Compounds capable of modulating endoplasmic reticulum aminopeptidase 1

Abstract

The present invention relates to a compound, in particular to a compound of formula (Ia), or a pharmaceutically acceptable salt or hydrate thereof, # imgabs0 #. Other aspects of the invention relate to the use of such compounds in the field of immunooncology and related applications.

Description

[0001] This patent application is a divisional application of the patent application with application number 201980076956.0, application date November 22, 2019, and invention name “Compound”. Technical Field

[0002] The present invention relates to compounds capable of modulating ERAP1. The compounds have potential therapeutic applications in the treatment of a variety of disorders including proliferative disorders, viral disorders, immune disorders and inflammatory disorders. Background Art

[0003] ERAP1 (endoplasmic reticulum aminopeptidase 1; also known as APPILS or ARTS1) is an aminopeptidase that is important in the generation of partial antigens and neoantigens as part of the antigen presentation pathway. 1 The antigen presentation pathway begins when proteins are broken down into peptides by the proteasome. These peptides are transported to the endoplasmic reticulum where a subset of them are processed by ERAP1 and then bound to the major histocompatibility complex class I (MHC class I). 1 Antigens bound to MHC class I are then transported to the cell surface and presented to CD8 + T cells and are recognized as self or non-self. Neoantigens are antigens that are specific to cancer and can be recognized as foreign by the immune system, leading to the destruction of cancer cells. Neoantigens are produced as a direct result of somatic mutations in the cancer cell DNA, resulting in mutant proteins, or indirectly through somatic mutations in protein processing and expression. Those cancers with higher mutation rates and correspondingly higher levels of neoantigens have much higher response rates to checkpoint inhibitor immunotherapy anti-PD-1 antibodies (e.g., pembrolizumab, nivolumab), anti-PD-L1 antibodies (e.g., atezolizumab, avelumab, durvalumab), and anti-CTLA4 antibodies (e.g., ipilimumab, tremelimumab) than cancers with lower numbers of neoantigens. 2,3 .

[0004] The role of ERAP1 in the antigen presentation pathway is to cleave a portion of the peptide through its aminopeptidase activity to generate antigens and neoantigens of optimal length for binding to MHC class I. ERAP1 can also over-cleave some neoantigens, thereby preventing these neoantigens from binding to MHC class I and being presented on the cell surface. 4 Ablation of ERAP1 activity has been shown to alter the antigenic repertoire of antigens and neoantigens, leading to increased presentation of certain antigens / neoantigens as well as completely new antigens / neoantigens. 5 Furthermore, ERAP1 ablation induces CD8 + T cell-dependent tumor rejection4 Therefore, modulators of ERAP1 activity may be useful for cancer treatment, either alone or in combination with current cancer immunotherapeutics, including checkpoint inhibitors, because modulators of ERAP1 activity alter the antigens and neoantigens presented on the surface of cancer cells and make these antigens and neoantigens more visible to the immune system, thereby leading to tumor attack and destruction.

[0005] It has also been shown that knockdown of ERAP1 can reduce the levels of regulatory-like T cells and enhance the killing of cancer cells by natural killer cells 6,7 This suggests that regulators of ERAP1 activity may enable effective cancer therapy by modulating cancer cell visibility and generating stronger anti-tumor immune responses. The role of ERAP1 in peptide processing during antigen presentation may also have applications in infectious viral diseases.

[0006] The present invention seeks to provide compounds that are capable of modulating ERAP1. Such compounds have potential therapeutic applications in the treatment of a variety of disorders including proliferative disorders, immune disorders and inflammatory disorders. Summary of the invention

[0007] The first aspect of the present invention relates to a compound of formula (Ia), or a pharmaceutically acceptable salt or hydrate thereof,

[0008]

[0009] in:

[0010] The group XY is -NHSO 2 -or-SO 2 NH-;

[0011] R 1 is H or alkyl;

[0012] R 2 is selected from COOH and tetrazolyl;

[0013] R 3 is selected from H, Cl and alkyl;

[0014] R 4 is selected from H, Cl and F;

[0015] R 5 Selected from H, alkyl, haloalkyl, SO 2 - alkyl, Cl, alkoxy, OH, CN, alkynyl, alkenyl, hydroxyalkyl, alkylthio, heteroaryl, cycloalkyl, heterocycloalkyl, and haloalkoxy;

[0016] R 6 is H;

[0017] R 7Selected from H, CN, haloalkyl, Cl, F, SO 2 -alkyl, SO 2 NR 13 R 14 , heteroaryl and alkyl, wherein the heteroaryl is optionally substituted with one or more substituents selected from alkyl, halogen, alkoxy, CN, haloalkyl and OH;

[0018] R 8 is selected from H, alkyl, haloalkyl and halogen;

[0019] R 9 H, C 1 -C 3 Alkyl or halogen;

[0020] R 10 and R 11 Together with the nitrogen to which they are attached, they form an azepanyl group, wherein (a) the azepanyl group is substituted with one or more groups selected from alkyl, CN, cycloalkyl, OH, alkoxy, halogen, haloalkyl and heteroaryl, wherein the heteroaryl group is further optionally substituted with one or more groups selected from halogen and alkyl, or (b) one or two carbons in the azepanyl group are replaced with a group selected from O, NH, S and CO, and the azepanyl group is optionally substituted with one or more groups selected from alkyl, CN, cycloalkyl, OH, alkoxy, halogen, haloalkyl and heteroaryl, wherein the heteroaryl group is further optionally substituted with one or more groups selected from halogen and alkyl; or

[0021] R 10 and R 11 Together with the nitrogen to which they are attached, they form an azetidinyl, pyrrolidinyl or piperidinyl group, wherein (a) the azetidinyl, pyrrolidinyl or piperidinyl group is substituted with one or more groups selected from alkyl, CN, cycloalkyl, OH, alkoxy, halogen, haloalkyl and heteroaryl, wherein the heteroaryl group is further optionally substituted with one or more groups selected from halogen and alkyl, or (b) one or two carbons of the azetidinyl, pyrrolidinyl or piperidinyl group are replaced with a group selected from NH, S and CO; or

[0022] R 10 and R 11 Together with the nitrogen to which they are attached, they form an 8-, 9- or 10-membered bicyclic heterocycloalkyl, wherein one or two carbons of the bicyclic heterocycloalkyl ring are optionally replaced by a group selected from O, NH, S and CO, and the bicyclic heterocycloalkyl is optionally substituted by one or more groups selected from alkyl, CN, cycloalkyl, OH, alkoxy, halogen, haloalkyl and heteroaryl; or

[0023] R10 and R 11 Together with the nitrogen to which they are attached, they form a 6- to 12-membered bicyclic group containing a spirocyclic carbon atom, wherein one or two carbons in the bicyclic group are optionally replaced by a group selected from O, NH, S and CO, and the bicyclic group is optionally substituted by one or more groups selected from alkyl, CN, cycloalkyl, OH, alkoxy, halogen, haloalkyl and heteroaryl, or the bicyclic group is optionally fused with a 5- or 6-membered aryl or heteroaryl; and

[0024] R 13 and R 14 Each is independently H or alkyl.

[0025] The second aspect of the present invention relates to a compound of formula (Ib), or a pharmaceutically acceptable salt or hydrate thereof,

[0026]

[0027] in:

[0028] The group XY is -NHSO 2 -or-SO 2 NH-;

[0029] R 1 is H or alkyl;

[0030] R 2 is a tetrazolyl group;

[0031] R 3 is selected from H, Cl and alkyl;

[0032] R 4 is selected from H, Cl and F;

[0033] R 5 Selected from H, alkyl, alkynyl, alkenyl, haloalkyl, SO 2 -alkyl, Cl, alkoxy, OH, CN, hydroxyalkyl, alkylthio, heteroaryl, cycloalkyl, heterocycloalkyl, and haloalkoxy;

[0034] R 6 is H;

[0035] R 7 Selected from H, CN, haloalkyl, Cl, F, SO 2 -alkyl, SO 2 NR 13 R 14 , heteroaryl and alkyl, wherein the heteroaryl is optionally substituted with one or more substituents selected from alkyl, halogen, alkoxy, CN, haloalkyl and OH;

[0036] R8 is selected from H, alkyl, haloalkyl and halogen;

[0037] R 9 H, C 1 To C 3 Alkyl or halogen;

[0038] R 10 is H or alkyl;

[0039] R 11 is optionally one or more selected from NH 2 , OH and NHCO 2 R 12 The substituents in the alkyl group substituted, wherein R 12 is an alkyl group; or

[0040] R 10 and R 11 Together with the nitrogen to which they are attached, they form a 4-, 5-, 6- or 7-membered monocyclic heterocycloalkyl, wherein one or two carbons in the monocyclic heterocycloalkyl are optionally replaced by a group selected from O, NH, S and CO, and the monocyclic heterocycloalkyl is optionally substituted by one or more groups selected from alkyl, CN, cycloalkyl, OH, alkoxy, halogen, haloalkyl and heteroaryl, wherein the heteroaryl is further optionally substituted by one or more groups selected from halogen and alkyl; or

[0041] R 10 and R 11 Together with the nitrogen to which they are attached, they form an 8-, 9- or 10-membered bicyclic heterocycloalkyl, wherein one or two carbons of the bicyclic heterocycloalkyl ring are optionally replaced by a group selected from O, NH, S and CO, and the bicyclic heterocycloalkyl is optionally substituted by one or more groups selected from alkyl, CN, cycloalkyl, OH, alkoxy, halogen, haloalkyl and heteroaryl; or

[0042] R 10 and R 11 Together with the nitrogen to which they are attached, they form a 6- to 12-membered bicyclic group containing a spirocyclic carbon atom, wherein one or two carbons in the bicyclic group are optionally replaced by a group selected from O, NH, S and CO, and the bicyclic group is optionally substituted by one or more groups selected from alkyl, CN, cycloalkyl, OH, alkoxy, halogen, haloalkyl and heteroaryl, or the bicyclic group is optionally fused with a 5- or 6-membered aryl or heteroaryl; and

[0043] R 13 and R 14 Each is independently H or alkyl.

[0044] The third aspect of the present invention relates to a compound of formula (Ic), or a pharmaceutically acceptable salt or hydrate thereof,

[0045]

[0046] in:

[0047] X is SO 2 ;

[0048] Y is NH;

[0049] R 1 is H or alkyl;

[0050] R 2 is selected from COOH and tetrazolyl;

[0051] R 3 is selected from H, Cl and alkyl;

[0052] R 4 is selected from H, Cl and F;

[0053] R 5 Selected from H, alkyl, alkynyl, alkenyl, haloalkyl, SO 2 -alkyl, Cl, alkoxy, OH, CN, hydroxyalkyl, alkylthio, heteroaryl, cycloalkyl, heterocycloalkyl, and haloalkoxy;

[0054] R 6 is H;

[0055] R 7 Selected from H, CN, haloalkyl, Cl, F, SO 2 -alkyl, SO 2 NR 13 R 14 , heteroaryl and alkyl, wherein the heteroaryl is optionally substituted with one or more substituents selected from alkyl, halogen, alkoxy, CN, haloalkyl and OH;

[0056] R 8 is selected from H, alkyl, haloalkyl and halogen;

[0057] R 9 H, C 1 To C 3 Alkyl or halogen;

[0058] R 10 is H or alkyl;

[0059] R 11 is optionally one or more selected from NH 2 , OH and NHCO 2 R 12The substituents in the alkyl group substituted, wherein R 12 is an alkyl group; or

[0060] R 10 and R 11 Together with the nitrogen to which they are attached, they form a 4-, 5-, 6- or 7-membered monocyclic heterocycloalkyl, wherein one or two carbons in the monocyclic heterocycloalkyl are optionally replaced by a group selected from O, NH, S and CO, and the monocyclic heterocycloalkyl is optionally substituted by one or more groups selected from alkyl, CN, cycloalkyl, OH, alkoxy, halogen, haloalkyl and heteroaryl, wherein the heteroaryl is further optionally substituted by one or more groups selected from halogen and alkyl; or

[0061] R 10 and R 11 Together with the nitrogen to which they are attached, they form an 8-, 9- or 10-membered bicyclic heterocycloalkyl, wherein one or two carbons of the bicyclic heterocycloalkyl ring are optionally replaced by a group selected from O, NH, S and CO, and the bicyclic heterocycloalkyl is optionally substituted by one or more groups selected from alkyl, CN, cycloalkyl, OH, alkoxy, halogen, haloalkyl and heteroaryl; or

[0062] R 10 and R 11 Together with the nitrogen to which they are attached, they form a 6- to 12-membered bicyclic group containing a spirocyclic carbon atom, wherein one or two carbons in the bicyclic group are optionally replaced by a group selected from O, NH, S and CO, and the bicyclic group is optionally substituted by one or more groups selected from alkyl, CN, cycloalkyl, OH, alkoxy, halogen, haloalkyl and heteroaryl, or the bicyclic group is optionally fused with a 5- or 6-membered aryl or heteroaryl; and

[0063] R 13 and R 14 Each is independently H or alkyl.

[0064] The fourth aspect of the present invention relates to a compound of formula (Id), or a pharmaceutically acceptable salt or hydrate thereof,

[0065]

[0066] in:

[0067] The group XY is -NHSO 2 -or-SO 2 NH-;

[0068] R 1 is H or alkyl;

[0069] R 2 is selected from COOH and tetrazolyl;

[0070] R 3 is selected from H, Cl and alkyl;

[0071] R 4 is selected from H, Cl and F;

[0072] R 5 Selected from H, alkyl, alkynyl, alkenyl, haloalkyl, SO 2 -alkyl, Cl, alkoxy, OH, CN, hydroxyalkyl, alkylthio, heteroaryl, cycloalkyl, heterocycloalkyl, and haloalkoxy;

[0073] R 6 is H;

[0074] R 7 For CN, SO 2 -alkyl, SO 2 NR 13 R 14 or heteroaryl, wherein the heteroaryl is optionally substituted with one or more substituents selected from alkyl, halogen, alkoxy, CN, haloalkyl and OH;

[0075] R 8 is selected from H, alkyl, haloalkyl and halogen;

[0076] R 9 H, C 1 To C 3 Alkyl or halogen;

[0077] R 10 is H or alkyl;

[0078] R 11 is optionally one or more selected from NH 2 , OH and NHCO 2 R 12 The substituents in the alkyl group substituted, wherein R 12 is an alkyl group; or

[0079] R 10 and R 11 Together with the nitrogen to which they are attached, they form a 4-, 5-, 6- or 7-membered monocyclic heterocycloalkyl, wherein one or two carbons in the monocyclic heterocycloalkyl are optionally replaced by a group selected from O, NH, S and CO, and the monocyclic heterocycloalkyl is optionally substituted by one or more groups selected from alkyl, CN, cycloalkyl, OH, alkoxy, halogen, haloalkyl and heteroaryl, wherein the heteroaryl is further optionally substituted by one or more groups selected from halogen and alkyl; or

[0080] R 10 and R 11Together with the nitrogen to which they are attached, they form an 8-, 9- or 10-membered bicyclic heterocycloalkyl, wherein one or two carbons of the bicyclic heterocycloalkyl ring are optionally replaced by a group selected from O, NH, S and CO, and the bicyclic heterocycloalkyl is optionally substituted by one or more groups selected from alkyl, CN, cycloalkyl, OH, alkoxy, halogen, haloalkyl and heteroaryl; or

[0081] R 10 and R 11 Together with the nitrogen to which they are attached, they form a 6- to 12-membered bicyclic group containing a spirocyclic carbon atom, wherein one or two carbons in the bicyclic group are optionally replaced by a group selected from O, NH, S and CO, and the bicyclic group is optionally substituted by one or more groups selected from alkyl, CN, cycloalkyl, OH, alkoxy, halogen, haloalkyl and heteroaryl, or the bicyclic group is optionally fused with a 5- or 6-membered aryl or heteroaryl; and

[0082] R 13 and R 14 Each is independently H or alkyl.

[0083] Advantageously, the compounds claimed in the present invention are capable of modulating ERAP1, thereby making the compounds of therapeutic interest in the treatment of various disorders, for example in the fields of oncology and immuno-oncology.

[0084] A fifth aspect of the present invention relates to a pharmaceutical composition comprising at least one compound as described above and a pharmaceutically acceptable carrier, diluent or excipient.

[0085] A sixth aspect of the present invention relates to the use of the compounds as described above in medicine.

[0086] A seventh aspect of the present invention relates to the use of a compound as described above for treating or preventing a disorder selected from the group consisting of a proliferative disorder, an immune disorder, a viral disorder and an inflammatory disorder.

[0087] An eighth aspect of the present 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 the group consisting of a proliferative disorder, an immune disorder, a viral disorder and an inflammatory disorder.

[0088] The ninth aspect of the present invention relates to the use of the compound as described above in preventing or treating a disorder caused by any abnormal ERAP1 activity, a disorder associated with any abnormal ERAP1 activity, or a disorder accompanied by any abnormal ERAP1 activity.

[0089] The tenth aspect of the present invention relates to use of the compound as described above in the preparation of a medicament for preventing or treating a disorder caused by abnormal ERAP1 activity, a disorder associated with abnormal ERAP1 activity, or a disorder accompanied by abnormal ERAP1 activity.

[0090] An eleventh aspect of the present invention relates to a method for treating a mammal suffering from a disease symptom alleviated by regulating ERAP1, wherein the method comprises administering to the mammal a therapeutically effective amount of a compound as described above.

[0091] The twelfth aspect of the present invention relates to the use of the compound as described above in treating or preventing the symptoms of a disease alleviated by regulating ERAP1.

[0092] The thirteenth aspect of the present invention relates to the use of the compound as described above in the preparation of a medicament for treating or preventing the symptoms of a disease alleviated by regulating ERAP1.

[0093] A fourteenth aspect of the invention relates to a method for treating or preventing a disorder in a subject, the disorder being selected from a proliferative disorder, an immune disorder, a viral disorder and an inflammatory disorder, wherein the method comprises administering to the subject a therapeutically effective amount of a compound as described above.

[0094] A fifteenth aspect of the present invention relates to the use of a compound of formula (I), or a pharmaceutically acceptable salt or hydrate thereof, in treating or preventing a condition in a subject, the condition being selected from a proliferative condition, an immune condition, a viral condition and an inflammatory condition:

[0095]

[0096] in:

[0097] The group XY is -NHSO 2 -or-SO 2 NH-;

[0098] R 1 is H or alkyl;

[0099] R 2 is selected from COOH and tetrazolyl;

[0100] R 3 is selected from H, Cl and alkyl;

[0101] R 4 is selected from H, Cl and F;

[0102] R 5 Selected from H, alkyl, alkynyl, alkenyl, haloalkyl, SO 2-alkyl, Cl, alkoxy, OH, CN, hydroxyalkyl, alkylthio, heteroaryl, cycloalkyl, heterocycloalkyl, and haloalkoxy;

[0103] R 6 is H;

[0104] R 7 Selected from H, CN, haloalkyl, Cl, F, SO 2 -alkyl, SO 2 NR 13 R 14 , heteroaryl and alkyl, wherein the heteroaryl is optionally substituted with one or more substituents selected from alkyl, halogen, alkoxy, CN, haloalkyl and OH;

[0105] R 8 is selected from H, alkyl, haloalkyl and halogen;

[0106] R 9 H, C 1 To C 3 Alkyl or halogen;

[0107] R 10 is H or alkyl;

[0108] R 11 is optionally one or more selected from NH 2 , OH and NHCO 2 R 12 The substituents in the alkyl group substituted, wherein R 12 is an alkyl group; or

[0109] R 10 and R 11 Together with the nitrogen to which they are attached, they form a 4-, 5-, 6- or 7-membered monocyclic heterocycloalkyl, wherein one or two carbons in the monocyclic heterocycloalkyl are optionally replaced by a group selected from O, NH, S and CO, and the monocyclic heterocycloalkyl is optionally substituted by one or more groups selected from alkyl, CN, cycloalkyl, OH, alkoxy, halogen, haloalkyl and heteroaryl, wherein the heteroaryl is further optionally substituted by one or more groups selected from halogen and alkyl; or

[0110] R 10 and R 11 Together with the nitrogen to which they are attached, they form an 8-, 9- or 10-membered bicyclic heterocycloalkyl, wherein one or two carbons of the bicyclic heterocycloalkyl ring are optionally replaced by a group selected from O, NH, S and CO, and the bicyclic heterocycloalkyl is optionally substituted by one or more groups selected from alkyl, CN, cycloalkyl, OH, alkoxy, halogen, haloalkyl and heteroaryl; or

[0111] R10 and R 11 Together with the nitrogen to which they are attached, they form a 6- to 12-membered bicyclic group containing a spirocyclic carbon atom, wherein one or two carbons in the bicyclic group are optionally replaced by a group selected from O, NH, S and CO, and the bicyclic group is optionally substituted by one or more groups selected from alkyl, CN, cycloalkyl, OH, alkoxy, halogen, haloalkyl and heteroaryl, or the bicyclic group is optionally fused with a 5- or 6-membered aryl or heteroaryl; and

[0112] R 13 and R 14 Each is independently H or alkyl.

[0113] Detailed description

[0114] The present invention relates to bis-arylsulfonamide compounds capable of modulating ERAP1. Preferably, the compounds selectively modulate ERAP1.

[0115] As used herein, "alkyl" is defined as a straight or branched chain alkyl group, preferably C 1-20 Alkyl, more preferably C 1-12 Alkyl, even more preferably C 1-10 Alkyl or C 1-6 Alkyl, or C 1-3 Alkyl. Examples of suitable alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, hexyl.

[0116] As used herein, "cycloalkyl" is defined as: a monocyclic alkyl ring, preferably C 3-7 Cycloalkyl, more preferably C 3-6 Cycloalkyl, preferred examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl; or a fused bicyclic ring system such as norbornane.

[0117] As used herein, "halogen" is defined as chlorine, fluorine, bromine or iodine.

[0118] As used herein, the term "aryl" refers to a C 6-12 An aromatic group, which may be a benzo-fused group, such as phenyl or naphthyl.

[0119] As used herein, "heteroaryl" is defined as a monocyclic or bicyclic C 2-12An aromatic ring comprising one or more heteroatoms (which may be the same or different), such as oxygen, nitrogen or sulfur. Examples of suitable heteroaryl groups include thienyl, furyl, pyrrolyl, pyridyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, tetrazolyl, 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, and the like, and benzo derivatives thereof, such as quinolyl, isoquinolyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, naphthyridinyl, and the like. Particularly preferred heteroaryl groups include 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, oxadiazol-1-yl, oxadiazol-5-yl, oxadiazol-3-yl, oxadiazol-4 ... 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, thiazol-5-yl -2-yl, 1H-1,2,3,4-tetrazol-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, pyridazin-3-yl, pyridazin-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-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.

[0120] "Heterocycloalkyl" refers to a cyclic aliphatic group containing one or more heteroatoms selected from nitrogen, oxygen and sulfur, which is optionally inserted with one or more -(CO)- groups in the ring and / or optionally contains one or more double bonds in the ring. Preferably, the heterocycloalkyl is monocyclic or bicyclic. Preferably, the heterocycloalkyl is C 3-7 Heterocycloalkyl, more preferably C 3-6 Alternatively, the heterocycloalkyl group is C 4-7 Heterocycloalkyl, more preferably C 4-6Heterocycloalkyl. Preferred heterocycloalkyl groups include, but are not limited to, piperazinyl, piperidinyl, morpholinyl, thiomorpholinyl, pyrrolidinyl, tetrahydrofuranyl, and tetrahydropyranyl. Preferably, the heterocycloalkyl group is fully saturated.

[0121] "Azepanyl" refers to a 7-membered saturated heterocyclic ring containing six carbon atoms and one nitrogen atom. "Piperidinyl" refers to a 6-membered saturated heterocyclic ring containing five carbon atoms and one nitrogen atom. "Pyrrolidinyl" refers to a 5-membered saturated heterocyclic ring containing four carbon atoms and one nitrogen atom. "Azetidinyl" refers to a 4-membered saturated heterocyclic ring containing three carbon atoms and one nitrogen atom.

[0122] Compounds of formula (Ia)

[0123] One aspect of the present invention relates to compounds of formula (Ia) as described above.

[0124] In a preferred embodiment, R 1 It is H or Me, and more preferably H.

[0125] In a preferred embodiment, R 2 is COOH.

[0126] In a preferred embodiment, XY is NH-SO.

[0127] In a preferred embodiment, R 5 Selected from alkyl, alkenyl, alkynyl, haloalkyl, SO 2 -alkyl, Cl, alkoxy, OH, CN, hydroxyalkyl, alkylthio, heteroaryl, cycloalkyl, heterocycloalkyl, and haloalkoxy.

[0128] In a preferred embodiment, R 5 Selected from H, Me, CF 3 , CHF 2 、SO 2 -Me, Cl, ethynyl, MeO, OH, CH 2 OH, SMe, cyclopropyl, triazolyl, oxetanyl and CN. More preferably, R 5 Selected from H, CN, Me, SO 2 -Me, CF 3 and CHF 2 , CH 2 OH, SMe, cyclopropyl, 3,4-triazol-1-yl, oxetane-3-yl. More preferably, R 5 Selected from H, CN, Me, SO 2 -Me, CF 3 and CHF 2 .

[0129] In another preferred embodiment, R 5 Selected from OMe, Me, Et, Pr, ethynyl and Cl, more preferably OMe, Me, Et, Pr and Cl, and more preferably OMe or Et.

[0130] In a preferred embodiment, R 7 Selected from H, CN, haloalkyl, Cl, F, SO 2 -alkyl, SO 2 NR 13 R 14 , heteroaryl and alkyl.

[0131] In a preferred embodiment, R 7 Selected from H, CN, CF 3 , CHF 2 , Cl, F, SO 2 -Me, SO 2 NH 2 , heteroaryl and Me. More preferably, R 7 Selected from H, CN, Me, SO 2 -Me, tetrazolyl, CF 3 and CHF 2 .

[0132] In a preferred embodiment, R 7 For CF 3 .

[0133] In a preferred embodiment, R 7 For CN.

[0134] In another preferred embodiment, R 7 For SO 2 -alkyl, more preferably SO 2 -Me.

[0135] In a preferred embodiment, R 7 For SO 2 NR 13 R 14 , more preferably SO 2 NH 2 .

[0136] In a preferred embodiment, R 7 is a heteroaryl group optionally substituted by one or more substituents selected from alkyl, halogen, alkoxy, CN, haloalkyl and OH.

[0137] In a preferred embodiment, R 7is a heteroaryl group selected from pyridyl, thienyl, imidazolyl, pyrimidinyl, pyrazolyl, pyrazinyl, pyridazinyl, thiazolyl, isothiazolyl, triazinyl, pyrrolyl, furanyl, oxazolyl, isoxazolyl, oxadiazolyl, tetrazolyl and triazolyl, wherein each heteroaryl group is optionally substituted with one or more substituents selected from alkyl, halogen, alkoxy, CN, haloalkyl and OH.

[0138] In a preferred embodiment, R 7 is a heteroaryl group selected from imidazolyl, pyrazolyl, pyrazinyl, pyridazinyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, tetrazolyl and triazolyl, wherein each heteroaryl group is optionally substituted with one or more substituents selected from alkyl, halogen, alkoxy, CN, haloalkyl and OH.

[0139] In a preferred embodiment, R 7 is selected from 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, thiazol-2-yl, 1H-1,2,3,4-tetrazol-4-yl, 2H-1,2 ,3,4-tetrazolyl-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, pyridazin-3-yl, pyridazin-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-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, each of which is optionally substituted with one or more substituents selected from alkyl, halogen, CN, alkoxy, haloalkyl and OH.

[0140] In a 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, isoxazol-4-yl, isoxazol-5-yl, isothiazol-5-yl, pyridazin-3-yl, pyridazin-4-yl, pyrazinyl and 1,3,4-oxadiazol-2-yl, wherein each heteroaryl group is optionally substituted with one or more substituents selected from Me, F, Cl, CN and MeO.

[0141] In a preferred embodiment, R 7 is heteroaryl optionally substituted by one or more alkyl groups, preferably one or more Me groups.

[0142] In a preferred embodiment, R 7 is a halogenated alkyl group or a heteroaryl group, and more preferably a tetrazolyl group.

[0143] In a preferred embodiment, R 7 is a halogenated alkyl group, more preferably CF 3 .

[0144] In a preferred embodiment, R 8 is H or a haloalkyl group, more preferably H or CF 3 , even more preferably H.

[0145] In a preferred embodiment, R 8 Selected from H, Me, CF 3 , Cl, Br and F.

[0146] In another preferred embodiment, R 8 is selected from H, haloalkyl and Cl.

[0147] In a preferred embodiment, R 9 is H, Me or F, more preferably H or F, more preferably H.

[0148] In a preferred embodiment, R 1 , R 3 , R 4 , R 6 , R 8 and R 9 Both are H.

[0149] In a preferred embodiment:

[0150] R 2 is COOH;

[0151] XY is NH-SO 2 ;

[0152] R 5 is selected from the group consisting of OMe, Me, Et, Pr and Cl, and more preferably OMe;

[0153] R 1 , R 3 , R 4 , R 6 , R 8 and R 9 are H; and

[0154] R 7 is a halogenated alkyl group, more preferably CF 3 .

[0155] In a preferred embodiment, R 10 and R 11 Together with the nitrogen to which they are attached, they form an azepanyl group, wherein (a) the azepanyl group is substituted with one or more groups (more preferably one or two groups) selected from alkyl, CN, halogen and heteroaryl, wherein the heteroaryl group is further optionally substituted with one or more groups (more preferably one or two groups) selected from halogen and alkyl, or (b) one or two carbon atoms in the azepanyl group are replaced with a group selected from O, NH, S and CO, and the azepanyl group is optionally substituted with one or more groups (more preferably one or two groups) selected from alkyl, CN, halogen and heteroaryl, wherein the heteroaryl group is further optionally substituted with one or more groups (more preferably one or two groups) selected from halogen and alkyl.

[0156] In a preferred embodiment, R 10 and R 11 Together with the nitrogen to which they are attached, they form an azetidinyl, pyrrolidinyl or piperidinyl group, wherein (a) the azetidinyl, pyrrolidinyl or piperidinyl group is substituted by one or more groups (more preferably one or two groups) selected from alkyl, CN, cycloalkyl, OH, alkoxy, halogen, haloalkyl and heteroaryl, wherein the heteroaryl group is further optionally substituted by one or more groups (more preferably one or two groups) selected from halogen and alkyl, or (b) one or two carbons of the azetidinyl, pyrrolidinyl or piperidinyl group are replaced by a group selected from NH, S and CO.

[0157] In a preferred embodiment, R 10 and R 11Together with the nitrogen to which they are attached, they form azetidinyl, pyrrolidinyl or piperidinyl, wherein the azetidinyl, pyrrolidinyl or piperidinyl is substituted by one or more groups (more preferably one or two groups) selected from alkyl, CN, cycloalkyl, OH, alkoxy, halogen, haloalkyl and heteroaryl, wherein the heteroaryl is further optionally substituted by one or more groups (more preferably one or two groups) selected from halogen and alkyl.

[0158] In a preferred embodiment, R 10 and R 11 Together with the nitrogen to which they are attached, they form an azetidinyl group which is substituted by one or more selected from C 1-3 Alkyl, CN, C 3-6 Cycloalkyl, OH, C 1-3 Alkoxy, halogen and CF 3 The group (more preferably one or two groups) in is substituted.

[0159] In a preferred embodiment, R 10 and R 11 Together with the nitrogen to which they are attached, they form a pyrrolidinyl group which is substituted by one or more selected from C 1-3 Alkyl, CN, C 3-6 Cycloalkyl, OH, C 1-3 Alkoxy, halogen and CF 3 The group (more preferably one or two groups) in is substituted.

[0160] In a preferred embodiment, R 10 and R 11 Together with the nitrogen to which they are attached, they form a piperidinyl group which is substituted by one or more selected from C 1-3 Alkyl, CN, C 3-6 Cycloalkyl, OH, C 1-3 Alkoxy, halogen and CF 3 The group (more preferably one or two groups) in is substituted.

[0161] In a preferred embodiment, R 10 and R 11 Together with the nitrogen to which they are attached, they form an 8-, 9- or 10-membered bicyclic heterocycloalkyl, wherein one or two carbons in the bicyclic heterocycloalkyl ring are optionally replaced by a group selected from O, NH, S and CO, and the bicyclic heterocycloalkyl is optionally substituted by one or more groups (more preferably one or two groups) selected from alkyl, CN, OH and halogen.

[0162] In a preferred embodiment, R 10 and R 11Together with the nitrogen to which they are attached, they form an 8-, 9- or 10-membered bridged bicyclic heterocycloalkyl, wherein one or two carbons of the bridged bicyclic heterocycloalkyl ring are optionally replaced by a group selected from O, NH, S and CO, and the bicyclic heterocycloalkyl is optionally substituted by one or more groups (more preferably one or two groups) selected from alkyl, CN, OH and halogen.

[0163] In a preferred embodiment, R 10 and R 11 Together with the nitrogen to which they are attached, they form a piperidinyl group, which is optionally substituted with one or more groups (more preferably one or two groups) selected from alkyl, CN, OH and halogen, and wherein two non-adjacent ring carbons in the piperidinyl group are connected to each other through a 2-carbon alkylene bridge or a 3-carbon alkylene bridge.

[0164] In a preferred embodiment, R 10 and R 11 Together with the nitrogen to which they are attached, a 6- to 12-membered bicyclic group containing a spirocyclic carbon atom is formed, wherein one carbon in the bicyclic group is optionally replaced by O, and the bicyclic group is optionally substituted by one or more groups (more preferably one or two groups) selected from alkyl, CN, halogen and heteroaryl, or the bicyclic group is optionally fused with a 5- or 6-membered aryl or heteroaryl. Preferably, R 10 and R 11 Together with the nitrogen to which they are attached they form a 7- to 12-membered bicyclic group containing a spirocyclic carbon atom.

[0165] In a preferred embodiment, R 10 and R 11 Together with the nitrogen to which they are attached, they form a bicyclic group containing a spirocyclic carbon atom having the following formula (Z):

[0166]

[0167] in:

[0168] m is 1 or 2;

[0169] n is 1, 2 or 3; and

[0170] Ring A is a 3-membered, 4-membered, 5-membered or 6-membered cycloalkyl or heterocycloalkyl group.

[0171] In a preferred embodiment, Ring A is a 3-membered cycloalkyl or heterocycloalkyl group.

[0172] In a preferred embodiment, Ring A is a 4-membered cycloalkyl or heterocycloalkyl group.

[0173] In a preferred embodiment, Ring A is a 5-membered cycloalkyl or heterocycloalkyl group.

[0174] In a preferred embodiment, Ring A is a 6-membered cycloalkyl or heterocycloalkyl group.

[0175] In a preferred embodiment, m is 1 and n is 1.

[0176] In a preferred embodiment, m is 1 and n is 2.

[0177] In a preferred embodiment, m is 2 and n is 2.

[0178] In a preferred embodiment, m is 2 and n is 3.

[0179] In a preferred embodiment, R 10 and R 11 Together with the nitrogen to which they are attached, they form a 7-membered bicyclic group containing a spirocyclic carbon atom, wherein one carbon in the bicyclic group is replaced by O, and the bicyclic group is optionally substituted by one or more groups (more preferably one or two groups) selected from alkyl, halogen and heteroaryl.

[0180] In a preferred embodiment, R 10 and R 11 Together with the nitrogen to which they are attached, they form an 8-membered bicyclic group containing a spirocyclic carbon atom, wherein one of the carbons in the bicyclic group is replaced by O, and the bicyclic group is optionally substituted by one or more groups selected from alkyl, halogen and heteroaryl.

[0181] In a preferred embodiment, R 10 and R 11 Together with the nitrogen to which they are attached, they form a 9-membered bicyclic group containing a spirocyclic carbon atom, wherein one carbon in the bicyclic group is replaced by O, and the bicyclic group is optionally substituted by one or more groups (more preferably one or two groups) selected from alkyl, halogen and heteroaryl.

[0182] In a preferred embodiment, R 10 and R 11 Together with the nitrogen to which they are attached, they form a 10-membered bicyclic group containing a spirocyclic carbon atom, wherein one carbon in the bicyclic group is replaced by O, and the bicyclic group is optionally substituted by one or more groups (more preferably one or two groups) selected from alkyl, halogen and heteroaryl.

[0183] In a preferred embodiment, R 10 and R 11Together with the nitrogen to which they are attached, they form an 11-membered bicyclic group containing a spirocyclic carbon atom, wherein one carbon in the bicyclic group is replaced by O, and the bicyclic group is optionally substituted by one or more groups (more preferably one or two groups) selected from alkyl, halogen and heteroaryl.

[0184] In a preferred embodiment, R 10 and R 11 Together with the nitrogen to which they are attached, they form a 12-membered bicyclic group containing a spirocyclic carbon atom, wherein one carbon in the bicyclic group is replaced by O, and the bicyclic group is optionally substituted by one or more groups (more preferably one or two groups) selected from alkyl, halogen and heteroaryl.

[0185] In a preferred embodiment, R 10 and R 11 Together with the nitrogen to which they are attached, they form a bicyclic radical comprising a ring system selected from the group consisting of spiro[3,3]heptane, spiro[3,4]octane, spiro[3,5]nonane, spiro[4,4]nonane, spiro[4,5]decane, spiro[3,6]decane, spiro[5,5]undecane and spiro[5,6]dodecane, wherein in each of the above bicyclic radicals, NR 10 R 11 The nitrogen of the group forms a member of a ring system, and another carbon in the ring system is optionally replaced by O, and the bicyclic group is optionally substituted by one or more groups (more preferably one or two groups) selected from alkyl, halogen and heteroaryl.

[0186] In a preferred embodiment, NR 10 R 11 Selected from the following groups:

[0187]

[0188] In a preferred embodiment, NR 10 R 11 Selected from the following groups:

[0189]

[0190] In a preferred embodiment, NR 10 R 11 Selected from the following groups:

[0191]

[0192]

[0193] In a preferred embodiment:

[0194] R 2is COOH;

[0195] XY is NH-SO 2 ;

[0196] R 5 is cyclopropyl;

[0197] R 1 , R 3 , R 4 , R 6 , R 8 and R 9 are H; and

[0198] R 7 Selected from CN, haloalkyl, heteroaryl and SO 2 -alkyl; and NR 10 R 11 Selected from the following groups:

[0199]

[0200] In a preferred embodiment:

[0201] R 2 is COOH;

[0202] XY is NH-SO 2 ;

[0203] R 5 is cyclopropyl;

[0204] R 1 , R 3 , R 4 , R 6 , R 8 and R 9 are H; and

[0205] R 7 Selected from CN, CF 3 , tetrazolyl and SO 2 -Me, more preferably CN and SO 2 -Me;NR 10 R 11 Selected from the following groups:

[0206]

[0207] In a preferred embodiment:

[0208] R 2 is COOH;

[0209] XY is NH-SO 2 ;

[0210] R 5 is ethyl;

[0211] R 1 , R 3 , R 4 , R 6 , R 8 and R 9 are H; and

[0212] R 7 Selected from CN, haloalkyl, heteroaryl and SO 2 -alkyl; and

[0213] NR 10 R 11 Selected from the following groups:

[0214]

[0215] In a preferred embodiment:

[0216] R 2 is COOH;

[0217] XY is NH-SO 2 ;

[0218] R 5 is ethyl;

[0219] R 1 , R 3 , R 4 , R 6 , R 8 and R 9 are H; and

[0220] R 7 Selected from CN and CF 3 ;as well as

[0221] NR 10 R 11 for:

[0222]

[0223] In a preferred embodiment:

[0224] R 2 is COOH;

[0225] XY is NH-SO 2 ;

[0226] R 5 OMe;

[0227] R 1, R 3 , R 4 , R 6 , R 8 and R 9 are H; and

[0228] R 7 Selected from CN, haloalkyl, heteroaryl and SO 2 -alkyl; and

[0229] NR 10 R 11 Selected from the following groups:

[0230]

[0231] In a preferred embodiment:

[0232] R 2 is COOH;

[0233] XY is NH-SO 2 ;

[0234] R 5 OMe;

[0235] R 1 , R 3 , R 4 , R 6 , R 8 and R 9 are H; and

[0236] R 7 Selected from CF 3 and SO 2 -Me; and

[0237] NR 10 R 11 Selected from the following groups:

[0238]

[0239] In a preferred embodiment, the compound of formula (Ia) is selected from the following:

[0240]

[0241]

[0242]

[0243]

[0244]

[0245]

[0246]

[0247]

[0248]

[0249]

[0250]

[0251] and pharmaceutically acceptable salts and hydrates thereof.

[0252] Compound of formula (Ib)

[0253] Another aspect of the present invention relates to a compound of formula (Ib), or a pharmaceutically acceptable salt or hydrate thereof,

[0254]

[0255] in:

[0256] The group XY is -NHSO 2 -or-SO 2 NH-;

[0257] R 1 is H or alkyl;

[0258] R 2 is a tetrazolyl group;

[0259] R 3 is selected from H, Cl and alkyl;

[0260] R 4 is selected from H, Cl and F;

[0261] R 5 Selected from H, alkyl, alkynyl, alkenyl, haloalkyl, SO 2 -alkyl, Cl, alkoxy, OH, CN, hydroxyalkyl, alkylthio, heteroaryl, cycloalkyl, heterocycloalkyl, and haloalkoxy;

[0262] R 6 is H;

[0263] R 7 Selected from H, CN, haloalkyl, Cl, F, SO 2 -alkyl, SO 2 NR 13 R 14, heteroaryl and alkyl, wherein the heteroaryl is optionally substituted with one or more substituents selected from alkyl, halogen, alkoxy, CN, haloalkyl and OH;

[0264] R 8 is selected from H, alkyl, haloalkyl and halogen;

[0265] R 9 is H;

[0266] R 9 H, C 1 To C 3 Alkyl or halogen;

[0267] R 11 is optionally one or more selected from NH 2 , OH and NHCO 2 R 12 The substituents in the alkyl group substituted, wherein R 12 is an alkyl group; or

[0268] R 10 and R 11 Together with the nitrogen to which they are attached, they form a 4-, 5-, 6- or 7-membered monocyclic heterocycloalkyl, wherein one or two carbons in the monocyclic heterocycloalkyl are optionally replaced by a group selected from O, NH, S and CO, and the monocyclic heterocycloalkyl is optionally substituted by one or more groups selected from alkyl, CN, cycloalkyl, OH, alkoxy, halogen, haloalkyl and heteroaryl, wherein the heteroaryl is further optionally substituted by one or more groups selected from halogen and alkyl; or

[0269] R 10 and R 11 Together with the nitrogen to which they are attached, they form an 8-, 9- or 10-membered bicyclic heterocycloalkyl, wherein one or two carbons of the bicyclic heterocycloalkyl ring are optionally replaced by a group selected from O, NH, S and CO, and the bicyclic heterocycloalkyl is optionally substituted by one or more groups selected from alkyl, CN, cycloalkyl, OH, alkoxy, halogen, haloalkyl and heteroaryl; or

[0270] R 10 and R 11 Together with the nitrogen to which they are attached, they form a 6- to 12-membered bicyclic group containing a spirocyclic carbon atom, wherein one or two carbons in the bicyclic group are optionally replaced by a group selected from O, NH, S and CO, and the bicyclic group is optionally substituted by one or more groups selected from alkyl, CN, cycloalkyl, OH, alkoxy, halogen, haloalkyl and heteroaryl, or the bicyclic group is optionally fused with a 5- or 6-membered aryl or heteroaryl; and

[0271] R13 and R 14 Each is independently H or alkyl.

[0272] In a preferred embodiment, R 10 and R 11 Together with the nitrogen to which they are attached, they form a 4-, 5-, 6- or 7-membered monocyclic heterocycloalkyl, wherein one or two carbons in the monocyclic heterocycloalkyl are optionally replaced by a group selected from O, NH, S and CO, and the monocyclic heterocycloalkyl is optionally substituted by one or more groups selected from alkyl, CN, cycloalkyl, OH, alkoxy, halogen, haloalkyl and heteroaryl, wherein the heteroaryl is further optionally substituted by one or more groups selected from halogen and alkyl. More preferably, R 10 and R 11 Together with the nitrogen to which they are attached they form piperidinyl, pyrrolidinyl, azepanyl or azetidinyl, each of which is optionally substituted with one or more groups selected from alkyl, CN, cycloalkyl, OH, alkoxy, halogen and haloalkyl.

[0273] In a preferred embodiment, R 10 and R 11 Together with the nitrogen to which they are attached, they form a 6-membered monocyclic heterocycloalkyl selected from piperidinyl, morpholinyl, thiomorpholinyl and piperazinyl, each of which is optionally substituted with one or more groups selected from alkyl, CN, cycloalkyl, OH, alkoxy, halogen, haloalkyl and heteroaryl, wherein the heteroaryl is further optionally substituted with one or more groups selected from halogen and alkyl. More preferably, R 10 and R 11 Together with the nitrogen to which they are attached they form a 6-membered monocyclic heterocycloalkyl group selected from piperidinyl, morpholinyl, thiomorpholinyl and piperazinyl, each of which is optionally substituted with one or more groups selected from alkyl, CN, cycloalkyl, OH, alkoxy, halogen and haloalkyl.

