Compounds

Abstract

This invention relates to compounds of formula (Ia), or pharmaceutically acceptable salts or hydrates thereof, wherein: groups X-Y are -NHSO2- or -SO2NH-; R1 is H or alkyl; R2 is selected from COOH and tetrazolyl; R3 is selected from H, Cl and alkyl; R4 is selected from H, Cl and F; R5 is selected from H, alkyl, alkynyl, alkenyl, haloalkyl, SO2-alkyl, Cl, alkoxy, OH, CN, hydroxyalkyl, alkylthio, heteroaryl, cycloalkyl, heterocycloalkyl and haloalkoxy; R6 is H; R7 is selected from H, CN, haloalkyl, Cl, F, SO2-alkyl, SO2NR 13 R 14 Optionally substituted heteroaryl and alkyl groups; R8 is selected from H, alkyl, haloalkyl, and halogen; R9 is H, C1-C3 alkyl, or halogen; R 10 and R 11 Together with the nitrogen atoms to which they are attached, they form an azircyclic heptyl group, wherein (a) the azircyclic heptyl group is substituted with one or more substituents, or (b) one or two carbons of the azircyclic heptyl group are substituted with a group selected from O, NH, S and CO, and the azircyclic heptyl group is optionally further substituted; or R 10 and R 11 Together with the nitrogen atoms to which they are attached, they form an azircyclic butyl, pyrrolidinyl, or piperidinyl group, wherein (a) the azircyclic butyl, pyrrolidinyl, or piperidinyl group is substituted by one or more substituents, or (b) one or two carbon atoms of the azircyclic butyl, pyrrolidinyl, or piperidinyl group are substituted by a group selected from NH, S, and CO; or R 10 and R 11 Together with the nitrogen atoms to which they are attached, they form 8-, 9-, or 10-membered bicyclic heterocyclic alkyl groups, wherein one or two carbons of the bicyclic heterocyclic alkyl ring are optionally replaced by groups selected from O, NH, S, and CO, and the bicyclic heterocyclic alkyl group is optionally substituted; or R 10 and R 11 Together with the nitrogen atoms to which they are attached, they form 6- to 12-membered bicyclic groups containing spirocyclic carbon atoms, wherein one or both carbons of the bicyclic group are optionally replaced by a group selected from O, NH, S, and CO, and the bicyclic group is optionally substituted or optionally fused with a 5- or 6-membered aryl or heteroaryl group; R 13 and R 14 Each compound is independently H or alkyl. Other aspects of the invention relate to the use of such compounds in the field of immuno-oncology and related applications.

Description

[0001] This invention relates to compounds capable of modulating ERAP1. These compounds have potential therapeutic applications in treating a variety of conditions, including proliferative disorders, viral disorders, immune disorders, and inflammatory disorders. Background Technology

[0002] ERAP1 (endoplasmic reticulum aminopeptidase 1; also known as APPILS or ARTS1) is an aminopeptidase that plays an important role in the production of partial antigens and neoantigens as part of the antigen presentation pathway. 1 The antigen presentation pathway begins with the breakdown of proteins into peptides by the proteasome. These peptides are transported to the endoplasmic reticulum (ER), where a portion of them are processed by ERAP1 and then bound to major histocompatibility complex class I (MHC class I). 1 Then, antigens bound to MHC class I are transported to the cell surface and presented to CD8. + T cells are cells that are recognized as either self or non-self substances. Neoantigens are cancer-specific antigens that can be recognized by the immune system as foreign substances, leading to the destruction of cancer cells. The production of neoantigens is a direct result of somatic mutations in cancer cell DNA, resulting in mutated proteins, or an indirect result of somatic mutations affecting protein processing and expression. Cancers with higher mutation rates and correspondingly higher levels of neoantigens respond much better to checkpoint inhibitor immunotherapy with anti-PD-1 antibodies (e.g., pembrolizumab, nivolumab), anti-PD-L1 antibodies (e.g., atezolizumab, avermab, durvalumab), and anti-CTLA4 antibodies (e.g., ipilimumab, trimemumab). 2,3 .

[0003] ERAP1 plays a role in antigen presentation by cleaving a portion of a peptide through its aminopeptidase activity to produce 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 It has been shown that the removal of ERAP1 activity can alter the antigen pool of antigens and neoantigens, thereby leading to an increase in the presentation of certain antigens / neoantigens as well as novel antigens / neoantigens. 5 Furthermore, ERAP1 removal induced CD8+ oxidase in a mouse cancer model 4. + T-cell-dependent tumor rejection 4Therefore, regulators of ERAP1 activity can be used for cancer treatment, whether used alone or in combination with current cancer immunotherapies, including checkpoint inhibitors, because they 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 the attack and destruction of the tumor.

[0004] It was also shown that ERAP1 knockdown reduced the level of regulatory-like T cells and enhanced the killing effect of natural killer cells on cancer cells. 6,7 This suggests that regulators of ERAP1 activity may enable effective cancer therapy by modulating cancer cell visibility and generating a stronger anti-tumor immune response. The peptide processing role of ERAP1 in antigen presentation could also be applied to infectious viral diseases.

[0005] This invention seeks to provide compounds capable of modulating ERAP1. Such compounds have potential therapeutic applications in treating a variety of conditions, including proliferative disorders, immune disorders, and inflammatory disorders. Summary of the Invention

[0006] The first aspect of the present invention relates to compounds of formula (Ia), or pharmaceutically acceptable salts or hydrates thereof.

[0007]

[0008] in:

[0009] The groups X and Y are -NHSO2- or -SO2NH-;

[0010] R1 is H or an alkyl group;

[0011] R2 is selected from COOH and tetrazolium;

[0012] R3 is selected from H, Cl, and alkyl groups;

[0013] R4 is selected from H, Cl, and F;

[0014] R5 is selected from H, alkyl, haloalkyl, SO2-alkyl, Cl, alkoxy, OH, CN, alkynyl, alkenyl, hydroxyalkyl, alkylthio, heteroaryl, cycloalkyl, heterocycloalkyl, and haloalkoxy;

[0015] R6 is H;

[0016] R7 is selected from H, CN, haloalkyl, Cl, F, SO2-alkyl, SO2NR. 13 R 14 The heteroaryl group and alkyl group, wherein the heteroaryl group is optionally substituted by one or more substituents selected from alkyl, halogen, alkoxy, CN, haloalkyl and OH;

[0017] R8 is selected from H, alkyl, haloalkyl, and halogen;

[0018] R9 is H, C1-C3 alkyl, or halogen;

[0019] R 10 and R 11 Together with the nitrogen atoms to which they are attached, they form an azircyclic heptyl group, wherein (a) the azircyclic heptyl group is 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, or (b) one or two carbon atoms of the azircyclic heptyl group are substituted by groups selected from O, NH, S, and CO, and the azircyclic heptyl 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; or

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

[0021] R 10 and R 11 Together with the nitrogen atoms to which they are attached, they form 8-, 9-, or 10-membered bicyclic heterocyclic alkyl groups, wherein one or two carbons of the bicyclic heterocyclic alkyl ring are optionally replaced by a group selected from O, NH, S, and CO, and the bicyclic heterocyclic alkyl group is optionally replaced by one or more groups selected from alkyl, CN, cycloalkyl, OH, alkoxy, halogen, haloalkyl, and heteroaryl groups; or

[0022] R 10 and R 11 Together with the nitrogen atoms to which they are attached, they form 6- to 12-membered bicyclic groups containing spirocyclic carbon atoms, wherein one or both carbons of the bicyclic group are optionally replaced by a group selected from O, NH, S, and CO, and the bicyclic group is optionally replaced 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 group; and

[0023] R 13 and R 14 Each is independently H or alkyl.

[0024] The second aspect of the invention relates to compounds of formula (Ib), or pharmaceutically acceptable salts or hydrates thereof.

[0025]

[0026] in:

[0027] The groups X and Y are -NHSO2- or -SO2NH-;

[0028] R1 is H or an alkyl group;

[0029] R2 is a tetrazolium group;

[0030] R3 is selected from H, Cl, and alkyl groups;

[0031] R4 is selected from H, Cl, and F;

[0032] R5 is selected from H, alkyl, alkynyl, alkenyl, haloalkyl, SO2-alkyl, Cl, alkoxy, OH, CN, hydroxyalkyl, alkylthio, heteroaryl, cycloalkyl, heterocycloalkyl, and haloalkoxy;

[0033] R6 is H;

[0034] R7 is selected from H, CN, haloalkyl, Cl, F, SO2-alkyl, SO2NR. 13 R 14 The heteroaryl group and alkyl group, wherein the heteroaryl group is optionally substituted by one or more substituents selected from alkyl, halogen, alkoxy, CN, haloalkyl and OH;

[0035] R8 is selected from H, alkyl, haloalkyl, and halogen;

[0036] R9 is H, C1 to C3 alkyl, or halogen;

[0037] R 10 It is H or alkyl;

[0038] R 11 To be optionally subjected to one or more of the following: NH2, OH and NHCO2R 12 The alkyl group substituted with substituents, wherein R 12 It is an alkyl group; or

[0039] R 10 and R 11Together with the nitrogen atoms to which they are attached, they form 4-, 5-, 6-, or 7-membered monocyclic heterocyclic alkyl groups, wherein one or two carbons of the monocyclic heterocyclic alkyl group are optionally replaced by groups selected from O, NH, S, and CO, and the monocyclic heterocyclic alkyl group is optionally replaced by one or more groups selected from alkyl, CN, cycloalkyl, OH, alkoxy, halogen, haloalkyl, and heteroaryl, wherein the heteroaryl group is further optionally replaced by one or more groups selected from halogen and alkyl; or

[0040] R 10 and R 11 Together with the nitrogen atoms to which they are attached, they form 8-, 9-, or 10-membered bicyclic heterocyclic alkyl groups, wherein one or two carbons of the bicyclic heterocyclic alkyl ring are optionally replaced by a group selected from O, NH, S, and CO, and the bicyclic heterocyclic alkyl group is optionally replaced by one or more groups selected from alkyl, CN, cycloalkyl, OH, alkoxy, halogen, haloalkyl, and heteroaryl groups; or

[0041] R 10 and R 11 Together with the nitrogen atoms to which they are attached, they form 6- to 12-membered bicyclic groups containing spirocyclic carbon atoms, wherein one or both carbons of the bicyclic group are optionally replaced by a group selected from O, NH, S, and CO, and the bicyclic group is optionally replaced 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 group; and

[0042] R 13 and R 14 Each is independently H or alkyl.

[0043] The third aspect of the invention relates to compounds of formula (Ic), or pharmaceutically acceptable salts or hydrates thereof.

[0044]

[0045] in:

[0046] X is SO2;

[0047] Y is NH;

[0048] R1 is H or an alkyl group;

[0049] R2 is selected from COOH and tetrazolium;

[0050] R3 is selected from H, Cl, and alkyl groups;

[0051] R4 is selected from H, Cl, and F;

[0052] R5 is selected from H, alkyl, alkynyl, alkenyl, haloalkyl, SO2-alkyl, Cl, alkoxy, OH, CN, hydroxyalkyl, alkylthio, heteroaryl, cycloalkyl, heterocycloalkyl, and haloalkoxy;

[0053] R6 is H;

[0054] R7 is selected from H, CN, haloalkyl, Cl, F, SO2-alkyl, SO2NR. 13 R 14 The heteroaryl group and alkyl group, wherein the heteroaryl group is optionally substituted by one or more substituents selected from alkyl, halogen, alkoxy, CN, haloalkyl and OH;

[0055] R8 is selected from H, alkyl, haloalkyl, and halogen;

[0056] R9 is H, C1 to C3 alkyl, or halogen;

[0057] R 10 It is H or alkyl;

[0058] R 11 To be optionally subjected to one or more of the following: NH2, OH and NHCO2R 12 The alkyl group substituted with substituents, wherein R 12 It is an alkyl group; or

[0059] R 10 and R 11 Together with the nitrogen atoms to which they are attached, they form 4-, 5-, 6-, or 7-membered monocyclic heterocyclic alkyl groups, wherein one or two carbons of the monocyclic heterocyclic alkyl group are optionally replaced by groups selected from O, NH, S, and CO, and the monocyclic heterocyclic alkyl group is optionally replaced by one or more groups selected from alkyl, CN, cycloalkyl, OH, alkoxy, halogen, haloalkyl, and heteroaryl, wherein the heteroaryl group is further optionally replaced by one or more groups selected from halogen and alkyl; or

[0060] R 10 and R 11 Together with the nitrogen atoms to which they are attached, they form 8-, 9-, or 10-membered bicyclic heterocyclic alkyl groups, wherein one or two carbons of the bicyclic heterocyclic alkyl ring are optionally replaced by a group selected from O, NH, S, and CO, and the bicyclic heterocyclic alkyl group is optionally replaced by one or more groups selected from alkyl, CN, cycloalkyl, OH, alkoxy, halogen, haloalkyl, and heteroaryl groups; or

[0061] R 10 and R 11Together with the nitrogen atoms to which they are attached, they form 6- to 12-membered bicyclic groups containing spirocyclic carbon atoms, wherein one or both carbons of the bicyclic group are optionally replaced by a group selected from O, NH, S, and CO, and the bicyclic group is optionally replaced 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 group; and

[0062] R 13 and R 14 Each is independently H or alkyl.

[0063] The fourth aspect of the present invention relates to compounds of formula (Id), or pharmaceutically acceptable salts or hydrates thereof.

[0064]

[0065] in:

[0066] The groups X and Y are -NHSO2- or -SO2NH-;

[0067] R1 is H or an alkyl group;

[0068] R2 is selected from COOH and tetrazolium;

[0069] R3 is selected from H, Cl, and alkyl groups;

[0070] R4 is selected from H, Cl, and F;

[0071] R5 is selected from H, alkyl, alkynyl, alkenyl, haloalkyl, SO2-alkyl, Cl, alkoxy, OH, CN, hydroxyalkyl, alkylthio, heteroaryl, cycloalkyl, heterocycloalkyl, and haloalkoxy;

[0072] R6 is H;

[0073] R7 represents CN, SO2-alkyl, or SO2NR. 13 R 14 Or a heteroaryl group, wherein the heteroaryl group is optionally substituted by one or more substituents selected from alkyl, halogen, alkoxy, CN, haloalkyl and OH;

[0074] R8 is selected from H, alkyl, haloalkyl, and halogen;

[0075] R9 is H, C1 to C3 alkyl, or halogen;

[0076] R 10 It is H or alkyl;

[0077] R 11 To be optionally subjected to one or more of the following: NH2, OH and NHCO2R 12The alkyl group substituted with substituents, wherein R 12 It is an alkyl group; or

[0078] R 10 and R 11 Together with the nitrogen atoms to which they are attached, they form 4-, 5-, 6-, or 7-membered monocyclic heterocyclic alkyl groups, wherein one or two carbons of the monocyclic heterocyclic alkyl group are optionally replaced by groups selected from O, NH, S, and CO, and the monocyclic heterocyclic alkyl group is optionally replaced by one or more groups selected from alkyl, CN, cycloalkyl, OH, alkoxy, halogen, haloalkyl, and heteroaryl, wherein the heteroaryl group is further optionally replaced by one or more groups selected from halogen and alkyl; or

[0079] R 10 and R 11 Together with the nitrogen atoms to which they are attached, they form 8-, 9-, or 10-membered bicyclic heterocyclic alkyl groups, wherein one or two carbons of the bicyclic heterocyclic alkyl ring are optionally replaced by a group selected from O, NH, S, and CO, and the bicyclic heterocyclic alkyl group is optionally replaced by one or more groups selected from alkyl, CN, cycloalkyl, OH, alkoxy, halogen, haloalkyl, and heteroaryl groups; or

[0080] R 10 and R 11 Together with the nitrogen atoms to which they are attached, they form 6- to 12-membered bicyclic groups containing spirocyclic carbon atoms, wherein one or both carbons of the bicyclic group are optionally replaced by a group selected from O, NH, S, and CO, and the bicyclic group is optionally replaced 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 group; and

[0081] R 13 and R 14 Each is independently H or alkyl.

[0082] Advantageously, the compound claimed in this invention is capable of modulating ERAP1, thereby making the compound therapeutically significant in treating various conditions, such as in the fields of oncology and immuno-oncology.

[0083] The fifth aspect of the invention relates to a pharmaceutical composition comprising at least one compound as described above and a pharmaceutically acceptable carrier, diluent, or excipient.

[0084] The sixth aspect of the invention relates to the use of the compounds described above in pharmaceuticals.

[0085] The seventh aspect of the invention relates to the use of the compounds described above in the treatment or prevention of diseases selected from proliferative diseases, immune diseases, viral diseases, and inflammatory diseases.

[0086] The eighth aspect of the invention relates to the use of the compounds described above in the preparation of medicaments for treating or preventing diseases selected from proliferative diseases, immune diseases, viral diseases, and inflammatory diseases.

[0087] The ninth aspect of the invention relates to the use of the compounds described above in the prevention or treatment of conditions caused by, associated with, or accompanied by any abnormal ERAP1 activity.

[0088] The tenth aspect of the invention relates to the use of the compounds described above in the preparation of medicaments for the prevention or treatment of conditions caused by abnormal ERAP1 activity, conditions associated with abnormal ERAP1 activity, or conditions accompanied by abnormal ERAP1 activity.

[0089] The eleventh aspect of the present invention relates to a method for treating mammals suffering from disease symptoms that are relieved by regulating ERAP1, wherein the method comprises administering to the mammal a therapeutically effective amount of the compound as described above.

[0090] The twelfth aspect of the invention relates to the use of the compounds described above in the treatment or prevention of disease symptoms relieved by regulating ERAP1.

[0091] The thirteenth aspect of the invention relates to the use of the compounds described above in the preparation of medicaments for treating or preventing disease symptoms that are relieved by regulating ERAP1.

[0092] The fourteenth aspect of the present invention relates to a method for treating or preventing a disease in a subject, said disease being selected from proliferative diseases, immune diseases, viral diseases, and inflammatory diseases, wherein said method comprises administering to the subject a therapeutically effective amount of the compound as described above.

[0093] The fifteenth aspect of the present invention relates to the use of compounds of formula (I), or pharmaceutically acceptable salts or hydrates thereof, in the treatment or prevention of a condition in a subject, said condition being selected from proliferative diseases, immune diseases, viral diseases, and inflammatory diseases:

[0094]

[0095] in:

[0096] The groups X and Y are -NHSO2- or -SO2NH-;

[0097] R1 is H or an alkyl group;

[0098] R2 is selected from COOH and tetrazolium;

[0099] R3 is selected from H, Cl, and alkyl groups;

[0100] R4 is selected from H, Cl, and F;

[0101] R5 is selected from H, alkyl, alkynyl, alkenyl, haloalkyl, SO2-alkyl, Cl, alkoxy, OH, CN, hydroxyalkyl, alkylthio, heteroaryl, cycloalkyl, heterocycloalkyl, and haloalkoxy;

[0102] R6 is H;

[0103] R7 is selected from H, CN, haloalkyl, Cl, F, SO2-alkyl, SO2NR. 13 R 14 The heteroaryl group and alkyl group, wherein the heteroaryl group is optionally substituted by one or more substituents selected from alkyl, halogen, alkoxy, CN, haloalkyl and OH;

[0104] R8 is selected from H, alkyl, haloalkyl, and halogen;

[0105] R9 is H, C1 to C3 alkyl, or halogen;

[0106] R 10 It is H or alkyl;

[0107] R 11 To be optionally subjected to one or more of the following: NH2, OH and NHCO2R 12 The alkyl group substituted with substituents, wherein R 12 It is an alkyl group; or

[0108] R 10 and R 11 Together with the nitrogen atoms to which they are attached, they form 4-, 5-, 6-, or 7-membered monocyclic heterocyclic alkyl groups, wherein one or two carbons of the monocyclic heterocyclic alkyl group are optionally replaced by groups selected from O, NH, S, and CO, and the monocyclic heterocyclic alkyl group is optionally replaced by one or more groups selected from alkyl, CN, cycloalkyl, OH, alkoxy, halogen, haloalkyl, and heteroaryl, wherein the heteroaryl group is further optionally replaced by one or more groups selected from halogen and alkyl; or

[0109] R 10 and R 11 Together with the nitrogen atoms to which they are attached, they form 8-, 9-, or 10-membered bicyclic heterocyclic alkyl groups, wherein one or two carbons of the bicyclic heterocyclic alkyl ring are optionally replaced by a group selected from O, NH, S, and CO, and the bicyclic heterocyclic alkyl group is optionally replaced by one or more groups selected from alkyl, CN, cycloalkyl, OH, alkoxy, halogen, haloalkyl, and heteroaryl groups; or

[0110] R 10 and R 11Together with the nitrogen atoms to which they are attached, they form 6- to 12-membered bicyclic groups containing spirocyclic carbon atoms, wherein one or both carbons of the bicyclic group are optionally replaced by a group selected from O, NH, S, and CO, and the bicyclic group is optionally replaced 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 group; and

[0111] R 13 and R 14 Each is independently H or alkyl. Detailed Implementation

[0112] This invention relates to bisarylsulfonamide compounds capable of modulating ERAP1. Preferably, the compounds selectively modulate ERAP1.

[0113] In this document, "alkyl" is defined as a straight-chain or branched alkyl group, preferably C10. 1-20 Alkyl, more preferably C 1-12 Alkyl, or even more preferably C 1-10 Alkyl or C 1-6 Alkyl, or C 1-3 Alkyl groups. Examples of suitable alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, and hexyl.

[0114] In this document, "cycloalkyl" is defined as: a monocyclic alkyl ring, preferably C10. 3-7 cycloalkyl, more preferably C 3-6 Cycloalkyl groups, preferred examples of which include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl; or fused bicyclic cyclic systems, such as norbornane.

[0115] In this article, "halogen" is defined as chlorine, fluorine, bromine or iodine.

[0116] As used herein, the term "aryl" refers to C 6-12 Aromatic groups, which may be benzofused groups, such as phenyl or naphthyl.

[0117] In this paper, "heteroaryl" is defined as monocyclic or bicyclic C 2-12An aromatic ring contains one or more heteroatoms (which may be the same or different), such as oxygen, nitrogen, or sulfur. Examples of suitable heteroaryl groups include thiophene, furanyl, pyrrole, pyridinyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, tetrazolyl, thiadiazolyl, etc., and their benzo[a] derivatives, such as benzofuranyl, benzothiophene, benzimidazolyl, indolyl, isoindolyl, indolyl, etc.; or pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl, etc., and their benzo[a] derivatives, such as quinolinyl, isoquinolinyl, cenolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, naphthidyl, etc. Particularly preferred heteroaryl groups include 1H-imidazol-5-yl, 1H-imidazol-4-yl, 1H-imidazol-2-yl, 1H-pyrrolo-1-yl, 1H-pyrrolo-2-yl, 1H-pyrrolo-3-yl, 1H-pyrrolo-4-yl, 1H-pyrrolo-5-yl, 1H-pyrazole-1-yl, 1H-pyrazole-5-yl, 1H-pyrazole-3-yl, 1H-pyrazole-4-yl, and oxadiazolyl. 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 thiazole-5-yl thiazole-4-yl thiazole -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, pyrazin-3-yl, pyrazin-4-yl, pyrazinyl, 1,3, 4-Oxadiazole-2-yl, 1,3,4-Oxadiazole-5-yl, 1,2,5-Oxadiazole-3-yl, 1,2,5-Oxadiazole-4-yl, 1,2,3-Oxadiazole-4-yl, 1,2,3-Oxadiazole-5-yl, 1,2,4-Oxadiazole-3-yl, 1,2,4-Oxadiazole-5-yl, isoxazol-5-yl, isoxazol-4-yl and isoxazol-3-yl.

[0118] "Heterocyclic alkyl" refers to a cyclic aliphatic group containing one or more heteroatoms selected from nitrogen, oxygen, and sulfur, optionally with one or more -(CO)- groups inserted into the ring and / or optionally containing one or more double bonds in the ring. Preferably, the heterocyclic alkyl is monocyclic or bicyclic. Preferably, the heterocyclic alkyl is C10-20-3 ... 3-7 Heterocyclic alkyl, more preferably C 3-6 Heterocyclic alkyl group. Alternatively, the heterocyclic alkyl group is C10. 4-7 Heterocyclic alkyl, more preferably C 4-6Heterocyclic alkyl groups. Preferred heterocyclic alkyl groups include, but are not limited to, piperazinyl, piperidinyl, morpholinyl, thiomorpholinyl, pyrrolyl, tetrahydrofuranyl, and tetrahydropyranyl. Preferably, the heterocyclic alkyl group is fully saturated.

[0119] "Azaheptanyl" refers to a 7-membered saturated heterocycle containing six carbon atoms and one nitrogen atom. "Piperidinyl" refers to a 6-membered saturated heterocycle containing five carbon atoms and one nitrogen atom. "Pyrrolidinyl" refers to a 5-membered saturated heterocycle containing four carbon atoms and one nitrogen atom. "Azaheptanylbutane" refers to a 4-membered saturated heterocycle containing three carbon atoms and one nitrogen atom.

[0120] Compounds of formula (Ia)

[0121] One aspect of the present invention relates to compounds of formula (Ia) as described above.

[0122] In a preferred embodiment, R1 is H or Me, more preferably H.

[0123] In a preferred embodiment, R2 is COOH.

[0124] In a preferred embodiment, XY is NH-SO.

[0125] In a preferred embodiment, R5 is selected from alkyl, alkenyl, alkynyl, haloalkyl, SO2-alkyl, Cl, alkoxy, OH, CN, hydroxyalkyl, alkylthio, heteroaryl, cycloalkyl, heterocycloalkyl, and haloalkoxy.

[0126] In a preferred embodiment, R5 is selected from H, Me, CF3, CHF2, SO2-Me, Cl, ethynyl, MeO, OH, CH2OH, SMe, cyclopropyl, triazolyl, oxetane-3-yl, and CN. More preferably, R5 is selected from H, CN, Me, SO2-Me, CF3, CHF2, CH2OH, SMe, cyclopropyl, 3,4-triazol-1-yl, and oxetane-3-yl. Even more preferably, R5 is selected from H, CN, Me, SO2-Me, CF3, and CHF2.

[0127] In another preferred embodiment, R5 is selected from OMe, Me, Et, Pr, ethynyl and Cl, more preferably OMe, Me, Et, Pr and Cl, and even more preferably OMe or Et.

[0128] In a preferred embodiment, R7 is selected from H, CN, haloalkyl, Cl, F, SO2-alkyl, SO2NR. 13 R 14 heteroaryl and alkyl.

[0129] In a preferred embodiment, R7 is selected from H, CN, CF3, CHF2, Cl, F, SO2-Me, SO2NH2, heteroaryl, and Me. More preferably, R7 is selected from H, CN, Me, SO2-Me, tetrazolyl, CF3, and CHF2.

[0130] In a preferred embodiment, R7 is CF3.

[0131] In a preferred embodiment, R7 is CN.

[0132] In another preferred embodiment, R7 is SO2-alkyl, more preferably SO2-Me.

[0133] In a preferred embodiment, R7 is SO2NR. 13 R 14 SO2NH2 is preferred.

[0134] In a preferred embodiment, R7 is a heteroaryl group optionally substituted with one or more substituents selected from alkyl, halogen, alkoxy, CN, haloalkyl and OH.

[0135] In a preferred embodiment, R7 is a heteroaryl group selected from pyridinyl, thiopheneyl, imidazolyl, pyrimidinyl, pyrazinyl, pyrazinyl, pyridazinyl, thiazolyl, isothiazolyl, triazinyl, pyrroleyl, furanyl, oxazolyl, isoxazolyl, oxadiazolyl, tetrazolyl, and triazolyl, wherein each heteroaryl group is optionally substituted by one or more substituents selected from alkyl, halogen, alkoxy, CN, haloalkyl, and OH.

[0136] In a preferred embodiment, R7 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 by one or more substituents selected from alkyl, halogen, alkoxy, CN, haloalkyl, and OH.

[0137] In a preferred embodiment, R7 is selected from 1H-imidazol-5-yl, 1H-imidazol-4-yl, 1H-imidazol-2-yl, 1H-pyrrolo-1-yl, 1H-pyrrolo-2-yl, 1H-pyrrolo-3-yl, 1H-pyrrolo-4-yl, 1H-pyrrolo-5-yl, 1H-pyrazole-1-yl, 1H-pyrazole-5-yl, 1H-pyrazole-3-yl, 1H-pyrazole-4-yl, oxazololo-2-yl, oxazololo -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, thiazolyl-5-yl, thiazolyl-4-yl, thiazolyl-2-yl, 1H-1,2,3,4-tetrazol-4-yl 2H-1,2,3,4-Tetrazol-5-yl, Oxazo-5-yl, Oxazo-4-yl, Oxazo-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 The heteroaryl group is selected from 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, wherein each heteroaryl group is optionally substituted by one or more substituents selected from alkyl, halogen, CN, alkoxy, haloalkyl and OH.

[0138] In a highly preferred embodiment, R7 is 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, thiazolyl-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, pyrazin-3-yl, pyrazin-4-yl, pyrazinyl, and 1,3,4-oxadiazol-2-yl, wherein each heteroaryl group is optionally substituted by one or more substituents selected from Me, F, Cl, CN, and MeO.

[0139] In a preferred embodiment, R7 is a heteroaryl group optionally substituted with one or more alkyl groups, preferably one or more Me groups.

[0140] In a preferred embodiment, R7 is a haloalkyl or heteroaryl, more preferably a tetrazolium.

[0141] In a preferred embodiment, R7 is a haloalkyl group, more preferably CF3.

[0142] In a preferred embodiment, R8 is H or a haloalkyl group, more preferably H or CF3, and even more preferably H.

[0143] In a preferred embodiment, R8 is selected from H, Me, CF3, Cl, Br, and F.

[0144] In another preferred embodiment, R8 is selected from H, haloalkyl and Cl.

[0145] In a preferred embodiment, R9 is H, Me, or F, more preferably H or F, and even more preferably H.

[0146] In a preferred embodiment, R1, R3, R4, R6, R8, and R9 are all H.

[0147] In a preferred embodiment:

[0148] R2 is COOH;

[0149] XY represents NH-SO2;

[0150] R5 is selected from OMe, Me, Et, Pr and Cl, and more preferably OMe;

[0151] R1, R3, R4, R6, R8, and R9 are all H; and

[0152] R7 is a haloalkyl group, more preferably CF3.

[0153] In a preferred embodiment, R 10 and R 11 Together with the nitrogen atoms to which they are attached, a nitrogen-containing heptyl groups are formed, wherein (a) the nitrogen-containing heptyl groups are substituted by one or more groups selected from alkyl, CN, halogen and heteroaryl groups (more preferably one or two groups), wherein the heteroaryl groups are further substituted by one or more groups selected from halogen and alkyl groups (more preferably one or two groups), or (b) one or two carbon atoms of the nitrogen-containing heptyl groups are substituted by groups selected from O, NH, S and CO, and the nitrogen-containing heptyl groups are further substituted by one or more groups selected from alkyl, CN, halogen and heteroaryl groups (more preferably one or two groups), wherein the heteroaryl groups are further substituted by one or more groups selected from halogen and alkyl groups (more preferably one or two groups).

[0154] In a preferred embodiment, R 10 and R 11Together with the nitrogen atoms to which they are attached, they form azircyclic butyl, pyrrolidinyl, or piperidinyl groups, wherein (a) the azircyclic butyl, pyrrolidinyl, or piperidinyl group is substituted by one or more groups selected from alkyl, CN, cycloalkyl, OH, alkoxy, halogen, haloalkyl, and heteroaryl groups (more preferably one or two groups), wherein the heteroaryl group is further optionally substituted by one or more groups selected from halogen and alkyl groups (more preferably one or two groups), or (b) one or two carbon atoms of the azircyclic butyl, pyrrolidinyl, or piperidinyl group are substituted by groups selected from NH, S, and CO.

[0155] In a preferred embodiment, R 10 and R 11 Together with the nitrogen to which they are attached, they form azircyclic butyl, pyrrolidinyl, or piperidinyl groups, wherein the azircyclic butyl, pyrrolidinyl, or piperidinyl groups are substituted by one or more groups selected from alkyl, CN, cycloalkyl, OH, alkoxy, halogen, haloalkyl, and heteroaryl groups (more preferably one or two groups), wherein the heteroaryl groups are further optionally substituted by one or more groups selected from halogen and alkyl groups (more preferably one or two groups).

[0156] In a preferred embodiment, R 10 and R 11 Together with the nitrogen atoms to which they are attached, they form a nitrogen-containing heterocyclic butyl group, which is formed by one or more nitrogen atoms selected from C16 and C26. 1-3 Alkyl, CN, C 3-6 cycloalkyl, OH, C 1-3 Substitution with alkoxy, halogen, and CF3 groups (more preferably one or two groups).

[0157] In a preferred embodiment, R 10 and R 11 Together with the nitrogen to which they are attached, they form pyrrolidinyl groups, which are selected from one or more C4 groups. 1-3 Alkyl, CN, C 3-6 cycloalkyl, OH, C 1-3 Substitution with alkoxy, halogen, and CF3 groups (more preferably one or two groups).

