(Hetero)aryl-sulfonamide compounds as modulators of GPR35

Abstract

One aspect of the present invention relates to a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein X-Y is -CONR6- or -NR6CO-; R6 and R7 are each independently H or alkyl; R8 is alkyl, cycloalkyl, (CH2) 26 , 32 , 25 , 30 , 24 , q , 23 , 28 , 27 , q , q , q , 31 , 21 , 29 , q -heterocycloalkyl or NR 34 R 35 ; ring C is phenyl or a 6-membered heteroaryl group containing at least one N, each of which is alkyl, haloalkyl, alkoxy, haloalkoxy, halo, CN, NR9SO2-R 10 , NR9COR 11 , NR 12 R 13 , OH, SO2NR 14 R 15 , CONR 16 R 17 , cycloalkyl, O(CH2) q NR 18 R 19 , (CH2) q -heterocycloalkyl and CO2R 20 and may be further substituted by one or more substituents selected from; ring A is phenyl or a 6-membered heteroaryl group; ring B is phenyl or a 6-membered heteroaryl group; n and p are each independently 0 to 4; each q is independently 0 to 4; R a and R b are alkyl, halo, haloalkyl, alkoxy, cycloalkoxy, haloalkoxy, cyano, NR 21 COR 22 , NR 21 SO2R 23 , (CH2) q SR 24 , (CH2) q SOR 25 , (CH2) q SO2R 26 , SO2NR 27 R 28 , (CH2) q OH, (CH2) q OR 29 , NR 30 R 31 , CONR 32 R33 , cycloalkyl and (CH2) q -Independently selected from heterocycloalkyl groups; L is a direct bond, or -O-CO-, -CO-O-, -O-CO-O-, -SO2-, -O-SO2-, -SO2-O-, -O-, -NR 36 -SO2-, -NR 36 -SO2-alkylene, -SO2-NR 36 -, -SO2-NR 36 -Selected from alkylene, alkylene, heteroalkylene, cycloalkylene, heterocycloalkylene, alkylene-cycloalkylene, alkylene-SO2-, -SO2-alkylene, alkylene-SO-, -SO-alkylene, alkylene-SO2-alkylene, alkylene-SO-alkylene, cycloalkylene-alkylene, alkylene-heterocycloalkylene, heterocycloalkylene-alkylene, -CO-heterocycloalkylene-alkylene, alkylene-heterocycloalkylene-CO-, CO2-heterocycloalkylene-alkylene, alkylene-heterocycloalkylene-CO2-, heteroalkylene-heterocycloalkylene, heterocycloalkylene-heteroalkylene, heteroalkylene-cycloalkylene, cycloalkylene-heteroalkylene, and the alkylene portion may be substituted. Further aspects of the present invention relate to pharmaceutical compositions and the use of the compounds in the treatment of various GPR35-related disorders. [Formula 1] JPEG2026521186000205.jpg33170

Description

[Technical Field]

[0001] This invention relates to a compound capable of modulating GPR35 function. This compound has potential therapeutic applications in the treatment of various disorders, including proliferative, immunological, and inflammatory disorders. [Background technology]

[0002] GPR35 is a class A, G protein-coupled receptor (Non-Patent Document 1, Non-Patent Document 2). The human gene can be expressed as three variants: variant 1 encodes a 309-amino acid polypeptide called GPR35a (short form), while variants 2 and 3 encode a longer form, GPR35b, with a 31-amino acid extension at the N-terminus. Although several ligands have been suggested as endogenous agonists of GPR35, GPCRs are formally still orphan receptors (Non-Patent Documents 3, 4, 5, 6, 7, 8, 9, 10, 11). Several synthetic and exogenous modulators, including agonists (Non-Patent Documents 12, 13, 14) and antagonists (Non-Patent Document 15), have also been reported. The synthetic chemical zaprinast, (5-(2-propoxyphenyl)-1H-[1,2,3]triazolo-[4,5-d]pyrimidine-7(4H)-one) is now a standard GPR35 agonist used as a reference compound (Non-Patent Literature 18). To date, however, the only GPR35 activator to have progressed to clinical trials is sodium cromoglycate (also known as RVT-1601 or PA101), which has been investigated in the treatment of chronic cough in idiopathic pulmonary fibrosis (Non-Patent Literature 1, Non-Patent Literature 37).

[0003] Both isoforms of GPR35 exhibit similar pharmacology with respect to reported agonists (Non-Patent Literature 13), and no potential unique functions are known. GPR35 is primarily expressed throughout the epithelium of the gastrointestinal (GI) tract, including the stomach, gallbladder, duodenum, small intestine, and colon (Non-Patent Literature 16, Non-Patent Literature 17), but its expression is particularly prominent in certain macrophages and dendritic cells (Non-Patent Literature 2, Non-Patent Literature 18). Evidence suggests a possible association between GPR35 and a range of conditions, including inflammation, asthma, cardiovascular disorders, and diabetes (Non-Patent Literature 18). Increased GPR35 expression is also associated with certain cancers (Non-Patent Literature 25). High GPR35 expression in gastric cancer is associated with a worse prognosis in patients. In vitro, GPR35 expression was associated with increased gastric cancer cell viability and proliferation, as well as reduced apoptosis (Non-Patent Literature 40). siRNA knockdown of GPR35 in macrophages further reduces the M2 markers ARG1 and PPARG, suggesting a role for GPR35 in supporting the cancer-promoting macrophage M2 phenotype.

[0004] GPR35 signaling therefore represents an attractive pathway for therapeutic interventions for the treatment of a range of diseases. Thus, there is a continued need to develop novel small molecule GPR35 modulators. [Prior art documents] [Non-patent literature]

[0005] [Non-Patent Document 1] Quon et al, ACS Pharmacology and Translational Science 3, 801-812 (2020) [Non-Patent Document 2] Kaya et al, Frontiers in Immunology 12: 717392 (2021) [Non-Patent Document 3] Wang et al, J Biol Chem 281, 22021-22028 (2006)

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Patent Document

[0006]

Patent Document 33

Summary of the Invention

Problems to be Solved by the Invention

[0007] The present invention aims to provide a compound capable of modulating GPR35. As is clear from the above considerations, such compounds have potential therapeutic uses in the treatment of various disorders including proliferative disorders, immune disorders, and inflammatory disorders.

Means for Solving the Problems

[0008] A first aspect of the present invention relates to a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof,

Chemical Formula

[0009] Advantageously, the compounds of the claims can modulate GPR35, thereby making them therapeutically interesting in the treatment of various disorders, including oncological applications, inflammatory disorders, and gastrointestinal disorders.

[0010] Another aspect of the present invention relates to a pharmaceutical composition comprising the above-mentioned compound and a pharmaceutically acceptable diluent, excipient, or carrier.

[0011] Another aspect of the present invention relates to the pharmaceutical composition described above for use as a pharmaceutical.

[0012] Another aspect of the present invention relates to the compounds described above for use in the treatment or prevention of disorders selected from proliferative disorders, gastrointestinal disorders, fibrotic disorders, cardiovascular diseases, and inflammatory disorders.

[0013] Another aspect of the present invention relates to the pharmaceutical composition described above for use in the treatment or prevention of a disorder selected from proliferative disorders, gastrointestinal disorders, fibrotic disorders, cardiovascular diseases, and inflammatory disorders.

[0014] Another aspect of the present invention relates to a method for treating a disorder, comprising administering the above-mentioned compound or pharmaceutical composition to a target.

[0015] Another aspect of the present invention relates to compounds as defined herein, or pharmaceutically acceptable salts or solvates thereof, for use in the treatment or prevention of GPR35-related diseases or disorders.

[0016] Another aspect of the present invention relates to the use of compounds as defined herein, or pharmaceutically acceptable salts or solvates thereof, in the preparation of pharmaceuticals for the treatment or prevention of GPR35-related diseases or disorders in a subject.

[0017] Another aspect of the present invention relates to the use of compounds as defined herein, or pharmaceutically acceptable salts or solvates thereof, in the preparation of pharmaceuticals for the treatment or prevention of disorders selected from proliferative disorders, gastrointestinal disorders, inflammatory disorders, fibrotic disorders, and cardiovascular diseases. [Modes for carrying out the invention]

[0018] This invention relates to compounds that can modulate GPR35.

[0019] "Alkyl" is defined herein as a linear or branched alkyl radical, preferably C 1-20 Alkyl, more preferably C 1-12 Alkyl, more preferably C 1-10 Alkyl or C 1-6 Alkyls include, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, and hexyl. More preferably, the alkyl is C 1-3 It is alkyl.

[0020] "Cycloalkyl" is defined herein as a cyclic alkyl ring, preferably C 3-7 -Cycloalkyl, more preferably C 3-6 -It is a cycloalkyl group. Preferred examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl, or condensed bicyclic ring systems, such as norbornane.

[0021] As used herein, the terms “aryl” or “aromatic” are C 6-12 This refers to an aromatic group, which may be benzo-condensed, for example, phenyl or naphthyl.

[0022] "Halogen" or "halo" is defined herein as chloro, fluoro, bromo or iodo.

[0023] "Haloalkyl" is defined herein as a straight-chain or branched alkyl radical as defined above, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, hexyl, which is substituted with one or more halogen atoms (which may be the same or different) such as fluorine, chlorine, bromine and iodine. Preferably, the haloalkyl group is C 1-20 haloalkyl, more preferably C 1-12 haloalkyl, even more preferably C 1-10 haloalkyl or C 1-6 haloalkyl. Preferred examples are CF3 and CHF2, with CF3 being particularly preferred.

[0024] "Alkoxy" is defined herein as an oxygen atom bonded to an alkyl group as defined above. Preferably, the alkoxy group is C 1-20 alkoxy, more preferably C 1-12 alkoxy, even more preferably C 1-10 alkoxy or C 1-6 alkoxy, for example, methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, tert-butoxy, pentoxy and hexoxy. A particularly preferred example is methoxy (-OCH3).

[0025] "Haloalkoxy" is defined herein as an alkoxy group substituted with one or more halogen atoms (which may be the same or different) such as fluorine, chlorine, bromine and iodine. Preferably, the haloalkoxy group is C 1-20 haloalkoxy, more preferably C 1-12 haloalkoxy, even more preferably C 1-10 haloalkoxy or C 1-6 haloalkoxy. A particularly preferred example is OCF3.

[0026] "Heteroaryl" is defined herein as a monocyclic aromatic ring containing one or more heteroatoms (which may be the same or different), such as oxygen, nitrogen or sulfur. Examples of suitable 6-member heteroaryl groups include pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl and triazinyl.

[0027] "Aralkyl" is defined herein as an alkyl group as defined above substituted by one or more aryl groups as defined above.

[0028] "Heterocycloalkyl" refers to a cyclic aliphatic group containing one or more heteroatoms selected from nitrogen, oxygen and sulfur, which may be interrupted by one or more -(CO)- groups in the ring and / or contain one or more double bonds in the ring. Preferably, the heterocycloalkyl group is monocyclic or bicyclic. Preferably, the heterocycloalkyl group is C 3-7 -heterocycloalkyl, more preferably C 3-6 -heterocycloalkyl. Alternatively, the heterocycloalkyl group is C 4-7 -heterocycloalkyl, more preferably C 4-6 -heterocycloalkyl. Preferred heterocycloalkyl groups include, but are not limited to, piperazinyl, piperidinyl, morpholinyl, thiomorpholinyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydropyranyl, oxetanyl and azetidinyl. Preferably, the heterocycloalkyl group is monovalent. Preferably, the heterocycloalkyl group is monocyclic. The heterocycloalkyl group may be bonded to an adjacent group via a carbon atom or via a heteroatom (e.g., nitrogen).

[0029] As used herein, the term "alkenyl" refers to both straight-chain and branched carbon chains having at least one carbon-carbon double bond. In some embodiments, the alkenyl group is C2-C 12It may contain an alkenyl group. In other embodiments, the alkenyl is C2-C 10 The group comprises a C2-C8 group, a C2-C6 group, or a C2-C4 alkenyl group. In one embodiment of the alkenyl, the number of double bonds is 1 to 3; in another embodiment of the alkenyl, the number of double bonds is 1. Other ranges of carbon-carbon double bonds and carbon numbers are also intended, depending on the position of the alkenyl moiety on the molecule. 10 The "-alkenyl" group can contain more than one double bond in its chain.

[0030] As used herein, the term "alkynyl" refers to both linear and branched carbon chains having at least one carbon-carbon triple bond. In some embodiments, the alkynyl group is C2-C 12 It may contain an alkynyl group. In other embodiments, the alkynyl is C2-C 10 The group comprises a C2-C8 group, a C2-C6 group, or a C2-C4 alkynyl group. In one embodiment of the alkynyl, the number of triple bonds is 1 to 3; in another embodiment of the alkenyl, the number of triple bonds is 1. A particularly preferred alkynyl group is -C≡CH.

[0031] As used herein, the term "alkylene" refers to a linear or branched saturated divalent hydrocarbon radical. Preferably, the alkylene group is a linear saturated divalent hydrocarbon radical containing 1 to 6 carbon atoms, or a branched saturated divalent hydrocarbon radical containing 3 to 6 carbon atoms.

[0032] As used herein, the term “heteroalkylene” refers to a divalent alkylene as defined above, having one or more carbon atoms replaced by heteroatoms such as sulfur, oxygen, or nitrogen (for example, in the form NR, where R is H or alkyl). Heteroalkylene groups can be linked to adjacent groups via carbon or heteroatoms.

[0033] Preferably, the heteroalkylene group is a divalent alkylene having one or two carbon atoms, more preferably one carbon atom, which are replaced by a group selected from sulfur, oxygen, and nitrogen.

[0034] Preferably, the heteroalkylene group is a divalent alkylene having one or more carbon atoms substituted with oxygen, more preferably one or two carbon atoms substituted with oxygen, and more preferably one carbon atom substituted with oxygen.

[0035] Preferably, the heteroalkylene group is a linear saturated divalent hydrocarbon radical containing 2 to 6 carbon atoms in which one carbon is replaced by a heteroatom, or a branched saturated divalent hydrocarbon radical containing 3 to 6 carbon atoms in which one carbon is replaced by a heteroatom.

[0036] As used herein, the term "cycloalkylene" refers to a divalent cyclic saturated hydrocarbon radical preferably containing 3 to 10 carbon atoms. Preferably, the cycloalkylene group is a 3-membered, 4-membered, 5-membered, or 6-membered cycloalkylene group, more preferably a 3-membered, 4-membered, or 5-membered cycloalkylene group.

[0037] As used herein, the term “heterocycloalkylene” refers to a divalent cycloalkylene group as defined above, having one or more carbon atoms replaced by heteroatoms, such as sulfur, oxygen, or nitrogen. When a carbon atom in a cycloalkylene group is replaced by nitrogen, the nitrogen may be in the form of NR, where R is H or alkyl, or the nitrogen may be linked to an adjacent group in the heterocycloalkylene group, as illustrated below, for example:

[0038] Preferably, the heterocycloalkylene group is a 3-membered, 4-membered, 5-membered, or 6-membered heterocycloalkylene group, more preferably a 3-membered, 4-membered, or 5-membered heterocycloalkylene group.

[0039] As used herein, preferably, alkyl is C 1- C6 alkyl, haloalkyl is C 1- C6 haloalkyl, haloalkoxy is C 1- C6 haloalkoxy, alkoxy is C 1- C6 alkoxy.

[0040] The compounds according to the invention One aspect of the present invention relates to a compound of formula (I'), or a pharmaceutically acceptable salt or solvate thereof,

Chemical formula

[0041] In one preferred embodiment, XY is NH-CO.

[0042] In one preferred embodiment, the compound is of formula (Ia'): [ka] (Ia') And, In the formula, X1, X2, X3, X4, and X5, together with the carbons to which X1 and X5 are bonded, form a phenyl group or a 6-membered heteroaryl group containing at least one N, where the phenyl or heteroaryl group is alkyl, CN, haloalkyl, alkoxy, haloalkoxy, halo, or NR9SO2R 10 NR9COR 11 , NR 12 R 13 OH, SO2NR 14 R 15 CONR 16 R 17 , cycloalkyl, O(CH2) q NR 18 R 19 , (CH2) q - Heterocycloalkyl and CO2R 20 They may be further substituted by one or more substituents selected from; A, B, Z, L, X, Y, R a , R b R7, R8, n, and p are as defined above.

[0043] In one preferred embodiment, the compound is of formula (Ib'): [ka] (Ib') And, During the ceremony: X1 is either N or CR1; X3 is either N or CR3; X4 is either N or CR4; X5 is either N or CR5; R1, R3, R4, and R5 are H, CN, alkyl, haloalkyl, alkoxy, haloalkoxy, halo, NR 12 R 13 OH,NR9SO2-alkyl,CONR 16 R 17 , cycloalkyl, O(CH2) q NR 18 R 19 and (CH2) q-Independently selected from heterocycloalkyl groups; In the formula, R a , R b R7, R8, n, p, L, A, B, X, Y, and Z are as defined above.

[0044] In a preferred embodiment, X1, X2, X3, X4, and X5, together with the carbons to which X1 and X5 are bonded, form a six-membered heteroaryl group containing one or two nitrogen atoms, preferably selected from pyridinyl, pyrimidinyl, pyrazidinyl, and pyrazinyl.

[0045] In one preferred embodiment, ring A is: [ka] (In the formula, ring A is a phenyl group or a 6-membered heteroaryl group.) B, C, Z, L, X, Y, R a , R b n and p are as defined above.

[0046] In another preferred embodiment, ring A is: [ka] And, In the formula, A is a 5-membered heteroaryl group, and n is an integer between 0 and 3.

[0047] In one preferred embodiment, A is selected from pyrrolyl, thiazolyl, oxazolyl, furanyl, thienyl, and pyrazolyl, each of which has 1 to 3 R as defined above. a It may be substituted by a base.

[0048] In a preferred embodiment, the compound is of formula (I), or a pharmaceutically acceptable salt or solvate thereof. [ka] (I) XY is -CONR6- or -NR6CO-; R6 and R7 are independently selected from H and alkyl, more preferably from H; R8 is alkyl, cycloalkyl, (CH2) q - Heterocycloalkyl and NR 34 R 35 Selected from; Ring C is a phenyl group or a 6-membered heteroaryl group containing at least one N, each of which is alkyl, haloalkyl, alkoxy, haloalkoxy, halo, CN, NR9SO2-R 10 NR9COR 11 , NR 12 R 13 OH, SO2NR 14 R 15 CONR 16 R 17 , cycloalkyl, O(CH2) q NR 18 R 19 , (CH2) q - Heterocycloalkyl and CO2R 20 They may be further substituted by one or more substituents selected from; Each R9 is independently selected from H and alkyl groups; R 10 -R 19 is independently selected from H, alkyl, aralkyl, alkoxy, alkoxyalkyl, hydroxyalkyl and cycloalkyl; or R 12 and R 13 Together with the nitrogen to which they are bonded, they form a 4- to 7-membered heterocyclic group which may contain further groups selected from O, NH, S, SO and SO2; R 14 and R 15 Together with the nitrogen to which they are bonded, they form a 4- to 7-membered heterocyclic group which may contain further groups selected from O, NH, S, SO and SO2; R 16 and R 17Together with the nitrogen to which they are bonded, they form a 4- to 7-membered heterocyclic group which may contain further groups selected from O, NH, S, SO and SO2; R 18 and R 19 Together with the nitrogen to which they are bonded, they form a 4- to 7-membered heterocyclic group which may contain further groups selected from O, NH, S, SO and SO2; R 20 The alkyl, aralkyl, alkoxyalkyl, hydroxyalkyl, and cycloalkyl elements are selected from alkyl, aralkyl, alkoxyalkyl, hydroxyalkyl, and cycloalkyl elements; Ring A is a phenyl group or a 6-membered heteroaryl group; Ring B is a phenyl group or a 6-membered heteroaryl group; n and p are each independent integers between 0 and 4; Each q is an independent integer between 0 and 4; Each R a and each R b These include alkyl, halo, haloalkyl, alkoxy, cycloalkoxy, haloalkoxy, cyano, and NR. 21 COR 22 , NR 21 SO2R 23 , (CH2) q SR 24 , (CH2) q SOR 25 , (CH2) q SO2R 26 SO2NR 27 R 28 , (CH2) q OH, (CH2) q Ure 29 , NR 30 R 31 CONR 32 R 33 , cycloalkyl and (CH2) q -Selected independently from heterocycloalkyl groups; Each R 21 is independently selected from H and alkyl; R 22 ~R 35is independently selected from H, alkyl, aralkyl, alkoxy, alkoxyalkyl, hydroxyalkyl and cycloalkyl; or R 27 and R 28 They form a 4- to 7-membered heterocyclic group, which may include further groups selected from O, NH, S, SO and SO2, together with the nitrogen to which they are bonded; or R 30 and R 31 They form a 4- to 7-membered heterocyclic group, which may include further groups selected from O, NH, S, SO and SO2, together with the nitrogen to which they are bonded; or R 32 and R 33 Together with the nitrogen to which they are bonded, they form a 4- to 7-membered heterocyclic group which may contain further groups selected from O, NH, S, SO and SO2; L is a direct bond, or -O-CO-, -CO-O-, -O-CO-O-, -SO2-, -O-SO2-, -SO2-O-, -O-, -NR 36 -SO2-, -NR 36 -SO2-alkylene, alkylene-SO2-NR 36 -, -SO2-NR 36 -, -SO2-NR 36 -Alkylene, Alkylene-NR 36-SO2-, alkylene, heteroalkylene, cycloalkylene, heterocycloalkylene, alkylene-cycloalkylene, alkylene-SO2-, -SO2-alkylene, alkylene-SO-, -SO-alkylene, alkylene-SO2-alkylene, alkylene-SO-alkylene, cycloalkylene-alkylene, alkylene-heterocycloalkylene, heterocycloalkylene-alkylene, -CO-heterocycloalkylene-alkylene, alkylene-heterocycloalkylene The group is selected from n-CO-, CO2-heterocycloalkylene-alkylene, alkylene-heterocycloalkylene-CO2-, heteroalkylene-heterocycloalkylene, heterocycloalkylene-heteroalkylene, heteroalkylene-cycloalkylene, and cycloalkylene-heteroalkylene, and the alkylene portion of the above group may be substituted with one or more substituents independently selected from halo, alkyl, haloalkyl and cycloalkyl; R 36 is independently selected from H and alkyl; Z is a group selected from alkyl, cycloalkyl, aryl, heteroaryl, and heterocycloalkyl groups, each of which may be further substituted with one or more groups independently selected from CN, halo, alkyl, OH, alkenyl, alkynyl, alkoxy, haloalkyl, and haloalkoxy groups.

[0049] In one preferred embodiment, A is selected from phenyl, pyridinyl, pyrimidinyl, and pyrazinyl, more preferably from phenyl and pyridinyl, each of which has 1 to 4 R a Base, 1 to 3 R a It may be substituted by a base.

[0050] In one preferred embodiment, each R a C 1-6 -alkyl, halo, C 1-6 -Haloalkyl, C 1-6 -alkoxy, C 3-6 -Cycloalkoxy, C 1-6- Haloalkoxy, cyano, NHCO-C 1-6 -alkyl, NHSO2-C 1-6 -alkyl, SC 1-6 -alkyl, SO-C 1-6 -alkyl, CH2SO2-C 1-6 -alkyl, SO2-C 1-6 -alkyl, SO2N(C 1-6 -alkyl)2,CH2OH,CH2O-C 1-6 -alkyl, N(C 1-6 -alkyl)2, CON(C 1-6 A CH2-heterocycloalkyl element is independently selected from CH2-alkyl, cycloalkyl, heterocycloalkyl, and CH2-heterocycloalkyl elements.

[0051] In one preferred embodiment, each R a C 1-6 -alkyl, halo, C 1-6 -Haloalkyl, C 1-6 -alkoxy, C 3-6 -Cycloalkoxy and C 1-6 - Selected independently of haloalkoxys.

[0052] In one preferred embodiment, each R a The element is independently selected from halo, alkyl, and alkoxy.

[0053] In one preferred embodiment, each R a The following are independently selected from Me, halo, CF3, OMe, OCF3, amino, cyano, NHCOMe, NHSO2Me, S-Me, CH2SO2Me, SO2Me, SO2NMe2, CH2OH, CH2OMe, cycloalkyl, CH2-(morpholine-4-yl), and morpholine-4-yl.

[0054] In one preferred embodiment, each R a It is selected independently from F, Me, and OMe.

[0055] In one preferred embodiment, n is 0.

[0056] In one preferred embodiment, the compound is of formula (Ic): [ka] (I C) And, During the ceremony: X1 is either N or CR1; X3 is either N or CR3; X4 is either N or CR4; X5 is either N or CR5; R1, R3, R4, and R5 are H, CN, alkyl, haloalkyl, alkoxy, haloalkoxy, halo, NR 12 R 13 OH,NR9SO2-alkyl,CONR 16 R 17 , cycloalkyl, O(CH2) q NR 18 R 19 and (CH2) q -Independently selected from heterocycloalkyl groups; A is a phenyl group or a pyridinyl group, more preferably phenyl; R a , R b R7, R8, n, p, L, A, B, X, Y, and Z are as defined above.

[0057] In one preferred embodiment, R1, R3, R4, and R5 are H, C 1-6 -alkyl, C 1-6 -Haloalkyl, C 1-6 -alkoxy, C 1-6 - Haloalkoxy, Cl, F, NH2, NH-C 1-6 -alkyl, NH-C 3-6 -Cycloalkyl, N(C) 1-6 -alkyl) 2、 OH, NHSO2-C 1-6 -alkyl, CONR 17 R 18 , C 3-6 -Cycloalkyl, NH-(hydroxy-C) 1-6 -alkyl), NH-(C 1-6-alkoxy), CH2-heterocycloalkyl, and heterocycloalkyl are each independently selected.

[0058] In a preferred embodiment, R1, R3, R4, and R5 are H, Me, MeO, CF3, Cl, F, NH2, NH-Me, NH-cyclopropyl, and NMe. 2、 Each of the following can be independently selected: OH, NHSO2Me, CONH2, cyclopropyl, NHCH2CH2OH, OCH2CH2NH2, NHCH2CH2OMe, CH2-(morpholine-4-yl), and morpholine-4-yl.

[0059] In a preferred embodiment: X1 is CR1; X3 is CR3; X4 is N; and X5 is CR5.

[0060] In a preferred embodiment: X1 is N; X3 is CR3; X4 is CR4; and X5 is CR5.

[0061] In a preferred embodiment: X1 is CR1; X3 is N; X4 is CR4; and X5 is CR5.

[0062] In a preferred embodiment: X1 is CR1; X3 is CR3; X4 is CR4; and X5 is N.

[0063] In a preferred embodiment: X1 is N; X3 is CR3; X4 is N; X5 is CR5.

[0064] In a preferred embodiment: X1 is N; X3 is CR3; X4 is CR4; and X5 is N.

[0065] In a preferred embodiment: X1 is N; X3 is N; X4 is CR4; and X5 is CR5.

[0066] In a preferred embodiment: X1 is CR1; X3 is N; X4 is N; X5 is CR5.

[0067] In a preferred embodiment: X1 is CR1; X3 is CR3; X4 is N; X5 is N.

[0068] In a preferred embodiment: X1 is CR1; X3 is N; X4 is CR4; and X5 is N.

[0069] In one preferred embodiment, R1, R4, and R5 are H.

[0070] In one preferred embodiment, X3 is CR3 and R3 is H, CN, C 1-6 -alkyl, C 3-6 -Cycloalkyl, halo, C 1-6 -alkoxy, C 1-6 -Haloalkyl, C 1-6 - Haloalkoxy and O(CH2) q NR 18 R 19 , more preferably H, CN, C 1-6 -alkyl, C 1-6 -alkoxy, C 3-6 -Cycloalkyl, halo, and O(CH2) q NR 18 R 19 Selected from.

[0071] In a preferred embodiment, X3 is CR3, and R3 is H, Me, CN, MeO, CF3, Cl, F, NH2, NH-Me, NH-cyclopropyl, NMe 2、 OH, NHSO2Me, CONH2, cyclopropyl, NHCH2CH2OH, NHCH2CH2OMe, CH2-(morpholine-4-yl), and morpholine-4-yl, more preferably selected from H, Me, OMe, CN, cyclopropyl, and OCH2CH2NH2.

[0072] In one preferred embodiment, X3 is CR3 and R3 is H, CN, C 1-6 -alkyl, C 3-6 -Cycloalkyl, halo, C 1-6-alkoxy, C 1-6 -Haloalkyl, C 1-6 - Haloalkoxy and O(CH2) q NR 18 R 19 , more preferably H, CN, C 1-6 -alkyl, C 1-6 -alkoxy, C 3-6 -Cycloalkyl, halo, and O(CH2) q NR 18 R 19 Selected from; R1, R4 and R5 are H.

[0073] In a preferred embodiment, X3 is CR3, and R3 is H, Me, CN, MeO, CF3, Cl, F, NH2, NH-Me, NH-cyclopropyl, NMe 2、 OH, NHSO2Me, CONH2, cyclopropyl, NHCH2CH2OH, NHCH2CH2OMe, CH2-(morpholine-4-yl), and morpholine-4-yl, more preferably selected from H, Me, OMe, CN, cyclopropyl, and OCH2CH2NH2; R1, R4, and R5 are H.

[0074] In one preferred embodiment, the compound is of formula (Id): [ka] (Id) And, During the ceremony: X1 is either N or CR1; X2 is either N or CR2; X4 is either N or CR4; X5 is either N or CR5; R1, R 2、 R4 and R5 are H, CN, alkyl, haloalkyl, alkoxy, haloalkoxy, halo, NR 12 R 13 OH,NR9SO2-alkyl,CONR 16 R 17 , cycloalkyl, O(CH2) q NR 18 R 19and (CH2) q -Independently selected from heterocycloalkyl groups; A is a phenyl group or a pyridinyl group, more preferably phenyl; R a , R b R7, R8, n, p, L, A, B, X, Y, and Z are as defined above.

[0075] In a preferred embodiment: X1 is N; X2 is CR2; X4 is N; X5 is CR5.