[0274] In a preferred embodiment, R 10 and R 11 Together with the nitrogen to which they are attached, they form a piperidinyl group, wherein one or two carbons of the monocyclic heterocycloalkyl group are optionally replaced by groups selected from O, NH, S and CO, and the piperidinyl group is optionally substituted by one or more groups selected from alkyl, CN, cycloalkyl, OH, alkoxy, halogen, haloalkyl and heteroaryl, wherein the heteroaryl group is further optionally substituted by one or more groups selected from halogen and alkyl. In a highly preferred embodiment, R 10 and R 11Together with the nitrogen to which they are attached they form an unsubstituted piperidinyl or pyrrolidinyl, more preferably an unsubstituted piperidinyl.

[0275] Group R 1 , R 3-11 Other preferred definitions of , X and Y are as described above for the compounds of formula (Ia) and apply mutatis mutandis to the compounds of formula (Ib).

[0276] In a preferred embodiment, the compound of formula (Ib) is:

[0277]

[0278] or pharmaceutically acceptable salts and hydrates thereof.

[0279] Compound of formula (Ic)

[0280] Another aspect of the present invention relates to a compound of formula (Ic), or a pharmaceutically acceptable salt or hydrate thereof,

[0281]

[0282] in:

[0283] X is SO 2 ;

[0284] Y is NH;

[0285] R 1 is H or alkyl;

[0286] R 2 is selected from COOH and tetrazolyl;

[0287] R 3 is selected from H, Cl and alkyl;

[0288] R 4 is selected from H, Cl and F;

[0289] R 5 Selected from H, alkyl, alkynyl, alkenyl, haloalkyl, SO 2 -alkyl, Cl, alkoxy, OH, CN, hydroxyalkyl, alkylthio, heteroaryl, cycloalkyl, heterocycloalkyl, and haloalkoxy;

[0290] R 6 is H;

[0291] R 7 Selected from H, CN, haloalkyl, Cl, F, SO 2 -alkyl, SO 2 NR 13 R 14, heteroaryl and alkyl, wherein the heteroaryl is optionally substituted with one or more substituents selected from alkyl, halogen, alkoxy, CN, haloalkyl and OH;

[0292] R 8 is selected from H, alkyl, haloalkyl and halogen;

[0293] R 9 H, C 1 To C 3 Alkyl or halogen;

[0294] R 10 is H or alkyl;

[0295] R 11 is optionally one or more selected from NH 2 , OH and NHCO 2 R 12 The substituents in the alkyl group substituted, wherein R 12 is an alkyl group; or

[0296] R 10 and R 11 Together with the nitrogen to which they are attached, they form a 4-, 5-, 6- or 7-membered monocyclic heterocycloalkyl, wherein one or two carbons in the monocyclic heterocycloalkyl are optionally replaced by a group selected from O, NH, S and CO, and the monocyclic heterocycloalkyl is optionally substituted by one or more groups selected from alkyl, CN, cycloalkyl, OH, alkoxy, halogen, haloalkyl and heteroaryl, wherein the heteroaryl is further optionally substituted by one or more groups selected from halogen and alkyl; or

[0297] R 10 and R 11 Together with the nitrogen to which they are attached, they form an 8-, 9- or 10-membered bicyclic heterocycloalkyl, wherein one or two carbons of the bicyclic heterocycloalkyl ring are optionally replaced by a group selected from O, NH, S and CO, and the bicyclic heterocycloalkyl is optionally substituted by one or more groups selected from alkyl, CN, cycloalkyl, OH, alkoxy, halogen, haloalkyl and heteroaryl; or

[0298] R 10 and R 11 Together with the nitrogen to which they are attached, they form a 6- to 12-membered bicyclic group containing a spirocyclic carbon atom, wherein one or two carbons in the bicyclic group are optionally replaced by a group selected from O, NH, S and CO, and the bicyclic group is optionally substituted by one or more groups selected from alkyl, CN, cycloalkyl, OH, alkoxy, halogen, haloalkyl and heteroaryl, or the bicyclic group is optionally fused with a 5- or 6-membered aryl or heteroaryl; and

[0299] R13 and R 14 Each is independently H or alkyl.

[0300] In a preferred embodiment, R 10 and R 11 Together with the nitrogen to which they are attached, they form a 4-, 5-, 6- or 7-membered monocyclic heterocycloalkyl, wherein one or two carbons in the monocyclic heterocycloalkyl are optionally replaced by a group selected from O, NH, S and CO, and the monocyclic heterocycloalkyl is optionally substituted by one or more groups selected from alkyl, CN, cycloalkyl, OH, alkoxy, halogen, haloalkyl and heteroaryl, wherein the heteroaryl is further optionally substituted by one or more groups selected from halogen and alkyl. More preferably, R 10 and R 11 Together with the nitrogen to which they are attached they form piperidinyl, pyrrolidinyl, azepanyl or azetidinyl, each of which is optionally substituted with one or more groups selected from alkyl, CN, cycloalkyl, OH, alkoxy, halogen and haloalkyl.

[0301] In a preferred embodiment, R 10 and R 11 Together with the nitrogen to which they are attached, they form a 6-membered monocyclic heterocycloalkyl selected from piperidinyl, morpholinyl, thiomorpholinyl and piperazinyl, each of which is optionally substituted with one or more groups selected from alkyl, CN, cycloalkyl, OH, alkoxy, halogen, haloalkyl and heteroaryl, wherein the heteroaryl is further optionally substituted with one or more groups selected from halogen and alkyl. More preferably, R 10 and R 11 Together with the nitrogen to which they are attached they form a 6-membered monocyclic heterocycloalkyl group selected from piperidinyl, morpholinyl, thiomorpholinyl and piperazinyl, each of which is optionally substituted with one or more groups selected from alkyl, CN, cycloalkyl, OH, alkoxy, halogen and haloalkyl.

[0302] In a preferred embodiment, R 10 and R 11 Together with the nitrogen to which they are attached, they form a piperidinyl group, wherein one or two carbons of the monocyclic heterocycloalkyl group are optionally replaced by groups selected from O, NH, S and CO, and the piperidinyl group is optionally substituted by one or more groups selected from alkyl, CN, cycloalkyl, OH, alkoxy, halogen, haloalkyl and heteroaryl, wherein the heteroaryl group is further optionally substituted by one or more groups selected from halogen and alkyl. In a highly preferred embodiment, R 10 and R 11Together with the nitrogen to which they are attached they form an unsubstituted piperidinyl or pyrrolidinyl, more preferably an unsubstituted piperidinyl.

[0303] Group R 1-11 Further preferred definitions of are as described above for the compounds of formula (Ia) and apply mutatis mutandis to the compounds of formula (Ic).

[0304] In one embodiment, the compound of formula (Ic) is selected from the following:

[0305]

[0306] and pharmaceutically acceptable salts and hydrates thereof.

[0307] Compound of formula (Id)

[0308] Another aspect of the present invention relates to a compound of formula (Id), or a pharmaceutically acceptable salt or hydrate thereof,

[0309]

[0310] in:

[0311] The group XY is -NHSO 2 -or-SO 2 NH-;

[0312] R 1 is H or alkyl;

[0313] R 2 is selected from COOH and tetrazolyl;

[0314] R 3 is selected from H, Cl and alkyl;

[0315] R 4 is selected from H, Cl and F;

[0316] R 5 Selected from H, alkyl, alkynyl, alkenyl, haloalkyl, SO 2 -alkyl, Cl, alkoxy, OH, CN, hydroxyalkyl, alkylthio, heteroaryl, cycloalkyl, heterocycloalkyl, and haloalkoxy;

[0317] R 6 is H;

[0318] R 7 For CN, SO 2 -alkyl, SO 2 NR 13 R 14or heteroaryl, wherein the heteroaryl is optionally substituted with one or more substituents selected from alkyl, halogen, alkoxy, CN, haloalkyl and OH;

[0319] R 8 is selected from H, alkyl, haloalkyl and halogen;

[0320] R 9 H, C 1 -C 3 Alkyl or halogen;

[0321] R 10 is H or alkyl;

[0322] R 11 is optionally one or more selected from NH 2 , OH and NHCO 2 R 12 The substituents in the alkyl group substituted, wherein R 12 is an alkyl group; or

[0323] R 10 and R 11 Together with the nitrogen to which they are attached, they form a 4-, 5-, 6- or 7-membered monocyclic heterocycloalkyl, wherein one or two carbons in the monocyclic heterocycloalkyl are optionally replaced by a group selected from O, NH, S and CO, and the monocyclic heterocycloalkyl is optionally substituted by one or more groups selected from alkyl, CN, cycloalkyl, OH, alkoxy, halogen, haloalkyl and heteroaryl, wherein the heteroaryl is further optionally substituted by one or more groups selected from halogen and alkyl; or

[0324] R 10 and R 11 Together with the nitrogen to which they are attached, they form an 8-, 9- or 10-membered bicyclic heterocycloalkyl, wherein one or two carbons of the bicyclic heterocycloalkyl ring are optionally replaced by a group selected from O, NH, S and CO, and the bicyclic heterocycloalkyl is optionally substituted by one or more groups selected from alkyl, CN, cycloalkyl, OH, alkoxy, halogen, haloalkyl and heteroaryl; or

[0325] R 10 and R 11 Together with the nitrogen to which they are attached, they form a 6- to 12-membered bicyclic group containing a spirocyclic carbon atom, wherein one or two carbons in the bicyclic group are optionally replaced by a group selected from O, NH, S and CO, and the bicyclic group is optionally substituted by one or more groups selected from alkyl, CN, cycloalkyl, OH, alkoxy, halogen, haloalkyl and heteroaryl, or the bicyclic group is optionally fused with a 5- or 6-membered aryl or heteroaryl; and

[0326] R13 and R 14 Each is independently H or alkyl.

[0327] Substituents X, Y, R 1-6 and R 8-11 Preferred definitions of are as described above for compounds of formula (Ia) and apply mutatis mutandis to compounds of formula (Id).

[0328] In a preferred embodiment, R 10 and R 11 Together with the nitrogen to which they are attached, they form a 4-, 5-, 6- or 7-membered monocyclic heterocycloalkyl, wherein one or two carbons in the monocyclic heterocycloalkyl are optionally replaced by a group selected from O, NH, S and CO, and the monocyclic heterocycloalkyl is optionally substituted by one or more groups selected from alkyl, CN, cycloalkyl, OH, alkoxy, halogen, haloalkyl and heteroaryl, wherein the heteroaryl is further optionally substituted by one or more groups selected from halogen and alkyl. More preferably, R 10 and R 11 Together with the nitrogen to which they are attached they form piperidinyl, pyrrolidinyl, azepanyl or azetidinyl, each of which is optionally substituted with one or more groups selected from alkyl, CN, cycloalkyl, OH, alkoxy, halogen and haloalkyl.

[0329] In a preferred embodiment, R 10 and R 11 Together with the nitrogen to which they are attached, they form a 6-membered monocyclic heterocycloalkyl, wherein one or two carbons in the monocyclic heterocycloalkyl are optionally replaced by a group selected from O, NH, S and CO, and the monocyclic heterocycloalkyl is optionally substituted by one or more groups selected from alkyl, CN, cycloalkyl, OH, alkoxy, halogen, haloalkyl and heteroaryl, wherein the heteroaryl is further optionally substituted by one or more groups selected from halogen and alkyl.

[0330] In a preferred embodiment, R 10 and R 11 Together with the nitrogen to which they are attached, they form a 6-membered monocyclic heterocycloalkyl selected from piperidinyl, morpholinyl, thiomorpholinyl and piperazinyl, each of which is optionally substituted with one or more groups selected from alkyl, CN, cycloalkyl, OH, alkoxy, halogen, haloalkyl and heteroaryl, wherein the heteroaryl is further optionally substituted with one or more groups selected from halogen and alkyl. More preferably, R 10 and R 11Together with the nitrogen to which they are attached they form a 6-membered monocyclic heterocycloalkyl group selected from piperidinyl, morpholinyl, thiomorpholinyl and piperazinyl, each of which is optionally substituted with one or more groups selected from alkyl, CN, cycloalkyl, OH, alkoxy, halogen and haloalkyl.

[0331] In a preferred embodiment, R 10 and R 11 Together with the nitrogen to which they are attached, they form a piperidinyl group, which is optionally substituted with one or more groups selected from alkyl, CN, cycloalkyl, OH, alkoxy, halogen, haloalkyl and heteroaryl, wherein the heteroaryl group is further optionally substituted with one or more groups selected from halogen and alkyl. More preferably, R 10 and R 11 Together with the nitrogen to which they are attached they form an unsubstituted piperidinyl.

[0332] In a preferred embodiment, R 7 For CN.

[0333] In another preferred embodiment, R 7 For SO 2 -alkyl, more preferably SO 2 -Me.

[0334] In a preferred embodiment, R 7 For SO 2 NR 13 R 14 , more preferably SO 2 NH 2 .

[0335] In a preferred embodiment, R 7 is a heteroaryl group optionally substituted by one or more substituents selected from alkyl, halogen, alkoxy, CN, haloalkyl and OH.

[0336] In a preferred embodiment, R 7 is a heteroaryl group selected from the group consisting of pyridyl, thienyl, imidazolyl, pyrimidinyl, pyrazolyl, pyrazinyl, pyridazinyl, thiazolyl, isothiazolyl, triazinyl, pyrrolyl, furanyl, oxazolyl, isoxazolyl, oxadiazolyl, tetrazolyl and triazolyl, each of which is optionally substituted with one or more substituents selected from the group consisting of alkyl, halogen, alkoxy, CN, haloalkyl and OH.

[0337] In a preferred embodiment, R 7is a heteroaryl group selected from the group consisting of imidazolyl, pyrazolyl, pyrazinyl, pyridazinyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, tetrazolyl and triazolyl, each of which is optionally substituted with one or more substituents selected from the group consisting of alkyl, halogen, alkoxy, CN, haloalkyl and OH.

[0338] In a preferred embodiment, R 7 is a heteroaryl group selected from the group consisting of 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, 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, thiazol-2-yl, 1H-1,2,3,4-tetrazol-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, pyridazin-3-yl, pyridazin-4-yl, pyrazinyl, 1,3,4-oxadiazol-2-yl, 1,3,4-oxadiazol-5-yl, 1,2,5-oxadiazol- 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, each of which is optionally substituted with one or more substituents selected from alkyl, halogen, CN, alkoxy, haloalkyl and OH.

[0339] In a highly preferred embodiment, R 7 is a heteroaryl group selected from the group consisting of 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, isoxazol-4-yl, isoxazol-5-yl, isothiazol-5-yl, pyridazin-3-yl, pyridazin-4-yl, pyrazinyl and 1,3,4-oxadiazol-2-yl, each of which is optionally substituted with one or more substituents selected from the group consisting of Me, F, Cl, CN and MeO.

[0340] In a preferred embodiment, R 7 is heteroaryl optionally substituted by one or more alkyl groups, preferably one or more Me groups.

[0341] In a highly preferred embodiment, the compound of formula (Id) is selected from the following:

[0342]

[0343]

[0344]

[0345]

[0346]

[0347] and pharmaceutically acceptable salts and hydrates thereof.

[0348] Another aspect of the present invention relates to a compound selected from the group consisting of:

[0349]

[0350]

[0351]

[0352] and pharmaceutically acceptable salts and hydrates thereof.

[0353] Therapeutic applications

[0354] Another aspect of the present invention relates to the use of a compound as described herein in medicine. As described in more detail below, the compound has particular use in the field of oncology and immuno-oncology.

[0355] Another aspect of the present invention relates to the use of a compound as described herein for the treatment or prevention of a disorder selected from the group consisting of a proliferative disorder, an immune disorder, an inflammatory disorder and a viral disorder.

[0356] In a preferred embodiment, the compounds of the invention modulate ERAP1. More preferably, the compounds modulate the cellular antigen processing activity of ERAP1.

[0357] In one embodiment, the compound inhibits the activity of ERAP1. More preferably, the compound inhibits the cellular antigen processing activity of ERAP1.

[0358] In an alternative embodiment, the compound increases the activity of ERAP1.

[0359] In one embodiment, the compounds of the invention may alter the antigenic repertoire of presented antigens.

[0360] One aspect of the present invention relates to the use of a compound as described herein in the treatment of a proliferative disorder. Preferably, the proliferative disorder is cancer or leukemia.

[0361] Cancer can be selected from: 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; stomach cancer (including gastrointestinal cancer); glioblastoma; liver cancer; hepatoma; intraepithelial neoplasm; kidney (kidney or renal) cancer; laryngeal cancer; leukemia; liver cancer; lung cancer (e.g., small cell lung cancer, non-small cell lung cancer, lung adenocarcinoma and lung squamous cell carcinoma); melanoma; myeloma; neuroblastoma; oral cancer (lip, tongue, mouth and pharynx); ovarian cancer; pancreatic cancer; prostate cancer; retinoblastoma; rhabdomyosarcoma; colorectal cancer; respiratory system cancer; salivary gland cancer; sarcoma; skin cancer; squamous cell carcinoma; gastric cancer; testicular cancer; thyroid cancer; uterine or endometrial cancer; urinary system cancer; vulvar cancer; lymphoma, including Hodgkin lymphoma and non-Hodgkin lymphoma, and B-cell lymphoma (including low-grade / follicular non-Hodgkin lymphoma (NHL)); small lymphocytic (SL) NHL; intermediate-grade / follicular NHL; intermediate-grade diffuse NHL; high-grade immunoblastic NHL; high-grade lymphoblastic NHL; high-grade small non-lytic cell NHL; bulky disease) NHL; mantle cell lymphoma; AIDS-related lymphoma; and Waldenstrom's macroglobulinemia; chronic lymphocytic leukemia (CLL); acute lymphoblastic leukemia (ALL); hairy cell leukemia; chronic myeloid leukemia; and other carcinomas and sarcomas; and post-transplantation lymphoproliferative disorder (PTLD), as well as abnormal blood vessel proliferation associated with phakomatoses, edema (e.g., associated with brain tumors), and Meigs' syndrome.

[0362] Without wishing to be bound by theory, it is understood that ERAP1 modulators are able to alter the antigenic repertoire of cancer cells' antigens and neoantigens by at least 10%, as determined using immunopeptidomics and mass spectrometry analysis. Approximately 50% of this alteration is upregulation in the presentation of certain antigens and neoantigens, while the other 50% is the presentation of completely new antigens and neoantigens. Both of these alterations increase the visibility of the tumor to the immune system, thereby causing CD8 + T cell repertoire and CD8 + Measurable changes in the activation state of T cells. CD8 +This change in T cell responses results in immune-mediated tumor clearance and can potentially be enhanced by combination with cancer therapies such as antibody checkpoint inhibitors (e.g., anti-PD-1).

[0363] Without wishing to be bound by theory, it is understood that regulators of ERAP1 cause cancer cell killing by natural killer (NK) cells due to disruption of the interaction between killer cell Ig-like receptors (KIR) or lectin-like receptor CD94-NKG2A on NK cells and classical or non-classical MHC-I-peptide (pMHC-I) complexes on cancer cells.

[0364] In a 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.

[0365] Another aspect of the invention relates to a method for increasing the visibility of cancer cells to a subject's immune system by altering the repertoire of antigens and neoantigens presented to the immune system, the method comprising administering to the subject a compound of Formula (I), (Ia), (Ib), (Ic) or (Id).

[0366] In a preferred embodiment, the compound enhances the response of CD8+ T cells to cancer cells.

[0367] In a preferred embodiment, the compounds of the present invention are used to treat diseases of uncontrolled cell growth, proliferation and / or survival, inappropriate cellular immune response or inappropriate cellular inflammatory response, in particular diseases of uncontrolled cell growth, proliferation and / or survival, inappropriate cellular immune response or inappropriate cellular inflammatory response which are regulated by the ERAP1 pathway.

[0368] In a preferred embodiment, the disease of uncontrolled cell growth, proliferation and / or survival, inappropriate cellular immune response or inappropriate cellular inflammatory response is selected from hematological tumors, solid tumors and / or metastases thereof.

[0369] More preferably, the compounds are used to treat a condition selected from the group consisting of leukemia and myelodysplastic syndrome, malignant lymphoma, head and neck tumors including brain tumors and brain metastases, thoracic tumors including non-small cell lung tumors and small cell lung tumors, gastrointestinal tumors, endocrine tumors, breast tumors and other gynecological tumors, urological tumors including kidney tumors, bladder tumors and prostate tumors, skin tumors and sarcomas and / or their metastases.

[0370] 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 comprising cancer cells. The compounds can reduce the number of metastatic cancer cells.

[0371] In one embodiment, the compound can be used to treat cancer in a subject who previously had cancer. The compound can be used to reduce the likelihood of cancer recurrence, or the likelihood of developing cancer again. The compound can induce neoantigens in a recurrent cancer or a further cancer, where the subject already has an existing immune response to the cancer. As such, the compound can enhance or strengthen the immune response against the cancer.

[0372] In one embodiment, the compound is used to prevent cancer. The compound can be used to prevent the development of cancer. That is, the compound can stimulate an immune response, such as a vaccine response, against future cancer. The compound can stimulate an immune response against a neoantigen in a subject. Once a subject has cancer, the subject can be treated again with the compound (or a different compound) to stimulate the production of the same neoantigen, thereby eliciting a pre-existing immune response to the neoantigen in the subject to treat or prevent cancer.

[0373] The same or different compounds may be used before and after a subject is diagnosed with cancer.

[0374] In one embodiment, the compounds are useful for preventing cancer.

[0375] In one embodiment, the subject may have previously had cancer, may have a family history of cancer, may be at high risk for cancer, may have a genetic predisposition to cancer, or may have been exposed to a carcinogen. In one embodiment, the subject may be in remission from cancer.

[0376] One embodiment provides antigen presenting cells, such as dendritic cells (DCs), generated ex vivo. Antigen presenting cells can be generated ex vivo to present neoantigens, such as neoantigens generated by compounds according to the invention. The compounds can be used in a method of generating antigen presenting cells ex vivo that present neoantigens, and wherein the cells can be used as anticancer vaccines.

[0377] Antigen presenting cells such as dendritic cells can be pulsed or loaded with neoantigens, or genetically modified (by DNA or RNA transfer) to express one, two or more neoantigens. Methods for preparing dendritic cell vaccines are known in the art.

[0378] Neoantigens can be generated from normal tissue of a subject in which ERAP1 is modulated with a compound according to the invention. The source of normal tissue can be fibroblasts or B cells, for example, cells that can be easily expanded in vitro. Alternatively, RNA from cancer, total RNA or mRNA enriched in polyA+ RNA can be used. PolyA+ RNA can also be amplified to generate enough antigen for DC loading, thereby limiting the ex vivo culture step.

[0379] In one embodiment, dendritic cells that have been treated with a compound as described above can be used to treat a subject. The dendritic cells can be contacted with the compound ex vivo, and then the dendritic cells can be administered to the subject. Thus, the compound can be used in vitro or in vivo, for example, for in situ treatment, or for ex vivo treatment followed by administration of the treated cells to the subject.

[0380] Another aspect of the invention relates to the use of a compound as described above in treating an immune disorder or modulating an immune response. In a preferred embodiment, the immune disorder is an autoimmune disorder, such as a T cell mediated autoimmune disorder.

[0381] 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 spondyloarthropathy, rheumatic fever, hypersensitivity pneumonitis, allergic bronchopulmonary aspergillosis, inorganic pneumoconiosis, sarcoidosis, autoimmune hemolytic anemia, immune platelet disorders, cold diseases such as cryofibrillinogenemia, psoriasis, Behcet's disease, shotgun chorioretinopathy, and autoimmune polyendocrine disease.

[0382] Polymorphisms in the ERAP1 gene that affect ERAP1 enzyme activity are strongly associated with an increased risk of autoimmunity, including ankylosing spondylitis, psoriasis, Behcet's disease, and birdshot chorioretinopathy 11 ERAP1 variants that reduce ERAP1 enzyme activity protect against disease, whereas ERAP1 variants that increase activity have been reported to be associated with increased disease risk 12 This suggests that modulation of ERAP1 activity could be an effective treatment for autoimmune diseases.

[0383] Thus, in a preferred embodiment, the immune disorder is selected from ankylosing spondylitis, psoriasis, Behcet's disease and birdshot chorioretinopathy.

[0384] In a preferred embodiment, the immune disorder is ankylosing spondylitis. Ankylosing spondylitis (AS) is a type of arthritis in which there is long-term inflammation of the joints of the spine. Typically, the joints where the spine joins the pelvis are also affected. Sometimes other joints such as the shoulders or hips are involved. Ankylosing spondylitis affects between 0.1% and 1.8% of the population, and it usually strikes young and middle-aged people. Although the cause of ankylosing spondylitis is unknown, it involves a combination of genetic and environmental factors. More than 90% of those affected have a specific human leukocyte antigen known as the HLA-B27 antigen. 13 Furthermore, certain variants of ERAP1 that associate with HLA-B27 are clearly associated with either increased or decreased disease risk, providing evidence for a clear role for regulated antigen presentation in disease. 18 There is no cure for ankylosing spondylitis, and current treatments are only intended to improve symptoms and prevent exacerbations. Medications used to date include NSAIDs, steroids, DMARDs (such as sulfasalazine), and biologic agents (such as infliximab).

[0385] In a preferred embodiment, the immune disorder is Behcet's disease (BD). Behcet's disease (BD) is an inflammatory disorder that affects multiple parts of the body. The most common symptoms include painful mouth ulcers, genital ulcers, eye inflammation, and arthritis. The cause is not well understood, and although environmental factors play a role, genetic studies have shown that the risk of the disease is increased in patients who carry HLA-B51 together with specific variants of ERAP1. 19 The main feature of the disease is autoinflammation of blood vessels, so it is sometimes called an autoinflammatory disease. Currently, Behcet's disease is incurable, but symptoms can be controlled with drugs that can reduce inflammation in the affected part of the body, such as corticosteroids, immunosuppressants, or biological therapeutic agents that target biological processes involved in the inflammatory process. In a preferred embodiment, the immune disorder is birdshot chorioretinopathy. Birdshot chorioretinopathy, also known as birdshot uveitis or HLA-A29 uveitis, is a rare form of bilateral posterior uveitis that infects the eye. Birdshot chorioretinopathy causes severe progressive inflammation of the choroid and retina. Symptoms include floaters, blurred vision, photopsias (flash sensations in the field of vision), color vision loss, and night blindness. Birdshot chorioretinopathy is considered to be an autoimmune disease. The disease has a strong correlation with human leukocyte antigen haplotype (HLA)-A29. This indicates the role of T lymphocytes in pathogenesis. Birdshot chorioretinopathy is associated with IL-17, a signature cytokine of TH17 cells that plays an important role in autoimmunity. 15,16Genome-wide association studies have identified HLA-A29:02 as a major risk factor and have determined that both ERAP1 and ERAP2 are associated with birdshot chorioretinopathy. 17,20 Genetic variants within the ERAP1 and ERAP2 loci regulate enzyme activity as well as mRNA and protein expression. ERAP2 is an aminopeptidase that, along with ERAP1, excises peptides in the endoplasmic reticulum and loads these peptides onto HLA molecules for presentation to T cells of the immune system.

[0386] In a 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 scaly and red patches. The cause is not well understood, but includes environmental and genetic factors. HLA-C06 is closely associated with risk of the disease, and variants in ERAP1 (possibly along with HLA-C06) are also closely associated with the disease. 21 There is no cure for psoriasis, and current treatments are only designed to improve symptoms and prevent worsening. Medications used for treatment include steroids, methotrexate, sulfasalazine, and biologic agents such as etanercept.

[0387] Another aspect of the invention relates to the use of compounds as described above in the treatment or prevention of viral conditions. ERAP1 modulators such as the compounds described herein are able to alter the antigenic repertoire of a variety of viruses, which allows recognition and destruction of virally infected cells. Therefore, ERAP1 modulators have potential therapeutic applications in the treatment of viral infections and diseases. ERAP1 modulates certain viral antigens, including antigens 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, leading to + Stronger recognition by T cells 8 .

[0388] In a preferred embodiment, the viral disorder is a viral disease or viral infection selected from HIV, HPV, CMV and HCV.

[0389] In a preferred embodiment, the viral disorder is HIV.

[0390] In a preferred embodiment, the viral disorder is HPV.

[0391] In a preferred embodiment, the viral disorder is CMV.

[0392] In a preferred embodiment, the viral disorder is HCV.

[0393] Another aspect of the present invention relates to the use of a compound as described above in the treatment or prevention of hypertension.

[0394] Another aspect relates to the use of a compound described herein for preventing or treating a disorder caused by, associated with, or accompanied by aberrant activity against ERAP1.

[0395] Another aspect relates to the use of the compounds described herein in preventing or treating ERAP1-related diseases or disorders

[0396] Yet another aspect relates to the use of a compound described herein in the preparation of a medicament for preventing or treating a disorder caused by, associated with, or accompanied by any aberrant activity against ERAP1.

[0397] As used herein, the phrase "the preparation of a medicament" includes the use of a component of the invention directly as a medicament in addition to its use at any stage in the preparation of such a medicament.

[0398] 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.

[0399] Yet another aspect relates to the use of a compound as described herein in the preparation of a medicament for preventing or treating an ERAP1-related disease or disorder.

[0400] Another aspect of the present invention relates to a method for treating an ERAP1-related disease or condition in a subject. As described in detail below, the method according to this aspect of the present invention is achieved by administering to a subject in need of treatment a therapeutically effective amount of a compound of the present invention as described above (either by itself or, more preferably, as part of a pharmaceutical composition mixed with, for example, a pharmaceutically acceptable carrier).

[0401] Yet another aspect of the invention relates to a method of treating a subject suffering from a disease state alleviated by modulation of ERAP1, wherein the method comprises administering to the subject a therapeutically effective amount of a compound of the invention.

[0402] Another aspect relates to a method of treating a disease state alleviated by modulation of ERAP1, wherein the method comprises administering to a subject a therapeutically effective amount of a compound according to the invention.

[0403] Preferably, the subject is a mammal, more preferably a human.

[0404] The term "method" refers to ways, means, techniques and processes for accomplishing a given task, including but not limited to those known ways, means, techniques and processes, or ways, means, techniques and processes that can be readily developed by technicians in the fields of chemistry, pharmacy, biology, biochemistry and medicine from known ways, means, techniques and processes.

[0405] As used herein, the term "treating" includes abrogating, substantially inhibiting, slowing, or reversing the progression of a disease or condition, substantially ameliorating the clinical symptoms of a disease or condition, or substantially preventing the appearance of clinical symptoms of a disease or condition.

[0406] As used herein, the term "prevention" refers to a method of preventing an organism from developing a condition or disease in the first place.

[0407] The term "therapeutically effective amount" means that amount of the compound being administered which will relieve to some extent one or more of the symptoms of the disease or condition being treated.

[0408] For any compound used in the present invention, the therapeutically effective amount is also referred to herein as the effective therapeutic dose, which can be initially estimated through cell culture assays. For example, a dose can be administered to an animal model to achieve a circulating concentration range that includes the IC determined by cell culture. 50 or IC 100 This information can be used to more accurately determine useful doses for humans. Initial doses can also be estimated using in vivo data. Using these preliminary guidelines, one of ordinary skill in the art will be able to determine effective doses for humans.

[0409] In addition, standard pharmaceutical techniques in cell cultures or experimental animals (e.g., by determining LD 50 and ED 50 ) can determine the toxicity and therapeutic efficacy of the compounds described herein. The dose ratio between toxicity and therapeutic efficacy is the therapeutic index and can be expressed as LD 50 With ED 50 The ratio between . Compounds that exhibit a high therapeutic index are preferred. The data obtained from these cell culture assays and animal studies can be used to determine a dosage range that does not produce toxicity for human use. The dosage of the compound is preferably within a circulating concentration (including ED 50). The dosage may vary within this range depending on the dosage form used and the route of administration used. The exact dosage form, route of administration and dosage can be selected by each physician based on the patient's condition (see, for example, Fingl et al, 1975, The Pharmacological Basis of Therapeutics, chapter 1, page 1).

[0410] The dose and interval can be adjusted individually to provide a plasma level of the active compound sufficient to maintain the therapeutic effect. The common patient dose range for oral administration is about 50 mg / kg / day to 2000 mg / kg / day, usually about 100 mg / kg / day to 1000 mg / kg / day, preferably about 150 mg / kg / day to 700 mg / kg / day, and most preferably about 250 mg / kg / day to 500 mg / kg / day. Preferably, the therapeutically effective serum level is achieved by administering multiple doses per day. In the case of local administration or selective absorption, the effective local concentration of the drug may be independent of the plasma concentration. Those skilled in the art will be able to optimize the therapeutically effective local dose without excessive experimentation. As used herein, "ERAP1-related diseases or disorders" refers to diseases or disorders characterized by inappropriate ERAP1 activity. Inappropriate activity refers to an increase or decrease in ERAP1 activity caused by changes in the ERAP1 protein sequence relative to wild-type ERAP1 (Uniprot ID Q9NZ08), as determined by an enzymatic assay or a cell assay. Inappropriate activity may also result from overexpression of ERAP1 in diseased tissues compared to healthy adjacent tissues.

[0411] Preferred diseases or disorders for which the compounds described herein are useful for preventing include proliferative disorders, viral disorders, immune disorders, and inflammatory disorders as described above.

[0412] Thus, the present invention further provides the use of a compound as defined herein in the preparation of a medicament for the treatment of a disease in which modulation of ERAP1 is required. Such diseases include proliferative disorders, viral disorders, immune disorders and inflammatory disorders as described above.

[0413] In a preferred embodiment, the compound activates the ERAP1 conversion of (L)-leucine-7-amido-4-methylcoumarin (L-AMC) to (L)-leucine and the fluorescent molecule 7-amino-4-methylcoumarin. Although the same assay can also identify inhibitors of ERAP1 cleavage of the amide bond in L-AMC, for the purposes of this application, this assay is referred to as the "L-AMC Activator Assay." The potency of all activators was calculated and expressed as the reduction of ERAP1 enzymatic activity compared to its baseline level (i.e., EC 50 ) to increase the activator concentration required by 50%.

[0414] In a preferred embodiment, the compound exhibits an EC of less than about 25 μM in the L-AMC activator assay. 50 More preferably, the compound exhibits an EC value 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, even more preferably less than about 0.01 μM in the L-AMC activator assay. 50 value.

[0415] In a 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 dinitrophenol (DNP) residues within the peptide. However, as ERAP1 hydrolyzes the N-terminal amide bond and releases tryptophan, this internal quenching is lost and the reaction is monitored by an increase in tryptophan fluorescence over the course of the assay. For the purposes of this application, this assay is referred to as the "10mer inhibition assay" and compound potency is calculated and expressed as IC, as is well known to those skilled in the art. 50 .

[0416] In a preferred embodiment, the compound exhibits an IC of less than about 25 μM in the 10mer assay. 50 More preferably, the compound exhibits an IC value 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, even more preferably less than about 0.01 μM in a 10mer assay. 50 value.

[0417] Therapeutic uses of compounds of formula I

[0418] Another aspect of the present invention relates to the use of a compound of formula (I), or a pharmaceutically acceptable salt or hydrate thereof, in the treatment or prevention of a disorder selected from a proliferative disorder, an autoimmune disorder, a viral disorder and an inflammatory disorder,

[0419]

[0420] in:

[0421] The group XY is -NHSO 2 -or-SO 2 NH-;

[0422] R 1 is H or alkyl;

[0423] R 2 is selected from COOH and tetrazolyl;

[0424] R 3 is selected from H, Cl and alkyl;

[0425] R 4 is selected from H, Cl and F;

[0426] R 5 Selected from H, alkyl, alkynyl, alkenyl, haloalkyl, SO 2 -alkyl, Cl, alkoxy, OH, CN, hydroxyalkyl, alkylthio, heteroaryl, cycloalkyl, heterocycloalkyl, and haloalkoxy;

[0427] R 6 is H;

[0428] R 7 Selected from H, CN, haloalkyl, Cl, F, SO 2 -alkyl, SO 2 NR 13 R 14 , heteroaryl and alkyl, wherein the heteroaryl is optionally substituted with one or more substituents selected from alkyl, halogen, alkoxy, CN, haloalkyl and OH;

[0429] R 8 is selected from H, alkyl, haloalkyl and halogen;

[0430] R 9 H, C 1 To C 3 Alkyl or halogen;

[0431] R 10 is H or alkyl;

[0432] R 11 is optionally one or more selected from NH 2 , OH and NHCO 2 R 12 The substituents in the alkyl group substituted, wherein R 12 is an alkyl group; or

[0433] R 10 and R 11Together with the nitrogen to which they are attached, they form a 4-, 5-, 6- or 7-membered monocyclic heterocycloalkyl, wherein one or two carbons in the monocyclic heterocycloalkyl are optionally replaced by a group selected from O, NH, S and CO, and the monocyclic heterocycloalkyl is optionally substituted by one or more groups selected from alkyl, CN, OH, halogen and heteroaryl, wherein the heteroaryl is further optionally substituted by one or more groups selected from halogen and alkyl; or

[0434] R 10 and R 11 Together with the nitrogen to which they are attached, they form an 8-, 9- or 10-membered bicyclic heterocycloalkyl, wherein one or two carbons in the bicyclic heterocycloalkyl ring are optionally replaced by a group selected from O, NH, S and CO, and the bicyclic heterocycloalkyl is optionally substituted by one or more groups selected from alkyl, CN and halogen; or

[0435] R 10 and R 11 Together with the nitrogen to which they are attached, they form a 6- to 12-membered bicyclic group containing a spirocyclic carbon atom, wherein one or two carbons in the bicyclic group are optionally replaced by a group selected from O, NH, S and CO, and the bicyclic group is optionally substituted by one or more groups selected from alkyl, CN, halogen and heteroaryl, or the bicyclic group is optionally fused with a 5- or 6-membered aryl or heteroaryl; and

[0436] R 13 and R 14 Each is independently H or alkyl.

[0437] Groups X, Y and R 1-11 Preferred definitions of are as described above for compounds of formula (Ia) and apply mutatis mutandis to compounds of formula (I). Details of suitable proliferative disorders, autoimmune disorders, viral disorders and inflammatory disorders are the same as described above under the heading "Therapeutic Uses".

[0438] In a preferred embodiment, the compound of formula (I) for use as described above is selected from the following substances:

[0439]

[0440]

[0441]

[0442]

[0443]

[0444]

[0445]

[0446]

[0447]

[0448]

[0449]

[0450]

[0451]

[0452]

[0453]

[0454]

[0455]

[0456]

[0457]

[0458]

[0459]

[0460]

[0461] and pharmaceutically acceptable salts and hydrates thereof.

[0462] Another aspect of the present invention relates to compounds of formula (I) as defined above except compounds (54), (64), (69), (71), (72), (73), (74), (78) and (165).

[0463] Another aspect relates to compounds of formula (I) as defined above, except compounds (54), (64), (69), (71), (72), (73), (74), (78) and (165) for use as defined above.

[0464] Pharmaceutical composition

[0465] Regarding the use of the present invention, the compounds described herein, or their physiologically acceptable salts, esters or other physiologically functional derivatives, can be prepared into pharmaceutical preparations, which contain the compounds or their physiologically acceptable salts, esters or other physiologically functional derivatives, and one or more pharmaceutically acceptable carriers and optional other therapeutic and / or preventive ingredients. One or more carriers must be acceptable in the sense of being compatible with the other ingredients of the preparation and harmless to its recipient. Pharmaceutical compositions can be used for human or animal use in human medicine and veterinary medicine.

[0466] Examples of such suitable excipients for use in the various forms of pharmaceutical compositions described herein can be found in "Handbook of Pharmaceutical Excipients, 2nd Edition, (1994), edited by A Wade and PJ Weller. The carrier, or each carrier if more than one is present, must be acceptable in the sense of being compatible with the other ingredients of the formulation and not deleterious to the recipient.

[0467] 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 Company (AR Gennaro ed., 1985).

[0468] Examples of suitable carriers include lactose, starch, glucose, methylcellulose, magnesium stearate, mannitol, sorbitol, etc. Examples of suitable diluents include ethanol, glycerol and water.

[0469] The selection of pharmaceutical carrier, excipient or diluent can be selected according to the expected route of administration and standard pharmaceutical practice. The pharmaceutical composition may include any suitable adhesive, lubricant, suspending agent, coating, solubilizing agent, buffer, flavoring agent, surfactant, thickening agent, preservative (including antioxidant) etc. and the material included to make the preparation isotonic with the blood of the expected recipient as carrier, excipient or diluent, or the pharmaceutical composition may also include any suitable adhesive, lubricant, suspending agent, coating, solubilizing agent, buffer, flavoring agent, surfactant, thickening agent, preservative (including antioxidant) etc. and the material included to make the preparation isotonic with the blood of the expected recipient except carrier, excipient or diluent.

[0470] Examples of suitable binders include starch, gelatin, natural sugars (such as glucose, anhydrous lactose, free-flowing lactose, beta-lactose, corn flavor), natural and synthetic gums (such as acacia, tragacanth or sodium alginate), carboxymethylcellulose and polyethylene glycol.

[0471] Examples of suitable lubricants include sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride, and the like.

[0472] Preservatives, stabilizers, dyes, and even flavoring agents may be added to 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.

[0473] Pharmaceutical preparations include those suitable for oral administration, topical administration (including transdermal, buccal and sublingual administration), rectal or parenteral administration (including subcutaneous, intradermal, intramuscular and intravenous administration), nasal and pulmonary administration (e.g., administration by inhalation). Where appropriate, the preparations can be conveniently provided in the form of discrete dosage units and can be prepared by any method known in the pharmaceutical art. All methods include the steps of combining the active compound with a liquid carrier and / or a finely divided solid carrier, and then, if necessary, shaping the product into the desired preparation.

[0474] Pharmaceutical formulations suitable for oral administration, wherein the carrier is a solid, are most preferably provided in the form of unit dose formulations such as pills, capsules or tablets each containing a predetermined amount of the active compound. Tablets may be obtained by compression or molding, optionally with one or more additional ingredients. Compressed tablets may be prepared by compressing the active compound in a free-flowing form such as a powder or granules, optionally mixed with a binder, lubricant, inert diluent, lubricant, surfactant or dispersant in a suitable machine. Molded tablets may be obtained by molding the active compound with an inert liquid diluent. The tablets may optionally be coated and, if uncoated, may optionally be scored. Capsules may be prepared by filling the active compound alone or in admixture with one or more additional ingredients into capsule shells which are then sealed in the usual manner. Cachets are similar to capsules in that the active compound and any one or more additional ingredients are sealed in a rice paper sleeve. The active compound may also be formulated as dispersible granules which, for example, may be suspended in water or sprinkled on food before administration. Capsules may be enclosed, for example, in sachets. Formulations suitable for oral administration wherein the carrier is a liquid may be provided as a solution or suspension in an aqueous or non-aqueous liquid, or as an oil-in-water liquid emulsion.

[0475] Preparations for oral administration include controlled release dosage forms (such as tablets), in which the active compound is formulated in an appropriate controlled release matrix or coated with a suitable controlled release membrane. Such preparations are particularly convenient for prophylactic use.

[0476] Pharmaceutical preparations suitable for rectal administration (wherein the carrier is a solid) are most preferably provided in the form of 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 one or more softened or melted carriers, then cooling and forming in a mold. Pharmaceutical preparations suitable for parenteral administration include sterile solutions or suspensions of the active compound in aqueous or oily carriers.

[0477] Injectable formulations may be suitable for bolus injection or continuous infusion. Such formulations are conveniently provided in unit dose or multi-dose containers which are sealed after introduction of the formulation until required for use. Alternatively, the active compound may be in powder form which is reconstituted with a suitable carrier such as sterile, pyrogen-free water prior to use.

[0478] The active compound may also be formulated as a long-acting depot preparation that can be administered by intramuscular injection or by implantation (e.g., subcutaneously or intramuscularly). The depot preparation may include, for example, a suitable polymeric or hydrophobic material, or an ion exchange resin. Such long-acting preparations are particularly convenient for prophylactic use.

[0479] Formulations suitable for pulmonary administration via the buccal space are provided so that particles containing the active compound and ideally having a diameter ranging from 0.5 microns to 7 microns are delivered within the recipient's bronchial tree.

[0480] As one possibility, such formulations are in the form of a finely divided powder which can be conveniently provided in a permeable capsule (e.g., a capsule of suitable gelatin) for use in an inhalation device, or in the form of a self-propelling formulation comprising the active compound, a suitable liquid or gaseous propellant and optionally other ingredients such as a surfactant and / or a solid diluent. 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 a solution or suspension may also be used.

[0481] Such self-propelling formulations are similar to those known in the art and can be prepared by established procedures. Suitably, the self-propelling formulation is provided in a container provided with a manually operable valve or an automatically operated valve having the desired spray characteristics; advantageously, the valve is of the metered type so that a fixed volume, for example 25 microliters to 100 microliters, is delivered on each operation of the valve.

