxazol-4-yl; R 8 is selected from H, Cl and F; R 9 is selected from H, Me, Cl and F; L and Z are as defined above.

[0129] In one particularly preferred embodiment, XY is NH-SO 2 and; L is a direct bond, CH 2 and CHMe; R 1 is H; R 2 is COOH; R 3 is H or F; R 4 is H or F; R 5 is selected from OMe, OEt, Me, Et and cyclopropyl, more preferably selected from OMe, cyclopropyl and Et; R 6 is H; R 7 is selected from CN, tetrazol-1-yl, isothiazol-5-yl and 5-methyl-isoxazol-4-yl; R 8 is selected from H, Cl and F; R 9 is selected from H, Me, Cl and F; Z is as defined above and is more preferably selected from Z-1, Z-2 and Z-3.

[0130] In one preferred embodiment, the compound of the present invention has formula (Ia) [ka] where L and Z are as defined according to any one of the above embodiments.

[0131] In one preferred embodiment, the compound of formula (I) is selected from: In the structures depicted herein, where the absolute stereochemistry of a bond is known (e.g., derived from the correct chiral starting material), the assignment is indicated by (R) or (S) in the conventional manner. When the absolute configuration is unknown, the bond is drawn planar (flat) and known descriptors are added, such as "trans racemate", "trans relative", "trans diastereomer D1", etc. [ka] JPEG2024530447000021.jpg155123JPEG2024530447000022.jpg167124JPEG2024530447000023.jpg183122JPEG2024530447000024 .jpg167121JPEG2024530447000025.jpg173124JPEG2024530447000026.jpg166124JPEG2024530447000027.jpg161124JPEG202453 0447000028.jpg180124JPEG2024530447000029.jpg176122JPEG2024530447000030.jpg181125JPEG2024530447000031.jpg186123JPEG2024530447000032.jpg190123JPEG2024530447000033.jpg183121JPEG2024530447000034.jpg132124 and pharma- ceutically acceptable salts and hydrates thereof.

[0132] In one preferred embodiment, the compounds of the invention have an IC of 100 nM to 500 nM, more preferably less than 100 nM, against the decapeptide WRVYEKC(Dnp)ALK-acid (Dnp is dinitrophenylmaleimide) (10mer). 50 Further details of this assay are detailed in the accompanying Examples.

[0133] In one preferred embodiment, the compound of the present invention is selected from compounds 1, 4, 6, 8-13, 16-37, 39-42, 44-51, 53-65, 68-94, 96-100, 102, 103, 105-111, 113-115, 117-126, 128, 130-134, 135-138, and 140-145.

[0134] In an even more preferred embodiment, the compound of the present invention is selected from the following compounds: 1, 8-12, 16-18, 20, 22-25, 27, 29, 33-35, 41, 42, 44, 47-48, 50, 51, 56-64, 69-74, 76-90, 92, 94, 96-100, 102, 103, 105-110, 113-115, 117-121, 123-126, 128, 131, 134, 136-138, 140-142, and 144.

[0135] therapeutic use A further aspect of the invention relates to the compounds described herein for use in medicine. The compounds have particular application in the fields of oncology and immuno-oncology, as described in more detail below.

[0136] Yet another aspect of the present invention pertains to a compound as described herein for use in the treatment or prevention of a disorder selected from a proliferative disorder, an immune disorder, an inflammatory disorder, and a viral disorder.

[0137] In a preferred embodiment, the compound of the present invention modulates ERAP1.

[0138] In one embodiment, the compound inhibits the activity of ERAP1.

[0139] In an alternative embodiment, the compound increases the activity of ERAP1.

[0140] In one embodiment, the compounds of the invention may alter the repertoire of antigens presented.

[0141] One aspect of the present invention pertains to a compound as described herein for use in the treatment of a proliferative disorder. Preferably, the proliferative disorder is cancer or leukemia.

[0142] Cancers include: basal cell carcinoma, biliary tract cancer; bladder cancer; bone cancer; brain and central nervous system cancer; breast cancer; peritoneal cancer; cervical cancer; choriocarcinoma; colon and rectal cancer; connective tissue cancer; digestive system cancer; endometrial cancer; esophageal cancer; eye cancer; head and neck cancer; gastrointestinal cancer (including gastrointestinal cancer); glioblastoma; liver cancer; hepatocellular carcinoma; intraepithelial neoplasia; kidney or renal cancer; laryngeal cancer; leukemia; liver cancer; lung cancer (e.g. small cell lung cancer, non-small cell lung cancer, adenocarcinoma of the lung, and squamous cell carcinoma of the lung); melanoma; myeloma; neuroblastoma; oral cancer (lips, tongue, mouth, and pharynx); ovarian cancer; pancreatic cancer. ;prostate cancer;retinoblastoma;rhabdomyosarcoma;rectal cancer;cancer of the respiratory system;salivary gland cancer;sarcoma;skin cancer;squamous cell carcinoma;gastric cancer;testicular cancer;thyroid cancer;uterine or endometrial cancer;cancer of the urinary system;vulvar cancer;lymphomas, including Hodgkin's and non-Hodgkin's lymphomas and B-cell lymphomas, e.g. low-grade / follicular non-Hodgkin's lymphoma (NHL);small lymphocytic (SL) NHL;intermediate-grade / follicular NHL;intermediate-grade diffuse NHL;high-grade immunoblastic NHL;high-grade immunoblastic NHL;high-grade small noncleaved cell NHL;bulky disease and Waldenstrom's macroglobulinemia; chronic lymphocytic leukemia (CLL); acute lymphoblastic leukemia (ALL); hairy cell leukemia; chronic myeloblastic leukemia; and other carcinomas and sarcomas; and post-transplant lymphoproliferative disorder (PTLD), and abnormal blood vessel proliferation associated with phacomatosis, edema (e.g., associated with brain tumors), and Meigs' syndrome.

[0143] Without wishing to be bound by theory, it is understood that ERAP1 modulators can change at least 10% of the antigen and neoantigen repertoire of cancer cells, as measured using immunopeptidomics and mass spectrometry. Approximately 50% of this change is upregulation of the presentation of certain antigens and neoantigens, while the remaining 50% is the presentation of completely new antigens and neoantigens. Both changes increase the visibility of tumors to the immune system and increase the upregulation of CD8 + T cell repertoire and CD8 + This results in a measurable change in T cell activation state. + Altered T cell responses result in immune-mediated tumor clearance and can potentially be enhanced by combining with cancer therapeutics such as antibody checkpoint inhibitors (e.g., anti-PD-1).

[0144] Without wishing to be bound by theory, it is understood that a modulator of ERAP1 causes the killing of cancer cells by natural killer (NK) cells by disrupting the interaction between a killer cell Ig-like receptor (KIR) or a lectin-like receptor CD94-NKG2A on NK cells and a classical or non-classical MHC-I-peptide (pMHC-I) complex on cancer cells.

[0145] In one preferred embodiment, the disorder is cancer and the compound increases the visibility of cancer cells to the immune system by altering the repertoire of antigens and neoantigens presented to the immune system.

[0146] A further aspect of the invention relates to a method of increasing the visibility of cancer cells to the immune system in a subject by altering the repertoire of antigens and neo-antigens presented to the immune system, said method comprising the step of administering to the subject a compound of formula (I).

[0147] In one preferred embodiment, the compound increases CD8+ T cell responses against cancer cells.

[0148] In one preferred embodiment, the compound of the present invention is for use in the treatment of a disease of uncontrolled cell proliferation, proliferation and / or survival, an inappropriate cellular immune response, or an inappropriate cellular inflammatory response, in particular, the uncontrolled cell proliferation, proliferation and / or survival, an inappropriate cellular immune response, or an inappropriate cellular inflammatory response is modulated by the ERAP1 pathway.

[0149] In one preferred embodiment, the disease of uncontrolled cell increase, proliferation and / or survival, inappropriate cellular immune response, or inappropriate cellular inflammatory response is selected from hematological tumors, solid tumors and / or metastases thereof.

[0150] More preferably, the compounds are for use in the treatment of a disorder selected from leukemia and myelodysplastic syndromes, malignant lymphomas, head and neck tumors including brain tumors and brain metastases, breast tumors including non-small cell and small cell lung tumors, gastrointestinal tumors, endocrine tumors, breast tumors and other gynecological tumors, urological tumors including kidney, bladder and prostate tumors, skin tumors, and sarcomas, and / or metastases thereof.

[0151] The compounds can kill cancer cells, reduce the number of proliferating cells in a cancer, and / or reduce the volume or size of a tumor containing the cancer cells. The compounds can reduce the number of metastatic cancer cells.

[0152] In one embodiment, the compounds may be used (or are intended for use) in the treatment of cancer in subjects who previously had cancer. The compounds may be used to reduce the likelihood of cancer recurrence or the development of additional cancers. The compounds may induce neo-antigens in recurrent or additional cancers to which the subject already has a pre-existing immune response. Thus, the compounds may increase or enhance the immune response against cancer.

[0153] In one embodiment, the compound is for use in preventing cancer. The compound can be used to prevent the onset of cancer. That is, the compound can stimulate an immune response, such as a vaccine response, against future cancers. The compound can stimulate an immune response against neoantigens in the subject. Once cancer has developed in the subject, it can be treated again with the compound (or a different compound) to stimulate the development of the same neoantigen, thereby triggering the subject's existing immune response against the neoantigen to treat or prevent cancer.

[0154] The same or different compounds may be used before and after cancer develops in a subject.

[0155] In one embodiment, the compounds may be used for the prevention of cancer.

[0156] In one embodiment, the subject may have previously had cancer, may have a family history of cancer, may have an elevated risk of developing cancer, may have a genetic predisposition to developing cancer, or may have been exposed to a carcinogen. In one embodiment, the subject may be in remission from cancer.

[0157] One embodiment provides ex vivo generated antigen presenting cells, e.g., dendritic cells (DCs). Antigen presenting cells can be generated ex vivo to present neoantigens, e.g., those generated by the compounds according to the invention. The compounds can be used in methods to generate ex vivo antigen presenting cells that present neoantigens, and the cells can be used as a vaccine against cancer.

[0158] Antigen-presenting cells such as dendritic cells may be pulsed or loaded with neoantigens or genetically modified (via DNA or RNA transfer) to express one, two or more neoantigens. Methods for preparing dendritic cell vaccines are known in the art. Neoantigens may be generated from normal tissues of subjects, and ERAP1 is modulated with a compound according to the present invention. The source of normal tissue may be fibroblasts or B cells, which can be easily expanded in vitro, for example. Alternatively, RNA from cancer, total or mRNA-enriched polyA+RNA may be used. PolyA+RNA may also be amplified to generate sufficient antigens for DC loading, thereby limiting ex vivo culture steps.

[0159] In one embodiment, dendritic cells treated with the above-mentioned compounds can be used to treat a subject. The dendritic cells can be contacted with the compounds ex vivo, and then the dendritic cells can be administered to a subject. Thus, the compounds can be used in vitro or in vivo, for example, following either in situ or ex vivo treatment, followed by administration of the treated cells to a subject.

[0160] Another aspect of the present invention relates to a compound as described above for use in the treatment of an immune disorder. In one preferred embodiment, the immune disorder is an autoimmune disorder.

[0161] Examples of autoimmune disorders include, but are not limited to, rheumatoid arthritis (RA), myasthenia gravis (MG), multiple sclerosis (MS), systemic lupus erythematosus (SLE), autoimmune thyroiditis (Hashimoto's thyroiditis), Graves' disease, inflammatory bowel disease, autoimmune uveoretinitis, polymyositis and certain types of diabetes, systemic vasculitis, polymyositis-dermatomyositis, systemic sclerosis (scleroderma), Sjogren's syndrome, ankylosing spondylitis and related spinal arthropathy, rheumatic fever, hypersensitivity pneumonitis, allergic bronchopulmonary aspergillosis, inorganic dust 53rimethylamine, sarcoidosis, autoimmune hemolytic anemia, and autoimmune 53rimethylamine-associated inflammatory diseases. anemia), immunological platelet disorders, cryopathies such as cryofibrinogenemia, psoriasis, Behcet's disease, scattershot retinochoroidopathy and autoimmune polyendocrinopathy.

[0162] Polymorphisms in the ERAP1 gene that affect ERAP1 enzyme activity are strongly associated with increased risk of autoimmune diseases, including ankylosing spondylitis, psoriasis, Behcet's disease, and shatter-like chorioretinopathy. 11 ERAP1 variants that reduce ERAP1 enzyme activity protect against disease, whereas those that increase activity have been reported to be associated with increased disease risk. 12 This suggests that modulating ERAP1 activity may be an effective treatment for autoimmune diseases.

[0163] Thus, in one preferred embodiment, the immune disorder is selected from ankylosing spondylitis, psoriasis, Behcet's disease and shotcretinopathy.

[0164] In one preferred embodiment, the immune disorder is ankylosing spondylitis. Ankylosing spondylitis (AS) is a type of arthritis in which there is long-term inflammation in the joints of the spine. Typically, the joints where the spine connects to the pelvis are also affected. Other joints such as the shoulder or hip may also be involved. It affects 0.1%-1.8% of the population, typically in young adults. The cause of ankylosing spondylitis is unknown, but a combination of genetic and environmental factors is involved. Over 90% of affected individuals have a specific human leukocyte antigen known as the HLA-B27 antigen. 13 Furthermore, certain variants of ERAP1, in conjunction with HLA-B27, are clearly associated with either increased or decreased risk of disease, providing evidence for a clear role of modulated antigen presentation in disease. 18 There is no cure for ankylosing spondylitis, and current treatments only provide symptomatic improvement and prevention of worsening. Medications used to date include NSAIDs, steroids, DMARDs such as sulfasalazine, and biologic agents such as infliximab.

[0165] In one preferred embodiment, the immune disorder is Behcet's disease (BD). Behcet's disease (BD) is a type of inflammatory disorder that affects multiple parts of the body. The most common symptoms include painful mouth sores, genital pain, inflammation of parts of the eye, and arthritis. The cause is unclear and environmental factors are involved, but genetic studies have shown an increased risk of the disease in patients with HLA-B51 in conjunction with certain variants of ERAP1. 19The disease is primarily characterized by autoinflammation of blood vessels and may therefore be characterized as an autoinflammatory disease. There is currently no cure for Behcet's disease, but symptoms can be controlled with medications that reduce inflammation in affected parts of the body, such as corticosteroids, immunosuppressants, or biological therapies that target biological processes involved in the inflammatory process. In one preferred embodiment, the immune disorder is shotgun retinochoroidopathy. Also known as Birdshot Uveitis or HLA-A29 uveitis, shotgun retinochoroidopathy is a rare form of bilateral posterior uveitis that affects the eyes. It causes severe and progressive inflammation of both the choroid and retina. Symptoms include floaters, blurred vision, photopsia (flashes of light in the eye), loss of color vision, and night blindness. Shotgun retinochoroidopathy is considered an autoimmune disease. The disease is strongly associated with human leukocyte antigen haplotype (HLA)-A29. This indicates a role for T lymphocytes in the pathogenesis. Scattershot chorioretinopathy is associated with IL-17, a signature cytokine of T cell type 17 (TH17) cells that play an important role in autoimmunity. 15,16 Genome-wide association studies have identified HLA-A29:02 as a major risk factor and both ERAP1 and ERAP2 as associated with shatter-like chorioretinopathy. 17,20 Genetic variants in the ERAP1 and ERAP2 loci modulate enzyme activity and also mRNA and protein expression. ERAP2, together with ERAP1, is an aminopeptidase that trims peptides in the endoplasmic reticulum and loads these peptides onto HLA molecules for presentation to T cells of the immune system.

[0166] In one preferred embodiment, the immune disorder is psoriasis. Psoriasis is a chronic skin disease in which skin cells rapidly accumulate on the surface of the skin, forming itchy and sometimes painful scales and red spots. The cause is unclear, but includes both environmental and genetic factors. HLA-C06 is strongly associated with the risk of the disease, and ERAP1 variants are also strongly associated with the disease, possibly in conjunction with HLA-C06. 21There is no cure for psoriasis, and current treatments only provide improvement in symptoms and prevention of worsening. Medications used in treatment include steroids, methotrexate, sulfasalazine, and biologic agents such as etanercept.

[0167] Another aspect of the present invention relates to the above-mentioned compound for use in the treatment or prevention of viral disorders. Modulators of ERAP1, such as compounds described herein, can change the antigen repertoire of multiple viruses, which leads to the recognition and destruction of virus-infected cells. Thus, ERAP1 modulators have potential therapeutic applications in the treatment of viral infections and diseases. ERAP1 modulates certain viral antigens, including those from human papillomavirus (HPV), human cytomegalovirus (CMV), hepatitis C (HCV), and human immunodeficiency virus (HIV). 8,9,10 Furthermore, knockdown of ERAP1 in HPV-infected cells altered the repertoire of HPV antigens presented and upregulated CD8 + Providing greater recognition by T cells 8 .

[0168] In one preferred embodiment, the viral disorder is a viral disease or infection selected from HIV, HPV, CMV and HCV.

[0169] In one preferred embodiment, the viral disorder is HIV.

[0170] In one preferred embodiment, the viral disorder is HPV.

[0171] In one preferred embodiment, the viral disorder is CMV.

[0172] In one preferred embodiment, the viral disorder is HCV.

[0173] Another aspect relates to a compound described herein for use in preventing or treating a disorder caused by, related to, or accompanied by abnormal activity against ERAP1.

[0174] Another aspect relates to a compound described herein for use in the prevention or treatment of an ERAP1-associated disease or disorder.

[0175] Yet another embodiment relates to use of a compound described herein in the preparation of a medicament for preventing or treating a disorder caused by, related to, or accompanied by any abnormal activity against ERAP1.

[0176] As used herein, the phrase "preparation of a medicament" includes the use of a component of the invention in any stage of the preparation of a medicament, as well as the use of a component of the invention directly as such a medicament.

[0177] Another aspect relates to the use of a compound as described above in the preparation of a medicament for the treatment or prevention of a disorder selected from a proliferative disorder, an immune disorder, a viral disorder and an inflammatory disorder.

[0178] Yet another aspect relates to use of a compound described herein in the preparation of a medicament for preventing or treating an ERAP1-related disease or disorder.

[0179] Another aspect of the present invention relates to a method for treating an ERAP1-related disease or disorder in a subject. The method according to this aspect of the present invention is achieved by administering a therapeutically effective amount of the compound of the present invention to a subject in need thereof, as described herein above, by itself, or more preferably, as a part of a pharmaceutical composition mixed with, for example, a pharma- ceutically acceptable carrier, as described in detail hereinafter.

[0180] Yet another aspect of the present invention relates to a method for treating a subject having a disease condition that is alleviated by modulating ERAP1, the method comprising administering to the subject a therapeutically effective amount of a compound according to the present invention.

[0181] Another aspect relates to a method for treating a disease condition alleviated by modulating ERAP1, the method comprising the step of administering to a subject a therapeutically effective amount of a compound according to the present invention.

[0182] Preferably, the subject is a mammal, more preferably a human.

[0183] The term "method" refers to manner, means, techniques, and procedures for accomplishing a given task, and includes, but is not limited to, manner, means, techniques, and procedures known to those of skill in the chemical, pharmacological, biological, biochemical, and medical arts, or readily developed from known manner, means, techniques, and procedures by such skilled artisans.

[0184] As used herein, the term "treating" includes negating, substantially inhibiting, slowing, or reversing the progression of a disease or disorder, substantially ameliorating a clinical symptom of a disease or disorder, or substantially preventing the onset of a clinical symptom of a disease or disorder.

[0185] As used herein, the term "prevent" refers to a method for barring an organism from acquiring a disorder or disease in the first place.

[0186] The term "therapeutically effective amount" refers to that amount of the compound being administered which will relieve to some extent one or more of the symptoms of the disease or disorder being treated.

[0187] For any compound used in the invention, the therapeutically effective amount, also referred to herein as the therapeutically effective dose, can be estimated initially from cell culture assays. For example, a dose can be estimated based on the IC 50 or IC 100The composition may be formulated to achieve a circulating concentration range that includes. Such information can be used to more accurately determine a useful dose in humans. Initial dosages can also be estimated from in vivo data. Using these initial guidelines, one skilled in the art can determine an effective dosage in humans.

[0188] Furthermore, the toxicity and therapeutic efficacy of the compounds described herein can be determined by standard pharmaceutical procedures in cell cultures or experimental animals, e.g., by LD 50 and ED 50 The dose ratio between toxic and therapeutic effects is the therapeutic index, and the LD 50 and ED 50 The therapeutic index may be expressed as a ratio between the ED and the ED. Compounds that exhibit high therapeutic indices are preferred. The data obtained from these cell culture assays and animal studies may be used to formulate a dosage range that is non-toxic for use in humans. The dosage of such compounds is preferably within the range of ED 50 The dosage may vary within this range depending on the dosage form employed and the route of administration utilized. The exact formulation, route of administration and dosage can be chosen by the individual physician in view of the patient's condition (see, e.g., Fingl et al, 1975, The Pharmacological Basis of Therapeutics, chapter 1, page 1).

[0189] Dosage and intervals may be individually adjusted to provide plasma levels of the active compound sufficient to maintain therapeutic efficacy. Dosages for oral administration in typical patients range from about 50 to 2000 mg / kg / day, generally about 100 to 1000 mg / kg / day, preferably about 150 to 700 mg / kg / day, and most preferably about 250 to 500 mg / kg / day. Preferably, therapeutically effective serum levels are achieved by administering multiple doses daily. In the case of local administration or selective uptake, the effective local concentration of the drug may not be related to the plasma concentration. One skilled in the art can optimize the therapeutically effective local dosage without undue experimentation.

[0190] As used herein, "ERAP1-related disease or disorder" refers to a disease or disorder characterized by inappropriate ERAP1 activity. Inappropriate activity refers to either an increase or decrease in ERAP1 activity compared to wild-type ERAP1 (Uniprot ID Q9NZ08) caused by variation in the ERAP1 protein sequence, as measured by enzyme or cell assay. Inappropriate activity may also be due to overexpression of ERAP1 in diseased tissue compared to healthy adjacent tissue.

[0191] Preferred diseases or disorders which the compounds described herein may be useful in preventing include the proliferative disorders, viral disorders, immune disorders and inflammatory disorders described herein above.

[0192] Therefore, the present invention further provides the use of a compound defined herein for the manufacture of a medicament for the treatment of a disease in which it is desirable to modulate ERAP1. Such diseases include the proliferation disorders, viral disorders, immune disorders and inflammatory disorders described herein above.

[0193] In one preferred embodiment, the compound activates the conversion of (L)-leucine-7-amido-4-methylcoumarin (L-AMC) to (L)-leucine and the fluorescent molecule 7-amino-4-methylcoumarin by ERAP1. Although the same assay can also identify inhibitors of cleavage of the amide bond in L-AMC by ERAP1, for the purposes of this application, this assay is referred to as the "L-AMC activator assay." The potency of any activator is determined by the concentration of the activator required to increase the enzymatic activity of ERAP1 by 50% from its baseline level (i.e., EC 50 )

[0194] In one preferred embodiment, the compound has an EC 50 More preferably, the compounds have an EC value in the L-AMC activator assay of less than about 10 μM, more preferably less than about 5 μM, even more preferably less than about 1 μM, even more preferably less than about 0.1 μM, and even more preferably less than about 0.01 μM. 50 Indicates the value.

[0195] In one preferred embodiment, the compound inhibits the ability of ERAP1 to hydrolyze the decapeptide substrate WRVYEKCdnpALK. This peptide has minimal fluorescence because the fluorescence of the N-terminal tryptophan residue is quenched by a dinitrophenol (DNP) residue within the peptide. However, as ERAP1 hydrolyzes the N-terminal amide bond and tryptophan is released, this internal quenching is lost, and the reaction is monitored by an increase in tryptophan fluorescence during the assay. For the purposes of this application, this assay is referred to as a "10mer inhibition assay," and the potency of the compound is measured using IC as is well known to those skilled in the art. 50 It is calculated and expressed as:

[0196] In one preferred embodiment, the compound has an IC of less than about 25 μM in the 10mer assay. 50More preferably, the compounds have an IC value in the 10mer assay of less than about 10 μM, more preferably less than about 5 μM, even more preferably less than about 1 μM, even more preferably less than about 0.1 μM, and even more preferably less than about 0.01 μM. 50 In one preferred embodiment, the compounds have an IC value of about 100 nM to about 500 nM, more preferably less than 100 nM, in the 10-mer assay. 50 Indicates the value.

[0197] Pharmaceutical Compositions For use according to the invention, the compounds described herein or their physiologically acceptable salts, esters or other physiologically functional derivatives may be provided in a pharmaceutical formulation comprising the compounds or their physiologically acceptable salts, esters or other physiologically functional derivatives together with one or more pharma- ceutically acceptable carriers, and optionally other therapeutic and / or prophylactic ingredients. The carrier must be acceptable in the sense of being compatible with the other ingredients of the formulation and not deleterious to the recipient thereof. The pharmaceutical compositions may be for use in humans or animals in human and veterinary medicine.

[0198] Examples of such suitable excipients for the various different forms of pharmaceutical compositions described herein can be found in "Handbook of Pharmaceutical Excipients, Volume 2, Issue 1, pp. 111-115, 2003." nd Edition, (1994), Edited by A Wade and PJ Weller. The carrier, or each of the carriers, if more than one carrier is present, must be acceptable in the sense of being compatible with the other ingredients of the formulation and not deleterious to the recipient.

[0199] Acceptable carriers or diluents for therapeutic use are well known in the pharmaceutical art and are described, for example, in Remington's Pharmaceutical Sciences, Mack Publishing Co. (AR Gennaro edit. 1985).

[0200] Examples of suitable carriers include lactose, starch, glucose, methyl cellulose, magnesium stearate, mannitol, sorbitol, etc. Examples of suitable diluents include ethanol, glycerol and water.

[0201] The choice of pharmaceutical carrier, excipient, or diluent may be selected having regard to the intended route of administration and standard pharmaceutical practice. The pharmaceutical compositions may include as, or in addition to, the carrier, excipient, or diluent any suitable binders, lubricants, suspending agents, coating agents, solubilizing agents, buffers, flavoring agents, surface active agents, thickening agents, preservatives (including antioxidants), and the like, as well as substances included for the purpose of rendering the formulation isotonic with the blood of the intended recipient.

[0202] Examples of suitable binders include starch, gelatin, natural sugars such as glucose, anhydrous lactose, liquid lactose, beta-lactose, corn sweeteners, natural and synthetic gums such as acacia, tragacanth or sodium alginate, carboxymethylcellulose and polyethylene glycol.

[0203] Examples of suitable lubricants include sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride and the like.

[0204] Preservatives, stabilizers, dyes and even flavoring agents may be provided in the pharmaceutical composition. Examples of preservatives include sodium benzoate, sorbic acid and esters of p-hydroxybenzoic acid. Antioxidants and suspending agents may also be used.

[0205] Pharmaceutical formulations include those suitable for oral, topical (including transdermal, buccal and sublingual), rectal or parenteral (including subcutaneous, intradermal, intramuscular and intravenous), nasal, and pulmonary administration, such as by inhalation. The formulations may, where appropriate, be conveniently presented in discrete dosage units and may be prepared by any of the methods well known in the art of pharmacy. All methods include the step of bringing into association the active compound with liquid carriers or finely divided solid carriers, or both, and then, if necessary, shaping the product into the desired formulation.

[0206] Pharmaceutical formulations suitable for oral administration in which the carrier is a solid are most preferably provided as unit dose formulations such as boluses, capsules or tablets, each containing a predetermined amount of the active compound. Tablets can be made by compression or molding, and may be made with one or more accessory ingredients. Compressed tablets can be prepared by compressing in a suitable machine the active compound in a free-flowing form such as a powder or granules, which may be mixed with a binder, lubricant, inert diluent, lubricant, surface active agent or dispersing agent. Molded tablets can be made by molding the active compound with an inert liquid diluent. Tablets may be coated or, if uncoated, may be grooved. Capsules can be prepared by filling capsule shells with the active compound, either alone or mixed with one or more accessory ingredients, and then sealing them in the usual manner. Cachets are similar to capsules, in which the active compound is sealed in a rice paper packet with any accessory ingredients. The active compound may also be formulated as dispersible granules, which may, for example, be suspended in water or sprinkled on food before administration. The granules may be packaged, for example, in a sachet.Formulations suitable for oral administration where the carrier is a liquid may be presented as a solution or suspension in an aqueous or non-aqueous liquid, or as an oil-in-water liquid emulsion.

[0207] Formulations for oral administration include controlled release dosage forms, such as tablets, in which the active compound is formulated in a suitable release-controlling matrix or coated with a suitable release-controlling film. Such formulations can be particularly convenient for prophylactic use.

[0208] The pharmaceutical preparation suitable for rectal administration, in which the carrier is solid, is most preferably provided as unit dose suppositories.Suitable carriers include cocoa butter and other materials commonly used in the art.Suppositories can be conveniently formed by mixing the active compound with a softened or melted carrier, followed by cooling and shaping in molds.The pharmaceutical preparation suitable for parenteral administration includes a sterile solution or suspension of the active compound in an aqueous or oily medium.

[0209] The preparation for injection can be adapted for bolus injection or continuous infusion. Such preparations are conveniently provided in unit-dose or multi-dose containers that are sealed after introduction of the formulation until required for use. Alternatively, the active compound can be in powder form that is reconstituted with a suitable medium, such as sterile pyrogen-free water, before use.

[0210] The active compound may also be formulated as a long-acting depot preparation, which may be administered, for example, subcutaneously or intramuscularly, by intramuscular injection or implantation. The depot preparation may, for example, comprise a suitable polymeric or hydrophobic material, or an ion exchange resin. Such long-acting formulations are particularly convenient for prophylactic use.

[0211] Formulations suitable for pulmonary administration via the buccal cavity are provided such that particles containing the active compound and desirably having a diameter within the range of 0.5 to 7 microns are delivered to the recipient's bronchial tree.

[0212] One possibility is that such formulation is in the form of a finely divided powder, which can be conveniently provided in a puncturable capsule, for example made of gelatin, for use in an inhalation device, or alternatively, as a self-propelling formulation, which includes the active compound, a suitable liquid or gaseous propellant, and may also include other components such as surfactants and / or solid diluents.Suitable liquid propellants include propane and chlorofluorocarbons, and suitable gaseous propellants include carbon dioxide.Self-propelling formulations, in which the active compound is dispensed in the form of droplets of solution or suspension, can also be used.

[0213] Such self-propelling formulations are similar to those known in the art and may be prepared by established procedures. Suitably, they are provided in a container equipped with a manually operable or automatically functioning valve having the desired spray characteristics, advantageously the valve being of the metered type which delivers a fixed volume, e.g., 25-100 microliters, upon each actuation thereof.

[0214] As a further possibility, the active compound may be in the form of a solution or suspension for use in a sprayer or nebulizer, which uses accelerated airflow or ultrasonic agitation to produce a fine droplet mist for inhalation.

[0215] Formulations suitable for nasal administration include preparations generally similar to those described above for pulmonary administration. When dispensed, such formulations should desirably have a particle diameter in the range of 10-200 microns to allow retention in the nasal cavity, which may be achieved by the use of powders of appropriate particle size or by selection of an appropriate valve, as appropriate. Other suitable formulations include coarse powders having a particle diameter in the range of 20-500 microns for administration by rapid inhalation through the nasal passages from a container held close to the nose, and nasal drops containing 0.2-5% w / v of the active compound in an aqueous or oily solution or suspension.