[0158] 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 atomized by one or more C-type atoms. 1-3 Alkyl, CN, C 3-6 cycloalkyl, OH, C 1-3 Substitution with alkoxy, halogen, and CF3 groups (more preferably one or two groups).

[0159] In a preferred embodiment, R10 and R 11 Together with the nitrogen to which they are attached, they form 8-, 9-, or 10-membered bicyclic heterocyclic alkyl groups, wherein one or two carbons of the bicyclic heterocyclic alkyl ring are optionally replaced by a group selected from O, NH, S, and CO, and the bicyclic heterocyclic alkyl group is optionally replaced by one or more groups selected from alkyl, CN, OH, and halogen (more preferably one or two groups).

[0160] In a preferred embodiment, R 10 and R 11 Together with the nitrogen to which they are attached, they form 8-, 9-, or 10-membered bridged bicyclic heterocyclic alkyl groups, wherein one or two carbons of the bridged bicyclic heterocyclic alkyl ring are optionally replaced by a group selected from O, NH, S, and CO, and the bicyclic heterocyclic alkyl group is optionally replaced by one or more groups selected from alkyl, CN, OH, and halogen (more preferably one or two groups).

[0161] 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, OH and halogen (more preferably one or two groups), and wherein the two non-adjacent cyclic carbons in the piperidinyl group are connected to each other by a 2-carboalkylene bridge or a 3-carboalkylene bridge.

[0162] In a preferred embodiment, R 10 and R 11 Together with the nitrogen atoms to which they are attached, they form 6- to 12-membered bicyclic groups containing spirocyclic carbon atoms, wherein one carbon atom in the bicyclic group is optionally replaced by O, and the bicyclic group is optionally replaced by one or more groups selected from alkyl, CN, halogen, and heteroaryl groups (more preferably one or two groups), or the bicyclic group is optionally fused with a 5- or 6-membered aryl or heteroaryl group. Preferably, R 10 and R 11 Together with the nitrogen atoms they are attached to, they form 7- to 12-membered bicyclic groups containing spirocyclic carbon atoms.

[0163] In a preferred embodiment, R 10 and R 11 Together with the nitrogen atoms they are attached to, they form a bicyclic group containing a spirocyclic carbon atom, which has the following formula (Z).

[0164]

[0165] in:

[0166] m is 1 or 2;

[0167] n is 1, 2, or 3; and

[0168] Ring A is a 3-, 4-, 5-, or 6-membered cycloalkyl or heterocycloalkyl.

[0169] In a preferred embodiment, ring A is a 3-membered cycloalkyl or heterocycloalkyl.

[0170] In a preferred embodiment, ring A is a 4-membered cycloalkyl or heterocycloalkyl.

[0171] In a preferred embodiment, ring A is a 5-membered cycloalkyl or heterocycloalkyl.

[0172] In a preferred embodiment, ring A is a 6-membered cycloalkyl or heterocycloalkyl.

[0173] In a preferred embodiment, m is 1 and n is 1.

[0174] In a preferred embodiment, m is 1 and n is 2.

[0175] In a preferred embodiment, m is 2 and n is 2.

[0176] In a preferred embodiment, m is 2 and n is 3.

[0177] In a preferred embodiment, R 10 and R 11 Together with the nitrogen atoms to which they are attached, they form a 7-membered bicyclic group containing a spirocyclic carbon atom, wherein one carbon atom in the bicyclic group is replaced by an O atom, and the bicyclic group is optionally replaced by one or more groups selected from alkyl, halogen, and heteroaryl groups (more preferably one or two groups).

[0178] In a preferred embodiment, R 10 and R 11 Together with the nitrogen atoms to which they are attached, they form an 8-membered bicyclic group containing a spirocyclic carbon atom, wherein one carbon atom in the bicyclic group is replaced by an O atom, and the bicyclic group is optionally replaced by one or more groups selected from alkyl, halogen, and heteroaryl groups.

[0179] In a preferred embodiment, R 10 and R 11 Together with the nitrogen atoms to which they are attached, they form a 9-membered bicyclic group containing a spirocyclic carbon atom, wherein one carbon atom in the bicyclic group is replaced by an O atom, and the bicyclic group is optionally replaced by one or more groups selected from alkyl, halogen, and heteroaryl groups (more preferably one or two groups).

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

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

[0182] In a preferred embodiment, R 10 and R 11 Together with the nitrogen atoms to which they are attached, they form a 12-membered bicyclic group containing a spirocyclic carbon atom, wherein one carbon atom in the bicyclic group is replaced by an O atom, and the bicyclic group is optionally replaced by one or more groups selected from alkyl, halogen, and heteroaryl groups (more preferably one or two groups).

[0183] In a preferred embodiment, R 10 and R 11 Together with the nitrogen atoms to which they are attached, they form bicyclic groups comprising a ring system selected from the following: 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 groups, NR 10 R 11 The nitrogen of the group forms a member of a cyclic system, and another carbon in the cyclic system is optionally replaced by O, and the bicyclic group is optionally replaced by one or more groups selected from alkyl, halogen and heteroaryl groups (more preferably one or two groups).

[0184] In a preferred embodiment, NR 10 R 11 Selected from the following groups:

[0185]

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

[0187]

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

[0189]

[0190] In a preferred embodiment:

[0191] R2 is COOH;

[0192] XY represents NH-SO2;

[0193] R5 is cyclopropyl;

[0194] R1, R3, R4, R6, R8, and R9 are all H; and

[0195] R7 is selected from CN, haloalkyl, heteroaryl, and SO2-alkyl; and

[0196] NR 10 R 11 Selected from the following groups:

[0197]

[0198] In a preferred embodiment:

[0199] R2 is COOH;

[0200] XY represents NH-SO2;

[0201] R5 is cyclopropyl;

[0202] R1, R3, R4, R6, R8, and R9 are all H; and

[0203] R7 is selected from CN, CF3, tetrazolyl and SO2-Me, more preferably CN and SO2-Me;

[0204] NR 10 R 11 Selected from the following groups:

[0205]

[0206] In a preferred embodiment:

[0207] R2 is COOH;

[0208] XY represents NH-SO2;

[0209] R5 is ethyl;

[0210] R1, R3, R4, R6, R8, and R9 are all H; and

[0211] R7 is selected from CN, haloalkyl, heteroaryl, and SO2-alkyl; and

[0212] NR 10 R 11 Selected from the following groups:

[0213]

[0214] In a preferred embodiment:

[0215] R2 is COOH;

[0216] XY represents NH-SO2;

[0217] R5 is ethyl;

[0218] R1, R3, R4, R6, R8, and R9 are all H; and

[0219] R7 is selected from CN and CF3; and

[0220] NR 10 R 11 for:

[0221]

[0222] In a preferred embodiment:

[0223] R2 is COOH;

[0224] XY represents NH-SO2;

[0225] R5 stands for OMe;

[0226] R1, R3, R4, R6, R8, and R9 are all H; and

[0227] R7 is selected from CN, haloalkyl, heteroaryl, and SO2-alkyl; and

[0228] NR 10 R 11 Selected from the following groups:

[0229]

[0230] In a preferred embodiment:

[0231] R2 is COOH;

[0232] XY represents NH-SO2;

[0233] R5 stands for OMe;

[0234] R1, R3, R4, R6, R8, and R9 are all H; and

[0235] R7 is selected from CF3 and SO2-Me; and

[0236] NR 10 R 11 Selected from the following groups:

[0237]

[0238] In a preferred embodiment, the compound of formula (Ia) is selected from the following substances:

[0239]

[0240]

[0241]

[0242]

[0243]

[0244]

[0245]

[0246]

[0247]

[0248]

[0249]

[0250] And their pharmaceutically acceptable salts and hydrates.

[0251] Compounds of formula (Ib)

[0252] Another aspect of the invention relates to compounds of formula (Ib), or pharmaceutically acceptable salts or hydrates thereof.

[0253]

[0254] in:

[0255] The groups X and Y are -NHSO2- or -SO2NH-;

[0256] R1 is H or an alkyl group;

[0257] R2 is a tetrazolium group;

[0258] R3 is selected from H, Cl, and alkyl groups;

[0259] R4 is selected from H, Cl, and F;

[0260] R5 is selected from H, alkyl, alkynyl, alkenyl, haloalkyl, SO2-alkyl, Cl, alkoxy, OH, CN, hydroxyalkyl, alkylthio, heteroaryl, cycloalkyl, heterocycloalkyl, and haloalkoxy;

[0261] R6 is H;

[0262] R7 is selected from H, CN, haloalkyl, Cl, F, SO2-alkyl, SO2NR. 13 R 14 The heteroaryl group and alkyl group, wherein the heteroaryl group is optionally substituted by one or more substituents selected from alkyl, halogen, alkoxy, CN, haloalkyl and OH;

[0263] R8 is selected from H, alkyl, haloalkyl, and halogen;

[0264] R9 is H;

[0265] R9 is H, C1 to C3 alkyl, or halogen;

[0266] R 11 To be optionally subjected to one or more of the following: NH2, OH and NHCO2R 12 The alkyl group substituted with substituents, wherein R 12 It is an alkyl group; or

[0267] R 10 and R 11 Together with the nitrogen atoms to which they are attached, they form 4-, 5-, 6-, or 7-membered monocyclic heterocyclic alkyl groups, wherein one or two carbons of the monocyclic heterocyclic alkyl group are optionally replaced by groups selected from O, NH, S, and CO, and the monocyclic heterocyclic alkyl group is optionally replaced by one or more groups selected from alkyl, CN, cycloalkyl, OH, alkoxy, halogen, haloalkyl, and heteroaryl, wherein the heteroaryl group is further optionally replaced by one or more groups selected from halogen and alkyl; or

[0268] R 10 and R 11 Together with the nitrogen atoms to which they are attached, they form 8-, 9-, or 10-membered bicyclic heterocyclic alkyl groups, wherein one or two carbons of the bicyclic heterocyclic alkyl ring are optionally replaced by a group selected from O, NH, S, and CO, and the bicyclic heterocyclic alkyl group is optionally replaced by one or more groups selected from alkyl, CN, cycloalkyl, OH, alkoxy, halogen, haloalkyl, and heteroaryl groups; or

[0269] R 10 and R 11Together with the nitrogen atoms to which they are attached, they form 6- to 12-membered bicyclic groups containing spirocyclic carbon atoms, wherein one or both carbons of the bicyclic group are optionally replaced by a group selected from O, NH, S, and CO, and the bicyclic group is optionally replaced 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 group; and

[0270] R 13 and R 14 Each is independently H or alkyl.

[0271] In a preferred embodiment, R 10 and R 11 Together with the nitrogen atoms to which they are attached, they form 4-, 5-, 6-, or 7-membered monocyclic heterocyclic alkyl groups, wherein one or two carbons of the monocyclic heterocyclic alkyl group are optionally replaced by groups selected from O, NH, S, and CO, and the monocyclic heterocyclic alkyl group is optionally replaced by one or more groups selected from alkyl, CN, cycloalkyl, OH, alkoxy, halogen, haloalkyl, and heteroaryl groups, wherein the heteroaryl group is further optionally replaced by one or more groups selected from halogen and alkyl groups. More preferably, R 10 and R 11 Together with the nitrogen to which they are attached, they form piperidinyl, pyrrolidinyl, azircycloheptyl, or azircyclobutyl, wherein each group is optionally substituted by one or more groups selected from alkyl, CN, cycloalkyl, OH, alkoxy, halogen, and haloalkyl.

[0272] In a preferred embodiment, R 10 and R 11 Together with the nitrogen atoms to which they are attached, they form a 6-membered monocyclic heterocyclic alkyl group selected from piperidinyl, morpholinyl, thiomorpholinyl, and piperazineyl, wherein each 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. More preferably, R 10 and R 11 Together with the nitrogen atoms to which they are attached, they form a 6-membered monocyclic heterocyclic alkyl group selected from piperidinyl, morpholinyl, thiomorpholinyl, and piperazineyl, wherein each group is optionally substituted by one or more groups selected from alkyl, CN, cycloalkyl, OH, alkoxy, halogen, and haloalkyl.

[0273] In a preferred embodiment, R 10 and R 11Together with the nitrogen atoms to which they are attached, a piperidinyl group is formed, wherein one or two carbons of the monocyclic heterocyclic alkyl group are optionally replaced by a group selected from O, NH, S, and CO, and the piperidinyl group is optionally replaced by one or more groups selected from alkyl, CN, cycloalkyl, OH, alkoxy, halogen, haloalkyl, and heteroaryl groups, wherein the heteroaryl group is further optionally replaced by one or more groups selected from halogen and alkyl groups. In a highly preferred embodiment, R 10 and R 11 Together with the nitrogen to which they are attached, they form unsubstituted piperidinyl or pyrrolidinyl groups, more preferably, unsubstituted piperidinyl groups.

[0274] Groups R1, R 3-11 Other preferred definitions of X and Y are as described above for compounds of formula (Ia) with necessary modifications to apply to compounds of formula (Ib).

[0275] In a preferred embodiment, the compound of formula (Ib) is:

[0276]

[0277] Or its pharmaceutically acceptable salts and hydrates.

[0278] Compounds of formula (Ic)

[0279] Another aspect of the present invention relates to compounds of formula (Ic), or pharmaceutically acceptable salts or hydrates thereof.

[0280]

[0281] in:

[0282] X is SO2;

[0283] Y is NH;

[0284] R1 is H or an alkyl group;

[0285] R2 is selected from COOH and tetrazolium;

[0286] R3 is selected from H, Cl, and alkyl groups;

[0287] R4 is selected from H, Cl, and F;

[0288] R5 is selected from H, alkyl, alkynyl, alkenyl, haloalkyl, SO2-alkyl, Cl, alkoxy, OH, CN, hydroxyalkyl, alkylthio, heteroaryl, cycloalkyl, heterocycloalkyl, and haloalkoxy;

[0289] R6 is H;

[0290] R7 is selected from H, CN, haloalkyl, Cl, F, SO2-alkyl, SO2NR. 13 R 14 The heteroaryl group and alkyl group, wherein the heteroaryl group is optionally substituted by one or more substituents selected from alkyl, halogen, alkoxy, CN, haloalkyl and OH;

[0291] R8 is selected from H, alkyl, haloalkyl, and halogen;

[0292] R9 is H, C1 to C3 alkyl, or halogen;

[0293] R 10 It is H or alkyl;

[0294] R 11 To be optionally subjected to one or more of the following: NH2, OH and NHCO2R 12 The alkyl group substituted with substituents, wherein R 12 It is an alkyl group; or

[0295] R 10 and R 11 Together with the nitrogen atoms to which they are attached, they form 4-, 5-, 6-, or 7-membered monocyclic heterocyclic alkyl groups, wherein one or two carbons of the monocyclic heterocyclic alkyl group are optionally replaced by groups selected from O, NH, S, and CO, and the monocyclic heterocyclic alkyl group is optionally replaced by one or more groups selected from alkyl, CN, cycloalkyl, OH, alkoxy, halogen, haloalkyl, and heteroaryl, wherein the heteroaryl group is further optionally replaced by one or more groups selected from halogen and alkyl; or

[0296] R 10 and R 11 Together with the nitrogen atoms to which they are attached, they form 8-, 9-, or 10-membered bicyclic heterocyclic alkyl groups, wherein one or two carbons of the bicyclic heterocyclic alkyl ring are optionally replaced by a group selected from O, NH, S, and CO, and the bicyclic heterocyclic alkyl group is optionally replaced by one or more groups selected from alkyl, CN, cycloalkyl, OH, alkoxy, halogen, haloalkyl, and heteroaryl groups; or

[0297] R 10 and R 11 Together with the nitrogen atoms to which they are attached, they form 6- to 12-membered bicyclic groups containing spirocyclic carbon atoms, wherein one or both carbons of the bicyclic group are optionally replaced by a group selected from O, NH, S, and CO, and the bicyclic group is optionally replaced 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 group; and

[0298] R 13 and R14 Each is independently H or alkyl.

[0299] In a preferred embodiment, R 10 and R 11 Together with the nitrogen atoms to which they are attached, they form 4-, 5-, 6-, or 7-membered monocyclic heterocyclic alkyl groups, wherein one or two carbons of the monocyclic heterocyclic alkyl group are optionally replaced by groups selected from O, NH, S, and CO, and the monocyclic heterocyclic alkyl group is optionally replaced by one or more groups selected from alkyl, CN, cycloalkyl, OH, alkoxy, halogen, haloalkyl, and heteroaryl groups, wherein the heteroaryl group is further optionally replaced by one or more groups selected from halogen and alkyl groups. More preferably, R 10 and R 11 Together with the nitrogen to which they are attached, they form piperidinyl, pyrrolidinyl, azircycloheptyl, or azircyclobutyl, wherein each group is optionally substituted by one or more groups selected from alkyl, CN, cycloalkyl, OH, alkoxy, halogen, and haloalkyl.

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

[0302] Group R 1-11 Other preferred definitions are as described above for compounds of formula (Ia) with necessary modifications to apply to compounds of formula (Ic).

[0303] In one embodiment, the compound of formula (Ic) is selected from the following substances:

[0304]

[0305] And their pharmaceutically acceptable salts and hydrates.

[0306] Compounds of formula (Id)

[0307] Another aspect of the present invention relates to compounds of formula (Id), or pharmaceutically acceptable salts or hydrates thereof.

[0308]

[0309] in:

[0310] The groups X and Y are -NHSO2- or -SO2NH-;

[0311] R1 is H or an alkyl group;

[0312] R2 is selected from COOH and tetrazolium;

[0313] R3 is selected from H, Cl, and alkyl groups;

[0314] R4 is selected from H, Cl, and F;

[0315] R5 is selected from H, alkyl, alkynyl, alkenyl, haloalkyl, SO2-alkyl, Cl, alkoxy, OH, CN, hydroxyalkyl, alkylthio, heteroaryl, cycloalkyl, heterocycloalkyl, and haloalkoxy;

[0316] R6 is H;

[0317] R7 represents CN, SO2-alkyl, or SO2NR. 13 R 14 Or a heteroaryl group, wherein the heteroaryl group is optionally substituted by one or more substituents selected from alkyl, halogen, alkoxy, CN, haloalkyl and OH;

[0318] R8 is selected from H, alkyl, haloalkyl, and halogen;

[0319] R9 is H, C1-C3 alkyl, or halogen;

[0320] R 10 It is H or alkyl;

[0321] R 11To be optionally subjected to one or more of the following: NH2, OH and NHCO2R 12 The alkyl group substituted with substituents, wherein R 12 It is an alkyl group; or

[0322] R 10 and R 11 Together with the nitrogen atoms to which they are attached, they form 4-, 5-, 6-, or 7-membered monocyclic heterocyclic alkyl groups, wherein one or two carbons of the monocyclic heterocyclic alkyl group are optionally replaced by groups selected from O, NH, S, and CO, and the monocyclic heterocyclic alkyl group is optionally replaced by one or more groups selected from alkyl, CN, cycloalkyl, OH, alkoxy, halogen, haloalkyl, and heteroaryl, wherein the heteroaryl group is further optionally replaced by one or more groups selected from halogen and alkyl; or

[0323] R 10 and R 11 Together with the nitrogen atoms to which they are attached, they form 8-, 9-, or 10-membered bicyclic heterocyclic alkyl groups, wherein one or two carbons of the bicyclic heterocyclic alkyl ring are optionally replaced by a group selected from O, NH, S, and CO, and the bicyclic heterocyclic alkyl group is optionally replaced by one or more groups selected from alkyl, CN, cycloalkyl, OH, alkoxy, halogen, haloalkyl, and heteroaryl groups; or

[0324] R 10 and R 11 Together with the nitrogen atoms to which they are attached, they form 6- to 12-membered bicyclic groups containing spirocyclic carbon atoms, wherein one or both carbons of the bicyclic group are optionally replaced by a group selected from O, NH, S, and CO, and the bicyclic group is optionally replaced 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 group; and

[0325] R 13 and R 14 Each is independently H or alkyl.

[0326] Substituents X, Y, R 1-6 and R 8-11 The preferred definition is as described above for compounds of formula (Ia) with necessary modifications to apply to compounds of formula (Id).

[0327] In a preferred embodiment, R 10 and R 11Together with the nitrogen atoms to which they are attached, they form 4-, 5-, 6-, or 7-membered monocyclic heterocyclic alkyl groups, wherein one or two carbons of the monocyclic heterocyclic alkyl group are optionally replaced by groups selected from O, NH, S, and CO, and the monocyclic heterocyclic alkyl group is optionally replaced by one or more groups selected from alkyl, CN, cycloalkyl, OH, alkoxy, halogen, haloalkyl, and heteroaryl groups, wherein the heteroaryl group is further optionally replaced by one or more groups selected from halogen and alkyl groups. More preferably, R 10 and R 11 Together with the nitrogen to which they are attached, they form piperidinyl, pyrrolidinyl, azircycloheptyl, or azircyclobutyl, wherein each group is optionally substituted by one or more groups selected from alkyl, CN, cycloalkyl, OH, alkoxy, halogen, and haloalkyl.

[0328] In a preferred embodiment, R 10 and R 11 Together with the nitrogen to which they are attached, they form a 6-membered monocyclic heterocyclic alkyl group, wherein one or two carbons of the monocyclic heterocyclic alkyl group are optionally replaced by a group selected from O, NH, S and CO, and the monocyclic heterocyclic alkyl group is optionally replaced by one or more groups selected from alkyl, CN, cycloalkyl, OH, alkoxy, halogen, haloalkyl and heteroaryl, wherein the heteroaryl group is further optionally replaced by one or more groups selected from halogen and alkyl.

[0329] In a preferred embodiment, R 10 and R 11 Together with the nitrogen atoms to which they are attached, they form a 6-membered monocyclic heterocyclic alkyl group selected from piperidinyl, morpholinyl, thiomorpholinyl, and piperazineyl, wherein each 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. More preferably, R 10 and R 11 Together with the nitrogen atoms to which they are attached, they form a 6-membered monocyclic heterocyclic alkyl group selected from piperidinyl, morpholinyl, thiomorpholinyl, and piperazineyl, wherein each group is optionally substituted by one or more groups selected from alkyl, CN, cycloalkyl, OH, alkoxy, halogen, and haloalkyl.

[0330] In a preferred embodiment, R 10 and R 11Together with the nitrogen atoms to which they are attached, a piperidinyl group is formed, which is optionally substituted by one or more groups selected from alkyl, CN, cycloalkyl, OH, alkoxy, halogen, haloalkyl, and heteroaryl groups, wherein the heteroaryl group is further optionally substituted by one or more groups selected from halogen and alkyl groups. More preferably, R 10 and R 11 Together with the nitrogen to which they are attached, they form unsubstituted piperidinyl groups.

[0331] In a preferred embodiment, R7 is CN.

[0332] In another preferred embodiment, R7 is SO2-alkyl, more preferably SO2-Me.

[0333] In a preferred embodiment, R7 is SO2NR. 13 R 14 SO2NH2 is more preferred.

[0334] In a preferred embodiment, R7 is a heteroaryl group optionally substituted with one or more substituents selected from alkyl, halogen, alkoxy, CN, haloalkyl and OH.

[0335] In a preferred embodiment, R7 is a heteroaryl group selected from the following: pyridinyl, thiopheneyl, imidazolyl, pyrimidinyl, pyrazinyl, pyrazinyl, pyridazinyl, thiazolyl, isothiazolyl, triazinyl, pyrroleyl, furanyl, oxazolyl, isoxazolyl, oxadiazolyl, tetrazolyl, and triazolyl, wherein each group is optionally substituted by one or more substituents selected from alkyl, halogen, alkoxy, CN, haloalkyl, and OH.

[0336] In a preferred embodiment, R7 is a heteroaryl group selected from the following: imidazolyl, pyrazolyl, pyrazinyl, pyridazinyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, tetrazolyl, and triazolyl, wherein each group is optionally substituted by one or more substituents selected from alkyl, halogen, alkoxy, CN, haloalkyl, and OH.

[0337] In a preferred embodiment, R7 is a heteroaryl group selected from the following: 1H-imidazol-5-yl, 1H-imidazol-4-yl, 1H-imidazol-2-yl, 1H-pyrrolo-1-yl, 1H-pyrrolo-2-yl, 1H-pyrrolo-3-yl, 1H-pyrrolo-4-yl, 1H-pyrrolo-5-yl, 1H-pyrazole-1-yl, 1H-pyrazole-5-yl, 1H-pyrazole-3-yl, 1H-pyrazole-4-yl, oxazole -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, thiazolyl-5-yl, thiazolyl-4-yl, thiazolyl-2-yl, 1H-1,2,3,4 -Tetrazole-4-yl, 2H-1,2,3,4-Tetrazole-5-yl, Oxazo-5-yl, Oxazo-4-yl, Oxazo-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-Oxadiazole-2-yl, 1,3,4-Oxadiazole-5-yl, 1,2,5 -oxadiazole-3-yl, 1,2,5-oxadiazole-4-yl, 1,2,3-oxadiazole-4-yl, 1,2,3-oxadiazole-5-yl, 1,2,4-oxadiazole-3-yl, 1,2,4-oxadiazole-5-yl, isoxadiazole-5-yl, isoxadiazole-4-yl and isoxadiazole-3-yl, each group optionally substituted by one or more substituents selected from alkyl, halogen, CN, alkoxy, haloalkyl and OH.

[0338] In a highly preferred embodiment, R7 is a heteroaryl group selected from the following: 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, thiazolyl-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, pyrazin-3-yl, pyrazin-4-yl, pyrazinyl, and 1,3,4-oxadiazol-2-yl, each group optionally substituted by one or more substituents selected from Me, F, Cl, CN, and MeO.

[0339] In a preferred embodiment, R7 is a heteroaryl group optionally substituted with one or more alkyl groups, preferably one or more Me groups.

[0340] In a highly preferred embodiment, the compound of formula (Id) is selected from the following substances:

[0341]

[0342]

[0343]

[0344]

[0345]

[0346] And their pharmaceutically acceptable salts and hydrates.

[0347] Another aspect of the present invention relates to a compound selected from the following substances:

[0348]

[0349]

[0350]

[0351] And their pharmaceutically acceptable salts and hydrates.

[0352] Therapeutic applications

[0353] Another aspect of the invention relates to the use of the compounds described herein in pharmaceuticals. As described in more detail below, these compounds have specific uses in the fields of oncology and immuno-oncology.

[0354] Another aspect of the invention relates to the use of the compounds described herein in the treatment or prevention of conditions selected from proliferative diseases, immune diseases, inflammatory diseases, and viral diseases.

[0355] In a preferred embodiment, the compound of the present invention modulates ERAP1. More preferably, the compound modulates the cell antigen treatment activity of ERAP1.

[0356] In one embodiment, the compound inhibits the activity of ERAP1. More preferably, the compound inhibits the cell antigen treatment activity of ERAP1.

[0357] In one alternative implementation, the compound enhances the activity of ERAP1.

[0358] In one embodiment, the compounds of the present invention can alter the repertoire of the antigens presenting the antigens.

[0359] One aspect of the invention relates to the use of the compounds described herein in the treatment of proliferative disorders. Preferably, the proliferative disorder is cancer or leukemia.

[0360] Cancers that can be selected include: basal cell carcinoma, bile duct cancer; bladder cancer; bone cancer; brain and central nervous system cancers; breast cancer; peritoneal cancer; cervical cancer; choriocarcinoma; colon and rectal cancer; connective tissue cancer; digestive system cancers; endometrial cancer; esophageal cancer; eye cancer; head and neck cancer; stomach cancer (including gastrointestinal cancer); glioblastoma; liver cancer; hepatocellular carcinoma; intraepithelial neoplasia; 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; rectal 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 / follicular NHL; intermediate diffuse NHL; advanced immunoblastic NHL; advanced lymphoblastic NHL; advanced small non-lytic cell NHL; large mass (bulky) NHL; mantle cell lymphoma; AIDS-related lymphoma; Waldenström macroglobulinemia; chronic lymphocytic leukemia (CLL); acute lymphoblastic leukemia (ALL); hairy cell leukemia; chronic medulloblastic leukemia; and other cancers and sarcomas; and post-transplant lymphoproliferative disorders (PTLD), as well as abnormal angiogenesis associated with phakomatoses, edema (e.g., edema associated with brain tumors), and Megs syndrome.

[0361] Without being bound by theoretical frameworks, such as those determined using immunopeptidomics and mass spectrometry, it should be understood that the ERAP1 regulator can alter at least 10% of the antigenic and neoantigen repertoire of cancer cells. Approximately 50% of this alteration is the upregulation of certain antigens and neoantigens presented, while the other 50% involves the presentation of entirely new antigens and neoantigens. Both alterations increase the visibility of the tumor to the immune system, thereby triggering CD8... + T cell repositories and CD8 + Measurable changes in T cell activation status. CD8 + This change in T-cell response leads to immune-mediated tumor clearance and can potentially be enhanced by combination with cancer therapies such as antibody checkpoint inhibitors (e.g., anti-PD-1).

[0362] To avoid being bound by theory, it should be understood that the regulator of ERAP1 causes cancer cell killing by natural killer (NK) cells because the interaction between the killer cell Ig-like receptor (KIR) or the lectin-like receptor CD94-NKG2A on NK cells and the typical or atypical MHC-I-peptide (pMHC-I) complex on cancer cells is disrupted.

[0363] In a preferred embodiment, the disease is cancer, and the compound enhances the visibility of cancer cells to the immune system by altering the library of antigens and neoantigens presented to the immune system.

[0364] Another aspect of the invention relates to a method for increasing the visibility of cancer cells to a subject’s immune system by altering a library 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).

[0365] In a preferred embodiment, the compound enhances the response of CD8+ T cells to cancer cells.

[0366] 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 responses or inappropriate cellular inflammatory responses, particularly those involving uncontrolled cell growth, proliferation and / or survival, inappropriate cellular immune responses or inappropriate cellular inflammatory responses regulated by the ERAP1 pathway.

[0367] In a preferred embodiment, the diseases characterized by uncontrolled cell growth, proliferation and / or survival, inappropriate cellular immune responses, or inappropriate cellular inflammatory responses are selected from hematologic malignancies, solid tumors, and / or their metastases.

[0368] More preferably, the compound is used to treat conditions selected from the following: leukemia and myelodysplastic syndromes, 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 gland 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.

[0369] The compound can kill cancer cells, reduce the number of proliferating cells in cancer, and / or reduce the volume or size of tumors containing cancer cells. The compound can reduce the number of metastatic cancer cells.

[0370] In one embodiment, the compound can be used to treat cancer in a subject who has previously had cancer. The compound can be used to reduce the likelihood of cancer recurrence or the possibility of developing cancer again. The compound can induce neoantigens in recurrent or further cancers, where the subject already has an existing immune response to that cancer. In this way, the compound can enhance or strengthen the immune response against cancer.

[0371] In one implementation, 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 against future cancer, such as a vaccine response. The compound can stimulate an immune response against a neoantigen in a subject. Once a subject has developed cancer, the subject can be retreated with the compound (or a different compound) to stimulate the production of the same neoantigen, thereby triggering a previously present immune response in the subject against said neoantigen to treat or prevent cancer.

[0372] The same or different compounds can be used before and after the subjects develop cancer.

[0373] In one implementation, the compound can be used to prevent cancer.

[0374] In one implementation, the subject may have a prior history of cancer, a family history of cancer, a high risk of developing cancer, a genetic predisposition to cancer, or may have been exposed to carcinogens. In another implementation, the subject may be in cancer remission.

[0375] One embodiment provides in vitro generated antigen-presenting cells, such as dendritic cells (DCs). Antigen-presenting cells can be generated in vitro to present neoantigens, such as neoantigens generated by compounds according to the invention. The compounds can be used in methods for in vitro generation of antigen-presenting cells that present neoantigens, and wherein the cells can be used as an anticancer vaccine.

[0376] Antigen-presenting cells, such as dendritic cells, can be pulsed, loaded with neoantigens, or genetically modified (via DNA or RNA transfer) to express one, two, or more neoantigens. Methods for preparing dendritic cell vaccines are known in the art.

[0377] Neoantigens can be generated from the subject's normal tissues, wherein ERAP1 is modulated with the compounds according to the invention. The source of normal tissues can be fibroblasts or B cells, for example, cells that can be readily expanded in vitro. Alternatively, RNA from cancer, total RNA rich in polyadenylate (polyA)+ RNA, or mRNA can be used. Polyadenylate+ RNA can also be amplified to generate sufficient antigen for DC loading, thereby limiting the in vitro culture step.

[0378] In one embodiment, dendritic cells treated with the compound as described above can be used to treat a subject. The dendritic cells can be exposed to the compound in vitro, and then the dendritic cells can be administered to the subject. Therefore, the compound can be used in vitro or in vivo, for example, for in situ therapy, or for in vitro treatment followed by administration of the treated cells to a subject.

[0379] Another aspect of the invention relates to the use of the compounds described above in treating immune disorders or modulating immune responses. In a preferred embodiment, the immune disorder is an autoimmune disorder, such as a T-cell-mediated autoimmune disorder.