[0482] As another possibility, the active compound may be in the form of a solution or suspension for use in a nebulizer or atomizer, whereby accelerating airflow or ultrasonic agitation is employed to produce a mist of fine droplets for inhalation.

[0483] Formulations suitable for nasal administration include formulations that are generally similar to the above-mentioned pulmonary administration formulations. When dispensing such formulations, the formulation should ideally have a particle size in the range of 10 microns to 200 microns to be able to stay in the nasal cavity; this can be achieved by appropriately adopting a powder of a suitable particle size or selecting a suitable valve. Other suitable formulations include: coarse-grained powders with a particle size in the range of 20 microns to 500 microns for rapid inhalation administration through the nostrils from a container close to the nose; and nasal drops containing 0.2% w / v to 5% w / v of an aqueous or oily solution or suspension of the active compound.

[0484] Pharmaceutically acceptable carriers are well known to those skilled in the art, including but not limited to 0.1M, and preferably 0.05M phosphate buffer or 0.8% saline. In addition, such pharmaceutically acceptable carriers can 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, alcohol / water solutions, emulsions or suspensions, including saline and buffered media. Parenteral carriers include sodium chloride solution, Ringer's dextrose, glucose and sodium chloride, sodium lactate Ringer's injection or fixed oil. Preservatives and other additives, such as antimicrobial agents, antioxidants, chelating agents, inert gases, etc., may also be present.

[0485] Preparations suitable for topical administration can be provided in the form of, for example, gels, creams or ointments. Such preparations can be applied to, for example, wounds or ulcers by applying the preparation directly to the surface of the wound or ulcer or by carrying it on a suitable support (such as a bandage, gauze, net, etc.) and then applying it to cover the area to be treated.

[0486] Also can provide liquid or powder preparation, this preparation can be sprayed or sprinkled directly to the position to be treated, for example wound or ulcer.Alternatively, preparation can be sprayed or sprinkled on carriers such as bandage, gauze, net, then applied to the position to be treated.

[0487] According to another aspect of the present invention there is provided a process for the preparation of a pharmaceutical or veterinary composition as described above, which process comprises combining one or more active compounds with a carrier, for example by mixing.

[0488] In general, the above formulations are prepared by uniformly and intimately bringing the active agent into association with liquid carriers and / or finely divided solid carriers and then, if necessary, shaping the product. The invention extends to a process for preparing a pharmaceutical composition comprising combining or associating a compound as described herein with a pharmaceutically or veterinarily acceptable carrier or excipient.

[0489] Salt / Ester

[0490] The compounds of the present invention may exist in the form of salts or esters, in particular in the form of pharmaceutically and veterinarily acceptable salts or esters.

[0491] Pharmaceutically acceptable salts of the compounds of the present invention include suitable acid addition salts or basic salts thereof. A review of suitable pharmaceutically acceptable salts can be found in Berge et al, J Pharm Sci, 66, 1-19 (1977). Salts are formed, for example, with strong inorganic acids, such as mineral acids, for example hydrohalic acids (e.g. hydrochloric acid, hydrobromic acid and hydroiodic acid), sulfuric acid, phosphoric acid, sulfates, hydrogensulfates, hemisulfates, thiocyanates, persulfates and sulfonic acids; strong organic carboxylic acids, for example unsubstituted or substituted (e.g. substituted with halogen) alkanecarboxylic acids having 1 to 4 carbon atoms, such as acetic acid; saturated or unsaturated dicarboxylic acids, for example oxalic acid, malonic acid, succinic acid, maleic acid, fumaric acid, phthalic acid or tetraphthalic acid; hydroxycarboxylic acids, for example ascorbic acid, glycolic acid, lactic acid, malic acid, tartaric acid or citric acid; amino acids, for example aspartic acid or glutamic acid; benzoic acid; or organic sulfonic acids, for example unsubstituted or substituted (e.g. substituted with halogen) (C 1 -C 4 ) alkylsulfonic acid, or arylsulfonic acid, for example methanesulfonic acid or p-toluenesulfonic acid. Pharmaceutically and veterinarily unacceptable salts may nevertheless be valuable as intermediates.

[0492] Preferred salts include, for example, acetate, trifluoroacetate, lactate, gluconate, citrate, tartrate, maleate, malate, pantothenate, adipate, alginate, aspartate, benzoate, butyrate, digluconate, cyclopentanoate, glucoheptonate, glycerophosphate, oxalate, heptanoate, hexanoate, fumarate, nicotinate, palmoate, pectinate, 3-phenylpropionate, picrate, pivalate, propionate, tartrate, lactobionate, pivolate, camphorate, undecanoate and succinate; organic sulfonates, such as methanesulfonate, ethanesulfonate, 2-hydroxyethanesulfonate, camphorsulfonate, 2-naphthalenesulfonate, benzenesulfonate, p-chlorobenzenesulfonate and p-toluenesulfonate; and inorganic acid salts, such as hydrochloride, hydrobromide, hydroiodide, sulfate, bisulfate, hemisulfate, thiocyanate, persulfate, phosphate and sulfonate.

[0493] Based on the functional group of esterification, esters are formed by using organic acids or alcohols / hydroxides. Organic acids include carboxylic acids, such as unsubstituted or substituted (e.g., halogen-substituted) alkane carboxylic acids (e.g., acetic acid) having 1 to 12 carbon atoms; saturated or unsaturated dicarboxylic acids, such as oxalic acid, malonic acid, succinic acid, maleic acid, fumaric acid, phthalic acid or tetraphthalic acid; hydroxycarboxylic 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., halogen-substituted) (C 1 -C 4 ) alkylsulfonic acid or arylsulfonic acid, such as methanesulfonic acid or p-toluenesulfonic acid. Suitable hydroxides include inorganic hydroxides, such as sodium hydroxide, potassium hydroxide, calcium hydroxide, aluminum hydroxide. Alcohols include unsubstituted or substituted (e.g., halogen-substituted) alkanols having 1 to 12 carbon atoms.

[0494] Enantiomers / tautomers

[0495] In all aspects of the invention discussed above, the invention includes (where appropriate) all enantiomers, diastereomers and tautomers of the compounds of the invention. Those skilled in the art will recognize compounds with optical activity (one or more chiral carbon atoms) or interconversion. The corresponding enantiomers and / or tautomers can be separated / prepared by methods known in the art.

[0496] Enantiomers are characterized by the absolute configuration of their chiral centers and are represented according to the R- and S-sequencing conventions of Cahn, Ingold, and Prelog. This convention is well known in the art (see, for example, 'Advanced Organic Chemistry', 3 rd edition, ed. March, J., John Wiley and Sons, New York, 1985).

[0497] The compounds of the present invention containing a chiral center may be used as racemic mixtures, enantiomerically enriched mixtures, or the racemic mixtures may be separated using known techniques so that the individual enantiomers may be used alone.

[0498] Stereoisomers and geometric isomers

[0499] Some compounds of the present invention may exist in the form of stereoisomers and / or geometric isomers, for example, they may have one or more asymmetric centers and / or geometric centers and therefore may exist in two or more stereoisomers and / or geometric isomers. The present invention encompasses the use of all individual stereoisomers and geometric isomers of those compounds, as well as mixtures thereof. The terms used in the claims include these forms, provided that the form retains the appropriate functional activity (although not necessarily to the same extent).

[0500] The present invention also includes all suitable isotopic variations of the compounds or their pharmaceutically acceptable salts. An isotopic variation of a compound of the present invention or its pharmaceutically acceptable salt is defined as a compound or its pharmaceutically acceptable salt 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 can be introduced into a pharmaceutical agent and its pharmaceutically acceptable salts include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine and chlorine, for example, they are respectively 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 agent and its pharmaceutically acceptable salts are useful in drug and / or substrate tissue distribution studies, such as those incorporating radioactive isotopes (e.g. 3 H or 14 C) isotopic variant. For ease of preparation and detection, tritium (i.e. 3 H) and carbon-14 (i.e. 14 C) isotopes are particularly preferred. In addition, the use of isotopes (e.g. deuterium, i.e. 2 H) can provide a certain degree of therapeutic advantage, which is attributed to its greater metabolic stability, such as an extension of the in vivo half-life or a reduction in dosage requirements, and therefore it may be preferred in some cases. For example, the present invention includes compounds of the general formula (I) in which any hydrogen atom is replaced by a deuterium atom. Generally, isotopic variations of the medicament of the present invention and its pharmaceutically acceptable salts can be prepared by conventional methods using appropriate isotopic variations of suitable drugs.

[0501] Atropisomers

[0502] Some compounds of the present invention may exist as atropisomers. Atropisomers are stereoisomers resulting from hindered rotation about a single bond, where energy differences due to steric strain or other contributing factors create a sufficiently high barrier to rotation to allow separation of the individual conformers. The present invention includes all such atropisomers.

[0503] Prodrug

[0504] The present invention also includes compounds of the present invention in the form of prodrugs, i.e., covalently bonded compounds of active parent drugs released in vivo. Such prodrugs are generally compounds of the present invention in which one or more suitable groups are modified so that the modification can be reversed after administration to a human or mammalian subject. Reversal is generally performed by enzymes naturally present in such subjects, but it is also possible to administer a second agent together with the prodrug to reverse in vivo. Examples of such modifications include esters (e.g., any of those described above), which can be reversed by esterases, etc. Other such systems are well known to those skilled in the art.

[0505] Solvate

[0506] The present invention also includes compounds of the present invention in the form of solvates. The terms used in the claims include these forms.

[0507] Polymorph

[0508] The present invention also relates to the compounds of the present invention in various crystalline forms, polymorphic forms and (anhydrous) hydrated forms. Such methods are well established in the pharmaceutical art: compounds in any such form can be isolated by slightly changing the purification methods and / or isolation forms of the solvents used to synthesize and prepare such compounds.

[0509] Mode of administration

[0510] The pharmaceutical composition of the present invention may be suitable for rectal administration, nasal administration, bronchial administration, topical administration (including oral and sublingual administration), vaginal or parenteral administration (including subcutaneous, intramuscular, intravenous, intraarterial and intradermal administration), abdominal or intrathecal administration. Preferred preparations are preparations for oral administration. The preparations may be conveniently provided in unit dosage form (i.e., in the form of discrete portions comprising a unit dose), or in unit doses of multiple units or subunits. As an example, the preparation may be in the form of tablets and sustained-release capsules, and may be prepared by any method known in the pharmaceutical field.

[0511] The oral formulations of the present invention may be provided in the following forms: discrete units containing a predetermined amount of active agent, such as capsules, gellules, drops, cachets, pills or tablets; powders or granules; solutions, emulsions or suspensions of active agents in aqueous or non-aqueous liquids; or oil-in-water emulsions or water-in-oil emulsions; or pills, etc. Preferably, these compositions contain 1 mg to 250 mg of active ingredient per dose, and more preferably 10 mg to 100 mg of active ingredient.

[0512] For compositions (e.g., tablets and capsules) for oral administration, the term "acceptable carrier" includes excipients such as common excipients, such as binders, for example, syrup, gum arabic, gelatin, sorbitol, gum 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, glyceryl stearate stearic acid, silicone oil, talcum wax, oil and colloidal silicon dioxide. Flavoring agents such as peppermint, wintergreen oil, cherry flavoring, etc. may also be used. It may be advantageous to add a colorant to make the dosage form easily recognizable. Tablets may also be coated using methods known in the art.

[0513] Tablets can be made by compression or molding, optionally with one or more additional ingredients. Compressed tablets can be prepared by compressing the active agent in a free-flowing form (such as a powder or granules), optionally mixed with a binder, lubricant, inert diluent, preservative, surfactant or dispersant in a suitable machine. Molded tablets can be made by molding a mixture of powdered compounds moistened with an inert liquid diluent in a suitable machine. Tablets can optionally be coated or scored, and they can be formulated for sustained or controlled release of the active agent.

[0514] Other suitable formulations for oral administration include lozenges comprising the active agent in a flavored basis, usually sucrose and acacia or tragacanth; pastilles comprising the active agent in an inert basis such as gelatin and glycerin, or sucrose and acacia; and mouthwashes comprising the active agent in a suitable liquid carrier.

[0515] 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 usually contain 10 mg to 1000 mg, preferably 10 mg to 250 mg of active ingredient per dose.

[0516] The pharmaceutical composition of the present invention may also be in the form of a suppository, pessary, suspension, emulsion, lotion, ointment, cream, gel, spray, solution or powder.

[0517] An alternative to transdermal administration is through the use of a skin patch. For example, the active ingredient can be incorporated into a cream consisting of an aqueous emulsion of polyethylene glycol or liquid paraffin. The active ingredient can also be incorporated into an ointment consisting of a white wax or white soft paraffin base at a concentration between 1% and 10% by weight, and such stabilizers and preservatives can be added as needed.

[0518] dose

[0519] Those of ordinary skill in the art can easily determine the appropriate dosage for one of the compositions of the present invention to be administered to a subject without undue experimentation. Typically, a doctor can determine the actual dosage that is most suitable for an individual patient, and this depends on a variety of factors, including the activity of the specific compound employed, 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, severity of a particular condition, and the individual being treated. The dosages disclosed herein are examples of average conditions. Of course, there may be individual examples where higher or lower dosage ranges should be used, and these dosage ranges are within the scope of the present invention.

[0520] The dosage can be further adjusted according to the mode of administration of the compound. For example, in order to achieve an "effective dose" for acute treatment, parenteral administration of the compound is generally preferred. Although intramuscular bolus injections are also useful, intravenous infusions of 5% glucose water or saline solution of the compound, or similar formulations with suitable excipients, are most effective. Typically, the parenteral dose is about 0.01 mg / kg to about 100 mg / kg; preferably between 0.1 mg / kg and 20 mg / kg, in a manner that maintains the drug concentration in the plasma at a concentration that is effective in regulating ERAP1. The compound is administered once to four times daily at a level that achieves a total daily dose of about 0.4 mg / kg / day to about 400 mg / kg / day. One of ordinary skill in the art can easily determine the exact therapeutically effective dose of the compound of the present invention, as well as the optimal route of administration of the compound, by comparing the blood level of the agent with the concentration required for therapeutic effect.

[0521] The compounds of the present invention can also be orally administered to a patient in a manner that provides a concentration of the drug sufficient to achieve one or more therapeutic indicators disclosed herein. Typically, the oral dose of a pharmaceutical composition comprising the compound is between about 0.1 mg / kg and about 50 mg / kg, and the administration method should be consistent with the patient's condition. Preferably, the oral dose can be about 0.5 mg / kg to about 20 mg / kg.

[0522] When the compounds of the invention are administered according to the invention, no unacceptable toxic effects are expected. Compounds of the invention that may have good bioavailability may be tested using one of several bioassay techniques to determine the concentration of compound required to achieve a given pharmaceutical effect.

[0523] joint

[0524] In a particularly preferred embodiment, one or more compounds of the present invention are administered in combination with one or more additional active agents (e.g., drugs that are already commercially available). Therefore, another aspect of the present invention relates to a combination comprising a compound as described herein and one or more additional active agents. In a preferred embodiment, the compounds of the present invention can be administered continuously, simultaneously, or sequentially with one or more other active agents.

[0525] When co-administered, drugs are usually more effective. In particular, in order to avoid the overlap of major toxicity, mechanism of action and resistance mechanism, combined therapy is advantageous. In addition, it is also desirable to use the most drugs at the maximum tolerated dose of drugs with the shortest time interval between such dosages. The major advantage of combining with chemotherapeutic drugs is that, through biochemical interactions, additive effects or possible synergistic effects can be promoted, and the appearance of drug resistance can also be reduced.

[0526] By studying the activity of the test compound with drugs known or suspected to play an important role in treating a particular condition, a beneficial combination can be indicated. The method can also be used to determine the order of administration of the drugs, i.e., before, at the same time, or after administration. This timing arrangement can be a feature of all active agents identified herein.

[0527] In a preferred embodiment, the additional active agent is an immunotherapeutic, more preferably a cancer immunotherapeutic. "Immunotherapeutic" refers to a therapeutic approach that uses the subject's own immune system to fight a disease such as cancer.

[0528] In a preferred embodiment, the compounds of the invention inhibit the activity of ERAP1 and the compounds are administered in combination with immunotherapy.

[0529] The compound can increase the sensitivity of cancer cells to immunotherapy. Immunotherapy can be mediated by T cells. In one embodiment, the compound can increase the number of CD8+ T cells in the tumor.

[0530] In one embodiment, the compounds can be used to treat cancers that are poorly or non-responsive to immunotherapy.

[0531] In a preferred embodiment, the additional active agent is a molecule capable of immune checkpoint intervention, a co-stimulatory antibody, a chemotherapeutic agent, a radiotherapeutic agent, a targeted therapeutic agent or an antibody, in particular a monoclonal antibody.

[0532] In a preferred embodiment, the additional active agent is a molecule capable of immune checkpoint intervention.

[0533] 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.

[0534] Immune checkpoint molecules include inhibitory molecules and activating molecules, and interventions can be applied to either or both types of molecules.

[0535] Immune checkpoint inhibitors include, but are not limited to, for example, PD-1 inhibitors, PD-L1 inhibitors, LAG-3 inhibitors, TIM-3 inhibitors, TIGIT inhibitors, BTLA inhibitors, and CTLA-4 inhibitors. Co-stimulatory antibodies transmit positive signals through immunomodulatory receptors, including but not limited to ICOS, CD137, CD27 OX-40, and GITR.

[0536] In a 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.

[0537] In a preferred embodiment, the antibody checkpoint inhibitor is an anti-PD-1 antibody, more preferably selected from pembrolizumab, cemiplimab and nivolumab.

[0538] In a preferred embodiment, the antibody checkpoint inhibitor is an anti-PD-L1 antibody, more preferably selected from atezolizumab, avelumab and durvalumab.

[0539] In a preferred embodiment, the antibody checkpoint inhibitor is an anti-CTLA4 antibody, more preferably selected from ipilimumab and tremelimumab.

[0540] In a preferred embodiment, the immunotherapy is an anti-cancer vaccine or a virus, such as an oncolytic virus.

[0541] In a preferred embodiment, the immunotherapy is a cell-based therapy. In one embodiment, the cell-based therapy can be a T cell therapy, such as adoptive T cell therapy, or a therapy using CAR-T cells.

[0542] Adoptive cell-based immunotherapy may include the following: 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, autologous immune enhancement therapy (AIET), cancer vaccines and / or antigen presenting cells. Such cell-based immunotherapy can be further improved to express one or more gene products to further modulate the immune response, such as expression of cytokines such as GM-CSF, and / or expression of tumor-associated antigens (TAA) antigens such as MAGE-1, gp-100, patient-specific neoantigen vaccines, etc.

[0543] In other embodiments, immunotherapy may include non-cell-based immunotherapy. In one embodiment, a composition comprising an antigen may be used, with or without a vaccine enhancing adjuvant. Such compositions exist in many well-known forms, such as peptide compositions, oncolytic viruses, and recombinant antigens comprising fusion proteins.

[0544] In an alternative embodiment, immunomodulatory interleukins, such as IL-2, IL-6, IL-7, IL-12, IL-17, IL-23, and their regulators (e.g., blocking antibodies or more effective or more persistent forms) can be used. Immunomodulatory cytokines, such as interferon, G-CSF, imiquimod, T Fα, etc., and their regulators (e.g., blocking antibodies or more effective or more persistent forms) can also be used. In another embodiment, immunomodulatory chemokines, such as CCL3, CCL26 and CXCL7, etc., and their regulators (e.g., blocking antibodies or more effective or more persistent forms) can be used. In another embodiment, immunomodulatory molecules of targeted immunosuppression can be used, such as STAT3 signaling regulators, FkappaB signaling regulators, and immune checkpoint regulators.

[0545] In another embodiment, immunomodulatory drugs, such as immunosuppressive drugs, glucocorticoids, cytostatic drugs, immunophilins and their modulators (e.g., rapamycin, calcineurin inhibitors, tacrolimus, cyclosporine (cyclosporine), pimecrolimus, abetolimus, gustationolimus, rufolimus, everolimus, temsirolimus, zotarolimus, etc.), hydrocortisone (Coripol), cortisone acetate, prednisone, prednisolone, methylprednisolone, dexamethasone, betamethasone, triamcinolone, beclomethasone, fludrocortisone acetate, deoxycorticosterone acetate (doca), aldosterone, non-glucocorticoid steroids, pyrimidine synthesis inhibitors, leflunomide, teriflunomide, folic acid analogs, methotrexate, antithymocyte globulin, antilymphocyte Cytoglobulin, thalidomide, lenalidomide, pentoxifylline, bupropion, curcumin, catechins, opioids, EVIPDH inhibitors, mycophenolic acid, myriocin, fingolimod, NF-xB inhibitors, raloxifene, tegaserod alfa, denosumab, F-xB signaling cascade inhibitors, disulfiram, olmesartan, dithiocarbamates, proteasome inhibitors, bortezomib, MG132, Prol, PI-0052, curcumin, genistein, resveratrol, parthenolide, thalidomide, lenalidomide, flavopiridol, nonsteroidal anti-inflammatory drugs (NSAIDs), arsenic trioxide, deshydroxymethylepoxyquinomycin (DHMEQ), I3C (indole-3-carbinol) / DIM (diindolylmethane) (13C / DIM), Bay 1 1-7082, luteolin, cell-penetrating peptide SN-50, IKBa-super repressor overexpression, FKB decoy oligodeoxynucleotide (ODN), or a derivative or analogue of any of them.

[0546] In yet another embodiment, immunomodulatory antibodies or proteins can be used. For example, antibodies that bind to CD40, Toll-like receptors (TLR), OX40, GITR, CD27 or 4-1BB, T cell bispecific antibodies, anti-IL-2 receptor antibodies, anti-CD3 antibodies, OKT3 (moromonab), oximab, teplizumab, visilizumab, anti-CD4 antibodies, cleximab, keliximab, zanarilimab, anti-CD11a antibodies, efalizumab, anti-CD18 antibodies, erlizumab, rovizumab, anti-CD20 antibodies, Afzumab, ocrelizumab, ofatumumab, pascolizumab, rituximab, anti-CD23 antibody, ruximab, anti-CD40 antibody, teneciximab, tocilizumab, anti-CD40L antibody, rulizumab, anti-CD62L antibody, asekizumab, anti-CD80 antibody, galiximab, anti-CD147 antibody, gavitumomab, B lymphocyte stimulator (BLyS) inhibitory antibody, belimumab, CTLA4-lg fusion protein, abatacept, belatacept, anti-CTLA4 Antibodies, ipilimumab, tremelimumab, anti-eotaxin 1 antibody, bertilimumab, anti-a4 integrin antibody, natalizumab, anti-IL-6R antibody, tocilizumab, anti-LFA-1 antibody, odumumab, anti-CD-25 antibody, basiliximab, daclizumab, inomucomab, anti-CD5 antibody, azotumomab, anti-CD2 antibody, siriglizumab, nerimumab, faramumab, atlizumab, atololimumab, siriglizumab, atrolimumab Toduzumab, doliximab, fontuzumab, gantuzumab, goliximab, leslizumab, masitumomab, muromumab, pexelizumab, reslizumab, rovizumab, talizumab, atemomab, valiximab, vepamomab, aflibercept, afacept, rilonacept, IL-2 receptor antagonist, anakinra, anti-IL-5 antibody, mepolizumab, IgE inhibitor, omalizumab, talizumab, IL12 inhibitor, IL23 inhibitor, ustekinumab.

[0547] In one embodiment, the subject may be undergoing or has previously been treated with a chemotherapeutic agent. Examples of chemotherapeutic agents include, but are not limited to, alkylating agents such as thiotepa and CYTOXAN cyclophosphamide; alkyl sulfonates such as busulfan, improsulfan, and piposulfan; aziridines such as benzodopa, carboquinone, meturedopa, and uredopa; ethyleneimines and methylmelamines, including hexamethylmelamine, trothamide, triethylenephosphoramide, triethylenethiophosphoramide, and triethylenethiophosphoramide. hosphoramide and trimethylolmelamine; acetogenins (e.g., bratacin and bratacinone); camptothecins (including the synthetic analogue topotecan); bryostatin; callystatin; CC-1065 (including its synthetic analogues adolesine, carzelesine and biszelesine); cryptophycins (e.g., cryptophycin 1 and cryptophycin 8); dolastatin; duocarmycins (including the synthetic analogues KW-2189 and CB 1-TM1); eleutherobin; pancratistatin; sarcodictyin; spongistatin; nitrogen mustards, such as chlorambucil, naphthyl mustard, cholophosphamide, estramustine, ifosfamide, dichloromethyl diethylamine, mechlorethamine oxide hydrochloride, hydrochloride), melphalan, novembichin, phenesterine, prednimustine, trofosfamide, uracil mustard; nitrosureas, such as carmustine, chlorozostatin, fotemustine, lomustine, nimustine, and ranimustine; antibiotics, such as enediyne antibiotics (e.g., calicheamicins, particularly calicheamicin gamma II and calicheamicin omega II (see, e.g., Agnew, Chem. Intl. Ed. Engl., 33:183-186 (1994)); anthracyclines, including dynemycin A; bisphosphonates, such as clodronate; esperamicins;and neocarzinostatin chromophores and related chromophores (enediyne antibiotic chromophores), aclacinomycin, actinomycin, authramycin, azaserine, bleomycin, actinomycin, carabicin, carminomycin, carzinophilin, chromomycin, actinomycin D, daunomycin, detorubicin, 6-diazo-5-oxo-L-norleucine, ADRIAMYCIN; doxorubicin (including morpholino doxorubicin, cyanomorpholino doxorubicin, 2-pyrrodotoxorubicin and deoxydoxorubicin), epirubicin, esorubicin, idarubicin, mexilomycin; mitomycins, such as mitomycin C, mycophenolic acid, norgamycin, olivomycin, peplomycin, potfilomycin, romycin), puromycin, triferon-doxorubicin, rhodorubicin, streptozocin, streptozotocin, tuberculocin, ubenimex, netastatin, zorubicin; antimetabolites, such as methotrexate and 5-fluorouracil (5-FU); folic acid analogs, such as dimethylfolate, methotrexate, pteropterin, trimetrexate; purine analogs, such as fludarabine, 6-mercaptopurine, thiamiprine, thioguanine; pyrimidine analogs, such as ancitabine, aztreonam, oxadiazine, thiabendazole, thioguanine, pyrimidine analogs, such as ancitabine, aztreonam, oxadiazine ... zacitidine, 6-azauridine, carmofur, cytarabine, dideoxyuridine, deoxyfluridine, enocitabine, floxuridine; androgens, such as calusterone, drostanolone propionate, epithioandrostrol, melastosane, testolactone; antiadrenal agents, such as aminoglutethimide, mitotane, trilostane; folic acid supplements, such as folinic acid; aceglucuronolide; aldophosphamide glycosides glycoside; aminolevulinic acid; eniluracil; amsacrine; bestrabucil; bisantrene; edatraxate; demecil; diaziquone; elformithine; elliptinium acetate; epothilones; etoglucid; gallium nitrate; hydroxyurea; lentinan; lonidamine; maytansinoids, such as maytansine and ansamitocin; mitoguanidine; mitoxantrone; mopidanmol; nitraerine; pentostatin; phenamet; pirarubicin; losoxantrone; podophyllinic acid; 2-ethylhydrazide; procarbazine;PSK polysaccharide complex (JHS Natural Products, Eugene, Oreg.); razoxane; rhizoxin; sizofuran; spirogermanamine; tenuazonic acid; triazoquinone; 2,2',2"-trichlorotriethylamine; trichothecenes (e.g., T-2 toxin, verracurin A, roridin A, and anguidine); urethan; vindesine; dacarbazine; mannitol mustard; dibromomannitol; dibromodulanol; pipobroman; gacytosine; arabinoside ("Ara-C"); cyclophosphamide; thiotepa; taxanes, such as TAXOL paclitaxel (Bristol-Myers Squibb Oncology, Princeton, N.J.), ABRAXANE Cremophor-free, 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; aminopterin; capecitabine (xeloda); ibandronate; irinotecan (Cam ptosar, CPT-11) (a regimen including irinotecan with 5-FU and folinic acid); topoisomerase inhibitor RFS2000; difluoromethylornithine (DMFO); retinoids, such as retinoic acid; capecitabine; Compredin; folinic acid (LV); oxaliplatin, including an oxaliplatin regimen (FOLFOX); lapatinib (Tykerb); inhibitors that reduce cell proliferation of PKC-a, Raf, H-Ras, EGFR (such as erlotinib (Tarceva)) and VEGF-A, and pharmaceutically 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. ; BRIEF DESCRIPTION OF THE DRAWINGS

[0548] The present invention is further described by way of the following non-limiting examples and with reference to the following drawings, in which:

[0549] Figure 1 The cellular effects of representative compounds 1 and 242 according to the present invention on antigen presentation are shown, which are determined by evaluating the presentation effects of the compounds on ovalbumin-specific peptide (SIINFEKL). More specifically, Figure 1 Representative ICs of exemplary compounds according to the present invention are shown. 50 Data were normalized to the signal obtained in the absence of compound (high) and in the absence of antigen (low) and are presented as mean ± STD (n=2).

[0550] Figure 2 The IC values ​​of exemplary compounds 1 and 242 according to the present invention determined by the above OVA antigen presentation assay are shown. 50 Summary of data. Data are expressed as mean ±

[0551] SEM (n=6).

[0552] Figure 3 The effect of compound 1 according to the present invention on global antigen processing determined using an unbiased proteomics pipeline is shown. More specifically, Figure 3 Shown are the effects of ERAP1 siRNA and compound inhibition (at 1 μM and 10 μM) on the immunopeptidome of SiHa cells compared to control as determined by the effects on total 8, 9, 10, 11, 12 and 13 amino acid peptides. DETAILED DESCRIPTION

[0553] Example

[0554] When the preparation of starting materials is not described, these starting materials are either commercially available, known in the literature, or readily obtained by those skilled in the art by standard methods. When compounds are indicated to be prepared by methods analogous to those of the preceding examples or intermediates, those skilled in the art will appreciate that reaction times, equivalents of reagents, solvents, concentrations, and temperatures may be adjusted for each particular reaction, and that different work-ups or purification techniques may be necessary or advantageous.

[0555] General solution

[0556] abbreviation

[0557] A list of some commonly used abbreviations is shown below - other abbreviations used therein that are not listed will be understood by those skilled in the art.

[0558] aq: aqueous; br: broad peak; ca.: approximately; d: double peak; DCM: dichloromethane; dioxane: 1,4-dioxane; DMAP: 4-dimethylaminopyridine; DMF: dimethylformamide; EDC: 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride; Et 3 N: triethylamine; EtOAc: ethyl acetate; EtOH: ethanol; h: hour; HPLC: high performance liquid chromatography; IPA, isopropanol; LC: liquid chromatography; m: multiplet; M: mole, molecular ion; MeCN: acetonitrile; MeOH: methanol; min: minute; MS: mass spectrometry; NMR: nuclear magnetic resonance; PDA: photodiode array; q: four peaks; RT: room temperature (about 20°C); R T : retention time; s: single peak, solid; t: tripot; TBME: tert-butyl methyl ether; TFA: trifluoroacetic acid; THF: tetrahydrofuran; UPLC: ultra-performance liquid chromatography; UV: ultraviolet light; quant.: quantitative; SEM: [2-(trimethylsilyl)ethoxy]methyl acetal; dppf: 1,1'-ferrocenyldiyl-bis(diphenylphosphine); NBS: N-bromosuccinimide; XantPhos-Pd-G3: [(4,5-bis(diphenylphosphino)-9,9-dimethylxanthene)-2-(2'-amino-1,1'-biphenyl)]palladium(II) methanesulfonate (CAS: 1445085-97-1); XPhos PdG3: (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) trifluoromethanesulfonate (CAS: 1798782-25-8); TBAF: tetra-n-butylammonium fluoride.

[0559] Other abbreviations are intended to convey their generally accepted meanings.

[0560] Solution 1

[0561]

[0562] Where R a = R of formula (I) 6 , R 7 , R 8 , R 9 NR 10 R 11 And R b = R of formula (I) 1 , R 3 , R 4 , R5

[0563] Reagents: (a) ClSO 3 H, 100°C; (b) amine, pyridine, DCM, RT

[0564] Chlorosulfonylation of 1-1 using chlorosulfonic acid affords the sulfonyl chloride 1-2. The sulfonyl chloride 1-2 reacts with an appropriate amine in the presence of pyridine to afford the sulfonamide 1-3.

[0565] Solution 2

[0566]

[0567] Where R b = R of formula (I) 1 , R 3 , R 4 , R 5

[0568] Reagents: (a) amine, DCM; (b) H 2 , 10% Pd / C, EtOH; (c) Fe, NH 4 Cl, IPA, water; (d) NH 4 OH(aq), Na 2 S 2 O 4 ,THF,H 2 O, RT; (e) Sulfonyl chloride, pyridine, DCM, RT; (f) LiOH(aq), THF, MeOH; (g) LiOH(aq), dioxane.

[0569] In a nucleophilic substitution reaction, fluoro-2-nitro-4-(trifluoromethyl)benzene (I-4) is reacted with an appropriate amine, and the resulting nitro compound I-5 is then reduced to the aniline I-6. The aniline I-6 is reacted with an appropriate sulfonyl chloride to give the sulfonamide I-7. Ester hydrolysis gives the corresponding carboxylic acid I-8.

[0570] Solution 3

[0571]

[0572] Reagents: (a) aniline, pyridine, DCM, RT; (b) amine, THF, 60°C; (c) LiOH(aq), THF, 50°C.

[0573] The sulfonyl chloride 1-9 is reacted with an appropriate aniline to give the sulfonamide 1-10. Nucleophilic substitution with an appropriate amine gives 1-11, which is hydrolyzed to give the corresponding carboxylic acid 1-12.

[0574] Solution 4

[0575]

[0576] Where R a = R of formula (I) 6 , R 7 , R 8 , R 9 And R b = R of formula (I) 1 , R 2 , R 3 , R 4 , R 5

[0577] Reagents: (a) Sulfonyl chloride, pyridine, DCM, RT; (b) LiOH(aq), dioxane or THF, RT.

[0578] Sulfonamide 1-14 is prepared by reaction of aniline 1-13 with an appropriate sulfonyl chloride. Ester hydrolysis affords the corresponding carboxylic acid 1-15.

[0579] Solution 5

[0580]

[0581] Reagents: (a) aniline, pyridine, DCM, RT; (b) NaOH(aq), MeOH, H 2 O, RT; (c) LiOH(aq), THF, RT.

[0582] Sulfonamide 1-17 is prepared by reaction of sulfonyl chloride 1-16 with an appropriate aniline. Ester hydrolysis affords the corresponding carboxylic acid 1-18.

[0583] Solution 6

[0584]

[0585] Reagents: (a) amine, MeCN; (b) bis(pinacol)diboron, PdCl 2 (dppf)·DCM, KOAc, dioxane; (c) H 2 , Pd / C, MeOH; (d) sulfonyl chloride, pyridine, DCM, RT; (e) aryl halide, Xphos Pd G3, K 3 PO 4 , dioxane, water; (f) LiOH(aq), THF, MeOH; (g) HCl, dioxane.

[0586] In a nucleophilic substitution reaction, 4-bromo-1-fluoro-2-nitrobenzene (1-19) is reacted with an appropriate amine and the resulting aryl bromide is then converted to the boronate ester 1-20. Reduction of the nitro group then affords the corresponding aniline 1-21. Reaction of 1-21 with an appropriate sulfonyl chloride affords the sulfonamide 1-22. The remaining substituents are introduced by Suzuki coupling followed by ester hydrolysis to afford the corresponding carboxylic acid 1-24. Alternatively, these steps may be performed in the indicated alternative order.

[0587] General experimental conditions

[0588] All starting materials and solvents were obtained from commercial sources or prepared according to literature citations. Unless otherwise stated, the reaction mixtures were stirred magnetically and reacted at room temperature (about 20° C.). Unless otherwise stated, column chromatography was performed on an automated flash chromatography system (e.g., CombiFlash Rf system) using pre-packed silica (40 μm) columns. The HPLC-MS / MS was performed using a Bruker 5 mm SmartProbe TM Bruker Avance III HD spectrometer recorded at 500MHz 1 H NMR spectra. Chemical shifts are expressed in parts per million and are referenced to the central peak of the residual protic solvent or tetramethylsilane internal standard. Spectra were recorded at 298 K unless otherwise stated. Analyses were performed using a Waters ACQUIETY PDA detector and an ACQUIETY QDa mass detector. Analytical UPLC-MS experiments to determine retention times and associated mass ions were performed using an H-class system running one of the following analytical methods. 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 following analytical methods. Preparative HPLC purifications were performed using a Waters X-Select CSH C18, 5μm, 19×50 mm column using a gradient of MeCN and water (both modified with 0.1% v / v formic acid) or a gradient of MeCN and 10 mM ammonium bicarbonate (aq) on a Waters X-Bridge BEH C18, 5μm, 19×50 mm column. Fractions were collected after detection by UV at a single wavelength measured by a variable wavelength detector. The HPLC-MS results were obtained using a flow cytometer from The "structure to name" conversion of Professional 17 (PerkinElmer) generated the names of the structures.

[0589] Analytical methods

[0590] Method 1 - Acidic 3 min method

[0591] Column: Waters ACQUITY CSH C18, 1.7 μm, 2.1×30 mm, 40 °C

[0592] Detection: UV at 254 nm unless otherwise specified, MS by electrospray ionization

[0593] Solvents: A: Aqueous solution of 0.1% v / v formic acid, B: MeCN solution of 0.1% v / v formic acid

[0594] Gradient:

[0595] time ％A ％B Flow rate (ml / min) 0.00 95 5 0.77 0.11 95 5 0.77 2.15 5 95 0.77 2.56 5 95 0.77 2.83 95 5 0.77 3.00 95 5 0.77

[0596] Method 2 - Basic 3 min method

[0597] Column: Waters ACQUITY BEH C18, 1.7 μm, 2.1×30 mm, 40 °C

[0598] Solvents: A: 10 mM ammonium bicarbonate (aq), B: MeCN

[0599] (Other parameters are the same as Method 1)

[0600] Method 3 - Acidic 4 min method

[0601] Column: Waters X-Select CSH C18, 2.5 μm, 4.6×30 mm, 40 °C

[0602] Detection: UV at 254 nm unless otherwise specified, MS by electrospray ionization

[0603] Solvents: A: Aqueous solution of 0.1% v / v formic acid, B: MeCN solution of 0.1% v / v formic acid

[0604] Gradient:

[0605] time ％A ％B Flow rate (ml / min) 0.0 95.0 5.0 2.5 3.0 5.0 95.0 2.5 3.01 5.0 95.0 4.5 3.6 5.0 95.0 4.5 3.7 95.0 5.0 2.5 4.0 95.0 5.0 2.5

[0606] Method 4 - Basic 4 min method

[0607] Column: Waters X-Bridge BEH C18, 2.5 μm, 4.6×30 mm, 40 °C

[0608] Solvents: A: 10 mM ammonium bicarbonate (aq), B: MeCN

[0609] (Other parameters are the same as Method 3)

[0610] Example 1: 4-ethyl-3-(N-(2-(piperidin-1-yl)-5-(trifluoromethyl)phenyl)sulfamoyl)benzoic acid

[0611]

[0612] Step 1: 3-(Chlorosulfonyl)-4-ethylbenzoic acid: A solution of 4-ethylbenzoic acid (1 g, 6.66 mmol) in chlorosulfonic acid (10 ml, 149 mmol) was heated at 100°C overnight. The mixture was cooled and carefully added to stirred ice. The resulting precipitate was collected by filtration to give the title compound (1.58 g, 6.04 mmol, 91% yield, 95% purity) as a white solid. 1 H NMR (500 MHz, DMSO-d 6 )δ8.34(d,J=1.9Hz,1H),7.82(dd,J=7.9,2.0Hz,1H),7.32(d,J=7.9Hz,1H),3.08(q,J=7.5Hz,2H),1.19(t,J=7.5Hz,3H). No exchangeable proton was observed.

[0613] Step 2: 4-ethyl-3-(N-(2-(piperidin-1-yl)-5-(trifluoromethyl)phenyl)sulfamoyl)benzoic acid: A solution of 2-(piperidin-1-yl)-5-(trifluoromethyl)aniline (0.200 g, 0.819 mmol) in pyridine (3 ml, 37.1 mmol) was treated with the product of Step 1 above (0.244 g, 0.983 mmol) and the solution was stirred at room temperature for 24 h. The solvent was removed under vacuum and the crude product was purified by silica gel column chromatography (24 g cartridge, 0-100% EtOAc / isohexane then 0-50% EtOAc / DCM) to give the title compound (36.3 mg, 0.076 mmol, 9.23% yield, 97% purity) as a tan solid. UPLC-MS (Method 1) m / z 457.4 at 1.87 min (M+H) + ,455.2(MH) - . 1 H NMR (500 MHz, DMSO-d 6)δ13.28(bs,1H),9.44(bs,1H),8.36(d,J=1.8Hz,1H),8.09(dd,J=8.0,1.8Hz,1H),7.60(d,J=8.0Hz,1H),7.42(dd,J=8.4,2.2Hz,1H),7.29(d,J =2.1Hz,1H),7.25(d,J=8.4Hz,1H),3.04(q,J=7.4Hz,2H),2.72(t,J=4.9 Hz, 4H), 1.57 (p, J = 5.0Hz, 4H), 1.50-1.45 (m, 2H), 1.21 (t, J = 7.4Hz, 3H).

[0614] Example 3: 4-isopropyl-3-(N-(2-(piperidin-1-yl)-5-(trifluoromethyl)phenyl)sulfamoyl)benzoic acid

[0615]

[0616] Step 1: 3-(Chlorosulfonyl)-4-isopropylbenzoic acid: A solution of 4-isopropylbenzoic acid (1 g, 6.09 mmol) in chlorosulfonic acid (5 ml, 74.7 mmol) was heated at 100°C overnight. The mixture was cooled and carefully added to stirred ice. The resulting precipitate was collected by filtration and dried in vacuo to give the title compound (1.28 g, 4.63 mmol, 76% yield, 95% purity) as a tan solid. 1 H NMR (500 MHz, DMSO-d 6 )δ12.50(bs,1H),8.36(d,J=1.9Hz,1H),7.83(dd,J=8.1,1.9Hz,1H),7.44(d,J=8.1Hz,1H),4.20(septet,J=6.8Hz,1H),1.16(d,J=6.9Hz,6H).

[0617] Step 2: 4-isopropyl-3-(N-(2-(piperidin-1-yl)-5-(trifluoromethyl)phenyl)sulfamoyl)benzoic acid: A solution of 2-(piperidin-1-yl)-5-(trifluoromethyl)aniline (0.070 g, 0.287 mmol) in DCM (1 ml) and pyridine (0.139 ml, 1.720 mmol) was added to a solution of the product of Step 1 above (0.090 g, 0.344 mmol) in DCM (1 ml) and the solution was stirred at room temperature for 16 h. The solvent was removed under vacuum and the residue was purified by silica gel column chromatography (24 g cartridge, 0-50% EtOAc / DCM) to give the title compound (14.3 mg, 0.029 mmol, 10% yield, 95% purity) as a light brown solid. UPLC-MS (method 1) m / z 471.4 (M+H) at 1.93 min + ,469.3(MH) - . 1 H NMR (500 MHz, DMSO-d 6 )δ13.29(bs,1H),9.40(bs,1H),8.45(d,J=1.9Hz,1H),8.13(dd,J=8.3,1.9Hz,1H),7.76(d,J=8.2Hz,1H),7.42(dd,J=8.2,1.9Hz,1H),7.27(d,J =8.3Hz, 1H), 7.19 (d, J = 1.9Hz, 1H), 3.86 (Sevent, J = 6.8Hz, 1H), 2.78 (t, J = 5.2Hz, 4H), 1.58 (p, J = 5.5Hz, 4H), 1.51-1.45 (m, 2H), 1.24-1.10 (m, 6H).

[0618] Example 4: 3-(N-(2-(piperidin-1-yl)-5-(trifluoromethyl)phenyl)sulfamoyl)-4-(trifluoromethoxy)benzoic acid

[0619]

[0620] Step 1: 3-(Chlorosulfonyl)-4-(trifluoromethoxy)benzoic acid: A solution of 4-(trifluoromethoxy)benzoic acid (1 g, 4.85 mmol) in chlorosulfonic acid (5 ml, 74.7 mmol) was heated at 100°C overnight. The mixture was cooled and carefully added to stirred ice. The resulting precipitate was collected by filtration and dried under vacuum to give the title compound (0.770 g, 2.28 mmol, 46.9% yield, 90% purity) as a cream solid. 1 H NMR (500 MHz, DMSO-d 6)δ12.50(bs,1H),8.40(d,J=2.2Hz,1H),8.00(dd,J=8.5,2.2Hz,1H),7.41(dq,J=8.5,1.8Hz,1H).