[0076] In one preferred embodiment, R1, R4, and R5 are H.

[0077] In one preferred embodiment, X2 is CR2, and R2 is H, CN, C 1-6 -alkyl, C 3-6 -Cycloalkyl, halo, C 1-6 -alkoxy, C 1-6 -Haloalkyl, C 1-6 - Haloalkoxy and O(CH2) q NR 18 R 19 , more preferably H, CN, C 1-6 -alkyl, C 1-6 -alkoxy, C 3-6 -Cycloalkyl, halo, and O(CH2) q NR 18 R 19 Selected from.

[0078] In one preferred embodiment, X2 is CR2, and R2 is H, CN, C 1-6 -alkyl, C 3-6 -Cycloalkyl, halo, C 1-6 -alkoxy, C 1-6 -Haloalkyl, C 1-6 - Haloalkoxy and O(CH2) q NR 18 R 19 , more preferably H, CN, C 1-6 -alkyl, C 1-6 -alkoxy, C 3-6-Cycloalkyl, halo, and O(CH2) q NR 18 R 19 Selected from; R1, R4 and R5 are H.

[0079] In one preferred embodiment, R7 is H.

[0080] In one preferred embodiment, R8 is selected from alkyl, cycloalkyl, heterocycloalkyl, and dialkylamino, more preferably from Me, cyclopropyl, morpholine-4-yl, and N(Me)2.

[0081] In a preferred embodiment, B is selected from phenyl, pyridinyl, pyrazidinel, pyrazinyl, pyrimidinyl, oxazolyl, isoxazolyl, thiadiazolyl, pyrazolyl and thiazolyl, each of which has 1 to 4 R as defined above. b It may be substituted by a base.

[0082] In one preferred embodiment, B is 1 to 4 R as described above. b Phenyl and pyridinyl, which may be substituted with a group, are selected, more preferably from phenyl.

[0083] In one preferred embodiment, each R b C 1-6 -alkyl, halo, C 1-6 -Haloalkyl, C 1-6 -alkoxy, C 3-6 -Cycloalkoxy and C 1-6 - Selected independently of haloalkoxys.

[0084] In one preferred embodiment, each R b The following are independently selected from Me, halo, CF3, OMe, OCF3, amino, cyano, NHCOMe, NHSO2Me, S-Me, CH2SO2Me, SO2Me, SO2NMe2, CH2OH, CH2OMe, cycloalkyl, CH2-(morpholine-4-yl), and morpholine-4-yl.

[0085] In all of the embodiments described herein, B is preferably a phenyl group or a pyridinyl group, each of which has 1 to 4 R groups as defined above. b It may be substituted by a base.

[0086] In a preferred embodiment, B is a phenyl group which may be substituted with one or two groups selected from halo and alkoxy groups.

[0087] In a preferred embodiment, B is a phenyl group which may be substituted with one or two groups selected from F and MeO.

[0088] In one preferred embodiment, B is a phenyl group which may be substituted with one or two halo groups.

[0089] In one preferred embodiment, p is 0.

[0090] In one preferred embodiment, Z is C 1-6 -alkyl, phenyl, heteroaryl, C 3-6 -A group selected from cycloalkyl and 4-membered, 5-membered, or 6-membered heterocycloalkyl groups, each of which may be further substituted with one or more groups selected from alkyl, alkenyl, alkynyl, OH, halo, haloalkyl, and alkoxy.

[0091] In a preferred embodiment, Z is a group selected from phenyl, pyridinyl, methoxyphenyl, alkyl, tolyl, morpholinyl, pyrazolyl, oxetanyl, cyclohexyl, cyclopentyl, cyclobutyl, cyclopropyl, and tetrahydropyranyl, more preferably phenyl.

[0092] In a preferred embodiment, Z is a group selected from phenyl, alkyl, tolyl, morpholinyl, pyrazolyl, oxetanyl, cyclohexyl, cyclopentyl, cyclobutyl, cyclopropyl, and tetrahydropyranyl.

[0093] In a preferred embodiment, Z is a group selected from phenyl, cyclopropyl, and tetrahydropyranyl, more preferably phenyl. More preferably, Z is phenyl.

[0094] In the compounds described herein, L is a direct bond, or -O-CO-, -CO-O-, -O-CO-O-, -SO2-, -O-SO2-, -SO2-O-, -O-, -NR 36 -SO2-, -NR 36 -SO2-alkylene, alkylene-SO2-NR 36 -, -SO2-NR 36 -, -SO2-NR 36 -Alkylene, Alkylene-NR 36 -SO2-, alkylene, heteroalkylene, cycloalkylene, heterocycloalkylene, alkylene-cycloalkylene, alkylene-SO2-, -SO2-alkylene, alkylene-SO-, -SO-alkylene, alkylene-SO2-alkylene, alkylene-SO-alkylene, cycloalkylene-alkylene, alkylene-heterocycloalkylene, heterocycloalkylene-alkylene, -CO-heterocycloalkylene-alkylene, alkylene-heterocycloalkylene-CO-, CO2-heterocycloalkylene-alkylene, alkylene The group is selected from n-heterocycloalkylene-CO2-, heteroalkylene-heterocycloalkylene, heterocycloalkylene-heteroalkylene, heteroalkylene-cycloalkylene, and cycloalkylene-heteroalkylene, wherein the alkylene portion of the above group may be substituted with one or more substituents independently selected from halo, alkyl, and cycloalkyl; the alkylene portion of the above group may be substituted with one or more substituents selected from halo, haloalkyl, alkyl, and cycloalkyl.

[0095] Preferably, R 36 is H or Me, more preferably H.

[0096] In one preferred embodiment, L is absent, and the Z group is directly bonded to the B ring.

[0097] In one preferred embodiment, L is present.

[0098] In one preferred embodiment, L is -O-.

[0099] In one preferred embodiment, L is a heteroalkylene group as defined above.

[0100] In one preferred embodiment, L is an alkylene group having one or two carbon atoms, more preferably one carbon atom, substituted with a group selected from sulfur, oxygen, and nitrogen. In one preferred embodiment, L is an alkylene group having one or two carbon atoms, more preferably one carbon atom, substituted with oxygen. In one preferred embodiment, the heteroalkylene is a group selected from -O-alkylene, alkylene-O-, and alkylene-O-alkylene.

[0101] In one preferred embodiment, L is -O-CO-, -CO-O-, -O-CO-O-, -O-, -NH-SO2-, -NH-SO2-(CR'R) a -,-(CR'R) a -SO2-NH-, -SO2-NH-, -SO2-NH-(CR'R”) a -,-(CR'R) a -NH-SO2-, -O-SO2-, -SO2-O-, -(CR'R”) a -,-(CH=CH) c -,-(CR'R) a -(CH=CH) c -,-(CH=CH) c -(CR'R) a -,-(CR'R) a-(CH=CH) c -(CR'R) b -,-(CR'R) a -O-, -O-(CR'R) a -,-(CR'R) a -O-(CR'R) b -,-(CR'R) a -S-(CR'R) b -,-(CR'R) a -SO2-, -SO2-(CR'R)" b -,-(CR'R) a -SO-, -SO-(CR'R) b -,-(CR'R) a -SO-(CR'R) b -,-(CR'R) a -SO2-(CR'R) b -,-(CR'R) a -S-(CR'R) b -O-, -O-(CR'R) a -S-(CR'R) b -,-(CR'R) a -O-(CR'R) b -S-, -S-(CR'R) a -O-(CR'R) b -,-(CR'R) a -S-, -S-(CR'R) a -, -O-(CR'R) a -O, heterocycloalkylene, cycloalkylene-O-, -O-cycloalkylene-, heterocycloalkylene-O-, -O-heterocycloalkylene-, heterocycloalkylene-(CR'R) a ,-(CR'R) a -heterocycloalkylene-, heterocycloalkylene-(CR'R) a -O-, -O-(CR'R) a -heterocycloalkylene-, -(CR'R)" a -O-heterocycloalkylene-, heterocycloalkylene-O-(CR'R) a ,-O-heterocycloalkylene-(CR'R) a -,-CO-heterocycloalkylene-(CR'R)a ,-(CR'R) a -heterocycloalkylene-CO-,-CO2-heterocycloalkylene-(CR'R)") a ,-(CR'R) a -heterocycloalkylene-CO2- and -(CR'R)'' a -Selected from heterocycloalkylene-O-, where a and b are each independently integers from 1 to 6, c is an integer from 1 to 3, and R' and R'' are each independently selected from H, alkyl, halo, and haloalkyl.

[0102] In one preferred embodiment, L is -O-CO-, -CO-O-, -O-CO-O-, -O-, -NH-SO2-, -NH-SO2-(CH2) a -, -SO2-NH-, -SO2-NH-(CH2) a -, -O-SO2-, -SO2-O-, -(CH2) a -,-(CH2) a -O-, -O-(CH2) a -,-(CH2) a -O-(CH2) b -,-(CH2) a -S-(CH2) b -,-(CH2) a -SO2-, -SO2-(CH2) b -,-(CH2) a -SO-, -SO-(CH2) b -,-(CH2) a -SO-(CH2) b -,-(CH2) a -SO2-(CH2) b -,-(CH2) a -S-(CH2) b -O-, -O-(CH2) a -S-(CH2) b -,-(CH2) a -O-(CH2) b -S-, -S-(CH2) a -O-(CH2) b -,-(CH2) a -S-, -S-(CH2) a -, -O-(CH2) a-O-, heterocycloalkylene-(CH2) a -O-, -O-(CH2) a -heterocycloalkylene-, -(CH2) a -O-heterocycloalkylene-, heterocycloalkylene-O-(CH2) a , -O-heterocycloalkylene-(CH2) a -,-CO-heterocycloalkylene-(CH2) a ,-(CH2) a -heterocycloalkylene-CO-, -CO2-heterocycloalkylene-(CH2) a ,-(CH2) a -heterocycloalkylene-CO2- and -(CH2) a -Selected from heterocycloalkylene-O-, where a and b are each independent integers from 1 to 6.

[0103] In one preferred embodiment, L is -O-, -O-CO-, -CO-O-, -O-CO-O-, -CH2-, -CH2CH2-, -CH2CH2CH2-, -CH2OCH2-, -CH2O-, -OCH2-, -CH2CH2O-, -OCH2CH2-, -CH2CH2S-, -SCH2CH2-, -CH2CH2CH2O-, -OCH2CH2CH2-, -OCH2CH2CH2O-, -CH2SO2CH2 -, -CH2SOCH2-, -CH2SCH2-, -NH-SO2-, -NH-SO2-CH2-, -O-SO2-, -SO2-O-, -SO2-NH-, -SO2-NH-CH2-, -CH2CH2CH2 CH2O-, -OCH2CH2CH2CH2-, -CH2SO2-, -SO2CH2-, -OCH2CO-, -COCH2O-, -CH2SO-, -SOCH2-, -CH2OCH2, -OCH2SCH2- 、 -CH2SCH2O-, CH2-SO2-NH-, -CH2-NH-SO2-, -SO2-NH-CH2CH2-, -CH2CH2-NH-SO2-, -CH=CH-, -OCH(Me )-, -CH(Me)O-, -OCH(CF3)-, -CH(CF3)O-, -CH2CH(CF3)-, -CH(CF3)CH2-, -SO2N(Me)-, -N(Me)SO2-, [ka] Selected from JPEG2026521186000012.jpg100170.

[0104] In all of the above embodiments, L is preferably -O-, -NH-SO2-, -NH-SO2-(CH2) a -, -SO2-NH-, -SO2-NH-(CH2) a -, -O-SO2-, -SO2-O-, -(CH2) a -,-(CH2) a -O-, O-(CH2) a -,-(CH2) a -O-(CH2) b -,-(CH2) a -S-(CH2) b -,-(CH2) a -SO-(CH2) b -,-(CH2) a -SO2-, -SO2-(CH2) b -,-(CH2) a -SO-, -SO-(CH2) b -,-(CH2) a -SO2-(CH2) b -,-(CH2) a -S-(CH2) b -O-, -O-(CH2) a -S-(CH2) b -,-(CH2) a -O-(CH2) b -S-, -S-(CH2) a -O-(CH2) b -, heterocycloalkylene-(CH2) a -O-, -O-(CH2) a -heterocycloalkylene-, -(CH2) a -O-heterocycloalkylene, heterocycloalkylene-O-(CH2) a -,-O-heterocycloalkylene-(CH2) a -and-(CH2) a-Selected from heterocycloalkylene-O-, where a and b are each independent integers from 1 to 6.

[0105] More preferably, L is -O-, -O-SO2-, -SO2-O-, -(CH2) a -,-(CH2) a -O-, O-(CH2) a -,-(CH2) a -O-(CH2) b -,-(CH2) a -S-(CH2) b -,-(CH2) a -S-(CH2) b -O-, -O-(CH2) a -S-(CH2) b -,-(CH2) a -O-(CH2) b -S-, -S-(CH2) a -O-(CH2) b -, heterocycloalkylene-(CH2) a -O- and -(CH2) a Selected from -O-heterocycloalkylenes, where a and b are each independent integers between 1 and 6.

[0106] In a preferred embodiment, L is selected from -CH2-, -CH2CH2CH2-, -CH2CH2O-, -NH-SO2-, -NH-SO2-CH2-, -SO2-NH-, -SO2-NH-CH2-, -OCH2CH2-, -CH2CH2CH2O-, -OCH2CH2CH2-, -CH2SO2CH2-, -CH2SO2-, -SO2CH2-, -CH2SO-, -SOCH2-, -CH2SOCH2-, -CH2SCH2-, -CH2CH2CH2CH2O-, -OCH2CH2CH2CH2-, -CH2OCH2 and -CH2SCH2O-.

[0107] In a preferred embodiment, LZ is -OCH2CH2Ph, -OCH2Ph, -OCH2CH2CH(Me)2, -OCH2CH(Me)2, -OSO2-(4-methylphenyl), -CH2SO2CH2-Ph, -OCH2-cyclopropyl, -OCH2CH2CH2CH3, -CH2OCH2Ph, -OCH2SCH2Ph, -CH2OCH2Ph [ka] That is the case.

[0108] In a preferred embodiment, LZ is -OCH2CH2CH2CH2Ph, -OCH2CH2CH2Ph, -OCH2CH2Ph, -OCH2Ph, -CH2CH2CH2CH2Ph, -CH2CH2CH2Ph, -OCH2CH2-pyrazole, -CH2CH2Ph, -CH2Ph, -OCH2CH2CH(Me)2, -OCH2CH(Me)2, -OCOCH2CH(Me)2, -OCH(Me)2, -OCH2CO-O-CH(Me)2, -O(CO)OCH2CH(Me)2, -OSO2-(4-methylphenyl), -CH2SO2-(4-methylphenyl), -CH2CH2O-(4-methylphenyl), -CH2SO2CH2-Ph, OMe, Ph, OPh, OCF3, t Bu, CF3, -OSO2Ph, -OCH2CH2CH2OPh, -OCH2-cyclopropyl, -CH2O-cyclopropyl, -OCH2CH2CH2CH3, -CH2OCH2Ph, -OCH2SCH2Ph, -CH2OCH2Ph, -CH2CH2-cyclopentyl, CH2CH2-cyclohexyl, -CH2CH2S-(4-chlorophenyl), -CH2-(2-fluorophenyl), -CH=CH-phenyl, -SO2-NH-CH2-phenyl, -SO2-NH-CH2-CH2-phenyl, -CH2OCH2-cyclopropyl, -OCH(Me)-cyclopropyl, -CH(Me)-O-cyclopropyl, -OCH(CF3)-cyclopropyl, -CH(CF3)-O-cyclopropyl, SO2Ph, -CH2-O-CH(CF3)-Ph, [ka] That is the case.

[0109] In one preferred embodiment, LZ is -OCH2CH2Ph, -OCH2CH2CH2CH2Ph, or -CH2OCH2Ph, more preferably -OCH2CH2Ph.

[0110] In one preferred embodiment, the compound is as follows: [Table 1] JPEG2026521186000016.jpg241170 JPEG2026521186000017.jpg250170 Selected from JPEG2026521186000018.jpg26170 and its pharmaceutically acceptable salts and solvates.

[0111] In a preferred embodiment, the compound of formula (I) is selected from the following compounds shown herein: 1-4, 6-10, 13, 14, 16-30, 33, 34, 36, 37 and 39-46, as well as their pharmaceutically acceptable salts and solvates.

[0112] In another preferred embodiment, the compound of formula (I) is as follows: [Table 2] JPEG2026521186000020.jpg249170 JPEG2026521186000021.jpg249170 Selected from JPEG2026521186000022.jpg174170.

[0113] method Further aspects of the present invention relate to methods for preparing compounds as defined herein. Further details of the synthesis methods are described in the appended Examples section.

[0114] therapeutic use Further aspects of the present invention relate to compounds described herein for medical use. These compounds have special uses in the fields of oncology, gastrointestinal disorders, and inflammatory disorders, as described in more detail below. In preferred embodiments, the compounds of the present invention modulate GPR35 function. More preferably, the compounds are GPR35 antagonists or inverse agonists.

[0115] One aspect of the present invention relates, therefore, to compounds described herein for use as pharmaceuticals.

[0116] Preferably, the compounds of the present invention are intended for use in the treatment or prevention of disorders selected from proliferative disorders, fibrotic disorders, gastrointestinal disorders, cardiovascular diseases, and inflammatory disorders.

[0117] In a preferred embodiment, the compound has applications in the field of oncology. For example, in a preferred embodiment, the compound is for use in the treatment of proliferative disorders, preferably cancer or leukemia. GPR35 expression is known to be associated with cancer. More specifically, GPR35 expression is commonly upregulated in GI duct cancers relative to normal tissue (Non-Patent Literature 24). GPR35 expression can be transformed into NIH3T3 mouse fibroblasts and expressed in gastric cancer cells (Non-Patent Literature 25). GPR35b is expressed in colon cancer cell lines and primary colon tumors, but the lymph nodes of patients involved may express high levels of GPR35b (Non-Patent Literature 26). High expression of GPR35b in the lymph nodes of colon cancer patients is a marker for poor prognosis. Furthermore, high expression of GPR35 in primary gastric tumors is associated with poor prognosis (Non-Patent Literature 40). Similarly, above-median GPR35 expression in primary tumors was observed as a poor prognostic marker in men with colorectal cancer, but the opposite effect was reported in women (Non-Patent Literature 27). siRNA knockdown of GPR35 reduced the viability and proliferation of human gastric cancer cells, and moreover, reversed the tumor-promoting M2 macrophage phenotype (Non-Patent Literature 40). Mouse Gpr35 has been shown to promote glycolysis, proliferation, and oncogenic signaling by interacting with the potassium-sodium pump (Na / K-ATPase) (Non-Patent Literature 21). Gpr35 deletion promoted Na / K-ATPase-mediated ion transport and reduced Src kinase activation and overall metabolic activity in both macrophages and intestinal epithelial cells. Gpr35 deletion or inhibition, along with a specific anti-Gpr35 peptide (peptucine) (Non-Patent Literature 28), prevented inflammation-related and spontaneous intestinal tumor formation in mice. Furthermore, it has been shown that activation of human GPR35 in human-induced pluripotent stem cell (iPSC)-derived macrophages promotes angiogenesis through enhanced release of pro-angiogenic factors, via the expression of T108M-enhanced variants (Non-Patent Literature 28). Ultimately, selective deletion of Gpr35 in macrophages is associated with inflammation-related and mutant (low-phenotype) tumor suppressors of adenomatous polyposis (APC). min), it significantly reduced tumor growth in spontaneously occurring tumor models.

[0118] In a preferred embodiment, the cancer is selected from cancers of the gastrointestinal tract (e.g., colon, rectum, stomach, and esophagus) and related tissues (e.g., pancreas, gallbladder, and bile ducts, liver), as well as cancers of the lung, kidney, gynecological, breast, testicular, skin, prostate, central nervous system, and brain tumors.

[0119] In one preferred embodiment, the compound has applications in the field of immuno-oncology and in the treatment of immune disorders. Therefore, in one preferred embodiment, the compound of the present invention is for use in the treatment of immune disorders. In another preferred embodiment, the compound of the present invention is for use in immunotherapy for the treatment of cancer.

[0120] In a preferred embodiment, the disorder is fibrosis or fibrous disorder. Fibrosis is defined by an excessive accumulation of fibrous connective tissue (components of the extracellular matrix (ECM), such as collagen and fibronectin) in and around inflamed or damaged tissue, which can lead to permanent scarring and organ failure.

[0121] In one preferred embodiment, the compound has uses in treating or preventing inflammatory disorders / diseases and / or inflammation.

[0122] In a preferred embodiment, the disorder is preferably a gastrointestinal disorder selected from inflammatory bowel disease, ulcerative colitis, primary sclerosing cholangitis, and Crohn's disease. Single nucleotide polymorphisms (SNPs) of human GPR35 have been investigated in genome-wide association studies (Non-Patent Literature 18). Six of these SNPs have been associated with inflammatory diseases of the GI duct. Types of inflammatory bowel disease (IBD) include ulcerative colitis, Crohn's disease, and primary sclerosing cholangitis (Non-Patent Literature 19, Non-Patent Literature 20). SNP rs3749171 is synonymous with coding variant T108M (GPR35a amino acid sequence number) and has been associated with IBD. Research has shown that this variant is upexpression-promoting and leads to activation of GPR35 and increased proliferation and metabolism in myeloid-induced macrophages (Non-Patent Literature 21). Furthermore, T108M GPR35 expression leads to increased macrophage production of VEGF and CXCL8 compared to the reference allele, which is reduced in GPR35-deficient cells (Non-Patent Literature 22). It has also been suggested that up-expression of T108M contributes to lesion formation in IBD patients and can act as a biomarker for patients who respond better to TNF inhibitors (Non-Patent Literature 2, Non-Patent Literature 23).

[0123] In a preferred embodiment, the disorder is preferably a cardiovascular disease selected from hypertension, heart failure, atherosclerosis, peripheral vascular disease, and stroke. Many recent publications suggest a role for GPR35 in both hypertension and the pathophysiology of heart failure and atherosclerosis. For example, the S294R SNP within GPR35 has been shown to be significantly associated with coronary artery calcification in a patient cohort (Non-Patent Literature 29). Further studies have demonstrated a correlation between GPR35 upregulation and traditional heart failure biomarkers, such as plasma brain natriuretic peptide, ejection fraction, and pulmonary artery pressure, thereby indicating that GPR35 plays a role in heart failure and hypertension (Non-Patent Literature 30).

[0124] Another aspect relates to the compounds described herein for use in the treatment or prevention of disorders caused by, in connection with, or associated with the abnormal activity of GPR35.

[0125] Another aspect relates to the compounds described herein for use in the treatment or prevention of GPR35-related diseases or disorders.

[0126] Another aspect of the present invention relates to a method for treating the above-described disorders, comprising administering the compounds described herein to the subject.

[0127] Another aspect of the present invention relates to a method for treating GPR35-related diseases or disorders in a subject. The method according to this aspect of the present invention is achieved by administering a therapeutically effective amount of the compound of the present invention described above to a subject in need, either by itself or, more preferably, as part of a pharmaceutical composition mixed with a pharmaceutically acceptable carrier, for example, as detailed later.

[0128] Another aspect of the present invention relates to a method for treating a subject having a disease condition that is mitigated by modulation of GPR35, wherein the method includes administering a therapeutically effective dose of the compound according to the present invention to the subject.

[0129] Another aspect relates to a method for treating a disease condition mitigated by modulation of GPR35, wherein the method includes administering a therapeutically effective dose of the compound according to the present invention to the target.

[0130] In a preferred embodiment, the compound inhibits GPR35 activity, as demonstrated, for example, in the functional GPR35 assay described in the attached Examples section.

[0131] In one preferred embodiment, the compound is a GPR35 antagonist that reverses the receptor's agonist-propelling function.

[0132] In another preferred embodiment, the compound is a reverse agonist of GPR35. A reverse agonist is a compound that interacts with a receptor signaling pathway having a constitutive level of activity and reduces its activity in the opposite direction to that of a pure agonist through interaction with the receptor.

[0133] Preferably, the subject is a mammal, more preferably a human.

[0134] The term “method” means, means, techniques and procedures for accomplishing a given task, including, but not limited to, methods, means, techniques and procedures known to or readily developed from methods, means, techniques and procedures known to practitioners of chemical, pharmacological, biological, biochemical and medical technologies.

[0135] In this specification, the term “treating” includes inhibiting, substantially inhibiting, slowing or reversing the progression of a disease or disorder, substantially relieving the clinical symptoms of a disease or disorder, or substantially preventing the appearance of the clinical symptoms of a disease or disorder.

[0136] In this specification, the term “prevention” refers to methods for preventing an organism from first acquiring a disability or disease.

[0137] The term "therapeutic dose" refers to the amount of a compound administered that alleviates, to some extent, one or more symptoms of the disease or disorder being treated.

[0138] For any compound used in this invention, the therapeutically effective dose, also referred to herein as the therapeutically effective dose, can be initially estimated from a cell culture assay. For example, the dose is determined in the cell culture assay. 50 or IC 90To achieve the circulating concentration range, including [specific concentration range], formulations can be developed in animal models. This information can be used to more accurately determine an effective dose in humans. Initial doses can also be estimated from in vivo data. Using these initial guidelines, those skilled in the art can determine an effective dose in humans.

[0139] Furthermore, the toxicity and therapeutic efficacy of the compounds described herein can be determined by standard pharmaceutical procedures in cell cultures or experimental animals, for example, by LD (Low-Dose) testing. 50 and ED 50 This can be determined by determining the dose ratio between toxicity and therapeutic effect, which is the therapeutic index, LD50. 50 and ED 50 It can be expressed as a ratio between [a certain value] and [another value]. Compounds exhibiting a high therapeutic index are preferred. Data obtained from these cell culture assays and animal studies can be used when formulating a dosage range that is not toxic for use in humans. Doses of such compounds are preferably ED with little or no toxicity. 50 The circulating concentration is within the range of [specific concentration]. The dosage may vary within this range depending on the dosage form used and the route of administration utilized. The exact prescription, route of administration, and dosage can be selected by the individual physician in consideration of the patient's condition (see, for example, Fingl et al, 1975, The Pharmacological Basis of Therapeutics, chapter 1, page 1).

[0140] The dosage and interval can be individually adjusted to provide plasma levels of the active compound sufficient to maintain the therapeutic effect. For oral administration, the usual patient dose ranges from approximately 50 to 2000 mg / day, commonly from approximately 100 to 1000 mg / day, preferably from approximately 150 to 700 mg / day, and most preferably from 50 to 150 mg / day. Preferably, therapeutically effective serum levels are achieved by administering multiple doses on each day. In the case of topical administration or selective uptake, the effective local concentration of the drug may not be related to the plasma concentration. Those skilled in the art can optimize the therapeutically effective local dose without using excessive experimental methods.

[0141] As used herein, “GPR35-related disease or disorder” refers to a disease or disorder characterized by inappropriate GPR35 activity. Inappropriate GPR35 activity refers to either an increase or decrease in GPR35 activity, as measured by an enzymatic or cellular assay, compared to activity in a healthy subject, for example. Inappropriate activity may also be due to overexpression of GPR35 in affected tissue compared to healthy adjacent tissue with lower GPR35 expression.

[0142] Preferred diseases or disorders for which the compounds described herein may be useful in prevention include those mentioned above.

[0143] Accordingly, the present invention further provides the use of the compounds defined herein in the preparation of pharmaceuticals for the treatment of diseases in which it is desirable to modulate GPR35. Such diseases include proliferative disorders, gastrointestinal disorders, fibrotic disorders, cardiovascular diseases, and inflammatory disorders. Proliferative disorders preferably include therapeutic applications in the field of oncology.

[0144] As used herein, the phrase “preparation of a pharmaceutical product” includes the direct use of the components of the present invention as pharmaceutical products, in addition to their use at any stage of such preparation of a pharmaceutical product.

[0145] The functional GPR35 assay described in the attached examples measures the ability of a GPR35 modulator to inhibit GPR35 agonist-induced phosphoERK signaling. This determines the modulator concentration required to reduce the phosphoERK signal by 50 percent, i.e., IC50. 50 This is expressed as a signal window defined as the difference between an agonist-plus-modulator medium (without modulator) and an agonist medium (without agonist) control.

[0146] In one preferred embodiment, the compound has an IC50 of less than approximately 50 μM in the previously described GPR35 assay. 50 The compound exhibits a value of less than approximately 10 μM, more preferably less than approximately 1 μM, in the GPR35 assay. 50 It exhibits a value.

[0147] In a preferred embodiment, the compound according to the present invention exhibits an IC50 of less than 10 μM in the previously described GPR35 assay. 50 The compound exhibits the following characteristics. In a preferred embodiment, the compound is selected from those indicated as "A" or "B" in Table 1.

[0148] In a preferred embodiment, the compound according to the present invention exhibits an IC50 greater than 1 μM and less than 10 μM in the previously described GPR35 assay. 50 It exhibits the following characteristics. In a preferred embodiment, the compound is selected from those indicated as "B" in Table 1.

[0149] In a more preferred embodiment, the compound according to the present invention exhibits an IC50 of less than 1 μM in the assay described above. 50 It exhibits the following characteristics. In a preferred embodiment, the compound is selected from those indicated as "A" in Table 1.

[0150] Pharmaceutical composition For use according to the present invention, the compounds or physiologically acceptable salts, esters, or other physiologically functional derivatives described herein may be presented as pharmaceutical formulations comprising the compound or physiologically acceptable salt, ester, or other physiologically functional derivative thereof together with one or more pharmaceutically acceptable carriers, excipients, or diluents and optionally other therapeutic and / or prophylactic components. The carrier(s) must be acceptable in the sense that they are compatible with the other components of the formulation and are not harmful to the recipient. The pharmaceutical compositions may be for human or animal use as pharmaceuticals for humans and animals.

[0151] Examples of such suitable excipients for various different forms of the pharmaceutical compositions described herein can be found in “Handbook of Pharmaceutical Excipients, 2 nd This can be found in Edition, (1994), Edited by A Wade and PJ Weller. If there are carriers, each of them must be acceptable in the sense that it is compatible with the other components of the formulation and is not harmful to the recipient.