[0216] Pharmaceutically acceptable carriers are well known to those skilled in the art and include, but are not limited to, 0.1M, preferably 0.05M, phosphate buffer or 0.8% saline. Furthermore, such pharma-ceutically acceptable carriers may be aqueous or non-aqueous solutions, suspensions and emulsions. Examples of non-aqueous solvents are propylene glycol, polyethylene glycol, vegetable oils such as olive oil, and injectable organic esters such as ethyl oleate. Aqueous carriers include water, alcoholic / aqueous solutions, emulsions or suspensions, including saline and buffered media. Parenteral vehicles include sodium chloride solution, Ringer's dextrose, dextrose and sodium chloride, lactated Ringer's or fixed oils. Preservatives and other additives may also be present, such as antibacterial agents, antioxidants, chelating agents, inert gases and the like.

[0217] Suitable formulations for topical use may be provided, for example, as gels, creams or ointments. Such preparations may be applied, for example, to a wound or ulcer, either by spreading it directly on the surface of the wound or ulcer, or on a suitable support such as a bandage, gauze, mesh, etc., which may be applied to and over the area to be treated.

[0218] Liquid or powder formulations may also be provided which may be sprayed or sprinkled directly onto the area to be treated, such as a wound or ulcer. Alternatively, the formulation may be sprayed or sprinkled onto a carrier such as a bandage, gauze, mesh, etc., and then applied to the area to be treated.

[0219] According to a further aspect of the present invention there is provided a process for the preparation of a pharmaceutical or veterinary composition as described above which comprises the step of bringing into association the active compound with the carrier, for example by mixing.

[0220] In general, the formulations are prepared by uniformly and intimately bringing into association the active agent with liquid carriers, or finely divided solid carriers, or both, and then, if necessary, shaping the product. The invention extends to a process for preparing a pharmaceutical composition which includes combining or bringing into association a compound described herein with a pharma- ceutically or veterinarily acceptable carrier or vehicle.

[0221] Salts / Esters The compounds of the present invention may exist as salts or esters, particularly pharma- ceutically and veterinarily acceptable salts or esters.

[0222] Pharmaceutically acceptable salts of the compounds of the present invention include suitable acid addition or base salts thereof. A summary of suitable pharmaceutical salts can be found in Berge et al, J Pharm Sci, 66, 1-19 (1977). Salts may, for example, be those of strong inorganic acids, such as mineral acids, for example hydrohalic acids, such as hydrochlorides, hydrobromides and hydroiodides, sulfuric acid, phosphoric acid, sulfates, bisulfates, hemisulfates, thiocyanates, persulfates and sulfonic acids; strong organic carboxylic acids, for example alkane carboxylic acids of 1 to 4 carbon atoms, unsubstituted or substituted (e.g. by halogens), such as acetic acid; saturated or unsaturated dicarboxylic acids, such as oxalic acid, malonic acid, succinic acid, maleic acid, fumaric acid, phthalic acid or tetraphthalic acid; hydroxy carboxylic acids, such as ascorbic acid, glycolic acid, lactic acid, malic acid, tartaric acid or citric acid; amino acids, such as aspartic acid or glutamic acid; benzoic acid; or organic sulfonic acids, such as unsubstituted or substituted (e.g. by halogens) (C 1 -C 4)-alkyl- or aryl-sulfonic acids, such as methane- or p-toluenesulfonic acid. Salts that are not pharma- citrate- or veterinarily acceptable may still be valuable as intermediates. Preferred salts are, for example, acetate, trifluoroacetate, lactate, gluconate, citrate, tartrate, maleate, malate, pantothenate, adipate, alginate, aspartate, benzoate, butyrate, digluconate, cyclopentanoate, glucoheptanoate, glycerophosphate, oxalate, heptanoate, hexanoate, fumarate, nicotinate, palmoate, pectinate, 3-phenylpropionate, picrate, pivalate, propionate, Salts include salts of tartrates, lactobionates, pivolates, camphorates, undecanoates and succinates, organic sulfonic acids such as methanesulfonates, ethanesulfonates, 2-hydroxyethanesulfonates, camphorsulfonates, 2-naphthalenesulfonates, benzenesulfonates, p-chlorobenzenesulfonates and p-toluenesulfonates; and inorganic acids such as hydrochlorides, hydrobromides, hydroiodides, sulfates, bisulfates, hemisulfates, thiocyanates, persulfates, phosphoric acids and sulfonic acids. More preferably, the salt is a hydrochloride.

[0223] Esters are formed using organic acids or alcohols / hydroxides depending on the functional group being esterified. Organic acids can be carboxylic acids, such as alkane carboxylic acids of 1 to 12 carbon atoms, unsubstituted or substituted (e.g. by halogen), e.g. acetic acid; saturated or unsaturated dicarboxylic acids, such as oxalic acid, malonic acid, succinic acid, maleic acid, fumaric acid, phthalic acid or tetraphthalic acid; hydroxy carboxylic acids, such as ascorbic acid, glycolic acid, lactic acid, malic acid, tartaric acid or citric acid; amino acids, such as aspartic acid or glutamic acid; benzoic acid; or organic sulfonic acids, such as unsubstituted or substituted (e.g. by halogen) (C 1 -C 4p-alkyl- or aryl-sulfonic acids, such as methane- or p-toluenesulfonic acid. Suitable hydroxides include inorganic hydroxides, such as sodium hydroxide, potassium hydroxide, calcium hydroxide, aluminium hydroxide. Alcohols include alkane alcohols of 1 to 12 carbon atoms, which may be unsubstituted or substituted (e.g. by halogen).

[0224] Enantiomers / Tautomers In all the above aspects of the invention, the invention includes, where appropriate, all enantiomers, diastereoisomers and tautomers of the compounds of the invention. Those skilled in the art will recognize compounds that have optical properties (one or more chiral carbon atoms) or tautomeric properties. The corresponding enantiomers and / or tautomers can be isolated / prepared by methods known in the art.

[0225] Enantiomers are characterized by the absolute configuration of their chiral centers and described by the R- and S-sequencing rules of Cahn, Ingold and Prelog. Such conventions are well known in the art (see, for example, 'Advanced Organic Chemistry', 3 rd edition, ed. March, J., John Wiley and Sons, New York, 1985).

[0226] Compounds of the invention that contain chiral centers may be used as racemic mixtures, enantiomerically enriched or racemic mixtures may be separated using well-known techniques, or the individual enantiomers may be used alone.

[0227] Stereoisomers and geometric isomers Some of the compounds of the present invention may exist as stereoisomers and / or geometric isomers, for example, they may have one or more asymmetric and / or geometric centers, and therefore may exist in two or more stereoisomeric and / or geometric isomeric forms. The present invention contemplates the use of all of the individual stereoisomers and geometric isomers of these compounds, as well as mixtures thereof. These terms used in the claims encompass these forms, so long as they retain the appropriate functional activity (although not necessarily to the same degree).

[0228] The present invention also includes all suitable isotopic variations of the compounds or pharma- ceutically acceptable salts thereof. An isotopic variation of a compound of the present invention or a pharma- ceutically acceptable salt thereof is defined as one in which at least one atom is replaced by an atom having the same atomic number but an atomic mass different from the atomic mass usually found in nature. Examples of isotopes that may be incorporated into the substances and their pharma- ceutically acceptable salts include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine and chlorine, e.g., 2 H, 3 H, 13 C. 14 C. 15 N, 17 O. 18 O. 31 P, 32 P, 35 S, 18 F and 36 Certain isotopic variations of the substance and pharma- ceutically acceptable salts thereof, e.g. 3 H or 14 Those incorporating radioactive isotopes such as C are useful for drug and / or substrate tissue distribution studies. Tritiated, i.e. 3 H and carbon-14, i.e. 14 C isotopes are particularly preferred for their ease of preparation and detectability. Additionally, deuterium, i.e. 2Substitution with an isotope such as H can provide certain therapeutic advantages resulting from greater metabolic stability, for example increased in vivo half-life or reduced dosage requirements, and therefore may be preferred in some circumstances. For example, the present invention includes compounds of general formula (I) in which any hydrogen atom is replaced with a deuterium atom. Isotopic variations of the substances of the present invention and their pharma-ceutically acceptable salts of the present invention can generally be prepared by conventional procedures using appropriate isotopic variations of suitable reagents.

[0229] Atropisomers Some of the compounds of the present invention may exist as atropisomers. Atropisomers are stereoisomers resulting from the inhibition of rotation around a single bond, where the energy difference due to steric strain or other contributing factors creates a sufficiently high barrier to rotation to allow the isolation of individual conformers. The present invention encompasses all such atropisomers.

[0230] Prodrug The present invention further includes compounds of the invention in prodrug form, i.e., covalently bonded compounds that release the active parent drug in vivo. Such prodrugs are generally compounds of the invention modified at one or more appropriate groups such that the modification can revert to the parent drug after administration to a human or mammalian subject. The reversion to the parent drug is usually performed by enzymes naturally present in such subjects, but it is possible to administer a second agent together with such a prodrug to perform the reversal in vivo. Examples of such modifications include esters (e.g., any of those mentioned above), where the reversion to the parent drug can be performed by esterases, etc. Other such systems are well known to those skilled in the art.

[0231] solvate The present invention also includes solvated forms of the compounds of the present invention. The terms used in the claims encompass these forms. Preferably, the solvates are hydrates.

[0232] polymorph The present invention further relates to the compounds of the present invention in their various crystalline forms, polymorphic forms, and hydrate (anhydrous) forms. It is well established in the pharmaceutical industry that chemical compounds may be isolated in any of such forms by minor modifications of the methods of purification and / or isolation from the solvents used in the synthetic preparation of such compounds.

[0233] Administration The pharmaceutical composition of the present invention may be adapted for rectal, nasal, intrabronchial, topical (including buccal and sublingual), vaginal or parenteral (including subcutaneous, intramuscular, intravenous, intraarterial and intradermal), intraperitoneal or intrathecal administration.Preferably, the formulation is an oral administration formulation.The formulation may be conveniently provided in unit dosage form, i.e., in the form of a unit dose, or individual portions containing a multiple or subunit of a unit dose.By way of example, the formulation may be in the form of a tablet and a sustained release capsule, and may be prepared by any method well known in the art of pharmacy.

[0234] Formulations for oral administration in the present invention may be provided as discrete units such as capsules, gellules, drops, cachets, pills or tablets, each containing a predetermined amount of the active agent; as powders or granules; as a solution, emulsion or suspension of the active agent in an aqueous or non-aqueous liquid; or as an oil-in-water or water-in-oil liquid emulsion; or as a bolus. Preferably, these compositions contain 1-250 mg, more preferably 10-100 mg, of active ingredient per dose.

[0235] In the case of compositions for oral administration (e.g., tablets and capsules), the term "acceptable carrier" includes common excipients, such as binders, such as syrup, acacia, gelatin, sorbitol, tragacanth, polyvinylpyrrolidone (povidone), methylcellulose, ethylcellulose, sodium carboxymethylcellulose, hydroxypropylmethylcellulose, sucrose and starch; fillers and carriers, such as corn starch, gelatin, lactose, sucrose, microcrystalline cellulose, kaolin, mannitol, dicalcium phosphate, sodium chloride and alginic acid; and lubricants, such as magnesium stearate, sodium stearate and other metal stearates, glycerol stearate, stearic acid, silicone fluids, talc wax, oils and colloidal silica and other vehicles. Flavoring agents, such as peppermint, oil of wintergreen, cherry flavoring, and the like, may also be used. It may be desirable to add coloring agents to make the dosage form easily identifiable. Tablets may also be coated by methods well known in the art.

[0236] Tablets may be made by compression or molding, and may be made with one or more accessory ingredients. Compressed tablets may be prepared by compressing in a suitable machine the active agent in a free-flowing form such as a powder or granules, which may be mixed with a binder, lubricant, inert diluent, preservative, surface active or dispersing agent. Molded tablets may be made by molding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent. Tablets may be coated or grooved and may be formulated to provide slow or controlled release of the active agent.

[0237] Other formulations suitable for oral administration include lozenges which contain the active agent in a flavored base, usually sucrose and acacia or tragacanth; pastilles which contain the active agent in an inert base such as gelatin and 70-trimethyl sucrose, or sucrose and acacia; and mouthwashes which contain the active agent in a suitable liquid carrier.

[0238] Other administration forms include solutions or emulsions that can be injected intravenously, intraarterially, intrathecally, subcutaneously, intradermally, intraperitoneally or intramuscularly, which are prepared from sterile or sterilizable solutions. Injectable forms typically contain between 10 and 1000 mg, preferably between 10 and 250 mg, of active ingredient per dose.

[0239] Pharmaceutical compositions of the present invention may also be in the form of a suppository, pessary, suspension, emulsion, lotion, ointment, cream, gel, spray, solution or dusting powder.

[0240] An alternative means of transdermal administration is by use of a skin patch. For example, the active ingredient may be incorporated into a cream consisting of an aqueous emulsion of polyethylene glycols or liquid paraffin. The active ingredient may also be incorporated at a concentration of between 1 and 10% by weight into an ointment consisting of a white wax or white soft paraffin base together with such stabilizers and preservatives as may be required.

[0241] Dosage Those skilled in the art can easily determine the appropriate dose of one of the compositions of the present invention to be administered to a subject without undue experimentation.Typically, a doctor will determine the actual dosage that will be most suitable for an individual patient, which will depend on a variety of factors, including the activity of the specific compound used, the metabolic stability and duration of action of the compound, age, body weight, general health, sex, diet, mode and time of administration, excretion rate, drug combination, the severity of the specific condition, and the treatment being performed individually.The dosages disclosed herein are examples of the average case.Of course, there may be individual situations where higher or lower dosage ranges are advantageous, and these are within the scope of the present invention.

[0242] The dosage will further vary depending on the mode of administration of the compound. For example, to achieve an "effective amount" for acute treatment, parenteral administration of the compound is typically preferred. Intravenous infusion of the compound in 5% dextrose in water or saline, or a similar formulation with appropriate excipients, is most effective, but intramuscular bolus injections are also useful. Typically, parenteral doses are between about 0.01 to about 100 mg / kg; preferably 0.1 to 20 mg / kg, in a manner that maintains the concentration of drug in the plasma at a concentration effective to modulate ERAP1. The compound may be administered 1 to 4 times daily at a level that achieves a total daily dose of about 0.4 to about 400 mg / kg / day. The exact amount of the compound of the present invention that is therapeutically effective, and the route by which such a compound is best administered, can be readily determined by one of skill in the art by comparing the blood levels of the drug with the concentration required to have a therapeutic effect.

[0243] The compounds of the present invention may also be orally administered to a patient in such a manner that the concentration of the drug is sufficient to achieve one or more of the therapeutic indices disclosed herein. Typically, pharmaceutical compositions containing the compounds are administered at an oral dose of between about 0.1 and about 50 mg / kg in a manner consistent with the patient's condition. Preferably, the oral dose is about 0.5 to about 20 mg / kg.

[0244] No unacceptable toxic effects are expected when the compounds of the present invention are administered according to the present invention. Compounds of the present invention that may have good bioavailability can be tested in one of several biological assays to determine the concentration of the compound required to have a given pharmacological effect.

[0245] combination A further aspect of the present invention relates to a combination comprising the compound described herein and one or more additional active agents.In a particularly preferred embodiment, one or more compounds of the present invention are administered in combination with one or more additional active agents, such as existing drugs available on the market.In such a case, the compound of the present invention can be administered sequentially, simultaneously or sequentially with one or more other active agents.

[0246] Drugs are generally more effective when used in combination. In particular, combination therapy is desirable to avoid major toxicities, overlapping mechanisms of action and resistance. In addition, it is also desirable to administer most drugs at their maximum tolerated doses with minimal time intervals between such doses. The main advantage of combining chemotherapy drugs is that it can promote additive or possible synergistic effects through biochemical interactions and reduce the occurrence of resistance.

[0247] Beneficial combinations may be suggested by studying the activity of the test compound together with agents known or suspected to be of value in the treatment of a particular disorder. This procedure may also be used to determine the order of administration of the agents, i.e., before, simultaneously with, or after delivery. Such scheduling may be a feature of all active agents identified herein.

[0248] In one preferred embodiment, the additional active agent is an immunotherapeutic agent, more preferably a cancer immunotherapeutic agent. "Immunotherapeutic agent" refers to a treatment that uses a subject's own immune system to fight a disease, such as cancer.

[0249] In one preferred embodiment, the compound of the present invention inhibits the activity of ERAP1, and the compound is administered in combination with immunotherapy. The compound can increase the sensitivity of cancer cells to immunotherapy. The immunotherapy can be mediated by T cells. In one embodiment, the compound can increase the number of CD8+ T cells in tumors.

[0250] In one embodiment, the compounds may be used to treat cancers that respond poorly or non-responsive to immunotherapy.

[0251] In one preferred embodiment, the additional active agent is a molecule capable of immune checkpoint intervention, a co-stimulatory antibody, a chemotherapy agent, a radiotherapy agent, a targeted therapy agent or an antibody, in particular a monoclonal antibody.

[0252] In one preferred embodiment, the additional active agent is a molecule capable of immune checkpoint intervention.

[0253] Immune checkpoint molecules include CTLA-4, PD-1, VISTA, B7-H2, B7-H3, PD-L1, B7-H4, B7-H6, ICOS, HVEM, PD-L2, CD160, gp49B, PIR-B, KIR family receptors, TIM-1, TIM-3, TIM-4, LAG-3, GITR, 4-IBB, OX-40, BTLA, SIRP, CD47, CD48, 2B4, B7.1, B7.2, ILT-2, ILT-4, TIGIT, HHLA2, IDO, CD39, CD73, A2aR, and butyrophilin.

[0254] Immune checkpoint molecules include both inhibitory and activating molecules, and intervention can be applied to either or both types of molecules.

[0255] Immune checkpoint inhibitors include, but are not limited to, PD-1 inhibitors, PD-L1 inhibitors, LAG-3 inhibitors, TIM-3 inhibitors, TIGIT inhibitors, BTLA inhibitors, and CTLA-4 inhibitors.Co-stimulatory antibodies deliver positive signals through immune regulatory receptors, including, but not limited to, ICOS, CD137, CD27, OX-40, and GITR.

[0256] In one highly preferred embodiment, the additional active agent is an antibody checkpoint inhibitor. Suitable examples of antibody checkpoint inhibitors include, but are not limited to, anti-PD-1 antibodies, anti-PD-L1 antibodies, and anti-CTLA4 antibodies.

[0257] In one preferred embodiment, the antibody checkpoint inhibitor is an anti-PD-1 antibody, more preferably selected from pembrolizumab, cemiplimab and nivolumab.

[0258] In one preferred embodiment, the antibody checkpoint inhibitor is an anti-PD-L1 antibody, more preferably selected from atezolizumab, avelumab and durvalumab.

[0259] In one preferred embodiment, the antibody checkpoint inhibitor is an anti-CTLA4 antibody, more preferably selected from ipilimumab and tremelimumab.

[0260] In one preferred embodiment, the immunotherapy is an anti-cancer vaccine or a virus, such as an oncolytic virus.

[0261] In one preferred embodiment, the immunotherapy is a cell-based therapy. In one embodiment, the cell-based therapy may be a T cell therapy, such as adoptive T cell therapy, or a therapy using CAR-T cells.

[0262] Adoptive cell-based immunotherapy may include irradiated autologous or allogeneic tumor cells, tumor lysates or apoptotic tumor cells, antigen-presenting cell-based immunotherapy, dendritic cell-based immunotherapy, adoptive T cell transfer, adoptive CAR T cell therapy, autoimmune enhancing therapy (AIET), cancer vaccines, and / or antigen-presenting cells. Such cell-based immunotherapy may be further modified to express one or more gene products to further modulate the immune response, for example to express a cytokine such as GM-CSF, and / or to express a tumor-associated antigen (TAA) antigen such as Mage-1, gp-100, patient-specific neoantigen vaccines.

[0263] In further embodiments, immunotherapy may include non-cell-based immunotherapy. In one embodiment, antigen-containing compositions, with or without vaccine-enhancing adjuvants, may be used. Such compositions exist in many well-known forms, for example as recombinant antigens, including peptide compositions, oncolytic viruses, and fusion proteins.

[0264] In alternative embodiments, immunomodulatory interleukins, such as IL-2, IL-6, IL-7, IL-12, IL-17, IL-23, and their modulators (e.g., blocking antibodies or more potent or longer-lasting forms) may be used. Immunomodulatory cytokines, such as interferons, G-CSF, imiquimod, TF alpha, and their modulators (e.g., blocking antibodies or more potent or longer-lasting forms) may also be used. In another embodiment, immunomodulatory chemokines, such as CCL3, CCL26, and CXCL7, and their modulators (e.g., blocking antibodies or more potent or longer-lasting forms) may be used. In further embodiments, immunomodulatory molecules targeting immunosuppression, such as STAT3 signaling modulators, FkappaB signaling modulators (FkappaB 75rimethyla modulators), and immune checkpoint modulators may be used.

[0265] In another embodiment, immunomodulatory drugs, such as immunocytostatic drugs, glucocorticoids, cytostatic drugs, immunophilins and their modulators (e.g., rapamycin, calcineurin inhibitors, tacrolimus, cyclosporine (75rimethylamine), pimecrolimus, avetimus, gusperimus, ridaforolimus, everolimus, temsirolimus, zotarolimus, etc.), hydrocortisone (cortisol), cortisone acetate, prednisone, prednisolone, methylprednisolone, dexamethasone, betamethasone, triamcinolone, 75rimethylamine, fludrocortisone acetate, , deoxycorticosterone acetate (doca) aldosterone, non-glucocorticoid steroids, pyrimidine synthesis inhibitors, leflunomide, teriflunomide, folic acid analogs, methotrexate, antithymocyte globulin, antilymphocyte globulin, thalidomide, lenalidomide, pentoxifylline, bupropion, curcumin, catechin, opioids, EVIPDH inhibitors, mycophenolic acid, myriocin, fingolimod, NF-xB inhibitors, raloxifene, drotrecogin alfa, denosumab, F-xB signaling cascade inhibitors (F-xB 75rimethyla cascade inhibitor), disulfiram, olmesartan, dithiocarbamate, proteasome inhibitor, bortezomib, MG132, Prol, PI-0052, curcumin, genistein, resveratrol, parthenolide, thalidomide, lenalidomide, flavopiridol, nonsteroidal anti-inflammatory drugs (NSAIDs), arsenic trioxide, dehydroxymethylepoxyquinomycin (DHMEQ), I3C (indole-3-carbinol) / DIM (di-indolemethane) (13C / DIM), Bay 11-7082, luteolin, cell penetrating peptide SN-50, IKBa-super repressor overexpression, FKB decoy oligodeoxynucleotide (ODN), or any derivative or analog thereof may be used.

[0266] In yet another embodiment, immune modulating antibodies or proteins may be used, such as antibodies that bind to CD40, Toll-like receptors (TLRs), OX40, GITR, CD27, or 4-IBB, T cell bispecific antibodies, anti-IL-2 receptor antibodies, anti-CD3 antibodies, OKT3 (muromonab), otelixizumab, teplizumab, visilizumab, anti-CD4 antibodies, clenoliximab, keliximab, zanolimumab, anti-CD11a antibodies, efalizumab, anti-CD18 antibodies, erlizumab, rovelizumab, anti-CD20 antibodies, afutuzumab, Ocrelizumab, ofatumumab, pascolizumab, rituximab, anti-CD23 antibody, rumiliximab, anti-CD40 antibody, teneliximab, toralizumab, anti-CD40L antibody, ruplizumab, anti-CD62L antibody, acelizumab, anti-CD80 antibody, galiximab, anti-CD147 antibody, gavilimomab, B-lymphocyte stimulator (BLyS) inhibitor antibody, belimumab, CTLA4-Ig fusion protein, abatacept, belatacept, anti-CTLA4 antibody, ipilimumab Mab, tremelimumab, anti-eotaxin 1 antibody, bertilimumab, anti-a4-integrin antibody, natalizumab, anti-IL-6R antibody, tocilizumab, anti-LFA-1 antibody, ozlimomab, anti-CD25 antibody, basiliximab, daclizumab, inolimomab, anti-CD5 antibody, zolimomab, anti-CD2 antibody, siplizumab, nerelimomab, faralimomab, atlizumab, atolimumab, cedelizumab, dorlixizumab, fonti These are: izumab, gentenerumab, gomilikimab, levrilizumab, maslimomab, morolimumab, pexelizumab, reslizumab, rovelizumab, talizumab, terimomab-alitox, bapaliximab, beparimomab, aflibercept, alefacept, rilonacept, IL-1 receptor antagonists, anakinra, anti-IL-5 antibodies, mepolizumab, IgE inhibitors, omalizumab, talizumab, IL12 inhibitors, IL23 inhibitors, and ustekinumab.

[0267] In one embodiment, the subject may be undergoing or may have previously been treated with a chemotherapy agent. Examples of chemotherapy agents include, but are not limited to, alkylating agents such as thiotepa and CYTOXAN cyclophosphamide; alkylsulfonates such as busulfan, improsulfan, and piposulfan; aziridines such as benzodopa, carboquone, meturedopa, and uredopa; ethylenimines and methylamelamines, including altretamine, triethylenemelamine, triethylenephosphoramide, triethylenethiophosphoramide, and trimethylolomelamine; acetogenins (e.g., bullatacin and bullatacinone); camptothecins (including the synthetic analog topotecan); bryostatin; kallistatin; CC-1065 (including its synthetic analogs adozelesin, carzelesin, and bizelesin). cryptophycins (e.g., cryptophycin 1 and cryptophycin 8); dolastatins; duocarmycins (including synthetic analogs, KW-2189 and CB1-TM1); eleutherobin; pancratistatin; sarcodictine; spongistatins; nitrogen mustards, such as chlorambucil, chloranafazine, colofosfamide, estramustine, ifosfamide, mechlorethamine, mechlorethamine oxide hydrochloride, melphalan, nobembitine, phenesterine, prednimustine, trophosfamide, uracil mustard; nitrosoureas, such as carmustine, chlorozotocin, fotemustine, lomustine, nimustine, and ranimnustin; antibiotics, such as enediyne antibiotics (e.g., calicheamicins, especially calicheamicin gamma II and calicheamicin omega II (e.g., Agnew, See Chem. Intl. Ed. Engl., 33: 183-186 (1994); dynemicins, including dynemicin A; bisphosphonates, such as clodronate; esperamicin;and neocarzinostatin chromophore and related chromoprotein enediyne antibiotic chromophores), aclacinomycin, actinomycin, ausramycin, azaserine, bleomycin, cactinomycin, carabicin, caminomycin, carzinophilin, chromomycinis, dactinomycin, daunorubicin, detorubicin, 6-diazo-5-oxo-L-norleucine, ADRIAMYCIN doxorubicin (including morpholinodoxorubicin, cyanomorpholinodoxorubicin, 2-pyrrolinodoxorubicin and deoxydoxorubicin), epirubicin, esorubicin, idarubicin, marcellomycin, mitomycins such as mitomycin C, mycophenolic acid, nogalamycin, olivomycin, peplomycin, potofilomycin, puromycin, queramycin, rodorubicin, streptonigrin , streptozocin, tubercidin, ubenimex, zinostatin, zorubicin; antimetabolites such as methotrexate and 5-fluorouracil (5-FU); folic acid analogues such as denopterin, methotrexate, pteropterin, trimetrexate; purine analogues such as fludarabine, 6-mercaptopurine, thiamiprine, thioguanine; pyrimidine analogues such as ancitabine, azacitidine, 6-azauridine androgens such as calsterone, dromostanolone propionate, epithiostanol, mepitiostane, testolactone; anti-adrenals such as aminoglutethimide, mitotane, trilostane; folic acid supplements such as frolinic acid acid);aceglatone;aldophosphamide glycosides;aminolevulinic acid;eniluracil;amsacrine;bestrabucil;bisantrene;edatraxate;demecolcine;diazicon;elformitin;elliptinium acetate;epothilone;etoglucide;gallium nitrate;hydroxyurea;lentinan;lonidynin;maytansinoids, such as maytansine and ansamitocin;mitoguazone;mitoxantrone;mopidamol;nitraelin;pentostatin;Phenamet; pirarubicin; losoxantrone; podophyllic acid; 2-ethylhydrazide; procarbazine; PSK polysaccharide complex (JHS Natural Products, Eugene, Oreg.); razoxane; rhizoxin; schizofuran; spirogermanium; tenuazonic acid; triazicon; 2,2',2"-trichlorotriethylamine; trichothecenes (e.g. T-2 toxin, veraculin A, roridin A and anguidin); 78rimethy; vindesine; dacarbazine; mannomustine; mitobronitol; mitolactol; pipobroman; gacytosine; arabinoside ("Ara-C"); cyclophosphamide; thiotepa; 78rimeth, e.g. TAXOL paclitaxel (Bristol-Myers Squibb Oncology, Princeton, NJ), ABRAXANE Cremophor Free, an albumin modified nanoparticle formulation of paclitaxel (American Pharmaceutical Partners, Schaumberg, 111.), and TAXOTERE doxetaxel (Rhone-Poulenc Rorer, Antony, France); chlorambucil; GEMZAR gemcitabine; 6-thioguanine; mercaptopurine; methotrexate; platinum analogs such as cisplatin, oxaliplatin and carboplatin; vinblastine; platinum; etoposide (VP-16); ifosfamide; mitoxantrone; vincristine; NAVELBINE vinorelbine; novantrone; teniposide; edatrexate; daunomycin; aminopeptide cisplatin;Xeloda;Ibandronate;Irinotecan (Camptosar, CPT-11) (including treatment regimens of irinotecan with 5-FU and leucovorin);Topoisomerase inhibitors RFS2000;Difluoromethylornithine (DMFO);Retinoids, such as retinoic acid;Capecitabine;Combretastatin;Leucovorin (LV);Oxaliplatin, including oxaliplatin treatment regimens (FOLFOX);Lapatinib (Tykerb);Inhibitors of PKC-a, Raf, H-Ras, EGFR (e.g., erlotinib (Tarceva)) and VEGF-A that reduce cell proliferation, as well as pharma- ceutically acceptable salts, acids or derivatives of any of the above. In addition, the method of treatment may further include the use of radiation. In addition, the method of treatment may further include the use of photodynamic therapy.

[0268] process Another aspect of the present invention relates to processes for preparing the compounds of formula (I) described herein.

[0269] In one aspect, the present invention relates to a process for preparing a compound of formula (I), comprising: 2 is COOH, X is NH, and Y is SO 2 and Z, L, R 1 , R 3 , R 4 ~R 9 is as defined above, and the process is (i) A compound of formula (II) is reacted with Cs 2 CO 3 and converting said compound to a compound of formula (III) by treating with ZL-OH; (ii) reducing the compound of formula (III) to form a compound of formula (IV); (iii) treating a compound of formula (IV) with a compound of formula (V) to form a compound of formula (VI); and (iv) hydrolyzing the compound of formula (VI) to form a compound of formula (I). Includes. [ka]

[0270] Preferably, step (i) is carried out in acetonitrile, more preferably at room temperature. The skilled artisan will appreciate that other organic solvents are also suitable. Preferably, step (ii) comprises reacting a compound of formula (III) with Fe, NH 4 Cl and EtOH / H 2Preferably, step (iii) is carried out in the presence of pyridine and dichloromethane at room temperature. Preferably, hydrolysis step (iv) is carried out in the presence of LiOH in THF at room temperature.

[0271] Preferred conditions for each step are set forth hereinafter in Scheme 1 and the accompanying Examples.