[0621] Step 2: 3-(N-(2-(piperidin-1-yl)-5-(trifluoromethyl)phenyl)sulfamoyl)-4-(trifluoromethoxy)benzoic acid: A solution of 2-(piperidin-1-yl)-5-(trifluoromethyl)aniline (0.070 g, 0.287 mmol) in DCM (1 ml) and pyridine (0.139 ml, 1.72 mmol) was added to a solution of the product of Step 1 above (0.105 g, 0.344 mmol) in DCM (1 ml), and the solution was stirred at room temperature for 16 h. The solvent was removed under vacuum and the residue was purified by silica gel column chromatography (24 g cartridge, 0-50% EtOAc / DCM) to give the title compound (5.6 mg, 10.4 μmol, 3.6% yield, 95% purity) as a cream solid. UPLC-MS (method 1) m / z 513.3 (M+H) at 1.94 min + ,511.1(MH) - . 1 H NMR (500 MHz, DMSO-d 6 )δ13.68(bs,1H),9.50(bs,1H),8.45(d,J=1.7Hz,1H),8.27(dd,J=8.2,1.5Hz,1H),7.68(d,J= 8.7Hz, 1H), 7.46-7.44 (m, 2H), 7.27 (d, J = 8.2Hz, 1H), 2.71 (t, J = 5.0Hz, 4H), 1.62-1.34 (m, 6H).

[0622] Example 6: 3-(N-(2-(cis-3,5-dimethylpiperidin-1-yl)-5-(trifluoromethyl)phenyl)sulfamoyl)-4-methoxybenzoic acid

[0623]

[0624] Step 1: cis-3,5-dimethyl-1-(2-nitro-4-(trifluoromethyl)phenyl)piperidine: Et 3N (0.5 ml, 3.59 mmol) was added to a solution of 1-fluoro-2-nitro-4-(trifluoromethyl)benzene (201 μl, 1.44 mmol) and cis-3,5-dimethylpiperidine (211 mg, 1.87 mmol) in DCM (6 ml) and the resulting solution was stirred at room temperature for 20 h. The crude product was purified by silica gel column chromatography (12 g cartridge, 0-100% EtOAc in isohexane, then 0-10% MeOH / DCM) to give the title compound (356 mg, 1.12 mmol, 78% yield, 95% purity) as a light orange solid. UPLC-MS (Method 1) m / z 303.4 at 2.01 min (M+H) + .

[0625] Step 2: 2-(cis-3,5-dimethylpiperidin-1-yl)-5-(trifluoromethyl)aniline: The product of step 1 above (150 mg, 0.496 mmol) was dissolved in EtOH (9.9 ml) and the reaction mixture was heated on a Thales Nano H- The reaction mixture was concentrated in vacuo and azeotroped with MeOH (6 ml) to give the title compound (133 mg, 0.479 mmol, 96% yield, 98% purity) as a light brown oil. UPLC-MS (Method 2) m / z 273.3 (M+H) at 2.00 min + ,271.1(MH) - .

[0626] Step 3: Methyl 3-(N-(2-(cis-3,5-dimethylpiperidin-1-yl)-5-(trifluoromethyl)phenyl)sulfamoyl)-4-methoxybenzoate: The product of Step 2 above (51.4 mg, 0.189 mmol) was dissolved in a mixture of DCM (1 ml) and pyridine (50 μl, 0.618 mmol) and treated with a solution of methyl 3-(chlorosulfonyl)-4-methoxybenzoate (60 mg, 0.227 mmol) in DCM (1 ml). The resulting solution was stirred at room temperature for 3 days. The reaction mixture was directly loaded and purified by silica gel column chromatography (12 g cartridge, 0-100% EtOAc / isohexane) to give the title compound (63 mg, 0.120 mmol, 63.3% yield, 95% purity) as a cream solid. UPLC-MS (method 1) m / z 501.4 (M+H) at 2.05 min + ,498.9(MH) - .

[0627] Step 4: 3-(N-(2-(cis-3,5-dimethylpiperidin-1-yl)-5-(trifluoromethyl)phenyl)sulfamoyl)-4-methoxybenzoic acid: The product of Step 3 above (61 mg, 0.122 mmol) was dissolved in THF (2 ml) and treated with 1.1 M LiOH(aq) (443 μl, 0.487 mmol). MeOH was added dropwise until a clear solution was formed. The reaction mixture was heated at 40°C for 24 h and then cooled to room temperature overnight. The reaction mixture was diluted with water (3 ml), concentrated in vacuo, and the resulting aqueous solution was diluted with water (5 ml). 1 M HCl(aq) was added dropwise to about pH 6. The resulting white precipitate was collected by filtration and washed with water. The solid was suspended in MeCN (4 ml), concentrated in vacuo, and dried at 45°C to give the title compound (55 mg, 0.113 mmol, 88% yield, 95% purity) as a light yellow solid. UPLC-MS (method 1) m / z 487.4 (M+H) at 1.89 min + ,485.2(MH) - . 1 H NMR (500 MHz, DMSO-d 6 )δ13.16(s,1H),8.82(s,1H),8.34(d,J=2.3Hz,1H),8.15(dd,J=8.7,2.3 Hz,1H),7.47(d,J=2.1Hz,1H),7.36(dd,J=8.5,2.1Hz,1H),7.30(d,J=8.7 Hz,1H),7.29(d,J=8.5Hz,1H),3.84(s,3H),2.89-2.80(m,2H),2.14(t,J= 11.0Hz, 2H), 1.82-1.65 (m, 3H), 0.81 (d, J = 6.4Hz, 6H), 0.67-0.59 (m, 1H).

[0628] Example 7: 3-(N-(2-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-5-(trifluoromethyl)phenyl)sulfamoyl)-4-methoxybenzoic acid

[0629]

[0630] Step 1: 3-(2-nitro-4-(trifluoromethyl)phenyl)-8-oxa-3-azabicyclo[3.2.1]octane: Et 3N (0.583 ml, 4.18 mmol) was added to a solution of 1-fluoro-2-nitro-4-(trifluoromethyl)benzene (0.167 ml, 1.20 mmol) and 8-oxa-3-azabicyclo[3.2.1]octane hydrochloride (221 mg, 1.44 mmol) in DCM (5 ml), and the resulting solution was stirred at room temperature for 2 h. 1 M HCl(aq) (2 ml) was added, the organic phase was separated by a phase separator and concentrated in vacuo to give the title compound (384 mg, 1.08 mmol) as a yellow solid. UPLC-MS (Method 2) m / z 303.2 (M+H) at 1.54 min + . 1 HNMR (500 MHz, DMSO-d 6 )δ8.13-8.08(m,1H),7.84(dd,J=8.9,2.3Hz,1H),7.46(d,J=8.9Hz,1H),4 .39-4.32(m,2H),3.16-3.11(m,2H),3.02-2.97(m,2H),1.89-1.77(m,4H).

[0631] Step 2: 2-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-5-(trifluoromethyl)aniline: The product of step 1 above (323 mg, 1.07 mmol) was dissolved in EtOH (21.2 ml) and the reaction mixture was heated on a Thales Nano H- The reaction mixture was concentrated in vacuo and azeotroped with MeOH (8 ml) to give the title compound (310 mg, 1.059 mmol, 100% yield, 93% purity) as an off-white solid. UPLC-MS (Method 2) m / z 273.3 (M+H) at 1.43 min + . 1 H NMR (500 MHz, DMSO-d 6 )δ7.05(d,J=8.2Hz,1H),7.02(d,J=2.2Hz,1H),6.86(dd,J=8.2,2.2Hz,1H),5.01(br s,2H),4.36-4.31(m,2H),2.88-2.82(m,2H),2.79(dd,J=11.5,2.0Hz,2H),2.09-2.03(m,2H),1.88-1.80(m,2H).

[0632] Step 3: Methyl 3-(N-(2-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-5-(trifluoromethyl)phenyl)sulfamoyl)-4-methoxybenzoate: Pyridine (58 μl, 0.72 mmol) was added to a solution of the product of Step 2 above (66.5 mg, 0.239 mmol) and methyl 3-(chlorosulfonyl)-4-methoxybenzoate (80 mg, 0.287 mmol) in DCM (2 ml) at room temperature. The resulting solution was stirred at 40° C. for 4 h, then additional methyl 3-(chlorosulfonyl)-4-methoxybenzoate (80 mg, 0.287 mmol) and pyridine (58 μl, 0.718 mmol) were added, and the mixture was stirred at 40° C. for another 19 h. The reaction mixture was concentrated in vacuo. The crude product was purified by silica gel column chromatography (25 g cartridge, 0-80% EtOAc / isohexane) to afford the title compound (88.3 mg, 0.173 mmol, 72.3% yield, 98% purity) as an off-white solid. UPLC-MS (Method 2) m / z 501.3 (M+H) at 1.59 min + ,499.2(MH) - .

[0633] Step 4: 3-(N-(2-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-5-(trifluoromethyl)phenyl)sulfamoyl)-4-methoxybenzoic acid: 1M LiOH(aq) (0.699ml, 0.699mmol) was added to a solution of the product of step 3 above (87.4mg, 0.175mmol) in THF (1.4ml) at room temperature, and the resulting solution was stirred at room temperature for 24h. The reaction mixture was concentrated in vacuo, and the residue was redissolved in water (3ml) and acidified to pH 4 to 5 using 1M HCl(aq). The precipitate was isolated by filtration and then dried to give the title compound (74mg, 0.152mmol, 87% yield, 100% purity) as a white solid. UPLC-MS (Method 1) m / z 487.3 (M+H) at 1.45min + ,485.1(MH) - . 1 H NMR (500 MHz, DMSO-d 6)δ13.13(br s,1H),8.88(br s,1H),8.24(d,J=2.2Hz,1H),8.18(dd,J=8.7,2.2Hz,1H),7.46-7.34(m,2H),7.27(d,J=8.5Hz,1H),6.98(d,J=2.1Hz,1H), 4.40-4.33(m,2H),3.95(s,3H),3.01(d,J=11.2Hz,2H),2.95(dd,J=11.6,2.0Hz,2H),2.13-2.05(m,2H),1.92-1.84(m,2H).

[0634] Example 8: 4-methoxy-3-(N-(2-(cis-5-methylhexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)-5-(trifluoromethyl)phenyl)sulfamoyl)benzoic acid

[0635]

[0636] Step 1: cis-2-methyl-5-(2-nitro-4-(trifluoromethyl)phenyl)octahydropyrrolo[3,4-c]pyrrole: Et 3 N (0.417 ml, 2.99 mmol) was added to a solution of 1-fluoro-2-nitro-4-(trifluoromethyl)benzene (0.167 ml, 1.20 mmol) and cis-2-methyloctahydropyrrolo[3,4-c]pyrrole (187 mg, 1.44 mmol) in DCM (5 ml), and the resulting solution was stirred at room temperature for 2 h. 1 M HCl(aq) (2 ml) was added, the organic phase was dried by a phase separator, and concentrated in vacuo to give the title compound as an orange solid (402 mg, 1.20 mmol, yield quantitative, purity 93%). UPLC-MS (Method 2) m / z 316.3 (M+H) at 1.40 min + . 1 H NMR (500 MHz, DMSO-d 6 )δ8.04-8.01 (m, 1H), 7.72 (dd, J = 9.1, 2.4 Hz, 1H), 7.22 (d, J = 9.0 Hz, 1H), 3.49-3.42 (m, 2H), 3.13 (dd, J = 10.8, 3.4 Hz, 2H), 2.94-2.85 (m, 2H), 2.53-2.44 (m, 4H), 2.24 (s, 3H). The DMSO signal obscured the signal at 2.49 ppm.

[0637] Step 2: 2-(cis-5-methylhexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)-5-(trifluoromethyl)aniline: The product of step 1 above (376 mg, 1.19 mmol) was dissolved in EtOH (23.9 ml) and the reaction mixture was heated in a Thales NanoH- The reaction mixture was concentrated in vacuo and azeotroped with MeOH (12 ml) to give the title compound (355 mg, 1.17 mmol, 98% yield, 94% purity) as an off-white solid. UPLC-MS (Method 2) 286.3 (M+H) at 1.24 min + .

[0638] Step 3: Methyl 4-methoxy-3-(N-(2-(cis-5-methylhexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)-5-(trifluoromethyl)phenyl)sulfamoyl)benzoate: Pyridine (58 μl, 0.72 mmol) was added to a slurry of the product of Step 2 above (72.6 mg, 0.239 mmol) and methyl 3-(chlorosulfonyl)-4-methoxybenzoate (80 mg, 0.287 mmol) in DCM (2 ml) at room temperature. The resulting solution was stirred at 40°C for 4 h, then additional methyl 3-(chlorosulfonyl)-4-methoxybenzoate (80 mg, 0.287 mmol) and pyridine (0.058 ml, 0.718 mmol) were added and the mixture was stirred at 40°C for an additional 19 h. The reaction mixture was concentrated in vacuo and the crude product was purified by silica gel column chromatography (25 g cartridge, 0-10% MeOH / DCM) to afford the title compound (158 mg, 0.193 mmol, 81% yield, 63% purity) as an off-white solid. UPLC-MS (Method 2) m / z 514.4 (M+H) at 1.26 min + ,512.2(MH) - .

[0639] Step 4: 4-methoxy-3-(N-(2-(cis-5-methylhexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)-5-(trifluoromethyl)phenyl)sulfamoyl)benzoic acid: 1M LiOH(aq) (1.23 ml, 1.23 mmol) was added to a solution of the product of step 3 above (158 mg, 0.308 mmol) in THF (2.5 ml) at room temperature and the solution was stirred at room temperature for 26 h. The reaction mixture was concentrated in vacuo and the residue was redissolved in water (3 ml) and acidified to pH 4 to 5 using 1M HCl(aq). The precipitate was isolated by filtration and then dried in vacuo to give the title compound (63.5 mg, 0.127 mmol, 41.3% yield, 98% purity) as an off-white solid. UPLC-MS (Method 2) m / z 500.3 (M+H) at 0.83 min + ,498.3(MH) - . 1 H NMR (500 MHz, DMSO-d 6 )δ8.22 (d, J = 2.2 Hz, 1H), 8.13 (dd, J = 8.7, 2.2 Hz, 1H), 7.31 (d, J = 8.7 Hz, 1H), 7.28-7.24 (m, 1H), 6.97-6.91 (m, 2H), 3.90 (s, 3H), 3.36 (dd, J = 9.8, 6.5 Hz, 2H), 3.22 (dd, J = 10.0, 2.7 Hz, 2H), 2.86-2.80 (m, 2H), 2.75-2.69 (m, 2H), 2.64-2.59 (m, 2H), 2.38 (s, 3H). Two exchangeable protons were not observed.

[0640] Example 9: 3-(N-(2-(3,3-difluoropiperidin-1-yl)-5-(trifluoromethyl)phenyl)sulfamoyl)-4-methoxybenzoic acid

[0641]

[0642] Step 1: 3,3-Difluoro-1-(2-nitro-4-(trifluoromethyl)phenyl)piperidine: Et 3N (0.500 ml, 3.59 mmol) was added to a solution of 1-fluoro-2-nitro-4-(trifluoromethyl)benzene (0.201 ml, 1.44 mmol) and 3,3-difluoropiperidine hydrochloride (271 mg, 1.72 mmol) in DCM (6 ml), and the resulting solution was stirred at room temperature for 20 h. Water (3 ml) was added and the phases were separated using a phase separator. The aqueous phase was extracted with DCM (2×3 ml), and the organic phases were combined, dried through a phase separator, and concentrated in vacuo. The crude product was purified by silica gel column chromatography (12 g cartridge, 0-100% EtOAc / isohexane) to give the title compound (399 mg, 1.26 mmol, 87.8% yield, purity>98%) as a bright yellow solid. UPLC-MS (Method 2) m / z 309.0 (MH) at 1.64 min - .

[0643] Step 2: 2-(3,3-difluoropiperidin-1-yl)-5-(trifluoromethyl)aniline: The product of step 1 above (156 mg, 0.503 mmol) was dissolved in EtOH (10.1 ml) and the reaction mixture was heated on a Thales Nano H- The reaction mixture was concentrated in vacuo and azeotroped with MeOH (6 ml) to give the title compound (119 mg, 0.408 mmol, 81% yield, 96% purity) as a colorless oil. UPLC-MS (Method 2) m / z 280.8 (M+H) at 1.64 min + .

[0644] Step 3: Methyl 3-(N-(2-(3,3-difluoropiperidin-1-yl)-5-(trifluoromethyl)phenyl)sulfamoyl)-4-methoxybenzoate: The product of Step 2 above (53.0 mg, 0.189 mmol) was dissolved in a mixture of DCM (1 ml) and pyridine (0.05 ml, 0.618 mmol) and treated with a solution of methyl 3-(chlorosulfonyl)-4-methoxybenzoate (60.0 mg, 0.227 mmol) in DCM (1 ml). The resulting solution was stirred at room temperature for 4 days. The crude product was purified by silica gel column chromatography (12 g cartridge, 0-10% MeOH / DCM) to give the title compound (39.9 mg, 0.075 mmol, 39.4% yield, 95% purity) as a white solid. UPLC-MS (method 1) m / z 509.4 (M+H) at 1.75 min + ,507.2(MH) - .

[0645] Step 4: 3-(N-(2-(3,3-difluoropiperidin-1-yl)-5-(trifluoromethyl)phenyl)sulfamoyl)-4-methoxybenzoic acid: The product of step 3 above (38 mg, 0.075 mmol) was dissolved in THF (2 ml) and treated with 1.1 M LiOH(aq) (272 μl, 0.299 mmol), and MeOH was added dropwise until the mixture became a solution. The reaction mixture was stirred at 30 °C for 4 days. The reaction mixture was diluted with water (3 ml), concentrated in vacuo, and the resulting aqueous solution was diluted with water (to about 5 ml) and neutralized with 1 M HCl to about pH 6. The resulting block suspension was sonicated to give a turbid solution. The white precipitate was collected by filtration, washed with water, and the solid was suspended in MeCN (4 ml), concentrated in vacuo, and dried at 45 °C to give the title compound (34 mg, 0.065 mmol, 87% yield, 95% purity) as a white solid. UPLC-MS (method 1) m / z 495.1 (M+H) at 1.59 min + ,493.1(MH) - , purity 98% (254nm). 1 H NMR (500 MHz, DMSO-d 6 )δ13.18(br s,1H),8.60(br s,1H),8.37(d,J=2.2Hz,1H),8.16(dd,J=8.7,2.2Hz,1H),7.41-7.36(m,3H),7.32(d,J=8.8Hz,1H) ,3.91(s,3H),3.17(t,J=11.1Hz,2H),2.95(t,J=5.3Hz,2H),2.13-2.00(m,2H),1.88-1.84(m,2H).

[0646] Example 10: 3-(N-(2-(8-azabicyclo[3.2.1]oct-8-yl)-5-(trifluoromethyl)phenyl)sulfamoyl)-4-methoxybenzoic acid

[0647]

[0648] Step 1: 8-(2-nitro-4-(trifluoromethyl)phenyl)-8-azabicyclo[3.2.1]octane: Et 3N (0.236 ml, 1.69 mmol) was added to a solution of 1-fluoro-2-nitro-4-(trifluoromethyl)benzene (0.095 ml, 0.677 mmol) and 8-azabicyclo[3.2.1]octane hydrochloride (100 mg, 0.677 mmol) in DCM (2 ml) and the resulting solution was stirred at room temperature for 20 h. Water (3 ml) was added and the phases were separated using a phase separator. The aqueous phase was extracted with DCM (2×3 ml) and the organic phases were combined, dried through a phase separator and concentrated in vacuo. The crude product was purified by silica gel column chromatography (12 g cartridge, 0-100% EtOAc / isohexane) to give the title compound (183 mg, 0.597 mmol, 88.2% yield, 98% purity). UPLC-MS (Method 2) m / z 301.3 (M+H) at 1.85 min + .

[0649] Step 2: 2-(8-Azabicyclo[3.2.1]octan-8-yl)-5-(trifluoromethyl)aniline: The product of Step 1 above (134 mg, 0.446 mmol) was dissolved in EtOH (8.9 ml) and the reaction mixture was heated on a Thales Nano H- The reaction mixture was concentrated in vacuo and azeotroped with MeOH (6 ml) to give the title compound (104 mg, 0.366 mmol, 82% yield, 95% purity) as a colorless oil. UPLC-MS (Method 2) m / z 271.3 (M+H) at 1.83 min + .

[0650] Step 3: methyl 3-(N-(2-(-8-azabicyclo[3.2.1]octan-8-yl)-5-(trifluoromethyl)phenyl)sulfamoyl)-4-methoxybenzoate: The product of step 2 above (51.1 mg, 0.189 mmol) was dissolved in a mixture of DCM (1 ml) and pyridine (0.05 ml, 0.618 mmol) and treated with a solution of methyl 3-(chlorosulfonyl)-4-methoxybenzoate (60.0 mg, 0.227 mmol) in DCM (1 ml). The resulting solution was stirred at room temperature for 4 days. The crude product was purified by silica gel column chromatography (12 g cartridge, 0-10% MeOH / DCM) to give the title compound (32.1 mg, 0.061 mmol, 32.4% yield, 95% purity) as a white solid. UPLC-MS (method 1) m / z 499.3 (M+H) at 1.90 min + ,497.2(MH) - .

[0651] Step 4: 3-(N-(2-(-8-azabicyclo[3.2.1]octan-8-yl)-5-(trifluoromethyl)phenyl)sulfamoyl)-4-methoxybenzoic acid: The product of Step 3 above (30 mg, 0.060 mmol) was dissolved in THF (2 ml) and treated with 1.1 M LiOH(aq) (219 μl, 0.241 mmol). MeOH was added dropwise until the mixture became a solution, and the reaction was stirred at 30°C for 4 days. The reaction mixture was diluted with water (3 ml), concentrated in vacuo, and the resulting aqueous solution was diluted with water (to about 5 ml) and neutralized to about pH 6 with 1 M HCl. The resulting blocky suspension was sonicated to give a turbid solution, and the precipitate was collected by filtration and washed with water. The solid was suspended in MeCN (4 ml), concentrated in vacuo, and dried at 45°C. The crude product was purified by preparative HPLC (Waters, acidic (0.1% formic acid), acidic, Waters X-Select Prep-C18, 5 μm, 19×50 mm column, 50% to 80% MeCN in water) to give the title compound (9.0 mg, 0.018 mmol, 29.3% yield, 95% purity) as a white solid. UPLC-MS (Method 1) m / z 485.2 (M+H) at 1.74 min + ,483.3(MH) - . 1 H NMR (500 MHz, DMSO-d 6 )δ13.12(br s,1H),8.96(br s,1H),8.21(d,J=2.2Hz,1H),8.16(dd,J=8.8,2.2Hz,1H),7.34(d,J=8.7Hz,1H),7.27(dd,J=8.7,2.3Hz,1H),7.01(d,J=8.7Hz ,1H),6.95-6.92(m,1H),4.29(s,2H),3.93(s,3H),1.91-1.86(m,2H),1.79-1.68(m,6H),1.55-1.46(m,1H),1.45-1.37(m,1H).

[0652] Example 11: 3-(N-(2-(5-oxa-2-azaspiro[3.4]oct-2-yl)-5-(trifluoromethyl)phenyl)sulfamoyl)-4-methoxybenzoic acid

[0653]

[0654] Step 1: 2-(2-nitro-4-(trifluoromethyl)phenyl)-5-oxa-2-azaspiro[3.4]octane: Et 3 N (500 μl, 3.59 mmol) was added to a solution of 1-fluoro-2-nitro-4-(trifluoromethyl)benzene (201 μl, 1.44 mmol) and 5-oxa-2-azaspiro[3.4]octane hemioxalate (349 mg, 2.21 mmol) in DCM (6 ml), and the resulting solution was stirred at room temperature for 20 h. 1 M HCl(aq) (2 ml) was added, and the organic phase was dried by a phase separator. The organic phase was concentrated in vacuo to give the title compound (438 mg, 1.44 mmol, yield 100%, purity 99%) as a light yellow viscous oil. UPLC-MS (Method 2) m / z 303.3 (M+H) at 1.59 min + .

[0655] Step 2: 2-(5-oxa-2-azaspiro[3.4]octan-2-yl)-5-(trifluoromethyl)aniline: The product of step 1 above (217 mg, 0.718 mmol) was dissolved in EtOH (14.4 ml) and the reaction mixture was heated on a Thales Nano H- The reaction mixture was concentrated in vacuo and azeotroped with MeOH (6 ml) to give the title compound (198 mg, 0.691 mmol, 96% yield, 95% purity) as a white solid. UPLC-MS (Method 2) m / z 273.3 (M+H) at 1.37 min + .

[0656] Step 3: Methyl 3-(N-(2-(5-oxa-2-azaspiro[3.4]octan-2-yl)-5-(trifluoromethyl)phenyl)sulfamoyl)-4-methoxybenzoate: The product of Step 2 above (0.073 g, 0.268 mmol) was dissolved in a mixture of DCM (1 ml) and pyridine (0.087 ml, 1.07 mmol) and treated with a solution of methyl 3-(chlorosulfonyl)-4-methoxybenzoate (0.085 g, 0.321 mmol) in DCM (1 ml). The resulting solution was stirred at room temperature for 20 h. The crude product was purified directly by silica gel column chromatography (12 g cartridge, 0-100% EtOAc / isohexane) to give the title compound (93.7 mg, 0.178 mmol, 70.0% yield, 95% purity) as an off-white solid. UPLC-MS (method 1) m / z 501.4 (M+H) at 1.54 min + ,498.8(MH)- .

[0657] Step 4: 3-(N-(2-(5-oxa-2-azaspiro[3.4]octan-2-yl)-5-(trifluoromethyl)phenyl)sulfamoyl)-4-methoxybenzoic acid: The product of Step 3 above (92 mg, 0.184 mmol) was dissolved in THF (2 ml) and treated with 1.1 M LiOH(aq) (668 μl, 0.735 mmol). MeOH was added dropwise until the mixture became a solution, and the reaction was stirred at 30°C for 3 days. The reaction mixture was diluted with water (3 ml), concentrated in vacuo, and the resulting aqueous solution was diluted with water (to about 5 ml) and neutralized to about pH 6 with 1 M HCl. The resulting bulk suspension was sonicated to give a turbid solution. The white precipitate was collected by filtration, washed with water, and the solid was suspended in MeCN (4 ml), concentrated in vacuo, and dried at 45°C. The crude product was purified by preparative HPLC (Waters, acidic (0.1% formic acid), acidic, Waters X-Select Prep-C18, 5 μm, 19×50 mm column, 35% to 65% MeCN in water) to give the title compound (3 mg, 5.98 μmol, 3.25% yield, 97% purity) as a fluffy white solid. UPLC-MS (Method 1) m / z 487.0 (M+H) at 1.37 min + ,485.2(MH) - . 1 H NMR (500 MHz, methanol-d 4 )δ8.33(d,J=2.2Hz,1H),8.29(dd,J=8.7,2.2Hz,1H),7.35(d,J=8.7Hz,1H),7.30(dd,J=8.6,2.2Hz,1H),6.70(d,J=2.1Hz,1H),6.55(d,J=8.6Hz,1H),4.21(d,J=9.0Hz,2H),4.08(d,J=9.0Hz,2H),4.02(s,3H),3.88(t,J=7.0Hz,2H),2.20(t,J=7.0Hz,2H),2.00(p,J=7.0Hz,2H). Two exchangeable protons were not observed.

[0658] Example 12: 3-(N-(2-(4,4-difluoropiperidin-1-yl)-5-(trifluoromethyl)phenyl)sulfamoyl)-4-methoxybenzoic acid

[0659]

[0660] Step 1: 4,4-difluoro-1-(2-nitro-4-(trifluoromethyl)phenyl)piperidine: Et 3 N (0.47 ml, 3.37 mmol) was added to a solution of 1-fluoro-2-nitro-4-(trifluoromethyl)benzene (0.188 ml, 1.34 mmol) and 4,4-difluoropiperidine (196 mg, 1.62 mmol) in DCM (5 ml), and the resulting solution was stirred at room temperature for 19 h. Water (2.5 ml) was added, the organic phase was separated using a phase separator, and concentrated in vacuo to give the title compound (434 mg, 1.04 mmol, 77% yield, 74% purity) as an orange oil. UPLC (Method 2) 1.67 min. 1 H NMR (500 MHz, DMSO-d 6 )δ8.20(d,J=2.3Hz,1H),7.89(dd,J=8.9,2.4Hz,1H),7.53(d,J=8.8Hz,1H),3.28-3.23(m,4H),2.16-2.06(m,4H).

[0661] Step 2: 2-(4,4-difluoropiperidin-1-yl)-5-(trifluoromethyl)aniline: The product of step 1 above (180 mg, 0.580 mmol) was dissolved in EtOH (23.2 ml) and the reaction mixture was heated on a Thales Nano H- The reaction mixture was concentrated in vacuo and azeotroped with MeOH (8 ml) to give the title compound (159 mg, 0.545 mmol, 94% yield, 96% purity) as an off-white solid. UPLC-MS (Method 2) m / z 281.3 (M+H) at 1.63 min + . 1 H NMR (500 MHz, DMSO-d 6 )δ7.04(d,J=8.1Hz,1H),6.97(d,J=2.2Hz,1H),6.82(dd,J=8.2,2.1Hz,1H),5.27(s,2H),2.93(br t,J=5.5Hz,4H),2.24-2.09(m,4H).

[0662] Step 3: Methyl 3-(N-(2-(4,4-difluoropiperidin-1-yl)-5-(trifluoromethyl)phenyl)sulfamoyl)-4-methoxybenzoate: Pyridine (0.058 ml, 0.718 mmol) was added to a solution of the product of Step 2 above (69.8 mg, 0.239 mmol) and methyl 3-(chlorosulfonyl)-4-methoxybenzoate (80 mg, 0.287 mmol) in DCM (2.0 ml) at room temperature. The reaction mixture was stirred and heated at 40°C for 18 h. Additional methyl 3-(chlorosulfonyl)-4-methoxybenzoate (33 mg, 0.120 mmol) was added and the resulting solution was stirred at 40°C for another 3 h. The reaction mixture was concentrated in vacuo and the crude product was purified by silica gel column chromatography (10 g cartridge, 0-30% EtOAc / isohexane) to afford the title compound (107 mg, 0.196 mmol, 82% yield, 93% purity) as an off-white solid. UPLC-MS (Method 2) m / z 509.3 (M+H) at 1.72 min + ,507.2(MH) - .

[0663] Step 4: 3-(N-(2-(4,4-difluoropiperidin-1-yl)-5-(trifluoromethyl)phenyl)sulfamoyl)-4-methoxybenzoic acid: 1 M LiOH(aq) (0.632 ml, 0.632 mmol) was added to a solution of the product of Step 3 above (107 mg, 0.210 mmol) in THF (1.26 ml) at room temperature. The resulting clear solution was stirred at room temperature for 20 h. Additional 1 M LiOH(aq) (0.211 ml, 0.211 mmol) was added and the solution was stirred for another 1 h. The reaction mixture was concentrated in vacuo and the residue was redissolved in water (3 ml) and acidified to pH 4 to 5 using 1 M HCl(aq). The precipitate was dissolved in DCM (10 ml) and the phases were separated. The aqueous phase was extracted with DCM (2×3 ml). The combined organic phases were dried over a phase separator and concentrated in vacuo. The crude product was purified by silica gel column chromatography (10 g cartridge, 0 to 3.5% MeOH / DCM) to give an off-white solid (40.1 mg). The product was purified by preparative HPLC (Waters, acidic (0.1% formic acid), acidic, Waters X-Select Prep-C18, 5 μm, 19×50 mm column, 50% to 80% MeCN in water) to give the title compound as a white solid (19 mg, 0.038 mmol, 18.3% yield, 100% purity). UPLC-MS (Method 1) m / z 495.3 (M+H) at 1.61 min + ,493.2(MH)- . 1 H NMR (500 MHz, DMSO-d 6 )δ13.15(br s,1H),9.30(br s,1H),8.36(d,J=2.2Hz,1H),8.16(dd,J=8.7,2.3Hz,1H),7.48-7.44(m,1H),7.41-7.35(m,1H), 7.35(d,J=8.5Hz,1H),7.32(d,J=8.8Hz,1H),3.87(s,3H),2.96-2.86(m,4H),2.18-2.08(m,4H).

[0664] Example 13: 3-(N-(2-(8-hydroxy-3-azabicyclo[3.2.1]oct-3-yl)-5-(trifluoromethyl)phenyl)sulfamoyl)-4-methoxybenzoic acid

[0665]

[0666] Step 1: 3-(2-nitro-4-(trifluoromethyl)phenyl)-3-azabicyclo[3.2.1]octan-8-ol: Et 3 N (500 μl, 3.59 mmol) was added to a solution of 1-fluoro-2-nitro-4-(trifluoromethyl)benzene (201 μl, 1.44 mmol) and 3-azabicyclo[3.2.1]octan-8-ol hydrochloride (250 mg, 1.53 mmol) in DCM (6 ml), and the resulting solution was stirred at room temperature for 20 h. 1 M HCl(aq) (2 ml) was added, and the organic phase was dried through a phase separator and concentrated in vacuo to give the title compound (468 mg, 1.44 mmol, yield 100%, purity 97%) as a light orange solid. UPLC-MS (Method 2) m / z 315.1 (MH) at 1.53 min - .

[0667] Step 2: 3-(2-amino-4-(trifluoromethyl)phenyl)-3-azabicyclo[3.2.1]octan-8-ol: The product of step 1 above (227 mg, 0.718 mmol) was dissolved in EtOH (14.4 ml) and the reaction mixture was heated on a Thales Nano H- The reaction mixture was concentrated in vacuo and azeotroped with MeOH (6 ml) to give the title compound (186 mg, 0.585 mmol, 81% yield, 90% purity) as a light pink solid. UPLC-MS (Method 2) m / z 287.3 (M+H) at 1.38 min + ,285.2(MH) - .

[0668] Step 3: Methyl 3-(N-(2-(8-hydroxy-3-azabicyclo[3.2.1]octan-3-yl)-5-(trifluoromethyl)phenyl)sulfamoyl)-4-methoxybenzoate: The product of Step 2 above (63.1 mg, 0.220 mmol) was dissolved in a mixture of DCM (1 ml) and pyridine (71.3 μl, 0.882 mmol) and treated with a solution of methyl 3-(chlorosulfonyl)-4-methoxybenzoate (70 mg, 0.264 mmol) in DCM (1 ml). The resulting solution was stirred at room temperature for 20 h. The crude product was purified by silica gel column chromatography (12 g cartridge, 0-100% EtOAc / isohexane) to give the title compound (51 mg, 0.087 mmol, 39.6% yield, 88% purity) as a white solid. UPLC-MS (method 1) m / z 515.4 (M+H) at 1.60 min + ,513.2(MH) - .

[0669] Step 4: 3-(N-(2-(8-hydroxy-3-azabicyclo[3.2.1]octan-3-yl)-5-(trifluoromethyl)phenyl)sulfamoyl)-4-methoxybenzoic acid: The product of Step 3 above (49 mg, 0.095 mmol) was dissolved in THF (2 ml) and treated with 1.1 M LiOH(aq) (346 μl, 0.381 mmol). MeOH was added dropwise until the mixture became a solution, and the reaction was stirred at 30°C for 20 h. The reaction mixture was diluted with water (3 ml), concentrated in vacuo, and the resulting aqueous solution was diluted with water (to about 5 ml). The aqueous phase was washed with EtOAc (2×5 ml) and neutralized to about pH 6 with 1 M HCl. The resulting clumpy suspension was sonicated to give a turbid solution, which was concentrated in vacuo to about 2 ml. The precipitate was collected by filtration and washed with water (2×2 mL). The solid was suspended in MeCN (4 ml) and concentrated in vacuo, and dried at 45°C to give the title compound as a white solid (21.9 mg, 0.042 mmol, 44.6% yield, 97% purity). UPLC-MS (Method 1) m / z 501.3 (M+H) at 1.42 min + ,499.2(MH) - . 1 H NMR (500 MHz, DMSO-d 6 )δ13.17(s,1H),8.69(s,1H),8.34(d,J=2.2Hz,1H),8.17(dd,J=8.7,2.2Hz,1H),7.40-7.32(m,3H),7.17(d,J=1.6Hz,1H),5.07 (s,1H),3.93(s,3H),3.90-3.82(m,1H),3.33-3.31(m,2H),2.61(dd,J=10.7,3.6Hz,2H),2.01-1.97(m,2H),1.86-1.73(m,4H).

[0670] The following examples were prepared by a procedure analogous to Example 13, substituting appropriate starting materials and intermediates where necessary:

[0671]

[0672]

[0673]

[0674]

[0675]

[0676]

[0677] Example 29: 3-(N-(2-(3-hydroxy-3-methylpiperidin-1-yl)-5-(trifluoromethyl)phenyl)sulfamoyl)-4-methoxybenzoic acid

[0678]

[0679] Step 1: 3-Methyl-1-(2-nitro-4-(trifluoromethyl)phenyl)piperidin-3-ol: Et 3 N (0.500 ml, 3.59 mmol) was added to a solution of 1-fluoro-2-nitro-4-(trifluoromethyl)benzene (0.201 ml, 1.44 mmol) and 3-methylpiperidin-3-ol (198 mg, 1.72 mmol) in DCM (6 ml). The clear solution was stirred at room temperature for 17 h. The organic phase was washed with 1M HCl (aq) (3 ml) and the organic phase was dried through a phase separator and concentrated in vacuo to give the title compound (452 ​​mg, 1.35 mmol, yield 94%, purity 91%) as a red / orange oil. UPLC-MS (Method 1) m / z 305.2 (M+H) at 1.49 min + . 1 H NMR (500 MHz, DMSO-d 6 )δ8.07(d,J=2.3Hz,1H),7.76(dd,J=9.0,2.4Hz,1H),7.44(d,J=8.9Hz,1H),4.51(s,1H),3.16(ddd,J=13.2,6.1,3.7Hz,1H),3.08(ddd,J=1 2.8,8.3,3.2Hz,1H),3.00(d,J=12.6Hz,1H),2.90(d,J=12.7Hz,1H),1.87-1.76(m,1H),1.60-1.55(m,2H),1.55-1.48(m,1H),1.10(s,3H).

[0680] Step 2: 1-(2-amino-4-(trifluoromethyl)phenyl)-3-methylpiperidin-3-ol: A solution of 87L-type 5% Pd / C (50% w / w water) (50 mg, 0.012 mmol) in EtOH (0.5 ml) was added to a solution of the product of step 1 above (224 mg, 0.670 mmol) in EtOH (3.0 ml) at room temperature. The reaction mixture was hydrogenated at 4 bar at room temperature for 19 h. The catalyst was removed by filtration and washing with MeOH (20 ml). The organic phase was concentrated in vacuo and the residue was redissolved in EtOAc (10 ml). The organic phase was washed with water (5 ml) and MgSO 4 Dry, filter and concentrate in vacuo to give the title compound as a light orange solid (112 mg, 0.404 mmol, 60.3% yield, 99% purity). UPLC-MS (Method 1) m / z 275.3 (M+H) at 1.42 min + . 1 H NMR (500 MHz, DMSO-d 6 )δ6.94(d,J=8.1Hz,1H),6.92(d,J=1.8Hz,1H),6.81(dd,J=8.1,1.8Hz,1H),5.27(br s,2H),4.58(s,1H),2.91-2.81(m,1H),2.73-2.67(m,1H),2.60-2.51(m,2 H),1.95-1.84(m,1H),1.60-1.50(m,2H),1.47-1.38(m,1H),1.15(s,3H).

[0681] Step 3: Methyl 3-(N-(2-(3-hydroxy-3-methylpiperidin-1-yl)-5-(trifluoromethyl)phenyl)sulfamoyl)-4-methoxybenzoate: Pyridine (0.075 ml, 0.933 mmol) was added to a cloudy solution of the product of Step 2 above (64.6 mg, 0.233 mmol) and methyl 3-(chlorosulfonyl)-4-methoxybenzoate (78 mg, 0.280 mmol) in DCM (2.0 ml) at room temperature. The resulting clear solution was stirred at room temperature for 20 h. The reaction mixture was concentrated in vacuo and the crude product was purified by silica gel column chromatography (12 g cartridge, 30% to 100% EtOAc / isohexane) to give the title compound (98.5 mg, 0.196 mmol, 84% yield, 100% purity) as an off-white foam. UPLC-MS (method 1) m / z 503.4 (M+H) at 1.66 min + ,501.2(MH) - .

[0682] Step 4: 3-(N-(2-(3-hydroxy-3-methylpiperidin-1-yl)-5-(trifluoromethyl)phenyl)sulfamoyl)-4-methoxybenzoic acid: 1M LiOH(aq) (0.784 ml, 0.784 mmol) was added to a solution of the product of step 3 above (98.5 mg, 0.196 mmol) in THF (1.57 ml) at room temperature. The solution was stirred at room temperature for 18 h and then concentrated in vacuo. The residue was redissolved in water (3 ml) and acidified to pH 4 to 5 using 1M HCl(aq). The precipitate was isolated by filtration and then redissolved in EtOAc (5 ml). The organic phase was washed with water (3 ml) and purified by MgSO 4 Dry, filter and concentrate in vacuo to give the title compound as an off-white solid (64 mg, 0.130 mmol, 73.4% yield, 99% purity). UPLC-MS (Method 1) m / z 489.4 (M+H) at 1.49 min + ,487.3(MH) - . 1 H NMR (500 MHz, DMSO-d 6 )δ13.14(br s,1H),9.44(br s,1H),8.41(d,J=2.2Hz,1H),8.14(dd,J=8.7,2.2Hz,1H),7.54(d,J=2.1Hz,1H),7.30(dd,J =8.4,1.7Hz,1H),7.27(d,J=8.8Hz,1H),7.20(d,J=8.3Hz,1H),5.02(brs,1H),3.78(s,3H),2 .93-2.85(m,1H),2.63(td,J=11.1,2.4Hz,1H),2.56-2.52(m,1H),2.52-2.48(m,1H),2.03-1 .90(m,1H),1.62-1.55(m,1H),1.54-1.46(m,1H),1.37(td,J=12.6,4.5Hz,1H),1.02(s,3H).

[0683] Example 30: 3-(N-(2-(cis-3,5-dimethylpiperidin-1-yl)-5-(trifluoromethyl)phenylsulfamoyl)-4-ethylbenzoic acid

[0684]

[0685] A solution of the product of Example 6, Step 2 (72 mg, 0.264 mmol) in DCM (1 ml) and pyridine (0.128 ml, 1.59 mmol) was added to a suspension of the product of Example 1, Step 1 (79 mg, 0.317 mmol) in DCM (1 ml) and the solution was stirred at room temperature for 4 days. The crude product was purified directly by silica gel column chromatography (12 g cartridge, 0-10% MeOH / DCM). The product from the chromatography was partitioned between isohexane (3 ml) and MeCN (3 ml). The phases were separated and the MeCN phase was washed with isohexane (2 x 3 ml) and concentrated in vacuo. The product was loaded onto a silica column with a minimal amount of DCM and the column was eluted with DCM (5 ml), isohexane (5 ml), 5% MeOH in EtOAc (5 ml), then 5% MeOH in EtOAc (5 ml) to afford the title compound as a white solid (26.7 mg, 0.052 mmol, 19.80% yield, 95% purity). UPLC-MS (Method 1) m / z 485.4 (M+H) at 2.06 min + ,483.3(MH) - . 1 H NMR (500 MHz, methanol-d 4 )δ8.54(d,J=1.8Hz,1H),8.15(dd,J=8.0,1.8Hz,1H),7.59(d,J=2.0Hz,1H),7.55(d,J=8.0Hz,1H),7.36-7.27(m,2H),3.07(q,J=7.5Hz,2H),2.79-2.72(m,2H),2.18(t,J=11.1Hz,2H),1.89-1.76(m,3H),1.28(t,J=7.5Hz,3H),0.90(d,J=6.5Hz,6H),0.75-0.64(m,1H). Two exchangeable protons were not observed.

[0686] Example 31: 3-(N-(2-(2,2-dimethylpiperidin-1-yl)-5-(trifluoromethyl)phenyl)sulfamoyl)-4-methoxybenzoic acid

[0687]

[0688] Step 1: 2,2-Dimethyl-1-(2-nitro-4-(trifluoromethyl)phenyl)piperidine: Et 3N (0.500ml, 3.59mmol) was added to a solution of 2,2-dimethylpiperidine (195mg, 1.72mmol) and 1-fluoro-2-nitro-4-(trifluoromethyl)benzene (0.201ml, 1.44mmol) in DCM (6ml), and the resulting solution was stirred at room temperature for 96h. Additional 2,2-dimethylpiperidine (75mg, 0.663mmol) was added, and the reaction was stirred at room temperature for 1 day. Water (3ml) was added, and the phases were separated, and the aqueous phase was extracted with DCM (2×3ml). The organic phases were combined, dried by a phase separator and concentrated in vacuo. The crude product was purified by silica gel column chromatography (12g cartridge, 0-100% EtOAc / isohexane) to give the title compound (163mg, 0.512mmol, 35.7% yield, 95% purity) as a dark orange viscous oil. UPLC-MS (method 2) m / z 303.3 (M+H) at 1.96 min + .