[0152] Acceptable carriers or diluents for therapeutic use are well known in pharmaceutical technology and are described, for example, in Remington's Pharmaceutical Sciences, Mack Publishing Co. (AR Gennaro edit. 1985).

[0153] Examples of suitable carriers include lactose, starch, glucose, methylcellulose, magnesium stearate, mannitol, and sorbitol. Examples of suitable diluents include ethanol, glycerol, and water.

[0154] The choice of pharmaceutical carriers, excipients, or diluents may be made in relation to the intended route of administration and standard pharmaceutical practices. Pharmaceutical compositions may include, or in addition to, any suitable binders, lubricants, suspending agents, coatings, solubilizers, buffers, flavoring agents, surfactants, thickeners, preservatives (including antioxidants), and substances included for the purpose of making the formulation isotonic with the blood of the intended recipient.

[0155] Examples of suitable binders include starch, gelatin, natural sugars such as glucose, anhydrous lactose, free-flow lactose, beta-lactose, corn sweeteners, natural or synthetic gums such as acacia, tragacanth, or sodium alginate, carboxymethylcellulose, and polyethylene glycol.

[0156] Examples of suitable lubricants include sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, and sodium chloride.

[0157] Preservatives, stabilizers, dyes, and even flavorings may be provided in the pharmaceutical composition. Examples of preservatives include sodium benzoate, sorbic acid, and esters of p-hydroxybenzoic acid. Antioxidants and suspending agents may also be used.

[0158] Examples of pharmaceutical formulations include those suitable for oral, topical (including cutaneous, buccal, and sublingual), rectal, or parenteral (including subcutaneous, intradermal, intramuscular, and intravenous), nasal, and, for example, pulmonary administration by inhalation. These formulations may, where appropriate and conveniently, be presented in individual dosage units and may be prepared by any method well known in the field of compounding. All methods involve associating the active compound with a liquid carrier or a micronized solid carrier or both, and then, if necessary, shaping the product into the desired formulation.

[0159] Pharmaceutical formulations suitable for oral administration, where the carrier is solid, are most preferably presented as unit-dose formulations such as boluses, capsules, or tablets, each containing a predetermined amount of the active compound. Tablets can be prepared by compression or molding, optionally with one or more adjuncts. Tablets can be prepared by compressing the active compound in a suitable machine into a free-flowing form such as a powder or granules, which may be mixed with a binder, lubricant, inert diluent, lubricant, surfactant, or dispersant. Molded tablets can be prepared by molding the active compound with an inert liquid diluent. Tablets may be coated, or if uncoated, they may be notched. Capsules can be prepared by filling a capsule shell with the active compound, either alone or in a mixture with one or more adjuncts, and then sealing them in a conventional manner. Cachetes are similar to capsules in which the active compound, along with any adjuncts, is sealed in a rice paper envelope. The active compound can also be formulated, for example, as dispersible granules that can be suspended in water or sprinkled on food before administration. Granules can be packaged, for example, in sachets. Formulations suitable for oral administration, in which the carrier is liquid, can be presented as a solution or suspension in an aqueous or non-aqueous liquid, or as an oil-in-water liquid emulsion.

[0160] Formulations for oral administration include controlled-release formulations, such as tablets in which the active compound is formulated in a suitable controlled-release matrix or coated with a suitable controlled-release film. Such formulations may be particularly advantageous for prophylactic use.

[0161] Pharmaceutical formulations suitable for rectal administration, in which the carrier is solid, are most preferably presented as unit-dose suppositories. Suitable carriers include cocoa butter and other materials commonly used in the art. Suppositories can conveniently be formed by adding a mixture of the active compound with a softened or melted carrier(s), followed by cooling and shaping in a mold. Pharmaceutical formulations suitable for parenteral administration include sterile solutions or suspensions of the active compound in an aqueous or oily medium.

[0162] Injectable preparations may be adapted for bolus injection or continuous infusion. Conveniently, these preparations are presented in sealed unit-dose or multi-dose containers after introduction of the formulation until required for use. Alternatively, the active compound may be in powder form, comprising a suitable medium such as sterile pyrogen-free water, before use.

[0163] The active compound can also be formulated as a long-acting depot preparation that can be administered by intramuscular injection or, for example, by subcutaneous or intramuscular implantation. The depot preparation may contain, for example, a suitable polymeric or hydrophobic material or an ion exchange resin. Such long-acting preparations are particularly convenient for prophylactic use.

[0164] Formulations suitable for pulmonary administration via the buccal oral cavity are presented so as to deliver particles containing the active compound, preferably having a diameter in the range of 0.5 to 7 microns, into the bronchial trees of the recipient.

[0165] One possibility is that such formulations may be presented in the form of a finely ground powder, preferably in a permeable capsule of gelatin for use in an inhalation device, or alternatively, as a self-propelled formulation comprising the active compound, a suitable liquid or gaseous spray, and optionally other components, such as a surfactant and / or a solid diluent. Suitable liquid sprays include propane and chlorofluorocarbons, and a suitable gaseous spray is 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.

[0166] Such self-propelled formulations are similar to those known in the art and can be prepared by established procedures. Preferably, they are presented in containers provided with either a manually operated or automatically functioning valve having the desired spray characteristics; advantageously, the valve is of a metering type that delivers a fixed volume, for example, 25 to 100 microliters, in each of its operations.

[0167] As a further possibility, the active compound may be in the form of a solution or suspension for use in an atomizer or nebulizer in which accelerated airflow or ultrasonic stirring is used to generate a fine droplet mist for inhalation.

[0168] Suitable formulations for nasal administration are generally the same as those described above for pulmonary administration. When dispensed, these formulations should preferably have a particle size in the range of 10 to 200 microns to allow retention in the nasal cavity; this can be achieved, where appropriate, by using a powder of appropriate particle size or by selecting an appropriate valve. Other suitable formulations include coarse powders with a particle size in the range of 20 to 500 microns for rapid inhalation via nasal passage from a container held close to the nose, and for administration by nasal sprays containing 0.2% to 5% w / v of the active compound in an aqueous or oily solution or suspension.

[0169] 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. In addition, such pharmaceutically acceptable carriers may be aqueous or non-aqueous solutions, suspensions, and emulsions. Examples of non-aqueous solvents are propylene glycol, polyethylene glycol, vegetable oils, e.g., olive oil, and injectable organic esters, e.g., ethyl oleate. Aqueous carriers include water, alcohol solutions / aqueous solutions, emulsions, or suspensions containing physiological saline and a buffering medium. Parenteral media include sodium chloride solution, ringer's dextrose, dextrose and sodium chloride, ringer's lactate, or non-volatile oils. Preservatives and other additives may also be present, such as antimicrobial agents, antioxidants, chelating agents, and inert gases.

[0170] Suitable formulations for topical use can be provided, for example, as gels, creams, or ointments. Such preparations can be applied, for example, to wounds or ulcers, either by being sprayed directly onto the surface of a wound or ulcer, or by being supported on a suitable support such as a bandage, gauze, or mesh that can be applied to and over the area to be treated.

[0171] Liquid or powder formulations can also be provided that can be sprayed or scattered directly onto the area to be treated, such as a wound or ulcer. Alternatively, a carrier, such as a bandage, gauze, or mesh, can be used to spray or scatter the formulation and then apply it to the area to be treated.

[0172] A further aspect of the present invention provides a method for preparing the above-described pharmaceutical or veterinary compositions, the method comprising associating an active compound(s) with a carrier, for example, an additive mixture.

[0173] Generally, formulations are prepared by uniformly and closely associating an active agent with a liquid carrier, a micronized solid carrier, or both, and then, if necessary, shaping the product. The present invention relates to methods for preparing pharmaceutical compositions, comprising binding or associating the compounds described herein with pharmaceutically or veterinarily acceptable carriers or media.

[0174] Salt / Ester The compounds of the present invention can exist as salts or esters, particularly as pharmaceutically and veterinarily acceptable salts or esters.

[0175] pharmaceutically acceptable salts of the compounds of the present invention include suitable acid addition salts or base salts thereof. A general overview of suitable pharmaceutical salts can be found in Berge et al, J Pharm Sci, 66, 1-19 (1977). Salts include, for example, strong inorganic acids, such as mineral acids, such as hydrohalic acids, such as hydrochlorides, hydrobromids and hydroiodides, sulfuric acid, phosphoric acid, sulfate, bisulfate, hemisulfate, thiocyanate, persulfate persulfate and sulfonic acid; strong organic carboxylic acids, such as alkane carboxylic acids with 1 to 4 carbon atoms that are unsubstituted or substituted (e.g. by halogens), such as acetic acid; saturated or unsaturated dicarboxylic acids, such as oxalic acid, malonic acid, succinic acid, maleic acid, fumaric acid, phthalic acid or tetraphthalic acid; 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. by halogens) (C 1- Formed from C4)-alkyl- or aryl-sulfonic acids, such as methane- or p-toluenesulfonic acid. Salts that are not pharmaceutically or veterinarily acceptable may also be valuable as intermediates.

[0176] Preferred salts include, for example, acetate, trifluoroacetate, lactate, gluconate, citrate, tartrate, maleate, malate, pantothenate, adipine, alginate, aspartate, benzoate, butyrate, digluconate, cyclopentane, glucoheptane, glycerophosphate, oxalate, heptane, hexanoate, fumarate, nicotinate, palmate, pectinate, 3-phenylpropionate, picrate, pivalate, proprionate, tartrate, lactobio This includes phosphates, pivotes, camphorates, undecanoates and succinates, organic sulfonic acids such as methanesulfonates, ethanesulfonates, 2-hydroxyethanesulfonates, camphorsulfonates, 2-naphthalenesulfonates, benzenesulfonates, p-chlorobenzenesulfonates and p-toluenesulfonates; and inorganic acids such as hydrochlorides, hydrobroms, hydroiodides, sulfates, bisulfates, hemisulfates, thiocyansates, persulfates, phosphoric acids and sulfonic acids.

[0177] Esters are formed using either an organic acid or an alcohol / hydroxide, depending on the functional group being esterified. Organic acids include carboxylic acids, e.g., alkanecarboxylic acids with 1 to 12 carbon atoms, unsubstituted or substituted (e.g., by halogens), e.g., acetic acid; saturated or unsaturated dicarboxylic acids, e.g., oxalic acid, malonic acid, succinic acid, maleic acid, fumaric acid, phthalic acid, or tetraphthalic acid; hydroxycarboxylic acids, e.g., ascorbic acid, glycolic acid, lactic acid, malic acid, tartaric acid, or citric acid; amino acids, e.g., aspartic acid or glutamic acid; benzoic acid; or organic sulfonic acids, e.g., unsubstituted or substituted (e.g., by halogens) (C 1-This includes C4)-alkyl- or aryl-sulfonic acids, such as methane- or p-toluenesulfonic acid. Suitable hydroxides include inorganic hydroxides, such as sodium hydroxide, potassium hydroxide, calcium hydroxide, and aluminum hydroxide. Alcohols include alkane alcohols with 1 to 12 carbon atoms, which may be unsubstituted or substituted (e.g., by halogens).

[0178] Enantiomer / Tautomer In all embodiments of the present invention discussed previously, the present invention includes, where appropriate, all enantiomers, diastereoisomers, and tautomers of the compounds of the present invention. Those skilled in the art will recognize compounds possessing optical properties (one or more chiral carbon atoms) or tautomeristic features. The corresponding enantiomers and / or tautomers can be isolated / prepared by methods known in the art.

[0179] Enantiomers are characterized by the absolute stereochemistry of their chiral centers and described by the R and S sequencing rules of Cahn, Ingold, and Prelog. These conventions are well-known in the art (e.g., 'Advanced Organic Chemistry', 3) rd (See edition, ed. March, J., John Wiley and Sons, New York, 1985).

[0180] The compounds of the present invention containing chiral centers can be used as racemic mixtures, enantiomer-enriched mixtures, or the racemic mixtures can be separated using well-known techniques, and the individual enantiomers can be used individually.

[0181] Stereomorphs and geometric isomers Some of the compounds of the present invention can exist as stereoisomers and / or geometric isomers, for example, they may possess one or more chiral and / or geometric centers, and thus may exist in two or more stereoisomers and / or geometric forms. The present invention intends to utilize all of the individual stereoisomers and geometric isomers of these compounds, as well as mixtures thereof. The terms used in the claims encompass these forms, and the provided forms retain (but not necessarily, to the same extent) appropriate functional activity.

[0182] The present invention also includes all appropriate isotopic variations of compounds or their pharmaceutically acceptable salts. An isotopic variation of a compound or its pharmaceutically acceptable salt is defined as one in which at least one atom is replaced by an atom having the same atomic number but a different atomic mass than that commonly found in nature. Examples of isotopes that can be incorporated into drugs and their pharmaceutically acceptable salts include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, and chlorine, for example, respectively. 2 H, 3 H, 11 C, 13 C, 14 C, 15 N, 17 O, 18 O, 31 P, 32 P, 35 S, 18 F and 36 Cl is one example. Certain isotopic variations in drugs and their pharmaceutically acceptable salts, for example, 3 H or 14 Those incorporating radioactive isotopes such as 13C are useful in drug and / or substrate tissue distribution studies. Tritiated, i.e. 3 H and carbon 14, that is 14 13C isotopes are particularly preferred due to their ease of preparation and detection. Furthermore, isotopes, such as deuterium, i.e. 2Substitution with H can result in certain therapeutic benefits due to greater metabolic stability, such as increased in vivo half-life or reduced dose requirements, and is therefore preferable in some situations. For example, the present invention includes compounds of general formula (I) in which any hydrogen atom is replaced by a deuterium atom. The isotopic variations of the agents of the present invention and their pharmaceutically acceptable salts can generally be prepared by conventional procedures using appropriate isotopic variations of appropriate reagents.

[0183] Atropisomer Some of the compounds of the present invention can exist as atropisomers. Atropisomers are stereoisomers that arise due to rotational hindrance around a single bond, where the energy difference due to steric strain or other contributors creates a rotational barrier high enough to allow the isolation of individual conformational isomers. The present invention encompasses all such atropisomers.

[0184] Prodrug The present invention further includes compounds of the present invention in prodrug form, i.e., covalently bonded compounds that release an active parent drug in vivo. Such prodrugs are generally compounds of the present invention modified such that one or more suitable groups can be reversed upon administration to a human or mammalian subject. Reversal is usually carried out by enzymes naturally present in such subjects, but it is possible to carry out reversal in vivo by administering a second drug together with such prodrug. Examples of such modifications include esters (e.g., any of those described above), where reversal can be carried out by an esterase, etc. Other such systems are well known to those skilled in the art.

[0185] solvate The present invention also includes solvate forms of the compounds of the present invention. The terms used in the claims encompass these forms. Preferably, the solvate is a hydrate.

[0186] combination Further aspects of the present invention relate to combinations comprising the compounds described herein and one or more additional active agents. In particularly preferred embodiments, one or more compounds of the present invention are administered in combination with one or more additional active agents, for example, existing drugs available on the market. In such cases, the compounds of the present invention can be administered sequentially, simultaneously, or sequentially with one or more other active agents.

[0187] Drugs are generally more effective when used in combination. Combination therapy is particularly desirable to avoid overlapping primary toxicities, mechanisms of action, and resistance mechanisms. Furthermore, it is desirable to administer most drugs at their maximum tolerated doses, with minimal time intervals between these doses. The main advantage of combining chemotherapy drugs is that it can promote additional or possible synergistic effects through biochemical interactions and, moreover, reduce the development of resistance.

[0188] Beneficial combinations may be suggested by studying the activity of the test compound with drugs known or expected to be valuable in the treatment of specific disorders. This procedure can also be used to determine the order of drug administration, i.e., before, simultaneously with, or after delivery. Such dosing schedules may be characteristic of all active drugs identified herein.

[0189] In the context of cancer, the compounds of the present invention can be used in combination with immunotherapies such as cancer vaccines and / or other immune modulators. Therefore, in one preferred embodiment, the additional active agent is an immunotherapeutic agent, more preferably a cancer immunotherapeutic agent. "Immunotherapeutic agent" refers to a treatment that uses the subject's own immune system to fight a disease such as cancer. For other disorders, the compounds of the present invention can be used in combination with agents that block or reduce inflammation, such as antibodies that target pro-inflammatory cytokines. The compounds of the present invention can also be used in combination with other chemotherapeutic agents and / or in conjunction with radiotherapy.

[0190] polymorph The present invention further relates to the compounds of the present invention in their various crystalline, polymorphic, and (non-)hydrated forms. It is well established in the pharmaceutical industry that any of these forms of a chemical substance can be isolated by slightly varying the methods of purification and / or isolation from the solvents used in the synthesis and preparation of such compounds.

[0191] Administration The pharmaceutical compositions of the present invention may be adapted for administration rectally, nasally, intrabronchally, topically (including buccally and sublingually), vaginally, or parenterally (including subcutaneously, intramuscularly, intravenously, intraarterially, and intradermally), intraperitoneally, or subarachnoidally. Preferably, the formulation is an orally administered formulation. The formulation may conveniently be presented in unit dosage form, i.e., in the form of a unit dose, or individual portions containing multiple or subunits of a unit dose. For example, the formulation may be in the form of tablets and sustained-release capsules and may be prepared by any method well known in the field of pharmacy.

[0192] The oral formulations of the present invention can be presented as: individual units, each containing a predetermined amount of the active agent, such as capsules, gels, drops, cachets, pills, or tablets; as powders or granules; as solutions, emulsions, or suspensions of the active agent in aqueous or non-aqueous liquids; or as oil-in-water or water-in-oil liquid emulsions; or as boluses, etc. Preferably, these compositions contain 1 mg to 250 mg and more preferably 10 to 100 mg of the active ingredient per dose.

[0193] For compositions for oral administration (e.g., tablets and capsules), the term "acceptable carrier" includes media, such as common excipients, such as binders, e.g., syrup, acacia, gelatin, sorbitol, tragacanth, polyvinylpyrrolidone (povidone), methylcellulose, ethylcellulose, sodium carboxymethylcellulose, hydroxypropyl methylcellulose, sucrose, and starch; fillers and carriers, e.g., corn starch, gelatin, lactose, sucrose, microcrystalline cellulose, kaolin, mannitol, dicalcium phosphate, sodium chloride, and alginic acid; and lubricants, e.g., magnesium stearate, sodium stearate, and other metal stearates, glycerol stearate, stearic acid, silicone fluids, talc wax, oils, and colloidal silica. Flavoring agents, e.g., peppermint, wintergreen oil, cherry flavoring, etc., may also be used. It may be desirable to add colorants to make the dosage form easily identifiable. Tablets may also be coated by methods well known in the art.

[0194] Tablets can be prepared by compression or molding with one or more optional adjuncts. Tablets can be prepared by compressing an active agent in a free-flowing form, such as a powder or granules, which may be mixed with a binder, lubricant, inert diluent, preservative, surfactant, or dispersant, in a suitable machine. Molded tablets can be prepared by molding a mixture of powdered compounds moistened with an inert liquid diluent in a suitable machine. The tablets may be coated or notched and can be formulated to provide a slow or controlled release of the active agent.

[0195] Other formulations suitable for oral administration include medicinal candies containing the active agent in a flavoring base, usually sucrose and acacia or tragacanth; aromatic tablets containing the active agent in an inert base such as gelatin and glycerin, or sucrose and acacia; and mouthwashes containing the active agent in a suitable liquid carrier.

[0196] Other forms of administration may be injected intravenously, intraarterially, subarachnoidally, subcutaneously, intradermally, intraperitoneally, or intramuscularly, and may include solutions or emulsions prepared from sterile or sterilizable solutions. Injectable forms typically contain between 10 and 1000 mg, preferably between 10 and 250 mg, of the active ingredient per dose.

[0197] The pharmaceutical composition of the present invention may be in the form of a suppository, pessary, suspension, emulsion, lotion, ointment, cream, gel, spray, solution, or powder.

[0198] An alternative to transdermal administration is the use of skin patches. For example, the active ingredient can be incorporated into a cream consisting of an aqueous emulsion of polyethylene glycol or liquid paraffin. The active ingredient can also be incorporated into an ointment consisting of a white wax or white soft paraffin base at a concentration between 1 and 10% by weight, together with stabilizers and preservatives as needed.

[0199] Dosage Those skilled in the art can easily determine an appropriate dose of one type of immediate composition for administration to a subject without excessive experimentation. Typically, a physician determines the actual dose that is most appropriate for an individual patient, and this depends on a variety of factors including the activity of the particular compound used, the metabolic stability and duration of action of that compound, age, weight, overall health, sex, diet, mode and time of administration, elimination rate, drug combination, severity of the particular condition, and the individual being treated. The doses disclosed herein are examples of average cases. Naturally, there are individual cases where higher or lower dose ranges are beneficial, and these are within the scope of this invention.

[0200] The dosage is further modified according to the mode of administration of the compound. For example, parenteral administration of the compound is typically preferred to achieve an "effective dose" for acute treatment. Intravenous infusion of the compound in 5% dextrose in water or standard saline or a similar formulation with appropriate excipients is most effective, but intramuscular bolus injection is also useful. Typically, the parenteral dose is between about 0.01 and about 100 mg; preferably between 0.1 and 20 mg, in a manner that maintains the concentration of the drug in plasma at a concentration effective in modulating GPR35. The compound can be administered 1 to 4 times daily at levels to achieve a total daily dose of about 0.4 to about 400 mg. The exact amount of the therapeutically effective compound of the invention, and the route of administration of such compounds, can be easily determined by those skilled in the art by comparing the blood level of the drug to the concentration required to have a therapeutic effect.

[0201] The compounds of this invention may also be administered orally to a patient in such a manner that the concentration of the drug is sufficient to achieve one or two or more of the therapeutic symptoms disclosed herein. Typically, a pharmaceutical composition containing the compound is administered in an oral dose between about 0.1 and about 500 mg or between about 0.1 and about 50 mg, in a manner consistent with the patient's condition. Preferably, the oral dose is between about 0.5 and about 50 mg or between about 0.5 and about 20 mg.

[0202] When the compounds of the present invention are administered in accordance with the present invention, no unacceptable toxicological effects are expected. The compounds of this invention, which may have good bioavailability, can be tested in one of several biological assays to determine the concentration of the compound required to have a given pharmacological effect.

[0203] The present invention is further described through the following non-limiting embodiments. [Examples]

[0204] If the preparation of starting materials is not described, they are commercially available, known in the literature, or readily obtainable by those skilled in the art using standard procedures. If it is indicated that a compound was prepared similarly to a previous example or intermediate, it will be recognized by those skilled in the art that reaction times, equivalent amounts of reagents, solvents, concentrations, and temperatures may be modified for each specific reaction, and that different workup or purification techniques may be necessary or desirable.

[0205] General scheme Abbreviation: Acetic acid (ACOH) AIBN Azobisisobutyronitrile aq. Water-based Aryl B2Pin2 Bis (Pinacolato) Diboron C18 Octadecyl Carbon Celite (registered trademark) diatomaceous earth d Number of days d Doublet (in the context of NMR) DCE 1,2-Dichloroethane DCM Dichloromethane Dioxane 1,4-dioxane DIPEA N,N-diisopropylethylamine DMA N,N-dimethylacetamide DMAP 4-dimethylaminopyridine DME 1,2-Dimethoxyethane DMF (N,N-dimethylformamide) DMSO (Dimethyl Sulfoxide) Et2O Diethyl ether HCl ethyl acetate EtOH Ethanol eq. Molar equivalent h hours (multiple hours possible) HATU 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate het complex ring iPnONO Isopentyl / Isoamylnitrile LC-MS (Liquid Chromatography Mass Spectroscopy) m multiplex MeCN acetonitrile MeOH methanol minutes (multiple minutes allowed) mol.eq. Molar equivalent Ms Methanesulfonyl NBS N-bromosuccinimide NEt3 Triethylamine p pentetto Pd-118 [1,1'-bis(di-tert-butylphosphino)ferrocene]dichloropalladium(II) Pd(dppf)Cl2[1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) PMB (Para-methoxybenzyl) q quartet rt room temperature RP inverse phase s singlet Sat. Saturation SCX SiliaBond® Propylsulfonic Acid (SiliaBond SCX-2) t triplet T3P 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosfinan 2,4,6-trioxide TBME tert-butylmethyl ether THF (Tetrahydrofuran) Tr Tritil X Halogen atom (bromine or chlorine)

[0206] Other abbreviations are intended to convey their generally accepted meanings.

[0207] General experimental conditions All starting materials and solvents were either obtained from commercially available sources or prepared according to literature methods.

[0208] Normal-phase ("flash") chromatography and RP ("flash") chromatography were performed on a CombiFlash Companion automated flash chromatography system using either Redisep® Silver (230-400 mesh, 40-63 μm irregularity) or Silicycle, SiliaSep C18 (230-400 mesh, 40-63 μm irregularity) pre-packed silica cartridges, respectively. RP flash chromatography was performed using a basic modifier (C18, 0-100% MeCN in 0.1% ammonia aqueous solution), except when an acidic modifier (C18, 0-100% MeCN in 0.1% HCO2H aqueous solution) was used.

[0209] Analytical LC-MS and UPLC-MS experiments were performed as described in the table below. [Table 3] [Table 4] [Table 5]

[0210] Preparative HPLC purification was performed as detailed below. [Table 6] [Table 7]

[0211] NMR spectra were measured at 298 K unless otherwise indicated, and solvent resonance was used as reference. Chemical shifts are reported in parts per million (δ ppm).

[0212] NMR spectra were recorded using a Bruker 500 MHz Avance III HD spectrometer equipped with a Bruker 5mm SmartProbe®, or a Bruker 400 MHz Avance Neo spectrometer fitted with a Bruker 5mm iProbe. Data were acquired using Bruker TopSpin software and processed using MestreNova software.

[0213] If the reaction likely involves two or more atoms (e.g., N-alkylation of a heterocycle containing two or more N atoms to provide N-protection), and a mixture of two or more isomers is obtained as determined by LC-MS, the mixture was used without further purification unless otherwise specified. Although only one isomer is depicted, the term "+isomer" is intended to convey a mixture of two or more isomers. Multiple peaks may be listed as characterizations along with the expected mass ions. Purification was achieved later in the synthesis following N-deprotection, and multiple isomers led to a single specific product.

[0214] If the procedure for identified intermediates in the synthetic scheme was not provided, these compounds were purchased.

[0215] Intermediate 1 N-(6-bromo-3-chloropyrazine-2-yl)methanesulfonamide(I-1) [ka] N-(6-bromo-3-chloropyrazine-2-yl)methanesulfonamide(I-1) [ka]

[0216] A solution of 6-bromo-3-chloropyrazine-2-amine (CAS 1082843-72-8, Fluorochem, 150 mg, 0.72 mmol) in DME (1 mL) was added to sodium hydride (104 mg, 2.16 mmol) in DME (2 mL) at room temperature. The mixture was stirred for 30 minutes, and then a solution of methanesulfonyl chloride (247 mg, 2.16 mmol) in DME (1 mL) was added over 10 minutes. The mixture was stirred at room temperature for 19 hours, and then saturated aqueous NH4Cl solution (5 mL) was added. The mixture was extracted with siRNA (3 × 10 mL), the combined organic phase was washed with water (2 mL), dried over Na2SO4, and concentrated under reduced pressure. Purification by flash chromatography (silica gel, isohexane 0-100% siRNA) yielded N-(6-bromo-3-chloropyrazine-2-yl)methanesulfonamide (150 mg, 68%). LCMS: Method A, 1.03 min, MSES + 285.9 / 288.0.

[0217] General procedure (sulfonylation) Following the procedure for intermediate 1, by substituting 6-bromo-3-chloropyrazine-2-amine and methanesulfonyl chloride with appropriate starting materials and using any of the minor modifications noted, the following intermediates 2-17 were obtained as mono- or bis-sulfonylated derivatives, or mixtures of both: [ka]

[0218] The mixture can be used directly in the next step, and it will be understood that under basic reaction conditions, any bis-sulfonylated derivative will be rapidly hydrolyzed to the required sulfonamide. For simplicity, only the main components are shown.

[0219] Intermediate 2 N-(6-bromo-3-chloropyrazine-2-yl)cyclopropanesulfonamide (I-2) [ka] Using cyclopropanesulfonyl chloride (CAS 139631-62-2, Apollo Scientific) instead of methanesulfonyl chloride, N-(6-bromo-3-chloropyrazine-2-yl)cyclopropanesulfonamide was obtained in 68% yield. LCMS: Method A, 1.27 min, MSES + 311.9 / 313.9.

[0220] Intermediate 3 N-(5-bromo-3-chloropyrazine-2-yl)-N-(methylsulfonyl)methanesulfonamide(I-3) [ka]

[0221] Using 5-bromo-3-chloropyrazine-2-amine (CAS 21943-13-5, Fluorochem) instead of 6-bromo-3-chloropyrazine-2-amine, N-(5-bromo-3-chloropyrazine-2-yl)-N-(methylsulfonyl)methanesulfonamide was obtained in 46% yield. LCMS: Method A, 1.19 min, MSES + 363.9 / 365.9.

[0222] Intermediate 4 N-(6-chloro-3-cyanopyrazine-2-yl)methanesulfonamide(I-4) [ka]

[0223] N-(6-chloro-3-cyanopyrazine-2-yl)methanesulfonamide was obtained in 60% yield without the use of 3-amino-5-chloropyrazine-2-carbonitrile (CAS 54632-11-0, Apollo Scientific) instead of 6-bromo-3-chloropyrazine-2-amine, and without purification. LCMS: Method A, 0.97 min, MSES+ 233.0.

[0224] Intermediate 5 N-(6-bromopyrazine-2-yl)-N-(methylsulfonyl)methanesulfonamide(I-5) [ka]

[0225] N-(6-bromopyrazine-2-yl)-N-(methylsulfonyl)methanesulfonamide was obtained in 37% yield using 6-bromopyrazine-2-amine (CAS 54237-53-5, Fluorochem) instead of 6-bromo-3-chloropyrazine-2-amine, and without purification. LCMS: Method A, 1.18 min, MSES + 329.9 / 331.9.