[0272] In another aspect, the present invention relates to a process for preparing a compound of formula (I), comprising: 2 is COOH, X is NH, and Y is SO 2 and R 7 is tetrazolyl, and Z, L, R 1 , R 3 , R 4 ~R 6 , R 8 and R 9 is as defined above, and the process is (i) NH of the compound of formula (VII) 2 protecting the group with a suitable protecting group PG to obtain a compound of formula (VIII); (ii) The compound of formula (VIII) is reacted with Cs in a solvent. 2 CO 3 and converting the compound of formula (VIII) to a compound of formula (IX) by treating with ZL-OH; (iii) removing the protecting group PG from the compound of formula (IX) to obtain a compound of formula (X); (iv) The compound of formula (X) is reacted with trimethoxymethane, NaN 3 and HOAc to form a compound of formula (XI); (v) reducing the compound of formula (XI) to form a compound of formula (XII); (vi) treating a compound of formula (XII) with a compound of formula (V) to form a compound of formula (XIII); and (vii) hydrolyzing the compound of formula (XIII) to form a compound of formula (I). Includes. [ka]

[0273] Preferably, the protecting group PG is Boc. Those skilled in the art will appreciate that other amine protecting groups are also suitable (see Green T., "Protective Groups in Organic Synthesis", Chapter 1, J. Wiley & Sons, Inc., 1991, 10-142). More preferably, step (i) comprises reacting a compound of formula (VII) with (Boc) in DCM at room temperature. 2 Preferably, step (ii) comprises treating the compound of formula (VIII) with Fe, NH 4 Cl and EtOH / H 2 Preferably, step (iii) comprises heating the compound of formula (IX) with an acid, more preferably with HCl in EtOAc. Preferably, step (iv) comprises heating the compound of formula (X), trimethoxymethane, NaN 3 and HOAc to a temperature of at least 80° C. Preferably, step (v) comprises reacting a compound of formula (XI) with Fe, NH 4 Cl and EtOH / H 2 2H 2 O (preferably v / v=4 / 1). Preferably, step (vi) is carried out in the presence of pyridine and dichloromethane at room temperature. Preferably, hydrolysis step (vii) is carried out in the presence of LiOH in THF at room temperature. Preferred conditions for each step are set out hereinafter in Scheme 2 and in the accompanying Examples.

[0274] The present invention is further illustrated by the following non-limiting examples.

[0275] [Example] Where the preparation of starting materials is not described, they are commercially available, known in the literature, or can be readily obtained by those skilled in the art using standard procedures. Where compounds are shown to have been prepared similarly to previous examples or intermediates, it will be understood by those skilled in the art that reaction times, number of equivalents of reagents, solvents, concentrations and temperatures may be modified for each particular reaction, and that it may be necessary or desirable to use different work-up or purification techniques.

[0276] Abbreviation AcOH: acetic acid; chloroform-d (deuterated chloroform); ca: ca; DMSO-d 6 (Deuterated dimethyl sulfoxide); Methanol-d 4 (Deuterated methanol);Boc(tert-butoxycarbonyl);Boc 2 O(di-tert-butyl dicarbonate);DMF(N,N-dimethylformamide);DCM(dichloromethane);PE(petroleum ether);ESI(electrospray atmospheric pressure ionization);IPA(isopropanol);TEA(triethylamine);TFA(trifluoroacetic acid);Dioxane(1,4-dioxane);THF(tetrahydrofuran);EtOH(ethanol);H 2 O (water); MeCN (acetonitrile); EtOAc (ethyl acetate); g (gram); h (hour); nm (nanometer); 1H NMR (proton nuclear magnetic resonance); Hz (hertz); LC-MS (liquid chromatography-mass spectrometry); MS (mass spectrometry); mg (milligram); MHz (megahertz); min (minute); mL (milliliter); mmol (millimol); ppm (parts per million); Rt (retention time); RT (room temperature); TLC (thin layer chromatography); v / v (volume / volume); m / z (mass-to-charge ratio); HCl (hydrochloric acid); K 3 PO 4 (Potassium phosphate tribasic);HOAc(Acetic acid);HCl(Hydrogen acid);CuCl(Copper(I) chloride);SOCl 2 (Thionyl chloride); Cs 2 CO 3 (Cesium carbonate);NH 4Cl(Ammonium chloride);Fe(Iron);DIPEA(N,N-Diisopropylethylamine);MW(Microwave);Pd(dppf)Cl 2 ([1,1'Bis(diphenylphosphino)ferrocene]dichloropalladium);Xphos Pd G3:(2-dicyclohexylphosphino-2,4,6-triisopropyl-1,1-biphenyl)[2-(2-amino-1,1-biphenyl)]palladium(II) methanesulfonate (CAS:1445085-55-1);Pd-174:Allyl(2-di-tert-butylphosphino-2,4,6-triisopropyl-1,1'-biphenyl)palladium(II) triflate (CAS:1798782-25-8);PdCl 2 (AmPhos) 2 :Bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II)(CAS:887919-35-9);dppf:1,1-ferrocenediyl-bis(diphenylphosphine);NaH(sodium hydride);DMAP(4-dimethylaminopyridine);NaN 3 (Sodium azide);LiOH (Lithium hydroxide);NH 2 -NH 2 (hydrazinium hydroxide solution); DEA (diethylamine); DAST (diethylaminosulfur trifluoride); Pd / C (palladium on carbon); NBS (N-bromosuccinimide); PE (petroleum ether); Aq (aqueous); LC: liquid chromatography; HPLC: high performance liquid chromatography; M: molar, molecular ion; UV: ultraviolet; UPLC: ultra-performance liquid chromatography; br: broad; d: doublet; ESI: electrospray ionization; m: multiplet; MeOH: methanol; min: minute; PDA: photodiode array; q: quartet; s: singlet, solid; t: triplet; TBME: tert-butyl methyl ether. Other abbreviations are intended to convey their generally accepted meaning.

[0277] General Scheme [ka] Reagents: (a) Cs 2 CO 3 (b) Fe, NH 4 Cl, EtOH / H 2 O (v / v=4 / 1), 80° C.; (c) Pyridine, DCM, RT; (d) LiOH, THF, RT. [ka] Reagent: (a) (Boc) 2 O, DMAP, TEA, DCM, RT; (b)Cs 2 CO 3 , MeCN, RT; (c) HCl 4 mol / L in EtOAc, RT; (d) trimethoxymethane, NaN 3 , HOAc, 80 °C; (e) Fe, NH 4 Cl, EtOH / H 2 O (v / v=4 / 1), 80° C.; (f) Pyridine, DCM, RT; (g) LiOH(aq), THF, RT.

[0278] General experimental conditions All starting materials and solvents were obtained from commercial sources or prepared according to the literature. Reaction mixtures were magnetically stirred and reactions were carried out at room temperature (ca. 20° C.) unless otherwise specified. Column chromatography was carried out on an automated flash chromatography system, e.g., Biotage Isolera Rf system, using pre-packed silica (40 μm) cartridges unless otherwise specified. 1 1 H NMR spectra were recorded using a Bruker AVANCE 400 MHz spectrometer. 1 Data for H are reported as chemical shifts (ppm) and multiplicities (s=singlet, d=doublet, t=triplet, q=quartet, m=multiplet). Chemical shifts are expressed in parts per million using the central peak of the residual protic solvent or an internal standard of tetramethylsilane as the reference substance. Spectra were recorded at 298 K unless otherwise specified.

[0279] Analytical UPLC-MS experiments to determine retention times and associated mass ions were performed using a Waters ACQUITY UPLC® H-Class system equipped with an ACQUITY PDA Detector and an ACQUITY QDa Mass Detector running one of the analytical methods described below. Analytical LC-MS experiments to determine retention times and associated mass ions were performed using an Agilent 1200 Series HPLC system coupled to an Agilent 1956, 6100 or 6120 Series single quadrupole mass spectrometer running one of the analytical methods described below.

[0280] General methodology for preparative HPLC: HPLC equipment: Shimadzu 20AP UV detector; SPD-20A. UV wavelength: 214nm and 254nm. Condition 1: Mobile phase A: water; Mobile phase B: acetonitrile. Condition 2: Mobile phase A: water containing 0.1% trifluoroacetic acid; Mobile phase B: acetonitrile. Condition 3: Mobile phase A: water with 0.1% formic acid; Mobile phase B: acetonitrile. Condition 4: Mobile phase A: water containing 0.1% ammonium hydroxide; Mobile phase B: acetonitrile. Column: Agilent 10 Prep-C18 250 x 21.2 mm. Column temperature: ambient temperature. LC gradient: 20% to 85% in 20 min, then 85% to 100% in 0.01 min, then held at 100% for 5 min, then 100% to 20% in 0.01 min, held at 20% for 5 min. LC flow rate: 20 mL / min, binary pump.

[0281] Structural nomenclature was generated using the structure-to-name converter from ChemDraw® Professional 17 (PerkinElmer).

[0282] The analysis method is as follows. Method 1 - Acid method (Shimadzu 3min) Column: Shimadzu LC-20AD series, binary pump, diode array detector. Agilent Poroshell 120 EC-C18, 2.7 μm, 4.6 × 50 mm column Detection: 2020, Quadrupole LC / MS, Ion source: API-ESI, TIC: 100-900m / z, Drying gas flow rate: 15L / min, Nebulizer pressure: 1.5L / min, Drying gas temperature: 250℃, Vcap: 4500V. Samples were dissolved in methanol at 1-10μg / mL and filtered through a 0.22μm filter membrane. Injection volume: 1-10μL. Detector: 214nm, 254nm. Detection wavelength: 214nm, 254nm. Solvents: A: 0.05% v / v formic acid in water, B: 0.05% v / v formic acid in MeCN gradient: [Table 1]

[0283] Method 2 - Acidic 5min method (Shimadzu 5min) Column: Shimadzu LC-20AD series, binary pump, diode array detector, Agilent Poroshell 120 EC-C18, 2.7 μm, 4.6 × 50 mm column. Detection: 2020, Quadrupole LC / MS, Ion source: API-ESI, TIC: 100-900m / z, Drying gas flow rate: 15L / min, Nebulizer pressure: 1.5L / min, Drying gas temperature: 250℃, Vcap: 4500V. Samples were dissolved in methanol at 1-10μg / mL and then filtered through a 0.22μm filter membrane. Injection volume: 1-10μL. Detection wavelength: 214nm, 254nm. Solvents: A: 0.05% v / v formic acid in water, B: 0.05% v / v formic acid in MeCN. gradient: [Table 2]

[0284] Method 3 - Acid method (Waters QDa 3min) Column: Waters QDa, binary pump, diode array detector, Waters CORTECS UPLC, C18, 1.6 μm, 2.1×50 mm column. Detection: QDa, Quadrupole LC / MS, Ion source: API-ES, TIC: 70-900 m / z, Fragmenter: 70, Drying gas flow rate: 12 L / min, Nebulizer pressure: 36 psi, Drying gas temperature: 350°C, Vcap: 3000 V. Samples were dissolved in methanol at 1-10 μg / mL and then filtered through a 0.22 μm filter membrane. Injection volume: 1-10 μL. Detectors: 214 nm, 254 nm. Solvents: A: 0.05% v / v formate in water, B: 0.05% v / v formate in MeCN. gradient: [Table 3]

[0285] Method 4 - Acidic trisection method Column: Waters ACQUITY UPLC® CSH C18, 1.7 μm, 2.1×30 mm, 40° C. Detection: UV PDA 210-400 nm, purity at 254 nm, ACQUITY QDa® ESI Solvents: A: 0.1% v / v formic acid in water, B: MeCN gradient: [Table 4]

[0286] Method 5 - Acidic quadrant method Column: YMC TRI ART C18, 1.6 μm, 2.1 × 50 mm Detection: UV PDA 210-400 nm, purity at 254 nm, ACQUITY QDa® ESI Solvents: A: 0.1% v / v formic acid in water, B: MeCN gradient: [Table 5]

[0287] Synthesis of Compounds: The compounds of the present invention may be prepared by methods well known to those skilled in the art using appropriate intermediates as depicted in the general synthetic schemes.

[0288] Intermediate 1. Methyl 3-(chlorosulfonyl)-4-methoxybenzoate [ka] Step 1: Methyl 3-(chlorosulfonyl)-4-methoxybenzoate: Dissolve 4-methoxybenzoic acid (5.0 g, 32.9 mmol) and chlorosulfonic acid (9.5 g, 82.3 mmol) in SOCl 2 The mixture in (30 mL) was stirred at room temperature for 12 h. The reaction mixture was concentrated to give the crude product. The crude product was purified by silica gel chromatography (eluted with 1 / 2 EtOAc / PE) to give the title compound as a white solid (5.34 g, 21.36 mmol, 65%). 1 H NMR (400MHz, DMSO-d 6 )δ11.15(s,1H), 8.29(d,J=2.3Hz,1H), 7.91(dd,J=8.6,2.3Hz,1H), 7.08(d,J=8.7Hz,1H), 3.83(s,3H).

[0289] Intermediate 2. 3-(Chlorosulfonyl)-4-ethylbenzoic acid [ka] Step 1: 3-(Chlorosulfonyl)-4-ethylbenzoic acid: Dissolve 4-ethylbenzoic acid (4.5 g, 30.0 mmol) and chlorosulfonic acid (8.77 g, 75.0 mmol) in SOCl 2The mixture in (45 mL) was heated at 85° C. for 12 h. After cooling to room temperature, the reaction mixture was concentrated to give the crude product. The crude product was purified by silica gel chromatography (eluted with 1 / 3 EtOAc / PE) to give the title compound as a yellow solid (2.2 g, 8.87 mmol, 30%). 1 H NMR (400MHz, DMSO-d 6 )δ13.38(s,1H), 8.36(d,J=1.9Hz,1H), 7.84(dd,J=7.9,2.0Hz,1H), 7.33(d,J=7.9Hz,1H), 3.09(q,J=7.5Hz,2H), 1.20(t,J=7.5Hz,3H).

[0290] Intermediate 3. Methyl 3-(chlorosulfonyl)-4-cyclopropylbenzoate [ka] Step 1: Methyl 4-cyclopropylbenzoate: To a solution of methyl 4-bromobenzoate (200 g, 934 mmol) in toluene (1800 ml) and water (400 ml) was added cyclopropylboronic acid (120.56 g, 1401 mmol), K 3 PO 4 (396.2 g, 1869 mmol) and tricyclohexylphosphine (26.16 g, 93.4 mmol) were added at room temperature. The mixture was then heated to 37° C. in a nitrogen 2 The mixture was purged with 500 mL of ethyl acetate for 45 min, and then palladium(II) acetate (10.46 g, 46.7 mmol) was added. The mixture was heated at 80° C. for 6 h. * The reaction mixture was cooled to room temperature, filtered through a bed of Celite, and washed with water (4.0 L) and EtOAc (2×5.0 L). The combined organic layers were washed with water (5 L) and sodium hydroxide. 2 SO 4 The mixture was dried at rt and concentrated under reduced pressure to give 1201 g of crude material, which was suspended in n-hexane (8 L) and stirred for 3 h at 0° C. The mixture was filtered through Celite and concentrated under reduced pressure to give the title ester as a brown oil (800 g, 4545 mmol, quantitative, 98% pure) which was used directly in the next step. * A total of five parallel reactions (2 x 100 g and 3 x 200 g scales) were performed and combined for workup. 1 H NMR (400MHz, DMSO) δ7.83~7.81(d,J=8.0Hz,2H), 7.20~7.18(d,J=8.4Hz,2H), 3.85(s,3H), 2.03~1.96(m,1H), 1.06~1.01(m,2H), 0.77~0.74(m,2H).

[0291] Step 2: Methyl 3-bromo-4-cyclopropylbenzoate: To a solution of the ester from step 1 (250 g, 1420 mmol) in TFA (3000 ml) was added NBS (252.8 g, 1420 mmol) portionwise at room temperature. The reaction mixture was heated at 50° C. for 16 h. * The mixture was cooled to room temperature, diluted with ice water (5.0 L) and extracted with n-hexane (2 x 5.0 L). The combined organic layers were washed with saturated Na 2 CO 3 solution (2 L), followed by washing with brine solution (2 L) and Na 2 SO 4 The crude material was purified by normal phase chromatography on silica gel (0-50% DCM in hexanes) to give the title ester as an oil (443 g, 1744 mmol, 39%, 95.7% pure). * A total of four parallel reactions (1 x 100 g, 1 x 200 g and 2 x 250 g scales) were performed and combined for workup. 1 H NMR (400MHz, DMSO) δ8.06(s,1H), 7.83(d,J=8.0Hz,1H), 7.12(d,J=8.4Hz,1H), 3.87(s,3H), 2.22(m,1H), 1.12~1.07(m,2H), 0.81~0.77(m,2H).

[0292] Step 3: Methyl 3-(benzylthio)-4-cyclopropylbenzoate: To a solution of the ester from step 2 (100 g, 393 mmol) in 1,4-dioxane (1400 ml) was added Xantphos (11.39 g, 19.6 mmol) and Pd2 (dba) 3 (9.01 g, 9.8 mmol) was added at room temperature. The reaction mixture was then cooled to 5° C. 2 DIPEA (145.1 ml, 787 mmol) and benzyl mercaptan (51.34 g, 413 mmol) were added and the reaction mixture was heated to 110° C. for 16 hours. * The reaction mixture was cooled to room temperature and filtered through a Celite bed, the bed was washed with hexane (3.0 L), and the combined organic filtrate was washed with distilled water (5.0 L). 2 SO 4 The crude product was purified by normal phase chromatography on silica gel (0-40% DCM in hexanes) to give the title mercaptoether as a yellow solid (425 g, 1429 mmol, 84%, 97% pure). * A total of four parallel reactions (1 x 100 g and 3 x 110 g scale) were performed and combined for workup. LCMS: 3.11 min, MS: ES+ 299.53 (M+1); 1 H NMR(400MHz,DMSO)δ7.86(s,1H), 7.68(d,J=8Hz,1H), 7.38(m,5H), 7.05(d,J= 8.0Hz,1H), 4.26(s,2H), 3.82(s,3H), 2.18(m,1H), 1.03(m,2H), 0.72(m,2H).

[0293] Step 4: Methyl 3-(chlorosulfonyl)-4-cyclopropylbenzoate: To a stirred solution of the mercaptoether from step 3 (142 g, 184 mmol) in a mixture of AcOH (114.3 ml), water (68.8 ml) and MeCN (3124 ml) was added 1,3-dichloro-5,5-dimethylhydantoin (187.6 g, 952 mmol) in one portion at 0° C. The mixture was stirred at the same temperature for 0.5 h. The reaction mixture was diluted with distilled water (10 L) and extracted with EtOAc (2×5.0 L). The combined organic layers were washed with distilled water (2×5.0) and concentrated with NaCl. 2 SO 4The crude product was purified by normal phase column chromatography on silica gel using 6-10% EtOAc in hexanes, followed by trituration with n-hexane to give the title sulfonyl chloride as a white crystalline solid (260 g, 970 mmol, 68%, 98% pure). * A total of three parallel reactions (142 g scale) were performed and combined for workup. LCMS: 2.480 min, MS: ES+ 275.1 (M+1); 1 H NMR(400MHz,DMSO)δ11.81(br,3H), 8.35(s,1H), 7.77(d,J=8.0Hz,1H), 6.84(d,J= 8.4Hz,1H), 3.83(s,3H), 3.14(m,1H), 1.03(d,J=6.8Hz,2H), 0.75(d,J=4.4Hz,2H).

[0294] Intermediate 4. Methyl 5-(chlorosulfonyl)-4-cyclopropyl-2-fluorobenzoate [ka] Step 1: Methyl 4-chloro-2-fluoro-5-nitrobenzoate: A solution of 4-chloro-2-fluoro-5-nitrobenzoic acid (10.0 g, 45.6 mmol) in MeOH (200 mL) was added with SOCl at 0 °C. 2 (30 mL) was added. The resulting mixture was heated at reflux overnight. The solvent was removed under reduced pressure and the residue was dissolved in EtOAc and saturated Na 2 CO 3 The organic layer was washed with Na 2 SO 4 The mixture was dried at 40° C. and concentrated to give the crude product, which was purified by silica gel chromatography (eluting with 1 / 10 EtOAc / PE) to give the title compound as an off-white solid (9.82 g, 42.1 mmol, 92%). 1 H NMR (400MHz, DMSO-d 6 )δ8.59(d,J=6.9Hz,1H), 8.06(d,J=10.2Hz,1H), 3.94(s,3H).

[0295] Step 2: Methyl 4-cyclopropyl-2-fluoro-5-nitrobenzoate: ester from step 1 (6.0 g, 25.8 mmol), cyclopropylboronic acid (6.60 g, 77.4 mmol), K 3 PO 4 (10.92 g, 51.6 mmol) and Pd(dppf)Cl 2 A mixture of (1.92 g, 2.58 mmol) in THF (50 mL) was heated at 90° C. for 16 h in a sealed tube. The resulting mixture was filtered through Celite, concentrated, and purified by silica gel chromatography (eluted with 1 / 5 EtOAc / PE) to give the title compound as an off-white solid (5.4 g, 22.6 mmol, 88%). 1H NMR (400 MHz, DMSO-d 6 )δ8.42(d,J=6.8Hz,1H), 7.27(d,J=12.1Hz,1H), 3.93(s,3H), 2.46~2.34(m,1H), 1.25~1.12(m,2H), 1.08~0.94(m,2H).

[0296] Step 3: Methyl 5-amino-4-cyclopropyl-2-fluorobenzoate: Mix the ester from step 2 (1.0 g, 4.2 mmol), iron powder (1.17 g, 21.0 mmol) and NH 4 A mixture of Cl (0.45 g, 8.4 mmol) in a mixture of ethanol and water (5:1) was heated at 85° C. for 2 h. The resulting mixture was filtered through Celite and concentrated to give the title compound as a grey solid (0.85 g, 4.1 mmol, 98%). UPLC-MS (Method 1) m / z 210.10 (M+H) at 1.32 min. + .

[0297] Step 4: Methyl 5-(chlorosulfonyl)-4-cyclopropyl-2-fluorobenzoate: Methyl 5-amino-4-cyclopropyl-2-fluorobenzoate (0.85 g, 4.1 mmol) in concentrated HCl (3 mL) and H 2 To a solution of NaNO in 20O (9.0 mL) 2(0.56 g, 8.2 mmol) was added in portions at 0 °C. The mixture was stirred at 0 °C for 30 min. 2 To a solution of SOCl in 300 (3 mL) 2 (1.75 mL) was added dropwise at 0° C. This solution was added dropwise to the above reaction and the mixture was stirred at 0° C. for 1 h. The reaction was diluted with EtOAc (50 mL) and H 2 The organic layer was diluted with 200 mL of EtOAc (50 mL×2) and the aqueous layer was extracted with EtOAc (50 mL×2). 2 SO 4 After drying at rt and concentration, the title compound was obtained as a yellow oil (0.65 g, 2.2 mmol, 54%). 1 H NMR (400MHz, DMSO-d 6 )8.29(d,J=8.1Hz,2H), 6.64(d,J=13.0Hz,2H), 3.92~3.82(m,1H), 3.82(s,3H), 1.14~0.98(m,2H), 0.90~0.71(m,2H).

[0298] Intermediate 5. Methyl 5-(chlorosulfonyl)-4-cyclopropyl-3-fluorobenzoate [ka] Step 1: Methyl 3-bromo-5-fluoro-4-hydroxybenzoate: To a solution of methyl 3-fluoro-4-hydroxybenzoate (5.0 g, 29.4 mmol) in HOAc (50 mL), 2 (4.64 g, 29.4 mmol) was added at 0° C. The resulting mixture was stirred at room temperature for 4 h. The solvent was removed under reduced pressure and the residue was dissolved in EtOAc and saturated Na 2 CO 3 The organic layer was washed with Na 2 SO 4The crude product was purified by silica gel chromatography (eluting with 1 / 3 EtOAc / PE) to give the title compound as a yellow solid (5.8 g, 23.4 mmol, 80%). UPLC-MS (Method 1) m / z 248.95 (MH) at 1.516 min. - 1 H NMR (400MHz, DMSO-d 6 )δ11.38(s,1H), 7.89(t,J=1.7Hz,1H), 7.69(dd,J=10.9,2.0Hz,1H), 3.85(s,3H).

[0299] Step 2: Methyl 3-fluoro-4-hydroxy-5-((4-methoxybenzyl)thio)benzoate: Methyl 3-bromo-5-fluoro-4-hydroxybenzoate (5.8 g, 23.4 mmol), (4-methoxyphenyl)methanethiol (7.2 g, 46.8 mmol), DIPEA (6.0 g, 46.8 mmol), Xantphos (2.7 g, 4.68 mmol) and Pd 2 (dba) 3 A mixture of (2.14 g, 2.34 mmol) in dioxane (50 mL) was heated at 110° C. for 16 h. The resulting mixture was filtered through Celite, concentrated, and purified by silica gel chromatography (eluted with 1 / 10 EtOAc / PE) to give the title compound as a white solid (2.85 g, 8.85 mmol, 38%). UPLC-MS (Method 3) m / z 321.0 (MH) at 1.654 min. - .

[0300] Step 3: Methyl 3-fluoro-5-((4-methoxybenzyl)thio)-4-(((trifluoromethyl)sulfonyl)oxy)benzoate: To a solution of methyl 3-fluoro-4-hydroxy-5-((4-methoxybenzyl)thio)benzoate (2.85 g, 8.85 mmol) in DCM (50 mL) was added Tf 2 2H2O (4.99 g, 17.7 mmol) was added at 0° C. Pyridine (1.39 g, 17.7 mmol) was added and the resulting mixture was stirred at room temperature for 1 h. The solvent was removed under reduced pressure and the residue was dissolved in EtOAc and saturated Na 2 CO3 The organic layer was washed with Na 2 SO 4 The mixture was dried at 40° C. and concentrated to give the crude product, which was purified by silica gel chromatography (eluting with 1 / 15 EtOAc / PE) to give the title compound as a yellow oil (1.43 g, 3.15 mmol, 36%). 1 H NMR (400MHz, DMSO-d 6 )δ7.72~7.46(m,3H), 7.32~7.24(m,2H), 6.94~6.83(m,2H), 4.17(s,2H), 3.86(s,3H), 3.78(s,3H).

[0301] Step 4: Methyl 4-cyclopropyl-3-fluoro-5-((4-methoxybenzyl)thio)benzoate: Methyl 3-fluoro-5-((4-methoxybenzyl)thio)-4-(((trifluoromethyl)sulfonyl)-oxy)benzoate (1.2 g, 2.64 mmol), cyclopropylboronic acid (0.45 g, 5.28 mmol), K 2 CO 3 (1.09 g, 7.92 mmol) and Pd(PPh 3 ) 4 A mixture of (0.3 g, 0.26 mmol) in dioxane (30 mL) was heated at 100° C. for 16 h. The resulting mixture was filtered through Celite, concentrated, and purified by silica gel chromatography (eluted with 1 / 10 EtOAc / PE) to give the title compound as a white solid (0.52 g, 1.5 mmol, 57%). 1 H NMR (400MHz, DMSO-d 6 )δ7.73~7.51(m,1H), 7.45~7.30(m,1H), 7.23(s,2H), 6.98~6.86(m,2H), 4.29(s,2H) , 3.87(s,3H), 3.76(s,3H), 2.12~1.97(m,1H), 1.09~0.99(m,2H), 0.84~0.75(m,2H).

[0302] Step 5: Methyl 3-(chlorosulfonyl)-4-cyclopropyl-5-fluorobenzoate: Methyl 4-cyclopropyl-3-fluoro-5-((4-methoxybenzyl)thio)benzoate (0.52 g, 1.5 mmol), HOAc (0.1 g, 1.65 mmol) and H 2 To a mixture of 2,4-dimethylimidazolidine-2,4-dione (0.44 g, 2.25 mmol) in MeCN (10 mL) was added 1,3-dichloro-5,5-dimethylimidazolidine-2,4-dione (0.44 g, 2.25 mmol) at -5 °C and the solution was stirred at the same temperature for 1 h. The mixture was extracted with EtOAc (100 mL) and diluted with Na 2 SO 4 After drying at rt and concentration, the crude title compound was obtained as a yellow oil (0.41 g, 1.4 mmol, 93%), which was used directly in the next step without further purification.

[0303] Intermediate 6. Preparation of 2-(cyclopentyloxy)-5-(5-methylisoxazol-4-yl)aniline [ka] Step 1: Synthesis of 4-bromo-1-(cyclopentyloxy)-2-nitrobenzene. Cyclopentanol (5.8 g, 68.18 mmol, 1.5 equiv.) and Cs 2 CO 3 (22.1 g, 68.68 mmol, 1.5 equiv) was added to acetonitrile (100 mL) and stirred at room temperature. 4-Bromo-1-fluoro-2-nitrobenzene (10.0 g, 45.45 mmol, 1.0 equiv) was added in portions and the resulting reaction mixture was stirred at room temperature for 6 h. The reaction mixture was diluted with water (200 mL) and extracted with EtOAc (3×150 mL). The combined organic layers were washed with Na 2 SO 4 It was dried at 40° C., filtered and concentrated under reduced pressure. The crude product was purified by column chromatography using 1% EtOAc in n-hexane to give the title compound as a pale yellow liquid (8.5 g, 65%). 1 H NMR (400MHz, DMSO-d 6):δ1.58~1.62(m,3H), 1.63~1.72(m,3H), 1.87~1.98(m,2H), 5.02~5.05 (m,1H), 7.33(d,J=9.2Hz,1H), 7.77~7.79(m,1H), 8.07(d,J=2.4Hz,1H).

[0304] Step 2: Synthesis of 2-(4-(cyclopentyloxy)-3-nitrophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane. The bromide from step 1 (4.0 g, 13.97 mmol, 1.0 equiv) and KOAc (4.1 g, 41.93 mmol, 3.0 equiv) were stirred in dioxane (40 mL) at room temperature. To this solution was added B 2 Pin 2 (5.3 g, 20.95 mmol, 1.5 equiv.) was added in portions and the resulting reaction mixture was cooled to 5° C. 2 Purge under gas for 10 min. 2 (dppf)DCM (1.1 g, 1.397 mmol, 0.1 equiv) was added and the reaction mixture was stirred at 90° C. for 16 h. The reaction mixture was filtered through a pad of Celite and washed with EtOAc (100 mL). The filtrate was concentrated under reduced pressure and the crude material was purified by column chromatography using 5% EtOAc in n-hexane to give the title dioxaborolane as a pale yellow liquid (3.0 g, 64%). 1 H NMR (400MHz, DMSO-d 6 ):δ1.31(s,12H), 1.57~1.59(m,2H), 1.59~1.73(m,4H), 1.90~1.95(m,2H), 5.0 7~5.09(m,1H), 7.36(d,J=8.4Hz,1H), 7.83~7.86(m,1H), 7.98(d,J=1.2Hz,1H).

[0305] Step 3: Synthesis of 2-(cyclopentyloxy)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline. The dioxaborolane from step 2 (3.0 g, 9.0 mmol, 1.0 equiv) was stirred in MeOH (40 mL) at room temperature. To this solution was added Pd / C (2.4 g, w / 80%) and the resulting reaction mixture was heated under H 2Purged under gas (hydrogen balloon) and stirred at room temperature for 16 h. The reaction mixture was filtered through a pad of Celite and washed with EtOAc (100 mL). The filtrate was concentrated under reduced pressure to give the title aniline as a light brown sticky liquid (2.6 g, 84%). LCMS [ESI, M+1]: 304.7. 1 H NMR (400MHz, DMSO-d 6 ):δ1.29(s,12H), 1.56~1.58(m,2H), 1.69~1.72(m,4H), 1.84~1.88(m,2H), 4.57(s,2H), 4. 77~4.79(t,J=5.6Hz,1H), 6.74(d,J=8.0Hz,1H), 6.85~6.88(m,1H), 6.98(d,J=1.2Hz,1H).