[0689] Step 2: 2-(2,2-dimethylpiperidin-1-yl)-5-(trifluoromethyl)aniline: Iron powder (297 mg, 5.33 mmol) was added to a solution of the product of Step 1 above (161 mg, 0.533 mmol) and ammonium chloride (34.2 mg, 0.639 mmol) in IPA (5 ml) and water (2.5 ml) at room temperature. The resulting suspension was heated and stirred at 90 °C for 1 h, then cooled to room temperature overnight. Additional iron powder (297 mg, 5.33 mmol) was added, and the reaction was heated at 90 °C for another 2 h, then cooled to room temperature. The reaction mixture was stirred by Filter, wash with excess MeOH (100 ml) and concentrate in vacuo. The residue was redissolved in DCM (25 ml) and washed with water (5 ml). The aqueous phase was extracted with DCM (2 x 5 ml) and the combined organic phases were washed with brine (10 ml) and MgSO 4 Dry, filter and concentrate in vacuo to give the title compound as a light yellow oil (78 mg, 0.215 mmol, 40.3% yield, 75% purity). UPLC-MS (Method 2) m / z 273.3 (M+H) at 1.95 min + .

[0690] Step 3: Methyl 3-(N-(2-(2,2-dimethylpiperidin-1-yl)-5-(trifluoromethyl)phenyl)sulfamoyl)-4-methoxybenzoate: The product of Step 2 above (51.4 mg, 0.189 mmol) was dissolved in a mixture of DCM (1 ml) and pyridine (0.05 ml, 0.618 mmol) and treated with a solution of methyl 3-(chlorosulfonyl)-4-methoxybenzoate (60 mg, 0.227 mmol) in DCM (1 ml). The resulting solution was stirred at room temperature for 18 h. The reaction mixture was directly loaded onto silica gel and purified by column chromatography (12 g cartridge, 0-100% EtOAc / isohexane) to give the title compound (64 mg, 0.121 mmol, 64.3% yield, 100% purity) as a white sticky solid. UPLC-MS (method 1) m / z 501.4 (M+H) at 1.95 min + ,499.1(MH) - .

[0691] Step 4: 3-(N-(2-(2,2-dimethylpiperidin-1-yl)-5-(trifluoromethyl)phenyl)sulfamoyl)-4-methoxybenzoic acid: The product of step 3 above (62 mg, 0.124 mmol) was dissolved in THF (2 ml) and treated with 1.1 M LiOH(aq) (450 μl, 0.495 mmol). The reaction mixture was stirred at room temperature for 1 day. MeOH was added dropwise until the mixture became a solution, and the reaction mixture was heated at 40°C for 4 h and then cooled to room temperature overnight. The reaction mixture was diluted with water (3 ml), concentrated in vacuo, and the resulting aqueous solution was diluted with water (5 ml). 1 M HCl(aq) was added dropwise to about pH 6. The resulting white precipitate was collected by filtration and washed with water. The solid was suspended in MeCN (4 ml), concentrated in vacuo and dried at 45°C to give the title compound (57 mg, 0.111 mmol, 90% yield, 99% purity) as a white solid. UPLC-MS (method 1) m / z 487.3 (M+H) at 1.80 min + ,485.2(MH) - . 1 H NMR (500 MHz, DMSO-d 6 )δ13.20(br s,1H),8.96(s,1H),8.41(d,J=2.2Hz,1H),8.14(dd,J=8.7,2.2Hz,1H),7.59(s,1H),7.4 7(d,J=8.3Hz,1H),7.33-7.27(m,2H),3.93(s,3H),1.73-1.55(m,6H),1.32-0.62(m,8H).

[0692] Example 32: 3-(N-(2-(1,4-oxazepan-4-yl)-5-(trifluoromethyl)phenyl)sulfamoyl)-4-methoxybenzoic acid

[0693]

[0694] Step 1: 4-(2-nitro-4-(trifluoromethyl)phenyl)-1,4-oxazepane: Et 3 N (0.500 ml, 3.59 mmol) was added to a solution of 1-fluoro-2-nitro-4-(trifluoromethyl)benzene (0.201 ml, 1.44 mmol) and 1,4-oxazepane hydrochloride (237 mg, 1.72 mmol) in DCM (6 ml), and the resulting solution was stirred at room temperature for 7 days. Water (3 ml) was added and the phases were separated using a phase separator. The aqueous phase was extracted with DCM (2×3 ml), and the organic phases were combined, dried by a phase separator and concentrated in vacuo to give the title compound (429 mg, 1.14 mmol, yield 98%, purity 95%) as a viscous orange oil. UPLC-MS (Method 2) m / z 290.8 (M+H) at 1.48 min + .

[0695] Step 2: 2-(1,4-oxaazepan-4-yl)-5-(trifluoromethyl)aniline: Iron powder (822 mg, 14.71 mmol) was added to a solution of the product of step 1 above (427 mg, 1.471 mmol) and ammonium chloride (94 mg, 1.765 mmol) in IPA (5 ml) and water (2.5 ml) at room temperature. The resulting suspension was heated and stirred at 90°C for 1 h and then cooled to room temperature. The reaction mixture was stirred by Filter, wash with excess MeOH (100 ml) and concentrate in vacuo. The residue was redissolved in DCM (25 ml) and washed with water (5 ml). The aqueous phase was extracted with DCM (2 x 5 ml) and the combined organic phases were washed with brine (10 ml) and MgSO 4 Dry, filter and concentrate in vacuo. The crude product was purified by silica gel column chromatography (12 g cartridge, 0-100% EtOAc / isohexane) to afford the title compound (186 mg, 0.700 mmol, 47.6% yield, 98% purity) as a dark orange solid. UPLC-MS (Method 2) m / z 261.3 (M+H) at 1.39 min + .

[0696] Step 3: Methyl 3-(N-(2-(1,4-oxazepan-4-yl)-5-(trifluoromethyl)phenyl)sulfamoyl)-4-methoxybenzoate: The product of Step 2 above (54.8 mg, 0.189 mmol) was dissolved in a mixture of DCM (1 ml) and pyridine (0.05 ml, 0.618 mmol) and treated with a solution of methyl 3-(chlorosulfonyl)-4-methoxybenzoate (60 mg, 0.227 mmol) in DCM (1 ml). The resulting solution was stirred at room temperature for 18 h. The reaction mixture was directly loaded onto silica gel and purified by column chromatography (12 g cartridge, 0-100% EtOAc / isohexane) to give the title compound (66 mg, 0.132 mmol, 70.1% yield, 98% purity) as a paste solid. UPLC-MS (method 1) m / z 489.3 (M+H) at 1.59 min + ,487.2(MH) - .

[0697] Step 4: 3-(N-(2-(1,4-oxazepan-4-yl)-5-(trifluoromethyl)phenyl)sulfamoyl)-4-methoxybenzoic acid: The product of Step 3 above (64 mg, 0.131 mmol) was dissolved in THF (2 ml), treated with 1.1 M LiOH(aq) (476 μl, 0.524 mmol), and stirred at room temperature for 1 day. MeOH was added dropwise until the mixture became a solution, and the reaction mixture was heated at 40°C for 4 h and then cooled to room temperature overnight. The reaction mixture was diluted with water (3 ml), concentrated in vacuo, and the resulting aqueous solution was diluted with water (to about 5 ml) and neutralized to about pH 6 with 1 M HCl. The resulting bulk suspension was sonicated to give a turbid solution, and the white precipitate was collected by filtration and washed with water. The solid was suspended in MeCN (4 ml), concentrated in vacuo and dried at 45 °C to give the title compound as a light grey solid (60 mg, 0.120 mmol, 92% yield, 95% purity). UPLC-MS (Method 1) m / z 475.4 (M+H) at 1.43 min + ,473.3(MH) - . 1 H NMR (500 MHz, DMSO-d 6)δ13.12(s,1H),9.11(s,1H),8.23(s,1H),8.16(dd,J=8.7,2.2Hz,1H),7.38-7.32(m,2H),7.23(d,J =8.5Hz,1H),7.10(s,1H),3.93(s,3H),3.76-3.70(m,4H),3.29-3.20(m,4H),1.91(t,J=5.8Hz,2H).

[0698] Example 33: 3-(N-(2-(Spiro[isobenzofuran-1,4'-piperidin]-1'-yl)-5-(trifluoromethyl)phenyl)sulfamoyl)-4-methoxybenzoic acid

[0699]

[0700] Step 1: 1'-(2-nitro-4-(trifluoromethyl)phenyl)spiro[isobenzofuran-1,4'-piperidine]: Et 3 N (0.417 ml, 2.99 mmol) was added to a solution of 1-fluoro-2-nitro-4-(trifluoromethyl)benzene (0.167 ml, 1.20 mmol) and spiro[isobenzofuran-1,4'-piperidine] hydrochloride (324 mg, 1.44 mmol) in DCM (6 ml), and the reaction mixture was stirred at room temperature for 68 h. Water (2 ml) was added and the phases were separated. The aqueous phase was extracted with DCM (2×3 ml), and the combined organic phases were dried by a phase separator and concentrated in vacuo to give the title compound (536 mg, 0.907 mmol, yield 76%, purity 64%) as an orange oil. UPLC-MS (Method 1) m / z 379.2 (M+H) at 1.91 min + . 1 H NMR (500 MHz, DMSO-d 6 )δ8.17(d,J=1.6Hz,1H),7.86(dd,J=8.9,2.3Hz,1H),7.53(d,J=8.8Hz,1H),7.34-7.27(m,4H ), 5.04 (s, 2H), 3.39-3.29 (m, 4H), 2.06 (dt, J = 17.4, 5.8Hz, 2H), 1.74 (dd, J = 13.9, 2.5Hz, 2H).

[0701] Step 2: 2-(Spiro[isobenzofuran-1,4'-piperidin]-1'-yl)-5-(trifluoromethyl)aniline: Iron powder (335 mg, 6.00 mmol) was added to a solution of the product of step 1 above (227 mg, 0.600 mmol) and ammonium chloride (38.5 mg, 0.720 mmol) in IPA (3.5 ml) and water (1.25 ml) and heated to 90 °C for 2 h. The reaction mixture was cooled to room temperature, filtered and washed with excess MeOH (100 ml). The filtrate was concentrated in vacuo, redissolved in DCM (25 ml) and washed with water (5 ml). The aqueous phase was extracted with DCM (2×5 ml) and the combined organic phases were washed with brine (10 ml), dried through a phase separator and concentrated in vacuo. The crude product was purified by silica gel column chromatography (12 g cartridge, 0 to 35% EtOAc / isohexane) to afford the title compound (144 mg, 0.401 mmol, 66.8% yield, 97% purity) as an orange powder. UPLC-MS (Method 1) m / z 349.2 (M+H) at 1.83 min + . 1 H NMR (500 MHz, DMSO-d 6 )δ7.36-7.24(m,4H),7.07(d,J=8.1Hz,1H),6.98(d,J=2.1Hz,1H),6.85(dd,J=8.2,2.1Hz,1H),5.22(s,2H),5 .03(s,2H),3.12-3.01(m,2H),2.91(td,J=12.0,2.3Hz,2H),2.18(td,J=12.9,4.5Hz,2H),1.79-1.67(m,2H).

[0702] Step 3: Methyl 3-(N-(2-(Spiro[isobenzofuran-1,4'-piperidin]-1'-yl)-5-(trifluoromethyl)phenyl)sulfamoyl)-4-methoxybenzoate: Pyridine (0.058 ml, 0.718 mmol) was added to a solution of the product of Step 2 above (86 mg, 0.239 mmol) and methyl 3-(chlorosulfonyl)-4-methoxybenzoate (80 mg, 0.287 mmol) in DCM (2 ml) at room temperature. The reaction mixture was stirred and heated at 40°C for 18 h. Additional methyl 3-(chlorosulfonyl)-4-methoxybenzoate (33 mg, 0.120 mmol) was added and the reaction mixture was stirred at 40°C for another 3 h. The reaction mixture was concentrated in vacuo and the crude product was purified by silica gel column chromatography (25 g cartridge, 0 to 45% EtOAc / isohexane) to afford the title compound (117 mg, 0.187 mmol, 78% yield, 92% purity) as an off-white solid. UPLC-MS (Method 2) m / z 577.4 (M+H) at 1.89 min + 575.2,(MH) - .

[0703] Step 4: 3-(N-(2-(Spiro[isobenzofuran-1,4'-piperidin]-1'-yl)-5-(trifluoromethyl)phenyl)sulfamoyl)-4-methoxybenzoic acid: 1M LiOH(aq) (0.812 ml, 0.812 mmol) was added to a solution of the product of step 3 above (117 mg, 0.203 mmol) in THF (1.6 ml) at room temperature. The solution was stirred at room temperature for 25 h and then concentrated in vacuo. The residue was redissolved in water (3 ml) and acidified to pH 4 to 5 using 1M HCl(aq). The precipitate was isolated by filtration and dried in vacuo to give the title compound (92 mg, 0.164 mmol, 81% yield, 94% purity) as an off-white solid. UPLC-MS (Method 1) m / z 563.3 (M+H) at 1.80 min + ,561.1(MH) - . 1 H NMR (500 MHz, DMSO-d 6)δ9.02(brs,1H),8.39(d,J=2.3Hz,1H),8.15(dd,J=8.7,2.2Hz,1H),7.51(d,J=1.7Hz,1H),7.39-7.27(m,7H),5.02(s,2H),3.88(s,3H),3.01(t,J=11.9Hz,2H),2.96-2.90(m,2H),2.19-2.08(m,2H),1.73-1.65(m,2H). No exchangeable proton was observed.

[0704] The following examples were prepared by a procedure analogous to Example 33, substituting appropriate starting materials and intermediates where necessary:

[0705]

[0706]

[0707]

[0708] Example 41: 4-methoxy-3-(N-(2-(2-oxopiperidin-1-yl)-5-(trifluoromethyl)phenyl)sulfamoyl)benzoic acid

[0709]

[0710] Step 1: 1-(2-nitro-4-(trifluoromethyl)phenyl)piperidin-2-one: 2 At 0°C, NaH (63.1 mg, 1.58 mmol, 60% w / w in mineral oil) was added to a solution of piperidin-2-one (142 mg, 1.44 mmol) in anhydrous DMF (3 ml). The reaction was stirred at this temperature for 10 min, and then a solution of 1-fluoro-2-nitro-4-(trifluoromethyl)benzene (0.201 ml, 1.44 mmol) in anhydrous DMF (3 ml) was added dropwise at 0°C. The reaction was stirred at room temperature overnight. The reaction mixture was diluted with EtOAc (100 ml) and washed with water (50 ml) and brine (2×50 ml) in sequence. The organic phase was separated and MgSO 4 Dry, filter and concentrate under reduced pressure. The crude product was purified by silica gel column chromatography (12 g cartridge, 0-100% EtOAc / isohexane) to give the title compound (245 mg, 0.808 mmol, 56.3% yield, 100% purity) as a light yellow solid. UPLC-MS (Method 2) m / z 289.5 (M+H) at 1.23 min + .

[0711] Step 2: 1-(2-amino-4-(trifluoromethyl)phenyl)piperidin-2-one: Iron powder (508 mg, 9.09 mmol) was added to a suspension of the product of step 1 above (131 mg, 0.455 mmol) and ammonium chloride (29.2 mg, 0.545 mmol) in propan-2-ol (5 ml) and water (2.5 ml) at room temperature. The resulting suspension was heated and stirred at 90°C for 2 h. The reaction was stirred for 1 h at room temperature. Filter, wash with excess MeOH (100 ml) and concentrate in vacuo. The residue was redissolved in DCM (25 ml) and washed successively with water (10 ml) and brine (10 ml), and precipitated with MgSO 4 Dry, filter and concentrate in vacuo. The crude product was purified by silica gel column chromatography (12 g cartridge, 0-100% EtOAc / isohexane) to give the title compound (22 mg, 0.076 mmol, 16.7% yield, 89% purity) as a cream solid. UPLC-MS (Method 2) m / z 259.3 (M+H) at 1.07 min + .

[0712] Step 3: Methyl 4-methoxy-3-(N-(2-(2-oxopiperidin-1-yl)-5-(trifluoromethyl)phenyl)sulfamoyl)benzoate: The product of Step 2 above (22 mg, 0.085 mmol) was dissolved in a mixture of DCM (0.5 ml) and pyridine (22.5 μl, 0.279 mmol) and treated with a solution of methyl 3-(chlorosulfonyl)-4-methoxybenzoate (27.1 mg, 0.102 mmol) in DCM (0.5 ml). The resulting solution was stirred at room temperature for 18 h. Methyl 3-(chlorosulfonyl)-4-methoxybenzoate (11.3 mg, 0.043 mmol) and pyridine (6.89 μl, 0.085 mmol) were added and the reaction mixture was stirred at room temperature for 1 h. The crude product was purified directly by silica gel column chromatography (12 g cartridge, 0-100% EtOAc / isohexane) to afford the title compound (18.6 mg, 0.037 mmol, 43.5% yield, 97% purity) as a white solid. UPLC-MS (Method 1) m / z 487.6 (M+H) at 1.40 min + ,484.8(MH) - .

[0713] Step 4: 4-Methoxy-3-(N-(2-(2-oxopiperidin-1-yl)-5-(trifluoromethyl)phenyl)sulfamoyl)benzoic acid: The product of Step 3 above (18.6 mg, 0.038 mmol) was dissolved in THF (1 ml) and treated with 1.1 M LiOH(aq) (139 μl, 0.153 mmol). The reaction was stirred at room temperature for 1 day, then MeOH was added dropwise until the mixture was in solution, and the reaction mixture was heated at 40 °C for 20 h, then cooled to room temperature. The reaction mixture was diluted with water (3 ml), concentrated in vacuo, and the resulting aqueous solution was diluted with water (to ~5 ml) and neutralized to ~pH 6 using 1 M HCl. The white precipitate was collected by filtration and washed with water. The solid was suspended in MeCN (4 ml), concentrated in vacuo and dried at 45 °C to give the title compound (17.1 mg, 0.034 mmol, 90% yield, 95% purity) as a light yellow solid. UPLC-MS (method 1) m / z 473.0 (M+H) at 1.23 min + ,471.1(MH) - . 1 H NMR (500 MHz, DMSO-d 6 )δ13.12(s,1H),9.70(s,1H),8.33(d,J=2.2Hz,1H),8.15(dd,J=8.7,2.2Hz,1H),7.65(s,1H),7.54-7. 39(m,2H),7.31(d,J=8.8Hz,1H),3.80(s,3H),3.09-3.23(m,2H),2.44-2.22(m,2H),1.90-1.70(m,4H).

[0714] Example 42: 3-(N-(2-(1,4-oxazepan-4-yl)-5-(trifluoromethyl)phenyl)sulfamoyl)-4-methylbenzoic acid

[0715]

[0716] A solution of the product of step 2 of Example 32 above (62 mg, 0.238 mmol) in DCM (1 ml) and pyridine (0.116 ml, 1.43 mmol) was added to a solution of 3-(chlorosulfonyl)-4-methylbenzoic acid (67.1 mg, 0.286 mmol) in DCM (1 ml) and the solution was stirred at room temperature for 4 days. The crude product was purified directly by silica gel column chromatography (12 g cartridge, 0-10% MeOH / DCM) to give a paste solid (23 mg). 8 mg of this crude product was loaded onto a silica column with a minimum amount of DCM and the column was eluted with DCM (5 ml), isohexane (5 ml), 5% MeOH in EtOAc (5 ml), then 20% MeOH in EtOAc (5 ml) to give the title compound (7.0 mg, 0.015 mmol, 6.09% yield, 95% purity) as a white solid. UPLC-MS (method 1) m / z 459.4 (M+H) at 1.64 min + ,457.3(MH) - . 1 H NMR (500MHz, Methanol-d 4 )δ8.58(d,J=2.1Hz,1H),8.48(s,1H),8.00(dd,J=7.9,2.1Hz,1H),7.52-7.42(m,3H),3.97(t,J=6.2Hz,2H),3.94-3.89(m,2H),3.28-3.22(m,4H),2.79(s,3H),2.15-2.07(m,2H). Two exchangeable protons were not observed.

[0717] Example 43: 3-(N-(2-(1,4-oxazepan-4-yl)-5-(trifluoromethyl)phenyl)sulfamoyl)-4-ethylbenzoic acid

[0718]

[0719] A solution of the product of step 2 of Example 32 above (62 mg, 0.238 mmol) in DCM (1 ml) and pyridine (0.116 ml, 1.429 mmol) was added to a solution of the product of step 1 of Example 1 above (71.1 mg, 0.286 mmol) in DCM (1 ml), and the solution was stirred at room temperature for 4 days. The crude product was purified directly by silica gel column chromatography (12 g cartridge, 0-10% MeOH / DCM) to give a paste solid. The paste solid was loaded onto a silica column with a minimum amount of DCM and the column was eluted with DCM (5 ml), isohexane (5 ml), 5% MeOH in EtOAc (5 ml), then 5% MeOH in EtOAc (5 ml) to give the title compound (11.7 mg, 0.024 mmol, 9.87% yield, 95% purity) as a white solid. UPLC-MS (method 1) m / z 473.4 (M+H) at 1.61 min + ,471.2(MH) - . 1 H NMR (500 MHz, methanol-d 4 )δ8.53 (d, J=1.8 Hz, 1H), 8.17 (dd, J=8.0, 1.8 Hz, 1H), 7.57 (d, J=8.0 Hz, 1H), 7.34-7.28 (m, 3H), 3.90 (t, J=5.9 Hz, 2H), 3.86-3.81 (m, 2H), 3.23-3.16 (m, 4H), 3.08 (q, J=7.5 Hz, 2H), 2.02 (p, J=5.8 Hz, 2H), 1.29 (t, J=7.5 Hz, 3H). Two exchangeable protons were not observed.

[0720] Example 46: 4-methoxy-3-(N-(2-(2-(3-methylisoxazol-5-yl)pyrrolidin-1-yl)-5-(trifluoromethyl)phenyl)sulfamoyl)benzoic acid

[0721]

[0722] Step 1: 3-methyl-5-(1-(2-nitro-4-(trifluoromethyl)phenyl)pyrrolidin-2-yl)isoxazole: Et 3N (302 mg, 2.99 mmol) was added to a solution of 1-fluoro-2-nitro-4-(trifluoromethyl)benzene (0.167 ml, 1.20 mmol) and 3-methyl-5-(pyrrolidin-2-yl)isoxazole (218 mg, 1.44 mmol) in DCM (5 ml), and the resulting solution was stirred at room temperature for 19 h. Water (2.5 ml) was added, and the organic phase was dried by a phase separator and concentrated in vacuo to give the title compound (489 mg, 1.19 mmol, yield 99%, purity 83%) as a yellow oil. UPLC-MS (Method 2) m / z 342.4 (M+H) at 1.61 min + . 1 H NMR (500 MHz, DMSO-d 6 )δ8.07(m,1H),7.71(dd,J=9.1,2.0Hz,1H),7.17(d,J=9.1Hz,1H),6.18(s,1H),5.34(t,J=7.3Hz,1H),3. 55-3.50(m,1H),3.02-2.98(m,1H),2.54-2.51(m,1H),2.16(s,3H),2.08-2.02(m,1H),2.02-1.89(m,2H).

[0723] Step 2: 2-(2-(3-methylisoxazol-5-yl)pyrrolidin-1-yl)-5-(trifluoromethyl)aniline: Ammonium hydroxide (28% aq solution) (0.319 ml, 2.30 mmol) and sodium dithionite (1.18 g, 5.74 mmol) were added to a solution of the product of step 1 above (236 mg, 0.574 mmol) in THF (2.5 ml) and water (2.5 ml) at room temperature, then stirred at room temperature for 2 h. The reaction mixture was concentrated in vacuo and the residue was redissolved in DCM (10 ml) and washed with water (5 ml). The aqueous phase was extracted with DCM (2×5 ml) and the organic phases were combined, washed with brine (5 ml), dried through a phase separator and concentrated in vacuo. The crude product was purified by silica gel column chromatography (10 g cartridge, 0-50% EtOAc / isohexane) to afford the title compound (95 mg, 0.302 mmol, 52.6% yield, 99% purity) as a red / brown oil. UPLC-MS (Method 1) m / z 312.1 (M+H) at 1.52 min + . 1 H NMR (500 MHz, DMSO-d 6)δ7.03(d,J=8.2Hz,1H),6.92(d,J=2.2Hz,1H),6.74(dd,J=8.3,2.1Hz,1H),6.05(s,1H),5.17(s,2H),4.98(dd,J=7.9, 5.9Hz,1H),3.72-3.65(m,1H),2.76-2.68(m,1H),2.45-2.37(m,1H),2.10(s,3H),2.08-1.99(m,1H),1.98-1.87(m,2H).

[0724] Step 3: Methyl 4-methoxy-3-(N-(2-(2-(3-methylisoxazol-5-yl)pyrrolidin-1-yl)-5-(trifluoromethyl)phenyl)sulfamoyl)benzoate: Pyridine (0.069 ml, 0.852 mmol) was added to a solution of the product of step 2 above (88 mg, 0.284 mmol) and methyl 3-(chlorosulfonyl)-4-methoxybenzoate (95 mg, 0.341 mmol) in DCM (2.5 ml) at room temperature. The reaction mixture was stirred at room temperature for 65 h and then at 40 °C for 5 h. The crude reaction mixture was filtered and the filtered product was redissolved in MeCN (10 ml) and concentrated in vacuo to give the title compound (69 mg, 0.123 mmol, 43.2% yield, 96% purity) as an off-white solid. UPLC-MS (Method 2) m / z 540.3 (M+H) at 1.58 min + ,538.2(MH) - .

[0725] Step 4: 4-methoxy-3-(N-(2-(2-(3-methylisoxazol-5-yl)pyrrolidin-1-yl)-5-(trifluoromethyl)phenyl)sulfamoyl)benzoic acid: 1 M LiOH(aq) (0.384 ml, 0.384 mmol) was added to a suspension of the product of Step 3 above (69 mg, 0.128 mmol) in THF (0.768 ml) at room temperature. The resulting clear solution was stirred at room temperature for 20 h. Additional 1 M LiOH(aq) (0.128 ml, 0.128 mmol) was added and the solution was stirred for another 1 h. The reaction mixture was concentrated in vacuo and the residue was redissolved in water (2 ml) and acidified with 1 M HCl(aq) until pH 4 to 5. The precipitate was dissolved in DCM (10 ml) and the phases were separated. The aqueous phase was extracted with DCM (2 x 3 ml) and the combined organic phases were dried through a phase separator and concentrated in vacuo to afford the title compound as a light yellow solid (47.9 mg, 0.091 mmol, 71.3% yield, 97% purity). UPLC-MS (Method 1) m / z 526.3 (M+H) at 1.46 min + ,524.2(MH) - . 1 H NMR (500 MHz, DMSO-d 6 )δ13.08(br s,1H),9.39(br s,1H),8.17(dd,J=8.7,2.3Hz,1H),8.10(d,J=2.2Hz,1H),7.38(d,J=8.8Hz,1H) ,7.27(dd,J=8.8,2.3Hz,1H),6.78(d,J=8.8Hz,1H),6.67(d,J=2.3Hz,1H),6.02( s,1H),5.35(t,J=6.4Hz,1H),4.01(app.dt,J=9.7,7.0Hz,1H),3.95(s,3H),3.45 (ddd,J=9.9,7.3,5.2Hz,1H),2.40-2.35(m,1H),2.13(s,3H),2.01-1.85(m,3H).

[0726] Example 49 Methyl ester: methyl 4-methoxy-3-((2-(piperidin-1-yl)-5-(trifluoromethyl)phenyl)sulfonylamino)benzoate

[0727]

[0728] Step 1: Methyl 3-(2-bromo-5-(trifluoromethyl)phenylsulfonylamino)-4-methoxybenzoate: A mixture of 2-bromo-5-(trifluoromethyl)benzene-1-sulfonyl chloride (230 μl, 1.32 mmol), methyl 3-amino-4-methoxybenzoate (200 mg, 1.10 mmol) and pyridine (268 μl, 3.31 mmol) in DCM (4 ml) was stirred at room temperature over the weekend. The mixture was concentrated onto silica and purified by silica gel column chromatography (24 g cartridge, 0-100% EtOAc / isohexane) to give the title compound (510 mg, 1.07 mmol, 97% yield, 98% purity) as a light beige solid. UPLC-MS (Method 2) m / z 468.0 / 470.0 at 1.43 min (M / M+2) + . 1 H NMR (500 MHz, DMSO-d 6 )δ10.26(s,1H),8.12(d,J=8.3Hz,1H),8.10(d,J=2.2Hz,1H),7.92(dd,J=8.3, 2.2Hz,1H),7.83-7.77(m,2H),7.08(d,J=8.6Hz,1H),3.80(s,3H),3.56(s,3H).

[0729] Step 2: Methyl 4-methoxy-3-(2-(piperidin-1-yl)-5-(trifluoromethyl)phenylsulfonamido)benzoate: A mixture of the product of Step 1 above (100 mg, 0.214 mmol) and piperidine (25 μl, 0.253 mmol) in THF (1 ml) was heated to 60° C. and stirred overnight. Additional piperidine (25 μl, 0.253 mmol) was added and stirring was continued at 60° C. for 7 hours. Additional piperidine (25 μl, 0.253 mmol) was added and stirring was continued at 60° C. overnight. After cooling to room temperature, the mixture was concentrated in vacuo and the residue was loaded onto silica and purified by silica gel column chromatography (12 g cartridge, 0-100% EtOAc / isohexane) to give the title compound (82 mg, 0.165 mmol, 78% yield, 95% purity) as a white solid. UPLC-MS (Method 2) m / z 473.3 (M+H) at 1.84 min + . 1 H NMR (500 MHz, DMSO-d 6)δ9.04(s,1H),8.05(s,1H),7.93(d,J=8.4Hz,1H),7.87(s,1H),7.67(d,J=8.7Hz,1H),7.59(d,J=8.4Hz,1H), 7.05(d,J=8.7Hz,1H),3.78(s,3H),3.73(s,3H),2.92(t,J=5.3Hz,4H),1.77-1.65(m,4H),1.57-1.51(m,2H).

[0730] Example 49: 4-methoxy-3-((2-(piperidin-1-yl)-5-(trifluoromethyl)phenyl)sulfonylamino)benzoic acid

[0731]

[0732] A mixture of the product of step 2 of Example 49 above (methyl ester, 70 mg, 148 mmol) in THF (1.25 ml) and 2M LiOH(aq) (0.25 ml, 0.500 mmol) was stirred at 50° C. overnight. Additional 2M LiOH(aq) (0.25 ml, 0.500 mmol) was added and stirring was continued at 50° C. for 5 h. The mixture was heated to 40° C. with H 2 The mixture was diluted with 1M HCl(aq) (5 ml), acidified to about pH 4 with 1M HCl(aq) and extracted with EtOAc (3×10 ml). The combined organic extracts were washed with brine (10 mL), passed through a phase separator and the solvent removed in vacuo. The residue was loaded onto silica and purified by silica gel column chromatography (4 g cartridge, 0-10% MeOH / DCM) and triturated with TBME to give the title compound (44.3 mg, 0.093 mmol, 62.6% yield, 96% purity) as a white solid. UPLC-MS (Method 2) m / z 459.3 (M+H) at 1.19 min + ,457.2(MH) - . 1 H NMR (500 MHz, DMSO-d 6 )δ12.71(s,1H),8.99(s,1H),8.05(d,J=2.3Hz,1H),7.93(dd,J=8.5,2.3Hz,1H),7.89(d,J=2.1Hz,1H),7.64(dd,J=8.7,2.1H z,1H),7.60(d,J=8.5Hz,1H),7.02(d,J=8.7Hz,1H),3.71(s,3H),2.92(t,J=5.1Hz,4H),1.76-1.65(m,4H),1.59-1.48(m,2H).

[0733] General compound A: 4-methoxy-2-((2-(piperidin-1-yl)-5-(trifluoromethyl)phenyl)sulfonylamino)benzoic acid

[0734]

[0735] Step 1: Methyl 2-(2-fluoro-5-(trifluoromethyl)phenylsulfonylamino)-4-methoxybenzoate: A mixture of 2-fluoro-5-(trifluoromethyl)benzene-1-sulfonyl chloride (87 mg, 0.331 mmol), methyl 2-amino-4-methoxybenzoate (50 mg, 0.276 mmol) and pyridine (0.067 ml, 0.828 mmol) in DCM (2 ml) was stirred at room temperature overnight. The mixture was concentrated onto silica and purified by silica gel column chromatography (12 g cartridge, 0-100% EtOAc / isohexane) to give the title compound (98 mg, 0.180 mmol, 65.4% yield, 75% purity) as a white solid. UPLC-MS (Method 2) 405.5 (MH) at 1.67 min - . 1 H NMR (500 MHz, DMSO-d 6 )δ11.13(s,1H),8.24-8.12(m,2H),7.87(d,J=8.9Hz,1H),7.73(t,J=9.5H z, 1H), 6.94 (d, J = 2.5Hz, 1H), 6.83-6.76 (m, 1H), 3.79 (s, 3H), 3.77 (s, 3H).

[0736] Step 2: Methyl 4-methoxy-2-(2-(piperidin-1-yl)-5-(trifluoromethyl)phenylsulfonamido)benzoate: A mixture of the product of Step 1 above (98 mg, 0.180 mmol) and piperidine (0.06 ml, 0.606 mmol) in THF (2 ml) was stirred at 60°C for 6 days. The mixture was concentrated onto silica and purified by silica gel column chromatography (12 g cartridge, 0-50% EtOAc / isohexane) to give the title compound as a white solid (52 mg, 0.109 mmol, 60.4% yield, 99% purity). UPLC-MS (Method 2) m / z 473.3 (M+H) at 2.01 min + . 1 H NMR (500 MHz, DMSO-d 6)δ11.11(s,1H),8.28(d,J=2.3Hz,1H),8.06-7.95(m,1H),7.85(d,J=8.9Hz,1H),7.59(d,J=8.5Hz,1H),6.73(d,J=2.5Hz ,1H),6.63(dd,J=8.9,2.5Hz,1H),3.84(s,3H),3.66(s,3H),2.84(t,J=5.3Hz,4H),1.74-1.64(m,4H),1.58-1.49(m,2H).

[0737] Step 3: 4-methoxy-2-(2-(piperidin-1-yl)-5-(trifluoromethyl)phenylsulfonylamino)benzoic acid: A mixture of the product of Step 2 above (52 mg, 0.109 mmol) and 2M LiOH(aq) (250 μl, 0.500 mmol) in THF (1.25 ml) was stirred at 50° C. overnight. The mixture was heated to 40° C. with H 2 The mixture was diluted with 1M HCl (2 ml) and acidified to about pH 4. The mixture was extracted with EtOAc (3×15 ml), the combined organic extracts were washed with brine, passed through a phase separator, and the solvent was removed under vacuum. The residue was loaded onto silica and purified by silica gel column chromatography (4 g cartridge, 0 to 5% MeOH / DCM) to give the title compound (14.1 mg, 0.030 mmol, 27.1% yield, 96% purity) as a white solid. UPLC-MS (Method 2) m / z 459.3 (M+H) at 1.22 min + ,457.2(MH) - . 1 H NMR (500 MHz, DMSO-d 6 )δ13.63(s,1H),11.65(s,1H),8.29(d,J=2.3Hz,1H),7.99(dd,J=8.5,2.3Hz,1H),7.83(d,J=8.9Hz,1H),7.58(d,J=8.5Hz,1H) ,6.65(d,J=2.4Hz,1H),6.57(dd,J=8.9,2.4Hz,1H),3.64(s,3H),2.86(t,J=5.1Hz,4H),1.77-1.66(m,4H),1.60-1.46(m,2H).

[0738] The following examples were prepared by methods analogous to general compound A, substituting appropriate starting materials and intermediates where necessary:

[0739]

[0740] Example 54 Methyl ester: methyl 4-methoxy-3-(N-(2-(piperidin-1-yl)-5-(trifluoromethyl)phenyl)sulfamoyl)benzoate

[0741]

[0742] A solution of 2-(piperidin-1-yl)-5-(trifluoromethyl)aniline (0.100 g, 0.409 mmol) in DCM (1 ml) and pyridine (0.1 ml, 1.236 mmol) was added to a solution of methyl 3-(chlorosulfonyl)-4-methoxybenzoate (0.130 g, 0.491 mmol) in DCM (1 ml), and the solution was stirred at room temperature for 23 h. The solvent was removed under vacuum, and the crude product was purified by silica gel column chromatography (12 g cartridge, 0-50% EtOAc / isohexane) to give an orange oil. The orange oil was repurified by silica gel column chromatography (24 g cartridge, 0-50% EtOAc / isohexane) to give the title compound (0.143 g, 0.294 mmol, 71.7% yield, 97% purity) as a light yellow, slowly crystallizing oil. UPLC-MS (Method 2) m / z 473.2 (M+H) at 1.83 min + ,471.1(MH) - . 1 H NMR (500 MHz, DMSO-d 6 )δ8.81(br s,1H),8.37(d,J=2.3Hz,1H),8.19(dd,J=8.7,2.3Hz,1H),7.45(d,J=2.0Hz,1H),7.40-7.30 (m,3H),3.94(s,3H),3.86(s,3H),2.78-2.75(m,4H),1.68-1.64(m,4H),1.56-1.52(m,2H).

[0743] Example 54: 4-methoxy-3-(N-(2-(piperidin-1-yl)-5-(trifluoromethyl)phenyl)sulfamoyl)benzoic acid

[0744]

[0745] 1M LiOH(aq) (3 ml, 3.00 mmol) was added to a solution of the product of Example 54 methyl ester (0.068 g, 0.144 mmol) in dioxane (3 ml), and the solution was stirred overnight at room temperature. The solvent was removed under vacuum, and the residue was redissolved in water (5 ml) and extracted with EtOAc (3 × 5 ml). The aqueous phase was acidified with 1M HCl(aq), and the product was extracted into EtOAc (3 × 10 ml). The combined organic phases were dried over MgSO 4 4, filtered, and the solvent was removed under vacuum to afford the title compound as an off-white solid (0.047 g, 0.100 mmol, 69.8% yield, 98% purity). UPLC-MS (Method 2) m / z 459.2 (M + H) + , 457.0 (M - H) - at 1.15 min. 1 1H NMR (500 MHz, DMSO-d 6 6) δ 13.16 (s, 1H), 8.76 (s, 1H), 8.37 (d, J = 2.2 Hz, 1H), 8.16 (dd, J = 8.7, 2.2 Hz, 1H), 7.45 (d, J = 1.9 Hz, 1H), 7.38 - 7.30 (m, 3H), 3.93 (s, 3H), 2.76 (t, J = 5.3 Hz, 4H), 1.67 (p, J = 5.3 Hz, 4H), 1.55 (p, J = 5.3 Hz, 2H).

[0746] Example 55: 3-(N-(2-(Azepan-1-yl)-5-(trifluoromethyl)phenyl)sulfamoyl)-4-isopropylbenzoic acid

[0747]

[0748] A solution of 2-(azepan-1-yl)-5-(trifluoromethyl)aniline (50 mg, 0.194 mmol) in DCM (1 ml) and pyridine (0.094 ml, 1.16 mmol) was added to a solution of 3-(chlorosulfonyl)-4-isopropylbenzoic acid (61.0 mg, 0.232 mmol) in DCM (1 ml), and the solution was stirred at room temperature for 4 days. The crude product was directly purified by silica gel column chromatography (12 g cartridge, 0-10% MeOH / DCM) to give a light yellow solid (11.1 mg). 9 mg of this light yellow solid was loaded onto a silica column with a minimum amount of DCM and the column was eluted with DCM (5 ml), isohexane (5 ml), 5% MeOH in EtOAc (5 ml), then 5% MeOH in EtOAc (5 ml) to give the title compound as a light yellow solid (5.4 mg, 10.6 μmol, 5.47% yield, 95% purity). UPLC-MS (Method 2) m / z 485.4 (M+H) at 1.99 min + ,483.1(MH) - . 1 H NMR (500 MHz, methanol-d 4 )δ8.58 (d, J=1.8 Hz, 1H), 8.20 (dd, J=8.2, 1.8 Hz, 1H), 7.70 (d, J=8.2 Hz, 1H), 7.33-7.21 (m, 3H), 3.90 (septet, J=6.8 Hz, 1H), 3.20-3.13 (m, 4H), 1.86-1.77 (m, 4H), 1.76-1.71 (m, 4H), 1.24 (d, J=6.7 Hz, 6H)H). Two exchangeable protons were not observed.

[0749] The following examples were prepared by a procedure analogous to Example 55, substituting appropriate starting materials and intermediates where necessary:

[0750]

[0751] Example 64: 4-methoxy-3-(N-(2-(piperidin-1-yl)phenyl)sulfamoyl)benzoic acid

[0752]

[0753] Step 1: Methyl 4-methoxy-3-(N-(2-(piperidin-1-yl)phenyl)sulfamoyl)benzoate: A solution of 2-(piperidin-1-yl)aniline hydrochloride (0.050 g, 0.235 mmol) in DCM (1 ml) and pyridine (0.114 ml, 1.410 mmol) was added to a solution of methyl 3-(chlorosulfonyl)-4-methoxybenzoate (0.075 g, 0.282 mmol) in DCM (1 ml) and the solution was stirred at room temperature for 96 h. The solvent was removed in vacuo and the crude product was purified by silica gel column chromatography (24 g cartridge, 0-50% EtOAc / isohexane) to give the title compound (0.095 g, 0.169 mmol, 71.9% yield, 72% purity) as a pale yellow, slowly crystallizing oil. UPLC-MS (Method 2) m / z 405.2 (M+H) at 1.69 min + ,403.4(MH) - .

[0754] Step 2: 4-Methoxy-3-(N-(2-(piperidin-1-yl)phenyl)sulfamoyl)benzoic acid: 1M LiOH(aq) (0.470 ml, 0.470 mmol) was added to a solution of the product of Step 1 above (0.095 g, 0.235 mmol) in dioxane (3 ml) and the solution was stirred at room temperature overnight. The solvent was removed under vacuum and the residue was redissolved in water (5 ml) and extracted with EtOAc (3×5 ml). The aqueous phase was acidified with 1M HCl(aq) and the product was extracted into EtOAc (3×10 ml). The combined organic phases were washed with MgSO 4 Dry, filter and remove solvent under vacuum. The crude product was purified by silica gel column chromatography (12 g cartridge, 0 to 70% EtOAc / isohexane) to give the title compound (40 mg, 0.097 mmol, 41.4% yield, 95% purity) as a white solid. UPLC-MS (Method 1) m / z 391.3 (M+H) at 1.41 min + ,389.3(MH) - . 1 H NMR (500 MHz, DMSO-d 6)δ13.23(bs,1H),8.60(s,1H),8.39(d,J=2.3Hz,1H),8.14(dd,J=8.7,2.3Hz,1H),7.31(d,J=8.8Hz,1H),7.25(dd,J=7.4,2.1Hz ,1H),7.22(dd,J=7.5,2.2Hz,1H),7.12-6.85(m,2H),3.96(s,3H),2.75-2.63(m,4H),1.69(p,J=5.5Hz,4H),1.58-1.52(m,2H).

[0755] Example 65: 3-(N-(4-chloro-2-(piperidin-1-yl)phenyl)sulfamoyl)-4-methoxybenzoic acid

[0756]

[0757] Step 1: Methyl 3-(N-(4-chloro-2-(piperidin-1-yl)phenyl)sulfamoyl)-4-methoxybenzoate: A solution of 4-chloro-2-(piperidin-1-yl)aniline (0.050 g, 0.237 mmol) in DCM (1 ml) and pyridine (0.115 ml, 1.42 mmol) was added to a solution of methyl 3-(chlorosulfonyl)-4-methoxybenzoate (0.075 g, 0.285 mmol) in DCM (1 ml) and the solution was stirred at room temperature for 96 h. The solvent was removed under vacuum and the crude product was purified by silica gel column chromatography (24 g cartridge, 0-50% EtOAc / isohexane) to give the title compound (0.093 g, 0.165 mmol, 69.6% yield) as a pale yellow, slowly crystallizing oil. UPLC-MS (Method 2) m / z 439.3 (M+H) at 1.81 min + ,437.2(MH) - .