[0226] Intermediate 6 N-(2-chloropyrimidine-4-yl)-N-(methylsulfonyl)methanesulfonamide(I-6) [ka]

[0227] Using 2-chloropyrimidine-4-amine (CAS 7461-50-9, BLD) instead of 6-bromo-3-chloropyrazine-2-amine, and without purification, N-(2-chloropyrimidine-4-yl)-N-(methylsulfonyl)methanesulfonamide was obtained in 31% yield. LCMS: Method A, 1.13 min, MSES + 286.0.

[0228] Intermediate 7 N-(6-bromopyridine-2-yl)-N-(methylsulfonyl)methanesulfonamide(I-7) [ka]

[0229] Using 6-bromopyridine-2-amine (CAS 19798-81-3, Fluorochem) instead of 6-bromo-3-chloropyrazine-2-amine, and without purification, N-(6-bromopyridine-2-yl)-N-(methylsulfonyl)methanesulfonamide was obtained in 17% yield. LCMS: Method A, 1.34 min, MSES + 329.0 / 331.0.

[0230] Intermediate 8 N-(6-bromopyrazine-2-yl)cyclopropanesulfonamide (I-8) [ka]

[0231] By using cyclopropanesulfonyl chloride (CAS 139631-62-2, Apollo Scientific) instead of methanesulfonyl chloride, and 6-bromopyrazine-2-amine (CAS 54237-53-5, Fluorochem) instead of 6-bromo-3-chloropyrazine-2-amine, N-(6-bromopyrazine-2-yl)cyclopropanesulfonamide was obtained in 12% yield. LCMS: Method A, 1.10 min, MSES + 277.9 / 279.9.

[0232] Intermediate 9 N-(5-bromopyrazine-2-yl)methanesulfonamide(I-9) [ka]

[0233] Using 5-bromopyrazine-2-amine (CAS 59489-71-3, BLD) instead of 6-bromo-3-chloropyrazine-2-amine, N-(5-bromopyrazine-2-yl)methanesulfonamide was obtained in 45% yield. LCMS: Method A, 0.63 min, MSES+ 249.9 / 251.9.

[0234] Intermediate 10 N-(5-bromopyrazine-2-yl)morpholine-4-sulfonamide(I-10) [ka]

[0235] By using morpholine-4-sulfonyl chloride (CAS 1828-66-6, BLD) instead of methanesulfonyl chloride, and 5-bromopyrazine-2-amine (CAS 59489-71-3, BLD) instead of 6-bromo-3-chloropyrazine-2-amine, and without purification, N-(5-bromopyrazine-2-yl)morpholine-4-sulfonamide was obtained in 41% yield. LCMS: Method A, 1.12 min, MSES + 323.0 / 325.0.

[0236] Intermediate 11 N-(2-chloro-5-methylpyrimidine-4-yl)-N-(methylsulfonyl)methanesulfonamide (I-11) [ka]

[0237] N-(2-chloro-5-methylpyrimidine-4-yl)-N-(methylsulfonyl)methanesulfonamide was obtained in 49% yield without using 2-chloro-5-methylpyrimidine-4-amine (CAS 14394-70-8, BLD) instead of 6-bromo-3-chloropyrazine-2-amine, and without purification. LCMS: Method A, 1.26 min, MSES + 300.0.

[0238] Intermediate 12 N-(5-bromo-2-methylpyridine-3-yl)-N-(methylsulfonyl)methanesulfonamide(I-12) [ka]

[0239] By using 5-bromo-2-methylpyridine-3-amine (CAS 914358-73-9, BLD) instead of 6-bromo-3-chloropyrazine-2-amine, and by stirring at 40°C instead of room temperature, N-(5-bromo-2-methylpyridine-3-yl)-N-(methylsulfonyl)methanesulfonamide was obtained in 20% yield. LCMS: Method A, 1.27 min, MSES + 343.0 / 345.0.

[0240] Intermediate 13 N,N'-(5-bromopyrazine-2,3-diyl)dimethanesulfonamide (I-13) [ka]

[0241] Using 5-bromopyrazine-2,3-diamine (CAS 89123-58-0, Combi-Blocks) instead of 6-bromo-3-chloropyrazine-2-amine, N,N'-(5-bromopyrazine-2,3-diyl)methanesulfonamide was obtained in 46% yield. LCMS: Method A, 1.18 min, MSES + 345.0 / 347.0.

[0242] Intermediate 14 N-(6-bromopyrazine-2-yl)morpholine-4-sulfonamide(I-14) [ka]

[0243] By using 6-bromopyrazine-2-amine (CAS 54237-53-5, Fluorochem) instead of 6-bromo-3-chloropyrazine-2-amine, and morpholine-4-sulfonyl chloride (CAS 1828-66-6, BLD) instead of methanesulfonyl chloride, N-(6-bromopyrazine-2-yl)morpholine-4-sulfonamide was obtained in 24% yield. LCMS: Method A, 1.13 min, MSES + 323.0 / 325.0.

[0244] Intermediate 15 N-(5-bromo-3-methoxypyrazine-2-yl)methanesulfonamide (I-15) [ka]

[0245] N-(5-bromo-3-methoxypyrazine-2-yl)methanesulfonamide was obtained in 51% yield using 5-bromo-3-methoxypyrazine-2-amine (CAS 5900-13-0, Apollo Scientific) instead of 6-bromo-3-chloropyrazine-2-amine, and without purification. LCMS: Method A, 1.07 min, MSES + 282.0 / 284.0.

[0246] Intermediate 16 N'-(6-bromo-2-pyrazinyl)-N,N-dimethylsulfamide (I-16) [ka]

[0247] N'-(6-bromo-2-pyrazine)-N,N-dimethylsulfamide was obtained in 27% yield without purification, using 6-bromopyrazine-2-amine (CAS 54237-53-5, BLD) instead of 6-bromo-3-chloropyrazine-2-amine, dimethylsulfamoyl chloride (CAS 13360-57-1, Sigma Aldrich) instead of methanesulfonyl chloride. LCMS: Method A, 1.19 min, MSES + 281.0 / 283.0.

[0248] Intermediate 17 N-(5-bromo-3-methylpyrazine-2-yl)-N-(methylsulfonyl)methanesulfonamide(I-17) [ka]

[0249] Using 5-bromo-3-methylpyrazine-2-amine (CAS 74290-67-8, BLD) instead of 6-bromo-3-chloropyrazine-2-amine, N-(5-bromo-3-methylpyrazine-2-yl)-N-(methylsulfonyl)methanesulfonamide was obtained in 86% yield. LCMS: Method A, 1.36 min, MSES + 343.9 / 345.9.

[0250] Intermediates 18, 19 4-Phenethoxyaniline (I-18) and N-(4-Phenethoxyphenyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (I-19) [ka]

[0251] Step 1: 1-Nitro-4-phenethoxybenzene [ka]

[0252] To a solution of 2-phenylethane-1-ol (CAS 60-12-8, Fluorochem, 3.38 g, 27.6 mmol) in DMF (20 mL), NaH (60% dispersed in mineral oil, 1.02 g, 25.5 mmol) was added, and the mixture was stirred at room temperature for 30 minutes. 1-fluoro-4-nitrobenzene (CAS 350-46-9, Alfa Aesar, 3.00 g, 21.3 mmol) was added. The mixture was stirred at room temperature for 18 hours, then poured into ice water (400 mL), and the product was extracted with siRNA (3 × 100 mL). The organic extract was washed with brine (50 mL), dried on MgSO4, and the filtrate was adsorbed onto silica gel. Purification by flash chromatography (silica gel, 0-30% siRNA in isohexane) yielded 1-nitro-4-phenethoxybenzene (4.80 g, 93%). LCMS: Method A, 2.00 min, MS: ES + 244.0.

[0253] Step 2: 4-Phenethoxyaniline (I-18) [ka]

[0254] To a solution of 1-nitro-4-phenethoxybenzene (4.50 g, 18.5 mmol) in EtOH (55 mL) and THF (30 mL), 10% Pd / C (wetted with 50% water, 0.98 g, 9.3 mmol) was added, and the mixture was stirred at room temperature under hydrogen (3 bar) for 18 hours. The reaction mixture was filtered through Celite® and concentrated under reduced pressure to obtain 4-phenethoxyaniline (3.50 g, 86%). LCMS: Method A, 0.99 min, MS: ES + 214.2.

[0255] Step 3: N-(4-phenethoxyphenyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide(I-19) [ka]

[0256] 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoic acid (CAS 269409-73-6, BLD, 4.48 g, 18.1 mmol) and DIPEA (8.6 mL, 49.2 mmol) in DMF (40 mL) were stirred together. HATU (7.49 g, 20.0 mmol) and 4-phenethoxyaniline (I-18, 3.50 g, 16.4 mmol) were added to this mixture. The mixture was stirred at 40°C for 18 hours, then cooled, poured into ice water (500 mL), and extracted with SiO2 (3 × 120 mL). The combined organic phase was washed with brine (50 mL), dried on MgSO4, adsorbed onto silica gel, and then purified by flash chromatography (silica gel, isohexane, 0-100% siRNA) to obtain N-(4-phenethoxyphenyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (7.10 g, 87%). LCMS: Method A, 2.27 min, MS: ES + 444.2.

[0257] Intermediates 20, 21 4-((benzyloxy)methyl)aniline (I-20) and N-(4-((benzyloxy)methyl)phenyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (I-21) [ka]

[0258] Step 1: 1-((benzyloxy)methyl)-4-nitrobenzene [ka]

[0259] Benzyl alcohol (CAS 100-51-6, Alfa Aesar, 3.47 mL, 33.3 mmol) was added to a stirred suspension of 1-(bromomethyl)-4-nitrobenzene (CAS 100-11-8, Combi-Blocks, 6.00 g, 27.8 mmol) and Ag2O (9.65 g, 41.7 mmol) in DCM (60 mL), and the mixture was stirred at 45°C for 18 hours. The reaction product was filtered through Celite®, and the filtrate was adsorbed onto silica gel. Subsequently, the filtrate was purified by flash chromatography (silica gel, heptane, 0-30% TBME) to obtain 1-((benzyloxy)methyl)-4-nitrobenzene (6.33 g, 94%). LCMS: Method A, 1.96 min, MS: ES + 244.1.

[0260] Step 2: 4-((benzyloxy)methyl)aniline(I-20) [ka]

[0261] AcOH (1.65 mL, 28.8 mmol) was added to a mixture of 1-((benzyloxy)methyl)-4-nitrobenzene (3.50 g, 14.4 mmol) and iron (4.02 g, 71.9 mmol) in EtOH (25 mL) and water (25 mL), and the reaction mixture was stirred at room temperature for 72 hours. The mixture was filtered through Celite®, the crude concentrate was captured on SCX, washed with MeOH, and eluted with a 10% 0.7 M ammonia / MeOH solution in DCM. Further purification by chromatography on silica gel (0-10% (0.7 M ammonia / MeOH) in DCM) yielded 4-((benzyloxy)methyl)aniline (2.58 g, 79%). LCMS: Method A, 1.09 min, MS: ES + 214.1.

[0262] Step 3: N-(4-((benzyloxy)methyl)phenyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide(I-21) [ka]

[0263] Following the procedure of step 3 of intermediate 19, 4-((benzyloxy)methyl)aniline (I-20) was used instead of 4-phenethoxyaniline (I-18) to obtain N-(4-((benzyloxy)methyl)phenyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide in 51% yield. LCMS: Method A, 2.27 min, MS: ES + 444.2.

[0264] Intermediate 22 N-(4-((benzyloxy)methyl)-2-methoxyphenyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide(I-22) [ka]

[0265] Step 1: 4-((benzyloxy)methyl)-2-methoxy-1-nitrobenzene [ka]

[0266] (3-methoxy-4-nitrophenyl)methanol (CAS:80866-88-2, BLD, 1.00 g, 5.46 mmol) was added to a stirred suspension of benzyl bromide (CAS 100-39-0, Sigma Aldrich, 0.811 mL, 6.82 mmol), LiOH (131 mg, 5.46 mmol), and Ag2O (1.90 g, 8.19 mmol) in DCM (20 mL). The mixture was stirred at 45°C for 16 hours, then diluted with DCM (100 mL) and filtered through Celite®. The filtrate was washed with water, dried over Na2SO4, and concentrated. Purification by flash chromatography (silica gel, 0-10% (0.7 M ammonia / MeOH) in DCM) yielded 4-((benzyloxy)methyl)-2-methoxy-1-nitrobenzene (1.30 g, 85%). LCMS: Method A, 1.94 min, MSES + 274.2.

[0267] Step 2: 4-((benzyloxy)methyl)-2-methoxyaniline [ka]

[0268] Iron (2.39 g, 42.8 mmol) was added to a stirred suspension of 4-((benzyloxy)methyl)-2-methoxy-1-nitrobenzene (1.30 g, 4.76 mmol) and CaCl2 (2.38 g, 21.4 mmol) in EtOH (10 mL) and water (2 mL). The mixture was stirred at 40°C for 16 hours. The mixture was diluted with saturated NaHCO3 aqueous solution (25 mL) and extracted with SiO2 (2 × 25 mL). The combined organic matter was dried on MgSO4 and concentrated to obtain 4-((benzyloxy)methyl)-2-methoxyaniline (1.14 g, 73%). LCMS: Method A, 1.27 min, MSES + 244.2.

[0269] Step 3: N-(4-((benzyloxy)methyl)-2-methoxyphenyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide(I-22) [ka]

[0270] Following the procedure of intermediate 19 step 3, using 4-((benzyloxy)methyl)-2-methoxyaniline instead of 4-phenethoxyaniline (I-18), and purified by flash chromatography (silica gel, 0-10% MeOH / DCM), N-(4-((benzyloxy)methyl)-2-methoxyphenyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide was obtained in 30% yield. LCMS: Method A, 2.38 min, MS ES + 474.2.

[0271] Intermediate 23 N-(3-fluoro-4-((pyridine-2-ylmethoxy)methyl)phenyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide(I-23) [ka]

[0272] Step 1: 2-(((2-fluoro-4-nitrobenzyl)oxy)methyl)pyridine [ka]

[0273] Following the procedure of Step 1 of Intermediate 20, 2-(((2-fluoro-4-nitrobenzyl)oxy)methyl)pyridine was obtained in 53% yield by using pyridine-2-ylmethanol (CAS 586-98-1, BLD) instead of benzyl alcohol, 1-(bromomethyl)-2-fluoro-4-nitrobenzene (CAS 127349-56-8, Apollo Scientific) instead of 1-(bromomethyl)-4-nitrobenzene, and by purification by flash chromatography (silica gel, isohexane, 0-100% siRNA). LCMS: Method A, 1.16 min, MS ES + 263.1.

[0274] Step 2: 3-Fluoro-4-((Pyridine-2-ylmethoxy)methyl)aniline [ka]

[0275] Following the procedure of step 2 of intermediate 22, 3-fluoro-4-((pyridine-2-ylmethoxy)methyl)aniline was obtained in 80% yield by using 2-(((2-fluoro-4-nitrobenzyl)oxy)methyl)pyridine instead of 4-((benzyloxy)methyl)-2-methoxy-1-nitrobenzene. LCMS: Method A, 0.62 min, MS ES + m / z233.2.

[0276] Step 3: N-(3-fluoro-4-((pyridine-2-ylmethoxy)methyl)phenyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide(I-23) [ka]

[0277] Following the procedure of step 3 of intermediate 19, 3-fluoro-4-((pyridine-2-ylmethoxy)methyl)aniline was used instead of 4-phenethoxyaniline (I-18) to obtain N-(3-fluoro-4-((pyridine-2-ylmethoxy)methyl)phenyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide in 72% yield. LCMS: Method A, 1.43 min, MSES + 463.2.

[0278] Intermediate 24 (3-((4-((benzyloxymethyl)phenyl)carbamoyl)-2,4-difluorophenyl)boronic acid (I-24) [ka] (3-((4-((benzyloxymethyl)phenyl)carbamoyl)-2,4-difluorophenyl)boronic acid (I-24) [ka]

[0279] Following the procedure of intermediate 19 step 3, 3-borono-2,6-difluorobenzoic acid (CAS 1451393-05-7, Combi-Blocks) was used instead of 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoic acid to obtain (3-((4-((benzyloxymethyl)phenyl)carbamoyl)-2,4-difluorophenyl)boronic acid in 35% yield. LCMS: Method A, 1.68 min, MSES + 398.1.

[0280] Intermediate 25 N-(4-((benzyloxy)methyl)phenyl)-4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide(I-25) [ka] N-(4-((benzyloxy)methyl)phenyl)-4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide(I-25) [ka]

[0281] Following the procedure of intermediate 19 step 3, 4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoic acid (CAS 515131-35-8, BLD) was used instead of 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoic acid to obtain N-(4-((benzyloxy)methyl)phenyl)-4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide in 57% yield. LCMS: Method A, 2.34 min, MS ES + 458.3.

[0282] Intermediate 26 N-(3-fluoro-4-(((4-methoxybenzyl)oxy)methyl)phenyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide(I-26) [ka]

[0283] Step 1: 1-(bromomethyl)-2-fluoro-4-nitrobenzene [ka]

[0284] To a stirred solution of 2-fluoro-1-methyl-4-nitrobenzene (CAS 455-88-9, Sigma Aldrich, 10.0 g, 64.46 mmol) in anhydrous DCE (100 mL), NBS (CAS 128-08-5, Apollo Scientific) (17.2 g, 96.7 mmol) and AIBN (CAS 78-67-1, Sigma Aldrich) (1.06 g, 6.45 mmol) were added at room temperature. The mixture was stirred under reflux for 18 hours, and then additional NBS (2.87 g, 16.1 mmol) and AIBN (212 mg, 1.29 mmol) were added. The mixture was stirred under reflux for 1 hour, cooled to room temperature, and diluted with water (20 mL). The mixture was extracted with DCM (50 mL), and the combined organic phase was dried over Na2SO4 and concentrated under reduced pressure. Purification by flash chromatography (silica gel, heptane, 0-100% (3:1 EtOH / siRNA)) yielded 1-(bromomethyl)-2-fluoro-4-nitrobenzene (5.40 g, 34%). 1 H NMR (400MHz, DMSO) δ8.16(dd,J=9.8,2.3Hz,1H), 8.10(ddd,J=8.4,2.3,0.8Hz,1H), 7.85(t,J=8.1Hz,1H), 4.79(d,J=1.0Hz,2H).

[0285] Step 2: 2-Fluoro-1-(((4-methoxybenzyl)oxy)methyl)-4-nitrobenzene [ka]

[0286] Following the procedure of Step 1 of Intermediate 20, 2-fluoro-1-(((4-methoxybenzyl)oxy)methyl)-4-nitrobenzene was obtained in 73% yield by using 4-methoxyphenyl)methanol (CAS 105-13-5, Apollo Scientific) instead of benzyl alcohol, 1-(bromomethyl)-2-fluoro-4-nitrobenzene instead of 1-(bromomethyl)-4-nitrobenzene, and by purification by flash chromatography (silica gel, isohexane, 0-100% ethyl phosphate). LCMS Method A, 1.66 min, MSES + Na (non-ionized).

[0287] Step 3: 3-Fluoro-4-(((4-Methoxybenzyl)oxy)methyl)aniline [ka]

[0288] Following the procedure of step 2 of intermediate 22, 3-fluoro-4-(((4-methoxybenzyl)oxy)methyl)aniline was obtained in 91% yield by using 2-fluoro-1-(((4-methoxybenzyl)oxy)methyl)-4-nitrobenzene instead of 4-((benzyloxy)methyl)-2-methoxy-1-nitrobenzene at 45°C for 24 hours. Method A, 1.24 minutes, MSES + 262.2.

[0289] Step 4: N-(3-fluoro-4-(((4-methoxybenzyl)oxy)methyl)phenyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide(I-26) [ka]

[0290] Following the procedure of step 3 of intermediate 19, 3-fluoro-4-(((4-methoxybenzyl)oxy)methyl)aniline was used instead of 4-phenethoxyaniline (I-18) to obtain N-(3-fluoro-4-(((4-methoxybenzyl)oxy)methyl)phenyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide in 49% yield. LCMS: Method A, 1.97 min, MSES + 492.2.

[0291] Intermediate 27 N-(4-(cyclopropylmethoxy)phenyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide(I-27) [ka]

[0292] Step 1: 1-(cyclopropylmethoxy)-4-nitrobenzene [ka]

[0293] Following the procedure of Step 1 of Intermediate 18, cyclopropyl methanol (CAS 2516-33-8, Fluorochem) was used instead of 2-phenylethane-1-ol to obtain 1-(cyclopropylmethoxy)-4-nitrobenzene in 71% yield. LCMS: Method A, 1.79 min, MSES + 194.2.

[0294] Step 2: 4-(cyclopropylmethoxy)aniline [ka]

[0295] Following the procedure of step 2 of intermediate 20, 4-(cyclopropylmethoxy)aniline was obtained in 60% yield by using 1-(cyclopropylmethoxy)-4-nitrobenzene instead of 1-((benzyloxy)methyl)-4-nitrobenzene, and without purification of the crude product. LCMS: Method A, 0.22 min, MSES + 164.2.

[0296] Step 3: N-(4-(cyclopropylmethoxy)phenyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide(I-27) [ka]

[0297] Following the procedure of intermediate 19 step 3, N-(4-(cyclopropylmethoxy)phenyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide was obtained in 86% yield by using 4-(cyclopropylmethoxy)aniline instead of 4-phenethoxyaniline (I-18). LCMS: Method A, 2.09 min, MSES + 394.2.

[0298] Intermediate 28 N-(3-fluoro-4-(((3-methoxybenzyl)oxy)methyl)phenyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide(I-28) [ka]

[0299] Step 1: 2-Fluoro-1-(((3-methoxybenzyl)oxy)methyl)-4-nitrobenzene [ka]

[0300] Following the procedure of Step 1 of Intermediate 20, 2-fluoro-1-(((3-methoxybenzyl)oxy)methyl)-4-nitrobenzene was obtained in 81% yield by using (3-methoxyphenyl)methanol (CAS 105-13-5, Apollo Scientific) instead of benzyl alcohol, 1-(bromomethyl)-2-fluoro-4-nitrobenzene (CAS 127349-56-8, Apollo Scientific) instead of 1-(bromomethyl)-4-nitrobenzene, and by purification by flash chromatography (silica gel, isohexane, 0-100% ethyl phosphate). LCMS: Method A, 1.67 min, MSES + 309.1(M+NH4) + .

[0301] Step 2: 3-Fluoro-4-(((3-Methoxybenzyl)oxy)methyl)aniline [ka]

[0302] Following the procedure of step 2 of intermediate 22, 3-fluoro-4-(((3-methoxybenzyl)oxy)methyl)aniline was obtained in 75% yield by stirring at 45°C for 24 hours and by purification by flash chromatography (silica gel, isohexane, 0-100% ELISA). Method A, 1.28 minutes, MSES + 262.1.

[0303] Step 3: N-(3-fluoro-4-(((3-methoxybenzyl)oxy)methyl)phenyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide(I-28) [ka]

[0304] Following the procedure of step 3 of intermediate 19, 3-fluoro-4-(((3-methoxybenzyl)oxy)methyl)aniline was used instead of 4-phenethoxyaniline (I-18) to obtain N-(3-fluoro-4-(((3-methoxybenzyl)oxy)methyl)phenyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide in 56% yield. LCMS: Method A, 1.99 min, MSES + 492.2.

[0305] Intermediate 29 N-(4-((benzyloxy)methyl)-3-fluorophenyl)-2-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide(I-29) [ka]

[0306] Step 1: 1-((benzyloxy)methyl)-2-fluoro-4-nitrobenzene [ka]

[0307] Following the procedure of Step 1 of Intermediate 20, (2-fluoro-4-nitrophenyl)methanol (CAS 127349-56-8, Apollo Scientific) was used instead of benzyl alcohol, and benzyl bromide (CAS 100-39-0, Sigma Aldrich) was used instead of 1-(bromomethyl)-4-nitrobenzene. 1-((benzyloxy)methyl)-2-fluoro-4-nitrobenzene was obtained in 43% yield without purification and at 45°C for 48 hours. 1H NMR (500MHz, DMSO) δ8.15~8.09(m,2H), 7.80(t,J=7.9Hz,1H), 7.41~7.27(m,5H), 4.71(s,2H), 4.63(s,2H).

[0308] Step 2: 4-((benzyloxy)methyl)-3-fluoroaniline [ka]

[0309] Following the procedure of step 2 of intermediate 22, 4-((benzyloxy)methyl)-3-fluoroaniline was obtained in 55% yield by washing with MeOH and eluting with 0.7 M ammonia / MeOH, using 1-((benzyloxy)methyl)-2-fluoro-4-nitrobenzene instead of 4-((benzyloxy)methyl)-2-methoxy-1-nitrobenzene, and purifying by stirring at 80°C for 16 hours and capturing the crude concentrate on SCX. LCMS: Method A, 1.57 min, MS ES + 232.2.

[0310] Step 3: N-(4-((benzyloxy)methyl)-3-fluorophenyl)-2-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide(I-29) [ka]

[0311] Following the procedure of intermediate 19 step 3, 2-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoic acid (CAS 882679-10-9, BLD) was used instead of 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoic acid, and 4-((benzyloxy)methyl)-3-fluoroaniline was used instead of 4-phenethoxyaniline (I-18) to obtain N-(4-((benzyloxy)methyl)-3-fluorophenyl)-2-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide in 44% yield. 1 H NMR(500MHz,DMSO)δ10.68(s,1H), 7.93(dd,J=7.6,1.7Hz,1H), 7.89~7.83(m,1H), 7.73~7.66(m,1H), 7 .50~7.43(m,2H), 7.41~7.34(m,5H), 7.31(td,J=6.0,2.6Hz,1H), 4.55(d,J=1.6Hz,4H), 1.32(s,12H).

[0312] Intermediate 30 2-Fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-N-(4-(tosylmethyl)phenyl)-benzamide(I-30) [ka] 2-Fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-N-(4-(tosylmethyl)phenyl)-benzamide(I-30) [ka]

[0313] Following the procedure of step 3 of intermediate 19, 2-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoic acid (CAS 882679-10-9, BLD) was used instead of 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoic acid (CAS 882679-10-9, BLD), 4-(tosylmethyl)aniline (CAS 54306-15-9, Fluorochem) was used instead of 4-phenethoxyaniline (I-18), and 2-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-N-(4-(tosylmethyl)phenyl)benzamide was obtained in 35% yield by isolation of the solid by filtration rather than extraction and chromatography. 1 H NMR(500MHz,DMSO)δ10.49(s,1H), 7.90(dd,J=7.6,1.7Hz,1H), 7.88~7.81(m,1H), 7.61(t,J=8.4Hz,4H), 7.4 1(d,J=8.1Hz,2H), 7.37(dd,J=10.4,8.3Hz,1H), 7.14~7.09(m,2H), 4.60(s,2H), 2.41(s,3H), 1.32(s,12H).

[0314] Intermediate 31 (3-((4-((benzyloxy)methyl)phenyl)carbamoyl)-4-methylphenyl)boronic acid (I-31) [ka] (3-((4-((benzyloxy)methyl)phenyl)carbamoyl)-4-methylphenyl)boronic acid (I-31) [ka]

[0315] Following the procedure of intermediate 19 step 3, (3-((4-((benzyloxy)methyl)phenyl)carbamoyl)-4-methylphenyl)boronic acid was obtained in 34% yield by using 5-borono-2-methylbenzoic acid (CAS 1256346-18-5, Combi-Blocks) instead of 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoic acid instead of 5-borono-2-methylbenzoic acid (CAS 1256346-18-5, Combi-Blocks), 4-((benzyloxy)methyl)aniline (I-20) instead of 4-phenethoxyaniline (I-18), and by purification by flash chromatography (silica gel, 0-10% MeOH in DCM). LCMS: Method A, 1.71 min, MSES + 376.2.

[0316] Intermediate 32 N-(4-((benzyloxy)methyl)-2-fluorophenyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide(I-32) [ka]

[0317] Step 1: 4-((benzyloxy)methyl)-2-fluoro-1-nitrobenzene [ka]

[0318] Following the procedure of step 1 of intermediate 20, 4-((benzyloxy)methyl)-2-fluoro-1-nitrobenzene (CAS 131858-37-2, Apollo) was used instead of 1-(bromomethyl)-4-nitrobenzene to obtain 4-((benzyloxy)methyl)-2-fluoro-1-nitrobenzene in 96% yield. LCMS: Method A, 1.94 min, MS: ES + 261.1.

[0319] Step 2: 4-((benzyloxy)methyl)-2-fluoroaniline [ka]

[0320] Following the procedure of step 2 of intermediate 20, 4-((benzyloxy)methyl)-2-fluoro-1-nitrobenzene was used instead of 1-((benzyloxy)methyl)-4-nitrobenzene, and 4-((benzyloxy)methyl)-2-fluoroaniline was obtained in 75% yield by purification by flash chromatography (silica gel, isohexane, 0-50% TBME). LCMS: Method A, 1.64 min, MSES + 232.1.

[0321] Step 3: N-(4-((benzyloxy)methyl)-2-fluorophenyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide(I-32) [ka]

[0322] Following the procedure of intermediate 19 step 3, 4-((benzyloxy)methyl)-2-fluoroaniline was used instead of 4-phenethoxyaniline (I-18) to obtain N-(4-((benzyloxy)methyl)-2-fluorophenyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide in 46% yield. LCMS: Method A, 2.26 min, MSES + 462.2.

[0323] Intermediate 33 N-(4-((benzyloxy)methyl)-2-fluorophenyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide(I-33) [ka] N-(4-((benzyloxy)methyl)-2-fluorophenyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide(I-33) [ka]

[0324] Following the procedure of intermediate 19 step 3, 4-((benzyloxy)methyl)aniline (I-20) was used instead of 4-phenethoxyaniline (I-18), and 2-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoic acid (CAS 882679-10-9, Fluorochem) was used instead of 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoic acid to obtain N-(4-((benzyloxy)methyl)-2-fluorophenyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide in 46% yield. LCMS: Method A, 2.26 min, MS: ES + 462.2.