[0306] Step 4: Synthesis of 2-(cyclopentyloxy)-5-(5-methylisoxazol-4-yl)aniline. The aniline from Step 3 (0.2 g, 0.66 mmol, 1.0 equiv.) and 4-iodo-5-methylisoxazole (0.17 g, 0.79 mmol, 1.2 equiv.) were dissolved in dioxane:H in a 30 mL glass microwave vial. 2 The solution was stirred at room temperature in 12.5 mL of K 2 CO 3 (0.3 g, 2.31 mmol, 3.5 equiv.) was added and the resulting reaction mixture was treated with N 2 Purge under gas for 10 min. 2 (dppf)DCM (0.05 g, 0.06 mmol, 0.1 equiv) was added to the reaction mixture and sealed with a cap. The resulting reaction mixture was heated at 100° C. under microwave for 1 h. Four separate batches were prepared on the same scale and the crude reaction mixtures were combined for workup and purification. The reaction mixture was filtered through a pad of Celite and washed with EtOAc (20 mL). The combined filtrate was diluted with water (25 mL) and extracted with EtOAc (3×25 mL). The combined organic layers were washed with Na 2 SO 4The mixture was dried at 40° C., filtered and concentrated under reduced pressure. The crude product was purified by flash chromatography using 15% EtOAc in n-hexane as the mobile phase to give the title aniline as a light brown sticky liquid (0.25 g, 30%). LCMS [ESI, M+1]: 259.7. 1 H NMR (400MHz, DMSO-d 6 ):δ1.57(s,2H), 1.73(s,4H), 1.86~1.88(d,2H), 2.49(s,3H), 4.74(s,2H), 4.78(s,1 H), 6.63(d,J=2.0Hz,1H), 6.76(d,J=1.6Hz,1H), 6.81(d,J=8.0Hz,1H), 8.66(s,1H).

[0307] Intermediate 7. Preparation of 2-(cyclopentyloxy)-4-fluoro-5-(5-methylisoxazol-4-yl)aniline [ka] Step 1: Synthesis of 1-bromo-4-(cyclopentyloxy)-2-fluoro-5-nitrobenzene. Cyclopentanol (4.3 g, 50.41 mmol, 1.0 equiv.) and NaH (60%) (4.0 g, 100.82 mmol, 2.0 equiv.) were stirred in anhydrous THF (100 mL) at 0° C. To this solution was added 4-bromo-1-fluoro-2-nitrobenzene (10.0 g, 42.01 mmol, 1.0 equiv.) in portions at 0° C., and the resulting reaction mixture was allowed to warm slowly and stirred at room temperature for 6 h. The reaction mixture was quenched with ice-cold water (150 mL) and extracted with EtOAc (3×200 mL). The combined organic layers were washed with Na 2 SO 4 The mixture was dried at 40° C., filtered and concentrated under reduced pressure. The crude product was purified by column chromatography using 1% EtOAc in n-hexane to give the title bromide as a pale yellow solid (9.0 g, 70%). LCMS [ESI, M+1]: 305.9. 1 H NMR (400MHz, DMSO-d 6): δ1.56~1.75(m,6H), 1.89~1.93(m,2H), 5.06~5.09(t,J=5.6Hz,1H), 7.54(d,J=10.8Hz,1H), 8.31(d,J=7.6Hz,1H).

[0308] Step 2: Synthesis of 2-(4-(cyclopentyloxy)-2-fluoro-5-nitrophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane. The bromide from step 1 (4.0 g, 13.15 mmol, 1.0 equiv) and KOAc (3.8 g, 39.45 mmol, 3.0 equiv) were stirred in dioxane (80 mL) at room temperature. To this solution was added B 2 Pin 2 (6.0 g, 23.67 mmol, 1.8 equiv.) was added and the resulting reaction mixture was treated with N 2 Purge under gas for 10 min. 2 (dppf)DCM (1.0 g, 1.315 mmol, 0.1 equiv) was added and the resulting reaction mixture was stirred at 100° C. for 5 h. The reaction mixture was filtered through a pad of Celite, washed with EtOAc (100 mL) and the combined filtrate was concentrated under reduced pressure. The crude product was purified by column chromatography using 3% EtOAc in n-hexane to give the title dioxaborolane as a light brown viscous liquid (3.0 g, 65%). 1 H NMR (400MHz, DMSO-d 6 ): δ1.29(s,12H), 1.59~1.61(m,2H), 1.64~1.75(m,4H), 1.91~1.96(m,2H), 5.10(d,J=5.2Hz,1H), 7.23(d,J=11.2Hz,1H), 8.07(d,J=6.0Hz,1H).

[0309] Step 3: Synthesis of 2-(cyclopentyloxy)-4-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline. Pd / C (2.4 g, w / 80%) was added to a stirred solution of dioxaborolane from step 2 (3.0 g, 8.54 mmol, 1.0 equiv) in MeOH (60 mL) at room temperature. The resulting reaction mixture was stirred at 4°C for 1 hour. 2Purge under gas (balloon) and stir for 6 h. The reaction mixture was filtered through a pad of Celite and washed with MeOH (200 mL). The combined filtrate was concentrated under reduced pressure to give the title aniline as a light brown sticky liquid (2.5 g, 91%). LCMS [ESI, M+1]: 322.7. 1 H NMR (400MHz, DMSO-d 6 ):δ1.25(s,12H), 1.56~1.58(m,2H), 1.71~1.72(m,4H), 1.89(s,2H), 4.66(s,2 H), 4.80~4.82(t,J=5.2Hz,1H), 6.60(d,J=11.2Hz,1H), 6.88(d,J=6.4Hz,1H).

[0310] Step 4: Synthesis of 2-(cyclopentyloxy)-4-fluoro-5-(5-methylisoxazol-4-yl)aniline. The aniline from step 3 (1.0 g, 31.13 mmol, 1.0 equiv.) and 4-iodo-5-methylisoxazole (0.97 g, 46.69 mmol, 1.5 equiv.) were dissolved in dioxane:H 2 The solution was stirred at room temperature in 1:200 mL of 1:200 sucrose (4:1). 3 PO 4 (0.86 g, 40.46 mmol, 1.5 equiv.) was added and the resulting reaction mixture was treated with N 2 The mixture was purged under gas for 15 minutes. X-phos Pd G2 (0.24 g, 0.3.11 mmol, 0.1 equiv) was added to the reaction mixture and sealed with a cap. The reaction mixture was heated at 110° C. under conventional heating for 1 hour, then diluted with water (200 mL) and extracted with EtOAc (3×100 mL). The combined organic layers were washed with Na 2 SO 4 The mixture was dried at 40° C., filtered and concentrated under reduced pressure. The crude product was purified by flash chromatography using 7% EtOAc in n-hexane to give the title aniline as a light brown sticky liquid (0.290 g, 34%). LCMS [ESI, M+1]: 277.7. 1 H NMR (400MHz, DMSO-d 6): δ1.57~1.61(m,2H), 1.73~1.75(m,4H), 1.89~1.92(m,2H), 2.49(s,3H), 4.61(s,2H), 4.80~4.83(t,J=5.2Hz,1H), 6.64(d,J=8.0Hz,1H), 6.80(d,J=8.4Hz,1H), 8.58(s,1H).

[0311] Intermediate 8. Preparation of 4-chloro-2-(cyclopentyloxy)-5-(5-methylisoxazol-4-yl)aniline [ka] Step 1: Synthesis of 1-bromo-2-chloro-4-(cyclopentyloxy)-5-nitrobenzene. A stirred solution of cyclopentanol (5.0 g, 58.95 mmol, 1.5 equiv.) and NaOtBu (5.6 g, 58.95 mmol, 1.5 equiv.) in anhydrous DMF (100 mL) was prepared at room temperature. To this solution was added 1-bromo-2-chloro-4-fluoro-5-nitrobenzene (10.0 g, 39.30 mmol, 1.0 equiv.) in portions, and the resulting reaction mixture was stirred at room temperature for 2 h. The reaction mixture was diluted with water (100 mL) and extracted with ethyl acetate (3×150 mL). The combined organic layers were washed with Na 2 SO 4 It was dried at 40° C., filtered and concentrated under reduced pressure. The crude product was purified by column chromatography using 1% ethyl acetate in n-hexane to give the title bromide as a pale yellow solid (7.8 g, 62%). 1 H NMR (400MHz, DMSO-d 6 ): δ1.56~1.60(m,2H), 1.62~1.74(m,4H), 1.87~1.92(m,2H), 5.12~5.14(t,J=5.6Hz,1H), 7.70(s,1H), 8.31(s,1H).

[0312] Step 2: Synthesis of 2-(2-chloro-4-(cyclopentyloxy)-5-nitrophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane. The bromide from step 1 (3.0 g, 9.35 mmol, 1.0 equiv) and KOAc (2.7 g, 28.07 mmol, 3.0 equiv) were stirred in dioxane (40 mL) at room temperature. To this solution was added B 2 Pin 2 (3.5 g, 14.02 mmol, 1.5 equiv.) was added in portions and the resulting reaction mixture was cooled to 5° C. 2 The mixture was purged under gas for 10 minutes. Then PdCl 2 (dppf)DCM (0.76 g, 0.93 mmol, 0.1 equiv) was added and the resulting reaction mixture was stirred at 90° C. for 16 h. The reaction mixture was filtered through a pad of Celite, the bed was washed with EtOAc (100 mL) and the combined filtrate was concentrated under reduced pressure. The crude product was purified by column chromatography using 5% ethyl acetate in n-hexane to give the title dioxaborolane as a yellow liquid (1.6 g, 47%). 1 H NMR (400MHz, DMSO-d 6 ): δ1.30(s,12H), 1.57~1.61(m,2H), 1.64~1.75(m,4H), 1.90~1.96(m,2H), 5.15~5.18(t,J=5.6Hz,1H), 7.44(s,1H), 8.06(s,1H).

[0313] Step 3: Synthesis of 4-chloro-2-(cyclopentyloxy)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline. The dioxaborolane from step 2 (1.2 g, 3.55 mmol, 1.0 equiv) was stirred in EtOAc (30 mL) at room temperature. To this solution was added SnCl 2 .2H 2 O (3.6 g, 17.77 mmol, 5.0 equiv) was added and the resulting reaction mixture was stirred at room temperature for 16 h, then diluted with water (200 mL) and extracted with EtOAc (3×200 mL). The combined organic layers were washed with Na 2 SO 4The mixture was dried at 40° C., filtered and concentrated under reduced pressure. The crude product was purified by flash chromatography using 10% ethyl acetate in n-hexane to give the title aniline as a light brown sticky solid (1.0 g, 98%). LCMS [ESI, M+1]: 338.8. 1 H NMR (400MHz, DMSO-d 6 ): δ1.23~1.30(m,12H), 1.55(s,2H), 1.70~1.72(d,4H), 1.87~1.88(d,2H), 4.74(s,2H), 4.81(s,1H), 6.73(s,1H), 6.95(s,1H).

[0314] Step 4: Synthesis of 4-chloro-2-(cyclopentyloxy)-5-(5-methylisoxazol-4-yl)aniline. The aniline from Step 3 (1.0 g, 2.96 mmol, 1.0 equiv.) and 4-iodo-5-methylisoxazole (0.17 g, 2.96 mmol, 1.0 equiv.) were dissolved in dioxane:H 2 The solution was stirred at room temperature in 12.5 mL of K 2 CO 3 (1.4 g, 10.36 mmol, 3.5 equiv.) was added and the resulting reaction mixture was treated with N 2 Purge under gas for 10 min, then add PdCl 2 (dppf).DCM (0.24 g, 0.296 mmol, 0.1 equiv) was added and sealed with a cap. The resulting reaction mixture was then stirred in a microwave at 100° C. for 1 h, then filtered through a pad of Celite bed and the bed was washed with EtOAc (25 mL). The combined filtrate was diluted with water (25 mL) and extracted with EtOAc (3×20 mL). The combined organic layers were washed with Na 2 SO 4 The mixture was dried at 40° C., filtered and concentrated under reduced pressure. The crude product was purified by flash chromatography using 15% ethyl acetate in n-hexane to give the title aniline as an off-white color (0.282 g, 33%). LCMS [ESI, M+1]: 293.7. 1 H NMR (400MHz, DMSO-d 6): δ1.57(s,2H), 1.73(s,4H), 1.88(s,2H), 2.32(s,3H), 4.83(s,2H), 4.91(s,1H), 6.60(s,1H), 6.90(s,1H), 8.57(s,1H).

[0315] Intermediate 9. Preparation of 2-((cyclopentyloxy)-5-(isothiazol-5-yl)aniline [ka] Step 1: 5-(tributylstannyl)isothiazole. To a solution of 5-bromoisothiazole (4.0 g, 24.38 mmol) in THF (200 mL) was added n-BuLi (1.6 M in hexanes, 22.86 mL, 36.58 mmol) dropwise at −78° C. under nitrogen atmosphere. The reaction mixture was stirred at −78° C. for 30 min, then tributyltin chloride (11.90 g, 36.58 mmol) was added dropwise at −78° C. The reaction mixture was stirred at −78° C. for an additional 1 h, then quenched in saturated ammonium chloride solution (500 mL) and extracted with diethyl ether (2×250 mL). The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure. * The crude material was purified by manual column chromatography using neutral alumina (eluting with hexane to 3% ethyl acetate in hexane as the mobile phase) to afford the title isothiazole as a pale yellow liquid (10.00 g, 54.8%). * The reaction was carried out in two parallel batches (4.0 g x 2 = 8.0 g) and combined for workup and purification. LCMS: 2.989 min, MS: ES+ 374.20, 376.10 (M, M+2): 1 H NMR (400MHz, DMSO) δ8.72(s,1H), 7.45~7.44(m,1H), 1.54~1.48(m,6H), 1.31~1.23(m,6H), 1.17~1.13(m,6H), 0.847(t,J=7.2Hz,9H).

[0316] Step 2: 5-(4-(cyclopentyloxy)-3-nitrophenyl)isothiazole. A solution of 4-bromo-1-(cyclopentyloxy)-2-nitrobenzene (Step 1 of Intermediate 6) (2.00 g, 6.98 mmol) in 1,4-dioxane (40 mL) was placed in a 100 mL sealed tube with N 2 The mixture was purged with gas for 10 minutes. Step 1 (5-(tributylstannyl)isothiazole) (3.92 g, 10.48 mmol) and tetrakis (0.808 g, 0.698 mmol) were added and N 2 Purge with gas for an additional 5 minutes. The sealed tube was capped and heated at 110° C. for 16 hours, then poured into water (100 mL) and extracted with ethyl acetate (2×100 mL). The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure. The crude was purified by FCC using neutral alumina (eluting with 20% ethyl acetate in hexanes as mobile phase) to give the title isothiazole as an off-white solid (1.4 g, 68.99%). LCMS: 2.785 min, MS: ES+ 291.2 (M+1); 1 H NMR(400MHz,DMSO)δ8.60(d,J=1.6Hz,1H), 8.26(d,J=2.0Hz,1H), 7.97(dd,J=8.8,2.4Hz,1H), 7.84( d,J=1.2Hz,1H), 7.47(d,J=8.8Hz,1H), 5.13(t,J=5.6Hz,1H), 1.95~1.92(m,2H), 1.77~1.60(m,6H).

[0317] Step 3: 2-(cyclopentyloxy)-5-(isothiazol-5-yl)aniline. To a solution of the isothiazole from step 2 (0.700 g, 2.41 mmol) in methanol:water (9:1) (14 mL) was added iron powder (0.675 g, 12.05 mmol) and ammonium chloride (0.645 g, 12.05 mmol) at room temperature. The reaction mixture was stirred at 90° C. for 3 h, then filtered through Celite, the bed was washed with ethyl acetate (2×50 mL), the filtrate was diluted with water (50 mL) and the organic layer was separated. The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude was triturated in n-pentane:diethyl ether (7:3) (10 mL) to give the title aniline as a light brown solid (0.299 g, 47.6%). LCMS: 2.717 min, MS: ES+ 261.6 (M+1); 1 H NMR (400MHz, DMSO) δ8.49(s,1H), 7.51(s,1H), 6.95~6.83(m,3H), 4.89(s,2H), 4.82(s,1H), 1.89(s,2H), 1.74(s,4H), 1.57(s,2H).

[0318] Intermediate 10. Preparation of 2-(cyclopentyloxy)-4-fluoro-5-(isothiazol-5-yl)aniline [ka] Step 1: 5-(4-(cyclopentyloxy)-2-fluoro-5-nitrophenyl)isothiazole. A solution of 1-bromo-4-(cyclopentyloxy)-2-fluoro-5-nitrobenzene (Step 1 of Intermediate 7) (2.00 g, 6.57 mmol) in 1,4-dioxane (40 mL) was placed in a 100 mL sealed tube under N 2 The mixture was purged with gas for 10 minutes. 5-(tributylstannyl)isothiazole (Step 1 of Intermediate 9) (3.69 g, 9.86 mmol) and tetrakis (0.759 g, 0.657 mmol) were added and N 2The mixture was further purged with gas for 5 minutes. The reaction mixture was capped and heated at 110° C. for 16 hours, then poured into water (100 mL) and extracted with ethyl acetate (2×75 mL). The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude was purified by FCC using neutral alumina (eluting with 12% ethyl acetate in hexanes as mobile phase) to give the title isothiazole as a white solid (0.9 g, 44.4%). LCMS: 2.968 min, MS: ES+ 309.1 (M+1); 1 H NMR(400MHz,DMSO)δ8.63(t,J=2.0Hz,1H), 8.59(d,J=8.0Hz,1H), 8.01(d,J=2.0Hz,1H ), 7.58(d,J=12.8Hz,1H), 5.15(t,J=5.6Hz,1H), 1.98~1.93(m,2H), 1.79~1.59(m,6H).

[0319] Step 2: 2-(cyclopentyloxy)-4-fluoro-5-(isothiazol-5-yl)aniline. To a solution of the isothiazole from step 1 (0.700 g, 2.27 mmol) in methanol:water (9:1) (14 mL) was added iron powder (0.635 g, 11.35 mmol) and ammonium chloride (0.607 g, 11.35 mmol) at room temperature. The reaction mixture was stirred at 90° C. for 3 h, filtered through Celite, the bed was washed with ethyl acetate (2×50 mL), the filtrate was diluted with water (75 mL) and the organic layer was separated. The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude was purified by FCC using neutral alumina (eluted with 10% ethyl acetate in hexane as mobile phase) to give a brown solid. The solid was diluted with DCM (2 mL), precipitated with n-pentane (10 mL), filtered and dried in vacuum to give the title aniline as a light brown solid (0.262 g, 41.5%). LCMS: 2.409 min, MS: ES+ 279.6 (M+1); 1H NMR(400MHz,DMSO)δ8.54(d,J=1.6Hz,1H), 7.58(d,J=1.6Hz,1H), 7.05(d,J=7.6Hz,1H), 6.90(d,J=12. 8Hz,1H), 4.87(t,J=5.6Hz,1H), 4.75(s,2H), 1.93~1.89(m,2H), 1.77~1.74(m,4H), 1.58~1.56(m,2H).

[0320] Intermediate 11. Preparation of 4-chloro-2-(cyclopentyloxy)-5-(isothiazol-5-yl)aniline [ka] Step 1: 5-(2-chloro-4-(cyclopentyloxy)-5-nitrophenyl)isothiazole. A solution of 1-bromo-2-chloro-4-(cyclopentyloxy)-5-nitrobenzene (Step 1 of Intermediate 8) (2.00 g, 6.23 mmol) in 1,4-dioxane (40 mL, 20 V) was placed in a 100 mL sealed tube and cooled with N 2 The mixture was purged with gas for 10 minutes. 5-(tributylstannyl)isothiazole (Step 1 of Intermediate 9) (3.50 g, 9.35 mmol) and tetrakis (0.721 g, 0.623 mmol) were added and the mixture was purged with N 2 The mixture was further purged with gas for 5 minutes. The reaction mixture was sealed with a cap and heated at 110° C. for 16 hours, then poured into water (100 mL) and extracted with ethyl acetate (2×100 mL). The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude was purified by FCC using neutral alumina (eluting with 8% ethyl acetate in hexanes as the mobile phase) to give the title isothiazole as a white solid (1.1 g, 54.3%). LCMS: 2.936 min, MS: ES+ 325.1 (M+1); 1 H NMR (400MHz, DMSO) δ8.64(d,J=1.6Hz,1H), 8.42(s,1H), 7.92(d,J=2.0Hz,1H), 7.71(s,1H), 5.21(s,1H), 1.97~1.92(m,2H), 1.78~1.59(m,6H).

[0321] Step 2: 4-Chloro-2-(cyclopentyloxy)-5-(isothiazol-5-yl)aniline. To a solution of the isothiazole from step 1 (0.700 g, 2.15 mmol) in methanol:water (9:1) (14 mL) was added iron powder (0.603 g, 10.77 mmol) and ammonium chloride (0.576 g, 10.77 mmol) at room temperature. The reaction mixture was stirred at 90° C. for 3 h, then cooled and filtered through a celite bed, washing the bed with ethyl acetate (2×50 mL). The combined filtrate was washed with water (100 mL) and the combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude was triturated with n-pentane:diethyl ether (7:3) (10 mL) to give the title aniline as a light brown solid (0.313 g, 49.4%). LCMS:2.954min, MS:ES+ 295.6(M+1); 1 H NMR(400MHz,DMSO)δ8.56(s,1H), 7.59(s,1H), 7.04(s,1H), 6.96(s,1H), 5. 03(s,2H), 4.88(s,1H), 1.92~1.90(m,2H), 1.77~1.74(m,4H), 1.58(s,2H).

[0322] Intermediate 12. Preparation of 4-chloro-2-cyclobutoxy-5-(5-methylisoxazol-4-yl)aniline [ka] Step 1: Synthesis of 1-bromo-2-chloro-4-cyclobutoxy-5-nitrobenzene. Cyclobutanol (CAS #2919-23-5, Angene) (1.71 g, 0.0237 mol, 1.0 equiv.) and Cs 2 CO 3A stirred solution of (15.45 g, 0.4745 mol, 2 equiv.) in ACN (60 mL) was prepared at room temperature. 1-Bromo-2-chloro-4-fluoro-5-nitrobenzene (CAS #111010-08-3, Combi block) (6 g, 0.0237 mol, 1.0 equiv.) was added portionwise to the reaction mixture and stirred at room temperature for 6 h. The reaction mixture was poured into ice-cold water and the precipitate was collected and dried to give the title ether as a pale yellow solid (5 g, 69.2%). 1 H NMR (400MHz, DMSO-d 6 ):δ8.34(s,1H), 7.48(s,1H), 4.99~4.85(m,1H), 2.53~2.43(m,2H), 2.08~2.00(m,2H), 1.84~1.79(m,1H), 1.66~1.59(m,1H)

[0323] Step 2: Synthesis of 5-bromo-4-chloro-2-cyclobutoxyaniline. A solution of the ether from step 1 (4 g, 0.013 mol, 1 eq.) and iron powder (3.67 g, 0.0655 mol, 5 eq.) in acetic acid (40 mL) was stirred at room temperature and then heated to 80° C. for 2 h. The mixture was cooled and filtered through a pad of Celite bed and washed with EtOAc (2×100 mL). The filtrate was concentrated under reduced pressure and the crude residue was purified by column chromatography using 2% EtOAc in n-hexane as the mobile phase to give the title aniline as a light pink solid (3.1 g, 85.9%). 1 H NMR (400MHz, DMSO-d 6 ):δ6.90(s,1H), 6.76(s,1H), 5.13(s,1H), 4.71~4.64(m,1H), 2.44~2.36(m,2H), 2.09~2.00(m,2H), 1.81~1.79(m,1H)1.76~1.74(m,1H)

[0324] Step 3: Synthesis of 4-chloro-2-cyclobutoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline. A solution of aniline from step 2 (1.2 g, 0.0043 mol, 1.0 equiv.) and KOAc (2.14 g, 0.0021 mol, 5.0 equiv.) in dioxane (12 ml, 10 V) was stirred at room temperature. To this solution was added B 2 Pin 2 (2.21 g, 0.0087 mol, 2.0 equiv.) was added in portions and the reaction mixture was purged under argon gas for 20 min. 2 (dppf)DCM (0.63 g, 0.00077 mol, 0.2 equiv) was added and the resulting reaction mixture was purged under argon for 10 min and then stirred at 80° C. for 16 h. The reaction mixture was cooled and then filtered through a pad of Celite bed and washed with EtOAc (2×100 mL). The filtrate was concentrated under reduced pressure and the crude residue was purified by column chromatography using 4% EtOAc in n-hexane as the mobile phase to give the title dioxaborolane as a pale pink solid (0.9 g, 2.78 mmol, 65%). UPLC-MS (Method 5) m / z 324.2 at 2.72 min (M+H) + .

[0325] Step 4: Synthesis of 4-chloro-2-cyclobutoxy-5-(5-methylisoxazol-4-yl)aniline. The reaction mixture was prepared by dissolving the dioxaborolane from Step 3 (0.7 g, 2.16 mol, 1.0 equiv.) and 4-iodo-5-methylisoxazole (CAS #7064-38-2, Enamine) (0.0.45 g, 2.16 mol, 1.0 equiv.) in dioxane:H 2 The solution in 100 mL of HO (8:2) was added to a 30 mL microwave glass vial at room temperature. 2 CO 3 (1.04 g, 7.58 mol, 3.5 equiv.) was added and the reaction mixture was purged under argon gas for 20 min. 2(dppf)DCM (0.17 g, 0.216 mol, 0.1 equiv) was added to the reaction mixture and heated at 110° C. under microwave for 1 h. The resulting reaction mixture was filtered through a pad of Celite and washed with EtOAc (2×100 mL). The filtrate was concentrated under reduced pressure and the crude material was purified by column chromatography using 5% EtOAc in n-hexane as the mobile phase to give the title aniline as a pale pink solid (0.25 g, 41.5%). UPLC-MS (Method 5) m / z 279.1 (M+H) at 2.46 min. + ; 1 H NMR (400MHz, DMSO-d 6 ):δ8.57(s,1H), 6.75(s,1H), 6.63(s,1H), 4.97(s,2H), 4.75~4.71(m,1H), 2.28( s,1H), 2.10~2.05(m,2H), 1.81~1.78(m,1H), 1.66~1.63(m,1H), 1.31~1.18(m,2H)

[0326] Preparation of Intermediate 13. 4-Chloro-2-(3,3-difluorocyclobutoxy)-5-(5-methylisoxazol-4-yl)aniline [ka] Step 1: Synthesis of 1-bromo-2-chloro-4-(3,3-difluorocyclobutoxy)-5-nitrobenzene. 3,3-Difluorocyclobutan-1-ol (CAS #637031-88-0, Angene) (2.56 g, 0.0237 mol, 1.0 equiv.) and Cs 2 CO 3 A solution of (15.45 g, 0.4745 mol, 2 equiv.) in MeCN (60 mL) was stirred at room temperature. 1-Bromo-2-chloro-4-fluoro-5-nitrobenzene (CAS #111010-08-3, Combi block) (6 g, 0.0237 mol, 1.0 equiv.) was added portionwise and the resulting reaction mixture was stirred at room temperature for 6 h. The reaction mixture was poured into ice-cold water and the precipitate was filtered and dried to give the title ether as a pale yellow solid (5 g, 14.6 mmol, 62%). 1H NMR (400MHz, DMSO-d 6 ): δ8.39(s,1H), 7.60(s,1H), 5.05~5.02(m,1H), 3.31~3.25(m,2H), 2.81~2.74(m,2H).

[0327] Step 2: Synthesis of 5-bromo-4-chloro-2-(3,3-difluorocyclobutoxy)aniline. A solution of the ether from step 1 (4 g, 0.012 mol, 1 eq.) and iron powder (3.28 g, 0.058 mol, 5 eq.) in acetic acid (40 mL) was prepared at room temperature and then stirred at 80° C. for 2 h. The reaction mixture was filtered through a pad of Celite bed and washed with EtOAc (2×100 mL). The combined filtrate was concentrated under reduced pressure and the crude residue was purified by column chromatography using 2% EtOAc in n-hexane as the mobile phase to give the title aniline as a light pink solid (3.1 g, 10 mmol, 76%). UPLC-MS (Method 5): m / z 311.8 (M+H) at 2.20 min. + , ; 1 H NMR (400MHz, DMSO-d 6 ): δ6.93(S,1H), 6.88(S,1H), 5.28(s,2H), 4.80~4.73(m,2H), 3.24~3.13(m,2H), 2.80~2.67(m,2H).

[0328] Step 3: Synthesis of 4-chloro-2-(3,3-difluorocyclobutoxy)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline. A solution of aniline from step 2 (1.2 g, 0.0038 mol, 1.0 equiv) and KOAc (2.14 g, 0.0021 mol, 5.0 equiv) was stirred in dioxane (12 mL) at room temperature. 2 Pin 2 (2.21 g, 0.0087 mol, 2.3 equiv) was added in portions and the reaction mixture was purged under argon gas for 20 min. 2(dppf)DCM (0.63 g, 0.00077 mol, 0.2 equiv) was added and the reaction mixture was purged under argon for 10 min and then stirred at 80° C. for 16 h. The reaction mixture was filtered through a pad of Celite bed and washed with EtOAc (2×100 mL). The combined filtrate was concentrated under reduced pressure and the crude residue was purified by column chromatography using 4% EtOAc in n-hexane as the mobile phase to give the title dioxaborolane as a pale pink solid (0.7 g, 50.4%). UPLC-MS (Method 5): m / z 360.1 (M+H) at 2.63 min. + .

[0329] Step 4: Synthesis of 4-chloro-2-(3,3-difluorocyclobutoxy)-5-(5-methylisoxazol-4-yl)aniline. A stirred solution of dioxaborolane from Step 3 (0.7 g, 1.94 mol, 1.0 equiv.) and 4-iodo-5-methylisoxazole (CAS #7064-38-2, Enamine) (0.400 g, 1.94 mol, 1.0 equiv.) was added to a 30 mL glass microwave vial in dioxane:H 2 The mixture was stirred at room temperature in 1:200 mL of K 2 CO 3 (0.94 g, 6.82 mol, 3.5 equiv.) was added and the reaction mixture was purged under argon gas for 20 min. 2 (dppf)DCM (0.17 g, 0.216 mol, 0.1 equiv) was added and sealed with a cap. The resulting reaction mixture was heated at 110° C. under microwave for 1 h, cooled, filtered through a pad of Celite, and washed with EtOAc (2×100 mL). The combined filtrate was then concentrated under reduced pressure and the crude residue was purified by column chromatography using 5% EtOAc in n-hexane as the mobile phase to give the title aniline as a pale pink solid (0.26 g, 0.72 mmol, 37%). UPLC-MS (Method 5): m / z 315.1 (M+H) at 2.35 min. + , ; 1 H NMR (400MHz, DMSO-d 6): δ8.58(S,1H), 6.86(s,1H), 6.63(s,1H), 5.12(m,2H), 4.83~4.80(m,1H), 3.23~3.18(m,2H), 2.79~2.74(m,2H). 2.37(S,3H).