[0758] Step 2: 3-(N-(4-chloro-2-(piperidin-1-yl)phenyl)sulfamoyl)-4-methoxybenzoic acid: 1M LiOH(aq) (0.424 ml, 0.424 mmol) was added to a solution of the product of Step 1 above (0.093 g, 0.212 mmol) in dioxane (3 ml) and the solution was stirred at room temperature overnight. The solvent was removed under vacuum and the residue was redissolved in water (5 ml) and extracted with EtOAc (3×5 ml). The aqueous phase was acidified with 1M HCl(aq) and the product was extracted into EtOAc (3×10 ml). The combined organic phases were washed with MgSO 4Dry, filter and remove solvent under vacuum. The crude product was purified by silica gel column chromatography (12 g cartridge, 0-80% EtOAc / isohexane) to give the title compound (34 mg, 0.076 mmol, 35.9% yield, 95% purity) as a white solid. UPLC-MS (Method 1) m / z 425.3 (M+H) at 1.69 min + ,423.2(MH) - . 1 H NMR (500 MHz, DMSO-d 6 )δ13.24(bs,1H),8.58(s,1H),8.36(d,J=2.3Hz,1H),8.16(dd,J=8.7,2.2Hz,1H),7.32(d,J=8.8Hz,1H),7.28-7. 14(m,2H),7.07(dd,J=8.8,2.4Hz,1H),3.96(s,3H),2.72-2.68(m,4H),1.66(p,J=5.5Hz,4H),1.56-1.50(m,2H).

[0759] Example 66: 3-(N-(5-chloro-2-(piperidin-1-yl)phenyl)sulfamoyl)-4-methoxybenzoic acid

[0760]

[0761] Step 1: Methyl 3-(N-(5-chloro-2-(piperidin-1-yl)phenyl)sulfamoyl)-4-methoxybenzoate: A solution of 5-chloro-2-(piperidin-1-yl)aniline hydrochloride (0.050 g, 0.202 mmol) in DCM (1 ml) and pyridine (0.098 ml, 1.21 mmol) was added to a solution of methyl 3-(chlorosulfonyl)-4-methoxybenzoate (0.064 g, 0.243 mmol) in DCM (1 ml) and the solution was stirred at room temperature for 96 h. The solvent was removed under vacuum and the crude product was purified by silica gel column chromatography (24 g cartridge, 0-50% EtOAc / isohexane) to give the title compound (0.066 g, 0.143 mmol, 70.6% yield, 95% purity) as a pale yellow, slowly crystallizing oil. UPLC-MS (Method 2) m / z 439.3 (M+H) at 1.81 min + ,437.3(MH) - .

[0762] Step 2: 3-(N-(5-chloro-2-(piperidin-1-yl)phenyl)sulfamoyl)-4-methoxybenzoic acid: 1M LiOH(aq) (0.301 ml, 0.301 mmol) was added to a solution of the product of Step 1 above (0.066 g, 0.150 mmol) in dioxane (3 ml) and the solution was stirred at room temperature overnight. The solvent was removed under vacuum and the residue was redissolved in water (5 ml) and extracted with EtOAc (3×5 ml). The aqueous phase was acidified with 1M HCl(aq) and the product was extracted into EtOAc (3×10 ml). The combined organic phases were washed with MgSO 4 Dry, filter and remove solvent under vacuum. The crude product was purified by silica gel column chromatography (12 g cartridge, 0 to 70% EtOAc / isohexane) to give the title compound (22 mg, 0.049 mmol, 32.7% yield, 95% purity) as a white solid. UPLC-MS (Method 1) m / z 425.1 (M+H) at 1.67 min + ,423.2(MH) - . 1 H NMR (500 MHz, DMSO-d 6 )δ13.25(br s,1H),8.69(br s,1H),8.38(d,J=2.2Hz,1H),8.17(dd,J=8.7,2.2Hz,1H),7.34(d,J=8.8Hz,1H),7.25(d,J=2.5Hz,1H),7.24(d,J= 8.5Hz,1H),7.05(dd,J=8.5,2.5Hz,1H),3.96(s,3H),2.75-2.61(m,4H),1.67(p,J=5.5Hz,4H),1.56-1.50(m,2H).

[0763] Example 67: 4-Methyl-3-(N-(2-(piperidin-1-yl)-5-(trifluoromethyl)phenyl)sulfamoyl)benzoic acid

[0764]

[0765] Step 1: Methyl 4-methyl-3-(N-(2-(piperidin-1-yl)-5-(trifluoromethyl)phenyl)sulfamoyl)benzoate: 2-(Piperidin-1-yl)-5-(trifluoromethyl)aniline (50 mg, 0.205 mmol) was dissolved in a mixture of DCM (1 ml) and pyridine (0.05 ml, 0.618 mmol) and treated with a solution of methyl 3-(chlorosulfonyl)-4-methylbenzoate (52 mg, 0.209 mmol) in DCM (1 ml). The resulting solution was stirred at room temperature for 18 h. Additional methyl 3-(chlorosulfonyl)-4-methylbenzoate (15 mg, 0.060 mmol) was added and the reaction was stirred at room temperature for an additional 24 h. The reaction mixture was loaded directly onto silica gel (12 g cartridge, 0-50% EtOAc / isohexane) and purified to give the title compound (73 mg, 0.155 mmol, 76% yield, 97% purity) as a colorless oil which crystallized on standing. UPLC-MS (Method 1) m / z 457.1 (M+H) at 1.95 min + ,455.3(MH) - .

[0766] Step 2: 4-methyl-3-(N-(2-(piperidin-1-yl)-5-(trifluoromethyl)phenyl)sulfamoyl)benzoic acid: The product of Step 1 above (71 mg, 0.151 mmol) was dissolved in THF (2 ml) and treated with 1.1 M LiOH(aq) (499 μl, 0.549 mmol). MeOH was added to give a clear solution, which was allowed to stand at room temperature. After 2 days, the solution was diluted with water (2 ml) and allowed to stand at room temperature for an additional 24 h. The solution was further diluted with water (2 ml) and concentrated in vacuo. The resulting aqueous suspension was diluted with water (2 ml) and filtered, and washed with water (1 ml). The resulting solution was neutralized with 1 M HCl(aq) (0.4 ml) and sonicated, then adjusted to about pH 6 with 1 M HCl(aq) (2 drops). The resulting off-white precipitate was collected by filtration and washed with water. The solid was suspended in MeCN (4 ml), concentrated in vacuo and dried at 45°C to give the title compound (55 mg, 0.122 mmol, 81% yield, 98% purity) as a tan powder. UPLC-MS (Method 1) m / z 443.3 (M+H) at 1.81 min + 441.3(MH) - .

[0767] Example 68: 3-(N-(2-(azepan-1-yl)-5-(trifluoromethyl)phenyl)sulfamoyl)-4-methoxybenzoic acid

[0768]

[0769] Step 1: Methyl 3-(N-(2-(azepan-1-yl)-5-(trifluoromethyl)phenyl)sulfamoyl)-4-methoxybenzoate: 2-(azepan-1-yl)-5-(trifluoromethyl)aniline (48.8 mg, 0.189 mmol) was dissolved in a mixture of DCM (1 ml) and pyridine (0.05 ml, 0.618 mmol) and treated with a solution of methyl 3-(chlorosulfonyl)-4-methoxybenzoate (60 mg, 0.227 mmol) in DCM (1 ml). The resulting solution was stirred at room temperature for 18 h. The reaction mixture was loaded directly onto silica gel and purified by silica gel column chromatography (12 g cartridge, 0 to 70% EtOAc / isohexane) to give the title compound (44 mg, 0.084 mmol, 44.5% yield, 93% purity) as a sticky light yellow solid. UPLC-MS (method 1) m / z 487.4 (M+H) at 1.91 min + ,485.2(MH) - .

[0770] Step 2: 3-(N-(2-(azepan-1-yl)-5-(trifluoromethyl)phenyl)sulfamoyl)-4-methoxybenzoic acid: The product of Step 1 above (42 mg, 0.086 mmol) was dissolved in THF (2 ml) and treated with 1.1 M LiOH(aq) (235 μl, 0.259 mmol). The reaction mixture was stirred at room temperature for 2 days. Additional 1.1 M LiOH(aq) (78 μl, 0.086 mmol) was added and the reaction was warmed to 30° C. for 18 h. The reaction mixture was diluted with water (3 ml), concentrated in vacuo, and the resulting aqueous solution was diluted with water (to about 5 ml) and neutralized with 1 M HCl(aq) (0.4 ml). The resulting bulk suspension was sonicated to give a turbid solution and neutralized to about pH 6 with 1 M HCl. The aqueous phase was acidified with 1 M HCl(aq) and the product was extracted into EtOAc (3×10 ml). The combined organic phases were washed with MgSO 4 Dry, filter and remove solvent under vacuum. The crude product was purified by silica gel column chromatography (12 g cartridge, 0 to 70% EtOAc / isohexane) to give the title compound as a white solid (2.2 mg, 4.42 μmol, 5.12% yield, 95% purity). UPLC-MS (Method 1) m / z 473.4 (M+H) at 1.79 min + ,471.1(MH) - . 1 H NMR (500 MHz, DMSO-d 6)δ13.13(br s,1H),8.76(br s,1H),8.36(d,J=2.2Hz,1H),8.14(dd,J=8.7,2.2Hz,1H),7.44(d,J=1.9Hz,1H),7.38-7.26(m,3H),3.91(s,3H),2.92 (d,J=11.4Hz,2H),2.67-2.57(m,2H),1.72-1.65(m,1H),1.55-1.43(m,1H),1.34-1.20(m,3H),0.97(d,J=6.5Hz,3H).

[0771] Example 69: 4-Chloro-3-(N-(2-(piperidin-1-yl)-5-(trifluoromethyl)phenyl)sulfamoyl)benzoic acid

[0772]

[0773] Step 1: Methyl 4-chloro-3-(N-(2-(piperidin-1-yl)-5-(trifluoromethyl)phenyl)sulfamoyl)benzoate: 2-(Piperidin-1-yl)-5-(trifluoromethyl)aniline (45.4 mg, 0.186 mmol) was dissolved in a mixture of DCM (1 ml) and pyridine (0.05 ml, 0.618 mmol) and treated with a solution of methyl 4-chloro-3-(chlorosulfonyl)benzoate (60 mg, 0.223 mmol) in DCM (1 ml). The resulting solution was stirred at room temperature for 18 h. The reaction mixture was loaded directly onto silica and purified by silica gel column chromatography (12 g cartridge, 0 to 70% EtOAc / isohexane) to give the title compound (45.5 mg, 0.094 mmol, 50.3% yield, 98% purity) as a tan solid. UPLC-MS (method 1) m / z 477.3 (M+H) at 2.00 min + ,475.1(MH) - .

[0774] Step 2: 4-Chloro-3-(N-(2-(piperidin-1-yl)-5-(trifluoromethyl)phenyl)sulfamoyl)benzoic acid: The product of Step 1 above (43 mg, 0.090 mmol) was dissolved in THF (2 ml) and treated with 1.1 M LiOH(aq) (328 μl, 0.361 mmol). The reaction mixture was stirred at room temperature for 2 days. The reaction mixture was diluted with water (3 ml), concentrated in vacuo, and the resulting aqueous solution was diluted with water (to about 5 ml) and neutralized with 1 M HCl(aq) (0.4 ml). The resulting bulk suspension was sonicated to give a turbid solution and neutralized to about pH 6 with 1 M HCl(aq). The aqueous phase was acidified with 1 M HCl(aq) and the product was extracted into EtOAc (3×10 ml). The combined organic phases were washed with MgSO 4 Dry, filter and remove the solvent under vacuum. The crude product was purified by silica gel column chromatography (12 g cartridge, 0-10% MeOH / DCM) to give the title compound as a white solid (20.5 mg, 0.042 mmol, 46.7% yield, 95% purity). UPLC-MS (Method 1) m / z 463.3 (M+H) at 1.88 min + ,461.2(MH) - . 1 H NMR (500 MHz, DMSO-d 6 )δ13.48(br s,1H),9.54(br s,1H),8.44(d,J=2.0Hz,1H),8.12(dd,J=8.3,2.1Hz,1H),7.80(d,J=8.3Hz,1H),7.42(d,J=8.3Hz,1 H), 7.34 (s, 1H), 7.29 (d, J = 8.4Hz, 1H), 2.77 (t, J = 5.1Hz, 4H), 1.58-1.51 (m, 4H), 1.50-1.43 (m, 2H).

[0775] The following examples were prepared by a procedure analogous to Example 69, substituting appropriate starting materials and intermediates where necessary:

[0776]

[0777]

[0778]

[0779]

[0780] Example 161: 4-Hydroxy-3-(N-(2-(piperidin-1-yl)-5-(trifluoromethyl)phenyl)sulfamoyl)benzoic acid

[0781]

[0782] Step 1: Methyl 4-methoxy-3-(N-(2-(piperidin-1-yl)-5-(trifluoromethyl)phenyl)sulfamoyl)benzoate: A solution of 2-(piperidin-1-yl)-5-(trifluoromethyl)aniline (0.130 g, 0.532 mmol) in DCM (1 ml) and pyridine (0.258 ml, 3.19 mmol) was added to a solution of methyl 3-(chlorosulfonyl)-4-methoxybenzoate (0.169 g, 0.639 mmol) in DCM (1 ml) and the solution was stirred at room temperature for 16 h. The solvent was removed under vacuum. The crude product was purified by silica gel column chromatography (24 g cartridge, 0-50% EtOAc / DCM) to give the title compound (0.230 g, 0.433 mmol, 81% yield, 89% purity) as a white solid. UPLC-MS (method 1) m / z 473.4 (M+H) at 1.86 min + ,471.3(MH) - . 1 H NMR (500 MHz, DMSO-d 6 )δ8.81(s,1H),8.37(d,J=2.3Hz,1H),8.19(dd,J=8.7,2.3Hz,1H),7.45(d,J=2.0Hz,1H),7.41-7. 28(m,3H),3.94(s,3H),3.86(s,3H),2.84-2.69(m,4H),1.66(p,J=5.6Hz,4H),1.57-1.51(m,2H).

[0783] Step 2: Methyl 4-hydroxy-3-(N-(2-(piperidin-1-yl)-5-(trifluoromethyl)phenyl)sulfamoyl)benzoate: Use 1.0 M BBr 3 The product of step 1 above (0.230 g, 0.438 mmol) in DCM (10 ml) was treated with a solution of DCM (0.166 ml, 1.75 mmol) and the solution was stirred at room temperature for 16 h. The solvent was removed under vacuum to give the title compound as a yellow oil (0.200 g, 0.393 mmol, 90% yield, 90% purity). UPLC-MS (Method 1) m / z 459 (M+H) at 1.7 min + .

[0784] Step 3: 4-Hydroxy-3-(N-(2-(piperidin-1-yl)-5-(trifluoromethyl)phenyl)sulfamoyl)benzoic acid: 1M LiOH(aq) (1.31 ml, 1.31 mmol) was added to a solution of the product of Step 2 above (0.2 g, 0.436 mmol) in MeOH (10 ml) and the solution was stirred at room temperature overnight. The solvent was removed under vacuum and the residue was redissolved in water (5 ml) and extracted with EtOAc (3×5 ml). The aqueous phase was acidified with 1M HCl(aq) and the product was extracted into EtOAc (3×10 ml). The combined organic phases were washed with MgSO 4 Dry, filter and remove the solvent under vacuum. The crude product was purified by silica gel column chromatography (24 g cartridge, 0-50% EtOAc / DCM) to give the title compound (60 mg, 0.128 mmol, 29.4% yield, 95% purity) as a white solid. UPLC-MS (Method 1) m / z 445.3 (M+H) at 1.56 min + ,443.2(MH) - . 1 H NMR (500 MHz, DMSO-d 6 )δ12.96(br s,1H),8.29(d,J=2.3Hz,1H),7.98(dd,J=8.6,2.3Hz,1H),7.52(d,J=1.8Hz,1H),7.37-7.33(m,2H),7.04(d,J=8.6Hz,1H),2.75(t,J=5.2Hz,4H),1.68(p,J=5.5Hz,4H),1.58-1.51(m,2H). Two exchangeable protons were not observed.

[0785] Example 165: 4-methoxy-3-(N-methyl-N-(2-(piperidin-1-yl)-5-(trifluoromethyl)phenyl)sulfamoyl)benzoic acid

[0786]

[0787] Step 1: Methyl 4-methoxy-3-(N-(2-(piperidin-1-yl)-5-(trifluoromethyl)phenyl)sulfamoyl)benzoate: A mixture of 2-(piperidin-1-yl)-5-(trifluoromethyl)aniline (100 mg, 0.409 mmol), methyl 3-(chlorosulfonyl)-4-methoxybenzoate (130 mg, 0.491 mmol), and pyridine (100 μl, 1.24 mmol) in DCM (1.5 ml) was stirred overnight at room temperature. The mixture was concentrated onto silica and purified by silica gel column chromatography (12 g column, 0 - 100% EtOAc / isohexane) to afford the title compound as a white solid (189 mg, 0.384 mmol, 94% yield, 96% purity). UPLC-MS (Method 2) m / z 473.3 (M+H) at 1.80 min + . 1 H NMR (500 MHz, DMSO-d 6 ) δ 8.80 (s, 1H), 8.36 (d, J = 2.2 Hz, 1H), 8.18 (dd, J = 8.8, 2.2 Hz, 1H), 7.44 (d, J = 2.0 Hz, 1H), 7.40 - 7.29 (m, 3H), 3.93 (s, 3H), 3.85 (s, 3H), 2.76 (t, J = 5.2 Hz, 4H), 1.70 - 1.61 (m, 4H), 1.59 - 1.49 (m, 2H).

[0788] Step 2: Methyl 4-methoxy-3-(N-methyl-N-(2-(piperidin-1-yl)-5-(trifluoromethyl)phenyl)sulfamoyl)benzoate: At 0 °C, a solution of the product from Step 1 (189 mg, 0.384 mmol) in THF (1 ml) was added to a suspension of sodium hydride (12 mg, 0.500 mmol) in THF (1 ml). The mixture was warmed to RT and stirred for 30 min, then iodomethane (30 μl, 0.480 mmol) was added and the mixture was stirred overnight at room temperature. The mixture was quenched with H 2 O (10 ml) and extracted with EtOAc (3 × 20 ml). The combined organic extracts were washed with brine (15 mL), passed through a phase separator, and the solvent was removed in vacuo. The residue was loaded onto silica and purified by silica gel column chromatography (12 g column, 0 - 50% EtOAc / isohexane) to afford the title compound as a clear colorless oil (172 mg, 0.283 mmol, 73.7% yield, 80% purity). UPLC-MS (Method 2) m / z 487.3 (M+H) at 1.83 min + . 1 H NMR (500 MHz, DMSO-d6 )δ8.25(dd,J=8.7,2.2Hz,1H),8.22(d,J=2.2Hz,1H),7.54(dd,J=8.6,2.2Hz,1H),7.48(d,J=8.7Hz,1H),7.21(d,J=8.6Hz,1H ),7.02(d,J=2.2Hz,1H),4.00(s,3H),3.83(s,3H),3.27(s,3H),3.06(t,J=5.1Hz,4H),1.64-1.57(m,4H),1.57-1.50(m,2H).

[0789] Step 3: 4-methoxy-3-(N-methyl-N-(2-(piperidin-1-yl)-5-(trifluoromethyl)phenyl)sulfamoyl)benzoic acid: A mixture of the product of Step 2 above (170 mg, 0.349 mmol) and 2M LiOH(aq) (0.35 ml, 0.700 mmol) in THF (1.5 ml) was stirred at 50° C. overnight. The mixture was heated to 40° C. with H 2 The mixture was diluted with 1 M HCl (aq) and acidified to about pH 4 with 1 M HCl (aq) and extracted with EtOAc (3 x 10 ml). The combined organic extracts were washed with brine (10 mL), passed through a phase separator, and the solvent was removed under vacuum. The residue was loaded onto silica and purified by silica gel column chromatography (4 g cartridge, 0-10% MeOH / DCM) to give the title compound (66.1 mg, 0.134 mmol, 38.3% yield, 96% purity) as a white solid. UPLC-MS (Method 2) m / z 473.3 (M+H) at 1.17 min + ,471.2(MH) - . 1 H NMR (500 MHz, DMSO-d 6 )δ13.10(s,1H),8.22(m,2H),7.53(dd,J=8.5,2.3Hz,1H),7.48-7.41(m,1H),7.20(d,J=8.5Hz,1H),7. 01(d,J=2.2Hz,1H),3.99(s,3H),3.28(s,3H),3.09-3.02(m,4H),1.65-1.57(m,4H),1.57-1.48(m,2H).

[0790] Example 171: 2-Methoxy-N-(2-(piperidin-1-yl)-5-(trifluoromethyl)phenyl)-5-(tetrazol-5-yl)benzenesulfonamide

[0791]

[0792] Step 1: 5-Cyano-2-methoxy-N-(2-(piperidin-1-yl)-5-(trifluoromethyl)phenyl)benzenesulfonamide: 2-(Piperidin-1-yl)-5-(trifluoromethyl)aniline (200 mg, 0.819 mmol) was dissolved in a mixture of DCM (2 ml) and pyridine (0.15 ml, 1.86 mmol) and treated with a solution of 5-cyano-2-methoxybenzenesulfonyl chloride (237 mg, 1.02 mmol) in DCM (1 ml). The resulting solution was allowed to stand at room temperature for 18 h, then diluted with water (ca. 0.1 ml) and concentrated in vacuo. The crude product was purified by silica gel column chromatography (12 g cartridge, 0-50% EtOAc / isohexane) to give the title compound (325 mg, 0.717 mmol, 88% yield, 99% purity) as a pale yellow solid. UPLC-MS (method 1) m / z 440.4 (M+H) at 1.82 min + ,438.1(MH) - .

[0793] Step 2: 2-Methoxy-N-(2-(piperidin-1-yl)-5-(trifluoromethyl)phenyl)-5-(tetrazol-5-yl)benzenesulfonamide: The product of Step 1 above (100 mg, 0.228 mmol) was mixed with sodium azide (74.0 mg, 1.14 mmol) and zinc bromide (102 mg, 0.455 mmol) in IPA (1 ml) and water (0.3 ml). The resulting mixture was heated at 80°C overnight and then concentrated in vacuo. The crude product was purified by silica gel column chromatography (24 g cartridge, 0-100% EtOAc / isohexane then 0-10% MeOH / DCM) to give the title compound (7.9 mg, 0.016 mmol, 6.84% yield, 95% purity) as a white solid. UPLC-MS (Method 1) m / z 483.4 at 1.67 min (M+H) + ,481.2(MH) - . 1 H NMR (500 MHz, DMSO-d 6 )δ8.79(s,1H),8.55(d,J=2.2Hz,1H),8.27(dd,J=8.7,2.2Hz,1H),7.51(s,1H),7.44(d,J=8.8Hz,1H),7.37-7.33(m,2H),3.94(s,3H),2.78(t,J=5.3Hz,4H),1.70-1.65(m,4H),1.57-1.50(m,2H). No exchangeable proton was observed.

[0794] Example 177: 3-(N-(2-(3-hydroxypiperidin-1-yl)-5-(trifluoromethyl)phenyl)sulfamoyl)-4-methoxybenzoic acid

[0795]

[0796] Step 1: 1-(2-nitro-4-(trifluoromethyl)phenyl)piperidin-3-ol: Et 3 N (0.500 ml, 3.59 mmol) was added to a solution of 1-fluoro-2-nitro-4-(trifluoromethyl)benzene (0.201 ml, 1.44 mmol) and piperidin-3-ol (174 mg, 1.72 mmol) in DCM (6 ml). The clear solution was stirred at room temperature for 17 h. The organic phase was washed with 1M HCl (3 ml), dried through a phase separator and concentrated in vacuo to give the title compound (468 mg, 1.40 mmol, yield 98%, purity 87%) as a red / orange oil. UPLC-MS (Method 1) m / z 291.5 (M+H) at 1.39 min + . 1 H NMR (500 MHz, DMSO-d 6 )δ8.12-8.07(m,1H),7.80(dd,J=9.0,2.4Hz,1H),7.41(d,J=8.9Hz,1H),4 .91(d,J=4.3Hz,1H),3.65-3.57(m,1H),3.26(dd,J=12.4,3.9Hz,1H),3.21 (dt,J=13.0,4.5Hz,1H),2.98-2.91(m,1H),2.75(dd,J=12.3,8.5Hz,1H),1 .93-1.85(m,1H),1.81-1.73(m,1H),1.56-1.46(m,1H),1.40-1.30(m,1H).

[0797] Step 2: 1-(2-amino-4-(trifluoromethyl)phenyl)piperidin-3-ol: A solution of 87L-type 5% Pd / C (50% w / w water) (50 mg, 0.012 mmol) in EtOH (0.5 ml) was added to a solution of the product of step 1 above (234 mg, 0.701 mmol) in EtOH (3.0 ml) at room temperature. The reaction mixture was hydrogenated (4 bar) at room temperature for 19 h. The catalyst was removed by filtration and washed with MeOH (15 ml). The filtrate was concentrated in vacuo and the residue was dissolved in MeOH (10 ml) and washed with MgSO 4Dry, filter and concentrate in vacuo to give a white solid. MeCN (10 ml) was added and the resulting slurry was washed with a large excess of MgSO 4 Dry, filter and concentrate in vacuo to give the title compound as a yellow solid (153 mg, 0.576 mmol, 82% yield, 98% purity). UPLC-MS (Method 1) m / z 261.4 (M+H) at 1.29 min + . 1 H NMR (500 MHz, DMSO-d 6 )δ6.96(d,J=8.1Hz,1H),6.94(d,J=2.2Hz,1H),6.84-6.80(m,1H),5.14(s,2H),4.79(d,J=5.4Hz,1H),3.74-3.66(m,1H),3.04- 2.96(m,1H),2.92-2.85(m,1H),2.58-2.50(m,1H),2.49-2.41(m,1H),1.86-1.75(m,2H),1.65-1.55(m,1H),1.37-1.28(m,1H).

[0798] Step 3: Methyl 3-(N-(2-(3-hydroxypiperidin-1-yl)-5-(trifluoromethyl)phenyl)sulfamoyl)-4-methoxybenzoate: Pyridine (0.075 ml, 0.933 mmol) was added to a cloudy solution of the product of Step 2 above (62.0 mg, 0.233 mmol) and methyl 3-(chlorosulfonyl)-4-methoxybenzoate (78 mg, 0.280 mmol) in DCM (2.0 ml) at room temperature. The resulting clear solution was stirred at room temperature for 20 h and the reaction mixture was concentrated in vacuo. The crude product was purified by silica gel column chromatography (10 g cartridge, 0-100% EtOAc / isohexane) to give the title compound (88.1 mg, 0.177 mmol, 76% yield, 98% purity) as a yellow oil. UPLC-MS (method 1) m / z 489.3 (M+H) at 1.59 min + ,487.2(MH) - .

[0799] Step 4: 3-(N-(2-(3-hydroxypiperidin-1-yl)-5-(trifluoromethyl)phenyl)sulfamoyl)-4-methoxybenzoic acid: 1M LiOH(aq) (0.707 ml, 0.707 mmol) was added to a solution of the product of step 3 above (88.1 mg, 0.177 mmol) in THF (1.4 ml) at room temperature. The reaction mixture was stirred at room temperature for 18 h and then concentrated in vacuo. The residue was dissolved in water (3 ml) and acidified with 1M HCl until pH 4 to 5. The precipitate was isolated by filtration and then dissolved in EtOAc (5 ml). The organic phase was washed with water (3 ml) and MgSO 4 Dry, filter and concentrate in vacuo to give the title compound as a light pink solid (50 mg, 0.104 mmol, 59% yield, 99% purity). UPLC-MS (Method 1) m / z 475.4 (M+H) at 1.38 min + ,473.1(MH) - . 1 H NMR (500 MHz, DMSO-d 6 )δ13.16(br s,1H),9.14(br s,1H),8.39(d,J=2.2Hz,1H),8.14(dd,J=8.7,2.2Hz,1H),7.46(d,J=1.8Hz,1H),7.33-7.27(m,2H),7.25(d,J=8.3Hz,1H),5.09(br s,1H),3.89(s,3H),3.79-3.73(m,1H),2.87-2.79(m,2H),2.74-2.68(m,1H),2.67-2. 62(m,1H),1.93-1.85(m,1H),1.77-1.69(m,1H),1.60-1.51(m,1H),1.51-1.43(m,1H).

[0800] Example 178: (S)-3-(N-(2-(3-hydroxypyrrolidin-1-yl)-5-(trifluoromethyl)phenyl)sulfamoyl)-4-methoxybenzoic acid

[0801]

[0802] Step 1: (S)-1-(2-nitro-4-(trifluoromethyl)phenyl)pyrrolidin-3-ol: Et 3N (0.500 ml, 3.59 mmol) was added to a solution of 1-fluoro-2-nitro-4-(trifluoromethyl)benzene (0.201 ml, 1.44 mmol) and (S)-pyrrolidin-3-ol (0.139 ml, 1.72 mmol) in DCM (6 ml). The clear solution was stirred at room temperature for 17 h. The organic phase was washed with 1 M HCl (3 ml), dried through a phase separator and concentrated in vacuo to give the title compound (445 mg, 1.37 mmol, yield 95%, purity 85%) as an orange oil. UPLC-MS (Method 1) m / z 277.2 (M+H) at 1.33 min + . 1 HNMR (500 MHz, DMSO-d 6 )δ8.06-8.03(m,1H),7.72(dd,J=9.1,2.3Hz,1H),7.19(d,J=9.1Hz,1H),5.05(d,J=3.4Hz,1H),4.41-4.36(m,1H),3.50(app.t d,J=9.8,6.8Hz,1H),3.41(dd,J=11.1,4.3Hz,1H),3.25-3.19(m,1H),2.85-2.80(m,1H),2.04-1.96(m,1H),1.94-1.88(m,1H).

[0803] Step 2: (S)-1-(2-amino-4-(trifluoromethyl)phenyl)pyrrolidin-3-ol: A solution of 87L-type 5% Pd / C (50% w / w water) (50 mg, 0.012 mmol) in EtOH (0.5 ml) was added to a solution of the product of step 1 above (220 mg, 0.677 mmol) in EtOH (3.0 ml) at room temperature. The reaction mixture was hydrogenated (4 bar) at room temperature for 19 h. The catalyst was removed by filtration and washing with MeOH (20 ml). The organic phase was concentrated in vacuo and the residue was dissolved in DCM (10 ml). The organic phase was washed with water (5 ml) and MgSO 4 Dry, filter and concentrate in vacuo to give the title compound as a dark brown oil (134 mg, 0.522 mmol, 77% yield, 96% purity). UPLC-MS (Method 1) m / z 247.3 (M+H) at 1.08 min + . 1 H NMR (500 MHz, DMSO-d 6)δ6.92(d,J=1.8Hz,1H),6.88(d,J=8.2Hz,1H),6.80(dd,J=8.2,1.5Hz,1H),4.97(br s,2H),4.86(d,J=4.9Hz,1H),4.35-4.28(m,1H),3.31-3.22(m,2H),2.99(ddd,J=9.1 ,7.9,5.0Hz,1H),2.90(dd,J=10.0,3.0Hz,1H),2.12-2.04(m,1H),1.79-1.71(m,1H).

[0804] Step 3: (S)-methyl 3-(N-(2-(3-hydroxypyrrolidin-1-yl)-5-(trifluoromethyl)phenyl)sulfamoyl)-4-methoxybenzoate: Pyridine (0.075 ml, 0.933 mmol) was added to a cloudy solution of the product of Step 2 above (60.5 mg, 0.233 mmol) and methyl 3-(chlorosulfonyl)-4-methoxybenzoate (78 mg, 0.280 mmol) in DCM (2.0 ml) at room temperature. The resulting clear solution was stirred at room temperature for 20 h and then concentrated in vacuo. The crude product was purified by silica gel column chromatography (10 g cartridge, 0-100% EtOAc / isohexane) to give the title compound (96.7 mg, 0.196 mmol, 84% yield, 96% purity) as an orange oil. UPLC-MS (method 1) m / z 475.4 (M+H) at 1.35 min + ,473.2(MH) - .

[0805] Step 4: (S)-3-(N-(2-(3-hydroxypyrrolidin-1-yl)-5-(trifluoromethyl)phenyl)sulfamoyl)-4-methoxybenzoic acid: 1M LiOH(aq) (0.783 ml, 0.783 mmol) was added to a solution of the product of step 3 above (96.7 mg, 0.196 mmol) in THF (1.6 ml) at room temperature. The reaction mixture was stirred at room temperature for 20 h and then concentrated in vacuo. The residue was dissolved in water (3 ml) and acidified with 1M HCl until pH 4 to 5. The precipitate was isolated by filtration and then dissolved in EtOAc (5 ml). The organic phase was washed with water (3 ml) and MgSO 4 Dry and concentrate in vacuo. The crude product was purified by silica gel column chromatography (10 g cartridge, 0 to 5% MeOH / DCM) to give the title compound (22.3 mg, 0.046 mmol, 26.3% yield, 96% purity) as an off-white solid. UPLC-MS (Method 1) m / z 461.3 (M+H) at 1.17 min+ ,459.2(MH) - . 1 H NMR (500 MHz, DMSO-d 6 )δ13.06(br s,1H),9.30(br s,1H),8.17(dd,J=8.7,2.2Hz,1H),8.06(d,J=2.2Hz,1H),7.39(d,J=8.8Hz,1H), 7.29(dd,J=8.8,2.4Hz,1H),6.74(d,J=8.9Hz,1H),6.50(d,J=2.3Hz,1H),4.96(br s,1H),4.37-4.31(m,1H),3.99(s,3H),3.79(dd,J=11.0,4.8Hz,1H),3.59-3.52(m ,1H),3.49-3.43(m,1H),3.38-3.34(m,1H),1.96-1.88(m,1H),1.87-1.81(m,1H).

[0806] Example 179: 4-methoxy-3-(N-(2-(3-methoxypiperidin-1-yl)-5-(trifluoromethyl)phenyl)sulfamoyl)benzoic acid

[0807]

[0808] Step 1: 3-methoxy-1-(2-nitro-4-(trifluoromethyl)phenyl)piperidine: At room temperature, add Et 3 N (0.500 ml, 3.59 mmol) was added to a solution of 1-fluoro-2-nitro-4-(trifluoromethyl)benzene (0.201 ml, 1.44 mmol) and 3-methoxypiperidine (198 mg, 1.72 mmol) in DCM (6 ml). The clear solution was stirred at room temperature for 16 h. The organic phase was washed with 1M HCl (3 ml), dried through a phase separator and concentrated in vacuo to give the title compound (438 mg, 1.41 mmol, yield 98%, purity 98%) as an orange oil. 1 H NMR (500 MHz, DMSO-d 6)δ8.13-8.10(m,1H),7.81(dd,J=8.9,2.4Hz,1H),7.43(d,J=8.9Hz,1H),3.42-3.33(m,2H),3.24(s,3H),3.19(app.dt,J=12.9,4.7H z,1H),3.03-2.96(m,1H),2.86(dd,J=12.2,7.5Hz,1H),2.00-1.93(m,1H),1.82-1.73(m,1H),1.57-1.47(m,1H),1.47-1.38(m,1H).

[0809] Step 2: 2-(3-methoxypiperidin-1-yl)-5-(trifluoromethyl)aniline: A solution of 87L-type 5% Pd / C (50% w / w water) (50 mg, 0.012 mmol) in EtOH (0.5 ml) was added to a solution of the product of step 1 above (214 mg, 0.689 mmol) in EtOH (3.0 ml) at room temperature. The reaction mixture was hydrogenated (4 bar) at room temperature for 18 h. The catalyst was removed by filtration through a pad of 4% paraffin wax and washed with EtOH (15 ml). The filtrate was concentrated in vacuo and azeotroped with MeOH (6 ml) to give the title compound (151 mg, 0.484 mmol, 70% yield, 88% purity) as an off-white solid. UPLC-MS (Method 1) m / z 275.3 (M+H)+ (ES+) at 1.58 min. 1 H NMR (500 MHz, DMSO-d 6 )δ6.99(d,J=8.1Hz,1H),6.95(d,J=2.2Hz,1H),6.83(dd,J=8.1,1.5Hz,1H),5.12(br s,2H),3.46-3.40(m,1H),3.29(s,3H),3.17-3.09(m,1H),2.99-2.93(m,1H),2.57-2. 46(m,2H),1.98-1.90(m,1H),1.80-1.73(m,1H),1.67-1.58(m,1H),1.40-1.29(m,1H).

[0810] Step 3: Methyl 4-methoxy-3-(N-(2-(3-methoxypiperidin-1-yl)-5-(trifluoromethyl)phenyl)sulfamoyl)benzoate: Pyridine (0.081 ml, 1.01 mmol) was added to a cloudy solution of the product of Step 2 above (79 mg, 0.252 mmol) and methyl 3-(chlorosulfonyl)-4-methoxybenzoate (80 mg, 0.302 mmol) in DCM (2.0 ml) at room temperature. The resulting clear solution was stirred at room temperature for 18 h and then concentrated in vacuo. The crude product was purified by silica gel column chromatography (10 g cartridge, 0-60% EtOAc / isohexane) to give the title compound (84 mg, 0.167 mmol, 66% yield, 100% purity) as a cream solid. UPLC-MS (Method 1) m / z 503.4 at 1.77 min (M+H) + ,501.2(MH)-.

[0811] Step 4: 4-methoxy-3-(N-(2-(3-methoxypiperidin-1-yl)-5-(trifluoromethyl)phenyl)sulfamoyl)benzoic acid: 1M LiOH(aq) (0.669ml, 0.669mmol) was added to a solution of the product of step 3 above (84mg, 0.167mmol) in THF (1.3ml) at room temperature. The reaction mixture was stirred at room temperature for 18h and then concentrated in vacuo. The residue was dissolved in water (3ml) and washed with EtOAc (5ml). The aqueous phase was acidified with 1M HCl until pH 4 to 5, and the product was extracted into EtOAc (5ml×3). The combined organic phases were washed with MgSO 4 Dry and concentrate in vacuo to give the title compound as a white solid (63 mg, 0.128 mmol, yield 77%, purity 100%). UPLC-MS (Method 1) m / z 489.3 (M+H) at 1.60 min + ,487.1(MH) - . 1 H NMR (500 MHz, DMSO-d 6 )δ13.19(br s,1H),9.06(br s,1H),8.39(d,J=2.2Hz,1H),8.15(dd,J=8.7,2.2Hz,1H),7.47(d,J=1.6Hz,1H),7.35-7.23(m,3H),3.89(s,3H ),3.47-3.41(m,1H),3.35(s,3H),2.98-2.88(m,2H),2.78-2.71(m,2H),1.85-1.70(m,2H),1.69-1.55(m,2H).

[0812] Example 180: 3-(N-(2-(4-ethoxypiperidin-1-yl)-5-(trifluoromethyl)phenyl)sulfamoyl)-4-methoxybenzoic acid

[0813]

[0814] Step 1: 4-ethoxy-1-(2-nitro-4-(trifluoromethyl)phenyl)piperidine: At room temperature, add Et 3 N (0.500 ml, 3.59 mmol) was added to a solution of 1-fluoro-2-nitro-4-(trifluoromethyl)benzene (0.201 ml, 1.44 mmol) and 4-ethoxypiperidine (222 mg, 1.72 mmol) in DCM (6 ml). The clear solution was stirred at room temperature for 16 h. The organic phase was washed with 1M HCl (3 ml), dried through a phase separator and concentrated in vacuo to give the title compound (471 mg, 1.435 mmol, 100% yield, 97% purity) as an orange oil. 1 H NMR (500 MHz, DMSO-d 6 )δ8.13-8.10(m,1H),7.81(dd,J=8.9,2.4Hz,1H),7.42(d,J=8.8Hz,1H),3.55-3.45(m,3H),3.3 0-3.25(m,2H),3.03-2.97(m,2H),1.95-1.87(m,2H),1.59-1.51(m,2H),1.12(t,J=7.0Hz,3H).

[0815] Step 2: 2-(4-ethoxypiperidin-1-yl)-5-(trifluoromethyl)aniline: A solution of 87L-type 5% Pd / C (50% w / w water) (50 mg, 0.012 mmol) in EtOH (0.5 ml) was added to a solution of the product of step 1 above (228 mg, 0.695 mmol) in EtOH (3.0 ml) at room temperature. The reaction mixture was hydrogenated (4 bar) at room temperature for 18 h. The catalyst was removed by filtration through a pad of 4% paraformaldehyde (1% paraformaldehyde) and washing with EtOH (15 ml). The filtrate was concentrated in vacuo and azeotroped with MeOH (6 ml) to give the title compound (179 mg, 0.559 mmol, 80% yield, 90% purity) as an off-white solid. UPLC-MS (Method 1) m / z 289.3 (M+H) at 1.66 min + . 1 H NMR (500 MHz, DMSO-d 6)δ6.99(d,J=8.1Hz,1H),6.95(d,J=2.2Hz,1H),6.82(dd,J=8.2,1.6Hz,1H),5.10(br s,2H),3.48(q,J=7.0Hz,2H),3.45-3.38(m,1H),3.06-2.99(m,2H),2.65- 2.57(m,2H),1.99-1.91(m,2H),1.68-1.59(m,2H),1.12(t,J=7.0Hz,3H).

[0816] Step 3: Methyl 3-(N-(2-(4-ethoxypiperidin-1-yl)-5-(trifluoromethyl)phenyl)sulfamoyl)-4-methoxybenzoate: Pyridine (0.081 ml, 1.01 mmol) was added to a cloudy solution of the product of Step 2 above (81 mg, 0.252 mmol) and methyl 3-(chlorosulfonyl)-4-methoxybenzoate (80 mg, 0.302 mmol) in DCM (2.0 ml) at room temperature. The resulting clear solution was stirred at room temperature for 18 h and then concentrated in vacuo. The crude product was purified by silica gel column chromatography (10 g cartridge, 0-60% EtOAc / isohexane) to give the title compound (92.5 mg, 0.159 mmol, 63% yield, 89% purity) as a colorless oil. UPLC-MS (Method 1) m / z 517.4 at 1.80 min (M+H) + ,515.2(MH) - .

[0817] Step 4: 3-(N-(2-(4-ethoxypiperidin-1-yl)-5-(trifluoromethyl)phenyl)sulfamoyl)-4-methoxybenzoic acid: 1M LiOH(aq) (0.634 ml, 0.634 mmol) was added to a solution of the product of step 3 above (92 mg, 0.159 mmol) in THF (1.3 ml) at room temperature. The reaction mixture was stirred at room temperature for 18 h and then concentrated in vacuo. The residue was dissolved in water (3 ml) and washed with EtOAc (2×5 ml). The aqueous phase was acidified with 1M HCl until pH 4 to 5 and the product was extracted into EtOAc (3×5 ml). The combined organic phases were washed with MgSO 4 Dry and concentrate in vacuo to give the title compound as an off-white solid (61 mg, 0.118 mmol, 74% yield, 97% purity). UPLC-MS (Method 1) m / z 503.3 (M+H) at 1.63 min + ,501.3(MH) - . 1 H NMR (500 MHz, DMSO-d6 )δ13.18(br s,1H),8.87(br s,1H),8.36(d,J=2.2Hz,1H),8.16(dd,J=8.7,2.2Hz,1H),7.44(d,J=1.7Hz,1H),7.36(dd,J=8.4,1.6Hz,1H),7.34-7.30(m,2H),3 .91(s,3H),3.52-3.42(m,3H),2.99-2.91(m,2H),2.72-2.64(m,2H),1.98-1.90(m,2H),1.67-1.58(m,2H),1.14(t,J=7.0Hz,3H).

[0818] Example 181: 4-methoxy-3-(N-(2-(4-methoxypiperidin-1-yl)-5-(trifluoromethyl)phenyl)sulfamoyl)benzoic acid

[0819]

[0820] Step 1: 4-methoxy-1-(2-nitro-4-(trifluoromethyl)phenyl)piperidine: Et 3 N (318 μl, 2.28 mmol) was added to a solution of 1-fluoro-2-nitro-4-(trifluoromethyl)benzene (128 μl, 0.912 mmol) and 4-methoxypiperidine (105 mg, 0.912 mmol) in DCM (3 ml), and the resulting solution was stirred at room temperature for 20 h. 1 M HCl (2 ml) was added, and the organic phase was dried by a phase separator. The organic phase was concentrated in vacuo to give the title compound (277 mg, 0.912 mmol, 100% yield, 100% purity) as a light orange oil. UPLC-MS (Method 1) m / z 305.6 (M+H) at 1.60 min + .

[0821] Step 2: 2-(4-methoxypiperidin-1-yl)-5-(trifluoromethyl)aniline: The product of step 1 above (277 mg, 0.912 mmol) was dissolved in EtOH (14.2 ml) and heated to 40 ℃ in a Thales Nano H- The reaction mixture was concentrated in vacuo and azeotroped with MeOH (6 ml) to give the title compound (239 mg, 0.854 mmol, 94% yield, 98% purity) as a cream solid. UPLC-MS (Method 2) m / z 275.3 (M+H) at 1.53 min + ,273.3(MH)- .

[0822] Step 3: Methyl 4-methoxy-3-(N-(2-(4-methoxypiperidin-1-yl)-5-(trifluoromethyl)phenyl)sulfamoyl)benzoate: The product of Step 2 above (69.1 mg, 0.252 mmol) was dissolved in a mixture of DCM (1 ml) and pyridine (81 μl, 1.01 mmol) and treated with a solution of methyl 3-(chlorosulfonyl)-4-methoxybenzoate (80 mg, 0.302 mmol) in DCM (1 ml). The resulting solution was stirred at room temperature for 4 days. The crude product was purified directly by silica gel column chromatography (12 g cartridge, 0-100% EtOAc / isohexane) to give the title compound (52.8 mg, 0.103 mmol, 40.9% yield, 98% purity) as a white solid. UPLC-MS (Method 1) m / z 503.4 (M+H)+(ES+); 501.2 (MH)-(ES-) at 1.71 min.