[0325] Intermediate 34 (5-((4-((benzyloxymethyl)phenyl)carbamoyl)-2-fluorophenyl)boronic acid (I-34) [ka] (5-((4-((benzyloxymethyl)phenyl)carbamoyl)-2-fluorophenyl)boronic acid (I-34) [ka]

[0326] Following the procedure of step 3 of intermediate 19, (5-((4-((benzyloxy)methyl)phenyl)carbamoyl)-2-fluorophenyl)boronic acid was obtained in 55% yield by using 2-fluoro-5-carboxybenzeneboronic acid (CAS 874219-59-7, BLD) instead of 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoic acid, and 4-((benzyloxy)methyl)aniline (I-20) instead of 4-phenethoxyaniline (I-18), and after RP chromatography (C18, 0-100% (0.1% HCO2H in MeCN) in (0.1% HCO2H aqueous solution)). LCMS: Method A, 1.68 min, MSES + 380.2.

[0327] Intermediate 35 N-(4-((benzyloxy)methyl)phenyl)-4-methoxy-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide(I-35) [ka] N-(4-((benzyloxy)methyl)phenyl)-4-methoxy-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide(I-35) [ka]

[0328] Following the procedure of step 3 of intermediate 19, 4-methoxy-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoic acid (CAS 269409-71-4, Manchester Organics) was used instead of 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoic acid, and 4-((benzyloxy)methyl)aniline (I-20) was used instead of 4-phenethoxyaniline (I-18) to obtain N-(4-((benzyloxy)methyl)phenyl)-4-methoxy-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide in 52% yield. LCMS: Method A, 2.12 min, MSES + 474.2

[0329] Intermediate 36 (3-((4-((benzyloxymethyl)phenyl)carbamoyl)-4-methoxyphenyl)boronic acid (I-36) [ka] (3-((4-((benzyloxymethyl)phenyl)carbamoyl)-4-methoxyphenyl)boronic acid (I-36) [ka]

[0330] Following the procedure of step 3 of intermediate 19, (3-((4-((benzyloxy)methyl)phenyl)carbamoyl)-4-methoxyphenyl)boronic acid was obtained in 87% yield by using 5-borono-2-methoxybenzoic acid (CAS 913836-12-1, BLD) instead of 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoic acid, and 4-((benzyloxy)methyl)aniline (I-20) instead of 4-phenethoxyaniline (I-18). LCMS: Method A, 1.74 min, MSES + 392.2.

[0331] Intermediate 37 N-(4-((1-phenylethoxy)methyl)phenyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide(I-37) [ka]

[0332] Step 1: 1-Nitro-4-((1-phenylethoxy)methyl)benzene [ka]

[0333] Following the procedure of intermediate 20 step 1, 1-phenylethane-1-ol (CAS 98-85-1, Sigma Aldrich) was used instead of benzyl alcohol, and 1-nitro-4-((1-phenylethoxy)methyl)benzene was obtained in 54% yield at 45°C and without purification. LCMS: Method A, 2.04 min, MSES + 258.1.

[0334] Step 2: 4-((1-phenylethoxy)methyl)aniline [ka]

[0335] AcOH (0.45 mL, 7.8 mmol) was added to a stirred suspension of 1-nitro-4-((1-phenylethoxy)methyl)benzene (1.00 g, 3.89 mmol) and iron (651 mg, 11.7 mmol) in water (20 mL) and ethanol (20 mL). The mixture was stirred at 45°C for 24 hours, then diluted with saturated NaHCO3 aqueous solution (150 mL) and extracted with SiO2 (3 × 60 mL). The combined organic phase was dried over Na2SO4 and concentrated under reduced pressure. Purification by flash chromatography (silica gel, 0-10% DCM (0.1% ammonia / MeOH)) yielded 4-((1-phenylethoxy)methyl)aniline (670 mg, 27%). LCMS: Method A, 1.22 min, MSES + 228.2.

[0336] Step 3: N-(4-((1-phenylethoxy)methyl)phenyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide(I-37) [ka]

[0337] Following the procedure of step 3 of intermediate 19, 4-((1-phenylethoxy)methyl)aniline was used instead of 4-phenethoxyaniline (I-18) to obtain N-(4-((1-phenylethoxy)methyl)phenyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide in 17% yield. LCMS: Method A, 2.30 min, MSES + 458.2.

[0338] Intermediate 38 N-(6-bromo-3-chloropyrazine-2-yl)methanesulfonamide (I-38) [ka] N-(6-bromo-3-chloropyrazine-2-yl)methanesulfonamide (I-38) [ka]

[0339] Following the procedure for Intermediate 1, morpholine-4-sulfonyl chloride (CAS 1828-66-6, BLD) was used instead of methanesulfonyl chloride to obtain N-(6-bromo-3-chloropyrazine-2-yl)methanesulfonamide in 27% yield. LCMS: Method A, 1.07 min, MSES + 385.8 / 287.9.

[0340] Intermediate 39 5-(6-amino-5-methylpyrazine-2-yl)-N-(4-((benzyloxy)methyl)phenyl)-2-fluorobenzamide(I-39) [ka]

[0341] Step 1: 6-Chloro-3-methylpyrazine-2-amine [ka]

[0342] A mixture of 3-bromo-6-chloropyrazine-2-amine (CAS:212779-21-0, BLD, 2.00 g, 9.60 mmol), 2,4,6-trimethyl-1,3,5,2,4,6-trioxatriborinane (2.96 mL, 50% Wt, 10.6 mmol), Pd-118 (625 mg, 0.960 mmol), and Cs2CO3 (6.25 g, 19.2 mmol) in MeCN / water (4:1, 20 mL) was sparged with N2 and then stirred at 80°C for 40 hours. After cooling to room temperature, the mixture was filtered through Celite and washed with siRNA (50 mL). The filtrate was diluted with brine (75 mL), and the aqueous components were extracted with siRNA (2 × 75 mL). The combined organic components were washed with brine (225 mL), dried over MgSO4, and concentrated under reduced pressure. Purification by flash chromatography (silica gel, 0-100% (3:1 Â1 / EtOH) / isohexane) yielded 6-chloro-3-methylpyrazine-2-amine (1.03 g, 73%). LCMS: Method A, 0.69 min, MSES + 144.0.

[0343] Step 2: 5-(6-amino-5-methylpyrazine-2-yl)-N-(4-((benzyloxy)methyl)phenyl)-2-fluorobenzamide(I-39) [ka]

[0344] A mixture of 6-chloro-3-methylpyrazine-2-amine (150 mg, 1.02 mmol), N-(4-((benzyloxy)methyl)phenyl)-2-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (577 mg, 1.13 mmol), Pd-118 (67 mg, 0.102 mmol), and Cs2CO3 (667 mg, 2.05 mmol) in MeCN / water (4:1, 7 mL) was sparged with N2 and then stirred at 80°C for 1.5 hours. After cooling to room temperature, the mixture was diluted with water (30 mL) and extracted with siRNA (3 × 30 mL). The combined organic matter was dried over MgSO4 and concentrated under reduced pressure. This was combined with a second batch starting from a 0.137 mmol scale of 6-chloro-3-methylpyrazine-2-amine and purified by flash chromatography (silica gel, 0-100% (3:1 siRNA / EtOH) / isohexane) to obtain 5-(6-amino-5-methylpyrazine-2-yl)-N-(4-((benzyloxy)methyl)phenyl)-2-fluorobenzamide (255 mg, 48%). LCMS: Method A, 1.70 min, MSES + 443.1.

[0345] Intermediate 40 5-(6-amino-5-cyclopropylpyrazine-2-yl)-N-(4-((benzyloxy)methyl)phenyl)-2-fluorobenzamide(I-40) [ka]

[0346] Step 1: 6-Chloro-3-cyclopropylpyrazine-2-amine [ka]

[0347] Following the procedure of Intermediate 39 Step 1, cyclopropaneboronic acid (CAS: 411235-57-9, Fluorochem) was used instead of 2,4,6-trimethyl-1,3,5,2,4,6-trioxatriborinane, and the mixture was stirred for 40 hours (additional cyclopropaneboronic acid (0.4 equivalents) and Pd-118 (0.05 equivalents) were added after 22 hours) to obtain 6-chloro-3-cyclopropylpyrazine-2-amine in 62% yield. LCMS: Method A, 1.06 min, MSES+170.0.

[0348] Step 2: 5-(6-amino-5-cyclopropylpyrazine-2-yl)-N-(4-((benzyloxy)methyl)phenyl)-2-fluorobenzamide(I-40) [ka]

[0349] Following the procedure of step 2 of intermediate 39, 5-(6-amino-5-cyclopropylpyrazine-2-yl)-N-(4-((benzyloxy)methyl)phenyl)-2-fluorobenzamide was obtained in 41% yield by using 6-chloro-3-cyclopropylpyrazine-2-amine instead of 6-chloro-3-methylpyrazine-2-amine. LCMS: Method A, 1.84 min, MSES+469.1. [Example 1]

[0350] 3-(5-chloro-6-(methylsulfonamide)pyrazine-2-yl)-N-(4-phenethoxyphenyl)benzamide [ka] 3-(5-chloro-6-(methylsulfonamide)pyrazine-2-yl)-N-(4-phenethoxyphenyl)benzamide [ka]

[0351] A mixture of N-(6-bromo-3-chloropyrazine-2-yl)methanesulfonamide (I-1, 110 mg, 0.384 mmol), Cs2CO3 (500 mg, 1.54 mmol), and N-(4-phenethoxyphenyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (I-19, 170 mg, 0.384 mmol) in water (2 mL) and dioxane (8 mL) was purged with nitrogen for 5 minutes. Then, Pd(dppf)Cl2 (43 mg, 0.077 mmol) was added, and the mixture was purged for a further 2 minutes. The mixture was stirred at 80°C for 3 hours. The mixture was cooled to room temperature, HCl aqueous solution (1 M, 5 mL) was added, and the mixture was extracted with HCl (3 × 15 mL). The combined organic phase was dried over Na2SO4 and concentrated under reduced pressure. Purification by RP chromatography (C18, 0-100% in 0.1% HCO2H aqueous solution (0.1% HCO2H in MeCN)) yielded 3-(5-chloro-6-(methylsulfonamide)pyrazine-2-yl)-N-(4-phenethoxyphenyl)benzamide (170 mg, 80%). LCMS: Method A, 1.98 min, MS ES + 523.2. 1 H NMR(500MHz,DMSO)δ10.98(s,1H), 10.27(s,1H), 8.90(s,1H), 8.61(s,1H), 8.27(d,J=7.8Hz,1H), 8.06(d,J=7.8Hz,1H), 7.72(t,J=7.7Hz,1H) , 7.68(d,J=8.6Hz,2H), 7.41~7.29(m,4H), 7.24(t,J=6.6Hz,1H), 7.00~ 6.93(m,2H), 4.20(t,J=6.9Hz,2H), 3.50(s,3H), 3.05(t,J=6.9Hz,2H).

[0352] Examples 2-9: Similar to Example 1, Examples 2-9 were prepared by substituting N-(6-bromo-3-chloropyrazine-2-yl)methanesulfonamide (I-1) and N-(4-phenethoxyphenyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (I-19) with appropriate starting materials and frothing with dioxane or acetonitrile at 80°C for 1 hour, and using any other minor modifications described. Examples 2, 3 and 4 were purified with a basic modifier. [ka] [Example 2]

[0353] N-(4-((benzyloxy)methyl)phenyl)-3-(5-chloro-6-(methylsulfonamide)pyrazine-2-yl)benzamide [ka]

[0354] N-(6-bromo-3-chloropyrazine-2-yl)methanesulfonamide (I-1) and N-(4-((benzyloxy)methyl)phenyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (I-21) were used to obtain N-(4-((benzyloxy)methyl)phenyl)-3-(5-chloro-6-(methylsulfonamide)pyrazine-2-yl)benzamide in 39% yield. LCMS: Method A, 1.96 min, MS ES + 523.1. 1¹H NMR (500MHz, DMSO) δ11.01(s,1H), 10.40(s,1H), 8.56(s,1H), 8.51(s,1H), 8.26(d,J=7.7Hz,1H), 8.02(d,J=7.7Hz,1H), 7.79(d,J=8.2Hz,2H), 7.69(t,J=7.7Hz,1H), 7.40~7.34(m,5H), 7.34~7.27(m,1H), 4.54(s,2H), 4.52(s,2H), 3.26(s,3H). ¹H was unclear / not observed. The isolated compound contains a maximum of 1 molar equivalent of ammonia. [Example 3]

[0355] 3-(5-chloro-6-(methylsulfonamide)pyrazine-2-yl)-N-(4-(cyclopropylmethoxy)phenyl)benzamide [ka]

[0356] Using N-(6-bromo-3-chloropyrazine-2-yl)methanesulfonamide (I-1) and N-(4-(cyclopropylmethoxy)phenyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (I-27), and by trituration with CH3CN and Et2O, 3-(5-chloro-6-(methylsulfonamide)pyrazine-2-yl)-N-(4-(cyclopropylmethoxy)phenyl)benzamide was obtained in 52% yield. LCMS: Method A, 1.76 min, MS ES + 473.1. 1¹H NMR (500MHz, DMSO) δ: 10.98 (s, 1H), 10.26 (s, 1H), 8.89 (s, 1H), 8.61 (s, 1H), 8.27 (d, J=7.9Hz, 1H), 8.06 (d, J=7.8Hz, 1H), 7.82~7.62 (m, 3H), 6.94 (d, J=8.6Hz, 2H), 3.81 (d, J=7.0Hz, 2H), 3.49 (s, 3H), 1.29~1.17 (m, 1H), 0.63~0.52 (m, 2H), 0.37~0.26 (m, 2H). The isolated compounds contained a maximum of 1 molar equivalent of ammonia. [Example 4]

[0357] N-(4-((benzyloxy)methyl)phenyl)-3-(5-chloro-6-(cyclopropanesulfonamide)pyrazine-2-yl)benzamide [ka]

[0358] N-(6-bromo-3-chloropyrazine-2-yl)cyclopropanesulfonamide (I-2) and N-(4-((benzyloxy)methyl)phenyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (I-21) were used to obtain N-(4-((benzyloxy)methyl)phenyl)-3-(5-chloro-6-(cyclopropanesulfonamide)pyrazine-2-yl)benzamide in 50% yield. LCMS: Method A, 2.00 min, MS ES + 549.1. 1¹H NMR (500MHz, DMSO) δ: 10.96 (s, 1H), 10.42 (s, 1H), 8.92 (s, 1H), 8.63 (d, J=1.9Hz, 1H), 8.34~8.29 (m, 1H), 8.10~8.05 (m, 1H), 7.82~7.77 (m, 2H), 7.74 (t, J=7.8Hz, 1H), 7.42~7.35 (m, 6H), 7.35~7.27 (m, 1H), 4.54 (s, 2H), 4.53 (s, 2H), 1.25~1.20 (m, 2H), 1.15~1.08 (m, 2H). ¹H was unclear / not observed. The isolated compounds contained a maximum of 1 molar equivalent of ammonia. [Example 5]

[0359] N-(4-((benzyloxy)methyl)-2-methoxyphenyl)-3-(5-chloro-6-(methylsulfonamide)pyrazine-2-yl)benzamide [ka]

[0360] N-(6-bromo-3-chloropyrazine-2-yl)methanesulfonamide (I-1) and N-(4-((benzyloxy)methyl)-2-methoxyphenyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (I-22) were used to obtain N-(4-((benzyloxy)methyl)-2-methoxyphenyl)-3-(5-chloro-6-(methylsulfonamide)pyrazine-2-yl)benzamide in 12% yield. LCMS: Method B, 1.34 min, MS ES + 553.2 1H NMR(400MHz,DMSO)δ10.98(s,1H), 9.63(s,1H), 8.92(s,1H), 8.64(s,1H), 8. 29(d,J=7.8Hz,1H), 8.09(d,J=7.8Hz,1H), 7.77(d,J=8.0Hz,1H), 7.72(t,J= 7.8Hz,1H), 7.43~7.34(m,4H), 7.34~7.27(m,1H), 7.10(d,J=1.8Hz,1H), 6.9 9(dd,J=8.1,1.7Hz,1H), 4.56(s,2H), 4.55(s,2H), 3.85(s,3H), 3.50(s,3H). [Example 6]

[0361] 3-(5-chloro-6-(methylsulfonamide)pyrazine-2-yl)-N-(3-fluoro-4-(((4-methoxybenzyl)oxy)methyl)phenyl)benzamide [ka]

[0362] Using N-(6-bromo-3-chloropyrazine-2-yl)methanesulfonamide (I-1) and N-(3-fluoro-4-(((4-methoxybenzyl)oxy)methyl)phenyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (I-26), 3-(5-chloro-6-(methylsulfonamide)pyrazine-2-yl)-N-(3-fluoro-4-(((4-methoxybenzyl)oxy)methyl)phenyl)benzamide was obtained in 43% yield. LCMS: Method A, 1.65 min, MS ES + 572.1. 1H NMR(500MHz,DMSO)δ10.99(s,1H), 10.60(s,1H), 8.93(s,1H), 8.62(t,J=1.8H z,1H), 8.31(dt,J=7.9,1.4Hz,1H), 8.08(dt,J=7.8,1.5Hz,1H), 7.81~7.72(m ,2H), 7.57(dd,J=8.4,2.0Hz,1H), 7.46(t,J=8.4Hz,1H), 7.29(d,J=8.6Hz,2H ), 6.93(d,J=8.6Hz,2H), 4.52(s,2H), 4.48(s,2H), 3.76(s,3H), 3.52(s,3H). [Example 7]

[0363] 3-(5-chloro-6-(methylsulfonamide)pyrazine-2-yl)-N-(3-fluoro-4-(((3-methoxybenzyl)oxy)methyl)phenyl)benzamide [ka]

[0364] Using N-(6-bromo-3-chloropyrazine-2-yl)methanesulfonamide (I-1) and N-(3-fluoro-4-(((3-methoxybenzyl)oxy)methyl)phenyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (I-28), and purified by preparative HPLC (prep method A, x=20, y=50), 3-(5-chloro-6-(methylsulfonamide)pyrazine-2-yl)-N-(3-fluoro-4-(((3-methoxybenzyl)oxy)methyl)phenyl)benzamide was obtained in 6% yield. LCMS: Method A, 1.67 min, MS ES + 571.2 1H NMR(500MHz,DMSO)δ10.99(s,1H), 10.61(s,1H), 8.92(s,1H), 8.62(t,J=1.9Hz, 1H), 8.31(d,J=7.9Hz,1H), 8.08(d,J=6.6Hz,1H), 7.84~7.71(m,2H), 7.58(dd,J= 8.4,2.0Hz,1H), 7.48(t,J=8.4Hz,1H), 7.29(t,J=7.8Hz,1H), 6.97~6.90(m,2H), 6.87(dd,J=8.6,2.5Hz,1H), 4.55(s,2H), 4.54(s,2H), 3.76(s,3H), 3.51(s,3H). [Example 8]

[0365] N-(4-((benzyloxy)methyl)-3-fluorophenyl)-5-(6-chloro-5-(methylsulfonamide)pyrazine-2-yl)-2-fluorobenzamide [ka]

[0366] N-(5-bromo-3-chloropyrazine-2-yl)-N-(methylsulfonyl)methanesulfonamide (I-3) and N-(4-((benzyloxy)methyl)-3-fluorophenyl)-2-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (I-29) were used to obtain N-(4-((benzyloxy)methyl)-3-fluorophenyl)-5-(6-chloro-5-(methylsulfonamide)pyrazine-2-yl)-2-fluorobenzamide in 14% yield. LCMS: Method A, 1.72 min, MS ES + 559.1. 1H NMR(500MHz,DMSO)δ10.94(s,1H), 10.79(s,1H), 9.07(s,1H), 8.32(dd,J=6.6,2.4Hz,1H), 8.26(m,1H), 7.76~7.70(m,1H), 7.54 (t,J=9.2Hz,1H), 7.53~7.44(m,2H), 7.41~7.35(m,1H), 7.37(s,3H), 7.35~7.27(m,1H), 4.56(s,2H), 4.55(s,2H), 3.40(s,3H). [Example 9]

[0367] 5-(5-chloro-6-(methylsulfonamide)pyrazine-2-yl)-2-fluoro-N-(4-(tosylmethyl)phenyl)benzamide [ka]

[0368] Using N-(6-bromo-3-chloropyrazine-2-yl)methanesulfonamide (I-1) and 2-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-N-(4-(tosylmethyl)phenyl)benzamide (I-30), 5-(5-chloro-6-(methylsulfonamide)pyrazine-2-yl)-2-fluoro-N-(4-(tosylmethyl)phenyl)benzamide was obtained in 8% yield. LCMS: Method A, 1.45 min, MS ES + 589.1 1 H NMR(500MHz,DMSO)δ10.98(s,1H), 10.62(s,1H), 8.81(s,1H), 8.37(dd,J=6.8,2.4Hz,1H), 8.27(m,1H), 7.65(d,J=8.3Hz,2H), 7.63~7.58(m,2H), 7.57(t,J=9.2Hz,1H), 7.42(d,J=8.0Hz,2H), 7.13(d,J=8.6Hz,2H), 4.62(s,2H), 3.43(s,3H), 2.41(s,3H).

[0369] Examples 10-21: Similar to Example 1, Examples 10–21 were prepared by substituting N-(6-bromo-3-chloropyrazine-2-yl)methanesulfonamide (I-1) and N-(4-phenethoxyphenyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (I-19) with appropriate starting materials, using Pd-118 instead of Pd(dppf)Cl2, and either dioxane or acetonitrile, and cooking at 80°C for 9–18 hours. Any other minor modifications are described. Examples 10–12, 14–15 and 18–21 were purified with a basic modifier. [ka] [Example 10]

[0370] 3-(6-chloro-5-(methylsulfonamide)pyrazine-2-yl)-N-(4-phenethoxyphenyl)benzamide [ka]

[0371] Using N-(5-bromo-3-chloropyrazine-2-yl)methanesulfonamide (I-3) and N-(4-phenethoxyphenyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (I-19), 3-(6-chloro-5-(methylsulfonamide)pyrazine-2-yl)-N-(4-phenethoxyphenyl)benzamide was obtained in 7% yield. LCMS: Method A, 1.97 min, MS ES + 523.1. 1¹H NMR (500MHz, DMSO) δ: 10.96 (s, 1H), 10.24 (s, 1H), 8.96 (s, 1H), 8.50 (s, 1H), 8.18 (d, J=7.8Hz, 1H), 7.97 (d, J=7.8Hz, 1H), 7.66 (m, 3H), 7.37~7.30 (m, 3H), 7.23 (t, J=6.8Hz, 1H), 6.95 (d, J=9.0Hz, 2H), 4.19 (t, J=6.9Hz, 2H), 3.28 (s, 3H), 3.04 (t, J=6.9Hz, 2H). ¹H was unclear / not observed. The isolated compound contains a maximum of 1 molar equivalent of ammonia. [Example 11]

[0372] 3-(5-cyano-6-(methylsulfonamide)pyrazine-2-yl)-N-(4-phenethoxyphenyl)benzamide [ka]

[0373] Using N-(6-chloro-3-cyanopyrazine-2-yl)methanesulfonamide (I-4) and N-(4-phenethoxyphenyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (I-19), 3-(5-cyano-6-(methylsulfonamide)pyrazine-2-yl)-N-(4-phenethoxyphenyl)benzamide was obtained in 21% yield. LCMS: Method B, 1.95 min, MS ES + 514.1. 1¹H NMR (500MHz, DMSO) δ12.04 (s, 1H), 10.29 (s, 1H), 8.44 (d, J=1.9Hz, 1H), 8.36 (s, 1H), 8.17 (d, J=7.8Hz, 1H), 8.15~8.09 (m, 1H), 7.78 (t, J=7.8Hz, 1H), 7.71~7.64 (m, 2H), 7.37~7.29 (m, 4H), 7.27~7.20 (m, 1H), 6.99~6.91 (m, 2H), 4.19 (t, J=6.9Hz, 2H), 3.45 (s, 3H), 3.04 (t, J=6.9Hz, 2H). The isolated compound contains a maximum of 1 molar equivalent of ammonia. [Example 12]

[0374] 3-(5-methyl-4-(methylsulfonamide)pyrimidine-2-yl)-N-(4-phenethoxyphenyl)benzamide [ka]

[0375] Using N-(2-chloro-5-methylpyrimidine-4-yl)-N-(methylsulfonyl)methanesulfonamide (I-11) and N-(4-phenethoxyphenyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (I-19), 3-(5-methyl-4-(methylsulfonamide)pyrimidine-2-yl)-N-(4-phenethoxyphenyl)benzamide was obtained in 23% yield. LCMS: Method A, 1.22 min, MS ES + 503.2. 1¹H NMR (500MHz, DMSO) δ: 10.75 (s, 1H), 10.31 (s, 1H), 8.84 (s, 1H), 8.53 (s, 1H), 8.47 (d, J=7.8Hz, 1H), 8.07 (d, J=7.7Hz, 1H), 7.68 (m, 3H), 7.38~7.29 (m, 4H), 7.27~7.20 (m, 1H), 6.99~6.92 (m, 2H), 4.19 (t, J=6.9Hz, 2H), 3.54 (s, 3H), 3.05 (t, J=6.9Hz, 2H), 2.21 (s, 3H). The isolated compound contains a maximum of 1 molar equivalent of ammonia. [Example 13]

[0376] 3-(6-methyl-5-(methylsulfonamide)pyridine-3-yl)-N-(4-phenethoxyphenyl)benzamide [ka]

[0377] Using N-(5-bromo-2-methylpyridine-3-yl)-N-(methylsulfonyl)methanesulfonamide (I-12) and N-(4-phenethoxyphenyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (I-19), 3-(6-methyl-5-(methylsulfonamide)pyridine-3-yl)-N-(4-phenethoxyphenyl)benzamide was obtained in 52% yield. LCMS: Method A, 1.81 min, MS ES + 502.1. 1 H NMR(500MHz,DMSO)δ10.24(s,1H), 9.49(s,1H), 8.75(d,J=2.2Hz,1H), 8.21(d,J=2.4Hz,1H), 7.97(q,J=2.9Hz,2H), 7.90(d,J=7.7Hz,1H), 7.70 ~7.63(m,3H), 7.40~7.29(m,4H), 7.27~7.21(m,1H), 6.98~6.92(m,2H), 4.19(t,J=6.9Hz,2H), 3.11(s,3H), 3.04(t,J=6.9Hz,2H), 2.58(s,3H). [Example 14]

[0378] 3-(6-(methylsulfonamide)pyrazine-2-yl)-N-(4-phenethoxyphenyl)benzamide [ka]

[0379] Using N-(6-bromopyrazine-2-yl)-N-(methylsulfonyl)methanesulfonamide (I-5) and N-(4-phenethoxyphenyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (I-19), 3-(6-(methylsulfonamide)pyrazine-2-yl)-N-(4-phenethoxyphenyl)benzamide was obtained in 43% yield. LCMS: Method A, 1.88 min, MS ES + 489.2. 1 ¹H NMR (500MHz, DMSO) δ11.22 (s, 1H), 10.27 (s, 1H), 9.01 (s, 1H), 8.62 (d, J=1.9Hz, 1H), 8.29 (d, J=8.4Hz, 2H), 8.05 (d, J=7.7Hz, 1H), 7.74~7.68 (m, 2H), 7.68 (d, J=2.2Hz, 1H), 7.38~7.29 (m, 4H), 7.27~7.20 (m, 1H), 7.00~6.93 (m, 2H), 4.20 (t, J=6.9Hz, 2H), 3.47 (s, 3H), 3.05 (t, J=6.9Hz, 2H). The isolated compound contains a maximum of 1 molar equivalent of ammonia. [Example 15]

[0380] 3-(4-(methylsulfonamide)pyrimidine-2-yl)-N-(4-phenethoxyphenyl)benzamide [ka]

[0381] Using N-(2-chloropyrimidine-4-yl)-N-(methylsulfonyl)methanesulfonamide (I-6) and N-(4-phenethoxyphenyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (I-19), 3-(4-(methylsulfonamide)pyrimidine-2-yl)-N-(4-phenethoxyphenyl)benzamide was obtained in 23% yield. LCMS: Method B, 1.85 min, MS ES + 489.2. 1 H NMR(500MHz,DMSO)δ11.41(s,1H), 10.32(s,1H), 8.88(s,1H), 8.68(d,J=5.7Hz,1H), 8.51(d,J=7.7Hz,1H), 8.08(d,J=7.6Hz,1H), 7.72~7.66(m,3H) ), 7.37~7.29(m,4H), 7.24(t,J=6.7Hz,1H), 6.95(d,J=8.9Hz,2H), 6.91(d ,J=5.6Hz,1H), 4.19(t,J=6.8Hz,2H), 3.49(s,3H), 3.05(t,J=6.9Hz,2H). The isolated compound contains a maximum of 1 molar equivalent of ammonia. [Example 16]

[0382] 3-(6-(methylsulfonamide)pyridine-2-yl)-N-(4-phenethoxyphenyl)benzamide [ka]

[0383] Using N-(6-bromopyridine-2-yl)-N-(methylsulfonyl)methanesulfonamide (I-7) and N-(4-phenethoxyphenyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (I-19), 3-(6-(methylsulfonamide)pyridine-2-yl)-N-(4-phenethoxyphenyl)benzamide was obtained in 19% yield by trituration with CH3CN and Et2O. LCMS: Method A, 1.97 min, MS ES+ 488.1. 1 H NMR(500MHz,DMSO)δ10.71(s,1H), 10.25(s,1H), 8.55(s,1H), 8.25(d,J=7. 8Hz,1H), 7.99(d,J=7.7Hz,1H), 7.87(t,J=7.9Hz,1H), 7.74(d,J=7.7Hz,1H ), 7.71~7.63(m,3H), 7.36~7.29(m,4H), 7.24(d,J=7.0Hz,1H), 6.95(dd,J= 8.3,5.6Hz,3H), 4.19(t,J=6.8Hz,2H), 3.44(s,3H), 3.05(t,J=6.9Hz,2H). [Example 17]