[0380] Examples of autoimmune diseases 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), Sjögren's syndrome, ankylosing spondylitis and related spondyloarthropathy, rheumatic fever, allergic pneumonia, allergic bronchopulmonary aspergillosis, inorganic pneumoconiosis, sarcoidosis, autoimmune hemolytic anemia, immune platelet disorders, cold diseases such as cryofibrillaremia, psoriasis, Behçet's disease, shotgun chorioretinopathy, and autoimmune polyendocrine disorders.

[0381] Polymorphisms in the ERAP1 gene, which affect ERAP1 enzyme activity, are closely associated with an increased risk of autoimmune diseases, including ankylosing spondylitis, psoriasis, Behçet's disease, and shotgun choroidoretinopathy. 11 ERAP1 variants with reduced ERAP1 enzyme activity may prevent disease, while ERAP1 variants with increased activity have been reported to be associated with an increased risk of disease. 12 This suggests that regulating ERAP1 activity may be an effective treatment for autoimmune diseases.

[0382] Therefore, in a preferred embodiment, the immune disease is selected from ankylosing spondylitis, psoriasis, Behçet's disease, and shotgun choroidal retinopathy.

[0383] In a preferred embodiment, the autoimmune condition is ankylosing spondylitis. Ankylosing spondylitis (AS) is a type of arthritis characterized by chronic inflammation of the joints of the spine. Typically, the joints at the junction of the spine and pelvis are also affected. Sometimes other joints, such as those in the shoulder or hip, are involved. Between 0.1% and 1.8% of people are affected by ankylosing spondylitis, and it typically occurs in young adults. While the etiology 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 called HLA-B27. 13 Furthermore, certain variants of ERAP1, which are associated with HLA-B27, are clearly associated with increased or decreased disease risk, thus providing evidence for a clear role of regulated antigen presentation in the disease. 18 Ankylosing spondylitis is incurable, and current treatments only aim to improve symptoms and prevent it from worsening. Medications used to date include NSAIDs, steroids, DMARDs (such as sulfasalazine), and biological agents (such as infliximab).

[0384] In a preferred embodiment, the immune condition is Behçet's disease (BD). Behçet's disease (BD) is an inflammatory condition that affects multiple parts of the body. The most common symptoms include painful oral ulcers, genital ulcers, eye inflammation, and arthritis. The cause is not well understood; although environmental factors play a role, genetic studies have shown an increased risk of disease in patients carrying specific variants of HLA-B51 along with ERAP1. 19 The main characteristic of this disease is autoinflammatory inflammation of the blood vessels, hence it is sometimes referred to as an autoinflammatory disease. Currently, Behçet's disease is incurable, but symptoms can be managed with medications that reduce inflammation at the affected site in the body, such as corticosteroids, immunosuppressants, or biologics targeting the biological processes involved in the inflammation. In a preferred embodiment, the autoimmune condition is shotgun-like chorioretinopathy. Shotgun-like chorioretinopathy, also known as shotgun-like uveitis or HLA-A29 uveitis, is a rare form of bilateral posterior uveitis affecting the eye. Shotgun-like chorioretinopathy causes severe, progressive inflammation of the choroid and retina. Symptoms include floaters, blurred vision, flashes of light (light flashes in the field of vision), loss of color vision, and night blindness. Shotgun-like chorioretinopathy is considered an autoimmune disease. The disease is strongly associated with human leukocyte antigen haplotype (HLA)-A29. This suggests a role for T lymphocytes in the pathogenesis. Shotgun-like chorioretinopathy is associated with IL-17, a hallmark 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 determined that both ERAP1 and ERAP2 are associated with shotgun-like choroidal retinopathy. 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, cleaves peptides from the endoplasmic reticulum and loads these peptides onto HLA molecules for presentation to T cells of the immune system.

[0385] In a preferred embodiment, the immunologic condition 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 patches and erythematous plaques. The cause is not well understood, but includes environmental and genetic factors. HLA-CO6 is strongly associated with the risk of the disease, and variants in ERAP1 (likely along with HLA-CO6) are also strongly associated with the disease. 21 Psoriasis is incurable; current treatments only aim to improve symptoms and prevent it from worsening. Medications used for treatment include steroids, methotrexate, sulfasalazine, and biological agents (such as etanercept).

[0386] Another aspect of the invention relates to the use of the compounds described above in the treatment or prevention of viral conditions. ERAP1 regulators, such as those described herein, are capable of altering the antigenic repertoire of a variety of viruses, enabling the recognition and destruction of virus-infected cells. Therefore, ERAP1 regulators have potential therapeutic applications in the treatment of viral infections and diseases. ERAP1 regulates certain viral antigens, including antigens from human papillomavirus (HPV), human cytomegalovirus (CMV), hepatitis C virus (HCV), and human immunodeficiency virus (HIV). 8,9,10 Furthermore, knocking down ERAP1 in HPV-infected cells alters the library of presented HPV antigens, thereby causing [the virus to] interact with CD8+. + Stronger recognition of T cells 8 .

[0387] In a preferred embodiment, the viral illness is a viral disease or viral infection selected from HIV, HPV, CMV, and HCV.

[0388] In a preferred embodiment, the viral illness is HIV.

[0389] In a preferred embodiment, the viral condition is HPV.

[0390] In a preferred embodiment, the viral illness is CMV.

[0391] In a preferred embodiment, the viral disease is HCV.

[0392] Another aspect of the invention relates to the use of the compounds described above in the treatment or prevention of hypertension.

[0393] On the other hand, it relates to the use of the compounds described herein in the prevention or treatment of conditions caused by abnormal activity against ERAP1, conditions associated with abnormal activity against ERAP1, or conditions accompanied by abnormal activity against ERAP1.

[0394] On the other hand, it relates to the use of the compounds described herein in the prevention or treatment of ERAP1-related diseases or conditions.

[0395] Another aspect relates to the use of the compounds described herein in the preparation of medicaments for the prevention or treatment of conditions caused by, associated with or accompanied by any abnormal activity against ERAP1.

[0396] As used herein, the phrase "preparation of a medicament" includes the use of the components of the invention, in addition to their use in any stage of the preparation of such a medicament, as well as their direct use as a medicament.

[0397] On the other hand, it relates to the use of the compounds described above in the preparation of medicaments for the treatment or prevention of diseases selected from proliferative disorders, immune disorders, viral disorders, and inflammatory disorders.

[0398] Another aspect relates to the use of the compounds described herein in the preparation of medicaments for the prevention or treatment of ERAP1-related diseases or conditions.

[0399] Another aspect of the invention relates to a method for treating a subject with ERAP1-related diseases or conditions. As detailed below, this method according to the invention is achieved by administering a therapeutically effective amount of the compound of the invention as described above (the compound itself, or more preferably, as part of a pharmaceutical composition mixed with, for example, a pharmaceutically acceptable carrier) to the subject requiring treatment.

[0400] Another aspect of the invention relates to a method for treating a subject suffering from a disease state that is alleviated by regulating ERAP1, wherein the method comprises administering to the subject a therapeutically effective amount of the compound of the invention.

[0401] On the other hand, it relates to a method for treating a disease state alleviated by regulating ERAP1, wherein the method comprises administering a therapeutically effective amount of the compound according to the invention to a subject.

[0402] Preferably, the subject is a mammal, more preferably a human.

[0403] The term "method" refers to the manner, means, technique, and process used to accomplish a given task, including (but not limited to) those known manner, means, techniques, and processes, or those manner, means, techniques, and processes that are readily developed by those skilled in the art of chemistry, pharmacy, biology, biochemistry, and medicine from known manner, means, techniques, and processes.

[0404] In this article, the term "treatment" includes eliminating, substantially inhibiting, slowing down, or reversing the development of a disease or condition, substantially improving the clinical symptoms of a disease or condition, or substantially preventing the occurrence of the clinical symptoms of a disease or condition.

[0405] In this article, the term "prevention" refers to methods used to initially prevent an organism from developing symptoms or diseases.

[0406] The term "therapeutic effective dose" refers to the amount of a compound applied that will, to a certain extent, alleviate one or more symptoms of the disease or condition being treated.

[0407] For any compound used in this invention, the therapeutically effective amount also refers herein to an effective therapeutic dose, which can be preliminarily estimated by cell culture assays. For example, a dose can be administered to an animal model to achieve a circulating concentration range, including the IC50 determined by cell culture. 50 or IC 100 This information can be used to more accurately determine the effective dose for human use. The initial dose can also be estimated using in vivo data. Using this initial guidance, those skilled in the art can determine the effective dose for human use.

[0408] In addition, standard pharmaceutical techniques performed in cell cultures or laboratory animals (e.g., by determining LD50) 50 and ED 50 The toxicity and efficacy of the compounds described herein can be determined. The dose ratio between toxicity and efficacy is the therapeutic index and can be expressed as LD50. 50 With ED 50 The ratio between them. Compounds exhibiting a high therapeutic index are preferred. Data obtained from these cell culture experiments and animal studies can be used to determine the dosage range that does not produce toxicity for human use. The dosage of the compound is preferably at cyclic concentrations with only minor or no toxicity (including ED). 50The dosage may vary within this range depending on the dosage form and route of administration used. The exact dosage form, route of administration, and dosage can be selected by the physician based on the patient's condition (see, for example, Fingl et al., 1975, The Pharmacological Basis of Therapeutics, Chapter 1, page 1).

[0409] The dosage and interval can be individually adjusted to provide plasma levels of the active compound sufficient to maintain therapeutic efficacy. Common patient doses for oral administration range from about 50 mg / kg / day to 2000 mg / kg / day, typically from about 100 mg / kg / day to 1000 mg / kg / day, preferably from about 150 mg / kg / day to 700 mg / kg / day, and most preferably from about 250 mg / kg / day to 500 mg / kg / day. Preferably, therapeutically effective serum levels are achieved by administering multiple doses daily. In cases of topical application or selective absorption, the effective local concentration of the drug may be independent of plasma concentration. Those skilled in the art can optimize the therapeutically effective local dose without extensive testing. As used herein, “ERAP1-related disease or condition” refers to a disease or condition characterized by inappropriate ERAP1 activity. Inappropriate activity refers to an increase or decrease in ERAP1 activity relative to wild-type ERAP1 (Uniprot ID Q9NZ08) caused by changes in the ERAP1 protein sequence, as determined by enzymatic or cellular assays. Inappropriate activity may also be due to the overexpression of ERAP1 in diseased tissues compared to healthy neighboring tissues.

[0410] The preferred diseases or conditions for which the compounds described herein can be used for prevention include proliferative diseases, viral diseases, immune diseases, and inflammatory diseases as described above.

[0411] Therefore, the present invention further provides the use of compounds as defined herein in the preparation of medicaments for treating diseases in which modulation of ERAP1 is required. These diseases include proliferative diseases, viral diseases, immune diseases, and inflammatory diseases as described above.

[0412] In a preferred embodiment, the compound activates (L)-leucine-7-acylamino-4-methylcoumarin (L-AMC) to convert (L)-leucine and the fluorescent molecule 7-amino-4-methylcoumarin into ERAP1. While 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 is calculated and expressed as the ratio of the enzymatic activity of ERAP1 to its baseline level (i.e., EC50). 50 Increase the required activator concentration by 50%.

[0413] In a preferred embodiment, the compound showed an EC50 of less than about 25 μM in an 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 test. 50 value.

[0414] In a preferred embodiment, the compound inhibits the ability of ERAP1 to hydrolyze the decapeptide substrate WRVYEKCdnpALK. This peptide exhibits minimal fluorescence because the fluorescence of the N-terminal tryptophan residue is quenched by the dinitrophenol (DNP) residue within the peptide. However, this internal quenching is lost as ERAP1 hydrolyzes the N-terminal amide bond and releases tryptophan, and the reaction is monitored by the increase in tryptophan fluorescence during the test. For the purposes of this application, this test is referred to as the “10mer inhibition test,” and, as is well known to those skilled in the art, the compound potency is calculated and expressed as IC50. 50 .

[0415] In a preferred embodiment, the compound exhibits an IC50 of less than about 25 μM in a 10-mer assay. 50 More preferably, the compound exhibits an IC50 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 10-mer test. 50 value.

[0416] Therapeutic uses of compounds of formula I

[0417] Another aspect of the invention relates to the use of compounds of formula (I), or pharmaceutically acceptable salts or hydrates thereof, in the treatment or prevention of conditions selected from proliferative diseases, autoimmune diseases, viral diseases, and inflammatory diseases.

[0418]

[0419] in:

[0420] The groups X and Y are -NHSO2- or -SO2NH-;

[0421] R1 is H or an alkyl group;

[0422] R2 is selected from COOH and tetrazolium;

[0423] R3 is selected from H, Cl, and alkyl groups;

[0424] R4 is selected from H, Cl, and F;

[0425] R5 is selected from H, alkyl, alkynyl, alkenyl, haloalkyl, SO2-alkyl, Cl, alkoxy, OH, CN, hydroxyalkyl, alkylthio, heteroaryl, cycloalkyl, heterocycloalkyl, and haloalkoxy;

[0426] R6 is H;

[0427] R7 is selected from H, CN, haloalkyl, Cl, F, SO2-alkyl, SO2NR. 13 R 14 The heteroaryl group and alkyl group, wherein the heteroaryl group is optionally substituted by one or more substituents selected from alkyl, halogen, alkoxy, CN, haloalkyl and OH;

[0428] R8 is selected from H, alkyl, haloalkyl, and halogen;

[0429] R9 is H, C1 to C3 alkyl, or halogen;

[0430] R 10 It is H or alkyl;

[0431] R 11 To be optionally subjected to one or more of the following: NH2, OH and NHCO2R 12 The alkyl group substituted with substituents, wherein R 12 It is an alkyl group; or

[0432] R 10 and R 11 Together with the nitrogen atoms to which they are attached, they form 4-, 5-, 6-, or 7-membered monocyclic heterocyclic alkyl groups, wherein one or two carbons of the monocyclic heterocyclic alkyl group are optionally replaced by groups selected from O, NH, S, and CO, and the monocyclic heterocyclic alkyl group is optionally replaced by one or more groups selected from alkyl, CN, OH, halogen, and heteroaryl groups, wherein the heteroaryl groups are further optionally replaced by one or more groups selected from halogen and alkyl groups; or

[0433] R 10 and R 11Together with the nitrogen atoms to which they are attached, they form 8-, 9-, or 10-membered bicyclic heterocyclic alkyl groups, wherein one or two carbons of the bicyclic heterocyclic alkyl ring are optionally replaced by groups selected from O, NH, S, and CO, and the bicyclic heterocyclic alkyl group is optionally replaced by one or more groups selected from alkyl, CN, and halogen groups; or

[0434] R 10 and R 11 Together with the nitrogen atoms to which they are attached, they form 6- to 12-membered bicyclic groups containing spirocyclic carbon atoms, wherein one or both carbons of the bicyclic group are optionally replaced by groups selected from O, NH, S, and CO, and the bicyclic group is optionally replaced by one or more groups selected from alkyl, CN, halogen, and heteroaryl groups, or the bicyclic group is optionally fused with a 5- or 6-membered aryl or heteroaryl group; and

[0435] R 13 and R 14 Each is independently H or alkyl.

[0436] Groups X, Y and R 1-11 The preferred definition is as described above for compounds of formula (Ia), with necessary modifications to apply to compounds of formula (I). Details regarding suitable proliferative disorders, autoimmune disorders, viral disorders, and inflammatory disorders are the same as those described above under the heading "Therapeutic Applications".

[0437] In a preferred embodiment, the compound of formula (I) used as described above is selected from the following substances:

[0438]

[0439]

[0440]

[0441]

[0442]

[0443]

[0444]

[0445]

[0446]

[0447]

[0448]

[0449]

[0450]

[0451]

[0452]

[0453]

[0454]

[0455]

[0456]

[0457]

[0458]

[0459]

[0460] And their pharmaceutically acceptable salts and hydrates.

[0461] Another aspect of the invention relates to compounds of formula (I) as defined above, other than compounds (54), (64), (69), (71), (72), (73), (74), (78), and (165).

[0462] On the other hand, it relates to compounds of formula (I) as defined above, other than compounds (54), (64), (69), (71), (72), (73), (74), (78), and (165) used as defined above.

[0463] Pharmaceutical Composition

[0464] Regarding the uses of this invention, the compounds described herein, or physiologically acceptable salts, esters, or other physiologically functional derivatives thereof, can be prepared into pharmaceutical formulations comprising the compounds, or physiologically acceptable salts, esters, or other physiologically functional derivatives thereof, and one or more pharmaceutically acceptable carriers and optionally other therapeutic and / or prophylactic ingredients. One or more carriers must be acceptable in the sense of compatibility with other components of the formulation and harmlessness to the recipient. The pharmaceutical compositions can be used for human or animal purposes in human medicine and veterinary medicine.

[0465] Examples of such suitable excipients for the various forms of pharmaceutical compositions described herein can be found in the "Handbook of Pharmaceutical Excipients," 2nd edition, (1994), edited by A. Wade and P.J. Weller. A carrier, or each carrier if more than one is present, must be acceptable in the sense of compatibility with other components of the formulation and harmlessness to the recipient.

[0466] Acceptable carriers or diluents for therapeutic use are well known in the pharmaceutical industry and are described, for example, in Remington's Pharmaceutical Sciences, Mack Publishing Company (ARGennaro, ed., 1985).

[0467] Examples of suitable carriers include lactose, starch, glucose, methylcellulose, magnesium stearate, mannitol, and sorbitol. Examples of suitable diluents include ethanol, glycerol, and water.

[0468] The choice of drug carrier, excipient, or diluent can be made based on the intended route of administration and standard pharmaceutical practice. A pharmaceutical composition may contain any suitable binder, lubricant, suspending agent, coating agent, solubilizer, buffer, flavoring agent, surfactant, thickener, preservative (including antioxidants), and substances included to make the formulation isotonic with the blood of the intended recipient as a carrier, excipient, or diluent. Alternatively, a pharmaceutical composition may contain, in addition to a carrier, excipient, or diluent, any suitable binder, lubricant, suspending agent, coating agent, solubilizer, buffer, flavoring agent, surfactant, thickener, preservative (including antioxidants), and substances included to make the formulation isotonic with the blood of the intended recipient.

[0469] Examples of suitable binders include starch, gelatin, natural sugars (such as glucose, anhydrous lactose, free-flowing lactose, β-lactose, corn flavoring), natural and synthetic gums (such as gum arabic, tragacanth, or sodium alginate), carboxymethyl cellulose, and polyethylene glycol.

[0470] Examples of suitable lubricants include sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, and sodium chloride.

[0471] Preservatives, stabilizers, dyes, and even flavorings may be added to pharmaceutical compositions. Examples of preservatives include sodium benzoate, esters of sorbic acid and p-hydroxybenzoic acid. Antioxidants and suspending agents may also be used.

[0472] Pharmaceutical formulations include those suitable for oral, topical (including transdermal, oral, and sublingual), rectal or parenteral (including subcutaneous, intradermal, intramuscular, and intravenous), and nasal and pulmonary (e.g., via inhalation) administration. Where appropriate, formulations may be conveniently provided in discrete dose units and may be prepared by any method known in the pharmaceutical field. All methods involve the step of combining the active compound with a liquid carrier and / or a finely chopped solid carrier, and then, if necessary, shaping the product into the desired formulation.

[0473] Pharmaceutical formulations suitable for oral administration (where the carrier is solid) are most preferably provided in the form of unit-dose formulations (such as pills, capsules, or tablets, each containing a predetermined amount of active compound). Tablets can be obtained by compression or molding, optionally with one or more adjuvants. Compressed tablets can be prepared by compressing an active compound in free-flowing form (such as powder or granules) in a suitable machine, optionally with a binder, lubricant, inert diluent, surfactant, or dispersant. Molded tablets can be obtained by molding an active compound with an inert liquid diluent. Tablets can optionally be coated, and if not coated, can optionally be scored. Capsules can be prepared by filling a capsule shell with the active compound alone or with a mixture of one or more adjuvants, and then sealing it in the usual manner. Flat capsules are similar to capsules, wherein the active compound and any one or more adjuvants are sealed in a rice paper sleeve. The active compound can also be formulated as dispersible granules, which, for example, can be suspended in water or sprinkled on food before administration. Capsules can be packaged in, for example, sachets. Formulations suitable for oral administration with a liquid carrier may be provided as solutions or suspensions in aqueous or non-aqueous liquids, or as oil-in-water emulsions.

[0474] Formulations intended for oral administration include controlled-release dosage forms (e.g., tablets), in which the active compound is formulated in a suitable controlled-release matrix or coated with a suitable controlled-release membrane. Such formulations are particularly convenient for prophylactic use.

[0475] Pharmaceutical formulations suitable for rectal administration (where the carrier is solid) are 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 readily formed by mixing the active compound with one or more softened or melted carriers, then cooling and molding in a mold. Pharmaceutical formulations suitable for parenteral administration include sterile solutions or suspensions of the active compound in aqueous or oily carriers.

[0476] Injectable formulations are suitable for bolus or continuous infusion. These formulations are conveniently provided in single-dose or multi-dose containers, which are then sealed after introduction until use. Alternatively, the active compound may be in powder form, reconstituted with a suitable carrier such as sterile, pyrogen-free water prior to use.

[0477] The active compound can also be formulated into a long-acting depot preparation, which can be administered by intramuscular injection or implantation (e.g., subcutaneous or intramuscular). Depot preparations may include, for example, suitable polymeric or hydrophobic materials, or ion exchange resins. Such long-acting preparations are particularly convenient for prophylactic use.

[0478] A formulation suitable for pulmonary administration via the buccal space is provided, enabling the delivery of particles containing the active compound and ideally ranging in diameter from 0.5 micrometers to 7 micrometers into the recipient's bronchial tree.

[0479] As one possibility, such formulations may be in the form of fine powders, which can be readily provided in a permeable capsule (e.g., a suitable gelatin capsule) for use in an inhalation device, or in the form of a self-propelled formulation comprising an active compound, a suitable liquid or gaseous propellant, and optional other components such as surfactants and / or solid diluents. Suitable liquid propellants include propane and chlorofluorocarbons, and suitable gaseous propellants include carbon dioxide. Self-propelled formulations in which the active compound is dispensed in the form of droplets of solution or suspension may also be used.

[0480] Such self-propelled formulations are similar to those known in the art and can be prepared by established procedures. Suitably, the self-propelled formulation is provided in a container equipped with a manually operable or automatically operated valve having the desired spray characteristics; advantageously, the valve is metering, thereby delivering a fixed volume, for example, 25 microliters to 100 microliters, with each operation of the valve.

[0481] As another possibility, the active compound may be in the form of a solution or suspension for use in a sprayer or atomizer, thereby employing accelerated airflow or ultrasonic agitation to produce a fine droplet mist for inhalation.

[0482] Suitable formulations for nasal administration include those substantially similar to those described for pulmonary administration. When dispensing such formulations, they should ideally have a particle size in the range of 10 to 200 micrometers to allow them to remain in the nasal cavity; this can be achieved by appropriately using powders of suitable particle size or selecting a suitable valve. Other suitable formulations include: coarse powders in the range of 20 to 500 micrometers for rapid inhalation administration through the nostrils from a container near the nose; and nasal drops containing an aqueous or oily solution or suspension of the active compound at a concentration of 0.2% w / v to 5% w / v.

[0483] Pharmaceutically acceptable carriers are well known to those skilled in the art and include, but are not limited to, 0.1 M, and preferably 0.05 M, phosphate buffer or 0.8% physiological saline. Furthermore, such pharmaceutically acceptable carriers can be aqueous or non-aqueous solutions, suspensions, and emulsions. Examples of non-aqueous solvents include propylene glycol, polyethylene glycol, vegetable oils (such as olive oil), and injectable organic esters (such as ethyl oleate). Aqueous carriers include water, alcohol / aqueous solutions, emulsions, or suspensions, including physiological saline and buffer media. Parenteral carriers include sodium chloride solution, Ringer's glucose, 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.

[0484] Preparations suitable for topical application may be provided in the form of gels, creams, or ointments, for example. Such preparations may be applied to wounds or ulcers by applying the preparation directly to the surface of the wound or ulcer or by placing it on a suitable support (such as a bandage, gauze, mesh, etc.) and then applying it to cover the area to be treated.

[0485] Liquid or powder formulations are also available, which can be sprayed or applied directly to the treatment site, such as a wound or ulcer. Alternatively, the formulation can be sprayed or applied onto a carrier such as a bandage, gauze, or mesh before being applied to the treatment site.

[0486] According to another aspect of the present invention, a method for preparing a pharmaceutical composition or veterinary drug composition as described above is provided, the method comprising combining one or more active compounds with a carrier, for example by mixing.

[0487] Typically, the above-mentioned formulations are prepared by uniformly and closely binding the active agent with a liquid carrier and / or a finely chopped solid carrier, and then shaping the product if necessary. This invention extends to methods for preparing pharmaceutical compositions comprising combining or integrating the compounds described herein with pharmaceutically or veterinarily acceptable carriers or excipients.

[0488] Salt / Ester

[0489] The compounds of the present invention can exist in the form of salts or esters, particularly in the form of pharmaceutically and veterinarily acceptable salts or esters.

[0490] Pharmaceutically acceptable salts of the compounds of the present invention include suitable acid addition salts or basic salts thereof. A review of suitable pharmaceutical salts can be found in Berge et al, J Pharm Sci, 66, 1-19 (1977). Salts are formed from, for example, the following acids: strong inorganic acids, such as mineral acids, such as hydrohalic acids (e.g., hydrochloric acid, hydrobromic acid, and hydroiodic acid), sulfuric acid, phosphoric acid, sulfates, hydrogen sulfates, hemisulfates, thiocyanates, persulfates, and sulfonic acids; strong organic carboxylic acids, such as unsubstituted or substituted (e.g., halogenated) alkane carboxylic acids having 1 to 4 carbon atoms, such as acetic acid; saturated or unsaturated dicarboxylic acids, such as oxalic acid, malonic acid, succinic acid, maleic acid, fumaric acid, phthalic acid, or tetraphthalic acid; 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., halogenated) (C1-C4) alkyl sulfonic acids, or aryl sulfonic acids, such as methanesulfonic acid or p-toluenesulfonic acid. Salts that are pharmaceutically and veterinarily unacceptable as intermediates may still be valuable.

[0491] Preferred salts include, for example, acetates, trifluoroacetates, lactates, gluconates, citrates, tartrates, maleates, malates, pantothenates, adipates, alginates, aspartates, benzoates, butates, digluconates, cyclopentanoates, glucono-p-gluconates, glyceryl phosphates, oxalates, heptaates, hexanoates, fumarates, nicotinates, palmoates, pectinates, 3-phenylpropionates, picrates, neopentanoates, propionates, tartrates, lacturonates, pivotates, camphorates, undecanoates, and succinates; organic sulfonates, such as methanesulfonates, ethanesulfonates, 2-hydroxyethanesulfonates, camphorsulfonates, 2-naphthalenesulfonates, benzenesulfonates, p-chlorobenzenesulfonates, and p-toluenesulfonates; and inorganic acid salts, such as hydrochlorides, hydrobromates, hydroiodates, sulfates, hydrogen sulfates, hemisulfates, thiocyanates, persulfates, phosphates, and sulfonates.

[0492] Esters are formed based on the functional group of esterification by using organic acids or alcohols / hydroxides. Organic acids include carboxylic acids, such as unsubstituted or substituted (e.g., halogenated) alkane carboxylic acids having 1 to 12 carbon atoms (e.g., acetic acid); saturated or unsaturated dicarboxylic acids, such as oxalic acid, malonic acid, succinic acid, maleic acid, fumaric acid, phthalic acid, or tetraphthalic acid; 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., halogenated) (C1-C4) alkyl sulfonic acids or aryl sulfonic acids, such as methanesulfonic acid or p-toluenesulfonic acid. Suitable hydroxides include inorganic hydroxides, such as sodium hydroxide, potassium hydroxide, calcium hydroxide, and aluminum hydroxide. Alcohols include unsubstituted or substituted (e.g., halogenated) alkane alcohols having 1 to 12 carbon atoms.

[0493] Enantiomers / Tautomers

[0494] In all aspects discussed above, this invention (appropriately) includes all enantiomers, diastereomers, and tautomers of the compounds of this invention. Those skilled in the art will recognize compounds exhibiting optical activity (one or more chiral carbon atoms) or tautomerism. The corresponding enantiomers and / or tautomers can be isolated / prepared using methods known in the art.

[0495] Enantiomers are characterized by the absolute configuration of their chiral centers and are represented according to the R- and S-ordering rules of Cahn, Ingold, and Prelog. This convention is well known in the art (e.g., see 'Advanced Organic Chemistry', 3). rd edition, ed. March, J., John Wiley and Sons, New York, 1985).

[0496] The compounds containing chiral centers of the present invention can be used as racemic mixtures, mixtures rich in enantiomers, or racemic mixtures can be separated using known techniques so that individual enantiomers can be used alone.

[0497] Stereoisomers and Geometric Isomers

[0498] Some compounds of the present invention may exist in stereoisomers and / or geometric isomers; for example, they may have one or more asymmetric centers and / or geometric centers, and thus may exist in two or more stereoisomers and / or geometric isomers. The present invention covers 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 said forms retain suitable functional activity (although not necessarily to the same degree).

[0499] This invention also includes all suitable isotopic variations of the compound or its pharmaceutically acceptable salt. An isotopic variation of the compound 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 a different atomic weight than those commonly found in nature. Examples of isotopes that can be introduced into pharmaceuticals and their pharmaceutically acceptable salts include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, and chlorine, for example, [list of isotopes]. 2 H, 3 H, 13 C 14 C 15 N、 17 O、 18 O、 31 P, 32 P, 35 S, 18 F and 36 Cl. Certain isotopic variants of pharmaceutical agents and their pharmaceutically acceptable salts are useful in studies of drug and / or basal tissue distribution, such as those introducing radioactive isotopes (e.g., ...). 3 H or 14 C) isotopic variations. For ease of preparation and detection, tritium (i.e., 3 H) and carbon-14 (i.e. 14 C) Isotopes are particularly preferred. Furthermore, isotopes (e.g., deuterium, i.e., 2 Substitution of H) can provide a degree of therapeutic advantage due to its greater metabolic stability, such as a prolonged half-life in vivo or a reduced dose requirement, and may therefore be preferred in some cases. For example, the present invention comprises compounds of general formula (I) in which all hydrogen atoms are substituted with deuterium atoms. Typically, isotopic variants of the pharmaceutical preparations of the present invention and their pharmaceutically acceptable salts can be prepared by conventional methods using appropriate isotopic variants of suitable drugs.

[0500] Resistive isomers

[0501] Some compounds of this invention can exist as trans-restricted isomers. Trans-restricted isomers are stereoisomers resulting from hindered rotation around a single bond, wherein a sufficiently high rotational barrier is created due to energy differences caused by steric strain or other contributing factors, thereby isolating individual conformational isomers. This invention includes all such trans-restricted isomers.

[0502] Prodrug

[0503] The present invention also includes compounds of the invention in prodrug form, i.e., compounds covalently bonded to an active parent drug released in vivo. Such prodrugs are typically compounds of the invention in which one or more suitable groups are modified such that the modification is reversible upon administration to a human or mammalian subject. Reversal is typically carried out by enzymes naturally present in such subjects, but it is also possible to reverse the modification in vivo by administering a second agent with such a prodrug. Examples of such modifications include esters (e.g., any of those described above), wherein the modification can be reversed by esterases, etc. Other such systems are well known to those skilled in the art.

[0504] solvates

[0505] The present invention also includes the compounds of the invention in solvate form. The terms used in the claims include these forms.

[0506] Polymorphs

[0507] This invention also relates to compounds of this invention in various crystalline, polymorphic, and (anhydrous) hydrated forms. Methods in the pharmaceutical field have been well established that compounds in any of these forms can be isolated by slightly altering the purification methods and / or the separation methods of the solvents used to synthesize such compounds.

[0508] Application method

[0509] The pharmaceutical compositions of the present invention are suitable for rectal, nasal, bronchial, topical (including oral and sublingual), vaginal, or parenteral (including subcutaneous, intramuscular, intravenous, intra-arterial, and intradermal), intraperitoneal, or intrathecal administration. Preferred formulations are those for oral administration. The formulations can be conveniently provided in unit dosage forms (i.e., in the form of discrete portions comprising unit doses) or in unit doses of multiple units or subunits. As examples, the formulations can be in the form of tablets and sustained-release capsules and can be prepared by any method known in the pharmaceutical field.

[0510] The oral formulations of the present invention may be provided in the following forms: discrete units containing a predetermined amount of active ingredient, such as capsules, pills, drops, sachets, pellets, or tablets; powders or granules; solutions, emulsions, or suspensions of the active ingredient 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.

[0511] For oral compositions (e.g., tablets and capsules), the term "acceptable carrier" includes excipients such as common excipients, such as binders like syrups, gum arabic, gelatin, sorbitol, tragacanth gum, polyvinylpyrrolidone (polyvinyl ether), methylcellulose, ethylcellulose, sodium carboxymethylcellulose, hydroxypropyl methylcellulose, sucrose, and starch; fillers and carriers such as corn starch, gelatin, lactose, sucrose, microcrystalline cellulose, kaolin, mannitol, dicalcium phosphate, sodium chloride, and alginate; and lubricants such as magnesium stearate, sodium stearate and other metal stearates, glyceryl stearate stearate, silicone oil, talc, oils, and colloidal silica. Flavoring agents such as peppermint, wintergreen oil, cherry flavoring, etc., may also be used. It may be advantageous to add coloring agents to make the dosage form easily identifiable. Tablet coating may also be performed using methods known in the art.