[0823]

[0136] Step 4: 4-Methoxy-3-(N-(2-(4-methoxypiperidin-1-yl)-5-(trifluoromethyl)phenyl)sulfamoyl)benzoic acid: The product of Step 3 above (50 mg, 0.100 mmol) was dissolved in THF (2 ml) and treated with 1.1 M LiOH(aq) (362 μl, 0.398 mmol). MeOH was added dropwise until the mixture became a solution and the reaction was stirred at 30 °C for 20 h. The reaction mixture was diluted with water (3 ml), concentrated in vacuo, and the resulting aqueous solution was diluted with water (to ~5 ml). The aqueous phase was washed with EtOAc (2×5 ml) and neutralized to ~pH 6 using 1 M HCl. The resulting bulk suspension was sonicated to give a turbid mixture. The turbid mixture was concentrated in vacuo to ~2 ml. The resulting precipitate was collected by filtration and washed with water (2×2 mL). The solid was suspended in MeCN (4 ml), concentrated in vacuo and dried at 45°C to give the title compound as a white solid (38.8 mg, 0.078 mmol, yield 78%, purity 98%). UPLC-MS (Method 1) m / z 489.2 (M+H) at 1.53 min + ,487.1(MH) - . 1 H NMR (500 MHz, DMSO-d 6)δ13.16(s,1H),8.88(s,1H),8.35(d,J=2.2Hz,1H),8.15(dd,J=8.7,2.2Hz,1H),7.43(d,J=2.0Hz,1H),7.38-7.28(m,3H) ,3.91(s,3H),3.35-3.28(m,1H),3.27(s,3H),2.98-2.90(m,2H),2.71-2.62(m,2H),1.99-1.90(m,2H),1.67-1.57(m,2H).

[0824] Example 182: 3-(N-(5-cyano-2-(piperidin-1-yl)phenyl)sulfamoyl)-4-methoxybenzoic acid

[0825]

[0826] Step 1: 3-nitro-4-(piperidin-1-yl)benzonitrile: 4-Fluoro-3-nitrobenzonitrile (300 mg, 1.81 mmol), piperidine (0.2 ml, 2.02 mmol) and Et 3 A mixture of N (0.65 ml, 4.66 mmol) in DCM (6 ml) was stirred at room temperature overnight. The mixture was washed with water (10 ml), passed through a phase separator, concentrated onto silica and purified by silica gel column chromatography (12 g cartridge, 0-100% EtOAc / isohexane) to give the title compound (400 mg, 1.73 mmol, 96% yield, 100% purity) as a light orange solid. UPLC-MS (Method 2) m / z 232.1 (M+H) at 1.60 min + . 1 H NMR (500 MHz, DMSO-d 6 )δ8.28(d,J=2.1Hz,1H),7.84(dd,J=8.9,2.1Hz,1H),7.34(d,J=8.9Hz,1H),3.18-3.10(m,4H),1.65-1.54(m,6H).

[0827] Step 2: 3-amino-4-(piperidin-1-yl)benzonitrile: A solution of the product of step 1 above (398 mg, 1.72 mmol) in EtOH (35 ml) was hydrogenated in a flow reactor (10% Pt / C, 30×4 mm, full hydrogen mode, 25° C., flow rate 1 ml / min, 1 pass). The mixture was concentrated onto silica and purified by silica gel column chromatography (12 g cartridge, 0-50% EtOAc / isohexane) to give the title compound (118 mg, 0.542 mmol, 32% yield, 93% purity) as a viscous red oil. UPLC-MS (Method 2) m / z 202.2 (M+H) at 1.58 min + . 1 H NMR (500 MHz, DMSO-d 6 )δ6.96-6.95(m,3H),5.07(s,2H),2.79(t,J=5.1Hz,4H),1.71-1.63(m,4H),1.57-1.48(m,2H).

[0828] Step 3: Methyl 3-(N-(5-cyano-2-(piperidin-1-yl)phenyl)sulfamoyl)-4-methoxybenzoate: A mixture of the product of Step 2 above (118 mg, 0.542 mmol), methyl 3-(chlorosulfonyl)-4-methoxybenzoate (172 mg, 0.651 mmol) and pyridine (130 μl, 1.61 mmol) in DCM (5 ml) was stirred at room temperature over the weekend. The mixture was concentrated onto silica and purified by silica gel column chromatography (12 g cartridge, 0-100% EtOAc / isohexane) to give the title compound (172 mg, 0.394 mmol, 73% yield, 98% purity) as a white solid. UPLC-MS (Method 2) m / z 430.2 (M+H) at 1.58 min + ,428.1(MH) - . 1 H NMR (500 MHz, DMSO-d 6 )δ8.94(s,1H),8.33(d,J=2.3Hz,1H),8.20(dd,J=8.7,2.3Hz,1H),7.50(dd,J=8.5,2.0Hz,1H),7.41-7.35(m,2H ),7.24(d,J=8.5Hz,1H),3.94(s,3H),3.86(s,3H),2.82(t,J=5.3Hz,4H),1.65-1.57(m,4H),1.55-1.46(m,2H).

[0829] Step 4: 3-(N-(5-cyano-2-(piperidin-1-yl)phenyl)sulfamoyl)-4-methoxybenzoic acid: The product of step 3 above (170 mg, 0.390 mmol) and LiOH (40 mg, 1.67 mmol) were mixed in THF / H 2 O (4:1, 4 ml) was stirred at room temperature for 1 h and then at 35 °C overnight. 2 The product was concentrated to 4% by volume with 1% 4-nitropropene (2% ethyl acetate) and diluted with 1% 4-nitropropene (10% by volume) DMF (10% by volume) and EtOAc (15% by volume) and acidified to ~pH 4 with 1M HCl. The phases were separated and the aqueous phase was extracted with EtOAc (2 x 15 ml). The combined organic extracts were washed with brine (15 mL), passed through a phase separator and the solvent removed under vacuum. The residue was loaded onto silica and purified by silica gel column chromatography (12 g cartridge, 0-100% EtOAc / isohexane) to give the title compound (105 mg, 0.243 mmol, 62% yield, 96% purity) as a white solid. UPLC-MS (Method 1) m / z 416.2 (M+H) at 1.47 min + ,413.7(MH) - . 1 H NMR (500 MHz, DMSO-d 6 )δ13.18(s,1H),8.88(s,1H),8.33(d,J=2.2Hz,1H),8.17(dd,J=8.7,2.2Hz,1H),7.50(dd,J=8.3,2.0Hz,1H),7.39(d,J=2.0H z,1H),7.34(d,J=8.7Hz,1H),7.24(d,J=8.3Hz,1H),3.92(s,3H),2.81(t,J=5.2Hz,4H),1.67-1.56(m,4H),1.56-1.45(m,2H).

[0830] Example 183: 4-ethyl-3-(N-(2-(3-hydroxyazetidin-1-yl)-5-(trifluoromethyl)phenyl)sulfamoyl)benzoic acid

[0831]

[0832] Step 1: Methyl 3-(chlorosulfonyl)-4-ethylbenzoate: Thionyl chloride (5 ml, 68.5 mmol) was added portionwise to the product of Step 1 of Example 1, 3-((chlorosulfonyl)-4-ethylbenzoic acid) (0.888 g, 3.57 mmol) at room temperature. The mixture was heated to 75°C for 1 h. The solution was cooled to room temperature and concentrated in vacuo. The residue was dissolved in DCM (5 ml) and treated with MeOH (0.144 ml, 3.57 mmol), followed by Et3 N (0.536 ml, 3.93 mmol) was added and stirred at room temperature overnight. The mixture was diluted with DCM (50 ml), washed with water (50 ml), and MgSO 4 Dry, filter and concentrate in vacuo to give the title compound as a light brown oil (0.450 g, 1.37 mmol, 38% yield, 80% purity). 1 H NMR (500 MHz, DMSO-d 6 )δ8.73(d,J=1.8Hz,1H),8.32(dd,J=8.1,1.8Hz,1H),7.61(d,J=8.0Hz,1H),3.99(s,3H),3.28(q,J=7.3Hz,2H),1.40(t,J=7.4Hz,3H).

[0833] Step 2: 1-(2-nitro-4-(trifluoromethyl)phenyl)azetidin-3-ol: Et 3 N (0.700ml, 5.02mmol) was added to a solution of 1-fluoro-2-nitro-4-(trifluoromethyl)benzene (0.201ml, 1.44mmol) and azetidine-3-ol hydrochloride (189mg, 1.72mmol) in DCM (6ml). The clear solution was stirred at room temperature for 16h. The organic phase was washed with 1M HCl (3ml) and dried over a hydrophobic frit and concentrated in vacuo to give the title compound (461mg, 1.39mmol, 97% yield, 79% purity) as an orange oil. 1 H NMR (500 MHz, DMSO-d 6 )δ8.09-8.05(m,1H),7.73(dd,J=9.0,2.3Hz,1H),6.90(d,J=8.9Hz,1H),5.79(d,J=6.3Hz,1 H), 4.55-4.49 (m, 1H), 4.19 (ddd, J=9.7, 6.7, 1.4Hz, 2H), 3.77 (ddd, J=9.7, 4.1, 1.3Hz, 2H).

[0834] Step 3: 1-(2-amino-4-(trifluoromethyl)phenyl)azetidin-3-ol: The product from Step 2 above (455 mg, 1.37 mmol) was dissolved in EtOH (27.4 ml) and heated in a Thales Nano H- The reaction mixture was concentrated in vacuo and azeotroped with MeOH (12 ml) to give the title compound (395 mg, 1.37 mmol, 100% yield, 81% purity) as a pale yellow oil. UPLC-MS (Method 1) m / z 233.3 (M+H) at 1.00 min + . 1 H NMR (500 MHz, DMSO-d 6 )δ6.86(d,J=2.1Hz,1H),6.83-6.79(m,1H),6.50(d,J=8.1Hz,1H),5.52(d,J=6.5Hz,1H),4.74(br s,2H),4.46(sextet,J=6.2Hz,1H),4.19-4.13(m,2H),3.45-3.40(m,2H).

[0835] Step 4: Methyl 4-ethyl-3-(N-(2-(3-hydroxyazetidin-1-yl)-5-(trifluoromethyl)phenyl)sulfamoyl)benzoate: Pyridine (0.072 ml, 0.896 mmol) was added to a solution of the product of step 3 above (65 mg, 0.224 mmol) and the product of step 1 above (92 mg, 0.280 mmol) in DCM (2.0 ml) at room temperature. The resulting cloudy solution was stirred at room temperature for 21 h. The reaction mixture was concentrated in vacuo and the crude product was purified by silica gel column chromatography (10 g cartridge, 0-65% EtOAc / isohexane) to give the title compound (51 mg, 0.102 mmol, 46% yield, 92% purity) as a red oil. UPLC-MS (Method 1) m / z 459.4 (M+H) at 0.66 min + ,457.2(MH) - .

[0836] Step 5: 4-ethyl-3-(N-(2-(3-hydroxyazetidin-1-yl)-5-(trifluoromethyl)phenyl)sulfamoyl)benzoic acid: 1M LiOH(aq) (0.409 ml, 0.409 mmol) was added to a solution of the product of step 4 above (51 mg, 0.102 mmol) in THF (0.82 ml) at room temperature. The solution was stirred at room temperature for 17 h and then concentrated in vacuo. The residue was dissolved in water (3 ml) and washed with EtOAc (5 ml). The aqueous phase was acidified with 1M HCl until pH 4 to 5, and the product was extracted into EtOAc (3×5 ml). The organic phases were combined and washed with MgSO 4Dry and concentrate in vacuo. The crude product was purified by preparative HPLC (Waters, acidic (0.1% formic acid), acidic, Waters X-Select Prep-C18, 5 μm, 19×50 mm column, 35% to 65% MeCN in water) to give the title compound (7.3 mg, 0.016 mmol, 16% yield, 99% purity) as a white solid. UPLC-MS (Method 1) m / z 445.3 (M+H) at 1.32 min + ,443.2(MH) - . 1 H NMR (500 MHz, DMSO-d 6 )δ13.24(br s,1H),9.55(br s,1H),8.25(d,J=1.8Hz,1H),8.11(dd,J=8.0,1.5Hz,1H),7.62(d,J=8.1Hz,1H),7.31(br d,J=8.7Hz,1H),6.51(d,J=8.6Hz,1H),6.24(br s,1H),5.63(br d,J=5.9Hz,1H),4.58-4.48(m,1H),4.40-4.33(m,2H),3.82(dd,J=8.7,4.8Hz,2H),2.94(q,J=7.4Hz,2H),1.17(t,J=7.4Hz,3H).

[0837] Example 184: 3-(N-(3-Fluoro-2-(piperidin-1-yl)-5-(trifluoromethyl)phenyl)sulfamoyl)-4-methoxybenzoic acid

[0838]

[0839] Step 1: 1-(2-Fluoro-6-nitro-4-(trifluoromethyl)phenyl)piperidine: At room temperature, add Et 3 N (0.767 ml, 5.50 mmol) was added to a solution of 1,2-difluoro-3-nitro-5-(trifluoromethyl)benzene (500 mg, 2.20 mmol) and piperidine (0.261 ml, 2.64 mmol) in DCM (6 ml). The clear solution was stirred at room temperature for 23 h. The organic phase was washed with 1 M HCl (3 ml), dried through a phase separator and concentrated in vacuo to give the title compound (676 mg, 2.20 mmol, yield 100%, purity 98%) as a brown oil. UPLC-MS (Method 1) m / z 293.5 (M+H) at 1.93 min + .

[0840] Step 2: 3-Fluoro-2-(piperidin-1-yl)-5-(trifluoromethyl)aniline: The product of step 1 above (0.642 g, 2.20 mmol) was dissolved in EtOH (44 ml) and heated to 40 ℃ in a Thales Nano H- Hydrogenation in a flow reactor (10% Pd / C, 30×4 mm, full hydrogen mode, room temperature, flow rate 1 ml / min, 1 pass). The crude product was concentrated in vacuo and azeotroped with MeOH (12 ml) to give the title compound (0.543 g, 1.97 mmol, yield 90%, purity 95%) as a light yellow oil. UPLC-MS (Method 1) m / z 263.3 (M+H) at 1.89 min + .

[0841] Step 3: Methyl 3-(N-(3-fluoro-2-(piperidin-1-yl)-5-(trifluoromethyl)phenyl)sulfamoyl)-4-methoxybenzoate: Pyridine (0.139 ml, 1.72 mmol) was added to a solution of the product of step 2 above (0.15 g, 0.572 mmol) and methyl 3-(chlorosulfonyl)-4-methoxybenzoate (0.189 g, 0.715 mmol) in DCM (10 ml) and the solution was stirred at room temperature for 18 h. The solution was concentrated in vacuo and the crude product was purified by silica gel column chromatography (12 g cartridge, 0-100% EtOAc / isohexane) to give the title compound (0.372 g, 0.546 mmol, 95% yield, 72% purity) as a white solid. UPLC-MS (Method 1) m / z 491.3 (M+H) at 1.96 min + ,489.2(MH) - .

[0842] Step 4: 3-(N-(3-Fluoro-2-(piperidin-1-yl)-5-(trifluoromethyl)phenyl)sulfamoyl)-4-methoxybenzoic acid: 1 M LiOH(aq) (3.28 ml, 3.28 mmol) was added to a solution of the product of step 3 above (0.268 g, 0.547 mmol) in THF (12 ml) and MeOH (3 ml), and the solution was stirred at room temperature overnight. The solvent was removed under vacuum and the residue was dissolved in water (5 ml) and extracted with TBME (3×5 ml). The aqueous phase was acidified with concentrated HCl and the product was extracted into TBME (3×10 ml). The organic phases were combined and dried through a phase separator. The solvent was removed under vacuum to give the title compound (0.184 g, 0.378 mmol, 69% yield, 98% purity) as an off-white solid. UPLC-MS (method 1) m / z 477.3 (M+H) at 1.81 min + ,474.9(MH)- . 1 H NMR (500 MHz, DMSO-d 6 )δ13.19(s,1H),8.99(s,1H),8.38(d,J=2.2Hz,1H),8.17(dd,J=8.7,2.2Hz,1H),7.3 7-7.31(m,3H),3.94(s,3H),2.91-2.81(m,4H),1.69-1.62(m,4H),1.58-1.51(m,2H).

[0843] The following examples were prepared by a procedure analogous to Example 184, substituting appropriate starting materials and intermediates where necessary:

[0844]

[0845]

[0846] Example 200: 3-(N-(2-(piperidin-1-yl)-5-(trifluoromethyl)phenyl)sulfamoyl)-4-(trifluoromethyl)benzoic acid

[0847]

[0848] Step 1: Methyl 3-(N-(2-(piperidin-1-yl)-5-(trifluoromethyl)phenyl)sulfamoyl)-4-(trifluoromethyl)benzoate: A mixture of 2-(piperidin-1-yl)-5-(trifluoromethyl)aniline (75 mg, 0.307 mmol), methyl 3-(chlorosulfonyl)-4-(trifluoromethyl)benzoate (101 mg, 0.335 mmol) and pyridine (75 μl, 0.927 mmol) in DCM (4 ml) was stirred at room temperature overnight and then at 35° C. for 11 days. The mixture was concentrated onto silica and purified by silica gel column chromatography (12 g cartridge, 0-50% EtOAc / isohexane) to give the title compound (91 mg, 0.178 mmol, 58.1% yield, 100% purity) as a pale yellow solid. UPLC-MS (method 1) m / z 511.2 (M+H) at 1.99 min + ,509.0(MH) - . 1H NMR (500MHz, DMSO-d6) δ9.73(s,1H),8.46(s,1H),8.34(d,J=8.2Hz,1H),8.19(d,J=8.2Hz,1H),7.50(d,J=8.4 Hz, 1H), 7.37 (d, J = 2.2Hz, 1H), 7.26 (dd, J = 8.4, 2.2Hz, 1H), 3.89 (s, 3H), 2.71-2.65 (m, 4H), 1.48-1.36 (m, 6H).

[0849] Step 2: 3-(N-(2-(piperidin-1-yl)-5-(trifluoromethyl)phenyl)sulfamoyl)-4-(trifluoromethyl)benzoic acid: A mixture of the product of Step 1 above (91 mg, 0.178 mmol) and LiOH (17 mg, 0.710 mmol) in THF / MeOH / water (4:1:1, 2.4 ml) was stirred at 35°C overnight. The mixture was diluted with water (10 ml) and EtOAc (15 ml) and acidified to ~pH 4 with 1 M HCl(aq). The phases were separated and the aqueous phase was extracted with EtOAc (2 x 15 ml). The organic extracts were combined and washed with brine (15 ml), dried through a phase separator and the solvent removed under vacuum. The residue was triturated with isohexane / TBME (5:1) to give the title compound as a beige solid (33.4 mg, 0.066 mmol, 37.0% yield, 98% purity). UPLC-MS (Method 1) m / z 497.2 (M+H) at 1.92 min + ,495.1(MH) - . 1 H NMR (500MHz, DMSO-d6) δ13.89(s,1H),9.69(s,1H),8.48(d,J=1.6Hz,1H),8.32(dd,J=8.2,1.6Hz,1H),8.16(d,J=8.2H z,1H),7.49(dd,J=8.5,2.2Hz,1H),7.35(d,J=2.2Hz,1H),7.26(d,J=8.5Hz,1H),2.73-2.64(m,4H),1.49-1.35(m,6H).

[0850] Example 201: 4-Ethoxy-3-(N-(2-(piperidin-1-yl)-5-(trifluoromethyl)phenyl)sulfamoyl)benzoic acid

[0851]

[0852] Step 1: Methyl 4-ethoxy-3-(N-(2-(piperidin-1-yl)-5-(trifluoromethyl)phenyl)sulfamoyl)benzoate: A solution of 2-(piperidin-1-yl)-5-(trifluoromethyl)aniline (0.100 g, 0.409 mmol) in DCM (5 ml) and pyridine (0.199 ml, 2.46 mmol) was added to a solution of methyl 3-(chlorosulfonyl)-4-ethoxybenzoate (0.114 g, 0.409 mmol) in DCM (10 ml) and the solution was stirred at room temperature for 24 h. The solvent was removed under vacuum and the crude product was purified by silica gel column chromatography (40 g cartridge, 0-50% EtOAc / isohexane) to give the title compound (0.160 g, 0.326 mmol, 80% yield, 99% purity) as a cream waxy solid. UPLC-MS (method 1) m / z 487.4 (M+H) at 1.93 min + ,485.2(MH) - .

[0853] Step 2: 4-ethoxy-3-(N-(2-(piperidin-1-yl)-5-(trifluoromethyl)phenyl)sulfamoyl)benzoic acid: 1M LiOH(aq) (0.024 g, 0.987 mmol) was added to a solution of the product of step 1 above (0.160 g, 0.329 mmol) in THF (5 ml) and the solution was stirred at room temperature overnight. The reaction mixture was concentrated to water in vacuo. The pH was adjusted to pH 6 with 1M HCl(aq) to form a precipitate which was filtered and washed with water (10 ml) and isohexane (20 ml) to give the title compound as a white solid (0.151 g, 0.304 mmol, 92% yield, 95% purity). UPLC-MS (Method 1) m / z 473.4 (M+H) at 1.78 min + ,471.2(MH) - . 1 H NMR(500MHz,DMSO-d6)δ13.20(br s,1H),8.55(br s,1H),8.40(d,J=2.2Hz,1H),8.13(dd,J=8.7,2.2Hz,1H),7.47(d,J=2.0Hz,1H),7.39-7.34(m,1H),7.32-7.30(m,2 H), 4.22 (q, J = 7.0Hz, 2H), 2.76 (t, J = 5.3Hz, 4H), 1.62 (p, J = 5.5Hz, 4H), 1.52 (p, J = 6.3Hz, 2H), 1.27 (t, J = 7.0Hz, 3H).

[0854] Example 202: 3-(N-(4,5-dichloro-2-(piperidin-1-yl)phenyl)sulfamoyl)-4-methoxybenzoic acid

[0855]

[0856] Step 1: Methyl 3-(N-(4,5-dichloro-2-(piperidin-1-yl)phenyl)sulfamoyl)-4-methoxybenzoate: Pyridine (0.166 ml, 2.06 mmol) was added to a solution of 4,5-dichloro-2-(piperidin-1-yl)aniline (0.168 g, 0.685 mmol) and methyl 3-(chlorosulfonyl)-4-methoxybenzoate (0.227 g, 0.857 mmol) in DCM (10 ml). The solution was stirred at room temperature for 18 h and then concentrated in vacuo. The crude product was purified by silica gel column chromatography (12 g cartridge, 0-100% EtOAc / isohexane) to give the title compound (0.257 g, 0.543 mmol, 79% yield, 81% purity) as a white solid. UPLC-MS (method 1) m / z 475.4 (M+H) at 1.75 min + ,472.8(MH) - .

[0857] Step 2: 3-(N-(4,5-dichloro-2-(piperidin-1-yl)phenyl)sulfamoyl)-4-methoxybenzoic acid: 1M LiOH(aq) (3.26ml, 3.26mmol) was added to a solution of the product of step 1 above (0.257g, 0.543mmol) in THF (13ml) and MeOH (3ml), and the solution was stirred at room temperature overnight. The solvent was removed under vacuum, and the residue was dissolved in water (5ml) and washed with TBME (3×5ml). The aqueous phase was acidified with concentrated HCl and extracted with TBME (3×10ml). The combined organic phases were dried through a phase separator and the solvent was removed under vacuum to give the title compound (0.229g, 0.494mmol, 91% yield, 97% purity) as an off-white solid. UPLC-MS (method 1) at 1.82 min, m / z 459.3 / 461.3 (M+H) + ,457.2 / 459.2(MH) - . 1H NMR (500MHz, DMSO-d6) δ13.22(s,1H),8.75(s,1H),8.35(d,J=2.2Hz,1H),8.17(dd,J=8.7,2.2Hz,1H),7.42(s, 1H),7.38(s,1H),7.34(d,J=8.8Hz,1H),3.94(s,3H),2.70-2.64(m,4H),1.67-1.56(m,4H),1.56-1.42(m,2H).

[0858] Example 203: 3-(N-(2-(4,4-difluoropiperidin-1-yl)-5-(trifluoromethyl)phenyl)sulfamoyl)-4-ethylbenzoic acid

[0859]

[0860] Step 1: 3-(Chlorosulfonyl)-4-ethylbenzoic acid: A solution of 4-ethylbenzoic acid (7 g, 46.6 mmol) in chlorosulfonic acid (20 ml, 299 mmol) was heated at 100°C for 5 h. The mixture was cooled and carefully added to stirred ice water (200 ml). The precipitated solid was collected by filtration, washed with water (100 mL) and dried in vacuo to give the title compound (10.9 g, 41.5 mmol, 89% yield, 95% purity) as a white solid. 1 H NMR (500 MHz, DMSO-d 6 )δ13.65(br s,1H),8.34(d,J=1.9Hz,1H),7.82(dd,J=7.9,2.0Hz,1H),7.32(d,J=7.9Hz,1H),3.08(q,J=7.5Hz,2H),1.18(t,J=7.5Hz,3H).

[0861] Step 2: Methyl 3-(chlorosulfonyl)-4-ethylbenzoate: Thionyl chloride (10 ml, 137 mmol) was added portionwise to the product of step 1 above (4 g, 16.1 mmol) at room temperature. The mixture was heated to 75°C for 2 h, cooled to room temperature, concentrated in vacuo, and azeotroped with toluene. The solid was dissolved in DCM (10 ml) and treated with MeOH (0.716 ml, 17.7 mmol), then with Et 3 N (2.41 ml, 17.7 mmol) was added and stirred at room temperature overnight. The mixture was diluted with DCM (50 ml), washed with water (50 ml), and dried (MgSO 4) and concentrated in vacuo. The crude product was purified by silica gel column chromatography (40 g cartridge, 0-50% EtOAc / isohexane) to afford the title compound (3.60 g, 13.02 mmol, 81% yield, 95% purity) as a white solid. 1 H NMR (500 MHz, DMSO-d 6 )δ8.74(d,J=1.8Hz,1H),8.32(dd,J=8.0,1.8Hz,1H),7.61(d,J=8.0Hz,1H),3.99(s,3H),3.28(q,J=7.5Hz,2H),1.41(t,J=7.5Hz,3H).

[0862] Step 3: Methyl 3-(N-(2-(4,4-difluoropiperidin-1-yl)-5-(trifluoromethyl)phenyl)sulfamoyl)-4-ethylbenzoate: Pyridine (0.069 ml, 0.856 mmol) was added to a solution of the product of step 2 of example 12 (0.08 g, 0.285 mmol) and the product of step 2 above (0.094 g, 0.357 mmol) in DCM (10 ml) and the solution was stirred at room temperature for 18 h. The solution was concentrated in vacuo and the crude product was purified by silica gel column chromatography (12 g cartridge, 0-100% EtOAc / isohexane) to give the title compound (0.137 g, 0.227 mmol, 80% yield, 84% purity) as a white solid. UPLC-MS (Method 1) m / z 507.4 at 1.90 min (M+H) + ,505.2(MH) - .

[0863] Step 4: 3-(N-(2-(4,4-difluoropiperidin-1-yl)-5-(trifluoromethyl)phenyl)sulfamoyl)-4-ethylbenzoic acid: 1M LiOH(aq) (1.35 ml, 1.35 mmol) was added to a solution of the product of step 3 above (0.137 g, 0.225 mmol) in THF (6 ml) and MeOH (1.3 ml), and the solution was stirred at room temperature overnight. The solvent was removed under vacuum, and the residue was dissolved in water (5 ml) and washed with TBME (3×5 ml). The aqueous phase was acidified with concentrated HCl and extracted with TBME (3×10 ml). The organic phases were combined, dried through a phase separator and the solvent was removed under vacuum to give the title compound (0.105 g, 0.209 mmol, 93% yield, 98% purity) as an off-white solid. UPLC-MS (method 1) m / z 493.3 (M+H) at 1.76 min + ,490.9(MH) - . 1H NMR (500 MHz, DMSO-d 6 )δ13.31(s,1H),9.85(s,1H),8.37(d,J=1.8Hz,1H),8.10(dd,J=8.0,1.8Hz,1H),7.61(d,J=8.0Hz,1H),7.44(dd,J=8 .5,2.1Hz,1H),7.36-7.31(m,2H),3.03(q,J=7.4Hz,2H),2.89-2.80(m,4H),2.13-2.00(m,4H),1.18(t,J=7.4Hz,3H).

[0864] Example 204: 3-(N-(2-(3,3-difluoropiperidin-1-yl)-5-(trifluoromethyl)phenyl)sulfamoyl)-4-ethylbenzoic acid

[0865]

[0866] Step 1: Methyl 3-(N-(2-(3,3-difluoropiperidin-1-yl)-5-(trifluoromethyl)phenyl)sulfamoyl)-4-ethylbenzoate: Pyridine (0.052 ml, 0.642 mmol) was added to a solution of the product of step 2 of example 9 (60 mg, 0.214 mmol) and the product of step 2 of example 203 (70 mg, 0.268 mmol) in DCM (10 ml). The solution was stirred at room temperature for 18 h and then concentrated in vacuo. The crude product was purified by silica gel column chromatography (12 g cartridge, 0-100% EtOAc / isohexane) to give the title compound (0.057 g, 0.113 mmol, 52.6% yield, 100% purity) as a white solid. UPLC-MS (method 1) m / z 507.7 (M+H) at 1.89 min + ,505.2(MH) - .

[0867] Step 2: 3-(N-(2-(3,3-difluoropiperidin-1-yl)-5-(trifluoromethyl)phenyl)sulfamoyl)-4-ethylbenzoic acid: 1M LiOH(aq) (0.675 ml, 0.675 mmol) was added to a solution of the product of step 1 above (0.057 g, 0.113 mmol) in THF (8 ml) and MeOH (2 ml). The solution was stirred at room temperature overnight and then concentrated in vacuo. The residue was dissolved in water (5 ml) and washed with TBME (3×5 ml). The aqueous phase was acidified with concentrated HCl and extracted with TBME (3×10 ml). The organic phases were combined, dried through a phase separator and concentrated in vacuo to give the title compound (0.056 g, 0.110 mmol, 98% yield, 97% purity) as an off-white solid. UPLC-MS (Method 1) m / z 493.7 (M+H) at 1.74 min + ,491.1(MH) - . 1 H NMR (500 MHz, DMSO-d 6 )δ13.30(s,1H),9.30(s,1H),8.35(d,J=1.8Hz,1H),8.11(dd,J=8.0,1.8Hz ,1H),7.62(d,J=8.0Hz,1H),7.45(dd,J=8.5,2.1Hz,1H),7.33(d,J=8.5Hz,1 H),7.12(d,J=2.1Hz,1H),3.21(t,J=11.4Hz,2H),3.00(q,J=7.4Hz,2H),2.9 8-2.94(m,2H),2.08-1.96(m,2H),1.84-1.75(m,2H),1.19(t,J=7.4Hz,3H).

[0868] Example 205: 4-ethyl-3-(N-(2-(4-fluoropiperidin-1-yl)-5-(trifluoromethyl)phenyl)sulfamoyl)benzoic acid

[0869]

[0870] Step 1: 4-Fluoro-1-(2-nitro-4-(trifluoromethyl)phenyl)piperidine: Et 3N (500 μl, 3.59 mmol) was added to a solution of 1-fluoro-2-nitro-4-(trifluoromethyl)benzene (201 μl, 1.44 mmol) and 4-fluoropiperidine (192 mg, 1.87 mmol) in DCM (6 ml), and the resulting solution was stirred at room temperature for 3 days. 1M HCl (aq) (2 ml) was added, and the organic phase was separated by a phase separator. The organic phase was concentrated in vacuo to give the title compound (419 mg, 1.44 mmol, yield 100%, purity 100%) as a light yellow viscous oil. UPLC-MS (Method 2) m / z 293.3 (M+H) at 1.62 min + .

[0871] Step 2: 2-(4-Fluoropiperidin-1-yl)-5-(trifluoromethyl)aniline: The product of step 1 above (419 mg, 1.44 mmol) was dissolved in EtOH (28.8 ml) and the reaction mixture was heated on a Thales Nano H- The reaction mixture was concentrated in vacuo and azeotroped with MeOH (6 ml) to give the title compound (371 mg, 1.27 mmol, 89% yield, 90% purity) as a clear viscous oil. UPLC-MS (Method 2) m / z 263.3 (M+H) at 1.59 min + .

[0872] Step 3: Methyl 4-ethyl-3-(N-(2-(4-fluoropiperidin-1-yl)-5-(trifluoromethyl)phenyl)sulfamoyl)benzoate: The product of Step 2 above (66.5 mg, 0.254 mmol) was dissolved in a mixture of DCM (1 ml) and pyridine (82 μl, 1.02 mmol) and treated with a suspension of the product of Step 2 of Example 203 (80 mg, 0.305 mmol) in DCM (1 ml). The resulting solution was stirred at room temperature for 20 h. The reaction mixture was purified directly by silica gel column chromatography (12 g cartridge, 0-100% EtOAc / isohexane) to give the title compound (61 mg, 0.112 mmol, 44.3% yield, 90% purity) as a cream solid. UPLC-MS (Method 1) m / z 489.3 (M+H) at 1.87 min + ,487.2(MH) - .

[0873]

[0136] Step 4: 4-Ethyl-3-(N-(2-(4-fluoropiperidin-1-yl)-5-(trifluoromethyl)phenyl)sulfamoyl)benzoic acid: The product of Step 3 above (59 mg, 0.121 mmol) was dissolved in THF (2 ml) and treated with 1.1 M LiOH(aq) (439 μl, 0.483 mmol). MeOH was added dropwise to give a solution, which was stirred at 30 °C for 20 h. The reaction mixture was diluted with water (3 ml), concentrated in vacuo, and the resulting aqueous solution was diluted with water (to ~5 ml). The aqueous phase was washed with EtOAc (2 x 5 ml) and neutralized to ~pH 6 using 1 M HCl. The bulk suspension was sonicated to give a turbid solution, which was concentrated in vacuo to ~2 ml. The resulting precipitate was collected by filtration and washed with water (2 x 2 ml). The solid was suspended in MeCN (4 ml), concentrated in vacuo and dried at 45 °C to give the title compound as a white solid (38.4 mg, 0.078 mmol, yield 64.3%, purity 96%). UPLC-MS (Method 1) m / z 475.4 (M+H) at 1.74 min + ,473.2(MH) - . 1 H NMR (500 MHz, DMSO-d 6 )δ13.29(br s,1H),9.68(br s,1H),8.34(d,J=1.8Hz,1H),8.09(dd,J=8.0,1.8Hz,1H),7.61(d,J=8.0Hz,1H),7.46-7.40(m,1H),7.31-7.24(m,2H),4.85-4.70( m,1H),3.03(q,J=7.4Hz,2H),2.89(t,J=9.9Hz,2H),2.74-2.67(m,2H),2.00-1.87(m,2H),1.85-1.73(m,2H),1.19(t,J=7.4Hz,3H).

[0874] Example 206: 3-(N-(2-(4-fluoropiperidin-1-yl)-5-(trifluoromethyl)phenyl)sulfamoyl)-4-methoxybenzoic acid

[0875]

[0876] Step 1: Methyl 3-(N-(2-(4-fluoropiperidin-1-yl)-5-(trifluoromethyl)phenyl)sulfamoyl)-4-methoxybenzoate: The product of Step 2 of Example 205 (66.1 mg, 0.252 mmol) was dissolved in a mixture of DCM (1 ml) and pyridine (81 μl, 1.01 mmol) and treated with a solution of methyl 3-(chlorosulfonyl)-4-methoxybenzoate (80 mg, 0.302 mmol) in DCM (1 ml). The resulting solution was stirred at room temperature for 20 h. The reaction mixture was purified directly by silica gel column chromatography (12 g cartridge, 0-100% EtOAc / isohexane) to give the title compound (88 mg, 0.161 mmol, 64.1% yield, 90% purity) as a viscous paste solid. UPLC-MS (method 1) m / z 491.4 (M+H) at 1.73 min + ,489.1(MH) - .

[0877]

[0136] Step 2: 3-(N-(2-(4-fluoropiperidin-1-yl)-5-(trifluoromethyl)phenyl)sulfamoyl)-4-methoxybenzoic acid: The product of Step 1 above (86 mg, 0.175 mmol) was dissolved in THF (2 ml) and treated with 1.1 M LiOH(aq) (638 μl, 0.701 mmol). MeOH was added dropwise to give a solution, which was stirred at 30 °C for 20 h. The reaction mixture was diluted with water (3 ml), concentrated in vacuo, and the resulting aqueous solution was diluted with water (to ~5 ml). The aqueous phase was washed with EtOAc (2 x 5 ml) and neutralized to ~pH 6 using 1 M HCl. The bulk suspension was sonicated to give a turbid solution, which was concentrated in vacuo to ~2 ml. The resulting precipitate was collected by filtration and washed with water (2 x 2 mL). The solid was suspended in MeCN (4 ml), concentrated in vacuo and dried at 45 °C to give the title compound as a white solid (52.7 mg, 0.108 mmol, yield 61.8%, purity 98%). UPLC-MS (Method 1) m / z 477.3 (M+H) at 1.56 min + ,475.1(MH) - . 1 H NMR (500 MHz, DMSO-d 6)δ13.16(br s,1H),9.00(br s,1H),8.35(d,J=2.2Hz,1H),8.16(dd,J=8.7,2.2Hz,1H),7.44(d,J=2.0Hz,1H),7.40-7.29(m,3H),4.93- 4.75(m,1H),3.90(s,3H),2.94(t,J=9.8Hz,2H),2.79-2.73(m,2H),2.10-1.94(m,2H),1.93-1.79(m,2H).

[0878] Example 207: 4-Methoxy-3-(N-(5-(methylsulfonyl)-2-(piperidin-1-yl)phenyl)sulfamoyl)benzoic acid

[0879]

[0880] Step 1: 1-(4-(Methylsulfonyl)-2-nitrophenyl)piperidine: At room temperature, add Et 3 N (0.795 ml, 5.70 mmol) was added to a solution of 1-fluoro-4-(methylsulfonyl)-2-nitrobenzene (500 mg, 2.28 mmol) and piperidine (0.226 ml, 2.28 mmol) in DCM (6 ml). The clear solution was stirred at room temperature for 23 h. The organic phase was washed with 1 M HCl (aq) (3 ml), dried through a phase separator and concentrated in vacuo to give the title compound as a brown oil (0.676 g, 2.28 mmol, yield 100%, purity 100%). UPLC-MS (Method 1) m / z 285.2 (M+H) at 1.32 min + .

[0881] Step 2: 5-(Methylsulfonyl)-2-(piperidin-1-yl)aniline: The product of Step 1 above (0.676 g, 2.38 mmol) was dissolved in EtOH (44 ml) and the reaction mixture was heated on a Thales Nano H- The reaction mixture was concentrated in vacuo and then azeotroped with MeOH (12 ml) to give the title compound (0.615 g, 2.370 mmol, 100% yield, 98% purity) as a pale yellow oil. UPLC-MS (Method 1) m / z 255.3 (M+H) at 1.20 min + .

[0882] Step 3: Methyl 4-methoxy-3-(N-(5-(methylsulfonyl)-2-(piperidin-1-yl)phenyl)sulfamoyl)benzoate: Pyridine (0.143 ml, 1.77 mmol) was added to a solution of the product of step 2 above (0.15 g, 0.590 mmol) and methyl 3-(chlorosulfonyl)-4-methoxybenzoate (0.195 g, 0.737 mmol) in DCM (10 ml). The resulting solution was stirred at room temperature for 18 h. The solution was concentrated in vacuo and the crude product was purified by silica gel column chromatography (12 g cartridge, 0-100% EtOAc / isohexane) to give the title compound (0.201 g, 0.412 mmol, 69.9% yield, 99% purity) as a white solid. UPLC-MS (Method 1) m / z 483.3 (M+H) at 1.49 min + ,481.0(MH) - .

[0883] Step 4: 4-methoxy-3-(N-(5-(methylsulfonyl)-2-(piperidin-1-yl)phenyl)sulfamoyl)benzoic acid: 1 M LiOH(aq) (2.47 ml, 2.47 mmol) was added to a solution of the product of step 3 above (0.199 g, 0.412 mmol) in THF (10 ml) and MeOH (2.5 ml), and the solution was stirred at room temperature overnight. The solvent was removed under vacuum, and the residue was dissolved in water (5 ml) and washed with TBME (3×5 ml). The aqueous phase was acidified with concentrated HCl and extracted with TBME (3×10 ml). The organic phases were combined and dried through a phase separator. The solvent was removed under vacuum to give the title compound (0.176 g, 0.372 mmol, 90% yield, 99% purity) as an off-white solid. UPLC-MS (method 1) m / z 469.4 (M+H) at 1.36 min + ,467.0(MH) - . 1 H NMR (500 MHz, DMSO-d 6 )δ13.17(s,1H),8.82(s,1H),8.35(d,J=2.2Hz,1H),8.15(dd,J=8.7,2.2Hz,1H),7.65(d,J=2.2Hz,1H),7.55(dd,J=8.4,2.2Hz,1H ),7.34(d,J=8.4Hz,1H),7.33(d,J=8.7Hz,1H),3.94(s,3H),3.00(s,3H),2.85-2.78(m,4H),1.71-1.60(m,4H),1.58-1.50(m,2H).

[0884] Example 208: (R)-3-(N-(2-(3-fluoropiperidin-1-yl)-5-(trifluoromethyl)phenyl)sulfamoyl)-4-methoxybenzoic acid

[0885]

[0886] Step 1: (R)-3-Fluoro-1-(2-nitro-4-(trifluoromethyl)phenyl)piperidine: Et 3 N (500 μl, 3.59 mmol) was added to a solution of 1-fluoro-2-nitro-4-(trifluoromethyl)benzene (300 mg, 1.44 mmol) and (R)-3-fluoropiperidine (250 mg, 2.42 mmol) in DCM (6 ml). The resulting solution was stirred at room temperature for 20 h. 1M HCl(aq) (2 ml) was added and the organic phase was separated by a phase separator. The organic phase was concentrated in vacuo to give the title compound (488 mg, 1.44 mmol, 100% yield, 86% purity) as a light orange viscous oil. UPLC-MS (Method 2) m / z 293.0 (M+H) at 1.59 min + .

[0887] Step 2: (R)-2-(3-fluoropiperidin-1-yl)-5-(trifluoromethyl)aniline: The product of step 1 above (419 mg, 1.44 mmol) was dissolved in EtOH (28.8 ml) and the reaction mixture was heated on a Thales Nano H- The reaction mixture was concentrated in vacuo and azeotroped with MeOH (6 ml) to give the title compound (457 mg, 1.394 mmol, 97% yield, 80% purity) as a milky white gel. UPLC-MS (Method 2) m / z 263.3 (M+H) at 1.59 min + .

[0888] Step 3: (R)-methyl 3-(N-(2-(3-fluoropiperidin-1-yl)-5-(trifluoromethyl)phenyl)sulfamoyl)-4-methoxybenzoate: The product of Step 3 above (66.1 mg, 0.252 mmol) was dissolved in a mixture of DCM (1 ml) and pyridine (81 μl, 1.01 mmol) and treated with a solution of methyl 3-(chlorosulfonyl)-4-methoxybenzoate (80 mg, 0.302 mmol) in DCM (1 ml). The resulting solution was stirred at room temperature for 3 days. The reaction mixture was purified directly by silica gel column chromatography (12 g cartridge, 0-100% EtOAc / isohexane) to give the title compound (72.4 mg, 0.118 mmol, 46.9% yield, 80% purity) as an off-white solid. UPLC-MS (method 1) m / z 491.3 (M+H) at 1.73 min + ,489.1(MH) - .

[0889] Step 4: (R)-3-(N-(2-(3-fluoropiperidin-1-yl)-5-(trifluoromethyl)phenyl)sulfamoyl)-4-methoxybenzoic acid: The product of Step 3 above (69 mg, 0.141 mmol) was dissolved in THF (2 ml) and treated with 1.1 M LiOH(aq) (512 μl, 0.563 mmol). MeOH was added dropwise to give a solution, which was stirred at 30 °C for 20 h. The reaction mixture was diluted with water (3 ml), concentrated in vacuo, and the resulting aqueous solution was diluted with water (to ~5 ml). The aqueous phase was washed with EtOAc (2×5 ml) and neutralized to ~pH 6 using 1 M HCl. The bulk suspension was sonicated to give a turbid solution, which was concentrated in vacuo to ~2 ml. The precipitate was collected by filtration and washed with water (2×2 mL). The solid was suspended in MeCN (4 ml), concentrated in vacuo and dried at 45°C to give the title compound as a white solid (55.2 mg, 0.110 mmol, yield 78%). UPLC-MS (Method 1) m / z 477.4 (M+H) at 1.57 min + ,475.1(MH) - . 1 H NMR (500 MHz, DMSO-d 6)δ13.19(br s,1H),8.75(br s,1H),8.38(d,J=2.2Hz,1H),8.16(dd,J=8.7,2.2Hz,1H),7.44(s,1H),7.38-7.33(m,2H),7.31(d,J=8.8Hz,1H ),4.95-4.79(m,1H),3.91(s,3H),3.09-2.86(m,3H),2.85-2.75(m,1H),1.95-1.75(m,3H),1.74-1.63(m,1H).