[0384] N-(4-((benzyloxy)methyl)phenyl)-3-(6-(methylsulfonamide)pyrazine-2-yl)benzamide [ka]

[0385] N-(6-bromopyrazine-2-yl)-N-(methylsulfonyl)methanesulfonamide (I-5) and N-(4-((benzyloxy)methyl)phenyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (I-21) were used to obtain N-(4-((benzyloxy)methyl)phenyl)-3-(6-(methylsulfonamide)pyrazine-2-yl)benzamide in 14% yield. LCMS: Method B, 1.84 min, MS ES + 489.1. 1¹H NMR (500MHz, DMSO) δ 10.41 (s, 1H), 8.82 (s, 1H), 8.60 (s, 1H), 8.29 (d, J=7.8Hz, 1H), 8.15 (s, 1H), 8.04 (d, J=7.8Hz, 1H), 7.80 (d, J=8.3Hz, 2H), 7.70 (t, J=7.8Hz, 1H), 7.40~7.27 (m, 7H), 4.54 (s, 2H), 4.52 (s, 2H), 3.27 (s, 3H). 1H was unclear / not observed. [Example 18]

[0386] 3-(6-(cyclopropanesulfonamide)pyrazine-2-yl)-N-(4-phenethoxyphenyl)benzamide [ka]

[0387] Using N-(6-bromopyrazine-2-yl)cyclopropanesulfonamide (I-8) and N-(4-phenethoxyphenyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (I-19), 3-(6-(cyclopropanesulfonamide)pyrazine-2-yl)-N-(4-phenethoxyphenyl)benzamide was obtained in 33% yield. LCMS: Method A, 1.92 min, MS ES + 515.1. 1 H NMR(500MHz,DMSO)δ11.18(s,1H), 10.26(s,1H), 8.99(s,1H), 8.65~8.60(m ,1H), 8.35~8.28(m,2H), 8.04(d,J=7.7Hz,1H), 7.74~7.65(m,3H), 7.38~7. 29(m,4H), 7.27~7.20(m,1H), 6.99~6.93(m,2H), 4.20(t,J=6.9Hz,2H), 3.2 3~3.15(m,1H), 3.05(t,J=6.9Hz,2H), 1.19~1.12(m,2H), 1.12~1.06(m,2H). The isolated compound contains a maximum of 1 molar equivalent of ammonia. [Example 19]

[0388] N-(4-((benzyloxy)methyl)phenyl)-3-(6-(cyclopropanesulfonamide)pyrazine-2-yl)benzamide [ka]

[0389] N-(6-bromopyrazine-2-yl)cyclopropanesulfonamide (I-8) and N-(4-((benzyloxy)methyl)phenyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (I-21) were used to obtain N-(4-((benzyloxy)methyl)phenyl)-3-(6-(cyclopropanesulfonamide)pyrazine-2-yl)benzamide in 44% yield. LCMS: Method A, 1.87 min, MS ES + 515.1. 1 ¹H NMR (500MHz, DMSO) δ11.19 (s,1H), 10.42 (s,1H), 8.99 (s,1H), 8.67~8.62 (m,1H), 8.35~8.31 (m,2H), 8.09~8.04 (m,1H), 7.82~7.77 (m,2H), 7.72 (t,J=7.8Hz,1H), 7.42~7.35 (m,6H), 7.35~7.27 (m,1H), 4.54 (s,2H), 4.52 (s,2H), 3.24~3.15 (m,1H), 1.19~1.12 (m,2H), 1.12~1.04 (m,2H). The isolated compound contains a maximum of 1 molar equivalent of ammonia. [Example 20]

[0390] 3-(5-(methylsulfonamide)pyrazine-2-yl)-N-(4-phenethoxyphenyl)benzamide [ka]

[0391] Using N-(5-bromopyrazine-2-yl)methanesulfonamide (I-9) and N-(4-phenethoxyphenyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (I-19), 3-(5-(methylsulfonamide)pyrazine-2-yl)-N-(4-phenethoxyphenyl)benzamide was obtained in 25% yield. LCMS: Method A, 1.88 min, MS ES + 489.1. 1 H NMR(500MHz,DMSO)δ11.20(s,1H), 10.24(s,1H), 9.05(d,J=1.5Hz,1H), 8.61~8.57(m,1H), 8.44~8.40(m,1H), 8.24(d,J=7.8Hz,1H), 8.00(d,J=7) .8Hz,1H), 7.71~7.63(m,3H), 7.38~7.29(m,4H), 7.27~7.20(m,1H), 6.98 ~6.92(m,2H), 4.19(t,J=6.9Hz,2H), 3.39(s,3H), 3.05(t,J=6.9Hz,2H). The isolated compound contains a maximum of 1 molar equivalent of ammonia. [Example 21]

[0392] 3-(5-(morpholine-4-sulfonamide)pyrazine-2-yl)-N-(4-phenethoxyphenyl)benzamide [ka]

[0393] Using N-(5-bromopyrazine-2-yl)morpholine-4-sulfonamide (I-10) and N-(4-phenethoxyphenyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (I-19), 3-(5-(morpholine-4-sulfonamide)pyrazine-2-yl)-N-(4-phenethoxyphenyl)benzamide was obtained in 17% yield. LCMS: Method A, 1.95 min, MS ES + 560.2. 1¹H NMR (400MHz, DMSO) δ 10.23 (s, 1H), 8.97 (s, 1H), 8.57 (t, J=1.8Hz, 1H), 8.44 (d, J=1.6Hz, 1H), 8.22 (m, 1H), 7.96 (m, 1H), 7.70~7.59 (m, 3H), 7.36~7.30 (m, 4H), 7.26~7.19 (m, 1H), 6.98~6.92 (m, 2H), 4.19 (t, J=6.9Hz, 2H), 3.66~3.60 (m, 4H), 3.20 (t, J=4.8Hz, 4H), 3.04 (t, J=6.9Hz, 2H). 1H was unclear / not observed. The isolated compound contains a maximum of 1 molar equivalent of ammonia. [Example 22]

[0394] N-(4-((benzyloxy)methyl)phenyl)-3-(5-cyclopropyl-6-(methylsulfonamide)pyrazine-2-yl)benzamide [ka] N-(4-((benzyloxy)methyl)phenyl)-3-(5-cyclopropyl-6-(methylsulfonamide)pyrazine-2-yl)benzamide [ka]

[0395] A mixture of 2-cyclopropyl-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (CAS 126689-01-8, BLD, 51 mg, 0.306 mmol), Cs2CO3 (100 mg, 0.306 mmol), and N-(4-((benzyloxy)methyl)phenyl)-3-(5-chloro-6-(methylsulfonamide)pyrazine-2-yl)benzamide (Example 2, 40 mg, 0.077 mmol) in dioxane (4 mL) and water (1 mL) was purged with nitrogen for 5 minutes. Then, Pd-118 (5 mg, 0.08 mmol) was added, and the mixture was purged for a further 2 minutes. The mixture was stirred at 80°C for 9 hours. The mixture was cooled to room temperature, aqueous HCl (1 M, 5 mL) was added, and the mixture was extracted with RINKAN (3 × 15 mL). The combined organic phase was dried over Na2SO4 and concentrated under reduced pressure. Purification by RP chromatography (C18, 0-100% MeCN in 0.1% NH4OH aqueous solution), followed by tritulation with CH3CN and Et2O, yielded N-(4-((benzyloxy)methyl)phenyl)-3-(5-cyclopropyl-6-(methylsulfonamide)pyrazine-2-yl)benzamide (18 mg, 42%). LCMS: Method A, 1.97 min, MS ES + 529.1. 1 H NMR(500MHz,DMSO)δ10.71(s,1H), 10.39(s,1H), 8.83(s,1H), 8.58~8.54( m,1H), 8.24(d,J=7.8Hz,1H), 8.02(d,J=7.7Hz,1H), 7.82~7.77(m,2H), 7. 69(t,J=7.8Hz,1H), 7.40~7.34(m,5H), 7.34~7.28(m,1H), 4.54(s,2H), 4. 52(s,2H), 3.48(s,3H), 1.05(d,J=7.7Hz,2H), 1.01(dd,J=5.4,2.7Hz,2H). 2H was unclear / not observed. 1H NMR (500MHz, acetone) δ9.69(s,1H), 9.31(br s,1H), 8.84(s,1H), 8.67(t,J=1.8Hz,1H), 8.33(dt,J=7.9,1.3Hz,1H), 8.08(dt,J=8.0,1.3Hz,1H), 7.94~7.84(m,2H), 7.69(t,J =7.8Hz,1H), 7.45~7.34(m,6H), 7.33~7.28(m,1H), 4.60(s,2H), 4.59(s,2H), 3.54(s,3H), 2.51~2.45(m,1H), 1.15~1.04(m,4H). The isolated compound contains a maximum of 1 molar equivalent of ammonia. [Example 23]

[0396] N-(4-((benzyloxy)methyl)phenyl)-3-(5-cyclopropyl-6-(morpholine-4-sulfonamide)pyrazine-2-yl)benzamide [ka]

[0397] Step 1: N-(4-((benzyloxy)methyl)phenyl)-3-(5-chloro-6-(morpholine-4-sulfonamide)pyrazine-2-yl)benzamide [ka]

[0398] Following the procedure of Example 1, N-(6-bromo-3-chloropyrazine-2-yl)methanesulfonamide (I-1) was replaced with N-(6-bromo-3-chloropyrazine-2-yl)morpholine-4-sulfonamide (I-38), and N-(4-phenethoxyphenyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (I-19) was replaced with N-(4-((benzyloxy)meth Using (I-21) phenyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide, N-(4-((benzyloxy)methyl)phenyl)-3-(5-chloro-6-(morpholine-4-sulfonamide)pyrazine-2-yl)benzamide was obtained in 44% yield by purification using flash chromatography (silica gel, isohexane, 0-100% ethyl phosphate). LCMS: Method A, 1.33 min, MS ES + 594.2. 1 ¹H NMR (500MHz, DMSO) δ: 10.75 (s, 1H), 10.41 (s, 1H), 8.88 (s, 1H), 8.63 (d, J=1.9Hz, 1H), 8.28 (d, J=7.8Hz, 1H), 8.08 (d, J=7.8Hz, 1H), 7.81~7.75 (m, 2H), 7.72 (t, J=7.8Hz, 1H), 7.37 (t, J=4.1Hz, 6H), 7.31 (m, 1H), 4.53 (d, J=9.0Hz, 4H), 3.58 (t, J=4.7Hz, 4H), 3.37 (d, J=9.4Hz, 2H). 2H was unclear / not observed.

[0399] Step 2: N-(4-((benzyloxy)methyl)phenyl)-3-(5-cyclopropyl-6-(morpholine-4-sulfonamide)pyrazine-2-yl)benzamide [ka]

[0400] Following the procedure of Example 22, N-(4-((benzyloxy)methyl)phenyl)-3-(5-chloro-6-(methylsulfonamide)pyrazine-2-yl)benzamide was used instead of N-(4-((benzyloxy)methyl)phenyl)-3-(5-chloro-6-(morpholine-4-sulfonamide)pyrazine-2-yl)benzamide (Example 2), and N-(4-((benzyloxy)methyl)phenyl)-3-(5-cyclopropyl-6-(morpholine-4-sulfonamide)pyrazine-2-yl)benzamide was obtained in 21% yield by fumigation at 80°C for 9 hours and purification by preparative HPLC (prep method A, x=20, y=50). LCMS: Method A, 2.04 min, MS ES + 600.2. 1 ¹H NMR (500MHz, DMSO) δ: 10.49 (s, 1H), 10.38 (s, 1H), 8.90 (s, 1H), 8.59 (s, 1H), 8.24 (d, J=7.8Hz, 1H), 8.02 (d, J=7.7Hz, 1H), 7.78 (d, J=8.2Hz, 2H), 7.69 (t, J=7.7Hz, 1H), 7.38 (d, J=4.2Hz, 6H), 7.33~7.28 (m, 1H), 4.54 (s, 2H), 4.52 (s, 2H), 3.62~3.55 (m, 4H), 1.10~1.06 (m, 2H), 1.04~1.00 (m, 2H). 5H was unclear / not observed. 1H NMR (500MHz, acetone) δ9.67(s,1H), 9.15(s,1H), 8.84(s,1H), 8.72(s,1H), 8.30(d,J=7.7Hz,1H), 8.08(d,J=7.7Hz,1H), 7.88(d,J=8.4Hz,2H), 7 .68(t,J=7.8Hz,1H), 7.45~7.26(m,7H), 4.60(s,2H), 4.58(s,2H), 3.72 ~3.60(m,4H), 3.56~3.42(m,4H), 2.53~2.45(m,1H), 1.16~1.02(m,4H). [Example 24]

[0401] 3-(5-methyl-6-(methylsulfonamide)pyrazine-2-yl)-N-(4-phenethoxyphenyl)benzamide [ka] 3-(5-methyl-6-(methylsulfonamide)pyrazine-2-yl)-N-(4-phenethoxyphenyl)benzamide [ka]

[0402] A mixture of 2,4,6-trimethyl-1,3,5,2,4,6-trioxatriborinane (0.024 mL, 0.172 mmol), Cs2CO3 (150 mg, 0.459 mmol), and 3-(5-chloro-6-(methylsulfonamide)pyrazine-2-yl)-N-(4-phenethoxyphenyl)benzamide (Example 1, 60 mg, 0.115 mmol) in dioxane (4 mL) and water (1 mL) was purged with nitrogen for 5 minutes. Then, Pd-118 (7 mg, 0.012 mmol) was added, and the mixture was purged for a further 2 minutes. The mixture was stirred at 80°C for 9 hours. The mixture was cooled to room temperature, an aqueous solution of HCl (1 M, 5 mL) was added, and the mixture was extracted with dimethylethanol (3 × 15 mL). The combined organic phase was dried over Na2SO4 and concentrated under reduced pressure. Purification by RP chromatography (C18, 0-100% in 0.1% HCO2H aqueous solution (0.1% HCO2H in MeCN)), followed by trituration with CH3CN and Et2O, yielded 3-(5-methyl-6-(methylsulfonamide)pyrazine-2-yl)-N-(4-phenethoxyphenyl)benzamide (15 mg, 25%). LCMS: Method A, 1.90 min, MS ES + 503.1. 1H NMR(500MHz,DMSO)δ10.48(s,1H), 10.25(s,1H), 8.92(s,1H), 8.58(s,1H), 8.26(d,J=7.8Hz,1H), 8.02(d,J=7.7Hz,1H), 7.73~7.65(m,3H) ), 7.37~7.29(m,4H), 7.24(t,J=6.8Hz,1H), 6.96(d,J=9.0Hz,2H), 4.20(t,J=6.9Hz,2H), 3.50(s,3H), 3.05(t,J=6.8Hz,2H), 2.53(s,3H).

[0403] Examples 25-30: Examples 25-30 were prepared in a manner similar to Example 24, by substituting 3-(5-chloro-6-(methylsulfonamide)pyrazine-2-yl)-N-(4-phenethoxyphenyl)benzamide (Example 1) with a suitable starting material and using dioxane or acetonitrile, at 80°C for 16-18 hours, and with any other minor modifications described. Examples 25-27 and 30 were purified with a basic modifier. [ka] [Example 25]

[0404] N-(4-((benzyloxy)methyl)phenyl)-3-(5-methyl-6-(methylsulfonamide)pyrazine-2-yl)benzamide [ka]

[0405] Using N-(4-((benzyloxy)methyl)phenyl)-3-(5-chloro-6-(methylsulfonamide)pyrazine-2-yl)benzamide (Example 2), N-(4-((benzyloxy)methyl)phenyl)-3-(5-methyl-6-(methylsulfonamide)pyrazine-2-yl)benzamide was obtained in 34% yield. LCMS: Method A, 1.80 min, MS ES + 503.2. 1¹H NMR (500MHz, DMSO) δ: 10.48 (s, 1H), 10.41 (s, 1H), 8.95 (s, 1H), 8.60 (s, 1H), 8.27 (d, J=9.3Hz, 1H), 8.04 (d, J=7.8Hz, 1H), 7.83~7.77 (m, 2H), 7.71 (t, J=7.7Hz, 1H), 7.43~7.34 (m, 6H), 7.35~7.28 (m, 1H), 4.54 (s, 2H), 4.52 (s, 2H), 3.52 (s, 3H), 2.54 (s, 3H). The isolated compound contains a maximum of 1 molar equivalent of ammonia. [Example 26]

[0406] N-(4-((benzyloxy)methyl)phenyl)-3-(5-methyl-6-(morpholine-4-sulfonamide)pyrazine-2-yl)benzamide [ka]

[0407] N-(4-((benzyloxy)methyl)phenyl)-3-(5-chloro-6-(morpholine-4-sulfonamide)pyrazine-2-yl)benzamide (Example 57) was used to obtain N-(4-((benzyloxy)methyl)phenyl)-3-(5-methyl-6-(morpholine-4-sulfonamide)pyrazine-2-yl)benzamide in 29% yield. LCMS: Method C, 4.53 min, MS ES + 574.2. 1 ¹H NMR (500MHz, DMSO) δ 10.39 (s, 1H), 8.82 (s, 1H), 8.62~8.58 (m, 1H), 8.27 (d, J=7.8Hz, 1H), 8.02 (d, J=7.8Hz, 1H), 7.79 (d, J=8.5Hz, 2H), 7.68 (t, J=7.8Hz, 1H), 7.41~7.35 (m, 6H), 7.35~7.27 (m, 1H), 4.54 (s, 2H), 4.52 (s, 2H), 3.62~3.55 (m, 4H), 3.33~3.25 (m, 4H), 2.53 (s, 3H). 1H was unclear / not observed. The isolated compound contains a maximum of 1 molar equivalent of ammonia. [Example 27]

[0408] N-(4-(cyclopropylmethoxy)phenyl)-3-(5-methyl-6-(methylsulfonamide)pyrazine-2-yl)benzamide [ka]

[0409] Using 3-(5-chloro-6-(methylsulfonamide)pyrazine-2-yl)-N-(4-(cyclopropylmethoxy)phenyl)-benzamide (Example 3), N-(4-(cyclopropylmethoxy)phenyl)-3-(5-methyl-6-(methylsulfonamide)pyrazine-2-yl)benzamide was obtained in 22% yield. LCMS: Method A, 1.67 min, MS ES + 453.2. 1 ¹H NMR (500MHz, DMSO) δ 10.20 (s, 1H), 8.47 (s, 1H), 8.29~8.11 (m, 2H), 7.89 (d, J=7.3Hz, 1H), 7.68 (d, J=8.7Hz, 2H), 7.59 (t, J=7.5Hz, 1H), 6.93 (d, J=9.0Hz, 2H), 3.81 (d, J=7.0Hz, 2H), 3.03 (d, J=22.8Hz, 3H), 2.28 (d, J=11.1Hz, 3H), 1.26~1.21 (m, 1H), 0.63~0.50 (m, 2H), 0.39~0.27 (m, 2H). ¹H was unclear / not observed. The isolated compound contains a maximum of 1 molar equivalent of ammonia. [Example 28]

[0410] N-(3-fluoro-4-(((3-methoxybenzyl)oxy)methyl)phenyl)-3-(5-methyl-6-(methylsulfonamide)-pyrazine-2-yl)benzamide [ka]

[0411] Using 3-(5-chloro-6-(methylsulfonamide)pyrazine-2-yl)-N-(3-fluoro-4-(((3-methoxybenzyl)oxy)methyl)phenyl)benzamide (Example 7), N-(3-fluoro-4-(((3-methoxybenzyl)oxy)methyl)phenyl)-3-(5-methyl-6-(methylsulfonamide)pyrazine-2-yl)benzamide was obtained in 22% yield. LCMS: Method A, 1.58 min, MS ES + 551.2. 1 H NMR(500MHz,DMSO)δ10.59(s,1H), 10.49(s,1H), 8.95(s,1H), 8.60(s,1H), 8.29(m ,1H), 8.04(m,1H), 7.80(dd,J=12.5,2.0Hz,1H), 7.73(t,J=7.8Hz,1H), 7.59(dd,J= 8.3,2.0Hz,1H), 7.47(t,J=8.4Hz,1H), 7.29(t,J=7.8Hz,1H), 6.98~6.90(m,2H), 6 .91~6.83(m,1H), 4.55(s,2H), 4.54(s,2H), 3.76(s,3H), 3.52(s,3H), 2.54(s,3H). [Example 29]

[0412] N-(3-fluoro-4-(((4-methoxybenzyl)oxy)methyl)phenyl)-3-(5-methyl-6-(methylsulfonamide)pyrazine-2-yl)benzamide [ka]

[0413] Using 3-(5-chloro-6-(methylsulfonamide)pyrazine-2-yl)-N-(3-fluoro-4-(((4-methoxybenzyl)oxy)methyl)phenyl)benzamide (Example 6), N-(3-fluoro-4-(((4-methoxybenzyl)oxy)methyl)phenyl)-3-(5-methyl-6-(methylsulfonamide)pyrazine-2-yl)benzamide was obtained in 23% yield. LCMS: Method A, 1.56 min, MS ES+ 551.1. 1 H NMR(500MHz,DMSO)δ10.58(s,1H), 10.49(s,1H), 8.95(s,1H), 8.60(s,1H), 8.29(d, J=7.9Hz,1H), 8.04(d,J=7.9Hz,1H), 7.79(dd,J=12.5,2.0Hz,1H), 7.73(t,J=7.7Hz ,1H), 7.58(dd,J=8.3,2.0Hz,1H), 7.45(t,J=8.4Hz,1H), 7.29(d,J=8.6Hz,2H), 6.9 3(d,J=8.5Hz,2H), 4.52(s,2H), 4.48(s,2H), 3.76(s,3H), 3.52(s,3H), 2.54(s,3H). [Example 30]

[0414] N-(4-((benzyloxy)methyl)phenyl)-3-(6-(cyclopropanesulfonamide)-5-methylpyrazine-2-yl)benzamide [ka]

[0415] Using N-(4-((benzyloxy)methyl)phenyl)-3-(5-chloro-6-(cyclopropanesulfonamide)pyrazine-2-yl)benzamide (Example 4), N-(4-((benzyloxy)methyl)phenyl)-3-(6-(cyclopropanesulfonamide)-5-methylpyrazine-2-yl)benzamide was obtained in 25% yield. LCMS: Method C, 4.60 min, MS ES + 529.2. 1¹H NMR (500MHz, DMSO) δ 10.40 (s, 2H), 8.87 (s, 1H), 8.60 (d, J=1.9Hz, 1H), 8.29 (d, J=7.7Hz, 1H), 8.02 (d, J=7.8Hz, 1H), 7.81~7.76 (m, 2H), 7.70 (t, J=7.8Hz, 1H), 7.37 (t, J=4.4Hz, 6H), 7.32 (m, 1H), 4.54 (s, 2H), 4.52 (s, 2H), 3.35 (dd, J=8.6, 4.1Hz, 1H), 1.15 (d, J=4.1Hz, 2H), 1.06 (d, J=7.6Hz, 2H). 3H was unclear / not observed. ¹H NMR (500 MHz, acetone) δ 9.69 (s, ¹H), 9.13 (br s,1H), 8.86(s,1H), 8.70(t,J=1.8Hz,1H), 8.36(dt,J=7.8,1.4Hz,1H), 8.08(dt,J=7.8,1.4Hz,1H), 7.93~7.85(m,2H), 7.69(t,J=7.8Hz,1H), 7.48~7.34(m,6H), 7.34~7.28(m,1H), 4.60(s,2H), 4.59(s,2H), 3.50~3.40(m,1H), 2.61(s,3H), 1.30~1.18(m,2H), 1.16~1.03(m,2H). The isolated compounds contain a maximum of 1 molar equivalent of ammonia. [Example 31]

[0416] N-(4-((benzyloxy)methyl)phenyl)-4-methoxy-3-(5-methyl-6-(methylsulfonamide)pyrazine-2-yl)benzamide [ka]

[0417] Step 1: N-(4-((benzyloxy)methyl)phenyl)-3-(5-chloro-6-(methylsulfonamide)pyrazine-2-yl)-4-methoxybenzamide [ka]

[0418] Following the procedure of Example 1, N-(4-((benzyloxymethyl)phenyl)-4-methoxy-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (I-35) was used instead of N-(4-phenethoxyphenyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (I-19), and N-(4-((benzyloxymethyl)phenyl)-3-(5-chloro-6-(methylsulfonamide)pyrazine-2-yl)-4-methoxybenzamide was obtained in 42% yield by chromatography (C18, 0.1% NH4OH aqueous solution, 0-100% MeCN) on RP chromatography. LCMS: Method A, 1.93 min, MSES + 553.1.

[0419] Step 2: N-(4-((benzyloxy)methyl)phenyl)-4-methoxy-3-(5-methyl-6-(methylsulfonamide)-pyrazine-2-yl)benzamide [ka]

[0420] Following the procedure of Example 24, N-(4-((benzyloxy)methyl)phenyl)-3-(5-chloro-6-(methylsulfonamide)pyrazine-2-yl)-4-methoxybenzamide was used instead of 3-(5-chloro-6-(methylsulfonamide)pyrazine-2-yl)benzamide (Example 1) and N-(4-((benzyloxy)methyl)phenyl)-4-methoxy-3-(5-methyl-6-(methylsulfonamide)pyrazine-2-yl)benzamide was obtained in 28% yield by 16 hours at 80°C and purification by RP chromatography (C18, 0-100% MeCN in 0.1% NH4OH aqueous solution). LCMS: Method A, 1.80 min, MS ES + 533.2. 1¹H NMR (400MHz, DMSO) δ: 10.40 (s, 1H), 10.22 (s, 1H), 8.72 (s, 1H), 8.35 (d, J=2.4Hz, 1H), 8.10 (dd, J=8.7, 2.4Hz, 1H), 7.76 (d, J=8.6Hz, 2H), 7.45~7.18 (m, 8H), 4.52 (s, 2H), 4.50 (s, 2H), 3.95 (s, 3H), 3.47 (s, 3H). 3H was indistinct / not observed. The isolated compound contains a maximum of 1 molar equivalent of ammonia. [Example 32]

[0421] N-(4-((benzyloxy)methyl)-2-fluorophenyl)-3-(5-methyl-6-(methylsulfonamide)pyrazine-2-yl)benzamide [ka]

[0422] Step 1: N-(4-((benzyloxy)methyl)-2-fluorophenyl)-3-(5-chloro-6-(methylsulfonamide)-pyrazine-2-yl)benzamide [ka]

[0423] Following the procedure of Example 1, N-(4-((benzyloxy)methyl)-2-fluorophenyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (I-32) was used instead of N-(4-phenethoxyphenyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (I-19), and N-(4-((benzyloxy)methyl)-2-fluorophenyl)-3-(5-chloro-6-(methylsulfonamide)pyrazine-2-yl)benzamide was obtained in 40% yield by chromatography (C18, 0.1% NH4OH aqueous solution, 0-100% MeCN) on RP chromatography. LCMS: Method A, 1.93 min, MSES+ 541.1

[0424] Step 2: N-(4-((benzyloxy)methyl)-2-fluorophenyl)-3-(5-methyl-6-(methylsulfonamide)-pyrazine-2-yl)benzamide [ka]

[0425] Following the procedure of Example 24, N-(4-((benzyloxy)methyl)-2-fluorophenyl)-3-(5-chloro-6-(methylsulfonamide)pyrazine-2-yl)benzamide was used instead of 3-(5-chloro-6-(methylsulfonamide)pyrazine-2-yl)benzamide (Example 1) and N-(4-((benzyloxy)methyl)-2-fluorophenyl)-3-(5-methyl-6-(methylsulfonamide)pyrazine-2-yl)benzamide was obtained in 37% yield by fermentation at 80°C for 16 hours and purification by RP chromatography (C18, 0-100% MeCN in 0.1% NH4OH aqueous solution). LCMS: Method A, 1.84 min, MS ES + 521.1. 1 ¹H NMR (500MHz, DMSO) δ: 10.48 (s, 1H), 10.27 (s, 1H), 8.93 (s, 1H), 8.65 (s, 1H), 8.29 (d, J=7.8Hz, 1H), 8.06 (d, J=7.8Hz, 1H), 7.71 (t, J=7.8Hz, 1H), 7.65 (t, J=8.0Hz, 1H), 7.46~7.34 (m, 4H), 7.35~7.29 (m, 2H), 7.25 (d, J=8.3Hz, 1H), 4.58 (s, 4H), 3.50 (s, 3H), 3.30 (s, 3H). The isolated compound contains a maximum of 1 molar equivalent of ammonia. [Example 33]

[0426] N-(4-((benzyloxy)methyl)phenyl)-2-methoxy-5-(5-methyl-6-(methylsulfonamide)pyrazine-2-yl)benzamide [ka]

[0427] Step 1: N-(4-((benzyloxy)methyl)phenyl)-5-(5-chloro-6-(methylsulfonamide)pyrazine-2-yl)-2-methoxybenzamide [ka]

[0428] Following the procedure of Example 1, (3-((4-((benzyloxymethyl)phenyl)carbamoyl)-4-methoxyphenyl)boronic acid (I-36) was used instead of N-(4-phenethoxyphenyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (I-19), and N-(4-((benzyloxymethyl)phenyl)-5-(5-chloro-6-(methylsulfonamide)pyrazine-2-yl)-2-methoxybenzamide was obtained in 42% yield by chromatography (C18, 0-100% MeCN in 0.1% NH4OH aqueous solution) on RP chromatography, and purification. LCMS: Method A, 1.99 min, MSES + 553.1

[0429] Step 2: N-(4-((benzyloxy)methyl)phenyl)-2-methoxy-5-(5-methyl-6-(methylsulfonamide-)pyrazine-2-yl)benzamide [ka]