[0512] Tablets can be obtained by compression or molding, optionally with one or more additional ingredients. Compressed tablets can be prepared by compressing an active agent in free-flowing form (such as powder or granules), optionally with a binder, lubricant, inert diluent, preservative, surfactant, or dispersant, in a suitable machine. Molded tablets can be obtained 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 can be formulated as sustained-release or controlled-release active agents.

[0513] Other formulations suitable for oral administration include: tablets containing an active agent in a flavoring matrix (typically sucrose and gum arabic or tragacanth); soft tablets containing an active agent in an inert matrix (such as gelatin and glycerin, or sucrose and gum arabic); and mouthwashes containing an active agent in a suitable liquid carrier.

[0514] Other forms of administration include solutions or emulsions that can be injected intravenously, intra-arterially, intrathecally, subcutaneously, intradermally, intraperitoneally, or intramuscularly, prepared from sterile or sterilizable solutions. Injectable formulations typically contain 10 mg to 1000 mg, preferably 10 mg to 250 mg, of the active ingredient per dose.

[0515] The pharmaceutical compositions of the present invention may also be in the form of suppositories, vaginal suppositories, suspensions, emulsions, lotions, ointments, creams, gels, sprays, solutions or powders.

[0516] Alternative methods of transdermal application include the use of skin patches. For example, the active ingredient can be incorporated into a cream composed of an aqueous emulsion of polyethylene glycol or liquid paraffin. The active ingredient can also be incorporated into an ointment composed of a paraffin or white soft paraffin matrix at a concentration between 1% and 10% by weight, with stabilizers and preservatives added as needed.

[0517] dose

[0518] Those skilled in the art can readily determine the appropriate dosage of one of the compositions of the present invention for administration to a subject without excessive trial. Typically, a physician can determine the most suitable actual dosage for an individual patient, which depends on a variety of factors, including the activity of the specific compound used, the metabolic stability and duration of action of said compound, age, weight, general health condition, sex, diet, route and time of administration, excretion rate, drug combinations, severity of the specific condition, and the individual receiving treatment. The dosages disclosed herein are examples of average cases. Individual examples are possible where higher or lower dosage ranges should be used, which are within the scope of the invention.

[0519] The dosage can be further adjusted according to the administration method of the compound. For example, parenteral administration of the compound is generally preferred to achieve an "effective dose" for acute treatment. While intramuscular bolus injection is also useful, intravenous infusion of the compound in 5% glucose or saline solution, or similar formulations with suitable excipients, is most effective. Typically, the parenteral dose is from 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 level that effectively regulates 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. Those skilled in the art can readily determine the precise therapeutically effective dose of the compound of the present invention, as well as the optimal route of administration, by comparing the blood levels of the drug with the concentrations required to achieve a therapeutic effect.

[0520] The compounds of the present invention can also be administered orally to patients in a manner that achieves a concentration sufficient to meet one or more therapeutic targets disclosed herein. Typically, the oral dose of the pharmaceutical composition comprising the compound is between about 0.1 mg / kg and about 50 mg / kg, and the administration method must be consistent with the patient's condition. Preferably, the oral dose is between about 0.5 mg / kg and about 20 mg / kg.

[0521] When the compounds of the present invention are administered according to the present invention, unacceptable toxic effects are not expected. The compounds of the present invention, which may have good bioavailability, can be detected using one of several bioassay techniques, thereby determining the concentration of the compound required to achieve a given pharmaceutical effect.

[0522] joint

[0523] 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., commercially available pharmaceuticals). Therefore, another aspect of the invention relates to combinations comprising the compounds described herein and one or more additional active agents. In a preferred embodiment, the compounds of the present invention may be administered sequentially, simultaneously, or in sequence with one or more other active agents.

[0524] When administered in combination, drugs are generally more effective. In particular, combination therapy is advantageous to avoid overlap in major toxicities, mechanisms of action, and resistance mechanisms. Furthermore, it is desirable to administer the maximum amount of drug at the maximum tolerated dose with the shortest possible time interval between such doses. A major advantage of combining with chemotherapy drugs is that, through biochemical interactions, an additive effect or potential synergistic effect can be promoted, and the development of drug resistance can also be reduced.

[0525] By studying the activity of test compounds in conjunction with drugs known or suspected of playing a significant role in the treatment of specific conditions, beneficial combinations can be indicated. This method can also be used to determine the order of drug administration—that is, before, simultaneously with, or after administration. This timing arrangement can be characteristic of all the active agents identified herein.

[0526] In a preferred embodiment, the additional active agent is an immunotherapeutic agent, more preferably a cancer immunotherapeutic agent. "Immunotherapeutic agent" refers to a treatment method that uses the subject's own immune system to fight diseases such as cancer.

[0527] In a preferred embodiment, the compound of the present invention inhibits the activity of ERAP1, and the compound is administered in combination with immunotherapy.

[0528] 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.

[0529] In one implementation, the compound can be used to treat cancers that respond poorly or not at all to immunotherapy.

[0530] In a preferred embodiment, the additional active agent is a molecule capable of immune checkpoint intervention, a co-stimulatory antibody, a chemotherapeutic agent, a radiotherapy agent, a targeted therapeutic agent, or an antibody, particularly a monoclonal antibody.

[0531] In a preferred embodiment, the additional active agent is a molecule capable of immune checkpoint intervention.

[0532] 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 prolactin.

[0533] Immune checkpoint molecules include inhibitory molecules and activating molecules, and intervention can be applied to either or both of these types of molecules.

[0534] 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.

[0535] 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.

[0536] In a preferred embodiment, the antibody checkpoint inhibitor is an anti-PD-1 antibody, more preferably selected from pembrolizumab, cimiprimab, and nivolumab.

[0537] In a preferred embodiment, the antibody checkpoint inhibitor is an anti-PD-L1 antibody, more preferably selected from atezolizumab, avermab, and durvalumab.

[0538] In a preferred embodiment, the antibody checkpoint inhibitor is an anti-CTLA4 antibody, more preferably selected from ipilimumab and trimemumab.

[0539] In a preferred embodiment, the immunotherapy is an anticancer vaccine or a virus, such as an oncolytic virus.

[0540] In a preferred embodiment, the immunotherapy is a cell-based therapy. In one embodiment, the cell-based therapy may be T-cell therapy, such as adoptive T-cell therapy, or therapy using CAR-T cells.

[0541] Adoptive cell-based immunotherapy can include the following: irradiated autologous or allogeneic tumor cells, tumor breakdown products 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. These cell-based immunotherapies can be further modified to express one or more gene products to further modulate the immune response, such as expressing cytokines like GM-CSF, and / or expressing tumor-associated antigens (TAAs) such as MAGE-1, gp-100, patient-specific neoantigen vaccines, etc.

[0542] In other embodiments, immunotherapy may include cell-based immunotherapy. In one embodiment, a composition comprising an antigen may be used, with or without a vaccine adjuvant. Such compositions exist in many known forms, such as peptide compositions, oncolytic viruses, and recombinant antigens comprising fusion proteins.

[0543] In one 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 durable forms) may be used. Immunomodulatory cytokines, such as interferon, G-CSF, imiquimod, TFα, etc., and their regulators (e.g., blocking antibodies or more effective or more durable forms) may 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 durable forms) may be used. In yet another embodiment, immunomodulatory molecules targeting immunosuppression, such as the STAT3 signaling regulator, the FkappaB signaling regulator, and immune checkpoint regulators, may be used.

[0544] In another implementation, immunomodulatory drugs may be used, such as immunosuppressive drugs, glucocorticoids, cell growth inhibitors, immunoaffinity and its regulators (e.g., rapamycin, calcineurin inhibitors, tacrolimus, cyclosporine, pimecrolimus, abelimus, guanitolimus, desfolimus, everolimus, tesiromolimus, zotalimus, 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, anti-thymocyte globulin, anti-lymphocyte... Cytospherin, Thalidomide, Lenalidomide, Pentoxoxetine, Bupropion, Curcumin, Catechins, Opioids, EVIPDH Inhibitors, Mycophenolic Acid, Polysaccharin, Fingolimod, NF-xB Inhibitors, Raloxifene, Tegaserod α, Dinosumab, F-xB Signaling Cascade Inhibitors, Disulfiram, Olmesartan, Dithiocarbamate, Proteasome Inhibitors, Bortezomib, MG132, Prol, PI-0052, Curcumin, Genistein, Resveratrol, Parthenolide, Thalidomide, Lenalidomide, Vrappine, Nonsteroidal Anti-inflammatory Drugs (NSAIDs), Arsenic Trioxide, Dehydroxymethylcycloquinonemycin (DHMEQ), I3C (Indole-3-Methanol) / DIM (Diindolemethane) (I3C / DIM), Bay 1 1-7082, luteolin, cell-penetrating peptide SN-50, IKBa-super repressor overexpression, FKB trap oligodeoxynucleotide (ODN) or derivatives or analogs thereof.

[0545] In another implementation, immunomodulatory antibodies or proteins may be used. Examples include antibodies binding to CD40, Toll-like receptors (TLRs), OX40, GITR, CD27, or 4-1BB; T-cell bispecific antibodies; anti-IL-2 receptor antibodies; anti-CD3 antibodies; OKT3 (moromab); oxizumab; taplezumab; vexizumab; anti-CD4 antibodies; crixacillinab; keliximab; zanalimab; and anti-CD11 antibodies. α antibody, efariziumab, anti-CD18 antibody, erlizumab, rovizumab, anti-CD20 antibody, afuzumab, olizumab, oflavumumab, pacozumab, rituximab, anti-CD23 antibody, ruxizumab, anti-CD40 antibody, tenesimab, toliszumab, anti-CD40L antibody, rulizumab, anti-CD62L antibody, asezizumab, anti-CD80 antibody, galilizumab, anti-CD147 antibody, gavimumab, B lymphocyte stimulator (BLyS) inhibitory antibody, belimumab, CTLA4-Ig fusion protein, abatacept, beracip, anti-CTLA4 antibody, ipilimumab, trimemumab, anti-eosinophil chemokine 1 antibody, bertilimumab, anti-α4 integrin antibody, natezumab, anti-IL-6R antibody, tocilizumab, anti-LFA- 1. Antibodies, Odomomab, Anti-CD25 Antibody, Baliximab, Dalizumab, Inomomab, Anti-CD5 Antibody, Atomomumab, Anti-CD2 Antibody, Cilizumab, Neremomumab, Faramomab, Atlizumab, Atorolizumab, Cilizumab, Atordolimab, Doliximab, Arantuzumab, Gantingrumab, Goliximab, Lelizumab Masmoxicillin, Moromumab, Pexacillin, Relizumab, Roveizumab, Talizumab, Atemomalizumab, Varliximab, Verpamomab, Aflibercept, Afaxicept, Linalcept, IL-2 receptor antagonists, Analepidocanine, Anti-IL-5 antibodies, Meporibumab, IgE inhibitors, Omalizumab, Talizumab, IL12 inhibitors, IL23 inhibitors, Utecumab.

[0546] In one implementation, the subject may be receiving or have previously received treatment with a chemotherapy agent. Examples of chemotherapy agents include, but are not limited to: alkylating agents, such as thiotepa and cyclophosphamide; alkyl sulfonates, such as busulfan, indomethacin, and piperazine; aziridines, such as benzodopa, carboquinone, meturedopa, and uredopa; ethylene imines and methylmelamines, including hexamethylmelamine, tratamine, trietylenephosphoramide, and triethiylenethiop. hosphoramide and tris(hydroxymethyl)melamine; acetogenins (e.g., bratacin and bratacinone); camptothecin (including the synthetic analogue topotecan); bryostatin; callystatin; CC-1065 (including its synthetic analogues adoralexin, calcein and pyrazin); cryptophycins (e.g., cryptophycin 1 and cryptophycin 8); dolasstatin; duocarmycins (including the synthetic analogues KW-2189 and CB). 1-TM1); eleutherobin; pancratistatin; sarcodictyin; spongistatin; nitrogen mustards, such as chlorambucil, naphthylambucil, cholophosphamide, estradiol, ifosfamide, dichloromethyldiethylamine, mechlorethamine oxide Hydrochlorides, melphalan, novobichin, phenesterine, prednisone, trofenoxam, uracil mustard; nitrosoureas, such as carmustine, chlorpromazine, formustine, lomustine, nimustine, and ranimustine; antibiotics, such as enediyne antibiotics (e.g., galicariin, especially galicariin γII and galicariin ωII (see, e.g., Agnew, Chem. Intl. Ed. Engl., 33:183-186 (1994)); anthracyclines, including danendomycin A; bisphosphonates, such as clophosphonates; esperamicin;In addition to neocarzinostatin chromophores and related chromoprotein ethynylene antibiotic chromophores), aclacinomysin, actinomycin, autramycin, diazoserine, bleomycin, actinomycin, carabicin, carminomycin, carzinophilin, chromomycin, actinomycin D, doxorubicin, detoxin, 6-diazo-5-oxo-L-leucine, adriamycin (including doxorubicin morpholino, cyanomorpholino, 2-pyrrolodoxomicin, and deoxydoxomicin), epirubicin, esopycin, edabrycin, ephedrine; mitomycins, such as mitomycin C, mycophenolic acid, nogamycin, olivomycin, pepromycin, prednisone. romycin), puromycin, triamcinolone acetonide, rhodopsin, streptomycin, streptozotocin, tuberculin, ubenimex, fentostatin, zorubicin; antimetabolites, such as methotrexate and 5-fluorouracil (5-FU); folic acid analogs, such as folate, methotrexate, pteroxate, trimethoprim; purine analogs, such as fludarabine, 6-mercaptopurine, thiamiprine, thioguanine; pyrimidine analogs, such as ancitabine, aspirin, etc. Zacitidine, 6-azauridine, carmoflurane, cytarabine, dideoxyuridine, deoxyfluorouridine, enoxabin, fluorouridine; androgens, such as calusterone, drotalonone propionate, epithranolol, meandranone, testosterone; antiadrenergics, such as aminoglutethimide, mitotane, trilosterone; folic acid supplements, such as folinic acid; aceglucuronolactone; aldophosphamide glycosides. glycoside; aminolevulinic acid; enuramicin; acridine; bestrabucil; bisantrene; edatraxate; dimethicone; diaziquone; elformithine; elformithine; epothilone; etoglucid; gallium nitrate; hydroxyurea; lentinan; chlordamine; maytansinoids, such as maytansin and anthraquinone; mitoxantrone; mopidanmol; nitraerine; pentostatin; phenamet; pirarubicin; loxoantrone; podophyllinic acid; 2-ethylhydrazine; procarbazine;PSK polysaccharide complex (JHS Natural Products, Eugene, Oreg.); razorubicin; sizofuran; germanospiramine; tenuazonic acid; triaminoquinone; 2,2′,2"-trichlorotriethylamine; trichothecenes (e.g., T-2 toxin, verracurin A, roridin A, and anguidine); urethan; vinblastine; dacarbazine; mannitol mustard; dibromomannitol; dibromoeutherol; piperbbromo; gacytosine; arabinoside (“Ara-C”); cyclophosphamide; thiotepa; taxanes, such as TAXOL paclitaxel (Bristol-Myers Squibb) Oncology (Princeton, NJ), ABRAXANE (cremophor-free), albumin-modified nanoparticle formulation of paclitaxel (American Pharmaceutical Partners, Schaumberg, 111.), and TAXOTERE (doxetaxel) (Rhone-Poulenc Roer, Antoine, France); chlorambucil; GEMZAR (gemcitabine); 6-thioguanine; mercaptopurine; methotrexate; platinum analogs such as cisplatin, oxaliplatin, and carboplatin; vincristine; platinum; etoposide (VP-16); ifosfamide; mitoxantrone; vincristine; NAVELBINE (vinorelbine); novantrone; teniposide; edaraxacin; donomycin; aminopterin; capecitabine (xeloda); ibandronate; irinotecan (Cam ptosar (CPT-11) (including irinotecan with 5-FU and leucovorin); topoisomerase inhibitor RFS2000; difluoromethylornithine (DMFO); retinoids such as retinoic acid; capecitabine; compressoritine; leucovorin (LV); oxaliplatin, including oxaliplatin regimens (FOLFOX); lapatinib (Tykerb); inhibitors of PKC-a, Raf, H-Ras, EGFR (e.g., erlotinib (Tarceva)) and VEGF-A that reduce cell proliferation, and pharmaceutically acceptable salts, acids, or derivatives of any of the above. Furthermore, the treatment may further include the use of radiation. Additionally, the treatment may further include the use of photodynamic therapy.

[0547] The invention is further described by way of the following non-limiting examples and with reference to the following figures, wherein:

[0548] Figure 1 The cellular effects of representative compounds 1 and 242 according to the invention on antigen presentation are illustrated, and these effects were determined by evaluating the presentation effect of the compounds on the ovalbumin-specific peptide (SIINFEKL). More specifically, Figure 1 A representative IC of an exemplary compound according to the present invention is shown. 50 Curves. The data are standardized relative to the signals obtained when there is no compound (high) and no antigen (low), and expressed as mean ± STD (n=2).

[0549] Figure 2 The IC50 values ​​produced by exemplary compounds 1 and 242 according to the present invention, as determined by the above-described OVA antigen presentation assay, are shown. 50 Data summary. Data is presented as mean ± SEM (n=6).

[0550] Figure 3 The effect of compound 1 according to the invention on global antigen treatment, as determined using an unbiased proteomics pipeline, is shown. More specifically, Figure 3 The effects of ERAP1 siRNA and compound inhibition (at 1 μM and 10 μM) on the immunopeptidome of SiHa cells, as determined by action on peptides with total proportions of 8, 9, 10, 11, 12, and 13 amino acids, are shown compared to the control group.

[0551] Example

[0552] Unless otherwise specified, the preparation of starting materials is commercially available, known in the literature, or readily obtainable by those skilled in the art using standard methods. When it is indicated that the compound was prepared using a method similar to that used in the preceding examples or intermediates, those skilled in the art will understand that, for each specific reaction, the reaction time, reagent equivalences, solvent, concentration, and temperature may be adjusted, and different work-ups or purification techniques may be required or advantageously employed.

[0553] General Solution

[0554] abbreviation

[0555] The following is a list of some commonly used abbreviations - other abbreviations not listed are those that should be understood by those skilled in the art.

[0556] aq: aqueous; br: broad peak; ca.: approx.; d: bimodal; DCM: dichloromethane; dioxane: 1,4-dioxane; DMAP: 4-dimethylaminopyridine; DMF: dimethylformamide; EDC: 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride; Et3N: triethylamine; EtOAc: ethyl acetate; EtOH: ethanol; h: hour; HPLC: high performance liquid chromatography; IPA: isopropanol; LC: liquid chromatography; m: multiplet; M: molar, molecular ion; MeCN: acetonitrile; MeOH: methanol; min: minute; MS: mass spectrometry; NMR: nuclear magnetic resonance; PDA: photodiode array; q: four peaks; RT: room temperature (approx. 20°C); R T Retention time; s: singlet, solid; t: three peaks; TBME: tert-butyl methyl ether; TFA: trifluoroacetic acid; THF: tetrahydrofuran; UPLC: ultra-high performance liquid chromatography; UV:

[0557] Ultraviolet light; quant.: quantitative; SEM: [2-(trimethylsilyl)ethoxy]methyl acetal;

[0558] dppf: 1,1′-ferrocene di-bis(diphenylphosphine); NBS: N-bromosuccinimide;

[0559] XantPhos-Pd-G3: [(4,5-bis(diphenylphosphino)-9,9-dimethyloxanthracene)-2-(2′-amino-1,1′-biphenyl)]palladium(II)methanesulfonate (CAS: 1445085-97-1); XPhos Pd G3:

[0560] (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:

[0561] 1798782-25-8); TBAF: Tetra-n-butylammonium fluoride.

[0562] Other abbreviations are intended to express their generally accepted meanings.

[0563] Option 1

[0564]

[0565] Where R a = R6, R7, R8, R9, NR of equation (I) 10 R 11 And Rb = R1, R3, R4, R5 of equation (I)

[0566] Reagents: (a) C1SO3H, 100℃; (b) amine, pyridine, DCM, RT

[0567] I-1 is chlorosulfonated with chlorosulfonic acid to give sulfonyl chloride I-2. In the presence of pyridine, sulfonyl chloride I-2 is reacted with a suitable amine to give sulfonamide I-3.

[0568] Option 2

[0569]

[0570] Where R b = R1, R3, R4, R5 of equation (I)

[0571] Reagents: (a) amine, DCM; (b) H2, 10% Pd / C, EtOH; (c) Fe, NH4Cl, IPA, water; (d) NH4OH(aq), Na2S2O4, THF, H2O, RT; (e) sulfonyl chloride, pyridine, DCM, RT; (f) LiOH(aq), THF, MeOH; (g) LiOH(aq), dioxane.

[0572] In a nucleophilic substitution reaction, fluoro-2-nitro-4-(trifluoromethyl)benzene (I-4) reacts with a suitable amine, and the resulting nitro compound I-5 is then reduced to aniline I-6. Aniline I-6 reacts with a suitable sulfonyl chloride to give sulfonamide I-7. Ester hydrolysis yields the corresponding carboxylic acid I-8.

[0573] Option 3

[0574]

[0575] Reagents: (a) aniline, pyridine, DCM, RT; (b) amine, THF, 60℃; (c) LiOH (aq), THF, 50℃.

[0576] Sulfonyl chloride I-9 reacts with a suitable aniline to give sulfonamide I-10. Nucleophilic substitution with a suitable amine yields I-11, which is then hydrolyzed to give the corresponding carboxylic acid I-12.

[0577] Option 4

[0578]

[0579] Where R a = Equation (I) R6, R7, R8, R9 and R b = R1, R2, R3, R4, R5 of equation (I)

[0580] Reagents: (a) sulfonyl chloride, pyridine, DCM, RT; (b) LiOH (aq), dioxane or THF, RT.

[0581] Sulfonamide I-14 is prepared by reacting aniline I-13 with a suitable sulfonyl chloride. Ester hydrolysis yields the corresponding carboxylic acid I-15.

[0582] Option 5

[0583]

[0584] Reagents: (a) aniline, pyridine, DCM, RT; (b) NaOH (aq), MeOH, H2O, RT; (c) LiOH (aq), THF, RT.

[0585] Sulfonamide I-17 was prepared by reacting sulfonyl chloride I-16 with a suitable aniline. The ester was then hydrolyzed to give the corresponding carboxylic acid I-18.

[0586] Option 6

[0587]

[0588] Reagents: (a) amine, MeCN; (b) di(pinacol)diboron, PdCl2(dppf)·DCM, KOAc, dioxane; (c) H2, Pd / C, MeOH; (d) sulfonyl chloride, pyridine, DCM, RT; (e) aryl halide, Xphos Pd G3, K3PO4, dioxane, water; (f) LiOH(aq), THF, MeOH; (g) HCl, dioxane.

[0589] In a nucleophilic substitution reaction, 4-bromo-1-fluoro-2-nitrobenzene (I-19) reacts with a suitable amine, and the resulting aryl bromide is then converted to a borate ester I-20. The nitro group is then reduced to the corresponding aniline I-21. I-21 reacts with a suitable sulfonyl chloride to give a sulfonamide I-22. The remaining substituent is introduced via Suzuki coupling, followed by ester hydrolysis to give the corresponding carboxylic acid I-24. Alternatively, these steps can be carried out in the indicated alternative order.

[0590] General experimental conditions

[0591] All starting materials and solvents were prepared from commercial sources or according to literature citations. Unless otherwise specified, the reaction mixture was magnetically stirred and reacted at room temperature (approximately 20°C). Unless otherwise specified, column chromatography was performed using a pre-packed silica (40 μm) column on an automated rapid chromatography system (e.g., a CombiFlash Rf system). A Bruker 5mm SmartProbe was used. TMThe Bruker Avance III HD spectrometer recorded at 500 MHz 1 1H NMR spectra. Chemical shifts are expressed in parts per million (ppm), with the central peak of the residual proton solvent or a tetramethylsilane internal standard used as a reference. Spectra were recorded at 298 K unless otherwise specified. Waters ACQUIETY detectors equipped with ACQUIETY PDA and ACQUIEY QDa mass detectors were used. Analytical UPLC-MS experiments were performed using an H-class system to determine retention times and associated mass ions, running one of the following analytical methods. Analytical LC-MS experiments were performed using an Agilent 1200 series HPLC system coupled to an Agilent 1956, 6100, or 6120 series single quadrupole mass spectrometer to determine retention times and associated mass ions, running one of the following analytical methods. Preparative HPLC purification was performed using a Waters X-Select CSH C18, 5 μm, 19 × 50 mm column with 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, 5 μm, 19 × 50 mm column. Fractions were collected after detection by UV at a single wavelength measured by a variable wavelength detector. Professional 17 (PerkinElmer)'s "Structure to Name" conversion produces the naming of structures.

[0592] Analytical methods

[0593] Method 1 - Acidic 3-min method

[0594] Column: Waters ACQUITY CSH C18, 1.7μm, 2.1×30mm, 40℃

[0595] Detection: Unless otherwise specified, 254nm UV light, MS detected by electro-jet ionization.

[0596] Solvents: A: 0.1% v / v aqueous solution of formic acid; B: 0.1% v / v MeCN solution of formic acid.

[0597] gradient:

[0598] 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

[0599] Method 2 - Alkaline 3-min method

[0600] Column: Waters ACQUITY BEH C18, 1.7μm, 2.1×30mm, 40℃

[0601] Solvents: A: 10mM ammonium bicarbonate (aq), B: MeCN

[0602] (Other parameters are the same as in Method 1)

[0603] Method 3 - Acidic 4min method

[0604] Column: Waters X-Select CSH C18, 2.5μm, 4.6×30mm, 40℃

[0605] Detection: Unless otherwise specified, 254nm UV light, MS detected by electro-jet ionization.

[0606] Solvents: A: 0.1% v / v aqueous solution of formic acid; B: 0.1% v / v MeCN solution of formic acid.

[0607] gradient:

[0608] 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

[0609] Method 4 - Alkaline 4min method

[0610] Column: Waters X-Bridge BEH C18, 2.5μm, 4.6×30mm, 40℃

[0611] Solvents: A: 10mM ammonium bicarbonate (aq), B: MeCN

[0612] (Other parameters are the same as in method 3)

[0613] Example 1: 4-Ethyl-3-(N-(2-(piperidin-1-yl)-5-(trifluoromethyl)phenyl)aminosulfonyl)benzoic acid

[0614]

[0615] 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 overnight at 100 °C. The mixture was cooled and carefully added to ice with stirring. The resulting precipitate was collected by filtration to give the title compound as a white solid (1.58 g, 6.04 mmol, yield 91%, purity 95%). 1¹H NMR (500MHz, DMSO-d⁶) δ 8.34 (d, J = 1.9 Hz, 1H), 7.82 (dd, J = 7.9, 2.0 Hz, 1H), 7.32 (d, J = 7.9 Hz, 1H), 3.08 (q, J = 7.5 Hz, 2H), 1.19 (t, J = 7.5 Hz, 3H). No exchangeable protons were observed.

[0616] Step 2: 4-Ethyl-3-(N-(2-(piperidin-1-yl)-5-(trifluoromethyl)phenyl)aminosulfonyl)benzoic acid: A solution of pyridine (3 mL, 37.1 mmol) of 2-(piperidin-1-yl)-5-(trifluoromethyl)aniline (0.200 g, 0.819 mmol) was treated with the product of Step 1 (0.244 g, 0.983 mmol) and 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 column, 0-100% EtOAc / isohexane, then 0-50% EtOAc / DCM) to give the title compound as a brown solid (36.3 mg, 0.076 mmol, yield 9.23%, purity 97%). UPLC-MS (Method 1) m / z 457.4 (M+H) at 1.87 min. + 455.2 (MH) - . 1 H NMR(500MHz,DMSO-d6)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=4.9Hz, 4H), 1.57 (p, J=5.0Hz, 4H), 1.50-1.45 (m, 2H), 1.21 (t, J=7.4Hz, 3H).

[0617] Example 3: 4-Isopropyl-3-(N-(2-(piperidin-1-yl)-5-(trifluoromethyl)phenyl)aminosulfonyl)benzoic acid

[0618]

[0619] 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 overnight at 100 °C. The mixture was cooled and carefully added to ice with stirring. The resulting precipitate was collected by filtration and dried under vacuum to give the title compound as a brown solid (1.28 g, 4.63 mmol, yield 76%, purity 95%). 1 ¹H NMR (500MHz, DMSO-d6) δ 12.50 (bs, 1H), 8.36 (d, J = 1.9 Hz, 1H), 7.83 (dd, J = 8.1, 1.9 Hz, 1H), 7.44 (d, J = 8.1 Hz, 1H), 4.20 (septet, J = 6.8 Hz, 1H), 1.16 (d, J = 6.9 Hz, 6H).

[0620] Step 2: 4-Isopropyl-3-(N-(2-(piperidin-1-yl)-5-(trifluoromethyl)phenyl)aminosulfonyl)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 from Step 1 (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 column, 0-50% EtOAc / DCM) to give the title compound as a light brown solid (14.3 mg, 0.029 mmol, yield 10%, purity 95%). UPLC-MS (Method 1) m / z 471.4 (M+H) at 1.93 min + 469.3 (MH) - . 1 H NMR(500MHz,DMSO-d6)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).

[0621] Example 4: 3-(N-(2-(piperidin-1-yl)-5-(trifluoromethyl)phenyl)aminosulfonyl)-4-(trifluoromethoxy)benzoic acid

[0622]

[0623] 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 overnight at 100 °C. The mixture was cooled and carefully added to ice with stirring. The resulting precipitate was collected by filtration and dried under vacuum to give the title compound as a paste-like solid (0.770 g, 2.28 mmol, yield 46.9%, purity 90%). 1 H NMR (500MHz, DMSO-d6) 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).

[0624] Step 2: 3-(N-(2-(piperidin-1-yl)-5-(trifluoromethyl)phenyl)aminosulfonyl)-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 from Step 1 (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 column, 0-50% EtOAc / DCM) to give the title compound as a paste solid (5.6 mg, 10.4 μmol, yield 3.6%, purity 95%). UPLC-MS (Method 1) m / z 513.3 (M+H) at 1.94 min + 511.1 (MH) - . 1 H NMR(500MHz,DMSO-d6)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).

[0625] Example 6: 3-(N-(2-(cis-3,5-dimethylpiperidin-1-yl)-5-(trifluoromethyl)phenyl)aminosulfonyl)-4-methoxybenzoic acid

[0626]

[0627] Step 1: cis-3,5-dimethyl-1-(2-nitro-4-(trifluoromethyl)phenyl)piperidine: Et3N (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 column, 0-100% EtOAc in isohexane solution, followed by 0-10% MeOH / DCM) to give the title compound as a pale orange solid (356 mg, 1.12 mmol, yield 78%, purity 95%). UPLC-MS (Method 1) 2.01 min m / z 303.4 (M+H) + .

[0628] Step 2: 2-(cis-3,5-dimethylpiperidin-1-yl)-5-(trifluoromethyl)aniline: Dissolve the product from Step 1 (150 mg, 0.496 mmol) in EtOH (9.9 ml), and transfer the reaction mixture to Thales Nano Hydrogenation was performed in a flow reactor (10% Pd / C, 30 × 4 mm column, all-hydrogen mode, 40 °C, flow rate 1 mL / min, 2 passes). The reaction mixture was concentrated under vacuum and azeotropically reacted with MeOH (6 mL) to give the title compound as a pale brown oil (133 mg, 0.479 mmol, yield 96%, purity 98%). UPLC-MS (Method 2) 2.00 min m / z 273.3 (M+H) + 271.1(M–H) – .

[0629] Step 3: Methyl 3-(N-(2-(cis-3,5-dimethylpiperidin-1-yl)-5-(trifluoromethyl)phenyl)aminosulfonyl)-4-methoxybenzoate: The product from 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 column, 0-100% EtOAc / isohexane) to give the title compound as a paste solid (63 mg, 0.120 mmol, yield 63.3%, purity 95%). UPLC-MS (Method 1) m / z 501.4 (M+H) at 2.05 min. + 498.9 (M–H) – .

[0630] Step 4: 3-(N-(2-(cis-3,5-dimethylpiperidin-1-yl)-5-(trifluoromethyl)phenyl)aminosulfonyl)-4-methoxybenzoic acid: The product from 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 under vacuum, and the resulting aqueous solution was diluted with water (5 ml). 1 M HCl (aq) was added dropwise to approximately pH 6. The resulting white precipitate was collected by filtration and washed with water. The solid was suspended in MeCN (4 ml), concentrated under vacuum, and dried at 45 °C to give the title compound as a pale yellow solid (55 mg, 0.113 mmol, yield 88%, purity 95%). UPLC-MS (Method 1) m / z 487.4 (M+H) at 1.89 min + 485.2 (M–H) – . 1H NMR(500MHz,DMSO-d6)δ13.16(s,1H),8.82(s,1H),8.34(d,J=2.3Hz,1H),8.15 (dd,J=8.7,2.3Hz,1H),7.47(d,J=2.1Hz,1H),7.36(dd,J=8.5,2.1Hz,1H),7.3 0(d,J=8.7Hz,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).