[0330] Intermediate 14. Preparation of 4-chloro-2-cyclobutoxy-5-(isothiazol-5-yl)aniline [ka] Step 1: Synthesis of 4-chloro-2-cyclobutoxy-5-(isothiazol-5-yl)aniline. A solution of step 2 of intermediate 12 (1.20 g, 4.34 mmol) in 1,4-dioxane (12 mL) was placed in a sealed 10 mL tube and cooled to room temperature with N 2 The mixture was purged with gas for 10 minutes. 5-(tributylstannyl)isothiazole (Step 1 of Intermediate 9; 2.4 g, 6.52 mmol) and tetrakis (0.500 g, 0.43 mmol) were added and N 2 Further purged with gas for 5 min and then heated at 110° C. for 16 h. The mixture was cooled, poured into water (100 mL) and extracted with ethyl acetate (2×100 mL). The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude was purified by FCC using neutral alumina (eluting with 5% ethyl acetate in hexane as mobile phase) to give the title aniline as an off-white solid (0.33 g, 27.5%). LCMS: 2.467 min, MS: ES+ 281.1 (M+1); 1 H NMR(400MHz,DMSO)δ8.57(d,J=1.6Hz,1H), 7.60(d,J=1.6Hz,1H), 7.05(s,1H), 6.80(s,1H), 5.10(s, 2H), 4.79~4.76(m,1H), 2.50~2.41(m,2H), 2.14~2.04(m,2H), 1.84~1.77(m,1H), 1.69~1.62(m,1H).

[0331] Intermediate 15. Preparation of 4-chloro-2-(3,3-difluorocyclobutoxy)-5-(isothiazol-5-yl)aniline [ka] Step 1: Synthesis of 4-chloro-2-(3,3-difluorocyclobutoxy)-5-(isothiazol-5-yl)aniline. A solution of step 2 of intermediate 13 (1.50 g, 4.84 mmol) in 1,4-dioxane (12 mL) was placed in a 10 mL sealed tube with N 2 The mixture was purged with gas for 10 minutes. Step 1 of Intermediate 9 (2.68 g, 7.22 mmol) and tetrakis (0.555 g, 0.48 mmol) were added and N 2 Further purged with gas for 5 min and then heated at 110° C. for 16 h. After cooling, the reaction mixture was poured into water (100 mL) and extracted with ethyl acetate (2×100 mL). The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude was purified by FCC using neutral alumina (eluted with 5% ethyl acetate in hexane as mobile phase) to give the title aniline as an off-white solid (0.33 g, 22%). UPLC-MS (Method 5): m / z 317.1 (M+H) at 2.37 min. + ; 1 H NMR(400MHz,DMSO)δ8.57(d,J=1.2Hz,1H), 7.61(d,J=1.2Hz,1H), 7.06(s,1H), 6 .92(s,1H), 5.25(brs,2H), 4.85(brs,1H), 3.29~3.18(m,2H), 2.84~2.72(m,2H). [Example 1]

[0332] 3-(N-(4-chloro-5-cyano-2-(cyclopentyloxy)phenyl)sulfamoyl)-4-cyclopropylbenzoic acid [ka] Step 1: 2-Chloro-4-fluoro-5-nitrobenzonitrile: 2-Chloro-4-fluorobenzonitrile (20.0 g, 129.0 mmol) in H 2 SO 4To a solution in (98%, 40 mL) was added fuming nitric acid (20 mL) dropwise at 0° C. The resulting mixture was stirred at 0° C. for 30 min. The solution was poured into ice water and the resulting white precipitate was collected by filtration and washed with water to give the title compound (20.7 g, 103.5 mmol, 80% yield) as a white solid. 1 H NMR (400MHz, DMSO-d 6 )δ8.95(d,J=7.7Hz,1H), 8.28(d,J=10.9Hz,1H).

[0333] Step 2: 2-Chloro-4-(cyclopentyloxy)-5-nitrobenzonitrile: 2-chloro-4-fluoro-5-nitrobenzonitrile (8.6 g, 43.0 mmol), cyclopentanol (1.85 g, 215.0 mmol) and Cs 2 CO 3 A mixture of (28.0 g, 86.0 mmol) in MeCN (100 mL) was stirred at room temperature overnight. The reaction mixture was filtered through Celite. The filtrate was concentrated and purified using Biotage Isolera One (C 18 Column, 10%-90% MeCN / H 2 Purification by chromatography (eluted with O) afforded the title compound (5.2 g, 19.5 mmol, 45% yield) as a white solid. 1 H NMR (400MHz, DMSO-d 6 )δ8.62(s,1H), 7.81(s,1H), 5.26(td,J=5.6,2.8Hz,1H), 2.04~1.90(m,2H), 1.88~1.69(m,2H), 1.73~1.56(m,4H).

[0334] Step 3: 5-Amino-2-chloro-4-(cyclopentyloxy)benzonitrile: 2-Chloro-4-(cyclopentyloxy)-5-nitrobenzonitrile (3.9 g, 14.7 mmol), iron powder (4.9 g, 88.2 mmol) and NH 4A mixture of Cl (1.6 g, 29.4 mmol) in a mixture of EtOH and water (v / v=5 / 1, 120 mL) was heated at 85° C. for 2 h. The resulting mixture was filtered through Celite and concentrated to give the title compound (2.36 g, 10.0 mmol, 68% yield) as a yellow solid. UPLC-MS (Method 3) m / z 235, 237 (MH) at 2.03 min. - .

[0335] Step 4: Methyl 3-(N-(4-chloro-5-cyano-2-(cyclopentyloxy)phenyl)sulfamoyl)-4-cyclopropylbenzoate: To a solution of 5-amino-2-chloro-4-(cyclopentyloxy)benzonitrile (2.36 g, 10.0 mmol) and pyridine (1.7 g, 21.6 mmol) in DCM (100 mL) was added methyl 3-(chlorosulfonyl)-4-cyclopropylbenzoate (Intermediate 3; 2.96 g, 10.8 mmol) at room temperature and the solution was stirred at room temperature overnight. The solvent was removed in vacuo and the crude product was purified using Biotage Isolera One (C 18 Column, 10%-90% MeCN / H 2 Purification by chromatography (eluted with 0) gave the title compound (1.20 g, 2.5 mmol, 25% yield) as a white solid. UPLC-MS (Method 1) m / z 473.05 (MH) at 2.383 min. - .

[0336] Step 5: 3-(N-(4-chloro-5-cyano-2-(cyclopentyloxy)phenyl)sulfamoyl)-4-cyclopropylbenzoic acid: Methyl 3-(N-(4-chloro-5-cyano-2-(cyclopentyloxy)phenyl)sulfamoyl)-4-cyclopropylbenzoate (1.2 g, 2.5 mmol) in THF and H 2 LiOH (360 mg, 15.0 mmol) was added to a solution of 1:1 HO (v / v=1:1, 40 mL) and the reaction was stirred at room temperature overnight. The solvent was removed in vacuo and the crude product was purified by Biotage Isolera One (C 18 Column, 10%-90% MeCN / H containing 0.1% HCOOH 2Purification by chromatography (eluted with 0) gave the title compound (1.06 g, 2.3 mmol, 92% yield) as a red solid. UPLC-MS (Method 1) m / z 2.459.05 (MH) at 150 min. - . 1 H NMR (400MHz, DMSO-d 6 )δ13.22(s,1H), 10.06(s,1H), 8.32(t,J=1.4Hz,1H), 8.00(dd,J=8.2,1.9 Hz,1H), 7.67(s,1H), 7.26(s,1H), 7.11(d,J=8.3Hz,1H), 4.77~4.80(m,1H) ), 2.68~2.60(td,J=8.4,4.2Hz,1H), 1.76~1.73(m,2H), 1.47~1.45(dt,J= 7.9,3.3Hz,1H), 1.44~1.38(m,5H), 0.99~0.96(m,2H), 0.79~0.78(m,2H).

[0337] The following examples were prepared in a similar manner to Example 1, substituting the appropriate starting materials and intermediates where necessary. When using intermediates 1 and 2 and following general scheme 1 below, the formation of the sulfonamide occurs in the presence of the free acid, and thus the target acid is prepared directly without the need for a penultimate ester hydrolysis. [Table 6] JPEG2024530447000061.jpg156120JPEG2024530447000062.jpg147119JPEG2024530447000063.jpg144124JPEG2024530447000064.jpg143124JPEG2024530447000065.jpg139123JPEG2024530447000066.jpg142123JPEG2024530447000067.jpg124124[Example 20]

[0338] 3-(N-(2-(cyclopentyloxy)-5-(isothiazol-5-yl)phenyl)sulfamoyl)-4-cyclopropylbenzoic acid [ka] Step 1: Methyl 3-(N-(2-(cyclopentyloxy)-5-(isothiazol-5-yl)phenyl)sulfamoyl)-4-cyclopropylbenzoate: A mixture of 2-(cyclopentyloxy)-5-(isothiazol-5-yl)aniline (Intermediate 9) (100 mg, 380 μmol, 99% purity), methyl 3-(chlorosulfonyl)-4-cyclopropylbenzoate (157 mg, 570 μmol) and pyridine (92.0 μL, 1.14 mmol) in DCM (2 mL) was heated to 35° C. and stirred for 3 days. The mixture was concentrated onto silica and purified by chromatography on silica gel (12 g cartridge, 0-100% EtOAc / isohexane) to give the title compound (171 mg, 340 μmol, 89%, 99% purity) as a pale yellow solid. UPLC-MS (method 4): m / z 499.4 (M+H) at 2.01 min + , 497.2(MH) - , 1 H NMR (500MHz, DMSO-d 6 )δ9.81(s,1H), 8.53(d,J=1.8Hz,1H), 8.41(d,J=1.9Hz,1H), 8.00(dd,J=8. 2,1.9Hz,1H), 7.58(d,J=1.8Hz,1H), 7.51~7.45(m,2H), 7.15(d,J=8.3Hz,1H ), 7.01(d,J=9.2Hz,1H), 4.76~4.70(m,1H), 3.84(s,3H), 2.80~2.73(m,1H), 1.82~1.75(m,2H), 1.56~1.40(m,6H), 1.06~0.98(m,2H), 0.84~0.77(m,2H).

[0339] Step 2: 3-(N-(2-(cyclopentyloxy)-5-(isothiazol-5-yl)phenyl)sulfamoyl)-4-cyclopropylbenzoic acid: the product from step 1 above (171 mg, 340 μmol, 99% purity) and LiOH H 2 HO (58.0 mg, 1.38 mmol) in THF / MeOH / H 2The mixture was stirred in H2O (4:1:1, 2.1 mL) at 40 °C overnight. 2 The mixture was diluted with 20O (5 mL), acidified to pH 4 with 1M (HCl) (aq) and extracted with EtOAc (3 x 15 mL). The organic extracts were combined, washed with brine (15 mL) and dried (MgSO 4 ) and the solvent removed in vacuo. The residue was loaded onto silica and purified by chromatography on silica gel (12 g cartridge, 0-10% MeOH / DCM) and then triturated with TBME to give the title compound (97.3 mg, 199 μmol, 59%, 99% pure) as a pale yellow solid. UPLC-MS (Method 4): m / z 485.3 (M+H) at 1.83 min. + , 483.2(MH) - , 1 H NMR (500MHz, DMSO-d 6 )δ13.23(s,1H), 9.76(s,1H), 8.52(d,J=1.8Hz,1H), 8.41(d,J=1.9Hz,1H), 7 .98(dd,J=8.2,1.9Hz,1H), 7.57(d,J=1.8Hz,1H), 7.49~7.45(m,2H), 7.12(d ,J=8.2Hz,1H), 7.01(d,J=8.8Hz,1H), 4.76~4.70(m,1H), 2.79~2.71(m,1H), 1.83~1.74(m,2H), 1.58~1.41(m,6H), 1.05~0.97(m,2H), 0.83~0.76(m,2H).

[0340] The following examples were prepared in a similar manner to Example 20, substituting the appropriate starting materials and intermediates where necessary. [Table 7] [Example 23]

[0341] 3-(N-(2-(cyclopentyloxy)-5-(isothiazol-5-yl)phenyl)sulfamoyl)-4-cyclopropylbenzoic acid [ka] Step 1: Methyl 3-(N-(2-(cyclopentyloxy)-5-(5-methylisoxazol-4-yl)phenyl)sulfamoyl)-4-cyclopropylbenzoate: A mixture of 2-(cyclopentyloxy)-5-(5-methylisoxazol-4-yl)aniline (Intermediate 6) (100 mg, 383 μmol, 99% purity), methyl 3-(chlorosulfonyl)-4-cyclopropylbenzoate (160 mg, 582 μmol) and pyridine (100 μL, 1.24 mmol) in DCM (2 mL) was heated to 35° C. and stirred over the weekend. The mixture was concentrated onto silica and purified by chromatography on silica gel (12 g cartridge, 0-100% EtOAc / isohexane) to give the title compound (178 mg, 0.35 mmol, 91%, 97% purity) as a pale orange foam. UPLC-MS (method 4): m / z 497.3 (M+H) at 1.96 min + , 495.3(MH) - .

[0342] Step 2: 3-(N-(2-(cyclopentyloxy)-5-(5-methylisoxazol-4-yl)phenyl)sulfamoyl)-4-cyclopropylbenzoic acid: a solution of the product from Step 1 above (180 mg, 352 μmol, 97% purity) and HCl (4 M in dioxane) (500 μL, 2.00 mmol) in dioxane / H2O 2 The mixture was heated to 50° C. in 2:1 O (1.5 mL) and stirred overnight. Concentrated HCl (500 μL, 37% w / w) and THF (0.50 mL) were added and the mixture was heated to 70° C. and stirred for 24 h. Additional concentrated HCl (500 μL, 37% w / w) was added and the reaction was stirred at 70° C. for 24 h. The mixture was diluted with H 2 The mixture was diluted with 2×O (10 mL) and extracted with EtOAc (3×20 mL). The organic extracts were combined, washed with brine (10 mL) and dried (MgSO 4 ) and concentrated onto silica. The crude product was partially purified by chromatography on silica gel (12 g cartridge, 0-10% MeOH / DCM) and then by preparative HPLC (Waters, X-Select CSH C 18Purification by ODB prep column, 130 Å, 5 μm, 30 mm×100 mm, 40-70% (0.1% formic acid (aq)) / MeCN) afforded the title compound (33 mg, 68 μmol, 19%, 99% purity) as a fluffy white solid. UPLC-MS (Method 4): m / z 483.4 (M+H) at 1.80 min. + , 481.3(MH) - , 1 H NMR (500MHz, DMSO-d 6 )δ13.23(br s,1H), 9.61(s,1H), 8.70(s,1H), 8.37(d,J=1.8Hz,1H), 7.96(dd,J=8.2,1.9 Hz,1H), 7.30(d,J=2.2Hz,1H), 7.23(dd,J=8.5,2.3Hz,1H), 7.11(d,J=8.3Hz, 1H), 6.97(d,J=8.6Hz,1H), 4.78~4.57(m,1H), 2.83~2.67(m,1H), 2.44(s,3H) , 1.84~1.71(m,2H), 1.59~1.38(m,6H), 1.06~0.95(m,2H), 0.86~0.76(m,2H).

[0343] The following examples were prepared in a similar manner to Example 23, substituting the appropriate starting materials and intermediates where necessary. [Table 8] [Example 8]

[0344] 3-(N-(2-(cyclopentyloxy)-5-(1H-tetrazol-1-yl)phenyl)sulfamoyl)-4-cyclopropylbenzoic acid [ka] Step 1: tert-Butyl (4-fluoro-3-nitrophenyl)carbamate: A mixture of 4-fluoro-3-nitroaniline (1.56 g, 10.0 mmol), di-tert-butyl dicarbonate (4.36 g, 20.0 mmol), TEA (4.04 g, 40.0 mmol) and DMAP (0.622 g, 5.0 mmol) in DCM (20 mL) was stirred at room temperature for 12 h. The solvent was removed under reduced pressure and the residue was dissolved in EtOAc and saturated Na 2 CO 3 The organic layer was washed with Na 2 SO 4 The crude product was purified by silica gel chromatography (eluted with 1 / 10 EtOAc / PE) to give the title compound (2.0 g, 7.81 mmol, 39%) as a yellow oil. 6 )δ8.13(dd,J=6.7,2.7Hz,1H), 7.76(ddd,J=8.9,4.0,2.7Hz,1H), 7.62(dd,J=10.9,8.9Hz,1H), 1.39(s,9H).

[0345] Step 2: tert-Butyl (4-(cyclopentyloxy)-3-nitrophenyl)carbamate. Mix the carbamate from step 1 (0.76 g, 3.0 mmol), cyclopentanol (0.52 g, 6.0 mmol) and Cs 2 CO 3 A mixture of (1.85 g, 6.0 mmol) in MeCN (20 mL) was stirred at room temperature for 12 h. The reaction mixture was filtered through Celite, and the filtrate was concentrated and purified by Biotage Isolera One (C 18 Column, 10%-90% MeCN / H 2 Purification by chromatography (eluted with 0) afforded the title compound (0.61 g, 1.89 mmol, 63%).

[0346] Step 3: 4-Cyclopentyloxy-3-nitroaniline: A solution of the carbamate from step 2 (0.61 g, 1.89 mmol) in HCl EtOAc (4 M, 3 mL) was stirred at room temperature for 2 h. The resulting mixture was concentrated and dried under vacuum to give the title compound (0.22 g, 0.97 mmol, 51%). UPLC-MS (Method 3) m / z 223.0 (M+H) at 0.94 min. + .

[0347] Step 4: 1-(4-Cyclopentyloxy-3-nitrophenyl)-1H-tetrazole: Mix the aniline from step 3 (0.22 g, 1.0 mmol), trimethyl orthoformate (0.63 g, 6.0 mmol), NaN 3 A mixture of (0.13 g, 2.0 mmol) in HOAc (5 mL) was heated at 80° C. for 2 h. The solvent was removed under reduced pressure and the residue was dissolved in EtOAc and saturated Na 2 CO 3 The organic layer was washed with Na 2 SO 4 The crude product was purified by Biotage Isolera One (C 18 Column, 10%-90% MeCN / H 2 Purification by chromatography (eluted with 0) gave the title compound (0.24 g, 0.88 mmol, 88%). UPLC-MS (Method 3) m / z 276.0 (M+H) at 1.22 min. + .

[0348] Step 5: 2-Cyclopentyloxy-5-(1H-tetrazol-1-yl)aniline: Mix the tetrazole from step 4 (0.24 g, 0.88 mmol), iron powder (0.29 g, 5.28 mmol) and NH 4 Cl (0.09 g, 1.78 mmol) in a mixture of EtOH and water (24 mL, EtOH / H 2 The mixture was heated at 85° C. for 2 h in O (v / v=5 / 1). The resulting mixture was filtered through Celite and concentrated to give the title compound (0.17 g, 0.69 mmol, 78%). UPLC-MS (Method 3) m / z 246.0 (M+H) at 1.21 min. + .

[0349] Step 6: Methyl 4-cyclopropyl-3-(N-(2-isopropoxy-5-(1H-tetrazol-1-yl)phenyl)sulfamoyl)benzoate: To a solution of the aniline from step 5 (0.17 g, 0.69 mmol) and pyridine (0.11 g, 1.38 mmol) in dry DCM (5 mL) was added methyl 3-(chlorosulfonyl)-4-cyclopropylbenzoate (Intermediate 3) (0.18 g, 0.68 mmol) and the solution was stirred at room temperature for 4 h. The solvent was removed in vacuo and the crude product was purified using Biotage Isolera One (C 18 Column, 10%~90%MeCN / H 2 Purification by chromatography (eluted with 0) gave the title compound (0.16 g, 0.33 mmol, 52%). UPLC-MS (Method 3) m / z 482.0 (MH) at 1.99 min. - .

[0350] Step 7: 3-(N-(2-(cyclopentyloxy)-5-(1H-tetrazol-1-yl)phenyl)sulfamoyl)-4-cyclopropylbenzoic acid. A mixture of the ester from step 6 (0.16 g, 0.33 mmol) and LiOH (0.069 g, 1.67 mmol) in THF (5 mL) and water (5 mL) was stirred at room temperature for 2 h. The THF was removed under reduced pressure and the pH of the aqueous solution was adjusted to 3 with 2 M HCl. The mixture was extracted with EtOAc (20 mL x 3) and washed with Na 2 SO 4 Drying at 40° C. and concentration in vacuo afforded the title compound (0.048 g, 0.108 mmol, 31%) as a white solid. UPLC-MS (Method 1) m / z 468.05 (MH) at 1.823 min. - 1 H NMR (400MHz, DMSO-d 6)δ13.20(s,1H), 9.95(s,2H), 8.37(d,J=1.9Hz,1H), 7.98~7.96(dd,J=8.2 ,1.9Hz,1H), 7.78(d,J=2.7Hz,1H), 7.62~7.60(dd,J=8.9,2.7Hz,1H), 7.15 ~7.12(dd,J=11.4,8.7Hz,2H), 4.73(m,1H), 2.73(td,J=8.5,4.3Hz,1H), 1 .79~1.78(m,2H), 1.50~1.43(m,6H), 1.01~0.97(m,2H), 0.80~0.77(m,2H).

[0351] The following examples were prepared in a similar manner to Example 8, substituting the appropriate starting materials and intermediates where necessary. [Table 9] JPEG2024530447000074.jpg26169 [Example 52]

[0352] 3-(N-(2-((2-oxaspiro[3.3]heptan-6-yl)oxy)-4-chloro-5-cyanophenyl)sulfamoyl)-4-cyclopropylbenzoic acid [ka] Step 1: 4-((2-oxaspiro[3.3]heptan-6-yl)oxy)-2-chloro-5-nitrobenzonitrile: A mixture of 2-chloro-4-fluoro-5-nitrobenzonitrile (Example 1, Step 1) (0.150 g, 0.75 mmol), 2-oxaspiro[3.3]heptan-6-ol (0.085 g, 0.75 mmol) and NaH (0.022 g, 0.90 mmol, 60%) in THF (5 mL) was stirred at room temperature for 12 h. The reaction mixture was filtered through Celite. The filtrate was concentrated and purified by silica gel chromatography (eluted with 50% EtOAc / PE) to give the title compound (0.180 g, 0.40 mmol, 53% yield, 65% purity) as a yellow solid. 1 H NMR (400MHz, DMSO-d 6 )δ8.67(s,1H), 7.61(s,1H), 4.97(p,J=6.8Hz,1H), 4.64(s,2H), 4.55(s,2H), 2.87(ddd,J=10.3,6.8,3.2Hz,2H), 2.34~2.23(m,2H).

[0353] Step 2: 4-((2-oxaspiro[3.3]heptan-6-yl)oxy)-5-amino-2-chlorobenzonitrile: 4-((2-oxaspiro[3.3]heptan-6-yl)oxy)-2-chloro-5-nitrobenzonitrile (0.180 g, 0.41 mmol, 65%), iron powder (0.114 g, 2.04 mmol) and NH 4 Cl (0.044 g, 0.82 mmol) in EtOH and water (3 mL, EtOH / H 2 The mixture was heated at 85° C. for 2 h in a mixture of 1000 mL of 1000 mL of 1.25% CO (v / v=5 / 1). The resulting mixture was filtered through Celite and concentrated to give the crude product, which was purified by Biotage Isolera One (C 18 Column, 10%-90% MeCN / H 2 Purification by chromatography (eluted with 0.025 mL) afforded the title compound (0.071 g, 0.27 mmol, 66% yield) as a yellow oil. UPLC-MS (Method 3) m / z 265.0 (M+H) at 1.089 min. + .

[0354] Step 3: Methyl 3-(N-(2-((2-oxaspiro[3.3]heptan-6-yl)oxy)-4-chloro-5-cyanophenyl)sulfamoyl)-4-cyclopropylbenzoate: To a solution of 4-((2-oxaspiro[3.3]heptan-6-yl)oxy)-5-amino-2-chlorobenzonitrile (0.071 g, 0.27 mmol) in pyridine (0.043 g, 0.54 mmol) was added methyl 3-(chlorosulfonyl)-4-cyclopropylbenzoate (0.074 g, 0.27 mmol) and the solution was stirred at room temperature for 16 h. The solvent was removed in vacuo and the crude product was purified using Biotage Isolera One (C 18 Column, 10%-90% MeCN / H 2 Purification by chromatography (eluted with 0) gave the title compound (0.073 g, 0.15 mmol, 55% yield) as a white solid. UPLC-MS (Method 3) m / z 1.570 min at 501.00 (MH) - .

[0355] Step 4: 3-(N-(2-((2-oxaspiro[3.3]heptan-6-yl)oxy)-4-chloro-5-cyanophenyl)sulfamoyl)-4-cyclopropylbenzoic acid: A mixture of methyl 3-(N-(2-((2-oxaspiro[3.3]heptan-6-yl)oxy)-4-chloro-5-cyanophenyl)sulfamoyl)-4-cyclopropylbenzoate (0.055 g, 0.11 mmol) and LiOH (0.013 g, 0.55 mmol) in a mixture of THF (1 mL) and water (1 mL) was stirred at room temperature for 16 h. THF was removed under reduced pressure and the pH of the aqueous solution was adjusted to 3 with 2 M HCl. The mixture was extracted with EtOAc (20 mL x 3) and diluted with Na 2 SO 4 The mixture was dried at 400 C and concentrated under vacuum to give the crude product, which was then purified by Biotage's Isolera One (C 18 Column, 10%-90% MeCN / H 2 Purification by chromatography (eluted with 0) gave the title compound (0.026 g, 0.053 mmol, 48% yield) as a white solid. UPLC-MS (Method 1) m / z 487.00 (MH) at 1.750 min. - 1H NMR (400MHz, DMSO-d 6 )δ13.28(s,1H), 10.18(s,1H), 8.30(d,J=1.8Hz,1H), 7.99(dd,J=8.2,1.8Hz ,1H), 7.75(s,1H), 7.18~7.10(m,2H), 4.63~4.51(m,1H), 4.55(s,2H), 4.43(s ,2H), 2.71(td,J=8.3,4.2Hz,1H), 2.62(ddd,J=10.1,6.9,3.3Hz,2H), 1.73( ddd,J=10.1,7.0,3.3Hz,2H), 1.02(dt,J=8.2,3.3Hz,2H), 0.91~0.78(m,2H).

[0356] The following examples were prepared in a similar manner to Examples 1 or 52, substituting the appropriate starting materials and intermediates where necessary. [Table 10] JPEG2024530447000077.jpg171124JPEG2024530447000078.jpg185123JPEG202 4530447000079.jpg180124JPEG2024530447000080.jpg181118JPEG20245304470 00081.jpg177121JPEG2024530447000082.jpg179122JPEG2024530447000083.j pg188121JPEG2024530447000084.jpg170118JPEG2024530447000085.jpg185121 JPEG2024530447000086.jpg182121JPEG2024530447000087.jpg178118JPEG2024530447000088.jpg180124JPEG2024530447000089.jpg166119JPEG2024530447000090.jpg166118JPEG2024530447000091.jpg185122JPEG2024530447000092.jpg183119JPEG2024530447000093.jpg185121JPEG2024530447000094.jpg26117[Example 50]

[0357] 3-(N-(4-chloro-2-(3,3-difluorocyclobutoxy)-5-(isothiazol-5-yl)phenyl)sulfamoyl)-4-cyclopropylbenzoic acid [ka] Step 1: Methyl 3-(N-(4-chloro-2-(3,3-difluorocyclobutoxy)-5-(isothiazol-5-yl)phenyl)sulfamoyl)-4-cyclopropylbenzoate: A solution of intermediate 15 (165 mg, 521 μmol), methyl 3-(chlorosulfonyl)-4-cyclopropylbenzoate (215 mg, 781 μmol; intermediate 3) and pyridine (126 μL, 1.56 mmol) in DCM (2 mL) was stirred at room temperature for 4 h. The reaction mixture was diluted with DCM (7 mL) and water (7 mL) and the phases were separated. The aqueous phase was extracted with DCM (2×7 mL) and the combined organic phases were concentrated in vacuo. The residue was purified by chromatography on silica gel (12 g cartridge, 0-100% EtOAc / isohexane) to give the title compound (236 mg, 0.41 mmol, 78% yield, 96% purity) as a white solid. UPLC (Method 4): m / z 556.3 (M+H) at 1.94 min + , 554.9(MH) - , 1H NMR(500MHz,DMSO)δ10.24(s,1H), 8.61(d,J=1.9Hz,1H), 8.41(s,1H), 8.00(d,J=8.2Hz,1H), 7.65(s,1H)7.61(s,1H), 7.15(m,2H) ), 4.83~4.67(m,1H), 3.85(s,3H), 3.16~3.02(m,2H), 2.88~2.77(m,1H), 2.54~2.49(m,2H), 1.10~1.01(m,2H), 0.88~0.78(m,2H). The two protons were obscured by the solvent.

[0358] Step 2: 3-(N-(4-chloro-2-(3,3-difluorocyclobutoxy)-5-(isothiazol-5-yl)phenyl)sulfamoyl)-4-cyclopropylbenzoic acid: the product from step 1 above (236 mg, 0.41 mmol, 96% purity) and LiOH H 2 A solution of 2H (71.4 mg, 1.70 mmol) in a mixture of THF (2 mL), water (0.5 mL) and MeOH (0.5 mL) was stirred at room temperature for 18 h. The reaction mixture was diluted with EtOAc (5 mL) and water (5 mL) and then acidified to pH ∼4. The layers were separated and the aqueous layer was extracted with EtOAc (2 × 5 mL). The organic phases were combined and concentrated in vacuo. The residue was purified by chromatography on silica gel (12 g cartridge, 0-5% (5% AcOH in MeOH) / DCM) to give the title compound (169 mg, 0.29 mmol, 68% yield, 92% purity) as a white solid. UPLC-MS (Method 4): m / z 541.7 (M+H) at 1.80 min. + , 539.3(MH) - , 1H NMR(500MHz,DMSO)δ13.27(s,1H), 10.20(s,1H), 8.58(d,J=1.8Hz,1H), 8.41(d,J=1.9Hz,1H), 7.98(dd,J=8.1,1.9Hz,1H), 7.64(s,1H), 7.61(d,J =1.9Hz,1H), 7.17~7.10(m,2H), 4.82~4.69(m,1H), 3.15~3.04(m,2H), 2. 85~2.75(m,1H), 2.62~2.52(m,2H), 1.09~1.01(m,2H), 0.86~0.79(m,2H). [Example 51]

[0359] 3-(N-(4-chloro-2-cyclobutoxy-5-(isothiazol-5-yl)phenyl)sulfamoyl)-4-cyclopropylbenzoic acid [ka] The title compound (2.6 mg, 4.0 μmol, 78% purity) was prepared in a similar manner to Example 50, using intermediate 14 instead of intermediate 15. UPLC-MS (Method 4): m / z 506.4 (M+H) at 1.91 min. + , 504.2(MH) - , 1 H NMR(500MHz,DMSO)δ13.26(s,1H), 10.05(s,1H), 8.58(d,J=1.8Hz,1H), 8.37(d,J=1.9Hz,1H), 8.03~7.97(m,1H), 7.65~7.61(m,2H), 7.15(d,J=8. 3Hz,1H), 6.97(s,1H), 4.65(apparent p,J=7.3Hz,1H), 2.85~2.76(m,1H), 2.2 9~2.21(m,2H), 1.77~1.47(m,4H), 1.08~1.01(m,2H), 0.85~0.80(m,2H). [Example 60]

[0360] 3-(N-(4-chloro-2-cyclobutoxy-5-(5-methylisoxazol-4-yl)phenyl)sulfamoyl)-4-cyclopropylbenzoic acid [ka] Step 1: Methyl 3-(N-(4-chloro-2-cyclobutoxy-5-(5-methylisoxazol-4-yl)phenyl)sulfamoyl)-4-cyclopropylbenzoate: A solution of intermediate 12 (120 mg, 431 μmol), methyl 3-(chlorosulfonyl)-4-cyclopropylbenzoate (215 mg, 781 μmol) and pyridine (126 μL, 1.56 mmol) in DCM (2 mL) was stirred at room temperature for 4 h. The reaction mixture was diluted with DCM (7 mL) and water (7 mL) and the phases were separated. The aqueous phase was extracted with DCM (2×7 mL) and the combined organic phases were concentrated in vacuo. The residue was purified by chromatography on silica gel (12 g cartridge, 0-100% EtOAc / isohexane) to give the title compound (193 mg, 0.366 mmol, 86% yield, 98% purity) as a pale red solid. UPLC-MS (method 4): m / z 517.4 (M+H) at 1.97 min + , 515.2(MH) - , 1 H NMR (500MHz, DMSO-d 6 )δ9.97(s,1H), 8.60(s,1H), 8.32(d,J=1.9Hz,1H), 8.01(d,J=8.2Hz,1H), 7.25(s,1H), 7.17(d,J=8.3Hz,1H), 6.91(s,1H), 4.59(p,J=6.9Hz) ,1H), 3.84(s,3H), 2.81(s,1H), 2.31(s,3H), 2.26~2.19(m,2H), 1.72~ 1.65(m,2H), 1.65~1.48(m,2H), 1.10~1.02(m,2H), 0.89~0.82(m,2H).