[0430] Following the procedure of Example 24, N-(4-((benzyloxy)methyl)phenyl)-5-(5-chloro-6-(methylsulfonamide)pyrazine-2-yl)-2-methoxybenzamide was used instead of 3-(5-chloro-6-(methylsulfonamide)pyrazine-2-yl)benzamide (Example 1) and N-(4-((benzyloxy)methyl)phenyl)-2-methoxy-5-(5-methyl-6-(methylsulfonamide)pyrazine-2-yl)benzamide was obtained in 14% yield by 16 hours at 80°C and purification by RP chromatography (C18, 0-100% MeCN in 0.1% NH4OH aqueous solution). LCMS: Method A, 1.90 min, MS ES + 533.2. 1 ¹H NMR (500MHz, DMSO) δ: 10.41 (s, 1H), 10.26 (s, 1H), 8.84 (s, 1H), 8.29 (d, J=2.4Hz, 1H), 8.21 (dd, J=8.8, 2.5Hz, 1H), 7.75 (d, J=8.2Hz, 2H), 7.42~7.26 (m, 7H), 4.53 (s, 2H), 4.51 (s, 2H), 3.96 (s, 3H), 3.49 (s, 3H). 4H was unclear / not observed. ¹H NMR (500 MHz, acetone) δ 9.94 (s, ¹H), 9.01 (br s, ¹H), 8.83 (s, ¹H), 8.79 (d, J=2.4 Hz, ¹H), 8.32 (dd, J=8.7, 2.5 Hz, ¹H), 7.86 (d, J=8.5 Hz, ²H), 7.46~7.34 (m, ⁷H), 7.34~7.28 (m, ¹H), 4.59 (s, ²H), 4.58 (s, ²H), 4.19 (s, ³H), 3.55 (s, ³H), 2.61 (s, ³H). The isolated compound contains a maximum of 1 molar equivalent of ammonia. [Example 34]

[0431] 3-(5-methyl-6-(methylsulfonamide)pyrazine-2-yl)-N-(4-((1-phenylethoxy)methyl)phenyl)-benzamide [ka]

[0432] Step 1: 3-(5-chloro-6-(methylsulfonamide)pyrazine-2-yl)-N-(4-((1-phenylethoxy)methyl)-phenyl)benzamide [ka]

[0433] Following the procedure of Example 1, N-(4-((1-phenylethoxy)methyl)phenyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (I-37) was used instead of N-(4-phenethoxyphenyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (I-19), and 3-(5-chloro-6-(methylsulfonamide)pyrazine-2-yl)-N-(4-((1-phenylethoxy)methyl)phenyl)benzamide was obtained in 51% yield without purification and at 80°C for 1 hour. LCMS: Method A, 1.99 min, MSES + 537.1

[0434] Step 2: 3-(5-methyl-6-(methylsulfonamide)pyrazine-2-yl)-N-(4-((1-phenylethoxy)methyl)-phenyl)benzamide [ka]

[0435] Following the procedure of Example 24, 3-(5-chloro-6-(methylsulfonamide)pyrazine-2-yl)-N-(4-((1-phenylethoxy)methyl)phenyl)benzamide was used instead of 3-(5-chloro-6-(methylsulfonamide)pyrazine-2-yl)-N-(4-phenethoxyphenyl)benzamide (Example 1), and 3-(5-methyl-6-(methylsulfonamide)pyrazine-2-yl)-N-(4-((1-phenylethoxy)methyl)phenyl)benzamide was obtained in 16% yield by 16 hours at 80°C and purification by RP chromatography (C18, 0-100% MeCN in 0.1% NH4OH aqueous solution). LCMS: Method A, 1.90 min, MS ES + 517.2. 1 H NMR(500MHz,DMSO)δ10.48(s,1H), 10.40(s,1H), 8.95(s,1H), 8.60(s,1H), 8.28(d,J=7.8Hz,1H), 8.04(d,J=7.8Hz,1H), 7.77(d,J=8.2Hz,2H), 7. 71(t,J=7.8Hz,1H), 7.43~7.35(m,4H), 7.33~7.26(m,3H), 4.56~4.53(m, 1H), 4.37~4.26(m,2H), 3.52(s,3H), 2.53(s,3H), 1.41(d,J=6.6Hz,3H). The isolated compound contains a maximum of 1 molar equivalent of ammonia. [Example 35]

[0436] N-(4-((benzyloxy)methyl)phenyl)-2-methyl-5-(5-methyl-6-(methylsulfonamide)pyrazine-2-yl)benzamide [ka]

[0437] Step 1: N-(4-((benzyloxy)methyl)phenyl)-5-(5-chloro-6-(methylsulfonamide)pyrazine-2-yl)-2-methylbenzamide [ka]

[0438] Following the procedure of Example 1, (3-((4-((benzyloxymethyl)phenyl)carbamoyl)-4-methylphenyl)boronic acid (I-31) was used instead of N-(4-phenethoxyphenyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (I-19) to obtain N-(4-((benzyloxymethyl)phenyl)-5-(5-chloro-6-(methylsulfonamide)pyrazine-2-yl)-2-methylbenzamide, which was used crudely in the next step. LCMS: Method A, 1.95 min, MSES + 537.1

[0439] Step 2: N-(4-((benzyloxy)methyl)phenyl)-2-methyl-5-(5-methyl-6-(methylsulfonamide)-pyrazine-2-yl)benzamide [ka]

[0440] Following the procedure of Example 24, N-(4-((benzyloxymethyl)phenyl)-5-(5-chloro-6-(methylsulfonamide)pyrazine-2-yl)-2-methylbenzamide was used instead of 3-(5-chloro-6-(methylsulfonamide)pyrazine-2-yl)benzamide (Example 1) to obtain N-(4-((benzyloxymethyl)phenyl)-2-methyl-5-(5-methyl-6-(methylsulfonamide)pyrazine-2-yl)benzamide in 2% yield by 16 hours at 80°C and purification by RP chromatography (C18, 0-100% MeCN in 0.1% NH4OH aqueous solution). LCMS: Method A, 1.87 min, MS ES + 517.2. 1¹H NMR (500 MHz, DMSO) δ10.46 (s, 1H), 8.20~8.11 (m, 1H), 8.07 (d, J=8.0 Hz, 1H), 7.76 (d, J=8.2 Hz, 2H), 7.48 (d, J=8.1 Hz, 1H), 7.40~7.34 (m, 6H), 7.31 (d, J=3.8 Hz, 1H), 4.53 (s, 2H), 4.51 (s, 2H), 3.43 (s, 3H), 2.44 (s, 3H). Based on the above analogues, pyrazine CH3 is indistinct at 2.5 ppm by NMR solvent (DMSO), and 2×NH is not observed. The isolated compound contains a maximum of 1 molar equivalent of ammonia. [Example 36]

[0441] N-(4-((benzyloxy)methyl)phenyl)-4-methyl-3-(5-methyl-6-(methylsulfonamide)pyrazine-2-yl)benzamide [ka]

[0442] Step 1: N-(4-((benzyloxy)methyl)phenyl)-3-(5-chloro-6-(methylsulfonamide)pyrazine-2-yl)-4-methylbenzamide [ka]

[0443] Following the procedure of Example 1, N-(4-((benzyloxymethyl)phenyl)-4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (I-25) was used instead of N-(4-phenethoxyphenyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (I-19), and N-(4-((benzyloxymethyl)phenyl)-3-(5-chloro-6-(methylsulfonamide)pyrazine-2-yl)-4-methylbenzamide was obtained in 58% yield without purification and at 80°C for 1 hour. LCMS: Method A, 1.97 min, MSES+ 537.1.

[0444] Step 2: N-(4-((benzyloxy)methyl)phenyl)-4-methyl-3-(5-methyl-6-(methylsulfonamide)-pyrazine-2-yl)benzamide [ka]

[0445] Following the procedure of Example 24, N-(4-((benzyloxymethyl)phenyl)-3-(5-chloro-6-(methylsulfonamide)pyrazine-2-yl)-4-methylbenzamide was used instead of 3-(5-chloro-6-(methylsulfonamide)pyrazine-2-yl)benzamide (Example 1) and N-(4-((benzyloxymethyl)phenyl)-4-methyl-3-(5-methyl-6-(methylsulfonamide)pyrazine-2-yl)benzamide was obtained in 32% yield by 16 hours at 80°C and purification by RP chromatography (C18, 0-100% MeCN in 0.1% NH4OH aqueous solution). LCMS: Method A, 1.88 min, MS ES + 517.2. 1 H NMR(500MHz,DMSO)δ10.45(s,1H), 10.27(s,1H), 8.51(s,1H), 8.05(s,1H), 7.97(d,J=7.6Hz,1H), 7.77(d,J=8.2H) z,2H), 7.52(d,J=8.0Hz,1H), 7.41~7.23(m,7H), 4.53(s,2H), 4.51(s,2H), 3.38(s,3H), 2.55(s,3H), 2.47(s,3H). [Example 37]

[0446] N-(4-((benzyloxy)methyl)phenyl)-2,6-difluoro-3-(5-methyl-6-(methylsulfonamide)pyrazine-2-yl)benzamide [ka]

[0447] Step 1: N-(4-((benzyloxy)methyl)phenyl)-3-(5-chloro-6-(methylsulfonamide)pyrazine-2-yl)-2,6-difluorobenzamide [ka]

[0448] Following the procedure of Example 1, (3-((4-((benzyloxymethyl)phenyl)carbamoyl)-2,4-difluorophenyl)boronic acid (I-24) was used instead of N-(4-phenethoxyphenyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (I-19), and N-(4-((benzyloxymethyl)phenyl)-3-(5-chloro-6-(methylsulfonamide)pyrazine-2-yl)-2,6-difluorobenzamide was obtained in 72% yield without purification and at 80°C for 1 hour. LCMS: Method A, 1.96 min, MSES + 559.1.

[0449] Step 2: N-(4-((benzyloxy)methyl)phenyl)-2,6-difluoro-3-(5-methyl-6-(methylsulfonamide)pyrazine-2-yl)benzamide [ka]

[0450] Following the procedure of Example 24, N-(4-((benzyloxymethyl)phenyl)-3-(5-chloro-6-(methylsulfonamide)pyrazine-2-yl)-2,6-difluorobenzamide was used instead of 3-(5-chloro-6-(methylsulfonamide)pyrazine-2-yl)benzamide (Example 1) and N-(4-((benzyloxymethyl)phenyl)-2,6-difluoro-3-(5-methyl-6-(methylsulfonamide)pyrazine-2-yl)benzamide was obtained in 15% yield by 16 hours at 80°C and purification by RP chromatography (C18, 0-100% MeCN in 0.1% NH4OH aqueous solution). LCMS: Method A, 1.87 min, MS ES + 539.1. 1 ¹H NMR (500MHz, DMSO) δ: 10.94 (s, 1H), 10.56 (s, 1H), 8.62 (s, 1H), 8.07 (q, J=8.1Hz, 1H), 7.70 (d, J=8.3Hz, 2H), 7.49 (t, J=8.6Hz, 1H), 7.43~7.33 (m, 6H), 7.34~7.25 (m, 1H), 4.53 (s, 2H), 4.52 (s, 2H), 3.44 (s, 3H), 2.54 (s, 3H). The isolated compound contains a maximum of 1 molar equivalent of ammonia. [Example 38]

[0451] N-(3-fluoro-4-((pyridine-2-ylmethoxy)methyl)phenyl)-3-(5-methyl-6-(methylsulfonamide)-pyrazine-2-yl)benzamide [ka]

[0452] Step 1: 3-(5-chloro-6-(methylsulfonamide)pyrazine-2-yl)-N-(3-fluoro-4-((pyridine-2-ylmethoxy)methyl)phenyl)benzamide [ka]

[0453] Following the procedure of Example 1, N-(3-fluoro-4-((pyridine-2-ylmethoxy)methyl)phenyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (I-23) was used instead of N-(4-phenethoxyphenyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (I-19) to obtain 3-(5-chloro-6-(methylsulfonamide)pyrazine-2-yl)-N-(3-fluoro-4-((pyridine-2-ylmethoxy)methyl)phenyl)benzamide in 54% yield without purification and at 80°C for 1 hour. LCMS: Method A, 1.08 min, MSES + 542.1

[0454] Step 2: N-(3-fluoro-4-((pyridine-2-ylmethoxy)methyl)phenyl)-3-(5-methyl-6-(methylsulfonamide)pyrazine-2-yl)benzamide [ka]

[0455] Following the procedure of Example 24, 3-(5-chloro-6-(methylsulfonamide)pyrazine-2-yl)-N-(4-phenethoxyphenyl)benzamide was used instead of 3-(5-chloro-6-(methylsulfonamide)pyrazine-2-yl)-N-(3-fluoro-4-((pyridine-2-ylmethoxy)methyl)phenyl)benzamide was prepared at 80°C for 16 hours and purified by RP chromatography (C18, 0-100% MeCN in 0.1% NH4OH aqueous solution) to obtain N-(3-fluoro-4-((pyridine-2-ylmethoxy)methyl)phenyl)-3-(5-methyl-6-(methylsulfonamide)pyrazine-2-yl)benzamide in 10% yield. LCMS: Method A, 1.00 min, MS ES + 522.2. 1¹H NMR (500MHz, DMSO) δ 10.59 (s,1H), 8.79 (s,1H), 8.58 (s,1H), 8.55~8.50 (m,1H), 8.28 (d,J=7.7Hz,1H), 8.15 (s,1H), 8.02 (d,J=7.5Hz,1H), 7.86~7.78 (m,2H), 7.71 (d,J=7.7Hz,1H), 7.60 (dd,J=8.3,2.0Hz,1H), 7.54~7.46 (m,2H), 7.35~7.28 (m,1H), 4.65~4.62 (m,4H), 3.43 (s,3H). 3H was unclear / not observed. The isolated compound contains a maximum of 1 molar equivalent of ammonia. [Example 39]

[0456] N-(4-((benzyloxy)methyl)phenyl)-4-fluoro-3-(5-methyl-6-(methylsulfonamide)pyrazine-2-yl)benzamide [ka]

[0457] Step 1: N-(4-((benzyloxy)methyl)phenyl)-3-(5-chloro-6-(methylsulfonamide)pyrazine-2-yl)-4-fluorobenzamide [ka]

[0458] Following the procedure of Example 1, (5-((4-((benzyloxymethyl)phenyl)carbamoyl)-2-fluorophenyl)boronic acid (I-34) was used instead of N-(4-phenethoxyphenyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (I-19), and N-(4-((benzyloxymethyl)phenyl)-3-(5-chloro-6-(methylsulfonamide)pyrazine-2-yl)-4-fluorobenzamide was obtained in 48% yield by chromatography (C18, 0-100% MeCN in 0.1% NH4OH aqueous solution) on RP chromatography, and by using (5-((4-((benzyloxymethyl)phenyl)-3-(5-chloro-6-(methylsulfonamide)pyrazine-2-yl)-4-fluorobenzamide. LCMS: Method A, 1.94 min, MSES + 541.1.

[0459] Step 2: N-(4-((benzyloxy)methyl)phenyl)-4-fluoro-3-(5-methyl-6-(methylsulfonamide)-pyrazine-2-yl)benzamide [ka]

[0460] Following the procedure of Example 24, N-(4-((benzyloxymethyl)phenyl)-3-(5-chloro-6-(methylsulfonamide)pyrazine-2-yl)-4-fluorobenzamide was used instead of 3-(5-chloro-6-(methylsulfonamide)pyrazine-2-yl)benzamide (Example 1) and N-(4-((benzyloxymethyl)phenyl)-4-fluoro-3-(5-methyl-6-(methylsulfonamide)pyrazine-2-yl)benzamide was obtained in 11% yield by 16 hours at 80°C and purification by RP chromatography (C18, 0-100% MeCN in 0.1% NH4OH aqueous solution). LCMS: Method A, 1.86 min, MS ES + 521.2. 1 ¹H NMR (500MHz, DMSO) δ: 10.55 (s, 1H), 10.39 (s, 1H), 8.56 (s, 1H), 8.48 (dd, J=7.5, 2.4Hz, 1H), 8.15~8.05 (m, 1H), 7.77 (d, J=8.4Hz, 2H), 7.56 (dd, J=10.8, 8.6Hz, 1H), 7.44~7.34 (m, 6H), 7.34~7.26 (m, 1H), 4.53 (s, 2H), 4.52 (s, 2H), 3.39 (s, 3H). 3H was unclear / not observed. The isolated compound contains a maximum of 1 molar equivalent of ammonia. [Example 40]

[0461] N-(4-((benzyloxy)methyl)phenyl)-2-fluoro-5-(5-methyl-6-(methylsulfonamide)pyrazine-2-yl)benzamide [ka]

[0462] Step 1: N-(4-((benzyloxy)methyl)phenyl)-5-(5-chloro-6-(methylsulfonamide)pyrazine-2-yl)-2-fluorobenzamide [ka]

[0463] Following the procedure of Example 1, N-(4-((benzyloxymethyl)phenyl)-2-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (I-33) was used instead of N-(4-phenethoxyphenyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (I-19), and N-(4-((benzyloxymethyl)phenyl)-5-(5-chloro-6-(methylsulfonamide)pyrazine-2-yl)-2-fluorobenzamide was obtained in 39% yield by chromatography (C18, 0.1% NH4OH aqueous solution, 0-100% MeCN) on RP chromatography, and by using N-(4-((benzyloxymethyl)phenyl)-5-(5-chloro-6-(methylsulfonamide)pyrazine-2-yl)-2-fluorobenzamide instead of N-(4-phenethoxyphenyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (I-33). LCMS: Method A, 1.94 min, MSES + 541.1.

[0464] Step 2: N-(4-((benzyloxy)methyl)phenyl)-2-fluoro-5-(5-methyl-6-(methylsulfonamide)-pyrazine-2-yl)benzamide [ka]

[0465] Following the procedure of Example 24, N-(4-((benzyloxymethyl)phenyl)-5-(5-chloro-6-(methylsulfonamide)pyrazine-2-yl)-2-fluorobenzamide was used instead of 3-(5-chloro-6-(methylsulfonamide)pyrazine-2-yl)benzamide (Example 1) and N-(4-((benzyloxymethyl)phenyl)-2-fluoro-5-(5-methyl-6-(methylsulfonamide)pyrazine-2-yl)benzamide was obtained in 41% yield by 16 hours at 80°C and purification by RP chromatography (C18, 0-100% MeCN in 0.1% NH4OH aqueous solution). LCMS: Method A, 1.86 min, MS ES + 521.2. 1 ¹H NMR (500MHz, DMSO) δ: 10.59 (s, 1H), 10.48 (s, 1H), 8.91 (s, 1H), 8.35 (dd, J=6.8, 2.4Hz, 1H), 8.30~8.21 (m, 1H), 7.74 (d, J=8.1Hz, 2H), 7.55 (t, J=9.1Hz, 1H), 7.41~7.34 (m, 5H), 7.34~7.28 (m, 1H), 4.53 (s, 2H), 4.52 (s, 2H), 3.48 (s, 3H), 2.52 (s, 3H). 1H was unclear / not observed. The isolated compound contains a maximum of 1 molar equivalent of ammonia. [Example 41]

[0466] 3-(5-(2-aminoethoxy)-6-(methylsulfonamide)pyrazine-2-yl)-N-(4-phenethoxyphenyl)-benzamide [ka] 3-(5-(2-aminoethoxy)-6-(methylsulfonamide)pyrazine-2-yl)-N-(4-phenethoxyphenyl)-benzamide [ka]

[0467] A mixture of 3-(5-chloro-6-(methylsulfonamide)pyrazine-2-yl)-N-(4-phenethoxyphenyl)-benzamide (Example 1, 25 mg, 0.048 mmol), 2-aminoethane-1-ol (0.019 mL, 0.239 mmol), and NEt3 (0.020 mL, 0.143 mmol) in THF (2 mL) was stirred at 40°C for 72 hours. Purification by RP chromatography (C18, 0-100% MeCN in 0.1% NH4OH aqueous solution) yielded 3-(5-(2-aminoethoxy)-6-(methylsulfonamide)pyrazine-2-yl)-N-(4-phenethoxyphenyl)benzamide (16 mg, 55%). LCMS: Method A, 1.54 min, MS ES + 548.1. 1H NMR(500MHz,DMSO)δ10.19(s,1H), 8.43(s,1H), 8.25(s,1H), 8.14(d,J=7.8Hz,1 H), 7.99(s,1H), 7.87(d,J=7.7Hz,1H), 7.68(d,J=9.0Hz,2H), 7.58(t,J=7.7Hz,1 H), 7.37~7.30 (m, 4H), 7.27~7.19 (m, 1H), 6.94 (d, J=9.0Hz, 2H), 4.53~4.43 (m, 2H), 4.18 (t, J=6.9Hz, 2H), 3.34~3.25 (m, 2H), 3.11 (s, 3H), 3.04 (t, J=6.9Hz, 2H). 2H was unclear / not observed. The isolated compounds contain a maximum of 1 molar equivalent of ammonia.

[0468] Examples 42-46: Similar to Example 1, Examples 42-46 were prepared by substituting N-(6-bromo-3-chloropyrazine-2-yl)methanesulfonamide (I-1) and N-(4-phenethoxyphenyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (I-19) with appropriate starting materials and using Pd-118 instead of Pd(dppf)Cl2, at 80-90°C for 9-18 hours. Any other minor modifications are described. All examples were purified with a basic modifier. [ka] [Example 42]

[0469] 3-(6-amino-5-(methylsulfonamide)pyrazine-2-yl)-N-(4-phenethoxyphenyl)benzamide [ka]

[0470] Using N,N'-(5-bromopyrazine-2,3-diyl)dimethanesulfonamide (I-13) and N-(4-phenethoxyphenyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (I-19), 3-(6-amino-5-(methylsulfonamide)pyrazine-2-yl)-N-(4-phenethoxyphenyl)benzamide was obtained in 13% yield. LCMS: Method A, 1.79 min, MS ES + 504.2. 1 ¹H NMR (500MHz, DMSO) δ 10.21 (s, 1H), 8.45 (s, 1H), 8.09 (d, J=7.8Hz, 1H), 7.91 (d, J=7.8Hz, 1H), 7.70~7.64 (m, 2H), 7.59 (t, J=7.8Hz, 1H), 7.38~7.29 (m, 4H), 7.27~7.20 (m, 1H), 6.98~6.92 (m, 2H), 6.58 (s, 2H), 4.19 (t, J=6.9Hz, 2H), 3.04 (t, J=6.9Hz, 2H). 5H was unclear / not observed. Regiochemistry was confirmed by ROESY NMR. The isolated compound contains a maximum of 1 molar equivalent of ammonia. [Example 43]

[0471] 3-(6-(morpholine-4-sulfonamide)pyrazine-2-yl)-N-(4-phenethoxyphenyl)benzamide [ka]

[0472] Using N-(6-bromopyrazine-2-yl)morpholine-4-sulfonamide (I-14) and N-(4-phenethoxyphenyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (I-19), 3-(6-(morpholine-4-sulfonamide)pyrazine-2-yl)-N-(4-phenethoxyphenyl)benzamide was obtained in 17% yield. LCMS: Method A, 1.92 min, MS ES + 560.2. 1 H NMR(500MHz,DMSO)δ11.19(s,1H), 10.25(s,1H), 8.99(s,1H), 8.66~8.61(m, 1H), 8.36(s,1H), 8.28(d,J=7.8Hz,1H), 8.05(d,J=7.7Hz,1H), 7.73~7.65(m ,3H), 7.38~7.29(m,4H), 7.27~7.20(m,1H), 6.99~6.93(m,2H), 4.19(t,J=6. 9Hz,2H), 3.59(t,J=4.8Hz,4H), 3.29(t,J=4.8Hz,4H), 3.05(t,J=6.9Hz,2H). The isolated compound contains a maximum of 1 molar equivalent of ammonia. [Example 44]

[0473] N-(4-((benzyloxy)methyl)phenyl)-3-(6-methyl-5-(methylsulfonamide)pyrazine-2-yl)benzamide [ka]

[0474] N-(5-bromo-3-methylpyrazine-2-yl)-N-(methylsulfonyl)methanesulfonamide (I-17) and N-(4-((benzyloxy)methyl)phenyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (I-21) were used to obtain N-(4-((benzyloxy)methyl)phenyl)-3-(6-methyl-5-(methylsulfonamide)pyrazine-2-yl)benzamide in 48% yield. LCMS: Method A, 1.87 min, MS ES + 503.1. 1 ¹H NMR (500MHz, DMSO) δ: 10.47 (s, 1H), 10.39 (s, 1H), 8.91 (s, 1H), 8.61~8.57 (m, 1H), 8.29~8.23 (m, 1H), 8.04~7.98 (m, 1H), 7.83~7.77 (m, 2H), 7.67 (t, J=7.7Hz, 1H), 7.42~7.35 (m, 6H), 7.35~7.27 (m, 1H), 4.54 (s, 2H), 4.52 (s, 2H), 3.42 (s, 3H), 2.58 (s, 3H). The isolated compound contains a maximum of 1 molar equivalent of ammonia. [Example 45]

[0475] 3-(6-Methoxy-5-(methylsulfonamide)pyrazine-2-yl)-N-(4-phenethoxyphenyl)benzamide [ka]

[0476] Using N-(5-bromo-3-methoxypyrazine-2-yl)methanesulfonamide (I-15) and N-(4-phenethoxyphenyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (I-19), 3-(6-methoxy-5-(methylsulfonamide)pyrazine-2-yl)-N-(4-phenethoxyphenyl)benzamide was obtained in 45% yield. LCMS: Method A, 1.97 min, MS ES + 519.2. 1¹H NMR (500MHz, DMSO) δ10.21 (s, 1H), 8.52 (dd, J=5.3, 3.4Hz, 2H), 8.21 (d, J=7.8Hz, 1H), 7.92 (d, J=7.7Hz, 1H), 7.72~7.65 (m, 2H), 7.62 (t, J=7.7Hz, 1H), 7.35~7.29 (m, 4H), 7.23 (m, 1H), 6.99~6.92 (m, 2H), 4.19 (t, J=6.9Hz, 2H), 4.04 (s, 3H), 3.29 (s, 3H), 3.04 (t, J=6.9Hz, 2H). 1H was unclear / not observed. The isolated compound contains a maximum of 1 molar equivalent of ammonia. [Example 46]

[0477] 3-(6-((N,N-dimethylsulfamoyl)amino)pyrazine-2-yl)-N-(4-phenethoxyphenyl)benzamide [ka]

[0478] Using N'-(6-bromo-2-pyrazinyl)-N,N-dimethylsulfamide (I-16) and N-(4-phenethoxyphenyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (I-19), 3-(6-((N,N-dimethylsulfamoyl)amino)pyrazine-2-yl)-N-(4-phenethoxyphenyl)benzamide was obtained in 20% yield. LCMS: Method A, 1.96 min, MS ES + 518.2. 1¹H NMR (500MHz, DMSO) δ: 10.94 (s, 1H), 10.16 (s, 1H), 8.82 (s, 1H), 8.54 (d, J=1.9Hz, 1H), 8.24 (s, 1H), 8.18 (d, J=7.8Hz, 1H), 7.95 (d, J=7.7Hz, 1H), 7.64~7.56 (m, 3H), 7.29~7.21 (m, 4H), 7.15 (m, 1H), 6.91~6.84 (m, 2H), 4.11 (t, J=6.9Hz, 2H), 2.96 (t, J=6.9Hz, 2H), 2.78 (s, 6H). The isolated compound contains a maximum of 1 molar equivalent of ammonia. [Example 58]

[0479] N-(4-((benzyloxy)methyl)phenyl)-5-(6-(cyclopropanesulfonamide)-5-methylpyrazine-2-yl)-2-fluorobenzamide [ka]

[0480] To 5-(6-amino-5-methylpyrazine-2-yl)-N-(4-((benzyloxy)methyl)phenyl)-2-fluorobenzamide (I-39, 50 mg, 0.110 mmol) in pyridine (0.20 mL), DMAP (1.3 mg, 0.011 mmol) and cyclopropanesulfonyl chloride (56 μL, 0.548 mmol) were added, and the mixture was stirred at 80°C for 16 hours. An additional cyclopropanesulfonyl chloride (56 μL, 0.548 mmol) was added, and the mixture was stirred at 80°C for 6 hours. This was combined with a second batch starting from a 0.055 mmol scale of 5-(6-amino-5-methylpyrazine-2-yl)-N-(4-((benzyloxy)methyl)phenyl)-2-fluorobenzamide. The mixture was diluted with dimethylethanol (10 mL), washed with water (2 × 10 mL), aqueous HCl solution (2 M, 2 × 10 mL), and brine (10 mL), dried on Na₂SO₄, and concentrated under reduced pressure. Purification by RP chromatography (C18, 10-50% MeCN in 0.1% NH₄OH aqueous solution) yielded N-(4-((benzyloxy)methyl)phenyl)-5-(6-(cyclopropanesulfonamide)-5-methylpyrazine-2-yl)-2-fluorobenzamide (32 mg, 35%). LCMS: Method A, 1.80 min, MS ES + 547.0 1 H NMR(400MHz,DMSO)δ10.57(s,1H), 10.42(br s,1H), 8.91(s,1H), 8.36(dd,J=6.8,2.4Hz,1H), 8.31~8.23(m,1H), 7.73(d,J=8.4Hz,2H), 7.54(t,J=9.2Hz,1H), 7.39~7.33 (m,6H), 7.33~7.27(m,1H), 4.53(s,2H), 4.51(s,2H), 3.31~3.26(m,1H), 2.52(s,3H), 1.21~1.12(m,2H), 1.11~1.03(m,2H). The isolated compound contains a maximum of 1 molar equivalent of ammonia. [Example 59]

[0481] N-(4-((benzyloxy)methyl)phenyl)-5-(5-cyclopropyl-6-(methylsulfonamide)pyrazine-2-yl)-2-fluorobenzamide [ka]

[0482] Following the procedure of Example 58, 5-(6-amino-5-methylpyrazine-2-yl)-N-(4-((benzyloxy)methyl)phenyl)-2-fluorobenzamide (I-40) was used instead of 5-(6-amino-5-methylpyrazine-2-yl)-N-(4-((benzyloxy)methyl)phenyl)-2-fluorobenzamide (I-39), and methanesulfonyl chloride was used instead of cyclopropanesulfonyl chloride to obtain N-(4-((benzyloxy)methyl)phenyl)-5-(5-cyclopropyl-6-(methylsulfonamide)pyrazine-2-yl)-2-fluorobenzamide in 13% yield. LCMS: Method A, 1.86 min, MS ES + 547.0 1 ¹H NMR (400MHz, DMSO) δ 10.72 (br s, 1H), 10.56 (s, 1H), 8.75 (s, 1H), 8.28 (dd, J=6.8, 2.4Hz, 1H), 8.24~8.15 (m, 1H), 7.72 (d, J=8.5Hz, 2H), 7.51 (t, J=9.2Hz, 1H), 7.38~7.33 (m, 6H), 7.32~7.26 (m, 1H), 4.51 (s, 2H), 4.50 (s, 2H), 3.41 (s, 3H), 1.07~0.99 (m, 2H), 0.99~0.91 (m, 2H). 1H is unclear / not observed. The isolated compound contains a maximum of 1 molar equivalent of ammonia.