[0631] Example 7: 3-(N-(2-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-5-(trifluoromethyl)phenyl)aminosulfonyl)-4-methoxybenzoic acid

[0632]

[0633] Step 1: 3-(2-nitro-4-(trifluoromethyl)phenyl)-8-oxa-3-azabicyclo[3.2.1]octane: Et3N (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 the solution was concentrated under vacuum 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 (500MHz, DMSO-d6) 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).

[0634] Step 2: 2-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-5-(trifluoromethyl)aniline: The product from Step 1 above (323 mg, 1.07 mmol) was dissolved in EtOH (21.2 ml), and the reaction mixture was placed in Thales Nano Hydrogenation was performed in a flow reactor (10% Pd / C, 30 × 4 mm column, all-hydrogen mode, 40 °C, flow rate 1 mL / min, 4 passes). The reaction mixture was concentrated under vacuum and azeotropically reacted with MeOH (8 mL) to give the title compound as a creamy white solid (310 mg, 1.059 mmol, 100% yield, 93% purity). UPLC-MS (Method 2) showed m / z 273.3 (M+H) at 1.43 min. + . 1 H NMR (500MHz, DMSO-d6) 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).

[0635] Step 3: Methyl 3-(N-(2-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-5-(trifluoromethyl)phenyl)aminosulfonyl)-4-methoxybenzoate: At room temperature, pyridine (58 μl, 0.72 mmol) was added to a 2 mL solution of the product from Step 2 (66.5 mg, 0.239 mmol) and methyl 3-(chlorosulfonyl)-4-methoxybenzoate (80 mg, 0.287 mmol). The resulting solution was stirred at 40 °C for 4 h, and then another 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 under vacuum. The crude product was purified by silica gel column chromatography (25 g column, 0-80% EtOAc / isohexane) to give the title compound as a creamy white solid (88.3 mg, 0.173 mmol, yield 72.3%, purity 98%). UPLC-MS (Method 2) showed m / z 501.3 (M+H) at 1.59 min. + 499.2 (MH) - .

[0636] Step 4: 3-(N-(2-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-5-(trifluoromethyl)phenyl)aminosulfonyl)-4-methoxybenzoic acid: At room temperature, 1 M LiOH (aq) (0.699 mL, 0.699 mmol) was added to a THF (1.4 mL) solution of the product from Step 3 (87.4 mg, 0.175 mmol) above, and the resulting solution was stirred at room temperature for 24 h. The reaction mixture was concentrated under vacuum, and the residue was redissolved in water (3 mL) and acidified to pH 4 to 5 with 1 M HCl (aq). The precipitate was separated by filtration and then dried to give the title compound as a white solid (74 mg, 0.152 mmol, yield 87%, purity 100%). UPLC-MS (Method 1) m / z 487.3 (M+H) at 1.45 min. + 485.1 (MH) - . 1 H NMR(500MHz,DMSO-d6)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).

[0637] Example 8: 4-Methoxy-3-(N-(2-(cis-5-methylhexahydropyrrolo[3,4-c]pyrrolo-2(1H)-yl)-5-(trifluoromethyl)phenyl)aminosulfonyl)benzoic acid

[0638]

[0639] Step 1: cis-2-methyl-5-(2-nitro-4-(trifluoromethyl)phenyl)octahydropyrrolo[3,4-c]pyrrole: At room temperature, Et3N (0.417 mL, 2.99 mmol) was added to a DCM (5 mL) 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), 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 through a phase separator, and concentrated under vacuum to give the title compound as an orange solid (402 mg, 1.20 mmol, yield quantified, purity 93%). UPLC-MS (Method 2) 1.40 min m / z 316.3 (M+H) + . 1 ¹H NMR (500MHz, DMSO-d⁶) δ 8.04–8.01 (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 masked the signal at 2.49 ppm.

[0640] Step 2: 2-(cis-5-methylhexahydropyrrolo[3,4-c]pyrrolo-2(1H)-yl)-5-(trifluoromethyl)aniline: The product from Step 1 above (376 mg, 1.19 mmol) was dissolved in EtOH (23.9 ml), and the reaction mixture was heated in Thales Nano Hydrogenation was performed in a flow reactor (10% Pd / C, 30 × 4 mm column, all-hydrogen mode, 40 °C, flow rate 1 mL / min, 2 passes). The reaction mixture was concentrated under vacuum and azeotropically reacted with MeOH (12 mL) to give the title compound as a creamy white solid (355 mg, 1.17 mmol, yield 98%, purity 94%). UPLC-MS (Method 2) showed 286.3 M+H at 1.24 min. + .

[0641] Step 3: Methyl 4-methoxy-3-(N-(2-(cis-5-methylhexahydropyrrolo[3,4-c]pyrrolo-2(1H)-yl)-5-(trifluoromethyl)phenyl)aminosulfonyl)benzoate: At room temperature, pyridine (58 μl, 0.72 mmol) was added to a slurry of the product from Step 2 above (72.6 mg, 0.239 mmol) and methyl 3-(chlorosulfonyl)-4-methoxybenzoate (80 mg, 0.287 mmol) in a DCM (2 ml). The resulting solution was stirred at 40 °C for 4 h, and then another 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 another 19 h. The reaction mixture was concentrated under vacuum, and the crude product was purified by silica gel column chromatography (25 g column, 0-10% MeOH / DCM) to give the title compound as a creamy white solid (158 mg, 0.193 mmol, yield 81%, purity 63%). UPLC-MS (Method 2) at 1.26 min, m / z 514.4 (M+H). + 512.2 (MH) - .

[0642] Step 4: 4-Methoxy-3-(N-(2-(cis-5-methylhexahydropyrrolo[3,4-c]pyrrolo-2(1H)-yl)-5-(trifluoromethyl)phenyl)aminosulfonyl)benzoic acid: At room temperature, 1M LiOH (aq) (1.23 mL, 1.23 mmol) was added to a THF (2.5 mL) solution of the product from Step 3 (158 mg, 0.308 mmol) above, and the solution was stirred at room temperature for 26 h. The reaction mixture was concentrated under vacuum, and the residue was redissolved in water (3 mL) and acidified to pH 4 to 5 with 1M HCl (aq). The precipitate was separated by filtration and then dried under vacuum to give the title compound as a creamy white solid (63.5 mg, 0.127 mmol, yield 41.3%, purity 98%). UPLC-MS (Method 2) m / z 500.3 (M+H) at 0.83 min. + 498.3 (MH) - . 1¹H NMR (500MHz, DMSO-d⁶) δ 8.22 (d, J = 2.2Hz, 1H), 8.13 (dd, J = 8.7, 2.2Hz, 1H), 7.31 (d, J = 8.7Hz, 1H), 7.28–7.24 (m, 1H), 6.97–6.91 (m, 2H), 3.90 (s, 3H), 3.36 (dd, J = 9.8, 6.5Hz, 2H), 3.22 (dd, J = 10.0, 2.7Hz, 2H), 2.86–2.80 (m, 2H), 2.75–2.69 (m, 2H), 2.64–2.59 (m, 2H), 2.38 (s, 3H). No two exchangeable protons were observed.

[0643] Example 9: 3-(N-(2-(3,3-difluoropiperidin-1-yl)-5-(trifluoromethyl)phenyl)aminosulfonyl)-4-methoxybenzoic acid

[0644]

[0645] Step 1: 3,3-Difluoro-1-(2-nitro-4-(trifluoromethyl)phenyl)piperidine: Et3N (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 under vacuum. The crude product was purified by silica gel column chromatography (12 g column, 0–100% EtOAc / isohexane) to give the title compound as a bright yellow solid (399 mg, 1.26 mmol, yield 87.8%, purity >98%). UPLC-MS (Method 2) m / z 309.0 (MH) at 1.64 min - .

[0646] Step 2: 2-(3,3-Difluoropiperidin-1-yl)-5-(trifluoromethyl)aniline: Dissolve the product from Step 1 (156 mg, 0.503 mmol) in EtOH (10.1 ml), and transfer the reaction mixture to Thales Nano Hydrogenation was performed in a flow reactor (10% Pd / C, 30 × 4 mm, all-hydrogen mode, 40 °C, flow rate 1 mL / min, 2 passes). The reaction mixture was concentrated under vacuum and azeotropically reacted with MeOH (6 mL) to give the title compound as a colorless oil (119 mg, 0.408 mmol, yield 81%, purity 96%). UPLC-MS (Method 2) showed m / z 280.8 (M+H) at 1.64 min. + .

[0647] Step 3: Methyl 3-(N-(2-(3,3-difluoropiperidin-1-yl)-5-(trifluoromethyl)phenyl)aminosulfonyl)-4-methoxybenzoate: The product from 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 column, 0-10% MeOH / DCM) to give the title compound as a white solid (39.9 mg, 0.075 mmol, yield 39.4%, purity 95%). UPLC-MS (Method 1) m / z 509.4 (M+H) at 1.75 min + 507.2 (MH) - .

[0648] Step 4: 3-(N-(2-(3,3-difluoropiperidin-1-yl)-5-(trifluoromethyl)phenyl)aminosulfonyl)-4-methoxybenzoic acid: The product from 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), with MeOH 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 under vacuum, 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 under vacuum, and dried at 45 °C to give the title compound as a white solid (34 mg, 0.065 mmol, yield 87%, purity 95%). UPLC-MS (Method 1) m / z 495.1 (M+H) at 1.59 min + 493.1 (MH) - Purity 98% (254nm). 1H NMR(500MHz,DMSO-d6)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).

[0649] Example 10: 3-(N-(2-(8-azabicyclo[3.2.1]oct-8-yl)-5-(trifluoromethyl)phenyl)aminosulfonyl)-4-methoxybenzoic acid

[0650]

[0651] Step 1: 8-(2-nitro-4-(trifluoromethyl)phenyl)-8-azabicyclo[3.2.1]octane: Et3N (0.236 ml, 1.69 mmol) was added to a DCM (2 ml) 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), 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 under vacuum. The crude product was purified by silica gel column chromatography (12 g column, 0-100% EtOAc / isohexane) to give the title compound (183 mg, 0.597 mmol, yield 88.2%, purity 98%). UPLC-MS (Method 2) showed m / z 301.3 (M+H) at 1.85 min. + .

[0652] Step 2: 2-(8-azabicyclo[3.2.1]oct-8-yl)-5-(trifluoromethyl)aniline: The product from Step 1 above (134 mg, 0.446 mmol) was dissolved in EtOH (8.9 ml), and the reaction mixture was placed in Thales Nano Hydrogenation was performed in a flow reactor (10% Pd / C, 30 × 4 mm, all-hydrogen mode, 40 °C, flow rate 1 mL / min, 2 passes). The reaction mixture was concentrated under vacuum and azeotropically reacted with MeOH (6 mL) to give the title compound as a colorless oil (104 mg, 0.366 mmol, yield 82%, purity 95%). UPLC-MS (Method 2) showed m / z 271.3 (M+H) at 1.83 min. + .

[0653] Step 3: Methyl 3-(N-(2-(-8-azabicyclo[3.2.1]oct-8-yl)-5-(trifluoromethyl)phenyl)aminosulfonyl)-4-methoxybenzoate: The product from 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 column, 0-10% MeOH / DCM) to give the title compound as a white solid (32.1 mg, 0.061 mmol, yield 32.4%, purity 95%). UPLC-MS (Method 1) m / z 499.3 (M+H) at 1.90 min + 497.2 (MH) - .

[0654] Step 4: 3-(N-(2-(-8-azabicyclo[3.2.1]oct-8-yl)-5-(trifluoromethyl)phenyl)aminosulfonyl)-4-methoxybenzoic acid: The product from 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 under vacuum, 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 obtain a turbid solution, and the precipitate was collected by filtration and washed with water. The solid was suspended in MeCN (4 ml), concentrated under vacuum, 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 aqueous solution) to give the title compound as a white solid (9.0 mg, 0.018 mmol, yield 29.3%, purity 95%). UPLC-MS (Method 1) showed a m / z of 485.2 (M+H) at 1.74 min. + 483.3 (MH) - . 1 H NMR(500MHz,DMSO-d6)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).

[0655] Example 11: 3-(N-(2-(5-oxa-2-azaspiro[3.4]oct-2-yl)-5-(trifluoromethyl)phenyl)aminosulfonyl)-4-methoxybenzoic acid

[0656]

[0657] Step 1: 2-(2-nitro-4-(trifluoromethyl)phenyl)-5-oxa-2-azaspiro[3.4]octane: Et3N (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 through a phase separator. The organic phase was concentrated under vacuum to give the title compound (438 mg, 1.44 mmol, 100% yield, 99% purity) as a pale yellow viscous oil. UPLC-MS (Method 2) m / z 303.3 (M+H) at 1.59 min. + .

[0658] Step 2: 2-(5-oxa-2-azaspiro[3.4]oct-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 placed in Thales Nano Hydrogenation was performed in a flow reactor (10% Pd / C, 30 × 4 mm, all-hydrogen mode, 40 °C, flow rate 1 mL / min, 2 passes). The reaction mixture was concentrated under vacuum and azeotropically reacted with MeOH (6 mL) to give the title compound as a white solid (198 mg, 0.691 mmol, yield 96%, purity 95%). UPLC-MS (Method 2) showed m / z 273.3 (M+H) at 1.37 min. + .

[0659] Step 3: Methyl 3-(N-(2-(5-oxa-2-azaspiro[3.4]oct-2-yl)-5-(trifluoromethyl)phenyl)aminosulfonyl)-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 column, 0-100% EtOAc / isohexane) to give the title compound as a white solid (93.7 mg, 0.178 mmol, yield 70.0%, purity 95%). UPLC-MS (Method 1) m / z 501.4 (M+H) at 1.54 min + 498.8 (MH) - .

[0660] Step 4: 3-(N-(2-(5-oxa-2-azaspiro[3.4]oct-2-yl)-5-(trifluoromethyl)phenyl)aminosulfonyl)-4-methoxybenzoic acid: The product from 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 under vacuum, 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 obtain a turbid solution. The white precipitate was collected by filtration, washed with water, and the solid was suspended in MeCN (4 ml), concentrated under vacuum, 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 aqueous solution) to give the title compound as a fluffy white solid (3 mg, 5.98 μmol, yield 3.25%, purity 97%). UPLC-MS (Method 1) showed a m / z of 487.0 (M+H) at 1.37 min. + 485.2 (MH) - . 1 ¹H NMR (500 MHz, methanol-d⁴) δ 8.33 (d, J = 2.2 Hz, 1H), 8.29 (dd, J = 8.7, 2.2 Hz, 1H), 7.35 (d, J = 8.7 Hz, 1H), 7.30 (dd, J = 8.6, 2.2 Hz, 1H), 6.70 (d, J = 2.1 Hz, 1H), 6.55 (d, J = 8.6 Hz, 1H), 4.21 (d, J = 9.0 Hz, 2H), 4.08 (d, J = 9.0 Hz, 2H), 4.02 (s, 3H), 3.88 (t, J = 7.0 Hz, 2H), 2.20 (t, J = 7.0 Hz, 2H), 2.00 (p, J = 7.0 Hz, 2H). No two exchangeable protons were observed.

[0661] Example 12: 3-(N-(2-(4,4-difluoropiperidin-1-yl)-5-(trifluoromethyl)phenyl)aminosulfonyl)-4-methoxybenzoic acid

[0662]

[0663] Step 1: 4,4-Difluoro-1-(2-nitro-4-(trifluoromethyl)phenyl)piperidine: Et3N (0.47 mL, 3.37 mmol) was added to a DCM (5 mL) solution of 1-fluoro-2-nitro-4-(trifluoromethyl)benzene (0.188 mL, 1.34 mmol) and 4,4-difluoropiperidine (196 mg, 1.62 mmol), 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 the solution was concentrated under vacuum to give the title compound as an orange oil (434 mg, 1.04 mmol, yield 77%, purity 74%). UPLC (Method 2) 1.67 min. 1 H NMR (500MHz, DMSO-d6) 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).

[0664] Step 2: 2-(4,4-Difluoropiperidin-1-yl)-5-(trifluoromethyl)aniline: Dissolve the product from Step 1 (180 mg, 0.580 mmol) in EtOH (23.2 ml), and transfer the reaction mixture to Thales Nano Hydrogenation was performed in a flow reactor (10% Pd / C, 30 × 4 mm, all-hydrogen mode, 21 °C, flow rate 1 mL / min, single pass). The reaction mixture was concentrated under vacuum and azeotropically reacted with MeOH (8 mL) to give the title compound as a creamy white solid (159 mg, 0.545 mmol, yield 94%, purity 96%). UPLC-MS (Method 2) showed m / z 281.3 (M+H) at 1.63 min. + . 1 H NMR (500MHz, DMSO-d6) 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).

[0665] Step 3: Methyl 3-(N-(2-(4,4-difluoropiperidin-1-yl)-5-(trifluoromethyl)phenyl)aminosulfonyl)-4-methoxybenzoate: At room temperature, pyridine (0.058 mL, 0.718 mmol) was added to a DCM (2.0 mL) solution of the product from Step 2 (69.8 mg, 0.239 mmol) and methyl 3-(chlorosulfonyl)-4-methoxybenzoate (80 mg, 0.287 mmol). The reaction mixture was stirred and heated at 40 °C for 18 h. An additional methyl 3-(chlorosulfonyl)-4-methoxybenzoate (33 mg, 0.120 mmol) was added, and the resulting solution was stirred again at 40 °C for 3 h. The reaction mixture was concentrated under vacuum, and the crude product was purified by silica gel column chromatography (10 g column, 0-30% EtOAc / isohexane) to give the title compound as a creamy white solid (107 mg, 0.196 mmol, yield 82%, purity 93%). UPLC-MS (Method 2) at 1.72 min, m / z 509.3 (M+H). + 507.2 (MH) - .

[0666] Step 4: 3-(N-(2-(4,4-difluoropiperidin-1-yl)-5-(trifluoromethyl)phenyl)aminosulfonyl)-4-methoxybenzoic acid: At room temperature, 1M LiOH (aq) (0.632 mL, 0.632 mmol) was added to a THF (1.26 mL) solution of the product (107 mg, 0.210 mmol) from Step 3 above. The resulting clear solution was stirred at room temperature for 20 h. Another 1M LiOH (aq) (0.211 mL, 0.211 mmol) was added, and the solution was stirred for another 1 h. The reaction mixture was concentrated under vacuum, and the residue was redissolved in water (3 mL) and acidified to pH 4 to 5 using 1M 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 using a phase separator and concentrated under vacuum. The crude product was purified by silica gel column chromatography (10 g column, 0 to 3.5% MeOH / DCM) to give an off-white solid (40.1 mg). The product was further 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% aqueous MeCN) to give the title compound as a white solid (19 mg, 0.038 mmol, yield 18.3%, purity 100%). UPLC-MS (Method 1) showed a m / z of 495.3 (M+H) at 1.61 min. + 493.2 (MH)- . 1 H NMR(500MHz,DMSO-d6)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).

[0667] Example 13: 3-(N-(2-(8-hydroxy-3-azabicyclo[3.2.1]oct-3-yl)-5-(trifluoromethyl)phenyl)aminosulfonyl)-4-methoxybenzoic acid

[0668]

[0669] Step 1: 3-(2-nitro-4-(trifluoromethyl)phenyl)-3-azabicyclo[3.2.1]oct-8-ol: Et3N (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]oct-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 under vacuum to give the title compound as a light orange solid (468 mg, 1.44 mmol, 100% yield, 97% purity). UPLC-MS (Method 2) 1.53 min m / z 315.1 (MH) - .

[0670] Step 2: 3-(2-amino-4-(trifluoromethyl)phenyl)-3-azabicyclo[3.2.1]oct-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 placed in Thales Nano Hydrogenation was performed in a flow reactor (10% Pd / C, 30 × 4 mm, all-hydrogen, 40 °C, flow rate 1 mL / min, 2 passes). The reaction mixture was concentrated under vacuum and azeotropically reacted with MeOH (6 mL) to give the title compound as a light pink solid (186 mg, 0.585 mmol, yield 81%, purity 90%). UPLC-MS (Method 2) showed m / z 287.3 (M+H) at 1.38 min. +285.2 (MH) - .

[0671] Step 3: Methyl 3-(N-(2-(8-hydroxy-3-azabicyclo[3.2.1]oct-3-yl)-5-(trifluoromethyl)phenyl)aminosulfonyl)-4-methoxybenzoate: The product from 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 column, 0-100% EtOAc / isohexane) to give the title compound as a white solid (51 mg, 0.087 mmol, yield 39.6%, purity 88%). UPLC-MS (Method 1) m / z 515.4 (M+H) at 1.60 min + , 513.2 (MH) - .

[0672] Step 4: 3-(N-(2-(8-hydroxy-3-azabicyclo[3.2.1]oct-3-yl)-5-(trifluoromethyl)phenyl)aminosulfonyl)-4-methoxybenzoic acid: The product from 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 under vacuum, 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 with 1 M HCl to about pH 6. The resulting block suspension was sonicated to obtain a turbid solution, which was concentrated under vacuum 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 under vacuum, then dried at 45 °C to give the title compound as a white solid (21.9 mg, 0.042 mmol, yield 44.6%, purity 97%). UPLC-MS (Method 1) showed m / z 501.3 (M+H) at 1.42 min. + 499.2 (MH) - . 1H NMR (500MHz, DMSO-d6) 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).

[0673] The following examples were prepared by a method similar to that of Example 13, with appropriate starting materials and intermediates substituted where necessary:

[0674]

[0675]

[0676]

[0677]

[0678]

[0679]

[0680] Example 29: 3-(N-(2-(3-hydroxy-3-methylpiperidin-1-yl)-5-(trifluoromethyl)phenyl)aminosulfonyl)-4-methoxybenzoic acid

[0681]

[0682] Step 1: 3-Methyl-1-(2-nitro-4-(trifluoromethyl)phenyl)piperidin-3-ol: At room temperature, Et3N (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 1 M HCl (aq) (3 mL), dried through a phase separator, and concentrated under vacuum to give the title compound as a red / orange oil (452 ​​mg, 1.35 mmol, yield 94%, purity 91%). UPLC-MS (Method 1) m / z 305.2 (M+H) at 1.49 min. + . 1H NMR (500MHz, DMSO-d6) 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),3.0 8(ddd,J=12.8,8.3,3.2Hz,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).

[0683] Step 2: 1-(2-amino-4-(trifluoromethyl)phenyl)-3-methylpiperidin-3-ol: At room temperature, a solution of 0.5 mL of EtOH (50 mg, 0.012 mmol) of 5% Pd / C (50% w / w water) of type 87L was added to a solution of EtOH (3.0 mL) of the product from Step 1 (224 mg, 0.670 mmol). The reaction mixture was hydrogenated at 4 bar and room temperature for 19 h. The catalyst was removed by filtration and washing with MeOH (20 ml). The organic phase was concentrated under vacuum, and the residue was redissolved in EtOAc (10 ml). The organic phase was washed with water (5 ml), dried over MgSO4, filtered, and concentrated under vacuum to give the title compound as a pale orange solid (112 mg, 0.404 mmol, yield 60.3%, purity 99%). UPLC-MS (Method 1) at 1.42 min, m / z 275.3 (M+H). + . 1 H NMR (500MHz, DMSO-d6) 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).

[0684] Step 3: Methyl 3-(N-(2-(3-hydroxy-3-methylpiperidin-1-yl)-5-(trifluoromethyl)phenyl)aminosulfonyl)-4-methoxybenzoate: At room temperature, pyridine (0.075 mL, 0.933 mmol) was added to a turbid solution of the product from Step 2 (64.6 mg, 0.233 mmol) and methyl 3-(chlorosulfonyl)-4-methoxybenzoate (78 mg, 0.280 mmol) in DCM (2.0 mL). The resulting clear solution was stirred at room temperature for 20 h. The reaction mixture was concentrated under vacuum, and the crude product was purified by silica gel column chromatography (12 g column, 30% to 100% EtOAc / isohexane) to give the title compound as a milky white foam (98.5 mg, 0.196 mmol, yield 84%, purity 100%). UPLC-MS (Method 1) m / z 503.4 (M+H) at 1.66 min + 501.2 (MH) - .

[0685] Step 4: 3-(N-(2-(3-hydroxy-3-methylpiperidin-1-yl)-5-(trifluoromethyl)phenyl)aminosulfonyl)-4-methoxybenzoic acid: At room temperature, 1 M LiOH (aq) (0.784 mL, 0.784 mmol) was added to a THF (1.57 mL) solution of the product from Step 3 (98.5 mg, 0.196 mmol). The solution was stirred at room temperature for 18 h and then concentrated under vacuum. The residue was redissolved in water (3 mL) and acidified to pH 4 to 5 with 1 M HCl (aq). The precipitate was separated by filtration and then dissolved in EtOAc (5 mL). The organic phase was washed with water (3 mL), dried over MgSO4, filtered, and concentrated under vacuum to give the title compound as a white solid (64 mg, 0.130 mmol, yield 73.4%, purity 99%). UPLC-MS (Method 1) m / z 489.4 (M+H) at 1.49 min + 487.3 (MH) - . 1H NMR(500MHz,DMSO-d6)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).

[0686] Example 30: 3-(N-(2-(cis-3,5-dimethylpiperidin-1-yl)-5-(trifluoromethyl)phenylaminosulfonyl)-4-ethylbenzoic acid

[0687]

[0688] A solution of DCM (1 ml) of the product (72 mg, 0.264 mmol) from step 2 of Example 6 and pyridine (0.128 ml, 1.59 mmol) was added to a suspension of DCM (1 ml) of the product (79 mg, 0.317 mmol) from step 1 of Example 1, and the solution was stirred at room temperature for 4 days. The crude product was purified directly by silica gel column chromatography (12 g column, 0-10% MeOH / DCM). The product obtained by chromatography was partitioned between isohexane (3 ml) and MeCN (3 ml). The phases were separated, and the MeCN phase was washed with isohexane (2 × 3 ml) and concentrated under vacuum. The product was loaded onto a silica column with a minimal amount of DCM and eluted with DCM (5 mL), isohexane (5 mL), a 5% MeOH solution in EtOAc (5 mL), and then another 5% MeOH solution in EtOAc (5 mL) to give the title compound as a white solid (26.7 mg, 0.052 mmol, yield 19.80%, purity 95%). UPLC-MS (Method 1) at 2.06 min showed m / z 485.4 (M+H). + 483.3 (MH) - . 1¹H NMR (500 MHz, methanol-d⁴) δ 8.54 (d, J = 1.8 Hz, 1H), 8.15 (dd, J = 8.0, 1.8 Hz, 1H), 7.59 (d, J = 2.0 Hz, 1H), 7.55 (d, J = 8.0 Hz, 1H), 7.36–7.27 (m, 2H), 3.07 (q, J = 7.5 Hz, 2H), 2.79–2.72 (m, 2H), 2.18 (t, J = 11.1 Hz, 2H), 1.89–1.76 (m, 3H), 1.28 (t, J = 7.5 Hz, 3H), 0.90 (d, J = 6.5 Hz, 6H), 0.75–0.64 (m, 1H). No exchangeable protons were observed.

[0689] Example 31: 3-(N-(2-(2,2-dimethylpiperidin-1-yl)-5-(trifluoromethyl)phenyl)aminosulfonyl)-4-methoxybenzoic acid

[0690]

[0691] Step 1: 2,2-Dimethyl-1-(2-nitro-4-(trifluoromethyl)phenyl)piperidine: Et3N (0.500 mL, 3.59 mmol) was added to a solution of 2,2-dimethylpiperidine (195 mg, 1.72 mmol) and 1-fluoro-2-nitro-4-(trifluoromethyl)benzene (0.201 mL, 1.44 mmol) in DCM (6 mL), and the resulting solution was stirred at room temperature for 96 h. Additional 2,2-dimethylpiperidine (75 mg, 0.663 mmol) was added, and the reaction was stirred at room temperature for 1 day. Water (3 mL) was added, and the phases were separated. The aqueous phase was then extracted with DCM (2 × 3 mL). The organic phases were combined, dried using a phase separator, and concentrated under vacuum. The crude product was purified by silica gel column chromatography (12 g column, 0-100% EtOAc / isohexane) to give the title compound as a deep orange viscous oil (163 mg, 0.512 mmol, yield 35.7%, purity 95%). UPLC-MS (Method 2) at 1.96 min, m / z 303.3 (M+H) + .

[0692] Step 2: 2-(2,2-Dimethylpiperidin-1-yl)-5-(trifluoromethyl)aniline: At room temperature, iron powder (297 mg, 5.33 mmol) was added to the product of Step 1 above (161 mg, 0.533 mmol) and ammonium chloride (34.2 mg, 0.639 mmol) in a solution of IPA (5 ml) and water (2.5 ml). 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 again at 90 °C for 2 h, then cooled to room temperature. The reaction mixture was then... Filter, wash with excess MeOH (100 ml), and concentrate under vacuum. Resolve the residue in DCM (25 ml) and wash with water (5 ml). Extract the aqueous phase with DCM (2 × 5 ml), wash the combined organic phases with brine (10 ml), dry with MgSO4, filter, and concentrate under vacuum to give the title compound as a pale yellow oil (78 mg, 0.215 mmol, yield 40.3%, purity 75%). UPLC-MS (Method 2) m / z 273.3 (M+H) at 1.95 min. + .

[0693] Step 3: Methyl 3-(N-(2-(2,2-dimethylpiperidin-1-yl)-5-(trifluoromethyl)phenyl)aminosulfonyl)-4-methoxybenzoate: The product from Step 2 (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 column, 0-100% EtOAc / isohexane) to give the title compound as a white viscous solid (64 mg, 0.121 mmol, yield 64.3%, purity 100%). UPLC-MS (Method 1) m / z 501.4 (M+H) at 1.95 min + 499.1 (MH) - .

[0694] Step 4: 3-(N-(2-(2,2-dimethylpiperidin-1-yl)-5-(trifluoromethyl)phenyl)aminosulfonyl)-4-methoxybenzoic acid: The product from 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, then cooled to room temperature overnight. The reaction mixture was diluted with water (3 ml), concentrated under vacuum, and the resulting aqueous solution was diluted with water (5 ml). 1 M HCl (aq) was added dropwise to approximately pH 6. The resulting white precipitate was collected by filtration and washed with water. The solid was suspended in MeCN (4 ml), concentrated under vacuum, and dried at 45 °C to give the title compound as a white solid (57 mg, 0.111 mmol, 90% yield, 99% purity). UPLC-MS (Method 1) at 1.80 min: m / z 487.3 (M+H) + 485.2 (MH) - . 1 H NMR(500MHz,DMSO-d6)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).

[0695] Example 32: 3-(N-(2-(1,4-oxazacycloheptane-4-yl)-5-(trifluoromethyl)phenyl)aminosulfonyl)-4-methoxybenzoic acid

[0696]

[0697] Step 1: 4-(2-nitro-4-(trifluoromethyl)phenyl)-1,4-oxazacycloheptane: Et3N (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-oxazacycloheptane 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 through a phase separator, and concentrated under vacuum to give the title compound as a viscous orange oil (429 mg, 1.14 mmol, 98% yield, 95% purity). UPLC-MS (Method 2) m / z 290.8 (M+H) at 1.48 min. + .

[0698] Step 2: 2-(1,4-oxazacycloheptane-4-yl)-5-(trifluoromethyl)aniline: At room temperature, iron powder (822 mg, 14.71 mmol) was added to the product of Step 1 above (427 mg, 1.471 mmol) and ammonium chloride (94 mg, 1.765 mmol) in a solution of IPA (5 ml) and water (2.5 ml). The resulting suspension was heated and stirred at 90 °C for 1 h, then cooled to room temperature. The reaction mixture was passed through... Filter, wash with excess MeOH (100 ml), and concentrate under vacuum. Resolve the residue in DCM (25 ml) and wash with water (5 ml). Extract the aqueous phase with DCM (2 × 5 ml), wash the combined organic phases with brine (10 ml), dry with MgSO4, filter, and concentrate under vacuum. Purify the crude product by silica gel column chromatography (12 g column, 0-100% EtOAc / isohexane) to give the title compound as a deep orange solid (186 mg, 0.700 mmol, yield 47.6%, purity 98%). UPLC-MS (Method 2) m / z 261.3 (M+H) at 1.39 min. + .

[0699] Step 3: Methyl 3-(N-(2-(1,4-oxazacycloheptane-4-yl)-5-(trifluoromethyl)phenyl)aminosulfonyl)-4-methoxybenzoate: The product from Step 2 (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 column, 0-100% EtOAc / isohexane) to give the title compound as a paste solid (66 mg, 0.132 mmol, yield 70.1%, purity 98%). UPLC-MS (Method 1) showed m / z 489.3 (M+H) at 1.59 min. + 487.2 (MH) - .