[0890] Example 209: (S)-3-(N-(2-(3-fluoropiperidin-1-yl)-5-(trifluoromethyl)phenyl)sulfamoyl)-4-methoxybenzoic acid

[0891]

[0892] Step 1: (S)-3-Fluoro-1-(2-nitro-4-(trifluoromethyl)phenyl)piperidine: Et 3 N (500 μl, 3.59 mmol) was added to a solution of 1-fluoro-2-nitro-4-(trifluoromethyl)benzene (300 mg, 1.44 mmol) and (S)-3-fluoropiperidine (250 mg, 2.42 mmol) in DCM (6 ml), and the resulting solution was stirred at room temperature for 20 h. 1 M HCl (aq) (2 ml) was added, and the organic phase was separated and concentrated in vacuo to give the title compound (461 mg, 1.44 mmol, yield 100%, purity 91%) as a light orange viscous oil. UPLC-MS (Method 2) m / z 293.1 (M+H) at 1.60 min + .

[0893] Step 2: (S)-2-(3-fluoropiperidin-1-yl)-5-(trifluoromethyl)aniline: The product of step 1 above (419 mg, 1.44 mmol) was dissolved in EtOH (28.8 ml). The reaction mixture was heated in a Thales Nano H- The reaction mixture was concentrated in vacuo and azeotroped with MeOH (6 ml) to give the title compound (475 mg, 1.43 mmol, 100% yield, 79% purity) as a milky white gel. UPLC-MS (Method 2) m / z 263.3 (M+H) at 1.59 min + .

[0894] Step 3: (S)-methyl 3-(N-(2-(3-fluoropiperidin-1-yl)-5-(trifluoromethyl)phenyl)sulfamoyl)-4-methoxybenzoate: The product of Step 2 above (66.1 mg, 0.252 mmol) was dissolved in a mixture of DCM (1 ml) and pyridine (81 μl, 1.01 mmol) and treated with a solution of methyl 3-(chlorosulfonyl)-4-methoxybenzoate (80 mg, 0.302 mmol) in DCM (1 ml). The resulting solution was stirred at room temperature for 3 days. The reaction mixture was purified directly by silica gel column chromatography (12 g cartridge, 0-100% EtOAc / isohexane) to give the title compound (81.4 mg, 0.133 mmol, 52.7% yield, 80% purity) as an off-white solid. UPLC-MS (method 1) m / z 491.4 (M+H) at 1.74 min + ,489.3(MH) - .

[0895] Step 4: (S)-3-(N-(2-(3-fluoropiperidin-1-yl)-5-(trifluoromethyl)phenyl)sulfamoyl)-4-methoxybenzoic acid: The product of Step 3 above (78 mg, 0.159 mmol) was dissolved in THF (2 ml) and treated with 1.1 M LiOH(aq) (578 μl, 0.636 mmol). MeOH was added dropwise to give a solution, which was stirred at 30 °C for 20 h. The reaction mixture was diluted with water (3 ml), concentrated in vacuo, and the resulting aqueous solution was diluted with water (to ~5 ml). The solution was washed with EtOAc (2×5 ml) and neutralized to ~pH 6 using 1 M HCl. The bulk suspension was sonicated to give a turbid solution, which was concentrated in vacuo to ~2 ml. The precipitate was collected by filtration and washed with water (2×2 mL). The solid was suspended in MeCN (4 ml), concentrated in vacuo and dried at 45°C to give the title compound as a white solid (55.2 mg, 0.110 mmol, yield 69.2%, purity 95%). UPLC-MS (Method 1) m / z 477.3 (M+H) at 1.57 min + ,475.2(MH) - . 1 H NMR (500 MHz, DMSO-d 6)δ13.18(br s,1H),8.74(br s,1H),8.37(d,J=2.2Hz,1H),8.15(dd,J=8.7,2.2Hz,1H),7.44(s,1H),7.39-7.27(m,3H),4.95-4. 79(m,1H),3.91(s,3H),3.08-2.86(m,3H),2.83-2.76(m,1H),1.95-1.75(m,3H),1.74-1.63(m,1H).

[0896] Example 210: (S)-4-ethyl-3-(N-(2-(3-fluoropiperidin-1-yl)-5-(trifluoromethyl)phenyl)sulfamoyl)benzoic acid

[0897]

[0898] Step 1: (S)-methyl 4-ethyl-3-(N-(2-(3-fluoropiperidin-1-yl)-5-(trifluoromethyl)phenyl)sulfamoyl)benzoate: The product of step 2 of example 209 (67 mg, 0.255 mmol) was dissolved in a mixture of DCM (1 ml) and pyridine (83 μl, 1.02 mmol) and treated with a suspension of the product of step 2 of example 203 (124 mg, 0.307 mmol) in DCM (1 ml). The resulting solution was stirred at room temperature for 3 days. The reaction mixture was purified directly by silica gel column chromatography (12 g cartridge, 0-100% EtOAc / isohexane) to give the title compound (65.9 mg, 0.108 mmol, 42.2% yield, 80% purity) as an off-white solid. UPLC-MS (method 1) m / z 489.4 (M+H) at 1.89 min + ,487.2(MH) - .

[0899] Step 2: (S)-4-ethyl-3-(N-(2-(3-fluoropiperidin-1-yl)-5-(trifluoromethyl)phenyl)sulfamoyl)benzoic acid: The product of Step 1 above (63 mg, 0.129 mmol) was dissolved in THF (2 ml) and treated with 1.1 LiOH(aq) (469 μl, 0.516 mmol). MeOH was added dropwise to give a solution, which was stirred at 30 °C for 20 h. The reaction mixture was diluted with water (3 ml), concentrated in vacuo, and the resulting aqueous solution was diluted with water (to ~5 ml). The aqueous phase was washed with EtOAc (2×5 ml) and neutralized to ~pH 6 using 1 M HCl. The bulk suspension was sonicated to give a turbid solution, which was concentrated in vacuo to ~2 ml. The precipitate was collected by filtration and washed with water (2×2 mL). The solid was suspended in MeCN (4 ml), concentrated in vacuo and dried at 45°C to give the title compound as a cream solid (35.9 mg, 0.072 mmol, 55.7% yield). UPLC-MS (Method 1) m / z 475.3 (M+H) at 1.74 min + ,473.2(MH) - . 1 H NMR (500 MHz, DMSO-d 6 )δ13.31(br s,1H),9.36(br s,1H),8.36(d,J=1.8Hz,1H),8.09(dd,J=8.0,1.8Hz,1H),7.61(d,J=8.1 Hz,1H),7.42(dd,J=8.4,2.1Hz,1H),7.33-7.24(m,2H),1.98-1.85(m,1H) ,3.13-2.97(m,3H),2.89-2.79(m,2H),2.71(td,J=8.1,4.0Hz,1H),1.98- 1.85(m,1H),1.82-1.71(m,1H),1.71-1.55(m,2H),1.19(t,J=7.4Hz,3H).

[0900] Example 211: (R)-4-ethyl-3-(N-(2-(3-fluoropiperidin-1-yl)-5-(trifluoromethyl)phenyl)sulfamoyl)benzoic acid

[0901]

[0902] Step 1: (R)-methyl 4-ethyl-3-(N-(2-(3-fluoropiperidin-1-yl)-5-(trifluoromethyl)phenyl)sulfamoyl)benzoate: The product of step 2 of example 208 (67 mg, 0.255 mmol) was dissolved in a mixture of DCM (1 ml) and pyridine (83 μl, 1.02 mmol) and treated with a suspension of the product of step 2 of example 203 (124 mg, 0.307 mmol) in DCM (1 ml). The resulting solution was stirred at room temperature for 3 days. The reaction mixture was purified directly by silica gel column chromatography (12 g cartridge, 0-100% EtOAc / isohexane) to give the title compound (76.7 mg, 0.126 mmol, 49.2% yield, 80% purity) as an off-white solid. UPLC-MS (method 1) m / z 489.3 (M+H) at 1.89 min + ,487.2(MH) - .

[0903] Step 2: (R)-4-ethyl-3-(N-(2-(3-fluoropiperidin-1-yl)-5-(trifluoromethyl)phenyl)sulfamoyl)benzoic acid: The product of Step 1 above (74 mg, 0.151 mmol) was dissolved in THF (2 ml) and treated with 1.1 M LiOH(aq) (551 μl, 0.606 mmol). MeOH was added dropwise to give a solution, which was stirred at 30 °C for 20 h. The reaction mixture was diluted with water (3 ml), concentrated in vacuo, and the resulting aqueous solution was diluted with water (to ~5 ml). The aqueous phase was washed with EtOAc (2×5 ml) and neutralized to ~pH 6 using 1 M HCl. The bulk suspension was sonicated to give a turbid solution, which was concentrated in vacuo to ~2 ml. The resulting precipitate was collected by filtration and washed with water (2×2 mL). The solid was suspended in MeCN (4 ml), concentrated in vacuo and dried at 45°C to give the title compound as a cream solid (43.5 mg, 0.087 mmol, 57.5% yield, 95% purity). UPLC-MS (Method 1) m / z 475.4 (M+H) at 1.74 min + ,473.2(MH) - . 1 H NMR (500 MHz, DMSO-d 6)δ13.31(br s,1H),9.36(br s,1H),8.36(d,J=1.8Hz,1H),8.09(dd,J=8.0,1.8Hz,1H),7.61(d,J=8.0Hz,1H),7.45-7.38(m,1H),7.33-7.25(m,2H),4.84-4.68(m,1H) ,3.13-2.96(m,3H),2.89-2.79(m,2H),2.75-2.67(m,1H),1.98-1.85(m,1H),1.82-1.72(m,1H),1.70-1.54(m,2H),1.19(t,J=7.4Hz,3H).

[0904] Example 212: 3-(N-(5-(difluoromethyl)-2-(piperidin-1-yl)phenyl)sulfamoyl)-4-methoxybenzoic acid

[0905]

[0906] Synthesis of 3-(Chlorosulfonyl)-4-methoxybenzoic acid

[0907] 4-Methoxybenzoic acid (6.5 g, 42.7 mmol) was added to chlorosulfonic acid (30 ml, 448 mmol) in portions at room temperature. The mixture was heated to 80 ° C for 2 hours, then cooled to room temperature and carefully added to ice water (300 ml), then stirred for 1 h. The solid was collected, washed with water (200 ml) and dried in vacuo to give the title compound (7.92 g, 30.0 mmol, 70.3% yield, 95% purity) as a white solid. 1 H NMR (500 MHz, DMSO-d 6 )δ13.31(br s,1H),8.30(d,J=2.3Hz,1H),7.90(dd,J=8.6,2.4Hz,1H),7.07(d,J=8.6Hz,1H),3.83(s,3H).

[0908] Synthesis of 3-(N-(5-(difluoromethyl)-2-(piperidin-1-yl)phenyl)sulfamoyl)-4-methoxybenzoic acid

[0909] Step 1: 1-(4-(difluoromethyl)-2-nitrophenyl)piperidine: Et 3N (547 μl, 3.92 mmol) was added to a solution of 4-(difluoromethyl)-1-fluoro-2-nitrobenzene (300 mg, 1.57 mmol) and piperidine (202 μl, 2.04 mmol) in DCM (6 ml), and the resulting solution was stirred at room temperature for 20 h. 1 M HCl (aq) (2 ml) was added, and the organic phase was separated by a phase separator. The organic phase was concentrated in vacuo to give the title compound (402 mg, 1.57 mmol, yield 100%, purity 100%) as a yellow viscous oil. UPLC-MS (Method 1) m / z 257.3 (M+H) at 1.63 min + .

[0910] Step 2: 5-(Difluoromethyl)-2-(piperidin-1-yl)aniline: The product from Step 1 above (402 mg, 1.57 mmol) was dissolved in EtOH (14.4 ml). The reaction mixture was heated in a Thales Nano H- The reaction mixture was concentrated in vacuo and azeotroped with MeOH (6 ml) to give the title compound (324 mg, 1.403 mmol, 89% yield, 98% purity) as a pale yellow oil. UPLC-MS (Method 1) m / z 227.3 (M+H) at 1.58 min + .

[0911] Step 3: 3-(N-(5-(difluoromethyl)-2-(piperidin-1-yl)phenyl)sulfamoyl)-4-methoxybenzoic acid: The product of Step 2 above (60.2 mg, 0.266 mmol) was dissolved in a mixture of DCM (1 ml) and pyridine (86 μl, 1.06 mmol) and treated with a suspension of 3-(chlorosulfonyl)-4-methoxybenzoic acid (80 mg, 0.319 mmol) in DCM (1 ml). The resulting solution was stirred at room temperature for 20 h. The reaction mixture was filtered and the filtrate was purified directly by silica gel column chromatography (12 g cartridge, 100% isohexane then 0-100% 10% MeOH in EtOAc / isohexane). The crude product was purified by preparative HPLC (Waters, acidic (0.1% formic acid), acidic, Waters X-Select Prep-C18, 5 μm, 19×50 mm column, 35% to 65% MeCN in water) to give the title compound (18 mg, 0.040 mmol, 14.9% yield, 97% purity) as a white solid. UPLC-MS (Method 1) m / z 441.2 (M+H) at 1.57 min +,439.1(MH) - . 1 H NMR (500 MHz, DMSO-d 6 )δ13.15(br s,1H),8.66(br s,1H),8.39(d,J=2.2Hz,1H),8.14(dd,J=8.7,2.2Hz,1H),7.42(s,1H),7.30(d,J=8.9Hz,1H),7.29(d,J=8.2Hz,1H),7. 18(d,J=8.2,1H),6.89(t,J=55.9Hz,1H),3.93(s,3H),2.71(t,J=5.2Hz,4H),1.67(p,J=5.5Hz,4H),1.57-1.50(m,2H).

[0912] Example 213: 3-(N-(5-(difluoromethyl)-2-(piperidin-1-yl)phenyl)sulfamoyl)-4-ethylbenzoic acid

[0913]

[0914] Step 1: Methyl 3-(N-(5-(difluoromethyl)-2-(piperidin-1-yl)phenyl)sulfamoyl)-4-ethylbenzoate: The product of step 2 of Example 212 (57.4 mg, 0.254 mmol) was dissolved in a mixture of DCM (1 ml) and pyridine (82 μl, 1.02 mmol) and treated with a suspension of the product of step 2 of Example 203 (80 mg, 0.305 mmol) in DCM (1 ml). The resulting solution was stirred at room temperature for 20 h. The reaction mixture was purified directly by silica gel column chromatography (12 g cartridge, 0-100% EtOAc / isohexane) to give the title compound (54 mg, 0.119 mmol, 47.0% yield, 100% purity) as a light yellow solid. UPLC-MS (Method 1) m / z 453.4 (M+H) at 1.91 min + ,451.1(MH) - .

[0915] Step 2: 3-(N-(5-(difluoromethyl)-2-(piperidin-1-yl)phenyl)sulfamoyl)-4-ethylbenzoic acid: Concentrated HCl (2.2 ml, 72.4 mmol) was added to water (0.737 ml) and this solution was added to a solution of the product of Step 1 above (52 mg, 0.115 mmol) in dioxane (2.2 ml). The reaction mixture was heated at 50 °C for 2 days. The solution was concentrated in vacuo and the crude product was purified by silica gel column chromatography (24 g cartridge, 0-100% 10% MeOH in EtOAc / pentane) to give the title compound (18 mg, 0.039 mmol, 33.9% yield, 95% purity) as a cream solid. UPLC-MS (Method 1) m / z 439.4 (M+H) at 1.75 min + ,437.3(MH) - . 1 H NMR (500 MHz, DMSO-d 6 )δ13.28(br s,1H),9.21(br s,1H),8.36(d,J=1.8Hz,1H),8.07(dd,J=8.0,1.8Hz,1H),7.59(d,J=8.1Hz,1H),7.32-7.18(m,3H),7.02-6.08 (m,1H),3.03(q,J=7.4Hz,2H),2.67-2.61(m,4H),1.59-1.50(m,4H),1.49-1.42(m,2H),1.20(t,J=7.4Hz,3H).

[0916] Example 214: 4-methoxy-3-(N-(2-(piperidin-1-yl)-5-(1H-tetrazol-1-yl)phenyl)sulfamoyl)benzoic acid

[0917]

[0918] Step 1: 1-(4-Fluoro-3-nitrophenyl)tetrazole: Trimethylsilyl azide (1.70 ml, 12.8 mmol) was added to a solution of 4-fluoro-3-nitroaniline (0.4 g, 2.56 mmol) and triethyl orthoformate (2.13 ml, 12.8 mmol) in acetic acid (9.97 ml) at 0°C. The resulting mixture was stirred for 30 min, then heated to 80°C over 1 h and stirred for 20 h. The solvent was removed under vacuum and the crude product was purified by silica gel column chromatography (12 g cartridge, 0-10% MeOH / DCM) to give the title compound (0.469 g, 2.220 mmol, 87% yield, 99% purity) as a white solid. UPLC-MS (Method 1) m / z not ionized at 1.75 min.1 H NMR (500 MHz, CDCl 3 )δ9.16(s,1H),8.50(dd,J=6.1,2.8Hz,1H),8.15-8.09(m,1H),7.61(app.t,J=9.4Hz,1H).

[0919] Step 2: 1-(2-nitro-4-(1H-tetrazol-1-yl)phenyl)piperidine: At room temperature, add Et 3 N (0.781 ml, 5.61 mmol) was added to a solution of the product of step 1 above (0.469 g, 2.24 mmol) and piperidine (0.266 ml, 2.69 mmol) in DCM (6 ml). The clear solution was stirred at room temperature for 23 h. The organic phase was washed with 1 M HCl (aq) (3 ml), dried through a phase separator and concentrated in vacuo to give the title compound (0.609 g, 2.20 mmol, yield 98%, purity 99%) as a brown oil. UPLC-MS (Method 1) m / z at 1.39 min. 1 H NMR (500 MHz, CDCl 3 )δ8.98(s,1H),8.12(d,J=2.7Hz,1H),7.78(dd,J=9.0,2.7Hz,1H),7.27( d,J=9.0Hz,1H),3.22-3.05(m,4H),1.81-1.71(m,4H),1.69-1.61(m,2H).

[0920] Step 3: 2-(Piperidin-1-yl)-5-(1H-tetrazolyl-1-yl)aniline: The product of Step 2 above (0.609 g, 2.22 mmol) was dissolved in EtOH (48 ml) and the reaction mixture was heated on a Thales Nano H- The reaction mixture was concentrated in vacuo and azeotroped with MeOH (12 ml) to give the title compound (0.531 g, 2.15 mmol, 97% yield, 99% purity) as a pale yellow oil. UPLC-MS (Method 1) No m / z at 1.18 min. 1 H NMR (500 MHz, DMSO-d 6)δ9.91(s,1H),7.14(d,J=2.5Hz,1H),7.05(d,J=8.4Hz,1H),6.98(dd,J=8.3,2.6Hz,1H),5.21(s,2H),2.91-2.69(m,4H),1.75-1.62(m,4H),1.60-1.47(m,2H).

[0921] Step 4: Methyl 4-methoxy-3-(N-(2-(piperidin-1-yl)-5-(1H-tetrazol-1-yl)phenyl)sulfamoyl)benzoate: Pyridine (0.199 ml, 2.46 mmol) was added to a solution of th...

Claims

1. A compound of formula (Ia), or a pharmaceutically acceptable salt or hydrate thereof, in: The group XY is -NHSO 2 -or-SO 2 NH-; R 1 is H or alkyl; R 2 is selected from COOH and tetrazolyl; R 3 is selected from H, Cl and alkyl; R 4 is selected from H, Cl and F; R 5 Selected from H, alkyl, alkynyl, alkenyl, haloalkyl, SO 2 -alkyl, Cl, alkoxy, OH, CN, hydroxyalkyl, alkylthio, heteroaryl, cycloalkyl, heterocycloalkyl, and haloalkoxy; R 6 is H; R 7 Selected from CN, haloalkyl, Cl, F, SO 2 -alkyl, SO 2 NR 13 R 14 , heteroaryl and alkyl, wherein the heteroaryl can be substituted by 1 or more substituents selected from alkyl, halogen, alkoxy, CN, haloalkyl and OH; R 8 is selected from H, alkyl, haloalkyl and halogen; R 9 H, C 1 -C 3 Alkyl or halogen; R 10 and R 11 Together with the nitrogen to which they are bound, they form an azepanyl group, wherein (a) the azepanyl group is substituted with one or two or more groups selected from alkyl, CN, cycloalkyl, OH, alkoxy, halogen, haloalkyl and heteroaryl, wherein the heteroaryl group can likewise be further substituted with one or two or more groups selected from halogen and alkyl, or (b) one or two carbon atoms in the azepanyl group are replaced with a group selected from O, NH, S and CO, and the azepanyl group can be substituted with one or two or more groups selected from alkyl, CN, cycloalkyl, OH, alkoxy, halogen, haloalkyl and heteroaryl, wherein the heteroaryl group can likewise be further substituted with one or two or more groups selected from halogen and alkyl; or R 10 and R 11 Together with the nitrogen to which they are bound, they form azetidinyl, pyrrolidinyl or piperidinyl, wherein (a) the azetidinyl, pyrrolidinyl or piperidinyl is substituted with one or more groups selected from alkyl, CN, cycloalkyl, OH, alkoxy, halogen, haloalkyl and heteroaryl, wherein the heteroaryl can likewise be further substituted with one or more groups selected from halogen and alkyl, or (b) one or two carbons in the azetidinyl, pyrrolidinyl or piperidinyl are replaced with a group selected from NH, S and CO; or R 10 and R 11 Together with the nitrogen to which they are bound, they form an 8-, 9- or 10-membered bicyclic heterocycloalkyl group, wherein one or two carbon atoms in the bicyclic heterocycloalkyl ring can be replaced by a group selected from O, NH, S and CO, and the bicyclic heterocycloalkyl group can be substituted by one or more groups selected from alkyl, CN, cycloalkyl, OH, alkoxy, halogen, haloalkyl and heteroaryl; or R 10 and R 11 Together with the nitrogen to which they are bound, they form a 6- to 12-membered bicyclic group containing a spirocyclic carbon atom, wherein one or two carbons in the bicyclic group can be replaced by a group selected from O, NH, S and CO, and the bicyclic group can be substituted by one or more groups selected from alkyl, CN, cycloalkyl, OH, alkoxy, halogen, haloalkyl and heteroaryl, or the bicyclic group can be fused with a 5- or 6-membered aryl or heteroaryl; and R 13 and R 14 Each is independently H or alkyl.

2. The compound of formula (Ia) according to claim 1, wherein R 2 is COOH, XY is NH-SO 2 , R 5 Selected from alkyl, alkynyl, alkenyl, haloalkyl, SO 2 -alkyl, Cl, alkoxy, OH, CN, hydroxyalkyl, alkylthio, heteroaryl, cycloalkyl, heterocycloalkyl and haloalkoxy, R 7 It is a halogenated alkyl group.

3. The compound of formula (Ia) according to claim 2, wherein R 5 It is OMe.

4. A compound of formula (Ia) according to claim 2 or 3, wherein R 7 For CF 3 .

5. A compound of formula (Ia) according to any one of claims 1 to 4, wherein R 1 , R 3 , R 4 , R 6 , R 8 and R 9 Both are H.

6. A compound of formula (Ia) according to any one of claims 1 to 5, wherein R 10 and R 11 Together with the nitrogen to which they are bound, they form an azetidinyl group which is replaced by one or more of the following: 1-3 Alkyl, CN, C 3-6 Cycloalkyl, OH, C 1-3 Alkoxy, halogen and CF 3 The group in is substituted.

7. A compound of formula (Ia) according to any one of claims 1 to 5, wherein R 10 and R 11 Together with the nitrogen to which they are bound, they form a pyrrolidinyl group which is substituted by one or more of the following: 1-3 -alkyl, CN, C 3-6 Cycloalkyl, OH, C 1-3 Alkoxy, halogen and CF 3 The group in is substituted.

8. A compound of formula (Ia) according to any one of claims 1 to 5, wherein R 10 and R 11 Together with the nitrogen to which they are bound, they form a piperidinyl group which is substituted by one or more of the following: 1-3 Alkyl, CN, C 3-6 Cycloalkyl, OH, C 1-3 Alkoxy, halogen and CF 3 The group in is substituted.

9. A compound of formula (Ia) according to any one of claims 1 to 5, wherein R 10 and R 11 Together with the nitrogen to which they are bound, they form an 8-membered, 9-membered or 10-membered bicyclic heterocycloalkyl group, wherein one or two carbon atoms in the bicyclic heterocycloalkyl ring can be replaced by a group selected from O, NH, S and CO, and the bicyclic heterocycloalkyl group can be substituted by one or more groups selected from CN, alkyl, OH and halogen.

10. The compound of formula (Ia) according to claim 9, wherein R 10 and R 11 Together with the nitrogen to which they are bonded, they form a piperidinyl group, which can be substituted by one or more groups selected from alkyl, CN, OH and halogen, and wherein the carbons of two non-adjacent rings in the piperidinyl group are connected to each other through a 2-carbon alkylene bridge or a 3-carbon alkylene bridge.

11. A compound of formula (Ia) according to any one of claims 1 to 5, wherein R 10 and R 11 Together with the nitrogen to which they are bound, they form a 6- to 12-membered bicyclic group containing a spirocyclic carbon atom, wherein one carbon in the bicyclic group can be replaced by O, and the bicyclic group can be substituted by one or more groups selected from CN, alkyl, halogen and heteroaryl, or the bicyclic group can be fused with a 5- or 6-membered aryl or heteroaryl.

12. The compound of formula (Ia) according to claim 11, wherein R 10 and R 11 Together with the nitrogen to which they are bound, they form a 7-membered, 8-membered or 9-membered bicyclic group containing a spirocyclic carbon atom, wherein one carbon in the bicyclic group is replaced by O, and the bicyclic group can be substituted by one or more groups selected from CN, alkyl, halogen and heteroaryl.

13. A compound of formula (Ia) according to any one of claims 1 to 5, wherein NR 10 R 11 Selected from the following groups: or NR 10 R 11 Selected from the following groups: or NR 10 R 11 Selected from the following groups:

14. The compound according to claim 1, which is selected from the following substances: and pharmaceutically acceptable salts and hydrates thereof.

15. A compound of formula (Id), or a pharmaceutically acceptable salt or hydrate thereof, in: The group XY is -NHSO 2 -or-SO 2 NH-; R 1 is H or alkyl; R 2 is selected from COOH and tetrazolyl; R 3 is selected from H, Cl and alkyl; R 4 is selected from H, Cl and F; R 5 Selected from alkyl, alkenyl, alkynyl, haloalkyl, SO 2 -alkyl, Cl, alkoxy, OH, CN, hydroxyalkyl, alkylthio, heteroaryl, cycloalkyl, heterocycloalkyl, and haloalkoxy; R 6 is H; R 7 For CN, SO 2 -alkyl, SO 2 NR 13 R 14 or heteroaryl, wherein the heteroaryl can be substituted by one or more substituents selected from alkyl, halogen, alkoxy, CN, haloalkyl and OH; R 8 is selected from H, alkyl, haloalkyl and halogen; R 9 H, C 1 -C 3 Alkyl or halogen; R 10 and R 11 Together with the nitrogen to which they are bound, they form a 4-membered, 5-membered, 6-membered or 7-membered monocyclic heterocycloalkyl group, wherein one or two carbon atoms in the monocyclic heterocycloalkyl group can be replaced by a group selected from O, NH, S and CO, and the monocyclic heterocycloalkyl group can be substituted by one or two or more groups selected from alkyl, CN, cycloalkyl, OH, alkoxy, halogen, haloalkyl and heteroaryl, wherein the heteroaryl group can be further substituted by one or two or more groups selected from halogen and alkyl; or R 10 and R 11 Together with the nitrogen to which they are bound, they form an 8-, 9- or 10-membered bicyclic heterocycloalkyl group, wherein one or two carbon atoms in the bicyclic heterocycloalkyl ring can be replaced by a group selected from O, NH, S and CO, and the bicyclic heterocycloalkyl group can be substituted by one or more groups selected from alkyl, CN, cycloalkyl, OH, alkoxy, halogen, haloalkyl and heteroaryl; or R 10 and R 11 Together with the nitrogen to which they are bound, they form a 6- to 12-membered bicyclic group containing a spirocyclic carbon atom, wherein one or two carbons in the bicyclic group can be replaced by a group selected from O, NH, S and CO, and the bicyclic group can be substituted by one or more groups selected from alkyl, CN, cycloalkyl, OH, alkoxy, halogen, haloalkyl and heteroaryl, or the bicyclic group can be fused with a 5- or 6-membered aryl or heteroaryl; and R 13 and R 14 Each is H.

16. The compound according to claim 15, wherein R 10 and R 11 Together with the nitrogen to which they are bound, they form a 6-membered monocyclic heterocycloalkyl group, wherein one or two carbon atoms in the monocyclic heterocycloalkyl group can be replaced by a group selected from O, NH, S and CO, and the monocyclic heterocycloalkyl group can be substituted by one or more groups selected from alkyl, CN, cycloalkyl, OH, alkoxy, halogen, haloalkyl and heteroaryl, wherein the heteroaryl group can also be further substituted by one or more groups selected from halogen and alkyl.

17. The compound according to claim 15 or 16, wherein R 10 and R 11 Together with the nitrogen to which they are bound, they form a piperidinyl group, which can be substituted by one or more groups selected from alkyl, CN, cycloalkyl, OH, alkoxy, halogen, haloalkyl and heteroaryl, wherein the heteroaryl group can likewise be further substituted by one or more groups selected from halogen and alkyl.

18. A compound according to any one of claims 15 to 17, wherein R 10 and R 11 Together with the nitrogen to which they are bound they form an unsubstituted piperidinyl.

19. A compound according to any one of claims 15 to 18, wherein R 8 is selected from H, haloalkyl and Cl.

20. A compound according to any one of claims 15 to 19, wherein R 2 is COOH.

21. A compound according to any one of claims 15 to 20, wherein R 7 is a heteroaryl group selected from the group consisting of imidazolyl, pyrazolyl, pyrazinyl, pyridazinyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, tetrazolyl and triazolyl, each of which may be substituted by one or more substituents selected from the group consisting of alkyl, halogen, alkoxy, CN, haloalkyl and OH.

22. The compound according to claim 21, wherein R 7 is a heteroaryl group selected from the group consisting of 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, isoxazol-4-yl, isoxazol-5-yl, isothiazol-5-yl, pyridazin-3-yl, pyridazin-4-yl, pyrazinyl and 1,3,4-oxadiazol-2-yl, each of which may be substituted by one or more substituents selected from the group consisting of Me, F, Cl, CN and MeO.

23. A compound according to any one of claims 15 to 20, wherein R 7 For CN.

24. The compound according to claim 15, wherein the compound of formula (Id) is selected from the following: and pharmaceutically acceptable salts and hydrates thereof.

25. A compound of formula (Ib), or a pharmaceutically acceptable salt or hydrate thereof, in: The group XY is -NHSO 2 -or-SO 2 NH-; R 1 is H or alkyl; R 2 is a tetrazolyl group; R 3 is selected from H, Cl and alkyl; R 4 is selected from H, Cl and F; R 5 Selected from alkyl, alkynyl, alkenyl, haloalkyl, SO 2 -alkyl, Cl, alkoxy, OH, CN, hydroxyalkyl, alkylthio, heteroaryl, cycloalkyl, heterocycloalkyl, and haloalkoxy; R 6 is H; R 7 Selected from H, CN, haloalkyl, Cl, F, SO 2 -alkyl, SO 2 NR 13 R 14 , heteroaryl and alkyl, wherein the heteroaryl can be substituted by 1 or more substituents selected from alkyl, halogen, alkoxy, CN, haloalkyl and OH; R 8 is selected from H, alkyl, haloalkyl and halogen; R 9 H, C 1 -C 3 Alkyl or halogen; R 10 and R 11 Together with the nitrogen to which they are bound, they form a 4-membered, 5-membered, 6-membered or 7-membered monocyclic heterocycloalkyl group, wherein one or two carbon atoms in the monocyclic heterocycloalkyl group can be replaced by a group selected from O, NH, S and CO, and the monocyclic heterocycloalkyl group can be substituted by one or two or more groups selected from alkyl, CN, cycloalkyl, OH, alkoxy, halogen, haloalkyl and heteroaryl, wherein the heteroaryl group can be further substituted by one or two or more groups selected from halogen and alkyl; or R 10 and R 11 Together with the nitrogen to which they are bound, they form an 8-, 9- or 10-membered bicyclic heterocycloalkyl group, wherein one or two carbon atoms in the bicyclic heterocycloalkyl ring can be replaced by a group selected from O, NH, S and CO, and the bicyclic heterocycloalkyl group can be substituted by one or more groups selected from alkyl, CN, cycloalkyl, OH, alkoxy, halogen, haloalkyl and heteroaryl; or R 10 and R 11 Together with the nitrogen to which they are bound, they form a 6- to 12-membered bicyclic group containing a spirocyclic carbon atom, wherein one or two carbons in the bicyclic group can be replaced by a group selected from O, NH, S and CO, and the bicyclic group can be substituted by one or more groups selected from alkyl, CN, cycloalkyl, OH, alkoxy, halogen, haloalkyl and heteroaryl, or the bicyclic group can be fused with a 5- or 6-membered aryl or heteroaryl; and R 13 and R 14 Each is independently H or alkyl.

26. A compound according to claim 25, which is: or a pharmaceutically acceptable salt or hydrate thereof.

27. A compound of formula (Ic), or a pharmaceutically acceptable salt or hydrate thereof, in: X is SO 2 ; Y is NH; R 1 is H or alkyl; R 2 is selected from COOH and tetrazolyl; R 3 is selected from H, Cl and alkyl; R 4 is selected from H, Cl and F; R 5 Selected from H, alkyl, alkynyl, alkenyl, haloalkyl, SO 2 -alkyl, Cl, alkoxy, OH, CN, hydroxyalkyl, alkylthio, heteroaryl, cycloalkyl, heterocycloalkyl, and haloalkoxy; R 6 is H; R 7 Selected from H, CN, haloalkyl, Cl, F, SO 2 -alkyl, SO 2 NR 13 R 14 , heteroaryl and alkyl, wherein the heteroaryl can be substituted by 1 or more substituents selected from alkyl, halogen, alkoxy, CN, haloalkyl and OH; R 8 is selected from H, alkyl, haloalkyl and halogen; R 9 H, C 1 -C 3 Alkyl or halogen; R 10 is an alkyl group; R 11 is an alkyl group; or R 10 and R 11 Together with the nitrogen to which they are bound, they form a 4-membered, 5-membered, 6-membered or 7-membered monocyclic heterocycloalkyl group, wherein one or two carbon atoms in the monocyclic heterocycloalkyl group can be replaced by a group selected from O, NH, S and CO, and the monocyclic heterocycloalkyl group can be substituted by one or two or more groups selected from alkyl, CN, cycloalkyl, OH, alkoxy, halogen, haloalkyl and heteroaryl, wherein the heteroaryl group can be further substituted by one or two or more groups selected from halogen and alkyl; or R 10 and R 11 Together with the nitrogen to which they are bound, they form an 8-, 9- or 10-membered bicyclic heterocycloalkyl group, wherein one or two carbon atoms in the bicyclic heterocycloalkyl ring can be replaced by a group selected from O, NH, S and CO, and the bicyclic heterocycloalkyl group can be substituted by one or more groups selected from alkyl, CN, cycloalkyl, OH, alkoxy, halogen, haloalkyl and heteroaryl; or R 10 and R 11 Together with the nitrogen to which they are bound, they form a 6- to 12-membered bicyclic group containing a spirocyclic carbon atom, wherein one or two carbons in the bicyclic group can be replaced by a group selected from O, NH, S and CO, and the bicyclic group can be substituted by one or more groups selected from alkyl, CN, cycloalkyl, OH, alkoxy, halogen, haloalkyl and heteroaryl, or the bicyclic group can be fused with a 5- or 6-membered aryl or heteroaryl; and R 13 and R 14 Each is independently H or alkyl.

28. The compound according to claim 27, which is selected from the following substances: and pharmaceutically acceptable salts and hydrates thereof.

29. A compound selected from the group consisting of: and pharmaceutically acceptable salts and hydrates thereof.

30. A pharmaceutical composition comprising a compound according to any one of claims 1 to 29, mixed with a pharmaceutically acceptable diluent, excipient or carrier.

31. A compound according to any one of claims 1 to 29 for use in medicine.

32. The pharmaceutical composition of claim 30, wherein the pharmaceutical composition is for use in treating or preventing a disorder selected from the group consisting of a proliferative disorder, an immune disorder, a viral disorder, and an inflammatory disorder.

33. A pharmaceutical composition for use in treating or preventing a condition in a subject, the condition being selected from a proliferative condition, an immune condition, a viral condition and an inflammatory condition, the pharmaceutical composition comprising a compound of formula (I), or a pharmaceutically acceptable salt or hydrate thereof, and admixed with a pharmaceutically acceptable diluent, excipient or carrier, in: The group XY is -NHSO 2 -or-SO 2 NH-; R 1 is H or alkyl; R 2 is selected from COOH and tetrazolyl; R 3 is selected from H, Cl and alkyl; R 4 is selected from H, Cl and F; R 5 Selected from H, alkyl, alkynyl, alkenyl, haloalkyl, SO 2 -alkyl, Cl, alkoxy, OH, CN, hydroxyalkyl, alkylthio, heteroaryl, cycloalkyl, heterocycloalkyl, and haloalkoxy; R 6 is H; R 7 Selected from H, CN, haloalkyl, Cl, F, SO 2 -alkyl, SO 2 NR 13 R 14 , heteroaryl and alkyl, wherein the heteroaryl can be substituted by 1 or more substituents selected from alkyl, halogen, alkoxy, CN, haloalkyl and OH; R 8 is selected from H, alkyl, haloalkyl and halogen; R 9 H, C 1 To C 3 Alkyl or halogen; R 10 is an alkyl group; R 11 is an alkyl group; or R 10 and R 11 Together with the nitrogen to which they are bound, they form a 4-membered, 5-membered, 6-membered or 7-membered monocyclic heterocycloalkyl group, wherein one or two carbon atoms in the monocyclic heterocycloalkyl group can be replaced by a group selected from O, NH, S and CO, and the monocyclic heterocycloalkyl group can be substituted by one or two or more groups selected from alkyl, CN, cycloalkyl, OH, alkoxy, halogen, haloalkyl and heteroaryl, wherein the heteroaryl group can be further substituted by one or two or more groups selected from halogen and alkyl; or R 10 and R 11 Together with the nitrogen to which they are bound, they form an 8-, 9- or 10-membered bicyclic heterocycloalkyl group, wherein one or two carbon atoms in the bicyclic heterocycloalkyl ring can be replaced by a group selected from O, NH, S and CO, and the bicyclic heterocycloalkyl group can be substituted by one or more groups selected from alkyl, CN, cycloalkyl, OH, alkoxy, halogen, haloalkyl and heteroaryl; or R 10 and R 11 Together with the nitrogen to which they are bound, they form a 6- to 12-membered bicyclic group containing a spirocyclic carbon atom, wherein one or two carbons in the bicyclic group can be replaced by a group selected from O, NH, S and CO, and the bicyclic group can be substituted by one or more groups selected from alkyl, CN, cycloalkyl, OH, alkoxy, halogen, haloalkyl and heteroaryl, or the bicyclic group can be fused with a 5- or 6-membered aryl or heteroaryl; and R 13 and R 14 Each is independently H or alkyl.

34. The pharmaceutical composition according to claim 33, wherein the compound is selected from the group consisting of: and pharmaceutically acceptable salts and hydrates thereof.

35. The pharmaceutical composition according to any one of claims 32 to 34, wherein the disorder is a proliferative disorder and the pharmaceutical composition is for use in treating or preventing a proliferative disorder.

36. The pharmaceutical composition of claim 35, wherein the proliferative disorder is cancer or leukemia.

37. The pharmaceutical composition of claim 35, wherein the pharmaceutical composition is used to kill cancer cells, reduce the number of proliferating cells in cancer, reduce the volume or size of a tumor comprising cancer cells, and / or reduce the number of metastatic cancer cells.

38. The pharmaceutical composition according to claim 37, wherein the pharmaceutical composition is used to prevent cancer.

39. The pharmaceutical composition of claim 38, wherein the pharmaceutical composition induces neoantigens in an existing immune response possessed by the subject.

40. A pharmaceutical composition according to claim 39, wherein the pharmaceutical composition is for use in a subject suffering from or susceptible to cancer, wherein the pharmaceutical composition comprises a compound as defined in any one of claims 1 to 29, or a compound contained in a pharmaceutical composition as defined in claim 33 or 34, as a first compound, to stimulate a neoantigen-directed immune response in the subject, and subsequently a second pharmaceutical composition is used, the second pharmaceutical composition comprising a second compound (which may be the same or different from the compound of the pharmaceutical composition) to stimulate the same neoantigen as the first compound, thereby directing the subject's immune response to the cancer.

41. A pharmaceutical composition according to any one of claims 35 to 40, for use in a subject who has previously had cancer, has a family history of cancer, is at high risk for cancer, has a genetic predisposition to cancer, has been exposed to a carcinogen, and / or is in remission from cancer.

42. An in vitro method for producing antigen presenting cells presenting neoantigens, the method comprising the step of inducing neoantigens in the antigen presenting cells using a compound according to any one of claims 1 to 29, 33 or 34.

43. A pharmaceutical composition for use in an in vivo method for producing antigen presenting cells presenting neoantigens, comprising a compound as defined in any one of claims 1 to 29, or a compound comprised in a pharmaceutical composition as defined in claim 33 or 34, the method comprising the step of inducing neoantigens in the antigen presenting cells with the pharmaceutical composition.

44. The method of claim 42, wherein the antigen presenting cells are dendritic cells.

45. The pharmaceutical composition of claim 43, wherein the antigen presenting cells are dendritic cells.

46. ​​A pharmaceutical composition for use in a method for increasing the sensitivity of cancer cells to immunotherapy, comprising a compound as defined in any one of claims 1 to 29, or a compound comprised in a pharmaceutical composition as defined in claim 33 or 34, said pharmaceutical composition being used in combination with immunotherapy.

47. The pharmaceutical composition of claim 46, wherein the subject has cancer and the compound increases the sensitivity of the cancer cells to immunotherapy.

48. A pharmaceutical composition according to claim 46 or 47, wherein the immunotherapy is immune checkpoint intervention.

49. The pharmaceutical composition of claim 48, wherein the immune checkpoint intervention is an antibody checkpoint inhibitor.

50. The pharmaceutical composition of claim 49, wherein the antibody checkpoint inhibitor is an anti-PD-1 antibody, an anti-PD-L1 antibody, or an anti-CTLA4 antibody.

51. A pharmaceutical composition according to any one of claims 32 to 34, wherein the disorder is an immune disorder and the pharmaceutical composition is for use in treating or preventing the disorder.

52. The pharmaceutical composition of claim 51, wherein the immune disorder is selected from ankylosing spondylitis, Behcet's disease, psoriasis, and birdshot chorioretinopathy.

53. A pharmaceutical composition according to any one of claims 32 to 34, wherein the disorder is an inflammatory disorder and the pharmaceutical composition is for use in treating or preventing the disorder.

54. The pharmaceutical composition of claim 53, wherein the inflammatory disorder is an autoinflammatory disorder.

55. A pharmaceutical composition according to any one of claims 32 to 34, wherein the condition is a viral condition and the pharmaceutical composition is for use in the treatment or prevention of an infectious viral condition selected from HIV, HPV, CMV and HCV.

56. A pharmaceutical composition for use in a method of increasing the visibility of cancer cells to the immune system, comprising a compound as defined in any one of claims 1 to 29, or a compound comprised in a pharmaceutical composition as defined in claim 33 or 34, wherein the disorder is cancer, and wherein the pharmaceutical composition increases the visibility of cancer cells to the immune system by altering the antigenic repertoire of antigens and neoantigens presented to the immune system.

57. A pharmaceutical composition for use in a method for increasing CD8+ T cell responses to cancer cells, comprising a compound as defined in any one of claims 1 to 29, or a compound contained in a pharmaceutical composition as defined in claim 33 or 34, wherein the CD8+ T cell responses to cancer cells are increased by using the pharmaceutical composition.

58. A pharmaceutical composition comprising a compound as defined in any one of claims 1 to 29, or a compound comprised in a pharmaceutical composition as defined in claim 33 or 34, and a further active agent.

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