[0361] Step 2: 3-(N-(4-chloro-2-cyclobutoxy-5-(5-methylisoxazol-4-yl)phenyl)sulfamoyl)-4-cyclopropylbenzoic acid: To a solution of the product from Step 1 above (193 mg, 366 μmol, 98% purity) in dioxane (800 μL) and water (400 μL) was added concentrated HCl(aq) (400 μL, 6.05 mmol) and the mixture was heated to 70 °C and stirred overnight. Additional concentrated HCl(aq) (400 μL, 6.05 mmol) was added and stirring at 70 °C was continued for 7 h. Upon cooling to room temperature, the mixture was diluted with water (20 mL) and extracted with EtOAc (3 × 30 mL). The combined organic extracts were washed with brine (20 mL), dried (MgSO 4 ) and the solvent removed in vacuo. The residue was loaded onto silica and purified by chromatography on silica gel (24 g cartridge, 0-10% MeOH / DCM) and triturated with TBME to give the title compound (48.8 mg, 92.2 μmol, 25% yield, 95% purity) as a light tan solid. UPLC-MS (Method 4): m / z 503.0 (M+H) at 1.84 min. + , 501.2(MH) - , 1 H NMR (500MHz, DMSO-d 6 )δ13.22(s,1H), 9.93(s,1H), 8.60(s,1H), 8.31(d,J=1.9Hz,1H), 7.99(dd,J =8.2,1.9Hz,1H), 7.24(s,1H), 7.15(d,J=8.2Hz,1H), 6.91(s,1H), 4.64~4.55 (m,1H), 2.84~2.75(m,1H), 2.30(s,3H), 2.28~2.19(m,2H), 1.75~1.66(m,2H) , 1.66~1.57(m,1H), 1.57~1.48(m,1H), 1.09~1.01(m,2H), 0.88~0.81(m,2H). [Example 61]

[0362] 3-(N-(4-chloro-2-(3,3-difluorocyclobutoxy)-5-(5-methylisoxazol-4-yl)phenyl)sulfamoyl)-4-cyclopropylbenzoic acid [ka] The title compound (57.3 mg, 102 μmol, 96% purity) was prepared in a similar manner to Example 60, using intermediate 13 instead of intermediate 12. UPLC-MS (Method 4): m / z 539.0 (M+H) at 1.74 min. + , 537.2(MH) - , 1 H NMR (500MHz, DMSO-d 6 )δ13.23(s,1H), 10.08(s,1H), 8.59(s,1H), 8.33(d,J=1.9Hz,1H), 7.97(dd,J=8.2,1.9Hz,1H), 7.28(s,1H), 7.12(d,J=8.2Hz,1H), 7.10 (s,1H), 4.78~4.67(m,1H), 3.14~3.02(m,2H), 2.84~2.75(m,1H), 2.59~2.44(m,2H), 2.28(s,3H), 1.08~1.01(m,2H), 0.87~0.80(m,2H). [Example 67]

[0363] 3-(N-(4-chloro-5-cyano-2-(cyclopentyloxy)phenyl)sulfamoyl)-4-cyclopropyl-2-fluorobenzoic acid [ka] Reagents: (a) Pd / C, H 2 , MeOH, RT; (b) NBS, MeCN, RT; (c) Pd 2 (dppf)Cl 2 , K 3 PO 4 , dioxane / H 2 O (v / v = 10:1), 100 °C; (d) NaNO 2 , CuCl, SOCl 2 , HCl(cn), THF / H 2 O(v / v=10 / 1), RT; (e) pyridine, DCM, RT; (f) LiOH(aq), THF, RT

[0364] Step 1: Methyl 3-amino-2-fluorobenzoate: A mixture of methyl 2-fluoro-3-nitrobenzoate (4.0 g, 4.2 mmol) and Pd / C (0.5 g, 10%) in methanol was stirred under hydrogen atmosphere at 25° C. for 2 h. The catalyst was removed by filtration through Celite and the filtrate was concentrated to give the title compound (3.38 g, 2.0 mmol, 47% yield) as a yellow solid. UPLC-MS (Method 1) m / z 170.10 (M+H) at 1.32 min. + .

[0365] Step 2: Methyl 3-amino-4-bromo-2-fluorobenzoate: To a solution of the aniline from step 1 (3.38 g, 20.0 mmol) in MeCN (20 mL) was added NBS (3.2 g, 18.0 mmol) at 0° C. The resulting mixture was stirred at room temperature for 16 h. The solvent was removed under reduced pressure and the residue was dissolved in EtOAc and saturated Na 2 CO 3 The organic layer was washed with Na 2 SO 4 The crude product was purified by silica gel chromatography (eluting with 1 / 10 EtOAc / PE) to give the title compound (4.69 g, 18.9 mmol, 94% yield) as a yellow solid. UPLC-MS (Method 1) m / z 248.0 at 1.516 min, 250.0 (MH) - 1H NMR (400MHz, DMSO-d 6 )δ7.17(dd,J=8.7,1.3Hz,1H), 6.81(dd,J=9.4,8.7Hz,1H), 5.62(s,2H).

[0366] Step 3: Methyl 3-amino-4-cyclopropyl-2-fluorobenzoate: Mix the bromide from step 2 (4.69 g, 18.9 mmol), cyclopropylboronic acid (4.47 g, 56.7 mmol), K 3 PO 4 (12.03 g, 56.7 mmol) and Pd(dppf)Cl 2 (1.39g, 1.90mmol) of dioxane and H 2The mixture in a mixture of 2H2O (v / v=10:1, 50 mL) was heated at 110 °C for 16 h in a sealed tube. The resulting mixture was filtered through Celite, concentrated, and purified by silica gel chromatography (eluted with 1 / 10 EtOAc / PE) to give the title compound (2.84 g, 13.6 mmol, 24% yield) as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ 6.80 (dt, J = 22.2, 9.0 Hz, 1H), 6.60 (d, J = 8.4 Hz, 1H), 5.17 (s, 2H), 2.32-2.21 (m, 1H), 0.87-0.74 (m, 2H), 0.59-0.45 (m, 2H).

[0367] Step 4: Methyl 3-(chlorosulfonyl)-4-cyclopropyl-2-fluorobenzoate: Dissolve the aniline from step 3 (0.627 g, 3.0 mmol) in concentrated HCl (2 mL) and H 2 To a solution of NaNO in 20O (4.0 mL) 2 (0.414 g, 6.0 mmol) was added in portions at 0 °C. The mixture was stirred at 0 °C for 30 min. 2 To a solution of SOCl in 20O (1 mL), 2 (2.0 mL) was added dropwise at 0° C. This solution was then added dropwise to the above reaction and the mixture was stirred at 0° C. for 1 h. The reaction was diluted with EtOAc (50 mL) and H 2 The combined organic layers were diluted with EtOAc (50 mL × 2). 2 SO 4 After drying at rt and concentration, the title compound (0.153 g, 1.17 mmol, 78% yield) was obtained as a yellow oil, which was used crude in the next step without purification.

[0368] Step 5: Methyl 3-(N-(4-chloro-5-cyano-2-(cyclopentyloxy)phenyl)sulfamoyl)-4-cyclopropyl-2-fluorobenzoate: To a solution of the sulfonyl chloride from step 4 (0.083 g, 0.35 mmol) in pyridine (1 mL) was added 5-amino-2-chloro-4-(cyclopentyloxy)benzonitrile (Example 1, step 3; 0.354 g, 1.5 mmol) and the solution was stirred at room temperature overnight. The solvent was removed in vacuo and the crude product was purified by Biotage Isolera One (C 18 Column, 10%-90% MeCN / H 2 Purification by chromatography (eluted with 0) gave the title compound (0.73 g, 0.15 mmol, 43% yield) as a white solid. UPLC-MS (Method 3) m / z 491.05 (MH) at 1.883 min. - .

[0369] Step 6: 3-(N-(4-chloro-5-cyano-2-(cyclopentyloxy)phenyl)sulfamoyl)-4-cyclopropyl-2-fluorobenzoic acid: Dissolve the ester from step 5 (0.073 g, 0.15 mmol) in THF and H 2 LiOH (35.5 mg, 1.5 mmol) was added to a solution of 1:1 HO (v / v=1:1, 4 mL) and the reaction was stirred at room temperature overnight. The solvent was removed in vacuo and the crude product was purified using Biotage Isolera One (C 18 Column, 10%-90% MeCN / H containing 0.1% HCOOH 2 Purification by chromatography (eluted with 0) gave the title compound (22.6 mg, 0.047 mmol, 31% yield) as a red solid. UPLC-MS (Method 1) m / z 477.00 (MH) at 2.083 min. - 1 H NMR (400MHz, DMSO-d 6)δ10.13(s,1H), 7.74(s,1H), 7.60(t,J=7.9Hz,1H), 7.29(s,1H), 6.87(d,J=8.4Hz,1H), 4.81(dq,J=6.5,3.0Hz,1H), 2.02(td ,J=8.3,4.2Hz,1H), 1.80(dt,J=11.8,6.7Hz,2H), 1.60~1.46(m,2H), 1.49~1.40(m,4H), 1.13~1.04(m,2H), 0.84~0.75(m,2H). [Example 70]

[0370] (S)-3-(N-(4-chloro-5-cyano-2-(1-cyclobutylethoxy)phenyl)sulfamoyl)-4-cyclopropylbenzoic acid [ka] Step 1: (S)-2-Chloro-4-(1-cyclobutylethoxy)-5-nitrobenzonitrile: To a suspension of NaH (60% in mineral oil) (257 mg, 6.42 mmol) in THF (15 mL) was added (S)-1-cyclobutylethan-1-ol (400 μL, 3.62 mmol) dropwise at 0 °C. The mixture was warmed to room temperature and stirred for 30 min. The product from step 1 of Example 1 (650 mg, 3.21 mmol, 99% purity) in THF (5 mL) was added and the mixture was heated to 60 °C and stirred overnight. The reaction was carefully quenched with water (20 mL) and extracted with EtOAc (3 x 50 mL). The combined organic extracts were washed with brine (20 mL), dried (MgSO 4 ) and the solvent was removed in vacuo. The residue was loaded onto silica and purified by chromatography on silica gel (24 g cartridge, 0-50% EtOAc / isohexane) to give the title compound (196 mg, 649 μmol, 20% yield, 93% purity) as a yellow oil. UPLC (Method 4):t R :1.88 minutes. 1 H NMR (500MHz, DMSO-d 6)δ8.62(s,1H), 7.90(s,1H), 4.94~4.85(m,1H), 2.61~2.51(m,1H), 1.98~1.70(m,6H), 1.17(d,J=6.0Hz,3H).

[0371] Step 2: (S)-5-Amino-2-chloro-4-(1-cyclobutylethoxy)benzonitrile: A mixture of the product from Step 1 above (198 mg, 656 μmol, 93% pure), ammonium chloride (211 mg, 3.94 mmol) and zinc (257 mg, 3.94 mmol) in THF (6 mL) and water (2 mL) was stirred at room temperature overnight. The mixture was filtered through Celite®, washed with EtOAc and the filtrate was extracted with EtOAc (3×15 mL). The combined organic extracts were washed with brine (15 mL), dried (MgSO 4 ), and the solvent was removed in vacuo to give the title compound (160 mg, 625 μmol, 95% yield, 98% purity) as a sticky brown gum. UPLC-MS (Method 4): m / z 251.2 (M+H) at 1.80 min. + 1 H NMR (500MHz, DMSO-d 6 )δ7.14(s,1H), 6.96(s,1H), 5.23(s,2H), 4.60~4.51(m,1H), 2.61~2.51(m,1H), 2.02~1.72(m,6H), 1.12(d,J=6.0Hz,3H).

[0372] Step 3: Methyl (S)-3-(N-(4-chloro-5-cyano-2-(1-cyclobutylethoxy)phenyl)sulfamoyl)-4-cyclopropylbenzoate: A mixture of the product from Step 2 above (160 mg, 625 μmol, 98% purity), methyl 3-(chlorosulfonyl)-4-cyclopropylbenzoate (258 mg, 938 μmol) and pyridine (160 μL, 1.99 mmol) in DCM (5 mL) was heated to 35° C. and stirred for 2 days. The mixture was concentrated onto silica and purified by chromatography on silica gel (12 g cartridge, 0-50% EtOAc / isohexane) to give the title compound (267 mg, 535 μmol, 86% yield, 98% purity) as a white solid. UPLC-MS (Method 4): m / z 487.2 (MH) at 2.04 min. - 1 H NMR (500MHz, DMSO-d 6 )δ10.09(s,1H), 8.31(d,J=1.9Hz,1H), 8.02(dd,J=8.2,1.9Hz,1H), 7.66(s,1H), 7.43(s,1H), 7.18(d,J=8.2Hz,1H), 4.60~4.51(m,1H), 3.85(s ,3H), 2.75~2.66(m,1H), 2.21~2.12(m,1H), 1.81~1.74(m,1H), 1.72~1. 55(m,5H), 1.06~0.99(m,2H), 0.91~0.82(m,2H), 0.78(d,J=6.0Hz,3H).

[0373] Step 4: (S)-3-(N-(4-chloro-5-cyano-2-(1-cyclobutylethoxy)phenyl)sulfamoyl)-4-cyclopropylbenzoic acid: the product from step 3 above (267 mg, 535 μmol, 98% purity) and LiOH H 2 A mixture of 2H2O (92.0 mg, 2.19 mmol) in THF / MeOH / water (4:1:1, 3 mL) was stirred at 40 °C overnight. The mixture was diluted with water (10 mL), acidified to pH 4 using 1 M HCl (aq) and extracted with EtOAc (3 × 15 mL). The combined organic extracts were washed with brine (10 mL), dried (MgSO 4) and the solvent removed in vacuo. The residue was loaded onto silica and purified by chromatography on silica gel (24 g cartridge, 0-100% EtOAc / isohexane) then triturated with TBME / isohexane to give the title compound (127 mg, 262 μmol, 49% yield, 98% purity) as a white solid. UPLC-MS (Method 4): m / z 473.3 (MH) at 1.88 min. - 1 H NMR (500MHz, DMSO-d 6 )δ13.23(s,1H), 10.05(s,1H), 8.31(d,J=1.9Hz,1H), 7.99(dd,J=8.3,1.9Hz ,1H), 7.64(s,1H), 7.42(s,1H), 7.15(d,J=8.3Hz,1H), 4.60~4.51(m,1H), 2. 76~2.66(m,1H), 2.21~2.12(m,1H), 1.82~1.74(m,1H), 1.73~1.65(m,2H), 1. 65~1.56(m,3H), 1.06~1.00(m,2H), 0.87~0.81(m,2H), 0.80(d,J=6.0Hz,3H).

[0374] The following examples were prepared in a similar manner to Example 70, substituting the appropriate starting materials and intermediates where necessary. [Table 11] JPEG2024530447000102.jpg185123 [Example 73]

[0375] 3-(N-(4-chloro-5-cyano-2-(((1R,2S)-2-fluorocyclopentyl)oxy)phenyl)sulfamoyl)-4-cyclopropylbenzoic acid [ka] Reagents: (a) Cs 2 CO 3 , MeCN, RT; (b) DAST, DCM, -78℃; (c) Fe, NH4 Cl, EtOH / H 2 O (v / v=4 / 1), 80° C.; (d) pyridine, DCM, RT; (e) LiOH(aq), THF, RT.

[0376] Step 1: 2-Chloro-4-(((1R,2R)-2-hydroxycyclopentyl)oxy)-5-nitrobenzonitrile: Prepared according to step 2 of example 1 from 2-chloro-4-fluoro-5-nitrobenzonitrile (example 1, step 1).

[0377] Step 2: 2-Chloro-4-(((1R,2S)-2-fluorocyclopentyl)oxy)-5-nitrobenzonitrile: To a solution of the alcohol from step 1 (0.200 g, 0.71 mmol) in DCM (5 mL) was added diethylaminosulfur trifluoride (0.686 g, 4.26 mmol) at -78 °C and the solution was stirred at room temperature for 16 h. The solvent was removed in vacuo and the crude product was purified by silica gel chromatography (eluting with 1 / 5 EtOAc / PE) to give the title compound (0.070 g, 0.25 mmol, 35% yield) as a white solid. 1H NMR (400 MHz, chloroform-d) δ 8.22 (s, 1H), 7.32 (s, 1H), 5.25-5.12 (t, J = 5.1 Hz, 1H), 4.89 (dt, J = 9.1, 4.3 Hz, 1H), 2.14 (dt, J = 13.1, 7.8 Hz, 6H).

[0378] Step 3: 5-amino-2-chloro-4-(((1R,2S)-2-fluorocyclopentyl)oxy)benzonitrile: Prepared according to step 3 of example 1 from 2-chloro-4-(((1R,2S)-2-fluorocyclopentyl)oxy)-5-nitrobenzonitrile. UPLC-MS (Method 1) m / z 255.10 (M+H) at 1.800 min. + .

[0379] Step 4: Methyl 3-(N-(4-chloro-5-cyano-2-(((1R,2S)-2-fluorocyclopentyl)oxy)phenyl)sulfamoyl)-4-cyclopropylbenzoate: Prepared according to step 4 of example 1 from the aniline of step 3 and intermediate 3. UPLC-MS (method 1) m / z 491.00 (MH) at 2.183 min. - .

[0380] Step 5: 3-(N-(4-chloro-5-cyano-2-(((1R,2S)-2-fluorocyclopentyl)oxy)phenyl)sulfamoyl)-4-cyclopropylbenzoic acid: Prepared according to step 5 of example 1 from the ester of step 4. UPLC-MS (method 1) m / z 477.00 (MH) at 1.950 min. - 1 H NMR (400MHz, DMSO-d 6 )δ13.19(s,1H), 10.22~10.01(m,1H), 8.34(s,1H), 7.98(d,J=8.2Hz,1H), 7.63(s,1H), 7.49(s,1H), 7.12(d,J=8.3Hz,1H), 5.03(dd, J=53.7,4.0Hz,1H), 4.82~4.72(m,1H), 2.67(s,1H), 1.90~1.69(m,4H), 1.64~1.42(m,2H), 1.05~0.96(m,2H), 0.81(d,J=3.9Hz,2H). [Example 91]

[0381] 3-(N-(4-chloro-5-cyano-2-(spiro[3.3]heptan-1-yloxy)phenyl)sulfamoyl)-4-cyclopropylbenzoic acid enantiomer E1 [ka] Example 77 (85 mg, 173 μmol, 99% purity) was dissolved in 2.5 mL of a DCM / MeOH mixture with sonication, filtered, and then purified by chiral SFC (Waters prep 100, UV detection over all wavelengths with PDA as well as QDA, 40° C., 120 bar, ChiralPak IH, 250×21 mm, 5 μM column, flow rate 65 mL / min, 25% MeOH / CO 2 The mixture was separated by SFC (eluted with 500 ppb). The clean fractions were pooled, rinsed with methanol / DCM and concentrated in vacuo to give the title compound (55 mg, 90 μmol, 52% yield, 80% purity) as a sticky white solid containing 20% ​​w / w DMSO. 2 , ChiralPak IH, 4.6 × 250 mm, 5 μm column, flow rate 4 mL / min, 25% (0.1% ammonia in MeOH) / CO 2 (Elute at t R 2.02 min. Other analytical data were consistent with Example 77. [Example 92]

[0382] 3-(N-(4-chloro-5-cyano-2-(spiro[3.3]heptan-1-yloxy)phenyl)sulfamoyl)-4-cyclopropylbenzoic acid enantiomer E2 [ka] The title compound (37 mg, 75 μmol, 43% yield, 99% purity) was obtained as a white solid from the chiral separation carried out in Example 91. 2 , ChiralPak IH 4.6 × 250 mm, 5 μm column, flow rate 4 mL / min, 25% (0.1% ammonia in MeOH) / CO 2 (Elute at t R 2.40 min. Other analytical data were consistent with Example 77. [Example 93]

[0383] 3-(N-(4-chloro-5-cyano-2-(2,2-dimethylcyclobutoxy)phenyl)-sulfamoyl)-4-cyclopropylbenzoic acid enantiomer E1 [ka] Example 80 (108 mg, 225 μmol, 99% purity) was dissolved in 3.5 mL DCM / MeOH mixture with sonication, filtered, and then analyzed by chiral SFC (Waters prep 100, UV detection over all wavelengths with PDA as well as QDA, 40° C., 120 bar, ChiralPak IH 250×21 mm, 5 μM column, flow rate 65 mL / min, 20% MeOH / CO 2 The clean fractions were pooled, rinsed with methanol / DCM and concentrated in vacuo to give the title compound (47 mg, 99 μmol, 44% yield, 99% purity) as a white solid. 2 , ChiralPak IH 4.6 × 250 mm, 5 μm column, flow rate 4 mL / min, 20% (0.1% ammonia in MeOH) / CO 2 (Elute at t R 2.42 min. Other analytical data were consistent with Example 80. [Example 94]

[0384] 3-(N-(4-chloro-5-cyano-2-(2,2-dimethylcyclobutoxy)phenyl)-sulfamoyl)-4-cyclopropylbenzoic acid enantiomer E2 [ka] The title compound (47 mg, 99 μmol, 44% yield, 99% purity) was obtained as a white solid from the chiral separation carried out in Example 93. 2 , ChiralPak IH 4.6 × 250 mm, 5 μm column, flow rate 4 mL / min, 20% (0.1% ammonia in MeOH) / CO 2(Elute at t R 2.80 min. Other analytical data were consistent with Example 80. [Example 99]

[0385] 3-(N-(4-chloro-5-cyano-2-((trans-2-methylcyclopentyl)oxy)-phenyl)sulfamoyl)-4-cyclopropylbenzoic acid diastereomer D1 [ka] Example 90 (477 mg, 934 μmol, 93% purity) was dissolved in DMSO (2.8 mL), filtered, and purified by reverse phase preparative HPLC (Waters 2767 Sample Manager, Waters 2545 Binary Gradient Module, Waters Systems Fluidics Organiser, Waters 515 ACD pump, Waters 515 Makeup pump, Waters 2998 Photodiode Array Detector, Waters QDa) using a Waters X-Select CSH C18 ODB prep column, 130 Å, 5 μm, 30 mm×100 mm, flow rate 40 mL / min, elution with 0.1% formic acid-MeCN gradient in water over 12.5 min, PDA and UV over all wavelengths by QDA and ELS detectors. The dilution pump on the column provided 2 mL / min of MeOH throughout the method, which is included in the percentages of MeCN below. Gradient information: 0.0-0.5 min, 50% MeCN; 0.5-10.5 min, ramp from 50% MeCN to 80% MeCN; 10.5-10.6 min, ramp from 80% MeCN to 100% MeCN; 10.6-12.5 min, hold at 100% MeCN. Clean fractions were concentrated in vacuum using a Genevac. The residue was dissolved in MeOH (30 mg / mL) with sonication, filtered and then analyzed by chiral SFC (Waters prep 100, PDA and QDA detectors, 40 °C, 120 bar, ChiralPak IH 5 μM, 21 mm x 250 mm column, flow rate 65 mL / min, 18% MeOH (0.1% TFA), 82% CO2 ). The clean fractions were pooled, rinsed with MeOH, and concentrated to dryness using a rocket evaporator. The residue was redissolved in methanol, transferred to a final vial, concentrated in vacuo on a Biotage V10, and dried in vacuo to give the title compound (117 mg, 246 μmol, 26% yield, 99% purity) as a white solid. SFC (Waters UPC) 2 , ChiralPak IH 4.6 × 250 mm, 5 μm column, flow rate 4 mL / min, 25% (0.1% ammonia in EtOH) / CO 2 (Elute at t R 2.66 min. Other analytical data were consistent with Example 90. [Example 100]

[0386] 3-(N-(4-chloro-5-cyano-2-((trans-2-methylcyclopentyl)oxy)-phenyl)sulfamoyl)-4-cyclopropylbenzoic acid diastereomer D2 [ka] The title compound (137 mg, 288 μmol, 30% yield, 99% purity) was obtained as a white solid from the chiral separation carried out in Example 93. 2 , ChiralPak IH 4.6 × 250 mm, 5 μm column, flow rate 4 mL / min, 25% (0.1% ammonia in EtOH) / CO 2 (Elute at t R 2.90 min. Other analytical data were consistent with Example 90. [Example 101]

[0387] 3-(N-(4-chloro-5-cyano-2-(2,2,4,4-tetramethylcyclobutoxy)phenyl)sulfamoyl)-4-cyclopropylbenzoic acid The title compound was prepared in a similar manner to Example 70, substituting the appropriate starting materials and intermediates where necessary. UPLC (Method 4): m / z 501.2 (MH) at 2.03 min. - 1H NMR(500MHz,DMSO)δ13.20(s,1H), 9.94(s,1H), 8.37(d,J=1.9Hz,1H), 7.98(dd,J=8.2,1.9Hz,1H), 7.63(s,1H), 7.08(d,J=8.3Hz) ,1H), 7.02(s,1H), 4.29(s,1H), 1.42(d,J=11.5Hz,1H), 1.35(d,J=11.4Hz,1H), 1.11(s,6H), 0.95~0.85(m,2H), 0.81~0.75(m,8H) (One proton is obscured by the DMSO signal) [ka] [Example 103]

[0388] 3-(N-(4-chloro-5-cyano-2-((trans-2-methoxycyclopentyl)-oxy)phenyl)sulfamoyl)-4-cyclopropylbenzoic acid diastereomer D1 [ka] Step 1: Methyl 3-(N-(4-chloro-5-cyano-2-((trans-2-methoxycyclopentyl)-oxy)phenyl)sulfamoyl)-4-cyclopropylbenzoate diastereomer D1: AcCl (100 μL, 1.41 mmol) was added dropwise to anhydrous MeOH (3.0 mL) and the resulting solution was allowed to stand at room temperature for 10 min to form a dry solution of HCl / MeOH. Example 85 (71.5 mg, 146 μmol) was suspended in the HCl / MeOH solution and the resulting mixture was stirred at room temperature for 4 days. The mixture was concentrated in vacuo and the residue was dissolved in MeOH (6.7 mg / mL), sonicated, filtered and then purified by chiral SFC (Waters prep 15, UV detection by DAD at 210-400 nm, 40 °C, 120 bar, C4, 10 × 250 mm, 5 μm column, flow rate 15 mL / min, 30% MeOH / CO 2). The clean fractions were pooled and concentrated in vacuo to give the title compound (24.3 mg, 48.1 μmol, 33% yield) as an off-white solid. UPLC-MS (Method 4): m / z 503.2 (MH) at 1.73 min. - SFC (Waters UPC 2 , C4, 4.6 × 250 mm, 5 μm column, flow rate 4 mL / min, 30% (0.1% ammonia in MeOH) / CO 2 )t R 2.45 minutes.

[0389] Step 2: 3-(N-(4-chloro-5-cyano-2-((trans-2-methoxycyclopentyl)oxy)phenyl)sulfamoyl)-4-cyclopropylbenzoic acid diastereomer D1: The product from Step 1 above (24.3 mg, 48.1 μmol) was combined with 1M LiOH(aq) (238 μL, 238 μmol) in THF (1 mL) and the resulting solution was stirred at room temperature for 20 h. The mixture was diluted with water (1 mL) and concentrated in vacuo to remove the THF. The resulting aqueous solution was acidified with 1M HCl (0.3 mL) and the resulting white precipitate was collected by filtration and washed with water. The solid was dissolved in MeCN and concentrated in vacuo to give the title compound (22 mg, 44 μmol, 91% yield, 98% purity) as a white powder. UPLC-MS (Method 4): m / z 490.9 (M+H) at 1.70 min + , 489.2(MH) - , 1 H NMR(500MHz,DMSO)δ13.26(s,1H), 10.15(s,1H), 8.32(d,J=1.9Hz,1H), 7.99(dd,J=8.2, 1.9Hz,1H), 7.69(s,1H), 7.35(s,1H), 7.13(d,J=8.3Hz,1H), 4.65(dt,J=6.5,3.3Hz,1H) , 3.43(dd,J=6.9,4.4Hz,1H), 3.13(s,3H), 2.73~2.60(m,1H), 1.96~1.86(m,1H), 1.76~1 .66(m,1H), 1.56~1.37(m,3H), 1.27~1.16(m,1H), 1.03~0.95(m,2H), 0.84~0.78(m,2H). [Example 104]

[0390] 3-(N-(4-chloro-5-cyano-2-((trans-2-methoxycyclopentyl)-oxy)phenyl)sulfamoyl)-4-cyclopropylbenzoic acid diastereomer D2 [ka] Step 1: Methyl 3-(N-(4-chloro-5-cyano-2-((trans-2-methoxycyclopentyl)-oxy)phenyl)sulfamoyl)-4-cyclopropylbenzoate diastereomer D2: The title compound (24.6 mg, 48.7 μmol, 34% yield) was obtained as an off-white solid from the chiral separation carried out in Example 103. SFC (Waters UPC) 2 , C4, 4.6 × 250 mm, 5 μm column, flow rate 4 mL / min, 30% (0.1% ammonia in MeOH) / CO 2 )t R 2.78 min. Other analytical data were consistent with Example 103, Step 1.