[0483] GPR35 assay The functional assay described measures the ability of a GPR35 modulator to inhibit GPR35 agonist-induced phospho-ERK signaling. This involves determining the modulator concentration, i.e., IC2, required to reduce the phospho-ERK signaling by 50 percent.50 It is expressed as; the signal window is defined as the difference between the agonist-plus-modulator medium (without modulator) and the agonist medium (without agonist) control.

[0484] This assay is a cellular GPR35 phospho-ERK homogeneous time-resolved fluorescence (HTRF) assay using the GPR35-CHO-K1-mt aequorin-Gα16 cell line. 80 Upon activation of GPR35 using agonistrodoxamide at a specific concentration, ERK1 / 2 is phosphorylated, and after cell membrane lysis, phospho-ERK1 / 2(Thr202 / Tyr204) is converted to Eu. 3+ -Detected in a sandwich assay using two specific antibodies, one labeled with a cryptotate (donor) and the other with d2 (acceptor). When the dyes are in close proximity, excitation of the donor using a light source (laser or flash lamp) triggers fluorescence resonance energy transfer (FRET) toward the acceptor, resulting in specific acceptor fluorescence (at 665 nm). The specific signal is directly proportional to the amount of phospho-ERK1 / 2(Thr202 / Tyr204) in the sample. Compounds that interfere with the level of phospho-ERK1 / 2(Thr202 / Tyr204) result in a low HTRF signal.

[0485] Various modifications and variations of the described embodiments of the present invention will be apparent to those skilled in the art without departing from the scope and spirit of the invention. Although the present invention has been described in relation to certain preferred embodiments, it should be understood that the claimed invention should not be unduly limited to such specific embodiments. In fact, various modifications of the modes of description for carrying out the invention, which will be apparent to those skilled in the art, are intended to fall within the scope of the following claims.

[0486] [Table 8] JPEG2026521186000191.jpg255170 JPEG2026521186000192.jpg8170

[0487] (References) 1 Quon et al, ACS Pharmacology and Translational Science 3, 801 - 812 (2020) 2 Kaya et al, Frontiers in Immunology 12: 717392 (2021) 3 Wang et al, J Biol Chem 281, 22021 - 22028 (2006) 4 Kapolka et al, PNAS 117, 13117 - 13126 (2020) 5 Giovanni et al, Cell 185, 815 - 830.e19 (2022) 6 Oka et al, Biochem & Biophys Res Comms 395, 232 - 237 (2010) 7 Deng et al. Scientific Reports 2, Article number: 373 (2012) 8 Maravillas - Montero et al, J Immunology 194, 29 - 33 (2015) 9 Lee et al Agricultural and Food Chem doi: 10.1021 / acs.jafc.2c01251. Online ahead of print (2022) 10 Jenkins et al, Biochem J 432, 451 - 419 (2010) 11 Yang et al, Pharmacology 86, 1 - 5. doi: 10.1159 / 000314164. Epub (2010) 12 According to Taniguchi et al. FEBS Letters 580, 5003–5008 (2006) 13 MacKenzie et al, Molecular Pharmacology 85, 91–104 (2014). 14 Wei et al, J Med Chem 64, 2634–2647 (2021) 15 According to Abdalhameed et al. Bioorg Med Chem Lett 27, 612–615 (2017) 16 https: / / www.ncbi.nlm.nih.gov / gene?Db=gene&Cmd=DetailsSearch&Term=2859 17 https: / / www.proteinatlas.org / ENSG00000178623-GPR35 / tissue 18 MacKenzie et al, Frontiers in Endocrinology (Lausanne) 2, 68, 1-10 (2011). 19 Imielinski et al, Nat Gene 41, 1335–1340 (2009) 20 Ellinghaus et al, Hepatology 58, 1074–1083 (2013). 21 Schneditz et al, Sci Signal 12:eaau9408 (2019) 22 Pagano et al, Good gut-2020-323363 (2021) 23 Kaya et al, Cell Rep 32:107979(2020) 24http: / / gepia.cancer-pku.cn / detail.php?gene=GPR35 25 Okumura et al, Cancer Sci 95, 131-135 (2004) 26 Ali et al, Tumor Biology 41 1-11 (2019) 27 Mackiewicz at al, Pharmacological Rep doi: 10.1007 / s43440-022-00371-2. Online ahead of print (2022) 28 Olson et al, Frontiers Chem, 9 article 671483 (2021) 29 Sun, YV et al, Genet.Epidemiol. 32, 350-360 30 Min, KD et al (2010) Biochem. Biophys. Res. Common. 393, 55-60 31 Ohshiro, H. et al (2008) Biochem. Biophys. Res. Common. 365, 344-348 32 Cosi, C. et al (2010). Neuropharmacology 60, 1227-1231 33 US20070077602; Leonard et al 34 Wang, J. et al (2006) J. Biol. Chem. 281, 22021-22028 35 Fallarini, S. et al (2010) Biochem. Bio-phys. Res. Commun. 398, 420-425 36Barth,M.C. et al (2009) J. Biol.Chem. 284, 19189-19195 37 Birring, S. S. et al (2017) Lancet Respir. Med. 5 (10), 806-815 38 Yang, Y. et al (2010) Pharmacology; 86(1):1-5 39 Smith J. A. (January 2015). Current Allergy and Asthma Reports. 15 (1): 489 40 Shu C. et al (November 2022), Cell Death Disc, 444

Claims

1. Compounds of formula (I), or pharmaceutically acceptable salts or solvates thereof 【Chemistry 1】 (I) [X-Y is -CONR ６ - or - NR ６ CO- is; R ６ and R ７ is independently selected from H and alkyl, more preferably from H; R ８ is selected from alkyl, cycloalkyl, (CH ２ ), ｑ -heterocycloalkyl and NR ３４ R ３５ ; Ring C is a phenyl group or a six-membered heteroaryl group containing at least one N, each of which is alkyl, haloalkyl, alkoxy, haloalkoxy, halo, CN, NR ９ SO ２ -R １０ , NR ９ COR １１ , NR １２ R １３ , OH, SO ２ NR １４ R １５ CONR １６ R １７ , cycloalkyl, O(CH ２ ) ｑ NR １８ R １９ , (CH ２ ) ｑ - Heterocycloalkyl and CO ２ R ２０ They may be further substituted by one or more substituents selected from; Each R ９ is independently selected from H and alkyl; R １０ ~R １９ is independently selected from H, alkyl, aralkyl, alkoxy, alkoxyalkyl, hydroxyalkyl and cycloalkyl; or R １２ and R １３ These, along with the nitrogen to which they are bound, are O, NH, S, SO and SO ２ It forms a 4- to 7-membered heterocyclic group which may include further groups selected from; R １４ and R １５ These, along with the nitrogen to which they are bound, are O, NH, S, SO and SO ２ It forms a 4- to 7-membered heterocyclic group which may include further groups selected from; R １６ and R １７ These, along with the nitrogen to which they are bound, are O, NH, S, SO and SO ２ It forms a 4- to 7-membered heterocyclic group which may include further groups selected from; R １８ and R １９ These, along with the nitrogen to which they are bound, are O, NH, S, SO and SO ２ It forms a 4- to 7-membered heterocyclic group which may include further groups selected from; R ２０ The alkyl, aralkyl, alkoxyalkyl, hydroxyalkyl, and cycloalkyl elements are selected from alkyl, aralkyl, alkoxyalkyl, hydroxyalkyl, and cycloalkyl elements; Ring A is a phenyl group or a six-membered heteroaryl group; Ring B is a phenyl group or a six-membered heteroaryl group; n and p are each independent integers between 0 and 4; Each q is an independent integer between 0 and 4; Each R ａ and each R ｂ Alkyl, halo, haloalkyl, alkoxy, cycloalkoxy, haloalkoxy, cyano, NR ２１ COR ２２ , NR ２１ SO ２ R ２３ , (CH ２ ) ｑ SR ２４ , (CH ２ ) ｑ SOR ２５ , (CH ２ ) ｑ SO ２ R ２６ SO ２ NR ２７ R ２８ , (CH ２ ) ｑ OH, (CH ２ ) ｑ OR ２９ , NR ３０ R ３１ CONR ３２ R ３３ , cycloalkyl and (CH ２ ) ｑ - Selected independently from heterocycloalkyl groups; Each R ２１ is independently selected from H and alkyl; R ２２ ~R ３５ is independently selected from H, alkyl, aralkyl, alkoxy, alkoxyalkyl, hydroxyalkyl and cycloalkyl; or R ２７ and R ２８ These, along with the nitrogen to which they are bound, are O, NH, S, SO and SO ２ Forming a 4- to 7-membered heterocyclic group which may include further groups selected from; or R ３０ and R ３１ These, along with the nitrogen to which they are bound, are O, NH, S, SO and SO ２ Forming a 4- to 7-membered heterocyclic group which may include further groups selected from; or R ３２ and R ３３ These, along with the nitrogen to which they are bound, are O, NH, S, SO and SO ２ It forms a 4- to 7-membered heterocyclic group which may include further groups selected from; L is a direct bond or is -O-CO-, -CO-O-, -O-CO-O-, -SO ２ -, -O-SO ２ -, -SO ２ -O-, -O-, -NR ３６ -SO ２ -, -NR ３６ -SO ２ -alkylene, alkylene-SO ２ -NR ３６ -, -SO ２ -NR ３６ -, -SO ２ -NR ３６ -alkylene, alkylene-NR ３６ -SO ２ -, alkylene, heteroalkylene, cycloalkylene, heterocycloalkylene, alkylene-cycloalkylene, alkylene-SO ２ -, -SO ２ -alkylene, alkylene-SO-, -SO-alkylene, alkylene-SO ２ -alkylene, alkylene-SO-alkylene, cycloalkylene-alkylene, alkylene-heterocycloalkylene, heterocycloalkylene-alkylene, -CO-heterocycloalkylene-alkylene, alkylene-heterocycloalkylene-CO-, CO ２ -heterocycloalkylene-alkylene, alkylene-heterocycloalkylene-CO ２ - is a group selected from heteroalkylene-heterocycloalkylene, heterocycloalkylene-heteroalkylene, heteroalkylene-cycloalkylene, and cycloalkylene-heteroalkylene, and the alkylene moiety in the above groups may be substituted by one or more substituents independently selected from halo, alkyl, haloalkyl, and cycloalkyl; R ３６ is independently selected from H and alkyl; Z is a group selected from alkyl, cycloalkyl, aryl, heteroaryl, and heterocycloalkyl groups, each of which may be further substituted with one or more groups independently selected from CN, halo, alkyl, OH, alkenyl, alkynyl, alkoxy, haloalkyl, and haloalkoxy groups.

2. Equation (Ia): 【Chemistry 2】 (Ia) (In the formula, X １ , X ２ , X ３ , X ４ , X ５ is, X １ and X ５ Together with the bonded carbon, it forms a phenyl group or a 6-membered heteroaryl group containing at least one N, and the phenyl or heteroaryl group is alkyl, CN, haloalkyl, alkoxy, haloalkoxy, halo, NR ９ SO ２ R １０ , NR ９ COR １１ , NR １２ R １３ , OH, SO ２ NR １４ R １５ CONR １６ R １７ , cycloalkyl, O(CH ２ ) ｑ NR １８ R １９ , (CH ２ ) ｑ - Heterocycloalkyl and CO ２ R ２０ They may be further substituted by one or more substituents selected from; A, B, Z, L, X, Y, R ａ , R ｂ , R ７ , R ８ (where n and p are as defined in claim 1) The compound according to claim 1, which is a compound of the above.

3. Formula (Ib): 【Transformation 3】 (Ib) (In the formula: X １ is N or CR １ And; X ３ is N or CR ３ And; X ４ is N or CR ４ And; X ５ is N or CR ５ And; R １ , R ３ , R ４ and R ５ H, CN, alkyl, haloalkyl, alkoxy, haloalkoxy, halo, NR １２ R １３ OH, NR ９ SO ２ - Alkyl, CONR １６ R １７ , cycloalkyl, O(CH ２ ) ｑ NR １８ R １９ and (CH ２ ) ｑ - Each is independently selected from heterocycloalkyl groups; R ａ , R ｂ , R ７ , R ８ (n, p, L, A, B, X, Y, and Z are as defined in claim 1) The compound according to claim 1 or 2, which is a compound of the above.

4. A is selected from phenyl, pyridinyl, pyrimidinyl, pyrazidinyl, and pyrazinyl, and each of these has 1 to 4 R ａ The compound according to any one of claims 1 to 3, which may be substituted with a group.

5. Each R ａ The compound according to any one of claims 1 to 4, wherein the compound is independently selected from halo, alkyl, and alkoxy, and more preferably selected from F, Me, and OMe.

6. A compound according to any one of claims 1 to 5, wherein n is 0.

7. X １ , X ２ , X ３ , X ４ and X ５ However, X １ and X ５ The compound according to any one of claims 2 to 6, wherein together with the carbon to which the carbon is bonded, it forms a six-membered heteroaryl group containing one or two nitrogen atoms, preferably selected from pyridinyl, pyrimidinyl, pyrazidinyl, and pyrazinyl.

8. The compound according to any one of claims 1 to 7, wherein X-Y is NH-CO.

9. Formula (Ic): 【Chemistry 4】 (I C) (In the formula: X １ is N or CR １ And; X ３ is N or CR ３ And; X ４ is N or CR ４ And; X ５ is N or CR ５ And; R １ , R ３ , R ４ and R ５ H, CN, alkyl, haloalkyl, alkoxy, haloalkoxy, halo, NR １２ R １３ OH, NR ９ SO ２ - Alkyl, CONR １６ R １７ , cycloalkyl, O(CH ２ ) ｑ NR １８ R １９ and (CH ２ ) ｑ - Each is independently selected from heterocycloalkyl groups; A is a phenyl group or a pyridinyl group, more preferably phenyl; R ａ , R ｂ , R ７ , R ８ (n, p, L, A, B, X, Y, and Z are as defined in claim 1) A compound according to any one of claims 1 to 8, which is a compound of the above.

10. R １ , R ３ , R ４ and R ５ However, H, C １－６ - Alkyl, C １－６ - Haloalkyl, C １－６ - Alkoxy, C １－６ - Haloalkoxy, Cl, F, NH ２ NH-C １－６ -Alkyl, NH-C ３－６ -Cycloalkyl, N(C) １－６ -Alkyl) ２、 OH, NHSO ２ -C １－６ - Alkyl, CONR １７ R １８ , C ３－６ -Cycloalkyl, NH-(hydroxy-C) １－６ -alkyl), NH-(C １－６ -alkoxy), CH ２ - The compound according to claim 9, independently selected from heterocycloalkyl and heterocycloalkyl.

11. R １ , R ３ , R ４ and R ５ But H, Me, MeO, CF ３ Cl, F, NH ２ NH-Me, NH-cyclopropyl, NMe ２、 OH, NHSO ２ Me, CONH ２ cyclopropyl, NHCH ２ CH ２ OH, OCH ２ CH ２ NH ２ , NHCH ２ CH ２ OMe, CH ２ The compound according to claim 9 or 10, independently selected from -(morpholine-4-yl) and morpholine-4-yl.

12. X １ CR １ And; X ３ CR ３ And; X ４ is N; X ５ CR ５ That is, The compound according to any one of claims 9 to 11.

13. X １ is N; X ３ CR ３ And; X ４ CR ４ And; X ５ CR ５ That is, The compound according to any one of claims 9 to 11.

14. X １ is N; X ３ CR ３ And; X ４ is N; X ５ CR ５ That is, The compound according to any one of claims 9 to 11.

15. X １ is N; X ３ CR ３ And; X ４ CR ４ And; X ５ N is The compound according to any one of claims 9 to 11.

16. X ３ CR ３ And R ３ However, H, CN, C １－６ - Alkyl, C ３－６ -Cycloalkyl, halo, C １－６ - Alkoxy, C １－６ - Haloalkyl, C １－６ - Haloalkoxy and O(CH ２ ) ｑ NR １８ R １９ More preferably, H, CN, C １－６ - Alkyl, C １－６ - Alkoxy, C ３－６ -Cycloalkyl, halo and O(CH ２ ) ｑ NR １８ R １９ Selected from; R １ , R ４ and R ５ The compound according to any one of claims 9 to 15, wherein H is present.

17. X ３ CR ３ And R ３ But H, Me, CN, MeO, CF ３ Cl, F, NH ２ NH-Me, NH-cyclopropyl, NMe ２ OH, NHSO ２ Me, CONH ２ cyclopropyl, NHCH ２ CH ２ OH, NHCH ２ CH ２ OMe, CH ２ - (morpholin-4-yl) and morpholin-4-yl are selected, more preferably H, Me, OMe, CN, cyclopropyl and OCH ２ CH ２ NH ２ Selected from; R １ , R ４ and R ５ The compound according to any one of claims 9 to 16, wherein H is present.

18. Formula (Id): 【Transformation 5】 (Id) (X １ is N or CR １ And; X ２ is N or CR ２ And; X ４ is N or CR ４ And; X ５ is N or CR ５ And; R １ , R ２ , R ４ and R ５ H, CN, alkyl, haloalkyl, alkoxy, haloalkoxy, halo, NR １２ R １３ OH, NR ９ SO ２ - Alkyl, CONR １６ R １７ , cycloalkyl, O(CH ２ ) ｑ NR １８ R １９ and (CH ２ ) ｑ - Each is independently selected from heterocycloalkyl groups; A is a phenyl group or a pyridinyl group, more preferably phenyl; R ａ , R ｂ , R ７ , R ８ (n, p, L, A, B, X, Y, and Z are as defined in claim 1) The compound according to claim 1 or 2, which is a compound of the above.

19. X １ is N; X ２ CR ２ And; X ４ is N; X ５ CR ５ That is, The compound according to claim 18.

20. X ２ CR ２ And R ２ However, H, CN, C １－６ - Alkyl, C ３－６ -Cycloalkyl, halo, C １－６ - Alkoxy, C １－６ - Haloalkyl, C １－６ - Haloalkoxy and O(CH ２ ) ｑ NR １８ R １９ Selected from, more preferably H, CN, C １－６ - Alkyl, C １－６ - Alkoxy, C ３－６ -Cycloalkyl, halo and O(CH ２ ) ｑ NR １８ R １９ Selected from; R １ , R ４ and R ５ The compound according to claim 18 or 19, wherein H is present.

21. R ７ A compound according to any one of claims 1 to 20, wherein is H.

22. R ８ However, from alkyl, cycloalkyl, heterocycloalkyl and dialkylamino, more preferably Me, cyclopropyl, morpholine-4-yl and N(Me) ２ A compound according to any one of claims 1 to 21, selected from the above.

23. B is a phenyl group or a pyridinyl group, and each of these has 1 to 4 R ｂ The compound according to any one of claims 1 to 22, which may be substituted with a group.

24. The compound according to any one of claims 1 to 23, wherein B is a phenyl group and may be substituted with one or two groups selected from halo and alkoxy, preferably selected from F and MeO.

25. Z is C １－６ - Alkyl, phenyl, heteroaryl, C ３－６ - A compound according to any one of claims 1 to 24, wherein the group is selected from cycloalkyl and 4-membered, 5-membered, or 6-membered heterocycloalkyl groups, each of which may be further substituted with one or more groups selected from alkyl, alkenyl, alkynyl, OH, halo, haloalkyl, and alkoxy.

26. The compound according to any one of claims 1 to 25, wherein Z is a group selected from phenyl, pyridinyl, methoxyphenyl, alkyl, tolyl, morpholinyl, pyrazolyl, oxetanyl, cyclohexyl, cyclopenyl, cyclobutyl, cyclopropyl, and tetrahydropyranyl, more preferably from phenyl.

27. Lが、-O-CO-、-CO-O-、-O-CO-O-、-O-、-NH-SO ２ -、-NH-SO ２ -(CR’R”) ａ -、-(CR’R”) ａ -SO ２ -NH-、-SO ２ -NH-、-SO ２ -NH-(CR’R”) ａ -、-(CR’R”) ａ -NH-SO ２ -、-O-SO ２ -、-SO ２ -O-、-(CR’R”) ａ -、-(CH=CH) ｃ -、-(CR’R”) ａ -(CH=CH) ｃ -、-(CH=CH) ｃ -(CR’R”) ａ -、-(CR’R”) ａ -(CH=CH) ｃ -(CR’R”) ｂ -、-(CR’R”) ａ -O-、-O-(CR’R”) ａ -、-(CR’R”) ａ -O-(CR’R”) ｂ -、-(CR’R”) ａ -S-(CR’R”) ｂ -、-(CR’R”) ａ -SO ２ -、-SO ２ -(CR’R”) ｂ -、-(CR’R”) ａ -SO-、-SO-(CR’R”) ｂ -、-(CR’R”) ａ -SO-(CR’R”) ｂ -、-(CR’R”) ａ -SO ２ -(CR’R”) ｂ -、-(CR’R”) ａ -S-(CR’R”) ｂ -O-、-O-(CR’R”) ａ -S-(CR’R”) ｂ -、-(CR’R”) ａ -O-(CR’R”) ｂ -S-, -S-(CR'R") ａ -O-(CR'R") ｂ -, - (CR'R") ａ -S-, -S-(CR'R") ａ -, -O-(CR'R") ａ -O, heterocycloalkylene, cycloalkylene-O-, -O-cycloalkylene-, heterocycloalkylene-O-, -O-heterocycloalkylene-, heterocycloalkylene-(CR'R") ａ ,-(CR'R") ａ - Heterocycloalkylene -, Heterocycloalkylene - (CR'R'') ａ -O-, -O-(CR'R") ａ - Heterocycloalkylene -, - (CR'R'') ａ -O-heterocycloalkylene-, heterocycloalkylene-O-(CR'R'') ａ , -O-heterocycloalkylene-(CR'R") ａ -,-CO-heterocycloalkylene-(CR'R") ａ ,-(CR'R") ａ -heterocycloalkylene-CO-, -CO ２ - Heterocycloalkylene - (CR'R'') ａ ,-(CR'R") ａ - Heterocycloalkylene - CO ２ - and - (CR'R") ａ A compound according to any one of claims 1 to 26, selected from -heterocycloalkylene-O-, wherein a and b are each independently integers from 1 to 6, c is an integer from 1 to 3, and R' and R'' are each independently selected from H, alkyl, halo, and haloalkyl.

28. Lが、-O-、-O-CO-、-CO-O-、-O-CO-O-、-CH ２ -CH ２ CH ２ -CH ２ CH ２ CH ２ -CH ２ OCH ２ -CH ２ OCH(Me)-、-CH(Me)OCH ２ -CH ２ O-OCH ２ -CH ２ CH ２ O-OCH ２ CH ２ -CH ２ CH ２ S-,-SCH ２ CH ２ -CH ２ CH ２ CH ２ O-OCH ２ CH ２ CH ２ -、-OCH ２ CH ２ CH ２ O-CH ２ SO ２ CH ２ -CH ２ SOCHISM ２ -CH ２ SCH ２ -、-NH-SO ２ -、-NH-SO ２ -CH ２ -CH ２ -SO ２ -NHH-、-CH ２ -NH-SO ２ -SO ２ -NH-CH ２ CH ２ -CH ２ CH ２ -NH-SO ２ -、-O-SO ２ -SO ２ -O-、-SO ２ -NHH-、-SO ２ -NH-CH ２ -CH ２ CH ２ CH ２ CH ２ O-、-OCH ２ CH ２ CH ２ CH ２ -、-CH ２ SO ２ -、-S ２ CH ２ -、-OCH ２ -----EH ２ O-、-EH ２ SO-、-SOCH ２ -、-CH ２ OCH ２ ,-OCH ２ SCH ２ - 、 -CH ２ SCH ２ O-、-EH=E-、-EH(Me)�-、-EH(F ３ )-、-EH(EF ３ )O-、-EH ２ CH(CF) ３ )-、-EH(EF ３ )CH ２ -、-S ２ N(Me)-、-N(Me)SO ２ -、 【Transformation 6】 【change】 A compound selected from any one of claims 1 to 27.

29. L-Z is -OCH ２ CH ２ CH ２ CH ２ Ph, -OCH ２ CH ２ CH ２ Ph, -OCH ２ CH ２ Ph, -OCH ２ Ph, -CH ２ CH ２ CH ２ CH ２ Ph, -CH ２ CH ２ CH ２ Ph, -OCH ２ CH ２ -pyrazole, -CH ２ CH ２ Ph, -CH ２ Ph, -OCH ２ CH ２ CH(Me) ２ , -OCH ２ CH(Me) ２ , -OCOCH ２ CH(Me) ２ , -OCH(Me) ２ , -OCH ２ CO-O-CH(Me) ２ , -O(CO)OCH ２ CH(Me) ２ , -OSO ２ -(4-methylphenyl), -CH ２ SO ２ -(4-methylphenyl), -CH ２ CH ２ O-(4-methylphenyl),-CH ２ SO ２ CH ２ -Ph, OMe, Ph, OPh, OCF ３ , ｔ Bu, CF ３ , -OSO ２ Ph, -OCH ２ CH ２ CH ２ OPh, -OCH ２ -Cyclopropyl, -CH ２ O-cyclopropyl, -OCH ２ CH ２ CH ２ CH ３ ien-CH ２ OCH ２ Ph, -CH(Me)OCH ２ Ph, -CH ２ OCH(Me)Ph, -CH ２ OCH ２ (2-pyridinyl), -CH ２ OCH ２ (3-pyridinyl), -CH ２ OCH ２ (4-pyridinyl), -CH ２ OCH ２ (4-methoxyphenyl), -CH ２ OCH ２ (3-methoxyphenyl), CH ２ OCH ２ (2-methoxyphenyl), -OCH ２ SCH ２ Ph, -CH ２ OCH ２ Ph, -CH ２ CH ２ - Cyclopentyl, CH ２ CH ２ -Cyclohexyl, -CH ２ CH ２ S-(4-chlorophenyl),-CH ２ -(2-fluorophenyl), -CH=CH-phenyl, -SO ２ -NH-CH ２ -phenyl, -SO ２ -NH-CH ２ -CH ２ -phenyl, -CH ２ OCH ２ -Cyclopropyl, -OCH(Me)-Cyclopropyl, -CH(Me)-O-Cyclopropyl, -OCH(CF ３ )-Cyclopropyl,-CH(CF ３ )-O-cyclopropyl, SO ２ Ph, -CH ２ -O-CH(CF ３ )-Ph, 【Transformation 7】 The compound according to any one of claims 1 to 28.

30. L-Z is -OCH ２ CH ２ Ph, -OCH ２ CH ２ CH ２ CH ２ Ph or -CH ２ OCH ２ Ph, more comfortably - OCH ２ CH ２ A compound according to any one of claims 1 to 29, wherein the pH is [value missing].

31. below: Table 1 The compound according to any one of claims 1 to 30, as well as selected from pharmaceutically acceptable salts and solvates thereof.

32. A pharmaceutical composition comprising a compound according to any one of claims 1 to 31, and a pharmaceutically acceptable diluent, excipient, or carrier.

33. A compound according to any one of claims 1 to 31, or a pharmaceutical composition according to claim 32, for use as a pharmaceutical.

34. A compound according to any one of claims 1 to 31, or a pharmaceutical composition according to claim 32, for use in the treatment or prevention of a disorder selected from proliferative disorders, fibrotic disorders, gastrointestinal disorders, inflammatory disorders, and cardiovascular diseases.

35. The compound or pharmaceutical composition for use according to claim 34, wherein the disorder is a proliferative disorder, particularly cancer or leukemia.

36. The compound or pharmaceutical composition for use according to claim 35, wherein the cancer is selected from cancers of the colon, rectum, stomach, esophagus, pancreas, gallbladder, bile duct, liver, lung, kidney, gynecological, breast, testis, skin, prostate, central nervous system, and brain tumors.

37. The compound or pharmaceutical composition for use according to claim 34, wherein the disorder is selected from gastrointestinal disorders, particularly inflammatory bowel disease, ulcerative colitis, primary sclerosing cholangitis, and Crohn's disease.

38. The compound or pharmaceutical composition for use according to claim 34, wherein the disorder is a cardiovascular disease selected from hypertension, heart failure, atherosclerosis, peripheral vascular disease and stroke.

39. A compound or pharmaceutical composition for use according to any one of claims 34 to 38, wherein the use comprises modulating GPR35, and preferably the use comprises inhibiting GPR35 signaling.

40. A method for treating a disorder defined in any of claims 34 to 38, comprising administering a compound defined in any of claims 1 to 31 or a pharmaceutical composition defined in claim 32 to a target.

41. A compound as defined in any of claims 1 to 31, or a pharmaceutically acceptable salt or solvate thereof, or the pharmaceutical composition according to claim 32, for use in the treatment or prevention of GPR35-related diseases or disorders.

42. Use of a compound defined in any of claims 1 to 31, or a pharmaceutically acceptable salt or solvate thereof, in the preparation of a medicament for the treatment or prevention of a GPR35-related disease or disorder in a subject.

43. Use of a compound defined in any of claims 1 to 31, or a pharmaceutically acceptable salt or solvate thereof, in the preparation of a medicament for the treatment or prevention of a disorder selected from proliferative disorders, gastrointestinal disorders, inflammatory disorders, and cardiovascular diseases.

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