[0700] Step 4: 3-(N-(2-(1,4-oxazacycloheptane-4-yl)-5-(trifluoromethyl)phenyl)aminosulfonyl)-4-methoxybenzoic acid: The product from Step 3 (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. The reaction mixture was heated at 40 °C for 4 h, then cooled to room temperature overnight. The reaction mixture was diluted with water (3 ml), concentrated under vacuum, 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 blocky suspension was sonicated to obtain a turbid solution, and the white precipitate was collected by filtration and washed with water. The solid was suspended in MeCN (4 ml), concentrated under vacuum, and dried at 45 °C to give the title compound as a pale gray solid (60 mg, 0.120 mmol, yield 92%, purity 95%). UPLC-MS (Method 1) showed a m / z of 475.4 (M+H) at 1.43 min. + 473.3 (MH) - . 1H NMR(500MHz,DMSO-d6)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).

[0701] Example 33: 3-(N-(2-(spiro[isobenzofuran-1,4′-piperidin]-1′-yl)-5-(trifluoromethyl)phenyl)aminosulfonyl)-4-methoxybenzoic acid

[0702]

[0703] Step 1: 1′-(2-nitro-4-(trifluoromethyl)phenyl)spiro[isobenzofuran-1,4′-piperidine]: At room temperature, Et3N (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 through a phase separator and concentrated under vacuum to give the title compound as an orange oil (536 mg, 0.907 mmol, yield 76%, purity 64%). UPLC-MS (Method 1) m / z 379.2 (M+H) at 1.91 min. + . 1 H NMR (500MHz, DMSO-d6) 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).

[0704] Step 2: 2-(spiro[isobenzofuran-1,4′-piperidin]-1′-yl)-5-(trifluoromethyl)aniline: Iron powder (335 mg, 6.00 mmol) was added to the product of Step 1 above (227 mg, 0.600 mmol) and ammonium chloride (38.5 mg, 0.720 mmol) in a solution of 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 under vacuum, dissolved 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 under vacuum. The crude product was purified by silica gel column chromatography (12 g column, 0 to 35% EtOAc / isohexane) to give the title compound as an orange powder (144 mg, 0.401 mmol, yield 66.8%, purity 97%). UPLC-MS (Method 1) showed m / z 349.2 (M+H) at 1.83 min. + . 1 H NMR (500MHz, DMSO-d6) 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),5.2 2(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).

[0705] Step 3: Methyl 3-(N-(2-(spiro[isobenzofuran-1,4′-piperidin]-1′-yl)-5-(trifluoromethyl)phenyl)aminosulfonyl)-4-methoxybenzoate: At room temperature, pyridine (0.058 ml, 0.718 mmol) was added to a DCM (2 ml) solution of the product from Step 2 above (86 mg, 0.239 mmol) and methyl 3-(chlorosulfonyl)-4-methoxybenzoate (80 mg, 0.287 mmol). The reaction mixture was stirred and heated at 40 °C for 18 h. An additional methyl 3-(chlorosulfonyl)-4-methoxybenzoate (33 mg, 0.120 mmol) was added, and the reaction mixture was stirred again at 40 °C for 3 h. The reaction mixture was concentrated under vacuum, and the crude product was purified by silica gel column chromatography (25 g column, 0 to 45% EtOAc / isohexane) to give the title compound as a creamy white solid (117 mg, 0.187 mmol, yield 78%, purity 92%). UPLC-MS (Method 2) showed m / z 577.4 (M+H) at 1.89 min. + 575.2, (MH) - .

[0706] Step 4: 3-(N-(2-(spiro[isobenzofuran-1,4′-piperidin]-1′-yl)-5-(trifluoromethyl)phenyl)aminosulfonyl)-4-methoxybenzoic acid: At room temperature, 1 M LiOH (aq) (0.812 mL, 0.812 mmol) was added to a THF (1.6 mL) solution of the product from Step 3 (117 mg, 0.203 mmol). The solution was stirred at room temperature for 25 h, then concentrated under vacuum. The residue was redissolved in water (3 mL) and acidified to pH 4-5 with 1 M HCl (aq). The precipitate was separated by filtration and dried under vacuum to give the title compound as a creamy white solid (92 mg, 0.164 mmol, yield 81%, purity 94%). UPLC-MS (Method 1) m / z 563.3 (M+H) at 1.80 min. + 561.1 (MH) - . 1 ¹H NMR (500MHz, DMSO-d⁶) δ 9.02 (brs, ¹H), 8.39 (d, J = 2.3 Hz, ¹H), 8.15 (dd, J = 8.7, 2.2 Hz, ¹H), 7.51 (d, J = 1.7 Hz, ¹H), 7.39–7.27 (m, 7H), 5.02 (s, 2H), 3.88 (s, 3H), 3.01 (t, J = 11.9 Hz, 2H), 2.96–2.90 (m, 2H), 2.19–2.08 (m, 2H), 1.73–1.65 (m, 2H). No exchangeable protons were observed.

[0707] The following examples were prepared by a method similar to that of Example 33, with appropriate starting materials and intermediates substituted where necessary:

[0708]

[0709]

[0710]

[0711] Example 41: 4-Methoxy-3-(N-(2-(2-oxopiperidin-1-yl)-5-(trifluoromethyl)phenyl)aminosulfonyl)benzoic acid

[0712]

[0713] Step 1: 1-(2-nitro-4-(trifluoromethyl)phenyl)piperidin-2-one: NaH (63.1 mg, 1.58 mmol, 60% w / w mineral oil solution) was added to an anhydrous DMF (3 ml) solution of piperidin-2-one (142 mg, 1.44 mmol) at N2 and 0 °C. The reaction was stirred at this temperature for 10 min, and then an anhydrous DMF (3 ml) solution of 1-fluoro-2-nitro-4-(trifluoromethyl)benzene (0.201 ml, 1.44 mmol) was added dropwise at 0 °C. The reaction was stirred overnight at room temperature. The reaction mixture was diluted with EtOAc (100 ml) and washed successively with water (50 ml) and brine (2 × 50 ml). The organic phase was separated, dried over MgSO4, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (12 g column, 0-100% EtOAc / isohexane) to give the title compound as a pale yellow solid (245 mg, 0.808 mmol, yield 56.3%, purity 100%). UPLC-MS (Method 2) at 1.23 min showed m / z 289.5 (M+H). + .

[0714] Step 2: 1-(2-amino-4-(trifluoromethyl)phenyl)piperidin-2-one: At room temperature, iron powder (508 mg, 9.09 mmol) was added to the product of Step 1 above (131 mg, 0.455 mmol) and ammonium chloride (29.2 mg, 0.545 mmol) in a suspension of propan-2-ol (5 ml) and water (2.5 ml). The resulting suspension was heated and stirred at 90 °C for 2 h. The reaction was carried out by... The sample was filtered, washed with excess MeOH (100 ml), and concentrated under vacuum. The residue was redissolved in DCM (25 ml), washed successively with water (10 ml) and brine (10 ml), dried over MgSO4, filtered, and concentrated under vacuum. The crude product was purified by silica gel column chromatography (12 g column, 0-100% EtOAc / isohexane) to give the title compound as a paste solid (22 mg, 0.076 mmol, yield 16.7%, purity 89%). UPLC-MS (Method 2) at 1.07 min, m / z 259.3 (M+H). + .

[0715] Step 3: Methyl 4-methoxy-3-(N-(2-(2-oxopiperidin-1-yl)-5-(trifluoromethyl)phenyl)aminosulfonyl)benzoate: The product from Step 2 (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. Then, 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 column, 0-100% EtOAc / isohexane) to give the title compound as a white solid (18.6 mg, 0.037 mmol, yield 43.5%, purity 97%). UPLC-MS (Method 1) showed a m / z of 487.6 (M+H) at 1.40 min. + 484.8 (MH) - .

[0716] Step 4: 4-Methoxy-3-(N-(2-(2-oxopiperidin-1-yl)-5-(trifluoromethyl)phenyl)aminosulfonyl)benzoic acid: The product from 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 mixture was stirred at room temperature for 1 day, and then MeOH was added dropwise until the mixture became a solution. The reaction mixture was heated at 40 °C for 20 h and then cooled to room temperature. The reaction mixture was diluted with water (3 ml), concentrated under vacuum, and the resulting aqueous solution was diluted with water (to ~5 ml) and neutralized with 1 M HCl to ~pH 6. The white precipitate was collected by filtration and washed with water. The solid was suspended in MeCN (4 ml), concentrated under vacuum, and dried at 45 °C to give the title compound as a pale yellow solid (17.1 mg, 0.034 mmol, 90% yield, 95% purity). UPLC-MS (Method 1) m / z 473.0 (M+H) at 1.23 min + 471.1 (MH) - . 1 H NMR (500MHz, DMSO-d6) 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).

[0717] Example 42: 3-(N-(2-(1,4-oxazacycloheptane-4-yl)-5-(trifluoromethyl)phenyl)aminosulfonyl)-4-methylbenzoic acid

[0718]

[0719] The product of step 2 of Example 32 (62 mg, 0.238 mmol) in DCM (1 ml) and a solution of pyridine (0.116 ml, 1.43 mmol) were 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 column, 0-10% MeOH / DCM) to give a paste solid (23 mg). 8 mg of the crude 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), a 5% MeOH solution in EtOAc (5 ml), and then a 20% MeOH solution in EtOAc (5 ml) to give the title compound as a white solid (7.0 mg, 0.015 mmol, yield 6.09%, purity 95%). UPLC-MS (Method 1) m / z 459.4 (M+H) at 1.64 min + 457.3 (MH) - . 1 ¹H NMR (500MHz, methanol-d⁴) δ 8.58 (d, J = 2.1 Hz, 1H), 8.48 (s, 1H), 8.00 (dd, J = 7.9, 2.1 Hz, 1H), 7.52–7.42 (m, 3H), 3.97 (t, J = 6.2 Hz, 2H), 3.94–3.89 (m, 2H), 3.28–3.22 (m, 4H), 2.79 (s, 3H), 2.15–2.07 (m, 2H). No two exchangeable protons were observed.

[0720] Example 43: 3-(N-(2-(1,4-oxazacycloheptane-4-yl)-5-(trifluoromethyl)phenyl)aminosulfonyl)-4-ethylbenzoic acid

[0721]

[0722] A solution of DCM (1 ml) of the product (62 mg, 0.238 mmol) from step 2 of Example 32 and a solution of pyridine (0.116 ml, 1.429 mmol) were added to a solution of DCM (1 ml) of the product (71.1 mg, 0.286 mmol) from step 1 of Example 1, and the solution was stirred at room temperature for 4 days. The crude product was purified directly by silica gel column chromatography (12 g column, 0-10% MeOH / DCM) to obtain a paste-like solid. The paste-like solid was loaded onto a silica column with a minimal amount of DCM and eluted sequentially with DCM (5 ml), isohexane (5 ml), a 5% MeOH solution in EtOAc (5 ml), and then a 5% MeOH solution in EtOAc (5 ml) to give the title compound as a white solid (11.7 mg, 0.024 mmol, yield 9.87%, purity 95%). UPLC-MS (Method 1) m / z 473.4 (M+H) at 1.61 min + 471.2 (MH) - . 1 ¹H NMR (500 MHz, methanol-d⁴) δ 8.53 (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). No two exchangeable protons were observed.

[0723] Example 46: 4-Methoxy-3-(N-(2-(2-(3-methylisoxazo-5-yl)pyrrolidine-1-yl)-5-(trifluoromethyl)phenyl)aminosulfonyl)benzoic acid

[0724]

[0725] Step 1: 3-Methyl-5-(1-(2-nitro-4-(trifluoromethyl)phenyl)pyrrolidine-2-yl)isoxazole: Et3N (302 mg, 2.99 mmol) was added to a DCM (5 mL) solution of 1-fluoro-2-nitro-4-(trifluoromethyl)benzene (0.167 mL, 1.20 mmol) and 3-methyl-5-(pyrrolidine-2-yl)isoxazole (218 mg, 1.44 mmol), and the resulting solution was stirred at room temperature for 19 h. Water (2.5 mL) was added, and the organic phase was dried through a phase separator and concentrated under vacuum to give the title compound as a yellow oil (489 mg, 1.19 mmol, yield 99%, purity 83%). UPLC-MS (Method 2) m / z 342.4 (M+H) at 1.61 min. + . 1 H NMR (500MHz, DMSO-d6) 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=7.3 Hz,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).

[0726] Step 2: 2-(2-(3-methylisoxazol-5-yl)pyrrolidine-1-yl)-5-(trifluoromethyl)aniline: At room temperature, ammonium hydroxide (28% AQ solution) (0.319 mL, 2.30 mmol) and sodium dithionite (1.18 g, 5.74 mmol) were added to the product of Step 1 above (236 mg, 0.574 mmol) in a solution of THF (2.5 mL) and water (2.5 mL), and then stirred at room temperature for 2 h. The reaction mixture was concentrated under vacuum, 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 under vacuum. The crude product was purified by silica gel column chromatography (10 g column, 0-50% EtOAc / isohexane) to give the title compound as a red / brown oil (95 mg, 0.302 mmol, yield 52.6%, purity 99%). UPLC-MS (Method 1) at 1.52 min, m / z 312.1 (M+H). + . 1H NMR (500MHz, DMSO-d6) 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).

[0727] Step 3: Methyl 4-methoxy-3-(N-(2-(2-(3-methylisoxazol-5-yl)pyrrolidine-1-yl)-5-(trifluoromethyl)phenyl)aminosulfonyl)benzoate: At room temperature, pyridine (0.069 mL, 0.852 mmol) was added to a solution of the product from Step 2 (88 mg, 0.284 mmol) and methyl 3-(chlorosulfonyl)-4-methoxybenzoate (95 mg, 0.341 mmol) in DCM (2.5 mL). The reaction mixture was stirred at room temperature for 65 h, 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 under vacuum to give the title compound as a creamy white solid (69 mg, 0.123 mmol, yield 43.2%, purity 96%). UPLC-MS (Method 2) m / z 540.3 (M+H) at 1.58 min + 538.2 (MH) - .

[0728] Step 4: 4-Methoxy-3-(N-(2-(2-(3-methylisoxazol-5-yl)pyrrolidine-1-yl)-5-(trifluoromethyl)phenyl)aminosulfonyl)benzoic acid: At room temperature, 1M LiOH (aq) (0.384 mL, 0.384 mmol) was added to a THF (0.768 mL) suspension of the product (69 mg, 0.128 mmol) from Step 3 above. The resulting clear solution was stirred at room temperature for 20 h. Another 1M LiOH (aq) (0.128 mL, 0.128 mmol) was added, and the solution was stirred for another 1 h. The reaction mixture was concentrated under vacuum, and the residue was redissolved in water (2 mL) and acidified with 1M 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 × 3 ml), and the combined organic phases were dried through a phase separator and concentrated under vacuum to give the title compound as a pale yellow solid (47.9 mg, 0.091 mmol, yield 71.3%, purity 97%). UPLC-MS (Method 1) showed a m / z of 526.3 (M+H) at 1.46 min. + 524.2 (MH) - . 1 H NMR(500MHz,DMSO-d6)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).

[0729] Example 49 Methyl ester: methyl 4-methoxy-3-((2-(piperidin-1-yl)-5-(trifluoromethyl)phenyl)sulfonylamino)benzoate

[0730]

[0731] Step 1: Methyl 3-(2-bromo-5-(trifluoromethyl)phenylsulfonylamino)-4-methoxybenzoate: A mixture of 2-bromo-5-(trifluoromethyl)phenyl-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 over the weekend at room temperature. The mixture was concentrated onto silica and purified by silica gel column chromatography (24 g column, 0–100% EtOAc / isohexane) to give the title compound as a pale yellow solid (510 mg, 1.07 mmol, yield 97%, purity 98%). UPLC-MS (Method 2) at 1.43 min m / z 468.0 / 470.0 (M / M+2) + . 1 H NMR (500MHz, DMSO-d6) 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).

[0732] Step 2: Methyl 4-methoxy-3-(2-(piperidin-1-yl)-5-(trifluoromethyl)phenylsulfonamide)benzoate: The mixture of the product from Step 1 (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 continued at 60 °C for 7 hours. Additional piperidine (25 μl, 0.253 mmol) was added, and stirring continued at 60 °C overnight. After cooling to room temperature, the mixture was concentrated under vacuum, and the residue was loaded onto silica and purified by silica gel column chromatography (12 g column, 0-100% EtOAc / isohexane) to give the title compound as a white solid (82 mg, 0.165 mmol, yield 78%, purity 95%). UPLC-MS (Method 2) m / z 473.3 (M+H) at 1.84 min + . 1H NMR (500MHz, DMSO-d6) 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).

[0733] Example 49: 4-Methoxy-3-((2-(piperidin-1-yl)-5-(trifluoromethyl)phenyl)sulfonamide)benzoic acid

[0734]

[0735] The product of step 2 of methyl ester in Example 49 (70 mg, 148 mmol) was mixed with THF (1.25 mL) and 2 M LiOH (aq) (0.25 mL, 0.500 mmol) and stirred overnight at 50 °C. An additional 2 M LiOH (aq) (0.25 mL, 0.500 mmol) was added, and stirring was continued at 50 °C for 5 h. The mixture was diluted with H₂O (5 mL), acidified with 1 M HCl (aq) to approximately pH 4, 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 was removed under vacuum. The residue was loaded onto silica and purified by silica gel column chromatography (4 g column, 0-10% MeOH / DCM), and milled with TBME to give the title compound as a white solid (44.3 mg, 0.093 mmol, yield 62.6%, purity 96%). UPLC-MS (Method 2) m / z 459.3 (M+H) at 1.19 min + 457.2 (MH) - . 1 H NMR (500MHz, DMSO-d6) 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, 2.1Hz, 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).

[0736] General compound A: 4-methoxy-2-((2-(piperidin-1-yl)-5-(trifluoromethyl)phenyl)sulfonamide)benzoic acid

[0737]

[0738] Step 1: Methyl 2-(2-fluoro-5-(trifluoromethyl)phenylsulfonylamino)-4-methoxybenzoate: A mixture of 2-fluoro-5-(trifluoromethyl)phenyl-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 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 give the title compound as a white solid (98 mg, 0.180 mmol, yield 65.4%, purity 75%). UPLC-MS (Method 2) 405.5 μmol / L at 1.67 min. - . 1 H NMR(500MHz,DMSO-d6)δ11.13(s,1H),8.24-8.12(m,2H),7.87(d,J=8.9Hz,1H),7.73 (t,J=9.5Hz,1H),6.94(d,J=2.5Hz,1H),6.83-6.76(m,1H),3.79(s,3H),3.77(s,3H).

[0739] Step 2: Methyl 4-methoxy-2-(2-(piperidin-1-yl)-5-(trifluoromethyl)phenylsulfinylamino)benzoate: A mixture of the product from Step 1 (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 column, 0-50% EtOAc / isohexane) to give the title compound as a white solid (52 mg, 0.109 mmol, yield 60.4%, purity 99%). UPLC-MS (Method 2) m / z 473.3 (M+H) at 2.01 min. + . 1H NMR (500MHz, DMSO-d6) 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).

[0740] Step 3: 4-Methoxy-2-(2-(piperidin-1-yl)-5-(trifluoromethyl)phenylsulfonamide)benzoic acid: The product of Step 2 above (52 mg, 0.109 mmol) and 2 M LiOH (aq) (250 μl, 0.500 mmol) in THF (1.25 mL) were stirred overnight at 50 °C. The mixture was diluted with H2O (2 mL) and acidified with 1 M HCl to approximately 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 column, 0 to 5% MeOH / DCM) to give the title compound as a white solid (14.1 mg, 0.030 mmol, yield 27.1%, purity 96%). UPLC-MS (Method 2) m / z 459.3 (M+H) at 1.22 min. + 457.2 (MH) - . 1 H NMR (500MHz, DMSO-d6) 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).

[0741] The following examples were prepared by a method similar to that used for general compound A, with appropriate starting materials and intermediates substituted where necessary:

[0742]

[0743]

[0744] Example 54 Methyl ester: methyl 4-methoxy-3-(N-(2-(piperidin-1-yl)-5-(trifluoromethyl)phenyl)aminosulfonyl)benzoate

[0745]

[0746] 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 column, 0-50% EtOAc / isohexane) to give an orange oil. The orange oil was further purified by silica gel column chromatography (24 g column, 0-50% EtOAc / isohexane) to give the title compound (0.143 g, 0.294 mmol, yield 71.7%, purity 97%) as a pale yellow, slowly crystalline oil. UPLC-MS (Method 2) m / z 473.2 (M+H) at 1.83 min + 471.1 (MH) - . 1 H NMR(500MHz,DMSO-d6)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).

[0747] Example 54: 4-Methoxy-3-(N-(2-(piperidin-1-yl)-5-(trifluoromethyl)phenyl)aminosulfonyl)benzoic acid

[0748]

[0749] 1 M LiOH (aq) (3 mL, 3.00 mmol) was added to a dioxane (3 mL) solution of the product of methyl ester (0.068 g, 0.144 mmol) from Example 54, 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 1 M HCl (aq), and the product was extracted into EtOAc (3 × 10 mL). The combined organic phases were dried over MgSO4, filtered, and the solvent was removed under vacuum to give the title compound as a creamy white solid (0.047 g, 0.100 mmol, yield 69.8%, purity 98%). UPLC-MS (Method 2) showed m / z 459.2 (M+H) at 1.15 min. + 457.0 (MH) - . 1 H NMR (500MHz, DMSO-d6) δ13.16(s,1H),8.76(s,1H),8.37(d,J=2.2Hz,1H),8.16(dd,J=8.7,2.2Hz,1H),7.45(d,J =1.9Hz,1H),7.38-7.30(m,3H),3.93(s,3H),2.76(t,J=5.3Hz,4H),1.67(p,J=5.3Hz,4H),1.55(p,J=5.3Hz,2H).

[0750] Example 55: 3-(N-(2-(azacycloheptane-1-yl)-5-(trifluoromethyl)phenyl)aminosulfonyl)-4-isopropylbenzoic acid

[0751]

[0752] A solution of 2-(azacycloheptane-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 purified directly by silica gel column chromatography (12 g column, 0-10% MeOH / DCM) to give a pale yellow solid (11.1 mg). Nine mg of the pale yellow solid was loaded onto a silica column with a minimal amount of DCM. The column was eluted with DCM (5 mL), isohexane (5 mL), a 5% MeOH solution in EtOAc (5 mL), and then another 5% MeOH solution in EtOAc (5 mL) to give the title compound as a pale yellow solid (5.4 mg, 10.6 μmol, yield 5.47%, purity 95%). UPLC-MS (Method 2) showed a m / z of 485.4 (M+H) at 1.99 min. + 483.1 (MH) - . 1 ¹H NMR (500 MHz, methanol-d⁴) δ 8.58 (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). No exchangeable protons were observed.

[0753] The following examples were prepared by a method similar to that of Example 55, with appropriate starting materials and intermediates substituted where necessary:

[0754]

[0755]

[0756] Example 64: 4-Methoxy-3-(N-(2-(piperidin-1-yl)phenyl)aminosulfonyl)benzoic acid

[0757]

[0758] Step 1: Methyl 4-methoxy-3-(N-(2-(piperidin-1-yl)phenyl)aminosulfonyl)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 under vacuum, and the crude product was purified by silica gel column chromatography (24 g column, 0-50% EtOAc / isohexane) to give the title compound (0.095 g, 0.169 mmol, yield 71.9%, purity 72%) as a pale yellow, slowly crystalline oil. UPLC-MS (Method 2) m / z 405.2 (M+H) at 1.69 min + 403.4 (MH) - .

[0759] Step 2: 4-Methoxy-3-(N-(2-(piperidin-1-yl)phenyl)aminosulfonyl)benzoic acid: 1 M LiOH (aq) (0.470 mL, 0.470 mmol) was added to a dioxane (3 mL) solution of the product (0.095 g, 0.235 mmol) from Step 1 above, 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 1 M HCl (aq), and the product was extracted into EtOAc (3 × 10 mL). The combined organic phases were dried over MgSO4, filtered, and the solvent was removed under vacuum. The crude product was purified by silica gel column chromatography (12 g column, 0 to 70% EtOAc / isohexane) to give the title compound as a white solid (40 mg, 0.097 mmol, yield 41.4%, purity 95%). UPLC-MS (Method 1) m / z 391.3 (M+H) at 1.41 min + 389.3 (MH) - . 1H NMR (500MHz, DMSO-d6) 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).

[0760] Example 65: 3-(N-(4-chloro-2-(piperidin-1-yl)phenyl)aminosulfonyl)-4-methoxybenzoic acid

[0761]

[0762] Step 1: Methyl 3-(N-(4-chloro-2-(piperidin-1-yl)phenyl)aminosulfonyl)-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 column, 0-50% EtOAc / isohexane) to give the title compound (0.093 g, 0.165 mmol, yield 69.6%) as a pale yellow, slowly crystalline oil. UPLC-MS (Method 2) m / z 439.3 (M+H) at 1.81 min + 437.2 (MH) - .

[0763] Step 2: 3-(N-(4-chloro-2-(piperidin-1-yl)phenyl)aminosulfonyl)-4-methoxybenzoic acid: 1M LiOH (aq) (0.424 mL, 0.424 mmol) was added to a dioxane (3 mL) solution of the product (0.093 g, 0.212 mmol) from Step 1 above, 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 MgSO4, filtered, and the solvent was removed under vacuum. The crude product was purified by silica gel column chromatography (12 g column, 0-80% EtOAc / isohexane) to give the title compound as a white solid (34 mg, 0.076 mmol, yield 35.9%, purity 95%). UPLC-MS (Method 1) showed m / z 425.3 (M+H) at 1.69 min. + 423.2 (MH) - . 1 H NMR (500MHz, DMSO-d6) 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).

[0764] Example 66: 3-(N-(5-chloro-2-(piperidin-1-yl)phenyl)aminosulfonyl)-4-methoxybenzoic acid

[0765]

[0766] Step 1: Methyl 3-(N-(5-chloro-2-(piperidin-1-yl)phenyl)aminosulfonyl)-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 column, 0-50% EtOAc / isohexane) to give the title compound (0.066 g, 0.143 mmol, yield 70.6%, purity 95%) as a pale yellow, slowly crystalline oil. UPLC-MS (Method 2) m / z 439.3 (M+H) at 1.81 min + 437.3 (MH) - .

[0767] Step 2: 3-(N-(5-chloro-2-(piperidin-1-yl)phenyl)aminosulfonyl)-4-methoxybenzoic acid: Add 1M LiOH (aq) (0.301 mL, 0.301 mmol) to a dioxane (3 mL) solution of the product (0.066 g, 0.150 mmol) from Step 1 above, and stir the solution overnight at room temperature. Remove the solvent under vacuum, and redissolve the residue in water (5 mL), and extract with EtOAc (3 × 5 mL). Acidify the aqueous phase with 1M HCl (aq), and extract the product into EtOAc (3 × 10 mL). Dry the combined organic phases with MgSO4, filter, and remove the solvent under vacuum. The crude product was purified by silica gel column chromatography (12 g column, 0 to 70% EtOAc / isohexane) to give the title compound as a white solid (22 mg, 0.049 mmol, yield 32.7%, purity 95%). UPLC-MS (Method 1) showed m / z 425.1 (M+H) at 1.67 min. + 423.2 (MH) - . 1H NMR(500MHz,DMSO-d6)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).

[0768] Example 67: 4-Methyl-3-(N-(2-(piperidin-1-yl)-5-(trifluoromethyl)phenyl)aminosulfonyl)benzoic acid

[0769]

[0770] Step 1: Methyl 4-methyl-3-(N-(2-(piperidin-1-yl)-5-(trifluoromethyl)phenyl)aminosulfonyl)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. An additional methyl 3-(chlorosulfonyl)-4-methylbenzoate (15 mg, 0.060 mmol) was added, and the reaction mixture was stirred again at room temperature for 24 h. The reaction mixture was directly loaded onto silica gel (12 g column, 0-50% EtOAc / isohexane) and purified to give the title compound as a colorless oil that crystallizes upon standing (73 mg, 0.155 mmol, yield 76%, purity 97%). UPLC-MS (Method 1) showed a m / z of 457.1 (M+H) at 1.95 min. + 455.3 (MH) - .

[0771] Step 2: 4-Methyl-3-(N-(2-(piperidin-1-yl)-5-(trifluoromethyl)phenyl)aminosulfonyl)benzoic acid: The product from Step 1 (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 obtain 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 another 24 h. The solution was further diluted with water (2 ml) and concentrated under vacuum. 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, and then adjusted to approximately 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 under vacuum, and dried at 45 °C to give the title compound as a brown powder (55 mg, 0.122 mmol, yield 81%, purity 98%). UPLC-MS (Method 1) showed m / z 443.3 (M+H) at 1.81 min. + 441.3 (MH) - .

[0772] Example 68: 3-(N-(2-(azacycloheptane-1-yl)-5-(trifluoromethyl)phenyl)aminosulfonyl)-4-methoxybenzoic acid

[0773]

[0774] Step 1: Methyl 3-(N-(2-(azacycloheptane-1-yl)-5-(trifluoromethyl)phenyl)aminosulfonyl)-4-methoxybenzoate: 2-(azacycloheptane-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 directly loaded onto silica gel and purified by silica gel column chromatography (12 g column, 0 to 70% EtOAc / isohexane) to give the title compound as a viscous pale yellow solid (44 mg, 0.084 mmol, yield 44.5%, purity 93%). UPLC-MS (Method 1) m / z 487.4 (M+H) at 1.91 min + 485.2 (MH) - .

[0775] Step 2: 3-(N-(2-(azacycloheptan-1-yl)-5-(trifluoromethyl)phenyl)aminosulfonyl)-4-methoxybenzoic acid: The product from Step 1 (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. An additional 1.1 M LiOH (aq) (78 μl, 0.086 mmol) was added, and the reaction mixture was heated to 30 °C and maintained for 18 h. The reaction mixture was diluted with water (3 ml), concentrated under vacuum, 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 block suspension was sonicated to obtain a turbid solution and neutralized with 1 M HCl to about pH 6. 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 MgSO4, filtered, and the solvent was removed under vacuum. The crude product was purified by silica gel column chromatography (12 g column, 0 to 70% EtOAc / isohexane) to give the title compound as a white solid (2.2 mg, 4.42 μmol, yield 5.12%, purity 95%). UPLC-MS (Method 1) showed m / z 473.4 (M+H) at 1.79 min. + 471.1 (MH) - . 1 H NMR(500MHz,DMSO-d6)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).

[0776] Example 69: 4-Chloro-3-(N-(2-(piperidin-1-yl)-5-(trifluoromethyl)phenyl)aminosulfonyl)benzoic acid

[0777]

[0778] Step 1: Methyl 4-chloro-3-(N-(2-(piperidin-1-yl)-5-(trifluoromethyl)phenyl)aminosulfonyl)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 directly loaded onto silica and purified by silica gel column chromatography (12 g column, 0 to 70% EtOAc / isohexane) to give the title compound as a brown solid (45.5 mg, 0.094 mmol, yield 50.3%, purity 98%). UPLC-MS (Method 1) at 2.00 min: m / z 477.3 (M+H) + 475.1 (MH) - .

[0779] Step 2: 4-Chloro-3-(N-(2-(piperidin-1-yl)-5-(trifluoromethyl)phenyl)aminosulfonyl)benzoic acid: The product from Step 1 (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 under vacuum, 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 lumpy suspension was sonicated to obtain a turbid solution and neutralized with 1 M HCl (aq) to about pH 6. 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 dried over MgSO4, filtered, and the solvent was removed under vacuum. The crude product was purified by silica gel column chromatography (12 g column, 0-10% MeOH / DCM) to give the title compound as a white solid (20.5 mg, 0.042 mmol, yield 46.7%, purity 95%). UPLC-MS (Method 1) showed m / z 463.3 (M+H) at 1.88 min. + 461.2 (MH) - . 1H NMR(500MHz,DMSO-d6)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).

[0780] The following examples were prepared by a method similar to that of Example 69, with appropriate starting materials and intermediates substituted where necessary:

[0781]

[0782]

[0783]

[0784]

[0785] Example 161: 4-Hydroxy-3-(N-(2-(piperidin-1-yl)-5-(trifluoromethyl)phenyl)aminosulfonyl)benzoic acid

[0786]

[0787] Step 1: Methyl 4-methoxy-3-(N-(2-(piperidin-1-yl)-5-(trifluoromethyl)phenyl)aminosulfonyl)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 column, 0-50% EtOAc / DCM) to give the title compound as a white solid (0.230 g, 0.433 mmol, yield 81%, purity 89%). UPLC-MS (Method 1) m / z 473.4 (M+H) at 1.86 min + 471.3 (MH) - . 1H NMR (500MHz, DMSO-d6) 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).

[0788] Step 2: Methyl 4-hydroxy-3-(N-(2-(piperidin-1-yl)-5-(trifluoromethyl)phenyl)aminosulfonyl)benzoate: A solution of the product from Step 1 (0.230 g, 0.438 mmol) in DCM (10 ml) was treated with a solution of 1.0 M BBr3 in 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) at 1.7 min, m / z 459 (M+H). + .