[0391] Step 2: 3-(N-(4-chloro-5-cyano-2-((trans-2-methoxycyclopentyl)oxy)phenyl)sulfamoyl)-4-cyclopropylbenzoic acid diastereomer D2: The title compound (22 mg, 43 μmol, 87% yield) was obtained as a white powder using a method similar to that of Step 2 of Example 103. Analytical data was consistent with Step 2 of Example 103. [Example 105]

[0392] 3-(N-(4-chloro-5-cyano-2-((cis-2-methylcyclopentyl)oxy)-phenyl)sulfamoyl)-4-cyclopropylbenzoic acid [ka] The title compound was prepared in a similar manner to Example 70, substituting the appropriate starting materials and intermediates where necessary. UPLC-MS (Method 4): m / z 473.2 (MH) at 1.87 min. - 1H NMR (500MHz, DMSO-d 6 ) δ13.19(br s,1H), 9.99(br s,1H), 8.35(d,J=1.8Hz,1H), 7.96(d,J=8.2Hz,1H), 7.58(s,1H), 7.41~7.25(m,1H), 7.09(d,J=8.3Hz,1H), 4.82~4.69(m,1H), 2.05~1.91(m, 1H), 1.91~1.82(m,1H), 1.64~1.56(m,1H), 1.56~1.47(m,1H), 1.46~1. 20(m,4H), 1.00~0.90(m,2H), 0.84~0.75(m,2H), 0.69(d,J=6.8Hz,3H). [Example 106]

[0393] 3-(N-(4-chloro-5-cyano-2-(spiro[2.3]hexan-4-yloxy)phenyl)-sulfamoyl)-4-cyclopropylbenzoic acid.1.50 diethylamine salt enantiomer E1 [ka] Example 56 (22 mg, 46.5 μmol) was dissolved in DCM / MeOH at 50 mg / mL, sonicated, filtered and then purified using chiral SFC (Waters prep 100, PDA and QDA detectors, 40° C., 120 bar, ChiralPak IH, 21×250 mm, 5 μm column, flow rate 65 mL / min, (25% (0.1% diethylamine / MeOH) / CO 2 ). The clean fractions were pooled, rinsed with MeOH, and concentrated in vacuo to give the title compound (5.3 mg, 8.9 μmol, 19% yield, 98% purity) as a clear, colorless glass. UPLC-MS (Method 4): m / z 473.0 (M+H) at 1.82 min. + , 471.2(MH) - , 1H NMR(500MHz,DMSO)δ8.38(d,J=1.8Hz,1H), 7.75(dd,J=8.1,1.9Hz,1H), 7.32(s,1H), 6. 76(d,J=8.1Hz,1H), 6.63(s,1H), 4.82(t,J=6.5Hz,1H), 3.30~3.23(m,1H), 2.85(q,J=7. 2Hz,6H), 2.47(td,J=5.7,3.1Hz,1H), 2.06~1.91(m,2H), 1.91~1.80(m,1H), 1.14(t,J= 7.2Hz, 9H), 1.02~0.81(m,3H), 0.72~0.60(m,2H), 0.60~0.43(m,2H), 0.42~0.30(m,1H). SFC (Waters UPC 2 , ChiralPak IH, 4.6 × 250 mm, 5 μm column, flow rate 4 mL / min, 25% (0.1% ammonia.MeOH) / CO 2 )t R 2.12 minutes. [Example 107]

[0394] 3-(N-(4-chloro-5-cyano-2-(spiro[2.3]hexan-4-yloxy)phenyl)-sulfamoyl)-4-cyclopropylbenzoic acid.1.65 diethylamine salt enantiomer E2 [ka] The title compound (8.4 mg, 14 μmol, 30% yield, 98% purity) was obtained as a colorless transparent glass from the chiral separation carried out in Example 106. 2 , ChiralPak IH 4.6×250 mm, 5 μm column, flow rate 4 mL / min, 25% (0.1% ammonia.MeOH) / CO 2 )t R 2.48 min. Other analytical data were consistent with Example 106. [Example 108]

[0395] 3-(N-(4-chloro-5-cyano-2-(2-cyclopropylcyclobutoxy)-phenyl)sulfamoyl)-4-cyclopropylbenzoic acid [ka] The title compound was prepared in a similar manner to Example 70, substituting the appropriate starting materials and intermediates where necessary. UPLC-MS (Method 4): m / z 485.2 (MH) at 1.88 min. - 1 H NMR (500MHz, DMSO-d 6 ) (10:1 mixture of diastereomers) δ13.23(br s,1H), 10.18(br s,1H), 8.28(d,J=1.9Hz,1H minor), 8.27(d,J=1.8Hz,1H main), 7.99(dd,J=8.2,1.9Hz,1H 7.96(dd,J=8.1,1.8Hz,1H sub), 7.72(s,1H), 7.22(s,1H), 7.15(d,J=8.4Hz,1H main), 7.14(d,J=8.4Hz,1H sub), 4.77(q,J=7.0Hz,1H secondary), 4.49(q,J=7.2Hz,1H main), 2.84~2.79(m,1H secondary), 2.79~2.69(m,1H main), 2.20~2.12(m,1H secondary), 2.12~2.03(m,1H primary), 1.80~1.70(m,1H secondary), 1.67~1.57(m,1H, primary), 1.54~1.44(m,1H sub), 1.44~1.34(m,1H main), 1.30~0.91(m,4H), 0.91~0.71(m,2H), 0.39~0.30(m,1H main), 0.30~0.22(m,1H main), 0.15~0.04(m,1H sub), 0.00~-0.08(m,1H Main), -0.11~-0.21(m,1H), -0.31~-0.42(m,1H secondary), -0.50~-0.61(m,1H secondary). [Example 114]

[0396] 3-(N-(4-chloro-5-cyano-2-(3-methylcyclobutoxy)phenyl)sulfamoyl)-4-cyclopropylbenzoic acid diastereomer D1 [ka] Step 1: Methyl 3-(N-(4-chloro-5-cyano-2-(3-methylcyclobutoxy)phenyl)sulfamoyl)-4-cyclopropylbenzoate diastereomer D1: Methyl 3-(N-(4-chloro-5-cyano-2-(3-methylcyclobutoxy)phenyl)sulfamoyl)-4-cyclopropylbenzoate (Example 88, 219 mg, 461 μmol) was dissolved in 5:1 EtOH:DCM (17.6 mg / mL) and then purified by SFC (Lux iC5, 21.2×250 mm, 5 μm column, 40° C., 125 bar, flow rate 50 mL / min, 20% EtOH / CO 2 ) to give the title compound (147 mg, 309 μmol, 67% yield) as a colorless glass. UPLC-MS (Method 4): m / z 475.2 (M+H) at 1.98 min. + , 473.2(MH) - SFC (Lux iC5, 4.6 × 250 mm, 5 μm column, 40 °C, 125 bar, flow rate 4 mL / min, 20% (0.1% ammonia / EtOH) / CO 2 )t R 10.1 minutes.

[0397] Step 2: 3-(N-(4-chloro-5-cyano-2-(3-methylcyclobutoxy)phenyl)sulfamoyl)-4-cyclopropylbenzoic acid diastereomer D1: The product from Step 1 above (147 mg, 309 μmol) was dissolved in THF (5 mL) and treated with 1M LiOH(aq) (1.55 mL, 1.55 mmol). The resulting mixture was stirred at room temperature for 24 h. The mixture was diluted with water (2 mL) and concentrated in vacuo to remove THF. The resulting solution was acidified using 1M HCl(aq) and the white precipitate was collected by filtration, washed with water, and then dried in vacuo to give the title compound (130 mg, 279 μmol, 90% yield, 99% purity) as a white solid. UPLC-MS (Method 4): m / z 461.3 (M+H) at 1.80 min + , 459.2(MH) - , 1H NMR(500MHz,DMSO)δ13.26(brs,1H), 10.16(br s,1H), 8.31(d,J=1.8Hz,1H), 7.99(dd,J=8.2,1.9Hz,1H), 7.70(s,1H), 7.14(d,J=8.2Hz,1H), 7.08(s,1H), 4.47(p,J=7.3Hz,1H), 2.7 6~2.68(m,1H), 2.44~2.36(m,2H), 1.88~1.75(m,1H), 1.25~1.15(m,2H), 1.05~0.99(m,2H), 0.97(d,J=6.6Hz,3H), 0.84~0.77(m,2H). [Example 115]

[0398] 3-(N-(4-chloro-5-cyano-2-(3-methylcyclobutoxy)phenyl)sulfamoyl)-4-cyclopropylbenzoic acid diastereomer D2 [ka] Step 1: Methyl 3-(N-(4-chloro-5-cyano-2-(3-methylcyclobutoxy)phenyl)sulfamoyl)-4-cyclopropylbenzoate diastereomer D2: The title compound (19 mg, 40.4 μmol, 9% yield) was obtained as a colorless glass from the separation carried out in step 1 of Example 114. SFC (Lux iC5, 4.6×250 mm, 5 μm column, 40° C., 125 bar, flow rate 4 mL / min, 20% (0.1% ammonia / EtOH) / CO 2 )t R 9.17 min. Other analytical data was consistent with Example 114, Step 1.

[0399] Step 2: 3-(N-(4-chloro-5-cyano-2-(3-methylcyclobutoxy)phenyl)sulfamoyl)-4-cyclopropylbenzoic acid diastereomer D2: The title compound (18.0 mg, 37.1 μmol, 92% yield, 95% purity) was prepared in a similar manner to Step 2 of Example 114, substituting the appropriate starting materials and intermediates where necessary. UPLC-MS (Method 4) m / z 461.6 (M+H) at 1.81 min. +, 459.2(MH) - , 1 H NMR(500MHz,DMSO)δ13.22(s,1H), 10.18(s,1H), 8.30(d,J=1.9Hz,1H), 7.99 (dd,J=8.2,1.9Hz,1H), 7.70(s,1H), 7.13(d,J=8.3Hz,1H), 7.04(s,1H), 4.82 (p,J=6.5Hz,1H), 2.80~2.69(m,1H), 2.21~2.09(m,1H), 1.95~1.87(m,2H), 1. 84~1.74(m,2H), 1.07(d,J=7.1Hz,3H), 1.04~0.98(m,2H), 0.84~0.78(m,2H). [Example 120]

[0400] 3-(N-(4-chloro-5-cyano-2-(2-methylcyclobutoxy)phenyl)sulfamoyl)-4-cyclopropylbenzoic acid stereoisomer D1 [ka] Step 1: Methyl 3-(N-(4-chloro-5-cyano-2-(2-methylcyclobutoxy)phenyl)sulfamoyl)-4-cyclopropylbenzoate: The title compound (1.2 g, 2.53 mmol) was prepared in a similar manner to steps 1-3 of example 70, substituting the appropriate starting materials and intermediates where necessary.

[0401] Step 2: Methyl 3-(N-(4-chloro-5-cyano-2-(2-methylcyclobutoxy)phenyl)sulfamoyl)-4-cyclopropylbenzoate stereoisomer D1: The product from step 1 above (1.2 g, 2.53 mmol) was dissolved in a mixture of MeOH (11 mL) and THF (5 mL), then sonicated, filtered, and purified by chiral SFC (Waters prep 100, PDA and QDA detectors, 40 °C, 120 bar, ChiralPak IH, 21 × 250 mm, 5 μm column, flow rate 65 mL / min, (25% MeOH) / CO 2) to give three fractions. The first eluted fraction was concentrated in vacuo to give the title compound (379 mg, 0.774 mmol, 31% yield, 97% purity (3 wt% MeOH)) as a colorless glass. UPLC-MS (Method 4): m / z 475.3 (M+H) at 1.99 min. + , 473.3(MH) - , 1 H NMR(500MHz,DMSO)δ10.23(s,1H), 8.31(d,J=1.9Hz,1H), 8.02(dd,J=8.3,1.9Hz, 1H), 7.71(s,1H), 7.17(d,J=8.3Hz,1H), 7.11(s,1H), 4.31(q,J=7.1Hz,1H), 3.84( s,3H), 2.80~2.71(m,1H), 2.23~2.05(m,2H), 1.80~1.70(m,1H), 1.26~1.14(m,1H) ), 1.13~1.00(m,3H), 0.96(d,J=6.7Hz,3H), 0.90~0.84(m,1H), 0.84~0.76(m,1H). SFC (Waters UPC 2 , ChiralPak IH 4.6×250 mm, 5 μm column, flow rate 4 mL / min, 25% (0.1% ammonia / MeOH) / CO 2 )t R 1.76 minutes.

[0402] Step 3: 3-(N-(4-chloro-5-cyano-2-(2-methylcyclobutoxy)phenyl)sulfamoyl)-4-cyclopropylbenzoic acid stereoisomer D1: the product from step 2 above (379 mg, 774 μmol, 97% purity) and LiOH H 2 A solution of 0 (134 mg, 3.19 mmol) in THF (4 mL), water (1 mL) and MeOH (1 mL) was stirred at room temperature for 24 h. The resulting mixture was concentrated in vacuo and the resulting aqueous solution was diluted with water (10 mL). The solution was acidified using 1M HCl (aq) and the resulting white precipitate was filtered off and washed with water (5 mL). The solid was dried in vacuo to give the title compound (275 mg, 591 μmol, 76% yield, 99% purity) as a white solid. UPLC-MS (Method 4): m / z 461.1 (M+H) at 1.82 min.+ , 459.2(MH) - , 1 H NMR(500MHz,DMSO)δ13.24(s,1H), 10.19(s,1H), 8.31(d,J=1.9Hz,1H), 7.99(dd,J =8.2,1.9Hz,1H), 7.69(s,1H), 7.14(d,J=8.3Hz,1H), 7.09(s,1H), 4.32(q,J=7.1H) z,1H), 2.80~2.72(m,1H), 2.24~2.07(m,2H), 1.76(q,J=9.4Hz,1H), 1.28~1.19(m, 1H), 1.14~1.01(m,3H), 0.97(d,J=6.7Hz,3H), 0.89~0.82(m,1H), 0.81~0.75(m,1H) [Example 121]

[0403] 3-(N-(4-chloro-5-cyano-2-(2-methylcyclobutoxy)phenyl)sulfamoyl)-4-cyclopropylbenzoic acid stereoisomer D2 [ka] Step 1: Methyl 3-(N-(4-chloro-5-cyano-2-(2-methylcyclobutoxy)phenyl)sulfamoyl)-4-cyclopropylbenzoate stereoisomer D2: The second eluting fraction from step 2 of Example 120 was purified by chiral SFC (Waters prep 100, PDA and QDA detectors, 40 °C, 120 bar, Lux C4, 21 × 250 mm, 5 μm column, flow rate 65 mL / min, 30% MeOH / CO 2 The first eluting fraction was purified further by chiral SFC (Waters prep 100, PDA and QDA detectors, 40 °C, 120 bar, Chiralpak IH, 21 × 250 mm, 5 μm column, flow rate 65 mL / min, 25% MeOH / CO 2 ) to give the title compound (275 mg, 0.538 mmol, 21% yield, 93% purity (7 wt% MeOH)) as a colorless glass. 2, ChiralPak IH 4.6×250 mm, 5 μm column, flow rate 4 mL / min, 25% (0.1% ammonia / MeOH) / CO 2 )t R 1.96 min. Other analytical data was consistent with Example 120, Step 2.

[0404] Step 2: 3-(N-(4-chloro-5-cyano-2-(2-methylcyclobutoxy)phenyl)sulfamoyl)-4-cyclopropylbenzoic acid Stereoisomer D2: The title compound (173 mg, 375 μmol, 70% yield) was prepared in a similar manner to Step 3 of Example 120, substituting the appropriate starting materials and intermediates where necessary. Analytical data was consistent with Example 120. [Example 122]

[0405] 3-(N-(4-chloro-5-cyano-2-(2-methylcyclobutoxy)phenyl)sulfamoyl)-4-cyclopropylbenzoic acid stereoisomer D3 [ka] Step 1: Methyl 3-(N-(4-chloro-5-cyano-2-(2-methylcyclobutoxy)phenyl)sulfamoyl)-4-cyclopropylbenzoate stereoisomer D3: The second eluting fraction from step 1 of Example 121 was purified by chiral SFC (Waters prep 100, PDA and QDA detectors, 40 °C, 120 bar, Lux C4, 21 × 250 mm, 5 μm column, flow rate 65 mL / min, 30% MeOH / CO 2 ) to give the title compound (51 mg, 106 mmol, 4% yield, 99% purity) as a white solid. UPLC (Method 4): m / z 475.3 (M+H) at 1.97 min + , 473.3(MH) - , 1H NMR(500MHz,DMSO)δ10.20(s,1H), 8.33(d,J=1.9Hz,1H), 8.00(dd,J=8.2,1.9Hz,1H ), 7.68(s,1H), 7.14(d,J=8.3Hz,1H), 7.07(s,1H), 4.65(q,J=7.3Hz,1H), 3.84(s,3 H), 2.73~2.65(m,2H), 2.18~2.09(m,1H), 2.01(p,J=10.0Hz,1H), 1.74(p,J=8.9Hz, 1H), 1.27~1.23(m,1H), 1.08~0.95(m,2H), 0.90~0.78(m,2H), 0.64(d,J=7.2Hz,3H). SFC (Waters UPC 2 , ChiralPak IH 4.6×250 mm, 5 μm column, flow rate 4 mL / min, 25% (0.1% ammonia / MeOH) / CO 2 )t R 2.00 minutes.

[0406] Step 2: 3-(N-(4-chloro-5-cyano-2-(2-methylcyclobutoxy)phenyl)sulfamoyl)-4-cyclopropylbenzoic acid stereoisomer D3: The title compound (12 mg, 26 μmol, 24% yield, 97% purity) was prepared in a similar manner to Step 3 of Example 120, substituting the appropriate starting materials and intermediates where necessary. UPLC-MS (Method 4): m / z 461.4 (M+H) at 1.81 min. + , 459.2(MH) - , 1 H NMR(500MHz,DMSO)δ13.22(s,1H), 10.17(s,1H), 8.33(d,J=1.9Hz,1H), 7.98(dd, J=8.2,1.9Hz,1H), 7.68(s,1H), 7.12(d,J=8.3Hz,1H), 7.08(s,1H), 4.66(q,J=7.2 Hz,1H), 2.74~2.65(m,2H), 2.18~2.10(m,1H), 2.06~1.97(m,1H), 1.79~1.69(m,1H) ), 1.30~1.22(m,1H), 1.09~0.94(m,2H), 0.89~0.77(m,2H), 0.65(d,J=7.2Hz,3H). [Example 123]

[0407] 3-(N-(4-chloro-5-cyano-2-(2-methylcyclobutoxy)phenyl)sulfamoyl)-4-cyclopropylbenzoic acid stereoisomer D4 [ka] Step 1: Methyl 3-(N-(4-chloro-5-cyano-2-(2-methylcyclobutoxy)phenyl)sulfamoyl)-4-cyclopropylbenzoate stereoisomer D4: The third eluting fraction from step 2 of Example 120 was purified by chiral SFC (Waters prep 100, PDA and QDA detectors, 40 °C, 120 bar, Chiralpak IH, 21 × 250 mm, 5 μm column, flow rate 65 mL / min, 25% MeOH / CO 2 ) to give the title compound (85 mg, 177 mmol, 7% yield, 99% purity) as a white solid. 2 , ChiralPak IH, 4.6 × 250 mm, 5 μm column, flow rate 4 mL / min, 25% (0.1% ammonia / MeOH) / CO 2 )t R 2.27 min. Other analytical data was consistent with Example 122, Step 1.

[0408] Step 2: 3-(N-(4-chloro-5-cyano-2-(2-methylcyclobutoxy)phenyl)sulfamoyl)-4-cyclopropylbenzoic acid stereoisomer D4: The title compound (67 mg, 135 μmol, 76% yield, 93% purity (6 wt% MeCN)) was prepared in a similar manner to Step 3 of Example 120, substituting the appropriate starting materials and intermediates where necessary. Analytical data consistent with Example 122. [Example 125]

[0409] (R)-4-Cyclopropyl-3-(N-(2-((2,2-dimethylcyclopentyl)oxy)-4-fluoro-5-(1H-tetrazol-1-yl)phenyl)sulfamoyl)benzoic acid [ka] Step 1: tert-Butyl (tert-butoxycarbonyl) (2,4-difluoro-5-nitrophenyl)carbamate: DMAP (0.18 g, 1.4 mmol) was added to a stirred solution of 2,4-difluoro-5-nitroaniline (2.5 g, 14 mmol) and di-tert-butyl dicarbonate (7.8 g, 36 mmol) in DCM (25 mL) and the resulting mixture was stirred at room temperature for 18 h. The reaction mixture was concentrated onto Celite® and purified by chromatography on silica gel (80 g cartridge, 0-50% EtOAc / isohexane) to give the title compound (2.62 g, 6.6 mmol, 46% yield, 94% purity) as a clear, colorless oil. 1 H NMR (500 MHz, CDCl 3 )δ8.05(t,J=7.6Hz,1H), 7.10(dd,J=10.2,8.9Hz,1H), 1.45(s,18H).

[0410] Step 2: tert-Butyl (R)-(tert-butoxycarbonyl)(4-((2,2-dimethylcyclopentyl)oxy)-2-fluoro-5-nitrophenyl)carbamate: A mixture of the product from Step 1 above (1.39 g, 3.50 mmol, 94% purity) and (R)-2,2-dimethylcyclopentan-1-ol (400 mg, 3.50 mmol) in DMF (8 mL) was diluted with Cs 2 CO 3 (1.71 g, 5.25 mmol). The resulting mixture was stirred at room temperature for 4 days. Additional (R)-2,2-dimethylcyclopentan-1-ol (350 mg, 3.07 mmol) was added and stirring was continued for another 3 days. The mixture was partitioned between TBME (40 mL) and water (40 mL) and the phases were separated. The organic phase was washed with water (40 mL), saturated NaHCO 3 Wash with (aq) (40 mL) and brine (2 x 40 mL), then MgSO 4The crude product was purified by chromatography on silica gel (24 g cartridge, 25-75% DCM / heptane) to give the title compound (1.14 g, 1.92 mmol, 55% yield, 79% purity) as a pale yellow oil. UPLC-MS (Method 4) m / z 491.4 (M+Na) at 2.31 min. + 1 H NMR (500 MHz, CDCl 3 )δ7.85(d,J=8.0Hz,1H), 6.77(d,J=11.3Hz,1H), 4.24~4.19(m,1H), 2.26~2.13(m, 1H), 1.90~1.66(m,3H), 1.45(s,18H), 1.54~1.41(m,2H), 1.16(s,3H), 1.03(s,3H).

[0411] Step 3: (R)-1-(4-((2,2-dimethylcyclopentyl)oxy)-2-fluoro-5-nitrophenyl)tetrazole: The product from Step 2 above (1.14 g, 1.92 mmol, 79% purity) was dissolved in DCM (12 mL) and treated with TFA (2 mL, 26.0 mmol). The resulting mixture was stirred at room temperature for 18 h then concentrated in vacuo and azeotroped with DCM (30 mL) to give a pale orange solid (891 mg). The solid was dissolved in triethylorthoformate (22.0 mL, 132 mmol) and treated with AcOH (1 mL, 17.5 mmol). The resulting mixture was heated at 80° C. for 1 h then trimethylsilyl azide (600 μL, 4.52 mmol) was added dropwise. Heating was continued for 2 h. Sodium acetate (300 mg, 3.66 mmol) was added and heating was continued for 10 min. The mixture was concentrated in vacuo and the residue was dissolved in TBME (25 mL) and saturated NaHCO 3 (aq) (15 mL). The phases were separated and the organic phase was washed with saturated NaHCO 3 Wash with (aq) (15 mL) and brine (15 mL), then MgSO 4The mixture was dried over 1000 cc, filtered, and concentrated in vacuo to give a pale yellow oil (750 mg). The oil was dissolved in AcOH (12 mL, 210 mmol) and treated with trimethyl orthoformate (1.53 mL, 14.0 mmol). Sodium azide (300 mg, 4.61 mmol) was added and the resulting mixture was heated at 80° C. for 2 h. The mixture was concentrated in vacuo and the residue was dissolved in TBME (25 mL) and saturated NaHCO 3 (aq) (15 mL). The phases were separated and the organic phase was washed with saturated NaHCO 3 Wash with (aq) (15 mL) and brine (15 mL), then MgSO 4 The mixture was dried at 40° C., filtered and concentrated in vacuo to give the title compound (662 mg, 1.67 mmol, 87% yield, 81% purity) as a pale yellow oil. UPLC-MS (Method 4): m / z 322.0 (M+H) at 1.77 min. + , 318.6(M+OH-HF) - , 1 H NMR (500 MHz, CDCl 3 )δ9.03(d,J=2.4Hz,1H), 8.50(d,J=7.7Hz,1H), 7.03(d,J=12.3Hz,1H), 4.32(dd,J=6.0,2.8 Hz,1H), 2.32~2.21(m,1H), 1.91~1.73(m,3H), 1.57~1.47(m,1H), 1.19(s,3H), 1.17(s,3H).

[0412] Step 4: (R)-2-((2,2-dimethylcyclopentyl)oxy)-4-fluoro-5-(tetrazol-1-yl)aniline: The product from Step 3 above (662 mg, 1.67 mmol, 81% purity) was dissolved in THF (6 mL) and water (2 mL) with NH 4Cl (893 mg, 16.7 mmol). The resulting rapidly stirring suspension was cooled in an ice bath and treated portionwise with zinc (1.09 g, 16.7 mmol). The resulting mixture was allowed to warm to room temperature and stirred for 4 h. The mixture was diluted with EtOAc (20 mL) and the phases separated. The aqueous phase was extracted with EtOAc (2 x 20 mL), the extracts were filtered through Celite®, combined and concentrated in vacuo to give a dark brown oil (574 mg). The oil was partitioned between DCM (8 mL) and water (4 mL) and the phases separated. The aqueous phase was extracted with DCM (2 x 2 mL), the organic phases were combined and concentrated in vacuo and the residue was purified by chromatography on silica gel (12 g cartridge, 0-10% EtOAc / DCM) to give the title compound (416 mg, 1.36 mmol, 81% yield, 95% purity) as an off-white solid. UPLC-MS (method 4): m / z 292.3 (M+H) at 1.64 min + 1 H NMR (500 MHz, CDCl 3 )δ8.98(d,J=2.3Hz,1H), 7.37(d,J=7.3Hz,1H), 6.76(d,J=12.3Hz,1H), 5.66(br s,2H), 4.21(dd,J=6.1,3.4Hz,1H), 2.28~2.17(m,1H), 1.90~1.68(m,4H), 1.55~1.46(m,1H), 1.15(s,3H), 1.06(s,3H).

[0413] Step 5: Methyl (R)-4-cyclopropyl-3-(N-(2-((2,2-dimethylcyclopentyl)oxy)-4-fluoro-5-(tetrazol-1-yl)phenyl)sulfamoyl)benzoate: The product from Step 4 above (206 mg, 672 μmol, 95% purity) was combined with methyl 3-(chlorosulfonyl)-4-cyclopropylbenzoate (233 mg, 848 μmol) in DCM (4 mL) and treated with pyridine (172 μL, 2.13 mmol). The resulting solution was allowed to stand at room temperature for 18 h. The solution was washed successively with 1 M HCl(aq) (2×5 mL) and water (5 mL) and dried (MgSO 4) and purified directly by chromatography on silica gel (12 g cartridge, 0-100% EtOAc / isohexane) to give the title compound (340 mg, 623 μmol, 93% yield, 97% purity) as a pale pink solid. UPLC-MS (Method 4): m / z 530.4 (M+H) at 1.90 min. + , 528.3(MH) - , 1 H NMR(500MHz,DMSO)δ9.88(s,1H), 9.83(d,J=1.4Hz,1H), 8.39(d,J=1.9Hz,1H), 7.99(dd,J=8 .3,1.9Hz,1H), 7.58(d,J=8.0Hz,1H), 7.34(d,J=12.7Hz,1H), 7.11(d,J=8.3Hz,1H), 4.31(dd ,J=6.3,4.2Hz,1H), 3.84(s,3H), 2.67~2.58(m,1H), 2.07(dq,J=13.8,6.6Hz,1H), 1.57~1.4 5(m,3H), 1.31~1.14(m,2H), 1.01~0.91(m,2H), 0.89(s,3H), 0.84~0.77(m,2H), 0.76(s,3H).

[0414] Step 6: (R)-4-Cyclopropyl-3-(N-(2-((2,2-dimethylcyclopentyl)oxy)-4-fluoro-5-(tetrazol-1-yl)phenyl)sulfamoyl)benzoic acid: The product from Step 5 above (337 mg, 617 μmol, 97% purity) was dissolved in THF (6 mL) and treated with 1M LiOH(aq) (3.09 mL, 3.09 mmol). The resulting mixture was stirred at room temperature for 3 days. The mixture was diluted with water (2 mL) to give a clear solution which was concentrated in vacuo to remove the THF. The resulting solution was acidified using 1M HCl(aq) and the pale pink precipitate was collected by filtration, washed with water and dried in vacuo to give the title compound (306 mg, 582 μmol, 94% yield, 98% purity) as an off-white powder. UPLC-MS (Method 4): m / z 516.1 (M+H) at 1.73 min. + , 514.2(MH) - , 1H NMR(500MHz,DMSO)δ13.22(brs,1H), 9.90(br s,1H), 9.82(d,J=1.4Hz,1H), 8.38(d,J=1.9Hz,1H), 7.96(dd,J=8.2,1.9Hz,1 H), 7.58(d,J=8.1Hz,1H), 7.32(d,J=12.6Hz,1H), 7.07(d,J=8.3Hz,1H), 4.31( dd,J=6.4,4.2Hz,1H), 2.64(s,1H), 2.12~2.02(m,1H), 1.57~1.45(m,3H), 1.33 ~1.15(m,2H), 0.99~0.86(m,2H), 0.89(s,3H), 0.82~0.74(m,2H), 0.78(s,3H). [Example 130]

[0415] 3-(N-(4-chloro-5-cyano-2-(2-cyclopropylcyclobutoxy)phenyl)sulfamoyl)-4-cyclopropylbenzoic acid stereoisomer D1 [ka] Step 1: 3-(N-(4-chloro-5-cyano-2-(2-cyclopropylcyclobutoxy)phenyl)sulfamoyl)-4-cyclopropylbenzoic acid: The title compound (162 mg, 333 μmol) was prepared in a similar manner to Example 70, substituting the appropriate starting materials and intermediates where necessary.

[0416] Step 2: Methyl 3-(N-(4-chloro-5-cyano-2-(2-cyclopropylcyclobutoxy)phenyl)sulfamoyl)-4-cyclopropylbenzoate stereoisomer D1: Separation 1: The product from step 1 above was dissolved in MeOH (25 mg / mL) with sonication, filtered and then purified by chiral SFC (Waters prep 15, UV detection by DAD at 210-400 nm, 40 °C, 120 bar, Chiralpak IH 10 × 150 mm, 5 μm column, flow rate 15 mL / min, 20% (0.1% DEA / MeOH) / CO 2). The clean fractions were pooled, rinsed with MeOH, and concentrated in vacuo to give three fractions, each containing DEA as an impurity. Separation 2: The first eluted fraction was dissolved in MeOH (40 mg / mL) with sonication, filtered, and then purified by chiral SFC (Waters prep 100, PDA and QDA detectors, 40 °C, 120 bar, Chiralpak IH, 21 mm × 250 mm, 5 μm column, flow rate 65 mL / min, 20% (0.1% TFA / MeOH) / CO 2 ). The clean fractions were pooled, rinsed with MeOH, and concentrated in vacuo to give two fractions, each of which underwent esterification during evaporation of the solvent.

[0417] Step 3: 3-(N-(4-chloro-5-cyano-2-(2-cyclopropylcyclobutoxy)phenyl)sulfamoyl)-4-cyclopropylbenzoic acid stereoisomer D1: The first eluted fraction from separation 2 in step 2 above was subjected to a procedure similar to step 4 in example 70 to give the title compound (47 mg, 96 μmol, 29% yield, 99% purity). UPLC-MS (method 4): m / z 487.2 (M+H) at 1.89 min. + , 485.2(MH) - , 1 H NMR(500MHz,DMSO)δ13.24(brs,1H), 10.17(br s,1H), 8.26(d,J=1.9Hz,1H), 7.99(dd,J=8.2,1.9Hz,1H), 7.72(s,1H), 7.22(s,1H), 7.15(d,J=8 .3Hz,1H), 4.49(q,J=7.1Hz,1H), 2.80~2.71(m,1H), 2.09(q,J=8.6Hz,1H), 1.62(q,J=9.8Hz,1H), 1.44~1.34(m,1H), 1.27~1.19(m,1H), 1.17~1.09(m,1H), 1.09~1.00(m,2H), 0.88~0.79(m,2H), 0. 79~0.71(m,1H), 0.39~0.30(m,1H), 0.30~0.23(m,1H), -0.00~-0.09(m,1H), -0.13~-0.21(m,1H). SFC (Waters UPC 2, ChiralPak IH 4.6×250 mm, 5 μm column, flow rate 4 mL / min, 20% (0.1% ammonia / MeOH) / CO 2 )t R 3.17 min, enantiomeric excess 76%. [Example 131]

[0418] 3-(N-(4-chloro-5-cyano-2-(2-cyclopropylcyclobutoxy)phenyl)sulfamoyl)-4-cyclopropylbenzoic acid stereoisomer D2 [ka] The second eluted fraction from separation 2 in step 2 of Example 130 was subjected to a procedure similar to that in step 3 of Example 120 to give the title compound (61 mg, 124 μmol, 37% yield, 99% purity). 2 , ChiralPak IH 4.6×250 mm, 5 μm column, flow rate 4 mL / min, 20% (0.1% ammonia / MeOH) / CO 2 )t R 3.41 min, enantiomeric excess 98%. Other analytical data were consistent with Example 130. [Example 132]

[0419] 3-(N-(4-chloro-5-cyano-2-(2-cyclopropylcyclobutoxy)phenyl)sulfamoyl)-4-cyclopropylbenzoic acid stereoisomer D3 [ka] The second eluting fraction from Separation 1, Step 2, Example 130 was subjected to a procedure similar to that of Step 3, Example 120, to give the title compound (3.8 mg, 7.3 μmol, 2% yield, 94% purity). UPLC-MS (Method 4): m / z 485.2 (MH) at 1.88 min. - 1H NMR(500MHz,DMSO)δ13.22(brs,1H), 10.19(br s,1H), 8.28(d,J=1.9Hz,1H), 7.96(dd,J=8.2,1.9Hz,1H), 7.72(s,1H), 7.14(d,J=8.3Hz,1H), 7.10( s,1H), 4.77(q,J=7.0Hz,1H), 2.86~2.77(m,1H), 2.21~2.09(m,2H), 1.97~1.88(m,1H), 1.80~1.68(m, 1H), 1.54~1.42(m,1H), 1.16~1.09(m,1H), 1.09~1.01(m,1H), 0.99~0.92(m,1H), 0.83~0.75(m,1H), 0 .37~0.21(m,1H), 0.15~0.01(m,1H), -0.13~-0.22(m,1H), -0.33~-0.43(m,1H), -0.51~-0.61(m,1H). SFC (Waters UPC 2 , ChiralPak IH 4.6×250 mm, 5 μm column, flow rate 4 mL / min, 20% (0.1% ammonia / MeOH) / CO 2 )t R 4.31 min, enantiomeric excess 98%. [Example 133]

[0420] 3-(N-(4-chloro-5-cyano-2-(2-cyclopropylcyclobutoxy)phenyl)sulfamoyl)-4-cyclopropylbenzoic acid stereoisomer D4 [ka] The third eluted fraction from separation 1 in step 2 of Example 130 was subjected to a procedure similar to that in step 3 of Example 120 to give the title compound (3.3 mg, 6.6 μmol, 1% yield, 98% purity). 2 , ChiralPak IH 4.6×250 mm, 5 μm column, flow rate 4 mL / min, 20% (0.1% ammonia / MeOH) / CO 2 )t R5.05 min, enantiomeric excess 90%. Other analytical data were consistent with Example 132. The following examples were prepared in a similar manner to Example 1 or Example 52, substituting the appropriate starting materials and intermediates where necessary.

[0421] The following chiral resolutions were also performed and individual enantiomers or diastereomers carried forward to the final examples in a similar manner to Example 1 or Example 52, substituting the appropriate starting materials and intermediates where necessary.

[0422] Intermediate of Example 85 → Example 103-Example 104 (Alternative Route 2) The intermediate of Example 85, racemic trans ester methyl 3-(N-(4-chloro-5-cyano-2-((2-methoxycyclopentyl)oxy)phenyl)sulfamoyl)-4-cyclopropylbenzoate (105 mg), was purified on a Unichiral CND-5H column (4.6×250 mm) and eluted with 90% n-hexane / 10% ethanol / 0.1% TFA (1 mL / min) at 25° C. with 254 nm UV detection. Appropriate fractions were pooled and reduced in vacuo to give peak 1 (51 mg), RT 13.18 min (99.8%) and peak 2 (45 mg), RT 15.48 min (99.9%). The ester of peak 1 was carried forward to give the trans diastereomer D1 (Example 103) and the ester of peak 2 was carried forward to give the trans diastereomer D2 (Example 104).

[0423] Intermediate of Example 84 → Example 116-Example 117 The racemic trans aniline 5-amino-2-chloro-4-((2-ethynylcyclopentyl)oxy)benzonitrile (150 mg), intermediate of Example 84, was purified on a Unichiral CMD-5H column (4.6×250 mm) and eluted with 90% n-hexane / 10% ethanol (1 mL / min) at 25° C. with 254 nm UV detection. Appropriate fractions were pooled and reduced in vacuo to give peak 1 (55 mg), RT 13.10 min (96.3%) and peak 2 (46 mg), RT 23.69 min (98.7%). The aniline in peak 1 was carried forward to give the trans diastereomer D1 (Example 116) and the aniline in peak 2 was carried forward to give the trans diastereomer D2 (Example 117).

[0424] Example 126-Example 127 The racemic cis acid 3-(N-(4-chloro-5-cyano-2-((2-ethynylcyclopentyl)oxy)phenyl)sulfamoyl)-4-cyclopropylbenzoic acid (131 mg) was purified on a Unichiral CMD-5H column (4.6×250 mm) and eluted with 60% n-hexane / 40% isopropanol / 0.1% TFA (1 mL / min) at 25° C. with 254 nm UV detection. Appropriate fractions were pooled and reduced in vacuo to give peak 1 (Example 126, cis diastereomer D1, 31 mg), RT 6.99 min (100%) and peak 2 (Example 127, cis diastereomer D2, 22 mg), RT 10.79 min (99.3%).

[0425] Example 118 to obtain Example 128 and Example 129 The racemic trans acid of Example 118, 3-(N-(4-chloro-5-cyano-2-(2-hydroxycyclobutoxy)phenyl)sulfamoyl)-4-cyclopropylbenzoic acid (150 mg), was purified on a Unichiral CMD-5H column (4.6×250 mm) and eluted with 70% n-hexane / 30% ethanol (1 mL / min) at 25° C. and 254 nm UV detection. Appropriate fractions were pooled and reduced in vacuo to give peak 1 (Example 128, trans diastereomer D1, 47 mg), RT 8.48 min (97.0%) and peak 2 (Example 129, trans diastereomer D2, 49 mg), RT 10.51 min (99.6%).

[0426] Intermediate of Example 113 → Example 135-Example 136 The racemic cis aniline 5-amino-2-chloro-4-(2-hydroxycyclobutoxy)benzonitrile (213 mg), an intermediate of Example 113, was purified on a Unichiral CMD-5H column (4.6×250 mm) and eluted with 80% n-hexane / 20% ethanol (1 mL / min) at 25° C. with 254 nm UV detection. Appropriate fractions were pooled and reduced in vacuo to give peak 1 (73 mg), RT 12.49 min (99.8%) and peak 2 (82 mg), RT 14.58 min (99.8%). The aniline in peak 1 was carried forward to give the cis diastereomer D1 (Example 135) and the aniline in peak 2 was carried forward to give the cis diastereomer D2 (Example 136).

[0427] Intermediate of Example 119 → Example 138-Example 139 The intermediate of Example 119, racemic trans ester methyl 3-(N-(4-chloro-5-cyano-2-(2-methoxycyclobutoxy)phenyl)sulfamoyl)-4-cyclopropylbenzoate (182 mg), was purified on a Unichiral CNZ-5H column (4.6×250 mm) and eluted with 80% n-hexane / 20% ethanol / 0.1% TFA (1 mL / min) at 25° C. with 254 nm UV detection. Appropriate fractions were pooled and reduced in vacuo to give peak 1 (72 mg), RT 13.76 min (100%) and peak 2 (67 mg), RT 16.49 min (99.7%). The ester of peak 1 was carried forward to give the trans diastereomer D1 (Example 138) and the ester of peak 2 was carried forward to give the trans diastereomer D2 (Example 139).

[0428] Intermediate of Example 134 → Example 140-Example 141 The intermediate of Example 134, racemic ester methyl 3-(N-(4-chloro-5-cyano-2-((3,3-difluorocyclopentyl)oxy)phenyl)sulfamoyl)-4-cyclopropylbenzoate (150 mg), was purified on a Unichiral CND-5H column (4.6×250 mm) and eluted with 90% n-hexane / 10% ethanol / 0.1% TFA (1 mL / min) at 25° C. with 254 nm UV detection. Appropriate fractions were pooled and reduced in vacuo to give peak 1 (32 mg), RT 19.69 min (>95%) and peak 2 (27 mg), RT 21.70 min (>95%). The ester of peak 1 was carried forward to give enantiomer E1 (Example 140) and the ester of peak 2 was carried forward to give enantiomer E2 (Example 141).

[0429] Intermediate of Example 102 → Example 142-Example 143 The racemic cis aniline 5-amino-2-chloro-4-((2-methoxycyclopentyl)oxy)benzonitrile (187 mg), an intermediate of Example 102, was purified on a Unichiral CMZ-5H column (4.6×250 mm) and eluted with 95% n-hexane / 5% ethanol (1 mL / min) at 25° C. with 254 nm UV detection. Appropriate fractions were pooled and reduced in vacuo to give peak 1 (59 mg), RT 24.14 min (100%) and peak 2 (56 mg), RT 25.64 min (98.8%). The aniline in peak 1 was carried forward to give the cis diastereomer D1 (Example 142) and the aniline in peak 2 was carried forward to give the cis diastereomer D2 (Example 143).

[0430] Intermediate of Example 137 → Example 144-Example 145 Intermediate for Example 137 Racemic cis aniline 5-amino-2-chloro-4-((2-methoxycyclobutyl)oxy)benzonitrile (250 mg) was purified on a Unichiral CMZ-5H column (4.6 x 250 mm) and eluted with 90% n-hexane / 10% ethanol (1 mL / min) at 25°C with 254 nm UV detection. Appropriate fractions were pooled and reduced in vacuo to give peak 1 (110 mg), RT 16.56 min (98.8%) and peak 2 (86 mg), RT 17.85 min (97.8%). The aniline in peak 1 was carried forward to give the cis diastereomer D1 (Example 144) and the aniline in peak 2 was carried forward to give the cis diastereomer D2 (Example 145). [Table 12] JPEG2024530447000129.jpg174125JPEG2024530447000130.jpg156121JPEG2024530447000131.jpg155121JPEG2024530447000132.jpg187121JPEG2024530447000133.jpg174124JPEG2024530447000134.jpg140119[Example 109]

[0431] 3-(N-(4-chloro-5-cyano-2-(((1R,2R)-2-methoxycyclopentyl)oxy)phenyl)sulfamoyl)-4-cyclopropylbenzoic acid [ka] Step 2: 2-Chloro-4-(((1R,2R)-2-methoxycyclopentyl)oxy)-5-nitrobenzonitrile: 2-Chloro-4-(((1R,2R)-2-hydroxycyclopentyl)oxy)-5-nitrobenzonitrile (0.141 g, 0.5 mmol), MeI (0.141 g, 1.0 mmol) and Ag 2 A mixture of 2H2O (0.23 g, 1.0 mmol) in MeCN (5 mL) was heated at 80 °C for 12 h. The reaction mixture was filtered through Celite. The filtrate was concentrated and purified by silica gel chromatography (eluted with 1 / 10 EtOAc / PE) to give the title compound (0.091 g, 0.31 mmol, 62% yield) as a yellow oil. 1H NMR (400 MHz, chloroform-d) δ 8.17 (d, J = 1.4 Hz, 1H), 7.40 (d, J = 1.4 Hz, 1H), 4.78-4.68 (m, 1H), 3.36 (d, J = 1.4 Hz, 3H), 2.22-2.13 (m, 1H), 2.11-2.00 (m, 3H), 1.87-1.72 (m, 4H).

[0432] The experimental process of step 1 is the same as in Example 52. The experimental process of steps 3, 4 and 5 is the same as in Example 1.

[0433] The following examples were prepared in a similar manner to Example 109, substituting the appropriate starting materials and intermediates where necessary. [Table 13] JPEG2024530447000137.jpg161118JPEG2024530447000138.jpg155117JPEG2024530447000139.jpg142121

[0434] Biological Survey The following assays can be used to illustrate the commercial utility of the compounds according to the invention.

[0435] Biological assay 1: ERAP1-mediated hydrolysis of amide substrates measured in a biochemical system Materials and solutions 1x Assay Buffer (AB): 25 mM Bis-Tris propane, 0.05% w / v hydroxypropyl methylcellulose made in Optima grade water, pH 7.75 Decapeptide WRVYEKC(Dnp)ALK-acid (Dnp is dinitrophenylmaleimide) (10-mer) L-Leucine 7-amido-4-methylcoumarin (L-AMC) Purified ERAP1(37-941)-10His(ERAP1)

[0436] Assay procedure: 12.5 μL of ERAP1 enzyme in 1×AB was combined with test compound in 250 nL of DMSO. 12.5 μL of either 240 μM L-AMC in 1×AB or 100 μM 10-mer in 1×AB was added to the reaction and incubated at 23° C. for 1 h. For detection, the plate was read at 365 nm excitation and 442 nm emission (L-AMC) or 279 nm excitation and 355 nm emission (10-mer). Compound IC was calculated using a four-parameter equation. 50 The results for selected compounds according to the invention are shown in Table 1.

[0437] OVA antigen presentation assay As previously described [Reeves et al, (2014) Proc. Natl. Acad. Sci. USA 111; 17594-17599], the cellular effect of a representative compound according to the present invention on antigen presentation can be measured by assessing its effect on the presentation of an ovalbumin-specific peptide (SIINFEKL) to T cells. Briefly, SiHa cells are transiently transfected with a plasmid encoding mouse H2Kb and an ER-targeting N-terminally extended precursor peptide derived from ovalbumin (MRYMILGLLALAAVCSAAIVMKSIINFEHL) using Lipofectamine 3000. Cells are harvested 6 h after transfection, and transfected SiHa cells are incubated with ERAP1 inhibitor IC 50 Compounds are seeded over a 12-point concentration-response curve to quantify the activity of the compound. SiHa cells are cultured in the presence of compounds for 48 h. B3Z cells [Karttunen et al, (1992) Proc. Natl. Acad. Sci. USA 89;6020-6024] are then added to the cell culture for 4 h; the B3Z T cell hybridoma encodes a TCR that specifically recognizes the SIINFEHL / H2Kb complex at the cell surface, which after activation triggers a signaling cascade leading to the transcription of the LacZ gene under the control of the IL-2 promoter. Intracellular β-galactosidase activity, as a readout of T cell activation, is measured by quantifying the conversion of chlorophenored-β-D-galacto-pyranoside (CPRG) to chlorophenol red by measuring the absorbance at 570 nm.

[0438] Immunopeptidemics An unbiased proteomics pipeline such as that described by Purcell et al. [Purcell et al, (2019) Nat Protoc. 14; 1687-1707] can be used to determine the effect of representative compounds according to the invention on global antigen processing. Briefly, 500 million SiHa cells are treated with compounds for 24 h or with siRNA for 72 h, then harvested, lysed, and MHC-binding peptides are isolated by immunoaffinity capture. Peptides are eluted using 10% (v / v) acetic acid by HPLC and separated from MHC-1 and β2-microglobulin proteins prior to analysis by LC-MS / MS.

[0439] Various modifications and variations of the described aspects of the invention will be apparent to those skilled in the art without departing from the scope and spirit of the invention. Although the invention has been described in connection with certain preferred embodiments, it should be understood that the invention as claimed should not be unduly limited to such specific embodiments. Indeed, various modifications of the described modes of carrying out the invention which will be apparent to those skilled in the relevant arts are intended to be included within the scope of the following claims.

[0440] [Table 14] JPEG2024530447000141.jpg14135

[0441] References 1.Serwold et al, (2002), ERAAP customizes peptides for MHC class I molecules in the endoplasmic reticulum; Nature: 419, p480. 2.Snyder et al, (2014), Genetic Basis for Clinical Response to CTLA-4 Blockade in Melanoma; NEJM: 371, p2189. 3.Van Allen et al, (2015), Genomic correlates of response to CTLA-4 blockade in metastatic melanoma; Science: 348, p124. 4.James et al, (2013), Induction of Protective Antitumor Immunity through Attenuation of ERAAP Function; J Immunol: 190, p5839. 5.Niranjana et al, (2016), ERAAP Shapes the Peptidome Associated with Classical and Nonclassical MHC Class I Molecules; J Immunol: 197, p1035. 6.Pepelyayeva et al, (2018), ERAP1 deficient mice have reduced Type 1 regulatory T cells and develop skeletal and intestinal features of Ankylosing Spondylitis; Sci.Reports: 8: p12464. 7.Cifaldi et al, (2015), ERAP1 Regulates Natural Killer Cell Function by Controlling the Engagement of Inhibitory Receptors, Cancer Res.: 75, p824. 8.Steinbach et al, (2017), ERAP1 overexpression in HPV-induced malignancies: A possible novel immune evasion mechanism, Oncoimmunol: 6, e1336594. 9.Kim et al, (2011), Human cytomegalovirus microRNA miR-US4-1 inhibits CD8+ T cell responses by targeting the aminopeptidase ERAP1, Nat. Immunol.: 12, p984. 10.Tenzer et al, (2009), Antigen processing influences HIV-specific cytotoxic T lymphocyte immunodominance, Nat. Immunol.: 10, p636. 11.Reeves et al, (2018), The role of polymorphic ERAP1 in autoinflammatory disease, Biosci. Rep.: 29, p38. 12.Chen et al, (2014), Silencing or inhibition of endoplasmic reticulum aminopeptidase 1 (ERAP1) suppresses free heavy chain expression and Th17 responses in ankylosing spondylitis, Ann Rheum Dis: 75, p916. 13.Sheehan, NJ (January 2004). “The ramifications of HLA-B27”. Journal of the Royal Society of Medicine. 97 (1): 10-4. 14.Smith, JA (January 2015). “Update on ankylosing spondylitis: current concepts in pathogenesis”. Current allergy and asthma reports. 15 (1): 489. 15.Kuiper JJW, Mutis T, de Jager W, de Groot-Mijnes JD, Rothova A (2011). “Intraocular interleukin-17 and proinflammatory cytokines in HLA-A29-associated birdshot chorioretinopathy”.Am J Ophthalmol. 152(2):177–182 16.Kuiper JJW, Emmelot ME, Rothova A, Mutis T (2013). “Interleukin-17 production and T helper 17 cells in peripheral blood mononuclear cells in response to ocular lysate in patients with birdshot chorioretinopathy”. Mol Screw. 19: 2606–14 17.Kuiper JJW, van Setten J, Ripke S, Van't Slot R, Mulder F, Missotten T, Baarsma GS, Francioli LC, Pulit SL, de Kovel CG, Ten Dam-van Loon N, den Hollander AI, Huis In Het Veld P, Hoyng CB, Cordero-Coma J, M, V, V, Lya Bren, Thomas, Thomas Bakker SC, Ophoff RA, Rothova A, de Bakker PI, Mutis T, Koeleman BP (2014). “A genome-wide association study identifies a functional ERAP2 haplotype associated with birdshot chorioretinopathy”.Hum Mol Genet. 23 (22): 6081-6087 18.Evans et al (2011), Interaction between ERAP1 and HLA-B27 in ankylosing spondylitis implicates peptide handling in the mechanism for HLA-B27 in disease susceptibility. Nat Genet. 10;43(8):761-7 19.Conde-Jaldon et al (2014), Epistatic interaction of ERAP1 and HLA-B in Behcet disease: a replication study in the Spanish population. PLoS One. 14;9(7) 20.Kuiper et al (2018), Functionally distinct ERAP1 and ERAP2 are a hallmark of HLA-A29-(Birdshot) Uveitis. Hum Mol Genet. doi: 10.1093 / hmg / ddy319 21.Strange et al (2010), A genome-wide association study identifies new psoriasis susceptibility loci and an interaction between HLA-C and ERAP1. Nat Genet.;42(11):985-90.

Claims

1. Formula (I) 【Chemical 1】 (wherein The X-Y group is -NHSO ２ -; Z is a monocyclic or polycyclic cycloalkyl group or a monocyclic or polycyclic heterocycloalkyl group, each of which may be substituted with one or more groups selected from haloalkyl, alkyl, alkenyl, alkynyl and -(CR １６ R １７ ) ｍ R １８ and m is from 0 to 6; L is a direct bond or (CR １４ R １５ ), ｎ a radical, and n is 1 or 2; R １ is selected from H, Cl, F, CN, and alkyl; R ２ is selected from COOH and tetrazolyl groups; R ３ is selected from H, halo, alkoxy and alkyl; R ４ is selected from H and halo; R ５ is selected from H, alkyl, haloalkyl, SO ２ -alkyl, Cl, alkoxy, OH, CN, hydroxyalkyl, alkylthio, heteroaryl, cycloalkyl, heterocycloalkyl and haloalkoxy; R ６ is H; R ７ is selected from H, CN, haloalkyl, halo, SO ２ -alkyl, SO ２ NR １２ R １３ , heteroaryl, CONR １０ R １１ and alkyl, and the heteroaryl group may be substituted with one or more substituents selected from alkyl, halo, alkoxy, CN, haloalkyl and OH; R ８ is selected from H, alkyl, haloalkyl and halo; R ９ is selected from H, alkyl, and halo; R １０ 、 R １１ 、 R １２ and R １３ are each independently selected from H and alkyl; R １４ and R １５ are each independently selected from H, halo, and alkyl; R １６ and R １７ are each independently selected from H, halo, haloalkyl and alkyl; Each R １８ is independently selected from OH, CN, alkoxy and halo) a compound of, or a pharmaceutically acceptable salt or hydrate thereof.

2. The compound according to claim 1, wherein L is a direct bond.

3. L is (CH ２ ) ｎ and n is 1 or 2, the compound according to claim 1.

4. L is CH ２ or CH(Me), more preferably CH ２ The compound according to claim 1, wherein it is such.

5. The compound according to claim 1, wherein Z is a 3- to 7-membered monocyclic cycloalkyl or 3- to 7-membered monocyclic heterocycloalkyl group, each of which may be substituted.

6. The compound according to claim 1, wherein Z is a 4-membered monocyclic cycloalkyl or 4-membered monocyclic heterocycloalkyl group, each of which may be substituted.

7. The compound according to claim 1, wherein Z is an optionally substituted 4-membered monocyclic cycloalkyl group.

8. Z is [[Chemical 2]] selected from, and each Q is independently selected from alkyl, alkoxy, haloalkyl, alkynyl, halo, OH and CN. The compound according to claim 7.

9. The compound according to claim 1, wherein Z is an optionally substituted 4-membered monocyclic heterocycloalkyl group.

10. The compound according to claim 1, wherein Z is a 5-membered monocyclic cycloalkyl or 5-membered monocyclic heterocycloalkyl group, each of which may be substituted.

11. The compound according to claim 10, wherein Z is an optionally substituted 5-membered monocyclic cycloalkyl group.

12. Z is 【Chemical Formula 3】 selected from, and each Q is independently selected from alkyl, alkoxy, haloalkyl, alkynyl, halo, OH and CN. The compound according to claim 11.

13. The compound according to claim 10, wherein Z is an optionally substituted 5-membered monocyclic heterocycloalkyl group.

14. The compound according to claim 1, wherein Z is an optionally substituted polycyclic cycloalkyl group or an optionally substituted polycyclic heterocycloalkyl group, and the polycyclic group is fused, unfused, bridged, or spirocyclized.

15. The compound according to claim 14, wherein Z is a bicyclic cycloalkyl or bicyclic heterocycloalkyl group, each of which is fused, unfused, bridged, or spirocyclized, and each of which may be substituted.

16. Z is [Chemical Formula 4] selected from. The compound according to claim 14.

17. Z is 【Chemical Formula 5】 【Chem.】 【Chem.】 【Chem.】 【Chem.】 【Chem.】 【Chem.】 【Chem.】 selected from. The compound according to claim 1.

18. The compound according to claim 17, wherein L is a direct bond.

19. L-Z is 【Chemical Formula 6】 【Chem.】 The compound according to claim 1, selected from.

20. R ２ The compound according to claim 1, wherein R is COOH.

21. R ４ The compound according to claim 1, wherein R is selected from H and F.

22. R ５ is selected from alkyl, haloalkyl, SO ２ -alkyl, Cl, alkoxy, OH, CN, hydroxyalkyl, alkylthio, heteroaryl, cycloalkyl, heterocycloalkyl and haloalkoxy, more preferably selected from alkyl, alkoxy and cycloalkyl, the compound according to claim 1.

23. R ５ The compound according to claim 1, wherein R is selected from OMe, OEt, Me, Et and cyclopropyl, more preferably selected from OMe, Et and cyclopropyl, and even more preferably cyclopropyl.

24. R ５ The compound according to claim 1, wherein R is cyclopropyl.

25. R ７ is selected from H, CN, haloalkyl, Cl, F, SO ２ -alkyl, CONR １０ R １１ , heteroaryl and alkyl, wherein the heteroaryl group is selected from pyrazol-3-yl, pyrazol-4-yl, pyrazol-5-yl, isothiazol-3-yl, isothiazol-4-yl, isothiazol-5-yl, 1,2,4-triazol-5-yl, tetrazol-1-yl, tetrazol-5-yl, isoxazol-3-yl, isoxazol-4-yl and isoxazol-5-yl, each of which may be substituted with one or more substituents selected from alkyl, halo, alkoxy, CN, haloalkyl and OH, The compound according to claim 1.

26. R ７ The compound according to claim 1, wherein R is selected from CN, tetrazol-1-yl, isothiazol-5-yl and isoxazol-4-yl, each of which may be substituted with one or more substituents selected from alkyl, halo, alkoxy, CN, haloalkyl and OH.

27. R ７ is CN, CF ３ , tetrazol-1-yl, isothiazol-5-yl and 5-methyl-isoxazol-4-yl, the compound according to claim 26, selected from.

28. R ７ The compound according to claim 1, wherein R is CN.

29. R ８ The compound according to claim 1, wherein R is selected from H and halo, more preferably H, Cl and F.

30. R ８ The compound according to claim 1, wherein R is Cl.

31. R ９ The compound according to claim 1, wherein R is H, Me, F or Cl, more preferably H.

32. R １ The compound according to claim 1, wherein R is H.

33. R １ 、R ３ 、R ４ 、and R ９ are all H, the compound according to claim 1.

34. X - Y is NH - SO ２ and; R １ is H; R ２ is COOH; R ３ is H or F; R ４ is H or F; R ５ is selected from OMe, OEt, Me, Et and cyclopropyl, more preferably selected from OMe, cyclopropyl and Et; R ６ is H; R ７ is selected from CN, tetrazol-1-yl, isothiazol-5-yl and 5-methyl-isoxazol-4-yl; R ８ is selected from H, Cl and F, R ９ is selected from H, Me, Cl, and F; The compound according to claim 1, wherein L and Z are as defined in any one of claims 1 to 19. The compound according to claim 1.

35. Formula (Ia) [Chemical Formula 7] (wherein L and Z are as defined in claim 1) The compound according to claim 1, which is.

36. The following: 【Chemical 8】 【Chem.】 【Chem.】 [Chemical] 【Chem.】 【Chem.】 【Chem.】 【Chem.】 [Chemical] 【Chem.】 【Chem.】 【Chem.】 【Chem.】 【Chem.】 [Chemical] 【Chem.】 The compound according to claim 1, selected from, and pharmaceutically acceptable salts and hydrates thereof.

37. A pharmaceutical composition comprising a compound of formula (I) as defined in any one of claims 1 to 36, mixed with a pharmaceutically acceptable excipient, diluent or carrier, said pharmaceutical composition optionally mixed with one or more additional active agents.

38. A compound of formula (I) as defined in any one of claims 1 to 36 for use in pharmaceuticals.

39. A compound of formula (I) as defined in any one of claims 1 to 36 for use in the treatment or prevention of a disorder selected from proliferative disorders, immune disorders, viral disorders and inflammatory disorders.

40. A compound for use according to claim 39, which modulates ERAP1.

41. A compound for use according to claim 39, wherein the disorder is a proliferative disorder, preferably cancer or leukemia.

42. A compound for use according to claim 39, which kills cancer cells, reduces the number of proliferating cells in cancer, reduces the volume or size of a tumor containing cancer cells, and / or reduces the number of metastatic cancer cells.

43. A compound for use according to claim 39, which is used to prevent cancer, preferably inducing a neoantigen in a subject having an existing immune response.

44. The compound is used in a subject having cancer or prone to developing cancer, said compound stimulates a neoantigen-directed immune response in said subject, and then a second compound (which may be the same as or different from the first compound) is used to stimulate the same neoantigen as the first compound, thereby directing the immune response of said subject against said cancer.

45. A compound for use according to claim 39, wherein the subject has had cancer previously, has a family history of cancer, has a high risk of developing cancer, has a genetic predisposition to developing cancer, has been exposed to carcinogens, and / or is in remission from cancer.

46. An in vitro or in vivo method for producing antigen-presenting cells that present neoantigens, the method comprising the step of inducing neoantigens in the antigen-presenting cells with a compound of formula (I) as defined in any one of claims 1 to 36, preferably, the antigen-presenting cells are dendritic cells.

47. An immunogenic composition comprising antigen-presenting cells obtainable by or obtainable from the method according to claim 46.

48. The immunogenic composition according to claim 47 for use in the treatment or prevention of cancer in a subject, preferably a vaccine.

49. A compound for use according to claim 39, wherein the compound is used in combination with immunotherapy, preferably the subject has cancer, and the compound increases the sensitivity of cancer cells to immunotherapy.

50. The compound for use according to claim 49, wherein the immunotherapy is an immune checkpoint intervention, preferably an antibody checkpoint inhibitor.

51. The compound for use according to claim 50, wherein the antibody checkpoint inhibitor is an anti-PD-1 antibody, an anti-PD-L1 antibody or an anti-CTLA4 antibody.

52. The compound for use according to claim 39, wherein the disorder is an immune disorder, preferably selected from ankylosing spondylitis, Behçet's disease, psoriasis and guttate choroiditis.

53. The compound for use according to claim 39, wherein the disorder is an inflammatory disorder, more preferably an autoinflammatory disorder.

54. The compound for use according to claim 39, wherein the viral disorder is an infectious viral disease selected from HIV, HPV, CMV and HCV.

55. The compound for use according to claim 39, wherein the disorder is cancer, and the compound increases the visibility of cancer cells to the immune system by modifying the repertoire of antigens and neoantigens presented to the immune system.

56. The compound for use according to claim 55, which increases the CD8+ T cell response against cancer cells.

57. A combination comprising a compound according to any one of claims 1 to 36 and a further active agent.

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