[0789] Step 3: 4-Hydroxy-3-(N-(2-(piperidin-1-yl)-5-(trifluoromethyl)phenyl)aminosulfonyl)benzoic acid: Add 1M LiOH (aq) (1.31 mL, 1.31 mmol) to a MeOH (10 mL) solution of the product (0.2 g, 0.436 mmol) from Step 2 above, and stir the solution overnight at room temperature. Remove the solvent under vacuum, and redissolve the residue in water (5 mL), and extract with EtOAc (3 × 5 mL). Acidify the aqueous phase with 1M HCl (aq), and extract the product into EtOAc (3 × 10 mL). Dry the combined organic phases with MgSO4, filter, and remove the solvent under vacuum. The crude product was purified by silica gel column chromatography (24 g column, 0-50% EtOAc / DCM) to give the title compound as a white solid (60 mg, 0.128 mmol, yield 29.4%, purity 95%). UPLC-MS (Method 1) showed m / z 445.3 (M+H) at 1.56 min. + 443.2 (MH) - . 1¹H NMR (500MHz, DMSO-d⁶) δ 12.96 (br s, 1H), 8.29 (d, J = 2.3 Hz, 1H), 7.98 (dd, J = 8.6, 2.3 Hz, 1H), 7.52 (d, J = 1.8 Hz, 1H), 7.37–7.33 (m, 2H), 7.04 (d, J = 8.6 Hz, 1H), 2.75 (t, J = 5.2 Hz, 4H), 1.68 (p, J = 5.5 Hz, 4H), 1.58–1.51 (m, 2H). No two exchangeable protons were observed.

[0790] Example 165: 4-Methoxy-3-(N-methyl-N-(2-(piperidin-1-yl)-5-(trifluoromethyl)phenyl)aminosulfonyl)benzoic acid

[0791]

[0792] Step 1: Methyl 4-methoxy-3-(N-(2-(piperidin-1-yl)-5-(trifluoromethyl)phenyl)aminosulfonyl)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 give the title compound as a white solid (189 mg, 0.384 mmol, yield 94%, purity 96%). UPLC-MS (Method 2) m / z 473.3 (M+H) at 1.80 min. + . 1 H NMR (500MHz, DMSO-d6) δ8.80(s,1H),8.36(d,J=2.2Hz,1H),8.18(dd,J=8.8,2.2Hz,1H),7.44(d,J=2.0Hz,1H ),7.40-7.29(m,3H),3.93(s,3H),3.85(s,3H),2.76(t,J=5.2Hz,4H),1.70-1.61(m,4H),1.59-1.49(m,2H).

[0793] Step 2: Methyl 4-methoxy-3-(N-methyl-N-(2-(piperidin-1-yl)-5-(trifluoromethyl)phenyl)aminosulfonyl)benzoate: At 0 °C, a THF (1 ml) solution of the product from Step 1 (189 mg, 0.384 mmol) was added to a THF (1 ml) suspension of sodium hydride (12 mg, 0.500 mmol). 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 H2O (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 under vacuum. The residue was loaded onto silica gel and purified by silica gel column chromatography (12 g column, 0-50% EtOAc / isohexane) to give the title compound as a clear, colorless oil (172 mg, 0.283 mmol, yield 73.7%, purity 80%). UPLC-MS (Method 2) showed m / z 487.3 (M+H) at 1.83 min. + . 1 H NMR (500MHz, 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).

[0794] Step 3: 4-Methoxy-3-(N-methyl-N-(2-(piperidin-1-yl)-5-(trifluoromethyl)phenyl)aminosulfonyl)benzoic acid: The product of Step 2 above (170 mg, 0.349 mmol) and 2 M LiOH (aq) (0.35 mL, 0.700 mmol) in THF (1.5 mL) were stirred overnight at 50 °C. The mixture was diluted with H2O (5 mL), acidified to approximately pH 4 with 1 M 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 was removed under vacuum. The residue was loaded onto silica and purified by silica gel column chromatography (4 g column, 0-10% MeOH / DCM) to give the title compound as a white solid (66.1 mg, 0.134 mmol, yield 38.3%, purity 96%). UPLC-MS (Method 2) m / z 473.3 (M+H) at 1.17 min + 471.2 (MH) - . 1 H NMR (500MHz, DMSO-d6) 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=8.5 Hz,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).

[0795] Example 171: 2-Methoxy-N-(2-(piperidin-1-yl)-5-(trifluoromethyl)phenyl)-5-(tetrazol-5-yl)benzenesulfonamide

[0796]

[0797] 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 (approximately 0.1 ml) and concentrated under vacuum. The crude product was purified by silica gel column chromatography (12 g column, 0-50% EtOAc / isohexane) to give the title compound as a pale yellow solid (325 mg, 0.717 mmol, yield 88%, purity 99%). UPLC-MS (Method 1) at 1.82 min: m / z 440.4 (M+H) + 438.1 (MH) - .

[0798] Step 2: 2-Methoxy-N-(2-(piperidin-1-yl)-5-(trifluoromethyl)phenyl)-5-(tetraazol-5-yl)benzenesulfonamide: The product from 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 overnight at 80 °C and then concentrated under vacuum. The crude product was purified by silica gel column chromatography (24 g column, 0-100% EtOAc / isohexane, then 0-10% MeOH / DCM) to give the title compound as a white solid (7.9 mg, 0.016 mmol, yield 6.84%, purity 95%). UPLC-MS (Method 1) m / z 483.4 (M+H) at 1.67 min. + 481.2 (MH) - . 1 ¹H NMR (500MHz, DMSO-d⁶) δ 8.79 (s, ¹H), 8.55 (d, J = 2.2 Hz, ¹H), 8.27 (dd, J = 8.7, 2.2 Hz, ¹H), 7.51 (s, ¹H), 7.44 (d, J = 8.8 Hz, ¹H), 7.37–7.33 (m, 2H), 3.94 (s, 3H), 2.78 (t, J = 5.3 Hz, 4H), 1.70–1.65 (m, 4H), 1.57–1.50 (m, 2H). No exchangeable protons were observed.

[0799] Example 177: 3-(N-(2-(3-hydroxypiperidin-1-yl)-5-(trifluoromethyl)phenyl)aminosulfonyl)-4-methoxybenzoic acid

[0800]

[0801] Step 1: 1-(2-nitro-4-(trifluoromethyl)phenyl)piperidine-3-ol: At room temperature, Et3N (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 piperin-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 1 M HCl (3 mL), dried through a phase separator, and concentrated under vacuum to give the title compound as a red / orange oil (468 mg, 1.40 mmol, yield 98%, purity 87%). UPLC-MS (Method 1) m / z 291.5 (M+H) at 1.39 min. + . 1 H NMR(500MHz,DMSO-d6)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).

[0802] Step 2: 1-(2-amino-4-(trifluoromethyl)phenyl)piperidin-3-ol: At room temperature, a solution of 0.5 mL of EtOH (50 mg, 0.012 mmol) of 5% Pd / C (50% w / w water) of type 87L was added to a solution of EtOH (3.0 mL) of the product from Step 1 above (234 mg, 0.701 mmol). The reaction mixture was hydrogenated (4 bar) at room temperature for 19 h. The catalyst was removed by filtration and washing with MeOH (15 ml). The filtrate was concentrated under vacuum, and the residue was dissolved in MeOH (10 ml), dried over MgSO4, filtered, and concentrated under vacuum to give a white solid. MeCN (10 ml) was added, and the resulting slurry was dried over a large excess of MgSO4, filtered, and concentrated under vacuum to give the title compound as a yellow solid (153 mg, 0.576 mmol, yield 82%, purity 98%). UPLC-MS (Method 1) m / z 261.4 (M+H) at 1.29 min. + . 1 H NMR (500MHz, DMSO-d6) 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).

[0803] Step 3: Methyl 3-(N-(2-(3-hydroxypiperidin-1-yl)-5-(trifluoromethyl)phenyl)aminosulfonyl)-4-methoxybenzoate: At room temperature, pyridine (0.075 mL, 0.933 mmol) was added to a turbid solution of the product from 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). The resulting clear solution was stirred at room temperature for 20 h, and the reaction mixture was concentrated under vacuum. The crude product was purified by silica gel column chromatography (10 g column, 0-100% EtOAc / isohexane) to give the title compound as a yellow oil (88.1 mg, 0.177 mmol, yield 76%, purity 98%). UPLC-MS (Method 1) m / z 489.3 (M+H) at 1.59 min + 487.2 (MH) - .

[0804] Step 4: 3-(N-(2-(3-hydroxypiperidin-1-yl)-5-(trifluoromethyl)phenyl)aminosulfonyl)-4-methoxybenzoic acid: At room temperature, 1 M LiOH (aq) (0.707 mL, 0.707 mmol) was added to a THF (1.4 mL) solution of the product from Step 3 above (88.1 mg, 0.177 mmol). The reaction mixture was stirred at room temperature for 18 h, then concentrated under vacuum. The residue was dissolved in water (3 mL) and acidified with 1 M HCl until pH 4 to 5. The precipitate was separated by filtration and then dissolved in EtOAc (5 mL). The organic phase was washed with water (3 mL), dried over MgSO4, filtered, and concentrated under vacuum to give the title compound as a light pink solid (50 mg, 0.104 mmol, yield 59%, purity 99%). UPLC-MS (Method 1) m / z 475.4 (M+H) at 1.38 min + 473.1 (MH) - . 1 H NMR(500MHz,DMSO-d6)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).

[0805] Example 178: (S)-3-(N-(2-(3-hydroxypyrrolidin-1-yl)-5-(trifluoromethyl)phenyl)aminosulfonyl)-4-methoxybenzoic acid

[0806]

[0807] Step 1: (S)-1-(2-nitro-4-(trifluoromethyl)phenyl)pyrrolidine-3-ol: At room temperature, Et3N (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)-pyrrolidine-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 under vacuum to give the title compound as an orange oil (445 mg, 1.37 mmol, yield 95%, purity 85%). UPLC-MS (Method 1) m / z 277.2 (M+H) at 1.33 min. + . 1 HNMR(500MHz,DMSO-d6)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.td,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).

[0808] Step 2: (S)-1-(2-amino-4-(trifluoromethyl)phenyl)pyrrolidine-3-ol: At room temperature, a solution of 0.5 mL of EtOH (50 mg, 0.012 mmol) of 5% Pd / C (50% w / w water) of type 87L was added to a solution of EtOH (3.0 mL) of the product from Step 1 above (220 mg, 0.677 mmol). 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 under vacuum, and the residue was dissolved in DCM (10 ml). The organic phase was washed with water (5 ml), dried over MgSO4, filtered, and concentrated under vacuum to give the title compound as a dark brown oil (134 mg, 0.522 mmol, yield 77%, purity 96%). UPLC-MS (Method 1) m / z 247.3 (M+H) at 1.08 min. + . 1H NMR (500MHz, DMSO-d6) 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).

[0809] Step 3: Methyl (S)-3-(N-(2-(3-hydroxypyrrolidin-1-yl)-5-(trifluoromethyl)phenyl)aminosulfonyl)-4-methoxybenzoate: At room temperature, pyridine (0.075 mL, 0.933 mmol) was added to a turbid solution of the product from 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). The resulting clear solution was stirred at room temperature for 20 h and then concentrated under vacuum. The crude product was purified by silica gel column chromatography (10 g column, 0-100% EtOAc / isohexane) to give the title compound as an orange oil (96.7 mg, 0.196 mmol, yield 84%, purity 96%). UPLC-MS (Method 1) m / z 475.4 (M+H) at 1.35 min + 473.2 (MH) - .

[0810] Step 4: (S)-3-(N-(2-(3-hydroxypyrrolidin-1-yl)-5-(trifluoromethyl)phenyl)aminosulfonyl)-4-methoxybenzoic acid: At room temperature, 1 M LiOH (aq) (0.783 mL, 0.783 mmol) was added to a THF (1.6 mL) solution of the product from Step 3 (96.7 mg, 0.196 mmol). The reaction mixture was stirred at room temperature for 20 h, then concentrated under vacuum. The residue was dissolved in water (3 mL) and acidified with 1 M HCl until pH 4 to 5. The precipitate was separated by filtration and then dissolved in EtOAc (5 mL). The organic phase was washed with water (3 mL), dried over MgSO4, and concentrated under vacuum. The crude product was purified by silica gel column chromatography (10 g column, 0 to 5% MeOH / DCM) to give the title compound as a creamy white solid (22.3 mg, 0.046 mmol, yield 26.3%, purity 96%). UPLC-MS (Method 1) showed a m / z of 461.3 (M+H) at 1.17 min.+ 459.2 (MH) - . 1 H NMR(500MHz,DMSO-d6)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).

[0811] Example 179: 4-Methoxy-3-(N-(2-(3-methoxypiperidin-1-yl)-5-(trifluoromethyl)phenyl)aminosulfonyl)benzoic acid

[0812]

[0813] Step 1: 3-Methoxy-1-(2-nitro-4-(trifluoromethyl)phenyl)piperidine: At room temperature, Et3N (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 1 M HCl (3 mL), dried through a phase separator, and concentrated under vacuum to give the title compound as an orange oil (438 mg, 1.41 mmol, 98% yield, 98% purity). 1 H NMR (500MHz, DMSO-d6) 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= 12.9,4.7Hz,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).

[0814] Step 2: 2-(3-Methoxypiperidin-1-yl)-5-(trifluoromethyl)aniline: At room temperature, a solution of 5% Pd / C (50% w / w water) (50 mg, 0.012 mmol) of EtOH (0.5 mL) was added to a solution of the product from Step 1 (214 mg, 0.689 mmol) of EtOH (3.0 mL). The reaction mixture was hydrogenated at room temperature (4 bar) for 18 h. The catalyst was removed by filtration with EtOH (15 ml). The filtrate was concentrated under vacuum and azeotropically reacted with MeOH (6 ml) to give the title compound as a creamy white solid (151 mg, 0.484 mmol, yield 70%, purity 88%). UPLC-MS (Method 1) showed a m / z of 275.3 (M+H)+ (ES+) at 1.58 min. 1 H NMR (500MHz, DMSO-d6) 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).

[0815] Step 3: Methyl 4-methoxy-3-(N-(2-(3-methoxypiperidin-1-yl)-5-(trifluoromethyl)phenyl)aminosulfonyl)benzoate: At room temperature, pyridine (0.081 mL, 1.01 mmol) was added to a turbid solution of the product from Step 2 (79 mg, 0.252 mmol) and methyl 3-(chlorosulfonyl)-4-methoxybenzoate (80 mg, 0.302 mmol) in DCM (2.0 mL). The resulting clear solution was stirred at room temperature for 18 h and then concentrated under vacuum. The crude product was purified by silica gel column chromatography (10 g column, 0-60% EtOAc / isohexane) to give the title compound as a paste solid (84 mg, 0.167 mmol, yield 66%, purity 100%). UPLC-MS (Method 1) m / z 503.4 (M+H) at 1.77 min. + ,501.2(MH)-.

[0816] Step 4: 4-Methoxy-3-(N-(2-(3-methoxypiperidin-1-yl)-5-(trifluoromethyl)phenyl)aminosulfonyl)benzoic acid: At room temperature, 1 M LiOH (aq) (0.669 mL, 0.669 mmol) was added to a THF (1.3 mL) solution of the product from Step 3 above (84 mg, 0.167 mmol). The reaction mixture was stirred at room temperature for 18 h, and then concentrated under vacuum. The residue was dissolved in water (3 mL) and washed with EtOAc (5 mL). The aqueous phase was acidified with 1 M HCl until pH 4 to 5, and the product was extracted into EtOAc (5 mL × 3). The combined organic phases were dried over MgSO4 and concentrated under vacuum 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(500MHz,DMSO-d6)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).

[0817] Example 180: 3-(N-(2-(4-ethoxypiperidin-1-yl)-5-(trifluoromethyl)phenyl)aminosulfonyl)-4-methoxybenzoic acid

[0818]

[0819] Step 1: 4-Ethoxy-1-(2-nitro-4-(trifluoromethyl)phenyl)piperidine: At room temperature, Et3N (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 1 M HCl (3 mL), dried through a phase separator, and concentrated under vacuum to give the title compound as an orange oil (471 mg, 1.435 mmol, 100% yield, 97% purity). 1H NMR (500MHz, DMSO-d6) 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),3.30-3.25(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).

[0820] Step 2: 2-(4-ethoxypiperidin-1-yl)-5-(trifluoromethyl)aniline: At room temperature, a solution of 5% Pd / C (50% w / w water) (50 mg, 0.012 mmol) of EtOH (0.5 mL) was added to a solution of the product from Step 1 (228 mg, 0.695 mmol) of EtOH (3.0 mL). The reaction mixture was hydrogenated at room temperature (4 bar) for 18 h. The catalyst was removed by filtration with EtOH (15 ml). The filtrate was concentrated under vacuum and azeotropically reacted with MeOH (6 ml) to give the title compound as a creamy white solid (179 mg, 0.559 mmol, yield 80%, purity 90%). UPLC-MS (Method 1) showed a m / z of 289.3 (M+H) at 1.66 min. + . 1 H NMR (500MHz, DMSO-d6) 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).

[0821] Step 3: Methyl 3-(N-(2-(4-ethoxypiperidin-1-yl)-5-(trifluoromethyl)phenyl)aminosulfonyl)-4-methoxybenzoate: At room temperature, pyridine (0.081 mL, 1.01 mmol) was added to a turbid solution of the product from Step 2 (81 mg, 0.252 mmol) and methyl 3-(chlorosulfonyl)-4-methoxybenzoate (80 mg, 0.302 mmol) in DCM (2.0 mL). The resulting clear solution was stirred at room temperature for 18 h and then concentrated under vacuum. The crude product was purified by silica gel column chromatography (10 g column, 0-60% EtOAc / isohexane) to give the title compound as a colorless oil (92.5 mg, 0.159 mmol, yield 63%, purity 89%). UPLC-MS (Method 1) m / z 517.4 (M+H) at 1.80 min. + 515.2 (MH) - .

[0822] Step 4: 3-(N-(2-(4-ethoxypiperidin-1-yl)-5-(trifluoromethyl)phenyl)aminosulfonyl)-4-methoxybenzoic acid: At room temperature, 1 M LiOH (aq) (0.634 mL, 0.634 mmol) was added to a THF (1.3 mL) solution of the product from Step 3 (92 mg, 0.159 mmol). The reaction mixture was stirred at room temperature for 18 h, then concentrated under vacuum. The residue was dissolved in water (3 mL) and washed with EtOAc (2 × 5 mL). The aqueous phase was acidified with 1 M HCl until pH 4 to 5, and the product was extracted into EtOAc (3 × 5 mL). The combined organic phases were dried over MgSO4 and concentrated under vacuum to give the title compound (61 mg, 0.118 mmol, yield 74%, purity 97%) as a creamy white solid. UPLC-MS (Method 1) m / z 503.3 (M+H) at 1.63 min + 501.3 (MH) - . 1H NMR(500MHz,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).

[0823] Example 181: 4-Methoxy-3-(N-(2-(4-methoxypiperidin-1-yl)-5-(trifluoromethyl)phenyl)aminosulfonyl)benzoic acid

[0824]

[0825] Step 1: 4-Methoxy-1-(2-nitro-4-(trifluoromethyl)phenyl)piperidine: Et3N (318 μl, 2.28 mmol) was added to a DCM (3 mL) solution of 1-fluoro-2-nitro-4-(trifluoromethyl)benzene (128 μl, 0.912 mmol) and 4-methoxypiperidine (105 mg, 0.912 mmol), 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 through a phase separator. The organic phase was concentrated under vacuum 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. + .

[0826] Step 2: 2-(4-Methoxypiperidin-1-yl)-5-(trifluoromethyl)aniline: The product from Step 1 (277 mg, 0.912 mmol) was dissolved in EtOH (14.2 ml) and then dissolved in Thales Nano Hydrogenation was performed in a flow reactor (10% Pd / C, 30 × 4 mm, all-hydrogen mode, 40 °C, flow rate 1 mL / min, 2 passes). The reaction mixture was concentrated under vacuum and azeotropically reacted with MeOH (6 mL) to give the title compound as a paste solid (239 mg, 0.854 mmol, yield 94%, purity 98%). UPLC-MS (Method 2) showed m / z 275.3 (M+H) at 1.53 min. + 273.3 (MH) - .

[0827] Step 3: Methyl 4-methoxy-3-(N-(2-(4-methoxypiperidin-1-yl)-5-(trifluoromethyl)phenyl)aminosulfonyl)benzoate: The product from 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 column, 0-100% EtOAc / isohexane) to give the title compound as a white solid (52.8 mg, 0.103 mmol, yield 40.9%, purity 98%). UPLC-MS (Method 1) m / z at 1.71 min: 503.4 (M+H)+(ES+); 501.2 (MH)-(ES-).

[0828] Step 4: 4-Methoxy-3-(N-(2-(4-methoxypiperidin-1-yl)-5-(trifluoromethyl)phenyl)aminosulfonyl)benzoic acid: The product from Step 3 (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 under vacuum, and the resulting aqueous solution was diluted with water (to ~5 ml). The aqueous phase was washed with EtOAc (2 × 5 ml) and neutralized with 1 M HCl to ~pH 6. The resulting lumpy suspension was sonicated to obtain a turbid mixture. The turbid mixture was concentrated under vacuum 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 under vacuum, 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) showed a m / z of 489.2 (M+H) at 1.53 min. + 487.1 (MH) - . 1H NMR (500MHz, DMSO-d6) 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).

[0829] Example 182: 3-(N-(5-cyano-2-(piperidin-1-yl)phenyl)aminosulfonyl)-4-methoxybenzoic acid

[0830]

[0831] Step 1: 3-Nitro-4-(piperidin-1-yl)benzyl nitrile: A mixture of 4-fluoro-3-nitrobenzyl nitrile (300 mg, 1.81 mmol), piperidine (0.2 mL, 2.02 mmol), and Et3N (0.65 mL, 4.66 mmol) in DCM (6 mL) was stirred overnight at room temperature. The mixture was washed with water (10 mL), concentrated onto silica using a phase separator, and purified by silica gel column chromatography (12 g column, 0-100% EtOAc / isohexane) to give the title compound as a pale orange solid (400 mg, 1.73 mmol, yield 96%, purity 100%). UPLC-MS (Method 2) 1.60 min m / z 232.1 (M+H) + . 1 H NMR (500MHz, DMSO-d6) 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).

[0832] Step 2: 3-Amino-4-(piperidin-1-yl)benzyl nitrile: in Thales Nano A solution of EtOH (35 ml) of the product from step 1 above (398 mg, 1.72 mmol) was hydrogenated in a flow reactor (10% Pt / C, 30 × 4 mm, all-hydrogen mode, 25 °C, flow rate 1 ml / min, single pass). The mixture was concentrated onto silica and purified by silica gel column chromatography (12 g column, 0–50% EtOAc / isohexane) to give the title compound as a viscous red oil (118 mg, 0.542 mmol, yield 32%, purity 93%). UPLC-MS (Method 2) at 1.58 min, m / z 202.2 (M+H). + . 1 H NMR (500MHz, DMSO-d6) 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).

[0833] Step 3: Methyl 3-(N-(5-cyano-2-(piperidin-1-yl)phenyl)aminosulfonyl)-4-methoxybenzoate: A mixture of the product from Step 2 (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 over a weekend at room temperature. The mixture was concentrated onto silica and purified by silica gel column chromatography (12 g column, 0–100% EtOAc / isohexane) to give the title compound as a white solid (172 mg, 0.394 mmol, yield 73%, purity 98%). UPLC-MS (Method 2) at 1.58 min, m / z 430.2 (M+H). + 428.1 (MH) - . 1 H NMR(500MHz,DMSO-d6)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).

[0834] Step 4: 3-(N-(5-cyano-2-(piperidin-1-yl)phenyl)aminosulfonyl)-4-methoxybenzoic acid: The product of Step 3 (170 mg, 0.390 mmol) and LiOH (40 mg, 1.67 mmol) in THF / H2O (4:1, 4 mL) were stirred at room temperature for 1 h, and then stirred overnight at 35 °C. The mixture was diluted with H2O (10 mL) and EtOAc (15 mL) and acidified to ~pH 4 with 1 M HCl. The phases were separated, and the aqueous phase was extracted with EtOAc (2 × 15 mL). The combined organic extracts were washed with brine (15 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 (12 g column, 0-100% EtOAc / isohexane) to give the title compound as a white solid (105 mg, 0.243 mmol, yield 62%, purity 96%). UPLC-MS (Method 1) showed m / z 416.2 (M+H) at 1.47 min. + 413.7 (MH) - . 1 H NMR (500MHz, DMSO-d6) 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=2.0Hz,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).

[0835] Example 183: 4-Ethyl-3-(N-(2-(3-hydroxyazacyclobutane-1-yl)-5-(trifluoromethyl)phenyl)aminosulfonyl)benzoic acid

[0836]

[0837] Step 1: Methyl 3-(chlorosulfonyl)-4-ethylbenzoate: At room temperature, thionyl chloride (5 ml, 68.5 mmol) was added in portions to the product 3-((chlorosulfonyl)-4-ethylbenzoic acid) (0.888 g, 3.57 mmol) from Step 1 of Example 1. The mixture was heated to 75 °C for 1 h. The solution was cooled to room temperature and concentrated under vacuum. The residue was dissolved in DCM (5 ml), treated with MeOH (0.144 ml, 3.57 mmol), then with Et3N (0.536 ml, 3.93 mmol), and stirred overnight at room temperature. The mixture was diluted with DCM (50 ml), washed with water (50 ml), dried over MgSO4, filtered, and concentrated under vacuum to give the title compound (0.450 g, 1.37 mmol, yield 38%, purity 80%) as a light brown oil. 1 H NMR(500MHz,DMSO-d6)δ8.73(d,J=1.8Hz,1H),8.32(dd,J=8.1,1.8Hz,1H),7. 61 (d, J = 8.0 Hz, 1H), 3.99 (s, 3H), 3.28 (q, J = 7.3 Hz, 2H), 1.40 (t, J = 7.4 Hz, 3H).

[0838] Step 2: 1-(2-nitro-4-(trifluoromethyl)phenyl)azacyclobutane-3-ol: At room temperature, Et3N (0.700 mL, 5.02 mmol) was added to a solution of 1-fluoro-2-nitro-4-(trifluoromethyl)benzene (0.201 mL, 1.44 mmol) and azacyclobutane-3-ol hydrochloride (189 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 1 M HCl (3 mL), dried over a hydrophobic frit, and concentrated under vacuum to give the title compound as an orange oil (461 mg, 1.39 mmol, yield 97%, purity 79%). 1 H NMR(500MHz,DMSO-d6)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,1H),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).

[0839] Step 3: 1-(2-amino-4-(trifluoromethyl)phenyl)azacyclobutane-3-ol: Dissolve the product from Step 2 (455 mg, 1.37 mmol) in EtOH (27.4 ml) and then... Hydrogenation was performed in a flow reactor (10% Pd / C, 30 × 4 mm, all-hydrogen mode, 40 °C, flow rate 1 mL / min, single pass). The reaction mixture was concentrated under vacuum and azeotropically reacted with MeOH (12 mL) to give the title compound as a pale yellow oil (395 mg, 1.37 mmol, 100% yield, 81% purity). UPLC-MS (Method 1) m / z 233.3 (M+H) at 1.00 min. + . 1 ¹H NMR (500MHz, DMSO-d⁶) δ 6.86 (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 (sextile, J = 6.2Hz, 1H), 4.19–4.13 (m, 2H), 3.45–3.40 (m, 2H).

[0840] Step 4: Methyl 4-ethyl-3-(N-(2-(3-hydroxyazacyclobutan-1-yl)-5-(trifluoromethyl)phenyl)aminosulfonyl)benzoate: At room temperature, pyridine (0.072 mL, 0.896 mmol) was added to a solution of the product from Step 3 (65 mg, 0.224 mmol) and the product from Step 1 (92 mg, 0.280 mmol) in DCM (2.0 mL). The resulting turbid solution was stirred at room temperature for 21 h. The reaction mixture was concentrated under vacuum, and the crude product was purified by silica gel column chromatography (10 g column, 0-65% EtOAc / isohexane) to give the title compound as a red oil (51 mg, 0.102 mmol, yield 46%, purity 92%). UPLC-MS (Method 1) m / z 459.4 (M+H) at 0.66 min. + 457.2 (MH) - .

[0841] Step 5: 4-Ethyl-3-(N-(2-(3-hydroxyazacyclobutane-1-yl)-5-(trifluoromethyl)phenyl)aminosulfonyl)benzoic acid: At room temperature, 1 M LiOH (aq) (0.409 mL, 0.409 mmol) was added to a THF (0.82 mL) solution of the product (51 mg, 0.102 mmol) from Step 4 above. The solution was stirred at room temperature for 17 h, then concentrated under vacuum. The residue was dissolved in water (3 mL) and washed with EtOAc (5 mL). The aqueous phase was acidified with 1 M HCl until pH 4 to 5, and the product was extracted into EtOAc (3 × 5 mL). The organic phases were combined, dried over MgSO4, and concentrated under vacuum. 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 aqueous solution) to give the title compound as a white solid (7.3 mg, 0.016 mmol, yield 16%, purity 99%). UPLC-MS (Method 1) showed a m / z of 445.3 (M+H) at 1.32 min. + 443.2 (MH) - . 1 H NMR (500MHz, DMSO-d6) 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).

[0842] Example 184: 3-(N-(3-fluoro-2-(piperidin-1-yl)-5-(trifluoromethyl)phenyl)aminosulfonyl)-4-methoxybenzoic acid

[0843]

[0844] Step 1: 1-(2-fluoro-6-nitro-4-(trifluoromethyl)phenyl)piperidine: At room temperature, Et3N (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 under vacuum to give the title compound as a brown oil (676 mg, 2.20 mmol, 100% yield, 98% purity). UPLC-MS (Method 1) m / z 293.5 (M+H) at 1.93 min. + .

[0845] Step 2: 3-Fluoro-2-(piperidin-1-yl)-5-(trifluoromethyl)aniline: Dissolve the product from Step 1 (0.642 g, 2.20 mmol) in EtOH (44 ml) and then... Hydrogenation was performed in a flow reactor (10% Pd / C, 30 × 4 mm, all-hydrogen mode, room temperature, flow rate 1 ml / min, single pass). The crude product was concentrated under vacuum and azeotropically reacted with MeOH (12 ml) to give the title compound as a pale yellow oil (0.543 g, 1.97 mmol, yield 90%, purity 95%). UPLC-MS (Method 1) showed m / z 263.3 (M+H) at 1.89 min. + .

[0846] Step 3: Methyl 3-(N-(3-fluoro-2-(piperidin-1-yl)-5-(trifluoromethyl)phenyl)aminosulfonyl)-4-methoxybenzoate: Pyridine (0.139 mL, 1.72 mmol) was added to a DCM (10 mL) solution of the product from Step 2 (0.15 g, 0.572 mmol) and methyl 3-(chlorosulfonyl)-4-methoxybenzoate (0.189 g, 0.715 mmol), and the solution was stirred at room temperature for 18 h. The solution was concentrated under vacuum, and the crude product was purified by silica gel column chromatography (12 g column, 0-100% EtOAc / isohexane) to give the title compound as a white solid (0.372 g, 0.546 mmol, yield 95%, purity 72%). UPLC-MS (Method 1) m / z 491.3 (M+H) at 1.96 min. + 489.2 (MH) - .

[0847] Step 4: 3-(N-(3-fluoro-2-(piperidin-1-yl)-5-(trifluoromethyl)phenyl)aminosulfonyl)-4-methoxybenzoic acid: 1 M LiOH (aq) (3.28 mL, 3.28 mmol) was added to a solution of the product from Step 3 (0.268 g, 0.547 mmol) in THF (12 mL) and MeOH (3 mL), and the solution was stirred overnight at room temperature. 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, yield 69%, purity 98%) as a creamy white solid. UPLC-MS (Method 1) at 1.81 min: m / z 477.3 (M+H) + 474.9 (MH) - . 1 H NMR (500MHz, DMSO-d6) δ13.19(s,1H),8.99(s,1H),8.38(d,J=2.2Hz,1H),8.17(dd,J=8.7,2.2H z,1H),7.37-7.31(m,3H),3.94(s,3H),2.91-2.81(m,4H),1.69-1.62(m,4H),1.58-1.51(m,2H).

[0848] The following examples were prepared by a method similar to that of Example 184, with appropriate starting materials and intermediates substituted where necessary:

[0849]

[0850]

[0851]

[0852] Example 200: 3-(N-(2-(piperidin-1-yl)-5-(trifluoromethyl)phenyl)aminosulfonyl)-4-(trifluoromethyl)benzoic acid

[0853]

[0854] Step 1: Methyl 3-(N-(2-(piperidin-1-yl)-5-(trifluoromethyl)phenyl)aminosulfonyl)-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 overnight at room temperature, followed by stirring at 35 °C for 11 days. The mixture was concentrated onto silica and purified by silica gel column chromatography (12 g column, 0-50% EtOAc / isohexane) to give the title compound as a pale yellow solid (91 mg, 0.178 mmol, yield 58.1%, purity 100%). UPLC-MS (Method 1) m / z 511.2 (M+H) at 1.99 min + 509.0 (MH) - . 1 H 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).

[0855] Step 2: 3-(N-(2-(piperidin-1-yl)-5-(trifluoromethyl)phenyl)aminosulfonyl)-4-(trifluoromethyl)benzoic acid: The product from Step 1 (91 mg, 0.178 mmol) and LiOH (17 mg, 0.710 mmol) in THF / MeOH / water (4:1:1, 2.4 ml) were stirred overnight at 35 °C. 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 × 15 ml). The organic extracts were combined, washed with brine (15 ml), dried through a phase separator, and the solvent was removed under vacuum. The residue was ground with isohexane / TBME (5:1) to give the title compound as a pale yellow solid (33.4 mg, 0.066 mmol, yield 37.0%, purity 98%). UPLC-MS (Method 1) showed m / z 497.2 (M+H) at 1.92 min. + 495.1 (MH) - . 1H 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).

[0856] Example 201: 4-ethoxy-3-(N-(2-(piperidin-1-yl)-5-(trifluoromethyl)phenyl)aminosulfonyl)benzoic acid

[0857]

[0858] Step 1: Methyl 4-ethoxy-3-(N-(2-(piperidin-1-yl)-5-(trifluoromethyl)phenyl)aminosulfonyl)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 column, 0-50% EtOAc / isohexane) to give the title compound (0.160 g, 0.326 mmol, yield 80%, purity 99%) as a creamy waxy solid. UPLC-MS (Method 1) showed m / z 487.4 (M+H) at 1.93 min. + 485.2 (MH) - .

[0859] Step 2: 4-Ethoxy-3-(N-(2-(piperidin-1-yl)-5-(trifluoromethyl)phenyl)aminosulfonyl)benzoic acid: 1 M LiOH (aq) (0.024 g, 0.987 mmol) was added to a THF (5 mL) solution of the product from Step 1 (0.160 g, 0.329 mmol), and the solution was stirred overnight at room temperature. The reaction mixture was concentrated to water under vacuum. The pH was adjusted to pH 6 with 1 M 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).

[0860] Example 202: 3-(N-(4,5-dichloro-2-(piperidin-1-yl)phenyl)aminosulfonyl)-4-methoxybenzoic acid

[0861]

[0862] Step 1: Methyl 3-(N-(4,5-dichloro-2-(piperidin-1-yl)phenyl)aminosulfonyl)-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 under vacuum. The crude product was purified by silica gel column chromatography (12 g column, 0-100% EtOAc / isohexane) to give the title compound as a white solid (0.257 g, 0.543 mmol, yield 79%, purity 81%). UPLC-MS (Method 1) m / z 475.4 (M+H) at 1.75 min + 472.8 (MH) - .

[0863] Step 2: 3-(N-(4,5-dichloro-2-(piperidin-1-yl)phenyl)aminosulfonyl)-4-methoxybenzoic acid: 1 M LiOH (aq) (3.26 mL, 3.26 mmol) was added to a solution of the product from Step 1 (0.257 g, 0.543 mmol) in THF (13 mL) and MeOH (3 mL), and the solution was stirred overnight at room temperature. 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 combined organic phases were dried through a phase separator and the solvent was removed under vacuum to give the title compound (0.229 g, 0.494 mmol, 91% yield, 97% purity) as a creamy white solid. UPLC-MS (Method 1) at 1.82 min: m / z 459.3 / 461.3 (M+H) + 457.2 / 459.2 (MH) - . 1 H 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).

[0864] Example 203: 3-(N-(2-(4,4-difluoropiperidin-1-yl)-5-(trifluoromethyl)phenyl)aminosulfonyl)-4-ethylbenzoic acid

[0865]

[0866] 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 under vacuum to give the title compound as a white solid (10.9 g, 41.5 mmol, yield 89%, purity 95%). 1 H NMR(500MHz,DMSO-d6)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).

[0867] Step 2: Methyl 3-(chlorosulfonyl)-4-ethylbenzoate: At room temperature, thionyl chloride (10 mL, 137 mmol) was added in portions to the product from Step 1 (4 g, 16.1 mmol). The mixture was heated to 75 °C for 2 h, cooled to room temperature, concentrated under vacuum, and azeotropically reacted with toluene. The solid was dissolved in DCM (10 mL), treated with MeOH (0.716 mL, 17.7 mmol), then treated with Et3N (2.41 mL, 17.7 mmol) and stirred overnight at room temperature. The mixture was diluted with DCM (50 mL), washed with water (50 mL), dried (MgSO4), and concentrated under vacuum. The crude product was purified by silica gel column chromatography (40 g column, 0-50% EtOAc / isohexane) to give the title compound as a white solid (3.60 g, 13.02 mmol, yield 81%, purity 95%). 1 H NMR(500MHz,DMSO-d6)δ8.74(d,J=1.8Hz,1H),8.32(dd,J=8.0,1.8Hz,1H),7. 61 (d, J = 8.0 Hz, 1H), 3.99 (s, 3H), 3.28 (q, J = 7.5 Hz, 2H), 1.41 (t, J = 7.5 Hz, 3H).

[0868] Step 3: Methyl 3-(N-(2-(4,4-difluoropiperidin-1-yl)-5-(trifluoromethyl)phenyl)aminosulfonyl)-4-ethylbenzoate: Pyridine (0.069 mL, 0.856 mmol) was added to a DCM (10 mL) solution of the product from Step 2 of Example 12 (0.08 g, 0.285 mmol) and the product from Step 2 above (0.094 g, 0.357 mmol), and the solution was stirred at room temperature for 18 h. The solution was concentrated under vacuum, and the crude product was purified by silica gel column chromatography (12 g column, 0-100% EtOAc / isohexane) to give the title compound as a white solid (0.137 g, 0.227 mmol, yield 80%, purity 84%). UPLC-MS (Method 1) m / z 507.4 (M+H) at 1.90 min. + 505.2 (MH) - .

[0869] Step 4: 3-(N-(2-(4,4-difluoropiperidin-1-yl)-5-(trifluoromethyl)phenyl)aminosulfonyl)-4-ethylbenzoic acid: 1M LiOH (aq) (1.35 mL, 1.35 mmol) was added to a solution of the product from Step 3 (0.137 g, 0.225 mmol) in THF (6 mL) and MeOH (1.3 mL), and the solution was stirred overnight at room temperature. 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 a creamy white solid. UPLC-MS (Method 1) m / z 493.3 (M+H) at 1.76 min + 490.9 (MH) - . 1 H NMR (500MHz, DMSO-d6) 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).

[0870] Example 204: 3-(N-(2-(3,3-difluoropiperidin-1-yl)-5-(trifluoromethyl)phenyl)aminosulfonyl)-4-ethylbenzoic acid

[0871]

[0872] Step 1: Methyl 3-(N-(2-(3,3-difluoropiperidin-1-yl)-5-(trifluoromethyl)phenyl)aminosulfonyl)-4-ethylbenzoate: Pyridine (0.052 mL, 0.642 mmol) was added to a DCM (10 mL) solution of the product from Step 2 of Example 9 (60 mg, 0.214 mmol) and the product from Step 2 of Example 203 (70 mg, 0.268 mmol). The solution was stirred at room temperature for 18 h and then concentrated under vacuum. The crude product was purified by silica gel column chromatography (12 g column, 0-100% EtOAc / isohexane) to give the title compound as a white solid (0.057 g, 0.113 mmol, yield 52.6%, purity 100%). UPLC-MS (Method 1) m / z 507.7 (M+H) at 1.89 min. + 505.2 (MH) - .

[0873] Step 2: 3-(N-(2-(3,3-difluoropiperidin-1-yl)-5-(trifluoromethyl)phenyl)aminosulfonyl)-4-ethylbenzoic acid: 1 M LiOH (aq) (0.675 mL, 0.675 mmol) was added to a solution of the product from Step 1 (0.057 g, 0.113 mmol) in THF (8 mL) and MeOH (2 mL). The solution was stirred overnight at room temperature and then concentrated under vacuum. 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 under vacuum to give the title compound as a creamy white solid (0.056 g, 0.110 mmol, 98% yield, 97% purity). UPLC-MS (Method 1) m / z 493.7 (M+H) at 1.74 min. + 491.1 (MH) - . 1H NMR(500MHz,DMSO-d6)δ13.30(s,1H),9.30(s,1H),8.35(d,J=1.8Hz,1H),8.11(d d,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,1H),7.12(d,J=2.1Hz,1H),3.21(t,J=11.4Hz,2H),3.00(q,J=7.4Hz,2H ),2.98-2.94(m,2H),2.08-1.96(m,2H),1.84-1.75(m,2H),1.19(t,J=7.4Hz,3H).

[0874] Example 205: 4-Ethyl-3-(N-(2-(4-fluoropiperidin-1-yl)-5-(trifluoromethyl)phenyl)aminosulfonyl)benzoic acid

[0875]

[0876] Step 1: 4-Fluoro-1-(2-nitro-4-(trifluoromethyl)phenyl)piperidine: Et3N (500 μl, 3.59 mmol) was added to a DCM solution of 1-fluoro-2-nitro-4-(trifluoromethyl)benzene (201 μl, 1.44 mmol) and 4-fluoropiperidine (192 mg, 1.87 mmol) (6 mL), and the resulting solution was stirred at room temperature for 3 days. 1 M HCl (aq) (2 mL) was added, and the organic phase was separated using a phase separator. The organic phase was concentrated under vacuum to give the title compound (419 mg, 1.44 mmol, 100% yield, 100% purity) as a pale yellow, viscous oil. UPLC-MS (Method 2) m / z 293.3 (M+H) at 1.62 min. + .

[0877] Step 2: 2-(4-Fluoroperidin-1-yl)-5-(trifluoromethyl)aniline: The product from Step 1 (419 mg, 1.44 mmol) was dissolved in EtOH (28.8 ml), and the reaction mixture was transferred to Thales Nano Hydrogenation was performed in a flow reactor (10% Pd / C, 30 × 4 mm, all-hydrogen mode, 40 °C, flow rate 1 mL / min, 2 passes). The reaction mixture was concentrated under vacuum and azeotropically reacted with MeOH (6 mL) to give the title compound as a clear, viscous oil (371 mg, 1.27 mmol, yield 89%, purity 90%). UPLC-MS (Method 2) showed m / z 263.3 (M+H) at 1.59 min. + .

[0878] Step 3: Methyl 4-ethyl-3-(N-(2-(4-fluoropiperidin-1-yl)-5-(trifluoromethyl)phenyl)aminosulfonyl)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 column, 0-100% EtOAc / isohexane) to give the title compound as a paste solid (61 mg, 0.112 mmol, yield 44.3%, purity 90%). UPLC-MS (Method 1) m / z 489.3 (M+H) at 1.87 min. + 487.2 (MH) - .

[0879] Step 4: 4-Ethyl-3-(N-(2-(4-fluoropiperidin-1-yl)-5-(trifluoromethyl)phenyl)aminosulfonyl)benzoic acid: The product from Step 3 (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 obtain a solution, which was stirred at 30 °C for 20 h. The reaction mixture was diluted with water (3 ml), concentrated under vacuum, and the resulting aqueous solution was diluted with water (to ~5 ml). The aqueous phase was washed with EtOAc (2 × 5 ml) and neutralized with 1 M HCl to ~pH 6. The lumpy suspension was sonicated to obtain a turbid solution, which was concentrated under vacuum 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 under vacuum, 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) showed a m / z of 475.4 (M+H) at 1.74 min. + 473.2 (MH) - . 1H NMR(500MHz,DMSO-d6)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).

[0880] Example 206: 3-(N-(2-(4-fluoropiperidin-1-yl)-5-(trifluoromethyl)phenyl)aminosulfonyl)-4-methoxybenzoic acid

[0881]

[0882] Step 1: Methyl 3-(N-(2-(4-fluoropiperidin-1-yl)-5-(trifluoromethyl)phenyl)aminosulfonyl)-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 column, 0-100% EtOAc / isohexane) to give the title compound as a viscous paste-like solid (88 mg, 0.161 mmol, yield 64.1%, purity 90%). UPLC-MS (Method 1) m / z 491.4 (M+H) at 1.73 min + 489.1 (MH) - .

[0883] Step 2: 3-(N-(2-(4-fluoropiperidin-1-yl)-5-(trifluoromethyl)phenyl)aminosulfonyl)-4-methoxybenzoic acid: The product from Step 1 (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 obtain a solution, which was stirred at 30 °C for 20 h. The reaction mixture was diluted with water (3 ml), concentrated under vacuum, and the resulting aqueous solution was diluted with water (to ~5 ml). The aqueous phase was washed with EtOAc (2 × 5 ml) and neutralized with 1 M HCl to ~pH 6. The lumpy suspension was sonicated to obtain a turbid solution, which was concentrated under vacuum 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 under vacuum, 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) showed a m / z of 477.3 (M+H) at 1.56 min. + 475.1 (MH) - . 1 H NMR(500MHz,DMSO-d6)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).

[0884] Example 207: 4-Methoxy-3-(N-(5-(methylsulfonyl)-2-(piperidin-1-yl)phenyl)aminosulfonyl)benzoic acid

[0885]

[0886] Step 1: 1-(4-(Methylsulfonyl)-2-nitrophenyl)piperidine: At room temperature, Et3N (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 under vacuum to give the title compound as a brown oil (0.676 g, 2.28 mmol, 100% yield, 100% purity). UPLC-MS (Method 1) m / z 285.2 (M+H) at 1.32 min. + .

[0887] Step 2: 5-(Methylsulfonyl)-2-(piperidin-1-yl)aniline: Dissolve the product from Step 1 (0.676 g, 2.38 mmol) in EtOH (44 ml), and transfer the reaction mixture to Thales Nano Hydrogenation was performed in a flow reactor (10% Pd / C, 30 × 4 mm, all-hydrogen mode, room temperature, flow rate 1 ml / min, single pass). The reaction mixture was concentrated under vacuum and then azeotropically reacted with MeOH (12 ml) to give the title compound as a pale yellow oil (0.615 g, 2.370 mmol, 100% yield, 98% purity). UPLC-MS (Method 1) at 1.20 min, m / z 255.3 (M+H). + .

[0888] Step 3: Methyl 4-methoxy-3-(N-(5-(methanesulfonyl)-2-(piperidin-1-yl)phenyl)aminosulfonyl)benzoate: Pyridine (0.143 mL, 1.77 mmol) was added to a solution of the product from Step 2 (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 under vacuum, and the crude product was purified by silica gel column chromatography (12 g column, 0-100% EtOAc / isohexane) to give the title compound as a white solid (0.201 g, 0.412 mmol, yield 69.9%, purity 99%). UPLC-MS (Method 1) m / z 483.3 (M+H) at 1.49 min. + 481.0 (MH) - .

[0889] Step 4: 4-Methoxy-3-(N-(5-(methanesulfonyl)-2-(piperidin-1-yl)phenyl)aminosulfonyl)benzoic acid: 1 M LiOH (aq) (2.47 mL, 2.47 mmol) was added to a solution of the product from Step 3 (0.199 g, 0.412 mmol) in THF (10 mL) and MeOH (2.5 mL), and the solution was stirred overnight at room temperature. 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 a creamy white solid. UPLC-MS (Method 1) m / z 469.4 (M+H) at 1.36 min + 467.0 (MH) - . 1 H NMR (500MHz, DMSO-d6) 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).

[0890] Example 208: (R)-3-(N-(2-(3-fluoropiperidin-1-yl)-5-(trifluoromethyl)phenyl)aminosulfonyl)-4-methoxybenzoic acid

[0891]

[0892] Step 1: (R)-3-fluoro-1-(2-nitro-4-(trifluoromethyl)phenyl)piperidine: Et3N (500 μl, 3.59 mmol) was added to a DCM solution of 1-fluoro-2-nitro-4-(trifluoromethyl)benzene (300 mg, 1.44 mmol) and (R)-3-fluoropiperidine (250 mg, 2.42 mmol) (6 mL). 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 under vacuum to give the title compound (488 mg, 1.44 mmol, 100% yield, 86% purity) as a pale orange viscous oil. UPLC-MS (Method 2) m / z 293.0 (M+H) at 1.59 min. + .

[0893] Step 2: (R)-2-(3-Fluoroperidin-1-yl)-5-(trifluoromethyl)aniline: Dissolve the product from Step 1 (419 mg, 1.44 mmol) in EtOH (28.8 ml), and transfer the reaction mixture to Thales Nano Hydrogenation was performed in a flow reactor (10% Pd / C, 30 × 4 mm, all-hydrogen mode, 40 °C, flow rate 1 mL / min, 2 passes). The reaction mixture was concentrated under vacuum and azeotropically reacted with MeOH (6 mL) to give the title compound as a milky white gel (457 mg, 1.394 mmol, yield 97%, purity 80%). UPLC-MS (Method 2) showed m / z 263.3 (M+H) at 1.59 min. + .

[0894] Step 3: Methyl (R)-3-(N-(2-(3-fluoropiperidin-1-yl)-5-(trifluoromethyl)phenyl)aminosulfonyl)-4-methoxybenzoate: The product from 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 column, 0-100% EtOAc / isohexane) to give the title compound as a white solid (72.4 mg, 0.118 mmol, yield 46.9%, purity 80%). UPLC-MS (Method 1) m / z 491.3 (M+H) at 1.73 min + 489.1 (MH) - .

[0895] Step 4: (R)-3-(N-(2-(3-fluoropiperidin-1-yl)-5-(trifluoromethyl)phenyl)aminosulfonyl)-4-methoxybenzoic acid: The product from Step 3 (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 obtain a solution, which was stirred at 30 °C for 20 h. The reaction mixture was diluted with water (3 ml), concentrated under vacuum, and the resulting aqueous solution was diluted with water (to ~5 ml). The aqueous phase was washed with EtOAc (2 × 5 ml) and neutralized with 1 M HCl to ~pH 6. The lumpy suspension was sonicated to obtain a turbid solution, which was concentrated under vacuum 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 under vacuum, 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) showed a m / z of 477.4 (M+H) at 1.57 min. + 475.1 (MH) - . 1 H NMR(500MHz,DMSO-d6)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).

[0896] Example 209: (S)-3-(N-(2-(3-fluoropiperidin-1-yl)-5-(trifluoromethyl)phenyl)aminosulfonyl)-4-methoxybenzoic acid

[0897]

[0898] Step 1: (S)-3-fluoro-1-(2-nitro-4-(trifluoromethyl)phenyl)piperidine: Et3N (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 under vacuum to give the title compound as a pale orange viscous oil (461 mg, 1.44 mmol, 100% yield, 91% purity). UPLC-MS (Method 2) 1.60 min m / z 293.1 (M+H) + .

[0899] Step 2: (S)-2-(3-Fluoroperidin-1-yl)-5-(trifluoromethyl)aniline: Dissolve the product from Step 1 (419 mg, 1.44 mmol) in EtOH (28.8 mL). Transfer the reaction mixture to Thales Nano Hydrogenation was performed in a flow reactor (10% Pd / C, 30 × 4 mm, all-hydrogen mode, 40 °C, flow rate 1 mL / min, 2 passes). The reaction mixture was concentrated under vacuum and azeotropically reacted with MeOH (6 mL) to give the title compound as a milky white gel (475 mg, 1.43 mmol, 100% yield, 79% purity). UPLC-MS (Method 2) showed m / z 263.3 (M+H) at 1.59 min. + .

[0900] Step 3: Methyl (S)-3-(N-(2-(3-fluoropiperidin-1-yl)-5-(trifluoromethyl)phenyl)aminosulfonyl)-4-methoxybenzoate: The product from 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 column, 0-100% EtOAc / isohexane) to give the title compound as a white solid (81.4 mg, 0.133 mmol, yield 52.7%, purity 80%). UPLC-MS (Method 1) m / z 491.4 (M+H) at 1.74 min + 489.3 (MH) - .

[0901] Step 4: (S)-3-(N-(2-(3-fluoropiperidin-1-yl)-5-(trifluoromethyl)phenyl)aminosulfonyl)-4-methoxybenzoic acid: The product from Step 3 (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 obtain a solution, which was stirred at 30 °C for 20 h. The reaction mixture was diluted with water (3 ml), concentrated under vacuum, and the resulting aqueous solution was diluted with water (to ~5 ml). The solution was washed with EtOAc (2 × 5 ml) and neutralized with 1 M HCl to ~pH 6. The lumpy suspension was sonicated to obtain a turbid solution, which was concentrated under vacuum 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 under vacuum, 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) showed a m / z of 477.3 (M+H) at 1.57 min. + 475.2 (MH) - . 1 H NMR(500MHz,DMSO-d6)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).

[0902] Example 210: (S)-4-ethyl-3-(N-(2-(3-fluoropiperidin-1-yl)-5-(trifluoromethyl)phenyl)aminosulfonyl)benzoic acid

[0903]

[0904] Step 1: Methyl (S)-4-ethyl-3-(N-(2-(3-fluoropiperidin-1-yl)-5-(trifluoromethyl)phenyl)aminosulfonyl)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 column, 0-100% EtOAc / isohexane) to give the title compound as a white solid (65.9 mg, 0.108 mmol, yield 42.2%, purity 80%). UPLC-MS (Method 1) m / z 489.4 (M+H) at 1.89 min. + 487.2 (MH) - .

[0905] Step 2: (S)-4-Ethyl-3-(N-(2-(3-fluoropiperidin-1-yl)-5-(trifluoromethyl)phenyl)aminosulfonyl)benzoic acid: The product from Step 1 (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 obtain a solution, which was stirred at 30 °C for 20 h. The reaction mixture was diluted with water (3 ml), concentrated under vacuum, and the resulting aqueous solution was diluted with water (to ~5 ml). The aqueous phase was washed with EtOAc (2 × 5 ml) and neutralized with 1 M HCl to ~pH 6. The lumpy suspension was sonicated to obtain a turbid solution, which was concentrated under vacuum 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 under vacuum, and dried at 45 °C to give the title compound as a paste (35.9 mg, 0.072 mmol, yield 55.7%). UPLC-MS (Method 1) showed a m / z of 475.3 (M+H) at 1.74 min. + 473.2 (MH) - . 1H NMR(500MHz,DMSO-d6)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).

[0906] Example 211: (R)-4-ethyl-3-(N-(2-(3-fluoropiperidin-1-yl)-5-(trifluoromethyl)phenyl)aminosulfonyl)benzoic acid

[0907]

[0908] Step 1: (R)-4-ethyl-3-(N-(2-(3-fluoropiperidin-1-yl)-5-(trifluoromethyl)phenyl)aminosulfonyl)methyl 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 column, 0-100% EtOAc / isohexane) to give the title compound as a white solid (76.7 mg, 0.126 mmol, yield 49.2%, purity 80%). UPLC-MS (Method 1) m / z 489.3 (M+H) at 1.89 min. + 487.2 (MH) - .

[0909] Step 2: (R)-4-ethyl-3-(N-(2-(3-fluoropiperidin-1-yl)-5-(trifluoromethyl)phenyl)aminosulfonyl)benzoic acid: The product from Step 1 (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 obtain a solution, which was stirred at 30 °C for 20 h. The reaction mixture was diluted with water (3 ml), concentrated under vacuum, and the resulting aqueous solution was diluted with water (to ~5 ml). The aqueous phase was washed with EtOAc (2 × 5 ml) and neutralized with 1 M HCl to ~pH 6. The lumpy suspension was sonicated to obtain a turbid solution, which was concentrated under vacuum 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 under vacuum, and dried at 45 °C to give the title compound as a paste (43.5 mg, 0.087 mmol, yield 57.5%, purity 95%). UPLC-MS (Method 1) showed a m / z of 475.4 (M+H) at 1.74 min. + 473.2 (MH) - . 1 H NMR(500MHz,DMSO-d6)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).

[0910] Example 212: 3-(N-(5-(difluoromethyl)-2-(piperidin-1-yl)phenyl)aminosulfonyl)-4-methoxybenzoic acid

[0911]

[0912] Synthesis of 3-(chlorosulfonyl)-4-methoxybenzoic acid

[0913] At room temperature, 4-methoxybenzoic acid (6.5 g, 42.7 mmol) was added in portions to chlorosulfonic acid (30 mL, 448 mmol). The mixture was heated to 80 °C for 2 hours, then cooled to room temperature and carefully added to ice water (300 mL), followed by stirring for 1 hour. The solid was collected, washed with water (200 mL), and dried under vacuum to give the title compound as a white solid (7.92 g, 30.0 mmol, yield 70.3%, purity 95%). 1 H NMR (500MHz, DMSO-d6) 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).

[0914] Synthesis of 3-(N-(5-(difluoromethyl)-2-(piperidin-1-yl)phenyl)aminosulfonyl)-4-methoxybenzoic acid

[0915] Step 1: 1-(4-(difluoromethyl)-2-nitrophenyl)piperidine: Et3N (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 using a phase separator. The organic phase was concentrated under vacuum to give the title compound as a yellow, viscous oil (402 mg, 1.57 mmol, 100% yield, 100% purity). UPLC-MS (Method 1) m / z 257.3 (M+H) at 1.63 min. + .

[0916] Step 2: 5-(difluoromethyl)-2-(piperidin-1-yl)aniline: Dissolve the product from Step 1 (402 mg, 1.57 mmol) in EtOH (14.4 ml). Transfer the reaction mixture to Thales Nano Hydrogenation was performed in a flow reactor (10% Pd / C, 30 × 4 mm, all-hydrogen mode, 40 °C, flow rate 1 ml / min, 2 passes). The reaction mixture was concentrated under vacuum and azeotropically reacted with MeOH (6 ml) to give the title compound as a pale yellow oil (324 mg, 1.403 mmol, yield 89%, purity 98%). UPLC-MS (Method 1) showed m / z 227.3 (M+H) at 1.58 min. + .

[0917] Step 3: 3-(N-(5-(difluoromethyl)-2-(piperidin-1-yl)phenyl)aminosulfonyl)-4-methoxybenzoic acid: The product from Step 2 (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 column, 100% isohexane, followed by a 0-100% EtOAc / isohexane solution of 10% MeOH). 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 aqueous solution) to give the title compound as a white solid (18 mg, 0.040 mmol, yield 14.9%, purity 97%). UPLC-MS (Method 1) showed a m / z of 441.2 (M+H) at 1.57 min. + 439.1 (MH) - . 1 H NMR(500MHz,DMSO-d6)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).

[0918] Example 213: 3-(N-(...

Claims

1. A compound of formula (Id), or a pharmaceutically acceptable salt thereof, in: The groups X and Y are -NHSO2- or -SO2NH-; R1 is H or C 1-6 alkyl; R2 is selected from COOH and tetrazolium; R3 is selected from H, Cl, and C. 1-6 alkyl; R4 is selected from H, Cl, and F; R5 is selected from C 1-6 Alkyl and C 3-6 cycloalkyl; R6 is H; R7 represents CN and SO2-C. 1-6 Alkyl, SO2NR 13 R 14 Or a heteroaryl group, wherein the heteroaryl group is selected from: imidazolyl, pyrazolyl, pyrazinyl, pyridazinyl, thiazolyl, thiadiazolyl, isothiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, tetrazolyl, and triazolyl, wherein the heteroaryl group is optionally surrounded by one or more C 1-6 Alkyl substitution; R8 is selected from H and C. 1-6 Alkyl, C 1-6 Halogenated alkyl groups and halogens; R9 is H, C1-C3 alkyl, or halogen; R 10 and R 11 Together with the nitrogen atoms to which they are attached, they form 4-, 5-, 6-, or 7-membered monocyclic heterocyclic alkyl groups, wherein one or two carbon atoms of the 4-, 5-, 6-, or 7-membered monocyclic heterocyclic alkyl group are optionally replaced by groups selected from O, NH, S, and CO, and the 4-, 5-, 6-, or 7-membered monocyclic heterocyclic alkyl group is optionally replaced by one or more carbon atoms selected from C. 1-6 Alkyl, CN, C 3-6 cycloalkyl, OH, C 1-6 Alkoxy, halogen and C 1-6 Group substitution in haloalkyl groups; or R 10 and R 11 Together with the nitrogen atoms to which they are attached, they form 8-, 9-, or 10-membered bicyclic heterocyclic alkyl groups, wherein one carbon atom in the 8-, 9-, or 10-membered bicyclic heterocyclic alkyl ring is optionally replaced by a group selected from O and NH, and the 8-, 9-, or 10-membered bicyclic heterocyclic alkyl group is optionally replaced by one or more groups selected from C. 1-6 Substitution of groups in alkyl and OH groups; and R 13 and R 14 Each is represented by H.

2. The compound of formula (Id) according to claim 1, or a pharmaceutically acceptable salt thereof, wherein R 10 and R 11 Together with the nitrogen atoms to which they are attached, they form a 6-membered monocyclic heterocyclic alkyl group, wherein one or two carbon atoms of the 6-membered monocyclic heterocyclic alkyl group are optionally replaced by a group selected from O, NH, S, and CO, and the 6-membered monocyclic heterocyclic alkyl group is optionally replaced by one or more carbon atoms selected from C. 1-6 Alkyl, CN, C 3-6 cycloalkyl, OH, C 1-6 Alkoxy, halogen, C 1-6 Substitution of groups in haloalkyl groups.

3. The compound of formula (Id) according to claim 1, or a pharmaceutically acceptable salt thereof, wherein R7 is a heteroaryl group selected from the following: imidazolyl, pyrazolyl, pyrazinyl, pyridazinyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, tetrazolyl, and triazolyl, each of which is optionally oxidized by one or more C14 groups. 1-6 Alkyl group substitution.

4. The compound of formula (Id) according to claim 1, or a pharmaceutically acceptable salt thereof, wherein R7 is a heteroaryl group selected from the following: 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, thiazolyl-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, pyrazin-3-yl, pyrazin-4-yl, pyrazinyl, and 1,3,4-oxadiazol-2-yl, each of which is optionally substituted by one or more Me groups.

5. The compound of formula (Id) according to claim 1, or a pharmaceutically acceptable salt thereof, wherein the compound of formula (Id) is selected from the following substances:

6. A pharmaceutical composition comprising a compound of formula (Id) according to any one of claims 1 to 5, or a pharmaceutically acceptable salt thereof, and mixed with a pharmaceutically acceptable diluent.

7. A pharmaceutical composition comprising a compound of formula (Id) according to any one of claims 1 to 5, or a pharmaceutically acceptable salt thereof, and mixed with a pharmaceutically acceptable excipient.

8. A pharmaceutical composition comprising a compound of formula (Id) according to any one of claims 1 to 5, or a pharmaceutically acceptable salt thereof, and mixed with a pharmaceutically acceptable carrier.

9. Use of a compound of formula (Id) according to any one of claims 1 to 5, or a pharmaceutically acceptable salt thereof, in the preparation of a pharmaceutical composition for the treatment or prevention of ERAP1-related conditions, said conditions being selected from proliferative conditions, immune conditions, viral conditions, and inflammatory conditions.

10. The use according to claim 9, wherein the condition is a proliferative condition.

11. The use according to claim 10, wherein the condition is cancer.

12. The use according to claim 11, wherein the cancer is leukemia.

13. Use of a compound of formula (Id) according to any one of claims 1 to 5, or a pharmaceutically acceptable salt thereof, in the preparation of a pharmaceutical composition for generating antigen-presenting cells that present neoantigens in vitro or in vivo.

14. Use of a compound of formula (Id) according to any one of claims 1 to 5, or a pharmaceutically acceptable salt thereof, in the preparation of a pharmaceutical composition for inducing neoantigens in antigen-presenting cells.

15. The use according to claim 13 or 14, wherein the antigen-presenting cell is a dendritic cell.

16. An immunogenic composition comprising antigen-presenting cells obtained or available through the use described in claim 13 or 14, wherein the antigen-presenting cells are dendritic cells.

17. Use of the immunogenic composition according to claim 16 in the preparation of a pharmaceutical composition for treating or preventing cancer in a subject.

18. The use according to claim 17, wherein the immunogenic composition is a vaccine.

19. The use according to claim 9, wherein the compound is used in combination with immunotherapy.

20. The use according to claim 19, wherein the immunotherapy is an immune checkpoint intervention.

21. The use according to claim 20, wherein the immunotherapy is an antibody checkpoint inhibitor.

22. The use according to claim 21, wherein the antibody checkpoint inhibitor is an anti-PD-1 antibody, an anti-PD-L1 antibody, or an anti-CTLA4 antibody.

23. The use according to claim 9, wherein the disease is an immune disease.

24. The use according to claim 23, wherein the disease is selected from ankylosing spondylitis, Behçet's disease, psoriasis, and shotgun choroidal retinopathy.

25. The use according to claim 9, wherein the condition is an inflammatory condition.

26. The use according to claim 25, wherein the condition is an autoinflammatory condition.

27. The use according to claim 9, wherein the viral disease is an infectious viral disease selected from HIV, HPV, CMV and HCV.

28. A combination comprising a compound as defined in any one of claims 1 to 4 and an additional active agent.

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